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病理学明显相关的生物标志物，即A-β 42（斑块中的主要蛋白质）和tau（在缠结中发现）可以区分AD患者和对照组。对轻度认知障碍（MCI）中的这些和其他生物标志物知之甚少，MCI通常是轻度AD的前驱阶段，与衰老以及AD的遗传和其他风险因素有关。在该提案中，4个AD研究中心将合作从年龄范围为20-80岁的AD、MCI和健康对照受试者中获得CSF和血浆样本。约50%的受试者将在12个月随访时提供一组连续CSF和血浆样本。该项目建立在现有的协作CSF和血浆库的基础上，旨在从500多名受试者中采集和储存样本。A-β的加工、产生、沉积和清除是AD的重要因素。将通过测量CSF中A-β（A-β 38、40和42）的种类和β-淀粉样前体蛋白（APP）（A-β的母体分子）的分泌、切割形式的水平来研究这些。将通过定量tau和磷酸化tau的CSF水平来研究神经变性和缠结形成的指标，并将从CSF中纯化tau并测序。作为氧化损伤和炎症的指标，将测量AD中神经元损伤所涉及的机制、生物标志物如F-2异前列腺素、S100 B和alpha 1ACT。将检查这些生物标志物与年龄、性别、诊断（正常、MCI、轻度AD）、认知障碍程度和AD遗传风险因素（载脂蛋白E [ApoE]和CYP 46基因型）之间的关系，并分析12个月内生物标志物的变化程度。储存的CSF和血浆将可用于进一步研究新的生物标志物，包括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.