Key Points: 1. This study details the consequences of concussion on changes in gene expression, biological processes, signaling pathways, and immune cell proportions across multiple time points in hundreds of collegiate athletes. 2. The signaling pathways activated in response to a concussion, along with changes in immune cell proportions inferred through deconvolution analysis, indicate a coordinated immune response that can remain dysregulated long after injury. 3. These findings are important because the transcriptome signatures of concussion reported herein reflect the known pathophysiology of this injury and reveal the immediate biological response and time course for recovery. Abstract Background: Molecular-based approaches to understanding concussion pathophysiology provide complex biological information that can advance concussion research and identify potential diagnostic and/or prognostic biomarkers of injury. Objective: The aim of this study was to identify gene expression changes in peripheral blood that are initiated following concussion and are relevant to concussion response and recovery. Methods: We analyzed whole blood transcriptomes in a large cohort of concussed and control collegiate athletes who were participating in the multicenter prospective cohort Concussion Assessment, Research, and Education (CARE) Consortium study. Blood samples were collected from collegiate athletes at preseason (baseline), within 6 h of concussion injury, and at four additional prescribed time points spanning 24 h to 6 months post-injury. RNA sequencing was performed on samples from 230 concussed, 130 contact control, and 102 non-contact control athletes. Differential gene expression and deconvolution analysis were performed at each time point relative to baseline. Results: Cytokine and immune response signaling pathways were activated immediately after concussion, but at later time points these pathways appeared to be suppressed relative to the contact control group. We also found that the proportion of neutrophils increased and natural killer cells decreased in the blood following concussion. Conclusions: Transcriptome signatures in the blood reflect the known pathophysiology of concussion and may be useful for defining the immediate biological response and the time course for recovery. In addition, the identified immune response pathways and changes in immune cell type proportions following a concussion may inform future treatment strategies.
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