OBJECTIVE:To evaluate whether the axonal protein neurofilament light (NFL) in serum is a sensitive biomarker to detect subtle brain injury or concussion in contact sports athletes.
METHODS:Two ...prospective cohort studies involving (1) 14 Swedish amateur boxers who underwent fluid biomarker assessments at 7–10 days after bout and after 3 months of rest from boxing and (2) 35 Swedish professional hockey players who underwent blood biomarker assessment at 1, 12, 36, and 144 hours after concussion and when the players returned to play were performed. Fourteen healthy nonathletic controls and 12 athletic controls were also enrolled. Serum NFL was measured using ultrasensitive single molecule array technology.
RESULTS:Serum NFL concentrations were increased in boxers 7–10 days after bout as compared to the levels after 3 months rest as well as compared with controls (p = 0.0007 and p < 0.0001, respectively). NFL decreased following 3 months of rest, but was still higher than in controls (p < 0.0001). Boxers who received many (>15) hits to the head or were groggy after bout had higher concentrations of serum NFL as compared to those who received fewer hits to the head (p = 0.0023). Serum NFL increased over time in hockey players, and the levels returned to normal at return to play. Importantly, serum NFL could separate players with rapidly resolving postconcussion symptoms (PCS) from those with prolonged PCS.
CONCLUSIONS:The results from these 2 independent cohort studies suggest that serum NFL is a highly sensitive biomarker for concussion.
OBJECTIVETo 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).
METHODSA 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.
RESULTSOf 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.
CONCLUSIONSerum 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.This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Axonal white matter injury is believed to be a major determinant of adverse outcomes following traumatic brain injury (TBI). We hypothesized that measurement of neurofilament light protein (NF-L), a ...protein found in long white-matter axons, in blood samples, may serve as a suitable biomarker for neuronal damage in TBI patients. To test our hypotheses, we designed a study in two parts: i) we developed an immunoassay based on Single molecule array technology for quantification of NF-L in blood, and ii) in a proof-of-concept study, we tested our newly developed method on serial serum samples from severe TBI (sTBI) patients (n = 72) and controls (n = 35). We also compared the diagnostic and prognostic utility of NF-L with the established blood biomarker S100B. NF-L levels were markedly increased in sTBI patients compared with controls. NF-L at admission yielded an AUC of 0.99 to detect TBI versus controls (AUC 0.96 for S100B), and increased to 1.00 at day 12 (0.65 for S100B). Importantly, initial NF-L levels predicted poor 12-month clinical outcome. In contrast, S100B was not related to outcome. Taken together, our data suggests that measurement of serum NF-L may be useful to assess the severity of neuronal injury following sTBI.
IMPORTANCE: Lack of objective biomarkers for brain damage hampers acute diagnosis and clinical decision making about return to play after sports-related concussion. OBJECTIVES: To determine whether ...sports-related concussion is associated with elevated levels of blood biochemical markers of injury to the central nervous system and to assess whether plasma levels of these biomarkers predict return to play in professional ice hockey players with sports-related concussion. DESIGN, SETTING, AND PARTICIPANTS: Multicenter prospective cohort study involving all 12 teams of the top professional ice hockey league in Sweden, the Swedish Hockey League. Two hundred eighty-eight professional ice hockey players from 12 teams contesting during the 2012-2013 season consented to participate. All players underwent clinical preseason baseline testing regarding concussion assessment measures. Forty-seven players from 2 of the 12 ice hockey teams underwent blood sampling prior to the start of the season. Thirty-five players had a concussion from September 13, 2012, to January 31, 2013; of these players, 28 underwent repeated blood sampling at 1, 12, 36, and 144 hours and when the players returned to play. MAIN OUTCOMES AND MEASURES: Total tau, S-100 calcium-binding protein B, and neuron-specific enolase concentrations in plasma and serum were measured. RESULTS: Concussed players had increased levels of the axonal injury biomarker total tau (median, 10.0 pg/mL; range, 2.0-102 pg/mL) compared with preseason values (median, 4.5 pg/mL; range, 0.06-22.7 pg/mL) (P < .001). The levels of the astroglial injury biomarker S-100 calcium-binding protein B were also increased in players with sports-related concussion (median, 0.075 μg/L; range, 0.037-0.24 μg/L) compared with preseason values (median, 0.045 μg/L; range, 0.005-0.45 μg/L) (P < .001). The highest biomarker concentrations of total tau and S-100 calcium-binding protein B were measured immediately after a concussion, and they decreased during rehabilitation. No significant changes were detected in the levels of neuron-specific enolase from preseason values (median, 6.5 μg/L; range, 3.45-18.0 μg/L) to postconcussion values (median, 6.1 μg/L; range, 3.6-12.8 μg/L) (P = .10). CONCLUSIONS AND RELEVANCE: Sports-related concussion in professional ice hockey players is associated with acute axonal and astroglial injury. This can be monitored using blood biomarkers, which may be developed into clinical tools to guide sport physicians in the medical counseling of athletes in return-to-play decisions.
OBJECTIVETo determine whether serum neurofilament light (NfL) correlates with CSF NfL, traumatic brain injury (TBI) diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) ...estimates of traumatic axonal injury (TAI).
METHODSParticipants were prospectively enrolled in Sweden and the United States between 2011 and 2019. The Swedish cohort included 45 hockey players with acute concussion sampled at 6 days, 31 with repetitive concussion with persistent postconcussive symptoms (PCS) assessed with paired CSF and serum (median 1.3 years after concussion), 28 preseason controls, and 14 nonathletic controls. Our second cohort included 230 clinic-based participants (162 with TBI and 68 controls). Patients with TBI also underwent serum, functional outcome, and imaging assessments at 30 (n = 30), 90 (n = 48), and 180 (n = 59) days and 1 (n = 84), 2 (n = 57), 3 (n = 46), 4 (n = 38), and 5 (n = 29) years after injury.
RESULTSIn athletes with paired specimens, CSF NfL and serum NfL were correlated (r = 0.71, p < 0.0001). CSF and serum NfL distinguished players with PCS >1 year from PCS ≤1 year (area under the receiver operating characteristic curve AUROC 0.81 and 0.80). The AUROC for PCS >1 year vs preseason controls was 0.97. In the clinic-based cohort, NfL at enrollment distinguished patients with mild from those with moderate and severe TBI (p < 0.001 and p = 0.048). Serum NfL decreased over the course of 5 years (ß = −0.09 log pg/mL, p < 0.0001) but remained significantly elevated compared to controls. Serum NfL correlated with measures of functional outcome, MRI brain atrophy, and DTI estimates of TAI.
CONCLUSIONSSerum NfL shows promise as a biomarker for acute and repetitive sports-related concussion and patients with subacute and chronic TBI.
CLASSIFICATION OF EVIDENCEThis study provides Class III evidence that increased concentrations of NfL distinguish patients with TBI from controls.
To determine whether a panel of blood-based biomarkers can discriminate between patients with suspected mild traumatic brain injury (mTBI) with and without neuroimaging findings (CT and MRI).
Study ...participants presented to the emergency department with suspected mTBI (n = 277) with a CT and MRI scan and healthy controls (n = 49). Plasma concentrations of tau, glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1, and neurofilament light chain (NFL) were measured using the single-molecule array technology.
Concentrations of GFAP, tau, and NFL were higher in patients with mTBI, compared with those of controls (
's < 0.01). GFAP yielded an area under the curve (AUC) of 0.93 (95% confidence interval CI 0.90-0.96), confirming its discriminatory power for distinguishing mTBI from controls. Levels of GFAP, tau, and NFL were higher in patients with trauma-related intracranial findings on CT compared with those with normal CT, with the only significant predictor being GFAP (AUC 0.77, 95% CI 0.70-0.84). Among patients with mTBI, tau, NFL, and GFAP differentiated subjects with and without MRI abnormalities with an AUC of 0.83, with GFAP being the strongest predictor. Combining tau, NFL, and GFAP showed a good discriminatory power (AUC 0.80, 95% CI 0.69-0.90) for detecting MRI abnormalities, even in patients with mTBI with a normal CT.
Our study confirms GFAP as a promising marker of brain injury in patients with acute mTBI. A combination of various biomarkers linked to different pathophysiologic mechanisms increases diagnostic subgroup accuracy. This multimarker strategy may guide medical decision making, facilitate the use of MRI scanning, and prove valuable in the stratification of patients with brain injuries in future clinical trials.
Class I evidence that blood concentrations of GFAP, tau, and NFL discriminate patients with mTBI with and without neuroimaging findings.
The diagnosis of sports-related concussion is mainly based on subjective clinical symptoms and neuropsychological tests. Therefore, reliable brain injury biomarkers to assess when it is safe to ...return to play are highly desirable. The overall objective of this study was to evaluate the utility of two newly described tau fragments for diagnosis and prognosis of sports-related concussions. This multi-center prospective cohort study involved all 12 teams of the top professional ice hockey league in Sweden. A total of 288 players consented to participate in the study. Thirty-five players sustained concussions, of whom 28 underwent repeated blood samplings at 1, 12, 36, and 144 h after the trauma, or when the player returned to play (7 to >90 days). There was no significant increase in the levels of Tau-A in post-concussion samples compared with preseason values. However, serum levels of Tau-C were significantly higher in post-concussion samples compared with preseason. Further, levels of Tau-A correlated with the duration of post-concussive symptoms. Tau-A in serum, which is newly discovered biomarker, could be used to predict when it is safe to return to play after a sports-related concussion.
Traumatic brain injury (TBI) is linked to long-term symptoms in a sub-set of patients who sustain an injury, but this risk is not universal, leading us and others to question the nature of individual ...variability in recovery trajectories. Extracellular vesicles (EVs) are a promising, novel avenue to identify blood-based biomarkers for TBI. Here, our aim was to determine if glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) measured 1-year postinjury in EVs could distinguish patients from controls, and whether these biomarkers relate to TBI severity or recovery outcomes. EV GFAP and EV NfL were measured using an ultrasensitive assay in 72 TBI patients and 20 controls. EV GFAP concentrations were elevated in moderate and severe TBI compared to controls (p's < 0.001) and could distinguish controls from moderate (AUC = 0.86) or severe TBI (AUC = 0.88). Increased EV GFAP and EV NfL levels were associated with lower 1-year Glasgow Outcome Scale-Extended (GOS-E) score (p's < 0.05). These findings suggest that blood-derived EV concentrations of GFAP and NfL drawn even 1 year after injury are higher in TBI patients compared to controls, and are related to injury severity and poor recovery outcomes, suggesting that TBIs alter the activity of these biomarkers, likely contributing to individual variability in recovery.
Abnormalities of postural sway have been extensively reported in traumatic brain injury (TBI). However, the underlying neural correlates of balance disturbances in TBI remain to be elucidated. ...Studies in children with TBI have reported associations between the Sensory Organization Test (SOT) and measures of white matter (WM) integrity with diffusion tensor imaging (DTI) in brain areas responsible for multisensory integration. This study seeks to replicate those associations in adults as well as explore relationships between DTI and the Limits of Stability (LOS) Test. Fifty-six participants (43±17 years old) with a history of TBI were tested 30 days to 5 years post-TBI. This study confirmed results in children for associations between the SOT and the medial lemniscus as well as middle cerebellar peduncle, and revealed additional associations with the posterior thalamic radiation. Additionally, this study found significant correlations between abnormal LOS scores and impaired WM integrity in the cingulum, corpus callosum, corticopontine and corticospinal tracts, fronto-occipital fasciculi, longitudinal fasciculi, medial lemniscus, optic tracts and thalamic radiations. Our findings indicate the involvement of a broad range of WM tracts in the control of posture, and demonstrate the impact of TBI on balance via disruptions to WM integrity.
Neurofilament proteins have been implicated to be altered in amyotrophic lateral sclerosis (ALS). The objectives of this study were to assess the diagnostic and prognostic utility of neurofilaments ...in ALS.
Studies were conducted in electronic databases (PubMed/MEDLINE, Embase, Web of Science, and Cochrane CENTRAL) from inception to 17 August 2023, and investigated neurofilament light (NfL) or phosphorylated neurofilament heavy chain (pNfH) in ALS. The study design, enrolment criteria, neurofilament concentrations, test accuracy, relationship between neurofilaments in cerebrospinal fluid (CSF) and blood, and clinical outcome were recorded. The protocol was registered with PROSPERO, CRD42022376939.
Sixty studies with 8801 participants were included. Both NfL and pNfH measured in CSF showed high sensitivity and specificity in distinguishing ALS from disease mimics. Both NfL and pNfH measured in CSF correlated with their corresponding levels in blood (plasma or serum); however, there were stronger correlations between CSF NfL and blood NfL. NfL measured in blood exhibited high sensitivity and specificity in distinguishing ALS from controls. Both higher levels of NfL and pNfH either measured in blood or CSF were correlated with more severe symptoms as assessed by the ALS Functional Rating Scale Revised score and with a faster disease progression rate; however, only blood NfL levels were associated with shorter survival.
Both NfL and pNfH measured in CSF or blood show high diagnostic utility and association with ALS functional scores and disease progression, while CSF NfL correlates strongly with blood (either plasma or serum) and is also associated with survival, supporting its use in clinical diagnostics and prognosis. Future work must be conducted in a prospective manner with standardized bio-specimen collection methods and analytical platforms, further improvement in immunoassays for quantification of pNfH in blood, and the identification of cut-offs across the ALS spectrum and controls.
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