Techniques for histopathological verification of

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Poster Presentations: P4

atlas. PiB uptake was normalized to the cerebellum, and global and regional PiB uptake ratios were calculated. Results: Three of the LPA subjects (33%) had MBs (Figure); two subjects had multiple MBs and one subject had just one MB. Microbleeds most commonly occurred in the frontal lobes, but were also present in temporal, parietal, and occipital lobes. Compared to the six subjects without MBs, the subjects with MBs were relatively older at onset (71 versus 65 years), more functionally impaired and had a greater total burden of WMH. All nine LPA subjects were PiB-positive, yet the global cortical PiB ratios were the highest in the three subjects with MBs. The regional distribution of MBs did not match the regional distribution of WMH or b-amyloid deposition. Conclusions: Microbleeds occur in subjects with LPA and appear to be associated with older age, greater functional impairment, greater burden of WMH and a greater burden of b- amyloid on PiB-PET imaging. These findings could influence prognosis and treatment approaches in LPA subjects. P4-166

LONG-TERM IN VIVO IMAGING OF TAU PATHOLOGY IN THE RETINA

Jochen Herms1, Christian Sch€on1, Boris Schmidt2, Hans Kretzschmar3, Michel Goedert4, 1Deutsches Zentrum f€ur Neurodegenerative Erkrankungen & Ludwig-Maximilians-University Munich, Munich, Germany; 2Clemens Schoepf Institut, Technische Universitaet Darmstadt, Darmstadt, Germany; 3Ludwig-Maximilians-University, Munich, Germany; 4 Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom. Background: Tauopathies are characterised by the acccumulation of fibrillar tau in neurons and glia cells. Since an early intervention is expected to substantially improve the outcome, much effort is spent on improving early diagnosis. Moreover, tools that allow the monitoring of therapeutical effects are of critical importance for the evaluation of new concepts. Methods: We modified a commercial confocal laser scanning ophthalmoscope for the in vivo detection of fibrillar tau in the mouse retina. As a transgenic mouse model we used a mouse that expresses human tau with a P301S mutation. A fluorescent strylbenzene derivative was applid systemically to label fibrillar tau aggregates. Results: We were able to monitor the aggregation of fibrillar tau in vivo by non-invasive means on a cellular level for the first time. Moreover, our technique allows us to monitoring the progression of the tau pathology in the retina over several months in individial animals. Conclusions: Thus an optical and easily applicalble approach for the detection of fibrillar tau in the retina has been established. This technique may be of great use in the evaluation of new therapeutical strategies in transgenic tau mouse models. Since individual animals can be studied longitudinally over several months, errors due to the well-known significant variation in strength of the pathology between singel mice can be reduced.Moreover if this technique can be translated into for use with humans if may allow the identification of individuals at risk to develop a tauopathy and might enable the monitoring of therapeutic interventions. P4-167

TECHNIQUES FOR HISTOPATHOLOGICAL VERIFICATION OF FLORBETABEN PET IN A GLOBAL PHASE III CLINICAL TRIAL

John Seibyl1, Osama Sabri2, Marwan Sabbagh3, Hiroyasu Akatsu4, Yasoumi Ouchi5, Thomas Beach6, Albert Charny6, Henryk Barthel2, Kohei Senda7, Shigeo Murayama8, Kenji Ishii8, James Leverenz9, Bernardino Ghetti10, James Ironside11, Katrin Roth12, Cornelia Reininger13, Anja Hoffmann12, Walter Schulz-Schaeffer14, 1MNI, New Haven, Connecticut, United States; 2University of Leipzig, Leipzig, Germany; 3 Banner Health, Sun City, Arizona, United States; 4Choju Medical Institute, Toyohashi, Japan; 5Hamamatsu Medical Center, Hamamatsu, Japan; 6 Banner Health, Sun City, Arizona, United States; 7Koseikai Hospital, Toyohashi-shi, Japan; 8Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan; 9University of Washington, Seattle, Washington, United States; 10 Indiana University School of Medicine, Indianapolis, Indiana, United States; 11University of Edinburgh, Edinburgh, United Kingdom; 12Bayer Healthcare, Berlin, Germany; 13Bayer Heealthcare, Berlin, Germany; 14 Georg-August University, Goettingen, Germany.

Background: Validation of PET ligands as in vivo biomarkers of brain b amyloid deposition in Alzheimer’s disease requires accurate comparison between identical brain regions in the PET scan with subsequent post mortem histopathology. Given the distribution pattern of b-amyloid it is technically challenging to ensure that the PET and post mortem assessments are performed in precisely the same brain areas. Methods: 204 end-of-life patients recruited from 17 centers across 4 continents underwent MRI and florbetaben PET scanning. A total of 31 brains were included in the analysis (184 regions and additional 60 regions from 10 healthy volunteers negative per default).Assessment of the data was done in different ways: 1. A regional comparison was performed for 6 pre-specified regions of interest (ROIs) each with a different likelihood of b -amyloid deposition. The pathology samples from these regions, which served as the standard of truth, were assessed for presence or absence of b -amyloid by a consensus panel of 3 neuropathologists. Based on a detailed photodocumentation of the autopsy, the precise location of these samples was transferred onto fused and aligned MRI and PET images. ROIs were drawn on the PET images and these regions were evaluated for absence or presence of b-amyloid by 3 independent blinded readers permitting unequivocal determination of the correspondence of a PET signal with pathology in a tissue sample. 2. Comparison was done on a subject level basis taking into account a visual scoring method proposed for clinical practice and compared against post mortem diagnosis. Results: Compared to histopathology both PET evaluations revealed a high sensitivity and specificity of florbetaben together with a reliable inter-reader agreement. Conclusions: T his is the first global phase 3 clinical trial in which exact and concise co-localization between pathology samples and imaging data was achieved. This trial confirmed that florbetaben PET can detect b -amyloid in the brain during life based on a regional comparison between scan and the respective post mortem specimen, supporting validation as a diagnostic biomarker in Alzheimer’s disease. P4-168

CORRECTING FOR VOLUMETRIC CHANGES REVEALS NOVEL PATTERNS OF GLUCOSE METABOLISM IN THE ALZHEIMER’S BRAIN

Joseph McQuail1, Kaycee Sink2, Michelle Nicolle2, Ann Peiffer2, 1Wake Forest University, Winston-Salem, North Carolina, United States; 2Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States. Background: Brain imaging technology offers vital neurological information to compliment traditional clinical evaluation in older patients with suspected Alzheimer’s disease (AD), particularly when seeking to differentiate this disease from subtle brain changes observed with normal aging or intermediate alterations associated with mild cognitive impairment (MCI), a heterogeneous clinical classification that bridges normal and AD states. Specific imaging modalities, such as structural magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET), have identified similar but not entirely overlapping regions of cerebral atrophy and reduced glucose metabolism. What’s more, as regional atrophy and metabolic reductions occur in tandem across the aging-MCI-AD spectrum, it is not fully understood how these parameters interact to influence neurological outcomes. Methods: Neuroimaging data obtained from 161 subjects (53 normal controls, 62 MCI and 42 AD) that underwent both MRI and FDG-PET scanning as part of the Alzheimer’s Disease Neuroimaging Initiative were analyzed using a traditional general linear model. A multi-modal analysis of covariance (Biological Parametric Mapping) was also used wherein FDG-PET results were compared between groups while using the structural MRI data as a regressor to correct for local, voxel-wise grey matter changes. Results: Using traditional morphometric analyses, we confirmed that our sample recapitulated reductions in grey matter volume and glucose metabolism within the temporal and parietal lobes consistently observed in MCI and AD. Correcting for differences in grey matter volume reduced some significant findings of glucose metabolism, including those between normal and MCI. However, posterior cingulate/precuneus remained a region of significant metabolic reduction further underscoring diminished functioning of the default mode network in AD pathology. This approach nevertheless did not reduce regions exhibiting relatively greater