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1.
BMJ ; 367: l6217, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31810978

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid ß in the form of extracellular plaques and by intracellular neurofibrillary tangles, with eventual neurodegeneration and dementia. There is currently no disease-modifying treatment though several symptomatic medications exist with modest benefit on cognition. Acetylcholinesterase inhibitors have a consistent benefit across all stages of dementia; their benefit in mild cognitive impairment and prodromal AD is unproven. Memantine has a smaller benefit on cognition overall which is limited to the moderate to severe stages, and the combination of a cholinesterase inhibitor and memantine may have additional efficacy. Evidence for the efficacy of vitamin E supplementation and medical foods is weak but might be considered in the context of cost, availability, and safety in individual patients. Apparently promising disease-modifying interventions, mostly addressing the amyloid cascade hypothesis of AD, have recently failed to demonstrate efficacy so novel approaches must be considered.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/farmacologia , Peptídeos beta-Amiloides/uso terapêutico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/prevenção & controle , Preparações de Ação Retardada , Quimioterapia Combinada , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
2.
J Agric Food Chem ; 67(49): 13767-13774, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31722531

RESUMO

Recent studies indicated that neuroinflammation contributes to the exacerbation of Alzheimer's disease (AD) and plays an important role in AD. The NOD-like receptor protein 3 (NLRP3) inflammasome, which is an important component of innate immune system, is associated with a wide range of human central nervous system disorders, including AD. Most of the studies focus on the protective effects of docosahexaenoic acid (DHA) in AD, but eicosapentaenoic acid (EPA) has rarely been involved. Here, we investigate the effects of EPA in the forms of phosphatidylcholine (EPA-PC) and ethyl esters (EPA-EE) in improving Aß1-42-induced neurotoxicity. The spatial memory ability and the biochemical changes in the hippocampus were measured, including glial cell activation, tumor necrosis factor α production, NLRP3 inflammasome activation, and autophagic flux. The present results showed that the AD rats were significantly protected from spatial memory loss by the supplementation (EPA + DHA = 60 mg/kg, i.g., 20 days) of EPA-PC, while EPA-EE showed no significant benefit. Further mechanism studies suggested that EPA-PC could inhibit Aß-induced neurotoxicity by alleviating NLRP3 inflammasome activation and enhancing autophagy. These findings indicate that EPA could improve cognitive deficiency in Aß1-42-induced AD rats via autophagic inflammasomal pathway and the bioactivity differs in its molecular form.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/toxicidade , Autofagia/efeitos dos fármacos , Ácido Eicosapentaenoico/administração & dosagem , Inflamassomos/efeitos dos fármacos , Fosfatidilcolinas/administração & dosagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Inflamassomos/genética , Inflamassomos/metabolismo , Masculino , Memória/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
3.
Clin Interv Aging ; 14: 1481-1492, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616139

RESUMO

Nutritional factors can influence the risk of developing Alzheimer's disease (AD) and its rate of progression, and there is, therefore, increasing interest in nutrition as a modifiable risk factor for the disease. Synaptic loss is an important feature of early AD, and the formation of new synapses is dependent on key nutritional elements that are known to be deficient in patients with AD. The daily medical food, Souvenaid, contains Fortasyn Connect, a multinutrient combination developed to specifically address these deficiencies, comprising docosahexaenoic acid, eicosapentaenoic acid, uridine monophosphate, choline, phospholipids, selenium, folic acid, and vitamins B12, B6, C, and E. Although yielding heterogeneous findings, clinical studies of Fortasyn Connect provide preliminary evidence of clinically relevant benefits on cognitive outcomes in prodromal and early AD. The LipiDiDiet trial investigated the effects of Fortasyn Connect on cognition and related measures in prodromal AD, and is the first randomized, controlled, double-blind, multicenter trial study of a non-pharmacological intervention in this setting. The primary efficacy endpoint was change over 24 months in a composite score of cognitive performance using a neuropsychological test battery. Fortasyn Connect had no significant effect on this endpoint, but demonstrated a significant benefit on secondary endpoints, including domains of cognition affected by AD (attention, memory, executive function) and hippocampal atrophy, suggesting a potential benefit on disease progression. Other studies have demonstrated benefits for Fortasyn Connect on nutritional markers and levels of plasma homocysteine. Taken together, current evidence indicates that Fortasyn Connect may show benefit on domains of cognition affected by AD and nutritional measures that influence risk factors for its progression; that it has greater potential for benefit earlier rather than later in the disease; and that it is safe and well tolerated, alone or in combination with AD medications. Further research into its potential role in AD management is therefore warranted.


Assuntos
Doença de Alzheimer/dietoterapia , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Estado Nutricional , Fosfolipídeos/uso terapêutico , Idoso , Doença de Alzheimer/fisiopatologia , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Testes Neuropsicológicos
4.
Expert Opin Investig Drugs ; 28(11): 967-975, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31661331

RESUMO

Introduction: The amyloid hypothesis of Alzheimer's disease (AD) states that brain accumulation of amyloid-ß (Aß) oligomers and soluble aggregates represents the major causal event of the disease. Several small organic molecules have been synthesized and developed to inhibit the enzyme (ß-site amyloid precursor protein cleaving enzyme-1 or BACE1) whose action represents the rate-limiting step in Aß production.Areas covered: We reviewed the pharmacology and clinical trials of major BACE1 inhibitors.Expert opinion: In transgenic mouse models of AD, BACE1 inhibitors dose-dependently lower Aß levels in brain and cerebrospinal fluid (CSF) but the evidence for attenuation or reversal cognitive or behavioral deficits is very scanty. In AD patients, BACE1 inhibitors robustly lower plasma and CSF Aß levels and reduce brain plaques but without cognitive, clinical, or functional benefit. To date, seventeen BACE1 inhibitors have failed in double-blind, placebo-controlled clinical trials in patients with mild-to-moderate or prodromal AD, or in cognitively normal subjects at risk of developing AD. Several of these studies were prematurely interrupted due to toxicity or cognitive and behavioral worsening compared to placebo-treated patients. Elenbecestat, the last BACE1 inhibitor remaining in late clinical testing for AD, was recently discontinued due to safety concerns.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Drogas em Investigação/administração & dosagem , Doença de Alzheimer/fisiopatologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos , Drogas em Investigação/farmacologia , Humanos , Camundongos , Camundongos Transgênicos
5.
Adv Exp Med Biol ; 1175: 273-324, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583592

RESUMO

Alzheimer's disease is the most common cause of dementia. Cellular changes in the brains of the patients suffering from Alzheimer's disease occur well in advance of the clinical symptoms. At the cellular level, the most dramatic is a demise of neurones. As astroglial cells carry out homeostatic functions of the brain, it is certain that these cells are at least in part a cause of Alzheimer's disease. Historically, Alois Alzheimer himself has recognised this at the dawn of the disease description. However, the role of astroglia in this disease has been understudied. In this chapter, we summarise the various aspects of glial contribution to this disease and outline the potential of using these cells in prevention (exercise and environmental enrichment) and intervention of this devastating disease.


Assuntos
Doença de Alzheimer/fisiopatologia , Astrócitos/citologia , Neuroglia/citologia , Encéfalo/fisiopatologia , Humanos
6.
Adv Exp Med Biol ; 1175: 325-333, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583593

RESUMO

Oligodendrocytes form the myelin that ensheaths CNS axons, which is essential for rapid neuronal signalling and underpins the massive computing power of the human brain. Oligodendrocytes and myelin also provide metabolic and trophic support for axons and their disruption results in axonal demise and neurodegeneration, which are key features of Alzheimer's disease (AD). Notably, the brain has a remarkable capacity for regenerating oligodendrocytes, which is the function of adult oligodendrocyte progenitor cells (OPCs) or NG2-glia. White matter loss is often among the earliest brain changes in AD, preceding the tangles and plaques that characterize neuronal deficits. The underlying causes of myelin loss include oxidative stress, neuroinflammation and excitotoxicity, associated with accumulation of Aß and tau hyperphosphorylation, pathological hallmarks of AD. Moreover, there is evidence that NG2-glia are disrupted in AD, which may be associated with disruption of synaptic signalling. This has led to the hypothesis that a vicious cycle of myelin loss and failure of regeneration from NG2-glia plays a key role in AD. Therapies that target NG2-glia are likely to have positive effects on myelination and neuroprotection in AD.


Assuntos
Doença de Alzheimer/fisiopatologia , Bainha de Mielina/patologia , Oligodendroglia/citologia , Axônios , Doenças Desmielinizantes/fisiopatologia , Humanos
7.
Clin Nucl Med ; 44(11): e597-e601, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31584490

RESUMO

AIM: In this study, we investigated the relationship of cerebral tau deposition (F-tau-AD-ML 104 PET/CT) with glucose metabolism (F-FDG PET/CT) and cognitive function in patients with Alzheimer disease (AD). PATIENTS AND METHODS: Seventy subjects (Mini Mental State Examination [MMSE] score <18 = 37 [AD]; MMSE score, 18-24 = 16 [early AD]) and 17 controls were included in this study. All participants underwent detailed neurological and neuropsychological evaluation, followed by F-tau-AD-ML 104 and F-FDG PET/CT imaging. Region-wise SUVmax ratios at 50 to 60 minutes postinjection were calculated for F-tau-AD-ML 104 and F-FDG, using the cerebellar cortex as the reference region. Linear models were used to investigate the association of regional F-tau-AD-ML 104 retention with F-FDG uptake and cognition (MMSE scores). RESULTS: F-Tau-AD-ML 104 retention was observed in the parietal lobe, temporal lobe, hippocampus, parahippocampus, frontal lobe, anterior and posterior cingulate, and precuneus in advanced and early AD patient as compared with normal controls with regional hypometabolism in overlapping regions on F-FDG PET. Significant negative association was found between F-tau-AD-ML 104 regional retention and glucose metabolism in the parietal lobe, temporal lobe, hippocampus, parahippocampus, frontal lobe, anterior and posterior cingulate, and precuneus among patients with advanced and early AD. In advanced and early AD patients, a negative association was found between F-tau-AD-ML 104 regional retention (precuneus) and cognition (MMSE score), whereas a positive association was observed between F-FDG regional uptake (precuneus) and cognition (MMSE score). CONCLUSIONS: Tau pathology overlapped with areas of hypometabolism on FDG PET in the brains of AD patients. Tau deposition was found to have negative association with cognitive scores in these patients.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Cognição , Glucose/metabolismo , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
8.
Clin Interv Aging ; 14: 1631-1642, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571843

RESUMO

Purpose: Recent studies have found associations of increased brain amyloid beta (Aß) accumulation and several abnormal sleep-wake patterns, including shorter latency and increased fragmentation in preclinical Alzheimer's disease (AD). There is little known about the relationship between sleep and tau. The objective of this study was to understand the associations of both tau and Aß with early signs of sleep and night-time behavior changes in clinically normal elderly adults. Specifically, we have addressed the question of how informant-based subjective sleep reports are linked to regional [18F]flortaucipir and [18F]florbetapir uptake. Methods: Imaging and behavioral data from 35 subjects were obtained from the Alzheimer's Disease Neuroimaging Initiative. The Neuropsychiatric Inventory Sleep (NPI-sleep) Questionnaire was used to assess the sleep and night-time behavior changes. Regional tau-positron emission tomography (PET) (entorhinal, brainstem) and Aß-PET (posterior cingulate, precuneus, medial orbitofrontal) uptake values were calculated. A series of linear regression analyses were used to determine the combination of sleep symptoms that built the best models to predict each pathology. Results: Informant-based reports of abnormal night-time behavior (NPI questions k3, k5, and k8) were significantly associated with increased entorhinal tau and Aß (all regions) accumulation. Interestingly, informant-based reports of sleep deficiencies without abnormal nigh-time activity (NPI questions k1, k2, and k6) were negatively associated with entorhinal tau burden. Conclusion: Detection of abnormal night-time behaviors (wandering, pacing, other inappropriate activities) by family members indicates early signs of both AD pathologies and may encourage the affected individuals to seek help by health care providers for detailed cognitive/neurobehavioral assessments.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Córtex Entorrinal/metabolismo , Sono , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Compostos de Anilina , Sintomas Comportamentais , Carbolinas , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Córtex Entorrinal/diagnóstico por imagem , Etilenoglicóis , Feminino , Humanos , Masculino , Neuroimagem , Tomografia por Emissão de Pósitrons/métodos , Inquéritos e Questionários , Fatores de Tempo
9.
Medicine (Baltimore) ; 98(42): e17557, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626119

RESUMO

BACKGROUND: Mild cognitive impairment (MCI) and Alzheimer's disease (AD) are neurodegenerative diseases associated with aging. The major clinical features of both are progressive memory loss and progressive cognitive loss. The objective of this systematic review protocol is to provide the methods for evaluating the effectiveness of acupuncture in the treatment on cognitive deficits in transgenic mouse. METHODS AND ANALYSIS: We will search the electronic databases of PubMed, Web of Science, Embase, PsycINFO, as well as the Chinese databases such as Chinese Biomedicine Literature (CBM), Chinese Medical Current Content (CMCC), Chinese Scientific Journal Database (VIP), WanFang Database and China National Knowledge Infrastructure (CNKI) from their inceptions to July 2019. RevMan 5.3 software will be used for the data synthesis and the quality of each study was assessed independently by use of the CAMARADES checklist. RESULTS: This review will provide a high-quality synthesis based on present evidence of acupuncture treatment for AD and MCI in transgenic mouse models. CONCLUSIONS: This systematic review will provide evidence for weather acupuncture is an effective intervention for AD and MCI in transgenic mouse models. ETHICS AND DISSEMINATION: Ethical approval is not necessary since this protocol is only for systematic review and does not involve privacy data or conduct an animal experiment. This protocol will be disseminated by a peer-review journal or conference presentation. TRIAL REGISTRATION NUMBER: PROSPERO CRD42019142985. STRENGTHS AND LIMITATIONS OF THIS STUDY: This systematic review will be the first to provide new knowledge underlying the effectiveness to improve cognitive function of acupuncture treatment for AD and MCI in transgenic mouse models. The result of this systematic review may provide experimental and theoretical basis for the future clinical application of acupuncture in the treatment of AD.The limitation of this systematic review may come from language barriers, because only English and Chinese can be included. Also, this study includes various kinds of acupuncture treatments which may result in essential heterogeneity.


Assuntos
Terapia por Acupuntura/métodos , Doença de Alzheimer/terapia , Cognição/fisiologia , Disfunção Cognitiva/terapia , Doença de Alzheimer/complicações , Doença de Alzheimer/fisiopatologia , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos
10.
Hypertension ; 74(5): 1172-1180, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31542965

RESUMO

Blood pressure variability (BPV) has been shown to have predictive value over blood pressure (BP) levels alone in stroke patients. We assessed whether BPV predicts cognitive and functional decline in Alzheimer disease, using data from a randomized trial (NILVAD [A European Multicentre Double-blind Placebo-controlled Phase III Trial of Nilvadipine in Mild to Moderate Alzheimer's Disease]). Patients with mild-to-moderate Alzheimer disease were included if they had ≥3 office BP measurements available to determine visit-to-visit BPV. Day-to-day BPV was assessed using home BP measurements in a subsample. The variation independent of mean was used to calculate BPV. Outcomes were change in Alzheimer's Disease Assessment Scale-cognitive subscale-12 and Disability Assessment for Dementia after 1 and 1.5 years. A total of 460 patients aged 72.1 (SD=8.1) years, with mean BP of 134.0/75.1 (10.9/6.3) mm Hg were included. After 1 year, patients in the highest quartile of BPV had deteriorated more on Alzheimer's Disease Assessment Scale-cognitive subscale compared with patients in the lowest quartile (systolic: ß, 2.24 [95% CI, 0.11-4.38], P=0.040; diastolic: ß, 2.54 [95% CI, 0.33-4.75] P=0.024). This association was still present after 1.5 years (systolic: ß, 2.86 [95% CI, 0.35-5.36], P=0.026; diastolic: ß, 3.30 [95% CI, 0.67-5.93], P=0.014). There was no effect of visit-to-visit BPV on Disability Assessment for Dementia. Day-to-day BPV was available for 46 patients. Significant associations were observed between day-to-day BPV and deterioration on Alzheimer's Disease Assessment Scale-cognitive subscale (systolic: P=0.036) and Disability Assessment for Dementia (systolic: P=0.020; diastolic: P=0.007) after 1 year, but not after 1.5 years. All associations were adjusted for potential confounders, including intervention group. In conclusion, this post hoc analysis indicates that higher visit-to-visit and day-to-day BPV might be associated with progression of Alzheimer disease. Targeting BPV may be a future target to slow decline in patients with Alzheimer disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02017340.


Assuntos
Doença de Alzheimer/fisiopatologia , Anti-Hipertensivos/uso terapêutico , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Nifedipino/análogos & derivados , Idoso , Doença de Alzheimer/epidemiologia , Determinação da Pressão Arterial/métodos , Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/fisiopatologia , Intervalos de Confiança , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Hipertensão/epidemiologia , Modelos Lineares , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Análise Multivariada , Nifedipino/uso terapêutico , Prognóstico , Medição de Risco , Índice de Gravidade de Doença
11.
Postgrad Med ; 131(7): 501-508, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31483196

RESUMO

Objectives: Aiginition Longitudinal Biomarker Investigation Of Neurodegeneration (ALBION) is a longitudinal ongoing study initiated in 2018 that takes place in the Cognitive Disorders Clinic of Aiginition Hospital of the National and Kapodistrian University of Athens. Its aim is to address several research questions concerning the preclinical and prodromal stage of Alzheimer's disease and explore potential markers for early detection, prediction, and primary prevention of dementia. Methods: We here present the design and the preliminary baseline characteristics of ALBION. The sample of our study consists of people aged over 50 who are concerned about their memory but are cognitively normal (CN) or have mild cognitive deficits. Each participant undergoes an extensive assessment including several demographic, medical, social, environmental, clinical, nutritional, neuropsychological determinants and lifestyle activities. Furthermore, we are collecting data from portable devices, neuroimaging techniques and biological samples (blood, stools, CSF). All participants are assessed annually for a period of 10 years. Results: In total, 47 participants have completed the initial evaluation up to date and are divided in two groups, CN individuals (N = 26) and MCI patients (N = 21), based on their cognitive status. The participants are, on average, 64 years old, 46.3% of the sample is male with an average of 12.73 years of education. MCI patients report more comorbidities and have a lower score in the MMSE test. Regarding APOE status, 2 participants are ε4 homozygotes and 10 ε4 heterozygotes. CSF analyses (Aß42, Τ-tau, P-tau) revealed no differences between the two groups. Conclusion: The ALBION study offers an opportunity to explore preclinical dementia and identify new and tailored markers, particularly relating to lifestyle. Further investigation of these populations may provide a wider profile of the changes taking place in the preclinical phase of dementia, leading to potentially effective therapeutic and preventive strategies.


Assuntos
Doença de Alzheimer/prevenção & controle , Disfunção Cognitiva/metabolismo , Prevenção Primária , Sintomas Prodrômicos , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/genética , Biomarcadores , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Diagnóstico Precoce , Eletroencefalografia , Feminino , Neuroimagem Funcional , Grécia , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Dados Preliminares , Proteínas tau/líquido cefalorraquidiano
12.
Hypertension ; 74(4): 1041-1051, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476904

RESUMO

Transient hypertension is a risk factor for Alzheimer disease (AD), but the effects of this interaction on brain vasculature are understudied. Addressing vascular pathology is a promising avenue to potentiate the efficacy of treatments for AD. We used arterial spin labeling magnetic resonance imaging to longitudinally assess brain vascular function and immunohistopathology to examine cerebrovascular remodeling and amyloid load. Hypertension was induced for 1 month by administration of l-NG-nitroarginine-methyl-ester in TgF344-AD rats at the prodromal stage. Following hypertension, nontransgenic rats showed transient cerebrovascular changes, whereas TgF344-AD animals exhibited sustained alterations in cerebrovascular function. Human umbilical cord perivascular cells in combination with scyllo-inositol, an inhibitor of Aß oligomerization, resulted in normalization of hippocampal vascular function and remodeling, in contrast to either treatment alone. Prodromal stage hypertension exacerbates latter AD pathology, and the combination of human umbilical cord perivascular cells with amyloid clearance promotes cerebrovascular functional recovery.


Assuntos
Doença de Alzheimer/fisiopatologia , Hipertensão/fisiopatologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Hemodinâmica/fisiologia , Hipertensão/complicações , Hipertensão/terapia , Imagem por Ressonância Magnética , Ratos , Marcadores de Spin
13.
Postgrad Med ; 131(7): 533-538, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31478419

RESUMO

Introduction: Depression in patients with mild cognitive impairment (MCI) and dementia of the Alzheimer's type (AD) is associated with worse prognosis. Indeed, depressed MCI patients have worse cognitive performance and greater loss of gray-matter volume in several brain areas. To date, knowledge of the factors that can mitigate this detrimental effect is still limited. The aim of the present study was to understand in what way cognitive reserve/brain reserve and depression interact and are linked to regional atrophy in early stage AD. Methods: Depression was evaluated with the Patient Health Questionnaire-9 in 90 patients with early AD, and a cutoff of ≥ 5 was used to separate depressed (n = 44) from non-depressed (n = 46) patients. Each group was further stratified into high/low cognitive reserve/brain reserve. Cognitive reserve was calculated using years of education as proxy, while normalized parenchymal volumes were used to estimate brain reserve. Voxel-based morphometry was carried out to extract and analyze gray-matter maps. 2 × 2 ANCOVAs were run to test the effect of the reserve-by-depression interaction on gray matter. Age and hippocampal ratio were used as covariates. Composite indices of major cognitive domains were also analyzed with comparable models. Results: No reserve-by-depression interaction was found in the analytical models of gray matter. Depression was associated with less gray matter volume in the cerebellum and parahippocampal gyrus. The brain reserve-by-depression interaction was a significant predictor of executive functioning. Among those with high brain reserve, depressed patients had poorer executive skills. No significant results were found in association with cognitive reserve. Conclusion: These findings suggest that brain reserve may modulate the association between neurodegeneration and depression in patients with MCI and dementia of the AD type, influencing in particular executive functioning.


Assuntos
Doença de Alzheimer/psicologia , Disfunção Cognitiva/psicologia , Reserva Cognitiva , Depressão/psicologia , Substância Cinzenta/diagnóstico por imagem , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Atrofia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Depressão/diagnóstico por imagem , Depressão/fisiopatologia , Feminino , Substância Cinzenta/patologia , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Giro Para-Hipocampal/diagnóstico por imagem , Giro Para-Hipocampal/patologia , Questionário de Saúde do Paciente
14.
Chaos ; 29(8): 083126, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31472487

RESUMO

We study the structural and dynamical consequences of damage in spatial neuronal networks. Inspired by real in vitro networks, we construct directed networks embedded in a two-dimensional space and follow biological rules for designing the wiring of the system. As a result, synthetic cultures display strong metric correlations similar to those observed in real experiments. In its turn, neuronal dynamics is incorporated through the Izhikevich model adopting the parameters derived from observation in real cultures. We consider two scenarios for damage, targeted attacks on those neurons with the highest out-degree and random failures. By analyzing the evolution of both the giant connected component and the dynamical patterns of the neurons as nodes are removed, we observe that network activity halts for a removal of 50% of the nodes in targeted attacks, much lower than the 70% node removal required in the case of random failures. Notably, the decrease of neuronal activity is not gradual. Both damage scenarios portray "boosts" of activity just before full silencing that are not present in equivalent random (Erdös-Rényi) graphs. These boosts correspond to small, spatially compact subnetworks that are able to maintain high levels of activity. Since these subnetworks are absent in the equivalent random graphs, we hypothesize that metric correlations facilitate the existence of local circuits sufficiently integrated to maintain activity, shaping an intrinsic mechanism for resilience.


Assuntos
Doença de Alzheimer/fisiopatologia , Encéfalo/fisiopatologia , Modelos Neurológicos , Rede Nervosa/fisiopatologia , Neurônios , Doença de Parkinson/fisiopatologia , Animais , Humanos
15.
J Stroke Cerebrovasc Dis ; 28(10): 104310, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31383622

RESUMO

BACKGROUND: The pathological impact of chronic cerebral hypoperfusion (CCH) on Alzheimer's disease (AD) is still poorly understood. In the present study, we investigated the role of CCH on an AD mouse model in phosphorylated tau and α-synuclein pathology, neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of a new antioxidant Twendee X (TwX). METHODS: APP23 mice were implanted to bilateral common carotid arteries stenosis with ameroid constrictors to gradually decrease the cerebral blood flow. The effects of the administration of TwX were evaluated by immunohistochemical analysis and Immunofluorescent histochemistry. RESULTS: The present study revealed that the expressions of phospho-tau and phospho-α-synuclein were significantly increased in the APP23 + CCH mice group as compared with wild type and APP23 mice groups (*P < .05 and ⁎⁎P < .01 versus WT; #P < .05 and ##P < .01 versus APP23). In addition, CCH significantly exacerbated MMP-9 activation relating to blood-brain barrier destruction (⁎⁎P < .01 versus WT; #P < .05, and ##P < .01 versus APP23), enhanced neurovascular remodeling, and impaired a neurovascular trophic coupling in the vascular endothelial BDNF expression of the APP23 + CCH group. TwX treatment (20 mg/kg/day, from 4.5 to 12 months) significantly reduced tau and α-synuclein pathologies, ameliorated neurovascular dysfunction compared with APP23 + CCH group. CONCLUSIONS: Our findings indicate that administration of a new antioxidative mixture TwX substantially reduced the above neuropathologic abnormalities, suggesting a potential therapeutic benefit of TwX for AD with CCH.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Encéfalo/efeitos dos fármacos , Transtornos Cerebrovasculares/tratamento farmacológico , Cistina/farmacologia , Glutamina/farmacologia , Acoplamento Neurovascular/efeitos dos fármacos , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Transtornos Cerebrovasculares/genética , Transtornos Cerebrovasculares/metabolismo , Transtornos Cerebrovasculares/fisiopatologia , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Fenótipo , Fosforilação
16.
Artigo em Inglês | MEDLINE | ID: mdl-31398817

RESUMO

Little is known about the association between environmental features and the risk of Alzheimer's dementia (AD). This study aims to investigate the association of physical and social environments with the incidence of AD. We identified 12,401 newly diagnosed AD cases aged ≥65 years in 2010, with the same no. of matched controls from National Health Insurance claims in Taiwan. Environmental data were collected from government statistics including three physical environments and three social environments. Multilevel logistic regression was conducted to calculate the odds ratios (OR) of AD in association with environmental features at the township level. Results showed that living in the areas with higher availability of playgrounds and sport venues was associated with a 3% decreased odds of AD (95% CI = 0.96-0.99), while higher density of elderly living alone was associated with a 5% increased odds of AD (95% CI = 1.01-1.11), after controlling for individual and other environmental factors. In further examination by urbanization level, the above relationships were found only in rural areas but not in urban areas. This study provides evidence that specific physical and social environmental features have different impacts on the risk of AD.


Assuntos
Doença de Alzheimer/epidemiologia , Doença de Alzheimer/fisiopatologia , Planejamento Ambiental/estatística & dados numéricos , Meio Social , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Incidência , Modelos Logísticos , Estudos Longitudinais , Masculino , Razão de Chances , Fatores de Risco , Taiwan/epidemiologia
17.
Neurochem Res ; 44(9): 2031-2043, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31410709

RESUMO

As one of the major cell organelles responsible for ATP production, it is important that neurons maintain mitochondria with structural and functional integrity; this is especially true for neurons with high metabolic requirements. When mitochondrial damage occurs, mitochondria are able to maintain a steady state of functioning through molecular and organellar quality control, thus ensuring neuronal function. And when mitochondrial quality control (MQC) fails, mitochondria mediate apoptosis. An apparently key molecule in MQC is the transcriptional coactivator peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α). Recent findings have demonstrated that upregulation of PGC-1α expression in neurons can modulate MQC to prevent mitochondrial dysfunction in certain in vivo and in vitro aging or neurodegenerative encephalopathy models, such as Huntington's disease, Alzheimer's disease, and Parkinson's disease. Because mitochondrial function and quality control disorders are the basis of pathogenesis in almost all neurodegenerative diseases (NDDs), the role of PGC-1α may make it a viable entry point for the treatment of such diseases. This review focuses on multi-level MQC in neurons, as well as the regulation of MQC by PGC-1α in these major NDDs.


Assuntos
Doença de Alzheimer/fisiopatologia , Doença de Huntington/fisiopatologia , Mitocôndrias/fisiologia , Doença de Parkinson/fisiopatologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/fisiologia , Animais , Humanos , Neurônios/fisiologia , Biogênese de Organelas
18.
Invest Ophthalmol Vis Sci ; 60(10): 3447-3455, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31408108

RESUMO

Purpose: Comparison of retinal microvasculature within the macula and the optic nerve head in the eyes of patients with Alzheimer's disease (AD), primary open-angle glaucoma (POAG), and in a healthy control (HC) group, using optical coherence tomography angiography (OCTA). Methods: In this cross-sectional study, 27 patients with AD, 27 with POAG, and 27 healthy controls were enrolled. The Mini-Mental State Examination test was used to assess cognitive function. Ophthalmic examination included OCTA, which was used for the imaging of vascular flow within the layer of radial peripapillary capillaries (RPCs), and also in the superficial vascular plexus (SVP) and deep vascular plexus (DVP) of the retina. Results: In the AD group, the density of vessels in DVP was significantly reduced and the foveal avascular zone was increased when compared to POAG and HC groups (P < 0.001). Patients with POAG had a significantly reduced vessel density in RPCs and SVP as compared to AD and HC groups (P < 0.001). The average thickness of peripapillary retinal nerve fiber layer was correlated with the vessel density in SVP in patients with POAG (Pearson's r = 0.66; P = 0.0002) and was significantly lower in POAG and AD groups than in the HC group (P < 0.001). Conclusions: AD and POAG are neurodegenerative diseases associated with apoptosis of nerve cells and impairment of microvasculature. Despite the fact that in both diseases there are abnormalities of the entire retinal vascular system, significant microcirculatory impairment in POAG patients affects superficial vessels, whereas in AD patients it affects vessels located in the deeper retinal layers.


Assuntos
Doença de Alzheimer/fisiopatologia , Glaucoma de Ângulo Aberto/fisiopatologia , Vasos Retinianos/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Estudos Transversais , Feminino , Angiofluoresceinografia , Glaucoma de Ângulo Aberto/diagnóstico por imagem , Humanos , Pressão Intraocular , Masculino , Microvasos/fisiopatologia , Pessoa de Meia-Idade , Fibras Nervosas/patologia , Disco Óptico/irrigação sanguínea , Células Ganglionares da Retina/patologia , Vasos Retinianos/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos
19.
Molecules ; 24(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370315

RESUMO

Conflicting values, obtained by different techniques and often under different experimental conditions have been reported on the affinity of Zn2+ for amyloid-ß, that is recognized as the major interaction responsible for Alzheimer's disease. Here, we compare the approaches employed so far, i.e., the evaluation of Kd and the determination of the stability constants to quantitatively express the affinity of Zn2+ for the amyloid-ß peptide, evidencing the pros and cons of the two approaches. We also comment on the different techniques and conditions employed that may lead to divergent data. Through the analysis of the species distribution obtained for two selected examples, we show the implications that the speciation, based on stoichiometric constants rather than on Kd, may have on data interpretation. The paper also demonstrates that the problem is further complicated by the occurrence of multiple equilibria over a relatively narrow pH range.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/química , Fragmentos de Peptídeos/química , Zinco/química , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Humanos , Concentração de Íons de Hidrogênio , Cinética , Fragmentos de Peptídeos/genética , Ligação Proteica/genética
20.
Rev Invest Clin ; 71(4): 246-254, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31448785

RESUMO

Background: Schizophrenia (SCZ) and dementia, often related, are two of the most common neuropsychiatric diseases; epidemiological studies have shown that SCZ patients present a 2-fold increased risk for dementia compared to non-schizophrenic individuals. We explored the presence of rare and novel damaging gene variants in patients diagnosed with late-onset dementia of Alzheimer's type (DAT) or SCZ. Methods: We included 7 DAT and 12 SCZ patients and performed high-depth targeted sequencing of 184 genes. Results: We found novel and rare damaging variants in 18 genes in these Mexican patients. Carriers of these variants showed extreme phenotypes, including, treatment-resistant SCZ or cognitive decline. Furthermore, we found a variation on ABCC1 as a possible link between psychosis and cognitive impairment. Discussion: As an exploratory analysis, we report some interesting variations that should be corroborated in larger sample size studies.


Assuntos
Doença de Alzheimer/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Demência/fisiopatologia , Esquizofrenia/fisiopatologia , Doença de Alzheimer/genética , Disfunção Cognitiva/genética , Demência/genética , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , México , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Fenótipo , Esquizofrenia/genética
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