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.

The brain-derived neurotrophic factor Val66met polymorphism is associated with better attention and working memory performance and resilience to mild chronic stress.

The val66met polymorphism of the brain-derived neurotrophic factor (BDNF) gene has been identified as a potential moderator for the relationship between chronic stress and executive functioning. However, whether the presence of the met allele increases cognitive vulnerability or resilience to stress has yet to be determined. Given the established effects of autonomic activity and psychological arousal on executive functioning, in the present study, 56 healthy university students completed self-report measures of chronic stress, positive arousal (vigour) and negative arousal (anxiety) and measured heart-rate variability to quantify autonomic activity. Participants then completed a cognitive test battery that measured attention, decision-making, visual learning and working memory. Regression analyses demonstrated that Val/met participants performed better on attention and working memory tasks than Val/val participants, but no differences were seen in decision-making and visual learning. Further, Val/met participants were protected from stress-related differences in attention seen in Val/val participants. Val66met was not associated with physiological or psychological arousal. This study demonstrates that val66met plays an important but selective role in cognitive performance.

Clinical and Blood Biomarker Trajectories after Concussion: New Insights from a Longitudinal Pilot Study of Professional Flat-Track Jockeys.

There is a recognized need for objective tools for detecting and tracking clinical and neuropathological recovery after sports-related concussion (SRC). Although computerized neurocognitive testing has been shown to be sensitive to cognitive deficits after SRC, and some blood biomarkers have shown promise as indicators of axonal and glial damage, the potential utility of these measures in isolation and combination for assisting SRC diagnosis and tracking recovery is not well understood. To provide new insights, we conducted a prospective study of 64 male and female professional flat-track jockeys (49 non-SRC, 15 SRC), with each jockey undergoing symptom evaluation, cognitive testing using the CogSport battery, and serum biomarker quantification of glial fibrillary acidic protein (GFAP), tau, and neurofilament light (NfL) using a Simoa HD-X Analyzer. Measures were performed at baseline (i.e., pre-injury), and 2 and 7 days and 1 and 12 months after SRC. Symptoms were most pronounced at 2 days and had largely resolved by either 7 days or 1 month. CogSport testing at 2 days revealed cognitive impairments relative to both non-concussed peers and their own pre-injury baselines, with SRC classification utility found at 2 days, and to a slightly lesser extent, at 7 days. Relatively prolonged changes in serum NfL were observed, with elevated levels and classification utility persisting beyond the resolution of SRC symptoms and cognitive deficits. Finally, SRC classification performance throughout the 1st month after SRC was optimized through the combination of cognitive testing and serum biomarkers. Considered together, these findings provide further evidence for a role of computerized cognitive testing and fluid biomarkers of neuropathology as objective measures to assist in the identification of SRC and the monitoring of clinical and neuropathological recovery.

Gender and Workplace Stress Affect the Association Between Concussion History and Depression Symptoms in Professional Jockeys.

OBJECTIVE: Professional jockeys experience high rates of concussion, workplace stress, and poor mental health. The present cross-sectional study, for the first time, concurrently assessed the potential interplay between concussion history and workplace stress with current depression symptoms. METHOD: Seventy-two professional flat-track jockeys (male = 49, female = 23) were grouped based on self-reported concussion history (CG; n = 56) and those who did not report a concussion history (NCG; total n = 16). Analyses featured both between (CG vs NCG) and within group (CG only) assessment on self-reported measures of workplace stress and depression symptoms (affect, daily functioning). RESULTS: Jockeys in the CG had more symptoms of negative affect than the NCG. This association, however, was nonsignificant after covarying for age, gender, and workplace stress. Higher workplace stress (p = .005) and gender (p = .001) were associated with poorer daily functioning after controlling for concussion history (CG vs. NCG) and age. Gender moderated the association between concussion group and poorer daily functioning (ß = -18.739, t (71) = -2.924, p = .005), with the difference between CG and NCG significant for females, but not males (ß = 33.648, t (71) = 3.420, p = .001). CONCLUSIONS: The findings provide preliminary evidence that previously concussed females may be more likely to report poorer daily functioning than males with a history of concussion, and that workplace stress may reduce the association between a history of concussion and depression symptoms. Prospective studies are required to validate and extend these findings.

Within subject rise in serum TNFα to IL-10 ratio is associated with poorer attention, decision-making and working memory in jockeys.

Jockeys work in high-risk environments that rely heavily on attention- and decision-making to perform well and safely. Workplace stress literature has often overlooked the impact of stress on cognition, and designs that include physiological measures are rare. This study assessed the prospective concurrent relationships between workplace stress, depression symptoms and low-grade inflammation with cognitive performance among professional jockeys. Professional jockeys (N = 35, Mage = 32.29) provided information on workplace stress and depression symptoms, with serum levels of inflammatory cytokines (IL-6, IL-10, TNFα) and cytokine balance (IL-6: IL-10, TNFα: IL-10) quantified with SIMOA, and cognitive performance with CogSport computer-based testing battery. These measures were repeated after a twelve-month interval. Increased workplace stress between testing intervals was associated to an increased cytokine imbalance (ß = 0.447, p = .015) after controlling for age and gender. Increases in cytokine imbalance occurred in unison with decreases in attention (ß = 0.516, p = .002), decision-making (ß = 0.452, p = .009) and working memory (ß = 0.492, p = .004). These preliminary findings suggest the underlying mechanisms linking workplace stress and reduced cognitive performance may be influenced by measures of low-grade inflammation and specifically a cytokine imbalance. Our findings suggest a measure of cytokine balance may explain the heterogenous findings in previous studies that have focussed solely on the association of workplace stress with pro-inflammatory cytokines. Future work is needed however, to provide a broader evidence-base for our claims to better inform designs to intervene in the higher workplace stress-poorer cognition relationship.

Prospective increases in depression symptoms and markers of inflammation increase coronary heart disease risk - The Whitehall II cohort study.

OBJECTIVE: Stress, inflammation, and depression are associated to coronary heart disease (CHD). However, how these constructs collectively contribute to CHD incidence is not well understood. For the first time, this study explored the concurrent relationship between workplace stress, depression symptomology and levels of low-grade inflammation with future CHD incidence. METHODS: Data from the 5-year intervals at phase 5, 7, and 9 of the Whitehall II study (N = 8348, Mage = 56) provided measures of workplace stress, depression symptomology, inflammation (interleukin-6, C-reactive protein, fibrinogen), and CHD incidence. The proposed stress-inflammation-depression-CHD pathway was assessed with a longitudinal design incorporating a structural equation model (SEM) that measured if changes in stress, depression, and inflammation between phase 5 to phase 7 predicted first-time CHD events between phases 7 and 9. RESULTS: The SEM empirically supported this proposed pathway and demonstrated excellent model fit, χ (72) = 3582.959, p < .001, CFI = 0.896, RMSEA = 0.076 (CI90 = 0.074, 0.079), while depression symptoms mediated the association between workplace stress and CHD incidence, B = 0.003 (CI90 = 0.001, 0.004). Further, survival analysis indicated that individuals with higher mean scores (across phases) of depression symptoms or fibrinogen levels were more likely to experience a first time CHD event. CONCLUSIONS: Increases in depression symptoms and fibrinogen levels may be good indicators of future CHD morbidity among older employees. Future research is encouraged to monitor negative affective states and the potential use of biobehavioural options to reduce depression and inflammation that may mitigate CHD risk.

Depression symptoms mediate the association between workplace stress and interleukin 6 in women, but not men: The Whitehall II study.

Workplace stress and depression are positively related with inflammation, and each other. Low-grade inflammation and concurrent high levels of workplace stress or depression has been related with future morbidity. The potential pathway between constructs however, remains elusive. For the first time, this study explored the concurrent relationship between workplace stress, depressive symptomology and low-grade inflammation, and considered the role of gender in these relationships. Data from the Whitehall II cohort study (N â€‹= â€‹2528, Mage â€‹= â€‹57.01, 23.7% females) provided measures of workplace stress (job demand-control; JDC), depressive symptomology (Centre for Epidemiological Studies Depression scale; CES-D) and circulating inflammatory markers, interleukin-6 (IL-6) and C-reactive protein (CRP) collected on the same day from a single time point. Females had higher workplace stress, depressive symptoms and lower serum IL-6 concentrations. For males, higher workplace stress was associated with higher depressive symptoms. For females, higher depressive symptoms were related with elevated IL-6 levels, and both higher workplace stress and IL-6 levels were associated with higher depressive symptoms. Higher depressive symptoms were related with higher CRP levels in men only. Higher depressive symptoms statistically mediated the relationship between higher workplace stress and IL-6 levels in females only, b â€‹= â€‹0.016, CI [0.002, 0.039]. Females in this large cohort had higher levels of job strain, depression and lower IL-6 concentrations than males. In females, higher depressive symptoms were associated with higher serum IL-6 levels and workplace stress was not. Considered together, these findings suggest that low job control may be more apparent in females than males, but it is primarily negative affect that drives the positive relationship between work stress and serum IL-6 concentrations in females. Replicating the current design with a suitably proximal follow-up is required to determine if the associations identified are causal.

Assessing the utility of a virtual-reality neuropsychological test battery, 'CONVIRT', in detecting alcohol-induced cognitive impairment.

New technologies such as virtual reality (VR) and eye-tracking software have paved the way for more sophisticated and ecologically valid measures of cognitive function. Testing the sensitivity and reliability of such measurements in response to acute alcohol intoxication provides a first step in establishing how these measures may operate in relation to cognitive impairments observed post-concussion. Healthy young adults (N = 54, M = 20.65, SD = 2.06, 30 females) completed the CONVIRT test battery (manual simple and choice reaction-time and saccade reaction-time) at three breath alcohol concentration (BrAC) levels: 0.00%T1, 0.05%T2, 0.08%T3. Participants consumed alcoholic beverages at 30-min intervals, with BrAC monitored at 15-min intervals using a breathalyser. All three CONVIRT measures were sensitive to changes in cognitive performance induced by alcohol at BrAC levels at or exceeding 0.05%. A composite measure was also sensitive to alcohol intoxication (Cohen's d = .85 at BrAC = 0.05%; d = 1.20 at BrAC = 0.08%). Strong test-retest reliability was observed (all r < .80), with no gender differences noted. CONVIRT measures were reliable and detected dose-dependent changes in alcohol-induced cognitive impairment. Potentially, the ecologically valid measures may assist in better quantifying the effects of conditions such as concussion, on cognitive performance.

Assessing the Long-Term Impact of Concussion upon Cognition: A 5-Year Prospective Investigation.

OBJECTIVE: Jockeys have high rates of concussion, with 5% of jockeys receiving at least one concussion annually. The impact of acute concussion upon cognition is well understood, but less is known about the long-term effects of concussion upon cognition. Our aim was to assess the impact of concussion upon jockeys who had provided pre-concussion assessments of cognition using a prospective design. METHOD: In this study, over a 5-year period, we assessed the cognitive performance of jockeys with ≥1 medically diagnosed concussion (MDC; n = 17, months since concussion, M = 29.18), against those who had not been concussed (NC; n = 41). Jockeys who had not been concussed in the preceding 6 months completed four computer-based cognitive assessments from the CogSport battery. RESULTS: Unlike the majority of the small existing literature, there was no difference (p ≥ .05) between the MDC and NC groups after controlling for age and baseline performance. Additionally, we used a measure of reliable change to assess for clinically meaningful decrements from baseline in each test and composite score 5 years later. None of the jockeys in the MDC group recorded significant decrements on any CogSport measure from baseline (z > -1.65). CONCLUSIONS: The findings suggest that the presence of concussion does not result in persistent decrements in cognitive performance and that when findings are considered collectively, assessing factors beyond medically diagnosed concussion (e.g., chronic stress, undiagnosed concussion) may improve the interpretation of our current findings.