Les déficits progressifs et inexorables des capacités de communication verbale chez les patients Alzheimer bouleversent leurs interactions avec autrui et entravent leur qualité de vie ainsi que celle de leur entourage. La question centrale de cette thèse est d’envisager si l’incapacité chronique des patients souffrant de la maladie d’Alzheimer à utiliser le langage articulé s’accompagne d’une détérioration du registre gestuel. Pour répondre à cette question, nous avons utilisé une tâche d’interaction sociale engagée à partir d’un matériel pictural. Cette situation se veut refléter le plus écologiquement possible des situations de communication au quotidien. Globalement, on observe que, si la production verbale des patients Alzheimer est déficitaire, leur production de gestes liés au discours n’est pas atteinte. Les résultats vont dans le sens d’une atteinte différenciée des capacités de communication verbales et gestuelles des patients et penchent en faveur de l’existence de deux systèmes de communication parallèles pouvant interagir entre eux à différents moments de l’élaboration du message. De surcroît, les résultats suggèrent que les patients présentant un niveau très sévère de la pathologie peuvent compenser l’atteinte lexicale par l’augmentation de la production de gestes déictiques, qui permettraient de rendre visible le référent verbal. Des perspectives fondamentales comme cliniques peuvent être envisagées afin que les gestes liés au discours et plus généralement la communication non verbale puissent constituer un levier thérapeutique dans la prise en soin des patients atteints d’une maladie d’Alzheimer et de leur entourage. / Progressive and inexorable deficits in verbal communication skills in Alzheimer's patients disrupt their relationship with others, impinge their quality of life and that of their caregivers. This thesis aimed at considering whether, in cases of chronic deficits such as Alzheimer's disease, the impaired use of spoken language in these patients went hand in hand with an impaired production of co-verbal gestures. To inquire about this issue, we used a social interaction task, using pictorial material in order to reflect, in an ecological way, everyday life communication situations. Overall, we observed that if the verbal production of Alzheimer's patients is deficient, production of gestures related to speech is not impaired. The results are consistent with a differentiated impairment of verbal and gestural communication skills in patients and sets ground for investigating the existence of two parallel systems of communication that would interact with each other at different levels of message processing. Moreover, results suggest that patients suffering from severe disease can compensate lexical deficits by increasing their production of deictic gestures, rendering visible the verbal referent. Theoretical and clinical perspectives can be considered so that co-verbal gestures and non-verbal communication may constitute a therapeutic lever in the intervention provided to Alzheimer’s patients and their caregivers.

Le vieillissement et la dégénérescence du cerveau, associés à des déficits cognitifs, comportementaux et neurologiques, représentent aujourd'hui un problème majeur de santé publique. L'une des principales maladies liées à l'âge est la maladie d'Alzheimer (MA). L'une des caractéristiques de la MA est l'apparition de plaques amyloïdes, résultant de l'agrégation du peptide ßA4. Physiologiquement, le précurseur de la protéine amyloïde (APP) est clivé par une alpha-sécrétase qui génère un fragment soluble de l'APP (sAPP), important pour la formation de nouvelles cellules nerveuses (neurogenèse). Ce clivage en prévient deux autres, par les béta- et gamma-sécrétases, impliqués dans la MA, et conduisant à la formation du ßA4 toxique. Une analyse du plexus choroïde (PCh) a mis en évidence la forte expression de l’APP par cette structure cérébrale. Le PCh est une structure facilement accessible et produisant le liquide cérébro-spinal : son impact peut donc être répercuté à l’ensemble du cerveau. Il pourrait être une source cérébrale importante d’APP, et contribuer fortement à la pathologie. Mon projet de thèse s'inscrivait dans la possibilité de réguler génétiquement l'expression des formes sauvages et mutées de l'APP au niveau de cette source, et suivre les conséquences sur la neurogenèse adulte et la formation des plaques amyloïdes, marqueur histopathologique de la MA. Par l’utilisation de la thérapie génique pour moduler l’expression de l’APP dans les PCh, nous avons confirmé l’importance de l’APP soluble provenant des PCh dans la neurogenèse adulte. Les PCh semble être une source importante d’APP dans le cerveau, et pourraient avoir un rôle clé dans la maladie d’Alzheimer. / Aging and degeneration of the brain with cognitive decline and neurologic symptoms are major individual and societal problems. The major age-related brain degeneration disease is Alzheimer’s disease (AD) with about 40 million people affected in 2015.Physiologically, the Amyloid Precursor Protein (APP) is cleaved by an alpha-secretase, releasing soluble APP (sAPP) an important regulator of adult neurogenesis. This cleavage prevents two others in positions beta and gamma that generate the ßA4 toxic peptide, a hallmark of Alzheimer Disease.Next generation RNA-sequencing has revealed that APP is the 16th most expressed genes in the choroid plexus (CP), suggesting that it may be a major source of sAPP and ßA4 in the cerebrospinal fluid (CSF). If so, adult neurogenesis in the SVZ and hippocampus may be regulated by the choroid plexus and impeded in mutations favoring ßA4 production. My thesis project fell under the possibility to regulate App expression in the CP, and follow consequences on adult neurogenesis and plaques formation in AD. Using viral vectors to modulate App expression in the CP, we confirmed the importance of sAPP coming from CP in adult neurogenesis. With so, CP seems to be an important source of APPin the brain, and could have a key role in AD.

Through successful personal training, verified assessments, and professional applications, a musician can establish a personal career as a performing artist. This study seeks not only to explore the ways in which musicians can better their own musicianship, but to how they can inspire and empower others through philanthropic applications of their art. A musician’s laboratory exists both in the practice room and on the concert stage. Therefore, for twelve months, the author sought out the most diverse research and performance opportunities, including performances as a featured soloist in Canada and as guest timpanist with the Moscow Symphony in Russia. The project culminated in a benefit concert titled, …in loving memory, raising nearly $5,000 for the Alzheimer's Association. Through personal experiences, the author outlines the solo, small ensemble, and large ensemble performance opportunities that were pursued in order to improve his own musicianship and then applied to the performance of the benefit concert. Offering a "look behind the curtain," this document will also address the logistical hurdles for tackling a charitable event of this scale.

Advances in high performance liquid chromatography-electrospray ionization-mass spectrometry made in proteomics and now applied to the emerging field of lipidomics has enabled the identification of lipid composition at the molecular level. These improvements have given fresh impetus to lipid research. Modulating lipid compositions has been suggested to represent a novel therapeutic target for intervention in Alzheimer’s disease. A better understanding of how metabolic alterations in the lipid landscape alter Alzheimer’s disease prognosis is required to realize this promise. To achieve this goal, further methodological improvement in lipidomic data acquisition and analysis are required as are comprehensive comparative analyses of lipid metabolism at the systems level in clinical samples and mouse models of human neurodegenerative disease. In this thesis, I present two new lipidomic bioinformatic tools Retention Time Standardization and Registration (RTStaR) and Visualization and Phospholipid Identification (VaLID) designed to facilitate analysis of high performance liquid chromatography-electrospray ionization-mass spectrometry lipidomic data. Using these tools and methodologies, I then comparatively profiled the glycerophosphocholine lipidome in the plasma of young adults, cognitively normal elderly with vascular impairment, mild cognitive impairment and late-onset Alzheimer’s disease patients and the entorhinal-hippocampal circuit of late-onset Alzheimer’s disease patients, TgCRND8 human amyloid beta precursor protein transgenic mice (Alzheimer’s disease mouse model), and across the lifespan of NonTg female littermates. Systems-level analyses identified aberrant glycerophosphocholine metabolic pathways systemically perturbed by age, disease, and amyloid beta biogenesis resulting in the regionally-specific accumulation of critical platelet-activating factor and, to a lesser extent, the lysoglycerophosphocholine, metabolites in brain that could be, in part, predicted by changes in plasma. Finally, using proteomic approaches I identified additional changes in lipid metabolic pathways associated with phenoconversion in the TgCRND8 mouse model of Alzheimer’s disease.

No description available.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22357号 / 医博第4598号 / 新制||医||1042(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 井上 治久, 教授 伊佐 正, 教授 渡邊 直樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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: När en person drabbas av Alzheimers sjukdom sker en drastisk förändring i både personens och anhörigas livssituation. Anhöriga tar på sig rollen som anhörigvårdare och träder in i en främmande livsvärld som präglas av lidande. För att lindra detta lidande krävs det att sjuksköterskan har stor kunskap och bättre förståelse för hur de anhöriga upplever den förändrade livssituationen. Syfte: Syftet med denna studie är att belysa hur anhörigas upplevelser av att vårda en närstående med AS porträtteras i spelfilm. Metod: En empirisk kvalitativ ansats med direkta och ostrukturerade observationer av tre filmer har gjorts. Fältanteckningar har förts och analyserats med hjälp av en kvalitativ innehållsanalys. Resultat: Anhörigas upplevelser av att vårda en närstående med AS framförs i fyra teman: när livsvärldsmönstret brister; sorg; förlust av frihet; att släppa taget. Slutsats: Anhöriga känner att det är deras ansvar att vårda sin partner. Att bli anhörigvårdare innebär en förlust av frihet, social isolering och en känsla av ensamhet. De känslomässiga upplevelserna är främsta orsaken till lidandet. Filmerna som har använts i studien är ett kraftfullt medium som kan användas i utbildningssyfte. / Background: When a person is diagnosed with AS, a drastic change takes place in both the patient's and the relatives' lives. The relatives become an informal caregiver, they enter into a foreign world of suffering. In order to alleviate this suffering, the nurse must have greater knowledge and a better understanding of how the relatives experience their changed lifeworld. Aim: The aim of this study is to explore how relatives experience taking care of a partner with AS portrayed in films. Methods: An empirical qualitative approach with direct and unstructured observations of three films has been used. The material consisted of field notes which were analyzed with the help of a qualitative content analysis. Results: Relatives' experiences of caring for a partner with AS are presented in four themes: when the lifeworld texture ruptures; sorrow; loss of freedom; letting go. Conclusion: Relatives feel a responsibility to care for their partner. Becoming an informal caregiver means a loss of freedom, social isolation and a feeling of loneliness. The emotional experiences are the main cause of the suffering. The films used in this study are a powerful medium that can be used for educational purposes.

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.