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

Alzheimer’s disease (AD) is the leading cause of dementia and is alone responsible for 60-70% of all cases of dementia. Though sharing clinical symptoms with other types of dementia, the hallmarks of AD are the abundance of extracellular depositions of β-amyloid (Aβ) plaques, intracellular neurofibrillary tangles of hyper phosphorylated tau proteins and synaptic depletion. The onset of the physiological hallmarks may precede clinical symptoms with a decade or more, and once clinical symptoms occur it may be difficult to separate AD from other types of dementia based on clinical symptoms alone. Since the introduction of radiolabeled Aβ tracer substances for positron emission tomography (PET) imaging it is possible to image the Aβ depositions in-vivo, strengthening the confidence in the diagnosis. Because the accumulation of Aβ may occur years before the first clinical symptoms are shown and even reach a plateau, Aβ PET imaging may not be feasible for disease progress monitoring. However, a negative scan may be used to rule out AD as the underlying cause to the clinical symptoms. It may also be used as a predictor to evaluate the risk of developing AD in patients with mild cognitive impairment (MCI) as well as monitoring potential effects of anti-amyloid drugs.Though currently validated for dichotomous visual assessment only, there is evidence to suggest that quantification of Aβ PET images may reduce inter-reader variability and aid in the monitoring of treatment effects from anti-amyloid drugs.The aim of this thesis was to refine existing methods and develop new ones for processing, quantification and visualization of Aβ PET images to aid in the diagnosis and monitoring of potential treatment of AD in clinical routine. Specifically, the focus for this thesis has been to find a way to fully automatically quantify and visualize a patient’s Aβ PET image in such way that it is presented in a uniform way and show how it relates to what is considered normal. To achieve the aim of the thesis registration algorithms, providing the means to register a patient’s Aβ PET image to a common stereotactic space avoiding the bias of different uptake patterns for Aβ- and Aβ+ images, a suitable region atlas and a 3-dimensional stereotactic surface projections (3D SSP) method, capable of projecting cortical activity onto the surface of a 3D model of the brain without sampling white matter, were developed and evaluated.The material for development and testing comprised 724 individual amyloid PET brain images from six distinct cohorts, ranging from healthy volunteers to definite AD. The new methods could be implemented in a fully automated workflow and were found to be highly accurate, when tested by comparisons to Standards of Truth, such as defining regional uptake from PET images co-registered to magnetic resonance images, post-mortem histopathology and the visual consensus diagnosis of imaging experts.

Master of Landscape Architecture / Department of Landscape Architecture/Regional and Community Planning / Timothy D. Keane / This thesis documents an exploratory design process that examines the efficacy of a framework for designing dementia gardens based on: theory, Stephen and Rachel Kaplan’s Attention Restoration Theory (A.R.T.), (Kaplan and Kaplan, 1989) and Roger Ulrich’s Theory of Supportive Gardens (Ulrich, 1999); John Zeisel’s (2007) process for designing dementia gardens; and design details, Claire Cooper Marcus’ Garden Audit Tool (2007) and Moore’s analysis of exemplary dementia gardens (2007). It documents the integration of theory that is not specific to dementia gardens (Kaplans’ A.R.T. and Ulrich’s Theory of Supportive Gardens) with process (Zeisel) and programming elements that are specific to dementia gardens (Cooper Marcus’ Garden Audit Tool Kit and Moore’s exemplary dementia gardens). The framework was developed during an illustrative courtyard design project for a retirement center whose clientele included patients with varying need levels. Throughout the illustrative design project, knowledge of the four A.R.T. characteristics (Being Away, Fascination; Compatibility and Extent) guided design decision-making in an effort to create an engaging environment, where improved health outcomes and restorative person-environment interactions could occur.

Orientador: Andriana Susana Lopes de Oliveira Campanharo / Resumo: O Alzheimer é uma doença degenerativa do cérebro, incurável, que se agrava ao longo do tempo e atinge sobretudo pessoas entre 65 e 90 anos. A doença de Alzheimer (DA) é a principal demência entre os idosos e caracteriza-se por perda de funções cognitivas (memória, orientação, comportamento e linguagem), causada pela morte de células cerebrais. Atualmente, o diagnóstico definitivo da DA é feito por meio de um exame do tecido cerebral obtido por biopsia ou necropsia. Como somente após a morte do paciente pode-se ter a certeza que o mesmo tinha a DA, seu diagnóstico é feito utilizando exames, avaliações e excluindo-se outras causas de demência do seu histórico clínico. Em paralelo, estudos têm sido desenvolvidos para o estudo da DA com base de dados de EletroEncefaloGrama (EEG), e nesse sentido, diversos métodos de análise de dados de EEG têm sido propostos. Contudo, o estudo da DA por meio de dados de EEG é ainda um desafio, e consequentemente, faz-se necessária a preposição de novos métodos com o intuito de capturar informações adicionais da doença. Nesse sentido, utilizamos o mapeamento de uma série temporal em uma rede complexa no estudo da dinâmica de séries temporais de EEG de pacientes com a DA. Mais especificamente, na distinção entre envelhecimento e a DA e na identificação, dos estágios da DA em pacientes doentes a partir, das ondas cerebrais, alfa, beta, teta e delta. / Abstract: Alzheimer’s is a degerative brain disease, incurable, which aggravates over time and mainly affects people between 65 and 90 years. Alzheimer’s disease (AD) is the leading dementia among the elderly and is characterized by cognitive functions loss (memory, orientation, behavior and language) caused by the death of brain cells. Currently, confirmatory diagnosis of AD can only be made through the examination the brain tissue obtained by biopsy or necropsy. Considering that only after the patient’s death it is possible to be sure that he or she had AD, the approximate diagnosis is made excluding other causes of dementia. In parallel, studies have been developed for the study of AD with the use of Electroencephalography (EEG), and in this sense, several methods of EEG data analysis have been proposed. However, the study of AD with the use of EEG data is still a challenge, and consequently, it is necessary the proposal of new methods to capture additional information about the disease. In this sense, we used the map from a time series to a network, recently proposed by Campanharo, in a novel application, that is, in the study of EEG time series of patients with AD. More specifically, to distinguish aging and AD and to identify the stages of AD in unhealthy patients based on alpha, beta, theta and delta brain waves information. / Mestre

Alzheimer's disease (AD) is a large and growing problem and while we today lack a full understanding of this disease, we know that the protein tau and the amyloid fibrils it forms play a central role in its development. We also know that these fibrils can have different morphologies in different diseases and that fibrils produced in vitro not necessarily adopt any of the morphologies found in patients. This means there is a need for more pathologically relevant fibrils in vitro to be able to understand this disease better. One approach to satisfy this need is to use fibrils found in patients as seeds and thus transfer their morphology to recombinantly purified protein. To facilitate this process this study has attempted to develop a way to differentiate between different fibril morphologies using a FRET based system. This involves fluorescent fusion proteins (tau-EXFPs) and fluorescent amyloid probes as well as seeding experiments with pseudo wild type tau (PWT) and tau with the P301L mutation. Greater differences in terms of fibrillation rates and ThT fluorescence between PWT and P301L was shown than previously reported between WT and P301L. They were also shown to differ in fibril morphology in TEM. The ThT fluorescence intensity was to a certain degree transferable from PWT to P301L by seeding. Furthermore, this study confirms that the tau-EXFP fusion protein can be incorporated into amyloid fibrils and strongly suggests that a FRET effect between EXFP and BTD14 (as well as X34 and ThT) can be achieved. It also demonstrates differences in FRET efficiency between PWT and P301L fibrils using FLIM. These results indicate that a FRET based approach could be a useful method to discern different fibril morphologies from each other, but further measurements and optimization are needed before this method could be reliably applied. The fusion proteins could also be used to investigate tau spreading in vivo, e.g. in D. melanogaster. To find suitable FRET partners to the fusion proteins, a ligand screen was conducted. This could be used as an alternative to the FRET method. With the right selection of fluorescent amyloid probes, a unique fingerprint for each fibril morphology could maybe be generated and fulfill the same intended function as the FRET method.

Apolipoprotein E (ApoE) ist eine verbreitet vorkommende Komponente der Plasmalipoproteine und spielt eine Schlüsselrolle bei Lipidtransport und Cholesterin-Homöostase über den Low Density Lipoprotein Rezeptor. Im ZNS wird ApoE hauptsächlich von Astrozyten synthetisiert und sekretiert. ApoE-Isoformen haben unterschiedliche Wirkung auf eine Zahl von pathologischen Prozessen, die der Alzheimerschen Krankheit zugrunde liegen. Um die Rolle des ApoE für die Alzheimersche Krankheit zu erhellen, ist es wichtig Kenntnisse über seine Regulation zu erlangen. Ein Ziel dieser Arbeit war zu untersuchen, ob die „Second-Messenger“-Signalpfade „Adenylatcyclase/Proteinkinase A (PKA)“ und/oder „Phospholipase C/Proteinkinase C (PLC/PKC)“ in die Regulation der astrozytären ApoE Sekretion eingreifen. Hierfür wurden primäre hippocampale Astrozytenkulturen von Ratten mit verschiedenen Analoga, Rezeptoragonisten und Neurotransmittern, die diese Signalpfade beeinflussen, inkubiert. Dibutyryl-cAMP (cAMP-Analogon) erhöhte die ApoE Sekretion. Auch Rezeptoragonisten des Adenylatcyclase/PKA-Signalwegs beeinflussten die ApoE Sekretion. Isoproterenol (beta-Adrenorezeptoragonist) erhöhte die ApoE Sekretion, während Clonidine (alpha-2 Adrenorezeptoragonist) sie senkte. Der PKC-Aktivator Phorbol 12-Myristat 13-Acetat senkte die ApoE Sekretion und kehrte die dibutyryl-cAMP-vermittelte Erhöhung der ApoE Sekretion um. Arterenol (alpha-1 Adrenorezeptoragonist) und Serotonin (Neurotransmitter) erhöhten die ApoE Sekretion, wohingegen Carbachol (Acetylcholiner muskarinischer Rezeptoragonist) die ApoE Sekretion senkte. Es wird gezeigt, dass die verwendeten Substanzen einen von der ApoE Sekretion verschiedenen Einfluss auf die Sekretion des Nervenwachstumsfaktors (NGF) haben. Dies legt die Vermutung nahe, dass die beobachteten Ergebnisse nicht auf einen generellen Effekt der Proteinsynthese zurückzuführen sind. Es kann gefolgert werden, dass die astrozytäre ApoE Sekretion von Faktoren beeinflusst werden kann, die die intrazelluläre Konzentration von cAMP verändern oder die PKC aktivieren. Das zweite Ziel der Arbeit war zu untersuchen ob Amyloid Fragmente einen Einfluss auf die astrozytäre ApoE Sekretion haben. Senile Amyloid-Plaques in Alzheimer-Gehirnen zeigen eine ApoE-Immunreaktivität, Astrozyten die diese Plaques umgeben dagegen nicht. Es wird gezeigt, dass gealtertes fibrilläres Amyloid (1-40) die ApoE Sekretion erhöht. Das sekretierte ApoE wird durch die, die Zellen umgebenden Amyloid-Konglomerate, gebunden. Die verwendeten Amyloid Fragmente beeinflussten nicht die Menge des sekretierten basischen Fibroblastenwachstumsfaktors. Dies legt nahe, dass die beobachteten Ergebnisse nicht auf einen generellen Effekt der Proteinsynthese zurückzuführen sind. / Apolipoprotein E (apoE) is an abundant component of plasma lipoproteins that plays a key role in lipid transport and cholesterol homeostasis via the low density lipoprotein receptor. In the CNS, apoE is synthesised and secreted especially by astrocytes. ApoE isoforms have different effects on a number of pathological processes underlying Alzheimer’s disease. Therefore, understanding the regulated synthesis of apoE is important for determining its role in Alzheimer’s disease. One aim of this work was to examine whether the second-messenger-pathways „adenylyl cyclase/proteinkinase A (PKA)“ and/or „phospholipase C/proteinkinase C (PLC/PKC) are involved in the regulation of apoE secretion in astrocytes. Therefore rat primary hippocampal astrocyte cultures were incubated with various analogues, receptor agonists and neurotransmitters which influence these pathways. Dibutyryl-cAMP (cAMP analogue) increased the apoE secretion. ApoE secretion was also modulated by receptor agonists of the adenylyl cyclase/PKA pathway. Isoproterenol (beta-adrenoceptor agonist) enhanced, while Clonidine (alpha 2-adrenoceptor agonist) decreased, the secreted apoE. In contrast, the PKC activator phorbol 12-myrisate 13-acetate decreased the apoE secretion. It also reversed the effects of dibutyryl-cAMP. Arterenol (alpha 1-adrenoceptor) and serotonin (neurotransmitter) enhanced, whereas carbachol (acetylcholine muscarinic receptor agonist) deceased secreted apoE. It is shown, that the used substances have different effects on the secretion of the nerve growth factor (NGF) as compared to apoE secretion, suggesting that the results obtained were unlikely to be due to a general effect on protein synthesis. It can be concluded that actrocytic apoE production can be regulated by factors that affect cAMP intracellular concentration or activate PKC. The second aim of this work was to examine whether amyloid fragments have an effect on the apoE secretion of astrocytes. Senile amyloid plaques in Alzheimer’s disease brains show apoE immunoreactivity, astrocytes which surround them do not. It is shown, that aged, fibrillic amyloid (1-40) increases apoE secretion. The secreted apoE is bound to the surrounding amyloid conglomerates. The used amyloid fragments did not increase or decrease basic fibroblast growth factor secretion, suggesting that the results obtained were unlikely to be due to a general effect on protein synthesis.

A doença de Alzheimer (DA) é uma patologia neurodegenerativa progressiva e a forma de demência mais prevalente no mundo. As alterações fisiopatológicas da DA têm sido associadas a dois marcadores neuropatológicos clássicos: a deposição de placas de β- amilóide e a formação de emaranhados neurofibrilares da proteína tau hiperfosforilada. Porém, devido a complexidade da DA, outros mecanismos têm sido propostos como coadjuvantes no processo neurodegenerativo, entre eles eventos neuroinflamatórios, a quebra da homeostasia de sistemas de neurotransmissão e disfunção sináptica. Esta pletora de eventos patológicos parece preceder a fase de demência por um longo período onde a doença age de forma silenciosa, ou seja, onde não existem evidências sintomatológicas. Na presente tese, avançamos no entendimento de vias de sinalização associadas com a hipersforforilação da proteína tau envolvendo a disfunção da proteína fosfatase 2A e neurotoxicidade do sistema glutamatérgico. Além disso, avaliamos os radiofármacos de tomografia de emissão de pósitrons (PET) disponíveis para visualização in vivo e não invasiva da fisiopatologia da DA. Finalmente, avaliamos um novo biomarcador de PET, o [11C]ABP688, para visualizar flutuações no sistema glutamatérgico e avançamos no entendimento do impacto das células gliais no sinal do PET [18F]FDG, o radiofármaco mais utilizado na clínica atualmente para visualizar metabolismo de glicose cerebral. O [11C]ABP688 pode ser diretamente incluído em estudos clínicos e a reconceptualização do [18F]FDG proposta nesta tese pode alterar a maneira atual como vemos o metabolismo de glicose na DA e em outras doenças neurodegenerativas. Finalmente, nesta tese, avançamos em termos de mecanismos, e no contexto da busca por um diagnóstico precoce e acurado da DA. / Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most prevalent cause of dementia worldwide. The AD pathophysiological features have been associated to two main classic neuropathological markers: depositon of β-amyloid plaques and formation of neurofibrillary tangles of hyperphosphorylated tau. Due to AD complexity, however, additional mechanisms have been proposed as contributors to the neurodegenerative process, such as neuroinflammatory changes, altered neurotransmission, and synaptic dysfunction. These pathological events seem to precede the dementia phase by many years, resulting in a long silent period, i.e., a preclinical phase. In this thesis, we advanced in the understanding of signaling pathways associated with tau hyperphosphorylation, which includes dysfunction of protein phosphatase 2A (PP2A) and glutamatergic neurotoxicity. Furthermore, we underscored radiopharmaceuticals currently available for imaging AD pathophysiology in vivo and non-invasively with positron emission tomography (PET). Finally, we evaluated a new PET biomarker, [11C]ABP688, for visualizing glutamatergic fluctuations and advanced in the understating of how glial cells contribute to the [18F]FDG signal, the widely used radiopharmaceutical in clinical settings for visualizing cerebral glucose metabolism. Our findings have high translational value and direct impact in clinical settings, which can potentially alter the way we interpret glucose metabolism in AD and other neurodegenerative disorders. In summary, in this thesis, we have advanced in terms of molecular mechanisms, and in the use of PET biomarkers toward an early and accurate diagnosis of AD.

Face au déclin cognitif, à la perte progressive de l'autonomie et aux troubles du comportement accompagnant l'évolution de la maladie d'Alzheimer et des maladies apparentées (MA2), l'implication de l'aidant naturel auprès de son proche atteint s'intensifie et s'accompagne d'un fardeau. Les données de la littérature montrent que les interventions psychosociales évaluées ont un impact modeste et à court terme sur le fardeau de l'aidant. Par ailleurs, les patients âgés atteints de MA2 et leurs aidants sont exposés à un risque important d'iatrogénie médicamenteuse. L'objectif de ce travail de thèse était de concevoir une prise en soin pharmaceutique intégrée à une intervention psychosociale efficiente permettant de réduire le fardeau des aidants de patients âgés atteints de MA2. Afin de garantir l'efficience de l'intervention à concevoir, des études préalables ont été réalisées afin : (1) d'identifier les facteurs prédictifs de fardeau de l'aidant via une étude transversale, une étude longitudinale et à partir des données de la littérature ; (2) d'identifier les besoins prioritaires des aidants via une enquête Delphi incluant le domaine pharmaceutique après réalisation d'une revue systématique de la littérature ; (3) d'identifier les critères d'efficacité des interventions psychosociales et l'étendue du rôle du pharmacien auprès de la dyade patient/aidant à partir des données de la littérature. Ces différents éléments ont permis de concevoir de façon multidisciplinaire et multicentrique, le protocole de l'étude interventionnelle PHARMAID. Il s'agit d'un essai clinique randomisé, contrôlé, à trois bras parallèles, multicentrique dont l'objectif principal est d'évaluer l'impact d'un suivi pharmaceutique personnalisé intégré à une intervention psychociale sur le fardeau des aidants de patients âgés atteints de MA2 à 18 mois. A ce jour, 72 dyades patient/aidant ont été inclues, soit 30% de l'effectif attendu. Si l'intervention psychosociale combinée ou non aux soins pharmaceutiques de l'étude PHARMAID s'avère efficace, sa pérénnité dans les centres participants et son extension au sein des autres centres mémoires, des services de neurologie ou de gériatrie pourront être envisagées. L'étude médico-économique associée permettra d'estimer les coûts engagés par la mise en place d'une telle intervention, tout en prenant en compte les coûts directs de consommation de soins / Alzheimer’s disease and Related Disorders (ADRD) are associated with a caregiver burden that increases with the progression of the disease. Previous psychosocial interventions reported a moderate improvement on caregiver burden. Patients with ADRD and their caregivers are also exposed to higher risk of developing drug-related problems.Our objective was to design an integrated pharmaceutical care at a multidisciplinary psychosocial intervention that reduces the caregiver burden of aged patient with ADRD.To guarantee the effectiveness of the intervention, preliminary studies were conducted to: (1) identify predicting factors that increase the caregiver burden through a cross-sectional study, a longitudinal study and from a literature review ; (2) to identify the prioritized caregivers’ needs through a Delphi survey, including the pharmaceutical field, after conducting a systematic review of the literature; (3) to identify the effectiveness criteria of psychosocial interventions and the extent of the pharmacist's role with the patient / caregiver dyad from a literature review. Our work leaded to design, in a multidisciplinary and multicentric way, the protocol of the PHARMAID study. The PHARMAID study is a 18-month randomized, controlled, with three parallel groups, and multi-center trial. The primary objective is to measure the impact of personalized pharmaceutical collaborative care integrated to a multidisciplinary psychosocial intervention on the caregiver burden of aged patient with ADRD. To date, 72 dyads have been included, representing 30% of the expected sample. If the effectiveness of this collaborative approach is demonstrated, its durability in the participating centers and its extension in the other memory centers, neurology or geriatric wards could be considered. The costs and the cost-effectiveness of different interventions will also be evaluated through detailed analyses of formal and informal resource consumption during the study

La maladie d'Azheimer (MA) est une pathologie neurodégénérative qui est liée dans ses stades précoces à un dysfonctionnement synaptique et une perte de synapses. De nombreuses données cliniques obtenues chez des patients mais également des données expérimentales obtenues sur des modèles murins de la MA montrent qu'il existe un dimorphisme sexuel s'exprimant par un dépôt de plaques amyloïdes supérieur et une apparition précoce de troubles mnésiques chez les souris femelles par rapport aux souris mâles. Dans ce travail, nous avons étudié les altérations moléculaires et cellulaires de la MA ainsi que les déficits cognitifs associés chez la souris femelle APP/PS1, un modèle murin double transgénique de la MA. En parallèle nous avons étudié les altérations de la transmission et de la plasticité synaptique dans le stratum moleculare, une couche proche du gyrus dentelé (DG) en raison de la forte densité de plaques amyloïdes dans cette région de l'hippocampe.Nous avons mis en évidence la présence de nombreuses plaques amyloïdes dans le DG en quantité supérieure chez les femelles âgées de 6 mois par rapport aux mâles du même âge ainsi qu'une forte activation des cellules gliales astrocytes et microglie. Ces altérations moléculaires et cellulaires s'accompagnent de déficits mnésiques hippocampo-dépendants (test du comportement de peur conditionné et test de la nouvelle localisation spatiale d'un objet) dès l'âge de 4 mois chez les femelles alors que les mâles ne présentent aucun déficit jusqu'à l'âge de 12 mois.Nous avons alors étudié les propriétés électriques des neurones du gyrus dentelé (DG), la transmission et la plasticité de la synapse voie perforante - neurones du gyrus dentelé (synapse PP-DG) chez la souris femelle âgée de 6 mois en comparant les deux génotypes APP/PS1 vs sauvage.Les neurones du DG présentent deux populations distinctes en terme de résistance d'entrée et de patron de décharge de potentiels d'action (PAs). A l'inverse, le potentiel membranaire de repos, la résistance d'entrée, le seuil d'activation et l'amplitude du potentiel d'action ne sont pas modifiés chez la souris APP/PS1 vs la souris sauvage. La fréquence de décharge des potentiels d'action est augmentée chez la souris APP/PS1 sans que la probabilité de décharge en fonction de la pente du pied du potentiel d'action (courbe E-S) soit différente entre la souris APP/PS1 et la souris sauvage. La transmission basale à la synapse PP-DG est modifiée chez la souris APP/PS1 vs la souris sauvage sans altérations du ratio AMPA/NMDA ni de l'index de rectification AMPA. La fréquence des courants miniatures NMDA est augmentée dans les neurones DG de la souris APP/PS1 vs la souris sauvage ce qui suggère le démasquage de synapses silencieuses qui n'expriment peu ou pas de récepteurs AMPA. La potentialisation à long terme (PLT) de l'amplitude des potentiels d'action synchrone est diminuée d'environ 50% chez la souris APP/PS1. La diminution de la PLT observée chez la souris APP/PS1 est en partie liée à des altérations des propriétés intrinsèques des neurones du DG comme le montre le déplacement des courbes E-S induit par la PLT qui traduit une augmentation d'excitabilité de la souris APP/PS1.En conclusion nos résultats montrent un dimorphisme sexuel important avec un dépôt des plaques amyloïdes et une activation neuroinflammatoire des cellules gliales plus précoce chez la souris femelle vs mâle. En parallèle, des déficits importants de la mémoire hippocampale-dépendante sont observés ainsi que des altérations de la transmission et de la plasticité synaptique à la synapse voie perforante - neurones du gyrus dentelé, une synapse clé de l'intégration des informations mnésiques en provenance du cortex enthorhinal. / Azheimer's disease (AD) is a neurodegenerative disease that is linked in its early stage to synaptic dysfunction and loss of synapses. Numerous clinical data obtained from patients but also experimental data obtained on mouse models of AD show that there is a sexual dimorphism evidenced by a higher amyloid plaque deposition and an early onset of memory disorders in female mice compared to male mice.In this work, we investigated the molecular and cellular alterations of AD as well as the associated cognitive deficits in female APP/PS1 mice, a double transgenic murine model of AD. In parallel we studied the alterations of hippocampal synaptic transmission and plasticity in the stratum moleculare, a layer in the vicinity of the dentate gyrus (DG) which specifically displayed a high density of amyloid plaques. We showed the presence of numerous amyloid plaques in the DG in a larger amount in 6 month old females compared to age-matched males as well as a strong activation of astrocyte and microglia glial cells. These molecular and cellular alterations are accompanied by hippocampo-dependent memory deficits (contextual fear conditioning and novel object place recognition task) from the age of 4 months in females whereas males have no deficit until the age of 12 months. We then studied the electrical properties of DG neurons, the transmission and the plasticity of the perforant pathway - DG neurons (PP-DG synapse) in the 6-month old female mouse by comparing the two genotypes APP/PS1 vs wild type (WT).In both genotypes, DG neurons displayed two distinct populations in terms of input resistance and action potential discharge pattern (APs). In contrast, the resting membrane potential, the input resistance, the activation threshold and the amplitude PAs were not modified in APP/PS1 vs WT. The frequency of discharge of APs was increased in APP/PS1 without shift of E-S curve which relates EPSP-slopes to the associated AP firing probability.Basal transmission at the PP-DG synapse was altered in the APP/PS1 mouse vs WT without alterations in the AMPA/NMDA ratio or the AMPA rectification index. The frequency of the NMDA miniature currents was increased in APP/PS1 DG neurons vs WT which suggests the unmasking of silent synapses that express almost no AMPA receptors. The long term potentiation (LTP) of population spike amplitude was decreased by approximately 50% in APP/PS1 mice. The decrease in LTP observed in APP/PS1 was partly related to alterations in the intrinsic properties of DG neurons as evidenced by LTP-induced shifts of E-S curves, which reflects an increased excitability for APP/PS1 mice.In conclusion our results show a prominent sexual dimorphism with much earlier amyloid plaque deposition, neuroinflammatory glial activation in female vs male APP/PS1. In parallel, significant deficits in hippocampal-dependent memory are observed as well as alterations of synaptic transmission and plasticity at the PP-DG synapse, a key synapse of the integration of mnesic informations originated from the entorhinal cortex

A neuroimaging feature extraction model is designed to extract region-based image features whose values are predicted by base learners trained on raw neuroimaging morphological variables. The main objectives are to identify Alzheimer’s disease (AD) in its earliest manifestations, and be able to predict and gauge progression of the disease through the stages of mild cognitive impairment (EMCI), late MCI (LMCI) and AD. The model was evaluated on the ADNI database and showed 75.26% accuracy for the challenging EMCI diagnosis based on the 10-fold cross-validation. Our approach also performed well for the other binary classifications: EMCI vs. LMCI (72.3%), EMCI vs. AD (95%), LMCI vs. AD (84.3%), CN vs. LMCI (77.5%), and CN vs. AD (96.5%). By applying the model to the Genome-wide Association Study, along with the sparse Partial Least Squares regression method, we successfully detected risk genes such as the APOE, TOMM40, RVRL2 and APOC1 along with the new finding of rs917100. Moreover, the research aimed to investigate the relationship of different biomarkers; especially the imaging biomarkers to better understand the precise biologic changes that characterize Alzheimer’s disease. The unique and independent contribution of APOE4 allele status (E4+\E4-), amyloid (Aβ) load status (Amy+\Amy-) and combined APOE4 and Aβ status on regional cortical thickness (CTh) and cognition were evaluated via a series of two-way ANCOVAs with post-hoc Tukey HSD tests. Results showed that decreased CTh is independently associated with Amy+ status in many brain regions, but with E4+ status in very restricted number of brain regions. Among CN and EMCI participants, E4+ status is associated with increased CTh, in medial and inferior temporal regions. Diverging association patterns of global and regional Aβ load with cortical volume were found in the entorhinal, temporal pole and parahippocampal regions, which were positively associated with regional Aβ load, but with a negative correlation for global Aβ load in MCI stages. In addition, strong positive correlations were shown between baseline regional CTh and the difference of CTh in each region between the CN and AD, even after adjusting for the regional Aβ and APOE genotype (E4+: r = 0.521 and E4-: r = 0.694).