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)

临床

基本信息

批准号：
10524430
负责人：
Kristen Dams-O'Connor
金额：
$ 500.57万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10524430
关键词：
Acute Age Algorithms Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid beta-42 Autopsy Biological Biological Markers Biological Models Blood Categories Characteristics Chronic Clinical Clinical Markers Code Cognition Cognitive Cohort Studies Common Data Element Communities Complex Control Groups Craniocerebral Trauma Data Data Collection Databases Dementia Diagnosis Diagnostic Diffusion Magnetic Resonance Imaging Disease Disease Progression Enrollment Ensure Environment Environmental Risk Factor Failure Funding Glial Fibrillary Acidic Protein Image Impairment Individual Inflammation Infrastructure Injury Investigation Late Effects Life Life Cycle Stages Light Liquid substance Longevity Longitudinal Studies Longitudinal prospective study Longterm Follow-up Measures Medical Methodology Methods Molecular Nerve Degeneration Neurodegenerative Disorders Outcome Participant Pathologic Pathology Patient Self-Report Patients Persons Population Positioning Attribute Prevalence Proteins Psychometrics Public Health Recording of previous events Reporting Research Personnel Risk Risk Factors Sampling Scientist Severities Statistical Methods Survivors Symptoms Syndrome Technology Telephone Testing Time Tissues Traumatic Brain Injury United States National Institutes of Health Validation Visit axon injury base candidate marker care systems chronic traumatic encephalopathy clinical phenotype cohort data resource dementia risk design early life adversity early life exposure epidemiology study follow-up imaging biomarker in vivo indexing individual variation magnetic resonance imaging biomarker mixed dementia motor behavior multimodal data multimodality neurobehavioral neurofilament neuroimaging neuropathology novel progressive neurodegeneration prospective recruit resilience response single molecule tau Proteins therapy development tool trauma exposure

项目摘要

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.

项目概要/摘要 R01 提案“创伤后神经变性的临床和生物学特征：利用 TBI 加速 TBI 迟发效应体内诊断的护理模型系统 (LETBI)”提交于对 PAR-22-024 的回应，要求调查区分的临床和生物学特征与进行性创伤后相关的创伤性脑损伤（csTBI）的慢性静态效应这将需要来自充分表征的多样化的纵向多模态数据。 TBI 幸存者队列是一项多模式临床前瞻性纵向研究。旨在表征 TBI 及其体内神经病理学特征的表征和尸检终点 LETBI 参与者是从正在进行的纵向研究（包括 TBI 模型）中招募的。系统可确保出色的 TBI 表征和广泛的纵向数据。遵循最初的 LETBI 队列，并通过招募扩大到包括 4 个额外的 TBI 模型系统中心。对于具有明确的中度至重度 TBI 病史且 TBI 发生后至少 5 年的个体，我们将研究一组有衰退风险的个体，并在 2-3 年进行多模式 LETBI 随访我们将应用先进的心理测量和统计方法来考虑生命历程中的暴露情况。增加阿尔茨海默病 (AD) 和 AD 相关痴呆 (ADRD) 的风险，新型神经影像处理工具、超灵敏单分子阵列 (Simoa) 技术和最先进的神经病理学方法我们将通过从总共 6 个 TBI 模型系统中心扩大招募来增强 LETBI 队列。利用 TBI 模型系统国家数据库中通过电话收集的现有数据来表征从受伤时到 LETBI 登记的临床过程在目标 1 中，我们将使用现有的 TBIMS 和新的 TBIMS。收集 LETBI 数据来识别那些从之前达到的伤后水平下降的个人功能（即 PTND）确定损伤特征和相关的终生头部外伤暴露阈值具有特定领域的 PTND 风险和创伤性脑病综合征 (TES) 风险，超出指标损伤严重程度。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隔离 TBI 以外的暴露对 PTND 和 AD/ADRD 风险的贡献在目标 3 中，我们将定义基础风险。通过识别体内液体（NfL、GFAP、T-tau、pTau、Aβ42/40）和成像（网络- 在目标 4 中，我们将寻找 PTND 的每个扩散 MRI (dMRI) 生物标志物的特定连接变化。在 LETBI 尸检队列中对这些体内生物标志物进行尸检验证，识别其尸检结果神经退行性疾病的组织相关性和负担，包括跨损伤暴露的 CTE 和 TES 我们强大的跨学科团队非常适合定义风险因素、临床和诊断。 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，加速AD/ADRD治疗的开发。