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) - 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.
