Neuroscience / La démence de type d’Alzheimer est la plus commune des démences. Elle entraîne un déclin dans les capacités cognitives et fonctionnelles, se traduisant dans des difficultés au niveau de la prise de décision, de l’accomplissement de tâches quotidiennes, de la communication ainsi qu’au niveau de la mémoire et de l’attention. On remarque également une diminution de l’état émotionnel et une apathie chez ces patients. Ce mémoire explore une nouvelle approche pour atténuer les effets psychologiques et cognitifs de la maladie. Les recherches effectuées dans ce mémoire explorent les impacts cognitifs et les effets sur le bien-être d'une intervention utilisant la réalité virtuelle sur les personnes souffrant de déclin cognitif subjectif. Deux environnements virtuels ont été testés : le premier étant un environnement dans lequel le participant voyage en train à travers différents climats, et le second étant un environnement de musicothérapie qui s’adapte en fonction de la réponse émotionnelle du participant. Pour mesurer les impacts sur l'état affectif, des lectures électroencéphalographiques ont été prises et analysées afin de déduire l'émotion ressentie par le participant avant, pendant et après l'expérience. Les résultats montrent une amélioration générale de l'état émotionnel pour les deux environnements. Quant à la mesure des effets sur les fonctions cognitives, des tâches d'attention et de mémoire ont été effectuées par les participants avant et après l'immersion. Les résultats montrent une légère amélioration des capacités d'attention et une meilleure amélioration de la mémoire. Nous approprions cet écart dans l'expérience de musicothérapie à l'activation musicale d'un réseau de structures cérébrales impliquées dans les expériences agréables : le circuit de récompense. Nous proposons que la musique facilite la rétention de la mémoire chez les personnes souffrant de démence. En effet, les résultats de l’amélioration des fonctions cognitives pour les deux expériences précédentes dépendent fortement de la précision de l'outil de mesure cognitive utilisé pour évaluer les performances d'attention et de mémoire avant et après l'intervention. Pour assurer cette précision, ce mémoire présente un outil de mesure des performances cognitives basé sur des tâches cognitives qui ont montré à plusieurs reprises leur fiabilité. Cet outil d’adresse aux personnes atteintes de la maladie d'Alzheimer pré-clinique et diagnostiquée. / Alzheimer’s disease is an irreversible disease which causes progressive memory loss and cognitive decline, eventually leading to severe inability to perform basic day-to-day tasks. The urgency to find an effective cure to the disease is crucial, as the medical and economical spin-offs could be disastrous. The present thesis explores a novel approach to help attenuate the psychological and cognitive effects of the disease. The research carried out for this thesis explored cognitive effects and impacts on overall well-being of a virtual reality intervention on people suffering from subjective cognitive decline. Two virtual environments were tested: the first being an environment in which the participant travels through different climates by train, and the second being a music therapy environment modified as a function of emotional response. To measure the effects on affective state, electroencephalography readings were taken and analyzed to infer the emotion felt by the participant before, during the experiment. Results show a general improvement in emotional state. To measure the effects of the environments on cognitive functions, attention and memory tasks were carried out by the participants before and after the immersion. Results show a small improvement in attention skills and a more substantial improvement in memory skills. We appropriate this discrepancy in the music therapy experiment to the musical activation of a network of brain structures involved in rewarding and pleasurable experiences. We propose that music could facilitate memory retention in people sufferance for dementia. Importantly, the results of the previous experiments rely heavily on the accuracy of the cognitive measurement tool used to evaluate attention and memory performances before and after the intervention. To provide this accuracy, this thesis presents a cognitive performance measurement tool based on cognitive tasks which have repeatedly shown to output reliable results. This tool is created to serve for people with pre-clinical Alzheimer’s disease and diagnosed Alzheimer’s disease. Additionally, this tool is designed in such a way as to minimize the effects of repetition as well as varying levels of education and language. This thesis presents a novel and promising research in the realms of computer sciences and health care.

Le vieillissement normal est caractérisé par un déclin cognitif subtil. Ce vieillissement cognitif est hétérogène : il existe des différences inter- et intra-individuelles dans la nature et l’étendue du déclin cognitif. L’hétérogénéité inter-individuelle se manifesterait par la présence de plusieurs profils cognitifs distincts parmi les personnes âgées normales (PAN). L’hétérogénéité cognitive peut également s’observer de manière intra-individuelle par une plus grande variabilité, soit une plus forte dispersion, dans les performances cognitives lors d’un contexte d’évaluation neuropsychologique chez un individu. Chez les PAN, certains profils cognitifs et mesures de dispersion ont été associés à un risque de développer une démence. Par ailleurs, la présence de biomarqueurs de la maladie d’Alzheimer (MA) est retrouvée chez une proportion significative de PAN et ces biomarqueurs auraient un impact délétère sur le fonctionnement cognitif dans le vieillissement normal. Ainsi, l’objectif de cette thèse est de mieux comprendre l’impact de différents biomarqueurs de la MA sur le fonctionnement cognitif des PAN, plus spécifiquement sur l’hétérogénéité cognitive que l’on retrouve au sein du vieillissement normal. Dans le cadre de cette thèse, composée de deux articles, 104 PAN ont réalisé une évaluation neuropsychologique approfondie, un examen de tomographie par émission de positons (PIB-TEP) permettant de quantifier la présence cérébrale du peptide bêta-amyloïde (βA), ainsi qu’un examen d’imagerie par résonance magnétique (IRM) permettant de mesurer les hyperintensités de la substance blanche (HSB) ainsi que l’épaisseur corticale. Le premier article de cette thèse porte sur l’hétérogénéité cognitive inter-individuelle. Les objectifs étaient : (1) de caractériser les différents profils cognitifs présents au sein du groupe PAN et (2) d’évaluer s’il existait des liens entre ces profils et les biomarqueurs de la MA. Trois profils cognitifs ont été identifiés : un profil où les performances cognitives sont globalement supérieures à la moyenne de l’échantillon, un profil où les performances sont généralement dans la moyenne et un dernier profil, minoritaire, où la majorité des performances se situent sous la moyenne. Uniquement ce dernier profil était associé à une charge amyloïde accrue et la présence plus importante d’HSB. Ces résultats suggèrent qu’au sein du vieillissement normal, un sous-groupe de participants présente un fonctionnement cognitif sous-optimal qui est en lien avec la présence de biomarqueurs de la MA. Le deuxième article porte sur l’hétérogénéité intra-individuelle et avait pour objectif de déterminer si la dispersion cognitive était associée à la présence des biomarqueurs de la MA. Les résultats montrent que, globalement, la dispersion n’est pas significativement associée à la présence de biomarqueurs de la MA. Seuls les scores de dispersion pour les domaines de la mémoire épisodique et en fonctionnement exécutif étaient associés aux HSB. Ces résultats suggèrent que la dispersion dans le vieillissement cognitif normal n’est pas directement associée à la pathologie Alzheimer. Cependant, certains éléments de cette dispersion pourraient être en lien avec une santé cérébrovasculaire sous-optimale. En conclusion, les résultats de cette thèse sont discutés à la lumière des connaissances actuelles. Les implications théoriques et cliniques de ces résultats sont abordées et différentes pistes de recherches futures sont évoquées. / Normal aging is characterized by subtle cognitive decline. This cognitive decline is heterogeneous: there are interindividual and intraindividual differences in the nature and extent of cognitive decline. Interindividual heterogeneity is thought to be manifested by the presence of several distinct cognitive profiles among normal older adults. Cognitive heterogeneity can also be observed in an intraindividual fashion through greater variability, or greater dispersion, in cognitive performance, in the context of an individual's neuropsychological assessment. In normal aging, certain cognitive profiles and measures of dispersion have been associated with a risk of developing dementia. Additionally, the presence of Alzheimer's disease (AD) biomarkers is found in a significant proportion of normal older adults and these biomarkers have a deleterious impact on cognitive functioning in normal aging. Thus, the objective of this thesis is to better understand the impact of different AD biomarkers on the cognitive functioning of normal older adults, more specifically, on the cognitive heterogeneity that is found in normal aging. As part of this thesis, composed of two articles, 104 normal older adults carried out an in-depth neuropsychological evaluation and cerebral imaging scan, a positron emission tomography (PIB-PET) examination and a magnetic resonance imaging (MRI) exam, to measure cerebral beta-amyloid peptides, white matter hyperintensities (WMH) and cortical thinning. The first article of this thesis deals with interindividual cognitive heterogeneity. The objectives were: (1) to characterize the different cognitive profiles present within the normal older adult group and (2) to assess whether there are links between these profiles and AD biomarkers. Three cognitive profiles have been identified: a profile where cognitive performance is overall higher than the sample average, a profile where performance is generally average and a final profile, where the majority of performance is below the average. This last profile was the only one associated with a greater amyloid load and an increased presence of WMH. These results suggest that within normal aging, a subgroup of participants exhibits suboptimal cognitive functioning and that this cognitive functioning is related to a greater AD biomarkers presence. The second article examines intraindividual heterogeneity and aimed to determine whether or not cognitive dispersion is associated with the presence of AD biomarkers. The results show that overall, dispersion is not significantly associated with the presence of AD biomarkers. Only dispersion scores for the domains of episodic memory and executive functioning were associated with WMH. These results suggest that dispersion in normal cognitive aging is not directly associated with AD biomarkers. However, some elements of cognitive dispersion could be linked to suboptimal cerebrovascular health. In conclusion, the results of this thesis are discussed in light of current knowledge. The theoretical and clinical implications of these results are explored and various avenues for future research are proposed.

Alzheimer’s sjukdom är en neurodegenerativ sjukdom som leder till demens. Den kan börja tyst i de tidiga stadierna och fortsätta under åren till en allvarlig och obotlig fas. Språkstörningar uppstår ofta som ett av de tidiga symptomen och kan till slut leda till fullständig mutism i de avancerade stadierna av sjukdomen. Därför är tal- och språkbaserad analys en lovande och icke-invasiv metod för att upptäcka Alzheimer’s sjukdom i dess tidiga stadier. Vårt mål är att använda maskininlärning för att jämföra informationmängden hos språkliga representationer i stora språkmodeller och förtränade akustiska representationer. Såvitt vi vet är detta första gången som GPT-3 och wav2vec2.0 har använts tillsammans för klassificering av Alzheimer’s sjukdom. Dessutom utnyttjade vi för första gången en kombination av två stora språkmodeller, GPT-3 och BERT, för denna specifika uppgift. Genom att utvärdera vår metod på två datamängder på engelska och svenska kan vi också belysa språkskillnaderna mellan dessa två språk. / Alzheimer’s disease is a neurodegenerative disease that leads to dementia. It can begin silently in the early stages and progresses over the years to a severe and incurable stage. Language impairment often emerges as one of the early symptoms and can eventually progress to complete mutism in advanced stages of the disease. As a result, speech processing is a promising and non-invasive approach for detecting Alzheimer’s disease in its early stages. Our objective is to compare the informativeness levels of linguistic embedding derived from large language models and pre-trained acoustic embedding extracted using wav2vec2.0, in a machine learning-based approach. To the best of our knowledge, this is the first time that fusing GPT-3 text embedding and wav2vec2.0 acoustic embedding has been explored for Alzheimer’s disease classification. In addition, we utilized a combination of two large language models, GPT-3 and BERT, for the first time on this specific task. By evaluating our method on two datasets in English and Swedish, we can also highlight the language differences between these two languages.

The number of dementia cases is increasing worldwide. Most research and development in this area is related to the prevention of dementia, and to the development of various prediction tools for dementia. The tools made available take most of the medical data into account while calculating risk scores, with only a small amount of non-medical data. There is a lot of data related to medical and non-medical risk factors available from various sources which can be retrieved and analysed in real time, but this is today not used in any risk score tool for risk score calculation. As part of the project Multimodal strategies to promote a healthy brain in ageing: Innovative evidence-based tools (MULTI-MODE), a new risk score is being developed to be used in a new ICT-based tool for dementia prediction. Identification of non-medical data and a good model to fill the gap between data available at the server and using this data in risk score calculation may help in increasing the predictability of tools. In this thesis, some of the existing risk factors for the prediction of dementia are described, and the importance of non-medical factors in calculating risk scores is discussed. Additional non-medical factors are identified that could be included in future versions of the risk score. A database design for storing risk score information efficiently is presented, as is an app structure that can be used at the server side to validate the user input and to increase the effectiveness of a prediction tool. / Antal demensfall ökar över hela världen. Forskning och utveckling inom detta område är relaterat till att förebygga demens och att utveckla olika prognosverktyg för demens. Flera tillgängliga verktyg tar hänsyn till medicinska data i beräkning av riskpoäng, med endast en liten mängd av icke-medicinska data. Det finns en hel del data om medicinska och icke-medicinska faktorer online, men de används idag inte för riskpoängberäkning. Som en del av projektet Multimodala strategier för att främja en frisk hjärna i åldrande: Innovativa evidensbaserade verktyg (MULTI-MODE), så har en ny metod utvecklats för att användas i ett nytt IT-baserat verktyg för demensförutsägelse. Identifiering av icke-medicinska data och en bra modell för att överbrygga gapet mellan tillgängliga data på servern och använda dessa data i riskberäkning kan bidra till att öka precisionen hos verktyg. I den här studien beskrivs en del befintliga riskfaktorer för förutsägelse av demens och vikten av icke-medicinska faktorer i beräkning av risk diskuteras. Ytterligare icke-medicinska faktorer identifieras som skulle kunna ingå i framtida versioner av riskverktyg (såsom appar). Vissa identifierade riskfaktorer har analyserats och visade att effekten av att införa icke-medicinska faktorer ökar precisionen i resultaten. En databasdesign för lagring av riskinformation på ett effektivt sätt presenteras, liksom en appstruktur som kan användas på serversidan för att validera några av de parametrar som kan öka effektiviteten av verktyget.

Alzheimers sjukdom (AD, eng. Alzheimer’s disease) upptäcktes för 111 år sedan av Alois Alz-heimer. Idag är det den ledande orsaken till demens hos äldre, och incidencen förväntas öka med befolkningens ökande livslängd. År 2050 förutspås antalet patienter med AD nå 10 miljoner personer [1]. Det har gjorts många försök att angripa AD via dess främsta kännetäcken, såsom plack av beta-amyloid (Aβ), Aβ-oligomerer, och ansamlingar av tau-protein, kallat tau-trassel. Trots att forskning om AD bedrivits i flera årtionden är dess orsak alltjämt okänd.På sistone har det funnits ett fokus på de inflammatoriska komponenterna inom AD. Det finns en utbredd aktivering av immunförsvaret i det centrala nervsystemet hos patienter med AD, men varken dess orsak eller dess roll inom AD är känd. Däremot finns det tydliga tecken på att inflammationen är av autoimmun art. Med detta i åtanke är det tydligt att det finns ett stort behov att utröna auto-immunitetens roll inom AD. I denna forskningsstudie användes proteomik-metoder för att bestämma autoantikroppsprofilerna inom plasma och cerebrospinalvätska (CSF, eng. cerebrospinal fluid) hos AD-patienter och en frisk kontrollgrupp.I denna studie användes par av plasma- och CSF-prover från 23 friska individer och 49 patien-ter. Dessutom inkluderades 2 plasmaprover och 18 CSF-prover från patienter. En 380-faldig och en 314-faldig riktad analys gjordes med hjälp utav suspension bead array-teknologi (SBA). Varje SBA bestod av färgkodade, magnetiska mikrosfärer i suspension, med antigen immobiliserade på kulornas yta. Denna analysmetod användes för att undersöka autoantikropssprofilerna i alla prover. Resul-taten visade en ökad respons från autoantikroppar mot antigenen SLC17A6 (Solute Carrier Family 17 Member 6), MAP1A (Microtubule Associated Protein 1A), och MAP2 (Microtubule Associated Protein 2) i patiener gentemot friska individer. Dock har dessa antigen uppvisat en bred reaktivitet i tidigare, opublicerade studier. Därför behövs ytterligare forskning för att fastställa deras roll inom AD.Dessutom användes paren av plasma- och CSF-prover för att undersöka autoantikroppsprofilernas överrensstämmelse inom varje patient. Det visade sig att korrelationen följde en normalfördelning, med starkare korrelation inom antigen med starkare reaktivitet mot den motsvarande autoantikroppen. Denna studie utgör en av de första storskaliga forskningsstudierna av överrensstämmelsen mellan autoantikroppsprofilerna inom plasma och CSF. / Alzheimer’s disease (AD) was discovered 111 years ago by Alois Alzheimer. Today, it is the leading cause of dementia in elderly, and incidence is expected to increase with life expectancy. By 2050, the number of a˙ected individuals is predicted to reach 10 million [1]. There have been numerous attempts to describe AD by its primary hallmarks, including amyloid plaques, amyloid beta (Aβ) oligomers, and tau tangles. However, despite several decades of intense research, the cause of AD remains unknown.Recently, there has been a focus on the inflammatory components of AD. There is an extensive activation of the immune system within the CNS of AD patients, but neither its cause nor its role in AD is known. However, there are strong indications that the inflammation has an autoimmune character. Considering this, there is an imperative need to examine autoimmunity within AD. In the present study, a proteomic approach was used to determine the autoantibody profiles within plasma and cerebrospinal fluid (CSF) within AD patients and healthy controls.Paired plasma and CSF samples from 23 healthy controls and 49 patients were included in the present study. In addition, 2 plasma samples and 18 CSF samples from patients were included (not paired). One 380-plex and one 314-plex targeted suspension bead array (SBA), each consisting of color-coded magnetic microspheres with immobilized antigens, were used to analyze autoantibody profiles in all samples. The resulting data revealed an increased autoantibody response towards anti-gens SLC17A6 (Solute Carrier Family 17 Member 6), MAP1A (Microtubule Associated Protein 1A), and MAP2 (Microtubule Associated Protein 2) in patients compared to healthy controls. However, as these antigens have displayed wide reactivities in previous, unpublished studies, they require further investigation to determine their role in AD.Furthermore, the paired CSF and plasma samples were used to investigate the correlation of autoantibody profiles within patients. The correlation was found to follow a normal distribution, with correlation being higher in antigens displaying stronger autoantibody reactivity. This work represents one of the first large-scale studies on the correlation of autoantibody profiles in plasma and CSF.

Alzheimer’s disease (AD) is a chronic and progressive, irreversible syndrome that deteriorates the cognitive functions. Official death certificates of 2013 reported 84,767 deaths from Alzheimer’s disease, making it the 6th leading cause of death in the United States. The rate of AD is estimated to double by 2050. The neurodegeneration of AD occurs decades before symptoms of dementia are evident. Therefore, having an efficient methodology for the early and proper diagnosis can lead to more effective treatments. Neuroimaging techniques such as magnetic resonance imaging (MRI) can detect changes in the brain of living subjects. Moreover, medical imaging techniques are the best diagnostic tools to determine brain atrophies; however, a significant limitation is the level of training, methodology, and experience of the diagnostician. Thus, Computer aided diagnosis (CAD) systems are part of a promising tool to help improve the diagnostic outcomes. No publications addressing the use of Feedforward Artificial Neural Networks (ANN), and MRI image attributes for the classification of AD were found. Consequently, the focus of this study is to investigate if the use of MRI images, specifically texture and frequency attributes along with a feedforward ANN model, can lead to the classification of individuals with AD. Moreover, this study compared the use of a single view versus a multi-view of MRI images and their performance. The frequency, texture, and MRI views in combination with the feedforward artificial neural network were tested to determine if they were comparable to the clinician’s performance. The clinician’s performances used were 78 percent accuracy, 87 percent sensitivity, 71 percent specificity, and 78 percent precision from a study with 1,073 individuals. The study found that the use of the Discrete Wavelet Transform (DWT) and Fourier Transform (FT) low frequency give comparable results to the clinicians; however, the FT outperformed the clinicians with an accuracy of 85 percent, precision of 87 percent, sensitivity of 90 percent and specificity of 75 percent. In the case of texture, a single texture feature, and the combination of two or more features gave results comparable to the clinicians. However, the Gray level co-occurrence matrix (GLCOM), which is the combination of texture features, was the highest performing texture method with 82 percent accuracy, 86 percent sensitivity, 76 percent specificity, and 86 percent precision. Combination CII (energy and entropy) outperformed all other combinations with 78 percent accuracy, 88 percent sensitivity, 72 percent specificity, and 78 percent precision. Additionally, a combination of views can increase performance for certain texture attributes; however, the axial view outperformed the sagittal and coronal views in the case of frequency attributes. In conclusion, this study found that both texture and frequency characteristics in combinations with a feedforward backpropagation neural network can perform at the level of the clinician and even higher depending on the attribute and the view or combination of views used.

Contexte. La démence est un problème de santé publique important. Toutefois, les stratégies actuelles en matière de santé publique ne tiennent pas compte des approches visant à renforcer les facteurs de protection pour en réduire le fardeau. Cela peut s’expliquer par le fait que le renforcement des facteurs de protection est un domaine de connaissance émergent. Son vocabulaire et ses notions de base sont encore en phase d’exploration et de définition. Parmi les termes et les notions à développer, citons la « santé positive » comme résultat du renforcement des facteurs de protection et les « atouts de santé », en tant que déterminant positif de la santé. Le développement de ces termes en promotion de la santé et leur adaptation pour les études sur la santé du cerveau contribueront à une meilleure compréhension des mécanismes permettant aux aînés de préserver leur santé cognitive, et donc ouvriront les portes à de nouvelles stratégies pour réduire le fardeau associé aux démences. L’objectif. Cette thèse vise à proposer un modèle pour l’étude de la santé cognitive des personnes âgées et à le tester dans une large base de données populationnelle. Pour atteindre cet objectif, nous avons i) dérivé la signification du terme de santé positive en examinant systématiquement la façon dont le concept est défini/utilisé par différents auteurs dans des publications sur la promotion de la santé ; ii) révisé les modèles existants de déterminants « positifs » de la santé (« modèles d’atouts de santé ») et proposer un nouveau modèle d’atouts de santé ; iii) discuté l’utilité du modèle pour la recherche sur la santé cognitive des personnes âgées, et iv) évalué l’apport indépendant des atouts de santé dans la probabilité d’une santé cognitive positive chez les personnes âgées, à l’aide du model développé. Méthodes. Un examen de la portée a été effectué pour atteindre les objectifs 1 et 2 ; une revue narrative a été réalisée pour atteindre les objectifs 3. L’analyse secondaire des données de l’étude de cohorte longitudinale « Survey on Health, Aging, and Retirement in Europe », vagues 5 et 7, a été réalisée pour atteindre l’objectif 4. Dans cette étude, les déterminants positifs avaient un effet indépendant sur la santé cognitive si i) leurs variables étaient statistiquement significatives dans le modèle entièrement ajusté et ii) ces variables améliorent significativement l’ajustement de la qualité du modèle. Résultats. 1) Aucun consensus sur la définition de la santé positive n’a été trouvé dans la littérature. Parmi les définitions proposées, il y a « bien-être », « extrêmement bonne santé », « résilience » et « capacités ». Nous avons proposé de définir la santé positive comme une réserve en capacités, permettant une plus grande résistance face aux agents pathologiques/adversités et un plus grand bien-être en leur absence. 2) Dans la littérature, des déterminants de la santé positive sont regroupés autour de traits individuels ou de caractéristiques environnementales. Nous avons proposé un nouveau cadre pour les atouts de santé. Dans ce cadre, les caractéristiques individuelles, les actions (orientées vers l’autodéveloppement ou le développement communautaire), les environnements (physique and social) et le soutien social (informel et institutionnalisé) sont interconnectés. Chaque composante précédente contribue à la suivante et à une santé positive. 3) L’état actuel des connaissances sur la santé cognitive permet l’opérationnalisation de la définition de la santé positive cognitive ainsi que du modèle des atouts de la santé. 4) Les variables de trois des quatre groupes d’atouts de santé (caractéristiques individuelles, actions et environnements) démontrent une contribution indépendante à la probabilité d’une santé cognitive positive chez les personnes âgées. L’inclusion des atouts de santé améliore significativement la qualité de l’ajustement du modèle : le pseudo-R-carré a augmenté de 0,31 à 0,33 ; l’aire sous la courbe ROC a augmenté de 77,8 % à 79,5 %, p<0,0001. Cela signifie que les atouts de santé expliquent davantage la probabilité de santé cognitive positive. Conclusion. L’étude sur les facteurs renforçant la santé cognitive pourrait aux nouvelles opportunités pour la diminution du fardeau de démence. Une validation plus poussée du modèle est nécessaire. Premièrement, des indicateurs plus spécifiques d’atouts de santé doivent être trouvés. Deuxièmement, les relations entre les groupes d’atouts de santé devraient être clarifiées. / Background. Dementia is a significant public health challenge; however, current strategies on public health hardly consider the potential of reinforcing protective factors to diminish its burden. A possible reason for this is that reinforcing protective factors represent an emerging field of knowledge. Its vocabulary and basic notions are still under development. Among the terms and notions needing further discussion are “positive health” as the outcome of these reinforcing protective factors and “health assets” as positive health determinants. Advances in the development of these terms in health promotion and their further adaptation to the realm of studies on cognitive health will contribute to a better understanding of how older adults maintain it, which, in turn, could open the doors to new strategies aimed at reducing the burden of dementia. Objective. This dissertation proposes a model for studying cognitive health in older adults and testing it in a large populational database. To achieve this objective, i) we derived the meaning of the term positive health by systematically reviewing how the concept is defined/used by different authors of publications in health promotion; ii) we revised existing models of “positive” determinants of health (“health assets models”) and proposed a new model of health assets; iii) discussed the utility of the model for research on cognitive health of older adults, and iv) we assessed the independent input of health assets into the probability of positive cognitive health among older adults, using developed model. Methods. A scoping review was conducted to achieve objectives 1 and 2, and a narrative review was conducted to achieve objective 3. Secondary analyses of the longitudinal cohort data “Survey on Health, Aging, and Retirement in Europe” data, waves 5 and 7, were performed to achieve objective 4. In this study, determinants were considered as having an independent effect on cognitive health if i) their variables were statistically significant in the fully adjusted model and ii) these variables significantly improved the model’s fit quality. Results. 1) No consensus on the definition of positive health was found in the literature. Among proposed definitions, there were “well-being,” “extremely good health,” “resilience,” and “capacities.” We proposed to define positive health as a reserve in capacities, enabling higher resistance in the face of pathologic agents/adversities and increased well-being in their absence. 2) In the literature, the determinants of positive health are grouped around individual traits or environmental characteristics. We proposed a new health assets framework. In it, individual characteristics, actions (directed to self-development or community development), environments (physical and social), and social support (informal and institutionalized) are interconnected. Each component contributes to the others and positive health. 3) The current state of knowledge on cognitive health allows operationalizing the definition of cognitive positive health and the elements of the health assets model. 4) Variables of three out of four groups of health assets (individual characteristics, actions, and environments) had independent relationships with the probability of cognitive health in older adults. Including health assets significantly improves the model’s fit statistics: pseudo-R-square increased from 0.31 to 0.33; area under ROC rose from 77.8% to 79.5%, p <0.0001. It means that positive health assets bring additional information on the probability of positive cognitive health in older adults. Conclusion. Studying health assets could open the doors to strategies to reduce the burden of dementia. Further validation of the model is required. Firstly, more specific indicators of health assets need to be found. Secondly, the relationships between health asset groups should be clarified.

Denna avhandling fokuserar på det meningsskapande och begripliggörande som fortgår vid tilltagande demenssjukdom, i det sociala samspelet, och de utmaningar för demens-omsorgen som detta innebär. Studien är aktörsorienterad och adresserar frågan om hur personer med åldersrelaterade progressiva demenssjukdomar i den vardagliga kommuni-kationen söker förstå sina situationer, omgivningen och sina liv – alltsammans inom ra-men för det dagliga samspelet på ett demensboende. Av särskilt intresse är hur dessa per-soner hanterar problem som har att göra med att handla tillsammans med andra i en gemensamt delad värld och hitta sin roll i det pågående samspelet, och hur de etablerar och upprätthåller en identitet i detta samspel. Detta trots svåra minnesproblem, desorien-tering i tid och rum, olika sätt att förstå den pågående situationen samt svårigheter att be-rätta om sina liv på ett sätt som både stämmer överens med biografiska data och har en tillfredsställande temporal organisering. Avhandlingen adresserar också frågan om hur omsorgspersonalen kan hantera det komplexa samspelet mellan de boende i den dagliga omsorgen, med avseende på att upprätthålla och respektera dessa personers värdighet. Studien ansluter till en växande tradition av att studera interaktion vid demens som meningsbaserad och situerad i en kontext snarare än enbart som beteende som orsakas av kognitiva svårigheter. Metodologiskt är studien etnografisk och bygger på observationer fördelade över en tidsperiod av sex månader. Materialet, som består av ca 150 h videoma-terial och kompletterande fältanteckningar, möjliggör att samspelet studeras både i detalj och i relation till det större sammanhang som det ingår i. Studien visar på kvarvarande kompetenser och bidrar med ny kunskap om strategier som personerna med demens använder sig av i ett aktivt, kreativt och på många sätt ratio-nellt meningsskapande i det sociala samspelet med andra människor. Detta diskuteras i termer av resurser för demensomsorgen i relation till den stora utmaning som det innebär att lappa ihop och upprätthålla en begriplig och socialt delad värld, samt upprätthålla kon-tinuitet med personernas livshistorier på ett sätt som möjliggör en önskad identitet. / This thesis focuses on the identity work and the meaning- or sense-making that continue in the face of evolving dementia diseases, in social interaction, and the challenges for care this involves. The study adopts an actor-oriented approach and addresses the question of how persons with age-related progressive dementia diseases in everyday communication make sense of their situations, their surroundings, and their lives – all within the context of daily life in residential care. Of particular interest is how these persons handle issues of joint action in a shared world and how they establish and maintain an identity in the inte-raction. This is in spite of severe memory problems, disorientation in time and space, dif-fering understandings of the current situation, and difficulties in telling “accurate” and temporally ordered stories about their lives. The thesis also addresses the question of how caregivers may handle the complex interplay between residents in daily care, in maintain-ing and respecting these persons’ dignity. The study follows a growing tradition of studying interaction in dementia as mean-ing-based and situated in a context rather than merely as behavior caused by cognitive impairment. Methodologically, this is an ethnographic study based on observations made within a period of six months. The data consist of around 150 hours of video recordings and complementary field notes. This extensive material has made it possible to study the social interaction both in detail and situated in a larger context. The findings point to remaining competences and strategies that persons with demen-tia use actively and creatively in the ongoing interaction – and, given the premises, often in a rational way. This is discussed in terms of resources for dementia care, in relation to the great challenge of patching up and putting together a comprehensive socially shared world as well as maintaining continuity with the persons’ previous life histories in a way that preserves a positive self-identity.

Un nombre croissant de travaux chez l’animal et chez l’homme suggèrent que les différentes structures composant le lobe temporal interne (LTI) contribuent de manière différentielle à la mémoire déclarative. Chez l’homme, deux réseaux neuraux impliquant le LTI sont décrits : un réseau mésiotemporal antérieur, constitué de structures pour lesquelles les études chez les patients cérébro-lésés indiquent qu’elles contribueraient à la mémoire décontextualisée (mémoire des objets et mémoire sémantique ou mémoire du « quoi ») ; un réseau mésiotemporal postérieur, constitué d’autres structures pour lesquelles ces études suggèrent plutôt une implication dans la mémoire contextualisée (mémoire spatiale, épisodique ou mémoire du «où » et du « quand»). Dans la Maladie d’Alzheimer (MA), les dégénérescences neurofibrillaires, dont la distribution topographique est corrélée à la nature des déficits cognitifs, se développent initialement dans les cortex sous-hippocampiques - transentorhinal et entorhinal - qui sont des composants du réseau mésiotemporal antérieur, avant de s’étendre à l’hippocampe. Les éventuels déficits cognitifs en relation avec l’atteinte de cette région ne sont pas clairement identifiés dans la MA. Les travaux présentés dans ce mémoire sont centrés sur l’étude des cortex sous-hippocampiques avec les méthodes de la neuropsychologie et la neuroimagerie. Ils suggèrent que la MA aux stades les plus précoces pourrait représenter un « modèle » d’étude privilégié des systèmes mnésiques auxquels contribue le LTI. Ces résultats sont en faveur de l’utilité de l’évaluation de la mémoire décontextualisée dans le diagnostic de la MA débutante. / There is increasing evidence from experiments in rodents and non-human primates, as well as from human studies, to suggest that the different structures within the medial temporal lobe (MTL) differentially contribute to declarative memory. In the human brain, two neural networks implicating MTL structures have been described: an anterior MTL network that includes brain areas that contribute to context-free memory (object memory and semantic memory or memory for « what ») and a posterior MTL network that contributes to context-rich memory (spatial memory, episodic memory or memory for “where” and “when”). In Alzheimer’s disease (AD), neurofibrillary tangles (NFT), associated with cognitive signs, initially appear in the sub-hippocampal (transentorhinal and entorhinal) cortex, which are part of the anterior MTL network, before reaching the hippocampus. Potential cognitive deficits related to the dysfunction of this brain area in AD are not clearly identified. In the presented studies, the emphasis is placed on the investigation of sub-hippocampal corteces using a neuropsychological approach and neuroimaging techniques. Our findings suggest that the very earliest stages of AD could represent a “model” leading to a better understanding of memory systems that involve the MTL. They also provide evidence that evaluating context-free memory may be useful in the diagnosis of early AD.

Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disorder, characterized clinically by a progressive loss of memory, cognitive function, ability to care for oneself and psychiatric symptoms. First-line agents for the treatment of AD are ChE inhibitors (DON, GAL), whose modest clinical efficacy and the high incidence of dose-limiting toxicities limit their clinical utility. In addition to AD, ChE inhibitors (PYR) are used for other medical conditions, such as myasthenia gravis (MG). Furthermore, ChE inhibitors (PYR) are used by military personnel prophylactically if impending exposure to chemical warfare agents, e.g., soman, is suspected. The purpose of this research project was to understand the effect of age on the in-vitro sensitivity of ChE inhibitors in human RBCs and plasma. Understanding possible covariates, such as age and gender, may assist in optimizing dosing regimens of ChE inhibitors and/or developing newer ChE inhibitors with better adverse effect profiles. Plasma PHYS concentrations were measured by a validated HPLC-FD method. RBC AChE activity and plasma BuChE activity were measured by a modified Ellman’s colorimetric method using the model substrates, acetylthiocholine and butyrylthiocholine, respectively. The kinetics of RBC and plasma ChE activity followed Michaelis-Menten kinetics. Acetylthiocholine was found to be a nonselective substrate (RBC AChE Km = 73 μM; plasma BuChE Km = 117 μM); while butyrylthiocholine was a selective substrate for plasma BuChE (RBC AChE Km = 130,000 μM; plasma BuChE Km = 72 μM). For the following studies, RBC AChE activity was measured using acetylthiocholine as the substrate and plasma BuChE activity was measured using butyrylthiocholine as the substrate. This research project was performed in two parts: First, mechanistic studies of PHYS, PYR, DON and GAL, explored and determined the mechanism of in-vitro inhibition of RBC AChE and plasma BuChE inhibition, as well as the in-vitro degradation of PHYS in human whole blood, plasma and RBC. PHYS was rapidly degraded in human whole blood, RBC and plasma and followed Michaelis-Menten kinetics but its degradation clearance - scaled to whole blood clearance - was only predicted to account for 4-6% (i.e., 195-261 ml/min) of the reported total body clearance for PHYS (4500 ml/min). RBCs were responsible for 60% of the whole blood clearance while plasma accounted for 40% of the whole blood clearance. Inhibition results indicated that both PHYS and PYR were nonselective and rapid suicide ChE inactivators. PYR inactivated RBC AChE more rapidly at low concentrations and inactivated plasma BuChE more rapidly at high concentrations, but inactivated both more rapidly than PHYS. PHYS was a more potent inactivator than PYR with a Ki for RBC AChE of 0.011 μM and 0.063 μM, respectively, and 0.023 μM and 0.036 μM, respectively for plasma BuChE. DON was found to be a noncompetitive inhibitor for RBC AChE (Ki,noncomp = 114 μM), but a competitive inhibitor for plasma BuChE (Ki,comp = 213 μM). GAL was found to be a competitive inhibitor for both RBC AChE (Ki,comp = 66 μM) and plasma BuChE (Ki,comp = 358 μM). The second part involved a clinical study with ten young and nine elderly healthy subjects, balanced for gender, who donated blood for an in-vitro study in order to assess any age- and gender-related differences in in-vitro sensitivity to RBC AChE and plasma BuChE inhibition to all four ChE inhibitors. Elderly adults were found to be 2-3-fold less sensitive compared to the young adults for PHYS (BuChE Ki,pss; 0.010 and 0.015 μM, young and elderly, respectively) and PYR (AChE Ki,pss; 0.12 and 0.25 μM, young and elderly, respectively) only, while neither DON nor GAL showed any age-related differences in sensitivity. The observed differences for PHYS and PYR may be due to kinetic differences in ChE inactivation between young and aged adults, rather then a difference in binding affinities/potencies. These carbamate ChE inhibitors, presumably, have a slower decarbamoylation rate in younger adults than elderly adults, which leads to the observed difference in in-vitro sensitivity. The above in-vitro results were consistent with results of a meta-analysis: In a study by Knapp et al. (1991), young males (n=6), receiving 18 mg, 24 mg and 30 mg PHYS tablets, showed similar ex-vivo plasma BuChE sensitivity to (28 %/(ng/ml)) as the in-vitro sensitivity for young males in the current study (33 %/(ng/ml)). On the other hand, in the study by Men (2004), elderly males (n=8) and females (n=8), receiving 6.7 μg/kg PHYS as 30-minute infusion, showed similar ex-vivo RBC AChE sensitivity (12 %/(ng/ml)) as the in-vitro sensitivity for elderly subjects in the current study (9.7 %/(ng/ml)). This suggests that in-vitro measurement of ChE sensitivity is predictive of ex-vivo sensitivity in clinical studies. The study results suggest that elderly adults may require a 2-3-fold higher blood concentration than young adults to achieve the same ChE inhibition. This may explain why for epistigmine, an investigational carbamate ChE inhibitor for the treatment of AD, the maximum tolerated dose observed in young adults (40 mg single dose) was lower than for older adults (90 mg/day). Higher sensitivity in young adults prevented further dose escalation, while all elderly subjects tolerated higher doses. This research may have implications for other diseases and conditions, most notably MG and as a prophylaxis of nerve gases poisoning. As patients with MG age, they may become less sensitive to PYR, the most common symptomatic treatment for MG, and an increase in dose may be required. Further, older military personnel assigned to receive PYR, may require increased doses to achieve the targeted 10% RBC AChE inhibition, necessary to protect against nerve gas poisoning.