No description available.

La difficulté de la plainte mnésique est son aspect subjectif et son évaluation. Le concept de Subjective Cognitive Impairment (SCI) est une réalité épidémiologique. Nous rapportons ici notre expérience, au sein du service de neurologie Comportementale des Hôpitaux sud de MARSEILLE d'une cohorte de sujets consultants sur une période de plus de 6 ans, sur le plan neurologique, neuropsychologique et de la neuroimagerie. Le SCI représente un état anatomo-clinique défini, qu'on peut séparer à la fois des Contrôles Normaux (CN) et des Mild Cognitive Impairment-Amnésiques (MCI-A), sur le plan neuropsychologique, anatomique en IRM. Un suivi, sur une relativement courte période, permet de noter le passage de SCI en MCI-A, voir beaucoup plus rarement de SCI en Maladie d'Alzheimer-Légère (MA-L). Ces sujets évolutifs peuvent être repérés dès le premier bilan, par un test de mémoire épisodique verbale, comme le RAVLT RD. Ce test permet de prédire l'évolutivité des SCI et de caractériser les sujets susceptibles d'évoluer vers un MCI-A à 1 an. Pour améliorer l'étude de la plainte cognitive, il est important d'avoir un outil adapté. Le Memory Functioning Questionnaire (MFQ) est incomparablement plus efficace et plus précis que le Subjective Cognitive Deficit (SCD), dans l'approche diagnostique CN / SCI. L'atteinte directe de l'aire 10, qui sous-tendrait la métamémoire, à ce stade n'est pas prouvée mais pourrait être dû à une dysconnexion par atteinte de la substance blanche du faisceau cingulaire, dans sa partie antérieure. A ce stade, les sujets vont donc se plaindre du fonctionnement de leur mémoire, à cause des mauvaises informations reçues et traitées par l'aire 10. / The difficulty of the memory complaint is its subjective expression and its evaluation. The concept of Subjective Cognitive Impairment (SCI) is an epidemiological reality. We report our experience in the neurology department of Behavioral Hôpitaux Sud in Marseille a cohort of subjects over a period of more than 6 years, neurologically, neuropsychological and neuroimaging. SCI is a clinicopathological state defined wich can be separated from both Normal Controls (NC) and amnestic Mild Cognitive Impairment (A-MCI). MRI does not distinguish between CN and SCI. The SCI are different from the MCI-A, in terms of cognitive-behavioral and neuropsychological tests. Anatomically, MRI, differ A-MCI from SCI, by lesions of cerebral diffuse atrophy of hippocampal atrophy, anterior cingulated and atrophy, indicating a more intense underlying neurobiological processes. We can observe on a relatively short period, allows you to note the passing of SCI in A-MCI, or more rarely in Alzheimer‟s Disease (AD). These evolutionary topics can be identified as the first assessment, a test of verbal episodic memory, as RAVLT DR. This test predicts the scalability of SCI and characterizes subjects likely to progress to A-MCI to 1 year. To improve the study of cognitive complaint, it is important to have a suitable tool. The Memory Functioning Questionnaire (MFQ) is incomparably more efficient and accurate than the Subjective Cognitive Deficit (SCD) in the diagnostic CN / SCI approach. The direct interference of area 10, wich underlies metamemory, at this point is not proven but could be due to a disconnection by reaching the white matter of the cingulated bundle in its anterior region.

No description available.

Tau proteins are members of the microtubule associated proteins (MAPs), and are predominantly expressed in neurons and enriched in the axonal compartment. These proteins are involved in many diseases therefore termed tauopathies . In the disease, tau is present in a hyperphosphorylated state that forms aggregates in the somato-dentritic compartment. In order to analyse the distribution of normal and tau proteins present in tauopathies in living cells, a pulse-escape fluorescence photoactivation approach was developed. A wild type wt , a R406W mutant mut , a hyperphosphorylation model PHP (pseudohyperphosphorylated), and a smaller fragment delta tau protein, and a control PA-GFPx3 were fused to the photoactivatable GFP protein. These proteins were expressed in differentiated PC12 cells and mice primary cortical cultures, and analysed in photoactivation experiments. The data showed that the wt protein was less mobile, both at the shaft or the tip of cell processes, than the delta or control proteins (higher immobile fraction, IF ). This could be attributed to the microtubule binding domain present only in the wt. Treatment of cells with drugs to disrupt microtubules, or detach tau from the filaments confirmed this interpretation. The mut mobility was comparable to that seen for the wt, suggesting that the interaction with microtubules was unaffected by the mutation. The PHP showed a lower IF compared to the wt, in agreement with a lower binding to microtubules. Furthermore, this behaviour could be reproduced by increasing the level of phosphorylation of the wt by drug treatment. A flux analysis was performed to determine the fraction of protein moving towards the distal or proximal portion of the process. Only delta and wt detached from the microtubules showed an increased flux towards the tip.The results suggest that the plasma membrane interaction is involved in the flux of wt tau proteins towards the distal portion.

Alzheimer¿s disease is associated with aging and is characterised by a progressive cognitive decline. Its onset in women coincides with the abrupt depletion of ovarian steroids prompting the investigation of utilising oestrogen replacement therapy as restoration or a preventative measure. Gonadal steroids have also recently been implicated in other disease states, particularly schizophrenia. In addition to the cognitive decline, sufferers of Alzheimer¿s disease and schizophrenia display anxiety related behaviour which gonadal steroids have also been shown to ameliorate. In this thesis several paradigms were used to investigate the effects of oestradiol benzoate (EB) on cognition and anxiety, utilising the NMDA receptor antagonist PCP, the muscarinic receptor antagonist scopolamine and the dopamine releasing agent amphetamine to induce a cognitive deficit in rats by different pharmacological mechanisms. The thesis also investigated the effects of EB on a delay dependent cognitive deficit model of forgetfulness in natural aging. Results showed that subchronic PCP dosing failed to induce a significant deficit in the novel object recognition task. Locomotor activity tests demonstrated that the PCP treated rats were sensitised to the treatment suggesting that the PCP dosing regimen was successful. There was no significant effect of oestrogen in the reversal learning model or in the plus maze task designed to explore EB¿s effects on anxiety. However, in the latter task there was a trend towards an anxiogenic effect of EB. Results from the delay dependent model of forgetfulness in natural aging demonstrated that EB could enhance recognition memory, but not spatial memory. The results are discussed in the context of the role of gonadal steroids especially oestrogen in combating the cognitive decline seen in schizophrenia, neurodegenerative disease and natural aging.

Purpose: The objective was to study how sedentary behaviour (SB) and physical activity (PA)change during a 6-months multimodal lifestyle intervention including a Multimodal Lifestyle Intervention, a Multimodal Lifestyle and Medical food intervention and a control subgroup, for people with prodromal Alzheimer's disease (AD). Further, the aim was to explore the predictive value of outcome expectancies and self-efficacy beliefs on level of PA in the two intervention subgroups.  Methods: A secondary analysis of existing data (n=66) from MIND-AD trial with a descriptive evaluation design was conducted. Descriptive and non-parametric statistical analysis were used for between- and within groups analysis. To explore the predictive value of a model with self-efficacy and outcome expectancies at baseline on PA at 6 months, regression analysis was conducted. Effect size was calculated for between-group and withingroup differences. Results: Objectively measured PA increased in the Multimodal Intervention subgroup. SB did not change during the intervention. Outcome expectancies for that impact of exercise is beneficial for health in the long run increased during the intervention. Participants higherinitial outcome expectancies for the impact of exercise would lead to less AD-related difficulties predicted higher PA level at 6 months. Self-efficacy for exercise or outcome expectancies for the impact of exercise on AD-related difficulties did not change during the intervention. Conclusions: PA increased in the Multimodal Intervention subgroup. This difference could not be shown with PA measured by questionnaire which indicates that objective measurements are better suited to measuring PA in people with prodromal AD than subjective measurements. Increased outcome expectancies for that impact of exercise arebeneficial for health in the long run demonstrate the participants strengthened intentions to improve their long-term health. Increasing outcome expectancies to manage AD-related difficulties can be an important part of interventions targeting PA in people with prodromal AD.

No / The 5-HT1A receptor has been extensively studied over the last two decades. There is a plethora of information describing its anatomical, physiological and biochemical roles in the brain. In addition, the development of selective pharmacological tools coupled with our understanding of psychiatric pathology has lead to multiple hypotheses for the therapeutic utility of 5- and in particular 5-HT1A receptor antagonists. Over the last decade it has been suggested that 5-HT1A receptor antagonists may have therapeutic utility in such diseases as depression, anxiety, drug and nicotine withdrawal as well as schizophrenia. However, a very compelling rationale has been developed for the therapeutic potential of 5-HT1A receptor antagonists in Alzheimer s disease and potentially other diseases with associated cognitive dysfunction. Receptor blockade by a 5-HT1A receptor antagonist appears to enhance activation and signaling through heterosynaptic neuronal circuits known to be involved in cognitive processes and, as such, represents a novel therapeutic approach to the treatment of cognitive deficits associated with Alzheimer s disease and potentially other disorders with underlying cognitive dysfunction.

A Doença de Alzheimer é uma doença neurodegenerativa progressiva e de início tardio, que compromete principalmente as areas da cognição, julgamento e estabilidade emocional. Esta doença se caracteriza por dois tipos de lesões cerebrais características: emaranhados neurofibrilares e placas senis. Os emaranhados neurofibrilares são compostos por uma proteína do citoesqueleto (proteína tau) hiperfosforilada e agregada. As placas senis são formadas por agregados da proteína β-amilóide. A doença de Alzheimer é resultado dainteração de vários fatores ainda incompletamente elucidados; não obstante, o estresse oxidativo e os processos inflamatórios ocupam posição de destaque dentre esses fatores. Neste trabalho, avaliamos as atividades das enzimas eritrocitárias superóxido dismutase, catalase e glutationa peroxidase, assim como o conteúdo plasmático de glutationa total, vitamina C, α-tocoferol, β-caroteno, licopeno e coenzima Q10. A esses parâmetros antioxidantes foram contrapostas medidas de oxidação de lipídios e proteínas plasmáticas. Adicionalmente, efetuamos a avaliação das expressões monocitárias de HLADR e CD-11b, e das citocinas IL-6, IL-1α e TNF-α. Nossos resultados mostram que os pacientes de doença de Alzheimer possuem níveis circulantes de atocoferol inferiores aos pacientes controles, e possuem monócitos que apresentam maior expressão basal de HLA-DR e maior produção de IL-1α quando estimulados por LPS. Esses resultados fortalecem a hipótese inflamatória na doença de Alzheimer, de acordo com trabalhos recentes que apontam bons resultados com o a-tocoferol na sua prevenção e tratamento. / Alzheimer\'s disease is a late-onset, progressive degenerative disease that affects mainly the judgement, emotional stability and memory domains. This disease is characterized by two telltale cerebral lesions: neurofibrillary tangles and senile plaques. Neurofibrillary tangles are constituted by hyperphosphorylated cytoskeleton protein tau aggregates, while senile plaques are mainly composed by β-amyloid protein aggregates. Alzheimer\'s disease is the outcome of a complex interaction among several factors which are not fully understood yet; nevertheless it is clear thar oxidative stress and inflammatory pathways rate high among these factors. In this work, we evaluated the erythrocytic acitivities of superoxide dismutase, catalase and glutathione peroxidase, as well as the plasma levels of total glutathione, α-tocopherol, α-carotene, lycopene, and coenzyme Q10. These antioxidant parameters were confronted with plasmatic levels of protein and lipid oxidation products. Additionally, we measured the basal expression of monocyte HLA-DR and CD-11b, as well as the monocyte production of the cytokines IL1-α, IL-6 and TNF-α. Our results show that Alzheimer\'s Disease patients show lower plasmatic levels of α-tocopherol when compared to control patients, and have higher basal monocyte HLA-DR expression associated with higher IL-1α production when stimulated by LPS. These results lend support to the inflammatory theory of Alzheimer\'s disease, according to recent works that indicate good results of α-tocopherol administration in both its prevention and treatment.

A Doença de Alzheimer é uma doença neurodegenerativa progressiva e de início tardio, que compromete principalmente as areas da cognição, julgamento e estabilidade emocional. Esta doença se caracteriza por dois tipos de lesões cerebrais características: emaranhados neurofibrilares e placas senis. Os emaranhados neurofibrilares são compostos por uma proteína do citoesqueleto (proteína tau) hiperfosforilada e agregada. As placas senis são formadas por agregados da proteína β-amilóide. A doença de Alzheimer é resultado dainteração de vários fatores ainda incompletamente elucidados; não obstante, o estresse oxidativo e os processos inflamatórios ocupam posição de destaque dentre esses fatores. Neste trabalho, avaliamos as atividades das enzimas eritrocitárias superóxido dismutase, catalase e glutationa peroxidase, assim como o conteúdo plasmático de glutationa total, vitamina C, α-tocoferol, β-caroteno, licopeno e coenzima Q10. A esses parâmetros antioxidantes foram contrapostas medidas de oxidação de lipídios e proteínas plasmáticas. Adicionalmente, efetuamos a avaliação das expressões monocitárias de HLADR e CD-11b, e das citocinas IL-6, IL-1α e TNF-α. Nossos resultados mostram que os pacientes de doença de Alzheimer possuem níveis circulantes de atocoferol inferiores aos pacientes controles, e possuem monócitos que apresentam maior expressão basal de HLA-DR e maior produção de IL-1α quando estimulados por LPS. Esses resultados fortalecem a hipótese inflamatória na doença de Alzheimer, de acordo com trabalhos recentes que apontam bons resultados com o a-tocoferol na sua prevenção e tratamento. / Alzheimer\'s disease is a late-onset, progressive degenerative disease that affects mainly the judgement, emotional stability and memory domains. This disease is characterized by two telltale cerebral lesions: neurofibrillary tangles and senile plaques. Neurofibrillary tangles are constituted by hyperphosphorylated cytoskeleton protein tau aggregates, while senile plaques are mainly composed by β-amyloid protein aggregates. Alzheimer\'s disease is the outcome of a complex interaction among several factors which are not fully understood yet; nevertheless it is clear thar oxidative stress and inflammatory pathways rate high among these factors. In this work, we evaluated the erythrocytic acitivities of superoxide dismutase, catalase and glutathione peroxidase, as well as the plasma levels of total glutathione, α-tocopherol, α-carotene, lycopene, and coenzyme Q10. These antioxidant parameters were confronted with plasmatic levels of protein and lipid oxidation products. Additionally, we measured the basal expression of monocyte HLA-DR and CD-11b, as well as the monocyte production of the cytokines IL1-α, IL-6 and TNF-α. Our results show that Alzheimer\'s Disease patients show lower plasmatic levels of α-tocopherol when compared to control patients, and have higher basal monocyte HLA-DR expression associated with higher IL-1α production when stimulated by LPS. These results lend support to the inflammatory theory of Alzheimer\'s disease, according to recent works that indicate good results of α-tocopherol administration in both its prevention and treatment.

Tauopathien sind Krankheiten, die mit einer abnormen intrazellulären Tau-Protein-Faltung, Tau-Protein-Aggregation und Filament-Bildung im ZNS und PNS einhergehen. Die Alzheimer Demenz stellt die häufigste Tauopathie dar. Bei ihr kommt es zu einer intra- und extrazellulären Ablagerung fehlgefalteter amyloidogener Proteinaggregate, welche durch β Amyloid und Tau gebildet werden. Es resultiert eine Neurodegeneration. Ein multifaktorieller Prozess führt bei den Tauopathien zur Umwandlung des Tau-Proteins hin zu unlöslichen Fibrillenbündeln. Primär kommt es zur Bildung eines Dimers, das durch Disulfid- und Wasserstoffbrückenbindungen stabilisiert wird. Durch die Zusammenlagerung mehrer Dimere entstehen Tau-Oligomere. Diese gelten als die neurotoxischen Komponenten. Die Primärstruktur des Tau-Proteins beeinflusst den Aggregationsprozess. Dabei spielen die Anwesenheit der Aggregationsdomänen PHF6* und PHF6 und die Anzahl der Cystein-Seitenketten überragende Rollen. In dieser Arbeit wurden durch ortsspezifische Mutagenesen Tau-Konstrukte generiert, die sich in ihrer Anzahl der Aggregationsdomänen und der Cystein-Reste unterschieden. Es konnte gezeigt werden, dass die Aggregationstendenz der Tau-Proteine mit nur einer Aggregationsdomäne und keinem Sulfhydryl-Rest stark sinkt. Auch durch Veränderungen des Redoxmilieus lässt sich das Tau-Aggregationsverhalten beeinflussen. Es wurde gezeigt, dass die Substanz TCEP als starkes Reduktionsmittel die Aggregation der 2 humanen Tau-Isoformen 2N3R und 2N4R wirkungsvoll inhibiert. Auch GSSG als Oxidationsmittel verhinderte in bestimmten Konzentrationen die Aggregation dieser 2 Isoformen. Es wird angenommen, dass die Verhinderung der Bildung einer intermolekularen Disulfidbrückenbindung zu diesem Phänomen führt.