Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 as Outcome Predictors in Traumatic Brain Injury

doi:10.1016/j.wneu.2015.10.066

World Neurosurgery

Volume 87, March 2016, Pages 8-20

https://doi.org/10.1016/j.wneu.2015.10.066 Get rights and content

Objective

Biomarkers ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) may help detect brain injury, assess its severity, and improve outcome prediction. This study aimed to evaluate the prognostic value of these biomarkers during the first days after brain injury.

Methods

Serum UCH-L1 and GFAP were measured in 324 patients with traumatic brain injury (TBI) enrolled in a prospective study. The outcome was assessed using the Glasgow Outcome Scale (GOS) or the extended version, Glasgow Outcome Scale–Extended (GOSE).

Results

Patients with full recovery had lower UCH-L1 concentrations on the second day and patients with favorable outcome had lower UCH-L1 concentrations during the first 2 days compared with patients with incomplete recovery and unfavorable outcome. Patients with full recovery and favorable outcome had significantly lower GFAP concentrations in the first 2 days than patients with incomplete recovery or unfavorable outcome. There was a strong negative correlation between outcome and UCH-L1 in the first 3 days and GFAP levels in the first 2 days. On arrival, both UCH-L1 and GFAP distinguished patients with GOS score 1–3 from patients with GOS score 4–5, but not patients with GOSE score 8 from patients with GOSE score 1–7. For UCH-L1 and GFAP to predict unfavorable outcome (GOS score ≤3), the area under the receiver operating characteristic curve was 0.727, and 0.723, respectively. Neither UCHL-1 nor GFAP was independently able to predict the outcome when age, worst Glasgow Coma Scale score, pupil reactivity, Injury Severity Score, and Marshall score were added into the multivariate logistic regression model.

Conclusions

GFAP and UCH-L1 are significantly associated with outcome, but they do not add predictive power to commonly used prognostic variables in a population of patients with TBI of varying severities.

Introduction

Traumatic brain injury (TBI) is a heterogeneous disease,¹ and diagnostic tools are limited. Imaging studies do not reveal all injuries,² and some patients with mild TBI and no visible lesions have permanent symptoms. Consequently, specific biochemical markers that would reveal even the mildest brain injury, help in assessing severity,3, 4 improve existing outcome prediction models,⁵ and monitor treatment efficacy are needed. S-100β has been a candidate biomarker,⁶ but it has low sensitivity6, 7 and lacks brain specificity.8, 9, 10

Ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) are promising new TBI biomarkers. GFAP is an intermediate filament protein of astroglial skeleton⁷ and represents glial injury.¹¹ Neuronal UCH-L1 is involved in either adding or removing ubiquitin from proteins¹² and represents neuronal injury.3, 13 Increased UCH-L1 concentrations have been linked to injury severity and worse outcome after TBI.14, 15, 16 GFAP has been found to correlate with axonal injury, elevated intracranial pressure, and mortality17, 18, 19 and has outperformed S-100β in detecting intracranial injuries on head computed tomography (CT) scans of patients with extracranial injuries.20, 21 Biomarkers may also help in identifying the injury types, as UCH-L1 seems to increase more in diffuse injuries, and GFAP seems to increase more in mass lesions.¹⁵ The aim of the present study was to assess whether UCH-L1 and GFAP concentrations during the first days after injury correlate with outcome of patients with TBI.

Section snippets

Patient Population

This prospective multicenter study was part of the European Union–funded TBIcare (Evidence-based Diagnostic and Treatment Planning Solution for Traumatic Brain Injuries) project. The ethical review board of the Hospital District of South-West Finland, the Cambridgeshire 2 Research Ethics Committee, and the Norfolk Research Ethics Committee approved the study. All patients or their proxies were given oral and written information about the study, and a written informed consent was obtained. All

Results

Biomarkers were evaluated from 324 patients with a mean age of 45.3 years ± 19.2 (73.8% male). Most patients had mild TBI, and one third had severe TBI. The patient characteristics are presented in Table 1. Injuries were mostly related to falls and traffic accidents. Most patients (88.9%) had available GOSE scores, and slightly more patients (92.3%) had available GOS scores. Numbers of available GOSE and GOS scores differ because general practitioners assessed some of the patients using only

Discussion

Patients with incomplete recovery and unfavorable outcome showed higher levels of UCH-L1 and GFAP during the acute phase after TBI, and there was a strong negative correlation between the outcome and admission levels of UCH-L1 and GFAP. Furthermore, both UCH-L1 and GFAP obtained on arrival were able to distinguish patients with GOS score 1–3 from patients with GOS score 4–5. In addition, GFAP distinguished patients who died from patients who survived. However, neither UCH-L1 nor GFAP was

Conclusions

Our results from patients representing the entire TBI severity spectrum suggest that both GFAP and UCH-L1 are significantly associated with outcome. However, GFAP and UCH-L1 do not add predictive power to commonly used prognostic clinical and imaging variables, at least not in a population of patients with varying severities of TBI. Further studies are warranted to find optimal cutoff values with higher sensitivity and specificity. Even after such studies, the true value of these biomarkers in

Acknowledgments

The authors thank Patricia Bertényi, R.N., and Satu Timlin, R.N., for their valuable work and effort during the recruitment period and during data collection and analysis.

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This narrative review discusses the potential clinical applications of core BBBMs in TBI. A literature search in PubMed, Scopus, and ISI Web of Knowledge focused on articles in English with the words “traumatic brain injury” together with the words “blood biomarkers”, “diagnostics”, “outcome prediction”, “extracranial injury” and “assay method” alone-, or in combination.
Glial fibrillary acidic protein (GFAP) combined with Ubiquitin C-terminal hydrolase-L1(UCH-L1) has received FDA clearance to aid computed tomography (CT)-detection of brain lesions in mild (m) TBI. Application of S100B led to reduction of head CT scans. GFAP may also predict magnetic resonance imaging (MRI) abnormalities in CT-negative cases of TBI. Further, UCH-L1, S100B, Neurofilament light (NF-L), and total tau showed value for predicting mortality or unfavourable outcome. Nevertheless, biomarkers have less role in outcome prediction in mTBI. S100B could serve as a tool in the multimodality monitoring of patients in the neurointensive care unit.
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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.
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We used data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core study. We included patients aged 14 years or older who had blood sampling within 24 h of injury, results from a CT scan, and outcome assessment according to the Glasgow Outcome Scale-Extended (GOSE) at 6 months. Amounts in serum of six biomarkers (S100 calcium-binding protein B, neuron-specific enolase, glial fibrillary acidic protein, ubiquitin C-terminal hydrolase L1 [UCH-L1], neurofilament protein-light, and total tau) were measured. The incremental prognostic value of these biomarkers was determined separately and in combination. The primary outcome was the GOSE 6 months after injury. Incremental prognostic value, using proportional odds and a dichotomised analysis, was assessed by delta C-statistic and delta R² between models with and without serum biomarkers, corrected for optimism with a bootstrapping procedure.
Serum biomarker values and 6-month GOSE were available for 2283 of 4509 patients. Higher biomarker levels were associated with worse outcome. Adding biomarkers improved the C-statistic by 0·014 (95% CI 0·009–0·020) and R² by 4·9% (3·6–6·5) for predicting GOSE compared with demographic, clinical, and radiological characteristics. UCH-L1 had the greatest incremental prognostic value. Adding biomarkers to established prognostic models resulted in a relative increase in R² of 48–65% for IMPACT and 30–34% for CRASH prognostic models.
Serum biomarkers have incremental prognostic value for functional outcome after traumatic brain injury. Our findings support integration of biomarkers—particularly UCH-L1—in established prognostic models.
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This is a single-center retrospective observational study of 179 patients with severe multiple trauma. The GFAP and S100β were measured upon patient arrival at the hospital. We divided the patients into the severe TBI group (with a Traumatic Coma Data Bank classification of ≥III), the non-severe TBI group (non-TBI group [absence of abnormality on the computed tomography scan and extracranial injury], and the mild to moderate TBI group [TCDB classification I and II]). We compared biomarker levels between the two groups and then evaluated the accuracy of predicting severe TBI using a receiver operating characteristic curve.
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The Clinical Use of Serum Biomarkers in Traumatic Brain Injury: A Systematic Review Stratified by Injury Severity
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Citation Excerpt :
NSE similarly predicted unfavorable outcomes; however, it was particularly accurate in discriminating between death (GOS 1) and unfavorable outcomes (GOS 2–5).103 On day 1 after TBI, the values of UCH-L1 and GFAP were significantly associated with unfavorable outcomes and on days 2 and 3 UCH-L1 was a significant predictor of death (GOS 1).70 Regarding TBI diagnosis across all severities, the number of articles providing statistically significant data in support of well-known markers such as Tau, S100B, GFAP, and UCH-L1 suggest that their values may exist on a scale directly correlated with severity.
Serum biomarkers have gained significant popularity as an adjunctive measure in the evaluation and prognostication of traumatic brain injury (TBI). However, a concise and clinically oriented report of the major markers in function of TBI severity is lacking. This systematic review aims to report current data on the diagnostic and prognostic utility of blood-based biomarkers across the spectrum of TBI.
A literature search of the PubMed/Medline electronic database was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We excluded systematic reviews and meta-analyses that did not provide novel data. The American College of Cardiology/American Heart Association criteria were used to assess levels of evidence.
An initial 1463 studies were identified. In total, 115 full-text articles reporting on 94 distinct biomarkers met the inclusion criteria. Glasgow Coma Scale scores, computed tomography/magnetic resonance imaging abnormalities, and injury severity scores were the most used clinical diagnostic variables. Glasgow Outcome Scores and 1-, 3-, and 6-month mortality were the most used clinical prognostic variables. Several biomarkers significantly correlated with these variables and had statistically significant different levels in TBI subjects when compared with healthy, orthopedic, and polytrauma controls. The biomarkers also displayed significant variability across mild, moderate, and severe TBI categories, as well as in concussion cases.
This review summarizes existing high-quality evidence that supports the use of severity-specific biomarkers in the diagnostic and prognostic evaluation of TBI. These data can be used as a launching platform for the validation of upcoming clinical studies.
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A biomarker is a characteristic that can be objectively measured as an indicator of normal biologic processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions. Biomarker modalities include molecular, histologic, radiographic, or physiologic characteristics. To improve the understanding and use of biomarker terminology in biomedical research, clinical practice, and medical product development, the Food and Drug Administration (FDA)–National Institutes of Health (NIH) Joint Leadership Council developed the BEST Resource (Biomarkers, EndpointS, and other Tools). The seven BEST biomarker categories include the following: (a) susceptibility/risk biomarkers, (b) diagnostic biomarkers, (c) monitoring biomarkers, (d) prognostic biomarkers, (e) predictive biomarkers, (f) pharmacodynamic/response biomarkers, and (g) safety biomarkers. We hypothesize some potential overlap between the reported biomarkers of traumatic brain injury (TBI), epilepsy, and posttraumatic epilepsy (PTE). Here, we tested this hypothesis by reviewing studies focusing on biomarker discovery for posttraumatic epileptogenesis and epilepsy. The biomarker modalities reviewed here include plasma/serum and cerebrospinal fluid molecular biomarkers, imaging biomarkers, and electrophysiologic biomarkers. Most of the reported biomarkers have an area under the receiver operating characteristic curve greater than 0.800, suggesting both high sensitivity and high specificity. Our results revealed little overlap in the biomarker candidates between TBI, epilepsy, and PTE. In addition to using single parameters as biomarkers, machine learning approaches have highlighted the potential for utilizing patterns of markers as biomarkers. Although published data suggest the possibility of identifying biomarkers for PTE, we are still in the early phase of the development curve. Many of the seven biomarker categories lack PTE-related biomarkers. Thus, further exploration using proper, statistically powered, and standardized study designs with validation cohorts, and by developing and applying novel analytical methods, is needed for PTE biomarker discovery.

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: Conflict of interest statement: This work was partially funded by the European Commission under the 7th Framework Programme (FP7-270259-TBIcare), the United Kingdom National Institute of Health Research Biomedical Research Centre at Cambridge, and a personal EVO grant (R.S.K.T.) from Hospital District of South-West Finland. V.F.N. is supported by a Health Foundation/Academy of Medical Sciences Clinician Scientist Fellowship. J.O., J.P.C., P.H., and D.K.M. were supported by the United Kingdom National Institute of Health Research Biomedical Research Centre at Cambridge, and D.K.M. was also supported by a Senior Investigator Award from the United Kingdom National Institute of Health Research.

: R.S.K.T. has received speaker's fees from Abbott, Baxter, Fresenius-Kabi, and UCB; has received financial support in the form of a congress fee and travel expenses paid by Pfizer; and is a stockholder of Orion. J.P.P. has received financial support in the form of a congress fee and travel expenses paid by Skulle Implants Ltd., J.F. is member of the board of directors in BonAlive Biomaterials Ltd., P.J.H. is a director of Technicam. O.T. has received speaker's fees from Orion. The remaining authors have no financial disclosures.

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Original ArticleGlial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 as Outcome Predictors in Traumatic Brain Injury

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Patient Population

Results

Discussion

Conclusions

Acknowledgments

Moderate and severe traumatic brain injury in adults

Lancet Neurol

Imaging concussion

Neurosurgery

Predictive markers in traumatic brain injury: opportunities for a serum biosignature

Br J Neurosurg

Clinical neuroproteomics and biomarkers

Neurosurgery

Brain injury biomarkers may improve the predictive power of the IMPACT outcome calculator

J Neurotrauma

Predictive value of S-100 protein for prognosis in patients with moderate and severe traumatic brain injury: systematic review and meta-analysis

BMJ

The use of serum biomarkers to predict outcome after traumatic brain injury in adults and children

J Head Trauma Rehabil

Serum S100β increases in marathon runners reflect extracranial release rather than glial damage

Neurology

The S100 protein family: history, function, and expression

Brain Res Bull

How does extracerebral trauma affect the clinical value of S100B measurements?

Emerg Med J

Update on protein biomarkers in traumatic brain injury with emphasis on clinical use in adults and pediatrics

Acta Neurochir (Wien)

Clinical utility of serum levels of ubiquitin C-terminal hydrolase as a biomarker for severe traumatic brain injury

Neurosurgery

Biomarkers for the diagnosis, prognosis, and evaluation of treatment efficacy for traumatic brain injury

Neurotherapeutics

Acute biomarkers of traumatic brain injury: relationship between plasma levels of ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein

J Neurotrauma

Neuronal and glial markers are differently associated with computed tomography findings and outcome in patients with severe traumatic brain injury: a case control study

Crit Care

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

Crit Care Med

GFAP versus S100B in serum after traumatic brain injury: relationship to brain damage and outcome

J Neurotrauma

GFAP and S100B are biomarkers of traumatic brain injury: an observational cohort study

Neurology

Original Article
Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 as Outcome Predictors in Traumatic Brain Injury