Concussion Biomarkers Assessed in Collegiate Student-Athletes (BASICS) I: Normative study

Abstract

Objective: To describe variability in concussion biomarker concentrations collected from serum in a sample of healthy collegiate athletes, as well as report reliability metrics in a subsample of female athletes.

Methods: In this observational cohort study, β-amyloid peptide 42 (Aβ₄₂), total tau, S100 calcium binding protein B (S100B), ubiquitin carboxy-terminal hydrolyzing enzyme L1 (UCH-L1), glial fibrillary acidic protein, microtubule associated protein 2, and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) serum concentrations were measured in 415 (61% male, 40% white, aged 19.0 ± 1.2 years) nonconcussed collegiate athletes without recent exposure to head impacts. Standardized normative distributions are reported for each biomarker. We evaluated main effects (analyses of variance) of sex and race, reporting demographic-specific normative metrics when appropriate. In a subset of 31 female participants, test-retest reliability (Pearson r) and reliable change indices (80%, 90%, and 95% confidence intervals) across a 6- to 12-month interval are reported for Aβ₄₂, total tau, S100B, and UCH-L1.

Results: Males exhibited higher UCH-L1 (p < 0.001, Cohen d = 0.75) and S100B (p < 0.001, d = 0.56) than females, while females had higher CNPase (p < 0.001, d = 0.43). Regarding race, black participants had higher baseline levels of UCH-L1 (p < 0.001, d = 0.61) and S100B (p < 0.001, d = 1.1) than white participants. Conversely, white participants had higher baseline levels of Aβ₄₂ (p = 0.005, d = 0.28) and CNPase (p < 0.001, d = 0.46). Test-retest reliability was generally poor, ranging from -0.02 to 0.40, and Aβ₄₂ significantly increased from time 1 to time 2.

Conclusion: Healthy collegiate athletes express concussion-related serum biomarkers in variable concentrations. Accounting for demographic factors such as sex and race is essential. Evidence suggested poor reliability for serum biomarkers; however, understanding how other factors influence biomarker expression, as well as knowledge of reliable change metrics, may improve clinical interpretation and future study designs.

Figure 1. Sex-related differences in baseline serum expression of UCH-L1 (A) and S100B (B)

Both differences were statistically significant (p < 0.001) with at least a medium effect size (d = 0.75 for UCH-L1, d = 0.56 for S100B). For the UCH-L1 (A), 5 data points >750 pg/mL (1.2% of sample) were not included in order to minimize y-axis distortion (4 male, 1 female). For the S100B (B), 2 data points >250 pg/mL (0.5% of sample) were not included (2 male). S100B = S100 calcium binding protein B; UCH-L1 = ubiquitin carboxy-terminal hydrolyzing enzyme L1.

Figure 2. Race-related differences in baseline serum expression of UCH-L1 (A) and S100B (B)

Both differences were statistically significant (p < 0.001) with a medium to large effect size (d = 0.61 for UCH-L1, d = 1.1 for S100B). For the UCH-L1 (A), 5 data points >750 pg/mL (1.2% of sample) were not included in order to minimize y-axis distortion (4 black, 1 white). For the S100B (B), 2 data points >250 pg/mL (0.5% of sample) were not included (2 black). S100B = S100 calcium binding protein B; UCH-L1 = ubiquitin carboxy-terminal hydrolyzing enzyme L1.