Epidemiology of Biomarkers of Risk and Progression in LOAD

描述（由申请人提供）：这个新项目的总体主题是建立和验证与晚发性阿尔茨海默病（LOAD）、轻度认知障碍（MCI）和晚年认知衰退率的风险和进展相关的血液和成像生物标志物。我们还建议建立一个框架，通过这个框架，我们可以了解生物标志物如何相互作用，以及它们如何适应从健康衰老到痴呆的时间序列。该建议是建立在20年多民族，华盛顿高地，汉密尔顿高地，因伍德，哥伦比亚老龄化项目（PO1AG07232）的流行病学研究和系统数据收集的基础上的。在过去的20年里，我们调查了曼哈顿北部这个城市社区的LOAD、MCI和认知能力下降率。我们调查了环境、健康相关和遗传风险因素的疾病和疾病进展的预测因素，通过收集纵向数据的认知表现、情绪健康、日常活动的独立性、血压、人体测量、心血管状态和选择的生物标志物，包括脂质、淀粉样肽、性激素、同型半胱氨酸、胰岛素和c反应蛋白（CRP），以及MRI。我们已经报道过，不同种族的发病率和疾病危险因素的频率各不相同。我们已经确定了一个最大的，多种族的事件LOAD病例群体，促进了疾病进展的研究。数千人的临床和遗传数据以及生物资源都存在。通常选择生物标志物，即在人体组织、细胞或体液中或通过放射手段可测量的细胞、生化或分子变化，因为它们直接或间接地处于疾病的因果途径中。结构和功能脑成像的出现彻底改变了流行病学研究，特别是那些使用阿尔茨海默病生物标志物的研究。使用11C匹兹堡化合物B的正电子发射断层扫描脑成像被认为是脑淀粉样斑块负荷的体内测量，而结构MRI，特别是脑容量和脑血流量（CBF）的变化，可以被认为是神经变性的体内测量。在这个新的建议中，我们将把这项纵向研究集中在两组血液生物标志物上，这两组血液生物标志物不仅显示出与LOAD、MCI和认知能力下降风险的一致和强大的关联，而且还解决了与淀粉样蛋白负担和胰岛素抵抗相关的假定机制。我们将充分利用这一多民族队列的前瞻性设计和收集的临床、生物学和脑成像数据来解决六个主要假设。前两个主要的具体目标认为血液生物标志物不仅是认知能力下降、MCI、LOAD和LOAD进展的预测因子，而且是疾病途径的中间步骤，包括神经变性和脑血管负荷（MRI）和淀粉样斑块负荷（PIB）。在最后一个主要的具体目标中，脑成像变量是预测因素，认知能力下降、MCI、LOAD和LOAD进展是主要结果。

DESCRIPTION (provided by applicant): The overall theme of this new project is to establish and validate blood- and imaging-based biomarkers associated with the risk and progression of late onset Alzheimer's disease (LOAD), mild cognitive impairment (MCI) and the rate of cognitive decline in late life. We also propose to develop a framework with which we can understand how biomarkers interact and how they fit into the temporal sequence from healthy aging to dementia. This proposal is built on two decades of epidemiological research and systematic data collection in the multi-ethnic, Washington Heights, Hamilton Heights, Inwood, Columbia Aging Project (PO1AG07232). Over the past 20 years, we have investigated the rates of LOAD, MCI and cognitive decline in this urban community in northern Manhattan. We have investigated environmental, health-related and genetic risk factors of disease and predictors of disease progression by collecting longitudinal data on cognitive performance, emotional health, independence in daily activities, blood pressure, anthropometric measures, cardiovascular status and selected biomarkers in this elderly, multi-ethnic cohort, including lipids, amyloid peptides, sex hormones, homocysteine, insulin and C-reactive protein (CRP), and MRI. We have reported that the rates of disease and the frequency of disease risk factors vary across ethnic groups. We have identified one of the largest, multi-ethnic groups of incident LOAD cases facilitating studies of disease progression. Clinical and genetic data as well as biological resources are present for several thousand individuals. Biomarkers, cellular, biochemical or molecular alterations measurable in human tissues, cells, or fluids or by radiological means, are typically chosen because they are directly or indirectly in the causal pathway of disease. The emergence of structural and functional brain imaging has revolutionized epidemiological studies, particularly those using biomarkers for Alzheimer's disease. Positron emission tomography brain imaging using 11C Pittsburgh compound B is considered an in vivo measure of brain amyloid plaque load, while structural MRI, especially changes in brain volume and cerebral blood flow (CBF), can be considered an in vivo measures of neurodegeneration. In this new proposal, we will focus this longitudinal investigation on two sets of blood biomarkers that not only show consistent and robust associations to the risk of LOAD, MCI and cognitive decline, but that address the putative mechanisms related to amyloid burden and insulin resistance. We will take full advantage of the prospective design in this multi-ethnic cohort and the clinical, biological and brain imaging data collected to address six major hypotheses. The first two primary specific aims consider blood biomarkers as not only predictors of cognitive decline, MCI, LOAD and LOAD progression, but also as intermediate steps in the disease pathway, including neurodegeneration and cerebrovascular burden (MRI) and amyloid plaque load (PIB). In the last primary specific aim, brain imaging variables are predictors and cognitive decline, MCI, LOAD as well as LOAD progression are main outcomes.