The Late Effects of TBI (LETBI) Study: Injury Patterns and Biological Markers of Post-Traumatic Neurodegeneration - Project Summary/Abstract Traumatic brain injury (TBI) is a recognized risk factor for Alzheimer’s disease (AD) and related dementias (ADRDs), and factors such as number of lifetime TBIs, TBI severity, and patterns of injury including exposure to repetitive head impacts (RHI) have important implications for long-term clinical and pathological sequelae. The clinical phenotypes and pathological processes through which a TBI initiates and/or accelerates AD/ADRD pathogenesis (i.e., post-traumatic neurodegeneration (PTND)) remain unknown. We will address this gap in the proposed competitive renewal by longitudinally following a large, well-characterized cohort of over 500 individuals living with chronic TBI: the Late Effects of TBI (LETBI) study. LETBI participants have completed cognitive and neurobehavioral evaluations, blood draws, neuroimaging, and have made known their wishes for brain donation. With unparalleled multimodal longitudinal data, we will identify in-vivo clinical and biological markers of PTND to inform early diagnosis, prognosis, disease monitoring, and future mechanistic studies. We will address the overarching hypothesis that distinct patterns of lifetime head trauma contribute to clinical decline that can be predicted during life by noninvasive blood biomarkers and reflected in neuroimaging indices of neurovascular, neuroinflammatory, and neurodegenerative disease. We will validate in-vivo biomarkers in the LETBI autopsy cohort by quantifying polypathology burden in decedents with distinct injury patterns. Identifying in-vivo biological markers of PTND is of high priority given the population prevalence of TBI and the urgent need to identify disease-modifying therapeutics for AD/ADRD. Our work is organized around 3 Specific Aims: 1. To test the hypothesis that greater number of TBIs, more severe TBI, and RHI exposures are associated with clinical decline by quantifying the contributions of distinct patterns of lifetime TBI exposure to cognitive, neurobehavioral, and motor function over time. 2. To test the hypothesis that a panel of clinically accessible blood biomarkers can predict a) multi-domain clinical decline, and b) are related to progression in neuroimaging indices of neurovascular disease, neuroinflammation, and neurodegeneration that are detectable on MRI. 3. In the LETBI autopsy cohort, we will determine the pathological substrates of distinct TBI exposure patterns by testing the hypotheses that a) vascular, inflammatory, and neurodegenerative pathology burden differs across head trauma exposure patterns; and b) quantitative polypathology burden is highest in pericontusional regions. Our multidisciplinary team is uniquely positioned to advance understanding of the late effects of TBI. We will apply a novel biomarker discovery platform, innovative neuroimaging techniques, and multimodal autopsy methods to a large heterogeneous cohort of TBI survivors to accelerate scientific knowledge of the complex polypathology of TBI and PTND for improved diagnostics and care.
