Contributions of Exposure to Traumatic Brain Injury and Repetitive Head Impacts to Alzheimer's Disease and Related Dementias and Chronic Traumatic Encephalopathy

远程中重度创伤性脑损伤(CTBI)长期以来被视为阿尔茨海默病的危险因素 疾病(AD)和AD相关痴呆(ADRD)。然而，尸检证据现在表明，脑外伤的病理包括 各种神经退行性疾病蛋白和其他病理(如白质)的聚集 退化)。这些关系和启动的病理可能取决于严重程度和数量 太棒了。越来越多的研究将接触运动和服兵役导致的重复性头部撞击(RHI)与AD联系起来， ADRD和神经退行性疾病、慢性创伤性脑病(CTE)。RHI已与 与其他病理因素有关，如白质变性和神经炎症。虽然未知，但它是 认为RHI通过反复脑震荡和无症状导致AD、ADRD、CTE和其他病理改变 亚脑震荡。证据还表明，单次cTBI足以使AD、ADRD和CTE沉淀。这个 各种脑损伤暴露的病理基础尚不清楚，所需的脑损伤的严重性和数量也尚不清楚。 AD、ADRD、CTE和其他病理疾病的风险尚不清楚。慢性骨质疏松症的发病机制研究 RHI的局限性在于缺乏对TBI角色的考虑，专注于男性足球运动员，缺乏“控制”， 招募偏见，以及未能考虑到遗传和非遗传风险因素。该项目将解决这些问题 限制并检查RHI和TBI(所有严重程度)与AD、ADRD、CTE和其他疾病的关联 病理学，以及研究这些效应的遗传和非遗传修饰因素。我们将研究RHI如何 与脑外伤相互作用，导致AD、ADRD、CTE等多种病理改变。最重要的假设是RHI 而脑损伤将具有明显的病理关联，这些关联将被遗传和非遗传风险因素改变。 我们将利用我们正在进行的NIH资助的联合研究的基础设施。我们将协调6个智囊团 波士顿大学，以及西奈山AD研究中心和脑损伤脑库的晚期效应。结果 将包括AD、ADRD和CTE状态，以及神经退行性蛋白的半定量测量 以及其他病理性疾病。我们将增加跨脑库的协调方法来评估RHI和TBI 并检查1500名脑捐赠者：1000名暴露于RHI/TBI的人，包括各种接触性运动运动员、军人 退伍军人和患有远程脑损伤(轻度-重度)的捐赠者；以及500名人口统计相似的非RHI/脑损伤脑捐赠者。 我们将收集新脑捐赠者的RHI和TBI数据，评估来自两个大脑的400名脑捐赠者的RHI和TBI 未评估RHI和TBI的银行(BU和西奈山AD中心)，并利用现有的RHI 和来自脑库的脑损伤数据。选拔偏见将通过纳入不招聘的智库来解决 基于RHI/TBI、逆概率加权和仿真模型。这个项目将导致世界上最大的 脑捐赠者具有协调的、特征良好的RHI和脑外伤病史。它将包括接触性运动运动员 在不同的运动和比赛水平上，退伍军人和患有远程脑外伤(轻度-重度)的脑部捐赠者。 研究结果将提供有关AD、ADRD、CTE和其他由RHI和TBI引起的慢性病理的具体风险。

Remote moderate-severe traumatic brain injury (cTBI) has long been viewed as a risk factor for Alzheimer's disease (AD) and AD related dementias (ADRD). Yet, autopsy evidence now shows that TBI pathologies include an aggregation of various neurodegenerative disease proteins and other pathologies (e.g. white matter degeneration). These relationships and the pathologies initiated might depend on the severity and number of TBIs. Growing research links repetitive head impacts (RHI) from contact sports and military service with AD, ADRD and the neurodegenerative disease, chronic traumatic encephalopathy (CTE). RHI has been associated with other pathologies, such as white matter degeneration and neuroinflammation. Although unknown, it is thought that RHI leads to AD, ADRD, CTE, and other pathologies via recurrent concussions and asymptomatic subconcussions. Evidence also suggests that a single cTBI is sufficient to precipitate AD, ADRD and CTE. The pathological substrates of the various TBI exposures remain unclear and the severity and number of TBIs needed to confer risk for AD, ADRD, CTE, and other pathologies is unknown. Research on the chronic pathologies of RHI is limited by lack of consideration for the role of TBI, focus on male football players, lack of “controls,” recruitment bias, and failure to account for genetic and non-genetic risk factors. This project will address these limitations and examine the association of RHI and TBI (of all severities) with AD, ADRD, CTE, and other pathologies, as well as investigate genetic and non-genetic modifiers of these effects. We will examine how RHI and TBI interact to lead to AD, ADRD, CTE, and other pathologies. The overarching hypotheses are that RHI and TBI will have distinct pathological associations that will be modified by genetic and non-genetic risk factors. We will leverage the infrastructure of our ongoing NIH-funded UNITE study. We will harmonize 6 brain banks at Boston University, and the AD Research Center and Late Effects of TBI brain banks at Mount Sinai. Outcomes will include AD, ADRD, and CTE status, and semi- and quantitative measures of neurodegenerative proteins and other pathologies. We will add harmonized methods across brain banks for the assessment of RHI and TBI and examine 1500 brain donors: 1000 exposed to RHI/TBI, including various contact sport athletes, military veterans, and donors with remote TBI (mild-severe); and 500 demographically-similar non-RHI/TBI brain donors. We will collect RHI and TBI data on new brain donors, assess RHI and TBI for 400 brain donors from two brain banks (BU and Mount Sinai AD Centers) where RHI and TBI have been unassessed, and leverage existing RHI and TBI data from brain banks. Selection bias will be addressed by including brain banks that do not recruit based on RHI/TBI, inverse probability weighting, and simulation models. This project will result in the largest brain donor cohort with harmonized, well-characterized RHI and TBI histories. It will include contact sport athletes across different sports and levels of play, military veterans, and brain donors with remote TBIs (mild-severe). Findings will inform on the specific risks for AD, ADRD, CTE, and other chronic pathologies from RHI and TBI.