Abstract
Sport concussions can be difficult to diagnose and if missed, they can expose athletes to greater injury risk and long-lasting neurological disabilities. Discovery of objective biomarkers to aid concussion diagnosis is critical to protecting athlete brain health. To this end, we performed targeted proteomics on plasma obtained from adolescent athletes suffering a sports concussion. A total of 11 concussed male athletes were enrolled at our academic Sport Medicine Concussion Clinic, as well as 24 sex-, age- and activity-matched healthy control subjects. Clinical evaluation was performed and blood was drawn within 72 h of injury. Proximity extension assays were performed for 1,472 plasma proteins; a total of six proteins were considered significantly different between cohorts (P < 0.01; five proteins decreased and one protein increased). Receiver operating characteristic curves on the six individual protein biomarkers identified had areas-under-the-curves (AUCs) for concussion diagnosis ≥0.78; antioxidant 1 copper chaperone (ATOX1; AUC 0.81, P = 0.003), secreted protein acidic and rich in cysteine (SPARC; AUC 0.81, P = 0.004), cluster of differentiation 34 (CD34; AUC 0.79, P = 0.006), polyglutamine binding protein 1 (PQBP1; AUC 0.78, P = 0.008), insulin-like growth factor-binding protein-like 1 (IGFBPL1; AUC 0.78, P = 0.008) and cytosolic 5'-nucleotidase 3A (NT5C3A; AUC 0.78, P = 0.009). Combining three of the protein biomarkers (ATOX1, SPARC and NT5C3A), produced an AUC of 0.98 for concussion diagnoses (P < 0.001; 95% CI: 0.95, 1.00). Despite a paucity of studies on these three identified proteins, the available evidence points to their roles in modulating tissue inflammation and regulating integrity of the cerebral microvasculature. Taken together, our exploratory data suggest that three or less novel proteins, which are amenable to a point-of-care immunoassay, may be future candidate biomarkers for screening adolescent sport concussion. Validation with protein assays is required in larger cohorts.
Highlights
METHODSConcussions are frequent in sport, resulting from either a direct blow to the head or as a consequence of transmitted forces from a blow to the body [1,2,3]
We identify a number of plasma proteins that change after concussion, with six proteins having good to very good diagnostic potential (AUC 0.78– 0.81)
Concussion diagnostics are complicated by patient and injury heterogeneity
Summary
Concussions are frequent in sport, resulting from either a direct blow to the head or as a consequence of transmitted forces from a blow to the body [1,2,3]. To the best of our knowledge, PEA has not yet been applied to biomarker discovery for concussion In this exploratory study, we hypothesized that the expression of numerous plasma proteins would be altered by concussion in adolescent athletes, thereby aiding identification of objective biomarkers either alone or in combinations. We report directional changes in six plasma proteins after concussion in adolescent athletes and provide a simplified diagnostic model utilizing three protein biomarkers. All patients with a suspected concussion, as well as non-injured control athletes, including their parents/guardians, completed a Sports Concussion Assessment Tool−3rd Edition [SCAT3 [20]; 13–14 years of age]. Receiver operating characteristic (ROC) curves were conducted and area-under-the-curve (AUC) was calculated to determine sensitivity and specificity of all individual proteins for predicting concussion.
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