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

经历过创伤性脑损伤(TBI)的人患痴呆症和 晚年的帕金森症。接触运动和服兵役造成的重复性头部撞击(RHI)是 也与基于tau的神经退行性变，慢性创伤性脑病(CTE)有关。我们的小案子 研究表明，颅脑损伤相关神经变性的神经病理基础是异质性的。 存在不同程度的β-淀粉样蛋白(A？)、磷酸化tau蛋白(Ptau)、pTDP-43和α-突触核蛋白的情况 不符合传统阿尔茨海默病(AD)或AD相关痴呆(ADRD)的病理。 我们的研究还表明，其他病理，包括灰质和白质萎缩，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了脑外伤后的神经变性。 还有RHI。此外，人们越来越认识到，创伤性脑损伤或呼吸窘迫综合征和其他疾病的类型、频率和严重程度 遗传因素和非遗传因素对长期预后有显著影响。TBI和RHI还没有 在脑库队列中得到了很好的研究，随后，脑损伤和RHI对AD、ADRD、CTE等疾病的贡献 病理学尚不清楚。有一个关键的未满足的需要来确定TBI和RHI与AD的关系， 通过ADRD、CTE等病理检查，了解颅脑损伤的神经病理表型，确定其临床意义。 脑库队列中脑损伤相关神经退行性变和CTE的患病率及其相互关系 脑外伤和RHI与认知功能减退和帕金森病的关系。为了实现我们的目标，我们将利用 我们成功了解神经损伤和创伤性脑病(UNIT)研究的基础 (U01NS086659，R01AG057902)以及我们与西奈山的合作(U01NS086625)。我们将调和8个 新的脑库：波士顿大学(BU)有6个，西奈山伊坎医学院(ISMMS)有2个。在……里面 在这项建议中，我们将研究RHI和TBI与AD、ADRD、CTE神经病理和其他疾病的关系 并研究这些效应的遗传和非遗传修饰物。最重要的假设 RHI和TBI将与AD、ADRD、CTE和其他病理有明显的关联；这些影响将 受遗传因素(如ApoEε4、TMEM106b)和非遗传因素(如首次接触RHI的年龄)的影响 ) 以及脑损伤、年龄、心血管疾病、抵抗力，以及其他RHI/脑损伤特征和人口统计学， 生活方式和病史；这些病理将与临床结果直接相关 痴呆症和帕金森症。这位U54将发展最大的脑捐赠者队列，具有良好的历史特征 在严重程度范围内的RHI和TBI。该项目将增进对特定风险的了解 RHI和TBI后AD、ADRD、CTE等退行性病变的病理发展 颅脑损伤相关神经退行性变的神经病理特点，并确定RHI后与 脑损伤神经病理学与痴呆和帕金森综合征的临床表型。这份U54提案将为 为未来干预、预防和治疗脑外伤相关神经变性和CTE的战略奠定基础。

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.