Die Alzheimer-Demenz drängt immer mehr in den Fokus unserer Gesellschaft, doch ihre Pathophysiologie ist bisher nicht vollständig verstanden. Seit einigen Jahren ist das Enzym Glutaminylzyklase (QC) als wichtiger Katalysator der Bildung von Pyroglutamat-ß-Amyloid Inhalt intensiver Forschung. Zielsetzung dieser Arbeit war es, die Expression der QC, welche bisher nur in Neuronen nachgewiesen wurde, in Astrozyten und Mikrogliazellen zu untersuchen. Da Gliazellen einen wichtigen Faktor der pathologischen Veränderungen neurodegenerativer Erkrankungen ausmachen, stellt sich die Frage nach ihrer kausalen Beteiligung an Prozessen, die zur Entstehung der Alzheimer-Demenz beitragen können. Für diese Studie wurden zwei Modelle gewählt, die zu einer spezifischen Aktivierung von Astrozyten und Mikrogliazellen als Reaktion auf eine Schädigung von Neuronen führten, zum einen nach Schädigung cholinerger Neurone durch das Neurotoxin 192-IgG-Saporin, zum anderen nach temporärer Okklusion der Arteria cerebri media. Die aktivierten Astrozyten zeigten eine deutliche Expression der QC, welche hingegen bei ruhenden Astrozyten im gesunden Gewebe nicht nachweisbar war, so dass von einer Hochregulation der Expression bei Aktivierung der Zellen ausgegangen werden kann. Weiterhin konnte die QC in Mikrogliazellen, die sich im phagozytierenden Stadium befinden, dargestellt werden. Diese Arbeit soll dazu beitragen die Zusammenhänge zwischen einer Aktivierung von Gliazellen nach einem Schädigungsereignis, wie zum Beispiel einer Ischämie bei Verschluss eines cerebralen Gefäßes, und der Entwicklung einer Alzheimer-Demenz aufzuklären.

Bakgrund: Alzheimers är en långsam progressiv sjukdom och är den vanligaste demenssjukdomen. Sjukdomen innebär försämrat närminne och begränsar kommunikationsförmågan. Hur smärta uttrycks i jämförelse med friska personer i samma ålder är oklart. Syfte: Syftet var att belysa hur personer med Alzheimers sjukdom uttrycker sin smärta. Metod: Arbetet var en litteraturöversikt med systematiska sökningar som gjordes i tre databaser. Resultat: Denna litteraturstudie belyste tre olika kategorier: Variation av uttalad smärtintensitet, manifestation av smärta och skattning av smärta. Slutsats: Det som framträdde var att hur personer med Alzheimers sjukdom uttryckte sin smärta inte gick att generalisera, smärta upplevdes olika för varje individ. Observerande skalor var att föredra framför självskattningsskalor vid bedömning av smärta hos personer med Alzheimers sjukdom. / Alzheimer disease is a slow progressive disease that is the most common type of dementia. The disease cause deterioration of cache and limit the ability to communicate. How pain is expressed in comparison to healthy people of the same age is unclear. Aim: The purpose was to highlight how people with Alzheimer's disease expressed their pain. Result: This literature study has highlighted three different categories: The variation of pain intensity, manifestation of pain and estimation of pain. Conclusion: What emerged was how people with Alzheimer's disease expressed their pain could not be generalized, pain was different for each individual. Observing scales was preferable to self-assessment scales for pain assessment in people with Alzheimer's disease.

Made available in DSpace on 2016-06-02T19:48:19Z (GMT). No. of bitstreams: 1 4177.pdf: 5761817 bytes, checksum: cb8d207716a1afe86708253767f3f7ee (MD5) Previous issue date: 2012-02-24 / Financiadora de Estudos e Projetos / Alzheimer's disease (AD) is the most common cause of dementia in people over 65 years. Platelet studies with ADAM10 have shown to decrease its expression in AD patients. The association between cognitive testing and molecular biomarkers such as levels of platelet ADAM10 protein can be important tools for the accurate and early diagnosis of AD. The aim of this research was to investigate the relationship between the Mini-Mental State Examination - MMSE and the Clinical Dementia Rating - CDR with the ADAM10 expression in two groups of elderly. 30 subjects with AD were compared with 25 matched controls by sex, age and education. All ethical considerations were observed. Individual evaluations were carried out and applied the CDR and MMSE, and then performed the collection of biological material of the elderly. The techniques SDS-PAGE and Western blotting were used to quantify the ADAM10 content in platelets. After collecting the data, they were analyzed using statistical methods of comparison, correlation, association, logistic regression and diagnostic accuracy. The results show that the ratio ADAM10/_-actin was reduced in elderly patients with AD and that this reduction is intensified with the progression of the disease. MMSE and CDR have significant correlations with the values of ratio ADAM10/_-actin, this being the only statistically significant variable (p = 0.01) to increase the probability of occurrence of AD. The cutoff value < 0.4212 in ROC curve captures 70% sensitivity and specificity of 80.77% for the presence of AD according to the ratio ADAM10/_-actin. Therefore, the ratio ADAM10/_-actin seems to be a relevant biomarker for AD. The results bring important contributions to an accurate diagnosis of Alzheimer's disease from the perspective of ADAM10 as a biomarker for this disease. The results are preliminary but encouraging. / A doença de Alzheimer (DA) é a causa mais comum de demência em pessoas com mais de 65 anos de idade. Estudos plaquetários com a ADAM10 têm demonstrado diminuição na sua expressão em pacientes com DA. A associação entre testes de avaliação cognitiva e biomarcadores moleculares, tais como os níveis plaquetários da proteína ADAM10 podem contribuir para o diagnóstico preciso e precoce da DA. O objetivo desta pesquisa foi verificar a relação entre o Mini-Exame do Estado Mental MEEM e o Clinical Dementia Rating CDR com a expressão da ADAM10 em dois grupos de idosos. 30 sujeitos com DA foram comparados com 25 controles, pareados segundo sexo, idade e escolaridade. Todos os cuidados éticos foram observados. Foram realizadas avaliações individuais e aplicados o CDR e MEEM e em seguida realizada a coleta do material biológico dos idosos. As técnicas SDSPAGE e Western Blotting foram utilizadas para detecção da ADAM10. Após a coleta dos dados, estes foram analisados por meio de métodos estatísticos de comparação, correlação, associação, regressão logística e acurácia diagnóstica. Os resultados mostram que a razão ADAM10/_-actina apresenta-se diminuída em idosos com DA e que esta redução se intensifica com o avanço da doença. O MEEM e o CDR apresentam correlações significativas com os valores da razão ADAM10/_-actina, sendo esta a única variável estatisticamente significativa (p = 0,01) para o aumento da probabilidade de ocorrência da DA. O ponto de corte < 0,4212 da curva ROC capta sensibilidade de 70% e especificidade de 80,77%, para a presença de DA segundo a razão ADAM10/_-actina. Portanto, a razão ADAM10/_-actina parece ser um relevante biomarcador para DA. Os resultados trazem contribuições importantes para um diagnóstico preciso da doença de Alzheimer na perspectiva da ADAM10 como um biomarcador para esta doença. Os resultados são preliminares, porém animadores.

Made available in DSpace on 2018-06-27T18:56:25Z (GMT). No. of bitstreams: 2 Ricardo Lorenzoni.pdf: 2169381 bytes, checksum: 9b086c1fe18c612a1d43ebe5f91c0f8f (MD5) Ricardo Lorenzoni.pdf.jpg: 3465 bytes, checksum: 60fb1578356f3148589233475ed9e01a (MD5) Previous issue date: 2012-04-23 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The hypothesis of Alzheimer s Disease (DA) may be related to high serum cholesterol levels made lipid-lowering drugs, as lovastatin (LV) and simvastatin (SV), potential choices of treatment against this disease. However, low levels of simvastatin and lovastatin are able to cross the blood brain barrier (BHE) and side effects associated to these drugs are a problem for their use in diseases affecting the central nervous system (SNC). Therefore, considering the therapeutic potentials of nanocapsules, the aim of this work was develop, characterize and evaluate the biological effect of NC containing SV or LV in animal models of DA induced by hypercholesterolemia. NC polymeric suspensions were prepared with SV (NCSV) or LV (NCLV) by interfacial deposition of preformed polymers. NCLV and NCSV exhibited average particle size of 204.0 ± 1.5 nm and 205.5 ± 0.5 nm, respectively, as monodispersed systems, with slightly acid pH (around 6) and negative zata potential (-23.29 ± 0.80 for NCLV and -19.5 ± 0.13 mV for NCSV). The analysis by fourier transform infrared spectroscopy and differential canning calorimetry (DSC) indicated that no chemical reactions occurred among components during nanocapsule preparation. The DSC analysis showed that sorbitan monostearate was dissolved in the oil core. The X-ray diffractometry, scanning electron microscopy (SEM), optical microscopy and drug content showed that a large amount lovastatine was presented in a crystalline form in NCLV, and they were not encapsulated. On the other hand, for NCSV, simvastatin was amorphous, indicating absent of drug crystals and that the drug was molecularly dispersed in NC. The encapsulation efficacy of LV was low (21.52 ± 1.4 %) while of SV was very high (99.18 ± 0.7 %). The animals fed with hyperlipemic diet showed significantly increase of serum cholesterol levels and LDL-cholesterol, however the treatment with unencapsulated SV and nanocapsules loading SV 1 mg/kg/dia and 3 mg/kg/day, during 45 days, not sufficient for reducing these biochemistry parameters. The serum triglycerides and VLDL-cholesterol levels did not show significant variations. The HDL-cholesterol was higher for animals treated with free SV (3mg/kg/day). The animals fed with hyperlipemic diet and/or treated with free drug or loaded in nanocapsules didi not show any increase of liver transaminases, indicating that there was no liver damage. The activity of pyruvate kinase and creatine kinase suggested that there were not any changes in neuronal energy metabolism. The hypercholesterolemia was capable of inducing alterations in cognition in Wistar rats. The NCSV showed promising effects in DA, once the animals were able to enhance memory when subjected to passive avoidance test. Free SV led to no significant alterations in learning and memory. The histology results suggested the presence of some brain lesions in some groups, indicating a possible neurodegeneration. Based on these results, we can conclude that simvastatin nanocapsules are a promising alternative in the treatment of cognitive loss due to high cholesterol levels and deserves more studies. / A hipótese de que o desenvolvimento da Doença de Alzheimer (DA) pode estar relacionado com altos níveis de colesterol plasmático faz dos fármacos hipolipemiantes, como Lovastatina (LV) e Sinvastatina (SV), potenciais terapêuticos frente a esta enfermidade. Contudo, a baixa penetração da LV e da SV através da barreira hematoencefálica (BHE) e os efeitos colaterais que elas podem ocasionar apresentam-se como um impasse para a utilização destes fármacos frente a doenças que acometem o sistema nervoso central. Deste modo, considerando as potencialidades terapêuticas que as nanocápsulas poliméricas (NC) podem promover, este trabalho teve como objetivo, desenvolver, caracterizar e avaliar o efeito biológico de NC contendo SV ou LV frente ao modelo animal da DA induzida por hipercolesterolemia. Assim, foram desenvolvidas suspensões de NC poliméricas contendo SV (NCSV) ou LV (NCLV) através do método de deposição interfacial do polímero pré-formado. As suspensões exibiram tamanho médio de partícula homogêneo (204,0 ± 1,5 nm para as NCLV e 205,5 ± 0,5 nm para as NCSV), com baixo índice de polidispersão, caracterizando sistema monodispersos, com pH levemente ácido (em torno de 6) e potencial zeta negativo (-23,29 ± 0,80 mV para as NCLV e -19,5 ± 0,13 mV para as NCSV). As análises de espectroscopia na região do infravermelho com transformada de Fourier e calorimetria exploratória diferencial (DSC) indicaram que não houve reação química entre os componentes da formulação durante a produção das formulações. A avaliação por DSC mostrou que o monoestearato de sorbitano encontra-se dissolvido no núcleo oleoso das partículas. A difração de raios-X, a microscopia eletrônica de varredura (MEV), microscopia óptica revelaram que grande quantidade de fármaco apresentou-se sob a forma cristalina nas suspensões de NCLV. Por outro lado, a difração de raios-X, MEV e microscopia óptica revelaram que a SV encontra-se molecularmente dispersa nas suspensões de NCSV. Assim, a eficiência de encapsulação da LV foi baixa (21,52 ± 1,4 %) enquanto que para a SV foi alta (99,18 ± 0,7 %). Os animais alimentados com dieta hiperlipídica apresentaram aumento significativo do colesterol total e do LDL-colesterol, porém os tratamentos com SV livre e nanoencapsulada nas doses de 1 mg/kg/dia e 3 mg/kg/dia, durante 45 dias, não foram suficientes para reduzir estes parâmetros bioquímicos. Os triglicerídeos séricos e VLDL-colesterol não apresentaram variações significativas induzidas pela dieta ou como consequência do tratamento medicamentoso. O HDL-colesterol apresentou-se mais elevado apenas para os animais tratados com SV livre. Não houveram evidências de aumento das aminotransferases séricas, sugerindo ausência de dano hepático. As atividades da piruvatoquinase e da creatinoquinase indicaram que não houve alteração no metabolismo energético neuronal. A hipercolesterolemia foi capaz de induzir alterações cognitivas em ratos. A SV nanoencapsulada apresentou efeitos promissores frente à cognição, pois foram capazes de melhorar a memória dos animais submetidos ao teste de esquiva passiva. A SV livre não provocou alterações significativas no aprendizado e na memória dos animais neste teste. Os resultados histopatológicos indicam que houveram lesões cerebrais em alguns grupos de animais, indicando um possível efeito de neurodegeneração. Com base nos resultados, podemos concluir que as nanocápsulas de sinvastina são uma alternativa de uso terapêutico promissora e que merece mais estudos nos casos de perdas cognitivas por excesso de colesterol plasmático.

A demanda de atenção para manter o equilíbrio postural aumenta com o envelhecimento e pode causar prejuízos na realização concomitante de duas ou mais tarefas. Indivíduos com doença de Alzheimer (DA) possuem menor reserva de atenção e, portanto, apresentam maior dificuldade em realizar uma tarefa motora associada à cognitiva, com conseqüente aumento do risco de quedas e suas conseqüências. O objetivo deste estudo foi verificar o desempenho do equilíbrio durante a realização concomitante de atividades funcionais (dinâmicas e estáticas) e tarefa cognitiva no idoso com DA. Foram avaliados 60 idosos, de ambos os sexos, com idade média de 77 ± 4 anos, divididos em dois grupos: Grupo-DA - indivíduos com DA (n=28) e Grupocontrole - indivíduos sem alteração cognitiva (n=32). O equilíbrio postural foi avaliado na atividade dinâmica através do TUGT e na atividade estática, pela plataforma fixa, Balance Master, NeuroCom. O teste estático foi realizado com os olhos abertos e fechados. Os indivíduos com DA apresentaram pior desempenho no TUGT com e sem a tarefa cognitiva concomitante. No teste estático, o desempenho do Grupo DA foi pior que do Grupo-controle no teste de olhos fechados sem tarefa cognitiva. O equilíbrio do Grupo-DA foi pior que do Grupo-controle nos testes dinâmicos. A DA interfere no desempenho do equilíbrio postural na atividade dinâmica associada à tarefa cognitiva, mas não interfere na atividade estática. A plataforma fixa de avaliação utilizada neste estudo não se mostrou um instrumento sensível para medir as alterações no equilíbrio postural estático causadas pela realização de tarefa cognitiva concomitante nos idosos com DA. / The attentional demand in order to keep the postural balance increases with the aging process and may cause damages in the concomitant performance of two or more tasks. Subjects with Alzheimers disease (AD) have less attentional reserve, and therefore present greater difficulty to perform a motor task associated with a cognitive task, increasing the risk of falls and their consequences. The aim of this study was to verify the balance of elderly people with AD during the concomitant performance of functional activities (dynamic and static) and cognitive tasks. Sixty aged people, male and female, with mean age of 77 ± 4 years, were evaluated; subjects were divided into two groups: AD Group composed by individuals with AD (n=28) and Control Group composed by individuals without cognitive alterations (n=32). The postural balance was evaluated through TUGT in the dynamic activity, and through the stable platform, Balance Master, NeuroCom in the static activity. The static test was done with opened and closed eyes. Patients with AD presented worse performance in the TUGT with and without the concomitant cognitive task. In the static test, the performance of the AD Group was worse than the performance of the Control Group in the test with closed eyes without cognitive task. The balance of the AD Group was worse than the balance of the Control Group during the dynamic tests. The AD interferes in the postural balance performance in the dynamic activity associated with a cognitive task, but it does not interfere in the static activity. The evaluation stable platform used in this study was unable to measure the alterations in static postural balance caused by the concomitant performance of the cognitive task in aged people with AD.

No description available.

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.