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

TBI 相关的多蛋白病以及多种神经变性在认知能力下降和帕金森病中的作用

• 批准号: 10227045
• 负责人: Thor Stein
• 金额: $ 33.94万
• 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/10227045
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Astrocytes; Astrocytosis; Atrophic; Autopsy; Axon; Biochemical; Blood Vessels; Brain; CCL2 gene; Characteristics; Chronic; Clinical; Communities; Data; Dementia; Development; Disease; Elderly; Exposure to; Frequencies; Frontotemporal Lobar Degenerations; Genetic Risk; Gliosis; Goals; Heterogeneity; Histologic; Impaired cognition; Inflammatory; Injury; Interferon Type II; Interleukin-1; Interleukin-6; Lesion; Lewy Body Disease; Measurement; Modeling; Myelin; Nature; Nerve Degeneration; Neurons; PGRN gene; Parkinsonian Disorders; Participant; Pathologic; Pathology; Pattern; Persons; Phenotype; Play; Post-Traumatic Stress Disorders; Prevalence; Recording of previous events; Relative Risks; Reporting; Research; Research Project Grants; Role; Senile Plaques; Symptoms; Syndrome; TNF gene; Trauma; Traumatic Brain Injury; alpha synuclein; base; brain tissue; chronic traumatic encephalopathy; cohort; comorbidity; cytokine; dementia risk; early onset; gray matter; head impact; neocortical; neuroimaging; neuroinflammation; neuron loss; neuropathology; protein TDP-43; white matter

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.

多种病理可导致认知障碍、痴呆和帕金森症，特别是在老年人中。 设置先进的年龄。慢性创伤性脑损伤（cTBI）或重复性头部撞击（RHI）病史 增加痴呆的风险，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）和其他病理学对创伤后痴呆的影响是未知的。在这个项目中，我们将使用8 分别关注RHI、TBI、AD、ADRD、ALS、PTSD和社区的Brain Bank Core的队列- 老化以系统地评估RHI和TBI相关神经变性的精确神经病理学。这些 联合脑库包含超过2500个病例，包括最大的神经病理学证实的尸检 CTE受试者队列（n= 361）以及>50例远端、中重度TBI伴慢性空洞性 病变（cTBI）。我们和其他人报道了临床，神经影像学和神经病理学特征， 受试者在多年前持续一次中度TBI后发生早发性痴呆 并发展出了多种独特的病症此外，我们的初步数据检查的病理， 数百名有或没有RHI的参与者证明，β-淀粉样蛋白斑块的类型和分布 在CTE中改变;新皮质LBD在CTE中很常见，并与RHI相关，50%的参与者 cTBI病史在ALS队列中有CTE。此外，我们发现RHI与小胶质细胞的改变有关， 与CTE共病病理学差异相关的星形胶质细胞表型。我们的假设，基于 根据我们的初步数据，RHI和cTBI与多发性脑梗死的发生频率增加有关。 神经退行性病变，并且改变病变的分布以反映损伤的模式。我们 进一步假设这些多种RHI和cTBI相关的病理，包括CTE，有助于 痴呆症和帕金森症的发展在不同的脑库队列。我们的长期目标是揭露 cTBI相关神经退行性变的相对风险、异质性和细胞机制， 痴呆和帕金森综合症的发展。本研究项目的直接目标是确定 RHI和cTBI相关疾病在各种神经退行性脑中的患病率和病理分布 银行的这项研究对于理解创伤如何触发或加速多种神经病理学至关重要。 总之，我们的目的是确定暴露于RHI的受试者中多种病理的患病率和异质性 和cTBI，并确定这些病理对认知下降和帕金森综合征的相对贡献。