Biomarkers Of Traumatic Brain Injury Research Articles

Distinct Serum Glial Fibrillary Acidic Protein and Neurofilament Light Time-Courses After Rapid Head Rotations.

Traumatic brain injury (TBI) causes significant neurophysiological deficits and is typically associated with rapid head accelerations common in sports-related incidents and automobile accidents. There are over 1.5 million TBIs in the United States each year, with children aged 0-4 being particularly vulnerable. TBI diagnosis is currently achieved through interpretation of clinical signs and symptoms and neuroimaging; however, there is increasing interest in minimally invasive fluid biomarkers to detect TBI objectively across all ages. Pre-clinical porcine models offer controlled conditions to evaluate TBI with known biomechanical conditions and without comorbidities. The objective of the current study was to establish pediatric porcine healthy reference ranges (RRs) of common human serum TBI biomarkers and to report their acute time-course after nonimpact rotational head injury. A retrospective analysis was completed to quantify biomarker concentrations in porcine serum samples collected from 4-week-old female (n = 215) and uncastrated male (n = 6) Yorkshire piglets. Subjects were assigned to one of three experimental groups (sham, sagittal-single, sagittal-multiple) or to a baseline only group. A rapid nonimpact rotational head injury model was used to produce mild-to-moderate TBI in piglets following a single rotation and moderate-to-severe TBI following multiple rotations. The Quanterix Simoa Human Neurology 4-Plex A assay was used to quantify glial fibrillary acidic protein (GFAP), neurofilament light (Nf-L), tau, and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1). The 95% healthy RRs for females were calculated and validated for GFAP (6.3-69.4 pg/mL), Nf-L (9.5-67.2 pg/mL), and UCH-L1 (3.8-533.7 pg/mL). Rising early, GFAP increased significantly above the healthy RRs for sagittal-single (to 164 and 243 pg/mL) and increased significantly higher in sagittal-multiple (to 494 and 413 pg/mL) groups at 30 min and 1 h postinjury, respectively, returning to healthy RRs by 1-week postinjury. Rising later, Nf-L increased significantly above the healthy RRs by 1 day in sagittal-single (to 69 pg/mL) and sagittal-multiple groups (to 140 pg/mL) and rising further at 1 week (single = 231 pg/mL, multiple = 481 pg/mL). Sagittal-single and sagittal-multiple UCH-L1 serum samples did not differ from shams or the healthy RRs. Sex differences were observed but inconsistent. Serum GFAP and Nf-L levels had distinct time-courses following head rotations in piglets, and both corresponded to load exposure. We conclude that serum GFAP and Nf-L offer promise for early TBI diagnosis and intervention decisions for TBI and other neurological trauma.

Hypobaria During Aeromedical Evacuation and Systemic Inflammation after Porcine Traumatic Brain Injury.

Traumatic brain injury (TBI)-related morbidity is caused largely by secondary injury resulting from hypoxia, excessive sympathetic drive, and uncontrolled inflammation. Aeromedical evacuation (AE) is utilized by the military for transport of wounded soldiers to higher levels of care. We hypothesized that the hypobaric, hypoxic conditions of AE may exacerbate uncontrolled inflammation following TBI that could contribute to more severe TBI-related secondary injury. Thirty-six female pigs were used to test TBI vs. TBI sham, hypoxia vs. normoxia, and hypobaria vs. ground conditions. TBI was induced by controlled cortical injury, hypobaric conditions of 12,000 feet were established in an altitude chamber, and hypoxic exposure was titrated to 85% SpO2 while at altitude. Serum cytokines, UCH-L1 and TBI biomarkers were analyzed via ELISA. Gross analysis and staining of cortex and hippocampus tissue was completed for glial fibrillary acidic protein (GFAP) and phosphorylated tau (p-tau). Serum IL-1b, IL-6, and TNFα were significantly elevated following TBI in pigs exposed to altitude-induced hypobaria/hypoxia, as well as hypobaria alone, compared to ground level/normoxia. No difference in TBI biomarkers following TBI or hypobaric, hypoxic exposure was noted. No difference in brain tissue GFAP or p-tau when comparing the most different conditions of sham TBI+ground/normoxia to the TBI+hypobaria/hypoxia group was noted. The hypobaric environment of AE induces systemic inflammation following TBI. Severe inflammation may play a role in exacerbating secondary injury associated with TBI and contribute to worse neurocognitive outcomes. Measures should be taken to minimize barometric and oxygenation changes during AE following TBI.

Parallel Cerebrospinal Fluid and Serum Temporal Profile Assessment of Axonal Injury Biomarkers Neurofilament-Light Chain and Phosphorylated Neurofilament-Heavy Chain: Associations With Patient Outcome in Moderate-Severe Traumatic Brain Injury.

Neurofilament-light chain (NF-L) and phosphorylated neurofilament-heavy chain (pNF-H) are axonal proteins that have been reported as potential diagnostic and prognostic biomarkers in traumatic brain injury (TBI). However, detailed temporal profiles for these proteins in blood, and interrelationships in the acute and chronic time periods post-TBI have not been established. Our objectives were: 1) to characterize acute-to-chronic serum NF-L and pNF-H profiles after moderate-severe TBI, as well as acute cerebrospinal fluid (CSF) levels; 2) to evaluate CSF and serum NF-L and pNF-H associations with each other; and 3) to assess biomarker associations with global patient outcome using both the Glasgow Outcome Scale-Extended (GOS-E) and Disability Rating Scale (DRS). In this multi-cohort study, we measured serum and CSF NF-L and pNF-H levels in samples collected from two clinical cohorts (University of Pittsburgh [UPITT] and Baylor College of Medicine [BCM]) of individuals with moderate-severe TBI. The UPITT cohort includes 279 subjects from an observational cohort study; we obtained serum (n = 277 unique subjects) and CSF (n = 95 unique subjects) daily for 1 week, and serum every 2 weeks for 6 months. The BCM cohort included 103 subjects from a previous randomized clinical trial of erythropoietin and blood transfusion threshold after severe TBI, which showed no effect on neurological outcome between treatment arms; serum (n = 99 unique subjects) and CSF (n = 54 unique subjects) NF-L and pNF-H levels were measured at least daily during Days (D) 0-10 post-injury. GOS-E and DRS were assessed at 6 months (both cohorts) and 12 months (UPITT cohort only). Results show serum NF-L and pNF-H gradually rise during the first 10 days and peak at D20-30 post-injury. In the UPITT cohort, acute (D0-6) NF-L and pNF-H levels correlate within CSF and serum (Spearman r = 0.44-0.48; p < 0.05). In the UPITT cohort, acute NF-L CSF and serum levels, as well as chronic (Months [M]2-6) serum NF-L levels, were higher among individuals with unfavorable GOS-E and worse DRS at 12 months (p < 0.05, all comparisons). In the BCM cohort, higher acute serum NF-L levels were also associated with unfavorable GOS-E. Higher pNF-H serum concentrations (D0-6 and M2-6), but not CSF pNF-H, were associated with unfavorable GOS-E and worse DRS (p < 0.05, all comparisons) in the UPITT cohort. Relationships between biomarker levels and favorable outcome persisted after controlling for age, sex, and Glasgow Coma Scale. This study shows for the first time that serum levels of NF-L and pNF-H peak at D20-30 post-TBI. Serum NF-L levels, and to a lesser extent pNF-H levels, are robustly associated with global patient outcomes and disability after moderate-severe TBI. Further studies on clinical utility as prognosis and treatment-response indicators are needed.

Development of a time-resolved immunochromatographic test strip for rapid and quantitative determination of GFAP in serum.

Glial fibrillary acidic protein (GFAP) in serum has been shown as a biomarker of traumatic brain injury (TBI) which is a significant global public health concern. Accurate and rapid detection of serum GFAP is critical for TBI diagnosis. In this study, a time-resolved fluorescence immunochromatographic test strip (TRFIS) was proposed for the quantitative detection of serum GFAP. This TRFIS possessed excellent linearity ranging from 0.05 to 2.5 ng/mL for the detection of serum GFAP and displayed good linearity (Y = 598723X + 797198, R2 = 0.99), with the lowest detection limit of 16 pg/mL. This TRFIS allowed for quantitative detection of serum GFAP within 15 min and showed high specificity. The intra-batch coefficient of variation (CV) and the inter-batch CV were both < 4.0%. Additionally, this TRFIS was applied to detect GFAP in the serum samples from healthy donors and patients with cerebral hemorrhage, and the results of TRFIS could efficiently discern the patients with cerebral hemorrhage from the healthy donors. Our developed TRFIS has the characteristics of high sensitivity, high accuracy, and a wide linear range and is suitable for rapid and quantitative determination of serum GFAP on-site.

Serum exosomes miR-206 and miR-549a-3p as potential biomarkers of traumatic brain injury

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. However, effective diagnostic, therapeutic and prognostic biomarkers are still lacking. Our research group previously revealed through high-throughput sequencing that the serum exosomes miR-133a-3p, miR-206, and miR-549a-3p differ significantly in severe TBI (sTBI), mild or moderate TBI (mTBI), and control groups. However, convincing experimental evidence is lacking. To solve this problem, we used qPCR in this study to further verify the expression levels of serum exosomes miR-133a-3p, miR-206 and miR-549a-3p in TBI patients. The results showed that the serum exosomes miR-206 and miR-549a-3p showed good predictive value as biomarkers of TBI. In addition, in order to further verify whether serum exosomes miR-206 and miR-549a-3p can be used as potential biomarkers in patients with TBI and to understand the mechanism of their possible effects, we further determined the contents of SOD, BDNF, VEGF, VEGI, NSE and S100β in the serum of TBI patients. The results showed that, serum exosomes miR-206 and miR-549a-3p showed good correlation with BDNF, NSE and S100β. In conclusion, serum exosomes miR-206 and miR-549a-3p have the potential to serve as potential biomarkers in patients with TBI.

Deformed graphene FET biosensor on textured glass coupled with dielectrophoretic trapping for ultrasensitive detection of GFAP

Numerous efforts have been undertaken to mitigate the Debye screening effect of FET biosensors for achieving higher sensitivity. There are few reports that show sub-femtomolar detection of biomolecules by FET mechanisms but they either suffer from significant background noise or lack robust control. In this aspect, deformed/crumpled graphene has been recently deployed by other researchers for various biomolecule detection like DNA, COVID-19 spike proteins and immunity markers like IL-6 at sub-femtomolar levels. However, the chemical vapor deposition (CVD) approach for graphene fabrication suffers from various surface contamination while the transfer process induces structural defects. In this paper, an alternative fabrication methodology has been proposed where glass substrate has been initially texturized by wet chemical etching through the sacrificial layer of synthesized silver nanoparticles, obtained by annealing of thin silver films leading to solid state dewetting. Graphene has been subsequently deposited by thermal reduction technique from graphene oxide solution. The resulting deformed graphene structure exhibits higher sensor response towards glial fibrillary acidic protein (GFAP) detection with respect to flat graphene owing to the combined effect of reduced Debye screening and higher surface area for receptor immobilization. Additionally, another interesting aspect of the reported work lies in the biomolecule capture by dielectrophoretic (DEP) transport on the crests of the convex surfaces of graphene in a coplanar gated topology structure which has resulted in 10 aM and 28 aM detection limits of GFAP in buffer and undiluted plasma respectively, within 15 min of application of analyte. The detection limit in buffer is almost four decades lower than that documented for GFAP using biosensors which is is expected to pave way for advancing graphene FET based sensors towards ultrasensitive point-of-care diagnosis of GFAP, a biomarker for traumatic brain injury.

A systematic review and meta-analysis of major blood protein biomarkers that predict unfavorable outcomes in severe traumatic brain injury

IntroductionSevere traumatic brain injury (TBI) presentation and late clinical outcomes are usually evaluated by the Glasgow Outcome Scale-Extended (GOS-E), which lacks strong prognostic predictability. Several blood biomarkers have been linked to TBI, such as Tau, GFAP, UCH-L1, S-100B, and NSE. Clinical values of TBI biomarkers have yet to be evaluated in a focused multi-study meta-analysis. We reviewed relevant articles evaluating potential relationships between TBI biomarkers and both early and 6-month outcomes. MethodsAll PubMed article publications from January 2000 to November 2023 with the search criteria “Protein Biomarker” AND “Traumatic Brain Injury” were included. Amongst all comparative studies, the sensitivity means and range values of biomarkers in predicting CT Rotterdam scores, ICU admission in the early period, or predicting GOS-E < 4 at the 6-month period were calculated from confusion matrices. Sensitivity values were modeled for each biomarker across studies and compared statistically for heterogeneity and differences. ResultsFrom the 65 articles that met the criteria, 13 were included in this study. Six articles involved early-period TBI outcomes and seven involved 6-month outcomes. In the early period TBI outcomes, GFAP had a superior sensitivity to UCH-L1 and S-100B, and similar sensitivity to the CT Rotterdam score. In the 6-month period TBI outcomes, total Tau and NSE both had significant interstudy heterogeneity, making them inferior to GFAP, phosphorylated Tau, UCH-L1, and S-100B, all four of which had similar sensitivities at 75 %. This sensitivity range at 6-month outcomes was still relatively inferior to the CT Rotterdam score. Total Tau did not show any prognostic advantage at six months with GOS-E < 4, and phosphorylated Tau was similar in its sensitivity to other biomarkers such as GFAP and UCH-L1 and still inferior to the CT Rotterdam score. ConclusionThis data suggests that TBI protein biomarkers do not possess better prognostic value with regards to outcomes.

Prolidase Enzyme Activity as a Potential Biomarker for Blast-Induced Traumatic Brain Injury: A Study in a Rat Model

AbstractBlast-induced traumatic brain injury (TBI) poses a significant threat to individuals exposed to explosive events. We hypothesized that blast-induced neurotrauma is an oxidative stress to brain and hence prolidase (PD) enzyme, which is an antioxidant is recommended; its serum levels are better markers of degree of injury in the acute phase for TBI in a rat blast injury model. Results revealed that PD enzyme activity in the hippocampus showed a slight increase across high, medium, and low blast pressures, but remained lower than the sham group. However, serum PD enzyme activity levels were significantly higher in the blast-exposed groups compared to the sham group. Tau protein levels were significantly elevated in the blast-exposed groups. Longitudinal analysis demonstrated a decline in hippocampal PD activity over time, while tau protein levels progressively increased, suggesting a shift from initial oxidative stress to neurodegeneration. These findings suggest that blast injury triggers oxidative stress and subsequent neurodegenerative processes. The correlation with tau protein levels further supports the involvement of oxidative stress in neurodegeneration. In conclusion, this study provides insights into the underlying pathophysiological mechanisms of blast-induced TBI and highlights the potential utility of PD enzyme activity as a diagnostic marker.

A Comprehensive and Broad Approach to Resting-State Functional Connectivity in Adult Patients with Mild Traumatic Brain Injury.

Several recent works using resting-state fMRI suggest possible alterations of resting-state functional connectivity after mild traumatic brain injury. However, the literature is plagued by various analysis approaches and small study cohorts, resulting in an inconsistent array of reported findings. In this study, we aimed to investigate differences in whole-brain resting-state functional connectivity between adult patients with mild traumatic brain injury within 1 month of injury and healthy control subjects using several comprehensive resting-state functional connectivity measurement methods and analyses. A total of 123 subjects (72 patients with mild traumatic brain injury and 51 healthy controls) were included. A standard fMRI preprocessing pipeline was used. ROI/seed-based analyses were conducted using 4 standard brain parcellation methods, and the independent component analysis method was applied to measure resting-state functional connectivity. The fractional amplitude of low-frequency fluctuations was also measured. Group comparisons were performed on all measurements with appropriate whole-brain multilevel statistical analysis and correction. There were no significant differences in age, sex, education, and hand preference between groups as well as no significant correlation between all measurements and these potential confounders. We found that each resting-state functional connectivity measurement revealed various regions or connections that were different between groups. However, after we corrected for multiple comparisons, the results showed no statistically significant differences between groups in terms of resting-state functional connectivity across methods and analyses. Although previous studies point to multiple regions and networks as possible mild traumatic brain injury biomarkers, this study shows that the effect of mild injury on brain resting-state functional connectivity has not survived after rigorous statistical correction. A further study using subject-level connectivity analyses may be necessary due to both subtle and variable effects of mild traumatic brain injury on brain functional connectivity across individuals.

Circulating MicroRNAs as Prognostic Biomarkers for Traumatic Brain Injury (P8-2.003)

Circulating MicroRNAs as Prognostic Biomarkers for Traumatic Brain Injury (P8-2.003)

Turbulent dynamics and whole-brain modeling: toward new clinical applications for traumatic brain injury.

Traumatic Brain Injury (TBI) is a prevalent disorder mostly characterized by persistent impairments in cognitive function that poses a substantial burden on caregivers and the healthcare system worldwide. Crucially, severity classification is primarily based on clinical evaluations, which are non-specific and poorly predictive of long-term disability. In this Mini Review, we first provide a description of our model-free and model-based approaches within the turbulent dynamics framework as well as our vision on how they can potentially contribute to provide new neuroimaging biomarkers for TBI. In addition, we report the main findings of our recent study examining longitudinal changes in moderate-severe TBI (msTBI) patients during a one year spontaneous recovery by applying the turbulent dynamics framework (model-free approach) and the Hopf whole-brain computational model (model-based approach) combined with in silico perturbations. Given the neuroinflammatory response and heightened risk for neurodegeneration after TBI, we also offer future directions to explore the association with genomic information. Moreover, we discuss how whole-brain computational modeling may advance our understanding of the impact of structural disconnection on whole-brain dynamics after msTBI in light of our recent findings. Lastly, we suggest future avenues whereby whole-brain computational modeling may assist the identification of optimal brain targets for deep brain stimulation to promote TBI recovery.

Applying Proteomics and Computational Approaches to Identify Novel Targets in Blast-Associated Post-Traumatic Epilepsy.

Traumatic brain injury (TBI) can lead to post-traumatic epilepsy (PTE). Blast TBI (bTBI) found in Veterans presents with several complications, including cognitive and behavioral disturbances and PTE; however, the underlying mechanisms that drive the long-term sequelae are not well understood. Using an unbiased proteomics approach in a mouse model of repeated bTBI (rbTBI), this study addresses this gap in the knowledge. After rbTBI, mice were monitored using continuous, uninterrupted video-EEG for up to four months. Following this period, we collected cortex and hippocampus tissues from three groups of mice: those with post-traumatic epilepsy (PTE+), those without epilepsy (PTE-), and the control group (sham). Hundreds of differentially expressed proteins were identified in the cortex and hippocampus of PTE+ and PTE- relative to sham. Focusing on protein pathways unique to PTE+, pathways related to mitochondrial function, post-translational modifications, and transport were disrupted. Computational metabolic modeling using dysregulated protein expression predicted mitochondrial proton pump dysregulation, suggesting electron transport chain dysregulation in the epileptic tissue relative to PTE-. Finally, data mining enabled the identification of several novel and previously validated TBI and epilepsy biomarkers in our data set, many of which were found to already be targeted by drugs in various phases of clinical testing. These findings highlight novel proteins and protein pathways that may drive the chronic PTE sequelae following rbTBI.

Transcriptomic Signatures of Neuronally Derived Extracellular Vesicles Reveal the Presence of Olfactory Receptors in Clinical Samples from Traumatic Brain Injury Patients.

Traumatic brain injury (TBI) is defined as an injury to the brain by external forces which can lead to cellular damage and the disruption of normal central nervous system functions. The recently approved blood-based biomarkers GFAP and UCH-L1 can only detect injuries which are detectable on CT, and are not sensitive enough to diagnose milder injuries or concussion. Exosomes are small microvesicles which are released from the cell as a part of extracellular communication in normal as well as diseased states. The objective of this study was to identify the messenger RNA content of the exosomes released by injured neurons to identify new potential blood-based biomarkers for TBI. Human severe traumatic brain injury samples were used for this study. RNA was isolated from neuronal exosomes and total transcriptomic sequencing was performed. RNA sequencing data from neuronal exosomes isolated from serum showed mRNA transcripts of several neuronal genes. In particular, mRNAs of several olfactory receptor genes were present at elevated concentrations in the neuronal exosomes. Some of these genes were OR10A6, OR14A2, OR6F1, OR1B1, and OR1L1. RNA sequencing data from exosomes isolated from CSF showed a similar elevation of these olfactory receptors. We further validated the expression of these samples in serum samples of mild TBI patients, and a similar up-regulation of these olfactory receptors was observed. The data from these experiments suggest that damage to the neurons in the olfactory neuroepithelium as well as in the brain following a TBI may cause the release of mRNA from these receptors in the exosomes. Hence, olfactory receptors can be further explored as biomarkers for the diagnosis of TBI.

A Systematic Review and Meta-Analysis of the Inflammatory Biomarkers in Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) accounts for most TBI cases, the leading cause of morbidity and mortality worldwide. Despite its high incidence, mTBI pathophysiology remains largely unknown. Recent studies have shown that the inflammatory response is activated early after mTBI and can persist for several weeks or months. However, limited evidence on the utility of inflammatory biomarkers as predictors of clinical outcomes in mTBI has been previously provided. Thus, this systematic review and meta-analysis aims to provide an overview of the current knowledge on the role of inflammation in the pathogenesis of mTBI and the potential of some inflammatory biomolecules as biomarkers of mTBI. In this regard, eight studies comprising 1184 individuals were selected. Thus, it was shown that the increase in IL-6, TNF-α, and IL-1β plasma levels could be implicated in the development of early post-concussion symptoms. On the other hand, the persistence of the increased plasmatic concentrations of IL-10 and IL-8 for as long as six months following the brain injury event could suggest chronic inflammation leading to neuroinflammation and late or persistent symptoms. In this context, our findings showed that inflammatory biomarkers could be relevant in diagnosing or predicting recovery or long-term outcomes of mTBI.

Blood and MRI biomarkers of mild traumatic brain injury in non-concussed collegiate football players

Football has one of the highest incidence rates of mild traumatic brain injury (mTBI) among contact sports; however, the effects of repeated sub-concussive head impacts on brain structure and function remain under-studied. We assessed the association between biomarkers of mTBI and structural and functional MRI scans over an entire season among non-concussed NCAA Division I linemen and non-linemen. Concentrations of S100B, GFAP, BDNF, NFL, and NSE were assessed in 48 collegiate football players (32 linemen; 16 non-linemen) before the start of pre-season training (pre-camp), at the end of pre-season training (pre-season), and at the end of the competitive season (post-season). Changes in brain structure and function were assessed in a sub-sample of 11 linemen and 6 non-linemen using structural and functional MRI during the execution of Stroop and attention network tasks. S100B, GFAP and BDNF concentrations were increased at post-season compared to pre-camp in linemen. White matter hyperintensities increased in linemen during pre-season camp training compared to pre-camp. This study showed that the effects of repeated head impacts are detectable in the blood of elite level non-concussed collegiate football players exposed to low-moderate impacts to the heads, which correlated with some neurological outcomes without translating to clinically-relevant changes in brain anatomy or function.

Extracellular cold-inducible RNA-binding protein mediated neuroinflammation and neuronal apoptosis after traumatic brain injury.

Extracellular cold-inducible RNA-binding protein (eCIRP) plays a vital role in the inflammatory response during cerebral ischaemia. However, the potential role and regulatory mechanism of eCIRP in traumatic brain injury (TBI) remain unclear. Here, we explored the effect of eCIRP on the development of TBI using a neural-specific CIRP knockout (KO) mouse model to determine the contribution of eCIRP to TBI-induced neuronal injury and to discover novel therapeutic targets for TBI. TBI animal models were generated in mice using the fluid percussion injury method. Microglia or neuron lines were subjected to different drug interventions. Histological and functional changes were observed by immunofluorescence and neurobehavioural testing. Apoptosis was examined by a TdT-mediated dUTP nick end labelling assay in vivo or by an annexin-V assay in vitro. Ultrastructural alterations in the cells were examined via electron microscopy. Tissue acetylation alterations were identified by non-labelled quantitative acetylation via proteomics. Protein or mRNA expression in cells and tissues was determined by western blot analysis or real-time quantitative polymerase chain reaction. The levels of inflammatory cytokines and mediators in the serum and supernatants were measured via enzyme-linked immunoassay. There were closely positive correlations between eCIRP and inflammatory mediators, and between eCIRP and TBI markers in human and mouse serum. Neural-specific eCIRP KO decreased hemispheric volume loss and neuronal apoptosis and alleviated glial cell activation and neurological function damage after TBI. In contrast, eCIRP treatment resulted in endoplasmic reticulum disruption and ER stress (ERS)-related death of neurons and enhanced inflammatory mediators by glial cells. Mechanistically, we noted that eCIRP-induced neural apoptosis was associated with the activation of the protein kinase RNA-like ER kinase-activating transcription factor 4 (ATF4)-C/EBP homologous protein signalling pathway, and that eCIRP-induced microglial inflammation was associated with histone H3 acetylation and the α7 nicotinic acetylcholine receptor. These results suggest that TBI obviously enhances the secretion of eCIRP, thereby resulting in neural damage and inflammation in TBI. eCIRP may be a biomarker of TBI that can mediate the apoptosis of neuronal cells through the ERS apoptotic pathway and regulate the inflammatory response of microglia via histone modification.

Biofluid-based Biomarkers in Traumatic Brain Injury: A Narrative Review.

Traumatic brain injury (TBI) is a complex condition characterized by a multifaceted pathophysiology. It presents significant diagnostic and prognostic challenges in clinical settings. This narrative review explores the evolving role of biofluid biomarkers as essential tools in the diagnosis, prognosis, and treatment of TBI. In recent times, preclinical and clinical trials utilizing these biofluid biomarkers have been actively pursued internationally. Among the biomarkers for nerve tissue proteins are neuronal biomarkers like neuronal specific enolase and ubiquitin C-terminal hydrolase L1; astroglia injury biomarkers such as S100B and glial fibrillary acidic protein; axonal injury and demyelination biomarkers, including neurofilaments and myelin basic protein; new axonal injury and neurodegeneration biomarkers like total tau and phosphorylated tau; and others such as spectrin breakdown products and microtubule-associated protein 2. The interpretation of these biomarkers can be influenced by various factors, including secretion from organs other than the injury site and systemic conditions. This review highlights the potential of these biomarkers to transform TBI management and emphasizes the need for continued research to validate their efficacy, refine testing platforms, and ultimately improve patient care and outcomes.

Exploring the Potential of Exosomal Biomarkers in Mild Traumatic Brain Injury and Post-Concussion Syndrome: A Systematic Review.

Alongside their long-term effects, post-concussion syndrome (PCS) and mild traumatic brain injuries (mTBI) are significant public health concerns. Currently, there is a lack of reliable biomarkers for diagnosing and monitoring mTBI and PCS. Exosomes are small extracellular vesicles secreted by cells that have recently emerged as a potential source of biomarkers for mTBI and PCS due to their ability to cross the blood-brain barrier and reflect the pathophysiology of brain injury. In this study, we aimed to investigate the role of salivary exosomal biomarkers in mTBI and PCS. A systematic review using the PRISMA guidelines was conducted, and studies were selected based on their relevance to the topic. The analyzed studies have shown that exosomal tau, phosphorylated tau (p-tau), amyloid beta (Aβ), and microRNAs (miRNAs) are potential biomarkers for mTBI and PCS. Specifically, elevated levels of exosomal tau and p-tau have been associated with mTBI and PCS as well as repetitive mTBI. Dysregulated exosomal miRNAs have also been observed in individuals with mTBI and PCS. Additionally, exosomal Prion cellular protein (PRPc), coagulation factor XIII (XIIIa), synaptogyrin-3, IL-6, and aquaporins have been identified as promising biomarkers for mTBI and PCS. Salivary exosomal biomarkers have the potential to serve as non-invasive and easily accessible diagnostic and prognostic tools for mTBI and PCS. Further studies are needed to validate these biomarkers and develop standardized protocols for their use in clinical settings. Salivary exosomal biomarkers can improve the diagnosis, monitoring, and treatment of mTBI and PCS, leading to improved patient outcomes.

Traumatic brain injury derived pathological tau polymorphs induce the distinct propagation pattern and neuroinflammatory response in wild type mice

The misfolding and aggregation of the tau protein into neurofibrillary tangles constitutes a central feature of tauopathies. Traumatic brain injury (TBI) has emerged as a potential risk factor, triggering the onset and progression of tauopathies. Our previous research revealed distinct polymorphisms in soluble tau oligomers originating from single versus repetitive mild TBIs. However, the mechanisms orchestrating the dissemination of TBI brain-derived tau polymorphs (TBI-BDTPs) remain elusive. In this study, we explored whether TBI-BDTPs could initiate pathological tau formation, leading to distinct pathogenic trajectories. Wild-type mice were exposed to TBI-BDTPs from sham, single-blast (SB), or repeated-blast (RB) conditions, and their memory function was assessed through behavioral assays at 2- and 8-month post-injection. Our findings revealed that RB-BDTPs induced cognitive and motor deficits, concurrently fostering the emergence of toxic tau aggregates within the injected hippocampus. Strikingly, this tau pathology propagated to cortical layers, intensifying over time. Importantly, RB-BDTP-exposed animals displayed heightened glial cell activation, NLRP3 inflammasome formation, and increased TBI biomarkers, particularly triggering the aggregation of S100B, which is indicative of a neuroinflammatory response. Collectively, our results shed light on the intricate mechanisms underlying TBI-BDTP-induced tau pathology and its association with neuroinflammatory processes. This investigation enhances our understanding of tauopathies and their interplay with neurodegenerative and inflammatory pathways following traumatic brain injury.

Research progress in the application of proteomics technology in brain injury.

The aim of this article is to review the application progress of proteomics technology in brain injury research in recent years, point out the current problems that need to be overcome, and explore the application prospects of proteomics analysis in brain injury. This study also aims to retrieve all literature on brain injury and proteomics and summarize it. Through searching and screening, the widespread application of proteomics technology in the treatment of traumatic brain injury (TBI) and the use of a large number of TBI biomarkers were discovered. The pathways mediated by some biomarkers and the physiological and pathological mechanisms of occurrence were elucidated. The current classification of brain injury is mainly based on subjective evaluation of clinical symptoms, combined with objective imaging. However, its practical value is often limited when applied to prognosis evaluation in brain injury. Proteomics technology can make up for this deficiency and provide a reference for the prevention and treatment of brain injury.