Biomarkers in Aging, MCI and Alzheimer's Disease

描述（由申请人提供）：该提案侧重于与阿尔茨海默病（AD）相关的脑脊液（CSF）中的生物标志物。与AD病理明显相关的生物标志物，即a - β 42（斑块中的主要蛋白）和tau（在缠结中发现）可以区分AD患者和对照组。轻度认知障碍（MCI）通常是轻度阿尔茨海默病的前驱阶段，与衰老、遗传和其他阿尔茨海默病的危险因素有关，但对这些和其他生物标志物的了解较少。在该提案中，4个AD研究中心将合作从年龄在20-80岁之间的AD、MCI和健康对照中获得CSF和血浆样本。约50%的受试者将在12个月的随访中提供一套系列CSF和血浆样本。该项目建立在现有的脑脊液和血浆库的基础上，旨在收集和储存来自500多名受试者的样本。a - β的加工、生产、沉积和清除是AD的重要因素。这些将通过测量脑脊液中a- β的种类（a- β 38、40和42）和分泌的、裂解形式的β -淀粉样前体蛋白（APP） （a- β的亲本分子）的水平来研究。通过测定脑脊液中tau蛋白和磷酸化tau蛋白的水平来研究神经变性和缠结形成的指标，并从脑脊液中纯化tau蛋白并对其进行测序。作为氧化损伤和炎症的指标，AD中涉及神经元损伤的机制，生物标志物如F-2异前列腺素，S100B和α 1act将被测量。将检查这些生物标志物与年龄、性别、诊断（正常、轻度认知障碍、轻度AD）、认知障碍程度和AD遗传危险因素（载脂蛋白E [ApoE]和CYP46基因型）之间的关系，并分析生物标志物在12个月内的变化程度。储存的脑脊液和血浆将用于新型生物标志物的进一步研究，包括基础广泛的蛋白质组学研究。

DESCRIPTION (provided by applicant): This proposal focuses on biological markers in cerebrospinal fluid (CSF) related to Alzheimer's Disease (AD). Biomarkers that are clearly related to the pathology of AD, namely A-beta42 (the major protein in plaques) and tau (found in tangles) can discriminate patients with AD from controls. Less is known about these and other biomarkers in mild cognitive impairment (MCI), which is often a prodromal stage of mild AD, and in relation to aging and to genetic and other risk factors for AD. In this proposal, 4 AD Research Centers will collaborate to obtain CSF and plasma samples from well-characterized subjects with AD, MCI and healthy controls spanning the age range 20-80. About 50% of subjects will contribute a set of serial CSF and plasma samples at 12 month follow-up. This project builds on an existing collaborative CSF and plasma bank, and aims to accrue and bank samples from over 500 subjects. A-beta processing, production, deposition and clearance are important factors in AD. These will be investigated by measuring levels of species of A-beta (A-beta 38, 40 and 42) and of secreted, cleaved forms of beta-amyloid precursor protein (APP), the parent molecule of A-beta, in CSF. Indices of neurodegeneration and tangle formation will be studied by quantifying CSF levels of tau and phospho-tau, and tau will be purified from CSF and sequenced. As indices of oxidative damage and inflammation, mechanisms implicated in neuronal damage in AD, biomarkers such as F-2 isoprostanes, S100B and alpha1ACT will be measured. The relationship between these biomarkers and age, sex, diagnosis (normal, MCI, mild AD), degree of cognitive impairment, and genetic risk factors for AD (apolipoprotein E [ApoE] and CYP46 genotypes) will be examined, and the extent of change in biomarkers over 12 months will be analyzed. Banked CSF and plasma will be available for further research into novel biomarkers, including broad-based proteomic studies.