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

经历创伤性脑损伤（TBI）的个体患痴呆症的风险增加， 帕金森病在以后的生活中暴露于接触性运动和服兵役的重复性头部撞击（RHI）， 还与基于tau的神经变性、慢性创伤性脑病（CTE）相关。我们的小案子 研究表明，TBI相关神经变性的神经病理学底物是异质性的， 具有不同程度的β-淀粉样蛋白（AAPs）、磷酸化tau（ptau）、pTDP-43和α-突触核蛋白的条件 不符合常规阿尔茨海默病（AD）或AD相关痴呆（ADRD）的病理。 我们的研究还表明，其他病理，包括灰色和白色物质萎缩，血管病理， 神经元、轴突和髓鞘丢失、星形胶质细胞增多和神经炎症导致TBI后神经变性 和RHI。此外，越来越多的人认识到，TBI或RHI和其他疾病的类型、频率和严重程度可能与TBI或RHI和其他疾病的类型、频率和严重程度有关。 遗传和非遗传因素对远期疗效有显著影响。TBI和RHI尚未被 在脑库队列中进行了充分的研究，随后，TBI和RHI对AD、ADRD、CTE和其他疾病的贡献 病理学尚不清楚。确定TBI和RHI与AD的关系是一个关键的未满足的需求， ADRD，CTE和其他病理，以了解TBI的神经病理表型，以确定TBI的神经病理学表型。 脑库队列中TBI相关神经变性和CTE的患病率，并确定 认知能力下降和帕金森综合征的风险。为了实现我们的目标，我们将利用 我们成功的了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 新的大脑银行：6个在波士顿大学（BU），2个在西奈山伊坎医学院（ISMMS）。在 在这项建议中，我们将研究RHI和TBI与AD，ADRD，CTE神经病理学和其他疾病的关系。 病理学和研究这些影响的遗传和非遗传修饰。总体假设 RHI和TBI将与AD、ADRD、CTE和其他病理学有不同的关联;这些影响将 通过遗传修饰（例如，APOE ε 4，TMEM 106 b）和非遗传因素（例如，首次暴露于RHI的年龄 ) 和TBI，年龄，心血管疾病，抵抗力，以及其他RHI/TBI特征和人口统计学， 生活方式和病史;这些病理学将与临床结果直接相关， 痴呆症和帕金森综合症。这个U54将开发最大的大脑捐赠者队列，具有良好的特征历史 RHI和TBI在严重程度上的差异。该项目将增进对特定风险的了解， AD、ADRD、CTE和RHI和TBI后其他退行性病理的病理发展， TBI相关神经退行性变的神经病理学特征，并确定RHI后与 具有痴呆和帕金森综合征临床表型的TBI神经病理学。U54提案将奠定 为未来干预、预防和治疗TBI相关神经变性和CTE的策略奠定基础。

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.