Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by beta-amyloid (Abeta) deposition, neurofibrillary tangles and cognitive decline. Clinical data suggest that diabetes may be a risk factor for AD and several studies have linked pro-diabetic diets with an acceleration of AD pathology. Consequently, we hypothesized that the 3xTg AD-like mouse model may show impaired glucose tolerance, therefore; we examined whether glucose tolerance was altered in the 3xTg mouse model of AD early in the pathogenesis (prior to Abeta plaques, neurofibrillary tangle sand cognitive decline) and if so, did it persist throughout. Specifically, 1, 2-3, 4-6, 8-10 and 17 month old male 3xTg mice and wild-type counterparts were assessed for fasting glucose levels, glucose tolerance, plasma insulin levels, insulin sensitivity and the neural and behavioral pathological characteristics of AD. At 1 month, 3xTg mice compared to wild-type controls exhibited impaired glucose tolerance during an intraperitoneal glucose tolerance test (ipGTT), a trend for reduced fasting plasma insulin levels at time 0 and significantly reduced fasting plasma insulin levels 15 minutes post glucose bolus suggesting a possible defect in beta cell function. Interestingly, the glucose intolerance was not a consequence of altered food intake or body weight since these parameters were similar between the 3xTg mice and wild-type controls. Moreover, responsiveness to exogenous insulin during the intraperitoneal insulin tolerance test was not significantly different suggesting equivalent insulin sensitivity. During aging both 3xTg mice and controls exhibited exacerbated changes in fasting glucose levels and glucose tolerance. Interestingly, while control animals show an increase in fasting insulin levels with age, 3xTg mice do not. Immunohistochemical staining for 6E10 and Abeta 1-42 revealed only intraneuronal deposition of reaction product in 3xTg mice with no extracellular depositions noted until 14 months of age. Immunoreactivity of p-tau was observed at 1 month in the hippocampus and cortex and worsened throughout the time period examined. Behavioral deficits began to be detected in 3xTg mice relative to wild-type controls at 21 months of age. The islets in the pancreas suggest that at 2-3 months of age 3xTg mice compared to wild-type controls have a significantly lower amount of immunoreactivity for insulin within their islets although islet size did not differ between groups and this persisted throughout all the time points examined (4-6 and 8-10 months). Taken together, these data reveal that the AD-like 3xTg mouse model exhibits a pro-diabetic phenotype early in the development of AD-like pathology and that this metabolic deficit persists throughout their lifespan raising the question of whether altered glucose regulation and insulin production/secretion could contribute to AD pathogenesis.

Background: There has been a rise in dementia awareness, with policy changes leading to increased diagnosis rates. However, the stigma of dementia is likely to cause challenges in diagnostic communication. This is complicated by the effect of dementia on cognitive functioning. The aims of this study were to (1) identify how diagnoses of dementia are communicated, (2) identify how people with dementia respond to the diagnosis, and (3) explore doctors’ perspectives on dementia diagnosis delivery. Methodology: A systematic literature review was conducted. Twenty doctors from 9 memory clinics across 4 NHS trusts participated. Eighty-one dementia diagnosis feedback meetings were video-recorded. Conversation analysis was used to identify patterns in diagnosis delivery. Four focus groups with the participating doctors were analysed using thematic analysis (inter-rater reliability 0.89). Findings: The literature review highlighted the dilemma of communicating both sensitively and honestly with people with dementia, as well as challenges stemming from cognitive impairment. This was also evident in diagnostic communication. Prior to diagnosis doctors elicited patient orientation to the meeting purpose (“do you know why you’re here?) and perspective into symptoms (“how is your memory?”). The majority of patients displayed some confusion as to the meeting purpose and offered non-medicalised explanations for their symptoms. Doctors attempted to address this through repeated explication of test results and statements of the clinic purpose. Dementia was always explicitly named. Diagnoses were often delivered indirectly (“that is dementia”), a practice to manage patient resistance and negative responses. However, over 40% were delivered directly (“you have dementia”), especially when patients were more cognitively impaired. Doctors pursued non-minimal responses to diagnosis, apparently to obtain perspective before progressing to treatment. However, resistance was not always addressed and prognosis was often avoided. Doctors highlighted pressure to make diagnoses and an aim to emphasise “living well” rather than discussing prognosis. Conclusion: The findings of this study highlighted the delicate balance between minimising likely resistance and distress and maximising understanding in the context of cognitive impairment. Instilling hope is evidently a priority for doctors. The diagnosis meeting is just one part of the journey of the person with dementia, and sufficient pre- and post-diagnosis support is integral.

Master of Science / Department of Statistics / Wei-Wen Hsu / BACKGROUND AND PURPOSE: Alzheimer's disease is currently a neurodegenerative diseases without any effective treatments to slow or reverse the progression. To develop any potential treatments, the need of a good statistical model to assess the progression of Alzheimer's disease is becoming increasingly urgent. This study proposed a latent transition model to monitor the progression of Alzheimer's disease which can help the development of a given proposed treatment. METHOD: A latent transition model was used to assess the progression of Alzheimer's disease. The volume of Hippocampus and fluorodeoxyglucose-PET (FDG) were employed as biomarkers in this model. These two biomarkers are very sensitive to the pathological signs of the Alzheimer's disease. The proposed latent transition model was performed with real data from Alzheimer's Disease Neuroimaging Initiative (ADNI), which contain 2,126 participants from 2005 to 2014. RESULTS/FINDINGS: The latent transition model suggested six states of disease progression and two different pathological profiles. One progression profile was mainly determined by the biomarker of FDG and the other by the volume of Hippocampus. CONCLUSION: The results revealed the existence of various progression profiles of Alzheimer's disease, suggesting a new way to evaluate the disease progression.

Disturbances in awareness of memory deficit have been observed in Alzheimer's disease (AD), yet few studies have systematically investigated the phenomena in this population. The present study has applied the concepts and instruments used in the metamemory literature to the study of awareness of memory deficit in twenty mild AD patients, eighteen individuals with memory impairment, and eighteen normal elderly controls. Specifically, a multidimensional approach to metamemory was selected including an evaluation of perception of memory change, knowledge about memory functioning, and self-monitoring of memory performance. Consistent with previous research, AD patients reported less change in memory functioning than did their informants, suggesting that these patients have diminished awareness of the extent of the decline in their memory abilities. No differences among the three groups were observed in self-report measures addressing the use of strategies, perception of control over memory functioning, and presence of anxiety in memory-related activities. Diminished self-monitoring abilities were observed in the AD patients' tendency to make a high number of intrusion errors with few self-corrections, and to overestimate their performance on memory tests. The results also suggest that relatives' evaluation of memory functioning may be particularly useful in differentiating AD patients from older adults displaying memory impairment and from normal elderly. / Graduate

Made available in DSpace on 2014-06-11T19:22:53Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-10-11Bitstream added on 2014-06-13T18:08:46Z : No. of bitstreams: 1 andrade_lp_me_rcla.pdf: 810592 bytes, checksum: f3cd1c31f6516de0865c11c34a27e61c (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O objetivo deste estudo foi analisar os efeitos de um programa de intervenção motora sistematizada, com tarefa dupla, no controle postural e nas funções cognitivas frontais em pacientes com doença de Alzheimer (DA). Participaram do estudo 30 pacientes. Destes, 14 participaram do grupo de intervenção motora (GI), com tarefa dupla (78,57 ± 7,13 anos) e 16 participaram do grupo controle (GC), (77,00 ± 6,29 anos) no qual não participaram de nenhum programa de intervenção motora. Para a avaliação das funções cognitivas foram utilizados os seguintes instrumentos: Montréal Cognitive Assessment (MoCA), Bateria de Avaliação Frontal (BAF), Teste do Desenho do Relógio (TDR) e Subteste Procurar Símbolos (SPS). Para a avaliação do controle postural, foi utilizado o método de posturografia, por plataforma de força, em quatro condições: 1) olhar dirigido a um alvo na altura dos olhos do indivíduo e braços ao longo do corpo; 2) condição 1 com tarefa cognitiva concomitante (contagem regressiva iniciada em 30); 3) condição 1 segurando uma bandeja; 4) condição 3 com tarefa cognitiva concomitante. Foram realizadas três tentativas de cada condição e a média da variável área do centro de pressão (CoP) foi analisada. Além destes, foram realizados testes que avaliam componentes da capacidade funcional: Timed Up and Go (TUG), Escala de Equilíbrio Funcional de Berg, Teste de Levantar-se e Sentar-se em 30 segundos e Teste de flexibilidade de Alcançar Sentado – da bateria da AAPHERD. A Análise Multivariada de Variância (MANOVA) apontou interação significativa entre grupos (GI e GC) e entre momentos (pré-intervenção e após-intervenção) para a pontuação total da BAF: (F= 18,52 e p=0,001), e em seus domínios: conceituação (F=10,29 e p=0,003), programação (F=31,08 e p=0,001), e controle inibitório... / The aim of this study was to analyze the effects of a systematic intervention program motor with dual task, postural control and cognitive function frontal in patients with Alzheimer's disease (AD). The study included 30 patients. Of these, 14 participated in the intervention group motor (IM), with dual task (78.57 ± 7.13 years) and 16 participated in the control group (CG), (77.00 ± 6.29 years) that didn´t participated in any motor intervention program. For the evaluation of cognitive functions were used the following instruments: Montreal Cognitive Assessment, Frontal Assessment Battery, Clock Drawing Test and Subtest Search symbols. For the assessment of postural control, we used the method of posturography, using a force platform, on four conditions: 1) gaze to a target at eye level of the individual and arms along the body, 2) condition 1 with a cognitive task concurrent (countdown started in 30), 3) condition 1 holding a tray, 4) condition 3 with concurrent cognitive task. Were performed three trials of each condition and the average of the variable area of the center of pressure (CoP) was analyzed. In addition, tests that assess components of functional capacity were carried out: Timed Up and Go (TUG), Functional Balance Scale, Berg, Test Stand up and sit down in 30 seconds and test flexibility to achieve Sitting - Battery the AAPHERD. A Multivariate Analysis of Variance (MANOVA) showed significant interaction between groups (GI and GC) and between times (preintervention and post-intervention) for the total score of BAF (F = 18.52, p = 0.001), and their domains: concept (F = 10.29, p = 0.003), programming (F = 31.08, p = 0.001), and inhibitory control (F = 6.61 p = 0.016), for a total score of the MoCA (F =18.37, p = 0.001), and their domains: attention (F = 5.73, p = 0.02), language (F = 6.25, p = 0.02) and... (Complete abstract click electronic access below)

Orientador: Florindo Stella / Banca: José Riani Costa / Banca: Gustavo Christofoletti / Resumo: O objetivo deste estudo foi analisar os efeitos de um programa de intervenção motora sistematizada, com tarefa dupla, no controle postural e nas funções cognitivas frontais em pacientes com doença de Alzheimer (DA). Participaram do estudo 30 pacientes. Destes, 14 participaram do grupo de intervenção motora (GI), com tarefa dupla (78,57 ± 7,13 anos) e 16 participaram do grupo controle (GC), (77,00 ± 6,29 anos) no qual não participaram de nenhum programa de intervenção motora. Para a avaliação das funções cognitivas foram utilizados os seguintes instrumentos: Montréal Cognitive Assessment (MoCA), Bateria de Avaliação Frontal (BAF), Teste do Desenho do Relógio (TDR) e Subteste Procurar Símbolos (SPS). Para a avaliação do controle postural, foi utilizado o método de posturografia, por plataforma de força, em quatro condições: 1) olhar dirigido a um alvo na altura dos olhos do indivíduo e braços ao longo do corpo; 2) condição 1 com tarefa cognitiva concomitante (contagem regressiva iniciada em 30); 3) condição 1 segurando uma bandeja; 4) condição 3 com tarefa cognitiva concomitante. Foram realizadas três tentativas de cada condição e a média da variável área do centro de pressão (CoP) foi analisada. Além destes, foram realizados testes que avaliam componentes da capacidade funcional: Timed Up and Go (TUG), Escala de Equilíbrio Funcional de Berg, Teste de Levantar-se e Sentar-se em 30 segundos e Teste de flexibilidade de Alcançar Sentado - da bateria da AAPHERD. A Análise Multivariada de Variância (MANOVA) apontou interação significativa entre grupos (GI e GC) e entre momentos (pré-intervenção e após-intervenção) para a pontuação total da BAF: (F= 18,52 e p=0,001), e em seus domínios: conceituação (F=10,29 e p=0,003), programação (F=31,08 e p=0,001), e controle inibitório... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The aim of this study was to analyze the effects of a systematic intervention program motor with dual task, postural control and cognitive function frontal in patients with Alzheimer's disease (AD). The study included 30 patients. Of these, 14 participated in the intervention group motor (IM), with dual task (78.57 ± 7.13 years) and 16 participated in the control group (CG), (77.00 ± 6.29 years) that didn't participated in any motor intervention program. For the evaluation of cognitive functions were used the following instruments: Montreal Cognitive Assessment, Frontal Assessment Battery, Clock Drawing Test and Subtest Search symbols. For the assessment of postural control, we used the method of posturography, using a force platform, on four conditions: 1) gaze to a target at eye level of the individual and arms along the body, 2) condition 1 with a cognitive task concurrent (countdown started in 30), 3) condition 1 holding a tray, 4) condition 3 with concurrent cognitive task. Were performed three trials of each condition and the average of the variable area of the center of pressure (CoP) was analyzed. In addition, tests that assess components of functional capacity were carried out: Timed Up and Go (TUG), Functional Balance Scale, Berg, Test Stand up and sit down in 30 seconds and test flexibility to achieve Sitting - Battery the AAPHERD. A Multivariate Analysis of Variance (MANOVA) showed significant interaction between groups (GI and GC) and between times (preintervention and post-intervention) for the total score of BAF (F = 18.52, p = 0.001), and their domains: concept (F = 10.29, p = 0.003), programming (F = 31.08, p = 0.001), and inhibitory control (F = 6.61 p = 0.016), for a total score of the MoCA (F =18.37, p = 0.001), and their domains: attention (F = 5.73, p = 0.02), language (F = 6.25, p = 0.02) and... (Complete abstract click electronic access below) / Mestre

Thesis (Master's Degree (Medical Technology)-- Cape Technikon, Cape Town, 1997 / There is, at present, no recognised diagnostic biochemical marker of Alzheimer's Disease (AD). Recently, Gunnerson and Haley, (1992), reported that the presence of glutamine synthetase (GS) in cerebrospinal fluid (CSF) samples showed a 97% correlation with patients diagnosed as having AD. GS was detected by photolabelling with [y32P]2-azido-ATP or [y32P]8azido- ATP and visualisation following sodium dodecyl sulphate polyacrylamide gel electrophoresis (SOS-PAGE) and autoradiography. This study set out to reproduce Gunnerson and Haley's methodology for labelling sheep GS in CSF using [y32P]8-azidoATP, to develop this assay or possibly another, using a fluorescent probe of ATP binding sites, into a robust procedure suitable for a routine diagnostic laboratory, and finally to assess whether the presence of GS in CSF is indeed a marker of AD.

abstract: Alzheimer's Disease (AD) is the sixth leading cause of death in the United States and the most common form of dementia. Its cause remains unknown, but it is known to involve two hallmark pathologies: Amyloid Beta plaques and neurofibrillary tangles (NFTs). Several proteins have been implicated in the formation of neurofibrillary tangles, including Tau and S100B. S100B is a dimeric protein that is typically found bound to Ca(II) or Zn(II). These experiments relate to the involvement of S100B in Alzheimer's Disease-related processes and the results suggest that future research of S100B is warranted. Zn(II)-S100B was found to increase the rate at which tau assembled into paired helical filaments, as well as affect the rate at which tubulin polymerized into microtubules and the morphology of SH-SY5Y neuroblastoma cells after 72 hours of incubation. Zn(II)-S100B also increased the firing rate of hippocampal neurons after 36 hours of incubation. Together, these results suggest several possibilities: Zn(II)-S100B may be a key part of the formation of paired helical filaments (PHFs) that subsequently form NFTs. Zn(II)-S100B may also be competing with tau to bind tubulin, which could lead to an instability of microtubules and subsequent cell death. This finding aligns with the neurodegeneration that is commonly seen in AD and which could be a result of this microtubule instability. Ultimately, these results suggest that S100B is likely involved in several AD-related processes, and if the goal is to find an efficient and effective therapeutic target for AD, the relationship between S100B, particularly Zn(II)-S100B, and tau needs to be further studied. / Dissertation/Thesis / M.S. Applied Biological Sciences 2013

La pathologie Tau est une lésion commune à plus d’une vingtaine de maladies neurodégénératives, regroupées sous le terme de Tauopathies. Elle correspond à l’accumulation intracellulaire de matériel fibrillaire constitué de protéines Tau hyper- et anormalement phosphorylées. Dans la maladie d’Alzheimer (MA), démence la plus courante chez la personne âgée, la progression et la distribution topographique de ces agrégats évoluent au cours du temps et sont corrélés aux déficits cognitifs observés. A ce jour, les traitements sont principalement symptomatiques. Cependant, plusieurs stratégies thérapeutiques sont étudiées parmi lesquelles l’immunothérapie. Les travaux présentés dans cette thèse ont pour objectif d’étudier les effets de l’immunothérapie Tau, active et passive, dans un modèle transgénique murin mimant la pathologie Tau de type Alzheimer. Les souris THY-Tau22, surexpriment une isoforme de Tau humaine mutée sur deux sites et sous contrôle d’un promoteur neuronal. Ce modèle présente dès l’âge de trois mois des altérations progressives de l’apprentissage et de la mémoire en parallèle d’une accumulation de protéine Tau principalement au niveau hippocampique, sans perte neuronale majeure, ce qui lui confère les caractéristiques d’un stade précoce de MA. Au sein du modèle THY-Tau22, on retrouve la protéine Tau phosphorylée en Ser422, un épitope particulièrement pertinent pour l’immunothérapie. En effet, la pSer422 est un épitope de phosphorylation anormale unique, présent dans la plupart des Tauopathies. Dans ces travaux de thèse, nous montrons que la vaccination précoce contre la Ser422 phosphorylée de la protéine Tau peut prévenir l'altération de mémoire spatiale mesurée par le test du labyrinthe en Y. Cette diminution de l'atteinte cognitive est associée à une diminution de la phosphorylation anormale de Tau au niveau de l'hippocampe et à une réduction significative des espèces insolubles de Tau. Les résultats de cette vaccination nous ont amenés à générer un anticorps monoclonal dirigé contre la pSer422 (2H9) afin d’évaluer les effets de l’immunothérapie passive. Selon la même cinétique d’âge, nous avons injecté, chaque semaine, par voie intrapéritonéale, des souris THY-Tau22 avec 5mg/kg et 10mg/kg de 2H9 ou une solution saline. Cette approche prévient l’apparition de déficits de mémoire spatiale mesurée par les tests du labyrinthe en Y et de la piscine de Morris. Les analyses immunohistochimiques révèlent également une réduction des protéines Tau anormalement phosphorylées au niveau de l’hippocampe. Afin d’étudier les mécanismes sous-jacents à l’immunothérapie anti Tau, nous avons injecté des anticorps anti-phosphoTau par stéréotaxie au niveau de l’hippocampe de souris THY-Tau22. Nous montrons, qu’une fois au sein du cerveau, ils sont capables d’entrer dans les neurones contrairement au contrôle isotypique. Plusieurs études récentes d’immunothérapie, suggèrent une implication de la macroautophagie dans la dégradation médiée par les anticorps. Nous montrons que les anticorps internalisés dans les neurones colocalisent avec différents marqueurs de la voie lysosomiale (NPC1, Lamp2) confirmant l’hypothèse d’une dégradation par le lysosome. Cependant, la barrière hémato encéphalique étant très sélective, il est fort probable que les anticorps générés restent en périphérie. [...] / Tau pathology is a common lesion observed in more than twenty neurological disorders, refered to as Tauopathies. It corresponds to the aggregation of the microtubule associated protein Tau hyper and abnormally phosphorylated into neurofibrillary tangles. In Alzheimer's disease (AD), the most common age-related dementia, the distribution and progression of Tau pathology have been reported to be well-correlated to the cognitive decline. Currently, treatments remain essentially symptomatic. However, several therapeutic approaches, including immunotherapy, are being developed to treat Tau pathology. The work presented in this thesis aim to investigate the effects of both active and passive Tau immunotherapy in a transgenic mouse model of Alzheimer’s disease-like Tau pathology. THY-Tau22 mice overexpress a double-mutated isoform of the human Tau protein, whose expression is under the control of a neuronal promoter. Several lines of evidence suggest that this transgenic mouse model is reproducing early stages of AD. Indeed, at three month old, the THY-Tau22 mouse model presents a progressive impairment of learning and memory without major neuronal loss, in parallel to Tau accumulation in the hippocampus. Moreover, Tau is hyper and abnormally phosphorylated at different sites including Ser422. Noteworthy, the pSer422 epitope is a single abnormal site of phosphorylation present only in pathological conditions, rendering it of particular interest for immunotherapy. In this present thesis work, we showed that early vaccination against the phosphorylated Ser422 Tau protein reduced spatial memory impairment as measured by the Y-maze test. Interestingly, this is associated with the decrease of the abnormal phosphorylation of Tau in the hippocampus and with a significant reduction of insoluble Tau species. Based on these results, we generated a new monoclonal antibody raised against pSer422 (2H9) to evaluate the effects of passive immunotherapy. The antibody was injected every week, intraperitoneally (5mg/kg and 10mg/kg of 2H9 or saline buffer) in the THY-Tau22 mice. We show that this approach can prevent the appearance of spatial memory deficits as measured by the Y maze and the Morris water maze tests. Immunohistochemical analysis also revealed a reduction of abnormally phosphorylated Tau proteins in the hippocampus. To investigate the mechanisms underlying Tau immunotherapy, we performed stereotaxic injections of anti-phosphoTau antibodies in the hippocampus of THY-Tau22 mice. We showed that, once in the brain, anti-phosphoTau antibodies were located inside the neurons in contrast to the isotype control. Several recent studies of immunotherapy, suggest an involvement of macroautophagy in the antibody-mediated degradation. We showed that internalized antibodies colocalized with different markers of the lysosomal pathway (NPC1, Lamp2) confirming this hypothesis of a lysosomal-mediated degradation. However, since the blood-brain barrier is highly selective, the antibodies may more likely act in the periphery. Indeed, we showed that peripheral administration of 250μg of the 2H9 generates a significant increase of Tau proteins levels in plasma, suggesting a peripheral sink mechanism as for Aβ immunotherapy. Vaccination, which generates a polyclonal response, leads to a greater increase of plasmatic Tau that confirms the peripheral degradation of Tau. Overall, the results of this PhD work confirmed the promising potential of Tau immunotherapy for Alzheimer\\\\\\\'s disease and other Tauopathies treatment. Moreover, it address a new hypothesis suggesting that the antibodies mediated degradation of Tau proteins might be through a peripheral sink such as for Aβ.

Pituitary adenylate cyclase activating polypeptide (PACAP) is associated with Alzheimer's disease (AD), but its age-related effects are unknown. We chose the rhesus macaque due to its closeness to human anatomy and physiology. We examined four variables: aging, cognitive performance, amyloid plaques and PACAP. Delayed nonmatching-to-sample recognition memory scores declined with age and correlated with PACAP levels in the striatum, parietal and temporal lobes. Because amyloid plaques were the only AD pathology in the old rhesus macaque, we further studied human amyloid precursor protein (hAPP) transgenic mice. Aging was associated with decreased performance in the Morris Water Maze (MWM). In wild type (WT) C57BL/ 6 mice, the performance was decreased at age 24-26 month whereas in hAPP transgenic mice, it was decreased as early as 9-12 month. Neuritic plaques in adult hAPP mice clustered in hippocampus and adjacent cortical regions, but did not propagate further into the frontal cortex. Cerebral PACAP protein levels were reduced in hAPP mice compared to age-matched WT mice, but the genetic predisposition dominated cognitive decline. Taken together, these data suggest an association among PACAP levels, aging, cognitive function and amyloid load in nonhuman primates, with both similarities and differences from human AD brains. Our results suggest caution in choosing animal models and in extrapolating data to human AD studies.