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

CTE 的神经病理学和 TBI 的延迟效应：走向体内诊断

• 批准号: 8990063
• 负责人: Wayne A. Gordon
• 金额: $ 149.97万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8990063
• 关键词: Accounting; Adult; Age; Age of Onset; Alzheimer' s Disease; Autopsy; Base of the Brain; Behavioral; Behavioral Genetics; Biological Markers; Biological Models; Blast Cell; Brain; Brain Injuries; Cessation of life; Characteristics; Classification; Clinical; Clinical Data; Cognitive; Cohort Studies; Communities; Consensus; Consensus Development; Consent; Craniocerebral Trauma; Data; Data Collection; Data Sources; Databases; Dementia; Development; Diagnosis; Diagnostic; Enrollment; Ensure; Epidemiology; Evaluation; Genetic; Genomics; Goals; Health; Image; Incidence; Individual; Knowledge; Late Effects; Lead; Lesion; Life; Link; Long-Term Effects; MRI Scans; Magnetic Resonance Imaging; Manufactured football; Medical; Methods; Military Personnel; Modality; Nerve Degeneration; Outcome; Parkinson Disease; Participant; Pathologic; Pathology; Pattern; Population; Prevalence; Procedures; Process; Protocols documentation; Public Health; Qualifying; Recording of previous events; Research; Research Design; Research Infrastructure; Research Personnel; Resolution; Resources; Risk Factors; Role; Sampling; Selection Bias; Signs and Symptoms; Site; Specimen; Statistical Methods; Subgroup; Survivors; Tauopathies; Techniques; Texas; Time; Tissues; Trauma; Traumatic Brain Injury; United States; United States National Institutes of Health; Universities; Work; accurate diagnosis; aging brain; associated symptom; base; chronic traumatic encephalopathy; cohort; design; experience; improved; in vivo; neurobehavioral; neuroimaging; neuropathology; population based; programs; prospective; tau Proteins; tool; validation studies

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.

描述（由申请人提供）：拟议项目“CTE 的神经病理学和 TBI 的后期影响：迈向体内诊断”是一项多中心、多学科研究，旨在显着提高我们对慢性创伤性脑病 (CTE) 和创伤性脑损伤 (TBI) 的其他后期影响的了解。 TBI 是一个主要的公共卫生问题 美国，目前 TBI 在美国的流行程度是史无前例的。一些 TBI 幸存者随着年龄的增长，会经历特别糟糕的结果；这些包括认知和健康加速衰退、痴呆，在某些情况下还包括慢性创伤性脑病（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方便样本中得到描述。对于患有轻度、中度和重度 TBI 的个体，CTE 的描述并不完整。多灶性 tau 蛋白病的人群发病率和患病率、危险因素以及相关症状的因果作用尚不清楚。 TBI、CTE 和阿尔茨海默氏病存在重叠的临床特征、死后病理和参与模式，这对准确诊断提出了挑战。目前不可能对 CTE 进行尸前诊断。单次轻度或中重度 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衰老前瞻性队列研究（成人思想变化；ACT，n=2,305）的广泛资源，其中包括队列的出色医学、行为和遗传特征（其中 20% 有轻度至中度 TBI 病史），以及最先进的死亡时神经病理学检查。 TBI 影响的神经病理学研究可以立即在现有的 ACT 尸检样本中开始（n = 489，20％有 TBI 暴露）。其他暴露于 TBI 的个体队列将来自西奈山脑损伤研究中心（n = 150 名患有中重度 TBI 的个体）、德克萨斯大学西南大学（n = 50 名重复暴露于 TBI 的退役拳击手）和国家橄榄球联盟（n = 76 名患有重复性 TBI 暴露的退休运动员）。拟议研究（ACT 和其他地点）的所有参与者都将接受统一协调的神经行为评估（选择以最大限度地符合现有大规模 TBI 和痴呆症研究）、MRI 扫描和基因组分析。那些在研究过程中死亡的个体将使用最先进的技术（例如 Histelide）进行离体神经影像学和广泛的神经病理学检查，这些技术旨在量化全脑标本中的 tau 蛋白和 A¿只有通过检查生前具有不同 TBI 暴露水平的个体样本的死后病理学（如本文所提出的），死后病理学才能有助于识别可充当诊断工具的体内生物标志物。该项目代表了迄今为止最系统、科学严谨的努力，旨在更全面地了解单次和多发 TBI 的长期临床和神经病理学后遗症。