Increased cerebrospinal fluid levels of neuroinflammatory biomarkers in athletes with persistent symptoms following sports-related concussion

A sports-related concussion (SRC) is often caused by rapid head rotation at impact, leading to shearing and stretching of axons in the white matter and initiation of secondary inflammatory processes that may exacerbate the initial injury. We hypothesized that athletes with persistent post-concussive symptoms (PPCS) display signs of ongoing neuroinflammation, as reflected by altered profiles of cerebrospinal fluid (CSF) biomarkers, in turn relating to symptom severity. We recruited athletes with PPCS for ≥ 6 months for symptom rating using the Sport Concussion Assessment Tool, version 5 (SCAT-5) and for cognitive assessment using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We analysed 27 CSF inflammatory biomarkers (pro-inflammatory chemokines and cytokine panels) by a multiplex immunoassay using antibodies as electrochemiluminescent labels to quantify concentrations in PPCS athletes, and in healthy age-, sex- and athletically matched controls. Thirty-six subjects were included, 24 athletes with PPCS and 12 controls. The SRC athletes had sustained a median of five concussions, the most recent at a median of 17 months prior to the investigation. When comparing CSF cytokines and chemokines levels in SRC athletes and controls, we found a significant increase in eight (IL-2, TNF-α, IL-15, TNF-β, VEGF, Eotaxin, IP-10, and TARC), a significant decrease in one (Eotaxin-3), and unaltered levels of 16, and two were un-detectable. The SRC athletes reported many and severe post-concussive symptoms on SCAT5, and 10 out of 24 athletes performed in the impaired range (Z<-1.5) on cognitive testing. Individual biomarker concentrations did not correlate with cognitive function. In conclusion, based on CSF inflammatory marker profiling we find signs of ongoing neuroinflammation persisting months to years after the last sport-related concussion in athletes with prolonged and persistent post-concussive symptoms. Since an ongoing inflammatory response may exacerbate the brain injury these results encourage studies of treatments targeting the post-injury inflammatory response in sports-related concussion.