Traumatic Brain Injury and Repetitive Head Impacts: Contributions to AD/ADRD and CTE Neuropathology and Resulting Clinical Syndromes

创伤性脑损伤和重复性头部撞击：导致 AD/ADRD 和 CTE 神经病理学及由此产生的临床综合征

• 批准号: 10460261
• 负责人: Ann C. McKee
• 金额: $ 198.99万
• 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/10460261
• 关键词: Acute; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Astrocytosis; Atrophic; Axon; Blood Vessels; Boston; Brain; Cardiovascular Diseases; Case Study; Characteristics; Chronic; Clinical; Collaborations; Dementia; Development; Disease Resistance; Dose; Emergency Situation; Evaluation; Exposure to; Foundations; Framingham Heart Study; Frequencies; Future; Genetic; Goals; Impaired cognition; Individual; Infrastructure; Injury; Knowledge; Late Effects; Life; Life Style; Medical; Medical History; Myelin; Nerve Degeneration; Nervous System Trauma; Neurons; Other Genetics; Outcome; Parkinsonian Disorders; Pathologic; Pathology; Phenotype; Post-Traumatic Stress Disorders; Prevalence; Proteins; Protocols documentation; Recording of previous events; Research; Risk; Risk Factors; Severities; Source; Syndrome; Testing; Time; Traumatic Brain Injury; Traumatic brain injury related dementia; United States; Universities; Validity and Reliability; Visit; alpha synuclein; apolipoprotein E-4; base; chronic traumatic encephalopathy; clinical phenotype; cohort; contact sports; dementia risk; experience; gray matter; head impact; indexing; medical schools; military service; neuroinflammation; neuropathology; non-genetic; novel; prevent; protein TDP-43; response; tau Proteins; tau-1; white matter

Individuals who experience traumatic brain injury (TBI) are at increased risk for developing dementia and parkinsonism later in life. Exposure to repetitive head impacts (RHI) from contact sports and military service is also associated with a tau-based neurodegeneration, chronic traumatic encephalopathy (CTE). Our small case studies indicate that the neuropathological substrate of TBI-related neurodegeneration is a heterogeneous condition with varying degrees of beta-amyloid (Aß), phosphorylated tau (ptau), pTDP-43, and alpha-synuclein pathologies that does not conform to conventional Alzheimer's disease (AD) or AD related dementias (ADRD). Our studies also suggest that other pathologies, including gray and white matter atrophy, vascular pathology, neuronal, axonal and myelin loss, astrocytosis, and neuroinflammation contribute to neurodegeneration after TBI and RHI. Moreover, it is increasingly recognized that the type, frequency and severity of TBI or RHI and other genetic and non-genetic factors exert striking influence on the long-term outcome. TBI and RHI have not been well studied in brain bank cohorts, subsequently, the contribution of TBI and RHI to AD, ADRD, CTE and other pathologies is not known. There is a critical unmet need to determine the relationship of TBI and RHI to AD, ADRD, CTE and other pathologies, to understand the neuropathological phenotype of TBI, to determine the prevalence of TBI-related neurodegeneration and CTE in brain bank cohorts, and to determine the relationship of TBI and RHI to cognitive decline and parkinsonism. To accomplish our goals, we will leverage the infrastructure of our successful Understanding Neurological Injury and Traumatic Encephalopathy (UNITE) study (U01NS086659, R01AG057902) and our collaboration with Mount Sinai (U01NS086625). We will harmonize 8 novel brain banks: 6 at Boston University (BU) and 2 at Icahn School of Medicine at Mount Sinai (ISMMS). In this proposal, we will examine the association of RHI and TBI with AD, ADRD, CTE neuropathology and other pathologies and investigate genetic and non-genetic modifiers of these effects. The overarching hypotheses are: RHI and TBI will have distinct associations with AD, ADRD, CTE and other pathologies; these effects will be modified by genetic (e.g., APOE ε4, TMEM106b) and non-genetic factors (e.g., age of first exposure to RHI ) and TBI, age, cardiovascular disease, resistance, among other RHI/TBI characteristics and demographic, lifestyle, and medical histories ; and these pathologies will have direct associations with clinical outcomes of dementia and parkinsonism. This U54 will develop the largest brain donor cohort with well-characterized histories of RHI and TBI across the severity spectrum. This project will advance knowledge on the specific risks for the pathological development of AD, ADRD, CTE and other degenerative pathologies after RHI and TBI, establish the neuropathological features of TBI-related neurodegeneration, and determine the association of post-RHI and TBI neuropathologies with the clinical phenotypes of dementia and parkinsonism. This U54 proposal will lay the foundation for future strategies to intervene, prevent and treat TBI-related neurodegeneration and CTE.

经历过创伤性脑损伤 (TBI) 的人患痴呆症和痴呆症的风险增加 晚年因接触运动和服兵役而遭受重复性头部撞击 (RHI) 是一种常见的症状。 还与基于 tau 的神经变性、慢性创伤性脑病 (CTE) 有关。 研究表明，TBI 相关神经变性的神经病理学基础是异质性的。 具有不同程度的 β-淀粉样蛋白 (Aß)、磷酸化 tau (ptau)、pTDP-43 和 α-突触核蛋白的病症 不符合传统阿尔茨海默病 (AD) 或 AD 相关痴呆 (ADRD) 的病理学。 我们的研究还表明其他病理学，包括灰质和白质萎缩、血管病理学、 神经元、轴突和髓磷脂损失、星形细胞增多和神经炎症导致 TBI 后神经退行性变 此外，人们越来越认识到 TBI 或 RHI 及其他疾病的类型、频率和严重程度。 遗传和非遗传因素对 TBI 和 RHI 的长期结果没有显着影响。 在脑库队列中进行了充分研究，随后，TBI 和 RHI 对 AD、ADRD、CTE 和其他疾病的贡献 病理学尚不清楚，但确定 TBI 和 RHI 与 AD 之间的关系尚有一个尚未满足的关键需求， ADRD、CTE 等病理学，了解 TBI 的神经病理表型，确定 脑库队列中 TBI 相关神经变性和 CTE 的患病率，并确定两者之间的关系 TBI 和 RHI 与认知能力下降和帕金森病的关系 为了实现我们的目标，我们将利用 我们成功的理解神经损伤和创伤性脑病 (UNITE) 研究的基础设施 （U01NS086659、R01AG057902）以及我们与西奈山的合作（U01NS086625）我们将协调 8。 新颖的脑库：波士顿大学（BU）有 6 个，西奈山伊坎医学院（ISMMS）有 2 个。 在这项提案中，我们将研究 RHI 和 TBI 与 AD、ADRD、CTE 神经病理学和其他疾病的关联 病理学并研究这些影响的遗传和非遗传修饰因素。 RHI 和 TBI 与 AD、ADRD、CTE 和其他病症有明显的关联； 被遗传因素（例如 APOE ε4、TMEM106b）和非遗传因素（例如首次接触 RHI 的年龄）改变 ） 和 TBI、年龄、心血管疾病、抵抗力以及其他 RHI/TBI 特征和人口统计数据， 生活方式和病史；这些病理学与临床结果有直接关系。 这个 U54 将培养出最大的、具有明确历史特征的大脑捐赠者群体。 该项目将增进对特定风险的了解。 RHI 和 TBI 后 AD、ADRD、CTE 和其他退行性病变的病理发展，建立 TBI 相关神经变性的神经病理学特征，并确定 RHI 后和 具有痴呆和帕金森病临床表型的 TBI 神经病理学此 U54 提案将奠定基础。 为未来干预、预防和治疗 TBI 相关神经变性和 CTE 策略奠定基础。