Precision Monitoring and Assessment in the Framingham Study: Cognitive, MRI, Genetic and Biomarker Precursors of AD & Dementia

自1976年以来，弗雷明翰心脏研究(FHS)一直在监测参与者的痴呆症事件，最初是在 第一代参与者，从1979年开始在第二代队列中，1994年与较小的多种族 OMNI第一代队列。作为第三代和第二代中最年长的一代，进入了 痴呆症风险，我们将监测扩展到这两个较年轻的队列。基线和重复神经心理学 (NP)评估和脑磁共振成像(MRI)扫描自1999年以来一直在 Gen 1、Gen 2和OmniGen 2队列，并自2008年以来与更年轻的队列一起使用。重要的是，超过7个 几十年来，FHS收集了许多与未来老年认知能力下降和 这些队列中的人在早年到中年时患上了痴呆症。补充健康和生活方式数据 是遗传和外周生物标记物数据的可用性。此外，从2005年开始，语音的数字捕获 回答被添加到NP测试中。这在2011年扩展到书面答复，允许量化 口头和书面反应的粒度，可以检测到传统的临床前认知变化 NP考试成绩不能衡量。在此之前，我们已经利用了多代独特性 识别AD风险和AD相关特征的新遗传关联的全基因组方法 在大到20倍的数据集中识别。FHS脑老化计划(FHS-BAP)的主要目标是 为了继续监测痴呆症，扩大认知表型和大脑的纵向特征 结构，为脑捐赠计划带来额外资源，包括神经病理检查，在 FHS队列，以确定新的和扩大已知的AD相关遗传和其他风险因素 生物标志物并对AD的血管和炎症基础进行创新性研究。另一个中央 FHS-BAP的目标是促进与 更广泛的科学界。在新的组织结构下，行政、临床、神经病理和 数据核心将提供正式管理和基础设施，以继续进行事件痴呆症监测 对所有FHS队列中幸存的参与者进行MRI评估，并进行神经病理学检查 通过FHS大脑捐赠计划获得的大脑。FHS-BAP将有三个相互关联的项目 重点关注AD的血管和炎症因素。一个项目将确定以下因素 使用FHS数据的纵向分析与AD风险和复原力相关，这些数据包括遗传的、不同的 遗传、临床、影像、生活方式等特征。第二个项目将调查阿尔茨海默病基因与 脆弱性和慢性外周炎症。第三个项目将确定基因和蛋白质的变化。 补体相关基因和神经胶质细胞表型调节认知轨迹和 神经病理特征。最后，该计划将促进使用FHS-BAP数据，特别是通过早期和 非AD调查人员通过试点项目方案和加强和积极主动的数据共享努力。

Since 1976, the Framingham Heart Study (FHS) has surveilled participants for incident dementia, initially, in the Generation 1 participants, starting 1979 in the Generation 2 cohorts and in 1994 with the smaller multi-ethnic Omni Generation 1 cohort. As the oldest of the Generation 3 and Omni Generation 2 move into the age of dementia risk, we extended surveillance to these two younger cohorts. Baseline and repeat neuropsychological (NP) assessments and brain magnetic resonance imaging (MRI) scans have been conducted since 1999 on the Gen 1, Gen 2 and OmniGen 2 cohorts and since 2008 with the younger cohorts. Importantly, over nearly 7 decades, FHS has collected many co- morbid features linked to future risk of late life cognitive decline and dementia across these cohorts when they were early to middle age. Complementing the health and lifestyle data is the availability of genetic and peripheral biomarker data. Further, beginning in 2005, digital capture of spoken responses was added to NP testing. This was extended to written responses in 2011, allowing quantification of spoken and written responses at levels of granularity that can detect preclinical cognitive changes that traditional NP test scores cannot measure. Previously, we have capitalized on the multi-generation uniqueness using genome-wide approaches to discern novel genetic associations for AD risk and AD-related traits that were not identified in datasets up to 20 times larger. The primary goal of this FHS Brain Aging Program (FHS-BAP) is to continue dementia surveillance, extend longitudinal characterization of cognitive phenotypes and brain structure, bring added resources to the brain donation program including neuropathological examination, in the FHS cohorts in order to identify new and expand on known AD-related genetic and other risk factors and biomarkers and to pursue innovative research about the vascular and inflammatory basis of AD. Another central objective of FHS-BAP is to facilitate more widespread sharing of this extraordinary AD data resource with the broader scientific community. Under a new organizational structure, Administrative, Clinical, Neuropathology and Data cores will provide a formal management and infrastructure to continue incident dementia surveillance, NP and MRI assessments of surviving participants of all FHS cohorts, and perform neuropathological examination of brains obtained through the FHS brain donation program. The FHS-BAP will feature three inter-related projects that have a focus on vascular and inflammatory contributors to AD. One project will identify factors that are associated with AD risk and resilience using longitudinal analyses of FHS data including genetic, various `omic genetic, clinical, imaging, lifestyle and other traits. A second project will investigate the link between AD genetic vulnerabilities and chronic peripheral inflammation. A third project will determine genetic and protein alterations of complement-related genes and glial cell phenotypes that modulate cognitive trajectories and neuropathological profiles. Finally, this program will promote using FHS-BAP data, especially by early-stage and non-AD investigators through a pilot projects program and through enhanced and proactive data sharing efforts.