Dataset Information

Study protocol for investigating the performance of an automated blood test measuring GFAP and UCH-L1 in a prospective observational cohort of patients with mild traumatic brain injury: European BRAINI study.

ABSTRACT:

Introduction

Mild traumatic brain injury (mTBI) is a common cause of clinical consultation in the emergency department. Patients with mTBI may undergo brain CT scans based on clinical criteria. However, the proportion of patients with brain lesions on CT is very low. Two serum biomarkers, glial fibrillar acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), have been shown to discriminate patients regarding the presence or absence of brain lesions on initial CT scan when assessed within the first 12 hours after TBI. However, the current technique for measuring serum concentrations of GFAP and UCH-L1 is manual and time consuming, which may hinder its use in routine clinical practice. This study assesses the diagnostic accuracy of an automated assay for the measurement of serum GFAP and UCH-L1 in a cohort of patients with mTBI who received a CT scan as the standard of care.

Methods and analysis

This is a prospective multicentre observational study of 1760 patients with mTBI recruited in France and Spain across 16 participating sites. Adult patients with an initial Glasgow Coma Scale score of 13-15 and a brain CT scan underwent blood sampling within 12 hours after TBI. The primary outcome measure is the diagnostic performance of an automated assay measuring serum concentrations of GFAP and UCH-L1 for discriminating between patients with positive and negative findings on brain CT-scans. Secondary outcome measures include the performance of these two biomarkers in predicting the neurological status and quality of life at 1?week and 3 months after the trauma.

Ethics and dissemination

Ethics approval was obtained by the Institutional Review Board of Sud-Ouest Outre Mer III in France (Re#2019-A01525-52) and Hospital 12 de Octubre in Spain (Re#19/322). The results will be presented at scientific meetings and published in peer-reviewed publications.

Trial registration number

ClinicalTrials.gov: NCT04032509.

SUBMITTER: Richard M

PROVIDER: S-EPMC7908910 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Study protocol for investigating the performance of an automated blood test measuring GFAP and UCH-L1 in a prospective observational cohort of patients with mild traumatic brain injury: European BRAINI study.

Richard Marion M Lagares Alfonso A Bondanese Victor V de la Cruz Javier J Mejan Odile O Pavlov Vladislav V Payen Jean-François JF

BMJ open 20210225 2

<h4>Introduction</h4>Mild traumatic brain injury (mTBI) is a common cause of clinical consultation in the emergency department. Patients with mTBI may undergo brain CT scans based on clinical criteria. However, the proportion of patients with brain lesions on CT is very low. Two serum biomarkers, glial fibrillar acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), have been shown to discriminate patients regarding the presence or absence of brain lesions on initial CT scan ...[more]

PMID: 33632753

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Project description: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.

Project description:ImportanceData on the performance of traumatic brain injury (TBI) biomarkers within minutes of injury are lacking.ObjectivesTo 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 participantsThis 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 measuresThe 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.ResultsOf 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 relevanceIn 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.

Project description:Traumatic brain injury (TBI) results in neuronal, axonal and glial damage. Interventions targeting neuroinflammation to enhance recovery from TBI are needed. Exercise is known to improve cognitive function in TBI patients. Omega-3 fatty acids and vitamin D reportedly reduce inflammation, and in combination, might improve TBI outcomes. This study examined how an anti-inflammatory diet affected plasma TBI biomarkers, voluntary exercise and behaviors following exposure to mild TBI (mTBI). Adult, male rats were individually housed in cages fitted with running wheels and daily running distance was recorded throughout the study. A modified weight drop method induced mTBI, and during 30 days post-injury, rats were fed diets supplemented with omega-3 fatty acids and vitamin D3 (AIDM diet), or non-supplemented AIN-76A diets (CON diet). Behavioral tests were periodically conducted to assess functional deficits. Plasma levels of Total tau (T-tau), glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1) and neurofilament light chain (NF-L) were measured at 48 h, 14 days, and 30 days post-injury. Fatty acid composition of food, plasma, and brain tissues was determined. In rats exposed to mTBI, NF-L levels were significantly elevated at 48 h post-injury (P < 0.005), and decreased to levels seen in uninjured rats by 14 days post-injury. T-tau, GFAP, and UCH-L1 plasma levels did not change at 48 h or 14 days post-injury. However, at 30 days post-injury, T-tau, GFAP and UCH-L1 all significantly increased in rats exposed to mTBI and fed CON diets (P < 0.005), but not in rats fed AIDM diets. Behavioral tests conducted post-injury showed that exercise counteracted cognitive deficits associated with mTBI. The AIDM diets significantly increased docosahexaenoic acid levels in plasma and brain tissue (P < 0.05), and in serum levels of vitamin D (P < 0.05). The temporal response of the four injury biomarkers examined is consistent with studies by others demonstrating acute and chronic neural tissue damage following exposure to TBI. The anti-inflammatory diet significantly altered the temporal profiles of plasma T-tau, GFAP, and UCH-L1 following mTBI. Voluntary exercise protected against mTBI-induced cognitive deficits, but had no impact on plasma levels of neurotrauma biomarkers. Thus, the prophylactic effect of exercise, when combined with an anti-inflammatory diet, may facilitate recovery in patients with mTBI.

Project description:ImportanceGlial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) have been widely studied and show promise for clinical usefulness in suspected traumatic brain injury (TBI) and concussion. Understanding their diagnostic accuracy over time will help translate them into clinical practice.ObjectivesTo evaluate the temporal profiles of GFAP and UCH-L1 in a large cohort of trauma patients seen at the emergency department and to assess their diagnostic accuracy over time, both individually and in combination, for detecting mild to moderate TBI (MMTBI), traumatic intracranial lesions on head computed tomography (CT), and neurosurgical intervention.Design, setting, and participantsThis prospective cohort study enrolled adult trauma patients seen at a level I trauma center from March 1, 2010, to March 5, 2014. All patients underwent rigorous screening to determine whether they had experienced an MMTBI (blunt head trauma with loss of consciousness, amnesia, or disorientation and a Glasgow Coma Scale score of 9-15). Of 3025 trauma patients assessed, 1030 met eligibility criteria for enrollment, and 446 declined participation. Initial blood samples were obtained in 584 patients enrolled within 4 hours of injury. Repeated blood sampling was conducted at 4, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180 hours after injury.Main outcomes and measuresDiagnosis of MMTBI, presence of traumatic intracranial lesions on head CT scan, and neurosurgical intervention.ResultsA total of 1831 blood samples were drawn from 584 patients (mean [SD] age, 40 [16] years; 62.0% [362 of 584] male) over 7 days. Both GFAP and UCH-L1 were detectible within 1 hour of injury. GFAP peaked at 20 hours after injury and slowly declined over 72 hours. UCH-L1 rose rapidly and peaked at 8 hours after injury and declined rapidly over 48 hours. Over the course of 1 week, GFAP demonstrated a diagnostic range of areas under the curve for detecting MMTBI of 0.73 (95% CI, 0.69-0.77) to 0.94 (95% CI, 0.78-1.00), and UCH-L1 demonstrated a diagnostic range of 0.30 (95% CI, 0.02-0.50) to 0.67 (95% CI, 0.53-0.81). For detecting intracranial lesions on CT, the diagnostic ranges of areas under the curve were 0.80 (95% CI, 0.67-0.92) to 0.97 (95% CI, 0.93-1.00)for GFAP and 0.31 (95% CI, 0-0.63) to 0.77 (95% CI, 0.68-0.85) for UCH-L1. For distinguishing patients with and without a neurosurgical intervention, the range for GFAP was 0.91 (95% CI, 0.79-1.00) to 1.00 (95% CI, 1.00-1.00), and the range for UCH-L1 was 0.50 (95% CI, 0-1.00) to 0.92 (95% CI, 0.83-1.00).Conclusions and relevanceGFAP performed consistently in detecting MMTBI, CT lesions, and neurosurgical intervention across 7 days. UCH-L1 performed best in the early postinjury period.

Project description:BackgroundThe prognostic value of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) as day-of-injury predictors of functional outcome after traumatic brain injury is not well understood. GFAP is a protein found in glial cells and UCH-L1 is found in neurons, and these biomarkers have been cleared to aid in decision making regarding whether brain CT should be performed after traumatic brain injury. We aimed to quantify their prognostic accuracy and investigate whether these biomarkers contribute novel prognostic information to existing clinical models.MethodsWe enrolled patients from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) observational cohort study. TRACK-TBI includes patients 17 years and older who are evaluated for TBI at 18 US level 1 trauma centres. All patients receive head CT at evaluation, have adequate visual acuity and hearing preinjury, and are fluent in either English or Spanish. In our analysis, we included participants aged 17-90 years who had day-of-injury plasma samples for measurement of GFAP and UCH-L1 and completed 6-month assessments for outcome due to traumatic brain injury with the Glasgow Outcome Scale-Extended (GOSE-TBI). Biomarkers were analysed as continuous variables and in quintiles. This study is registered with ClinicalTrials.gov, NCT02119182.FindingsWe enrolled 2552 patients from Feb 26, 2014, to Aug 8, 2018. Of the 1696 participants with brain injury and data available at baseline and at 6 months who were included in the analysis, 120 (7·1%) died (GOSE-TBI=1), 235 (13·9%) had an unfavourable outcome (ie, GOSE-TBI ≤4), 1135 (66·9%) had incomplete recovery (ie, GOSE-TBI <8), and 561 (33·1%) recovered fully (ie, GOSE-TBI=8). The area under the curve (AUC) of GFAP for predicting death at 6 months in all patients was 0·87 (95% CI 0·83-0·91), for unfavourable outcome was 0·86 (0·83-0·89), and for incomplete recovery was 0·62 (0·59-0·64). The corresponding AUCs for UCH-L1 were 0·89 (95% CI 0·86-0·92) for predicting death, 0·86 (0·84-0·89) for unfavourable outcome, and 0·61 (0·59-0·64) for incomplete recovery at 6 months. AUCs were higher for participants with traumatic brain injury and Glasgow Coma Scale (GCS) score of 3-12 than for those with GCS score of 13-15. Among participants with GCS score of 3-12 (n=353), adding GFAP and UCH-L1 (alone or combined) to each of the three International Mission for Prognosis and Analysis of Clinical Trials in traumatic brain injury models significantly increased their AUCs for predicting death (AUC range 0·90-0·94) and unfavourable outcome (AUC range 0·83-0·89). However, among participants with GCS score of 13-15 (n=1297), adding GFAP and UCH-L1 to the UPFRONT study model modestly increased the AUC for predicting incomplete recovery (AUC range 0·69-0·69, p=0·025).InterpretationIn addition to their known diagnostic value, day-of-injury GFAP and UCH-L1 plasma concentrations have good to excellent prognostic value for predicting death and unfavourable outcome, but not for predicting incomplete recovery at 6 months. These biomarkers contribute the most prognostic information for participants presenting with a GCS score of 3-12.FundingUS National Institutes of Health, National Institute of Neurologic Disorders and Stroke, US Department of Defense, One Mind, US Army Medical Research and Development Command.

Project description:Objectives:To evaluate the ability of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1) to detect concussion in children and adult trauma patients with a normal mental status and assess biomarker concentrations over time as gradients of injury in concussive and non-concussive head and body trauma. Design:Large prospective cohort study. Setting:Three level I trauma centres in the USA. Participants:Paediatric and adult trauma patients of all ages, with and without head trauma, presenting with a normal mental status (Glasgow Coma Scale score of 15) within 4?hours of injury. Rigorous screening for concussive symptoms was conducted. Of 3462 trauma patients screened, 751 were enrolled and 712 had biomarker data. 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?hours postinjury in adults. Main outcomes:Detection of concussion and gradients of injury in children versus adults by comparing three groups of patients: (1) those with concussion; (2) those with head trauma without overt signs of concussion (non-concussive head trauma controls) and (3) those with peripheral (body) trauma without head trauma or concussion (non-concussive body trauma controls). Results:A total of 1904 samples from 712 trauma patients were analysed. Within 4?hours of injury, there were incremental increases in levels of both GFAP and UCH-L1 from non-concussive body trauma (lowest), to mild elevations in non-concussive head trauma, to highest levels in patients with concussion. In concussion patients, GFAP concentrations were significantly higher compared with body trauma controls (p<0.001) and with head trauma controls (p<0.001) in both children and adults, after controlling for multiple comparisons. However, for UCH-L1, there were no significant differences between concussion patients and head trauma controls (p=0.894) and between body trauma and head trauma controls in children. The AUC for initial GFAP levels to detect concussion was 0.80 (0.73-0.87) in children and 0.76 (0.71-0.80) in adults. This differed significantly from UCH-L1 with AUCs of 0.62 (0.53-0.72) in children and 0.69 (0.64-0.74) in adults. Conclusions:In a cohort of trauma patients with normal mental status, GFAP outperformed UCH-L1 in detecting concussion in both children and adults. Blood levels of GFAP and UCH-L1 showed incremental elevations across three injury groups: from non-concussive body trauma, to non-concussive head trauma, to concussion. However, UCH-L1 was expressed at much higher levels than GFAP in those with non-concussive trauma, particularly in children. Elevations in both biomarkers in patients with non-concussive head trauma may be reflective of a subconcussive brain injury. This will require further study.

Dataset Information

Study protocol for investigating the performance of an automated blood test measuring GFAP and UCH-L1 in a prospective observational cohort of patients with mild traumatic brain injury: European BRAINI study.

Introduction

Methods and analysis

Ethics and dissemination

Trial registration number

Publications

Study protocol for investigating the performance of an automated blood test measuring GFAP and UCH-L1 in a prospective observational cohort of patients with mild traumatic brain injury: European BRAINI study.

Similar Datasets

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