Le langage demeure préservé des effets du vieillissement mais précocement atteint dans la Maladie d'Alzheimer (MA). Le discours, en mobilisant l'ensemble des fonctions cognitives, pourrait mettre en évidence davantage de difficultés. Ce travail vise à analyser des productions de patients et de participants âgés typiques en lien avec les changements cognitifs et cérébraux. Une étude s'est intéressée à la production de discours portant sur des événements personnellement vécus. Une deuxième visait à comparer ce type de discours à un discours sur support imagé. Les résultats montrent que les difficultés rencontrées lors d'un discours d'événements vécus seraient corrélées à l'atteinte mnésique des patients. A l'inverse, elles seraient associées à l'atteinte exécutive et lexicale dans un discours imagé. Une dernière étude s'est focalisée sur la variabilité existant chez les participants âgés "typiques". Une analyse en cluster a montré quatre profils de locuteurs, dont un profil "hors-sujet" qui pourrait refléter une zone ambiguë entre vieillissement normal et pathologique. Ce travail pointe des marqueurs de MA prodromale, en lien avec les modifications cognitives et cérébrales. Certaines difficultés seraient liées à une atteinte mnésique ou exécutive indépendamment de l'altération langagière. / Language is the most preserved cognitive function from the effects of aging. Unlike typical aging, Alzheimer's disease (AD) is characterized by an early impairment. Analysis of discourse may reveal more difficulties than other tests since it mobilizes a large set of cognitive functions. This work aims to analyze various discourses in AD patients and participants with typical aging, in relation to various cognitive tests as well as neuroimaging data. One study focused on a memory-based discourse. A second study compared a memory-based and in a picture-based discourse. Patients' difficulties were correlated on one hand with memory impairment in the memory-based discourse and on the second hand with lexical-executive impairment in the picture-based discourse. A final study focused on discourse variability in the general aging population. A cluster analysis revealed four profiles of speakers. Among them, an "off-topic" profile could reflect a grey zone between normal and pathological aging. This work allowed us to shed light on deficit markers and compensatory strategies in prodromal AD, in relation with cognitive and cerebral changes. In particular, many difficulties may actually be related to memory or executive impairment, regardless of a language alteration.

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It was hypothesized that 192 IgG-saporin lesions of the basal forebrain cholinergic system (BFCS) would disrupt differential reinforcement of low rate (DRL) learning in an uncued DRL task, but would not impair acquisition and performance in the cued version of the task. Results suggest that BFCS lesions impair vigilance to the external cues despite continued practice in the cued DRL, whereas continuous attention to internally produced cues recovers with extended practice in the uncued DRL.

La barrière hémato-encéphalique (BHE) régule finement l’apport en oxygène et en nutriments du cerveau et le protège d’éventuels pathogènes, notamment en bloquant le passage des molécules de poids moléculaire supérieur à 400 Da. Malheureusement, cette barrière est un obstacle à la délivrance de nombreux médicaments. Les ultrasons focalisés de basse intensité, combinés avec des microbulles, représentent un outil de choix pour perméabiliser la BHE, de façon sûre et réversible, et ainsi permettre de délivrer efficacement des médicaments ou des agents de contraste dans le cerveau. Dans la première partie de ma thèse, j’ai développé de nouvelles stratégies ultrasonores de perméabilisation de la BHE chez le rongeur. J’ai mesuré l’atténuation du faisceau ultrasonore par le crâne et étudié l’influence des paramètres acoustiques sur l’intensité et la durée de la perméabilisation. Ces développements m’ont ensuite permis de délivrer des nanoparticules dans le cerveau de rongeurs et d’observer cette délivrance par imagerie par résonance magnétique (IRM), tomographie par émission de positrons, imagerie de contraste de phase par rayons-X, spectrométrie de masse ou encore histologie. La seconde partie de mon travail a porté sur l’application de cette technologie ultrasonore à la maladie d’Alzheimer (MA). J’ai tout d’abord optimisé un protocole IRM T2* à très haute résolution permettant l’imagerie ex vivo des plaques amyloïdes de souris modèles de la MA. J’ai développé un traitement semi-automatique des images pour détecter et quantifier la charge amyloïde dans le cortex. Enfin, j’ai évalué la perméabilisation répétée de la BHE en tant que thérapie pour la MA et démontré que des perméabilisations répétées de la BHE pouvaient avoir un effet bénéfique sur la mémoire de rongeurs modèles de la maladie. / The blood-brain barrier (BBB) plays a crucial role in maintaining the hemostasis of the brain and protects it from pathogens. The BBB prevents molecules with a molecular weight higher than 400 Da to enter the brain. Crucial, the BBB becomes a limit to deliver drugs to the brain. Low intensity focused ultrasound and microbubbles are a unique tool to open the BBB, in a safe and reversible way, to deliver drugs to the brain. The first part of the PhD was dedicated to developing new strategies for BBB opening. To do so, I measured the attenuation of the ultrasound beam by the skull and studied the dependency of the intensity and of the duration of the BBB opening on the acoustic parameters. Thanks to these developments, I was able to deliver many kinds of nanoparticles to rodent brains and I could observe their delivery with techniques such as magnetic resonance imaging (MRI), positron emission tomography, phase-contrast X-ray imaging, mass spectroscopy or histology. The second part of my PhD was focused on applying this technology to Alzheimer’s disease (AD). I optimized a T2* MRI protocol at very high resolution for ex vivo imaging of amyloid plaques in the cortex of mice modeling AD. I developed a semi-automatic image treatment to detect and quantify the amyloid load. Finally, I tested a repeated BBB opening as a therapy for AD and showed that repeated BBB openings could have a beneficial impact on the memory on rodents modeling AD.

OBJECTIVE: To determine whether volumetric measures of the hippocampus or entorhinal cortex in combination with other cortical measures can differentiate between cognitively normal individuals and participants with amnestic mild cognitive impairment (MCI). METHODS: T1-weighted magnetic resonance imaging (MRI) data acquired from 46 cognitively normal participants and 50 participants with amnestic MCI as part of the Boston University Alzheimer's Disease Center research registry and the Alzheimer's Disease Neuroimaging Initiative were used in this cross-sectional study. Cortical and subcortical volumes, including hippocampal subfield volumes, were automatically generated from each participant’s structural MRI data using FreeSurfer v6.0. Nominal logistic regression models containing these variables were used to evaluate their ability to identify participants with MCI. RESULTS: A model containing 11 regions of interest (insula, superior parietal cortex, rostral middle frontal cortex, middle temporal cortex, pars opercularis, paracentral lobule, whole hippocampus, subiculum, superior temporal cortex, precentral cortex and caudal anterior cingulate cortex) fit the data best (R2 = 0.7710, whole model test chi square = 102.4794, p < 0.0001). CONCLUSIONS: Volumetric measures acquired from MRI were able to correctly identify most healthy control subjects and those with amnestic MCI using measures of selected medial temporal lobe structures in combination with those from other cortical areas yielding an overall classification of 95.83% for this dataset. These findings support the notion that while clinical features of amnestic MCI may reflect medial temporal atrophy, differences that can be used to distinguish between these two populations are present elsewhere in the brain. This finding further affirming that atrophy can be identified before clinical features are expressed. Additional studies are needed to assess how well other imaging modalities, such as resting state functional connectivity, diffusion imaging, and amyloid and tau position emission tomography (PET), perform in classifying participants who are cognitively normal versus those who are amnestic MCI.

Neurodegenerative diseases are highly multifaceted. Despite their heavy burden, treatment options are limited and our understanding of their molecular triggers even less so. In this thesis, I focus on the pathogenesis of Alzheimer’s Disease (AD) due to familial, sporadic and environmental causes. Previous research shows that early AD stages are characterized by upregulated functionality of mitochondria-associated endoplasmic reticulum (ER) membranes. These “MAM” domains of the ER are dynamic contacts between the ER and mitochondria distinguished by a unique lipid composition equivalent to a lipid raft. These sites cluster a specific set of metabolic enzymes that regulate cellular lipid uptake, trafficking and turnover. We find that cleavage of the amyloid precursor protein at MAM domains is intimately involved in MAM regulation through localization of its C-terminal fragment of 99 a.a., C99, to MAM regions. C99 upregulates MAM functionality by promoting cholesterol uptake and trafficking to the ER for esterification, observable in both familial and sporadic AD samples. Here, we recapitulated these phenotypes in a mouse model of an environmental AD trigger: traumatic brain injury (TBI). Through biochemical, transcriptional and lipidomic analyses, we observed MAM functionality to be upregulated following a single brain injury. This was determined by assessment of phospholipid synthesis and cholesterol esterification. This correlated with increased deposition of C99 in MAM domains as well as cell type-specific lipidomic alterations. Specifically, cholesterol esterification was predominant in microglia, triglyceride elevations were predominant in microglia and astrocytes, and polyunsaturated phospholipid elevations were predominant in neurons. We hypothesize that, in the acute phase, MAM upregulation serves to promote lipid synthesis for tissue repair. However, if these phenotypes are sustained (such as after multiple injuries), cognitive functions dependent on neuronal functionality could become compromised. Altogether, we propose that the induction of AD pathogenesis following brain injury may arise from chronic upregulation of MAM activities. This work advances our understanding of neurodegenerative disease etiology.

Background: Subjective cognitive decline (SCD; self-perceived decrements in cognitive functioning in spite of objective cognitive performance within the normal range) subtle cognitive decline (subtle CD; objective sub-clinical decrements in cognitive functioning), and APOE 4 genotype have each been identified as potential risk factors for Alzheimer’s and other pathological cognitive decline in later life. However, despite considerable research attention, our accrued knowledge of potential dementia risk factors has failed to coalesce into a reliable screening measure or assessment method at the earliest preclinical stages of decline. A key issue undermining this effort is the challenge of discriminating older adults experiencing age-normative cognitive changes and complaints from those with dementia risk-relevant concerns and experiences. This, in turn, may result from a fractured field that emphasizes some sources of information (e.g., cognitive test performance) at the expense of others entirely (e.g., self-reported experiences). In light of this, a mixed-methods approach integrating the various methods of enquiry and sources of data may be appropriate at this juncture. Sample and data collection: n=65 healthy community-dwelling older adults from Victoria, BC, Canada completed a brief neuropsychological assessment, participated in interviews related to their first-hand experiences of aging and cognitive change, and provided saliva samples for the purposes of genotype analysis. Chapter 1: This chapter presents a systematic review authored by the Principal Investigator and several Supervisory Committee Members prior to the commencement of this dissertation. This paper presents the current evidence regarding the relationship between SCD and APOE 4 genotype. It is included in this dissertation to contextualize our analysis and overall findings. Chapter 2: This chapter provides an overview of the methods and materials used for the subsequent dissertation studies. Chapter 3: The objective of this investigation was to identify specific psychosocial and demographic predictors of SCD and subtle CD and, by extension, to determine whether these two variables may reflect similar underlying factors. Our findings determined that the predictors for SCD and subtle CD were entirely separable. Moreover, SCD and subtle CD were not found to be related. Chapter 4: This study explored which commonly endorsed qualitative experiences correspond with SCD and subtle CD. Commonly endorsed qualitative experiences were categorized according to commonality and clinical convention. MANOVA and Mann-Whitney U analyses were performed to determine the association of SCD and subtle CD with categories of experience controlling for other demographic and psychosocial factors. Executive functioning declines and related compensatory strategies were strongly associated with both SCD and subtle CD – challenging the traditionally memory-centric focus of the majority of dementia risk research. Conclusions: As a first step, this work provides evidence that SCD may not relate to early sub-clinical objective cognitive declines. Further, executive functioning – and not episodic memory – may be a key area to explore when determining early risk-predicting cognitive declines. Overall, this work presents the potential utility of more qualitatively-oriented research to inform the development of comprehensive and multimodal risk assessment approaches. Caveats, limitations, clinical implications, and future directions are discussed. / Graduate / 2021-07-31

Understanding the effect of the environment on human health has benefited from progress made in measuring the exposome. High resolution mass spectrometry (HRMS) has made it possible to measure small molecules across a large dynamic range, allowing researchers to study the role of low abundance environmental toxicants in causing human disease, including examining their effects on biochemistry. Alzheimer’s disease is the most prevalent neurodegenerative disease in the world. While aging is the largest risk factor of the disease, evidence of risk factors for dementias show that lifestyle choices and the environment may modify disease onset and alter the projected prevalence. Observational epidemiological studies have linked exposure to the persistent pesticide dichlorodiphenytrichloroethane (DDT) with increased risk of Alzheimer’s disease (AD). In Chapter 2, using an aging cohort based in Washington Heights and Inwood in Northern Manhattan, I investigated systemic biochemical changes associated with Alzheimer’s disease (AD). Small molecules in plasma were measured in 59 AD cases and 60 healthy participants of African American, Caribbean Hispanic, and non-Hispanic white ancestry using untargeted liquid-chromatography–based ultra-high-resolution mass spectrometry. Metabolite differences between AD and healthy, the different ethnic groups and apolipoprotein E gene (APOE) ε allele status were analyzed. Untargeted network analysis identified pathways enriched by AD-associated metabolites. Then, in Chapter 3, using the genetically tractable nematode model Caenorhabditis elegans, I investigated whether DDT can exacerbate AD-related pathology. DDT is a persistent organic pollutant which, despite its ban in 1972, can be detected in the blood of most people in the U.S. I investigated whether DDT can exacerbate AD-related pathology using a transgenic C. elegans strain that expresses a mutant tau protein fragment that is prone to aggregation, as well as a mutant strain expressing a non-aggregating form of tau protein. DDT restricted the growth in all strains; however, the restriction was more severe in the aggregating tau transgenic strain. Further, I found that DDT exacerbates the inhibitory effects of aggregating tau protein on basal mitochondrial respiration, and increases the amount of time the worms spent curled/coiled. High-resolution metabolomics in the whole worm suggests that DDT reduces levels of several amino acids but increases levels of uric acid and adenosylselenohomocysteine. Surprisingly, developmental exposure to DDT blunts the lifespan reduction caused by aggregating tau protein suggesting a mitohormetic effect of the “double-hit” from DDT and aggregating tau protein or an antagonistic effect which could ultimately turn on lifespan extension pathways. Our data suggest that exposure to DDT likely exacerbates the mitochondrial inhibitory effects of aggregating tau protein in C. elegans. DDT may mimic some of the mitochondrial inhibitory effects induced by increased tau protein aggregation, suggesting that the genetic and environmental insult converge on a common mitochondrial inhibitory pathway, which has been associated with AD in several other studies. Finally, in Chapter 4, I determined changes in global metabolism associated with aggregating tau protein in both C. elegans and humans. We performed high-resolution metabolomic analysis on cerebrospinal fluid (CSF) and plasma obtained from patients of AD and mild cognitive impairment, and cognitively normal controls. Using a transgenic strain of C. elegans which expresses aggregating tau protein in all neurons, I studied the effect of aggregating tau protein on metabolism using high-resolution metabolomic analysis in the whole worm. In the population study, I found >300 features associated (p < 0.05) with phosphorylated tau levels in CSF. Metabolic pathway enrichment identified alterations in fatty acid and amino acid metabolism. Worms expressing aggregating tau showed >900 features altered. Pathway enrichment suggested alterations in glycerophospholipid, fatty acid and amino acid metabolism pathways. To determine which metabolic features are altered in both species, I analyzed annotated features for overlap. Five metabolites were concordant between human plasma and C. elegans, and four concordant between human CSF and C. elegans. Thus, in this analysis I provide evidence in support of using C. elegans to study changes in global metabolism associated with Alzheimer’s disease. In conclusion, using liquid and gas-based chromatography coupled with high-resolution mass spectrometry, we can measure levels of endogenous and exogenously derived small molecules in different biological matrices. By using the appropriate study design, we can identify candidate molecules and biochemical pathways associated with environmental exposures or disease in human populations. These candidates can be followed up by exposing an appropriate C. elegans strain: transgenic strains, mutant strains, or strains that are susceptible to RNAi based knockdown. Given their short life cycle and being amenable to high-throughput behavioral assays, they can readily provide functional and molecular readouts of the perturbation. The findings can provide leads for relevant policy around environmental exposures, understanding mechanisms of toxicity and disease, and identifying potential therapeutic targets.

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第22505号 / 農博第2409号 / 新制||農||1077(附属図書館) / 学位論文||R2||N5285(農学部図書室) / 京都大学大学院農学研究科食品生物科学専攻 / (主査)教授 保川 清, 教授 宮川 恒, 教授 入江 一浩 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

Bakgrund: Alzheimers sjukdom är den vanligaste demenssjukdomen. Sjukdomen är obotlig och genererar mycket tankar, oro och i många fall depression. Vid diagnostiseringen upplever många personer identitetsförlust och ångest. Detta bidrar till minskad livskvalitet hos personer med Alzheimers sjukdom. Med hjälp av olika omvårdnadsåtgärder kan dessa personer få hjälp att återskapa sin identitet, minska oro och ångest och därmed öka sin livskvalitet. Syfte: Syftet med denna studie var att sammanställa omvårdnadsåtgärder som gynnar livskvaliteten hos personer med Alzheimers sjukdom. Metod: Deskriptiv litteraturstudie baserat på 12 vetenskapliga artiklar. Huvudresultat: Huvudresultatet presenteras i fem olika teman, omvårdnadsåtgärder ur ett socialt perspektiv, kognitiv rehabilitering, estetiska åtgärder, fysisk aktivitet samt djurterapi.  Resultatet visar att det viktigaste för att öka livskvaliteten för dessa personer, oavsett kategori, är att individanpassa omvårdnaden och aktiviteterna. Slutsats: Slutsatsen från denna studie är att det finns olika omvårdnadsåtgärder som gynnar livskvaliteten hos personer med Alzheimers sjukdom. Detta genom att minska oro, ångest och aggressivitet. Resultatet blir således en högre livskvalitet hos vårdtagaren samtidigt som det minskar på vårdpersonalens arbetsbelastning. / Background:  Alzheimer's disease is the most common of the dementia diseases. The disease is not curable which contributes to many thoughts, concerns and sometimes depression. When diagnosed, most of the patients experience an identity crisis and anxiety. This results in a lower rank of quality of life in a person with Alzheimer's disease. Using different types of nursing inventions, these persons can be helped through to recreate their identity, reduce concerns and anxiety which can increase the quality of life. Aim: The aim of this study was to identify different nursing inventions that can improve the quality of life of people with Alzheimer's disease. Method: This is a descriptive literature study based on 12 scientific articles. Main results: The result was categorized into five different themes. The themes were nursing interventions from a social perspective, cognitive rehabilitation, aesthetic methods, physical activity and animal therapy. The result showed that the most important thing in order to increase quality of life, regardless of the activity, is to adapt the care and activities to the needs of the individual. Conclusion: Different types of nursing inventions can help persons with Alzheimer's disease to increase their quality of life. The result shows on a lower anxiety level, a reduced level of concerns and less aggression. This can help both persons with Alzheimer’s to experience a higher level of quality of life and the caregivers through a lower workload.