Hiding in Plain Sight: Factors Influencing the Neuroinflammatory Response to Sport-Related Concussion

Sport-related concussion (SRC) is a major concern among athletes and clinicians around the world. Research into fluid biomarkers of SRC has made significant progress in understanding the complex underlying pathophysiology of concussion. However, little headway has been made toward clinically validating any biomarkers to improve the clinical management of SRC. A major obstacle toward clinical translation of any fluid biomarker is the heterogeneity of SRC overlapping with multiple physiological systems involved in pathology and recovery. Neuroinflammation post-SRC is one such system that may confound fluid biomarker data on many fronts. Neuroinflammatory processes consist of cell mediators, both within the central nervous system and the periphery, that play vital roles in regulating the response to brain injury. Further, neuroinflammation is influenced by many biopsychosocial variables present in most athletic populations. In this commentary, we propose that future fluid biomarker research should take a systems biology approach in the context of the neuroinflammatory response to SRC. We highlight how biological variables, such as age, sex, immune challenges, and hypothalamic-pituitary-adrenal (HPA)-axis responses to stress, may alter neuroinflammation. Further, we underscore the importance of accounting for health and lifestyle variables, such as diet, exercise, sleep, and pre-morbid medical factors, when measuring inflammatory markers of SRC. To successfully move toward clinical translation, fluid biomarker research should take a more holistic approach in study design and data interpretation, collecting information on hidden variables that may be influencing the neuroinflammatory response to SRC.