10th International Conference on Frontotemporal

10th International Conference on Frontotemporal Dementias Munich/Germany; August 31-September 2, 2016 Table of Contents Scientific Conference Oral Presentations

Day 1 (Wednesday, August 31, 2016) Session 1: FTLD: current perspectives - future directions S1–S2 O1–O2 Session 2: Social cognition and behavior: challenges and interventions S3–S4 O3–O4 DB1–DB6 Session 3: Genetics of FTLD S5, S6 O5–O6 DB7–DB10

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Day 2 (Thursday, September 1, 2016)

Session 4: Molecular neuropathology of FTLD S7–S8 O7–O8 DB11–DB14 Session 5: Progressive aphasias S9–S10 O9–O10 DB15–DB18 Session 6: CBS, PSP, and MND S11–S12 O11–O12 DB19–DB22 Session 7: Biomarkers for FTLD S13–S14 O13–O14 DB23–DB26

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Day 3 (Friday, September 2, 2016)

Session 8: Hot topics O15 DB27–DB30 Session 9: Mechanisms of cell death S15, S16, S17 O16–O17 DB31–DB34

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© 2016 The Authors Journal of Neurochemistry © 2016 International Society for Neurochemistry J. Neurochem. (Suppl. 1) (2016), 222–428

Session 10: Disease modulation S18–S19 O18–O19 Session 11: Treatment S20 O20–O22

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Poster Presentations Day 1 (Wednesday, August 31, 2016)

Caregiver (P35–P49) Social cognition and behavior (P50– P156)

Day 2 (Thursday, September 1, 2016)

Genetics (P157–P217) Neuropathology (P218–P252) Progressive aphasias (P253–P304)

Day 3 (Friday, September 2, 2016)

CBS, PSP, MND (P305– P335) Blood and Imaging biomarkers (P336–P425) Mechanisms of cell death (P426–P448) Disease modulation (P449–P459) Treatment (P460–P478)

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Abbreviations S = Speaker Abstract O = Oral Presentation DB = Data Blitz Presentation P = Poster Presentation

© 2016 The Authors Journal of Neurochemistry © 2016 International Society for Neurochemistry J. Neurochem. (Suppl. 1) (2016), 222–428

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doi: 10.1111/jnc.13692

Journal of Neurochemistry (2016), 138 (Suppl. 1), 222–428

S1 Changing perspectives on FTD J. Snowden1,2 1 Salford Royal Foundation Trust, Cerebral Function Unit, Manchester, Great Britain 2 University of Manchester, Manchester, Great Britain It is now 30 years since the first FTD conference in Lund. The subsequent burgeoning of research has resulted in increased understanding and shifts in the conceptualisation of FTD. A principal development is the recognition of clinical heterogeneity. Although typically construed as an early onset dementia, there is now evidence for a wide range in age at onset, with around a third of people developing symptoms after the age of 65 years. Although the mean length of illness to death is about 8 years, there is substantial individual variation, ranging from 1 to 20 years. Progression can be rapid but also remarkably slow. Clinical presentations include disorders of behaviour, language and praxis and clinical syndromes may overlap. Behavioural profiles are not uniform across patients. Psychotic features are rare in FTD, yet are prominent in some patients. Non-fluent aphasias encompass distinct forms of language disorder. FTD patients are often physically well, yet not invariably so. There are now established associations with amyotrophic lateral sclerosis, progressive supranuclear palsy and corticobasal degeneration. In this talk I discuss the clinical heterogeneity of FTD, examine the factors that influence those clinical differences and explore the nature of the relationship between FTD and motor disorders. I consider the implications for our understanding of FTD.

S2 Frontotemporal dementia neuroanatomy: onset, spread, and implications for treatment W. Seeley1 1 UCSF, Neurology, San Francisco, USA The anatomy of neurodegenerative disease can be understood in terms of two key aspects: onset and progression. Mechanisms controlling onset timing and location remain mysterious, and each disease features striking heterogeneity in its onset sites. Network analyses have revealed that each clinical syndrome reflects degeneration of a specific large-scale network. Each vulnerable network, in turn, is anchored by a key “epicenter” whose functionalanatomical connections govern vulnerability of other regions, perhaps because prion-like corruptive templating begets transsynaptic disease protein spread. In behavioral variant frontotemporal dementia (bvFTD), disease begins within a “salience network”, anchored by the anterior cingulate and frontoinsular cortices, regions specialized for social-emotional-autonomic processing. Patients lose the capacity for adaptive, real-time behavioral guidance, possibly in part because salience-driven viscero-autonomic cues and responses are late, degraded, or lacking modulation. Within the salience network hubs, Layer 5 von Economo neurons and fork cells show a particular predilection for disease protein aggregation and cell death, providing a cellular focus for bvFTD selective vulnerability research

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akin to the motor neuron focus leveraged by amyotrophic lateral sclerosis researchers. How can selective vulnerability studies help us on the road toward FTD treatments? Human clinical and neuropathological research has and will continue to play a major role in uncovering potential pathogenic mechanisms and prioritizing therapeutic targets. The finer details of FTD neuroanatomy can be productively deployed in the analysis of disease models at all levels, from human induced pluripotent stem cell-derived neurons to transgenic or disease protein-inoculated rodents. Focusing these critical research tools on the most relevant neural systems may prove critical for enhancing the signals a model can provide about therapeutic avenues. Nonetheless, the most important disease model will remain the living patient, in whom determining therapeutic efficacy will require more elegant tools, crafted using theoretical principles and data, to detect onset and measure network-based spread.

O1 Social and economic burden of frontotemporal degeneration J. Galvin1, D. Howard2, N. Tatton3, S. Denny3 1 Florida Atlantic University, Boca Raton, USA 2 Emory University, Atlanta, USA 3 The Association for Frontotemporal Degeneration, Radnor, USA Frontotemporal Degeneration (FTD), a common cause of earlyonset dementia places unique burden on patients, families, and society. To better understand the socioeconomic burden of FTD, we conducted a web-based survey of FTD caregivers (n = 1103) to characterize patient and caregiver experience, resource utilization, and costs. Caregivers (mean age 60.9 + 10.1 year) were 78% female, and 81% spouses. FTD patients (mean age 65.9 + 8.5 year) were 68% Male and 65% lived with the respondent. FTD subtypes included 53% bvFTD, 21% PPA, 7% FTD-ALS, 5% PSP or CBD, and 14% undifferentiated FTD. Of caregivers who still worked (45%), only 74% worked fulltime; 37% stopped working due to the patient’s FTD diagnosis. 67% of FTD caregivers reported significant decline in their health, and 53% reported significant personal health care costs. 31.6% employed some form of paid caregiver. Additional patient-related health costs included an average of 6 overnight respite stays, 16 daytime respite stays, 35 clinician visits, and 2 hospitalizations or emergency room visits in the past year. Additional caregiver-related health costs included an average of 7 clinician visits and just under 1 hospitalization in the past year. Health Utilities Index scores worsened across disease severity and were poorest in PSP/CBD (p = 0.02) compared with other subtypes. Zarit Caregiver Burden and Neuropsychiatric Inventory scores also worsened across disease severity and were poorest in bvFTD (ZBI p = 0.02; NPI p < 0.001). Overall costs increased with disease severity, duration, and behavioral symptoms. Furthermore, FTD was associated with a significant overall median reduction in household income ($75-$99K in the year prior to diagnosis vs. $50–$59K current income; p < 0.001). These data reveal that FTD is associated with significant financial burden. A better understanding

© 2016 The Authors Journal of Neurochemistry © 2016 International Society for Neurochemistry J. Neurochem. (Suppl. 1) (2016), 222--428

Session 1: FTLD: current perspectives - future directions

of the socioeconomic impact of FTD will help inform healthcare policy, drive research agendas and targeted allocation of community resources, and provide much needed support to patients and families currently living with FTD.

O2 Toward tau PET imaging in FTLD: An update B. Dickerson1, S. McGinnis1, S. Makaretz1, C. Caso1, A. Schultz1, K. Johnson1 1 MGH/Harvard, Charlestown, USA Objective: To image tau pathology in vivo using PET in patients with Frontotemporal Lobar Degeneration (FTLD) Background: A critical unmet need for FTLD research, especially therapeutic trials, is the development of biomarkers to identify and localize FTLD-tau in living patients. Methods: We have used [18F] AV-1451 to scan a series of patients with sporadic FTLD. We have also scanned symptomatic and asymptomatic individuals with MAPT mutations as well as some with C9ORF72 and GRN mutations. We analyzed SUVR (cerebellum reference) data to localize and quantify [18F] AV-1451 signal. We also co-registered analyzed [18F] AV-1451 images to MRI images for visualization and calculation of % atrophy relative to controls. Results: [18F] AV-1451 signal was elevated in frontal, insular, and anterior temporal cortex in symptomatic MAPT carriers, and colocalized with atrophy. Signal was elevated above that of controls in asymptomatic MAPT carriers. In non-fluent aphasic patients, [18F] AV-1451 signal was highest in frontal cortex with marked asymmetry, most prominent in the dominant hemisphere, and localized remarkably well with atrophy. Semantic variant PPA patients showed elevated anterior temporal signal. Initial in vivo to post-mortem comparisons in PSP will also be discussed. Conclusions: Although [18F] AV-1451 PET is teaching us many lessons about the goal of imaging tau in FTLD-spectrum tauopathies, some of its properties present challenges.


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Session 2: Social cognition and behavior: challenges and interventions S3 Current Concepts of social cognition and assessment in FTD B. Dubois1 1 Salpêtriere Hospital UPMC, Behavioral Neurology Unit APHP and FRONTLAB Inserm Research Unit ICM, Paris, France Social cognition refers to a set of cognitive processes that allow adequate social interactions. It relies on complex brain networks that mainly encompass the ventral medial and dorsal medial prefrontal cortices, the insula, as well as the temporo-parietal junction and the temporal pole. This social cognition network is involved in (1) social perception (such as emotion recognition or context processing), (2) empathy and (3) theory of mind for attribution of internal state of others and (4) social behavioral response. The largely distributed nature of social cognition through numerous brain regions makes it particularly vulnerable to various neurological (neurodegenerative brain diseases including behavioral variant Fronto-Temporal Dementia, traumatic brain injury, vascular brain lesions. . .), psychiatric (mood and anxiety disorders, schizophrenia and anti-social personality disorders, social phobia. . .) and developmental disorders (autism, Williams syndrome. . .). In particular, studies carried on autism and neurodegeneration have provided critical information allowing us to identify key mechanisms and anatomical structures involved in social processing and behavior. Impact of these brain disorders on social cognition is highly variable, depending on the genetic and psychological context of the patient and on possible intervention of functional reorganization and compensatory mechanisms following brain damage. All these factors together with the social context and culture have to be taken into account when assessing social cognition. When possible, the clinical assessment should rely on an investigation of the 4 identified domains. Standardized self-report, carrier questionnaire, objective assessment and clinical observation have been developed in this purpose during the past decade. The social cognitive deficit identified should trigger specific intervention.

S4 Empathy and socioemotional processing in bvFTD K. Rankin1 1 University of California, San Francisco, Neurology, San Francisco, USA The socioemotional symptoms evident in behavioral variant FTD (bvFTD) arise from specific functional changes in the neural networks that underpin emotional expressiveness and social information processing in healthy individuals. Investigation into these brain-behavior relationships in bvFTD patients using informant-based questionnaires and direct face-to-face testing provides insight into the neural basis for the capacity for empathy, “social intuition”, self-awareness, emotion reading, perspective taking, sense of humor, theory of mind, and comprehending indirect and insincere forms of communication, such as sarcasm and deception.

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Key intrinsic connectivity networks (ICNs) mediating basic socioemotional functions include the salience network (SN), which alerts one to socioemotional cues that are personally relevant, and the limbic or “semantic appraisal” network (SAN), comprising the subgenual cingulate, anterior temporal, caudate head, and amygdala regions, which conveys the capacity for learning and applying personally nuanced evaluations to entities and experiences. Patients with the bvFTD syndrome demonstrate heterogeneous neuroanatomy, but automated classification analysis reveals 4 distinct anatomic subtypes of bvFTD in whom one or both of these networks is compromised. Early data suggest that each subtype shows a distinct pattern of socioemotional functioning that reflects the underlying anatomy. For instance, patients with primarily right SAN damage are more likely to be compulsive, socially assertive, and fail to read social cues, while patients with predominantly subcortical atrophy and a “cortical disconnection” version of the bvFTD syndrome lack interpersonal warmth but can detect paralinguistic sarcasm cues. Also, interview and questionnaire data reveal higher rates of psychiatric symptoms such as dysphoria and euphoria, grief, rumination, and negative self-appraisal in some anatomic subtypes of bvFTD, providing evidence of the anatomic pattern and nature of ICN disruption in each individual bvFTD patient.

O3 An analysis of the trajectories of illness severity measurements in behavioral variant frontotemporal dementia K. Kansal1, H. Amjad1,2, S. Saxena1,3, C. Onyike1 1 Johns Hopkins University, Psychiatry and Behavioral Sciences, Baltimore, USA 2 Johns Hopkins University, Internal Medicine/Geriatric Medicine and Gerontology, Baltimore, USA 3 Johns Hopkins University, Bloomberg School of Public Health, Baltimore, USA Global severity scores of subjects with behavioral variant frontotemporal dementia (bvFTD) were examined for their sensitivity to decline in different illness stages. We studied 407 cases from the National Alzheimer Coordinating Centers. The Mini-Mental State Examination (MMSE), Functional Activities Questionnaire (FAQ) and Clinical Dementia Rating Sum of Boxes (CDR-SB) were used as indices of neurodegeneration in latent class mixed models that yielded a two-class solution (class 1 – “usual progression”, class 2 – “slow progression”). The classes did not differ demographically. For each class, we fit sigmoid mixed effects models for MMSE, FAQ, CDRSB, Neuropsychiatric Inventory Questionnaire (NPI-Q) scores as functions of illness duration, plus 100 non-parametric bootstraps per model to assess reliability and derive means and 90% confidence intervals for curve parameters. Classes 1 (n = 293) and 2 (n = 114) did not differ in age at onset (mean 57.8 vs. 57.9 respectively, p = 0.506), years of education (mean 15.1 vs. 15.4, p = 0.432) or sex (males 59.7% vs. 70.2%, p = 0.065). In class 1, the mean trajectory for FAQ showed early decline – mean illness duration when the curve covered 5% of the difference between asymptotes was 0.32 years (CI: [-0.34, 0.91]) and 5.09 years (CI: [4.66, 5.55]) when the curve


Session 2: Social cognition and behavior: challenges and interventions

covered 95% of the difference. The MMSE and CDR-SB were reliable measures of decline after 2–4 years of illness and showed floor effects after 7–8 years. On average, the FAQ, MMSE and CDR-SB retained utility for 4–5 years after score decline began – mean intervals denoting the middle 90% of the scoring ranges were 4.77 years (CI: [4.05, 5.59]), 4.88 years (CI: [3.67, 6.22]) and 4.42 years (CI: [3.47, 5.58]), respectively. Bootstrap plots showed mean trajectory of the NPI-Q had high variance. In class 2, all tests had high variance. To conclude, the FAQ can be used to index early decline in bvFTD subjects with usual progression. MMSE and CDR-SB are sensitive in the middle stage, and NPI-Q is unreliable as a measure of disease progression. There is a need for novel psychometric measures for slow progression bvFTD.

O4 Phenotype, neuropsychology and psychopathology of C9orf72 mutation carriers from the German FTLDConsortium J. Diehl-Schmid1, C. Rossmeier1, S. Straub2, T. Kelm2, J. Kornhuber3, K. Fliessbach4, T. Grimmer1, A. Kehl2, M. Otto2, M. L. Schroeter5, German FTLD-Consortium2 1 Technical University Munich, Department of Psychiatry, Munich, Germany 2 University of Ulm, Department of Neurology, Ulm, Germany 3 Universit€atsklinikum Erlangen, Psychiatrische und Psychotherapeutische Klinik, Erlangen, Germany 4 Rheinische Friedrich-Wilhelms-Universit€ at, DZNE, Klinik und Poliklinik f€ur Psychiatrie und Psychotherapie, Bonn, Germany 5 Max-Planck-Institute for Human Cognitive and Brain Sciences, Department of Neurology, Leipzig, Germany It has been suggested, that the clinical phenotype of behavioral variant frontotemporal dementia (bvFTD) patients with C9orf72 mutation differs from non-carriers. It has been stated, that disturbances of episodic memory as well as psychotic symptoms are more frequent in C9orf72 mutation carriers and that mutation carriers less likely meet the diagnostic criteria for bvFTD. From 386 tested, 23 bvFTD-patients with C9orf72 mutations were identified in the German FTLD-Consortium. Firstly, it was rated, if the patients fulfilled the diagnostic criteria for possible or probable bvFTD. In a second step, mutation carriers with early bvFTD (< 5 years after onset, N = 16) were identified and neuropsychological test performance, psychopathology and imaging was compared to non-mutation carriers with early probable bvFTD. Among the mutation carriers one patient had a “psychiatric” phenotype with severe hallucinations of body sensations. One patient had a 10 year long history of therapy-refractory depression before symptoms of bvFTD occurred and one patient showed clinical symptoms typical for Alzheimer’s disease. In the group of early bvFTD patients no significant differences were detected between mutation carriers and non-mutation carriers regarding the prevalence of cognitive and psychiatric symptoms. None of the mutation carriers suffered from visual or auditory hallucinations. Likewise, no significant differences were detected regarding neuropsychological test performance. However, there was a (statistically not significant) trend that forgetfulness was more often reported as first symptom in mutation carriers than in non-carriers. A preliminary analysis revealed no significant differences in MRI- and PET imaging, a finding that needs, however, to be confirmed in further voxel based analyses.

Taken together, results do not support the hypothesis that phenotypes of C9orf72 mutation carriers differ from non-carriers. A selection bias, however, needs to be considered.

DB1 Reward deficits in behavioral variant frontotemporal dementia include insensitivity to negative stimuli D. Perry1, S. Datta1, V. Sturm1, K. Wood1, J. Zakrzewski1, B. Miller1, J. Kramer1, H. Rosen1 1 University of California San Francisco, San Francisco, CA, USA Several common symptoms in behavioral variant frontotemporal dementia (bvFTD) indicate a change in reward value, including overeating, hypersexuality, increased alcohol use, and overspending. It has not been established whether these behaviors are due to increased desire for rewards or decreased sensitivity to the negative consequences of one’s actions. Our objective was to identify the reward processing deficits in bvFTD and link these to their neuroanatomic correlates. 25 patients with bvFTD and 21 agematched controls completed an olfactory paradigm with pleasant and unpleasant odorants. In one task, participants were asked to rate each odorant on valence (pleasantness) using a 9-point scale. In a second task, participants were presented with the same olfactory stimuli after an anticipatory period during which a description of the smell was displayed. Physiological measurements, including skin conductance response (SCR), were taken. The anatomic correlates of valence ratings were determined by voxel-based morphometry. A significant valence by diagnosis interaction was found (p < 0.05) for participants’ pleasantness ratings. Patients with bvFTD rated unpleasant stimuli significantly more positively than controls (p < 0.05), while there were no significant differences in ratings of pleasant or neutral stimuli. During the anticipation task, there was a significant valence by diagnosis interaction for SCR (p < 0.05). When anticipating unpleasant smells, bvFTD patients had a smaller SCR than controls. Anticipation of pleasant smells yielded similar responses in both groups. Atrophy in the right insula and amygdala correlated with having a smaller difference between valence ratings of pleasant and unpleasant odors (p < 0.05 Family Wise Error corrected). Higher positive ratings of unpleasant odors correlated with left insula atrophy. Compared to controls, patients with bvFTD display less aversion to unpleasant odorants in their behavioral and physiological responses. These reward changes relate to atrophy of bilateral reward-related structures, including insula.

DB2 Embodied cognition of dynamic emotion in frontotemporal lobar degeneration C. Marshall1,2, C. Hardy1, L. Russell1, C. Clark1, K. Dick1, E. Brotherhood1, J. Nicholas1, J. Rohrer1, J. Kilner2, J. Warren1 1 UCL, Dementia Research Centre, London, Great Britain 2 UCL, Sobell Department of Motor Neuroscience, London, Great Britain Facial emotion recognition in health is associated with automatic imitation of facial expressions, which can be measured by facial EMG. Building on recent work showing abnormalities of implicit physiological reactivity in FTD, we present the first study of facial EMG in these diseases. Patients with canonical


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FTLD syndromes (13 bvFTD, 9 PNFA, 9 SD, 6 rtvFTD) and 21 age-matched healthy controls performed an emotion recognition paradigm, viewing dynamic facial emotions (videos of universal facial expressions) while EMG was recorded from corrugator supercilii, zygomaticus major and levator labii muscles. FTD patients showed impaired EMG reactivity, which correlated with emotion recognition deficits. Disgust reactivity was particularly reduced in bvFTD, and fear reactivity in PNFA. Voxel based morphometry of patients’ brain MR images revealed distinct but overlapping grey matter correlates of impaired emotion recognition and automatic imitation, which varied by syndrome. Correlation between recognition of dynamic stimuli and grey matter volume in the supplementary motor cortex was found in all groups, as well as other syndrome-specific correlates. Reduction in automatic imitation was associated with atrophy of supplementary motor cortex in bvFTD, a visuomotor network in PNFA, parahippocampal and fusiform gyri in SD and posterior middle temporal gyrus in rtvFTD: together these areas delineate a distributed neural network previously linked to embodied cognition in the healthy brain and suggesting a novel neurobiological mechanism of disordered socio-emotional signal processing in FTLD.

DB3 Longitudinal decline in cognitive functioning in presymptomatic frontotemporal dementia J. Papma1, L. Jiskoot1, E. Dopper1, T. Den Heijer2, R. Timman3, R. Van Minkelen4, J. Van Swieten1 1 Erasmus Medical Center, Neurology, Rotterdam, Netherlands 2 Sint Franciscus Gasthuis, Neurology, Rotterdam, Netherlands 3 Erasmus Medical Center, Psychiatry, Rotterdam, Netherlands 4 Erasmus Medical Center, Clinical Genetics, Rotterdam, Netherlands Frontotemporal dementia (FTD) is characterized by cognitive disorders in language, executive function and social cognition. Increasing evidence suggests a presymptomatic phase, in which early disease-related changes can be examined and potentially serve as biomarkers for symptom onset and disease progression. In the present study we performed a 2-year follow-up study with neuropsychological assessment in the presymptomatic phase of familial FTD due to GRN and MAPT mutations in order to explore the prognostic value of neuropsychological assessment in the earliest FTD disease stages. Healthy at-risk first-degree relatives of FTD patients with a MAPT (n = 13) or GRN mutation (n = 30) and controls from the same families (n = 39) underwent extensive neuropsychological assessment at baseline and 2-year follow-up. We investigated baseline and longitudinal differences, as well as the relationship with age and estimated years before symptom onset. At 2 year follow-up MAPT mutation carriers showed a steeper decline than GRN mutation carriers on social cognition (p = 0.002). Higher age was related with cognitive decline in visuoconstruction (p = 0.005) and social cognition (p = 0.026) in MAPT. Memory significantly declined around 8–6 years before estimated onset in MAPT and GRN mutation carriers, and language and social cognition declined only in MAPT mutation carriers from respectively 7 and 5 years before estimated onset (p < 0.05). Using longitudinal neuropsychological assessment, we detected gene-specific predictive neuropsychological patterns. Our results confirm the prognostic value of

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neuropsychological assessment as potential clinical biomarker in the presymptomatic phase of familial FTD.

DB4 The impact of context on emotion decoding in frontotemporal dementia F. Kumfor1,2,3, A. Iba~ nez4,5,6, J. Hodges1,2,3, O. Piguet1,2,3 1 Neuroscience Research Australia, Randwick, Sydney, Australia 2 University of New South Wales, School of Medical Sciences, Sydney, Australia 3 ARC Centre of Excellence in Cognition and its Disorders, Sydney, Australia 4 Institute of Cognitive Neurology INECO, Buenos Aires, Argentina 5 Diego Portales University, UDP-INECO Foundation Coreon Neuroscience UIFCoN, Santiago, Argentina 6 Favaloro University, Institute of Neuroscience, Buenos Aires, Argentina The ability to decode emotional information is variably affected in frontotemporal dementia. Individuals with semantic dementia (SD) and behavioural-variant frontotemporal dementia (bvFTD) show pervasive emotion recognition deficits, whereas Alzheimer’s disease (AD) patients usually perform within normal limits. To date, most studies have investigated recognition of facial emotions only. Here, we aimed to investigate how contextual information (e.g., body language) influences emotion recognition, within the framework of the social context network model. Twenty-seven dementia patients (7 SD, 12 bvFTD, 8 AD) and 12 demographically-matched healthy controls were recruited. Participants completed a facial emotion recognition task, where faces were either presented in an emotionally congruent or incongruent context (emotional body language). Averaged across conditions, both SD (p = 0.021) and bvFTD (p = 0.059) performed worse than controls, whereas AD performed within normal limits (p = 0.150). Notably, however, the effect of contextual information differed across syndromes. On congruent trials, SD showed reduced sensitivity to context, performing significantly worse than bvFTD (p = 0.034), whereas both bvFTD and AD performed similarly to controls (ps > 0.05). In contrast in the incongruent condition, bvFTD (p < 0.001) and AD (p = 0.006) performed worse than controls, whereas incongruent contextual information did not influence performance in SD (p > 0.05). Our results reveal that in individuals with SD, who show disproportionate anterior temporal lobe atrophy, the integration of contextual information to inform emotion decoding is abnormal. In individuals where this region is less affected (i.e., bvFTD, AD), however, provision of congruent contextual information improves emotion decoding, supporting the social context network model. Clinically, these results open new avenues for rehabilitation of social impairments in dementia.



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Neuropsychological profiles in behavioural variant Frontotemporal Dementia and Psychiatric disorders E. Vijverberg1,2, S. Schouws3, P. D. Meesters3, S. Sikkes1, E. Verwijk4, H. Comijs3, P. Scheltens1, M. Stek3, Y. Pijnenburg1, A. Dols3 1 VUmc, Alzheimer Centre and Department of Neurology, Amsterdam, Netherlands 2 Haga Ziekenhuis, Department of Neurology, The Hague, Netherlands 3 GGZ InGeest, Department of Old Age Psychiatry, Amsterdam, Netherlands 4 GGZ Parnassia, Department of Old Age Psychiatry, The Hague, Netherlands

Frontotemporal dementia in patients of African descent K. Josephs1, W. Hu2, A. Hillis3, B. Dickerson4, N. Graff-Radford5, C. Davis3, R. Akinyemi6, A. Ogunniyi6, N. Taner5, J. Graff-Radford1, A. Ali7, D. Tang-Wai8, M. Wicklund9, F. Pasquier10, F. Lebert10, J. Snowden11, N. Fox12, M. Grossman13, C. Onyike14 1 Mayo Clinic, Neurology, Rochester, USA 2 Emory University School of Medicine, Neurology, Atlanta, USA 3 Johns Hopkins Medicine, Neurology, Baltimore, USA 4 Massachusets General Hospital, Neurology, Boston, USA 5 Mayo Clinic, Neurology, Jacksonville, USA 6 University of Ibadan, Neurology, Ibadan, Nigeria 7 University Hospital of the West Indies, Neurology, Mona, Jamaica 8 University of Toronto, Neurology, Toronto, Canada 9 University of Florida, Neurology, Gainesville, USA 10 Centre Hospitalier Regionale et Universitaire de Lille, Neurology, Lille, France 11 University of Manchester, Neurology, Manchester, Great Britain 12 University College London, Institute of Neurology, London, Great Britain 13 University of Pennsylvania, Neurology, Philadelphia, USA 14 Johns Hopkins Medicine, Neuropsychiatry, Baltimore, USA

Background: Executive dysfunction with relative sparing of memory is a hallmark of behavioural variant Frontotemporal dementia (bvFTD) compared to other types of dementia. However, it is unknown if this cognitive profile can discriminate bvFTD from psychiatric disorders. Aims: To compare neuropsychological profiles in bvFTD with the most common psychiatric bvFTD misdiagnoses; Major Depression (MD), Bipolar Disorder (BD) and Schizophrenia (SZ) in older patients with current symptoms. Methods: We included older patients from different cohorts with MD (n = 42), non-euthymic BD (n = 41), non-remitted SZ (n = 47), probable/definite bvFTD (n = 173) and healthy controls (n = 78). The neuropsychological tests concerned the domains of attention and working memory, verbal memory, verbal fluency and executive functioning. Results: Executive function was worse in all psychiatric disorders compared to BvFTD. Attention/working memory were significantly better in bvFTD and SZ compared to the affective disorders. For verbal memory, bvFTD scored significantly higher compared to SZ. MD and BD had both the lowest performance on the memory tests. BvFTD had the lowest score on the verbal fluency, however, not significantly different in relation to SZ patients. Conclusions: We found that the neuropsychological profile of bvFTD differs in severity from psychiatric disorders with current symptoms by less impairment on executive functions and verbal memory. In contrast, bvFTD showed more impairment on verbal fluency tests compared to MD and BD. Therefore, in the differential diagnosis of bvFTD clinicians should not be misled by the severity of cognitive impairment to rule out a psychiatric diagnosis.

The frontotemporal dementias (FTDs) are a group of neurodegenerative disorders, reported to afflict Caucasians. FTD patients present young with a relatively confined symptom set that underlie three well defined syndromes: the behavioral variant of FTD, semantic dementia (SD), and nonfluent/agrammatic aphasia. There are strong genetic factors underlying FTD, particularly in those of Western European descent. No data is available on patients of African descent. Demographic and clinical information were collected from 10 FTD research centers in Europe and North America, as well as two dementia centers in Africa, and the Caribbean, on all patients of African descent who had been diagnosed with FTD. Patients were classified based on place of birth, into African (born in Africa), African-American (born in the USA) or African-Caribbean (born in the Caribbean). Sixty-five patients were identified, 37 (66%) African-American, 11 (20%) African-Caribbean and 8 (14%) African. Median age of symptom onset was 59.5 years (range: 30–86); 63% were female. The most common diagnosis was behavioral variant FTD (N = 34, 52%), followed by SD (N = 21, 32%), and then nonfluent/agrammatic aphasia (N = 10, 15%). Of the SD cases, half presented with behavioral changes and prosopagnosia, and showed right more than left anteromedial temporal lobe atrophy. Motor neuron disease was uncommon, documented in 4 (6%). Of 39 patients with detailed clinical information, hallucinations and paranoid delusions were noted in 11 (28%) and 7 (18%) respectively, and a positive family history was present in 7 (18%). Three patients were carriers of a C9ORF72 repeat expansion. Pathological diagnosis obtained on 3 patients showed FTLD-tau in 2 and FTLD-TDP in 1. As in Caucasians, all three canonical FTD syndromes afflict patients of African descent, are associated with young onset, and have familial tendencies and genetic associations. The frequency of right temporal dominant SD, hallucinations and paranoid delusions were, however, higher than expected. More research on FTD in non-Caucasian populations is warranted.


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Session 3: Genetics of FTLD S5 Next generation sequencing approaches in ALS and related disorders S. Zuchner1 1 University of Miami, Department of Human Genetics and Hussman Institute for Human Genomics, Miami, USA More then ever we appreciate neurodegenerative diseases as an extremely heterogeneous spectrum disorder, which may include one or many neuronal populations in the central and peripheral nervous system. Not at least the recent enormous progress in elucidating the genetic etiology of these diseases has shown the increasingly overlapping nature of genotypes and phenotypes, the importance of “deep” phenotyping, and the large and growing number of involved monogenic and risk genes. We are pursuing a number of synergistic projects with a focus on related disorders that have already yielded significant genetic findings. This includes the new CReATe ALS consortium to whole genome sequence 700 + patients with ALS and related disorders, the Inherited Neuropathy Consortium with the largest exome and genome collection in the world, an international network of centers focused on hereditary spastic paraplegias, and ataxia genomics. Together, these efforts have already resulted in the largest genomic database for neurodegenerative diseases, with over 5,000 families. Clinical access to each patient is possible. At this scale we have learned that data analysis, management, and sharing is becoming a defining aspect for success. Thus, we have developed the GENESIS platform to accomplish an uncomplicated and worldwide available academic resource. With over 60 published papers, GENESIS has contributed to the majority of published gene identifications in a number of neurodegenerative disorders in recent years. This presentation will summarize these projects and experiences, and present specific highlights of this research.

O5 Identification Of A novel FTD-MND gene on chromosome 16 C. Dobson-Stone1,2, A. Luty1,2, E. Thompson3, P. Blumbergs4, W. Brooks1,5, C. Shepherd1,2, J. Yerbury6, G. Halliday1,2, P. Schofield1,2, J. Kwok1,2 1 Neuroscience Research Australia, Sydney, Australia 2 University of New South Wales, School of Medical Sciences, Sydney, Australia 3 Women’s and Children’s Hospital, SA Clinical Genetics Service, SA Pathology, Adelaide, Australia 4 Institute of Medical and Veterinary Science, Adelaide, Australia 5 University of New South Wales, Prince of Wales Clinical School, Sydney, Australia 6 University of Wollongong, Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, Wollongong, Australia Numerous families exhibiting both frontotemporal dementia (FTD) and motor neuron disease (MND) have been described, and most of them harbour C9orf72 repeat expansions. However, several

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C9orf72-negative FTD-MND families remain and the genetic cause of their disease is unknown. The aim of this study was to determine the gene responsible for disease in a large European Australian kindred (Aus-12) with autosomal dominant inheritance of dementia and/or MND. Neuropathology was most consistent with frontotemporal lobar degeneration with type B TDP pathology, but with additional phosphorylated tau pathology consistent with corticobasal degeneration (CBD). Affected individuals were negative for mutations in known dementia and MND genes. Genome-wide linkage analysis identified a disease locus on chromosome 16p12.1–q12.2 (maximum LOD = 3.325), a region excluding FUS but overlapping with a previously published MND family. Whole-exome sequencing revealed one variant within this region that segregated with disease and was absent from databases of normal variation. This variant leads to substitution of a conserved amino acid in an autophagy gene that negatively regulates NF-jB and interacts with the FTD/MND genes OPTN, SQSTM1 and TBK1. This Aus-12 variant increases catalytic activity of the autophagy protein 4-fold relative to wildtype (p < 0.001). We also observed a significant increase in NF-jB inhibition, as assessed by luciferase reporter assay, and reduced proteasome function in a tomato-CL1 proteasome reporter assay. In conclusion, we have identified a variant in a novel gene that is likely responsible for disease in this FTD-MND family with concurrent TDP and tau pathology, further reinforcing the importance of the autophagy pathway in the pathogenesis of FTD and MND.

O6 Global initiative to identify genetic modifiers of disease onset and presentation in patients with progranulin mutations C. Pottier1, D. J. Serie2, E. D. Huey3, M. Neumann4, P. Johannsen5, J. Slawek6, E. C. Finger7, C. F. Lippa8, C. L. I. White9, T. G. Beach10, J. B. Kwok11, S. Sorbi12, B. Ghetti13, M. M. Mesulam14, E. H. Bigio15, R. Sanchez-valle16, S. Pickering-Brown17, A. Bruni18, E. Rogaeva19, J. D. Rohrer20, C. Graff21, I. R. Mackenzie22, T. D. Bird23, C. Cruchaga24, J. C. van Swieten25, B. L. Miller26, A. Lopez de Munain27, V. M. Van Deerlin28, G. Rossi29, L. Benussi30, B. Borroni31, D. Galimberti32, R. Ghidoni30, I. Le Ber33, J. Biernacka34, D. W. Dickson1, N. R. Graff-Radford35, B. F. Boeve36, R. Rademakers1 1 Mayo Clinic, Neuroscience, Jacksonville, USA 2 Mayo Clinic, Division of Biomedical Statistics and Informatics, Jacksonville, USA 3 Columbia University, Taub Institute for Research on Alzheimer’s disease and the Aging Brain, The Gertrude H. Sergievsky Center, New York, USA 4 University of T€ ubingen, Department of Neuropathology, T€ ubingen, Germany 5 Copenhagen University Hospital, Danish Dementia Research Centre, Department of Neurology, Copenhagen, Denmark 6 St. Adalbert Hospital, Neurology Department, Gda nsk, Poland 7 Western University, Clinical Neurological Sciences, Schulich School of Medicine, London Ontario, Canada


Session 3: Genetics of FTLD 8

Drexel University College of Medicine, Department of Neurology, Philadelphia, USA 9 University of Texas Southwestern Medical Center, Department of Pathology, Dallas, USA 10 Banner Sun Health Research Institute, Sun City, USA 11 University of New South Wales, Neuroscience Research Australia, Sydney, Australia 12 University of Florence, Department of Neuroscience, Psychology, Drug Research and Child Health, Florence, Italy 13 Indiana University School of Medicine, Department of Pathology and Laboratory Medicine, Indianapolis, USA 14 Northwestern University Feinberg School of Medicine, Cognitive Neurology and Alzheimer's Disease Center and Department of Neurology, Chicago, USA 15 Northwestern University Feinberg School of Medicine, Northwestern ADC Neuropathology Core, Chicago, USA 16 Hospital Clínic, Barcelona, Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Barcelona, Spain 17 University of Manchester, Institute of Brain, Behaviour and Mental Health, Manchester, Great Britain 18 Centro Regionale di Neurogenetica, ASP Catanzaro, Lamezia terme, Italy 19 University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Toronto, Canada 20 University College London, Dementia Research Centre, London, Great Britain 21 Karolinska Institutet, Alzheimer's Disease Research Center, Department of Neurobiology, Care Sciences and Society, Stockholm, Sweden 22 University of British Columbia, Department of Pathology, Vancouver General Hospital, Vancouver, Canada 23 University of Washington, Department of Neurology, Seattle, USA 24 Washington University School of Medicine, Department of Psychiatry, Saint Louis, USA 25 Erasmus Medical Centre, Department of Neurology, Rotterdam, Netherlands 26 University of California San Francisco, Memory and Aging Centre Department of Neurology, San Francisco, USA 27 Hospital Universitario Donostia, Department of Neurology, San Sebastian, Spain 28 Perelman School of Medicine at the University of Pennsylvania, Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Philadelphia, USA 29 Neurological Institute “Carlo Besta” Foundation IRCCS, Division of Neurology V and Neuropathology, Milan, Italy 30 IRCCS Istituto Centro San Giovanni di Dio- Fatebenefratelli, Molecular Markers Laboratory, Brescia, Italy 31 University of Brescia, Centre of Brain Aging, Neurology Unit, Department of Clinical and Experimental Sciences, Brescia, Italy 32 University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Neurology Unit, Department of Pathophysiology and Transplantation, Milan, Italy 33 Sorbonne Universités, Université Pierre et Marie Curie, Institut du Cerveau et de la Moelle épinière, Paris, France 34 Mayo Clinic, Department of Health Sciences Research, Rochester, USA 35 Mayo Clinic, Department of Neurology, Jacksonville, USA 36 Mayo Clinic, Department of Neurology, Rochester, USA Frontotemporal lobar degeneration (FTLD) is considered a young onset dementia but strong variability in age at onset and presenting

symptoms are observed. Progranulin (GRN) mutations are a major cause of FTLD which cause disease through a uniform disease mechanism, i.e. all mutations lead to a loss of 50% of functional progranulin, making this an ideal group of patients to study genetic modifiers of disease. In fact, by comparing GRN mutation carriers to controls, TMEM106B has already been shown as a major protective factor in GRN mutation carriers, confirming that genetic modifiers play a role in the phenotypic variability. To identify additional genetic modifiers of disease onset and presentation in GRN mutation carriers, we initiated a global initiative to collect DNA from all GRN mutation carriers from more than 30 different sites for genetic studies. To date, we performed a common variant genome wide association study using the Illumina Human OmniExpress chip in 501 symptomatic mutation carriers representing 114 different GRN mutations and 1173 matched controls (468 newly genotyped and 705 from publicly available datasets). In patients, onset age ranged from 39 to 87 years. When more than 600 000 variants passing quality control in all patients and controls were included in the analysis, we found that the only signal reaching genome-wide significant association was rs6966915 in TMEM106B (p = 7.89e10, OR = 0.54 [0.45–0.66]). A linear regression analysis with age at onset in all unrelated patients using an additive model and adjusting for gender and the first four principal components, further identified 8 SNPs at 7 loci with p < 1.0e-5 near or in multiple genes involved in neurodevelopment processes and immunity (e.g. HDAC9, DOCK2). Analysis of the subgroup of patients with the common Italian p.Thr272Serfs*10 mutation is also currently ongoing. Further study of our unique population may provide insight into the understanding of phenotypic variability in GRN mutation carriers and FTLD patients in general.

DB7 Loss of function mutations in dipeptidyl peptidase 6 in Alzheimer disease and Frontotemporal dementia: a novel pathway in neurodegeneration R. Cacace1,2, T. Van den Bossche1,2,3,4, J. Lippiat5, J. Janssens1,2,6, G. De Baets7, S. Engelborghs2,4, A. Sieben1,2, M. Vandenbulcke8,9, P. de Rijk10, E. Cuyvers1,2, C. Van Cauwenberghe1,2, C. Robberecht1,2, L. Dillen1,2, C. Merlin1,2, N. Geerts1,2, R. Vandenberghe8,11, J.-J. Martin2, P. P. De Deyn2,4, J. Schymkowitz7, S. Maudsley6,10, M. Cruts1,2, J. van der Zee1,2, K. Sleegers1,2, C. Van Broeckhoven1,2 1 University of Antwerp, Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 3 Antwerp University Hospital UZA, Department of Neurology, Edegem, Belgium 4 Hospital Network Antwerp ZNA Middelheim and Hoge Beuken, Department of Neurology and Memory Clinic, Antwerp, Belgium 5 University of Leeds, School of Biomedical Sciences, Faculty of Biological Sciences, Leeds, Great Britain 6 University of Antwerp, Translational Neurobiology Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 7 Katholieke Universiteit Leuven and Vrije Universiteit Brussel, VIB Switch Laboratory, Department of Cellular and Molecular Medicine, Leuven, Belgium 8 KU Leuven, Department of Neurosciences, Faculty of Medicine, Leuven, Belgium 9 University of Leuven and University Hospitals Leuven


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Session 3: Genetics of FTLD

Gasthuisberg, Department of Old Age Psychiatry and Memory Clinic, Leuven, Belgium 10 Bioinformatics Unit, Department of Molecular Genetics, VIB, Antwerp, Belgium 11 University Hospitals Leuven, Department of Neurology, Leuven, Belgium Molecular genetic studies have contributed importantly to our current knowledge of the pathogenesis of neurodegenerative dementia such as Alzheimer disease (AD) and frontotemporal dementia (FTD). Yet the genetic underpinnings still remain to be completely disclosed, as proven by the missing genetic etiology in families as well as patients with very young age at onset and/or positive family history. In a previous genome-wide linkage study on an autosomal dominant AD family, we identified a genetic locus of 5.44 Mb at chromosome 7q36, but the underlying disease-linked mutation remained to be identified (Rademakers et al. Am J Hum Genet. 2005; 77 643–52). The rationale of the current study is the reinvestigation of the unresolved linkage locus. Whole genome sequencing (WGS) was performed on 4 patients from the pedigree. This led to the identification of a genomic inversion of ~ 4 Mb on the disease haplotype with the distal breakpoint in intron 1 of dipeptidyl peptidase 6 (DPP6) and the proximal breakpoint outside the linked locus in an intergenic region. DPP6 is mostly expressed in brain where it modulates the expression and the function of the potassium channel Kv4.2, regulating synaptic excitability. Massive parallel DPP6 re-sequencing was performed in both Belgian AD (n = 335) and FTD (n = 453) patients as well as control individuals (n = 755). This revealed a significant enrichment of rare variants in the FTD cohort (23/453, 5.08%) compared to control individuals (13/755, 1.72%; SKAT-O p-value = 0.001, relative risk (RR) = 3.0, 95% confidence interval (CI) = 1.51–5.95). In the smaller AD cohort, we observed a non-significant trend in the same direction (RR = 2.1, 95% CI = 0.95–43.63; SKAT-O p-value 0.15). Expression studies on brain tissue of mutation carriers showed a decreased expression of DPP6 transcript (p-value = 0.0096), which was further confirmed on protein level. A decreased Kv4.2 protein expression was also detected in patient carriers when compared to control individuals. Electrophysiology studies in Xenopus laevis oocytes showed a significant negative effect (p-value < 0.05) on Kv4.2 gating properties when the channel was co-expressed with protein truncating loss-of-function (LoF) variants, identified only in patients. In this study, we identified a chromosomal inversion on the 7q36 genomic locus segregating with the disease, thus explaining the linkage signal previously detected in the family. This inversion is predicted to lead to LoF of DPP6 by detaching the first coding exon from the gene. Additional premature protein truncating LoF variants were also identified only in patients. We suggest that LoF variants in DPP6 may lead to synaptic hyperexcitability, thus providing genetic support to the emerging concept of brain network activity alteration as an early event in the neurodegenerative process.

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DB8 Symptom onset in genetic frontotemporal dementia K. M. Dick1, B. F. Boeve2, B. Borroni3, A. Boxer4, A. Brice5, C. R. Butler6, P. Couratier7, B. C. Dickerson8, S. Ducharme9, E. Finger10, D. Galimberti11, A. Gerhard12, N. Ghoshal13, C. Graff14, M. Grossman15, J. R. Hodges16, E. D. Huey17, R. LaforceJr18, I. Le Ber19, J. Levin20, I. R. Mackenzie21, M. Masellis22, O. Martinaud23, A. Mendoncßa24, F. Moreno25, J. M. Nicholas1,26, C. U. Onyike27, M. Otto28, E. D. Roberson29, E. Rogalski30, H. J. Rosen4, J. B. Rowe31, R. Sanchez-Valle32, I. Santana33, S. Sorbi34, J. van Swieten35, M. Synofzik36, F. Tagliavini37, R. Vandenberghe38, J. D. Roher1 1 Institute of Neurology, UCL, Dementia Research Centre, London, Great Britain 2 Department of Neurology and Centre for Sleep Medicine, Mayo Clinic, Rochester, Minnesota, USA, USA 3 Neurology Unit, Department of Medical and Experimental Sciences, University of Brescia, Brescia, Italy 4 Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA 5 Universite Pierre et Marie Curie-Paris 6, Centre de Recherche de l’Institut du Cerveau et de la Moelle epiniere, Paris, France 6 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK, Great Britain 7 Service de Neurologie, CHU Dupuytren, Limoges, France 8 Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, USA 9 Montreal Neurological Institute, McConnell Brain Imaging Centre, McGill University, 3801 University Street, Montreal, QC, Canada 10 Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada 11 Neurology Unit, Department of Physiopathology and Transplantation, University of Milan, Fondazione C a Granda, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Policlinico, Milan, Italy 12 Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK, Great Britain 13 Washington University School of Medicine, St. Louis, MO, USA, USA 14 Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden, Department of Geriatric Medicine, Genetics Unit, Karolinska University Hospital, Stockholm, Sweden 15 Department of Neurology, Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA 19104, USA, USA 16 Neuroscience Research Australia, Sydney, Australia; Australian Research Council Centre of Excellence in Cognition and its Disorders, Sydney, Australia, School of Medical Sciences, The University of New South Wales, Sydney, Australia 17 Departments of Psychiatry and Neurology, Columbia University, New York, USA, USA 18 Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, Hôpital de l'Enfant-Jésus, and Faculté de Médecine, Université Laval, QC, Canada 19 Institut du Cerveau et de la Moelle épinière ICM, INSERM U1127, CNRS UMR 7225, Sorbonne Universités, Université Pierre et Marie Curie, Univ Paris 06, UPMC-P6 UMR S 1127 Hôpital de la Pitié-Salpêtrière, Paris, France; Centre de Référence des Démences Rares, Assistance Publique-Hôpitaux de Paris AP-HP,



Hôpital de la Pitié-Salpêêtrière, Paris, France 20 Neurology Department, Ludwig-Maximilians-Universitat Munchen, Marchioninistr., Munich, Germany 21 Division of Neuropathology, Department of Pathology and Lab Medicine, University of British Columbia, Canada 22 LC Campbell Cognitive Neurology Research Unit, Department of Medicine, Division of Neurology, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto Canada 23 Department of Neurology, Rouen University Hospital, France 24 Laboratory of Neurosciences, Institute of Molecular Medicine, Lisbon, Portugal, Portugal 25 Neuroscience Area, Institute Biodonostia, and Department of Neurosciences, University of Basque Country, San Sebasti an,

Spain 26

Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK, Great Britain 27 Johns Hopkins University, Baltimore, MD, USA, USA 28 Department of Neurology, University of Ulm, Ulm, Germany 29 Center for Neurodegeneration and Experimental Therapeutics, Departments of Neurology and Neurobiology, USA, USA 30 Cognitive Neurology and Alzheimer''s Disease Center, Northwestern University, USA 31 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK, Great Britain 32 Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer IDIBAPS, Barcelona, Spain 33 Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal 34 Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy 35 Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands 36 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany, German Research Center for Neurodegenerative Diseases DZNE, Tübingen, Germany 37 Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milano, Italy 38 Laboratory for Cognitive Neurology, Department of Neurology, University of Leuven and University Hospitals Leuven Gasthuisberg, Leuven, Belgium Genetic frontotemporal dementia (FTD) is caused by mutations in three main genes: C9orf72, progranulin (GRN) and microtubuleassociated protein tau (MAPT). Little is currently known about the factors that influence age at symptom onset in FTD. This study aimed to investigate this through data collected from multiple families through the Frontotemporal dementia Prevention Initiative (FPI), a group connecting research centres within four large studies: GENFI, ARTFL, LEFFTDS and an Australian genetic FTD study. We collected data on ages at symptom onset from 1508 individuals from 632 families: 694 C9orf72 (352 families), 333 MAPT (102 families: 33 different mutations, most commonly P301L), and 480 GRN (193 families: 69 different mutations, most commonly T272 fs). The mean age at symptom onset was 58.4 (standard deviation 10.4) in C9orf72, 51.9 (8.4) in MAPT, and 61.2 (9.1) in GRN. In a preliminary analysis we assessed the correlation of age at symptom onset with parental age at onset and mean age at onset within the family. The strongest correlation between individual age at onset and both parental age at onset (r = 0.47, p < 0.001) and

mean age at onset in the family (r = 0.54, p < 0.001) was seen in MAPT. In C9orf72, there was a significant correlation between individual age at onset and both parental age at onset (r = 0.29, p = 0.001) and mean age at onset in the family (r = 0.30, p < 0.001) but to a lesser extent than MAPT. In the GRN group there was a significant correlation between individual age at onset and parental age at onset (r = 0.38, p < 0.001) but only a trend to correlation with mean family age at onset (r = 0.11, p = 0.060). Whilst a proportion of the observed variance in age at symptom onset in genetic FTD can be explained by family history this is variable by mutation type.

DB9 ATXN2 polyQ intermediate repeats influence Frontotemporal Lobar Degeneration phenotype E. Rubino1, C. Mancini2, P. Ferrero3, M. Ferrone4, S. Bianca1, S. Boschi1, M. Zucca1, L. Orsi3, S. Gentile3, L. Pinessi1,3, A. Brusco2,4, I. Rainero1,3 1 University of Turin, Department of Neuroscience “Rita Levi Montalcini”, Turin, Italy 2 University of Turin, Department of Medical Sciences, Turin, Italy 3 Citt a della Salute e della Scienza, Department of Neuroscience and Mental Health, Turin, Italy 4 Citt a della Salute e della Scienza, Medical Genetics Unit, Turin, Italy There are several evidences that common genetic risk factors underlie frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Intermediate repeat expansions (27–33 CAG repeats, polyQ) of the Ataxin2 (ATXN2) gene are risk factor for amyotrophic lateral sclerosis and influence ALS phenotype, while expansions ≥ 34 repeats are known to cause spinocerebellar ataxia type 2. At present, the role of ATXN2 in FTLD has been poorly investigated. The purpose of this study was to assess whether ATXN2 is a risk factor for frontotemporal lobar degeneration or influence the clinical presentation. Two hundred and forty-three unrelated patients with FTLD and 176 healthy controls were involved in the study. The ATXN2 CAG repeat in exon 1 (Ref Seq NM_002973.3) was amplified in cases and controls. FTLD patients included in this cohort had previously been screened for genetic variants in known FTLD-related genes. No difference in the frequency of intermediate CAG repeats in ATXN2 gene was found between FTLD patients and controls (p = 0.234). Neither patients nor controls showed a fully expanded ATXN2 allele. Patients with an increased polyQ repeats had an earlier onset of the disease than those without intermediate expansions (p = 0.037). Interestingly, patients with intermediate repeat expansions presented more frequently with parkinsonism (p = 0.006). The odds ratio (OR) for FTLD patient with intermediate polyQ repeats of having parkinsonism was 4.2 (95% confidence interval 1.4–12.6). In this large series of FTLD patients, we confirmed that intermediate CAG expansion of the ATXN2 gene is not a genetic risk factor for FTLD. However, intermediate CAG polyQ repeats influence the clinical phenotype, being associated to a significantly earlier onset of the disease and parkinsonian features.


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DB10

S6

Gene-based analysis detects novel loci associated with frontotemporal dementia and its clinical subtypes A. Mishra1, R. Ferrari2, F.-G. Consortium2, P. Heutink3, J. Hardy2, Y. Pijnenburg4, D. Posthuma1,4 1 VU University, Center for Neurogenomics and Cognitive Research, Amsterdam, Complex Trait Genetics, Amsterdam, Netherlands 2 University College London, Molecular Neuroscience, London, UK, Great Britain 3 University of T€ubingen, Hertie Institute for Clinical Brain Research, Neurodegenerative Diseases, T€ ubingen, Germany 4 University Medical Center VUMC, Neursocience Campus Amsterdam, Alzheimer Center and Department of Neurology, Amsterdam, Netherlands

How do we move from large scale genotyping and sequencing efforts in genetics to biology? P. Heutink1 1 Eberhard Karls Universit€ at T€ ubingen, German Center for Neurodegenerative Diseases DZNE, T€ ubingen, Germany

Recent single marker genome-wide association study (GWAS) on FTD showed limited success in identifying associated loci possibly due to underpowered samples and allelic heterogeneity. In this study, we performed an alternative joint-SNP gene-based analyses using the GWAS summary data on 3526 clinically identified frontotemporal dementia (FTD) cases and 9402 controls reported by Ferrari et al. (Ferrari et al. Lancet Neurol. 2014 Jul; 13 (7) 686–99) to identify genes associated with FTD and its clinical subtypes. The MAGMA method (de Leeuw et al. PLoS Comput Biol. 2015 Apr 17; 11(4): e1004219), which is based on a multiple linear principal components regression model, was used to perform the gene-based association analyses. We performed separate twocohort (discovery and replication) gene-based analyses for each FTD subtype (behavioural FTD, semantic dementia, progressive non-fluent aphasia and FTD with motor neuron disease); we then combined the association test statistics from discovery and replication cohorts using the Stouffer’s combination approach for the sample size weighted combination of p-values to identify associated genes with specific FTD subtypes. We identified association of the APOE locus (APOE and TOMM40 genes) with behavioural FTD, and ARHGAP35 and SERPINA1 genes with progressive non-fluent aphasia. The APOE gene association with behavioural FTD point towards its role across different clinically observed neurodegenerative diseases. To the best of our knowledge, this is the first work reporting a significant genetic association with progressive nonfluent aphasia: SERPINA1 and ARHGAP35 point to a potential role of a stress-pathway in the pathogenesis of progressive non-fluent aphasia.

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Human genetics has been very successful in adopting large scale genotyping studies such as GWAS and whole exome/genome sequencing to identify risk variants associated with disease. However, interpreting the wealth of data obtained from these studies has not been straightforward. GWAS point to specific genomic locations where risk variants are located but these loci often contain multiple genes and identification of the causal variant (s) has proven to be problematic. Whole exome/genome sequencing studies have revealed large numbers of genome variants that are predicted to be harmful by bioinformatic algorithms. However, suitable replication datasets are currently lacking and most cases carry multiple mutations predicted to be harmful, making it difficult to determine which mutations are relevant for disease. Consequently, the field phases the challenge of investigating and validating large numbers of genes and genomic variants for their relevance in the disease process. GWAS for FTD have had limited power to detect and/or replicate genetic associations and larger datasets with well phenotyped cases will be needed. In addition, the identified loci contain coding and non-coding regions and the causal variant(s) might therefore be in regulatory elements for genes that could even be located outside the associated regions. We therefore need improved functional annotation of the human genome and design experiments to test function and effect of variants in regulatory elements. Whole exome/genome sequencing studies for FTD are underway at different laboratories but in most cases lack power and appropriate replication datasets. Collaborative efforts to join available datasets could overcome this problem but in addition we need large scale functional follow up of predicted mutations in model organisms such as fly or cellular models (including iPS) to prioritize candidate genes. In the following panel discussion we aim to discuss the best ways to move forward from our genetic findings to biological meaningful data.


Session 4: Molecular neuropathology of FTLD

Session 4: Molecular neuropathology of FTLD S7 Molecular neuropathology of FTLD with focus on C9orf72 mutations I. Mackenzie1, M. Neumann2 1 University of British Columbia, Department of Pathology and Laboratory Medicine, Vancouver, Canada 2 University of Tubingen, Department of Neuropathology, Tubingen, Germany Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. The past decade has seen the discovery of several new FTD causing genetic mutations and the identification of many of the relevant pathological proteins. The current neuropathological classification is based on the predominant protein abnormality and allows most cases of FTD to be placed into one of three broad molecular subgroups; frontotemporal lobar degeneration with tau, TDP-43 or FET protein accumulation (FTLD-tau, FTLD-TDP, FTLD-FET; respectively). Further subclassification is based on more detailed patterns of pathology, some of which have relatively specific clinical or genetic correlations. Cases of FTD and ALS associated with the recently discovered C9orf72 mutation present a unique challenge. In addition to FTLDTDP, these cases are consistently found to have cellular inclusions composed of novel dipeptide repeat proteins that are generated by the unconventional translation of the abnormally expanded hexanucleotide repeat, as well as focal aggregation of the mutant RNA (RNA foci). This presentation will provide an overview of the current molecular classification of FTD and will summarize how findings from human postmortem studies provide insight into the relative importance of the different pathologies in the pathogenesis of C9orf72 related disease.

S8 Evidence from human studies for spreading/staging of TDP-43 pathology in FTLD and ALS G. Halliday1, R. Tan1, M. Fatima1,2, J. Hodges1, M. Kiernan2, J. Kril2 1 University of New South Wales, Neuroscience Research Australia, Randwick, Australia 2 University of Sydney, Sydney Medical School, Sydney, Australia The type of TDP-43 pathology differs in different forms of FTLD (type A, B, C and D) and is more uniform in ALS. Regional patterns of TDP-43 pathology indicative of different disease stages diverge for these clinically different syndromes and are strikingly different and more widespread and severe in FTLD. In ALS, the motor cortex, brainstem V, VII and X-XII cranial nerve nuclei, and spinal cord motor neurons are always affected, with prefrontal neocortex, brainstem reticular formation, precerebellar nuclei, and the red nucleus affected by stage 2. Other prefrontal and postcentral cortices as well as the striatum are affected in stage 3, with anteromedial temporal lobe involvement by end-stage ALS. In FTLD prefrontal limbic cortices and amygdala are always affected, with dorsolateral frontal and temporal lobe areas, striatum, red nucleus, thalamus, and

precerebellar nuclei become affected by stage 2. The motor cortex, brainstem somatomotor neurons, and spinal cord motor neurons become involved by stage 3, while the brainstem and basal forebrain monoaminergic regions and the visual cortex become affected by end-stage FTLD. Regional grey matter oligodendrocytes are involved early in these diseases, abnormally depositing TDP-43 protein and potentially participating in the propagation of the protein. In contrast, the white matter oligodendrocytes involved lose myelin in a compensatory response to associated neuronal/axonal involvement. The most convincing evidence of spreading pathology is from objective serial measures of cellular changes in life (imaging and neurophysiology), with such studies clearly showing increasing structural neuronal/axonal loss over time in nearly all forms of FTLD and ALS.

O7 New models for Alzheimer’s and other related tauopathies By transmission of neuronal and glial tau pathology J. Trojanowski1 1 University of Pennsylvania, Department of Pathology and Laboratory Medicine, Philadelphia, USA Filamentous intracellular tau inclusions are hallmarks of neurodegenerative tauopathies such as Alzheimer’s disease (AD) and related tauopathies including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). The progression of tau pathology is hypothesized to result from the cell-to-cell spread of pathological tau proteins. For example, we showed cell type-specific spread of pathological tau following intracerebral injections of CBD or AD brain extracts enriched in pathological tau (CBD-Tau, ADTau, respectively) in young P301S tau transgenic (Tg) mice (line PS19). At 1 mo post-injection of CBD-Tau, tau inclusions developed predominantly in white matter oligodendrocytes with rare neuronal tau aggregates while AD-Tau induced tau pathology predominantly in neurons with very rare glial tau inclusions. After post-injection survival times of 6 mo, CBD-Tau and AD-Tau induced tau pathology showed distinctly different patterns of spread to distant CNS regions while maintaining cell type specific patterns noted above, and only AD-Tau resulted in neurodegeneration. Thus, AD-Tau and CBD-Tau may be distinct pathological tau strains that account for the diverse pathological features of these two tauopathies. In contrast, injections of synthetic human tau preformed fibrils (PFFs) into the locus coreuleus of young PS19 mice led exclusively to neuronal tau pathology that spread to LC afferents and efferents further emphasizing that the LC connectome determines the pathways for the spread of the neuronal tau pathology induced by tau PFFs in LC neurons. More recently,we found that intracerebral injections of more highly enriched AD-Tau resulted in the formation of abundant tau inclusions in anatomically connected brain regions in young non-Tg mice. Recombinant human tau seeded by AD-Tau revealed unique conformational features that are distinct from synthetic tau fibrils. Hence, we establish a mouse model of sporadic tauopathies and suggest there are important


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differences between tau fibrils generated in vitro vs. those derived from AD brains.

O8 Clinicopathological correlations in early vs. late age-ofonset frontotemporal dementia and frontotemporal lobar degeneration S. W. Seo1, M.-P. Thibodeau1, D. C. Perry1, A. Hua1, M. Sidhu1, S. E. Gaus1, G. Rabinovici1, K. D. Rankin1, A. L. Boxer1, J. H. Kramer1, H. J. Rosen1, M. L. Gorno-Tempini1, L. T. Grinberg1, E. J. Huang1, S. J. DeArmond1, J. Q. Trojanowski1, B. L. Miller1, W. W. Seeley1 1 University of San Francisco, San Francisco, USA Background: Frontotemporal dementia (FTD) is often considered an early age-of-onset dementia associated with underlying frontotemporal lobar degeneration (FTLD) pathology. FTD prevalence and pathological correlates in the elderly remain less clear. In this study, we sought to examine clinico-pathological correlations in early vs. late age-of-onset FTD or FTLD. Methods: All patients were clinically evaluated at the UCSF Memory and Aging Center, an outpatient dementia referral center. Two consecutive series were included: 1) patients with a clinically diagnosed FTD syndrome who underwent autopsy and 2) patients with pathologically diagnosed FTLD. These series were divided according to age at symptom onset (cut-off 65 years). Groups were compared in terms of demographic and clinical variables and clinical and pathological diagnoses. Results: In 190 clinically diagnosed FTD spectrum patients, corticobasal syndrome (CBS) (29.2%) and behavioral variant FTD (bvFTD) (20.8%) were the most common clinical diagnoses in late onset (LO)-FTD and early onset (EO)-FTD, respectively. Distinct pathological substrates gave rise to CBS and progressive non-fluent aphasia (nfvPPA) according to age of onset: progressive supranuclear palsy (PSP) for 42.9% of LO-CBS, Alzheimer’s disease (AD) for 40.7% of EO-CBS, corticobasal degeneration (CBD) for 44.4% of EO-nfvPPA and Pick’s disease or PSP for 66.6% of LO-nfvPPA. In 203 pathologically proven 203 FTLD cases, 58 (28.6%) were classified as LO-FTLD while 145 (71.4%) cases were classified as EO-FTLD. FTLD-tau (70.7%), especially PSP (41.4%), was the most common pathological diagnosis found in LO-FTLD while FTLD-transactive response DNA binding protein 43 (TDP-43) (50.3%) was the most common pathology found in EO-FTLD. 19.2% of LO-FTLD and 6.9% of EO-FTLD had been clinically diagnosed as other disease categories, especially AD, rather than FTD. Finally, compared to EO-FTLD, LO-FTLD showed more mixed pathological diagnoses, including moderate or severe AD neuropathological change, cerebral vascular disease, argyrophilic grain disease, and hippocampal sclerosis. Conclusion: Our findings suggest that age-of-onset represents an important consideration when making antemortem neuropathological predictions.

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DB11 TTBK1/2 hyper-activation drives pTau and pTDP accumulation L. Taylor1, P. McMillan2, N. Liachko1,2, A. Saxton2,3, T. Strovas2, B. Kraemer1,2,3 1 University of Washington, Medicine: Gerontology and Geriatric Medicine, Seattle, USA 2 Veterans Affairs Puget Sound Health Care System, Geriatrics Research Education and Clinical Center, Seattle, USA 3 Seattle Institute of Biomedical and Clinical Research, Seattle, USA Progressive neuron death in the frontal and temporal lobes of the cerebral cortex characterizes Frontotemporal lobar degeneration (FTLD). FTLD is sub-classified by the presence of aggregated protein deposits, consisting of either aberrantly processed, ubiquitinated, and phosphorylated TDP-43 or hyperphosphorylated tau inclusions. Recent studies identified the tau tubulin kinases 1 and 2 (TTBK1/2) as direct tau kinases in the context of Alzheimer’s disease. Our lab recently found that TTBK1/2 also robustly phosphorylate TDP-43 and are co-localized with phosphorylated TDP-43 in human postmortem tissues of FTLD. Additionally, we have shown increased expression of TTBK1/2 in both FTLD-TDP and FTLD-tau brain tissue, indicating that increased TTBK1/2 levels may be integral to disease progression. This connection between tau and TDP-43 phosphorylation could help to explain the etiology of the two most prominent FTLD disease subtypes. To further elucidate how TTBK1/2 contribute to both TDP-43 and tau phosphorylation in the context of FTLD progression, we examined the consequences of TTBK1/2 kinase overexpression in vivo. We hypothesize that TTBK1/2 kinase hyperactivation drives proteotoxicity. To test this hypothesis we constructed both human TTBK1 and TTBK2 kinase domain overexpression transgenic lines in C.elegans. The trangenes were crossed with both human tau and human TDP-43 overexpression lines. Behavioral and biochemical phenotypes were then assessed. We found that animals expressing either tau/TTBK or TDP-43/TTBK transgenes together exhibit statistically significant motor neuron dysfunction in the form of decreased locomotion. Additionally we observed an increase in both tau and TDP-43 phosphorylation. These results give evidence for a kinase-driven mechanism of early disease progression involving TTBK1/2 hyperactivity.

DB12 Cerebrospinal fluid phosphorylated tau levels are associated with post-mortem tau inclusion burden in frontotemporal lobar degeneration D. Irwin1, A. Lleo2, C. McMillan1, F. Cooper1, D. Wolk1, L. Shaw1, E. Lee1, J. Trojanowski1, M. Grossman1 1 University of Pennsylvania, Neurology, Philadelphia, USA 2 Hospital de la Santa Creu i Sant Pau, Neurology, Barcelona, Spain Previous reports of cerebrospinal fluid (CSF) levels of phosphorylated (threonine181) tau (p-tau) in frontotemporal lobar degeneration (FTLD) are inconsistent. This may be due in part to pathological heterogeneity (i.e. FTLD-Tau and FTLD-TDP subgroups or co-morbid Alzheimer’s disease, AD). There is minimal data on the relationship of CSF p-tau levels and histological tau burden in FTLD. Here we examine an autopsy cohort of FTLD-Tau (n = 28) and FTLD-TDP (n = 45) with ante mortem CSF p-tau levels from Luminex or ELISA assays. ELISA values were



transformed using a previously validated formula for study. Ordinal scores for severity of microscopic tau pathology were averaged in 5 cortical regions to develop a composite score. Patient groups did not differ in age or time interval between onset/death and date of CSF collection (p > 0.1). FTLD-Tau had higher levels of p-tau (12.0 pg/ mL, IQR = 11.2, 15.9) than FTLD-TDP (8.0 pg/mL, IQR = 6.0,13.8; p = 0.04). Cortical tau scores across groups correlated with CSF p-tau values (rho = 0.5, p < 0.001). Exclusion of 14 cases (FTLD-Tau=6, FTLD-TDP = 8) with co-morbid AD tau (Braak AD tau stage > II) found a more robust difference between groups (p = 0.01). Multivariate regression using demographics, assay type and neuropathological data as independent variables found average cortical tau score (b=11.5 SE=2.1, p < 0.001) and FTLD-Tau diagnosis (b 21.1 SE = 4.5, p < 0.001) have the most robust association with CSF p-tau in the final model (R2=0.31). CSF p-tau levels directly correlate with the severity of FTLD-tau neuropathology and thus could potentially serve as a clinical trial outcome. In vivo assessments of co-morbid AD pathology in FTLD may interpretation of CSF p-tau values to distinguish FTLD-Tau and FTLD-TDP.

DB13 Testing reversibility of pathology in a new in vitro model for C9orf72 ALS/FTD F. Riemslagh1, R. Hukema1, S. Nanhoe1, C. den Hollander1, H. de Boer1, J. van Swieten2, R. Willemsen1 1 Erasmus Medical Center, Clinical Genetics, Rotterdam, Netherlands 2 Erasmus Medical Center, Neurology, Rotterdam, Netherlands Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two devastating neurodegenerative disorders that share clinical, genetic and pathological overlap. In 2011, a hexanucleotide repeat expansion in the C9orf72 gene was identified as a cause of FTD and ALS. Since then, many different theories about the possible pathogenic mechanisms of this repeat have been proposed, including haploinsufficiency leading to a loss of function of the endogenous C9orf72 protein product, RNA toxicity caused by the sequestration of RNA-binding proteins or production of toxic dipeptide repeat proteins (DPR) by non-ATG initiated translation (RAN) of the repeat. The recent development of mouse models indicates a major role of gain-of-function pathogenesis. To investigate this in more detail, we focus on the role of RNA gain-offunction and generated an inducible mouse model for the C9orf72 repeat expansion. This mouse exhibits 80 GGGGCC repeats, is doxycycline (dox)-inducible and expresses GFP in the brain upon dox administration. From this mouse model, we generated mouse primary hippocampal neurons. Both in vivo as in vitro models show

ubiquitin-positive inclusions, which is a pathological hallmark of C9orf72 ALS and FTD patients. In primary hippocampal neurons, the number of GFP-positive neurons containing an ubiquitinpositive inclusion raises from 5% after 2 weeks dox to 35% after 4 weeks dox treatment. The inducible system allows for reversibility studies that can elucidate possible and critical time periods to halt or reverse the observed phenotype. Performing a wash-out on primary hippocampal neurons shows a halt in inclusion formation, illustrating reversibility of neuropathology. We will use our in vitro model to screen for drugs including antisense oligonucleotides (AONs) and small compounds.

DB14 Abundant lower motor neuron RNA foci with perinucleolar studding in C9orf72 FTD-ALS S. Vatsavayai1, S. Gaus1, J.-H. Hwang1, B. Miller1, W. Seeley1 1 University of California San Francisco, Neurology, San Francisco, USA Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are distinct syndromes unified by a GGGGCC repeat expansion in C9orf72, which is the most common known genetic cause of these disorders. Multiple inclusion types are associated with this mutation, including RNA foci, dipeptide repeat protein aggregates, and TDP-43 inclusions. RNA foci present in the brain and spinal cord are composed of sense or antisense repeatcontaining transcripts and were shown to sequester RNA binding proteins. In spinal cord motor neurons, previous studies have shown that TDP-43 inclusions are abundant whereas dipeptide repeat protein aggregates are infrequent. Limited information is available about the frequency and distribution of RNA foci in these neurons. After staining for sense and antisense RNA foci in the same tissue sections, we used Z-stack images to quantify foci in Nissl-stained lower motor neurons in hypoglossal nucleus (n = 33 neurons across cases) and spinal cord anterior horn (n = 30 neurons across cases) in three patients with C9orf72 FTD-ALS. In the hypoglossal nucleus, 73% of motor neurons had RNA foci. Of these, 29% had only sense foci, 17% had only antisense foci, and 54% had both types. In the spinal cord, 87% neurons had RNA foci. Of these, 19% had sense foci, 62% had antisense foci, and 19% had both types. Nuclear sense and antisense RNA foci often showed a perinucleolar location, wherein 67% of RNA foci-positive neurons in the hypoglossal nucleus and 58% in the spinal cord had at least one RNA focus in a perinucleolar position. At times multiple foci were seen studding the nucleolar exterior. In conclusion, the findings described here suggest that, unlike dipeptide repeat protein inclusions, RNA foci are an abundant pathological feature in lower motor neurons that undergo selective vulnerability in C9orf72 FTD-ALS.


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Session 5: Progressive aphasias S9 Apraxia of speech and its rehabilitation M. Henry1 1 University of Texas, Austin, United States Apraxia of speech (AOS) is a motor speech disorder characterized by difficulty coordinating articulatory movements required for speech production. It is understood to reflect an impairment of speech motor planning and can occur independently of dysarthria and aphasia. AOS can be caused by stroke, tumor, or brain injury and, more recently, has been recognized as an initial symptom of neurodegenerative disease. In fact, it is a core feature of the nonfluent variant of primary progressive aphasia (nfvPPA). Whereas there has been a great deal of research addressing ideal modes of assessment and treatment in AOS caused by stroke, little work has been dedicated to the management of progressive cases of AOS in the context of nvfPPA/primary progressive apraxia of speech. In this talk, we will outline the characteristic speech features in AOS, describe its neural bases, and discuss approaches to assessment and rehabilitation. We will outline a staged treatment approach for management of AOS in neurodegenerative disease, where initial symptoms may be very mild, with ultimate progression to mutism. Further, we will discuss findings from the first group treatment study addressing speech production and fluency in nfvPPA. In this study, we implemented a script training protocol involving daily unison speech production (“speech entrainment”) practice with a video model of a healthy speaker. Results indicate that video-implemented script training leads to improved fluency and intelligibility of speech, with linguistic benefits in the domain of syntax as well. Benefits were maintained at three and 6 months post-treatment, with additional follow-up data forthcoming. These data indicate that treatment for speech production in nfvPPA can result in significant and lasting changes in communicative function. The goal of this work is to provide a model for management of progressive AOS, with evidence to support an ongoing role for speech therapy in assessment and treatment.

S10 The right hemisphere and its semantics P. Garrard1 1 St George’s, University of London, Cardiovascular and Cell Sciences Research Institute, London, Great Britain Advances in automatic text classification have been necessitated by the rapid increase in the availability of digital documents. Machine learning (ML) algorithms can ‘learn’ from data: for instance a ML system can be trained on a set of features derived from written texts belonging to known categories, and learn to distinguish between them. Such a trained system can then be used to classify unseen texts. In this paper, I present the results of a technique by which transcribed speech samples are classified along clinical dimensions, using vocabulary data alone. Two related ML algorithms [naive Bayes Gaussian (NBG) and naive Bayes multinomial (NBM)] were used to categorize picture descriptions produced by: 32 semantic dementia (SD) patients versus 10 healthy, age-matched controls. SD patients with left- (n = 21) and right-

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predominant (n = 11) patterns of temporal lobe atrophy were also. iInformation gain (IG) to identify the vocabulary features that were most informative to each of these two distinctions. In the SD versus control classification task, both algorithms achieved accuracies of greater than 90%. In the right- versus lefttemporal lobe predominant classification, NBM achieved a high level of accuracy (88%) when the features used in the training set were restricted to those with high values of IG. The most informative features for the patient versus control task were low frequency content words, generic terms and components of metanarrative statements. Interpretation of the informative lexical features in the right- versus left-temporal atrophy contrast is more specultative, and are discussed here in the context of previous attempts to disentangle the contributions of the two temporal lobes to the representation of long term conceptual knowledge. An ML approach based on an enriched feature set, including values derived from Quantitative Production Analysis (QPA) may shed further light on this little understood distinction.

O9 In vivo correlates of pathological diagnosis in clinical variants of primary progressive aphasia E. G. Spinelli1,2, M. L. Mandelli2, M. Santos2, S. M. Wilson3, F. Agosta1, J. Q. Trojanowski4, E. J. Huang2, L. T. Grinberg2, M. Filippi1, B. L. Miller2, W. W. Seeley2, M. L. Gorno-Tempini2 1 San Raffaele Scientific Institute, Neuroimaging Research Unit, Department of Neuroscience, Milan, Italy 2 University of California, San Francisco, Memory and Aging Center, San Francisco, United States 3 University of Arizona, Department of Speech, Language and Hearing Sciences, Tucson, United States 4 University of Pennsylvania, Department of Pathology and Laboratory Medicine, Philadelphia, United States Clinical and neuroanatomical heterogeneity within clinical variants of primary progressive aphasia (PPA) is thought to derive from specific pathologic correlates. Large clinicopathological series of prospectively evaluated PPA patients are still lacking. The aim of this study was to investigate the relationship between in vivo clinical, cognitive and neuroimaging features and neuropathological findings in a large cohort of PPA patients defined by current diagnostic criteria. Data were collected from 69 patients with sporadic PPA, divided into 29 semantic (svPPA), 26 non-fluent/ agrammatic (nfvPPA), 10 logopenic (lvPPA) and 4 mixed PPA. Patterns of grey matter (GM) and white matter (WM) atrophy at presentation were assessed and tested as predictors of pathological diagnosis using support vector machine (SVM) algorithms. A clinical diagnosis of PPA was associated with FTLD with TDP inclusions in 42%, FTLD-tau in 41%, and AD pathology in 17% of cases. Each variant was associated with one typical pathology: 25/29 (86%) svPPA patients showed FTLD-TDP, 22/26 (85%) nfvPPA showed FTLD-tau, and all 10 lvPPA had AD. Within FTLD-tau, Pick’s disease (PiD) was observed across all clinical variants but lvPPA. Compared with pathologically typical svPPA-TDP, svPPAtau showed significant extrapyramidal signs, greater behavioral and executive impairment, and severe striatal, medial temporal and


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orbitofrontal GM and WM atrophy. Compared with nfvPPA-tau, nfvPPA-TDP patients showed absence of behavioral symptoms and selective GM atrophy. PiD was associated with early neuropsychiatric symptoms and extensive frontotemporal atrophy. Combining GM and WM volumes, SVM analysis showed the highest accuracy (92.9%) to distinguish FTLD-tau and FTLD-TDP pathologies across variants. The application of current criteria allowed for strong clinicopathological relationships within PPA variants. Specific clinical and early anatomical features may suggest atypical pathological diagnosis within each variant in vivo.

O10 Imaging tDCS effects in primary progressive aphasia K. Tsapkini1, Y. Webb-Vargas2, A. Faria3, B. Ficek1, T. Chakravarty1, C. Frangakis2, J. Desmond1, M. Lindquist2, A. Hillis1 1 Johns Hopkins Medicine, Neurology, Baltimore, United States 2 Johns Hopkins School of Public Health, Baltimore, United States 3 Johns Hopkins Medicine, Radiology, Baltimore, United States Primary progressive aphasia (PPA) is a clinical neurodegenerative syndrome that first and foremost affects language abilities. Recent evidence supports beneficial effects of tDCS after 10–15 sessions of intervention; however, the neural mechanism for these effects remains unclear. We used a multi-modality imaging approach (Faria et al. Neuroimage 2012; 61(3) 613–621) to identify changes in functional and structural connectivity associated with tDCS in individuals with PPA. We report on volumetric (MPRAGE), resting-state fMRI (rsfMRI) and diffusion tensor imaging (DTI) data from 13 participants before, immediately after, and 2 months after intervention. The intervention was anodal tDCS at the left inferior temporal gyrus (IFG) or sham stimulation for 15 daily sessions coupled with language therapy targeting written word production. The rsfMRI analysis revealed no differential change in connectivity from pre- to post-treatment for the tDCS condition compared to sham as measured by the correlation between the stimulated area and the rest of the spelling ROIs within the left hemisphere. However, the functional connectivity between left and right IFG increased significantly more in the tDCS condition relative to sham. This connectivity between right and left IFG positively correlated with volume of right IFG and with improvement in behavioral scores even 2 months post-treatment. Functional anisotropy (FA) in white matter beneath both right and left IFG did not change due to either tDCS or sham. A possible brain mechanism for the advantage of tDCS over sham may be the strengthening of the functional connectivity between the stimulated area (left IFG) and homologous right IFG. The predictive value of the volume of right IFG for tDCS effectiveness has important implications for the prognosis and timing of intervention effects: intervention at earlier stages of the disease progression – when there is less atrophy in the right hemisphere – may be more beneficial than later intervention.

DB15 Bilingualism in primary progressive aphasia: systematic review and case reports from two European centers A. S. Costa1, J. Wojtala2, S. Rocha1, K. Reetz2, A. Machado1 1 Hospital de Braga, Neurology, Braga, Portugal 2 RWTH Aachen University Hospital, Neurology, Aachen, Germany Primary progressive aphasia (PPA) is characterized by progressive language deterioration with sparing of other cognitive functions, generally associated with FTLD or AD. Despite its low incidence, it’s surprising that only a few cases of PPA have been reported in multilingual patients, since more than half of the world population is multilingual. Given its clinical and theoretical interest, we aim to characterize clinical manifestations of bilingual patients with PPA. We conducted a systematic literature search of all peerreview published cases of multilingual PPA and present three new cases retrospectively identified in our centers. We present descriptive analyses, emphasizing symptom presentation and language deficits pattern in their first (L1) and second language (L2). We collected data on 15 bilingual PPA patients, of which ten were male. Mean age was 65.7 years (SD 7.3), the majority having completed high school or higher education. Seven patients were diagnosed with agrammatical/non-fluent progressive aphasia, four with semantic dementia, and four with logopenic aphasia, with a median symptom onset of 3 years (range 2–6 years). Regardless of subtype, first symptom was word-finding difficulties (n = 8), anomia (n = 5), effortful speech (n = 1) or comprehension problems (n = 1). With few exceptions, symptoms were firstly noticed in the language they most commonly used at that time (L1 n = 4, L2 n = 6). Structural (n = 14) and/or functional neuroimaging (n = 7) showed predominantly left frontotemporal dysfunction. The majority of patients (n = 10) showed more severe language deficits in L2 in comparison to L1, which seems to deteriorate later on the disease course. Despite several methodological limitations regarding data availability and possible bias, this analysis shows that the pattern of impairment in bilingual PPA patients is heterogeneous, with frequent dissociation between first and second languages, thus warranting the need for specific language assessment in both languages, particularly when language therapeutic compensation interventions is attainable.

DB16 Differential binding of AV-1451 tau-PET across variants of primary progressive aphasia J. Whitwell1, N. Tosakulwong2, J. Duffy3, H. Clark3, M. Machulda4, E. Strand3, M. Senjem1,5, R. Petersen3, C. Jack1, V. Lowe1, K. Josephs3 1 Mayo Clinic, Radiology, Rochester, United States 2 Mayo Clinic, Health Sciences Research, Rochester, United States 3 Mayo Clinic, Neurology, Rochester, United States 4 Mayo Clinic, Psychiatry and Psychology, Rochester, United States 5 Mayo Clinic, Information Technology, Rochester, United States The primary progressive aphasia (PPA) variants are each associated with different abnormal proteins in the brain. Abnormal tau is most commonly associated with logopenic PPA, in the form of Alzheimer’s disease, and agrammatic PPA in the form of 4R tauopathies. Abnormal deposition of TDP-43 is typically observed in semantic PPA. It is now possible to detect tau in the brain in vivo using PET imaging; although the utility of tau-PET in PPA is


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unclear. We aimed to compare regional tau-PET binding across the PPA variants. Twelve subjects with PPA underwent AV-1451 tauPET imaging. These subjects were compared to 239 normal controls and 30 subjects with Alzheimer’s dementia. Regional tau-PET uptake was assessed using the automated anatomical labelling atlas. The logopenic PPA subjects all showed elevated uptake compared to controls, particularly involving lateral temporal and parietal regions, with the left hemisphere typically showing greater uptake than the right. The degree of uptake was similar to the degree of uptake observed in Alzheimer’s dementia. Uptake in medial and lateral parietal lobes was significantly greater in logopenic PPA compared to the other PPA variants. Tau-PET uptake was subtly elevated in entorhinal cortex, amygdala, fusiform, hippocampus, parahippocampal gyrus, temporal pole and inferior and middle temporal gyri in semantic PPA compared to controls. However, the degree of uptake in these regions was less than that observed in both logopenic PPA and Alzheimer’s dementia. Agrammatic PPA showed the lowest uptake in temporal regions, and slightly elevated uptake in pars opercularis compared to controls and semantic PPA, but not compared to logopenic PPA or Alzheimer’s dementia. TauPET imaging shows strong signal in logopenic PPA and has potential to help differentiate logopenic PPA from the other two PPA variants. Its role in the other PPA variants is less certain given the low levels of uptake observed. The fact that the tau PET patterns mirrored patterns of atrophy in these variants suggests that neurodegeneration is a possible confounder.

DB17 Deficits in rhythm processing in PPA are linked to SMA atrophy J. Schaeverbeke1, R. Bruffaerts1,2, M. Grube3,4, V. Neyens1, B. Bergmans5, E. Dries2, T. Griffiths4, R. Vandenberghe1,2 1 KU Leuven, Neurosciences, Leuven, Belgium 2 UZ Leuven, Neurology, Leuven, Belgium 3 Berlin Institute of Technology, Computer Science, Berlin, Great Britain 4 Newcastle University, Neuroscience, Newcastle-upon-Tyne, Great Britain 5 AZ Sint-Jan Brugge-Oostende AV, Neurology, Brugge, Belgium Primary progressive aphasia (PPA) patients exhibit deficits in processing of rhythm and timing of sequences of non-linguistic acoustic stimuli, in particular the non-fluent variant (NFV). The current study aimed to determine the neuranatomical bases of these deficits. A consecutive case series of 17 PPA patients (65.7 8.8 years) (four logopenic variant (LV), six NFV, seven semantic variant (SV)) and 22 cognitively intact controls (63.8 6.5 years) participated. All participants underwent a T1weighted MRI, analyzed using Voxel Based Morphometry (VBM8), and received psychoacoustic testing on four rhythm tasks (single time-interval duration discrimination, isochrony deviation detection, and strongly/weakly metrical pattern discrimination). The outcome measure for each of the tasks was the threshold obtained by adaptively adjusting the difference between reference and target stimuli. For each task, a voxel-wise linear regression was conducted between modulated cortical gray matter (GM, SPM8) and task performance, with age and gender as nuisance variables. PPA variants did not differ in age (p = 0.34) or gender (p = 0.87). The

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significance threshold was set at voxel-level uncorrected p < 0.001 and cluster-level family wise error (FWE)-corrected p < 0.05, and Bonferroni-corrected (n = 4). In PPA patients, performance on strongly metrical pattern discrimination correlated with GM loss in a cluster containing the left superior frontal gyrus and the left supplemental motor area (SMA) (PFWE-corrected = 0.04, 829 voxels, Z = 4.73; 18, 5, 66; Z = 4.28; 6, 20, 60). Patients who needed a higher threshold to discriminate between strongly metrical patterns showed less GM in this cluster (q = 0.94). No other significant correlation was found in the PPA group, and no significant correlation was found in controls. Atrophy of SMA may be causally involved in both the rhythm processing deficits in NFV and speech apraxia. The SMA is likely playing a role in one shared timing system relevant for speech production and rhythm perception.

DB18 Anatomo-functional segregation of the mental lexicon: the model of Primary Progressive Aphasia C. Sanches1, M. Teichmann1,2, O. Colliot1,3, A. Routier1,3, R. Miggliaccio1,3 1 Institute du Cerveau et de la Moelle épiniere, Paris, France 2 Centre de réference Demences Rares, Neurology, Paris, France 3 Inserm U1127, CNRS UMR 7225, Sorbonne Universites, Paris, France Most models claim that the lexicon contains three distinct components for formal, syntactic and semantic word information (Caramazza Cogn Neuropsychol 1997; 14 177–208). However, most studies are case reports or small cohort studies that did not assess the three lexical components with comparable tasks. fMRI studies suggest that lexical processing involves lateral temporal cortices. We evaluated the functional and anatomical segregation of lexical components in a cohort of twenty native French patients with the semantic and logopenic variants of primary progressive aphasia (PPA) and 23 healthy controls. We used priming tasks tapping semantic, syntactic and formal word information-relationship. Prime-target pairs had semantic links, grammatical gender agreement or formal similarity, respectively. We also applied three explicit tasks assessing semantic, gender and orthographic relationships to screen for ‘good’ and ‘poor’ performers in each domain. Patients and 12 controls had MRI for cortical thickness evaluation. Cortical thickness analyses showed that the atrophy pattern in the PPA cohort differentially involved the lateral temporal cortex. Controls had significant priming effects in the three tasks whereas we did not find significant effects in the whole PPA group. Results of the explicit tasks subdivided the PPA group into ‘good’ and ‘poor’ performers for each lexical domain, and revealed double dissociations within the priming tasks: ‘good’ performers in a specific domain had significant priming in that specific domain but not in the other two. Our findings support the existence of distinct semantic, syntactic and formal representations within the mental lexicon and yielded double intra-lexical dissociations. This functional segregation of the lexicon and its differential breakdown in PPA patients also suggests that lexical components are anatomically segregated within the lateral temporal cortex. Anatomo-functional correlation analyses are currently conducted to identify the precise structural correlates of the semantic/syntactic/formal lexicon.


Session 6: CBS, PSP, and MND S11 PSP & CBD: Overlaps and distinctions within the FTLD spectrum G. Ho¨glinger1 1 Technical University Munich, Neurology, Munich, Germany Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD) are disease entities defined neuropathologically by the accumulation of the microtubule-associated protein tau in the somatodendritic compartment of neurons, in oligodendrocytes and astrocytes. The morphology of the astrocytic tau deposits (tufts vs. plaques) is the predominant distinction between PSP and CBD. Classically, PSP has been considered to present clinically with a combination of supranuclear gaze palsy, postural instability, akinesiarigidity, pseudobulbar dysarthria, and some degree of frontal lobar dysfunction, termed Richardson Syndrome. CBD has been thought to cause a strikingly asymmetric manifestation of extrapyramidal and cortical symptoms, termed cortico-basal syndrome (CBS). Recent clinico-pathological studies clearly demonstrated that pathologically defined PSP and CBD generate a range of clinical manifestations much broader than initially thought, including behavioral, speech and language manifestations of the FTLD spectrum. Therefore, PSP and CBD are diagnostically challenging disease entities at the border between movement disorders and frontotemporal dementias. This talk will present current knowledge about the overlaps and distinctions of PSP and CBD within the FTLD spectrum.

S12 ALS - genotypes and phenotypes A. C. Ludolph1 1 Universit€ats- und Rehabilitationskliniken Ulm, Abteilung f€ ur Neurologie, Ulm, Germany Our epidemiological data show that about 5% of ALS patients in Germany have a family history. The majority carry the C9orf72 mutation (24%), next is the SOD mutation (13%), TBK1, FUS and TDP-43 (each about 4%) follow. Most of these mutations do not only encode mutations in the genome of ALS patients, but also of FTD patients. Therefore, the phenotype - genotype relation is poorly understood. Recent neuropathological findings emphazise that staging (“Braak Staging”) for ALS is also possible. The results demonstrate that the pathology as shown by the molecular marker TDP-43 spreads from the motor cortex into the direction of the gyrus rectus and the orbitofrontal cortex. In a similar longitudinal fashion it affects the corticofugal tracts, the corticospinal tract (stage 1), the tracts to the precerebellar nuclei (stage 2), the corticostriatal tract (stage 3) and the perforant pathway (stage 4). These findings include ALS in the group of diseases which are characterized by an “initiation and propagation” pattern along anatomically defined pathways similar to Parkinson`s and Alzheimer`s disease. It is interesting to note, that the neuropathological pattern associated with the most frequent mutation, in the C9ORF72 gene

does not differ much qualitatively, but rather quantitatively from the pattern in sporadic patients. On the other hand, the pattern seen in the behavioural variant of FTD is completely different, suggesting, that ALS and FTD are rather different entities than a spectrum of diseases. The translation of these neuropathological findings into phenotypes is at its beginning. However, measurement of fractional anisotropy by DTI shows that the neuropathological staging is mirrored by affection of the respective tracts. Also, spreading of the disease is a characteristic feature clinically and the predominant affection of monosynaptically supplied muscles characterizes the disease. Whether, these novel findings and these new concepts of ALS can be exploited therapeutically, will be shown in the future.

O11 Plasma neurofilament light chain predicts disease progression in progressive supranuclear palsy J. Rojas1, A. Karydas1, J. Bang1, R. Tsai1, K. Blennow2, V. Liman2, J. Kramer1, H. Rosen1, B. Miller1, H. Zetterberg2,3, A. Boxer1 1 UCSF, Memory and Aging Center, San Francisco, CA, United States 2 University of Gothenburg, Sahlgrenska academy, Institute of neuroscience and physiology, Gothenburg, Sweden 3 UCL Insitute of Neurology, Department of Molecular Neuroscience, London, Sweden Blood-based biomarkers for neurodegenerative conditions could improve diagnosis and support further treatment development. Neurofilament light chain (NfL) is a marker of axonal injury and is elevated in CSF of patients with progressive supranuclear palsy (PSP). The goal of the present study was to determine the diagnostic and prognostic value of plasma NfL in patients with PSP. Plasma NfL was measured with ultrasensitive digital immunoassay-based single molecule array (Simoa) technology. Measurements were performed at baseline and 1-year follow up in a pilot cohort of 15 PSP patients and 12 healthy controls and a validation cohort of 147 PSP patients. In the pilot cohort, classification of controls and patients based on plasma NfL levels was tested by means of principal component analysis with inclusion of baseline characteristics (i.e. age, gender, education level, MMSE, CDR-sb and plasma NfL). In the validation cohort, mixed linear models tested the ability of plasma NfL to predict neurological, cognitive and functional decline, and brain atrophy. Baseline mean plasma NfL levels were elevated in PSP (31 4 pg/mL, vs control, 17.5 1 pg/mL, p < 0.05) and this difference persisted at follow up. A cutoff value of 20 pg/mL related to the diagnosis of PSP with a sensitivity of .80 and specificity of 0.83 (positive likelihood ratio = 4.7 and a negative likelihood radio of 0.24). High median NfL levels related to more severe neurological (PSPRS, 36.9% vs. 28.9%, p = 0.04), functional (SEADL, 38.2% vs. 20%, p = 0.03) and neuropsychological (RBANS, 23.9% vs. 12.3%, p = 001) deterioration over 1 year, compared to low median NfL levels. Higher median baseline NfL levels also predicted greater wholebrain (6% vs. 1%, p = 0.02) and superior cerebellar peduncle


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Session 6: CBS, PSP, and MND

(9.1% vs. 4.5%, p = 0.005) volume loss over 1 year. Plasma and CSF NfL were significantly correlated (r = 0.74, p = 0.002). Plasma NfL is elevated in PSP and could be of value as a diagnostic biomarker.

O12 Converging multimodal evidence of myelin associated proteins as biomarkers in four-repeat tauopathy C. McMillan1, D. Irwin1, M. Byrne1, F. Cooper1, K. Firn1, C. Jester1, E. Suh1, V. Van Deerlin1, J. Trojanowski1, M. Grossman1 1 University of Pennsylvania, Neurology, Philadelphia, United States Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are pathologically characterized by four-repeat tau (4Rtau) pathological inclusions within grey matter (GM) and white matter (WM). Recent genome wide association studies have identified single nucleotide polymorphisms (SNPs) located in or near the myelin oligodendrocyte basic protein (MOBP) gene that are associated with increased risk of autopsy-confirmed PSP or CBD. Recent imaging-genetic studies identified an association between MOBP risk alleles and diffusion tensor imaging (DTI) evidence of reduced white matter integrity in FTD. Here we evaluate whether myelin basic protein (MBP), closely related to MOBP, is associated with neuroanatomic structure in 4Rtau. To assess in vivo evidence of MBP we evaluated 16 clinically-diagnosed PSP and CBD patients with likely 4Rtau who completed a DTI scan and a clinical cerebrospinal fluid (CSF) lumbar puncture interrogated for MBP (ARUP Laboratories). We found that elevated MBP is associated with reduced diffusion using radial diffusivity (RD) in cerebral peduncle WM, superior longitudinal fasciculus, and other frontal WM areas previously associated with tau pathology. To evaluate ex vivo evidence of MBP we genotyped 40 pathology-confirmed 4Rtau patients for rs1768208 (near MOBP) and quantified MBP immunohistochemistry in the cerebral peduncle white matter tissue using digital image analysis. We observed that one or more risk allele copies is associated with reduced MBP reactivity in tissue. Together, these analyses provide convergent sources of evidence suggesting that MBP relates to white matter integrity in 4Rtau. Comparative evaluations are necessary to assess the specificity of this candidate biomarker for 4Rtau.

DB19 Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis Z. Zou1, C. Che1, C. Liu1, H. Huang1 1 Fujian Medical University Union Hospital, Department of Neurology, Fuzhou, China Genetic studies have showed that C9orf72, SOD1, TARDBP and FUS are the most common mutated genes in amyotrophic lateral sclerosis (ALS). However, a systematic review and meta-analysis of the genetic epidemiology of ALS has never been performed. We performed a Medline literature review to identify all original articles reporting mutation rate of C9orf72, SOD1, TARDBP, FUS, OPTN, and SQSTM1 gene in ALS. Studies were grouped according to the gene screened and examined for sources of case ascertainment. A systematic review and meta-analysis of reported mutation rate of C9orf72, SOD1, TARDBP, FUS, OPTN, and SQSTM1 gene in

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ALS was then conducted to calculate a pooled mutation rate of each gene. Furthermore, the pooled mutation rate of each gene was compared between Caucasian and Asian population. Altogether one hundred and fifty six papers were included in the meta-analysis. The pooled mutation rate of these six major ALS-related genes was 63.3% in FALS (C9orf72 32.7%, SOD1 16.9%, TARDBP 7.4%, FUS 3.9%, SQSTM1 1.3%, OPTN 1.1%) and 10.1% in SALS (C9orf72 4.8%, SOD1 1.4%, TARDBP 1.6%, FUS 0.6%, SQSTM1 1.3%, OPTN 0.4%). A statistically significant difference was identified when comparing the frequencies of mutations in major ALS genes between Caucasian patients and Asian patients. The C9orf72 expansions (10.0% vs 0.7%, p < 0.0001) and mutations in TARDBP (3.0% vs. 0.7%, p < 0.001) were significantly more common among Caucasian patients, whereas the frequency of FUS mutations was more common among Asian patients (2.2% vs. 1.2%, p < 0.01). The frequencies of SOD1, OPTN and SQSTM1 mutations were similar (all p > 0.05). These findings confirm that the genetic architecture of ALS in Asian population is distinct from that in Caucasian populations.

DB20 [18F]AV-1451 PET imaging differentiates the tauopathies of Progressive Supranuclear Palsy (PSP) and Alzheimer’s disease (AD) P. Vazquez Rodriguez1, L. Passamonti1 1 University of Cambridge, Clinical Neuroscience, Cambridge, Great Britain The objectives were to evaluate brain tau pathology using 18[F] AV1451 PET in vivo in two degenerative tauopathies: progressive supranuclear palsy (PSP, n = 17) and Alzheimer’s disease (AD, n = 9 with AD, n = 6 with biomarker positive MCI). In addition to diagnostic accuracy, we determined whether tau imaging correlates with disease severity; and whether the distribution in vivo accords with the expected post mortem distribution of tau pathology. Binding potential estimates from 90 min’ dynamic imaging of [18F] AV-1451 PET was used to compare between patient groups and against controls (n = 8). Participants also underwent cognitive evaluation for memory, language, and visuo-spatial functions. Binding potential was corrected for partial volume effects and analyzed using ANOVA models for group effects and group-by-region of interest (ROI) interactions; and ANCOVA to examine correlations with disease severity. The potential for differential diagnosis was tested by inclusion of [18F]AV-1451 binding potentials in ROIs in multivariate supervised machine learning, using a support vector machine (SVM). Relative to controls, PSP patients displayed increased [18F]AV-1451 uptake in the midbrain and pallidum, consistent with post mortem studies. AD patients showed increased [18F]AV-1451 uptake in the hippocampus, amygdala, and extensive cortical regions. We did not confirm the presence of significant correlations between regional [18F]AV-1451 binding potential and disease severity, either Addenbrooke’s Cognitive Examination or the Progressive Supranuclear Palsy Rating Scale (PSPRS). However, the SVM analyses showed that the binding of [18F]AV-1451 in the midbrain and hippocampus separated PSP from AD groups with an accuracy of 96%. Our results suggest that [18F]AV-1451 PET is a useful in vivo tool to assess neuropathology in PSP and AD. Further studies are required to determine how [18F]AV-1451 relates to severity, progression and therapy.


Session 6: CBS, PSP, and MND

DB21

DB22

On the clinical overlap between progressive supranuclear palsy and corticobasal syndrome: evidence from the PiPPIN epidemiology study J. Rowe1, I. Gilchrist1 1 Cambridge University, Cambridge, Great Britain

Clinical comparison of FTLD and ALS-FTD patients - is there a difference? A. Rosenbohm1, R. S. Peter2, E. Semler1, G. Nagel2, D. Rothenbacher2, M. Otto1, A. C. Ludolph1, A.- F. R. Study Group1 1 University of Ulm, Neurology, Ulm, Germany 2 University of Ulm, Institute of Epidemiology and Medical Biometry, Ulm, Germany

The current clinical diagnostic criteria for Progressive Supranuclear Palsy-Richardson Syndrome (PSP-RS) are highly specific for PSP-neuropathology with the exception of corticobasal degeneration (CBD) (Litvan, 1996). Clinical features of the corticobasal syndrome (CBS) have been exclusion criteria for a diagnosis of PSP, although this is increasingly difficult to reconcile with the broad range of clinical syndromes associated with PSP neuropathology (Williams, 2009). The criteria for the diagnosis of Corticobasal Syndrome (CBS) and Corticobasal Degeneration (CBD) were recently revised (Armstrong, 2013) to incorporate a wider range of clinical syndromes that may be associated with CBD pathology, including CBS-PSP. However, clinicopathological correlations remain challenging (Alexander, 2014). We reviewed the clinical features of 95 patients with a clinical diagnosis of CBS or PSP in the PiPPIN epidemiological study of syndromes associated with Frontemporal Lobar Degeneration (Coyle-Gilchrist, 2016). 40% met criteria for both possible CBD and possible PSP. 88% of those meeting criteria for possible PSP met criteria for possible CBD. Only 5 met criteria for probable PSP and not possible CBD, while 41 met criteria for probable CBD and not possible PSP. Current diagnostic criteria for PSP and CBS/CBD remain problematic. In order to facilitate clinical trials, we suggest it will be helpful to revise the criteria for PSP, clarifying the syndromic overlap between PSP/CBS and the nosological status of patients with intermediate features.

In addition to the well-established ALS Registry Swabia, we implemented the first epidemiological FTLD registry in cooperation with all main neurological departments and an increasing number of psychiatric cooperation partners in a defined geographic region. Swabia comprises a target population of 8.4 million in Southern Germany. Main objectives are to investigate risk factors, epidemiology and diagnostic criteria in FTLD in a register-based study. In this project, we thought to examine clinical differences between pure FTLD patients and combined cases with ALS-FTD. So far (until March 2016), 927 ALS cases were prospectively registered. Additional collection of FTLD cases started in 2014. We collected 69 cases (mean age: 65.6 years, 62% male) of FTLD spectrum diseases (39 behavioral variant of FTD, 30 primary progressive aphasia (PPA)) fulfilling the Rascovsky criteria for bvFTD or the Gorno-Tempini criteria for the language variants. 36 patients provided additional data by questionnaire, including information on initial symptoms. So far, 2.7% of ALS cases are combined ALS-FTD. 22% of the FTD cases had a positive family history and 2/69 cases were genetic (C9ORF72). In ALS-FTD (18 patients), the median time interval between first symptom of ALS and first symptom of FTD was 10.5 months. In two cases, ALS was manifest before FTD, in 15 cases it was opposite, and one patient experienced first symptoms of ALS as well as FTD within the same month. First symptoms in the ALS-FTD sample were “depression” (56%), “aphasia” (33%) and “loss of empathy”(22%). Median diagnostic delay in the cohorts from first symptom of FTLD to diagnosis was 19 months for ALS-FTD and 27 months for pure bvFTD and 22 months for PPA, compared to 6.8 months in pure ALS patients. The expansion of the successful ALS registry Swabia to the FTLD spectrum diseases is challenging, since symptoms can be purely psychiatric at the beginning. Most of the registered cases are non-genetic. Combined forms of ALS and FTD started with motor neuron disease in most cases in our register.


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Session 7: Biomarkers for FTLD S13 New physiological biomarkers of frontotemporal lobar degeneration J. Warren1 1 University College London, Dementia Research Centre, London, Great Britain The frontotemporal lobar degenerations (FTLD) continue to present substantial problems of nosology, diagnosis and disease tracking that will need to be resolved if rational, targeted therapies are to be realised. A key challenge is to establish the mechanisms that link pathogenic protein spread with large-scale neural network disintegration and clinical phenotypes in FTLD: that is, to understand these diseases in pathophysiological terms. This is particularly pressing to support earlier diagnosis (and potentially, intervention) because conventional (in particular, structural MRI) biomarkers of FTLD are based on the measurement of irrecoverable tissue loss. The significant genetic burden of FTLD presents a unique opportunity to apply dynamic biomarkers in guiding interventions before clinical disease becomes established; equally, there is a need for disease metrics that can track disease into its later stages when most currently available cognitive and neuroimaging biomarkers lose sensitivity and specificity. There has been much recent progress in defining pathophysiological processes in FTLD and in deriving metrics of these processes that could constitute dynamic biomarkers for detecting and monitoring disease activity and the impact of therapy. Candidate physiological biomarkers are diverse, encompassing autonomic, electrophysiological, metabolic and functional neuroimaging modalities and offer the exciting prospect of identifying pathophysiological signatures of proteinopathies that differentiate traditional broad syndromic categories. Here, I review some recent representative work to give a snapshot of the field and an indication of future directions for this new paradigm, the ‘physiological phenotyping’ of FTLD and other neurodegenerative diseases.

S14 Blood and CSF biomarkers in the presymptomatic stage of hereditary FTD J. C. van Swieten1 1 Erasmus Medical Centre Rotterdam and Free University VU, Genetics of Dementia, Amsterdam, Netherlands Families with autosomal dominant frontotemporal dementia (FTD) are the ideal population to detect sensitive biomarkers for the conversion from from the presymptomatic into the symptomatic stage. Several protein levels have shown decreased or increased levels in cerebrospinal fluid and/or serum of patients with microtubule-associated protein tau (MAPT), Progranulin (GRN), and chromosome 9 open reading frame 72 (C9orf72) mutations. Neurofilament light chain (NfL) protein levels have shown to be increased in small series of symptomatic carriers with one of three major gene defects, whereas Progranulin levels are decreased in serum and CSF levels of symptomatic PGRN carriers. Very

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recently, poly(GP) c9RAN proteins have been detected in CSF of c9ALS patients. Information about levels of these proteins are lacking in the presymptomatic stage of mutation carriers, but may be very crucial in determining the time to start with pharmacological interventions in the future. In a collaborative study on a large series of samples collected from different European centers, levels of Progranuline, NfL and/or poly(GP) c9RAN proteins were measured in CSF and/or serum of presymptomatic and presymptomatic carriers. Analysis of these protein levels with clinical and neuroimaging data (voxel based morphometry, diffusion tensor imaging) gave insight nto the pathophysiological significance of these biomarkers. Correlation analysis of Progranulin and NfL levels between CSF and serum showed that measurements of serum levels of biomarkers may be sufficiently informative for the clinical ssetting. Longitudinal changes of NfL levels in a few converters suggest the clinical relevance of this biomarker to predict the onset of the disease. Levels of poly(GP) c9RAN proteins are already significantly increased in the presymptomatic stage. In conclusion, based on first results, some optimism is warranted about the clinical usefulness of potential biomarkers.

O13 Data-driven Regions of Interest for Longitudinal Change in Three Variants of Frontotemporal Lobar Degeneration H. Rosen1, R. Binney1, A. Pankov1, G. Marx1, F. McKenna1, X. He1, A. Staffaroni1, J. Kornak1, S. Attygalle1, A. Boxer1, N. Schuff1, M.-L. Gorno-Tempini1, M. Weiner1, J. Kramer1, B. Miller1 1 University of California, San Francisco, Neurology, San Francisco, United States Longitudinal changes in brain structure can be measured with precision, and could serve as a biomarker for drug trials in neurodegenerative disease. In Alzheimer’s disease (AD), recent studies have demonstrated that empirically derived regions of interest (ROIs) can provide more reliable measurement of change over time compared with a-priori ROIs. Frontotemporal lobar degeneration (FTLD) is a devastating neurodegenerative disorder for which there are no approved treatments. The goal of this study was to identify ROIs that maximize the effect size for the annual rate of brain atrophy in three major variants of FTLD, and to generate power estimates for a theoretical study that would use change within this ROI as an outcome measure. One hundred and ninety nine participants were studied, including 44 with behavioral variant of FTD (bvFTD), 30 with the semantic variant of primary progressive aphasia (svPPA), 26 with the nonfluent variant of PPA (nfvPPA) and 97cognitively normal comparison subjects. Empirically-derived maps showing regions where patient groups atrophy more than controls were generated for each variant. In bvFTD, the map included the insular and medial frontal regions bilaterally, as well as medial and lateral parietal regions. In nfvPPA the maps included perisylvian and medial and lateral frontal regions and in svPPA, maps included primarily the temporal and inferior frontal regions.


Session 7: Biomarkers for FTLD

Sample size estimates for hypothetical clinical trails varied significantly across groups being 103 per arm in bvFTD, 31 in nfvPPA and 10 in svPPA for a trial that would seek to identify a forty percent reduction in annual rate of atrophy. For all groups the sample sizes than those estimated using a-priori ROIs. The variability in location of peak regions of atrophy across individuals was highest in bvFTD and lowest in svPPA, likely accounting for the differences in effect size. These findings suggest that, while cross-validated maps of change can be generated for each variant of FTLD and improve sensitivity to change compared with a-priori regions, the reliability of these maps varies considerably across syndromes. Future studies can utilize these maps to design clinical trials, and should try to identify factors accounting for the variability in patterns of atrophy across individuals, particularly those with bvFTD.

O14 Multimodal imaging analysis of C9orf72-associated FTD in the Genetic Frontotemporal dementia Initiative (GENFI) study M. Bocchetta1, N. Toussaint1,2, M. Hutel1,2, M. Modat1,2, M. J. Cardoso1,2, E. Gordon1, K. M. Dick1, D. M. Cash1,2, J. van Swieten3, B. Borroni4, D. Galimberti5, M. Masellis6, C. Graff7,8, F. Tagliavini9, G. B. Frisoni10, R. LaforceJr11, E. Finger12, A. de Mendoncßa13, S. Sorbi14, J. D. Warren1, S. Ourselin1,2, J. D. Rohrer1, on behalf of the Genetic FTD Initiative (GENFI) 1 1 Dementia Research Centre, Institute of Neurology, University College London, London, Great Britain 2 Translational Imaging Group, Centre for Medical Image Computing (CMIC), University College London, London, Great Britain 3 Erasmus Medical Center, Departments of Neurology, Rotterdam, Netherlands 4 Centre for Ageing Brain and Neurodegenerative Disorders, Brescia, Italy 5 University of Milan, Fondazione C a Granda, IRCCS Ospedale Policlinico, Department of Physiopathology and Transplantation, Milan, Italy 6 Sunnybrook Health Sciences Centre, Toronto, Canada 7 Karolinska Institutet, Center for Alzheimer Research, Division for Neurogeriatrics, Huddinge, Sweden 8 Karolinska University Hospital-Huddinge, Department of Geriatric Medicine, Stockholm, Sweden 9 Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy 10 IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy 11 Universite Laval, Centre Hospitalier Universitaire de Quebec, Quebec City, Canada 12 University of Western Ontario, Departments of Clinical Neurological Sciences, London Ontario, Canada 13 Faculty of Medicine, University of Lisbon, Lisbon, Portugal 14 University of Florence, Department of Neuroscience, Psychology, Drug Research and Child Health, Florence, Italy Hexanucleotide repeat expansions in the C9orf72 gene represent the most common genetic cause of frontotemporal dementia (FTD). 33 symptomatic participants with C9orf72 expansions were recruited in the first phase of GENFI of whom 26 had available MRI for analysis. In a preliminary analysis we investigated functional and structural neuroanatomical changes, comparing

C9orf72-associated FTD with cognitively normal controls. T1weighted 3D images were used for voxel-based morphometry (VBM) analysis with SPM12 (with correction for age, gender and total intracranial volume), and for automated segmentation using the Neuromorphometrics protocol, to extract cortical and subcortical regions of interest. Diffusion-weighted images were pre-processed and analyzed to extract diffusion measures in white matter (WM) tracts of interest, and perform a tract-based spatial statistics (TBSS) analysis. Independent Component Analysis of resting state-functional MRI data was performed using MELODIC. Results were corrected for multiple comparisons. The C9orf72 group showed significantly lower volumes than controls in the thalamus (18%, p = 0.000001), accumbens and hippocampus (16% and 13% respectively, p ≤ 0.001), and the cortex, in particular the frontal, parietal and insular cortices (13–15%, p ≤ 0.0003). There was also involvement of the cerebellum (8%, p = 0.004). VBM analysis confirmed involvement of the same regions, with specific involvement of the superior-posterior cerebellum, the orbitofrontal and dorsolateral prefrontal cortices and the temporal pole. Both TBSS and regional WM analyses showed involvement of the posterior thalamic radiation, sagittal stratum, fornix, corpus callosum, cingulum, middle cerebellar peduncle, and superior longitudinal fasciculus. Functional analyses revealed decreased connectivity in the C9orf72 group in multiple intrinsic networks including the limbic, sensorimotor and both ventral and dorsal components of the default mode network, as well as a thalamic-posterior cortical network. Preliminary multimodal analysis of C9orf72-associated FTD reveals widespread degeneration but particularly involving a corticothalamic-cerebellar network, specific to this genetic subtype of FTD.

DB23 Increased CSF levels of biomarkers for neurodegeneration in FTLD-GRN mutation carriers J. Goossens1, S. Van Mossevelde2,3,4, T. Van den Bossche2,3,4, A. Sieben3,5, J.-J. Martin5, J. Goeman2, P. P. De Deyn1,2,5, C. Van Broeckhoven3,4, J. van der Zee3,4, S. Engelborghs1,2 1 Reference Center for Biological Markers of Dementia, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 2 Department of Neurology and Memory Clinic, Hospital Network Antwerp ZNA Middelheim and Hoge Beuken, Antwerp, Belgium 3 Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 4 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 5 Biobank, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium Most patients with frontotemporal lobar degeneration (FTLD) have pathology of TDP-43 or tau aggregation. While each pathology is associated with mutations in specific genes, there is clinical overlap between both and with Alzheimer’s disease (AD). The only validated biomarker for FTLD is progranulin in blood or cerebrospinal fluid (CSF), which is decreased in patients with a GRN mutation. This study aimed to determine if CSF progranulin levels and other biomarkers are only dependent on mutation status or related to pathology as well. Definite FTLD patients (n = 45), clinically diagnosed AD patients (n = 45) and cognitively healthy controls (n = 20) were included in this study. FTLD-TDP (n = 28, including 10 GRN and


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17 C9orf72 mutation carriers), FTLD-tau (n = 10) and FTLD-other (n = 7) subgroups were defined by carrier status and/or neuropathological confirmation. Biomarker levels were quantified using singleanalyte ELISA kits (progranulin, Adipogen Inc.; Ab1-42, hTau and pTau181P, INNOTEST, Fujirebio Europe; NF-light, UmanDiagnostics, IBL International GmbH). FTLD-GRN patients had the lowest serum and CSF progranulin levels of all groups, which determined significances when comparing FTLD-TDP and FTLD-tau groups (p < 0.05) and when comparing FTLD, AD and controls (p < 0.02). Progranulin levels in CSF and serum were significantly correlated in all FTLD subgroups except C9orf72 carriers. CSF levels of markers for neurodegeneration (hTau and NF-light) were highest in FTLD-GRN patients as compared to other FTLD-subgroups. A cox hazard regression analysis in another cohort of dementia patients without motor neuron disease, showed a mean disease duration of 5.6y 2.6 year in GRN carriers (n = 40) and 8.2 5.0 year in C9orf72 carriers (n = 30) (p = 0.051). Our results confirm that CSF and serum progranulin levels can reliably identify GRN mutation carriers in a dementia cohort. The increased CSF levels of tau and NF-light chain in GRN mutation carrying FTLD patients suggest more neurodegeneration in this subgroup. GRN carriers indeed have a shorter disease duration than C9orf72 carriers.

DB24 Presymptomatic structural connectivity loss in familial frontotemporal dementia - a four year follow-up study of Dutch FTD pedigrees L. Jiskoot1, J. Panman1, E. Dopper1, J. Papma1, M. Bouts2, C. M€oller2, T. den Heijer1, R. van Minkelen3, S. Rombouts2, J. van Swieten1 1 Erasmus MC, Neurology, Rotterdam, Netherlands 2 Leiden University Medical Center, Radiology, Leiden, Netherlands 3 Erasmus MC, Clinical Genetics, Rotterdam, Netherlands Families with autosomal dominant frontotemporal dementia (FTD) are the ideal population to detect sensitive biomarkers for disease onset and tracking disease progression from the presymptomatic to the symptomatic stage. From 2010 our center performed a two-yearly MRI and neuropsychological follow-up study of 63 healthy at-risk individuals from families with GRN or MAPT mutations (25 GRN mutation carriers, 9 MAPT mutation carriers, 29 controls), and compared data at baseline and second follow-up 4 years later. We used VBM and TBSS in FSL to perform longitudinal (4-year follow-up versus baseline) whole-brain and region-of-interest analyses on grey and white matter. Six mutation carriers (3 MAPT, 3 GRN) converted to clinical FTD during followup, clinical diagnoses being bvFTD (3 MAPT, 1 GRN) and PNFA (2 GRN). Over time, MAPT carriers demonstrated significant more volume loss in bilateral frontal, temporal and insular cortex than controls (pFWE < 0.05), whereas GRN carriers did not show more atrophy over time than controls. Furthermore, both GRN (DFA = 0.04; p = 0.006) and MAPT (DFA = 0.07; p = 0.029) carriers had significant more white matter integrity loss of the right uncinate fasciculus than controls (DFA = 0.03). Individual measurements of the converters in this tract revealed particular integrity loss in the carriers that developed bvFTD (DFA = 0.16), whereas in the two PNFA converters the mean FA values remained stable over time (DFA = 0). A comparable pattern was found in the

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temporal part of the right superior longitudinal fasciculus (DFA bvFTD = 0.07; DFA PNFA = +0.04). This study demonstrates longitudinal grey matter volume and white matter integrity loss in presymptomatic MAPT and GRN carriers, suggesting both a geneand clinical diagnosis-specific pattern while progressing into the symptomatic stage. Our results underline the importance of longitudinal follow-up of a large cohort of at-risk subjects, and suggest that volumetric and connectivity imaging have unique potential to become sensitive disease detection and tracking biomarkers for presymptomatic and early stage FTD.

DB25 Exosomal microRNAs in the cerebrospinal fluid as biomarkers in familial FTD R. Schneider1,2, T. Kim3,4, P. McKeever1,2, C. Graff5, J. van Swieten6, R. Laforce Jr7, D. Galimberti8, M. Masellis9, J. Rohrer10, Z. Zhang4,11, J. Robertson1,2, M. C. Tartaglia2,12 1 University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, Canada 2 University of Toronto, Tanz Centre for Research in Neurodegenerative Disease, Toronto, Canada 3 University of Toronto, Department of Computer Science, Toronto, Canada 4 University of Toronto, The Donnelly Centre for Cellular and Biomolecular Research, Toronto, Canada 5 Karolinska Institutet, Department of Neurobiology, Stockholm, Sweden 6 Erasmus Medical Center, Department of Neurology, Rotterdam, Netherlands 7 Universite Laval, Departement des Sciences Neurologiques, Quebec City, Canada 8 University of Milan, Department of Physiopathology and Transplantation, Milan, Italy 9 University of Toronto, LC Campbell Cognitive Neurology Research Unit, Toronto, Canada 10 University College London, Dementia Research Centre, London, Great Britain 11 University of Toronto, Department of Molecular Genetics, Toronto, Canada 12 University Health Network, Memory Clinic, Toronto, Canada Background: The lack of biomarkers for FTD results in diagnostic delays and hinders drug development. Hence, there is an urgent need for diagnostic biomarkers in FTD at its earliest stage. Investigating familial FTD (fFTD) provides the opportunity to study pre-symptomatic or asymptomatic individuals who are at risk to develop FTD. Recent research has shown that microRNAs have remarkable potential as biomarkers. MicroRNAs are secreted by various cell types and are stable in circulating body fluids due to vesicular protection in exosomes. The main function of microRNAs is silencing of mRNA, which results in decreased protein expression. Objectives: To assess microRNAs in the CSF of patients with fFTD and their presymptomatic family members, we characterized the microRNA expression profile in exosomes from CSF of 42 individuals enrolled in the Genetic Frontotemporal Dementia Initiative. Methods: All 42 individuals enrolled were carriers of one of the three most common disease-causing mutations (C9ORF72, GRN, MAPT), 16 were symptomatic for fFTD. We isolated exosomes



from CSF using a commercially available kit. RNA extraction was followed by real-time PCR amplification in 384 well plates containing a total of 752 human microRNA primer sets. We used Fisher’s exact test to compare the expression of microRNAs in patients and presymptomatic individuals. Results: The expression of seven microRNAs was significantly decreased in patients diagnosed with fFTD as compared to presymptomatic individuals: miR26a-5p, miR29a-3p, miR30b-5p, miR99a-5p, miR143-3p, miR373-3p. Discussion and conclusions: We have identified microRNAs that were decreased in the CSF of fFTD compared to presymptomatic individuals carrying one of the disease-causing mutations. To our knowledge, none of the microRNAs described here have been previously identified as being altered in FTD. We hypothesize that the absence of a single microRNA or a combination of microRNAs could result in aberrant mRNA and/or protein expression in individuals diagnosed with fFTD.

DB26 Brain glucose metabolic abnormalities differ between predementia carriers of GRN and C9ORF72 mutations C. Jacova1, G.-Y. R. Hsiung2, E. Shahinfard2, K. Dinelle2, P. Sengdy2, S. McCormick2, V. Sossi2, A. J. Stoessl2, H. Feldman2, I. R. Mackenzie2 1 Pacific University, Psychology, Hillsboro, United States 2 University of British Columbia, Neurology, Vancouver, Canada Early brain imaging abnormalities in autosomal dominant FTD remain to be fully characterized. Here we investigated anterior and posterior brain glucose metabolism on FDG-PET in carriers of

mutations in the GRN and C9ORF72 gene. Members of families with either mutation underwent genetic testing, and FDG-PET and MR imaging. Bilateral 8-mm anterior (lateral, medial and ventral prefrontal, anterior temporal), and posterior (temporal, parietal) regions-of-interest (ROIs) were applied to co-registered individual MRI/PET. FDG uptake was calculated as the ratio between each ROI’s radioactivity concentration and that of the pons. Anterior and posterior regional uptakes were averaged, and an anterior-toposterior (AP) ratio computed. ANCOVA and ROC analyses were performed. GRN family members included 10 mutation carriers, (age = 51+9.5) and 13 non-carriers, (age = 52+10.0) while C9ORF72 family members included 11 mutation carriers (age = 43+11.0) and 17 non-carriers (age=55+10.0). Mutation carriers did not meet FTD diagnostic criteria and had normal scores on clinical measures. Compared to non-carrier family members, GRN mutation carriers had a reduced AP ratio (0.86+0.08 vs. 0.92+0.05, p = 0.019), mildly lower anterior uptake (1.42+0.27 vs. 1.54+0.20, p = 0.060) but comparable posterior uptake (1.65+0.28 vs.1.67+0.23, p = 0.496). AP ratio had 78% discriminative accuracy for carrier status in this group. Compared to non-carrier family members, C9ORF72 mutation carriers had a comparable AP ratio (0.87+0.20 vs. 0.90+0.04, p = 0.424), but lower anterior and posterior uptakes (1.32+0.32 vs.1.46+0.16, p = 0.029 and 1.51+0.12 vs.1.64+0.19, p = 0.012). Average posterior uptake achieved 69% discriminative accuracy in this group. These findings suggest that there are early neurodegenerative processes in carriers of both mutations but that GRN-related neurodegeneration has more focal anterior involvement, whereas C9ORF72-related neurodegeneration has diffuse involvement of both anterior and posterior regions. Imaging markers of early disease may need to be mutationspecific.


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Session 8: Hot topics DB27

O15 A mouse model for FTD-like syndrome due to TREM2 mutations G. Kleinberger1,2, B. Wefers3, M. Su arez-Calvet1, F. Mazaheri3, 4 5 A. Todorov , M. Brendel , E. Mracsko6, W. Wurst3, T. Mueggler6, A. Rominger5,2, I. Knuesel6, C. Haass1,3,2 1 LMU Munich, BioMedical Center, Biochemistry, Munich, Germany 2 SyNergy Cluster for Systems Neurology, Munich, Germany 3 DZNE Munich, Munich, Germany 4 University Hospital Basel, Institute for Surgical Research and Hospital Management, Basel, Switzerland 5 LMU Munich, Dept. of Nuclear Medicine, Munich, Germany 6 F. Hoffmann-La Roche Ltd., pRED, Basel, Germany Genetic variations in the triggering receptor expressed on myeloid cells 2 (TREM2) have been reported to increase the risk for several neurodegenerative diseases including frontotemporal dementia (FTD). TREM2 is a type-I transmembrane glycoprotein that is expressed in microglia. Proteolytic processing of TREM2 results in the release of a soluble form (sTREM2), which is detectable in the cerebrospinal fluid (CSF) and may be a biomarker of microglial activity in Alzheimer’s disease. Homozygous TREM2 missense mutations, such as p.T66M, lead to a FTD-like syndrome most likely due to loss of TREM2 function. The misfolded mutant protein is retained in the endoplasmic reticulum and fails to reach the plasma membrane. Consequently, TREM2 shedding is dramatically reduced and sTREM2 is absent in CSF of homozygous mutation carriers. Reduced TREM2 activity results in impaired phagocytic activity of microglial cells. Using CRISPR/Cas9 genome editing, we generated a knock-in mouse model for a FTD-like syndrome due to the TREM2 p.T66M mutation. Biochemical analyses of the brain and primary macrophages revealed an impaired maturation of mutant TREM2 resulting in reduced sTREM2 thus recapitulating the phenotypes observed in homozygous mutation carriers. In vitro studies revealed significantly reduced phagocytic activity of macrophages and microglia derived from TREM2 p.T66M mice. Microstructural analyses of the bones showed no detectable abnormalities, consistent with the absence of a bone phenotype in a FTD-like patient. In vivo imaging of the brain using MRI combined with small animal PET to measure microglial activity revealed a localized increase of microglial activity in periventricular areas, a decreased absolute brain perfusion as well as a delayed midbrain development in TREM2 p.T66M mice. Taken together, we have generated a mouse model for a FTD-like syndrome, which recapitulates key features of the human syndrome. This model will be valuable for investigating TREM2 modulating therapeutic strategies with the aim of improving microglia activity and reducing neurodegeneration.

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TDP-43 loss of function inhibits endosomal trafficking and alters signaling in neurons B. Schwenk1, H. Hartmann1, A. Serdaroglu1, M. Schludi1, D. Hornburg2, F. Meißner2, M. Peitz3, T. Klopstock4, A. Ludolph5, T. Arzberger1, P.-H. Kuhn6, D. Edbauer1 1 DZNE Munich, Translational Neurobiochemistry, Munich, Germany 2 MPI of Biochemistry, Martinsried, Germany 3 University of Bonn, Institute of Reconstructive Neurobiology, Bonn, Germany 4 LMU Munich, Department of Neurology, Friedrich-Baur-Institute, Munich, Germany 5 University of Ulm, Department of Neurology, Ulm, Germany 6 Technical University Munich, Institute for Advanced Study, Munich, Germany TARDBP/TDP-43 is genetically, pathologically and mechanistically linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Nuclear clearance of TDP-43 into cytoplasmic aggregates is a key driver of neurodegeneration in both diseases, but the mechanism of cell death remain elusive so far. However, deficits in organelle trafficking have been heavily implicated in the development of neurodegenerative diseases in recent years. Here, we show that TDP-43 knockdown specifically reduces number and motility of RAB11-positive recycling endosomes in dendrites without generally disturbing organelle transport, while TDP-43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP-43 knockdown neurons and decreased b2-transferrin levels in patient CSF. Whole proteome quantification identified upregulation of the ESCRT component VPS4B upon TDP-43 knockdown in neurons. Preventing VPS4B upregulation completely restores trafficking of recycling endosomes. Proteomic analysis revealed broad reduction in surface expression of receptors and cell adhesion factors. Thus, impaired recycling of key factors to the cell surface may contribute to TDP-43 induced neurodegeneration by blocking signaling.

DB28 Neuronal progranulin overexpression reverses social deficits in progranulin-insufficient mice A. Arrant1, A. Filiano1, D. Unger1, A. Young1, E. Roberson1 1 University of Alabama at Birmingham, Neurology, Neurobiology, Birmingham, AL, United States Loss-of-function mutations in progranulin (GRN), a secreted glyocoprotein expressed by neurons and microglia, are a common autosomal dominant cause of frontotemporal dementia (FTD). These mutations are thought to cause FTD through progranulin haploinsufficiency, so boosting progranulin expression from the intact allele is a promising treatment strategy. However, this approach has not been tested against FTD-like deficits in an animal model. Here, we show that overexpression of progranulin with an AAV vector (AAV-Grn) in the medial prefrontal cortex reverses FTD-like social


Session 8: Hot topics

behavior deficits in Grn+/- mice, an animal model of FTD due to GRN mutations. Viral progranulin was detected in neurons, but not microglia, indicating that restoration of neuronal progranulin is sufficient to correct FTD-like deficits in Grn+/- mice. To further test the role of neuronal progranulin in the development of FTD-like deficits, we generated a neuronal progranulin-deficient mouse line using CaMKII-Cre. This mouse line exhibited progranulin deficiency throughout the cortex, as well as in regions of the amygdala and hippocampus. Neuronal progranulin-deficient mice developed similar FTD-like social deficits as global Grn+/- mice, showing that neuronal progranulin deficiency is sufficient to disrupt social behavior. Taken together, these data suggest that neuronal progranulin levels are an important target for progranulin-boosting therapies.

DB29 Trehalose enhances progranulin expression in progranulin-deficient patient cells and mouse brain C. Holler1, G. Taylor1, Z. McEachin2,3, Q. Deng1, W. Watkins1, K. Hudson1, C. Easley2,4, W. Hu4,5, C. Hales4,5, W. Rossoll2,4, G. Bassell2,3,4, T. Kukar1,4,5 1 Emory University, Pharmacology, Atlanta, United States 2 Emory University, Department of Cell Biology, Atlanta, United States 3 Georgia Institute of Technology, Coulter Department of Biomedical Engineering, Atlanta, United States 4 Emory University, Center for Neurodegenerative Disease, Atlanta, United States 5 Emory University, Department of Neurology, Atlanta, United States Progranulin (PGRN) is a secreted growth factor important for neuronal survival and may do so, in part, by regulating lysosome homeostasis. Mutations in the PGRN gene (GRN) are a common cause of frontotemporal lobar degeneration (FTLD) caused by PGRN haploinsufficiency. Additionally, complete loss of PGRN in humans leads to neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Importantly, Grn-/- mouse models recapitulate pathogenic lysosomal features of NCL. Further, GRN variants that decrease PGRN expression increase the risk of developing Alzheimer’s disease (AD) and Parkinson’s disease (PD), both of which display lysosomal abnormalities. Taken together, these findings demonstrate that insufficient PGRN predisposes neurons to degeneration. Therefore, compounds that increase PGRN are potential therapeutics for multiple neurodegenerative diseases. Here, we performed a cell-based screen of a custom library of compounds that modulate the autophagy-lysosome pathway and identified novel activators of a human GRN gene promoter reporter. These

compounds included several mTOR inhibitors and an mTORindependent activator of autophagy, trehalose. Secondary cellular screens identified trehalose, a non-reducing disaccharide, as the most promising lead compound because it increased endogenous PGRN in all cell lines tested and has multiple reported neuroprotective properties. Trehalose dose-dependently increased GRN mRNA as well as intracellular and secreted PGRN in mouse and human cell lines. Moreover, trehalose rescued PGRN deficiency in human fibroblasts and neurons derived from induced pluripotent stem cells (iPSCs) generated from GRN mutation carriers. Finally, oral administration of trehalose to Grn haploinsufficient mice significantly increased PGRN expression in the brain. These findings suggest that compounds targeting the lysosomal pathway such as trehalose and potentially mTOR inhibitors may be good candidates for raising PGRN levels to treat multiple neurodegenerative diseases. Ongoing experiments will determine if novel synthesized trehalose derivatives can increase PGRN in vitro and in vivo.

DB30 Chloroquine rescues Cerebrospinal fluid progranulin deficiency in FTD D. Bittner1, P. K€ ortvelyessy1, H.-J. Heinze1, M. Busse2, S. Busse2 1 University of Magdeburg, Neurology, Magdeburg, Germany 2 University of Magdeburg, Psychiatry, Magdeburg, Germany PGRN has been demonstrated to be significantly reduced in cases of fronto-temporal dementia (FTD) where a PGRN mutation is present. More recently slight decreases have also been found in sporadic FTD. Today no effective treatment is available for FTD, however in cell experiments it has been shown that an increase of PGRN can be elicited by chloroquine application. In 3 patients with FTD with lower PGRN CSF level (p = 0.04) compared to 67 patients with different diagnosis where a follow-up lumbar puncture was present, including 7 FTD patients chloroquine was administered. During follow-up of 1 year (0.99 0.38 years) a significant increase of PGRN was observed compared to the other subjects (Mann–Whitney U test: Z = 2.4, p = 0.008). Moreover an initial increased htau (p = 0.04) decreased during follow-up (Z = 2.1, p = 0.02). For the control group no differences during follow-up were observed for htau or PGRN. Longitudinal changes are of relevance for the understanding of the underlying disease and possibly for monitoring of treatment effects. In our small sample a consistent effect of chloroquine, e.g. increase of CSF-PGRN was seen that can not be attributed to follow-up as in the control group PGRN was rather stable. Moreover there was some evidence of an ameliorated disease course in the 3 patients. From our study results larger studies should be encouraged.


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Session 9: Mechanisms of cell death S15 Insights on motor neuron degeneration in a mouse model of TDP-43 proteinopathy V. M. Lee1 1 University of Pennsylvania, Philadelphia, Pennsylvania, United States The accumulation of phosphorylated TDP-43 aggregates in the cytoplasm of neurons and glia in brain and spinal cord are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We generated new inducible rNLS8 transgenic (Tg) mouse model of TDP-43 proteinopathy and found that these mice recapitulated many aspects of ALDS/FTD. We have used the rNLS8 mice to study motor neuron (MN) degeneration and found striking differences in MN responses to TDP-43 pathology among the 7 MN pools studied. Only MNs in the hypoglossal nucleus and the spinal cord (SC) are lost after 8 weeks of induced mutant human TDP-43 expression, whereas those in the oculomotor, trigeminal, and facial nuclei are spared. Within the SC, slow MNs survive to end-stage, while fast fatigable MNs are lost. Following transgene suppression, resistant MNs sprout collaterals to re-innervate previously denervated neuromuscular junctions (NMJs), concurrent with expression of matrix metalloproteinase 9 (MMP-9), a marker of fast MNs. Thus, although pathological TDP-43 is linked to MN degeneration, the process is not stochastic and mirrors highly selective patterns of MN degeneration observed in ALS patients. Other studies using an RNA sequencing approach on the cortex identify differentially expressed genes before, during and after disease that could be relevant for ALS/FTD.

O16 Insights from iPSC and Drosophila Models of C9ORF72Related ALS/FTD F.-B. Gao1 1 University of Massachusetts Medical School, Worcester, United States FTD is the second most common presenile dementia and shares extensive overlaps with ALS. In recent years, many disease-causing mutations have been identified such as CHMP2B, progranulin, C9ORF72 and others. However, the underlying pathogenic mechanisms remain poorly understood. To address this important question, we have been using multidisciplinary approaches including patient-specific iPSCs and Drosophila genetics. For instance, we generated multiple iPSC lines from control subjects and GRN patients (Almeida et al., Cell Reports 2012) as well as C9ORF72 patients (Almeida et al., Acta Neuropathol. 2013). We also studied different Drosophila models and performed several genetic screens such as for modifiers of mutant CHMP2B (Ahmad et al., PNAS 2009; Lu et al., Mol. Cell 2003). More recently, my laboratory established a novel Drosophila model expressing up to 160 G4C2 repeats (160R) flanked by human intronic and exonic sequences and found that their toxicity is influenced by their molecular context and subcellular localization (Tran et al., Neuron 2015). In a genetic screen done in

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collaboration with Dr. J. Paul Taylor lab, we found that expression of expanded G4C2 repeats in flies compromised nucleocytoplasmic transport, a defect also observed in iPSC-derived cortical neurons (Freibaum*, Lu* et al., Nature 2015). This defect seemed to be caused at least in part by DPR proteins, since expression of (GR)50 alone caused similar phenotypes in flies. To further understand DPR toxicity, my lab generated transgenic flies that expressed longer DPR proteins and found that non-aggregated form of (GR)80 impairs the Notch pathway and that (GA)80 decreases (GR)80 toxicity through inclusion formation (Yang et al., Acta Neuropathol. 2015). Recently, through another genetic screen, we identified many modifiers of (GR)80 toxicity. Some new results obtained from both Drosophila and iPSC-derived neurons will be presented.

O17 Loss of TDP-43 contributes to non-coding RNA mediated toxicity E. Liu1, J. Russ1, E. Lee1 1 University of Pennsylvania, Philadelphia, Pennsylvania, United States Non-coding RNA species may be toxic via sequestering RNA binding proteins (RNABP) away from their site of action. In fact, an intronic hexanucleotide repeat expansion in C9orf72, which was identified as the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, forms RNA foci that may sequester RNABPs. Importantly, all C9orf72 expansion carriers develop TDP-43 pathology, namely the loss of nuclear TDP-43 into cytoplasmic aggregates. TDP-43 is a heterogenous nucleoriboprotein particle (hnRNP) that regulates RNA processing. It is unclear how loss of nuclear TDP-43 contributes to neurodegeneration. To understand the effects of nuclear TDP-43 loss and C9orf72 mutation, we developed a novel method to fractionate postmortem human brain to isolate neuronal nuclei with and without TDP-43 for RNA sequencing. Analysis of 1.6 billion uniquely mapped reads from fractionated frontal neocortex of 15 C9orf72 mutation carriers or controls demonstrated widespread transcriptome differences, including 5576 differentially expressed genes (DEGs) due to loss of TDP-43 compared to 323 DEGs linked to the C9orf72 mutation. Gene expression changes linked to the C9orf72 mutation were highly correlated with reductions in C9orf72 RNA expression. DEG analysis showed that loss of TDP-43 protein led to altered auto-regulation of the gene encoding TDP-43 (TARDBP). Further analysis showed that loss of TDP-43 was associated with 5337 differentially used genic elements (DUGEs) with enrichment for non-coding intronic and 3’ untranslated RNA segments. Of interest, DUGEs associated with TDP-43 loss were highly enriched for hnRNP binding sites. Similar changes in non-coding RNA elements were recapitulated upon CRISPR-Cas9 knockout of TARDBP in 293T cells. Ongoing experiments will test whether experimental manipulation of non-coding RNA elements contribute to toxicity via hnRNP sequestration. We propose a model where loss of TDP-43 leads to aberrant non-coding RNA segment processing, whereby these non-coding RNA segments contribute to cellular toxicity.


Session 9: Mechanisms of cell death

DB31 Fus regulates the transcriptome of the developing mouse brain through several mechanisms C. Valori1, C. Kerimoglu2, C.-Y. Cheng1, V. Sakthivelu1, R. Naumann3, A. Fischer2, M. Neumann1,4 1 DZNE, T€ubingen, Germany 2 DZNE, G€ottingen, Germany 3 MPI, Dresden, Germany 4 University of T€ubingen, Neuropathology, T€ ubingen, Germany Cytoplasmic depositions of the DNA/RNA binding protein FUS (Fused in Sarcoma) are the neuropathological hallmark of a subset of patients with frontotemporal lobe dementia (FTLD-FUS) and, rarely, amyotrophic lateral sclerosis (ALS-FUS). In healthy cells, FUS is mainly expressed in the nucleus and it tunes several aspects of nucleic acid metabolism. In inclusion carrying cells, the physiological nuclear staining is depleted, thereby eliciting two pathogenetic hypothesis: is toxicity due to loss-of-function or to gain-of-toxicity? Here, we aim at investigating transcriptome and epigenome changes secondary to Fus ablation in the developing mouse brain. To this end, Fus-/- mice were generated from stem cells carrying a Fus targeted allele (EUCOMM). Brains from Fus-/embryos (E18.5) do not express any residual Fus and were used for RNA extraction followed by deep-sequencing. Differential expression analysis uncovered a wide effect of Fus ablation on brain transcriptome (826 upregulated and 922 downregulated genes; adj p < 0.05). RT-Q-PCR and quantitative in situ hybridization with RNAscope technology confirmed expression changes of selected transcripts. Gene Ontology analysis (DAVID) reveals an overrepresentation of genes linked to organelle biology and RNA translation among upregulated transcripts and of those related to the homeostasis of the electric potential among downregulated ones. Functional analysis (Ingenuity Pathway Analysis, Qiagen) predicts abnomalities in central nervous system development and cell morphology. Furthermore, Fus-/- brains display the alternative splicing of 438 elements associated with 390 individual genes. Among these, only 83 are also differentially expressed, thus suggesting that Fus regulates gene expression through several mechanisms. To further address this, ChIP-seq on sorted nuclei from neuronal and non-neuronal cells is currently performed using antibodies against specific histone modifications and RNAPII to receive a global landscape of alterations in chromatin marks and chromatin modifying enzymes upon Fus depletion.

DB32 Progranulin is neurotrophic in vivo, stimulating functional recovery after nerve crush injury S. Beel1,2, L. De Muynck1,2, L. Van Den Bosch1,2, W. Robberecht1,3,2, P. Van Damme1,3,2 1 KU Leuven - University of Leuven, Department of Neurosciences Exp. Neurology, Leuven, Belgium 2 VIB, Vesalius Research Center, Laboratory of Neurobiology, Leuven, Belgium 3 University Hospitals Leuven, Department of Neurology, Leuven, Belgium Frontotemporal dementia (FTD) is a primary progressive, neurodegenerative disorder that is most common between the ages of 40–60 years and is clinically subdivided in one behavioral and two language variants. Approximately 40% of the patients have a

familial history of neurodegenerative disease and in about 20% of these families loss of function mutations in the gene encoding progranulin (GRN) are causing the disease. A reduction of 50% or more in the levels of GRN in the blood and cerebrospinal is observed, suggesting haploinsufficiency of the GRN gene as pathogenic mechanism. In vitro experiments already showed that GRN is a neurotrophic factor that stimulates nerve outgrowth and improves survival of primary neuronal cultures. To unravel the mechanisms by which GRN exerts its neurotrophic functions in the CNS, we used an in vivo paradigm of nerve regeneration. To this end, we generated GRN knockout mice and developed a nerve crush model to study axonal regeneration and functional recovery. A comparative study of our nerve crush model and a nerve axotomy model in the sciatic nerve showed complete degeneration of the distal part of the nerves. These observations were highly reproducible and showed low variability due to a homogeneous crush in all animals. To study the effect of GRN on functional recovery after crush, we subjected 8 to 12 week old GRN knockout mice and wild type littermates to a crush of the facial nerve. Whisker movement was scored daily and showed complete functional recovery by day 13 post crush in non-transgenic animals. In the absence of GRN, the overall functional recovery was delayed by 1 day and complete recovery was observed at day 16 post crush. Overexpression of hGRN could completely rescue this deficit. These observations suggest that GRN is an essential component in the nerve regenerative process and that hGRN can mediate these effects.

DB33 C9orf72 differential expression in brain and monocytes suggests a possible role for C9orf72 in monocyte function E. Lynes1, P. Rizzu1, A. Dhingra1, M. Castillo-Lizardo1, M. Franscescatto1, C. Blauwendraat1, S. Heetveld1, E. Pyz1, J. Simon-Sanchez1,2, M. Synofzik1,2, P. Heutink1 1 German Center for Neurodegenerative Diseases DZNE, T€ ubingen, Germany 2 Hertie Institute for Clinical Brain Research, T€ ubingen, Germany C9orf72 is a major gene for amyotrophic lateral sclerosis and frontotemporal dementia. To fully understand how C9orf72 expression is regulated we surveyed the C9orf72 locus using Cap Analysis of Gene Expression sequence data (CAGEseq). C9orf72 was highly expressed (up to 6-fold) in a subset of myeloid cells, particularly CD14 + monocytes, as compared to brain and other tissues. The expression profile of C9orf72 transcription start sites (TSSs) showed a complex architecture with the two TSSs for the annotated C9orf72 transcripts differentially expressed, between myeloid and brain tissues hinting to a C9orf72 transcript specific tissue function. We detected new TSSs in the sense and antisense strand at the C9orf72 locus and confirmed their expression in brain tissues and monocytes from patients and controls. We observed a negative correlation between C9orf72 sense transcripts and the novel antisense transcript AS3 in brain tissues from C9orf72 patients. Currently we are investigating whether AS3 influences the hexanucleotide repeat expansion. Interestingly we observed a decrease of C9orf72 coding transcripts in brain and monocytes from C9orf72 patients together with an increase of the novel antisense transcripts. Moreover, monocytes from C9orf72 patients present with abundant antisense RNA foci. These observations prompted us to hypothesize that C9orf72 plays a special role in monocytes as corroborated by


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Session 9: Mechanisms of cell death

the observed 5-fold increase in C9orf72 expression after challenging CD14 + monocytes with lipopolysaccharide for 18 h. Furthermore, we detected a gradual decrease in C9orf72 expression over a 6-daytime-course differentiation experiment from CD14 + monocytes into macrophages. Additionally, CAGEseq analysis of CD14 + monocytes from C9orf72 patients and controls showed down-regulation in the C9orf72 cases of genes involved in chemotaxis and cell motility. Our future work will aim to determine the function of C9orf72 in monocytes and elucidate how the C9orf72 repeat expansion might impact this role.

DB34 RNA destabilization in frontotemporal lobar dementia and amyotrophic lateral sclerosis H. Archbold1, E. Tank1, M. Paulsen2, M. Ljungmann2, S. Barmada1 1 University of Michigan, Department of Neurology, Ann Arbor, United States 2 University of Michigan, Department of Radiation Oncology, Ann Arbor, United States RNA decay is a crucial aspect of RNA metabolism that is regulated by a series of highly conserved pathways. Our work directly implicates abnormalities in RNA decay as a primary mechanism of disease in the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Both ALS and the most common subtype of FTLD (FTLD-TDP) share key molecular pathologic features, including cytoplasmic deposition of the RNA binding protein TDP43. TDP43 binds to and regulates thousands of RNA transcripts, and as a result, TDP43 deposition dramatically perturbs RNA metabolism. In healthy cells, TDP43 regulates itself by binding its own mRNA and triggering RNA decay through a pathway that requires the RNA helicase UPF1 (up frameshift 1). We previously demonstrated that UPF1 expression extends neuronal survival in models of ALS and FTLD-TDP. Rescue by UPF1 requires RNA decay, and expression of other RNA decay components also suppresses toxicity. We have now identified a set of transcripts that are destabilized by TDP43 using Bru-seq, a powerful RNA labeling and sequencing technique. TDP43 deposition consistently destabilized ribosome proteinencoding transcripts and those involved in mitochondrial function. Importantly, we detected a similar destabilization of these transcripts in cells from patients with familial ALS and FTLD-TDP43 due to C9orf72 mutations, the most prevalent mutation responsible for both conditions. Our data therefore suggest that TDP43 is a fundamental regulator of RNA stability. In addition, the accumulation of TDP43 in ALS and FTLD-TDP may trigger widespread transcript destabilization and consequent interruption of basic processes such as protein translation and energy metabolism, as evident in patientderived cells. Ongoing work seeks to determine if cell type-specific differences in RNA stability underlie the selective vulnerability of motor neurons or forebrain projection neurons in ALS and FTLDTDP, and whether the expression of RNA helicases such as UPF1 can rescue RNA destabilization and neurodegeneration.

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S16 Poly-GA initiates the disease cascade in C9orf72 FTLD/ ALS D. Edbauer1 1 DZNE, Munich, Germany A massive GGGGCC repeat expansion upstream of the coding region of C9orf72 leads to FTLD and/or ALS with TDP-43 pathology. Three mechanisms contribute to pathogenesis. Reduced expression of the mutant allele C9orf72 may impair lysosomal function in myeloid cells and promote inflammation, but knockout mice show no neurodegeneration. The repeat RNA may sequester many RNA-binding proteins in nuclear RNA foci, but different studies show little overlap and no clear relation to neurodegeneration has been shown. In addition, sense and antisense repeat transcripts are translated in all reading frames into five aggregating dipeptide repeat (DPR) proteins. poly-GA, -GP, -GR, -PA and -PR are coaggregating in p62-positive inclusions. So far only high level expression of both repeat RNA and DPR proteins has been shown to trigger significant TDP-43 aggregation. Some patients show only DPR inclusions suggesting they arise prior to TDP-43 pathology and already cause symptoms. Cross-sectional MRI studies detected brain atrophy accompanied by cognitive impairment long before clinical disease onset. For several reasons I favor a dominant role of poly-GA in C9orf72 pathogenesis. Only poly-GA expression leads to the typical p62-positive cytoplasmic inclusions and expression of repeat RNA without strong DPR expression shows little toxicity in most systems. In cellular models poly-GA causes neurotoxicity, induces ER-stress and sequesters the trafficking factor Unc119. In some systems polyGR and especially poly-PR appear to be more toxic, but form no patient-like cytoplasmic aggregates. In patients poly-GA inclusions are about 100-fold more abundant than poly-PR. Higher poly-GA levels in the cerebellum are correlated with development of an FTLD phenotype rather than ALS. By itself only poly-GA forms amyloid-fibrils like many other aggregating proteins, including Ab and Tau. Thus, I suggest a cascade model where chronic accumulation of poly-GA aided by the other DPRs, toxic RNA and impaired microglial function initiates neurodegeneration in C9orf72 FLTD/ ALS.

S17 Panel discussion: What is the toxic species for C9FTD/ ALS? A. Isaacs1 1 UCL Institute of Neurology, London, Great Britain An intronic GGGGCC repeat expansion in C9orf72 is the most common genetic cause of both FTD and ALS. Three potential disease mechanisms have been proposed: 1) Loss of function of C9orf72. 2) RNA toxicity through sequestration of RNA-binding proteins by sense and antisense GGGGCC repeat RNA. 3) Protein toxicity through dipeptide repeat proteins (DPRs) generated by repeat-associated non-ATG translation. Five distinct DPRs are generated: poly(GA), poly(GP), poly(GR), poly(PR) and poly(AP). In addition TDP-43 pathology is observed in C9orf72 FTD/ALS, but the link to the three potential modes of toxicity described above is unknown. We will discuss the arguments in favour and against each of these mechanisms.


Session 10: Disease modulation S18 Gene silencing therapy for human neurodegenerative disease D. W. Cleveland1 1 University of California at San Diego, Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, La Jolla, United States The genes whose mutation causes human neurodegenerative disease are widely expressed within neurons and non-neurons of the nervous system, producing damage not only within the most vulnerable neurons but also within their partner neurons, glia, and endothelia. Sustained gene silencing or altered pre-mRNA splicing broadly within neurons and non-neurons throughout the nervous system has been achieved using a clinically feasible antisense oligonucleotide (ASO) injection into the nervous system. Beginning with the founding example for inherited ALS caused by mutation in superoxide dismutase, single doses of this “designer DNA-based” drug approach have been shown to produce sustained, catalytic (RNase H-dependent) RNA degradation of a target gene, thereby producing slowing of disease progression (for ALS-like disease in rodents) or sustained partial disease reversal for Huntington’s-like disease from single dose injection. Therapy with ASO injection is now in trial for ALS, Huntington’s disease, myotonic dystrophy, and spinal muscular atrophy (SMA). An additional trial is anticipated to initiate in 2017 for the most frequent cause of frontal temporal dementia, hexanucleotide expansion in the C9orf72 gene. An extension of this approach is development of synthetic CRISPR RNAs to induce transient activation of Cas9 nuclease to cleave and permanently inactivate a selected target gene.

S19 Therapeutic reduction of ataxin 2 improves motor performance and extends lifespan in a mouse model of TDP-43 proteinopathy A. Gitler1 1 Stanford University, Department of Genetics, Stanford, United States Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Nearly all ALS patients contain aggregates of the RNAbinding protein TDP-43 in the brain and spinal cord. There are currently no TDP-43-directed therapies for ALS or related TDP-43 proteinopathies, such as frontotemporal dementia (FTD). Targeting TDP-43 itself is probably not warranted given its critical normal cellular function. Here we present an alternative therapeutic strategy, by targeting ataxin 2. Intermediate-length polyglutamine expansions in the ataxin 2 gene are a common genetic risk factor for ALS. These mutations increase the stability of ataxin 2 and results from yeast and flies indicate lowering levels of ataxin 2 is sufficient to suppress TDP-43 toxicity. We used two independent approaches to test the ability of reducing ataxin 2 levels to mitigate phenotypes in a mouse model of TDP-43 proteinopathy. First, we used a genetic approach by crossing ataxin 2 knockout mice to TDP-43 transgenic

mice. Lowering levels of ataxin 2 reduced TDP-43 aggregation, had a dramatic effect on survival and improved motor function. Second, in a more therapeutically relevant approach, we administered antisense oligonucleotides targeting ataxin 2 to the central nervous system of TDP-43 transgenic mice. This single treatment extended survival by over 50%. Because TDP-43 aggregation is a component of nearly all ALS cases and nearly half of FTD cases, targeting ataxin 2 may represent a broadly effective therapeutic strategy.

O18 hnRNP proteins as general enhancers or suppressors of TDP-43 gain- and loss-of-function pathological properties E. Buratti1, C. Appocher1, S. Cappelli1, C. Stuani1, M. Romano1, F. Mohagheghi1, F. Feiguin1 1 ICGEB, Trieste, Italy TDP-43 is a member of the hnRNP protein family of nuclear factors that play an important role in several neurodegenerative pathologies such as ALS, FTD and Alzheimer’s Disease. In general, hnRNP factors are extremely abundant within the eukaryotic nucleus and co-operatively bind to both coding and non-coding transcribed RNAs to determine their processing, transport, stability, and eventual translation. It has already been established that the interaction of TDP-43 with other hnRNP proteins, especially those belonging to the hnRNP A/B family is important both for its splicing regulatory functions and its solubility. However, very little is known with regards to the general importance of hnRNP proteins in affecting TDP-43 normal and pathological functions. Using Drosophila as a model system, we have now performed a functional screening aiming at establishing the effects of known hnRNP proteins on TDP-43 overexpression/depletion. As expected, lowering major hnRNP expression together with TDP-43 has generally a harmful effect on flies locomotor abilities. However, our study has also identified a distinct set of hnRNPs that is capable of powerfully rescuing TDP-43 gain-of-function toxicity in the fly eye. Most importantly, removing the human homologues of these hnRNPs in human neuronal cell lines can correct both pre-mRNA splicing and gene expression processes altered by the absence of TDP-43. Taken together, our results suggest that modulation of specific sets of hnRNP protein expression can successfully rescue pathological events connected with TDP-43 overexpression or aggregation.


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O19 Reducing levels of Tmem106b as a therapeutic strategy in an FTLD-TDP mouse model A. Nicholson1, R. Perkerson1, J. Chew1, A. Kurti1, T. Parsons1, E. Perkerson1, K. Jansen-West1, M. Castanedes-Casey1, L. Rousseau1, J. Stankowski1, D. Dickson1, J. Fryer1, L. Petrucelli1, R. Rademakers1 1 Mayo Clinic Jacksonville, Neuroscience, Jacksonville, United States Two of the most common genetic causes of frontotemporal lobar degeneration (FTLD) are loss-of-function mutations in the progranulin gene (GRN), and a hexanucleotide GGGGCC repeat expansion in the chromosome 9 open reading frame 72 gene (C9ORF72). Characteristic abnormal intracellular aggregates of the TAR DNAbinding protein 43 (TDP-43) are found in the brain of mutation carriers. Recently, variants in the lysosomal transmembrane protein 106b gene (TMEM106B) were shown to protect against GRN- and C9ORF72-dependent FTLD, possibly by reducing TMEM106B levels; however, this has never been directly tested. We therefore generated a Tmem106b knockout mouse model and showed that loss of Tmem106b affects neither lysosomal function at 3 months of age, nor mouse survival up to 15 months. Quantitative PCR and western blotting of brains from Tmem106b +/+, +/-, and -/- mice at 3, 8, and 15 months of age revealed that Tmem106b reduction did not change the expression of the other Tmem106 family members, Tmem106a and Tmem106c. Additionally, loss of Tmem106b did not influence plasma Grn levels, nor brain Grn or Tdp-43 levels. To directly test the hypothesis that reducing Tmem106b can protect against FTLDTDP, we overexpressed expanded [(GGGGCC)66] or non-expanded [(GGGGCC)2] repeat sequences in the brains of neonatal Tmem106b +/+, +/-, or -/- mice using adeno-associated virus (≥ 17 mice per genotype for each virus). Overexpression of (GGGGCC)66 in wildtype mice was previously shown to induce FTLD-related behavioral and pathological changes, including TDP-43 pathology, by 6 months of age, therefore serving as an excellent model to address possible protective effects of Tmem106b reduction. Behavioral assessments and tissue harvests for biochemical studies in 6-monthold injected mice will be completed by June of this year and resulting data will be presented.

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Session 11: Treatment S20 Therapeutic development for FTLD: a panel discussion A. Boxer1, J. Rohrer2 1 UCSF, Memory and Aging Center, San Francisco, United States 2 UCL Institute of Neurology, London, Great Britain Advances in understanding the pathophysiology of FTLD have identified targets for disease modifying and symptomatic therapies for a variety of clinical syndromes. Novel therapeutic agents have entered human clinical trials and more studies are planned in the next few years. The first Phase 3 clinical trial for a bvFTD therapeutic is scheduled to complete in mid-2016 and other taurelated compounds are progressing through early stage studies. Clinical trials in GRN-related FTLD are underway, and studies in C9ORF72-related ALS are planned. This panel discussion will bring together a group of industry and academic clinical trial experts for a lively discussion focused on their experience with FTLD clinical trials, the challenges ahead, and how to accelerate FTLD therapeutic development.

O20 A phase 3 trial of the tau and TDP-43 aggregation inhibitor, leuco-methylthioninium-bis (hydromethanesulfonate) (LMTM), for behavioural variant frontotemporal dementia (bvFTD) H. Feldman1, S. Gauthier2, L. Schneider3, G. Wilcock4, G. Frisoni5, P. Bentham6, J. Hardlund7, K. Kook8, D. Wischik7, B. Schelter9, J. Storey9,7, C. Harrington9,7, C. Wischik9,7 1 University of California, San Diego, La Jolla, United States 2 McGill Centre for Studies in Aging, Quebec, Canada 3 University of Southern California, Los Angeles, United States 4 University of Oxford, Oxford, Great Britain 5 University of Geneva, Geneva, Switzerland 6 University of Birmingham, Birmingham, Great Britain 7 TauRx Therapeutics Ltd., Aberdeen, Great Britain 8 Salamandra LLC, Bethesda, United States 9 University of Aberdeen, Aberdeen, Great Britain Behavioural frontotemporal dementia (bvFTD) is a clinical syndrome associated with focal frontotemporal atrophy and pathological aggregates of tau protein or TAR DNA binding protein 43 (TDP-43). Clinical features include prominent and often disabling social and behavioral changes and executive dysfunction. In transgenic mouse (Melis et al. Behav Pharmacol 2015;26:353) and in vitro (Yamashita et al. FEBS Letters 2009; 583:2419; Harrington et al. J Biol Chem 2015; 290:10862) models leucomethylthioninium-bis(hydromethanesulfonate) (LMTM; TRx-0237) acts as an inhibitor of tau and TDP-43 protein aggregation. A multinational, randomized, placebo-controlled, double-blind, parallel-group, 12-month safety and efficacy trial of LMTM (NCT01626378) was performed in patients with a diagnosis of probable bvFTD according to Rascovsky et al. (Alzheimer Dis Assoc Disord 2007; 21:S14) criteria. Inclusion criteria included age < 80 years, Mini-Mental State Examination (MMSE) score ≥ 20 at

screening, and evidence of definite frontal and/or temporal lobe atrophy by magnetic resonance imaging (MRI) at Kipps level 2 or greater (Kipps et al. Dement Geriatr Cogn Disord 2007;23:334). Patients were randomized in 1 : 1 ratio to receive oral LMTM (200 mg/day) or placebo (including LMTM 8 mg/day, to maintain blinding). Primary study efficacy outcomes were change in scores from baseline for the Addenbrooke’s Cognitive ExaminationRevised (ACE-R), and the Functional Activities Questionnaire (FAQ) or whole brain volume by MRI as alternative co-primary outcomes with a Bonferroni-Holme correction. A total of 220 patients were randomized and 48 withdrew prematurely from the study (21.8%). At baseline, the safety population (138 males, 80 females) had a mean age of 63.0 (SD 7.4) years, with ACE-R score 68.9 (SD 15.6) and MMSE score 24.5 (SD 3.9). The study efficacy and safety outcomes will be reported.

O21 An 8-week, open-label, dose-finding study of Nimodipine for the treatment of progranulin insufficiency from GRN gene mutations S. Sha1, Z. Miller2, S.-W. Min3, Y. Zhou3, L. Mitic4,2, A. Karydas2, M. Koestler2, R. Tsai2, C. Corbetta-Rastelli2, S. Lin2, E. Hare2, J. Brown2, R. Fitch2, R. Powers2, L. H. Martens3, M. Shamloo5, A. Fagan6, R. Farese, Jr3, W. Seeley2, R. Pearlman4, B. Miller2, L. Gan3, A. Boxer2 1 Stanford University, Center for Memory Disorders, Palo Alto, United States 2 University of California, San Francisco, Memory and Aging Center, San Francisco, United States 3 Gladstone Institutes, San Francisco, United States 4 Bluefield Project to Cure FTD, San Francisco, United States 5 Stanford University, Knight Institute for Neuro-Inovation and Translational Neurosciences, Palo Alto, United States 6 Washington University School of Medicine, Alzheimer’s Disease Research Center, St. Louis, United States The discovery that ~20% of familial FTD results from mutations in the progranulin (GRN) gene leading to low progranulin (PGRN) levels sparked the idea that increasing PGRN in mutation carriers could improve disease progression. In cultured cells, we found that reducing intracellular calcium by blocking calcium channels increased PGRN secretion. Nimodipine is a FDA-approved L-type calcium channel blocker that crosses the blood brain barrier. Twoweek treatment with nimodipine elevated hippocampal PGRN levels in both wild-type (p < 0.001) and Grn+/ mice (p < 0.05) compared to vehicle-treated mice. These data suggested that nimodipine might restore PGRN levels in humans with GRN mutations. In a phase one clinical trial, we sought to determine the safety and tolerability of oral nimodipine treatment in GRN mutation carriers and the best dose of nimodipine for longer-term efficacy studies. Secondarily, we screened for effects of nimodipine on plasma or CSF PGRN, a subset of inflammatory and neurodegenerationassociated proteins, and brain volume. Eight subjects with GRN mutations (4 asymptomatic, 4 symptomatic) received escalating


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doses of oral nimodipine for 4 weeks to a target dose of 360 mg/ day, followed by the maximally tolerated dose for 4 weeks. Six of 8 participants tolerated the maximum daily dose. There were no serious adverse events. PGRN concentrations (CSF & plasma) did not change significantly from baseline after treatment with nimodipine (percent change -5.2 10.9 (Mean SEM) in plasma and 10.2% 7.8 in CSF). One patient experienced a 65% increase in plasma PGRN levels during a comorbid urinary tract infection. While nimodipine was generally well tolerated, there was no evidence that treatment altered concentrations of PGRN or other secondary outcomes. The demonstration that PGRN levels increased in response to infection and then returned to baseline in a GRN carrier suggests that plasma PGRN levels are modifiable. Although negative, this study demonstrated the feasibility of conducting small, proof-of-concept trials of novel PGRN therapies in human GRN carriers.

functional polymorphism status) and fMRI data (scans at baseline, tolcapone treatment, and placebo) collected during the trial and plan to present these data as well at the meeting. A longer trial of a COMT-inhibitor, ideally one without the possible hepatotoxicity associated with tolcapone, may be warranted to attempt to improve the symptoms of patients with FTD.

O22 Clinical trial of COMT-inhibition in 28 patients with FTD E. Huey1, V. Mattay2, C. Habeck3, M. Manoocheheri3, N. Armstrong4, D. P. Devanand5, D. Weinberger2, J. Grafman6 1 Columbia University, Psychiatry and Neurology, New York, NY, United States 2 Johns Hopkins University, Lieber Institute for Brain Development, Baltimore, MD, United States 3 Columbia University, Neurology, New York, NY, United States 4 Johns Hopkins University, Baltimore, MD, United States 5 Columbia University, Psychiatry, New York, NY, United States 6 Rehabilitation Institute of Chicago, Brain Injury Research Program, Chicago, IL, United States A functional polymorphism in the COMT gene that is associated with increased synaptic dopamine catabolism is associated with greater neurodegeneration within dopamine-innervated brain areas in FTD. We performed a 24-day clinical trial of a COMT-inhibitor, tolcapone, that selectively increases dopamine in the frontal cortex, in 28 patients with FTD using a cross-over, placebo-controlled design. We compared the baseline, treatment, and placebo phases using repeated measures ANOVAs and two-tailed post-hoc t-tests. There was a significant difference on the Clinical Global Impressions (CGI) scale [F(2, 27) = 3.59, p = 0.035]. Post-hoc t-tests showed a significant difference on the CGI between tolcapone and baseline [t (27) = 2.90, p = 0.008, ES = 0.57] and a trend difference between tolcapone and placebo [t (27) = 1.83, p = 0.078, ES = 0.35]. A significant effect was observed on the total score on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [F (4, 27) = 6.86, p < 0.001], with significant differences between tolcapone and baseline [t(27)=3.86, p = 0.001, ES = 0.60] and significant sub-effects on working memory [t (27) = 2.55, p = 0.02], language [t(27) = 2.88, p = 0.01], and attention [t(27) = 2.45, p = 0.02]. There was not a significant difference between treatment and placebo on the total RBANS [t (27) = 1.17, p = 0.25, ES = 0.22)]. The Neuropsychiatric Inventory (NPI) showed a significant difference between tolcapone and baseline [F (1,25) = 10.19, p = 0.004] [t(25) = 3.19, p = 0.004, ES = 0.63], but the difference between tolcapone and placebo was non-significant [t(25) = 1.28, p = 0.21, ES = 0.25]. All of these results favored tolcapone treatment (i.e., cognitive and behavioral symptoms were improved during the tolcapone phase). Tolcapone was well-tolerated. We are currently analyzing the genetic (COMT

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Poster Presentations Poster Session I: Caregiver P35 Spouses’ experience of behavioural-variant frontotemporal dementia in the pre-diagnostic phase K. Rogers1, A. Brodtmann2,3, D. Darby2,3, V. Anderson1,4 1 University of Melbourne, Melbourne School of Psychological Science, Parkville, Australia 2 Florey Institute for Neuroscience, Behavioural Neuroscience, Heidelberg, Australia 3 Box Hill Hospital, Neuroscience Department, Box Hill, Australia 4 Murdoch Childrens Research Institute, Clinical Sciences Research, Parkville, Australia Behavioural-variant frontotemporal dementia (bvFTD) is an early-onset dementia presenting with changes in social behaviour, including displays of inappropriate behaviours, apathy and disinhibition as well as loss of empathy and limited insight. Patients and families experience greater diagnostic delays and greater caregiver burden than other dementias, in part due to the age of onset and nature of symptoms. Despite the impact on caregivers, qualitative research exploring caregivers’ experiences with bvFTD has been limited. This exploratory study aimed to develop a conceptual model of the pre-diagnostic phase of bvFTD from the perspective of spousal caregivers, with a focus on the implications for improving clinical communication and informing client-focused interventions. We conducted in-depth interviews with 15 spouses (13 female) of persons with probable behavioural-variant frontotemporal dementia, diagnosed according to the consensus criteria (Rascovsky et al., Brain 2011; 134 2456–2477). Participants were recruited through a specialist behavioural neurology clinic. Data were analysed using a grounded theory approach. Analysis resulted in three overarching themes: understanding of changes associated with the disease, processing of changes by the caregiver, and social implications of changes at a family and community level. Understanding the history of the caregiver, the couple, and their social context shed light on how caregivers made sense of the onset of dementia. These results were integrated into a conceptual framework, with consideration of how this can aid case formulation for diagnosis and management. The nature of the symptoms in bvFTD present unique challenges relative to other dementias, and a more holistic model incorporating the experience of dementia from the perspective of caregivers provides insight into the nature of the disease and the impact it has on people’s lives. Focusing on the modifiable aspects of this model provides a conceptual framework to address clinical priorities such as timely and accurate diagnosis and caregiver support.

P36 Emotional behavior in dementia patients and spousal caregivers: relationship with caregiver depression A. Verstaen1, A. Sapozhnikova1, S. Lwi1, M. Otero1, C. Brown1, D. Connelly1, R. Levenson1 1 University of California, Berkeley, Psychology, Berkeley, United States The associated burden of caring with a spouse with dementia has been linked to a number of mental health problems, such as

depression. The existing literature has explored differences in caregiver depression from the qualities of both the caregiver and the patient, but rarely on the qualities of the relationship. The present study examined whether differences in the emotional quality of interactions between caregivers and patients were associated with differences in depressive symptoms of caregivers. We recruited 24 patients with behavioral variant frontotemporal dementia, 18 patients with Alzheimer’s disease, and their spousal caregivers. In the laboratory, couples engaged in a 10 min conversation on a topic of disagreement, and emotional behaviors were subsequently coded using the Specific Affect Coding System (comprised of positive and negative speaker codes, based on verbal content, facial expression, and body movements). Codes were aggregated into total positive and negative emotion scores for each spouse, controlling for total emotion expressed by each spouse. Caregiver depression was assessed using the depression subscale of the Symptom Checklist Inventory. We conducted a linear regression with caregiver depression as the dependent variable. Predictors were the four different emotion variables (caregiver positive and negative, patient positive and negative). Controlling for diagnosis, results indicated that only higher levels of caregiver negative emotion were significantly associated with higher levels of caregiver depression, b = 0.697, p = 0.001, suggesting that across dementia groups, caregiver depression is greater in couples where caregivers express higher levels of negative emotion. Because of the correlational design, directionality is unknown: something about these interactions could be productive of negative emotion in caregivers, causing an increase in depression; or caregivers may become depressed due to other factors, causing an increase in the level of negative emotion they express. We expect that both of these relationships may be at play.

P37 The Marte Meo-concept as a useful tool in understanding and counseling in FTD U. Becker1 1 Freelancer, Alfter, Germany Most FTD-patients show challenging behaviour which is difficult for carers to understand and deal with. Using videos of daily life situations can help to understand the changes caused by the disease and develop ideas for better interaction. In order to find a helpful tool in analysing such videos the author will demonstrate how the Marte Meoâ-concept can be useful. Originally developed as a counseling tool for parents of autistic children, it soon proved to be helpful in dyads of asymmetric relationship in general. It provides concrete and practical information about providing a supportive attitude and positive interaction in situations in which development is slow or problematic. Carers are often unaware of this supportive behaviour which usually is intuitive. However, it is precisely these intuitive moments that the counselor is looking for and focuses on. The video needed to work in this way should last about five to 10 min and represent a normal daily situation. If such moments can be identified it becomes evident


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that they represent positive moments for both carer and patient. Using the technical opportunities of video, enables these sequences of interaction to be highlighted and seen second per second. The next step in counseling is linking the observable behaviour of the carer with the information about the effects on the patient referring to his lost abilities. This provides carers with a greater sense of autonomy and promotes a more attentive attitude in carers’ actions and feelings. Carers should be encouraged to replicate and focus on these moments in social interactions. This shifts the centre of attention from the challenging behaviour itself. Instead, by focusing on the underlying causes and anticipating potential problems in advance, instancies of this kind of behaviour actually tend to decrease in many daily situations. At such moments patients are able to profit from supportive interaction much more than in moments of extreme stress. The more often this happens the calmer the situation becomes.

P38 Do neuropsychiatric symptoms lead to nursing home placement in bvFTD? Differences and similarities between community and nursing home residents C. Giebel1, R. Winson2, D. Knopman3, E. Mioshi2 1 The University of Manchester, PSSRU, Manchester, Great Britain 2 University of East Anglia, Faculty of Medicine and Health Sciences, Norwich, Great Britain 3 Mayo Clinic at Minnesota, Rochester, United States Neuropsychiatric symptoms are the hallmark of bvFTD, and, understandably, tend to be clinically attributed as one of the key reasons for nursing home (NH) placement. However, very little systematic research has been done to investigate potential clinical differences between community dwellers and NH residents. This study included data from the Uniform Data Set of the National Alzheimer’s Coordinating Center (NACC), which collects annual data on demographics, neuropsychological testing, and clinical diagnosis, including the Clinical Dementia Rating (CDR) scale, Mini-Mental State Examination (MMSE), Functional Assessment Questionnaire (FAQ), and the Neuropsychiatric Inventory Questionnaire (NPI-Q), as well as information on parkinsonian symptoms (changes in gait, falls, tremors and slowness). The dataset was locked in November 2012, and data were extracted up to that occasion. Community residents with bvFTD (n = 153) and AD (n = 593) and nursing home residents (bvFTD = 31; AD = 92) were consecutively included in this study. People with bvFTD residing in nursing homes were significantly poorer on cognition (MMSE) (p < 0.05) and all areas of everyday functioning (FAQ) (p < 0.001), had a greater proportion of delusions (p < 0.05), and had significantly slower movements (p < 0.05) than people living at home. Patients from both settings had similar high levels of neuropsychiatric symptoms in all NPI-Q domains, except for delusions (p < 0.05). In AD, however, behavioural (p < 0.01) and movement problems (p < 0.01) were significantly worse in NH residents, in addition to poorer cognition (p < 0.001) and everyday functioning (p < .001). This study indicates that in AD, behavioural problems and motor disturbances are more pronounced in NH residents, as opposed to bvFTD, where neuropsychiatric symptoms are largely equal between settings. Future research will examine which factors predict nursing home placement in bvFTD in comparison to AD, with a view of applying novel therapeutic approaches to delay NH placement and reducing carer burden.

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P39 Dimensions and predictors of perceived burden among caregivers of patients with frontotemporal degeneration J. Galvin1 1 Florida Atlantic University, Boca Raton, United States The diverse clinical features of Frontotemporal Degeneration (FTD) may lead to unique caregiver perceptions of burden. To better understand caregiver burden and associated features, a web-based survey of 1103 FTD caregivers (n = 1103; 694 completers) charactered clinical and behavioral features of disease, and subjective burden (12-item Zarit Burden Inventory, ZBI). Caregivers (mean age 60.9 + 10.1 year) were 78% female and 81% spouses. FTD patients (mean age 65.9 + 8.5 year) were 68% Male, and 65% lived with respondent. FTD subtypes included 53% bvFTD, 21% PPA, 7% FTD-ALS, 5% PSP or CBD, and 14% undifferentiated FTD. Caregivers showed moderate-severe burden (mean ZBI = 27.8 + 7.9) that did not differ across FTD severity (p = 0.16), but did differ by FTD subtype (p = 0.03). Factor analysis revealed 3 burden dimensions: Role strain (37.8% variance), Personal strain (13.4% variance), and Performance strain (10.2% variance). The mean item score was 2.31, which was higher than reported in prior research on Alzheimer’s (range 0.99–1.53), and Lewy body dementia (mean score = 2.13). Role strain received the highest mean endorsement (2.67/item), followed by Performance strain (2.39/item) and Personal strain (1.88/item). Role strain predictors included living with FTD patient, decline in caregiver health, activities of daily living, feelings of isolation, and caregiving costs (R2=0.434, p L) (n = 12), and with SD (left-sided predominant atrophy: L>R) (n = 12) and age- and duration of illness-matched patients with Alzheimer’s disease (AD; n = 25) were recruited. Caregiver burden was assessed by using the Zarit Burden Interview (ZBI). The ZBI score was significantly higher in bvFTD than in AD and SD (L>R), especially in earlier stage. In AD and SD (R>L), the score significantly increased with dementia stage. In SD (L>R), the ZBI score was consistently low. The ZBI score was significantly correlated with behavioral and psychological symptoms of dementia assessed by the Neuropsychiatric Inventory (NPI) in AD, SD (L>R) and SD (R>L). Especially, agitation/aggression, depression/dysphoria, and irritability/lability in the NPI were significantly correlated with the ZBI score in AD, SD (L>R), and SD (R>L), respectively. In supporting caregivers of patients with FTLD, it would be important to understand the features of burden in each diagnostic group.

P42 Family experiences of living with behavioural variant Frontotemporal Dementia (bvFTD): implications of a qualitative longitudinal research study for coping and interventions J. Oyebode1, J. LaFontaine1, M. Larkin2 1 University of Bradford, School of Dementia Studies, Bradford, Great Britain 2 University of Birmingham, Psychology, Birmingham, Great Britain Dementia presents challenges for whole families requiring ongoing adjustment and adaptation. Family relationships provide important social and emotional benefits, thus understanding the impact of dementia and the support needs of families is critical to facilitating opportunities to live well. BvFTD brings specific challenges for relationships, however little is understood about how these are experienced or how families adapt and adjust. This research sought to develop an in-depth understanding of intergenerational family experience of bvFTD over time. Using a qualitative longitudinal design, 19 people from 7 families were interviewed, including people living with bvFTD. Interviews occurred at 3 time points, resulting in 46 joint and individual interviews. Narrative analysis and modified constructivist grounded theory were used to understand the way in which relationships were affected and the psycho-social processes involved in adjustment and coping. Four themes were identified; We/I before bvFTD; Challenges to we/I (and the factors influencing these); Reconstructing, assimilating and adjusting – Resisting, denying, remaining stuck and A changing we/I – an entrenched we/I. Results illustrate the influence of pre-existing family relationships on the experience of living with bvFTD. Early and ongoing challenges to relationships between family members including the person with bvFTD occurred, including changes in reciprocity and responsibility. Levels of awareness and understanding, influenced by factors such as emotional proximity and the subtlety of early changes impacted upon individual and family adjustment and adaptation. Assimilating these changes was critical to developing strategies for managing the impact on the relationship and adapting to ‘a changing we’. For partners, grief and loss for the past relationship also occurred resulting in a parallel adaptation to a changing ‘I’. Family acceptance and adaptation was critical to supporting and maintaining the well-being of the person with bvFTD. Potential interventions will be discussed.

P43 An intervention program for caregivers of early-onset dementia patients with frontal behavioral changes: an explorative study increasing their sense of competence F. Gossink1,2, Y. Pijnenburg1,2, P. Scheltens1, R. Kleverwal2, A. Pera1, N. Korten2, M. Stek2, R.-M. Droes2,3, A. Dols1,2 1 VUmc, Alzheimer Center, Amsterdam, Netherlands 2 GGZinGeest, Neuropsychiatry and Old Age Psychiatry, Amsterdam, Netherlands 3 VUmc, General practice and Elderly care medicine, Amsterdam, Netherlands Caregivers of dementia patients experience high levels of burden, especially caregivers of early onset dementia patients with behavioral problems. As intervention studies for these caregivers are still lacking, we conducted an explorative pilot study on the efficacy of a


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support program. Participants were caregivers of dementia patients affected by apathy, disinhibition and/or stereotypical behavior. The behavioral variant of frontotemporal dementia was the most frequent underlying neurodegenerative disease (60% of cases). Caregivers were randomized to the intervention or control group (both n = 15). The intervention consisted of psychoeducation, social support and cognitive behavioral therapy and was given during 6 months. Quantitative and qualitative data were collected at baseline and after the intervention. Increased sense of competence was found in the intervention group. Burden, perceived stress and depressive symptoms decreased, although not significantly different from the control group. The sense of competence of caregivers improved by the support program and caregivers reported additional supportive effects. Further research into the efficacy of the program, on a larger scale, is recommended.

P44 Family repercussions as a consequence of the alterations of social cognition present in a patient diagnosed with frontotemporal dementia – behavioral variant D. Martinez Martinez1, D. A. Garz on Mu~ noz1, J. A. Ramırez Torres1, A. Bedoya Salcedo1, M. Garcıa Garcıa1 1 Hospital Universitario de San Ignacio, Cundinamarca, Bogot a, Colombia In the behavioral variant of the frontotemporal dementia (FTDbv) alterations of social cognition are identified, in particular on the mental operations that underlay the interpersonal interactions required to understand and respond adequately to the intentions, dispositions and conduct of others. These alterations may generate tensions and conflicts in the family as an answer to the changes perceived during the initial evolution of the illness. This research, with a qualitative approach, through the analysis of study cases and the collection of data by means of a semi-structured interview, aims to describe the repercussions in the famiy dynamics (in the parental and conjugal sub-systems) as a consequence of the alterations in social cognition present in a 75 year old patient diagnosed with FTDbv concerning comunication, sexuality, emotional processing, role reciprocity and decisi on making. On the family members responses of anguish, uncertainty, hopelessness and resignation have been identified, mostly in the face of alterations in social cognition framed by the patient difficulty to identify and recognize the emotions of others and, in this way, generate assertive conduct patterns. These changes have disturbed the stability of the family system due to lack of predictability and responsability in the affective and economic dimensions, resulting in negative repercussions in the family cohesion and ecnomic stability. The results and conclusions will allow to establish parameters of clinical professional intervention directed towards the family, to minimize the identified repercussions that occur as a consequence of the alterations in social cognition described in these patients.

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P45 Care for people with young onset dementia: a web-based intervention aiming to support family carers S. Saxl1, H. Schneider-Schelte1 1 Deutsche Alzheimer Gesellschaft e.V. Selbsthilfe Demenz, Berlin, Germany When dementia starts before the age of 65, it is associated with specific and distinctive needs for those with the diagnosis, relatives and healthcare professionals. Frontotemporal degeneration (FTD) is one of the most common causes for Young Onset Dementia (YOD). Existing health and social care structures are tailored for the elderly and do not meet the needs of patients with YOD and particularly those with FTD. Specific services have only recently been implemented. Therefore, counselling and support of family and other carers are of outstanding importance. RHAPSODY (Research to Assess Policies and Strategies for Dementia in the Young) is a European project conducted by eight partner institutions from six countries – France, Germany, the Netherlands, Portugal, Sweden, and the United Kingdom. Main goal of RHAPSODY is to improve care for people with Young Onset Dementia (YOD) by supporting their carers. Based on an analysis of the needs as well as existing health and social care services for people with YOD and their families RHAPSODY developed a web-based, educational and skill-building intervention for family carers in three languages. Participants of the e-learning programme gain knowledge about neurobiological basis and treatment of dementia, dealing with frequent problems and challenging behaviours, looking for themselves and how to get help. The intervention is being evaluated in a pilot study. RHAPSODY is an EU Joint Programme – Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND: Germany: Bundesministerium f€ ur Bildung und Forschung (BMBF); France: The French National Research Agency (ANR); UK: Economic and Social Research Council (ESRC); The Netherlands: The Netherlands Organization for Health Research and Development (ZonMW); Portugal: Fundacß~ao para a Ciência e a Technologia (FCT); Sweden: Swedish Research Council (SRC). www.jpnd.eu

P46 Caregivers’ attitudes toward family participation in frontotemporal degeneration biomarker research C. Igne1, L. Massimo2, C. McMillan1, R. Langey1, C. York1, K. Firn1, O. Kofman1, A. Halpin1, M. Grossman1 1 University of Pennsylvania, Neurology, Philadelphia, United States 2 The Pennsylvania State University, College of Nursing, University Park, PA, United States While the collection of biomarkers from patients with a neurodegenerative disease is an important part of clinical research, willingness to participate in biomarker research is not welldocumented. Examining the attitudes of caregivers is crucial because they ultimately decide whether the patient will participate in research. A ‘Biomarker Attitude Survey’ was completed by 35 caregivers of patients with Frontotemporal Degeneration (FTD). Caregivers were asked to rank their willingness to consent their loved one to undergo neuropsychological testing, MRI, and lumbar punctures. Overall caregivers first preference was for MRI and their least preference was for lumbar puncture. When we compared



willingness ratings on a 1–5 scale to participate in lumbar puncture to other modalities, there was a preference for MRI (MRI vs LP: Z = 2.69, p = 0.007) and neuropsychological testing (NP vs LP: Z = 2.85; p = 0.004). However, when caregivers were asked their willingness to participate for research purposes only or if there was a direct benefit, they were more likely to consent if there was a direct benefit. Willingness to participate was not correlated with caregiver education level or patient disease duration. In summary, our findings suggest that MRI is the preferred biomarker test among caregivers, but they are more willing to consent if there is a direct benefit including therapeutic treatment. Understanding the factors that influence caregivers’ decision to consent to biomarker research has the potential to aid investigators when framing discussions to increase research participation and clinical trial enrollment.

P47 Service needs in young onset dementia: How ‘closest’ relatives balance being a carer, being a care manager and meeting their own needs J. Oyebode1, B. Jones2, H. Blakey3, S. Parveen1, C. Bakker4, J. Millenaar5, M. de Vugt5, A. Kurz6, H. Gage2 1 University of Bradford, School of Dementia Studies, Bradford, Great Britain 2 University of Surrey, Guildford, Great Britain 3 University of Leeds, Leeds, Great Britain 4 Radboud University, Nijmegen, Netherlands 5 Maastricht University, Maastricht, Netherlands 6 Technical University of Munich, Munich, Germany The majority of people with FTD are diagnosed < 65 years and share life-stage issues with others with young onset dementia (YOD). To better address the far-reaching impact of YOD, a large European study (known as RHAPSODY) is being conducted to develop and test a carer-based intervention. This paper presents UK data from RHAPSODY on close relatives’ experiences of services and views of their own and their relative’s support needs. Understanding such needs is vital for developing appropriate services. Two focus groups were conducted with 16 partners of a relative diagnosed < 65 years at least 6 months ago. Transcripts were subject to inductive thematic analysis. Participants’ mean age was 63 and 10/16 were male. Those with YOD had a mean age of 63 and had been diagnosed a mean of 5.1 years, 2 with FTD, 14 with Alzheimer’s disease. Analysis led to 3 super-ordinate themes. (i) As care provider the closest carried out personal and instrumental care, and organised age-appropriate day-to-day activities in a way that maintained the person’s identity and their relationship. This yielded satisfaction but eroded the closest’s own independent life. (ii) As care manager, in the absence of coordinated provision for YOD, the closest negotiated formal care. Lack of services and their opaque organisation often made this frustrating and, often, huge effort led to unsatisfactory outcome. Committed service providers were treasured and made a huge difference. (iii) By contrast, participants did not always recognise they had needs of their own. Where they did, these were seen as secondary. In conclusion, participants viewed themselves not as carers but as the ‘closest’ to the person with YOD. Each unique situation was grounded in the relationship from which came the roles of care provider and care manager, which involved calling on intimate knowledge of the person with YOD. Our data illustrate positives relating to providing care but negatives in managing care. The more difficult the management, the more effort

required to maintain the role of closest and the more squeezed out the closest’s own needs.

P48 The CARE pathway model for dementia: integrating psychosocial and rehabilitative strategies for care of persons with FTD disorders D. Morhardt1, S. Weintraub1, B. Khayum2, E. Rogalski1, M. Mesulam1 1 Northwestern University, Cognitive Neurology and Alzheimer’s Disease Center, Chicago, United States 2 MemoryCare Corporation, Chicago, United States The Care Pathway Model for Dementia incorporates the development of tailored care plans for persons with dementia based on individual psychosocial and neuropsychological assessments of the person’s abilities and strengths. In an outpatient neurologically based and multidisciplinary clinical setting social workers play the bridging role of connecting patients and families to phenotype-based intervention modalities. Aphasic patients are referred for speechlanguage pathology assessment to delineate a treatment plan that includes the patient as well as the family. Occupational therapy (OT) referrals are coordinated for those with progressive visuospatial impairments. For behavioral variant frontotemporal dementia (bvFTD), social workers provide counseling on how to maximize communication around problem behaviors. Predominately amnestic patients are referred to trained therapists to recommend practical interventions for minimizing the impact of memory weakness on everyday life. Psychosocial assessment of the family system by the social worker identifies family dimensions of cohesion, flexibility and communication, in addition to the underlying historical interpersonal relationships that may promote or hinder the ability to incorporate therapeutic recommendations. In this presentation, the integration of the Care Pathway Model in the clinical setting is illustrated through examples of two individuals with FTD: one, a patient with Primary Progressive Aphasia and the other with bvFTD. The family functioning and relational context is juxtaposed with recommended rehabilitative strategies and associated outcomes.

P49 Dissociation of clinical diagnostic and caregiver distress neuropsychiatric features in FTD L. Hatfield1, J. Wynne Taylor1, M. Harris1, N. Greger-Holt1, D. I. Kaufer1 1 University of North Carolina at Chapel Hill, Departments of Neurology and Physical Medicine and Rehabilitation, Chapel Hill, United States The Neuropsychiatric Inventory Questionnaire (NPI-Q) was developed from the parent NPI interview in order to provide brevity while maintaining outcome measures in a research setting. Though the NPI-Q has become a gold-standard for research registries, domain scores alone do not provide an adequate level of granularity to support clinical care. The NPI-Q2 (validation study ongoing) was designed for use in a clinical setting by adding representative symptom manifestations as check boxes for which informants rate the most severe manifestation on severity for the patient and distress for the caregiver. We present data on 79 Frontotemporal Dementia


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(FTD) subjects (62 bvFTD, 17 primary progressive aphasia), evaluating the prevalence, intensity and clinical impact of the symptom domains and manifestations. Among the five most prevalent symptoms, apathy (73%) and aberrant motor behaviors (61%) represent core diagnostic features. Apathy, primarily reflecting decreased social engagement and spontaneity, was also the most severe symptom reported, on average. The three most distressing single symptoms reported by caregivers were disinhibition (insensitivity), agitation/aggression (being hard to handle), and nighttime behaviors (awakens others at night). Though agitation is only reported in 51% of cases, being hard to handle is the single most distressing manifestation across all domains (avg. 2.42/3). These data highlight the potential utility of the NPI-Q2 in providing more nuanced information related to clinical diagnosis and management.

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Poster Session I: Social cognition and behavior P50 In extremis: decision-making deficit in behavioral variant frontotemporal dementia G. Carle1, N. Borderies2, C. Azuar1,3, A. Guignebert1,3, M. Camus1,3, G. Gagliardi3, R. Le Bouc2, R. Levy1,3, M. Pessiglione2, B. Garcin1 1 Brain and Spine Institute, Frontlab, Paris, France 2 Brain and Spine Institute, Motivation, Brain and Behaviour Lab, Paris, France 3 Pitie-Salpêtriere Hospital, French Reference Centre for Rare Dementias, Paris, France Apathy can be defined as a quantitative reduction of selfgenerated voluntary and purposeful behaviors. It has been found as the most frequent behavioral syndrome in neurological disorders, especially in the behavioral variant frontotemporal dementia (bvFTD), and identified as playing an important role in the impairment of the patients’ quality of life. bvFTD patients have been described as being not only apathetic but also impulsive, less sensitive to rewards, and less prone to empathy (Rascovsky et al. Brain 2011; 134 2456–2477). Moreover, they have exhibited difficulties in reinforcement learning and decision-making processes. To better characterize apathy in bvFTD patients, we have investigated how they assign subjective values to choice options in order to make a decision. 15 bvFTD patients were compared to 15 controls, recruited from The French Reference Centre for Rare Dementias (Pitie-Salpêtriere Hospital, Paris). They responded to various questionnaires (such as the Apathy Evaluation Scale (AES)) and performed a battery of neuropsychological tests, as well as specific behavioral tasks developed in our research center, which we analyzed within a decision theoretic framework. Compared to controls, bvFTD patients were all apathetic (mean AES score (IQR): 5.9(5) vs. 25.1(8.5), p < 0.001) and revealed a specific motivational profile. When asked to assign subjective values to various reward and effort items on a continuous scale, they tended to product bimodal ratings. When they had to choose the better of two rewards or the lesser of two efforts, they made more inconsistent choices than controls (difference in choice stochasticity between controls and patients: 2.16 2.3 vs. 0.58 0.23, p = 0.01). These results suggest that bvFTD patients lose the ability to discriminate what is good and bad for them, and consequently appear highly volatile in their decisions. Further ongoing studies are aimed at linking these results to the pattern of neural degeneration occurring in our population of patients.

P51 Moral judgments in frontotemporal dementia I. Uttner1, L. Petersdorff1, S. Anderl-Straub1, E. Semler1, S. B€ ohm1, D. Lule1, H. Fangerau2, M. Otto1 1 Universit€at Ulm, Neurologische Klinik, Ulm, Germany 2 Heinrich-Heine Universit€ at D€ usseldorf, D€ usseldorf, Germany The behavior variant of the frontotemporal dementia (bvFTD) is associated with social alterations, which can range up to the development of delinquent behavior. To what extent moral

judgment as a possible cause of these alterations is impaired and whether bvFTD patients differ in terms of their ethical attitude from healthy individuals, has been rarely addressed as yet. 12 bvFTD patients (median age 62 years; MMSE> 23) and 19 age, sex and education matched (p > 0.25) healthy controls (median age 64 years) were assessed with the “Moral Competence Test” (MCT, Lind 2013) and the “Ethics Position Questionnaire” (EPQ, Forsyth 1980). In the MCT, two decisions in a moral dilemma situation were presented. Subjects had to evaluate on the basis of predefined arguments (12 per dilemma, 6 pro, 6 contra) why the judgments were right or wrong. Based on their responses a competence index (C-score) was determined, which describes how consistently a person’s own moral guidance was incorporated in the evaluation of a specific situation. The EPQ contains 20 questions and assesses, whether individuals prefer binding ethical standards or not. Cognition was assessed with the CERAD plus. The statistical analysis was based on nonparametric tests (significance threshold: p = 0.05). BvFTD patients showed a significantly lower C-score than healthy controls (p = 0.03), but did not differ in their fundamental value systems (p-range 0.21–0.72). No association was found between C-score and EPQ results (p-range 0.06–0.92). Similarly, apart from one exception in the group of healthy subjects (nonverbal episodic memory, p = 0.04), no correlation was found between the C-score and the CERAD-findings (p-range 0.26–0.88). Results indicate that bvFTD patients take similar ethical positions as healthy controls, but are less able to incorporate their own moral value systems in situational judgments. These difficulties are independent of cognitive skills.

P52 Cross frequency coupling during response inhibition in behavioural variant frontotemporal dementia L. Hughes1, J. Rowe1 1 University of Cambridge, Clinical Neurosciences, Cambridge, Great Britain Patients with behavioural variant frontotemporal dementia (bvFTD) are characteristically impulsive and disinhibited; behaviours linked to prefrontal atrophy, abnormal connectivity, and reduced neurophysiological activity. What remains unclear is the mechanism by which prefrontal dysfunction disrupts behavioural control. In health, action and action inhibition are characterised by oscillatory power changes in the Beta band (event related desynchronisation and resynchronisation, ERD and ERS) thought to reflect hierarchical interactions between prefrontal cortex and motor regions to enable task dependent action control. Here, we used MEG to examine frequency specific interactions between prefrontal and motor regions during a Go-NoGo task of action control. 18 patients with bvFTD and 20 controls were included in the study. The paradigm comprised 400 Go trials to which the participants pressed a button with their right hand, interspersed pseudo-randomly with 100 NoGo trials to which participants withheld their button press. Time frequency power spectra (4–80 Hz) were computed and


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Poster Session I: Social cognition and behavior

significant power differences localised using beamformer. Effective connectivity between right inferior frontal gyrus, preSMA and left motor cortex was examined using induced dynamic causal modelling. The characteristic pattern of beta oscillations was observed in controls and associated with an increase in theta-alpha bands (4– 12 Hz) in all regions and by Gamma bands (60–80 Hz) in a topdown hierarchy. In bvFTD, the power spectra were significantly attenuated and the cross-frequency power couplings were diminished. Interestingly, in the patient group, we did not just reveal a loss of connectivity but also an increase in gamma to gamma coupling between motor regions. These differences indicate pathological network reorganisation in bvFTD, interpreted in light of known physiological and dynamical properties of connectivity between cortical layers that generate and entrain different frequencies.

P53 Prolonged visual facial gaze in frontotemporal dementia P. Paholpak1,2,3, L. Li-Jung4, D. R. Carr2, E. Jimenez2,3, R. J. Barrows2,3, V. Sabodash2,3, M. F. Mendez2,3 1 Khon Kaen University, Psychiatry, Khon Kaen, Thailand 2 University of California Los Angeles, Neurology, Los Angeles, United States 3 Greater Los Angeles VA Healthcare System, Neurology, Los Angeles, United States 4 University of California Los Angeles, Medicine, Los Angeles, United States Gaze and eye contact is a critical aspect of social interaction.Patients with behavioral variant Frontotemporal dementia (bvFTD) may exhibit abnormally prolonged staretoward human faces. This study aimed to explore characteristics of social gaze in patients with bvFTD compared to age and education matchedpatients with early-onset Alzheimer’s disease(eAD) and healthy controls(HC). Fifty picture stimuli, from Internation Affective Picture System (IAPs), were presented to each participant (bvFTD = 12, eAD = 18, HC = 13).Each stimuli contained two properties: face (facial vs.non-facial) and valence (positive, negative and neutral).The”facial” stimuli contained human faces.The participants Visual Fixation Time (VFT) was measured for each picture stimuli of interest (per facial expressions on the Facial Action Coding System). A linear mixed-effects regression model with participant-level of random effects was used to compare VFTs between groups. The results indicated that the patients with bvFTD showed significantly prolonged VFTs to faces than the patients with eAD and the HC, regardless of valence (all p < 0.01).There were no differences in VFTs for non-facial stimuli between patients with bvFTD and eAD. However, patients with bvFTD and eAD had significantly prolonged VFTs to negative non-facial stimuli than the HC (p = 0.006 and 0.019, respectively). We concluded that patients with bvFTD exhibited a prolonged stare toward human faces, while both dementia groups tended to stare at negative stimuli whether faces or non-faces. This prolonged visual facial gaze may contribute to the disturbed social interactions of patients with bvFTD and can help distinguish them from those with Alzheimer’s disease and other conditions.

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P54 Person-based vs. generalized impulsivity disinhibition in frontotemporal dementia and Alzheimer’s disease P. Paholpak1,2,3, D. R. Carr2,3, J. P. Barsuglia3, R. J. Barrows2,3, E. Jimenez2,3, G. J. Lee4, M. F. Mendez2,3 1 Khon Kaen University, Psychiatry, Khon Kaen, Thailand 2 University of California Los Angeles, Neurology, Los Angeles, United States 3 Greater Los Angeles VA Healthcare System, Neurology, Los Angeles, United States 4 University of Loma Linda, Psychology, Loma Linda, United States While much disinhibition in dementia results from generalized impulsivity, disinhibition in behavioral variant frontotemporal dementia(bvFTD) may also result from disordered social cognition and have different neural correlates. This study aimed to deconstruct disinhibition and its neural correlates in bvFTD vs. early-onset Alzheimer’s disease (eAD). A total of 37 caregivers (16 bvFTD and 21 matched-eAD patients) completed the Frontal Systems Behavior Scale disinhibition items, which further categorized into (i) “personbased” subscale of social propriety violations and personal boundaries and (ii) “generalized-impulsivity” subscale of general rule violations. Subscale scores were correlated with grey matter volumes (tensor-based morphometry) on magnetic resonance images. The results showed that the patients with bvFTD developed greater person-based disinhibition (p < 0.001) than the patients with eAD. However, both groups developed comparable severity of generalized-impulsivity disinhibition. TBM analyses demonstrated that the person-based disinhibition subscale score significantly correlated with the left anterior superior temporal sulcus (STS), while generalized-impulsivity disinhibition subscale score correlated with the right orbitofrontal cortex (OFC) and the left anterior temporal lobe (aTL). We concluded that a predominant disinhibition in bvFTD, namely person-based disinhibition, may result from a disturbance of social cognition, probably involving dysfunction of a fronto-parieto-temporal network of Theory of Mind(ToM). Generalized impulsivity disinhibition in both dementia may result from an impaired inhibition circuit, which involves the OFC and aTL.

P55 Emotion and moral dilemmas in behavioral variant frontotemporal dementia S. S. Fong1,2, C. D. Navarrete3, S. E. Perfecto1, A. R. Carr2, E. E. Jimenez1,2, M. F. Mendez1,4,2 1 University of California, Los Angeles, Neurology, Los Angeles, United States 2 V.A. Greater Los Angeles Healthcare Center, Neurology, Los Angeles, United States 3 Michigan State University, Psychology, East Lansing, United States 4 University of California, Los Angeles, Psychiatry & Biobehavioral Sciences, Los Angeles, United States Patients with behavioral variant frontotemporal dementia (bvFTD), a neurodegenerative disease characterized by apathy, social disengagement and behavioral disinhibition, demonstrate impairments during “personal” moral decision-making tasks that depend on an emotional empathic responsiveness to others. This study investigated behavioral and autonomic reactivity to moral dilemmas in patients with bvFTD, compared to patients with



Alzheimer’s disease (AD) and healthy controls (HC). We presented “personal” and “impersonal” moral dilemmas to 10 bvFTD, 11 Alzheimer’s disease (AD), and 9 HC participants while recording skin conductance responses (SCRs), a measure of emotional arousal. We evaluated their behavioral and autonomic responses, verbalized self-reports of subjective emotions and performance on the Social Norms Questionnaire. Consistent with prior studies, bvFTD participants were more willing to harm in the “personal” but not the “impersonal” dilemma, compared to AD and HC groups. SCRs indicated that bvFTD participants had lower arousal and less of an increase in conflict on the personal vs. the impersonal dilemma, in contrast to increased arousal and conflict for the AD and HC groups. In addition, bvFTD participants verbalized less discomfort and displayed positive emotional responses towards decisions to harm another person, whereas the AD and HC groups expressed distress and discomfort. This was the first study to investigate subjective responses and autonomic arousal to moral dilemmas in patients with bvFTD, compared to patients with AD and HCs. These findings indicate decreased autonomic and emotional arousal in bvFTD and suggest that impaired emotional empathy alters moral decisionmaking in bvFTD.

P56 The pitfall of behavioral variant frontotemporal dementia mimics despite multidisciplinary application of the FTDC criteria W. Krudop1, A. Dols2, C. Kerssens2, P. Eikelenboom2, N. Prins1, C. M€oller1, S. Schouws2, D. Rhebergen2, E. Exel, van2, W. Flier, van der1, S. Sikkes1, P. Scheltens1, M. Stek2 1 VU medical center, Alzheimer center, Amsterdam, Netherlands 2 GGZ InGeest, Psychiatry, Amsterdam, Netherlands The behavioral variant of frontotemporal dementia (bvFTD) has a broad differential diagnosis including other neurological and psychiatric disorders. Psychiatric misdiagnoses occur in up to 50% of bvFTD patients. Numbers on misdiagnosis of bvFTD in psychiatric disorders are lacking. The aim of our study was to investigate the frequency and characteristics of bvFTD misdiagnoses in psychiatric disorders and other neurologic disorders. Thirty-five patients with a (possible or probable) bvFTD diagnosis made by a specialized memory clinic neurologist were included. Change in diagnosis after consulting a psychiatrist at baseline was recorded as well as change in diagnosis after 2 years of multidisciplinary neuropsychiatric follow-up. Differences in cognitive and behavioral profiles were investigated per diagnostic group after follow-up (bvFTD, psychiatry, other neurologic disorders).

that otherwise would have been missed. Our findings suggest a limited specificity and a limited positive predictive value of the bvFTD criteria.

P57 Neuropsychiatric effects of neurodegeneration of the medial versus lateral ventral prefrontal cortex in humans E. Huey1, S. Lee2, A. Brickman3, M. Manoochehri3, E. Griffith3, D. P. Devanand4, Y. Stern3, J. Grafman5 1 Columbia University, Psychiatry and Neurology, New York, NY, United States 2 Columbia University, Biostatistics, New York, NY, United States 3 Columbia University, Neurology, New York, NY, United States 4 Columbia University, Psychiatry, New York, NY, United States 5 Rehabilitation Institute of Chicago, Brain Injury Research Program, Chicago, IL, United States Animal evidence suggests that a brain network involving the medial and rostral ventral prefrontal cortex (PFC) is central for threat response and arousal and a network involving the lateral and caudal PFC plays an important role in reward learning and behavioral control. In this study, we contrasted the neuropsychiatric effects of degeneration of the medial versus lateral PFC in 43 patients with Frontotemporal dementia (FTD) and 11 patients with Corticobasal Syndrome (CBS) using MRI, the Neuropsychiatric Inventory (NPI), and the Sorting, Tower, Twenty Questions, and Fluency tests of the Delis-Kaplan Executive Function System (DKEFS). Deviations in MRI grey matter volume from 86 agematched healthy control subjects were determined for the patients using FreeSurfer. Multivariate regression was used to determine which brain areas were associated with specific neuropsychiatric and cognitive symptoms. Decreased grey matter volume of the right medial ventral PFC was associated with increased anxiety and apathy, decreased volume of the right lateral ventral PFC with apathy and inappropriate repetitive behaviors, and of the left lateral ventral PFC with poor performance on the sorting and Twenty Questions task in patients with FTD and CBS. Similar to in animal studies, damage to the medial OFC appears to be associated with a disruption of arousal, and damage to the lateral OFC appears to be associated with deficits in trial-and-error learning and behavioral dysregulation. Studies of brain dysfunction in humans are valuable to bridge animal and human neuropsychiatric research.

Clinical profiles of the patients are described in detail. In 16 patients (45.5%) the bvFTD baseline diagnosis changed: 2 at baseline after psychiatric consultation and 14 after 2 years of multidisciplinary follow-up. A majority of 10 (62.5%) of these 16 patients (28.5% of total) were reclassified with a psychiatric diagnosis. We found no differences for cognitive and behavioral baseline profiles between patients with bvFTD versus psychiatric diagnoses. In conclusion, in almost half of the initial bvFTD cases, diagnosis was changed after follow-up, most often into a psychiatric disorder. A multidisciplinary neuropsychiatric approach in the diagnostic process of bvFTD results in the identification of treatable disorders


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Combined intensity ratings of congruent and incongruent facial emotions highly discriminate between behavioralvariant frontotemporal dementia and major depressive disorder I. Chiu1,2, O. Piguet3, J. Diehl-Schmid4, L. Riedl4, J. Beck5, T. Leyhe6, E. Holsboer-Trachsler5, M. Berres7, A. U. Monsch1, M. Sollberger1,2 1 Memory Clinic, University Center for Medicine of Aging Basel, Felix Platter-Hospital, Basel, Switzerland, Basel, Switzerland 2 University Hospital Basel, Department of Neurology, Basel, Switzerland 3 ARC Centre of Excellence in Cognition and its Disorders, Sydney, Australia 4 Technical University Munich, Department of Psychiatry, Munich, Germany 5 Psychiatric Clinics of the University of Basel, Center for Affective, Stress and Sleep Disorders, Basel, Switzerland 6 Psychiatric Clinics of the University of Basel, Center of Old Age Psychiatry, Basel, Switzerland 7 University of Applied Sciences Koblenz, Department of Mathematics and Technology, Koblenz, Germany

Executive functioning and mental attribution predict environmentally-driven behaviours in behavioural variant frontotemporal dementia E. Flanagan1, M. Bertoux1,2, B. Dubois2, V. Hahn3, E. GuichartGomez3, E. Mioshi1, M. Sarazin3, M. Hornberger1 1 University of East Anglia, Faculty of Medicine and Health Sciences, Norwich, Great Britain 2 Hôpital de la Pitie-Salpêtriere, Departement de Neurologie, Paris, France 3 Centre Hospitalier Sainte Anne, Service de Neurologie - Pôle des Neurosciences, Paris, France

In its early stages, behavioral-variant frontotemporal dementia (bvFTD) is frequently misdiagnosed as major depressive disorder (MDD) due to overlapping symptoms. Recent studies have revealed the potential of emotion processing paradigms for improving the differentiation between the two diseases. The current study compared 25 bvFTD patients, 20 MDD patients, 21 Alzheimer’s disease dementia patients, and 31 healthy controls on a novel emotion intensity perception task. Participants were asked to rate the intensity of morphed faces from the Ekman and Friesen stimulus set on the congruent emotion (i.e., sad stimulus and rating on sadness) and on the five incongruent basic emotions (i.e., sad stimulus and separate ratings on anger, disgust, fear, happiness, and surprise). In contrast to the other groups, bvFTD patients misrecognized emotions, in particular negative emotions. MDD patients showed a negative response bias for congruent negative facial emotions, but not for incongruent negative facial emotions. Although both ratings of congruent and incongruent negative facial emotions differentiated well between bvFTD and MDD, the highest discrimination between the two diseases was achieved by combining both types of rating. This emotion intensity perception task, which is easy to administer in the clinic, appears to be a valuable tool to discriminate between early bvFTD and MDD patients, and therefore to improve the diagnostic accuracy of bvFTD.

Environmentally-driven behaviours (EDB), including grasping, imitation (IB) and utilisation (UB) behaviours, are classically attributed to a frontal injury and have been repeatedly reported in behavioural variant frontotemporal dementia (bvFTD). These behaviours have often been attributed to executive dysfunction, however inconsistent associations between EDB and poor executive performance has led to an alternative “social hypothesis”, instead implicating patients’ misinterpretation of the examiner’s intention. We investigated the possible explanatory cognitive mechanisms of EDB in bvFTD by relating them to performance on tests of executive functioning and theory of mind (ToM). Retrospective data of 32 bvFTD patients were analysed. Data included severity scores of grasping, IB and UB, various executive measures, and ToM measured using the faux pas test, from which we extracted a mental attribution score. Grasping, IB and UB were respectively observed in 46.9%, 40.6% and 15.6% of bvFTD patients. Automatic linear modelling was performed with executive and ToM measures as predictor variables and grasping, IB and UB sequentially considered as target variables. ToM mental attribution and performance on the Wisconsin Card Sorting Test significantly (p’s < 0.01) predicted grasping (35.8% of variance explained) and IB (64.4% of variance explained), the latter of which was additionally predicted by motor sequence performance. No significant predictors were found for UB. These findings reveal a complex interaction between executive dysfunction and ToM deficits influencing the prevalence of EDB, and further investigation is required to improve our understanding of the mechanisms underlying these behaviours.

P60 Emotion recognition in presymptomatic CHMP2B mutation carriers J. Stokholm1, P. Roos1, J. Nielsen1,2, A. M. Isaacs3, J. Brown4, P. Johannsen1 1 Danish Dementia Research Center, Department of Neurology, Copenhagen, Denmark 2 University of Copenhagen, Section of neurogenetics, Panum, Copenhagen, Denmark 3 Department of Neurodegenerative Disease, Institute of Neurology, London, Great Britain 4 Addenbrookes Hospital, Department of Neurology, Cambridge, Great Britain Background: Mutation in the CHMP2B gene on chromosome 3 is a rare cause of familial dementia. The disease is referred to as FTD-3 as the early clinical presentation often resembles the behavioral form of FTD. Deficits in executive functions and social cognition are the core neuropsychological deficits in bvFTD. In an

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earlier study we found that executive dysfunctions could be detected in presymptomatic CHMP2B gene carriers 5–8 years before they fulfilled the criteria for dementia. Objective: To investigate whether impairment in social cognition can be detected in presymptomatic CHMP2B mutation carriers. Method: We administered the emotion recognition test from the mini-SEA battery (Bertoux et al.; Brain Image Beh 2014; 8 1–6) to eight presymptomatic CHMP2B mutation carriers (mean: 52 YOA, range: 35–68) and a control group of 16 family members known to be non-mutation carriers (mean: 59 YOA, range: 38–71). The number of correct answers (0–35) was registered and a MannWhitney U test was used to compare group scores. Also the number of subjects scoring below 26 points (1 SD below mean in the control group) was investigated and a chi-square test was applied to assess the difference in distribution. Results: Mean score was 26.5 (SD 2.9) in the presymptomatic group and 29.3 (SD 3.7) in the control group (p = 0.052). In the mutation positive group four of the subjects scored below 26 points, while this was only the case for two in the control group (p = 0.046). Conclusion: The study shows a strong trend towards poorer emotion recognition in presymptomatic CHMP2B mutation carriers. This indicates that changes in emotion recognition are among the first symptoms in FTD-3.

P61 Emotion network breakdown relates to baseline autonomic dysfunction in behavioral variant frontotemporal dementia V. Sturm1, J. Brown1, A. Hua2, S. Lwi2, H. Rosen1, B. Miller1, R. Levenson2, W. Seeley1 1 University of California, San Francisco, Neurology, San Francisco, United States 2 University of California, Berkeley, Psychology, San Francisco, United States Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disease that impacts empathy, emotion, and social behavior. There is emerging evidence that patients with bvFTD have diminished parasympathetic and sympathetic nervous system functioning at baseline, deficits that may reflect deterioration of specific neural circuits that support emotion and autonomic nervous system physiology. We measured baseline respiratory sinus arrhythmia (RSA), a parasympathetic measure, and skin conductance level (SCL), a sympathetic measure, during a 6-min resting period in 15 patients with bvFTD and 14 healthy controls who later underwent structural and task-free functional magnetic resonance imaging. The Neuropsychiatric Inventory was used to assess affective symptoms in the patients with bvFTD. Guided by a novel neuroanatomical model, we conducted whole-brain voxel-based morphometry analyses to identify regions where atrophy was associated with baseline autonomic deficits. We also extracted the functional connectivity time series from 21 emotion network nodes and used hierarchical multiple regression analyses to examine whether functional connectivity deficits in specific node-pairs related to baseline autonomic dysfunction. As expected, patients with bvFTD had significantly lower baseline RSA (p < 0.05) and SCL (p < 0.05) than healthy controls. Lower baseline RSA was associated with smaller left ventral anterior insula volume, weaker functional connectivity between bilateral ventral anterior insula and anterior cingulate

cortex, and stronger functional connectivity in predominantly right hemisphere hypothalamus- and amygdala-based nodes. Lower baseline SCL, in contrast, was associated with smaller volume in inferior temporal gyrus, dorsal anterior insula, hypothalamus, and periaqueductal gray; weaker functional connectivity between right hypothalamus/amygdala and anterior cingulate cortex; and stronger functional connectivity between dorsal anterior insula and periaqueductal gray. In bvFTD, higher irritability was correlated with weaker ventral anterior insula – anterior cingulate cortex connectivity whereas higher euphoria was correlated with weaker anterior cingulate cortex – hypothalamus connectivity. Our results suggest that baseline parasympathetic and sympathetic activity depend on the integrity of distinct nodes in a neural network that supports emotion. Resting autonomic physiology is the product of both strong and weak nodal connections, and deterioration of both types of connections is associated with baseline autonomic dysfunction and affective symptoms in bvFTD.

P62 The eating behavior inventory (EBI): a new clinical tool for the early diagnosis of frontotemporal dementia C. Azuar1,2, A. Amaya1, M. Camus1, A. Funkiewiez1, T. Mauras1, R. Levy1,2, I. Le Ber1, B. Dubois1,2 1 APHP, Federation de neurologie, Paris, France 2 INSERM, UPMC, ICM, Frontlab, UMRS 975, Paris, France Changes in eating behaviors and food preference are very frequent in patients with frontotemporal dementia. Despite a specific pattern, this behavioral change is not used as a diagnosis tool. In this study we proposed a new caregiver questionnaire named Eating Behavior Inventory (EBI). This questionnaire consisted in 30 questions investigating four domains of eating behavior (eating habits, food preference, table manners, and swallowing problems). The aim of this study was to show how this questionnaire could be used as a clinical tool allowing to distinguish frontotemporal dementia from Alzheimer’s disease. Two groups of patients were studied using the EBI: 50 patients with frontal variant frontotemporal dementias (fv-FTD) and 40 patients with Alzheimer’s diseases (AD) confirmed by CSF biomarkers. Results showed that the EBI scores were significantly different in the two groups with mean scores ( SD) of 12.5/30 ( 4.3) in fvFTD patients and 3.4/30 ( 2.6) in AD patients. The ROC curves analyzes showed a high area under the curve (AUC = 0.97) and revealed a best cut-off value of > 6/30 for fv-FTD diagnosis, with 95.8% sensitivity and 86.8% specificity. The sub-score investigating table manners seemed to have the best predictive value for FTD diagnosis. The EBI, shown as a rapid and simple caregiver questionnaire, could be proposed as a new diagnosis tool distinguishing fv-FTD patients from AD patients.


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P63 Clinical types of FTD in elderly patients of Alzheimer’s disease outpatients clinic (clinical-neuropsychological study) Y. Fedorova1, I. Roshchina1, E. Ponomareva1, I. Kolykhalov1, N. Mikhaylova1, S. Gavrilova1 1 Mental Health Research Center, Alzheimer’s disease department, Moscow, Russian Federation The aim of the study: to investigate the clinical types of frontotemporal dementia in patients, having referred to outpatient Alzheimer clinic. The FTD patients were composed 3.7% (n = 48), 20 males and 28 females, among all the patients having referred to Alzheimer centre for the first time. The diagnosis was made in accordance with the criteria of K. Rascovsky et al. (2011) and M.L. Gorno-Tempini et al. (2011). There were 22 patients with mild dementia, 18 patients moderate dementia, and 8 patients suffered severe dementia. The average age was 62.5 years. Psychopathological, psychometric, neuropsychological methods were applied. The clinical examination showed that 34 patients had behavioral variant FTD. At the initial stages of the disease these patients demonstrated impairments of behavior: socially inadequate behavior; loss of liking, hygiene impairments; overeating; stereotyped motor behavior. Neuropsychological examination showed a combination of dysfunction of frontal and left temporal brain structures (systemic perseverations, impairments of control of activity, reduction of voluntary attention, regulatory and dynamic apraxia, impairment of voluntary memory, acoustic-mnestic aphasia). In 10 patients with primary progressing aphasia marked speech impairments were combined with behavioral impairments. Neuropsychological evaluation showed that predominant symptoms of dynamic and acousticmnestic aphasia coexisted with dysfunction of frontal brain structures. Four patients were related to the most rare FTD type – semantic dementia with expressive speech impairments. Neuropsychological syndrome was characterized by marked symptoms only in the left temporal brain lobe: literal paraphasias in oral and writing speech, impairment of nominative speech function and specific modal audio-verbal memory.

P64 Functional dissociation between anterior temporal lobe and inferior frontal gyrus in the processing of dynamic body expressions: Insights from behavioral variant frontotemporal dementia J. Jastorff1, F. De Winter1, J. Van Den Stock1, M. Vandenbulcke1 1 KU Leuven, Translational Neuropsychiatry, Leuven, Belgium A large brain network is involved in the processing of emotional stimuli, however, the contribution of individual nodes within this network to emotion perception is still under debate. To investigate this issue, we combined behavioral testing, structural and resting state imaging in patients diagnosed with behavioral variant frontotemporal dementia (bvFTD) and age matched controls, with task based functional imaging in young, healthy volunteers. As expected, bvFTD patients were impaired in emotion detection as well as emotion categorization tasks, testing dynamic emotional body expressions as stimuli. Interestingly, their performance in the two tasks correlated with gray matter volume in two distinct brain regions, the left anterior temporal lobe (ATL) for emotion detection and the left inferior frontal gyrus (IFG) for emotion categorization.

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Confirming this observation, multivoxel pattern analysis in healthy volunteers demonstrated that both ROIs contained information for emotion detection, but that emotion categorization was only possible from the pattern in the IFG. Further, functional connectivity analysis showed reduced connectivity between the two regions in bvFTD patients. Our results illustrate that the mentalizing network and the action observation network perform distinct tasks during emotion processing. In bvFTD, communication between the networks is reduced, indicating one possible cause underlying the behavioral symptoms.

P65 Determinants of theory of mind performance in Alzheimer’s disease S. Ramanan1, L. C. de Souza2, M. Sarazin3,4, A. L. Teixeira2, P. Caramelli2, B. Dubois3,4, M. Hornberger5, M. Bertoux5 1 Manipal Hospital, Bangalore, Bangalore, India 2 Federal University of Minas Gerais, Belo Horizonte, Brazil 3 Centre Hospitalier Sainte-Anne, Pôle des Neurosciences, Paris, France 4 Hôpital de la Pitie-Salpêtriere, Departement de Neurologie, Paris, France 5 University of East Anglia, Norwich Medical School, Norwich, Great Britain Theory of mind (ToM), the capacity to infer the thoughts, feelings and beliefs in others, is critically impaired in bvFTD. Recent studies have showed that ToM performance might also be altered in Alzheimer’s disease (AD) though to a lesser extent than in bvFTD. This has led some authors to suggest that these may reflect a genuine deficit in ToM while others attribute this impairment to a general decrease of cognitive functioning in AD. In order to investigate the neuropsychological determinants of ToM performance in AD, a data-mining study was conducted on 29 AD patients (from France), then replicated in an independent age-matched group of 19 AD patients (from Brazil) to perform an independent cross-validation of the results. A comparison group of 44 bvFTD patients was also included. All patients underwent a comprehensive neuropsychological examination including the short version of the faux-pas test from the mini-SEA. Hierarchical clustering analysis showed that ToM score in AD clustered with all measures of executive functioning (Frontal Assessment Battery, digit spans, lexical and semantic fluency). ToM performance was also specifically and significantly correlated with the executive component extracted from a principal component analysis. In a final step, an automated linear modelling conducted to determine the predictors of ToM performance was run. Results showed that 53.6% of ToM performance was significantly predicted by executive measures. Importantly, similar findings across the three analyses were observed in independent groups of AD patients, thereby cross-validating our results. By contrast, results showed that in bvFTD, ToM impairment was largely independent of other neuropsychological dysfunctions. These results suggest that ToM performance in AD is highly related to general cognition and particularly to executive/attentional functioning, which accounted for 54% of the faux pas test’s variance. This suggests that difficulties of AD patients on the faux pas test do not reflect a genuine ToM deficit, but rather a general cognitive decline.



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Brain structural correlates of executive and social cognition profiles in behavioral variant Frontotemporal Dementia and elderly Bipolar Disorder T. Torralva1, S. Baez1, C. Pinasco1, M. Roca1, J. Ferrari1, B. Couto1, I. Cordero1, A. Iba~nez2, I. Cordero2, C. Francy3, P. Reyes3, D. Matellana3, M. Cetkovich4, F. Manes5 1 Institute of Cognitive neurology, Neuropsychology, Buenos Aires, Argentina 2 Institute of Cognitive Neurology, Laboratory of Experimental Psychology, Buenos Aires, Argentina 3 Universidad Javariana, Departamento de Psiquiatrıa y Salud Mental, Bogota, Colombia 4 Institute of Cognitive Neurology, Psychiatry, Buenos Aires, Argentina 5 Institute of Cognitive Neurology, Neurology, Buenos Aires, Argentina

Uncovering the neural bases of cognitive and affective empathy loss in the behavioural-variant of frontotemporal dementia M. Irish1,2,3, N. Dermody1,2, S. Wong1,3, J. Hodges1,3,4, O. Piguet1,3,4 1 Neuroscience Research Australia, Sydney, Australia 2 University of New South Wales, School of Psychology, Sydney, Australia 3 Australian Research Council Centre of Excellence in Cognition and its Disorders, Sydney, Australia 4 University of New South Wales, School of Medical Sciences, Sydney, Australia

Frequently, the initial clinical presentation of the behavioral variant frontotemporal is frequently the presence of a constellation of psychiatric symptoms or behavioral disorders mimicking those found in bipolar disorder (BD), making its differential diagnosis a big challenge. However, no studies have compared these pathologies from neuropsychological and neuroanatomical perspectives. The aim of the present study was to compare the neuropsychological and social cognition profiles as well as the structural neuroimaging of bvFTD and elderly patients with BD. First, we compared the executive and social cognition performances of 16 bvFTD patients, 13 BD patients and 22 healthy controls. Second, we compared grey matter volumes in both groups of patients and controls using voxelbased morphometry. Finally, we examined the brain regions where atrophy might be associated with specific impairments in bvFTD and BD patients. Compared to controls, bvFTD patients showed deficits in working memory, abstraction capacity, inhibitory control, cognitive flexibility, verbal fluency and theory of mind (ToM). No significant differences were observed in the executive or social cognition performances of BD patients and controls. In bvFTD patients, atrophy of frontal (orbitofrontal, inferior frontal gyrus), temporal (superior and inferior temporal gyri, amygdala, hippocampus, parahippocampal and fusiform gyri) and insular cortices was related to executive functions deficits. Atrophy of amygdala, hippocampus, parahippocampal gyrus, putamen, insula, precuneus, right temporo-parietal junction and superior temporal pole was associated to ToM impairments. Our results provide the first comparison of neuropsychological, social cognition and neuroanatomical profiles of bvFTD and elderly BD patients. These findings shed light on differential diagnosis of these disorders and may have important clinical implications.

Loss of empathy represents a core presenting feature of the behavioural-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties, behavioural transgressions, and carer distress. In contrast, interpersonal functioning is held to remain relatively intact in Alzheimer’s disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Perspective Taking and Empathic Concern subscales of the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. While perspective taking was comparably compromised in AD and bvFTD, empathic concern was impaired exclusively in the bvFTD group. Controlling for overall level of cognitive dysfunction served to ameliorate perspective-taking deficits in AD, however, empathy loss in bvFTD persisted across cognitive and affective domains. Voxel-based morphometry analyses revealed discrete neural correlates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral atrophy in frontoinsular, temporal and parietal structures was implicated in bvFTD. Further, reduced capacity for empathic concern in bvFTD was associated with atrophy in the left or bitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Finally, an overlap analyses revealed that atrophy in the left orbitofrontal and insular cortices underpinned empathy loss in bvFTD irrespective of subscale. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a primary empathy disturbance per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed neural network, centred on the frontoinsular cortices, that appears crucial for the monitoring and processing of social information.

P68 Multimodal evidence of interoceptive dimensions in neurodegeneration and stroke no1, T. Torralva1, L. de la Fuente1, I. Garcıa-Cordero1, L. Sede~ J. Ferrari1, C. Rodriguez1, S. Baez1, A. Yoris1, S. Esteves1, nez1 M. Melloni1, P. Salamone1, F. Manes1, A. Garcia1, A. Iba~ 1 Institute of Cognitive neurology, Neuropsychology, Buenos Aires, Argentina Interoception encompasses multiple dimensions and relies on widespread neural hubs. To examine neurocognitive process in such brain network, we assessed cardiac interoceptive accuracy, learning, © 2016 The Authors Journal of Neurochemistry © 2016 International Society for Neurochemistry J. Neurochem. (Suppl. 1) (2016), 222--428

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and awareness in healthy subjects and patients offering contrastive lesion models of neurodegeneration and stroke: behavioral variant frontotemporal dementia (bvFTD), Alzheimer’s disease (AD), and fronto-insular stroke. Neural correlates of the three dimensions were examined through structural and functional resting-state imaging and online measurements of the heart-evoked potential (HEP). The three patient groups presented deficits in interoceptive accuracy, associated to insular affectation, connectivity alterations, and abnormal HEP modulations. Interoceptive learning was differentially impaired in AD patients, suggesting a key role of memory skills. Interoceptive awareness results showed that bvFTD and AD patients overestimated their performance, indexed by abnormal anterior regions and associated networks engaged in to metacognitive process, and probably related to the well known insight deficits of this population. Findings specify how damage to specific hubs in a broad fronto-temporo-insular network compromises differentially interoceptive dimensions, and how such disturbances affect widespread connections beyond those critical hubs.

P69 Bilingualism effect on cognitive development in Mongolian children D. Chuluundorj1, N. Dorjpalam2, C. Begz3 1 University of the Humanities, Brain Research Laboratory, Ulaanbaatar, Mongolia 2 University of the Humanities, Department of Foreign Languages, Ulaanbaatar, Mongolia 3 University of the Humanities, Ulaanbaatar, Mongolia Bilingualism is advantageous in cognitive development and prevention of dementia. Advantages of bilingualism are well studied and not limited to improvements in cognitive flexibility, inhibition and sensitivity to language structures. Interestingly, bilinguals have a later onset of dementia in elderly, including frontotemporal dementia, as well as slower progression of the disease. Although it is well known that the earlier bilingualism is obtained, the greater it’s benefit, it is not clear how bilingualism affects cognitive function, semantic and syntactic sensitivity at younger ages. Our ongoing study aims to look at effect of bilingualism on cognitive development in Mongolian children. 39 healthy Mongolian mono- and English-Mongolian bilingual children were randomly selected from Ulaanbaatar city. Quantitative electro-encephalography method was used to collect ERP data to test word and metaphor recognition, sensitivity to semantic and syntactic violations and cognitive function (Stroop test, Switch and Operation span tasks). EnglishMongolian bilinguals showed better response to cognitive flexibility tasks, as well as in recognizing metaphor meanings which showed variability among different ages. From the other side, Mongolian monolinguals had a greater sensitivity to grammar violations in Mongolian language which can be related to their higher exposure to the native language, in comparison to bilinguals in younger children. However, this difference was not prominent in older children. Various results were also obtained in word recognition, cognitive inhibition and working memory tasks. Overall, our ongoing study suggests that bilingualism is beneficial in cognitive development of children and adopting bilingualism at young ages can be considered as a tool for prevention of dementia.

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P70 Multidimensional Apathy and Insight in Frontotemporal Lobar Degeneration and Alzheimer’s Disease R. Radakovic1,2,3,4,5, S. Colville2,4, D. Cranley2, J. Starr3,5, S. Pal2,4,6, S. Abrahams1,2,3,4,5 1 University of Edinburgh, Psychology, Edinburgh, Great Britain 2 University of Edinburgh, Anne Rowling Regenerative Neurology Clinic, Edinburgh, Great Britain 3 University of Edinburgh, Alzheimer Scotland Dementia Research Centre, Edinburgh, Great Britain 4 University of Edinburgh, Euan MacDonald Centre for MND Research, Edinburgh, Great Britain 5 University of Edinburgh, Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, Great Britain 6 University of Edinburgh, Centre for Clinical Brain Sciences, Edinburgh, Great Britain Apathy is prevalent in Frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD). Furthermore, patients’ insight of this symptom may be impaired. However, apathy is multidimensional and it is unclear which subtypes of apathy are affected in these neurodegenerative diseases. The aim was to investigate the differences in apathy subtypes between these patient groups and levels of insight. 12 patients with FTLD (and their carers) and 14 patients with AD (and their carers) participated in the study. The FTLD group was composed of behavioural variant Frontotemporal dementia (n = 9), non-fluent progressive aphasia (N = 2) and semantic dementia (n = 1). All participants and carers completed- Dimensional Apathy Scale (DAS), used to assess 3 apathy subtypes (Executive, Emotional and Initiation Apathy), Apathy Evaluation Scale (AES) and Geriatric Depression ScaleShort Form (GDS-15). In the analysis of the DAS for the FTLD group only there was a significant main effect of patient self-rating and carer-ratings (F(1,22) = 12.495, p < 0.01). Post hoc tests showed carer-rating were significantly higher than self ratings on all subscales; Executive (p < 0.05), Emotional (p < 0.01) and Executive (p < 0.05), indicating a global lack of insight in to apathy subtype. This was also confirmed by a difference on the AES (p < 0.01). No such relationship was observed in the AD group. When comparing carer-rated patient groups at a subtype level, the FTLD group scored significantly higher on Emotional apathy compared to the AD group (p < 0.05). No such difference was observed on other DAS subscales, the AES or the GDS-15. To conclude, there was an apathy subtype difference found between the FTLD and AD groups, where patients with FTLD displayed more Emotional apathy only. This manifests as indifference and emotional neutrality. Also, the FTLD (but not AD group) showed impaired insight over all apathy subtypes. Further research may investigate the development of interventions specific to these types of apathy.



P71 Do you have a strategy? multimodal signatures of social bargaining in neurodegeneration and frontal lesion M. Melloni1, T. Torralva1, P. Billeke2, S. Baez1, E. Hesse1, L. de La Fuente1, A. Birba1, I. Garcia Cordero1, A. Garcia1, nez1 L. Sede~no1, F. Manes1, A. Iba~ 1 Institute of Cognitive neurology, Neuropsychology, Buenos Aires, Argentina 2 Laboratory of Cognitive Neuroscience, Universidad del Desarrollo, Santiago, Chile Recursive social decision making requires the use of flexible, context-sensitive long-term strategies for negotiation. To succeed in social bargaining, participants’ own perspectives must be dynamically integrated with those of interactors to maximize self-benefits and adapt to the other’s preferences, respectively. This is a pre-requisite to develop a successful long-term self-other integration strategy (SOIS). While such form of strategic interaction is critical to social decision making, little is known about its neurocognitive correlates. To bridge this gap, we analyzed social bargaining behavior in relation to its structural neural correlates, ongoing brain dynamics (oscillations and related source space), and functional connectivity signatures in healthy subjects and patients offering contrastive lesion models of neurodegeneration and focal stroke: behavioral variant frontotemporal dementia (bvFTD), Alzheimer’s disease (AD), and frontal lesions (FL). All groups showed preserved basic bargaining indexes. However, impaired SOIS was found in bvFTD and FL patients, suggesting that social bargaining critically depends on the integrity of prefrontal regions. Also, associations between behavioral performance and data from voxel-based morphometry (VBM) and voxel-based lesion-symptom mapping (VLSM) revealed a critical role of prefrontal regions in value integration and strategic decisions for SOIS. Furthermore, as shown by measures of brain dynamics and related sources during the task, SOIS was predicted by anticipatory activity (alpha/beta oscillations with sources in fronto-temporal regions) associated with expectations about others’ decisions. This pattern was reduced in all clinical groups, with greater impairments for bvFTD and FL than AD. Finally, fMRI connectivity analysis highlighted a fronto-temporo-parietal network involved in successful SOIS, with selective compromise of longdistance connections in frontal disorders (bvFTD and FL). In sum, this work provides unprecedented evidence of convergent behavioral and neurocognitive signatures of strategic social bargaining in different lesion models. Our findings offer new insights into the critical roles of frontal hubs and associated temporo-parietal networks for strategic social negotiation.

P72 Changing the artistic experience in Behavioral variant of Frontotemporal Dementia C. Boutoleau-Bretonniere1,2, C. Bretonni ere3, C. Evrard1, L. Rocher1, A. Mazzietti2, O. Koenig2, M. Vercelletto1, erion2,4 P. Derkinderen1, C. Thomas-Ant 1 CHU Nantes, CMRR, Nantes, France 2 Universite Lyon 2, Laboratoire d’etudes des mecanismes cognitifs, EA 3082, Bron, France 3 Universite de Nantes, EA 3826, Nantes, France 4 Plein ciel, Lyon, France Introduction: Patients with behavioral variant of frontotemporal dementia (bvFTD) have an early change in the emotional

processing. The aesthetic experience of art is a window into the study of emotions. Methods: We designed a computerized task using 32 abstract paintings in order to assess the aesthetic judgment, emotional relevance, emotional valence and emotional reaction in patients and control subjects. BvFTD patients also underwent a set of tests assessing cognitive functions and behavior. Results: Fifteen patients with bvFTD and 15 controls were included. The bvFTD patients were less affected by the paintings than controls and they found the paintings more often ugly and unpleasant than controls. Valence and aesthetic judgments correlated in both groups. They also preferentially chose the “sad” adjective. A higher score for behavioral assessment was significantly linked to reduced emotional feeling, ugliness judgment and negative valence. MMSE score was linked to ugliness aesthetic judgment. Discussion: Our results suggest that patients can give an aesthetic judgment but they have difficulties in terms of emotional processes with the loss of the ability to feel the emotion in front of art, linked notably to behavioral disorders. They have also difficulties, as spectators, in the cognitive processes involved, like executive functions and the ability to make abstraction. This approach contributes to a better understanding of interactions between emotions and behavior disorders. It could also be applied in the psychosocial field to improve the interface between care of FTD patients and their subjective needs.

P73 Distinct neuropsychiatric subtypes of behavioural variant FTD have different functional profiles C. M. O’Connor1, L. Clemson1, C. Kaizik2, N. Daveson2, J. R. Hodges2,3,4, S. Hsieh2,4,5, O. Piguet2,3,4, E. Mioshi6 1 University of Sydney, Ageing, Work & Health Research Unit, Sydney, Australia 2 Neuroscience Research Australia, Sydney, Australia 3 University of New South Wales, School of Medical Sciences, Sydney, Australia 4 University of New South Wales, ARC Centre of Excellence in Cognition and its disorders, Sydney, Australia 5 University of Sydney, Brain and Mind Research Centre, Sydney, Australia 6 University of East Anglia, Faculty of Medicine and Health Sciences, Norwich, Great Britain This study investigated functional differences between apathetic and disinhibited phenotypes of bvFTD, and explored if specific behavioural subtypes would present with greater disability or have worse prognosis. It was hypothesised that severe apathy would contribute to more functional disability, and to a more rapid progression to death, than would a more mildly apathetic or severely disinhibited profile. Eighty-eight patients with bvFTD recruited by the FRONTIER Research Group (Sydney, Australia) between November-2007 and June-2015 were included. Disinhibited and apathetic behaviours were measured with the Cambridge Behavioural Inventory Revised (CBI-R), function was assessed with the Disability Assessment for Dementia (DAD), and cognition was evaluated with the Addenbrooke’s Cognitive Examination Revised (ACE-R). A two-step cluster analysis using Akaike’s information criterion (AIC) generated four patient subgroups (data driven), labelled to reflect behavioural symptoms: “Primary severe apathy”; “Severe apathy and severe disinhibition”; “Mild apathy and mild


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disinhibition”; and “Primary severe disinhibition”. These subgroups differed in every area of everyday function measured: global ADLs (X2(3) = 14.753, p < 0.005), basic ADLs (X2(3)=11.719, p < 0.01), instrumental ADLs (X2(3) = 13.236, p < 0.005), and the three subcomponents of activity performance: initiation (X2(3) = 16.068, p < 0.005), planning (X2(3)=9.957, p < 0.05) and execution (X2(3)=10.391, p < 0.05). Post hoc analyses revealed that people with severe apathy were more functionally disabled than those with mild apathy. In comparison, patients with a primarily disinhibited presentation and more mild apathy retained some functional abilities, and tended to have better cognitive scores. Paradoxically, there were no functional differences between the “primary severe apathy” and “primary severe disinhibition” groups, suggesting apathy and disinhibition are not the sole factors contributing to functional impairment in bvFTD. Finally, no differences in survival were found between the four behavioural phenotypes. This study supports the existence of distinct bvFTD phenotypes (a gradient of apathetic and disinhibited presentations), and these subgroups differ in their disability, but not in survival.

P74 Neural basis of motivational approach and withdrawal behaviors in neurodegenerative disease S. Shinagawa1,2, A. Babu2, V. Sturm2, T. Shany-Ur2, P. Toofanian Ross2, P. Poorzand2, S. Grossman2, B. Miller2, K. Rankin2 1 Jikei University, Department of Psychiatry, Tokyo, Japan 2 University of California, San Francisco, Memory and Aging Center, Department of Neurology, San Francisco, United States Introduction: The Behavioral Inhibition System (BIS) and the Behavioral Acti- vation System (BAS) have been theorized as neural systems that regulate approach/withdrawal behaviors. Behavioral activation/inhibition balance may change in neurodegenerative disease based on underlying alterations in systems supporting motivation and approach/withdrawal behaviors, which may in turn be reflected in neuropsychiatric symptoms. Method: A total of 187 participants (31 patients diagnosed with behavioral variant of FTD [bvFTD], 13 semantic variant of primary progressive aphasia [svPPA], 14 right temporal variant FTD [rtFTD], 54 Alzheimer’s disease [AD], and 75 older healthy controls [NCs]) were included in this study. Changes in behavioral inhibition/activation were measured using the BIS/BAS scale. We analyzed the correlation between regional atrophy pattern and BIS/BAS score, using voxelbased morphometry (VBM). Results: ADs had significantly higher BIS scores than bvFTDs and NCs. bvFTDs activation-reward response (BAS-RR) was significantly lower than ADs and NCs, though their activation-drive (BAS-D) was significantly higher than in ADs. Both AD and rtFTD patients had abnormally low activation fun- seeking (BAS-FS) scores. BIS score correlated positively with right anterior cingulate and middle frontal gyrus volume, as well as volume in the right precentral gyrus and left insula/operculum. Conclusions: AD, bvFTD, and rtFTD patients show divergent patterns of change in approach/withdrawal reactivity. High BIS scores correlated with preservation of right-predominant structures involved in task control and self-protective avoidance of potentially negative reinforcers. Damage to these regions in bvFTD may create a punishment insensitivity that underlies patients’ lack of selfconsciousness in social contexts.

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P75 Categorization impairment in bvFTD, PSP and AD B. Garcin1,2, E. Volle1, A. Funkiewiez2, N. Defoor2, B. Dubois1,2, R. Levy1,2 1 Brain and Spine Institute ICM, Frontlab, Paris, France 2 Institut de la memoire et de la maladie d’Alzheimer IMMA, Paris, France Patients with neurodegenerative diseases affecting the frontal lobe have difficulties in categorization tasks, such as the similarity task: they often fail to answer “they are fruits” to the question: “In what way are an orange and a banana alike?” The objective of our study was to characterize the deficit of frontal patients in categorization, and to develop a short diagnostic tool to target the specific difficulties of these patients. For this purpose, we analyzed the responses provided by frontal and nonfrontal neurodegenerative patients as well as healthy subjects in a new verbal similarity task. We built a similarity task based on 27 pairs of taxonomically related words. The instruction was: “what is the similarity between a ___ (e.g:banana) and a ____(e.g:orange). We included 34 frontal patients with probable or definite behavior variant fronto-temporal dementia (bvFTD, n = 14) and progressive supranuclear palsy (PSP, n = 20), 18 patients with probable Alzheimer’s disease (AD), as well as 34 healthy controls matched for age, sex, and education. Responses that did not correspond to the expected semantic category (e.g: fruits) were considered as errors. Frontal patients (bvFTD:67% errors, PSP:56% errors) and AD patients (29% errors) were significantly impaired as compared to controls (9,9% errors). More than half of frontal patients’ errors (bvFTD: 62%; PSP:42%) consisted in the description of the differences between the items: “one is yellow, the other is orange”. The number of errors characterized as “differences” was correlated with the severity of the frontal syndrome. This type of errors was not observed in controls or in AD patients, suggesting that it could discriminate FTD from AD patients. A short version of the test is proposed as a diagnostic tool to differentiate FTD from AD.

P76 So close yet so far: executive contribution to memory processing in behavioural variant frontotemporal dementia M. Bertoux1, S. Ramanan2, A. Slachevsky3, C. Delgado3, F. Henriquez3, G. Musa3, F. Lamari4, M. Bottlaender5, M. Sarazin6, M. Hornberger1, B. Dubois4 1 University of East Anglia, Bob Champion Research and Education Building, Norwich Medical School, Norwich, Great Britain 2 Manipal Hospitals, Department of Neurology, Bangalore, India 3 University of Chile, Santiago, Chile 4 Sorbonnes Universites, Paris, France 5 Commissariat a l’Energie Atomique, NeuroSpin, Saclay, France 6 Sainte-Anne, Centre Psychiatrie & Neurosciences, Paris, France For a long time memory impairment in bvFTD patients was considered to be mild and attributed to prefrontal cortex (PFC) dysfunction. However, an increasing number of studies have shown that some bvFTD patients can present with severe memory/ hippocampal impairment, showing storage and consolidation deficit in addition to the more executive/prefrontal encoding and strategic difficulties. This study aimed to study the relationship between



executive functions (EF) and memory processes in bvFTD via a data-driven approach. Participants consisted of 71 bvFTD (60.6% having biomarker evidences of diagnosis) and 60 controls (45% having amyloid imaging showing negative amyloid deposition). EF were assessed by the Frontal Assessment Battery, semantic/lexical verbal fluency tests and forward/backward digit spans. Patients were split into amnestic (n = 33) and non-amnestic (n = 38) subgroups based on normative data of the Free and Cued Selective Reminding Test (FCSRT). Relationship between FCSRT subscores and EF measures were explored through a hierarchical clustering analysis, partial correlation analysis with an EF component and an automated linear modelling. Convergent findings across the statistical approaches show that, overall, memory performance was independent from EF in both bvFTD subgroups whereas the relationship was stronger in controls. Indeed, in bvFTD, memory processes did not cluster with EF, were not correlated with the EF component and only a small amount (4–12.7%) of memory performance was predicted by EF. Importantly, this result was similar in both amnestic and non-amnestic subgroups of bvFTD. By contrast, most of the FSCRT subscores were related to EF in controls, although only partially. Our findings confirm previous investigations by showing that some bvFTD patients can present with a pure episodic amnesia affecting not only encoding and retrieval processes but also memory storage and consolidation abilities. It also suggests that executive dysfunctions cannot solely explain the memory deficits occurring in bvFTD.

P77 Apathy and impulsivity in frontotemporal lobar degeneration syndromes C. Lansdall1, I. T. S. Coyle-Gilchrist1, P. V azquez Rodrıguez1, 2 1 3 E. Wehmann , A. Wilcox , K. M. Dick , P. S. Jones1, K. Patterson1, J. B. Rowe1 1 University of Cambridge, Cambridge, Great Britain 2 University Medical Centre Eppendorf, Hamburg, Germany 3 University College London, Dementia Research Centre, London, Great Britain Apathy and impulsivity are common and disabling consequences of frontotemporal lobar degeneration (FTLD) disorders. These behavioural changes often coexist, although their aetiology remains elusive. We aimed to determine the relationship between apathy and impulsivity and identify their underlying dimensions across FTLD syndromes. The PiPPIN study recruited 204 FTLD patients and 50 controls. Participants underwent an extensive assessment battery, combining patient, carer and physician questionnaires and behavioural tasks. We derived dimensions of apathy and impulsivity using a principal component analysis on a subset of 199 patients and controls. Eight principal components were identified, separating patient-rated questionnaires, carer-rated questionnaires and behavioural tasks. Apathy and impulsivity measures frequently loaded onto the same components, suggesting they overlap in their underlying mechanisms. Behavioural tasks and questionnaires correlated poorly, with direct implications for translational studies. Furthermore, carer and patient ratings loaded onto separate components, highlighting differences in recognition of behavioural change. We suggest that loss of patient insight and increased carer distress contribute to this effect. This dimensional approach indicates common components of apathy and impulsivity, which are differentially sensitive to behavioural tasks, patient and carer ratings. We

propose that evaluating dimensions observed across neurodegenerative disorders may help to identify novel treatment targets, synergistic with the National Institute of Mental Health’s Research Domain Criteria (‘RDoC’) approach to psychiatric symptomatology. Therapies will offer a broader impact if they are relevant for several different diagnoses.

P78 Fronto-striatal correlates of behavioural disturbances in behavioural-variant frontotemporal dementia M. Bertoux1, E. Flanagan1, O. Piguet2, J. Hodges2, M. Hornberger1 1 University of East Anglia, Bob Champion Research and Education Building, Norwich Medical School, Norwich, Great Britain 2 Neuroscience Research Australia, Sydney, Australia Patients with behavioural-variant frontotemporal dementia (bvFTD) show substantial fronto-striatal atrophy affecting the ventral and the dorsolateral prefrontal cortices (PFC) as well as the connected striatal sub-regions, but so far, it is unclear to which extent it can explain the observed behavioural symptomatology. This study aimed to investigate the contributions of these frontostriatal networks to bvFTD behavioural symptomatology. Correlations (pFDR< 0.05) between the Cambridge Behavioural Inventory (CBI) subscores and fronto-striatal degeneration were explored in 23 bvFTD patients who underwent a T1 whole brain MRI. Voxel-based morphometry correlations were performed with FSL using masks of PFC and sub-striatal regions segmented according to their whitematter connectivity (using the Oxford-GSK-Imanova Striatal Connectivity Atlas), resulting in ventral, anterior-dorsal and posteriordorsal fronto-striatal networks. CBI’s abnormal behaviours covaried with atrophy in the ventral network. Eating disturbances and motivation deficit covaried with bilateral ventral and anterior dorsal fronto-striatal networks, as well as with the posterior dorsal PFC. Self-care decrease and stereotypic behaviours covaried with the atrophy of the ventral fronto-striatal network as well as the anterior and posterior PFC. Partial correlations were then explored, with either striatal or PFC grey matter intensity being considered a nuisance variable in the model. These analyses revealed that whilst behavioural symptoms are related to both striatum and PFC atrophy, the latter region has the greater contribution, except for abnormal behaviour. These findings show that whilst striatal and PFC atrophy contribute to behavioural symptoms in bvFTD, their severity appears to be related predominantly to PFC atrophy.

P79 The brain network abnormalities underlying apathy and impulsivity in frontotemporal lobar degeneration C. Lansdall1, I. T. S. Coyle-Gilchrist1, P. V azquez Rodrıguez1, 2 1 3 E. Wehmann , A. Wilcox , K. M. Dick , P. S. Jones1, K. Patterson1, J. B. Rowe1 1 University of Cambridge, Cambridge, Great Britain 2 University Medical Centre Eppendorf, Hamburg, Germany 3 University College London, Dementia Research Centre, London, Great Britain Apathy and impulsivity cause substantial patient morbidity and carer distress in frontotemporal lobar degeneration (FTLD) associated disorders. They are recognised as multifaceted constructs that


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often coexist, although the neural mechanisms underlying their overlap remain unknown. Symptomatic therapies for apathy and impulsivity will become increasingly important as disease modifying treatments are developed to slow progression. We aimed to identify the neural correlates of apathy and impulsivity components, extracted from a principal component analysis on data from the PiPPIN study of FTLD disorders. Voxel based morphometry (VBM) analysis of T1-weighted MRI images was conducted on a subset of 100 FTLD patients and controls. Eight extracted components were employed in volumetric analyses of grey and white matter in SPM12. VBM revealed corticospinal tract changes in proportion to the patient rated apathy/impulsivity component. We propose that this reflects preserved patient awareness of disease-related motor deficits, while insight into cognitive decline is limited. In contrast, carer rated components were associated with changes in frontostriatal circuits and brain stem systems. We suggest that these associations reflect underlying changes in social, affective and motivational functions. This dimensional approach provides new insights into the neural basis of apathy and impulsivity in FTLD. Our data indicate common overlapping components related to corticospinal, thalamic and frontostriatal systems which are, however, differentially sensitive to objective tests, patient and carer ratings.

P80 Loss of white matter connectivity related to apathy and impulsivity in frontotemporal lobar degeneration disorders C. Lansdall1, I. T. S. Coyle-Gilchrist1, P. V azquez Rodrıguez1, E. Wehmann2, A. Wilcox1, P. S. Jones1, K. Patterson1, J. B. Rowe1 1 University of Cambridge, Cambridge, Great Britain 2 University Medical Centre Eppendorf, Hamburg, Germany Frontotemporal lobar degeneration (FTLD) results in progressive atrophy of the frontal and temporal lobes and encompasses a spectrum of syndromes including the behavioural and language variants of frontotemporal dementia, progressive supranuclear palsy and corticobasal syndromes. White matter (WM) changes on MRI have been described in the FTLD variants, however, diffusion tensor imaging (DTI) of WM tracts offers potential insights into the neural basis of behavioural changes over and above its ability to differentiate syndromes. We aimed to identify the WM correlates of apathy and impulsivity across FTLD syndromes, using DTI at 3T (963 directions) in 100 patients and controls from the PiPPIN study. Tract-based spatial statistics was used to correlate fractional anisotropy (FA) with the principal components (PC) derived from a neuropsychological and behavioral battery assessing apathy and impulsivity. Carer rated changes in apathy/everyday skills (PC2) and impulsivity/abnormal behaviours (PC3) were associated with widespread bilateral WM changes in frontal, temporal and parietal tracts. Behavioural tests of apathy and impulsivity (PC4: motor and saccade Go/NoGO tasks, information sampling task and cued reinforcement reaction time task) correlated with FA changes in the anterior corpus callosum, and WM tracts connecting orbitofrontal and frontopolar cortex. We have proposed that efforts to target effective symptomatic treatments should adopt a dimensional approach, consistent with the recent NIMH ‘RDoC’ initiative. The current study supports this approach and provides evidence of diffuse structural network changes associated with the neurobehavioural components of apathy and impulsivity across FTLD associated disorders.

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P81 Cognitive profile in the C9ORF72 expansion related frontotemporal lobar degeneration N.-M. Suhonen1,2, R. M. Haanp€ a€ a3, T. H€ anninen4, A. M. Remes3,4 1 Oulu University Hospital, Neurology, Oulu, Finland 2 University of Oulu, Unit of Clinical Neuroscience, Neurology, Oulu, Finland 3 University of Eastern Finland, Institute of Clinical Medicine, Neurology, Kuopio, Finland 4 Kuopio University Hospital, Neurology, Kuopio, Finland The hexanucleotide expansion in chromosome 9 open reading frame 72 (C9ORF72) has been found to be a major cause of FTLD, especially in Finnish patients (Majounie et al. Lancet Neurol 2012; 11(4) 323–330). Neuropsychological testing is considered to be an important method for identifying FTLD subgroups and discriminating the syndrome from other types of dementia. However, there is very little knowledge of the neuropsychological profile associated with the C9ORF72 expansion. The aim of this study is to investigate the cognitive performance in FTLD patients carrying the C9ORF72 expansion compared to non-carrier FTLD patients. The study population consisted of 20 FTLD patients tested to be the C9ORF72 expansion carriers and 20 non-carrier FTLD patients from two memory outpatient clinics in Finland (Oulu University Hospital and Kuopio University Hospital). All of the patients had undergone clinical neuropsychological examinations, including tests of memory, executive functions, language, visuospatial abilities and psychomotor speed. There were no significant differences between the groups on age, educational level or MMSE scores (mean 23/30). The preliminary results showed that the C9ORF72 expansion carriers performed better than non-carriers on logical memory test but worse on phonemic verbal fluency test and the Rey-Osterrieth Complex Figure Test (ROCFT). The expansion carriers also made more errors in the Stroop Test than non-carriers. Phonemic fluency, the ROCFT and the Stroop Test are all measures of different aspects of executive functioning. In addition, the finger tapping test was slower in the expansion carrier group. In conclusion, our results suggest that the C9ORF72 expansion carriers may have less severe memory problems but more pronounced executive deficits and slower psychomotor speed than non-carrier FTLD patients.

P82 Frontotemporal dysfunction in elderly patients with bipolar disorder Y. Kalyn1, E. Shipilova1, I. Roshchina1, Y. Vologdina1, T. Safarova1 1 Mental Health Research Centre, Geriatric Psychiatry, Moscow, Russian Federation Objective: A study to correlate mood disorders and the dysfunction of frontotemporal brain regions in elderly patients with bipolar disorder. Methods: psychopathological, psychometrical and neuropsychological assessment according to Luria’s method. Cohort: 51 in-patients (31 men and 20 women) of the psychogeriatric unit of FMHRC with bipolar disorder were diagnosed according to ICD-10. Patients’ average age was 70.5 years. Average MMSE score was 27.5 1.5 points. The majority of patients (80.4%, n = 40) had depressive episodes, predominantly adynamic depression with apathy and apathetic



depression with anxiety. In 11 cases (19.6%) we observed hypomanic states. Results: In patients with depressive episodes (1st group) apathy, adynamia, anhedonia, decreased activity of daily living down to partial loss of self-care skills, grief, anxiety, hypochondria, selfblame, suicidal ideations, lack of appetite and insomnia were mostly dominant. Hypomanic states (2nd group) were presented by thought acceleration, motor excitement, circumlocution, disinhibition, lack of attention concentration, lack of sleep requirements, socially unacceptable behavior, dysphoria, aggression, non critical thinking, attractions towards alcohol and benzodiazepines. In neuropsychological investigation left hemispherical (frontal and temporal) impairment was more common for depressive elderly patients with BD: complexities of attention concentration, retention and development of self-performance programme, increasing latent period during actualization of tasks, inertia of mental process, disturbances of dynamic praxis, tendency to micrography, reduction of nominative speaking functions, selectivity mistakes in auditory and verbal memory, exhaustibility of mental activity. Dysfunction of right hemispherical frontal brain region was more common in patients with hypomanic episodes: voluntary regulation decreased as a result of selection disturbances of mental process, impulsivity of action, elements of field behavior, echolalia, reduction of random memory acquision, non critical self-assessment of current state and trial outcomes.

P83 Looking but not seeing: Understanding emotional face perception in behavioural-variant frontotemporal dementia R. Hutchings1, R. Palermo2, J. Bruggemann3, J. Hodges1, O. Piguet1, F. Kumfor1 1 Neuroscience Research Australia, Randwick, Australia 2 University of Western Australia, Crawley, Australia 3 University of New South Wales, Kensington, Australia Faces offer an incredible wealth of information for social interactions. Emerging evidence suggests that some clinical groups (e.g., autism) who show impaired emotion recognition do not attend appropriately to parts of the face that display emotion (e.g., eyes). Behavioural-variant frontotemporal dementia (bvFTD) is characterised by changes in social behaviour and personality. Existing evidence has shown that bvFTD patients have deficits in labelling facial expressions. Whether inappropriate facial scanning contributes to impaired facial expression recognition in bvFTD is unknown. Here, we employed eye-tracking to investigate whether bvFTD patients show different patterns of facial scanning compared to controls. Twenty bvFTD participants and 20 healthy, agematched controls were presented with 8 fearful, 8 happy and 8 neutral faces over 72 trials. Dwell time was recorded while participants passively viewed each face for 3 s. Across all trials, dwell time on the whole face did not differ between groups (p = 0.42). However, bvFTD patients spent a longer dwell time on the eyes compared to controls (p = 0.0497), averaged across emotions. When individual emotions were examined, bvFTD participants showed longer dwell time on the eyes for fear trials only (p = 0.03). Interestingly, dwell time on the eyes during fear trials significantly correlated with expression labelling accuracy in controls (r = 0.41, p = 0.04), but not in bvFTD (r = 0.14, p = 0.29). These results indicate that despite looking at emotionally

relevant face regions, bvFTD patients are unable to interpret emotional cues from facial expressions. Our results provide impetus for further investigation into the mechanisms of face and emotion processing in bvFTD.

P84 Should I trust you? Learning and memory of socially relevant information in dementia S. Wong1, C. O’Callaghan2, F. Kumfor1, G. Savage3, J. Hodges1, O. Piguet1, M. Hornberger4 1 Neuroscience Research Australia, Randwick, Australia 2 University of Cambridge, Behavioural and Clinical Neuroscience Institute, Cambridge, Australia 3 ARC Centre of Excellence in Cognition and its Disorders, Sydney, Australia 4 University of East Anglia, Norwich Medical School, Norwich, Great Britain Interpersonal trust can be learned through evaluating the outcomes of repeated social interactions with others. The enhancing effect of social relevance on learning and subsequent memory retrieval is well established in healthy adults. While both Alzheimer’s disease (AD) and behavioural-variant frontotemporal dementia (bvFTD) patients show deficits in learning and memory, it is unclear whether these patient groups show the typical memory advantage for socially relevant information. In the current study, AD (n = 13) and bvFTD (n = 17) patients and age-matched healthy controls (n = 22) played a computerised ‘trust game’, where they invested virtual money with individuals who acted either in a trustworthy or untrustworthy manner over repeated interactions. In the neutral condition, no trust-related interaction took place. Subsequently, participants’ memory for the faces of individuals encountered during the ‘trust game’ was assessed using a forcedchoice recognition test, followed by a source memory test for whether the face was encountered in the trustworthy, untrustworthy or neutral condition. Relative to controls, both patient groups showed slower learning of trustworthy/untrustworthy responses throughout the ‘trust game’. Subsequent memory for the faces and associated behaviours of the trustworthy and untrustworthy counterparts was also reduced in patients. Similar to controls, however, both AD and bvFTD patients showed significantly better memory for both trustworthy and untrustworthy compared to neutral counterparts. While learning and source memory for socially relevant information was attenuated in both AD and bvFTD, both patient groups retained a significant social relevance enhancement effect on memory retrieval. Our findings provide further insights regarding interactions between social cognition and memory. Future analyses are planned to investigate correlations with social behaviour in everyday life, as well as neural correlates of social memory in these dementia syndromes.


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P85 Motivated to remember? modulation of value-based learning and memory in dementia S. Wong1, G. Savage2, J. Hodges1, O. Piguet1, M. Hornberger3 1 Neuroscience Research Australia, Randwick, Australia 2 ARC Centre of Excellence in Cognition and its Disorders, Sydney, Australia 3 University of East Anglia, Norwich Medical School, Norwich, Great Britain The ability to prioritize memory for information according to its relative value is important for maximizing memory efficiency. Evidence from healthy older adults indicates that such value-based strategic encoding enhances subsequent memory retrieval for higher valued stimuli. While both behavioural-variant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD) patients show deficits in learning and memory, it is unclear whether these patient groups show a typical memory bias for higher valued stimuli. In the current study, we administered a novel word-list learning task to bvFTD (n = 17) and AD (n = 12) patients and age-matched healthy controls (n = 17). Each word was assigned a low, medium or high point value and participants were instructed to maximize the number of points earned across three successive learning trials. Subsequently, participants’ memory for the words was assessed on a delayed recall trial, followed by an item and source recognition memory test for the words and corresponding point values. In line with previous studies, both patient groups showed impaired learning and delayed recall of items relative to controls. Across the learning trials, controls and AD patients recalled more high value items than low value items, whereas bvFTD patients did not show preferential recall of high value items. While subsequent item and source recognition accuracy was lower in both bvFTD and AD compared to controls, both patient groups showed a significant value-based enhancement effect in recognition memory. Our findings point to a potential disconnection between memory for value-based information and the ability to apply this in a motivationally-salient context in bvFTD. Future analyses are planned to investigate correlations with executive function, as well as neural correlates of value-based memory in these dementia syndromes.

P86 The Awareness of Social Inference Test (TASIT): Application of a short version of the TASIT for the clinical diagnosis of behavioural-variant frontotemporal dementia F. Kumfor1,2,3, C. Honan4, J. Hazelton1, J. R. Hodges1,2,3, S. McDonald5, O. Piguet1,2,3 1 Neuroscience Research Australia, Randwick, Sydney, Australia 2 University of New South Wales, School of Medical Sciences, Sydney, Australia 3 ARC Centre of Excellence in Cognition and its Disorders, Sydney, Australia 4 University of Tasmania, School of Psychology, Launceston, Australia 5 University of New South Wales, School of Psychology, Sydney, Australia Assessment of social cognition is increasingly recognised as an important component towards an accurate clinical diagnosis of behavioural-variant frontotemporal dementia (bvFTD). It is also helpful for differentiating bvFTD from typical Alzheimer’s disease

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(AD). Surprisingly, however, few validated clinical instruments to assess social cognition exist, and, when available, these tests typically focus on facial emotion recognition only. The Awareness of Social Inference Test (TASIT) assesses the ability to interpret basic emotions as well as sincere and sarcastic interactions, using ecologically valid video vignettes. While it has shown good sensitivity to detect bvFTD, its lengthy administration has limited the translation of the TASIT to the clinic. This study investigates the new short version of the TASIT - the TASIT-S - in 25 bvFTD patients compared with 23 AD patients and 25 healthy controls. The TASIT-S was recently developed based on data from an acquired brain injury population using Rasch analysis and confirmatory factor analysis to reduce the number of items, while maintaining the structure of the original TASIT. Here, we focused on Part 1 (Emotion Evaluation - 10 trials) and Part 2 (Social Inference - 9 trials), which is further divided into “Sincere (4 trials)” and “Sarcastic (5 trials)” exchanges. On Part 1, both bvFTD and AD groups were impaired when compared with controls (both p values < 0.001). After controlling for cognitive impairment, as measured by Addenbrooke’s Cognitive Examination-Revised (ACE-R), however, only bvFTD were impaired (p = 0.034), whereas the AD group was not significantly different from controls (p = 0.492). On Part 2, both bvFTD and AD group performed within normal limits in their ability to interpret sincere exchanges (both p values > 0.05). Importantly, however, the bvFTD group was impaired in the interpretation of sarcastic exchanges (p = 0.004), whereas again AD performed within normal limits (p = 0.477), even after accounting for cognitive ability. These results confirm the utility of the TASITS in identifying social cognition impairment in bvFTD. The test is much shorter than the original TASIT (administration time ~20 mins) and should be included in the clinical assessment when considering a differential diagnosis of bvFTD.

P87 Changes in sexual behaviour and intimacy in frontotemporal dementia: impact on spousal carers. C. Kaizik1, R. Ahmed1,2,3,4, C. O’Connor5, E. Mioshi6, O. Piguet1,3,7, J. Hodges1,3,7 1 Neuroscience Research Australia, Frontier Research Group, Randwick, Australia 2 The University of New South Wales, Prince of Wales Clinical School, Sydney, Australia 3 The University of New South Wales, ARC Centre of Excellence in Cognition and its Disorders, Sydney, Australia 4 The Univesity of Sydney, The Brain and Mind Research Institute, Sydney, Australia 5 The University of Sydney, Faculty of Health Science, Sydney, Australia 6 The University of East Anglia, Faculty of Medicine and Health Sciences, Norwich, Great Britain 7 The University of New South Wales, School of Medical Sciences, Sydney, Australia Frontotemporal dementia (FTD) is characterised by prominent behavioural changes, known to contribute to carer burden and depression. This study examines the impact of changed sexual behaviour on depression, anxiety, stress and overall burden in spousal carers. The Sexual Behaviour and Intimacy Questionnaire (SIQ), designed to assess change in sexual function across multiple domains and record presence of hypersexual/aberrant behaviours,



(e.g. new interest in pornography, new sexual interest in another person or uncharacteristic sexual comments/advances) was administered to 81 spouses of participants with dementia (37 behavioural variant [bvFTD], 14 semantic dementia [SD], 30 Alzheimer disease [AD]). Carer burden and emotional state were evaluated using Zarit Burden Interview (ZBI) and the short version of Depression, Anxiety and Stress Scale (DASS 21). Comments from carers regarding changes were collected anda thematic analysis of these conducted. Decreased sexual interest was reportedin 81% of bvFTD, 86% of SD and 70% of AD participants. Overall, decreased sexual interest correlated with higher scores on ZBI(rs = 0.336, p = 0.002) and on DASS 21 anxiety subscore (rs = 0.241, p = 0.03). Presence of aberrant sexual behaviour occurred in a minority of cases (34% bvFTD, 29% SD, 7% AD) and correlated with higher scores on ZBI (rs = 0.280, p = 0.01) and higher scores on each DASS subscore (D: rs = 0.291, p = 0.008; A: rs = 0.220, p = 0.047; S: rs = 0.268, p = 0.015). While this study indicates an association between hypersexual/aberrant behaviours and carer distress, results also indicate the impact that decreased sexual interest may have on spouses’ emotional wellbeing. Themesof ‘grief/loss’ and ‘changed role’ that emerged from spouses’ comments also highlight the impact for spousal carers.

P88 Neurodegeneration With Brain Iron Accumulation Can Mimic Frontotemporal Dementia A. Evlice1, H. Bozdemir1, K. Aslan1 1 Cukurova University Faculty of Medicine, Neurology, Adana, Turkey Here is described a case of neurodegeneration with brain iron accumulation (NBIA) presenting as frontotemporal dementia (FTD). A male patient presented at age 38 with change of personality: disinhibition, socially inappropriate behavior. His two brothers were diagnosed as dementia. One of them died because of rapidly progressive dementia at age 42 and the other one is a live. Apathy, bradimimi, hypophonia, palilali, spactic laughing, resting and postural tremor were observed on neurological examination of our case. Neuropsychologic performance was globally reduced especially executive functions (Minimental state examination 24/30, frontal assesment battery 9/18, clock drawing test 6/10, semantic fluency 6). Magnetic resonance imaging showed general cortical atrophy, and mild iron deposits in bilateral globus pallidus. Electromyoneurography showed signs of chronic neurogenic motor unit potentials especially in the upper extremities. Paroxysms of slow activity at bilateral parieto-occipital areas and diffuse ground arrhythmia were observed on electroencephalography. The patient was diagnosed with NBIA but fulfilled consensus criteria for FTD. Our finding suggest that NBIA should be considered for differential diagnosis of FTD.

P89 Behavioral variant frontotemporal dementia can be conceptualized and individually predicted with metaanalyses & pattern classification of imaging data M. Schroeter1, S. Meyer1, J. Neumann1, A. Laird1, K. Mueller1, M. Otto1 1 Max Planck Institute for Human Cognitive & Brain Sciences, Cognitive Neurology, Leipzig, Germany Recently, new diagnostic criteria suggested imaging biomarkers for behavioral variant frontotemporal dementia (bvFTD) (Rascovsky et al. Brain 2011;134:2456–77). Imaging criteria were validated by conducting quantitative anatomical likelihood estimate meta-analyses across studies published in the literature. Analyses were conducted separately for atrophy measured with magnetic resonance imaging (MRI) and glucose metabolism measured with [F18] fluorodeoxyglucose positron emission tomography (FDG-PET). Both imaging methods revealed specific regional patterns for MRI and FDG-PET in the frontal lobes and basal ganglia (Schroeter et al. Neuroimage 2007; 36:497–510, Neurobiol Aging 2008;29:418–26, Cortex 2014;57:22–37). Results might open the road to methodspecific imaging criteria as already suggested for Alzheimer’s disease. Moreover, we combined the aforementioned structural meta-analyses with activation likelihood estimate meta-analyses and behavioral domain profiles to extract mental functions associated with bvFTD. This analysis in the comprehensive probabilistic functional brain atlas of the BrainMap database enabled a conceptualization of bvFTD and identified the frontomedian cortex as the most important hub in this disease (Schroeter et al. 2014 & J Neurol Neurosurg Psychiatry 2015; 86:700–1). If new imaging criteria are valid they shall enable early individual diagnosis in single patients. Accordingly, we investigated whether bvFTD might be diagnosed with cutting edge pattern classification algorithms in structural MRI data (Dukart et al. PLoS One 2011; 6:e18111, Psych Res Neuroimaging 2013;212:230–6). Support vector machine classification (SVM) enabled early individual detection of bvFTD in multicentric data from the FTLD Consortium’s study Germany. Limiting SVM classification regionally to disease-specific networks even improved discrimination accuracy. In conclusion, our results support and refine the application of imaging criteria, develop disease concepts, and suggest that pattern classification algorithms enable early individual diagnosis of bvFTD - a precondition for early intervention strategies.

P90 Neural correlates of verbal and nonverbal memory for item-item and item-location information: Evidence from semantic dementia and Alzheimer’s disease M. Dalton1,2,3, M. Hornberger3,4, J. Hodges1,3,5, O. Piguet1,3,5 1 Neuroscience Research Australia, Sydney, Australia 2 University College London, London, UK, Australia 3 ARC Centre of Excellence in Cognition and its Disorders, Sydney, Australia 4 University of East Anglia, Norwich, UK 5 University of New South Wales, Sydney, Australia Semantic dementia (SD) and Alzheimer’s disease (AD) are characterized by differential patterns of medial temporal lobe atrophy (SD: perirhinal cortex; AD: hippocampus). As such, these two dementia syndromes offer a unique clinical lesion model to


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study the specific contributions of MTL structures to associative memory. This study investigated associative memory for novel verbal (compound word pairs or word-location pairs) and nonverbal (item-item or item-location pairs) material in 10 AD and 10 SD patients (mean age = 64 years; range = 58–74 years), as well as 10 age-matched healthy controls, using a forced-choice recognition paradigm (Old/New). Participants also underwent a brain MRI to determine the relations between memory performance and integrity of the MTL structures. On the verbal associative memory task, both clinical groups were impaired to a similar degree compared with controls, with no significant difference between AD and SD. On the non-verbal associative memory task, controls outperformed SD patients, while AD tended to show a performance similar to that of controls. Voxel-based morphometry analyses showed the right perirhinal cortex to be related to item-item nonverbal memory and the left perirhinal cortex and hippocampus to be associated with memory for compound words. Verbal and nonverbal item-location recognition memory was associated with left, respectively right, posterior hippocampus and parahippocampal cortex integrity. These findings demonstrate the asymmetric involvement of left and right MTL structures during verbal and nonverbal mnemonic processes respectively.

P91 A spatial anticipation deficit is revealed by eyetracking metrics in behavioural variant frontotemporal dementia. S. Primativo1, C. Clark1, K. Yong1, J. Warren1, J. Rohrer1, S. Crutch1 1 UCL, Institute of Neurology, London, Great Britain Eyetracking technology has been widely used in cognitive psychology and neuropsychology and offers the potential to gathering important information not only about basic oculomotor measures, but also about high level cognitive functions. However, in the field of dementia research, most eyetracking studies have focused on the discrimination of diseases or syndrome subgroups on the basis of basic oculomotor metrics. In the present study we applied detailed analysis of eye movement metrics to examine a specific component of executive function, namely spatial anticipation, in an adaptation of the paper and pencil Brixton spatial anticipation test (Burgess & Shallice, 1977). Twelve behavioural variant frontotemporal dementia (bvFTD) patients, 6 semantic dementia (SD) patients and 38 age matched healthy controls were presented with a 10 9 7 matrix of white circles. On each trial a black dot moved across 7 positions within the matrix. The passage of the target dot followed 3 different patterns (straight line, zigzag, displaced zigzag). Participants were asked to press a button as soon as they saw each target, whilst their eye movements were recorded. The bvFTD, SD and control groups did not differ in terms of basic eye movement measures such as first saccade latency, time to reaching the first target of the trial and saccade velocity, suggesting that reflexive saccades were preserved. The bvFTD group of patients made fewer correct spatial anticipations to the location of the forthcoming target as compared with controls for all pattern conditions. Moreover, bvFTD patients made more erroneous anticipations compared to both SD patients and controls, suggesting a particular difficulty in anticipating subsequent events. Results suggest that eyetracking measures provide insights into not only basic oculomotor function but also specific cognitive components of executive function in bvFTD. Difficulties in correctly programming

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and executing anticipatory eye movements may provide a valuable marker of a spatial anticipation deficit in bvFTD.

P92 Autonomic and facial expressive emotional responses: relationships with disease severity and frontotemporal dementia subtypes A. Hua1, S. Lwi1, B. Miller2, R. Levenson1 1 University of California, Berkeley, Psychology, Berkeley, United States 2 University of California, Neurology, San Francisco, United States Frontotemporal dementia (FTD) refers to a group of neurodegenerative diseases that target the frontal and temporal lobes. Previous work has shown that patterns of degeneration differentiate in behavioral variant frontotemporal dementia (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), and semantic variant primary progressive aphasia (svPPA). Given distinct degeneration patterns in these FTD subtypes, changes to emotional functioning are likely to manifest differently. Although deficits in emotional functioning have been studied in FTD, few studies have utilized laboratory methods to differentiate FTD subtypes based on these emotional changes. We assessed autonomic and facial expressive aspects of emotional reactivity in the early stages of FTD, including 31 patients with bvFTD, 22 patients with nfvPPA, 30 patients with svPPA, and 23 healthy controls. Participants viewed three film clips known to elicit amusement, sadness, and disgust while emotional facial behavior and autonomic physiology were recorded. Additionally, we administered the Clinical Dementia Rating (CDR) scale, a measure of disease severity based on cognitive and functional symptoms. Analyses revealed that FTD patients had faster heart rate and faster breathing rate at rest, in addition to smaller increases in breathing rate compared to healthy controls. Specifically, patients with bvFTD had the fastest resting heart rate, and patients with svPPA had the fastest resting respiration rate and smallest increases in breathing rate. Facial expression data did not distinguish FTD patients from controls or differentiate among FTD subtypes. Smaller heart rate and breathing rate increases and less facial expressive behavior in response to the films were associated with greater disease severity. These findings indicate that autonomic physiology reflects disease severity and distinguishes FTD from controls and differentiates FTD subtypes, whereas facial behavior predicts disease severity but may not be as useful in distinguishing FTD and its subtypes at this stage of disease progression.

P93 Processing of auditory conflict in frontotemporal dementia C. Clark1, J. Agustus1, J. Nicholas1,2, C. Hardy1, C. Mummery1, J. Schott1, J. Rohrer1, S. Crutch1, J. Warren1 1 Institute of Neurology, UCL, Dementia Research Centre, London, Great Britain 2 University of London, London school of hygiene and tropical medicine, London, Great Britain A capacity to evaluate and resolve conflicting signals is fundamental to successful negotiation of complex sensory and social environments and loss of this capacity may be a generic



mechanism of impaired socio-emotional functioning in frontotemporal dementia (FTD). Here we designed a novel neuropsychological paradigm in which paired nonverbal sounds (animal and human vocalisations, man-made and natural environmental noises) were superimposed to create auditory ‘scenes’ in which the perceptual, semantic and/or emotional congruity of each pair was varied. The task was to decide whether the sounds were the same or different things (perceptual condition) or whether the sounds did or did not belong together (semantic/emotional conditions). The paradigm was administered to a cohort of patients with behavioural variant FTD (bvFTD; n = 19) and semantic dementia (SD; n = 12) and to healthy age-matched controls (n = 20). In the perceptual condition, the bvFTD group performed worse than both the control group and the SD group (which performed normally on this task). In the semantic and emotional conditions, both the bvFTD and SD groups performed worse than controls, with particular difficulty in processing incongruent sound combinations and comparable performance profiles in each patient group. bvFTD patients rated incongruent scenes as more pleasant than healthy controls. In a VBM analysis of patients’ brain MR images, grey matter correlates of patient performance were demonstrated in distributed salience and reward circuitry. Sound is a promising model paradigm with which to deconstruct generic deficits exhibited by patients with FTD when confronted by the complex, conflicting signals of daily life.

P94 Expectation and reward in frontotemporal dementia: the case of music C. Clark1,2, H. Golden1, O. McCallion1, J. Nicholas1,2, M. Cohen1, C. Slattery1, R. Paterson1, A. Foulkes1, C. Mummery1, J. Schott1, J. Rohrer1, S. Crutch1, J. Warren1 1 Institute of Neurology, UCL, Dementia Research Centre, London, Great Britain 2 University of London, London school of hygiene and tropical medicine, London, Great Britain Music is a universal stimulus that generates powerful emotion and reward in listeners based on internalised ‘rules’ and psychological expectancies; it is therefore an attractive model system for probing aberrant reward valuation in FTD syndromes. Here we addressed this issue in patients with canonical FTD syndromes [behavioural variant frontotemporal dementia (bvFTD; n = 11), semantic dementia (SD; n = 6) and progressive nonfluent aphasia (n = 8)] in relation to patients with typical Alzheimer’s disease (AD; n = 14) and logopenic aphasia (LPA; n = 5) and healthy agematched individuals (n = 22). We created short novel melodies in which cadence was manipulated such that the melodies sounded either ‘finished’ or ‘unfinished’; the task was to classify each melody as ‘finished’/’unfinished’ and rate its pleasantness. Relative to healthy controls, the AD, LPA and bvFTD groups showed less accurate labelling of melodies while the SD and LPA groups rated ‘unfinished’ melodies as more pleasing than the healthy control group. In a VBM analysis of patients’ brain MR images, significant grey matter associations with melody classification accuracy and emotion rating were identified in a fronto-temporal network including orbitofrontal cortex. Our findings suggest that musical rules and reward are differentially impaired in dementia syndromes. Music is a promising tool with which to probe the effects of dementia diseases on reward and rule-based processes that are relevant to more complex, daily life social behaviours.

P95 Longitudinal profiles of autobiographical memory retrieval in FTD A. Mothakunnel1, S. Hsieh2, R. Landin-Romero1,3, J. R. Hodges1,3,4, O. Piguet1,3,4, M. Irish1,4,5 1 Neuroscience Research Australia, Sydney, Australia 2 Brain and Mind Centre, The University of Sydney, Sydney Medical School, Sydney, Australia 3 University of New South Wales, School of Medical Sciences, Sydney, Australia 4 Australian Research Council Centre of Excellence in Cognition and its Disorders, Sydney, Australia 5 University of New South Wales, School of Psychology, Sydney, Australia Autobiographical memory (ABM) comprises recollection for events specific in time and place, accompanied by rich sensoryperceptual and emotional information. To date, no study has investigated how ABM potentially changes with disease progression in FTD. We investigated ABM retrieval in 13 frontotemporal dementia (FTD) participants (7 bvFTD; 6 sv-PPA) and contrasted their performance with that of 11 Alzheimer’s disease (AD) patients and 23 Controls. The Autobiographical Interview (AI) was used to assess retrieval of Recent (within the past 12 months) and Remote autobiographical events during free and structured probing conditions. Patients were assessed at baseline and at ~1 year follow-up. We also examined the relationship between total ABM retrieval and performance on standardised neuropsychological tests using Pearson R correlations. This allowed us to compare how ABM retrieval is affected by advancing disease severity and the potential cognitive mechanisms driving these deficits. At baseline, the FTD group was impaired relative to Controls for Remote ABM retrieval, yet scored at Control levels when recalling Recent events. In contrast, AD patients showed significant deficits across Remote and Recent time periods. At follow-up, FTD and AD patients showed comparable memory profiles, with no significant differences between recall of Remote and Recent events. Baseline total ABM retrieval in AD was associated with verbal fluency, while follow-up total ABM performance correlated with verbal fluency, semantic naming, and standardised measures of episodic memory. No significant associations were found between total ABM performance and neuropsychological test measures or indices of behavioural dysfunction in the FTD group. To our knowledge, this represents the first longitudinal investigation of ABM in FTD. Our preliminary findings emphasise that deficits in ABM become global as the disease progresses and suggest that distinct underlying cognitive processes may drive ABM impairments across different dementia syndromes.

P96 Personal space In frontotemporal dementia S. Anderl-Straub1, M. Nagl1, J. Dreyhaupt2, H.-P. M€ uller1, M. Otto1, 1 I. Uttner 1 University of Ulm, Department of Neurology, Ulm, Germany 2 University of Ulm, Department of Biometry, Ulm, Germany The behavioral variant of frontotemporal dementia (bvFTD) mainly affects the frontal lobe of the brain and is associated with proceeding disturbances in personal and social behavior. Frequently described alterations are changes in personal space perception, but systematic studies are lacking so far.


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We assessed personal space preferences in 18 bvFTD patients with solely mild cognitive impairment and 16 healthy control subjects and compared the degree of unpleasantness when the intimate distance defined as an area of 45 cm around the body is violated by intrusion of others. We expected that the preferred distances to another person depend on clinical subtype of the disease (i.e. whether disinhibition or apathy is the primary symptom of the disease). Data indicated that in contrast to healthy controls bvFTD patients vary substantially more in their preferred distance to an unfamiliar person and that this is independent from clinical subtype. In case of maximal spatial proximity, bvFTD patients rate the intrusion into their intimate distance as less uncomfortable than healthy persons. This is most significant for disinhibited patients that show reduced interpersonal distance in everyday life as rated by caregivers. We suspect that the impairment in personal space perception found in bvFTD may be a consequence of a dysfunction of a neural circuit connecting frontal areas with the amygdala.

P97 All is not lost: Positive behaviors in Alzheimer’s disease and behavioral-variant frontotemporal dementia with disease severity A. Midorikawa1,2, C. Leyton2,3,4, D. Foxe2,4, R. Landin-Romero2,4,5, J. Hodges2,4,5, O. Piguet2,4,5 1 Chuo University, Department of Psychology, Hachioji-shi, Japan 2 Neuroscience Research Australi, Sydney, Australia 3 The University of Sydney, Faculty of Health Sciences, Sydney, Australia 4 Australia Research Council Centre of Excellence in Cognition and its Disorders, Sydney, Australia 5 The University of New South Wales, Sydney, Australia, School of Medical Sciences, Sydney, Australia Dementia is associated with widespread changes in cognition and social interactions, as well as emergence of abnormal behaviour and psychiatric symptomatology. Anecdotal evidence, however, indicates that some dementia patients exhibit increased or novel positive behaviours, such as painting, increasing of activities or functions after the disease onset. Due to the lack of objective measures, the nature of these changes has not been formally investigated. This study aimed to systematically investigate these behaviours in the two most common younger-onset dementia syndromes: Alzheimer’s disease (AD) and behavioural-variant frontotemporal dementia (bvFTD). Sixty-three caregivers of patients with dementia (32 caregivers of AD patients and 31 caregivers of bvFTD patients) participated in the study. Caregivers rated the presence and frequency of positive and negative behaviour change after the onset of dementia using a novel instrument: the Hyper-sensory and Social/ Emotional Scale (HSS) questionnaire. The HSS contains three factors with two components in each factor: Sensory Factor (Hypersensitivity, Sensitivity to details), Cognitive Factor (Language related activities, Visuospatial related activities), and Social Factor (Social attitude, Music related activities). Differences across scores and ratios of increased/decreased behaviours were analysed between AD and bvFTD, at increasing disease severity. Compared with before onset, both components of Sensory Factor were significantly increased in the early and moderate disease stages. Increase in the Sensory Factor was more frequently observed in AD than in bvFTD. Whilst no significant changes in behaviours

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associated with the Cognitive Factor and Social Factor were observed, a small number of patients exhibited increased behaviours at all disease stages. We provide the first systematic investigation of novel or increased behaviours in AD and bvFTD, which has clinical implications for the management of these patients. The newly developed HSS questionnaire is a useful instrument to characterize the change and progression of positive behaviours in patients with dementia.

P98 Clinical differentiation of psychiatric disorders from behavioural variant frontotemporal Dementia: a prospective STUDY E. Vijverberg1,2, F. Gossink3, W. Krudop1, S. Sikkes1, C. Kerssens3, N. Prins1, M. Stek3, P. Scheltens1, Y. Pijnenburg1, A. Dols3 1 VUmc, Alzheimer Centre and Department of Neurology, Amsterdam, Netherlands 2 Haga Ziekenhuis, Department of Neurology, The Hague, Netherlands 3 GGZ InGeest, Department of Old Age Psychiatry, Amsterdam, Netherlands Background: The diagnostic value of clinical features and additional investigations to distinguish between psychiatric disorders (PsD) and behavioural variant frontotemporal dementia (bvFTD) is unknown. Aims: To determine the role of clinical variables and additional investigations/tests in diagnosing PsD versus bvFTD. Methods: A prospective cohort of patients with late onset behavioural disturbances was followed. Odds ratio (ORs) were calculated for baseline clinical variables and additional investigations/tests for the final 2-year-follow-up diagnosis of PsD (n = 46) versus bvFTD (n = 27). Results: Male gender (OR 5.9 CI 95% 1.3–26.0), less stereotypy (OR 0.08 CI 95% 0.02–0.34) and more depressive symptoms (OR 1.13 CI 95% 1.04–1.24) explained 86% of the variance in diagnosis of PsD versus bvFTD (Chi-test 29.4, do 3, p < 0.001). An additional 2.4% in explaining the variance in diagnosis was gained by neuroimaging (Chi-test 44.06, df 3, p < 0.001). Conclusions: We found that clinical phenotyping has the highest impact on diagnostic decision making between PsD and bvFTD, whereas neuroimaging was of only limited added value in a cohort of PsD with potential bvFTD.

P99 Music defines fMRI signatures of molecular nexopathies J. L. Agustus1, C. N. Clark1, H. L. Golden1, C. F. Slattery1, P. D. Fletcher1, J. D. Rohrer1, J. D. Warren1 1 University College London, Dementia Research Centre, Department of Neurodegenerative Disease, London, Great Britain It has been proposed that neurodegenerative disease phenotypes are defined by specific interactions between pathogenic protein and neural network characteristics: ‘molecular nexopathies’. Work in the GenFI cohort has demonstrated early structural nexopathy signatures in presymptomatic mutation carriers. However, the molecular nexopathies concept has not been widely validated and it remains unclear whether nexopathies manifest as protein-specific profiles of



network dysfunction before irreversible tissue loss occurs. Here we addressed this issue using fMRI in a cohort of patients with predictable neurodegenerative pathologies. We used music as a probe of information processing in distributed cerebral networks, building on work in basic auditory neuroscience. We studied patients with C9orf72 and MAPT mutations causing behavioural variant frontotemporal dementia (bvFTD, n = 9); semantic variant primary progressive aphasia (svPPA, n = 10), linked to TDP-C pathology; and logopenic variant primary progressive aphasia (lvPPA, n = 5) linked to Alzheimer’s disease, relative to healthy older individuals (n = 26). Separable functional network profiles of predicted molecular pathologies were identified during passive processing of specified musical signals, relative to healthy controls: auditory stimulation by music was associated with dysfunction of a fronto-parietal network in svPPA; rhythm processing was associated with dysfunction of a fronto-temporal network in TDP pathologies (svPPA, C9orf72 mutations); and semantic processing of melodies was associated with dysfunction of mesial temporal lobe in MAPT mutations, and insula and postero-medial cortex in lvPPA. These findings suggest that molecular phenotypes can be differentiated using profiles of altered network information processing, complementing structural neuroimaging signatures and potentially constituting a novel biomarker for underlying proteinopathies.

P100 Do criteria for behavioural variant frontotemporal dementia capture the cognitive and behavioural profile of ALS/FTD? J. Adams1,2, J. Thompson1,2, M. Jones1,2, J. Harris1,2, A. Richardson1,2, T. Langheinrich1,2, D. Neary1,2, J. Snowden1,2 1 University of Manchester, Greater Manchester Neuroscience Centre, Salford, Great Britain 2 Salford Royal NHS Foundation Trust, Salford, Great Britain Current diagnostic criteria for amyotrophic lateral sclerosis with accompanying frontotemporal dementia (ALS/FTD) require that patients meet legacy criteria for FTD. However, it is not known how sensitive the more recently updated consensus criteria for bvFTD, described by Rascovsky and colleagues in 2011, are in detecting frontotemporal dementia syndromes in ALS. Case notes from a retrospective cohort of patients with clinical diagnoses of bvFTD with and without ALS were assessed against current consensus criteria for bvFTD. Whilst one key behavioural criterion, apathy, was common in both groups, a number of core bvFTD features were absent in a large proportion of ALS/FTD patients. Loss of sympathy or empathy occurred rarely in ALS/FTD patients, who were also less likely than bvFTD patients to demonstrate social disinhibition. Dietary changes/altered food preferences were notably less common in ALS/FTD than in bvFTD. Interestingly, the key bvFTD neuropsychological criterion, executive dysfunction with relative preservation of memory and visuospatial skills, was met by the majority of patients in both groups, suggesting that cognitive changes may be more characteristic of ALS/bvFTD syndromes than behavioural features per se. It is relevant to consider that specific challenges in ALS/FTD may lead to differences in the reporting of behavioural changes. Physical impairments may serve to conceal potentially disinhibited behaviour and emotional changes may be attributed to a normal reaction to a life-changing diagnosis. However, it is also important to consider that there may be qualitative differences in the cognitive and behavioural profile of

bvFTD where it accompanies ALS; to date, no direct comparisons are reported in the literature. Any revised criteria should take into consideration the possibility of differences in the profile of ALS/ bvFTD from ‘pure’ bvFTD, as well as possible reporting differences in these groups.

P101 Progression in late onset frontal lobe syndrome F. Gossink1,2, E. Vijverberg2, W. Krudop2, P. Scheltens2, M. Stek1, Y. Pijnenburg1,2, A. Dols1,2 1 GGZinGeest, Neuropsychiatry, Amsterdam, Netherlands 2 VUmc, Alzheimer Center, Amsterdam, Netherlands A late onset frontal lobe syndrome (LOF) refers to a clinical syndrome associated with functional or structural changes in the frontal cortex leading to apathy, disinhibition or compulsive/ stereotypical behavior arising in middle or late adulthood. The main form of dementia presenting with a LOF is the behavioral variant of frontotemporal dementia but also other neurodegenerative diseases and psychiatric disorders can cause this syndrome. Neurodegenerative diseases are known to progress with time but also psychiatric disorders can have a progressive course with brain atrophy (neuroprogression). From a prognostic perspective, knowledge about factors predicting a progressive course is necessary. The aim of our study was twofold. First we investigated whether we could find clinical predictors for progression in LOF. Second, we studied if progression in LOF is correlated with the underlying pathology of having a neurodegenerative disease and if a lack of progression is correlated with having an underlying psychiatric disorder. In our prospective study on LOF patients, 116 patients were followed for 2 years. ‘Progressors’ were defined as those who showed progression within a period of 2 years after inclusion, as became apparent through decease, institutionalisation or progression of frontal or temporal atrophy at MRI. At baseline age, gender, symptom duration, education, medical history, family history, the presence of lateralization, gait disturbances and corticospinal tract disturbances were determined as well as scores at MMSE, FAB, SRI, FBI and MADRS. The only predictors for progression we found were being female (OR 4.16, CI 95% 1.22–14.15, p 0.02) and a higher SRI score (OR 0.30 CI 95% 0.09–0.98, p 0.046). Patients who showed progression had significantly more often a neurodegenerative disease while patients without progression turned out to have a psychiatric disorder (p

P102 Body schema processing in frontotemporal dementia R. Bond1, C. Hardy1, L. Russell1, C. Marshall1, C. Clark1, S. Crutch1, J. Rohrer1, J. Warren1 1 University College London, Dementia Research Centre, London, Great Britain Alterations of body schema and self/non-self demarcation may contribute to behavioural and neuropsychiatric symptoms in frontotemporal dementia (FTD) and there is evidence of some neuroanatomical and molecular specificity, particularly for C9orf72 mutations and in differentiating FTD from Alzheimer’s disease (AD). However, the representation of one’s own body and its relation to others have not been studied systematically in


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dementias. We addressed these issues in a cohort of patients with syndromes of FTD and AD compared with healthy age-matched individuals, using a novel neuropsychological battery in which we systematically probed levels of body schema encoding ranging from elementary tactile discrimination to cognitive self-representations and attribution of agency. Patients with FTD syndromes showed evidence of impaired tactile coding of body schema, particularly marked in association with C9orf72 mutations; while patients with AD had greater difficulty with cognitive attributions to self versus others. Body schema may constitute a novel paradigm for probing abnormalities of inter-personal and social behaviour and neuropsychiatric symptoms that are intractable to conventional assessment tools in patients with FTD and other dementias.

P103 Vascular Frontotemporal Disorder M. Hoffmann1,2, F. Rossi1,2, R. Rodriguez Cruz1,2, A. Khaki1,2, K. Malik1,2 1 OVAMC, University of Central Florida, Neurology, Orlando, Florida, United States 2 University of Central Florida, Neurology, Orlando, United States Frontotemporal lobe disorders (FTD) are increasingly ascribed to differing pathophysiologies including frontotemporal lobe dementias, chronic traumatic encephalopathy, traumatic brain injury, autoimmune processes and mild FTD phenocopy subtypes. Vascular causes have not been well described in this context. We sought to determine the frequency of FTD in a cohort of stroke patients. Study setting: A cognitive vascular registry of cerebrovascular patients admitted to a comprehensive stroke center over a 3 year period, with 6 monthly follow up. FTD diagnosis was made using the International Consensus Criteria of Rascovsky et al. (R). Metric tests included the Frontal Systems Behavioral Examination (FRSBE), Bar-On Emotional Intelligence tests (EQ-i) and the Wisconsin Card Sorting Test (WCST). In 80 patients able to complete testing, instances of FTD numbered 26, if 3/6 R criteria were applied and 10 by ≥ 5 R criteria. Individual frontal deficit domains and lesion location was variable. Lesion topography included 13 frontal lobe lesions, 9 subcortical and 4 temporal lesions. Analysis of variance for mean T-scores for abulia differed for frontal (F) (70.1), temporal (T) (79) versus subcortical (SC) (60.6) and parieto-occipital (PO) stroke lesions (52.2) (p = 0.006). Disinhibition mean T scores differed for F (57.1), T (74.3), SC (53) and PO (50.3) (p = 0.01). The executive mean T scores differed for F (63.5), T (75.8) versus SC (56.7) and PO (50) (p = 0.003). The mean EQ-i standard scores for F (87.3) and T (71.5) differed from SC (92.6) and PO (113.1) (p = 0.0001). The most common vascular lesions included lobar hemorrhages (n = 10), arteriovenous malformations (AVM’s) (n = 7), atypical infarcts (n = 5) and small vessel disease related (n = 4). In conclusion: 1. Frontotemporal syndromes may occur in up to one quarter of subacute and chronic stroke patients affecting the frontotemporal subcortical circuitry. 2. Frequent causes are lobar hemorrhages, AVM’s and atypical infarcts.

P104 Risk of suicide in patients with behavioral variant Frontotemporal Dementia I. Rainero1, M. Zucca1, E. Rubino1, F. Govone1, A. Vacca1, L. Pinessi1 1 University of Turin, Department of Neuroscience “Rita Levi Montalcini”, Turin, Italy Behavioral variant Frontotemporal Dementia Frontotemporal dementia (bvFTD) is a clinically heterogeneous syndrome characterized by changes in personality and social conduct. The risk of suicidal behavior was reported to be more likely among bvFTD patients as compared with controls. The purpose of this study was to determine possible risk factors associated to suicidal thoughts in bvFTD patients using neuropsychological and neuropsychiatric evaluations. Twenty bvFTD patients were recruited at Department of Neuroscience “Rita Levi Montalcini” in Turin, Italy. BvFTD patients were divided in two groups according to the score obtained at the Scale for Suicide Ideation: 9 bvFTD patients with risk of suicide (5 subjects with suicide ideation and 4 patients who have attempted suicide) and 11 bvFTD patients without risk of suicide. Twenty controls were also included in the study. Each group underwent an extensive neuropsychological and neuropsychiatric assessment. Statistical analysis was performed using SPSS software ver 21.0. BvFTD patients with suicide risk are 45% of the overall bvFTD sample, and present higher levels of anxiety, stress, depression and hopelessness compared with bvFTD patients without risk of suicide (p < 0.001) and with control group (p < 0.05). We did not find a significant difference in levels of apathy and cognitive impairment between the three groups. Both groups of bvFTD patients present higher levels of impulsivity than controls (p < 0.001). Interestingly, within the group of bvFTD patients with risk of suicide, subjects who have attempted suicide present a longer disease duration than bvFTD patients with only suicide ideation (p = 0.001). Our study shows that, in bvFTD patients there is a high risk of suicide and this finding could have social and therapeutic implications. The risk of suicidal behavior is related to neuropsychiatric aspects such as anxiety, depression and stress. In line with stress-diathesis model, we can speculate that FTD patients present a neurobiological vulnerability to suicide behavior.

P105 Moral processing deficit in behavioral variant frontotemporal dementia is associated with emotion recognition deficits and both structural and functional lateral orbitofrontal abnormalities J. Van den Stock1,2, F. De Winter1,2, D. Mantini3, J. Jastorff1, R. Vandenberghe1,4, M. Vandenbulcke2,3 1 KU Leuven, Department of Neurosciences, Leuven, Belgium 2 University Hospitals Leuven, Department of Old Age Psychiatry, Leuven, Belgium 3 KU Leuven, Department of Kinesiology, Leuven, Belgium 4 University Hospitals Leuven, Department of Neurology, Leuven, Belgium The behavioral variant of fronto-temporal dementia (bvFTD) is associated with both emotion recognition and moral processing deficits. We investigated both abilities in a sample of 13 probable bvFTD patients and 19 matched controls by means of a hierarchically composed series of experiments. We assessed emotion

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detection, discrimination, matching, selection and categorization as well as judgements of non-moral, moral impersonal, moral personal low-conflict and moral personal high-conflict scenarios. bvFTD patients were impaired on a composite measure of the emotion processing experiments (derived through Principal Component Analysis with an a-priori defined single factor structure) and gave more utilitarian responses on low-conflict personal moral dilemmas. There was a significant correlation between the emotion processing measure and utilitarian responses on low-conflict personal scenarios in the bvFTD group, but not in the control group (controlling for MMSE-score; p < 0.05). In addition, we performed structural and resting-state functional Magnetic Resonance Imaging. Voxel-based morphometric multiple regression analysis in the bvFTD group revealed a significant association between the proportion of utilitarian responses on personal low-conflict dilemmas and grey matter volume in the right lateral orbitofrontal cortex (l_OFC; p < 0.001). This area showed reduced functional connectivity with the temporo-parietal junction (TPJ), medio-dorsal thalamic nucleus temporal pole and contra-lateral l_OFC (p < 0.001). In addition, there was a correlation between utilitarian responses on low-conflict personal scenarios in the bvFTD group and fractional Amplitude of Low Frequency Fluctuations (fALFF) in the l_OFC, TPJ, inferior frontal gyrus (pars opercularis) and anterior insula (p < 0.001). The results link emotion processing deficits to moral reasoning abnormalities in bvFTD. The structural and functional brain abnormalities associated with the moral reasoning change in bvFTD include areas involved in theory of mind, emotion and salience processing.

P106 Demographic influence in depression prevalence in frontotemporal dementia (FTD): a meta-regression perspective A. Sepehry1, A. Afshinkia1, G.-Y. R. Hsiung1 1 The University of British Columbia, Division of Neurology, Vancouver, Canada Evidence shows that depressive symptoms are common in FTD (33%), albeit somewhat lower than that of Alzheimer’s disease (AD) (42%). We speculate that the difference is affected by demographic variables (age, sex, and MMSE) of the dementia patients enrolled in the studies. Thus, using meta-analytic technique on published data, we examine the effect of demographic factors including sex, age, and MMSE on the prevalence of depression in FTD and AD. We used data from a 2015 meta-analysis for the current study. After confirming the previous results, single variable meta-regressions were run comparing the demographic factors. Thirteen crosssectional comparisons (FTD to AD) were identified (depression prevalence for FTD: 26%; for AD: 34%). The single variable metaregression of MMSE absolute score difference was statistically significant [coefficient: 0.294; SE: 0.124; p-value: 0.018; N = 11], but not age or sex. Specifically, a statistically significant inverse relationship was observed for FTD MMSE score and the group difference on depression prevalence [Coefficient: 0.145; SE: 0.072; p-value: 0.0423]. In contrast, a non-significant inverse relationship was observed for AD MMSE score and the group difference on depression prevalence [Coefficient: -0.184; SE: 0.127; p-value: 0.149]. These suggest that as the FTD MMSE score increases, the prevalence of depression in FTD increases, whereas the opposite trend was observed in AD. This also demonstrates that the disease severity based on MMSE score is not comparable

between FTD and AD. MMSE score, as a proxy for global cognition, influences prevalence of depression in FTD and AD, which suggests that the prevalence of depressive symptoms is affected by disease stage or severity. Since depressive symptoms are amenable to treatment and may improve quality of life, our findings highlights the importance of screening for depression at specific stages of disease, and provide insights into the pathophysiology of psychiatric disorders in neurodegenerative dementias.

P108 Psychotic symptoms and formal thought disorders in behavioral variant frontotemporal dementia F. Gossink1,2, E. Vijverberg1, W. Krudop1, P. Scheltens1, M. Stek2, Y. Pijnenburg1,2, A. Dols1,2 1 VUmc, Alzheimer Center, Amsterdam, Netherlands 2 GGZinGeest, Neuropsychiatry and Old Age Psychiatry, Amsterdam, Netherlands The behavioural variant of frontotemporal dementia is characterized by prominent neuropsychiatric symptoms which clinically often leads to psychiatric misdiagnosis. Although misdiagnosis in bvFTD with a psychotic disorder is well known, insight in the specific psychotic symptoms that characterize bvFTD and that might differentiate bvFTD from psychiatric disorders is still missing. We aimed at systematically and prospectively subtyping the broad spectrum of psychotic and general psychiatric symptoms in probable and definite bvFTD patients (n = 22) and compare them to patients with a psychiatric diagnosis (n = 35) in a late onset frontal lobe cohort. We employed a commonly used and validated clinical scale for psychosis and schizophrenia symptoms (the Positive and Negative Symptom Scale-PANSS) which quantifies the broad spectrum of psychotic symptoms including positive and negative psychotic symptoms, formal thought disorders and general psychiatric symptoms. We found that 76.9% of bvFTD patients showed any psychotic symptom, although not the typical positive psychotic symptoms (delusions, hallucinations and paranoia) but formal thought disorders (stereotypical thinking and difficulty in abstract thinking). Patients with a psychiatric disorder were characterized by anxiety, guilt feeling and tension (general subscale). The combined predictors difficulty in abstract thinking, stereotypical thinking, anxiety, guilt feeling and tension explained 75.4% of the variance in diagnosis of bvFTD versus psychiatric diagnoses (v 32.26, df 5, p < 0.001). This is the first study prospectively exploring the broad spectrum of psychotic symptoms in bvFTD and our results indicate that classic psychotic symptoms are infrequently present in bvFTD, however formal thought disorders are present. Misdiagnosis in bvFTD can be reduced by exploring additional general psychiatric symptoms as these are indicative for a different psychiatric diagnosis. In suspected bvFTD cases a close collaboration between neurologists and psychiatrists will advance diagnostics and subsequent treatment.


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P109 Profile of memory impairment in behavioral variant of the FTD M. Garcıá Garcıá1, C. Trivi~ no Martinez2, J. Santacruz Escudero1, D. L. Matallana Eslava2 1 Hospital Universitario San Ignacio, Bogot a, Colombia 2 Pontificia Universidad Javeriana, Bogot a, Colombia Although alterations in episodic memory were though to present in atypical behavioral variants of FTD, recently difficulties in verbal learning tasks, similar to those of patients with other dementias, have been reported in patients with FTD bv. The aim of this study was to describe the performance profile for verbal explicit memory (short and long term) using the Groober and Buschke test, in comparison with subjects with AD of similar severity, and determine the correlation with other variables in the behavioral sphere and executive functioning that may interfere with the clinical evaluation, leading to errors in the differential diagnosis. 106 subjects with FTDbv, 92 with AD (GDS 4) and 32 healthy subjects of similar demographic characteristics were studied. Participants were diagnosed with dementia by consensus of the interdisciplinary group of the Memory Clinic (Hospital Universitario San Ignacio, Bogota-Colombia). The results show that the memory profile of patients with FTDbv differs from that of the healthy group and AD; Memory deficiencies are not commonly reported as one of the main symptoms of FTDbv. However, the report of family members and clinical findings indicate the presence of an alteration in memory, perhaps associated with strategies of information recovery and storage volume. These alterations could also correlate with the performance in other tasks of executive functioning.

P110 Semantic categorization into the variants of FTD C. Trivinõ Martıńez1, M. Garcıa Garcıa2, H. Santamarıa-Garcıa1, D. L. Matallana Eslava1 1 Pontificia Universidad Javeriana, Bogot a, Colombia 2 Hospital Universitario San Ignacio, Bogot a, Colombia Although semantic processing has been extensively investigated in patients with semantic dementia (SD), little has been explored this function in other variants of the Frontotemporal Dementia (FTD). The main aim of this study was to examine the semantic categorization of animate and inanimate elements presented in verbal and visual path and cognitive functioning particularly executive functions in a group of patients with variants of FTD. A sample of 27 patients with behavioral variant of Frontotemporal Dementia (FTDbv), 11 with Primary Progressive Aphasia (PPA) and 6 with Semantic Dementia (SD) were diagnosed and selected to integrate this study by the interdisciplinary group of the Memory Clinic at the Hospital San Ignacio, Bogota-Colombia following international criteria. A group of 23 healthy individuals similar in demographic characteristics was also integrated. Our results showed that all patients with FTD differ from healthy group in semantic processing of animated and inanimated elements irrespective of sensory modality of the stimulus presentation. Moreover, particular differences were detected between group of patients. SD patients had lowest performance in semantic processing comparing other variants. FTDbv group showed differences in semantic processing in both sensory modalities comparing to APP and SD group. SD and PPA groups only differed in categorizing

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animate elements. While semantic processing in SD group was highly associated to language deficits, the semantic performance in patients with PPA andFTDbv was explained by in executive functions as showed different linear regression models. Our results highlight the predictive value of semantic categorization in understanding cognitive processing of FTD patients. Future studies should be conducted to evaluate the value of semantic processing of animated and inanimated elements and its relationship with social cognitive domains as a way to discriminate which cognitive domains are impaired in each FTD variant.

P111 A longitudinal study of neuropsychiatric and cognitive symptoms in patients with FTDbv M. Garcıá Garcıá1, C. Trivi~ no Martinez2, J. Santacruz Escudero1, D. L. Matallana Eslava2 1 Hospital Universitario San Ignacio, Bogot a, Colombia 2 Pontificia Universidad Javeriana, Bogot a, Colombia The most common variant of FTD is the behavioral variant. However, and given the heterogeneity of neuropsychiatric symptoms that occur in the early stages of the disease, diagnosis is difficult due to the paucity in changes in other cognitive areas that could guide differential analysis. The aim of this study was to analyze in a cohort of patients, whether with the passage of time the evolution of neuropsychiatric symptoms would result in different diagnosis. 14 patients were evaluated longitudinally 1 year after diagnosis following international criteria and according to the consensus of the interdisciplinary group of the Memory Clinic (Hospital Universitario San Ignacio, Bogota-Colombia). After the second assessment, 4 out of 14 patients had no progression in cognitive changes, and presented with new psychiatric symptoms, thus resulting in change in the initial diagnosis. By contrast in patients whose diagnosis remained unchanged, the alterations in executive functioning increased significantly. These results indicate that even though the presentation of neuropsychiatric symptoms such as disinhibition, apathy, depression, exaltation or paranoid ideation may correspond to the behavioral variant of FTD, the initial diagnosis should be reevaluated in depth over time, given the similarity in symptomatology to other psychiatric disorders, or due to phenocopies.

P112 Differences in social cognition between behavioral-variant frontotemporal dementia and depression: preliminary results M. Lichtenstein1, N. Fallah2,3, A. Howard4, P. Eslinger5, H. Feldman1,6 1 University of British Columbia, Neurology, Vancouver, USA 2 University of British Columbia, Medicine, Vancouver, Canada 3 Rick Hansen Institute, Research, Vancouver, Canada 4 University of British Columbia, Psychiatry, Vancouver, Canada 5 Penn State Hershey Medical Center, Neurology, Hershey, USA 6 University of California San Diego, Neuroscience, San Diego, USA Behavioral-variant frontotemporal dementia (bvFTD) is challenging to diagnose. With few deficits on standard tests, bvFTD is often misdiagnosed with depression (DEP). Social cognition



(SoCog) can discriminate bvFTD from DEP, but further study is needed to develop a clinical tool. Here we report preliminary results from a study comparing SoCog in 6 bvFTD and 4 DEP subjects. Cognitive screen comprised of MoCA, FAB, and VVT. SoCog tests included: Emotion recognition (ER) with Penn ER Task; Theory of Mind with Reading the Mind in the Eyes (RME), Faux Pas (FP), 1st and 2nd-order belief and sarcasm vignettes; affective (aEmp) and cognitive empathy (cEmp) with Interpersonal Reactivity Index (IRI); metacognitive deficits with differences between subject and informant IRI. There were no group differences in cognitive screen except lower MoCA scores in bvFTD (median 20, mean 21 (SD 4.6) vs. 26.5, 26.3 (2.8)]. bvFTD made more errors in ER [23.5, 23.8, (6.1) vs. 35.5, 35.8 (3.5)], notably for fear and neutral faces. bvFTD performed worse in RME [17.5, 18.2 (6.4) vs. 27.5, 28.5 (2.4)] and FP detection [83%, 81% (14%) vs. 98%, 98% (3%)], particularly in falsely identifying control stories as FP. There were no group differences in 1st-order beliefs, but bvFTD performed worse in 2ndorder beliefs [33%, 38% (19%) vs. 60%, 65% (10%)] and sarcasm detection [40%, 43% (21%) vs. 80%, 65% (44%)]. Though Emp self-report was similar by group, bvFTD-informants rated them lower in cEmp [2.0, 3.3 (4.0) vs. 20.5, 20.5 (3.6)] and aEmp [9.0, 11.3 (8.4) vs. 22.0, 21.3 (3.4)]. There were greater differences between bvFTD self and informant-ratings of cEmp [12.5, 12.5 (3.1) vs. 0.5, 0.8 (1.0)] and aEmp [14, 11.2 (6.1) vs. 2.5, 2.5 (1.3)], indicating metacognitive deficits. Though these are preliminary results, they highlight the potential for SoCog bedside tests to detect meaningful differences between bvFTD and DEP. This is the first report demonstrating that bvFTD make errors of both commission and omission in SoCog tasks. We are currently recruiting a larger sample to allow development of a bedside tool that differentiates bvFTD from DEP.

P113 Behavioral variant frontotemporal dementia mimicked by right carotid artery stenosis without observable lesion on MRI Y. B. Kim1, P.-W. Chung1, H.-S. Moon1, B. C. Suh1, W. T. Yoon1 1 Kangbuk Samsung Hospital Sungkyunkwan University school of medicine, Neurology, Seoul, South Korea Many diseases including degenerative, psychiatric and cerebrovascular diseases (CVD) can mimic behavioral variant frontotemporal dementia (bvFTD). We discuss a patient with clinical syndrome of bvFTD caused by right carotid artery severe stenosis without any lesion on MRI or positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET) who was successfully treated by carotid angioplasty with stenting. A 73-year-old woman presented with apathy, personality change and persecutory delusion. Since last year, she gradually alienated herself from her friends and neighbors, almost confining herself to her house. She would express delusional idea that neighbors would harm her. She became quite abusive and often swore at others. Recently she obsessively repeated her persecutory delusion against her son-in-law, which eventually made her family decide to bring her to the dementia clinic. She denied any memory problem beyond simple forgetfulness and she had no difficulty in maintaining her household. Past medical history revealed hypertension, dyslipidemia and angina. Mini-Mental State Examination (MMSE) was 22. She had no cranial nerve, motor, sensory, reflex or gait abnormalities. Neuropsychological examination revealed frontal/executive, visuospatial, and mild memory

dysfunction. Routine blood tests showed no abnormalities. Thyroid status was normal. Brain MRI and FDG-PET was normal. However, MR and conventional angiography showed severe right carotid stenosis (> 95%). Right frontal perfusion was decreased. Carotid angioplasty with stenting (CAS) was performed successfully and she was discharged with antiplatelet, lipid lowering and antihypertensive agent. In a month, her symptoms disappeared without any medication against her abnormal behavior. On follow-up neuropsychological examination of 2 month after CAS, cognitive dysfunction was improved. In early bvFTD patients who have multiple risk factors for CVD, MR angiography should not be omitted in the diagnostic plan considering the ominous prognosis of the diagnosis of bvFTD.

P114 Neuropsychological assessment of medial frontal functioning in frontotemporal dementia J. MacKinley1, M. Blair1, K. Coleman1, S. Gill1, D. Bhatty1, E. Warriner2, K. Smolewska2, S. Pasternak1, M. Kershaw3, E. Finger1 1 Lawson Research Institute, London, Canada 2 Hamilton Health Sciences, Hamilton, Canada 3 Private Practice, Victoria, Australia Financial capacity, defined as the ability to manage one’s financial affairs, is affected in patients with mild cognitive impairment and Alzheimer’s disease (AD). In patients with frontotemporal dementia (FTD), family subjective reports have indicated impaired financial decision-making; however, evidence from performance based measures is lacking in these patients. Since FTD is characterized by executive function deficits, investigating financial abilities using performance and self-report measures may further clarify the nature of financial skills in these patients. Using performance measures of financial capacity, we aimed to (1) examine if FTD patients exhibit financial difficulties when compared to the healthy controls; (2) compare the financial skills of FTD patients to that of AD patients; and (3) examine the extent to which family reports are comparable to patients’ self-reports and actual performance. We predicted that FTD patients would show poor financial capacity skills relative to controls, and explored their financial skills relative to AD patients. Lastly, because of reduced insight in FTD patients, we predicted that family reports of patients’ abilities would be discrepant with patients’ self-reports and actual performance. In this ongoing study, patient groups (FTD = 11, AD = 15) and healthy controls (15) underwent financial capacity assessment using two measures: Financial Competence Assessment Inventory (FCAI) and the Financial Assessment and Capacity Test (FACT). Thus far, trends in preliminary results indicate that FTD patients show a range of performance deficits on financial measures, some of which were below that of healthy controls but similar to that of AD patients. Additionally, FTD patients’ self-report and performance was generally discordant with family members’ reports on most scales of the FCAI. Taken together, general trends in this ongoing work reveal compromised financial capacity in FTD patients. Identifying objective financial difficulties may add a beneficial component to the diagnostic process in FTD.


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P115 Neural correlates of reversal learning deficits in behavioral variant frontotemporal degeneration K. Ternes1, J. Kable2, J. McGuire3, K. Rascovsky1, C. McMillan1, M. Grossman1 1 Penn Frontotemporal Degeneration Center, Perelman School of Medicine, Philadelphia, USA 2 University of Pennsylvania, Psychology, Philadelphia, USA 3 Boston University, Psychological and Brain Sciences, Boston, USA Behavioral variant frontotemporal degeneration (bvFTD) is characterized by executive dysfunction and cognitive inflexibility but the neuroanatomic bases of this deficit is poorly understood. Reversal learning tasks evaluate simple strategy learning and flexible adaptation of these strategies. We examined the neural basis of reversal learning in bvFTD (N = 25), mild Alzheimer’s disease (AD; N = 12), and comparable healthy controls (HC; N = 17) who also had MRI. In a computerized task subjects responded yes/no to an object containing two shape and color features. We used a probabilistic reinforcement paradigm to reinforce selection of two of the four features in the first “learning” block and implicitly reinforced two novel features in the second “reversal” block. We categorized subjects as “learners” if they endorsed the target features in > 50% of first block trials. Of the “learners”, we categorized “reversers” as those that endorsed the novel features in > 50% of second block trials. Chi-square analyses evaluated the proportion of “learners” and “reversers” in patient groups. We observed an equal distribution of learners between each group: 76% HC, 76% bvFTD, 58% AD (X2 = 1.51; p = 0.68). However, within-group analysis showed the rate of reversers was less in bvFTD (42%; X2 = 5.23, p = 0.02) unlike AD (57%; X2 = 0.003; p = 0.96) and HC (77%; X2 = 0.001; p = 0.98) who were equally likely to reverse. The rate of reversal in bvFTD also differed from HC and AD (X2 = 3.80; p = 0.05). Neuroimaging analyses showed gray matter atrophy in orbitofrontal cortex (BA 10/ 47) and dorsolateral prefrontal cortex (BA 9) in bvFTD nonreversers relative to HC (q < 0.005 TFCE FWE-corrected). Together, the behavioral and imaging findings provide evidence of DLPFC and OFC contribution to selective reversal learning deficits in bvFTD.

P116 Compulsory mental care among patients with a neuropathologically confirmed dementing disorder M. Liljegren1, M. Landqvist Wald€ o2, R. Rydbeck3, E. Englund1 1 Lund University, Division of Oncology and Pathology, Department of Clinical Sciences, Lund, Sweden 2 Lund University, Geriatric Psychiatry, Department of Clinical Sciences, Lund, Sweden 3 Lund University Hospital, Department of Forensic Psychiatry, Lund, Sweden The Swedish Compulsory Mental Care Act allows seriously mentally ill people to be taken into care against their wishes. There must be a risk to the individual’s own life or health or for the safety, physical or mental health of other persons and care refusal of the subject is a prerequisite. Little is known about how this law is being applied on people suffering from dementia. To investigate the frequency of compulsory mental care among patients with a neuropathologically confirmed dementing disorder,

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we conducted a retrospective medical record review of 283 patients, seen at the Memory Clinic at Lund University Hospital 1969–2013, including 102 patients with Alzheimer’s disease (AD), 98 patients with Frontotemporal dementia (FTD), 43 patients with Vascular dementia (VaD) and 40 patients with Alzheimer’s disease and Vascular dementia (AD/VaD). Clinical records of compulsory mental care during the patients’ lifetime were reviewed. Numbers of compulsory mental care and time during the course of the disease were calculated among the different diagnostic groups. The reason behind the decision of compulsory mental care was studied. Of the 283 patients studied, 72 (25.4%) had a history of being taken into Swedish compulsory mental care during the course of their illness. The prevalence among the different diagnostic groups was: FTD 32 patients (32.7%), AD 25 patients (24.5%), AD/VaD 9 patients (22,5%) and VaD 6 patients (14.0%). Compulsory mental care was being practiced both in the early and the late stages of the patients’ illnesses. Among different reasons behind the decisions on compulsory care, we found physical aggressiveness, confusion, severe or near accidents at home or exhaustion of caregivers. We found that compulsory mental care was more common in FTD patients as compared to AD, VaD and AD/VaD patients.

P117 Qualitative assessment of verbal fluency performance in patients with bvFTD and PPA E. van den Berg1, L. Jiskoot1, M. Grosveld1, J. van Swieten1 1 Erasmus MC University Medical Center, Neurology, Rotterdam, Netherlands Verbal fluency is impaired in patients with frontotemporal dementia and primary progressive aphasia. The test score is based on the total number of generated words only, without assessment of qualitative aspects of verbal fluency, such as clustering of words and switching between strategies. This study explored qualitative differences in verbal fluency performance. 92 Patients with FTLD (43 behavioural variant (bv) FTD, 13 progressive nonfluent aphasia (PNFA), 14 semantic dementia (SD), 22 logopenic progressive aphasia (LPA)) performed a semantic (animals) and phonologic (letters “D, A, T”) verbal fluency task as part of their standardized memory clinic evaluation between 2012 and 2015. The total number of words was recorded. In addition, clustering was defined as the number of multiword strings (≥ 2 words). Switching was defined as the number of transitions between clustered and nonclustered words. Between group differences were examined with age- and sex-adjusted analysis of variance. Semantic fluency showed a significant main group effect in total words, number of clusters and cluster size (all p < 0.05), whereas phonologic fluency did not show a difference in total words, but a significant difference in number of clusters and number of switches (p < 0.05). Posthoc analyses indicated that patients with bvFTD generated more words than SD (13 0.9 vs. 8 1.5) and produced more and larger clusters than LPA and PNFA (number of clusters 5 vs. 2 and 3; cluster size 13 vs 7 and 7). Patients with PNFA and LPA used fewer switches than SD (7 and 7 vs. 16). Correlations with measures of memory, language and executive functioning and longitudinal data of a subsample of patients are currently performed. These results showed that qualitative performance on a verbal fluency task, including measures of clustering and switching,



differed between patients with different forms of FTLD. Qualitative assessment of verbal fluency performance reveals additional information on patients’ ability to structure their thinking that can be used in neuropsychological assessment.

P118 Similar findings on clinical and neuropsychological measures in asymptomatic mutation versus non-mutation carriers: preliminary data from LEFFTDS B. Boeve1, H. Rosen2, A. Boxer2, G. Coppola3, C. Dheel1, B. Dickerson4, K. Faber5, J. Fields1, T. Foroud5, R. Gavrilova1, N. Ghoshal6, J. Goldman7, N. Graff-Radford8, M. Grossman9, H. Heuer2, J. Hsiao10, R. Hsiung11, E. Huey7, D. Irwin9, K. Kantarci1, A. Karydas2, D. Knopman1, J. Kornak2, J. Kramer2, W. Kukull12, I. Mackenzie11, B. Miller2, C. Phelps10, R. Rademakers8, K. Rankin2, L. Shaw9, M. Sutherland13, A. Toga14, J. Trojanowski9, A. Vetor5, S. Weintraub15, Z. Wszolek8 1 Mayo Clinic, Rochester, USA 2 UCSF, San Francisco, USA 3 UCLA, Los Angeles, USA 4 Massachusetts General Hospital, Boston, USA 5 Indiana University, Indianapolis, USA 6 Washington University, St. Louis, USA 7 Columbia University, New York, USA 8 Mayo Clinic, Jacksonville, USA 9 University of Pennsylvania, Philadelphia, USA 10 NIA, Bethesda, USA 11 University of British Columbia, Vancouver, Canada 12 University of Washington, Seattle, USA 13 NINDS, Bethesda, USA 14 USC, LONI, Los Angeles, USA 15 Northwestern University, Chicago, USA We hypothesized that differences might exist between asymptomatic non-mutation (-mCDR = 0) versus mutation (+mCDR = 0) carriers in the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Consortium, which involves subjects in kindreds with mutations in microtubule associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72). We analyzed demographic, clinical and neuropsychological data among –mCDR = 0 (n = 24) and +mCDR=0 (n = 34) subjects evaluated through February 2016. Measures included the Functional Assessment Questionnaire, Montreal Cognitive Assessment, motor subtest of the Unified Parkinson’s Disease Rating Scale, Progressive Supranuclear Palsy Rating Scale, Geriatric Depression Scale, Neuropsychiatric Inventory, neuropsychological tests as part of the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set, and novel informant-based and neuropsychological measures as part of the NACC Frontotemporal Lobar Degeneration Module. No differences existed on any demographic, clinical, behavioral or neuropsychological measure. These preliminary data suggest that standard and novel clinical and neuropsychological measures may not differentiate asymptomatic mutation from non-mutation carriers in familial FTD.

P119 Differences on neuropsychiatric measures in asymptomatic (CDR = 0) versus mildly symptomatic (CDR = 0.5) mutation carriers: preliminary data from LEFFTDS H. Rosen1, B. Boeve2, A. Boxer1, G. Coppola3, C. Dheel2, B. Dickerson4, K. Faber5, J. Fields2, T. Faroud5, R. Gavrilova2, N. Ghoshal6, J. Goldman7, N. Graff-Radford8, M. Grossman9, H. Heuer1, J. Hsiao10, G.- Y. R. Hsiung11, E. D. Huey7, D. Irwin9, K. Kantarci2, A. Karydas1, D. Knopman2, J. Kornak1, J. Kramer1, W. Kukull12, I. Mackenzie11, B. Miller1, C. Phelps10, R. Rademakers8, K. Rankin1, L. Shaw9, M. Sutherland13, A. Toga3, J. Trojanowski9, A. Vetor5, S. Weintraub14, Z. Wszolek8 1 University of California, San Francisco, Neurology, San Francisco, USA 2 Mayo Clinic, Rochester, USA 3 UCLA, Los Angeles, USA 4 Massachusetts General Hospital, Boston, USA 5 Indiana University, Indianapolis, USA 6 Washington University, St. Louis, USA 7 Columbia University, New York, USA 8 Mayo Clinic, Jacksonville, USA 9 University of Pennsylvania, Philadelphia, USA 10 National Institute on Aging, Bethesda, USA 11 University of British Columbia, Vancouver, Canada 12 University of Washington, Seattle, USA 13 National Institute of Neurological Disorders and Stroke, Bethesda, USA 14 Norhtwestern University, Chicago, USA We analyzed data from the short version of the neuropsychiatric inventory (NPI-Q) and Geriatric Depression Scale (GDS) among subjects enrolled in the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Consortium, which involves subjects in kindreds with mutations in microtubule associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72). We hypothesized that there were be differences between carriers with no symptoms (+mCDR = 0, n = 34),and carriers with mild symptoms (+mCDR=0.5, n = 35). We identified statistically significant differences in the NPI-Q total score (7.1 vs. 2.9), as well as prevalence of symptoms in the following NPI domains: agitation (30.3% vs. 3.3%), apathy (57.6% vs. 12.9%), disinhibition (43.8% vs. 6.5%), irritability (51.5% vs. 9.7%), and aberrant motor behavior (27.3% vs. 6.5%). No differences were shown for the GDS or the NPI-Q domains of anxiety, appetite change, delusions, depression, elation, hallucinations or night-time behavior. As expected, these preliminary data suggest a higher frequency of neuropsychiatric features among mildly symptomatic compared to asymptomatic mutation carriers in familial FTD kindreds. Yet some degree of neuropsychiatric abnormality are also endorsed by informants of asymptomatic mutation carriers which may or may not reflect evolving disease.


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P120 Investigating the role of face processing in behavioural variant frontotemporal dementia L. Russell1, M. Bocchetta1, S. Harding1, S. Crutch1, J. Warren1, J. Rohrer1 1 University College London, Dementia Research Centre, London, Great Britain Impairment of emotional processing is a core feature of behavioural variant frontotemporal dementia (bvFTD) but has been poorly studied. This study investigated simple and complex emotional face recognition both cross-sectionally and on a longitudinal basis. 30 individuals were recruited to the study: 18 with bvFTD and 12 controls. Individuals completed a facial perception task, the Benton Facial Recognition Test, and two tasks of facial emotion recognition: the Ekman simple emotion recognition Task and the more complex Reading the Mind in the Eyes Test (RMET). 16 of the 18 bvFTD patients underwent volumetric T1-weighted MRI which were used for voxel-based morphometry (VBM) analysis in SPM12 (with correction for age, gender and total intracranial volume). 7 bvFTD patients completed follow-up assessments at a mean (standard deviation, SD) of 1.1 (0.1) years from baseline. The bvFTD patients scored significantly worse than controls on both the Ekman Task and the RMET but there were no differences observed on the Benton Test. BvFTD patients performed worse on recognition of negative emotions (30.0% lower than controls) than positive emotions (18.6% lower than controls) on the Ekman Task. Performance on the Ekman task correlated with grey matter loss bilaterally in the inferior frontal gyrus (IFG) and the anterior cingulate, whilst performance on the RMET correlated with grey matter loss in the IFG and the right superior temporal gyrus. The annualised mean (SD) change in score was 1.6 (4.5) on the Benton Test, 1.4 (1.3) on the Ekman Task and -1.8 (4.7) on the RMET. These results suggest that while bvFTD patients have relatively intact recognition of faces, they are impaired at processing simple and complex emotions and this deteriorates over time. Furthermore, bvFTD patients appear to have greater impairment in processing negative compared with positive emotions. Facial emotion processing in bvFTD appears to rely on a network of anatomical areas particularly involving the dorsolateral prefrontal cortex.

P121 Neuropsychological profiles in familial frontotemporal dementia S. Leijdesdorff1, E. van den Berg1, L. Jiskoot1, J. Papma1, J. van Swieten1 1 Erasmus MC, Neurology, Rotterdam, Netherlands In the last two decades three genetic mutations have been discovered covering most cases of familial frontotemporal dementia (FTD): MAPT, GRN and C9orf72 repeat expansion. Differentiation between different FTD mutations clinically will become more important with forthcoming trials on disease modifying treatments. The aim of the current study is to distinguish between cognitive and/ or behavioral profiles in symptomatic FTD patients with a MAPT, GRN or C9orf72 mutation. In this study we compared neuropsychological and behavioral data of patients diagnosed with familial FTD due to a MAPT (n = 26), GRN (n = 16) or C9orf72 (n = 20) mutation and healthy

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controls (HC) (n = 42). Raw neuropsychological test scores were converted into standardized z-scores, and we calculated composite z-scores for the domains language, attention, executive functioning, social cognition, memory immediate recall, memory delayed recall, memory recognition, working memory and visuo-constructive ability. The presence of 16 behavioral features was scored, such as disinhibition, apathy, roaming, perseveration, hyperorality, parkinsonism and hallucinations. Between group analyses were performed with ANCOVA, adjusted for sex, age, education and disease duration, and post-hoc t-tests. All mutation groups showed a cognitive profile of domains language, attention and executive functioning deficits compared to HC. MAPT patients have significant lower scores for the memory domain compared to GRN patients and HC. Concerning behavior, GRN patients presented with the most roaming, MAPT patients with apathy/inertia and in C9orf72 patients hyperorality and language problems were most reported. These results indicate that we cannot distinguish between FTD due to MAPT, GRN and C9orf72 mutations on the basis of neuropsychological profiles in the symptomatic stage, with subtle differences on the memory domain in MAPT versus GRN mutation carriers. There is a need for other measures distinguishing different FTD mutations clinically, which may be found in behavioral features.

P122 Longitudinal analysis of cognitive test score trajectories in behavior variant frontotemporal dementia K. Kansal1, H. Amjad1,2, S. Saxena1,3, C. Onyike1 1 Johns Hopkins University, Psychiatry and Behavioral Sciences, Baltimore, USA 2 Johns Hopkins University, Internal Medicine/Geriatric Medicine and Gerontology, Baltimore, USA 3 Johns Hopkins University, Bloomberg School of Public Health, Baltimore, USA We examined temporal trajectories of cognitive test scores in 407 behavioral variant frontotemporal dementia (bvFTD) subjects from the National Alzheimer Coordinating Centers. We used Mini-Mental State Examination, Functional Activities Questionnaire and Clinical Dementia Rating Sum of Boxes to index neurodegeneration in latent class mixed models that yielded a two-class solution (class 1 – “usual progression”, class 2 – “slow progression”). The classes did not differ demographically. For each class, we fit sigmoid mixed effects models for test z-scores as functions of illness duration. The tests were: Logical Memory (immediate, LMI, and delayed, LMD), Digit Span (forward, DSF, and backward, DSB), Category Fluency (animals and vegetables), Boston Naming Test (BNT), Trail Making Test Part B (TMT) and WAIS-R Digit Symbol (DS). We performed 100 non-parametric bootstraps per model to assess reliability and used them to derive means and 90% confidence intervals (CI) for: (i) testing range (the difference between the asymptotes), (ii) time at 5% decline (T5; illness duration when the curve covered 5% of the testing range), (iii) time at 95% decline (T95; illness duration when the curve covered 95% of the testing range), (iv) functional period (FP; the interval denoting the middle 90% of the testing range, i.e., FP = T95-T5). In bvFTD with usual progression, category fluency tasks and LMD showed early decline (upper limit of the T5 CI < 2 years), but lacked utility after 5–6 years. In the middle stage, i.e., 4–5 years, TMT B was the most sensitive indicator of decline –



mean FP 0.88 years (CI: [0.00, 2.72]). In the late stages (> 6 years), BNT, DSF and DS showed decline (lower limits of T95 CI > 6 years). In the slow progression group, the tests lacked reliable trajectories. The data indicate early decline in semantic knowledge, logical memory and executive function in usual progression bvFTD, while confrontation naming, attention and processing speed are better indices of the later stages of illness. Current measures are insensitive to change in bvFTD with slow progression; new measures are needed.

P123 Social behavioral changes differ in frontotemporal dementia and semantic dementia H. Duclos1, S. Belliard1, C. Merck1, V. de la Sayette1, F. Eustache1, B. Desgranges1, M. Laisney1 1 U1077-INSERM-EPHE-UNICAEN, Caen, France If the severity and the number of behavioral symptoms were mainly reported to discriminate frontotemporal dementia (FTD) from Semantic Dementia (SD), previous studies failed to dissociate the finer cognitive and anatomical mechanisms driving social behavioral disturbances that occur in each disease. Using a novel inventory, this study aimed to compare the cognitive processes and their neural substrates of social behavioral disturbances between SD and FTD. Informants of 8 patients with SD, 7 patients with FTD, and 20 matched healthy subjects (HS) completed a social behavioral scale including 22 items describing egocentric (e.g., speaking excessively about his/her pains) or exocentric behaviors (e.g., being docile and doing whatever we asked). Informants rated the frequency of each behavior before and after the beginning of the disease in a likert 5-point scale to compute behavior change scores. Patients completed a standard neuropsychological assessment, a social cognition battery and a structural MRI. Both SD and FTD social behavior change scores differed significantly from those of HS (p < 0.001) with no significant difference between patient groups. The difference between egocentric and exocentric behavior changes differed between SD and FTD patients (p < 0.03) with more pronounced egocentric changes in SD and exocentric changes in FTD. Voxel-based morphometry analyses showed significant correlations between exocentric changes and grey matter density of bilateral frontal regions especially the orbitofrontal cortices. Exocentric changes were negatively correlated with social knowledge measure in SD patients (p < 0.04) and with cognitive theory of mind performance in FTD (p < 0.04). Exocentric changes were correlated with executive functions scores in both groups (p < 0.04). No significant correlation was found with egocentric behavior.SD and FTD patients differ qualitatively in their social functioning, with preferentially egocentric behavior in SD and exocentric behavior in FTD. Exocentric behaviors seem supported by frontal regions dysfunctioning. Cognitively, exocentric changes are associated with cognitive theory of mind deficits in FTD and social knowledge in SD.

P124 Longitudinal analysis of electronic messages to characterize language decline in frontotemporal dementia with bulbar amyotrophic lateral sclerosis K. Kansal1, E. Abraham1,2, A. Rao1,2, C. Onyike1 1 Johns Hopkins University, Psychiatry and Behavioral Sciences, Baltimore, USA 2 Johns Hopkin University, Krieger School of Arts and Sciences, Baltimore, USA The aim of this analysis of emails authored by an FTD-ALS subject was to examine illness-related decline in real-life language. The subject developed abnormal conduct at age 70 and survived 32 months. Dysarthria and dysphagia developed at 7 months, and anarthria by month 24. Limb weakness was mild at death. TDP-43 inclusions were seen postmortem in temporal cortices and spinal cord motor neurons. We had 1019 emails (996 after removing duplicates and forwarded content) covering 825 days from onset to 4 months before death. We computed for each email: time since preceding message, total sentences and words, fractions from each lexical class (nouns, adjectives, etc.), Flesch-Kincaid grade level, word perseverations and phrase length, using the R package ‘koRpus’ and the ‘TreeTagger’ program. Expected vocabulary size was estimated at 20 tokens using the R package ‘zipfR’. In thematic analysis, two independent raters assigned content to 12 predefined themes (inter-rater correlations for themes and subthemes per message were 85.5% and 93.4%, respectively). We used averaged ratings to computed theme and subtheme frequencies, and ratios of words to themes (i.e., verbosity) and subthemes to themes (i.e., richness). Mean slopes were computed for all parameters. Sentences, words, average sentence length, grade level, noun fraction, adverb fraction, determiner fraction, conjunctions per sentence, phrase length, vocabulary size, themes, verbosity and richness showed mean decline (p < 0.05), while message interval, verb fraction, pronoun fraction and word perseverations increased. Fraction of functional words (including prepositions, determiners and conjunctions) did not change. On visual inspection, late emails were vacuous and lacked sentence structure. Altogether, the data show progressive loss of volume, content, complexity and grammar. This study demonstrates that quantitative analysis of naturalistic writing can describe language decline in patients who no longer produce speech. Next steps include defining metrics for syntax breakdown and validation studies.

P125 Longitudinal performance of global measures of illness severity in semantic dementia K. Kansal1, H. Amjad1,2, S. Saxena1,3, C. Onyike1 1 Johns Hopkins University, Psychiatry and Behavioral Sciences, Baltimore, USA 2 Johns Hopkin University, internal Medicine/Geriatric Medicine and Gerontology, Baltimore, USA 3 Johns Hopkins University, Bloomberg School of Public Health, Baltimore, USA We characterized the trajectories of illness severity scores in semantic dementia and examined their sensitivity to decline in different stages of disease. The study included 33 subjects from the National Alzheimer Coordinating Centers. Sigmoid mixed effects models were used to analyze z-scores of the MMSE, Functional


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Activity Questionnaire (FAQ), and Clinical Dementia Rating Sum of Boxes (CDR-SB), and raw scores of the Neuropsychiatric Inventory Questionnaire (NPI-Q), as functions of illness duration. We performed 100 non-parametric bootstraps per model to assess reliability, and derived means and 90% confidence intervals for: (i) testing range (the difference between the asymptotes), (ii) time at 5% decline (T5; illness duration when the curve has covered 5% of the testing range), and (iii) time at 95% decline (T95; illness duration when the curve has covered 95% of the testing range). Of all the tests, CDR-SB showed the largest testing range (51.11, CI: [49.38, 53.48]), followed by the MMSE (-18.57, CI: [14.73, 21.59]). Testing range was much smaller with other tests. The upper limit of the NPI-Q T5 confidence interval was 2.46 years (the lower limit was out of bounds), suggesting early change. The upper limits of the T5 confidence intervals for FAQ, MMSE and CDR-SB were 3.5–4.5 years. The MMSE and CDR-SB scores were plateaued in the first 1–3 years of illness. The CDR-SB also showed late floor effects (at 9.38 years, its lower limit of the confidence interval for T95 was the highest of the measures). In summary, the CDR-SB and MMSE provide good sensitivity for decline in the intermediate period of illness, but not at the beginning, and CDR-SB retains utility until late into the illness. Owing to the small sample size, computations of mean trajectories are imprecise for the other tests, which appear to show higher between-individual variability.

P126 Neuropsychiatric symptoms in the genetic frontotemporal dementia initiative (GENFI) cohort L. Sellami1,2, M. Bocchetta3, J. van Swieten4, B. Borroni5, D. Galimberti6, M. Masellis7, J. B Rowe8, C. Graff9, F. Tagliavini10, G. Frisoni11, E. Finger12, A. Mendoncßa13, S. Sorbi14, K. M. Dick15, J. D. Rohrer15, R. LaforceJr1,2 1 Faculte de Medecine Universite Laval, Quebec, Canada 2 Clinique Interdisciplinaire de Memoire Hôpital de l’Enfant-Jesus, Sciences Neurologiques, Quebec, Canada 3 Institute of Neurology, Dementia Research Centre, London, United Kingdom, Great Britain 4 Erasmus Medical Center, Department of Neurology, Rotterdam, Netherlands 5 Centre for Neurodegenerative Disorders, University of Brescia, Brescia, Italy 6 University of Milan, Fondazione C a Granda, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Policlinico, Milan, Italy 7 Sunnybrook Health Sciences Centre, Toronto, Canada 8 University of Cambridge, Department of Clinical Neurosciences, Cambridge, Great Britain 9 Karolinska Institutet, Huddinge, Stockholm, Sweden 10 Istituto Neurologico Carlo Besta, Milano, Italy 11 Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy 12 London Health Sciences Centre, London Ontario, Canada 13 Memoclınica, Lisboa, Portugal 14 University of Florence, Department of Neuroscience, Psychology, Drug Research and Child Health, Florence, Italy 15 Dementia Research Centre Institute of Neurology, UCL, London, Great Britain It is now well-accepted that various neuropsychiatric symptoms (NPS) expand the phenotype of frontotemporal dementia (FTD) beyond its traditional behavioral alterations such as disinhibition, apathy and lack of empathy. Among the three main genes

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responsible for FTD (microtubule-associated protein tau or MAPT, progranulin or GRN and chromosome 9 open reading frame 72 or C9orf72), mutations in C9orf72 have been associated with the most florid combination of NPS. This study explored the NPS within presymptomatic and affected FTD mutation carriers between the three genes in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort. More precisely, NPS such as hallucinations (visual, auditory, tactile), delusions, depression and anxiety were studied. Clinical data were compared according to the mutation status. The GENFI cohort consists of 365 participants of whom 205 are mutation carriers: data from these carriers was analyzed, consisting of 134 presymptomatic (MAPT = 24, GRN = 67, C9orf72 = 43) (mean age 45 11) and 71 affected (MAPT = 17, GRN = 21, C9orf72 = 33) (mean age 62 7) cases. In the presymptomatic group, there was a trend towards more C9orf72 mutation carriers presenting with one or more NPS as compared to other genes (27.9% vs. 15.4%, p = 0.087). C9orf72 mutations tended to be associated with depression (23.3% vs. 12.1%, p = 0.097). In the affected group, NPS were common across all mutations (C9orf72 = 78.8%, MAPT = 82.4%, GRN = 71.4%, p = 0.7), without significant differences in either frequency or severity. Altogether, NPS and particularly depression appeared more associated with C9orf72 gene carriers presymptomatically but during the symptomatic period no differences were seen between the genes. Distinct underlying structural and neurobiological changes driving these differences may help develop behavioral biomarkers that might be useful as a diagnostic, prognostic, and progression tool for the monitoring of efficacy in upcoming therapeutic trials.

P127 Differences on neuropsychological measures in asymptomatic (CDR = 0) versus mildly symptomatic (CDR = 0.5) mutation carriers: preliminary data from LEFFTDS J. Kramer1, S. Weintraub2, B. Boeve3, H. Rosen1, A. Boxer1, G. Coppola4, C. Dheel3, B. Dickerson5, K. Faber6, J. Fields3, T. Faroud6, R. Gavrilova3, N. Ghoshal7, J. Goldman8, N. GraffRadford9, M. Grossman10, H. Heuer1, J. Hsiao11, R. Hsiung12, E. Huey8, D. Irwin10, K. Kantarci3, A. Karydas1, D. Knopman3, J. Kornak1, W. Kukull13, I. Mackenzie12, B. Miller1, C. Phelps11, R. Rademakers9, K. Rankin1, L. Shaw10, M. Sutherland14, A. Toga15, J. Trojanowski10, A. Vetor6, Z. Wszolek9 1 UCSF, San Francisco, USA 2 Northwestern, Chicago, USA 3 Mayo Clinic, Rochester, USA 4 UCLA, Los Angeles, USA 5 Massachusetts General Hospital, Boston, USA 6 Indiana University, Indianapolis, USA 7 Washington University, St. Louis, USA 8 Columbia University, New York, USA 9 Mayo Clinic, Jacksonville, USA 10 University of Pennsylvania, Philadelphia, USA 11 NIA, Bethesda, USA 12 University of British Columbia, Vancouver, Canada 13 University of Washington, Seattle, USA 14 NINDS, Bethesda, USA 15 USC, LONI, Los Angeles, USA We hypothesized that differences on various measures would exist between asymptomatic (+mCDR = 0) and mildly symptomatic



(+mCDR = 0.5) mutation carriers in the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Consortium, which involves subjects in kindreds with mutations in microtubule associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72). We analyzed data from the California Verbal Learning Test (CVLT) and National Alzheimer’s Coordinating Center Uniform Data Set (UDS) neuropsychological battery among +mCDR = 0 (n = 34) and +mCDR=0.5 (n = 35) subjects evaluated through February 2016. Measures in the UDS battery included the following: Craft StoryImmediate (CS-I) and Delayed (CS-D) Recall, Number SpanForward (NS-F) and Backward (NS-B), Trail Making Test – parts A (TMT-A) and B (TMT-B), Category Fluency using Animals (CF-A) and Vegetables (CF-V), Verbal Fluency using the letters F (VF-F) and L (VF-L), Multilingual Naming Test (MINT), and Benson Complex Figure-Copy (BCF-C) and Recall (BCF-R). Comparing data between the +mCDR = 0.5 vs. +mCDR = 0 groups, statistically-significant mean differences (p < 0.05) were shown for NS-F for correct trials (7.6 vs. 8.9) and longest span (6.4 vs. 7.4), NS-B for correct trials (6.4 vs. 8.3) and longest span (4.8 vs. 5.7), TMT-A (33.5 vs. 23.8 s), TMT-B (85.6 vs. 59.4 s), VF-F (11.4 vs. 17.1), VF-L (11.7 vs. 15.6), and BCF-R (11.5 vs. 13.1). No differences were shown for the CVLT, CS-I, CS-D, CF-A, CF-V, MINT or BCF-C. These preliminary data suggest there is reduced performance on measures of attention, verbal fluency and visual memory, and similar performance on measures of verbal memory, category fluency and constructional praxis, among mildly symptomatic compared to asymptomatic mutation carriers in familial FTD kindreds.

P128 Depressive symptoms in patients with frontotemporal lobar degeneration M. Hashimoto1, R. Fukuhara1, K. Kaneda1, M. Ikeda1 1 Kumamoto University, Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto, Japan Depression is common symptom in Alzheimer’s disease, dementia with Lewy bodies and vascular dementia and is associated with poorer outcomes. However, less is known about the clinical features of depression on frontotemporal lobar degeneration (FTLD). In this study we investigated the prevalence and the clinical features of depression in patients with FTLD. The subjects were 18 probable behavioral variant of frontotemporal dementia (bvFTD) and 25 semantic dementia (SD) patients who visited to Kumamoto university hospital outpatient dementia clinic for examination between April 2007 and December 2014. Depressive symptoms were assessed by both the Japanese version of the Geriatric Depression Scale (GDS, 15-items) and the depression/dysphoria item on the Japanese version of the Neuropsychiatric Inventory (NPI). A score equaling or higher than 6 on the GDS was taken as the cut-off point for presence of depressive symptoms. In the bvFTD group, mean GDS score was 4.1 and 6 patients (33%) had depressive symptoms with the GDS. Among the 6 patients, 4 also showed depressive symptoms with the NPI. In the SD group, mean GDS score was 7.2 and 16 patients (64%) showed depressive symptoms with the GDS. However, only 6 patients of the 16 had depression with the NPI. In the present study, depression was common symptom in both bvFTD and SD. SD was associated with a higher incidence of depression than bvFTD. The difference of the

prevalence seen between GDS and NPI in SD suggests that patients with SD might be more strongly aware of depressive symptoms than one looks.

P129 Virtual reality as an assessment of cognition in behavioural variant Frontotemporal Dementia: A Feasibility Study E. Brotherhood1, J. Drummond2, D. Swapp2, L. Russell1, S. Primativo1, C. Hardy1, A. Steed2, M. Slater2, J. D. Rohrer1, J. Warren1, S. Crutch1 1 University College London, Institute of Neurology, London, UK, Great Britain 2 University College London, Computer Science, London, UK, Great Britain Evidence suggests that Virtual Reality (VR), a simulated computer-generated environment, is a useful tool to assess various cognitive domains in people with dementia. To date, feasibility studies of VR investigations in people with behavioural variant Frontotemporal Dementia (bvFTD) have focused on head-mounted display setups in which participants remain seated throughout the scene (Mendez et al. Dis & Rehab 2014; 10 160–164). We report here on the feasibility of assessing individuals with bvFTD, typical Alzheimer’s disease (tAD) and healthy participants in short VR investigations presented in a Cave-like Trimension ReaCTor system (CAVE). In this setup, VR scenarios are projected onto a cuboid space, and participants are able to stand and move around the scene. 10 individuals with bvFTD, 10 with tAD and 20 healthy volunteers will be immersed in a 5-min virtual cafe scene. The scenarios have been developed to measure social behaviour, and include the following manipulations: the visual and social distinctiveness of the customers, the extent to which the participant is privy to social exchanges, and the valence of those exchanges. The scene also includes a ‘slapstick’ style accident. Observational measures include verbal and physical reactions, location and proximity data, direction of gaze and pre-/post-immersion questionnaires and interviews. Correlational measures include carer questionnaire reports of behaviour, and Mini-SEA assessment performance. We will report on overall performance and group differences across all measures. Early analyses indicate that CAVE setup VR scenarios are welltolerated in individuals with bvFTD and healthy volunteers. Data from the pre- and post-immersion questionnaires indicate no significant differences between levels of comfort pre- and postimmersion in either the control or the bvFTD groups. Overall, preliminary data analyses support previous studies suggesting that individuals with bvFTD tolerate VR scenarios well, and contribute to the current feasibility literature to include tolerance for VR scenarios in a CAVE setup.


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P130 Mistakes, I’ve made a few: Intact awareness, but impaired emotional processing of errors in bvFTD H. Rosen1, C. Scherllng1,2, J. Zakrzewski1,3, S. Datta1, R. Levenson4, V. Sturm1, B. Miller1 1 University of California, San Francisco, Neurology, San Francisco, USA 2 University of San Francisco, San Francisco, USA 3 University of Florida, Gainsville, USA 4 University of California, Berkeley, Berkeley, USA Anosognosia, or lack of awareness of one’s deficits, is a core feature of the behavioral variant of frontotemporal dementia (bvFTD). We hypothesized that this deficit has its origins in impaired emotional processing of errors. We studied patients with bvFTD (n = 17), Alzheimer’s disease (AD, n = 20) and controls (CON, n = 35) using a timed two-alternative choice button press task designed to induce errors. Facial reactivity was monitored via video, blindly coded, and grouped into self-conscious (amusement, embarrassment) and negative (fear, sadness, anger, disgust, contempt) emotions. Skin conductance response (SCR) was monitored via digital sensors. The SCR and intensity-by-duration product for facial emotions was calculated for each trial. Controls corrected the vast majority of their errors and showed a tendency to slow down on trials that followed errors. Surprisingly, bvFTD patients corrected the majority of their errors as well, although the proportion was significantly reduced compared with controls, and AD corrected significantly fewer errors than controls or bvFTD. All groups showed similar post-error slowing. Controls produced significant increases in SCR and facial reactivity, including both negative and self-conscious emotions, for errors compared with non-error trials. In contrast, although bvFTD patients produced negative emotional responses to a similar degree as controls, they failed to produce selfconscious emotions and also showed no significant increase in SCR for errors. AD showed no deficit in facial reactivity to errors. Although SCR was generally reduced in AD, they showed a preserved increase in SCR for errors relative to correct trials. These results demonstrate a specific deficit in emotional responses to errors in bvFTD, encompassing both physiological response and a specific deficit in self-conscious emotions, despite intact awareness and behavioral response to errors. The results provide a potential mechanism for anosognosia in bvFTD and possibly other behavioral abnormalities.

P131 Misdiagnosis of very early frontotemporal dementia F. Stella1,2,3, L. Mella3, V. Marques3, T. Fontana3, J. Loureiro2,3, L. Silva3 1 UNESP - Universidade Estadual Paulista, Biosciences Institute, Rio Claro-SP, Brazil, Brazil 2 Laboratory of Neurosciences LIM-27, IPq, FCM-USP, SP, Brazil, Instituto of Psychiatry, S~ ao Paulo, Brazil 3 University of Campinas, Neuropsychiatry and Geriatric Psychiatry Clinic, Campinas-SP, Brazil The aim was to discuss the misdiagnosis of FTD, having special reference to a clinical case. A 30 year-old female, married, with no previous report of mental disorders, drugs abuse, or medical illnesses was diagnosed with schizophrenia in 2013. Her father had a psychiatric disease, however not clearly explained. She was a

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normal person with good affective and emotional control, normal cognition and functionality before she became ill. Her family reported a 3-year history of progressive behavioural disturbances (social isolation, sleep disorders, aberrant behaviours, compulsive eating of uneatable products, aggression, delusions, hallucinations, persecutory attitudes, sexual affairs and disinhibition) needing three hospitalizations since she got sick. The patient also exhibited progressive cognitive impairment mainly attributed to decay of reasoning and thinking control. Despite psychopharmacological treatment with antipsychotics, antidepressants, benzodiazepines, and anticonvulsants the patient rapidly had worsened, losing behaviour control, executive processes, global cognition, and instrumental activities becoming dependent for all basic procedures (bathing, feeding, personal hygiene). Recently she was referred to the University Hospital for investigation. Her history, clinical examination and MRI support the diagnosis of frontotemporal dementia. The MRI displays a very prominent atrophy of frontal and temporal regions, notwithstanding the neurodegeneration had reached the whole brain. Based on clinical data and MRI the diagnosis of schizophrenia was changed to frontotemporal lobar degeneration (behaviour variant). Nowadays she remains at severe level of dementia needing complete care for bathing, eating, and personal hygiene. The clinicians had prescribed trazodone and quetiapine to control behavioural disturbances, however with limited efficacy. The main lesson from this case comprises the misidentification of early neuropsychiatric manifestations of frontotemporal dementia and the delay of reaching the accurate diagnosis.

P132 Clinical and neurocognitive correlates underlying the first symptoms in behavioral variant of frontotemporal dementia (BVFTD) H. Santamarıá Garcıá1,2, P. Reyes1, S. B aez2, ^ı Martınez1, 1 3 a~ nez2 J. Santacruz , M. Sigman , D. Matallana1, A. Ib 1 Pontificia Universidad Javeriana, Medicina, Bogot a, Colombia 2 Laboratorio de Psicologıa Experimental y Neurociencias LPEN, Instituto de Neurociencia Cognitiva y Traslacional INCyT, Neuroscience, Buenos Aires, Colombia 3 Laboratorio de Neurociencias, Universidad Torcuato Di Tella, Buenos Aires, Argentina Previous works highlight the neurocognitive differences between apathetic and disinhibited clinical presentations of the behavioral variant frontotemporal dementia (bvFTD). However, little is known regarding how the early presentation (i.e., first symptom) shapes the neurocognitive correlates of the disease’s clinical presentation and progression. In this study we evaluated the neuropsychological, clinical and neuroanatomical (3T structural images) correlates in a group of healthy controls (n = 30) and two groups of bvFTD patients (presented with apathy [AbvFTD, n = 18] or disinhibition [DbvFTD, n = 16]). To differentiate groups according to first symptoms, we used multivariate analyses (factorial Discriminant Analysis (FDA) and Support Vector Machine (SVM)). Our results showed that the first symptom in patients was critical in describing the course and evolution of the disease. AbvFTD and DbvFTD patients showed increased brain atrophy (voxel based morphometry, VBM) and increased levels of disinhibition and apathy, respectively. Whole brain analyzes in AbvFTD revealed atrophy in the frontal, insular and temporal areas. DbvFTD, in turn, presented atrophy in the prefrontal regions, temporoparietal junction, insula and



temporoparietal region. Increased atrophy in DbvFTD patients (compared to AbvFTD) was observed in frontotemporal regions. Multivariate analyses (FDA and SVM) confirmed that a set of four variables (right orbitofrontal cortex, left caudate, and different clinical features including behavioral scores of apathy and disinhibition) were enough to distinguish the patients’ subgroups. Taken together, our study shows that the first symptom in bvFTD patients is critical in describing the course of neuropsychological and neuroanatomical impairments, playing an important role in the early detection, disease tracking, and neuroanatomical specification of bvFTD, as well as in future research on potential disease-modifying treatments.

P133 Frontotemporal dementia and schizophrenia – whats the connection I? An updated case series and review of the literature D. Velakoulis1, S. Loi1 1 Royal Melbourne Hospital, Neuropsychiatry, Melbourne, Australia Background: The relationship between schizophrenia and frontotemporal dementia has attracted interest in recent years. Clinical, neuropathological and neurogenetic studies have identified an association between schizophrenia and frontotemporal dementia. A 2009 study (Velakoulis et al.) showed that up to 33% of younger patients with FTD (< 40 y.o) presented with a schizophrenia like illness while clinicopathological/genetic series have shown that psychosis is a common presentating syndrome in patients with the C9ORF mutation. The current study reviews patients seen in our neuropsychiatry service who presented with a history of schizophrenia and were diagnosed with FTD. Methods: We identified patients referred to our clinical neuropsychiatry inpatient service for diagnostic assessment between 2009 and 2014 who had a presenting diagnosis of schizophrenia and who were then diagnosed with behavioural variant FTD. Results: Of the 600 admissions between 2009 and 2014, we identified 10 patients who had been referred with a diagnosis of schizophrenia and were diagnosed with FTD. Clinical characteristics of this group were: 6 female: 4 male; mean age at diagnosis of FTD 51.7 (range 36–60), mean age at schizophrenia onset 40.3 (range 19–54); mean duration of schizophrenia 11.9 years (range 4–32). Three patients had a very long history of schizophrenia (20– 32 years) while the other 7 patients had a history of schizophrenia < 8 years. Discussion: We identified two groups of patients in this small cohort. The first group consists of patients with longstanding schizophrenia who slowly develop cognitive decline and clinical features of an FTD while the second group have a relatively short prodrome of psychosis which begins later in life and heralds the development of FTD. A review of cases in the literature reveals a similar grouping of patients. These data suggest two alternative hypotheses that: 1. Schizophrenia and FTD lie along a spectrum of disease or 2. The observed relationship between schizophrenia and FTD is a frontotemporal ‘coincidence’.

P134 Neuronal correlates of theory of mind and emotion comprehension during insincere communication in neurodegenerative disease G. Toller1, T. Shany-Ur1, S. Shdo1, L. Bouvet1, C. Mielke1, S. N. Grossman1, P. Poorzand1, B. L. Miller1, K. P. Rankin1 1 University of California San Francisco, Memory and Aging Center, Department of Neurology, San Francisco, USA Comprehension of insincere communication requires interpretation of the speaker’s intention, a complex process that involves integration of theory of mind reasoning (ToM), emotion reading, and contextual information. Using Part 3 of The Awareness of Social Inference Test, we studied structural correlates of ToM and emotion reading during insincere communication in 152 subjects [23 behavioural variant frontotemporal dementia (bvFTD) patients, 16 semantic variant primary progressive aphasia (svPPA), 46 Alzheimer’s disease (AD), 16 progressive supranuclear palsy (PSP), 51 healthy older controls (NC)]. We used item subtotals for visual perspective taking with concrete objects (VIS), identification of beliefs (VERB), understanding intentions (DO), and identifying emotions (FEEL). Compared with NCs, patients with svPPA and bvFTD had impaired VIS, VERB, DO, and FEEL scores (p < 0.05). PSPs were clinically impaired relative to NCs on VERB and DO scores, and ADs were impaired on FEEL score. Voxelbased morphometry showed that reduced VERB (belief identification) scores related to atrophy in right lateral temporal lobe, frontoinsula, and subcortical reward regions, while DO (intention identification) scores involved bilateral fronto-insula and subcortical reward regions. More simple visual perspective taking (VIS) deficits correlated with left hippocampal atrophy, while inability to identify emotions (FEEL) correlated with left amygdala atrophy. These results suggest that complex belief and intention representation engage complex bilateral fronto-temporal and subcortical networks involved in evaluating complex or ambiguous social signals, whereas simpler visual perspective taking and emotion reading rely on left medial temporal regions mediating memory and perception of social salience. Patients with svPPA and bvFTD had impaired comprehension of insincere communication, attributable to neurodegeneration of the circuits necessary for perceiving social salience and manipulating belief and intention in the context of complex indirect communication.

P135 Intra-individual variability in cognitive measures as a differential marker of genetic variant FTD: a neuropsychological perspective A. Sepehry1, D. Wittenberg1, P. Sengdy1, P. Slack1, M. Baker2, R. Rademakers2, H. Feldman1, I. Mackenzie3, G.-Y. Hsiung1 1 The University of British Columbia, Division of Neurology, Vancouver, Canada 2 Mayo Clinic, Department of Neuroscience, Jacksonville, USA 3 The University of British Columbia, Centre for Brain Health, Department of Pathology and Laboratory Medicine, Vancouver, Canada Within-person cognitive performance variability across repeated administrations has been found to be sensitive in age-related cognitive decline. Additionally, individuals with neurodegenerative conditions demonstrate greater intra-individual variability (IIV) on


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cognitive tasks compared to healthy controls. We hypothesize that the index of IIV in cognitive measure is a potential marker in early disease state, and will differentiate individuals carrying mutations in C9ORF72 (C9) and GRN from non-carriers prior to onset of clinical dementia. Longitudinal neuropsychological assessments on attention, executive function, language, memory and global cognition were used to calculate a coefficient of variation (CV) as a measure of IIV for each asymptomatic subject at risk for familial FTD. General liner model via multi-variables analyses of variance (mANOVA) group differences were used to compare the CV scores. We found that the variation in non-verbal memory Z scores differentiated genetic status among four groups [C9 mutation carriers, C9 family noncarriers, GRN mutation carriers, GRN family non-carriers] [p = 0.041 in those with 3 or more assessments; p = 0.026 in those with 2 assessments only]. Subgroup analysis for C9 carriers vs. noncarriers further showed that the variability in attention Z scores [p = 0.048] and non-verbal memory Z scores [p = 0.016] differentiated carriers from non-carriers. No significant differences in IIV were observed in other measures. In summary, we found that IIV in test scores on non-verbal memory and attention are sensitive measures that can differentiate mutation status between carriers and non-carriers, especially in C9 families, and may be applied in the clinical setting to detect early symptoms in individuals beginning to suffer from FTD. Future studies with larger sample size are warrented.

P136 The moral emotions assessment: a new tool for the early diagnosis of frontotemporal dementia C. Daigmorte1, M. Camus2, T. Mauras2,3, A. Funkiewiez1,2, I. Le Ber2, B. Dubois1,2, R. Levy1,2, M. Teichmann1,2, C. Azuar1,2 1 Institut National de la Sante et de la Recherche Medicale INSERM, Institut du Cerveau et de la Moelle epiniere ICM, Universite Pierre et Marie Curie, Paris 6, UMRS 975, Paris, France 2 AP-HP, Federation de Neurologie, Institut de la Memoire et de la Maladie d’Alzheimer, Unite de Neuro-Psychiatrie Comportementale IHU, Centre de Reference des Demences Rares, Groupe Hospitalier Pitie-Salpêtriere, Paris, France 3 Service de Psychiatrie, Centre hospitalier Sainte-Anne, Paris, France Moral cognition is crucial for human interaction, and is markedly impaired in the frontal variant of frontotemporal dementia (fvFTD), a disorder characterised by antisocial acts and potential acquired sociopathy. Changes in personality and behaviour seen in fvFTD may reflect impairment in moral sentiments processing. In this study we proposed a new battery investigating moral cognition, called Moral Emotions Assessment (MEA). MEA explored positive and negative feelings (as admiration, gratitude, pity, guilt, shame or anger) andconsisted in 66 scenarios followed by four moral emotions among which the participant had to choose the most appropriate.Three groups of participants were studied using MEA: 20 patients with fv-FTD, 15 patients with Alzheimer’s diseases (AD) confirmed by CSF biomarkers and 50 healthy controls. Results showed that the moral scores were significantly different in the three groups with a maximum impairment in fv-FTD patients, especially in negative “self-conscious” moral feelings such as guilt or shame. MEA seemed to be a sensitive test when compared with other cognitive tests used in this context.

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MEA opens a new window on human behaviour and could be proposed as a new diagnosis tool helping to diagnose fv-FTD patients in early stages.

P137 ECOCAPTURE. A quantitative evaluation of apathy close to real life situation by means of a multimodal sensor system integrated B. Batrancourt1,2,3,4,5, K. Lecouturier1,2,3,4,5, C. Araujo1,2,3,4,5, V. Guillemot2,3,4,5,6, C. Azuar1,2,3,4,5,7, R. Levy1,2,3,4,5,7 1 INSERM, FrontLAB, ICM, Paris, France 2 INSERM, U 1127, F-75013, Paris, France 3 CNRS, UMR 7225, F-75013, Paris, France 4 Sorbonne Universites, UPMC Univ Paris 06, UMR S 1127, F75013, Paris, France 5 Institut du Cerveau et de la Moelle epiniere, ICM, F-75013, Paris, France 6 ICM, Biostatistics/Bioinformatics Core Facilty, F-75013, Paris, France 7 AP-HP, Hôpital de la Pitie Salpêtriere, Federation de Neurologie, Institut de la Memoire et de la Maladie d’Alzheimer, F-75013, Paris, France Apathy is the most frequent behavioral syndrome in neurological diseases. It is almost constant in the behavioral variant of frontotemporal dementia (FTD). Historically, apathy has been viewed as a clinical syndrome due to a lack of motivation. We adopt a behaviorist point of view considering apathy as the quantitative reduction of self-generated voluntary and purposeful behaviors. We attempt to quantify the subject’s behavior and to detect a signature of apathy. The study ECOCAPTURE implements a quantitative evaluation of apathy close to real-life situation by means of a multimodal registering system (sensor, video). The study takes place into the ICM’s core facility (PRISME) dedicated to the functional exploration of human behavior. This pilot study focused on FTD patients (n = 6) and healthy controls subjects (n = 6). The subject was led into a welcome room and we explained to him that he could use the space and objects at his own convenience. The scenario incites the subject to explore the room during the 45 min long experimental session. An ethogram-based method is used to observe and record behavioral data. Results are confronted with the Starkstein apathy scale score (STARK). We extracted 54 variables of interest belonging to 3 blocks of variables: SENSOR (26 var.), VIDEO (14 var.) and TESTING (14 var.). Principal Component Analysis is used on each data block. All the resulting graphs show that the two-first principal components distinguish patients from controls. We used Regularized Generalized Canonical Correlation Analysis to determine links between VIDEO, SENSOR and STARK measures. All the obtained components are strongly correlated (> 0.7) and the graph of components strongly separates patients from controls. A differential analysis (Student’s t-test of comparison between patients and controls applied to each variable, followed by a correction for multiple testing) provides 25 significantly different variables. In particular, variables rating the activity and the physical position during the first 3 min show a very small p-value (≤ 0.0005).



P138 Physical aggressiveness among patients with a neuropathologically confirmed dementing disorder M. Liljegren1, M. Landqvist Wald€ o2, A. Frizell Santillo3, E. Englund1 1 Lund University, Division of Oncology and Pathology, Department of Clinical Sciences, Lund, Sweden 2 Lund University, Geriatric Psychiatry, Department of Clinical Sciences, Lund, Sweden 3 Lund University, Clinical Memory Research Unit, Department of Clinical Sciences, Malm€ o, Sweden Physical aggressiveness is encountered among demented individuals. We investigated the frequency and time at onset of physical aggressiveness among patients with a neuropathologically confirmed dementing disorder. We conducted a retrospective medical record review of 283 patients who were seen at the Memory Clinic at Lund University Hospital between 1969 and 2013. This included patients with Alzheimer’s disease (AD, n = 102), Frontotemporal dementia (FTD, n = 98), Vascular dementia (VaD, n = 43) and Alzheimer’s disease and Vascular dementia (AD/VaD, n = 40). Patient notes during the patients’ illnesses were reviewed. Noting physical aggressiveness, as for prevalence and time during the course of disease, the frequency of violent behavior was assessed among the different diagnostic groups. Of the 283 patients studied, 97 (34.3%) had a history of physical aggressiveness at some point during the course of their illness. The prevalence among the different diagnostic groups was: AD 42 cases (41.2%), FTD 29 cases (29,6%), AD/VaD 14 cases (35.0%) and VaD 12 cases (27.9%). Physical aggressiveness was exerted both in the early and the late stages of the patients’ illnesses. Among patients with FTD, 48.3% exerted physical aggressiveness in the early stages of the disease. In AD, VaD and AD/VaD physical aggressiveness was markedly more prevalent in the later stages of the disease. The physical aggressiveness ranged from occurring in nursing situations to unprovoked assault. Aggressive and violent behaviors pose a great burden for people living with or taking care of patients suffering from dementia. Physical aggressiveness can be an early sign of frontotemporal dementia and is more likely to be a late manifestation of other dementing disorders.

P140 Association between MoCA subitem scores and corresponding cognitive test performance in patients with bvFTD K. Coleman1, B. Coleman2, J. MacKinley1, S. Pasternak1, E. Finger1 1 St. Joseph’s Health Care, London, Cognitive Neurology, London, Canada 2 Mount Sinai Hospital, Infectious Disease Epidemiology Research Unit, Toronto, Canada The Montreal Cognitive Assessment (MoCA) is a brief cognitive screening test originally developed to detect patients with mild cognitive impairment (Nasreddine et al.J Am Geriatr Soc 2005; 53 695–9) is now widely used in clinical settings across North America. The MoCA has recently been demonstrated to be sensitive to cognitive deficits in Frontotemporal Dementias (FTD) and related disorders (Coleman et al. ADAD 2015). Given attentional impairments in patients with FTD, whether and to what extent the abbreviated items on the MoCA may predict performance on

corresponding longer neuropsychological assessments is not yet known. This knowledge would inform interpretation of subitem scores on the MoCA and efficient allocation of resources for patient assessment. Testing and demographic data was extracted from a clinical database using a sample of 43 probable bvFTD patients. The relationship between MoCA items and corresponding neuropsychological tasks was assessed through McNamar Tests for categorical items and Spearman correlations for linear items. Results demonstrated that patients with bvFTD were more likely to fail the full Trails B test than MoCA Trails (p = 0.001) but that other MoCA abbreviated items were strongly correlated with or predictive of performance on longer cognitive tests. These results indicate that in addition to use as a screening tool, some of the abbreviated items on the MoCA may be used as accurate indicators of bvFTD patients’ performance on longer cognitive tests in specific domains.

P141 The differences of characteristics in abnormal eating behaviors in semantic dementia between right and left predominant temporal lobe atrophy R. Fukuhara1, M. Hashimoto1, S. Shinagawa2, K. Shigenobu3, H. Tanaka1, K. Kawahara1, Y. Miyagawa1, N. Ichimi4, M. Ikeda1 1 Kumamoto University, Department of neuropsychiatry, Kumamoto-city, Japan 2 The Jikei University School of Medicine, Department of Psychiatry, Tokyo, Japan 3 Asakayama Hospital, Osaka, Japan 4 Kumamoto University Hospital, Kumamoto-city, Japan Introduction: It is well known that various abnormal eating behaviors including changes of appetite and food preference, and pica occur in patients with semantic dementia (SD) in course of the disease. In SD, pattern of temporal lobe atrophy are usually asymmetric. Some reports mentioned to the relationship between predominance of atrophy and characteristic cognitive dysfunctions, but the relationship between predominance of atrophy and abnormal behaviors still remains unknown. The aim of this study is to investigate the relationship of the asymmetry of temporal lobe atrophy and characteristics of abnormal eating behaviors in SD. Methods: Subjects were entered from consecutive patients in higher brain function clinic in Kumamoto University Hospital, Ehime University Hospital and Asakayama Hospital, who met the international consensus criteria of SD. All subjects underwent neurological examinations and psychiatric evaluation as well as laboratory testing, neuropsychological testing, brain MRI/CT scan and the care-giver-based assessment scale of eating behaviors. The scale for abnormal eating behaviors consists of 36 items investigating five domains: swallowing problem, appetite change, food preference, eating habits and other oral behaviors. Predominance of atrophy side was decided by visual inspection of morphological images. Results: Fifty-one subjects were analyzed. Thirty-one cases showed left predominant atrophy and 20 cases showed right. There were no differences between two groups in age at examination, years of education and the score of MMSE. In eating behaviors, there are significant differences in 4 items such as “hoarding sweets and other food”, “tendency to overfill his/her mouth”, “eat non-ediblefoodstuffs or things not normally eaten” and “tendency to snatch or grasp any food items within reach” between two groups. Conclusion: There are no significant differences in the domain of swallowing problem and appetite change. SD with right


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predominant atrophy had more abnormal eating behaviors than with left atrophy.

P142 Relationship between cognitive declines and independency in the activities of daily living in patients with frontotemporal dementia M. Hotta1, M. Hashimoto2, R. Fukuhara2, A. Koyama2, M. Murata1, K. Yoshiura1, T. Ishikawa2, H. Tanaka1, M. Ikeda2 1 Kumamoto University Hospital, Neuropsychiatry, Kumamoto, Japan 2 Kumamoto University, Kumamoto, Japan Daily life-at home for dementia patients is desirable to keep QOL, but worsening of ADLs is one of the factors inhibiting their independency life. Worsening of ADLs for frontotemporal labor degeneration (FTLD) patients is not better known than Alzheimer’s disease (AD) patients about how ADLs worsens by cognitive declines. The aim of this study is to analyze the relationship between cognitive function and ADLs in AD and FTLD patients and to clarify factors inhibit daily life-at home, we will be able to prepare for the care environment for them sending independent life more longer. 50 (male/22, female/28) FTLD patients and their caregivers participated in this study, and 671 (male/219, female/452) AD for comparison similarly. All subjects were recruited from the Dementia Clinic in the Department of Neuropsychiatry, Kumamoto University Hospital, for evaluation from April 2007 to November 2014. To assess ADLs of each patient, the Physical Self- Maintenance Scale (PSMS) and the instrumental activities of daily living scale (IADL) are used. We checked the transition of the ratio of the patients in complete independence about the change of each item of PSMS and IADL score, and analyzed relationship between the Mini-Mental State Examination (MMSE) ortheClinical Dementia Rating (CDR) andADLs declines by using the Moving-average method. As a result, tendency to decrease gently was seen in ADLs according to decline of MMSE and CDR score in AD, no meaningful correlation was seen in MMSE score and ADLs in FTLD. However, tendency was seen in the relationship between CDR score and ADLs.When CDR sum of box was worse than 4–7 points, ADLs deteriorated rapidly. It was revealed that ADLs decline was not related to MMSE score in FTLD patient, because MMSE is used to evaluate AD and does not apply to FTLD. However, CDR evaluation tended to reflect the activities of daily living declines in FTLD patients. The characteristic relationship between CDR and ADLs score shown in FTLD patients suggests that ADLs in FTLD might be more strongly influenced by behavioral disturbance rather than cognitive dysfunction.

P143 Neurobiological subtract of false-belief reasoning: insights from frontotemporal dementia and Alzheimer’s disease B. Pascual1, S. Bajaj1, J. C. Masdeu1 1 Houston Methodist Research Institute, Cornell University, Houston, USA Recent fMRI studies in healthy individuals have suggested that the temporoparietal junction and medial prefrontal cortex subserve the attribution of false belief reasoning (FB), a crucial aspect of theory of mind (ToM). However, in these studies, many other regions are activated as well and fMRI alone cannot define what modules of the system are critical for the performance of this task. Frontotemporal dementia (FTD) and Alzheimer’s disease (AD) affect selectively some areas of the cortex more than others and therefore may be used to determine more precisely the cortical areas critical for FB. Including all the regions significantly activated in published fMRI studies of FB, we created eleven different regions of interest located in the temporoparietal junction, posterior inferior parietal lobe, medial prefrontal cortex (dorsal, anterior, and ventral), posterior cingulate and retroesplenial cortex, lateral temporal cortex, temporal pole, hippocampal formation and parahippocampal cortex. In a group of 12 patients, 3 with the behavioral variant of FTD (bvFTD), 4 with semantic dementia (SD), and 5 with the logopenic variant of primary progressive aphasia (lvPPA), we calculated the association between cortical thickness in the 11 regions of interest and performance in a ToM battery comprised of 8 first order and 8 s order FB tasks. All patients had PIB PET and tests of executive and general neuropsychological ability. The left temporoparietal junction was the only area associated with FB performance across the entire group. This correlation was independent of the severity of the disease. By diagnosis, patients with lvPPA showed more atrophy in the temporoparietal junction and worse FB performance than patients with bvFTD or SD. Patients with SD did not have atrophy in the temporoparietal junction or difficulty resolving FB tasks. Our results suggest that impaired ToM tends to correlate with temporoparietal junction thinning, rather than anterior temporal or frontal involvement.

P144 Altered fronto-thalamic functional connectivity and its association with emotion recognition deficits in frontotemporal dementia N. Multani1,2, C. J. Anor2, D. F. Tang-Wai1, R. Keren1, M. C. Tartaglia1,2 1 Toronto Western Hospital, University Health Network, Toronto, Canada 2 University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Toronto, Canada Recent literature suggests that fronto-thalamic connectivity decreases in certain psychiatric diseases, such as obsessivecompulsive disorder and schizophrenia. The different thalamic nuclei are involved in various functions and the medial dorsal nucleus (MDN) of the thalamus is implicated in the limbic system. The limbic system is often affected in frontotemporal dementia (FTD) therefore we examined the functional connectivity of the MDN. Patients diagnosed with FTD, (behavioral variant, semantic variant or non-fluent variant; N = 9, 66.1 + 9 years) and healthy

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controls (HC; N = 8, 59.9 + 5 years), underwent neuroimaging, neuropsychological examination and performed an emotion evaluation task (EET). Using rs-fMRI data and CONN toolbox, we carried out seed-to-voxel analysis of the MDN to assess for group differences in functional connectivity. Probabilistic tractography between the MDN and the region determined with rs-fMRI was performed using FSL software. The fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) values were obtained for the tract. The two groups did not differ in age, however, the HC group significantly outperformed the FTD group on the EET (HC=20, FTD=13; p = 0.005). There was a significant difference in connectivity between the left MDN and the left dorsolateral prefrontal cortex (DLPFC) between the two groups (p < 0.001). The HC group demonstrated positive connectivity between the MDN and DLPFC (r = 0.21, p < 0.001), whereas, individuals with FTD exhibited no connectivity between the two regions (r = 0.026). Furthermore, we found a significant positive correlation between MDN-DLPFC functional connectivity and EET (r = 0.77, p < 0.001). The MDN-DLPFC tract did not reveal any significant group differences in FA, AD, MD and RD. The findings of the current study suggest that the MDN-DLPFC functional connectivity is absent in FTD and this cannot be attributed to the anatomical connectivity between the two regions. Additionally, emotion recognition deficits in FTD can be due to altered MDNDLPFC connectivity.

P145 Frontal lobe dysfunction in early recovery period of ischemic stroke L. Pustokhanova1, E. Morozova1 1 Perm State Medical University, Department of Neurology, Perm, Russian Federation The neurodegenerative and cerebrovascular diseases such as ischemic stroke not only coexist, but also interact with or affect each other in the aging population. The objective of study was to evaluate the severity of frontal lobe dysfunction in poststroke patients. Methods: 173 patients (aged 33–84, 106 males, 67 females) were examined after the first hemispheric ischemic stroke. Clinical and neuropsychological investigation [NIHSS, MMSE, FAB, Semantic Verbal Fluency test (SVFT) and attention test (AT)] was carried out at 1 and 3 months after the stroke. The control group consisted of 40 people without stroke. Results: The data differences between patients and control group were fixed in MMSE (p = 0.0027), SVFT (p = 0.0000), AT (p = 0.0006) at the 1st visit. The differences were found between patients and control group in FAB total (p = 0.0000) and subtest scores: similarities (p = 0.0000), lexical fluency (p = 0.0000), motor series “Luria” test (p = 0.0000), conflicting instructions (p = 0.0046), go-no go (p = 0.0180). Cognitive decline didn’t depend on sex. The FAB subtest “lexical fluency” was reduced (p = 0.0183) in patients with left hemisphere stroke. The age was associated with MMSE (p = 0.0042); FAB total (p = 0.0009) and subtest scores: similarities (p = 0.0289), motor series (p = 0.0103), conflicting instructions (p = 0.0070), go-no go (p = 0.0212); SVFT (p = 0.0000), AT (p = 0.0001). The correlations between NIHSS and cognitive tests: MMSE (p = 0.0003), FAB (p = 0.0001), AT (p = 0.0001), SVFT (p = 0.0024) were revealed at the 1st visit. Neuropsychological reinvestigation demonstrated that MMSE (p = 0.0000), FAB total (p = 0.0000) and subtest scores:

similarities (p = 0.0000), motor series “Luria” test (p = 0.0000), conflicting instructions (p = 0.0005), go-no go (p = 0.0023) and SVFT (p = 0.0092) significantly increased. The FAB subtest “lexical fluency” and AT were statistically unchanged from previous study. Conclusions: Frontal lobe dysfunction is characteristic of poststroke patients. It doesn’t depend on sex, but is associated with the patient’s age and the level of neurological deficit.

P146 Longitudinal neuropsychological evaluation of progranulin (GRN) mutation carriers D. Wittenberg1, R. G. Y. Hsiung1, P. Sengdy1, M. Baker1, R. Rademakers1, P. Slack1, H. H. Feldman1, I. R. Mackenzie1 1 University of British Columbia, Medicine, Vancouver, Canada Identifying the earliest pre-symptomatic changes in the prodromal phase of dementia may allow for timely diagnosis and implementation of therapy. Based on cross-sectional analysis completed previously with baseline data, we hypothesized that nonverbal memory would continue to be discrepant between the GRN mutation carriers and controls over time as they approach the average age of disease onset in their respective families. We followed a cohort of GRN mutation carriers (N = 7) and their noncarrier familial controls (N = 10) to determine if there are any differences in their cognitive abilities over time in the pre-clinical phase. Complete neuropsychological batteries were conducted annually and composite scores calculated by cognitive domain (Predicted IQ, Attention, Working Memory, Verbal Memory, Nonverbal Memory, Language, Visuospatial, and Executive Function). A repeated measures ANOVA was calculated to determine change over four visits. Significant results were found in two domains: Nonverbal Memory (p = 0.05) and Language (p = 0.01). These results further support the use of nonverbal memory tests to monitor disease progression in GRN mutation carriers during the preclinical phase and call attention to the possible use of language as an additional measure of disease progression.

P147 Cognitive and behavioral trajectory of behavioral-variant frontotemporal dementia differs according to underlying pathology J. Phillips1, D. Irwin1, K. Rascovsky1, V. Van Deerlin2, V. Lee2, J. Trojanowski2, C. McMillan1, M. Grossman1 1 University of Pennsylvania, Neurology, Philadelphia, USA 2 University of Pennsylvania, Pathology and Laboratory Medicine, Philadelphia, USA Behavioral-variant frontotemporal dementia (bvFTD) is caused by a range of pathologies, including tau or TDP-43 proteinopathy. Frontal-variant Alzheimer’s disease (fvAD) may also be diagnosed as bvFTD due to similar behavioral presentation. We evaluated whether patterns of longitudinal decline differed in pathologically distinct bvFTD cohorts, drawn from the National Alzheimer’s Coordinating Center (NIA/NIH Grant U01-AG016976) database and the Penn Frontotemporal Degeneration Center (NIA/NIH Grant P01-AG017586). We assessed bvFTD patients with autopsy or genetic evidence of TDP-43 (n = 18) or tau (n = 58) pathology; and


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patients clinically diagnosed with bvFTD who had autopsy or biomarker evidence of AD pathology (n = 32). We predicted faster cognitive decline in bvFTD-tau than bvFTD-TDP, and faster memory decline in fvAD than in bvFTD-tau and bvFTD-TDP. Cognitive and behavioral changes were examined using linear mixed effects models with a random effect of patient and fixed effects of group (bvFTD-tau, bvFTD-TDP, or fvAD), disease duration, and their interaction. BvFTD-TDP cases had significantly slower decline than bvFTD-tau for backward digit span (p < 0.05) and Logical Memory immediate recall (p < 0.005), and both bvFTD-tau and fvAD declined more slowly than TDP-43 on the letter fluency task (both p < 0.05). In contrast, fvAD had significantly worse global cognition (MMSE) and higher failure rates on immediate and delayed recall. Behaviorally, all groups exhibited apathy, disinhibition, and appetitive changes. These symptoms worsened significantly over time in bvFTD-TDP (p < 0.01) but not bvFTD-tau or fvAD. Results indicate distinct patterns of decline in bvFTD patients with known pathology and highlight the need for in vivo biomarker assessment. Additionally, they suggest dissociations in the longitudinal course of cognitive and behavioral symptoms in bvFTD.

P148 Variables affecting emotional reactivity to socioemotional stimuli in frontotemporal dementia S. Fong1,2, M. F. Mendez1,2 1 University of California, Los Angeles, Neurology, Los Angeles, USA 2 V.A. Greater Los Angeles Healthcare Center, Neurology, Los Angeles, USA Impaired emotional functioning is a characteristic feature of behavioral variant frontotemporal dementia (bvFTD). Emotional reactivity to socioemotional scenarios among bvFTD patients may be affected by the emotional intensity and valence of socioemotional stimuli. This study used video and audio-only presentations of socioemotional scenarios, conveyed with differences in emotional intensity and different valence (“pleasant” vs. “unpleasant”) to investigate emotional reactivity, both self-report and physiological (skin conductance response (SCR)), among 10 patients with bvFTD, 10 comparably impaired patients with early-onset AD, and 9 normal controls (NC). We found significant overall group differences in both self-reported emotional reactions and SCR results. The bvFTD patients reported higher Likert scores, indicating more positive emotions, than AD and NC groups (p < 0.001), whereas both dementia groups showed increased SCRs, compared to NC (p = 0.013). Self-report scores were higher for the pleasant vs. the unpleasant stimuli for all groups, but there were no clear differences based on emotional intensity. The results suggest that, among bvFTD patients, there is a disconnection between emotional reactivity at the physiological level, regardless of intensity and valence of socioemotional stimuli, and subjective reports of emotional experience. The bvFTD patients reported far less discomfort, yet showed significantly more physiological change than normal controls when viewing socioemotional stimuli, suggesting disconnection of autonomic and cognitive mechanisms of emotional functioning and expression in bvFTD.

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P149 Patterns of neuropsychiatric symptoms in a Mexican sample diagnosed with Alzheimer’s disease and frontotemporal dementia (behavioral and language variants) according to stage of cognitive decline. J. F. Flores-Vazquez1, G. I. Acosta-Castillo1, A. Campos-Jim enez1, L. Alvarez-Diaz1, A. Martınez Ruiz2, A. L. Sosa-Ortiz1 1 National Neurology and Neurosurgery Institute, Dementia Unit, Mexico City, Mexico 2 National Geriatrics Institute, Geriatric Epidemiology, Mexico City, Mexico Background: Certain neuropsychiatric symptoms (NPS) are more frequently found in frontotemporal dementia (FTD) than in Alzheimer’s disease (AD). Behavioral variant frontotemporal dementia (bvFTD), has a higher rate of apathy, disinhibition, and eating disorders. Relatively few studies have addressed LatinAmerican populations diagnosed with FTD. Methods: For this study we used 2-year data from the registry of the Dementia Unit at the National Neurology and Neurosurgery Institute in Mexico City. Data from 82 patients with AD, 18 with bvFTD and 17 with language variant frontotemporal dementia (lvFTD) were analyzed. The clinimetric scales used were the Neuropsychiatric Inventory (NPI) and the Short Form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Based on the stage of cognitive decline from IQCODE scores, two groups were formed (3.3–4.4 and 4.5–5) for each diagnostic group. Fisher’s exact test was used to compare NPI scores among groups of patients. Results: The more advanced cognitive decline, AD patients showed a higher rate of delusions and hallucinations than FTD patients (p = 0.019). Disorders of alimentation and appetite were more frequently found in more advanced lvFTD and bvFTD patients, than in AD patients (p = 0.008). Disinhibition (p = 0.002) and agitation/aggression (p = 0.033) were more frequently found in less advanced bvFTD patients, while euphoria was more frequent in later-stage bvFTD (p = 0.004). Conclusion: We found distinct patterns of NPS characterizing earlier and later-stage dementia in the studied groups. Larger studies are needed to characterize the neuropsychiatric course of degenerative dementias in seldom-studied populations, since the expression of neuropsychiatric symptoms may be influenced by cultural variants.



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Differences on novel measures of social comportment in asymptomatic (CDR=0) versus mildly symptomatic (CDR=0.5) mutation carriers: preliminary data from LEFFTDS K. Rankin1, J. Kramer1, H. Rosen1, B. Boeve2, A. Boxer1, G. Coppola3, B. Dickerson4, C. Dheel2, J. Fields2, R. Gavrilova2, N. Ghoshal5, J. Goldman6, N. Graff-Radford7, M. Grossman8, H. Heuer1, J. Hsiao9, R. Hsiung10, E. Huey6, D. Irwin8, K. Kantarci2, A. Karydas1, J. Kornak1, D. Knopman2, W. Kukull11, I. Mackenzie10, B. Miller1, C. Phelps9, R. Rademakers7, L. Shaw8, M. Sutherland12, A. Toga13, J. Trojanowski8, A. Vetor14, S. Weintraub15, Z. Wszolek7 1 University of California, San Francisco, Neurology, San Francisco, USA 2 Mayo Clinic, Rochester, USA 3 University of California, Los Angeles, Los Angeles, USA 4 Massachusetts General Hospital, Boston, USA 5 Washington University, St. Louis, USA 6 Columbia University, New York, USA 7 Mayo Clinic, Jacksonville, USA 8 University of Pennsylvania, Philadelphia, USA 9 NIA, Bethesda, USA 10 University of British Columbia, Vancouver, USA 11 University of Washington, Seattle, USA 12 NINDS, Bethesda, USA 13 USC LONI, Los Angeles, USA 14 Indiana University, Indianapolis, USA 15 Northwestern University, Chicago, USA

Greater facial expressive versus self-reported emotional reactivity correlates with diminished right posterior insular volume in bvFTD P. Pressman1,2, J. J. Casey2, K. Hua-Chen2, C. Mielke1, K. Rankin1, R. W. Levenson2 1 University of California, San Francisco, Neurology, San Francisco, USA 2 University of California, Berkeley, Psychology, Berkeley, USA

We hypothesized that subtle differences in social comportment would exist between asymptomatic (+mCDR=0) and mildly symptomatic (+mCDR=0.5) mutation carriers in the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Consortium, which involves participants in kindreds with mutations in microtubule associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72). We analyzed data from the National Alzheimer’s Coordinating Center Frontotemporal Lobar Degeneration (NACC-FTLD) Module social comportment battery among +mCDR=0 (n = 34) and +mCDR=0.5 (n = 35) participants evaluated through February 2016. Measures included informant reports for: the Social Norms Questionnaire (SNQ) Break and Overadhere scales; the Behavior Inhibition Scale (BIS); the Interpersonal Reactivity Index Empathic Concern (IRIEC) and Perspective-taking (IRI-PT) scales; the Sensitivity to Socioemotional Expressiveness Score (RSMS-EX), Ability to Modify Self-presentation Score (RSMS-SP), and Total Score (RSMS-TS) from the Revised Self-Monitoring Scale (RSMS); as well as clinician ratings on the Social Behavior Observer Checklist (SBOCL) Descriptor and Checklist total scores.

Emotions consist of facial expressive, subjective, and autonomic components, which are typically linked in healthy individuals. In bvFTD, however, dissociations among these components have been observed. We quantified the extent to which facial expressive responses to an emotion eliciting film exceeded self-reported emotional experience. We hypothesized that greater facial than subjective emotional reactivity would correlate with smaller right posterior insula volume, a region involved with sensory-limbic integration in bvFTD. In this study, 24 patients with bvFTD watched films designed to elicit amusement, sadness, and disgust. During each film, facial expressions of amusement, sadness, and disgust, respectively, were coded by trained coders using the Emotional Expressive Behavior system. After each film, patients reported the degree to which they experienced different emotions during the viewing. We first quantified the extent to which facial expression exceeded self-reported emotional experience by computing difference scores between these two measures. These difference scores were then regressed against cortical thickness using whole-brain voxel-based morphometry. We found that greater level of dissociation (facial expression > self-reported emotion) was correlated with lower grey matter volume in the right posterior insula. We also performed a parallel set of analyses using the caregiver-rated Toronto Alexithymia Scale to regress against grey matter volume, but did not find any significant correlation. These findings yield important insights about the role of the posterior insula in integrating different aspects of emotion, and suggest that this mechanism may be impaired in bvFTD.

P152 Frontotemporal dementia and schizophrenia - whats the connection II? A neuropsychological and social cognition comparison of patients with chronic schizophrenia and FTD D. Velakoulis1, H.-M. Chan1, W. Kelso1, R. Stalky2 1 Royal Melbourne Hospital, Neuropsychiatry, Melbourne, Australia 2 Monash University, School of Psychological Sciences, Melbourne, Australia Background: Patients with chronic schizophrenia (CSz) who exhibit a clinical course of recurrent hospitalisations, cognitive impairment and dependency in daily living often raise the suspicion of an underlying dementia. Parallels have been drawn between the clinical, cognitive and neuroimaging profiles of patients with CSz patients and frontotemporal dementia (FTD). The aim of this work was to compare patients with CSz and patients with FTD on neurocognitive and social cognitive domains. Methods/Results: Study 1 Retrospective neuropsychological data was compared between 26 CSz inpatients and 34 FTD inpatients. Of 16 cognitive domains,


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the two groups differed significantly only in executive function subdomain of set-switching/cognitive flexibility. This significant group difference was associated with a 45% overlap in score distributions between the groups. Study 2 Seven inpatients with severe CSz, 13 outpatients with CSz who maintained independent living, 12 patients with FTD and 18 healthy controls were administered a neuropsychological battery. Across 16 cognitive domains, the CSz inpatients performed more similarly to the FTD group, while the outpatient CSz group outperformed the inpatients. Study 3 The groups from Study 2 were administered a social cognition battery including the TASIT. Compared to controls, the FTD group had severe impairments in all aspects of social cognition, whereas both CSz groups only had significant deficits in one facet of theory of mind. CSz inpatients were more similar than the outpatients to the FTD group. Discussion: It is possible to delineate a subgroup of CSz patients who share similar cognitive profiles with FTD. Patients with CSz can exhibit cognitive deficits equivalent in severity to patients with frontotemporal dementia and such deficits need to be considered in management of this patient group. Secondly the findings provide some support for the concept that a subgroup of patients with schizophrenia may have an insidious and “slow burning” frontotemporal dementia.

intrinsically-driven action with or without animacy). This study used Heider and Simmel’s original film (1944) of moving geometric shapes to investigate the attribution of animacy and of agency among 11 patients with bvFTD, 9 comparably impaired patients with early-onset AD, and 12 normal controls (NC). Spontaneous and solicited verbal responses to the moving geometric shapes were video-recorded. Independent raters used two separate coding systems to score the verbal responses on capacity to perceive animacy and agency, attribute cognitive and affective ToM, and perceive social and emotional meaning. The bvFTD patients, but not the AD patients, were significantly impaired in the attribution of animacy, compared to the NC (p = 0.018). In contrast, both bvFTD and AD groups were significantly impaired on the attribution of agency, compared to the NC (p < 0.0001 and p = 0.001, respectively). There were no explanatory correlations with measures of ToM or socioemotional perception. On analysis of frontotemporal cortical regions of interest (ROIs), bvFTD had significantly more atrophy in the left medial orbitofrontal region. Both dementia groups exhibited impaired agency attribution, but only the bvFTD patients had additional difficulties with animacy, suggesting that impaired agency attribution is a more general effect of dementia whereas impaired animacy attribution in bvFTD is a more specific deficit, not due to other deficits in social cognition, and possibly related to medial orbitofrontal dysfunction.

P154 P153 The attribution of animacy and agency in frontotemporal dementia vs. Alzheimer’s disease S. S. Fong1,2, A. R. Carr2, M. Daianu3, M. B. Deutsch1,2,4, E. E. Jimenez1,2, K. O. Juarez1,2, M. M. Mather1,2, P. P. Paholpak1,2,5, S. E. Perfecto1, P. M. Thompson3,6,7,8,9,10,11, M. F. Mendez1,2 1 University of California, Los Angeles, Neurology, Los Angeles, USA 2 V.A. Greater Los Angeles Healthcare Center, Neurology, Los Angeles, USA 3 Imaging Genetics Center, Mark & Mary Stevens Neuroimaging & Informatics Institute, University of Southern California, Los Angeles, USA 4 Icahn School of Medicine at Mount Sinai, Neurology, New York, USA 5 Khon Kaen University, Psychiatry, Khon Khaen, Thailand 6 University of Southern California, Psychiatry, Los Angeles, USA 7 University of Southern California, Radiology, Los Angeles, USA 8 University of Southern California, Engineering, Los Angeles, USA 9 University of Southern California, Pediatrics, Los Angeles, USA 10 University of Southern California, Ophthalmology, Los Angeles, USA 11 University of Southern California, Neurology, Los Angeles, USA Social or interpersonal behavior is characteristically disturbed in behavioral variant frontotemporal dementia (bvFTD) but relatively spared in early stages of Alzheimer’s disease (AD). Prior studies of social disturbances in bvFTD have implicated alterations in Theory of Mind (ToM) and in the perception of social and emotional awareness and meaning. Two additional mechanisms may impact on social behavior in dementia: alterations in the attribution of animacy (the state of living or being sentient) and of agency (the capability of

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Social emotions in behavioral variant frontotemporal (bvFTD) patients. How FTD patients experience schadenfreude and envy H. Santamarıá Garcıá1,2, S. Baez1,2, P. Reyes1, D. Matallana1, A. Ib a~ nez2 1 Pontificia Universidad Javeriana, Medicine, Bogot a, Colombia 2 Laboratorio de Psicologıa Experimental y Neurociencias LPEN, Instituto de Neurociencia Cognitiva y Traslacional INCyT, Fundaci on INECO, Buenos Aires, Colombia Schadenfreude (pleasure at others’ misfortunes) and envy (unpleasent emotion in presence of other’s succes)have been systematically reported as critical social emotions affected in patients with reported impairments in social cognition processes including patients with Huntington disease and schizophrenia. However, no studies have investigated the schadenfreude and envy experience in behavioral variant frontotemporal dementia (bvFTD). Twenty-one patients with behavioral variant of FTD patients, and 23 healthy control participants performed an experimental task designed to trigger schadenfreude, envy and control situations. Our results showed that patients with FTD experienced lower schadenfreude in response to other’s misfortunes, and lower envy score facing other’s success comparing with healthy controls. Present results shown a new and specific dimension of the impaired social cognitive processing in FTD patients. The present findings contribute to the understanding of emotions processing impairments in FTD patients which should be correlated with another deficits in more general cognitive processes and other social cognitive processes.



P155 Cross-cultural Adaptation and Validity of the Brazilian version of the Clinical staging scale and disease progression in frontotemporal dementia T. Bento Lima da Silva1, V. Bahia1, M. Amore Cecchini1, aes1, L. Cassimiro1, V. Amaral Carvalho1, H. Cerqueira Guimar~ P. Caramelli1, M. Balthazar1, B. Damasceno1, C. Bottino1, S. Brucki1, L. Cruz de Souza1, E. Mioshi1, R. Nitrini1, M. Yassuda1 1 Faculty of Medicine, Neurology Department, University of S~ ao Paulo, SAO PAULO, Brazil Background: Staging scales for dementia were devised for grading Alzheimer’s disease (AD) and do not include the specific symptoms of FTLD. Objective: To translate and adapt the Frontotemporal Dementia Rating Scale (FTD-FRS) to Brazilian Portuguese and to evaluate its validity. Methods: The cross-cultural adaptation process consisted of the following steps: translation, back-translation (prepared by independent translators), discussion with specialists, and development of a final version after minor adjustments. The FRS was administered to 61 patients classified previously as: 13 normal controls (NC), 08 Mild Cognitive Impairment (MCI), 20 behavioral variant Frontotemporal Dementia (bvFTD), 20 Alzheimer’s disease (AD), matched for disease severity(CDR = 1.0).The evaluation protocol included: Addenbrooke’s Cognitive Examination-Revised (ACE-R), Mini Mental State Examination (MMSE),Executive Interview (EXIT-25), Neuropsychiatric Inventory (NPI), the Frontotemporal Dementia Rating Scale (FTD-FRS) and Clinical Dementia Rating scale (CDR). Results: The Brazilian versionof the FTD-FRS seemed appropriate for use in this country. The results revealed greater levels of disability in bvFTD than in AD patients (bvFTD: 18.75% moderate; 56.25 severe and 25% very severe; AD: 14.29% mild, 21.43% moderate, 50% severe, 14.29% very severe; MCI: 37.50% very mild, 25% moderate, 25% severe, 12.50% very severe; NC: 92.31% very mild and 7,69% mild). It appears that the CDR underrates disease severity in bvFTD since a relevant proportion of these patients rated as having mild dementia (CDR = 1.0) in fact had moderate or severe levels of disability according to the FTD-FRS. The results indicated good internal consistency (Cronbach’s Total: 0.973) in the total sample. Conclusions: The Brazilian version of the FTD-FRS seems suitable to aid in staging and determining disease progression. The

FTD-FRS can document degrees of severity of functional impairment among Brazilian older adults.

P156 Distinct patterns of cognitive behavioral change in emerging FTLD in the presence and absence of MND support a ‘bottom-up’ model of FTLD onset C. Flaherty1 1 Penn State College of Medicine, Neurology, Hershey, USA Objective: Estimates of the prevalence of cognitive or behavioral impairment (ci or bi) in MND consistent with Frontotemporal Degeneration (FTLD) approach 50%, while only about 15% progress to dementia. Our goal was to explore ci and bi gender and site of onset differences, in comparison to a non-motor sample. Methods: We administered a comprehensive neuropsychological assessment battery comprised of language and executive functioning measures, as well as the Frontal Systems of Behavior (FrSBe). We applied independent sample t-tests to evaluate differences in cognitive and behavioral profile between gender and site of onset in 10 female and 10 male non-demented MND participants and 20 non-motor variant participants classified by current consensus criteria with ci with or without bi. Findings: Between gender analyses for each subgroup found significantly better naming ability for bulbar (p = 0.05) and nonbulbar onset (p = 0.046) females. Non-bulbar females also performed better on a Guilford measure of cause and effect in relationships (p = 0.024). Non-motor females demonstrated an advantage in comprehension of ideational material (p = 0.005) and reading comprehension (p = 0.033). No gender differences were detected for FrSBe behavioral domains within motor and nonmotor subtypes, including Apathy, Disinhibition and Executive Dysfunction. However, analysis of MND by site of onset subtypes evidenced a significantly greater degree of FrSBe Apathy (p = 0.017) and Executive Dysfunction (p = 0.05) for bulbar onset. Conclusions: Findings support a hierarchical hypothesis of FTLD emergence in ALSci and ALSbi, distinct from non-motor variants, implicating “bottom up” ascending cerebellar-midbrainprefrontal pathways in MND. Keywords: Frontotemporal lobar degeneration, gender, motor neuron disease, executive functioning, cognitive decline, behavioral decline


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Poster Session II: Genetics P158

P157 C9orf72, does the size matter? C. Fournier1, V. Anquetil1, A. Camuzat1, M. Barbier1, V. Buee-Scherrer2, V. Deramecourt2, N. Sergeant2, F. Pasquier2, G. N. Network3, B. Dubois1,4, C. Duyckaerts1,5, A. Brice1, I. Le Ber1,6 1 ICM Inserm 1127, Paris, France 2 Universite Lille Nord de France, Lille, France 3 Hôpital de la Pitie-Salpêtriere, AP-HP, Paris, France 4 IM2A Hôpital de la Pitie-Salpêtriere, AP-HP, Paris, France 5 Laboratoire de Neuropathologie Raymond-Escourolle, Hopital de la Pitie-Salpetriere, Paris, France 6 IM2A Centre de reference Demences Rares H^ opital de la PitieSalpêtriere, AP-HP, Paris, France Hexanucleotide repeat expansion in C9orf72 is the major familial cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). To date, the correlation between the repeat expansion size, molecular mechanisms and clinical data is still unclear. Several studies reached a consensus to rule out the correlation between the length of the expansion and the type of the disease, i.e. FTD, ALS, FTD/ALS. However, some identified a positive correlation between the size of the expansion and age at onset (van Blitterswijk et al. Lancet Neurol 2013; 12 978–88) when others observed a significantly later onset age in shorter expansion carriers (Gijselinck et al. Mol. Psychiatry 2015; 1–13). If these results are not incompatible we would like to gain a clearer picture and tease out a common answer from a complex heterogeneous molecular background of C9orf72 patients. Thus we are elucidating the possible link between repeat size in our cohort of FTD and FTD/ALS patients and the different data collected by our group: clinical and neuropathological studies, high-throughput RNA sequencing analysis (RNAseq). To do so, and to evaluate precisely the length of the hexanucleotide expansion we analyzed, by Southern Blot, genomic DNA from C9orf72 repeat carriers, either FTD, FTD/ALS or pure ALS. Comparing DNA extracted from the frontal cortex and occipital region, where degeneration is much weaker, will provide insights on the influence of the expansion length on neuronal toxicity. If there is no correlation between the repeat size and subtypes of the neuropathological classification of FTLDs, it seems unlikely that the nature and the length of the repeat does not influence the retention of RNA binding proteins and subsequently impacts the transcriptome of the C9ORF72 mutation carriers. Also, the correlation between the expansion length and some carefully chosen transcripts from our RNAseq experiments is being assessed.

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RNA metabolism in frontotemporal dementia V. Anquetil1, A. Camuzat1, C. Fournier1, P. de la Grange2, ee-Scherrer3, V. Deramecourt4, N. Sergeant3, M. Barbier1, V. Bu ee3, F. Pasquier4, B. Dubois1,5, V. Sazdovitch6, D. Seilhean6, L. Bu 1 6 1,7,8 A. Brice , C. Duyckaerts , I. Le Ber 1 ICM - Inserm U1127, Paris, France 2 GenoSplice technology, Paris, France 3 Inserm UMR 1172, Lille, France 4 Universite Lille 2, Faculte de Medecine, Lille, France 5 H^ opital de la Pitie-Salpêtriere, Institut de la memoire et de la maladie d’Alzheimer, Department of Neurology, Paris, France 6 H^ opital de la Salpêtriere, AP-HP, Laboratoire de Neuropathologie, Paris, France 7 Centre de Reference des Demences Rares, Paris, France 8 L’Institut de la Memoire et de la Maladie d’Alzheimer - AP-HP, Paris, France FrontoTemporal Lobar Degeneration (FTLD) is a highly heritable disorder with up to 50% of the cases reporting a positive family history. Mutations in 3 genes are responsible of most of these genetic cases: microtubule associated protein tau (MAPT), progranulin (PGRN) and chromosome 9 open reading frame 72 (C9orf72). Subsequently sporadic cases are mathematically responsible of more than 50% of the remaining cases. Genetic or sporadic FTLDs share common neuropathological features such as neuronal TDP43 or FUS inclusions. Thus, independently of the genetic origin and because of the global and significant neurodegeneration, mostly frontal and temporal, it seems highly probable that the different subtypes share some similar molecular mechanisms. In addition, to increase the level of complexity, either due to the different genetic origin or to the nature of the protein aggregates we can also expect some specific molecular mechanisms to be involved in the disease. We challenged these two non exclusive possibilities by analyzing the frontal cortex at the latest stage of the disease. High-throughput RNA sequencing was performed with a coverage sufficient to analyze not only transcriptome but also splicing profiles and antisense RNAs. The samples were sorted according to the genetic mutation they carry: C9orf72, MAPT and PGRN. In addition, we compared sporadic cases presenting TDP43 inclusions and a set of controls. Performing clustering analysis on the full set of data revealed that the mutations in MAPT and PGRN have an extremely homogenous RNA metabolism response while sporadic cases, controls, and C9orf72 mutant carriers have a surprisingly higher heterogeneity. Strikingly, this heterogeneity is increased even further when including already published RNAseq data from a set of controls (Prudencio et al. Nat Neurosci. 2015;18(8):1175–82). Nevertheless, we observed differences at transcriptional level that are mutation dependent. In addition, some splicing profiles are also specific of genetic mutations, while others appear to be linked to the type of pathology (FTLD, FTLD/ALS). With these results we clearly contribute to prove that FTLD are not only proteinopathies and spliceopathies but also general RNAopathies.


Poster Session II: Genetics

P159 A cluster of progranulin C157KfsX97 mutations in Southern Italy: clinical characterisation and genetic correlations D. Saracino1, C. Coppola1, G. Puoti1, G. Lus1, C. Dato1, I. Le Ber2, P. Caroppo3, E. Piccoli3, F. Tagliavini3, G. Di Iorio1, G. Rossi3 1 Second University of Naples, Second Division of Neurology, Naples, Italy 2 ICM Institut du Cerveau et de la Moelle epiniere, Paris, France 3 Fondazione IRCCS Istituto Neurologico Carlo Besta, Division of Neurology V - Neuropathology, Milan, Italy Frontotemporal lobar degeneration (FTLD) is a group of neurodegenerative diseases displaying high clinical, pathological and genetic heterogeneity. The main genes involved are the genes coding for microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9ORF72). Several autosomal dominant GRN mutations have been reported, accounting for 5–10% of FTLD cases worldwide. In this study we described the clinical characteristics of seven Italian patients carrying the GRN C157KfsX97 null mutation (Le Ber et al. Brain. 2008; 131 732–46. Coppola et al. Neurol Sci. 2012; 33 93–7) and demonstrated the existence of a founder effect by means of haplotype sharing analysis. All the patients underwent a complete clinical, neuropsychological and instrumental assessment, including morphological and functional brain imaging and CSF biomarkers assay. Clinical diagnoses were Frontotemporal dementia behavioural variant (bvFTD) in 5 cases and Corticobasal syndrome (CBS) in 2 cases. Five cases were familial. We performed plasma progranulin dosage, GRN gene sequencing and haplotype sharing study, analysing 10 short tandem repeat (STR) markers, spanning a region of 11.08 Mb flanking GRN on chromosome 17q21. The deletion g.101349_101355delCTGCTGT, resulting in the C157KfsX97 null mutation, was found in all patients. We observed shared alleles among 6 patients for 8 consecutive STR markers spanning a 7.29 Mb region. This common haplotype strongly supports a founder effect. Our observations confirm the elevated clinical variability described among GRN-mutated FTLD cases also with this particular mutation. Moreover this is the first study reporting the likely existence of a founder effect for C157KfsX97 mutation in Southern Italy.

P160 Genetic screening of C9orf72 and TBK1 mutations and clinical correlations in combined FTLD/ALS phenotypes E. Go´mez-Tortosa1, M. Ruggiero1, E. Franco-Macıas2, as3, S. Gil Navarro1, C. Prieto-Jurczynska3, B. Venegas3, C. Ord 4 5 1 R. Guerrero , J. Perez-Perez , M. Sainz 1 Fundacion Jimenez Dıaz, Neurology, Madrid, Spain 2 Hospital Virgen del Rocıo, Neurology, Seville, Spain 3 Hospital Rey Juan Carlos and Hospital Infanta Elena, Neurology, Madrid, Spain 4 Instituto de Investigaci on Sanitaria Fundaci on Jimenez Dıaz IISFJD and CIBERER, Neurology, Madrid, Spain 5 Secugen SL, Genetics, Madrid, Spain We screened for the C9 expansion and for TBK1 mutations in 19 cases (9% of our FTLD cohort) with FTLD and ALS (n = 9, 5 sporadic), or with dementia alone but who reported a sibling with ALS (n = 10). All cases had normal plasma progranulin levels.

Five cases (26.5%), all with family history, were genetically diagnosed. Three (16%) carried the C9 expansion: two had cognitive decline followed by ALS (onset at 58 and 70 years), and one presented as non-fluent aphasia at 60 years developing full dementia syndrome with no motor signs. Two cases (10.5%) carried a mutation in the TBK1 gene (Thr79del and Arg573Gly) and had been diagnosed by the European Early-Onset Dementia consortium. The family with the pathogenic Thr79del mutation included a) one index case starting with cognitive decline at 58 years with topographic disorientation, anomia, visuoconstructive and memory deficits as early symptoms, developing frontal features (hyperphagia, logopenia, apraxia) at middle stages of the disease, and bilateral parkinsonism at late stages (deceased at 69); and b) two siblings with ALS alone with spinal and bulbar signs and 12–20 months survival. The Arg573Gly mutation is “probably damaging”, has not been found in 1109 controls and segregates in three affected siblings, which supports a relationship with the autosomal dominant inherited disease of this family (implication of C9, MAPT, TARDBP, FUS and VCP had been excluded). The six affected siblings (three deceased) presented heterogeneous phenotypes at 60–65 years: one behavioral variant, one progressive aphasia leading to mutism, two with AD type dementia (early memory deficits and disorientation), and two with upper motor neuron disease with predominant bulbar involvement (spastic dysarthria and dysphagia). Conclusion: C9orf72 and TBK1 genes explain around a quarter of our Spanish FTLD/ALS combined phenotypes. Cases with TBK1 mutations have some particular dementia and motor neuron features.

P161 TBK1 mutation frequencies and associated phenotypes in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts A. Camuzat1, P. Caroppo2, A. De Septenville2, S. Millecamps2, P. Couratier3, M. Barbier2, F. Blanc4, L. Lacomblez5, F. Sellal6, M.-C. Fleury4, A. Brice2, I. Le Ber2, F. C. A. French Clinical, Genetic Research Network on FT7 1 INSERM U1127, Paris, France 2 ICM, Paris, France 3 CHU Dupuytren, Limoges, France 4 H^ opitaux universitaires de Strasbourg, Strasbourg, France 5 H^ opital Pitie-Salpêtriere, Paris, France 6 Hospices civils de Strasbourg, Strasbourg, France 7 French Clinical and Genetic Research Network on FTLD/FTLDALS, France TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4% to 4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. TBK1 was sequenced in a cohort of 416 French patients, including 217 probands with FTD (100 familial) as well as in an independent population of 199 ALS probands (113 familial), excluded for all known genes. We studied mRNA level by quantitative real-time PCR in patient-derived cell lines and the protein level by Western-Blot.


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We identified 5 LoF mutations in 4 FTD-ALS and 1 ALS patients; and 5 heterozygous missense variants predicted to be deleterious. We demonstrated that LoF mutations lead to a 50% reduction in TBK1 mRNA and in TBK1 protein. Interestingly, the LoF mutations were associated with semantic and nonfluent aphasic variants, secondarily associated with amyotrophic lateral sclerosis and a remarkable temporo-polar or perisylvian atrophy. This study establishes that TBK1 LoF mutations are more frequent in the subgroup of patients with FTD/ALS (10.8%, after exclusion of C9ORF72) than in isolated ALS, and that semantic and nvFTD can be the initial presentation of the disease.

P162 Clinical features of TBK1 carriers and comparison with Belgian FTD patients carrying another FTD-TDP causing mutation S. Van Mossevelde1,2,3,4, J. van der Zee1,2, I. Gijselinck1,2, S. Engelborghs2,3, A. Sieben1,2,5, T. Van Langenhove1,2,4, J. De Bleecker5, J. Baets1,2,4, M. Vandenbulcke6,7, K. Van Laere8, S. Ceyssens9,10, M. Van den Broeck1,2, K. Peeters1,2, M. Mattheijssens1,2, P. Cras2,4, R. Vandenberghe6,11, P. De Jonghe1,2,4, J.-J. Martin2, P. P. De Deyn2,3, M. Cruts1,2, C. Van Broeckhoven1,2 1 University of Antwerp, Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Wilrijk, Belgium 3 Hospital Network Antwerp ZNA Middelheim and Hoge Beuken, Department of Neurology and Memory Clinic, Antwerp, Belgium 4 Antwerp University Hospital UZA, Department of Neurology, Edegem, Belgium 5 University of Ghent, Department of Neurology, Ghent, Belgium 6 KU Leuven, Department of Neurosciences, Faculty of Medicine, Leuven, Belgium 7 University Hospitals Leuven, Department of Old Age Psychiatry and Memory Clinic, Leuven, Belgium 8 KU Leuven, Department of Nuclear Medicine and Molecular Imaging, Leuven, Belgium 9 University of Antwerp, Molecular Imaging Center Antwerp, Faculty of Medicine and Health Sciences, Antwerp, Belgium 10 Antwerp University Hospital UZA, Department of Nuclear Medicine, Edegem, Belgium 11 University Hospitals Leuven, Department of Neurology, Leuven, Belgium In a cohort of patients with frontotemporal dementia (FTD) (n = 481) or amyotrophic lateral sclerosis (ALS) (n = 147), we identified 10 index patients carrying a TBK1 loss-of-function mutation reducing TBK1 expression by 50%. We provide a clinical and pathological description of the ten index patients and of six of their affected relatives carrying a TBK1 mutation. Six TBK1 carriers were diagnosed with FTD, seven with ALS, one with both clinical phenotypes and two with dementia unspecified. The mean age at onset of all 16 TBK1 carriers was 62.1 8.9 years (range 41–73) with a mean disease duration of 4.7 4.5 years (range 1–13). TBK1 carriers with ALS had a shorter disease duration than carriers with FTD. Six of the seven TBK1 carriers were diagnosed with the behavioral variant of FTD, presenting with disinhibition as predominant symptom. In the initial phase of the disease, memory loss was present in all but one of the carriers with FTD. Three of the patients with ALS exhibited pronounced upper motor neuron

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symptoms. Overall, neuroimaging displayed widespread atrophy, both symmetric as asymmetric. Brain perfusion SPECT or FDGPET showed asymmetric and predominantly frontotemporal involvement. Neuropathology in two patients demonstrated TDP43 type B pathology. Further, we compared genotype-phenotype data of FTD patients with a TBK1 mutation (n = 7), with those of FTD patients carrying another FTD-TDP causing mutation (C9orf72 repeat expansion (n = 65) or a GRN mutation (n = 52)) and with FTD patients (n = 259) negative for mutations in currently known causal genes. TBK1 carriers had a later age at onset (63.3 years) than C9orf72 carriers (54.3 years) (p = 0.019). In clear contrast with TBK1 carriers, GRN carriers were more often diagnosed with the language variant than the behavioral variant, and presented in case of the diagnosis of behavioral variant, more often than TBK1 carriers with apathy as predominant characteristic (p = 0.004). Also, TBK1 carriers exhibited more often extrapyramidal symptoms than C9orf72 carriers (p = 0.038). In conclusion, our study identified clinical differences between carriers of the three main FTD-TDP causing genes (TBK1, C9orf72 and GRN) which allow to formulate guidelines for genetic diagnosis. After a negative result for C9orf72, patients with both FTD and ALS should be tested first for mutations in TBK1. Specifically in FTD patients with early memory difficulties, a relatively late age at onset or extrapyramidal symptoms, screening for TBK1 mutations should be considered.

P163 TBK1 loss-of function and dominant-negative mutations in an extended European cohort of FTD and ALS patients J. van der Zee1,2, I. Gijselinck1,2, S. Van Mossevelde1,2,3, F. Perrone1,2, S. Engelborghs2,4, J. De Bleecker5, J. Baets2,3,6, on8,9, A. Lle o8,9, E. Gelpi7, R. Rojas-Garcıa8, J. Clarim 10 10 J. Diehl-Schmid , P. Alexopoulos , R. Perneczky10,11,12, ols13,14, C. Graff15,16, M. Synofzik13,14, J. Just13,14, L. Sch€ 15,16 17 , B. Borroni , A. Padovani17, A. Jordanova1,2,18, H. Thonberg S. Sarafov19, I. Tournev20, A. de Mendoncßa21,22, G. Miltenbergeroes do Couto21,22, A. Ramirez23,24, Milt enyi21,22, F. Sim~ omez-Tortosa28, F. Jessen23,25,26, M. T. Heneka25,27, E. G 29,30 2,3 , P. Cras , R. Vandenberghe31,32, P. De Jonghe2,3,6, A. Danek P. P. De Deyn2,4, K. Sleegers1,2, M. Cruts1,2, C. Van Broeckhoven1,2, BELNEU consortium1,2, EUEOD consortium1,2 1 University of Antwerp, Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 3 Department of Neurology, Antwerp University Hospital, Antwerp, Belgium 4 Department of Neurology and Memory Clinic, Hospital Network Antwerp ZNA Middelheim and Hoge Beuken, Antwerp, Belgium 5 Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium 6 University of Antwerp, Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 7 Neurological Tissue Bank of the Biobanc - Hospital Clinic-Institut d’Investigacions Biomediques August Pi i Sunyer IDIBAPS, Barcelona, Belgium 8 Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Aut onoma de Barcelona, Barcelona, Spain 9 Center for Networker Biomedical Research in Neurodegenerative Diseases CIBERNED, Madrid, Spain 10 Department of Psychiatry and Psychotherapy, Technical



University Munich, Munich, Germany 11 Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology and Medicine, London, Germany 12 West London Cognitive Disorders Treatment and Research Unit, West London Mental Health Trust, London, Germany 13 Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and Centre of Neurology, T€ ubingen, Germany 14 German Research Center for Neurodegenerative Diseases DZNE, T€ubingen, Germany 15 Karolinska Institutet, Department of Neurobiology, Care sciences and society NVS, KI-Alzheimer Disease Research Center, Stockholm, Sweden 16 Department of Geriatric Medicine, Genetics unit, Karolinska University Hospital, Stockholm, Sweden 17 Neurology Unit, University of Brescia, Brescia, Italy 18 Department of Biochemistry, Molecular Medicine Center, Medical University-Sofia, Sofia, Belgium 19 Department of Neurology, Medical University-Sofia, Sofia, Bulgaria 20 Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria 21 Hospital Santa Maria, Lisbon, Portugal 22 Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal 23 Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany 24 Institute of Human Genetics, University of Bonn, Bonn, Germany 25 German Center for Neurodegenerative Diseases DZNE, Bonn, Germany 26 Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany 27 Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Bonn, Germany 28 Department of Neurology, Fundaci on Jim enez Dıaz, Madrid,

Spain 29

Department of Neurology, Ludwig-Maximilians-University Munich, Munich, Germany 30 German Center for Neurodegenerative Diseases DZNE, Munich, Germany 31 Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium 32 Department of Neurology, University Hospitals Leuven, Leuven, Belgium Reduced expression of the TANK-Binding Kinase 1 (TBK1) has recently been associated with ALS and FTD in carriers of a heterozygous TBK1 loss-of-function (LoF) mutation. In addition, numerous rare missense mutations and single-amino acid deletions were identified in patients and unaffected individuals. Pathogenicity of a larger fraction of the latter mutations remained unclear, hampering molecular genetic testing and counseling, particularly in the absence of supportive co-segregation data in affected FTD or ALS families. In the present study, we investigated the genetic contribution of TBK1 in a cohort of 2538 patients with FTD, ALS or FTD plus ALS, ascertained within the European Early-Onset Dementia (EU EOD) Consortium. We aimed to acquire a better understanding of the mutation frequency and mutation spectrum of TBK1 in FTD and ALS, and to perform genotype-phenotype correlation studies in order to outline the clinical profile of TBK1 mutation carriers. We assessed the pathogenicity of predicted nonsense and frameshift

mutations by measuring loss of RNA expression by non-sense mediated mRNA decay of transcripts containing premature stop codons. We also analyzed the effect of other types of TBK1 mutations, comprising in-frame single-amino acid deletions and missense mutations, on NFjB activity in the IFN pathway using an in vitro luciferase assay. The results indicated that all in-frame amino acid deletions and a significant fraction of the missense mutations were LoF mutations reducing protein expression. Overall, we observed a mutation frequency for TBK1 of 1.1%, with frequencies in the clinical subgroups of 0.6% in FTD, 2.2% in ALS and 5.4% in FTD-ALS patients.

P164 Large-scale whole genome sequencing in ALS: project MinE M. van Es1 1 UMC Utrecht, Neurology, Utrecht, Netherlands Michael van Es on behalf of The Project MinE consortium: Over the last decade more than 20 genes have been discovered for ALS. Approximately 70% of familial ALS and 10% of sporadic form of the disease can now be attributed to these genes. Despite this progress many genetic factors, particularly in sporadic ALS, still remain to be discovered. Studies of the genetic architecture of ALS suggest that these genetic risk factors are made up out of rare genetic variants. This would suggest that the way forward would be Whole Genome Sequencing (WGS) studies rather than larger GWAS. Therefore Project MinE was started, which is a large-scale international study with the aim of whole genome sequencing 15,000 ALS patients and 7,500 control subjects. ALS research centers and funding agencies from 16 different countries have come together in this consortium to reach this ambitious goal. In this abstract project design, methodology, project governance, data handling, first results and future directions in the gene discovery era will be discussed. All samples are being sequenced on the Illumina HiSeq X platform in combination with SNP and methylation arrays. A project of this size creates tremendous data handling, processing and storage challenges. These have been addressed by directly transferring genetic data from the core sequencing facility to a High Performance Computing data center (SURFsara), which can be accessed remotely and permits data storage, transfer as well as analyses. Individual research group retain ownership of their data and this data cannot be accessed by other consortium members unless permission for access or sharing has been explicitly granted. Although all partners have agreed to a combined analysis. The first 2,000 genomes have been used for imputation in a GWAS (15 000 ALS patients, 25 000 controls) to improve power for association detection for rare variants (0.1–5%). Novel associations to be disclosed pending publication. At the time of submission of this abstract > 9000 genomes have been sequenced, quality control has been performed and burden testing is underway.


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Investigating the genetic impact of TUBA4A in a Belgian cohort of FTD and ALS patients F. Perrone1,2, H. Nguyen Phuoc1,2, S. Van Mossevelde1,2, A. Sieben1,2,3, J. De Bleecker3, M. Vandenbulcke4,5, R. Vandenberghe4,6, S. Engelborghs2,7, J. Baets2,8,9, P. De Jonghe2,8,9, P. Cras2,9, P. De Deyn2,7, J.-J. Martin2, J. van der Zee1,2, C. Van Broeckhoven1,2 1 University of Antwerp, Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 3 University Hospital Ghent and University of Ghent, Department of Neurology, Ghent, Belgium 4 KU Leuven, Faculty of Medicine, Department of Neurosciences, Leuven, Belgium 5 University of Leuven, Department of Old Age Psychiatry and Memory Clinic, Leuven, Belgium 6 University Hospitals Leuven, Department of Neurology, Leuven, Belgium 7 Hospital Network Antwerp Middelheim and Hoge Beuken, Department of Neurology and Memory Clinic, Antwerp, Belgium 8 University of Antwerp, Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 9 Antwerp University Hospital, Department of Neurology, Antwerp, Belgium

Investigating the role of rare heterozygous CHCHD10 variants in a Belgian cohort of FTD and ALS patients H. Nguyen Phuoc1,2, F. Perrone1,2, S. Van Mossevelde1,2, A. Sieben1,3,2, P. Santens3, J. De Bleecker3, R. Vandenberghe4,5, M. Vandenbulcke4,6, S. Engelborghs2,7, J. Baets2,8,9, P. De Jonghe2,8,9, P. Cras2,8, P. De Deyn2,7, J. Jacques Martin2, J. Van Der Zee1,2, C. Van Broeckhoven1,2 1 VIB-University of Antwerp, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 3 University Hospital Ghent and University of Ghent, Department of Neurology, Ghent, Belgium 4 KU Leuven, Leuven, Department of Neurosciences, Faculty of Medicine, Leuven, Belgium 5 University Hospitals Leuven, Leuven, Department of Neurology, Leuven, Belgium 6 University of Leuven, Department of Old Age Psychiatry and Memory Clinic, Leuven, Belgium 7 Hospital Network Antwerp Middelheim and Hoge Beuken, Antwerp, Department of Neurology and Memory Clinic, Antwerp, Belgium 8 Antwerp University Hospital, Department of Neurology, Antwerp, Belgium 9 VIB-University of Antwerp, Neurogenetics group, Department of Molecular Genetics, Antwerp, Belgium

Recently, mutations in TUBA4A, a gene that encodes one of eight human a-tubulins, has been linked to frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, its exact contribution to the genetic etiology of the FTD-ALS spectrum remains to be established. In the present study, massive parallel resequencing of TUBA4A was performed in a Belgian cohort of 459 FTD, 28 FTD-ALS and 157 ALS patients and 574 healthy individuals. We identified a novel TUBA4A frameshift mutation (p.Arg64Glyfs*90) predicting to lead to a truncated protein. Nonsense-mediated decay (NMD), which normally assures degradation of transcripts leading to truncated proteins, was tested to see if the protein was then degraded. We observed the presence of the frameshift mutation on cDNA of the mutation carrier, indicating that the truncated protein was not degraded. The mutation carrier was diagnosed with semantic dementia, with disease onset of 49 years, and no signs of motor neuron disease. Previous mutation screenings excluded mutations in the known FTD-ALS genes in this patient. To our knowledge, this is the first report of a TUBA4A mutation carrier with FTD (1/459). In a previous study, a similar truncating mutation (p.Trp407*) was investigated in vitro: this truncated protein lost the ability to incorporate into microtubules and resulted in the accumulation of multiple aggregate-like inclusions. FTD is also characterized by abnormal ubiquitinated protein aggregates in cytoplasm or nuclei of neuronal cells, therefore TUBA4A mutations could play a role in the formation of these protein inclusions. We also found a novel missense mutation (p.Thr381Met) in a familial ALS patient (1/157) with disease onset of 47 years. Notably, this patient also carried a C9orf72 repeat expansion. This mutation is located in exon 4 where it may affect the interaction with b-tubulin. Both variants were absent from 574 neurologically healthy control subjects. The present study confirms the role of TUBA4A in the FTD-ALS spectrum, although genetic variations in this gene are extremely rare in the Belgian FTD-ALS patient cohort.

Mutations in CHCHD10 have been linked to frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, the exact contribution to the genetic etiology of the FTD-ALS spectrum remains unclear. The aim of this study is to assess the mutation frequency and clinical characteristics of CHCHD10 in a Belgian cohort of 459 FTD, 28 FTD-ALS and 157 ALS patients by Sanger sequencing. We identified a novel nonsense mutation (p.Q108*) in 1/459 (0.22%) FTD patient that was absent from 574 control individuals. This patient initially was clinical diagnosed with behavioral variant FTD (bvFTD). Upon autopsy however, his diagnosis was revised to definite Parkinson’s disease (PD). We demonstrated that the p.Q108* premature stop codon mutation leads to loss of the mutated transcript, suggesting that loss-of-function is the disease mechanism for pathogenic mutations in CHCHD10. Further, we observed 3 already described heterozygous missense mutations (p.P80L, p.P34S and p.P96T). The p.P80L mutation was identified in 1 unrelated FTD patient with disease onset of 65 years devoid of mutations in known FTD/ALS genes. This mutation was recently reported in 3 ALS patients, yet we found the same mutation also in one control individual. Because the control subject was just 57 years at inclusion and thus disease may still develop disease, it can be speculated that p.P80L is a possible pathogenic mutation with reduced disease penetrance. The p.P34S mutation was found in 3 unrelated FTD patients, 1 ALS patient and more than 1% (6/574) of the control individuals (p = 0.41), making it unlikely that this mutation is pathogenic. We identified the p.P96T mutation in 2 unrelated patients (1 FTD and 1 ALS) and one control individual. This mutation is a reported common variation and was also seen in other studies in control individuals, and thus is likely a benign polymorphism. In conclusion, we observed two probable disease-causing mutations in CHCHD10, in 2 FTD patients. Nonetheless, the mutation frequency of CHCHD10 was extremely low in the FTDALS cohort compared to the other FTD-ALS genes like C9orf72, VCP and TBK1.

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Founder effect of P301L MAPT mutation in families with FTD in Baix Llobregat County (Barcelona, Spain) ne4, L. Palencia-Madrid1, S. Borrego2, O. Grau-Rivera3, R. Re~ I. Hernandez5, C. Almenar6, A. Antonell2, M. Balasa2, A. Llado2, E. Gelpi2, M. M. de Pancorbo1, R. Sanchez-Valle2 1 Lascaray Research Center, University of the Basque Country UPV/ EHU, BIOMICs Research Group, Vitoria, Spain 2 Hospital Clinic/IDIBAPS, Alzheimer’s disease and other cognitive disorders unit, Barcelona, Spain 3 IDIBAPS, Neurological Tissue Bank-Biobank, Barcelona, Spain 4 Hospital Universitario de Bellvitge, Neurology, Barcelona, Spain 5 Memory Clinic of Fundaci o ACE, Institut Catal a de Neurociencies Aplicades, Barcelona, Spain 6 Hospital Benito Menni, Sant Boi de Llobregat, Barcelona, Spain

Analysis of genetic polimorphisms and genetic mutations in Frontotemporal Lobar Degeneration M. Gil Moreno1,2, M. Manzano Palomo3, M. Cuadrado P erez4, M. Calero Lara2, A. Ra´bano Gutie´rrez2 1 Hospital Universitario de Torrej on, Neurologıa, Torrej on de Ardoz, Spain 2 Fundaci on Centro de Investigaci on en Enfermedades Neurol ogicas, Instituto de Salud Carlos III, Banco de Tejidos, Madrid, Spain 3 Hospital Universitario Infanta Cristina, Neurologıa, Parla, Madrid, Spain 4 Hospital Clınico San Carlos, Universidad Complutense, Neurologıa, Madrid, Spain

Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder with a strong genetic component. Mutations in the microtubule associated protein tau gene (MAPT), located on chromosome 17 cause familiar FTD with 4-repeats tau deposits. P301L mutation (rs63751273) is one of the most frequent mutations in MAPT, although its prevalence varies in different populations. The high incidence of familial frontotemporal dementia linked to the P301L mutation in MAPT gene in the County of Baix Llobregat (Barcelona, Spain) might reflect a unique ancestral origin of the chromosome carrying this mutation. With the aim of studying the origin of the P301L mutation in these families, 20 SNPs with a Minor allele frequency (MAF) ≥ 0.2 in the MAPT (17q21-22) gene, surrounding the P301L mutation, were selected and analysed. Twenty subjects from 9 different, apparently non-related, families affected by FTD linked to the P301L mutation from Baix Llobregat County were studied, being 15 of them mutation carriers. Additionally, 60 unrelated and healthy individuals from the province of Barcelona were analysed as control population. To perform the genetic analysis of these 21 SNPs, including rs63751273 (P301L mutation), a multiplex single-base extension (SBE) reaction was designed and the results were studied by capillary electrophoresis. The analysis revealed that all the affected individuals carried the same haplotype for the SNPs analysed, suggesting a common ancestor. This common ancestor would have originated or brought in the P301L mutation to this region, producing a founder mutation effect. The same haplotype, free of P301L mutation, was found in < 10% of the control population of Barcelona. In conclusion, the common haplotype found in the mutation carriers studied strongly support a founder effect of the P301L MAPT mutation in the area of Baix Llobregat. Acknowledgement: Fundaci o Marat o de TV3 (20143810)

Frontotemporal dementia (FTD) results from different neurodegenerative diseases which are heterogeneous from a clinical, neuropathological and genetic view point. The objective of this study was to analyze the molecular characteristics of a series of cases with Frontotemporal Lobar Degeneration (FTLD). Retrospective study from different Tissue Banks and pathological diagnosis of FTLD. Clinical data: Age of onset and death, average time of disease, personal history and cardiovascular risk factors, clinical diagnosis, first clinical symptom and evolution of the disease. Pathological data: TDP43 inclusions, Braak stage, CERAD and vascular pathology. Molecular data: Apolipoprotein E (APOE) genotype, H1/H2 MAPT gene polymorphism and 129 codon gene of the human prion protein (PRNP). Fifty-one cases were analyzed. In APOE analysis, the e3/e3 haplotype was predominant (64.7%); APOE4 allele was present in 17.6% and was associated with more b-amyloid pathology (p = 0.001) and shorter disease duration (p = 0.082). The most frequent haplotype for the MAPT gene was H1/H1 (48,6%), which was frequent in PSP cases. Parkinsonism was related to H1/H1 cases (75%) and behavioral disturbances to H1/H2 (38:9%) as the most frequent initial symptom. The most frequent polymorphism in the PRNP gene was methionine-methionine (MM; 58.3%), associated with younger age at death (p = 0.090), longer disase duration (p = 0.034) and greater brain atrophy (p = 0.066). No mutation was found in MAPT and PRNP genes. APOE4 allele was associated with worse prognosis over time. Phenotypic characteristics at onset were different in H1/H2 haplotype in MAPT gene. MM polymorphism shows different disease prognosis. This preliminary study propsed genetic and clinical predictors in FTLD progression. The identification of diseasemodifying predictors of prognosis opens a new avenue in FTLD and may contribute to define outocomes and to monitor pharmacological targets. APOE; MAPT gene polymorphism; PRNP codon 129; Frontotemporal Lobar Degeneration


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Impaired LTP-like cortical plasticity and intra-cortical facilitation in presymptomatic FTLD mutation carriers A. Benussi1, M. Cosseddu1, I. Filareto1, V. Dell’Era1, S. Archetti2, M. S. Cotelli3, A. Micheli4, A. Padovani1, B. Borroni1 1 University of Brescia, Center for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, Brescia, Italy 2 Spedali Civili Hospital, III Laboratory of Analysis, Brescia, Italy 3 Valle Camonica Hospital, Neurology Unit, Brescia, Italy 4 Casa di Cura San Francesco, Bergamo, Italy

Frontotemporal lobar degeneration spectrum: the first genetic screen in a Greek cohort S. Lee1, E. M. Ramos2, C. Kroupis3, C. Koros3, V. Van Berlo2, K. Wojta2, Q. Wang2, D. Dokuru2, M. Pribadi2, A. Bonakis3, V. Papastefanopoulou3, J. Papatriantafyllou3, B. Miller1, L. Stefanis3, G. Coppola2, S. G. Papageorgiou3 1 UCSF Memory and Aging Center, San Francisco, USA 2 Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA 3 2nd Department of Neurology, 2nd Department of Biochemistry, National and Kapodistrian University of Athens, Attikon University General Hospital, Athens, USA

Transcranial magnetic stimulation (TMS) has become a safe, non-invasive, and promising tool to assess specific cortical circuits in the central nervous system. Multiple neurophysiological biomarkers were assessed using a TMS multi-paradigm approach in 10 symptomatic (n = 8 GRN, n = 2 C9orf72) and 10 presymptomatic (n = 9 GRN, n = 1 MAPT) FTLD mutation carriers, and 19 healthy controls (HC). TMS was used to assess short-interval intracortical inhibition (SICI), intra-cortical facilitation (ICF), long-interval intracortical inhibition (LICI), short-latency afferent inhibition (SAI) and LTP-like cortical plasticity by using a paired-pulse paradigm. Mean ICF was reduced in presymptomatic carriers (expected symptom onset in 17.0 7.0 years) compared to age-matched HC (95.7 24.6 vs 145.3 33.4 respectively, p = 0.001, expressed as percentage of the mean motor evoked potential (MEP) amplitude evoked by single pulse TMS) as well as LTP-like cortical plasticity (99.1 15.7 vs 166.8 31.8 respectively, p < 0.001, expressed as percentage of mean MEP amplitude after paired associative stimulation protocol). SICI, LICI and SAI did not differ significantly between groups (p = 0.359, p = 0.186, p = 0.811 respectively). In symptomatic carriers, we observed an impairment in SICI compared to presymptomatic carriers (81.9 31.4 vs 39.7 12.2, p = 0.001). ICF and LTP-like cortical plasticity were reduced in symptomatic carriers and did not differ significantly from presymptomatic carriers. LICI and SAI were within normal range. There was a significant correlation between years till expected disease onset (in the presymptomatic group) or disease duration (in the symptomatic group) and mean SICI, r(17) = 0.659, p = 0.002. In conclusion, the assessment of ICF and LTP-like plasticity could support the diagnosis of autosomal dominant FTD, and be used as a screening tool to predict mutation status in at-risk subjects. Moreover, ICF, LTP-like plasticity and SICI could provide the footprints of specific pathophysiological processes in the development of FTLD.

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Frontotemporal lobar degeneration (FTLD) is the leading cause of dementia in middle age. To date, no studies investigating genetic mutations for FTLD have been performed in the Greek population. We examined 42 consecutive FTLD spectrum patients from our dementia clinic. Clinical diagnoses included 26 behavioral variant frontotemporal dementia (bvFTD), 4 nonfluent primary progressive aphasia (nfvPPA), 5 semantic PPA (svPPA), 4 progressive supranuclear palsy (PSP) and 3 corticobasal syndrome (CBS). All subjects were screened for genetic mutations within genes known to cause AD or FTLD: amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2), microtubule-associated protein Tau (MAPT), progranulin (GRN), TAR DNA-binding protein 43 (TARDBP), fused in sarcoma RNA-binding protein (FUS), and the hexanucleotide repeat expansion in C9ORF72. Three patients carried probable causative variants: one CBS patient carried a MAPT variant previously reported as pathogenic, while one bvFTD and one svPPA patients had novel loss-of-function GRN variants. Additionally, three patients diagnosed with bvFTD (2) and FTDALS (1) had expanded C9ORF72 repeats. Intriguingly, 8 patients were found to have rare variants in MAPT, GRN, APP, and PSEN2. Among these, two bvFTD carried rare MAPT variants while those with rare GRN variants included one bvFTD, two svPPA, and one with PSP syndrome. Notably, rare APP and PSEN2 variants were observed in one bvFTD and one nfvPPA patient, respectively. All but one of the individuals carrying a probable causative or rare variant had no known family history of dementia. In conclusion, we present the first FTLD genetics study in a Greek cohort. Despite an absence of a known family history in most cases, 14% had a probable disease-causing FTLD mutation, and an additional 19% showed rare variants in known dementia genes. Both known and novel predicted-pathogenic variants were identified, suggesting that previously unreported mutations may be present in the Greek population.



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More than two-hundred and fifty FTD patients looking for genes: results from Italian FTD Network A. Alberici1, B. Nacmias2, G. Logroscino3, A. Bruni4, F. Tagliavini5, R. Ghidoni6, D. Galimberti7, L. Bonanni8, A. Cagnin9, M. Bozzali10, V. Silani11, R. Turrone1, C. Ferrari2, G. Lombardi2, V. Bessi2, R. Capozzo3, C. Zecca3, S. Arcuti3, C. Cupidi4, L. Bernardi4, N. Smirne4, F. Frangipane4, G. Rossi5, P. Caroppo5, P. Tiraboschi5, L. Benussi6, G. Binetti6, M. Ciani6, S. Fostinelli6, A. Arighi7, C. Fenoglio7, G. Fumagalli7, M. Onofrj8, E. Scarpini7, S. Sorbi2, A. Padovani1, B. Borroni1,12, V. Bessi2 1 Neurology Unit-Spedali Civili, University of Brescia, Brescia, Italy 2 Unibersity Of Florence, Florence, Italy 3 University of Bari, Lecce, Italy 4 Centro Regionale di Neurogenetica, Lamezia Terme, Catanzaro, Italy 5 Carlo Besta Neurological Institute INCB, Milan, Italy 6 IRCCS San Giovanni di Dio-FBF, Brescia, Italy 7 University of Milan, Milan, Italy 8 University of Chieti, Chieti, Italy 9 University of Padua, Padua, Italy 10 IRCCS Santa Lucia, Rome, Italy 11 IRCCS Istituto Auxologico Italiano, Milan, Italy 12 on behalf of the Italian Network on Frontotemporal Dementia, Brescia, Italy

Characteristics and Progress on the Initial 147 Subjects in the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Protocol B. Boeve1, H. Rosen2, A. Boxer2, G. Coppola3, C. Dheel1, B. Dickerson4, K. Faber5, J. Fields1, T. Foroud5, R. Gavrilova1, N. Ghoshal6, J. Goldman7, N. Graff-Radford8, M. Grossman9, H. Heuer2, J. Hsiao10, R. Hsiung11, E. Huey7, D. Irwin9, K. Kantarci1, A. Karydas2, D. Knopman1, J. Kornak2, J. Kramer2, W. Kukull12, I. Mackenzie11, B. Miller2, C. Phelps10, R. Rademakers8, K. Rankin2, L. Shaw9, M. Sutherland13, A. Toga14, J. Trojanowski9, A. Vetor5, S. Weintraub15, Z. Wszolek8 1 Mayo Clinic, Rochester, USA 2 UCSF, San Francisco, USA 3 UCLA, Los Angeles, USA 4 Massachusetts General Hospital, Boston, USA 5 Indiana University, Indianapolis, USA 6 Washington University, St. Louis, USA 7 Columbia University, New York, USA 8 Mayo Clinic, Jacksonville, USA 9 University of Pennsylvania, Philadelphia, USA 10 NIA, Bethesda, USA 11 University of British Columbia, Vancouver, USA 12 University of Washington, Seattle, USA 13 NINDS, Bethesda, USA 14 USC, LONI, Los Angeles, USA 15 Northwestern University, Chicago, USA

Background: The Italian Frontotemporal Dementia (FTD) Network has been recently established by 11 tertiary referral centres, joining the already existing German FTD Network. The aim is to share and harmonize common diagnostic procedures, to improve disease management, and to evaluate natural disease history. Up to now, despite giant step forward in identifying genetic determinants of FTD, a considerable number of patients is still negative to genetic screening. The most interesting cases are represented by those with an autosomal dominant trait of inheritance or early disease onset. Objective: To assess the number and to provide the main clinical features of FTD patients with either positive family history or early disease onset (or both), but still negative to genetic analyses in GRN, MAPT and C9orf72 genes. Methods and subjects: A retrospective study was undertaken on FTD cases with positive family history for dementing or psychiatric conditions (FH+) or early disease onset (EO, age at onset 65 years), and 3) both EO and FH+ (EOFH+). Results: Retrospective analysis covering the last 15 years identified 269 FTD patients without known causative gene. In particular, 117 patients belonged to EOFH- group (mean age of onset = 56.2 6.4 years, female 47%), 65 patients to LOFH+ (mean age of onset = 71.7 4.1 years, female 44%), and 87 patients to EO and FH+ (mean age of onset = 58.5 5.0 years, female 58.6%). No differences were found among the clinical variants of FTD in the three groups, with the majority of patients showing a disease presentation with behavioural FTD (almost 70%), and an equal representation of language variants (20–30%). Interestingly, in FTD patients with EO and FH+, no cases of FTD with Motor Neuron Disease were found. Conclusions: There is a considerable number of FTD patients suggestive for a genetic aetiology of the disease, but still missing of identified genetic determinants. Genetic studies on patients belonging to harmonised networks and sharing common genetic background might be useful to identify novel causative genes.

The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Consortium (U01 AG045390) involves investigators at 8 centers in North America who are evaluating subjects in kindreds with mutations in microtubule associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72) genes using a standardized battery of measures. We report here the characteristics of subjects evaluated through February 2016. There are 147 subjects among 49 kindreds enrolled to date with the following characteristics: 77 (52%) female, 139 (95%) Caucasian (and 5 Asian, 1 African-American, 1 American Indian and 1 Middle-Eastern American), mean age 52 (range 28–80) years, and mean education 15 (range 12–20) years. Subjects are classified as follows: symptomatic mutation carriers (+mCDR>0), asymptomatic mutation carriers (+mCDR = 0) and asymptomatic non-mutation carriers (-mCDR = 0). Characteristics for each genetic group are as follows: MAPT - 10 kindreds with one of the following mutations: N279K, P301L, S305N, +16, V337M, G389R and R406W; 39 subjects (15 + mCDR>0, 8 + mCDR = 0, 4 -mCDR=0 and 12 with variable clinical status but as-yet-unknown mutation status); GRN 14 kindreds with one of the following mutations: A9D, C31LfsX35, R52HfsX2, R110X, R198GfsX19, S226WfsX28, A237WfsX4, V279GfsX5, Q300X, W304LfsX58, R418X, I422Efs and R493X; 58 subjects (22 + mCDR>0, 12 + mCDR=0, 12 -mCDR=0 and 12 with variable clinical status but as-yet-unknown mutation status); and C9orf72 - 25 kindreds with the expansion; 50 subjects (18 + mCDR>0, 14 + mCDR=0, 9 -mCDR=0 and 9 with variable clinical status but as-yet-unknown mutation status). Almost all subjects have had volumetric MRI performed as well as DNA, plasma, RNA and PBMC samples collected. CSF has been collected in 40% of subjects. These clinical, neuropsychological and biomarker data, which will be available to interested investigators worldwide, should facilitate planning for upcoming disease-modifying therapeutic trials in familial frontotemporal lobar degeneration.


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P173 TREM2 variant p.His157Tyr in Colombian patients with frontotemporal dementia A. Lopez-Caceres1, A. Laserna1, C. Trivi~ no-Martınez2, omez-Vega1, P. Ayala-Ramırez1, E. Garcia-Cifuentes3, J. C. G P. Reyes4, H. Santamarıa-Garcıa5, J. M. Santacruz5, I. Zarante1, D. Matallana2 1 Pontificia Universidad Javeriana, Instituto de Genetica Humana, Bogota, Colombia 2 Pontificia Universidad Javeriana, Instituto de Envejecimiento, Bogota, Colombia 3 Pontificia Universidad Javeriana, Semillero de Neurociencias y Envejecimiento, Bogota, Colombia 4 Hospital Universitario San Igancio, Radiology, Bogota, Colombia 5 Pontificia Universidad Javeriana, Psychiatry, Bogota, Colombia Several causal genes have been identified associated in Frontotemporal Dementia (FTD), some of which have been associated with the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene, whose deficiency is particularly associated with Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), in which homozygous mutations have been associated with early onset dementia similar to FTD and bone cysts. Recently, TREM2 homozygous variants in families with FTD have been reported without associated bone involvement, and heterozygous variants have been associated with increased risk of developing Alzheimer’s disease (AD). In the present descriptive observational study, consisting of a cohort of 177 patients diagnosed with FTD by consensus through clinical, radiological, and genetic studies, two patients with the same heterozygous variant of rs2234255 (TREM2 c.469C>T, p.His157Tyr) using a targeted next-generation sequencing panel designed to detect genetic variations in 45 genes associated with several neurodegenerative disorders, were found to have similar clinical presentation characterized in particular by apathy-related symptoms, impaired social behavior, disinhibition towards inappropriate sexual behavior and impaired risk assessment. This observation is important because it indicates that not only homozygous mutation but also heterozygous mutations in TREM2 gene modulate the risk of presenting clinical features of FTD. Study supported by: Colciencias 371–2011

P174 Utilizing FTD-associated MAPT-S305 mutations to develop cell models that express 4R Tau K. Bowles1, A. Goate1 1 Mount Sinai School of Medicine, Friedman Brain Institute, New York, USA Accurate human iPSC-derived models of tauopathy have been a challenge to develop, as neurons derived from iPSC are immature and do not express all isoforms of Tau present in the adult brain. Isoforms that include the expression of MAPT exon 10, which result in a Tau protein containing four microtubule binding repeats (4R Tau), are found to be overexpressed in multiple tauopathies and have a propensity for aggregation. However, 4R tau is notably absent or in very low abundance from immortalised cell lines and from hiPSC-derived neurons. Using a model to estimate the effect of FTD mutations within MAPT exon 10 and intron 10 on the stability of its RNA hairpin structure, we predict that single nucleotide mutations at the S305 codon would significantly destabilize this

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structure, resulting in increased inclusion of exon 10, and increased expression of 4R Tau. A MAPT minigene was altered by site directed mutagenesis to contain any one of the three known FTDassociated S305 mutations in order to test the effect of these mutations on exon 10 splicing. Expression of this construct in HEK293T, SH-SY5Y and iPSC-derived neural progenitor cell lines shifted splicing of the minigene from equal inclusion and exclusion of exon 10, to predominantly exon 10 inclusion. By utilizing the RNA instability, and therefore altered splicing, that results from mutations at S305, we predict that we can develop cell lines that stably express 4R Tau, which can be used as a model for FTD research. As such, we are in the process of genome editing hiPSC lines using the CRISPR/Cas9 system to induce these S305 mutations into endogenous DNA, and will characterize the effect of altered 4R expression in these cells.

P175 Unraveling the genetic role of SORT1 in the Belgian frontotemporal dementia population S. Philtjens1,2, E. Wauters1,2, S. Van Mossevelde1,2, J. van der Zee1,2, T. Van Langenhove1,2, S. Engelborghs2,3, M. Vandenbulcke4, M. Versteven1,2, K. Peeters1,2, M. Mattheijssens1,2, M. Van den Broeck1,2, P. Cras2,5, R. Vandenberghe6, P. P. De Deyn2,3, M. Cruts1,2, C. Van Broeckhoven1,2 1 University of Antwerp, Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 3 Department of Neurology and Memory Clinic, Hospital Network Antwerp, Middelheim and Hoge Beuken, Antwerp, Belgium 4 Brain and Emotion Laboratory Leuven, Department of Psychiatry, University of Leuven and University Hospitals Leuven Gasthuisberg, Leuven, Belgium 5 Department of Neurology, University of Antwerp, Antwerp, Belgium 6 Laboratory for Cognitive Neurology, Department of Neurology, University of Leuven and University Hospitals Leuven Gasthuisberg, Leuven, Belgium Sortilin (SORT1) was the first, and thus far, only identified neuronal receptor for granulin (GRN), a growth factor involved in cell growth, inflammation and cancer development. Loss of function mutations in the GRN gene were demonstrated to result in a systemic reduction of GRN protein to about 50% of normal levels in FTD patients, which can be diagnostically detected in bodily fluids including plasma, serum and CSF. A genome-wide association study identified two common single nucleotide polymorphisms (SNPs), rs646776 and rs611917, located in the vicinity of SORT1 to be associated with decreased GRN plasma levels. We replicated the association study between these two common SNPs, rs646776 and rs611917, and GRN serum levels in healthy control individuals, FTD patients and GRN loss-of-function mutation carriers. As was previously reported, we observed a significant reduction in serum GRN levels in patients and controls carrying at least one minor G or C allele from rs646776 and rs611917, respectively. In addition, we present the first report on the identification of SORT1 missense mutations (n = 6) in 1.7% of the Belgian FTD patient cohort (n = 683). All six novel missense mutations occurred at highly conserved amino acids and were absent in over 1000 age- and geographically matched control individuals. In addition, five out of



six missense mutations were located in the b-propeller region of SORT1, which was previously shown to be responsible for the binding between SORT1 and GRN. Furthermore, we calculated that the burden of rare variants (MAF ≤1%) was significantly higher in FTD patients (2.0%) compared to control individuals (0.7%) (p = 0.0001), resulting in a new genetic risk association of FTD with rare coding SORT1 variants.

P176 Differences in rate of participation in clinical research studies in asymptomatic members of families with frontotemporal dementia (FTD) G.-Y. R. Hsiung1, P. Sengdy1, E. Dwosh1, M. Baker2, R. Rademakers2, H. Feldman1, I. R. Mackenzie1 1 University of British Columbia, Medicine, Vancouver, Canada 2 Mayo Clinic Jacksonville, Neuroscience, Jacksonville, USA Participation in observational clinical research studies is an altruistic behaviour of the subjects whose goal is to help advance our knowledge of the disease process with no immediate benefits to themselves. However, casual observations from our familial FTD cohort suggest that there is a lower rate of participation among asymptomatic mutation carriers compared to non-carriers, which may reflect an underlying behavioural trait of prodromal FTD. To formally investigate this impression, we compared the recruitment rate of asymptomatic mutation carriers with that of non-carrier family members using Chi square statistic. Eighty-five asymptomatic subjects with a first-degree relative affected by familial FTD or known to carry a mutation in either GRN or C9ORF72 were considered to be at-risk for developing FTD and therefore eligible to be in our longitudinal study. As expected, there were fewer eligible mutation carriers (N = 32, 38%) and than non-carriers (N = 53, 62%), since those who were already displaying symptoms were excluded from this part of our study. The overall recruitment rate of mutation carriers was 75% (24/32) compared to 83% (44/53) for non-carriers (n.s.). However, there is a significant difference between recruitment for GRN (67%) vs. C9ORF72 (93%) families (p = 0.0024). The rate of recruitment for C9ORF72 mutation carriers is high (100%) and not significantly different from their non-carrier relatives (90%, p = 0.19), while recruitment rate for GRN carriers is lower (53%) than that of their non-carrier counterparts (76%, p = 0.12). Furthermore, of all groups, male GRN mutation carriers were the least likely to agree to participate in our longitudinal study (40%, p = 0.0025). This difference in rate of participation may reflect an underlying behavioural trait among male GRN mutation carriers and may have important implications when planning future clinical studies in genetic FTD cohorts.

P177 Right temporal variant frontotemporal dementia with motor neuron disease: a novel association with the C9orf72 expansion I. Woollacott1, K. Dick1, E. Gordon1, M. Bocchetta1, S. Harding1, K. Sidle2, J. Warren1, J. Rohrer1 1 Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, Great Britain 2 Department of Molecular Neuroscience, UCL Institute of Neurology, London, Great Britain Frontotemporal dementia (FTD) causes progressive deterioration in behaviour or language. Right temporal variant FTD (RT-FTD) manifests as selective right temporal lobe atrophy with prosopagnosia, prominent behavioural change and/or impairment of semantic knowledge. Although approximately 15% of patients with FTD develop motor neuron disease (MND), patients with RT-FTD rarely develop MND. The few reported cases of RT-FTD-MND have been due to either TDP-43 Type B or C pathology but no genetic cause has previously been described. The chromosome 9 open reading frame 72 (C9orf72) expansion is the most common genetic mutation identified in familial FTD and MND and is usually associated with TDP-43 Type A or B pathology. Patients usually present with behavioural variant FTD and/or the amyotrophic lateral sclerosis (ALS) variant of MND, with symmetric brain atrophy. We describe a 67 year-old patient with a pathogenic C9orf72 expansion, who presented with prosopagnosia and behavioural change and subsequently developed profound semantic impairment and progressive spasticity in the upper and lower limbs. She had a family history of MND. Examination revealed asymmetric upper motor neuron signs consistent with primary lateral sclerosis. Electromyography studies were normal on two occasions. Cervical spine MRI showed no spinal cord abnormalities but volumetric brain MRI revealed focal right temporal lobe atrophy. Detailed neuropsychological assessment demonstrated severe executive dysfunction, semantic impairment and prosopagnosia. To our knowledge, this is the first case identifying a genetic basis for RT-FTD-MND. This adds to the growing heterogeneity of cognitive and motor presentations associated with the C9orf72 expansion.

P178 Validation of frontotemporal lobar degeneration pedigree classification criteria in a Northern Italy cohort: implications for genetic testing and counseling L. Benussi1, S. Fostinelli1, M. Ciani1, R. Zanardini1, G. Binetti1,2, R. Ghidoni1 1 IRCCS Fatebenefratelli, Molecular Markers Laboratory, Brescia, Italy 2 IRCCS Fatebenefratelli, MAC- Memory Clinic, Brescia, Italy In the last years the progress in the genetic of Frontotemporal Lobar Degeneration (FTLD) and the possibility, for patients and at genetic risk subjects, of pharmacological trials directed to pathogenic mutations carriers are raising the interest of clinicians and researchers to identify these families. Genetic counseling should always precede a genetic test to provide patients and family members all the information about the genetic test and its implications. The collection of family history is the first important step to be achieved in genetic counseling, with the aim of estimating family-risk and to provide geneticist information on the real need of


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a genetic testing and priority on which gene or genes to test. In this study we applied the recently proposed criteria (Wood et al. JAMA Neurol 2013; 70:1411-7) to classify Italian FTLD pedigrees. The analyzed 402 pedigrees were classified as follows: 50(12.4%) with high family history of dementia, 26 (6.5%) medium, 62 (15.4%) low; 157 (39.1%) were apparent sporadic cases and 107 (26.6%) of unknown significance pedigrees. On the whole, the mutation frequency was 13.7%, with GRN (69.1% of mutation rate) and C9ORF72 (25.4%) as the most common associated genes. The mutation detection rate was highest in the high family history group (74%) and, as expected, decreased in other categories (medium: 15.4%, low: 9.7%, sporadic: 1.3%). Of note, 6 (5.6%) of FTLD belonging to pedigrees of unknown significance carried a pathogenic mutation: this category mostly included patients that did not have family history information. Globally, we found that an high rate of FTLD patients asked for genetic counseling, especially among subjects belonging to high risk pedigrees (42%); as expected, the request for genetic counseling decreased according to family risk (medium: 27%, low: 18%, apparent sporadic: 5%). In conclusion, the proposed pedigree classification criteria resulted to be a useful tool to rate for known genetic causes of FTLD and for genetic counseling requests.

P179 Molecular mechanism of genetic anticipation in C9orf72 repeat expansion families M. Cruts1,2, I. Gijselinck1,2, S. Van Mossevelde1,2, J. van der Zee1,2, A. Sieben1,2, S. Engelborghs2,3, J. De Bleecker4, A. Ivanoiu5, aumer1,2, M. Van den Broeck1,2, O. Deryck6, B. Heeman1,2, V. B€ 1,2 M. Mattheijssens , K. Peeters1,2, P. De Jonghe7,2,8, P. Cras2,8, J.-J. Martin2, P. P. De Deyn2,3, C. Van Broeckhoven1,2 1 University of Antwerp, Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 3 Hospital Network Antwerp ZNA Middelheim and Hoge Beuken, Department of Neurology and Memory Clinic, Antwerp, Belgium 4 University Hospital Ghent and University of Ghent, Department of Neurology, Ghent, Belgium 5 Saint-Luc University Hospital and Institute of Neuroscience, Universite Catholique de Louvain, Department of Neurology, Brussels, Belgium 6 General Hospital Sint-Jan Brugge-Oostende, Department of Neurology, Bruges, Belgium 7 University of Antwerp, Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 8 Antwerp University Hospital, Department of Neurology, Edegem, Belgium A pathological expansion of the G4C2 repeat in the 5’ regulatory region of C9orf72 (MIM *614260) is the most common genetic cause of frontotemporal dementia and/or amyotrophic lateral sclerosis (FTD-ALS MIM #105550). The onset age associated with a C9orf72 expansion is highly variable suggesting the presence of modifying factors and/or genetic anticipation. Several studies reported an inverse correlation between generation number and onset age in C9orf72 families, with a decrease in onset age of 7 to 11 years in the younger of two subsequent generations. However, in the absence of exact repeat size information of patients in successive generations of extended FTLD-ALS families, direct molecular evidence of genetic anticipation was not demonstrated. In this study,

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first we showed in 72 unrelated repeat expansion carriers of the Belgian FTD cohort an association between the repeat size and onset age (pC9orf72 repeat expansion. In one parent-offspring pair, we observed an increased size of the repeat expansion with about 1000 units, indicating repeat instability. Next, we used the DNA methylation state of the C9orf72 CpG island as a proxy of the repeat size, because exact expansion size information was lacking in most of the 15 available parent-offspring pairs. We observed an increase of DNA methylation of up to 35.6% in 13 pairs (p = 0.0034), supportive of an intergenerational repeat amplification. Together, these data demonstrate that the observed decrease in onset age of FTD-ALS in families segregating a C9orf72 repeat expansion is likely due to genetic anticipation resulting from the instable G4C2 repeat. Longer repeat sizes may have a more severe impact on putative disease mechanisms including gene expression, RNA toxicity and dipeptide repeat production.

P180 The genetic landscape of clinical FTD: a systematic whole-exome sequencing study of 125 consecutive cases C. Blauwendraat1, C. Wilke2, I. Jansen1, P. Rizzu1, J. Sim on-S anchez1, P. Heutink1, M. Synofzik2 1 German Center for Neurodegenerative Diseases DZNE, Genome Biology of Neurodegenerative Diseases, T€ ubingen, Germany 2 Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, T€ ubingen, Germany Frontotemporal dementias (FTD) define a clinically and genetically heterogeneous group of disorders characterized by progressive degeneration of frontotemporal networks. Genes in manifold pathways have recently been implicated in the complex molecular pathogenesis of FTD, but the types and relative proportion at which these different genes contribute to FTD phenotypes have not yet systematically been explored in a consecutive series. Here we investigated the frequencies and mutations in Mendelian genes known to contribute to neurodegenerative diseases in a large series of clinical FTD subjects. A consecutive series of 125 index subjects from Germany diagnosed with clinical FTD according to international consensus criteria was screened for C9orf72 repeat expansions, GRN and MAPT mutations, and, if negative, for mutations in known neurodegenerative disease genes by whole exome sequencing (WES). Preliminary analysis reveals likely pathogenic mutations explaining the FTD syndrome in ~20% subjects, including mutations in C9orf72 (n = 8, 6%), GRN (n = 6, including an 11-exon macro-deletion, 5%), and, more rarely, TBK1, CHCHD10, TARDBP and SQSTM1 (each n = 1, MAPT. Interestingly, WES also unraveled pathogenic mutations in several genes not commonly linked to FTD pathogenesis, including mutations in Alzheimer (PSEN1, PSEN2), lipofuscinosis (CTSF), and cholesterol homeostasis pathways (CYP27A1). Our study presents the first systematic genetic in-depth study of a consecutive series with clinical FTD, including > 90 WES datasets. It demonstrates that molecular genetic defects in various pathways play a central role in the pathogenesis of FTD, explaining a substantial proportion of clinical FTD cases even in the absence of a positive family history. Mutations are found not only in pathways commonly linked to FTD, but also in a wide range of other pathways. This suggests that clinical FTD is the converging downstream result of manifold pathways, arising from a delicate susceptibility of frontotemporal brain networks to insults in these pathways.



P181 Myelin oligodendrocyte basic protein and longitudinal decline in behavioral-variant frontotemporal degeneration L. Massimo1, L. Rennert2, S. Xie2, V. Van Deerlin3, D. Irwin1, C. McMillan1, M. Grossman1 1 University of Pennsylvania, Neurology, Philadelphia, USA 2 University of Pennsylvania, Biostatistics and Epidemiology, Philadelphia, USA 3 University of Pennsylvania, Pathology and Laboratory Medicine, Philadelphia, USA There is increasing interest in the influence of single nucleotide polymorphisms (SNPs) on disease in frontotemporal lobar degeneration (FTLD). Specifically, cross-sectional studies have associated the T risk allele in rs1768208 located in or near the myelin oligodendrocyte basic protein gene (MOBP) as a risk factor for progressive supranuclear palsy (PSP) pathology, reduced survival in behavioral variant frontotemporal degeneration (bvFTD), and reduced white matter integrity in FTLD-tau. Here we evaluate the hypothesis that rs1768208 risk allele copies are associated with longitudinal cognitive decline in bvFTD. We studied 43 individuals clinically diagnosed with bvFTD (mean baseline age =60.1 years + 7.7, mean disease duration at baseline 3.6 years+ 2.2 mean baseline MMSE 26.2 years+ 7.1). All subjects had at least 2 verbal fluency (FAS) observations. Patients were genotyped for rs1768208 using a custom pan-neurodegenerative disease SNP genotyping panel (PANDoRA) and were coded according to the number of risk (T) alleles (0,1,2). Linear mixedeffects models evaluated the interaction of FAS performance changes with rs1768208 genotype. We found a significant dosedependent genotype by time interaction (F[2, 29] = 8.42; p = 0.001) for declining performance on FAS (B values refer to words per month): 2 risk alleles (B = 0.48; p < 0.0001), 1 risk allele (B = 0.23; p = 0.0036), and no risk alleles (B = 0.05; p = 0.4822). Individuals with rs1768208 risk alleles are at risk for a more rapid decline in executive function. We previously reported shorter disease course in carriers of risk alleles in rs1768208 in bvFTD. In this longitudinal study, the risk polymorphism at rs1768208 appears to confer a worse prognosis in patients with bvFTD.

P182 Genetic overlap between 4-repeat tauopathies suggests a role for development in the pathobiology of corticobasal degeneration J. Yokoyama1, C. Fan2, Y. Wang3, N. Kouri4, R. Ferrari5, O. Andreassen3, J. Hardy5, A. Boxer1, B. Miller1, G. Schellenberg6, D. Dickson4, A. Dale2, R. Desikan7 1 University of California, San Francisco, Neurology, San Francisco, USA 2 University of California, San Diego, San Diego, USA 3 NORMENT, Oslo, Norway 4 Mayo Clinic College of Medicine, Jacksonville, USA 5 UCL, London, Great Britain 6 University of Pennsylvania, Philadelphia, USA 7 University of California, San Francisco, Radiology and Biomedical Imaging, San Francisco, USA Corticobasal degeneration (CBD) is a 4-repeat (4R) tauopathy characterized by tau inclusions in neurons and glia and astrocytic plaques. Little is known about the genetic etiology of CBD. A recent

genome-wide association study (GWAS) confirmed MAPT, the gene encoding tau, and identified MOBP as genetic loci associated with risk in pathologically confirmed CBD cases. Both of these loci are also associated with risk for related 4R tauopathy, progressive supranuclear palsy (PSP). We used established methods to identify genetic overlap between CBD and other tauopathies leveraging available PSP and frontotemporal dementia (FTD) GWAS data. Five genetic loci, including the MAPT region on chromosome 17, showed significant genetic overlap between CBD and PSP (falsediscovery rate pMAPT, the next associated locus was MOBP. MOBP encodes myelin-associated oligodendrocyte basic protein, a Rab GTPase critical for myelin sheath stabilization. The first novel risk locus showing shared genetic risk for CBD and PSP was at chemokine receptor CXCR4, which encodes a protein important in vascularization and cerebellar development. The second novel locus was at EGFR, which encodes epidermal growth factor receptor. The third novel locus of shared genetic risk was at GLDC encoding glycine dehydrogenase, a critical enzyme required for glycine degradation. Mutations in GLDC cause glycine encephalopathy due to abnormally high levels of glycine in brain. There was minimal genetic overlap between CBD and FTD except in the MAPT region, likely due to the pathological heterogeneity of tau and TDP-43 pathology in sporadic FTD. Taken together, our findings show abundant genetic pleiotropy specifically between CBD and PSP suggesting overlapping pathobiology between these two 4R tauopathies. Beyond MAPT and MOBP, these results implicate three novel shared risk loci that play important roles in development.

P183 Effects of multiple genetic loci on age at onset in frontotemporal dementia R. Ferrari1, M. Grassi2, F. Graziano2, F. Palluzzi2, S. Archetti3, E. Bonomi4, A. Bruni5, R. Maletta5, L. Bernardi5, C. Cupidi5, R. Colao5, I. Rainero6, E. Rubino6, L. Pinessi6, D. Galimberti7, E. Scarpini7, M. Serpente7, B. Nacmias8, I. Piaceri8, S. Bagnoli8, G. Rossi8,9, G. Rossi9, G. Giaccone9, F. Tagliavini9, L. Benussi10, G. Binetti10, R. Ghidoni10, A. Singleton11, J. Hardy1, P. Momeni12, A. Padovani4, B. Borroni4 1 University College London, Molecular Neuroscience, London, Great Britain 2 University of Pavia, Department of Brain and Behavioural Sciences, Medical and Genomic Statistics Unit, Pavia, Italy 3 Brescia Hospital, Department of Laboratories, III Laboratory of Analysis, Brescia, Italy 4 University of Brescia, Neurology Unit, Department of Clinical and Experimental Science, Brescia, Italy 5 Neurogenetic Regional Centre ASPCZ Lamezia Terme, Lamezia Terme, Italy 6 University of Torino and Citt a della Salute e della Scienza di Torino, Neurology I, Department of Neuroscience, Torino, Italy 7 University of Milan, Fondazione C a Granda, IRCCS Ospedale Policlinico, Neurology Unit, Department of Pathophysiology and Transplantation, Milan, Italy 8 University of Florence, Department of Neuroscience, Psychology, Drug Research and Child Health, Florence, Italy 9 Fondazione IRCCS Istituto Neurologico Carlo Besta, Division of Neurology V and Neuropathology, Milan, Italy 10 IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Molecular Markers Laboratory, Brescia, Italy


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Poster Session II: Genetics 11

National Institutes of Health, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, USA 12 Omixy, London, Great Britain In Frontotemporal Dementia (FTD), age at disease onset (AAO) is unpredictable, with early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO of patients FTD. Genotyping data of DNA samples diagnosed with FTD were available from the International FTD-GWAS dataset. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis (PCA) to infer continuous axes of genetic variation, and linear regression models were applied. A genetic Score (GS) was calculated on the basis of suggestive Single Nucleotide Polymorphisms (SNPs) found by association analyses. GS was computed for 6 SNPs, mapping to genes involved in neuronal development and signaling, axonal myelinization and glutamatergic/GABA neurotransmission. GS showed genome-wide significant slope decrease by 3.86 (95% CI: 4.64 to 3.07, p < 2 9 1016) per standard deviation of the GS, thus an increase of the GS was associated with a decrease of the AAO. Our data indicate that there is a genetic architecture that underpins and modulates up to 14.5% of variability of AAO in FTD. Future studies on genetic modifiers in FTD are warranted.

P184 Epigenetic modification in Italian FTLD patients carrying the C9orf72 repeat expansion I. Piaceri1, A. Tedde1, G. Lombardi1, C. Ferrari1, V. Bessi1, S. Sorbi1, B. Nacmias1, S. Bagnoli1 1 University of Florence, Department Neurofarba, Florence, Italy Recently, a methylation analysis of the 5’CpG-island in C9orf72 promoter near the G4C2 repeat expansion in patients with Frontotemporal lobar degeneration (FTLD) revealed an expansionspecific hypermethylation in a fraction of carriers (up to 36%) (Xi Z. et al. Acta Neuropathol 2015; 129 715-727, Liu EY. et al. Acta Neuropathol 2014; 128 525-541). We investigated the methylation profile of genomic DNA in 86 Italian subjects: 45 FTLD patients [17 expansion carriers (mean age at onset 60.3 10.1), 28 non carriers (mean age at onset 65.4 6.5)] and 41 controls (mean age at samples collection 73.15 7.9). To assess the level of methylation we performed direct bisulfite sequencing that showed the total number of methylated CpG sites. Samples were categorized to three methylation levels (no methylation, low methylation and high methylation). Methylation levels of the CpG island resulted significantly higher in FTLD patients carrying the C9orf72 expansion than in non carriers (patients, pvalue < 0.0001 and healthy subjects pvalue < 0.00001). Within the C9orf72 expansion carriers, methylation levels did not correlate with the age at onset (42–74 years old; Spearman coefficient = 0.16176, pvalue = 0.53). Our study confirms that hypermethylation of the CpG island is expansion-specific, since in any of the 69 non carriers (patients and controls) a high level of methylation was observed. Moreover, the study reveals that DNA methylation is not a major modifying factor for disease. Further validation will be necessary to confirm the role of this or other epigenetic mechanisms in the C9orf72 linked diseases.

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P185 NIH EXAMINER as tool for tracking executive dysfunction in carriers of FTLD-causing mutations within the LEFFTDS Consortium H. Rosen1, P. Ljubenkov1, B. Boeve2, J. Kramer1, A. Boxer1, G. Coppola3, C. Dheel2, J. Fields2, R. Gavrilova2, N. Ghoshal4, J. Goldman5, N. Graff-Radford6, M. Grossman7, H. Heuer1, J. Hsiao8, G.- Y. R. Hsiung9, E. D. Huey5, D. Irwin7, K. Kantarci2, A. Karydas1, D. Knopman2, J. Kornak1, W. Kukull10, I. Mackensie9, B. Miller1, C. Phelps8, R. Rademakers6, L. Shaw7, M. Sutherland11, A. Toga12, S. Weintraub13, Z. Wszolek6, T. Faroud14, K. Faber14, A. Vetor14, J. Trojanowski7, K. Rankin1 1 University of California, San Francisco, Neurology, San Francisco, USA 2 Mayo Clinic, Rochester, USA 3 UCLA, Los Angeles, USA 4 Washington University, St. Louis, USA 5 Columbia University, New York, USA 6 Mayo Clinic, Jacksonville, USA 7 University of Pennsylvania, Philadelphia, USA 8 National Institute on Aging, Bethesda, USA 9 University of British Columbia, Vancouver, USA 10 University of Washington, Seattle, USA 11 National Institute of Neurological Disorders and Stroke, Bethesda, USA 12 University of Southern California, Los Angeles, USA 13 Norhtwestern University, Chicago, USA 14 Indiana University, Indianapolis, USA The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Consortium has been established to identify the earliest symptoms of neurodegenerative disease in kindreds with mutations in microtubule associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72) genes. Executive dysfunction is a common feature in patients with frontotemporal lobar degeneration (FTLD), and may be an early indicator of disease. The NIH Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) tool is a freely available, open source, computerized module designed to test multiple domains of executive function. We assessed EXAMINER performance in 49 individuals whose genotyping has been completed, including asymptomatic non-mutation carriers (-mCDR0), asymptomatic mutation carriers (+mCDR0), mildly symptomatic mutation carriers (+mCDR 0.5), and symptomatic mutation carriers (+mCDR ≥1). There was a statistically significant decline in the NIH EXAMINER mean executive composite score (EC), with increasing level of functional impairment. Direct comparisons between levels of impairment indicated statistically significant differences between +mCDR0 and +mCDR0.5 (difference of 0.76 U, CI 0.25–1.27, p < 0.01), and between +mCDR 0.5 and +mCDR ≥1 (difference of 1.2 U, CI 0.44– 1.97, p < 0.01). The EC score was reduced in the +mCDR0 group compared with the -mCDR0 group, but the difference did not reach statistical significance (difference of 0.44 U, CI 0.21 to 1.18, p = 0.165). These data suggest that NIH examiner is a sensitive tool for quantifying executive dysfunction, even at very mild levels of functional change. Further work will be pursued to compare the relative value of EXAMINER versus with more standard assessments of executive function for quantifying executive dysfunction and tracking executive impairments over time.



P186 TMEM106B polymorphism is associated with lower cortical volumes in a clinically diagnosed FTD cohort S. R. Harding1, M. Bocchetta1, E. Gordon1, D. M. Cash1,2, M. J. Cardoso1,2, G. Adamson3, S. Ourselin1,2, J. D. Warren1, S. Mead3, J. D. Rohrer1 1 UCL Institute of Neurology, Dementia Research Centre, London, Great Britain 2 Translational Imaging Group, Centre for Medical Image Computing CMIC, UCL, London, Great Britain 3 Medical Research Council Prion Unit, Department of Neurodegnerative Disease, UCL, London, Great Britain Frontotemporal dementia (FTD) is a clinically heterogeneous neurodegenerative disease associated with impairment of behaviour, language and motor function. Recently, the TMEM106B rs1990622 A/G polymorphism has been shown to modify the risk of developing FTD, with the risk highest in those homozygous for the A allele. In this study we analysed data from 142 patients with FTD disorders who had been genotyped and also had available MRI scans. Automated segmentations were performed on volumetric T1weighted MRI scans to extract cortical regions of interest and total intracranial volume (TIV). We compared the difference in cortical volumes in the frontal lobe, temporal lobe, parietal lobe, occipital lobe, cingulate and insula, after correcting for TIV, between AA carriers and AG/GG carriers. The two groups did not differ in disease duration (mean (standard deviation), AA: 4.8 (2.4), AG/GG: 4.8 (3.4), or age at scan (AA: 62.6 (6.7), AG/GG; 62.9 (8.7)). When compared with AG/GG carriers, AA carriers showed significantly lower volumes in the cingulate [AG/GG: 1.51 (0.15) % of TIV, AA: 1.43 (0.12) (p = 0.003)], insula [AG/GG: 0.73 (0.11), AA: 0.68 (0.13) (p = 0.027)], frontal [AG/GG: 9.5 (0.9), AA: 9.2 (1.0) (p = 0.032)], and temporal cortices [AG/GG: 6.2 (0.8), AA: 5.9 (0.8) (p = 0.045)]. These findings suggest that the TMEM106B risk allele is associated with decreased brain volumes in key areas of the brain that are implicated in FTD.

P187 The genetic correlation between Frontotemporal Dementia (FTD), and neurodevelopmental diseases, and the convergence in functional pathways E. Taskesen1,2, A. Mishra2, D. Posthuma1,2, Y. Pijnenburg1,3 1 VU University Medical Center VUmc, Alzheimercentrum, Amsterdam, Netherlands 2 VU University Amsterdam, Complex Trait Genetics CTG, Amsterdam, Netherlands 3 International FTD-GWAS Consortium IFGC, Londen, Netherlands The behavioral variant of frontotemporal dementia (bvFTD) is a neurodegenerative disease in which the clinical symptoms are related to selective neurodegeneration of the frontal and anterior temporal brain regions. Both the symptoms (such as apathy and stereotypy) and the affected brain regions show overlap with those of Bipolar disorder (BD), Autism Spectrum Disorder (ASD) and Schizophrenia (SCZ). We hypothesized that bvFTD shares genetic risk factors with BD, ASD, and SCZ because of this clinicoanatomical overlap. We therefore set out to investigate the genetic overlap between FTD versus BD, ASD and SCZ separately. To quantify the overlap, we used a SNP based approach and separately a gene-based approach. For the SNP based approach, we

used the LD score regression method (Bulik-Sullivan et al. Nat.Genet. 2015) to compute the genetic correlation across all four diseases for which summary statistics from the Psychiatric Genomic Consortium (PGC) were used. For bvFTD we used the recent GWAS summary statistics of 3526 cases (Ferrari et al., 2014). We detected significant correlations between bvFTD and BD (r2=0.539, p = 1.48 9 105), bvFTD and SCZ (r2=0.302, P = 2.569103), but no significant correlation between bvFTD and ASD (r2=0.061, p = 0.592). For the gene-based approach we first used diseaseassociated genes from Autworks and analyzed the functional overlap. Here again we detected that frontotemporal dementia significantly overlapped with BD (PBY = 4.59 9 106), and SCZ but now also with ASD (PBY = 9.52 9 1010), (PBY = 5.13 9 104). We finally assessed whether the diseaseassociated genes converged on specific pathways, which can be indicative for a common neurodegenerative biological mechanism. We detected convergence in 6 pathways (PBY)

P188 Familial frontotemporal dementia - ALS syndrome by TARDBP gene mutation M. Olabarrieta1, F. Pujadas1, A. Palasi1, A. Turon2, A. Antonell3, anchez-Valle3 E. Gelpi4, R. S 1 Hospital Vall d’Hebron, Neurology, Barcelona, Spain 2 Hospital Santa Caterina - IAS, Neurologia, Salt Girona, Spain 3 Hospital Clinic - IDIBAPS, Programa de informaci on y consejo genetico para demencias familiares PICOGEN, Barcelona, Spain 4 Hospital Clinic - IDIBAPS, Banco de Tejidos Neurol ogicos, Barcelona, Spain C9ORF72 hexanucleotide expansion is the most common genetic finding in family cases of frontotemporal lobar degeneration associated with motor neuron disease (FTLD-ALS), being mutations in other genes less frequent. We present a 31 year old man with one year progressive behavioural and cognitive decline, meeting behavioural variant FTD criteria, who inmediately after develops rapidly evolving motor neuron disease (MND), dying at 3 years of the onset of symptoms. His father had died at 56 of cancer, referring unstudied behaviour disorder. A paternal uncle, at age of 62 years suffered from progressive cognitive decline, highlighting marked anomy and semantic deficit, associated with disrupting behaviour, being diagnosed of semantic dementia. He died ten years later with severe dementia without clinically MND. Neuropathological examination and genetic analysis of key genes was performed in both cases. In the first case, necropsy showed a marked degeneration of motor neurons (upper and lower) and found exclusively diffuse TDP-43 deposits. In the second case a pattern of frontotemporal lobar degeneration with complex aggregates was defined, underlying a proteinopathy with TDP-43, alpha-synuclein and phosphorylated tau aggregates. The genetic study ruled out mutations in C9ORF72, MAPT, GRN or SOD, aiming p.Ile383Val mutation in the TARDBP gene in both cases. We conclude that other TDP-43 proteinopathies, such as those caused by mutation of its precursor gene (TARDBP), do also confirm the complex and variable genotype-phenotype relationship of familial FTLD-ALS.


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P190

Absence of differences on key measures in mildly (CDR = 0.5) versus overtly (CDR≥1) symptomatic mutation carriers: preliminary data from LEFFTDS D. Knopman1, B. Boeve1, H. Rosen2, A. Boxer2, G. Coppola3, C. Dheel1, B. Dickerson4, K. Faber5, J. Fields6, T. Foroud5, R. Gavrilova6, N. Ghoshal7, J. Goldman8, N. Graff-Radford9, M. Grossman10, H. Heuer2, J. Hsiao11, E. Huey8, R. Hsiung12, D. Irwin10, K. Kantarci6, A. Karydas2, J. Kornak2, J. Kramer2, W. Kukull13, I. Mackenzie12, B. Miller2, C. Phelps11, R. Rademakers9, K. Rankin2, L. Shaw10, M. Sutherland11, A. Toga14, J. Trojanowski10, S. Weintraub15, Z. Wszolek9, A. Vetor5 1 Mayo Clinic, Neurology, Rochester, USA 2 University of California, San Francisco, Neurology, San Francisco, USA 3 UCLA, Los Angeles, USA 4 Massachusetts General Hospital, Boston, USA 5 Indiana University, Indianapolis, USA 6 Mayo Clinic, Rochester, USA 7 Washington University, St. Louis, USA 8 Columbia University, New York, USA 9 Mayo Clinic, Jacksonville, USA 10 University of Pennsylvania, Philadelphia, USA 11 National Institutes of Health, Bethesda, USA 12 University of British Columbia, Vancouver, Canada 13 University of Washington, Seattle, USA 14 USC, LONI, Los Angeles, USA 15 Northwestern University, Chicago, USA

The genetic and epidemiology of frontotemporal dementia in Sardinia F. Di Stefano1, G. Borghero1, A. Cannas1, A. Sanna1, M. R. Murru2, o3, D. Corongiu2, S. Cuccu2, S. Tranquilli2, M. G. Marrosu2, A. Chi 1 1 F. Marrosu , G. Floris 1 Department of Neurology, University of Cagliari, Monserrato, Italy 2 Multiple Sclerosis Centre, University of Cagliari, Cagliari, Italy 3 ALS Center, ‘Rita Levi Montalcini’ Department of Neuroscience, University of Torino, AOU Citt a della Salute e della Scienza, Torino, and Neuroscience Institute of Torino NIT, Turin, Italy

One would expect that numerous differences exist between mildly symptomatic (+mCDR = 0.5) and overtly symptomatic (+mCDR≥1) mutation carriers in the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Consortium, which involves subjects in kindreds with mutations in microtubule associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72). Those measures which do not differentiate dementia severity may be less likely to be useful scales for future therapeutic trials. We analyzed demographic, clinical, behavioral and neuropsychological data among +mCDR = 0.5 (n = 35) and +mCDR≥1 (n = 20) subjects evaluated through February 2016. As expected, the findings on almost all clinical and neuropsychological measures were significantly different (p < 0.05) between these two groups. Features and measures which were NOT different included the following (CDR 0.5 vs. ≥ 1): mean age (57 vs. 60), mean education (14.6 vs. 15.9), Geriatric Depression Scale (2.8 vs. 3.3), total NPI score (7.1 vs. 10.1) as well as scores on all Neuropsychiatric Inventory domains, the Social Norms Questionnaire-SNQ (18.8 vs. 17.6), Behavioral Inhibition Score-BIS (17.2 vs. 15.7), Word Reading Test (WRT)-Regular (14.7 vs. 14.2) and Irregular (13.8 vs. 12.9) Words. These preliminary data suggest that the GDS, NPI, SNQ, BIS and WRT may be less likely to track progression in familial FTD (using CDR as standard) than other measures. Longitudinal data in this cohort will be required to better inform clinical trial design on measures most likely to track disease progression.

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Several studies suggest that Sardinians have a genetic and epidemiology for many diseases distinct from other Europeans including mainland Italians. Little is known about the epidemiology and genetic of FTD in this population. In this study we aim to describe the epidemiological and genetic data on FTD derived from the cognitive disorders center of the University of Cagliari. We recruited all the patients in our database that fulfilled the Rascovsky’s criteria for bvFTD or Gorno-Tempini criteria for PPA and who were of Sardinian ancestry from at least three generation. All the patients underwent a genetic screening for C9ORF72 and p.A382T mutations. 25 patients were also screened for progranulin mutations. Demographic and genetic data, familiarity for ALS and/or FTD and clinical records were reviewed for all the patients. Our FTD cohort included 75 patients (42 males and 33 females): 45 patients were classified as pure bvFTD (60%), 8 as mixed forms of FTD (bvFTD+PPA) (10.6%), 9 as PNFA (12%), 8 as SD (10.6%), 5 as primary progressive aphasia unspecified (PPA) (6.8%). In the cohort, 24 patients had a positive familial history (32,5%). Motor neuron disease (MND) was associated to FTD in 6 patients (8%) and all but one were familial cases. Parkinsonism was a high prevalence feature (28/75 cases, 37,3%). Genetic screening identified 14 patients with C9ORF72 mutation and 6 patients with p.A382T TARDBP mutation (one patient was carrier of both mutations and two other were from the same kindred). C9ORF72 mutation was responsible for the 37,5% of familial cases and the 17% of the whole cohort. p.A382T TARDBP mutation was present in the 25% of the familial cases and the 8% of all FTD cohort. Our Sardinian FTD cohort have a high frequency of C9ORF72 + and p.A382T TARDBP mutations, especially in familial form of FTD. The prevalence of these mutations is one of the highest reported in European populations and higher than in mainland Italians. The prevalence of TARDBP mutations is the highest reported in literature worldwide. These data highlight the peculiar genetic characteristics of Sardinian population.



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Differences on clinical measures in asymptomatic (CDR = 0) versus mildly symptomatic (CDR = 0.5) mutation carriers: preliminary data from LEFFTDS D. Knopman1, B. Boeve1, H. Rosen2, A. Boxer2, G. Coppola3, C. Dheel1, B. Dickerson4, K. Faber5, J. Fields6, T. Foroud5, R. Gavrilova1, N. Ghoshal7, J. Goldman8, N. Graff-Radford9, M. Grossman10, H. Heuer2, J. Hsiao11, R. Hsiung12, E. Huey8, D. Irwin10, K. Kantarci13, A. Karydas2, J. Kramer2, W. Kukull14, I. Mackenzie12, B. Miller2, C. Phelps11, R. Rademakers9, K. Rankin2, L. Shaw10, M. Sutherland11, A. Toga15, J. Trojanowski10, A. Vetor5, S. Weintraub16, Z. Wszolek9 1 Mayo Clinic, Neurology, Rochester, USA 2 University of California, San Francisco, Neurology, San Francisco, USA 3 UCLA, Los Angeles, USA 4 Massachusetts General Hospital, Boston, USA 5 Indiana University, Indianapolis, USA 6 Mayo Clinic, Psychiatry, Rochester, USA 7 Washington University, St. Louis, USA 8 Columbia University, New York, USA 9 Mayo Clinic, Jacksonville, USA 10 University of Pennsylvania, Philadelphia, USA 11 National Institutes of Health, Bethesda, USA 12 University of British Columbia, Vancouver, Canada 13 Mayo Clinic, Radiology, Rochester, USA 14 University of Washington, Seattle, USA 15 USC, LONI, Los Angeles, USA 16 Northwestern University, Chicago, USA

Estimation of age of onset in presymptomatic frontotemporal degeneration P. Vaddi1, E. Mccarty Wood1, V. Van Deerlin1, D. Irwin1, M. Grossman1, C. McMillan1 1 University of Pennsylvania, Philadelphia, USA

We hypothesized that differences would exist between asymptomatic (+mCDR = 0) and mildly symptomatic (+mCDR = 0.5) mutation carriers in the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Consortium, which involves subjects in kindreds with mutations in microtubule associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72). We analyzed demographic and clinical data among +mCDR = 0 (n = 34) and +mCDR=0.5 (n = 35) subjects evaluated through February 2016. Measures included the Clinical Global Impression of Change Scale-Severity (CGIC-S), Schwab and England Activities of Daily Living Scale (SEADL), Functional Assessment Questionnaire (FAQ), Montreal Cognitive Assessment (MoCA), motor subtest of the Unified Parkinson’s Disease Rating Scale (UPDRS), and Progressive Supranuclear Palsy Rating Scale (PSPRS). Comparing data between the +mCDR = 0.5 vs. +mCDR = 0 groups, statistically-significant mean differences (p < 0.05) were shown for age (57 vs. 48 years), CGIC-S (2.1 vs. 1.1), SEADL (89 vs. 94), FAQ (3.3 vs. 0.03), MoCA (24.5 vs. 27.4), UPDRS (3.1 vs. 0.6), and PSPRS (2.5 vs. 0.5). No differences existed for sex or education. As expected, these preliminary data suggest mild but significant differences between asymptomatic and mildly symptomatic mutation carriers in familial FTD kindreds.

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Roughly 20% of frontotemporal degeneration (FTD) patients have a known genetic mutation with high penetrance. Presymptomatic mutation carriers are optimal candidates for neuroprotective clinical trials of disease-modifying agents. One challenge for trials is estimating when an individual is likely to become symptomatic. Prior evidence suggests a correlation between an individual’s age of onset and their family member’s age of onset; however, the predictive accuracy has not been assessed. In this study we investigated 25 pedigrees, or a total of 65 individuals. 32 of our cases have GRN mutations while 33 cases have clinical diagnoses compatible with an FTD phenotype (e.g., behavioral-variant or primary progressive aphasia) or related early-onset disorder. The latter 33 cases are also assumed to have GRN mutations because they are affected family members of the 32 cases confirmed for GRN mutations. There was an average of 3.79 individuals per family pedigree and an average of 2.49 generations per pedigree. Linear regression analyses revealed an association between an individual’s onset and family mean onset (b = 1.2015, pMAPT, C9orf72) to evaluate the validity of age of onset estimates in presymptomatic FTD.

Targeted multi-gene panel sequencing in Korean patients with frontotemporal dementia: A preliminary result E.-J. Kim1, Y.-E. Kim2, J.-H. Jang2, E.-H. Cho2, J. C. Kwon3, K.-H. Park4, K. W. Park5, J.-H. Lee6, S. H. Choi7, S. J. Yoon8, J. H. Jeong9, B.-O. Choi10, D. L. Na10, C.-S. Ki10, S. H. Kim11 1 Pusan National University Hospital, Neurology, Busan, South Korea 2 Green Cross Genome, Yongin, South Korea 3 Changwon Fatima Hospital, Changwon, South Korea 4 Gachon University Gil Medical center, Incheon, South Korea 5 Dong-A medical center, Busan, South Korea 6 Asan Medical Center, Seoul, South Korea 7 Inha University school of Medicine, Incheon, South Korea 8 Eulji university hospital, Neurology, Daejeon, South Korea 9 Ewha womans university, Neurology, Seoul, South Korea 10 Samsung Medical Center, Seoul, South Korea 11 Hanyang University College of Medicine, Seoul, South Korea Frontotemporal dementia (FTD) has a strong genetic component. Approximately 40–50% of patients with FTD have a family history for dementia. However, the prevalence of genetic FTD is relatively rare in Asian population. Thus, to identify new or previously known variants in the set of disease-relevant genes, we performed targeted exome sequencing of 52 FTD-amyotrophic lateral sclerosis (ALS) and other dementia causative genes on 57 sporadic Korean FTD patients who had no repeat expansion in C9ORF72, using TruSightTM One Sequencing Panel (Illumina Inc., Sand Diego, CA, USA) covering 4,813 genes associated with known clinical phenotypes. We identified one known pathogenic variant (c.708 + 1G>A in GRN gene) in a patient with behavioral variant FTD (bvFTD)/semantic variant primary progressive aphasia who


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had severe left frontotemporal atrophy and 1 novel inframe deletion of unknown significance [c.2675_2683del (p.892_895del) in CSF1R gene] in a patient with typical bvFTD syndrome who had severe bifrontal atrophy with frontal subcortical white matter changes. In addition, 23 missense variants of uncertain significance were detected in GRN, CSF1R, APP, DAO, SETX, NOTCH3, PSEN2, or OPTN gene.Our preliminary results of wide-spectrum genetic analysis in Korean patients with FTD suggest that (i) multi-gene panel testing is useful for identifying disease-relevant novel or rare variants, (ii) Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia caused by CSF1R mutation should be considered as one of the differential diagnosis of FTD syndromes.

P194 Effect of predictive testing in adult onset neurodegenerative diseases on social and personal life - a pilot study P. Cohn-Hokke1, J. van Swieten1,2, A. Tibben3, H. Meijers-Heijboer1, A. Kievit2 1 VU University Medical Center, Amsterdam, Netherlands 2 Erasmus MC, Rotterdam, Netherlands 3 Leiden University Medical Center, Leiden, Netherlands Follow-up studies on predictive testing for neurodegenerative diseases mainly focussed on psychological outcome such as depression, anxiety and distress. Studies addressing the impact of predictive testing on employment, financial issues, lifestyle, relations and family life are scarce. Our objective was to investigate whether the course of life of mutation carriers of adult-onset neurodegenerative diseases differs negatively from non-carriers and untested at risk individuals. We invited individuals, aged ≥ 35 years, tested while asymptomatic for Huntington’s disease, frontotemporal dementia or Alzheimer’s disease more than 2 years before the start of the study or at 50% risk for one of these diseases, to complete a questionnaire of 70 items. Within a year, an additional questionnaire was completed, comprising 47 items with adjusted and additional questions. Of the 283 selected individuals, 112 returned a positive informed consent (response rate 39,6%). Of these, 17 carriers, 30 non-carriers and 27 untested persons fulfilled the criteria and completed both questionnaires. We found no significant differences between carriers and non-carriers or untested individuals at risk in employment, financial situation and lifestyle or anxiety and depression. Carriers were more often single and childless, though these differences were not significant. Although the low response rate requires caution when interpreting our observations, the findings of this pilot study suggest that the outcome of predictive testing on adult onset neurodegenerative diseases does not have a large negative effect on social and personal life.

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P195 Gene-group based genetic burden tests reveals additional candidate genes for FTD J. van Rooij1,2, T.-H. Wong1, J. Sim on-S anchez3,4, C. Blauwendraat5, P. Rizzu5, P. Heutink3,4,6, M. Synofzik3,7, A. Uitterlinden2, J. van Meurs2, J. van Swieten1 1 Erasmus Medical Center, Department of Neurology, Rotterdam, Netherlands 2 Erasmus Medical Center, Department of Internal Medicine, Rotterdam, Netherlands 3 Hertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, T€ ubingen, Germany 4 German Center for Neurodegenerative Diseases DZNE, Genome Biology of Neurodegenerative Diseases, T€ ubingen, Germany 5 German Center for Neurodegenerative Diseases DZNE, Applied Genomics for Neurodegenerative Diseases, T€ ubingen, Germany 6 VU University Medical Center, Department of Clinical Genetics, Amsterdam, Germany 7 German Center for Neurodegenerative Diseases DZNE, Neurodegeneration, T€ ubingen, Germany With the arrival of next generation sequencing (NGS) techniques, the scope of genetic studies have drastically changed. Also, novel techniques for analyzing this additional genetic variation are being developed, e.g; testing rare variant burden across whole genes. We propose an extension to these tests by testing variant burden in groups of genes, and will show preliminary results using FTD whole exome sequencing data obtained through the RiMOD-FTD consortium. After QC, 163 cases, 1,634 controls and 193,960 exonic SNVs remained. We annotated all 16,535 genes with their respective GOterms, and ran rare (< 1% MAF, 168,137) variant burden tests using plinkseq. This resulted in five significantly enriched (Bonferoni corrected) GO-Biological Process categories, four of which were driven by CRIPAK, amongst these were Regulation of cytoskeleton organization (p = 1.8E-13) and Response to estrogen (p = 1.8E12). The fifth was Detection of chemical stimulus involved in sensory perception and was driven by OR4A16 and OR10K1. In GO-Cellular Component no terms were significantly enriched (p < 4.1E-5), but three terms were suggestive; Endoplasmic reticulum Sec complex (p = 4.5E-5), Citrate lyase complex (p = 1.5E-4) and Early endosome lumen (p = 1.5E-4), driven by CFTR, ACLY and RAB38, respectively. Finally, three GO-Molecular Function terms were significantly enriched; N-sulfoglucosamine sulfohydrolase activity (p = 9.3E-9), ribose-5-phosphate isomerase activity (p = 3.5E-7) and transmembrane signaling receptor activity (p = 7.5E-7), driven by, amongst others, SGSH, ERBB3 and TLR2, and RP1A, respectively. All results were driven by a small number of rare (< 1%) variants that need further investigation, but our results suggest that gene-group based burden analysis might uncover additional genes and their relevant functions in genetic studies. Further work onto the test mechanisms and results will be presented at the conference.



P196 The phenotypic variability of c9orf72 mutations: at the interface between neurology and psychiatry C. Rossmeier1, D. Edbauer2, J. Diehl-Schmid1 1 Technical Universitiy of Munich, Psychiatry, Munich, Germany 2 German Center for Neurodegenerative Diseases, Munich, Germany C9orf72 hexanucleotide repeat expansions have been identified as frequent cause of sporadic and familial frontotemporal dementia (FTD) and amyotrophic lateral-sclerosis (ALS). To determine the prevalence of c9orf72 hexanucleotide repeat expansions in Germany and to describe the clinical phenotypes and family histories, 250 patients with a diagnosis of possible or probable frontotemporal dementia, which were diagnosed at a German memory clinic, were tested for c9orf72 mutations. 12 patients (4.8%) were tested positive. Seven patients were female. Mean age of onset was 56 years with a range from 30 to 76 years. In seven patients a behavioral variant FTD, in one patient semantic variant FTD was diagnosed. In the other patients, the phenotypic presentation preceding the FTD diagnosis varied considerably. Two patients presented with clinical symptoms of Alzheimer’s disease, one patient had a therapy refractory depression with body dysmorphophobia as first symptom, before a diagnosis of bvFTD was made 10 years later. One patient was diagnosed with therapy refractory schizophrenia/ schizoaffective disorders with severe body hallucinations, before symptoms of FTD became obvious eight years later. Three of the patients with bvFTD developed amyotrophic lateral sclerosis later in the course. Family history was positive for neuropsychiatric disorders in eight cases (dementia, ALS, bipolar disorder, major depression) The clinical phenotype of c9orf72 mutations varies considerably. Clinicopathological studies need to reveal, if the cerebral distribution of pathology causes the different clinical presentations.

P197 Anthropometric measures of asymptomatic individuals atrisk for familial frontotemporal dementia G.-Y. Hsiung1, P. Sengdy1, M. Baker2, R. Rademakers2, H. Feldman1, I. Mackenzie1 1 University of British Columbia, Medicine, Vancouver, Canada 2 Mayo Clinic Jacksonville, Neuroscience, Jacksonville, USA Progranulin (PGRN) is a widely expressed secreted glycoprotein with growth factor-like properties. Mutations in the granulin gene (GRN) is a cause of famililal frontotemporal dementia (FTD). Recently, PGRN has been found to have a metabolic effect on dietinduced obesity and insulin resistance. In addition, patients with FTD may have an altered diet that may affect their weight and body mass index (BMI). In the current study, we examined the anthropometric measures in our longitudinal cohort of asymptomatic subjects at risk for developing familial FTLD-TDP (i.e. first degree relatives of a patient or known carrier with FTLD-TDP due to GRN or C9ORF72 mutations). We compared the baseline (N = 99) and annual measures (up to 10 visits) of the subjects’ weight, height, BMI, and hip-waist ratio (HWR), as well as systolic and diastolic blood pressure by their genetic status using multiple variable ANOVA, including sex and age as covariates. Interestingly, we found that GRN mutation carriers are significantly shorter than GRN noncarriers (p = 0.018, mean difference 6 cm) and all C9ORF72 family

members, but there was no significant differences between C9ORF72 mutation carriers and non-carriers. This effect remained significant after adjustment for sex and age (p = 0.006). By contrast, while GRN mutation carriers weighed less than their non-carrier siblings and C9ORF72 mutation family members, this effect is no longer significant when sex and age are taken into account. No significant differences were found in BMI, HWR, or blood pressure measures between mutation carriers and non-carriers. While this difference in adult height may not adversely affect the general health of the individual, our findings suggests that life-long PGRN haploinsufficiency may have an effect on growth that may be reflected on the final height attained in adulthood.

P198 TMEM106B and APOE as genetic modifiers of FTD-3 in the Danish CHMP2B family P. Roos1, N. Rostgaard1, P. Johannsen1, J. M. Brown2, A. M. Isaacs3, G. Waldemar1, T. T. Nielsen1, J. Nielsen1,4 1 Danish Dementia Research Centre, Rigshospitalet, Section 6911, Copenhagen, Denmark 2 Addenbrooke’s Hospital, Department of Neurology, Cambridge, UK, Great Britain 3 UCL, Institute of Neurology, London, UK, Great Britain 4 Institute of Cellular and Molecular Medicine, University of Copenhagen, Section of Neurogenetics, Copenhagen, DK, Denmark Single nucleotide polymorphisms (SNPs) in TMEM106B have recently been identified as possible risk factors in sporadic frontotemporal dementia (FTD) and as modifiers of disease in FTD with GRN and C9orf72 mutations. Though an established risk factor in Alzheimers disease, the role of Apolipoprotein E (ApoE) in FTD is still uncertain. In a large Danish family with autosomal dominant inheritance FTD, the cause of disease has been identified to the CHMP2B gene on chromosome 3 (hence the name FTD-3). In this study we evaluated TMEM106B and ApoE as modifiers of disease in FTD-3. Blood samples from 80 members of the FTD-3 family were analyzed for CHMP2B, TMEM106B (rs3173615) and ApoE genotypes, and participants were categorized as either clinically affected (N = 19), presymptomatic carriers (N = 14) or controls (N = 47). Additionally, carrier status was deduced in deceased family members (N = 16). In affected patients, age of onset (AoO) was defined as first symptoms reported by relatives. AoO was correlated to genotype in dominant, co-dominant and recessive models. Carriers of the minor allele of TMEM106B had an increase in mean AoO of 4.9 years when compared to major allele homozygotes (56.4 (95% CI 52.6, 60.2) to 61.3 (56.1,64.4), p = 0.04). AoO increased 5.5 years from non-ApoE e4 carriers to e4carriers (55.0 (95%CI 50.6,59.4) to 60.5 (56.3,63.2), p = 0.03), and increased 8.7 years in e4 homozygotes (to 63.7 (3.3124.0), p = 0.07). e2-carriers had a lower AoO of 5.6 years when compared to none2 carriers (53.3 (95% CI 44.1, 62.5) to 58.91 (55.9, 61.8), p = 0.11), supported by survival analysis in an e2 dominant model (HR 4.44 (95% CI 1.06, 18.5), p = 0.04). To conclude, TMEM106B polymorphisms and ApoE genotypes are potential modifiers of FTD-3 with the TMEM106B minor allele and the ApoE e4 having the protective effect of an increased AoO, while ApoE e2 is a risk factor of early onset. These data are


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consistent with the previously reported protective effect of theTMEM106B minor allele in GRN and C9orf72 cases. Our findings provide a link between CHMP2B, GRN and C9orf72 and suggest TMEM106B is a broad modifier of FTD.

P199 Probing FTD genetics with a next-generation sequencing gene panel C. Koriath1, G. Adamson2, R. Druyeh2, J. Kenny2, M. Rossor3, J. Schott3, C. Mummery3, N. Fox3, J. Warren3, J. Collinge2, J. Rohrer3, S. Mead2 1 University College London, Neurodegenerative Disease, London, Great Britain 2 Institute of Neurology, Prion Unit, London, Great Britain 3 University College London, Dementia Research Centre, London, Great Britain In a previous study of the UCL frontotemporal dementia (FTD) cohort, around 40% of patients reported some family history of dementia but only 20% carried a mutation in either GRN or MAPT. Since then, mutations in other genes have been shown to be a cause of FTD and more widespread next generation sequencing technologies (NGS) offer the potential to simultaneously screen for all known causal genes. We applied a validated 17-gene NGS dementia panel in combination with PCR-based assessments of the C9orf72 and PRNP expansions to the UCL FTD DNA cohort (n = 380). We classified mutations by likelihood of pathogenicity and compared with demographic and clinical data. All patients were also allocated a modified Goldman score (GS) from 1 (a clear autosomal-dominant history of FTD) through to 4 (no family history). 39% of patients report some family history of dementia (GS 1, 2, 3, or 3.5) but only 13% had a clear autosomal-dominant history. 27.6% of patients were found to have a deleterious or likely deleterious variant; a further 6.0% presented with variants that were risk factors and/or potentially deleterious. The majority of deleterious mutations were found in C9orf72, GRN or MAPT, while variants in other genes amounted to 6.8% - 8.1%. 2.4% had variants in two genes. Only 24.4%–26.9% of patients with a strong family history (GS 1 and 2) did not have a deleterious mutation. A custom panel provides affordable high quality sequencing. With additional C9orf72 testing, these panels can now identify the major FTD genes, although in some cases with a strong family history no genetic mutation is found. Double mutations and those in less frequently implicated genes occur at a significant rate. The abundance of uncertain, novel or possibly pathogenic variants identified with NGS will require considerable work to classify correctly.

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P200 Reduced disease penetrance of progranulin mutation p.tyr294* - a case report L. Oïjerstedt1,2, C. Andersson3,4, V. Jelic1,2, C. Graff1,2 1 Karolinska Institutet, Neurobiology, Care Sciences and Society, Stockholm, Sweden 2 Karolinska university hospital, Geriatric medicine, Huddinge, Stockholm, Sweden 3 Karolinska university hospital, Psychology, Huddinge, Stockholm, Sweden 4 Karolinska Insitutet, Clinical Neuroscience, Huddinge, Stockholm, Sweden Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous group of neurodegenerative diseases with an onset usually below the age of 65 years. About half of cases present a positive family history of dementia and several mutations have been shown to cause autosomal dominant FTD and these are most frequently found in C9orf72, progranulin (GRN) and microtubuleassociated protein tau (MAPT) genes. We present a cognitively healthy 95-year-old female with a progranulin mutation (p.tyr294*). Serum GRN is reduced (53.8 ng/ ml; reference > 100 ng/ml) supporting that the mutation causes haploinsufficiency, which is the common mechanism for pathogenic GRN mutations. At clinical work-up no cognitive or significant neurological abnormalities were found (MMSE 29/30 and MoCA 25/30). She has a medical history of breast cancer, hypothyroidism, asthma and hearing disability. MRI brain showed parietal, frontal and temporal cortical atrophy (GCA 2) and medial temporal atrophy, MTA 2, bilaterally. There was no hippocampal atrophy. This was considered as normal age-related changes. The neuropsychological assessment confirmed a cognitively normal profile (i.a. FAB 15/18). Analyse of TMEM106B single nucleotide polymorphism showed heterogeneity of rs1990622. A first-degree relative, carrying the GRN p.tyr294* mutation with serum GRN level of 47.4 ng/ml, was diagnosed at age 64 with bvFTD. He presented with personality changes, apathy and memory problems at least 2 years before the diagnosis. MRI brain showed initially predominant right-sided anterior temporal lobe atrophy as in right-sided semantic dementia variant, which progressed over time to fronto-temporo-parietal regions. This report demonstrates a case of reduced disease penetrance in an aged GRN stop-mutation carrier. This individual also has significantly reduced serum GRN and the mechanism for the reduced penetrance could thus not be due to modulated GRN levels. It is still unknown why this individual has not developed dementia and further studies on this family will be performed.



P201 Prevalence, phenotypic variability and neuropsychological findings of C9orf72 mutations in a Bulgarian dementia cohort S. Mehrabian1, H. Thonberg2, B. Winblad2, M. Raycheva1, L. Lilius2, K. Stoyanova1, C. Forsell2, D. Toncheva3, L. Cavallin4, E. Westman2, L. Traykov1, C. Graff2 1 Medical University, UH “Alexandrovska”, Department of Neurology, Sofia, Bulgaria 2 Karolinska Institutet, KI-Alzheimer Disease Research Center, Department of NVS, Stockholm, Sweden 3 Medical University, Department of Medical Genetics, Sofia, Bulgaria 4 Karolinska Institutet, Department of Clinical Science, Intervention and Technology, Stockholm, Sweden The GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in several European populations. The objective of this study was to determine the prevalence of the C9orf72 mutations in a Bulgarian dementia cohort, and to delineate the associated clinical features. PCR based assessments of the C9orf72 hexanucleotide repeat expansion in all study samples were performed. We report the clinical, neuropsychological, and neuroimaging findings of the C9orf72 mutation carriers. Of the 135 cases screened, 3/82 (3.7%) of all FTD cases and 1/37 (2.7%) of all clinical Alzheimer’s disease (AD) cases had a C9orf72 mutation. The GGGGCC expansion was found only in 1/7 (14.3%) of the FTD-ALS patients. In our cohort, the C9orf72 pathological expansion was found in clinical diagnoses bridging the FTD, parkinsonism, ALS and AD spectrum. Interestingly, we showed early writing errors without aphasia in 2 subjects with C9orf72 expansions. This study represents the first genetic screening of C9orf72 mutations in a Bulgarian FTD/AD cohort. The C9orf72 repeat expansion does not appear to be a common cause of FTD and related disorders in Bulgarian population. This report highlights the notion that C9orf72 mutations underlie a broad spectrum of neurodegenerative phenotypes. Relatively isolated agraphia in our cases is a strong motivation to provide detailed and sophisticated language assessments in order to more precisely characterize cognitive deficits and probably detect sensitive indicators of these neuropathologically heterogeneous conditions.

P202 Frequency and contribution of variants in 17 dementia related genes in a Bulgarian dementia cohort H. Thonberg1, S. Mehrabian2, B. Winblad1, K. Stoyanova2, C. Forsell1, M. Raycheva2, L. Lilius1, D. Toncheva3, L. Traykov2, C. Graff1 1 Karolinska Institutet, KI-Alzheimer Disease Research Center, Department of NVS, Stockholm, Sweden 2 Medical University, UH “Alexandrovska”, Department of Neurology, Sofia, Bulgaria 3 Medical University, Department of Medical Genetics, Sofia, Bulgaria Neurodegenerative disorders could be a suitable candidate group diseases for application of next-generation sequencing (NGS) in the genetic diagnosis. We employed massive parallel-sequencing of 17 known dementia genes to investigate the frequency and contribution

of variants of these genes in 135 Bulgarian dementia (82 frontotemporal dementia (FTD), 37 Alzheimer’s disease (AD), and 16 other neurodegenerative disorders) patients. The genetic screening identified 32 rare/novel coding variants in PSEN1, APP, PSEN2, PRNP, GRN, MAPT, FUS, CHMP2B, C9orf72, LRRK2, TREM2, SQSTM1, and SIGMAR1 genes in 36 individuals. There was also one novel non-coding variant in GRN gene in 3 individuals, where splice-site mutation was predicted by in-silico methods. The identified variants were confirmed by Sanger sequencing. Novel pathogenic GRN mutations leading to reduced progranulin serum levels were found in 7.3% (6/82) of the FTD patients and 2.7% (1/ 37) of the AD patients. Novel probable pathogenic CHMP2B and FUS mutations were detected in 2 patients with atypical clinical features. A homozygote TREM2 mutation was found in a patient with atypical picture of FTD without clinical evidence of bone involvement. The pathogenicity of variants in AD related genes were unclear. Additionally, PCR based methods revealed C9orf72 expansions in 3.7% (3/82) of the FTD patients and 2.7% (1/37) of the AD patients. GRN mutations are the most common in Bulgarian dementia cohort, followed by C9orf72 mutations. This study reports the first extensive genetic screening of Bulgarian dementia patients. The results highlighted the different distribution of variants in Bulgarian dementia cohort which are useful for developing genetic screening and counseling strategies for such patients. The highly variable phenotypic expression of nonsynonymous variants associated with neurodegenerative disorders make them attractive candidates for the development of NGS gene panels.

P203 Double mutations in TREM2 and C9orf72 genes in a Bulgarian individual with atypical FTD phenotype and rapid progression L. Traykov1, S. Mehrabian1, H. Thonberg2, M. Raycheva1, C. Forsell2, K. Stoyanova1, L. Lilius2, D. Toncheva3, M. Harangi4, G. G. Kovacs5, B. Winblad2, C. Graff2 1 Medical University, UH “Alexandrovska”, Department of Neurology, Sofia, Bulgaria 2 Karolinska Institutet, KI-Alzheimer Disease Research Center, Department of NVS, Stockholm, Sweden 3 Medical University, Department of Medical Genetics, Sofia, Bulgaria 4 Institute of Internal Medicine, University of Debrecen Faculty of Medicine, Department of Metabolic Diseases, Debrecen, Hungary 5 Institute of Neurology, Medical University Vienna, Vienna, Austria TREM2 mutations have been first identified in polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, a rare autosomal recessive disease also known as Nasu-Hakola disease. The same type of mutations leading to pure early-onset dementia without bone cysts have only been previously reported in a few families. Here, we report a homozygous mutation in TREM2, which was found to be associated with atypical phenotype resembling FTD without clinical evidence of bone involvement in a Bulgarian individual. Massive parallel-sequencing of 17 dementia genes identified a homozygote mutation in TREM2 gene that leads to premature truncation of the protein (c.97C>T; p.Gln33X) in combination with a new missense Val235Ile variant in C9orf72 gene (c.703G>A). Initial symptoms in this patient began at age 41 with behavioral changes and subsequent cognitive impairment and spastic paraparesis. Brain MRI showed atrophy mainly located in


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the frontal and temporal cortices, and subcortical leukoencephalopathy with marked thinning of the corpus callosum. Brain CT did not reveal calcifications in basal ganglia. The patient died at 44 years old showing very short disease duration. He was the second of 2 siblings from non-consanguineous parents. Detailed neuropsychological examinations in the parents showed normal cognitive functions (79 and 84 years). This study underlies the implication of TREM2 mutations in atypical FTD phenotypes. To best of our knowledge, such short disease duration in homozygote TREM2 mutation carriers has not been reported previously. The results suggest that the combination of TREM2 homozygote mutation with missense variant in C9orf72 gene might modulate the disease progression in this individual. Further studies on the role of C9orf72 missense mutations in dementia pathogenesis seem warranted.

P204 Colombian familial dementia with frontotemporal features associated with a presenilin-1 mutation D. Matallana1, K. Rascovsky2, P. Ayala3, A. Lopez3, I. Zarante3, C. McMillan2, D. Irwin2, B. McCarty-Wood2, V. Van Deerlin2, E. Suh2, M. Grossman2 1 Pontificia Universidad Javeriana, School of Medicine Aging Institute, Bogota, Colombia 2 University of Pennsylvania, Penn Frontotemporal Degeneration Center, Philadelphia, PA, USA 3 Pontificia Universidad Javeriana, Instituto de genetica, Bogot a, Colombia We describe the clinical and molecular characteristics of a family with young-onset dementia and frontotemporal features associated with a presenilin 1 (PSEN1) mutation. Family history was collected for 6 symptomatic and 8 asymptomatic members of the same family at the Pontificia Universidad Javeriana in Colombia. Proband DNA was sequenced at the University of Pennsylvania using a targeted next-generation sequencing panel designed to detect genetic variations in 45 genes associated with several neurodegenerative disorders. PSEN1 c.428T>C, p.Ile143Thr was detected in the proband and Sanger sequencing identified this mutation in two affected siblings with available DNA. The proband presented at age 35 with significant executive dysfunction, apathy, lack of social engagement and indifference to the feelings of others. He subsequently developed impairments in memory, language and spatial abilities, as well as myoclonus and seizures. MRI at 3 and 4years post-onset showed progressive insular atrophy with relative preservation of posterior structures. One brother presented at age 34 with memory problems and subsequent apathy and aphasia; he died at age 38. The third sibling presented at age 35 with disinhibition, lack of empathy, repetitive behaviors and hyperorality; she died at age 43. Per report, the remaining 3 symptomatic siblings (not tested) had heterogeneous dementia presentations with prominent behavioral features; all died before the age of 48. In conclusion, PSEN1 mutations may produce FTD-like features or phenotypes ranging from typical bvFTD to syndromes with predominant dysexecutive dysfunction and apathy. Screening for PSEN1 mutations should be considered in kindreds with early-onset frontotemporal dementia. Study supported by: AG046499, AG017586, AG032953, AG043503, Colciencias 371-2011 and 370-201, and Wyncote Foundation

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P205 Sporadic frontotemporal dementia: polygenicity and pleiotropy R. Ferrari1, Y. Wang2, J. Vandrovcova1, A. M. Dale3, O. A. Andreassen2, B. Miller4, R. S. Desikan4 1 University College London, Molecular Neuroscience, London, Great Britain 2 University of Oslo and Division of Mental Health and Addiction, Institute of Clinical Medicine, Oslo, Norway 3 Washington University, Department of Psychiatry, St. Louis, USA 4 University of California San Francisco, Neuroradiology Section, Department of Radiology and Biomedical Imaging, San Francisco, USA Sporadic frontotemporal dementia (FTD) consists of a spectrum of clinical syndromes characterized by fronto-lobar degeneration. Although clinical, pathological and genetic evidence suggests overlapping pathobiology between FTD and other neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), the relationship between these disorders is yet not well understood. Using summary statistics (odds ratios and p-values) from large genome-wide association studies (total n > 75,000 cases and controls), we investigated pleiotropy between sporadic FTD and AD or PD. We found > 120-fold enrichment of FTD SNPs for different levels of association with AD and PD at a false discovery rate of < 0.05. Particularly, SNPs within the HLA, MAPT and APOE regions were shared between FTD and either AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD: meta-analysis across two independent FTD cohorts demonstrated a genome-wide signal within the APOE region (rs6857, chromosome 19, 3’UTR = PVRL2, meta-analysis p = 2.21 9 1012), and a suggestive signal for rs1358071 within the MAPT region (chromosome 17, intronic = CRHR1, meta-analysis p = 9.89 9 107) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs in the HLA and MAPT regions associated with expression changes in cis genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes. Our findings demonstrate genetic pleiotropy in three common neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk.

P206 NeuroX to screen neuro-genes in large FTLD cohort R. Ferrari1, J. Hardy1 1 University College London, Molecular Neuroscience, London, Great Britain The NeuroX chip is an affordable genotyping platform to test genetic mutations and risk factors associated with neurodegeneration. It comprises over 24,000 custom variants targeting neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). NeuroX allows to swiftly and economically evaluate known mutations in disease causing genes related with different



neurodegenerative conditions in a trait of interest and to discover new association between genes and a specific neurological disease. We here present a preliminary analysis of 1639 FTLD cases (833 bvFTD; 211 SD; 247 PNFA; 113 FTD-MND; 235 FTLD-U) and 4750 matched controls (after QC) assessed for (i) FTD and/or FTDALS and (ii) neuro markers targeting AD, PD and pure ALS. We screened 38 and 52 genes for group one (i) and two (ii), respectively, looking for exonic/coding variant(s)/mutation(s) discriminating cases from controls with MAF< 0.0005. Our preliminary results revealed mutations in: i) 9 FTD and/or FTD-ALS genes (including MAPT, GRN, CHMP2B, SQSTM1 and VCP) in 1.1% of FTLD cases, several of which (27%) were also C9orf72 expansion carriers; ii) 6 PD genes (including GBA, LRRK2 and PINK1) in 0.5% FTLD cases, a third of which (33%) were also C9orf72 expansion carriers; iii) 3 AD genes (including APP) and 1 pure ALS gene (SOD1) in 0.3% and 0.07% FTLD cases, respectively. Provided replication and validation, this preliminary data is of notable importance because it allows to: i) swiftly dissect FTLD genetics in a large cohort; ii) evaluate the extent and type of mutations and genes shared across FTLD and other neurodegenerative disease; iii) identify co-existence of multiple variants/mutations, and; iv) increase the resolution of genotype-phenotype correlation.

P207 GRN c.708 + 1_+4del TGAG deletion in a large family diagnosed with fronto-temporal dementia G. Babacan-Yildiz1, G. Guven2, H. Hanagasi3, B. Bilgic3, H. Gurvit3, N. Erginel-Unaltuna2, R. Gueirreiro2, E. Lohmann2,4 1 Bezmiâlem University Faculty of Medicine, Department of Neurology, Istanbul, Turkey 2 Istanbul University, Department of Genetics, Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey 3 Istanbul Faculty of Medicine, Istanbul University, Behavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul, Turkey 4 University of T€ubingen, Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, T€ ubingen, Germany Mutations in the progranulin gene (GRN) are an important cause of fronto-temporal dementia (FTD) with ubiquitin and TAR DNAbinding protein 43 (TDP43)-positive pathology. Most mutations identified to date are predicted to cause the pathology via haploinsuffiency mechanism through creating premature stop codon. Here we present a Turkish FTD family with a probably pathogenic frameshift TGAG deletion (c.708 + 1_+4del TGAG) in the splice donor site of GRN exon 6. The family extended over 5 generations and comprised 46 individuals, 6 diagnosed with FTD. 19 family members were available for genetic analysis. Whole exome sequencing (WES) was performed to identify pathogenic gene variants in the proband and Sanger sequencing was performed to confirm the mutations found by WES in the proband and tested family members. Alamut software (Interactive-Biosoftware, Rouen, France) which integrates different splice site prediction tools (MaxEntScan, NNSPLICE, Human Splicing Finder, SpliceSiteFinder, GeneSplicer) was used to investigate the splicing effect of this variant.

This c.708 + 1_+4del TGAG deletion found in the proband was predicted to decrease the splicing of exon 6 due to decreased 5’ donor site score by the Alamut software. Sequencing analysis of the family revealed that one affected sibling was a carrier of the deletion whereas five non-affected individuals were asymptomatic carriers of the mutation and twelve were non-carriers. Serum PGRN levels were found to be decreased in deletion carriers when compared with non-carriers. Our data supports a role for GRN mutations in patients with clinically diagnosed FTD. Further studies, however, are necessary in order to investigate the functional consequences of this deletion.

P208 Evaluation of a Novel PCR Technology for the Quantification of C9orf72 Hexanucleotide Repeat Expansions E. Bram1, K. Culp1, N. Nevitt1, J. Kemppainen1, G. Latham1, E. Suh2, K. Grando2, V. Van Deerlin2 1 Asuragen, Inc., Research and Technology Development, Austin, USA 2 University of Pennsylvania, Department of Pathology and Lab Medicine, Perelman School of Medicine, Philadelphia, USA Hexanucleotide repeat expansions in the noncoding region of the C9orf72 gene are present in ~7% of all clinical cases of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). These expansions are of considerable interest for both clinical research and diagnostic and screening applications. The GCrich repeat element poses formidable challenges to PCR and consequently a combination of multiple PCR assays and Southern blot (SB) are typically used to profile this region. Here we describe the performance of an innovative PCR technology with capabilities that exceed current amplification assays. Novel PCR reagents were optimized for the amplification of G4C2 hexanucleotide repeats. Amplicons were sized using capillary electrophoresis (CE) on a 3500xL Genetic Analyzer (Thermo Fisher) or agarose gel electrophoresis (AGE) (NuSieve, Lonza). A total of 102 genomic DNA samples from the Coriell ALS sample repository (30 unexpanded and 72 expanded) were assessed at Asuragen. The assay was also independently evaluated at The Hospital of the University of Pennsylvania using a subset of these samples. Across both lab sites, repeat values were resolved consistent with previous annotations for all unexpanded samples and up to 145 repeats for all expanded samples (limited only by the sizing range of CE). Expanded samples, irrespective of repeat size, were categorically identified in each case using the same PCR. AGE further confirmed these expansions, resolving high molecular weight products consistent with ~800 repeats along with extensive size mosaicism. Heterogeneity in expanded repeat lengths could be detected down to a 5% mass fraction. This PCR technology can amplify repeat expansions that are more than 10-fold larger than those in existing literature reports. As a result, this assay can help advance clinical research and emerging diagnostic and therapeutic applications. Pending studies will explore its utility with residual patient blood and brain specimens compared with SB.


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Clinical and genetic analyses of familial and sporadic Frontotemporal Dementia patients in Southern Italy (The Apulia_FTD_Registry) R. Capozzo1, C. Sassi2,3, M. Benahmed-Hammer2, S. Arcuti1, C. Zecca1, M. R. Barulli1, R. Tortelli1, F. Carnicella4, C. Dell’Aquila4, F. Valluzzi5, F. Panza1,6, A. Singleton2, G. Logroscino1,7 1 University of Bari, Department of Clinical Neurology and Research,”Pia Fondazione Cardinale G. Panico”, Tricase LE, Italy, Tricase, Lecce, Italy 2 National Institute on Aging, Neurogenetics Laboratory, National Institutes of Health, Bethesda, MD, USA, Bethesda, MD, USA, USA 3 University College London, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK, USA 4 ‘Bonomo’ Hospital, Department of Neurology, Andria, Italy 5 ”S. Giacomo” Hospital, Unit of Neurology, Monopoli, Italy 6 Department Interdisciplinary Medicine, University of Study Aldo Moro, Geriatric Medicine-Memory Unit, Rare disease Centre, Bari, Italy 7 University of Bari, Italy, Neurodegenerative Diseases Unit, Department of Basic Medical Science, Neuroscience and Sense Organs, Bari, Italy

Frontotemporal lobar degeneration spectrum: first genetic screen in a Greek cohort E. M. Ramos1, S. Lee2, C. Kroupis3, C. Koros4, V. Van Berlo1, K. Wojta1, Q. Wang1, D. Dokuru1, M. Pribadi1, A. Bonakis4, V. Papastefanopoulou4, J. Papatriantafyllou4, B. Miller2, L. Stefanis4, G. Coppola1, S. G. Papageorgiou4 1 David Geffen School of Medicine University of California Los Angeles, Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA, USA 2 University of California, San Francisco, CA, USA, Memory and Aging Center, Department of Neurology, San Francisco, USA 3 National and Kapodistrian University of Athens, Attikon University General Hospital, 2nd Department of Biochemistry, Athens, Greece 4 National and Kapodistrian University of Athens, Attikon University General Hospital, 2nd Department of Neurology, Athens, Greece

Objective: 1) To investigate the clinical differences between familial and sporadic FTD 2) To screen mutations in known FTD genes. Background: FTD is characterized by progressive changes in behavior/personality and/or language. Up to 45% of FTD are familial. It is still not clear if clinical presentation of FTD with family history is different when compared to sporadic cases. To date, only few genes have been associated with familial and sporadic FTD. In FTD, the contribution of genotype to the clinical phenotype including age of onset, symptoms, progression of disease remains unclear. Methods: 22 affected individuals belonging to 8 families and 43 sporadic cases with clinically defined FTD, collected with an epidemiological network (Apulia_FTD_registry) in Apulia (area of 4 millions people, in South East Italy) were studied. Differences in clinical presentation between familial and sporadic FTD were analyzed. Mutations in the most common FTD genes (GRN, MAPT, VCP and TARDBP) and C9ORF72 expansions were screened. Results: BvFTD was the most common clinical entity. Social conduct impairment/ disinhibition, loss of insight, apathy, reduced personal hygiene, anomies and reduced speech were the most frequent clinical features observed at onset in the entire cohort. Memory impairment at onset was found in 32% of familial and in none of sporadic FTD patients. No SD were diagnosed. One mutation was identified in GRN in family A (published elsewhere). For all the remaining cases, no known variants were identified in the genes screened. Conclusion: Familial and sporadic FTD showed no significant differences in clinical presentation, although disease onset in sporadic subjects was characterized by a clustering of behavioral symptoms, with apathy and loss of personal hygiene being the most prevalent. Sporadic cases with memory-onset are likely not diagnosed as FTD. Mutations in common causative FTD genes are not a major cause of familial and sporadic FTD in the south Italian population.

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Frontotemporal lobar degeneration (FTLD) is the leading cause of dementia in middle age. Yet, to date, no studies investigating known genetic mutations for FTLD have been performed in the Greek population. We examined a cohort of 42 FTLD spectrum patients seen at our dementia clinic. Clinical diagnoses included 26 behavioral variant frontotemporal dementia (bvFTD), 4 nonfluent primary progressive aphasia (nfvPPA), 5 semantic PPA (svPPA), 4 progressive supranuclear palsy (PSP) and 3 corticobasal syndrome (CBS). All subjects were screened for genetic mutations within genes known to cause AD or FTLD: amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2), microtubuleassociated protein Tau (MAPT), progranulin (GRN), TAR DNAbinding protein 43 (TARDBP), fused in sarcoma RNA-binding protein (FUS), and the hexanucleotide repeat expansion in C9ORF72. Three patients carried probable causative variants: one CBS patient carried a MAPT variant previously reported as pathogenic, while one bvFTD and one svPPA patients had novel loss-of-function GRN variants. Additionally, three patients diagnosed with bvFTD (2) and FTD-ALS (1) had expanded C9ORF72 repeats. Intriguingly, 8 patients were found to have rare variants in MAPT, GRN, APP, and PSEN2. Among these, two bvFTD carried rare MAPT variants while those with rare GRN variants included one bvFTD, two svPPA, and one with PSP syndrome. Notably, rare APP and PSEN2 variants were observed in one bvFTD and one nfvPPA patient, respectively. All but one of the individuals carrying a probable causative or rare variant had no known family history of dementia. In conclusion, we present the first FTLD genetics study in a Greek cohort. Despite an absence of a known family history in most cases, 14% had a probable disease-causing FTLD mutation, and an additional 19% showed rare variants in known dementia genes. Both known and novel predicted-pathogenic variants were identified, suggesting that previously unreported mutations may be present in the Greek population.



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Psychiatric symptoms in CDR=0 MAPT mutation carriers E. Huey1, G. Cheran2, J. Goldman2, M. Manoochehri2, S. Cines2, T. Lynch3, B. Kelly3, S. Shair4, J. Heidebrink4, H. Paulson4, S. Cosentino2 1 Columbia University, Psychiatry and Neurology, New York, NY, USA 2 Columbia University, Neurology, New York, NY, USA 3 Dublin Neurological Institute, Dublin, Ireland 4 The University of Michigan, Neurology, Ann Arbor, USA

Investigation of mutation related covariance pattern in asymptomatic carriers of GRN and C9ORF72 mutations using [F18]-FDG PET E. Shahinfard1,2, J. Fu3, C. Jacova4, D. Katie3, P. Sengdy1, S. McCormick3, V. Sossi5,3, A. J. Stoessl2,6, H. Feldman1,2,6, I. Mackenzie1,6, G.-Y. R. Hsiung1,2,6 1 Univesity of British Columbia, UBC Hospital Clinic for Alzheimer Disease and Related Disorders, Vancouver, B.C., Canada 2 Univesity of British Columbia, Faculty of Medicine, Department of Neurology, Vancouver, B.C., Canada 3 Univesity of British Columbia, Physics and Astronomy, Vancouver, B.C., Canada 4 Pacific University, Oregon, USA 5 Univesity of British Columbia, Neurology, Vancouver, Canada 6 Univesity of British Columbia, Djavad Mowafaghian Centre for Brain Health, Vancouver, B.C., Canada

A wide range of psychiatric symptoms have been reported in patients with early FTD. We prospectively assessed psychiatric symptoms using the research gold standard of a Psychiatric Structured Clinical Interview (SCID-I/P) in 47 CDR = 0 members of families with MAPT mutations, the majority of whom (36) were from one large family with an exon 10 + 14 MAPT mutation. Five subjects were CDR = 0 mutation carriers, the remainder were CDR = 0 non-carriers. The mean age of the mutation carriers was 44.5 years old (range 31–54 years old), the mean age of the noncarriers was 44.6 years old (range 22–62 years old). The prevalence of DSM Axis 1 disorders detected in the 47 subjects was higher than has been reported for the general population, but qualitative examination of the results did not reveal any clear difference in the prevalence of Axis 1 or 2 psychiatric disorders meeting DSM criteria between CDR = 0 mutation carriers and CDR = 0 nonmutation carriers. However, we found a significantly higher current point prevalence in the CDR = 0 mutation carriers of atypical depressive syndromes that did not meet DSM criteria for Major Depressive Disorder (MDD), defined as endorsing significant symptoms of depressed mood or anhedonia that did not meet the DSM MDD criteria for severity, length, or number of depressive symptoms. Three of 5 CDR = 0 mutation carriers had current atypical depressive syndromes at time of evaluation (and one additional CDR = 0 mutation carrier did not have current symptoms, but had a previous atypical depressive syndrome) compared to 5 out of 42 non-mutation carriers (significant by chi square = 4.78 with 1 degree of freedom, p = 0.03). The atypical depressive symptoms observed in CDR = 0 mutation carriers varied from episodes occurring every few months meeting symptom criteria for MDD but lasting only 3–4 days, to isolated anhedonia or depressed mood, to increased mood reactivity and depressed mood. These findings indicate that a subset of CDR = 0 MAPT mutation carriers may present with prodromal atypical depressive syndromes not meeting DSM criteria for MDD. The degree of “atypicality” for DSM psychiatric syndromes may prove to be a useful feature to distinguish prodromic psychiatric syndromes associated with FTD from psychiatric disorders.

Changes in cerebral glucose metabolism have been shown to be a sensitive marker of early changes in neurodegenerative diseases. Here, we used [F18]-FDG PET imaging in an analysis based on a statistical regional covariance model, namely the Scaled Subprofile Model (SSM), to investigate whether asymptomatic GRN mutation carriers would exhibit a different pattern of radioactivity concentration compared to C9ORF72 mutation carriers. Ten subjects with the C9ORF72 mutation (mean age = 42 + 10.7, 24–57) and nine subjects with a GRN mutation (mean age = 48 + 9.3, 36–63) underwent clinical assessments, FDG-PET and MR imaging. Twenty-six bilateral anterior and posterior regions-of-interest (ROIs) were applied to co-registered individual MRI/PET images. FDG uptake was calculated as the ratio between each ROI’s radioactivity concentration and that of the pons. SSM analysis was done on these ROI’s FDG uptake values. The Akaike Information Criterion-based combination of two principal components accounting for 33% of the total variance was found to yield a highly significant separation between the C9ORF72 and GRN groups (p < 0.0034). The spatial pattern comprised of a relative increased FDG uptake in caudate, dorsolateral prefrontal cortex (dorsolatPF) and superior parietal lobe (supPar) and relative decreased FDG uptake in the orbitofrontal region. The individual subject scores for this covariance pattern were significantly higher for GRN compared to C9ORF72. Comparing the absolute FDG uptake values for each ROI between the two groups showed that the GRN mutation carriers have higher FDG uptake in left supPar, right superior temporal lobe and dorsolatPF compared to the C9ORF72 mutation carriers (p < 0.05). These findings, although obtained with a small number of subjects, suggest that there is a mutation-specific regional covariance pattern.

P213 Results of a diagnostic NGS gene panel for patients with dementia R. Vervenne - van Spaendonk1, F. van Ruissen2, M. Smit1, D. van Beek1, P. Cohn-Hokke1, E. Sistermans1, J. Weiss1 1 VU University Medical Center, Clinical Genetics, Amsterdam, Netherlands 2 Academic Medical Center, Clinical genetics, Amsterdam, Netherlands In the Netherlands, diagnostic testing is offered to an increasing number of patients suffering from dementia. The identification of a © 2016 The Authors Journal of Neurochemistry © 2016 International Society for Neurochemistry J. Neurochem. (Suppl. 1) (2016), 222--428

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causal mutation supports the clinical diagnosis, especially in patients with dementia of unknown etiology. Furthermore, when a causal mutation is found, presymptomatic testing becomes an option for their relatives. During the last decade, our laboratory offered diagnostic testing for the 5 most prevalent dementia genes by Sanger sequencing. Since September 2014, we also offer a virtual gene panel based on next generation sequencing (NGS). Our virtual panels consist of whole exome sequence (WES) data filtered for specific disease genes. The advantage of virtual panels is that they are flexible and can be immediately changed when new genes are discovered. Copy number variations (CNV) analysis on WES data is possible and will be implemented as well. For dementia we started with a panel comprising 41 genes that have been associated with Mendelian inherited dementia at an early age. Here we present the outcome of the results in the first 88 tested individuals and compare the diagnostic yield of the NGS gene panel with the Sanger gene panel. Furthermore, we show that the DNA diagnostics changed the clinical diagnosis in some of these patients.

P214 Genetic mutations in Frontemporal dementia – report from the memory clinic from Serbia E. Stefanova1, G. Mandic1, V. Dobricic1, T. Stojkovic1, M. Jankovic1, I. Novakovic1, V. Kostic1 1 School of Medicine, University of Belgrade, Neurology clinicDepartment for neurodegenerative disorders, Belgrade, Serbien and Montenegro Background: Fronto-temporal dementia (FTD) is the second most common cause of early onset dementia (EOD), characterized by behavioral changes (behavioral variant; bvFTD) or language deficits. Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Methods: The aim of this study was to assess the genetic mutations in a cohort of 233 Serbian patients with EOD and to report phenotypic features of identified carriers. Results: A family history of dementia is found in 30% of cases of FTD and about 10% have a clear autosomal-dominant inheritance. Some patients have an associated movement disorder, either parkinsonism, as in progressive supranuclear palsy and corticobasal syndrome, or motor neuron disease (FTD-MND). There was no MAPT mutation in our cohort. Four patients have been diagnosed with mutation in progranulin gene (GRN). Three patients were classified in the FTD spectrum and one with possible Alzheimer disease. We identified 4 patients with EOD to have C9orf72 hexanucleotide expansions. All patients were classified in the FTD disease spectrum group (8.2%): 3 patients fulfilled the criteria for bvFTD, and 1 patient had FTD-MND. None of the patients with the C9orf72 hexanucleotide expansion fulfilled the diagnostic criteria for language variants of FTD, FTD-progressive supranuclear palsy overlap syndrome, dementia with Lewy bodies or Alzheimer’s dementia. Mutations in valosin-containing protein (VCP) was found in 3 patients with isolated bvFTD, and no inclusion body myopathy or Paget disease. Conclusion: Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation.

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P215 Closing the tau loop: the missing tau mutation A. McCarthy1, R. Lonergan1, D. Olszewska1, S. O’Dowd1, G. Cummins2, B. Magennis1, E. Fallon1, N. Pender1, E. Huey3, S. Cosentino4, K. O’Rourke1, B. Kelly1, M. O’Connell1, I. Delon5, M. Farrell6, M. G. Spillantini7, L. Roland4, S. Fahn4, P. Craig8, M. Hutton8, T. Lynch1 1 The Dublin Neurological Institute, Dublin, Ireland 2 Centre for Brain Repair, Clinical Neuroscience, Cambridge, Great Britain 3 Columbia University, Psychiatry and Neurology, New York, NY, USA 4 Columbia University, Neurology, New York, NY, USA 5 Cambridge Hospital, Medical Genetics Service, Cambridge, Great Britain 6 Beaumont Hospital, Neuropathology, Dublin, Ireland 7 University of Cambridge, Clinical Neurosciences, Cambridge, Great Britain 8 Eli Lilly, Surrey, Great Britain Frontotemporal lobar degeneration comprises a group of disorders characterized by behavioural, executive, language impairment and sometimes features of parkinsonism and motor neuron disease. In 1994 we described an Irish-American family with frontotemporal dementia linked to chromosome 17 associated with extensive tau pathology. We named this disinhibition-dementia-parkinsonismamyotrophy complex. We subsequently identified mutations in the MAPT gene. Eleven MAPT gene splice site stem loop mutations were identified over time except for 50 splice site of exon 10. We recently identified another Irish family with autosomal dominant early amnesia and behavioural change or parkinsonism associated with the ‘missing’ + 15 mutation at the intronic boundary of exon 10. We performed a clinical, neuropsychological and neuroimaging study on the proband and four siblings, including two affected siblings. We sequenced MAPTand performed segregation analysis. We looked for a biological effect of the tau variant by performing real-time polymerase chain reaction analysis of RNA extracted from human embryonic kidney cells transfected with exon trapping constructs. We found a c.915 + 15A 4C exon 10/intron 10 stem loop mutation in all affected subjects but not in the unaffected. The c.915 + 15A 4C variant caused a shift in tau splicing pattern to a predominantly exon 10 + pattern presumably resulting in predominant 4 repeat tau and little 3 repeat tau. This strongly suggests that the c.915 + 15A 4C variant is a mutation and that it causes frontotemporal dementia linked to chromosome 17 in this pedigree by shifting tau transcription and translation to + 4 repeat tau. Tau (MAPT) screening should be considered in families where amnesia or atypical parkinsonism coexists with behavioural disturbance early in the disease process. We describe the final missing stem loop tau mutation predicted 15 years ago. Mutations have now been identified at all predicted sites within the ‘stem’ when the stemloop model was first proposed and no mutations have been found within the ‘loop’ region as expected. Therefore we ‘close the tau loop’ having ‘opened the loop’ 21 years ago (Brain, 2015 Oct;138 (Pt 10):3100–9).



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Bioinformatics and FTD: using genes to untangle molecular underpinnings of disease R. Ferrari1 1 University College London, Molecular Neuroscience, London, Great Britain

C9orf72 repeat expansions and TARDBP mutations in two Brazilian dementia research centers L. Takada1, V. Bahia1, H. Guimar~ aes2, L. Souza2, T. Costa1, T. Vale2, R. Rodriguez1, F. Porto1, J. Machado2, R. Beato2, K. Cesar1, J. Smid1, S. Brucki1, J. Maximino1, S. Camargos2, G. Chadi1, P. Caramelli2, R. Nitrini1 1 University of Sao Paulo, Neurology, Sao Paulo, Brazil 2 Federal University of Minas Gerais, Internal Medicine, Belo Horizonte, Brazil

In frontotemporal dementia (FTD) there is a critical lack in the understanding of biological and molecular mechanisms underpinning disease pathogenesis. Systems biology is a promising approach that aids in shedding light on biological processes involved in a trait of interest. Using FTD-genes, we sought to build and analyze FTD-specific networks based on (i) gene co-expression patterns (weighted genes co-expression network analysis [WGCNA]) and (ii) protein-protein interactions (PPIs). As moving from genetics to biochemistry (one gene at a time) has largely proven inefficient and underpowered, such approach, coupled with functional annotation analysis, is promising in providing: (i) instant clues on common and genespecific functions and biological processes altered in FTD, and; (ii) a list of new potential key players that set the risk-prone background architecture underneath the FTD-mendelian genes. Building on our own WGCNA work, we here investigated the complete (as per state of the art) PPIs network gravitating around FTD genes. We developed an ad hoc custom pipeline to: i) download PPIs from the IMEX; ii) generate a two-layered FTD interaction-network after filtering steps through custom-made R scripts; iii) cluster and topologically analyze the weighted network using graph theory, and; iv) perform functional enrichment analysis. Our preliminary analyses allowed to: i) evaluate topological and functional differences or similarities among the protein interactomes of FTD genes (presence of discrete network clusters); ii) describe common functions as well as funcitons controlled by each genespecific cluster likely implicated in FTD, and; iii) identify novel protein-interactors modulating FTD relevant pathways.

Introduction: Hexanucleotide repeat expansions in C9ORF72 are among the most common causes of monogenic Frontotemporal Dementia (FTD). Mutations in the TARDBP gene, which encodes the TDP-43 protein, are rare causes of monogenic FTD. Mutations in both genes also cause Motor Neuron Disease (MND). Methods: We included patients diagnosed with FTD spectrum disorders, seen at two university-affiliated dementia research centers in Brazil (University of S~ao Paulo, USP, and Federal University of Minas Gerais, UFMG). Patients were diagnosed with behavioral variant of FTD (bvFTD), semantic variant of Primary Progressive Aphasia (svPPA), or nonfluent variant of PPA (nfvPPA), according to current diagnostic criteria. DNA was obtained from peripheral blood. Hexanucleotide repeat expansions in C9ORF72 were assessed using repeat-primed PCR, and more than 30 repeats were considered pathogenic. Sanger sequencing was used to sequence exons 1–6 of TARDBP. Results: Ninety-two probands with FTD were included in this study (USP cohort = 68 probands and UFMG cohort = 24 probands). Pathogenic repeat expansions were identified in seven probands, diagnosed with bvFTD (n = 6) or FTD-MND (n = 1). One of the C9ORF72 mutation carriers had slowly progressive bvFTD. A TARDBP p.I383V mutation was identified in a patient with svPPA. Conclusions: In this Brazilian cohort of patients with FTD, mutations in C9ORF72 were found in 7.6% of probands, and they were less common than mutations in the progranulin gene (GRN). A mutation in TARDBP was identified in a patient with svPPA.


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Poster Session II: Neuropathology P218 Multiple accumulation of neurodegenerative diseaserelated proteins in familial granulin mutation brains M. Hosokawa1, T. Arai1,2, H. Kondo3, G. Serrano4, T. Beach4, M. Hasegawa1, H. Akiyama1 1 Tokyo Metropolitan Institute of Medical Science, Department of Dementia and Higher Brain Function, Tokyo, Japan 2 University of Tsukuba, Department of Neuropsychiatry, Tsukuba, Japan 3 Tokyo Metropolitan Institute of Medical Science, Histrogy center, Tokyo, Japan 4 Banner Sun Health Research Institute, Civin Laboratory for Neuropathology, Sun City, USA Granulin (GRN) mutations were identified in patients with familial frontotemporal lobar degeneration (FTLD) with ubiquitin pathology in 2006 studies. GRN transcript haploinsufficiency has been proposed as a disease mechanism that leads to the loss of functional progranulin (PGRN) protein. GRN mutations were first found in tau-negative FTLD patients, however, recent findings indicate that these mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer’s disease and corticobasal degeneration. Moreover, PGRN reduction in tau transgenic mice is associated with increasing tau phosphorylation and accumulation. To investigate the influence of a decline in PGRN protein on other forms of neurodegenerative-related protein accumulation, human GRN mutation cases were investigated by histochemical and biochemical analyses. The results showed neuronal and glial tau accumulation in all cases analyzed. Massive neuronal tau staining revealed pretangle forms and glial tau in both astrocytes and oligodendrocytes. Furthermore, phosphorylated a-synuclein-positive structures were also found in oligodendrocytes and the neuropil. Immunoblot analysis of fresh frozen brain tissues revealed that tau protein was present in the sarkosyl-insoluble fraction, which was composed of three- and four-repeat tau isoforms, resembling Alzheimer’s disease. Our data suggest that PGRN reduction might be the cause of neuronoglial multiple proteinopathies, including TDP-43 proteinopathy, tauopathy and a-synucleinopathy, due to the accelerating accumulation of abnormal proteins.

P219 P301L MAPT mutation with globular glial inclusions S. Borrego1, J. Morgado2, O. Grau3, C. Almenar4, M. Balasa1, A. Llado1, R. Sanchez-Valle1, E. Gelpi3 1 Hospital Clınic - IDIBAPS, Alzheimer’s Disease and other cognitive disorders unit, Neurology department, Barcelona, Spain 2 Centro Hospitalar Lisboa Central, Neurology, Lisboa, Portugal 3 Hospital Clınic - IDIBAPS, Neurological Tissue Bank of the Biobanc, Barcelona, Spain 4 Hospital Benito Menni, Sant Boi de Llobregat, Spain Globular glial tauopathies (GGTs) are 4-repeat tauopathies neuropathologically characterized by tau-positive globular glial

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inclusions. The clinical presentation of GGTs is variable and includes behavioral variant frontotemporal dementia, progressive supranuclear palsy, primary lateral sclerosis, corticobasal syndrome and motor neuron disease. Until now, only one pathogenic mutation, K317N, in microtubule associated protein tau (MAPT) gene, has been related to GGT. The P301L MAPT mutation is a well-known mutation that induces frontotemporal lobar degeneration and parkinsonism. P301L MAPT mutation has not been previously related with GGT. Herein, we present the post-mortem neuropathologic study of a 61-year-old woman, diagnosed with frontotemporal lobar dementia associated to P301L MAPT mutation. The clinical phenotype was characterized by a rapidly progressive behavior change and memory impairment. The were no parkinsonism or signs of motor neuron disease. Neuropathology revealed severe atrophy, predominantly in frontal and temporal lobes and enlargement of the lateral ventricles. Substantia nigra showed moderate loss of pigment. Histologically, severe neuronal loss, superficial spongiosis and abundant ballooned neurons were observed in cerebral cortex. Numerous hyperphosphorylated and 4-repeat tau immunoreactive tangles, pretangles and neuropil threads were seen with frequent mini-Pick-like bodies in the dentate gyrus, as characteristically observed in P301L mutation. Additionally, tau-immunoreactive globular glial inclusions (GGI) were observed in fronto-temporal white matter, with only mild involvement of corticospinal tract. This case evidences that MAPT mutations can cause different neuropathological patterns, including GGT-like patterns.

P220 Clinical and neuropathological features of Frontotemporal dementia caused by the P301L MAPT mutation in Baix Llobregat County (Barcelona, Spain) S. Borrego1, J. Morgado2, O. Grau3, R. Re~ n e4, I. Hern andez5, 6 1 1 1 o , E. Gelpi3, C. Almenar , M. Balasa , A. Antonell , A. Llad R. S anchez-Valle1 1 Hospital Clınic - IDIBAPS, Alzheimer’s Disease and other cognitive disorders unit, Neurology department, Barcelona, Spain 2 Centro Hospitalar Lisboa Central, Neurology, Lisboa, Portugal 3 Hospital Clınic - IDIBAPS, Neurological Tissue Bank of the Biobanc, Barcelona, Spain 4 Hospital Universitario de Bellvitge, Neurology, Hospitalet del Llobregat, Spain 5 Institut Catal a de Neurociencies Aplicades, Memory Clinic of Fundaci o ACE, Barcelona, Spain 6 Hospital Benito Menni, Sant Boi de Llobregat, Spain Mutations in the microtubule-associated protein tau (MAPT) gene are responsible for 10–23% of genetic frontotemporal lobar degeneration (gFTLD). We retrospectively reviewed the database of the Genetic counseling program for familial dementia (PICOGEN) at the Hospital Clınic (Barcelona, Spain) for the period 2003 -2015 in order to identify patients with proven MAPT mutations. We identified 13 patients (28.8% of gFTLD), all of them with the P301L MAPT mutation and all coming from the same county (Baix Llobregat) in Barcelona. All available clinical records were


Poster Session II: Neuropathology

reviewed. The mean age of onset was 51 years (43–69). Twelve patients (92%) had a positive family history of dementia in a first degree family member. The most common initial symptoms were behavioral changes in 7 patients (54%), followed by language disturbances, characterized by difficulties in confrontational naming and single-word comprehension, in 4 (31%) and memory impairment in 2 (15.5%). Seven subjects (54%) developed relevant language features and four (31%) developed Parkinsonism during the disease progression. None developed motor neuron disease. Neuroimaging showed bilateral temporofrontal atrophy in most cases. The mean disease duration was 7 years (4–13). Neuropathological studies were performed in 9 subjects. Total brain weight (mean 1087gr) inversely correlated with disease duration (Spearman’s rho -0,78, pneuropathological examination showed frontotemporal atrophy with nigral pallor, associated with an extensive underlying neuronal and glial 4-repeat tauopathy with frequent “mini-Pick”-like bodies in dentate gyrus. In summary, these findings suggest a relative homogeneous clinical and neuropathological phenotype in P301L MAPT mutation carriers in our series. The presence of neuronal, astro and oligodendroglial 4R tau aggregates with “mini-Pick”-like bodies may help in the differential diagnosis from other tauopathies. The geographical aggregation of the cases suggests a founder effect of the P301L mutation in this area. Acknowledgement: Fundaci o Marat o de TV3 (20143810).

P221 Generation of specific and sensitive antibodies against C9orf72 P. Frick1, D. Edbauer2, E. Kremmer3, R. Feederle3, I. Mackenzie4, J. Pasterkamp5, M. Neumann1 1 DZNE, Neuropathology, T€ ubingen, Germany 2 DZNE, Neurobiochemistry, Munich, Germany 3 DZNE, Core Facility Monoclonal Antibodies, Munich, Germany 4 Vancouver General Hospital, Pathology and Laboratory Medicine, Vancouver, Canada 5 University Medical Center Utrech, Translational Neuroscience, Utrecht, Netherlands Hexanucleotide repeat expansion mutations in C9orf72 are the most common genetic cause of FTLD and ALS. Insights on the function of C9orf72 and whether hexanucleotide repeat expansions in C9orf72 might contribute to disease pathogenesis through haploinsufficiency is currently limited due to the lack of specific and sensitive antibodies against C9orf72 protein. Therefore, we developed monoclonal antibodies raised against distinct peptides of C9orf72. The high specificity of our antibodies was validated using recombinant C9orf72 isoforms expressed in HEK293 cells and most importantly whole brain lysates from C9orf72 knockout mice. Immunofluorescence staining revealed that both C9-L and C9-S were spread diffusely throughout the cytoplasm and to lesser extent to the nucleus. To gain further insights into the subcellular distribution of endogenous C9orf72, different fractionation protocols were performed using mouse brain tissue, which confirmed localization in nuclear and cytoplasmic fractions and specifically in fractions enriched for synaptosomes. Sequential protein extraction from human brain tissue detected C9-L as a single band ~50 kDa mainly in the soluble low-salt fraction and at lower levels in the high-salt Triton fraction while no band corresponding to C9-S was detected. No differences in the biochemical profile of C9-L were found between C9orf72 mutation cases and controls. Notably, no

significant change in the expression level of C9orf72 was found by immunoblots of low salt fractions from frontal cortex and cerebellar tissue between C9orf72 mutation carriers and controls (n = 8 each). While these results on C9orf72 protein levels in human tissue do not support a key role of haploinsufficieny in C9orf72 disease pathogenesis, they should be considered as preliminary given the low number of cases analyzed so far and the limitations of accurate quantification of low abundant proteins which might be overcome by further improvement of fractionation protocols and methods for signal enhancement.

P222 Clinical and neuropathological classification of Frontotemporal dementia: analysys of common and specific characteristics M. Gil Moreno1, M. Manzano Palomo2, M. Cuadrado P erez3, 1 A. Rabano Gutierrez 1 Fundaci on Centro de Investigaci on en Enfermedades Neurol ogicas, Instituto de Salud Carlos III, Banco de Tejidos, Madrid, Spain 2 Hospital Universitario Infanta Cristina, Neurologıa, Parla, Madrid, Spain 3 Hospital Clınico San Carlos, Universidad Complutense, Neurologıa, Madrid, Spain Frontotemporal dementia (FTD) results from different neurodegenerative diseases, heterogeneous from a clinical, neuropathological and genetic view point. The objective of this study was to analyze the sociodemographic, clinical and neuropathological characteristics of cases with Frontotemporal Lobar Degeneration (FTLD). Retrospective study from different Tissue Banks and pathological diagnosis of FTLD. Clinical data: Age of onset and death, average time of disease, personal history and cardiovascular risk factors, clinical diagnosis, first clinical symptom and evolution of the disease. Pathological data: TDP43 inclusions, Braak stage, CERAD, alpha-synuclein, vascular pathology, argyrophilic grains (AGD) and hippocampal sclerosis (HS). Seventy-one patients (56.3% male) were distribuited in 9 groups: PiD, PSP, CBD, FTLD-Tau, TDP, FUS, AGD-Alzheimer (AGD+AD), AGD+Vascular (AGD+Vas), AGD-other. Age of symptom onset: 66.6 years (men in younger age); age of death: 74.8 years. FUS and TDP cases showed the earliest age of onset and death, AGD-vascular the oldest. Median duration of disease: 7 years, highest in PiD cases. Most common symptom at onset: memory impairment; language impairment was associated with worse prognosis. Apathy and irritability were the most common behavioral symptoms. Brain atrophy was proportionate to disease duration, greater in PiD and FUS cases. DFT-vc was mostly associated with TDP and PiD pathology, semantic dementia with TDP and MND-FTD with TDP pathology. AD pathology was more frequent in AG+AD group. AGD+Vasc and PiD cases showed more vascular pathology. AGD was related to age, PSP and more AD and vascular pathology. HS was more frequent in TDP cases. FTD diagnosis at higher ages is increasingly common. In this study, there was a correlation between clinical symptoms and disease course with certain neuropathological diagnoses, with different distribution depending on age and sex. In regards to pathology, there were differences between subgroups; combined pathology with Alzheimer’s and vascular pathology was observed,


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as the presence of AG and HS, with a different distribution in the different subgroups and a particular clinical and progression phenotype. Frontotemporal Lobar Degeneration; Frontotemporal Dementia; Neuropathology.

P223 Cerebrovascular pathology in Frontotemporal Lobar Degeneration: a neuropathological study M. Gil Moreno1,2, M. Manzano Palomo3, M. Cuadrado P erez4, 2 A. Rabano Guiterrez 1 Hospital Universitario de Torrej on, Neurologıa, Torrej on de Ardoz, Spain 2 Fundacion Centro de Investigaci on en Enfermedades Neurologicas, Instituto de Salud Carlos III, Banco de Tejidos, Madrid, Spain 3 Hospital Universitario Infanta Cristina, Neurologıa, Parla, Madrid, Spain 4 Hospital Clınico San Carlos, Universidad Complutense, Neurologıa, Madrid, Spain Cerebrovascular lesions are frequently observed in neurodegenerative disorders, usually Alzheimer0 s disease and vascular cognitive impairment. AD-related pathology and cerebrovascular lesions are commonly found in elderly brains. It is not clear whether there are differences regarding AD and/or vascular pathology among FTLD subtypes and whether there are respective differences regarding the age range at death. Retrospective study from different Tissue Banks and pathological diagnosis of Frontotemporal Lobar Dementia (FTLD). Clinical data: Age of onset and death, average time of disease, clinical diagnosis, first clinical symptom and evolution of the disease. Pathological data: Vascular pathology (VP) - small vessel disease (SVD) in 4 regions: frontal, temporal lobe, hippocampus and basal ganglia (Deramecout et al. Neurology 2012; 78 1043–1050), amyloid angiopathy and superficial and macroscopic vascular pathology; Braak stage, CERAD, TDP43 inclusions, argyrophilic grains (AG) and hippocampal sclerosis. Vascular pathology was related to older age of onset and death (p = 0.004; p = 0.001) and it was more frequent in women. Clinical diagnosis of Alzheimer0 s and Pick disease were more frequent and memory loss was the first clinical symptom (p = 0.064). Predominant staging score of the cerebrovascular lesions was level 1-2 (mild or moderate modification of vessel walls or perivascular spaces). Micro and large infarts were common in basal ganglia. Small vessel disease (SVD) was more frequent in AG with vascular pathology (AG+Va), AG with AD pathology (AG+AD) and Pick. Amyloid angiopathy was more frequent in AG+AD cases (p = 0.014). According to vascular topography, AG+Va cases show more pathology in frontal and temporal lobes (p = 0.005; p = 0.003) and basal ganglia (p = 0.026), and AG+AD in hippocampus (p = 0.002). In FTLD cases, VP is related to older age, longer time of disease, women predominance and clinical diagnosis of AD and Pick disease. A mild degree of vascular pathology was observed in most cases, specially in AG+Va, AG+AD and Pick disease. Vascular topography distribution was different in these groups, indicating interesting differences between these different FTLD entities. Vascular pathology, Small vessel disease, Amyloid angiopathy

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P224 Argyrophilic grains pathology in frontotemporal lobar degeneration M. Gil Moreno1,2, M. Manzano Palomo3, M. Cuadrado P erez4, A. R abano Guti errez2 1 Hospital Universitario de Torrej on, Neurologıa, Torrej on de Ardoz, Spain 2 Fundaci on Centro de Investigaci on en Enfermedades Neurol ogicas, Instituto de Salud Carlos III, Banco de Tejidos, Madrid, Spain 3 Hospital Universitario Infanta Cristina, Neurologıa, Parla, Madrid, Spain 4 Hospital Clınico San Carlos, Universidad Complutense, Neurologıa, Madrid, Spain Argyropilic grain disease (AGD) is a late-onset tauopathy characterized by small spindle-shaped stain-positive structures in the neuropil of hippocampus, entorhinal cortex and other limib structures. AGD is often accompanied varying degrees of Alzheimer type pathology. The objective of this study was to analyze the sociodemographic, clinical and neuropathological characteristics of a series of AGD with Frontotemporal Lobar Degeneration (FTLD). Retrospective study from different Tissue Banks and pathological diagnosis of FTLD. Clinical data: Age of onset and death, average time of disease, personal history and cardiovascular risk factors, clinical diagnosis, first clinical symptom and evolution of the disease. Pathological data: Argyrophilic grains (AG), Braak stage, CERAD, alpha-synuclein, vascular pathology, TDP43 inclusions and hippocampal sclerosis (HS). AGD was found in 52.1% of 71 FTLD cases (54.1% women). The presence of AGD increased with age (88.9% older than 80 years; p < 0.001) and is related to higher ages at onset and death (p < 0.001). AGD is more frequent in clinical diagnosis of PSP and gait disturbance is the most common symptom (p = 0.023). Behavioral and language symptoms was less frequent in AGD cases (p = 0.055; p = 0.012). PSP and AGD-Alzheimer (AGD+AD) are the most frequent pathological diagnosis. Brain atrophy is lower in AGD cases (p = 0.094), most of AGD cases were grade 3 (Thal et al. Neuropathol Appl Neurobiol 2005; 31 270–9). AGD cases appeared in relantionship to Alzheimer (p = 0.002) and vascular pathology (p = 0.047). AGD in PSP cases was related to higher ages at onset and death, longer time of disease and parkinsonian symptoms (no significant differences). AGD in FTLD cases is related to older age, longer time of disease and PSP diagnosis. Alzheimer and vascular pathology is more frequent in AGD cases. There are no significant differences between subgroups of AGD pathology in PSP cases. Argyropilic grain disease; Tauopathies; Frontotemporal Lobar Degeneration

P225 Neuropathology of ALS with dementia E. Bigio1, Y. Nishihira1, Q. Mao1, S. Weintraub1, N. Siddique1, T. Siddique1, M.-M. Mesulam1 1 Northwestern University Feinberg School of Medicine, Chicago, USA This study examined autopsy cases of clinical ALS with or without dementia in order to determine the prevalence of FTLDTDP in a large ALS cohort. We also compared the distribution of



FTLD-TDP sub-types in ALS cases and in FTLD-TDP presenting with dementia. Lastly, we aimed to determine the pathologic basis of dementia in those cases of clinical ALS with dementia having no FTLD-TDP pathology. Two hundred fifty cases of ALS with (n = 37) or without (n = 161) dementia, and dementia without clinical ALS and with pathologic FTLD-TDP (n = 52) were examined clinicopathologically. TDP-43 immunostains were performed on all cases. Seventeen cases with clinical ALS without dementia (11%) had pathologic FTLD-TDP and 30 cases (81%) with clinical ALS with dementia had FTLD-TDP pathology. Twelve cases (23%) with clinical dementia without clinical ALS and with FTLD-TDP pathology also had ALS pathology. Interestingly, seven cases (19%) of ALS with dementia had no FTLD-TDP pathology. Most brains from patients with clinical ALS with FTLD-TDP pathology had FTLD-TDP type B, and in clinical dementia without clinical ALS and with FTLD-TDP pathology FTLD-TDP type A predominated. In the seven cases of clinical ALS with dementia but without FTLD-TDP pathology, there was one case of Alzheimer disease pathology with hippocampal sclerosis and medial temporal TDP-43 pathology, one case with a thalamic microinfarct, and two cases with neuronal loss and gliosis in the thalamus and unique ubiquitin and p62 positive cytoplasmic inclusions in the thalamus and other brain regions. The other three cases had no pathologic changes to correlate with dementia. The findings suggest that not all brains from patients with clinical ALS with dementia have FTLDTDP. Interestingly, pathologic evaluation of two cases of clinical ALS with dementia but no FTLD-TDP pathology revealed unique ubiquitin and p62 positive pathology.

Many of these cases were collected in the earlier years and were diagnosed with frontotemporal lobar degeneration (FTLD) with tau inclusions (FTLD-Tau) or DLDH (dementia lacking distinctive histopathology). Since the application of an anti-ubiquitin antibody, starting in the 800 s, a subgroup diagnosis of FTLD with ubiquitinpositive inclusions (FTLD-U) was created. Many of the neuropathological diagnoses were linked with a pathological mutation. Also, we received brain tissue from other brain banks of partners of the European Early-Onset Dementia consortium. We re-analyzed every case with a diagnosis of FTD. Standardized locations were sampled and stained for classic histology and extensive IHC. As cerebral vasculopathy is a common finding in Alzheimer’s and Parkinson’s Dementia, we examined the degree of cerebral small vessel disease in these patient populations, using the staging system by Deramecourt (Deramecourt et al. Neurology 2012, Apr 3;78(14): 1043–50). We present our data. As expected, FTLD with TDP-43 pathology (FTLD-TDP) and FTLD-Tau comprised the majority of our cases, whereas FTLD with FUS inclusions (FTLD-FUS) was rare. Occasionally a diagnosis of FTLD-UPS (ubiquitin proteasome system) could be made. We sub classified the TDP and tau proteinopathies, using the most recent criteria. In about one-third of our cases, a gene mutation was present. Next to the data of the proteinopathies, we added the description of vascular pathology.

P228 106 FTD cases with refined neuropathological confirmation. A. Sieben1,2,3, S. Van Mossevelde1,3, J. van der Zee1,3, J. Goossens1, P. P. De Deyn1,4,5, P. Cras1,6, S. Engelborghs1,5, C. Van Broeckhoven1,3,5, J.-J. Martin1 1 Institute Born Bunge Antwerp University, Lab of neuropathology, Wilrijk, Belgium 2 Gent University Hospital, Gent University, Neurology, Gent, Belgium 3 University of Antwerp, Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 4 University of Groningen and University Medical Center Groningen, Department of Neurology and Alzheimer research Center, Groningen, Belgium 5 Hospital Network Antwerp ZNA Middelheim and Hoge Beuken, Department of Neurology and Memory Clinic, Antwerp, Belgium 6 Antwerp University Hospital, Department of Neurology, Edegem, Belgium

The effect of fetal and perinatal asphyxia on familial frontotemporal dementia gene transcription as studied in a rat model M. Barkhuizen1,2,3, P. van der Ploeg1, F. van Dijck1, K. Cox-Limpens1,3, D. van den Hove3,4, H. Steinbusch3, B. Kramer1,3, D. Gavilanes1,3,5 1 School for Mental Health and Neuroscience, Maastricht University, Department of Pediatrics, Maastricht, The Netherlands, Netherlands 2 North-West University, DST/NWU Preclinical Drug Development Platform, Potchefstroom, South Africa, Netherlands 3 School for Mental Health and Neuroscience, Maastricht University, Department of Translational Neuroscience, Maastricht, The Netherlands, Netherlands 4 University of Wuerzburg, Department of Psychiatry, Psychosomatics and Psychotherapy, Wuerzburg, Germany, Netherlands 5 Institute of Biomedicine, Universidad Cat olica de Santiago de Guayaquil, Facultad de Ciencias Medicas, Guayaquil, Equador, Netherlands

The Institute Born Bunge (IBB) maintains a large biobank of neurodegenerative brain diseases (NDD), founded by Ludo Van Bogaert in 1933. Since then over 6000 brains have been collected. In previous decades the lack of specific antibodies against protein aggregates induced a big challenge in NDD diagnostics. Nowadays, thanks to the introduction of extensive immunohistochemistry (IHC), this knowledge has advanced considerably. In the IBB, brains of 106 patients with a clinical diagnosis of frontotemporal dementia (FTD) were collected. In about 60, Alzheimer or vascular dementia neuropathological changes could be excluded.

Encephalopathy due to hypoxic-ischemia in the pre- and perinatal period is a common cause of long-term neurological impairment in the neonatal period. In this study, we investigated the effect of moderate fetal asphyxia (FA) at embryonic day 17 or severe perinatal asphyxia (PA) during birth on the transcription of genes associated with familial frontotemporal dementia (FTD). The transcriptome of a brain hemisphere was analyzed at 6 and 96 h after birth with an Affymetrix Gene1.OST Chip. Array data was analyzed with the Bioconductor Limma package (Cox-Limpens et al. BMC Neurosci 2014; 15.1, 67). In addition, we screened the frontotemporal regions of 10 month old PA rats for thioflavin-S

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reactivity which is a marker of amyloidogenic proteins, including mature tau fibrils. Our results indicate that fetal and perinatal asphyxia causes small, but non-significant, increases in the transcription of VCP (PA: 1.03 fold), MAPT (PA: 1.05 fold), GRN (FA: 1.01, PA: 1.04 fold), CHCHD10 (FA: 1.02 fold, PA: 1.20 fold) and SQSTM1 (FA: 1.03 fold, PA: 1.16 fold) on top of increases seen in the control groups over the first 4 days of life. The greatest changes were seen in CHCHD10 and SQSTM1 transcription. CHCHD10 is a protein of the mitochondrial intermembrane space, whilst p62/SQSTM1 is an ubiquitin-associated protein involved in the proteasomal degradation of tau. p62/SQSTM1 is also a component of the neuronal and glial inclusions in FTD. Other FTD-genes TARDBP1, CHMP2B, FUS and UBQLN did not have altered transcription in response to asphyxia. FTD typically presents between 40 and 60 years of age. An immunofluorescent analysis of middle-aged rats (10 months) did not find an increase in thioflavin-S reactivity in the hippocampus or prefrontal cortex. Whilst FA and PA cause small increases in FTD-linked gene transcription at 4 days, these changes do not appear to contribute to tau-associated FTD neuropathology in the middle-aged rat brain.

P229 MAPT mutations and sporadic frontotemporal tauopathies: lost in translation? S. Forrest1, J. Kril1, J. Kwok2, M. G. Spillantini3, J. Hodges2, G. Halliday2 1 The University of Sydney, Discipline of Pathology, Charles Perkins Centre, Camperdown, Australia 2 Neuroscience Research Australia, Randwick, Australia 3 The University of Cambridge, Department of Clinical Neurosciences, Cambridge, Great Britain Genetic and familial forms of neurodegenerative disorders have provided important insights into the pathogenesis of many sporadic neurodegenerative disorders. In contrast to other neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) with TDP-43-immunopositive inclusions, FTLD patients with mutations in the microtubule associated protein tau (MAPT) gene are considered independently of sporadic FTLD with tau-immunopositive inclusions (FTLD-tau) in neuropathological diagnostic criteria. FTLD cases with mutations in MAPT show considerable heterogeneity in biochemistry and neuropathological features observed, making diagnosis more challenging. Pathologically there are four main subtypes of FTLD-tau: Pick’s disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and globular glial tauopathy (GGT). All FTLD cases with a mutation in MAPT in the Sydney-Cambridge cohorts were screened for differentiating features used to diagnose FTLD-tau subtypes to determine whether categorical separation of MAPT mutations from sporadic FTLD-tau is valid. Using a variety of tau antibodies, the type and distribution of neuropathological features were compared between 11 cases with a mutation in MAPT (including 3 siblings with a S305S mutation) and 16 sporadic FTLD-tau cases (PiD = 4, CBD = 4, PSP = 4, GGT = 4). Cases with a mutation in MAPT were younger at age of symptom onset (57 5 vs. 70 6 years) but showed no difference in disease duration. The neuropathological phenotype associated with MAPT mutations varied between mutations as well as within families with the same mutation. Each case with a mutation in MAPT had similar neuropathological features to one of the sporadic FTLD-tau subtypes and could be classified into a

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comparable diagnostic subtype: PiD (Lys257Thr), CBD (S305S, IVS10 + 16, R406W), PSP (S305S), GGT (P301L, IVS10 + 16). This study demonstrates similarities in neuropathology between genetic and sporadic forms of FTLD-tau indicating that cases with a MAPT mutation should be considered as familial forms of FTLD-tau and on a disease continuum with sporadic FTLD-tau, simplifying neuropathological criteria.

P230 Targeting the cytoskeleton in frontotemporal dementia A. King1, N. Tian1, R. Atkinson1, J. Vickers1 1 University of Tasmania, Wicking Dementia Research and Education Centre, Hobart, Australia Cytoskeletal pathology is a key feature of a number of neurodegenerative diseases and mutations in cytoskeletal proteins are a cause of neurodegeneration in FTD. Currently clinical trials are underway that aim to protect neurons from cytoskeletal alterations, for example by stabilizing the microtubule cytoskeleton. The aim of our work is to investigate cytoskeletal alterations in FTD to provide more directed therapeutic strategies. FTD and other neurodegenerative diseases usually do not manifest until later in life, despite the presence of mutant proteins, suggesting that alterations during ageing contribute towards the neuronal vulnerability to disease. Little is known about alterations to the cytoskeleton during aging, therefore our initial studies have investigated alterations to microtubules and microtubule associated proteins in C57Bl/6 mice at 22 months of age relative to adult (10 week) mice. Cortical and hippocampal tissue was harvested from mice (n = 5), and Western blot analysis performed to examine microtubule subunits, microtubule post-translations modifications and microtubules associated proteins that affect microtubule stability. Our findings show that whilst post-translational modifications of microtubule proteins were not significantly changed with ageing, there was significant (p < 0.05) increase in CRMP2 expression in both cortex and hippocampus, with increased phospho-CRMP2 at Thr514, although phosphorylation at Ser522 levels were not significantly different to adult mice. CRMP2 is a microtubule-associated protein that is often associated with neuronal plasticity. Our ongoing studies are using in vitro and in vivo techniques, including a visual system model of the axon, to investigate whether pathologic alterations in the FTD associated protein TDP-43 affects the cytoskeletal in adult mice or in the context of ageing. These data suggest that the ageing cytoskeleton may increase the vulnerability of neurons to pathological alterations.



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Clinical and pathological study of FTLD-FUS presenting chorea I. Kawakami1,2, T. Arai1,3, Z. Kobayashi1, O. Yokota4, T. Nonaka1, K. Niizato2, K. Oshima2, S. Higashi1,3, M. Hosokawa1, M. Hasegawa1, H. Akiyama1 1 Tokyo Metropolitan Institute of Medical Science, Dementia Research Project, Tokyo, Japan 2 Tokyo Metropolitan Matsuzawa Hospital, Psychiatry, Tokyo, Japan 3 University of Tsukuba, Neuropsychiatry, Tsukuba, Japan 4 Okayama University, Neuropsychiatry, Okayama, Japan

Clinicopathological correlation of frontotemporal dementia disorders C. Nilsson1, C. Elfgren2, K. Nilsson2, U. Passant2, o2, A. Frizell Santillo1, S. Vestberg3, M. Landqvist Wald€ 1 4 D. van Westen , E. Englund 1 Lund University, Department of Clinical Sciences, Lund, Sweden 2 Lund University, Department of Geriatric Psychiatry, Lund, Sweden 3 Lund University, Department of Psychology, Lund, Sweden 4 Lund University, Department of Laboratory Sciences, Lund, Sweden

Background: Choreoathetoid involuntary movements are rarely reported in patients with frontotemporal lobar degeneration (FTLD), suggesting their exclusion as a supportive feature in clinical diagnostic criteria for FTLD. The classical form of chorea occurs in Huntington’s disease (HD), in which atrophy of the striatum is the predominant pathology. Methods: We identified three cases of the behavioral variant of frontotemporal dementia (bvFTD) that display chorea with fused in sarcoma (FUS)-positive inclusions (FTLD-FUS) and the basophilic inclusion body disease (BIBD) subtype neuropathologically. We determined the behavioral and cognitive features in this group that were distinct from other FTLD-FUS cases. We also reviewed the clinical records of 72 FTLD cases, and clarified additional clinical features that are predictive of the BIBD pathology. Results: Symptom onset in the three patients with chorea was at 44.0 years of age ( 12.0 years), and occurred in the absence of a family history of dementia. The cases were reduced neurological muscle tone in addition to chorea. The patients showed no or mild parkinsonism, which by contrast, increased substantially in the other FTLD cases until a later stage of disease. The patients exhibited severe caudate atrophy, which has previously been reported as a histological feature distinguishing FTLD-FUS from FTLD-tau or FTLD-TAR DNA-binding protein 43. In the striatum of FTLDFUS, both large and small neurons were severely affected and the topographic distribution pattern of the area is different from HD. Biochemically, a strong band at approximately 33 kDa was detected in the sample from the patient with chorea, but this band was less prominent in the samples from the other FTLD-FUS patients. Conclusions: Our results suggest that choreoathetosis observed in patients with bvFTD could be a clinical marker of the underlying pathology of BIBD. In these cases, severe atrophy of the caudate nucleus and relatively preserved nigral dopaminergic regulation might be associated with chorea in the absence of parkinsonism in BIBD.

The Lund Prospective Frontotemporal dementia Study (LUPROFS) is a longitudinal cohort study of patients (n = 110) diagnosed with behavioural variant FTD (bvFTD), progressive nonfluent aphasia (PNFA), semantic dementia (SD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Consensus diagnosis was established by a team of specialists on FTD at the Memory Clinic in Lund, Sweden, based on clinical examination, neuropsychology, imaging and CSF analysis. In an interim analysis we compared the clinical and neuropathological diagnosis in the patients where autopsy has been performed so far. Neuropathological diagnoses were available for 21/54 (39%): 10 FTLD-TDP (48%), 8 PSP (38%), 1 CBD (5%), 2 Alzheimer dementia (AD; 9%). The clinical syndromes diagnosed at inclusion and the corresponding neuropathological diagnoses (within brackets) were: 9 bvFTD (7 FTLD-TDP, 2 PSP), 4 PSP (4 PSP), 4 PNFA (1 PSP, 1 CBD, 2 AD), 3 SD (3 FTLD-TDP), 1 CBD (1 PSP). Thus, an underlying FTD pathology could be confirmed in 19/21 patients, while the molecular subtype could be predicted only in clinically diagnosed PSP and SD (total 7/21). The clinical presentation of patients with PSP varied, although a correct diagnosis increased from 4/8 to 7/8 between inclusion and the last assessment. In summary, good clinicopathological correlation can be attained for an FTD disorder in general by rigorous clinical work-up and longitudinal follow-up. However, there is an urgent need of new in vivo biomarkers for molecular characterization of the underlying disease process.

P233 pThr175 tau is associated with tau pathology in a spectrum of tauopathies A. Moszczynski1, W. Yang1, M. Strong1 1 Schulich School of Medicine and Dentistry, Western University, London, Canada Microtubule associated protein tau (tau) deposition is associated with a spectrum of neurodegenerative diseases collectively termed tauopathies. We have previously shown that amyotrophic lateral sclerosis (ALS) with cognitive impairment (ALSci) is associated with tau phosphorylation at Thr175 and that this leads to pathological tau fibril formation through a GSK3b mediated pathway resulting in pThr231. To determine the involvement of this pathway in multiple tauopathies we have examined the extent of pThr175 expression across a range of frontotemporal degenerations. Representative sections from the superior frontal cortex, anterior cingulate cortex (ACC), amygdala, hippocampal formation, basal ganglia, and substantia nigra were selected from neuropathologically confirmed cases of Alzheimer’s disease (AD; n = 3), vascular dementia


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(n = 2), frontotemporal lobar degeneration (FTLD; n = 4), ALS (n = 5), ALSci (n = 5), ALS-FTD (n = 1), Parkinson’s disease (PD; n = 5), corticobasal degeneration (CBD; n = 2), diffuse Lewy body dementia (DLBD; n = 4), mixed DLBD (n = 3), multisystem atrophy (MSA; n = 6) and Pick’s disease n = (1). Sections were stained by H&E, Gallyas, and immunohistochemistry using a panel of phospho-tau antibodies (pSer208,210, pThr217, pThr175, and pSer202). pThr231 and T22 (oligomerized tau) were used to stain one case of AD, ALSci, MSA, DLDB, mDLDB, and FTLD. Semiquantitation was used to score pathological load. Across diseases, tau load was heaviest in layers II/III of the entorhinal cortex and amygdala and CA1/2 of hippocampus with all antibodies. With the exception of DLDB, we observed pThr175 co-localizing with pThr231, suggesting that this pathway may be a common mechanism of toxicity across the tauopathies.

P234 An AAV9 mediated rat model of pThr175 tau protein toxicity A. Moszczynski1, J. Gopaul1, P. Mccunn1, K. Volkening1, M. Harvey1, R. Bartha1, S. Schmid1, M. Strong1 1 Schulich School of Medicine and Dentistry, Western University, London, Canada Aberrantly phosphorylated microtubule associated protein tau (tau) has been implicated in multiple neurodegenerative diseases. We have previously shown that amyotrophic lateral sclerosis with cognitive impairment (ALSci) is associated with pathological tau phosphorylation at Thr175. In vitro expression of pseudophosphorylated human tau (Thr175Asp tau) leads to tau fibril formation and cell death mediated through Thr175Asp tau induction of GSK3b leading to phosphorylation of Thr231 – the direct consequence of which is fibril formation. To determine the replicability of this pathway in vivo, adult female Sprague-Dawley rats were injected bilaterally in the hippocampus with GFP-tagged tau constructbearing recombinant adeno-associated virus (rAAV9). 4 groups of 10 rats were injected with either 1) GFP, 2) GFP-WT tau, 3) GFPThr175Ala tau (cannot be phosphorylated), or 4) GFP-Thr175Asp tau. Behaviour was assessed at 1, 3, 6, 9, and 12 months post injection by Morris water maze, open field, and startle box testing. Magnetic resonance imaging (MRI) was conducted on a 9.4 T MRI scanner and diffusion tensor imaging was assessed. At 3, 6, and 12 months post injection pathology was investigated by immunohistochemistry. No change in behaviour or imaging was observed between groups. On IHC analysis GFP staining revealed hippocampal expression in all groups through 12 months. Tau pathology was observed as fibrillar inclusions, plaques, and torsional processes. The lack of behavioural correlate may be a result of inadequate protein load to cause widespread neuronal death. The observed pathology indicates the toxicity of tau protein, and future studies investigate inhibition of GSK3b as a means of modulating this pathology.

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P235 pThr175 tau as a toxic phosphoepitope in CTE and ALSci A. Moszczynski1, A. McKee2, W. Strong1, M. Strong1 1 Schulich School of Medicine and Dentistry, Western University, London, Canada 2 Boston University School of Medicine, Boston, USA CTE is a progressive neurodegenerative disease associated with head trauma, and characterized by widespread deposition of aberrantly phosphorylated microtubule associated protein tau (tau). 10% of patients develop motor dysfunction consistent with ALS (CTEM). ALSci tau has been characterized by aberrant phosphorylation at Thr175 (pThr175) and the inclusion of all 6 isoforms in the insoluble fraction. Toxicity of pThr175 tau has been associated with increased GSK3b activation and phosphorylation of Thr231. Here we investigated the presence and colocalization of pThr175 and pThr231 in CTE, and the tau isoform composition. CTEM (n = 5), CTE (n = 5), and control (n = 5) brain tissue slides were obtained from the Boston University Brain Bank. Hippocampal formation and spinal cord slides were stained with antibodies for tau (pThr175 and pThr231), activated GSK3b (pTyr216), and T22 (tau oligomer) and analyzed by both light and confocal microscopy. Tau protein from temporal pole and anterior cingulate cortex from 6 stage III CTE cases was isolated and separated into soluble and insoluble fractions. Isolated protein was analyzed by western blot and probed for pThr175, total tau, 3R and 4R tau. All 6 tau isoforms were present in the insoluble fraction in western blots. Histological analysis revealed punctate and fibrillar inclusions accompanied by neuritic and plaque pathology in the hippocampal formation in all CTE and CTEM cases. pThr231 colocalized with pThr175, T22 and active GSK3b. Both CTE and CTEM cases contained tau pathology in ventral and lateral horn spinal motor neurons. This suggests overlapping pathological processes in ALSci and CTE and that GSK3b inhibition may be of therapeutic use in both disorders.

P236 Selective vulnerability of the locus coeruleus in frontotemporal lobar degeneration (FTLD) with tau pathology D. Irwin1, M. Byrne1, D. Wolk1, E. Lee1, M. Grossman1, J. Trojanowski1 1 UPENN, Neurology, Philadelphia, USA The two main FTLD proteinopathies (FTLD-Tau, FTLD-TDP) can present with indistinguishable clinical syndromes. Identification of brain regions selectively affected by FTLD-Tau or FTLD-TDP can guide future studies to improve ante mortem diagnosis. In our prior histopathological staging studies of FTLD-TDP and Pick’s disease (FTLD-Tau) we found the majority of Pick’s disease had severe neurodegeneration in the locus coeruleus (LC) while FTLDTDP had only mild LC disease in only advanced stage cases. Here, we build on these studies to perform a comparative study of the LC across all forms of FTLD-Tau and FTLD-TDP. Selected patients had a primary neuropathological diagnosis of FTLD-Tau (n = 109) or FTLD-TDP (n = 61) with available ordinal scores obtained at autopsy for either gross examination of LC depigmentation (FTLDTau n = 109, FTLD-TDP n = 61) or microscopic rating of inclusion severity (FTLD-Tau n = 105, FTLD-TDP n = 30). Group comparisons were made using non-parametric Mann-Whitney U and Spearman correlation. FTLD-Tau had a higher inclusion burden



score (median = 2, IQR = 2.3; p < 0.001) and gross depigmentation of LC (median = 0, IQR = 0.1; p = 0.03) than FTLD-TDP (inclusion score median = 0, IQR = 0.0.25) (gross depigmentation median = 0, IQR = 0.0). Age at death did not correlate with LC pathology (p > 0.1). To control for co-morbid AD tau pathology, we excluded cases with AD tau Braak stage> III (FTLD-Tau=10, FTLD-TDP=2) and found a similar higher inclusion burden in LC for FTLD-Tau compared with FTLD-TDP (p < 0.001). Progression of FTLD-Tau may preferentially affect LC compared to FTLD-TDP. Clinical markers of LC integrity could potentially help distinguish FTLD-Tau from FTLD-TDP during life.

P237 Prevalence of amyloid pathology and PiB positivity in frontotemporal dementia R. Tan1,2, J. Kril3, Y. Yang1, O. Piguet1,2, L. Ittner2, J. Kwok1,2, J. Hodges1,2, G. Halliday1,2 1 Neuroscience Research Australia, Randwick, Australia 2 University of New South Wales, School of medical science, Sydney, Australia 3 The University of Sydney, Discipline of Pathology, Sydney Medical School, Sydney, Australia Pittsburgh compound B (PiB)-PET imaging enables in vivo detection of b-amyloid (Ab) plaques, a core neuropathological feature of Alzheimer’s disease (AD). However, its diagnostic utility in frontotemporal dementia (FTD) is unclear as the prevalence and severity of Ab deposition is not known, and one-fourth of patients that come to autopsy have a pathological diagnosis of AD (Chare et al. JNNP 2014; 85 866–871). The objective of the present study was to determine the prevalence, distribution (using Montine bamyloid scores) and severity (using CERAD cortical scores) of Ab deposition in pathologically-confirmed FTD syndromes, and assess the accuracy of PiB-PET imaging in FTD patients followed to autopsy. Importantly, cases with cerebrovascular disease, intermediate or high likelihood of AD were excluded. Ninety-two pathologically-confirmed FTD (FTLD) and 26 cognitively normal individuals from the Sydney and Cambridge Brain Banks met these criteria. Of the 11 FTD cases that had undertaken in vivo PiB-PET imaging, 8 had FTLD and frozen tissue for APOE genotyping was available in 45% FTLD (41/92) and 54% controls (14/26). Overall 41% of FTLD cases and 77% of controls had Ab deposition, with no association to APOE e4 status. Ab occurred in all FTD syndromes [bvFTD (40%, 17/43), PSP (83%, 5/6), CBS (31%, 4/13), sv-PPA (40%, 10/25) and nfv-PPA (20%, 1/5)] with increased prevalence and severity in those who were older at disease onset and death (p)

P239 Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology E. Clayton1, S. Mizielinska1, J. Edgar2, T. T. Nielsen3, I. Holm4,5, P. Johannsen3, J. Nielsen3, E. Asante6, J. Collinge1,6, F. Consortium7, A. Isaacs1 1 UCL Institute of Neurology, London, Great Britain 2 University of Cambridge, Cambridge, Great Britain 3 University of Copenhagen, Rigshospitalet, Copenhagen, Denmark 4 Randers Hospital, Department of Pathology, Randers, Denmark 5 Aarhus University, Institute of Clinical Medicine, Aarhus, Denmark 6 MRC Prion Unit, London, Great Britain 7 Frontotemporal Dementia Research in Jutland Association, Jutland, Great Britain Truncating mutations in the charged multivesicular body protein 2B (CHMP2B) gene cause frontotemporal dementia (FTD). CHMP2B is a member of the endosomal sorting complex required for transport (ESCRT). ESCRT proteins facilitate delivery of cargoes to intraluminal vesicles within late endosomes, which then fuse with lysosomes enabling cargo degradation. We show that mice which express FTD-causative mutant truncated CHMP2B at physiological levels develop a novel lysosomal storage pathology characterised by large neuronal autofluorescent aggregates. The aggregates are an early pathology, occurring at 3 months of age and increasing in number and size over time. Mice expressing wild-type CHMP2B, or non-transgenic controls do not have these autofluorescent aggregates, indicating that they are a specific pathology caused by mutant CHMP2B. Ultrastructural analysis and immunogold labelling confirmed that they are derived from the endolysosomal system. Furthermore, brains of patients with CHMP2B mutation contain morphologically similar autofluorescent aggregates. These aggregates occur significantly more frequently in human CHMP2B mutation brain than in neurodegenerative disease or age-matched control brains. These data suggest that lysosomal storage pathology is the major neuronal pathology in FTD caused by CHMP2B mutation. Recent evidence suggests that two other genes associated with FTD, GRN and TMEM106B are important for lysosomal function. Our identification of lysosomal storage pathology in FTD caused by CHMP2B mutation now provides evidence that endolysosomal dysfunction is an important degenerative pathway in FTD.

P240 Pathological prediction in behavioral variant frontotemporal dementia D. Perry1, J. Brown1, K. Possin1, A. Trujillo1, A. Radke1, A. Karydas1, A. Sias1, G. Rabinovici1, M. L. Gorno-Tempini1, A. Boxer1, M. De May1, E. Huang1, K. Rankin1, S. Lee1, M. Sidhu1, S. Gaus1, J. Vargas1, R. Ossenkoppele1, A. Brown1, G. Coppola2, H. Rosen1, D. Geschwind2, J. Trojanowski3, L. Grinberg1, J. Kramer1, B. Miller1, W. Seeley1 1 University of California San Francisco, San Francisco, CA, USA 2 University of California Los Angeles, Los Angeles, CA, USA 3 University of Pennsylvania, Philadelphia, PA, USA Accurately predicting the molecular pathological diagnosis in patients with behavioral variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians and will become


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increasingly important with the development of disease-modifying therapies. We sought to improve pathological prediction by exploring the clinical and neuroimaging features of a large autopsied bvFTD cohort. We analyzed 117 patients in whom bvFTD was either the top or an alternate possible diagnosis. Of these, 98 (84%) had a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD). The ten most frequent primary neuropathological diagnoses were distributed among subtypes of FTLD-tau (including corticobasal degeneration, progressive supranuclear palsy, and Pick’s disease), FTLD-TDP (types A, B, C, and unclassifiable), and FTLD-FUS (aFTLD-U), as well as Alzheimer’s disease (AD, 13%), and amyotrophic lateral sclerosis (3%) without neurodegenerative pathological changes outside of the motor system. We applied principal component analyses to the available clinical, neuroimaging, and neuropsychological data to identify components that explain variance among patients. The predictive value of these components was then tested by discriminant function analysis with cross-validation. We also leveraged the predictive value of factors with previously reported links to pathological subtypes, including genetic mutations, motor features, or striking atrophy patterns. Focusing on the top 10 most common pathological subtypes, pathological classification was most accurate (63.9%) when using a combination of a priori predictors and the results of the discriminant function analysis. While discerning the pathological diagnosis remains difficult in many patients with bvFTD, specific clinical, genetic, and neuroimaging profiles allow the clinician to make a prediction with high confidence.

P241 TDP-43 pre-inclusions in primary progressive aphasia: morphology and distribution G. Kim1, Z. Parton1, S. Weintraub1, E. Bigio1, M.-M. Mesulam1, C. Geula1 1 Northwestern University, Feinberg School of Medicine, Cognitive Neurology and Alzheimer’s Disease Center, Chicago, USA A hallmark of neurodegenerative disorders is aggregation of misfolded proteins in inclusions, such as accumulation of abnormally phosphorylated TAR-DNA binding protein-43 (TDP-43) in frontotemporal lobar degeneration (FTLD). In recent years, TDP-43positive pre-inclusions (diffuse cytoplasmic staining) were described, suggesting that TDP-43 inclusions develop in stages. Here we investigated morphologic subtypes and distribution of TDP-43 pre-inclusions in primary progressive aphasia (PPA), a clinical language dementia syndrome in which a subpopulation is characterized by TDP-43 inclusions (PPA-TDP). Frozen and paraffin embedded sections were immunohistochemically stained for phosphorylated TDP-43, and subtypes and densities of preinclusions were examined in brains from one cognitively normal and three PPA-TDP participants. Three distinct morphologic subtypes of pre-inclusions were identified in the PPA brains: 1) smooth, nongranular, non-fibrillar immunoreactivity in cytoplasm and proximal dendrites; 2) granular staining and/or small fibrils in cytoplasm; 3) diffuse nuclear staining. A subpopulation of neurons with granular and fibrillar cytoplasmic staining also contained mature TDP-43 inclusions. The normal brain was devoid of inclusions and preinclusions. Cortical areas with a high density of mature TDP inclusions contained lower densities of pre-inclusions than areas with low densities of inclusions. Consistent with the clinical PPA phenotype, the language dominant hemisphere showed higher pre-

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inclusion densities. Pre-inclusions were considerably more numerous in fixed frozen sections than in paraffin embedded sections from the same regions. These observations suggest that TDP-43 inclusions originate in neurons with pre-inclusions, which may go through progressive stages. These findings also suggest that fixed frozen sections are advantageous to paraffin embedded sections in studying pre-inclusions. It remains to be seen whether subtypes and distribution of TDP-43 pre-inclusions are common to all TDP-43 proteinopathies.

P242 Sporadic FTLD TDP type C is a distinct clinicopathological entity from FTLD types A/B G. M. Baer1,2, M. Byrne1,2, F. Cooper1,2, E. Suh2, L. McCluskey3, L. Elman3, D. Wolk4, V. M. Van Deerlin2, V. Lee2, E. Lee5, M. Grossman1, J. Trojanowski2, D. J. Irwin1,2 1 University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology, Philadelphia, USA 2 University of Pennsylvania Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Philadelphia, USA 3 University of Pennsylvania, ALS Center, Department of Neurology, Philadelphia, USA 4 University of Pennsylvania, Alzheimer’s Disease Center, Department of Neurology, Philadelphia, USA 5 Perelman School of Medicine, University of Pennsylvania, Translational Neuropathology Research Laboratory, Philadelphia, USA There are 3 histological subtypes (i.e. A-C) of sporadic FTLDTDP; we previously found types A and B to be indistinguishable using 70 lm sections. Comparative studies of sporadic FTLD-TDP A/B and C are lacking. Patients selected had a primary neuropathological diagnosis of FTLD-TDP types A/B (n = 26) or C (n = 21), with or without clinical ALS and were negative for mutations in GRN and C9orf72. We examined tissue from 4 regions stained for phospho-TDP (p409/410) using digital image analysis to quantify the % area occupied % (%AO) of stain with previously validated sampling methods for cortex. Due to observed effects of neuron loss to %AO in the anterior horn we adjusted spinal cord %AO by a conversion factor using blinded ordinal rating of motor neuron loss. Group-wise comparisons were made using chi-square analysis for categorical variables and Mann-Whitney U for non-normally distributed %AO. Clinical ALS was exclusive to type A/B (7/26) and A/B cases had a shorter disease duration (5.48 4.6) compared to type C (0/21 ALS, p = 0.01; mean disease duration 10.48 5.6, p = 0.002). Comparison of regional pathology finds TDP type C had higher %AO in the entorhinal cortex (0.360 0.270, p = 0.004) compared to type A/B (%AO 0.149 0.109) while type A/B cases had a higher %AO in the cervical spinal cord (0.215 0.248, p = 0.004) compared to type C (%AO 0.048 0.093). There was a higher %AO in the posterior frontal cortex (motor) for type C compared with type A/B (p = 0.042) while both groups had a similar %AO in mid-frontal cortex (p > 0.1). FTLD-TDP type C is not associated with clinical ALS or significant spinal cord pathology and has a better prognosis than types A/B. Future efforts to distinguish subtypes of sporadic FTLDTDP ante mortem may improve clinical trials.



P243 Tau aggregation and neurodegeneration predict regional atrophy and intrinsic connectivity disruption in progressive supranuclear palsy S. Spina1, J. A. Brown1, J. Deng1, A. Nana Li1, N. Lee1, J.-H. Hwang1, S. E. Gaus1, E. J. Huang2, A. Boxer1, H. J. Rosen1, B. L. Miller1, L. Grinberg1, W. W. Seeley1 1 UCSF, Neurology, San Francisco, USA 2 UCSF, Pathology, San Francisco, USA Neurodegenerative diseases affect specific large scale neuronal networks and propagate along specific pathways of brain functional intrinsic connectivity (IC). The histopathological substrates of normal and disrupted IC are not well characterized. We hypothesized that pathological tau burden and a composite score of neurodegeneration would correlate with regional brain atrophy and reduced IC in patients with clinical and pathologically confirmed progressive supranuclear palsy (PSP). T1-weighted MP-RAGE and task-free fMRI (tf-fMRI) scans were acquired in 8 PSP subjects and two groups of healthy controls: HC1 (structural, 288 subjects) and HC2 (tf-fMRI, 165 subjects). Structural MRI data were analyzed using voxel-based morphometry. For tf-fMRI, a rostral midbrain tegmentum region-of-interest (ROI) was used to derive whole-brain IC maps. Voxelwise regression, taking into consideration age, sex, handedness, total intracranial volume and education, was used to estimate W-statistic maps (La Joie, 2012) of grey matter loss and IC dysfunction within 24 patient-specific ROIs, which were manually traced to mirror the regions dissected post-mortem for histopathological analysis. Measures of neurodegeneration (neuronal loss, gliosis, and microvacuolar changes) and tau inclusion burden were assessed for each ROI post-mortem in the 8 patients with PSP. Regional grey matter loss was more severe in ROIs with a higher quantitative tau burden (rho = 0.19, p = 0.009), whereas IC dysfunction correlated with overall neurodegeneration (rho = 0.19; p = 0.01). Semiquantitative tau burden also predicted IC dysfunction (rho = 0.21; p = 0.005), an effect that remained (rho = 0.17, p = 0.027) in a partial correlation with grey matter loss. Our data support the role of tau protein deposition as a driving force of neurodegeneration and IC dysfunction in PSP. In vivo IC disruption may function as a predictor of the severity and distribution of neurodegeneration and pathological tau burden in PSP.

P244 TDP-43 protein pathology in mouse model’s of Alzheimer’s disease L. Kaylor1,2 1 Wells College, Biological and Chemical Sciences, Aurora, USA 2 University of Tasmania, Hobart, USA The transactive response DNA-binding protein 43 (TDP 43) has been reported as a potential contributor to the severity of Alzheimer’s Disease (AD). TDP-43 is a neurofilament light (NFL) messenger RNA (mRNA)- binding protein, and its implication in AD has been suggested in studies whose patients had amyotrophic lateral sclerosis and down-regulation of NF-L mRNA. Pathological TDP-43 mislocalizes from the nucleus, accumulating in the cytoplasm and forming insoluble plaques that contribute to the loss of synaptic function observed in AD. Direct links between TDP-43 and AD, however, are still limited. In this study, we investigated the expression of molecular TDP-43 through western blotting of

cerebral protein extracts and quantitative analysis with normalization. Additionally, we examined the localization of TDP-43 through immunohistochemistry and qualitative analysis of transverse coronal sections of the mice brains. We concluded that there were no significant differences (p values < 0.05) in the expression of TDP43 between wild-type (WT) and amyloid precursor protein (APP)/ presenelin 1 (PS1) mutant mice, at either 9 months or eighteen months of age. Immunohistochemistry revealed that TDP-43 did not mislocalize from the nucleus in either WT or APP/PS1 mice at 9 months or eighteen months of age. Our results indicate that while TDP-43 does not hold direct links to AD, it may be a contributor to a pathology that includes much more complicated pathways and cellular interactions.

P245 Disproportionate von Economo neuron and fork cell TDP43 aggregation is associated with somatodendritic degeneration in sporadic behavioral variant FTD A. Nana1, M. Sidhu1, S. Gaus1, J.-H. Hwang1, L. Li1,2, Y. Park1, E.-J. Kim1, S. DeArmond3, L. Grinberg1, E. Huang3, B. Miller1, W. Seeley1 1 University of California, San Francisco, Department of Neurology and Memory and Aging Center, San Francisco, USA 2 Qiqihar Medical University, Department of Pharmacology, Qiqihar, China 3 University of California, San Francisco, Department of Pathology, San Francisco, USA Patients with behavioral variant frontotemporal dementia (bvFTD) show progressive loss of social-emotional functions. The frontoinsular (FI) and anterior cingulate cortices show early, selective degeneration with loss of Layer 5 von Economo neurons (VENs) and fork cells. TDP-43 aggregation is found in affected brain and spinal cord regions in over 50% of patients with bvFTD and 95% of those with amyotrophic lateral sclerosis (ALS), but the impact of TDP aggregation on neuronal integrity remains unclear. We compared the proportion of TDP-43-inclusion-bearing FI VENs, fork cells, neighboring Layer 5 neurons, and Layer 2-3 neurons in 17 bvFTD/ALS patients (6 bvFTD, 8 bvFTD-MND, 3 ALS; 7 females, mean age 62) who lacked known FTD mutations and represented a range of clinical and anatomical severities. We related cell-type specific TDP-43 aggregation to Broe stage, neuronal loss, gliosis, and clinical severity. We also assessed the effect of TDP-43 aggregation on neuronal morphology in seven bvFTD patients and four controls. VENs (28% inclusion fraction) and fork cells (29%) were significantly more prone to TDP-43 aggregation than neighboring layer 5 neurons (8%), whereas layer 2-3 neurons showed a TDP-43 inclusion formation rate (23%) more similar to VENs and fork cells. In bvFTD, VEN and fork cell apical and basal dendritic diameter and somatic area were significantly smaller (20-39%) in cells with TDP-43 inclusions than those without in the same patients. Interestingly, in bvFTD, VENs without TDP-43 inclusions showed higher nuclear (16%) and somatic area (18%) compared to VENs in controls. Our findings suggest that the vulnerability of FI VENs and fork cells to TDP-43 aggregation is associated with altered neuronal morphology. Future studies should explore whether increased neuronal size in vulnerable neurons lacking inclusions is part of an early compensatory mechanism or is linked to a neuronal hyperexcitability phase that precedes TDP aggregation, neuronal atrophy, and eventually cell death.


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Utility of Ubiquitin/p62 aggregates screening in granular neurons of the cerebellar cortex in a Brain Bank: experience of the neurological tissue bank of the biobanchospital clinic-IDIBAPS, barcelona (Spain) R. Avila1,2, O. Ramos3,2, O. Grau2, A. Antonell4, A. Llad o4, R. Sanchez-Valle4, E. Gelpi2 1 Hospital Universitario Virgen del Rocıo, Department of Anatomical Pathology, Sevilla, Spain 2 Biobanc-Hospital Clinic-IDIBAPS, Neurological Tissue Bank, Barcelona, Spain 3 Hospital Clinic, Department of Neurology, Barcelona, Spain 4 Hospital Clinic, Alzheimer disease & other Cognitive disorders Unit, Barcelona, Spain

Hypertrophic microglia are associated with more tangles and less neurons in primary progressive aphasia with Alzheimer pathology D. Ohm1, A. Rademaker1,2, E. Bigio1,3, M.-M. Mesulam1,4, E. Rogalski1, C. Geula1 1 Northwestern University, Cognitive Neurology and Alzheimer’s Disease Center, Chicago, USA 2 Northwestern University, Department of Preventive Medicine, Chicago, USA 3 Northwestern University, Department of Pathology, Chicago, USA 4 Northwestern University, Department of Neurology, Chicago, USA

A hexanucleotide expansion in C9orf72 gen has been observed in 20–40% of patients with fronto-temporal lobar degeneration (FTLD) and amyothrophic lateral sclerosis (ALS). They show small ubiquitin/p62 positive, TDP43 negative aggregates in granular neurons of the dentate gyrus of the hippocampus and cerebellar cortex, among others. These neuropathological alterations seem to be highly predictive of the presence of the mutation. Aim: To assess the presence of ubiquitin/p62 positive inclusions (UPPI) in granule cells of cerebellum in a post-mortem series of brains from the NTB to establish: a) the prevalence in patients with Neurodegenerative diseases; b) its predictive value for an underling C9orf72 hexanucleotide expansion; c) the specificity of the mutation to FTLD and ALS phenotypes; d) the presence and severity of copathology in the brains with those aggregates. Results: We assessed a cohort of 1800 brains from adult donors independently of their clinical or neuropathological ND phenotypes. UPPI screening was performed on 5 micrometer thick sections from formalin-fixed paraffin embedded tissue blocks. We had already found UPPI in 3 donors in whom the mutation had been detected during life (2 FTLD, 1 ALS) and in 5 donors with FTLD that had been genetically studied from post-mortem brain tissue. Now 4 additional cases have been found: 2 patient with clinically FTLD and 2 patients with cognitive deterioration and parkinsonism diagnosed as Lewy body dementia (LBD). In all patients the C9orf72 hexanucleotide expansion was genetically confirmed. Conclusion: Screening of cerebellar cortex for ubiquitin/p62 aggregates in brain tissue is a feasible and reliable method to identify previously not recognized C9orf72 expansion carriers, especially in cases with a different clinical diagnosis such as LBD. This finding offers the possibility of genetic counselling and longitudinal follow-up of family members of these brain donors, and increases the high value of Brain Bank samples.

Alzheimer disease (AD) pathology (i.e., amyloid-ß plaques [APs] and neurofibrillary tangles [NFTs]) can cause primary progressive aphasia (PPA), a clinical dementia syndrome characterized primarily by language deficits and asymmetric cortical atrophy concentrated in the left perisylvian language network. Activated microglia are associated with AD pathology, and the “hypertrophic” microglia (HM) subtype is more closely linked to pathologic insults than “ramified” microglia (RM). However, the presence of microglial subtypes and their relationships with APs, NFTs, and neurons have not been described in PPA patients with AD pathology (PPA-AD). The first goal of the current study was to determine the relative distribution of HM versus RM between hemispheres and between language versus non-language cortical regions. The second goal was to identify the relationships between HM and densities of APs, NFTs, and neurons. Unbiased stereology was performed on whole-hemisphere sections to quantify postmortem markers in five language regions of interest (ROIs) and two non-language ROIs, bilaterally. Wilcoxon signed rank tests revealed HM densities exceeded RM densities across all ROIs in both cases (p < 0.0001). In addition, HM were greater in left versus right ROIs (p = 0.025), and the left versus right difference in HM density was greater than the left versus right difference in RM density across all ROIs (p = 0.017). Spearman correlations combining all marker densities (n = 28 ROI densities per marker across the two participants) revealed a significant positive correlation between HM and NFT (r = 0.41, p = 0.029), and significant negative correlations between HM and AP (r = 0.53, p = 0.004) and neurons (r = 0.44, p = 0.018). Taken together, these preliminary findings suggest that HM may be a more sensitive correlate of NFT than AP accumulations, and an increase in HM and/ or NFTs may contribute to the smaller neuronal densities potentially underlying cortical atrophy and cognitive decline in PPA-AD.

P248 Biopsy in dementia: a case report C. Prix1, J. Levin1,2, N. Ackl1,3, E. Wlasich1, R. Egensperger4, C. Schwartz5, F.-W. Kreth5, A. Giese4, A. Danek1 1 Ludwig-Maximilians-University, Department of Neurology, Munich, Germany 2 German Center of Neurodegenerative Diseases DZNE, Site Munich, Munich, Germany 3 Spital Thurgau, Memory Clinic, Muensterlingen, Switzerland 4 Ludwig-Maximilians-University, Center for Neuropathology and Prion Research, Munich, Germany 5 Ludwig-Maximilians-University, Department of Neurosurgery, Munich, Germany Very often in vivo diagnosis in patients with dementia lacks precision. Most diagnostic criteria require a neuropathological

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examination to establish a definite diagnosis. Hence, except cases with known mutations in some diseases, to clarify the final diagnosis in vivo, a biopsy is mandatory. We report a case of a 46 year old male patient suffering from dementia and changed interpersonal behaviour. All clinical and biochemistry examinations like MRI, FDG-PET, CSF und neuropsychology didn’t lead to a satisfying diagnosis. After 3 years of lack of clarity we chose in a multidisciplinary setting brain biopsy for further investigations. The stereotactic biopsy of the right frontal lobe was performed in our department for neurosurgery without any complications. The neuropathology showed TDP43-positive deposits. Post mortem a neuropathology examination and genetic analysis have been conducted. So the diagnosis of frontotemporal dementia with TDP-43 inclusions was confirmed, but no mutation was found. Brain biopsies are rarely performed in patients with dementia. In our opinion, stereotactic brain biopsy performed secondary to full use of alternative examination techniques in a centre with an appropriate set up may be justified upon individual decision in cases with unclear dementia a possibility to solve unclear cases.

P249 C9ORF72 in 3D: a novel dimension in FTD-MND iPSN cultures V. Porterfield1, Q. Zhong1, P. Gant1, E. Foff1 1 University of Virginia, Neurology, Charlottesville, USA Frontotemporal degeneration (FTD) is the second most common presenile dementia of individuals under the age of 65. The discovery that the most common cause of familial FTD is a hexanucleotide repeat expansion (GGGGCC)n in the first intron of C9ORF72 led quickly to the development of new models to study these disorders. These models have yielded valuable insight but they have limitations and development of new models is a prime objective of the US research enterprise. Cell culture models typically employ cells grown in a monolayer, making connections only with neighboring cells which is incongruent with how cells grow in vivo. Additionally, 2 dimensional (2D) neurons have altered morphology, lifespan, and function compared to those in 3D, and the surrounding media lacks a normal gradient of nutrients, waste, and exported proteins found in complex in vivo environments. We hypothesized that a 3D neuronal culture system derived from neural stem cells (NSC) generated from C9ORF72 patients would provide a highly accurate and more biologically relevant model for studying disease. To study our hypothesis, we created two independent 3D mixed neuronal/ glial models and set out to characterize the systems. Cells were analyzed for (i) differentiation and survival (ii) morphological and structural changes, (iii) neurophysiologic activity and (iv) recapitulation of known deficits. We have been able to demonstrate altered soma morphology and cell viability in 2D compared to 3D systems. Preliminary work suggests that C9 + cells have a selective disadvantage in 2D, and may demonstrate changes in neurite structure as well. Further characterization is necessary to inform the use of this model in future studies.

P250 ER chaperones in the pathogenesis of amyotrophic lateral sclerosis (ALS) A. Goswami1, A. Yamoah1, A. Dreser1, D. Troost2, J. Weis1 1 RWTH Aachen University Hospital, Institute of Neuropathology, Aachen, Germany 2 Academic Medical Centre, Division of Neuropathology, Department of Pathology, Amesterdam, Netherlands ALS is a multisystemic degenerative disease, in which the most severe degenerative changes affect upper and lower motor neurons (MNs). Even among MNs, there is selective vulnerability. For example, oculomotor MNs in the midbrain and MNs of Onuf’s nucleus in the sacral spinal cord tend to be spared in ALS (Mannen T. Neuropathology 2000; 20: Suppl: S30–3). Moreover, in SOD1G93A ALS mice, high-firing-threshold fast fatigable (FF) MNs are most vulnerable compared to low-firing-threshold slow (S) MNs. In addition, FF MNs are most prone to the ER stress-associated unfolded protein response (Saxena etal. Nat Neurosci. 2009; 12:627–36). Thus the major objective of our research is to elucidate the molecular mechanisms of selective vulnerability/neuroprotection focusing on ER proteins/chaperones involved in ALS and other neurodegenerative disorders (Filezac de L’Etang et al. Nature Neurosci 2015; 18: 227– 238, Prause J& Goswami A et al. Hum Mol Genet. 2013; 15:1581– 600, Vollrath et al. Cell Death and Disease 2014; 5:1290–1297). We used biochemical and immunohistochemical approaches to examine autopsy tissue (brain, spinal cord) from human ALS patients, transgenic ALS mouse models, human iPS cell-derived MNs and cell lines expressing ALS mutations. We confirmed that disease resistant (S) MNs show increased level of ER chaperones, and reduced ER stress and protein aggregations in ALS. Similarly oculomotor neuron also shows increased levels of ER chaperone proteins. Loss of these ER chaperones in mouse and cell culture models led to neurodegeneration. Thus differential expression of ER proteins and other molecular chaperones in the MNs confers resistance towards neurodegeneration.

P251 Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers T. Gendron1, M. van Blitterswijk1, K. Bieniek1, L. Daughrity1, J. Jiang2, B. Rush3, O. Pedraza3, J. Lucas3, M. Murray1, P. Desaro3, A. Robertson3, K. Overstreet3, C. Thomas4, J. Crook4, M. Castanedes-Casey1, L. Rousseau1, K. Josephs5, J. Parisi5, D. Knopman5, R. Petersen5, B. Boeve5, N. Graff-Radford3, R. Rademakers1, C. Lagier-Tourenne6, D. Edbauer7, D. Cleveland2, D. Dickson1, L. Petrucelli1, K. Boylan3 1 Mayo Clinic, Neuroscience, Jacksonville, USA 2 University of California at San Diego, Ludwig Institute, La Jolla, USA 3 Mayo Clinic, Neurology, Jacksonville, USA 4 Mayo Clinic, Section of Biostatistics, Jacksonville, USA 5 Mayo Clinic, Neurology, Rochester, USA 6 Massachusetts General Hospital, Institute for Neurodegenerative Diseases, Charlestown, USA 7 Ludwig-Maximilians University Munich, Institute for Metabolic Biochemistry, Munich, Germany A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72), the most common cause of


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frontotemporal dementia and amyotrophic lateral sclerosis (ALS), gives rise to varied clinical and neuropathological characteristics. To investigate the molecular basis for this heterogeneity, we evaluated associations between features of disease and levels of two abundantly expressed “c9RAN proteins” atypically translated from the expanded repeat. Taking a departure from traditional immunohistochemical approaches, we employed immunoassays to quantitatively measure poly(GP) and poly(GA) protein levels in cerebellum, frontal cortex, motor cortex, and/or hippocampus from 55 C9ORF72 mutation carriers [24 patients with frontotemporal lobar degeneration (FTLD), 19 with FTLD and motor neuron disease (FTLD-MND), and 12 with ALS]. We additionally investigated associations between levels of poly(GP) or poly(GA) and cognitive impairment in 15 C9ORF72 ALS patients for whom neuropsychological data were available. Poly(GP) levels were highest in the cerebellum, and associations between cerebellar poly(GP) and both neuropathological and clinical features were detected. Specifically, cerebellar poly(GP) levels were significantly higher in patients with FTLD or FTLD-MND compared to patients with ALS. Furthermore, cerebellar poly(GP) associated with cognitive score in our cohort of 15 ALS patients. In the cerebellum, poly(GA) levels similarly trended higher in the FTLD or FTLDMND subgroups compared to the ALS subgroup, but no association between cerebellar poly(GA) and cognitive score of ALS patients was detected. Both cerebellar poly(GP) and poly(GA) associated with C9ORF72 variant 3 mRNA expression, but not variant 1 expression, repeat size, disease onset, or survival after onset. Overall, these data indicate that cerebellar abnormalities, as evidenced by poly(GP) accumulation, associate with neuropathological and clinical phenotypes, in particular cognitive impairment, of C9ORF72 mutation carriers.

and radiation leucoencephalopathy, characterized pathologically by reactive astrogliosis, focal necrosis, demyelination, axonal loss, and clinically by progressive subcortical deficits (ataxia, amnesia, cognitive decline), with relative sparing of cortical function. Although subcortical features may overlap with neurodegenerative conditions (e.g. frontotemporal dementia), focal cortical atrophy of FTD causes loss of language function in addition to memory, and specific histopathological features characterise FTD subtypes (e.g. Pick disease). Association between mitotic disease and tauopathy has not been reported widely. Diagnostic accuracy may guide management. A 54 year old man presented with increased seizure frequency and progressive ataxia, aphasia, personality changes, memory loss, incontinence, somnolence, binge-eating. Left frontal oligodendroglioma had been resected 7 years before, with radiotherapy for local recurrence 2 years earlier. MRI brain showed left frontal ‘post-op’ gliosis only. Radiation leucoencephalopathy with possible necrosis was diagnosed, although clinical progression was steroid-resistant and disproportionate to imaging. Chemotherapy was considered, despite absent proof of recurrence, due to overall deterioration. Because of marked aphasia and mild rigidity, initial surgical tissue was reexamined. Neuropathology revealed neuronal loss in cortical tissue surrounding oligodendroglioma, gliosis, Pick cells, argentophilic inclusions (Pick bodies). Progressive aphasia is uncharacteristic of radiation leucoencephalopathy. Despite absence of recurrence on MRI, chemotherapy, with potential morbidity, was considered due to progressive deterioration. Re-examination of pathology specimen, looking for additional (Tau) pathology clarified diagnosis as Pick disease, a frontotemporal dementia. Although no specific therapy could modify disease, diagnostic clarification helped family to accept symptoms. This highlights the importance of reconsidering the possibility of dual pathology when clinical signs do not correlate with working pathological diagnosis.

P252 Pick ‘n’ mix: neuropathological detection of peri-tumour tauopathy R. Lonergan1, V. Ashankar1, F. Carty1, M. Alexander1, P. Kelly1, K. O’Rourke1, M. Farrell2, T. Lynch1 1 Mater Misericordiae University Hospital, Neurology, Dublin, Ireland 2 Beaumont Hospital, Neuropathology, Dublin, Ireland Potential morbidities of radiotherapy, used to treat recurrent oligodendrogliomas, include steroid-responsive radiation necrosis

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Poster Session II: Progressive aphasias P253 Eyes reveal semantic deficit early in primary progressive aphasia A. Hillis1, D. Race1 1 Johns Hopkins, Neurology, Baltimore, USA Background: All variants of Primary Progressive Aphasia (PPA) usually begin with anomia and/or dysgraphia; it is often impossible to identify the variant early in the course because they do not have “core features” of any of the variants. Patients with semantic variant PPA (svPPA) have a distinct pathology and distinct course relative to other variants of PPA. They are more likely to develop behavioral impairments and less likely to respond to language therapy than other patients with PPA. Prognostically, it would be helpful to identify those with svPPA early in the course, even before they make errors on traditional tests of word comprehension (e.g. wordpicture matching tasks). Aims: We hypothesized that (1) patients with svPPA show a distinct pattern of eye-tracking in word-picture matching tasks, compared to controls and other variants of PPA, with a higher percentage of looks to unrelated pictures even beyond 1200 msec, and (2) patients with unclassifiable PPA who later developed svPPA would show the same eye tracking pattern as svPPA, even when they were accurate in selecting the target in the off-line task. We also hypothesized that the mean time to look to the target more than the unrelated foils would correlate with atrophy in temporal poles (areas critical for object knowledge and areas that atrophy in svPPA). Methods: We tested 19 participants with PPA (8 svPPA, 4 nonfluent agrammatic variant (nfvPPA), 3 logopenic variant (lvPPA), 4 unclassifiable) and 3 controls on spoken wordpicture matching task with eye-tracking. We measured percent looks to target and percent looks to each unrelated foil over time. We identified how long it took to: look to target ≥ 50% of the time, and ≥ 80% of the time. Each participant had two high resolution MRI scans (MPRAGE), at baseline and 9–12 months later. Atrophy in each individual was identified by registering the second scan to the first, and identifying the voxels of tissue that decreased or voxels of space (ventricles, sulci) that increased between the two scans. Pearson correlations were identified between voxels of atrophy and time to target more than foils across participants, after FDR correction for multiple comparisons. Results: All participants showed high accuracy on selecting the target in the word-picture matching task with unrelated foils. Controls, lvPPA, nfvPPA patients showed very similar patterns of eye-tracking, with ≥ 80% of looks to the target by 1200 ms. Those with svPPA showed a very different pattern of eye-tracking, with 30–50% of looks to unrelated targets beyond 1200 ms, often beyond 1800 ms. Of the participants with unclassifiable PPA (who had only naming and spelling deficits), 2 showed a pattern identical to svPPA; 2 years later these 2 patients met criteria for svPPA. The other 2 participants with unclassifiable PPA showed the pattern shown by normal controls, lvPPA, and nfvPPPA; 2 years later 1 met criteria for lvPPA; 1 remained unclassifiable. Failure to meet the threshold of 80% looks to target by 1200 ms was strongly associated with eventual development of svPPA (Χ2 = 15.4; p < 0.0001). The time to look at the target more often than the foils significantly correlated with atrophy in voxels within left and right temporal poles.Conclusions:

Eye-tracking reveals semantic deficits in people with svPPA even before they make errors on word comprehension tasks. This performance may indicate a lack of confidence in their understanding of the word even early in the course. Eye-tracking may be useful for early identification of svPPA.

P254 Semantic dementia and the left and right temporal lobes J. Snowden1,2, J. Harris1,2, J. Thompson1,2, C. Kobylecki1,2, M. Jones1,2, A. Richardson1,2, D. Neary1 1 Salford Royal Foundation Trust, Cerebral Function Unit, Manchester, Great Britain 2 University of Manchester, Manchester, Great Britain Semantic dementia (SD), otherwise known as semantic variant PPA, is characterised by profound loss of the ability to name and understand words. It is associated with bilateral, albeit often asymmetric, atrophy of the temporal lobes. The relative contribution of the two hemispheres in underpinning patients’ semantic impairment remains open to debate. Moreover, whereas studies of semantics in SD have suggested a critical role of the anterior temporal lobes, referred to as a ‘semantic hub’, stroke aphasia data have implicated posterior temporal regions. The present study examined picture naming and word comprehension performance in 41 SD patients and explored the relationship to blinded ratings of regional atrophy using a validated visual rating scale. Naming performance correlated strongly with atrophy in both anterior (p = 0.003) and posterior (p < 0.001) regions of the left temporal lobe, but not with the right temporal lobe. Word comprehension performance correlated with left posterior temporal atrophy only (p = 0.001). The nature of naming errors was associated with regional differences in atrophy. The number of semantic errors (e.g. “dog” for lion) correlated with atrophy in the right posterior temporal lobe (p = 0.001). By contrast, associative (e.g. “In Africa” for lion) and functional (e.g. “doing your hair” for comb) errors correlated with left anterior temporal atrophy (p = 0.007) and were inversely related to right anterior (p = 0.01) and posterior temporal (p = 0.006) atrophy. Omissions (“don’t know” responses) correlated with left posterior temporal atrophy (p = 0.004). Correlations with frontal lobe atrophy were non-significant. The findings reinforce the importance of the temporal lobes in underpinning semantic knowledge for words. They point to a differential contribution of the left and right temporal lobes and highlight a crucial role of posterior temporal regions. The findings challenge influential accounts of SD in terms of damage to an amodal semantic hub in the anterior temporal lobes.


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Poster Session II: Progressive aphasias

P255 UK speech and language therapy services for Primary Progressive Aphasia (PPA): Referral patterns and barriers to access A. Volkmer1, J. Warren2, A. Spector1, S. Beeke1 1 University College London, Division of Psychology and Language Science, London, Great Britain 2 University College London, Dementia Research Centre, London, Great Britain People with dementia are considered the biggest expanding caseload for speech and language therapists (SLTs) (Mahendra & Arkin, JCD 2003; 36 395–422). The Royal College of Speech and Language Therapists’ (RCSLT) dementia position paper (RCSLT 2014) advocates that, by providing support and recommending communication strategies, SLTs facilitate the maintenance of interpersonal relationships. People with primary progressive aphasia (PPA) present with a history of slowly worsening communication, and often struggle to manage family life, work and social relationships (Volkmer, J&R Press 2013). One intervention approach that is commonly used by SLTs working with PPA is naming therapy. Naming interventions have demonstrated maintenance of language skills through repetitive drilling (Jokel et al., Aphasiology 2013; 28 1038–1068). Yet many patients disengage from these programs due to frustration at practicing words they will eventually lose as the disease progresses. There is a paucity of research examining the effectiveness of functional communication interventions (Carthery-Goulart et al., Dementia & Neuropsycholgia 2013; 7 121–131), yet informal investigations suggest that SLTs focus more on functional interventions than on naming (Volkmer, Bulletin 2015; 756 11). This presentation will report results of a UK wide survey of SLTs working in clinical practice with people with PPA. Referral patterns, referral reasons and barriers to accessing speech and language therapy will be discussed. Data on therapy practices, including assessment and therapy tools, and support services, will also be presented. The clinical implications will be discussed with reference to clarification of referral practice to SLT services.

P256 Dynamic perceptual ‘stress tests’ in primary progressive aphasia C. Hardy1, R. Bond1, K. Jaisin1, C. Marshall1, C. Clark1, L. Russell1, J. Rohrer1, S. Crutch1, J. Warren1 1 UCL, Dementia Research Centre, London, Great Britain The pathophysiological basis of primary progressive aphasia (PPA) syndromes remains poorly understood but is likely to hold the key to early diagnosis and rational management of these conditions. Here we probed the pathophysiology of PPA by assessing patients’ ability to process speech signals under two classical perceptual transformations: sinewave reduction (removing spectral detail from speech sounds) and delayed auditory feedback (DAF; distorting sensorimotor recoding of own speech production). Patients representing major PPA syndromes and healthy age-matched controls were tested for recognition of speech sounds and nonverbal vocal characteristics of spoken phrases in sinewave form; and while reading aloud and producing propositional speech under DAF at 200 ms. The healthy control group showed evidence of rapid adaptation and perceptual learning of sinewave speech and variable

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sensitivity to DAF. Patients with PPA showed deficient learning of sinewave speech and abnormal profiles of sensitivity to DAF, most marked in PNFA. Paradoxical improved fluency of speech output was also observed in PNFA, in line with previous work in individuals with developmental stammering. Our findings suggest that dynamic distortions of the speech stream – perceptual ‘stress tests’ of the failing language system – can be used to capture pathophysiological signatures of PPA, with implications for diagnosis (assessing residual plasticity and detecting impaired reserve) and designing interventions.

P257 Distinctive clinical presentations in Asian patients with left and right anterior temporal atrophy A. Ghosh1, R. Fukuhara2, A. Ng Su Lyn3, J. Dominguez4, P. Anam Ong5, A. Dutt1, K. Karan6, M. Ikeda2 1 Apollo Gleneagles Hospitals, Department of Neurology, Cognitive Neurology Unit, Kolkata, India 2 Kumamoto University, Department of Neuropsychiatry, Faculty of Life Science, Kumamoto, Japan 3 National Neuroscience Institute, Department of Neurology, Singapore, Singapore 4 St. Lukes Medical Center, Manila, Philippines 5 Hasan Sadikin Hospital, Padjadjaran University, Department of Neurology, Bandung, Indonesia 6 Apollo Gleneagles Hospitals, Department of Neurology, Kolkata, India Recent research has highlighted clinical and genetic differences in Asian patients with frontotemporal dementia (FTD) compared with their western counterparts. However, clinical patterns in Asian patients with predominantly left or right anterior temporal atrophy remain unexplored. Characteristically, left temporal atrophy (LTLA) patients present with semantic dementia (SD), which may be associated with some behavioral features but not amounting to florid behavioral variant FTD (bvFTD) at least in the early part of the illness. Right temporal atrophy (RTLA) can present as SD or as bvFTD. The objective of our study was to assess the clinical presentations of Asian patients, across different countries, who had imaging evidence of predominant LTLA or RTLA. Clinical data of consecutive patients with predominant, asymmetric LTLA or RTLA as the most prominent imaging finding were assessed, particularly for presence of diagnostic symptoms of SD and bvFTD and for prosopagnosia. Out of 51 consecutive patients (27 female), 20 had RTLA and 31 had LTLA. All but one LTLA patient had SD but 48% patients also fulfilled the clinical criteria of bvFTD within 2 years of disease onset. Among the RTLA patients, 55% fulfilled the clinical criteria for SD but 50% also fulfilled the clinical criteria for bvFTD within 2 years of disease onset. Prosopagnosia occurred in 85% RTLA patients but also in 50% LTLA patients, with around two-third of patients in each group exhibiting prosopagnosia within one year of disease onset. We conclude that (i) distinctive differences exist in Asian patients with anterior temporal atrophy, both in frequency and clinical presentation, when compared with western reports, (ii) Asian patients with right or left anterior temporal atrophy frequently fulfill criteria for both SD and bvFTD, even in the early stages, (iii) together with the occurrence of early prosopagnosia in many LTLA patients, our results strongly argue for the recognition of global variations in clinical presentation and early progression of these disorders.



P258 Functional neuroanatomy of speech signal decoding in primary progressive aphasias C. Hardy1, C. Marshall1, C. Clark1, L. Russell1, E. Brotherhood1, D. Thomas1,2, S. Crutch1, J. Rohrer1, J. Agustus1, J. Warren1 1 UCL, Dementia Research Centre, London, Great Britain 2 UCL, Leonard Wolfson Experimental Neurology Centre, London, Great Britain Improved understanding of the brain mechanisms that underpin primary progressive aphasias (PPA) will be essential if we are to resolve the substantial diagnostic and nosological difficulties that surround these heterogeneous language-led dementias. Here we addressed this issue using activation fMRI to probe the deconstruction of speech signals to informational building blocks in patients with PPA versus healthy age-matched individuals. Thirty patients representing all major syndromes of PPA (12 nonfluent variant; 10 semantic variant; eight logopenic variant) and 16 healthy elderly controls underwent 3T-fMRI using a sparse acquisition protocol with passive listening to spoken phoneme sequences that manipulated three fundamental characteristics of speech signals: temporal regularity, basic information (entropy) content (i.e. sequence predictability) and phonemic structure (speech object encoding). All PPA subgroups showed functional neuroanatomical signatures of disordered speech signal decoding, involving both canonical language areas and non-canonical postero-medial cortical areas. These fMRI profiles suggest that disrupted interaction between language and ‘default-mode’ networks may be a generic mechanism of defective information processing in PPA. Our findings invite a reformulation of major PPA syndromes as more fundamental disorders of speech signal decoding. This novel framework for understanding the pathophysiology of PPA has implications for diagnosis and development of new biomarkers.

P259 Progressive aphasias as disorders of auditory information processing: behavioural signatures and structural neuroanatomy C. Hardy1, C. Marshall1, C. Clark1, L. Russell1, E. Brotherhood1, D. Thomas1,2, S. Crutch1, J. Rohrer1, J. Agustus1, J. Warren1 1 UCL, Dementia Research Centre, London, Great Britain 2 UCL, Leonard Wolfson Experimental Neurology Centre, London, Great Britain Impaired processing of speech in primary progressive aphasias (PPA) may be underpinned by more fundamental deficits of acoustic signal decoding that remain to be fully defined. We used a novel neuropsychological battery to probe the processing of acoustic information in patients with semantic dementia (SD; n = 9) and progressive nonfluent aphasia (PNFA; n = 10) relative to 20 elderly age-matched controls; and assessed group neuroanatomical correlates using voxel-based morphometry. In a series of two-alternative forced-choice tasks, participants were required to discriminate between short sequences of spoken phonemes manipulated for three basic characteristics: phoneme intelligibility (natural vs spectrally rotated speech); temporal regularity (isochronous vs anisochronous); and signal entropy (highly predictable sequences vs sequences with low predictability). Both patient groups were impaired relative to controls across all three tasks, with no significant differences between patient groups. However, voxel-

based morphometry correlating behavioural task scores with regional grey matter volume in the patient cohort revealed separate syndromic profiles of grey matter loss affecting dominant anterior temporal cortices (correlated with processing temporal regularity), amygdala (phoneme intelligibility) and posterior cingulate (signal entropy) in SD, and a frontoinsular network in PNFA (correlated with processing temporal regularity) with atrophy also affecting the supramarginal gyrus (correlated with phoneme intelligibility). Our findings suggest that PPA syndromes are underpinned by generic mechanisms of impaired speech signal decoding with differentiable neuroanatomical substrates. The findings have implications for the clinical diagnosis and nosology of PPA as more fundamental disorders of cortical information processing.

P260 Cross-sectional and longitudinal features of non-fluent/ agrammatic primary progressive aphasia with underlying corticobasal degeneration or progressive supranuclear palsy pathology. M. A. Santos-Santos1, M. L. Mandelli1, R. J. Binney2,1, E. Spinelli3,1, J. Ogar1, M. L. Henry4,1, I. Hubbard1, S. M. Wilson5,1, J. Q. Trojanowski6, L. T. Grinberg1, H. Rosen1, A. L. Boxer1, B. L. Miller1, W. W. Seeley1, M. L. Gorno-Tempini1 1 University of California San Francisco, Memory and Aging Center, San Francisco, USA 2 Temple University, Department of Communication Sciences and Disorders, Philadelphia, USA 3 San Raffaele Scientific Institute, Milan, Italy 4 University of Texas at Austin, Communication Sciences and Disorders, Austin, USA 5 University of Arizona, Department of Speech, Language, and Hearing Sciences, Tuscon, USA 6 University of Pennsylvania, Philadelphia, USA Our objective was to characterize the neurological, cognitive and neuroimaging characteristics, at initial presentation and at 1-year follow-up, and identify features that may aid in predicting underlying pathology in patients with non-fluent/agrammatic primary progressive aphasia (nfvPPA) in whom either progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) was eventually confirmed at autopsy. Patients were evaluated as part of a prospective, longitudinal research study between 2002 and 2014. Patients were included if they had a clinical diagnosis of nfvPPA, availability of speech, language, and cognitive testing for at least one evaluation, magnetic resonance imaging within 6 months of initial evaluation, and a postmortem pathological diagnosis of PSP or CBD. Clinical, cognitive, and neuroimaging data were analyzed to characterize the whole nfvPPA-4R tau group and identify differences between nfvPPA-PSP and nfvPPA-CBD at presentation and longitudinally. Motor speech impairment and left frontal white matter atrophy were the most prominent common features. At presentation, dysarthria, depression and relatively selective white matter atrophy were typical of nfvPPA-PSP, while greater grey matter atrophy and a trend for greater sentence comprehension deficits were found in nfvPPA-CBD. At 1 year follow-up, we observed no significant differences in any speech or language measures. Furthermore, atrophy in PSP progressed within the subcortical/brainstem motor system generating greater oculomotor deficits and swallowing difficulty, while in CBD, it spread anteriorly in prefrontal regions consistent with their greater working memory impairment and development of behavioral


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symptoms. We conclude that in patients presenting with nfvPPA, presence of early severe dysarthria, relatively selective white matter atrophy at presentation and greater rate of change in the brainstem measured by longitudinal imaging may be useful for differentiating underlying PSP from CBD pathology during life.

P261 Grammatical dissociation in a primary progressive aphasia patient: a prospective assessment G. Borovinsky1, J. Ferrari1, N. Pontello1, J. P. Barreyro1, T. Torralva1, F. Manes1, M. Martinez-Cuiti~ no1 1 Institute of Cognitive Neurology, Buenos Aires, Argentina Primary Progressive Aphasia (PPA) is a neurodegenerative disorder which affects patient’s linguistic skills since the beginning of the disease. Recent studies divided the PPA in three variants: nonfluent (PPA-nfv), semantic (PPA-sv) and logopenic (PPA-lv). The impairment of the different grammatical categories in each of these variants is a current research topic. For example, some studies showed that patients with PPA-sv had better performance with verbs than nouns. In PPA-nfv patients there is an inverse processing (Kave et al., 2007; Bird et al., 2000; Hillis et al., 2004). However, other studies failed to find a correlation between PPA subtype and grammaticalprocessing (Rhee et al., 2001; Marcotte et al., 2014.). The goal of this research is to describe a longitudinal grammatical performance of a PPA-sv patient to identify possible differences in comprehension and production of verbs and The patient was evaluated twice during 16 months with the following tests: Boston naming test (nouns), the picture naming of the Aphasia Assemment Battery (AAB) (verbs); Comprehension Tasks of nouns and verbs (BEA). A Chi Square for two related samples (McNemar) was performed to compare the performance in these two moments. The results showed a decrease in performance only in nouns. Both tasks (noun production and comprehension) showed a worst performance. However, the differences were only significant in the Boston Naming Test (X2 = 33.03; p = 0.000) No differences were found in production and comprehension of verbs between the two assessments. The longitudinal evaluation of PPA-sv patient showed a worst performance in noun production, while the comprehension did not decrease significantly. Both comprehension and production of verbs remained stable during this period. This results accords with the possibility of a grammatical dissociation in PPA-sv but more research is needed to understand the physiopathology of these findings.

P262 Concreteness effect in a semantic variant of primary progressive aphasia patient: semantic processing and neuroanatomic areas G. Borovinsky1, J. Ferrari1, N. Pontello1, T. Torralva2, no1 F. Manes1, M. Martinez-Cuiti~ 1 Institute of Cognitive Neurology, Buenos Aires, Argentina 2 Institute of Cognitive neurology, Neuropsychology, Buenos Aires, Argentina Semantic variant Primary Progressive Aphasia (sv-PPA) is characterized by a progressive impairment of conceptual knowledge. In sv-PPA, as well as in control subjects, there is a concreteness effect (more severe impairment in abstract words). However, some

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research has shown a reversal of this standard effect in these patients. Neuroanatomic studies with fMRI and PET showed the different areas that process concrete and abstract concepts in control subjects. Abstract concepts elicited greater activity in the left inferior frontal gyrus and the left middle temporal gyrus compared to concrete concepts. Concrete concepts activated the left posterior cingulate, precuneus, fusiform gyrus and parahippocampal gyrus. The aim of this study was to evaluate abstract and concrete concepts in a patient with sv-PPA and correlate the results with the neuroimaging in a visual-cualitative way. For this purpose we asked the patient to perform a synonym judgment task (SJT) including nouns and verbs manipulating imageability (concrete and abstract words). We assessed a right handed 76-year-old woman, with 7 years of education and 2 years and a half of disease evolution. The brain MRI showed a bilateral temporal polar atrophy (with atrophy of the temporal middle gyrus). The atrophy increased compared to the prior MRI from 3 years before. Regarding the performance of the SJT, we performed an analysis using chi squared test to identify the differences between concretes and abstracts concepts. The results showed a significant concrete effect (X2(1) = 5.192; p < 0.05). These results agree with previous studies regarding that there is not a reversal concreteness effect in sv-PPA. Also the neuroanatomic regions affected could explain the abstract concepts deficits in this patient and in all patients with sv-APP that have an atrophy in the same regions.

P263 Distinct neural correlates underlying the relative preservation of episodic memory in semantic-variant PPA M. Irish1,2,3, S. Bunk1, S. Tu1,3,4, M. Hornberger3,5, J. Hodges1,3,4, O. Piguet1,3,4 1 Neuroscience Research Australia, Sydney, Australia 2 University of New South Wales, School of Psychology, Sydney, Australia 3 Australian Research Council Centre of Excellence in Cognition and its Disorders, Sydney, Australia 4 University of New South Wales, School of Medical Sciences, Sydney, Australia 5 University of East Anglia, Norwich Medical School, Norwich, Great Britain Relative sparing of episodic memory, particularly for non-verbal material, is commonly observed in the semantic variant of Primary Progressive Aphasia (sv-PPA), in the context of marked conceptual knowledge loss. This observation is somewhat paradoxical given that striking hippocampal atrophy is present in this syndrome. The neural substrates mediating the preservation of episodic memory in sv-PPA remain unclear, yet are important for the development of effective strategies to reinstate or refresh vocabulary in this syndrome. We investigated the neural substrates of episodic memory retrieval in 20 patients with sv-PPA and 21 diseasematched cases of Alzheimer’s disease (AD) and compared their performance to that of 35 age- and education-matched healthy older Controls. Participants completed the Rey Complex Figure and the memory subscale of the Addenbrooke’s Cognitive ExaminationRevised as indices of visual and verbal episodic recall, respectively. Relative to Controls, AD patients showed compromised memory performance on both visual and verbal memory tasks. In contrast, memory deficits in sv-PPA were modality-specific occurring exclusively for conceptually-loaded material. Controlling for



semantic processing ameliorated these deficits in sv-PPA, while memory impairments persisted in AD. Voxel-based morphometry analyses revealed significant overlap in the neural correlates of verbal episodic memory in AD and sv-PPA with predominantly anteromedial regions, including the bilateral hippocampus, strongly implicated. Controlling for semantic processing negated this effect in sv-PPA, however, a distributed network of frontal, medial temporal, and parietal regions was implicated in AD. Our findings corroborate the view that episodic memory deficits in sv-PPA arise very largely as a consequence of the conceptual loading of traditional tasks. Functional integrity of frontal and parietal regions likely enables new learning to occur in sv-PPA in the face of significant hippocampal and anteromedial temporal lobe pathology.

P264 Focal temporal pole atrophy and network degeneration in semantic variant primary progressive aphasia J. Collins1,2, V. Montal3, M. L. Gorno-Tempini4, B. Dickerson1,2 1 Massachusetts General Hospital, Neurology, Charlestown, USA 2 Harvard Medical School, Charlestown, USA 3 Universitat Autonoma de Barcelona, Neurology, Barcelona, Spain 4 University of California at San Francisco, Neurology, San Francisco, USA The Semantic Variant of Primary Progressive Aphasia (svPPA) is a devastating neurodegenerative disease characterized by the progressive loss of semantic memory. Despite a wealth of neuroimaging research that has associated svPPA with a distributed pattern of cortical atrophy that is most prominent in the left anterior temporal lobe, there is little consensus regarding which region within this heterogeneous structure is most damaged, which may indicate the putative origin of neurodegeneration. In this study, we localized the most consistent region of atrophy in svPPA using cortical thickness analysis and surface-based inter-subject registration in two independent patient samples. Across both samples the point of maximal cortical atrophy was located in same region of the left dorsolateral temporal pole. Individual subject analyses localized the point of maximal atrophy for 100% of patients in both svPPA samples to the same temporopolar region. Using resting state functional connectivity (rs-fcMRI) we showed that the focal atrophy point anchored a largescale network in healthy young adults that closely resembled the distributed atrophy pattern in svPPA and included several brain regions that are commonly implicated in semantic memory. In both patient samples, the magnitude of atrophy within a brain region was predicted by that region’s strength of functional connectivity to the focal atrophy point in healthy adults. These findings suggest that cortical atrophy in svPPA may follow connectional pathways within a large-scale semantic network that converges on the temporal pole.

P265 Limited abstract word processing in behavioral variant frontotemporal degeneration K. Cousins1, S. Ash1, M. Grossman1 1 University of Pennsylvania, Philadelphia, USA Patients with behavioral variant Frontotemporal Degeneration (bvFTD) are typified by profound changes to behavior and personality. By comparison, their language and speech production is

preserved relative to patients with the temporal variant FTD. However, traditional language measures, such as visual confrontation naming, might lack sufficient sensitivity to detect subtle language impairments in bvFTD; extensive disease to the frontal lobe in bvFTD often includes areas implicated in semantic selection and the processing of abstract words. Here, we investigate how abstract word processing is affected by atrophy to these non-canonical language processing regions in the frontal lobe. We examine noun production in non-aphasic bvFTD patients using semi-structured speech samples elicited by Cookie Theft picture descriptions, and we relate performance to areas of significant grey matter atrophy. Concreteness ratings for nouns produced were obtained based on published norms. Speech samples from bvFTD (n = 42) and control subjects (n = 32) contained an equivalent proportion of nouns. bvFTD patients produced a significantly smaller proportion of abstract nouns (p < 0.001), and the average noun concreteness rating was significantly higher than for controls (p < 0.001). Regression analyses related this reduced concreteness to grey matter atrophy of the left inferior frontal gyrus and the left and right caudate. These results suggest that frontal lobe degeneration can impair abstract word processing in non-aphasic bvFTD patients.

P266 Patterns of hippocampal atrophy and memory loss among language subtypes of Frontotemporal dementia and Alzheimer’s disease J. Pillai1, A. Bonner-Jackson1, M. Parsons1, J. Leverenz1 1 Cleveland Clinic, Neurology, Cleveland, USA Background: Right and left temporal variants of frontotemporal dementia (tvFTD) have been associated with behavioral and language subtypes. The nature of memory loss noted in the language subtypes of tvFTD has not been well characterized. Methods: In this case series, we report the neuropsychological, MRI brain volumetric analysis, FDG PET brain and Ab,sau and psau cerebrospinal fluid biomarker characteristics of right temporal language subtype of tvFTD (n = 3) in comparison to left temporal language subtype of tvFTD (semantic dementia, n = 3), progressive nonfluent aphasia (PNFA, n = 5), logopenic variant of Alzheimer’s disease (LPA, n = 4) and classical AD (cAD, n = 10). Results: The right tvFTD language subtype had significant deficits specifically in learning and recall of non-verbal information, as well as word finding difficulty and moderate naming impairments, while the left tvFTD language subtype had relatively preserved learning and recall of non-verbal information, but deficits in verbal memory, phonemic and semantic verbal fluency, and verbal abstraction, as well as more severe deficits in naming. In the PNFA, memory in both verbal and non-verbal domains was largely within normal limits. The severity and nature of memory deficits correlated with asymmetrical right hippocampal atrophy in right tvFTD, asymmetrical left hippocampal atrophy in left tvFTD and relatively preserved hippocampal volumes in PNFA. The memory profiles for cAD showed significant deficits in both verbal and nonverbal memory and corresponding symmetrical hippocampal atrophy, but the LPA subtype of AD had minimal hippocampal atrophy compared to age norms but significant learning deficits impacting delayed recall assessment. Conclusions: We observed a pattern of non-verbal and verbal memory domain impairments across right and left tvFTD, LPA and cAD that closely correlated with the corresponding regional


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hippocampal volume loss. Specifically, right tvFTD was associated with non-verbal memory deficits that related to asymmetric right hippocampal predominant atrophy. Further study of these patient phenotypes will be needed to confirm each of the expected underling pathologies (i.e., TDP43opathy, tauopathy, or Alzheimer’s pathology).

P267 Transcranial direct current stimulation as a potential therapy for symptoms of Primary Progressive Aphasia N. White1, F. Gervits1, S. Ash1, H. B. Coslett1, R. Hamilton1, M. Grossman1 1 University of Pennsylvania, Neurology, Philadelphia, USA Primary Progressive Aphasia (PPA) is a neurodegenerative condition characterized by insidious irreversible loss of language abilities. Prior studies suggest that transcranial direct current stimulation (tDCS) directed toward language areas of the brain may help to ameliorate symptoms of PPA, but have only focused on a narrow range of language deficits. This sham-controlled study aimed to assess whether tDCS may be used to treat a variety of PPA-related language difficulties. Participants were recruited from the Penn Frontotemporal Dementia Center to receive 10 consecutive days of both real and sham tDCS (counter-balanced, full-crossover design; participants na€ıve to stimulation condition). A battery of language tests was administered at baseline, immediately post-tDCS (real and sham), and 6 weeks and twelve weeks following stimulation. The language battery included the Boston Naming Test (BNT), a measure of ability to read, write and repeat sentences and lists of words (from the NACC-UDS FTLD Module), Pyramids and Palm Trees (PPT; words and picture categorization), a sentence-picture matching test of grammatical comprehension (L-TROG Short), FAS Verbal Fluency and Category Fluency assessment. Data for each battery item for participants (n = 6) were blind-coded and submitted to linear mixedeffects analysis to assess whether real and sham tDCS are associated with changes in performance relative to baseline. All participants tolerated both real and sham tDCS well and no side effects were observed. Real tDCS was associated with a marginally significant increase in performance on measures of sentence writing and the picture version of the PPT. Promising trends were also demonstrated for BNT and L-TROG Short performance. In reading from a list of words, performance accuracy tended to increase following sham tDCS. Real tDCS may improve language performance on some measures but not others. There is no evidence to suggest that sham tDCS improves language performance relative to baseline, with the possible exception of word reading.

P268 Neural network underlying abnormal syntax processing in primary progressive aphasia: evidence from resting state functional magnetic resonance imaging B. Bonakdarpour1, A. Wang1, E. Rogalski1, R. Hurley1, M. Mesulam1 1 Northwestern University Feinberg School of Medicine, Cognitive Neurology and Alzheimer Disease Center, Chicago, USA

Structural imaging has shown that agrammatism in primary progressive aphasia (PPA) is associated with atrophy within the dorsal language network, but this has not been well investigated at a physiologic level. In this study, we investigated the relationship between connectivity of the dorsal language network regions and sentence production in PPA using resting state fMRI. Forty eight persons with PPA who were examined scored 14.65 + - 6.64 (/30) on a combined test of grammatical sentence production (Northwestern Assessment of Verbs and Sentences, [NAVS]; and Northwestern Anagram Test, [NAT]). We investigated strength of resting state functional connectivity (RSFC) between two language nodes: the supramarginal gyrus (SMG) and pars opercularis (PO; a part of Broca’s area) and with a sensorimotor (SM) node which is positioned between them. In addition, we probed the strength of RSFC between the contralateral PO and SMG nodes as a control network. Connectivity between PO and SMG in the left hemisphere was found to correlate significantly with grammar scores (r = 0.409, p = 0.0088). In contrast, the RSFC between right POSMG and the RSFC between PO/SMG nodes and the SM node did not show significant correlation, confirming specificity of our finding. Our physiological finding adds to a growing literature that supports involvement of a network (containing both PO and SMG) in syntax processing. By providing targets for intervention, these results may be useful for guiding therapeutic neuromodulation of the language network.

P269 Recognizing primary progressive aphasia between frontotemporal dementia variants: denomination mistakes like a tool for differential diagnosis N. Rodriguez1, M. Mayorga Sierra1, D. L. Matallana Eslava1 1 Pontifica Universidad Javeriana, Bogot a, Colombia Frontotemporal dementia (FTD) affects different cortical areas in the brain. This study aim to analyze, in all FTD variants, naming errors in a visual denomination task (48 Snodgrass figures). All patients underwent a structured clinical interview, a full neurological, psychiatry and neuropsychological examination as well as neuroimaging and genetic data to support a consensus clinical diagnosis. From a Colombian cohort of 153 FTD patients, naming errors of 42 patients are reported here: 23 with behavioral variant (BV), 12 with primary progressive aphasia (PPA) and 7 with semantic dementia (SD); all subjects had more than 5 years of education and ages were between 48 and 86 years old. Results show qualitative discrepancies between variants, with high rate of semantic errors in SD group and distinct pattern when living (L) versus non-living (N-L) images where compared (in L images, PPA showed more anomic responses while BV had a high rate visualsemantic errors). We found a response pattern for some denominations errors items than can provide clinic information for differential diagnosis process. In conclusion, the type of errors can differentiate FTD patients by variants PPA, SD and BV when analyzing a type of errors.

Processing of syntax relies on a dorsal perisylvian language network which includes, but is not limited to the Broca’s area.

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P270 Principal components analysis of neuropsychological features in nonfluent and logopenic variant PPA J. Harris1,2, J. Adams1,2, M. Jones1,2, A. Richardson1,2, D. Neary1,2, J. Snowden1,2, J. Thompson1,2 1 Salford Royal NHS Foundation Trust, Cerebral Function Unit, Manchester, Great Britain 2 The University of Manchester, Institute of Brain, Behaviour and Mental Health, Manchester, Great Britain We aimed to delineate core factors that underlie language symptoms in logopenic variant primary progressive aphasia (lvPPA), nonfluent variant primary progressive aphasia (nfvPPA) and Alzheimer’s disease (AD) affecting multiple cognitive domains, and to determine the utility of these factors for clinical diagnosis.41 patients with PPA and multi-domain AD together with 19 agematched controls carried out a large battery of working memory and language tests. Patients’ test scores on variables with the largest effect sizes compared to controls were entered into a principal components analysis (PCA) with varimax rotation. Linear discriminant analysis (LDA) was used to determine how well factor scores could predict clinical diagnosis. Thirty-six patients had sufficient data for the PCA (10 nfvPPA, 11 lvPPA, 2 unclassified PPA and 13 multi-domain AD). The PCA revealed a three-factor solution, which were interpreted as reflecting: ‘phonology’ (verbal working memory, reading and naming), ‘grammar and speech production’, and ‘visual working memory and calculation’. The LDA revealed that only the factors associated with ‘grammar and speech production’ and ‘visual working memory and calculation’ were useful at classifying the three groups. These factors were excellent at classifying nfvPPA but less good at differentiating lvPPA from multi-domain AD.In conclusion, a combination of tests of grammar, speech production and visual working memory is useful in classifying lvPPA and nfvPPA. It is difficult to distinguish multidomain AD from lvPPA on these measures, suggesting a similar profile of language and working memory disturbance in patients with expected underlying AD pathology.

P271 Characterising primary progressive aphasia - a neuropsychological study J. Harris1,2, J. Adams1,2, M. Jones1,2, A. Richardson1,2, D. Neary1,2, J. Snowden1,2, J. Thompson1,2 1 Salford Royal NHS Foundation Trust, Cerebral Function Unit, Manchester, Great Britain 2 The University of Manchester, Institute of Brain, Behaviour and Mental Health, Manchester, Great Britain Primary progressive aphasia (PPA) refers to a group of heterogeneous neurodegenerative language disorders. We aimed to further characterise the neuropsychological and behavioural profile of nonfluent variant PPA (nfvPPA) and logopenic variant PPA (lvPPA), and to compare these groups to patients with Alzheimer’s disease (AD) and semantic dementia (SD). 48 patients were recruited for the study with diagnoses of lvPPA (13), nfvPPA (12), SD (9) and multi-domain AD (14), together with 19 healthy controls. All participants carried out a comprehensive neuropsychological battery focusing on tests of language, working memory and praxis. A behavioural questionnaire was given to carers/ relatives. Relative to the other patient groups, impairments were

predominantly apparent on tests tapping speech production and grammaticality in nfvPPA and single word comprehension in svPPA.The nfvPPA group exhibited considerable apraxia beyond the realms of apraxia of speech. Behavioural changes were frequently reported in SD and nfvPPA. The lvPPA group did not exhibit a characteristic profile of impairment that allowed differentiation from nfvPPA or AD. Indeed, some features included in diagnostic criteria for lvPPA occurred more frequently in nfvPPA.Our findings suggestthat lvPPA may be part of the AD spectrum, since patients with multi-domain AD and lvPPA performed similarly on tests of language and working memory. Phonological errors and impaired repetition are accepted as characteristic features of lvPPA, yet patients with nfvPPA were at least as impaired as lvPPA patients in tests assessing these features. This suggests that current core features of lvPPA lack diagnostic specificity.

P272 MRI in nonfluent and logopenic variant PPA: ASl, DTI and VBM J. Harris1,2, J. Adams1,2, J. Thompson1,2, L. Parkes3, S. Carter3, A. Richardson1,3, D. Neary1,3, J. Snowden1,3, M. Jones1,3 1 Salford Royal NHS Foundation Trust, Cerebral Function Unit, Manchester, Great Britain 2 The University of Manchester, Institute of Brain, Behaviour and Mental Health, Manchester, Great Britain 3 The University of Manchester, Manchester, Great Britain We aimed to explore differences between nonfluent (nfvPPA) and logopenic variant primary progressive aphasia (lvPPA) in grey matter volume, structural connectivity and cerebral perfusion. We also aimed to determine whether cognitive measures correlated with neuroimaging metrics. 17 participants (8 nfvPPA and 9 lvPPA) underwent neuropsychological assessment with tests of visual and verbal working memory, syntax production and buccofacial praxis. The participants had 3T MRI scans with volumetric T1, diffusion tensor imaging (DTI) and arterial spin labelling (ASL) protocols. We used control neuroimaging data from 10 participants collected in previous studies. Voxel-wise analysis revealed regional changes in grey matter structure, cerebral perfusion (CBF), arterial arrival time (AAT) and DTI metrics in both PPA groups relative to controls. Both groups showed a preponderance of left sided temporal changes but in nfvPPA changes were more anterior, affecting the left frontal regions too. Left sided dorsal and ventral white matter tracts were affected in both groups, albeit with more anterior tract involvement in nfvPPA and more posterior tract involvement in lvPPA. Grey matter volume, CBF, AAT and axial diffusivity in temporal regions were associated with measures of working memory. CBF in superior frontal regions including the supplementary motor area was associated with grammar production. NfvPPA and lvPPA are associated with differing yet overlapping patterns of atrophy, perfusion and white matter tract abnormalities. The significant overlap in MRI changes helps to explain why the syndromes can be hard to differentiate clinically. Heterogeneity within these groups may be as important as the differences between groups.


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P273 Different biomarkers of neurodegeneration in the CSF distinguishing progressive non-fluent aphasia from other frontotemporal dementias P. Koertvelyessy1,2, J. Prudlo3,4, H.-J. Heinze1,2, D. Bittner1,2 1 Universityhospital Magdeburg, Department of Neurology, Magdeburg, Germany 2 German Center for Neurodegenerative Diseases, Magdeburg, Germany 3 Universityhospital Rostock, Department od Neurology, Rostock, Germany 4 German Center for Neurodegenerative Diseases, Rostock, Germany Fronto-temporal dementia (FTD) comprises of different clinical syndromes mediated by different neuropathological mechanisms, including tau and progranulin (PGRN), thus forming very heterogeneous groups. Recently, FTD with progressive non-fluent aphasia (PNFA) has been histopathologically proven to be caused predominantly by a tau-mediated pathomechanism. We addressed the question whether common CSF biomarkers of neurodegeneration (phospho-tau, total-tau, beta-amyloid 1-40 and 1-42, Neurofilament light chain (NfL) and progranulin) mirror the different neuropathological mechanisms in a cohort of 58 clinically confirmed FTDpatients including all types of FTDs (PNFA and nonPNFA such as semantic dementia and behavioral variant FTD) diagnosed at the DZNE sites in Rostock and Magdeburg. A control group of 58 neurologically healthy patients and another group of 18 patients with progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS) were included for comparisons. There were no age or gender differences between the groups. We excluded patients with known PGRN-mutations. Our results confirm findings by other groups showing a highly significant difference between Neurofilament light chain level in FTDs overall compared to controls with other neurological diseases (p < 0.001). The comparison of the biomarkers in PNFA vs. nonPNFA showed no significant differences for pTau (p = 0.952), for Total-Tau (p = 0.748), for AmyloidBeta1-42 (p = 0.214) and for Neurofilament light chain (p = 0.91). There was a highly significant result for PGRN (p = 0.01) meaning that PGRN was lower in patients suffering from a semantic dementia or behavioral variant FTD. We conclude that via CSF-PGRN a difference between the taupathology-mediated PNFA and nonPNFA could be revealed. Further studies on FTD and CSF-Progranulin should exclude PNFA patients.

P274 Quantification of motor speech in primary progressive aphasia and frontotemporal dementia M. Poole1,2, A. Brodtmann3,2, D. Darby3,2, A. Vogel1,2,4 1 The University of Melbourne, Centre for Neuroscience of Speech, Parkville, Australia 2 Eastern Cognitive Disorders Clinic, Melbourne, Australia 3 Florey Institute of Neuroscience and Mental Health, Melbourne, Australia 4 University of T€ubingen, Hertie Institute for Clinical Brain Research, T€ubingen, Germany Primary progressive aphasias are a group of language onset dementias which are classified into the semantic (svPPA), nonfluent (nfvPPA) and logopenic (lvPPA) variants. Each variant presents with characteristic impairments of language and speech. Researchers

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and clinicians usually assess speech with listener-based rating scales, which pose a challenge for identifying subtle changes to speech. Objective measures of speech may therefore assist with the identification and classification of speech impairment in PPA. In this study, we assessed the speech of 45 people with PPA or behavioural variant FTD (8 svPPA, 5 nfvPPA, 9 lvPPA, 23 bvFTD) and 24 healthy controls. We used both subjective listener-based speech ratings, as well as acoustic measures. Speech was objectively quantified with measures of lexical stress (pairwise variability index [PVI]), vowel production (vowel articulation index [VAI]), timing (speech rate, pause duration, and variability of pause time while reading) and diadochokinetic (DDK) speech rate (repetitions of ‘pataka’). Lexical stress patterns (PVI) were observed to be impaired in both nfvPPA (p = 0.020) and bvFTD (p = 0.016) compared to controls. Disruptions to speech rate were observed in all PPA subtypes and bvFTD (p < 0.0125). DDK rate was found to be reduced in all pathological groups (p < 0.001), and perturbation of DDK period differentiated nfvPPA from the other PPA variants (p < 0.034). Findings add to the documentation of speech production in PPA and FTD by establishing acoustic variances from the healthy population. Two measures (PVI and DDK) demonstrated capacity to differentiate nfvPPA from other PPA subtypes and may assist in clinical classification of PPA subtype.

P275 Apraxia profiles - A novel cognitive marker for differentiating clinical variants of FTLD and AD A. Johnen1, S. Reul1, T. Duning1, H. Lohmann1 1 University Clinic Muenster, Department of Neurology, Muenster, Germany Apraxia is a common and early symptom of neurodegenerative diseases and may contribute to early diagnosis of Alzheimer’s dementia (AD) and frontotemporal lobar degeneration (FTLD). Despite that, it is rarely investigated in clinical practice and standardized tests are lacking. Previously, we introduced the Dementia Apraxia Test (DATE) that revealed disease-specific profiles of apraxia in behavioural variant frontotemporal dementia (bvFTD) and AD, supporting differential diagnoses of these dementia syndromes (Johnen et al., 2015). In the current study, we explored patterns of praxis disturbance in language variants of FTLD. Patients who fulfil current diagnostic criteria for semantic variant primary-progressive aphasia (svPPA; N = 16), non-fluent primaryprogressive aphasia (nfPPA; N = 9), bvFTD (N = 25), AD (N = 32) and healthy elderly controls (HC; N = 34) were examined. We employed the DATE composing of five praxis domains which place varying demands on spatial and semantic processing. To detect group-specific praxis profiles, a MANOVA and subsequent stepwise discriminant function analysis was carried out. All four patient groups were disturbed in each praxis domain compared with HC, validating apraxia as a relevant cognitive marker in neurodegenerative diseases. We moreover found characteristic profiles of impairment for each dementia subtype: svPPA showed pronounced disturbances in semantically meaningful communicative gestures (emblems), nfPPA were globally impaired including speech apraxia, bvFTD showed unique deficits in facial (emotional) imitation and patients with AD were distinctively impaired in imitation of spatially complex limb postures. A classification of all four dementia subtypes was feasible only using the DATE.



Screening for praxis impairments using the DATE is a timeefficient method to delineate different clinical variants of FTLD and AD and facilitates differential diagnoses of these dementia syndromes. Praxis assessment seems to tap into a range of cognitive dysfunctions of neurodegenerative diseases, reflecting core deficits within the respective dementia syndrome (e.g., visuo-spatial, linguistic-semantic, social-affective), and should thus be employed in routine neuropsychological diagnostic.

P276 PPA interventions with impact: Making everyone happy R. Jokel1 1 Rotman Research Institute, Toronto, Canada Non-pharmacological interventions in Primary Progressive Aphasia (PPA) are rare and typically focused on functional communication or relearning lost vocabulary. They address the most immediate needs of Individuals with PPA. Through a number of different interventions designed for our PPA patients, we arrived at one that seems optimal for both patients and their caregivers. This unique 10-week program included elements of language therapy, education, and counselling and was offered in a group setting, which, based on published studies, appears to be a very successful and ecologically sound approach. In view of the constant need to advocate for funding, the program is also economically attractive. Both the form and content of each session were shaped by an experienced speech-language pathologist in collaboration with patients and their family members. We will describe how each aspect of the intervention naturally fits with the goals of the program and present favourable changes on all outcome measures.

P277 Artificial grammar learning in vascular and progressive non-fluent aphasia identifies domain general impairments T. E. Cope1, B. Wilson2, H. Robson3, L. Dean2, M. Grube2, K. Patterson1,4, T. D. Griffiths2, J. B. Rowe1,4, C. Petkov2 1 University of Cambridge, Clinical Neurosciences, Cambridge, Great Britain 2 Newcastle University, Institute of Neuroscience, Newcastle, Great Britain 3 University of Reading, School of Psychology and Clinical Language Sciences, Reading, Great Britain 4 Medical Research Council Cognition and Brain Sciences Unit, Cambridge, Great Britain There is debate about the extent to which the grammatical abnormalities in non-fluent aphasia reflect language specific or domain general impairments. 10 patients with nonfluent/agrammatic variant primary progressive aphasia, 12 with non-fluent aphasia due to stroke and 11 matched controls were tested on their ability to implicitly learn an artificial grammar comprised of either consonant-vowel-consonant (CVC) or tone sweep auditory tokens. The grammar structure was parametrically varied to create easy (linear), medium (configurational) and hard (hierarchical) sequence ordering relationships. In a final experiment, ability to detect oddball CVC tokens was evaluated. Neither patient group was poorer than controls at detecting oddball tokens. For the CVC language, discriminability followed the

expected pattern for all groups, being progressively poorer for increasingly difficult rule violations. Both patient groups were impaired relative to controls, but the magnitude of this impairment did not vary by rule complexity. All groups improved across repeated exposure-test cycles, demonstrating ongoing implicit learning from exposure. For tone based sequences, controls again outperformed patients, but here discriminability consistently varied by individual sequence rather than by rule complexity. Hierarchical cluster analysis demonstrated that learning profiles were linked by task but not by group, confirming that this domain separation was maintained in both patient groups. Taken together, these results suggest: 1) vascular and neurodegenerative non-fluent patients perform similarly on implicit learning of artificial grammar, 2) they are impaired at easy as well as difficult grammatical structures, 3) implicit grammar learning is domain specific, and 4) this specificity is maintained even in the presence of left frontal pathology.

P278 PET-florbetapir findings in primary progressive aphasia A. Villarejo1, S. Llamas-Velasco1, A. Gomez-Grande1, andez1, V. Puertas-Martın1, P. Sarandeses-Fern M. Gonzalez-S anchez1, S. Ruiz-Solis1, P. Pilkington1, D. A. P erez-Martınez1, A. Herrero-San Martın1 1 Hospital Universitario Doce de Octubre, Neurology, Madrid, Spain Introduction: PPA is considered an heterogeneous syndrome, with different clinical subtypes and neuropathological causes. Novel PET biomarkers may help to predict the underlying neuropathology, but many aspects remain unclear. We studied the relationship between amyloid PET status and PPA clinical variant in a clinical series of PPA patients. Methods: Patients with PPA were assesed over a 2-year period in a specialist centre, and classified based on language testing and the International Consensus Criteria as non-fluent/agrammatic (nfvPPA), semantic (svPPA), logopenic variant (lvPPA) or as unclassifiable (uPPA). All patient underwent a Florbetapir (18-F) PET scan, and images were analyzed by two nuclear medicine physicians, using a previously validated binary visual reading method. Results: Twenty-three PPA patients were included (14 women, mean age 68.8 8.3 years; range: 54-83 years). Overall, 12/23 were amyloid positive: 0/2 (0%) nfvPPA, 0/4 (0%) svPPA, 9/13 (69%) lvPPA and 3/4 (75%) uPPA. Conclusions: Amyloid PET may help to identify the underlying neuropathology in PPA. It can be specially useful in lvPPA and uPPA, that are frequently, but not always, associated with Alzheimer0 s pathology.

P279 Developing an international graded naming task O. Billette1, Z. Cs efalvay1, E. Tute1, P. Nestor1 1 DZNE, Magdeburg, Germany Naming tests are a cornerstone of language assessment and simple to administer. They are, however, prone to cultural and regional biases which undesirable in international studies. Ceiling


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effects also limit utility in longitudinal studies. The aim of this project is to create an international graded naming task to monitor change in naming ability over time in different pathologies including Primary progressive aphasia (PPA). A battery of 230 pictures was first compiled with a view to creating graded difficulty in healthy elders that would avoid ceiling effects while avoiding floor-effects in patients. Items were deliberately chosen to be as universal and free of cultural and geographical biases as possible. N = 50 German healthy controls (HC) were recruited to rate the naming difficulty of each item. Preliminary screening identified that 111 of the items covered the complete range of difficulty: in German HC performance ranged from items named correctly by 100% of subjects down to 3%. The 111 items were administered to further N = 38 German HC, N = 70 German patients (21 PPA, 15 AD, 20 MCI and 14 SCI) as well N = 26 Slovak HC to test the internationality of our results. 26 items named by 100% of the healthy controls showed a range of performance in patients. Moreover patients showed inferior naming performance compared to HC. PPA patients showed the worst performance, followed by AD and MCI. SCI subjects performed normally. Finally comparing scores in the German and Slovak HC samples confirmed that selected items covered the complete range of difficulty. Of the 111 items, 3 did not work in the Slovak sample and were, therefore, removed. The results suggest an internationally validated graded naming task can be developed to facilitate international language related trials. The findings will need to be strengthened by testing the items in further languages.

P280 Classifying primary progressive aphasias individually with support vector machine approaches in MRI data S. Bisenius1, K. Mueller1, J. Diehl-Schmid2, K. Fassbender3, F. Jessen4, J. Kassubek5, J. Kornhuber6, A. Schneider7, K. Stuke1, A. Danek8, M. Otto5, M. L. Schroeter1, F. Study Group Germany5 1 Max Planck Institute for Human Cognitive and Brain Sciences & Clinic for Cognitive Neurology, University Leipzig, Leipzig, Germany 2 Clinic and Polyclinic for Psychiatry and Psychotherapy, Technical University of Munich, Munich, Germany 3 Clinic and Polyclinic for Neurology, Saarland University Homburg, Homburg, Germany 4 Clinic and Polyclinic for Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany 5 Clinic and Polyclinic for Neurology, University of Ulm, Ulm, Germany 6 Clinic for Psychiatry and Psychotherapy, University of Erlangen, Erlangen, Germany 7 Clinic for Psychiatry and Psychotherapy, University of G€ ottingen, G€ottingen, Germany 8 Clinic of Neurology, Ludwig Maximilian University of Munich, Munich, Germany Primary progressive aphasia (PPA) encompasses the three subtypes progressive nonfluent aphasia (PNFA), semantic dementia (SD), and logopenic progressive aphasia (LPA), which are each characterized by distinct language difficulties and specific patterns of atrophy (Gorno-Tempini et al. Neurology 2011;76 1006–1014). It is often difficult to accurately evaluate atrophy in magnetic resonance imaging (MRI) scans of individual subjects by eye.

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Therefore, it might be highly interesting to support the clinical diagnosis of PPA using automated algorithms on MRI scans. Here, we investigated the utility of whole-brain and regions-of-interest based support vector machine (SVM) classification of grey matter probability maps to discriminate the subtypes of primary progressive aphasia from healthy controls and PNFA from SD. We used structural MRI data and included patients with the three subtypes (16 PNFA, 17 SD, and 11 LPA) from the multi-centric study of the German consortium for frontotemporal lobar degeneration. Cohorts were matched for sample size, age, and gender. SVM classification between the subtypes of primary progressive aphasia and healthy controls showed accuracies ranging from 82%-100%. Interestingly, the regions that contributed the most to the correct classification of patients corresponded to regions that were significantly atrophied in these patients as shown by group comparisons (t-tests, p < 0.05 FWE corrected at cluster-level). For PNFA and SD, the regions-ofinterest based SVM classification between patients and healthy controls showed a similar or even higher accuracy than the wholebrain based approach. The SVM classification between PNFA and SD showed an accuracy of 78% for both (whole-brain and regionsof-interest) approaches. All in all, SVM classification of MRI scans might constitute a useful supporting tool for the diagnosis of primary progressive aphasia in clinical routine.

P281 Electrostimulation effects in the logopenic and non-fluent variants of primary progressive aphasia K. Tsapkini1, T. Chakravarty2, B. Ficek2, K. Webster2, J. Desmond2, C. Onyike3, C. Frangakis4, A. Hillis2 1 Johns Hopkins Medicine, Radiology, Baltimore, USA 2 Johns Hopkins Medicine, Neurology, Baltimore, USA 3 Johns Hopkins Medicine, Psychiatry and Behavioral Sciences, Baltimore, USA 4 Johns Hopkins School of Public Health, Baltimore, USA Primary progressive aphasia (PPA) is characterized by deterioration in language abilities with distinct regions of progressive cortical atrophy. Anodal transcranial direct current stimulation (tDCS) over the frontal and prefrontal cortex combined with language therapy has been shown to improve spelling and naming (Cotelli et al. Dement Geriatr Cogn Disord 2012; 34 164–65; Tsapkini et al. Aphasiology; 2014; 28(8–9) 1112–30). We tested the hypothesis that tDCS effects differ for logopenic versus non-fluent PPA. Fourteen subjects, (7 nfvPPA, 7 lvPPA), received tDCS and sham treatments coupled with language therapy for 10–15 sessions in a within-subjects crossover design. We targeted the inferior frontal gyrus (IFG) for stimulation as a written language (spelling) area. Subjects were evaluated before, immediately after, and 2 weeks and 2 months post-intervention. In lvPPA participants, tDCS over the left IFG was more beneficial than sham for trained items, and was associated with greater retention at 2-month followup. Also, treatment gains generalized to untrained items and were sustained only in the tDCS condition. In nfvPPA participants, tDCS was not more beneficial than sham for trained items. Furthermore, tDCS improved generalization of treatment to untrained items immediately after and up to 2 weeks post-intervention, but not up 2 months. Our findings validate earlier evidence for generalization and sustained gains for tDCS relative to sham and show that the benefits of tDCS plus language therapy are better sustained and generalized in lvPPA than in nfvPPA. These between-group



differences in treatment effects may reflect contrasting distributions of atrophy and have implications for tDCS interventions.

P282 Verb regularization errors as an analogue for surface dyslexia in semantic dementia in languages with high grapheme-phoneme transparency O. Billette1, D. Preiß1, P. Nestor1 1 DZNE, Magdeburg, Germany Surface dyslexia is a diagnostic feature of semantic dementia (SD) (Gorno-Tempini et al. Neurology 2011; 76 1006–1014). This can be however, difficult to observe in languages with high grapheme-phoneme correspondence such as Italian or German. As an alternative method to reveal the regularization effect that underpins surface dyslexia, we investigated inflectional morphology of verbs in German with two past tense forms, in patients with SD, Alzheimer0 s Disease (AD) or amyloid positive Primary Progressive Aphasia (Aß+PPA). The prediction being that SD would be specifically associated with regularization of irregular verbs. N = 23 Healthy Controls (HC) and 12 patients (N = 4 SD, N = 4 AD, N = 4 Aß+PPA) were given 24 verbs to inflect the German perfect and preterite tenses—12 regular (homologue English example work/worked/have worked) and 12 irregular (homologue English example swim/swam/have swum); for each, 6 were high and 6 low frequency. Participants were given a sentence in present “I work. . ./I swim. . .” followed by two sentences written in a way to elicit the two different past forms. The results of this pilot study showed that the highest proportion of mistakes in inflectional morphology occurred in Aß+PPA, followed by SD, while errors were rare in AD. In Aß+PPA, however, there was a wide range of mistakes (e.g. substituting another verb, verb agreement or tense errors) whereas, as predicted, errors in SD particularly involved regularization of irregular verbs (homologue English example: I swim, I swimmed, I have swimmed) SD patients show specific regularization mistakes that do not feature prominently in Aß+PPA although the latter make a range of other errors. Regularization of irregular verbs offers potential as an analogue to surface dyslexia in languages with high grapheme-phoneme transparency.

P283 Aspects of natural conversation in primary progressive aphasia C. Taylor-Rubin1,2, K. Croot3, E. Power4, S. A. Savage5, J. R. Hodges6, L. Togher4 1 War Memorial Hospital SESLHD, Speech Pathology, Waverley, Sydney, Australia 2 Macquarie University, Cognitive Science, Sydney, Australia 3 University of Sydney, Psychology, Sydney, Australia 4 University of Sydney, Faculty of Health Sciences, Sydney, Australia 5 University of Exeter, Department of Cognitive and Behavioural Neurology, Exeter, Great Britain 6 Neuroscience Research Australia, University of NSW, School of Medical Sciences, Sydney, Australia Primary progressive aphasia (PPA) affects a range of language and cognitive domains that impact on conversation. Little is known about the nature of conversation breakdown in the semantic variant

of PPA (svPPA, also known as semantic dementia). This paper reports on a study which investigated trouble in conversation, how it is repaired, and the success of repair in the conversation of people with svPPA. Dyadic conversations about everyday activities between seven individuals with svPPA and their partners and seven participants in control dyads were video recorded, transcribed and examined. Individuals with svPPA were active participants in conversation, generally taking an equal proportion of turns in conversation. While there was a wide variety of words per turn across the individual participants with svPPA, as a group their output was not sparse. The patterns of trouble and repair observed were unlike the patterns previously reported in non-fluent variant PPA, logopenic variant PPA and Dementia of the Alzheimer’s Type. There was a trend for greater naming impairment to be associated with less successful repair. Finally, in the dyads examined in this study, where one person had svPPA, the contribution of the communication partner appeared to be a critical factor in the success of repair behaviours in conversation. These findings should be considered in planning behavioural interventions with this clinical population and their families to enhance success and satisfaction in conversation. Examining trouble and repair in ten-minute conversations of individuals with svPPA has the potential to enhance assessment and inform clinical practice

P284 Semantic dementia with combined TDP-43 and FUS pathology M. Landqvist Wald€ o1, C. Elfgren1, L. Gustafson1, U. Passant1, A. Frizell Santillo2, E. Englund3 1 Lund University, Geriatric Psychiatry, Department of Clinical Sciences, Lund, Sweden 2 Lund University, Clinical Memory Research Unit, Department of Clinical Sciences, Malm€ o, Sweden 3 Lund University, Division of Oncology and Pathology, Department of Clinical Sciences, Lund, Sweden Semantic dementia (SD) is a progressive neurodegenerative disorder characterised by a gradual loss of semantic memory such as impaired confrontation naming and single word comprehension. Relatively early behavioural changes may also be seen. Imaging showing anterior temporal pathology supports the diagnosis. The majority of SD cases exhibit TDP-43 protein pathology (type C), however, single cases with AD and tau pathology have been described. To our knowledge, FUS pathology has never been described with SD phenotype. On her own initiative, a 58 year old woman attended our clinic with a2 year history of word-finding difficulties. Neuropsychological tests revealed marked anomia and brain imaging showed left anterior temporal pathology. CSF biomarkers were within normal ranges except elevated neurofilament light (NFL). She was diagnosed with SD. Two years later she was still working fulltime as an office secretary. She developed coping strategies such as delegating working tasks and drawing shopping lists. Gradually, behavioural and executive dysfunction appeared. Imaging findings extended to include the frontal lobes. 10 years after onset the behavioural and semantic dementia symptoms had progressed severely and resulted in nursing home care. A marked hypoalgesia was noted. 15 years after onset she died from a heart attack and neuropathology was consistent with FTLD with predominantly left temporal atrophy, but also involvement of the frontal lobes, anterior


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cingulate cortex (ACC), amygdala, basal ganglia, insula and white matter. Immunohistochemistry showed mixed TDP-43 type C and FUS protein pathology. Our study demonstates a case of typical SD that upon neuropathological examination exhibits an unusual pathology, with a combination of FUS and TDP-positive inclusions. To our knowledge, this has not been previously described.

P285 Common and divergent neural correlates of anomia in amnestic and logopenic presentations of Alzheimer’s disease C. Leyton1,2, J. Hodges1, O. Piguet1, K. Ballard1,2 1 Neuroscience Research Australia, Sydney, Australia 2 The University of Sydney, Speech Pathology, Sydney, Australia The majority of logopenic variant primary progressive aphasia (lv-PPA) cases harbour Alzheimer pathology in the brain, suggesting that lv-PPA constitutes an atypical presentation of Alzheimer’s disease (AD). However, even if caused by Alzheimer pathology, clinical manifestations of lv-PPA differ from those observed in typical AD: in lv-PPA, aphasia is the main feature while typical AD is characterised by impaired episodic memory. Anomia or impaired naming, however, is present in both disorders. Whether these AD presentations share anatomical and mechanistic processes of anomia has not been fully investigated. Accordingly, we studied naming performance and its relationship with regions of brain atrophy in 23 typical AD and 22 lv-PPA cases with presumed underlying Alzheimer pathology. Whereas both AD groups displayed some degree of anomia and impaired word comprehension, those deficits were severe in lv-PPA and accompanied by a range of linguistic deficits, comprising phonological substitutions, superordinate semantic paraphasias and abnormal single-word repetition. Analysis of cortical thickness revealed that anomia was correlated with thinning in left superior temporal gyrus in both groups. In typical AD it was also associated with thinning in right inferior temporal regions. The analysis of single-word comprehension in turn evidenced convergent cortical thinning involving both fusiform gyri in typical AD and in lv-PPA. These findings suggest that these common areas of atrophy are involved in the shared semantic deficits of both groups. This evidence shows that anomia in lv-PPA and typical AD results from the involvement at multiple steps of word processing, in particular semantic and lexical retrieval; however, lv-PPA display a more marked involvement spanning phonological processing.

P286 Dissecting neurocognitive mechanisms underpinning sentence-processing deficits in PPA C. Leyton1,2, J. Hodges1, O. Piguet1, K. Ballard1,2 1 Neuroscience Research Australia, Sydney, Australia 2 The University of Sydney, Speech Pathology, Sydney, Australia Production and comprehension of sentences hinges on multiple neurocognitive processes subserved by anatomically segregated cortical regions. Given the distinctive neurolinguistic profiles and distribution of brain atrophy in primary progressive aphasia (PPA), we hypothesised that the involvement of working memory and

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executive functions play a differential role in sentence-processing deficits in each PPA variant. We investigated sentence comprehension and production performances in 44 PPA participants (semantic (svPPA) = 10, nonfluent (nfvPPA) = 16, logopenic (lvPPA) = 18). Tasks of receptive and productive sentence processing demonstrated a group effect determined by the normal performance of svPPA and low performance of lvPPA and nfvPPA; however, the effect on sentence comprehension disappeared when it was covaried by shortterm memory and executive function performances. The analysis of Cookie Theft Scene description revealed that nfvPPA displayed the lowest fluency and number of verbs per utterance, suggesting production of less complex sentence structures and agrammatism. A preliminary imaging analysis evidenced divergent neural correlates of receptive and productive sentence processing, which are partially modified after covarying for verbal short-term memory and executive tasks. These results suggest that sentence processing is a complex task that can be strongly influenced by other neurocognitive processes. Whereas nfvPPA seems to present mainly sentence production deficits linked to agrammatism, lvPPA seems to have mainly receptive sentence processing deficits which are associated to verbal short-term memory and executive function deficits.

P287 Convergent language network involvement in nonsemantic PPA variants C. Leyton1,2, R. Landin-Romero1, F. Kumfor1, J. Burrell1, J. Hodges1, O. Piguet1 1 Neuroscience Research Australia, Sydney, Australia 2 The University of Sydney, Speech Pathology, Sydney, Australia Primary progressive aphasia (PPA) comprises a diverse group of neurodegenerative conditions that gradually destroy the language brain network. Three clinical PPA variants with distinctive linguistic profiles have been recognised. The semantic variant, which has the most robust clinico-pathological correlation, can be readily differentiated from the other PPA variants. In contrast, the nonfluent/ agrammatic (nfvPPA) and logopenic (lvPPA) variants are both characterised by word production deficits, which can make clinical differentiation difficult. Importantly, a correct syndromic diagnosis can suggest a specific underlying pathology, given the association of lvPPA with Alzheimer’s pathology. Here, we investigated 29 nonsemantic cases who underwent baseline amyloid imaging, as well as longitudinal clinical and structural neuroimaging assessments. All cases with high amyloid retention presented with lvPPA, and had more severe naming and semantic deficits at baseline, in association with widespread cortical atrophy, compared to patients with low amyloid burden. Both groups demonstrated equivalent decline in word repetition over time, but naming declined more rapidly in patients with high compared to those with low amyloid retention. Longitudinal analyses of cortical thickness demonstrated that both groups showed greater cortical thinning in the left anterior temporal lobe and left inferior posterior frontal gyrus over time, but high amyloid cases showed more rapid thinning in the left posterior inferior parietal lobe than cases with low amyloid. These findings suggest that although these two non-semantic PPA variants present initially with separate epicentres of atrophy and different patterns of progression, neurodegeneration preferentially spreads throughout the language network resulting in overlapping language deficits in both phenotypes.



P288 Domain specific learning disabilities within atypical neurodenerative diseases primary progressive aphasia and posterior cortical atrophy Z. Miller1, L. Rosenberg2, M. Santos1, M. Stephens1, M. L. Mandelli1, G. Rabinovici1, B. Miller1, M. L. Gorno-Tempini1 1 University of California San Francisco, San Francisco, USA 2 Weill Cornell Medical College, New York, USA Previously, we have shown that neurodevelopmental factors like language-based learning disability (LD) and hand preference differentially distribute across variants of primary progressive (PPA). Compared to the general population, we observed an increased rate of non-right-handedness in semantic variant PPA and developmental dyslexia in logopenic variant PPA (lvPPA). We hypothesized that the presence of language-based LD in a large subset of our lvPPA cohort reflected unique underlying disease susceptibility of the language network to neurodegenerative disease, in a domain specific manner. Given this, we hypothesized that nonlanguage-based LD might provide similar disease susceptibility in corresponding networks and investigated the prevalence and type of LD in an expanded lvPPA cohort (n = 84), posterior cortical atrophy (PCA) (n = 95), and a matched group of amnestic type AD (n = 100). Retrospective chart review for history of LD showed that 25% (21/84) lvPPA, 19% (18/95) PCA, and 3% (3/100) endorsed a history of LD. In both lvPPA and PCA these rates were greater than the 10% expected amount of LD for the general population, p < 0.001 and p = 0.007, respectively, and greater than the amnestic AD group, p < 0.001. In lvPPA and amnestic AD all individuals with LD possessed language based LDs and only a small number of individuals also possessed non-language based, whereas in PCA more than half were non-language-based, mathematical and/ or visuospatial. Mathematical LD is estimated to occur at rates of up to 6% in the general population. Compared to general population rates, these non-language-based LDs occurred at a significantly higher rate in our PCA cohort, 13% (12/95) p = 0.01. Comparisons of PCA to lvPPA and amnestic AD were also highly significant, p = 0.004. As such, non-language-based LD appears to be overrepresented in PCA. Together, our findings suggest that underlying modality specific neurodevelopmental differences in brain structures influence the phenotypic presentation of late-life focal neurodegenerative diseases.

P289 Lexical representation and parsing of morphologically complex words in non-fluent variant PPA and non-fluent post-stroke aphasia E. Peristeri1, I.-M. Tsimpli2, G. Jarema3, K. Tsapkini4 1 Aristotle University of Thessaloniki, English Studies, Thessaloniki, Greece 2 University of Cambridge, Theoretical and Applied Linguistics, Cambridge, Great Britain 3 Universite de Montreal and Research Center, Institut Universitaire de geriatrie de Montreal, Linguistics and Translation, Montreal, Canada 4 Johns Hopkins Medicine, Neurology, Baltimore, USA Morphological decomposition has been found to be impaired in both post-stroke aphasia and Primary Progressive Aphasia (PPA) (Luzzatti et al. Brain Lang 2001; 79 345–359, Wilson et al. Brain

Lang 2014; 136 58–68). However, morphological impairment in these populations has been defined in terms of the regular versis irregular inflection dichotomy in verbs and nouns in production, with the parsing underlying the processing of morphologically complex words receiving less attention. This study investigates the impact of morpho-orthographic and frequency parameters on PPA and non-fluent post-stroke patients’ parsing using two tasks. The first task was an online lexical decision task with high- (HF) and low-frequency (LF) prefixed and simple words matched for length and surface frequency. The second was a semantic judgment task necessitating categorical judgments for HF and LF inflected real words and pseudohomophones created by either an orthographic error at the stem or a homophonous (but incorrect) inflectional suffix. Data were collected from 8 Greek-speaking patients with non-fluent variant (nfv-) PPA, 8 with non-fluent post-stroke aphasia and 8 healthy controls. In the first task, the post-stroke group and controls were only influenced by the morphological operations rather than frequency: prefixed words were slower than simple words. The PPA group was faster in prefixed (vs. simple) words but only for the prefixed words having HF roots. In the second task, there were no differences in accuracy between HF and LF words for either group. Both patient groups and controls were faster in detecting orthographic errors in the root (vs. the inflectional suffix) of the pseudohomophones, yet, such sensitivity was exhibited by the PPA group only for HF words. The overall results confirm previous findings that in non-fluent post-stroke aphasia morphological operations are costly but show for the first time that in PPA at least prefixation is not. The nfv-PPA group was rather influenced by lexical attributes such as frequency: performance on LF words was more costly than on HF words.

P290 Executive functions in non-fluent variant PPA: A comparison to non-fluent post-stroke aphasia E. Peristeri1, I.-M. Tsimpli2, K. Tsapkini3 1 Aristotle University of Thessaloniki, English Studies, Thessaloniki, Greece 2 University of Cambridge, Theoretical and Applied Linguistics, Cambridge, Great Britain 3 Johns Hopkins Medicine, Neurology, Baltimore, USA Post-stroke damage in the left-hemisphere frontal cortex (LFC) has been often associated with cognitive control impairments in tasks in which recently seen but irrelevant stimuli must be inhibited (Hamilton et al. CABN 2005; 5 1–13). What remains untested is whether left temporal atrophy in non-fluent variant Primary Progressive Aphasia (nfv-PPA) may also lead to cognitive control impairments. We tested 8 patients with nfv-PPA and 8 with LFC damage and non-fluent post-stoke aphasia (along with healthy controls) on two executive function tasks. The two tasks differed in the type of inhibition they tested, but they shared a common need to ignore irrelevant stimuli. The first was a flanker task in which a response had to be made to a central arrow while ignoring flanking arrows. To isolate stimulus-response inhibition-related processes, we compared incongruent trials (i.e. flanking arrows pointing in opposite direction to target arrow) with congruent trials (i.e. flanking arrows pointing in the same direction as the target arrow). The second was a go/no-go (GNG) paradigm, in which a response had to be withheld on presentation of one imperative stimulus but a response had to be executed upon presentation of a different


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stimulus. We compared “no-go” trials, which required response inhibition, with “go” trials in which the response was executed (Aron Neurosci 2007; 13 214–228). In contrast to controls who have exhibited significant Congruency effects in the flanker task, neither patient group exhibited differences between congruent and incongruent trials in either RTs or accuracy. In the GNG task, the PPA group exhibited lower accuracy in the “no-go” trials than both controls and the post-stroke group, while there was no difference among groups in the stop stimulus RT measure, i.e. in the latency of the stop process in the “no-go” trials. The results suggest that though both patient groups with left frontal damage were impaired in detecting incongruency in the flanker task, the PPA group was more impaired in response inhibition than the post-stroke group and controls in the GNG task.

although they exhibited overall low syntactic comprehension accuracy, and in passives lower than the post-stroke group. The results show the nfv-PPA group was more impaired than the poststroke group in syntactic comprehension, yet, such impairment did not seem to affect their word-recall performance.

P291

In recent years a large and growing body of research has greatly furthered our understanding of primary progressive aphasia (PPA) and progressive apraxia of speech (PAOS). Although several cohorts were limited to right hand dominant (RH) subjects, it has been suggested that nRH may be over-represented in cases of semantic dementia (SD) group. PAOS has not been evaluated. This study evaluated the clinical and imaging findings in nRH compared to RH subjects in a large, prospective cohort of subjects with PPA or PAOS. 163 patients were included, of which 19 were nRH (15 left handed, 4 ambidextrous). A greater proportion of subjects in the SD group were nRH (3/12, 25%), whereas it was around the expected level for other groups: 7/53 (13.2%) subjects with PAOS, 5/62 (8.1%) subjects with logopenic progressive aphasia, 2/17 (11.8%) subjects with progressive agrammatic aphasia, 0/5 (0%) subjects with progressive fluent aphasia and 2/14 (14.3%) subjects with PPAUnclassified. A novel finding was the high proportion of nRH in the subset of PAOS subjects with isolated apraxia of speech, previously described as primary progressive apraxia of speech (6/30, 20%). There were no differences in demographics, disease duration, neuropsychometric results or speech and language findings in nRH compared to RH subjects. FDG-PET imaging revealed left greater than right sided hypometabolism in all groups, regardless of handedness. Although there were subjects with predominantly right sided hypometabolism, they were no more likely to be nRH. The hypometabolism asymmetry index did not differ between RH and nRH subjects either. In keeping with prior reports, nRH is over represented in subjects with SD. This is the first report of a higher rate of nRH in subjects with isolated apraxia of speech. We speculate on the intriguing lack of differences between RH and nRH subjects given the suspected differences in hemispheric organization.

The effect of verbal working memory capacity in sentence comprehension: a comparison between non-fluent poststroke aphasia and non-fluent variant PPA E. Peristeri1, I.-M. Tsimpli2, K. Tsapkini3 1 Aristotle University of Thessaloniki, English Studies, Thessaloniki, Greece 2 University of Cambridge, Theoretical and Applied Linguistics, Cambridge, Great Britain 3 Johns Hopkins Medicine, Neurology, Baltimore, USA The issue of whether general verbal working memory (WM) is used in syntactic processing (King et al. J Mem Lang 1991; 30 580– 602) or not (Caplan et al. Brain Behav Sci 1999; 22 77–126) is a debated topic in healthy, let alone in language-impaired populations. This study investigates the interaction between WM and syntactic processing in 8 patients with non-fluent variant Primary Progressive Aphasia (nfv-PPA) and 8 with non-fluent post-stroke aphasia (along with healthy controls) with a dual-task paradigm where two tasks had to be performed in parallel: sentence comprehension through blocks of sentence-picture matching (SPM) tasks and a word-recall task (Ivanova et al. J Commun Disord 2014; 52 58–78) in which subjects had to recall a word at the end of a sentence of varied syntactic complexity (see example below). Syntactic complexity was manipulated by varying the structural complexity of the sentences (Sentences of low complexity: 4 transitives & 4 subject relatives; Sentences with high-complexity: 4 passives & 4 object relatives). Example 1st SPMT: The bike follows the bus (transitive) 1st word to be recalled: boot 2nd SPMT: The dog is bitten by the cat (passive) 2nd word to be recalled: clock 3rd SPMT: The lady that kisses the man pushes the girl (subject relative) 3rd word to be recalled: nose 4th SPMT: The girl that the young man kicks hugs the child (object relative) 4th word to be recalled: milk Both SPM accuracy and word-recall scores were calculated. On the word-recall measure, both the post-stroke group and controls showed a significant Syntactic Complexity effect, with word-recall being more erroneous after processing passives and object relatives (vs. transitives and subject relatives). Contrary, the nfv-PPA group did not show an effect of syntactic complexity on word-recall

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P292 Non-right handed primary progressive aphasia and apraxia of speech H. Botha1, J. Whitwell2, J. Duffy1, E. Strand1, M. Machulda3, V. Lowe2, K. Josephs1 1 Mayo Clinic, Neurology, Rochester, USA 2 Mayo Clinic, Radiology, Rochester, USA 3 Mayo Clinic, Psychiatry and Psychology, Rochester, USA



P293 Neurochemical markers in the differential diagnosis of primary progressive aphasias: Data from the German FTLD consortium P. Oeckl1, S. Anderl-Straub1, J. Diehl-Schmid2, C. A. F. von Arnim1, orstl2, H. Jahn5, K. Fassbender3, E. Feneberg1, K. Fliessbach4, H. F€ B. Landwehrmeyer1, M. Lauer6, J. Levin7, A. C. Ludolph1, J. Prudlo8, A. Schneider9, M. Schroeter10, E. Semler1, P. Steinacker1, I. Uttner1, J. Wiltfang9, A. Danek7, M. Otto1 1 Ulm University Hospital, Department of Neurology, Ulm, Germany 2 Technical University Munich, Department of Psychiatry and Psychotherapy, Munich, Germany 3 Saarland University, Department of Neurology, Homburg, Germany 4 University of Bonn and DZNE Bonn, Department of Psychiatry and Psychotherapy, Bonn, Germany 5 University Medical Center Hamburg-Eppendorf, Department of Psychiatry and Psychotherapy, Hamburg, Germany 6 University of Wuerzburg, Department of Psychiatry and Psychotherapy, Wuerzburg, Germany 7 Ludwig-Maximilians-University LMU Munich, Department of Neurology, Munich, Germany 8 University of Rostock, Department of Neurology, Rostock, Germany 9 University of G€ottingen, Department of Psychiatry and Psychotherapy, G€ottingen, Germany 10 Max Planck Institute for Human Cognitive and Brain Sciences and University of Leipzig, Department of Cognitive Neurology and Clinic for Cognitive Neurology, Leipzig, Germany Primary progressive aphasias (PPA), including the semantic variant (svPPA), non-fluent variant (nfvPPA) and logopenic variant (lvPPA), are neurodegenerative diseases characterized by a progressive decline in speach. Neuropathologically, svPPA and nfvPPA are assigned to frontotemporal dementia whereas lvPPA is mainly associated with Alzheimer0 s disease (AD). Differential diagnosis of PPAs is based on clinical symptoms and objective neurochemical biomarkers are highly appreciated to improve diagnostic accuracy. Here, we investigated a panel of biomarker candidates in cerebrospinal fluid (CSF) of PPA patients (n = 66) in a multicenter cohort from the German FTLD consortium. There were no significant differences in CSF concentrations of ubiquitin (Kruskal-Wallis test, p = 0.50), progranulin (p = 0.12), Tau (p = 0.12) and pTau181 (p = 0.07) between PPAs. Ab42 was significantly reduced in lvPPA versus nfvPPA (p < 0.05) but not svPPA and there was a great overlap between groups. The ratio of the AD biomarkers Ab42/pTau181 significantly differentiated lvPPA from nfvPPA (p < 0.01) and svPPA (p < 0.05) and showed a sensitivity and specificity of 91.7% and 64.3% (lvPPA vs. nfv+svPPA). Neurofilament light chain (NfL) was significantly lower in lvPPA compared with nfvPPA (p < 0.01) and svPPA (p < 0.001) and sensitivity and specificity was 70.8% and 92.9%. Combination of NfL and AD biomarkers in the term Ab42*NfL/ pTau181 improved diagnostic accuracy for the differentiation of lvPPA from nfvPPA and svPPA patients (sensitivity 87.5% and specificity 85.7%). The phosphorylated neurofilament heavy chain (pNFH) was significantly increased in nfvPPA vs. svPPA (p < 0.05) and lvPPA (p < 0.01) and showed a sensitivity and specificity of 80.0% and 64.3% to discriminate nfvPPA and svPPA. In conclusion, the combination of the AD biomarkers Ab42 and pTau181 with NfL is promising in the discrimination of lvPPA patients from nfvPPA and svPPA. CSF pNfH concentrations may

assist in the differential diagnosis of nfvPPA and svPPA although additional biomarkers are appreciated to increase sensitivity and specificity of pNfH.

P294 Speech fluency as a tool to differentiate between FTLD variants A. Martıńez1,2, D. Matallana1, F. Gayraud2 1 Pontificia Universidad Javeriana, Medicina, Bogot a, Colombia 2 Universite Lumiere Lyon 2, Laboratoire Dynamique du Langage, Lyon, France Fluency can be defined as the ability to produce speech as a continuous phenomenon, without any evident effort. Reaching the goal of producing speech as a continuous signal implies to access the lexicon matching, building a grammatical, and identify the phonemes to produce and ultimately articulate speech. Our goal is to distinguish witch fluency variables allow us to isolate FTLD variants. We assessed three data sets of two narrative samples: a day in the life, and Cinderella. The first set will measure the effectiveness of communication and the complexity of the structures (number of words, clauses, sentences, and syntactic rates). The second one takes into account the time variable (duration, time speech, pauses and filled pauses). And the third group the disruption markers (repetition, rephrasing and retractions, syllabic lengthening and interruptions between two syllables). Patients with the tree variants of FTLD were included (31 samples of the two variants of Primary Progressive Aphasia (PPA), 14 Semantic Dementia (SD) samples and 36 transcripts for the behavioral variant group (BV)), and a control subjects group (CG) (31 samples). CG show higher speech rates and complexity than all the FTLD groups. As expected, PPA patients show less efficiency in general speech rates and an increased number of pauses and disruptions of fluency. In a constrained narrative as Cinderella SD patients show more disruptions, and general speech rates and number of words. The BV patients show greater number of reformulations that seems to be highly influenced by executive functions. All the variables related to time management seem to be the most significant to differentiated the two groups of PPA patients.

P295 Predicting rate of clinical decline using neuroimaging in progressive agrammatic aphasia and apraxia of speech J. Whitwell1, S. Weigand2, J. Duffy3, H. Clark3, E. Strand3, M. Machulda4, A. Spychalla1, M. Senjem1,5, C. Jack1, K. Josephs3 1 Mayo Clinic, Radiology, Rochester, USA 2 Mayo Clinic, Health Sciences Research, Rochester, USA 3 Mayo Clinic, Neurology, Rochester, USA 4 Mayo Clinic, Psychiatry and Psychology, Rochester, USA 5 Mayo Clinic, Information Technology, Rochester, USA Progressive agrammatic aphasia and apraxia of speech (AOS) often co-exist, but can occur in isolation early in the disease course. Over time, patients with agrammatic aphasia and/or AOS can develop Parkinsonism and behavioral changes. In order to improve prognostic estimates of clinical change in such patients we determined whether baseline regional brain volumes would help predict future rate of decline of agrammatism, AOS, Parkinsonism


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and behavioral dyscontrol. Thirty-eight subjects meeting diagnostic criteria for agrammatic variant of primary progressive aphasia (agPPA) or primary progressive AOS (PPAOS) with baseline MRI were identified and followed longitudinally for up to four visits. Severity of aphasia, AOS, Parkinsonism and behavioral dyscontrol, were measured using the Western Aphasia Battery Aphasia Quotient (WAB-AQ), Motor Speech Disorders (MSD) Scale, Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) and Frontal Behavioral Inventory (FBI). Regional grey matter volumes were calculated at baseline. Mixed effects models were used to determine the degree to which baseline volumes predict future rate of decline. Median rate of change (points/year) was 0.9 (IQR:1.3, 0.5) for MSD, 4 (7, 1) for WAB-AQ, 7 (2,14) for UPDRS-III, and 2.1 (0.9, 5.9) for FBI. Small baseline right lateral premotor volume, and degree of asymmetry in lateral premotor cortex, was associated with faster rates of MSD decline. In contrast, faster rates of WABAQ decline were associated with left-sided asymmetry at baseline and small baseline Broca’s area volume. Fast rates of UPDRS-III decline were associated with small right Broca’s area and with bilateral precentral and lateral premotor reduction. Fast rates of FBI decline were associated with baseline volume reduction across frontal and striatal regions. Neuroimaging measures, therefore, have the potential to be useful predictors of decline in agPPA and PPAOS. In fact, rate of decline of the four clinical features assessed in this study were each associated with different regional patterns of atrophy at baseline.

P296 Cross-cultural adaptation of the boston diagnostic aphasia examination - short form in filipino H. H. Bayona1,2, I. P. Bondoc3, E. L. Namoro2, F. F. Aclan2, A. L. Domingo2, J. Dominguez1 1 St. Luke’s Medical Center, International Institute for Neurosciences, Taguig City, Philippines 2 University of the Philippines Manila, Department of Speech Pathology, Manila, Philippines, Philippines 3 University of Hawaii at M anoa, Department of Linguistics, Honolulu, Hawaii, USA Current methods for assessing various aphasia types in the Philippines lack diagnostic accuracy and compromise management as clinicians often use aphasia batteries developed abroad or correlate symptoms to lesion sites. Our study aimed to create an aphasia test that is culturally and linguistically appropriate for Filipinos by adapting the Boston Diagnostic Aphasia Examination-Short Form (BDAE-SF). The BDAE-SF is designed to comprehensively evaluate language function in all modalities and classify aphasia syndromes. A narrative literature review was done to assess relevance of constructs measured by the BDAE and the influence of Filipino culture and language on aphasia testing. Keyword searches to multiple online bases and grey literature review were done. Three bilingual translators independently translated the original instructions and items. Translations were synthesized and contextually adapted by a multidisciplinary expert panel to resolve discrepancies and attain item equivalence. The resulting adaptation I and the original BDAE-SF were pre-tested to 30 lay people to appraise comprehensibility and cultural acceptability. Group differences in error rates between test versions were evaluated using paired samples t-test. Final modifications were made by the expert panel to produce adaptation II. Despite the increasing number of research on aphasia in culturally and

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linguistically diverse groups, none of these focused on Filipinos. Constructs in the BDAE-SF are mostly applicable in the Philippines due to influence of Western countries in Philippine culture and language. 60% of the items exhibited equivalence issues, with majority being cultural (48%), followed by structural/linguistic (36%), conceptual (8%) and operational (8%). Pre-test participants made significantly lower error rates in adaptation I than in the original BDAE-SF at 2.7% and 6.3%, respectively (p = .009). Overall, we adapted 85 out of 118 items to produce adaptation I and modified 5 items for adaptation II. A BDAE-SF version appropriate for the linguistic and cultural background of Filipinos was then produced. To maximize its clinical utility, succeeding studies are needed to establish its psychometric properties.

P297 Long-term functional and behavior features of primary progressive aphasia syndrome I. L. Calandri1, M. Amengual1, D. Actis1, R. F. Allegri1 1 FLENI, Memory and Ageing Center, Buenos Aires, Argentina Introduction: Primary Progressive Aphasia is a clinical syndrome defined as progressive isolated language impairment. Despite of this, other symptoms (as behavior) could be present but hidden by the aphasia. Our aim is to evaluate the presence and magnitude of behavioral symptoms and functional status in different stages and variants. Methods: All patients were evaluated trough semistructured interview including Functional Assesment Questionnaire (FAQ), FTD modified Clinical Dementia Rating with sum of boxes scoring (FTD-CDR SoB) and Neuropsychiatric Inventory (NPI). All participants were splited according evolution time in short-term (< 3 year) middle-term (3–6 year) and long-term (> 9 year) and its clinical variant. Results: Twenty patients were evaluated (Logopenic n = 9, Non fluent-NF- n = 4, Semantic n = 7), time of follow up was 5.45 2.41 years from disease onset. FAQ was 11.21 6.05 and CDRSoB was 17.78 11.31 without significant differences between variants or stage. Regarding the NPI, there was no patient lacking of neuropsychiatric features, being apathy (75%) anxiety (55%), depression, irritability, disinhibition (50%) and abnormal alimentation behavior (45%) the most frequent. Remarkably, sleep disturbances (25%) was a distinctive feature of the NF (X2 6.68 p 0.035). These findings were constant in each stage group. Conclusions: Neuropsychiatric symptoms remain constant in PPA even in early stages as well as functional impairment. Within neuropsychiatric symptoms, mood disorders are the most frequent.

P298 Is the impairment on Luria three-step examination in FTD patients associated with language impairments? L. Repetto1, P. Connick2, S. Colville2, S. Pal2, T. H. Bak1,2 1 University of Edinburgh, College of Medicine and Veterinary Science, Edinburgh, Great Britain 2 Anne Rowling Regenerative Neurology Clinic, The University of Edinburgh, Edinburgh, Great Britain Motor impairment is increasingly recognised as a frequent and potentially diagnostically relevant feature of frontotemporal



dementia (FTD). The aim of the study was to examine the relationship between complex motor symptoms (in particular Luria three-step examination) and language impairment in FTD patients (including FTD associated with motor disorders). Data was collected from the clinical letters of 45 patients (23 males) diagnosed with Frontotemporal Dementia (FTD). The subdiagnoses were Corticobasal degeneration (n = 5), non-specified Primary Progressive Aphasia (PPA) (n = 8), Non-fluent Progressive Aphasia (n = 3), Logopenic Aphasia (n = 3), Semantic Dementia (n = 1), Behavioural Variant (n = 20), Progressive Supranuclear Palsy (n = 5). The data on Luria three-step examination was obtained through each patient’s score on the Edinburgh Motor Assessment Scale (EMAS), a brief motor screening test for dementia patients. Significant correlation was seen between language difficulties and impairment on the Luria three-step examination (v²=6.508, p = 0.011, φ=0.38). Furthermore, patients diagnosed with PPA and its subtypes (33.4%) were all found to be at least slightly impaired in the Luria examination performance. Specifically, an association has been found between score on the Luria examination and impairment in word finding ability (v²=4.034, p = 0.045, φ = 0.299). Interestingly, no significant association has resulted from comparing the Luria score and motor speech problems or spelling mistakes. These findings suggest that the performance on Luria three-step examination is mainly related to higher-level motor sequencing rather than to peripheral motor dysfunction. We propose that both language symptoms and the impairment on the Luria three-step examination might reflect the same underlying deficit in higher-level sequencing.

P299 Different patterns of motor impairment in the behavioural and aphasic form of Frontotemporal Dementia G. Melchiorre1, P. Connick2,3, S. Colville3, S. Pal2, T. H. Bak3,4 1 University of Edinburgh, College of Medicine and Veterinary Science, Edinburgh, Great Britain 2 University of Edinburgh, Centre for Clinical Brain Sciences, Edinburgh, Great Britain 3 University of Edinburgh, Anne Rowling Regenerative Neurology Clinic, Edinburgh, Great Britain 4 University of Edinburgh, School of Philosophy, Psychology and Language Sciences, Edinburgh, Great Britain Although it is well recognised that frontotemporal dementia (FTD) can be associated with motor neurone disease and different extrapyramidal syndromes, the motor profile of patients with FTD has not been well characterised. The aim of this study was to systematically examine the patterns of motor impairment in patients with the behavioural and aphasic FTD variants. A total of 234 patients at the Anne Rowling Regenerative Neurology Clinic completed the Edinburgh Motor Assessment (EMAS). EMAS is a brief motor screening test focusing on motor functions particularly relevant to dementia. It assesses extrapyramidal, amyotrophic, and cerebellar symptoms, as well as complex movements. Twenty patients diagnosed with behavioural variant FTD (bvFTD) and 15 patients with primary progressive aphasia (PPA) were identified. For statistical analyses, the EMAS subscores were normalised relative to the total EMAS score for each patient. The average age of the bvFTD patients (64.15 years) and the aphasic FTD patients (67.20 years) was not significantly different. Significant motor

impairment was defined in comparison to 100 age-matched healthy controls as a total EMAS score above 14.4, and it was found that 45% of bvFTD and 20% of PPA patients presented with significant motor impairment. bvFTD and aphasic patients did not differ on their mean total EMAS scores, but aphasic patients had a significantly higher relative subscore on complex items [t (33) = 2.09, p = 0.045]. Analysis of raw data indicated that bvFTD patients were more impaired on extrapyramidal items than aphasic patients, however, this difference was not statistically significant when relative subscores were analysed. These results suggest that different patterns of motor impairment are observed in behavioural and aphasic variants of FTD. Aphasic patients show more deficits on complex motor tasks, whereas bvFTD patients appear more impaired on extrapyramidal symptoms.

P300 Predictors of conversion to dementia in primary progressive aphasia L. Veronelli1,2,3, S. J. Makaretz2,3, M. Quimby2,3, M. Corbo1, B. C. Dickerson2,3 1 Casa Cura Policlinico, Department of Neurorehabilitation Sciences, Milan, Italy 2 Massachusetts General Hospital/Harvard Medical School, Department of Neurology, Boston, MA, USA 3 Massachusetts General Hospital/Harvard Medical School, Athinoula A. Martinos Center for Biomedical Imaging, Boston, MA, USA In Primary Progressive Aphasia (PPA) very little is known about possible baseline predictors of progression from a stage of functional independence to one consistent with dementia. The overall goal of the present study is to investigate the utility of baseline clinical, neuropsychological and neuroanatomical measures in predicting disease progression in PPA patients, in order to develop a prognostic model that might be possible to apply at individual level. We hypothesized that composite indexes of functional impairment outside language (CDR-SoB) and of aphasia severity (PASS-SoB) could better predict time of conversion to dementia than specific linguistic measures (BNT). In a similar fashion subtle cortical thinning affecting brain regions outside the language network, namely cognitive-affective peri-linguistic areas in the left hemisphere (LH) and homologous areas in the right one (RH), could be better predictors than mean atrophy measured within the language network and in control regions (pericalcarine areas). Finally, cortical thickness – that could be considered a direct measure of neurodegeneration – may be a more reliable index than clinical and neuropsychological scores. Thirty selected patients meeting PPA criteria (12 non-fluent/agrammatic, 9 semantic, 9 logopenic) underwent a clinical, neuropsychological and MRI evaluation at baseline. Univariate and multivariate Cox regression analyses were performed using time from first visit to loss of independence in daily activities mainly due to cognitive impairment other than language, as abscissa. The multivariate model, adjusted for education, demonstrated that cortical thickness in cognitiveaffective peri-linguistic areas of the LH was the strongest predictor, followed by the PASS-SoB score. In conclusion, the present study identified some baseline clinical and neuroanatomical measures critical in predicting time to conversion to dementia in PPA, giving useful indexes relevant for medical management and patient care.


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P301 Distinctive profile of verbal fluency tasks and overall cognitive functioning in a Mexican sample in patients with frontotemporal dementia and Alzheimer’s disease J. Te´llez Martıńez1, J. F. Flores V azquez1, G. I. Acosta Castillo1, 1 A. Campos Jimenez , L. Alvarez Dıaz1, A. Martınez Ruız2, A. L. Sosa Ortız1 1 National Institute of Neurology and Neurosurgery, Dementia Unit, Mexico 2 National Institute of Geriatry, Geriatric epidemiology, Mexico Background: Differences in performance of verbal fluency (VF) in frontotemporal dementias and Alzheimer’s disease are well documented. However, there are few studies in clinical samples from low and middle income countries, where the education level tends to be lower. Methods: We conducted a transversal study using data from the Dementia Unit database at the National Institute of Neurology and Neurosurgery in Mexico City. We included data from 66 patients with Alzheimer’s disease (AD), 8 patients with language variant frontotemporal dementia (lvFTD) and 10 patients with behaviorvariant frontotemporal dementia (bvFTD). Using ANOVA test we analyzed the performance scores for VF tasks (semantic and phonological) and a global cognitive score of the Mini-Mental Status Examination (MMSE) among the 3 groups. Results: Patients with lvFTD showed the worst performance in semantic (mean 4.38 standard deviation 4.44) and phonological fluency tasks (1.38 1.55) when comparing with bvFTD (10.4 7.56 and 5.9 4.91), and with AD (7.52 3.91 and 5.59 4). The most striking difference was found for semantic (p = 0.018) and phonological fluency (p = 0.05) among lvFTD and bvFTD groups. The lvFTD group had the worst overall cognitive performance, followed by AD (17.3 5.1) lvFTD (12.9 6.1) bvFTD: 19.6 6.3). The only significant differences were found when comparing lvFTD and bvFTD groups (p = 0.028). Conclusion: As expected, AD group had less severe language deficits than patients with FTD, but didn0 t show the worst performance in overall cognitive functioning. In this study VF tasks allowed to differentiate between groups of FTD. We have to consider that in lvFTD the language comprehension in the lvFTD might be a bias for global cognitive performance, in addition, the MMSE seems not to be the best screening test for this group. Larger studies are needed to characterize the language profiles of degenerative dementias in different populations.

P302 Assessment of frontal function and behavioral symptoms across subtypes of primary progressive aphasia, semantic dementia and progressive apraxia of speech E. Golden1, H. Botha1, J. Duffy1, E. Strand1, H. Clark1, M. Machulda2, J. Whitwell3, K. Josephs1 1 Mayo Clinic, Neurology, Rochester, USA 2 Mayo Clinic, Psychiatry and Psychology Neuropsychology, Rochester, USA 3 Mayo Clinic, Radiology, Rochester, USA Neurocognitive profiles across subtypes of primary progressive aphasia (PPA), semantic dementia (SD) and progressive apraxia of speech (PAOS) differ, reflecting differentially affected neuroanatomical regions. However, there is a relative lack of data on

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bedside tools to assess frontal function and behavioral symptoms in these disorders. We aimed to address this gap by evaluating the Frontal Assessment Battery (FAB) and Frontal Behavioral Inventory (FBI) in a large, prospective cohort of subjects with PPA, SD, or PAOS. A total of 149 subjects were included and diagnosed with progressive agrammatic aphasia (PAA) (n = 17), logopenic progressive aphasia (LPA) (n = 62), progressive fluent aphasia (PFA) (n = 5), SD (n = 12), or PAOS (n = 53). FAB and FBI scores were compared across groups, as were measures of aphasia severity (using Western Aphasia Battery Aphasia Quotient, WAB-AQ) and cognitive impairment (using the Mini Mental Status Examination, MMSE). Significant group differences were noted on FAB between LPA and PAOS, LPA and PFA, LPA and SD, and PAOS and PAA. Both the WAB-AQ and MMSE scores correlated significantly with FAB scores. After correcting for aphasia and cognitive severity, the FAB score in the LPA group was significantly lower than that in the SD group but not the PFA group or PAOS. The only significant group difference on the FBI, between LPA and PAOS, was not significant after correcting for severity. The findings suggests that executive dysfunction is more prominent in LPA compared to SD which may further help to differentiate LPA from SD. The severity of behavioral symptoms, as measured by the FBI, did not appear to vary significantly amongst groups. While the FBI has particular appeal in this population given its relative independence from confounders, data from this cohort did not support its utility in differentiating PPA variants, SD and PAOS from each other.

P303 Cognitive and neuroanatomical features of amyloid positivity in primary progressive aphasia (PPA) M. A. Santos-Santos1, G. D. Rabinovici1, N. Ayakta1, L. Iaccarino1, G. Tammewar1, M. L. Henry1, A. Lazaris1, Z. Miller1, M. L. Mandelli1, E. Spinelli1, H. I. Hubbard1, H. Rosen1, W. Jagust1, B. L. Miller1, L. T. Grinberg1, W. W. Seeley1, M. L. Gorno-Tempini1 1 University of California San Francisco, Neurology, San Francisco, USA To determine the rates of amyloid positivity and the cognitive and neuroanatomical features associated with presumptive Alzheimer’s disease (AD) pathology in primary progressive aphasia (PPA) diagnosed according to current consensus criteria. We report the prospective clinical diagnoses along with cognitive, neuroimaging (MRI and amyloid PET), and available pathology data of 109 subjects (age: 66 8; sex: 56%F; MMSE: 23 6) who presented with language complaints. 28 subjects received a diagnosis of semantic variant PPA (svPPA: age: 64 7; sex: 46%F; MMSE: 23 7; Amyloid positive: 4), 31 non fluent variant PPA (nfvPPA: age: 68 7; sex: 71%F; MMSE: 26 4; Amyloid positive: 3), 26 logopenic variant PPA (lvPPA: age: 63 8; sex: 65%F; MMSE: 22 6; Amyloid positive: 25), four PPA unclassified (PPAu: age: 64 6; sex: 75%F; MMSE: 23 7; Amyloid positive: 3), and 20 non-PPA. Pathology data was available for five svPPA (tdpC+psp, tdpB+tau, PiD, tdpC + AD[2]), twelve nfvPPA (PSP[2], CBD[6], PiD[2], CBD +tdpA +AD, PiD +AD), and two lvPPA (AD[2]). The amyloid positive svPPA and nfvPPA cases with available autopsy data (2/4 and 2/3 respectively) all received a mixed (primary FTLD and secondary AD) pathological diagnosis. Amyloid positive PPA patients performed worse in sentence repetition, calculations, visual memory, digits backward and modified trails. Bilateral mid-posterior temporal and inferior parietal grey matter atrophy predicted amyloid



positivity whereas left frontal-temporal and diencephalic white matter atrophy predicted amyloid negativity. In conclusion, diagnosis according to current PPA consensus criteria was highly predictive of AD biomarker status. Sentence repetition, motor speech, and visual memory were the measures that best differentiated between amyloid positive and negative PPA. Positive amyloid neuroimaging in patients with typical nfvPPPA and svPPA does not rule out the possibility of a primary FTLD pathological diagnosis driving the clinical syndrome.

P304 Differentiating frontotemporal dementia phenotypes in a cinical setting using the computerized self-test (CST) M. Crane1, R. Anthony1, K. Sellers1, K. Knolton1, J. H. Dougherty1 1 University of Tennessee Medical Center-Knoxville, Dept of Medicine, Cole Neuroscience Center, Knoxville, USA The Computerized Self-Test (CST) is a computerized screening instrument designed to screen for cognitive impairment in the primary care setting. The CST has evidence of high reliability, construct validity, and sensitivity for Alzheimer’s disease (AD). Given the paucity of screening tools, frequently, community frontotemporal dementia (FTD) patients are followed with AD tools. In this pilot study, the CST was studied as a screening tool to differentiate among known FTD phenotypes: behavioral variant

FTD (bvFTD), motor variants (Corticobasilar Syndrome [CBS] and progressive supranuclear palsy [PSP]), and language variants (semantic dementia [SD] and progressive non-fluent aphasia [PNFA]). Of 592 new patients attending a memory clinic, 146 fulfilled inclusion criteria. Groups included healthy controls (n = 45), bvFTD (n = 85), motor variant (n = 29) and language variant (n = 26). All FTD patients met criteria set forth by the FTLD consensus panel. All patients had comprehensive neurological testing and radiologic correlation (FDG-PET and MRI). Significant differences were observed between groups on the basis of age F(3, 181)=3.548, p < 0.05; sex F(3, 181) = 2.877, p < 0.05; visuospatial reasoning F(3, 181) = 11.397, p < 0.001; semantic verbal fluency F(3, 181) = 12.901, p < 0.001; memory recall F(3, 181) = 25.959, p < 0.001; attention F(3, 181) = 8.317, p < 0.001; orientation F(3, 181) = 7.636, p < 0.001; composite CST score F (3, 181) = 22.543, p < 0.001; time to complete CST F(3, 187) = 19.883, p < 0.001. As compared to controls, each FTD group showed significant differences in total score (p < 0.001). Differences were observed among the bvFTD, language variant and motor variant as compared to one another in the total CST composite score, F(2, 137) = 4.515, p < 0.05. The CST screening tool has the potential to detect differences among the FTD subtypes. Given that community practices commonly do not specify a phenotype of FTD, simple tools are needed to help distinguish subtypes. A larger study is underway following the cognitive patterns of FTD phenotypes in a community setting.


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Poster Session III: CBS, PSP, MND P306

P305 PLS-FTLD, expanding the spectrum of dementia in motor neuron disease M. van Es1, B. de Vries1, L. Rustemijer1, A. van der Kooi2, J. Raaphorst2,3, C. Schroder4, T. Nijboer4,5, J. Hendrikse6, J. Veldink1, L. van den Berg1 1 UMC Utrecht, Neurology, Utrecht, Netherlands 2 Academic Medical Center, Neurology, Amsterdam, Netherlands 3 Radboud University Medical Centre, Neurology, Nijmegen, Netherlands 4 UMC Utrecht, Center of Excellence for Rehabilitation Medicine, Utrecht, Netherlands 5 University of Utrecht, Department of Experimental Psychology, Utrecht, Netherlands 6 UMC Utrecht, Department of Radiology, Utrecht, Netherlands Primary lateral sclerosis (PLS) is a rare motor neuron disease, characterized by the exclusive degeneration of upper motor neurons leading to slowly progressive spasticity. In contrast to ALS, where cognitive impairment and frontotemporal dementia (FTD) are frequently seen, relatively little is known about cognition in PLS. The objective of this study is to report the clinical findings and frequency of PLS patients that developed FTD in a referral-based cohort and provide a review of the literature. Six out of 180 (3.3%) PLS patients developed FTD. All patients showed slow motor deterioration over the course of many years (average 7 years) before developing rapidly progressive behavioral changes and language deficits. The average time between the first cognitive changes and the diagnosis of FTD was 6 months. Subclinical cognitive deficits have reported in PLS, but to date only 7 cases of PLS and FTD have been reported in the literature. We demonstrate that PLS patients may develop FTD and that perhaps motor decline and cognitive deterioration occur at different speeds in motor neuron disease. Moreover, our data suggests that FTD in PLS patients is underreported. Literature and this report suggest the cognitive profile in PLS to be similar to ALS (within the spectrum of FTD), which raises the question whether PLS is a slow form of ALS.

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A voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) whole-brain analysis of gray matter and white matter changes in amyotrophic lateral sclerosis (ALS) without dementia F. Christidi1, E. Karavasilis2, S. Xirou1, M. Rentzos1, G. Velonakis2, V. Zouvelou1, I. Zalonis1, P. Ferentinos3, L. Poulou2, P. Toulas2, T. Zambelis1, N. Karandreas1, N. Kelekis2, I. Evdokimidis1 1 Medical School, National & Kapodistrian University of Athens, GR, First Department of Neurology, Aeginition Hospital, Athens, Greece 2 Medical School, National & Kapodistrian University, Second Department of Radiology, Attikon Hospital, Athens, Greece 3 Medical School, National & Kapodistrian University, Second Department of Psychiatry, Attikon Hospital, Athens, Greece The heterogeneity of phenotype (motor; cognitive; behavioural features) in amyotrophic lateral sclerosis (ALS) implies that patients show structural changes within but also beyond the motor cortex and corticospinal tract and furthermore outside the frontal lobes, even if frank dementia is not detected. Advanced neuroimaging techniques and whole-brain analysis can reveal the structural pattern and identify overlapping areas with both gray matter (GM) and white matter (WM) abnormalities. Thus, we aimed to investigate GM and WM changes and overlapping anatomical pattern in non-demented patients with ALS using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS). Seventy five participants (50 patients with ALS; 25 healthy controls [HC]) underwent the same imaging protocol including High Resolution 3D-T1-weighted (HR_3DT1w) and 30-directional diffusion-weighted images (DWI) on a 3T Philips Achieva-Tx MR scanner. Whole-brain VBM and TBSS analysis were performed to examine GM and WM differences between ALS and HC, with age, gender and total intracranial volume as covariates of no interest. For TBSS analysis, fractional anisotropy, axial and radial diffusivity were examined (FA, Daxial, Dradial, respectively). Patients with ALS showed decreased GM volume (p < 0.001 uncorrected, extent threshold k = 244) in frontal lobes (inferior and superior orbitofrontal; medial; left inferior orbitofrontal; right precentral gyrus); anterior cingulate cortex bilaterally; right lingual gyrus; left fusiform; left superior temporal gyrus; right cuneus/precuneus; right uncus/parahippocampal gyrus; posterior cerebellum bilaterally. TBSS analysis revealed diffuse WM abnormalities in ALS patients when compared to HC in several intra- and inter-hemispheric WM pathways (both motor and extra-motor) considering the FA, Daxial and Dradial maps (p < 0.05 TFCE corrected) with more widespread changes being detected for Daxial and especially Dradial. By overlaying the results of VBM and TBSS analyses on the same anatomical image, areas of anatomical correspondence between regions with microstructure WM abnormalities (decreased FA or increased Daxial or Dradial) and adjacent regions of GM atrophy were visually identified. The combination of HR_3DT1w and DWI allows identifying motor and extra-motor GM volume reduction and widespread WM abnormalities in non-demented patients with ALS and directly relate GM and WM pathology in vivo.


Poster Session III: CBS, PSP, MND

P307 Impaired corticopontocerebellar tracts underlie pseudobulbar affect in motor neuron disorders M. K. Floeter1, R. Katipally1, M. Kim1, O. Schanz1, M. Stephen1, L. Danielian1, T. Wu1, E. Huey2, A. Meoded1 1 NIH, NINDS, Bethesda, MD, USA 2 Columbia University, Psychiatry and Neurology, New York, NY, USA Objective: The objectives of the study were (1) to determine the prevalence and characteristics of pseudobulbar affect (PBA) in patients with primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS) in an outpatient clinic population, and (2) to test the hypothesis that damage of inputs to the cerebellum, leading to cerebellar dysmodulation, is associated with PBA. Methods: Chart review of all patients with PLS and ALS seen between 2000 and 2013. The examining neurologist documented the presence or absence of PBA in 87 patients. Fortyseven patients also had diffusion tensor imaging (DTI) studies. Tract-based spatial statistics were used to compare DTI of patients with and without PBA to identify altered white matter tracts associated with PBA. Results: Thirty-one of 50 patients with PLS and 12 of 37 patients with ALS had PBA. Psychiatric/emotional assessment found congruence between mood and affect during episodes, but excessive magnitude of the response. DTI studies of 25 PLS and 22 ALS patient brains showed reduced fractional anisotropy of the corticospinal and callosal white matter tracts in all patients. Patients with PBA additionally had increased mean diffusivity of white matter tracts underlying the frontotemporal cortex, the transverse pontine fibers, and the middle cerebellar peduncle. Conclusions: PBA is common in PLS. Imaging findings showing disruption of corticopontocerebellar pathways support the hypothesis that PBA can be viewed as a “dysmetria”of emotional expression resulting from cerebellar dysmodulation.

P308 Visuoperception test predicts pathologic diagnosis of Alzheimer disease in corticobasal syndrome C. Boyd1, M. Tierney2, E. Wassermann2, S. Spina3, A. Oblak3, B. Ghetti3, J. Grafman4, E. Huey5 1 Columbia University, Neurology, New York, NY, USA 2 NIH, NINDS, Bethesda, MD, USA 3 Indiana University, Pathology, Indianapolis, IN, USA 4 Rehabilitation Institute of Chicago, Brain Injury Research Program, Chicago, IL, USA 5 Columbia University, Psychiatry and Neurology, New York, NY, USA Objective: To use the Visual Object and Space Perception Battery (VOSP) to distinguish Alzheimer disease (AD) from nonAD pathology in corticobasal syndrome (CBS). Methods: This clinicopathologic study assessed 36 patients with CBS on the VOSP. All were autopsied. The primary dependent variable was a binary pathologic outcome: patients with CBS who had primary pathologic diagnosis of AD (CBS-AD, n = 10) versus patients with CBS without primary pathologic diagnosis of AD (CBS-nonAD, n = 26). We also determined sensitivity and specificity of individual VOSP subtests. Results: Patients with CBS-AD had younger onset (54.5 vs. 63.6 years, p = 0.001) and lower memory scores on the Mattis

Dementia Rating Scale-2 (16 vs. 22 points, p = 0.003). Failure on the VOSP subtests Incomplete Letters (odds ratio [OR] 11.5, p = 0.006), Position Discrimination (OR 10.86, p = 0.008), Number Location (OR 12.27, p = 0.026), and Cube Analysis (OR 45.71 p = 0.0001) had significantly greater odds of CBS-AD than CBSnonAD. These associations remained when adjusting for total Mattis Dementia Rating score, disease laterality, education, age, and sex. Receiver operating characteristic curves demonstrated significant accuracy for Incomplete Letters and all VOSP spatial subtests, with Cube Analysis performing best (area under the curve 0.91, p = 0.0004). Conclusions: In patients with CBS, failure on specific VOSP subtests is associated with greater odds of having underlying AD. There may be preferential involvement of the dorsal stream in CBSAD. Classification of evidence: This study provides Class II evidence that some subtests of the VOSP accurately distinguish patients with CBS-AD from those without AD pathology (e.g., Cube Analysis sensitivity 100%, specificity 77%).

P309 Investigating progressive supranuclear palsy using VBM and SVM classification K. Mueller1, R. Jech2,3, C. Bonnet2,3, J. Tint era4, H. E. M€ oller1, uzicka2,3, K. Fassbender5, J. Kassubek6, M. Otto6, E. R M. L. Schroeter1,7 1 Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany 2 Charles University in Prague, Department of Neurology and Center of Clinical Neuroscience, Prague, Czech Republic 3 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic 4 Institute for Clinical and Experimental Medicine, Prague, Czech Republic 5 Saarland University Homburg, Clinic and Polyclinic for Neurology, Homburg, Germany 6 University of Ulm, Clinic and Polyclinic for Neurology, Ulm, Germany 7 University Hospital Leipzig, Clinic for Cognitive Neurology, Leipzig, Germany To investigate progressive supranuclear palsy (PSP) and structural brain changes caused by this rare disease, a cohort of 20 PSP patients (7 female, age 67.3 7.8 years, meanstdev) was compared with a group of 20 age and gender matched healthy controls (HC) (8 female, age 66.3 7.8 years). T1-weighted images were acquired on four different centers with the MP-RAGE protocol using MAGNETOMâ scanners (Siemens, Germany) at 3T. In order to differentiate PSP patients from HC, support vector machine (SVM) classification was performed with voxel-based morphometry (VBM) and the libSVM software package. Classification accuracy was obtained with cross-validation using the “one leave out” approach with 400 models leaving a patient and a control subject out when building the classifier. The analysis was performed with two different approaches of feature selection: First, voxels were used with the SPM’s gray matter tissue probability map (TPM) using different minimum gray matter probabilities between 0 and 80 percent. Second, several regions-of-interest (ROIs) were defined with the WFU-Pickatlas selecting striatum, thalamus, caudate, and midbrain, as suggested as PSP’s core network in the literature.


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Using SVM classification using all voxels with the TPM showing a probability larger 0.4, PSP patients and HC were detected with a classification accuracy of 79.2 and 84.2 percent, respectively. The resulting sensitivity was 0.83 and the specificity was 0.80. Using different TPM thresholds showed accuracy values in the same order of magnitude. The ROI-based SVM approach focusing on the striatum and midbrain outperformed the classification with all gray matter voxels of the brain. Here, we obtained an accuracy of 84.2 and 86.2 percent for the PSP patients and HC that is a sensitivity of 0.86 and specificity of 0.85. Both the ROI-based and the full-brain feature selection approach showed a higher sensitivity of disease detection than specificity of correctly classified controls.

P310 Genome-wide association study of plasma tau levels identifies risk variants for PSP and CBD J.-T. Yu1, J. Chen1, H.-F. Wang1, H. Zetterberg1, K. Blennow1, J. Yokoyama1, M. Weiner1, J. Kramer1, H. Rosen1, B. Miller1, G. Coppola1, A. Boxer1 1 University of California, San Francisco, Memory and Aging Center, Department of Neurology, San Francisco, USA Background: Cerebrospinal fluid (CSF) tau concentration is an established biomarker for Alzheimer’s disease (AD) and has been used as an endophenotype for genetic analyses. Recent technical developments also allow for measurement of tau in plasma. Here, we hypothesized that plasma tau, similar to CSF tau, may constitute a suitable endophenotype for identifying genetic risk factors for tauopathies. Methods: In this study, non-Hispanic Caucasian individuals whose data met all quality control (QC) criteria were included. Association of plasma tau with the genetic variants was performed using PLINK with the additive genetic model. The effects of genotypes on plasma tau levels were also examined with a multiple linear regression model. The Spearman rank correlation coefficient was used to determine correlations of plasma tau concentrations with CSF tau concentrations. p < 0.05 was considered statistically significant after adjustment for the high number of multiple comparisons using Bonferroni correction. Results: There was no correlation between tau levels in plasma and CSF. The common SNP (rs242557, representing the H1c haplotype) in the microtubule-associated protein tau gene (MAPT) displayed association with plasma tau levels at genome-wide significance. Moreover, this locus survived both permutation-based and Bonferroni corrections for multiple testing. As expected, the minor allele (A) of rs242557 was associated with higher plasma tau levels in a dose-dependent fashion. IL2RA (rs7072793 and rs7073236) and PARK2 (rs2187213) were identified as two suggestive loci associated with lower plasma tau levels. Conclusion: We detected a genome-wide significant SNP, rs242557 in MAPT, and 2 suggestive loci (in IL2RA and PARK2) associated with plasma tau levels. As rs242557 represents the MAPT H1c haplotype and has previously been identified as a major genetic risk factor for both PSP and CBD, these findings suggest that plasma tau concentration could be a useful endophenotype for identifying risk for 4-repeat tauopathies. Our findings also suggest the presence of preclinical plasma tau changes in healthy individuals who could be at risk for PSP and CBD. Further replication studies with independent, larger, and ideally longitudinal datasets will be required to confirm these findings.

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P311 The sequence of progression of symptom domains in the PSP-Rating Scale (PSP-RS) C. Brittain1, M. Irizarry1, J. Lebrec1, A. Boxer2 1 Eli Lilly, Windlesham, Portugal 2 University of California, Memory and Aging Center, San Francisco, USA The PSP-RS is the most commonly used assessment of disease progression in PSP clinical trials. It assesses 28 signs/symptoms of PSP in six domains—Daily Activities, Mentation, Bulbar, Gait/ Midline, Ocular Motor, and Limb Motor; total scores range from zero (no impairment) to 100 (most disability). By determining the contributions of each domain to overall disease severity, we can better understand the sequence of symptomatic decline in patients with PSP (Richardson’s Syndrome) and therefore characterize the sequence in which symptom domains decline. Baseline clinical trial data were analyzed from 308 patients with mild-moderate PSP from the Phase 2/3 clinical trial of davunetide in PSP. Proportional-odds logistic regression models were applied to model normalized PSPRS subscales, using the PSP-RS total score as the index of disease severity. Probabilities of start of impairment and severe impairment were estimated at each PSP-RS domain score level. Additional analyses utilized the Schwab and England Activities of Daily Living (SEADL) and Clinical Global Impression of Disease Severity (CGIds) as the index of disease severity. From the estimated probabilities for each PSP-RS subscale as a function of the PSP-RS total score, the earliest symptom domain impaired was ocular motor, followed jointly by gait/midline and daily activities, followed by limb motor, then mentation and finally bulbar. For severe impairment in subscales, the sequence is the same; however, results suggest a greater separation between the decline in ocular, gait/ midline and daily activities and the decline in the other subscales. The sequence of decline in PSP can be described using probability estimates, and hence an expected order of progression of symptom domains can be elicited from the PSP-RS, CGIds and SEADL. This maybe useful for clinicians to set expectations on disease progression for patients/caregivers, and gives a suggestion of the symptom domains that may be most sensitive to progression and detection of treatment effects at each disease stage in PSP clinical trials. Further studies of longitudinal PSP-RS datasets will be necessary to understand how well this sequence of change captures events in individual PSP patients.

P312 Disentangling the neural correlates of corticobasal syndrome & corticobasal degeneration with systematic & quantitative ALE meta-analyses F. Albrecht1, S. Bisenius1, R. Morales Schaack1, M. Schroeter1 1 Max-Planck-Institute for Human Cognitive and Brain Sciences, Neurology, Leipzig, Germany Corticobasal Degeneration (CBD) is a scarce neurodegenerative disease, which can only be confirmed by histopathological examination. Reported to be associated with various clinical syndromes, its classical clinical phenotype is corticobasal syndrome (CBS). Due to the rareness of CBS/CBD and low numbers of patients included in single studies, meta-analyses are particularly suited to disentangle features of the clinical syndrome and histopathology. Using PubMed, we identified 11 magnetic resonance imaging (MRI)



studies measuring atrophy in 22 independent cohorts with 200 patients contrasted to 318 healthy controls. The anatomic likelihood estimation method (ALE) was applied to reveal affected brain regions across studies. CBS was related to gray matter loss in the basal ganglia/thalamus, frontal, parietal and temporal lobes. In CBD patients, atrophy in the thalamus, frontal, temporal and occipital lobes were found. Finally, in a conjunction analysis the bilateral thalamus, the bilateral posterior frontomedian cortex, posterior midcingulate cortex and pre-/supplementary motor area, and the left posterior superior and middle frontal gyrus/precentral gyrus were identified as areas associated with both, CBS and CBD. Remarkably, atrophy in the pre-/supplementary motor area & posterior midcingulate/frontomedian cortex seems to be specific for CBS/ CBD, whereas atrophy in the thalamus and the left posterior superior and middle frontal gyrus/precentral gyrus are also associated with other neurodegenerative diseases according to ALE meta-analyses. Our study creates a new conceptual framework to understand and distinguish between clinical features (CBS) and histopathological findings (CBD) by powerful data-driven meta-analytical approaches. Furthermore, it proposes region-specific atrophy as an imaging biomarker for diagnosis of CBS/CBD ante-mortem.

CBS 1.92%/year, PSP: 0.87%, p < 0.05) regions, but midbrain (CBS: -2.31%/year, PSP: 2.46%/year) and pontine (CBS: 1.77%/year, PSP: 2.27%/year) atrophy rates were similar. Atrophy rates in PSP were replicated in the trial cohort (midbrain: 2.70%/year, pons: 2.48%). The midbrain/pons volumetric ratio differed between diagnoses (PSP = 0.44, CBS = 0.46, p < 0.05), but remained stable over time. Brainstem atrophy rates were correlated with disease progression measured using the PSP Rating Scale (PSPRS) (midbrain: r = 0.43, p < 0.01; pons: r = 0.38, p < 0.05). Volume loss is quantifiable in CBS and PSP over an interval of 6 months, and by focusing on brainstem volume and PSPRS as outcome measures, combined 4R tauopathy trials may be feasible.

P313

Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), and Parkinson Disease (PD), including PD with MCI and PD with dementia, are characterized by overlapping parkinsonian motor and cognitive features. However, there are distinct sources of pathology in PSP and CBD (4Rtau) compared to PD (alpha-synuclein). Both sources of pathology are associated with heterogeneous rates of survival, with a median of 5 years in PSP and 9 years in PD. Thus objective prognostic markers are essential to improve management of patient care and to stratify clinical trials. Cerebrospinal fluid (CSF) phosphorylated tau (ptau) is associated with tau pathological inclusions, and thus we hypothesize it will have specificity for 4Rtau survival, but not PD. CSF total tau (ttau), in contrast, is a marker of neuronal degeneration and thus is hypothesized to lack specificity. We evaluated survival in 33 4Rtau patients and 42 age-matched PD patients. All patients participated in a CSF lumbar puncture < 3 years from disease onset, and exclusion criteria included CSF evidence of amyloid pathology (amyloidbeta< 192) to exclude co-morbid AD pathology. Survival was calculated from reported age at onset to age at death, or patients were censored using reported year of last clinical visit. Cox regression models covaried gender, disease duration at CSF collection, and age of onset. Ptau was associated with reduced survival in the 4Rtau cohort (b = 0.535; p < 0.005). Ptau was not associated with survival in PD, and ttau was not associated with survival in 4Rtau or PD (all p > 0.1). Together, these findings suggest that CSF ptau may provide a specific prognostic marker of survival in 4Rtau and should be considered as covariate in tautargeted clinical trials.

Rapid progression of brain atrophy in progressive supranuclear palsy and corticobasal degeneration S. Dutt1, R. Binney1,2, H. Heuer1, P. Luong1, S. Attygalle1, P. Bhatt1, G. Marx1, J. Elofson1, M. C. Tartaglia3, I. Litvan4, S. McGinnis5, B. Dickerson5, J. Kornak6, D. Waltzman1,7, L. Voltarelli1, N. Schuff8, G. Rabinovici1, J. Kramer1, C. Jack9, B. Miller1, A. Boxer1 1 UCSF, Neurology, San Francisco, USA 2 Temple University, Communication Sciences & Disorders, Philadelphia, USA 3 University of Toronto, Toronto, USA 4 UC San Diego, Neurosciences, San Diego, USA 5 Massachusetts General Hospital, Gerontology, Charlestown, USA 6 UCSF, Epidemiology & Biostatistics, San Francisco, USA 7 Stanford University, Psychiatry & Behavioral Sciences, Stanford, USA 8 UCSF, Radiology, San Francisco, USA 9 Mayo Clinic, Radiology, Rochester, USA Volumetric MRI may be a useful outcome measure in 4R tauopathy clinical trials. Studies of progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) have identified specific patterns of atrophy over 1 year or longer, but have not examined shorter intervals. MRIs from PSP (n = 55), CBS (n = 33), and normal controls (NC; n = 30) were acquired at 3T at 6-month and 12-month intervals at four centers; 226 PSP patients from the AL108–231 clinical trial served as a replication cohort. Longitudinal voxel-based morphometric analyses identified patterns of volume loss, and region of interest (ROI) analyses examined rates of loss. There were distinct patterns of longitudinal atrophy in each group compared to NC (p < 0.05 FWE corrected). Over 6 months, PSP volume loss was most prominent in the brainstem, whereas CBS had greater loss of superior frontoparietal grey and white matter. Over 1 year, pons and midbrain atrophy progressed in PSP, while CBS developed modest brainstem atrophy with more pronounced frontoparietal loss. In ROI analyses, CBS patients exhibited greater atrophy rates than PSP in cortical (precentral gyrus: CBS -5.08%/ year, PSP -2.15%/year, p < 0.001) and basal ganglia (putamen:

P314 Cerebrospinal fluid phosphorylated tau associated with survival in 4-repeat tauopathies K. Firn1, L. M. Shaw2, D. J. Irwin2, M. Grossman1, C. T. McMillan1 1 University of Pennsylvania, Neurology, Philadelphia, USA 2 Perelman School of Medicine, Pathology and Laboratory Medicine, Philadelphia, USA


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The relationship of iron accumulation to motor and cognitive performance in amyotrophic lateral sclerosis N. Spotorno1, J. Acosta-Cabronero2, J. Machts3, S. Abdulla3, K. Kollewe4, S. Preti4, S. Vielhaber3, P. J. Nestor2 1 Deutsches Zentrum f€ ur Neurodegenerative Erkrankungen DZNE, Brainplasticity & Neurodegeneration Group, Magdeburg, Germany 2 German Center for Neurodegenerative Diseases DZNE, Brain Plasticity and Neurodegeneration Group, Magdeburg, Germany 3 Otto-von-Guericke University, Department of Neurology, Magdeburg, Germany 4 Hannover Medical School, Neurology Clinic, Hannover, Germany Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD) can co-occur, however, the mechanism by which only a subset of ALS patients develop overt FTD is unclear. Brain iron accumulation occurs in aging and is associated with neurodegeneration. Whether this is clinically relevant is largely unknown. In the current study we employed a newly developed MRI contrast, quantitative magnetic susceptibility mapping (QSM)—a validated proxy of iron deposition and suitable for whole brain analyses—to examine the relevance of iron deposition to motor and cognitive performance in N = 36 ALS patients (no ALS-FTD). A negative correlation between QSM and motor performance (ALSFRS-R score) was identified in the corticospinal tract, red nuclei, substantia nigra and ventral striatum. Diminished performance in verbal fluency correlated with increased QSM signal in a network of prefrontal regions, including dorsolateral prefrontal cortex (dlPFC) and both medial and lateral orbitofrontal cortex (m-lOFG) that extended to the insular cortex and temporal pole. Delayed free recall showed a negative correlation with QSM in dlPFC, mOFC, lOFC and superior temporal cortex (all results: p < 0.05 FWE corrected). Covarying for age slight attenuated the effects but the overall patterns remained. In contrast, voxel-based morphometry (VBM) regressions of structural data showed no relationship to clinical scores. The results revealed a direct link between QSM and clinical features of ALS. Moreover, the correlations pointed to brain regions known to underpin the respective functions. The lack of VBM results suggests this is an upstream event to atrophy. Iron accumulation may be an important marker in understanding the link between ALS and FTD.

P316 Revised clinical diagnostic criteria for progressive supranuclear palsy (PSP) G. Ho¨glinger1, G. Respondek1, M. Stamelou2, C. Kurz1, K. Josephs3, uller6, C. Nilsson7, J. Whitwell3, A. Lang4, B. Mollenhauer5, U. M€ 8 9 T. Arzberger , E. Gelpi , A. Giese8, D. Irwin10, W. Meissner11, A. Pantelyat12, J. van Swieten13, C. Troakes14, A. Antonini15, K. Bhatia16, Y. Bordelon17, J. C. Corvol18, C. Colosimo19, R. Dodel20, M. Grossman10, J. Kassubek21, F. Krismer22, J. Levin8, H. Morris16, P. Nestor23, W. Oertel20, G. Rabinovici24, J. Rowe25, T. van Eimeren26, G. Wenning22, J.-T. Yu24, L. I. Golbe27, I. Litvan28, A. Boxer24 1 TUM, Neurology, Munich, Germany 2 University of Athens, Neurology, Neurology, Greece 3 Mayo Clinic, Rochester, USA 4 University of Toronto, Neurology, Toronto, Canada 5 Paracelsus-Elena-Klinik, Kassel, Germany

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Justus-Liebig-Universit€ at, Giessen, Germany Lund University, Lund, Sweden 8 Ludwig-Maximilians-University, Munich, Germany 9 Hospital Clinic de Barcelona, Barcelona, Spain 10 University of Pennsylvania, Philadelphia, USA 11 University Hospital Bordeaux, Bordeaux, France 12 Johns Hopkins University School of Medicine, Baltimore, USA 13 Erasmus University Medical Center, Rotterdam, Netherlands 14 King0 s College, London, Great Britain 15 IRCCS San Camillo, Venice, Italy 16 UCL Institute of Neurology, London, Great Britain 17 David Geffen School of Medicine, Los Angeles, USA 18 H^ opital Pitie-Salpêtriere, Paris, France 19 University of Roma “La Sapienza”, Roma, Italy 20 University Hospital Gießen and Marburg, Marburg, Germany 21 University of Ulm, Ulm, Germany 22 Medical University of Innsbruck, Innsbruck, Austria 23 DZNE, Magdeburg, Germany 24 University of California San Francisco, San Francisco, USA 25 University of Cambridge, Cambridge, Great Britain 26 University Hospital of Cologne, Cologne, Germany 27 Robert Wood Johnson Medical School, New Brunswick, USA 28 University of California San Diego, San Diego, USA 7

PSP is a neuropathologically defined disease entity. Clinical diagnosis remains a challenge. The NINDS-SPSP criteria for the clinical diagnosis of PSP (Litvan et al., Neurology 1996; 46:922– 930) are widely accepted because of their high specificity. However, their sensitivity is limited for patients early in the clinical course and for phenotypic PSP variants other than Richardson’s syndrome that have been described recently. We aimed to provide an evidencebased revision of the clinical diagnostic criteria for PSP. We inquired the PubMed, Cochrane, Medline, PSYCInfo databases for original research articles, systematic reviews and meta-analyses, published in English language from 1996 to 2015, using postmortem diagnosis or the NINDS-SPSP criteria as the diagnostic standard. Published evidence was evaluated as proposed by the Scottish Intercollegiate Guidelines Network. Secondly, standardized clinical data were extracted from charts of patients with pathologically diagnosed PSP (N = 198), CBD (N = 50), MSA-P (N = 51), PD (N = 51), and FTLD (N = 64). On this basis, criteria were drafted, optimized in two modified Delphi evaluations, and submitted to a structured discussion and consensus procedure during a 1.5 day in-person meeting. From N = 5894 identified articles, N = 469 met the inclusion standards. We identified the functional domains of ocular motor dysfunction, postural instability, akinesia-rigidity, and cognitive dysfunction as clinical predictors of PSP. Within these domains, distinct clinical features provide varying levels of predictive values. Specific combinations of these do provide different degrees of diagnostic certainty (probable > possible > oligosymptomatic). Defined imaging findings support the diagnosis. Defined clinical, imaging, laboratory and genetic findings help to rule out alternative diagnoses. In summary, we propose new criteria for the early, sensitive and specific clinical diagnosis of PSP on the basis of currently available evidence, to be validated in prospective clinico-pathological studies.



P317 Whole-brain pattern of iron-aware tissue magnetostatics in amyotrophic lateral sclerosis J. Acosta-Cabronero1, J. Machts2, K. Kollewe3, S. Abdulla2, S. Petri3, S. Vielhaber2, P. Nestor1 1 German Centre for Neurodegenerative Diseases DZNE, Brain Plasticity and Neurodegeneration Group, Magdeburg, Germany 2 Otto-von-Guericke University, Department of Neurology, Magdeburg, Germany 3 Hannover Medical School, Neurology Clinic, Hannover, Germany The aim of the study was to determine the whole-brain landscape of magnetostatic alterations in amyotrophic lateral sclerosis (ALS) with the new iron-sensitive MRI contrast, namely quantitative susceptibility mapping (QSM). N = 28 patients with classic (Charcot) ALS without dementia (age = 61 10 y.o., disease duration = 18 12 months, ALSFRS-R = 38 6) and N = 39 tightly-matched controls (age = 61 11 y.o.) were recruited. All MRI measurements were performed in a Siemens Verio 3T scanner. Susceptibility-weighted MRI signals were reconstructed, postprocessed and analysed using state-of-the-art quantitative methods (Acosta-Cabronero et al. J Neurosci 2016; 36:364). QSM identified in vivo evidence for metal (almost certainly iron) accumulation in ALS in the primary motor cortex, corticospinal tract, posterior corpus striatum, mesencephalic nuclei and lateral prefrontal cortex (PFC). Notably the results suggest pathological accumulation in the primary motor cortex and globus pallidus, which could be contributing to a toxic insult; whereas increased susceptibility effects in the putamen, substantia nigra and red nucleus appear to be common to a range of degenerative states, as we have previously observed them in Alzheimer’s (putamen only, Acosta-Cabronero et al. Plos One 2013; 8:e81093) and in normal aging (Acosta-Cabronero et al. 2016). The primary motor and corticospinal changes appear unique to ALS in contrast to the disorders thus far examined with QSM and, obviously, are strongly coherent with the known degeneration of this disease. The lateral PFC abnormality is intriguing and possibly points to a bridge between ALS and the comorbid risk of frontotemporal dementia—a hypothesis that warrants further investigation.

P318 Progressive supranuclear palsy in the spectrum of frontotemporal dementia: a neuropsychological and neuroimaging study L. Cruz de Souza1, E. D. P. Francßa Resende1, F. E. C. Cardoso1, H. C. Guimar~aes1, L. Boson1, M. Hornberger2, M. Bertoux2, P. Caramelli1, A. Teixeira1 1 Universidade Federal de Minas Gerais, Belo Horizonte, Brazil 2 University of East Anglia, Norwich, Great Britain Progressive supranuclear palsy (PSP) and behavioral variant frontotemporal dementia (bvFTD) share clinical and neuropsychological features of frontal syndrome, but the cognitive performance of PSP patients in social cognition tasks is not completely understood. The neural basis of social cognition abilities in PSP also remains to be explored. This study aimed to investigate social cognition in PSP patients, in comparison with bvFTD. We also aimed to contrast both groups in terms of patterns of brain atrophy in volumetric analysis. We included 81 participants (24 healthy controls, 15 early PSP and 24 early bvFTD). All of them underwent a full clinical and

neuropsychological exam. Cognitive assessment included the MiniMental State Exam (MMSE), the Frontal Assessment Battery (FAB) and the short version of the Social Cognition and Emotional Assessment (Mini-SEA), which is composed by the Faux-pas test and a facial emotions recognition test (Ekman). Gray matter volume was compared between control and pathological groups and between PSP and bvFTD through voxel-based morphometry analysis (FSL software). There was no significant difference between PSP and bvFTD groups regarding sex, educational level, MMSE and FAB scores. Compared to controls, PSP patients showed significantly lower performances in all scores of the Mini-SEA (p < 0.01). There was no difference between PSP and bvFTD groups regarding their scores in the Mini-SEA. Compared to controls, PSP and bvFTD patients had marked frontal atrophy, with a more severe pattern in bvFTD patients. In summary, patients with PSP had worse scores on social cognition tests compared to healthy controls and showed an intermediate pattern of prefrontal atrophy compared to bvFTD patients. Importantly, the neuropsychological deficits were similar to those observed in bvFTD participants. This aspect should be considered in the perspective of the differential neuropsychological and radiological diagnosis between PSP and bvFTD.

P319 H46R SOD1 mutation is consistently associated with a relatively benign form of Amyotrophic Lateral Sclerosis with very slow progression Z. Zou1, M. Liu2, X. Li2, L. Cui2 1 Fujian Medical University Union Hospital, Department of Neurology, Fuzhou, China 2 Peking Union Medical College Hospital, Department of Neurology, Beijing, China Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive loss of motor neurons in motor cortex, brainstem, and spinal cord. Over 60% of patients die from respiratory failure within 3 years of presentation. Here reported two ALS patients carrying the p.H46R missense mutation in SOD1 gene presented with a characteristic clinical phenotype of very slow progression. We also reviewed the 11 pedigrees harboring p.H46R mutations reported previously. These finding suggested that SOD1 p.H46R mutation is associated with a specific phenotype, that is, lower limb onset with rare bulbar involvement, and a slow progression with longer survival. It is therefore important to recognize the typical clinical picture, and SOD1 sequencing may be necessary to give the patient correct diagnosis and prognosis.

P320 Mutations in FUS are the most frequent genetic cause in juvenile sporadic ALS patients of Chinese origin Z. Zou1, X. Li2, M. Liu2, L. Cui2 1 Fujian Medical University Union Hospital, Department of Neurology, Fuzhou, China 2 Peking Union Medical College Hospital, Department of Neurology, Beijing, China Juvenile onset Amyotrophic lateral sclerosis (ALS) is a very rare form of motor neuron disease, with the first symptoms of motor


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neuron degeneration manifested before 25 years of age. Mutations in the alsin (ALS2), senataxin (SETX), and Spatacsin (SPG11) have been associated with familial ALS with juvenile onset and slowly progression, whereas the genetic architecture of sporadic juvenile ALS remains unclear. We screened mutations in C9orf72, SOD1, FUS, TARDBP, ANG, VCP and PFN1 in 16 juvenile sporadic ALS patients. Four cases (25%) carrying FUS mutations (p.P525L (2 cases), p.G504Wfs*12, and p.R495X) and one individual (6%) harboring a SOD1 mutation (p.L84F) were identified. Two FUS mutations (p.G504Wfs*12 and p.P525L) in our cohort were proved to be de novo mutations. All of the five mutation carriers had an aggressive disease course. Our results suggest that FUS mutations are the most frequent genetic cause in early-onset sporadic ALS patients of Chinese origin. Genetic testing of FUS should be performed in early-onset ALS patients especially those with an aggressive disease course.

P321 Predicting disease progression in progressive supranuclear palsy in multicenter clinical trials J. Bang1, I. Lobach2, A. Lang3, M. Grossman4, D. Knopman5, B. Miller1, L. Schneider6, R. Doody7, A. Lees8, M. Gold9, B. Morimoto10, A. Boxer1 1 University of California San Francisco, Neurology, San Francisco, USA 2 University of California San Francisco, Epidemiology and Biostatistics, San Francisco, USA 3 University of Toronto, Neurology, Toronto, Canada 4 University of Pennsylvania, Neurology, Philadelphia, USA 5 Mayo Clinic, Neurology, Rochester, USA 6 University of Southern California, Neurology, Los Angeles, USA 7 Baylor College of Medicine, Neurology, Houston, USA 8 University College of London, Neurology, London, Great Britain 9 UCB BioSciences, Research Triangle, USA 10 Celerion, Lincoln, USA There is an increasing interest in pursuing clinical trials of taudirected therapies in PSP due to its strong genetic and neuropathological links to tau protein. Clinical and MRI measurements can track disease progression in PSP, but many have not been extensively evaluated in multicenter clinical trials. We identified optimal measures to capture clinical decline and predict disease progression in multicenter PSP trials. Longitudinal clinical rating scales, neuropsychological test scores, and volumetric MRI data from an international, phase 2/3 clinical trial of davunetide for PSP (intent to treat population, n = 303) were used to identify measurements with largest effect size, strongest correlation with clinical change, and best ability to predict dropout or clinical decline over 1 year as measured by PSP Rating Scale (PSPRS). Baseline cognition as measured by Repeatable Battery for Assessing Neuropsychological Status (RBANS) was associated with attrition, but had only a small effect. PSPRS and Clinical Global Impression (CGI) had the largest effect size for measuring change. Annual change in CGI (R2=0.44 [95% CI: 0.33, 0.54]), RBANS (R2=-0.33 [95% CI: 0.45, 0.21]), and MRI midbrain (R2=0.31 [95% CI: 0.43, 0.18]) volume were most strongly correlated with annual PSPRS and had the largest effect sizes for detecting annual change (p < 0.05). At baseline, shorter disease duration, more severe depression, and lower performance on RBANS and executive function tests were associated with faster worsening of the PSPRS in

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completers. In the overall population including the dropouts, the following baseline evaluations had significant effect on PSPRS trajectory of change: color trails 2 (z = 3.2), color trails 1 (z = 3.09), phonemic fluency (z = 2.9), RBANS [z = 2.32(scaled) and z = 2.28(raw)] and SEADL (z = 2.06). Baseline cognitive status and mood influence the rate of disease progression in PSP. Multiple clinical, neuropsychological, and volumetric MRI measurements are sensitive to change over 1 year in PSP and appropriate for use in multicenter clinical trials.

P322 Unusual sporadic 4R-tauopathy with bulbar onset MNDlike syndrome preceding bvFTD J. Prudlo1, S. Teipel2, A. Buettner3, M. Neumann4 1 Rostock University Medical Center and German Center for Neurodegenerative Diseases DZNE, Department of Neurology, Rostock, Germany 2 Rostock University Medical Center and German Center for Neurodegenerative Diseases DZNE, Department of Psychosomatic Medicine, Rostock, Germany 3 Rostock University Medical Center, Institute of Forensic Medicine, Rostock, Germany 4 University Hospital of T€ ubingen and German Center for Neurodegenerative Diseases DZNE, Department of Neuropathology, T€ ubingen, Germany This study describes a 77 year-old woman who, at the age of 62, developed a slowly progressive dysphagia, followed years later by a dysarthria. Owing to severe aspiration and critical weight loss a percutaneous endoscopic gastrostomy became necessary. After 14 years, the patient became mute. In the last 3 years of her life, her tongue was small but not furrowed and displayed no fasciculations; her pharyngeal musculature was paralysed, and marked drooling was thus notable. Her jaw jerk was not brisk. Her deep tendon reflexes were brisk, with no Babinski sign. A gradual progressive character change became apparent 9 years after the bulbar onset of the disease. The patient became disinhibited, logorrheic, emotionally unstable, suffering from anxiety and depressive episodes. Six months prior to her death, the patient became bed-ridden: she was unable to sit in a wheelchair due to camptocormia and was urine incontinent. Electromyography showed chronic denervation without spontaneous activity, not even in the tongue. There were no asymmetric parkinsonism and no signs of lateralised cortical dysfunction. The MRI displayed prominent right-sided temporal lobe atrophy. No mutation was detected in the MAPT gene. The post-mortem analysis revealed frontotemporal atrophy, ballooned neurons, and tau-pathology with numerous threads in the gray and subcortical white matter, astrocytic plaques, pretangles and neurofibrillary tangles as well as coiled bodies, fulfilling the neuropathological criteria for corticobasal degeneration (CBD). Unusually however, several tufted astrocytes were also detectable in affected cortical regions. The prominent and early bulbar motor neuron signs of the patient are exclusion criteria for both clinical research criteria for probable sporadic CBD and possible CBD (Armstrong 2013). Moreover, the co-occurrence of both astrocytic plaques and tufted astrocytes are unusual (Katsuse 2003; Tan 2005). What has yet to be determined is whether this case is an atypical form of CBD or a new clinicopathological entity within the sporadic 4R-tauopathies.



P323 TDP-43 in the hypoglossal nucleus identifies amyotrophic lateral sclerosis in behavioral variant frontotemporal dementia R. Tan1,2, M. Kiernan3, J. Kril4, M. Hasegawa5, M. Masada-Suzukake5, C. Dobson-Stone1,2, J. Kwok1,2, M. Hornberger6, J. Hodges1,2, G. Halliday1,2 1 Neuroscience Research Australia, Randwick, Australia 2 University of New South Wales, School of Medical Sciences, Sydney, Australia 3 The University of Sydney, Brain and Mind Centre, Sydney Medical School, Sydney, Australia 4 The University of Sydney, Discipline of Pathology, Sydney Medical School, Sydney, Australia 5 Tokyo Metropolitan Institute of Medical Science, Neuropathology and Cell Biology, Japan 6 University of East Anglia, Norwich Medical School, Norwich, Great Britain The hypoglossal nucleus was recently identified as a key brain region in which the presence of TDP-43 pathology could accurately discriminate TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis (ALS). The objective of the present study was to assess the hypoglossal nucleus in behavioral variant frontotemporal dementia (bvFTD), and determine whether TDP-43 in this region is associated with clinical ALS. Twenty-nine cases with neuropathological FTLD-TDP and clinical bvFTD that had not been previously assessed for hypoglossal TDP-43 pathology were included in this study. Of these 29 cases, 41% (n = 12) had a dual diagnosis of bvFTD-ALS at presentation, all 100% (n = 12) of which demonstrated hypoglossal TDP-43 pathology. Of the 59% (n = 17) cohort that presented with pure bvFTD, 35% (n = 6) were identified with hypoglossal TDP-43 pathology. Review of the case files of all pure bvFTD cases revealed evidence of possible or probable ALS in 5 of the 6 hypoglossal-positive cases (83%) towards the end of disease, and this was absent from all cases without such pathology. In conclusion, the present study validates grading the presence of TDP43 in the hypoglossal nucleus for the pathological identification of bvFTD cases with clinical ALS, and extends this to include the identification of cases with possible ALS at end-stage.

P325 Natural history and progression to dementia in progressive supranuclear palsy A. Pilotto1,2, S. Gazzina1, A. Benussi1, M. Manes1, V. Dell’Era1, M. Cosseddu1, R. Turrone1, B. Borroni1, A. Padovani1 1 University of Brescia, Department of Clinical and Experimental Sciences, Brescia, Italy 2 University of T€ubingen, Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, T€ ubingen, Germany Current clinical criteria for Progressive Supranuclear Palsy (PSP) account for early cognitive impairment only as supportive for diagnosis (NINDS-SPSP). The prevalence of mild cognitive impairment (MCI) or dementia at disease onset and over disease course is still unrecognized. We retrospectively evaluated 47 PSP patients who completed 2-year follow-up, and we assessed the diagnosis of MCI or dementia at baseline, at 1-year and at 2-year follow-up with a standardised neurological, neuropsychological and

behavioural assessment. MCI was defined as a deficit in at least two tests of our battery without impairment of activities of daily living (ADL). A cognitive dysfunction in more than one cognitive domain with ADL impairment (independent of motor/autonomic symptoms) defined dementia. At baseline, 31% of PSP patients (n = 15) presented dementia, 47% MCI (n = 22) and 22% (n = 10) fulfilled PSP criteria but with normal cognition (NC). Demographic characteristics and motor functions, as measured by UPDRS, were comparable at baseline. At 1-year follow-up, other 47% of PSP patients converted to dementia (15 patients out of 32 with MCI or NC). At 2-year follow-up, 3 other subjects (3 of 17), namely the 18%, converted to dementia. At 2-year follow-up, when converters to dementia were compared to non-converters, no significant differences of baseline demographic characteristics and baseline motor features were found. Analysis of baseline cognitive profile and behavioural disturbances did not identify any significant difference between groups. Conversely, diagnosis of MCI at baseline was associated with high risk to conversion to dementia, as the 73% of MCI subjects had dementia at 2-year follow-up, as compared to 20% of patients diagnosed as having NC. The present study showed that dementia occurs in a great proportion of PSP patients early during disease course, independently of motor deficits. In absence of a specific motor phenotype or cognitive trait, the nosological label of MCI might identify PSP patients who have the greatest risk to early progression to dementia.

P326 Description of progressive supranuclear palsy subtypes from the navarra brain bank 2 J. Sańchez Ruiz de Gordoa1, M. Zelaya Huerta2, T. Tu~ non Alvarez , F. Garcıa Bragado2, M. Mendioroz Iriarte1, V. Coca Pueyo3, E. Erro Aguirre1 1 Hospital of Navarra, Neurology, Pamplona, Spain 2 Hospital of Navarra, Pathology, Pamplona, Spain 3 Brain Bank of Navarra, Pamplona, Spain Objective: To analyze the frequency of the different clinical subtypes of Progressive Supranuclear Palsy (PSP) in a series of patients with a confirmed pathological diagnosis and to find out the delay time to clinical diagnosis and the relative survival of the different subtypes. Materials: We studied 34 confirmed PSP cases, following the protocol established by the Brain Bank of Navarre, between August 2005 to March 2016 and we made a retrospective review of clinical data. Results: Sex distribution: 16 men and 18 women. Average of age presentation: 72.2 years. Mean time to clinical diagnosis: 4.65 years. Clinical subtypes distribution: Richardson Syndrome (RS) (23, 67,6%), PSP-parkinsonism (PSP-p) (4, 11.8%), progressive non-fluent aphasia (PNFA) (3, 8.8%), Frontal dementia (FD) (2, 5.9%), Corticobasal Syndrome (CBS) and pure akinesia with gait freezing (PAGF) (1, 2.9%). Mean overall survival: 7.42 years. Survival by clinical subtypes: RS (6 years), PSP-p (13.35 years), PNFA (7.3 years), FD (10.5 years), CBS (6.3 years) PAGF (9.5 years). Correct diagnosis in life: 88.2%. Pathologic Study: exclusive PSP findings (14, 41.2%). PSP associated with: Alzheimer disease (9); congophilic angiopathy (9); alpha-synuclein deposits: as a Parkinson disease (3), Multisystem Atrophy (1) or isolated Lewy bodies (2); deposits of TDP-43 (2) and argyrophilic grains in the limbic system (2).


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Conclusions: This series contains a representation of all the different clinical subtypes of PSP already defined. A high percentage of patients had a correct clinical diagnosis in life. Overall survival is very variable among the different subtypes, however RS has a significant lower survival than other PSP subtypes. The correct identification of clinical subtypes of PSP will improve the clinical diagnosis and will allow future research.

P327 Joint analysis of GWAS with epigenetic data revealed candidate markers in FTD/MND, and convergence in pathways E. Taskesen1,2, A. Mishra2, D. Posthuma1,2, Y. Pijnenburg1 1 VU University Medical Center VUmc, Alzheimercentrum, Amsterdam, Netherlands 2 VU University, Complex Trait Genetics CTG, Amsterdam, Netherlands The use of Genome-wide association studies (GWAS) have become a standard approach to identify genetic risk variants. However, in Frontotemporal dementia (FTD) only a handful of highly penetrant genetic variants have so far been identified. It becomes clear that a substantial part of the genetic risk variants has a small effect. A currently important open question is the role of epigenetic factors, and whether these converge on biological processes, and as such cause degeneration of the frontal and temporal lobes. In this study we stepwise integrated the DNA-Methylation Profiles (DMP) with SNPs from a FTD GWAS study to detect novel risk-SNPs that may have been missed using conventional methods. We furthermore analyzed whether genetic and epigenetic processes converge on biological processes. Analysis of FTD patients revealed a heterogeneous DMP whereas patients with Motor Neuron Disease (FTD/MND) showed a homogeneous profile. The latter group showed in total 224 unique genes with significantly differential cytosine DNA-methylated levels (PFDRP) For the detection of novel candidate genetic markers, we extracted SNPs from GWAS FTD/MND that reached significance under PP = 0.0005) which indicates non-random behavior of genes that are target in FTD/MND. These genes are described with function in neuron or brain. Moreover, independent pathway analysis of GWAS and DMP genes showed convergence in biological processes. With these results we clearly show that understanding genetic and epigenetic factors are critical for unravelling the road to abnormal neurological development.

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P328 Multiple pathologies and heterogeneity in corticobasal syndrome and corticobasal degeneration: complications in a complex disease R. A. Santibanez1,2,3, I. R. Mackenzie4, M. Marnane1,2, S. Mortazavi2, C. Keller2, J. Li2, A. Kim2, G.-Y. R. Hsiung1,2 1 University of British Columbia, Faculty of Medicine, Department of Neurology, Vancouver, Canada 2 UBC Hospital Clinic for Alzheimer Disease and Related Disorders, University of British Columbia, Vancouver, Canada 3 Pontificia Universidad Cat olica de Chile, Department of Neurology, Santiago, Chile 4 University of British Columbia, Department of Pathology and Laboratory Medicine, Vancouver, Canada Corticobasal degeneration (CBD) is a rare neurodegenerative disorder that can manifest as different clinical syndromes. Corticobasal syndrome (CBS) is the clinical phenotype originally described for CBD, characterized by asymmetric parkinsonism, apraxia, cortical sensory deficits, dystonia, myoclonus, and cognitive dysfunction. However, patients with CBS can have neurodegenerative pathology other than CBD. We identified cases with CBS or pathological findings of CBD in the UBC neuropathology archives. Of the 42 cases that met our inclusion criteria, 37 had clinical features consistent with CBS. Within this group, 28 (76%) cases did not have CBD in the autopsy. The pathological diagnoses were Alzheimer’s disease (AD) (n = 9), AD+Lewy body disease (LBD) (n = 3), progressive supranuclear palsy (PSP) (n = 3), AD+PSP (n = 2), AD+cerebrovascular disease (CVD) (n = 1), AD+Parkinson’s disease (PD) (n = 1), AD+multiple system atrophy (n = 1), frontotemporal lobar degeneration-TDP-43 (FTLD-TDP) (n = 1), FTLD-TDP+hippocampal sclerosis (HS) (n = 1), FTLDTDP+CVD+HS (n = 1), PD+CVD (n = 1), Creutzfeldt-Jakob disease (n = 1), unclassifiable tauopathy (n = 1), developmental abnormality (n = 1), and PSP+CVD+LBD+AD (n = 1). The remaining 9 (24%) cases with CBS had CBD at autopsy. The pathological diagnoses were pure CBD (n = 7), CBD+AD (n = 1), and CBD+AD+CVD (n = 1). Another five cases with pathologic CBD were identified. Three cases had pure CBD (clinical diagnoses were Frontotemporal dementia (FTD) (n = 1), FTD/AD (n = 1), and AD/CVD (n = 1). The remaining cases had CBD+FTLD-TDP and CBD+AD+FTLD-TDP (clinical diagnoses were AD). In summary, the majority of patients with CBS had pathology other than CBD. Furthermore, multiple pathologies were found in 38% (n = 14) of cases with CBS and in 29% (n = 4) of cases with CBD pathology. Our findings highlight the heterogeneous pathological basis of CBS and the high frequency of concomitant pathologies in cases with CBD and CBS. Development of in vivo biomarkers and careful clinicopathological studies are needed to improve the diagnosis of CBD and its treatment.



P329 Disease-specific relationship between cerebrospinal fluid & longitudinal neuroimaging C. Jester1, K. Firn1, K. Ternes1, L. M. Shaw2, D. Irwin1, D. Weintraub3, M. Grossman1, C. McMillan1 1 University of Pennsylvania, Neurology, Philadelphia, United States 2 University of Pennsylvania, Center for Neurodegenerative Disease Research, Philadelphia, United States 3 University of Pennsylvania, Psychiatry, Philadelphia, United States Progressive supranuclear palsy (PSP) and Parkinson disease (PD) are both characterized by parkinsonism. However, PSP is associated with elevated cerebrospinal fluid (CSF) phosphorylated tau (ptau) and tau pathology while PD has alpha-synuclein (asyn) pathology. Neuropathological studies suggest that tau inclusions are abundant in white matter (WM), while asyn inclusions are relatively restricted to grey matter (GM) in PD. Thus multimodal neuroimaging provides a potential marker of pathology-specific longitudinal change. Here we investigate whether CSF markers of tau phosphorylated in the threonine 181 position (ptau) and total tau (ttau) can differentiate neuroimaging change in PSP (N = 15) and PD (N = 15). All patients had longitudinal (mean duration = 1.05 years 0.45) T1 MRI of GM and DTI of WM and a lumbar puncture near baseline scan. We used Advanced Normalization Tools (ANTs) to evaluate annualized GM atrophy in 112 cortical and subcortical ROIs and annualized WM change with fractional anisotropy (FA), in 48 WM ROIs. CSF was analyzed using ADNI standard operating procedures. Regression related baseline ptau and ttau to annualized change in PSP and PD (all p < 0.01). Reduced ptau was uniquely associated with PSP WM change in cerebellar peduncle, bilateral cerebral peduncle, and fornix. Increased ttau, which is more broadly related to neuronal degeneration, was uniquely associated with PD GM atrophy in right pallidum, putamen, frontal pole, planum temporale and left thalamus. Thus, we report a double dissociation for baseline CSF and longitudinal neuroanatomic change, with WM decline in PSP related to ptau and GM decline in PD related to ttau. CSF may be a useful prognostic marker to stratify patients in protein-specific disease-modifying treatment trials.

P330 Creutzfeldt Jakob Disease (CJD) and Supranuclear Palsy (PSP) in one patient - two sides of the same medal? F. Mueller-Sarnowski1, W. Valentin1, J. Diehl-Schmid1 1 Technical University of Munich, Center for Cognitive Disorders, Munich, Germany A 56 year old female former surgeon presented with disturbed gait, muscle fasciculations and subjective memory complaints which were not obvious in neuropsychological testing. 1 year earlier she had suffered from an upper airway infection, a spontaneous remitting facial palsy and from arterial embolism of the left brachial artery. Due to an obstructive sleep apnoea she was treated with a CPAP device during night. Otherwise the medical history was unremarkable. EEG and neurography were normal, no pathologic spontaneous activity was detected during electromyography. Screening for paraneoplastic antibodies was negative. Total Tau and phospho-Tau in CSF were elevated while beta-amyloid was normal. Aside from an arachnoidal cyst at level of thoracic vertebrae 4/5 structural imaging of the complete spinal axis and the brain revealed no pathology. The patient was sent to psychosomatic rehabilitation.

Only 2 months later she could move only with assistance of a wheeled walking aid and fell almost every day – mostly backwards. Nonetheless, no significant pathology was detected during an electrophysiological workup. Meanwhile urge incontinence, head tremor and rigor augmented the spectrum of complaints. Finally, a supranuclear palsy occurred so that the clinical picture of Richardson’s Syndrome had developed suggesting PSP. In a second lumbar puncture 14-3-3 protein and RT-QuIC test for prion protein were positive. Together with hyperintense signals of the basal ganglia in FLAIR sequences of MRI and myoclonia this lead to the diagnosis CJD. A DATscan was in line with a Parkinson syndrome. FDG-PET uncovered hypometabolism frontomesial, temporoparietal and in the basal ganglia. Given similar case reports we hypothesize, that Richardson’s Syndrome, myoclonia and hyperintens basal ganglia in MRI flair sequences might be less pathognomic for PSP and CJD respectively than anticipated. Instead they might be clinical correlates of pathophysiologic modules that can mix almost deliberately forming a vast variety of phenotypes.

P331 The edinburgh cognitive and behavioural ALS screen (ECAS); the effect of age, education, and IQ M. M. De Icaza Valenzuela1, T. Bak1, S. Pal1, S. Abrahams1 1 The University of Edinburgh, Psychology, Edinburgh, Great Britain The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was developed to assess the changes of cognition and behaviour related to frontotemporal dementia (FTD) and cognitive impairment in Motor Neurone Disease (MND)/Amyotrophic Lateral Sclerosis (ALS). The test was designed to assess those functions typically affected in ALS and FTD (executive and language functions, fluency and behaviour) in addition to functions more typically affected in other dementias (memory and visuospatial functions). Our aim was to investigate the effects of age, education, and IQ on the ECAS with the goal of creating appropriate cut-off scores to determine abnormality. Our second aim was to investigate the relationship of the ECAS with the Addenbrooke’s Cognitive Examination (ACE-III). We assessed 120 healthy participants between the ages of 35 to 80. Participants were divided into six groups according to age and education; and were tested with the ECAS, ACE-III and Wechsler Abbreviated Scale of Intelligence (WASI-II). Results showed that the ECAS and the ACE-III have a strong convergent validity with a significant correlation. Regression analysis revealed that IQ was the strongest significant predictor of the score of the ECAS, followed by age. Education was not a significant predictor when taking IQ into account, since these factors are highly correlated. To create cut-off scores participants were divided in two IQ groups: 75–114 and 115–148. These two groups showed a significant difference in ECAS scores. This difference was also significant for most of the sub-scores. The difference between scores according to IQ was stronger in the oldest group (ages 66– 80). In conclusion IQ and age should be taken into account when interpreting the ECAS.


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P332 Serum neurofilament light chain (NfL) in Progressive Supranuclear Palsy (PSP) L. Donker Kaat1, L. Meeter1, A. Boon1, W. Z. Chiu1, J. van Swieten1 1 Erasmus Medical Centre, Neurology, Rotterdam, Netherlands There is a need for the development of sensitive, easily accessible biomarkers in neurodegenerative disorders to monitor disease progression. Neurofilament light chain (NfL) is a neuronal cytoskeletal protein and elevated levels in cerebrospinal fluid have been described in several neurodegenerative disorders like Progressive Supranuclear Palsy (PSP), Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). These increased NfL levels are suggested to correspond to neuroaxonal breakdown. Interestingly, NfL-levels are also elevated in plasma of patients with neurological disorders. A recent study in PSP patients demonstrated elevated plasma NfL levels which predicted disease progression. (Rojas et al. Ann Clin Transl Neurol. 2016 Feb 1;3(3):216–25). In the current study, we will present the data of serum NfL levels in a large cohort of PSP patients from the Netherlands. NfL levels in PSP patients (n = 136) will be compared to control subjects (n = 95). Detailed clinical data from these PSP patients are available, including age at onset, PSP-rating scale scores, disease duration and survival. In a subset of neuropathologically confirmed PSP patients (n = 24), a semiquantitative assessment of the tau pathology will be calculated and these scores will be correlated to the serum NfL levels. The data of the current study are in progress and will be presented on the FTD meeting.

P333 Neuropathologic and neurobiologic characterization of early onset amyotrophic lateral sclerosis associated with a novel TDP43 S375G variant K. Newell1, B. Ghetti2, J. Murrell2, M. Romano3, E. Salis3, C. Stuani3, E. Buratti3 1 University of Kansas School of Medicine, Pathology & Laboratory Medicine, Kansas City, United States 2 Indiana University School of Medicine, Pathology & Laboratory Medicine, Indianapolis, United States 3 University of Trieste and International Centre for Genetic Engineering and Biotechnology, Trieste, Italy Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with onset most frequently occurring in middle age. Familial ALS may have an earlier onset. A 22 year-old woman presented with painless weakness of the right foot and leg. An EMG showed denervation involving the muscles of the right lower extremity. Weakness progressed to the left lower extremity and subsequently to the upper extremities. The clinical diagnosis was ALS. By the age of 24, she used a wheelchair and required a tracheostomy. She died at age 26. A family history of ALS was reported in distant relatives. An autopsy was carried out, and the neuropathologic evaluation showed upper and lower motor neuron loss, corticospinal tract degeneration, and neurogenic changes in skeletal muscle. TDP43 and FUS-immunoreactive neuronal and glial inclusions were present in motor cortex, putamen, globus pallidus, thalamus, substantia nigra, inferior olivary nucleus, and anterior horns of the spinal cord. DNA was extracted from brain tissue, and a TDP43 S375G change was found. A C9ORF72

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expansion was not identified. To determine whether the TDP43 variant is pathogenic, we have studied a recombinant protein carrying the S375G change via transfection in HeLa cells. Our results show that this variant does not appear to alter the predominantly nuclear localization of TDP43. However, the variant protein shows increased ability to induce CFTR exon 9 skipping in a minigene-based add-back splicing assay with respect to wild-type TDP43. This result suggests that the S375G substitution may act through a gain-of-function mechanism. We tested a nearby TDP43 mutation, N378D, previously identified in other patients, and found that it also caused a similar gain-of-function effect on the splicing ability of TDP43. Taken together, these results highlight the possible presence in the C-terminus of a novel region capable of affecting the splicing regulation function of TDP43.

P334 Social cognition in amyotrophic lateral sclerosis in an argentinean-cohort. preliminary data F. E. Nahas1,2, B. De Ambrosi1, I. Calandri1, F. Tapajoz1, P. Zanuso1, M. Nogues1, R. Allegri1,2 1 Instituto FLENI, Neurologıa Cognitiva, Ciudad Autonoma de Buenos Aires, Argentina 2 Consejo Nacional de Investigaciones Cientıficas y Tecnicas CONICET, Buenos Aires, Argentina Background: It has been described cognitive impairment in Amyotrophic Lateral Sclerosis (ALS) patients. Due to the association with Frontotemporal lobar degeneration (FTLD), social cognition (SC) could be involved as a nonmotor feature of this disease. Our aim is to study cognitive and SC involvement in ALS. Methods: 32 patients recently diagnosed with sporadic-ALS and 23 healthy controls matched by sex, age and education level were assessed with an extensive neurological and cognitive battery that included Theory of Mind (ToM) Test: Faux Pas and Reading the mind in the eyes (RME), and Decision Making (DM) Test: Reversal Learning. Patients underwent pulmonary function testing using spirometry. Results: 18 men, 14 women, mean age 61, mean education 13.5 years. Comparing mean values with controls, significant differences were observed in behavior: Depression Scale (p = 0.0007) and Neuropsychiatric Inventory (NPI-Q) 4,6 (p = 0.0002). ToM Test: “identification of misstep” in Faux Pas (p = 0.017), “Recognizing the correct expression” in RME Test (p = 0.043), and “number of revertions” in DM Test (p = 0.034). There was found a significant correlation between ToM with language and executive functions, DM correlated with executive functions, and all SC test correlated between them. RME test, language, Executive functions, and Desinhibition and dysphoria NPI-Q subitems correlated with low Forced Vital Capacity, PiMax or PeMax in spirometry. Conclusions: ALS patients have shown a clear impairment in language and executive functions, as reported previously in literature. ToM and DM test showed an impaired SC profile in ALS patients that correlates with failure in cognitive test, as in FTLD patients.



P335 Measuring clinical and cognitive decline in CBD and PSP for multicenter clinical trials – the 4-repeat tauopathy neuroimaging initiative (4RTNI) D. Luong1, L. Voltarelli1, H. Heuer1, J. Kornak1, K. Domoto-Reilly2, B. Dickerson2, I. Litvan3, M. C. Tartaglia4, B. Miller1, A. Boxer1 1 University of California, San Francisco, Memory & Aging Center – Department of Neurology, San Francisco, United States 2 Massachusetts General Hospital, Frontotemporal Disorders Unit, Boston, United States 3 University of California, San Diego, Movement Disorder Center – Department of Neurosciences, San Diego, United States 4 University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Toronto, Canada Novel treatments targeting tau, a neuronal scaffolding protein that accumulates in neurodegenerative diseases such as Alzheimer’s Disease (AD), are beginning to enter human trials. Comorbid pathologies that could influence clinical assessments are not uncommon in AD; ‘pure tauopathies’ with predictable pathologies therefore are an appealing focus for clinical trials. The 4-Repeat Tauopathy Neuroimaging Initiative (4RTNI) was designed to identify biomarkers of disease progression in two “pure tauopathies” – corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) – for potential use in clinical trials. 27 subjects meeting CBD criteria (Armstrong, 2013) and 45 subjects meeting PSP criteria (NINDS-SPSP, 1996) were recruited at four North American sites. Clinical rating scales, neuropsychological tests (NPT), brain MR imaging, and biospecimen collection were conducted at three time points over the course of 12 months. Clinical rating scales and NPT were evaluated to identify measurements with the best ability to capture disease progression over 12 months. The PSP Rating Scale (PSPRS) changed over 12 months in both groups (CBD: 21.2% [SD = 30.0] and 39.8% [SD = 49.1] increase from baseline after 6 and 12 months, respectively, p < 0.05; PSP: +19.3% 29.5 and +38.0% 42.3, p < 0.001). In PSP, the PSPRS oculomotor and gait subscores changed the most (+38.6% 80.2 and +80.9% 150.0, p < 0.001; +30.0% 58.6 and +55.5% 58.6, p < 0.001). In contrast, in CBD, only the gait subscore changed (+38.0 86.5 and +89.4% 138.2, p < 0.05). MMSE scores did not change significantly in PSP over 12 months, but did in CBD (5.7% 12.1 and -22.5% 34.6, p < 0.05). Both cohorts showed changes in several of the same NPT, e.g. executive tasks, as well as in different tests from one another, e.g. visuospatial tasks only in PSP. This analysis demonstrates that certain clinical measurements and NPT can detect disease progression and can show distinct changes over time in both CBD and PSP. As such, a subset of these assessments may be appropriate for multicenter clinical trials for “pure tauopathies”.


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Poster Session III: Blood and Imaging biomarkers P337

P336 Identifying cortical atrophy in the main variants of frontotemporal dementia, in 48 Colombian patients: a VBM analysis P. Reyes1,2, M. Ortega1, S. Gutierrez1, H. Santamarıa-Garcıa1,2, F. Uriza1,2, D. Matallana1 1 Pontificia Universidad Javeriana, Bogot a, Colombia 2 Hospital Universitario San Ignacio, Radiologıa, Bogot a, Colombia The aim of this study is to approach to the different patterns of atrophy between the main variants of frontotemporal dementia (FTD): Behavioral, semantic and primary progressive aphasia using Voxel-Based Morphometry. From a cohort of 153 patients with FTD of Center of memory and cognition Hospital Universitario San Ignacio; 26 patients with a behavioral variant of FTD (bvFTD), 12 with primary progressive aphasia (PPA), 10 with semantic (SD) variants of frontotemporal dementia and 32 controls were selected. All patients underwent to clinical evaluation with tests for general cognition, memory, language, praxis, attention, personality. The diagnosis was made by consensus in a memory clinic (neurology, neuropsychology, psychiatry, geriatric). Magnetic resonance images were obtained and analyzed with Voxel-based morphometry. Comparisons with control groups and between variants of FTD were made. BvFTD: differences were found in the frontal middle orbital region, superior frontal gyrus, and Insula without hemispheric predominance, also in the temporal middle circumvolution, and temporo-parietal union. SD: atrophy was found in temporal regions bilaterally, with mild left predominance, likewise right hippocampus and parahippocampal regions and left frontal opercular regions were affected. PPA: clear asymmetric atrophy of the temporal lobe, and the triangular region of the frontal lobe with left predominance. SD and BvFTD Vs PPA: we found differences in the middle temporal lobe, left inferior parietal and orbital frontal regions. PPA and BvFTD versus SD: alterations of the right temporal lobe in its mid and superior portion, with involvement of some right insular regions. We have observed the presence of posterior atrophy in BvFTD, right temporal compromise in SD and a predominance of compromise in the left hemisphere in PPA as well.

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The diffuse not focal frontal atrophy subtype shows worse prognosis in behavioral variant frontotemporal dementia J. S. Lee1, N.-Y. Jung2, E.-J. Kim2, J. Lee3, Y. K. Jang1, Y. J. Kim1, H. J. Kim1, S. W. Seo1, J.-H. Lee4, B. C. Kim5, K.-W. Park6, S. J. Yoon7, J. H. Jeong8, S. Y. Kim9, K.-C. Park10, D. S. Knopman11, D. L. Na1 1 Samsung Medical Center, Neurology, Seoul, South Korea 2 Pusan National University Hospital, Neurology, Busan, South Korea 3 Chungnam National University Hospital, Neurology, Daejeon, South Korea 4 Asan Medical Center, Neurology, Seoul, South Korea 5 Chonnam National University Medical School, Neurology, Gwangju, South Korea 6 Dong-A Medical Center, Neurology, Busan, South Korea 7 Eulji University Hospital, Neurology, Daejeon, South Korea 8 Ewha Womans University Mokdong Hospital, Neurology, Seoul, South Korea 9 Seoul National University Bundang Hospital, Neurology, Seongnam, South Korea 10 Kyung Hee University School of Medicine, Neurology, Seoul, South Korea 11 Mayo Clinic, Neurology, Rochester, United States We hypothesized that there are different clinical characteristics between patients with behavioral variant frontotemporal dementia (bvFTD) who show diffuse frontal lobe atrophy (D-type) on axial MRI scans versus those with focal or circumscribed frontal lobe atrophy (F-type). The objectives of this study were (i) to classify patients with bvFTD into D- and F-types by use of axial MRI scans, and (ii) to compare the two groups in terms of baseline characteristics, progression in motor and cognitive symptoms, and survival time. An MRI visual rating scale was used to classify 74 patients with bvFTD into D- (n = 33) and F- (n = 41) types. In this retrospective study, we compared baseline clinical characteristics, progression in motor and cognitive symptoms, and survival times between D- and F-types. Survival analyses were performed for 62/ 74 patients. Although D-type patients performed better on neuropsychological tests than F-type patients at baseline, D-type patients had higher Unified Parkinson’s Disease Rating Scale (UPDRS) Part III scores at baseline (13.5 14.8 vs. 5.8 9.9). Evaluation of motor progression showed that the mean disease duration without motor symptoms was shorter in D-type than in Ftype. Moreover, the median survival time in D-type (6.8 years) was shorter than in F-type (9.5 years). Cox regression analyses revealed that the high UPDRS Part III score at baseline contributed to an increased risk of mortality, regardless of atrophy pattern. bvFTD patients with D-type had a poorer prognosis than those with F-type. Shorter survival in D-type may be associated with earlier motor symptoms.


Poster Session III: Blood and Imaging biomarkers

P338 Tau imaging in patients with ALS/PDC in the Kii Peninsula Y. Kokubo1, H. Shinotoh2,3, H. Shimada2, F. Niwa2, R. Sasaki4, S. Morimoto5, H. Endo2, S. Kitamura2, S. Hirano2,6, I. Aiba7, M. Miyamura8, N. Sahara2, S. Kuzuhara9, M. Higuchi2, T. Suhara2 1 Mie University, Graduate School of Regional Innovation Studies, Tsu, Japan 2 National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Functional Brain Imaging Research, Chiba, Japan 3 Neurology Chiba Clinic, Chiba, Japan 4 National Mie Hospital, Neurology, Tsu, Japan 5 Mie University, Oncologic Pathology, Tsu, Japan 6 Chiba University, Neurology, Chiba, Japan 7 National Hospital Organization, Higashinagoya National Hospital, Neurology, Nagoya, Japan 8 Ise Municipal General Hospital, Neurology, Ise, Japan 9 Suzuka University of Medical Science, Neurology, Suzuka, Japan Background: Amyotrophic lateral sclerosis/parkinsonismdementia complex of the Kii peninsula of Japan (Kii ALS/PDC) is a unique tauopathy. To elucidate the distribution of tau pathology, tau imaging using [11C]PBB3 as a ligand was performed. Objective: A 71 year-old man with progressive dementia and parkinsonism for 18 years (Pt1), a 81 year-old man with progressive dementia for 16 years (Pt2), and a 68 year-old man with progressive parkinsonism and upper motor neuron signs for 8 years (Pt3) participated in this study. All of them were natives of the high incidence focus and had family history of Kii ALS/PDC. Methods: Dynamic PET scans were performed following [11C] PBB3 injection, and an injection of [11C]PiB, an amyloid imaging ligand, on the same day in each subject. Parametric PET images were generated by calculation of target-to-cerebellar cortex standardized uptake value ratios (SUVR). Two-sample t-test was performed on [11C]PBB3 SUVR images between each patient and NCs using SPM5. Statistical threshold was set to P. Results: All subjects except Pt2 were negative for PiB (amyloid). SPM analysis showed high PBB3 (tau) accumulation in fronto-temporal lobes, putamen, globus pallidus, subthalamic nucleus in Pt1. There was high PBB3 accumulation in frontotemporo-parietal lobes in Pt2. There was high PBB3 accumulation in fronto-parital lobes, especially in the white matter, brainstem in Pt3. Conclusion: [11C] PBB3 PET detects the distinct distribution of tau pathology in each clinical phenotype of Kii ALS/PDC.

P339 Analysis of regional MRI volumes and thicknesses on frontotemporal dementia patients with C9ORF72 expansion R. Haanpaä¨1, Y. Liu1, A. Hall1, P. Hartikainen2, V. Moilanen3, H. Soininen1, A. Remes1,2 1 University of Eastern Finland, Institute of Clinical Medicine, Neurology, Kuopio, Finland 2 Kuopio University Hospital, Department of Neurology, Kuopio, Finland 3 Oulu University Hospital, Department of Neurology, Oulu, Finland With MRI neuroimaging it is possible to obtain useful clinical markers for examining neurodegenerative diseases, such as regional

cortical volumes and thicknesses in the brain. We have applied this to investigating different phenotypes of the C9ORF72 expansion carriers with frontotemporal lober degeneration. The objective of our study was to discover the neuroimaging profile of patients with the C9ORF72 repeat expansion and how it differs from the C9ORF72 non-carriers and healthy controls. The regional cortical thicknesses were measured from 30 areas and regional volumes from 46 areas based on magnetic resonance imaging and using an automated image analysis pipeline. The study population consisted of 24 tested C9ORF72 expansion carrier patients and 19 non-carrier patients with frontotemporal lobar degeneration diagnosed in the memory outpatient clinic of Kuopio University Hospital and Oulu University Hospital, Finland and also 30 healthy age and gender matched controls. The preliminary results showed that the cortical thicknesses were diminished widely in the frontal and temporal areas in the both the C9ORF72 expansion carrier and non-carrier groups compared to the control group, but significant differences in the cortical thicknesses were not found between the C9ORF72 carrier and non-carrier groups. However in the volume analysis the C9ORF72 expansion carriers had significantly minor volumes in the left thalamus (nearly significant also in the right thalamus, p = 0.065), in the left ventral diencephalon and in the right accumbens area than the C9ORF72 non-carrier group. The previous studies of neuroimaging features of the C9ORF72 expansion carriers have shown involvement of frontotemporal regions and cingulate, subcortical regions, especially the thalami, but also parietal and occipital lobes.

P340 Brain network organization in frontotemporal dementia across countries, recordings and methods L. Sedenõ1, O. Piguet2, A. Garcıa1, S. Fitipaldi1, S. Abrevaya1, I. Garcıa-Cordero1, S. Baez1, L. Alethia de la Fuente1, F. Kumfor2, T. Torralva1, J. Hodges2, A. Ibanez1 1 INECO, Buenos Aires, Argentina 2 Australian Research Council ACR, Centre of Excellence in Cognition and its Disorders, Sydney, Australia Behavioral-variant frontotemporal dementia (bvFTD) is characterized by marked functional connectivity alterations, which may represent a key biomarker contributing to its early diagnosis. However, to achieve this, it is critical to assess the robustness and replicability of functional connectivity alterations across heterogeneous contexts (due to differences in MRI equipment and acquisition parameters, clinical diagnostic teams and participants’ sociocultural profiles). We explored whether graph measures could robustly distinguish bvFTD patients from controls. To this end, we enrolled patients and controls from three international clinical centers (Argentina, Australia and Colombia) with extensive experience in neurodegeneration. To assess the specificity of our results, we replicated our study with three disease control groups: frontoinsular stroke, Alzheimer disease, and primary progressive aphasia. All participants underwent an fMRI resting-state recording with different MRI acquisition parameters. Based on the graph-theory approach, we measured several global and local indexes. Compared to controls, bvFTD presented consistent alterations in all measures across centers. In addition, they discriminate bvFTD patients from the other disease control groups. To our knowledge, this is the first multicenter report to assess bvFTD via graph-theory. This approach was robust enough to discriminate bvFTD patients from healthy


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controls and also from other neurological patients. The consistency of these findings in a highly heterogeneous context highlights graphtheory method as a potential gold-standard approach for brain network analysis. This represents a critical step in its possible clinical application as a biomarker signature for neurodegenerative diseases. Study supported by: CONICYT/FONDECYT Regular (1130920-1140114), PICT 2012-0412, and PICT 2012-1309, CONICET, FONDAP-15150012, and the INECO Foundation; NHMRC Research Project Grant (510106) and by funding to ForeFront from the NHMRC (APP1037746) and the ACR (CE11000102).

P341 Frontotemporal dementia and language networks: cortical thinning is driven by dyslexia susceptibility genes M. A. Manes1, D. Paternic o1, E. Premi1, M. Cosseddu1, S. Gazzina1, 1 2 A. Alberici , S. Archetti , E. Bonomi2, M. S. Cotelli3, M. Turla3, M. Cotelli3,4, A. Micheli5, R. Gasparotti6, B. Borroni1, A. Padovani1 1 Centre for Aging Brain and Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy 2 Spedali Civili Hospital, Brescia, Italy, III Laboratory, Biotechnology, Brescia, Italy 3 Valle Camonica Hospital, Brescia, Italy, Neurology Unit, Brescia, Italy 4 IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy, Brescia, Italy 5 Casa di Cura S. Francesco, Bergamo, Italy, Bergamo, Italy 6 Neuroradiology Unit, University of Brescia, Brescia, Italy Variations within genes associated with dyslexia result in a language network vulnerability, and in patients with Frontotemporal Dementia (FTD), language disturbances represent a disease core feature. Here we explored whether variations within three relateddyslexia genes, namely KIAA0319, DCDC2, and CNTNAP, might affect cortical thickness measures in FTD patients. One-hundred and twelve FTD patients underwent clinical and neuropsychological examination, genetic analyses and brain Magnetic Resonance Imaging (MRI). KIAA0319 rs17243157 G/A, DCDC2 rs793842 A/G and CNTNAP2 rs17236239 A/G genetic variations were assessed. Cortical thickness was analysed by Freesurfer. Patients carrying KIAA0319 A*(AG or AA) carriers showed greater cortical thickness in the left fusiform and inferior temporal gyri, compared to KIAA0319 GG (p ≤ 0.001). Patients carrying CNTNAP2 G* (GA or GG) showed greater cortical thinning in the left insula thenCNTNAP2 AA carriers (p ≤ 0.001). When patients with both at-risk polymorphisms were considered (KIAA0319 A*and CNTNAP2 G*), greater and addictive cortical thickness of the left insula and the inferior temporal gyrus was demonstrated (p ≤ 0.001). No significant effect of DCDC2 was found. In FTD, variations of KIAA0319 and CNTNAP2 genes were related to cortical thickness abnormalities in those brain areas involved in language abilities. These findings shed light on genetic predisposition in defining phenotypic variability in FTD.

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P342 A novel approach to investigate a rare Frontotemporal Disorder: proteomic studies about Nasu-Hakola Disease A. M. Agresta1, A. De Palma1, D. Di Silvestre1, A. M. Bardoni2, R. Salvini2, P. Iadarola3, P. L. Mauri1 1 Institute for Biomedical Technologies - National Research Council CNR, Proteomics and Metabolomics Unit, Segrate Milan, Italy 2 University of Pavia, Department of Molecular Medicine Biochemistry Unit, Pavia, Italy 3 University of Pavia, Department of Biology and Biotechnologies Biochemistry Unit, Pavia, Italy Frontotemporal dementias (FTD) include a large spectrum of pathologies based on different triggers. Among the FTD related to genetic causes and behavioral disorders (bvFTD), a rare recessively inherited systemic disorder named Nasu-Hakola Disease (NHD) is worthy of note. It is phenotypically characterized by simultaneous impairment of nervous and skeletal systems and genetically related to a structural defect of the two genes DAP12 and TREM2. These genes encode for different subunits of the membrane receptor signaling complex and are expressed by cells of both systems involved. To date, the diagnosis of NHD is carried out by genetic or psychological tests only; no biochemical/molecular studies being available to obtain an early diagnosis or a follow-up of the NHD progression. In the present study we used MudPIT (Multidimensional Protein Identification Technology) approach for the characterization of Lymphoblastoid cells from NHD patients and healthy controls. Aim of this research was to obtain a more complete picture about the mechanisms involved into NHD onset and to evaluate the presence of possible blood biomarkers of this pathology. Specifically, two NHD patients (DS), four healthy carriers (HC) and one healthy subject (HS) belonging to the same Italian family have been submitted to blood withdrawal to isolate and immortalize the BLymphocytes. MudPIT allowed the identification of more than 3000 distinct proteins, a number 100-fold higher than that of proteins identified by gel electrophoresis (2-DE) [Giuliano et al. PLoS One 2014; 9]. The comparison of protein profiles from DS, HC and HS groups by means of MAProMa software showed that 10% of identified proteins was peculiar of each group. In addition, network analysis of proteomics data evidenced the disease-related pathways, such as energy metabolism, including glucose pathway. This work represents a proof of principle for characterizing dysregulated proteins and related metabolic pathways involved in functional alterations of this pathology.



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Evolution of cerebral PET glucose metabolism from presymptomatic to symtomatic frontotemporal dementia linked to chromosome 3 (FTD-3) - a voxel based SPM analysis P. Johannsen1, I. Law2, C. Hansen2, P. Roos1, J. Stokholm1, A. M. Isaacs3, J. Brown4, J. E. Nielsen1,5 1 Rigshospitalet, Memory Clinic, Copenhagen, Denmark 2 Rigshospitalet, Department of Clinical Physiology, Nuclear Medicine & PET, Copenhagen, Denmark 3 UCL, Institute of Neurology, London, Great Britain 4 Addenbrooke’s Hospital, Department of Neurology, Cambridge, Great Britain 5 University of Copenhagen, Section of Neurogenetics, Institute of Cellular and Molecular Medicine, Copenhagen, Denmark

Tau [18F]AV-1451 PET uptake in patients with suspected 4-repeat tauopathy C. McMillan1, D. Schonhaut2, D. Russell3, A. Boxer2, I. Litvan4, E. Roberson5, I. Nasrallah6, A. Siderowf7, M. Devous7, M. Grossman1, G. Rabinovici2 1 University of Pennsylvania, Neurology, Philadelphia, United States 2 UCSF, Neurology, San Francisco, United States 3 Institute for Neurodegenerative Disorders, New Haven, CT, United States 4 UCSD, Neurology, San Diego, United States 5 University of Alabama at Birmingham, Neurology, Birmingham, AL, United States 6 University of Pennsylvania, Radiology, Philadelphia, United States 7 Avid Radiopharmaceuticals, Philadelphia, United States

Changes in the distribution of regional cerebral metabolic rate of glucose (rCMRglc) were assessed by SPM12 voxel based analysis in a large Danish family with autosomal dominant FTD-3. FTD-3 is caused by a truncating mutation in CHMP2B (Skibinski et al. Nature Genetics 2005; 37: 806–8), and is clinically characterized by a bvFTD syndrome (Gydesen et al. Neurology 2002; 59: 1585–94). The rCMRglc distribution was assessed using 18F-flourodeoxyglucose (FDG) and PET. Twelve early symptomatic (S) and 9 presymptomatic (preS) CHMP2B mutation carriers, and 22 healthy controls (C) were scanned 40 min after injection of 200 MBq FDG. Images were transformed into a stereotactic MNI space, activity was normalized to the cerebellum, and corrected for age. The conservative Gaussian Family-Wise-Error (FWE) statistical correction was used. We present results on a cluster level from contrasts between S < preS, preS > C, and a correlation analysis with the Addenbrookes Cognitive Examination (ACE). With the FWE-correction preSymptomatic mutation carriers had decreased rCMRglc in the posterior cingulate (p < 0.001) and medial frontal lobe (p < 0.001). Symptomatic patients compared to preS mutation carriers have decreased glucose metabolism (p < 0.0005) in cortical bilateral frontal and left and right temporal regions. Four clusters in frontal and temporal regions showed a significant (p < 0.0005) correlation between rCMRglc and the ACE, the biggest being frontal, followed by left temporal and right temporal. The voxel analysis indicates that the preSymptomatic FTD-3 stage may affect medial (posterior) areas and once symptoms develop the metabolic deficits evolves to primarily affect fronto-temporal regions. This analysis can shed more light on the fact that the structural atrophy in symptomatic FTD-3 has a more global distribution, despite the clinical bv-FTD presentation.

PSP and CBD are characterized by atypical progressive parkinsonism with cognitive dysfunction and 4-repeat tau pathology (4Rtau) in midbrain, cerebellar and subcortical structures. In vivo biomarkers of 4Rtau are urgently needed. A novel PET radiotracer, AV-1451, has selective binding to a spectrum of tau-positive inclusions in postmortem samples. We report results of the A09 clinical trial, sponsored by Avid Radiopharmaceuticals who own the tau-PET ligand [18F]AV-1451 patent. Five sites recruited 20 mildto-moderate PSP, 5 CBD and 20 matched cognitively normal controls (NC). SUVR uptake at 75–105 min was calculated for the globus pallidus (GP) and cerebellar dentate nucleus (DN) relative to cerebellar grey matter. Group level t-tests revealed increased uptake in GP (1.84 0.20) and DN (1.32 0.10) for PSP relative to NC (GP = 1.56 0.20; p < 0.001; DN = 1.23 0.14; p = 0.02) with no asymmetries. ROC analyses of individual level uptake identified a GP SUVR cut off (1.71) with 80% sensitivity and specificity (AUC = 0.84, p < 0.001) for distinguishing PSP from NC. CBD and NC group uptake did not differ but CBD asymmetry trended toward GP L>R (AI = 11.41 10.87, p = 0.08) and DN R>L (AI=3.77 3.08, p = 0.05). Disease duration and clinical severity correlations with PSP uptake did not survive multiple comparisons. AV-1451 uptake in PSP converges with regional 4Rtau burden in prior autopsy studies including a relatively bilateral PSP and asymmetric CBD distribution. However, individual diagnostic utility is modest and may be related to off-target binding in NC. We suggest AV-1451 may be a useful in vivo biomarker of PSP 4Rtau but PET-to-autopsy validation and longitudinal, larger and increased severity studies are needed to evaluate tracer specificity.


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In genetic frontotemporal dementia, functional network efficiency is maintained until the onset of symptoms: evidence for functional resilience to structural change T. Rittman1, R. Borchert1, S. Jones1, J. Van Swieten2, B. Borroni3, D. Galimberta4, M. Marsellis5, C. Graff6, F. Tagliavini7, G. Frisoni8, R. La Force9, E. Finger10, A. Mendoncßa11, S. Sorbi12, J. Rohrer13, J. Rowe1, O. B. O. (GENFI)13 1 University of Cambridge, Clinical Neurosciences, Cambridge, Great Britain 2 Erasmus Medical Centre, Department of Radiology, Rotterdam, Netherlands 3 Universita Degli Studi di Brescia, Clinical and Experimental Sciences, Brescia, Italy 4 University of Milan, Pathophysiology and transplantation, Milan, Italy 5 University of Toronto, Neurology, Toronto, Canada 6 Karolinska Institute, Neurobiology, Care Sciences and Society, Stockholm, Sweden 7 Carlo Besta Institute of Neurology, Milan, Italy 8 University of Geneva, Neuroscience Centre, Geneva, Switzerland 9 CHU de Quebec, The CHU de Quebec Research Centre, Quebec, Canada 10 Western University, The Brain and Mind Institute, London, Canada 11 University of Lisbon, Faculty of Medicine, Lisbon, Portugal 12 University of Florance, Neuroscience, Florence, Italy 13 University College London, Dementia Research Centre, London, Great Britain

Disease-specific patterns of cortical and subcortical degeneration in a longitudinal study of Alzheimer’s disease and behavioural-variant frontotemporal dementia R. Landin-Romero1,2,3, F. Kumfor1,2,3, C. Leyton1,2,4, M. Irish1,2,5, J. Hodges1,2,3, O. Piguet1,2,3 1 Neuroscience Research Australia, Frontier, Sydney, Australia 2 ARC Centre of Excellence in Cognition and its Disorders, Sydney, Australia 3 The University of New South Wales, School of Medical Sciences, Sydney, Australia 4 The University of Sydney, Faculty of Health Sciences, Sydney, Australia 5 The University of New South Wales, School of Psychology, Sydney, Australia

Structural brain changes occur decades before symptom onset in genetic frontotemporal dementia (Rohrer et al., 2015); cognitive function can be well maintained presymptomatically. We assessed whether the integrity of functional networks would be maintained despite significant atrophy. 99 subjects from the Genetic Frontotemporal Dementia Initiative (GENFI) were recruited; 7 were removed because of movement artefacts to leave 24 with genetic FTD (11 C9orf72, 4 GRN and 9 MAPT genes) and 68 asymptomatic related gene carriers (17 C9orf72, 38 GRN, 13 MAPT). Functional MRI was acquired at 11 sites at a field strength of 1.5T (TR 2.5 or 3secs, TE 50 msec) or 3T (TR 2.2, TE 30 msec) to acquire 286–616 volumes. Preprocessing was optimised for atrophic brains and included motion correction using wavelet despiking. We assessed topological properties in a binarised network (3% equidense threshold) normalised against 500 random networks with identical degree distribution. Breakpoint analysis used a piecewise linear regression model. We found a significant breakpoint in global efficiency (the sum of the inverse path lengths) at the time of disease onset (p = 0.027). Edge length (the physical distance between regions) had no such breakpoint, but a linear reduction in edge length (p = 0.031). We propose that resilience in functional brain networks protects function despite significant neuropathology, but that a decompensation in global efficiency precipitates a sharp decline in cognitive function.

Differentiation between Alzheimer’s disease (AD) and behavioural-variant frontotemporal dementia (bvFTD) is challenging due to their overlapping clinical features and changes on brain neuroimaging at presentation. While diagnostic criteria for both disorders incorporate evidence of frontal and temporal cortical atrophy, understanding of the progression of atrophy in these disorders is limited. This study aimed to elucidate common and disease specific progressive changes in cortical and subcortical brain structures in AD and bvFTD. Forty-one AD, 37 bvFTD and 33 healthy controls underwent baseline MRI. Among these, longitudinal annual follow-up was obtained for 20 AD and 20 bvFTD (1– 4 years). The results uncovered cortical and subcortical diseasespecific trajectories of neurodegeneration in AD and bvFTD. Specifically, direct comparisons between patients groups revealed that over time AD showed greater cortical atrophy in the inferior parietal and posterior cingulate cortex than bvFTD. Conversely, bvFTD patients showed greater atrophy in the striatum than AD over time. These results indicate that atrophy in the posterior cingulate and the striatum diverge with disease progression in these dementia syndromes and may represent a potential diagnostic biomarker for tracking rates of progression of AD and bvFTD. These findings may help inform future drug trials by identifying appropriate outcome measures to quantify drug efficacy and their ability to modulate disease progression over time.

P347 White matter changes in frontotemporal dementia and the C9ORF72 gene expansions R. Landin-Romero1,2,3, B. Yin Ka Lam4, F. Kumfor1,2,3, E. Devenney1,5,6, L. Bartley1, G. Halliday1,3, J. Hodges1,2,3, O. Piguet1,2,3 1 Neuroscience Research Australia, Frontier, Sydney, Australia 2 ARC Centre of Excellence in Cognition and its Disorders, Sydney, Australia 3 The University of New South Wales, School of Medical Sciences, Sydney, Australia 4 The Chinese University of Hong Kong, Department of Medicine and Therapeutics, Hong Kong, Hong Kong 5 The University of Sydney, Brain and Mind Centre, Sydney, Australia 6 The University of Sydney, Sydney Medical School, Sydney, Australia The clinical features and brain changes of familial FTD cases carrying the C9ORF72 gene expansions remain poorly understood. This is in part due to the mixed clinical samples reported in the

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literature, which have included a mixture of behavioural, linguistic and motor phenotypes. Moreover, the associations between the clinical features and changes in brain white matter have not been fully studied to date. Diffusion weighted and T1 brain images were collected from patients with sporadic bvFTD (n = 35), bvFTD with C9ORF72 expansions (n = 14), sporadic FTD-MND (n = 17), FTD-MND with C9ORF72 gene expansions (n = 7) and matched healthy controls (n = 27). Behavioural and cognitive assessments were conducted across all patients. White matter integrity was assessed with tract-based spatial statistics and correlational analyses were used to explore associations between clinical features and white matter changes. Imaging results uncovered an anterior to posterior gradient of white matter changes with sporadic cases showing decreased integrity in frontotemporal tracts and C9ORF72 expansion carriers showing decreased integrity in posterior tracts and the cerebellum. Direct comparisons between sporadic cases and C9ORF72 expansion carriers within the same clinical phenotypes showed impairments in memory, language and belief formation in C9ORF72 expansion carriers. These changes correlated with white matter integrity in the uncinate fasciculus and the forceps minor. Given the limited information currently available on the biological/ clinical associations between C9ORF72 expansion carriers and noncarriers within a single phenotype, these results improve the characterisation in the FTD-MND continuum with C9ORF72 gene expansions.

P348 The synaptic protein neurogranin as a clinical CSF biomarker in the diagnosis of FTD A. Santillo1, S. Janelidze1, J. Hertze1, H. Zetterberg2, M. Landqvist Wald€o3, K. Blennow2, O. Hansson1 1 Lund University, Clinical Memory Research Unit, Department of Clinical Sciences, Malm€ o, Sweden 2 The Sahlgrenska Academy at the University of Gothenburgh, Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, M€olndal, Sweden 3 Lund University, Section of Geriatric Psychiatry, Lund, Sweden Neurogranin is a calmodulin-binding postsynaptic protein involved in calcium dependent signalling. Neurogranin levels reflect synaptic degeneration, a process possibly preceding the frank neuronal loss in neurodegenerative disorders. We have previously shown that CSF neurogranin levels are altered in FTD, with a reduction compared with controls. In AD the situation is oppositei.e. neurogranin levels are increased. However, the utility of CSF neurogranin as a clinical diagnostic biomarker for FTD has not been explored. In 160 cases (33 with FTD, 74 AD and 53 controls), CSF neurogranin was measured using an in-house sandwich ELISA, while CSF Ab42, Ab 40, and tau were measured using a commercially available ELISA system. 5 cases (one control, one FTD and 3 AD) had neurogranin levels below detection level and were assigned the value of the lower detection level (120 pg/mL). Direct comparison showed a significant decrease of CSF neurogranin in FTD compared with AD and controls. In FTD, all other biomarkers differed significantly compared with AD. The ROC area under curve (AUC) in separating FTD and AD was for CSF neurogranin 0.80, not superior to any of the other biomarkers or ratios thereof (AUC for Ab42 0.95, Ab42/Ab40 ratio 0.97, tau 0.89, Ab42/tau ratio 0.98). In the comparison between FTD and controls, neurogranin was the only of the assessed biomarkers with a

statistically significant difference when demographical covariates were taken into account (Cohens d = 0.69, p = 0.007), with a ROC AUC of 0.688 (95% CI 0.574–0.802, p = 0.003). Our conclusion is that compared to established CSF amyloid and tau biomarkers, CSFneurogranin does not aid in the differential diagnosis between FTD and AD. Neurogranin could however potentially be a useful clinical CSF biomarker in separating FTD from controls- where currently few are available. Further studies exploring the relationship to neuropathological subtypes and different stages of disease are warranted.

P349 Different binding behavior of the Tau-PET tracer [F-18]AV-1451 in AD and Tau-positive FTLD J. Hammes1, G. Bischof1,2, K. Fliessbach3, K. Giehl1, F. Jessen4, B. Neumaier5, J. Kukolja6, ^ı Onur6, A. Drzezga1, T. van Eimeren1,2,6 1 University Hospital Cologne, Department of Nuclear Medicine, Cologne, Germany 2 Research Center Juelich, Cognitive Neuroscience, Institute of Neuroscience and Medicine, Juelich, Germany 3 University Hospital Bonn, Department of Psychiatry and Psychotherapy, Bonn, Germany 4 University Hospital Cologne, Department of Psychiatry, Cologne, Germany 5 University of Cologne, Institute of Radiochemistry and Experimental Molecular Imaging, Cologne, Germany 6 University Hospital Cologne, Department of Neurology, Cologne, Germany In Alzheimer’s disease (AD) tau accumulation primarily occurs as paired helical filaments (PHF) whereas mainly straight tau filaments (SF) are found in pure tauopathies like tau-positive (Tau+) frontotemporal lobar degeneration (FTLD). Recent ex vivo studies showed that the tau-PET tracer [F-18]-AV-1451 has significantly higher binding to PHF in comparison to SF. Here, we compare in vivo [F-18]-AV-1451 uptake in amyloid-positive (Amy+)/Tau+ AD cases and Amy-/Tau+ FTLD cases in regions affected by neuronal dysfunction. In a cohort of 22 patients with symptoms of dementia displaying regional metabolic deficit in [F-18]-FDG-PET and clearly increased cortical uptake in [F-18]-AV-1451 tau-PET, we performed [C-11]-PiB PET to assess Amyloid-positivity. We found 15 Amy+ and 7 Amy- cases. FDG and tau-images were spatially normalized. We created SUVR images by intensitynormalization to the cerebellum and compared regional average and maximum SUVRs between Amy+ and Amy- cases. Average cortical FDG SUVRs were comparable between Amy+ and Amycases in affected areas. Average subject maximum [F-18]-AV-1451 uptake was 2.26 in Amy+ cases and 1.60 in Amy- cases. The group difference was significant (pDespite similar regional FDG hypometabolism, regional cortical SUVRs and white to gray matter SUVR quotients of [F-18]-AV-1451 may differentiate Amy+ (AD) and Amy- (FTLD) forms of Tau+ neurodegeneration. This may represent higher in vivo binding affinity of the tracer to PHF as compared to SF or lower amount of tau-deposition in Amy- cases.


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Transcriptome analysis in FTD patients: genes, pathways and networks W. De Coster1,2, S. Van Mossevelde1,2, S. Engelborghs2,3, M. Vandenbulcke4, L. Mateiu5, M. Mattheijssens1,2, K. Peeters1,2, R. Vandenberghe6,7, P. Cras2,4, P. P. De Deyn2,3,8, M. Cruts1,2, C. Van Broeckhoven1,2 1 University of Antwerp, Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 3 Hospital Network Antwerp, Middelheim and Hoge Beuken, Department of Neurology and Memory Clinic, Antwerp, Belgium 4 Antwerp University Hospital, Department of Neurology, Edegem, Belgium 5 University of Antwerp, BIOINFO Unit, Department of Molecular Genetics, VIB, Antwerp, Belgium 6 University Hospitals Leuven, Department of Neurology and Memory Clinic, Leuven, Belgium 7 University of Leuven, Laboratory for Cognitive Neurology, Department of Neurology, Leuven, Belgium 8 University Medical Center Groningen, Department of Neurology and Alzheimer Research Center, Groningen, Belgium

Neural network organization in frontotemporal degeneration by means of graph theory on resting-state EEG recordings: a study on behalf of the Italian FTD Network L. Bonanni1, R. Franciotti1, A. Benussi2, M. Bozzali3, A. Cagnin4, A. Bruni5, S. Vincenzo6, G. Logroscino7, R. Ghidoni8, B. Nacmias9, F. Tagliavini10, A. Padovani2, M. Onofrj1, D. Galimberti11, B. Borroni2 1 University G.d’Annunzio of Chieti-Pescara, Department of Neuroscience, Imaging and Clinical Sciences, Chieti, Italy 2 University of Brescia, Department of Clinical and Experimental Sciences, Brescia, Italy 3 IRCCS Santa Lucia Foundation, Neuroimaging Laboratory, Rome, Italy 4 University of Padua, Department of Neurosciences, Padua, Italy 5 Regional Center of Neurogenetics, Lamezia Terme, Italy 6 University of Milan Medical School, IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, Milan, Italy 7 University of Bari, Department of Clinical Research in Neurology, Bari, Italy 8 IRCCS Fatebenefratelli, Molecular Markers Laboratory, Brescia, Italy 9 University of Florence, Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Florence, Italy 10 IRCCS Foundation “Carlo Besta” Neurological Institute, Division of Neurology V and Neuropathology, Milano, Italy 11 University of Milan, Department of Neurological Sciences, Milan, Italy

Frontotemporal dementia (FTD) is characterized by a striking heterogeneity with regard to the genetic architecture, clinical presentation and neuropathological features. Genetic research has broadly extended our understanding of key factors in the disease process; however, the downstream effects are insufficiently understood and we lack both targets amenable to therapy and biomarkers applicable for diagnosis. The aim of this project is to contribute to our knowledge by performing a genome-wide expression analysis. Using 30 mRNA fragment sequencing we investigated the transcriptomic profile of lymphoblast cell lines of a cohort of 90 individuals composed of i) 34 FTD patients with identified causal mutations, ii) 24 FTD patients with unknown genetic cause but dominant familial history and iii) 32 age- and sex-matched neurologically healthy individuals. Differential gene expression analysis using DESeq2 and edgeR highlights heterogeneity on the transcriptomic level and points to downstream affected genes. Dependent of the causal gene, expression of a different set of genes is influenced on top of a group of genes overlapping between subgroups. In depth pathway and overrepresentation analysis identified networks associated with neurodegeneration and shed light on the complex etiology of this devastating disease. Differential co-expression analysis using WGCNA revealed gene modules of biological significance with altered expression correlation. In agreement with previous research we observed deregulated transcripts encoding ribosomal proteins and factors involved in RNA processing and translation, among other relevant pathways. This project has the objective to facilitate discovery of novel disease causing genes, elucidate key factors leading to neurodegeneration and provide novel insights in the pathomechanism. Additionally, this research project has the potential to reveal disease or subtype specific biomarkers with diagnostic value in easily accessible tissue.

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Graph-theoretical analyses of functional networks obtained with resting-state recordings have recently proven to be a useful approach for the study of brain disease including Alzheimer’s disease (Sporn, Nat Neurosci 2014; 17 652–660 for a review), frontotemporal degeneration (FTD) (de Haan et al. BMC Neurosci 2009;10 101), dementia with Lewy bodies (Peraza et al. Neurobiol Aging 2015; 36 2458–67) challenging the classical concept of neurological disorders being either “local” or “global”. Electroencephalogram (EEG) was recorded from 21 unipolar scalp derivations of FTD patients and age-matched control subjects. We used Granger causality analysis which evaluates the direction of information transfer and the strength of the connection between each couple of nodes as functional connectivity measure into graph theory approach. Local and global efficiency of the network, links node degree, clustering coefficient, characteristic path length and assortativity coefficient were compared statistically between the two groups. Preliminary results on 8 FTD patients (4 behavioural variant, 4 semantic variant primary progressive aphasia, mean age 68 6 years, MMSE 21.3 7.4) and 6 controls (mean age 70 7 years) showed significant differences on assortativity coefficient degree, for undirected (p < 0.05) and directed graph (p < 0.03). The assortativity coefficient is a correlation coefficient between the degrees of all nodes on two opposite ends of a link, thus is a measure of resilience. A positive assortativity coefficient indicates that nodes tend to link to other nodes with the same or similar degree. In our data assortativity coefficients were negative for FTD and control group with higher values for FTD than control. These results reveal a cortical reorganization of FTD patients in which the network tends to be less assortative and less robust to network damage compared to healthy subjects. In conclusion small-



world properties measured by graph theory could be used to obtain a better understanding of the organizational properties of brain in FTD patients.

P352 Characteristics and progress on the Initial 256 participants in the advancing research and treatment in frontotemporal lobar degeneration (ARTFL) North American Rare disease clinical research consortium A. Boxer1, H. Rosen1, B. Boeve2, H. Heuer1, S. Laxineta1, M. Grossman3, G. Coppola4, B. Dickerson5, Y. Bordelon4, R. Conwit6, C. Dheel2, K. Faber7, H. Feldman8, J. Ferguson6, J. Fields2, J. Fong1, T. Foroud7, W. Galpern9, N. Ghoshal10, N. Graff-Radford11, R. Hsiung8, E. Huey12, D. Irwin3, K. Kantarci2, D. Kaufer13, A. Karydas1, A. Klein14, D. Knopman2, J. Kornak1, J. Kramer1, W. Kukull15, I. Litvan16, I. Mackenzie8, M. Mendez4,17, B. Miller1, M. Miller2, C. Onyike17, A. Pantelyat17, R. Rademakers11, E. Roberson11,18, M. Sutherland6, M. C. Tartaglia19, N. Tatton20, A. Toga21, A. Vetor7, S. Weintraub22, Z. Wszolek11 1 UCSF, San Francisco, United States 2 Mayo Clinic Rochester, Rochester, United States 3 University of Pennsylvania, Philadelphia, United States 4 UCLA, Los Angeles, United States 5 Massachusetts General Hospital, Cambridge, MA, United States 6 NIH, Bethesda, United States 7 NCRAD, Indianapolis, IN, United States 8 UBC, Vancouver, Canada 9 Janssen Pharmaceuticals, Washington, DC, United States 10 Washington University, St. Louis, United States 11 Mayo Clinic Jacksonville, Jacksonville, FL, United States 12 Columbia University, New York, United States 13 University of North Carolina, Chapel Hill, United States 14 CurePSP, New York, United States 15 University of Washington, Seattle, United States 16 UCSD, San Diego, United States 17 Johns Hopkins University, Baltimore, MD, United States 18 University of Alabama, Birmingham, Birmingham, United States 19 University of Toronto, Toronto, Canada 20 AFTD, Radnor, PA, United States 21 University of Southern California, Los Angeles, United States 22 Northwestern University, Chicago, United States The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) consortium (U54NS092089; https:// www.rarediseasesnetwork.org/cms/artfl/) began enrollment in 2015 at 15 North American research centers. Participants are either symptomatic with a sporadic FTLD spectrum disorder, including bvFTD, CBS, FTD-ALS, nfvPPA, PSP, or svPPA (Project 1) or are at risk for or symptomatic with familial FTLD (fFTLD) with a potentially autosomal dominant syndrome, regardless of whether there is a known underlying mutation (Project 2). Project 1 aims to characterize the North American population of FTLD patients in preparation for clinical trials. Project 2 aims to characterize longitudinal changes in fFTLD over 1 year and discover new genetic mutations. Participants are genotyped for genes known to cause FTLD and other dementias. ARTFL partners with patient advocacy groups including the Association for FTD, Bluefield Project, CBD Solutions, CurePSP, and the Tau Consortium, and is supported by an online FTD Disorders Registry. ARTFL is closely

linked to the LEFFTDS project, sharing a common database and assessments. We report here the characteristics of participants evaluated through February 2016. There are 256 subjects enrolled (118 (46%) male). Project 1 has enrolled 95 sporadic FTLD individuals (mean age 67.4 years [range 49–89]) with the most common diagnoses being PSP (29.6%), svPPAbvFTD (21.1%), and bvFTD (16.9%). CDR-SB scores were highest in bvFTD > PSP > svPPA, whereas MDS-UPDRS was highest in PSP > bvFTD >> svPPA (normal). MoCA scores were similar in bvFTD and svPPA and higher in PSP. Project 2 has enrolled 61 symptomatic (mean age 56.9 years; mean CDR-SB: 5.67) and 95 asymptomatic (mean age 48.9; mean CDR-SB: 0.04) fFTLD. FTLD-associated mutations were identified in two participants not already known to have one in their family. An infrastructure to share clinical, biomarker, genetic, and imaging data from ARTFL will be soon available to FTLD investigators worldwide.

P353 Grey matter disease distributions in a colombian cohort of patients with frontotemporal degeneration P. Reyes1, H. Santamarıa-Garcia2,3, F. Uriza1,2, A. Martinez2, A. Iragorri2,3, D. Matallana2,3, J. Santacruz2,3, C. Cano2,3, K. Rascovsky4, C. MacMillan4, M. Grossman4 1 Hospital Universitario San Ignacio, Centro de Memoria y Cognicion - Radiologıa, Bogota, Colombia 2 Pontificia Universidad Javeriana, Facultad de Medicina, Bogota, Colombia 3 Hospital Universitario San Ignacio, Centro de Memoria y Cognici on, Bogota, Colombia 4 University of Pennsylvania, Penn Frontotemporal Degeneration Center, Philadelphia, PA, United States Despite FTD affecting individuals worldwide, distributions of gray matter (GM) disease in FTD syndromes has rarely been validated in Latin America. We performed a comparative validation of GM disease distributions in two cohorts of FTD patients evaluated at the Center of Memory and Cognition Hospital Universitario San Ignacio in Colombia (CMCH, n = 30) and the Penn Frontotemporal Degeneration Center (PFTDC, n = 30). FTD samples were matched by syndrome (bvFTD, naPPA, svPPA), age, education, disease duration and MMSE scores. All subjects completed a high-resolution T1-weighted MRI scan; MRI volumes were resampled to 1 mm3 and processed using Advanced Normalization Tools (ANTs). Voxelbased morphometry analysis of structural GM atrophy was performed for each FTD syndrome relative to 31 healthy controls at each site (p50). Overall, we observed patterns of reduced GM cortical thickness that are consistent with previous reports. Relative to controls, naPPA at both sites had reduced GM in bilateral inferior frontal cortex extending to left anterior, middle, and superior temporal cortex, while svPPA had reduced GM in bilateral anterior temporal cortex. Both bvFTD samples had reduced GM in bilateral insula, dorsolateral prefrontal cortex and anterior cingulate. However, PFTDC patients had more bilateral inferior and orbital frontal GM disease, while CMCH patients had less overall GM disease that extended to posterior cortical regions. Although these imaging findings largely converge with previous neuroimaging reports of FTD syndromes, future work is required to determine sources of heterogeneity in the bvFTD samples. This feasibility study opens the way for cross-cultural imaging studies with specialized FTD sites in Latin America. CMCH.


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EEG dominant frequency peak differentiates between Alzheimer’s disease and frontotemporal lobar degeneration J. Goossens1, J. Laton2, J. Van Schependom2, J. Gielen2, H. Struyfs1, S. Van Mossevelde3,4,5, T. Van den Bossche3,4,5, J. Goeman3, P. P. De Deyn1,3,6, A. Sieben4,6, J.-J. Martin6, C. Van Broeckhoven4,5, J. van der Zee4,5, G. Nagels2, S. Engelborghs1,3 1 Reference Center for Biological Markers of Dementia BIODEM, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 2 Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium 3 Department of Neurology and Memory Clinic, Hospital Network Antwerp ZNA Middelheim and Hoge Beuken, Antwerp, Belgium 4 Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 5 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 6 Biobank, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

The sAPPb/YKL-40 ratio in cerebrospinal fluid as a novel diagnostic marker in frontotemporal lobar degenerationrelated syndromes: a multicentre study arez-Calvet1,2, R. Blesa1,2, D. Alcolea1,2, E. Vilaplana1,2, M. Su 1,2 3 J. Clarimon , A. Llado , R. Sanchez-Valle3, J. Molinuevo3, nol-Ripoll6, G. Garcıa-Ribas4, Y. Compta2,5, M. Martı2,5, G. Pi~ 7 7 7 G. Amer-Ferrer , A. Noguera , A. Garcıa-Martın , J. Fortea1,2, A. Lleo´1,2 1 Institut d’Investigacions Biomediques Sant Pau - Hospital de Sant Pau, Department of Neurology, Barcelona, Spain 2 Centro de Investigaci on Biomedica en Red en Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain 3 Hospital Clınic, Institut d’Investigaci o Biomedica August Pi I Sunyer, Alzheimer’s Disease and other Cognitive Disorders Unit, Department of Neurology, Barcelona, Spain 4 Hospital Universitario Ram on y Cajal, Servicio de Neurologıa, Madrid, Spain 5 Institute of Clinical Neurosciences, Hospital Clınic/IDIBAPS and University of Barcelona, Parkinson’s disease and Movement Disorders Unit, Neurology Service, Barcelona, Spain 6 Hospital Santa Maria, Unitat de Trastorns Cognitius, Lleida, Spain 7 Hospital Universitari Son Espases, Unidad de Neurologıa Cognitiva, Servicio de Neurologıa, Palma de Mallorca, Spain

Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are both prevalent causes of dementia and may be difficult to distinguish on a clinical level. Analysis of electroencephalogram (EEG) recordings can serve as a non-invasive biomarker to increase differential diagnostic accuracy. To objectively assess EEG recordings, EEG characteristics should be quantified rather than visually analyzed. We aim to differentiate between AD and FTLD by using a very straightforward measure that is easily determined from a short EEG. EEG was recorded from age-matched patients with AD (n = 55) and FTLD (n = 51), of which 37 (AD: n = 19; FTLD: n = 18) had a definite diagnosis. Subgroups of definite AD and definite FTLD dementia patients were defined by genetic carrier status and/or by postmortem neuropathological confirmation of brain pathology. After selection of artifact-free fragments in the eyes-closed state, the dominant frequency peaks were extracted in the [5–15] Hz interval for each of the 19 channels, for each individual patient. The dominant frequency peak with the highest amplitude across channels was categorized as the maxpeak for each patient. The average maxpeak frequency was significantly lower in AD (7.80 1.44 Hz) than in FTLD patients (8.57 1.34 Hz) (p = 0.006). This difference was visible for all dominant frequency peaks, independent of channel. When analyzing only the definite patient subgroups, this difference was even more pronounced (AD: 7.22 1.11 Hz; FTD: 8.90 1.26 Hz; p. Quantitative analysis of the EEG maxpeak frequency is an easy and useful measure for the differentiation between AD and FTLD.

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One of the challenges in the diagnosis of frontotemporal lobar degeneration (FTLD) is that the correspondence between clinical syndromes and the underlying neuropathology is usually unpredictable. Unlike for Alzheimer’s disease (AD), accurate cerebrospinal fluid (CSF) biomarkers for the diagnosis of FTLD are lacking. We measured levels of YKL-40, sAPPb, Ab42, T-Tau and P-Tau in the CSF of a clinical cohort of 304 participants that included patients with FTLD-related clinical syndromes (n = 159), patients with AD (n = 69) and cognitively normal controls (CN, n = 76). A subset of 146 participants had a high level of certainty in their diagnosis (known FTD-causing mutation, motor-neuron disease, autopsy-confirmed diagnosis in FTLD-related syndromes, or amyloid pathology excluded in the controls). In 97 participants, a structural 3T MRI was available and suitable for quantitative analyses. We compared biomarkers across groups, determined their relationship with structural MRI findings and assessed their diagnostic utility. Levels of sAPPb in CSF were lower in patients with FTLD-related syndromes than in CN and AD patients, and correlated with cortical thickness in FTLD-vulnerable areas in MRI. YKL-40 levels in CSF were higher in all symptomatic groups than in controls. In the ROC analysis, the sAPPb/YKL-40 ratio had an area under the curve (AUC) of 0.91, distinguishing FTLD patients from CN. The AUC for the sAPPb/YKL-40 ratio to distinguish FTLD patients from AD patients was 0.85 (95% CI 0.80–0.91). The sAPPb/YKL-40 ratio is a novel CSF biomarker in FTLD that could be useful to increase the certainty of the diagnosis in clinical practice.



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CSF exploratory biomarker study for (differential) diagnosis of frontotemporal lobar degeneration J. Goossens1, J. van der Zee2,3, S. Van Mossevelde4,2,3,5, E. Vanmechelen6, T. Van den Bossche4,2,3,5, B. De Vil7,8, A. Sieben2,9, J.-J. Martin9, P. Cras5,7,8, J. Goeman4, P. P. De Deyn1,4,9, C. Van Broeckhoven2,3, S. Engelborghs1,4 1 Reference Center for Biological Markers of Dementia BIODEM, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 2 Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 3 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 4 Department of Neurology and Memory Clinic, Hospital Network Antwerp ZNA Middelheim and Hoge Beuken, Antwerp, Belgium 5 Department of Neurology, Antwerp University Hospital, Edegem, Belgium 6 ADx NeuroSciences, Ghent, Belgium 7 Laboratory of Neurology, Translational Neurosciences, University of Antwerp, Antwerp, Belgium 8 Laboratory of Neurobiology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 9 Biobank, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

Dynamic connectivity state oscillations in presymptomatic GRN disease: from Connectome to Chronnectome E. Premi1, M. Diano2, S. Gazzina1, F. Cauda2, S. Archetti3, R. Gasparotti4, A. Padovani1, B. Borroni1 1 University of Brescia, Department of Neurology, Brescia, Italy 2 University of Turin, Department of Psychology, Turin, Italy 3 Brescia Hospital, Brescia, Italy, Department of Laboratories, III Laboratory of Analysis, Brescia, Italy 4 University of Brescia, Neuroradiology Unit, Brescia, Italy

There is a need for biomarkers allowing early and differential diagnosis between frontotemporal lobar degeneration (FTLD) and other dementias. Notable candidates include routine Alzheimer’s disease (AD) CSF biomarkers (pTau181P, hTau, Ab1–42), nonphosphorylated tau fraction (pTau rel), neurofilament light chain (NF-light), phosphorylated neurofilament heavy chain (pNF-H), and progranulin. Using a cohort of definite FTLD patients, we aimed to explore the performance of these cerebrospinal fluid (CSF) biomarkers. Definite FTLD patients (n = 45), clinically diagnosed AD patients (n = 45), definite Creutzfeldt-Jakob disease (CJD) patients (n = 20) and cognitively healthy controls (n = 20) were included in this study. FTLD-TDP (n = 28), FTLD-tau (n = 10) and FTLDother (n = 7) subgroups were defined by genetic carrier status and/ or postmortem neuropathological confirmation. CSF biomarker levels were quantified using commercially available single-analyte ELISA kits. CSF progranulin levels were significantly lower in FTLD-TDP patients as compared to the FTLD-tau subgroup, due to low levels in GRN mutation carriers. To differentiate between FTLD and AD, pTau181P was the best single marker (AUC = 0.922). For further differentiation between FTLD and AD patients, a decision tree was constructed, which showed an added value for NF-light and hTau, correctly classifying 90.8% of the patients. Differentiation between FTLD and controls still proves difficult, with NF-light being the best single marker (AUC = 0.700). A decision tree showed that besides NF-light, Ab1–42 could aid as well, correctly classifying 80.6% of the subjects. The easiest differentiation was that between FTLD and CJD with pTAU rel as the best single marker (AUC = 0.999). pNFH did not contribute to (differential) diagnosis of FTLD. In conclusion, using single markers, pTau181P and hTau together with NF-light can correctly classify up to 90.8% of FTLD and AD dementia patients. Differentiation between FTLD and controls remains suboptimal, even when combining NF-light and Ab1–42 (correct classification of 80.6%).

It is widely recognized that brain changes occur years before symptom onset in those subjects carrying pathogenic mutation leading to Frontotemporal Dementia. Resting-state functional MRI is a promising tool to capture complex functional relationships among brain regions (connectome). Recently, the assumption of a static nature of connectivity over the MRI scanning period had been challenged, prompting the identification of time-varying patterns (states) of coupling among brain regions (chronnectome). Aim of the present study was to explore dynamic network synchronization in asymptomatic subjects carrying Granulin mutations. We applied Independent Component Analysis (ICA), sliding time window correlation and k-means clustering of windowed correlation matrices to resting state fMRI. We considered 59 subjects (19 asymptomatic GRN carriers (aGRN), 40 healthy controls (HC)), extracting 8 ICA networks (Dorsal Attentional (DAN), Default Mode (anterior and posterior DMN), Frontoparietal (left and right FPN), Executive (EN), Salience (ventral and dorsal SN)) subsequently used for dynamic connectivity analysis. Mean dwell time (MDT) was computed as the average number of consecutive windows classified as instances of the same state, also considering flexible coupling among networks in each state. We identified 5 states (state 1 with tightly connected nodes and state 4 with the highest density of connections; state 2, 3, and 5 were in-between). aGRN spent more time (MDT) in state 1 (p = 0.041) and less in state 4 (p = 0.047) as compared to HC. In aGRN, reduced flexible connections between FPN and EN (state 4) and between DMN and ventral SN (in state 5) were identified. Conversely, increased functional coupling between DMN and dorsal SN was reported in state 3. Dynamic connectivity abnormalities characterize the prodromal phases of GRN disease. Beyond giving information on specific network (i.e. SN and FPN) involvement, the study of the chronnectome allowed us to shed new light on the “global” effect of GRN disease, with the desynchronization of the “inner rhythm” of the brain.


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Structural deficits and altered network connectivity in presymptomatic C9ORF72 S. Lee1, A. C. Sias1, M. L. Mandelli1, J. A. Brown1, A. B. Brown1, A. M. Khazenzon2, A. A. Vidovszky3, T. P. Zanto4, A. M. Karydas1, M. Pribadi5, G. Coppola5, D. H. Geschwind5, R. Rademakers6, M. L. Gorno-Tempini1, H. J. Rosen1, B. L. Miller1, W. W. Seeley7,1 1 University of California, San Francisco, Memory and Aging Center, Department of Neurology, San Francisco, USA 2 Stanford University, Department of Neuroscience, Stanford, USA 3 University of San Francisco, San Francisco, USA 4 University of California, San Francisco, Department of Neurology, San Francisco, USA 5 University of California, Los Angeles, Neurobehavior Division, Department of Neurology, Los Angeles, USA 6 Mayo Clinic, Department of Neuroscience, Jacksonville, USA 7 University of California, San Francisco, Department of Pathology, San Francisco, USA

Longitudinal decline of cerebral glucose metabolism in Frontotemporal Lobar Degeneration Continuum A. Bejanin1, N. Ayakta1, D. R. Schonhaut1, G. Marx1, G. Tammewar1, Y. Cobigo1, F. McKenna1, L. Iaccarino1, M. Gorno-Tempini1, B. L. Miller1, W. J. Jagust1, H. J. Rosen1, G. D. Rabinovici1 1 University of California, San Francisco, San Francisco, USA

Hexanucleotide repeat expansions in C9ORF72 represent the most common known genetic cause of familial and sporadic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis. Previous work has shown that presymptomatic C9ORF72 expansion carriers exhibit gray matter deficits in regions showing atrophy during the symptomatic phase. It remains unknown whether these gray matter deficits are accompanied by abnormal brain connectivity. We compared 18 presymptomatic carriers to matched healthy controls using voxel-based morphometry to delineate gray matter differences, diffusion tensor imaging to compare white matter tract integrity, and task-free fMRI to probe the salience, sensorimotor, and default mode networks, and a medial pulvinar region-of-interest we previously linked to salience network disruption in C9ORF72behavioral variant FTD. We ascertained psychiatric histories by retrospective chart review and compared carriers to non-carrier family members. Carriers showed largely preserved cognition and behavior despite gray matter and brain connectivity deficits apparent as early as the fourth decade of life. Gray matter volume deficits were topographically similar though less severe than those reported in symptomatic carriers and included regions in posterior midcingulate, medial pulvinar thalamus, and insula. Reduced white matter integrity arose in bilateral corpus callosum, cingulum bundle, corticospinal tract, uncinate fasciculus, and inferior longitudinal fasciculi. Connectivity was diminished in all four networks, with no enhancements relative to controls. Within the observed deficit patterns, carriers and controls showed comparable relationships between imaging metrics and age, suggesting that deficits emerge no later than early adulthood. Comparable psychiatric histories were obtained in carriers and non-carriers. Taken together, the findings suggest that presymptomatic C9ORF72 expansion carriers exhibit functionally compensated brain volume and connectivity deficits that resemble deficits reported during the symptomatic phase. Across modalities, deficits emerged by the fourth decade of life or earlier, raising the possibility that they represent developmental differences rather than prodromal neurodegeneration.

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A sensitive biomarker for monitoring disease progression of frontotemporal dementia (FTD) would help to test new diseasemodifying therapies. The aim of this study was to assess the ability of 18FDG-PET to detect longitudinal changes in cerebral glucose metabolism in FTD syndromes. Eighteen patients with behavioralvariant FTD (bvFTD), 10 with non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), 12 with semantic variant PPA (svPPA) and 37 matched healthy controls were enrolled in Neuroimaging In Frontotemporal Dementia (NIFD) study and underwent 2–3 MRI and 18FDG-PET scans. All 11C-PiB-positive patients (n = 2/34) were excluded from the analyses. Betweengroup comparisons were first performed cross-sectionally to identify regions showing hypometabolism in each syndrome at baseline and follow-up (SPM12). Voxelwise mixed-effects models were then carried out to determine regions showing greater decreased metabolism over time in patients than controls (R Software). Results showed that baseline dorsolateral and medial prefrontal hypometabolism in bvFTD extended into both adjacent structures and parietal cortex with follow-up. In nfvPPA, hypometabolism was restricted to supplementary motor cortex at baseline and extended with time into the precentral gyrus and frontal operculum. In svPPA, baseline hypometabolism encompassed the left greater than right anterior temporal and medial prefrontal cortex and significant changes with time were observed in the right temporal, orbitofrontal and lateral parietal cortex. Altogether, our result highlighted specific patterns of metabolic change over time in each variant and further suggests the sensitivity of 18FDG-PET for tracking disease progression in FTD.



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Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia I. Woollacott1, J. Rohrer1, K. Dick1, E. Brotherhood1, E. Gordon1, A. Fellows1, J. Toombs2, R. Druyeh3, M. J. Cardoso1,4, S. Ourselin1,4, J. Nicholas1,5, N. Norgren6, S. Mead3, U. Andreasson7, K. Blennow7, J. Schott1, N. Fox1, J. Warren1, H. Zetterberg2,7 1 Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, Great Britain 2 Department of Molecular Neuroscience, UCL Institute of Neurology, London, Sweden 3 MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, Great Britain 4 Centre for Medical Image Computing, University College London, London, Great Britain 5 Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, Great Britain 6 Uman Diagnostics, Umea Sweden, Umea, Sweden 7 Clinical Neurochemistry Laboratory, Department of Psyschiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Default, salience, and executive control network functional connectivity changes in behavioural variant FTD and Alzheimer’s disease J. Wang1, A. Ng2, J. Lim1, B. L. Choo1, C. See2, L. Lim2, T. T. Yong2, R. Chander2, H. Foo2, A. Zhang2, J. Su1, A. Vipin1, S. Ting2, S. Hameed2, N. Kandiah2,1, H. Zhou1 1 Duke-NUS Graduate Medical School, Centre for Cognitive Neuroscience, Singapore, Singapore 2 National Neuroscience Institute, Neurology, Singapore, Singapore

Despite forthcoming clinical trials in frontotemporal dementia (FTD), few biomarkers of disease state or progression are available. Previous studies suggest that cerebrospinal fluid neurofilament light chain (NfL) concentrations are associated with the severity of disease in FTD, but serum levels have yet to be investigated. We developed a novel ultrasensitive immunoassay to investigate serum NfL concentrations in a group of patients with FTD, including different clinical and genetic subgroups. Serum samples were collected from 74 patients (34 with behavioural variant FTD (bvFTD), three with FTD and motor neuron disease and 37 with primary progressive aphasia (PPA)) and 28 healthy controls. Twenty-four FTD patients carried a pathogenic mutation in C9orf72 (9), MAPT (11) or GRN (4). Serum NfL concentrations were measured using the NF-Light kit transferred onto the Simoa platform, and compared between FTD and control groups, as well as between the clinical and genetic subgroups. We also assessed relationships between NfL concentrations and measures of cognition and brain volume. Serum NfL concentrations were higher in FTD patients overall (mean 77.9 (SD 51.3) pg/ml) than controls (19.6 (8.2) pg/ml; p < 0.001). Concentrations were significantly higher in bvFTD (57.8 (33.1) pg/ml) and both the nonfluent and semantic variants of PPA (82.5 (33.8) pg/ml and 95.9 (33.0) pg/ml respectively) compared with controls, and in semantic variant PPA compared with logopenic variant PPA (49.5 (19.4) pg/ml). Concentrations were significantly higher than controls in both the C9orf72 and MAPT subgroups (79.2 (48.2) pg/ml and 40.5 (20.9) pg/ml respectively) with a trend towards a higher concentration in the GRN subgroup (138.5 (103.3) pg/ml) and no significant difference between genetic subgroups. Serum concentrations correlated particularly with frontal lobe atrophy rate (r = 0.53, p = 0.003). These results suggest that increased serum NfL concentrations reflect the intensity of the disease in FTD and are associated with more rapid disease progression.

Behavioural variant FTD (bvFTD) and Alzheimer’s disease (AD) have shown distinct atrophy patterns and divergent brain functional connectivity in the salience network (SN) and default mode network (DMN). The frontoparietal-based executive control network (ECN), however, has been less studied. We compared functional connectivity patterns in 3 large-scale networks (DMN, SN, and ECN) in a Singaporean sample of bvFTD, early-onset AD (EOAD), and healthy older adults. We included 13 EOAD subjects (3 males, all righthanded, age 61.9(7.8) years), 10 bvFTD subjects (3 males, one lefthanded, age 61.6(6.1) years), and 12 age-/gender- matched healthy controls (2 males, all right-handed, age 61.5(6.5) years) who underwent 8-min eyes-open (with fixation) task-free fMRI (Siemens, 3T). Three seeds corresponding to the hubs of DMN (right angular gyrus, ANG), SN (right frontoinsula, FI) and ECN (right dorsolateral prefrontal cortex, DLPFC) were used to construct whole-brain functional connectivity maps. Group-level voxel-wise two-sample ttests were performed to reveal group differences in functional connectivity (height threshold of p < 0.01 and cluster threshold of p < 0.05) with age and gender as covariates. Compared with controls, AD and bvFTD showed similar functional connectivity reductions in the ECN both within and between networks, including connectivity between right DLPFC and parietal regions and between right DLPFC and subcortical/temporal regions. Both groups exhibited divergent connectivity patterns in DMN and SN consistent with previous findings: AD weakened DMN connectivity in anterior and posterior DMN but strengthened SN connectivity (right FI ventromedial prefrontal cortex), while bvFTD strengthened DMN connectivity in posterior DMN regions, but weakened SN connectivity (right FI - medial superior frontal gyrus and mid- and anterior cingulate cortex). Reduced ECN connectivity in bvFTD and EOAD provides insight into and contributes to the “network-based neurodegeneration” hypothesis in both disorders.

P362 Principal component analysis of [18F]-AV-1451 tau PET in Alzheimer disease and frontotemporal dementia K. Friedrichsen1, S. Mishra1, N. Ghoshal2,3, B. Gordon1,3, N. Joseph-Mathurin1, Y. Su1, J. Christensen1, P. Aldea1, J. McConathy1, B. Ances2,3, N. Cairns2,3,4, J. Morris2,3, T. Benzinger1,3,5 1 Washington University, Radiology, Saint Louis, USA 2 Washington University, Neurology, Saint Louis, USA 3 Washington University, Knight Alzheimer’s Disease Research Center, Saint Louis, USA 4 Washington University, Pathology and Immunology, Division of Neuropathology, Saint Louis, USA 5 Washington University, Neurosurgery, Saint Louis, USA Background: Development of radiotracers for imaging tau protein in vivo holds potential as an early biomarker among


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tauopathies, such as Alzheimer Disease (AD) and Frontotemporal Dementia (FTD), even prior to clinical presentation. Our aim is to identify binding topographies and relate them to disease and aging processes. Methods: Seventy-one adults (12 with global Clinical Dementia Ratings (CDR) > 0) underwent [F-18]-AV-1451 positron emission tomography (PET). Seven participants were from a familial tau (MAPT) FTD cohort (6 mutation carriers). Regions of interest (ROI) were determined using FreeSurfer. PET data were partial-volume corrected, converted to Standardized Uptake Value Ratios (SUVRs) normalized to whole cerebellum, and averaged across hemispheres. Data from 37 ROIs were entered into a principal component analysis. Sixty-two participants also underwent beta-amyloid PET scans and were categorized as positive or negative by a mean cortical SUVR cutoff. Results: Three components were identified, accounting for 83% of the binding variance. The first component (61% total variance) had positive loadings in the temporal, parietal, and occipital lobes. Component 2 was almost entirely comprised by the choroid plexus. Component 3 had positive loadings for the medial temporal lobes and negative for the posterior areas of component 1. Component 1 was higher in beta-amyloid positive participants. Component 2 correlated with age. Component 3 was higher in the FTD cohort compared to the AD cohort. Conclusions: Our analysis showed three separate tau deposition processes. The first component was similar to the tau topography associated with preclinical AD and correlated with beta-amyloid deposition. Component two was weakly associated with age, and was not associated with disease processes. The third component was higher in the FTD cohort than either cognitively normal or demented persons not in the FTD group. Additionally, differences were observed in component 3 between the different MAPT mutation groups, though a larger number of participants is required for validation.

P363 Grey matter network differences between behavioural variant frontotemporal dementia and Alzheimer’s disease E. Vijverberg1,2, B. Tijms1, J. Dopp1, Y. Jeong Hong1, P. Scheltens1, F. Barkhof3, Y. Pijnenburg1 1 VUmc, Alzheimer Centre and Department of Neurology, Amsterdam, Netherlands 2 Haga Ziekenhuis, Department of Neurology, The Hague, Netherlands 3 VUmc, Department of Radiology, Amsterdam, Netherlands Objective: The clinical differentiation between FTD and AD is sometimes difficult. We set out to determine whether behavioural variant Frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD) could be discriminated based on single-subject grey matter networks. Methods: We included patients with bvFTD (n = 59) and age, gender and scanner matched patients with AD (n = 90) from the Amsterdam Dementia Cohort. Grey matter segmentations (obtained with SPM12) were used to extract single subject grey matter networks from T1 weighted structural MRI scans. Local and global network properties were calculated, and compared with ANOVAs taking into account age, gender, grey matter volume and scanner type. Lasso logistic regression analysis was used to selected the set of variables that resulted in the most accurate disease classification.

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Results: AD patients had a lower connectivity density than FTD patients (F = 14.64, p = 0.0002; Mean SD FTD 16.10% 1.19; Mean SD AD 15.64% 1.02). The following set of variables was selected using lasso regression as the best classifier for FTD versus AD: Local grey matter volume of the left gyrus rectus, left angular gyrus and left nucleus caudate, the degree of left and right occipital area, left fusiform, superior parietal gyrus, right paracentral and the right temporal area and the clustering of the right paracentral area (McFadden R2 = 0.52; p = right), and to a lesser extend on bilateral parietal and occipital lobes in FTD patients. Cognitive score (MoCA) was significantly lower in patients with mild or severe frontal hypoperfusion (n = 23; MoCA=10.6) compared to those without frontal hypoperfusion (n = 5; MoCA=23.8) (U = 8.0; z = 3.0; p = 0.001). No FTD patient showed genetic mutation tested on GRN (24/24) and MAPT (24/24), and C9orf72 (8/8). In summary, FTD is the second most common early-onset dementia. There is evidence of motor disturbances while no genetic association was found to date in the Chinese FTD subjects but a larger sample size is needed to validate the above observations.



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Distinct subcortical atrophy patterns across four different neurodegenerative syndromes J. Neitzel1, M. Watts1, J. Diehl-Schmid2, M. Ortner2, T. Grimmer2, I. Yakushev3, P. Bublak4, C. Preul4, K. Finke1, C. Sorg5,2 1 Ludwig-Maximilians-University Munich, General and Experimental Psychology, Munich, Germany 2 Klinikum rechts der Isar, Psychiatry and Psychotherapy, Munich, Germany 3 Klinikum rechts der Isar, Nuclear Medicine, Munich, Germany 4 University Hospital Jena, Hans-Berger Department of Neurology, Jena, Germany 5 Klinikum rechts der Isar, Neuroradiology, Munich, Germany

Testing the network degeneration hypothesis for intrinsic brain networks and four distinct neurodegenerative syndromes J. Neitzel1,2, M. Watts1, J. Diehl-Schmid3, M. Ortner3, T. Grimmer3, I. Yakushev4, P. Bublak5, C. Preul5, K. Finke1, C. Sorg6,3 1 Ludwig-Maximilians-University Munich, General and Experimental Psychology, Munich, Germany 2 Klinikum rechts der Isar, Neuroradiology, Munich, Germany 3 Klinikum rechts der Isar, Psychiatry and Psychotherapy, Munich, Germany 4 Klinikum rechts der Isar, Nuclear Medicine, Munich, Germany 5 University Hospital Jena, Hans-Berger Department of Neurology, Jena, Germany 6 Klinikum rechts der Isar, Neuroradiology, Munich, Germany

Variants of Alzheimer’s disease (AD) and different syndromes of frontotemporal lobar degeneration (FTLD) differ specifically in cortical atrophy patterns. However, less is known whether neurodegeneration of subcortical systems show the same distinctiveness in these diseases. To elucidate differences in subcortical atrophy patterns, we focused on four distinct syndromes: 37 biomarker-confirmed FTLD subjects, of which 19 presented with behavioral variant frontotemporal dementia (bvFTD) and 18 with primary progressive aphasia (PPA), and 36 biomarker-confirmed AD subjects, of which 23 presented with the amnestic variant (aAD) and 13 with posterior cortical atrophy (PCA). To systematically investigate atrophy patterns along the vertical cortical-subcortical axis we focused on three regions of interest: whole cortex, basal ganglia and thalamus. Voxel based morphometry on structural MR images was used to quantify and compare atrophy patterns first between patients and 18 healthy control participants and second between patient groups. Compared to healthy controls all patient groups showed significant volumetric reductions in all regions of interest. On the cortical level we found syndrome-specific atrophy patterns. In addition, we found specific structural changes on the subcortical level. In the basal ganglia, bvFTD patients showed atrophy in the medial striatum and aAD patients primarily in the lateral striatum. In the whole FTLD group the dorso-medial thalamic nucleus showed significant atrophy, in all patients with AD pathology, irrespective of clinical diagnosis, the most significant atrophy appeared in the lateral pulvinar. These results demonstrate that different neurodegenerative syndromes not only impair cortical areas in an anatomically specific way, but also demonstrate syndrome-specific atrophy patterns in subcortical brain areas. Consequently, neurodegenerative syndromes seem to specifically affect whole vertical cortico-subcortical systems.

The network degeneration hypothesis suggests that for a given neurodegenerative syndrome, onset and spread of neurodegeneration is associated with a specific brain network and its dysfunction. Here, we tested this assumption for intrinsic brain networks (IBN) in different syndromes of frontotemporal lobar degeneration (FTLD) and two variants of Alzheimer’s disease (AD). We expected that each syndrome is associated with reduced intrinsic functional connectivity (iFC) in one core network and potentially in additional networks. 37 biomarker-confirmed FTLD subjects, of which 19 presented with behavioral variant frontotemporal dementia (bvFTD) and 18 with primary progressive aphasia (PPA), and 36 biomarkerconfirmed AD subjects, of which 23 presented with the amnestic variant (aAD) and 13 with posterior cortical atrophy (PCA) were assessed by resting-state functional MRI. The following network connectivity measures were determined for canonical IBNs such as default mode network or dorsal attention network: (i) network iFC derived from independent component analysis and (ii) degree centrality (DC iFC) derived from graph theory analysis within IBN boundaries. Compared to 18 healthy controls, both AD patient groups showed reduced network iFC in syndrome-associated core networks. Specifically, in aAD patients we found reduced iFC in the default-mode network and in the right attention network. In PCA patients, iFC was reduced in the dorsal attention network and in the default-mode network. In addition, areas of reduced DC iFC overlapped with standard IBN templates taken from the literature. In contrast, reduced iFC was not restricted to one core network in the FTLD patient groups. The patterns of reduced DC iFC were also less strictly associated with IBN templates, but rather mirrored atrophy patterns. The present findings suggest that the assumptions made by the network degeneration hypothesis does not fully apply to large-scale IBN. It seems that the onset of iFC changes is less specifically tied to the functional network architecture, while the spread of reduced iFC might follow it more closely.


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P367 Neurofilament light chain: a biomarker for disease onset and survival in genetic frontotemporal dementia L. Meeter1, E. Dopper1, L. Jiskoot1, R. Sanchez-Valle2, C. Graff3, L. Benussi4, R. Ghidoni4, Y. Pijnenburg5, B. Borroni6, D. Galimberti7, R. J. Laforce8, M. Masellis9, R. Vandenberghe10, I. Le Ber11, M. Otto12, R. van Minkelen13, J. Papma1, 3 € , V. Jelic3, D. Cash15,16, S. Rombouts14, M. Balasa2, L. Oijerstedt S. Harding15, M. J. Cardoso15,16, S. Ourselin16, K. Dick15, M. Rossor15, G. Binetti4, A. Padovani6, E. Scarpini7, C. Fenoglio7, C. Tartaglia9, F. Lamari17, C. Barro18, J. Kuhle18, J. Rohrer15, C. Teunissen19, J. van Swieten1,20 1 Erasmus Medical Center, Neuroloy, Rotterdam, Netherlands 2 Hospital Clınic de Barcelona, Neurology, Barcelona, Spain 3 Karolinska Institutet, Neurogeriatrics, Stockholm, Sweden 4 IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy 5 VU University Medical Center, Neurology, Amsterdam, Netherlands 6 University of Brescia, Clinical and Experimental Sciences, Brescia, Italy 7 University of Milan, Milano, Italy 8 Universite Laval, Dpt des Sciences Neurologiques, Quebec, Canada 9 University of Toronto, Medicine, Toronto, Canada 10 University Hospital Leuven, Neurology, Leuven, Belgium 11 Hôpital Pitie-Salpêtriere, Institut du Cerveau et de la Mo€elle epiniere, Paris, France 12 University of Ulm, Ulm, Germany 13 Erasmus Medical Center, Clinical Genetics, Rotterdam, Netherlands 14 Leiden University, Psychology, Leiden, Netherlands 15 University College London, Neurodegenerative diseases, London, Great Britain 16 University College London, Translational Imaging Group, London, Great Britain 17 Hôpital Piti e-Salpêtriere, Laboratoire de Biochimie, Paris,

France 18

University Hospital Basel, Neurology, Basel, Switzerland VU University Medical Center, Clinical Chemistry, Amsterdam, Netherlands 20 VU University Medical Center, Clinical Genetics, Amsterdam, Netherlands 19

Neurofilament light chain (NfL) in cerebrospinal fluid (CSF) has been proven to be elevated in sporadic frontotemporal dementia and to be highly correlated to blood-derived NfL in other diseases. However, the role of this biomarker in presymptomatic and symptomatic genetic frontotemporal dementia, is thus far unknown. In this multicenter case-control study, we investigated CSF NfL in 174 subjects (48 controls, 40 presymptomatic carriers and 86 patients with microtubule-associated protein tau (MAPT), progranulin (GRN), and chromosome 9 open reading frame 72 (C9orf72) mutations), and serum NfL in 118 subjects (39 controls, 44 presymptomatic carriers, 35 patients). In 55 subjects both CSF and serum was determined. In two subjects CSF was available before and after symptom onset (converters). Additionally, NfL levels were correlated with clinical parameters, survival and regional brain atrophy. CSF NfL levels in patients (median 6762 pg/ml, interquartile range 3186–9309 pg/ml) were strongly elevated compared with presymptomatic carriers (804 pg/ml, 627–1173 pg/ml, p < 0.001), resulting in a good diagnostic performance to discriminate both

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groups. Serum NfL correlated highly with CSF NfL (rs = 0.87, p < 0.001) and was similarly elevated in patients. Longitudinal samples in the converters showed a three- to four-fold increase of CSF NfL after disease onset. Additionally, NfL levels in patients correlated with disease severity, brain atrophy, annualized brain atrophy rate and survival. In conclusion, NfL in both serum and CSF has the potential to serve as a biomarker for clinical disease onset and has a prognostic value in genetic FTD.

P368 Novel CSF biomarkers discriminating FTLD-TDP from non-demented controls M. del Campo1, N. Elias1, M. Koel-Simmelink1, L. Boonkamp1, D. Galimberti2, W. Hu3, C. Teunissen1 1 VU University Medical Center, Amsterdam, Netherlands 2 University of Milan, Centro Dino Ferrari, Milan, Italy 3 Emory University Hospital, Atlanta, USA Frontotemporal dementia (FTD) is the second most prevalent dementia in patients below the age of 65 and has the strongest reduction in life expectancy. FTD is characterized by the presence of two main protein aggregates in the brain: tau (FTD-tau) or TDP43 (FTD-TDP), which likely require distinct pharmacological therapy. Unfortunately, there are not effective biomarkers able to discriminate FTLD from other dementias nor the different FTLD subtypes. We previously identified potential biomarkers in cerebrospinal fluid (CSF) able to discriminate the two pathological FTLD subtypes and related dementias. Now, we aimed to further validate the clinical performance of the identified biomarkers using two larger and independent CSF cohorts. We analyzed the levels of YKL40, FABP4, MFGE8 and Catalase enzyme activity in CSF cohorts from two different centers: the Emory university and Milan University. These cohorts included patients with FTD with confirmed Tau (n = 20) or TDP43 (n = 30) pathology, Alzheimer’s disease (AD, n = 30), dementia with Lewy bodies (DLB, n = 29), vascular dementia (VaD, n = 7) and non-demented controls (n = 29). YKL40 was increased in FTLD-TDP patients not only compared to controls (fold-change -f.c-:1.6, p < 0.0001) but also compared to FTLD-Tau, DLB and VaD (fc:1.2–1.6; p < 0.05). The highest levels of MFGE-8 were found in AD patients and were significantly different from those observed in both FTLD subtypes and DLB (f.c:0.8–1.4; p < 0.05). We observed up to 1.5-fold increase in catalase activity in FTLD-TDP and other dementias compared to controls (p < 0.05). Combination of YKL-40, MFGE-8 and Catalase activity in CSF could discriminate FTLD-TDP patients from non-demented controls with 90% sensitivity and 76% specificity (AUC:0.88, p < 0.0001). In summary, we revealed a novel biomarker combination able to discriminate FTLD-TDP from nondemented controls with acceptable accuracy using two independent CSF cohorts. Interestingly, the biomarkers analyzed are related to inflammatory processes, and thus these data further support a role of inflammation in the pathogenesis of FTLD, especially in those cases with TDP deposition.



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Analysis of frontotemporal lobar degeneration patients using automated magnetic resonance imaging analyzing tool: the MRI characteristics of C9ORF72 expansion carriers A. Cajanus1,2, A. Hall1, Y. Liu1, T. Urhemaa3, J. Koikkalainen4, D. Rueckert5, S. Hasselbalch6, P. Mecocci7, W. van der Flier8, onen4, A. Remes1,2 H. Soininen1, J. L€otj€ 1 University of Eastern Finland, Institute of Clinical Medicine, Neurology, Kuopio, Finland 2 Kuopio University Hospital, Department of Neurology, Kuopio, Finland 3 VTT Technical Research Centre of Finland, Tampere, Finland 4 Combinostics Ltd, Tampere, Finland 5 Imperial College London, Department of Computing, London, Great Britain 6 Copenhagen University Hospital, Department of Neurology, Copenhagen, Denmark 7 University of Perugia, Section of Gerontology and Geriatrics, Perugia, Italy 8 VU University Medical Centre, Alzheimer Center, Amsterdam, Netherlands

Accelerated structural gray matter and white matter changes in preclinical progranulin mutation carriers C. Olm1, C. McMillan1, D. Irwin1,2, V. Van Deerlin2, J. Gee3, M. Grossman1 1 University of Pennsylvania, Neurology, Philadelphia, USA 2 University of Pennsylvania, Pathology and Laboratory Medicine, Philadelphia, USA 3 University of Pennsylvania, Radiology, Philadelphia, USA

The clinical diagnosis of frontotemporal lobar degeneration (FTLD) is lacking objective and reliable biomarkers indicating the disease. Differential diagnosis between FTLD and other dementias as well as some psychiatric diseases using clinical profile or brain MRI findings may be difficult. Genetic testing is the only definite diagnostic biomarker of FTLD during lifetime. The C9ORF72 repeat expansion is the most common genetic etiology of FTLD, and it is assumed to be responsible up to 40–50% of familial FTLD worldwide. Visual evaluation of brain atrophy and other changes concerning different types of FTLD is very difficult and automated MRI analyzing methods could provide more objective and reliable data. The PredictND tool (www.predictnd.eu) is an automated computing software that uses six different methods for computing imaging biomarkers from MRI scans. In addition to volumetric data, modern morphometric imaging biomarkers are computed. The tool generates an individual patient’s profile by combining all available biomarkers, and measures the similarity of this profile to various profiles of different diagnostic groups. Finally, it suggests the most likely diagnosis for the patient with an estimate of its confidence. The aim of our study is to demonstrate the PredictND tool as a novel clinical diagnostic protocol for neurodegenerative diseases and identify the characteristic brain MRI findings in FTLD. We analyzed MRI scans (T1 and FLAIR) of FTLD patients with the C9ORF72 expansion and compare them to similar data of a same amount of non-carrier FTLD patients. We hypothesize that PredictND tool can provide valuable data in differential diagnosis of FTLD and its subtypes by detecting changes in the brain in the early stage of the disease. We also presume that in the future PredictND can be used also in clinical practice to assist clinicians in differential diagnosis of FTLD.

It is essential to identify brain regions exhibiting longitudinal changes in asymptomatic progranulin mutation carriers (aGRN+), relative to a group of family members who are non-carriers (aGRN-) to develop disease markers in treatment trials. GRN mutation is associated with frontotemporal degeneration (FTD) spectrum disorders due to TDP-43 inclusions. Cognitively normal relatives of clinically diagnosed GRN+ FTD patients were identified as either aGRN+ (N = 11, mean age = 46.5) or aGRN- (N = 6, mean age = 39.7). For inclusion in this study each participant completed two MRI sessions with T1-weighted and diffusion tensor imaging (DTI) sequences. Voxel-wise difference images were created for each participant by subtracting the follow-up cortical gray matter probability (GMP) image from the baseline GMP image, expecting most voxels to be small positive values representing normal aging related changes, with larger values perhaps due to a disease process. Voxel-wise whole-brain comparisons of GMP difference images between the aGRN+ and aGRN- groups (p < 0.05, k > 600 mm3) reveal aGRN+ had greater changes in left inferior temporal and supramarginal cortices. Similarly, difference images were created using radial diffusivity (RD) to examine white matter (WM) changes. These comparisons (p < 0.05, k > 600 mm3) reveal greater change in aGRN+, indicating worsening WM integrity, in bilateral superior longitudinal fasciculi (SLF) and corona radiata. We then found the WM tracts connected to the identified GM regions using DTI tractography and observed overlap between these tracts and the clusters of worsening WM in the left SLF. We interpret these findings as evidence of GM and WM structural changes preceding FTD symptom onset.

P371 Local thalamic atrophy in behavioural variant FTD A. Santillo1, D. Jakabek2, M. Walterfang3, K. Nilsson4, D. van Westen5, J. Looi6, B. Power7 1 Lund University, Clinical Memory Research Unit, Department of Clinical Sciences, Malm€ o, Sweden 2 University of Wollongong, Graduate School of Medicine, Wollongong, Australia 3 Royal Melbourne Hospital, Melbourne Neuropsychiatry Centre, Neuropsychiatry Unit, Melbourne, Australia 4 Lund University, Section of Geriatric Psychiatry, Department of Clinical Sciences, Lund, Sweden 5 Sk ane University Hospital, Center for Medical Imaging and Physiology, Lund, Sweden 6 Australian National University Medical School, Research Centre for the Neurosciences of Ageing, Academic Unit of Psychiatry and Addiction Medicine, School of Clinical Medicine, Canberra, Australia 7 The University of Notre Dame Australia, School of Medicine Fremantle, Fremantle, Australia


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The thalamus appears to be critically involved in FTD. Most previous MRI studies addressing the thalamus have either been of whole thalamic volume, voxel based, or have used a thalamic subsegmentation based on predefined boundaries. The purpose of the current study is to study thalamic involvement in bvFTD using a method that allows for local estimations of atrophy. 28 patients with bvFTD and 26 age and sex- matched controls underwent a 3T MRI as part of a comprehensive work-up. On T1-weighted 3D volumetric sequence (voxel size of 1 9 1x1 mm3), the thalami were manually segmented. The resulting 3-D objects underwent both volumetric analysis and shape analysis, the latter through spherical harmonic description with point distribution models (SPHARM). This method assesses local deviations in the surface of the thalamus as a measure of local atrophy, avoiding assumptions of thalamic nuclei boundaries. Age, gender and intracranial volume were covariates in all analyses. Thalamic volumes were, as expected, reduced in bvFTD patients compared with controls, slightly more pronounced on the left side than on the right (15.3%, g2 = 0.16, p = 0.004 for left and 12.8%, g2 = 0.10, p = 0.021 for the right thalamus). The shape analysis showed, in the left thalamus, a generalized, global deflation of surface (atrophy), with no local variations, that did not survive FDR corrections. In contrast, on the right side there were local deflations of surface (atrophy), most pronounced in regions corresponding to the superior anterior and superior medial pulvinar nucleus, which survived FDR correction. Surprisingly, regions corresponding to the mediodorsal nucleus showed no deflation. This map of local thalamic atrophy partly conforms to previous studies on the thalami in bvFTD, and to what is expected from cortical atrophy patterns in bvFTD, yet differs markedly in some aspects. The picture of thalamic involvement that emerges is a more complex one than a direct correspondence between cortical and thalamic atrophy, important when understanding the contribution of the thalamus in this disorder.

P372 Structural brain imaging differentiates behavioral variant of frontotemporal dementia from late life depression D. Tosun1, H. Rosen2, J. Zakrzewski3, B. Miller2, J. Kramer2, M. Weiner1, O. Wolkowitz3, C. Nelson3, S. Mackin3 1 UCSF, Radiology, San Francisco, USA 2 UCSF, Neurology, San Francisco, USA 3 UCSF, San Francisco, USA The primary manifestations of behavioral variant of frontotemporal dementia (bvFTD) include changes in socioemotional behavior including apathy, loss of empathy, disinhibition, obsessivecompulsive behavior, and euphoria. Because of these prominent neuropsychiatric features and young age of onset, many patients with bvFTD are misdiagnosed with non-neurodegenerative psychiatric disorders, the most common being major depression disorder (MDD), prior to receiving a diagnosis of bvFTD. The initial misdiagnosis results in critical delays in implementing evidence based intervention for the treatment as well as management of bvFTD symptoms. The objective of this study was to evaluate the degree to which structural brain abnormalities and cognitive testing can differentiate individuals with consensus-diagnosed bvFTD from age-matched individuals with MDD, independently and jointly. Structural magnetic resonance imaging and cognitive performance data of seventy-three participants were studied including 23 patients with bvFTD, 23 patients with unipolar MDD who were in the same

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age range as the bvFTD patients, and 27 age-matched cognitively normal individuals. bvFTD was associated with significantly more frontal, anterior temporal and subcortical atrophy than MDD. In contrast, compared with bvFTD, MDD showed significantly greater atrophy in parietal and occipital lobes. These structural imaging markers discriminated bvFTD and MDD patients at 85% accuracy (ACC) with 93% sensitivity (SENS) and 77% specificity (SPEC). Among five cognitive tests considered in this study, semantic fluency was the only one that independently predicted diagnosis (79% ACC, 75% SENS, and 82% SPEC). Furthermore, multimodal analysis of behavioral and imaging data indicated that cognitive tasks sensitive to frontal lobe function, such as the semantic fluency sequencing and Trail Making tests could improve discriminative power of structural brain abnormalities (90% ACC, 90% SENS, and 92% SPEC). These findings might have important implications for assessment of psychiatric symptomatology.

P373 Diagnostic utility of arterial spin labeled magnetic resonance imaging and flourodeoxyglucose positron emission tomography in the behavioral variant of frontotemporal dementia and Alzheimer’s disease D. Tosun1, N. Schuff1, G. Rabinovici2, N. Ayakta3, B. Miller2, W. Jagust4, J. Kramer2, M. Weiner1, H. Rosen2 1 UCSF, Radiology, San Francisco, USA 2 UCSF, Neurology, San Francisco, USA 3 UCSF, San Francisco, USA 4 UC Berkeley, Berkeley, USA A large body of work has demonstrated that brain imaging, in particular functional imaging of cerebral blood flow (CBF) with arterial spin labeled (ASL) magnetic resonance imaging (MRI) or cerebral metabolic rate of glucose (CMRgl) with fluorodeoxyglucose (FDG) positron emission tomography (PET), can improve the accuracy of differential diagnosis in behavioral variant of frontotemporal dementia (bvFTD). Although recent studies have indicated that patterns of CBF and CMRgl abnormalities are similar in bvFTD, no studies have yet compared the diagnostic value of CBF with the diagnostic utility of CMRgl in differentiating bvFTD from other dementias such as Alzheimer’s disease (AD Therefore, the goal of the current study was to compare the diagnostic value of these two imaging techniques in differentiating bvFTD from AD. Partial least squares logistic regression was used to identify voxels with diagnostic value in CBF and CMRgl images from patients with bvFTD (n = 32) and AD (n = 28), who were compared with each other and with cognitively normal controls (CN, n = 15). Diagnostic values of these maps were compared with each other. Regions that differentiated each disorder from controls were similar for CBF and CMRgl. For differentiating AD from CN, the areas under the curve (AUC) for CBF (0.89) and CMRgl (0.91) were similar, with similar sensitivity (CBF: 86%, CMRgl: 78%) and specificity (CBF: 92%, CMRgl: 100%). Likewise for differentiating bvFTD from CN performance of CBF (AUC = 0.83) and CMRgl (AUC = 0.85) were equivalent, with similar sensitivity (CBF: 78%, CMRgl: 79%) and specificity (CBF: 92%, CMRgl: 100%). In differentiating bvFTD from AD, classification was again similar for CBF (AUC = 0.87) and CMRgl (AUC = 0.79), as were sensitivity (CBF: 83%, CMRgl: 89%) and specificity (CBF: 93%, CMRgl: 78%). None of the differences in any performance measure were statistically significant. Our results suggest that ASL-MRI has



similar diagnostic utility as FDG-PET in diagnosis of AD and bvFTD. Continued development of ASL-MRI as a diagnostic tool for neurodegenerative dementias is warranted.

P374 Replication of pathology-confirmed atrophy patterns via cortical thickness analysis in dementia J. H. Roh1, J. Hwang1, C. M. Kim1, S. Park1, J.-H. Lee1 1 Asan Medical Center, Neurology, Seoul, South Korea Background and Objective: Pathologically defined subtypes of Alzheimer’s disease (AD) represented distinctive atrophy patterns and clinical characteristics. We investigated whether a cortical thickness-based clustering method can reflect such findings. Methods: A total of 77 AD subjects from the Alzheimer’s Disease Neuroimaging Initiative 2 data set who underwent 3-T magnetic resonance imaging, [18F]-fluorodeoxyglucose-positron emission tomography (PET), [18F]-Florbetapir PET, and cerebrospinal fluid (CSF) tests were enrolled. After clustering based on cortical thickness patterns, diverse imaging and biofluid biomarkers were compared between these groups. Results: Three cortical thinning patterns were noted: medial temporal (MT; 19.5%), diffuse (55.8%), and parietal dominant (P; 24.7%) atrophy subtypes. The P subtype was the youngest and represented more glucose hypometabolism in the parietal and occipital cortices and marked amyloid-beta accumulation in most brain regions. The MT subtype revealed more glucose hypometabolism in the left hippocampus and bilateral frontal cortices and less performance in memory tests. CSF test results did not differ between the groups. Conclusion: With successful replication of pathology-confirmed atrophy patterns via cortical thickness analysis in AD, current methods would be valuable to be applied in other neurodegenerative disorders, including frontotemrpoal dementia.

P375 Neuroanatomic and neuropsychological evidence of cognitive reserve in the ALS-FTD spectrum K. Placek1, K. Ternes1, L. Massimo1, J. Woo1, L. Elman1, D. Irwin1, M. Grossman1, C. T. McMillan1 1 University of Pennsylvania, Philadelphia, USA Evidence suggests a clinicopathological spectrum between frontotemporal dementia(FTD) and amyotrophic lateral sclerosis (ALS): 50% of ALS patients experience cognitive decline in executive, language, and social function due to extramotor frontotemporal atrophy consistent with the clinical profile of FTD, and both diseases share TDP-43 pathology and genetic mutations. Cognitive reserve (CR), a measure of lifetime cognitive demand, is associated with less frontal atrophy, longer survival, and attenuated cognitive decline in FTD, but has not yet been investigated in ALS. We report 86 ALS patients (59 ALS, 11 ALS-MCI, 16 ALS-FTD) with T1weighted MRI processed using ANTs to compute grey matter (GM) density; patients were behaviorally assessed on the ALS Functional Rating Scale (ALS-FRS-R) and on specific measures of executive function (verbal letter fluency, F-words) and cognitive flexibility (visual-verbal test, VVT). CR was assessed by patient education and occupation. We identified widespread bilateral GM atrophy in ALS-

MCI/ALS-FTD relative to ALS (TFCE-corrected p < 0.01); regression analyses indicated higher CR in ALS-MCI/ALS-FTD related to attenuated GM atrophy in left premotor and superior temporal cortices and bilateral inferior frontal gyri (uncorrected p < 0.05). In all patients, CR but not ALS-FRS-R predicted better performance on VVT (b = 0.23, p = 0.04) and F-words (b = 0.22, p = 0.03). We conclude CR accounts in part for the heterogeneous incidence of frontotemporal atrophy and cognitive decline in ALS, consistent with models viewing ALS and FTD along a spectrum. We speculate CR may be protective due to earlier cognitive symptom detection in ALS patients with higher education or occupation. Study support: NIH (AG043503 AG017586 AG010124 AG032953 NS063111) Dana Foundation and Wyncote Foundation.

P376 Alteration of the brain morphometry and metabolism following donepezil treatment in Alzheimer’s disease: VBM with DARTEL and 1H-MR spectroscopy G.-W. Jeong1, C.-M. Mooon1 1 Chonnam National University Medical School, Radiology, GwangJu, South Korea The purpose of this study was to evaluate the gray matter (GM) and white matter (WM) volume alterations and metabolic changes in patients with Alzheimer’s disease (AD) following donepezil treatment, as well as to reveal the correlations of the scores of various neuropsychological scales with the volumetric and metabolic changes. Twenty-one subjects comprising of 11 patients with AD and 10 age-matched healthy controls participated in this study. All the patients participated in the follow-up study 24 weeks after donepezil treatment. In this study, the voxel-based morphometry (VBM) and proton magnetic resonance spectroscopy (1H-MRS) were used to assess the brain morphometric and metabolic alterations in AD. In the GM volumetric analysis, both of the untreated and treated patients with donepezil showed significantly reduced volumes in the hippocampus, parahippocampal gyrus, precuneus and middle frontal gyrus compared with healthy controls. However, donepezil-treated patients showed significantly increased volumes in the hippocampus, precuneus, fusiform gyrus and caudate nucleus compared to untreated patients. In the WM volumetric analysis, untreated and treated patients showed significant volume reductions in the posterior limb of internal capsule, cerebral peduncle of the midbrain and parahippocampal gyrus compared to healthy controls. However, there was no significant WM morphological change after donepezil treatment in patients with AD. In MRS study, untreated patients with AD showed decreased NAA/Cr and increased mI/Cr compared to healthy controls, while treated patients showed only decreased NAA/Cr in the same comparison. However, the treated patients showed simultaneously increased NAA/Cr and decreased mI/Cr and Cho/Cr ratios compared to untreated patients. This study shows the regional GM and WM volume changes in combination with metabolic changes following donepezil treatment in AD. These findings would be helpful to aid our understanding of the neuroanatomical mechanisms associated with effects of donepezil on the cognitive function in AD.


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P377 Progranulin plasma levels predict the presence of GRN mutations but not the development of symptoms D. Galimberti1, C. Fenoglio1, S. Cioffi1, G. Fumagalli1, A. Arighi1, B. Borroni2, A. Padovani2, F. Tagliavini3, M. Masellis4, C. Tartaglia5, J. Van Swieten6, L. Meeter6, C. Graff7, A. Mendonca8, J. Rohrer9, E. Scarpini1, O. B. O (GENFI)9 1 University of Milan, Ospedale Policlinico, Neurology, Milan, Italy 2 University of Brescia, Brescia, Italy 3 Istituto Besta, Milan, Italy 4 Sunnybrook Health Sciences Centre, Toronto, Canada 5 University Health Network memory clinic, Toronto Western Hospital, Toronto, Canada 6 Erasmus Medical Center, Rotterdam, Netherlands 7 Karolinska University Hospital, Stockholm, Sweden 8 University of Lisbon, Lisbon, Portugal 9 UCL Institute of Neurology, London, Great Britain Progranulin plasma levels are decreased in carriers of GRN mutations, either symptomatics or asymptomatics. The normality reference value previously proposed is > 61 ng/mL. As the method is low cost and easy to develop, it has been proposed as a screening procedure to identify mutation carriers, to be then confirmed with sequencing, which is instead expensive and feasible only in specialized centers. Nevertheless, a limit of previous studies is the small number of subjects considered. Here, we analyzed progranulin plasma levels in a large cohort of patients with GRN mutations, as well as at risk individuals from the same families, collected in the Genfi initiative, including 19 patients, 64 asymptomatic carriers and 77 non-carriers. MeanSD levels in patients and asymptomatic carriers were significantly decreased as compared with non-carriers (30.5 13.0 and 27.7 7.5 versus 99.6 24.8 ng/mL, P61 ng/ mL, the test had a sensitivity of 98.8% and a specificity of 97.5% in predicting the presence of a mutation, independent of symptoms. Conversely, no correlations were found between progranulin plasma levels and age or years from average age at onset in each family (p > 0.05). These data demonstrate that progranulin plasma levels is an excellent predictor of the presence of a GRN mutation and could be used in clinical setting to identify people to be further screened by sequencing, but is not useful to predict the appearance of symptoms in asymptomatic carriers.

P378 Regional differences in FDG-PET uptake in asymptomatic FTD patients with GRN and C9ORF72 mutations K. Popuri1, M. Bhalla1, A. Buller1, S. Towfighi1, P. Sengdy2, C. Jacova3, R. Rademakers4, H. Feldman2, L. Wang5, G.Y. Hsiung2, I. R. Mackenzie2, M. F. Beg1 1 Simon Fraser University, Burnaby, Canada 2 University of British Columbia, Vancouver, Canada 3 Pacific University, Oregon, USA 4 Mayo Clinic, Jacksonville, USA 5 Northwestern University, Chicago, USA The aim of this study is to investigate the group-wise differences in the glucose metabolism in the brain among asymptomatic members of frontotemporal dementia (FTD) families with and without GRN and C9ORF72 mutations using fluorodeoxyglucose (FDG) tracer-based positron emission tomography (PET) images. Our cohort consisted of 19 asymptomatic members of families with

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FTD caused by GRN mutations (7 mutation carriers vs. 12 noncarriers) and 28 asymptomatic members of families with the C9ORF72 mutation (12 mutation carriers vs. 16 non-carriers). Magnetic resonance imaging (MRI) images for each subject were processed using Freesurfer to obtain the parcellation into subcortical and cortical regions of interest (ROI). The FDG-PET images were co-registered to the corresponding MRI images and the mean FDG uptake in each of the ROIs was computed. The mean FDG uptake value in each ROI was normalized using the mean uptake in the brainstem region. ROI-wise two sample t-tests were conducted to determine the differences between the mutation carrier and noncarrier groups. In subjects from the GRN mutation families, the cerebellum cortex and paracentral ROIs in the left hemisphere showed a significant (p < 0.05) reduction in the FDG uptake in the mutation carriers when compared with non-carrier family members. Further, in the right hemisphere, the banks of the superior temporal sulcus, lateral orbitofrontal, paracentral and frontal pole ROIs also showed significantly (p < 0.05) reduced FDG uptake. In subjects from the C9ORF72 families, the ROIs with significantly (p < 0.05) reduced FDG uptake in the mutation carriers were found to be widespread across the left and right hemispheres of the brain including both the cerebral cortex and subcortical regions. In particular, the thalamus, inferior temporal cortex and middle temporal cortex showed a highly significant (p < 0.001) reduction in the FDG uptake bilaterally. These results suggest that i) the FDGPET changes are observable in the asymptomatic phase of FTD and ii) the observed patterns are mutation specific.

P379 Network measures of glucose metabolism are altered in asymptomatic FTD subjects K. Popuri1, M. Bhalla1, A. Buller1, S. Towfighi1, P. Sengdy2, C. Jacova3, R. Rademakers4, H. Feldman2, L. Wang5, G.-Y. Hsiung2, I. R. Mackenzie2, M. F. Beg1 1 Simon Fraser University, Burnaby, Canada 2 University of British Columbia, Vancouver, Canada 3 Pacific University, Oregon, USA 4 Mayo Clinic, Jacksonville, USA 5 Northwestern University, Chicago, USA The aim of this study is to determine mutation specific patterns of altered glucose metabolism in asymptomatic frontotemporal dementia (FTD) patients through a network-based analysis of regional uptake measures derived from fluorodeoxyglucose (FDG) tracer based positron emission tomography (PET) images. We analyzed a cohort of 19 asymptomatic members of families with FTD caused by GRN mutations (7 mutation carriers vs. 12 non-carriers) and 28 asymptomatic members of families with the C9ORF72 mutation (12 mutation carriers vs. 16 non-carriers). Magnetic resonance imaging (MRI) images for each subject were processed using Freesurfer to obtain the parcellation into subcortical and cortical regions of interest (ROI). The FDG-PET images were co-registered to MRI images and the FDG uptake at each voxel was normalized using the mean uptake in the brainstem. The median uptake value in each of the cortical and subcortical ROIs was computed from the normalized to brainstem FDG-PET images. Patient specific networks were built using the median normalized FDG uptake measures from the different ROIs. In the network construction, a pairwise dissimilarity criterion was used as the linking function to determine the edges in the network. A pair of ROIs in the network were linked by an edge if



the dissimilarity between their FDG uptake values was greater than a chosen threshold. A set of network features were extracted from each patient’s individual FDG uptake network. Using the variational Bayes probablistic multikernel (VBpMKL) framework, classification analysis was performed using the FDG uptake network features to discriminate between the mutation carriers and non-carriers. In a cross-validation experiment, an area under the curve (AUC) of ~ 87% was achieved for the discrimination of GRN mutation carriers from non-carriers, whereas an AUC of ~ 96% was achieved for the C9ORF72 mutation carrier discrimination. Network features describing the FDG uptake measures are able to successfully capture the specific patterns of glucose metabolism changes in FTD caused by the GRN and C9ORF72 mutations.

P380 Network-level analysis of cortical gray matter atrophy in asymptomatic FTD subjects K. Popuri1, M. Bhalla1, A. Buller1, S. Towfighi1, P. Sengdy2, R. Rademakers3, H. Feldman2, G.-Y. Hsiung2, L. Wang4, I. R. Mackenzie2, M. F. Beg1 1 Simon Fraser University, Burnaby, Canada 2 University of British Columbia, Vancouver, Canada 3 Mayo Clinic, Jacksonville, USA 4 Northwestern University, Chicago, USA The aim of this study is to determine the mutation specific patterns of cortical gray matter atrophy in asymptomatic frontotemporal dementia (FTD) patients through a network-based analysis of cortical thickness measures derived from magnetic resonance imaging (MRI) images. We analyzed a cohort of 22 asymptomatic members of families with FTD caused by GRN mutations (8 mutation carriers vs. 14 non-carriers) and 36 asymptomatic members of families with the C9ORF72 mutation (15 mutation carriers vs. 21 non-carriers). MRI images for each subject were processed using Freesurfer to extract the pial (gray matter and cerebrospinal fluid boundary) and inner (gray and white matter boundary) surfaces of the cerebral cortex, and obtain a parcellation of these surfaces into 68 ROIs. Cortical thickness was computed as the distance between the corresponding points on the pial and inner surfaces using a topologically-aware thickness computation method (Gibson et al. Org. HBM 2009). Patient specific networks were built using the median cortical thickness measures in each of the 68 ROIs. The network was constructed using a pairwise dissimilarity criterion as the linking function, where a pair of ROIs were linked by an edge if the dissimilarity between their cortical thickness values was greater than a chosen threshold. A set of network features were extracted from each patient’s cortical thickness network. Using the variational Bayes probablistic multikernel (VBpMKL) framework, classification analysis was performed using the thickness network features to discriminate between the mutation carriers and noncarriers. In a cross-validation experiment, an area under the curve (AUC) of ~ 89% was achieved for the discrimination of GRN mutation carriers from non-carriers, whereas an AUC of ~ 67% was achieved for the C9ORF72 mutation carrier discrimination. Network features describing cortical thickness are thus observed to capture the specific patterns of gray matter atrophy in FTD caused by the GRN and C9ORF72 mutations, and they may provide a marker to confirm and follow the progression of the disease.

P381 Distinct patterns of brain atrophy in genetic frontotemporal dementia: visual rating scales in the GENFI cohort G. G. Fumagalli1, P. Basilico1, S. Harding2, A. Arighi1, M. Bocchetta2, M. Mercurio1, K. Dick2, J. van Swieten3, B. Borroni4, C. Graff5, M. Masellis6, F. Tagliavini7, J. Rowe8, R. Laforce9, E. Finger10, G. Frisoni11, A. Mendoca12, S. Sorbi13, E. Scarpini1, J. Rohrer2, D. Galimberti1 1 University of Milan, Pathophysiology and Transplantation, Milan, Italy 2 University College London, Dementia Research Centre, London, Great Britain 3 Erasmus Medical Centre, Department of Neurology, Rotterdam, Netherlands 4 University of Brescia, Brescia, Italy 5 Karolinska Institutet, Stockholm, Sweden 6 University of Toronto, Toronto, Canada 7 Besta Hospital, Milan, Italy 8 University of Cambridge, Cambridge, Great Britain 9 Universite Laval, Quebec, Canada 10 University of Western Ontario, London Ontario, Canada 11 IRCCS Fatebenefratelli Brescia, Brescia, Italy 12 Universidade de Lisboa, Lisbon, Portugal 13 University of Florence, Florence, Italy Frontotemporal dementia (FTD) is a clinically, radiologically and genetically heterogeneous disorder. Mutations in the three main genes (MAPT, GRN, C9orf72 expansion) can have different profiles of brain atrophy. The objectives of our study were to compare the pattern of atrophy of symptomatic subjects among different genetic groups and to look for pre-symptomatic signs of atrophy in at-risk subjects. We used six visual rating scales of brain atrophy: orbitofrontal (OF), anterior cingulate (AC), fronto-insula (FI), anterior temporal (AT), medial temporal (MT) and posterior (PA). Two raters, blind for clinical and genetic data, reviewed 343 scans from the GENFI cohort that consisted of 150 controls, 130 presymptomatic (64 GRN, 24 MAPT, 42 C9orf72) and 63 symptomatic (17 GRN, 15 MAPT, 31 C9orf72). Inter rater reliability of scan assessment was good with intraclass correlation coefficients (ICC) ranging from 0.73 of PA to 0.88 of MT. MAPT mutation carriers compared with GRN were more atrophic in the AT (Mann Whitney U test 0.002) and MT (0.005) but less in OF (0.016), AC (0.004), FI (0.014) and PA (< 0.001). C9orf72 patients compared to GRN show less OF atrophy (0.043) while compared to MAPT had greater PA (< 0.001) but less AT (0.001). Comparing presymptomatic to controls only the MAPT mutation carrier group showed a significant difference in the scores of MT atrophy (0.037). The identification of typical pattern of atrophy at the MRI (more frontal and parietal in GRN, more anterior and medial temporal in MAPT, widespread in C9orf72) can help in directing genetic analysis in symptomatic patients. Signs of atrophy can be identified in presymptomatic subjects even by using visual rating scales.


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P382 Comparison of diagnostic significance of voxel-based diffusion tensor imaging and FDG-PET in bvFTD G. Lueg1, J. Julia Lange-Grumfeld1, A. Vrachimis2, H. Lohmann1, A. Johnen1, T. Duning1 1 University Hospital M€ unster, Neurology, M€ unster, Germany 2 University Hospital M€ unster, Nuclear Medicine, M€ unster, Germany The importance of neuroimaging in diagnosing behavioral variant frontotemporal dementia (bvFTD) increases SinceFDG positron emmission tomography (PET) is rather established, studies on voxel-based magnetic resonance imaging (MRI) analysis techniques or diffusor tensor imaging (DTI) in bvFTD are still rare and, thus, are hardly used in clinical routine. In the current study we analyzed the diagnostic significance of voxel-based DTI analyses in early stages of bvFTD. A total of 30 bvFTD patients underwent a detailed neuropsychological examination, CSF analyses, conventional MRI, FDGPET as well as extensive structural brain imaging analyses, including DTI, compared with the data of 44 age-matched healthy controls (HC). All patients matched the current diagnostic criteria and were rated as probable bvFTD. Based on the FDG-PET data analysis, the experienced investigators unanimously rated 20 of 30 patients as typical for bvFTD with bifrontal and/or frontotemporal hypometabolism (z-scores ≤ 3), whereas 10 patients showed untypically/ normal PET pattern Then, the patient group was dichotomized in bvFTD with typical PET findings and in patients with normal/ untypical PET results. DTI data of both bvFTD groups were compared with HC in a voxel-based analysis. In contrast to the PET data, voxel-based DTI analyses of both bvFTD groups revealed rather similar significant clusters of lesions in bilateral frontal and temporal areas that are typically affected in bvFTD. Furthermore, a linear regression analysis of DTI data showed significant correlations of structural deficits in prefrontal and parahippocampal areas with typical neuropsychological deficits, rated by the frontal behavioral inventory manual. DTI analysis might be more sensitive that FDG-PET in early stages of bvFTD. DTI findings seemed to be of functional relevance since the structural lesions were associated with typical early neuropsychological deficits. DTI analyses might increase the diagnostic confidence in the detection of bvFTD compared to the more commonly performed FDG-PET.

P383 Novel connectome approach identifies imaging-genetic associations in sporadic frontotemporal degeneration R. Madhavan1, A. Singanamalli2, R. Mullick1, V. Vaidya1, C. Kodira2, V. Van Deerlin3, M. Grossman3, D. Irwin3, C. McMillan3 1 GE Global Research, Bangalore, India 2 GE Global Research, Niskayuna, USA 3 University of Pennsylvania, Neurology, Philadelphia, USA Frontotemporal degeneration (FTD) is a clinically, genetically and pathologically heterogeneous condition. While 20% of FTD patients have an inherited genetic mutation, the majority of patients have sporadic disease. Genome wide association studies have identified single nucleotide polymorphisms (SNPs) associated with disease risk and quantitative trait analyses have identified imaging-

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genetic associations. Multimodal analyses integrating functional resting state MRI (rsfMRI), diffusion imaging (dMRI), and structural MRI (sMRI) connectomes with genetics are lacking. Here we integrate 3 imaging modalities to identify novel imaging-genetic associations. We evaluated 129 FTD patients with MRI and derived 91 rsfMRI, 36 dMRI, and 34 sMRI network features with genotyping of 37 SNPs associated with neurodegenerative disease (FTD, Alzheimer’s, Parkinson’s). To reduce the feature space and in-parallel find associations between variables, we applied sparse multi CCA (mCCA) that maximizes the sum of pairwise multivariate correlations between all features. Using mCCA with 5-fold cross validation and 1000 permutations, we identified associations between rs6687758 (intergenic) and rs11568563 (SLC01A2) with diffusion executive control-subcortical network, functional executive control network, and subcortical volumes (p < 0.001). Both of these SNPs have been associated with risk of progressive supranuclear palsy (PSP), a disorder associated with white matter degeneration. The gene SLC01A2 is also highly expressed in subcortical structures affected by PSP. We suggest that multivariate imaginggenetic approaches can enhance our toolkit for identifying biologically plausible genetic modifiers of sporadic FTD.

P384 Altered expression of non-coding RNAs in neural-derived serum exosomes in patients with FTD C. Fenoglio1, M. Serpente1, S. Cioffi1, M. Arcaro1, E. Oldoni1, G. Fumagalli1, A. Arighi1, P. Basilico1, A. Cattaneo2, L. Porretti2, D. Galimberti1, E. Scarpini1 1 University of Milan, Pathophysiology and Transplantation, Milan, Italy 2 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Clinical Chemistry and Microbiology Laboratory, Flow Cytometry Service, Milan, Italy Blood contains exosomes released by various cell types, which may serve as potential biomarkers for diagnostic and prognostic use. Exosomes are a class of endosome-derived membrane vesicles shed by neural cells, which contain proteins and other constituents of their cellular origin. Exosomes are a naturally enriched source of non-coding (nc)RNAs such as micro(mi)RNA and long non coding (lnc)RNA; therefore, their identification at serum level in neural derived exosomes would provide new insights for the identification of reliable peripheral biomarkers in FTD. The aim of our study was to detect a specific neuronal signature of ncRNAs at serum level that could be considered as biomarker of pathology. We set up methods for total ncRNA extraction from neural derived exosomes. Serum from 5 FTD, 5 healthy controls was incubated with ExoQuick exosome precipitation solution (SBI). Subsequently, exosomes were enriched for neural sources by antihuman L1CAM antibody immunolabel and analyzed by flow cytometry (FACS Aria, BD). The total exosome RNA and Protein isolation kit (Thermo Fisher) was used to isolate ncRNAs from neural derived exosomes. ncRNA profiling was performed by testing the expression of 84 miRNAs (miFinder array, Qiagen) and the expression of 160 lncRNAs (lncRNA Finder and Inflammatory response and Autoimmunity lncRNA arrays, Qiagen). Results showed robust dysregulation in several ncRNAs levels in patients compared with controls. In particular, 7 miRNAs were



downregulated and 5 out of 84 showed upregulated expression levels. Conversely, 58 lncRNAs were found to be downregulated whereas 25 out of 160 were found to be upregulated. Among these, TUG-1 levels, a lncRNA expressed in brain and found to be involved in neurodegeneration, was found to be significantly increased in patients compared with controls (2.5 fold change, p < 0.05). These preliminary results showed a different signature between FTD patients versus controls. The investigation for the first time of a specific signature constructed by ncRNAs from neural derived serum exosomes could have a great potential in the field of clinical biomarkers discovery for FTD, and could also contribute to clarify the molecular mechanisms underneath FTD pathology.

P385 Autosomal dominant and sporadic frontotemporal lobar degeneration: from non-coding RNAs to the identification of preclinical biomarkers and therapeutic targets M. Serpente1, C. Fenoglio1, S. Cioffi1, M. Arcaro1, E. Oldoni1, A. Arighi1, G. Fumagalli1, E. Scarpini1, D. Galimberti1 1 University of Milan, Department of Pathophysiology and Transplantation, Milan, Italy Recently, an active role of ncRNAs, miRNAs and long noncoding (lnc)RNAs, was observed in different neurodegenerative diseases. Therefore, the main aims of this study were to investigate a specific profile of nCRNAs in serum and PBMCs of FLTD patients (sporadic and genetic forms) and to identify possible preclinical biomarkers in order to better understand pathogenic mechanisms. Specific PCR arrays were used to screen miRNA serum levels and PBMC lncRNAs expression levels in a population composed by: 5 healthy subjects, 5 sporadic FTLD patients, 5 GRN mutation carriers and 5 C9orf72 expansion carriers. Statistically significant decreased serum levels of miR122-5p, miR22-3p (p < 0.001) and significant increased levels of miR-31-5p and miR-103a-3p (p < 0.05) in FTLD patients compared with controls were observed. The downregulation observed, appears even stronger when C9orf72 FTLD expansion carriers were considered. Regarding lncRNAs PBMC expression, results showed a generalized up-regulation of several molecules in sporadic FTLD patients compared with controls. Interestingly, BC200 resulted to be upregulated in sporadic patients or C9orf72 carriers compared to controls (5.09 and 5.7 fold change increase respectively, p < 0.05). This trend was not confirmed when GRN mutation carriers were compared with controls (1.9 fold change, p > 0.05). Moreover, ANRIL showed an opposite trend between sporadic FTLD (29.68 fold change, p < 0.05) and GRN mutations carriers (0.7 fold change, p < 0.05). These preliminary data suggest that a number of miRNAs and lncRNAs are dysregulated in FTLD patients, and that different pathways may be involved in genetic forms as compared with sporadic ones. Moreover, these molecules, such as circulating miRNAs, could be useful as biomarkers, to identify in life the ongoing pathology and develop disease modifying tailored treatments. However, further studies addressing this topic are required.

P386 In vivo molecular imaging of beta-amyloid and tau aggregates in monozygotic twins with discordant clinical phenotypes R. Townley1, D. Jones1, B. Boeve1, D. Knopman1, R. Peterson1, V. Lowe1, C. Jack1 1 Mayo Clinic, Neurology, Rochester, USA Monozygotic twin studies play an essential role in studying phenotypic variations of complex diseases. The present study describes neuropsychological data, MRI, F-18 FDG PET/CT, C11 PIB beta-amyloid, and tau AV-1451 imaging for a pair of 70 year old monozygotic male twins with discordant clinical phenotypes. The first patient presented with an 8 year progression of symptoms notable for personality changes, apathy, inappropriate social interactions, compulsions, and short term memory problems. His twin brother reportedly had similar memory symptoms. There was no other family history of neurodegenerative diseases. MRI demonstrated a nonspecific moderate cerebral parenchymal volume loss. PET imaging showed decreased metabolic activity in the bilateral temporal lobes. His twin brother was evaluated 1 year later. He had a 5 year history of memory predominant symptoms. He had mild compulsive obsessions, but did not have inappropriate social interactions or major personality changes. MRI demonstrated moderate generalized cerebral parenchymal volume loss, more prominent in the temporal lobes and hippocampal formations. PET imaging showed decreased metabolic activity in the right temporal lobe, right posterior parietal lobe, right frontal lobe, and bilateral posterior cingulate gyri. In vivo molecular imaging was performed for research purposes and demonstrated both patients were positive for beta-amyloid. The patient with frontotemporal dementia phenotype had negative tau AV-1451 imaging while his twin brother with Alzheimer disease phenotype had positive tau imaging. This case provides further evidence for the benefit of tau imaging in differentiating Alzheimer disease from other neurodegenerative disorders, including other tauopathies. The case also highlights the importance of environmental and epigenetic differences in developing neurodegenerative diseases.

P387 CSF neurofilament-light chain and p-Tau180/t-Tau for discrimination of frontotemporal lobar degeneration pathology subtypes J. Rojas1, C. Scherling1, A. Karydas1, J. Kramer1, H. Rosen1, G. Rabinovici1, Z. Miller1, B. Miller1, A. Boxer1 1 UCSF, Memory and Aging Center, San Francisco, CA, USA Identification of frontotemporal lobar degeneration (FTLD) fluid biomarkers is fundamental for therapy development. Currently, a definite diagnosis of FTLD and its subtypes is only possible postmortem. In FTLD-TDP, CSF ratios of p-Tau181 over total Tau (p/tTau) are decreased, whereas neurofilament-light chain (NfL), a marker of axonal injury, is increased. We further analyzed the discriminant value of NfL and p/t-Tau in FTLD. Amyloid b42, total Tau, p-Tau181 and NfL levels were measured by ELISA in CSF samples from 78 FTD clinical spectrum cases (behavioral variant frontotemporal dementia, semantic dementia, progressive non-fluent aphasia, progressive supranuclear palsy, corticobasal degeneration), 30 pathology or biomarker-supported AD and 55 healthy controls. FTD cases were divided into pathology-confirmed (cohort 1,


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n = 37) and biomarker-enriched, clinically-predicted FTLD (cohort 2, n = 41). Relationships between biomarker levels and neuropsychological and functional scores were determined. FTLD-TDP patients had younger disease onset, but were matched for disease duration with FTLD-Tau and AD cases. In cohort 1, FTLD-TDP had higher median NfL (11333 3528 pg/mL vs. 3894.8 3036 pg/ mL, p = 0.001) and lower p/t-Tau levels (0.18 0.1 vs. 0.33 0.1, p = 0.003), compared to FTLD-Tau. NfL higher than 6757.5 pg/mL and p/t-Tau lower than .28 discriminated FTLD-TDP from FTLD-Tau with sensitivities of 81% and 80% and specificities of 84% and 80%, respectively. The NfL index Ln[(NfL x t-Tau)/pTau] increased the sensitivity to 88.9% and the specificity to 84%. In cohort 2, high NfL (p < 0.001) and low p/t-Tau (p = 0.01) were observed in FTLD-TDP compared to FTLD-Tau, AD and controls. The NfL index, but not p/t-Tau, correlated with MMSE scores (r = 0.35, p < 0.001) and with the change in CDRsb over a median of 17 months (r = 0.30, p = 0.004). High CSF NfL and low p/t-Tau provide a fluid biomarker signature highly sensitive to FTLD-TDP in vivo.

P388 18 F-AV-1451 in frontotemporal dementia spectrum disorders R. Tsai1, A. Bejanin1, D. Schonhaut1,2, R. Ossenkoppele3, J. O’Neil4, M. Janabi4, S. Baker4, A. Lazaris1, N. Ayakta1,2, G. Tammewar1,2, M. Gorno-Tempini1, B. Miller1, A. Boxer1, W. Jagust2,4, G. Rabinovici1,2 1 UCSF, Memory and Aging Center, San Francisco, USA 2 University of California, Berkeley, Helen Wills Neuroscience Institute, Berkeley, USA 3 VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, Netherlands 4 Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, USA

The utility of 18F-AV-1451 tau PET in frontotemporal dementia (FTD) spectrum disorders is currently unknown. We evaluated behavioral variant frontotemporal dementia (bvFTD, n = 3), nonfluent variant primary progressive aphasia (nfvPPA, n = 4), semantic variant primary progressive aphasia (svPPA, n = 2), progressive supranculear palsy (PSP, n = 10), corticobasal syndrome (CBS, n = 7), C9ORF72 mutation (n = 3), MAPT mutation carriers (n = 4) and amyloid-negative normal controls (NC, N = 24) with 18 F-AV-1451 PET. 18F -AV-1451 images were summed, and standardized uptake value ratios were calculated for t = 80–100 min using mean activity in the cerebellar gray matter (excluding dentate nucleus) as the reference region. NC showed various degrees of uptake in medial temporal cortex, midbrain, basal ganglia and cerebellum. Symptomatic MAPT carriers (CDR 2) showed increased frontotemporal 18F-AV-1451 uptake compared to mild or asymptomatic carriers (CDR 0-0.5). In two bvFTD cases, uptake was seen in the frontotemporal and parietal regions. In PSP and nfvPPA voxel-wise comparison to NC showed increased uptake bilaterally in globus pallidus (p(FWE)< 0.05), putamen, thalamus, subthalamic nucleus, dorsal midbrain, cerebellar dentate nucleus (p < 0.001 uncorrected) in PSP and left frontal operculum, basal forebrain in nfvPPA (p(FWE)< 0.05) and right frontal operculum (p < 0.001 uncorrected). CBS subjects showed varying degrees of uptake in the putamen, globus pallidus and white matter. Uptake lateralization matched symptom laterality for nfvPPA and CBS.

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Uptake was seen in bilateral lateral and temporal poles in svPPA cases, and the frontal pole in C9ORF72 cases. In summary, elevated 18 F-AV-1451 uptake matched the expected distribution of tau pathology in FTD spectrum disorders. However, elevated retention in subcortical regions in NC and neurodegenerative regions in patients with predicted TDP-43 pathology raise questions about specificity of binding. The 18F-AV-1451 tracer warrants further exploration in FTD spectrum disorders.

P389 Differential longitudinal decline of white matter integrity in frontotemporal lobar degeneration and Alzheimer’s disease G. Marx1, F. Elahi1, H. Rosen1 1 UCSF, Neurology, Oakland, USA Objective: To identify imaging biomarkers of disease progression in frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD) that can be used in longitudinal assessments. Background: Recent years have witnessed the emergence of treatment trials for FTLD and AD, creating a need for sensitive biomarkers of disease progression. Cross-sectional studies have shown that white matter integrity, measured via diffusion tensor imaging (DTI), is affected by both AD and FTLD. Few studies have quantified or compared the rates of change in white matter integrity in these disorders. Methods: Diffusion weighted 3T MRIs from a cohort of 60 FTLD patients (27 behavioral-variant, 19 semantic-variant, 14 progressive non-fluent aphasia), 19 AD, and 69 healthy controls were acquired at baseline and 1-year on average follow up. Images were processed using a longitudinal DTI pipeline implemented in SPM12 to identify annualized changes in fractional anisotropy (FA). Results: Compared to controls, FTLD showed more reduction in FA over 1-year in the corpus callosum (CC), superior longitudinal fasciculus, inferior longitudinal fasciculus, the uncinate, and anterior portions of the internal capsule and corona radiata. In AD, FA reductions were seen in the splenium and posterior portions of the thalamic radiation. Conclusions: Decline in white matter integrity in FTLD and AD is measurable over 1 year and reflects established patterns of brain pathology in these two disorders. This suggests that changes in white matter integrity can provide a viable surrogate marker in both FTLD and AD for future clinical trials. In addition, similar to previous clinical and volumetric studies, white matter is shown to degrade nearly twice as rapidly in FLTD compared to AD.

P390 Patient-tailored disease epicenters in behavioral variant frontal temporal dementia and semantic variant primary progressive aphasia J. Brown1, J. Deng1, I. Sible1, A. Sias1, S. Lee1, M. Gorno-Tempini1, H. Rosen1, B. Miller1, W. Seeley1 1 University of California San Francisco, Neurology, San Francisco, USA Frontotemporal dementia syndromes result from characteristic brain atrophy patterns. These patterns are thought to originate at syndrome-specific epicenters and spread throughout intrinsic



connectivity networks (Zhou et al., 2012). Within a syndrome, patients display variable atrophy patterns, which may, in turn, reflect variable epicenter localization. To identify patient-tailored epicenters, we began by creating individual gray matter atrophy W-statistic maps (La Joie et al., 2012). We then parcellated the whole brain into 482 regions using task-free fMRI data from the Human Connectome Project. Parcel-based functional intrinsic connectivity maps were next compared to each patient’s atrophy map to determine that patient’s epicenter, defined as the parcel whose connectivity map in controls most closely resembled the patient’s atrophy. Using the whole brain connectivity matrix from controls, we built a model for each patient to predict their parcel-wise atrophy based on the network path length from their own epicenter. In semantic variant primary progressive aphasia (svPPA), epicenters were located in the left and right anterior temporal lobes, whereas in behavioral variant frontotemporal dementia (bvFTD), epicenters predominated in bilateral anterior insula, orbitofrontal cortex, and anterior temporal lobe. Shorter regional path length from the tailored epicenter was associated with greater regional atrophy in 40/41 svPPA patients (mean r = 0.36, mean p = 0.017) and in 43/48 bvFTD patients (mean r = 0.34, mean p = 0.032). In a clustering analysis of atrophy maps, svPPA patients split into two subtypes, with overall atrophy and epicenters concentrated in either the left or right anterior temporal lobe. Patients with bvFTD clustered into mild and severe paralimbic atrophy patterns, with epicenters again converging in anterior insula and orbitofrontal cortex. Patient-tailored atrophy modeling may help clinicians predict clinico-anatomical progression by identifying the most vulnerable brain systems based on a patient’s unique site of estimated disease onset.

contributed to an emerging topic that FTD and ALS are two extremes of a continuum of neurodegenerative diseases with a common disease pathway. Approximately 40% of FTD patients and 10% of ALS patients have a positive family history. The most common cause of familial FTD, ALS or patients with a mixed presentation of both diseases (FTD/ALS) is a hexanucleotide expansion mutation in a noncoding region of c9orf72. Results from the genetic frontotemporal dementia initiative (GENFI) provide evidence for an early affection of thalamus and cerebellum in c9orf72 expansion carriers compared to healthy controls as well as to GRN and MAPT mutation carriers (Rohrer et al. Lancet Neurology 2015; 14 253–262). We aimed to determine the amount of thalamic and cerebellar atrophy in c9orf72 expansion carriers compared to patients with sporadic FTD, ALS or FTD/ALS. Therefore atlas-based volumetric MRI analysis was performed in c9orf72 expansion carriers and noncarriers from the German consortium for frontotemporal lobar degeneration and patients seen at the Ludwig-Maximilians-University Munich and the Technical University of Munich.

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There are some evidences of an important role of neuroinflammation in the pathway of dementia in aged. A frontotemporal dementia (FTD) is a neurodegenerative disease with unknown pathway. The aim of this pilot study was to study the inflammatory markers in blood plasma of patients with FTD: activity of leukocyte elastase (LE) and a1- proteinase inhibitor (a1-PI, antitrypsin) functional activity, levels of interleukin-6 (IL-6) and C-reactive protein (CRP) compared to control. A clinical material made up 17 patients (11m/6f; mean age 61.6). A control group was presented with 30 healthy aged persons. A diagnosis of FTD was established according to criteria (LaMarre et al. Neurol. 2013; 80 1973–1977). There were 13 cases with behavioral variant FTD (bvFTD) and 4 cases with non-fluent primary progressive aphasia (nfvPPA). There were no patients with semantic dementia in this side. LEactivity and functional activity ofa1-PI were determined by method of spectrophotometry; CRP and IL-6 concentrations were measured by ELISE methods. It was found a significant increase of LE activity anda1-PI (p < 0.01, p < 0.001) in FTD compared to control. It was shown a significant increase ofa1-PI activity (p < 0.001) and CRP concentration (p < 0.05) in bvFTD, since the LE activity increase did not reach significance (p = 0.09). The significant increase of LE level anda1-PI activity (p< 0.001, p < 0.05) in nfvPPA was found, since a CRP concentration did not differ compared to control. CRP concentration was significantly higher (p < 0.05) in bvFTD compared to nfvPPA. FTD is characterized by a significant increase of LE anda1-PI activity and CRP level. Activity/level of studied indicators depends on the different variants of this disease. Immune indices of inflammation in blood plasmamay be useful in the discovery of biomarkersfor clinical and differential diagnostics of neurodegenerative dementia in aged.

Atlas-based volumetric MRI analysis of c9orf72 mutation carriers S. Scho¨necker1, C. Neuhofer1, J. Diehl-Schmid2, M. Otto3, C. Prix1, German FTLD-Consortium4, Bavarian Brain Banking Alliance5, T. Arzberger6,7,8, D. Edbauer6,9,10, B. Feddersen11, T. Klopstock1,6,9, J. Levin1,6 1 Ludwig-Maximilians-University, Department of Neurology, Munich, Germany 2 Technical University of Munich, Department of Psychiatry, Munich, Germany 3 University of Ulm, Department of Neurology, Munich, Germany 4 German FTLD-Consortium, Germany, Germany 5 Bavarian Brain Banking Alliance, Bavaria, Germany 6 German Center for Neurodegenerative Diseases DZNE, Munich, Germany 7 Ludwig-Maximilians-University, Center for Neuropathology and Prion research, Munich, Germany 8 Ludwig-Maximilians-University, Department of Psychiatry and Psychotherapy, Munich, Germany 9 Munich Cluster of Systems Neurology SyNergy, Munich, Germany 10 Ludwig-Maximilians-University, Institute for Metabolic Biochemistry, Munich, Germany 11 Ludwig-Maximilians-University, Department of Palliative Medicine, Munich, Germany Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are heterogenous neurodegenerative disorders that are associated with one another in approximately 15% of the cases. Evidence from clinical, pathologic and genetic studies have

P392 Blood markers of neuroinflammation in frontotemporal dementia N. Mikhaylova1, L. Androsova2, S. Zozulya2, Y. Fedorova1, I. Kolykhalov1, T. Kliushnik2 1 Mental Health Research Centre, Alzheimers’ Desease Department, Moscow, Russian Federation 2 Mental Health Research Centre, Immunology, Moscow, Russian Federation


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P393 Results from the frontotemporal lobar degeneration neuroimaging initiative (FTLDNI) H. Rosen1, D. Knopman2, B. Dickerson3, B. Boeve2, M. Urbano1, A. Caplan1, S. Laxineta1, B. Miller1 1 University of California, San Francisco, Neurology, San Francisco, USA 2 Mayo Clinic, Rochester, USA 3 Massachusetts General Hospital, Boston, USA The FTLDNI was designed to provide a comprehensive longitudinal characterization of the three canonical variants of FTLD: the behavioral variant of frontotemporal dementia (bvFTD), and the semantic and nonfluent variants of primary progressive aphasia (svPPA, nfvPPA), including multiple clinical and imaging timepoints. Through FTLDNI and related projects, we examined longitudinal change in several clinical variables and structural imaging in 61 bvFTD, 32 svPPA and 33 nfvPPA patients and 80 controls, who participated in 1–4 visits over 2.5 years (mean of 2.3 visits). Through graphical and linear mixed effects models we identified significant changes over time for the clinical dementia rating scale sum-of-boxes score (CDR-SB) the mmse, and categorical fluency, and frontal and temporal lobe volumes for all diagnostic groups. For other clinical variables, including a modified Trails task, forward and backward digit span, and phonemic fluency, and picture naming, there were significant effects of time in some groups but not others, and borderline significant effects in some groups. There was no significant effect of time for the NPI-Q for any group. There was no evidence for non-linear patterns of decline over the span of < 2.5 years for any variable in any group. Examination of relationships between imaging and clinical variables demonstrated that baseline lobar volumes modified the rate of change with time for CDR-SB score for bvFTD and nfvPPA, for MMSE score in bvFTD, and for picture naming in svPPA and nfvPPA. Additional analyses are being conducted to examine rates of change for other imaging modalities, including diffusion tensor MRI, ASL-perfusion MRI and FDG-PET and to examine the relationships between these variables and clinical changes. All data are available for download from the Laboratory of Neuroimaging (LONI). The FTLDNI provides a rich dataset for examination of longitudinal change in FTLD.

P394 Decreased prefrontal cortex and posterior cingulate activation during matrix reasoning in asymptomatic carriers of GRN mutations C. Alexander1, D. Zeithamova2, G.- Y. R. Hsiung3, I. Mackenzie3, C. Jacova1 1 Pacific University, Psychology, Hillsboro, USA 2 University of Oregon, Psychology, Eugene, USA 3 University of British Columbia, Neurology, Vancouver, Canada Early functional brain imaging abnormalities in frontotemporal dementia (FTD) associated with granulin gene mutations (GRN) have not been well characterized. We used event-based fMRI to evaluate brain activation during increasingly complex matrix reasoning in unaffected carriers of GRN mutations and non-carrier family members. Participants performed a version of Raven’s Progressive Matrices previously shown to specifically recruit the prefrontal cortex. Participants were randomly presented with one of

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three types of relational integration problems: 0-relational required no relational reasoning, 1-relational processing of a single relation, 2-relational the integration of two relations. Participants included 5 mutation carriers (age 51 + 9.5 years) and 10 non-carriers (age 53 + 7.6 years). Mutation carriers’ task performance did not differ from those of non-carriers at any relational level. Whole brain exploratory analysis, uncorrected p < 0.01, extension = 20 voxels, was performed. Two- vs. 0-relational problems revealed decreased activation in carriers compared to non-carriers bilaterally in the rostrolateral and medial prefrontal cortex (cluster size 1817), cingulate gyrus (729), and anterior vermis (200). Two- vs. 1relational contrast revealed decreased activation in rostro-, dorsolateral and medial prefrontal cortex (2503) and posterior cingulate (857). One- vs. 0-relational contrast revealed no group differences in activation. The regions of decreased activation in GRN mutation carriers highly overlap with regions implicated in relational processing in healthy adults. These findings suggest the existence of very early functional brain changes associated with complex problem-solving in GRN-related neurodegeneration. Task-based fMRI may be a marker of these abnormalities.

P395 Comparison of [18F]T807 PET regional retention patterns in FTLD-tau and FTLD-TDP C. Burke1,2, N. Multani1,2, K. Misquitta1,2, P. Rusjan3, A. Wilson3, S. Houle3, D. Tang-Wai4,5,6, M. C. Tartaglia1,2,4,6 1 University of Toronto, Tanz Centre for Research in Neurodegenerative Disease, Toronto, Canada 2 University Health Network, Toronto Western Hospital, Toronto, Canada 3 Centre for Addiction and Mental Health, Research Imaging Centre, Toronto, Canada 4 University of Toronto, Division of Neurology, Toronto, Canada 5 University of Toronto, Division of Geriatric Medicine, Toronto, Canada 6 University Health Network, Memory Clinic, Toronto, Canada Frontotemporal lobar degeneration (FTLD) encompasses a group of disorders with heterogeneous syndromes and pathology. There is considerable overlap of symptoms between different clinical phenotypes of FTLD and pathological diagnosis in vivo of FTLDtau or FTLD-TDP-43 as the causative proteinopathy is not possible. Some phenotypes such as progressive supranuclear palsy are associated with FTLD-tau while others such as FTD-with motor neuron disease (FTD-MND) or semantic variant primary progressive aphasia (svPPA) are associated with FTLD-TDP. The positron emission tomography (PET) radiotracer [18F]T807 shows specificity for tau in vivo. Here we examine [18F]T807 retention patterns in FTLD-tau contrasted to FTLD-TDP. Five PSP patients with presumed FTLD-tau (mean age 70.2 5.7 years) and five subjects with presumed FTLD-TDP (3 FTD-MND and 2 svPPA, mean age 66.8 5.8 years) underwent a tau PET scan using [18F]T807. Regions of interest (ROI) were automatically delineated based on a coregistered MRI. A standardized uptake value ratio (SUVR) was calculated for each ROI at 50–80 min post injection relative to the white matter of the pons. There was a trend for greater [18F]T807 SUVR in the FTLD-tau group than the FTLD-TDP group in the orbitofrontal cortex (1.33 0.22 vs 1.10 0.09, p = 0.067), insula (1.19 0.08 vs. 1.09 0.08, p = 0.065), and right hippocampus (1.52 0.31 vs. 1.18 0.13, p = 0.054). Our preliminary findings



suggest [18F]T807 PET may show different retention patterns in FTLD-tau in contrast to FTLD-TDP. Ongoing studies will help to better understand the relationship of [18F]T807 PET retention and tau pathology as well as its relationship to cognitive/behavioral function.

P396 Patterns of longitudinal neuroanatomical change in genetic FTD: results from the Genetic FTD Initiative (GENFI) J. Rohrer1, M. Bocchetta1, E. Gordon1, D. Cash1, K. Dick1, D. Thomas1, J. Nicholas1, M. J. Cardoso1, S. Ourselin1, J. van Swieten2, B. Borroni3, D. Galimberti4, M. Masellis5, C. Graff6, F. Tagliavini7, G. Frisoni8, R. LaforceJr9, E. Finger10, A. Mendonca11, S. Sorbi12, M. Rossor1 1 UCL, Institute of Neurology, London, Great Britain 2 Erasmus Medical Center, Rotterdam, Netherlands 3 University of Brescia, Brescia, Italy 4 University of Milan, Milano, Italy 5 Sunnybrook Research Institute, Toronto, Canada 6 Karolinska Institute, Stockholm, Sweden 7 Istituto Neurologico Carlo Besta, Milano, Italy 8 Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy 9 Universite Laval, Quebec, Canada 10 University of Western Ontario, London Ontario, Canada 11 University of Lisbon, Lisbon, Portugal 12 University of Florence, Firenze, Italy Cross-sectional results from the Genetic FTD Initiative (GENFI) have previously shown evidence for presymptomatic neuroanatomical changes in genetic FTD. In the first longitudinal analysis of the GENFI study, 148 participants were included (81 GRN, 47 C9orf72 and 20 MAPT) of whom 25 were symptomatic at baseline with a further 5 converting between baseline and follow-up assessment. Of the 123 participants presymptomatic at baseline, 56 were mutation carriers, and 67 non-carriers. The mean (standard deviation) interval between assessments was 1.3 (0.4) years. Participants underwent standardised assessments at baseline and follow-up including MR imaging (available in 129 participants: 60 non-carriers, 51 presymptomatic carriers and 18 symptomatic carriers). Cortical and subcortical volumes were generated using a parcellation of the volumetric T1-weighted MRI scan, and used to calculate annualised rates of regional atrophy. Atrophy rates were significantly greater in the symptomatic group compared with non-carriers in the following regions: frontal lobe mean 1.8 (2.0) versus 0.5 (1.2)%, temporal lobe 1.4 (1.3), 0.0 (1.6)%, cingulate 1.3 (1.6), -0.1 (1.7)%, insula 1.6 (2.3), -0.1 (1.7)%, cerebellum 1.1 (1.5), 0.1 (0.9)%, amygdala 3.0 (4.4), -0.5 (2.0)%, striatum 1.7 (3.0), -0.3 (2.0)% and thalamus 0.9 (4.4), -0.5 (4.2)%. In the presymptomatic carrier group we compared an ‘early’ group (more than 10 years from expected symptom onset) and a ‘late’ group (within 10 years). In the early group, there were no significant differences from non-carriers. However in the late group, atrophy rates were significantly greater than non-carriers in the temporal lobe 1.1 (1.5)%, cingulate 1.0 (2.1)%, amygdala 1.7 (3.5)% and striatum 1.1 (2.8)%. These results extend previous crosssectional findings of the GENFI study showing that presymptomatic changes can also be found in a longitudinal dataset. The results suggest that volumetric MRI measures in the form of regional brain atrophy rates may be used as markers of disease progression in future trials even during the presymptomatic period.

P397 A case of Wilson’s disease presenting with depression as the initial symptom H. Chang1, H. Park1, J. Cheong1 1 Wonkwang University Hospital, Neurology, Iksan, South Korea Wilson’s disease is a chronic disorder resulting from abnormal accumulation of copper in various organs, which is usually accompanied with disorders of metabolism of copper due to specific gene abnormality. Many neurologic symptoms, such as slurred speech, dysarthria, dystonia, parkinsonian feature, chorea and ataxia, are widely known as initial symptoms and syndromes of Wilson’s disease. But dementia or frontal lobe syndrome also can be seen in Wilson’s disease. Herein we report a case of 17 year old male presenting executive dysfunction and apathy with depressive mood as the initial symptom of Wilson’s disease. A 17-year old male derived at our emergency department with apathy which had occurred about 3 days before. His vital signs and lab finding were nonspecific. In initial neurologic examination, executive dysfunctions were suspected. During observation for about 3 h in hospital, he presented mild bilateral action-postural tremor and suspicious slurred speech was noted. In T2-weighted magnetic resonance images, bilateral symmetric high signal intensities in putamen and caudate nucleus. On his past diet history, he had eaten liver of pigs and shellfishes excessively for months, which contents high proportion of copper. Urine copper concentration were elevated (2123.2 lg/24 h) and serum ceruloplasmin level were decreased (< 4 mg/dL). On diagnosis of Wilson’s disease, he was treated with zinc and trientine. Wilson’s disease can lead to neuropsychiatric symptoms including subcortical dementia and frontal lobe syndrome. Generally, hepatic dysfunction or motor symptoms are frequently noted in early stage of the disease. But, in young age, acute onset of cognition disorders should be considered to Wilson’s disease and close observation for neurologic symptoms are needed.

P398 A patient with frontotemporal dementia presenting with unilateral apraxia H. Park1, H. Chang1, J. Cheong1 1 Wonkwang University Hospital, Neurology, Iksan, South Korea Apraxia covers a wide spectrum of disorders that have in common the inability to perform a skilled or learned act that cannot be explained by an elementary motor or sensory deficit or language comprehension disorder. Limb-kinetic apraxia, a type of apraxia, is loss of hand and finger dexterity resulting from inability to connect or isolate individual movements, and may be caused by a variety of neurodegenerative disease including corticobasal degeneration, Pick disease or primary progressive apraxia. We report a patient who suffered from limb-kinetic apraxia diagnosed as frontotemporal dementia (FTD) by neuropsychological and neuroimaging analysis. A 69-year-old right-handed woman was visited for the left clumsiness of the hand and reduced conversation. A neurologic evaluation showed limb-kinetic apraxia and frontal lobe dysfunction on the neuropsychological tests with 24/30 of Korean version of mini-mental state examination. Brain MRI showed cortical atrophy in right frontal lobes and 18F-FDG-PET revealed bilateral frontal decreases in glucose metabolism, right more than left. She was clinically diagnosed with FTD. Our case shows that limb-kinetic apraxia can be the initial manifestation of FTD. Careful description


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of the neurological presentation of FTD may be of help for further understanding of the disease.

P399 DTI changes in individuals with primary progressive aphasia D. Preiß1, O. Billette1, J. Acosta-Cabronero1, P. Nestor1 1 DZNE, Brainplasticity & Neurodegeneration, Magdeburg, Germany Two clinical phenotypes with non-Alzheimer’s pathology are recognised in the spectrum of primary progressive aphasia; namely semantic variant PPA (svPPA) typically associated with TDP-43 pathology and non-fluent variant PPA (nfvPPA) often associated with primary tauopathies. Diffusion tensor imaging (DTI) is a measurement of water diffusion in tissues and previous work has suggested that there is a diffuse alteration in white matter diffusivity in the primary tauopathies—progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD)—that may serve as a diagnostic biomarker (Sajjadi et al. Brain 2013; 136(7) 2253– 2261). In the present prospective series, therefore, we expected to find diffuse abnormalities in Fractional Anisotropy (FA) to be more often associated with nfvPPA than with svPPA or Alzheimer-related PPA. Six patients with a negative and eight with a positive amyloid PET scan (Florbetaben) and a clinical diagnosis of PPA entered the analysis. From the amyloid-negative patients three had nfvPPA and three had svPPA. The DTI maps for FA of single patients were compared with a healthy control group with Tract-Based Spatial Statistics. Diffuse abnormality of FA of the white matter tracts was present in the three nfvPPA cases, whereas svPPA cases revealed none or only minor abnormalities of FA maps. Amyloid-positive PPA cases were also generally negative for FA abnormalities. MMSE scores of all patient subgroups were not systematically different, ruling out correlation of disease severity and DTI lesions. The diffuse FA abnormality in nfvPPA patients are thought to relate to the prominent white matter tau pathology in PSP and CBD. DTI continues to show promise for in vivo detection of tauopathy in individual patients but clinicopathological studies are needed to further validate the findings.

P400 Clinical, genetic and pathological stratification in frontotemporal dementia: implications for clinical trial design E. Gordon1, M. Bocchetta1, M. J. Cardoso1,2, S. Ourselin1,2, J. D. Warren1, J. D. Rohrer1 1 Institute of Neurology, University College London, Dementia Research Centre, London, Great Britain 2 Centre for Medical Image Computing, UCL, Translational Imaging Group, London, Great Britain Targeted patient enrolment and biomarker choice is critical to optimising the detection of treatment effects in trials. We investigated the effect of varying stratification criteria on sample size estimates in 140 frontotemporal dementia (FTD) patients [87 female, mean (standard deviation) age = 63.5 (8.8), disease duration = 5.3 (7.1)]. Subgroups were divided by clinical diagnosis (62 behavioural variant FTD (bvFTD), 42 semantic variant primary

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progressive aphasia (svPPA), and 36 non-fluent variant); genetic diagnosis (12 MAPT, 8 C9orf72 and 3 GRN mutation patients); or pathological diagnosis (14 tauopathy and 23 TDP-43opathy patients). All participants had two 3D T1-volumetric images (interval = 1.7 (0.9) years). Whole-brain volumes were manually segmented and annual rates of change calculated using the brain boundary shift integral (BBSI). An automated parcellation extracted grey matter volumes for the frontal, temporal, parietal, occipital, cingulate and insula cortices and rates of change calculated as annual percentage of baseline volume change. Sample sizes were calculated to detect a 30% reduction in annual volume loss, with 90% power and a = 0.05. In the clinical subgroups, sample sizes were relatively high for bvFTD, with BBSI providing the smallest values of 221 participants per treatment arm. In PPA, smaller sample sizes were required to detect a similar treatment effect, e.g. in svPPA the use of temporal lobe atrophy rate would only require 56 participants. Stratifying by genetic diagnosis resulted in fewer required participants than in a clinical bvFTD cohort: in the C9orf72 subgroup, BBSI resulted in sample sizes of 118, whereas for MAPT and GRN temporal lobe measures performed best with only 68 and < 10 participants per arm respectively. Finally, pathological stratification also differentially affected estimates (tauopathy = 42 but TDP-43opathy = 177 participants for temporal lobe measures). In conclusion, patient stratification significantly affected sample size estimates and influenced which regional atrophy rate would be the optimal outcome measure.

P401 Computational modelling of combined M/EEG in FTD: layer specific insights into altered neurobiology during the auditory mismatch negativity A. Shaw1, L. Hughes1, J. Rowe1 1 University of Cambridge, Clinical Neurosciences, Cambridge, Great Britain Event related potentials (ERPs), which can be measured noninvasively with electro- or magnetoencephalography (E/MEG), reflect the summation of (electrical) neuronal activity across cortical layers and within a patch of cortex. Dynamic causal modelling (DCM) provides a computational framework for understanding ERPs in terms of plausible neuronal mechanisms. This combined approach is powerful for studying neuropathologies and disease progression because it permits characterization of usually unobservable neurobiology - for example, a change in excitatory postsynaptic currents between layer specific neuronal populations resulting from an experimental condition. We applied this methodology to combined M/EEG data obtained during an auditory mismatch negativity paradigm, passively evoking ERPs, on individuals with clinically confirmed FTD (n = 16) and healthy controls (n = 8). A 4-population canonical microcircuit model was used to explain ERPs arising in primary auditory cortex. Change in neuronal parameter values were calculated as the difference between standard and deviant tones. Correlative analysis demonstrated two neuronal parameters predicted clinical measures: the strength of glutamatergic projections from superficial layer pyramidal cells to inhibitory interneurons predicted visuospatial ability (r2=45), while the decay time-constant of layer 5/6 pyramidal cell populations predicted total mini-mental state examination score (r2=23) as well as memory (r2=33) and language (r2=46) ability. Notably, although the correlation with memory ability was significant in both FTD and



control groups, the correlations showed a significant difference (p = 0.0139), with controls demonstrating a positive correlation and FTD showing a negative correlation. Together these preliminary data describe the detail to which M/EEG and DCM can be used in conjunction to provide detailed computational assays of altered neurobiology in-vivo and will continue to be a valuable tool in understanding ongoing changes in FTD patients.

P402 Frailty correlates with insula hypometabolism and frontal cortex atrophy in bvFTD I. Rainero1, M. Amanzio2, F. D’Agata1, A. Galati3, S. Palermo1, E. Rubino1, M. Zucca1, L. Pinessi1,4, G. Castellano3 1 University of Turin, Department of Neuroscience “Rita Levi Montalcini”, Turin, Italy 2 University of Turin, Department of Psychology, Turin, Italy 3 Citta della Salute e della Scienza, Nuclear Medicine Unit, Turin, Italy 4 Citta della Salute e della Scienza, Department of Neuroscience and Mental Health, Turin, Italy Frailty is a common clinical syndrome in older adults and carries an increased risk for poor health outcomes, incident disability, hospitalization, and mortality. Increasing frailty is associated with incident Alzheimer’s disease, vascular dementia, nonAD dementias, and the rate of cognitive decline. The objective of this study was to investigate the neural correlates of frailty in patients with the behavioral variant of Frontotemporal Dementia (bvFTD). Eighteen bvFTD patients (7 men, 11 women; mean age SD: 67.0 9.2 yrs), attending the Memory Clinic of the Department of Neuroscience of the University of Torino, were selected for the study. Diagnosis was made according to the International Behavioral Variant FTD Consortium Criteria. Patients underwent extensive clinical, neuropsychological, and neuroradiological (including brain 18FDG-PET and structural MRI) investigations. The clinical diagnosis was supported by CSF biomarkers. A group of 18 healthy subjects (11 men, 7 women; mean age SD: 64.5 8.6 yrs) served as controls. Frailty was assessed using the Multidimensional Prognostic Index (MPI). Voxel-based statistical analyses of both FDG-PET and MRI data were performed. MPI scores were significantly increased in bvFTD patients when compared with controls (p < 0.01). A highly significant (p < 0.001) correlation between reduction in cerebral metabolic rate of glucose consumption and frailty scores was found in the left Insula. Gray matter reduction was significantly (p< 0.01) associated with MPI scores in the left Superior Frontal gyrus and left Orbital Frontal gyrus. Our study shows that, in patients with bvFTD, there is a significant correlation between functional and structural impairment in left insula and frontal cortex and a comprehensive frailty index. Further studies are needed to explore the clinical relevance of our data.

P403 Phenomenology and anatomy of abnormal behaviours in frontotemporal dementia as measured by the Cambridge Behavioural Inventory E. Gordon1, J. D. Warren1, J. D. Rohrer1 1 Institute of Neurology, University College London, London, Great Britain The Cambridge Behavioural Inventory (CBI) is an informantbased questionnaire profiling behavioural and neuropsychiatric deficits. Studies of the neural correlates and differential profiles across the frontotemporal dementia (FTD) spectrum are lacking. Eighty-three FTD patients were recruited: 37 behavioural variant (bvFTD), and 45 primary progressive aphasia (25 non-fluent variant (nfvPPA) and 21 semantic variant (svPPA)). Patient informants completed the revised version of the CBI (CBI-R). For each of the 10 CBI-R domains, scores were compared between FTD groups using linear regression, correcting for age, gender and disease duration. Patients also underwent T1-volumetric imaging. Neural correlates associated with each CBI-R domain were investigated using voxel-based morphometry (VBM), correcting for age, gender and total intracranial volume. The bvFTD group showed the greatest deficits across domains, followed by svPPA and then nfvPPA. Comparing bvFTD and nfvPPA, deficits were significantly more severe in bvFTD for Memory and Orientation, Abnormal Behaviour, Eating habits, Stereotypic and Motor behaviours and Motivation domains. These five domains were also significantly more affected in svPPA compared with nfvPPA, alongside the Beliefs domain. The only significant difference between the bvFTD and svPPA groups was in Eating habits, with bvFTD showing greater deficits. Neural correlates of behavioural deficits differed across CBI-R domains. Memory and Orientation correlated with bilateral orbitofrontal and medial temporal lobe atrophy (right > left), whilst Self Care correlated with bilateral atrophy in the orbitofrontal lobe, insula, thalamus and cingulate. Stereotypic and Motor Behaviours correlated with atrophy across the temporal lobe and cingulate cortex (right > left), whilst Motivation scores were associated with bilateral atrophy in the orbitofrontal and medial temporal lobes, thalamus and posterior cingulate. The CBI-R captures differences in behavioural deficits between the FTD syndromes, with the different domains having distinct neural correlates.

P404 Alteration in plasma lipids in frontotemporal dementia W. Kim1,2, E. Jary1, R. Pickford2, L. Bartley1, O. Piguet1,2, J. Hodges1,2, G. Halliday1,2 1 Neuroscience Research Australia, Sydney, Australia 2 University of New South Wales, Sydney, Australia Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative syndrome, commonly presenting with progressive impairment in behaviour (bvFTD). With identification of a number of genes associated with FTD, advances have been made in development of both genetic and protein biomarkers for FTD in recent years. In contrast to Alzheimer’s disease (AD), FTD is characterized by considerable early loss of significant amounts of brain tissue. Lipid is a major constituent of brain tissue and lipid dysregulation has been implicated in a number of neurodegenerative processes. However, very little is known about


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lipid changes in FTD. The aim of this study is to assess lipid changes in FTD with a goal of developing lipid biomarkers for FTD. We collected blood from 16 bvFTD, 11 AD and 22 healthy agematched controls and extracted total lipids from plasma using methanol and chloroform. We then analyzed the abundance of two major lipids associated with lipoproteins - triglyceride and phosphatidylserine - using liquid chromatography-mass spectrometry. We found that 97 triglyceride species (from 1115 identified) were significantly increased in FTD and that the total triglyceride level in FTD increased by 26%. The total level of phosphatidylserine was significantly decreased (by 18%) in FTD; 18 out of 91 species were decreased. In contrast, both triglyceride and phosphatidylserine levels were unaltered in AD. These data indicate that plasma lipids are altered in FTD and provide evidence for lipoprotein lipid dysfunction in FTD pathology. Specific lipid species have also been identified that could potentially serve as biomarkers to differentiate the two dementias.

P405 [18F]AV1451 PET in frontotemporal dementia from a MAPT mutation W. Bevan-Jones1, T. Cope2, L. Passamonti2, T. Fryer3, Y. Hong3, S. Jones2, J. Coles3,4, P. Vazquez Rodriguez2, A. Surendranathan1, R. Arnold1, F. Aigbirhio3, J. O’Brien1, J. Rowe2 1 University of Cambridge, Psychiatry, Cambridge, Great Britain 2 University of Cambridge, Clinical Neurosciences, Cambridge, Great Britain 3 University of Cambridge, Wolfson Brain Imaging Centre, Cambridge, Great Britain 4 University of Cambridge, Anaesthesia, Cambridge, Great Britain A 49 year old lady presented with behavioural variant Frontotemporal Dementia in the absence of Parkinsonism, supported by neuropsychological testing and frontotemporal atrophy on Magnetic Resonance imaging. Her father had presented with behavioural variant Frontotemporal Dementia at 59, with post mortem Tau neuropathology resembling corticobasal degeneration (tau-positive neuronal and glial inclusions, ballooned abnormal achromatic neurons, neuronal loss). His mother had developed psychiatric symptoms with behavioural disturbance and died in her 50’s without a diagnosis. Genetic testing confirmed a mutation in the MAPT gene, encoding the microtubule associated protein tau (10+16C>T). Positron Emission Tomography imaging using the novel Tau radioligand [18F]AV-1451 showed increased binding potential bilaterally in the temporal lobes. PET radio-ligands are potentially important biomarkers to detect and monitor tau in many neurodegenerative diseases. In this case, the genetic mutation in the proband and her father along with his confirmed pathology typical of 10+16 MAPT mutations, support the case for [18F]AV-1451 as a biomarker of non-Alzheimer tau neuropathology. Further work will evaluate the potential for [18F] AV-1451 to monitor pre-symptomatic mutation carriers; to differentiate tauopathies from other neurodegenerative disorders; and to monitor disease progression and response to new therapies.

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P406 The inverse cingulate island sign in hippocampal sclerosis dementia W. Mantyh1, D. Knopman1, J. Graff-Radford1, M. Murray2, D. Dickson2, D. Jones1 1 Mayo Clinic, Neurology, Rochester, USA 2 Mayo Clinic, Anatomic Pathology, Jacksonville, USA Hippocampal sclerosis dementia (HpScl) is characterized by atrophy and loss of neuronal populations of the CA1 and subiculum that is disproportionate to any concomitant neurodegenerative disease. Although it is considered a distinct pathophysiological entity, it is commonly misdiagnosed on clinical grounds as Alzheimer’s disease (AD). The current article seeks to use FDG-PET in combination with PiB-PET neuroimaging to differentiate HpScl from AD. Two patients at our institution underwent comprehensive evaluation by a behavioral neurologist with objective testing including head MRI, PiB-PET, FDG-PET, and neuropsychometric testing. One patient had definite HpScl alongside AD based on neuropathological confirmation. The other patient, who is alive at time of publication, has probable HpScl based on disproportionate atrophy of the hippocampus on MRI, compatible clinical history, and lack of other explainable neuropathology given absence of amyloid on PiB-PET. Both patients showed isolated hypometabolism of the posterior cingulate cortex (PCC), without significant temporoparietal hypometabolism. Both patients also had marked bilateral hippocampal atrophy on head MRI. PCC hypometabolism without accompanying hypometabolism of the association cortices, along with atrophied hippocampi, may be a useful neuroimaging feature to detect HpScl.

P407 Serum neuron-specific enolase is increased in mild neurocognitive disorder/mild cognitive impairment and related to white matter hyperintensities M. Polyakova1,2,3, K. Arelin1,2, L. Lampe1,2, F. Then4,2, T. Luck4,2, J. Kratzsch2,5, K.-T. Hoffmann2,6, S. Rieder-Heller4,2, A. Villringer1,2, P. Schoenknecht2,3, M. L. Schroeter1,2,7 1 Max Planck Institute for human cognitive and brain sciences, Leipzig, Germany 2 LIFE—Leipzig Research Center for Civilization Diseases, Leipzig University, Leipzig, Germany 3 University Clinic for Psychiatry and Psychotherapy, Leipzig University, Leipzig, Germany 4 Institute of Social Medicine, Occupational Health and Public Health ISAP, University of Leipzig, Leipzig, Germany 5 Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig University, Leipzig, Germany 6 Department of Neuroradiology, Leipzig University, Leipzig, Germany 7 Clinic for Cognitive Neurology, University of Leipzig, Leipzig, Germany Mild cognitive impairment (MCI) is considered a prestage of different dementia syndromes. Despite refined by Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 diagnostic criteria and introduction of a new term for MCI - mild neurocognitive disorder (mild NCD) - this diagnosis remains purely clinical. Peripheral biomarkers provide a link to the underlying pathophysiology. In this study we assessed the degree of white matter hyperintensities (measured on the Fazekas scale) and peripheral



biomarkers for neuronal integrity (neuron-specific enolase, NSE), plasticity (brain-derived neurotrophic factor, BDNF), and glial function (S100B) in 158 community-dwelling subjects with mild NCD and 82 healthy controls. Mild NCD was defined according to DSM-5 criteria. All participants (63–79 years old) were selected from the Leipzig population-based study of adults (LIFE-ADULTStudy). Serum NSE levels were increased in mild NCD in comparison to controls (p = 0.03). In subjects with mild NCD Fazekas scores correlated with serum NSE levels (rs = 0.210, p = 0.009). Fazekas scores correlated positively with age in healthy subjects (rs=0.338, p = 0.002) and in subjects with mild NCD (rs = 0.281, pElevated NSE serum levels indicate the presence of neuronal injury in mild NCD and might be used as a biomarker for white matter lesions in the future.

P408 Can neuroimaging measures of hippocampal structure predict Alzheimer’s vs. FTLD neuropathologies? L. Wang1, V. Hanko1, K. Alpert1, J. Schneider2, K. Arfanakis2,3, D. Bennett2 1 Northwestern University Feinberg School of Medicine, Department of Psychiatry and Behavioral Sciences, Chicago, USA 2 Rush University Medical Center, Rush Alzheimer’s Disease Center, Chicago, USA 3 Illinois Institute of Technology, Department of Biomedical Engineering, Chicago, USA Despite advances in the development of biomarkers for early detection of Alzheimer’s and frontotemporal dementias, accurate ante-mortem diagnosis remains a challenge. Few studies using structural MRI to classify dementia have the ability to confirm with neuropathologic indices. We performed a neuroimaging study to directly correlate ante-mortem hippocampal shape with postmortem Alzheimer’s and TDP-43 neuropathology burden. Ante-mortem T1-weighted MRI were collected from 42 subjects from the Rush Alzheimer’s Disease Center’s Memory and Aging Project and Religious Orders Study. Postmortem neuropathologic burden was quantified for PHFtau tangles, b-amyloid, and TDP-43 by immunohistochemistry. The mean age at imaging was 87.6 years with interval between imaging and death of 2.7 years. In the antemortem MRI, we generated hippocampal surfaces using multi-atlas FS-LDDMM pipeline. We then computed a population average surface and vertex-wise deformation for each subject from this average. At each vertex, we applied generalized linear model using surface deformation to predict neuropathology, accounting first for ante-mortem covariates (i.e., age at imaging, gender), and then for post-mortem covariates (i.e., age at death, indices of arteriolosclerosis, cerebral atherosclerosis, cerebral infarctions, hippocampal sclerosis, DLB). We mapped the standardized predictor coefficients onto the surface to visualize distribution patterns. When covarying for ante-mortem covariates, significant relationships existed between higher global PHFtau tangle burden and inward surface shape deformation in CA1 and subiculum, between higher b-amyloid burden and inward subiculum deformation, and between more severe TDP-43 neuropathology and inward CA1 deformation, with differing patterns along the hippocampal surface. These relationships persisted when covarying for post-mortem covariates except for TDP-43. Our findings of PHFtau tangles, b-amyloid and TDP-43 neuropathology burdens relating to specific regional hippocampal

shape with distinct patterns along the surface provide support that patterns of hippocampal atrophy may be biomarkers for specific AD and FTLD neuropathologies. These results need to be further validated in larger samples.

P409 [18F]AV1451 PET imaging in semantic dementia W. Bevan-Jones1, T. Cope2, L. Passamonti2, P. Vazquez Rodriguez2, A. Surendranathan1, R. Arnold1, S. Jones2, T. Fryer3, Y. Hong3, J. Coles3,4, F. Aigbirhio3, J. O’Brien1, J. Rowe2 1 University of Cambridge, Psychiatry, Cambridge, Great Britain 2 University of Cambridge, Clinical Neurosciences, Cambridge, Great Britain 3 University of Cambridge, Wolfson Brain Imaging Centre, Cambridge, Great Britain 4 University of Cambridge, Anaesthesia, Cambridge, Great Britain A 60 year old man presented with a neuropsychological profile of right sided semantic dementia (prosopagnosia, impaired emotional recognition, rigid and obsessional behaviours along with anomia and surface dyslexia.) MRI revealed severe bilateral but asymmetric temporal pole atrophy, worse on the right. PET imaging with [18F] AV1451, indicated increased binding potential in both temporal lobes, more significant on the right than left. This is of special interest as the syndrome of semantic dementia has a strong correlation with TDP-43 pathology, and occasionally Alzheimer pathology, but rarely primary tauopathy. PET radio-ligands are potentially important biomarkers to detect and monitor tau in many neurodegenerative diseases. However, questions arise as to the specificity of [18F]AV-1451 binding for primary tauopathies over other proteinopathies responsible for Frontotemporal lobar degeneration. For example, there have been reports of positive AV1451 PET scanning in typical left-hemisphere dominant semantic dementia (ICFTD 2014). “Off target” binding has also been noted in post mortem studies. Further in vivo and post mortem work in neurodegenerative disorders with and without primary Tau pathology will be required to establish the potential clinical and research applications of Tau PET ligands in dementia.

P410 Presymptomatic changes in gray matter volume, white matter integrity and neuropsychological assessment in C9orf72 mutation carriers J. L. Panman1,2, L. C. Jiskoot1,2,3, E. G. P. Dopper1,2,3, S. A. R. Rombouts2, T. den Heijer4, S. Franzen1, Y. A. L. Pijnenburg3, R. van Minkelen5, J. M. Papma1, J. C. van Swieten1,6 1 Erasmus Medical Center, Neurology, Rotterdam, Netherlands 2 Leiden University Medical Center, Radiology, Leiden, Netherlands 3 VU Medical Center, Neurology, Amsterdam, Netherlands 4 Sint Franciscus Gasthuis, Neurology, Rotterdam, Netherlands 5 Erasmus Medical Center, Clinical Genetics, Rotterdam, Netherlands 6 VU Medical Center, Clinical Genetics, Amsterdam, Netherlands The C9orf72 repeat expansion is one of the major causes of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Tracking the presymptomatic phase of C9orf72


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carriers offers a unique time window to investigate early FTD or ALS disease-related changes on neuroimaging or neuropsychological assessment. These changes can serve as potential biomarkers for disease onset or disease progression and may function as outcome measures for therapeutic trials. In the present cross-sectional study, we examine changes in gray and white matter, through T1W MRI and diffusion tensor imaging and neuropsychological assesment in presymptomatic C9orf72 mutation carriers (n = 14) compared with age-matched controls, without the C9orf72 mutation, from the same families (n = 11). Structural connectivity was measured by means of FSL, using voxel-based morphometry (VBM, T1W) and tractbased spatial statistics (TBSS, DTI). Higher age, as predictor for approaching disease onset, was correlated with gray matter volume and white matter integrity. Preliminary analyses showed that C9orf72 mutation carriers had lower scores than controls on executive function tests. Higher age, as a predictor for approaching disease onset, correlated with worse performance on language and theory of mind. Mutation carriers showed lower gray matter volume within the left thalamus and bilateral cerebellum, and higher age correlated with gray matter volume decline in the right temporal lobe (pFWEC9orf72 repeat expansion, and is associated with higher age, and thus symptom onset approach. With these findings, we confirm the possible biomarker value of structural neuroimaging and neuropsychological assessment in the presymptomatic FTD stage. We are currently analyzing white matter integrity and explore correlations between brain structure and connectivity with neuropsychological assessment.

P411 Tau PET, amyloid PET, and structural imaging in primary progressive aphasia A. Martersteck1,2, M.-M. Mesulam2,3, E. Rogalski2 1 Northwestern University Feinberg School of Medicine, Department of Radiology, Chicago, USA 2 Northwestern University Feinberg School of Medicine, Cognitive Neurology and Alzheimer’s Disease Center, Chicago, USA 3 Northwestern University Feinberg School of Medicine, Department of Neurology, Chicago, USA Primary progressive aphasia (PPA) is a clinical dementia syndrome caused by neurodegenerative disease and characterized by asymmetric atrophy of the language-dominant (usually left) hemisphere. The most common neuropathologies reported for PPA are Alzheimer’s disease (AD; ~40%), frontotemporal lobar degeneration with tauopathy (~30%), or with TDP-43 proteinopathy (~30%). Recent innovations in PET technology have allowed quantitation and spatial localization of amyloid and tau. These technologies are particularly promising in diseases such as PPA where there is no one-to-one relationship between clinical symptoms and underlying pathology. We used the tau ligand [18F] AV-1451 to scan three PPA participants whom also underwent [18F] AV-45 amyloid PET and structural MRI (sMRI). Two participants were diagnosed with the agrammatic subtype of PPA (PPA-G) and the other was diagnosed with the logopenic subtype (PPA-L). The sMRI was processed with FreeSurfer to derive measures of cortical atrophy. Amyloid was quantified using a previously described FreeSurfer method (Landau et al. J Nucl Med 2013). Two participants (1 PPA-L and 1 PPA-G) showed elevated amyloid binding (Ab+; using the 1.11 whole cerebellar SUVR threshold), consistent with AD pathology. Both of these Ab+ patients had

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elevated tau PET uptake patterns that mirrored the asymmetric left hemisphere atrophy, presumably reflecting the distribution of the neurofibrillary degeneration underlying the cortical atrophy. The amyloid-negative PPA-G patient had asymmetric left cortical atrophy and low tau PET binding. Longitudinal studies of neuropsychological performance, MR imaging, amyloid PET, and tau PET are needed in PPA to determine the temporal relationship among these measures and the usefulness of tau PET as biomarker for tracking the progression of disease.

P412 PET tau imaging with AV-1451 in N279K and S305N microtubule associated protein Tau (MAPT) mutation carriers relative to Alzheimer’s disease dementia and controls B. Boeve1, D. Jones1, V. Lowe1, H. Wiste1, M. Senjem1, K. Kantarci1, D. Knopman1, C. Dheel1, Z. Wszolek2, R. Rademakers2, R. Petersen1, C. Jack, Jr1 1 Mayo Clinic, Rochester, USA 2 Mayo Clinic Florida, Jacksonville, USA Tau-PET imaging with AV-1451 is a promising research tool for investigating tau pathology in Alzheimer’s disease. One would predict that increased AV-1451 binding would be present in those with mutations in the gene encoding microtubule associated protein tau (MAPT). We therefore investigated AV-1451 binding in subjects with MAPT mutations (MAPT) relative to those with Alzheimer’s disease dementia (ADem) and clinically normal (CN). Tau PET with AV-1451 imaging was performed in MAPT subjects with MAPT mutations (n = 6, age range 42–50), ADem (n = 24, age range 54– 90), and CN (n = 26, age range 40–55). Among the MAPT cases, 4 had the N279K mutation and 2 had the S305N mutation; these mutations are associated with 4 repeat (4R) tau isoforms in neurons and glia. All but one were symptomatic - 3 with moderate to severe frontotemporal dementia with parkinsonism (FTDP), 1 with mild FTDP, and 1 with mild parkinsonism. Uptake of AV-1451 was assessed by visual read and by regional analysis with intensity standardization to cerebellar grey matter (SUVR). On visual inspection there appears to be AV-1451 binding in the three most severely affected MAPT subjects (all with moderate to severe FTDP). However, the SUVR quantification shows that the AV-1451 binding in the MAPT cases was far below that seen in ADem, and largely in the range of binding in CNs. These findings indicate that AV-1451 binding levels in these specific MAPT mutations were largely within the CN range. The minimal uptake in these MAPT subjects suggests that AV-1451 does not bind avidly to the 4R isoforms of tau specific to these mutations, compared to 3R/4R paired helical filaments in Alzheimer’s disease. Alternatively, the concentrations of AV-1451 binding sites in MAPT mutation carriers are far lower than in Alzheimer’s disease.



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Neurofilament light chain protein concentration in CSF and atrophy are correlated in bvFTD patients - Data from the multicentric FTLD consortium’s study S. Meyer1, K. Mueller1, S. Bisenius1, J. Diehl-Schmid2, H. Foerstl1,2, K. Fassbender3, J. Kassubek4, B. Landwehrmeyer4, A. C. Ludolph4, J. Kornhuber5, J. Prudlo6, A. Schneider7, K. Stuke1, M. Schroeter1,8 1 Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany 2 Technical University of Munich, Clinic and Polyclinic for Psychiatry and Psychotherapy, Munich, Germany 3 Saarland University Homburg, Clinic and Polyclinic for Neurology, Homburg, Germany 4 University of Ulm, Clinic and Polyclinic for Neurology, Ulm, Germany 5 University of Erlangen, Clinic for Psychiatry and Psychotherapy, Erlangen, Germany 6 University of Rostock, Clinic and Polyclinic for Neurology, Rostock, Germany 7 University of G€ottingen, Clinic for Psychiatry and Psychotherapy, G€ ottingen, Germany 8 University of Leipzig, Clinic for Cognitive Neurology, Leipzig, Germany

Evolution from the asymptomatic to symptomatic state in familial FTD: longitudinal neuropsychological and MRI findings in three MAPT mutation carriers C. Dheel1, S. Przybelski2, M. Senjem2, K. Kantarci2, D. Jones2, J. Fields2, M. Machulda2, C. Jack, Jr2, R. Rademakers3, D. Knopman2, Z. Wszolek3, R. Petersen2, B. Boeve2 1 Mayo Clinic, Neurology, Rochester, USA 2 Mayo Clinic, Rochester, USA 3 Mayo Clinic, Jacksonville, USA

Frontotemporal lobar degeneration (FTLD) is one of the most common types of early onset dementia. The behavioral variant (bvFTD), its most common subtype, is clinically characterized by a progressive deterioration of personality, social comportment, and cognition. Neurofilaments are structural components of axons. An increase of neurofilaments’ light chain (NfL) has been shown in bvFTD in cerebrospinal fluid (CSF) and discussed as a biomarker for neuronal death and axonal degeneration. In this study we correlated CSF NfL concentration with gray matter density (GMD) in bvFTD patients in order to determine injured brain areas. The cohort consisted of 34 bvFTD patients (12 female, age 62.5 9.5 years, mean stdev). We used 3T T1-weighted images acquired with the MP-RAGE sequence by seven different centers with overall five different scanners. CSF NfL-concentration was 2671.5 pg/ml 1689.2 pg/ml. SPM8 was used to analyze the imaging data, and the VBM8 toolbox was used to create segmented gray matter volumes. These volumes were smoothed with a 12 mm full width at half maximum Gaussian filter. The statistical analysis was performed using the general linear model, correlating GMD and CSF - NfL. CSF NfL concentration correlated inversely with GMD, i.e. higher NfL was associated with lower values of GMD, lateralized in the right hemisphere. More specifically a correlation was found in the putamen, insular cortex, superior-, middle-, and inferior temporal gyrus, and the planum temporale. These findings suggest a neuronal injury in the aforementioned brain regions in bvFTD.

It is important to characterize the cognitive and imaging features in familial frontotemporal dementia from the asymptomatic to symptomatic state in order to plan for future disease-modifying trials. We identified three members of a kindred with the N279K mutation in MAPT who have been followed annually with cognitive measures and high resolution 3D T1-weighted MRI scans, and became symptomatic. Cognitive measures included Mini-Mental State Exam (MMSE), Dementia Rating Scale (DRS), Auditory-Verbal Learning Test (AVLT), Boston Naming Test (BNT), Category Fluency (CF), Trailmaking Test (TMT) A and B and WAIS-R Digit Symbol Total Score (DS). The Symmetric Diffeomorphic Image Normalization method was used to obtain Tensor Based Morphometry (TBM-SyN) maps on MRI to measure volume changes in frontal (FV), temporal (TV) and frontotemporal (FTV) regions. Annualized rates of change (i.e., slope estimates) were calculated using least squares from a linear regression model, with slope estimates different from 0 (with p < 0.05) considered statistically significant. The three subjects had the following features: Case 1 (male)- initial exam age 39, onset age 44, current age 48; Case 2 (female)-initial exam age 41, onset age 48, current age 49; Case 3 (male)-initial exam age 36, onset age 39, current age 42. The most robust slope estimates for all 3 patients were in TV, FV and FTV (each p < 0.01), with at least 2 patients showing statistically significant changes in BNT, CF, TMTA and DS. Structural MRI changes preceded symptom onset in each patient, whereas neuropsychological performance was more variable. These findings suggest that changes in frontal and temporal volume on MRI precede symptom onset, and more consistently track the evolution from the asymptomatic to symptomatic state in MAPT mutation carriers than traditional neuropsychological measures.

P415 Neurofilament light chain, progranulin, and S-100B in longitudinal serum samples of patients with amyotrophic lateral sclerosis P. Steinacker1, A. Huss1, B. Mayer2, P. Oeckl1, D. Lul e1, J. Weishaupt1, J. Kuhle3, T. Meyer4, S. Petri5, A. C. Ludolph1, M. Otto1 1 University Ulm, Department of Neurology, Ulm, Germany 2 University Ulm, Institute of Epidemiology and Medical Biometry, Ulm, Germany 3 University Hospital Basel, Department of Neurology, Basel, Switzerland 4 Charite University Hospital, Department of Neurology, Berlin, Germany 5 Hannover Medical School, Department of Neurology, Hannover, Germany Blood biomarkers for amyotrophic lateral sclerosis (ALS) are needed, that preferentially allow for prognosis. We performed a


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comparative analysis of blood markers reported to be indicative for progression and outcome of ALS. Therefore, longitudinal blood samples were taken from one hundred twenty-four ALS patients at regular intervals of 6 month for up to two and a half years. We quantified neurofilament light chain (NF-L) and S-100B by electrochemiluminescence-immunoassays, and progranulin (PGRN) by an enzyme-linked immunosorbent assay. Marker concentrations were analyzed with respect to patient’s baseline characteristics, to disease progression rates as determined on the basis of the ALS functional rating scale score (ALS-FRS-R), and to survival times. We found that serum NF-L levels were higher in ALS compared to controls, remained relatively stable during disease progression, and correlated with the time from onset to sampling as well as with survival time of ALS patients. The levels of PGRN and S-100B were not significantly different compared to controls. Serum NF-L at baseline examination correlated with the ALS-FRS-R progression rate and also with patient’s survival times. Low S-100B levels were associated with short survival times. In conclusion, NF-L is the most promising blood biomarker for diagnosis and prognosis of ALS.

P416 Presymptomatic cerebral perfusion biomarker changes in genetic frontotemporal dementia: results from the GENetic Frontotemporal dementia Initiative (GENFI) H. Mutsaerts1, S. S. Mirza1, J. Rohrer2, D. Thomas2, D. Cash2, E. De Vita2, K. Dick2, S. Ourselin2, J. van Swieten3, D. Galimberti4, J. B. Rowe5, C. Graff6, F. Tagliavini4, R. LaforceJr7, E. Finger8, A. Mendoncßa9, J. Knight10, B. MacIntosh1, M. Masellis1 1 Sunnybrook Research Institute, Toronto, Canada 2 University College London, London, Great Britain 3 Erasmus Medical Center, Rotterdam, Netherlands 4 Istituto Neurologico Carlo Besta, Milan, Italy 5 University of Cambridge, Cambridge, Great Britain 6 Karolinski Institutet, Stockholm, Sweden 7 University of Laval, Quebec, Canada 8 University of Western Ontario, London, Canada 9 University of Lisbon, Lisbon, Portugal 10 University of Lancaster, Lancaster, Great Britain Background: Frontotemporal dementia (FTD) is a common cause of early onset dementia characterized by prominent behaviour and/or language disruption. The current study investigates whether perfusion patterns derived from non-invasive arterial spin labeling (ASL) MRI can be used as an early functional neuroimaging biomarker in presymptomatic genetic FTD participants. Methods: Data were drawn from the GENetic Frontotemporal dementia Initiative (GENFI). From the second GENFI data freeze (n = 365), 247 participants (40.9% male, age 49.8 13.5) had 3T ASL from which this analysis considers only the presymptomatic carriers (n = 105, 38.1% male, age 46.2 11.6) and controls (n = 110, 37.3% male, age 49.5 14.1). We performed a voxelwise general linear mixed effects model to explore the interaction between years to expected age of disease onset and mutation status on GM CBF, accounting for sex and family membership as fixed and random effects, respectively (primary threshold pp Results: Eight clusters were identified with a significant GM CBF interaction between years to expected age of disease onset and mutation carrier status. At post-hoc stratification for mutation carrier

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status within these clusters, regions with the highest significant interactions were found in the left frontal pole (p = 0.02) and orbitofrontal and insular cortices (p=0.02) for chromosome 9 open reading frame 72 (C9ORF72), in the superior and inferior parietal lobules (p = 0.004) for progranulin (GRN) and in the left (p = 0.001) and right (p = 0.008) frontal pole for microtubuleassociated protein tau (MAPT). Conclusions: CBF decreased as presymptomatic mutation carriers approached the expected age of disease onset in key regions implicated in FTD, which was not the case in non-carriers. These findings demonstrate the potential utility of non-invasive perfusion MRI as an early presymptomatic biomarker for genetic FTD.

P417 Decreased global field synchronization (GFS) is an EEG classifier of frontotemporal dementia 2 € V. Jelic1, P. Ostberg , L.-O. Wahlund1, T. Koenig3 1 Karolinska Institutet, Department NVS, Clinical Geriatrics, Stockhom, Sweden 2 Karolinska Institutet, Department CLINTEC, Stockholm, Sweden 3 University of Bern, Translational Research Center, University Hospital of Psychiatry, Bern, Switzerland Patients with frontotemporal dementia (FTD) show very few pathological changes in visually analyzed electroencephalogram (EEG) as compared to the patients with Alzheimer’s disease (AD). In the present study we further explored this hypothesis by using more advanced methods of quantitative EEG (qEEG) analysis: EEG dipole sources estimation and Global Field Synchronization (GFS). Both methods are complementary to each other, former showing strength and localization of the generators of EEG activity and later functional synchronization in EEG frequency-domain. Study sample encompassed 24 AD patients, 26 FTD patients and 17 healthy control subjects (C). Study groups had similar demographic characteristics. AD and FTD patients did not differ significantly in MMSE scores. Global Field Power (GFP) corresponding to the generalized EEG amplitude, antero-posterior localization of generators of EEG activity and GFS, which measures relative presence or absence of a common phase over all electrodes, were computed using the FFT approximation algorithm. Chosen parameters were averaged over conventional frequency bands. AD patients had significantly higher slow, delta and theta, GFP and lower fast, alpha and beta 2, GFP as compared to C and FTD. FTD did not differ significantly from C in slow frequency bands, but had lower GFP in all fast frequencies, alpha and beta 1–3. AD patients had more anterior localization of generators of alpha activity as compared to C and FTD. FTD patients had significantly lower GFS in all frequency bands when compared to both, AD and C. AD patients had significantly lower alpha and beta 1 GFS compared to C. Principal axis factoring established GFS as a separate EEG factor in patient samples. The diagnosis of FTD versus AD was predicted by strongly decreased GFS factor scores in the former, in particular reflecting GFS decrease in the fast beta frequency bands. This finding may imply different pathophysiological processes behind two dementing diseases. In addition GFS is a promising noninvasive neurophysiological marker of FTD.



P418 Longitudinal arterial spin labeling in the behavioral variant of frontotemporal lobar degeneration F. McKenna1, Y. Cobigo1, G. Marx1, S. Attygale1, H. Rosen1, B. Miller1 1 University of California, San Francisco, Memory and Aging Center, San Francisco, CA, USA The goal of this study is to analyze arterial spin labeling (ASL) perfusion brain images of patients diagnosed with the behavioral variant (BV) of frontotemporal lobar degeneration (FTLD) at three time-points. BV FTLD patients were matched with healthy controls at three time points: time-point one (N = 79: BV = 24, CN = 55), time-point two (N = 79: BV = 24, CN = 55), time-point three (N = 33: BV = 12, CN = 21). All ASL images were acquired at the Memory and Aging Center (MAC) at the University of California, San Francisco on a 3T Siemens Trio scanner. The ASL images were post-processed through a novel in-house ASL processing pipeline. FSL Randomise software was used to conduct permutation test analyses and statistics on the data. Our results show the progression of the BV FTLD pathology on blood perfusion in the brain. The specific regions identified as having hypoperfusion in the BV FTLD patients at the p = 0.05 FWE-corrected level are consistent with brain regions highlighted from prior studies looking at atrophy and perfusion in FTLD. The hope is that this study will show, for the first time, longitudinal ASL perfusion in the brain of BV FTLD patients so that ASL can be evaluated as a powerful tool for detecting and evaluating the progression of FTLD.

P419 longstanding bipolar affective disorder and behavioral variant frontotemporal dementia. findings in clinical and neuroanatomical phenotypic patterns F. Cruz Sanabria1, R. Pardo Turriago1, D. Matallana Eslava2, P. Reyes Gavilan2 1 Universidad Nacional de Colombia, Bogot a, Colombia 2 Pontificia Universidad Javeriana, Bogot a, Colombia In the Bipolar Affective Disorder (BAD) there are cognitive alterations that can have a progressive course, so is questioned whether some patients develop dementia associated with their psychiatric disease, or whether they have comorbidity with diseases properly neurodegenerative; particularly with frontotemporal dementia (FTD), according to the reports of clinic cases that describe a difficulty to achieve a differential diagnosis. The aim of the preset study is to compare the clinical profiles of a sample of patients with longstanding BAD (L-BAD), patients with Behavioral Variant of FTD (BvFTD) and healthy subjects. All patients underwent a structured clinical interview, a full neurological, psychiatry and neuropsychological examination as well as neuroimaging and genetic data to support a consensus clinical diagnosis. The cognitive performances are compared though nonparametric statistical analyses, the risk factors associated to cognitive impairment are explored through multiple correlation analyses and volumetric comparisons are performed through the voxel based morphometric technique. We identified differential markers between the L-BAD and BvFTD. The volumetric analyses show a decrease in density of gray matter in both clinical groups in the prefrontal, anterior temporal, insular and cingulate cortex, and structures of the limbic system; when comparing within the clinical

groups, FTD have decrease in cingulum, fusiform and parahipocampal Gyrus, and small regions of the temporal and frontal cortex. The most neuropsychological instruments show significant differences between clinical groups and healthy subjects, but between L-BAD and BvFTD the differences only involve processes of memory and mental flexibility, however, the extent of cognitive alteration is greater in BvFTD and it’s not related to risk factors. Correlations between the number of affective episodes and cognitive performance suggest that the most chronicle cases of BAD may present a larger cognitive impairment, which supports the hypothesis that associates the chronicity of the disease to a higher susceptibility to neurodegenerative processes.

P420 Cerebral glucose metabolism in C9orf72 mutation carriers T. Grimmer1, J. Diehl-Schmid1, I. Yakushev1, G. FTLD-Consortium2 1 Technische University Munich, Department of Psychiatry, Munich, Germany 2 University of Ulm, Department of Neurology, Ulm, Germany Small structural imaging studies have suggested, that in C9orf72 carriers frontotemporal atrophy is fairly symmetrical and that the areas involved are variable: involvement of the posterior cingulate, the parietal lobe, the thalamus and the cerebellum have been described. Out of the FTLD patients of a German memory clinic specialized on FTD, twelve C9orf72 mutation carriers were identified who had got a cerebral 18-FDG-PET scan at the time of their first assessment. Patient scans were compared with scans of cognitively healthy, age matched control subjects. Furthermore, a visual rating by two independent, blinded raters was performed in order to rate the metabolism and symmetry of different brain structures. Patients were diagnosed with bvFTD (N = 11) and svPPA (N = 1). Compared to a healthy control population (n = 15) a significant hypometabolism was detected in frontal and temporal areas. Visual rating of the PET scans showed a frontal hypometabolism in all but two cases (one svPPA, one bvFTD). Frontal hypometabolism was symmetric in six cases and mildly asymmetric in the remaining 4 cases. Hypometabolism was reduced in the anterior temporal lobes of nine cases and in the parietal lobes of five cases. Two cases showed a hypometabolism in the posterior cingulate, one in the cerebellum, and one in the thalamus. Visual rating revealed, that glucose metabolism is only rarely reduced in the posterior cingulate, the thalamus and the cerebellum of C9orf72 mutation carriers. Voxel based analyses will be performed in order to investigate this preliminary data further.


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P421 Increased neurofilament light chain correlates with decreased white matter integrity in presymptomatic and symptomatic granulin carriers J. L. Panman1,2, L. H. H. Meeter1, E. G. P. Dopper1,2,3, oller2, R. van Minkelen4, L. C. Jiskoot1,2,3, M. J. M. Bouts2, C. M€ 6,7 € , R. Sanchez-Valle5, M. Balasa5, C. Graff6,7, L. Oijerstedt 6,7 8 8 8 V. Jelic , L. Benussi , R. Ghidoni , G. Binetti , B. Barbara9, A. Padovani9, D. Galimberti10, E. Scarpini10, C. Fenoglio10, R. J. Laforce11, R. Vandenberghe12, I. Le Ber13,14, F. Lamari14, M. Otto15, J. D. Rohrer16, D. M. Cash16,17, S. A. R. Rombouts2, C. E. Teunissen18, J. M. Papma1, J. C. van Swieten1,19 1 Erasmus Medical Center, Neurology, Rotterdam, Netherlands 2 Leiden University Medical Center, Radiology, Leiden, Netherlands 3 VU Medical Center, Neurology, Amsterdam, Netherlands 4 Erasmus Medical Center, Clinical Genetics, Rotterdam, Netherlands 5 Institut d’Investigaci o Biomedica August Pi i Sunyer, Neurology, Alzheimer’s Disease and Other Cognitive Disordes Unit, Barcelona, Spain 6 Karolinska Institutet, NVS, Center for Alzheimer Research, Division of Neurogeriatrics, Huddinge, Sweden 7 Karolinska University Hospital, Geriatric Medicine, Stockholm, Sweden 8 Molecul Markers Laboratory, Brescia, Italy 9 University of Brescia, Centre for Neurodegenerative Diseases, Neurology Unit, Department of Clinical and Experimental Sciences, Brescia, Italy 10 University of Milan, Milan, Italy 11 Universite Laval, Clinique Interdisciplinaire de Memoire CIME, CHU de Quebec, Department des Sciences Neurologiques, Quebec, Canada 12 University Hospitals Leuven, Neurology, Leuven, Belgium 13 Universite Pierre et Marie Curie, Institut du Cerveau et de la Moelle epiniere (ICM), Paris, France 14 Hôpital de la Pitie-Salpêtriere, Departement de maladies du systeme nerveux, Paris, France 15 University of Ulm, Ulm, Germany 16 University College London, Dementia Research Centre, Department of Neurodegenerative disease, London, Great Britain 17 University College London, Translational Imaging Group, Center for Medical Imaging Computing, London, Great Britain 18 VU Medical Center, Neurochemistry and Biobank, department of Clinical Chemistry, Amsterdam, Netherlands 19 VU Medical Center, Clinical Genetics, Amsterdam, Netherlands Pathogenic mutations in the granulin gene (GRN) are a common cause of autosomal dominant frontotemporal dementia (FTD). Preliminary data on symptomatic GRN patients have shown an elevation of neurofilament light chain levels (NfL) in CSF, while levels were low in both presymptomatic GRN carriers and controls (Meeter et. al). Distinction in NfL levels between presymptomatic and symptomatic stage was less eminent in MAPT and C9orf72 carriers. Circulating NfL may reflect axonal damage, thus impairing white matter integrity in GRN. Examining the relation between NfL levels and white matter integrity using diffusion tensor imaging (DTI) in presymptomatic and symptomatic GRN carriers may clarify disease mechanisms in GRN mutations. Sixty-four subjects (41 controls, 15 presymptomatic GRN carriers, 8 symptomatic GRN carriers) from three centers (Rotterdam, Barcelona, Milano) were included in our analysis, on basis of

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available CSF and DTI scans (3T). CSF NfL levels were measured by ELISA. White matter integrity was established using tract-based spatial statistics, and region of interest analyses. Statistical models included correction for age, gender and center-effect. Using TBSS, a significant negative relationship between NfL and fractional anisotropy (FA) (pFWE < 0.05) was found in widespread white matter tracts, predominantly those in frontal regions. Also, ROI analysis of JHU probabilistic tracts showed extensive white matter loss in several tracts in symptomatic carriers, compared to controls and presymptomatic carriers, including the uncinate fasciculus. Corrected partial correlations (Spearman’s rho) in GRN carriers showed significant involvement of NfL in the left cingulate gyrus (r -0.464, p 0.046), forceps major (r -0.553, p 0.014), forceps minor (r -0.637, p 0.003), and left inferior fronto-occpital fasciculus (r -0.576, p 0.010). Our results prove that NfL levels strongly correlate with decreased white matter integrity in frontal tracts across different stages of GRN carriers, which indicates that CSF NfL levels in GRN indeed reflects axonal damage.

P422 Tau-PET imaging with THK-5351 in patients with clinically diagnosed progressive supranuclear palsy S. Scho¨necker1, M. Brendel2, J. Havla3, G. H€ oglinger4,5, K. B€ otzel1, A. Danek1, A. Rominger2, J. Levin1,5 1 Ludwig-Maximilians-University, Department of Neurology, Munich, Germany 2 Ludwig-Maximilians-University, Department of Nuclear Medicine, Munich, Germany 3 Ludwig-Maximilians-University, Institute of Clinical Neuroimmunology, Munich, Germany 4 Technical University of Munich, Department of Neurology, Munich, Germany 5 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany Intracellular inclusions composed of the abnormally-modified microtubule-binding protein tau, are the second most common cause of frontotemporal lobar degeneration neuropathology (i.e. FTLDtau). FTLD-tau pathology can manifest clinically with several forms of frontotemporal dementia (FTD) syndromes, like behaviouralvariant FTD, progressive non-fluent aphasia, corticobasal syndrome and progressive supranuclear palsy (PSP). Especially in early stages of the disease when many clinical phenotypes overlap there are at present no reliable means to identify the underlying neuropathology in vivo. However, as effective disease-modifying treatments should be administered before irreversible neuronal damage has occurred, an early detection of the underlying neuropathological process becomes increasingly important. THK-5351 is a novel Tau-PET ligand that may allow in vivo visualization and quantification of tau deposits. THK-5351 PET was performed in 7 patients with probable PSP according to current criteria. PET scans were acquired 40–60 min post injection and were co-registered to MRI. Visual and semiquantitative analysis of tracer binding (standardized uptake value ratio) in predefined cortical areas was performed using the cerebellar cortex a reference. Increased THK-5351 binding was detectable in striatum, thalamus and brainstem, especially in the midbrain. 6/7 subjects indicated clearly elevated THK-5351 uptake in the midbrain (SUVR: 2.8 -



3.9) compared to non-suspect PSP (SUVR: 2.2). One subject suspect to PSP with innate hydrocephalus, did not show an elevated THK-5351 midbrain signal (SUVR: 2.1), suggesting no underlying tauopathy in this case. THK-5351 binding patterns correlated well with the known distribution of tau-pathology at autopsy in PSP. THK-5351 seems to be a useful in vivo biomarker of tau burden and may therefore facilitate earlier and more reliable diagnosis of an underlying tauopathy.

P423 Multivariate diagnostic approaches in Frontotemporal lobar degeneration - Data from the german FTLDc S. Straub1, M. L. Schroeter2, J. Diehl-Schmid3, A. Danek4, C. v. Arnim1, L. Bertram5, B. Einsiedler6, K. Fassbender7, E. Feneberg1, K. Fliessbach8, H. F€ orstl3, H.-J. Huppertz9, H. Jahn10, 11 12 F. Jessen , E. Kasper , J. Kassubek1, H. A. Kestler13, J. Kornhuber14, C. Kubisch10, B. Landwehrmeyer1, M. Lauer15, L. Lausser13, C. M. Lill5, A. Ludolph1, M. Maler14, R. Muche13, E. Pinkhardt1,13, J. Prudlo12, L. Riedl4,12, A. Schneider16, R. Schomburg7, S. Teipel12, I. Uttner1, A. E. Volk10, M. Otto1 1 University of Ulm, Department of Neurology, Ulm, Germany 2 MPI, Max Planck Institute for Human Cognitive and Brain Sciences & Clinic for Cognitive Neurology, Leipzig, Germany 3 TU Munich, Department of Psychiatry, Munich, Germany 4 LMU, Department of Neurology, Munich, Germany 5 MPI, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics BerlinDepartment of Vertebrate Genomics, Max Planck Institute for Molecular Genetics Berlin, Berlin, Germany 6 University of Ulm, Institute of Epidemiology and Medical Biometry, Ulm, Germany 7 Saarland University, Homburg/Saar, Germany 8 University of Bonn, Bonn, Germany 9 University of Zurich, Zurich, Switzerland 10 University Medical Center Hamburg-Eppendorf, Hamburg, Germany 11 University of Cologne, Cologne, Germany 12 University of Rostock, Rostock, Germany 13 University of Ulm, Ulm, Germany 14 University of Erlangen, Erlangen, Germany 15 University of W€urzburg, W€ urzburg, Germany 16 University of G€ottingen, G€ ottingen, Germany Objective: A major challenge for clinical trials in frontotemporal lobar degeneration (FTLD) is the overlap of clinical syndromes, the change of symptoms during progression and the limited data on possible clinical endpoints. Therefore we asked, if by specific combinations of test results (neuropsychological, imaging and neurochemistry) a minimal data-set can be defined which can serve as objective diagnostic criteria and is suitable to be defined as baseline inclusion criteria into clinical studies. Methods: Within this multicentre study data-driven multivariate analysis were used to identify disease specific parameter patterns. Analyses were done on baseline cross-sectional data from the German FTLD-trace study: 123 behavioral variant frontotemporal dementia (bvFTD), 26 corticobasal syndrome, 35 progressive supranuclear palsy, primary progressive aphasia (PPA; 35 nonfluent, 26 semantic, 17 logopenic variant, 28 amyotrophic lateral sclerosis (ALS)+FTD, and controls, including 16 ALS, 44

Alzheimer0 s disease (AD), 69 other neurological diseases, and 48 healthy controls. Results: Specific clinical and biomarker patterns yielding a high diagnostic accuracy for the differential diagnostic questions within the group of FTLD and vs AD could be observed. Neurochemical markers in CSF (tau, ptau, Abeta1-42, neurofilaments and progranulin) and serum (neurofilaments) were especially relevant for the differential diagnostic question bvFTD vs AD, whereas for PPAs, PSP and CBS imaging markers were more relevant. Interpretation: Our results provide evidence that by multivariate approaches a reduced data-set of quantifiable biological and clinical alterations can be used to allocate patients into diagnostic groups. These might serve as objective clinical baseline parameter.

P424 Functional connectivity differences between behavioralvariant frontotemporal dementia and early-onset Alzheimer’s disease G. Castrillon1,2, L. Velilla3, M. Giraldo3, A. Zapata3, C. bustamante1, F. Lopera3, Y. Quiroz3,4 1 Instituto de Alta Tecnologia Medica, Medellin, Colombia 2 Technical University Munich, TUM-NIC, Munich, Colombia 3 Grupo de Neurociencias de Antioquia, Medellin, USA 4 Massachusetts General Hospital, Boston, USA Introduction: Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are the most common types of young-onset dementia. Resting state functional magnetic resonance imaging (rs-fMRI) can be helpful to differentiate between these dementia types. Methods: We investigated large-scale functional brain networks in patients with AD and bvFTD by means of graph theoretical analysis of rs-fMRI. Fourteen patients with mild to moderate earlyonset AD, 12 bvFTD patients, and 12 non-demented individuals were scanned during eyes-opened resting-state. Imaging data were analyzed with the Configurable Pipeline for the Analysis of Connectomes. A brain graph analysis was performed using 160 regions of interest (ROI) as graph nodes. For each ROI, the average time-series of a 5mm sphere radius was extracted, and the connectivity matrix was computed based on the pairwise Pearson correlations between all nodes. An ANOVA was conducted to compare functional brain network strengths between groups. Results: Between-group differences were found in all functional brain networks (i.e. cingulo-opercular, default mode network-DMN, fronto-parietal, occipital and sensorimotor), but the cerebellum network, after correcting for multiple comparisons (p< 0.05). In addition, differences in the cingulo-opercular, DMN, fronto-parietal, occipital and sensorimotor networks were found between controls and early-onset AD patients. Only differences in the cinguloopercular network were seen between bv-FTD and early-onset AD patients. Conclusions: Our results suggest that the pathophysiology of functional brain connectivity is different between early-onset AD and bvFTD. Findings also suggest that the graph theoretical measure of local strength can be used to distinguish between young-onset dementias. Further research is needed to determine whether these patterns of functional connectivity can be used to inform diagnosis and clinical management.


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P425 A mass spectrometry based search for biomarkers in FTD-PGRN D. Nijholt1, L. Meeter1, L. Dekker1, J. van Rooij1,2, T. M. Luider1, J. van Swieten1 1 Erasmus Medical Centre, Department of Neurology, Rotterdam, Netherlands 2 Erasmus Medical Centre, Department of Internal Medicine, Rotterdam, Netherlands In hereditary frontotemporal dementia (FTD) mutations in the progranulin (PGRN) gene are amongst the most common gene defects. Levels of progranulin are low both in presymptomatic and symptomatic PGRN mutation carriers and can therefore not be used to predict the onset of disease. In this study, we investigated the CSF proteins of 2 Dutch families with hereditary FTD. In this unique sample set, CSF is available from symptomatic (8) and presymptomatic (20) cases that harbour a PGRNmutation as well as family members (23) with the wild-type allele. We aim to identify potential biomarker candidates in CSF that mark conversion from presymptomatic to symptomatic disease using advanced liquid chromatography (LC) and high-resolution mass spectrometry (MS) techniques. Using a ‘shotgun’ approach on our dataset an accumulated number of 916 proteins (99% protein probability) were identified in 0.25 ll [TL1] CSF that was enzymatically digested before injection in the LC-MS system. Peptide raw files were loaded into ProgenesisQI software (NonLinear Dynamics/Waters) for label free quantification. A > 1.5 fold change (p-value < 0.01) in expression between groups was observed for 100 proteins. The majority of these proteins were involved with the immune system (e.g. complement components) and the acute phase response to damage. These proteins are often observed in neurodegenerative disease and are thought to reflect ongoing inflammatory mechanisms that might be secondary to the disease process. Albumin and IgG are highly abundant proteins in CSF and their presence masks the detection of lower abundant proteins. Depletion columns were used to remove albumin and IgG from CSF, increasing the volume of lower abundant proteins in the CSF sample that could be therefore be detected in the LC-MS system. The depletion approach was optimized for amount of sample input[TL2] and reproducibility was tested using a small sample set. This approach resulted in a 25% increase in protein identifications. We are currently applying the depletion method to all samples in the cohort and the resulting data will be presented at the conference.

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Poster Session III: Mechanisms of cell death P426 Cellular changes and toxicity in mouse neuronal cell cultures produced by the cerebrospinal fluid from motor neuron disease patients A. Spalloni1, M. Nutini1, A. Alberici2, B. Borroni2, A. Padovani2, P. Longone1 1 Fondazione Santa Lucia, Experimental Neurology, Roma, Italy 2 University of Brescia, Neurology Unit, Brescia, Italy The neurotoxicity of the cerebrospinal fluid (CSF) from patients with neurodegenerative diseases has been reported by various authors. Here we uncover that the CSF from patients affected by frontotemporal dementia and motor neuron disease (henceforth defined MND) is toxic to primary spinal cord and cortical cultures from mice. The study was conducted using neuronal cultures prepared from the same embryos (E14) and kept in culture for 7 days. Cultures were exposed to the Neurobasal medium containing CSF obtained from randomly selected MND patients (MND-CSF) and age-matched healthy controls. We observed a different reaction to the patient’s CSF amongst the two neuronal populations. Cortical cultures probed with the microtubule associate protein 2 (MAP2) and the nuclear marker Hoechst, used to stain DNA, showed a slight increase in nuclear condensation and a wallerian-like degeneration along the axons, but without any significant cellular loss. On the contrary, the addition of the MND-CSF to the spianl cord cultures, resulted in a significant increase in neuronal death compared with control-CSF. The spinal cord cultures were probed with the motor neuron marker SMI32, with GABA, to detect the GABAergic+ neurons and the nuclear marker Hoechst. Three days after the addition of CSF, the number of GABA+ neurons, on randomly chosen areas, decreased by a 30% in the MND-CSF treated cultures compared to the control-CSF, while the number of the SMI32+ neurons was not affected by the toxicity of the MND-CSF. These results show that the MND-CSF is toxic to neurons, primarily to GABAergic interneurons, and less to SMI32+ (motor neuron) cells, which is somehow surprising. An additional interesting observation is that cortical cultures, although affected by the MND-CSF toxicity appear to be more resistant than the spinal cord cultures. The toxic pathways activated by the MND-CSF will be discussed.

P427 Simulation of pathogenic protein spread in an artificial neural network K. Georgiadis1, S. Wray2, S. Ourselin1,3, J. D. Warren3, M. Modat1,3 1 University College London, Translational Imaging Group, Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, London, Great Britain 2 University College London, Department of Molecular Neuroscience, Institute of Neurology, London, Great Britain 3 University College London, Dementia Research Centre, Institute of Neurology, London, Great Britain

converge among patients. Most computational research has been focused on diagnosis, classification and atrophy prediction, rather than attempting to elucidate the mechanisms that produce these patterns. We computationally modeled key components of pathogenic protein effects on neural circuitry - pathogenic protein production, “prion-like” misfolding of normally folded protein, intracellular and trans-synaptic intercellular diffusion, reduced neuronal firing rate as a toxic effect and cell death - in an artificial neural network of cortical columns, simulated using the NEURON software. We varied the seed location and diffusion speed of the pathogenic protein to study the effects of these factors on spread patterns and their convergence. Results revealed that patterns of spread follow rules depending on the parameters. In simulations with higher diffusion speeds the network is destroyed faster, spread patterns arising from different seed locations converge earlier and hub neurons are more vulnerable and reach cellular death early, whereas neurons close to the seed are less vulnerable. Our findings are consistent with the hypothesis that atrophy spread patterns are related to protein characteristics and neural network connectivity: the concept of “molecular nexopathies”. In future work we will increase the biological plausibility of our model and upscale our model to in vitro cell circuits, and to the full brain, combined with MR and PET imaging datasets.

P428 Regulation of synaptic growth by Rab8, IK2/TBK1 and AKT, modifiers of frontotemporal dementia S. Sweeney1, R. West1 1 University of York, Department of Biology, York, Great Britain We previously identified mutations in the small GTPase Rab8 acting as potent enhancers of a Drosophila model of Frontotemporal Dementia. When examined at the larval neuromuscular junction synapse, Rab8 mutants showed significant perturbations to normal synaptic growth and function mediated by the JNK scaffold protein ‘plenty-of-SH3s’ (POSH). The mechanism by which Rab8 mediates POSH accumulation is currently unknown. We reveal novel roles and a pathway for IK2/TBK1 and AKT, known modulators of the POSH signalling complex, in regulating synaptic growth and POSH accumulation in Rab8 mutants. In addition, we show that pharmacological activation of AKT can alleviate synaptic overgrowth and POSH accumulation in Rab8 mutants, suggesting a potential therapeutic target for neuronal disorders and neurodegenerative diseases. We have examined other Drosophila models of FTD for similar events and find a pathway described by Rab8, IK2/TBK1, POSH and AKT in other forms of FTD

Pathogenic proteins accumulate in many neurodegenerative diseases and brain imaging has revealed atrophy spread patterns © 2016 The Authors Journal of Neurochemistry © 2016 International Society for Neurochemistry J. Neurochem. (Suppl. 1) (2016), 222--428

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Poster Session III: Mechanisms of cell death

P429 The C9ORF72 repeat expansion induces apoptosis by the DNA damage response (DDR) J. Atkin1 1 Macquarie University, Sydney, Australia Hexanucleotide (GGGGCC) repeat expansions in a noncoding region of C9ORF72 are the major cause of familial FTD and ALS worldwide. The C9ORF72 repeat expansion undergoes repeatassociated non-ATG (RAN) translation on both sense and antisense strands, resulting in expression of dipeptide repeat proteins (DRPs), including polyGP, polyPR and polyGR. Whilst it remains unclear how mutations in C9ORF72 lead to neurodegeneration in FTD and ALS, recently, nucleolar stress and R loop formation by the C9ORF72 repeat expansion were implicated as pathogenic mechanisms. Both of these events damage DNA and hence are a serious threat to genome integrity. DNA damage occurs in many forms, and the cell activates the DNA damage response (DDR) with the aim of repairing this damage. Whilst the DDR is initially protective, prolonged DDR triggers apoptosis, hence the DDR controls cellular viability. In cells expressing C9ORF72 codon-optimised poly(GP) 40, poly(GR)100 or poly(PR)100, we demonstrated significant upregulation of the most widely used marker of DNA damage: phosphorylated histone 2AX (c-H2AX), compared to control cells, thus implying that the DRPs rather than RNA trigger DNA damage. These findings were confirmed by examining motor neurons from lumbar spinal cords of C9ORF72-positive ALS patients: significant upregulation of c-H2AX, phosphorylated ATM, cleaved PARP-1 and tumour suppressor p53-binding protein (53BP1) were detected. Furthermore, overexpression of B23 inhibited activation of caspase3 in DRP-expressing cells, thus linking DNA damage to nucleolar stress and apoptosis. This study therefore demonstrates that DNA damage is activated by the C9ORF72 repeat expansion in FTD and ALS.

P430 Prion-like properties of fragmented a-synuclein fibrils A. Tarutani1,2, G. Suzuki1, A. Shimozawa1,2, T. Nonaka1, S.-I. Hisanaga2, M. Hasegawa1 1 Tokyo Metropolitan Institute of Medical Science, Dementia and Higher Brain Function, Tokyo, Japan 2 Tokyo Metropolitan University, Biological Science, Tokyo, Japan The depositions of abnormal proteins in neuronal and glial cells are the defining feature of many neurodegenerative diseases. The localization and spreading of the pathologies are shown to correlate with selective neurodegeneration. Recent experimental data support the concept that structurally changed abnormal proteins convert normal proteins into an abnormal form and spread to neighboring cells in a prion-like manner. This prion-like conversion may account for not only the onset but also the progression of diseases. However, it has not been characterized yet what kind of abnormal proteins efficiently function as seeds induce the pathologies and propagation. In this study, we tried to determine the most pathogenic species of asynuclein, the main component of Lewy bodies and Lewy neurites observed in a-synucleinopathies, using several experimental models of the prion-like propagation. We prepared soluble and insoluble asynuclein in various conditions and examined their seeding properties in vitro, cellular and mouse models. We also characterized these a-synuclein species by electron microscopy and thioflavin

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fluorescence assays, and found that fragmented beta-sheet rich fibrous structures of a-synuclein efficiently induced the accumulations of phosphorylated a-synuclein, the hallmark lesions of asynucleinopathies, in cultured cells and mice. These results indicate the possibility that breaking into short fragments of once elongated fibrils in vivo enhance the seeding activity in the prion-like mechanism.

P431 Loss-of progranulin leads to early cell type-specific changes in lysosomes of Progranulin knockout mice J. Go¨tzl1, A.-V. Colombo2, F. Mazaheri2, S. Smith3, K. Fellerer1, O. Butovsky3, S. Tahirovic2, A. Capell1, C. Haass1,2,4 1 Biomedical Center, Biochemistry, Ludwig-Maximilians University, Munich, Germany 2 German Center for Neurodegenerative Diseases-Munich DZNE, Munich, Germany 3 Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA 4 SyNergy –Munich Cluster for Systems Neurology, Munich, Germany Heterozygous loss-of-function mutations in the progranulin (GRN) gene result in GRN haploinsufficiency, which is a major cause for familial frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) -43 and ubiquitin-positive inclusions. Homozygous loss-of-function mutations in GRN lead to an adult variant of neuronal ceroid lipofuscinosis (NCL), which is associated with severe neurodegeneration. Brains of Grn knockout mice show some features of FTLD pathology such as pathological phosphorylation of TDP-43, but also an age dependent increase of lysosomal proteins and an accumulation of lipofuscin indicating lysosomal dysfunction. We showed previously (G€ otzl et al., Acta Neuropathol. 2014, 127(6):845-60) that the levels of the lysosomal membrane protein TMEM106B, a risk factor for FTLD-TDP associated with GRN mutations, are increased among other lysosomal proteins such as cathepsin D, the transmembrane protein LAMP1, and saposin D, a disease signifying storage component in NCL patients. The accumulation of lysosomal proteins in Grn knockout mice and two GRN NCL cases suggests that GRN may play a crucial role in the integrity and function of lysosomes in brain tissue. We have now investigated, which cells in the brain contribute to the observed increase of lysosomal proteins in brains of Grn knockout mice. While LAMP1 is selectively increased in microglia cells, saposin D accumulated in a cell type-independent manner. Microglia cells are the main source of GRN in the brain, thus cell autonomous effects would be expected. To identify potential changes in microglia function and activity, we compared their homeostatic RNA signature in the presence and absence of GRN. Our data suggest that glial and neuronal cells differently contribute to the lysosomal phenotype in Grn knockout mice brains.



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P434

Role of Trem2 in Neurodegeneration: A systems biology approach F. Mazaheri1, G. Kleinberger1, A. Daria1, G. Werner1, S. Tahirovic1, D. Tr€umbach2, S. Bultmann3, O. Butovsky4, C. Haass1,3 1 DZNE, Munich, Germany 2 Helmholz, Munich, Germany 3 LMU, Munich, Germany 4 Harvard Medical school, Munich, USA

Characterization of the expression and effects of C9ORF72 in cell-based models and human brain S. Leskel€ a1, V. Juutilainen1, M. Takalo1,2, M. Marttinen2, H. Soininen3,4, M. Hiltunen3,2, A. Remes3,4, A. Haapasalo1,3 1 University of Eastern Finland, Neurobiology, A. I. Virtanen Insititute, Kuopio, Finland 2 University of Eastern Finland, Biomedicine, Kuopio, Finland 3 Kuopio University Hospital, NeuroCenter, Neurology, Kuopio, Finland 4 University of Eastern Finland, Institute of Clinical Medicine – Neurology, Kuopio, Finland

The Triggering Receptor Expressed on Myeloid cells 2 (Trem2) is a type-I transmembrane glycoprotein expressed in brain exclusively within microglia. Recently, Trem2 has been reported as a risk factor for several neurodegenerative diseases including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Trem2 missense mutations lead to its reduced maturation and impaired cell surface transport. Trem2 is required for the phagocytic capacity of microglia cells and apparently affects inflammatory responses. However, how exactly the intracellular signaling pathways downstream of Trem2 modulate microglial functions during neurodegeneration, and influence their inflammatory status remains unknown. To address this issue, we took a systems biological approach and determined the gene expression signature in wildtype and Trem2 knockout murine microglia in vivo. Our results indicate an important role for Trem2 in impairment of microglial homeostatic and revealed novel functions of Trem2 in microglial cytokine response and chemotaxis.

P433 Disease model for GRN-linked FTLD using patient- and engineered stem cells J. Terryn1,2,3, P. Van Damme2,3, C. Verfaillie1 1 Stem Cell Institute Leuven, KU Leuven, Development and Regeneration, Leuven, Belgium 2 University Hospitals Leuven, Neurology, Leuven, Belgium 3 VIB Vesalius Research Center, KU Leuven, Neuroscience, Leuven, Belgium The use of patient derived stem cells provides a unique opportunity to study the mechanisms underlying neurodegeneration. Additionally, stem cell derived disease models can easily be adapted for large scale drug screening. We focus on Frontotemporal lobar degeneration (FTLD) mediated by progranulin haploinsufficiency. Provoked by the great clinical heterogeneity seen in these patients, we sought to study the specific contribution of the progranulin mutation versus its genetic background and disease modifiers. We generated multiple patient derived iPSC lines and seamlessly inserted the granulin gene mutation (IVS1 + 5G>C) into a control iPSC line and embryonic stem cell line. Genome engineering was performed using TALE nucleases and the Piggybac transposon system. Stem cells were then differentiated into cortical neurons using published methods (Shi et al. Nature protocols 2012; 7 18361846) (Espuny-Camacho et al. Neuron 2013; 77 440–456). Functional characterization is ongoing with the aim to identify robust disease phenotypes and to prove the causal relationship with progranulin haploinsufficiency.

C9ORF72 hexanucleotide repeat expansion is the major genetic cause of frontotemporal dementia (FTD) via mechanisms possibly involving haploinsufficiency and aberrant RNA metabolism and protein translation. Also impaired protein degradation and neuroinflammation may contribute to neurodegeneration in FTD. Biological functions of C9orf72 proteins themselves are not well known, but may relate to intracellular protein trafficking. Here, we have examined expression and effects of C9ORF72 in cell-based models and human brain. We observed that the levels of ubiquilin-1, a protein regulating protein trafficking and degradation, significantly decreased in neuronal cells overexpressing C9orf72 protein isoform A but not B. The levels of TDP-43 or FUS were unchanged. In human frontal cortex, ubiquilin-1 protein levels were lower in C9ORF72 expansion carriers as compared to non-carriers, while the levels of TDP-43 and FUS remained unaltered. As detected by a commercially available antibody, there were no significant differences in C9orf72 protein isoform levels in expansion carriers vs. non-carries. However, C9ORF72 mRNA levels decreased in relation to advancing neurofibrillary pathology in human temporal cortex, suggesting decreased C9ORF72 expression upon increasing neurodegeneration. In co-culture of mouse neurons and microglial cells under neuroinflammation, overexpression of C9orf72 isoforms A or B led to significantly decreased TNF-a levels, but this did not correlate with diminished neuronal loss. Moreover, the levels of both C9orf72 isoforms were observed to decrease upon neuroinflammation. Collectively, these studies provide novel data on the expression and biological effects of C9orf72 protein isoforms.

P435 Expression and function of frontotemporal dementia gene C9ORF72 in neuronal cells S. Leskela¨1, M. Takalo1,2, H. Soininen3,4, A. Remes3,4, M. Hiltunen2,3, A. Haapasalo1,3 1 University of Eastern Finland, Neurobiology, A.I. Virtanen Institute, Kuopio, Finland 2 University of Eastern Finland, Institute of Biomedicine, Kuopio, Finland 3 Kuopio University Hospital, NeuroCenter, Neurology, Kuopio, Finland 4 University of Eastern Finland, Institute of Clinical MedicineNeurology, Kuopio, Finland The second most common cause of dementia within the workingage population is frontotemporal dementia (FTD). Molecular pathogenesis of FTD is suggested to involve impairment of protein degradation pathways, including the proteasome, leading to formation of intracellular inclusions containing e.g. TDP-43, FUS or


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ubiquilin proteins. Here, we have studied the expression and function of C9ORF72, which is the major genetic contributor of FTD and the motor neuron disease amyotrophic lateral sclerosis (ALS), by utilizing overexpression of C9orf72 protein isoforms A and B and induction of proteasomal stress by lactacystin in SHSY5Y human neuroblastoma cells. The levels of both isoforms significantly increased after proteasomal inhibition, suggesting that C9orf72 protein levels are regulated by proteasomal degradation. There were no signs of C9orf72 aggregation in the cells. Overexpression of isoform A specifically decreased the levels of endogenous ubiquilin-1, a protein associated with the ubiquitin-proteasome system, in SH-SY5Y cells. Moreover, fluorescence microscopy suggested that the isoforms A and B display differential subcellular localization. These results imply the possibility that the two isoforms have a different interactome and function. A recent report suggested that C9orf72 may regulate endosomal trafficking of TrkB receptor, which regulates cell survival signaling as well as mechanisms of memory formation. Our preliminary examinations indicate differences in TrkB signaling pathway in SH-SY5Y cells overexpressing isoform A. Future studies will provide further insights on the physiological and pathophysiological functions of C9ORF72.

P436 Modeling frontotemporal lobar degeneration using patient-specific iPSCs and iPSC-derived cortical neurons J. Japtok1, A. Pal1, B. Kretner1, V. Zimyanin1, X. Lojewski1, M. Naumann1, J. Sterneckert2, T. M. Boeckers3, A. Storch4, A. Hermann1 1 Technical University Dresden, Neurology, Dresden, Germany 2 Center for Regenerative Therapies Dresden CRTD, Dresden, Germany 3 University of Ulm, Institute of Anatomy and Cell Biology, Ulm, Germany 4 University of Rostock, Neurology, Rostock, Germany Frontotemporal lobar degeneration (FTLD) and motor neuron diseases are nowadays considered as a two tips of a common disease spectrum. Both are considered as aggregate prone diseases with spreading of disease pathology during disease progression. We therefore develop human induced pluripotent stem cell models of FTLD using different monogenetic form of the disease including C9ORF72, TDP43, FUS mutants. We analyze patient-derived cortical neurons during different steps of cortical layer differentiation and maturation and compare these to hindbrain/spinal neuronal phenotypes. We found typicall hallmarks of neuropathology including aggregates formation and neurodegeneration. Furthermore, we are investigating axonal transport impairment of human neurons using live cell imaging approaches. By this we develop a platform for drug target validation in human neurons already providing first putative future drug target for preventing aggregate formation and neurodegeneration. Our study thereby highlights the value and usefulness of patient-derived cell models in FUS-ALS and the importance to study pathophysiology in cell types specifically affected in disease. Acknowledgement: The work was supported in part by the Helmholtz Virtual Institute “RNA dysmetabolism in ALS and FTD (VI-510)” to A.H., T.M.B. and A.S., and the NOMIS foundation to A.H.

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P437 Using induced pluripotent stem cells to model C9orf72linked Frontotemporal Dementia E. Preza1, M. Zhang2, E. Rogaeva2, A. Isaacs3, M. Rossor4, J. Hardy1, S. Wray1 1 UCL Institute of Neurology, Department of Molecular Neuroscience, London, Great Britain 2 Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada 3 UCL Institute of Neurology, Department of Neurodegenerative Disease, London, Great Britain 4 Dementia Research Centre, National Hospital for Neurology and Neurosurgery, London, Great Britain An expanded GGGGCC intronic repeat in C9orf72 is the most common genetic cause of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). Recent studies support both toxic gain and loss of C9orf72 function mechanisms may be involved in disease pathogenesis. In order to model C9orf72-FTD, we have differentiated control and patient-derived induced pluripotent stem cells (iPSCs) into cortical neurons using a dual SMAD inhibition protocol followed by an extended period of in vitro neurogenesis. Cortical identity was confirmed by immunofluorescence to both deep layer (Tbr1) and upper layer (Satb2) markers. In order to dissect C9orf72 loss of function mechanisms, we have used CRISPR/Cas9 nucleases to generate C9orf72 knock-out iPSCs. Here we show the results of the analysis of temporal C9orf72 RNA and protein expression levels during cortical development in control and patient-derived neurons. Moreover, we have assessed the temporal methylation of the GGGGCC repeat expansion and the proximal CpG islands in patient and control-derived neurons. Our cohort of cell models will elucidate some aspects of C9orf72 biological function and its role in frontotemporal dementia pathogenesis.

P439 Impaired TDP-43 repression of nonconserved cryptic exons in Alzheimer’s disease L. Chen1 1 Johns Hopkins Hospital, Pathology, Baltimore, USA Initially implicated in the pathogenesis of amyotrophic lateral sclerosis/frontotemporal dementia (ALS-FTD), TDP-43 proteinopathy (Neumann et al., Science 2006) – abnormally phosphorylated in neuronal cytoplasmic inclusions with accompanying nuclear clearance – has been documented in 30-70% of subjects with Alzheimer’s disease (AD) neuropathology (Josephs et al., Acta Neuropathologica 2015). Moreover, TDP-43 pathology has been shown to be significantly associated with cognitive impairment and brain atrophy in AD (Josephs et al., Acta Neuropathologica 2014). Previously, we found that TDP-43 represses nonconserved cryptic exons, a function that is compromised in ALS-FTD (Ling et al., Science 2015). To determine whether loss of TDP-43 function occurs in AD exhibiting TDP-43 pathology, we screened postmortem brain tissues for the presence of cryptic exons. We examined TDP-43 pathology and screened for the incorporation of cryptic exons in twenty-one brains: nine with low-level, eight with high-level AD neuropathologic changes according to NIA-AA guidelines and 4 age matched controls. TDP-43 proteinopathy was confirmed by immunohistochemistry in four of eight cases with high-level AD changes and not identified in the



remaining high-level AD, low-level AD and control cases. Cryptic exon incorporation was identified in seven (87.5%) of eight highlevel AD brains, but not observed in low-level AD or control cases, suggesting that this splicing defect could potentially underlie the clinicopathological manifestations of AD. To our surprise, the presence of cryptic exons were detected not only in all four cases with TDP-43 proteinopathy, but also in three of four high-level AD brains with nuclear clearance without detectable TDP-43 cytoplasmic inclusions.

P440 Modelling dipeptide pathology in C9orf72-linked frontotemporal dementia S. Ryan1, J. Bennion Callister1, J. Sim1, S. Rollinson1, S. Pickering-Brown1 1 University of Manchester, Manchester, Great Britain A GGGGCC repeat expansion in a non-coding region of C9orf72 is the most common cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, the pathogenesis of FTD/ALS remains unclear, and there are no effective treatments available. Despite its location in a non-coding region of the gene, the C9orf72 expansion is translated to produce 5 different dipeptide repeat proteins (DPRs) in patient tissue. This is known as repeatassociated non-ATG translation (RAN-translation), a phenomenon which allows repetitive RNA transcripts to be translated in the absence of a start codon. Immunohistochemical studies have shown that these peptides form intraneuronal inclusions in patient tissue. Since the expansion is only translated in disease, dipeptides arising from it are completely novel and their impact on neuronal function is unclear. However, recent studies in cell culture and Drosophila models suggest that DPRs may contribute to neurodegeneration in C9orf72-linked FTD/ALS. We have used alternative codons in a randomised fashion to generate less repetitive DNA sequences coding for each DPR. This allows us to express each peptide in human cell culture separately, without production of the repetitive RNA sequences found in disease. Importantly, our constructs express the DPRs at physiologically-relevant repeat-lengths of over 1000 units, and several length-dependent differences have been noted in the distribution and toxicity of each DPR. In our models, alanine-rich DPRs were primarily cytoplasmic, with poly-GA forming inclusions comparable to those observed in patient tissue. Conversely, arginine-rich DPRs translocated to the nucleolus, causing signs of nucleolar stress. DPR expression altered the electrophysiological properties of differentiated SH-SY5Y cells in a repeat length-dependent manner, suggesting that longer dipeptides are more toxic to neuronal cell types. Our findings demonstrate the importance of using DPRs of physiological length when modelling DPR pathology, and provide a valuable tool to study the role of DPRs in FTD/ALS.

P441 Developmental regulation of tau splicing and phosphorylation is conserved in iPSC-neurons and disrupted by the 10 + 16 intronic mutation in MAPT T. Sposito1, E. Preza1, A. Alatza1, C. Mahoney1, T. Bushell2, M. Zagnoni3, T. Kunath4, N. Fox1, M. Rossor1, J. Hardy1, S. Wray1 1 University College London, Institute of Neurology, London, Great Britain 2 University of Strathclyde, Institute of Pharmacy and Biomedical Sciences, Glasgow, Great Britain 3 University of Strathclyde, Centre for Microsystems and Photonics, Glasgow, Great Britain 4 University of Edinburgh, MRC Centre for Regenerative Medicine, Edinburgh, Great Britain The alternative splicing of the tau gene, MAPT, generates six protein isoforms in the adult human central nervous system. The splicing of MAPT is developmentally regulated and dysregulated in disease. Mutations in MAPT that alter tau splicing cause frontotemporal dementia (FTD) with tau pathology, providing evidence for a causal link between altered tau splicing and disease. As many MAPT mutations are located within or around the alternatively spliced exon 10, it is important to have disease models that express and splice tau in a physiologically relevant way. To address this issue, we analyzed the expression and splicing of tau in induced pluripotent stem cell (iPSC)-derived cortical neurons from control patients and FTD patients with the 10 + 16 intronic mutation in MAPT. We show that developmental regulation of tau splicing is conserved in iPSCneurons, with predominantly fetal (0N3R) tau expression at early time points followed by a switch to the full complement of tau isoforms after extended in vitro culture of > 300 days. Tau is phosphorylated throughout early in vitro differentiation, in keeping with its high phosphorylation during development. The switch to expression of all tau isoforms is accompanied by a dramatic decrease in tau phosphorylation. Neurons from FTD patients with the 10 + 16 mutation in MAPT express 3R and 4R tau isoforms at all time points, with an excess of 4R tau, demonstrating that this mutation overrides the developmental regulation of exon 10 inclusion in our in vitro model. Further, tau phosphorylation persists in MAPT mutation neurons at extended time points. Together, these results suggest that iPSC-neurons represent a useful in vitro system to understand the role of tau in neuronal development and neurodegenerative disease, and highlight the importance of extended in vitro culture times to identify pathological changes to tau above the developmental background of the system. We are currently investigating other post-translational modifications to tau and other neuronal genes with developmentally regulated splicing.


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P442 CAGE expression profiling of the human iPS-derived neurons carrying mutations in the C9orf72 A. Dhingra1, E. Pyz1, J. Simon-Sanchez1,2, M. Castillo-Lizardo1, ols1,2,3, D. Timmann-Braun4, J. Prudlo5, Y. Theurer2, L. Sch€ 2,3 M. Synofzik , P. Rizzu1, P. Heutink1 1 German Center for Neurodegenerative Diseases, T€ ubingen, Germany 2 Hertie Institute for Clinical Brain Research, University of T€ ubingen, T€ubingen, Germany 3 Center for Neurology, University of T€ ubingen, T€ ubingen, Germany 4 Neurologische Universit€ atsklinik, Universit€ at Essen, Essen, Germany 5 Universit€atsmedizin Rostock Zentrum f€ ur Nervenheilkunde Klinik und Poliklinik f€ur Neurologie, Rostock, Germany A hexanucleotide (GGGGCC)n repeat expansion in the noncoding region of the C9orf72 gene is the most common pathogenic mutation in patients affected with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). The exact function of C9orf72 remains largely unknown. We have identified two point mutations in the C9orf72 gene. The first patient with clinical ALS carried (hg19) Chr9:27556694 C to A resulting in the following amino acid change P319Q, and the second patient carrying Chr9:27566700 G to A (R140Q) presents with ataxia but not ALS/FTD. The mutations are highly conserved and predicted to be damaging using insilico predictions (PolyPhen-2 and MutationTaster) but definite evidence for their pathogenicity is lacking. We therefore generated induced pluripotent stem cells (iPS) from both patients and characterized the lines on a molecular level. The iPS cells from the point mutations grew normally with morphology similar to hES cells and can be differentiatied into neurons with similar potential to control lines and as expected do not show RNA foci characteristic hallmarks of repeat expansion carriers. To investigate global transcriptional changes we prepared Cap Analysis of Gene Expression (CAGE) libraries from RNA of iPS and iPS differentiated neurons, derived from both point mutations, C9orf72 repeat expansion carriers and controls. CAGE libraries were, sequenced on Illumina HiSeq2500 at an average depth of 15 million reads. The resulting data was processed through an in-house CAGE pipeline. We observed a general transcriptional downregulation in the repeat expansion carriers when compared to controls. We are integrating the CAGE data from the repeat expansion carriers with the point mutations carrier cells with the aim to build gene network models using Ingenuity Pathway Analysis and will validate our findings of relevant pathways via perturbation of the key genes in our iPS lines.

P443 TDP-43 aggregation reflects its loss of function at the proteome level S. Prpar Mihevc1, E. Buratti2, M. Baralle2, F. E. Baralle2, B. Rogelj1,3 1 Jozef Stefan Institute, Department of Biotechnology, Ljubljana, Slovenia 2 International Centre for Genetic Engineering and Biotechnology ICGEB, Trieste, Italy 3 Biomedical Research Institute BRIS, Ljubljana, Slovenia TDP-43 protein plays an important role in regulating transcriptional repression, RNA metabolism, and gene splicing. Typically it

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is shuttled between the nucleus and cytoplasm to perform its functions, but abnormal cytoplasmic aggregation of TDP-43 has been associated with neurodegenerative diseases. Aggregation of TDP-43 is most probably the root cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). For the purpose of this study we selected a set of proteins that were misregulated following silencing of TDP-43 and analysed their expression in a TDP-43-aggregation model cell line HEK293 Flp-in Flag-TDP-43-12x-Q/N F4L. Following TDP-43 sequestration in insoluble aggregates, nuclear levels of HNRNPA3, EIF4A3, and POLDIP3b increased, whereas nuclear levels of PABPC1, DNMT3A, and POLDIP3a decreased, and quantities of cytoplasmic protein RANBP1 dropped. In addition, immunofluorescence signal intensity quantifications revealed increased nuclear expression of HNRNPL, YARS, and TIAL1, and downregulation of cytoplasmic DPCD. Furthermore, cytoplasmic levels of predominantly nuclear protein, ALYREF, increased. RANBP1 E5 and POLDIP3 E3 were spliced in SH-SY5Y and HEK Flp-in cells with normal TDP-43 levels, whereas when TDP-43 was silenced/aggregated the exons were not excised. This study shows that aggregation and sequestration of endogenous TDP-43 in HEK293 Flp-in Flag-TDP-43-12xQ/N F4L cell line leads to TDP-43 loss of function-like properties also at the proteome level. Further studies need to be conducted on these proteins in ALS/FTLD patient derived samples to elucidate the in vivo distribution.

P444 C9orf72 loss of function in mice produces FTD like behavioral deficits M. B. Lopez Herdoiza1, B. Wilmet2, S. Godart2, D. Roussel2, C. Le Duigou2, M. Frah2, J. Beal2, D. Bouteiller2, S. Dussaud2, G. Bruneteau2, I. La Ber2, S. Nicole2, A. Brice2, M. Latouche2 1 UPMC, Paris, France 2 ICM, EPHE, UMR1127, Paris, France The GGGGCC intronic repeat expansion within C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The precise mechanisms through which the C9orf72 mutation causes “c9FTD/ALS” have not yet been elucidated, but several hypotheses have been proposed. The mutation may cause a toxic gain of function either through a bidirectional transcribed RNA from the expansion that aggregates and captures RNA-binding proteins; or through the translation of small aggregation peptides that are produced by repeat-associated non-ATG (RAN) translation. Both the RNA foci and the c9RAN proteins are present in brains of patients carrying the C9orf72 mutation and are suspected to cause or participate in the neurotoxicity. Furthermore, the loss of one to three of alternatively spliced C9orf72 transcripts and a decreased protein level in the frontal cortex have been observed in patients, implying a loss of function mechanism. To investigate the role of this partial loss of function in ALS and FTD disease pathogenesis, we have generated C9orf72 knock-down mice by targeting the RNA mouse homologous of C9orf72. We found that by knocking down C9orf72 intrinsically, mice develop cognitive deficits in social interaction and depression like behavior, which relate to FTD-like anomalies. They have conserved spatial memory and normal motility through all their lifespan. When looking for ALS-like abnormalities, we found that C9orf72 knock-down mice develop lessening of strength that appears at a later age and that is maintained without aggravation.



They do not present axonal loss or signs of muscle atrophy and/or wasting. Further analysis showed that C9orf72 knock-down mice present neuromuscular junction deficits at an older age that aggravate with aging. These findings suggest that C9orf72 partial loss of function leads disease pathogenicity course to a more likely FTD-like phenotype, and that gain of function mechanisms as RNA foci and/or c9RAN proteins may be needed to trigger motor neuron disease and massive neurodegeneration.

P445 Intranuclear (GGGGCC)n RNA foci induce formation of paraspeckle-like structures 1 , Y.-B. Lee2, J. Pohleven2, M. Modic3, S. Darovic1, M. Stalekar M. Fonovic1, B. Turk1, M. Drukker3, C. Shaw3, B. Rogelj1 1 Jozef Stefan Instiute, Ljubljana, Slovenia 2 King’s College London, London, Slovenia 3 Helmholtz Center Munich, Munich, Great Britain Expansion of GGGGCC (G4C2) hexanucleotide repeat in the gene C9orf72 is the most common pathogenic mutation in families with autosomal dominant FTD, FTD/ALS and ALS. Normally, there are < 10 repeats in healthy individuals, however, in C9orf72 associated cases hundreds or thousands of repeats can be detected. The expanded repeat is transcribed and can form intranuclear RNA foci. Here we show that the paraspeckle proteins SFPQ, NONO and PSPC1 bind to (G4C2)n RNA in vitro and colocalize with intranuclear RNA foci in cells transfected with expanded repeats. Paraspeckles are nuclear structures that function in nuclear retention of adenosine to inosine edited RNA. They are formed on a backbone of the long non-coding RNA NEAT1. The presence of RNA foci increased the number of SFPQ stained subnuclear bodies, however only a small fraction of G4C2 RNA foci colocalized with NEAT1. Our results suggest that (G4C2)n RNA may replace NEAT1 and lead to formation of paraspecle-like structures, which could cause an increase in the nuclear retention of edited RNA. We have identified an additional mechanism through which hexanucleotide expansion may lead to neurodegeneration.

P446 Early markers of tau pathology in young Tau.P301L mice: synaptic plasticity, cognition and neuronal synchrony A. Latif-Hernandez1, A. Schreurs1, T. Ahmed1, D. Shah2, F. Van Leuven3, A. Van der Linden2, R. D’Hooge1, D. Balschun1 1 KU Leuven, Laboratory of Biological Psychology, Brain and Cognition, Leuven, Belgium 2 University of Antwerp, Bio-Imaging lab, Department of Biomedical Sciences, Antwerp, Belgium 3 KU Leuven, Experimental Genetics Group - LEGTEGG, Department of Human Genetics, Leuven, Belgium Fronto-temporal lobe dementia (FTLD) comprises a complex set of neurodegenerative disorders, characterized not only by memory deficits but also executive dysfunctions in the early stages of the disease. Hyperphosphorylation of protein Tau is a primary pathogenic mechanism in sub-types of FTLD leading to the accumulation and distribution of neurofibrillar threads and tangles (NFTs) in prefrontal cortex (PFC) and hippocampus (HC). The synaptotoxic effects of protein Tau are proposed to alter neuronal

functions before NFTs can be detected, ultimately leading to cognitive dysfunction and brain circuit-disconnections. We investigated the Tau.P301L mouse model (Terwel et al., 2008) that recapitulate tau pathology and examined the pathophysiological consequences of human Tau at synaptic, behavioral and brain connectivity levels in the early stages of disease. Because FTLD is in first instance a synaptopathy, we measured synaptic plasticity using long-term potentiation (LTP) and depression (LTD) as sensitive and most informative readouts. In addition, executive (dys)functioning was reliably assed in touchscreen boxes, which depends on nearly identical features as in human studies. Finally, the temporal correlation of blood-oxygenation-level-dependent (BOLD) fluctuations between spatially distinct areas allowed us to study impairments in functional connectivity (FC) in pre-NFT Tau.P301L transgenic mice. Our results demonstrate that PFC and HC are brain regions that are most sensitive to Tau pathology and severely affected before NFTs begin to accumulate. We observed defective (1) basal synaptic transmission in the dentate gyrus, (2) LTP in PFC and CA1 region, (3) LTD in CA1, (4) response inhibition and discrimination learning abilities and (5) reduced functional connectivity in CA1 in transgenic mice compared to wild-type control mice. In conclusion, our study provides insight into early alterations in synaptic plasticity, cognitive abilities and brain functional connectivity of Tau.P301L mice, which is proposed to be crucial for research on therapeutic strategies that target the earliest stages of this disease.

P447 A biphasic social dominance phenotype in progranulininsufficient mice is associated With abnormal cell signaling and neuronal morphology in the amygdala and prefrontal cortex A. Arrant1, A. Filiano1, B. Warmus1, A. Hall1, E. Roberson1 1 University of Alabama at Birmingham, Neurology, Neurobiology, Birmingham, AL, USA Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia (FTD). Progranulin-insufficient mice, both Grn+/- and Grn-/-, are used as models of FTD due to GRN mutations and develop abnormal social behavior beginning around 6 months of age. Grn+/ mice have increased social dominance in the tube test at 6 months, though this phenotype has not been reported in Grn/ mice. In this study, we further investigated how the social dominance phenotype of progranulin-insufficient mice and the mechanisms underlying this phenotype. We observed biphasic social dominance abnormalities in Grn+/ mice: at 6-8 months, Grn+/ mice were more socially dominant than wild-type littermates, while after 9 months of age, Grn+/ mice were less dominant. When the tube test was used to examine within-cage dominance hierarchies in mice older than 9 months, Grn+/ mice were less dominant than wild-type or Grn/ cagemates, showing that this phenotype is manifest in more ethologically relevant testing conditions. In contrast, Grn/ mice did not exhibit abnormal social dominance, suggesting that progranulin haploinsufficiency has distinct effects from complete progranulin deficiency. To investigate the mechanism underlying this biphasic social dominance phenotype, we examined the amygdala and prefrontal cortex. We observed abnormal cellular signaling and dendritic arbors in the amygdala of Grn+/ mice that was temporally associated with their transient dominant phenotype


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at around 6 months of age. Additionally, basal dendritic arbors of the prelimbic cortex were reduced in 9-16 month-old Grn+/ mice, providing a potential mechanism for the low dominance phenotype of older mice. These data demonstrate a progressive change in social dominance in Grn+/ mice that is associated with biochemical and cellular abnormalities in brain regions affected in FTD.

P448 Production, detection, and characterization of proganulin (PGRN) and granulins (GRNs) C. Holler1, G. Taylor1, T. Kukar1,2,3 1 Emory University, Pharmacology, Atlanta, USA 2 Emory University, Neurology, Atlanta, USA 3 Emory University, Center for Neurodegenerative Disease, Atlanta, USA Mutations in the GRN gene, which encodes the progranulin (PGRN) protein, are a common cause of frontotemporal lobar degeneration (FTLD). The vast majority of FTLD linked GRNmutations lead to haploinsufficiency of PGRN. PGRN is a secreted growth factor that appears important for neuronal health and survival during aging, however the mechanism is unclear. PGRN is composed of 7.5 repeating domains termed granulins (paragranulin

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and GRNs 1-7) that are joined by divergent linker regions. Each granulin domain is defined by a consensus cysteine-rich sequence. Once secreted, PGRN can be cleaved into ~6 kDa GRNs by a variety of extracellular proteases. Intriguingly, multiple, and in some cases opposing, activities have been attributed to PGRN and GRNs. For example, PGRN has anti-inflammatory properties and induces cell growth, while GRNs are pro-inflammatory and inhibit cell growth in some experimental systems. In vitro, PGRN and some GRNs increase neurite extension, neuronal survival, and neuronal differentiation, supporting a neurotrophic-like activity. However, the precise roles the various PGRN/GRNs species play in neuronal function and/or inflammation is unclear. In order to develop treatments for FTLD caused by GRN mutations it is critically important to understand the normal function of PGRN and GRNs in the brain and if the levels of these proteins are altered in disease. A major roadblock for the field has been lack of 1) recombinant purified PGRN and GRN fragments and 2) antibodies that detect and discriminate between full-length PGRN and the cleaved GRNs. To overcome this gap, we have developed a system to express and purify properly folded full length PGRN, paragranulin, and GRNs 17. We are using these valuable reagents to epitope map existing PGRN antibodies, develop novel domain specific antibodies, and ultimately dissect the functions of PGRN/GRNs in the central nervous system.


Poster Session III: Disease modulation P449 Drug screening for progranulin-deficient FTD J. J. Doyle1,2,3, C. Maios3, A. Bateman1,2, H. Bennett1,2, J. A. Parker3,4 1 Research Institute of the MUHC, Division of Endocrinology and Metabolism, Montreal, Canada 2 McGill University, Division of Experimental Medicine, Faculty of Medicine, Montreal, Canada 3 Centre de Recherche du CHUM, Axe Neurosciences, Montreal, Canada 4 Universite de Montreal, Departement de Neurosciences, Faculte de Medecine, Montreal, Canada Frontotemporal dementia cases due to progranulin deficiency account for 5-20% of all familial FTD cases. Although various treatments are used to manage symptoms, there are no drugs which can halt the progression of the disease. Current drug development pipelines are costly, and can take upwards of 15 years before new drugs are available for patient use. To circumvent this conventional approach, our lab has developed a novel, whole-animal drug screening platform using the roundworm Caenorhabditis elegans. Of their 19,000 genes, 80% of them are orthologues of human genes, including pgrn-1, the worm orthologue of the human GRN gene. When assessed in liquid media, pgrn-1 knockout worms present a motility defect, and so we screened over 4000 FDAapproved compounds to identify drugs which could correct this movement defect. In all, 35 compounds were identified as being able to best restore motility to pgrn-1 mutant worms. We then further tested these compounds against various phenotypes observed in pgrn-1 mutant worms for their ability to restore them to normal. The work presented here represents the first steps of a collaborative effort to move drugs from the bench to the clinics, although further work is needed to validate the molecular action of these compounds and their effects in other systems.

P450 Clinical evidence for disease anticipation in C9orf72 families S. Van Mossevelde1,2,3,4, S. Engelborghs2,3, I. Gijselinck1,2, J. De Bleecker5, J. van der Zee1,2, A. Sieben1,2,5, K. Sleegers1,2, R. Vandenberghe6,7, T. Van Langenhove1,2,4, J. Baets1,2,4, aumer1,2, O. Deryck4,8, P. Santens5, A. Ivanoiu9, C. Willems10, V. B€ V. D. B. Marleen1,2, K. Peeters1,2, M. Mattheijssens1,2, D. J. Peter1,2,4, P. Cras2,4, J.-J. Martin2,4, M. Cruts1,2, P. P. De Deyn2,3, C. Van Broeckhoven1,2 1 University of Antwerp, Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 2 University of Antwerp, Institute Born-Bunge, Antwerp, Belgium 3 Hospital Network Antwerp ZNA Middelheim and Hoge Beuken, Department of Neurology and Memory Clinic, Antwerp, Belgium 4 Antwerp University Hospital UZA, Department of Neurology, Edegem, Belgium 5 University of Ghent, Department of Neurology, Ghent, Belgium

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KU Leuven, Department of Neurosciences, Leuven, Belgium University Hospitals Leuven, Department of Neurology, Leuven, Belgium 8 General Hospital Sint-Jan Brugge-Oostende, Department of Neurology, Bruges, Belgium 9 Saint-Luc University Hospital and Institute of Neuroscience, Universite Catholique de Louvain, Department of Neurology, Brussels, Belgium 10 Jessa Hospital, Department of Neurology, Hasselt, Belgium 7

Patients carrying a C9orf72 repeat expansion have highly variable onset ages suggesting the presence of modifying factors. We have provided molecular evidence for the association of the G4C2 repeat size with onset age, methylation state of the 50 flanking CpG island and transcriptional downregulation. In some C9orf72 parent-child transmissions, we observed increasing expansion sizes or methylation states of the 50 CpG island and earlier onset ages, in accordance with anticipation. Presently, it is not feasible to measure precisely the size of expanded C9orf72 repeats when sized above 80 repeat units, which complicates the observation of disease anticipation in most of the C9orf72 parent-child transmissions. We aimed to provide additional evidence for disease anticipation based on clinical data. We examined ages at onset and at death, disease durations and clinical phenotypes in parent-offspring pairs and successive generations of 46 families with frontotemporal dementia and/or amyotrophic lateral sclerosis caused by a C9orf72 repeat expansion. The onset age differences in parent-child pairs suggested both repeat expansions and retractions though the latter were far less frequent (23% versus 70%). Patients in the youngest generation had an earlier onset age (p < 0.001) and earlier age at death (p = 0.041) than patients in the second generation. In parent-offspring pairs, a significantly earlier onset age of on average 7.2 years and a significantly earlier age at death of on average 5.7 years was calculated in the offspring in comparison with their respective parent. Disease duration was not significantly different between successive generations or between parents and their offspring, but patients with amyotrophic lateral sclerosis had a shorter disease duration than patients with pure dementia (p < 0.001). Furthermore, disease duration was inversely correlated with onset age (p < 0.001). The phenotype in the offspring was correlated with the phenotype in the parent (p = 0.016). In conclusion, our clinical data provided supportive evidence for the occurrence of disease anticipation in C9orf72 repeat expansion carriers with an earlier onset age in younger generations, but no increased disease severity. We did not observe a significant influence of gender of the transmitting parent on the occurrence of anticipation, although some observed trends need further investigation. Notably, a significant correlation was found between the clinical phenotype of the parent and that of the affected child suggesting that genetic factors might be involved in the phenotypic development of frontotemporal dementia or amyotrophic lateral sclerosis in C9orf72 repeat expansion carriers.


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Poster Session III: Disease modulation

P451 Intracerebroventricular infusion of streptozotocin alters brain neurochemistry: Embelin attenuates streptozotocininduced neurochemical alterations and cognitive impairment in rats R. Deshmukh1, R. Arora1 1 ISF College of Pharmacy, Pharmacology, Moga, India Intracerebroventricular (ICV) infusion of streptozotocin (STZ) has been reported to produce neuropathological alterations similar to that of AD. In recent years Embelin has been reported to be antioxidant and neuroprotective in experimental animals. The purpose of the current study was to investigate the effect of ICV STZ on hippocampal/cortical neurochemistry and its association with cognitive impairment. Further to identify neuroprotective mechanisms of embelin against STZ-induced cognitive dysfunction. STZ was infused ICV [bilaterally 3 mg/kg; 5 ll] on alternate days in Wistar rats. Following infusion animals were sacrificed on weekly intervals up to four weeks to know hippocampal neurochemical alterations. On the other hand, STZ infused rats were treated with embelin (2.5 and 5 mg/kg i.p.) for 2 weeks [day 8–21st day], i.e. 1 week following 1st STZ infusion in rats. The cognitive behavior was assessed using Morris water maze and object recognition and terminally cortical and hippocampal brain tissues were used to determine oxidative stress, neuroinflammatory cytokines and the alterations in monoamines, GABA and glutamate. STZ produced progressive alteration in hippocampal and cortical neurochemistry and the maximum alterations were observed following three weeks. STZ produced cognitive impairment, which was associated with elevation in oxidative stress, cytokine levels and disturbed pattern of hippocampal/cortical neurochemistry. Treatment with embelin improved cognitive behavior attenuated STZ-induced oxidative stress, neuroinflammation and restored the levels of cortical/ hippocampal neurotransmitters in rats. In conclusion, STZ -induced alterations in hippocampal and cortical neurochemistry may contribute to the development of cognitive dysfunction in rats. Further, embelin through its antioxidant and antiinfllammatory actions and its neuromodulatory actions may help to improve cognitive functions in STZ infused rats. Thus our results indicate the therapeutic potential of embelin in neurodegenerative disorders associated with cognitive dysfunction.

P452 The role of FTD/ALS assciated protein, TDP-43, in neurite and synapse health and function R. Atkinson1, J. Leung1, C. Fernandez-Martos1, J. Atkin2, J. Vickers1, A. King1 1 University of Tasmania, Wicking Centre, Hobart, Australia 2 Macquarie University, Department of Biomedical Sciences, Sydney, Australia A number of proteins have been identified that are pathologically or genetically associated with FTD and ALS, including TDP-43. These diseases are characterized by significant neurite defects, including cytoskeletal pathology. The way in which TDP-43 is involved in the degeneration of neurons in disease is not yet well understood, however there is accumulating evidence that it is involved in neurite outgrowth and maintenance by transporting cargo in neurites. Our initial studies have investigated the normal role of TDP-43 showing that protein levels are upregulated during

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neurite outgrowth and synapse formation. Using lentiviruses to overexpress wild type (WT) TDP-43 in primary rat cortical neurons, preliminary data shows that overexpression results in an increased number of primary neurites when compared to an empty vector control. Current studies in this in vitro model will further investigate cytoskeletal alterations caused by overexpression of TDP-43. In order to study the role of pathogenic TDP-43 in vivo we are developing a model using the visual system. Intraocular injection of WT TDP-43 AAV2 vectors using C57Bl/6 mice resulted in transduction of approximately 40% of retinal ganglion cells (RGCs) with no significant effect on vision at 1 month as tested with the optomotor response. Our current studies involve determining whether TDP-43 overexpression causes aggregation in RGCs as well as the downstream effects on the axon, in the optic nerve and the synapses of optic target areas. These studies will help us to gain insight into the effect of disease-associated proteins and determine potential avenues for therapeutic intervention for axonal protection.

P453 The Belgian GRN founder family anno 2016: a textbook example of phenotype heterogeneity E. Wauters1,2, S. Van Mossevelde1,2, K. Sleegers1,2, I. Gijselinck1,2, S. Philtjens1,2, A. Sieben1,2, T. Van Langenhove1,2,3, S. Engelborghs2,4, M. Vandenbulcke5, M. Mattheijssens1,2, K. Peeters1,2, I. Cuijt1,2, J.-J. Martin2, P. Cras2,3, P. Santens6, R. Vandenberghe7,8, P. P. De Deyn2,4,9, J. van der Zee1,2, M. Cruts1,2, C. Van Broeckhoven1,2 1 University of Antwerp, Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 3 Department of Neurology, Antwerp University Hospital, Edegem, Belgium 4 Department of Neurology and Memory Clinic, Hospital Network Antwerp, Middelheim and Hoge Beuken, Antwerp, Belgium 5 Department of Psychiatry and Memory Clinic, University Hospitals Leuven, Leuven, Belgium 6 Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium 7 Department of Neurology and Memory Clinic, University Hospitals Leuven, Leuven, Belgium 8 Laboratory for Cognitive Neurology, Department of Neurology, University of Leuven, Leuven, Belgium 9 Department of Neurology and Alzheimer Research Center, University Medical Center Groningen, Groningen, The Netherlands, Belgium The IVS1 + 5 G>C null mutation in the progranulin gene (GRN) exhibits a founder effect in the Belgian FTD population. We detected the mutation in 21 index patients in a cohort of 608 unrelated FTD patients (3.5%). Furthermore, we identified mutation carriers diagnosed with Alzheimer disease (AD) and Parkinson disease (PD). Since the identification of the mutation in 2006 the GRN founder family has been expanded to 29 branches spanning at least 7 generations. Biomaterials are available for 79 mutation carriers, 45 of whom were diagnosed with FTD (68.9%), AD (13.3%), PD (8.9%) or unspecified dementia (8.9%). Among the FTD patients, both the behavioral variant of FTD (51.6%) as well as primary progressive aphasia (38.7%) was observed. Brain pathology in 11 mutation carriers was compatible with a TDP proteinopathy type A. In several patients mild



AD-related pathology was identified, as well as Lewy body pathology in a patient presenting with a combination of FTD and PD. Variability in the onset age adds further to the observed phenotypic heterogeneity. The age at onset (AAO) ranged from 45 to 80 years, with a mean of 62.9 7.7 years (n = 76). The disease duration was 6.5 3.7 years on average and death occurred at 69.8 7.6 years (range 48–86 years (n = 69)). We investigated potential effects of the expression levels of the unaffected copy of GRN and did not detect a correlation between GRN serum levels and AAO. We observed an earlier AAO for patients who carried one intermediate allele (7–24 repeats) of the C9orf72 G4C2 repeat compared to patients homozygous for the short allele. We did not detect a significant effect on AAO of risk variations in GRN, SORT1, PSAP, TMEM106B, MAPT and APOE. We explored the possibility of double mutations as a disease modifier and identified one mutation carrier who carried both the pathogenic TARDBP p.G287S mutation as well as the GRN null mutation. The TARDBP mutation is present in only one branch of the family, indicating that other factors are responsible for the heterogeneity in AAO in the family. Such modifiers are targets that hold promises for disease-delaying therapies.

P454 Loss-of progranulin leads to a cell-autonomous lysosomal phenotype G. Werner1, K. Fellerer1, C. M. Lang1, C. Haass1,2,3, A. Capell1 1 Ludwig-Maximilians-University, Biomedical Center BMC, Biochemistry, Munich, Germany 2 Munich Cluster for Systems Neurology SyNergy, Munich, Germany 3 German Center for Neurodegenerative Diseases, DZNE, Munich, Germany Heterozygous loss-of-function mutations in the progranulin (GRN) gene result in GRN haploinsufficiency, which is, besides the C9orf72 repeat expansions, the major cause of familial frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) -43 positive inclusions. In GRN-associated FTLD, as in the majority of FTLD cases, pathological protein inclusions are also positive for ubiquitin and p62/sequestosome 1 indicating that they are targeted for degradation. The strongest evidence that GRN plays a key role in proteostasis was provided by the finding that the total loss of GRN results in neuronal ceroid lipofuscinosis, a lysosomal storage disease. Previously, we demonstrated that Grn / mice revealed in addition to some features of FTLD pathology an age dependent increase of lysosomal abnormalities in the brain. We detected an accumulation of saposin D, the subunit c of the mitochondrial ATP-synthase and an increase of lysosomal proteins. To investigate how GRN is involved in maintaining lysosomal integrity and protein degradation we immortalized MEF cell lines from wild type and Grn / mice. Grn / MEF cells recapitulate lysosomal abnormalities such as elevated cathepsin D and saposin D, suggesting a cell autonomous function of GRN. These cells might be used to screen drugs rescuing the lysosomal phenotype caused by GRN haploinsufficiency. In addition we used this system to decipher how TMEM106b, a risk factor for FTLD-TDP associated with GRN mutation carriers, is affecting the lysosomal integrity. Some genetic studies suggested a beneficial effect of TMEM106b reduction on the phenotype caused by GRN deficiency. Complete loss of TMEM106b expression in Grn / cells was achieved using the CRISPR technology. These cell lines were used

to investigate whether GRN loss-of-function phenotypes are affected by the reduction of TMEM106b levels. Further, we investigated whether pathological changes in TDP-43 cellular localization and phosphorylation occur. Our preliminary findings suggest a more severe GRN phenotype following TMEM106b reduction.

P455 Nature and nurture in modulating brain damage in presymptomatic monogenic FTD: results from the GENFI study E. Premi1, J. Rohrer2, M. Grassi3, J. van Swieten4, D. Galimberti5, C. Graff6, M. Masellis7, F. Tagliavini8, J. Rowe9, R. Laforce10, E. Finger11, G. Frisoni12, A. de Mendocßa13, S. Sorbi14, S. Gazzina1, M. Cosseddu1, S. Archetti15, R. Gasparotti16, M. Manes1, A. Padovani1, B. Borroni1 1 University of Brescia, Department of Neurology, Brescia, Italy 2 University College London, Dementia Research Centre, London, UK, Great Britain 3 University of Pavia, Department of Epidemiology and Statistics, Pavia, Italy 4 Erasmus Medical Center, Department of Neurology, Rotterdam, Netherlands 5 Department of Physiopathology and Transplantation, University of Milan, Fondazione C a Granda, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Policlinico, Neurology Unit, Milan, Italy 6 Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Department of Neurobiology, Huddinge, Sweden 7 LC Campbell Cognitive Neurology Research Unit, Department of Medicine, Division of Neurology, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada 8 IRCCS Istituto Neurologico Carlo Besta, Istituto Neurologico Carlo Besta, Milan, Italy 9 University of Cambridge, Department of Clinical Neurosciences, Cambridge, UK, Great Britain 10 H^ opital de l’Enfant-Jesus, and Faculte de Medecine, Universite Laval, Clinique Interdisciplinaire de Memoire, Departement des Sciences Neurologiques, Laval, QC, Canada 11 University of Western Ontario, London, ON, Department of Clinical Neurological Sciences, London, ON, Canada 12 IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy 13 Faculty of Medicine, University of Lisbon, Lisbon, Institute of Molecular Medicine, Lisbon, Portugal 14 University of Florence, Department of Neuroscience, Psychology, Drug Research and Child Health, Florence, Italy 15 Brescia Hospital, Brescia, Italy, Department of Laboratories, III Laboratory of Analysis, Brescia, Italy 16 University of Brescia, Neuroradiology Unit, Brescia, Italy The role of cognitive reserve in affecting brain damage in neurodegenerative dementias is well documented. Recently, the rule of cognitive reserve has been demonstrated even in monogenic FTD, such as in pre-symptomatic subjects. Along with environmental risk factors, it has been found that genetic background, i.e. TMEM106B polymorphism (rs1990622 T/C), was able to modify the age at


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disease onset and resting-state functional brain connectivity in presymptomatic subjects carrying GRN mutations. Aim of this study was to investigate the effect of environment (i.e., cognitive reserve as measured by years of education) and genetic background (i.e., TMEM106B polymorphism, rs1990622 T/ C) on the large GENFI cohort of pre-symptomatic mutation carriers. We considered 203 at-risk subjects carrying or not GRN, MAPT or C9orf72 mutations (Genetic Status, GS = 0 mutation negative, GS = 1 mutation positive). For each subject, MRI scan was analysed, considering grey matter (GM) density of Regions of Interest (ROIs) on those areas involved in FTD. TMEM rs1990622 T/C genotyping was carried out and years of education carefully recorded. By principal component analysis weighted by the graph structure of the selected ROIs, a composite measure of ROIs was computed. The effect of GS on GM and the role of possible modulators (TMEM 106B and education) was then determined by fitting a three-way interaction model. GS, education and TMEM106B polymorphism differently modulated GM. In particular, significant average GS-GM association (p = 0.001) and average education-GM association (p = 0.02) were observed. TMEM106B polymorphism did not influence GM directly, but modulated the relationship between GS and GM. Moreover, education might have an epigenetic effect on TMEM106B action (p = 0.039 for the three- way interaction GS*TMEM*Education). Progressive brain damage in pre-symptomatic subjects with monogenic disorder is affected by both genetic and environmental factors. These findings should be considered in defying expected age at onset and in future pharmacological and non pharmacological trials aimed at modifying disease course.

P456 New onset Autoimmune disease presenting in symptomatic Fronotemporal dementia patients Z. Miller1, N. Russek1, R. Ketelle1, A. Karydas1, L. Grinberg1, M. L. Gorno-Tempini1, B. Seeley1, B. Miller1 1 University of California San Francisco, San Francisco, USA Previously, we observed an increased amount of select nonthyroid autoimmune conditions in PGRN and semantic variant primary progressive aphasia (svPPA), and subsequently in C9 and frontotemporal dementia with motor neuron disease (FTD/MND) cohorts. As PGRN, svPPA, C9, and FTD/MND are all unified by underlying FTLD-TDP pathology, it suggests that autoimmune inflammation may be intrinsically linked to TDP pathophysiology. In all our prior detailed cases, autoimmune disease presented within a subject’s past medical history and no known individuals developed new onset autoimmune disease after having developed neurological symptoms. Following our initial reports, we observed two cases who developed new onset autoimmune disease following diagnoses of FTD. Case 1 is a PGRN mutation carrier who presented with progressive changes in behavior and executive function meeting criteria for bvFTD. During visits we identified intermittently resolving neutropenia. Work up initiated ultimately led to a diagnosis of autoimmune neutropenia, possibly representing a case of Good syndrome. Case 2 is an individual who possessed a history of psoriasis prior to developing progressive loss of word and concept meaning. Shortly after being diagnosed with svPPA this individual developed vitiligo. The coexistence of psoriasis and vitiligo is rare enough that the phenomenon alone is case reportable,

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as is the presentation of Good syndrome in case 1. Recent evidence from C9 knockouts suggests that separate and dual immunological and neurological mechanisms might be behind C90 s actions. Similarly, in our prior reports, despite the fact that all cases possessed autoimmune disease before receiving FTD diagnoses, we remained agnostic on the directionality of this relationship. These two individuals strongly support this more nuanced interaction, of a shared etiology to both autoimmunity and the neurodegenerative process, in FTLD-TDP spectrum diseases. Further, these two case highlight the importance of monitoring immune function in addition to neurologic progression in symptomatic FTLD-TDP cases.

P457 Lifecourse factors and cognitive reserve in FTD: education, bilingualism, and place of dwelling play a role S. Alladi1, T. H. Bak2, S. Mekala3, D. Gollahalli3, B. Surampudi4, V. Duggirala5, J. R. Chaudhuri6, S. Kaul3 1 National Institute of Mental Health and Neurosciences, Neurology, Bengaluru, India 2 University of Edinburgh, Centre for Cognitive Ageing and Cognitive Epidemiology CCACE, Edinburgh, Great Britain 3 Nizam’s Institute of Medical Sciences, Neurology, Hyderabad, India 4 IIIT, Cognitive Science Laboratory, Hyderabad, India 5 Osmania University, Linguistics, Hyderabad, India 6 Yashoda Hospitals, Neurology, Hyderabad, India Emerging evidence suggests that several lifecourse factors influence clinical expression of dementia. Risk and protective factor studies have so far focussed on Alzheimer’s disease and limited evidence is available for their role in Frontotemporal dementia (FTD). The aim of the study was to evaluate the potential impact of a range of lifecourse factors including education, occupation, bilingualism and urban/rural dwelling on the age at onset of FTD and its subtypes. 193 subjects evaluated in a memory clinic in India underwent clinical evaluation, neuropsychological assessment and brain imaging. Diagnosis of FTD and its subtypes was made using FTLD consensus criteria. Higher levels of education (p = 0.044), bilingualism (p = 0.017) and urban dwelling (p = 0.042) were associated with a later age at onset of FTD. Among patients with behavioural variant FTD (n = 67), higher levels of education (p = 0.043), bilingualism (p = 0.024) and urban dwelling (p = 0.032) were associated with a later age at onset, while there was no association between any of these factors and language variants of FTD (progressive nonfluent aphasia and semantic dementia, n = 62) and FTD syndromes with predominantly motor manifestations (Progressive Supranuclear Palsy, Corticobasal Degeneration and FTD-Motor neuron disease, n = 64). Univariate general linear model showed that bilingualism was the only factor independently associated with age at onset of bvFTD (p = 0.002). Our study adds to the body of evidence demonstrating a complex relationship between lifetime experiences and clinical expression of FTD. The differential role for individual factors such as bilingualism and education is relevant for understanding mechanisms underlying the concept of cognitive reserve in dementia.



P458

P459

TDP-43 and FUS are exported from the nucleus independent of Exportin-1/CRM1 H. Ederle1, D. Dormann1 1 Ludwig Maximilians University Munich, BioMedical Center, Department of Cell Biology, Planegg-Martinsried, Germany

Chronic consumption of Annona muricata juice triggers and aggravates cerebral tau pathology in wild-type and MAPT transgenic mice R. Rottscholl1, M. Lunow1, B. Jainsch1, G. Respondek1,2,3, osler1,2, H. Xu1,2, E. Bony4, J. Le Ven4, M. H€ ollerhage1,2,3, T. W. R€ V. Gu erineau5, I. Schmitz-Afonso5,6, P. Champy4, W. H. Oertel1, oglinger1,2,3 E. S. Yamada1,7, G. H€ 1 University of Marburg, Experimental Neurology, Marburg, Germany 2 German Center for Neurodegenerative Diseases, Dept. of Translational Neurodegeneration, Munich, Germany 3 Technical University Munich, Department of Neurology, Munich, Germany 4 BioCIS, Laboratoire de Pharmacognosie, Ch^ atenay-Malabry, France 5 Centre de recherche de Gif, Institut de Chimie des Substances Naturelles, Gif-sur-Yvette, France 6 Normandie Universite, COBRA, UMR 6014 et FR3038, MontSaint-Aignan Cedex, France 7 Jo~ ao de Barros Barreto University Hospital, Laboratory of Experimental Neuropathology-ICB, Belem, Brazil

TDP-43 (TAR DNA-binding protein of 43 kDa) and FUS (Fused in sarcoma) are nuclear DNA/RNA-binding proteins that play a key role in FTD (Frontotemporal dementia) and ALS (Amyotrophic lateral sclerosis). In ALS and FTD patients both proteins accumulate in insoluble cytoplasmic inclusions, and it has been shown that defects in nuclear import critically contribute to this pathology. As intranuclear inclusions of TDP-43 and FUS are also occasionally found in ALS and FTD patients, it can be speculated that defects in nuclear export of TDP-43 and FUS might also contribute to the pathogenesis of ALS and FTD. However, the mechanisms of nuclear export of TDP-43 and FUS are currently unknown. In this study we focus on the identification of the nuclear export pathways of TDP-43 and FUS. Using the interspecies heterokaryon assay as a nuclear export assay, we could show that both TDP-43 and FUS undergo rapid nucleocytoplasmic shuttling. Bioinformatic predictions identified two putative CRM1/Exportin 1-dependent nuclear export signals (NESs) in both proteins. However, neither mutagenesis of these predicted NESs nor the CRM1-specific inhibitor leptomycin B impaired nuclear export of TDP-43 and FUS, demonstrating that export of TDP-43 and FUS is CRM1independent. Furthermore, mutation or deletion of various functional domains of TDP-43 and FUS did not inhibit nuclear export of both proteins. Currently, we are using siRNA-mediated knockdown of different export factors (e.g. Exportins or mRNA export factors), in order to test which alternative export factors may mediate nuclear export of TDP-43 and FUS.

Both genetic and environmental factors have been identified in the pathogenesis of tauopathies. Mutations in MAPT encoding the microtubule-associated protein tauhave been identified in familial forms, whereas the plant-derived mitochondrial complex I inhibitor annonacin has been implicated in the pathogenesis of a sporadic tauopathy endemic in Guadeloupe. The present work studied the interaction of both factors in a realistic paradigm over a period of 12 months. Non-transgenic mice and mice overexpressing either human wild-type tau or R406W mutant tau received either regular drinking water or commercially available tropical fruit juice made of soursop (Annona muricata L.) as dietary source of neurotoxins. In this juice, we identified several Annonaceous acetogenins, mainly annonacin (16.2 mg/L), and 41 isoquinoline alkaloids (18.0 mg/L, mainly asimilobine and reticuline) by HPLC-MS. Behavioral testing showed reduced spontaneous locomotor activity and suggested altered fear- and depression-related behaviors in all three genotypes upon chronic juice consumption. We further found an increased number of neurons with phosphorylated tau in the somatodendritic compartment in several brain regions of R406W mice. Nontransgenic mice and mice overexpressing human wild-type tau also developed a juice-induced tauopathy, albeit to a much lower extent. All juice drinking mice exhibited a reduction in synaptophysin immunoreactivity, with unchanged GFAP and Iba1 signals. This study provides first experimental evidence that long-lasting exposition to an orally ingested environmental factor can trigger somatodendritic accumulation of hyperphosphorylated tau in mice expressing rodent or human wild-type tau, and can aggravate tau pathology in R406W-MAPT transgenic mice.


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Poster Session III: Treatment P460 TREM2-deficiency reduces the efficacy of immunotherapeutic amyloid clearance X. Xiang1,2, G. Werner1, B. Bohrmann3, F. Mazaheri4, A. Capell1, R. Feederle4,5,6, I. Knuesel3, G. Kleinberger1,6, C. Haass1,4,6 1 LMU, Biomedizinisches Centrum BMC, Stoffwechselbiochemie, Munich, Germany 2 Graduate School of Systemic Neuroscience, Ludwig- MaximiliansUniversity Munich, Munich, Germany 3 Roche Innovation Center Basel, Basel, Switzerland 4 German Center for Neurodegenerative Diseases DZNE Munich, Munich, Germany 5 Helmholtz Zentrum Munich, Munich, Germany 6 Munich Cluster for Systems Neurology SyNergy, Munich, Germany Immunotherapeutic approaches are currently the most advanced therapies for treatment of Alzheimer’s disease (AD). Antibodies raised to amyloid b-peptide (Ab) cross the blood-brain-barrier and bind to amyloid plaques in the brain of AD patients. Bound antibodies induce clearance of amyloid plaques by microglia via Fc receptor-mediated phagocytosis of Ab. Dysfunctions of microglia may play a pivotal role in AD pathogenesis and could result in reduced efficacy of antibody-mediated Ab clearance. Recently, heterozygous mutations in the triggering receptor expressed on myeloid cells 2 (Trem2), a microglial gene involved in phagocytosis, were genetically linked to late onset AD. Loss of TREM2 has been shown to reduce the ability of microglia to engulf Ab. We have now investigated if loss of TREM2 function affects the efficacy of immunotherapeutic approaches. We show that anti-Ab antibodies stimulate Ab uptake and amyloid plaque clearance in a dosedependent manner in the presence or absence of TREM2. However, TREM2-deficient N9 cells as well as macrophages and microglia derived from Trem2 knockout mice showed significantly reduced uptake of antibody bound Ab and as a consequence reduced clearance of amyloid plaques. Titration experiments revealed that reduced efficacy of amyloid plaque clearance and Ab uptake by Trem2 knockout cells can be compensated by elevating the concentration of therapeutic antibodies.

P461 Low-dose Lithium treatment for agitation in Frontotemporal dementia: A case series D. P. Devanand1, G. Pelton1, K. D’Antonio1, J. Strickler1, W. Kreisl2, J. Noble2, K. Marder2, A. Skomorowsky1, E. Huey3 1 Columbia University, Psychiatry, New York, NY, USA 2 Columbia University, Neurology, New York, NY, USA 3 Columbia University, Psychiatry and Neurology, New York, NY, USA Agitation is a common problem in FTD. Lithium is used to treat agitation in bipolar disorder. We report three patients with FTD presenting with agitation who were treated with low-dose (150 mg-600 mg daily) of lithium; all patients improved to varying degrees.

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CASE 1: A 77-year-old female with bv-FTD was referred for evaluation after staff at her assisted living facility threatened to eject her due to severe agitation and aggression. The patient was physically aggressive toward staff at the facility and was stealing food from other residents’ trays. At the time of evaluation, the patient was being treated with paroxetine 20 mg, risperidone 1.5 mg, and trazodone 200 mg. The patient started lithium 150 mg that was increased to 300 mg daily. Symptoms decreased and the patient was able to remain relatively stable in the assisted living facility. The last recorded Lithium level was 0.8 mmol/L. CASE 2: A 55-year-old male with sv-PPA was evaluated for worsening symptoms including agitation outbursts, skin picking, and frequent elopement attempts. At the time of evaluation, the patient was being treated with donepezil 23 mg, clonazepam 1 mg, duloxetine 60 mg, fluvoxamine 100 mg, venlafaxine 37.5 mg, and lisdexamfetamine 30 mg. Lithium was started and increased to a maximum dose of 1200 mg daily, which was reduced to 600 mg daily when the patient became sedated and developed a tremor. Behavioral symptoms improved on the 600 mg daily and all other psychiatric medications were tapered and discontinued. The patient remained on lithium until his death, two years after starting treatment. CASE 3: A 65-year-old male with FTD was admitted via a hospital emergency room for episodes of agitation with increasing severity. The patient was physically violent, experiencing auditory and visual hallucinations, and was ingesting inedible materials at the time of hospitalization for these symptoms. At admission he was being treated with chlorpromazine 250 mg, sertraline 100 mg, and haloperidol 2 mg daily. He was started on lithium 300 mg that was increased to a maximum dose of 450 mg daily. Behavioral disturbances improved significantly from the time of admission. The last serum lithium level was recorded as 0.40 mmol/L.

P462 Communication bridge: an internet-based person centered intervention for improving access to care and quality of life for individuals with dementia E. Rogalski1, M. Saxon1, M. Corden1, M.-M. Mesulam1, K. Borio1, B. Khayum1 1 Northwestern University, CNADC, Chicago, USA Individuals with aphasia symptoms due to neurodegenerative dementia [(e.g., primary progressive aphasia] are under-referred for speech-language therapy (SLT) services. The goal of this study was to bridge geographic limitations and improve access to care for individuals with dementia by providing person centered SLT via the Internet using a custom web-application. Participants received an Initial Evaluation, 8 person centered web-based SLT sessions, followed by 2- and 6-month Evaluations. Outcome measures assessed the feasibility of providing web-based SLT, strategy use and compliance, functional gains, and the duration of benefit using data from therapist reports, participant questionnaires and posttherapy interviews. Over forty participants from 21 states and Canada have been enrolled thus far, suggesting web-based therapy is


Poster Session III: Treatment

feasible and improves access to care. Functional gains were identified at 2-months and maintained at 6-months. Participants reported significantly higher levels of confidence in communication at the 2-month Evaluation and no significant decline at 6-months. Therapist reports suggested care-partner involvement is a critical and essential element for SLT. Internet-based speech-language therapy using a person centered intervention approach appears to provide an effective method for providing care to individuals with dementia and mild/moderate aphasia symptoms who have an engaged care-partner and prior familiarity with a computer.

P463 Improving speech production in progressive non-fluent aphasia: a study protocol C. Wilke1, M. Himmelbach2, M. Synofzik1 1 Hertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, T€ ubingen, Germany 2 Hertie Institute for Clinical Brain Research, Department of Cognitive Neurology, T€ ubingen, Germany Progressive non-fluent aphasia (PNFA) is a neurodegenerative disorder characterised by slow and effortful speech. Evidencebased therapies for PNFA do not exist. Recently, non-fluent aphasia in chronic stroke patients proved responsive to speech entrainment (Fridriksson et al. 2012, Brain). Patients were enabled to produce speech with increased fluency by mimicking audiovisual speech stimuli in real time. However, rehabilitation of nonfluent aphasia in PNFA - unlike in stroke - faces the challenges of continuing neurodegeneration and the broader range of accompanying neuropsychological impairments. The interventional pilot study proposed here intends to test the effect of speech entrainment on spontaneous connected speech in PNFA. Speech entrainment therapy is administered to PNFA patients over four consecutive weeks and compared to patients’ standard care during the preceding four weeks in an intra-individually controlled design. The intervention consists of (a) daily selfadministered speech entrainment with personalised dialogue scripts and (b) weekly face-to-face treatment sessions. Dialogue scripts are generated with recurrent conversation situations of individual relevance in mind. Video-recordings of these scripts serve as audio-visual speech stimuli for patients’ home-based speech entrainment practice. As the primary outcome, speech fluency is quantified by patients’ speech rate in unpaced speech samples which are elicited by the Amsterdam-Nijmegen Everyday Language Test. Secondary outcomes include measures of phonological errors, agrammatism, speech intelligibility and content understandability. MRI morphometry and tractography may identify cortical and white matter atrophy patterns predictive of speech entrainment efficacy in PNFA, while functional MRI may reveal neuronal substrates of speech entrainment. Therapeutic efficacy of speech entrainment in PNFA is expected to result in decreased cortical activation, particularly of left parietal areas.

P464 Interactive system design to maintain functionality in FTLD patients A. Martıńez1,2,3, D. Patino-Hernandez1, E. Garcıa-Cifuentes1, no1, C. A. Cano-Guti errez1,3, O. Ramırez Perez4, S. Suarez1, A. Pati~ 1,3 D. A. Chavarro-Carvajal 1 Pontificia Universidad Javeriana, Medicina, Bogot a, Colombia 2 Universite Lumiere Lyon 2, Laboratoire Dynamique du Langage, Lyon, France 3 Hospital Universitario de San Ignacio, Bogot a, Colombia 4 Pontificia Universidad Javeriana, Dise~ no, Bogot a, Colombia An assistive technology is mented to increase, maintain or extend functionality of individuals with disabilities. Medical literature does not describe previous adjustment of assistive technologies in patients with FTLD, however, these have proved to be useful and increase quality of life in patients with other dementias. An experimental longitudinal prospective pilot study was designed in order to generate assistive technologies for patients with FTLD. In order to accomplish a homogeneous sample n = 18 patients were included (two patients for each variant, and academic level (3)). All patients had a rate of functional decline less than 25% according to Barthel’s scale for daily living activities, Lawton and Brody’s scale for instrumental activities and the FAQ-1. Previous approval by the Ethics Committee at Pontificia Universidad Javeriana, and signed consent form. First, functional and cognitive variables prone to intervention are identified. Then the patent, their family, the design team and healthcare providers, raise the initial design. The patients were divided in two groups: executive or linguistic disabilities. Afterwards, patient’s difficulties are translated into a prototype which is later adapted to fit each patient. Subjects with executive disabilities, adapt easier to the prototype (80% p < 0.05) while in those with linguistic disabilities therapeutic support is required for adaptation (60% P,0.05). Assistive technologies are more useful for subjects with mobility difficulties. Treatment adherence increased to 85% and caregivers report less burnout syndrome.

P465 Neuroprotective effects of Cerebrolysin in triple repeat (3R) tau transgenic model of Pick’s disease and frontotemporal tauopathies E. Rockenstein1, K. Ubhi1, M. Mante1, J. Florio1, A. Adame1, S. Winter2, D. Meier2, E. Masliah1, H. Brandstaetter2 1 University of California San Diego, Neurosciences, La Jolla, USA 2 EVER Neuro Pharma GmbH, Research and Medical, Unterach, Austria Tauopathies are a group of neurodegenerative disorders with accumulation of three-repeat (3R) or four-repeat (4R) tau. While 4R tau is more abundant in corticobasal degeneration, progressive supranuclear palsy and Alzheimer’s disease (AD), 3R tau is found in Pick’s disease, which corresponds to the clinical behavioral variant FTD. Cerebrolysin, a neuroprotective peptide fraction derived from porcine brain proteins, which is already used in the treatment of AD, vascular dementia, stroke, and traumatic brain injury, has been shown to improve pathomolecular and behavioral deficits in a specific transgenic mouse model for a 3R tauopathy mimicking FTD, as described in (Rockenstein et al. PLOS One 2015; 10:3). In this study mice expressing 3R tau (L266V and G272V mutations) under the mThy-1 promoter were treated with a three months


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Cerebrolysin course in two separate groups: the preventive study arm received treatment at 3, the therapeutic group at 6 months of age. We found that although the levels of total 3R tau protein were unchanged, Cerebrolysin treated mice showed markedly reduced levels of hyperphosphorylated tau, a hallmark of FTD. Cerebrolysin treatment induced activation of the Akt kinase and inhibition of its downstream target GSK3-b, a kinase known to phosphorylate tau. In the 3R tau mouse model these molecular changes were accompanied by reduced neurodegenerative pathology of neuronal loss and gliosis in the neocortex and hippocampus in both groups following Cerebrolysin treatment. This correlated with improvements in behavioral deficits in the nest-building test in the preventive group and with ameliorated memory retention ability, as assessed in the water maze probe test in both therapeutic groups. Taken together these results support the notion that Cerebrolysin may be beneficial in FTD tauopathies by reducing the levels of aberrantly phosphorylated tau, targeting the GSK3-b kinase. This study is published in (Rockenstein et al. BMC Neuroscience 2015; 16:85).

P466 Disease Modifing Treatment for a bvFTD case M. Tainta1, M. Barandiar an1, A. Gabilondo1, F. Moreno1, opez de Munain1 B. Indakoetxea1, A. L 1 Donostia University Hospital, Neurology, San Sebastian, Spain Objective: Report a case of behavioral variant FTD (bvFTD) as a clinical phenotype of Cerebrotendinous Xanthomatosis (CTX). Material and Methods: Case study. 55 years-old woman who develops in 2 years progressive apathy and loss of empathy without response to antidepressant drugs. Previously diagosticated with depression, chronic diahrrea and juvenile cataracts. Her family report a loss of social skills and a neglect of her hygiene and food habits. Her brother is diagnosed of CTX. In the physical examination there were xantomas in her skin and tendoms; there was a global bradikinesia with no motor or sensitive deficits and there was no cerebellar sign. The neuropsychological tests revealed severe executive and attention deficits compatible with a frontal syndrome. The MRI is compatible with the diagnosis of CTX with cortical and cerebellar atrophy. She started treatment with chenodeoxicholic acid (CDCA) with an improvement of her executive functions and behavioural sympthoms. After five years of treatment she is is still physically and socially active but is starting a very slow decline with a predominant frontal syndrome. Discussion: Cerebrotendinous xanthomatosis (CTX) is a rare and severe, but treatable, inborn disorder of bile acid biosynthesis and sterol storage due to a mutation in the CYP27A1 gene located on chromosome 2, with autosomal recessive inheritance. It has a variable clinical presentation, including psychiatric manifestations. In early ages the disease course learning difficulties or mental retardation, and in middle ages it can develop dementia with rich neuropsychiatric syndromes such as frontotemporal syndromes of cortico-subcortical dementia encompassing behavioral/personality. Conclusion: Although CTX is a very rare cause of a bvFTD syndrome it could be a reversible cause of dementia in middle ages.

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P468 Non-invasive salience network modulation in behavioral variant frontotemporal dementia: preliminary results from a case series L. Pini1,2, I. Boscolo Galazzo3,4, C. Cobelli5, C. Ferrari6, M. Cotelli5, G. B. Frisoni1,7, R. Manenti5, F. B. Pizzini3, M. Pievani1 1 IRCCS Fatebenefratelli, Alzheimer’s Neuroimaging & Epidemiology, Brescia, Italy 2 University of Brescia, Department of Molecular and Translational Medicine, Brescia, Italy 3 Verona University Hospital, Neuroradiology, Department of Diagnostics and Pathology, Verona, Italy 4 University College London, Institute of Nuclear Medicine, London, Italy 5 IRCCS Fatebenefratelli, Neuropsychology Unit, Brescia, Italy 6 IRCCS Fatebenefratelli, Service of Statistics, Brescia, Italy 7 University Hospitals and University of Geneva, Memory Clinic and LANVIE — Laboratory of Neuroimaging of Aging, Geneva, Italy Treatments for behavioral variant frontotemporal dementia (bvFTD) are lacking. Available drugs are only symptomatic and unrelated to disease pathophysiology. Imaging studies reported reduced Salience Network (SN) and increased Default Mode Network (DMN) connectivity in bvFTD patients, offering a potential target for non-pharmacological interventions such as brain stimulation. This pilot study aims to test the feasibility of transcranial direct current stimulation (tDCS) of the SN in bvFTD and its effect on cognition. Patients with a diagnosis of bvFTD were recruited and underwent a clinical-neuropsychological assessment and 3T restingstate fMRI both performed at baseline and immediately after ten 25minutes tDCS sessions. SN modulation was performed through anodal stimulation of SN frontal hubs or cathodal stimulation of DMN parietal hubs. Changes from baseline in cognition and SN connectivity were defined as outcome measures. SN connectivity was measured through Spatial group ICA of the GIFT Toolbox. Three patients have completed the treatment to date. No patient experienced adverse events (e.g., itching, dizziness, etc.. . .). At baseline, two patients showed abnormal SN connectivity (< 5th percentile compared with a healthy sample), which increased to normal values after tDCS (> 50th percentile). These changes were accompanied by an improvement on MMSE after tDCS (+4 and +2 points, respectively). The third patient showed normal baseline SN connectivity that slightly decreased after tDCS but still in the normal range. These changes were accompanied by a decreased in MMSE of 2 points. Clinical scales did not show any change in these patients. This is the first study testing a non-pharmacological treatment for bvFTD and targeting a disease-specific brain network. These preliminary data support the feasibility of tDCS stimulation in bvFTD patients and are promising for identifying surrogate markers of response to tDCS. Future investigations are needed to extend the case series and to investigate in-depth network, behavioral and cognitive effect of tDCS intervention.



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Identification of best-practice-strategies in caring for people with behavioral variant frontotemporal dementia (bvFTD): Exploration of clinical expertise - Study protocol C. Dinand1,2, M. Berwig1,2,3, M. Halek1,2 1 German Center for Neurodegenerative Diseases DZNE, Witten, Germany 2 Witten/Herdecke University, Faculty of Health, School of Nursing Science, Witten, Germany 3 University of Leipzig, Medical Faculty, Clinic and Policlinic for Psychiatry and Psychotherapy, Leipzig, Germany

Efficacy of a group visual art therapy with frontotemporal dementia patients: a pilot study S. Fostinelli1,2, G. Uggeri3, M. Facchinetti4, L. Benussi1, R. Ghidoni1, G. Di Giovanni2, G. Rossi5, E. Bertocchi5, R. Pioli5, G. Binetti2 1 IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Molecular Markers Laboratory, Brescia, Italy 2 IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Memory Clinic, Brescia, Italy 3 IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Art Laboratory, Brescia, Italy 4 IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy 5 IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Psychiatric Unit, Brescia, Italy

Behavioral variant frontotemporal dementia (bvFTD) is the most common subtype of frontotemporal lobar degenerations (FTLD) and associated with strong changes in judgement, behaviour, personality and emotions. These changes vary individually and cause significant problems in everyday life. Psycho-social interventions are referred to be the first line-interventions for people with bvFTD and are most effective if they match the specific needs and demands of the persons concerned. Currently, evidence on these interventions is weak. Therefore practical experiences from close actors in the field or stakeholders are a potential source to seek hidden knowledge about helpful interventions. The aim of this study is to identify, collect and consolidate clinical expertise as a basis for further development and evaluation of psycho-social interventions for people with bvFTD. An explorative and reconstructive design is chosen and includes three steps: 1. Development of a literaturebased guideline for conducting interviews. 2. Consultation of elected informal and formal stakeholders with multi-professional backgrounds by a) guided face-to-face interviews (max. 10 interviews with 2 persons per profession, b) focus-groups (max. 4, composed of 4 - 8 participants), if there is a naturalistic group formation (e.g. caring staff, caregiver support groups), c) blogs written by people with FTD. 3. Analysis of recorded and verbally transcribed interviews using an interpretative approach for thematic analysis of expert consultations and a content-orientated multimodal approach for blog analysis. Data analysis includes the identification, arrangement and graduation of the categories of applied interventions using the software for qualitative data analysis (MAXQDA). Expected findings explore currently inaccessible knowledge and latent successful strategies of clinical expertise. Further consolidation fills a gap within the health care research. Finally, best practice strategies in caring for people with bvFTD from multidisciplinary perspectives will be recommended.

Frontotemporal lobar degeneration (FTLD) is characterized by a selective cerebral atrophy in the frontal and anterior temporal lobes of the brain. Is accompanied by different principal symptoms, depending on the affected region, such as behavioral disorders in the behavioural variant frontotemporal dementia (bvFTD) or language disorders in the primary progressive aphasia (PPA). Some scientific studies have described individual cases of visual artistic production in people with FTLD with a greater propensity toward the visual arts after the beginning of the disease. In these patients, areas delegated to the visuo-spatial abilities are not affected and this can help us to understand why this form of dementia can allows the emergence of visual creativity. The aim of this project was to test the effectiveness of a visual art therapy with FTLD patients. The artistic stimulation protocol is developed and conducted by qualified staff at the Art Laboratory of the hospital. A group of patients with a diagnosis of FTLD attended 12 sessions of artistic program while another group with the same diagnosis undergo classic cognitive stimulation for the same number of sessions. All patients were assessed with a neuropsychological and behavioral battery before and after the rehabilitation programs. Even the caregivers are evaluated before and after the rehabilitation in order to measure their physical and psychological stress. Statistical analysis comparing neuropsychological and behavioral variables detected in both study groups suggest a better performance in Rey Recall test in the experimental group than controls; statistical analysis in groups divided for clinical phenotype shows improvement of behavioral disorders measured with the Neuropsychiatric Inventory in bvFTD undergoing creative stimulation compared to bvFTD of the control group and better performance in Letter Fluency test of PPA in control group than PPA of experimental group. In conclusion, art therapy can become an important tool for rehabilitation in FTD patients especially the bvFTD.


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Application of MarteMeo Counselling to people with behavior variant frontotemporal dementia and their caregivers (AMEO-FTD) - Study protocol for a feasibility study M. Berwig1,2,3, C. Dinand1,2, M. Halek1,2 1 German Center for Neurodegenerative Diseases DZNE, Witten, Germany 2 Witten/Herdecke University, Faculty of Health, School of Nursing Science, Witten, Germany 3 Leipzig University, Medical Faculty, Clinic and Policlinic for Psychiatry and Psychotherapy, Leipzig, Germany Behavior variant frontotemporal dementia (bvFTD) is associated with impaired social cognition abilities. Therefore it is often challenging to get in contact with people with bvFTD, particular for their caregivers. MarteMeoâ Counselling (MMC) is a videobased intervention to promote the sensitive adaption of communication behaviors resulting in a better quality of relationship. Primarily MMC was developed for enabling parents of children with autism in skills of social interaction. It is based on the presumption, that a good and meaningful relationship in terms of reciprocity is a prerequisite for the development and maintenance of social cognitive abilities. In the field of gerontopsychiatry the aim of MMC is not supporting development but activating resources for functioning and self-maintenance. In this feasibility study MMC is applied for the first time to people with bvFTD and their caregivers. The aim is to evaluate the usefulness of MMC for this population and to explore potential effects. The study uses a quasi-experimental one-group-pre-post-design with double pre-measurement and an embedded mixed-method approach. Ten dyads will be enrolled. Primary outcome is sensitiveness of the caregivers and secondary outcomes are quality of caregiver-patient relationship and quality of life and challenging behaviors of people with bvFTD. At three time points of examination (T0, T1 after two weeks, and T2 after six weeks) a video of a dyadic interaction in a daily life situation (mealtime) will be recorded and data collection will be conducted. Time between T0 and T1 serves as control period. Between T1 and T2 the caregiver receives five MMC sessions. Video sequences will be micro-analyzed by means of video-interaction analysis to proof the assumed impact mechanism of the intervention. Variance of effects on outcomes will be determined. Moreover collected process data will be used to evaluate the benefit and acceptance of the intervention. Expected results provide indications for the feasibility of the intervention as well as of a large scale main study.

P472 Effect of repetitive transcranial magnetic stimulation on cognitive, behavioral and emotional functioning in behavioral variant of frontotemporal dementia K. Kowalska1, J. Antczak1, M. Banach1, A. Klimkowicz - Mrowiec1 1 University Hospital in Krak ow, Neurology, Krak ow, Poland Behavioral variant of frontotemporal degeneration (bvFTD) is the neurodegenerative disorder characterized by cognitive disturbances and significant changes in emotional, social and personal behavior. Currently, there is no established treatment of the cognitive deficits associated with bvFTD. Repetitive transcranial magnetic stimulation (rTMS) is the noninvasive method of induction of brain plasticity with therapeutic potential in neurodegenerative diseases. The

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purpose of this study was to evaluate the effect of rTMS on cognitive, behavioral and emotional functioning in bvFTD. Seven patients (4F, 3M, mean age 59.7 10.6) underwent ten daily sessions of 10 Hz rTMS to left and right dorsolateral prefrontal cortex (DLPFC). Stimulation intensity was 90% of the resting motor threshold and every hemisphere received daily 1500 stimuli. Before and after therapy patients were assessed with the battery of neurocognitive tests (MontrealCognitive Assessment Test (MOCA), Stroop Test, Letter and Number Cancellation Test, Frontal Assessment Battery (FAB)) and depression rating questionnaires (Hamilton Rating Scale for Depression (HRSD), Geriatric Depression Scale). The Frontal Behavioral Inventory (FBI) was used for assessing frontal lobe dementia through behavioral changes as reported by caregivers. After 10 days of rTMS therapy there was a significant improvement in processing speed in interference task in Stroop Test and significantly better performance in Letter Cancellation Test. The significant improvement was also shown in patients behavior as reported by caregivers (significantly lower scoring on FBI). In conclusion our results suggest that repetitive transcranial magnetic stimulation has therapeutic potential and improves cognitive and behavioral functioning in patients with behavioral variant of frontotemporal dementia.

P473 Advanced frontotemporal dementia - an indication for palliative care? L. Riedl1, J. Diehl-Schmid1 1 Technical Universitiy of Munich, Psychiatry, Munich, Germany Whereas clinical symptoms in the early stages of frontotemporal dementia (FTD) have been topic of numerous studies in the last years, there are little data available about the clinical progression. So far, no studies have been performed to clinically characterize the advanced stages of FTD. The aim of the study was to describe the clinical symptoms of advanced FTD and somatic comorbidities. 110 caregivers of patients with FTD (74 with behavioral variant FTD, bvFTD; 19 with semantic variant FTD, svPPA; 17 with nonfluent variant FTD, nfvPPA) were interviewed in average 4.2 years after patients’ first visit at a German memory clinic that is specialized in FTD. At the time of the interview, half of the patients had already died. At the time of the interview or before death, respectively, all patients were in moderate or severe dementia stages as measured by Clinical Dementia Rating (CDR global score = 2 or 3). In addition to moderate or severe cognitive impairment, about half of the patients suffered from severe disabilities including impairment of gait, swallowing and the inability to communicate. 35% of the patients were completely bedridden. 33% needed feeding, 19% had got enteral tube feeding. SvPPA patients in advanced dementia stages were physically less impaired than patients with bvFTD and nfvPPA. Behavioral symptoms varied considerably between patients. Somatic illnesses were diagnosed in the majority of patients. FTD is a terminal disease. Cognitive and physical impairment of patients with advanced FTD is an indication for palliative care provision in order to maximize quality of life by providing comfort.



P474 Improvement of speed processing and neuropsychiatric symptoms in Fronto-Temporal Dementia after transcranial Direct Current Stimulation S. Gardini1, R. Ferrucci2, F. Ruggiero2, M. Vergari2, F. Mameli2, M. Spallazzi1, F. Barocco1, A. Miucci1, A. Arighi2, P. Caffarra1,3, E. Scarpini2, A. Priori2 1 University of Parma, Department of Neurosciences, Parma, Italy 2 University of Milan, Fondazione IRCCS Ca’ Granda, Milan, Italy 3 AUSL of Parma, Centre for Cognitive Disorders and Dementia CDCD, Parma, Italy Recent studies showed the effectiveness of transcranial Direct Current Stimulation (tDCS) in the treatment of neurodegenerative diseases. The present research aimed to assess neuropsychological and behavioral effects of tDCS in patients with Frontotemporal Dementia (FTD), presenting primary progressive aphasia (PPA) variants and behavioral variant FTD (bvFTD). Thirteen patients (aged 63-67, 6 males and 7 females) diagnosed as having FTD were recruited (five PPA; eight bvFTD). Bilateral frontotemporal anodal (2 mA, 20 minutes, five consecutive days) and sham (placebo) tDCS were delivered in two separate cycles, at intervals of at least 1 month. In each cycles, the Neuropsychiatric Inventory (NPI), Phonemic Fluency Task (PFT), Visual Recognition Task (VRT), Picture Naming Task (PNT) and Simple Reaction Time Task (sRT), and Go-No-Go Tasks were administered before (baseline T0), after the last tDCS cycle on day 5 (T1), one week (T2) and one month (T3) after the end of the treatment. Statistical analysis were carried out comparing the mean difference at performance scores obtained by FTD patients after the two treatment conditions at different assessments. Compared with the placebo group, the anodal tDCS one had statistical improvement in neuropsychiatric symptoms at T1 and T2 and acceleration of reaction times at T1, respect to T0. Splitting the group on the base of FTD variant, the same pattern of results was found only for the bvFTD. The present results showed significant benefits in FTD patients (especially in the bvFTD) on speed processing (marker of neurophysiological integrity) and neuropsychiatric symptoms after anodal bilateral frontotemporal tDCS. This study support the use of tDCS in the treatment of FTD, especially in the bvFTD.

P475 Targeting tau protein in therapy of human tauopathies: Can we use the same vaccine for treatment of various tau neurodegenerative diseases? N. Zilka1, B. Kovacech1, E. Kontsekova1, M. Novak1 1 AXON Neuroscience SE, Bratislava, Slovakia

in vitro (tau oligomerization assay) and in vivo (mouse model). The proteomic and immunological analyses revealed that the antibody recognize specific areas on tau which drive tau oligomerization in various human tauopathies including Alzheimer’s disease, progressive supranuclear palsy and corticobasal degeneration. These areas are localized in the repeat domains of tau protein. Immunohistochemical study demonstrated that the antibody recognized neurofibrillary lesions in AD and glial tau pathology in PSP and CBD. In conclusion, we identified structural determinants on tau that can drive tau oligomerization in various pathological conditions. The vaccine AADvac2 is able to inhibit the process of tau-tau interaction targeting abovementioned areas on tau. Based on these result we suggest that the vaccine might be effective in the clearance of misfolded tau in various human tauopathies.

P476 Frontotemporal dementia (FTD): A review and a general approach to non-pharmacological treatment - the Hong Kong experience C. T. Y. Yan1, J. Tsoh2, D. S. Law3 1 Shatin Hospital, Psychiatry, Hong Kong, Hong Kong 2 The Chinese University of Hong Kong, Department of Psychiatry, Faculty of Medicine, Hong Kong 3 Shatin Hospital, Occupational Therapy, Hong Kong Frontotemporal dementia (FTD) is a process characterized by degeneration of the frontal and temporal lobes with diverse symptomatology and distinct clinical syndromes. There had been little report on this population and their clinical, cognitive and neuropsychiatric features in Hong Kong. The old age psychiatry team of a tertiary teaching hospital in the north-eastern part of the territory identified 38 probable and 16 possible subjects with FTD by clinical symptoms, neurocognitive profile and neuroimaging results. Here we reviewed the patient demographics, initial presentation, cognitive profile and investigations results, then proceeded to outline the team’s management approach, with an emphasis on nonpharmacological treatments. This was further illustrated with case vignettes on how to understand the correlation between presenting behavioural disturbances and underlying neurocognitive deficits, design strategic interventions and apply them in ameliorating symptoms, mitigating disturbances and utilizing the subjects’ remaining cognition to improve their care and quality of life. We also described our experience in enlisting the caregivers of FTD clients in a therapeutic alliance by education, support, training, expectation management and care plan formulation. Finally, a brief discussion on the need for timely referral in suspected FTD cases as early assessment and diagnostic confirmation are paramount to initiating the care pathway.

Tau represents an attractive target for disease modifying therapy. One of the most promising approaches to promote the clearance of misfolded tau is immunotherapy. The current concept of tau immunotherapy is based on the notion that all areas on tau protein are equally suitable for targeted therapy. However this concept does not reflect the diversity of tau proteome in various human tauopathies. Previously, we identified common denominators of pathologically mis-disordered tau species that are responsible for pathological tau oligomerization in various human tauopathies. Our monoclonal antibody DC8E8 - the main constituent of the AXON passive vaccine AADvac2, is able to inhibit pathological tau assembly both © 2016 The Authors Journal of Neurochemistry © 2016 International Society for Neurochemistry J. Neurochem. (Suppl. 1) (2016), 222--428

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Study design of a phase 2 randomized controlled trial of intranasal oxytocin for symptomatic treatment in FTD E. Finger1,2, H. Feldman3,4, J. Cummings5, A. Boxer6 1 Western University, Clinical Neurological Sciences, London, Canada 2 Parkwood Institute, London, Canada 3 UCSD, San Diego, USA 4 UBC, Neurology, Vancouver, USA 5 Cleveland Clinic, Lou Ruvo Center for Brain Health, Las Vegas, USA 6 UCSF, Neurology, San Francisco, USA

Clinical drug trials in behavioral variant frontotemporal dementia: problems and challenges J. Diehl-Schmid1 1 Technical University Munich, Department of Psychiatry, Munich, Germany

Oxytocin is a neuropeptide now recognized as an important mediator of fundamental aspects of social cognition and behaviour. We have conducted the first studies of intranasal oxytocin as a potential symptomatic treatment in patients with FTD which indicate that oxytocin may improve apathy/indifference and related empathic behaviours (Jesso et al. 2011; Finger et al. 2015). Based on these findings, a phase 2 randomized controlled trial of intranasal oxytocin for symptoms of social apathy and empathy deficits in FTD is planned. One-hundred patients with FTD with empathy and social apathy deficits will be enrolled across 4 Canadian and 11 US sites including the ARTFL network beginning in January 2017. As new evidence suggests that the pharmacokinetics of oxytocin may vary with chronic use, an adaptive cross-over design with 6 week treatment intervals will be used to identify the best dose schedule. In the second phase, remaining patients are enrolled at the most promising dose. The primary outcome measure is change on the NPI apathy/indifference score. Secondary outcome measures include change in the Interpersonal reactivity index (IRI), caregiver distress/ burden ratings, facial expression recognition performance, and total NPI scores. Oxytocin levels will be measured in CSF in each treatment period to confirm entry into the CNS. Results of the trial will be used to determine if a phase 3 trial of intranasal oxytocin for symptoms in FTD is warranted.

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Participation as a recruiting site with 11 patients in the multicenter, randomized, double-blind, placebo-controlled, 12 month safety and efficacy trial of LMTXTM in subjects with behavioral variant frontotemporal dementia (bvFTD) revealed several problems that occur when a clinical drug trial with this particular patient group is conducted: Patient recruitment was extremely difficult due to various reasons, e.g. low prevalence of FTD, patient’s lack of insight into the disease, caregivers’ time constraints, and - as long as a significant improvement is not a realistic therapeutic goal caregivers’ doubts about the aim of the treatment. Particularly disinhibited or aggressive patients were unwilling and unable to comply with protocol requirements. Therefore, a selection bias towards apathetic patients was likely. Measures of cognition seemed to be more dependent on the degree of the patients’ motivation and cooperativeness rather than their actual cognitive or functional ability. Motor symptoms including dysarthria, that emerged in two patients during the course of the trial, hampered patients’ performance not only in their activities of daily living but also in trialrelated cognitive tests. In general, assessments of behavior and functional status mainly depend on caregiver information and existing assessments for behavior are not able to reliably detect any improvement. Onsite staff had to deal with behavioral disturbances including verbal and physical aggression. Adverse event reporting was difficult as most patients did not seem to have any insight into somatic symptoms. In a few cases it was necessary to initiate sedative or antipsychotic drugs during the course of the trial, which might have influenced cognition and behavior. Better measures of functional abilities and behavior and more flexible study protocols are needed in order to successfully conduct clinical drug trials in bvFTD.
