Outcome Of Traumatic Brain Injury Research Articles

Tufm lactylation regulates neuronal apoptosis by modulating mitophagy in traumatic brain injury.

Lactates accumulation following traumatic brain injury (TBI) is detrimental. However, whether lactylation is triggered and involved in the deterioration of TBI remains unknown. Here, we first report that Tufm lactylation pathway induces neuronal apoptosis in TBI. Lactylation is found significantly increased in brain tissues from patients with TBI and mice with controlled cortical impact (CCI), and in neuronal injury cell models. Tufm, a key factor in mitophagy, is screened and identified to be mostly lactylated. Tufm is detected to be lactylated at K286 and the lactylation inhibits the interaction of Tufm and Tomm40 on mitochondria. The mitochondrial distribution of Tufm is then inhibited. Consequently, Tufm-mediated mitophagy is suppressed while mitochondria-induced neuronal apoptosis is increased. In contrast, the knockin of a lactylation-deficient TufmK286R mutant in mice rescues the mitochondrial distribution of Tufm and Tufm-mediated mitophagy, and improves functional outcome after CCI. Likewise, mild hypothermia, as a critical therapeutic method in neuroprotection, helps in downregulating Tufm lactylation, increasing Tufm-mediated mitophagy, mitigating neuronal apoptosis, and eventually ameliorating the outcome of TBI. A novel molecular mechanism in neuronal apoptosis, TBI-initiated Tufm lactylation suppressing mitophagy, is thus revealed.

Alteration of Serum MLKL Levels and Their Association with Severity and Clinical Outcomes in Human Severe Traumatic Brain Injury: A Prospective Cohort Study

Alteration of Serum MLKL Levels and Their Association with Severity and Clinical Outcomes in Human Severe Traumatic Brain Injury: A Prospective Cohort Study

Severe Traumatic Brain Injury Outcomes In Patients With Premorbid Psychiatric Illness

ObjectiveIndividuals with psychiatric illnesses (PI) have increased rates of traumatic brain injury (TBI). Nonetheless, the influence of underlying PI on TBI outcomes is poorly understood. MethodsWe analyzed the medical records of 633 adult-severe TBI (sTBI) patients admitted to our institution between 2010-2021. We identified patients with premorbid PI (Psych(+) group, n=129) and a subset with only a substance use disorder (SUD(+) group, n=60) and compared them to patients without PI (Psych(-) group, n=480). Outcome measures included discharge Glasgow Coma Scale (GCS), length of stay (LOS), in-hospital survival, and Glasgow Outcome Scale-Extended (GOS-E). ResultsThe Psych(+) group had increased in-hospital survival (69.8% v. 55.0%, P=0.003) and fewer patients with severe (3-8) discharge-GCS (28.7% v. 46.0%, P<0.001). The SUD(+) group had increased in-hospital survival (70.0% v. 55.0%, P=0.028) and fewer patients with severe discharge-GCS (28.3% v. 46.0%, P=0.009). However, the Psych(+) (21.0 v. 10.0 days, P<0.001) and SUD(+) (16.0 v. 10.0 days, P=0.011) groups had longer LOS. The Psych(+) group had a higher mean GOS-E at discharge (2.7 v. 2.4, P=0.004), six-months (3.8 v. 3.0, P=0.006) and one-year (3.4 v. 2.3, P=0.027). The SUD(+) group also had a higher mean GOS-E at discharge (2.8 v. 2.4, P=0.034), six months (3.8 v. 3.0, P=0.035), and one year (3.5 v. 2.3, P=0.008). Additionally, there were no significant differences in injury severity or CT scan findings. ConclusionsIndividuals with PI and SUD appeared to have better outcomes but more complicated hospital stays following sTBI. Future studies should investigate the mechanisms underlying these outcomes.

Hyperbaric Oxygen Therapy (HBOT) in Moderate Traumatic Brain Injury (TBI): A Randomized Controlled Trial

Abstract Introduction Hyperbaric oxygen therapy (HBOT) is a novel technique recently under investigation with intention to improve outcomes in traumatic brain injury (TBI). It increases the partial pressure of oxygen in the blood and tissues by inhaling pure oxygen in an environment pressurized to at least 1.4 times normal atmospheric pressure (ATM) at sea level. The rationale behind the use of HBOT in TBI is its potential to mitigate the secondary brain injury cascade initiated by the primary mechanical trauma. Tissue damage and neuroinflammation secondary to intricate and complex cellular biochemical processes are expected to be counteracted by increased oxygen availability during HBOT, which reduces oxidative stress and improves neuroplasticity. Materials and Methods All patients, except whose legal guardians denied informed consent, with moderate TBI presenting to the neurotrauma center, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India, were included within the study period of June 2022 to July 2023. Patient allocation was randomized into two arms: namely, treatment and control arm. Simple randomization was done using randomization mobile app, RRApp. Each patient received standard of care per the Brain Trauma Foundation guidelines. Patients randomized under the treatment arm additionally received adjuvant HBOT sessions. One session daily for 10 consecutive days. Session duration was for 60 minutes each at 1.4 ATM. The primary objective of the study was to compare the Glasgow Coma Score (GCS) at discharge and 3-month post-TBI Glasgow Outcome Scale-Extended (GOS-E) among patients in the treatment arm (those who received adjuvant HBOT) with those in the control arm (those who received only standard of care). Results The mean GCS (±standard deviation [SD]) at discharge in the treatment arm was 14.37 (±00.51) with a median of 14 and a range of 14 to 15. Comparatively, the mean GCS (±SD) at discharge in the control arm was 13.40 (±00.84) with a median of 13 and a range of 12 to 15. The difference between the two arms was statistically significant (p &lt; 0.001). GOS-E at 3 months postinjury for the treatment arm was 7.62 ± 00.51 (mean ± SD) with a median of 8 (range: 7–8). For the control arm, GOS-E at 3 months postinjury was 6.40 ± 1.50 (mean ± SD) with a median of 7 (range: 4–8). The difference between the two arms was statistically significant (p &lt; 0.001). Conclusion The current study concludes that early adjuvant HBOT using 1.4 ATM with one session of one-hour daily for 10 days among adults sustaining moderate TBI significantly improves GCS at 10 days. Early adjuvant HBOT is also associated with significantly improved GOS-E at 3 months postinjury compared to standard of care alone.

Modified Revised Trauma–Marshall Score as a Proposed Tool in Predicting the Outcome of Moderate and Severe Traumatic Brain Injury

Modified Revised Trauma–Marshall Score as a Proposed Tool in Predicting the Outcome of Moderate and Severe Traumatic Brain Injury

Exploring Synaptic Pathways in Traumatic Brain Injury: A Cross-Phenotype Genomics Approach.

Traumatic brain injury (TBI), a global leading cause of mortality and disability, lacks effective treatments to enhance recovery. Synaptic remodeling has been postulated as one mechanism that influences outcomes after TBI. We sought to investigate whether common mechanisms affecting synapse maintenance are shared between TBI and other neuropsychiatric conditions using pathway enrichment tools and genome-wide genotype data, with the goal of highlighting novel treatment targets. We leveraged an integrative approach, combining data from genome-wide association studies with pathway and gene-set enrichment analyses. Literature review-based and Reactome database-driven approaches were combined to identify synapse-related pathways of interest in TBI outcome and to assess for shared associations with conditions in which synapse-related pathobiological mechanisms have been implicated, including Alzheimer's disease, schizophrenia (SCZ), major depressive disorder, post-traumatic stress disorder, attention-deficit hyperactivity disorder, and autism spectrum disorder. Gene and pathway-level enrichment analyses were conducted using MAGMA and its extensions, e- and H-MAGMA, followed by Mendelian randomization to investigate potential causal associations. Of the 98 pathways tested, 32 were significantly enriched in the included conditions. In TBI outcome, we identified significant enrichment in five pathways: "Serotonin clearance from the synaptic cleft" (p = 0.0001), "Presynaptic nicotinic acetylcholine receptors" (p = 0.0003), "Postsynaptic nicotinic acetylcholine receptors" (p = 0.0003), "Highly sodium permeable postsynaptic acetylcholine nicotinic receptors" (p = 0.0001), and "Acetylcholine binding and downstream events" pathways (p = 0.0003). These associations highlight potential involvement of the cholinergic and serotonergic systems in post-TBI recovery. Three of those pathways were shared between TBI and SCZ, suggesting possible pathophysiologic commonalities. In this study, we utilize comparative and integrative genomic approaches across brain conditions that share synaptic mechanisms to explore the pathophysiology of TBI outcomes. Our results implicate associations between TBI outcome and synaptic pathways as well as pathobiological overlap with other neuropsychiatric diseases.

Improvement in edema and cognitive recovery after moderate traumatic brain injury with the neurosteroid prodrug NTS-104

Neuroactive steroids reduce mortality, decrease edema, and improve functional outcomes in preclinical and clinical traumatic brain injury (TBI) studies. In this study, we tested the efficacy of two related novel neuroactive steroids, NTS-104 and NTS-105, in a rat model of TBI. NTS-104 is a water-soluble prodrug of NTS-105, a partial progesterone receptor agonist. To investigate the effects of NTS-104 on TBI recovery, adult male Sprague Dawley rats received moderate parasagittal fluid-percussion injury or sham surgery and were treated with vehicle or NTS-104 (10 ​mg/kg, intramuscularly) at 4, 10, 24, and 48 ​h post-TBI. The therapeutic time window was also assessed using the neuroactive steroid NTS-105 (3 ​mg/kg, intramuscularly). Edema in the parietal cortex and hippocampus, measured at 3 days post-injury (DPI), was reduced by NTS-104 and NTS-105. NTS-105 was effective in reducing edema when given at 4, 10, or 24 ​h post-injury. Sensorimotor deficits in the cylinder test at 3 DPI were ameliorated by NTS-104 and NTS-105 treatment. Cognitive recovery, assessed with cue and contextual fear conditioning and retention of the water maze task assessed subacutely 1–3 weeks post-injury, also improved with NTS-104 treatment. Cortical and hippocampal atrophy at 22 DPI did not improve, indicating that NTS-104/NTS-105 may promote post-TBI cognitive recovery by controlling edema and other processes. These results demonstrate that NTS-104/NTS-105 is a promising therapeutic approach to improve motor and cognitive recovery after moderate TBI.

Racial and Ethnic Differences in Traumatic Brain Injury Outcomes From 2009 to 2023: Protocol for a Systematic Review.

In 2009, Gary and colleagues reviewed prior research examining racial and ethnic differences in outcomes after traumatic brain injury (TBI). Over the past 15 years, advances in research and changes in the demographic composition of the United States warrant a comprehensive understanding of racial and ethnic disparities after TBI. A systematic review will be conducted to examine racial and ethnic differences in TBI outcomes from 2009 to 2023. Preliminary searches and study screening processes will identify relevant English-language articles published from January 2009 to December 2023 using the CINAHL, Gale OneFile, PsycINFO (Ovid), and PubMed electronic databases. Relevant articles will include quantitative or mixed method approaches, involve individuals with TBI or their caregivers, and compare 2 or more groups by race or ethnicity on post-TBI outcomes. Quality will be assessed using the Newcastle-Ottawa Scale. This systematic review protocol was developed following PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) guidelines. Results will be summarized, and a subgroup analysis may be conducted based on demographics (eg, age, gender, or sex). We have already identified abstracts using the search strategy for all 4 of the included electronic databases. We recently updated the search and will begin abstract screening of the additional abstracts identified from the last search completed in January 2024. This systematic review is anticipated to be completed by fall 2024, and its findings will be disseminated to the scientific community, persons with TBI, caregivers, and the lay audience. This systematic review will advance our understanding regarding outcome disparities among minoritized individuals with TBI, examine progress over the past 15 years in minimizing barriers encountered by these racial and ethnic groups, and provide professionals with a roadmap illustrating existing gaps in rehabilitation care, making way for further development and implementation of evidence-based interventions to improve health equity in TBI outcomes. PROSPERO CRD42023394529; https://tinyurl.com/53mtcz9b. PRR1-10.2196/58763.

266 The Association of Early Brain-Based Biomarker Levels and Clinical Outcomes in Traumatic Brain Injury: A Secondary Analysis of the Prehospital TXA for TBI Trial

266 The Association of Early Brain-Based Biomarker Levels and Clinical Outcomes in Traumatic Brain Injury: A Secondary Analysis of the Prehospital TXA for TBI Trial

Could Hypertonic Saline Improve Clinical Outcomes in Traumatic Brain Injury? A Trial Sequential Analysis.

Could Hypertonic Saline Improve Clinical Outcomes in Traumatic Brain Injury? A Trial Sequential Analysis.

Computational modeling of predicting cerebrovascular injury in traumatic brain injury patients

Despite significant progress in understanding traumatic brain injury (TBI) and subsequent outcomes, predicting and preventing cerebrovascular injury (CVI) remains challenging. We introduces a novel computational modeling approach using advanced fluid-structure interaction (FSI) models, which incorporate high-resolution magnetic resonance imaging (MRI) data to analyze changes in intracranial pressure and blood flow in cerebral arteries post-TBI. We analyzed the mechanical fields between the PCOMA, ICA, PCA, and ACA areas by conducting a region of interest analysis in this research. The approach uniquely integrates detailed patient-specific brain vasculature geometries and dynamic boundary conditions to enhance predictive accuracy. The model indicates that peak pressure in the anterior cerebral artery (ACA) reaches 130 kPa within the first hour post-injury, with a 20% increase observed at 2 milliseconds. Wall shear stress (WSS) in the posterior communicating artery (PCOMA) reaches 140 kPa, which exceeds the typical physiological range of 10–20 kPa and may lead to endothelial damage. Regions such as the PCOMA and ACA are identified as particularly vulnerable to high mechanical stress and strain, which suggests the need for timely medical intervention to reduce the risk of CVI. Further validation with clinical data is required to improve the predictive accuracy of the model.

Traumatic brain injury outcomes at the “epicenter of the epicenter” of the united states COVID-19 pandemic amidst ongoing socio-demographic challenges

Abstract Introduction Traumatic brain injury (TBI) poses a significant public health challenge with profound impacts at individual, family, community, and societal levels. Early during the COVID-19 pandemic, the neighborhood of Elmhurst, Queens in New York City was a hotspot dubbed the “epicenter of the epicenter” of the crisis in the United States, requiring major changes in healthcare resource allocation. This study investigates how different phases of the COVID-19 pandemic affected the incidence, severity, and clinical outcomes of TBI in this geographical area. Methods TBI admissions to NYC Health + Hospitals/Elmhurst, a Level 1 Trauma Center, during the first six months of 2019, 2020, and 2021 were retrospectively analyzed. Data were grouped into three periods: pre-pandemic (1/1/19–6/30/19 and 1/1/20–2/29/20) [Group 1], first COVID-19 wave (3/1/20–6/30/20) [Group 2], and second COVID-19 wave (1/1/21–6/30/21) [Group 3]. Univariate analyses were conducted to explore factors potentially associated with TBI outcomes; variables that reached statistical significance (p &lt; 0.05) were included in a binary logistic regression analysis dichotomized into good outcome (discharge to home or acute rehabilitation disposition) and poor outcome (discharge to skilled nursing facility/subacute rehabilitation, hospice, or in-hospital mortality). Results Analysis of 443 TBI patients (median age 56 [range 38, 73]; mean admissions/week 5.6 ± 2.7) demonstrated no significant variance in age (H = 0.92; p = 0.63), sex (χ2 = 1.4, p = 0.51), or ethnicity (χ2 = 17.1; p = 0.07) across groups. Group 2 had significantly fewer weekly admissions (3.9 ± 2.6) compared to Groups 1 (5.9 ± 2.2; p = 0.02) and 3 (6.1 ± 2.9; p = 0.01). Over the course of the pandemic, the proportion of uninsured patients decreased from 15 to 4%, while Medicaid and Medicare coverage rates rose from 25 to 41% and 20% to 28%, respectively (p &lt; 0.001). A binary logistic regression model dichotomized by discharge outcome for all 443 TBI patients confirmed that increasing age (OR = 0.95; 95% CI 0.93–0.97; p &lt; 0.001) and Injury Severity Score (OR = 0.88; 95% CI 0.83–0.93; p &lt; 0.001) were inversely correlated with good outcome, while higher Glasgow Coma Scale (OR = 1.26; 95% CI 1.17–1.36; p &lt; 0.001) was positively correlated. Of particular interest, Black/Hispanic ethnicity (OR = 0.36; 95% CI 0.19–0.66; p = 0.002) and public health insurance (Medicaid/Medicare) coverage (OR = 0.83; 95% CI 0.68–1.00; p = 0.05) were both associated with less favorable outcomes. Neither group designation, patient sex, COVID-19 status, or need for neurosurgical intervention was correlated with outcome (p &gt; 0.05). Conclusion Despite the changes in TBI admission patterns throughout New York City during the COVID-19 pandemic, the quality of patient outcomes at our institution remained relatively consistent across the pandemic’s different phases, as assessed by discharge disposition. However, two important socioeconomic factors—ethnicity and health insurance status—were significantly associated with outcome, underscoring the need for systemic changes to address ongoing disparities in neurotrauma care.

An Analysis of Emergency Surgical Outcomes for Pediatric Traumatic Brain Injury: A Ten-Year Single-Institute Retrospective Study in Taiwan.

Background and Objectives: Pediatric traumatic brain injury (pTBI) remains a major pediatric public health problem, despite well-developed injury prevention programs. The purpose of this study is to analyze the emergency surgical outcomes of pTBI in a single institute ten-year retrospective study to offer a real-world clinical result. Materials and Methods: Our institute presented a clinical retrospective, single-institute research study of 150 pediatric TBI cases that were diagnosed and underwent emergency surgical treatment from 2010 to 2019. Results: The incidence of radiological findings is detailed as follows: brain edema (30%, 45/150), followed by acute subdural hematoma (27.3%, 41/150), epidural hematoma (21.3%, 32/150), chronic subdural hemorrhage (10%, 15/150), skull fracture (6.7%, 10/150), and traumatic subarachnoid hemorrhage (4.7%, 7/150). Surgical intervention data revealed that decompressive craniectomy was still the main effective surgical method. The results showed longer hospital stays and higher morbidity rates in the brain edema, acute subdural hematoma, and chronic subdural hemorrhage groups, which were viewed as poor surgical outcome groups. Epidural hematoma, skull fracture and traumatic subarachnoid hemorrhage were categorized into good surgical outcome groups. Notably, the data revealed gross improvement in Glasgow Coma Scale/Score (GCS) evolution after surgical interventions, and the time to cranioplasty was a significant factor in the development of post-traumatic hydrocephalus (PTH). Conclusions: Our study provided real-world data for the distribution of etiology in pTBI and also categorized it into six groups, indicating disease-orientated treatment. In addition, our data supported that decompressive craniectomy (DC) remains a mainstay surgical treatment in pTBI and early cranioplasty could decrease the incidence of PTH.

Traumatic Brain Injury and Risk of Incident Dementia: Forensic Applications of Current Research

Abstract Objective Traumatic Brain Injury (TBI) has been purported to increase risk for later developing neurodegenerative disorders (ND). Forensic neuropsychologists are frequently asked to opine on risk for ND after an alleged TBI. We provide an evidence-based foundation to aid forensic practice by summarizing the: role of the neuropsychologist in TBI-related litigation, complexities associated with identifying TBIs in forensic cases, science of TBI in relation to incident dementia, and current scientific evidence for chronic traumatic encephalopathy. Data Selection The most applicable studies to forensic settings are large prospective cohort and population-based cohort studies given their wider generalizability and long periods of follow-up/tracking for outcomes. Data Synthesis Developing ND after TBI is the exception rather than the rule. Only a small subset (&amp;lt; 5%) of individuals with moderate-to-severe TBI, and even fewer (&amp;lt; 1%) with mild TBI, appear to develop ND, and the characteristics that place some at risk remain unclear. Positive evidence for risk of ND after mild TBI is weak and mostly consists of observational studies characterized by methodological limitations. Conclusions Forensic methods used to establish the likely occurrence of TBI are typically more extensive than those used in clinical evaluations, while TBI definitions used in current research are even more rudimentary and inconsistent. Applying clinical research findings regarding TBI and dementia outcomes to forensic cases at an individual level carries significant limitations. Estimating the contribution of remote TBI/concussion in a causal manner to ND risk is a challenge forensic experts sometimes face, yet at present, the task is impossible beyond correlations and speculation.

The role of nutrition in mild traumatic brain injury rehabilitation for service members and veterans.

Veterans Affairs and the Department of Defense (DOD) acknowledge that nutrition may be a modifier of mild traumatic brain injury (TBI) sequelae. Military clinicians are considering nutritional supplements and dietary interventions when managing patients with mild TBI. Therefore, clinicians should be familiar with the current evidence for nutritional interventions in mild TBI and special considerations related to the military lifestyle. This narrative review aims to summarize the existing evidence surrounding the role of special diets and select nutrients in mild TBI outcomes, gut microbiota changes, and special considerations for Service members and Veterans recovering from mild TBI. We conducted a literature review in PubMed and Google Scholar limited to nutritional interventions and nine topics with primary focus on mild TBI, although we included some articles related to moderate-to-severe TBI where relevant: 1) ketogenic diet, 2) Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, 3) omega-3 fatty acids, 4) creatine, 5) vitamin D, 6) weight management, 7) gut microbiota, 8) caffeine, and 9) alcohol. We summarized key findings and safety factors where appropriate for each intervention. We also identified nutritional supplement safety and operational rations considerations and areas in need of further research. Preclinical studies and early human trials suggest that the specific nutrients and diets discussed in the current article may offer neuroprotection or benefit during mild TBI rehabilitation. Omega-3 fatty acids, creatine, and vitamin D are generally safe when taken within recommended guidelines. More evidence is needed to support nutritional recommendations for enhancing neuroprotection and mitigating mild TBI symptoms in humans. The DOD's Warfighter Nutrition Guide recommends a whole food diet rich in antioxidants, phytonutrients, omega-3 fatty acids, micronutrients, probiotics, and fiber to optimize long-term health and performance.

The bioenergetics of traumatic brain injury and its long-term impact for brain plasticity and function

Mitochondria provide the energy to keep cells alive and functioning and they have the capacity to influence highly complex molecular events. Mitochondria are essential to maintain cellular energy homeostasis that determines the course of neurological disorders, including traumatic brain injury (TBI). Various aspects of mitochondria metabolism such as autophagy can have long-term consequences for brain function and plasticity. In turn, mitochondria bioenergetics can impinge on molecular events associated with epigenetic modifications of DNA, which can extend cellular memory for a long time. Mitochondrial dysfunction leads to pathological manifestations such as oxidative stress, inflammation, and calcium imbalance that threaten brain plasticity and function. Hence, targeting mitochondrial function may have great potential to lessen the outcomes of TBI.

Clinical Significance of the Control CT Rotterdam Score Compared With the Admission CT Rotterdam Score in Patients With Isolated Severe Traumatic Brain Injury in the Intensive Care Unit.

The Rotterdam scale is one of the most commonly used radiological scales for evaluating and predicting outcomes in traumatic brain injury (TBI) cases. Given the evolving nature of TBI, our study is designed to compare the Rotterdam score of computed tomography (CT) findings upon admission (Rotterdam score I) with the score after 72 hours (Rotterdam score II) of treatment in the trauma intensive care unit (ICU). A retrospective observational study was conducted on 54 patients who received intensive care treatment for isolated severe TBI over five years. We included severe TBI patients with no age restrictions who required admission to the ICU within 12 hours of the onset of trauma. An initial Rotterdam CT score was obtained via a CT head scan within four hours of the trauma, followed by a control CT head scan 72 hours after ICU admission. It was essential to have documentation on the clinical and laboratory treatment course and access to radiological CT diagnostics. Receiver operating characteristic (ROC) curves were employed in this study to evaluate the accuracy of diagnostic tests, such as the Rotterdam score. The ROC curves provided a graphical representation of the tests' diagnostic performance, which helped assess their effectiveness. There was a significant difference (p < 0.001) in the diagnostic scores of CT scans upon admission (Rotterdam score I) and control CT scans after 72 hours (Rotterdam score II) in the total sample. The Rotterdam score I was notably higher, 3.6 (±0.8), in patients requiring neurosurgical intervention compared to those who did not, 2.8 (±0.9), with significance (p = 0.003). The Rotterdam score I demonstrated a substantial predictive value for unfavorable outcomes (p = 0.048), as did the Rotterdam score II after the 72-hour mark (p = 0.006). The control Rotterdam score 72 hours after admission predicts mortality in isolated TBI patients more significantly than the Rotterdam score determined at the patient's admission to the intensive care unit.

Tetramerization of PKM2 Alleviates Traumatic Brain Injury by Ameliorating Mitochondrial Damage in Microglia.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial activation and neuroinflammation are key cellular events that determine the outcome of TBI, especially neuronal and cognitive function. Studies have suggested that the metabolic characteristics of microglia dictate their inflammatory response. The pyruvate kinase isoform M2 (PKM2), a key glycolytic enzyme, is involved in the regulation of various cellular metabolic processes, including mitochondrial metabolism. This suggests that PKM2 may also participate in the regulation of microglial activation during TBI. Therefore, the present study aimed to evaluate the role of PKM2 in regulating microglial activation and neuroinflammation and its effects on cognitive function following TBI. A controlled cortical impact (CCI) mouse model and inflammation-induced primary mouse microglial cells in vitro were used to investigate the potential effects of PKM2 inhibition and regulation. PKM2 was significantly increased during the acute and subacute phases of TBI and was predominantly detected in microglia rather than in neurons. Our results demonstrate that shikonin and TEPP-46 can inhibit microglial inflammation, improving mitochondria, improving mouse behavior, reducing brain defect volume, and alleviating pathological changes after TBI. There is a difference in the intervention of shikonin and TEPP-46 on PKM2. Shikonin directly inhibits General PKM2; TEPP-46 can promote the expression of PKM2 tetramer. In vitro experiments, TEPP-46 can promote the expression of PKM2 tetramer, enhance the interaction between PKM2 and MFN2, improve mitochondria, alleviate neuroinflammation. General inhibition and tetramerization activation of PKM2 attenuated cognitive function caused by TBI, whereas PKM2 tetramerization exhibited a better treatment effect. Our experiments demonstrated the non-metabolic role of PKM2 in the regulation of microglial activation following TBI. Both shikonin and TEPP-46 can inhibit pro-inflammatory factors, but only TEPP-46 can promote PKM2 tetramerization and upregulate the release of anti-inflammatory factors from microglia.

A Pilot Study of Saliva MicroRNA Signatures in Children with Moderate-to-Severe Traumatic Brain Injury.

Background/Objectives: Traumatic brain injury (TBI) is a leading cause of death and disability in children. Currently, no biological test can predict outcomes in pediatric TBI, complicating medical management. This study sought to identify brain-related micro-ribosomal nucleic acids (miRNAs) in saliva associated with moderate-to-severe TBI in children, offering a potential non-invasive, prognostic tool. Methods: A case-control design was used, enrolling participants ≤ 18 years old from three pediatric trauma centers. Participants were divided into moderate-to-severe TBI and non-TBI trauma control groups. Saliva samples were collected within 24 h of injury, with additional samples at 24-48 h and >48 h post-injury from the TBI group. miRNA profiles were visualized with partial least squares discriminant analysis (PLSDA) and hierarchical clustering. Mann-Whitney testing was used to compare miRNAs between groups, and mixed models were used to assess longitudinal expression patterns. DIANA miRPath v3.0 was used to interrogate the physiological functions of miRNAs. Results: Twenty-three participants were enrolled (14 TBI, nine controls). TBI and control groups displayed complete separation of miRNA profiles on PLSDA. Three miRNAs were elevated (adj. p < 0.05) in TBI (miR-1255b-5p, miR-3142, and miR-4320), and two were lower (miR-326 and miR-4646-5p). Three miRNAs (miR-3907, miR-4254, and miR-1273g-5p) showed temporal changes post-injury. Brain-related targets of these miRNAs included the glutamatergic synapse and GRIN2B. Conclusions: This study shows that saliva miRNA profiles in children with moderate-to-severe TBI may differ from those with non-TBI trauma and exhibit temporal changes post-injury. These miRNAs could serve as non-invasive biomarkers for prognosticating pediatric TBI outcomes. Further studies are needed to confirm these findings.

Mild Traumatic Brain Injury in U.S. Military Veterans: Results from the National Health and Resilience in Veterans Study

Objective This study provides nationally representative data on the prevalence, risk factors, and associated mental health and functional outcomes of mild traumatic brain injury (mTBI) in U.S. military veterans. Methods Data (N = 4,069) were analyzed from the National Health and Resilience in Veterans Study (NHRVS). Analyses estimated mTBI prevalence, exposure to different mTBI injuries, and past-week mTBI symptoms (i.e. persistent post-concussive symptoms [PCS]). Comparisons were made between veterans with and without mTBI+PCS on sociodemographic, military, trauma, and psychiatric characteristics. Associations between mTBI+PCS and measures of cognitive, mental, and psychosocial functioning were examined. Results Overall, 43.7% endorsed a possible mTBI event on the Veterans Affairs’ Mild TBI Injury Screening and Evaluation tool, and 10.0% screened positive for mTBI. After combining a self-reported healthcare professional diagnosis of concussion/mTBI/TBI (5.8%) with a positive mTBI screen, the prevalence of mTBI+PCS was 3.0%. Veterans with specific trauma characteristics (e.g. adverse childhood events), military service (e.g. combat), and lifetime psychiatric conditions were more likely to have mTBI+PCS. mTBI+PCS was associated with increased odds of current posttraumatic stress disorder, major depressive disorder, generalized anxiety disorder, and drug use disorder. These veterans also scored significantly lower on cognitive, mental, and psychosocial functioning. Conclusions Overall, 3.0% of veterans had mTBI+PCS, suggesting that while mTBI may be prevalent in this population, the majority will likely recover without developing chronic symptoms. Those with mTBI+PCS are at significant risk for comorbid psychiatric diagnoses and poorer psychosocial functioning relative to those without mTBI+PCS, and early targeted identification may assist in prevention of disability and recovery.