Dataset Information

Magnetic Resonance Imaging Pilot Study of Intravenous Glyburide in Traumatic Brain Injury.

ABSTRACT: Pre-clinical studies of traumatic brain injury (TBI) show that glyburide reduces edema and hemorrhagic progression of contusions. We conducted a small Phase II, three-institution, randomized placebo-controlled trial of subjects with TBI to assess the safety and efficacy of intravenous (IV) glyburide. Twenty-eight subjects were randomized and underwent a 72-h infusion of IV glyburide or placebo, beginning within 10?h of trauma. Of the 28 subjects, 25 had Glasgow Coma Scale (GCS) scores of 6-10, and 14 had contusions. There were no differences in adverse events (AEs) or severe adverse events (ASEs) between groups. The magnetic resonance imaging (MRI) percent change at 72-168?h from screening/baseline was compared between the glyburide and placebo groups. Analysis of contusions (7 per group) showed that lesion volumes (hemorrhage plus edema) increased 1036% with placebo versus 136% with glyburide (p?=?0.15), and that hemorrhage volumes increased 11.6% with placebo but decreased 29.6% with glyburide (p?=?0.62). Three diffusion MRI measures of edema were quantified: mean diffusivity (MD), free water (FW), and tissue MD (MDt), corresponding to overall, extracellular, and intracellular water, respectively. The percent change with time for each measure was compared in lesions (n?=?14) versus uninjured white matter (n?=?24) in subjects receiving placebo (n?=?20) or glyburide (n?=?18). For placebo, the percent change in lesions for all three measures was significantly different compared with uninjured white matter (analysis of variance [ANOVA], p?

SUBMITTER: Eisenberg HM

PROVIDER: S-EPMC6921286 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Magnetic Resonance Imaging Pilot Study of Intravenous Glyburide in Traumatic Brain Injury.

Eisenberg Howard M HM Shenton Martha E ME Pasternak Ofer O Simard J Marc JM Okonkwo David O DO Aldrich Christina C He Feng F Jain Sonia S Hayman Erik G EG

Journal of neurotrauma 20190827 1

Pre-clinical studies of traumatic brain injury (TBI) show that glyburide reduces edema and hemorrhagic progression of contusions. We conducted a small Phase II, three-institution, randomized placebo-controlled trial of subjects with TBI to assess the safety and efficacy of intravenous (IV) glyburide. Twenty-eight subjects were randomized and underwent a 72-h infusion of IV glyburide or placebo, beginning within 10 h of trauma. Of the 28 subjects, 25 had Glasgow Coma Scale (GCS) scores of 6-10, a ...[more]

PMID: 31354055

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Project description:Novel and non-routine tasks often require information processing and behavior to adapt from moment to moment depending on task requirements and current performance. This ability to adapt is an executive function that is referred to as cognitive control. Patients with moderate-to-severe traumatic brain injury (TBI) have been reported to exhibit impairments in cognitive control and functional magnetic resonance imaging (fMRI) has provided evidence for TBI-related alterations in brain activation using various fMRI cognitive control paradigms. There is some support for greater and more extensive cognitive control-related brain activation in patients with moderate-to-severe TBI, relative to comparison subjects without TBI. In addition, some studies have reported a correlation between these activation increases and measures of injury severity. Explanations that have been proposed for increased activation within structures that are thought to be directly involved in cognitive control, as well as the extension of this over-activation into other brain structures, have included compensatory mechanisms, increased demand upon normal processes required to maintain adequate performance, less efficient utilization of neural resources, and greater vulnerability to cognitive fatigue. Recent findings are also consistent with the possibility that activation increases within some structures, such as the posterior cingulate gyrus, may reflect a failure to deactivate components of the default mode network (DMN) and that some cognitive control impairment may result from ineffective coordination between the DMN and components of the salience network. Functional neuroimaging studies examining cognitive control-related activation following mild TBI (mTBI) have yielded more variable results, with reports of increases, decreases, and no significant change. These discrepancies may reflect differences among the various mTBI samples under study, recovery of function in some patients, different task characteristics, and the presence of comorbid conditions such as depression and posttraumatic stress disorder that also alter brain activation. There may be mTBI populations with activation changes that overlap with those found following more severe injuries, including symptomatic mTBI patients and those with acute injuries, but future research to address such dysfunction will require well-defined samples with adequate controls for injury characteristics, comorbid disorders, and severity of post-concussive symptoms.

Project description:Background and Objectives: The annual global incidence of traumatic brain injury (TBI) is over 10 million. An estimated 29% of TBI patients with negative computed tomography (CT-) have positive magnetic resonance imaging (MRI+) findings. Judicious use of serum biomarkers with MRI may aid in diagnosis of CT-occult TBI. The current manuscript aimed to evaluate the diagnostic, therapeutic and risk-stratification utility of known biomarkers and intracranial MRI pathology. Materials and Methods: The PubMed database was queried with keywords (plasma OR serum) AND (biomarker OR marker OR protein) AND (brain injury/trauma OR head injury/trauma OR concussion) AND (magnetic resonance imaging/MRI) (title/abstract) in English. Seventeen articles on TBI biomarkers and MRI were included: S100 calcium-binding protein B (S100B; N = 6), glial fibrillary acidic protein (GFAP; N = 3), GFAP/ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1; N = 2), Tau (N = 2), neurofilament-light (NF-L; N = 2), alpha-synuclein (N = 1), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor peptide (AMPAR; N = 1). Results: Acute GFAP distinguished CT-/MRI+ from CT-/MRI- (AUC = 0.777, 0.852 at 9-16 h). GFAP discriminated CT-/diffuse axonal injury (DAI+) from controls (AUC = 0.903). Tau correlated directly with number of head strikes and inversely with white matter fractional anisotropy (FA), and a cutoff > 1.5 pg/mL discriminated between DAI+ and DAI- (sensitivity = 74%/specificity = 69%). NF-L had 100% discrimination of DAI in severe TBI and correlated with FA. Low alpha-synuclein was associated with poorer functional connectivity. AMPAR cutoff > 0.4 ng/mL had a sensitivity of 91% and a specificity of 92% for concussion and was associated with minor MRI findings. Low/undetectable S100B had a high negative predictive value for CT/MRI pathology. UCH-L1 showed no notable correlations with MRI. Conclusions: An acute circulating biomarker capable of discriminating intracranial MRI abnormalities is critical to establishing diagnosis for CT-occult TBI and can triage patients who may benefit from outpatient MRI, surveillance and/or follow up with TBI specialists. GFAP has shown diagnostic potential for MRI findings such as DAI and awaits further validation. Tau shows promise in detecting DAI and disrupted functional connectivity. Candidate biomarkers should be evaluated within the context of analytical performance of the assays used, as well as the post-injury timeframe for blood collection relative to MRI abnormalities.

Project description:Adolescent traumatic brain injury (TBI) is a major public health concern, resulting in >35,000 hospitalizations in the United States each year. Although neuroimaging is a primary diagnostic tool in the clinical assessment of TBI, our understanding of how specific neuroimaging findings relate to outcome remains limited. Our study aims to identify imaging biomarkers of long-term neurocognitive outcome after severe adolescent TBI. Twenty-four adolescents with severe TBI (Glasgow Coma Scale ≤8) enrolled in the ADAPT (Approaches and Decisions after Pediatric TBI) study were recruited for magnetic resonance imaging (MRI) scanning 1-2 years post-injury at 13 participating sites. Subjects underwent outcome assessments ∼1-year post-injury, including the Wechsler Abbreviated Scale of Intelligence (IQ) and the Pediatric Glasgow Outcome Scale-Extended (GOSE-Peds). A typically developing control cohort of 38 age-matched adolescents also underwent scanning and neurocognitive assessment. Brain-image segmentation was performed on T1-weighted images using Freesurfer. Brain and ventricular cerebrospinal fluid volumes were used to compute a ventricle-to-brain ratio (VBR) for each subject, and the corpus callosum cross-sectional area was determined in the midline for each subject. The TBI group demonstrated higher VBR and lower corpus callosum area compared to the control cohort. After adjusting for age and sex, VBR was significantly related with GOSE-Peds score in the TBI group (n = 24, p = 0.01, cumulative odds ratio = 2.18). After adjusting for age, sex, intracranial volume, and brain volume, corpus callosum cross-sectional area correlated significantly with IQ score in the TBI group (partial cor = 0.68, n = 18, p = 0.007) and with PSI (partial cor = 0.33, p = 0.02). No association was found between VBR and IQ or between corpus callosum and GOSE-Peds. After severe adolescent TBI, quantitative MRI measures of VBR and corpus callosum cross-sectional area are associated with global functional outcome and neurocognitive outcomes, respectively.

Project description:ImportancePersistent symptoms after mild traumatic brain injury (mTBI) represent a major public health problem.ObjectiveTo identify neuroanatomical substrates of mTBI and the optimal timing for magnetic resonance imaging (MRI).Design, setting, and participantsThis prospective multicenter cohort study encompassed all eligible patients from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study (December 19, 2014, to December 17, 2017) and a local cohort (November 20, 2012, to December 19, 2013). Patients presented to the hospital within 24 hours of an mTBI (Glasgow Coma Score, 13-15), satisfied local criteria for computed tomographic scanning, and underwent MRI scanning less than 72 hours (MR1) and 2 to 3 weeks (MR2) after injury. In addition, 104 control participants were enrolled across all sites. Data were analyzed from January 1, 2019, to December 31, 2020.ExposureMild TBI.Main outcomes and measuresVolumes and diffusion parameters were extracted via automated bespoke pipelines. Symptoms were measured using the Rivermead Post Concussion Symptoms Questionnaire in the short term and the extended Glasgow Outcome Scale at 3 months.ResultsAmong the 81 patients included in the analysis (73 CENTER-TBI and 8 local), the median age was 45 (interquartile range [IQR], 24-59; range, 14-85) years, and 57 (70.4%) were male. Structural sequences were available for all scans; diffusion data, for 73 MR1 and 79 MR2 scans. After adjustment for multiple comparisons between scans, visible lesions did not differ significantly, but cerebral white matter volume decreased (MR2:MR1 ratio, 0.98; 95% CI, 0.96-0.99) and ventricular volume increased (MR2:MR1 ratio, 1.06; 95% CI, 1.02-1.10). White matter volume was within reference limits on MR1 scans (patient to control ratio, 0.99; 95% CI, 0.97-1.01) and reduced on MR2 scans (patient to control ratio, 0.97; 95% CI, 0.95-0.99). Diffusion parameters changed significantly between scans in 13 tracts, following 1 of 3 trajectories. Symptoms measured by Rivermead Post Concussion Symptoms Questionnaire scores worsened in the progressive injury phenotype (median, +5.00; IQR, +2.00 to +5.00]), improved in the minimal change phenotype (median, -4.50; IQR, -9.25 to +1.75), and were variable in the pseudonormalization phenotype (median, 0.00; IQR, -6.25 to +9.00) (P = .02). Recovery was favorable for 33 of 65 patients (51%) and was more closely associated with MR1 than MR2 (area under the curve, 0.87 [95% CI, 0.78-0.96] vs 0.75 [95% CI, 0.62-0.87]; P = .009).Conclusions and relevanceThese findings suggest that advanced MRI reveals potential neuroanatomical substrates of mTBI in white matter and is most strongly associated with odds of recovery if performed within 72 hours, although future validation is required.

Dataset Information

Magnetic Resonance Imaging Pilot Study of Intravenous Glyburide in Traumatic Brain Injury.

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Magnetic Resonance Imaging Pilot Study of Intravenous Glyburide in Traumatic Brain Injury.

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