Biomarkers Of Traumatic Brain Injury Research Articles

Reliability of serum S100B measurement following mild traumatic brain injury: a comparison of assay measurements from two laboratories

ABSTRACT Objective There is enormous research and clinical interest in blood-based biomarkers of mild traumatic brain injury (MTBI) sustained in sports, daily life, or military service. We examined the reliability of a commercially available assay for S100B used on the same samples by two different laboratories separated by 2 years in time. Methods and Procedures A cohort of 163 adult patients (head CT-scanned, n = 110) with mild head injury were enrolled from the emergency department (ED). All had Glasgow Coma Scale scores of 14 or 15 in the ED (94.4% = 15). The mean time between injury and venous blood sampling was 2.9 h (SD = 1.4; Range = 0.5–6.0 h). Serum S100B was measured at two independent centers using the same high throughput clinical assay (Elecsys S100B®; Roche Diagnostics). Results The Spearman correlation between the two assays in the total sample (N = 163) was r = 0.93. A Wilcoxson Signed Ranks test indicated that the median scores for the values differed (Z = 2,082, p < .001, Cohen’s d = 0.151, small effect size). The values obtained from the two laboratories were very similar for identifying traumatic intracranial abnormalities (sensitivity = 80.1% versus 85.7%). Conclusions The serum S100B results measured using the same assay in different laboratories yielded highly correlated and clinically similar, but clearly not identical, results.

Plasma extracellular vesicles as a source of biomarkers in traumatic brain injury.

The objective of this study was to isolate extracellular vesicles (EVs) from plasma in a cohort of patients with traumatic brain injury (TBI) and analyze their contents for novel biomarkers that could prove useful for rapid diagnosis and classification of brain injury during initial evaluation. Plasma EVs were isolated by serial ultracentrifugation from patients with TBI (n = 15) and healthy controls (n = 5). Samples were obtained from the TRACK-TBI biorepository (2010-present). Size and concentration were determined by nanoparticle tracking. Glial fibrillary acidic protein (GFAP) concentration was determined in EV protein. EV RNA was isolated and deep sequencing of short noncoding RNA was performed. Plasma EVs are physically similar but contained approximately 10 times more GFAP in TBI patients with altered consciousness than patients and controls with normal consciousness. Eleven highly differentially expressed microRNAs (miRNAs) were identified between these groups. Genes targeted by these miRNAs are highly associated with biologically relevant cellular pathways, including organismal injury, cellular development, and organismal development. Multiple additional coding and noncoding RNA species with potential biomarker utility were identified. Isolating plasma EVs in patients with TBI is feasible. Increased GFAP concentration-a validated plasma TBI marker-in EVs from TBI patients with altered consciousness, along with differential expression of multiple miRNAs targeting TBI-relevant pathways, suggests that EVs may be a useful source of TBI biomarkers. Additional evaluation in larger patient cohorts is indicated.

Extracellular Vesicle Proteins and MicroRNAs as Biomarkers for Traumatic Brain Injury.

Traumatic brain injury (TBI) is a heterogeneous condition, associated with diverse etiologies, clinical presentations and degrees of severity, and may result in chronic neurobehavioral sequelae. The field of TBI biomarkers is rapidly evolving to address the many facets of TBI pathology and improve its clinical management. Recent years have witnessed a marked increase in the number of publications and interest in the role of extracellular vesicles (EVs), which include exosomes, cell signaling, immune responses, and as biomarkers in a number of pathologies. Exosomes have a well-defined lipid bilayer with surface markers that reflect the cell of origin and an aqueous core that contains a variety of biological material including proteins (e.g., cytokines and growth factors) and nucleic acids (e.g., microRNAs). The presence of proteins associated with neurodegenerative changes such as amyloid-β, α-synuclein and phosphorylated tau in exosomes suggests a role in the initiation and propagation of neurological diseases. However, mechanisms of cell communication involving exosomes in the brain and their role in TBI pathology are poorly understood. Exosomes are promising TBI biomarkers as they can cross the blood-brain barrier and can be isolated from peripheral fluids, including serum, saliva, sweat, and urine. Exosomal content is protected from enzymatic degradation by exosome membranes and reflects the internal environment of their cell of origin, offering insights into tissue-specific pathological processes. Challenges in the clinical use of exosomal cargo as biomarkers include difficulty in isolating pure exosomes, variable yields of the isolation processes, quantification of vesicles, and lack of specificity of exosomal markers. Moreover, there is no consensus regarding nomenclature and characteristics of EV subtypes. In this review, we discuss current technical limitations and challenges of using exosomes and other EVs as blood-based biomarkers, highlighting their potential as diagnostic and prognostic tools in TBI.

Neurofilament light as a biomarker in traumatic brain injury.

To determine whether serum neurofilament light (NfL) correlates with CSF NfL, traumatic brain injury (TBI) diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) estimates of traumatic axonal injury (TAI). Participants were prospectively enrolled in Sweden and the United States between 2011 and 2019. The Swedish cohort included 45 hockey players with acute concussion sampled at 6 days, 31 with repetitive concussion with persistent postconcussive symptoms (PCS) assessed with paired CSF and serum (median 1.3 years after concussion), 28 preseason controls, and 14 nonathletic controls. Our second cohort included 230 clinic-based participants (162 with TBI and 68 controls). Patients with TBI also underwent serum, functional outcome, and imaging assessments at 30 (n = 30), 90 (n = 48), and 180 (n = 59) days and 1 (n = 84), 2 (n = 57), 3 (n = 46), 4 (n = 38), and 5 (n = 29) years after injury. In athletes with paired specimens, CSF NfL and serum NfL were correlated (r = 0.71, p < 0.0001). CSF and serum NfL distinguished players with PCS >1 year from PCS ≤1 year (area under the receiver operating characteristic curve [AUROC] 0.81 and 0.80). The AUROC for PCS >1 year vs preseason controls was 0.97. In the clinic-based cohort, NfL at enrollment distinguished patients with mild from those with moderate and severe TBI (p < 0.001 and p = 0.048). Serum NfL decreased over the course of 5 years (ß = -0.09 log pg/mL, p < 0.0001) but remained significantly elevated compared to controls. Serum NfL correlated with measures of functional outcome, MRI brain atrophy, and DTI estimates of TAI. Serum NfL shows promise as a biomarker for acute and repetitive sports-related concussion and patients with subacute and chronic TBI. This study provides Class III evidence that increased concentrations of NfL distinguish patients with TBI from controls.

Utility of biomarkers in traumatic brain injury: a narrative review

Introduction: With the evolution of diagnostic techniques in traumatic brain injury (TBI), the study of neurological injury has made progress based on the concepts of primary and secondary injury, leading to the era of proteomics to understand the complex molecular events involved in the process.&#x0D; Objectives: This narrative review is intended to discuss the state of the art of the most frequently used biomarkers in TBI, their clinical utility, and the implications for therapeutic decisionmaking protocols.&#x0D; Materials and methods: In order to fulfill the objective of this paper, a literature review was conducted of the most important databases.&#x0D; Results: Several biomarkers have been studied as prognostic factors in patients with TBI. Learning about their sensitivity and specificity in neurological injury, and its post-trauma evolution over time, has been the goal of various papers in the past few years.&#x0D; Conclusion: Breakthroughs in the study of protein degradation make it necessary to broaden the spectrumand knowledge of new diagnostic methods in TBI. Further studies are needed to define the role of biomarkers and to promote protocols integrating specific values.

Plasma glial fibrillary acidic protein and neurofilament light chain, but not tau, are biomarkers of sports-related mild traumatic brain injury.

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 were analysed at the group and individual player level. Plasma glial fibrillary acidic protein concentration was significantly increased 1-h 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-h and 3- to 10-day 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-h 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-h post-match control players from 1-h 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 h 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.

Early versus Late Profiles of Inflammatory Cytokines after Mild Traumatic Brain Injury and Their Association with Neuropsychological Outcomes.

Despite pre-clinical evidence for the role of inflammation in traumatic brain injury (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. 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 h 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. 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 interleukin (IL)-2 (p = 0.01) and IL-6 (p = 0.01) within 24 h post-injury were significantly higher for mTBI patients compared with OI controls. Elevated plasma IL-2 at 24 h was associated with more severe 1-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). Plasma cytokine levels (within 24 h 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.

Blood biomarkers of traumatic brain injury and cognitive impairment in older veterans.

To determine whether blood-based biomarkers can differentiate older veterans with and without traumatic brain injury (TBI) and cognitive impairment (CogI). We enrolled 155 veterans from 2 veterans' retirement homes: 90 without TBI and 65 with TBI history. Participants were further separated into CogI groups: controls (no TBI, no CogI), n = 60; no TBI with CogI, n = 30; TBI without CogI, n = 30; and TBI with CogI, n = 35. TBI was determined by the Ohio State University TBI Identification Method. CogI was defined as impaired cognitive testing, dementia diagnosis, or use of dementia medication. Blood specimens were enriched for CNS-derived exosomes. Proteins (neurofilament light [NfL], total tau, glial fibrillary acidic protein [GFAP], α-synuclein, β-amyloid 42 [Aβ42], and phosphorylated tau [p-tau]) and cytokines (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-10) were measured using ultrasensitive immunoassays. Veterans were, on average, 79 years old. In participants with TBI history, 65% had mild TBI; average time from most recent TBI was 37 years. In adjusted analyses, the TBI and CogI groups differed on CNS-enriched exosome concentration of p-tau, NfL, IL-6, TNF-α (all p < 0.05), and GFAP (p = 0.06), but not on Aβ42 or other markers. Adjusted area under the curve (AUC) analyses found that all significantly associated biomarkers combined separated TBI with/without CogI (AUC, 0.85; 95% confidence interval [CI], 0.74-0.95) and CogI with/without TBI (AUC, 0.88; 95% CI, 0.77-0.99). Increased levels of blood-based, CNS-enriched exosomal biomarkers associated with TBI and CogI can be detected even decades after TBI. This study provides Class II evidence that in veterans with a history of TBI, CNS-enriched exosome concentration of p-tau, NfL, IL-6, and TNF-α are associated with CogI.

Is Salivary S100B a Biomarker of Traumatic Brain Injury? A Pilot Study.

Traumatic brain injury (TBI) results in short and long-term disability neurodegeneration. Mild traumatic brain injury (mTBI) represents up to 85% of head injuries; diagnosis and early management is based on computed tomography (CT) or in-hospital observation, which are time- and cost- intensive. CT involves exposure to potentially harmful ionizing radiation and >90% of the scans are negative. Blood-brain barrier (BBB) damage is suspected pathological event post-TBI contributing to long-term sequelae and a reliable and rapid point-of-care test to screen those who can safely forego acute head CT would be of great help in evaluating patients with an acute mTBI. In this pilot study, 15 adult patients with suspected TBI (mean age = 47 years, range 18–79) and 15 control subjects (mean age = 33 years, range 23–53) were enrolled. We found that the average salivary S100B level was 3.9 fold higher than blood S100B, regardless of the presence of pathology. [S100B]saliva positively correlated with [S100B]serum (Pearson' coefficient = 0.79; p < 0.01). Salivary S100B levels were as effective in differentiating TBI patients from control subjects as serum levels (Control vs. TBI: p < 0.01; Serum ROCAUC = 0.94 and Saliva ROCAUC = 0.75). I These initial results suggest that measuring salivary S100B could represent an alternative to serum S100B in the diagnosis of TBI. Larger and confirmatory trials are needed to define salivary biomarker kinetics in relation to TBI severity and the possible roles of gender, ethnicity and age in influencing salivary S100B levels.

Bioinformatic analysis of brain-specific miRNAs for identification of candidate traumatic brain injury blood biomarkers

ABSTRACT Background Detection of brain-specific miRNAs in the peripheral blood could serve as a surrogate marker of traumatic brain injury (TBI). Here, we systematically identified brain-enriched miRNAs, and tested their utility as TBI biomarkers in the acute phase of care. Methods Publically available microarray data generated from 29 postmortem human tissues were used to rank 1,364 miRNAs in terms of their degree of brain-specific expression. Levels of the top six ranked miRNAs were then prospectively measured in serum samples collected from 10 Patients with TBI at hospital admission, as well as from 10 controls. Results The top six miRNAs identified in our analysis (miR-124-3p, miR-219a-5p, miR-9-5p, miR-9-3p, miR-137, and miR-128-3p) were enriched 70 to 320-fold in brain relative to other tissues, and exhibited dramatically greater brain specificity compared to several miRNAs previously proposed as biomarkers. Furthermore, their levels were elevated in serum from patients with TBI compared to controls, and could collectively discriminate between groups with 90% sensitivity and 100% specificity. Interestingly, subsequent informatic pathway analysis revealed that their target transcripts were enriched for components of signaling pathways active in peripheral organs involved in common post-TBI complications. Conclusions The six candidate miRNAs identified in this preliminary study have promise as blood biomarkers of TBI, and could also be molecular contributors to systemic physiologic changes commonly observed post-injury.

Interleukin 10 and Heart Fatty Acid-Binding Protein as Early Outcome Predictors in Patients With Traumatic Brain Injury.

Background: Patients with traumatic brain injury (TBI) exhibit a variable and unpredictable outcome. The proteins interleukin 10 (IL-10) and heart fatty acid-binding protein (H-FABP) have shown predictive values for the presence of intracranial lesions.Aim: To evaluate the individual and combined outcome prediction ability of IL-10 and H-FABP, and to compare them to the more studied proteins S100β, glial fibrillary acidic protein (GFAP), and neurofilament light (NF-L), both with and without clinical predictors.Methods: Blood samples from patients with acute TBI (all severities) were collected <24 h post trauma. The outcome was measured >6 months post injury using the Glasgow Outcome Scale Extended (GOSE) score, dichotomizing patients into: (i) those with favorable (GOSE≥5)/unfavorable outcome (GOSE ≤ 4) and complete (GOSE = 8)/incomplete (GOSE ≤ 7) recovery, and (ii) patients with mild TBI (mTBI) and patients with TBIs of all severities.Results: When sensitivity was set at 95–100%, the proteins' individual specificities remained low. H-FABP showed the best specificity (%) and sensitivity (100%) in predicting complete recovery in patients with mTBI. IL-10 had the best specificity (50%) and sensitivity (96%) in identifying patients with favorable outcome in patients with TBIs of all severities. When individual proteins were combined with clinical parameters, a model including H-FABP, NF-L, and ISS yielded a specificity of 56% and a sensitivity of 96% in predicting complete recovery in patients with mTBI. In predicting favorable outcome, a model consisting IL-10, age, and TBI severity reached a specificity of 80% and a sensitivity of 96% in patients with TBIs of all severities.Conclusion: Combining novel TBI biomarkers H-FABP and IL-10 with GFAP, NF-L and S100β and clinical parameters improves outcome prediction models in TBI.

Rapid detection of traumatic brain injury.

An optofluidic chip incorporating a surface-enhanced Raman-scattering substrate rapidly detects picomolar concentrations of biomarkers of traumatic brain injury in finger-prick blood samples from patients.

ENIGMA brain injury: Framework, challenges, and opportunities.

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.

Traumatic Brain Injury: A Forensic Approach: A Literature Review.

Traumatic brain injury (TBI) is the principal cause of invalidity and death in the population under 45 years of age worldwide.This mini-review aims to systematize the forensic approach in neuropathological studies, highlighting the proper elements to be noted during external, radiological, autoptical, and histological examinations with particular attention paid to immunohistochemistry and molecular biology.In the light of the results of this mini-review, an accurate forensic approach can be considered mandatory in the examination of suspected TBI with medico-legal importance, in order to gather all the possible evidence to corroborate the diagnosis of a lesion that may have caused, or contributed to, death. From this point of view, only the use of an evidence-based protocol can reach a suitable diagnosis, especially in those cases in which there are other neuropathological conditions (ischemia, neurodegeneration, neuro-inflammation, dementia) that may have played a role in death.This is even more relevant when corpses, in an advanced state of decomposition, are studied, where the radiological, macroscopic and histological analyses fail to give meaningful answers. In these cases, immune-histochemical and molecular biology diagnostics are of fundamental importance and a forensic neuropathologist has to know them. Particularly, MiRNAs are promising biomarkers for TBI both for brain damage identification and for medico-legal aspects, even if further investigations are required to validate the first experimental studies. In the same way, the genetic substrate should be examined during any forensic examination, considering its importance in the outcome of TBI.

Comment: Biomarkers for mild traumatic brain injury: Role of the exosomes.

While the majority of mild traumatic brain injuries (mTBIs) are single and uncomplicated and complete recovery is expected, a subset of individuals experience persistent postconcussive symptoms (PCS) and substantial disability. There is a need for accurate and reliable biomarkers that are tied to the pathophysiologic mechanisms of mTBI, and that track and predict neuropsychiatric outcomes.1

Soluble terminal complement activation fragment sC5b-9: a new serum biomarker for traumatic brain injury?

Terminal complement pathway activation after traumatic brain injury (TBI) leads to formation of the membrane attack complex (MAC/C5b-9) which induces neuronal cell death and host-mediated secondary brain injury. Serum levels of soluble MAC (sC5b-9) have not been previously determined in patients with isolated TBI. A prospective observational cohort study was performed during a 5-year time-period on adult patients with isolated TBI admitted to an academic level I trauma center in the United States. Controls consisted of patients with femur shaft fractures with or without TBI to mitigate the effect of systemic complement activation by peripheral trauma. Healthy volunteers served as internal controls. The sC5b-9 serum concentrations were measured on the day of admission by enzyme-linked immunosorbent assay (ELISA) and compared between the study cohorts. Univariate analysis was performed to determine independent predictive variables of major complications during hospital admission. Serum sC5b-9 levels were significantly elevated in patients with isolated TBI (n = 42), compared to patients with isolated femoral shaft fractures (n = 36) or combined TBI and femoral shaft fractures (n = 30; p < 0.05). There was no significant difference in serum sC5b-9 levels between the femur group and the combined injury group, compared to the healthy volunteers (n = 21). Univariate analysis revealed serum sC5b-9 levels as an independent predictor of major postinjury complications after isolated TBI (p < 0.01). The soluble terminal complement complex sC5b-9 represents a potential novel serum biomarker specific for isolated head injuries, since peripheral trauma did not appear to affect the serum sC5b-9 levels.

MiR-146a Mimics Ameliorates Traumatic Brain Injury Involving JNK and NF-κB Signaling Pathway.

Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality among the world, while the advance of TBI management is rather limited in recent years. The deregulation of microRNAs (miRNAs) has been widely reported in TBI patients and animal models, and certain miRNAs have been identified as the emerging biomarkers of TBI. However, the role of miRNAs in the regulatory mechanism of TBI remains unclear. To demonstrate the effect of miR-146a mimic on TBI-induced neural damages, TBI mouse model was constructed by cortical impact injury (CCI). The chemokine levels were examined by ELISA assays. Behavioral experiments were used to estimate the impact of miR-146a mimics on neurological functions in mice. Western blot assays were performed to demonstrate the protein levels. qRT-PCR assays were utilized to investigate the expression alteration of RNA levels. It was found that miR-146a was upregulated both in brain and serum in TBI mice. miR-146a mimic downregulated inflammatory cytokines secretion in mouse brain. The NF-κB signaling pathway was inhibited by miR-146a mimic. miR-146a treatment attenuated the impact caused by TBI to mouse brain and improve the long-term neurological function. In conclusion, miR-146a mimics ameliorate TBI-related injuries via JNK and NF-κB signaling pathway.

Searching for a traumatic brain injury biomarker to aid clinical decision making in the emergency department.

The need for objective prognostic biomarkers to help in the clinical management of head injury is huge: missed diagnoses and different injuries and susceptibilities limit efforts to predict consequences, advise victims, and offer useful prognosis. Most traumatic brain injury (TBI) is represented by concussion or mild TBI, for which there are no simple, objective, reliable tests [1]. The long-term consequence of chronic traumatic encephalopathy (CTE) [2] is not currently predictable except from awareness that repetitive trauma from contact sports increases risk [3].

Predictive Performance of Traumatic Brain Injury Biomarkers in High-Risk Elderly Patients.

Predictive Performance of Traumatic Brain Injury Biomarkers in High-Risk Elderly Patients.

High-sensitivity C-reactive protein as a prognostic biomarker for traumatic brain injury (TBI): A TRACK-TBI Study (1550)

High-sensitivity C-reactive protein as a prognostic biomarker for traumatic brain injury (TBI): A TRACK-TBI Study (1550)