Gene Expression Alterations in Peripheral Blood Following Sport-Related Concussion in a Prospective Cohort of Collegiate Athletes: A Concussion Assessment, Research and Education (CARE) Consortium Study

Abstract Rapid diagnosis of concussion is essential to effective treatment and recovery. Concussion biomarker research has focused primarily on blood-based protein assays to detect markers of brain injury. However, transcriptomic data provides insight into the complex biological response to concussion. In this study, we investigated RNA-seq transcriptome analysis of whole blood in a large cohort of concussed and control collegiate athletes who were participating in the Concussion Assessment, Research and Education (CARE) Consortium. In this multicenter prospective cohort study, blood samples were collected from collegiate athletes at preseason (baseline), post-injury (0–6 hours), 24–48 hours postinjury, time of symptom resolution, 7 days after unrestricted return to play and 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 analysis was performed at each timepoint relative to baseline. Deconvolution analysis was used to identify differences in immune cell types. We identified key genes and pathways that were activated in response to concussion. Cytokine and immune response signaling pathways were activated immediately after concussion, but at later time points, these pathways appeared to be suppressed relative to contact controls. RNA-seq data also revealed that the proportion of neutrophils increased and natural killer cells decreased in the blood following concussion. 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 concussion could inform future treatment strategies.