Biomarkers Of Traumatic Brain Injury Research Articles

Genetic and peripheral biomarkers of comorbid posttraumatic stress disorder and traumatic brain injury: a systematic review

BackgroundPosttraumatic stress disorder (PTSD) commonly cooccurs with traumatic brain injury (TBI) in military populations and is a significant predictor of poor long-term outcomes; however, it is unclear to what extent specific biological variables are associated with comorbidity. This PROSPERO-registered systematic review evaluates the current body of literature on genetic and peripheral biomarkers associated with comorbid TBI and PTSD.MethodsSearches were conducted in four databases (PubMed, PsycInfo, PTSDPubs, Scopus). We included published studies examining differences in peripheral biomarkers among civilian, military, and veteran participants with both TBI and PTSD compared to those with TBI alone as well as, in some cases, PTSD alone and healthy controls. Data were extracted from included studies and evidence quality was assessed.ResultsOur final analysis included 16 studies, the majority of which were based on data from active duty military and veteran participants. The results suggest that multiple gene variants are likely to contribute to the cumulative risk of PTSD comorbid with TBI. An elevated circulating level of the pro-inflammatory cytokine IL-6 was the most consistently replicated blood-based indicator of comorbid illness, compared to mTBI alone.ConclusionSeveral genetic and protein markers of cellular injury and inflammation appear to be promising indicators of chronic pathology in comorbid TBI and PTSD. Additional research is needed to determine how such factors indicate, predict, and contribute to comorbidity and to what extent they represent viable targets for the development of novel diagnostic tools and therapeutic interventions.

Translational Outcomes Project in Neurotrauma (TOP-NT) Pre-Clinical Consortium Study: A Synopsis.

Traumatic brain injury (TBI) has long been a leading cause of death and disability, yet research has failed to successfully translate findings from the pre-clinical, animal setting into the clinic. One factor that contributes significantly to this struggle is the heterogeneity observed in the clinical setting where patients present with injuries of varying types, severities, and comorbidities. Modeling this highly varied population in the laboratory remains challenging. Given feasibility constraints, individual laboratories often focus on single injury types and are limited to an abridged set of outcome measures. Furthermore, laboratories tend to use different injury or outcome methodologies from one another, making it difficult to compare studies and identify which pre-clinical findings may be best suited for clinical translation. The NINDS-funded Translational Outcomes Project in Neurotrauma (TOP-NT) is a multi-site consortium designed to address the reproducibility, rigor, and transparency of pre-clinical development and validation of clinically relevant biomarkers for TBI. The current overview article provides a detailed description of the infrastructure and strategic approach undertaken by the consortium. We outline the TOP-NT strategy to address three goals: (1) selection and cross-center validation of biomarker tools, (2) development and population of a data infrastructure to allow for the sharing and reuse of pre-clinical, animal research following findable, accessible, interoperable, and reusable data guidelines, and (3) demonstration of feasibility, reproducibility, and transparency in conducting a multi-center, pre-clinical research trial for TBI biomarker development. The synthesized scientific analysis and results of the TOP-NT efforts will be the topic of future articles.

Neurofilament Light Chain under the Lens of Structural Mass Spectrometry.

Neurofilament light chain (NfL) is an early nonspecific biomarker in neurodegenerative diseases and traumatic brain injury, indicating axonal damage. This work describes the detailed structural characterization of a selected primary calibrator with the potential to be used in future reference measurement procedure (RMP) development for the accurate quantification of NfL. As a part of the described workflow, the sequence, higher-order structure as well as solvent accessibility, and hydrogen-bonding profile were assessed under three different conditions in KPBS, artificial cerebrospinal fluid, and artificial cerebrospinal fluid in the presence of human serum albumin. The results revealed that NfL is a structurally heterogeneous protein, eliciting a large conformational flexibility. Its structural ensemble changed when it was diluted with an aqueous buffer versus a surrogate matrix, artificial cerebrospinal fluid (aCSF), and/or aCSF with human serum albumin. Various regions of protection and deprotection in the protein head, central helical, and tail domains that experienced altered solvent accessibility and conformational changes caused by different solvent conditions were identified. Moreover, interfacial residues, which may play a role in a potential direct interaction between NfL and human serum albumin, emerged from hydrogen-deuterium exchange mass spectrometry (HDX-MS). These data pinpointed distinct regions of the protein that may participate in such an interaction. Overall, critical quality attributes of a potential primary calibrator for NfL measurements are provided. These findings will ultimately inform ongoing biochemical and clinical assay development procedures and manufacturing practices, giving careful consideration during sample handling and method development.

Diagnostic and prognostic performance of urine ubiquitin carboxy-terminal hydrolase L1 across multiple acute brain injury types - A longitudinal prospective cohort study.

Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is recognized as a diagnostic and prognostic blood biomarker for traumatic brain injury (TBI). This study aimed to evaluate whether UCH-L1 concentrations measured in patients' urine post-injury could serve as a diagnostic or prognostic biomarker for outcomes in various types of acute brain injuries (ABI). This pilot study included 46 ABI patients: aneurysmal subarachnoid hemorrhage (n=22), ischemic stroke (n=16), and traumatic brain injury (n=8), along with three healthy controls. Urine samples were collected at early (1.50±0.70 days) and late (9.17±3.40 days) periods post-admission. UCH-L1 and creatinine levels were quantified using ELISA. UCH-L1 concentrations were compared to functional outcomes (modified Rankin Scale, mRS) and dichotomized into favorable (mRS 0-3) and unfavorable (mRS 4-6) groups. Non-parametric statistical tests and ROC analysis was performed. UCH-L1 concentrations in healthy controls were significantly lower compared to both early and late samples after ABI (p≤0.001). The diagnostic performance of urine UCH-L1 at early timepoint showed excellent discriminatory ability, with AUC of 97.6% (95% CI: 93.0-100, p=0.006 (sensitivity 98%, specificity 100%). Urine UCH-L1 concentrations, both with and without creatinine normalization, did not distinguish between favorable and unfavorable outcomes in either early (p=0.88 and p=0.36) or late samples (p=0.98 and p=0.30) in any types of ABI. Although UCH-L1 concentrations in urine did not differentiate between favorable and unfavorable outcomes, a significant difference was observed between healthy subjects and ABI patients. This finding underscores the significant diagnostic utility of urine UCH-L1 concentrations, regardless of the type of acute brain injury.

Unveiling the predictive power of biomarkers in traumatic brain injury: A narrative review focused on clinical outcomes.

Traumatic brain injury (TBI) has long-term consequences, including neurodegenerative disease risk. Current diagnostic tools are limited in detecting subtle brain damage. This review explores emerging biomarkers for TBI, including those related to neuronal injury, inflammation, EVs, and ncRNAs, evaluating their potential to predict clinical outcomes like mortality, recovery, and cognitive impairment. It addresses challenges and opportunities for implementing biomarkers in clinical practice, aiming to improve TBI diagnosis, prognosis, and treatment.

Utility of systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio as a predictive biomarker in pediatric traumatic brain injury.

Traumatic brain injury (TBI) remains the predominant cause of mortality and disability among the pediatric population. At present, there are no radiation-free, simple, and cost-effective tools available to assess the severity and prognosis of pediatric TBI. The systemic immune-inflammation index (SII), neutrophilto-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) serve as inflammatory biomarkers that may assist in predicting the outcome of pediatric TBI. This research aims to assess the utility of SII, NLR, and PLR as a predictive biomarker in children with TBI. A retrospective analysis was conducted on SII, NLR, and PLR by reviewing the medical records of all pediatric (age ≤18 years) TBI cases who came to the emergency department in the period from January 2023 to August 2024. Patients were categorized according to 28-day mortality and the severity of TBI. The correlation between the biomarkers and outcomes was analyzed. A total of 206 patients were included in this study. The mean age was 13.81 (1-18). The 28-day mortality rate was 5.3% (n = 11). There were no significant differences in SII, NLR, and PLR between the survivor and mortality groups (P = 0.317, P = 0.288, and P = 0.200, respectively). Based on the TBI severity, there was a significant difference in the SII, NLR, and PLR across mild, moderate, and severe TBI (P = 0.006, P = 0.002, P = 0.001, respectively). The findings of our study did not reveal a significant predictive relationship between SII, NLR, and PLR to 28-day mortality. Nonetheless, there were significant differences in SII, NLR, and PLR among mild, moderate, and severe TBI groups. Further research under more controlled conditions is essential to facilitate the use of SII, NLR, and PLR as predictive biomarkers in pediatric TBI.

Traumatic Brain Injury and Alzheimer's Disease Biomarkers: A Systematic Review of Findings from Amyloid and Tau Positron Emission Tomography.

Traumatic brain injury (TBI) has been discussed as a risk factor for Alzheimer's disease (AD) due to its association with AD risk and earlier cognitive symptom onset. However, the mechanisms behind this relationship are unclear. Some studies have suggested TBI may increase pathological protein deposition in an AD-like pattern; others have failed to find such associations. This review covers literature that uses positron emission tomography (PET) of β-amyloid (Aβ) and/or tau to examine individuals with a history of TBI who are at increased risk for AD due to age. A comprehensive literature search was conducted on January 9, 2023, and 26 resulting citations met inclusion criteria. Common methodological concerns included small samples, limited clinical detail about participants' TBI, recall bias due to reliance on self-reported TBI, and an inability to establish causation. For both Aβ and tau, results were widespread but inconsistent. The regions that showed the most compelling evidence for increased Aβ deposition were the cingulate gyrus and cuneus/precuneus. Evidence for elevated tau was strongest in the medial temporal lobe, entorhinal cortex, precuneus, and frontal, temporal, parietal, and occipital lobes. However, conflicting findings across most regions in both Aβ- and tau-PET studies indicate the critical need for future work in expanded samples and with greater clinical detail to offer a clearer picture of the relationship between TBI and protein deposition in older individuals at risk for AD.

NaHS alters synaptic plasticity proteins and enhances dendritic arborization to improve cognitive and motor deficits after traumatic brain injury in mice.

Traumatic brain injury (TBI) is a complex medical condition affecting people globally. Hydrogen sulfide (H2S) is a recently discovered gaseous mediator and is dysregulated in the brain after TBI. Sodium hydrogen sulfide (NaHS), a known donor of H2S, is beneficial in various biological processes involving aging and diseases, including injury. It is neuroprotective against oxidative stress, neuroinflammation, and other secondary injury processes. However, the NaHS-H2S system has not been investigated as a regulator of injury-mediated synaptic plasticity proteins and the underlying mechanisms after TBI. We developed a model of TBI in Swiss albino mice to study the effects of exogenous H2S, administered as NaHS. We assessed cognitive function (Barnes maze and novel object recognition) and motor function (rotarod). Brain tissue was analysed with ELISA, qRT-PCR, immunoblotting, Golgi-cox staining, and immunofluorescence. NaHS administration restored the injury-caused decline in H2S levels. Injury-mediated oxidative stress parameters were improved following NaHS. It down-regulated TBI biomarkers, ameliorated the synaptic marker proteins, and improved cognitive and motor deficits. These changes were accompanied by enhanced dendritic arborization and spine number. Restoration of N-methyl D-aspartate receptor subunits and diminished glutamate and calcium levels, along with marked changes in microtubule-associated protein 2 A and calcium/calmodulin-dependent protein kinase II, formed the basis of the underlying mechanism(s). Our findings suggest that NaHS could have therapeutic activity against TBI, as it ameliorated cognitive and motor deficits caused by changes in synaptic plasticity proteins and dendritic arborisation, in our model.

Neutrophil-albumin ratio serves as a superior prognostic biomarker for traumatic brain injury

Traumatic brain injury (TBI) represents a common and severe medical condition necessitating prompt risk stratification to enhance patient outcomes. Although substantial research has been conducted on the prognostic utility of various biomarkers for TBI, no single biomarker has been definitively recognized as the most precise predictor of disease outcomes. In comparison to other markers, the neutrophil-albumin ratio (NAR) has emerged as a cost-effective and reproducible inflammatory biomarker, demonstrating potential in evaluating the severity of inflammation and prognosticating outcomes in infections and cerebrovascular diseases. This study evaluated the prognostic significance of the NAR in comparison to two other readily accessible and cost-effective composite indices: the Neutrophil-Lymphocyte Ratio (NLR) and the Platelet-Lymphocyte Ratio (PLR) in individuals with TBI. We conducted a retrospective cohort analysis involving 297 hospitalized TBI patients, gathering comprehensive demographic, anthropometric, medical, clinical, laboratory, and imaging data to assess the expression changes of these biomarkers. Our findings suggest that both the NAR and the NLR possess predictive value regarding prognosis following TBI. However, receiver operating characteristic (ROC) curve analysis revealed that NAR outperformed NLR as a prognostic predictor. In conclusion, our examination of blood biochemistry composite indicators indicates that, while both NAR and NLR serve as significant prognostic markers, NAR is a more effective predictor of outcomes in patients with TBI.

Exploiting blood-based biomarkers to align preclinical models with human traumatic brain injury.

Rodent models are important research tools for studying the pathophysiology of traumatic brain injury (TBI) and developing new therapeutic interventions for this devastating neurological disorder. However, the failure rate for the translation of drugs from animal testing to human treatments for TBI is 100%. While there are several potential explanations for this, previous clinical trials have relied on extrapolation from preclinical studies for critical design considerations, including drug dose optimization, post-injury drug treatment initiation and duration. Incorporating clinically relevant biomarkers in preclinical studies may provide an opportunity to calibrate preclinical models to identical (or similar) measurements in humans, link to human TBI biomechanics and pathophysiology, and guide therapeutic decisions. To support this translational goal, we conducted a systematic literature review of preclinical TBI studies in rodents measuring blood levels of clinically used GFAP, UCH-L1, NfL, t-Tau, or p-Tau, published in PubMed/EMBASE up to April 10th, 2024. Although many factors influence clinical TBI outcomes, many of those cannot routinely be assessed in rodent studies (e.g., ICP monitoring), thus we focused on blood biomarkers' temporal trajectories and discuss our findings in the context of the latest clinical TBI biomarker data. Out of the 805 original preclinical studies, 74 met the inclusion criteria, with a median quality score of 5 (25th-75th percentiles: 4-7) on the CAMARADES checklist. GFAP was measured in 43 studies, UCH-L1 in 21, NfL in 20, t-Tau in 19, and p-Tau in seven. Data in rodent models indicate that all biomarkers exhibited injury severity-dependent elevations with distinct temporal profiles. GFAP and UCH-L1 peaked within the first day after TBI (30- and 4-fold increases, respectively, in moderate-to-severe TBI versus sham) with the highest levels observed in the contusion TBI model. NfL peaked within days (18-fold increase) and remained elevated up to 6 months post-injury. GFAP and NfL show a pharmacodynamic response in 64.7% and 60%, respectively, of studies evaluating neuroprotective therapies in preclinical models. However, GFAP's rapid decline post-injury may limit its utility for understanding the response to new therapeutics beyond the hyperacute phase after experimental TBI. Furthermore, as in humans, subacute NfL levels inform on chronic white matter loss after TBI. t-Tau and p-Tau levels increased over weeks after TBI (up to 6- and 16-fold, respectively); however, their relationship with underlying neurodegeneration has yet to be addressed. Further investigation into biomarker levels in the subacute and chronic phases after TBI will be needed to fully understand the pathomechanisms underpinning blood biomarkers' trajectories and select the most suitable experimental model to optimally relate preclinical mechanistic studies to clinical observations in humans. This new approach could accelerate the translation of neuroprotective treatments from laboratory experiments to real-world clinical practices.

Systemic Inflammatory Effect of Hypobaria During Aeromedical Evacuation 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 used 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 after TBI that could contribute to more severe TBI-related secondary injury. Thirty-six female pigs were used to test TBI vs Sham TBI, hypoxia vs normoxia, and hypobaria vs ground conditions. TBI was induced by controlled cortical injury, hypobaric conditions of 12,000 ft were established in an altitude chamber, and hypoxic exposure was titrated to 85% SpO 2 while at altitude. Serum cytokines, ubiquitin C-terminal hydrolase L1, and TBI biomarkers were analyzed via ELISA. Gross analysis and staining of cortex and hippocampus tissue was completed for glial fibrillary acidic protein and phosphorylated tau. Serum interleukin-1β, interleukin-6, and tumor necrosis factor-α were significantly elevated after TBI in pigs exposed to altitude-induced hypobaria/hypoxia, as well as hypobaria alone, compared with ground level/normoxia. No difference in TBI biomarkers after TBI or hypobaric, hypoxic exposure was noted. No difference in brain tissue glial fibrillary acidic protein or phosphorylated tau when comparing the most different conditions of Sham TBI + ground or normoxia with the TBI + hypobaria/hypoxia group was noted. The hypobaric environment of AE induces systemic inflammation after 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 after TBI.

Fluid biomarkers of chronic traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of long-term disability across the world. Evidence for the usefulness of imaging and fluid biomarkers to predict outcomes and screen for the need to monitor complications in the acute stage is steadily increasing. Still, many people experience symptoms such as fatigue and cognitive and motor dysfunction in the chronic phase of TBI, where objective assessments for brain injury are lacking. Consensus criteria for traumatic encephalopathy syndrome, a clinical syndrome possibly associated with the neurodegenerative disease chronic traumatic encephalopathy, which iscommonly associated with sports concussion, have been defined only recently. However, these criteria do not fit all individuals living with chronic consequences of TBI. The pathophysiology of chronic TBI shares many similarities with other neurodegenerative and neuroinflammatory conditions, such as Alzheimer disease. As with Alzheimer disease, advancements in fluid biomarkers represent one of the most promising paths for unravelling the chain of pathophysiological events to enable discrimination between these conditions and, with time, provide prediction modelling and therapeutic end points. This Review summarizes fluid biomarker findings in the chronic phase of TBI (≥6 months after injury) that demonstrate the involvement of inflammation, glial biology and neurodegeneration in the long-term complications of TBI. We explore how the biomarkers associate with outcome and imaging findings and aim to establish mechanistic differences in biomarker patterns between types of chronic TBI and other neurodegenerative conditions. Finally, current limitations and areas of priority for future fluid biomarker research are highlighted.

A-090 Performance of GFAP and UCH-L1 Biomarkers for Traumatic Brain Injury in the ARCHITECT i1000SR TBI Test

Abstract Background Traumatic Brain Injury (TBI) has been recognized as an important cause of death and disability and is a growing public health problem. An estimated 69 million people globally experience a TBI annually. The vast majority (80%) of patients evaluated for TBI in the Emergency Department will receive head CT scans, however less than 10% will have findings of acute traumatic abnormalities. This highlights the need for objective, rapid, accurate tools to help clinicians evaluate and triage patients with suspected TBI and reduce unnecessary radiation exposure. Blood based biomarkers such as glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) have shown utility to predict acute traumatic intracranial injury on CT scan after TBI. Methods The ARCHITECT TBI test is a panel of in vitro diagnostic chemiluminescent microparticle immunoassays for the measurement of GFAP and UCH-L1 in plasma and serum. A method comparison study was performed to compare the GFAP and UCH-L1 assays on ARCHITECT i1000SR to the FDA cleared Alinity i assays. Performance characteristics such as detection limits, imprecision, linearity, and measuring interval were established following CLSI guidance. Results The analytical measuring interval (AMI) extends from the limit of quantitation (LoQ) to the upper LoQ and is determined by the range that demonstrates acceptable performance for linearity, imprecision, and bias. The AMI is 6.1 to 42,000 pg/mL for GFAP and 26.3 to 25,000 pg/mL for UCH-L1. Within-laboratory imprecision ranged from 2.2 to 6.2% CV for GFAP and 2.2 to 4.5% CV for UCH-L1. The Overall Reproducibility (includes repeatability, between-run, between-day, between-instrument variance components) results ranged from 2.7 to 6.8% CV for GFAP and 2.4 to 3.9 %CV for UCH-L1. The method comparison study evaluated 123 specimens across the range of 6.5-32,548.6 pg/mL for GFAP, and 51.5-24,127.7 for UCH-L1. The correlation coefficients were 1.0, with a slope of 1.03 and 1.06, an intercept of -0.6 and -6.0, for GFAP and UCH-L1, respectively. The results support use of the established GFAP and UCH-L1 cutoffs and clinical performance findings in a multi-site pivotal study which enrolled 1899 mild TBI (Glasgow Coma Scale score 13 to 15) subjects. 116 of the 120 specimens with a positive CT scan had a positive TBI interpretation (Sensitivity 96.7%). Of the 1779 subjects with negative CT scan results, 713 had a negative TBI interpretation (Specificity 40.1%). The negative predictive value (NPV) of the test was 99.4% (713/717). Conclusions The ARCHITECT TBI test performance was evaluated compared to the Alinity i TBI test across a broad concentration range of GFAP and UCH-L1. The results support equivalence of the ARCHITECT TBI test to the Alinity i TBI test. The established cutoffs were evaluated in a prospective cohort of mild TBI subjects and demonstrated high sensitivity and NPV relative to head CT scan results, supporting the utility to rule out the need for CT scan in mild TBI subjects presenting to the emergency department. Funding This work is in collaboration with the US Army Medical Materiel Development Activity, US Army Medical Research and Development Command CRADA 20-1266-CRA.

Plasma biomarkers in chronic single moderate-severe traumatic brain injury.

Blood biomarkers are an emerging diagnostic and prognostic tool that reflect a range of neuropathological processes following traumatic brain injury (TBI). Their effectiveness in identifying long-term neuropathological processes after TBI is unclear. Studying biomarkers in the chronic phase is vital because elevated levels in TBI might result from distinct neuropathological mechanisms during acute and chronic phases. Here, we examine plasma biomarkers in the chronic period following TBI and their association with amyloid and tau PET, white matter microarchitecture, brain age and cognition. We recruited participants ≥40 years of age who had suffered a single moderate-severe TBI ≥10 years previously between January 2018 and March 2021. We measured plasma biomarkers using single molecule array technology [ubiquitin C-terminal hydrolase L1 (UCH-L1), neurofilament light (NfL), tau, glial fibrillary acidic protein (GFAP) and phosphorylated tau (P-tau181)]; PET tracers to measure amyloid-β (18F-NAV4694) and tau neurofibrillary tangles (18F-MK6240); MRI to assess white matter microstructure and brain age; and the Rey Auditory Verbal Learning Test to measure verbal-episodic memory. A total of 90 post-TBI participants (73% male; mean = 58.2 years) were recruited on average 22 years (range = 10-33 years) post-injury, and 32 non-TBI control participants (66% male; mean = 57.9 years) were recruited. Plasma UCH-L1 levels were 67% higher {exp(b) = 1.67, P = 0.018, adjusted P = 0.044, 95% confidence interval (CI) [10% to 155%], area under the curve = 0.616} and P-tau181 were 27% higher {exp(b) = 1.24, P = 0.011, adjusted P = 0.044, 95% CI [5% to 46%], area under the curve = 0.632} in TBI participants compared with controls. Amyloid and tau PET were not elevated in TBI participants. Higher concentrations of plasma P-tau181, UCH-L1, GFAP and NfL were significantly associated with worse white matter microstructure but not brain age in TBI participants. For TBI participants, poorer verbal-episodic memory was associated with higher concentration of P-tau181 {short delay: b = -2.17, SE = 1.06, P = 0.043, 95% CI [-4.28, -0.07]; long delay: bP-tau = -2.56, SE = 1.08, P = 0.020, 95% CI [-4.71, -0.41]}, tau {immediate memory: bTau = -6.22, SE = 2.47, P = 0.014, 95% CI [-11.14, -1.30]} and UCH-L1 {immediate memory: bUCH-L1 = -2.14, SE = 1.07, P = 0.048, 95% CI [-4.26, -0.01]}, but was not associated with functional outcome. Elevated plasma markers related to neuronal damage and accumulation of phosphorylated tau suggest the presence of ongoing neuropathology in the chronic phase following a single moderate-severe TBI. Plasma biomarkers were associated with measures of microstructural brain disruption on MRI and disordered cognition, further highlighting their utility as potential objective tools to monitor evolving neuropathology post-TBI.

Development and Optimization of Micro‐Nanotopographical Platforms for Surface Enhanced Raman Scattering Biomolecular Detection

AbstractTopologically designed micro‐ and nanostructured surface‐enhanced Raman scattering (SERS) substrates propel the advancements of innovative applications, including environmental and forensic point‐of‐care miniaturised devices via enhancing the localised electric fields for accurate analyte sensing. Herein, a method for designing, optimising and fabricating fine‐tuneable concentric hexagonal, triangular and rectangular SERS‐active micronano‐substrates is developed, with each unit yielding significant enhancement. Numerical simulations of the 3D near‐field electric field guided the optimal design process. While the coaxial SERS substrates consistently outperformed their solid counterparts, the hexagonal micro‐nano topologies exhibited ×21 higher signal than coaxial square arrays and a 12‐15‐fold increase over the triangle structures. Alternation of the topological designs from square to triangle lattice yielded more uniform plasmonic modes propagating along the 60°‐directions with various resonance modes playing key roles in light reflectance. This enables the engineering of platforms with tailor‐enhanced signals by changing the arrangement of micro‐nano patterned coaxial arrays. The fabricated SERS substrates are validated by detecting traumatic brain injury biomarkers, effectively yielding the characteristic fingerprint spectra of each neuro‐molecule. The straightforward development of sub‐micrometre tuneable SERS‐active architectures enables anelegant route for high‐throughput biochemical sensing, laying a platform for amplified bimolecular detection of disease biomarkers and integration in bioanalytical systems.

Performance of Diagnostic Biomarkers for Traumatic Brain Injury Within the First Hour-Expanding Their Clinical Utility.

Performance of Diagnostic Biomarkers for Traumatic Brain Injury Within the First Hour-Expanding Their Clinical Utility.

The neuronal biomarker NSE correlates with the volume of lung contusion in polytraumatized patients.

Severe injuries caused by accidents, like traumatic brain injury (TBI) or thoracic trauma (TT) continue to be the leading cause of death in younger people with relevant socio-economic impact. Fast and targeted diagnostics is essential for further therapy decisions and prognosis. The following study investigates NSE as a potential biomarker for lung injury after blunt TT. This is a retrospective analysis of prospectively collected data in a level-1 trauma center from 2014 to 2020. Serum levels of Neuron-specific Enolase (NSE) and Interleukins (IL-6, IL-10) in injured patients (n = 41) with isolated TT (AISthorax ≥ 3) compared to isolated TBI (AIShead ≥ 3) were assessed from day 0 to 5 after trauma. The extend of lung injury was quantified by Hounsfield scale in CT scans. 30 patients with TT (ISSmed = 20, age 50y ± 17, 83,3% male) and 11 patients with TBI (ISSmed = 25, age 54y ± 17,27,3% male) were included. After TT, NSE concentration increased initially after trauma with a peak value on the day of admission (8.51 ± 3.68 ng/ml) compared to healthy controls (4.51 ± 1.504 ng/ml, p < 0.001). Isolated thoracic trauma and TBI lead to equally strong NSE release ad the day of admission. There is a significant linear relationship (r = 0.636, p = 0.035) between serum NSE levels and severity of pulmonary contusion at the time of admission and after 24 hours. A significant NSE release after isolated thoracic trauma peaks on the day of admission. The extent of lung contusion volume (defined as alveolar parenchymal density) correlates with NSE serum concentration. Thus, NSE has predictive value for the extent of pulmonary contusion. However, according to these data, NSE seems to have no diagnostic value as a TBI biomarker in concomitant TT.

Diagnostic Performance of GFAP, UCH-L1, and MAP-2 Within 30 and 60 Minutes of Traumatic Brain Injury.

Data on the performance of traumatic brain injury (TBI) biomarkers within minutes of injury are lacking. To examine the performance of glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and microtubule-associated protein 2 (MAP-2) within 30 and 60 minutes of TBI in identifying intracranial lesions on computed tomography (CT) scan, need for neurosurgical intervention (NSI), and clinically important early outcomes (CIEO). This cohort study is a biomarker analysis of a multicenter prehospital TBI cohort from the Prehospital Tranexamic Acid Use for TBI clinical trial conducted across 20 centers and 39 emergency medical systems in North America from May 2015 to March 2017. Prehospital hemodynamically stable adult patients with traumatic injury and suspected moderate to severe TBI were included. Blood samples were measured for GFAP, UCH-L1, and MAP-2. Data were analyzed from December 1, 2023, to March 15, 2024. The presence of CT lesions, diffuse injury severity on CT, NSI within 24 hours of injury, and CIEO (composite outcome including early death, neurosurgery, or prolonged mechanical ventilation ≥7 days) within 7 days of injury. Of 966 patients enrolled, 804 patients (mean [SD] age, 41 [19] years; 418 [74.2%] male) had blood samples, including 563 within 60 minutes and 375 within 30 minutes of injury. Among patients with blood drawn within 30 minutes of injury, 212 patients (56.5%) had CT lesions, 61 patients (16.3%) had NSI, and 112 patients (30.0%) had CIEO. Among those with blood drawn within 60 minutes, 316 patients (56.1%) had CT lesions, 95 patients (16.9%) had NSI, and 172 patients (30.6%) had CIEO. All biomarkers showed significant elevations with worsening diffuse injury on CT within 30 and 60 minutes of injury. Among blood samples taken within 30 minutes, GFAP had the highest area under the receiver operating characteristic curve (AUC) to detect CT lesions, at 0.88 (95% CI, 0.85-0.92), followed by MAP-2 (AUC, 0.78; 95% CI, 0.73-0.83) and UCH-L1 (AUC, 0.75; 95% CI, 0.70-0.80). Among blood samples taken within 60 minutes, AUCs for CT lesions were 0.89 (95% CI, 0.86-0.92) for GFAP, 0.76 (95% CI, 0.72-0.80) for MAP-2, and 0.73 (95% CI, 0.69-0.77) for UCH-L1. Among blood samples taken within 30 minutes, AUCs for NSI were 0.78 (95% CI, 0.72-0.84) for GFAP, 0.75 (95% CI, 0.68-0.81) for MAP-2, and 0.69 (95% CI, 0.63-0.75) for UCH-L1; and for CIEO, AUCs were 0.89 (95% CI, 0.85-0.93) for GFAP, 0.83 (95% CI, 0.78-0.87) for MAP-2, and 0.77 (95% CI, 0.72-0.82) for UCH-L1. Combining the biomarkers was no better than GFAP alone for all outcomes. At GFAP of 30 pg/mL within 30 minutes, sensitivity for CT lesions was 98.1% (95% CI, 94.9%-99.4%) and specificity was 34.4% (95% CI, 27.2%-42.2%). GFAP levels greater than 6200 pg/mL were associated with high risk of NSI and CIEO. In this cohort study of prehospital patients with TBI, GFAP, UCH-L1, and MAP-2 measured within 30 and 60 minutes of injury were significantly associated with traumatic intracranial lesions and diffuse injury severity on CT scan, 24-hour NSI, and 7-day CIEO. GFAP was the strongest independent marker associated with all outcomes. This study sets a precedent for the early utility of GFAP in the first 30 minutes from injury in future clinical and research endeavors.

Development and Analytical Validation of a Surface-Enhanced Raman Scattering Paper Lateral Flow Immunoassay for Detection of the Ubiquitin C-Terminal Hydrolase-L1 Traumatic Brain Injury Biomarker.

Paper lateral flow immunoassays combined with surface-enhanced Raman scattering (SERS) technology have gained increasing attention due to their high sensitivity characteristics resulting from the amplified SERS signals of the plasmon-enhanced optical probes. In contrast to conventional colorimetric lateral flow strips, SERS paper lateral flow strips (SERS-PLFSs) are currently not commercially available for widespread use. Analytical validation is the key step for commercialization. In this work, we have developed a PLFS with a hierarchical SERS probe (gold-silver nanoparticle@Raman reporter@silica) for detection of the US Food and Drug Administration (FDA)-approved traumatic brain injury (TBI) protein biomarker, ubiquitin C-terminal hydrolase-L1 (UCH-L1), in blood plasma samples. Analytical validation has been performed on this SERS-PLFS in terms of the limit of detection (LOD), limit of quantification (LOQ), accuracy, precision, selectivity, and stability. The SERS-PLFS exhibits a reportable range of 0.2-100 ng/mL with a LOD of 0.08 ng/mL toward measurement of UCH-L1 in blood plasma. The SERS-PLFS has been applied to clinical TBI samples. The test results were compared with those from enzyme-linked immunosorbent assay (ELISA), demonstrating a strong correlation between the two analytical methods. This study has important implications in the commercialization of SERS-PLFSs for rapid TBI detection in clinical practice.

Systemic and cerebro-cardiac biomarkers following traumatic brain injury: an interim analysis of randomized controlled clinical trial of early administration of beta blockers

This is an interim analysis of the Beta-blocker (Propranolol) use in traumatic brain injury (TBI) based on the high-sensitive troponin status (BBTBBT) study. The BBTBBT is an ongoing double-blind placebo-controlled randomized clinical trial with a target sample size of 771 patients with TBI. We sought, after attaining 50% of the sample size, to explore the impact of early administration of beta-blockers (BBs) on the adrenergic surge, pro-inflammatory cytokines, and the TBI biomarkers linked to the status of high-sensitivity troponin T (HsTnT). Patients were stratified based on the severity of TBI using the Glasgow coma scale (GCS) and HsTnT status (positive vs negative) before randomization. Patients with positive HsTnT (non-randomized) received propranolol (Group-1; n = 110), and those with negative test were randomized to receive propranolol (Group-2; n = 129) or placebo (Group-3; n = 111). Propranolol was administered within 24 h of injury for 6 days, guided by the heart rate (> 60 bpm), systolic blood pressure (≥ 100 mmHg), or mean arterial pressure (> 70 mmHg). Luminex and ELISA-based immunoassays were used to quantify the serum levels of pro-inflammatory cytokines (Interleukin (IL)-1β, IL-6, IL-8, and IL-18), TBI biomarkers [S100B, Neuron-Specific Enolase (NSE), and epinephrine]. Three hundred and fifty patients with comparable age (mean 34.8 ± 9.9 years) and gender were enrolled in the interim analysis. Group 1 had significantly higher baseline levels of IL-6, IL-1B, S100B, lactate, and base deficit than the randomized groups (p = 0.001). Group 1 showed a significant temporal reduction in serum IL-6, IL-1β, epinephrine, and NSE levels from baseline to 48 h post-injury (p = 0.001). Patients with severe head injuries had higher baseline levels of IL-6, IL-1B, S100B, and HsTnT than mild and moderate TBI (p = 0.01). HsTnT levels significantly correlated with the Injury Severity Score (ISS) (r = 0.275, p = 0.001), GCS (r = − 0.125, p = 0.02), and serum S100B (r = 0.205, p = 0.001). Early Propranolol administration showed a significant reduction in cytokine levels and TBI biomarkers from baseline to 48 h post-injury, particularly among patients with positive HsTnT, indicating the potential role in modulating inflammation post-TBI.Trial registration: ClinicalTrials.gov NCT04508244. It was registered first on 11/08/2020. Recruitment started on 29 December 2020 and is ongoing. The study was partly presented at the 23rd European Congress of Trauma and Emergency Surgery (ECTES), April 28–30, 2024, in Estoril, Lisbon, Portugal.