INTRODUÇÃO: O comprometimento cognitivo leve tem sido estudado em tarefas de linguagem com alta demanda cognitiva. Análises com base em compreensão de textos que exigem realização de inferências são recentes. Este estudo teve como objetivo verificar o desempenho de sujeitos com comprometimento cognitivo leve em tarefas de compreensão textual que necessitem da realização de inferências e compara-lo ao desempenho de sujeitos normais. MÉTODOS: Foram avaliados 60 sujeitos com idade entre 60 e 89 anos, de ambos os sexos. Os sujeitos foram divididos em dois grupos, sendo 30 sujeitos normais e 30 sujeitos com comprometimento cognitivo leve e pareados por faixa de escolaridade (até 4 anos, de 4 a 8 anos e acima de 9 anos). O instrumento utilizado foi a versão em português do teste do \"Gerenciamento do Implícito\" que utiliza cinco tipos distintos de inferências (explícitas, lógicas, pragmáticas, distratoras e outras). Foi avaliado o raciocínio inferencial ao fornecer a resposta de 60 questões referentes à leitura de 20 textos pequenos e comparado o desempenho entre os grupos. RESULTADOS: O grupo de sujeitos com comprometimento cognitivo leve mostrou desempenho significativamente menor na realização de inferências do tipo pragmáticas do que o grupo de sujeitos normais. Para os demais tipos de inferências não houve diferença estatística. CONCLUSÃO: Sujeitos com comprometimento cognitivo leve apresentam pior desempenho na realização de inferências do tipo pragmáticas. A semelhança no desempenho entre os grupos para realizar as demais inferências reforça a preservação de aspectos linguístico-cognitivos no comprometimento cognitivo leve. Os resultados confirmam a possibilidade de diferenciar sujeitos com comprometimento cognitivo leve e normais por meio de testes de linguagem / INTRODUCTION: The mild cognitive impairment has been studied in language tasks with high cognitive demand. Analyses based on comprehension of texts that require carrying out inferences are recent. This study aimed to verify the performance of subjects with mild cognitive impairment in textual comprehension tasks that require carrying out inferences and compares it to the performance of normal subjects. METHODS: We evaluated 60 subjects aged between 60 and 89 years, of both sexes. The subjects were divided into two groups, 30 normal subjects and 30 subjects with mild cognitive impairment, matched for education (up to 4 years, 4-8 years and over 9 years). The instrument used was the Portuguese version of the test of \"Managing the implied\" that uses five distinct types of inferences (explicit, logical, pragmatic, distracting and other). We evaluated the inferential reasoning to provide the answer 60 questions about reading 20 small texts and compared the performance between groups. RESULTS: The mild cognitive impairment group showed significantly lower performance in the type inferences pragmatic than the group of normal subjects. For other types of inferences there was statistical difference. CONCLUSION: The group with mild cognitive impairment showed worse performance in carrying out pragmatic type inferences. The similarity in performance between the groups to perform the other inferences demonstrates the preservation of linguistic-cognitive aspects in mild cognitive impairment. The results confirm the possibility of differentiating subjects with mild cognitive impairment and normal through language tests

On admet aujourd'hui que les tests psychométriques traditionnels paraissent insuffisants pour détecter précocement des troubles cognitifs. Parallèlement, des cliniciens observent une perte de l'automaticité de la marche lors du vieillissement normal ou de pathologies neurodégénératives qui peut être directement imputée au déclin des fonctions exécutives (FE) et aggravé lors des situations de double-tâche (DT). Plusieurs auteurs ont montré que la présence prématurée d'une atteinte motrice pouvait prédire une évolution défavorable vers une démence de type Alzheimer. Dans ce contexte, il devient évident que l'évaluation de la marche doit faire l'objet d'une investigation spécifique lors d'un bilan cognitif. Les travaux de cette thèse s'articulent autour du concept de troubles cognitifs légers, des FE et de l'évaluation motrice lors de diverses situations de marche.L'objectif principal est de déterminer si l'évaluation de la marche spontanée et/ou en DT constitue un outil de détection précoce des troubles cognitifs. Un objectif secondaire est de préciser les FE qui affectent la performance motrice dans les situations de DT. L'originalité de ce travail de thèse réside dans le développement de nouveaux exercices de DT de navigation spatiale basés sur l'adaptation de tests neuropsychologiques (test de Corsi, de Stroop et Trail Making Test) à la marche. Finalement, nous avons aussi proposé un « stroop écologique » qui s'intéresse à la prise de décision de traverser de rue au feu piéton.Les résultats révèlent que les interférences provoquées par les situations de DT entrainent une modification spécifique du schéma de marche du sujet âgé ayant des troubles cognitifs même lorsqu'ils sont infracliniques. De plus, la résolution des tests de DT nécessite la participation commune de plusieurs FE.En conclusion, la batterie de test que nous proposons présente un intérêt potentiel dans la détection précoce des troubles cognitifs chez les sujets âgés, mais aussi dans la compréhension des mécanismes régulant les FE. / Traditional psychometric and/or neuropsychologic tests alone, are not powerful enough to detect cognitive disturbances in aging subjects and therefore new criteria and tests should be developed to get relevant screening tools. Since walking is not anymore considered as a pure automatic motor task but as a task depending both on cognitive and executive functions (EF), clinicians became interested in studying walking disturbances in the course of neurodegenerative pathology development. Walking tasks can be complex and could be assimilated as a double-task (DT) when individuals have to simultaneously proceed with cognitive and motor tasks. Several authors have suggested that disturbances in walking abilities could predict cognitive disorders (e.g. Alzheimer Disease, Mild Cognitive Impairment (MCI)). Therefore, walking abilities should specifically be evaluated during cognitive clinical investigation.The main goal of our work is to evaluate whether a walking task alone and/or walking tasks in the context of DT could be of interest in detecting early stages of cognitive disorders in the elderly. A secondary goal is to investigate what are the executive functions that can influence walking during a DT. The originality of our approach also stems from the new motor ability tests we have developed. They are based on validated neuropsychological tests (Corsi, Stroop and Trail Making Tests) and are adapted to the context of walking. Moreover, we also present an adaptation of the Stroop test in the situation of a pedestrian at the cross light intending to cross a street ("ecological Stroop test").Our results show that DT situations induce specific changes in walking scheme in the elderly with established cognitive disorders and also -and this is one of our most important result- with borderline patients. We also show that the DT we tested required the involment of several EF.In conclusion, the new tests we present could be of interest in detecting early stages of cognitive disorders in elderly subjects and moreover can give clues to the mechanisms involved in the regulation of executive functions.

A neuroimaging feature extraction model is designed to extract region-based image features whose values are predicted by base learners trained on raw neuroimaging morphological variables. The main objectives are to identify Alzheimer’s disease (AD) in its earliest manifestations, and be able to predict and gauge progression of the disease through the stages of mild cognitive impairment (EMCI), late MCI (LMCI) and AD. The model was evaluated on the ADNI database and showed 75.26% accuracy for the challenging EMCI diagnosis based on the 10-fold cross-validation. Our approach also performed well for the other binary classifications: EMCI vs. LMCI (72.3%), EMCI vs. AD (95%), LMCI vs. AD (84.3%), CN vs. LMCI (77.5%), and CN vs. AD (96.5%). By applying the model to the Genome-wide Association Study, along with the sparse Partial Least Squares regression method, we successfully detected risk genes such as the APOE, TOMM40, RVRL2 and APOC1 along with the new finding of rs917100. Moreover, the research aimed to investigate the relationship of different biomarkers; especially the imaging biomarkers to better understand the precise biologic changes that characterize Alzheimer’s disease. The unique and independent contribution of APOE4 allele status (E4+\E4-), amyloid (Aβ) load status (Amy+\Amy-) and combined APOE4 and Aβ status on regional cortical thickness (CTh) and cognition were evaluated via a series of two-way ANCOVAs with post-hoc Tukey HSD tests. Results showed that decreased CTh is independently associated with Amy+ status in many brain regions, but with E4+ status in very restricted number of brain regions. Among CN and EMCI participants, E4+ status is associated with increased CTh, in medial and inferior temporal regions. Diverging association patterns of global and regional Aβ load with cortical volume were found in the entorhinal, temporal pole and parahippocampal regions, which were positively associated with regional Aβ load, but with a negative correlation for global Aβ load in MCI stages. In addition, strong positive correlations were shown between baseline regional CTh and the difference of CTh in each region between the CN and AD, even after adjusting for the regional Aβ and APOE genotype (E4+: r = 0.521 and E4-: r = 0.694).

<p>Skrivning är en biomekaniskt invecklad process som kräver en viss nivå av såväl motorisksom kognitiv förmåga. Forskning om Alzheimers sjukdom tyder på att nedsättningar i flerakognitiva domäner förekommer innan den kliniska diagnosen ställs. Det finns även forskningsom tyder på att ett innehållsrikt skriftspråk i unga år minskar risken för demensutveckling påäldre dagar. För att studera om mått från texter kunde predicera demens på ett tidigt stadiumanalyserades 141 skriftliga bildbeskrivningar insamlade inom ramen för rutinmässigaminnesutredningar vid Karolinska universitetssjukhuset, Huddinge. Deltagarna delades in itre grupper utifrån diagnos (minnesutredning, lindrig kognitiv svikt och demens).Utgångspunkt för studien var de fyra textmåtten: idétäthet, verbtäthet, läsbarhetsindex (LIX)och T-enheter. Då texterna i de flesta fall var skrivna av personer med kognitiv nedsättninghar måtten varit tvungna att modifieras och särskilda instruktioner för bedömning av texternahar utformats. Resultaten tyder på att skriftliga bildbeskrivningar utförda av individer meddemens innehåller färre totalt antal ord än de skrivna av individer diagnostiserade medlindrig kognitiv svikt eller mindre svårigheter än så. De innehåller även färre propositioner,verb, långa ord, T-enheter, ord per T-enhet, har en kortare meningslängd samt har i snitt ettlägre LIX-värde. En logistisk regressionsanalys visade att demens (kontra minnesutredningarmed subjektiva besvär) predicerades signifikant (p < 0.01) av antalet verb samt av LIXvärdet.Totalt 85 % av fallen klassificerades korrekt.</p> / <p>Writing is a biomechanically complex process which demands a certain level of motor aswell as cognitive ability. Research concerning Alzheimer’s disease shows that impairmentsin multiple cognitive domains are notable before a clinical diagnosis can be made. There isalso research which indicates that written language ability in early life predicts the risk ofdementia in old age. The purpose of this study was to analyze whether measures derivedfrom narrative writing could predict dementia cross-sectionally. The material was 141 writtenpicture descriptions collected during routine investigations of cognitive disorders at theMemory Clinic, Karolinska University Hospital, Stockholm. The participants were classifiedinto three groups based on their diagnosis (subjective memory complaints, mild cognitiveimpairment and dementia). This study was based essentially on the four text measures: ideadensity, verb density, index of readability (LIX) and T-unit. As most of the texts were writtenby participants with some degree of cognitive decline the measures had to be modified tosome extent and detailed scoring protocols were worked out. The results indicate that writtenpicture descriptions made by individuals with dementia contained fewer words than thosewritten by individuals diagnosed with mild cognitive impairment or subjective cognitivecomplaints. They also contained fewer propositions, verbs, long words, T-units, words per Tunit,had a shorter mean sentence length and had a lower average LIX-value. A logisticregression analysis showed that cases of dementia, as opposed to subjective cognitivecomplaints, were significally predicted (p < 0.01) by the number of verbs and also by theLIX-value. Overall, 85 % of the cases were correctly classified.</p>

Skrivning är en biomekaniskt invecklad process som kräver en viss nivå av såväl motorisksom kognitiv förmåga. Forskning om Alzheimers sjukdom tyder på att nedsättningar i flerakognitiva domäner förekommer innan den kliniska diagnosen ställs. Det finns även forskningsom tyder på att ett innehållsrikt skriftspråk i unga år minskar risken för demensutveckling påäldre dagar. För att studera om mått från texter kunde predicera demens på ett tidigt stadiumanalyserades 141 skriftliga bildbeskrivningar insamlade inom ramen för rutinmässigaminnesutredningar vid Karolinska universitetssjukhuset, Huddinge. Deltagarna delades in itre grupper utifrån diagnos (minnesutredning, lindrig kognitiv svikt och demens).Utgångspunkt för studien var de fyra textmåtten: idétäthet, verbtäthet, läsbarhetsindex (LIX)och T-enheter. Då texterna i de flesta fall var skrivna av personer med kognitiv nedsättninghar måtten varit tvungna att modifieras och särskilda instruktioner för bedömning av texternahar utformats. Resultaten tyder på att skriftliga bildbeskrivningar utförda av individer meddemens innehåller färre totalt antal ord än de skrivna av individer diagnostiserade medlindrig kognitiv svikt eller mindre svårigheter än så. De innehåller även färre propositioner,verb, långa ord, T-enheter, ord per T-enhet, har en kortare meningslängd samt har i snitt ettlägre LIX-värde. En logistisk regressionsanalys visade att demens (kontra minnesutredningarmed subjektiva besvär) predicerades signifikant (p &lt; 0.01) av antalet verb samt av LIXvärdet.Totalt 85 % av fallen klassificerades korrekt. / Writing is a biomechanically complex process which demands a certain level of motor aswell as cognitive ability. Research concerning Alzheimer’s disease shows that impairmentsin multiple cognitive domains are notable before a clinical diagnosis can be made. There isalso research which indicates that written language ability in early life predicts the risk ofdementia in old age. The purpose of this study was to analyze whether measures derivedfrom narrative writing could predict dementia cross-sectionally. The material was 141 writtenpicture descriptions collected during routine investigations of cognitive disorders at theMemory Clinic, Karolinska University Hospital, Stockholm. The participants were classifiedinto three groups based on their diagnosis (subjective memory complaints, mild cognitiveimpairment and dementia). This study was based essentially on the four text measures: ideadensity, verb density, index of readability (LIX) and T-unit. As most of the texts were writtenby participants with some degree of cognitive decline the measures had to be modified tosome extent and detailed scoring protocols were worked out. The results indicate that writtenpicture descriptions made by individuals with dementia contained fewer words than thosewritten by individuals diagnosed with mild cognitive impairment or subjective cognitivecomplaints. They also contained fewer propositions, verbs, long words, T-units, words per Tunit,had a shorter mean sentence length and had a lower average LIX-value. A logisticregression analysis showed that cases of dementia, as opposed to subjective cognitivecomplaints, were significally predicted (p &lt; 0.01) by the number of verbs and also by theLIX-value. Overall, 85 % of the cases were correctly classified.

Introduction : Les individus présentant des troubles cognitifs légers ou Mild Cognitive Impairment (MCI) sont plus à risque de développer une maladie d’Alzheimer (MA) que le reste de la population âgée. Objectif : Cette étude repose sur le recours à un devis de type étude de cas multiples dont l’objectif est de contribuer à l’identification d’indices biologiques en quantifiant, à l’aide de la résonance magnétique spectroscopique (MRS), des changements métaboliques précoces chez les individus avec MCI, susceptibles d’évoluer vers la MA. Méthodologie : Huit individus MCI sont comparés à huit individus âgés normaux. Chaque participant est soumis à un examen MRS. Résultats : Parmi les huit participants MCI recrutés, l’un d’entre eux présente désormais un profil cognitif concordant avec une MA. L’analyse spectrale des métabolites de cet individu montre des ratios de glutamate plus élevés au niveau du cortex préfrontal gauche et de la régioncingulaire postérieure gauche. Bien qu’une diminution de NAA/Cr soit fréquemment observée chez la population MCI en voie d’évoluer vers la démence, les résultats obtenus ne démontrent rien en ce sens. Discussion/Conclusion : Le rôle du glutamate dans les processus neurodégénératifs est encore mal établi. L’augmentation de glutamate observée est contraire à la diminution habituellement observée au cours de la MA. Ces résultats sont toutefois explicables par l’existence possible d’excitotoxicité précoce chez les MCI en voie de d’évoluervers la démence. Cela pourrait aussi illustrer des mécanismes de compensation présents avant qu’un déclin cognitif ne soit objectivable. / Background: Mild cognitive impairment (MCI) characterizes individuals who present some cognitive impairment without criteria for dementia. Known as a highly plausible transitional stage between normal aging and Alzheimer’s disease (AD), the majority of individuals with MCI will eventually evolve to AD. Objective: The general aim of this multiple-cases study is to explore the contribution of magnetic resonance spectroscopy (MRS) to the neurochemical identification individuals with MCI in the process of evolving toward an AD. Methodology: Eight individuals were compared to eight age and education matched-controls. For each participant, MRS measures for XX neurometabolites were taken from the left prefrontal and left posterior cingulate gyrus. Results: Among all the MCI participants, one of them converted to AD during the time of the study. The spectral analysis of this participant showed higher glutamate/glutamine ratios in both regions. Although a reduction of Naa/Cr is often/generally observed among the MCI population moving/headed toward dementia, the obtained/experimental results show/demonstrate nothing in this sense. Discussion/Conclusion: The role of glutamate in pathological processes is not well-known. These results suggest the probable existence of excitotoxicity mechanisms in MCI subjects who will convert to AD, a mechanism that could express the presence of some compensatory processes. While reporting the challenge of MRS measures in this population, this study provide indications of its potential for the early detection of AD in a MCI population.

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Parkinson’s disease patients present with the highest risk of dementia development. The thalamus, integral to several functions and behaviours is involved in the pathophysiology of Parkinson’s disease. The aim of this thesis was to determine if anatomical abnormalities in the thalamus are associated with the development of dementia in Parkinson’s disease. We examined the thalamus using macro and microstructural techniques and the white matter pathways that connect the thalamus with areas of the surrounding cortex using diffusion tensor imaging (DTI) based tractography. T1-weighted magnetic resonance and DT images were collected in 56 Parkinson’s disease patients with no cognitive impairment, 19 patients with mild cognitive impairment, 17 patients with dementia and 25 healthy individuals who acted as control subjects. An established automated segmentation procedure (FIRST FSL) was used to delineate the thalamus and a modified k-means clustering algorithm applied to segment the thalamus into clusters assumed to represent thalamic nuclei. Fibre tracts were determined using DTI probabilistic tracking methods available in FIRST. Microstructural integrity was quantified by fractional anisotropy and mean diffusivity (MD) DTI measures. Results show that microstructural measures of thalamic integrity are more sensitive to cognitive dysfunction in PD than macrostructural measures. For the first time we showed a progressive worsening of cellular integrity (MD) in the groups who had greater levels of cognitive dysfunction. Thalamic degeneration was regionally specific and most advanced in the limbic thalamic nuclei which influenced executive function and attention, areas of cognition that are known to be affected in the earliest stages of PD. The integrity of the fibre tracts corresponding to these thalamic regions was also compromised. Degeneration of fibre tracts was most evident in the dementia group, indicating that they may be more protected against Lewy pathology than the nuclei of the thalamus. Our findings confirm previous histological, animal and lesion studies and provide a reliable estimate of cortical degeneration in PD that can be applied non-invasively and in vivo. A longitudinal study is needed to monitor the progression of cognitive decline in PD but we have provided the basis for further investigation into the predictive validity of thalamic degeneration for cognitive dysfunction. In the future, the microstructural changes of the thalamus could be used as biomarkers for the identification of individuals with a higher risk for dementia development and for the longitudinal monitoring of any interventions into cognitive decline.

Mild cognitive impairment (MCI) is a transition phase between normal aging and Alzheimer’s disease. Individuals with MCI show impairment in cognition as well as corresponding damage to areas of their brain. Performance on tasks such as discriminating objects with ambiguous features has been associated with damage to the perirhinal cortex, while scenes with structural (spatial) elements have been associated with damage to the hippocampus. In addition, attention is regarded as one of the first non-memory domains to decline in MCI. A relatively new MRI technique called diffusion tensor imaging (DTI) is sensitive to white matter microstructural integrity and has been associated with changes due to cognitive decline. 18 MCI (14 amnesic, 4 vascular) and 12 healthy matched controls were assessed in feature ambiguity, attention and structural learning to assess associated deficits in MCI. Associations with white matter microstructural integrity were then investigated. The MCI groups were discovered to perform worse than controls on the test of structural learning. In addition, altered attention networks were found in MCI and were associated with white matter microstructural integrity. No significant differences were found for feature ambiguity. These findings suggest there may be specific damage to the hippocampus while the perirhinal cortex may be preserved in MCI. Furthermore, dysfunction in attention was found to be associated with white matter microstructural integrity. These experimental tests may be useful in assessing dysfunction in MCI and identifying degeneration in white matter microstructural integrity. Further studies with larger sample sizes are needed to validate these findings.

Studies presented in this dissertation were conducted to gain more insight into the role of phospholipid asymmetry and amyloid-β (Aβ)-induced oxidative stress in brain of subjects with amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD). AD is a largely sporadic, age-associated neurodegenerative disorder clinically characterized by the vast, progressive loss of memory and cognition commonly in populations over the age of ~65 years, with the exception of those with familial AD, which develop AD symptoms as early as ~30 years-old. Neuropathologically, both AD and FAD can be characterized by synapse and neuronal cell loss in conjunction with accumulation of neurofibrillary tangles and senile plaques. Elevated levels of oxidative stress and damage to brain proteins, lipids, and nucleic acids are observed, as well. Likewise, aMCI, arguably the earliest form of AD, displays many of these same clinical and pathological characteristics, with a few exceptions (e.g., no dementia) and to a lesser extent. Studies in this dissertation focused on the contributions of oxidative stress to the exposure of phosphatidylserine (PtdSer) to the outer-leaflet of the lipid membrane, how and when PtdSer asymmetric collapse contributes to the progression of aMCI, AD, and FAD, and the role played by methionine-35 (Met-35) of Aβ in oxidative stress and damage, as measured in a transgenic mouse model of Aβ pathology. Normally, the PtdSer is sequestered to the cytosolic, inner-leaflet of the bilayer by the adenosine triphosphate (ATP)-dependent, membrane-bound translocase, flippase, which unidirectionally transports PtdSer inward against its concentration gradient. Oxidative stress-induced modification of flippase and/or PtdSer, however, leads to prolonged extracellular exposure of PtdSer on the outer membrane leaflet, a known signal for both early apoptosis and selective recognition and mononuclear phagocytosis of dying cells. Within the inferior parietal lobule (IPL) of subjects with aMCI and AD, a significant collapse in PtdSer asymmetry was found in association with increased levels of both pro- and anti-apoptotic proteins, Bax, caspase-3, and Bcl-2. Moreover, a significant collapse in PtdSer asymmetry was also found in whole brain of human double-mutant knock-in mouse models of Aβ pathology, together with significantly reduced Mg2+ATPase activity, representing flippase activity, and increased levels of pro-apoptotic caspase-3. Significant PtdSer externalization corresponded to the age at which significant soluble Aβ(1-42) deposition occurs in this particular mouse model (9 months), and not of plaque deposition (12 months), suggesting that elevated levels of Aβ(1-42), together with increasing oxidative stress and apoptosis, may contribute to altered PtdSer membrane localization. Also in this dissertation, transgenic mice carrying Swedish and Indiana mutations on the human amyloid precursor protein (APPSw,In) and APPSw,In mice carrying a Met35Leu mutation on Aβ were derived to investigate the role of Met-35 in Aβ(1-42)-induced oxidative stress in vivo. Oxidative stress analyses revealed that Aβ-induced oxidative stress requires the presence of Met-35, as all indices of oxidative damage (i.e., protein carbonylation, nitration, and protein-bound 4-hydroxy-2-trans-nonenal [HNE]) in brain of Met35Leu mice were completely prevented. Moreover, immunohistochemical analyses indicated that the Met35Leu mutation influences plaque formation, as a clear reduction in Aβ-immunoreactive plaques in Met35Leu mice was found in conjunction with a significant increase in microglial activation. In contrast, behavioral analyses suggested that spatial learning and memory was independent of Met-35 of Aβ, as Met35Leu mice demonstrated inferior water-maze performance compared to non-transgenic mice. Differential expression and redox proteomic analyses to pinpoint proteins significantly altered by the APPSw,In and Met35Leu mutations was performed, as well. Expression proteomics showed significant increases and decreases in APPSw,In and Met35Leu mouse brain, respectively, in proteins involved in cell signaling, detoxification, structure, metabolism, molecular chaperoning, protein degradation, mitochondrial function, etc. Redox proteomics found many of these same proteins to be oxidatively modified (i.e., protein carbonylation and nitration) in both APPSw,In and Met35Leu mouse brain, providing additional insights into the critical nature of Met-35 of Aβ for in vivo oxidative stress in a mammalian species brain, and strongly suggesting similar importance of Met-35 of Aβ(1-42) in brain of subjects with aMCI and AD. Taken together, studies presented in this dissertation demonstrate the role of oxidative stress-induced alteration of PtdSer asymmetry and Met-35 in Aβ-induced oxidative stress in aMCI, AD, and FAD brain.