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）长期以来一直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 TBI 病理包括 各种神经退行性疾病蛋白质和其他病理的聚集（例如白质 退化）。这些关系和引发的病理可能取决于严重程度和数量 创伤性脑损伤。越来越多的研究将接触性运动和兵役造成的重复性头部撞击 (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已关联 与其他病理，如白质变性和神经炎症。虽然不为人知，但确实 认为 RHI 通过反复脑震荡和无症状导致 AD、ADRD、CTE 和其他病症 亚脑震荡。证据还表明，一次 cTBI 足以引发 AD、ADRD 和 CTE。的 各种 TBI 暴露的病理基础仍不清楚，以及所需 TBI 的严重程度和数量 是否会带来 AD、ADRD、CTE 和其他病症的风险尚不清楚。慢性病的研究 RHI 的局限性在于缺乏对 TBI 作用的考虑、关注男性足球运动员、缺乏“控制”、 招募偏见，以及未能考虑遗传和非遗传风险因素。该项目将解决这些 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，并研究这些影响的遗传和非遗传修饰因素。我们将研究 RHI 如何 和 TBI 相互作用，导致 AD、ADRD、CTE 和其他病症。总体假设是 RHI TBI 具有独特的病理关联，并会受到遗传和非遗传风险因素的影响。 我们将利用 NIH 资助的正在进行的 UNITE 研究的基础设施。我们将协调 6 个脑库 波士顿大学、西奈山 AD 研究中心和 TBI 脑库的晚期影响。结果 将包括 AD、ADRD 和 CTE 状态，以及神经退行性蛋白的半定量和定量测量 和其他病症。我们将在脑库中添加统一的方法来评估 RHI 和 TBI 并检查 1500 名脑捐献者：1000 名暴露于 RHI/TBI 的人，包括各种接触运动运动员、军人 退伍军人和患有远程 TBI 的捐赠者（轻度至重度）；以及 500 名人口统计相似的非 RHI/TBI 脑捐献者。 我们将收集新脑捐献者的RHI和TBI数据，评估来自两个大脑的400名脑捐献者的RHI和TBI 尚未评估 RHI 和 TBI 的银行（BU 和西奈山 AD 中心），并利用现有的 RHI 以及来自脑库的 TBI 数据。选择偏差将通过纳入不招募的脑库来解决 基于 RHI/TBI、逆概率加权和仿真模型。该项目将产生最大的 具有协调一致、特征明确的 RHI 和 TBI 历史的脑捐赠者队列。它将包括接触运动运动员 不同运动项目和比赛水平的退伍军人以及患有远程 TBI（轻度至重度）的大脑捐赠者。 研究结果将揭示 AD、ADRD、CTE 以及 RHI 和 TBI 引起的其他慢性疾病的具体风险。

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.