Characterizing factors influencing baseline plasma biomarkers for sport-related concussion in youth.

Developing objective means to clinically diagnose sport-related concussion (SRC) is a top priority in sport medicine, particularly in the pediatric context given the vulnerability of the developing brain. While advances in SRC blood biomarkers are being made in adult populations, little work is being done in youth. Clinical validation of these biomarkers post-SRC will first require investigation into their presentation in a healthy uninjured state. Furthermore, rapid pubertal changes in this age group may implicate possible interactions with circulating sex hormones, and specifically the menstrual cycle for female athletes. This cross-sectional study aimed to characterize pre-injury plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light (NF-L), ubiquitin C-terminal hydrolase-L1 (UCH-L1), total tau (T-tau), and phosphorylated tau-181 (P-tau-181) considering the influence of previous concussion, age, and sex in healthy youth sport participants. Possible associations with menstrual cycle phase and circulating sex hormone levels (progesterone, estradiol, and testosterone) were also explored. Pre-injury blood samples were obtained from 149 healthy youth (48% female, ages 11-18) participating in the larger SHRed Concussions multi-site longitudinal cohort study. Main outcomes were natural log (ln) transformed plasma GFAP, NF-L, UCH-L1, T-tau, and P-tau-181 concentrations (quantified on the Quanterix Simoa HD-X platform). Mixed-effects multivariable linear regression was used to assess the associations between biomarkers and self-reported history of previous concussion (yes/no), age (years), sex (male/female), objectively determined menstrual cycle phase (follicular/luteal), plasma progesterone, estradiol, and testosterone. Males had 19.8% lower UCH-L1 (β=-0.221, 95% CI [-0.396, -0.046]), 18.9% lower GFAP (β=-0.210, 95% CI [-0.352, -0.068]), and 21.8% higher P-tau-181 (β=0.197, 95% CI [0.048, 0.346]) compared to females, adjusting for age and previous concussion. GFAP decreased 9.5% with each 1-year increase in age, adjusting for previous concussion and sex (β=-0.100, 95% CI [-0.152, -0.049]). No biomarkers were associated with a history of previous concussion. Exploratory investigations found no associations between biomarkers and menstrual cycle phase. However, females displayed an age-adjusted negative association between T-tau and progesterone (β=-0.010, 95%CI [-0.018, -0.002]), whereas males had a negative age-adjusted association between UCH-L1 and testosterone (β=-0.020, 95%CI [-0.037, -0.002]). These results indicate age and sex-specific reference intervals may be warranted for pediatric athlete populations prior to clinical validation of blood biomarkers for SRC. Additionally, hormonal associations highlight the need to consider puberty and development in adolescent studies. Overall, findings suggest these biomarkers are resilient to a history of previous concussion and menstrual cycle phase, supporting their continued research in youth SRC.