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: 10021467
• 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/10021467
• 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; Services; Severities; Slide; Soccer; Socioeconomic Status; Source; Sports; Structure; Syndrome; Testing; Time; Training; Traumatic Brain Injury; United States National Institutes of Health; Universities; Veterans; Weight; apolipoprotein E-4; base; cerebral atrophy; chronic traumatic encephalopathy; cohort; college; combat; demographics; digital; dosage; head impact; high school; indexing; lifestyle factors; male; medical schools; models and simulation; neuroinflammation; neuropathology; non-genetic; recruit; resistance factors; response; sex; 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.

远程中重度创伤性脑损伤（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（ADRD）。然而，尸检证据现在表明，创伤性脑损伤的病理包括 各种神经退行性疾病蛋白质和其它病理（例如白色物质）的聚集 退化）。这些关系和引发的病理可能取决于严重程度和数量， TBI。越来越多的研究将接触性运动和兵役中的重复性头部撞击（RHI）与AD联系起来， ADRD与神经退行性疾病慢性创伤性脑病（CTE）。RHI与 与其他病理，如白色物质变性和神经炎症。虽然不为人知， 我认为RHI通过复发性脑震荡和无症状性脑震荡导致AD、ADRD、CTE和其他病理， 亚脑震荡证据还表明，单次cTBI足以沉淀AD、ADRD和CTE。的 各种TBI暴露的病理学基质仍不清楚， 导致AD、ADRD、CTE和其他病理的风险尚不清楚。研究慢性病理学， 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。该项目将解决这些问题 限制，并检查RHI和TBI（所有严重程度）与AD，ADRD，CTE和其他 病理学，以及研究这些影响的遗传和非遗传修饰剂。我们将研究如何RHI TBI和TBI相互作用导致AD、ADRD、CTE和其它病理。总体假设是，RHI 和TBI将具有不同的病理学关联，其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UNITE研究的基础设施。我们将协调6个脑库， 波士顿大学和AD研究中心以及西奈山TBI脑库的晚期效应。成果 将包括AD、ADRD和CTE状态，以及神经退行性蛋白质的半定量测量 和其他病理学。我们将在脑库中增加用于评估RHI和TBI的协调方法 并检查了1500名脑捐赠者：1000名暴露于RHI/TBI，包括各种接触性运动员，军人 退伍军人和远程TBI（轻度-重度）供体;以及500名人口统计学相似的非RHI/TBI脑供体。 我们将收集新脑供体的RHI和TBI数据，评估来自两个脑组织的400名脑供体的RHI和TBI 未评估RHI和TBI的银行（BU和西奈山广告中心），并利用现有的RHI 和脑库中的创伤性脑损伤数据选择偏见将通过包括不招募人才的人才库来解决 基于RHI/TBI、逆概率加权和仿真模型。该项目将产生最大的 具有协调的、良好表征的RHI和TBI病史的脑供体队列。它将包括接触运动员 在不同的运动和水平的发挥，退伍军人和大脑捐赠者与远程TBI（轻度-重度）。 研究结果将告知AD，ADRD，CTE和RHI和TBI的其他慢性病理学的特定风险。