Clinical & biological signatures of post-traumatic neurodegeneration: Leveraging the TBI Model Systems of Care to accelerate in vivo diagnosis of the late effects of TBI (LETBI)

项目摘要/摘要 这份R01提案《创伤后神经变性的临床和生物学特征：利用脑损伤 加速脑外伤后遗症体内诊断的护理模式系统(LETBI)“提交于 对PAR-22-024的回应，其中要求对区别于 创伤后进行性脑损伤(CsTBI)患者的慢性静态效应 神经变性(PTND)。这将需要来自具有良好特征的多样化的纵向多模式数据 一群脑外伤幸存者。LETBI研究是一项多模式临床前瞻性纵向研究 用于表征脑外伤及其活体神经病理的特征和尸检终点 临床特征。LETBI参与者是从包括TBI模型在内的正在进行的纵向研究中招募的 确保出色的TBI表征和广泛的纵向数据的系统。在此，我们建议 遵循原来的LETBI队列，并扩展到包括4个额外的TBI模型系统中心。通过招聘 有良好特征的中-重度脑损伤病史且至少在脑损伤后5年的患者，我们将 研究一组有下降风险的个人，并在2-3年进行多模式LETBI随访 间隔时间。我们将应用先进的心理测量学和统计学方法来考虑生命过程中 增加阿尔茨海默病(AD)和AD相关痴呆(ADRD)的风险--新的神经成像处理 工具、超灵敏单分子阵列(SIMOA)技术和最先进的神经病理学方法 通过从总共6个TBI模型系统中心扩大征聘，加强了LETBI队列。我们会 利用通过电话在TBI模型系统国家数据库中收集的现有数据来表征 从受伤时到LETBI入院的临床疗程。在目标1中，我们将使用现有的TBIMS和新的 收集LETBI数据以确定已从先前达到的受伤后水平下降的个人 确定损伤特征和相关的终身头部创伤暴露阈值的功能(即PTND) 具有特定领域的PTND风险和创伤性脑病综合征(TES)风险，超出损伤严重程度指数。 在目标2中，我们将应用先进的因果推理方法来量化早期生活环境并分离出 暴露于非创伤性脑损伤对PTND和AD/ADRD风险的贡献。在目标3中，我们将定义潜在的 通过在体液(NFL、GFAP、T-tau、ptau、Aβ42/40)和成像(网络- PTND的特异性连接改变/弥散磁共振成像(DMRI)生物标记物。在目标4中，我们将寻求 在LETBI尸检队列中对这些活体生物标记物的死后验证，确定它们的身体 神经退行性疾病的组织相关性和负担，包括跨损伤暴露和TES的CTE 诊断组。我们强大的跨学科团队非常适合定义风险因素、临床和 PTND的生物学特征，从而确定诊断和疾病进展的工具，同时创建 丰富的数据资源，与科学界共享，加快AD/ADRD治疗的发展。

Project Summary/Abstract This R01 Proposal, “Clinical & biological signatures of post-traumatic neurodegeneration: Leveraging the TBI Model Systems of Care to accelerate in vivo diagnosis of the late effects of TBI (LETBI)” is submitted in response to PAR-22-024, which requests investigation into the clinical and biological features that distinguish chronic static effects of traumatic brain injury (csTBI) from those associated with progressive post-traumatic neurodegeneration (PTND). This will require longitudinal, multimodal data from a well-characterized diverse cohort of TBI survivors. The LETBI study is a prospective longitudinal study with multimodal clinical characterization and autopsy endpoints designed to characterize the neuropathology of TBI and its in vivo clinical signatures. LETBI participants were recruited from ongoing longitudinal studies including the TBI Model Systems which ensures excellent TBI characterization and extensive longitudinal data. Here, we propose to follow the original LETBI cohort, and expand to include 4 additional TBI Model Systems centers. By recruiting individuals with a history of well-characterized moderate-severe TBI who are at least 5 years post-TBI, we will study a cohort of individuals at risk for decline, with multimodal LETBI follow-up visits conducted at 2-3 year intervals. We will apply advanced psychometric and statistical methods to consider life course exposures that elevate risk for Alzheimer’s disease (AD) and AD-related dementias (ADRDs), novel neuroimaging processing tools, ultra-sensitive single molecule array (Simoa) technology, and state-of-the-art neuropathology methods in a LETBI cohort enhanced by expanded recruitment from a total of 6 TBI Model System centers. We will leverage existing data collected via telephone in the TBI Model System National Database to characterize clinical course from the time of injury to LETBI enrollment. In Aim 1 we will use existing TBIMS and newly collected LETBI data to identify individuals who have declined from a previously achieved post-injury level of function (i.e., PTND) to determine injury characteristics and lifetime head trauma exposure thresholds associated with domain-specific PTND risk and traumatic encephalopathy syndrome (TES) risk, beyond index injury severity. In Aim 2 we will apply advanced causal inference methods to quantify early life environment and isolate the contribution of exposures other than TBI to PTND and AD/ADRD risk. In Aim 3 we will define the underlying pathology(s) of PTND by identifying in vivo fluid (NfL, GFAP, T-tau, pTau, Aβ42/40) and imaging (network- specific connectivity changes per diffusion MRI (dMRI)) biomarkers of PTND. In Aim 4 we will seek postmortem validation of these in vivo biomarkers in the LETBI autopsy cohort, identifying their postmortem tissue correlates and burden of neurodegenerative disease including CTE across injury exposure and TES diagnostic groups. Our strong transdisciplinary team is ideally positioned to define the risk factors, clinical, and biological signatures of PTND, thereby identifying tools for diagnosis and disease progression while creating rich data resources to share with the scientific community to accelerate AD/ADRD treatment development.