Neuroimaging Findings Related to Behavioral ...

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RESEARCH ARTICLE

Neuroimaging Findings Related to Behavioral Disturbances in Alzheimer’s Disease: A Systematic Review Gilberto Sousa Alvesa,b,*, André Férrer Carvalhob , Luiza de Amorim de Carvalhob, Felipe Kenji Sudoc, José Ibiapina Siqueira-Netob, Viola Oertel-Knöcheld, Alina Jurcoanee, Christian Knöcheld, Henning Boeckere, Jerson Laksc,f and Johannes Pantela,* a

Institute of General Medicine, Goethe Univ., Frankfurt/Main, Germany; bTranslational Psychiatry Research Group and Department of Clinical Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; cInstitute of Psychiatry, Federal University of Rio de Janeiro; dLaboratory of Neuroscience, Dept. of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe Univ., Frankfurt/Main, Germany; eClinical Functional Neuroimaging Group, Department of Radiology, Bonn University, Bonn, Germany; fCentre for Studies and Research on Aging, Instituto Vital Brazil; Translational Biomedicine Program, Unigranrio, Rio de Janeiro, Brazil. Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) associated with Alzheimer´s Disease (AD) have been linked to structural and functional alterations in fronto-temporal circuits and cortical abnormalities. However, little is known on how specific volumetric and functional brain changes may be associated with the frequency, severity and pattern of BPSD.

ARTICLE HISTORY Received: January 18, 2016 Revised: May 20, 2016 Accepted: May 27, 2016 DOI: 10.2174/15672050136661606030 10203

Methods: A systematic review of the literature regarding neuroimaging and BPSD changes in AD was performed through Pubmed/Medline, ISI, and EMBASE electronic databases from January 2000 to May 2015. Eligible references (n=40) included clinical studies in which structural or functional neuroimaging assessment was performed in AD subjects presenting BPSD features. Results: BPSD symptoms, particularly apathy and psychosis have been associated in most of studies with either volume reductions or decreased metabolism in the prefrontal cortex (orbital and dorsolateral portions), anterior cingulate, insula and temporal lobes (middle portion). WM lacunes associated with AD progression have been associated with depressive symptoms. Conclusion: The sum of evidence highlights the importance of BPSD-related imaging findings for the understanding of the non-cognitive symptom spectrum in AD. Results suggest that structural and functional changes in fronto-limbic areas may lead to emotional deregulation and symptom unawareness. As these findings may be present early on the AD clinical course, they may have a relevance for the development of imaging markers that could be used in diagnosis, disease monitoring and prediction of therapeutic response.

Keywords: Behavior, psychological, symptoms, BPSD, Alzheimer´s disease, cognition, neuroimaging, cortical, white matter. 1. INTRODUCTION Alzheimer´s disease (AD) is a leading cause of dementia and is characterized by a progressive brain degeneration, resulting in great functional and social impairment [1]. In addition to cognitive dysfunction (e.g. episodic memory, visuospatial and semantic abilities), a hallmark of dementia, behavioral disorders may figure as one of the earliest impairments of AD, eventually leading to faster deterioration, greater impairment in patient and caregiver quality of life, and earlier institutionalization [2]. Behavioral and Psychological Symptoms in Dementia (BPSD) [3, 4] is a term that refers to a variety of non cognitive symptoms which are *Address correspondence to this author at the Rua Prof. Costa Mendes 1608, 4o andar, Fortaleza, Ceara, Brazil; Tel: ++5585 33668052; Fax: ++55 85 3366 8054; E-mail: [email protected]

1567-2050/17 $58.00+.00

common in neurodegenerative disorders, no matter the etiology. This concept has been most useful to acknowledge the neuropsychiatric dimension of dementias, in addition to the cognitive decline which was for a long time the primary concern of researchers and clinicians [5]. The Cache County study found that the five-year prevalence of BPSD, with at least one dementia symptom being present at some point during their illness, was 97% [6-8], with the most common symptoms being apathy, depression and anxiety [7]. Neuropsychiatric symptoms of dementia occur within clusters as an heterogeneous array of symptoms often comprising psychosis (delusions and hallucinations), hyperactivity (agitation, aggression, disinhibition, socially and sexually inappropriate behaviors, sundowning), affective symptoms (depression, anxiety), or apathy [6, 9-11]. Although these symptoms are found almost universally in dementia, regard-

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less of the underlying cause, the evolution of AD is associated with certain behaviors. In other words, BPSD may occur across all stages of AD, but the type and intensity usually depends on the stage. For instance, anxiety and depression are common in early stage of AD and may progress along the clinical course. Similarly, some form of hyperactivity is common, mostly persistent, and may increase with disease severity [7, 12-15]. Apathy may be found across all stages of AD and tends to become more evident with disease severity, albeit delusions, hallucinations and aggression may manifest more occasionally and are more commonly found in moderate to severe stages [12]. Among the most used instruments to assess BPSD, the Neuropsychiatric Inventory (NPI) assesses a wide range of psychopathology domains and is obtained from a caregiver familiar with the patient behavior [16]. AD may directly lead to BPSD by disrupting brain circuitry involved in behavior and emotion [17]. Several brain regions have been implicated in the pathophysiology of BPSD symptoms, for instance the temporal, ventromedial and orbitofrontal cortex, the anterior cingulate and the nucleus accumbens [2, 5, 6, 18]. Lack of interest and apathy may rely on frontal lobe medial atrophy, while decreased neurotransmitter function in monoaminergic circuits and frontal and temporal lobe volume reductions have been associated with depressive mood [2, 18]. Conversely, cholinergic transmission might be affected by a disruption in distinct areas, e.g., anterior cingulate, insula, lateral frontal and lateral temporal regions, leading to agitation and aggression [19]. The circuit model assumes that frontal-subcortical circuit disruption may affect frontal, basal ganglia and thalamic networks [6]. Synaptic disconnections may involve a number of circuits, particularly those connecting the dorsolateral area, which is relevant for planning and working memory, the prefrontal-basal ganglia circuits, related to motivated behavior [20] and the orbitofrontal circuit, responsible for inhibitory control and adequacy to social rules [11] (Fig. 1). There are also five large scale overlapping and reciprocal “cortico-cortical” networks involved in emotion and cognition processing [17, 21]. The so called limbic zone have massive reciprocal connections with the hypothalamus and coordinates the emotional and motivational behavior [17]. The ascending monoaminergic system, which involve the serotonergic, noradrenergic and dopaminergic projection fibers that spread to all brain regions. Additionally, cortical dysfunction in the anterior cingulate may lead to depression and agitation, while increased D2/D3 receptor availability in the striatum is associated with agitation and aggressive behavior [2, 6]. The widespread use of magnetic resonance imaging (MRI) and new post-processing techniques of volumetric measures, and functional MRI, diffusion tensor imaging, but also tracer based nuclear medicine methods such as single positron emission tomography (SPECT) and [(18F)] fluorodeoxyglucose positron emission tomograph (FDG-PET) allowing measures in metabolism, have been of great importance in understanding the neurobiology of AD-related BPSD [22, 23]. Evidence from AD studies with subjects at pre-dementia stage have shown that reductions in the medial

Alves et al.

temporal lobe and hippocampus may figure as the best neuroimaging phenotypes to predict conversion to dementia [24]. In addition, vascular lesions, often recognized as white matter hyperintensities (WMH), have been associated with depressive onset and symptoms in AD, increasing the rate of dementia conversion [25, 26]. Despite the great achievement of neuroimaging methods, it is still poorly understood whether BPSD result from brain abnormalities in regional networks and how these brain abnormalities may be related with different patterns of behavioral disturbances and different levels of severity [27]. As the single approach of a selected neuroimaging method may not be sufficient to clarify these questions, the translational analysis of those data integrated from different imaging modalities, in combination with histopathological and neuropsychological evidence, may provide additional and more in depth insights. The current work aims at reviewing the main structural imaging findings of BPSD in AD, focusing on structural and functional MRI, and also on PET and SPECT. The neurobiological mechanisms of BPSD, the common shared pathways among symptoms of AD are critically discussed on the light of the clinical evidence, highlighting the potential role of neuroimaging evidence for early diagnosis, disease monitoring and therapeutic intervention in AD. 2. MATERIAL AND METHODS A review of the literature (Fig. 2) from January 2000 to 2015 was performed through searches in the electronic databases PubMed/MEDLINE (http://www.ncbi.nlm.nih.gov/ pubmed/), Institute for Scientific Information Web of Knowledge (http://www.isiknowledge.com) and EMBASE (http://www.embase.com), using the following terms: “behaviour”, “behavior”, “psychological”, “symptoms”, “dementia”, BPSD, Alzheimer disease,“depression”, “delusions”, “aging”, “neuroimaging”, “agitation”, “apathy”, “functional resonance”, “diffusion tensor imaging”, “MRI”, “VBM”, “SPECT”, “PET” and “DTI” search. Firstly, the complete abstract was read, with the first paper assortment. A second selection included the full reading of the papers. Inclusion criteria were as follows: original articles written in English and focusing on neuroimaging aspects observed in patients with AD and BPSD. Reviews and case reports were excluded from this review; studies that used clinical constructs other than AD (e.g., fronto-temporal dementia) were also excluded from this study. This search strategy was augmented with a hand search of reference lists of included studies. The current study followed the standard protocols of PRISMA statement [28] and the complete description is depicted in the flow chart. In addition, the clinical and therapeutic applications of novel neuroimaging techniques in the assessment of BPSD symptoms, including the transcranial magnetic stimulation (rTMS) and magnetic resonance spectroscopy (MRS), were also retrieved and discussed. 3. RESULTS The most frequent reported BPSD for which neuroanatomical correlates were investigated was apathy (n=16).

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Fig. (1). Main Neurobiological mechanisms underpinning BPSD in AD. For abbreviations, please refer to the abbreviation list.

Fig. (2). Systematic review procedures.

These studies were performed solely in AD [25, 29-40] or along with mild cognitive impairment (MCI) [41-43] patients. The occurrence of psychosis (n=7) [25, 44-49], agitation (n=5) [47, 49-52], aberrant motor activity (n=2) [53, 54], delusions (n=1) [55], and hallucinations (n=1) [42] and mood-related disturbances, particularly depression (n=10) [33, 36, 40, 47, 51, 56-62] and irritability (n=3) [25, 39, 63] have been also present in most of the studies; in addition, disinhibition (n=2) [55, 64], unawareness of behaviors (n=1) [64, 65] and anxiety [66, 67] have been also described. Conversely, the most frequent reported areas with either structural or functional changes related to BPSD were the frontal lobes, particularly the orbitofrontal [32, 33, 35, 46, 56, 58] and dorsolateral portions [35, 51, 56, 58], the anterior cingulate [29, 30, 32, 37, 38, 54, 63], the temporal lobe, namely the medial [29, 30, 32, 37, 38, 54, 63], the temporal lobe, namely the medial [47] and superior [46, 49] areas, the parie-

tal lobe [30, 45, 48, 49, 56, 64] and the insula [32, 39, 49, 54]. A summary of these studies is depicted in the Table 1. 3.1. Depression Symptoms One study that visually assessed volumes of medial temporal lobe through Scheltens scale showed that AD patients with depressive symptoms had less atrophy of the right medial temporal lobe (OR= 0.39; 95% CI= 0.16-0.99) and less atrophy in the left medial temporal lobe (OR= 0.43, 95% CI= 0.19-0.96) in comparison with AD patients without depressive symptoms [40]. In contrast, another study reported that AD patients with depression showed significantly more medial temporal atrophy than those without depression [57]. Consistently, one study reported that AD patients with depression [geriatric depression scale (GDS) > 20] showed greater atrophy in the inferior left temporal gyrus than AD

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Table 1.

Summary of selected studies. Subjects (Mean Age/Gender M:F)

Autors (sample]

Mega et al., (2000] [44]

Psychotic AD

not-psychotic AD

(n=10)*

(n=10)*

(n=20]

0:10

01:09

Neuroimaging Method

Neuroimaging vs. Behavioral Changes

SPECT with (99mTcHMPAO)

Psychotic symptoms were related to lower perfusion in the prefrontal cortex (bilaterally), the left anterior cingulate, ventral striatum, pulvinar, and dorsolateral parietal cortex.

MRI 1.5 T

Both total brain volume and WMH did not correlate with apathy, delusion, irritation or any neuropsychological measure.

MRI and FDGPET

Patients with apathy exhibited lower glucose metabolism in the left orbitofrontal cortex in comparison with other patients with no such symptoms. Depressed group showed hypometabolism in left prefrontal cortex and superior frontal cortex, when compared with no depressed subjects.

SPECT with 1100MBq of (99 m) Tc labeled bicisate.

AD group had lower regional cerebral flow in both parietal-temporal area than “controls”, which was associated to severity of AD symptoms. rCBF in the left middle temporal gyrus and left parahippocampal gyrus was smaller in AD wanderers than in AD without wandering.

FDG-PET

Higher NPI anxiety (frequency versus severity) was associated with lower metabolism in bilateral entorhinal cortex, anterior parahippocampal gyrus, left superior temporal gyrus and insula.

FDG-PET

AD-apathy patients had reduced activity in the bilateral anterior cingulate region extending inferiorly to the medial orbitofrontal region as well as in the bilateral medial thalamus.

AD

Hirono et al., 2000 [25]

(n=76)

(n=76]

75.6/12:64

Holthoff et al., 2005 [33]

Apathy

not apathy

Depressed

(n=53]

(n=17)

(n=17)

(n=10)

66.7/6:11

70.5/9:8

69.5/4:6

Rolland et al., 2005 [53] (n=39]

!

Alves et al.

Wandering AD

not wandering AD

not Depressed (n=10) 63.2/4:6

Controls

(n=13)

(n=13)

(n=13)

73.1/4:9

73.7/4:9

72.6/4:9

Hashimoto et al., 2006 [66]

anxiety AD

Not-anxiety AD

(n=19)

(n=13)

(n=41]

72

74.1

Marshall et al., 2007 [29]

apathy

not apathy

(n=14)

(n=27)

(n=41]

78.6/13:01

73.6/23:04

Apostolova et al., 2007 [93]

apathy

not apathy

(n=17)

(n=18)

(n=35]

73.9/7:10

78.9/7:10

Levy-Cooperman et al., 2008 [94]

depressed AD

not-depressed AD

(n=27)

(n=29)

(n=56]

78.3/9:08

75.5/16:13

MRI 1.5 T ROI oriented SPECT with (Technetium99m ethyl cysteinate dimer); MRI 1.5T ROI oriented.

Depressed AD subjects presented a trend for diminished perfusion in the right superior and bilateral middle frontal gyri, left superior frontal and anterior cingulate gyri.

MRI 1.5

Apathetic DA subjects presented GM atrophy in the right inferior frontal gyrus, orbitofrontal cortex, bilateral dorsolateral prefrontal cortex, putamen and head of the left caudate nucleus.

AD

Bruen et al., 2008 [95]

(n=31)

(n=31]

77.1/19:12

Apathetic DA subjects presented GM atrophy in supracallosal cingulate (BA 24) and left medial frontal cortex (BA 8/9).

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(Table 1) contd…. Subjects (Mean Age/Gender M:F)

Autors (sample)

Starkstein et al., 2009 [96] (n=79)

not-apathynot depressed

Neuroimaging Method

apathy-not depressed

not-apathy depressed

apathy depressed

(n=14)

(n=15)

(n=10)

MRI 1.5 T ROI-oriented

(n=40) Serra et al., 2010 [97] (n=69)

AD

MCI

Controls

MRI 3 T

(n =27)

(n=19)

(n=23)

VBM

AD patients

Berlow et al., 2010 [98] (n=37)

(n=37)

aware (n=15)

(n=14)

74.47/6:9

75.64/6:8

Ota et al., 2012

AD (n=21)

[99]

73.8/8:13

(n=21)

MRI 1.5 T

Reduced functional recruitment of the cingulum and parietal-temporal regions was associated with the unawareness of deficits in early AD during a response inhibition task. Apathy and disinhibition appear as the first significant behavioral changes in unaware subjects.

MRI 1T

Lower FA in the right anterior cingulate, right thalamus and bilateral parietal regions correlated with more severe apathy scale in AD patients.

MRI 1.5T

Higher atrophy in frontal, parietal and temporal WM among DP along 2 years and had higher rates of conversion to AD compared with the no symptoms group.

MRI 1.5T.

Left medial orbitofrontal and superior temporal cortices were significantly thinner in those with paranoid delusions. Female participants with paranoid delusions showed reduced cortical thickness in left medial orbitofrontal and left superior temporal regions.

MRI (n=8) and all others the CT

Occurrence of lacunes in the left basal ganglia associated with increased risk of delusions and hallucinations; presence of lacunes in the right basal ganglia associated with risk of depressive symptoms. Increased global atrophy associated with agitation.

MCI (n=243) Lee et al., 2012

Depressed

ONPS

No symptoms

[45] (n=243)

(n=44)

(n=93)

(n=106)

75/29:15

74.8/63:30

75.3/70:36

AD (n=113) Whitehead et al., 2012

not delusions

Paranoid delusion

[46] (n=113)

(n=90)

(n=23)

72.5/31:59

75.7/6:17

Palmqvist et al., 2011

AD (n=259) 75/83:176

[47] (n=259)

Kim et al., 2011 [100] (n=51) Tunnard et al., 2011 [101] (n=111)

!

apathy

not apathy

(n=24)

(n=27)

72.96/

69.19/

apathy

not apathy

(n=63)

(n=48)

75.7/19:44

74.6/16:32

Decreased GM volume in bilateral cingulate correlated with severity of disinhibition and dellusions in AD. Low volumes of WMH were associated with disinhibition. High WMH volumes associated with anxiety.

unaware

[64] (n=29)

Depressed AD patients had a larger volume of right parietal WMH than patients without depression. Apathetic DA subjects presented larger WMH in frontal regions than nonapathetic GM.

MRI 1.5 T

77.6/18:19

Amanzio et al., 2011

Neuroimaging vs. Behavioral Changes

MRI 3T DTI ROI oriented

MRI 1.5 T

Lower FA values in left anterior cingulum in apathetic mild and very mild AD in comparison to non-apathetic AD.

Apathetic AD patients had greater cortical thinning in left caudal anterior cingulate cortex, left lateral orbitofrontal cortex, left superior and ventrolateral frontal regions than those without apathy.

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Alves et al.

(Table 1) contd…. Subjects (Mean Age/Gender M:F)

Autors (sample) Poulin et al., 2011

Mild AD

[102]

Sample 1 (n=90) Sample 2 (n=174)

(n=264) Tighe et al., 2012

MCI

AD

[63] (n=45)

(n=22)*

(n=23)*

apathy

not apathy

Hahn et al., 2013 [31] (n=60)

(n=30)

(n=30)

75.5/15:15

77.4/13:17

Trzepacz et al., 2013

AD

MCI converters

MCI stable

(n=163)

(n=122)

(n=177)

[50] (n=462)

75.3/86:77

74.6/78:42

74.4/118:59

(n=25)

[51] (n=26)

AD (n=31)

[32] (n=31)

73.9/13:15

AD

MCI

(n =49)

(n=57)

MRI 3T and ROI oriented.

FA of the anterior cingulum and fornix regions was associated with neuropsychiatric symptoms, mainly irritability in both groups.

MRI 3T, DTI and TBSS processing.

FA values of genu, body and splenium of CC, superior longitudinal fasciculus and left cingulum correlated negatively with the severity of apathy in apathetic AD subjects.

MRI

Atrophy in frontolimbic regions, right posterior cingulate, and left hippocampus were related to greater severity of agitation and aggression.

MRI 1.5 T

Regional levels of brain metabolites were related to the severity of cognitive impairment, agitation and depression in AD. Agitation scores were negatively correlated with the NAA/Cr ratio over the left posterior cingulate gyrus, whereas the depression scores were positively correlated with the Cho/Cr ratio over the left DLPF.

MRI 1.5T; (11C) PIB PET.

(11C)PIB retention in the bilateral superior, middle and inferior frontal gyri; bilateral orbitofrontal gyri, bilateral medial frontal gyri, bilateral insula and right anterior cingulate gyrus was related to apathy severity.

MRI 3T

(n=50)

VBM

Lebedev et al., 2014

AD-not depression

AD - depression

[58]

(n=30)

(n=23)

(n=74)

!

Level of motor aberrant behavior correlated with more severe amygdala atrophy in AD subjects.

Controls

[103] (n=156)

[58] (n=189)

MRI 1.5 T

75/12:14

Mori et al., 2014

Lebedev et al., 2014

Neuroimaging vs. Behavioral Changes

AD

Tsai et al., 2013

Son et al., 2013

Neuroimaging Method

Lewy dementia - notdepression

Lewy dementiadepression

(n=9)

(n=12)

1st cohort

2nd cohort

AD (n=41)

AD (n=148)

Depressed (n=16)

not-depressed (n=25)

(n=84)

66/9:7

67.5/7:18

76/44:40

notdepressed

Depressed

MRI 1.5 T VBM

AD patients with depression showed decreased GM volume in the left inferior temporal gyrus compared with AD without depression. Cortical thinning was found in left dorsolateral prefrontal, anterior temporal regions, and right medial prefrontal, orbitofrontal, and inferior temporal areas in in depressed subjects with either AD or LBD.

MRI 3 and 1.5 T

Significant association between depression and cortical thinning in temporal and parietal regions in AD patients, even in those with mild and subsyndromal depression.

Structural and functional 3T MRI

Altered intrinsic connectivity of the anterior SN predicted behavioral symptoms in AD patients, e.g., hyperkinetic behavior. Hyperconnectivity of the salient network in the anterior cingulate cortex and right insula.

(n=64) 75/33:31

Balthazar et al., 2014

AD

Controls

(n=37)

(n=30)

[54] (n=57)

73.8*

72.3*

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(Table 1) contd…. Subjects (Mean Age/Gender M:F)

Autors (sample) Delrieu et al., 2015

MCI apathy

Neuroimaging Method

MCI not apathy

[41]

(n=11)

(n=54)

(n=65)

76.6/8:3

74.2/40:14

MRI 1.5T; FDG-PET.

Neuroimaging vs. Behavioral Changes Glucose hypo metabolism in the posterior cingulate was found among apathetic MCI subjects. Higher ventricular volume was also reported for the apathetic patient group.

AD or MCI (n=389) Rafii et al., 2014 [48] (n=389)

not Psychosis AE or Antipsychotic Use

Psychosis AE and/or

(n=342)

(n=47)

75.08/205:137

74.79/29:13

(n=32)

[49] (n=32)

73.3/10:22

Dhikav et al., 2014 [104] (n=37)

AD

MCI

(n=26)

(n=11)

Donovan et al., 2014

CN

MCI

AD

(n=229)

(n=395)

(n=188)

[105](n=812)

76.0

74.8

75.3

AD

Moon et al., 2014[106]

(n=22)

(n=38)

58.5/9:13

60.8/ 22:16

Chung et al., 2015

MCI

AD

(n=608)[62]

(n=455)

(153)

Mah et al., 2015 (n=376)[67]

ADNI study

Baseline bilateral inferior temporal cortices thickness correlated with increased apathy over time. Apathy and hallucinations independently predicted global functional impairment over time by the Clinical Dementia Rating Scale

ROI oriented

71.90/31:9

MCI

(n=60) [61]

1.5 T

Medial temporal volume was higher in depressed individuals diagnosed either AD or MCI than those AD or MCI without mood alterations.

3T

(n=40)

SCI

Auning et al., 2015

SPECT with 99mTc-ECD

Agitation correlated negatively with rCBF in the right superior temporal gyrus and the right inferior frontal gyrus. Agitation also correlated negatively with rCBF in the left insula, and the left inferior frontal gyrus. Psychosis symptoms are negatively correlated with rCBF in the right parietal lobe and the right occipital lobe.

Antipsychotic Use

AD

Banno et al., 2014

MRI 1.5T

Accelerated atrophy in the lateral frontal lobe and lateral parietal lobe were related to neuropsychiatric symptoms and the need for chronic medication to treat such symptoms.

MCI – not Anxiety

MCI - Anxiety

(n=220)

(n=156)

75.2/ 154:68

74.7/ 87:69

Scores in apathy and irritability correlated with volume ratio of bilateral anterior insular cortex.

18F-FDG, PET and CT imaging

AD-type brain changes are not associated with symptoms of depression in SCI and MCI. These findings did not differ when SCI and MCI were assessed separately or when we studied only those with pathological CSF AD markers, indicating that in predementia AD, mild depressive symptoms are not associated with pathological AD changes.

18F-florbetapir PET (AV-45).

Current depressive symptoms were not linked to cortical Aβ deposition in patients with MCI and AD.

MRI 1.5T

Anxiety severity in MCI increased rates of conversion to AD, independent of depression or extent of memory decline. The association between anxiety and AD remained significant even with inclusion of baseline hippocampal, amygdala and entorhinal cortex volumes, or their extent of atrophy over time in the model.

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(Table 1) contd…. Subjects (Mean Age/Gender M:F)

Autors (sample)

Controls

Torso et al., 2015 (n=57) [43]

Enache et al., 2015 [107]

(n=31)

(n=26)

71.3/ 17:14

67.5/ 14:11 MCI (n=130)

MRI 3.0 T

Despite a more widespread anatomical distribution, a-MCI patients did not differ from controls in WML volumes. Damage to the ATRs is strategic for the occurrence of apathy in patients with a-MCI.

AD (n=99)

DeP

not DeP

DeP

not DeP

DeP

n=79

n=69

n=61

n=57

n=42

(n=368) n=60

Neuroimaging vs. Behavioral Changes

MCI

SCI (n=139) NDP

Neuroimaging Method

Perrotin et al., 2015 [65]

Controls (n=31)

(n=31)

(n=53)

68.37/ 19:11

69.83/ 10:13

MRI 1.5 T ROI oriented

AD FDG-PET

AD patients with depressive symptoms had less atrophy in medial temporal cortices than AD patients without depressive symptoms.

Anosognosia in AD subjects correlated with lower metabolism in the posterior cingulate and orbitofrontal cortices. The disruption in these regions may lead to the lack of awareness of memory deficits in AD.

ATR: (Anterior Thalamic Radiation); M:F (Male:Female); MCI (Mild Cognitive Impairment); AD (Alzheimer’s Disease); NDP (Non Depressive Patients); MRI (Magnetic Resonance Imaging); VBM (Voxel-based morphometric analysis); ROI (Region Of Interested); DTI (Diffusion Tensor Imaging); ONPS (Other Neuropsychiatric Symptoms); TBSS (Tract-Based SpatialSstatistics); FA (Fractional Anisotropy); SCI (Subjective Cognitive Impairment); SN (Salience Network); Dep (depressed patients); ACC (anterior cingulate cortex); *Mean Age and gender were not described, but was affirmed that were not significant difference between the groups in those parameters.

subjects without depression [59]. Another study reported two cohorts of depressed and non-depressed AD patients. The first cohort showed diminished cortical volume in the left temporal and inferior parietal regions, including supramarginal, superior and inferior temporal and fusiform gyri in depressed AD. The second also presented smaller volumes in temporal and parietal areas, mainly in bilateral superior temporal, left supramarginal, right posterior cingulate and precuneus in the depressed group. Compared with nondepressed AD, depressive AD demonstrated significantly higher negative correlation between cerebral spinal fluid (CSF) levels of tau-protein and cortical thickness in the right medial temporal and cingulate regions [58]. Mean cortical thickness was lower in left dorsolateral prefrontal, anterior temporal regions, and right medial prefrontal, orbitofrontal, and inferior temporal areas of depressed mild AD (MMSE ≥ 20) and LBD [58]. A study using semi-automated method for quantifiying the amount of WMH showed that depressed patients had a larger cumulative WMH volume in the right parietal lobe as compared to AD patients without depression (F=6.46, df=3, 222, p