Neuropathology of CTE and Delayed Effects of TBI: Toward In-Vivo Diagnostics

描述(申请人提供)：拟议的项目“CTE的神经病理学和脑创伤的后遗症：走向活体诊断”是一项多中心、多学科的研究，旨在极大地提高我们对慢性创伤性脑病(CTE)和创伤性脑损伤(TBI)的其他后遗症的了解。TBI是一个主要的公共卫生问题 美国，因为目前脑外伤在美国的流行程度是史无前例的。一些脑外伤幸存者随着年龄的增长会经历特别糟糕的结果；其中包括认知和健康加速下降、痴呆症，在某些情况下还会发生CTE。CTE被认为是一种后遗症，但仅在反复头部创伤患者的方便样本中被描述。CTE在轻度、中度和重度脑外伤患者中的描述并不完整。人群发病率和患病率、危险因素以及多灶性脊椎病对相关症状的因果作用尚不清楚。颅脑损伤、CTE和阿尔茨海默病存在重叠的临床特征、死后病理和受累模式，对准确诊断提出了挑战。目前不可能对CTE进行死前诊断。单发轻度或中重度脑外伤的神经病理后果及其与CTE和已知痴呆的关系尚不清楚。拟议的项目将利用正在进行的基于人群的大脑老化前瞻性队列研究(成人思维变化；ACT，n=2,305)的广泛资源，除了死亡时最先进的神经病理学检查外，该研究还包括队列的出色医疗、行为和基因特征(其中20%有轻中度脑损伤病史)。脑外伤影响的神经病理学研究可以在现有的ACT尸检样本中立即开始(n=489，20%，暴露于脑外伤)。其他暴露于脑损伤的人将来自西奈山脑损伤研究中心(n=150名中-重度脑损伤患者)、德克萨斯大学西南分校(n=50名反复暴露于脑损伤的退役拳击手)和国家橄榄球联盟(n=76名反复暴露于脑损伤的退役球员)。拟议研究的所有参与者(ACT和其他地点)将接受统一的协调神经行为评估(选择以最大限度地与现有的大规模脑损伤和痴呆症研究保持一致)、核磁共振扫描和基因组分析。那些在研究过程中死亡的人将接受体外神经成像和广泛的神经病理学检查，使用最先进的技术(如组胺)，旨在量化整个大脑样本中的tau和A�。只有通过检查具有不同水平的脑损伤暴露的个体样本的死后病理，这些个体在生活中具有良好的特征(如本文所建议的)，死后病理才能促进识别可作为诊断工具的体内生物标记物。这个项目代表了迄今为止最系统和最科学的努力，以更全面地了解单发和多发脑外伤的长期临床和神经病理后遗症。

DESCRIPTION (provided by applicant): The proposed project, "Neuropathology of CTE and Late Effects of TBI: Toward In-Vivo Diagnostics" is a multi- center and multi-disciplinary study designed to dramatically increase our understanding of chronic traumatic encephalopathy (CTE) and other late effects of traumatic brain injury (TBI). TBI is a major public health concern in the US, as the current prevalence of TBI in the US is unprecedented. Some TBI survivors experience particularly poor outcomes as they age; these include accelerated cognitive and health decline, dementia, and in some cases, CTE. CTE is thought to be a tauopathy but has been described only in convenience samples of people with repetitive head trauma. CTE is incompletely described in individuals with mild, moderate and severe TBI. The population incidence and prevalence, risk factors, and causal role of multifocal tauopathy on associated symptoms are unknown. Overlapping clinical features, postmortem pathologies and patterns of involvement exist in TBI, CTE, and Alzheimer's disease pose challenges to accurate diagnosis. Premortem diagnosis of CTE is currently impossible. The neuropathological consequences of single mild or moderate-severe TBI and its relationship with CTE and known dementias are unclear. The proposed project will leverage extensive resources from an ongoing population-based prospective cohort study of brain aging (Adult Changes in Thought; ACT, n=2,305) which includes excellent medical, behavioral, and genetic characterization of a cohort (20% of whom have a history of mild-moderate TBI) in addition to state-of-the-art neuropathology workup upon death. Neuropathological study of TBI effects can begin immediately in the existing ACT autopsy sample (n=489, 20% with TBI exposure). Additional cohorts of TBI- exposed individuals will come from the Brain Injury Research Center at Mount Sinai (n=150 individuals with moderate-severe TBI), the University of Texas Southwestern (n=50 retired boxers with repetitive TBI exposure), and the National Football League (n=76 retired players with repetitive TBI exposure). All participants in the proposed study (ACT and other sites) will undergo uniform harmonized neurobehavioral assessment (chosen to maximize correspondence with existing large-scale TBI and dementia studies), MRI scan, and genomic analysis. Those individuals who expire during the course of the study will undergo ex-vivo neuroimaging and extensive neuropathological exam using state-of-the-art techniques (such as Histelide) designed to quantify tau and A� in whole brain specimens. Only by examining postmortem pathology in a sample of individuals with varying levels of TBI exposure who are well characterized during life (as proposed herein) can postmortem pathology facilitate identification of in-vivo biomarkers that can act as diagnostic tools. This project represents the most systematic and scientifically rigorous effort to date to develop a more complete understanding of the long-term clinical and neuropathological sequelae of single and multiple TBI.