CTE and Posttraumatic Neurodegeneration: Neuropathology and Ex Vivo Imaging

描述（由申请人提供）：创伤性脑损伤（TBI）在临床上与进行性认知下降和痴呆相关，在病理学上与轴突损伤和多种聚集蛋白沉积相关。反复轻度TBI可引发慢性创伤性脑病（CTE），这是一种独特的tau蛋白病，而单次TBI可引发阿尔茨海默病样神经变性。不幸的是，诊断这些创伤后神经退行性变（包括CTE）的唯一方法是通过死后的大脑检查。为了对发病率、患病率、危险因素、临床病程进行前瞻性研究， 创伤后神经变性的治疗，诊断的共识标准以及疾病的客观生物标志物必须首先建立。该计划将组建一个多中心的专家神经科学家团队，以评估TBI的后期影响，包括不同严重程度的单一和重复TBI，以及CTE，使用死后生物标本的组织学检查和神经成像工具作为开发体内诊断的基础。作为第一个目标，该提案将汇集一个由5名在神经退行性疾病方面有成就的神经病理学家组成的团队，以建立CTE死后诊断的共识标准。该团队还将定义CTE病理学的阶段，将CTE与其他神经变性和药物滥用的影响区分开来的特征，以及单次TBI后创伤后神经变性的特征。作为第二个目标，该提案将建立一个国家生物标本和数据库，用于TBI（了解神经损伤和创伤性脑病（UNITE）生物库），方法是建立一个全国性的脑捐赠登记处和热线，以获取高质量的生物标本和数据。UNITE库将使用严格标准化的协议和基于网络的界面，以确保合格的研究人员随时可以获得组织和数据。将全面的回顾性临床数据（包括临床症状、脑创伤和药物滥用史）以及医疗记录（包括常见数据元素）输入安全数据库。行为/情绪功能障碍、认知变化、物质滥用和创伤暴露将与多灶性tau蛋白病、Ass沉积和轴突损伤的定量评估相关。作为第三个目标，将使用高空间分辨率扩散张量成像（DTI）和放射自显影术（使用高选择性的tau PET配体）在死后组织中确定神经病理学的神经成像特征。轴突损伤、tau和Ass的定量评估将与离体DTI异常和tau配体放射自显影相关。在提案的最后2年，还将对CTE发展高风险个体进行试点神经影像学研究。该提案将确定CTE和创伤后神经变性的临床和神经影像学相关性，并为确定其发病率和患病率奠定基础。这项研究将对数百万美国人的公共健康产生巨大影响，并大大增加我们对脑创伤潜在影响的了解。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is associated clinically with progressive cognitive decline and dementia and pathologically with axonal injury and the deposition of multiple aggregated proteins. Repetitive mild TBI can trigger chronic traumatic encephalopathy (CTE), a unique tauopathy, and single TBI can provoke an Alzheimer's-like neurodegeneration. Unfortunately, the only way to diagnose these posttraumatic neurodegenerations, including CTE, is by post-mortem brain examination. In order to conduct prospective research into the incidence, prevalence, risk factors, clinical course, and ultimately, treatment for posttraumatic neurodegeneration, consensus criteria for diagnosis as well as objective biomarkers for disease must first be established. This initiative will assemble a multicenter team of expert neuroscientists to evaluate the late effects of TBI, including single and repetitive TBI of varying severity, and CTE, using histological examination of postmortem bio specimens and neuroimaging tools as a foundation to develop in vivo diagnostics. As a first aim, this proposal will bring together a team of 5 accomplished neuropathologists in neurodegenerative disease to establish consensus criteria for the post-mortem diagnosis of CTE. This team will also define the stages of CTE pathology, the features that differentiate CTE from other neurodegenerations and the effects of substance abuse, and the characteristics of posttraumatic neurodegeneration after single TBI. As a second aim, this proposal will establish a national bio specimen and data bank for TBI (Understanding Neurological Injury and Traumatic Encephalopathy (UNITE) bio bank) by developing a nationwide brain donor registry and hotline to acquire high quality bio specimens and data. The UNITE bank will use strictly standardized protocols and a web-based interface to ensure that tissue and data are readily available to qualified investigators. Comprehensive retrospective clinical data including clinical symptoms, brain trauma and substance abuse history, and medical records (including common data elements) will be entered into a secure database. Behavioral/ mood dysfunction, cognitive changes, substance abuse and traumatic exposure will be correlated with quantitative assessment of the multifocal tauopathy, Ass deposition and axonal injury. As a third aim, neuroimaging signatures of the neuropathology will be determined in post-mortem tissue using high spatial resolution diffusion tensor imaging (DTI) and autoradiography using a highly selective PET ligand for tau. Quantitative assessment of axonal injury, tau, and Ass will be correlated with ex vivo DTI abnormalities and tau ligand autoradiography. Pilot neuroimaging studies of individuals at high risk for the development of CTE will also be conducted in the final 2 years of the proposal. This proposal will determine the clinical and neuroimaging correlates of CTE and posttraumatic neurodegeneration and create the groundwork for establishing their incidence and prevalence. This study will have a tremendous impact on public health of millions of Americans and greatly increase our understanding of the latent effects of brain trauma.