Neurofilament light and tau as blood biomarkers for sports-related concussion

OBJECTIVE: To compare neurofilament light (NfL) and tau as blood-based biomarkers for acute sports-related concussion (SRC) and determine whether their concentrations at different time points after the injury are associated with prolonged time to return to play (RTP).METHODS: A total of 288 professional hockey players were followed longitudinally from September 1, 2012, to April 30, 2015. Data collection and biomarker analyses were conducted between 2015 and 2017. Associations were tested between blood concentrations of NfL and tau, and RTP time. Serum concentrations of S100B and neuron-specific enolase (NSE) were also measured for comparison.RESULTS: Of 288 players, 105 sustained an SRC. Of these, 87 underwent blood sampling 1, 12, 36, and 144 hours after SRC and at the RTP time point. Serum NfL concentrations 1, 12, 36, and 144 hours after SRC were related to prolonged RTP time, and could separate players with RTP >10 days from those with RTP ≤10 days (area under the receiver operating characteristic curve [AUROC] 0.82). Also, serum NfL 144 hours after SRC discriminated players who resigned from the game due to persistent postconcussion symptoms (PCS) from those who returned to play (AUROC 0.89). Plasma tau 1 hour after SRC was related to RTP but less strongly than NfL, while S100B and NSE showed no such associations.CONCLUSION: Serum NfL outperformed tau, S100B, and NSE as a biomarker for SRC. From a clinical standpoint, serum NfL may be useful to identify individuals at risk of prolonged PCS, and may aid in biomarker-informed decisions with regard to when RTP should be considered

Blood biomarkers for traumatic brain injury

Traumatic brain injury (TBI) is the major cause of death and disability following blunt head trauma. The term mild TBI (mTBI) or concussion are used interchangeably in the literature. Concussion or mTBI is recognized as a clinical syndrome caused by biochemically induced alterations of brain function secondary to head trauma, typically affecting memory and orientation and may involve loss of consciousness. The diagnosis of mTBI is mainly based on clinical symptoms. Objective tools such as computed tomography or magnetic resonance imaging are mainly used to exclude structural brain damage, e.g., intracranial bleeding. Biomarkers are molecules that can be measured in accessible biological fluids, that reflect physiological, pharmacological, or disease processes and can suggest the etiology of, susceptibility to, activity level of, or progress of a disease. The overall aim of this dissertation was to assess both novel and previously studied blood biomarkers reflecting neuronal injury and dysfunction in individuals with mild to severe traumatic brain injury (sTBI). The main research question we sought to answer was whether mTBI was associated with biomarker evidence of axonal injury. For this purpose we used sera from ice hockey players competing in the Swedish Hockey League. In addition, we developed a novel ultrasensitive digital ELISA based on Single molecule array (Simoa) platform for detection of neurofilament light protein (NFL) in serum. NFL is a neuron-specific protein, which is difficult to measure in blood using standard immunochemical techniques due to suboptimal analytical sensitivity. We assessed the diagnostic and prognostic utility of this assay in patients with sTBI, who were treated at the Neurointensive Care Unit at the Sahlgrenska University Hospital. The main findings of these studies were that mTBI in professional ice hockey players is associated with altered serum levels of biomarkers associated with neuronal injury. The levels of these biomarkers were also related to the number of days it took for the athletes to return to play. In the context of sTBI, NFL levels assessed in serum showed high diagnostic accuracy, and the levels in serum were also related to overall clinical outcome at follow-up 12 months after the injury. Our overall conclusion is that the novel blood biomarkers presented in this thesis are promising diagnostic and prognostic tools for mild to severe TBI. Furthermore, the findings of this thesis may be extended to other neurological disorders associated with axonal injury, where tracking disease progression and evaluating the efficacy of novel therapy were previously limited to analyses of cerebrospinal fluid

Test-retest reliability of high spatial resolution diffusion tensor and diffusion kurtosis imaging

Abstract We assessed the test-retest reliability of high spatial resolution diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI). Diffusion MRI was acquired using a Siemens 3 Tesla Prisma scanner with 80 mT/m gradients and a 32-channel head coil from each of 3 concussive traumatic brain injury (cTBI) patients and 4 controls twice 0 to 24 days apart. Coefficients of variation (CoV) for DTI parameters were calculated in each DTI Studio parcellated white matter tract at 1.25 mm and 1.75 mm isotropic voxel resolution, as well as DKI parameters at 1.75 mm isotropic. Overall, fractional anisotropy had the best reliability, with mean CoV at 5% for 1.25 mm and 3.5% for 1.75 mm isotropic voxels. Mean CoV for the other DTI metrics were <7.0% for both 1.25 and 1.75 mm isotropic voxels. The mean CoV was ≤4.5% across the DKI metrics. In the commonly injured orbitofrontal and temporal pole regions CoV was <3.5% for all parameters. Thus, with appropriate processing, high spatial resolution advanced diffusion MRI has good to excellent test-retest reproducibility in both human cTBI patients and controls. However, further technical improvements will be needed to reliably discern the most subtle diffusion abnormalities, especially at high spatial resolution

Concussed athletes are more prone to injury both before and after their index concussion : A data base analysis of 699 concussed contact sports athletes

Background: Ice hockey and football players suffering concussions might have an increased risk for injuries afterwards. We aimed to investigate if concussions predisposed athletes for subsequent sport injuries. Methods: Patient data were obtained from a data base established at the University Hospital in Umea, Sweden. Athletes who had suffered a concussion were included if they had been aged between 15 and 35 years of age, and played ice hockey, football (soccer), floorball and handball. They were studied in terms of all new or previous injuries during 24 months before and after their concussion. Results were compared with a control group of athletes from the same four sports with an ankle injury. Results: Athletes with a concussion were more likely to sustain injuries compared with the control group, both before (OR 1.98. 95% CI 1.45 to 2.72) and after the concussion (OR 1.72. 95% CI 1.26 to 2.37). No increase in frequency of injury was found after a concussion compared with before. This was true for athletes in all four sports and for both sexes. Conclusions: This study indicates that athletes sustaining a concussion may have a more aggressive or risk-taking style of play than their counterparts. Our data do not suggest that a concussion injury, per se, leads to subsequent injuries

Quality of life of ice hockey players after retirement due to concussions

Background: Sports-related concussion (SRC) is increasingly recognized as a potential health problem in ice hockey. Quality of life (QoL) in players retiring due to SRC has not been thoroughly addressed. Materials & methods: QoL using the Sports Concussion Assessment Tool 5th Edition, Impact of Event Scale-Revised and Short Form Health Survey was measured in Swedish ice hockey players who retired due to persistence of postconcussion symptoms or fear of attaining additional SRC. Results: A total of 76 players were assessed, on average of 5 years after their most recent SRC. Overall, retired players had a high burden of postconcussion symptoms and reduced QoL. Conclusion: Retired concussed ice hockey players have a reduced QoL, particularly those retiring due to postconcussion symptoms. Symptom burden should be continuously evaluated and guide the decision to retire

Association of Plasma Biomarker Levels With Their CSF Concentration and the Number and Severity of Concussions in Professional Athletes

OBJECTIVE: To examine whether the brain biomarkers total-tau (T-tau), glial fibrillary acidic protein (GFAP), and β-amyloid (Aβ) isomers 40 and 42 in plasma relate to the corresponding concentrations in cerebrospinal fluid (CSF), blood-brain barrier integrity, and duration of post-concussion syndrome (PCS) due to repetitive head impacts (RHI) in professional athletes. METHOD: In this cross-sectional study, professional athletes with persistent PCS due to RHI (median of 1.5 years after recent concussion) and uninjured controls were assessed with blood and CSF sampling. The diagnosis of PCS was based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). The athletes were enrolled through information flyers about the study sent to the Swedish hockey league (SHL) and the SHL Medicine Committee. The controls were enrolled through flyers at University of Gothenburg and Sahlgrenska University Hospital, Sweden. The participants underwent lumbar puncture and blood assessment at Sahlgrenska University Hospital. The main outcome measures were history of RHI and PCS severity (PCS> 1 year versus PCS< 1 year) in relation to plasma and CSF concentrations of T-tau, GFAP, Aβ40, and Aβ42. Plasma T-tau, GFAP, Aβ40, and Aβ42 were quantified using an ultrasensitive assay technology. RESULTS: A total of 47 participants (28 athletes [median age 28 years, range 18-52] with persistent PCS, due to RHI and 19 controls [median age, 25 years, range 21-35]) underwent paired blood and cerebrospinal fluid (CSF) sampling. T-tau, Aβ40 and Aβ42 concentrations measured in plasma did not correlate with the corresponding CSF concentrations, while there was a correlation between plasma and CSF levels of GFAP (r=0.45, p=0.020). There were no significant relationships between plasma T-tau, GFAP, and blood-brain barrier integrity as measured by CSF:serum albumin ratio. T-tau, GFAP, Aβ40, and Aβ42 measured in plasma did not relate to PCS severity. None of the markers measured in plasma correlated with number of concussions, except decreased Aβ42 in those with higher number of concussions (r=-0.40, p=0.04). CONCLUSIONS: T-tau, GFAP, Aβ40 and Aβ42 measured in plasma do not correspond to CSF measures, and may have limited utility for the evaluation of the late effects of RHI, compared with when measured in CSF. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in professional athletes with post-concussion symptoms, plasma concentrations of T-tau, GFAP, Aβ40, and Aβ42 are not informative in the diagnosis of late effects of repetitive head injuries