CTE and Posttraumatic Neurodegeneration: Neuropathology and Ex Vivo Imaging

描述(申请人提供)：创伤性脑损伤(TBI)在临床上与进行性认知功能减退和痴呆有关，在病理学上与轴突损伤和多种聚集蛋白的沉积有关。重复性轻度脑损伤可引发慢性创伤性脑病(CTE)，这是一种独特的脑损伤，单次脑损伤可引发类似阿尔茨海默氏症的神经变性。不幸的是，诊断包括CTE在内的这些创伤后神经退行性变的唯一方法是通过尸检。为了对发病率、患病率、危险因素、临床病程，以及最终， 必须首先建立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记物。这一倡议将召集一个由专家神经学家组成的多中心团队来评估脑外伤和CTE的晚期影响，包括不同严重程度的单发和重复脑损伤，并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活体诊断的基础。作为第一个目标，这项提案将汇集一个由5名神经退行性疾病方面的资深神经病理学家组成的团队，为CTE的尸检诊断建立一致的标准。该团队还将确定CTE的病理阶段、CTE与其他神经退行性变的区别特征和药物滥用的影响，以及单次脑外伤后创伤后神经退行性变的特征。作为第二个目标，这项建议将通过建立全国性的脑捐赠者登记和热线来获得高质量的生物标本和数据，建立一个国家生物标本和数据库，以了解神经损伤和创伤性脑病(UNIT)生物库。联合银行将使用严格标准化协议和基于网络的界面，以确保合格的调查人员随时可以获得组织和数据。全面的回顾性临床数据，包括临床症状、脑损伤和药物滥用史，以及医疗记录(包括通用数据元素)将输入一个安全的数据库。行为/情绪障碍、认知改变、药物滥用和创伤暴露将与多灶性肌萎缩症、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)和使用高选择性的tau的PET配体进行放射自显影，在身体组织中确定神经病理的神经成像特征。轴突损伤、tau和ASS的定量评估将与体外DTI异常和tau配体放射自显影相关。在该提案的最后两年，还将对CTE高危人群进行先导性神经成像研究。这项建议将确定CTE和创伤后神经变性的临床和神经影像相关性，并为确定其发病率和流行率奠定基础。这项研究将对数百万美国人的公共健康产生巨大影响，并极大地提高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.