Search

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

Head computed tomography (CT) imaging is still a commonly obtained diagnostic test for patients with minor head injury despite availability of clinical decision rules to guide imaging use and recommendations to reduce radiation exposure resulting from unnecessary imaging. This prospective multicenter observational study of 251 patients with suspected mild to moderate traumatic brain injury (TBI) evaluated three serum biomarkers' (glial fibrillary acidic protein [GFAP], ubiquitin C-terminal hydrolase-L1 [UCH-L1] and S100B measured within 6 h of injury) ability to differentiate CT negative and CT positive findings. Of the 251 patients, 60.2% were male and 225 (89.6%) had a presenting Glasgow Coma Scale score of 15. A positive head CT (intracranial injury) was found in 36 (14.3%). UCH-L1 was 100% sensitive and 39% specific at a cutoff value >40 pg/mL. To retain 100% sensitivity, GFAP was 0% specific (cutoff value 0 pg/mL) and S100B had a specificity of only 2% (cutoff value 30 pg/mL). All three biomarkers had similar values for areas under the receiver operator characteristic curve: 0.79 (95% confidence interval; 0.70-0.88) for GFAP, 0.80 (0.71-0.89) for UCH-L1, and 0.75 (0.65-0.85) for S100B. Neither GFAP nor UCH-L1 curve values differed significantly from S100B (p = 0.21 and p = 0.77, respectively). In our patient cohort, UCH-L1 outperformed GFAP and S100B when the goal was to reduce CT use without sacrificing sensitivity. UCH-L1 values <40 pg/mL could potentially have aided in eliminating 83 of the 215 negative CT scans. These results require replication in other studies before the test is used in actual clinical practice.

Mild traumatic brain injury (mTBI) is a major public health concern. Functional MRI has reported alterations in several brain networks following mTBI. However, the connectome-scale brain network changes are still unknown. In this study, sixteen mTBI patients were prospectively recruited from an emergency department and followed up at 4-6 weeks after injury. Twenty-four healthy controls were also scanned twice with the same time interval. Three hundred fifty-eight brain landmarks that preserve structural and functional correspondence of brain networks across individuals were used to investigate longitudinal brain connectivity. Network-based statistic (NBS) analysis did not find significant difference in the group-by-time interaction and time effects. However, 258 functional pairs show group differences in which mTBI patients have higher functional connectivity. Meta-analysis showed that "Action" and "Cognition" are the most affected functional domains. Categorization of connectomic signatures using multiview group-wise cluster analysis identified two patterns of functional hyperconnectivity among mTBI patients: (I) between the posterior cingulate cortex and the association areas of the brain and (II) between the occipital and the frontal lobes of the brain. Our results demonstrate that brain concussion renders connectome-scale brain network connectivity changes, and the brain tends to be hyperactivated to compensate the pathophysiological disturbances.

Mild traumatic brain injury (mTBI) accounts for more than 1 million emergency visits each year. Most of the injured stay in the emergency department for a few hours and are discharged home without a specific follow-up plan because of their negative clinical structural imaging. Advanced magnetic resonance imaging (MRI), particularly functional MRI (fMRI), has been reported as being sensitive to functional disturbances after brain injury. In this study, a cohort of 12 patients with mTBI were prospectively recruited from the emergency department of our local Level-1 trauma center for an advanced MRI scan at the acute stage. Sixteen age- and sex-matched controls were also recruited for comparison. Both group-based and individual-based independent component analysis of resting-state fMRI (rsfMRI) demonstrated reduced functional connectivity in both posterior cingulate cortex (PCC) and precuneus regions in comparison with controls, which is part of the default mode network (DMN). Further seed-based analysis confirmed reduced functional connectivity in these two regions and also demonstrated increased connectivity between these regions and other regions of the brain in mTBI. Seed-based analysis using the thalamus, hippocampus, and amygdala regions further demonstrated increased functional connectivity between these regions and other regions of the brain, particularly in the frontal lobe, in mTBI. Our data demonstrate alterations of multiple brain networks at the resting state, particularly increased functional connectivity in the frontal lobe, in response to brain concussion at the acute stage. Resting-state functional connectivity of the DMN could serve as a potential biomarker for improved detection of mTBI in the acute setting.

Mild traumatic brain injury (mTBI) is a significant public health care burden in the United States. However, we lack a detailed understanding of the pathophysiology following mTBI and its relation to symptoms and recovery. With advanced magnetic resonance imaging (MRI), we can investigate brain perfusion and oxygenation in regions known to be implicated in symptoms, including cortical gray matter and subcortical structures. In this study, we assessed 14 mTBI patients and 18 controls with susceptibility weighted imaging and mapping (SWIM) for blood oxygenation quantification. In addition to SWIM, 7 patients and 12 controls had cerebral perfusion measured with arterial spin labeling (ASL). We found increases in regional cerebral blood flow (CBF) in the left striatum, and in frontal and occipital lobes in patients as compared to controls (p = 0.01, 0.03, 0.03 respectively). We also found decreases in venous susceptibility, indicating increases in venous oxygenation, in the left thalamostriate vein and right basal vein of Rosenthal (p = 0.04 in both). mTBI patients had significantly lower delayed recall scores on the standardized assessment of concussion, but neither susceptibility nor CBF measures were found to correlate with symptoms as assessed by neuropsychological testing. The increased CBF combined with increased venous oxygenation suggests an increase in cerebral blood flow that exceeds the oxygen demand of the tissue, in contrast to the regional hypoxia seen in more severe TBI. This may represent a neuroprotective response following mTBI, which warrants further investigation.

Background: Mild traumatic brain injury (mTBI) is a significant healthcare burden and its diagnosis remains a challenge in the emergency department. Serum biomarkers and advanced magnetic resonance imaging (MRI) techniques have already demonstrated their potential to improve the detection of brain injury even in patients with negative computed tomography (CT) findings. The objective of this study was to determine the clinical value of a combinational use of both blood biomarkers and MRI in mTBI detection and their characterization in the acute setting (within 24 hours after injury)., Methods: Nine patients with mTBI were prospectively recruited from the emergency department. Serum samples were collected at the time of hospital admission and every 6 hours up to 24 hours post injury. Neuronal (Ubiquitin C-terminal Hydrolase-L1 [UCH-L1]) and glial (glial fibrillary acidic protein [GFAP]) biomarker levels were analyzed. Advanced MRI data were acquired at 9 ± 6.91 hours after injury. Patients' neurocognitive status was assessed by using the Standard Assessment of Concussion (SAC) instrument., Results: The median serum levels of UCH-L1 and GFAP on admission were increased 4.9 folds and 10.6 folds, respectively, compared to reference values. Three patients were found to have intracranial hemorrhages on SWI, all of whom had very high GFAP levels. Total volume of brain white matter (WM) with abnormal fractional anisotropy (FA) measures of diffusion tensor imaging (DTI) were negatively correlated with patients' SAC scores, including delayed recall. Both increased and decreased DTI-FA values were observed in the same subjects. Serum biomarker level was not correlated with patients' DTI data nor SAC score., Conclusions: Blood biomarkers and advanced MRI may correlate or complement each other in different aspects of mTBI detection and characterization. GFAP might have potential to serve as a clinical screening tool for intracranial bleeding. UCH-L1 complements MRI in injury detection. Impairment at WM tracts may account for the patients' neurocognitive symptoms.

Despite an estimated 2.8 million annual ED visits, traumatic brain injury (TBI) is a syndromic diagnosis largely based on report of loss of consciousness, post-traumatic amnesia, and/or confusion, without readily available objective diagnostic tests at the time of presentation, nor an ability to identify a patient's prognosis at the time of injury. The recognition that "mild" forms of TBI and even sub-clinical impacts can result in persistent neuropsychiatric consequences, particularly when repetitive, highlights the need for objective assessments that can complement the clinical diagnosis and provide prognostic information about long-term outcomes. Biomarkers and neurocognitive testing can identify brain injured patients and those likely to have post-concussive symptoms, regardless of imaging testing results, thus providing a physiologic basis for a diagnosis of acute traumatic encephalopathy (ATE). The goal of the HeadSMART II (HEAD injury Serum markers and Multi-modalities for Assessing Response to Trauma) clinical study is to develop an in-vitro diagnostic test for ATE. The BRAINBox TBI Test will be developed in the current clinical study to serve as an aid in evaluation of patients with ATE by incorporating blood protein biomarkers, clinical assessments, and tools to measure, identify, and define associated pathologic evidence and neurocognitive impairments. This protocol proposes to collect data on TBI subjects by a multi-modality approach that includes serum biomarkers, clinical assessments, neurocognitive performance, and neuropsychological characteristics, to determine the accuracy of the BRAINBox TBI test as an aid to the diagnosis of ATE, defined herein, and to objectively determine a patient's risk of developing post-concussive symptoms. [ABSTRACT FROM AUTHOR]

Objective: The objective was to determine the accuracy of a new, rapid blood test combining measurements of both glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl‐terminal hydrolase L1 (UCH‐L1) for predicting acute traumatic intracranial injury (TII) on head CT scan after mild traumatic brain injury (mTBI). Methods: Analysis of banked venous plasma samples from subjects completing the Prospective Clinical Evaluation of Biomarkers of Traumatic Brain Injury (ALERT‐TBI) trial, enrolled 2012–2014 at 22 investigational sites in the United States and Europe. All subjects were ≥18 years old, presented to an emergency department (ED) with a nonpenetrating head injury and Glasgow Coma Scale score (GCS) 9–15 (mild to moderate TBI), underwent head CT scanning as part of their clinical care, and had blood sampling within 12 h of injury. Plasma concentrations of GFAP and UCH‐L1 were measured using i‐STAT Alinity and TBI plasma cartridge and compared to acute TII on head CT scan. Results: Of the 2011 subjects enrolled in ALERT‐TBI, 1918 had valid CT scans and plasma specimens for testing and 1901 (99.1%) had GCS 13–15 (mTBI), for which the rapid test was intended. Among these subjects, the rapid test had a sensitivity of 0.958 (95% confidence interval [CI] = 0.906 to 0.982), specificity of 0.404 (95% CI = 0.382 to 0.427), negative predictive value of 0.993 (95% CI = 0.985 to 0.997), and positive predictive value of 0.098 (95% CI = 0.082 to 0.116) for acute TII. Conclusions: A rapid i‐STAT–based test had high sensitivity for prediction of acute TII, comparable to lab‐based platforms. The speed, portability, and high accuracy of this test may facilitate clinical adoption of brain biomarker testing as an aid to head CT decision making in EDs. [ABSTRACT FROM AUTHOR]

Background: Serum glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal esterase L1 (UCH-L1) have recently received US Food and Drug Administration approval for prediction of abnormal computed tomography (CT) in mild traumatic brain injury patients (mTBI). However, their performance in elderly patients has not been characterized. Methods: We performed a posthoc analysis using the A Prospective Clinical Evaluation of Biomarkers of Traumatic Brain Injury (ALERT-TBI) study data. Previously recorded patient variables and serum values of GFAP and UCH-L1 from mTBI patients were partitioned at 65 years of age (herein referred to as ≥65, high-risk; <65, low-risk). We sought to assess the influence of age on predictive performance, sensitivity, and negative predictive value (NPV) of serum UCH-L1 and GFAP to predict intracranial injury by CT. Results: Elderly mTBI patients constituted 25.7% of the patient cohort (n = 504/1959). Sensitivity and NPV of GFAP/UCH-L1 were 100%, with no significant difference from younger patients (P = 0.5525 and P > 0.9999, respectively). Specificity was significantly lower in elderly patients (0.131 vs 0.442; P < 0.0001) and decreased stepwise with older age. Compared to younger patients, elderly mTBI patients without abnormal (i.e., normal) CT findings also had a significantly higher GFAP (38.6 vs 16.2 pg/mL; P < 0.0001) and UCH-L1 (347.4 vs 232.1 pg/mL; P < 0.0001). Conclusions: Sensitivity and NPV to predict intracranial injury by CT was nearly identical between younger and elderly mTBI patients. Decrements in specificity and increased serum values suggest that special deference may be warranted for elderly patients. [ABSTRACT FROM AUTHOR]

Glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1), and S100B have been shown to be predictive of patients with brain injury. Kinetics of these biomarkers in injured humans have not been extensively examined. This prospective multi-center study included patients with mild-to-moderate traumatic brain injury. Blood samples obtained at enrollment and every 6 h up to 24 h post-injury were assayed for GFAP, UCH-L1, and S100B. Random effects models examined changes in the biomarkers' level over time. A total of 167 patients were enrolled; mean age was 46.0 ± 17.8, 61.1% were male, 143 (85.6%) had a Glasgow Coma Scale score of 15, and 33 (19.8%) had a positive head computed tomography (CT) scan. Baseline median biomarker concentrations for all three were higher among CT-positive patients ( p < 0.0001) but GFAP was the only biomarker that significantly increased over time among CT-positive patients relative to CT-negative patients (log transformed values 0.037; 95% confidence interval 0.02, 0.05; p < 0.001), indicating a 3.7% per hour rise in GFAP concentration. There was no significant increase in either UCH-L1 or S100B in CT-positive patients ( p = 0.15 and p = 0.47, respectively). GFAP concentrations increased 3.7% per hour among CT-positive patients whereas neither UCH-L1 nor S100B increased, compared with CT-negative patients. The kinetics and temporal profile of GFAP suggest it may be a more robust biomarker to detect patients with positive CT findings, particularly at later post-injury times. Further study is needed to determine if GFAP is a useful test to follow throughout a patient's clinical course. [ABSTRACT FROM AUTHOR]

Objective The objective was to compare test characteristics of a single serum concentration of glial fibrillary acidic protein ( GFAP), S-100β, and ubiquitin carboxyl terminal hydrolase L1 ( UCH-L1), obtained within 6 hours of head injury, to diagnose mild traumatic brain injury ( mTBI) in head-injured subjects. Methods Adults aged 18 to 80 years who presented to one of seven EDs with a blunt closed head injury underwent head CT within 4 hours of injury and had blood drawn for biomarker analysis within 6 hours of injury were eligible. Subjects were considered to have mTBI if they had an initial Glasgow Coma Scale ( GCS) > 13 and met one or more of the following criteria: loss of consciousness ( LOC), posttraumatic amnesia, or confusion. Subjects with mTBI and an abnormal head computed tomography ( CT) scan were categorized as complicated mTBI; those with a normal head CT were categorized as uncomplicated mTBI; and subjects with a GCS = 15, no LOC, no posttraumatic amnesia, and no confusion were considered to not have a mTBI. Biomarker concentration measurements for GFAP and UCH-L1 were performed using an enzyme-linked immunosorbent assay. S-100β concentration was determined using an electrochemiluminescence immunoassay. Median biomarker concentration for each group was compared using the Kruskal-Wallis test. Logistic regression was used to determine area under the receiver operating curve ( AUC) for each of the three biomarkers. Sensitivity, specificity, negative predictive value ( NPV), positive predictive value ( PPV), and negative and positive likelihood ratios ( LRs) for the three biomarkers to differentiate between complicated mTBI, uncomplicated mTBI, and no mTBI were calculated. Results A total of 247 subjects were enrolled and had adequate clinical and biomarker information for analysis. A total of 188 met criteria for mTBI, with 34 (18.1%) having an acute abnormality on CT (complicated mTBI). The mean (± SD) age of the study population was 45.8 (±17.3) years, and 59.9% were male. Median serum concentrations for all biomarkers were significantly different between groups, lowest in the no mTBI group, and progressively increasing in the uncomplicated and complicated mTBI groups (p < 0.0001). All three biomarkers were significant classifiers of mTBI versus no mTBI, with the following AUCs: GFAP, 0.70; S-100β, 0.69; and UCH-L1, 0.65 (p = 0.17). Sensitivity for mTBI was highest for S-100β (96.5%). NPVs ranged from 31% for UCH-L1 to 35% for GFAP. PPVs ranged from 75.5% for S-100β to 96.5% for GFAP. Negative LR ranged from 0.59 for GFAP to 0.71 for UCH-L1, with positive LR ranging from 1.0 for both UCH-L1 and S-100β to 8.7 for GFAP. Conclusion A single serum concentration of GFAP, UCH-L1, or S-100β within 6 hours of head injury may be useful in identifying and stratifying the severity of brain injury in emergency department patients with head trauma, but cannot reliably exclude a diagnosis of concussion. A positive GFAP was associated with the presence of concussion. [ABSTRACT FROM AUTHOR]

Mild traumatic brain injury (mTBI) is a major public health concern. Functional MRI has reported alterations in several brain networks following mTBI. However, the connectome-scale brain network changes are still unknown. In this study, sixteen mTBI patients were prospectively recruited from an emergency department and followed up at 4–6 weeks after injury. Twenty-four healthy controls were also scanned twice with the same time interval. Three hundred fifty-eight brain landmarks that preserve structural and functional correspondence of brain networks across individuals were used to investigate longitudinal brain connectivity. Network-based statistic (NBS) analysis did not find significant difference in the group-by-time interaction and time effects. However, 258 functional pairs show group differences in which mTBI patients have higher functional connectivity. Meta-analysis showed that “Action” and “Cognition” are the most affected functional domains. Categorization of connectomic signatures using multiview group-wise cluster analysis identified two patterns of functional hyperconnectivity among mTBI patients: (I) between the posterior cingulate cortex and the association areas of the brain and (II) between the occipital and the frontal lobes of the brain. Our results demonstrate that brain concussion renders connectome-scale brain network connectivity changes, and the brain tends to be hyperactivated to compensate the pathophysiological disturbances. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine if initial or repeat measurements of serum concentrations of glial fibrillary acidic protein (GFAP) or ubiquitin C-terminal hydrolase L1 (UCH-L1) are predictive of an acute unfavorable neurological outcome in patients who present to the emergency department (ED) with brain injury and an initial Glasgow Coma Scale Score (GCS) of 14–15. This multi-center observational trial included brain-injured adults presenting to the ED, receiving a head computed tomography (CT) and venipuncture for biomarker concentration measurements within 6 h of injury. Subjects had repeat serum sampling and GCS scores every 4 h for the first 24 h, if available for assessment. We analyzed blood samples using an enzyme-linked immunosorbent assay approved by the Food and Drug Administration (FDA). Wilcoxin two-sample test was used to compare initial and repeat serum concentrations for both biomarkers between CT-positive patients who did not have an acute unfavorable neurological outcome and those patients who did. A total of 145 enrolled subjects had adequate data for analysis; 69 were CT-positive, 74 were CT-negative, and 2 were CT-inconclusive. Five subjects developed an acute unfavorable neurological outcome, defined as need for intracranial pressure monitoring, craniotomy, persistent neurological deficits, or death resulting from brain injury. Initial median serum concentrations of GFAP and UCH-L1 (obtained <6 h from injury) were significantly greater in CT-positive patients who had an acute unfavorable neurological outcome than in CT-positive patients who did not (GFAP: 5237 pg/mL [IQR 4511, 8180] versus 283.5 pg/mL [IQR 107, 1123]; p = 0.026; UCH-L1: 3329 pg/mL [QR 1423, 5010] versus 679.5 pg/mL [IQR 363, 1100] p = 0.014). Repeat serum testing (6- < 12 h from injury) showed that UCH-L1 serum concentration, but not GFAP, was also significantly greater in the acute unfavorable neurological outcome group than in those without an unfavorable outcome: 1088 pg/mL versus 374 pg/mL; p = 0.041. [ABSTRACT FROM AUTHOR]

While resting state functional magnetic resonance imaging (rsfMRI) studies in mild traumatic brain injury (mTBI) report alterations in brain function, the heterogeneity of mTBI remains a major obstacle to characterizing these alterations. Each patient is unique in terms injury location and biomechanical profile, making generalization of group-level findings to the individual level difficult. However, we hypothesize that mTBI patients follow similar patterns of alterations in higher-order brain functions despite the heterogeneity. We investigated the relationship between group-level and individual-level alterations in the default mode network (DMN) after mTBI in seventeen mTBI patients at the acute stage and 17 healthy controls using the connectivity domain, a new innovative approach recently developed by the authors. rsfMRI data was transformed into the connectivity domain using predefined seed networks. With a nonparametric statistical comparison of the connectivity matrices that represents the relationship between the seed networks and intrinsic connectivity networks, we observed decreased activity within the DMN after mTBI at the group level, similar to previous findings. The connectivity strength between the DMN and seed networks associated with the DMN was decreased, as was connectivity strength between the DMN and seed networks inversely linked to the DMN. A significant correlation was observed between neuroimaging findings and neurocognitive performance. A subject-level analysis shows that, in general, the same pattern was observed at the subject level as at the group level; 56 out of 60 statistically significant subject-level differences reveal a decrease in connectivity strengths. In conclusion, despite a high level of heterogeneity and inter-individual variability, mTBI patients do share commons patterns of alterations in the DMN. This finding serves to validate previous grouplevel findings despite current doubt in the field about their relevance. [ABSTRACT FROM AUTHOR]