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.

项目摘要/摘要 R01提案：“创伤后神经变性的临床和生物学特征：利用TBI 在体内诊断TBI（LETBI）的体内诊断的模型系统中” 对PAR-22-024的响应，该反应要求研究区分临床和生物学特征与进行性创伤后脑损伤（CSTBI）创伤性脑损伤（CSTBI）的慢性静态效应神经变性（PTND）。这将需要来自特征良好的多样化的纵向多模式数据 TBI生存队列。 LETBI研究是一项具有多模式临床的前瞻性纵向研究旨在表征TBI及其体内神经病理学的表征和尸检端点临床特征。从正在进行的纵向研究中招募了Letbi参与者，包括TBI模型确保出色的TBI表征和广泛的纵向数据的系统。在这里，我们建议遵循原始的Letbi队列，并扩展到包括4个其他TBI模型系统中心。通过招聘具有特征良好的中度重度TBI历史的人至少在TBI之后5年，我们将研究有下降风险的个体，在2 - 3年进行多模式的LETBI随访访问间隔。我们将应用高级心理测量和统计方法来考虑生活课程的暴露升高阿尔茨海默氏病（AD）和广告相关痴呆症（ADRDS）的风险，新型神经成像处理工具，超敏感的单分子阵列（SIMOA）技术以及最新的神经病理学方法通过从总共6个TBI模型系统中心扩大招聘，增强了LETBI队列。我们将利用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临床课程从受伤到诱因到入学。在AIM 1中，我们将使用现有的TBIM和新的收集了Letbi数据，以识别从先前达到的伤害后级别拒绝的个人功能（即PTND）确定损伤特征和终生头部创伤暴露阈值特定于域的PTND风险和创伤性脑病综合征（TES）风险，超出指数损伤严重程度。在AIM 2中，我们将采用高级因果推理方法来量化早期生活环境并隔离 TBI以外的其他暴露贡献对PTND和AD/ADRD风险。在AIM 3中，我们将定义基础 PTND的病理学通过鉴定体内流体（NFL，GFAP，T-TAU，PTAU，Aβ42/40）和成像（网络 - PTND的每个扩散MRI（DMRI））生物标志物的特定连通性变化。在目标4中，我们将寻求在Letbi尸检队列中对这些体内生物标志物的验证后验证，识别其验尸组织相关和燃烧神经退行性疾病，包括跨损伤暴露和TES的CTE 诊断组。我们强大的跨学科团队的理想位置可以定义风险因素，临床和 PTND的生物学特征，从而在创建时识别用于诊断和疾病进展的工具丰富的数据资源与科学界共享，以加速AD/ADRD治疗开发。