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.