Project Summary/Abstract Sport-related concussion (SRC) is a major public health concern, causing chronic symptoms in significant numbers of people, and increasing the risk for adverse long-term health outcomes. Prognostic models for predicting recovery following SRC are limited, and identifying potential modifiable factors is critical for understanding mechanism and ultimately personalizing treatment. One such potential factor is cytomegalovirus (CMV), a common neurotropic herpesvirus, that is reactivated by inflammation and has been implicated as a pathological co-factor in multiple inflammatory diseases. Given that SRC results in an acute inflammatory response, this application proposes to investigate the role of CMV in the physiological and clinical outcomes following SRC. To ensure a well-powered and rigorous assessment of our hypotheses, we propose leveraging an existing cohort of athletes enrolled in the Concussion Assessment, Research and Education (CARE) Consortium. Participants (191 athletes with SRC, 151 contact controls, and 155 non-contact controls) previously completed MRI scans, clinical assessments, and blood draws at baseline (pre-injury), 24 hours post-injury, when asymptomatic, and 7 days following unrestricted return to play. Through these baseline and follow-up assessments of brain structure and function, blood-based biomarkers, and clinical phenotypes this study aims to test the hypothesis that CMV serostatus moderates SRC outcomes. The major outcomes include microstructural changes on diffusion MRI, cortical thickness, and resting state functional connectivity (Aim 1), circulating measures of neural injury and inflammation (Aim 2), and severity and duration of post-injury symptoms and cognitive performance (Aim 3). Additionally, the study will use multivariate biclustering to identify subgroups of participants with distinct physiological and clinical trajectories (exploratory Aim 4). Within each aim, the study will also explore the role of two additional common, neurotropic herpesviruses, i.e., herpes simplex virus 1 (HSV-1) and Epstein Barr virus (EBV), which have recently been implicated in Alzheimer’s disease and multiple sclerosis, respectively. The information gathered from this research will advance our understanding of the complex biopsychosocial forces shaping response to and recovery from SRC, potentially improving the precision medicine approach to the assessment and management of patients with SRC and opening a new avenue of treatment given the existence of well-tolerated anti-CMV medications.

Project Narrative Response to and recovery from mild traumatic brain injury (mTBI) is complex, reflecting the interaction of multiple biological, psychological, social, and environmental factors. Ultimately, accurate prognosis and the development of new effective treatments will require the identification of these factors and an elucidation of their mechanistic effects. Based on extensive preliminary data, this application proposes to test the hypothesis that a common herpesvirus, cytomegalovirus (CMV), is an overlooked but treatable source of adverse mTBI outcomes.