Le premier objectif de cette thèse était d’explorer l’effet de référence à soi (ERS) sur la mémoire dans le vieillissement, l’amnestic Mild Cognitive Impairment (aMCI) et la maladie d’Alzheimer (MA) à un stade précoce de l’évolution. Le second fut de revisiter les théories actuelles pour expliquer ce bénéfice mnésique, puis de tenter d’élucider ses mécanismes. Nous avons montré que l’ERS sur les représentations sémantiques de ses propres traits de personnalité (qui est une composante de notre identité) était préservé dans le vieillissement. Par ailleurs, nous avons montré que la profondeur de traitement, longtemps considérée comme le processus sous-tendant l’ERS, n’intervenait pas dans ce dernier. A contrario, l’interaction de l’âge et de l’estime de soi, ainsi que les expériences de vie des individus modulaient l’ERS. Nous avons montré que l’ERS pouvait résulter de deux processus : celui de la consistance des traits de caractère et celui de l’élaboration automatique des traits de caractère avec l’identité des individus. Nous avons par ailleurs rapporté pour la première fois que ce bénéfice mnésique s’opérait chez des patients atteints d’aMCI, un stade symptomatique et pré-démentiel de la MA, et qu’il pouvait s’observer dans une moindre mesure chez des patients MA. En outre, l’ERS agit comme mécanisme de self-défense chez les patients aMCI et MA, en les protégeant d’informations menaçantes pour l’intégrité de leur soi. Nous suggérons en dernier lieu que la référence à soi pourrait servir d’outil de réhabilitation sociale ou clinique pour augmenter l’estime de soi de certains individus et préserver leur mémoire et leur bien-être. / The first aim of this thesis was to examine the self-reference effect (SRE) on memory in aging, amnestic mild cognitive impairment (aMCI) and early-stage of Alzheimer’s disease (AD). The second aim was to review the whole literature on the SRE and to attempt understanding its mechanisms. We showed that the SRE on semantic summary representations of one’s traits (which is a component of identity) was preserved in aging. Besides, we showed that depth of processing, which was hitherto regarded as the mechanism responsible for the SRE, did not actually play a role in the latter. By contrast, the interaction of age and self-esteem, as well as individuals’ life experiences modulated the SRE. We showed that the SRE resulted from two processes: the congruency of traits as well as the elaboration of traits with individuals’ identity. We also reported for the first time that aMCI patients benefited from the SRE, as well as AD patients in the early stage of the disease to a lesser extent. Furthermore, the SRE acted as a self-defense mechanism in patients with aMCI and AD by protecting them from negative feedback that constituted a threat to the integrity of their selves. Finally, we suggest that referencing the self could serve as a tool for social or clinical rehabilitation programs, by increasing the self-esteem of some individuals and preserving their memory and well-being.

BACKGROUND: Mild cognitive impairment (MCI) is a clinical condition that is characterized by mild changes in cognition. The amnestic form of MCI (aMCI) primarily affects memory and is thought to represent a stage between healthy aging and Alzheimer’s disease (AD). The medial temporal lobe (MTL) and the limbic system are two areas of the brain that have been implicated in the amnestic form of MCI. While MCI represents a risk factor for AD, it does not always lead to dementias. Being a carrier of the APOE Ɛ4 allele has also shown to increase chances of progression from MCI to AD. OBJECTIVE: To determine whether the subnuclei of the amygdala, along with other specific regions within the MTL, can differentiate between cognitively normal individuals and age-matched subjects with aMCI. METHODS: T1-weighted magnetic resonance imaging (MRI) data from two sources, the Boston University Alzheimer’s Disease Center (BU-ADC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), was compiled for cross-sectional analysis. 95 scans in total from 45 cognitively normal participants and 50 diagnosed with aMCI were analyzed and the volumes of interest were automatically generated by the developmental version of FreeSurfer v6.0. To evaluate how well the volumes could predict either group membership (i.e. control group or MCI group) or APOE Ɛ4 status (i.e. carrier or noncarrier), the variables were assessed by nominal logistic regression models. RESULTS: Six of the nine nuclei of the amygdala had significantly reduced volumes in the aMCI group compared to controls. The whole amygdala and the perirhinal cortex also demonstrated reduced volumes in the aMCI group compared to the control group. The whole amygdala was a good predictor of group membership (R2 = 0.1386, whole model test chi square = 18.21558, p = 0.0004), but none of the subnuclei were good predictors individually. A model containing the 9 nuclei, the entorhinal cortex, and the perirhinal cortex provided a good fit for predicting APOE Ɛ4 status fit (R2 = 0.3000, whole model test chi square = 36.29563, p = 0.0002) and the best predictor was the corticoamygdaloid transition area of the amygdala. CONCLUSIONS: The results of our study confirm previous findings of reduced whole amygdala volume and add to the limited literature of reduced perirhinal cortex and amygdaloid nuclei volumes in MCI compared to healthy controls. To the best of our knowledge, this was the first time the automatic segmentation atlas was used to analyze the volumes of nine subnuclei of the amygdala in a population of aMCI. Our model testing the volume of the whole amygdala accurately predicted aMCI subjects with 58% accuracy and controls with 70% accuracy; the accuracy rose to 69% when the entorhinal cortex and the perirhinal cortex were added to the model to predict aMCI subjects from controls. Additionally, the model for predicting APOE Ɛ4 status identified noncarriers of the allele at 85% accuracy. Future studies should consider increasing the sample size to better assess small ROIs and assess for differences in the separate hemispheres.

Although not all persons with mild cognitive impairment (MCI) go on to develop Alzheimer's disease (AD), MCI is recognized as an early stage of AD. The effects of AD are devastating to all concerned. Research has identified that recognition of AD in its earliest stages and institution of known treatment modalities can forestall the ultimate outcome. Identification of the first subtle signs of MCI can assist in the recognition of this prodromal phase, and allow for institution of therapy while still in the initial stages. Unfortunately, the development of MCI is insidious in nature, thus making it difficult to detect. The purpose of this study was to identify areas of functional decline that occur in MCI in an effort to improve its early identification. A mixed-methods design that combined qualitative and quantitative methods was used. Fifty-three participants with memory complaints were interviewed using a semi structured interview technique with open-ended questions, the Montreal Cognitive Assessment (MoCA), the Geriatric Depression Scale (GDS) and a list of eighty-five items previously identified as indicative of functional decline. Twenty-nine persons were divided into two groups: 1) those identified as probable MCI (consensus diagnosis) (n=15) and possible MCI (based on screening examination) (n=14) and 2) those identified as Normal (no cognitive impairment) (n=10), and their subjective functional deficits compared. The findings suggest that there were certain areas of functional decline more commonly experienced by persons in the MCI group than by unimpaired. These include difficulty recalling details of information and forgetting conversations. There were also other changes identified, such as adaptations on the part of persons with MCI (an increased dependence on memory aids, for example, lists and calendars) and a dec rease in social activities leading to an increase in social isolation. Additionally identified were functional activities that appear to remain intact in persons with early MCI. This study highlights the subtlety with which MCI assaults the functional abilities of individuals, thus making its early identification problematic. The results of this study will contribute by providing information that will help professionals who are assessing persons experiencing memory issues for the possible presence of MCI. Additionally, it is hoped that these findings will assist in the development of a measurement tool designed to assess for possible MCI. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2015. / FAU Electronic Theses and Dissertations Collection

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.

No description available.

La mémoire de reconnaissance visuelle (MRV) est atteinte précocement dans la maladie d'Alzheimer (MA). Or, elle reposerait sur deux processus : la familiarité (simple sentiment d'avoir déjà rencontré un item) et la recollection (récupération de détails associés à l'item lors de son encodage). Si la recollection est clairement atteinte au début de la MA, les résultats concernant la familiarité sont à ce jour contradictoires. Supposée plus rapide que la recollection, la familiarité devrait pouvoir être évaluée directement par une approche temporelle. Son atteinte dans la MA pourrait alors être mieux comprise.Pour tester ces hypthèses, la procédure comportementale SAB (Speed and Accuracy Boosting) a été créée. Permettant d'étudier les propriétés de la MRV (sa vitesse-limite, Articles 1 et 2, ou sa nature « bottom-up », Article 3), ainsi que l'hypothèse que la familiarité est plus rapide que la recollection, cette méthode s'est montrée évaluer majoritairement la familiarité (Article 1). Chez des patients à risque de MA, une dissociation inattendue au sein de la familiarité a alors pu être révélée, avec une atteinte des signaux tardifs de familiarité (utilisés lors d'un jugement classique), mais une préservation des premiers signaux (supportant la détection rapide évaluée en SAB) (Article 4).En outre, la segmentation manuelle d'images IRM du lobe temporal interne (premières régions cérébrales touchées dans la MA, et clées pour la MRV) a été appliquée à la problématique connexe de l'effet de l'âge au début de la MA (Article 5).Indépendamment, ces méthodes ont permis de mieux comprendre la MRV et son atteinte au début de la MA ; leur combinaison s'annonce très prometteuse. / Visual recognition memory (VRM) is impaired early in Alzheimer's Disease (AD), but would rely on two processes : familiarity (mere feeling that an item has been seen previously) and recollection (retrieval of details associated to the item at encoding). If recollection is clearly impaired in early AD, results concerning familiarity remain contradictory. Supposed to be faster than recollection, familiarity should be better understood using a temporal approach. Its possible impairment in AD could then be better understood.In order to test this, a behavioural procedure was designed: the SAB (Speed and Accuracy Boosting). Revealing different properties of VRM (its speed-limit, Articles 1 and 2; its « bottom-up » nature, Article 3) and some of its processes (familiarity appeares indeed faster than recollection, Article 1), results showed that the SAB procedure was mainly assessing familiarity (Article 1). In patients at risk of AD, an unexpected dissociation within familiarity processes was evidenced, with an impairment of late signals of familiarity (as used for classical judgements), but a preservation of the first signals (supporting fast detection assessed with the SAB) (Article 4).Last, manual segmentation of MRI images of the medial temporal lobe (first cerebral regions affected in AD, known for their key role in VRM) was also used to assess age effect at the early stage of AD (Article 5).Independently, both methods allowed understanding better the VRM and its impairment in early AD; their combination appears very promising.

Orientador: Gabriela Castellano / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Fisica Gleb Wataghin / Made available in DSpace on 2018-08-15T22:34:24Z (GMT). No. of bitstreams: 1 Oliveira_MarciaSilvade_D.pdf: 17533323 bytes, checksum: 32a83eb4815b68f061baa91a4b0ab2e4 (MD5) Previous issue date: 2010 / Resumo: Análise de textura em imagens digitais é um termo que se refere a um grupo de técnicas de processamento de imagens que objetivam a extração de descritores da imagem ou de regiões de interesse (ROIs) de forma a simplificar a caracterização das mesmas. A textura pode ser entendida como características intrínsecas da imagem (por exemplo: brilho, cor e distribuição de formas) que remetem à ideia de regularidade, rugosidade, suavidade, entre outras, por isso o nome 'textura'. Um tipo particular de análise de textura, bastante utilizado em imagens médicas, se baseia em medidas estatítsticas relativas à distribuição de níveis de cinza da imagem (matriz de coocorrência). Os descritores de textura, baseados na matriz de coocorrência, são conhecidos como descritores de Haralick. Este trabalho consistiu na aplicação de vídeo deste tipo de análise em imagens de Tomografia Computadorizada (TC) de vítimas de Acidente Vascular Cerebral Isquêmico e em imagens de Ressonância Magnetica (RM) de portadores de Epilepsia Mioclônica Juvenil, Doença de Machado-Joseph, Déficit Cognitivo Leve e Doença de Alzheimer, visando o desenvolvimento de uma ferramenta computacional que auxilie o neurologista na identificação de areas atingidas por estas doenças e que não sejam distinguíveis em uma análise visual. Neste trabalho foram selecionadas regiões de interesse (ROIs) e calculados os parâmetros de textura para cada grupo de imagens. Após o cálculo dos descritores de textura foi realizada uma análise estatística para verificar se havia diferenciação entre os vários tipos de tecidos. Os resultados obtidos mostraram que a análise de textura pode, de fato, ser utilizada para a extração de características discriminantes, tanto nas imagens de TC quanto nas imagens de RM para as cinco patologias analisadas / Abstract: Texture analysis in digital images is a term that refers to a group of image processing techniques that aim to extract descriptors of the image or regions of interest (ROIs) in order to simplify their characterization. Texture may be understood as intrinsic characteristics of the image (such as brightness, color and distribution of forms) that refer to the idea of regularity, roughness and smoothness, hence the name 'texture'. A particular type of texture analysis, widely used in medical imaging, is based on statistical measurements related to the image gray level distribution (coocurrence matrix). The texture descriptors based on the coocurrence matrix are known as Haralick descriptors. This work consisted on applying this type of analysis to computed tomography (CT) images of victims of Ischemic Stroke and magnetic resonance images (MRI) of patients with Juvenile Myoclonic Epilepsy, Machado-Joseph disease, mild cognitive impairment and Alzheimer's disease, in order to develop a computational tool to assist neurologists in the identification of areas affected by these diseases and which are not perceived in a visual analysis. In this work we selected regions of interest (ROIs) and calculated the texture parameters for each group of images. After the calculation of the texture descriptors, a statistical analysis was performed to determine whether there was differentiation between the various types of tissues. The results showed that texture analysis can indeed be used for the extraction of discriminant features in both the CT an the MR images for the five studied pathologies / Doutorado / Física / Doutora em Ciências