Mild Cognitive Impairment: a Prospective Community Study

 描述(由申请人提供)：这项竞争性续签申请旨在将Monongahela-Youghiogheny Healthy Aging Team(MYHAT)项目再延长5年，这是一项为期10年的纵向研究，对宾夕法尼亚州匹兹堡附近一个经济不景气的小城镇地区的代表性人群进行研究。到目前为止，MYHAT一直专注于MCI的特征和确定从MCI发展到偶发痴呆的风险因素，并确定了风险关系中相当大的异质性。根据迄今的调查结果，我们的 新的目标是：(1)确定90岁以上人群痴呆症的风险/保护因素，这些人的发病率继续上升，但几乎没有发现危险因素；(2)在整个队列中确定痴呆症的血管/炎症/代谢风险因素，特别是与糖尿病相关的因素；(3)检查出生队列对痴呆症和认知能力下降发生率的影响，并确定它们是否可以用风险和保护因素的长期趋势来解释；(4)利用现有的全基因组基因数据确定与认知能力下降相关的基因表型，然后在复制样本中进行证实。作为一个独立项目的一部分，我们还提出了一个探索性目标，将淀粉样蛋白和tau PET神经成像扩展到120名MYHAT参与者的子组中，而这项研究是免费的。这里的科学目标是确定与大脑淀粉样蛋白和tau沉积相关的因素和 确定这些变量是否预测整个MYHAT队列中的痴呆症。最初的MYHAT队列(N~2,000)在研究开始时年龄超过65岁，现在已经超过75岁，拥有10年的丰富纵向数据，这对于实现我们的目标是理想的。在过去的9年里，大约有一半的人死于自然减员，包括疾病和死亡。我们将通过招募700名年龄在65-74岁之间的新参与者来补充队列，他们能够贡献最长的人-年跟踪，并将增强我们调查队列效应的能力。我们的总体主题是调查总体人群中MCI和痴呆症的异质性，解构结果以及预测变量，以确定更细粒度的关系，从而揭示潜在的疾病机制。这一方法与转化流行病学的目标是一致的，超越了简单的描述，以确定具有临床和公共卫生意义的风险和保护因素，以及这些因素所在的亚组；产生和测试机械性假设；以及确定对政策和规划有影响的人口趋势。

 DESCRIPTION (provided by applicant): This competing renewal application seeks to extend, for a further 5 years, the Monongahela-Youghiogheny Healthy Aging Team (MYHAT) project, a 10-year longitudinal study of a representative population-based cohort in an economically depressed small-town region near Pittsburgh, PA. MYHAT has thus far focused on characterizing MCI and identifying risk factors for progression from MCI to incident dementia, and identified considerable heterogeneity in risk relationships. Building on findings to date, our new aims are: (1) To identify risk /protective factors for dementia in those aged 90+ years, in whom incidence continues to rise but few risk factors have been found; (2) To identify vascular / inflammatory/ metabolic risk factors, particularly diabetes-related factors, for dementia in the cohort as a whole ; (3) To examine birth cohort effects in the incidence of dementia and cognitive decline, and determine whether they can be explained by secular trends in risk and protective factors; (4) To identify genes associated with cognitive decline endophenotypes using existing genome-wide genotype data and then confirming in a replication sample. We also propose an exploratory aim to extend amyloid and tau PET neuroimaging into a subgroup of 120 MYHAT participants, at no cost to this study, as part of an independent project. Here the scientific objective is to identify factors associated with cerebral amyloid and tau deposition and determine whether those variables predict dementia in the MYHAT cohort as a whole. The original MYHAT cohort (N~2,000) aged 65+ years at study entry is now aged 75+ and has 10 years of rich longitudinal data that are ideal for achieving our aims. About half the cohort has been lost to attrition, including illness and mortality, over the past 9 years. We will replenish te cohort by recruiting 700 new participants aged 65-74 who are able to contribute the maximum person-years of followup, and will also enhance our ability to investigate cohort effects. Our over-arching theme is to investigate the heterogeneity of MCI and dementia in the population at large, deconstructing the outcomes as well as the predictor variables to identify finer-grained relationships which will shed light on underlying disease mechanisms. This approach is consistent with the goals of translational epidemiology, going beyond simple description to identify risk and protective factors with clinical and public health significance, and the subgroup in which these factors operate; generate and test mechanistic hypotheses; and identify population trends with implications for policy and planning.