Interest in hippocampus increased sharply after his significance in the process of learning and retention of information was published. In particular, considerable interest was in its volume changes and their effect on Alzheimer’s disease. Understanding the structure and function hippocampus would contribute to a more accurate diagnosis of this disease. In this work was created a method of hippocampal segmentation using active contours. With its help, the data composed of both healthy and a diseased patients was segmented and the results were then statistically analyzed using statistical methods such as Kruskal-Walis test, Mann-Whitney test. The level of significance given by results of analysis supports alternative hypothesis that attaches significance of the difference in volume of the hippocampus between studied groups.

Ce travail porte sur l’étude du risque de démence chez les personnes âgées ayant consommé des benzodiazépines. Ces médicaments méritent une attention particulière du fait de (i) leur utilisation trop systématique et le plus souvent chronique contrairement aux recommandations préconisant des durées d’utilisation courtes (ii) leurs effets délétères sur la cognition demeurant mal évalués à long terme. La plupart des études conduites sur ce sujet ont conclu à une augmentation du risque de démence chez les sujets ayant utilisé des benzodiazépines. Un biais protopathique pouvait cependant, en partie du moins, avoir expliqué ces résultats : la prescription de benzodiazépines pouvait avoir été motivée par des prodromes souvent observés au cours des années précédant le diagnostic de la maladie. Afin de mieux prendre en considération ce biais, le projet BENZODEM a utilisé les ressources de la cohorte PAQUID (3777 sujets ≥ 65 ans tirés au sort sur les listes électorales de Dordogne et Gironde bénéficiant d’un suivi de plus de 20 ans). Ce projet, combinant deux études de cohorte et une étude cas-­‐témoins, a conclu à un risque de démence augmenté de 46 à 62% chez les utilisateurs de benzodiazépines et retardé de 5 à 15 ans par rapport à l’initiation du traitement. La seconde partie du programme (BENZODEM2) a consisté en une étude cas-­‐témoins conduite sur un large échantillon de sujets de plus de 65 ans enregistrés sur la base de données de la Régie de l’Assurance Maladie du Québec (RAMQ). Ce programme a permis (1) de valider les précédents résultats (risque augmenté de 30 à 80% en fonction de la dose, la durée du traitement et la nature des molécules) (2) d’identifier les profils de consommation associés à un excès de risque : consommateurs de plus de 3 mois avec une relation dose-­‐effet marquée et molécules à longue demi-­‐ vie d’élimination. Des explorations complémentaires ont permis de conclure que cet excès de risque n’était pas expliqué par une mortalité différentielle entre groupes comparés ni par la prescription d’autres médicaments psychotropes. Une autre étude menée sur PAQUID montrait une absence de différence entre consommateurs et non consommateurs de benzodiazépines vis-­‐à-­‐vis de l’évolution des scores mesurant les fonctions cognitives. Ces résultats ont permis d’émettre des hypothèses concernant le mécanisme de l’association entre utilisation de benzodiazépines et démence: (1) les benzodiazépines pourraient constituer des marqueurs précoces de la maladie ; (2) les benzodiazépines pourraient aussi diminuer les capacités de recours à la réserve cognitive en réponses aux lésions précoces de la maladie au stade préclinique ; (3) il est aussi possible que ces deux explications soient combinées. / This work deals with the risk of dementia in elderly individuals who have used benzodiazepines. These drugs deserve particular attention because (i) their use appears to be too systematic and most often chronic despite good practice guidelines recommending short durations of use (ii) their deleterious effects on cognition remain underevaluated for the long-­‐term. Most of the studies conducted concluded that there was an increased risk of dementia among benzodiazepine users. In fact, a protopathic bias could, at least in part, have explained these results. Indeed, the prescription of benzodiazepines could have been motivated by the prodromes often observed several years before the clinical diagnosis of a dementia. With the aim of better controlling for this bias, the BENZODEM project used the resources of the PAQUID cohort (3777 subjects ≥65 years randomly sampled from electoral lists in South-­‐West France, with a 20-­‐ year follow-­‐up). This project combined two cohort studies and one case-­‐control. These studies concluded in a risk of dementia increased by 46 to 62% in benzodiazepine users and delayed by 5 to 15 years after treatment initiation. The second part of the programme (BENZODEM2) consisted of a case-­‐control study conducted in a large sample of subjects >65 years registered in the Quebec Health care database (Régie de l’Assurance Maladie du Québec, RAMQ). It was thus possible(1) to validate the previous results by using a different population (the risk was found to be increased by 30 to 80% depending on the patterns of use regarding dose, duration and type of molecule), (2) to identify the patterns of use which appeared to be at risk; excess risk was only apparent for uses of more than three months with a marked dose-­‐effect relationship, and was higher for molecules with a long elimination half-­‐life. Complementary explorations using the PAQUID cohort indicated that the excess risk in exposed was not explained by a differential mortality rate between the groups compared. Other studies suggested that the link found remained independently of the prescription of other psychotropics. Another analysis in the PAQUID cohort showed that, in the absence of dementia, no difference was observed between benzodiazepine users and non-­‐users with regards to the evolution of scores evaluating cognitive functions. These results led to several assumptions about the putative mechanism explaining the relationship found between benzodiazepine use and dementia: (1) benzodiazepines could be early markers of symptoms such as anxiety, depression or insomnia, which are potential prodromes or risk factors for this disease, (2) these drugs could also reduce the ability to use cognitive reserve in order to cope with early lesions of the disease during the preclinical stage, (3) the association found could also result from these two mechanisms.

Bakgrund: Demenssjukdomar drabbar ungefär 50 miljoner människor i världen och den vanligaste formen av demens är Alzheimers sjukdom (AD). Det finns inte någon behandling som botar AD utan endast läkemedel som ska lindra symtomen som till exempel acetylkolinesteras-hämmare. Symtomen vid AD kommer smygande och börjar oftast med amnesi och övergår gradvist till språksvårigheter, förståelsesvårigheter och svårt att utföra vardagliga sysslor. Svår AD omfattar även symtom som depression, hallucinationer och vanföreställningar. Orsaken bakom AD är förlusten av neuroner och synapser och det finns teorier till varför detta sker. En teori är amyloidkaskadprincipen som beskriver uppkomsten av peptiden beta-amyloid som är svår att bryta ner och kan därför ackumuleras och bilda plack som förstör neuronen. Andra faktorer som är länkade till AD är hyperfosforylering av tau proteinet, mutationer på apolipoprotein E-genen samt mutationer på preseinilin-genen. En annan teori bakom orsaken till AD är oxidativ stress som uppkommer i samband med elektrontransportkedjan då det bildas reaktiva föreningar som kan interagera med lipider, proteiner, polysackarider och nukleinsyror i form av oxidativa reaktioner. Detta leder till bildandet och ackumulering av beta-amyloidplacken och neurofibrilla trassel och i sin tur till att neuroner dör. Antioxidanter är molekyler som motverkar oxidativ stress genom att interagera med de reaktiva ämnena så att de blir neutrala. Vitamin E är en antioxidant som kan neutralisera oxidation av molekyler i cellerna och är en vitamin som det har visat sig vara brist på hos patienter med AD. Det har därför gjorts studier på vitamin E som behandling vid AD. Syfte: Syftet med arbetet var att undersöka om vitamin E har någon effekt som behandling vid AD. Utifrån syftet ställdes frågorna 1: Har vitamin E någon effekt på AD? 2: kan vitamin E hejda utvecklingen av AD? 3: kan en kombination med nuvarande behandling och vitamin E bidra till bromsning av AD-utveckling? Metod: Arbetet är ett litteraturarbete och baseras på 5 vetenskapliga artiklar varav 4 behandlar AD och 1 artikel behandlar Down syndrom. Resultat: Endast en av de fem studierna visade en statistiskt signifikant skillnad för vitamin E i försämringen av symtom hos patienterna i jämförelse med placebo och deltagarna i studien behandlades samtidigt med acetylkolinesterashämmare vilket indikerar att en kombination med vitamin E kan hjälpa med att hejda utvecklingen av AD. Resultatet från de andra fyra studierna visar dock att vitamin E inte har en signifikant effekt på AD eller för att hejda utvecklingen. Slutsats: Eftersom biverkningsprofilen från studierna visar att det inte fanns allvarliga biverkningar bör patienterna inte avrådas från att ta vitamin E.Vitamin E har ytterst minimal effekt på AD och fungerar inte som behandling för att stoppa sjukdomsförloppet. / Background: Dementia affects approximately 50 million people in the world and the most common form of dementia is Alzheimer's disease (AD). There is no treatment to cure AD, only treatments to relieve the symptoms, one of them being acetylcholinesterase inhibitors. The symptoms of AD are recognized stealthily and often begin with amnesia and gradually transition to language difficulties, comprehension difficulties and difficulties to perform everyday chores. Severe AD also includes symptoms such as depression, hallucination, and delusions. The cause of AD is loss of neurons and synapses and there are different theories of why this happens. One theory is the amyloid cascade principle which describes the occurrence of the beta-amyloid peptide that is difficult to metabolize and can accumulate and form plaques which leads to the death of neurons. Other factors linked to AD are hyperphosphorylation of the tau protein, mutations in the apolipoprotein E-gene and mutations in the preseniline gene. Another theory behind the cause of AD is oxidative stress that occurs because of the electronic transport chain when reactive compounds are formed that can interact with lipids, proteins, polysaccharides, and nucleic acids and form oxidative reactions. This leads to the formation and accumulation of the beta-amyloid plaque and neurofibrillary tangles and in turn the loss of neurons. Antioxidants are molecules that counteract oxidative substances by interacting with the reactive substances so that they become neutral. Vitamin E is an antioxidant that can neutralize the oxidation of molecules in the cells and is a vitamin that has been shown to be deficient in patients with AD. Objective: The aim of this study was to investigate whether vitamin E has any effect in treating AD. Based on the objective, three questions were set. 1: what effect does vitamin E have in AD? 2: Can vitamin E stop the development of AD? 3: Can a combination with current treatment and vitamin E slow down the development of AD? Method: This study is a literature study and is based on 5 scientific articles of which 4 are based on AD and 1 is based on Down syndrome. Results: Only one of the five studies showed statistical significance for vitamin E in slowing down the process of symptoms in AD compared to placebo. Participants being treated concomitantly with acetylcholinesterase inhibitors indicated that combining with vitamin E may help halt the development of AD. However, the results from the other four studies indicate that vitamin E does not have a significant effect on AD. Conclusion: The data on adverse events in the studies show that there were no serious side effects, therefore patients should not be advised not to take vitamin E but it should be known that vitamin E has extremely minimal effect on AD and does not work as treatment to stop the disease process.

Émotions et nouvelles technologies apparaissent le plus souvent comme une alliance impossible. Pourtant, ces dernières années, les nouvelles technologies, telles que les capteurs portés et les logiciels de reconnaissance d’activités, ont permis une évaluation plus fine des émotions. A travers cette thèse notre objectif était de développer et de tester divers instruments technologiques permettant l’évaluation et la prise en charge des émotions que ce soit au niveau comportemental, physiologique ou cognitif. Nous avons commencé par faire un état des lieux des nouvelles technologies disponibles pour l’évaluation et la prise en charge des troubles émotionnels. Nous avons ensuite recueilli les recommandations d’experts pour leur utilisation ainsi que l’avis des internes de psychiatrie et des médecins généralistes. Au sein de notre deuxième étude, nous avons développé un test informatisé permettant de mesurer les défauts de ressenti et de régulation des émotions propres aux composantes physiologique et cognitive des émotions. Notre troisième étude a consisté à élaborer une prise en charge des troubles émotionnels dans ces deux composantes par une immersion sensori-virtuelle et à étudier l’effet de cette dernière sur le langage de patients avec et sans troubles cognitifs. Enfin, notre quatrième étude a visé à développer une plateforme automatisée d’évaluation et de prise en charge des troubles émotionnels dans la composante comportementale. Nous avons développé et évalué l’intérêt des algorithmes de reconnaissance d’activité pour leur détection et des solutions non pharmacologiques basées sur l’aromathérapie, la musicothérapie et les serious games pour leur prise en charge. / Emotions and new technologies often sound as an impossible association. However, in recent years, new Information and Communication Technologies (nICT) such as wearable sensors and software for activity recognition have enabled to assess emotions more accurately. This dissertation aimed at developing and testing various nICT-based tools allowing a better assessment and management of emotions, either at the behavioral, physiological or cognitive level. I started with a literature review of the existing nICT for the assessment and management of emotional disorders. I then gathered recommendations for the use of nICT from experts in the field, as well from interns in psychiatry and general practitioners (Study 1). Next, I developed a computerized test to assess impairments in emotional experience and emotion regulation at the physiological and cognitive level (Study 2). Study 3 consisted in developing a tool to manage emotional disorders at the physiological and cognitive level by means of a multisensory, virtual immersion, and assessing the effects of this immersion on the verbal ability of patients with and without cognitive impairment. Finally, in Study 4 I developed an automated platform for the assessment and management of emotional disorders at the behavioral level. In this context, I developed and evaluated the interest of employing activity recognition algorithms for the detection of behavioral emotional disorders, and I evaluated the effects of nonpharmacological solutions based on aromatherapy, music therapy and serious games for the management of these disorders.

Cette thèse avait pour objectif de tester la théorie de la rétrogenèse appliquée au langage des personnes atteintes de la maladie d’Alzheimer, afin de tirer des conclusions permettant d’adapter notre comportement aux patients et de mettre en place des méthodes de maintient dans le langage plus appropriées.Pour ce faire, trois tâches ont été mises en place : une tâche de fluence verbale (phonémique (lettre initiale P) puis sémantique (animaux)), une tâche de dénomination d’images, ainsi qu’une tâche de répétition de phrases. Trois groupes de participants ont été créés : un groupe de 80 personnes atteintes de la maladie d’Alzheimer, un groupe de 60 enfants, âgés de 3 à 11 ans, puis un groupe contrôle de personnes âgées saines. Le groupe des patients était divisé en 4 sous-groupes en fonction de leur score au MMSE. Il en était de même pour les enfants, répartis en trois sous-groupes.Les analyses effectuées par le biais de modèles mixtes, ont permis de montrer que le déclin du langage dans la maladie d’Alzheimer semble bien suivre un ordre symétrique à celui de son acquisition. L’effet d’AoA permet souvent d’expliquer ce phénomène. Toutefois, des différences entre les enfants et les personnes Alzheimer sont également observables : si le langage semble suivre une involution symétrique à celle de l’enfant, il n’en est pas moins que les processus sous-jacents impliqués ne sont pas les mêmes que chez l’enfant. / The aim of this thesis was to test retrogenesis hypothesis applied to the language of people with Alzheimer's disease, in order to draw conclusions allowing us to adapt our behavior to patients and to implement appropriate methods of maintaining language.To do this, three tasks were established: a verbal fluency task (phonemic (initial letter P) and then semantic (animals)), an picture naming task, and a sentence repetition task. Three groups of participants were created: a group of 80 people with Alzheimer's disease, a group of 60 children, aged 3 to 11, and a healthy elderly control group. The patient group was divided into 4 subgroups based on their MMSE score. It was the same for children, divided into three subgroups.Analyzes conducted runing mixed models have shown that the decline of language in Alzheimer's disease seems to follow a symmetrical order to that of its acquisition. The effect of AoA can often explain this phenomenon. However, differences between children and Alzheimer's patients are also observable: if the language seems to follow an involution symmetrical to that of the child, it is nonetheless that the underlying processes involved are not the same as in the child.

Active learning strategies are important for facilitating deep learning that may be carried throughout life, but which is still finding its way into the college setting. Educators are not often trained in effective learning practices, which reduces the cognitive and proficiency gains of their students. By providing such guidance in the formative years of a teacher’s training, we hypothesize that the learning environment will be greatly enriched and enhanced. On the opposite end of the spectrum of life and cognition, the plague of dementia also warrants examination. Alzheimer’s disease (AD), an incurable neurodegenerative disorder progressing from the medial temporal lobe, is the most common form of dementia diagnosed in people over age 65, afflicting 30-40% of those 85 years and older. Despite its prevalence, effective treatments are limited because the principal causes and triggers of AD are not entirely understood. Growing evidence demonstrates that oxidative stress (OS) is an important factor contributing to the initiation and progression of AD. A key player contributing to this OS is iron, an essential trace mineral which is required for proper neuronal function, but which generates reactive oxygen species during redox transitions. Intracellular labile iron pool (LIP) levels are strictly regulated by proteins such as transferrin (import), ferroportin (export), and ferritin (storage). However, when these proteins become dysregulated, excess iron associates with other proteins such as amyloid beta (Aβ) and tau, aggregations of which are hallmarks of AD. In our hypothetical model, under extensive or prolonged OS, as occurs in AD, much larger Aβ plaques form because the stress does not abate. Hyperphosphorylated tau is the last resort to protect the cell against free iron, and aggregates when the LIP is elevated because neither iron storage in ferritin nor iron export through ferroportin can relieve the neurons of the free iron.

Fluorodeoxyglucose Positron Emission Tomography (FDG PET) and Magnetic Resonance Imaging (MRI) are commonly used in a clinical setting as an examination in Alzheimer’s Disease (AD) patients. FDG PET is an imaging tool to evaluate hypometabolism; meanwhile, the MRI observes the brain volume. However, it is still unclear which examination better reflects the tau tangles, which have been known as the hallmark’s pathology of AD. Therefore, this study was conducted to compare FDG PET and MRI in assessing tau pathology in AD, by utilizing a database from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The presence of tau tangles was confirmed by using the Tau-PET images. In total, 275 cognitively impaired subjects were included as well as a subgroup of 147 subjects with positive amyloid status. Based on the analysis, it was observed that higher Tau-PET is significantly associated with FDG PET hypometabolism and MRI atrophy. A similar result was also seen in the amyloid positive subgroups. By comparing the spearman’s correlation coefficients, it was found that that the correlation was stronger between Tau PET and FDG PET (r=-0.414, p<0.001, and r=-0.475, p<0.001 in the positive amyloid subgroup) compared to Tau-PET and MRI (r=-0.331, p<0.001 and r=-0.440, p<0.001 in the positive amyloid subgroup). Inconclusion, FDG PET better reflects the tau pathology compared to MRI in AD.

Alzheimer’s disease (AD) is a multifactorial neurological condition associated with genetic profiles that are still not completely understood. We performed a family-based low-density genome-wide association analysis of age at onset (AAO) in AD (244 patients and their relatives) using Illumina 6 K single-nucleotide polymorphisms (SNPs) panel and the FBAT-logrank statistic. We observed 10 SNPs associated with AAO in AD with p < 2 × 10−3. The most significant hit within a known gene, the neuronal protein astrotactin 2 (ASTN2), was SNP rs1334071 (p = 8.74 × 10−4). ASTN2 has been implicated in several neuropsychiatric disorders, including cognitive disorders, autism and schizophrenia. We then conducted a replication study focusing on ASTN2 gene in a Canadian sample of 791 AD patients and 782 controls using the logrank test. Five ASTN2 SNPs (highest association is rs16933774 with p = 0.0053) showed associations with AAO in this Canadian sample (p < 0.05). Furthermore, Kaplan–Meier survival analysis of SNP rs16933774 showed that the AAO of AD in individuals heterozygous for AG genotype of rs16933774 (median of AAO = 68.5 years) was approximately 4.5 years earlier than those individuals having the AA genotype (median of AAO = 73 years). In conclusion, a significant association of ASTN2 genetic variants with AAO of AD in two independent samples demonstrates a role for ASTN2 in the pathogenesis of AD. Future functional studies of this gene may help to characterize the genetic architecture of the AAO of AD. Genetic factors in AAO may be a critical factor for early AD intervention and prevention efforts.

No study has focussed on the longitudinal effect of APOE-ε4 genotype on the logical memory delayed recall total (LDELTOTAL) score in late-onset Alzheimer’s disease (AD). The LDELTOTAL scores were collected at baseline, 12, 24, 36 and 48 months from 382 participants with AD, 503 with cognitive normal (CN), 1293 with mild cognitive impairment (MCI) in the Alzheimer's Disease Neuroimaging Initiative (ADNI). A linear mixed model (LMM) was used to investigate the effect of APOE-ε4 on the longitudinal changes in the LDELTOTAL scores adjusted for age, gender, education and baseline Mini Mental State Examination score. There were significant differences in LDELTOTAL scores among AD, CN, and MCI (P < 0.0001) and among APOE-ε4 alleles at baseline (P < 0.0001). In the multivariable LMM, elders with 75+ years (P = 0.0051), females (P < 0.0001), lower education (P < 0.0001), AD and MCI (both P values < 0.0001) were associated with decreased LDELTOTAL values, while the individuals with 1 or 2 APOE-ε4 allele revealed significantly lower LDELTOTAL scores (both P values <0.0001) compared with individuals without APOE-ε4 allele. Further, APOE-ε4 alleles had significant interactions with four follow-up visits, where all follow-up visits showed significantly higher LDELTOTAL score. In addition, gender showed interaction with age, education and APOE-ε4 with follow-up visits. Our findings provide the first evidence of the effect of APOE-ε4 genotype on the logical memory declines related to AD. Further, APOE-ε4 alleles showed interactions with gender and follow-up visits.

Ammonia is a toxic by-product of protein catabolism and is involved in changes in glutamate metabolism. Therefore, ammonia metabolism genes may link a range of diseases involving glutamate signaling such as Alzheimer’s disease (AD), major depressive disorder (MDD), and type 2 diabetes (T2D). We analyzed data from a National Institute on Aging study with a family-based design to determine if 45 single nucleotide polymorphisms (SNPs) in glutaminase (GLS), carbamoyl phosphate synthetase 1 (CPS1), or glutamate-ammonia ligase (GLUL) genes were associated with AD, MDD, or T2D using PLINK software. HAPLOVIEW software was used to calculate linkage disequilibrium measures for the SNPs. Next, we analyzed the associated variations for potential effects on transcriptional control sites to identify possible functional effects of the SNPs. Of the SNPs that passed the quality control tests, four SNPs in the GLS gene were significantly associated with AD, two SNPs in the GLS gene were associated with T2D, and one SNP in the GLUL gene and three SNPs in the CPS1 gene were associated with MDD before Bonferroni correction. The in silico bioinformatic analysis suggested probable functional roles for six associated SNPs. Glutamate signaling pathways have been implicated in all these diseases, and other studies have detected similar brain pathologies such as cortical thinning in AD, MDD, and T2D. Taken together, these data potentially link GLS with AD, GLS with T2D, and CPS1 and GLUL with MDD and stimulate the generation of testable hypotheses that may help explain the molecular basis of pathologies shared by these disorders.