INTRODUÇÃO: A busca pelo diagnóstico cada vez mais precoce das demências traz a necessidade de estratégias mais eficientes na utilização dos testes cognitivos. A definição dos parâmetros de normalidade para esses testes é particularmente desafiadora no contexto brasileiro de baixa escolaridade e grande heterogeneidade sociocultural. OBJETIVO: Avaliar os efeitos de diferentes estratégias de ajuste de normas nas propriedades do Mini-Exame do Estado Mental (MEEM). MÉTODOS: Duzentos e trinta idosos encaminhados a um serviço de Geriatria por suspeita de comprometimento cognitivo foram recrutados sequencialmente e submetidos ao MEEM. Todos os pacientes passaram por uma segunda avaliação cega para o resultado do MEEM, constituída de testagem neuropsicológica e entrevista com um informante para obtenção de diagnóstico padrão-ouro. Para o ajuste de normas, quatro fatores preditores foram testados: (1) características sociodemográficas; (2) uma classificação simples de alfabetismo funcional com quatro níveis; (3) um questionário de habilidades cognitivas pré-morbidas respondido pelo informante; (4) um teste de leitura de palavras aplicado diretamente ao paciente. Três técnicas de predição foram testadas: (1) agrupamento em níveis; (2) regressão linear; (3) regressão não-linear por modelo polinomial fracional. As combinações de fatores preditores e técnicas de predição deram origem a vinte modelos que foram testados individualmente na comparação com o MEEM sem ajuste. Os desfechos avaliados foram a acurácia do modelo na detecção de comprometimento cognitivo e a variação da sensibilidade e da especificidade entre os níveis socioeconômicos. RESULTADOS: Entre os 230 idosos recrutados, 106 (46%) apresentavam envelhecimento cognitivo normal, 56 (24%) comprometimento cognitivo sem demência e 68 (29%) demência. A classificação de alfabetismo funcional, o questionário de habilidades cognitivas pré-mórbidas e o teste de leitura de palavras não apresentaram propriedades adequadas para ajuste de normas, mas as limitações podem estar relacionadas a problemas específicos dos instrumentos utilizados e não devem ser generalizadas. Alguns modelos baseados em fatores sociodemográficos foram capazes de melhorar a acurácia do MEEM, resultado que diverge da literatura atual e que deve ser confirmado em outros estudos com populações de baixa escolaridade. Um modelo polinomial fracional utilizando variáveis sociodemográficas apresentou propriedades ótimas de acurácia e promoveu estabilização da sensibilidade e da especificidade entre os níveis socioeconômicos. A partir das equações geradas por esse modelo podem ser construídas tabelas simples de uso clínico para converter o resultado bruto em escore z ou percentil. CONCLUSÕES: Nossos resultados apontam o modelo polinomial fracional baseado em variáveis sociodemográficas como a melhor opção para ajuste de normas de testes cognitivos em nosso meio / INTRODUCTION: The need for diagnosing dementia early demands effective strategies on the use of cognitive tests. Establishing criteria of normality for these tests is a challenging task in environments of low education and enormous sociocultural heterogeneity such as observed in Brazil. OBJETIVE: To evaluate how different strategies for adjusting norms can change the properties of the Mini-Mental Status Examination (MMSE). METHODS: Two hundred and thirty older adults referred for a geriatric service because of suspected cognitive impairment were recruited sequentially and completed the MMSE. All the patients underwent a second assessment, blind to the result of the MMSE, which was composed of a neuropsychological battery and an interview with a close informant for the establishment a gold-standard diagnosis. For the adjustment of the norms, four predictive factors were evaluated: (1) demographic characteristics; (2) a simple classification of functional literacy with four levels; (3) a premorbid abilities questionnaire; (4) a word-reading test. Three techniques of prediction were evaluated: (1) grouping in demographic or ability levels; (2) simple or multivariate linear regression; (3) nonlinear regression by using a fractional polynomial model. Some possible combinations of predictive factors and prediction techniques originated twenty models that were assessed individually in comparison with the raw MMSE scores. The endpoints assessed were accuracy of the model for detecting cognitive impairment and the variation of the sensibility and specificity across socioeconomic levels. RESULTS: Of the 230 older adults recruited, 106 (46%) had normal cognitive aging, 56 (24%) presented cognitive impairment no dementia (CIND) and 68 (29%) had dementia. The functional literacy classification, the premorbid cognitive abilities questionnaire and the word-reading test did not present adequate properties for the adjustment of norms, but the limitations may be associated to specific problems of the instruments an cannot be generalized. Some models based on the demographic characteristics were able to improve the accuracy of the MMSE. This finding diverges from the currently available literature and should be confirmed in further studies with low-educated populations. A fractional polynomial model employing demographic factors presented very good properties and was able to stabilize the sensibility and the specificity across the socioeconomic levels. The equations generated by this model can be employed to construct practical tables for converting raw scores into z scores and percentiles. CONCLUSIONS: Our results point to the fractional polynomial model based on demographic variables as the best choice to adjust norms for cognitive tests in our context

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No. of bitstreams: 1 Josélia Braz dos Santos Ferreira.pdf: 3515861 bytes, checksum: 7ce85c03078e93aebb216e487af5816e (MD5) Previous issue date: 2014 / Mestrado Acadêmico em Ciências do Cuidado em Saúde / Trata-se de um estudo quantitativo com uma abordagem quase experimental, cujo objetivo geral foi analisar os efeitos das atividades psicomotoras para o equilíbrio em idosos com distúrbio cognitivo leve e os objetivos específicos foram identificar o déficit psicomotor nos idosos com Déficit Cognitivo Leve utilizando a Escala Motora para a Terceira Idade (EMTI) e a Escala de Tinetti; implementar atividades e exercícios psicomotores para o idoso com Déficit Cognitivo Leve visando a melhora dos fatores psicomotores com ênfase ao equilíbrio e marcha; comparar as condições psicomotoras dos idosos com Déficit Cognitivo Leve antes e após a implementação de atividades e exercícios psicomotores. A pesquisa foi realizada em um período de 4 (quatro) meses, com início em abril de 2014 e término em julho de 2014. Os sujeitos do estudo foram 43 idosos de duas instituições públicas, na faixa etária entre 64 a 88 anos, 86,04% do sexo feminino. O estudo desenvolveu metas que foram cumpridas de acordo com a Teoria do Alcance de Metas de Imogene King. Foi aplicado o MEEM (Mini Exame do Estado Mental) em todos os idosos para avaliação da memória. Para avaliar os parâmetros motores foi utilizada a Escala Motora para Terceira Idade (EMTI) e para avaliar o Equilíbrio e a Marcha, a Escala de Tinetti; foi utilizado também o Diário de Quedas do Idoso. As escalas foram aplicadas antes e após a implementação das atividades psicomotoras, que foram realizadas durante 10 (dez) sessões. Nos resultados, utilizou-se do software estatístico SAS versão 9.3.1, tal que primeiramente realizou-se uma análise descritiva dos dados, dividindo em primeira medida (primeira avaliação) e segunda medida (segunda avaliação). A avaliação do MEEM mostrou 15 (quinze), 34,88%, dos idosos avaliados apresentaram sinais sugestivos de déficit cognitivo. Resultados relacionados ao desempenho dos idosos nos parâmetros motores Motricidade Fina, Organização Espacial e Organização temporal, tanto na primeira como na segunda medidas apresentaram bons resultados e ficaram na classificação normal médio da EMTI. No entanto, na primeira avaliação, os parâmetros Motricidade Global, obteve média de 34,88 pontos, equivalente a classificação muito inferior; o Esquema Corporal com média de 76,46 pontos correspondeu a classificação inferior; e também o Equilíbrio com média de 79,81 pontos ficou na classificação inferior. Estes resultados corresponderam aos resultados do Equilíbrio e Marcha da Escala de Tinetti, que apresentou 22 (51,16%) idosos com média de 17,22 pontos e ficaram, segundo a escala, com alto risco para quedas. Os resultados destas escalas foram corroborados com os resultados do Diário de Quedas dos Idosos, onde 26 (60,47%) idosos sofreram 52 quedas, sendo que 33 (63,46%) quedas ocorreram por desequilíbrios e 31 (59,62%) quedas foram na rua. Na segunda avaliação após as atividades implementadas, os idosos apresentaram melhores resultados com mudança da classificação de acordo com os escores, exceto a Motricidade Global, que permaneceu na classificação muito inferior. No entanto, o Esquema Corporal mudou para a classificação normal baixo com média de 86,93 pontos, o Equilíbrio mudou da classificação inferior para normal médio com média de 92,37 pontos. O Equilíbrio e marcha da Escala de Tinetti apresentou aumento em seus escores e a maioria dos idosos, 28 (65,11%), ficaram com risco moderado para quedas segundo a escala. Concluiu-se com os resultados na segunda medida, que as metas foram alcançadas e a hipótese de que o exercício de estimulação psicomotora favorece o equilíbrio de idosos com distúrbio cognitivo leve foi confirmada / This is a quantitative study with a quasi-experimental approach, whose general objective was to analyze the effects of psychomotor activities for balance in elderly people with mild cognitive impairment and specific objectives were to identify the psychomotor deficit in the elderly with mild cognitive deficit using the Scale motor for the Elderly (EMTI) and the Tinetti scale; implement activities and psychomotor exercises for the elderly with Mild Cognitive Deficit aimed at improving the psychomotor factors with emphasis on balance and gait; compare psychomotor conditions of elderly people with Mild Cognitive Deficit before and after the implementation of activities and psychomotor exercises. The survey was conducted over a period of four (4) months, starting in April 2014 and ending in July 2014. The study subjects were 43 elderly two public institutions, aged between 64 and 88 years, 86, 04% female. The study developed goals that were performed in accordance with the Scope of the Theory of Imogene King Goals. The MMSE (Mini Mental State Examination) in all the elderly to assess memory was applied. To evaluate the motor parameters we used the Motor Scale for the Elderly (EMTI) and to assess the balance and the March, the Tinetti Scale; we used the Elderly Falls Journal. The scales were applied before and after the implementation of psychomotor activities, which were performed for 10 (ten) sessions. In the results, we used the SAS statistical software version 9.3.1, such that first carried out a descriptive analysis of data, sharing in a first step (first evaluation) and second measurement (second evaluation). The assessment of the MMSE was 15 (fifteen), 34.88% of the sample respectively showed signs suggestive of cognitive impairment. Results related to the performance of the elderly in the parameters Motricity Thin engines, Space Organization and temporal organization, both in the first and second measurements showed good results and were in the normal average rating of EMTI. However, the first evaluation, the Global Kinetics parameters obtained an average of 34.88 points, equivalent to much lower rating; the Body Scheme averaging 76.46 points corresponded to a lower classification; and also the balance with an average of 79.81 points was in a lower classification. These results corresponded to the results of Balance and Gait Tinetti Scale, which showed 22 (51.16%) elderly with an average of 17.22 points and were, according to the scale at high risk for falls. The results of these scales were corroborated by the results of the Seniors' Falls Gazette, where 26 (60.47%) elderly suffered 52 falls, of which 33 (63.46%) decreases occurred by imbalances and 31 (59.62%) falls were in the street. In the second evaluation after the implemented activities, the elderly showed better results with rating change according to the scores, except the Global Mobility, which remained much lower rating. However, the Body Scheme moved to low normal rating with an average of 86.93 points, the balance changed the lower rating for average normal with an average of 92.37 points. The Balance and Gait Tinetti Scale showed an increase in their scores and most elderly, 28 (65.11%) were at moderate risk for falls under the scale. Concluded with the results in the second measure, which targets have been achieved and the hypothesis that the psychomotor stimulation exercise favors the balance of elderly patients with mild cognitive impairment was confirmed

Personer med kognitiva nedsättningar tillhör en av de största grupperna av funktionsnedsatta personer. Premium Comai är ett hjälpmedel för att hjälpa personer med kognitiva nedsättningar att bli mer självständiga i deras vardag. Denna målgrupp har framförallt svårigheter med de exekutiva funktionerna så till exempel att minnas saker de ska genomföra eller att uppfatta hur lång tid aktiviteter tar. Denna studie undersöker hur användandet av en digital kalender som hjälpmedel för personer med kognitiva nedsättningar ser ut och hur användare av upplever hjälpmedlet, om de upplever att det hjälper dem planera sin tid och att komma ihåg. För att undersöka detta intervjuades användare av Premium Comai, där intervjutekniken var semistrukturerade intervjuer. Användare upplever att hjälpmedlet är enkelt att använda och att det hjälper dem planera sin tid. Premium Comai skapar trygghet. / People with cognitive impairments belong to one of the largest groups of disabled persons. Premium Comai is a tool to help people with cognitive impairments to become more independent in their daily lives. These peoples have particular difficulties with the executive functions such as remembering things or to perceive the time an activity will take. This study examines how the use of a digital calendar that is accessible for people with cognitive impairments, how users perceive the means, if they feel it helps them manage their time and to remember. To examine this, users of Premium Comai were interviewed, using semi-structured interviews. Users perceive that the device is easy to use and it helps them to plan their time. Premium Comai makes users feel safe.

Le plan Alzheimer 2008-2012 prévoyait la création d’une base de données nationale recueillant des données d’activité de l’ensemble des centres mémoire français. La banque nationale Alzheimer (BNA) s’est vu assignée un double objectif : contribuer à adapter l’offre de soins spécialisés et générer des données épidémiologiques sur la maladie d’Alzheimer et les maladies apparentées. Les bases de données médico-administratives sont utiles dans le champ de l’épidémiologie car les effectifs sont importants, les données reflètent les pratiques quotidiennes et le suivi longitudinal est le plus souvent possible. Des problèmes spécifiques se posent également car elles n’ont en général pas été conçues dans un objectif de recherche, manquent d’informations spécifiques d’une problématique donnée et présentent des limites en termes de validité. L’objectif de ce travail est d’étudier la BNA comme outil épidémiologique. Pour ce faire nous avons effectué des travaux relatifs à la qualité des données et à la validité externe de la base de données, nous avons également mené un travail spécifique sur l’atrophie corticale postérieure afin de montrer les possibilités de la BNA comme outil pour l’étude des affections neuro-dégénératives rares. Notre travail montre que la qualité des données est perfectible par la mise en place d’un contrôle qualité plus structuré. La BNA est actuellement capable de reproduire des résultats de recherche décrits dans la littérature et semble sensible aux grandes tendances décrites dans l’environnement. Nous proposons une série de mesures qui permettrait à la BNA d’être un meilleur outil pour la recherche en épidémiologie. / The French Alzheimer database (BNA) is part of the third French plan against Alzheimer’s disease and related disorders. The objective of this database is to collect activity data of all French memory centers in order to help health authorities to organize the care offer and to generate epidemiologic knowledge on dementia. Administrative database have advantages and drawback in terms of medical research. It can gather data related to a large population, reflects the “real life” of patients and medical practices and allows longitudinal follow-up. On this other side some specific problems exists among them validity is a real concern. The objective of this work was to assess the BNA as an epidemiologic tool. We performed quality analyses and external validity studies in this perspective and initiated a research on posterior cortical atrophy to illustrate the potential of the database for the study of rare conditions. Our work shows that quality can be increased by the setup of a more structured quality program. The BNA is currently able to reproduce known published results and is sensitive to the environment. In this work we give some recommendations to increase the value of the BNA for epidemiological research.

The side-effects of chemotherapy treatment are an increasingly important research focus as more cancer patients are reaching survivorship. While treatment allows for survival, it can also lead to problems which can significantly affect quality of life. Cognitive impairments after chemotherapy treatment are one such factor. First presented as anecdotal patient reports, over the last decade empirical evidence for this cognitive concern has been obtained. Much attention has been focused on post-chemotherapy research, yet little attention has been granted to these same patients’ cognition before treatment commences. Breast cancer (BC) patients face many obstacles before chemotherapy treatment such as: surgery and side-effects of anesthesia, increased cytokine activity, stress of a new disease diagnosis and upcoming challenges, and emotional burdens such as depression and anxiety. Many of these factors have independently been shown to affect cognitive abilities in both healthy populations as well as other patient groups. Therefore, the pre-treatment (or baseline) BC patient status warrants systematic study. This would then reduce mistakenly attributing carried-over cognitive deficits to side effects of chemotherapy. As well, it is possible that certain confounding variables may have neural manifestations at baseline that could be exacerbated by chemotherapy agents. The following thesis first presents a review paper which critically describes the current literature examining chemotherapy-related cognitive impairments (CRCIs), as well as possible confound variables affecting this population. Subsequently, three original research papers present pre-chemotherapy data showing significant neuroanatomical and neurofunctional differences in BC patients compared to controls. In particular, these neural differences are present in brain regions that have been reported in post-chemotherapy papers. This, as well as the effects of variables such as the number of days since surgery, depression and anxiety scores and more, support the initiative that research attention should increase focus on these patients at baseline in order to better understand their post-chemotherapy results.

La segmentation des données par la langue et le thème des tests psycholinguistiques devient de plus en plus un obstacle important à la généralisation des modèles de prédiction. Cela limite notre capacité à comprendre le cœur du dysfonctionnement linguistique et cognitif, car les modèles sont surajustés pour les détails d'une langue ou d'un sujet particulier. Dans ce travail, nous étudions les approches potentielles pour surmonter ces limitations. Nous discutons des propriétés de divers modèles de plonjement de mots FastText pour l'anglais et le français et proposons un ensemble des caractéristiques, dérivées de ces propriétés. Nous montrons que malgré les différences dans les langues et les algorithmes de plonjement, un ensemble universel de caractéristiques de vecteurs de mots indépendantes de la langage est capable de capturer le dysfonctionnement cognitif. Nous soutenons que dans le contexte de données rares, les caractéristiques de vecteur de mots fabriquées à la main sont une alternative raisonnable pour l'apprentissage des caractéristiques, ce qui nous permet de généraliser sur les limites de la langue et du sujet. / Data segmentation by the language and the topic of psycholinguistic tests increasingly becomes a significant obstacle for generalization of predicting models. It limits our ability to understand the core of linguistic and cognitive dysfunction because the models overfit the details of a particular language or topic. In this work, we study potential approaches to overcome such limitations. We discuss the properties of various FastText word embedding models for English and French and propose a set of features derived from these properties. We show that despite the differences in the languages and the embedding algorithms, a universal language-agnostic set of word-vector features can capture cognitive dysfunction. We argue that in the context of scarce data, the hand-crafted word-vector features is a reasonable alternative for feature learning, which allows us to generalize over the language and topic boundaries.

Nous présentons dans cette thèse un nouveau paradigme pour caractériser la maladie d’Alzheimer à travers l’écriture manuscrite acquise sur tablette graphique. L’état de l’art est dominé par des méthodes qui supposent un comportement unique ou homogène au sein de chaque profil cognitif. Ces travaux exploitent des paramètres cinématiques globaux, sur lesquels ils appliquent des tests statistiques ou des algorithmes de classification pour discriminer les différents profils cognitifs (les patients Alzheimer, les troubles cognitifs légers (« Mild Cognitive impairment » : MCI) et les sujets Contrôle (HC)). Notre travail aborde ces deux limites de la littérature de la façon suivante : premièrement au lieu de considérer un comportement homogène au sein de chaque profil cognitif ou classe (HC, MCI, ES-AD : « Early-Stage Alzheimer Disease »), nous nous sommes affranchis de cette hypothèse (ou contrainte) forte de la littérature. Nous considérons qu’il peut y avoir plusieurs comportements au sein de chaque profil cognitif. Ainsi, nous proposons un apprentissage semi-supervisé pour trouver des groupes homogènes de sujets et analysons l’information contenue dans ces clusters ou groupes sur les profils cognitifs. Deuxièmement, au lieu d’exploiter les paramètres cinématiques globaux (ex : vitesse moyenne, pression moyenne, etc.), nous avons défini deux paramétrisations ou codages : une paramétrisation semi-globale, puis locale en modélisant la dynamique complète de chaque paramètre. L’un de nos résultats importants met en évidence deux clusters majeurs qui sont découverts, l’un dominé par les sujets HC et MCI et l’autre par les MCI et ES-AD, révélant ainsi que les patients atteints de MCI ont une motricité fine qui est proche soit des sujets HC, soit des patients ES-AD. Notre travail montre également que la vitesse prise localement regroupe un ensemble riche des caractéristiques telles que la taille, l’inclinaison, la fluidité et la régularité, et révèle comment ces paramètres spatiotemporels peuvent conjointement caractériser les profils cognitifs. / We present, in this thesis, a novel paradigm for assessing Alzheimer’s disease by analyzing impairment of handwriting (HW) on tablets, a challenging problem that is still in its infancy. The state of the art is dominated by methods that assume a unique behavioral trend for each cognitive profile, and that extract global kinematic parameters, assessed by standard statistical tests or classification models, for discriminating the neuropathological disorders (Alzheimer’s (AD), Mild Cognitive Impairment (MCI)) from Healthy Controls (HC). Our work tackles these two major limitations as follows. First, instead of considering a unique behavioral pattern for each cognitive profile, we relax this heavy constraint by allowing the emergence of multimodal behavioral patterns. We achieve this by performing semi-supervised learning to uncover homogeneous clusters of subjects, and then we analyze how much information these clusters carry on the cognitive profiles. Second, instead of relying on global kinematic parameters, mostly consisting of their average, we refine the encoding either by a semi-global parameterization, or by modeling the full dynamics of each parameter, harnessing thereby the rich temporal information inherently characterizing online HW. Thanks to our modeling, we obtain new findings that are the first of their kind on this research field. A striking finding is revealed: two major clusters are unveiled, one dominated by HC and MCI subjects, and one by MCI and ES-AD, thus revealing that MCI patients have fine motor skills leaning towards either HC’s or ES-AD’s. This thesis introduces also a new finding from HW trajectories that uncovers a rich set of features simultaneously like the full velocity profile, size and slant, fluidity, and shakiness, and reveals, in a naturally explainable way, how these HW features conjointly characterize, with fine and subtle details, the cognitive profiles.

L’objectif général de cette thèse était de caractériser les trajectoires de déclin cognitif et fonctionnel dans les phases précliniques et précoces de la maladie d’Alzheimer, faisant appel à deux grandes approches: l’étude du trouble cognitif léger dans la maladie d’Alzheimer sporadique et l’étude du phénotype cognitif d’individus porteurs de mutations autosomiques dominantes dans la maladie d’Alzheimer familiale. La thèse comprend 6 articles, dont 4 empiriques. Le premier article (Chapitre II) visait à faire une revue de littérature sur le trouble cognitif léger, son contexte historique, ses critères diagnostiques et les connaissances actuelles dans les domaines cognitif, génétique et de neuroimagerie. L’objectif de la deuxième étude (Chapitre III) visait à caractériser les différents domaines cognitifs (mémoire épisodique, fonctions exécutives, mémoire de travail, traitement visuospatial et langage) et leurs trajectoires dans le temps, chez des personnes avec un trouble cognitif léger, en distinguant celles qui ultérieurement progressent vers une démence, ou progresseurs, et celles qui ne progressent pas vers une démence, ou non-progresseurs. Les résultats indiquent que, chez les progresseurs, les trajectoires de déclin se distinguent selon le domaine cognitif : une fonction quadratique (fonction polynomiale de second degré, qui peut être interprétée comme représentant un plateau suivi d’un déclin accéléré) caractérise le rappel différé en mémoire épisodique et la mémoire de travail/vitesse de traitement de l’information et une fonction linéaire (plus graduelle et progressive) caractérise le rappel immédiat en mémoire, les fonctions exécutives et les habiletés visuospatiales. L’objectif de la troisième étude (Chapitre IV) était de caractériser les trajectoires de déclin des capacités à réaliser les activités de la vie quotidienne instrumentales chez ces mêmes individus ayant un trouble cognitif léger qui ont progressé vers une démence et de comparer ces trajectoires à celles que l’on retrouve chez les individus avec un trouble cognitif léger n’ayant pas progressé. Les résultats montrent que les capacités autorapportées à réaliser les activités de la vie quotidienne suivent une trajectoire quadratique chez les progresseurs (ont rencontré les critères de démence au cours de l’étude), linéaire chez les déclineurs (ont présenté un déclin cognitif sans rencontrer les critères de démence au cours de l’étude) et n’ont pas changé à travers le temps chez les stables (sont demeurés cognitivement stables au cours de l’étude). Les résultats indiquent que ces patrons peuvent être surtout expliqués par une catégorie d’activités, les activités complexes (p.ex. gérer le budget), qui suivent les mêmes trajectoires. L’objectif du quatrième article (Chapitre V) était de présenter les différentes composantes (génétique, imagerie et cognition) d’un projet de collaboration initié en 2012 entre le Canada et la Chine, ayant pour but d’étudier les phrases précliniques de la maladie d’Alzheimer de type familial. L’objectif de la cinquième étude (Chapitre VI) était d’examiner l’apparition et l’évolution des atteintes cognitives dans la maladie d’Alzheimer de type familial, en distinguant les personnes porteuses de mutations PSEN1 menant à un diagnostic de démence de celles non-porteuses de ces mutations. Les résultats montrent que, chez les porteurs de mutation, le temps estimé au diagnostic suit une trajectoire quadratique pour le rappel différé et la reconnaissance en mémoire épisodique et une trajectoire linéaire pour le rappel immédiat en mémoire, la fluence verbale sémantique/catégorielle et les habiletés visuoconstructives. Enfin, l’objectif de la sixième étude (Chapitre VII) était de présenter les données d’imagerie préliminaires de la cohorte canadienne avec mutations PSEN1, avec une série de cas. Chez les porteurs de mutation, l’amyloïde est un marqueur précoce, significatif même chez les individus non symptomatiques. Le marqueur tau est significatif uniquement près de l’âge estimé du diagnostic chez les porteurs et semble être davantage associé aux déficits cognitifs. / The main objective of this thesis was to characterize the trajectories of cognitive and functional decline in the preclinical and early stages of Alzheimer's disease, using two methodological approaches: the study of mild cognitive impairment in sporadic Alzheimer's disease and the study of the cognitive phenotype of individuals with autosomal dominant mutations in familial Alzheimer's disease. The thesis comprises 6 articles, 4 of which are empirical. The first article (Chapter II) aimed to review the literature on mild cognitive impairment, its historical context, its diagnostic criteria and current knowledge in the cognitive, genetic and neuroimaging fields. The objective of the second study (Chapter III) was to characterize the different cognitive domains (episodic memory, executive functions, working memory, visuospatial processing and language) and their trajectories over time, in individuals with mild cognitive impairment, by distinguishing those who progressed to dementia, or progressors, and those that did not progress to dementia, or non-progressors. The results indicate that, in the case of progressors, the trajectories of decline are distinguished according to the cognitive domain: a quadratic function (a plateau followed by an accelerated decline) characterizes the delayed recall in episodic memory and working memory/processing speed and a linear function characterizes immediate recall, executive functions and visuospatial abilities. The objective of the third study (Chapter IV) was to characterize the trajectories of decline in the ability to perform instrumental activities of daily living in these same individuals with mild cognitive impairment who progressed to dementia and to compare these trajectories with those found in individuals with mild cognitive impairment who did not progress. The results show that the self-reported abilities to perform activities of daily living follow a quadratic trajectory in the progressors (met the dementia criteria during the study), a linear trajectory in the declinors (presented a cognitive decline without meeting the dementia criteria during the course of the study) and did not change over time in the stable (remained cognitively stable during the study). The results indicate that these patterns can be mainly explained by a category of activities, the complex activities (e.g. managing the budget), which follow the same trajectories. The objective of the fourth article (Chapter V) was to present the different components (genetics, imaging and cognition) of a collaborative project initiated in 2012 between Canada and China, aimed at studying the preclinical phases of familial Alzheimer’s disease. The objective of the fifth study (Chapter VI) was to examine the onset and course of cognitive impairment in familial Alzheimer's disease, by distinguishing individuals with PSEN1 mutations leading to a diagnosis of dementia from those not carrying these mutations. The results show that, in mutation carriers, the time to the estimated age of onset follows a quadratic trajectory for delayed recall and recognition in episodic memory and a linear trajectory for immediate recall, semantic/categorical verbal fluency and visuospatial abilities. Finally, the objective of the sixth study (Chapter VII) was to present preliminary imaging data for the Canadian cohort with PSEN1 mutations, using a case series. In mutation carriers, amyloid is an early marker, with a significant deposition, even in non-symptomatic individuals. The tau marker is significant only near the estimated age of onset in mutation carriers and appears to be more associated with cognitive deficits.

Background: Subjective cognitive decline (SCD), i.e., the self-perceived feeling of worsening cognitive function, may be the first notable syndrome of preclinical Alzheimer’s disease and other dementias. However, not all individuals with SCD progress. Stability of SCD, i.e., repeated reports of SCD, could contribute to identify individuals at risk, as stable SCD may more likely reflect the continuous neurodegenerative process of Alzheimer’s and other dementias. Methods: Cox regression analyses were used to assess the association between stability of SCD and progression to MCI and dementia in data derived from the population-based Leipzig Longitudinal Study of the Aged (LEILA75+). Results: Of 453 cognitively unimpaired individuals with a mean age of 80.5 years (SD = 4.2), 139 (30.7 %) reported SCD at baseline. Over the study period (M = 4.8 years, SD = 2.2), 84 (18.5 %) individuals had stable SCD, 195 (43.1 %) unstable SCD and 174 (38.4 %) never reported SCD. Stable SCD was associated with increased risk of progression to MCI and dementia (unadjusted HR = 1.8, 95 % CI = 1.2–2.6; p < .01), whereas unstable SCD yielded a decreased progression risk (unadjusted HR = 0.5, 95 % CI = 0.4–0.7; p < .001) compared to no SCD. When adjusted for baseline cognitive functioning, progression risk in individuals with stable SCD was significantly increased in comparison to individuals with unstable SCD, but not compared to individuals without SCD. Conclusions: Our results, though preliminary, suggest that stable SCD, i.e., repeated reports of SCD, may yield an increased risk of progression to MCI and dementia compared to unstable SCD. Baseline cognitive scores, though within a normal range, seem to be a driver of progression in stable SCD. Future research is warranted to investigate whether stability could hold as a SCD research feature.

Objective: To study awareness of cognitive dysfunction in patients with very mild Alzheimer’s disease (AD) and subjects with mild cognitive impairment (MCI). Methods: A complaint interview covering 13 cognitive domains was administered to 82 AD and 79 MCI patients and their caregivers. The patient groups were comparable according to age and education, and Mini Mental State Examination (MMSE) scores were ≥24 in all cases. The discrepancy between the patients’ and caregivers’ estimations of impairments was taken as a measure of anosognosia. Results: Self-reports of cognitive difficulties were comparable for AD and MCI patients. However, while in comparison to caregivers MCI patients reported significantly more cognitive impairment (p < 0.05), AD patients complained significantly less cognitive dysfunctions (p < 0.001). Conclusions: While most MCI patients tend to overestimate cognitive deficits when compared to their caregiver’s assessment, AD patients in early stages of disease underestimate cognitive dysfunctions. Anosognosia can thus be regarded as a characteristic symptom at a stage of very mild AD (MMSE ≥24) but not MCI. Accordingly, medical history even in mildly affected patients should always include information from both patient and caregiver. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.