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

描述（由申请人提供）：拟议项目“CTE的神经病理学和TBI的晚期效应：走向体内诊断”是一项多中心和多学科研究，旨在显著增加我们对慢性创伤性脑病（CTE）和创伤性脑损伤（TBI）的其他晚期效应的理解。TBI是一个主要的公共卫生问题， 美国，因为目前TBI在美国的患病率是前所未有的。一些TBI幸存者随着年龄的增长而经历特别糟糕的结果;这些包括加速认知和健康下降，痴呆症，在某些情况下，CTE。CTE被认为是一种tau蛋白病，但仅在重复性头部创伤患者的便利样本中进行了描述。CTE在轻度、中度和重度TBI患者中的描述不完全。多灶性tau蛋白病的人群发病率和患病率、危险因素以及对相关症状的因果作用尚不清楚。重叠的临床特征，死后病理和参与模式存在于TBI，CTE和阿尔茨海默病的准确诊断提出了挑战。CTE的死前诊断目前是不可能的。单一轻度或中重度TBI的神经病理学后果及其与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，其中包括队列的优秀医学，行为和遗传特征（其中20%有轻度-中度TBI病史），以及死亡后最先进的神经病理学检查。TBI影响的神经病理学研究可以在现有ACT尸检样本中立即开始（n=489，20%接触TBI）。TBI暴露个体的其他队列将来自西奈山脑损伤研究中心（n=150名中重度TBI患者）、德克萨斯大学西南分校（n=50名重复TBI暴露的退役拳击手）和国家橄榄球联盟（n=76名重复TBI暴露的退役球员）。拟议研究的所有参与者（ACT和其他研究中心）将接受统一协调的神经行为评估（选择与现有大规模TBI和痴呆研究最大限度地一致），MRI扫描和基因组分析。在研究过程中死亡的个体将使用最先进的技术（如Histelide）进行离体神经成像和广泛的神经病理学检查，旨在量化全脑标本中的tau和A？。只有通过检查在生命期间被充分表征的具有不同水平的TBI暴露的个体的样品中的死后病理学（如本文所提出的），死后病理学才能促进可以用作诊断工具的体内生物标志物的鉴定。该项目代表了迄今为止最系统和科学严谨的努力，以更全面地了解单次和多次TBI的长期临床和神经病理学后遗症。

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.