Cerebrospinal fluid levels of neuroinflammatory biomarkers are increased in athletes with persistent post-concussive symptoms following sports-related concussion.

A sports-related concussion (SRC) is often caused by rapid head rotation at impact, leading to shearing and stretching of axons in the white matter and initiation of secondary inflammatory processes that may exacerbate the initial injury. We hypothesized that athletes with persistent post-concussive symptoms (PPCS) display signs of ongoing neuroinflammation, as reflected by altered profiles of cerebrospinal fluid (CSF) biomarkers, in turn relating to symptom severity. We recruited athletes with PPCS preventing sports participation as well as limiting work, school and/or social activities for ≥ 6 months for symptom rating using the Sport Concussion Assessment Tool, version 5 (SCAT-5) and for cognitive assessment using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Following a spinal tap, we analysed 27 CSF inflammatory biomarkers (pro-inflammatory chemokines and cytokine panels) by a multiplex immunoassay using antibodies as electrochemiluminescent labels to quantify concentrations in PPCS athletes, and in healthy age- and sex-matched controls exercising ≤ 2 times/week at low-to-moderate intensity. Thirty-six subjects were included, 24 athletes with PPCS and 12 controls. The SRC athletes had sustained a median of five concussions, the most recent at a median of 17 months prior to the investigation. CSF cytokines and chemokines levels were significantly increased in eight (IL-2, TNF-α, IL-15, TNF-ß, VEGF, Eotaxin, IP-10, and TARC), significantly decreased in one (Eotaxin-3), and unaltered in 16 in SRC athletes when compared to controls, and two were un-detectable. The SRC athletes reported many and severe post-concussive symptoms on SCAT5, and 10 out of 24 athletes performed in the impaired range (Z < - 1.5) on cognitive testing. Individual biomarker concentrations did not strongly correlate with symptom rating or cognitive function. Limitations include evaluation at a single post-injury time point in relatively small cohorts, and no control group of concussed athletes without persisting symptoms was included. Based on CSF inflammatory marker profiling we find signs of ongoing neuroinflammation persisting months to years after the last SRC in athletes with persistent post-concussive symptoms. Since an ongoing inflammatory response may exacerbate the brain injury these results encourage studies of treatments targeting the post-injury inflammatory response in sports-related concussion.

Chronic cerebral blood flow alterations in traumatic brain injury and sports-related concussions.

PRIMARY OBJECTIVE: Traumatic brain injury (TBI) and sports-related concussion (SRC) may result in chronic functional and neuroanatomical changes. We tested the hypothesis that neuroimaging findings (cerebral blood flow (CBF), cortical thickness, and 1H-magnetic resonance (MR) spectroscopy (MRS)) were associated to cognitive function, TBI severity, and sex. RESEARCH DESIGN: Eleven controls, 12 athletes symptomatic following ≥3SRCs and 6 patients with moderate-severe TBI underwent MR scanning for evaluation of cortical thickness, brain metabolites (MRS), and CBF using pseudo-continuous arterial spin labeling (ASL). Cognitive screening was performed using the RBANS cognitive test battery. MAIN OUTCOMES AND RESULTS: RBANS-index was impaired in both injury groups and correlated with the injury severity, although not with any neuroimaging parameter. Cortical thickness correlated with injury severity (p = 0.02), while neuronal density, using the MRS marker ((NAA+NAAG)/Cr, did not. On multivariate analysis, injury severity (p = 0.0003) and sex (p = 0.002) were associated with CBF. Patients with TBI had decreased gray (p = 0.02) and white matter (p = 0.02) CBF compared to controls. CBF was significantly lower in total gray, white matter and in 16 of the 20 gray matter brain regions in female but not male athletes when compared to female and male controls, respectively. CONCLUSIONS: Injury severity correlated with CBF, cognitive function, and cortical thickness. CBF also correlated with sex and was reduced in female, not male, athletes. Chronic CBF changes may contribute to the persistent injury mechanisms in TBI and rSRC.

Refined Analysis of Chronic White Matter Changes after Traumatic Brain Injury and Repeated Sports-Related Concussions: Of Use in Targeted Rehabilitative Approaches?

Traumatic brain injury (TBI) or repeated sport-related concussions (rSRC) may lead to long-term memory impairment. Diffusion tensor imaging (DTI) is helpful to reveal global white matter damage but may underestimate focal abnormalities. We investigated the distribution of post-injury regional white matter changes after TBI and rSRC. Six patients with moderate/severe TBI, and 12 athletes with rSRC were included ≥6 months post-injury, and 10 (age-matched) healthy controls (HC) were analyzed. The Repeatable Battery for the Assessment of Neuropsychological Status was performed at the time of DTI. Major white matter pathways were tracked using q-space diffeomorphic reconstruction and analyzed for global and regional changes with a controlled false discovery rate. TBI patients displayed multiple classic white matter injuries compared with HC (p < 0.01). At the regional white matter analysis, the left frontal aslant tract, anterior thalamic radiation, and the genu of the corpus callosum displayed focal changes in both groups compared with HC but with different trends. Both TBI and rSRC displayed worse memory performance compared with HC (p < 0.05). While global analysis of DTI-based parameters did not reveal common abnormalities in TBI and rSRC, abnormalities to the fronto-thalamic network were observed in both groups using regional analysis of the white matter pathways. These results may be valuable to tailor individualized rehabilitative approaches for post-injury cognitive impairment in both TBI and rSRC patients.

Tau aggregation and increased neuroinflammation in athletes after sports-related concussions and in traumatic brain injury patients - A PET/MR study.

Traumatic brain injury (TBI) and repeated sports-related concussions (rSRCs) are associated with an increased risk for neurodegeneration. Autopsy findings of selected cohorts of long-term TBI survivors and rSRC athletes reveal increased tau aggregation and a persistent neuroinflammation. To assess in vivo tau aggregation and neuroinflammation in young adult TBI and rSRC cohorts, we evaluated 9 healthy controls (mean age 26 ± 5 years; 4 males, 5 females), 12 symptomatic athletes (26 ± 7 years; 6 males, 6 females) attaining ≥3 previous SRCs, and 6 moderate-to severe TBI patients (27 ± 7 years; 4 males, 2 females) in a combined positron emission tomography (PET)/magnetic resonance (MR) scanner ≥6 months post-injury. Dual PET tracers, [18F]THK5317 for tau aggregation and [11C]PK11195 for neuroinflammation/microglial activation, were investigated on the same day. The Repeated Battery Assessment of Neurological Status (RBANS) scores, used for cognitive evaluation, were lower in both the rSRC and TBI groups (p < 0.05). Neurofilament-light (NF-L) levels were increased in plasma and cerebrospinal fluid (CSF; p < 0.05), and serum tau levels lower, in TBI although not in rSRC. In rSRC athletes, PET imaging showed increased neuroinflammation in the hippocampus and tau aggregation in the corpus callosum. In TBI patients, tau aggregation was observed in thalami, temporal white matter and midbrain; widespread neuroinflammation was found e.g. in temporal white matter, hippocampus and corpus callosum. In mixed-sex cohorts of young adult athletes with persistent post-concussion symptoms and in TBI patients, increased tau aggregation and neuroinflammation are observed at ≥6 months post-injury using PET. Studies with extended clinical follow-up, biomarker examinations and renewed PET imaging are needed to evaluate whether these findings progress to a neurodegenerative disorder or if spontaneous resolution is possible.

Soccer-Related Concussions Among Swedish Elite Soccer Players: A Descriptive Study of 1,030 Players.

Objective: There are growing concerns about the short- and long-term consequences of sports-related concussion, which account for about 5-9% of all sports injuries. We hypothesized there may be sex differences in concussion history and concussion-related symptoms, evaluated among elite soccer players in Sweden. Design: Retrospective survey study. Participants and Setting: Soccer players (n = 1,030) from 55 Swedish elite soccer teams. Questionnaires were completed prior to the start of the 2017 season. Assessment of Risk Factors: Player history of soccer-related concussion (SoRC), symptoms and management following a SoRC were evaluated. Main Outcome Measures: Before the start of the season the players completed a baseline questionnaire assessing previous concussions. The Sports Concussion Assessment Tool 3 was included with regard to symptom evaluation. Results: Out of 993 responding players 334 (34.6%) reported a previous SoRC and 103 players (10.4%) reported a SoRC during the past year. After sustaining a SoRC, 114 players (34.2%) reported that they continued their ongoing activity without a period of rest, more commonly female (44.9%) than male players (27.7%; P = 0.002). Symptom resolution time was 1 week or less for 61.3% of the players that reported having persisting symptoms. A positive correlation was observed between number of previous concussions and prevalence of three persisting symptoms: fatigue (P < 0.001), concentration/memory issues (P = 0.002) and headache (P = 0.047). Conclusion: About 35% of male and female elite soccer players in Sweden have experienced a previous SoRC, and about 10% experienced a SoRC during the last year. Female players continued to play after a SoRC, without a period of rest, more often than males. A higher risk of persisting symptoms was observed in players with a history of multiple concussions.

Concussion incidence and recovery in Swedish elite soccer - Prolonged recovery in female players.

OBJECTIVES: Sport-related concussions are an increasingly recognized health problem. Soccer is the most popular sport in the world although recent studies on concussion incidence are scarce. Here, a nationwide prospective study on concussion incidence, symptom severity, risk factors, gender differences, and return-to-play after concussion was performed in 51 Swedish elite soccer teams during the 2017 season. METHODS: In the 1st and 2nd soccer leagues for men and women, a Sport Concussion Assessment Tool (SCAT)-based questionnaire study was performed at preseason (baseline) and from 48 hours to 3 months post-concussion. RESULTS: We followed 959 players (389 women, 570 men) for 25 146 player game hours (9867 hours for women, 15 279 hours for men). Concussion incidence (n = 36 concussions during the season) was 1.19/1000 player game hours (females 1.22/1000 hours, males 1.18/1000 hours; P = .85). Twenty-seven percent of all players (8% of females, 40% of males) continued to play immediately after the concussion. When compared to male players, female players had worse initial symptom severity scores (median and IQR 30 (17-50.5) vs 11 (4-26.25), P = .02) on SCAT and longer return-to-play (P = .02). Risk factors for concussion were baseline symptoms and previous concussion. CONCLUSION: In Swedish elite soccer, the concussion incidence was 1.19/1000 without gender differences. Most players recovered to play within 4 weeks post-injury. Almost one third of players continued to play at time of concussion. Female players had worse initial symptoms and longer return-to-play time than males, and a prolonged recovery beyond 3 months was only observed among female players.