Concussion BASICS III

Abstract

ObjectiveTo evaluate changes in serum biomarker concentrations (β-amyloid peptide 42 [Aβ42], total tau, ubiquitin carboxy-terminal hydrolyzing enzyme L1, S100 calcium binding protein B [S100B], glial fibrillary acidic protein [GFAP], microtubule associated protein 2 [MAP2], and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase [CNPase]) after sport-related concussion (SRC) in a sample of collegiate athletes. Associations with clinical outcomes were also investigated.MethodsParticipants in this case-control study included 36 athletes (50% male, 61% white, aged 19.7 ± 1.0 years) with SRC. Twenty-nine also had baseline blood drawn, allowing for within-patient analyses of concentration changes. Between-group analyses incorporated 86 demographically matched controls (51% male, 63% white, aged 19.6 ± 1.1 years). Biomarker sensitivity/specificity for SRC vs controls and relative to standardized normative cutoffs was evaluated (receiver operating characteristics). We also analyzed associations between post-SRC clinical outcomes and both biomarker change from baseline and post-SRC concentrations.ResultsThe majority of blood samples had concentrations of GFAP, MAP2, and CNPase below limits of quantification. Within-patient analyses indicated elevated S100B after SRC (p = 0.003, 67% of patients elevated), especially for blood samples collected <4 hours post-SRC (88% of patients). Significant between-group differences were limited to blood draws <4 hours post-SRC: Aβ42 (81% of SRC > control median, area under the curve [AUC] = 0.75 [95% confidence interval 0.59–0.91]), total tau (75% SRC > control, AUC = 0.74 [0.56–0.79]), and S100B (88% SRC > control; AUC [specific to white race] = 0.82 [0.72–0.93]). Using standardized normative cutoffs (z > 1.0), specificity ranged from 79.1% to 89.3% while sensitivity was <70%. Biomarkers were not associated with clinical outcomes.ConclusionFor SRC, diagnostic accuracy of serum biomarkers appears best if blood is collected within a few hours. Accurate blood marker identification of SRC appears somewhat dependent on the “healthy” comparison. Additional research must evaluate whether physiologic changes in the absence of clinical changes, or vice versa, are relevant for concurrent or future neurologic health.Classification of evidenceThis study provides Class III evidence that certain serum biomarkers are elevated from baseline and higher than demographically matched controls after sport-related concussion.

Serum Protein Biomarker Findings Reflective of Oxidative Stress and Vascular Abnormalities in Male, but Not Female, Collision Sport Athletes

“…There were no differences among the different groups of athletes in the serum levels of astroglial damage markers (GFAP, BLBP, PEA15), neuronal and axonal injury makers (UCH-L1, NfL, tau and p-tau) or HMGB1 (a marker of cellular damage and initiator of inflammatory response). These findings are congruent with previous findings reporting no association between a HoC and fluid biomarkers outside the acute (i.e., < 14 days) postinjury phase (32)(33)(34). For example, in a study of 415 athletes, there were no significant relationships between the number of previous concussions or cumulative head injury with baseline levels of serum biomarkers GFAP, S100B, and UCH-L1 (32).…”

“…However, other studies have failed to find a relationship between RHI exposure and neurological outcomes in American footballers (33), suggesting other factors may have contributed to our findings. For example, there are a number of preclinical studies (34), and initial human studies (6,35,36) indicating that males and females have inherent biological differences in their response to mTBI. A possible contributor to differences in circulating biomarkers between males and females are sex hormones, as well as fluctuation in hormones across the female menstrual cycle (37,38).…”

Plasma Biomarker Concentrations Associated With Return to Sport Following Sport-Related Concussion in Collegiate Athletes—A Concussion Assessment, Research, and Education (CARE) Consortium Study

“…For example, higher GFAP levels acutely following an mTBI are associated with having lesions detected by both computed tomography and magnetic resonance imaging 20 and by identifying athletes with an SRC compared with controls with no injuries. 21 Indeed, our group has previously reported that higher GFAP concentrations were associated with SRCs with LOC. 22 Therefore, these results may actually support the association, given that the group with less than 14 days before RTS did report significantly higher incidence of LOC (Table 1).…”

Sex Differences in Circulating T-Tau Trajectories After Sports-Concussion and Correlation With Outcome

“…Several candidate biomarkers have emerged as potential blood tests to aid concussion management. Aside from objectively assessing SRC presence, such markers have been suggested to predict and monitor recovery, while advancing our understanding of the underlying pathophysiological mechanisms of concussion (4)(5)(6)(7). Nonetheless, there has been a preponderant focus on male athletes, and very few studies have explored sex-related variability of brain injury biomarkers and their relationships with the underlying neuropathological and clinical characteristics of SRC (8,9).…”