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

暴露于创伤性脑损伤和重复性头部撞击对阿尔茨海默病和相关痴呆以及慢性创伤性脑病的影响

• 批准号: 10227042
• 负责人: Michael Alosco
• 金额: $ 27.18万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227042
• 关键词: Address; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Autopsy; Boston; Brain; Brain Concussion; Cardiovascular Diseases; Characteristics; Chronic; Clinical; Data; Disease Resistance; Dose; Equation; Exposure to; Failure; Foundations; Frequencies; Funding; Genetic; Ice Hockey; Infrastructure; Late Effects; Lead; Link; Manufactured football; Measures; Mediating; Medical History; Methods; Military Personnel; Modeling; Nerve Degeneration; Nervous System Trauma; Neurodegenerative Disorders; Outcome; Pathologic; Pathology; Play; Positioning Attribute; Probability; Proteins; Recording of previous events; Recurrence; Research; Role; Scanning; Selection Bias; Severities; Slide; Soccer; Socioeconomic Status; Source; Sports; Structure; Syndrome; Testing; Time; Training; Traumatic Brain Injury; United States National Institutes of Health; Universities; Weight; apolipoprotein E-4; base; blast exposure; cerebral atrophy; chronic traumatic encephalopathy; cohort; college; combat; contact sports; demographics; digital; dosage; head impact; high school; indexing; lifestyle factors; male; medical schools; military service; military veteran; models and simulation; neuroinflammation; neuropathology; non-genetic; recruit; resistance factors; response; sex; subconcussion; vascular injury; white matter

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.

远程现代重度创伤性脑损伤（CTBI）长期以来一直被视为阿尔茨海默氏症的危险因素 疾病（AD）和AD相关痴呆症（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和其他病理的聚集（例如，白质） 退化）。这些关系和发起的病理可能取决于严重性和数量 tbis。与广告接触体育和兵役的AD联系，不断增长 ADRD和神经退行性疾病，慢性创伤性脑病（CTE）。 RHI一直关联 与其他病理，例如白质变性和神经炎症。虽然未知，但 认为RHI通过反复咨询和渐近性导致AD，ADRD，CTE和其他病理 亚障碍。证据还表明，单个CTBI足以沉淀AD，ADRD和CTE。这 各种TBI暴露的病理底物尚不清楚，需要的严重程度和数量 对于AD，ADRD，CTE和其他病理的会议风险是未知的。关于慢性病的研究 RHI因缺乏对TBI的角色的考虑而受到限制，专注于男性足球运动员，缺乏“控制”， 招聘偏见，以及未考虑遗传和非遗传危险因素。这个项目将解决这些问题 局限性和检查RHI和TBI（所有严重性）与AD，ADRD，CTE和其他 病理学以及研究这些作用的遗传和非遗传修饰剂。我们将研究RHI TBI相互作用以导致AD，ADRD，CTE和其他病理。总体假设是Rhi TBI将具有不同的病理关联，这将通过遗传和非遗传危险因素来改变。 我们将利用正在进行的NIH资助的Unite研究的基础设施。我们将在 波士顿大学和广告研究中心以及西奈山的TBI脑库的后期影响。结果 将包括AD，ADRD和CTE状态以及神经退行性蛋白的半定量测量 和其他病理。我们将在整个大脑库中添加统一的方法，以评估RHI和TBI 并检查1500个大脑捐献者：1000次接触RHI/TBI，包括各种接触运动员，军事 退伍军人和远程TBI（温和严重的捐赠者）；和500个人口相似的非RHI/TBI脑供体。 我们将收集有关新脑供体的RHI和TBI数据，评估来自两个大脑的400个脑供体的RHI和TBI RHI和TBI未经评估的银行（BU和Sinai Ad Ad Centers），并利用现有的RHI 和来自脑库的TBI数据。选择偏见将通过包括不招募的大脑银行来解决 基于RHI/TBI，逆概率加权和仿真模型。这个项目将导致最大的 脑供体队列，具有统一的，良好的RHI和TBI历史。它将包括联系运动员 在不同的运动和比赛水平，军事退伍军人和偏远TBI（轻度重度）的大脑捐助者中。 调查结果将告知RHI和TBI的AD，ADRD，CTE和其他慢性病理的特定风险。