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.

Project Narrative The implications of traumatic brain injury (TBI) for Alzheimer’s Disease (AD) and Alzheimer’s Disease Related Dementias (ADRD) are of great public health concern, as TBI is a known risk factor for AD/ADRD. By leveraging the infrastructure of the nationwide longitudinal TBI Model Systems of Care (TBIMS) to enroll individuals who are >5 years post-injury into the Late Effects of TBI (LETBI) study for 2 multimodal study visits including cognitive, neurobehavioral, fluid biomarker, and neuroimaging data collection, we will determine injury characteristics and lifetime head trauma exposure thresholds associated with post-traumatic neurodegeneration (PTND) and their in vivo clinical, fluid, and imaging biomarkers. Our strong transdisciplinary team is ideally positioned to apply state-of-the-art statistical, molecular, neuroimaging, and neuropathological methods to define the risk factors and clinical and biological signatures of PTND and identify tools for diagnosis and disease progression, while creating rich data resources to share with the scientific community to accelerate treatment of AD/ADRDs.