MRI, Cognitive, Genetic & Biomarker Precursors of AD & Dementia in Young Adults

描述（由主要研究者提供）：人们越来越认识到，尽管许多神经系统疾病的临床表现发生在几十年后，但个体对疾病的易感性在生命早期就已确定。在Fracture Heart研究中，我们已经确定了与原始Gen 1老年队列中AD后续发展相关的遗传、心血管风险因素和生物标志物数据，这些数据也与后代Gen 2中年队列中的结构和认知内表型（可遗传中间表型）相关。在拟议的MRI中，年轻人中AD和痴呆症的遗传，认知和生物标志物前体授予我们假设，我们在年轻的Gen 2参与者中观察到的结构和认知连续体 代表着一个连续体的延长，这个连续体甚至在生命的早期就开始了，并将扩展到这个更年轻的第三代群体。Gen 3代表了一组特征丰富的成年人，其中有密集的基因分型、全面的生物标志物和丰富的血管风险因子、记录的AD和痴呆等疾病的家族发生率以及亚临床动脉粥样硬化数据。 我们的主要目标是在第三代队列中描述MRI上的脑形态和认知功能， 先前特别鉴定的AD和痴呆的内表型（例如全脑和局部脑 体积、白色物质病变、海马和内嗅皮质的区域定量测量以及记忆和执行功能。）我们预测，在这个年轻的第三代队列中，有一个可识别的连续的结构和认知指标与痴呆和大脑老化有关。我们还将先前测量的血管、代谢、炎症、AD/痴呆的家族发生率和这些受试者已有的其他风险因素数据与结构和功能性AD/痴呆内表型的范围相关。我们认为，先前在较老的第二代队列中确定的一部分风险因素将在第三代中显示出类似的关联。此外，我们预计将发现与该年轻队列特有的AD/痴呆内表型相关的其他风险因素。最后，我们将利用目前在所有三代Frachial cohort中可用的广泛遗传资源来揭示年龄特异性遗传效应，基因环境相互作用和新的遗传关系。 该申请代表了一种资源有效的机制，可以利用在该年轻成人社区人群中收集的大量遗传、风险因素和生物标志物数据，极大地丰富我们对临床前AD和疾病病理生理学的理解。公共卫生相关性拟议项目的主要目标，MRI，认知，遗传和生物标志物前体的AD和痴呆症的年轻人是确定最早的指标的倾向发展AD和痴呆症在以后的生活。为了实现这一目标，我们寻求在Frachial Heart研究的第三代队列中建立与AD/痴呆相关的脑形态和认知功能的基线测量。我们将把这些数据与先前测量的风险因素联系起来， 在这些受试者中已经可用的生物标志物来确定AD和痴呆的结构和功能指数的“前MCI”连续体。

DESCRIPTION (provided by principal investigator): It is increasingly recognized that although clinical manifestations of many neurological disorders occur in later decades, an individual's susceptibility to disease is determined early in life. In the Framingham Heart Study, we have identified genetic, cardiovascular risk factor and biomarker data related to the subsequent development of AD in our Original Gen1, elderly cohort that are also associated with structural and cognitive endophenotypes (heritable intermediate phenotypes) in our Offspring Gen2, middle aged cohort. In the proposed MRI, Genetic, Cognitive & Biomarker Precursors of AD & Dementia in Young Adults grant we hypothesize that the structural and cognitive continuum we have observed in our younger Gen2 participants represents the lengthening of a continuum that begins even earlier in life and will be extended to this still younger Gen3 cohort. Gen 3 represents a richly characterized group of young-adults in whom dense genotyping, comprehensive biomarker and abundant vascular risk factor, documented family occurrence of disease such as AD and dementia, and subclinical atherosclerosis data are available. Our primary goal is to characterize brain morphology on MRI and cognitive function in the Gen3 cohort, specifically previously identified endophenotypes of AD and dementia (such as total and regional brain volumes, white matter lesions, and regional quantitative measures of the hippocampal and entorhinal cortex as well as memory and executive function.) We predict within this younger Gen3 cohort there is an identifiable continuum of structural and cognitive indices linked to dementia and brain aging. We will also relate previously measured vascular, metabolic, inflammatory, family occurrence of AD/dementia and other risk factor data already available on these subjects to the range of structural and functional AD/dementia endophenotypes. We posit that a subset of the risk factors previously identified in the older Gen2 cohort will show similar associations in Gen 3. Further we anticipate uncovering additional risk factors related to AD/dementia endophenotypes unique to this younger cohort. Finally, we will utilize the extensive genetic resources currently available in all three generations of the Framingham cohorts to uncover age-specific genetic effects, gene environment interactions and novel genetic relationships. This application represents a resource-effective mechanism to leverage the wealth of genetic, risk factor and biomarker data collected in this younger adult community-based population to greatly enrich our understanding of preclinical AD and pathophysiology of disease. PUBLIC HEALTH RELEVANCE The primary objective of the proposed project, MRI, Cognitive, Genetic & Biomarker Precursors of AD & Dementia in Young Adults is to identify the earliest indicators of a propensity to develop AD and dementia in later life. To accomplish this goal we seek to establish, within the Framingham Heart Study's third generation cohort, baseline measures of brain morphology and cognitive function that have been linked to AD/dementia. We will relate these data to previously measured risk factors and biomarkers already available on these subjects to determine a "pre-MCI" continuum of structural and functional indices of AD and dementia.