Leveraging Existing Aging Research Networks to investigate TBI and AD/ADRD risk (LEARN TBI & AD)

项目摘要/摘要 这份R01提案《利用现有的老龄化研究网络调查创伤性脑损伤(TBI)》 和阿尔茨海默病(AD)和AD相关痴呆(ADRD)风险(了解TBI和AD)，是对 PAR 17-088，要求对现有数据资源进行二次分析，以解决临床老化研究 问题。在这个跨学科的项目中，我们将使用现有的和新收集的来自5个最大的 美国国立卫生研究院资助的老龄化研究(成人思维变化研究、宗教秩序研究、记忆与衰老 项目，少数民族老龄化研究，和弗雷明翰心脏研究)，以检查脑外伤和 AD/ADRD的重复头部撞击(RHI)。头部创伤与脑损伤关系的数十年研究 和痴呆症仍然没有定论；研究报告了相互矛盾的发现，但方法和 测量排除了直接比较。个别研究受到样本量和不足的限制。 人口多样性，因此AD/ADRD风险的效应修正和亚组差异的复杂模型 都是不可能的。在这项提案中，我们将使用来自5项研究的19,700人的数据，最多 24年的纵向临床数据和尸检终点，以明确表征 社区中的TBI/RHI和AD/ADRD。我们将使用先进的心理测量方法来协调关键 队列中的变量，并对所有5个患者的个体数据进行综合或协调分析 学习。在目标1中，我们将测试脑外伤与临床诊断的痴呆症的关联，包括AD和其他 常见的神经退行性疾病，如路易体痴呆和帕金森氏病 (Pd)。我们还将评估常见的AD/ADRD内表型，包括认知、日常生活能力 (ADLS)、情绪和运动功能，以及慢性病共病。在目标2中，我们将使用神经病理学 来自所有5个尸检队列的数据，以测试脑外伤与病理证实的AD、LBD、PD和 其他ADRD。我们还将考虑半定量和定量的病理终点 与痴呆症相关的神经病理包括神经原纤维缠结、弥漫性和 神经炎斑块，路易小体，TDP-43和血管病理。在目标1和目标2中，我们都将确定 与大脑功能和疾病相关的遗传风险基因是否会改变这些关联。在目标3中，我们 将确定慢性创伤性脑病(CTE)神经病理的频率，由 社区中的共识得出的诊断标准。到目前为止，对CTE的研究仅限于高度 选定的运动员队列，对CTE病理的存在或其与 以社区为基础的AD/ADRD临床结果。拟议中的项目将显著地 促进对TBI/RHI和AD/ADRD之间复杂关联的科学理解。通过利用数据 从具有大量表型数据的多个不同的队列研究中，这项研究的结果将为策略提供参考 用于AD/ADRD的预防、干预开发和发病率降低。

Project Summary/Abstract This R01 proposal, “Leveraging Existing Aging Research Networks to investigate Traumatic Brain Injury (TBI) and Alzheimer’s Disease (AD) and AD related dementia (ADRD) risk” (LEARN TBI & AD), is in response to PAR 17-088 which requests secondary analyses of existing data resources to address clinical aging research questions. In this interdisciplinary project, we will use existing and newly collected data from 5 of the largest NIH-funded studies of aging (Adult Change in Thought Study, Religious Orders Study, Memory and Aging Project, Minority Aging Research Study, and Framingham Heart Study), to examine the association of TBI and repetitive head impacts (RHI) with AD/ADRD. Decades of research on the relationship between head trauma and dementia remain inconclusive; studies have reported contradictory findings but differences in methods and measurements preclude direct comparisons. Individual studies are limited by sample size and insufficient demographic diversity, so complex models of effect modification and subgroup differences in AD/ADRD risk have not been possible. In this proposal, we will use data from >19,700 individuals across 5 studies with up to 24 years of longitudinal clinical data and autopsy endpoints to definitively characterize the associations of TBI/RHI and AD/ADRD in the community. We will use advanced psychometric methods to harmonize key variables across cohorts and conduct integrative or coordinated analyses of individual patient data from all 5 studies. In Aim 1, we will test the association of TBI with clinically diagnosed dementia, including AD and other common neurodegenerative conditions such as dementia with Lewy bodies (DLB) and Parkinson’s disease (PD). We also will evaluate common AD/ADRD endophenotypes including cognition, activities of daily living (ADLs), mood and motor function, and chronic disease comorbidity. In Aim 2, we will use neuropathological data from all 5 autopsy cohorts to test the association of TBI with pathologically confirmed AD, LBD, PD, and other ADRDs. We will also consider semi-quantitative and quantitative pathological endpoints that have been implicated as dementia-related neuropathology including measures of neurofibrillary tangles, diffuse and neuritic plaques, Lewy bodies, TDP-43 and vascular pathology. In both Aims 1 and 2, we will determine whether genetic risk loci associated with brain function and disease modify these associations. In Aim 3, we will determine the frequency of chronic traumatic encephalopathy (CTE) neuropathology, defined by consensus-derived diagnostic criteria, in the community. To date, research on CTE has been limited to highly selected cohorts of athletes, and little is known about the presence of CTE pathology or its relevance to AD/ADRD clinical outcomes in community-based settings. The proposed project stands to significantly advance scientific understanding of the complex associations of TBI/RHI and AD/ADRD. By leveraging data from multiple diverse cohort studies with extensive phenotypic data, results of this study will inform strategies for prevention, intervention development, and morbidity abatement for AD/ADRD.