Establishing Mechanisms Between Traumatic Brain Injury and Dementia Using Epidemiology, Clinical Studies, Blood-Based Biomarkers, and Neuroimaging Biomarkers

PROJECT SUMMARY / ABSTRACT Traumatic brain injury (TBI) is common and is associated with significant morbidity and mortality. The sequelae from TBI can be long-lasting, and multiple studies have reported an increased rate of cognitive decline and higher risk of dementia among persons with TBI. However, the mechanisms linking TBI to dementia remain poorly understood, although vascular dysfunction, neuroinflammation, and aggregation of proteins have been proposed. This gap in knowledge was recently highlighted in the 2020 Lancet Commission on Dementia, which added TBI as one of twelve potentially modifiable risk factors for dementia, and in the 2019 NINDS Alzheimer’s Disease-Related Dementias (ADRD) Summit, which formally recommended further study into the role of TBI in dementia, including an emphasis on studying mechanism and developing TBI-AD/ADRD-related biomarkers. To directly address this research need, this application builds on my prior NINDS R25 award and proposes to use epidemiology, clinical studies, and vascular-related blood-based and neuroimaging biomarkers to investigate vascular injury and subsequent vascular dysfunction as mechanisms linking TBI and dementia. The central hypothesis of this proposal is that TBI is associated with cognitive decline and dementia risk in part via vasculopathy-mediated pathways which accelerate neurodegeneration for years post-TBI. This proposal will leverage existing data from 2 ongoing prospective cohort studies (Aims 1 and 2) and new data from a prospectively recruited cohort (Aim 3). The aims of this study are: 1) to determine if acute vascular injury is associated with poor short-term TBI-related cognitive outcomes in the trauma center-based Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Study, 2) to investigate if chronic vascular dysfunction mediates associations of TBI with poor long-term cognitive outcomes in the community-based Atherosclerosis Risk in Communities (ARIC) Study, and 3) to evaluate if the trajectory of post-TBI vascular dysfunction is associated with short-term cognitive outcomes in a prospectively recruited cohort nested within ongoing studies at the University of Pennsylvania Trauma Center. The overall objective of this proposal is to use multi-modal biomarkers of vasculopathy to investigate mechanisms linking TBI and neurocognitive outcomes and to identify time-periods during which future interventions may be effective at preventing TBI-related dementia. In addition to the proposed research, this project will provide me with critical gap-based training, including in the design, conduct, and implementation of clinical-epidemiologic studies and in the use of biomarkers as a method to investigate disease mechanisms linking TBI to outcomes in clinical-epidemiologic studies. This training will enable me to build an independent research program focused on vascular health in TBI with the goal of elucidating disease mechanisms and characterizing TBI outcomes using well-designed prospective clinical- epidemiologic studies of individuals with TBI. Completion of the proposed study will be facilitated by an institutional environment that prioritizes collaboration and provides exemplary research and career support.