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As per the latest ILAE definition, status epilepticus (SE) may lead to long-term irreversible consequences, such as neuronal death, neuronal injury, and alterations in neuronal networks. Consequently, there is growing interest in identifying biomarkers that can demonstrate and quantify the extent of neuronal and glial injury. Despite numerous studies conducted on animal models of status epilepticus, which clearly indicate seizure-induced neuronal and glial injury, as well as signs of atrophy and gliosis, evidence in humans remains limited to case reports and small case series. The implications of identifying such biomarkers in clinical practice are significant, including improved prognostic stratification of patients and the early identification of those at high risk of developing irreversible complications. Moreover, the clinical validation of these biomarkers could be crucial in promoting neuroprotective strategies in addition to antiseizure medications. In this study, we present a systematic review of research on biomarkers of neuro-glial injury in patients with status epilepticus.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus attacks multiple organs of coronavirus disease 2019 (COVID-19) patients, including the brain. There are worldwide descriptions of neurological deficits in COVID-19 patients. Central nervous system (CNS) symptoms can be present early in the course of the disease. As many as 55% of hospitalized COVID-19 patients have been reported to have neurological disturbances three months after infection by SARS-CoV-2. The mutability of the SARS-COV-2 virus and its potential to directly affect the CNS highlight the urgency of developing technology to diagnose, manage, and treat brain injury in COVID-19 patients. The pathobiology of CNS infection by SARS-CoV-2 and the associated neurological sequelae of this infection remain poorly understood. In this review, we outline the rationale for the use of blood biomarkers (BBs) for diagnosis of brain injury in COVID-19 patients, the research needed to incorporate their use into clinical practice, and the improvements in patient management and outcomes that can result. BBs of brain injury could potentially provide tools for detection of brain injury in COVID-19 patients. Elevations of BBs have been reported in cerebrospinal fluid (CSF) and blood of COVID-19 patients. BB proteins have been analyzed in CSF to detect CNS involvement in patients with infectious diseases, including human immunodeficiency virus and tuberculous meningitis. BBs are approved by the U.S. Food and Drug Administration for diagnosis of mild versus moderate traumatic brain injury and have identified brain injury after stroke, cardiac arrest, hypoxia, and epilepsy. BBs, integrated with other diagnostic tools, could enhance understanding of viral mechanisms of brain injury, predict severity of neurological deficits, guide triage of patients and assignment to appropriate medical pathways, and assess efficacy of therapeutic interventions in COVID-19 patients.

Objective: Biomarkers ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) may help detect brain injury, assess its severity, and improve outcome prediction. This study aimed to evaluate the prognostic value of these biomarkers during the first days after brain injury., Methods: Serum UCH-L1 and GFAP were measured in 324 patients with traumatic brain injury (TBI) enrolled in a prospective study. The outcome was assessed using the Glasgow Outcome Scale (GOS) or the extended version, Glasgow Outcome Scale-Extended (GOSE)., Results: Patients with full recovery had lower UCH-L1 concentrations on the second day and patients with favorable outcome had lower UCH-L1 concentrations during the first 2 days compared with patients with incomplete recovery and unfavorable outcome. Patients with full recovery and favorable outcome had significantly lower GFAP concentrations in the first 2 days than patients with incomplete recovery or unfavorable outcome. There was a strong negative correlation between outcome and UCH-L1 in the first 3 days and GFAP levels in the first 2 days. On arrival, both UCH-L1 and GFAP distinguished patients with GOS score 1-3 from patients with GOS score 4-5, but not patients with GOSE score 8 from patients with GOSE score 1-7. For UCH-L1 and GFAP to predict unfavorable outcome (GOS score ≤ 3), the area under the receiver operating characteristic curve was 0.727, and 0.723, respectively. Neither UCHL-1 nor GFAP was independently able to predict the outcome when age, worst Glasgow Coma Scale score, pupil reactivity, Injury Severity Score, and Marshall score were added into the multivariate logistic regression model., Conclusions: GFAP and UCH-L1 are significantly associated with outcome, but they do not add predictive power to commonly used prognostic variables in a population of patients with TBI of varying severities., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Blood-based biomarkers for traumatic brain injury (TBI) have been investigated and proposed for decades, yet the current clinical assessment of TBI is largely based on clinical symptoms that can vary widely amongst patients, and have significant overlap with unrelated disease states. A careful review of current treatment guidelines for TBI further highlights the potential utility of a blood-based TBI biomarker panel in augmenting clinical decision making. Numerous expert reviews on blood-based TBI biomarkers have been published but a close look at the methods used and the astonishing paucity of validation and quality control data has not been undertaken from the vantage point of the clinical laboratory. Further, the field of blood-based TBI biomarker research has failed to adequately examine sex and gender differences between men and women with respect to the clinical care settings, as well as differences in physiological outcomes of TBI biomarker studies. Discussions of tried-and-true laboratory techniques in addition to a few new ones already operating in the clinical laboratory are summarized with a consideration of their utility in TBI biomarker assessment. In the context of TBI biomarkers, the central concerns discussed in this review are the readiness of the clinical laboratory, the willingness of the research environment and the inherent ability of each to radically affect patient outcomes in TBI., (Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Objective: Traumatic brain injury (TBI) is a leading cause of disability and death worldwide, with an estimated 64-74 million cases annually. The current gold standard for diagnosis is a computed tomography (CT) scan, which has limitations such as access, cost, and radiation risk. Therefore, a simple, accessible, and safe diagnostic modality is needed, one of which is biomarker examination. This study aims to establish the relationship between blood levels of the biomarker ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) and the severity of TBI based on the Glasgow Coma Scale (GCS) and Rotterdam CT score. Material and Methods: This observational analytic study with a cross-sectional design involved 41 samples aged 18-50 years who presented to the Emergency Department of Dr. Soetomo General Hospital, Surabaya, within 3-24 hours of the incident. UCH-L1 levels were measured from blood samples using the ELISA method, and the data on UCH-L1, GCS, and Rotterdam CT scores were analyzed with SPSS 29. Results: The mean UCH-L1 level was 0.522 ± 0.592, with a cutoff value of > 0.2057, indicating moderate to severe TBI if UCH-L1 levels exceeded 0.2057. Spearman's test and correlation coefficient analysis showed a strong relationship between UCH-L1 levels and Rotterdam CT score (p < 0.05), as well as between UCH-L1 levels and TBI severity based on GCS (p < 0.05). The cutoff value for Rotterdam CT score was > 2, indicating moderate to severe TBI if the score exceeded 2. Conclusion: Serum UCH-L1 levels are significantly associated with the severity of TBI based on GCS and Rotterdam CT score. [ABSTRACT FROM AUTHOR]

To compare for the first time the performance of "GFAP and UCH-L1" vs. S100B in a cohort of patients managed for mild traumatic brain injury (mTBI) according to actualized French guidelines. A prospective study was recently carried at the Emergency Department of Clermont-Ferrand University Hospital in France. Patients with mTBI presenting a medium risk of complications were enrolled. Blood S100B and "GFAP and UCHL-1" were sampled and measured according to French guidelines. S100B was measured in patients with samples within 3 h of trauma (Cobas®, Roche Diagnostics), while GFAP and UCHL-1 were measured in all patients (samples <3 h and 3–12 h) using another automated assay (i-STAT® Alinity, Abbott). For sampling <3 h, serum S100B correctly identifies intracranial lesions with a specificity of 25.7 % (95 % CI; 19.5–32.6 %), a sensitivity of 100 % (95 % CI; 66.4–100 %), and a negative predictive value of 100 % (95 % CI; 92.5–100 %). For sampling <12 h, plasma "GFAP and UCH-L1" levels correctly identify intracranial lesions with a specificity of 31.7 % (95 % CI; 25.7–38.2 %), a sensitivity of 100 % (95 % CI; 73.5–100 %), and a negative predictive value of 100 % (95 % CI; 95–100 %). Comparison of specificities (25.7 vs. 31.7 %) did not reveal a statistically significant difference (p=0.16). We highlight the usefulness of measuring plasma "GFAP and UCH-L1" levels to target mTBI patients (sampling within 12 h post-injury) and optimize the reduction of CT scans. [ABSTRACT FROM AUTHOR]

Acute ischemic stroke (AIS) is one of the leading causes of morbidity worldwide, thus, early recognition is essential to accelerate treatment. The only definite way to diagnose AIS is radiological imaging, which is limited to hospitals. However, two serum neuromarkers, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1), have been proven as indicators of brain trauma and AIS. We aimed to investigate the potential utility of these markers in distinguishing between large vessel occlusion (LVO) and small vessel occlusion (SVO), considering differences in treatment. Sixty-nine AIS patients were included in our study and divided into LVO and SVO groups based on radiological imaging. Control group consisted of 22 participants without history of neurological disorders. Results showed differences in serum levels of both GFAP and UHC-L1 between all groups; control vs. SVO vs. LVO (GFAP: 30.19 pg/mL vs. 58.6 pg/mL vs. 321.3 pg/mL; UCH-L1: 117.7 pg/mL vs. 251.8 pg/mL vs. 573.1 pg/mL; p < 0.0001), with LVO having the highest values. Other prognostic factors of stroke severity were analyzed and did not correlate with serum biomarkers. In conclusion, a combination of GFAP and UCH-L1 could potentially be a valuable diagnostic tool for differentiating LVO and SVO in AIS patients. [ABSTRACT FROM AUTHOR]

Aim: There is a critical need to validate biofluid-based biomarkers as diagnostic and drug development tools for traumatic brain injury (TBI). As part of the TBI Endpoints Development Initiative, we identified four potentially predictive and pharmacodynamic biomarkers for TBI: astroglial markers GFAP and S100B and the neuronal markers UCH-L1 and Tau. Materials & methods: Several commonly used platforms for these four biomarkers were identified and compared on analytic performance and ability to detect gold standard recombinant protein antigens and to pool control versus TBI cerebrospinal fluid (CSF). Results: For each marker, only some assay formats could differentiate TBI CSF from the control CSF. Also, different assays for the same biomarker reported divergent biomarker values for the same biosamples. Conclusion: Due to the variability of TBI marker assay in performance and reported values, standardization strategies are recommended when comparing reported biomarker levels across assay platforms.

Research in the field of TBI (traumatic brain injury) has long been focused on severe brain injury, while the number of mild injuries far overweigh severe injuries. Mild head injuries constitute up to 95% of all traumatic head injuries. The purpose of this work is to identify mTBI (mild traumatic brain injury) patients who are unlikely to benefit from CT (computed tomography) scanning. Biomarkers capable of clearly discriminating between CT-positive and CT-negative subjects are needed. Biomarkers hold the potential to document whether a concussion occurred, especially when the history is unclear and neurocognitive sequelae persist. Recently, following advances in proteomics analysis, investigators have introduced ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) as two promising brain injury biomarkers. The authors provide an update on the current knowledge of TBI biomarkers, especially protein biomarkers for neuronal cell body injury (UCH-L1) and astroglial injury (GFAP, S100B), and a focused literature review dealing with implementation of mTBI biomarkers in clinical practice. [ABSTRACT FROM AUTHOR]

The use of UCH-L1 detection with point-of-care (POC) assay alone has not been characterized for clinical use. This study compares the accuracies of POC UCH-L1 and Neuron-Specific Enolase (NSE) Elecsys® levels for identifying TBI patients with structural abnormalities on neuroimaging. The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Phase 1 Cohort, enrolled 1375 TBI patients (GCS 3-15) presenting to one of 18 US Level I trauma centers within 24 h of injury who had an admission head CT; blood samples were collected, along with 122 orthopedic and 209 healthy controls. The TBI cohort consisted of 810 CT-negative (CT-) and 549 CT-positive (CT+) subjects. Of the CT-subjects who had MRIs, 121 were MRI-positive (MRI+) and 333 were MRI-negative (MRI-). UCH-L1 POC showed best diagnostic performance for CT + versus CT-, 0-8 h post-injury with an AUC of 0·779 [0·708-0.850] when compared to the 0-25 h interval, with an AUC of 0.684 [0.655-0.712]. NSE assay has an AUC of 0.695 [0.619-0.770] for the 0-8 h interval and 0.634 [0.603-0.665] for the 0-25 h interval. During the first 8 after injury, POC UCH-L1 outperforms NSE in identifying TBI patients with structural abnormalities on neuroimaging. [ABSTRACT FROM AUTHOR]

This paper reviews the predictive capabilities of blood-based biomarkers to quantify traumatic brain injury (TBI). Biomarkers for concussive conditions also known as mild, to moderate and severe TBI identified along with post-traumatic stress disorder (PTSD) and chronic traumatic encephalopathy (CTE) that occur due to repeated blows to the head during one's lifetime. Since the pathways of these biomarkers into the blood are not fully understood whether there is disruption in the blood–brain barrier (BBB) and the time it takes after injury for the expression of the biomarkers to be able to predict the injury effectively, there is a need to understand the protein biomarker structure and other physical properties. The injury events in terms of brain and mechanics are a result of external force with or without the shrapnel, in the wake of a wave result in local tissue damage. Thus, these mechanisms express specific biomarkers kinetics of which reaches half-life within a few hours after injury to few days. Therefore, there is a need to determine the concentration levels that follow injury. Even though current diagnostics linking biomarkers with TBI severity are not fully developed, there is a need to quantify protein structures and their viability after injury. This research was conducted to fully understand the structures of 12 biomarkers by performing molecular dynamics simulations involving atomic movement and energies of forming hydrogen bonds. Molecular dynamics software, NAMD and VMD were used to determine and compare the approximate thermodynamic stabilities of the biomarkers and their bonding energies. Five biomarkers used clinically were S100B, GFAP, UCHL1, NF-L and tau, the kinetics obtained from literature show that the concentration values abruptly change with time after injury. For a given protein length, associated number of hydrogen bonds and bond energy describe a lower bound region where proteins self-dissolve and do not have long enough half-life to be detected in the fluids. However, above this lower bound, involving higher number of bonds and energy, we hypothesize that biomarkers will be viable to disrupt the BBB and stay longer to be modeled for kinetics for diagnosis and therefore may help in the discoveries of new biomarkers. [ABSTRACT FROM AUTHOR]

Accumulating data suggest that various neurologic manifestations are reported in critically-ill COVID-19 patients. Although low testosterone levels were associated with poor outcomes, the relationship between testosterone levels and indices of brain injury are still poorly understood. Therefore, we aimed to explore whether testosterone levels are associated with glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), biomarkers of brain injury, in patients with a severe form of COVID-19. The present study was conducted on 65 male patients aged 18–65 with severe COVID-19. Blood samples were collected at three time points: upon admission to ICU, 7 days after, and 14 days after. In patients with neurological sequels (n = 20), UCH-L1 serum concentrations at admission were markedly higher than in patients without them (240.0 (155.4–366.4) vs. 146.4 (92.5–243.9) pg/mL, p = 0.022). GFAP concentrations on admission did not differ between the groups (32.2 (24.2–40.1) vs. 29.8 (21.8–39.4) pg/mL, p = 0.372). Unlike GFAP, UCH-L1 serum concentrations exhibited a negative correlation with serum testosterone in all three time points (r = −0.452, p < 0.001; r = −0.430, p < 0.001 and r = −0.476, p = 0.001, respectively). The present study suggests that the traumatic brain injury biomarker UCH-L1 may be associated with neurological impairments seen in severe COVID-19. Moreover, a negative correlation between UCH-L1 and serum testosterone concentrations implies that testosterone may have a role in the development of neurological sequels in critically-ill COVID-19 patients. [ABSTRACT FROM AUTHOR]

The objective of this work was to analyze the relationships between traumatic brain injury (TBI) on computed tomographic (CT) imaging and blood concentration of glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), and S100B. This prospective cohort study involved 644 TBI patients referred to Stanford Hospital's Emergency Department between November 2015 and April 2017. Plasma and serum samples of 462 patients were analyzed for levels of GFAP, UCH-L1, and S100B. Glial neuronal ratio (GNR) was calculated as the ratio between GFAP and UCH-L1 concentrations. Admission head CT scans were reviewed for TBI imaging common data elements, and performance of biomarkers for identifying TBI was assessed via area under the receiver operating characteristic curve (ROC). We also dichotomized biomarkers at established thresholds and estimated standard measures of classification accuracy. We assessed the ability of GFAP, UCH-L1, and GNR to discriminate small and large/diffuse lesions based on CT imaging using an ROC analysis. In our cohort of mostly mild TBI patients, GFAP was significantly more accurate in detecting all types of acute brain injuries than UCH-L1 in terms of area under the curve (AUC) values (p < 0.001), and also compared with S100B (p < 0.001). UCH-L1 and S100B had similar performance (comparable AUC values, p = 0.342). Sensitivity exceeded 0.8 for each biomarker across all different types of TBI injuries, and no significant differences were observed by type of injury. There was a significant difference between GFAP and GNR in distinguishing between small lesions and large/diffuse lesions in all injuries (p = 0.004, p = 0.007). In conclusion, GFAP, UCH-L1, and S100B show high sensitivity and negative predictive values for all types of TBI lesions on head CT. A combination of negative blood biomarkers (GFAP and UCH-L1) in a patient suspected of TBI may be used to safely obviate the need for a head CT scan. GFAP is a promising indicator to discriminate between small and large/diffuse TBI lesions. [ABSTRACT FROM AUTHOR]

Objective: To determine the concentrations of four neuroprotein biomarkers and 68 miRNAs in neonates with low cord pH and/or mild hypoxic-ischemic encephalopathy (HIE). Study Design: A prospective cohort study enrolled neonates with low cord pH (n = 18), moderate-severe HIE (n = 40), and healthy controls (n = 38). Groups provided serum samples at 0-6 h of life. The concentrations of biomarkers and miRNAs were compared between cohorts. Result: The low cord pH and moderate-severe HIE groups had increased concentrations of GFAP, NFL and Tau compared to controls (P < 0.05, P < 0.001, respectively). NFL concentrations in mild HIE was higher than controls (P < 0.05) but less than moderate-severe HIE (P < 0.001). Of 68 miRNAs, 36 in low cord pH group and 40 in moderate-severe HIE were upregulated compared to controls (P < 0.05). Five miRNAs in low cord pH group (P < 0.05) and 3 in moderate-severe HIE were downregulated compared to controls (P < 0.05). Conclusion: A biomarker panel in neonates with low cord pH may help clinicians make real-time decisions. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to explore the potential of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) as biomarkers for diagnosis and prognosis in mild and severe TBI cases, including TBI-related deaths.This prospective cohort study includes 40 cases each of mild, severe, fatal TBI cases, and 40 healthy controls. Serum samples were collected from live patients at 8 and 20 h post injury for UCH-L1 and GFAP respectively, and from deceased patients within 6 h of death.Elevated levels of both GFAP and UCH-L1 were observed in patients with severe and fatal TBI cases. These biomarkers exhibited promising potential for predicting various Glasgow Outcome Scale Extended (GOSE) categories. Combining GFAP and UCH-L1 yielded higher predictive accuracy both for diagnosis and prognosis in TBI cases. The study additionally established specific cut-off levels for GFAP and UCH-L1 stratified according to the severity and prognosis.GFAP and UCH-L1 individually demonstrated moderate to good discrimination capacity in predicting TBI severity and functional outcomes. However, combining these biomarkers is recommended for improved diagnostic and prognostic utility. This precision tool can enhance patient care, enabling tailored treatment plans, ultimately reducing morbidity and mortality rates in TBI cases.Methods: This study aimed to explore the potential of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) as biomarkers for diagnosis and prognosis in mild and severe TBI cases, including TBI-related deaths.This prospective cohort study includes 40 cases each of mild, severe, fatal TBI cases, and 40 healthy controls. Serum samples were collected from live patients at 8 and 20 h post injury for UCH-L1 and GFAP respectively, and from deceased patients within 6 h of death.Elevated levels of both GFAP and UCH-L1 were observed in patients with severe and fatal TBI cases. These biomarkers exhibited promising potential for predicting various Glasgow Outcome Scale Extended (GOSE) categories. Combining GFAP and UCH-L1 yielded higher predictive accuracy both for diagnosis and prognosis in TBI cases. The study additionally established specific cut-off levels for GFAP and UCH-L1 stratified according to the severity and prognosis.GFAP and UCH-L1 individually demonstrated moderate to good discrimination capacity in predicting TBI severity and functional outcomes. However, combining these biomarkers is recommended for improved diagnostic and prognostic utility. This precision tool can enhance patient care, enabling tailored treatment plans, ultimately reducing morbidity and mortality rates in TBI cases.Results: This study aimed to explore the potential of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) as biomarkers for diagnosis and prognosis in mild and severe TBI cases, including TBI-related deaths.This prospective cohort study includes 40 cases each of mild, severe, fatal TBI cases, and 40 healthy controls. Serum samples were collected from live patients at 8 and 20 h post injury for UCH-L1 and GFAP respectively, and from deceased patients within 6 h of death.Elevated levels of both GFAP and UCH-L1 were observed in patients with severe and fatal TBI cases. These biomarkers exhibited promising potential for predicting various Glasgow Outcome Scale Extended (GOSE) categories. Combining GFAP and UCH-L1 yielded higher predictive accuracy both for diagnosis and prognosis in TBI cases. The study additionally established specific cut-off levels for GFAP and UCH-L1 stratified according to the severity and prognosis.GFAP and UCH-L1 individually demonstrated moderate to good discrimination capacity in predicting TBI severity and functional outcomes. However, combining these biomarkers is recommended for improved diagnostic and prognostic utility. This precision tool can enhance patient care, enabling tailored treatment plans, ultimately reducing morbidity and mortality rates in TBI cases.Conclusion: This study aimed to explore the potential of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) as biomarkers for diagnosis and prognosis in mild and severe TBI cases, including TBI-related deaths.This prospective cohort study includes 40 cases each of mild, severe, fatal TBI cases, and 40 healthy controls. Serum samples were collected from live patients at 8 and 20 h post injury for UCH-L1 and GFAP respectively, and from deceased patients within 6 h of death.Elevated levels of both GFAP and UCH-L1 were observed in patients with severe and fatal TBI cases. These biomarkers exhibited promising potential for predicting various Glasgow Outcome Scale Extended (GOSE) categories. Combining GFAP and UCH-L1 yielded higher predictive accuracy both for diagnosis and prognosis in TBI cases. The study additionally established specific cut-off levels for GFAP and UCH-L1 stratified according to the severity and prognosis.GFAP and UCH-L1 individually demonstrated moderate to good discrimination capacity in predicting TBI severity and functional outcomes. However, combining these biomarkers is recommended for improved diagnostic and prognostic utility. This precision tool can enhance patient care, enabling tailored treatment plans, ultimately reducing morbidity and mortality rates in TBI cases. [ABSTRACT FROM AUTHOR]

Background: Interest has mounted into the use of objective clinical biomarkers for traumatic brain injury (TBI). This systematic review and meta-analysis aimed to synthesise the existing evidence investigating the use of serum & plasma biomarkers to exclude significant intracranial injuries seen on CT head scans in patients that present to ED with TBI.Methods: The primary outcome was to review the diagnostic accuracy (sensitivity & specificity) of S100B, GFAP and UCH-L1 to exclude significant intracranial pathology on CT head scan in adults presenting with TBI. Secondary outcomes investigated biomarker performance at different time points, in isolated TBI and multi-trauma and with pre-specified cut offs. Systematic searches were conducted on MEDLINE ® (via PubMed), Cochrane electronic databases and EMBASE from 1st January 2000 until June 2020. Bias was assessed using QUADAS 2 tool. A narrative synthesis and meta-analysis were performed. PROSPERO registration number CRD42020212206.Results: After screening, 22 papers were included. The total number of patients with TBI was 9,416. There was significant variation regarding study design, population selection and the clinical threshold/decision rule for CT head request. The diagnostic accuracy of S100B as measured by the range of individual sensitivities and specificities were 63-100% and 5-58%, respectively. Individual sensitivities and specificities for GFAP were 67-100% and 0-89% and for UCH-L1 were 61-100% and 21-63.7% respectively. When measured within 3 hours individual sensitivities & specificities for S100B were 98-100% & 20-58% respectively. The quality of evidence for the primary outcome overall was low. The quality of evidence was low for all secondary outcomes apart from studies that used a pre-specified cut off for S100B which had a moderate strength of evidence.Conclusion: The overall quality of evidence regarding the diagnostic accuracy of single biomarkers as a rule out for significant intracranial injury seen on CT head scans in ED patients with TBI is low. Based on current evidence, S100B is the only single biomarker with a validated clinical platform, pre-determined cut off threshold and moderate quality evidence; at this stage making it the biomarker of choice. More robust clinical outcome and economic impact data is required to support its incorporation into clinical decision tools. [ABSTRACT FROM AUTHOR]

A major obstacle for translational research in acute spinal cord injury (SCI) is the lack of biomarkers that can objectively stratify injury severity and predict outcome. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a neuron-specific enzyme that shows promise as a diagnostic biomarker in traumatic brain injury (TBI), but has not been studied in SCI. In this study, cerebrospinal fluid (CSF) and serum samples were collected over the first 72–96 h post-injury from 32 acute SCI patients who were followed prospectively to determine neurological outcomes at 6 months post-injury. UCH-L1 concentration was measured using the Quanterix Simoa platform (Quanterix, Billerica, MA) and correlated to injury severity, time, and neurological recovery. We found that CSF UCH-L1 was significantly elevated by 10- to 100-fold over laminectomy controls in an injury severity- and time-dependent manner. Twenty-four-hour post-injury CSF UCH-L1 concentrations distinguished between American Spinal Injury Association Impairment Scale (AIS) A and AIS B, and AIS A and AIS C patients in the acute setting, and predicted who would remain "motor complete" (AIS A/B) at 6 months with a sensitivity of 100% and a specificity of 86%. AIS A patients who did not improve their AIS grade at 6 months post-injury were characterized by sustained elevations in CSF UCH-L1 up to 96 h. Similarly, the failure to gain >8 points on the total motor score at 6 months post-injury was associated with higher 24-h CSF UCH-L1. Unfortunately, serum UCH-L1 levels were not informative about injury severity or outcome. In conclusion, CSF UCH-L1 in acute SCI shows promise as a biomarker to reflect injury severity and predict outcome. [ABSTRACT FROM AUTHOR]

Objective: This study examines the relationship of serum total tau, neurofilament light (NFL), ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) with neurocognitive performance in service members and veterans with a history of traumatic brain injury (TBI). Method: Service members (n = 488) with a history of uncomplicated mild (n = 172), complicated mild, moderate, severe, or penetrating TBI (sTBI; n = 126), injured controls (n = 116), and non-injured controls (n = 74) prospectively enrolled from Military Treatment Facilities. Participants completed a blood draw and neuropsychological assessment a year or more post-injury. Six neuropsychological composite scores and presence/absence of mild neurocognitive disorder (MNCD) were evaluated. Within each group, stepwise hierarchical regression models were conducted. Results: Within the sTBI group, increased serum UCH-L1 was related to worse immediate memory and delayed memory (R2Δ =.065–.084, ps <.05) performance, while increased GFAP was related to worse perceptual reasoning (R2Δ =.030, p =.036). Unexpectedly, within injured controls, UCH-L1 and GFAP were inversely related to working memory (R2Δ =.052–.071, ps <.05), and NFL was related to executive functioning (R2Δ =.039, p =.021) and MNCD (Exp(B) = 1.119, p =.029). Conclusions: Results suggest GFAP and UCH-L1 could play a role in predicting poor cognitive outcome following complicated mild and more severe TBI. Further investigation of blood biomarkers and cognition is warranted. [ABSTRACT FROM AUTHOR]

• The S100B protein can be used in the clinical routine in the management of mTBI. • S100B levels combined with a clinical algorithm, could reduce for CT scans by 1/3. • Sampling should take place within 3 h of trauma for S100B assay. • For S100B and probably other biomarkers, specific cut-off levels and paediatric reference ranges had to be defined. • GFAP in combination with H-FABP could improve the specificity of S100B. Mild traumatic brain injury (mTBI) is one of the common causes of emergency department visits around the world. Up to 90% of injuries are classified as mTBI. Cranial computed tomography (CCT) is a standard diagnostic tool for adults with mTBI. Alternatively, children can be admitted for inpatient observation with CCT scans performed only on those with clinical deterioration. The use of blood biomarkers is a supplementary tool for identifying patients at risk of intracerebral lesions who may need imaging. This review provides a contemporary clinical and laboratory framework for blood biomarker testing in mTBI management. The S100B protein is used routinely in the management of mTBI in Europe together with clinical guidelines. Due to its excellent negative predictive value, S100B protein is an alternative choice to CCT scanning for mTBI management under considered, consensual and pragmatic use. In this review, we propose points to help clinicians and clinical pathologists use serum S100B protein in the clinical routine. A review of the literature on the different biomarkers (GFAP, UCH-L1, NF [H or L], tau, H-FABP, SNTF, NSE, miRNAs, MBP, β trace protein) is also conducted. Some of these other blood biomarkers, used alone (GFAP, UCH-L1) or in combination (GFAP + H-FABP ± S100B ± IL10) can improve the specificity of S100B. [ABSTRACT FROM AUTHOR]

Several serum biomarkers have been studied to diagnose incidence and severity of traumatic brain injury (TBI), but a reliable biomarker in TBI has yet to be identified. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) has been proposed as a biomarker in clinical and preclinical studies, largely in the setting of isolated TBI or concussion. The aim of this study was to evaluate the performance of UCH-L1 as a serum biomarker in the setting of polytrauma and TBI. Multiple variations of murine TBI and polytrauma models were used to evaluate serum biomarkers. The different models included TBI with and without hemorrhagic shock and resuscitation, isolated extremity vascular ligation, extremity ischemia/reperfusion, and blunt tail injury. Blood was drawn at intervals after injury, and serum levels of neuron-specific enolase, UCH-L1, creatine kinase, and syndecan-1 were evaluated by enzyme-linked immunosorbent assay. UCH-L1 levels were not significantly different between TBI, tail injury, and sham TBI. By contrast, neuron-specific enolase levels were increased in TBI mice compared with tail injury and sham TBI mice. UCH-L1 levels increased regardless of TBI status at 30 min and 4 h after hemorrhagic shock and resuscitation. In mice that underwent femoral artery cannulation followed by hemorrhagic shock/resuscitation, UCH-L1 levels were significantly elevated compared with shock sham mice at 4 h (3158 ± 2168 pg/mL, 4 h shock versus 0 ± 0 pg/mL, 4 h shock sham; P < 0.01) and at 24 h (3253 ± 2954 pg/mL, 24 h shock versus 324 ± 482 pg/mL, 24 h shock sham; P = 0.03). No differences were observed in UCH-L1 levels between the sham shock and the arterial ligation, vein ligation, or extremity ischemia/reperfusion groups at any time point. Similar to UCH-L1, creatine kinase was elevated only after shock compared with sham mice at 4, 24, and 72 h after injury. Our study demonstrates that UCH-L1 is not a specific marker for TBI but is elevated in models that induce central and peripheral nerve ischemia. Given the increase in UCH-L1 levels observed after hemorrhagic shock, we propose that UCH-L1 may be a useful adjunct in quantifying severity of shock or global ischemia rather than as a specific marker of TBI. [ABSTRACT FROM AUTHOR]

Rapid risk-stratification of patients with acute traumatic brain injury (TBI) would inform management decisions and prognostication. The objective of this serum biomarker study (Biomarkers of Injury and Outcome [BIO]-Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment [ProTECT]) was to test the hypothesis that serum biomarkers of structural brain injury, measured at a single, very early time-point, add value beyond relevant clinical covariates when predicting unfavorable outcome 6 months after moderate-to-severe acute TBI. BIO-ProTECT utilized prospectively collected samples obtained from subjects with moderate-to-severe TBI enrolled in the ProTECT III clinical trial of progesterone. Serum samples were obtained within 4 h after injury. Glial fibrillary acidic protein (GFAP), S100B, αII-spectrin breakdown product of molecular weight 150 (SBDP150), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) were measured. The association between log-transformed biomarker levels and poor outcome, defined by a Glasgow Outcome Scale-Extended (GOS-E) score of 1–4 at 6 months post-injury, were estimated via logistic regression. Prognostic models and a biomarker risk score were developed using bootstrapping techniques. Of 882 ProTECT III subjects, samples were available for 566. Each biomarker was associated with 6-month GOS-E (p < 0.001). Compared with a model containing baseline patient variables/characteristics, inclusion of S100B and GFAP significantly improved prognostic capacity (p ≤ 0.05 both comparisons); conversely, UCH-L1 and SBDP did not. A final predictive model incorporating baseline patient variables/characteristics and biomarker data (S100B and GFAP) had the best prognostic capability (area under the curve [AUC] = 0.85, 95% confidence interval [CI]: CI 0.81-0.89). Very early measurements of brain-specific biomarkers are independently associated with 6-month outcome after moderate-to-severe TBI and enhance outcome prediction. [ABSTRACT FROM AUTHOR]

Glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), and matrix metalloproteinase 9 (MMP-9) are potential biomarkers of traumatic brain injury (TBI) but also of secondary insults to the brain. The aim of this study was to describe the cerebral distribution of GFAP, UCH-L1, and MMP-9 in a rat model of diffuse TBI associated with standardized hypoxia-hypotension (HH). Adult male Sprague-Dawley rats were allocated to Sham (n = 10), TBI (n = 10), HH (n = 10), and TBI+HH (n = 10) groups. After 4 hours, brains were rapidly removed and immunostaining of GFAP, UCH-L1, and MMP-9 was performed. Areas of interest that have been described as particularly sensitive to hypoxic insults were analyzed. For GFAP, in the neocortex, immunostaining revealed a significant decrease in strong staining for HH and TBI+HH groups compared with TBI group (P <.0001). For UCH-L1, the total immunostaining (6 regions of interest) reported a significant increase in strong staining (P <.0001) and decrease in weak staining (P <.0001) for the HH and TBI+HH groups compared with the Sham and TBI groups. For MMP-9, for the HH and TBI+HH groups, a significant increase in moderate (P <.0001) and weak staining (P <.0001) and a decrease in negative staining (P <.0001) compared with the Sham and TBI groups were observed. UCH-L1 and MMP-9 immunostainings increased after HH alone or HH combined with TBI compared with TBI alone. GFAP immunostaining decreased particularly in the neocortex after HH alone or HH combined with TBI compared with TBI alone. These three biomarkers could therefore be considered as potential biomarkers of HH insults independently of TBI. [ABSTRACT FROM AUTHOR]

Abstract Brain-specific biomolecules are being increasingly investigated as a viable alternative to the clinical scores and radiological features, on which we still rely upon for stratification, therapy and predicting outcome in traumatic brain injury (TBI). TBI generally leads to release of various chemical compound within the cerebrospinal fluid (CSF) or blood depending on the severity of injury, which were studied variedly in last decades. However, most of these compounds being non-specific to brain, their applicability was challenged further. This review encompasses the novel and promising biomarkers being studied in the present decade, with encouraging results in laboratory and animal or human models. Highlights • Grading and prognostication of traumatic brain injury are difficult. • Brain trauma results in alteration of level of some specific biomolecules. • Some of the newly identified biomolecules are promising biomarkers. • Biomarkers can provide vital information in the diagnosis of traumatic brain injury. [ABSTRACT FROM AUTHOR]

We present a lateral flow immunoassay (LFA) for the quantitative, fluorescence-based detection of the trauma brain injury (TBI) biomarker ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) that features a layer of graphene oxide (GO) particles over the test zone of nitrocellulose (NC) strips. The introduction of 80 ng of GO at test lines increased fluorescence signals 2–3-fold. This was attributed to an increase in the immobilization of capture antibodies in the top layer of NC, which increased the density of recognition complexes at the surface and hence the signals reaching the reader used. A linear concentration–response relationship was observed in the 0–200 pg/mL UCH-L1 range with an inter assay CoV of 2.65 %. The LOD and LOQ values of 11.1 pg/mL and 33.5 pg/mL were compatible with threshold levels of UCH-L1. Finally, mock plasma samples with UCH-L1 levels characteristic of TBI patients with negative (60 pg/mL) and positive (130 pg/mL) CT scans were successfully analyzed. Storage stability testing further showed that GO did not affect the biological activity of the capture antibody. In summary, we demonstrate that the use of GO particles in the top layers of the test zone of NC strips improves signal intensity, which could potentially enhance the accuracy and efficiency of LFA-based diagnosis. • A new lateral flow immunoassay for the quantitative detection of TBI biomarker UCH-L1 is presented. • The LFA features a layer of graphene oxide particles over the test zone of nitrocellulose strips. • The introduction of GO particles increased fluorescence signals 2–3-fold. • The LFA exhibited a linear concentration-response relationship in the 0–200 pg/mL UCH-L1 range. • The LFA achieved LOD and LOQ values compatible with the threshold levels of UCH-L1. [ABSTRACT FROM AUTHOR]

There is a pressing need to identify objective biomarkers for the assessment of sport-related concussion (SRC) to reduce the reliance on clinical judgment for the management of these injuries. The goal of the current study was to prospectively establish the acute effects of SRC on serum levels of S100 calcium-binding protein beta (S100B), glial fibrillary acidic protein (GFAP), and ubiquitin C-terminal hydrolase-L1 (UCH-L1). Collegiate and high school football players were enrolled and provided blood at pre-season. Injured athletes participated in follow-up visits at ∼6 and 24-48 h following documented SRC ( n = 32). Uninjured football players participated in similar follow-up visits and served as controls ( n = 29). The median time between injury and blood collection was 2 h (6 h visit) and 22.5 h (24-48 h visit) in concussed athletes. Concussed athletes had significantly elevated UCH-L1 levels at the 6 h visit relative to pre-season levels (Z = 2.22, p = 0.03) and levels in control athletes (Z = 3.02, p = 0.003). Concussed athletes also had elevated S100B at 6 h relative to pre-season (Z = 2.07, p = 0.04) and controls (Z = 2.75, p = 0.006). Both markers showed fair discrimination between concussed and control athletes (UCH-L1 area under receiver operating characteristic curve [AUC] [95% CI] = 0.74 [0.61-0.88], S100B AUC = 0.72 [0.58-0.87]). Percent-change of UCH-L1 and S100B at 6 h relative to pre-season also showed fair discrimination (AUC = 0.79 [0.66-0.92] and AUC = 0.77 [0.64-0.90]). GFAP levels did not differ between groups or in concussed athletes relative to pre-season. This study provides prospective evidence of significant increases in serum levels of UCH-L1 and S100B during the early acute period following SRC, and lays the foundation for future studies examining the clinical potential for blood-based biomarkers in the early detection of concussion. [ABSTRACT FROM AUTHOR]

Objective:We examined two potential biomarkers of brain damage in hypoxic-ischemic encephalopathy (HIE) neonates: glial fibrillary acidic protein (GFAP; a marker of gliosis) and ubiquitin C-terminal hydrolase L1 (UCH-L1; a marker of neuronal injury).We hypothesized that the biomarkers would be measurable in cord blood of healthy neonates and could serve as a normative reference for brain injury in HIE infants. We further hypothesized that higher levels would be detected in serum samples of HIE neonates and would correlate with brain damage on magnetic resonance imaging (MRI) and later developmental outcomes.? Study Design: Serum UCH-L1 and GFAP concentrations from HIE neonates (n D16) were compared to controls (nD11). The relationship between biomarker concentrations of HIE neonates and brain damage (MRI) and developmental outcomes (Bayley-III) was examined using Pearson correlation coefficients and a mixed model design. Result: Both biomarkers were detectable in cord blood from control subjects. UCH-L1 concentrations were higher in HIE neonates (p <0.001), and associated with cortical injury (p <0.055) and later motor and cognitive developmental outcomes (p <0.05). The temporal change in GFAP concentrations during (from birth to 96 h of age) predicted motor developmental outcomes (p <0.05) and injury to the basal ganglia and white matter. Conclusion: Ubiquitin C-terminal hydrolase L1 and GFAP should be explored further as promising serum biomarkers of brain damage and later neurodevelopmental outcomes in neonates with HIE. [ABSTRACT FROM AUTHOR]

Background: Clinical and experimental studies have demonstrated that seizures can cause molecular and cellular responses resulting in neuronal damage. At present, there are no valid tests for assessing organic damage to the brain associated with seizure. The aim of this study was to investigate cerebrospinal fluid (CSF) and plasma concentrations of Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a sensitive indicator of acute injury to brain neurons, in patients with tonic-clonic or partial secondarily generalized seizures due to various etiologies. Methods: CSF and plasma concentrations of UCH-L1 were assessed in 52 patients within 48 hours after epileptic seizure and in 19 controls using ELISA assays. Results: CSF obtained within 48 hours after seizure or status epilepticus (SE) presented significantly higher levels of UCH-L1 compared to controls (p = 0.008). Plasma UCH-L1 concentrations were negatively correlated with time to sample withdrawal. An analysis conducted using only the first 12 hours post-seizure revealed significant differences between concentrations of UCH-L1 in plasma and controls (p = 0.025). CSF and plasma concentrations were strongly correlated with age in patients with seizure, but not in control patients. Plasma UCH-L1 levels were also significantly higher in patients after recurrent seizures (n = 4) than in those after one or two seizures (p = 0.013 and p = 0.024, respectively). Conclusion: Our results suggest that determining levels of neuronal proteins may provide valuable information on the assessment of brain damage following seizure. These data might allow clinicians to make more accurate therapeutic decisions, to identify patients at risk of progression and, ultimately, to provide new opportunities for monitoring therapy and targeted therapeutic interventions. [ABSTRACT FROM AUTHOR]

Brain injury exosomal proteins are promising blood biomarker candidates in traumatic brain injury (TBI). A better understanding of their role in the diagnosis, characterization, and management of TBI is essential for upcoming clinical implementation. In the current investigation, we aimed to explore longitudinal trajectories of brain injury exosomal proteins in blood of patients with moderate-to-severe TBI, and to evaluate the relation with the free-circulating counterpart and patient imaging and clinical parameters. Exosomal levels of glial (glial fibrillary acidic protein (GFAP)) and neuronal/axonal (ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), neurofilament light chain (NFL), and total-tau (t-tau)) proteins were measured in serum of 21 patients for up 5 days after injury using single molecule array (Simoa) technology. Group-based trajectory analysis was used to generate distinct temporal exosomal biomarker profiles. We found altered profiles of serum brain injury exosomal proteins following injury. The dynamics and levels of exosomal and related free-circulating markers, although correlated, showed differences. Patients with diffuse injury displayed higher acute exosomal NFL and GFAP concentrations in serum than those with focal lesions. Exosomal UCH-L1 profile characterized by acutely elevated values and a secondary steep rise was associated with early mortality (n = 2) with a sensitivity and specificity of 100%. Serum brain injury exosomal proteins yielded important diagnostic and prognostic information and represent a novel means to unveil underlying pathophysiology in patients with moderate-to-severe TBI. Our findings support their utility as potential tools to improve patient phenotyping in clinical practice and therapeutic trials. [ABSTRACT FROM AUTHOR]

This work, part of the Operation Brain Trauma Therapy (OBTT) a multi-center pre-clinical drug screening consortium, investigated the temporal course of circulating brain damage biomarkers and their associations with behavioral and histo-pathological outcomes across multiple traumatic brain injury (TBI) models. Levels of ubiquitin C-terminal hydrolase (UCH-L1) and glial fibrillary acid protein (GFAP) were serially measured 1 hr, 6 hr, and 24 hr following injury in rats subjected to controlled cortical impact (CCI), fluid percussion (FPI), or penetrating ballistic-like brain injury (PBBI). Sham rats underwent all manipulations except trauma. Both biomarkers were significantly increased as early as 1 hr after injury compared to shams with the exception of UCH-L1 in CCI. Higher UCH-L1 levels were consistently observed in sham and injured CCI groups when compared to the other models, albeit the levels remained unchanged over study duration across the groups. Conversely, GFAP concentration changed over time following injury, with magnitude and temporal profile differing significantly by group (interaction P < 0.001). Specifically, contrasting the acute elevation following FPI and PBBI, a delayed peak in GFAP at 6 hr was observed after CCI. UCH-L1 and GFAP at 1 hr correlated with latency to find the platform across models, and with the performance in the probe trial in FPI and PBBI. UCH-L1 at 1 hr also correlated with lesion volume and tissue loss in CCI. This study provides direct evidence of differential release kinetics of GFAP across distinct injury models supporting the adoption of an adjusted diagnostic time window for detection of TBI based on the injury type. Furthermore, these data support the acute measurement of UCH-L1 and GFAP as potential surrogates for behavioral outcomes. [ABSTRACT FROM AUTHOR]

Care for severe traumatic brain injury (sTBI) centers around avoidance of intracranial hypertension (ICH) and other secondary insults. Biomarkers Biomarkers predicting the development of ICH and ICH trajectory may help guide care. Using FDA compliant assays we evaluated the utility of cytoplasmic ubiquitin C-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein breakdown products (GFAP-BDP's) as candidate biomarkers to predict the development of ICH and ICH trajectories in children with sTBI. Using a threshold of 20mmHg to define ICH we calculated pressure-time area under the curve values (AUC-ICH) to quantify ICH trajectories. When measured 6 h post-injury, both biomarkers predicted development of ICH in the first 12 h post-injury (Cstatistic = 0.99 and 0.98 respectively). For ICH trajectories, UCH-L1 measured 6 h post injury predicted ICH-AUC (coefficient of 1.57; p < 0.01), andGFAP-SBDP-s was a reliable predictor at 24 h (coefficient of 2.65; p < 0.01).Weevaluated the utility of combining both biomarkers into the neuronal-astrocytic injury index (NAII = sample quantile of UCHL-1 × sample quantile ofGFAP-SBDP).Whenmeasured 24 h postinjury the NAII predicted total 72 h cumulative ICH exposure (1 NAII unit increase = 1,490mmHg$h increase in total ICH-AUC; p < 0.001) and the patient's ICH-AUC on day 3 post injury (1 NAII unit increase = ICH-AUC on day 3 increases by 405.15mmHg$h; p = 0.009). Both linear regression models included intensity of ICH therapy in the first 24 h and patient characteristics that may affect outcome (age, gender and race). The NAII correlated with outcome at 24 and 48 h post injury (r = -0.5, t = -3.4 and; r = -0.34, t = -2.17 respectively). [ABSTRACT FROM AUTHOR]

Objectives: Glial fibrillary acidic protein (GFAP) and ubiquitin Cterminal hydrolase-L1 (UCH-L1) have been studied as potential biomarkers of mild traumatic brain injury (mTBI). We report the levels of GFAP and UCH-L1 in patients with acute orthopedic injuries without central nervous system involvement and relate them to the levels in patients with CT-negative mTBI. Methods: Serum UCH-L1 and GFAP were measured from 73 patients with acute orthopedic injury. The injury types were recorded and most of the patients underwent also a head MRI. The results were compared to those found in patients with CT-negative mTBI (n = 93). Results: The levels of GFAP were higher in patients with acute orthopedic trauma than in patients with CT-negative mTBI (p = 0.026). The levels of UCH-L1 were not significantly different between these two groups. Those patients with orthopedic trauma, who had levels of either or both of these biomarkers in the upper quartile, had significantly higher levels of both biomarkers than patients with CT-negative mTBI (p < 0.001). Conclusions: Levels of GFAP and UCH-L1 were not able to distinguish patients with CT negative mTBI from patients with orthopedic trauma. Patients with orthopedic trauma and high levels of UCH-L1 or GFAP values may be falsely diagnosed as having a concomitant mTBI. This casts a significant doubt on their diagnostic value in cases with mTBI. [ABSTRACT FROM AUTHOR]