Assessment of Blood Biomarker Profile After Acute Concussion During Combative Training Among US Military Cadets: A Prospective Study From the NCAA and US Department of Defense CARE Consortium.

Importance: Validation of protein biomarkers for concussion diagnosis and management in military combative training is important, as these injuries occur outside of traditional health care settings and are generally difficult to diagnose. Objective: To investigate acute blood protein levels in military cadets after combative training-associated concussions. Design, Setting, and Participants: This multicenter prospective case-control study was part of a larger cohort study conducted by the National Collegiate Athletic Association and the US Department of Defense Concussion Assessment Research and Education (CARE) Consortium from February 20, 2015, to May 31, 2018. The study was performed among cadets from 2 CARE Consortium Advanced Research Core sites: the US Military Academy at West Point and the US Air Force Academy. Cadets who incurred concussions during combative training (concussion group) were compared with cadets who participated in the same combative training exercises but did not incur concussions (contact-control group). Clinical measures and blood sample collection occurred at baseline, the acute postinjury point (<6 hours), the 24- to 48-hour postinjury point, the asymptomatic postinjury point (defined as the point at which the cadet reported being asymptomatic and began the return-to-activity protocol), and 7 days after return to activity. Biomarker levels and estimated mean differences in biomarker levels were natural log (ln) transformed to decrease the skewness of their distributions. Data were collected from August 1, 2016, to May 31, 2018, and analyses were conducted from March 1, 2019, to January 14, 2020. Exposure: Concussion incurred during combative training. Main Outcomes and Measures: Proteins examined included glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, neurofilament light chain, and tau. Quantification was conducted using a multiplex assay (Simoa; Quanterix Corp). Clinical measures included the Sport Concussion Assessment Tool-Third Edition symptom severity evaluation, the Standardized Assessment of Concussion, the Balance Error Scoring System, and the 18-item Brief Symptom Inventory. Results: Among 103 military service academy cadets, 67 cadets incurred concussions during combative training, and 36 matched cadets who engaged in the same training exercises did not incur concussions. The mean (SD) age of cadets in the concussion group was 18.6 (1.3) years, and 40 cadets (59.7%) were male. The mean (SD) age of matched cadets in the contact-control group was 19.5 (1.3) years, and 25 cadets (69.4%) were male. Compared with cadets in the contact-control group, those in the concussion group had significant increases in glial fibrillary acidic protein (mean difference in ln values, 0.34; 95% CI, 0.18-0.50; P < .001) and ubiquitin C-terminal hydrolase-L1 (mean difference in ln values, 0.97; 95% CI, 0.44-1.50; P < .001) levels at the acute postinjury point. The glial fibrillary acidic protein level remained high in the concussion group compared with the contact-control group at the 24- to 48-hour postinjury point (mean difference in ln values, 0.22; 95% CI, 0.06-0.38; P = .007) and the asymptomatic postinjury point (mean difference in ln values, 0.21; 95% CI, 0.05-0.36; P = .01). The area under the curve for all biomarkers combined, which was used to differentiate cadets in the concussion and contact-control groups, was 0.80 (95% CI, 0.68-0.93; P < .001) at the acute postinjury point. Conclusions and Relevance: This study's findings indicate that blood biomarkers have potential for use as research tools to better understand the pathobiological changes associated with concussion and to assist with injury identification and recovery from combative training-associated concussions among military service academy cadets. These results extend the previous findings of studies of collegiate athletes with sport-associated concussions.

Use of Blood Biomarkers in the Assessment of Sports-Related Concussion-A Systematic Review in the Context of Their Biological Significance.

OBJECTIVES: To critically review current knowledge on the positive and negative predictive value of blood biomarkers for concussion; to illustrate the clinical and biological contexts that help evaluate the use of these markers in sport-related traumatic brain injuries (TBIs). METHODS: This systematic review was performed in accordance with PRISMA guidelines. We reviewed the measurement, clinical utility, endpoint, and biological significance of blood biomarkers in concussion. RESULTS: A total of 4352 publications were identified. Twenty-six articles relating to blood biomarkers were included in the review. Four common blood biomarkers, namely S100B, tau, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP), were examined. Overall, the studies showed S100B measurement and use, either acutely or at several time points, can distinguish injured from noninjured patients with an uncertain degree of utility in predicting mortality. At present, S100B has largely become an acceptable biomarker of TBI; however, studies have begun to highlight the need to incorporate clinical symptoms instead of S100B concentration in isolation on the basis of inconsistent results and lack of specificity across published studies. Further research is needed to evaluate and validate the use of tau, NSE, and GFAP as a diagnostic aid in the management of concussion and TBI. CONCLUSIONS: At present, blood biomarkers have only a limited role in the evaluation and management of concussion. Although several biomarkers of brain injury have been identified, continued research is required. S100B holds promise as the most clinically useful diagnostic biomarker. Blood biomarkers, in combination with other clinical data, such as head computed tomography, would maximize the diagnostic accuracy. The methodological limitations evident in blood biomarker research results in the need for the clinical utility of blood biomarker use in concussion to be further explored.

Prospective Assessment of Acute Blood Markers of Brain Injury in Sport-Related Concussion.

There is a pressing need to identify objective biomarkers for the assessment of sport-related concussion (SRC) to reduce the reliance on clinical judgment for the management of these injuries. The goal of the current study was to prospectively establish the acute effects of SRC on serum levels of S100 calcium-binding protein beta (S100B), glial fibrillary acidic protein (GFAP), and ubiquitin C-terminal hydrolase-L1 (UCH-L1). Collegiate and high school football players were enrolled and provided blood at pre-season. Injured athletes participated in follow-up visits at ∼6 and 24-48 h following documented SRC (n = 32). Uninjured football players participated in similar follow-up visits and served as controls (n = 29). The median time between injury and blood collection was 2 h (6 h visit) and 22.5 h (24-48 h visit) in concussed athletes. Concussed athletes had significantly elevated UCH-L1 levels at the 6 h visit relative to pre-season levels (Z = 2.22, p = 0.03) and levels in control athletes (Z = 3.02, p = 0.003). Concussed athletes also had elevated S100B at 6 h relative to pre-season (Z = 2.07, p = 0.04) and controls (Z = 2.75, p = 0.006). Both markers showed fair discrimination between concussed and control athletes (UCH-L1 area under receiver operating characteristic curve [AUC] [95% CI] = 0.74 [0.61-0.88], S100B AUC = 0.72 [0.58-0.87]). Percent-change of UCH-L1 and S100B at 6 h relative to pre-season also showed fair discrimination (AUC = 0.79 [0.66-0.92] and AUC = 0.77 [0.64-0.90]). GFAP levels did not differ between groups or in concussed athletes relative to pre-season. This study provides prospective evidence of significant increases in serum levels of UCH-L1 and S100B during the early acute period following SRC, and lays the foundation for future studies examining the clinical potential for blood-based biomarkers in the early detection of concussion.

Serial Assessment of Gray Matter Abnormalities after Sport-Related Concussion.

There is an urgent need to characterize the acute physiological effects of sport-related concussion (SRC). We investigated the effects of SRC on gray matter structure and diffusion metrics in collegiate athletes at 1.64 (T1; n = 33), 8.33 (T2; n = 30), and 32.15 days (T3; n = 36) post-concussion, with healthy collegiate contact-sport athletes serving as controls (HA; n = 46). Plasma levels of glial fibrillary acidic protein (GFAP) were assessed in a subset of athletes. We hypothesized that acute SRC would be associated with increased fractional anisotropy (FA), decreased mean diffusivity (MD), and increased GFAP relative to noninjured HA, without acute differences in gray matter volume or cortical thickness. Further, we hypothesized that neither diffusion nor structure would show longitudinal changes across the first month post-SRC. Finally, we hypothesized that gray matter diffusion metrics would correlate with plasma GFAP levels, as indicated by pre-clinical literature. Consistent with our hypothesis, acute SRC was associated with decreased MD in the left pallidum, increased FA in the right amygdala, and a significantly greater number and volume of subject-specific clusters with increased FA compared to HA. No differences in gray matter volume, cortical thickness, or GFAP were observed between groups. There were no longitudinal changes in any measure across the first month post-SRC. Finally, FA in the right amygdala was inversely correlated with GFAP at T2. These results suggest that gray matter diffusion metrics may be useful in determining the physiological effects of SRC.

Suppression of Serum Prolactin Levels after Sports Concussion with Prompt Resolution Upon Independent Clinical Assessment To Permit Return-to-Play.

A significant outflow of neurotransmitters and metabolites with associated enhanced cortical excitation occurs after concussive head trauma. Cellular changes in the acute post-injury period cannot be observed directly in humans, and as such, require indirect evidence from systems sufficiently sensitive to central neuronal cellular excitation. Dopamine is a neurotransmitter with numerous targets in the central and peripheral nervous system. Changes to central dopaminergic tone result in reciprocal responses to the level of serum prolactin (PRL). Thus, a concussion may lead to abnormal dopaminergic tone, resulting in dynamic perturbations in the serum PRL concentration. To determine the effect of concussion on serum PRL concentrations, venipuncture was performed in the morning in four male intercollegiate athletes (age, 20 ± 1 years; height, 71 ± 5 inches; weight, 174 ± 21 pounds) within 48 h of concussion and again at 7 and 14 days post-injury. Serum PRL concentrations for each visit were categorized by quartile within the normal range. In all athletes, serum PRL concentrations increased from the lower quartiles in samples obtained closer to the time of injury to the higher quartiles at 14 days post-injury. These serum PRL changes accompanied the resolution of symptoms and the clinical decision to permit return-to-play. It may be postulated that transient augmentation of central dopaminergic tone resulted in inhibition of PRL secretion early after concussion and that disinhibition of PRL release occurred when central dopaminergic tone subsequently returned to baseline levels. This novel observation provides evidence for dopaminergic dysfunction after concussion that may be tracked by determination of serum PRL levels.