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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
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.
... Due to the type of cells found in the central nervous system, it is necessary to study biomarkers that allow us to demonstrate not only glial injury but also neuronal. One of the most studied biomarkers in this sense is the C-terminal hydrolase of ubiquitin-L1, which is a highly specific cytoplasmic neuronal enzyme [11,12]. Finally, we will delve into glial fibrillary acidic protein (GFAP), which is also a glial protein and is part of the cytoskeleton of astrocytes and is also related to the disruption of the blood-brain barrier [11,13]. ...
... One of the most studied biomarkers in this sense is the C-terminal hydrolase of ubiquitin-L1, which is a highly specific cytoplasmic neuronal enzyme [11,12]. Finally, we will delve into glial fibrillary acidic protein (GFAP), which is also a glial protein and is part of the cytoskeleton of astrocytes and is also related to the disruption of the blood-brain barrier [11,13]. ...
... The C-terminal hydrolase of ubiquitin-L1 (ubiquitin C-terminal hydrolase-L1, UCH-L1) is an E2 conjugation enzyme present in the cytoplasm of almost all neurons [13] and has previously been used as a neuronal histological marker due to its great abundance and specific expression in these cells [11]. Its location has also been shown in neurons of the peripheral nervous system, particularly in the neuromuscular junction [12], as well as in cells of the neuroendocrine system. ...
... 2 The present study augments the previous pilot study by evaluating daily, individualized pressure exposure data in addition to the data streams reported in the pilot study. 2 Several brain-enriched or central nervous system-specific biomarkers have been shown to provide diagnostic and/or prognostic information about TBI (from severe to mild). 3,4 Such markers include neuronal-cell body-protein ubiquitin C-terminal hydrolase-L1 (UCH-L1), axonally enriched cytoskeletal protein alphaII-spectrin-derived breakdown products (SBDPs), phospho-neurofilament protein-heavy, glial fibrillary acidic protein (GFAP), and its breakdown product (GFAP-BDP). Both UCH-L1 and GFAP/GFAP-BDP have the ability to detect mild-to-moderate TBI. ...
... Both UCH-L1 and GFAP/GFAP-BDP have the ability to detect mild-to-moderate TBI. 3,4 In addition, two recent studies independently confirmed the utilities of GFAP-BDP and its combination with UCH-L1 as diagnostic and/or prognostic tool for TBI. 5,6 Although Tate et al. 2 measured three candidate brain biomarkers that might be responsive to blast-induced brain perturbation (SBDP150, UCH-L1, GFAP), GFAP will be the main biomarker of this case study. ...
... Blood samples were drawn at multiple time points during the study and serum was processed in line with previous works. 3,4 Serum samples were analyzed for concentration levels (ng/mL) of GFAP, UCH-L1, and SBDP150. Seven pre-exposure control blood samples were obtained from the volunteer in the 3 days before the first blast exposure to determine baseline biomarker concentration. ...
We report a case study on a single military member who received moderate blast overpressure (OP) exposure during routine breacher training. We extend previous research on blast exposure during training, which lacked sufficient data to assess symptom profiles and OP exposure. The present work was conducted because a subjective symptom profile similar to that seen in sports concussion has been reported by military personnel exposed to blast. Data collection for this study was carried out under a research protocol approved by the relevant Human Subjects Review Committees on one subject, who received the highest OP exposure during training. The volunteer was a 20-year-old male with no prior history of traumatic brain injury (TBI) or blast exposure. The volunteer was part of a breacher training team that completed a 2-week explosive entry course. The course included 3 classroom days and 9 days of practical training, held in the morning, afternoon, and evening sessions. Blast exposure occurred on five of the nine practical training days, with multiple exposures over the course of each day. Assessments of serum, self-reported symptoms, magnetic resonance imaging, and blast characterization were conducted. Results indicated changes in glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 postblast exposure but did not manifest changes in spectrin-derived breakdown product 150 or magnetic resonance imaging. No additional symptoms were reported by the subject. Objective markers of mild TBI remain elusive, but support for serum biomarkers as an early detection mechanism is promising. Additionally, this case study demonstrated an association between OP and high level of neurotrauma biomarker in an individual.
... 22 UCH-L1, however, is a deubiquitylating enzyme expressed by neuronal cells exclusively and has been proposed as a more specific biomarker of TBI. 23,24 Current evidence suggests that these biomarkers are potentially sensitive enough to exclude significant anatomical injury/brain haemorrhage. This information mitigates the need for a CT scan 19 and potentially provides quantitative information regarding the size of injury burden and its prognosis. ...
... In particular, two serum biomarkers, GFAP and UCH-L1, were approved by the FDA in February 2018 as a blood test for use within the context of mTBI within the first 12 h post injury. As previously discussed, both biomarkers are detectable in serum within 1 h and are reported as being able to distinguish between mTBI patients with structural pathology and those without, 23,49,50 in both children and adults. 51 Therefore, the intended use is to exclude or confirm the requirement for axial imaging where there is equipoise or uncertainty as to the requirement. ...
Establishing a diagnosis of concussion within the context of competitive sport is frequently difficult due to the heterogeneity of presentation. Over the years, many endogenous proteins, including the recent Food and Drug Administration approved for mild-to-moderate traumatic brain injury, glial fibrillary acid protein and ubiquitin carboxy-terminal hydrolase, have been studied as potential biomarkers for the diagnosis of mild traumatic brain injury. Recently, a new class of potential biomarkers, the microRNAs, has shown promise as indicators of traumatic brain injury. In this pilot study, we have analysed the ability of pre-validated serum microRNAs (mi-425-5p and miR-502) to diagnose concussion, in cases without structural pathology. Their performance has been assessed alongside a set of identified protein biomarkers for traumatic brain injury in cohort of 41 concussed athletes. Athletes with a confirmed concussion underwent blood sampling after 48 h from concussion along with magnetic resonance imaging. Serum mi-425-5p and miR-502 were analysed by quantitative reverse transcription polymerase chain reaction, and digital immunoassay was used to determine serum concentrations of ubiquitin carboxy-terminal hydrolase, glial fibrillary acid protein, neurofilament light and Tau. Results were matched with 15 healthy volunteers. No structural/haemorrhagic pathology was identified. Protein biomarkers demonstrated variability among groups reflecting previous performance in the literature. Neurofilament light was the only marker to positively correlate with symptoms reported and SCAT5 scores. Despite the sub optimal timing of sampling beyond the optimal window for many of the protein biomarkers measured, miR-502 was significantly downregulated at all time points within a week form concussion ictus, showing a diagnostic sensitivity in cases beyond 48 h and without structural pathology.
... Some studies have reported similar results with UCH-L1, a neuron-specific biomarker, wherein serum UCH-L1 concentrations were higher in concussed patients and correlated with CT-positive scans (Papa et al., 2012) and predicted outcome better than S100B in pediatric patients (Berger, Hayes, Richichi, Beers, & Wang, 2012). Conversely, Posti and colleagues (2017) found no differences in UCH-L1 or GFAP between concussed patients and orthopedic-injured controls at any time point between 1 and 7 days post-injury. ...
Concussions occur frequently among the general population, with athletes and certain
military personnel being particularly vulnerable. Population differences (demographics,
risk factors, injury frequency, injury severity, etc.) require that both clinicians and
researchers carefully consider individual patient or participant characteristics. Recent
evidence suggests that the physiological alterations associated with concussion may
outlast the symptoms that manifest, although current concussion management is almost
exclusively dictated by clinical presentation. Accordingly, there has been a rapid rise in
research aiming to better characterize the neurophysiological effects of concussion and
time course of neurobiological recovery after injury, particularly through employment of
advanced neuroimaging metrics and fluid-based biomarkers. Concussion prevention
efforts, particularly in athletic settings, range from limiting head impact exposure to
mitigating recovery time (e.g., post-concussion syndrome) through identification of both
neurobiological and psychosocial risk factors. Recommendations for extended periods of
complete physical and cognitive rest after concussion have been replaced with guidelines
for symptom-limited activity much earlier in the recovery process. Ultimately,
improvements in both physiological and clinical injury identification, as well as
concussion rehabilitation, may reduce the long-term impact of single-event or multiple
concussions. The current literature on the relationship between concussion history and
late-life risk for neurodegeneration or dementia is mixed. Several important topics
related to the acute, subacute, and long-term outcomes of concussion require further
study and clarification. Ongoing large-scale research initiatives hold the promise of
accelerating access to essential, yet complex, answers.
... However, the Banyan BTI TM test takes over 2 h to run, potentially rendering the results unactionable within current clinical management workflows. The BTI TM has been useful in several clinical studies to establish the kinetics [95], diagnostic accuracy [99], and association with CT findings [96,100,104,105] of GFAP and UCH-L1, but the treatment decisions did not depend on the test results. To improve the assay time and render the test usable for making treatment decisions in real time, Banyan Biomarkers provided a non-exclusive license of their TBI biomarkers to Abbott [116]. ...
Traumatic brain injury (TBI) is associated with high rates of morbidity and mortality partially due to the limited tools available for diagnosis and classification. Measuring panels of protein biomarkers released into the bloodstream after injury has been proposed to diagnose TBI, inform treatment decisions, and monitor the progression of the injury. Being able to measure these protein biomarkers at the point-of-care would enable assessment of TBIs from the point-of-injury to the patient’s hospital bedside. In this review, we provide a detailed discussion of devices reported in the academic literature and available on the market that have been designed to measure TBI protein biomarkers in various biofluids and contexts. We also assess the challenges associated with TBI biomarker measurement devices and suggest future research directions to encourage translation of these devices to clinical use.
... of blood GFAP and UCH-L1 levels was used to grade brain injury after TBI. GFAP and UCH-L1 levels were increased in nonconcussive and concussive head trauma as compared to body trauma (73,74). The analysis of blood GFAP (or S100B) levels within 24 h from the head injury was proposed as a means to improve the detection of TBI and to identify patients in need of a subsequent MRI, in addition to routine CT surveillance (75,76). ...
Within the neurovascular unit (NVU), the blood-brain barrier (BBB) operates as a key cerebrovascular interface, dynamically insulating the brain parenchyma from peripheral blood and compartments. Increased BBB permeability is clinically relevant for at least two reasons: it actively participates in the etiology of central nervous system (CNS) diseases, and it enables the diagnosis of neurological disorders based on the detection of CNS molecules in peripheral body fluids. In pathological conditions, a suite of glial, neuronal, and pericyte biomarkers can exit the brain reaching the peripheral blood and, after a process of filtration, may also appear in saliva or urine according to varying temporal trajectories. Here, we specifically examine the evidence in favor of or against the use of protein biomarkers of NVU damage and BBB permeability in traumatic head injury, including sport (sub)concussive impacts, seizure disorders, and neurodegenerative processes such as Alzheimer's disease. We further extend this analysis by focusing on the correlates of human extreme physiology applied to the NVU and its biomarkers. To this end, we report NVU changes after prolonged exercise, freediving, and gravitational stress, focusing on the presence of peripheral biomarkers in these conditions. The development of a biomarker toolkit will enable minimally invasive routines for the assessment of brain health in a broad spectrum of clinical, emergency, and sport settings.
... Previous work showed that serum UCHL1 (< 4 h) levels in patients with scores of 15 on the Glasgow Coma Scale (GCS) were significantly elevated above non-trauma controls and trauma controls. 25 Both proteins can be used as reliable markers for neuronal cell body damage. 26,27 Considering the heterogeneous nature of the initial impact and complexity of secondary injury in mTBI, with the lack of prior knowledge about the potential neuronal injury mechanisms involved in abnormal brain connectivity, combining serum neuronal biomarkers with networklevel properties of neuroimaging to assess global influence may provide important information. ...
Mild traumatic brain injury (mTBI) is the most prevalent neurological insult and leads to long-lasting cognitive impairment. Neuroimaging studies have discovered abnormalities in brain network connectivity following mTBI as the underlying neural basis of cognitive deficits. However, the pathophysiologic mechanisms involved in imaging alterations remain elusive. Proteins neuron-specific enolase (NSE) and ubiquitin C terminal hydrolase 1 (UCHL1) are reliable markers for neuronal cell-body damage, both of which have been demonstrated to be increased in serum following mTBI. Therefore, we conducted a longitudinal study to examine relationships between abnormal brain network connectivity and serum neuronal biomarkers and their associations with cognitive recovery following mTBI. Sixty patients were followed-up at 1week and 3 months post-injury and 41 controls were recruited. Resting-state functional MRI was used to build a functional connectivity matrix within large-scale intrinsic networks, their topological properties were analysed using graph theory measures. We found that, compared to controls, mTBI patients showed significant decreases in a number of nodal characteristics in default mode network (DMN), salience network (SN) and executive network (EN) (P < 0.05, FDR corrected) at 3 months post-injury. Linear regression analysis found elevated serum NSE in acute phase could predict lower efficiency and degree centrality of anterior DMN at 3 months post-injury. And efficiency and degree centrality of anterior DMN were negatively associated with working memory. Our study showed neuronal injury was associated with alterations in brain network connectivity after mTBI. These findings can facilitate capability to predict the brain functional outcomes and cognitive recovery in mTBI.
... 20 21 Further studies are required to confirm our results. 22 Additionally, some factors were not studied due to the retrospective design, including Injury Severity Score, coagulation factor, anticoagulant or antiplatelet therapy, and some laboratory tests such as serum ubiquitin C-terminal hydrolase L1. [23][24][25][26] Finally, treatment and treatment outcomes were not reported. ...
Background
Although there are eight factors known to indicate a high risk of intracranial hemorrhage (ICH) in mild traumatic brain injury (TBI), identification of the strongest of these factors may optimize the utility of brain CT in clinical practice. This study aimed to evaluate the predictors of ICH based on baseline characteristics/mode of injury, indications for brain CT, and a combination of both to determine the strongest indicator.
Methods
This was a descriptive, retrospective, analytical study. The inclusion criteria were diagnosis of mild TBI, high risk of ICH, and having undergone a CT scan of the brain. The outcome of the study was any type of ICH. Stepwise logistic regression analysis was used to find the strongest predictors according to three models: (1) injury pattern and baseline characteristics, (2) indications for CT scan of the brain, and (3) a combination of models 1 and 2.
Results
There were 100 patients determined to be at risk of ICH based on indications for CT of the brain in patients with acute head injury. Of these, 24 (24.00%) had ICH. Model 1 found that injury due to motor vehicle crash was a significant predictor of ICH, with an adjusted OR (95% CI) of 11.53 (3.05 to 43.58). Models 2 and 3 showed Glasgow Coma Scale (GCS) score of 13 to 14 after 2 hours of observation and open skull or base of skull fracture to be independent predictors, with adjusted OR (95% CI) of 11.77 (1.32 to 104.96) and 5.88 (1.08 to 31.99) according to model 2.
Discussion
Open skull or base of skull fracture and GCS score of 13 to 14 after 2 hours of observation were the two strongest predictors of ICH in mild TBI.
Level of evidence
III.
... Preclinical studies of blast exposures have demonstrated altered gene expression, including cognitive impairment (20,21) and immune function (22). Recent work in military training that involves personnel exposure to blast has demonstrated that ubiquitin carboxyterminal hydrolase-1 (UCH-L1) is weakly correlated with repeated exposure to low-level blast (12), which is consistent with previous work in TBI (23) and blast exposure (11,24). In particular, Heinzelmann et al. (11) found protein ubiquitination genes (associated with neuronal recovery, central regulator in IPA) to be downregulated in military personnel with chronic symptoms following blast head injury. ...
Blast exposure is common in military personnel during training and combat operations, yet biological mechanisms related to cell survival and function that coordinate recovery remain poorly understood. This study explored how moderate blast exposure influences gene expression; specifically, gene-network changes following moderate blast exposure. On day 1 (baseline) of a 10-day military training program, blood samples were drawn, and health and demographic information collected. Helmets equipped with bilateral sensors worn throughout training measured overpressure in pounds per square inch (psi). On day 7, some participants experienced moderate blast exposure (peak pressure ≥5 psi). On day 10, 3 days post-exposure, blood was collected and compared to baseline with RNA-sequencing to establish gene expression changes. Based on dysregulation data from RNA-sequencing, followed by top gene networks identified with Ingenuity Pathway Analysis, a subset of genes was validated (NanoString). Five gene networks were dysregulated; specifically, two highly significant networks: (1) Cell Death and Survival (score: 42), including 70 genes, with 50 downregulated and (2) Cell Structure, Function, and Metabolism (score: 41), including 69 genes, with 41 downregulated. Genes related to ubiquitination, including neuronal development and repair: UPF1, RNA Helicase and ATPase (UPF1) was upregulated while UPF3 Regulator of Nonsense Transcripts Homolog B (UPF3B) was downregulated. Genes related to inflammation were upregulated, including AKT serine/threonine kinase 1 (AKT1), a gene coordinating cellular recovery following TBIs. Moderate blast exposure induced significant gene expression changes including gene networks involved in (1) cell death and survival and (2) cellular development and function. The present findings may have implications for understanding blast exposure pathology and subsequent recovery efforts.
... www.nature.com/scientificreports/ is elevated in moderate and mild TBI patients, and can be used to distinguish mild TBI patients requiring computed tomography (CT) imaging [9][10][11][12][13] . In 2018, UCHL1 was approved by the United States of America Food and Drug Administration (FDA) to be used in the assessment of mild TBI in lieu of head CT imaging. ...
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.
... The aggregate HSROC incorporating all cutoffs is provided along with the individual ROCs for each study (Fig. 4). The optimal cutoff was 0.719 μg/L, with a sensitivity of 61% (95% CI 50-72) and a specificity of 69% (95% CI [64][65][66][67][68][69][70][71][72][73][74]. The sensitivity of S100B at the internationally accepted threshold value of 0.1 μg/L was 87% (95%CI [81][82][83][84][85][86][87][88][89][90][91][92], and the specificity was 32% (95%CI 25-39). ...
Biomarkers such as calcium channel binding protein S100 subunit beta (S100B), glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1) and neuron-specific enolase (NSE) have been proposed to aid in screening patients presenting with mild traumatic brain injury (mTBI). As such, we aimed to characterise their accuracy at various thresholds. MEDLINE, SCOPUS and EMBASE were searched, and articles reporting the diagnostic performance of included biomarkers were eligible for inclusion. Risk of bias was assessed using the QUADAS-II criteria. A meta-analysis was performed to assess the predictive value of biomarkers for imaging abnormalities on CT. A total of 2939 citations were identified, and 38 studies were included. Thirty-two studies reported data for S100B. At its conventional threshold of 0.1 μg/L, S100B had a pooled sensitivity of 91% (95%CI 87–94) and a specificity of 30% (95%CI 26–34). The optimal threshold for S100B was 0.72 μg/L, with a sensitivity of 61% (95% CI 50–72) and a specificity of 69% (95% CI 64–74). Nine studies reported data for GFAP. The optimal threshold for GFAP was 626 pg/mL, at which the sensitivity was 71% (95%CI 41–91) and specificity was 71% (95%CI 43–90). Sensitivity of GFAP was maximised at a threshold of 22 pg/mL, which had a sensitivity of 93% (95%CI 73–99) and a specificity of 36% (95%CI 12–68%). Three studies reported data for NSE and two studies for UCH-L1, which precluded meta-analysis. There is evidence to support the use of S100B as a screening tool in mild TBI, and potential advantages to the use of GFAP, which requires further investigation.
... [60][61][62][63][64] In addition, Papa et al. reported a marked increase in serum UCH-L1 in patients with mild and moderate TBI in which the biomarker levels were detectable in the serum within 1 h post-injury and was associated with measures of injury severity (including GCS score), CT lesions, and neurological intervention. 65 Likewise, several studies reported that the elevation of serum GFAP levels in patients with severe TBI is correlated with injury severity and clinical outcomes. 28,[66][67][68][69] The GFAP blood levels were shown to predict cerebral hypoxia, which is a secondary insult occurring after brain injury, in patients with severe TBI. ...
raumatic brain injury (TBI) is a major cause of mortality and morbidity affecting all ages. It remains to be a diagnostic and thera-peutic challenge, in which, to date, there is no Food and Drug Administration-approved drug for treating patients suffering fromTBI. The heterogeneity of the disease and the associated complex pathophysiology make it difficult to assess the level of the traumaand to predict the clinical outcome. Current injury severity assessment relies primarily on the Glasgow Coma Scale score or throughneuroimaging, including magnetic resonance imaging and computed tomography scans. Nevertheless, such approaches have cer-tain limitations when it comes to accuracy and cost efficiency, as well as exposing patients to unnecessary radiation. Consequently,extensive research work has been carried out to improve the diagnostic accuracy of TBI, especially in mild injuries, because theyare often difficult to diagnose. The need for accurate and objective diagnostic measures led to the discovery of biomarkers signifi-cantly associated with TBI. Among the most well-characterized biomarkers are ubiquitin C-terminal hydrolase-L1 and glial fibrillaryacidic protein. The current review presents an overview regarding the structure and function of these distinctive protein biomark-ers, along with their clinical significance that led to their approval by the US Food and Drug Administration to evaluate mild TBI inpatients.
... GFAP is concentrated in the cytoskeleton of astrocytes and is upregulated following brain injury corresponding to astrocytic activation, making it an ideal candidate marker for brain injury patients (Pekny and Pekna, 2004). Several reports have suggest that an increased blood level of GFAP is associated with severe and moderate TBI, as well as a reliable predictor of trauma patients with mTBI (Lumpkins et al., 2008;Metting et al., 2012;Papa, Lewis, Falk, et al., 2012;Papa, Lewis, Silvestri, et al., 2012;Lewis et al., 2017). ...
Mild traumatic brain injury is a relatively common event in contact sports and there is increasing interest in the long-term neurocognitive effects. The diagnosis largely relies on symptom reporting and there is a need for objective tools to aid diagnosis and prognosis. There are recent reports that blood biomarkers could potentially help triage patients with suspected injury and normal CT findings. We have measured plasma concentrations of glial and neuronal proteins and explored their potential in the assessment of mild traumatic brain injury in contact sport.
We recruited a prospective cohort of active male rugby players, who had pre-season baseline plasma sampling. From this prospective cohort, we recruited 25 players diagnosed with mild traumatic brain injury. We sampled post-match rugby players without head injuries as post-match controls. We measured plasma neurofilament light chain, tau and glial fibrillary acidic protein levels using ultrasensitive single molecule array technology. The data was analysed at the group and individual player level.
Plasma glial fibrillary acidic protein concentration was significantly increased 1-hour post-injury in mild traumatic brain injury cases compared to the non-injured group (p = 0.017). Pairwise comparison also showed that glial fibrillary acidic protein levels were higher in players after a head injury in comparison to their pre-season levels at both 1-hour and 3 to 10-days post-injury time points (p = 0.039 and 0.040, respectively). There was also an increase in neurofilament light chain concentration in brain injury cases compared to the pre-season levels within the same individual at both time points (p = 0.023 and 0.002, respectively). Tau was elevated in both the non-injured control group and the 1-hour post-injury group compared to pre-season levels (p = 0.007 and 0.015, respectively). Furthermore, receiver operating characteristic analysis showed that glial fibrillary acidic protein and neurofilament light chain can separate head injury cases from control players. The highest diagnostic power was detected when biomarkers were combined in differentiating 1-hour post-match control players from 1-hour post head injury players (area under curve 0.90, 95% confidence interval 0.79-1.00, p < 0.0002).
The brain astrocytic marker glial fibrillary acidic protein is elevated in blood 1 hour after mild traumatic brain injury and in combination with neurofilament light chain displayed the potential as a reliable biomarker for brain injury evaluation. Plasma total tau is elevated following competitive rugby with and without a head injury, perhaps related to peripheral nerve trauma, and therefore total tau does not appear to be suitable as a blood biomarker.
... Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1) have been evaluated in several studies to determine the need for CT scan and neurosurgical intervention in mild to moderate traumatic brain injury patients (mmTBI) in adults [1][2][3][4][5][6][7] and more recently in children with mmTBI. [8][9][10] In early 2018, GFAP and UCH-L1 were Food and Drug Administration-approved for clinical use in adult patients with mmTBI to help determine the need for CT scan within 12 hours of injury. ...
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.
... The identification of protein biomarkers in acute TBI has been accomplished through both broad mass spectrometry approaches [8][9][10][11][12] and also with more narrow, targeted approaches that evaluate specific biomarker candidates [12,13]. For example, UCH-L1 (ubiquitin carboxy-terminal hydrolase L1) and GFAP (glial fibrillary acidic protein) have been routinely demonstrated as diagnostic biomarkers in human and animal TBI studies [14][15][16][17][18][19][20][21][22]. Importantly, the extensive study of UCH-L1 and GFAP in TBI has culminated in the FDA approval in February 2018 of a serum biomarker test for mild TBI (the "Brain Trauma Indicator", Banyan Biomarkers, San Diego, CA) [23]. ...
Study design:
This is a narrative review of the literature on neurochemical biomarkers in spinal cord injury (SCI).
Objectives:
The objective was to summarize the literature on neurochemical biomarkers in SCI and describe their use in facilitating clinical trials for SCI. Clinical trials in spinal cord injury (SCI) have been notoriously difficult to conduct, as exemplified by the paucity of definitive prospective randomized trials that have been completed, to date. This is related to the relatively low incidence and the complexity and heterogeneity of the human SCI condition. Given the increasing number of promising approaches that are emerging from the laboratory which are vying for clinical evaluation, novel strategies to help facilitate clinical trials are needed.
Methods:
A literature review was conducted, with a focus on neurochemical biomarkers that have been described in human neurotrauma.
Results:
We describe advances in our understanding of neurochemical biomarkers as they pertain to human SCI. The application of biomarkers from serum and cerebrospinal fluid (CSF) has been led by efforts in the human traumatic brain injury (TBI) literature. A number of promising biomarkers have been described in human SCI whereby they may assist in stratifying injury severity and predicting outcome.
Conclusions:
Several time-specific biomarkers have been described for acute SCI and for chronic SCI. These appear promising for stratifying injury severity and potentially predicting outcome. The subsequent application within a clinical trial will help to demonstrate their utility in facilitating the study of novel approaches for SCI.
... 45 Although being correlated with both TBI severity on admission CT scans and relevant outcomes, early S100B and UCH-L1 levels were also associated with presence of associated non-cranial injuries, replicating previous findings. [46][47][48][49] The other biomarkers displayed limited correlations with extracranial injury, in line with their restricted expression to nervous tissues. 27 Notably, the temporal sliding window approach used in this study and the relatively few samples in the first 24 h likely will underestimate the impact of extracranial contribution (Supplementary Fig. S3C). ...
Brain-enriched protein biomarkers of tissue fate are being introduced clinically to aid in traumatic brain injury (TBI) management. The aim of this study was to determine how concentrations of six different protein biomarkers, measured in samples collected during the first weeks after TBI, relate to injury severity and outcome. We included neuro-critical care TBI patients that were prospectively enrolled from 2007 to 2013, all having 1 to 3 blood samples drawn during the first two weeks. The biomarkers analyzed were S100B, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), tau and neurofilament-Light (NF-L). Glasgow Outcome Score (GOS) was assessed at 12 months. In total, 172 patients were included. All serum markers were associated with injury severity as classified on computed tomography scans at admission. Almost all biomarkers outperformed other known outcome predictors with higher levels the first five days, correlating with unfavorable outcomes, and UCH-L1 (0.260 pseduo-R2) displaying the best discrimination in univariate analyses. After adjusting for acknowledged TBI outcome predictors, GFAP and NF-L added most independent information to predict favorable/unfavorable GOS, improving the model from 0.38 to 0.51 pseudo-R2. A correlation matrix indicated substantial co-variance, with the strongest correlation between UCH-L1, GFAP and tau (r=0.827 to 0.880). Additionally, the principal component analysis exhibited clustering of UCH-L1 and tau, as well as GFAP, S100B and NSE, which was separate from NF-L. In summary, a panel of several different protein biomarkers, all associated with injury severity, with different cellular origin and temporal trajectories, improve outcome prediction models.
... The current diagnostic approaches to TBI lack objective markers to triage patients (Papa et al., 2012;Welch et al., 2016). Existing neurotrauma biomarkers include glial fibrillary acid protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), tau and neurofilament light chain (NFL) (Bazarian et al., 2018;Hossain et al., 2018); however, with the noted exception of GFAP (Zhang et al., 2014), several of these proteins lack either the sensitivity or specificity to quantify the magnitude of the injury. ...
The degree of brain injury is the governing factor for the magnitude of the patient's psycho- and physiological deficits post-injury, and the associated long-term consequences. The present scaling method used to segregate the patients among mild, moderate and severe phases of traumatic brain injury (TBI) has major limitations; however, a more continuous stratification of TBI is still elusive. With the anticipation that differentiating molecular markers could be the backbone of a robust method to triage TBI, we used a modified closed-head injury (CHI) Marmarou model with two impact heights (IH). By definition, IH directly correlates with the impact force causing TBI. In our modified CHI model, the rat skull was fitted with a helmet to permit a diffuse axonal injury. With the frontal cortex as the focal point of injury, the adjacent brain regions (hippocampus, HC and cerebellum, CB) were susceptible to diffuse secondary shock injury. At 8 days post injury (po.i.), rats impacted by 120 cm IH (IH120) took a longer time to find an escape route in the Barnes maze as compared to those impacted by 100 cm IH (IH100). Using a time-resolved interrogation of the transcriptomic landscape of HC and CB tissues, we mined those genes that altered their regulations in correlation with the variable IHs. At 14 days po.i., when all rats demonstrated nearly normal visuomotor performance, the bio-functional analysis suggested an advanced healing mechanism in the HC of IH100 group. In contrast, the HC of IH120 group displayed a delayed healing with evidence of active cell death networks. Combining whole genome rat microarrays with behavioral analysis provided the insight of neuroprotective signals that could be the foundation of the next generation triage for TBI patients.
Introduction Despite pre-clinical evidence for the role of inflammation in TBI, there is limited data on inflammatory biomarkers in mild TBI (mTBI). In this study, we describe the profile of plasma inflammatory cytokines and explore associations between these cytokines and neuropsychological outcomes after mTBI. Methods Patients with mTBI with negative computed tomography and orthopedic injury (OI) controls without mTBI were prospectively recruited from emergency rooms at three trauma centers. Plasma inflammatory cytokine levels were measured from venous whole blood samples that were collected at enrollment (within 24 hours of injury) and at 6 months after injury. Neuropsychological tests were performed at 1 week, 1 month, 3 months and 6 months after the injury. Multivariate regression analysis was performed to identify associations between inflammatory cytokines and neuropsychological outcomes. Results A total of 53 mTBI and 24 OI controls were included in this study. The majority of patients were male (62.3%), and injured in motor vehicle accidents (37.7%). Plasma IL-2 (p=0.014) and IL-6 (p=0.01) within 24 hours post-injury were significantly higher for mTBI patients as compared to OI controls. Elevated plasma IL-2 at 24 hours was associated with more severe one week post-concussive symptoms (p=0.001). At 6 months elevated plasma IL-10 was associated with greater depression scores (p=0.004) and more severe post-traumatic stress disorder (PTSD) symptoms (p=0.001). Conclusions Plasma cytokine levels (within 24 hours and at 6 months post-injury) were significantly associated with early and late post-concussive symptoms, PTSD, and depression scores after mTBI. These results highlight the potential role of inflammation in the pathophysiology of post-traumatic symptoms after mTBI.
The management of severe traumatic brain injury (TBI) is complex and difficult as patients present with a vast heterogeneity of injuries and may deteriorate due to secondary injuries despite treatment. Cerebrally enriched proteins of brain tissue fate in serum have been introduced as biomarkers attempting to better evaluate damage extent and trajectories. In this narrative chapter, we review the most commonly studied protein biomarkers, S100B, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and neurofilament light (NF-L), and how they predict injury severity and functional outcome, monitor deterioration, and may be used to determine treatment efficacy in trials. Further, we highlight opportunities and pitfalls in combinations of biomarkers, extracranial trauma, pediatric use, and available assays with the focus on creating a working manual for implementing protein biomarkers in clinical use of severe TBI.
Traumatic brain injury (TBI) is a major cause of disability worldwide, but the heterogeneous nature of TBI with respect to injury severity and health comorbidities make patient outcome difficult to predict. Injury severity accounts for only some of this variance, and a wide range of preinjury, injury‐related, and postinjury factors may influence outcome, such as sex, socioeconomic status, injury mechanism, and social support. Neuroimaging research in this area has generally been limited by insufficient sample sizes. Additionally, development of reliable biomarkers of mild TBI or repeated subconcussive impacts has been slow, likely due, in part, to subtle effects of injury and the aforementioned variability. The ENIGMA Consortium has established a framework for global collaboration that has resulted in the largest‐ever neuroimaging studies of multiple psychiatric and neurological disorders. Here we describe the organization, recent progress, and future goals of the Brain Injury working group. Graphical Abstract
TBI (traumatic brain injury) is a major cause of death among youth in industrialized societies. Brain damage following traumatic injury is a result of direct and indirect mechanisms; indirect or secondary injury involves the initiation of an acute inflammatory response, including the breakdown of the blood–brain barrier (BBB), brain edema, infiltration of peripheral blood cells, and activation of resident immunocompetent cells, as well as the release of numerous immune mediators such as interleukins and chemotactic factors. TBI can cause changes in molecular signaling and cellular functions and structures, in addition to tissue damage, such as hemorrhage, diffuse axonal damages, and contusions. TBI typically disturbs brain functions such as executive actions, cognitive grade, attention, memory data processing, and language abilities. Animal models have been developed to reproduce the different features of human TBI, better understand its pathophysiology, and discover potential new treatments. For many years, the first approach to manage TBI has been treatment of the injured tissue with interventions designed to reduce the complex secondary-injury cascade. Several studies in the literature have stressed the importance of more closely examining injuries, including endothelial, microglia, astroglia, oligodendroglia, and precursor cells. Significant effort has been invested in developing neuroprotective agents. The aim of this work is to review TBI pathophysiology and existing and potential new therapeutic strategies in the management of inflammatory events and behavioral deficits associated with TBI.
Repetitive traumatic brain injuries (TBIs) among military personnel have been linked to chronic behavioral and neurological symptoms, and poor health outcomes. Repetitive TBIs may impact inflammation, which may offer some explanation of the biological basis of these long-term risks, and may improve the care that is provided to these individuals. This study examines the concentrations of TNFα, IL-6 and IL-10 and associations with behavioral symptoms, including post-traumatic stress disorder symptoms and depression in a cohort of 106 military personnel and Veterans with a history of TBI. Group comparisons conducted for those with repetitive TBIs (> 3; n = 44), to participants with less than three TBIs (n = 29), and controls with no TBIs (n = 33). The primary outcomes were serum levels of inflammatory related proteins TNF-α, IL-6 and IL-10, TBI history, and PTSD symptoms. IL-6 mean concentration was significantly higher in the repetitive TBI group compared to those with 1-2 TBI or no TBI history (p = 0.050). Additionally, for participants with a history of TBI, PTSD symptom severity, specifically, intrusion (p = .006 and p = .007) and avoidance (p = .034 and .009), were significant predictors of higher IL-6 and IL-10 concentrations respectively. These findings suggest that repetitive TBIs concurrent with high PTSD symptoms in military personnel and Veterans are associated with chronic inflammation, and specifically elevated concentrations of IL-6. Examining the changes in inflammatory processes may identify potential therapeutic targets for early intervention after TBI in order to prevent the development of neurological deficits and disorders.
Aim
We evaluated the prognostic value of serum- and cerebrospinal fluid (CSF)-ubiquitin carboxyl-terminal esterase L1 protein (UCHL1) measurements in post- post-out of hospital cardiac arrest (OHCA) patients treated with target temperature management (TTM), to predict neurologic outcome.
Methods
This was a prospective single-centre observational cohort study, conducted from April 2018 to September 2019. Serum- and CSF-UCHL1 were obtained immediately (UCHL1initial), 24 h (UCHL124), 48 h (UCHL148), and 72 h (UCHL172) after return of spontaneous circulation (ROSC). The area under the receiver operating characteristic curves (AUROC) and Delong method were used to identify cut-off values of serum- and CSF-UCHL1initial, UCHL124, UCHL148, UCHL172 for predicting neurologic outcomes.
Results
Of 38 patients enrolled, 16 comprised the poor outcome group. The AUROCs for serum- and CSF-UCHL1initial were 0.71 and 0.93 in predicting poor neurological outcomes, respectively (p = 0.01). The AUROCs for serum- and CSF-UCHL124 were 0.85 and 0.91, (p = 0.24). The AUROCs for serum- and CSF-UCHL148 were 0.90 and 0.97, (p = 0.07). The AUROCs for serum- and CSF-UCHL172 were 0.94 and 0.98, (p = 0.25).
Conclusion
Findings of this study demonstrate that CSF-UCHL1 measured immediately, 24 h, 48 h, and 72 h after ROSC is a valuable predictor for evaluating neurologic outcomes, whereas serum-UCHL1 measured at 24 h, 48 h, and 72 h after ROSC showed a significant performance in the prognostication of poor outcomes in post-OHCA patients treated with TTM.
Background:
Early identification of traumatic intracranial hemorrhage (ICH) has implications for triage and intervention. Blood-based biomarkers were recently FDA approved for prediction of ICH in patients with mild TBI. We sought to determine if biomarkers measured early after injury improve prediction of mortality and clinical/radiologic outcomes compared to GCS alone in patients with moderate or severe TBI (MS-TBI).
Methods:
We measured glial-fibrillary-acidic-protein (GFAP), ubiquitin-C-terminal-hydrolase-L1 (UCH-L1), and microtubule-associated-protein-2 (MAP-2) on arrival to the ED in patients with blunt TBI enrolled in the placebo arm of the Prehospital TXA for TBI Trial (prehospital GCS 3-12, SPB > 90). Biomarkers were modeled individually and together with prehospital predictor variables [PH] (GCS, age, gender). Data was divided into a training dataset and test dataset for model derivation and evaluation. Models were evaluated for prediction of ICH, mass lesion, 48-hour and 28-day mortality, and 6-month Glasgow Outcome Scale-Extended [GOSE] and Disability Rating Scale [DRS]. AUC was evaluated in test data for PH alone, PH+individual biomarkers, and PH+3 biomarkers.
Results:
Of 243 patients with baseline samples (obtained a median 84 min after injury), prehospital GCS was 8 (IQR 5,10), 55% had ICH, and 48-hr and 28-day mortality was 7 and 13%. Poor neurologic outcome at 6 months was observed in 34% based on GOS-E ≤4, and 24% based on DRS >7. Addition of each biomarker to PH improved AUC in the majority of predictive models. GFAP+PH compared to PH alone significantly improved AUC in all models [ICH: 0.82 vs 0.64; 48-hour mortality 0.84 vs 0.71; 28-day mortality: 0.84 vs 0.66; GOSE: 0.78 vs 0.69; DRS 0.84 vs 0.81, all p<0.001].
Conclusions:
Circulating blood-based biomarkers may improve prediction neurological outcomes and mortality in patients with MS-TBI over prehospital characteristics alone. GFAP appears to be the most promising. Future evaluation in the prehospital setting is warranted.
Level of evidence:
Prognostic and Epidemiological Level II, Prospective.
Traumatic brain injury (TBI) is a serious public health concern for which sensitive and objective diagnostic methods remain lacking. While advances in neuroimaging have improved diagnostic capabilities, the complementary use of molecular biomarkers can provide clinicians with additional insight into the nature and severity of TBI. In this study, a panel of eight metabolites involved in distinct pathophysiological processes related to concussion was quantified using high-performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS). Specifically, the newly developed method can simultaneously determine urinary concentrations of glutamic acid, homovanillic acid, 5-hydroxyindoleacetic acid, methionine sulfoxide, lactic acid, pyruvic acid, N-acetylaspartic acid, and F2α-isoprostane without intensive sample preparation or preconcentration. The method was systematically validated to assess sensitivity (method detection limits: 1-20 μg/L), accuracy (81-124% spike recoveries in urine), and reproducibility (relative standard deviation: 4-12%). The method was ultimately applied to a small cohort of urine specimens obtained from healthy college student volunteers. The method presented here provides a new technique to facilitate future work aiming to assess the clinical efficacy of these putative biomarkers for noninvasive assessment of TBI.
Mild traumatic brain injuries (mTBI) are prevalent and can result in significant debilitation. Current diagnostic methods have implicit limitations, with clinical assessment tools reliant on subjective self-reported symptoms or non-specific clinical observations, and commonly available imaging techniques lacking sufficient sensitivity to detect mTBI. A blood biomarker would provide a readily accessible detector of mTBI to meet the current measurement gap. Suitable options would provide objective and quantifiable information in diagnosing mTBI, in monitoring recovery, and in establishing a prognosis of resultant neurodegenerative disease, such as chronic traumatic encephalopathy (CTE). A biomarker would also assist in progressing research, providing suitable endpoints for testing therapeutic modalities and for further exploring mTBI pathophysiology. This review highlights the most promising blood-based protein candidates that are expressed in the central nervous system (CNS) and released into systemic circulation following mTBI. To date, neurofilament light (NF-L) may be the most suitable candidate for assessing neuronal damage, and glial fibrillary acidic protein (GFAP) for assessing astrocyte activation, although further work is required. Ultimately, the heterogeneity of cells in the brain and each marker’s limitations may require a combination of biomarkers, and recent developments in microRNA (miRNA) markers of mTBI show promise and warrant further exploration.
Although concussion has been a subject of interest for centuries, this condition remains poorly understood. The mechanistic underpinnings and accepted definition of concussion remain elusive. To make sense of these issues, this article presents a brief history of concussion studies, detailing the evolution of motivations and experimental conclusions over time. Interest in concussion as a subject of scientific inquiry has increased with growing concern about the long-term consequences of mild traumatic brain injury (TBI). Although concussion is often associated with mild TBI, these conditions-the former a neurological syndrome, the latter a neurological event-are distinct, both mechanistically and pathobiologically. Modern research primarily focuses on the study of the biomechanics, pathophysiology, potential biomarkers and neuroimaging to distinguish concussion from mild TBI. In addition, mild TBI and concussion outcomes are influenced by age, sex, and genetic differences in people. With converging experimental objectives and methodologies, future concussion research has the potential to improve clinical assessment, treatment, and preventative measures.
Traumatic brain injury (TBI) can trigger progressive neurodegeneration, with tau pathology seen years after a single moderate-severe TBI. Identifying this type of posttraumatic pathology in vivo might help to understand the role of tau pathology in TBI pathophysiology. We used flortaucipir positron emission tomography (PET) to investigate whether tau pathology is present many years after a single TBI in humans. We examined PET data in relation to markers of neurodegeneration in the cerebrospinal fluid (CSF), structural magnetic resonance imaging measures, and cognitive performance. Cerebral flortaucipir binding was variable, with many participants with TBI showing increases in cortical and white matter regions. At the group level, flortaucipir binding was increased in the right occipital cortex in TBI when compared to healthy controls. Flortaucipir binding was associated with increased total tau, phosphorylated tau, and ubiquitin carboxyl-terminal hydrolase L1 CSF concentrations, as well as with reduced fractional anisotropy and white matter tissue density in TBI. Apolipoprotein E ( APOE ) ε4 genotype affected the relationship between flortaucipir binding and time since injury, CSF β amyloid 1–42 (Aβ42) concentration, white matter tissue density, and longitudinal Mini-Mental State Examination scores in TBI. The results demonstrate that tau PET is a promising approach to investigating progressive neurodegeneration associated with tauopathy after TBI.
Ubiquitin C-terminal hydrolase L1 (UCHL-1) and glial fibrillary acidic protein (GFAP) are two blood-based biomarkers which have been investigated as a combined assay to predict traumatic intracranial injuries on head CT. Ubiquitin is found in nearly all cells of the body and is a regulatory protein, whereas GFAP is a member of the intermediate filament family of cytoskeletal proteins that provide a structural support to the neuroglia. The ALERT-traumatic brain injury study investigated GFAP/UCHL1 and found a sensitivity of 0.973 for prediction of acute intracranial injury on CT for all patients suffering a minor traumatic brain injury (GCS14–15) and a specificity of 0.006 (1) for identifying neurosurgically manageable lesions. These biomarkers could be useful in ruling out intracranial hemorrhages but further research will be needed to look at the impact on current clinical care models.
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.
Mild traumatic brain injury (mTBI) is one of the common causes of emergency department visits around the world. Up to 90% of injuries are classified as mTBI. Cranial computed tomography (CCT) is a standard diagnostic tool for adults with mTBI. Alternatively, children can be admitted for inpatient observation with CCT scans performed only on those with clinical deterioration. The use of blood biomarkers is a supplementary tool for identifying patients at risk of intracerebral lesions who may need imaging. This review provides a contemporary clinical and laboratory framework for blood biomarker testing in mTBI management. The S100B protein is used routinely in the management of mTBI in Europe together with clinical guidelines. Due to its excellent negative predictive value, S100B protein is an alternative choice to CCT scanning for mTBI management under considered, consensual and pragmatic use. In this review, we propose points to help clinicians and clinical pathologists use serum S100B protein in the clinical routine. A review of the literature on the different biomarkers (GFAP, UCH-L1, NF [H or L], tau, H-FABP, SNTF, NSE, miRNAs, MBP, β trace protein) is also conducted. Some of these other blood biomarkers, used alone (GFAP, UCH-L1) or in combination (GFAP + H-FABP ± S100B ± IL10) can improve the specificity of S100B.
Introduction
Traumatic brain injury (TBI) is a major global health issue, resulting in debilitating consequences to families, communities, and healthcare systems. Prior research has found that biomarkers aid in the pathophysiological characterization and diagnosis of TBI. Significantly, the FDA has recently cleared both a bench-top assay and a rapid point-of-care assays of tandem biomarker (UCH-L1/GFAP)-based blood test to aid in the diagnosis mTBI patients. With the global necessity of TBI biomarkers research, several major consortium multicenter observational studies with biosample collection and biomarker analysis have been created in the USA, Europe, and Canada. As each geographical region regulates its data and findings, the International Initiative for Traumatic Brain Injury Research (InTBIR) was formed to facilitate data integration and dissemination across these consortia.
Areas Covered
This paper covers heavily investigated TBI biomarkers and emerging non-protein markers. Finally, we analyze the regulatory pathways for converting promising TBI biomarkers into approved in-vitro diagnostic tests in the United States, European Union, and Canada.
Expert Opinion
TBI biomarker research has significantly advanced in the last decade. The recent approval of an iSTAT point of care test to detect mild TBI has paved the way for future biomarker clearance and appropriate clinical use across the globe.
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.
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.
Importance:
In 2018, the combination of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1) levels became the first US Food and Drug Administration-approved blood test to detect intracranial lesions after mild to moderate traumatic brain injury (MTBI). How this blood test compares with validated clinical decision rules remains unknown.
Objectives:
To compare the performance of GFAP and UCH-L1 levels vs 3 validated clinical decision rules for detecting traumatic intracranial lesions on computed tomography (CT) in patients with MTBI and to evaluate combining biomarkers with clinical decision rules.
Design, setting, and participants:
This prospective cohort study from a level I trauma center enrolled adults with suspected MTBI presenting within 4 hours of injury. The clinical decision rules included the Canadian CT Head Rule (CCHR), New Orleans Criteria (NOC), and National Emergency X-Radiography Utilization Study II (NEXUS II) criteria. Emergency physicians prospectively completed data forms for each clinical decision rule before the patients' CT scans. Blood samples for measuring GFAP and UCH-L1 levels were drawn, but laboratory personnel were blinded to clinical results. Of 2274 potential patients screened, 697 met eligibility criteria, 320 declined to participate, and 377 were enrolled. Data were collected from March 16, 2010, to March 5, 2014, and analyzed on August 11, 2021.
Main outcomes and measures:
The presence of acute traumatic intracranial lesions on head CT scan (positive CT finding).
Results:
Among enrolled patients, 349 (93%) had a CT scan performed and were included in the analysis. The mean (SD) age was 40 (16) years; 230 patients (66%) were men, 314 (90%) had a Glasgow Coma Scale score of 15, and 23 (7%) had positive CT findings. For the CCHR, sensitivity was 100% (95% CI, 82%-100%), specificity was 33% (95% CI, 28%-39%), and negative predictive value (NPV) was 100% (95% CI, 96%-100%). For the NOC, sensitivity was 100% (95% CI, 82%-100%), specificity was 16% (95% CI, 12%-20%), and NPV was 100% (95% CI, 91%-100%). For NEXUS II, sensitivity was 83% (95% CI, 60%-94%), specificity was 52% (95% CI, 47%-58%), and NPV was 98% (95% CI, 94%-99%). For GFAP and UCH-L1 levels combined with cutoffs at 67 and 189 pg/mL, respectively, sensitivity was 100% (95% CI, 82%-100%), specificity was 25% (95% CI, 20%-30%), and NPV was 100%; with cutoffs at 30 and 327 pg/mL, respectively, sensitivity was 91% (95% CI, 70%-98%), specificity was 20% (95% CI, 16%-24%), and NPV was 97%. The area under the receiver operating characteristic curve (AUROC) for GFAP alone was 0.83; for GFAP plus NEXUS II, 0.83; for GFAP plus NOC, 0.85; and for GFAP plus CCHR, 0.88. The AUROC for UCH-L1 alone was 0.72; for UCH-L1 plus NEXUS II, 0.77; for UCH-L1 plus NOC, 0.77; and for UCH-L1 plus CCHR, 0.79. The GFAP biomarker alone (without UCH-L1) contributed the most improvement to the clinical decision rules.
Conclusions and relevance:
In this cohort study, the CCHR, the NOC, and GFAP plus UCH-L1 biomarkers had equally high sensitivities, and the CCHR had the highest specificity. However, using different cutoff values reduced both sensitivity and specificity of GFAP plus UCH-L1. Use of GFAP significantly improved the performance of the clinical decision rules, independently of UCH-L1. Together, the CCHR and GFAP had the highest diagnostic performance.
For nearly 100 years, it was erroneously believed that the loss of consciousness and/or the altered mental status associated with a mild traumatic brain injury (mTBI) offered protection from the development of posttraumatic stress disorder (PTSD). However, it is now accepted that it is possible for PTSD to result from mTBI, and that the co-occurrence of these two conditions creates a more difficult condition to treat and worsens prognosis. In addition, it is known that the symptomology associated with PTSD and mTBI have a great deal of overlap, complicating diagnoses. The objective of this chapter is to review the current state of biomarkers aimed at diagnosing comorbid mTBI and PTSD that are useful on a single-patient basis and are not reliant on self-report or arduous interviews. Further, implications for future research and treatment are discussed.
Aim: There is a critical need to validate biofluid-based biomarkers as diagnostic and drug development tools for traumatic brain injury (TBI). As part of the TBI Endpoints Development Initiative, we identified four potentially predictive and pharmacodynamic biomarkers for TBI: astroglial markers GFAP and S100B and the neuronal markers UCH-L1 and Tau. Materials & methods: Several commonly used platforms for these four biomarkers were identified and compared on analytic performance and ability to detect gold standard recombinant protein antigens and to pool control versus TBI cerebrospinal fluid (CSF). Results: For each marker, only some assay formats could differentiate TBI CSF from the control CSF. Also, different assays for the same biomarker reported divergent biomarker values for the same biosamples. Conclusion: Due to the variability of TBI marker assay in performance and reported values, standardization strategies are recommended when comparing reported biomarker levels across assay platforms.
Purpose: Recognizing sport-related concussion (SRC) is challenging and relies heavily on subjective symptom reports. An objective, biologic marker could improve recognition and understanding of SRC. There is emerging evidence that salivary micro-ribonucleic acids (miRNAs) may serve as biomarkers of concussion; however, it remains unclear whether concussion-related miRNAs are impacted by exercise. We sought to determine whether 40 miRNAs previously implicated in concussion pathophysiology were affected by participation in a variety of contact and non-contact sports. Our goal was to refine a miRNA-based tool capable of identifying athletes with SRC without the confounding effects of exercise.
Methods: This case-control study harmonized data from concussed and non-concussed athletes recruited across 10 sites. Levels of salivary miRNAs within 455 samples from 314 individuals were measured with RNA sequencing. Within-subjects testing was used to identify and exclude miRNAs that changed with either: a) a single episode of exercise (166 samples from 83 individuals); or b) season-long participation in contact sports (212 samples from 106 individuals). The miRNAs that were not impacted by exercise were interrogated for SRC diagnostic utility using logistic regression (172 samples from 75 concussed and 97 non-concussed individuals).
Results: Two miRNAs (miR-532-5p, miR-182-5p) decreased (adjusted p < 0.05) after a single episode of exercise, and 1 miRNA (miR-4510) increased only after contact sports participation. Twenty-three miRNAs changed at the end of a contact sports season. Two of these miRNAs (miR-26b-3p, miR-29c-3p) were associated (R > 0.5; adjusted p < 0.05) with the number of head impacts sustained in a single football practice. Among the 15 miRNAs not confounded by exercise or season-long contact sports participation, 11 demonstrated a significant difference (adj. p < 0.05) between concussed and non-concussed participants, and 6 displayed moderate ability (AUC > 0.70) to identify concussion. A single ratio (miR-27a-5p/miR-30a-3p) displayed the highest accuracy (AUC = 0.810, sensitivity = 82.4%, specificity = 73.3%) for differentiating concussed and non-concussed participants. Accuracy did not differ between participants with SRC and non-SRC (z = 0.5, p = 0.60).
Conclusion: Salivary miRNA levels may accurately identify SRC when not confounded by exercise. Refinement of this approach in a large cohort of athletes could eventually lead to a non-invasive, sideline adjunct for SRC assessment.
Purpose of review:
Traumatic brain injury (TBI) is highly prevalent among service members and Veterans (SMVs) and associated with changes in blood-based biomarkers. This manuscript reviews candidate biomarkers months/years following military-associated TBI.
Recent findings:
Several blood-based biomarkers have been investigated for diagnostic or prognostic use to inform care years after military-associated TBI. The most promising include increased levels of plasma/serum and exosomal proteins reflecting neuronal, axonal and/or vascular injury, and inflammation, as well as altered microRNA expression and auto-antibodies of central nervous system markers. Diagnostic and prognostic biomarkers of remote TBI outcomes remain in the discovery phase. Current evidence does not yet support single or combination biomarkers for clinical diagnostic use remotely after injury, but there are promising candidates that require validation in larger, longitudinal studies. The use of prognostic biomarkers of future neurodegeneration, however, holds much promise and could improve treatments and/or preventive measures for serious TBI outcomes.
Background
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.
Objective
This systematic review aims to report current data on the diagnostic and prognostic utility of blood-based biomarkers across the spectrum of TBI.
Methods
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.
Results
An initial 1463 studies were identified. 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, 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 to healthy, orthopedic, and polytrauma controls. The biomarkers also displayed significant variability across mild, moderate, and severe TBI categories, as well as in concussion cases.
Conclusion
This review summarizes existing high-quality evidence that supports the use of severity-specific biomarkers in the diagnostic and prognostic evaluation of TBI. This data can be used as a launching platform for the validation of upcoming clinical studies.
Diagnostic and prognostic tools for risk stratification of concussion patients are limited in the early stages of injury in the acute setting. Research in the field of traumatic brain injury (TBI) biomarkers has increased exponentially over the last 20 years with a barrage of publications on the topic in the last decade. 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 most welcomed clinical tool. Previously, 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. Recently, two biomarkers have now been FDA approved for clinical use in adult patients with mild-to-moderate TBI to help determine the need for CT scan acutely after injury. More work is also being done to detect subclinical injuries. In an effort to prevent chronic traumatic encephalopathy (CTE) and long-term consequences of concussion/mild TBI, early diagnostic and prognostic tools are becoming increasingly important, particularly in sports injuries and in military personnel where concussions/mild TBI are common occurrences. Should biofluid biomarkers for TBI be validated and become widely available, they could have many roles. They could help with clinical decision-making by clarifying injury severity and help monitor the progression of injury and/or recovery. Biomarkers could have a role in managing patients at high risk of repeated brain injury and could be incorporated into guidelines for return to duty, work, or sports activities. 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 reviews the most widely studied proteomic biomarkers for mild TBI and concussion in humans and introduces a novel group of promising transcriptomic biomarkers.
Traumatic brain injury (TBI) is a global health burden. Most cases diagnosed with
TBI are mild traumatic brain injury (mTBI), however, no unanimous definition of
mTBI exists. Although most of the patients with mTBI recover well, a group of
patients develop persistent post-injury symptoms. Blood biomarkers could be used
as the surrogate markers of injury and could assist in assessing the true severity and
prognosis of the eventual brain damage.
Three studies were conducted for this project. Firstly, blood levels of glial
fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1
(UCH-L1) were analysed in patients with orthopedic trauma without any central
nervous system (CNS) insults compared to patients with computed tomography
(CT)-negative mTBI at multiple time points after admission and during follow-up
visits. The second study correlated the admission levels (≤24 hours) of GFAP
and neurofilament light (NF-L) with outcome in patients with mTBI to explore the
prediction abilities of these blood biomarkers. In the last study, the prognostic value
of the neurodegenerative biomarkers, total tau (T-tau) and β-amyloid isoforms 1–40
(Aβ40), and 1–42 (Aβ42) were investigated using admission samples. Combinations
of biomarkers panels were formed to study the sensitivity and specificity of these
biomarkers for outcome prediction (studies II and III). A multiparameter panel
including the clinical parameters and blood biomarkers was devised to study the best
prediction model (study III).
This project, focusing on the acute biochemical diagnostics of mTBI, reported
that GFAP and UCH-L1 are not specific biomarkers for CT-negative mTBI.
However, we found that the early levels of GFAP and NF-L are significantly
correlated with the outcome in patients with mTBI. The admission level of NF-L has
a significant predictive value for mTBI, also in a multi-variate model. Finally, the
admission levels of T-tau were significantly correlated with the outcome in patients
with mTBI.
Keywords: traumatic brain injury, orthopedic injury, glial fibrillary acidic
protein, ubiquitin carboxy-terminal hydrolase L1, neurofilament light, total tau, β-
amyloid 1–40, β-amyloid 1–42, outcome
Background: Mild traumatic brain injury (mTBI) is one of the most common causes of emergency department visits around the world. Up to 90% of injuries are classified as mTBI. Cranial computed tomography (CCT) is a standard diagnosis tool to identify intracranial complications in adults with mTBI.Alternatively, children can be admitted for inpatient observation with CCT scans performed only on those with clinical deterioration. The use of blood biomarkers is a supplementary tool for identifying patients at risk of intracerebral lesions who may need imaging.
Method: We realised a bibliographic state of art providing a contemporary clinical and laboratory framework for blood biomarker testing in mTBI management.
Results: The S100B protein is the only biomarker that can be used today in the clinical routine for management of mTBI with appropriate evidence-based medicine. Due to its excellent negative predictive value, S100B protein is an alternative choice to CCT scanning for mTBI management with considered, consensual and pragmatic use. In this state of art, we propose points to help clinicians and clinical pathologists use serum S100B protein in the clinical routine. A state of art on the different biomarkers (GFAP, UCH-L1, NF [H or L], tau, H-FABP, SNTF, NSE, miRNAs, MBP) is also conducted. Some of these other biomarkers, used alone (GFAP, UCH-L1) or in combination (GFAP + H-FABP ± S100B ± IL10) can improve the specificity of S100B.
Conclusion: Using a bibliographic state of art, we highlighted the added values of the blood biomarkers for the clinical management of mTBI.
The last twenty years have seen the advent of new technologies that enhance the diagnosis and prognosis of traumatic brain injury (TBI). There is recognition that TBI affects the brain beyond initial injury, in some cases inciting a progressive neuropathology that leads to chronic impairments. Medical researchers are now searching for biomarkers to detect and monitor this condition. Perhaps the most promising developments are in the biomolecular and neuroimaging domains. Molecular assays can identify proteins indicative of neuronal injury and/or degeneration. Diffusion imaging now allows sensitive evaluations of the brain's cellular microstructure. As the pace of discovery accelerates, it is important to survey the research landscape and identify promising avenues of investigation. In this review, we discuss the potential of molecular and diffusion tensor imaging (DTI) biomarkers in TBI research. Integration of these technologies could advance models of disease prognosis, ultimately improving care. However, to date, few studies have explored relationships between molecular and DTI variables in TBI patients. Here, we provide a short primer on each technology, review the latest research, and discuss how these biomarkers may be incorporated in future studies.
Traumatic brain injury (TBI), defined as a traumatic blow or jolt to the head, or penetrating trauma to the skull that injures the brain, is a worldwide epidemic that has a substantial impact on global health and function. In this chapter, we overview TBI epidemiology and health care costs as well as discuss the fundamental pathophysiology associated with primary and secondary injury. We discuss TBI across the injury severity spectrum and continuum of care and also in the context of other injury complex elements such as injury due to blast, hypoxic-ischemic brain injury, polytrauma, and shaken-baby syndrome. We discuss how TBI influences neurotransmission and the myriad of secondary symptoms, conditions, and complications that arise due to TBI. Key testing and medical management approaches are discussed, and the roles of rehabilitation team members across the continuum of care are outlined. Translational research perspectives, including biomarkers and imaging modalities, as well as community integration and TBI prevention strategies are discussed. This comprehensive overview of TBI provides up-to-date perspectives and the fundamental literature needed for rehabilitation clinicians to be knowledgeable and address TBI epidemiology, pathophysiology, secondary conditions, management, prognostication, outcome, community reintegration, and prevention. Pediatric perspectives on these areas as also provided.
Bearing a strong resemblance to the phenotypic and functional remodeling of the immune system that occurs during aging (termed immunesenescence), the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 2019 (COVID-19), is characterized by an expansion of inflammatory monocytes, functional exhaustion of lymphocytes, dysregulated myeloid responses and the presence of highly activated senescent T cells. Alongside advanced age, male gender and pre-existing co-morbidities [e.g., obesity and type 2 diabetes (T2D)] are emerging as significant risk factors for COVID-19. Interestingly, immunesenescence is more profound in males when compared to females, whilst accelerated aging of the immune system, termed premature immunesenescence, has been described in obese subjects and T2D patients. Thus, as three distinct demographic groups with an increased susceptibility to COVID-19 share a common immune profile, could immunesenescence be a generic contributory factor in the development of severe COVID-19? Here, by focussing on three key aspects of an immune response, namely pathogen recognition, elimination and resolution, we address this question by discussing how immunesenescence may weaken or exacerbate the immune response to SARS-CoV-2. We also highlight how aspects of immunesenescence could render potential COVID-19 treatments less effective in older adults and draw attention to certain therapeutic options, which by reversing or circumventing certain features of immunesenescence may prove to be beneficial for the treatment of groups at high risk of severe COVID-19.
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.
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.
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.
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.
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.
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.
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.
Developed by the Mild Traumatic Brain Injury Committee of the Head Injury Interdisciplinary Special Interest Group of the 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)
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-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 (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.
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.
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.
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.
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 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.
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 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.