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

描述(由首席研究人员提供)：越来越多的人认识到，尽管许多神经疾病的临床表现发生在几十年后，但个人对疾病的易感性是在生命的早期确定的。在Framingham心脏研究中，我们已经在我们最初的Gen1老年队列中确定了与AD后续发展相关的遗传、心血管风险因素和生物标记物数据，这些数据也与我们的后代Gen2中年队列中的结构和认知内表型(可遗传的中间表型)相关。在拟议的磁共振成像中，青年AD和痴呆的遗传、认知和生物标记物前体允许我们假设，我们在年轻的第二代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更早的时候就开始了，并将延伸到更年轻的第三代人群。Gen 3代表了一个特征丰富的年轻人群体，在他们中，密集的基因分型，全面的生物标志物和丰富的血管危险因素，有记录的家族性疾病发生，如AD和痴呆，以及亚临床动脉粥样硬化数据。 我们的主要目标是在MRI上表征第三代队列中的大脑形态和认知功能， 先前明确的阿尔茨海默病和痴呆的内表型(如全脑和局部脑 体积、白质损伤、海马区和内嗅区皮质的局部定量测量，以及记忆和执行功能。)我们预测，在这个更年轻的第三代队列中，会有一系列可识别的结构和认知指标与痴呆症和大脑老化有关。我们还将把先前测量的血管、代谢、炎症、阿尔茨海默病/痴呆症的家族发病情况以及这些受试者已有的其他危险因素数据与结构和功能性阿尔茨海默病/痴呆症内表型的范围联系起来。我们假设，先前在较老的第二代队列中发现的风险因素的子集将在第三代中显示出类似的相关性。此外，我们预计会发现与这一较年轻队列特有的AD/痴呆内表型相关的更多风险因素。最后，我们将利用目前在所有三代Framingham队列中可用的广泛遗传资源来揭示特定年龄的遗传效应、基因环境相互作用和新的遗传关系。 这项应用代表了一种资源有效的机制，可以利用在这个以社区为基础的年轻成年人群体中收集的丰富的遗传、风险因素和生物标记物数据，极大地丰富我们对临床前AD和疾病病理生理学的理解。与公众健康相关这项名为“青少年阿尔茨海默病和痴呆症的核磁共振成像、认知、遗传和生物标志物前体”项目的主要目标是确定在晚年发展为阿尔茨海默病和痴呆症倾向的最早指标。为了实现这一目标，我们试图在弗雷明翰心脏研究的第三代队列中，建立与AD/痴呆症有关的大脑形态和认知功能的基线测量。我们将把这些数据与以前测量的风险因素和 这些受试者已经可以用生物标记物来确定AD和痴呆症的结构和功能指标的“MCI前”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.