Biomarker Core

项目总结(APOE U19 Core D：BioMarker Core) 生物标记物核心(核心D)的总体目标是进行和支持生物标记物评估 阿尔茨海默病(AD)和与年龄相关的认知能力下降的液体生物标本，包括血浆和 在U19计划的项目和核心中使用脑脊液(CSF)，并特别关注APOE。vt.给出 我们发现，载脂蛋白E基因(ε2、ε3和ε4)会影响老年人的认知能力 假设载脂蛋白E(ApoE)的生化性质(量、脂化、聚集和 翻译后修饰)及其基因类型影响已建立和正在出现的生物流体标记 AD的级别。我们将在2-3个时间跨度内进行基于载脂蛋白E基因的纵向生物标记物研究 老年人(≥，65岁)临床痴呆评定量表的变化 在梅奥诊所和位于圣彼得堡的华盛顿大学医学院的两次既定队列访问之间。 路易。我们将利用美国国立卫生研究院支持的生物标本库中的大量样本 项目包括梅奥老年临床研究(MCSA)和阿尔茨海默病研究中心(ADRC) 在两所学校都有。在目标1中，我们将从队列中组织可用的数据集和流体生物样品。如果 ，我们还将把生物显微镜与死后脑样本/神经病理信息结合起来。 通过神经病理核心(Core C)和外周血单核细胞产生诱导 通过项目5和人类IPSC模型CORE(CORE E)获得多能干细胞。在目标2中，我们计划 建立临床痴呆进展的载脂蛋白E相关流体生物标志物。我们的目标是开发apoE目标 通过评估数量和潜在的翻译后能力来评估与年龄相关的认知障碍和AD的生物标记物 血浆和脑脊液样品中载脂蛋白E的LC-MS/MS修饰脂化状态和 载脂蛋白E颗粒的结构特性也将通过项目1和生物化学和结构 造型核心(核心B)。在目标3中，我们的目标是发现临床痴呆进展的潜在液体生物标记物。 使用‘Omics方法通过多Omics核心(Core F)。在目标4中，我们将产生一个流体生物标记物 通过测量新出现的AD相关指标阐明APOE对临床痴呆进展的影响 突触损伤和神经胶质激活的生物标志物，以及炎症/血管生物标志物。在Aim 5中，我们 将支持流体生物标记物测量，包括apoE测量和AD相关流体生物标记物 应要求对项目2-4中的鼠标模型和项目5中的IPSC模型进行评估。总而言之，这 全面和创新的Biomarker Core将允许进行基于系统的多学科综合研究 通过关注疾病中的载脂蛋白E亚型，AD和年龄相关的认知能力下降的级联反应。监控方式 在表型良好的队列中，生物标记物在无症状和早期症状阶段随时间变化 使我们能够定义患者当前的疾病阶段，并更准确地预测临床进展 举止。

PROJECT SUMMARY (APOE U19 Core D: Biomarker Core) The overall goal of the Biomarker Core (Core D) is to conduct and support the biomarker assessments for Alzheimer’s disease (AD) and age-related cognitive decline in fluid biospecimens including plasma and cerebrospinal fluid (CSF) among Projects and Cores in the U19 program with a specific focus on APOE. Given that APOE genotype (ε2, ε3 and ε4) has been shown to impact cognitive performances in the elderly, we hypothesize that apolipoprotein E (apoE) biochemical property (amount, lipidation, aggregation and post-translational modification) as well as its genotypes influence established and emerging biofluid-marker levels for AD. We will perform longitudinal biomarker studies based on APOE genotype over a time span of 2-3 years in elderly (≥65 years old) individuals by focusing on the change of Clinical Dementia Rating (CDR) between two visits in established cohorts from Mayo Clinic and Washington University School of Medicine in St. Louis. We will take advantage of the large sample numbers of biospecimens banked in the NIH-supported programs including Mayo Clinic Study of Aging (MCSA) and the Alzheimer's Disease Research Centers (ADRC) at both institutions. In Aim 1, we will organize the available dataset and fluid biospecimens from the cohorts. If available, we will also integrate the biospecimens with postmortem brain samples/neuropathological information through the Neuropathological Core (Core C) and peripheral blood mononuclear cells to generate induce pluripotent stem cells through Project 5 and the Human iPSC Models Core (Core E). In Aim 2, we plan to establish apoE-related fluid biomarkers for clinical dementia progression. We aim to develop apoE-targeted biomarkers for age-related cognitive decline and AD by assessing amounts and potential post-translational modification of apoE through LC-MS/MS approaches in plasma and CSF samples. Lipidation status and structural properties of apoE particles will also be explored through Project 1 and the Biochemistry and Structural Modeling Core (Core B). In Aim 3, we aim to uncover potential fluid biomarkers for clinical dementia progression using an ‘Omics approach through the Multi-Omics Core (Core F). In Aim 4, we will generate a fluid biomarker dataset to elucidate the effects of APOE on clinical dementia progression by measuring emerging AD-related biomarkers for synaptic damage and glial activation, as well as inflammation/vascular biomarkers. In Aim 5, we will support fluid biomarker measurements including apoE measurements and AD-related fluid biomarker assessments in mouse models from Projects 2-4 and iPSC models from Project 5 upon requests. Together, this comprehensive and innovative Biomarker Core will allow for integrated, systems-based, multidisciplinary studies by focusing on apoE isoforms in the disease cascade for AD and age-related cognitive decline. Monitoring how biomarkers change over time in asymptomatic and early symptomatic stages in well-phenotyped cohorts might allow us to define the current disease phases of patients and predict clinical progression in a more precise manner.