Article

Serum levels of ubiquitin C-terminal hydrolase distinguish mild traumatic brain injury from trauma controls and are elevated in mild and moderate traumatic brain injury patients with intracranial lesions and neurosurgical intervention

May 2012
Journal of Trauma and Acute Care Surgery 72(5):1335-44

DOI:10.1097/TA.0b013e3182491e3d

Source
PubMed

Authors:

Lawrence M Lewis

Washington University in St. Louis

Salvatore Silvestri

Orlando Health (Orlando Regional Medical Center)

Jay L Falk

Orlando Health

Show all 16 authorsHide

This study compared early serum levels of ubiquitin C-terminal hydrolase (UCH-L1) from patients with mild and moderate traumatic brain injury (TBI) with uninjured and injured controls and examined their association with traumatic intracranial lesions on computed tomography (CT) scan (CT positive) and the need for neurosurgical intervention (NSI). This prospective cohort study enrolled adult patients presenting to three tertiary care Level I trauma centers after blunt head trauma with loss of consciousness, amnesia, or disorientation and a Glasgow Coma Scale (GCS) score 9 to 15. Control groups included normal uninjured controls and nonhead injured trauma controls presenting to the emergency department with orthopedic injuries or motor vehicle crash without TBI. Blood samples were obtained in all trauma patients within 4 hours of injury and measured by enzyme-linked immunosorbent assay for UCH-L1 (ng/mL ± standard error of the mean). There were 295 patients enrolled, 96 TBI patients (86 with GCS score 13-15 and 10 with GCS score 9-12), and 199 controls (176 uninjured, 16 motor vehicle crash controls, and 7 orthopedic controls). The AUC for distinguishing TBI from uninjured controls was 0.87 (95% confidence interval [CI], 0.82-0.92) and for distinguishing those TBIs with GCS score 15 from controls was AUC 0.87 (95% CI, 0.81-0.93). Mean UCH-L1 levels in patients with CT negative versus CT positive were 0.620 (± 0.254) and 1.618 (± 0.474), respectively (p < 0.001), and the AUC was 0.73 (95% CI, 0.62-0.84). For patients without and with NSI, levels were 0.627 (0.218) versus 2.568 (0.854; p < 0.001), and the AUC was 0.85 (95% CI, 0.76-0.94). UCH-L1 is detectable in serum within an hour of injury and is associated with measures of injury severity including the GCS score, CT lesions, and NSI. Further study is required to validate these findings before clinical application. II, prognostic study.

Accuracy of GFAP and UCH-L1 in predicting brain abnormalities on CT scans after mild traumatic brain injury: a systematic review and meta-analysis

Article

Full-text available

Jan 2025
EUR J TRAUMA EMERG S

Purpose Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. In recent years, blood biomarkers including glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) have shown a promising ability to detect head CT abnormalities following TBI. This review aims to combine the existing research on GFAP and UCH-L1 biomarkers and examine how well they can predict abnormal CT results after mild TBI. Methods Our study protocol was registered in PROSPERO (CRD42024556264). PubMed, Google Scholar, and Cochrane electronic databases were searched. We reviewed 37 full-text articles for eligibility and included 14 in our systematic review and meta-analysis. Results Thirteen studies reported data for GFAP. The optimal cutoff of GFAP was 65.1 pg/mL with a sensitivity of 76% (95% CI 37 ̶ 95) and a specificity of 74% (95% CI 39 ̶ 93). In patients with GCS 13 ̶ 15 the optimal cutoff was 68.5 pg/mL, showing a sensitivity of 75% (95% CI 17 ̶ 98), and a specificity of 73% (95% CI 20 ̶ 97). Seven studies provided data on UCH-L1. The optimal cutoff was 225 pg/mL, with a sensitivity of 86% (95% CI 50 ̶ 97) and a specificity of 51% (95% CI 19 ̶ 83). In patients with GCS 13 ̶ 15, the optimal cutoff was 237.7 pg/mL, with a sensitivity of 89% (95% CI 74 ̶ 96), and a specificity of 36% (95% CI 29 ̶ 44). Modeling the diagnostic performance of GFAP showed that in adult patients with GCS 13–15 for ruling out CT abnormalities, at the threshold of 4 pg/mL, the optimal diagnostic accuracy was achieved with a sensitivity of 98% (95% CI 94–99) and (negative predictive value) NPV of 97%. For UCH-L1, the optimal diagnostic accuracy for ruling out intracranial abnormalities in adults with GCS 13–15 was achieved at the threshold of 64 pg/mL, with a sensitivity of 99% (95% CI 92–100) and NPV of 99%. Conclusion Present results suggest that GFAP and UCH-L1 have the clinical potential for screening mild TBI patients for intracranial abnormalities on head CT scans.

Challenges of the Effectiveness of Traumatic Brain Injuries Biomarkers in the Sports-Related Context

Article

Full-text available

Mar 2023

Traumatic brain injury affects 69 million people every year. One of the main limitations in managing TBI patients is the lack of univocal diagnostic criteria, including the absence of standardized assessment methods and guidelines. Computerized axial tomography is the first-choice examination, despite the limited prevalence of positivity; moreover, its performance is undesirable due to the risk of radiological exposure, prolonged stay in emergency departments, inefficient use of resources, high cost, and complexity. Furthermore, immediacy and accuracy in diagnosis and management of TBIs are critically unmet medical needs. Especially in the context of sports-associated TBI, there is a strong need for prognostic indicators to help diagnose and identify at-risk subjects to avoid their returning to play while the brain is still highly vulnerable. Fluid biomarkers may emerge as new prognostic indicators to develop more accurate prediction models, improving risk stratification and clinical decision making. This review describes the current understanding of the cellular sources, temporal profile, and potential utility of leading and emerging blood-based protein biomarkers of TBI; its focus is on biomarkers that could improve the management of mild TBI cases and can be measured readily and directly in the field, as in the case of sports-related contexts.

Galvos smegenų traumos žymenys. Literatūros apžvalga Biomarkers of traumatic brain injury. Literature review

Article

Full-text available

Aug 2019

Galvos smegenų trauma (GST) – tai struktūriniai pažeidimai ir (ar) smegenų funkcionavimo sutrikdymai dėl išorinės jėgos poveikio, kuri sukelia bent vieną ūminį simptomą arba kliniškai reikšmingą šio (-ių) simptomo (-ų) pablogėjimą iš karto po įvykio: sąmonės praradimą, atminties sutrikimą apie iš karto po traumos ar prieš buvusius įvykius, psichinės būklės pokyčius traumos metu ir tam tikrus neurologinius požymius. Galvos kompiuterinė tomografija (KT) yra greitai atliekamas tyrimas, galintis nustatyti daugumą gyvybei pavojingų ir chirurginiu būdu gydomų būklių. Nors yra sudarytos galvos KT atlikimo dėl GST gairės, tačiau šio tyrimo taikymas skubios pagalbos skyriuose vis dar išlieka per dažnas dėl įtariamų lengvų GST. Norint išvengti nereikalingų KT, greitai ir efektyviai diagnozuoti GST, nustatyti jos sunkumą ir prognozuoti tolimesnę eigą, vis daugiau nagrinėjami trauminio smegenų pažeidimo žymenys. 2013 m. Skandinavijos neurotraumos komitetas (angl. Scandinavian Neurotrauma Committee) į lengvos GST diagnostikos gaires įtraukė žymens S-100 kalcio jonus surišančio baltymo β tyrimą kraujyje. 2018 m. vasario mėnesį JAV Maisto ir vaistų administracija (angl. Food and Drug Administration) patvirtino glijos skaidulinio rūgštinio baltymo ir ubikvitino C-galo hidrolazės L1 derinio naudojimą lengvos GST atveju. Tyrinėjami ir įvairūs kiti trauminio smegenų pažeidimo žymenys, tačiau jie kol kas nėra taikomi medicininėje praktikoje.

Examining four blood biomarkers for the detection of acute intracranial abnormalities following mild traumatic brain injury in older adults

Article

Full-text available

Nov 2022

Blood-based biomarkers have been increasingly studied for diagnostic and prognostic purposes in patients with mild traumatic brain injury (MTBI). Biomarker levels in blood have been shown to vary throughout age groups. Our aim was to study four blood biomarkers, glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament light (NF-L), and total tau (t-tau), in older adult patients with MTBI. The study sample was collected in the emergency department in Tampere University Hospital, Finland, between November 2015 and November 2016. All consecutive adult patients with head injury were eligible for inclusion. Serum samples were collected from the enrolled patients, which were frozen and later sent for biomarker analyses. Patients aged 60 years or older with MTBI, head computed tomography (CT) imaging, and available biomarker levels were eligible for this study. A total of 83 patients (mean age = 79.0, SD = 9.58, range = 60–100; 41.0% men) were included in the analysis. GFAP was the only biomarker to show statistically significant differentiation between patients with and without acute head CT abnormalities [U(83) = 280, p < 0.001, r = 0.44; area under the curve (AUC) = 0.79, 95% CI = 0.67–0.91]. The median UCH-L1 values were modestly greater in the abnormal head CT group vs. normal head CT group [U (83) = 492, p = 0.065, r = 0.20; AUC = 0.63, 95% CI = 0.49–0.77]. Older age was associated with biomarker levels in the normal head CT group, with the most prominent age associations being with NF-L (r = 0.56) and GFAP (r = 0.54). The results support the use of GFAP in detecting abnormal head CT findings in older adults with MTBIs. However, small sample sizes run the risk for producing non-replicable findings that may not generalize to the population and do not translate well to clinical use. Further studies should consider the potential effect of age on biomarker levels when establishing clinical cut-off values for detecting head CT abnormalities.

Blood-Based Biomarkers for Improved Characterization of Traumatic Brain Injury: Recommendations from the 2024 National Institute for Neurological Disorders and Stroke Traumatic Brain Injury Classification and Nomenclature Initiative Blood-Based Biomarkers Working Group

Article

Full-text available

May 2025
J NEUROTRAUM

Use of serum biomarkers in the diagnosis of traumatic brain injury

Article

Full-text available

Dec 2024

Objective: Traumatic brain injury (TBI) is a leading cause of death and disability in the pediatric age group. This study aimed to investigate the effectiveness of serum S100 calcium-binding protein B (S100b), ubiquitin carboxyterminal hydrolase-like1 (UCH-L1), glial fibrillary acidic protein (GFAP), and neurofilament (NF) protein levels in predicting the diagnosis and prognosis of traumatic brain injury. Methods: The research comprised head trauma patients aged 1 month to 18 years hospitalized at Mersin University Faculty of Medicine between October 2018 and November 2019. We recorded the demographic data of the patients, the type of trauma, the treatments administered in the pediatric intensive care unit (PICU), the Glasgow Coma Scale (GCS), the Pediatric Trauma Score (PTS), and the computed cerebral tomography (CT) reports. S-100b protein, UCHL-1, GFAP, and NF levels of the patients and control group were checked. The correlation between serum levels of biomarkers and GCS, CT findings, Rotterdam score, and Glasgow Outcome Scale-Extended (GOS-E) score of the patients was analyzed statistically. Results: The study included 73 patients, 49 males and 24 females. Comparing the groups revealed no statistically significant correlation between GFAP and TBI (p>0.05). However, the correlation between S-100b, UCHL-1, and NF and patient groups was statistically significant (p<0.05). The NF level was statistically higher in the PICU 24-hour group than in the control and pediatric emergency groups but statistically lower compared to the PICU 48-hour group (p<0.05). UCHL-1 levels in the PICU 24-hour group were statistically higher than those in the control group (p<0.05). The inverse correlation between GOS-E and UCHL-1 in the PICU 24-hour group was statistically significant (p<0.05). Patients with CT findings had a higher UCHL-1 level than those without (p<0.05). Conclusion: S-100b, UCHL-1, and NF may be used for the diagnosis of TBI and evaluation of its severity. Furthermore, UCHL-1 has the potential to be useful in forecasting patients’ prognoses.

Brain Injury Biomarkers and Applications in Neurological Diseases

Article

Full-text available

Jun 2024
CHINESE MED J-PEKING

Neurological diseases are a major health concern, and brain injury is a typical pathological process in various neurological disorders. Different biomarkers in the blood or the cerebrospinal fluid are associated with specific physiological and pathological processes. They are vital in identifying, diagnosing, and treating brain injuries. In this review, we described biomarkers for neuronal cell body injury (neuron-specific enolase, ubiquitin C-terminal hydrolase-L1, αII-spectrin), axonal injury (neurofilament proteins, tau), astrocyte injury (S100β, glial fibrillary acidic protein), demyelination (myelin basic protein), autoantibodies, and other emerging biomarkers (extracellular vesicles, microRNAs). We aimed to summarize the applications of these biomarkers and their related interests and limits in the diagnosis and prognosis for neurological diseases, including traumatic brain injury, status epilepticus, stroke, Alzheimer’s disease, and infection. In addition, a reasonable outlook for brain injury biomarkers as ideal detection tools for neurological diseases is presented.

Enhancing hospital course and outcome prediction in patients with traumatic brain injury: A machine learning study

Article

Nov 2023

Purpose: We aimed to use machine learning (ML) algorithms with clinical, lab, and imaging data as input to predict various outcomes in traumatic brain injury (TBI) patients. Methods: In this retrospective study, blood samples were analyzed for glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1). The non-contrast head CTs were reviewed by two neuroradiologists for TBI common data elements (CDE). Three outcomes were designed to predict: discharged or admitted for further management (prediction 1), deceased or not deceased (prediction 2), and admission only, prolonged stay, or neurosurgery performed (prediction 3). Five ML models were trained. SHapley Additive exPlanations (SHAP) analyses were used to assess the relative significance of variables. Results: Four hundred forty patients were used to predict predictions 1 and 2, while 271 patients were used in prediction 3. Due to Prediction 3's hospitalization requirement, deceased and discharged patients could not be utilized. The Random Forest model achieved an average accuracy of 1.00 for prediction 1 and an accuracy of 0.99 for prediction 2. The Random Forest model achieved a mean accuracy of 0.93 for prediction 3. Key features were extracranial injury, hemorrhage, UCH-L1 for prediction 1; The Glasgow Coma Scale, age, GFAP for prediction 2; and GFAP, subdural hemorrhage volume, and pneumocephalus for prediction 3, per SHAP analysis. Conclusion: Combining clinical and laboratory parameters with non-contrast CT CDEs allowed our ML models to accurately predict the designed outcomes of TBI patients. GFAP and UCH-L1 were among the significant predictor variables, demonstrating the importance of these biomarkers.

Evaluation of UCH-L1 and T-Tau as prognostic biomarkers of traumatic brain injury

Article

Full-text available

Apr 2023

Concussion in the UK: a contemporary narrative review

Article

Full-text available

Oct 2022

Concussion has been receiving an increasing amount of media exposure following several high-profile professional sports controversies and multimillion-dollar lawsuits. The potential life-changing sequalae of concussion and the rare, but devasting, second impact syndrome have also gained much attention. Despite this, our knowledge of the pathological processes involved is limited and often extrapolated from research into more severe brain injuries. As there is no objective diagnostic test for concussion. Relying on history and examination only, the diagnosis of concussion has become the rate-limiting step in widening research into the disease. Clinical study protocols therefore frequently exclude the most vulnerable groups of patients such as those with existing cognitive impairment, concurrent intoxication, mental health issues or learning difficulties. This up-to-date narrative review aims to summarize our current concussion knowledge and provides an insight into promising avenues for future research.

Integration of proteomics and bioinformatics in traumatic brain injury biomarker discovery

Article

Jun 2025

Background Traumatic brain injury (TBI) is a significant medical crisis with no FDA-approved therapies to improve functional outcomes. Key biomarkers, such as glial fibrillary acidic protein (GFAP), S-100 calcium-binding protein B (S-100B), and ubiquitin C-terminal hydrolase L1 (UCH-L1), are crucial for understanding TBI pathology. Material and methods This study integrates proteomic and bioinformatic approaches to explore established TBI biomarkers’ structural and functional complexities: GFAP, S-100B, and UCH-L1. Results Our comprehensive secondary structure and solvent accessibility assessment, conducted with PredictProtein, confirmed the predominance of alpha-helices in GFAP and S-100B, while UCH-L1 displayed a balanced mix of helices (65.00, 67.39, and 40.81%), beta strands (6.20, 0, and 17.94%), and coils (40.81, 17.94, and 41.26%). AlphaFold and I-TASSER were identified as the best servers for full-length tertiary structure prediction for the three target proteins, based on root-mean-square deviation (RMSD), TM-score, and C-score assessments. Protein motif database scans predicted four, eight, and one protein-binding motifs and two, three, and one post-translational modifications for GFAP, S-100B, and UCH-L1, respectively. Conclusions GFAP’s role in axonal transport and synaptic plasticity was emphasized through motifs such as Filament and DUF1664. S-100B’s association with neuroinflammation and oxidative stress post-TBI was supported by the S-100/ICaBP-type calcium-binding domain. UCH-L1’s dualistic impact on TBI was further clarified by the Peptidase_C12 motif. This approach deepens our comprehension of these biomarkers and paves the way for targeted diagnostics in TBI.

GFAP/UCH-L1 as a Biomarker for Rapid Assessment of Mild TBI in Emergency Departments

Article

Full-text available

May 2025
MED SCI MONITOR

Traumatic brain injury (TBI) is a major cause of mortality and disability in Western countries. The diagnosis of TBI mainly involves computed tomography (CT), and Glasgow Coma Scale assessment. As frequent use of CT is associated with excessive radiation exposure, discovery of a biomarker for TBI could reduce unnecessary head CT scans. Thus, the main aim of this study was to evaluate a TBI assessment kit measuring glial fibrillary acid- ic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1), for its suitability to diagnose mild TBI in emergency departments (EDs). The records of 123 patients with head injuries admitted to the Clinical Emergency Department of the Regional Specialist Hospital in Olsztyn, Poland between December 2023 and August 2024, were prospectively analyzed. Patients underwent CT, were classified as isolated head injury (IHI, n=61) or injuries beside TBI (non-IHI, n=62), and tested for serum GFAP and UCH-L1 concentrations using immuno-chemical chemiluminescence. No significant differences in GFAP and UCH-L1 concentrations were observed between IHI and Non-IHI patients. While CT showed brain alterations in 7 patients, GFAP and UCH-L1 concentrations were above the threshold in 6 patients with brain injury confirmed by CT. The sensitivity of the TBI test was 83.3%, with specificity 29.1%. The sensitivity of GFAP was 83.3% and that of UCH-L1 was 50.0%, with specificities of 37.9% and 65.0%, respectively. Based on our study, further investigations are required before GFAP and UCH-L1 blood test samples can be recommended as an adjunct to CT scans as a standard procedure.

Can Serum GFAP and UCH-L1 Replace CT in Assessing Acute Ischemic Stroke Severity?

Article

Full-text available

Mar 2025

As acute ischemic stroke (AIS) is still a significant cause of morbidity globally, new methods of rapid diagnostics are continually being researched and improved. Still, the only definite way to diagnose AIS is radiological imaging. Lately, serum biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) have shown their usefulness in AIS as potential complementary tools in early recognition. We aimed to investigate if GFAP and UCH-L1 can correlate with comprehensive diagnostic information provided by computed tomography (CT) and several clinical parameters in AIS severity assessment and subsequently with clinical outcomes. Fifty-two patients with AIS and a potential for mechanical thrombectomy (MT) were included in our study. Thirty-seven patients underwent MT. Results showed no correlation of biomarkers with any analyzed CT parameter (thrombus length, volume, and density, clot burden score, collateral score, AIS core and penumbra volume, differences in perfusion between healthy and affected brain tissue). In addition, none of the clinical parameters, such as sex, symptom onset time, or the National Institutes of Health Stroke Scale, correlated with biomarkers. However, lower biomarker levels corresponded with a good clinical outcome, and higher levels to a poor outcome following hospital discharge, irrespective of the performed MT (p = 0.005 for GFAP, p = 0.001 for UCH-L1). In patients with successful MT, there were also differences between patients with a good clinical outcome compared with patients with a poor clinical outcome (p = 0.007 for GFAP, p = 0.004 for UCH-L1). In conclusion, these biomarkers cannot replace imaging modalities but can provide complementary diagnostic information in the setting of AIS.

mTBI Biological Biomarkers as Predictors of Postconcussion Syndrome—Review

Article

Full-text available

May 2024
BSRCCS

Postconcussion syndrome (PCS) is one of the leading complications that may appear in patients after mild head trauma. Every day, thousands of people, regardless of age, gender, and race, are diagnosed in emergency departments due to head injuries. Traumatic Brain Injury (TBI) is a significant public health problem, impacting an estimated 1.5 million people in the United States and up to 69 million people worldwide each year, with 80% of these cases being mild. An analysis of the available research and a systematic review were conducted to search for a solution to predicting the occurrence of postconcussion syndrome. Particular biomarkers that can be examined upon admission to the emergency department after head injury were found as possible predictive factors of PCS development. Setting one unequivocal definition of PCS is still a challenge that causes inconsistent results. Neuron Specific Enolase (NSE), Glial Fibrillary Acidic Protein (GFAP), Ubiquitin C-terminal Hydrolase-L1 (UCH-L1), Serum Protein 100 B (s100B), and tau protein are found to be the best predictors of PCS development. The presence of all mentioned biomarkers is confirmed in severe TBI. All mentioned biomarkers are used as predictors of PCS. A combined examination of NSE, GFAP, UCH-1, S100B, and tau protein should be performed to detect mTBI and predict the development of PCS.

Blood Biomarkers for the Management of Mild Traumatic Brain Injury in Clinical Practice

Article

Apr 2024
CLIN CHEM

Background Despite the use of validated guidelines in the management of mild traumatic brain injury (mTBI), processes to limit unnecessary brain scans are still not sufficient and need to be improved. The use of blood biomarkers represents a relevant adjunct to identify patients at risk for intracranial injury requiring computed tomography (CT) scan. Content Biomarkers currently recommended in the management of mTBI in adults and children are discussed in this review. Protein S100 beta (S100B) is the best-documented blood biomarker due to its validation in large observational and interventional studies. Glial fibrillary acidic protein (GFAP) and ubiquitin carboxyterminal hydrolase L-1 (UCH-L1) have also recently demonstrated their usefulness in patients with mTBI. Preanalytical, analytical, and postanalytical performance are presented to aid in their interpretation in clinical practice. Finally, new perspectives on biomarkers and mTBI are discussed. Summary In adults, the inclusion of S100B in Scandinavian and French guidelines has reduced the need for CT scans by at least 30%. S100B has significant potential as a diagnostic biomarker, but limitations include its rapid half-life, which requires blood collection within 3 h of trauma, and its lack of neurospecificity. In 2018, the FDA approved the use of combined determination of GFAP and UCH-L1 to aid in the assessment of mTBI. Since 2022, new French guidelines also recommend the determination of GFAP and UCH-L1 in order to target a larger number of patients (sampling within 12 h post-injury) and optimize the reduction of CT scans. In the future, new cut-offs related to age and promising new biomarkers are expected for both diagnostic and prognostic applications.

Biofluid-based Biomarkers in Traumatic Brain Injury: A Narrative Review

Article

Full-text available

Mar 2024

Traumatic brain injury (TBI) is a complex condition characterized by a multifaceted pathophysiology. It presents significant diagnostic and prognostic challenges in clinical settings. This narrative review explores the evolving role of biofluid biomarkers as essential tools in the diagnosis, prognosis, and treatment of TBI. In recent times, preclinical and clinical trials utilizing these biofluid biomarkers have been actively pursued internationally. Among the biomarkers for nerve tissue proteins are neuronal biomarkers like neuronal specific enolase and ubiquitin C-terminal hydrolase L1; astroglia injury biomarkers such as S100B and glial fibrillary acidic protein; axonal injury and demyelination biomarkers, including neurofilaments and myelin basic protein; new axonal injury and neurodegeneration biomarkers like total tau and phosphorylated tau; and others such as spectrin breakdown products and microtubule-associated protein 2. The interpretation of these biomarkers can be influenced by various factors, including secretion from organs other than the injury site and systemic conditions. This review highlights the potential of these biomarkers to transform TBI management and emphasizes the need for continued research to validate their efficacy, refine testing platforms, and ultimately improve patient care and outcomes.

The Importance of Increased Serum GFAP and UCH-L1 Levels in Distinguishing Large Vessel from Small Vessel Occlusion in Acute Ischemic Stroke

Article

Full-text available

Mar 2024

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.

Modulation of Inflammatory Response by Electromagnetic Field Stimulation in Traumatic Brain Injury in Yucatan Swine

Article

Full-text available

Jan 2024

Traumatic brain injury is a leading cause of disability and death worldwide and represents a high economic burden for families and national health systems. After mechanical impact to the head, the first stage of the damage comprising edema, physical damage, and cell loss gives rise to a second phase characterized by glial activation, increased oxidative stress and excitotoxicity, mitochondrial damage, and exacerbated neuroinflammatory state, among other molecular calamities. Inflammation strongly influences the molecular events involved in the pathogenesis of TBI. Therefore, several components of the inflammatory cascade have been targeted in experimental therapies. Application of Electromagnetic Field (EMF) stimulation has been found to be effective in some inflammatory conditions. However, its effect in the neuronal recovery after TBI is not known. In this pilot study, Yucatan miniswine were subjected to TBI using controlled cortical impact approach. EMF stimulation via a helmet was applied immediately or two days after mechanical impact. Three weeks later, inflammatory markers were assessed in the brain tissues of injured and contralateral non-injured areas of control and EMF-treated animals by histomorphometry, immunohistochemistry, RT-qPCR, Western blot, and ELISA. Our results revealed that EMF stimulation induced beneficial effect with the preservation of neuronal tissue morphology as well as the reduction of inflammatory markers at the transcriptional and translational levels. Immediate EMF application showed better resolution of inflammation. Although further studies are warranted, our findings contribute to the notion that EMF stimulation could be an effective therapeutic approach in TBI patients.

First Demonstration of GaN HEMT-Based Handheld System for Noninvasive Detection of Traumatic Brain Injury Using Saliva

Article

Dec 2023

Traumatic brain injury (TBI) is an insult to the brain caused by an external mechanical force that is neither congenital nor degenerative leading to morbidity and mortality among people of various age groups globally. The work reports design, development, and validation of novel GaN HEMT on Si-based handheld system for noninvasive detection of food and drug administration (FDA)-approved TBI biomarkers UCH-L1 and GFAP in clinically relevant concentration ranges. The developed system can detect and differentiate TBI biomarkers in saliva in almost imperceptible amount of pg/mL using specific conjugation of TBI antibody and target analyte over biofunctionalized chips. The platform offers a peak sensitivity of

17.42 ~\mu \text{A}

/pg/mL with high resolution and a pre-eminent selectivity toward target TBI biomarkers. The system is portable, easy to handle, ultrasensitive with volant response time of less than 5 s, and compact with a potential for point-of-care applications. It can be utilized for clinical analysis and on-field application areas for TBI diagnosis and prognosis. The system can be imperative in early medical diagnosis, patient management, and decision-making for computed tomography (CT) or magnetic resonance imaging (MRI). To the best of our knowledge, this is the first-time reporting of a label-free noninvasive TBI detection system based on GaN HEMT on Si.

Identifying the Target Traumatic Brain Injury Population for Hyperbaric Oxygen Therapy

Article

Full-text available

Sep 2023
INT J MOL SCI

Traumatic brain injury (TBI) results from direct penetrating and indirect non-penetrating forces that alters brain functions, affecting millions of individuals annually. Primary injury following TBI is exacerbated by secondary brain injury; foremost is the deleterious inflammatory response. One therapeutic intervention being increasingly explored for TBI is hyperbaric oxygen therapy (HBOT), which is already approved clinically for treating open wounds. HBOT consists of 100% oxygen administration, usually between 1.5 and 3 atm and has been found to increase brain oxygenation levels after hypoxia in addition to decreasing levels of inflammation, apoptosis, intracranial pressure, and edema, reducing subsequent secondary injury. The following review examines recent preclinical and clinical studies on HBOT in the context of TBI with a focus on contributing mechanisms and clinical potential. Several preclinical studies have identified pathways, such as TLR4/NF-kB, that are affected by HBOT and contribute to its therapeutic effect. Thus far, the mechanisms mediating HBOT treatment have yet to be fully elucidated and are of interest to researchers. Nonetheless, multiple clinical studies presented in this review have examined the safety of HBOT and demonstrated the improved neurological function of TBI patients after HBOT, deeming it a promising avenue for treatment.

Precision Concussion Management: Approaches to Quantifying Head Injury Severity and Recovery

Article

Full-text available

Sep 2023
BSRCCS

Mitigating the substantial public health impact of concussion is a particularly difficult challenge. This is partly because concussion is a highly prevalent condition, and diagnosis is predominantly symptom-based. Much of contemporary concussion management relies on symptom interpretation and accurate reporting by patients. These types of reports may be influenced by a variety of factors for each individual, such as preexisting mental health conditions, headache disorders, and sleep conditions, among other factors. This can all be contributory to non-specific and potentially misleading clinical manifestations in the aftermath of a concussion. This review aimed to conduct an examination of the existing literature on emerging approaches for objectively evaluating potential concussion, as well as to highlight current gaps in understanding where further research is necessary. Objective assessments of visual and ocular motor concussion symptoms, specialized imaging techniques, and tissue-based concentrations of specific biomarkers have all shown promise for specifically characterizing diffuse brain injuries, and will be important to the future of concussion diagnosis and management. The consolidation of these approaches into a comprehensive examination progression will be the next horizon for increased precision in concussion diagnosis and treatment.

Assessment of Risk Factors for Postoperative Delirium in Older Adults Who Underwent Spinal Surgery and Identifying Associated Biomarkers Using Exosomal Protein

Article

Full-text available

Aug 2023

Purpose: With an increase in the aging population, the number of patients with degenerative spinal diseases undergoing surgery has risen, as has the incidence of postoperative delirium. This study aimed to investigate the risk factors affecting postoperative delirium in older adults who had undergone spine surgery and to identify the associated biomarkers. Methods: This study is a prospective study. Data of 100 patients aged ≥ 70 years who underwent spinal surgery were analyzed. Demographic data, medical history, clinical characteristics, cognitive function, depression symptoms, functional status, frailty, and nutritional status were investigated to identify the risk factors for delirium. The Confusion Assessment Method, Delirium Rating Scale-R-98, and Nursing Delirium Scale were also used for diagnosing delirium. To discover the biomarkers, urine extracellular vesicles (EVs) were analyzed for tau, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), neurofilament light, and glial fibrillary acidic protein using digital immunoassay technology. Results: Nine patients were excluded, and data obtained from the remaining 91 were analyzed. Among them, 18 (19.8%) developed delirium. Differences were observed between participants with and without delirium in the contexts of a history of mental disorder and use of benzodiazepines (p = .005 and p = .026, respectively). Tau and UCH-L1-concentrations of urine EVs-were comparatively higher in participants with severe delirium than that in participants without delirium (p = .002 and p = .001, respectively). Conclusion: These findings can assist clinicians in accurately identifying the risk factors before surgery, classifying high-risk patients, and predicting and detecting delirium in older patients. Moreover, urine EV analysis revealed that postoperative delirium following spinal surgery is most likely associated with brain damage.

Loss of Consciousness and Righting Reflex Following Traumatic Brain Injury: Predictors of Post-Injury Symptom Development (A Narrative Review)

Article

Full-text available

Apr 2023
BSRCCS

Identifying predictors for individuals vulnerable to the adverse effects of traumatic brain injury (TBI) remains an ongoing research pursuit. This is especially important for patients with mild TBI (mTBI), whose condition is often overlooked. TBI severity in humans is determined by several criteria, including the duration of loss of consciousness (LOC): LOC < 30 min for mTBI and LOC > 30 min for moderate-to-severe TBI. However, in experimental TBI models, there is no standard guideline for assessing the severity of TBI. One commonly used metric is the loss of righting reflex (LRR), a rodent analogue of LOC. However, LRR is highly variable across studies and rodents, making strict numeric cutoffs difficult to define. Instead, LRR may best be used as predictor of symptom development and severity. This review summarizes the current knowledge on the associations between LOC and outcomes after mTBI in humans and between LRR and outcomes after experimental TBI in rodents. In clinical literature, LOC following mTBI is associated with various adverse outcome measures, such as cognitive and memory deficits; psychiatric disorders; physical symptoms; and brain abnormalities associated with the aforementioned impairments. In preclinical studies, longer LRR following TBI is associated with greater motor and sensorimotor impairments; cognitive and memory impairments; peripheral and neuropathology; and physiologic abnormalities. Because of the similarities in associations, LRR in experimental TBI models may serve as a useful proxy for LOC to contribute to the ongoing development of evidence-based personalized treatment strategies for patients sustaining head trauma. Analysis of highly symptomatic rodents may shed light on the biological underpinnings of symptom development after rodent TBI, which may translate to therapeutic targets for mTBI in humans.

Recent trends and innovations in biosensors development for biomarkers towards monitoring traumatic brain injury

Article

Full-text available

Sep 2022

Traumatic brain injury (TBI) is a serious health concern and a leading cause of death in all age groups, especially adults. Although the processes of prevention, lifestyle modification, accident safety, and therapeutic management of TBI are constantly evolving, the development of accurate and trustworthy procedures for diagnosing brain damage, such as detecting specific biomarkers is still in its infancy. Early detection of TBI biomarkers, especially blood biomarkers, can improve treatment approaches and significantly reduce diagnostic costs. Different routine analytical methods, including ELISA and PCR techniques, have been used to detect TBI biomarkers. These procedures are generally complex, expensive, time-consuming, and require trained personnel. In contrast, biosensing techniques have been developed precisely through addressing the aforementioned weaknesses along with offering an accessible, affordable, rapid, highly sensitive, and specific approach. This comprehensive review presents the six main TBI biomarkers (S100β, NSE, GFAP, UCHL-1, MBP, and TAU). It also focuses on the design mechanism of biosensing pathways of TBI biomarkers and nanotechnology integration methods, including the nanoparticles and nanostructures application in surface modification and improving the performance of the sensing procedures. Furthermore, through this study, the TBI-specific biosensors platform from the viewpoint of the transducer types and analysis output are evaluated. Finally, the current challenges and future perspectives regarding the development of biosensors for the early diagnosis of TBI are discussed.

Ubiquitin carboxyl-terminal esterase L1 is not elevated in the serum of concussed rugby players: an observational cross-sectional study

Article

Full-text available

Jul 2022

Concussion diagnosis is complicated by a lack of objective measures. Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is a biomarker that has been shown to increase following traumatic brain injury but has not been investigated in concussed athletes on the sideline of athletic events. Therefore, this study was conducted to determine if UCHL1 can be used to aid in sideline concussion diagnosis. Blood was taken via standard venipuncture from a recreationally active control group, a group of rugby players prior to match play (pre-match), rugby players following match-play (match-control), and rugby players after suffering a sport-related concussion (SRC). UCHL1 was not significantly different among groups (p > 0.05) and was unable to distinguish between SRC and controls (AUROC < 0.400, p > 0.05). However, when sex-matched data were used, it was found that the female match-control group had a significantly higher serum UCHL1 concentration than the pre-match group (p = 0.041). Differences were also found in serum UCHL1 concentrations between male and female athletes in the match-control group (p = 0.007). This study does not provide evidence supporting the use of UCHL1 in sideline concussion diagnosis when blood is collected soon after concussion but does show differences in serum UCHL1 accumulation between males and females.

Biomarkers of traumatic brain injury: narrative review and future prospects in neurointensive care

Article

Full-text available

Jun 2025

Traumatic brain injury (TBI) is a significant medical problem because of its high early mortality rate in intensive care and high risk of severe neurological complications in long-term follow-ups. Craniocerebral injuries are one of the most important issues in intensive therapy due to the limited prognostic possibilities for the neurological consequences of such injuries. Computed tomography and magnetic resonance imaging are the most common and available radiological tools for presenting and describing morphological brain damage in the acute and chronic phases of TBI. The use of biomarkers may improve the accuracy of establishing the severity and prognoses in patients with severe traumatic brain damage. Based on the available publications, there is no definitive and accurate single marker that has high prognostic value regarding neurological brain tissue damage; however, the combination of several biomolecules (i.e., biomarkers of neuronal, astrocyte, and cytoskeleton disruption and chemokines) significantly increases the diagnostic value. Most scientific studies are based on serum and cerebrospinal fluid assays. This publication presents the current state of the knowledge about the markers of nervous tissue damage in the brain and their clinical utility in mortality prediction and neurological prognosis in critical neurointensive care. Moreover, this review article presents the correlations between the biomarkers, radiological signs of brain injury, and clinical scales, as well as the latest scientific and publication trends, such as microRNA genetic studies and different laboratory assay methodologies using various biological materials.

PLAU serves as a prognostic biomarker correlated with perineural invasion in HNSCC

Article

Apr 2025

Can the Association of the Biomarkers GFAP and UCH-L1 Predict Intracranial Injury After Mild Traumatic Brain Injury in Adults? A Systematic Review and Meta-Analysis

Article

Apr 2025

Blood and cerebrospinal fluid biomarkers in disorders of consciousness

Article

Feb 2025

The study of blood and cerebrospinal fluid biomarkers is a promising and rapidly advancing field in the research of disorders of consciousness (DoC). The use of advanced biochemical and analytic techniques in biomarker research has improved our ability to identify new biomarkers that can aid in the diagnosis, prognosis, and treatment of patients with brain injury. However, the use of biomarkers in clinical practice is limited by several challenges, including the lack of standardization in test and research methodologies. Despite this, identifying the most promising biomarkers and supporting their findings with strong evidence can improve their clinical utility. This chapter discusses the most promising biomarkers for DoC, which fall into four categories: neuronal, glial, inflammatory, and metabolic biomarkers. Understanding the role of each category in DoC can provide valuable insights into the mechanisms of brain injury and inform the development of more effective diagnostic and treatment strategies. By integrating biomarker research with clinical practice, we can improve our understanding of DoC and provide better care for these patients.

Diagnostic and prognostic performance of urine ubiquitin carboxy-terminal hydrolase L1 across multiple acute brain injury types – A longitudinal prospective cohort study

Article

Dec 2024

Introduction Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is recognized as a diagnostic and prognostic blood biomarker for traumatic brain injury (TBI). This study aimed to evaluate whether UCH-L1 concentrations measured in patients' urine post-injury could serve as a diagnostic or prognostic biomarker for outcomes in various types of acute brain injuries (ABI). Material and methods This pilot study included 46 ABI patients: aneurysmal subarachnoid hemorrhage (n = 22), ischemic stroke (n = 16), and traumatic brain injury (n = 8), along with three healthy controls. Urine samples were collected at early (1.50 ± 0.70 days) and late (9.17 ± 3.40 days) periods post-admission. UCH-L1 and creatinine levels were quantified using ELISA. UCH-L1 concentrations were compared to functional outcomes (modified Rankin Scale, mRS) and dichotomized into favorable (mRS 0–3) and unfavorable (mRS 4–6) groups. Non-parametric statistical tests and ROC analysis was performed. Results UCH-L1 concentrations in healthy controls were significantly lower compared to both early and late samples after ABI (p ≤ 0.001). The diagnostic performance of urine UCH-L1 at early timepoint showed excellent discriminatory ability, with AUC of 97.6% (95% CI: 93.0–100, p = 0.006 (sensitivity 98%, specificity 100%). Urine UCH-L1 concentrations, both with and without creatinine normalization, did not distinguish between favorable and unfavorable outcomes in either early (p = 0.88 and p = 0.36) or late samples (p = 0.98 and p = 0.30) in any types of ABI. Discussion and conclusions Although UCH-L1 concentrations in urine did not differentiate between favorable and unfavorable outcomes, a significant difference was observed between healthy subjects and ABI patients. This finding underscores the significant diagnostic utility of urine UCH-L1 concentrations, regardless of the type of acute brain injury.

Correlation of UCH-L1 and GFAP in predicting severity of traumatic brain injury in an Asian population

Article

Full-text available

Dec 2024

The application of biomarkers in TBI management remains underutilised with paucity of data in Asian populations. This study investigated the correlation between UCH-L1 and GFAP with TBI severity and patient outcomes in a Malaysian tertiary centre. The study was conducted at Universiti Malaya Medical Centre in Kuala Lumpur, Malaysia, from February 1, 2017, to November 30, 2019. GFAP and UCH-L1 were measured in 61 TBI cases and 19 controls. Correlations between biomarkers and TBI severity, as well as patient outcomes, were assessed using Spearman's rank correlation coefficient. GFAP/UCHL1 showed significant correlation with Marshall CT classification (r=0.437, p<0.001), Glasgow Coma Scale on arrival (r=-0.444, p<0.001), and Acute Physiology and Chronic Health Evaluation II (APACHEII) score (r=0.501, p<0.001). GFAP demonstrated fair-to-good accuracy in predicting TBI severity and outcomes. A consistent cut-off value of 0.01845 ng/mL for GFAP and 0.01960 for GFAP/UCHL1 predicted TBI severity, with high sensitivity (72.2-100%) and acceptable specificity (38.8-80.0%). GFAP and GFAP/UCHL1 showed promising utility in predicting TBI severity and patient outcomes in the Asian population. The findings underscore the potential clinical significance of biomarker assessment in TBI management, though further validation in larger cohorts is warranted.

Exploiting blood-based biomarkers to align preclinical models with human traumatic brain injury

Article

Full-text available

Nov 2024

Rodent models are important research tools for studying the pathophysiology of traumatic brain injury (TBI) and developing new therapeutic interventions for this devastating neurological disorder. However, the failure rate for the translation of drugs from animal testing to human treatments for TBI is 100%. While there are several potential explanations for this, previous clinical trials have relied on extrapolation from preclinical studies for critical design considerations, including drug dose optimization, post-injury drug treatment initiation and duration. Incorporating clinically relevant biomarkers in preclinical studies may provide an opportunity to calibrate preclinical models to identical (or similar) measurements in humans, link to human TBI biomechanics and pathophysiology, and guide therapeutic decisions. To support this translational goal, we conducted a systematic literature review of preclinical TBI studies in rodents measuring blood levels of clinically used GFAP, UCH-L1, NfL, t-Tau, or p-Tau, published in PubMed/EMBASE up to April 10th, 2024. Although many factors influence clinical TBI outcomes, many of those cannot routinely be assessed in rodent studies (e.g., ICP monitoring), thus we focused on blood biomarkers’ temporal trajectories and discuss our findings in the context of the latest clinical TBI biomarker data. Out of the 805 original preclinical studies, 74 met the inclusion criteria, with a median quality score of 5 (25th-75th percentiles: 4-7) on the CAMARADES checklist. GFAP was measured in 43 studies, UCH-L1 in 21, NfL in 20, t-Tau in 19, and p-Tau in seven. Data in rodent models indicate that all biomarkers exhibited injury severity-dependent elevations with distinct temporal profiles. GFAP and UCH-L1 peaked within the first day after TBI (30- and 4-fold increases, respectively, in moderate-to-severe TBI versus sham) with the highest levels observed in the contusion TBI model. NfL peaked within days (18-fold increase) and remained elevated up to 6 months post-injury. GFAP and NfL show a pharmacodynamic response in 64.7% and 60%, respectively, of studies evaluating neuroprotective therapies in preclinical models. However, GFAP’s rapid decline post-injury may limit its utility for understanding the response to new therapeutics beyond the hyperacute phase after experimental TBI. Furthermore, as in humans, subacute NfL levels inform on chronic white matter loss after TBI. t-Tau and p-Tau levels increased over weeks after TBI (up to 6- and 16-fold, respectively); however, their relationship with underlying neurodegeneration has yet to be addressed. Further investigation into biomarker levels in the subacute and chronic phases after TBI will be needed to fully understand the pathomechanisms underpinning blood biomarkers’ trajectories and select the most suitable experimental model to optimally relate preclinical mechanistic studies to clinical observations in humans. This new approach could accelerate the translation of neuroprotective treatments from laboratory experiments to real-world clinical practices.

Diagnostic Performance of GFAP, UCH-L1, and MAP-2 Within 30 and 60 Minutes of Traumatic Brain Injury

Article

Sep 2024

Importance Data on the performance of traumatic brain injury (TBI) biomarkers within minutes of injury are lacking. Objectives To examine the performance of glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and microtubule-associated protein 2 (MAP-2) within 30 and 60 minutes of TBI in identifying intracranial lesions on computed tomography (CT) scan, need for neurosurgical intervention (NSI), and clinically important early outcomes (CIEO). Design, Setting, and Participants This cohort study is a biomarker analysis of a multicenter prehospital TBI cohort from the Prehospital Tranexamic Acid Use for TBI clinical trial conducted across 20 centers and 39 emergency medical systems in North America from May 2015 to March 2017. Prehospital hemodynamically stable adult patients with traumatic injury and suspected moderate to severe TBI were included. Blood samples were measured for GFAP, UCH-L1, and MAP-2. Data were analyzed from December 1, 2023, to March 15, 2024. Main Outcomes and Measures The presence of CT lesions, diffuse injury severity on CT, NSI within 24 hours of injury, and CIEO (composite outcome including early death, neurosurgery, or prolonged mechanical ventilation ≥7 days) within 7 days of injury. Results Of 966 patients enrolled, 804 patients (mean [SD] age, 41 [19] years; 418 [74.2%] male) had blood samples, including 563 within 60 minutes and 375 within 30 minutes of injury. Among patients with blood drawn within 30 minutes of injury, 212 patients (56.5%) had CT lesions, 61 patients (16.3%) had NSI, and 112 patients (30.0%) had CIEO. Among those with blood drawn within 60 minutes, 316 patients (56.1%) had CT lesions, 95 patients (16.9%) had NSI, and 172 patients (30.6%) had CIEO. All biomarkers showed significant elevations with worsening diffuse injury on CT within 30 and 60 minutes of injury. Among blood samples taken within 30 minutes, GFAP had the highest area under the receiver operating characteristic curve (AUC) to detect CT lesions, at 0.88 (95% CI, 0.85-0.92), followed by MAP-2 (AUC, 0.78; 95% CI, 0.73-0.83) and UCH-L1 (AUC, 0.75; 95% CI, 0.70-0.80). Among blood samples taken within 60 minutes, AUCs for CT lesions were 0.89 (95% CI, 0.86-0.92) for GFAP, 0.76 (95% CI, 0.72-0.80) for MAP-2, and 0.73 (95% CI, 0.69-0.77) for UCH-L1. Among blood samples taken within 30 minutes, AUCs for NSI were 0.78 (95% CI, 0.72-0.84) for GFAP, 0.75 (95% CI, 0.68-0.81) for MAP-2, and 0.69 (95% CI, 0.63-0.75) for UCH-L1; and for CIEO, AUCs were 0.89 (95% CI, 0.85-0.93) for GFAP, 0.83 (95% CI, 0.78-0.87) for MAP-2, and 0.77 (95% CI, 0.72-0.82) for UCH-L1. Combining the biomarkers was no better than GFAP alone for all outcomes. At GFAP of 30 pg/mL within 30 minutes, sensitivity for CT lesions was 98.1% (95% CI, 94.9%-99.4%) and specificity was 34.4% (95% CI, 27.2%-42.2%). GFAP levels greater than 6200 pg/mL were associated with high risk of NSI and CIEO. Conclusions and Relevance In this cohort study of prehospital patients with TBI, GFAP, UCH-L1, and MAP-2 measured within 30 and 60 minutes of injury were significantly associated with traumatic intracranial lesions and diffuse injury severity on CT scan, 24-hour NSI, and 7-day CIEO. GFAP was the strongest independent marker associated with all outcomes. This study sets a precedent for the early utility of GFAP in the first 30 minutes from injury in future clinical and research endeavors.

Distinct Serum GFAP and Nf-L Time-Courses after Rapid Head Rotations

Article

May 2024
J NEUROTRAUM

Traumatic brain injury (TBI) causes significant neurophysiological deficits and is typically associated with rapid head accelerations common in sports-related incidents and automobile accidents. There are over 1.5 million TBIs in the United States each year, with children aged 0-4 being particularly vulnerable. TBI diagnosis is currently achieved through interpretation of clinical signs and symptoms and neuroimaging; however, there is increasing interest in minimally invasive fluid biomarkers to detect TBI objectively across all ages. Pre-clinical porcine models offer controlled conditions to evaluate TBI with known biomechanical conditions and without comorbidities. The objective of the current study was to establish pediatric porcine healthy reference ranges (RRs) of common human serum TBI biomarkers and to report their acute time-course after nonimpact rotational head injury. A retrospective analysis was completed to quantify biomarker concentrations in porcine serum samples collected from 4-week-old female (n = 215) and uncastrated male (n = 6) Yorkshire piglets. Subjects were assigned to one of three experimental groups (sham, sagittal-single, sagittal-multiple) or to a baseline only group. A rapid nonimpact rotational head injury model was used to produce mild-to-moderate TBI in piglets following a single rotation and moderate-to-severe TBI following multiple rotations. The Quanterix Simoa Human Neurology 4-Plex A assay was used to quantify glial fibrillary acidic protein (GFAP), neurofilament light (Nf-L), tau, and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1). The 95% healthy RRs for females were calculated and validated for GFAP (6.3-69.4 pg/mL), Nf-L (9.5-67.2 pg/mL), and UCH-L1 (3.8-533.7 pg/mL). Rising early, GFAP increased significantly above the healthy RRs for sagittal-single (to 164 and 243 pg/mL) and increased significantly higher in sagittal-multiple (to 494 and 413 pg/mL) groups at 30 min and 1 h postinjury, respectively, returning to healthy RRs by 1-week postinjury. Rising later, Nf-L increased significantly above the healthy RRs by 1 day in sagittal-single (to 69 pg/mL) and sagittal-multiple groups (to 140 pg/mL) and rising further at 1 week (single = 231 pg/mL, multiple = 481 pg/mL). Sagittal-single and sagittal-multiple UCH-L1 serum samples did not differ from shams or the healthy RRs. Sex differences were observed but inconsistent. Serum GFAP and Nf-L levels had distinct time-courses following head rotations in piglets, and both corresponded to load exposure. We conclude that serum GFAP and Nf-L offer promise for early TBI diagnosis and intervention decisions for TBI and other neurological trauma.

Biomarkers: Revolutionizing disease monitoring and therapeutic strategies

Chapter

Jan 2024

Development of prognostic models for predicting 90-day neurological function and mortality after cardiac arrest

Article

Feb 2024
AM J EMERG MED

Connecting cellular mechanisms and extracellular vesicle cargo in traumatic brain injury

Article

Full-text available

Dec 2023

Traumatic brain injury is followed by a cascade of dynamic and complex events occurring at the cellular level. These events include: diffuse axonal injury, neuronal cell death, blood-brain barrier break down, glial activation and neuroinflammation, edema, ischemia, vascular injury, energy failure, and peripheral immune cell infiltration. The timing of these events post injury has been linked to injury severity and functional outcome. Extracellular vesicles are membrane bound secretory vesicles that contain markers and cargo pertaining to their cell of origin and can cross the blood-brain barrier. These qualities make extracellular vesicles intriguing candidates for a liquid biopsy into the pathophysiologic changes occurring at the cellular level post traumatic brain injury. Herein, we review the most commonly reported cargo changes in extracellular vesicles from clinical traumatic brain injury samples. We then use knowledge from animal and in vitro models to help infer what these changes may indicate regrading cellular responses post traumatic brain injury. Future research should prioritize labeling extracellular vesicles with markers for distinct cell types across a range of timepoints post traumatic brain injury.

Raman Spectroscopy Spectral Fingerprints of Biomarkers of Traumatic Brain Injury

Article

Full-text available

Nov 2023

Traumatic brain injury (TBI) affects millions of people of all ages around the globe. TBI is notoriously hard to diagnose at the point of care, resulting in incorrect patient management, avoidable death and disability, long-term neurodegenerative complications, and increased costs. It is vital to develop timely, alternative diagnostics for TBI to assist triage and clinical decision-making, complementary to current techniques such as neuroimaging and cognitive assessment. These could deliver rapid, quantitative TBI detection, by obtaining information on biochemical changes from patient’s biofluids. If available, this would reduce mis-triage, save healthcare providers costs (both over- and under-triage are expensive) and improve outcomes by guiding early management. Herein, we utilize Raman spectroscopy-based detection to profile a panel of 18 raw (human, animal, and synthetically derived) TBI-indicative biomarkers (N-acetyl-aspartic acid (NAA), Ganglioside, Glutathione (GSH), Neuron Specific Enolase (NSE), Glial Fibrillary Acidic Protein (GFAP), Ubiquitin C-terminal Hydrolase L1 (UCHL1), Cholesterol, D-Serine, Sphingomyelin, Sulfatides, Cardiolipin, Interleukin-6 (IL-6), S100B, Galactocerebroside, Beta-D-(+)-Glucose, Myo-Inositol, Interleukin-18 (IL-18), Neurofilament Light Chain (NFL)) and their aqueous solution. The subsequently derived unique spectral reference library, exploiting four excitation lasers of 514, 633, 785, and 830 nm, will aid the development of rapid, non-destructive, and label-free spectroscopy-based neuro-diagnostic technologies. These biomolecules, released during cellular damage, provide additional means of diagnosing TBI and assessing the severity of injury. The spectroscopic temporal profiles of the studied biofluid neuro-markers are classed according to their acute, sub-acute, and chronic temporal injury phases and we have further generated detailed peak assignment tables for each brain-specific biomolecule within each injury phase. The intensity ratios of significant peaks, yielding the combined unique spectroscopic barcode for each brain-injury marker, are compared to assess variance between lasers, with the smallest variance found for UCHL1 (σ² = 0.000164) and the highest for sulfatide (σ² = 0.158). Overall, this work paves the way for defining and setting the most appropriate diagnostic time window for detection following brain injury. Further rapid and specific detection of these biomarkers, from easily accessible biofluids, would not only enable the triage of TBI, predict outcomes, indicate the progress of recovery, and save healthcare providers costs, but also cement the potential of Raman-based spectroscopy as a powerful tool for neurodiagnostics.

TXA does not affect levels of TBI-related biomarkers in blunt TBI with ICH: A secondary analysis of the prehospital TXA for TBI trial

Article

Oct 2023

Background Brain specific biomarkers such as glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), and microtubule-associated protein-2 (MAP-2) have been identified as tools for diagnosis in traumatic brain injury (TBI). Tranexamic acid (TXA) has been shown to decrease mortality in patients with intracranial hemorrhage (ICH). The effect of TXA on these biomarkers is unknown. We investigated whether TXA affects levels of GFAP, UCH-L1, and MAP-2, and whether biomarker levels are associated with mortality in patients receiving TXA. Methods Patients enrolled in the prehospital TXA for TBI trial had GFAP, UCHL-1 and MAP-2 levels drawn at 0 and 24 hours post injury(n = 422). Patients with ICH from blunt trauma with a GCS <13 and SBP >90 were randomized to placebo, 2 g TXA bolus, or 1 g bolus +1 g/8 hrs TXA infusion. Associations of TXA and 24-hour biomarker change were assessed with multivariate linear regression. Association of biomarkers with 28-day mortality was assessed with multivariate logistic regression. All models were controlled for age, GCS, ISS, and AIS head. Results Administration of TXA was not associated with a change in biomarkers over 24 hours post-injury. Changes in biomarker levels were associated with AIS head and age. On admission, higher GFAP (OR 1.75, CI 1.31-2.38, p < 0.001) was associated with increased 28-day mortality. At 24 hours post injury, higher levels of GFAP (OR 2.09, CI 1.37-3.30, p < 0.001 and UCHL-1(OR 2.98, CI 1.77-5.25, p < 0.001) were associated with mortality. A change in UCH levels from 0 to 24 hours post-injury was also associated with increased mortality (OR 1.68, CI 1.15-2.49, p < 0.01). Conclusion Administration of TXA does not impact change in GFAP, UCHL-1, or MAP-2 during the first 24 hours after blunt TBI with ICH. Higher levels of GFAP and UCH early after injury may help identify patients at high risk for 28-day mortality. Level of Evidence II, therapeutic/care management

Changes in the ubiquitination system in children with cerebral palsySerebral palsili çocuklarda ubiqinitasyon sistemindeki değişiklikler

Article

Jul 2023

Objective: We aimed to investigate the levels of Ubiquitin Carboxy Terminal Hydrolase-L1 enzyme (UHC-L1), Transactive Response DNA Binding Protein-43 (TDP-43) and Cullin-3 in peripheral blood associated with ubiquitination processes in children with cerebral palsy (CP). Materials and Methods: We included 50 children with CP in the first patient group. In the control group, there were 30 healthy children who were matched with the patient groups in terms of age and gender. We also recorded risk factors for CP, CP type, botox application, orthosis use, maternal age at birth, and additional problems. Patients aged 6-10 years, diagnosed with CP, without genetic, metabolic disease or mental retardation history were included in this study. Results: There were 32 female and 18 male patients in the CP group, while there were 19 female and 11 male volunteers in the control group. Maternal age was significantly higher in the CP group (p=0.002). In our study, as a result of the comparison between the control group and the CP group in terms of UCH-L1, TDP-43 and Cullin 3 levels; the levels of UCH-L1 (p=0.048), TDP-43 (p=0.028) and Cullin 3 (p=0.042) in the CP group were found to be statistically significantly lower than the levels of the control group. Conclusion: The low serum concentrations of UCHL-L1, Cullin 3 and TDP-43 molecules in the CP group and the statistically positive correlation of these molecules with each other may help to understand the neuronal pathophysiology after disruption of the ubiquitination system.

Sex differences in time course and diagnostic accuracy of GFAP and UCH-L1 in trauma patients with mild traumatic brain injury

Article

Full-text available

Jul 2023

Glial Fibrillary Acidic Protein (GFAP) and Ubiquitin C-terminal hydrolase (UCH-L1) have been FDA-approved for clinical use in mild and moderate traumatic brain injury (TBI). Understanding sex differences in their diagnostic accuracy over time will help inform clinical practice. We sought to evaluate the sex differences in the temporal profile of GFAP and UCH-L1 in a large cohort of trauma patients presenting to the emergency department. To compare the biomarkers’ diagnostic accuracy in male versus female patients for detecting mild TBI (MTBI), and traumatic intracranial lesions on head CT. This prospective cohort study enrolled female and male adult trauma patients presenting to a Level 1 Trauma Center. All patients underwent rigorous screening to determine whether or not they had experienced a MTBI. Of 3025 trauma patients assessed, 1030 met eligibility criteria and 446 declined. Initial blood samples were obtained in 584 patients enrolled within 4 h of injury. Repeated blood sampling was conducted at 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180-h post-injury. The main outcomes included the diagnostic accuracy in detection of MTBI and traumatic intracranial lesions on head CT scan. A total of 1831 samples were drawn in 584 patients over 7 days, 362 (62%) were male and 222 (38%) were female. The pattern of elevation was similar in both sexes. Although the pattern of elevation was similar between male and female for both biomarkers, male patients had significantly higher concentrations of UCH-L1 compared to female patients at several timepoints post-injury, particularly within 24 h of injury. There were no significant differences in diagnostic accuracy for detecting MTBI or for detecting CT lesions between male and female patients at any timepoint for both GFAP and UCH-L1. Although patterns of GFAP and UCH-L1 release in trauma patients over a week post-injury was similar between the sexes, there were significantly higher concentrations of UCH-L1 in males at several timepoints post-injury. Despite this, the overall diagnostic accuracies of both GFAP and UCH-L1 over time for detecting MTBI and CT lesions were not significantly different between male and female trauma patients.

Biomarker

Chapter

Jun 2023

Spoedeisende hulp en acute fase

Chapter

Nov 2021

Korné Jellema

Bij patiënten met traumatisch hoofd-hersenletsel (THL) vindt beoordeling en behandeling in de acute fase plaats volgens de gestandaardiseerde Advanced Trauma Life Support (ATLS)-methode. Het is belangrijk dat (intra-)craniële traumatische afwijkingen tijdig worden geïdentificeerd en secundaire schade wordt voorkomen. Voor patiënten met THL zijn adequate respiratoire en hemodynamische parameters zeer belangrijk. Monitoring van de vitale parameters, inclusief de Glasgow Coma Schaal (GCS)-score en pupilreacties, zijn derhalve onderdeel van de eerste opvang. De kans op een traumatische (intra)craniële afwijking is afhankelijk van de ernst van het THL. Er zijn diverse beslisregels ontwikkeld voor het laten maken van een CT-scan. Indien er sprake is van een intracraniële traumatische bloeding is het tijdelijk staken van antitrombotica aangewezen. Mogelijke complicaties die in de acute fase kunnen optreden zijn onrust, liquorlekkage en epilepsie. Hyperosmolaire therapie met mannitol of hypertoon zout speelt een belangrijke rol in de acute behandeling van eventueel verhoogde intracraniële druk.

Traumatic Brain Injury

Chapter

Jan 2018

Mazlina Mazlan

Effects of Physical Exertion on Early Changes in Blood-Based Brain Biomarkers: Implications for the Acute Point of Care Diagnosis of Concussion

Article

Full-text available

Oct 2022

Blood-based brain biomarkers (BBM) such as glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) have potential to aid in the diagnosis of concussion. Recently developed point-of-care test devices would enable BBMs to be measured in field settings such military and sport environments within minutes of a suspicious head hit. However, head hits in these environments typically occur in the setting of vigorous physical exertion, which can itself increase BBMs levels. Thus, efforts to develop BBMs as acute concussion aids in field settings need to account for the effects of physical exertion. In order to determine the acute effects of physical exertion on the BBMs, we measured GFAP, UCH-L1, tau and neurofilament light chain (NF-L) immediately before, immediately after and 45 minutes after a single workout session consisting of aerobic and resistance exercises in 30 collegiate football players. Subjects wore body sensors measuring several aspects of exertion and underwent diffusion tensor imaging 24 hours before and 48 hours after exertion. All subjects were male with a mean age of 19.5+1.2 years. The mean duration of activity during the workout session was 94+31 minutes. There was a significant decrease in serum GFAP immediately after (median decrease of 27.76%, p<0.0001) and a significant increase in serum UCH-L1 45-minutes after (median increase of 37.11%, p=0.016) exertion, compared to pre-exertion baseline. No significant changes in tau or NF-L were identified. The duration of exertion had a significant independent linear correlation to the increase in serum UCHL1 from pre-exertion to 45-minutes after exertion (r =0.68, p=0.004). There were no significant pre- to post-exertional changes in any of the 39 examined brain white matter regions, and biomarker changes did not correlate to variation in white matter integrity in any of these regions. Thus, exertion appeared to be associated with immediate decreases in serum GFAP and very acute (45 minutes) increases in UCH-L1. These changes were related to the duration of exertion, but not to changes in brain white matter integrity. Our results have important implications for how these BBMs might be used to aid in the on-scene diagnosis of concussion occurring in the setting of physical exertion.

Serum Tau, NFL, GFAP and UHCL-1 are Associated with the Chronic Deterioration of Neurobehavioral Symptoms following Traumatic Brain Injury

Article

Sep 2022

The purpose of this study was to examine the association of serum tau, neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and ubiquitin carboxy-terminal hydrolase L1 (UCHL-1) concentrations evaluated within the first 12 months following a military-related TBI, with longitudinal changes in neurobehavioral functioning extending 2-or-more years post-injury. Participants were 84 United States service members and veterans (SMVs) prospectively enrolled in the Defense and Veterans Brain Injury Center/Traumatic Brain Injury Center 15-Year Longitudinal TBI Study, separated into three discreet groups: (a) uncomplicated mild TBI [MTBI; n=28], (b) complicated mild, moderate, severe, and penetrating TBI combined [STBI; n=29], and (c) non-injured controls [NIC, n=27]). Participants completed a battery of self-report neurobehavioral symptom measures (e.g., depression, PTSD, postconcussion, anxiety, somatic, cognitive, and neurological symptoms) within 12 months of injury (baseline), and then again at 2-or-more years-post-injury (follow-up). At baseline, participants also completed a blood draw to determine serum concentrations of tau, NFL, GFAP, and UCHL-1 using an ultra-sensitivity assay method. In the MTBI and STBI groups (using hierarchical regression analyses), [1] baseline tau concentrations predicted the deterioration of neurobehavioral symptoms from baseline to follow-up on measures of anxiety, PTSD, depression, postconcussion, somatic, and neurological symptoms (accounting for 10-28% of the variance); [2] NFL predicted the deterioration of depression, postconcussion, somatic, cognitive, and neurological symptoms (10-32% variance); [3] GFAP predicted the deterioration of postconcussion, PTSD, depression, anxiety, somatic, neurological, and cognitive symptoms (11-43% variance); and [4] UCHL-1 predicted the deterioration of anxiety, somatic, and neurological symptoms (10-16% variance). In the NIC group, no meaningful associations were found between baseline biomarker concentrations and the deterioration of neurobehavioral symptoms on the majority of measures. This study reports that elevated tau, NFL, GFAP, and UCHL-1 concentrations within the first 12 months of injury are associated with the deterioration of neurobehavioral symptoms that extends to the chronic phase of recovery following a TBI. These findings suggest that a blood-based panel including these biomarkers could be a useful prognostic tool to identifying those individuals at risk of poor future outcome following TBI.

Label-free, ultrasensitive and rapid detection of FDA-approved TBI specific UCHL1 biomarker in plasma using MWCNT-PPY nanocomposite as bio-electrical transducer: A step closer to point-of-care diagnosis of TBI

Article

Aug 2022
BIOSENS BIOELECTRON

Traumatic Brain Injury (TBI), a major cause of mortality and neurological disability affecting people of all ages worldwide, remains a diagnostic and therapeutic challenge to date. Rapid, ultra-sensitive, selective, and wide-range detection of TBI biomarkers in easily accessible body fluids is an unmet clinical need. Considering this, in this work, we report the design and development of a facile, label-free, highly stable and sensitive, chemi-impedance-based sensing platform for rapid and wide range detection of Ubiquitin-carboxy terminal hydrolase L1 (UCHL1: FDA-approved TBI specific plasma biomarker), using carboxylic functionalized MWCNTs embedded polypyrrole (PPY) nanocomposites (PPY/f-MWCNT). The said nanocomposites were synthesized using chemical oxidative polymerization method. Herein, the functionalized MWCNTs are used as conducting fillers so as to increase the polymer's dielectric constant according to the micro-capacitor model, thereby augmenting both DC electrical conductivity and AC dielectric property of the nanocomposite. The proposed immunosensing platform comprises of PPY/f-MWCNT modified interdigitated microelectrode (IDμEs) array, on which anti-UCHL1-antibodies are immobilized using suitable covalent chemistry. The AC electrical characterization of the nanocomposite modified IDμEs, with and without the antibodies, was performed through generic capacitance vs. frequency (C–F, 1 KHz – 1 MHz) and capacitance vs. applied bias (C–V, 0.1 V–1 V) measurements, using an Agilent B1500A parametric analyzer. The binding event of UCHL1 peptides to anti-UCHL1-antibodies was transduced in terms of normalised changes in parallel capacitance, via the C–F analysis. Further, we have tested the detection efficiency of the said immunoassay against UCHL1 spiked human plasma samples in the concentration range 10 fg/mL – 1 μg/mL. The proposed sensing platform detected UCHL1 in spiked-plasma samples linearly in the range of 10 fg/mL – 1 ng/mL with a sensitivity and LoD of 4.22 ((ΔC/C0)/ng.mL⁻¹)/cm² and 0.363 fg/mL, respectively. Further, it showed excellent stability (30 weeks), repeatability, reproducibility, selectivity and interference-resistance. The proposed approach is label-free, and if desired, can be used in conjunction with DC measurements, for biosensing applications.

Blood Biomarkers Predict Future Cognitive Decline after Military-Related Traumatic Brain Injury

Article

Mar 2022

Background: Traumatic brain injury (TBI) has been associated with increased likelihood of late-life dementia; however, the mechanisms driving this relationship are elusive. Blood-based biomarkers may provide insight into these mechanisms and serve as useful prognostic indicators of cognitive recovery or decline following a TBI. Objective The aim of this study was to examine blood biomarkers within one year of TBI and explore their relationship with cognitive decline. Methods Service members and veterans (n=224) without injury (n=77), or with history of bodily injury (n=37), uncomplicated mild TBI (n=55), or more severe TBI (n=55), underwent a blood draw and neuropsychological assessment within one year of their injury as part of a case-control study. A subsample (n=87) completed follow-up cognitive assessment. Results In the more severe TBI group, baseline glial fibrillary acidic protein (p=.008) and ubiquitin C-terminal hydrolase-L1 (p=.026) were associated with processing speed at baseline, and baseline ubiquitin C-terminal hydrolase-L1 predicted change in immediate (R2Δ=.244, p=.005) and delayed memory (R2Δ=.390, p=.003) over time. In the mild TBI group, higher baseline tau predicted greater negative change in perceptual reasoning (R2Δ=.188, p=.033) and executive functioning (R2Δ=.298, p=.007); higher baseline neurofilament light predicted greater negative change in perceptual reasoning (R2Δ=.211, p=.012). Conclusion Baseline ubiquitin C-terminal hydrolase-L1 strongly predicted memory decline in the more severe TBI group, while tau and neurofilament light strongly predicted decline in the mild TBI group. A panel including these biomarkers could be particularly helpful in identifying those at risk for future cognitive decline following TBI.

The Path Toward a Blood Test for Concussion: A Review of Biofluid Biomarkers for Concussive and Subconcussive Brain Trauma

Chapter

Mar 2022

Linda Papa

The pursuit of a blood test for traumatic brain injury (TBI), and more specifically concussion, has been very active over the last decade with a barrage of publications seeking the best biomarkers for the job. As with other organ-based diseases, the employment of a rapid, accurate, and widely available blood test to guide diagnosis and treatment of TBI and concussion would be a welcome clinical tool. Such a blood test has considerable diagnostic and prognostic promise given the number of critical applications it would have. Early human trials examined only moderate-to-severe TBI but are now expanding to include injuries on the milder end of the TBI spectrum, such as concussion and subconcussive injuries. In the USA, two biomarkers have now been FDA-approved for clinical use in adult patients with mild-to-moderate TBI to help determine need for CT scan acutely after injury. More work is now being done to detect concussive and subconcussive injuries. Mechanism and severity of injury, timing of sample collection, type of biofluid collected, biokinetic profiles of select biomarkers, and individual patient physiology can all impact biomarker release following concussion. Careful consideration of these factors will be essential when designing future concussion biomarker studies and interpreting results. As technology advances and integrates neuroproteomics, metabolomics, bioinformatics, genetics, and neuroimaging, the path from discovery to validation of potential TBI biomarkers will be swift. This chapter will review the most widely studied proteomic biomarkers for mild TBI and concussion in humans and will introduce a novel group of promising transcriptomic biomarkers.

Development of an electrochemical impedance spectroscopy based biosensor for detection of ubiquitin C-Terminal hydrolase L1

Article

Mar 2022
BIOSENS BIOELECTRON

Year over year, the incidence of traumatic brain injury (TBI) in the population is dramatically increasing; thus, timely diagnosis is crucial for improving patient outcomes in the clinic. Ubiquitin C-terminal hydrolase L1 (UCH-L1), a blood-based biomarker, has been approved by the FDA as a promising quantitative indicator of mild TBI that arises in blood serum shortly after injury. Current gold standard techniques for its quantitation are time-consuming and require specific laboratory equipment. Hence, development of a hand-held device is an attractive alternative. In this study, we report a novel system for rapid, one-step electrochemical UCH-L1 detection. Electrodes were functionalized with anti-UCH-L1 antibody, which was used as a molecular recognition element for selective sensing of UCH-L1. Electrochemical impedance spectroscopy (EIS) was used as a transduction method to quantify its binding. When the electrode was incubated with different concentrations of UCH-L1, impedance signal increased against a concentration gradient with high logarithmic correlation. Upon single-frequency analysis, a second calibration curve with greater signal to noise was obtained, which was used to distinguish physiologically relevant concentrations of UCH-L1. Notably, our system could detect UCH-L1 within 5 minutes, without a washing step nor bound/free separation, and had resolution across concentrations ranging from 1 pM to 1 nM within an artificial serum sample. These attributes, together with the miniaturization potential afforded by an impedimetric sensing platform, make this system an attractive candidate for rapid on-site detection of TBI. These findings may aid in the future development of devices for quantitative TBI detection.

Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths.

Article

Full-text available

Apr 2010

Use of biomarkers for diagnosis and management of traumatic brain injury patients

Article

Full-text available

Aug 2008

Background: Advances in the understanding of human biochemistry and physiology have provided insight into new pathways by which we can understand traumatic brain injury (TBI). Increased sophistication of laboratory techniques and developments in the field of proteomics has led to the discovery and rapid detection of new biomarkers not previously available. Objective: To review recent advances in biomarker research for traumatic brain injury, describe the features of the ideal biomarker and to explore the potential role of these biomarkers in improving clinical management of brain injured patients. Methods: Through a literature review of recent research on TBI biomarkers and through experience with TBI research, important elements of biomarker development are described together with potential applications to patient care. Conclusions: TBI biomarkers could have a significant impact on patient care by assisting in the diagnosis, risk stratification and management of TBI. Biomarkers could provide major opportunities for the conduct of clinical research, including confirmation of injury mechanism(s) and drug target identification. Continuing studies by the authors' group are now being conducted to elucidate more fully the relationships between new biomarkers and severity of injury and clinical outcomes in all severities of TBI patients.

Biokinetic Analysis of Ubiquitin C-Terminal Hydrolase-L1 UCH-L1 in Severe Traumatic Brain Injury Patient Biofluids

Article

Full-text available

Feb 2011
J NEUROTRAUM

Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is a neuron-specific enzyme that has been identified as a potential biomarker of traumatic brain injury (TBI). The study objectives were to determine UCH-L1 exposure and kinetic metrics, determine correlations between biofluids, and assess outcome correlations in severe TBI patients. Data were analyzed from a prospective, multicenter study of severe TBI (Glasgow Coma Scale [GCS] score ≤ 8). Cerebrospinal fluid (CSF) and serum data from samples taken every 6 h after injury were analyzed by enzyme-linked immunosorbent assay (ELISA). UCH-L1 CSF and serum data from 59 patients were used to determine biofluid correlations. Serum samples from 86 patients and CSF from 59 patients were used to determine outcome correlations. Exposure and kinetic metrics were evaluated acutely and up to 7 days post-injury and compared to mortality at 3 months. There were significant correlations between UCH-L1 CSF and serum median concentrations (r(s)=0.59, p<0.001), AUC (r(s)=0.3, p=0.027), Tmax (r(s)=0.68, p<0.001), and MRT (r(s)=0.65, p<0.001). Outcome analysis showed significant increases in median serum AUC (2016 versus 265 ng/mL*min, p=0.006), and Cmax (2 versus 0.4 ng/mL, p=0.003), and a shorter Tmax (8 versus 19 h, p=0.04) in those who died versus those who survived, respectively. In the first 24 h after injury, there was a statistically significant acute increase in CSF and serum median Cmax((0-24h)) in those who died. This study shows a significant correlation between UCH-L1 CSF and serum median concentrations and biokinetics in severe TBI patients, and relationships with clinical outcome were detected.

A Panel of Neuron-Enriched Proteins as Markers for Traumatic Brain Injury in Humans

Article

Full-text available

Oct 2009
J NEUROTRAUM

Surrogate markers have enormous potential for contributing to the diagnosis, prognosis, and therapeutic evaluation of acute brain damage, but extensive prior study of individual candidates has not yielded a biomarker in widespread clinical practice. We hypothesize that a panel of neuron-enriched proteins measurable in cerebrospinal fluid (CSF) and blood should vastly improve clinical evaluation and therapeutic management of acute brain injuries. Previously, we developed such a panel based initially on the study of protein release from degenerating cultured neurons, and subsequently on rodent models of traumatic brain injury (TBI) and ischemia, consisting of 14-3-3beta, 14-3-3zeta, three distinct phosphoforms of neurofilament H, ubiquitin hydrolase L1, neuron-specific enolase, alpha-spectrin, and three calpain- and caspase-derived fragments of alpha-spectrin. In the present study, this panel of 11 proteins was evaluated as CSF and serum biomarkers for severe TBI in humans. By quantitative Western blotting and sandwich immunoassays, the CSF protein levels were near or below the limit of detection in pre-surgical and most normal pressure hydrocephalus (NPH) controls, but following TBI nine of the 11 were routinely elevated in CSF. Whereas different markers peaked coordinately, the time to peak varied across TBI cases from 24-96 h post-injury. In serum, TBI increased all four members of the marker panel for which sandwich immunoassays are currently available: a calpain-derived NH(2)-terminal alpha-spectrin fragment and the three neurofilament H phosphoforms. Our results identify neuron-enriched proteins that may serve as a panel of CSF and blood surrogate markers for the minimally invasive detection, management, mechanistic, and therapeutic evaluation of human TBI.

Comparison of the Canadian CT Head Rule and the New Orleans Criteria in Patients With Minor Head Injury

Article

Full-text available

Sep 2005
J Am Med Assoc

Current use of cranial computed tomography (CT) for minor head injury is increasing rapidly, highly variable, and inefficient. The Canadian CT Head Rule (CCHR) and New Orleans Criteria (NOC) are previously developed clinical decision rules to guide CT use for patients with minor head injury and with Glasgow Coma Scale (GCS) scores of 13 to 15 for the CCHR and a score of 15 for the NOC. However, uncertainty about the clinical performance of these rules exists. To compare the clinical performance of these 2 decision rules for detecting the need for neurosurgical intervention and clinically important brain injury. In a prospective cohort study (June 2000-December 2002) that included 9 emergency departments in large Canadian community and university hospitals, the CCHR was evaluated in a convenience sample of 2707 adults who presented to the emergency department with blunt head trauma resulting in witnessed loss of consciousness, disorientation, or definite amnesia and a GCS score of 13 to 15. The CCHR and NOC were compared in a subgroup of 1822 adults with minor head injury and GCS score of 15. Neurosurgical intervention and clinically important brain injury evaluated by CT and a structured follow-up telephone interview. Among 1822 patients with GCS score of 15, 8 (0.4%) required neurosurgical intervention and 97 (5.3%) had clinically important brain injury. The NOC and the CCHR both had 100% sensitivity but the CCHR was more specific (76.3% vs 12.1%, P<.001) for predicting need for neurosurgical intervention. For clinically important brain injury, the CCHR and the NOC had similar sensitivity (100% vs 100%; 95% confidence interval [CI], 96%-100%) but the CCHR was more specific (50.6% vs 12.7%, P<.001), and would result in lower CT rates (52.1% vs 88.0%, P<.001). The kappa values for physician interpretation of the rules, CCHR vs NOC, were 0.85 vs 0.47. Physicians misinterpreted the rules as not requiring imaging for 4.0% of patients according to CCHR and 5.5% according to NOC (P = .04). Among all 2707 patients with a GCS score of 13 to 15, the CCHR had sensitivities of 100% (95% CI, 91%-100%) for 41 patients requiring neurosurgical intervention and 100% (95% CI, 98%-100%) for 231 patients with clinically important brain injury. For patients with minor head injury and GCS score of 15, the CCHR and the NOC have equivalent high sensitivities for need for neurosurgical intervention and clinically important brain injury, but the CCHR has higher specificity for important clinical outcomes than does the NOC, and its use may result in reduced imaging rates.

Novel Differential Neuroproteomics Analysis of Traumatic Brain Injury in Rats

Article

Full-text available

Nov 2006

Approximately two million traumatic brain injury (TBI) incidents occur annually in the United States, yet there are no specific therapeutic treatments. The absence of brain injury diagnostic endpoints was identified as a significant roadblock to TBI therapeutic development. To this end, our laboratory has studied mechanisms of cellular injury for biomarker discovery and possible therapeutic strategies. In this study, pooled naïve and injured cortical samples (48 h postinjury; rat controlled cortical impact model) were processed and analyzed using a differential neuroproteomics platform. Protein separation was performed using combined cation/anion exchange chromatography-PAGE. Differential proteins were then trypsinized and analyzed with reversed-phase LC-MSMS for protein identification and quantitative confirmation. The results included 59 differential protein components of which 21 decreased and 38 increased in abundance after TBI. Proteins with decreased abundance included collapsin response mediator protein 2 (CRMP-2), glyceraldehyde-3-phosphate dehydrogenase, microtubule-associated proteins MAP2A/2B, and hexokinase. Conversely C-reactive protein, transferrin, and breakdown products of CRMP-2, synaptotagmin, and alphaII-spectrin were found to be elevated after TBI. Differential changes in the above mentioned proteins were confirmed by quantitative immunoblotting. Results from this work provide insight into mechanisms of traumatic brain injury and yield putative biochemical markers to potentially facilitate patient management by monitoring the severity, progression, and treatment of injury.

S100B Is Not a Reliable Prognostic Index in Paediatric TBI

Article

Full-text available

Feb 2007

As far as paediatric traumatic brain injury is concerned, it is difficult to quantify the extent of the primary insult, to monitor secondary changes and to predict neurological outcomes by means of the currently used diagnostic tools: physical examination, Glasgow Coma Scale (GCS) score and computed tomography. For this reason, several papers focused on the use of biochemical markers (S100B, neuron-specific enolase) to detect and define the severity of brain damage and predict outcome after traumatic head injury or cardiac arrest. The aim of this paper is measuring the range of S100B serum concentrations in children affected by traumatic brain injury and describing the possible roles of this protein in the reaction to trauma. Fifteen children aged 1-15 years were included in the study. Traumatic brain injury severity was defined by paediatric GCS score as mild (9 patients), moderate (2 patients) or severe (4 patients). Blood samples for S100B serum measurement were taken at emergency department admission and after 48 h. The serum S100B concentration was higher in the group of severe trauma patients, who scored the lowest on the GCS at admission, and among them, the highest values were reported by the children with concomitant peripheral lesions. The role of S100B in paediatric traumatic brain injury has not been clarified yet, and the interpretation of its increase when the head trauma is associated with other injuries needs the understanding of the physiopathological mechanisms that rule its release in the systemic circulation. The levels of S100B in serum after a brain injury could be related to the mechanical discharge from a destroyed blood-brain barrier, or they could be due to the active expression by the brain, as a part of its involvement in the systemic inflammatory reaction. Early increase of this protein is not a reliable prognostic index of neurological outcome after pediatric traumatic brain injury, since even very elevated values are compatible with a complete neurological recovery.

Imaging After Head Trauma

Article

Nov 1991
EMERG MED CLIN N AM

Decisions about the optimal imaging strategy in patients after acute head trauma can be based on clinical observations (see Tables 1 and 3, Fig. 1). Low-risk patients do not require radiographic imaging. CT is the procedure of choice for imaging moderate- and high-risk patients after head trauma. Because of its limited ability to guide therapy, plain skull radiography should be used sparingly; it may be useful in equivocal cases of bony injury not detected by CT or in selected moderate-risk patients (especially children under the age of 2 years.) MR imaging rivals CT in the detection of intracranial injuries but is more expensive and cumbersome in seriously ill subjects and does not image bony structures. MR imaging is recommended after initial CT if subtle acute nonhemorrhagic and subacute hemorrhagic lesions are suspected, especially in the evaluation of child abuse. Otherwise, MR imaging is rarely needed in the emergency department management of acute head injury patients.

The demonstration of new human brain-specific proteins by high-resolution two-dimensional polyacrylamide gel electrophoresis.

Article

Mar 1981
J NEUROL SCI

Ct-An increasing source of radiation exposure

Article

Jan 2007

Definition of Mild Traumatic Brain Injury

Article

Sep 1993
J HEAD TRAUMA REHAB

NA; &NA

Developed by the Mild Traumatic Brain Injury Committee of the Head Injury Interdisciplinary Special Interest Group of the American Congress of Rehabilitation Medicine

The Canadian CT Head Rule for patients with minor head injury

Article

Jan 2001

[PDF]

Comparison of the Canadian CT Head Rule and the New Orleans Criteria in Patients With Minor Head …

Article

Jan 2005
J Am Med Assoc

[PDF]

Definition of mild traumatic brain injury

Article

Jan 1993
J HEAD TRAUMA REHAB

American Congress of Rehabilitation Medicine

Describes mild traumatic brain injury (TBI) as a traumatically induced physiological disruption of brain function manifested by at least one of the following: (1) any period of loss of consciousness, (2) any loss of memory for events immediately before or after the accident, (3) any alteration in mental state at the time of the accident, and (4) focal neurological deficit(s) that may or may not be transient. Severity of injury in mild TBI does not exceed the following: (1) loss of consciousness of 30 min or less, (2) after 30 min, an initial Glasgow Coma Scale of 13-25, and (3) posttraumatic amnesia not greater than 24 hrs. (PsycINFO Database Record (c) 2006 APA, all rights reserved)

NIH Consensus Development Panel on Rehabilitation of Persons with Traumatic Brain Injury

Article

Feb 2000
J HEAD TRAUMA REHAB

Andrea Laborde

Elevated Levels of Serum Glial Fibrillary Acidic Protein Breakdown Products in Mild and Moderate Traumatic Brain Injury Are Associated With Intracranial Lesions and Neurosurgical Intervention

Article

Nov 2011

This study examines whether serum levels of glial fibrillary acidic protein breakdown products (GFAP-BDP) are elevated in patients with mild and moderate traumatic brain injury compared with controls and whether they are associated with traumatic intracranial lesions on computed tomography (CT) scan (positive CT result) and with having a neurosurgical intervention. This prospective cohort study enrolled adult patients presenting to 3 Level I trauma centers after blunt head trauma with loss of consciousness, amnesia, or disorientation and a Glasgow Coma Scale (GCS) score of 9 to 15. Control groups included normal uninjured controls and trauma controls presenting to the emergency department with orthopedic injuries or a motor vehicle crash without traumatic brain injury. Blood samples were obtained in all patients within 4 hours of injury and measured by enzyme-linked immunosorbent assay for GFAP-BDP (nanograms/milliliter). Of the 307 patients enrolled, 108 were patients with traumatic brain injury (97 with GCS score 13 to 15 and 11 with GCS score 9 to 12) and 199 were controls (176 normal controls and 16 motor vehicle crash controls and 7 orthopedic controls). Receiver operating characteristic curves demonstrated that early GFAP-BDP levels were able to distinguish patients with traumatic brain injury from uninjured controls with an area under the curve of 0.90 (95% confidence interval [CI] 0.86 to 0.94) and differentiated traumatic brain injury with a GCS score of 15 with an area under the curve of 0.88 (95% CI 0.82 to 0.93). Thirty-two patients with traumatic brain injury (30%) had lesions on CT. The area under these curves for discriminating patients with CT lesions versus those without CT lesions was 0.79 (95% CI 0.69 to 0.89). Moreover, the receiver operating characteristic curve for distinguishing neurosurgical intervention from no neurosurgical intervention yielded an area under the curve of 0.87 (95% CI 0.77 to 0.96). GFAP-BDP is detectable in serum within an hour of injury and is associated with measures of injury severity, including the GCS score, CT lesions, and neurosurgical intervention. Further study is required to validate these findings before clinical application.

Ubiquitin-C-Terminal Hydrolase as a Novel Biomarker for stroke and Traumatic Brain Injury in Rats

Article

Feb 2010
EUR J NEUROSCI

Ubiquitin C-terminal hydrolase-L1 (UCH-L1), also called neuronal-specific protein gene product 9.5, is a highly abundant protein in the neuronal cell body and has been identified as a possible biomarker on the basis of a recent proteomic study. In this study, we examined whether UCH-L1 was significantly elevated in cerebrospinal fluid (CSF) following controlled cortical impact (CCI) and middle cerebral artery occlusion (MCAO; model of ischemic stroke) in rats. Quantitative immunoblots of rat CSF revealed a dramatic elevation of UCH-L1 protein 48 h after severe CCI and as early as 6 h after mild (30 min) and severe (2 h) MCAO. A sandwich enzyme-linked immunosorbent assay constructed to measure UCH-L1 sensitively and quantitatively showed that CSF UCH-L1 levels were significantly elevated as early as 2 h and up to 48 h after CCI. Similarly, UCH-L1 levels were also significantly elevated in CSF from 6 to 72 h after 30 min of MCAO and from 6 to 120 h after 2 h of MCAO. These data are comparable to the profile of the calpain-produced alphaII-spectrin breakdown product of 145 kDa biomarker. Importantly, serum UCH-L1 biomarker levels were also significantly elevated after CCI. Similarly, serum UCH-L1 levels in the 2-h MCAO group were significantly higher than those in the 30-min group. Taken together, these data from two rat models of acute brain injury strongly suggest that UCH-L1 is a candidate brain injury biomarker detectable in biofluid compartments (CSF and serum).

Ubiquitin C-terminal hydrolase is a novel biomarker in humans for severe traumatic brain injury

Article

Sep 2009

Ubiquitin C-terminal hydrolase (UCH-L1), also called neuronal-specific protein gene product (PGP 9.3), is highly abundant in neurons. To assess the reliability of UCH-L1 as a potential biomarker for traumatic brain injury (TBI) this study compared cerebrospinal fluid (CSF) levels of UCH-L1 from adult patients with severe TBI to uninjured controls; and examined the relationship between levels with severity of injury, complications and functional outcome. This study was designed as prospective case control study. This study enrolled 66 patients, 41 with severe TBI, defined by a Glasgow coma scale (GCS) score of < or =8, who underwent intraventricular intracranial pressure monitoring and 25 controls without TBI requiring CSF drainage for other medical reasons. : Two hospital system level I trauma centers. Ventricular CSF was sampled from each patient at 6, 12, 24, 48, 72, 96, 120, 144, and 168 hrs following TBI and analyzed for UCH-L1. Injury severity was assessed by the GCS score, Marshall Classification on computed tomography and a complicated postinjury course. Mortality was assessed at 6 wks and long-term outcome was assessed using the Glasgow outcome score 6 months after injury. TBI patients had significantly elevated CSF levels of UCH-L1 at each time point after injury compared to uninjured controls. Overall mean levels of UCH-L1 in TBI patients was 44.2 ng/mL (+/-7.9) compared with 2.7 ng/mL (+/-0.7) in controls (p <.001). There were significantly higher levels of UCH-L1 in patients with a lower GCS score at 24 hrs, in those with postinjury complications, in those with 6-wk mortality, and in those with a poor 6-month dichotomized Glasgow outcome score. These data suggest that this novel biomarker has the potential to determine injury severity in TBI patients. Further studies are needed to validate these findings in a larger sample.

Serum S100B protein in early management of patients after mild traumatic brain injury

Article

Jun 2009
EUR J NEUROL

Neuronal protein S100B assays are available now with a perspective of being an early screening tool for serious intracranial injury. The aim of the study was to correlate early S100B measurements and initial CCT findings in the patients sustaining mild traumatic brain injury (MTBI). The prospective study included patients of all ages with a history of MTBI. CCT scans and venous blood sampling for S100B analysis were performed within 6 h after injury. Levels of S100B above 0.1 ng/ml (S100B+) and any CCT detectable trauma-relevant intracranial lesions were considered positive (CCT+). A series of 102 patients were involved in the study. CCT+ scans were present in eighteen (17.6%) and CCT- scans in 84 (82.4%) patients. There were 74 (72.5%) patients in S100B+ and 28 (27.5%) in S100B- group. Sensitivity of S100B assay attained 83.3% with a negative predictive value of 89.3%. Three patients from CCT+ group had negative plasma level of S100B. Two of them required surgical treatment. S100B serum protein marker seems to be an unrealiable screening tool for determination of an intracranial injury risk group due to low sensitivity and negative predictive value seen from samples taken greater than 3 h after an MTBI.

Estimating Radiation Risk from Computed Tomography Scanning

Article

May 2009
LUNG

Medical imaging is the largest contributor to per capita radiation dose in the United States. A majority of that medical imaging dose can be attributed to the increasing number of computed tomography (CT) procedures performed every year, at last count more than 62 million scans. As a result, increased attention to the possible risks of radiation exposure has entered the popular media and therefore the public at large. This review informs the medical practitioner on the nomenclature, dosimetry, and estimated risk of CT scan radiation exposure, thereby better allowing the clinician to address the risks/benefits of CT scanning and to answer questions concerning risk.

Regional Variability in the Use of CT for Patients with Suspected Mild Traumatic Brain Injury

Article

Jan 2009

To investigate the use of computed tomography (CT) scans in patients with suspected acute mild traumatic brain injury (mTBI) presenting to emergency departments. 850 potential mTBI cases were identified through reviews of three months of health records from nine selected emergency departments across the province of Ontario. Records for review were selected using the International Classification of Disease, 9th revision, Clinical Modification codes and Injury codes. Patients who received head CT were significantly older (p<0.01), had documented loss-of-consciousness (LOC) &/or Post-Traumatic Amnesia (PTA) (p<0.001), documented nausea (p<0.01), documented vomiting (p<0.001), abnormal neurological exam results (p<0.01), had visited an urban center (p<0.001), and/or arrived by ambulance (p<0.001). The significant predictors of CT scan prescription (in a forward stepwise logistic regression) were urban location of hospital (OR=5.14; p<0.001), LOC &/or PTA (OR=4.83; p< or =0.001), vomiting (OR=2.56; p< or =0.01), arrival by ambulance (OR=2.15; p< or =0.001), nausea (OR=1.92; p< or =0.02) and older age (OR=1.02; p< or =0.01). These data extend our knowledge regarding the use of CT during acute diagnosis and management of suspected mTBI patients. In addition to confirming previously reported risk factors of intracranial complication, geographical location of hospital and arrival mode were found to be significant predictors of CT use. The results suggest that the management patterns for acute mTBI are inconsistent. The implications of this are discussed.

Predicting outcome after severe traumatic brain injury using the serum S100B biomarker: Results using a single (24 h) time-point

Article

Mar 2009
RESUSCITATION

In recent years, biochemical markers have been employed to predict the outcome of patients with traumatic brain injury (TBI). In mild TBI, S100B has shown the most promise as a marker of outcome. The objective of this study in patients with severe TBI was to: show the range of serum S100B levels during the acute phase after trauma: determine if S100B has potential to discriminate favourable from unfavourable outcome in patients with similar brain injury severity scores and to establish an S100B 'cut-off' predictive for death. All patients with severe TBI, admitted to this neurointensive care unit within 24h of injury were eligible for inclusion in the study. One serum blood sample was obtained from each patient at the 24h post-injury time-point. S100B levels were measured using enzyme-linked immunosorbent assay. Injuries were coded using an internationally recognised injury severity scoring system (ISS). Three-month follow-up was undertaken with outcome assessed using the Glasgow outcome score (GOS). One hundred patients were recruited. Serum S100B levels ranged from 0.08 to 12.62microgL(-1) S100B levels were significantly higher in patients with a GOS of 1 (death) 2 and 3 (unfavourable outcome) compared with those with GOS 4 and 5 (good recovery). In this study a cut-off point of 0.53microgL(-1) has sensitivity of >80% and specificity of 60% to predict unfavourable outcome and 49% to predict death. In 100 patients studied with similar brain injury severity scores, serum S100B measured at the 24-h time-point after injury is significantly associated with outcome but a cut-off 0.53microgL(-1) does not have good prognostic performance.

Medical radiation exposure in the U.S. in 2006: Preliminary results

Article

Dec 2008
HEALTH PHYS

Medical radiation exposure of the U.S. population has not been systematically evaluated for almost 25 y. In 1982, the per capita dose was estimated to be 0.54 mSv and the collective dose 124,000 person-Sv. The preliminary estimates of the NCRP Scientific Committee 6-2 medical subgroup are that, in 2006, the per capita dose from medical exposure (not including dental or radiotherapy) had increased almost 600% to about 3.0 mSv and the collective dose had increased over 700% to about 900,000 person-Sv. The largest contributions and increases have come primarily from CT scanning and nuclear medicine. The 62 million CT procedures accounted for 15% of the total number procedures (excluding dental) and over half of the collective dose. Nuclear medicine accounted for about 4% of all procedures but 26% of the total collective dose. Medical radiation exposure is now approximately equal to natural background radiation.

Assessment and Prognosis of Coma after Head Injury

Article

Feb 1976

The Glasgow Coma Scale, based upon eye opening, verbal and motor responses has proved a practical and consistent means of monitoring the state of head injured patients. Observations made in the early stages after injury define the depth and duration of coma and, when combined with clinical features such as a patient's age and brain stem function, have been used to predict outcome. Series of cases in comparable depths of coma in Glasgow and the Netherlands showed remarkably similar outcomes at 3 months. Based upon observations made in the first 24 hours of coma after injury, data from 255 previous cases reliably predicted outcome in the majority of 92 new patients. The exceptions were patients with potential to recover who later developed complications: no patient did significantly better than predicted.

The Management of Mild and Moderate Head Injuries

Article

May 1991
NEUROSURG CLIN N AM

The majority of patients seeking medical care after head trauma have sustained injuries of mild or moderate severity, i.e., GCS scores of 13 to 15 or 9 to 12, respectively. Mortality rates under these circumstances are generally low; however, serious complications must be detected and treated early. The initial evaluation involves determination of level of consciousness and examination for the presence of focal neurologic deficits. Skull radiography has a limited role in the management of mild and moderate head injuries, but consideration must be given to local factors such as the availability of cranial CT. CT scanning is a safe, noninvasive, and generally cost-effective means of assessing patients at risk for developing intracranial complications. The role of MR imaging in evaluating minor head injuries is not yet established. Patients with an altered level of consciousness require hospitalization in essentially all cases. Selected patients with a GCS score of 15 also benefit from overnight hospitalization and observation. After mild and moderate head injury, significant neuropsychologic deficits are frequent, but are generally finite in their duration. Postconcussive symptoms are also generally self-limited. Although objective evidence suggests that structural brain damage results from mild injuries, the relationship between postconcussional symptoms and structural damage is unclear. Persistent postconcussional symptomatology probably arises from a combination of physiogenic and psychogenic causes. It is possible that early patient education and reassurance will reduce the incidence of prolonged postconcussional symptomatology.

Imaging after head trauma. Who needs what?

Article

Dec 1991
EMERG MED CLIN N AM

Decisions about the optimal imaging strategy in patients after acute head trauma can be based on clinical observations. Low-risk patients do not require radiographic imaging. CT is the procedure of choice for imaging moderate- and high-risk patients after head trauma. Because of its limited ability to guide therapy, plain skull radiography should be used sparingly; it may be useful in equivocal cases of bony injury not detected by CT or in selected moderate-risk patients (especially children under the age of 2 years). MR imaging rivals CT in the detection of intracranial injuries but is more expensive and cumbersome in seriously ill subjects and does not image bony structures. MR imaging is recommended after initial CT if subtle acute nonhemorrhagic and subacute hemorrhagic lesions are suspected, especially in the evaluation of child abuse. Otherwise, MR imaging is rarely needed in the emergency department management of acute head injury patients.

Radiographic Decision-Making by the Emergency Physician

Article

Sep 1985
EMERG MED CLIN N AM

Adrian E. Long

To assist emergency clinicians in appropriately requesting x-ray examinations of their patients, this article looks at the factors that affect the decision to order a radiograph, describes methods of determining the efficacy of a radiograph, discusses several radiographic studies frequently requested by emergency physicians and when they are most efficacious, and reviews the ways physician decision-making may be influenced to decrease radiographic wastage.

Assessment of Coma and Impaired Consciousness. A Practical Scale

Article

Aug 1974

A clinical scale has been evolved for assessing the depth and duration of impaired consciousness and coma. Three aspects of behaviour are independently measured—motor responsiveness, verbal performance, and eye opening. These can be evaluated consistently by doctors and nurses and recorded on a simple chart which has proved practical both in a neurosurgical unit and in a general hospital. The scale facilitates consultations between general and special units in cases of recent brain damage, and is useful also in defining the duration of prolonged coma.

The demonstration of new human brain-specific proteins by high-resolution 2D polyacrylamide gel electrophoresis

Article

Apr 1981
J NEUROL SCI

High-resolution multiple two-dimensional polyacrylamide gel electrophoresis (ISODALT) has been used to analyse soluble protein extracts from human brain and 12 other human organs. Approximately 200 protein gene products can be visualised on an electrophoretogram of soluble human brain proteins. By electrophoresing extracts of different human organs separately and mixed with brain extract, 8 proteins have been found which appear to be present in brain in concentrations at least 20 times greater than in any other organ. Four of these brain-specific proteins have been identified by co-electrophoresis with purified proteins as 14-3-2 protein, creatine kinase-BB isoenzyme, aldolase C4 isoenzyme, and 14-3-3 protein. The identities of the remaining 4 proteins are unknown.

Analysis of Wounds Incurred by U.S. Army Seventh Corps Personnel Treated in Corps Hospitals during Operation Desert Storm, February 20 to March 10, 1991

Article

Apr 1996
J TRAUMA

Michael E. Carey

One hundred and forty-three soldiers who received ballistic injury were actively treated at U.S. Army Seventh Corps hospitals during Operation Desert Storm. Ninety-five percent were wounded by fragments, 5% by bullets. Many had wounds of several body parts, including 17.3% who received a head wound; 4.3% a neck wound; 5.8% a chest wound; 9.3% an abdominal wound; and 90% who had extremity wounds. Three hospital deaths occurred--a 2.1% mortality rate. Only two soldiers sustained a brain wound; in both, the missile entered below the skull area protected by the Kevlar helmet. One brainwounded individual was treated and lived; the other died from hemorrhage and shock from concomitant traumatic lower-extremity amputations. The current U.S. helmet appears to provide significant protection from fragmenting ordnance as does the armored vest. Hemorrhage from proximal extremity wounds caused hospital deaths. Treatment of such wounds will have to be improved to reduce future combat mortality.

Serum Neuron–specific Enolase as a Prognostic Marker for Irreversible Brain Damage in Comatose Cardiac Arrest Survivors

Article

Mar 1996

Patrick R Martens

To assess the use of serum neuron-specific enolase (S-NSE) level as a noninvasive predictor of CNS injury irreversibility in comatose cardiac arrest survivors. An observational, prospective clinical study was performed in a community hospital ED and intensive care unit. All cardiac arrest survivors (n = 52) with impaired neurologic status admitted between February 1994 and May 1995 were followed until return of consciousness (1) or death due to CNS failure (0). Serum samples for S-NSE determination (ng/mL) using the radioimmunoassay technique were obtained 24 hours after cardiac arrest. Data were analyzed using stepwise logistic regression with dichotomized predictors to validate the correlation between S-NSE (X) and outcome (Y), where X = 0 if < or = median and 1 if > median S-NSE level. Adjustment was made for the following variables: glucose level on admission, total epinephrine dose used before return of spontaneous circulation, and best Glasgow Coma Scale score on admission. These data were all available in 34 cases. In 16 cases, CSF enzymes at 48 hours postarrest were obtained and compared with S-NSE. The logistic equation determining the influence of S-NSE (X) on outcome (Y) was: Y = 0.606-1.785X (odds ratio = 6; p = 0.020). There was no confounding effect of the other variables related to survival. The mean S-NSE value for all the patients was 34 (7.9-188). All the patients recovering consciousness (n = 15) had an S-NSE mean +/- SEM value of 17.5 +/- 2.4, with a maximum of 47. These data support the conclusion that measurement of S-NSE at 24 hours post-cardiac arrest may supplement clinical assessment of hypoxic-ischemic encephalopathy after cardiac arrest.

Sequential computerized tomography changes and related final outcome in severe head injury patients

Article

Feb 1997

The authors analysed the serial computerized tomography (CT) findings in a large series of severely head injured patients in order to assess the variability in gross intracranial pathology through the acute posttraumatic period and determine the most common patterns of CT change. A second aim was to compare the prognostic significance of the different CT diagnostic categories used in the study (Traumatic Coma Data Bank CT pathological classification) when gleaned either from the initial (postadmission) or the control CT scans, and determine the extent to which having a second CT scan provides more prognostic information than only one scan. 92 patients (13.3% of the total population) died soon after injury. Of the 587 who survived long enough to have at least one control CT scan 23.6% developed new diffuse brain swelling, and 20.9% new focal mass lesions most of which had to be evacuated. The relative risk for requiring a delayed operation as related to the diagnostic category established by using the initial CT scans was by decreasing order: diffuse injury IV (30.7%), diffuse injury III (30.5%), non evacuated mass (20%), evacuated mass (20.2%), diffuse injury II (12.1%), and diffuse injury I (8.6%). Overall, 51.2% of the patients developed significant CT changes (for worse or better) occurring either spontaneously or following surgery, and their final outcomes were more closely related to the control than to the initial CT diagnoses. In fact, the final outcome was more accurately predicted by using the control CT scans (81.2% of the cases) than by using the initial CT scans (71.5% of the cases only). Since the majority of relevant CT changes developed within 48 hours after injury a pathological categorization made by using an early control CT scan seems to be most useful for prognostic purposes. Prognosis associated with the CT pathological categories used in the study was similar independently of the moment of the acute posttraumatic period at which diagnoses were made.

Variation in ED Use of Computed Tomography for Patients With Minor Head Injury

Article

Aug 1997
ANN EMERG MED

To determine the frequency of utilization, yield for brain injury, incidence of missed injury, and variation in the use of computed tomography (CT) for ED patients with minor head injury. This retrospective health records survey was conducted over a 12-month period in the EDs at seven Canadian teaching institutions. Included in this review were adult patients who sustained acute minor head injury, defined as witnessed loss of consciousness or amnesia and a Glasgow Coma Scale score of 13 or greater. Data were collected by research assistants who were trained to select cases and abstract data in a standardized fashion according to a resource manual. Subsequently, patient eligibility was reviewed by the study coordinator and principal investigator. Of the 1,699 patients seen, 521 (30.7%) were referred for CT, and 418 (79.8%) of these scans were negative for any type of brain injury. Overall, 105 (6.2%) of these patients sustained acute brain injury, including 9 (.5%) with an epidural hematoma Cochran's Q test for homogeneity demonstrated significant variation between the seven centers for rate of ordering CT (P < .0001), from a low of 15.9% to a high of 70.4%. All five cases of "missed" hematoma occurred at the institutions with the highest and third highest rates of CT use. After controlling for possible differences in case severity and patient characteristics at each hospital, logistic regression analysis revealed that five of seven hospitals were significantly associated with the use of CT (respected odds ratios [OR], .4, .5, .5, 3.2, and 4.7). Three of the centers (two with the highest ordering rates) showed significant heterogeneity in the ordering of CT among their attending staff physicians, from a low of 6.5% to a high of 80.0%. There was considerable variation among institutions and individual physicians in the ordering of CT for patients with minor head injury. Although emergency physicians were selective when ordering CT, the yield of radiography was very low at all hospitals. None of the cases of "missed" intracranial hematoma came from the lowest ordering institutions, indicating that patients may be managed safely with a selective approach to CT use. These findings suggest great potential for more standardized and efficient use of CT of the head, possibly through the use of a clinical decision rule.

Return to play guidelines after a head injury

Article

Feb 1998
CLIN SPORT MED

Robert C Cantu

Presently there are no universally accepted definitions of the grades of concussion or criteria for when to allow the athlete to return to competition after a head injury. What is agreed upon is that in order to avoid cumulative brain damage and the second impact syndrome, no athlete still suffering post-concussion symptoms should return to competition. This article is meant to serve only as a guideline as the final decision in every instance is a clinical judgement.

Trauma Radiology: Part IV. Imaging of Acute Craniocerebral Trauma

Article

Nov 1994

Diagnostic imaging has a key role in diagnosis and management of patients sustaining craniocerebral injuries from trauma. We review the current role of skull radiography, computed tomography (CT), and magnetic resonance (MR) in imaging patients sustaining craniocerebral trauma, and we describe the appearance of major forms of pathology as depicted by each modality. CT scan is used to assess quickly the extent of injury and to triage patients to observation, medical, or neurosurgical management. CT findings can be divided into primary craniocerebral injuries, including skull fractures; extraaxial hematomas (subdural and epidural); intraparenchymal injury, such as hematoma, contusion, and diffuse axonal shearing; and intraventricular or subarachnoid hemorrhage. Secondary manifestations of injury, such as cerebral edema and herniation, are also identified, and their course can be followed by serial CT. CT is crucial in assessing the outcome of surgical intervention and in identifying potential delayed complications of either head trauma or surgical intervention, including infection, delayed hemorrhage, cerebral infarction, and tension pneumocephalus. In recent years, MRI has been shown to be valuable in diagnosing cerebral injury. MRI has generally been shown to have greater overall accuracy than CT in identifying and characterizing most forms of traumatic cerebral pathology, but it is less accurate at demonstrating subarachnoid hemorrhage acutely, pneumocephalus, and calvarial fractures, particularly those involving the skull base. Moreover, MRI is still more difficult to perform than CT in critically ill patients, and it is generally far more time-consuming. However, MRI is unequivocally more accurate than CT at revealing certain lesions, particularly brainstem contusion, diffuse axonal shearing, predominantly nonhemorrhagic contusions, and thin collections of blood adjacent to bone, and it should be used selectively when these injuries are suspected.

Structural basis for the specificity of Ub C-terminal hydrolases

Article

Aug 1999

The release of ubiquitin from attachment to other proteins and adducts is critical for ubiquitin biosynthesis, proteasomal degradation and other cellular processes. De-ubiquitination is accomplished in part by members of the UCH (ubiquitin C-terminal hydrolase) family of enzymes. We have determined the 2.25 A resolution crystal structure of the yeast UCH, Yuh1, in a complex with the inhibitor ubiquitin aldehyde (Ubal). The structure mimics the tetrahedral intermediate in the reaction pathway and explains the very high enzyme specificity. Comparison with a related, unliganded UCH structure indicates that ubiquitin binding is coupled to rearrangements which block the active-site cleft in the absence of authentic substrate. Remarkably, a 21-residue loop that becomes ordered upon binding Ubal lies directly over the active site. Efficiently processed substrates apparently pass through this loop, and constraints on the loop conformation probably function to control UCH specificity.

FORUM Neuropsychology of Sports-Related Head Injury: Dementia Pugilistica to Post Concussion Syndrome

Article

Jun 1999

This article reviews the existing literature in the following areas of sports neuropsychology: Dementia Pugilistica, concussion and Post Concussion Syndrome, Second Impact Syndrome, and the emerging role of the sports neuropsychologist regarding return to play decisions. Dementia Pugilistica is discussed as a condition that exists along a continuum: Although many boxers will develop mild neurocognitive deficits, it is not yet known what percent of these mild presentations will progress to diagnosable Dementia Pugilistica. Factors contributing to both increased and reduced risk are detailed. The role of neuropsychological assessment in research and clinical management is reviewed. Existing studies of concussion incurred during contact sports provide evidence of an important role for neuropsychology in assessment and management of mild head injuries. Issues in clinical assessment of concussion are reviewed. The importance of grading of concussions, monitoring of postconcussive symptom resolution, and the use of neuropsychological test results in return to play decisions is detailed. The Second Impact Syndrome is discussed with regard to return to play decisions. Recommendations are proposed for research and for clinical application of findings in sports neuropsychology.

The Canadian CT Head Rule for patients with minor head injury

Article

May 2001

There is much controversy about the use of computed tomography (CT) for patients with minor head injury. We aimed to develop a highly sensitive clinical decision rule for use of CT in patients with minor head injuries. We carried out this prospective cohort study in the emergency departments of ten large Canadian hospitals and included consecutive adults who presented with a Glasgow Coma Scale (GCS) score of 13-15 after head injury. We did standardised clinical assessments before the CT scan. The main outcome measures were need for neurological intervention and clinically important brain injury on CT. The 3121 patients had the following characteristics: mean age 38.7 years); GCS scores of 13 (3.5%), 14 (16.7%), 15 (79.8%); 8% had clinically important brain injury; and 1% required neurological intervention. We derived a CT head rule which consists of five high-risk factors (failure to reach GCS of 15 within 2 h, suspected open skull fracture, any sign of basal skull fracture, vomiting >2 episodes, or age >65 years) and two additional medium-risk factors (amnesia before impact >30 min and dangerous mechanism of injury). The high-risk factors were 100% sensitive (95% CI 92-100%) for predicting need for neurological intervention, and would require only 32% of patients to undergo CT. The medium-risk factors were 98.4% sensitive (95% CI 96-99%) and 49.6% specific for predicting clinically important brain injury, and would require only 54% of patients to undergo CT. We have developed the Canadian CT Head Rule, a highly sensitive decision rule for use of CT. This rule has the potential to significantly standardise and improve the emergency management of patients with minor head injury.

Penetrating Brain Injury In Military Conflict: Does It Merit More Research?

Article

Apr 2003

W Sapsford

The neurophysiology of brain injury

Article

Feb 2004
CLIN NEUROPHYSIOL

Michael Gaetz

This article reviews the mechanisms and pathophysiology of traumatic brain injury (TBI). Research on the pathophysiology of diffuse and focal TBI is reviewed with an emphasis on damage that occurs at the cellular level. The mechanisms of injury are discussed in detail including the factors and time course associated with mild to severe diffuse injury as well as the pathophysiology of focal injuries. Examples of electrophysiologic procedures consistent with recent theory and research evidence are presented. Acceleration/deceleration (A/D) forces rarely cause shearing of nervous tissue, but instead, initiate a pathophysiologic process with a well defined temporal progression. The injury foci are considered to be diffuse trauma to white matter with damage occurring at the superficial layers of the brain, and extending inward as A/D forces increase. Focal injuries result in primary injuries to neurons and the surrounding cerebrovasculature, with secondary damage occurring due to ischemia and a cytotoxic cascade. A subset of electrophysiologic procedures consistent with current TBI research is briefly reviewed. The pathophysiology of TBI occurs over time, in a pattern consistent with the physics of injury. The development of electrophysiologic procedures designed to detect specific patterns of change related to TBI may be of most use to the neurophysiologist. This article provides an up-to-date review of the mechanisms and pathophysiology of TBI and attempts to address misconceptions in the existing literature.

Traumatic Brain Injury in the War Zone

Article

Jun 2005
NEW ENGL J MED

Susan Okie

Ming-Xiong Huang, Sharon Nichols, Ashley Robb, Annemarie Angeles, Angela Drake, Martin Holland, Sarah Asmussen, John D'Andrea, Won Chun, Michael Levy, Li Cui, Tao Song, Dewleen G. Baker, Paul Hammer, Robert McLay, Rebecca J. Theilmann, Raul Coimbra, Mithun Diwakar, Cynthia Boyd, John Neff, Thomas T. Liu, Jennifer Webb-Murphy, Roxanna Farinpour, Catherine Cheung, Deborah L. Harrington, David Heister, Roland R. Lee. (2012) An automatic MEG low-frequency source imaging approach for detecting injuries in mild and moderate TBI patients with blast and non-blast causes. NeuroImage 61, 1067-1082 CrossRef

Serum S-100B and cleaved-tau are poor predictors of long-term outcome after mild traumatic brain injury

Article

Jul 2006

To determine the relationship of serum S-100B and C-tau levels to long-term outcome after mild traumatic brain injury (mild TBI). A prospective study of 35 mild TBI subjects presenting to the emergency department. Six hour serum S-100B and C-tau levels compared to 3-month Rivermead Post Concussion Questionnaire (RPCQ) scores and post-concussive syndrome (PCS). The linear correlation between marker levels and RPCQ scores was weak (S-100B: r = 0.071, C-tau: r = -0.21). There was no statistically significant correlation between marker levels and 3-month PCS (S-100B: AUC = 0.589, 95%CI. 038, 0.80; C-tau: AUC = 0.634, 95%CI 0.43, 0.84). The sensitivity of these markers ranged from 43.8-56.3% and the specificity from 35.7-71.4%. Initial serum S-100B and C-tau levels appear to be poor predictors of 3-month outcome after mild TBI.

Protein S-100 and neuropsychological functioning following severe traumatic brain injury

Article

Sep 2006

To examine the relationship between serum concentrations of protein S-100beta and neuropsychological functioning following severe traumatic brain injury. Matched control group. Blood samples were taken within 12 hours of injury and then daily up to 7 days post-injury (n=23). Within 2 weeks of emerging from post-traumatic amnesia (PTA), participants completed a battery of neuropsychological measures. These results were compared with a matched sample of healthy controls. Early measurement of S-100 not only reflected overall brain injury severity, but also related to neuropsychological deficits, with higher serum concentrations associated with poorer performance across most cognitive domains. PTA duration, measured by the Westmead PTA Scale, was found to be the strongest predictor of S-100 concentration (R2=0.59, p<0.001). These findings show that measurement of serum protein S-100 may further aid in the identification of individuals with severe TBI who are likely to experience cognitive difficulties.

The Role of Negative CT of the Abdomen and Pelvis in the Decision to Admit Adults From the Emergency Department After Blunt Trauma

Article

Nov 2005

Computed tomography (CT) is widely used in the initial evaluation of blunt trauma patients and is associated with a high rate of negative imaging. A described benefit of negative imaging is prompt discharge. This study examined a single level 1 trauma center to determine whether adult blunt trauma patients are discharged from the emergency department (ED) after negative CT of the abdomen and pelvis (CT AP). The authors retrospectively created a data set of adult blunt trauma patients who received CT AP in the ED from August to November 2003. Statistical analysis of admission rates on the basis of positivity or negativity on CT AP was performed to determine if the test influenced admission rates. Additional subgroup analysis was made between the patients admitted with negative CT AP and those who were discharged from the ED. Two thirds (316/469) had negative CT AP. Whereas 80.4% of the patients (254/316) with negative CT AP were admitted, 98.0% (148/151) with positive CT AP were admitted, a statistically significant difference in admission rate (P < .0001). The vast majority (208/254, 81.9%) of patients with negative CT AP were admitted for extra-abdominal injuries. There was no statistical difference in the characteristics of a subgroup of 45 patients who were admitted without any documented injuries from the group discharged from the ED in terms of age, gender, comorbidity, Glasgow Coma Scale score, or intoxication. Under current practice, negative CT AP after blunt trauma results in a statistically significant decrease in admissions.

Current concepts - Computed tomography - An increasing source of radiation exposure

Article

Dec 2007
NEW ENGL J MED

The number of computed tomographic (CT) studies performed is increasing rapidly. Because CT scans involve much higher doses of radiation than plain films, we are seeing a marked increase in radiation exposure in the general population. Epidemiologic studies indicate that the radiation dose from even two or three CT scans results in a detectable increase in the risk of cancer, especially in children. This article summarizes the facts about this form of radiation exposure and the implications for public health.

Hall EJ, Brenner DJCancer risks from diagnostic radiology. Br J Radiol 81(965): 362-378

Article

Jun 2008
BRIT J RADIOL

In recent years, there has been a rapid increase in the number of CT scans performed, both in the US and the UK, which has fuelled concern about the long-term consequences of these exposures, particularly in terms of cancer induction. Statistics from the US and the UK indicate a 20-fold and 12-fold increase, respectively, in CT usage over the past two decades, with per caput CT usage in the US being about five times that in the UK. In both countries, most of the collective dose from diagnostic radiology comes from high-dose (in the radiological context) procedures such as CT, interventional radiology and barium enemas; for these procedures, the relevant organ doses are in the range for which there is now direct credible epidemiological evidence of an excess risk of cancer, without the need to extrapolate risks from higher doses. Even for high-dose radiological procedures, the risk to the individual patient is small, so that the benefit/risk balance is generally in the patients' favour. Concerns arise when CT examinations are used without a proven clinical rationale, when alternative modalities could be used with equal efficacy, or when CT scans are repeated unnecessarily. It has been estimated, at least in the US, that these scenarios account for up to one-third of all CT scans. A further issue is the increasing use of CT scans as a screening procedure in asymptomatic patients; at this time, the benefit/risk balance for any of the commonly suggested CT screening techniques has yet to be established.

Structuralbasisforthespecificity of ubiquitin C-terminal hydrolases Papa et al

3877-3887

Johnstonsc
Riddlesm
Cohenre

JohnstonSC,RiddleSM,CohenRE,HillCP.Structuralbasisforthespecificity of ubiquitin C-terminal hydrolases. EMBO J. 1999;18:3877–3887. Papa et al. J Trauma Volume 72, Number 5 © 2012 Lippincott Williams & Wilkins 1344

The association between levels of a novel serum biomarker and severity of injury in patients with mild and moderate traumatic brain injury

L Papa
L Diaz
L Akinyi

Papa L, Diaz L, Akinyi L, et al. The association between levels of a novel serum biomarker and severity of injury in patients with mild and moderate traumatic brain injury [Abstract].

Cancer risks from diagnostic radiology.

Jan 2008
362

Hall

Hall EJ, Brenner DJ. Cancer risks from diagnostic radiology. Br J Radiol. May; 2008 81(965):362-378. [PubMed: 18440940]

Rehabilitation of persons with traumatic brain injury. NIH consensus development panel on rehabilitation of persons with traumatic brain injury.

Jan 1999
974

Consensus conference. Rehabilitation of persons with traumatic brain injury. NIH Consensus Development Panel on Rehabilitation of Persons With Traumatic Brain Injury. Jama. 1999; 282(10): 974-983. [PubMed: 10485684]

Serum levels of ubiquitin C-terminal hydrolase distinguish mild traumatic brain injury from trauma controls and are elevated in mild and moderate traumatic brain injury patients with intracranial lesions and neurosurgical intervention

Abstract

No full-text available

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