Serum neurofilament light chain, inflammatory markers, and kynurenine metabolites in patients with persistent post-concussion symptoms: A cohort study.

BACKGROUND: Concussion leads to persistent post-concussion symptoms (PPCS) in up to one-third of those affected. While previous research has linked the initial trauma to elevated serum levels of neurofilament light chain (NFL), inflammatory markers, and neurotoxic metabolites within the kynurenine pathway, few studies have explored their relevance in PPCS. This study aims to investigate these biomarkers in PPCS patients, elucidating their relevance in the prolonged phase of concussion. METHODS: Serum samples from 86 PPCS individuals aged 18-30 years, 2-6 months post-trauma were analyzed, with 54 providing follow-up samples after seven months. NFL was measured using single-molecule array (Simoa) technology, 13 inflammatory markers via a Luminex immunoassay, and five kynurenine metabolites using liquid chromatography-mass spectrometry. A control group of 120 healthy anonymous blood donors was recruited for comparison. RESULTS: No significant NFL differences were found in PPCS participants compared with healthy individuals (p = 0.22). Intriguingly, a subset (9.3%) of PPCS participants initially exhibited abnormally high NFL levels (>9.7 pg/mL), which normalized upon follow-up (p = 0.032). Additionally, serum levels of the inflammatory markers, monocyte chemoattractant protein-1 (MCP-1/CCL2), and eotaxin-1/CCL11 were 25-40% lower than in healthy individuals (p ≤ 0.001). As hypothesized, PPCS participants exhibited a 22% reduction in the ratio of kynurenic acid to quinolinic acid (neuroprotective index) (p < 0.0001), indicating a shift towards the formation of neurotoxic metabolites. CONCLUSION: NFL may serve as a biomarker to monitor recovery, and future studies should investigate the potential therapeutic benefits of modulating the kynurenine pathway to improve PPCS.

Serum calcitonin gene-related peptide in patients with persistent post-concussion symptoms, including headache: a cohort study.

BACKGROUND: Calcitonin gene-related peptide (CGRP) plays an important role in migraine pathophysiology, and post-traumatic headache (PTH) frequently presents with migraine-like features. Despite several clinical similarities, few studies have explored CGRP in PTH and concussion. This study investigates serum CGRP levels in patients with persistent post-concussion symptoms (PPCS), including PTH. METHODS: This cohort study was based on serum samples from individuals aged 18-30 years with PPCS who participated in a previously published randomized controlled trial of a non-pharmacological intervention. The primary outcome was serum CGRP concentrations, determined at baseline before randomization and at follow-up 7 months later, using an enzyme-linked immunosorbent assay (ELISA). CGRP levels at baseline were compared with healthy anonymous blood donors in the same age group. RESULTS: Baseline serum samples were collected from 86 participants with PPCS. The participants were most often female (78%) and migraine-like headache was the most frequent headache phenotype (74%). Serum CGRP levels were higher in participants with PPCS than in 120 healthy individuals (median: 158.5 pg/mL vs. 76.3 pg/mL, p = 0.050). A stratified analysis revealed that females with PPCS had a fivefold higher median than healthy females (166.3 pg/mL vs. 32.1 pg/mL, p = 0.0006), while no differences were observed in males (p = 0.83). At follow-up, CGRP levels decreased with a median change of - 1.3 pg/mL (95% confidence interval: - 17.6-0, p = 0.024). DISCUSSION: Elevated serum levels of CGRP in patients with PPCS and a decrease over time suggest an involvement of CGRP in PTH/PPCS. If confirmed in other studies, it could pave the way for CGRP-targeted therapies, which could have clinical significance.

Early versus Late Profiles of Inflammatory Cytokines after Mild Traumatic Brain Injury and Their Association with Neuropsychological Outcomes.

Despite pre-clinical evidence for the role of inflammation in traumatic brain injury (TBI), there is limited data on inflammatory biomarkers in mild TBI (mTBI). In this study, we describe the profile of plasma inflammatory cytokines and explore associations between these cytokines and neuropsychological outcomes after mTBI. Patients with mTBI with negative computed tomography and orthopedic injury (OI) controls without mTBI were prospectively recruited from emergency rooms at three trauma centers. Plasma inflammatory cytokine levels were measured from venous whole-blood samples that were collected at enrollment (within 24 h of injury) and at 6 months after injury. Neuropsychological tests were performed at 1 week, 1 month, 3 months, and 6 months after the injury. Multivariate regression analysis was performed to identify associations between inflammatory cytokines and neuropsychological outcomes. A total of 53 mTBI and 24 OI controls were included in this study. The majority of patients were male (62.3%), and injured in motor vehicle accidents (37.7%). Plasma interleukin (IL)-2 (p = 0.01) and IL-6 (p = 0.01) within 24 h post-injury were significantly higher for mTBI patients compared with OI controls. Elevated plasma IL-2 at 24 h was associated with more severe 1-week post-concussive symptoms (p = 0.001). At 6 months, elevated plasma IL-10 was associated with greater depression scores (p = 0.004) and more severe post-traumatic stress disorder (PTSD) symptoms (p = 0.001). Plasma cytokine levels (within 24 h and at 6 months post-injury) were significantly associated with early and late post-concussive symptoms, PTSD, and depression scores after mTBI. These results highlight the potential role of inflammation in the pathophysiology of post-traumatic symptoms after mTBI.

Exosomal neurofilament light: A prognostic biomarker for remote symptoms after mild traumatic brain injury?

OBJECTIVE: To measure exosomal and plasma levels of candidate blood biomarkers in veterans with history of mild traumatic brain injury (mTBI) and test their relationship with chronic symptoms. METHODS: Exosomal and plasma levels of neurofilament light (NfL) chain, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and vascular endothelial growth factor (VEGF) were measured using an ultrasensitive assay in a cohort of 195 veterans, enrolled in the Chronic Effects of Neurotrauma Consortium Longitudinal Study. We examined relationships between candidate biomarkers and symptoms of postconcussive syndrome (PCS), posttraumatic stress disorder (PTSD), and depression. Biomarker levels were compared among those with no traumatic brain injury (TBI) (controls), 1-2 mTBIs, and repetitive (3 or more) mTBIs. RESULTS: Elevated exosomal and plasma levels of NfL were associated with repetitive mTBIs and with chronic PCS, PTSD, and depression symptoms. Plasma TNF-α levels correlated with PCS and PTSD symptoms. The total number of mTBIs correlated with exosomal and plasma NfL levels and plasma IL-6. Increased number of years since the most recent TBI correlated with higher exosomal NfL and lower plasma IL-6 levels, while increased number of years since first TBI correlated with higher levels of exosomal and plasma NfL, as well as plasma TNF-α and VEGF. CONCLUSION: Repetitive mTBIs are associated with elevated exosomal and plasma levels of NfL, even years following these injuries, with the greatest elevations in those with chronic PCS, PTSD, and depression symptoms. Our results suggest a possible neuroinflammatory and axonal disruptive basis for symptoms that persist years after mTBI, especially repetitive.

Elevated Tau in Military Personnel Relates to Chronic Symptoms Following Traumatic Brain Injury.

OBJECTIVE: To understand the relationships between traumatic brain injury (TBI), blood biomarkers, and symptoms of posttraumatic stress disorder (PTSD), depression, and postconcussive syndrome symptoms. DESIGN: Cross-sectional cohort study using multivariate analyses. PARTICIPANTS: One hundred nine military personnel and veterans, both with and without a history of TBI. MAIN MEASURES: PTSD Checklist-Civilian Version (PCL-C); Neurobehavioral Symptom Inventory (NSI); Ohio State University TBI Identification Method; Patient Health Questionnaire-9 (PHQ-9); Simoa-measured concentrations of tau, amyloid-beta (Aß) 40, Aß42, and neurofilament light (NFL). RESULTS: Controlling for age, sex, time since last injury (TSLI), and antianxiety/depression medication use, NFL was trending toward being significantly elevated in participants who had sustained 3 or more TBIs compared with those who had sustained 1 or 2 TBIs. Within the TBI group, partial correlations that controlled for age, sex, TSLI, and antianxiety/depression medication use showed that tau concentrations were significantly correlated with greater symptom severity, as measured with the NSI, PCL, and PHQ-9. CONCLUSIONS: Elevations in tau are associated with symptom severity after TBI, while NFL levels are elevated in those with a history of repetitive TBIs and in military personnel and veterans. This study shows the utility of measuring biomarkers chronically postinjury. Furthermore, there is a critical need for studies of biomarkers longitudinally following TBI.

Lower Posttraumatic α-Synuclein Level Associated With Altered Default Mode Network Connectivity Following Acute Mild Traumatic Brain Injury.

This study aimed to investigate the changes of α-synuclein in serum and its relationship with default mode network (DMN) connectivity after acute mild traumatic brain injury (mild TBI). Fifty-two patients with mild TBI at the acute phase and 47 matched healthy controls were enrolled in the study. All participants received resting-state functional magnetic resonance imaging (fMRI) and neuropsychological assessments. Relations between the levels of α-synuclein in serum and clinical assessments were obtained using multivariate linear regression. Results showed that the patients with lower α-synuclein presented more complaints on post-concussion symptoms and depression. Moreover, patients with high levels of α-synuclein exhibited significantly decreased functional connectivity in the left precuneus and increased functional connectivity in both the left anterior cingulate cortex and ventro-medial prefrontal cortex (MPFC) compared with patients with low levels of α-synuclein. These findings supported that α-synuclein may modulate the functional connectivity within the DMN and suggest the feasibility of using α-synuclein as an objective biomarker for diagnosis and prognosis of mild TBI.

Distinguishing and phenotype monitoring of traumatic brain injury and post-concussion syndrome including chronic migraine in serum of Iraq and Afghanistan war veterans.

Traumatic Brain Injury (TBI) and persistent post-concussion syndrome (PCS) including chronic migraine (CM) are major health issues for civilians and the military. It is important to understand underlying biochemical mechanisms of these conditions, and be able to monitor them in an accurate and minimally invasive manner. This study describes the initial use of a novel serum analytical platform to help distinguish TBI patients, including those with post-traumatic headache (PTH), and to help identify phenotypes at play in these disorders. The hypothesis is that physiological responses to disease states like TBI and PTH and related bodily stresses are reflected in biomolecules in the blood in disease-specific manner. Leave one out (serum sample) cross validations (LOOCV) and sample randomizations were utilized to distinguished serum samples from the following TBI patient groups: TBI +PTSD + CM + severe depression (TBI "most affected" group) vs healthy controls, TBI "most affected" vs TBI, TBI vs controls, TBI + CM vs controls, and TBI + CM vs TBI. Inter-group discriminatory p values were ≤ 10-10, and sample group randomizations resulted in p non-significant values. Peptide/protein identifications of discriminatory mass peaks from the TBI "most affected" vs controls and from the TBI plus vs TBI minus CM groups yielded information of the cellular/molecular effects of these disorders (immune responses, amyloidosis/Alzheimer's disease/dementia, neuronal development). More specific biochemical disease effects appear to involve blood brain barrier, depression, migraine headache, autoimmunity, and autophagy pathways. This study demonstrated the ability for the first time of a novel, accurate, biomarker platform to monitor these conditions in serum, and help identify biochemical relationships leading to better understanding of these disorders and to potential therapeutic approaches.

Plasma Tumor Necrosis Factor Alpha Is a Predictor of Persisting Symptoms Post-Concussion in Children.

Mild traumatic brain injury (mTBI)-associated blood proteomics have become an emerging focus in the past decade, with the U.S. Food and Drug Administration recently approving the use of a blood test to determine the necessity of a computed tomography scan after adult mTBI. We now also know that the blood proteome of children is different from that of adults, and new evidence suggests that children may take longer to recover from an mTBI. Despite this, comparatively fewer studies have analyzed changes in blood protein expression after pediatric mTBI. Concussions, an mTBI subset, often go underreported, despite the potential for post-concussive symptoms to last more than one month in up to 30% of children. In the current study, we used a multiplex immunoassay to measure blood protein expression of Apolipoprotein, enolase 2, glial fibrillary acidic protein, interleukin (IL)-1B, IL-6, IL-8, IL-10, S100 calcium-binding protein B, tau and tumor necrosis factor alpha (TNFα) at admission, one to four days, two weeks, and three months post-pediatric concussion, comparing patients with normal recovery (n = 9) with those with persisting symptoms (n = 9). We identified significant differences in IL-6 (p < 0.001) and tau (p = 0.048) protein expression across time post-injury irrespective of clinical outcome and in IL-8 protein expression (p = 0.041) across time post-injury specific to children with persisting symptoms. Significantly, we have identified an increase in TNFα protein expression at one to four days post-injury (p = 0.031) in children with persisting symptoms compared with normal recovery. To our knowledge, this is the first study to identify TNFα as a potential blood biomarker for persisting symptoms post-pediatric concussion.

Prognostic value of neuron-specific enolase (NSE) for prediction of post-concussion symptoms following a mild traumatic brain injury: a systematic review.

BACKGROUND: This systematic review aimed to determine the prognostic value of neuron-specific enolase (NSE) to predict post-concussion symptoms following mild traumatic brain injury (TBI). METHODS: Seven databases were searched for studies evaluating the association between NSE levels and post-concussion symptoms assessed ≥ 3 months (persistent) or ≥ 7 days < 3 months (early) after mild TBI. Two researchers independently screened studies for inclusion, extracted data and appraised quality using the Quality in Prognostic Studies (QUIPS) tool. RESULTS: The search strategy yielded a total of 23,298 citations from which 8 cohorts presented in 10 studies were included. Studies included between 45 and 141 patients (total 608 patients). The outcomes most frequently assessed were post-concussion syndrome (PCS, 12 assessments) and neuropsychological performance deficits (10 assessments). No association was found between an elevated NSE serum level and PCS. Only one study reported a statistically significant association between a higher NSE serum level and alteration of at least three cognitive domains at 2 weeks but this association was no longer significant at 6 weeks. Overall, risk of bias of the included studies was considered moderate. CONCLUSIONS: Early NSE serum level is not a strong independent predictor of post-concussion symptoms following mild TBI.

Prognostic Value of S-100ß Protein for Prediction of Post-Concussion Symptoms after a Mild Traumatic Brain Injury: Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aimed to determine the prognostic value of S-100ß protein to identify patients with post-concussion symptoms after a mild traumatic brain injury (mTBI). A search strategy was submitted to seven databases from their inception to October 2016. Individual patient data were requested. Cohort studies evaluating the association between S-100ß protein level and post-concussion symptoms assessed at least seven days after the mTBI were considered. Outcomes were dichotomized as persistent (≥3 months) or early (≥7 days <3 months). Our search strategy yielded 23,298 citations of which 29 studies including between seven and 223 patients (n = 2505) were included. Post-concussion syndrome (PCS) (16 studies) and neuropsychological symptoms (9 studies) were the most frequently assessed outcomes. The odds of having persistent PCS (odds ratio [OR] 0.62, 95% confidence interval [CI]: 0.34-1.12, p = 0.11, I2 0% [n = five studies]) in patients with an elevated S-100ß protein serum level were not significantly different from those of patients with normal values while the odds of having early PCS (OR 1.67, 95% CI: 0.98-2.85, p = 0.06, I2 38% [n = five studies]) were close to statistical significance. Similarly, having an elevated S-100ß protein serum level was not associated with the odds of returning to work at six months (OR 2.31, 95% CI: 0.50-10.64, p = 0.28, I2 22% [n = two studies]). Overall risk of bias was considered moderate. Results suggest that the prognostic biomarker S-100ß protein has a low clinical value to identify patients at risk of persistent post-concussion symptoms. Variability in injury to S-100ß protein sample time, mTBI populations, and outcomes assessed could potentially explain the lack of association and needs further evaluation.

Characteristics of patients included and enrolled in studies on the prognostic value of serum biomarkers for prediction of postconcussion symptoms following a mild traumatic brain injury: a systematic review.

OBJECTIVE: Mild traumatic brain injury (mTBI) has been insufficiently researched, and its definition remains elusive. Investigators are confronted by heterogeneity in patients, mechanism of injury and outcomes. Findings are thus often limited in generalisability and clinical application. Serum protein biomarkers are increasingly assessed to enhance prognostication of outcomes, but their translation into clinical practice has yet to be achieved. A systematic review was performed to describe the adult populations included and enrolled in studies that evaluated the prognostic value of protein biomarkers to predict postconcussion symptoms following an mTBI. DATA SOURCES: Searches of MEDLINE, Embase, CENTRAL, CINAHL, Web of Science, PsycBITE and PsycINFO up to October 2016. DATA SELECTION AND EXTRACTION: Two reviewers independently screened for potentially eligible studies, extracted data and assessed the overall quality of evidence by outcome using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: A total of 23 298 citations were obtained from which 166 manuscripts were reviewed. Thirty-six cohort studies (2812 patients) having enrolled between 7 and 311 patients (median 89) fulfilled our inclusion criteria. Most studies excluded patients based on advanced age (n=10 (28%)), neurological disorders (n=20 (56%)), psychiatric disorders (n=17 (47%)), substance abuse disorders (n=13 (36%)) or previous traumatic brain injury (n=10 (28%)). Twenty-one studies (58%) used at least two of these exclusion criteria. The pooled mean age of included patients was 39.3 (SD 4.6) years old (34 studies). The criteria used to define a mTBI were inconsistent. The most frequently reported outcome was postconcussion syndrome using the Rivermead Post-Concussion Symptoms Questionnaire (n=18 (50%)) with follow-ups ranging from 7 days to 5 years after the mTBI. CONCLUSIONS: Most studies have recruited samples that are not representative and generalisable to the mTBI population. These exclusion criteria limit the potential use and translation of promising serum protein biomarkers to predict postconcussion symptoms.

Assessing the accuracy of blood RNA profiles to identify patients with post-concussion syndrome: A pilot study in a military patient population.

Mild traumatic brain injury (mTBI) is a complex, neurophysiological condition that can have detrimental outcomes. Yet, to date, no objective method of diagnosis exists. Physical damage to the blood-brain-barrier and normal waste clearance via the lymphatic system may enable the detection of biomarkers of mTBI in peripheral circulation. Here we evaluate the accuracy of whole transcriptome analysis of blood to predict the clinical diagnosis of post-concussion syndrome (PCS) in a military cohort. Sixty patients with clinically diagnosed chronic concussion and controls (no history of concussion) were recruited (retrospective study design). Male patients (46) were split into a training set comprised of 20 long-term concussed (> 6 months and symptomatic) and 12 controls (no documented history of concussion). Models were validated in a testing set (control = 9, concussed = 5). RNA_Seq libraries were prepared from whole blood samples for sequencing using a SOLiD5500XL sequencer and aligned to hg19 reference genome. Patterns of differential exon expression were used for diagnostic modeling using support vector machine classification, and then validated in a second patient cohort. The accuracy of RNA profiles to predict the clinical diagnosis of post-concussion syndrome patients from controls was 86% (sensitivity 80%; specificity 89%). In addition, RNA profiles reveal duration of concussion. This pilot study shows the potential utility of whole transcriptome analysis to establish the clinical diagnosis of chronic concussion syndrome.

Correlation of ubiquitin C terminal hydrolase and S100ß with cognitive deficits in young adults with mild traumatic brain injury.

OBJECTIVE: To study the acute phase serum biomarkers in patients with mild traumatic brain injury (mTBI) and to correlate them with short term cognitive deficits. MATERIALS AND METHODS: This is a prospective observational study conducted at a tertiary care center for neurotrauma. The participants included patients with mTBI (n = 20) and age, gender, and education-status matched healthy controls (n = 20). In both the groups, the serum concentrations of biomarkers ubiquitin C terminal hydrolase (UCH-L1) and S100 calcium-binding protein B (S100B) were measured. Both the groups underwent neuropsychological tests. The serum tests were done in the acute stage after injury and the neuropsychological tests were done 3 months after injury. RESULTS: There was no significant increase in the serum S100B and UCH-L1 levels in patients with mTBI. Patients with mTBI had significant cognitive deficits at 3 months after injury, which was suggestive of involvement of diffuse areas of the brain, in particular, the premotor, prefrontal, and medial inferior frontal lobes and the basitemporal region. The correlation of biomarkers with cognitive deficits in patients with mTBI was found in the following domains: working memory, verbal learning, verbal fluency, and visual memory. CONCLUSION: The serum biomarkers of mTBI have a correlation with selective domains of neuropsychological outcome.

Plasma micro-RNA biomarkers for diagnosis and prognosis after traumatic brain injury: A pilot study.

Prediction of post-concussive syndrome after apparent mild traumatic brain injury (TBI) and subsequent cognitive recovery remains challenging, with substantial limitations of current methods of cognitive testing. This pilot study aimed to determine if levels of micro ribonucleic acids (RNAs) circulating in plasma are altered following TBI, and if changes to levels of such biomarkers over time could assist in determination of prognosis after TBI. Patients were enrolled after TBI on presentation to the Emergency Department and allocated to three groups: A - TBI (physical trauma to the head), witnessed loss of consciousness, amnesia, GCS=15, a normal CT Brain and a recorded first pass after post-traumatic amnesia (PTA) scale; B TBI, witnessed LOC, amnesia, GCS=15, a normal CT brain and a PTA scale test fail and: C - TBI and initial GCS <13 on arrival to the ED. Venous blood was collected at three time points (arrival, day 5 and day 30). Isolation of cell-free total RNA was then assayed using a custom miRNA PCR array. Two micro-RNAs, mir142-3p and mir423-3p demonstrated potential clinical utility differentiating patients after mild head injury into those at greater risk of developing amnesia and therefore, post-concussive syndromes. In addition, these miRNA demonstrated a decrease in expression over time, possibly indicative of brain healing after the injury. Further evaluation of these identified miRNA markers with larger patient cohorts, correlation with clinical symptoms and analysis over longer time periods are essential next steps in developing objective markers of severity of TBI.

Mood symptoms correlate with kynurenine pathway metabolites following sports-related concussion.

OBJECTIVE: An imbalance of neuroactive kynurenine pathway metabolites has been proposed as one mechanism behind the neuropsychiatric sequelae of certain neurological disorders. We hypothesized that concussed football players would have elevated plasma levels of neurotoxic kynurenine metabolites and reduced levels of neuroprotective metabolites relative to healthy football players and that altered kynurenine levels would correlate with post-concussion mood symptoms. METHODS: Mood scales and plasma concentrations of kynurenine metabolites were assessed in concussed (N=18; 1.61 days post-injury) and healthy football players (N=18). A subset of football players returned at 1-week (N=14; 9.29 days) and 1-month post-concussion (N=14, 30.93 days). RESULTS: Concussed athletes had significantly elevated levels of quinolinic acid (QUIN) and significantly lower ratios of kynurenic acid (KYNA) to QUIN at all time points compared with healthy athletes (p's<0.05), with no longitudinal evidence of normalization of KYNA or KYNA/QUIN. At 1-day post-injury, concussed athletes with lower levels of the putatively neuroprotective KYNA/QUIN ratio reported significantly worse depressive symptoms (p=0.04), and a trend toward worse anxiety symptoms (p=0.06), while at 1-month higher QUIN levels were associated with worse mood symptoms (p's<0.01). Finally, concussed athletes with worse concussion outcome, defined as number of days until return-to-play, had higher QUIN and lower KYNA/QUIN at 1-month post-injury (p's<0.05). CONCLUSIONS: These results converge with existing kynurenine literature on psychiatric patients and provide the first evidence of altered peripheral levels of kynurenine metabolites following sports-related concussion.

Current status of fluid biomarkers in mild traumatic brain injury.

Mild traumatic brain injury (mTBI) affects millions of people annually and is difficult to diagnose. Mild injury is insensitive to conventional imaging techniques and diagnoses are often made using subjective criteria such as self-reported symptoms. Many people who sustain a mTBI develop persistent post-concussive symptoms. Athletes and military personnel are at great risk for repeat injury which can result in second impact syndrome or chronic traumatic encephalopathy. An objective and quantifiable measure, such as a serum biomarker, is needed to aid in mTBI diagnosis, prognosis, return to play/duty assessments, and would further elucidate mTBI pathophysiology. The majority of TBI biomarker research focuses on severe TBI with few studies specific to mild injury. Most studies use a hypothesis-driven approach, screening biofluids for markers known to be associated with TBI pathophysiology. This approach has yielded limited success in identifying markers that can be used clinically, additional candidate biomarkers are needed. Innovative and unbiased methods such as proteomics, microRNA arrays, urinary screens, autoantibody identification and phage display would complement more traditional approaches to aid in the discovery of novel mTBI biomarkers.

Acute S100B in serum is associated with cognitive symptoms and memory performance 4 months after paediatric mild traumatic brain injury.

OBJECTIVE: This study explored whether acute serum marker S100B is related with post-concussive symptoms (PCS) and neuropsychological performance 4 months after paediatric mild traumatic brain injury (mTBI). RESEARCH DESIGN AND METHODS: This prospective short-term longitudinal study investigated children (aged 6-16 years) with mTBI (n = 36, 16 males) and children with orthopaedic injuries (OI, n = 27, 18 males) as a control group. S100B in serum was measured during the acute phase and was correlated with parent-rated PCS and neuropsychological performance 4 months after the injury. MAIN OUTCOMES AND RESULTS: The results revealed no between-group difference regarding acute S100B serum concentration. In children after mTBI, group-specific significant Spearman correlations were found between S100B and post-acute cognitive PCS (r = 0.54, p = 0.001) as well as S100B and verbal memory performance (r = -0.47, p = 0.006). In children after OI, there were insignificant positive relations between S100B and post-acute somatic PCS. In addition, insignificant positive correlations were found between neuropsychological outcome and S100B in children after OI. CONCLUSIONS: S100B was not specific for mild brain injuries and may also be elevated after OI. The group-specific association between S100B and ongoing cognitive PCS in children after mTBI should motivate to examine further the role of S100B as a diagnostic biomarker in paediatric mTBI.

Serum SNTF Increases in Concussed Professional Ice Hockey Players and Relates to the Severity of Postconcussion Symptoms.

Biomarkers for diffuse axonal injury could have utilities for the acute diagnosis and clinical care of concussion, including those related to sports. The calpain-derived αII-spectrin N-terminal fragment (SNTF) accumulates in axons after traumatic injury and increases in human blood after mild traumatic brain injury (mTBI) in relation to white matter abnormalities and persistent cognitive dysfunction. However, SNTF has never been evaluated as a biomarker for sports-related concussion. Here, we conducted longitudinal analysis of serum SNTF in professional ice hockey players, 28 of whom had a concussion, along with 45 players evaluated during the preseason, 17 of whom were also tested after a concussion-free training game. Compared with preseason levels, serum SNTF increased at 1 h after concussion and remained significantly elevated from 12 h to 6 days, before declining to preseason baseline. In contrast, serum SNTF levels were unchanged after training. In 8 players, postconcussion symptoms resolved within a few days, and in these cases serum SNTF levels were at baseline. On the other hand, for the 20 players withheld from play for 6 days or longer, serum SNTF levels rose from 1 h to 6 days postconcussion, and at 12-36 h differed significantly from the less-severe concussions (p=0.004). Serum SNTF exhibited diagnostic accuracy for concussion, especially so with delayed return to play (area under the curve=0.87). Multi-variate analyses of serum SNTF and tau improved the diagnostic accuracy, the relationship with the delay in return to play, and the temporal window beyond tau alone. These results provide evidence that blood SNTF, a biomarker for axonal injury after mTBI, may be useful for diagnosis and prognosis of sports-related concussion, as well as for guiding neurobiologically informed decisions on return to play.

Prediction of neuropsychological outcome after mild traumatic brain injury using clinical parameters, serum S100B protein and findings on computed tomography.

PRIMARY OBJECTIVE: To identify if demographics, clinical and computed tomographic (CT) characteristics at first presentation and S100B concentrations at 3 and 6 hours after mild traumatic brain injury (MTBI) predict the development of post-concussion syndrome (PCS) after 1 month. RESEARCH DESIGN AND METHODS: All consecutive MTBI patients (Glasgow Coma Scale [GCS] score 13-15) admitted to the Emergency Department aged older than 15 were included in this prospective, observational study. Outcome was assessed using a Rivermead Post-Concussion Symptoms Questionnaire to identify the patients with and without PCS 1 month after the injury. MAIN OUTCOMES AND RESULTS: A total of 176 patients with isolated MTBI were included in the study. After multivariate analysis of the demographics, clinical variables, and CT abnormalities, headache (OR = 2.09, 95% CI = 1.04-4.21, p = 0.038), seizure (OR = 5.64, 95% CI = 1.55-20.54, p = 0.009), the presence of subarachnoid haemorrhage on CT (OR = 3.67, 95% CI = 1.46-9.24, p = 0.006) and 6-hour S100B concentration (OR = 2.22, 95% CI = 1.15-4.28, p = 0.017) were independently significant predictors of the outcome. CONCLUSIONS: Outcome prediction using baseline characteristics (post-traumatic headache and seizure), CT and laboratory findings (6-hour S100B) were valuable factors for identification of the individual MTBI patient at risk for developing PCS 1 month after the injury.