Biomarkers in Aging, MCI and Alzheimer's Disease

描述(申请人提供)：本提案重点介绍与阿尔茨海默病(AD)相关的脑脊液(CSF)中的生物标记物。与AD的病理明显相关的生物标志物，即A-β42(斑块中的主要蛋白质)和tau(在斑块中发现)可以区分AD患者和对照组。这些和其他生物标志物在轻度认知障碍(MCI)中的了解较少，MCI通常是轻度AD的前驱阶段，与衰老、遗传和AD的其他危险因素有关。在这项提案中，4个AD研究中心将合作，从20-80岁年龄段的AD、MCI和健康对照组的特征良好的受试者那里获取脑脊液和血浆样本。约50%的受试者将在12个月的随访中提供一套连续的脑脊液和血浆样本。该项目建立在现有的协作脑脊液和血浆库的基础上，目标是收集和储存来自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。这将通过测量脑脊液中A-β(A-β38、40和42)的种类以及A-β的母体分子--β-淀粉样前体蛋白(APP)的分泌、裂解形式的水平来进行研究。神经退行性变和缠结形成的指标将通过量化脑脊液中tau和磷酸化tau的水平来研究，并将从脑脊液中提纯tau并进行测序。作为氧化损伤和炎症的指标，涉及AD神经元损伤的机制，生物标记物如F-2异前列腺素、S100B和α1ACT将被检测。研究这些生物标记物与年龄、性别、诊断(正常、MCI、轻度AD)、认知损害程度以及AD的遗传危险因素(载脂蛋白E[ApoE]和细胞色素P46型)之间的关系，并分析12个月后生物标记物的变化程度。储存的脑脊液和血浆将可用于新生物标记物的进一步研究，包括基础广泛的蛋白质组研究。

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.