Biomarkers Of Traumatic Brain Injury Research Articles

Cerebrospinal Fluid Levels of Lysophosphatidic Acids Can Provide Suitable Biomarkers of Blast-Induced Traumatic Brain Injury.

Blast-induced traumatic brain injury (bTBI) has been identified as the signature injury of Operation Iraqi Freedom and Operation Enduring Freedom. Although the incidence of bTBI increased significantly after the introduction of improvised explosive devices, the mechanism of the injury is still uncertain, which is negatively impacting the development of suitable countermeasures. Identification of suitable biomarkers that could aid in the proper diagnosis of and prognosis for both acute and chronic bTBI is essential since bTBI frequently is occult and may not be associated with overtly detectable injuries to the head. Lysophosphatidic acid (LPA) is a bioactive phospholipid generated by activated platelets, astrocytes, choroidal plexus cells and microglia and is reported to play major roles in stimulating inflammatory processes. The levels of LPA in the cerebrospinal fluid (CSF) have been reported to increase acutely after non-blast related brain injuries. In the present study, we have evaluated the utility of LPA levels measured in the CSF and plasma of laboratory rats as an acute and chronic biomarker of brain injury resulting from single and tightly coupled repeated blast overpressure exposures. In the CSF, many LPA species increased at acute time-points, returned to normal levels at 1 month, and increased again at 6 months and 1 year post-blast overpressure exposures. In the plasma, several LPA species increased acutely, returned to normal levels by 24 h, and were significantly decreased at 1 year post-blast overpressure exposures. These decreases in LPA species in the plasma were associated with decreased levels of lysophosphatidyl choline, suggesting a defective upstream biosynthetic pathway of LPAs in the plasma. Notably, the changes in LPA levels in the CSF (but not plasma) negatively correlated with neurobehavioral functions in these rats, suggesting that CSF levels of LPAs may provide a suitable biomarker of bTBI that reflects severity of injury.

Circulating extracellular vesicles from patients with traumatic brain injury induce cerebrovascular endothelial dysfunction

Endothelial dysfunction is a key proponent of pathophysiological process of traumatic brain injury (TBI). We previously demonstrated that extracellular vesicles (EVs) released from injured brains led to endothelial barrier disruption and vascular leakage. However, the molecular mechanisms of this EV-induced endothelial dysfunction (endotheliopathy) remain unclear. Here, we enriched plasma EVs from TBI patients (TEVs), and detected high mobility group box 1 (HMGB1) exposure to 50.33 ± 10.17% of TEVs and the number of HMGB1+TEVs correlated with injury severity. We then investigated for the first time the impact of TEVs on endothelial function using adoptive transfer models. We found that TEVs induced dysfunction of cultured human umbilical vein endothelial cells and mediated endothelial dysfunction in both normal and TBI mice, which were propagated through the HMGB1-activated receptor for advanced glycation end products (RAGE)/Cathepsin B signaling, and the resultant NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and canonical caspase-1/gasdermin D (GSDMD)-dependent pyroptosis. Finally, von Willebrand factor (VWF) was detected on the surface of 77.01 ± 7.51% of HMGB1+TEVs. The TEV-mediated endotheliopathy was reversed by a polyclonal VWF antibody, indicating that VWF might serve a coupling factor that tethered TEVs to ECs, thus facilitating HMGB1-induced endotheliopathy. These results suggest that circulating EVs isolated from patients with TBI alone are sufficient to induce endothelial dysfunction and contribute to secondary brain injury that are dependent on immunologically active HMGB1 exposed on their surface. This finding provided new insight for the development of potential therapeutic targets and diagnostic biomarkers for TBI.

A prospective observational study on utility of serum mesencephalic astrocyte-derived neurotrophic factor as a promising prognostic biomarker of severe traumatic brain injury in humans

BackgroundMesencephalic astrocyte-derived neurotrophic factor (MANF) is released under endoplasmic reticulum stress, thereby exerting neuroprotective effects. We determined whether serum MANF may be a prognostic biomarker of human severe traumatic brain injury (sTBI). MethodsSerum MANF concentrations of 137 sTBI patients and 137 controls were quantified in this prospective cohort study. Patients with extended Glasgow outcome scale (GOSE) scores of 1–4 at post-traumatic 6 months were considered to have poor prognosis. Relationships between serum MANF concentrations and severity plus prognosis were investigated using multivariate analyses. Area under receiver operating characteristic curve (AUC) was calculated for reflecting prognostic efficiency. ResultsAs compared to controls, there was a significant increase of serum MANF concentrations after sTBI (median, 18.5 ng/ml versus 3.0 ng/ml; P < 0.001), which was independently correlated with Glasgow coma scale (GCS) scores [β, −3.000; 95% confidence interval (CI), −4.525--1.476; VIF, 2.216; P = 0.001], Rotterdam computed tomography (CT) scores (β, 4.020; 95% CI, 1.446–6.593; VIF, 2.234; P = 0.002) and GOSE scores (β, −0.056; 95% CI, −0.089--0.023; VIF, 1.743; P = 0.011). Serum MANF concentrations substantially distinguished risk of poor prognosis with AUC of 0.795 (95% CI, 0.718–0.859) and its concentrations > 23.9 ng/ml was predictive of poor prognosis with 67.7% sensitivity and 81.9% specificity. Serum MANF concentrations combined with GCS scores and Rotterdam CT scores displayed markedly higher prognostic predictive ability than each of them (all P < 0.05). Using restricted cubic spline, there was a linear correlation between serum MANF concentrations and poor prognosis (P = 0.256). Serum MANF concentrations > 23.9 ng/ml was independently associated with poor prognosis (odds ratio, 2.911; 95% CI, 1.057–8.020; P = 0.039). A nomogram was built, where serum MANF concentrations > 23.9 ng/ml, GCS scores and Rotterdam CT scores were integrated. Hosmer and Lemeshow test, calibration curve and decision curve analysis demonstrated such a prediction model was comparatively stable and was of relatively high clinical benefit. ConclusionsSubstantially increased serum MANF concentrations after sTBI are highly correlated with traumatic severity and are independently predictive of long-term poor prognosis, suggesting that serum MANF may represent a useful prognostic biochemical marker of human sTBI.

Proteomics of Deep Cervical Lymph Nodes After Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) damages the glymphatic-lymphatic system. We hypothesized that brain injury associated with trauma results in the enrichment of brain-relevant proteins in deep cervical lymph nodes (DCLNs), the end station of meningeal lymphatic vessels, and that some of these proteins will present mechanistic tissue biomarkers for TBI. Proteomes of rat DCLNs were investigated in the left DCLN (ipsilateral to injury) and right DCLN at 6.5 months after severe TBI induced by lateral fluid percussion injury or after sham operation. DCLN proteomes were identified using sequential window acquisition of all theoretical mass spectra. Group comparisons, together with functional protein annotation analyses, were used to identify regulated protein candidates for further validation and pathway analyses. Validation of a selected candidate was assessed using enzyme-linked immunosorbent assay. Analysis comparing post-TBI animals with sham-operated controls revealed 25 upregulated and 16 downregulated proteins in the ipsilateral DCLN and 20 upregulated and 28 downregulated proteins in the contralateral DCLN of post-TBI animals. Protein class and function analyses highlighted the dysregulation of enzymes and binding proteins. Pathway analysis indicated an increase in autophagy. Biomarker analysis suggested that a subgroup of post-TBI animals had an increase in zonula occludens-1 coexpressed with proteins linked to molecular transport and amyloid precursor protein. We propose here that, after TBI, a subgroup of animals exhibit dysregulation of the TBI-relevant protein interactome in DCLNs, and that DCLNs might thus serve as an interesting biomarker source in future studies aiming to elucidate pathological brain functioning.

Research on the Potential Biomarkers of Mild Traumatic Brain Injury: a Systematic Review and Bibliometric Analysis.

Reliable diagnostic methods for mild traumatic brain injury (mTBI) are lacking, and many researchers continue to search for objective biomarkers that can both define and detect mTBI. Although much research has been conducted in this field, there have not been many bibliometric studies. In this study, we aim to analyze the development over the last two decades in scientific output relating to the diagnosis of mTBI. To do this, we extracted documents from Web of Science, PubMed, and Embase and performed descriptive analysis (number of publications, primary journals, authors, and countries/regions), trend topics analysis, and citation analysis for papers across the globe, with a particular focus on molecular markers. One thousand twenty-three publications spanning 390 journals were identified on Web of Science, PubMed, and Embase for the period from 2000 to 2022. The number of publications increased every year (from 2 in 2000 to 137 in 2022). Of all the publications we analyzed, 58.7% had authors from the USA. Our analysis shows that molecular markers are the most studied markers in the field of mTBI diagnostics, accounting for 28.4% of all publications, and that the number of studies focused on this specific aspect has increased sharply in the past 5years, indicating that molecular markers may become a research trend in the future.

BDNF: New Views of an Old Player in Traumatic Brain Injury.

Traumatic brain injury is a common health problem affecting millions of people each year. BDNF has been investigated in the context of traumatic brain injury due to its crucial role in maintaining brain homeostasis. Val66Met is a functional single-nucleotide polymorphism that results in a valine-to-methionine amino acid substitution at codon 66 in the BDNF prodomain, which ultimately reduces secretion of BDNF. Here, we review experimental animal models as well as clinical studies investigating the role of the Val66Met single-nucleotide polymorphism in traumatic brain injury outcomes, including cognitive function, motor function, neuropsychiatric symptoms, and nociception. We also review studies investigating the role of BDNF on traumatic brain injury pathophysiology as well as circulating BDNF as a biomarker of traumatic brain injury.

Trajectories of interleukin 10 and heart fatty acid-binding protein levels in traumatic brain injury patients with or without extracranial injuries.

Interleukin 10 (IL-10) and heart fatty acid-binding protein (H-FABP) have gained interest as diagnostic biomarkers of traumatic brain injury (TBI), but factors affecting their blood levels in patients with moderate-to-severe TBI are largely unknown. To investigate the trajectories of IL-10 and H-FABP between TBI patients with and without extracranial injuries (ECI); to investigate if there is a correlation between the levels of IL-10 and H-FABP with the levels of inflammation/infection markers C-reactive protein (CRP) and leukocytes; and to investigate if there is a correlation between the admission level of H-FABP with admission levels of cardiac injury markers, troponin (TnT), creatine kinase (CK), and creatine kinase MB isoenzyme mass (CK-MBm). The admission levels of IL-10, H-FABP, CRP, and leukocytes were measured within 24 h post-TBI and on days 1, 2, 3, and 7 after TBI. The admission levels of TnT, CK, and CK-MBm were measured within 24 h post-TBI. There was a significant difference in the concentration of H-FABP between TBI patients with and without ECI on day 0 (48.2 ± 20.5 and 12.4 ± 14.7 ng/ml, p = 0.02, respectively). There was no significant difference in the levels of IL-10 between these groups at any timepoints. There was a statistically significant positive correlation between IL-10 and CRP on days 2 (R = 0.43, p < 0.01) and 7 (R = 0.46, p = 0.03) after injury, and a negative correlation between H-FABP and CRP on day 0 (R = -0.45, p = 0.01). The levels of IL-10 or H-FABP did not correlate with leukocyte counts at any timepoint. The admission levels of H-FABP correlated with CK (R = 0.70, p < 0.001) and CK-MBm (R = 0.61, p < 0.001), but not with TnT. Inflammatory reactions during the early days after a TBI do not significantly confound the use of IL-10 and H-FABP as TBI biomarkers. Extracranial injuries and cardiac sources may influence the levels of H-FABP in patients with moderate-to-severe TBI.

Evaluation of UCH-L1 and T-Tau as prognostic biomarkers of traumatic brain injury

Evaluation of UCH-L1 and T-Tau as prognostic biomarkers of traumatic brain injury

S100B, Actor and Biomarker of Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) accounts for approximately 80% of all TBI cases and is a growing source of morbidity and mortality worldwide. To improve the management of children and adults with mTBI, a series of candidate biomarkers have been investigated in recent years. In this context, the measurement of blood biomarkers in the acute phase after a traumatic event helps reduce unnecessary CT scans and hospitalizations. In athletes, improved management of sports-related concussions is also sought to ensure athletes' safety. S100B protein has emerged as the most widely studied and used biomarker for clinical decision making in patients with mTBI. In addition to its use as a diagnostic biomarker, S100B plays an active role in the molecular pathogenic processes accompanying acute brain injury. This review describes S100B protein as a diagnostic tool as well as a potential therapeutic target in patients with mTBI.

Utility of Serum Neurofilament Light Protein as a Biomarker in Traumatic Brain Injury

Utility of Serum Neurofilament Light Protein as a Biomarker in Traumatic Brain Injury

Using Biomarkers for Traumatic Brain Injury: Are There Lessons That Can Be Learned from Implementing Cardiac Troponin?

Using Biomarkers for Traumatic Brain Injury: Are There Lessons That Can Be Learned from Implementing Cardiac Troponin?

Can Adropin peptides be a biomarker for traumatic brain injury? A prospective study

Can Adropin peptides be a biomarker for traumatic brain injury? A prospective study

Prognostic Role of Serum Soluble Tim-3 in Severe Traumatic Brain Injury: A Prospective Observational Study

T cell immunoglobulin and mucin domain-3 (Tim-3) may be implicated in neuroinflammation. Herein, we attempted to discern the role of serum soluble (s) Tim-3 as an inflammatory prognostic biomarker of severe traumatic brain injury (sTBI). In this prospective observational study of 112 sTBI patients and 112 controls, serum sTim-3 levels were determined, Rotterdam computed tomography (CT) classification and Glasgow coma scale (GCS) were selected as the two severity indicators, serum C-reactive protein (CRP) was regarded as an inflammatory biomarker, and poor prognosis was referred to as extended Glasgow outcome scale (GOSE) scores 1-4 at 180 days after trauma. Serum sTim-3 levels were markedly higher in patients than in controls (median, 4.2 ng/mL versus 0.7 ng/mL; P<0.001). Serum sTim-3 levels of patients were independently related to Rotterdam CT scores (β=1.126), GCS scores (β=-0.589), serum CRP levels (β=0.155) and GOSE scores (β=-0.211). Serum sTim-3 appeared as an independent predictor of post-traumatic 180-day mortality (odds ratio=1.289), overall survival (hazard ratio=1.208) and poor prognosis (odds ratio=1.293). Serum sTim-3 levels discriminated patients at risk of post-injury 180-day mortality and poor prognosis with areas under curve (AUCs) at 0.753 and 0.782, respectively. Serum sTim-3 levels combined with GCS scores and Rotterdam CT scores (AUC=0.869) exhibited significantly higher AUC than Rotterdam CT scores (P=0.026), but not than GCS scores (P=0.181) for death prediction and their combination (AUC=0.895) had significantly higher AUC than GCS scores (P=0.036) or Rotterdam CT scores (P=0.005) for outcome prediction. Elevated serum sTim-3 levels, in close correlation with traumatic severity and inflammation, are substantially associated with long-term death and poor outcome, indicating that serum sTim-3, as an inflammatory biomarker, may be of clinical significance in severity assessment and prediction of prognosis following sTBI.

Protein Blood Biomarkers in Paediatric Mild Traumatic Brain Injury for Patient Triage at Admission

Protein Blood Biomarkers in Paediatric Mild Traumatic Brain Injury for Patient Triage at Admission

Cerebral Hemodynamics and Microvasculature Changes in Relation to White Matter Microstructure After Pediatric Mild Traumatic Brain Injury: An A-CAP Pilot Study.

Advanced neuroimaging techniques show promise as a biomarker for mild traumatic brain injury (mTBI). However, little research has evaluated cerebral hemodynamics or its relation to white matter microstructure post-mTBI in children. This novel pilot study examined differences in cerebral hemodynamics, as measured using functional near-infrared spectroscopy (fNIRS), and its association with diffusion tensor imaging (DTI) metrics in children with mTBI or mild orthopedic injury (OI) to address these gaps. Children 8.00-16.99 years of age with mTBI (n = 9) or OI (n = 6) were recruited in a pediatric emergency department, where acute injury characteristics were assessed. Participants completed DTI twice, post-acutely (2-33 days) and chronically (3 or 6 months), and fNIRS ∼1 month post-injury. Automated deterministic tractography was used to compute DTI metrics. There was reduced absolute phase globally and coherence in the dorsolateral pre-frontal cortex (DLPFC) after mTBI compared to the OI group. Coherence in the DLPFC and absolute phase globally showed distinct associations with fractional anisotropy in interhemispheric white matter pathways. Two fNIRS metrics (coherence and absolute phase) differentiated mTBI from OI in children. Variability in cerebral hemodynamics related to white matter microstructure. The results provide initial evidence that fNIRS may have utility as a clinical biomarker of pediatric mTBI.

Biomedical research brings mTBI biomarkers a step closer to the bedside - implementation in clinical practice.

Research in the field of TBI (traumatic brain injury) has long been focused on severe brain injury, while the number of mild injuries far overweigh severe injuries. Mild head injuries constitute up to 95% of all traumatic head injuries. The purpose of this work is to identify mTBI (mild traumatic brain injury) patients who are unlikely to benefit from CT (computed tomography) scanning. Biomarkers capable of clearly discriminating between CT-positive and CT-negative subjects are needed. Biomarkers hold the potential to document whether a concussion occurred, especially when the history is unclear and neurocognitive sequelae persist. Recently, following advances in proteomics analysis, investigators have introduced ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) as two promising brain injury biomarkers. The authors provide an update on the current knowledge of TBI biomarkers, especially protein biomarkers for neuronal cell body injury (UCH-L1) and astroglial injury (GFAP, S100B), and a focused literature review dealing with implementation of mTBI biomarkers in clinical practice.

A novel point-of-care diagnostic prototype system for the simultaneous electrochemiluminescent sensing of multiple traumatic brain injury biomarkers.

Traumatic brain injuries (TBI) are typically acquired when a sudden violent event causes damage to the brain tissue. A high percentage (70-85%) of all TBI patients are suffering from mild TBI (mTBI), which is often difficult to detect and diagnose with standard imaging tools (MRI, CT scan) due to the absence of significant lesions and specific symptoms. Recent studies suggest that a screening test based on the measurement of a protein biomarker panel directly from a patient's blood can facilitate mTBI diagnosis. Herein, we report a novel prototype system designed as a precursor of a future hand-held point-of-care (POC) diagnostic device for the simultaneous multi-biomarker sensing, employing a microarray-type spatially resolved electrochemiluminescence immunoassay (SR-ECLIA). The small tabletop prototype consists of a screen-printed electrode compartment to conduct multi-analyte ECL sandwich assays, a potentiostat module and a light collection module, all integrated into a compact 3D-printed housing (18.2 × 16.5 × 5.0 cm), as well as an sCMOS detector. Based on this design concept, further miniaturization, system integration, performance optimization and clinical evaluation shall pave the way towards the development of a portable instrument for use at the site of accident and healthcare. To demonstrate the system's feasibility, current performance and efficiency, the simultaneous detection of three mTBI biomarkers (GFAP, h-FABP, S100β) in 50% serum was achieved in the upper pg mL-1 range. The proposed device is amenable to the detection of other biomarker panels and thus could open new medical diagnostic avenues for sensitive multi-analyte measurements with low-volume biological sample requirements.

The role of spectrin breakdown products in patients with traumatic brain injury: a systematic review and meta-analysis.

Spectrin Breakdown Products (SBDPs) accumulate in the brain after traumatic brain injury (TBI) and are expected to become a potentially promising biomarker of TBI. This systematic review and meta-analysis were undertaken to evaluate the role of SBDPs in the diagnosis and prognosis of TBI. We systematically searched the following databases up to 31 October 2022: Ovid MEDLINE, PubMed, EMBASE, Cochrane Library, and Web of Science Database, and studies were only included if they had sufficient data on SBDP concentrations in TBI patients. We calculated the standardized mean differences (SMDs) and 95% confidence intervals (CIs) for continuous outcomes and assessed the potential publication bias by using Egger's test and funnel plots. The statistical analysis was conducted by RevMan 5.4 and Stata 17. Of 1429 identified studies, 10 studies involving 417 participants were included in our systematic review and meta-analysis. The results demonstrated that serum and cerebrospinal fluid (CSF) SBDP concentrations were significantly increased in TBI compared to controls (SBDP120: SMD = 1.42, 95% CI = 0.71 ~ 2.12, P < 0.00001; SBDP145: SMD = 1.32, 95% CI = 0.78 ~ 1.86, P < 0.00001; SBDP150: SMD = 1.39, 95% CI = 0.97 ~ 1.80, P < 0.00001), and CSF SBDPs were significantly associated with poor functional outcomes (PFO) (SBDP145: SMD = 1.75, 95% CI = 1.37 ~ 2.13, P < 0.00001; SBDP150: SMD = 1.14, 95% CI = 0.75 ~ 1.52, P < 0.00001). In addition, CSF and serum SBDP145 are valuable in diagnosing TBI (AUC = 0.89, 95% CI = 0.80 ~ 0.99, P < 0.00001), and CSF SBDP145 also has diagnostic value for PFO (AUC = 0.80, 95% CI = 0.76 ~ 0.84,P < 0.00001). The limited evidence supports that the SBDPs can be employed as potential biomarkers for the diagnosis and prognosis of TBI.

Statistical assessment of the prognostic and the predictive value of biomarkers-A biomarker assessment framework with applications to traumatic brain injury biomarker studies.

Studies that investigate the performance of prognostic and predictive biomarkers are commonplace in medicine. Evaluating the performance of biomarkers is challenging in traumatic brain injury (TBI) and other conditions when both the time factor (i.e. time from injury to biomarker measurement) and different levels or doses of treatments are in play. Such factors need to be accounted for when assessing the biomarker's performance in relation to a clinical outcome. The Hyperbaric Oxygen in Brain Injury Treatment (HOBIT) trial, a phase II randomized control clinical trial seeks to determine the dose of hyperbaric oxygen therapy (HBOT) for treating severe TBI that has the highest likelihood of demonstrating efficacy in a phase III trial. Hyperbaric Oxygen in Brain Injury Treatment will study up to 200 participants with severe TBI. This paper discusses the statistical approaches to assess the prognostic and predictive performance of the biomarkers studied in this trial, where prognosis refers to the association between a biomarker and the clinical outcome while the predictiveness refers to the ability of the biomarker to identify patient subgroups that benefit from therapy. Analyses based on initial biomarker levels accounting for different levels of HBOT and other baseline clinical characteristics, and analyses of longitudinal changes in biomarker levels are discussed from a statistical point of view. Methods for combining biomarkers that are of complementary nature are also considered and the relevant algorithms are illustrated in detail along with an extensive simulation study that assesses the performance of the statistical methods. Even though the discussed approaches are motivated by the HOBIT trial, their applications are broader. They can be applied in studies assessing the predictiveness and prognostic ability of biomarkers in relation to a well-defined therapeutic intervention and clinical outcome.

Troponin I New Biomarker in Traumatic Brain Injury

Mortality in traumatic brain injury (TBI) is thought to be pathology in the heart-brain axis but its effect on the prognosis of traumatic brain injury remains unclear. Our study aimed to investigate the relationship between cardiac troponin I (cTnI) level and prognosis in TBI patients. Between January 2017 and May 2021, 480 patients diagnosed with TBI, who applied to the emergency department, were retrospectively included in this multicentric study. The databases of the hospitals were examined comprehensively and the demographic, clinical, laboratory, radiological, and therapeutic data and results of the patients were obtained. The severity of trauma and clinical status was evaluated with AIS, Injury Severity Score (ISS), ASA physical status, and Glasgow Coma Scale (GCS). The severity of the trauma was evaluated with the ISS. The modified Rankin Scale (mRS) and the Glasgow Outcome Scale (GOS) at discharge were used to evaluate in-hospital clinical outcomes. cTnI levels were classified into three categories: normal (< 0.05 ng/ml), mildly elevated (0.05–0.99 ng/ml), and severely elevated (≥ 1 ng/ml). The mean age of the patients was 41.7 and 75.4% of them were men. It was observed that mortality among patients over 65 years (13.9%) increased. High cTnI was detected in 284 (59.1%) patients. Although it was not statistically significant regarding the elevation of cTnI in patients under 65 years of age (P = 0.62), the difference was significant for cTnI in patients over 65 years of age (P < 0.001). The relationship between cTnI elevation was found to be statistically significant (P < 0.001) as the severity of the trauma increased and when severe additional traumas (thoracic, abdominal, or pelvic) occurred. A high cTnI level is associated with poor prognosis in TBI patients. cTnI measurement is a useful tool for early risk stratification and accelerated care; however, further prospective studies are needed.