TBI-related polyproteinopathy and the role of multiple neurodegenerations in cognitive decline and parkinsonism

多种病理可导致认知障碍、痴呆症和帕金森氏症，尤其是在 设置高龄。慢性创伤性脑损伤(CTBI)或反复头部撞击(RHI)病史 增加痴呆症的风险，尽管慢性创伤性脑病(CTE)的相对贡献， 阿尔茨海默病(AD)、路易体病(LBD)、额颞叶变性、肌萎缩侧索硬化 硬化症(ALS)和其他创伤后痴呆的病理机制尚不清楚。在本项目中，我们将使用8 分别关注RHI、TBI、AD、ADRD、ALS、PTSD和社区的Brain Bank Core队列- 老龄化以系统地评估RHI和脑外伤相关神经变性的精确神经病理学。这些 合并的脑库包含2500多个病例，其中包括最大的神经病理确认的尸检 CTE受试者队列(n=361)以及50例伴有慢性空洞性的远端、中、重度脑外伤患者 病变(CTBI)。我们和其他人已经报道了该病的临床、神经影像和神经病理学特征。 在多年前持续一次中-重度脑外伤后出现早发性痴呆的受试者 并发展出多种独特的病理。此外，我们检查病理的初步数据 数百名患有和不患有RHI的参与者表明，β-淀粉样斑块的类型和分布 在CTE中有改变；新皮质LBD在CTE中很常见，并与RHI有关，50%的参与者有 CTBI的病史中有ALS队列中的CTE。此外，我们还发现RHI与改变的小胶质细胞和 星形胶质细胞表型与CTE的共病病理不同相关。我们的假设，基于 根据我们的初步数据，RHI和cTBI与多发性硬化的频率增加有关 神经退行性病理和病理的分布被改变以反映损伤的模式。我们 进一步假设，这些与RHI和cTBI相关的多种病理，包括CTE，有助于 不同脑库队列中痴呆症和帕金森症的发展。我们的长期目标是发现 CTBI相关神经变性的相对风险、异质性和细胞机制 痴呆症和帕金森症的发展。这项研究项目的直接目标是确定 RHI和cTBI相关疾病在多种神经退行性脑损伤中的患病率和病理分布 银行。这项研究对于理解创伤如何触发或加速多种神经病理至关重要。 总体而言，我们的目标是确定暴露于RHI的受试者中多种病理的患病率和异质性。 和cTBI，并确定这些病理在认知能力下降和帕金森病中的相对贡献。

Multiple pathologies can contribute to cognitive impairment, dementia and parkinsonism, particularly in the setting of advanced age. A history of chronic traumatic brain injury (cTBI) or repetitive head impacts (RHI) increases the risk for dementia, although the relative contributions of chronic traumatic encephalopathy (CTE), Alzheimer disease (AD), Lewy body disease (LBD), frontotemporal lobar degeneration, amyotrophic lateral sclerosis (ALS) and other pathologies to post-traumatic dementia are unknown. In this project we will use the 8 cohorts of the Brain Bank Core that are separately focused on RHI, TBI, AD, ADRD, ALS, PTSD, and community- aging to systematically evaluate the precise neuropathology of RHI and TBI-related neurodegeneration. These combined brain banks contain over 2500 cases, and include the largest neuropathologically-confirmed autopsy cohort of CTE subjects (n= 361) as well as >50 cases of remote, moderately-severe TBI with a chronic cavitary lesion (cTBI). We and others have reported the clinical, neuroimaging, and neuropathologic characteristics of subjects who developed early onset dementia after sustaining a single moderate-severe TBI many years earlier and developed multiple unique pathologies. Furthermore, our preliminary data examining the pathology in hundreds of participants with and without RHI demonstrate that the type and distribution of beta-amyloid plaques are altered in CTE; neocortical LBD is common in CTE and associated with RHI, and 50% of participants with a history of cTBI had CTE in an ALS cohort. In addition, we show that RHI is associated with altered microglial and astrocyte phenotypes that are differentially associated with comorbid pathology in CTE. Our hypothesis, based on our preliminary data, is that RHI and cTBI are associated with increased frequency of multiple neurodegenerative pathologies and that the distribution of pathology is altered to reflect the pattern of injury. We further hypothesize that these multiple RHI and cTBI-related pathologies, including CTE, contribute to the development of dementia and parkinsonism in various brain bank cohorts. Our long-term goal is to uncover the relative risk, heterogeneity, and cellular mechanisms of cTBI-related neurodegeneration that underlie the development of dementia and parkinsonism. The immediate goal of this research project is to determine the prevalence and pathological distribution of RHI and cTBI-related disease in a variety of neurodegenerative brain banks. This research is critical to understanding how trauma triggers or accelerates multiple neuropathologies. Overall, we aim to determine prevalence and heterogeneity of multiple pathologies in subjects exposed to RHI and cTBI and to determine the relative contributions of these pathologies to cognitive decline and parkinsonism.