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基于血液和成像的生物标记物，这些生物标记物与晚发性阿尔茨海默病(LOAD)、轻度认知障碍(MCI)和晚年认知衰退的风险和进展相关。我们还建议开发一个框架，用来了解生物标记物如何相互作用，以及它们如何适应从健康老龄化到痴呆症的时间序列。这项建议建立在多种族、华盛顿高地、汉密尔顿高地、因伍德、哥伦比亚老龄化项目(PO1AG07232)20年来的流行病学研究和系统数据收集的基础上。在过去的20年里，我们调查了曼哈顿北部这个城市社区的负荷、MCI和认知衰退的比率。我们通过收集认知表现、情绪健康、日常活动独立性、血压、人体测量、心血管状况和选定的生物标记物(包括血脂、淀粉样肽、性激素、同型半胱氨酸、胰岛素和C反应蛋白)以及磁共振成像等纵向数据，研究了疾病的环境、健康和遗传风险因素以及疾病进展的预测因素。我们已经报告，各族裔群体的发病率和疾病风险因素的频率各不相同。我们已经确定了最大的、多种族的事件负荷病例组之一，促进了对疾病进展的研究。目前有数千人的临床和遗传数据以及生物资源。生物标志物，即可在人体组织、细胞或体液中或通过放射手段测量的细胞、生化或分子变化，通常被选为生物标记物，因为它们直接或间接地处于疾病的起因途径中。结构和功能脑成像的出现使流行病学研究发生了革命性的变化，特别是那些使用阿尔茨海默病生物标记物的研究。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活体测量，而结构MRI，特别是脑体积和脑血流量的变化，可以被认为是神经退化的活体测量。在这个新的提案中，我们将把这项纵向研究的重点放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负荷、MCI和认知功能下降的风险一致和强有力的关联，而且还涉及与淀粉样蛋白负荷和胰岛素抵抗相关的可能机制。我们将充分利用这一多种族队列中的前瞻性设计以及收集的临床、生物和脑成像数据来解决六个主要假设。前两个主要的特异性目标认为血液生物标志物不仅是认知能力下降、MCI、负荷和负荷进展的预测因子，而且是疾病途径的中间步骤，包括神经退行性变和脑血管负荷(MRI)和淀粉样斑块负荷(PIB)。在最后一个主要的特定目标中，脑成像变量是预测因素，认知衰退、MCI、负荷以及负荷进展是主要结果。 公共卫生相关性：人们普遍同意，开发生物标记物来衡量认知能力下降、负荷和相关疾病的风险以及疾病进展速度，将极大地促进临床、流行病学和药理学研究。此外，开发可通过血液样本或脑成像等标准和可接受的医疗程序轻松获得的生物标记物，将有助于在一般社区中开发延缓或预防疾病的方法。因此，在多种族社区开发可靠和有效的生物标记物对公共健康的潜在影响是这项拟议调查的主要好处。

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. PUBLIC HEALTH RELEVANCE: There is general agreement that developing biomarkers that measure the risk of cognitive decline, LOAD and related diseases as well as the rate of disease progression would greatly enhance clinical, epidemiological, and pharmacological research. Furthermore developing biomarkers that can be easily obtained using standard and acceptable medical procedures such as blood samples or brain imaging would facilitate their use in developing methods to delay or prevent disease in the general community. Therefore the potential public health impact of developing reliable and valid biomarkers in a multi-ethnic community is a major benefit of this proposed investigation.