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.

经历创伤性脑损伤（TBI）的个人患痴呆症的风险增加 帕金森氏症后来。接触接触运动和兵役的重复性头部影响（RHI）是 也与基于TAU的神经变性，慢性创伤性脑病（CTE）有关。我们的小案例 研究表明，与TBI相关神经变性的神经病理底物是一种异质 具有不同程度的β-淀粉样蛋白（Aß），磷酸化tau（PTAU），PTDP-43和α-突触核蛋白的条件 不符合常规阿尔茨海默氏病（AD）或AD相关痴呆症（ADRD）的病理学。 我们的研究还表明，其他病理，包括灰质和白质萎缩，血管病理学， 神经元，轴突和髓磷脂损失，星形细胞增多症和神经炎症在TBI后有助于神经变性 和Rhi。此外，越来越多地认识到TBI或RHI和其他的类型，频率和严重性 遗传和非遗传因素对罢工对长期结果的影响。 TBI和RHI还没有 在脑库队列中的研究良好，随后是TBI和RHI对AD，ADRD，CTE和其他的贡献 病理尚不清楚。确定TBI和RHI与AD的关系存在至关重要的需求， ADRD，CTE和其他病理学了解TBI的神经病理表型，以确定 脑库队列中与TBI相关的神经变性和CTE的患病率，并确定关系 TBI和RHI的认知衰落和帕金森氏症。为了实现我们的目标，我们将利用 我们成功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Sinai Mount（U01NS086625）的合作。我们将协调8 新颖的大脑银行：波士顿大学（BU）的6和2在西奈山（ISMMS）的伊坎医学院。 这项建议，我们将研究RHI和TBI与AD，ADRD，CTE神经病理学和其他的协会 病理和研究这些作用的遗传和非遗传修饰剂。总体假设 是：RHI和TBI将与AD，ADRD，CTE和其他病理有着不同的关联；这些效果将会 通过遗传（例如APOEε4，TMEM106B）和非遗传因素（例如，首次暴露于RHI的年龄）来修饰 ） 和TBI，年龄，心血管疾病，抗药性，以及其他RHI/TBI特征和人口统计学 生活方式和病史；这些病理将与 痴呆和帕金森氏症。该U54将开发出具有良好特征历史的最大脑供体队列 遍布严重性谱的RHI和TBI。该项目将促进有关特定风险的知识 RHI和TBI之后的AD，ADRD，CTE和其他退行性病理的病理发展建立了 TBI相关神经变性的神经病理特征，并确定RHI后和 TBI神经病理学具有痴呆症和帕金森氏症的临床表型。这个U54提案将提出 未来干预，预防和治疗与TBI相关的神经变性和CTE的策略的基础。