CSF and Blood Neurofilament Levels in Athletes Participating in Physical Contact Sports: A Systematic Review.

OBJECTIVE: To evaluate whether participating in physical contact sports is associated with a release of neurofilaments and whether such release is related to future clinical neurologic and/or psychiatric impairment. METHODS: We performed a systematic review of the PubMed, MEDLINE, and Cochrane Library databases using a combination of the search terms neurofilament(s)/intermediate filament and sport(s)/athletes. Original studies, written in English, reporting on neurofilaments in CSF and/or serum/plasma of contact sport athletes were included. This review was conducted following the Preferred Reporting Items for Systematic Review and Analyses guidelines. RESULTS: Eighteen studies in 8 different contact sports (i.e., boxing, American football, ice hockey, soccer, mixed martial arts, lacrosse, rugby, and wrestling) matched our criteria. Elevated light chain neurofilament (NfL) levels were described in 13/18 cohorts. Most compelling evidence was present in boxing and American football, where exposure-related increases were appreciable at the intraindividual level (up to 4.1- and 2.0-fold, respectively) in well-defined groups. Differences in exposure severity (including previous cumulative effects), sampling/measurement time points (with regard to expected peak values), and definitions of the baseline setting are considered as main contributors to the variability in findings. No studies were encountered that have investigated the relationship with the targeted clinical end points; therefore no NfL cutoffs exist that are associated with a poor outcome. CONCLUSION: NfL release can be seen, as a potential marker of neuronal brain damage, in participants of physical contact sports, particularly boxing and American football. The exact significance regarding the risk for future clinical impairment remains to be elucidated.

Neurochemical Aftermath of Repetitive Mild Traumatic Brain Injury.

IMPORTANCE: Evidence is accumulating that repeated mild traumatic brain injury (mTBI) incidents can lead to persistent, long-term debilitating symptoms and in some cases a progressive neurodegenerative condition referred to as chronic traumatic encephalopathy. However, to our knowledge, there are no objective tools to examine to which degree persistent symptoms after mTBI are caused by neuronal injury. OBJECTIVE: To determine whether persistent symptoms after mTBI are associated with brain injury as evaluated by cerebrospinal fluid biochemical markers for axonal damage and other aspects of central nervous system injury. DESIGN, SETTINGS, AND PARTICIPANTS: A multicenter cross-sectional study involving professional Swedish ice hockey players who have had repeated mTBI, had postconcussion symptoms for more than 3 months, and fulfilled the criteria for postconcussion syndrome (PCS) according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) matched with neurologically healthy control individuals. The participants were enrolled between January 2014 and February 2016. The players were also assessed with Rivermead Post Concussion Symptoms Questionnaire and magnetic resonance imaging. MAIN OUTCOMES AND MEASURES: Neurofilament light protein, total tau, glial fibrillary acidic protein, amyloid ß, phosphorylated tau, and neurogranin concentrations in cerebrospinal fluid. RESULTS: A total of 31 participants (16 men with PCS; median age, 31 years; range, 22-53 years; and 15 control individuals [11 men and 4 women]; median age, 25 years; range, 21-35 years) were assessed. Of 16 players with PCS, 9 had PCS symptoms for more than 1 year, while the remaining 7 returned to play within a year. Neurofilament light proteins were significantly increased in players with PCS for more than 1 year (median, 410 pg/mL; range, 230-1440 pg/mL) compared with players whose PCS resolved within 1 year (median, 210 pg/mL; range, 140-460 pg/mL) as well as control individuals (median 238 pg/mL, range 128-526 pg/mL; P = .04 and P = .02, respectively). Furthermore, neurofilament light protein concentrations correlated with Rivermead Post Concussion Symptoms Questionnaire scores and lifetime concussion events (ρ = 0.58, P = .02 and ρ = 0.52, P = .04, respectively). Overall, players with PCS had significantly lower cerebrospinal fluid amyloid-ß levels compared with control individuals (median, 1094 pg/mL; range, 845-1305 pg/mL; P = .05). CONCLUSIONS AND RELEVANCE: Increased cerebrospinal fluid neurofilament light proteins and reduced amyloid ß were observed in patients with PCS, suggestive of axonal white matter injury and amyloid deposition. Measurement of these biomarkers may be an objective tool to assess the degree of central nervous system injury in individuals with PCS and to distinguish individuals who are at risk of developing chronic traumatic encephalopathy.

Systematic review of clinical studies examining biomarkers of brain injury in athletes after sports-related concussion.

The aim of this study was to systematically review clinical studies examining biofluid biomarkers of brain injury for concussion in athletes. Data sources included PubMed, MEDLINE, and the Cochrane Database from 1966 to October 2013. Studies were included if they recruited athletes participating in organized sports who experienced concussion or head injury during a sports-related activity and had brain injury biomarkers measured. Acceptable research designs included experimental, observational, and case-control studies. Review articles, opinion papers, and editorials were excluded. After title and abstract screening of potential articles, full texts were independently reviewed to identify articles that met inclusion criteria. A composite evidentiary table was then constructed and documented the study title, design, population, methods, sample size, outcome measures, and results. The search identified 52 publications, of which 13 were selected and critically reviewed. All of the included studies were prospective and were published either in or after the year 2000. Sports included boxing (six studies), soccer (five studies), running/jogging (two studies), hockey (one study), basketball (one study), cycling (one study), and swimming (one study). The majority of studies (92%) had fewer than 100 patients. Three studies (23%) evaluated biomarkers in cerebrospinal fluid (CSF), one in both serum and CSF, and 10 (77%) in serum exclusively. There were 11 different biomarkers assessed, including S100ß, glial fibrillary acidic protein, neuron-specific enolase, tau, neurofilament light protein, amyloid beta, brain-derived neurotrophic factor, creatine kinase and heart-type fatty acid binding protein, prolactin, cortisol, and albumin. A handful of biomarkers showed a correlation with number of hits to the head (soccer), acceleration/deceleration forces (jumps, collisions, and falls), postconcussive symptoms, trauma to the body versus the head, and dynamics of different sports. Although there are no validated biomarkers for concussion as yet, there is potential for biomarkers to provide diagnostic, prognostic, and monitoring information postinjury. They could also be combined with neuroimaging to assess injury evolution and recovery.