Biomarkers of Neurobiologic Recovery in Adults With Sport-Related Concussion.

Importance: Sport-related concussion (SRC), a form of mild traumatic brain injury, is a prevalent occurrence in collision sports. There are no well-established approaches for tracking neurobiologic recovery after SRC. Objective: To examine the levels of serum glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) in Australian football athletes who experience SRC. Design, Setting, and Participants: A cohort study recruiting from April 10, 2021, to September 17, 2022, was conducted through the Victorian Amateur Football Association, Melbourne, Australia. Participants included adult Australian football players with or without SRC. Data analysis was performed from May 26, 2023, to March 27, 2024. Exposure: Sport-related concussion, defined as at least 1 observable sign and/or 2 or more symptoms. Main Outcomes and Measures: Primary outcomes were serum GFAP and NfL levels at 24 hours, and 1, 2, 4, 6, 8, 12, and 26 weeks. Secondary outcomes were symptoms, cognitive performance, and return to training times. Results: Eighty-one individuals with SRC (median age, 22.8 [IQR, 21.3-26.0] years; 89% male) and 56 control individuals (median age, 24.6 [IQR, 22.4-27.3] years; 96% male) completed a total of 945 of 1057 eligible testing sessions. Compared with control participants, those with SRC exhibited higher GFAP levels at 24 hours (mean difference [MD] in natural log, pg/mL, 0.66 [95% CI, 0.50-0.82]) and 4 weeks (MD, 0.17 [95% CI, 0.02-0.32]), and NfL from 1 to 12 weeks (1-week MD, 0.31 [95% CI, 0.12-0.51]; 2-week MD, 0.38 [95% CI, 0.19-0.58]; 4-week MD, 0.31 [95% CI, 0.12-0.51]; 6-week MD, 0.27 [95% CI, 0.07-0.47]; 8-week MD, 0.36 [95% CI, 0.15-0.56]; and 12-week MD, 0.25 [95% CI, 0.04-0.46]). Growth mixture modeling identified 2 GFAP subgroups: extreme prolonged (16%) and moderate transient (84%). For NfL, 3 subgroups were identified: extreme prolonged (7%), moderate prolonged (15%), and minimal or no change (78%). Individuals with SRC who reported loss of consciousness (LOC) (33% of SRC cases) had higher GFAP at 24 hours (MD, 1.01 [95% CI, 0.77-1.24]), 1 week (MD, 0.27 [95% CI, 0.06-0.49]), 2 weeks (MD, 0.21 [95% CI, 0.004-0.42]) and 4 weeks (MD, 0.34 [95% CI, 0.13-0.55]), and higher NfL from 1 week to 12 weeks (1-week MD, 0.73 [95% CI, 0.42-1.03]; 2-week MD, 0.91 [95% CI, 0.61-1.21]; 4-week MD, 0.90 [95% CI, 0.59-1.20]; 6-week MD, 0.81 [95% CI, 0.50-1.13]; 8-week MD, 0.73 [95% CI, 0.42-1.04]; and 12-week MD, 0.54 [95% CI, 0.22-0.85]) compared with SRC participants without LOC. Return to training times were longer in the GFAP extreme compared with moderate subgroup (incident rate ratio [IRR], 1.99 [95% CI, 1.69-2.34]; NfL extreme (IRR, 3.24 [95% CI, 2.63-3.97]) and moderate (IRR, 1.43 [95% CI, 1.18-1.72]) subgroups compared with the minimal subgroup, and for individuals with LOC compared with those without LOC (IRR, 1.65 [95% CI, 1.41-1.93]). Conclusions and Relevance: In this cohort study, a subset of SRC cases, particularly those with LOC, showed heightened and prolonged increases in GFAP and NfL levels, that persisted for at least 4 weeks. These findings suggest that serial biomarker measurement could identify such cases, guiding return to play decisions based on neurobiologic recovery. While further investigation is warranted, the association between prolonged biomarker elevations and LOC may support the use of more conservative return to play timelines for athletes with this clinical feature.

Mild Traumatic Brain Injury in Adolescent Mice Alters Skull Bone Properties to Influence a Subsequent Brain Impact at Adulthood: A Pilot Study.

Mild traumatic brain injuries (mTBI) are common during adolescence, and limited clinical evidence suggests that a younger age at first exposure to a mTBI may lead to worse long-term outcomes. In this study, we hypothesized that a mTBI during adolescence would predispose toward poorer neurobehavioral and neuropathological outcomes after a subsequent injury at adulthood. Mice received a mild weight drop injury (mTBI) at adolescence (postnatal day 35; P35) and/or at adulthood (P70). Mice were randomized to 6 groups: 'sham' (sham-surgery at P35 only); 'P35' (mTBI at P35 only); 'P35 + sham' (mTBI at P35 + sham at P70); 'sham + P70' (sham at P35 + mTBI at P70); 'sham + sham' (sham at both P35 and P70); or 'P35 + P70' (mTBI at both P35 and P70). Acute apnea and an extended righting reflex time confirmed a mTBI injury at P35 and/or P70. Cognitive, psychosocial, and sensorimotor function was assessed over 1-week post-injury. Injured groups performed similarly to sham controls across all tasks. Immunofluorescence staining at 1 week detected an increase in glial activation markers in Sham + P70 brains only. Strikingly, 63% of Sham + P70 mice exhibited a skull fracture at impact, compared to 13% of P35 + P70 mice. Micro computed tomography of parietal skull bones found that a mTBI at P35 resulted in increased bone volume and strength, which may account for the difference in fracture incidence. In summary, a single mTBI to the adolescent mouse brain did not exacerbate the cerebral effects of a subsequent mTBI in adulthood. However, the head impact at P35 induced significant changes in skull bone structure and integrity. These novel findings support future investigation into the consequences of mTBI on skull bone.