Evaluation of the transcriptomic response of an Alzheimer's disease murine model induced at different ages: searching for predictors

Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disease, characterized by the impairment of mnesic and cognitive functions, that represents the most frequent type of dementia in older people worldwide. Aging is the most important risk factor for the sporadic form of the pathology and it is associated to the progressive impairment of the proteostasis network. The endoplasmic reticulum (ER), the main cellular actor involved in proteostasis, appears significantly compromised in AD due to the accumulation of β-amyloid (Aβ) protein and phosphorylated-tau protein. Increasing proteins misfolding activates a specific cellular response known as Unfolded Protein response (UPR) which orchestrates the recovery of ER function. The aim of the present study was to investigate the role of UPR and aging process in a murine model of AD induced by intracerebroventricular (i.c.v.) injection of Aβ1-42 oligomers at 3 or 18 months. The oligomers injection in aged animals caused the increased of memory impairment, oxidative stress, and the depletion of glutathione reserve. Furthermore, the RNA-sequencing analysis was performed and the bioinformatic analysis showed the enrichment of several pathways involved in neurodegeneration and protein regulations. The following analysis highlighted the significant dysregulation of the three branches of the UPR, the protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF-6). In turn, ER stress affected the PI3K/Akt/Gsk3β and MAPK/ERK pathways, highlighting Mapkapk5 as a potential marker of the neurodegenerative process, which regulation could lead to the definition of new pharmacological and neuroprotective strategies to counteract AD.

Machine Learning in Applicazione alla Prevenzione del Morbo di Alzheimer

Il morbo di Alzheimer è ancora una malattia incurabile. Negli ultimi anni l'aumento progressivo dell'aspettativa di vita ha contribuito a un'insorgenza maggiore di questa patologia, specialmente negli stati con l'età media più alta, tra cui l'Italia. La prevenzione risulta una delle poche vie con cui è possibile arginarne lo sviluppo, ed in questo testo vengono analizzate le potenzialità di alcune tecniche di Machine Learning atte alla creazione di modelli di supporto diagnostico per Alzheimer. Dopo un'opportuna introduzione al morbo di Alzheimer ed al funzionamento generale del Machine Learning, vengono presentate e approfondite due delle tecniche più promettenti per la diagnosi di patologie neurologiche, ovvero la Support Vector Machine (macchina a supporto vettoriale, SVM) e la Convolutional Neural Network (rete neurale convoluzionale, CNN), con annessi risultati, punti di forza e principali debolezze. La conclusione verterà sul possibile futuro delle intelligenze artificiali, con particolare attenzione all'ambito sanitario, e verranno discusse le principali difficoltà nelle quali queste incombono prima di essere commercializzate, insieme a plausibili soluzioni.

Local and nonlocal integro-differential reaction-diffusion models for protein dynamics in Alzheimer's disease

In this work, integro-differential reaction-diffusion models are presented for the description of the temporal and spatial evolution of the concentrations of Abeta and tau proteins involved in Alzheimer's disease. Initially, a local model is analysed: this is obtained by coupling with an interaction term two heterodimer models, modified by adding diffusion and Holling functional terms of the second type. We then move on to the presentation of three nonlocal models, which differ according to the type of the growth (exponential, logistic or Gompertzian) considered for healthy proteins. In these models integral terms are introduced to consider the interaction between proteins that are located at different spatial points possibly far apart. For each of the models introduced, the determination of equilibrium points with their stability and a study of the clearance inequalities are carried out. In addition, since the integrals introduced imply a spatial nonlocality in the models exhibited, some general features of nonlocal models are presented. Afterwards, with the aim of developing simulations, it is decided to transfer the nonlocal models to a brain graph called connectome. Therefore, after setting out the construction of such a graph, we move on to the description of Laplacian and convolution operations on a graph. Taking advantage of all these elements, we finally move on to the translation of the continuous models described above into discrete models on the connectome. To conclude, the results of some simulations concerning the discrete models just derived are presented.

A perda de peso em pacientes com doença de alzheimer

Ilustração de diagrama sobre perda de peso em pacientes com Doença de Alzheimer

Como melhorar as práticas de alimentação para o paciente com demência de Alzheimer

A Doença de Alzheimer é uma enfermidade que se agrava ao longo do tempo. O comprometimento mais marcante é uma acentuada perda de peso, que normalmente vem acompanhada de desidratação e resulta freqüentemente em um quadro de subnutrição. Avaliação e reavaliação nutricional periódica com dados laboratoriais, anamnese alimentar e a avaliação do estágio da doença são importantes para a melhoria na estratégia da alimentação do idoso.

Doença de Alzheimer: a principal causa de demência nos idosos e seus impactos na vida dos familiares e cuidadores

O envelhecimento da população brasileira tem algumas tendências que são similares ao nível internacional. O aumento da população de idade avançada devido a baixa natalidade, o aumento de esperança de vida, o desenvolvimento de novas tecnologias a proporcionar tratamentos que até a alguns anos eram impossíveis, uma perspectiva e um prognóstico favorável de vida para alguns transtornos, dentre eles as demências. Este trabalho prevê, de maneira simples, sobre a doença de Alzheimer como principal causa de demência e é direcionado às famílias e ao público em geral. Apresenta informações úteis e práticas sobre como lidar com a doença e como organizar a auto-ajuda e apoio mútuo a famílias com membros afetados por demência. Quando em casa existe um enfermo da Doença de Alzheimer todos têm que contribuir em algo para a sua vida pessoal. Convém buscar a situação melhor para todos, embora obviamente a família encontrar-se-á mais ocupada e angustiada. Os cuidados curativos ou paliativos devem ser feitos com continuidade e sem abandonos, evitando e protegendo a família contra a desesperança. Com uma informação adequada em cada momento e incluindo a família como objetivo terapêutico.

Assistência da Equipe Saúde da Família ao paciente com doença de Alzheimer e seus cuidadores

O estudo trata-se uma pesquisa bibliográfica que objetiva ampliar o conhecimento sobre a doença de Alzheimer, a repercussão no cuidador do idoso e a sua importância no contexto da enfermagem da Estratégia Saúde da Família. Frente ao envelhecimento da população brasileira, torna-se crescente a demanda por prevenção e assistência aos pacientes idosos, havendo a necessidade de reestruturação de serviços e de programas de saúde que possam responder às suas necessidades, uma vez que essa faixa etária representa a maior consumidora dos serviços de saúde. A doença de Alzheimer, enquanto uma forma de demência; acomete principalmente a integridade física, mental e social, acarretando uma situação de dependência total, com cuidados cada vez mais complexos. Desta forma, os cuidadores de idosos devem estar preparados para lidar com esta realidade, que exige, dentre outros, ao pensamento crítico. Contudo, cabe à equipe da Estratégia Saúde da Família, enquanto integrante da rede da atenção básica, atuação primordial neste crescente cenário, visando e valorizando o processo de ensino-aprendizagem, como forma de promoção à saúde.

Plano de ação para o cuidado ao portador de Alzheimer e seu familiar/cuidador - desafio da Estratégia Saúde da Família Novo Tempo São Geraldo - MG

Embora se estime que a proporção de idosos duplicará até 2050, alcançando 15% do total da população, as doenças crônico degenerativas e distúrbios mentais já têm determinado, atualmente, maciça utilização dos serviços de saúde (CHAIMOWICZ, 1997). Este estudo foi realizado a partir do diagnóstico situacional realizado pela Equipe da Estratégia de Saúde da Família Novo Tempo do município de São Geraldo - MG que revelou esta realidade, em especial à pessoa idosa com doença de Alzheimer. Para fundamentar o plano de ação proposto, recorreu-se à literatura disponível nas bases de dados Medline, SciELO e Lilacs no período de 1997 à 2013 visando agregar evidências para o desenvolvimento do projeto de intervenção a ser implantado pela equipe. Embora não atinja todos os problemas diagnosticados, este plano pretende ser um instrumento de ação proporcionando mudanças consideráveis no cuidado à pessoa idosa com doença de Alzheimer, oferecendo uma resposta progressiva às suas necessidades e contribuir na qualidade da assistência e nas orientações prestadas ao seu familiar/cuidador.

Assistência da Equipe Saúde da Família ao paciente com doença de Alzheimer e seus cuidadores

O estudo trata-se uma pesquisa bibliográfica que objetiva ampliar o conhecimento sobre a doença de Alzheimer, a repercussão no cuidador do idoso e a sua importância no contexto da enfermagem da Estratégia Saúde da Família. Frente ao envelhecimento da população brasileira, torna-se crescente a demanda por prevenção e assistência aos pacientes idosos, havendo a necessidade de reestruturação de serviços e de programas de saúde que possam responder às suas necessidades, uma vez que essa faixa etária representa a maior consumidora dos serviços de saúde. A doença de Alzheimer, enquanto uma forma de demência; acomete principalmente a integridade física, mental e social, acarretando uma situação de dependência total, com cuidados cada vez mais complexos. Desta forma, os cuidadores de idosos devem estar preparados para lidar com esta realidade, que exige, dentre outros, ao pensamento crítico. Contudo, cabe à equipe da Estratégia Saúde da Família, enquanto integrante da rede da atenção básica, atuação primordial neste crescente cenário, visando e valorizando o processo de ensino-aprendizagem, como forma de promoção à saúde.

Memantine prevents cardiomyocytes nuclear size reduction in the left ventricle of rats exposed to cold stress

OBJECTIVES: Memantine is an N-methyl-d-aspartate (NMDA) glutamate receptor antagonist used to treat Alzheimer's disease. Previous studies have suggested that receptor blockers act as neuroprotective agents; however, no study has specifically investigated the impact that these drugs have on the heart. We sought to evaluate the effects of memantine on nuclear size reduction in cardiac cells exposed to cold stress. METHOD: We used male EPM-Wistar rats (n=40) divided into 4 groups: 1) Matched control (CON); 2) Memantine-treated rats (MEM); 3) Rats undergoing induced hypothermia (IH) and 4) Rats undergoing induced hypothermia that were also treated with memantine (IHM). Animals in the MEM and IHM groups were treated by oral gavage administration of 20 mg/kg/day memantine over an eight-day period. Animals in the IH and IHM groups were submitted to 4 hours of hypothermia in a controlled environment with a temperature of - 8ºC on the last day of the study. RESULTS: The MEM group had the largest cardiomyocyte nuclear size (151 ± 3.5 μm³ vs. CON: 142 ± 2.3 μm³; p<0.05), while the IH group had the smallest mean value of nuclear size. The nuclear size of the IHM group was preserved (125 ± 2.9 μm³) compared to the IH group (108 ± 1.7 μm³; p<0.05). CONCLUSION: Memantine prevented the nuclear size reduction of cardiomyocytes in rats exposed to cold stress.

Subclinical hyperthyroidism and dementia: the Sao Paulo Ageing & Health Study (SPAH)

Background: Several epidemiologic studies have shown a possible association between thyroid function and cognitive decline. Our aim was to evaluate the association of subclinical hyperthyroidism and dementia in a population sample of older people Methods: A cross-sectional study - Sao Paulo Ageing & Health Study (SPAH) - in a population sample of low-income elderly people >= 65 years-old to evaluate presence of subclinical thyroid disease as a risk factor for dementia. Thyroid function was assessed using thyrotropic hormone and free-thyroxine as well as routine use of thyroid hormones or antithyroid medications. Cases of dementia were assessed using a harmonized one-phase dementia diagnostic procedure by the ""10/66 Dementia Research Group"" including Alzheimer's disease and vascular dementia. Logistic regression models were used to test a possible association between subclinical hyperthyroidism and dementia. Results and discussion: Prevalence of dementia and of subclinical hyperthyroidism were respectively of 4.4% and 3.0%. After age adjustment, we found an association of subclinical hyperthyroidism and any type of dementia and vascular dementia (Odds Ratio, 4.1, 95% Confidence Interval [95% CI] 1.3-13.1, and 5.3 95% CI, 1.1-26.4; respectively). Analyzing data by gender, we found an association of subclinical hyperthyroidism with dementia and Alzheimer's disease only for men (OR, 8.0; 95% CI, 1.5-43.4; OR, 12.4; 95% CI, 1.2-128.4; respectively). No women with subclinical hypothyroidism presented Alzheimer's disease in the sample. Conclusion: The results suggest a consistent association among people with subclinical hyperthyroidism and dementia.

Molecular determinants of improved cathepsin B inhibition by new cystatins obtained by DNA shuffling

Background: Cystatins are inhibitors of cysteine proteases. The majority are only weak inhibitors of human cathepsin B, which has been associated with cancer, Alzheimer's disease and arthritis. Results: Starting from the sequences of oryzacystatin-1 and canecystatin-1, a shuffling library was designed and a hybrid clone obtained, which presented higher inhibitory activity towards cathepsin B. This clone presented two unanticipated point mutations as well as an N-terminal deletion. Reversing each point mutation independently or both simultaneously abolishes the inhibitory activity towards cathepsin B. Homology modeling together with experimental studies of the reverse mutants revealed the likely molecular determinants of the improved inhibitory activity to be related to decreased protein stability. Conclusion: A combination of experimental approaches including gene shuffling, enzyme assays and reverse mutation allied to molecular modeling has shed light upon the unexpected inhibitory properties of certain cystatin mutants against Cathepsin B. We conclude that mutations disrupting the hydrophobic core of phytocystatins increase the flexibility of the N-terminus, leading to an increase in inhibitory activity. Such mutations need not affect the inhibitory site directly but may be observed distant from it and manifest their effects via an uncoupling of its three components as a result of increased protein flexibility.

Role of kinin B1 and B2 receptors in memory consolidation during the aging process of mice

Under physiological conditions, elderly people present memory deficit associated with neuronal loss. This pattern is also associated with Alzheimer`s disease but, in this case, in a dramatically intensified level. Kinin receptors have been involved in neurodegeneration and increase of amyloid-beta concentration, associated with Alzheimer`s disease (AD). Considering these findings, this work evaluated the role of kinin receptors in memory consolidation during the aging process. Male C57BI/6 (wt), knock-out B1 (koB1) or B2 (koB2) mice (3, 6, 12 and 18-month-old - mo; n = 10 per group) were submitted to an acquisition session, reinforcement to learning (24 h later: test 1) and final test (7 days later: test 2), in an active avoidance apparatus, to evaluate memory. Conditioned avoidance responses (CAR, % of 50 trials) were registered. In acquisition sessions, similar CAR were obtained among age matched animals from all strains. However, a significant decrease in CAR was observed throughout the aging process (3mo: 8.8 +/- 2.3%; 6mo: 4.1 +/- 0.6%; 12mo: 2.2 +/- 0.6%, 18mo: 3.6 +/- 0.6%, P < 0.01), indicating a reduction in the learning process. In test 1, as expected, memory retention increased significantly (P < 0.05) in all 3- and 6-month-old animals as well as in 12-month-old-wt and 12-month-old-koB1 (P < 0.01), compared to the training session. However, 12-month-old-koB2 and all 18-month-old animals did not show an increase in memory retention. In test 2, 3- and 6-month-old wt and koB1 mice of all ages showed a significant improvement in memory (P < 0.05) compared to test 1. However, 12-month-old wt and koB2 mice of all ages showed no difference in memory retention. We suggest that, during the aging process, the B1 receptor could be involved in neurodegeneration and memory loss. Nevertheless, the B2 receptor is apparently acting as a neuroprotective factor. (C) 2009 Elsevier Ltd. All rights reserved.

Participation of kinin receptors on memory impairment after chronic infusion of human amyloid-beta 1-40 peptide in mice

Chronic infusion of human amyloid-beta 1-40 (A beta) in the lateral ventricle (LV) of rats is associated with memory impairment and increase of kinin receptors in cortical and hippocampal areas. Deletion of kinin B1 or B2 receptors abolished memory impairment caused by an acute single injection of A beta in the LV. As brain tissue and kinin receptors could unlikely react to acute or chronic administration of a similar quantity of A beta, we evaluated the participation of B1 or B2 receptors in memory impairment after chronic infusion of A beta. Male C57BI/6 J (wt), knock-out B1 (koB1) or B2 (koB2) mice (12 weeks of age) previously trained in a two-way shuttle-box and achieving conditioned avoidance responses (CAR, % of 50 trials) were infused with AB (550 pmol, 0.12 mu L/h, 28 days) or vehicle in the LV using a mini-osmotic pump. They were tested before the surgery (TO), 7 and 35 days after the infusion started (T7; T35). In T0, no difference was observed between CAR of the control (Cwt = 59.7 +/- 6.7%; CkoB1 = 46.7 +/- 4.0%; CkoB2 = 64.4 +/- 5.8%) and A beta (A beta wt = 66.0 +/- 3.0%; A beta koB1 = 66.8 +/- 8.2%; A beta koB2 = 58.7 +/- 5.9%) groups. In T7, A beta koB2 showed a significant decrease in CAR (41.0 +/- 8.6%) compared to the control-koB2 (72.8 +/- 2.2%, P <0.05). In T35, a significant decrease (P <0.05) was observed in A beta wt (40.7 +/- 3.3%) and A beta koB2 (41.2 +/- 10.7%) but not in the A beta koB1 (64.0 +/- 14.0%) compared to their control groups. No changes were observed in the controls at T35. We suggest that in chronic infusion of BA, B1 receptors could playan important role in the neurodegenerative process. Conversely, the premature memory impairment of koB2 suggests that it may be a protective factor. (C) 2009 Elsevier Ltd. All rights reserved.

Short Cognitive Performance Test: Diagnostic Accuracy and Education Bias in Older Brazilian Adults

The ""Short Cognitive Performance Test"" (Syndrom Kurztest, SKT) is a cognitive screening battery designed to detect memory and attention deficits. The aim of this study was to evaluate the diagnostic accuracy of the SKT as a screening tool for mild cognitive impairment (MCI) and dementia. A total of 46 patients with Alzheimer`s disease (AD), 82 with MCI, and 56 healthy controls were included in the study. Patients and controls were allocated into two groups according to educational level (< 8 years or > 8 years). ROC analyses suggested that the SKT adequately discriminates AD from non-demented subjects (MCI and controls), irrespective of the education group. The test had good sensitivity to discriminate MCI from unimpaired controls in the sub-sample of individuals with more than 8 years of schooling. Our findings suggest that the SKT is a good screening test for cognitive impairment and dementia. However, test results must be interpreted with caution when administered to less-educated individuals.