Effects Of Traumatic Brain Injury Research Articles

Endothelial deletion of EPH receptor A4 alters single-cell profile and Tie2/Akap12 signaling to preserve blood–brain barrier integrity

Neurobiological consequences of traumatic brain injury (TBI) result from a complex interplay of secondary injury responses and sequela that mediates chronic disability. Endothelial cells are important regulators of the cerebrovascular response to TBI. Our work demonstrates that genetic deletion of endothelial cell (EC)-specific EPH receptor A4 (EphA4) using conditional EphA4f/f/Tie2-Cre and EphA4f/f/VE-Cadherin-CreERT2 knockout (KO) mice promotes blood-brain barrier (BBB) integrity and tissue protection, which correlates with improved motor function and cerebral blood flow recovery following controlled cortical impact (CCI) injury. scRNAseq of capillary-derived KO ECs showed increased differential gene expression of BBB-related junctional and actin cytoskeletal regulators, namely, A-kinase anchor protein 12, Akap12, whose presence at Tie2 clustering domains is enhanced in KO microvessels. Transcript and protein analysis of CCI-injured whole cortical tissue or cortical-derived ECs suggests that EphA4 limits the expression of Cldn5, Akt, and Akap12 and promotes Ang2. Blocking Tie2 using sTie2-Fc attenuated protection and reversed Akap12 mRNA and protein levels cortical-derived ECs. Direct stimulation of Tie2 using Vasculotide, angiopoietin-1 memetic peptide, phenocopied the neuroprotection. Finally, we report a noteworthy rise in soluble Ang2 in the sera of individuals with acute TBI, highlighting its promising role as a vascular biomarker for early detection of BBB disruption. These findings describe a contribution of the axon guidance molecule, EphA4, in mediating TBI microvascular dysfunction through negative regulation of Tie2/Akap12 signaling.

SAT270 Parity Increases Corticosterone Response To Restraint-induced Stress After Mild Blast Traumatic Brain Injury In Mice

Abstract Disclosure: S. Anisowicz: None. M. Bodemeier Loayza Careaga: None. T. Wu: None. Background: Traumatic brain injury (TBI) is a common problem worldwide, with an estimated incidence of 69 million injuries per year. In the US military, one of the most common forms of TBI during operational deployments after Sep 11, 2001 was the blast TBI, thought to be responsible for over 80% of TBI sustained in theater. One consequence of TBI is dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis. HPA axis dysregulation is linked to increased risk for psychiatric disorders. Furthermore, prior research has shown that TBI may dysregulate the HPA axis in a sex-dependent manner. Throughout a female’s life span, there are several sentinel events of hormonal consequence, including pubarche, menopause, and parity, which are known to be times of changes in risks for psychiatric disorders. Objectives: The role of parity on TBI response has not yet been studied, though parity has been shown to decrease fear-related behaviors and decreased corticosterone load in multiparous mice when compared to nulliparous (NP) controls. Our objective is to determine if parity alters corticosterone (CORT) response to restraint, a mild psychological stressor, in mice exposed to mild blast TBI (mbTBI). Methods: One hundred thirteen NP or primiparous (PP) C57Bl6/J mice were randomly assigned to receive sham or mbTBI. Among those that received mbTBI (19.2 ± 0.12 psi), 32 were NP and 24 were PP. Among sham mice, 32 were NP and 26 were PP. All mice received isoflurane anesthesia prior to sham or mbTBI treatment. At 7-8 days after mbTBI, half the mice within each treatment group were subjected to a mild 20-min restraint before being anesthetized by CO2 followed by collection of trunk blood. Serum was harvested and analyzed for CORT concentrations by ELISA (Enzo Life Sciences). Results: All mice that received mbTBI had a longer (p<0.05) righting time compared to those that did not. There was no main effect of parity in the righting time (p>0.1). PP mice who experienced mbTBI demonstrated a greater (p<0.05) CORT response to restraint (157.3 ± 21 pg/mL) when compared to NP mice (95.9 ± 7.2 pg/mL). CORT response to restraint did not differ (p>0.1) between NP and PP mice who did not experience mbTBI (96.1 ± 7.6 vs 109.2 ± 16 pg/mL). Conclusions: Our data indicates that mbTBI alters HPA axis reactivity in PP mice compared to NP mice, increasing the CORT response to restraint induced stress. Parity alone did not alter CORT response to restraint stress or baseline CORT levels. The results of our finding highlight the importance of parity as a factor in an individual’s lifespan. Presentation: Saturday, June 17, 2023

Modern content for personalized rehabilitation of patients with a consequences of traumatic brain injury

Objective: to substantiate the significance of quality of life indicators in the formation of modern content of personalized rehabilitation of patients with a consequences of traumatic brain injury. Material and methods. The study included 414 respondents of working age (93.6% men). 54% of the respondents had a traumatic brain injury within 1 to 5 years, in 62,0%, cases the traumatic brain injury was of severe degree. Longitudinal sociological study of the quality of life using the WHOQOL-100 questionnaire was carried out. The Dembo-Rubinstein test was used to diagnose the adequacy of self-assessment of the respondents with TBI. The dynamics of the respondents' neurological status and quality of life were assessed annually during 2020-2022. Results. In the annual study, 64.7% of respondents showed clinical deterioration in 96% of cases, which was manifested by increased severity of general cerebral symptoms, cognitive impairment, and asthenic syndrome. In 4.0% of cases new symptoms manifested (posttraumatic epilepsy). In the dynamic of respondents' quality of life, clinical deterioration in parameters "Physical sphere", "Psychological sphere", "Environment" and "General quality of life and health status" was revealed. Conclusion. In the absence of specific laboratory markers in clinical practice and not always sufficient informativeness of neuroimaging methods for the verification of the consequences of traumatic brain injury, the quality of life can be considered as an important criterion of prognosis, which determines the content of personalised rehabilitation of patients with the consequences of traumatic brain injury.

Age and anatomical-functional nuances of traumatic brain injury in children

The purpose. Traumatic brain injury in children is a serious medical problem that requires special attention and research. As the child's body develops and grows, the anatomical and functional characteristics of children can affect the pathological consequences of traumatic brain injury. Given the growing number of children who are injured in sports events, accidents and other factors, understanding the characteristics of this category of injury can play an important role in improving their treatment and rehabilitation. Children respond to injury differently than adults and may exhibit different symptoms and require specialized medical care and approaches to treatment and rehabilitation. Understanding these age and anatomical and functional differences can help improve the diagnosis and treatment of brain injury in children and increase their chances of full recovery and normal development. Materials and methods. 154 charts of inpatients aged from 1 month to 17 years who were receiving inpatient treatment at the regional children's hospital during 2022 were analyzed. The basic methods of examination were radiographs, MRI of the brain.Research results. The most craniocerebral traumas were observed in children aged 7-17 years, which constituted 47.4%. Children aged 3-6 were often injured, accounting for almost 20%, older children (15-17 years old) were injured less often, accounting for 15%. Babies under one year old (9.7%) and children under 2 years old (8.4%) suffered the least amount of damage. The largest number of injured children (60.4%) was observed in the warm season when they are active outside without proper parental supervision.Conclusions. The largest number of brain injuries is characteristic of adolescence, against the background of changes in all body systems, the formation of new behavioral reactions for them, which were not characteristic of them before, and contribute to the increase in traumatism. Babies suffered the least damage, which is due to the anatomical features of the structure of the child's head.

Automated intracranial hemorrhage detection in traumatic brain injury using 3D CNN.

Intracranial hemorrhage (ICH) is a prevalent and potentially fatal consequence of traumatic brain injury (TBI). Timely identification of ICH is crucial to ensure timely intervention and to optimize better patient outcomes. However, the current methods for diagnosing ICH from head computed tomography (CT) scans require skilled personnel (Radiologists and/or Neurosurgeons) who may be unavailable in all centers, especially in rural areas. The aim of this study is to develop a neurotrauma screening tool for identifying ICH from head CT scans of TBI patients. We prospectively collected head CT scans from the Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi. Approximately 738 consecutive head CT scans from patients enrolled in the department were collected for this study spanning a duration of 9 months, that is, January 2020 to September 2020. The metadata collected along with the head CT scans consisted of demographic and clinical details and the radiologist's report which was used as the gold standard. A deep learning-based 3D convolutional neural network (CNN) model was trained on the dataset. The pre-processing, hyperparameters, and augmentation were common for training the 3D CNN model whereas the training modules were set differently. The model was trained along with the save best model option and was monitored by validation metrics. The Institute Ethics Committee permission was taken before starting the study. We developed a 3D CNN model for automatically detecting the ICH from head CT scans. The screening tool was tested in 20 cases and trained on 200 head CT scans, with 99 normal head CT and 101 CT scans with some type of ICH. The final model performed with 90% sensitivity, 70% specificity, and 80% accuracy. Our study reveals that the automated screening tool exhibits a commendable level of accuracy and sensitivity in detecting ICH from the head CT scans. The results indicate that the 3D CNN approach has a potential for further exploring the TBI-related pathologies.

Massive Solubility Changes in Neuronal Proteins upon Simulated Traumatic Brain Injury Reveal the Role of Shockwaves in Irreversible Damage.

We investigated the immediate molecular consequences of traumatic brain injuries (TBIs) using a novel proteomics approach. We simulated TBIs using an innovative laboratory apparatus that employed a 5.1 kg dummy head that held neuronal cells and generated a ≤4000 g-force acceleration upon impact. A Proteome Integral Solubility Alteration (PISA) assay was then employed to monitor protein solubility changes in a system-wide manner. Dynamic impacts led to both a reduction in neuron viability and massive solubility changes in the proteome. The affected proteins mapped not only to the expected pathways, such as those of cell adhesion, collagen, and laminin structures, as well as the response to stress, but also to other dense protein networks, such as immune response, complement, and coagulation cascades. The cellular effects were found to be mainly due to the shockwave rather than the g-force acceleration. Soft materials could reduce the impact's severity only until they were fully compressed. This study shows a way of developing a proteome-based meter for measuring irreversible shockwave-induced cell damage and provides a resource for identifying protein biomarkers of TBIs and potential drug targets for the development of products aimed at primary prevention and intervention.

Outcomes and associated factors of traumatic brain injury among adult patients treated in Amhara regional state comprehensive specialized hospitals

BackgroundGlobally, traumatic brain injury is the leading cause of death and disability which affects more than 69 million individuals a year.ObjectiveThis study aimed to assess the outcome and associated factors of traumatic brain injury among adult patients treated in Amhara regional state comprehensive specialized hospitals.MethodInstitutional-based cross-sectional study design was conducted from January 1, 2018, to December 30, 2020. A simple random sampling technique was used and a checklist was used to extract data between March 15 and April 15, 2021. The data were entered into Epi-data version 4.2 and exported to SPSS version 25 for analysis after being checked for consistency. Associated variables with outcomes of traumatic brain injury were determined by a binary logistic regression model. The degree of association was interpreted by using AOR and a 95% confidence interval with a p-value less than or equal to 0.05 at 95% CI was considered statistically significant.ResultIn this study road traffic injury was the most frequent cause of traumatic brain injuries among adult patients, accounting for 181 (37.5%), followed by assault, accounting for 117 (24.2%) which affects adult age groups. One-third of the participant had a moderate Glasgow coma scale of 174(36%). Only 128(26.8%) patients arrived within one hour. One hundred sixty, 160 (33.1%) of patients had a mild traumatic brain injury, whereas, 149(36%) of patients had a severe traumatic brain injury. Regarding computerized tomography scans findings, the hematoma was the most common (n = 163, 33.7%). Ninety-one, 91(18.8%) of participants had cerebrospinal fluid otorrhea, and, 92(19%) were diagnosed with a positive battle sign. The overall prevalence of unfavorable outcomes after traumatic brain injury was found to be 35.2% (95%CI (30.8–39.1). Having additional Injury, hypoxia, time to hospital presentation after 24 h, severe Glasgow Coma Scale, moderate Glasgow Coma Scale, tachypnea, bradypnea, and cerebrospinal fluid Othorrhea, were factors associated with unfavorable outcomes.Conclusion and recommendationIn this study, the overall unfavorable outcome was experienced by about four out of every 10 victims of traumatic brain injury. Time of arrival > 24 h, low Glasgow coma scale, additional injury, Cerebrospinal fluid otorrhea, abnormal respiration, and hypoxia were significant predictors of unfavorable outcomes. To reduce the adverse effects of traumatic brain injury in adults, it is therefore desirable to guarantee safe road traffic flow and improve health care services.

Research Letter: TBI Severity Moderates the Association Between Subjective and Objective Attention in Older Veterans.

This study examined the moderating effect of traumatic brain injury (TBI) history on subjective and objective cognition across multiple cognitive domains. Participants included 242 Vietnam-era veterans with a history of no TBI (n = 86), mild TBI (n = 74), or moderate-to-severe TBI (n = 82) from the observational Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DoD-ADNI) study. Objective cognition was the outcome and was measured using neuropsychological measures in the domains of memory, attention/executive functioning, and language. Subjective cognition was measured using the memory, divided attention, and language subscales from the Everyday Cognition (ECog) measure. TBI severity status was the moderating variable. Veterans with a history of moderate-to-severe TBI had a stronger negative association between subjective and objective attention relative to participants without a TBI ( P = .002). Although this association did not differ between mild TBI and no TBI history groups ( P = .100), the association between subjective and objective attention for the mild TBI group was intermediate to the no TBI and moderate-to-severe TBI history groups. TBI status did not moderate associations between subjective and objective memory or language. Results highlight the importance of assessing subjective and objective cognition in older veterans and the relevance of attention in the context of TBI history. More work is needed to better understand the intersection of TBI and aging and how these factors may be used to guide individualized assessment and treatment approaches for older veterans.

Use of Bridge with Path Drawings with Military Service Members Experiencing Traumatic Brain Injury and Post-Traumatic Stress Disorder

This article introduces the use of an art therapy assessment, the Bridge with Path Drawing, for service members experiencing effects of Traumatic Brain Injury (TBI) and/or Post-Traumatic Stress Disorder (PTSD) during treatment at an outpatient clinic. Brief clinical vignettes describe the processes and outcomes of Bridge with Path Drawing Assessment for two service members. Bridge to Path Drawing aided service members with TBI/PTSD in discovering and disclosing thoughts and feelings through symbolic and metaphorical associations to their drawings. Service members shared meanings related to their senses of identity, their futures, the transitions to civilian lives, strategies to overcome obstacles, and purposes and meanings in their lives. Providers working with service members experiencing effects of TBI/PTSD and military-to-civilian transition found an art therapy assessment, the Bridge with Path Drawing, useful to explore patients’ meaning in life at an outpatient medical clinic on a military base.

Levels of Arachidonic Acid-Derived Oxylipins and Anandamide Are Elevated Among Military APOE ɛ4 Carriers With a History of Mild Traumatic Brain Injury and Post-Traumatic Stress Disorder Symptoms.

Currently approved blood biomarkers detect intracranial lesions in adult patients with mild to moderate traumatic brain injury (TBI) acutely post-injury. However, blood biomarkers are still needed to help with a differential diagnosis of mild TBI (mTBI) and post-traumatic stress disorder (PTSD) at chronic post-injury time points. Owing to the association between phospholipid (PL) dysfunction and chronic consequences of TBI, we hypothesized that examining bioactive PL metabolites (oxylipins and ethanolamides) would help identify long-term lipid changes associated with mTBI and PTSD. Lipid extracts of plasma from active-duty soldiers deployed to the Iraq/Afghanistan wars (control = 52, mTBI = 21, PTSD = 34, and TBI + PTSD = 13) were subjected to liquid chromatography/mass spectrometry analysis to examine oxylipins and ethanolamides. Linear regression analyses followed by post hoc comparisons were performed to assess the association of these lipids with diagnostic classifications. Significant differences were found in oxylipins derived from arachidonic acid (AA) between controls and mTBI, PTSD, and mTBI + PTSD groups. Levels of AA-derived oxylipins through the cytochrome P450 pathways and anandamide were significantly elevated among mTBI + PTSD patients who were carriers of the apolipoprotein E E4 allele. These studies demonstrate that AA-derived oxylipins and anandamide may be unique blood biomarkers of PTSD and mTBI + PTSD. Further, these AA metabolites may be indicative of an underlying inflammatory process that warrants further investigation. Future validation studies in larger cohorts are required to determine a potential application of this approach in providing a differential diagnosis of mTBI and PTSD in a clinical setting.

Management of Traumatic Brain Injury in Older Adults: What You Need to Know.

Older adults represent the fastest growing population in the United States (US) and this portion of the population is expected to double to more than 80 million by 2050.1 Currently, older adults have more active lifestyles, therefore are at an increased risk of injury.2 Older adults currently represent 23% of trauma admissions.3 This number is projected to increase to 39% by 2050.3 In fact, over the last decade, unintentional injuries have climbed from the 9th to the 7th leading cause of death among older adults. Traumatic brain injury (TBI) accounts for over 200,000 cases annually.4 The consequences of TBI in older adults are severe with high mortality rates5 and significant cognitive and functional impairment for survivors.6-8 Many who were previously independent in their daily activities become dependent on assistance after sustaining a TBI.2 Moreover, older adults experience accelerated cognitive decline, sleep disturbances, and depression following a TBI, which can further hinder their recovery.9 The financial impact of TBI on patients, caregivers, and the health care system is substantial, with annual hospital charges exceeding 8.2 billion for the treatment of TBI in older adults.10 This review aims to highlight the specific considerations and challenges faced by older adults with TBI.

Psychiatric sequelae of traumatic brain injury - future directions in research.

Despite growing appreciation that traumatic brain injury (TBI) is an important public health burden, our understanding of the psychiatric and behavioural consequences of TBI remains limited. These changes are particularly detrimental to a person's sense of self, their relationships and theirparticipation in the wider community, and they continue to have devastating individual and cumulative effects long after TBI. This Review relates specifically to TBIs that confer objective clinical or biomarker evidence of structural brain injury; symptomatic head injuries without such evidence are outside the scope of this article. Common psychiatric, affective and behavioural sequelae of TBI and their proposed underlying mechanisms are outlined, along with a brief overview of current treatments. Suggestions for how scientists and clinicians can work together in the future to address the chasms in clinical care and knowledge are discussed in depth.

FETAL AND NEONATAL STATUS IN WOMEN WITH CEREBRO-VASCULAR DISORDERS AND RISK FACTORS FOR THEIR DEVELOPMENT

Introduction. Cerebrovascular diseases in pregnant women are one of the most important problems of modern obstetrics and perinatology due to the steady increase in maternal and neonatal morbidity. Diabetes mellitus and hypertensive disorders are two of the most common complications of pregnancy, which negatively affect both short-term and long-term outcomes for the mother, fetus and newborn.The aim of the study was to determine the state of the fetus and the newborn in pregnant women with cerebral disorders, taking into account risk factors (hypertension, diabetes mellitus).Material and methods. 92 pregnant women were examined, of which the main group (77 pregnant women) consisted of women with extragenital pathology, in particular, cerebrovascular disease - 20 (21.7%), hypertension - 23 (29.8%), diabetes mellitus - 34 (44.1%), the control group consisted of 15 pregnant women (16.3%) with physiological pregnancy and their newborns.Scientific research passed the bioethics commission, no violations were found (Protocol No. 7 of 05.04.2023).Statistical processing of the data obtained during the study was carried out using Microsoft Office Excel 2016 (Microsoft, USA) and Statistica 10.0 (StatSoft, USA). The significance of differences in the characteristics of dependent groups with signs of normal distribution was assessed by the paired Student's t-test (t-test of dependent samples).This work is a fragment of the complex research work of the Department of Obstetrics and Gynaecology №2 of Kharkiv National Medical University "Optimisation of diagnostics, treatment of diseases of the reproductive system and pregnancy complications in women with extragenital pathology", state registration number 0121U11923).Results. Cerebrovascular disease was represented by the consequences of traumatic brain injury in 8 (40%) cases, acute cerebrovascular accident (ischaemic, haemorrhagic) - in 5 (25%), epilepsy - in 5 (25%), encephalopathy in cerebral palsy - in 3 (15%), arteriovenous transformation, angiomatous cavity - in 2 (10%) cases. Among women of the hypertension group, pre-eclampsia was found in 11 (47.8%), gestational hypertension - in 8 (34.7%), and chronic hypertension - in 4 (17.4%) cases. Pre-gestational diabetes was detected in 8 (23.5%) pregnant women in the diabetic group, and gestational diabetes in 26 (76.5%).Doppler flowmetry examination of blood flow in the middle cerebral artery (MCA) revealed a significant decrease (p<0.05) in the pulsatile index in pregnant patients of the main group (1.24±0.09) compared with women with a physiological course of the gestational process (1.82±0.11). There was a difference in the systolic-diastolic ratio in the SMA between women of the main and control groups (2.4±0.2 and 3.5±0.3, respectively) (p<0.05).When analysing the acid-base status of newborns, it was noted that the pH values in the groups with extragenital pathology had a shift to the acidic side. These shifts were most pronounced in the group with placental dysfunction due to diabetes mellitus, where the pH averaged 7.18±0.05, against the background of increased PCO2 to 56.3±3.4 mm Hg (p<0.05), indicating the presence of respiratory acidosis in fetuses. A decrease in the deficit of alkaline bases in the fruits of this group to an average of -7.1±0.69 mmol/l (p<0.05) indicated the occurrence of manifestations of metabolic acidosis in them.Conclusions. Cerebrovascular disease was more common in pregnant women over 30 years of age, mostly residents of the region (80%), which may be due to high trauma, insufficient examination and treatment, housewives, due to the underlying disease, as well as with Rh-negative blood type (35%), hypertensive disorders, diabetes mellitus, placental dysfunction, and early delivery, which increases the risk of neonatal complications and perinatal morbidity. Hypertensive disorders and diabetes mellitus can be considered risk factors for the development of cerebrovascular disorders in pregnant women and perinatal complications.

Using home monitoring technology to study the effects of traumatic brain injury in older multimorbid adults.

Internet of things (IOT) based in-home monitoring systems can passively collect high temporal resolution data in the community, offering valuable insight into the impact of health conditions on patients' day-to-day lives. We used this technology to monitor activity and sleep patterns in older adults recently discharged after traumatic brain injury (TBI). The demographics of TBI are changing, and it is now a leading cause of hospitalisation in older adults. However, research in this population is minimal. We present three cases, showcasing the potential of in-home monitoring systems in understanding and managing early recovery in older adults following TBI.

Prognosis at Your Fingertips: A Machine Learning-Based Web Application for Outcome Prediction in Acute Traumatic Epidural Hematoma.

Traumatic brain injury (TBI) affects 69 million people worldwide each year, and acute traumatic epidural hematoma (atEDH) is a frequent and severe consequence of TBI. The aim of the study is to use machine learning (ML) algorithms to predict in-hospital death, non-home discharges, prolonged length of stay (LOS), prolonged length of intensive care unit stay (ICU-LOS), and major complications in patients with atEDH and incorporate the resulting ML models into a user-friendly web application for use in the clinical settings. The American College of Surgeons (ACS) Trauma Quality Program (TQP) database was used to identify patients with atEDH. Four ML algorithms (XGBoost, LightGBM, CatBoost, and Random Forest) were utilized, and the best performing models were incorporated into an open-access web application to predict the outcomes of interest. The study found that the ML algorithms had high area under the receiver operating characteristic curve (AUROC) values in predicting outcomes for patients with atEDH. In particular, the algorithms had an AUROC value range of between 0.874 to 0.956 for in-hospital mortality, 0.776 to 0.798 for non-home discharges, 0.737 to 0.758 for prolonged LOS, 0.712 to 0.774 for prolonged ICU-LOS, and 0.674 to 0.733 for major complications. The following link will take users to the open-access web application designed to generate predictions for individual patients based on their characteristics: huggingface.co/spaces/MSHS-Neurosurgery-Research/TQP-atEDH. This study aimed to improve the prognostication of patients with atEDH using ML algorithms and developed a web application for easy integration in clinical practice. It found that ML algorithms can aid in risk stratification and have significant potential for predicting in-hospital outcomes. Results demonstrated excellent performance for predicting in-hospital death and fair performance for non-home discharges, prolonged LOS and ICU-LOS, and poor performance for major complications.

An exhaustive analysis of post-traumatic brain injury dementia using bibliometric methodologies.

It is widely accepted that traumatic brain injury (TBI) increases the risk of developing long-term dementia, although some controversies surrounding this topic exist. Annually, approximately 69 million individuals suffer from TBI all around the world. Such a large population of TBI patients could lead to a future surge in the number of dementia patients. Due to the potentially severe consequences of TBI, various research projects on post-TBI dementia have emerged worldwide. Therefore, it is essential to comprehend the current status and development of post-TBI dementia for future research. The purpose of the study was to provide an overview of the field and identify hotspots, research frontiers, and future research trends for post-TBI dementia. Articles related to post-TBI dementia were retrieved from the Web of Science Core Collection for the period between 2007 and 2022, and analyzing them based on factors such as citations, authors, institutions, countries, journals, keywords, and references. Data analysis and visualization were conducted using VOSviewer, CiteSpace, and an online bibliometric platform (https://bibliometric.com). From 2007 to 2022, we obtained a total of 727 articles from 3,780 authors and 1,126 institutions across 52 countries, published in 262 journals. These articles received a total of 29,353 citations, citing 25,713 references from 3,921 journals. Over the last 15 years, there has been a significant upward trend in both publications and citations. The most productive country was the United States, the most productive institution was Boston University, and the most productive author was McKee AC. Journal of Neurotrauma has been identified as the periodical with the greatest number of publications. Three clusters were identified through cluster analysis of keywords. A burst in the use of the term "outcome" in 2019 is indicative of a future research hotspot. The timeline view of references showed 14 clusters, of which the first 4 clusters collected the majority of papers. The first 4 clusters were "chronic traumatic encephalopathy," "age of onset," "tauopathy," and "cognitive decline," respectively, suggesting some areas of interest in the field. The subject of post-TBI dementia has raised much interest from scientists. Notably, America is at the forefront of research in this area. Further collaborative research between different countries is imperative. Two topical issues in this field are "The association between TBI and dementia-related alterations" and "chronic traumatic encephalopathy (CTE)." Studies on clinical manifestation, therapy, pathology, and pathogenic mechanisms are also popular in the field.

Exploring the Therapeutic Potential of Phosphorylated Cis-Tau Antibody in a Pig Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) results in the generation of tau. As hyperphosphorylated tau (p-tau) is one of the major consequences of TBI, targeting p-tau in TBI may lead to the development of new therapy. Twenty-five pigs underwent a controlled cortical impact. One hour after TBI, pigs were administered either vehicle (n = 13) or PNT001 (n = 12), a monoclonal antibody for the cis conformer of tau phosphorylated at threonine 231. Plasma biomarkers of neural injury were assessed for 14 days. Diffusion tensor imaging was performed at day 1 and 14 after injury, and these were compared to historical control animals (n = 4). The fractional anisotropy data showed significant white matter injury for groups at 1 day after injury in the corona radiata. At 14 days, the vehicle-treated pigs, but not the PNT001-treated animals, exhibited significant white matter injury compared to sham pigs in the ipsilateral corona radiata. The PNT001-treated pigs had significantly lower levels of plasma glial fibrillary acidic protein (GFAP) at day 2 and day 4. These findings demonstrate a subtle reduction in the areas of white matter injury and biomarkers of neurological injury after treatment with PNT001 following TBI. These findings support additional studies for PNT001 as well as the potential use of this agent in clinical trials in the near future.

Deletion of glutamate carboxypeptidase II (GCPII), but not GCPIII, provided long-term benefits in mice with traumatic brain injury.

N-acetylaspartylglutamate (NAAG) has neuroprotective effects in traumatic brain injury (TBI) by activating metabotropic glutamate receptor 3 (mGluR3) and reducing glutamate release. Glutamate carboxypeptidase II (GCPII) is the primary enzyme responsible for the hydrolysis of NAAG. It remains unclear whether glutamate carboxypeptidase III (GCPIII), a homolog of GCPII, can partially compensate for GCPII's function. GCPII-/- , GCPIII-/- , and GCPII/III-/- mice were generated using CRISPR/Cas9 technology. Mice brain injury model was established through moderate controlled cortical impact (CCI). The relationship between GCPII and GCPIII was explored by analyzing injury response signals in the hippocampus and cortex of mice with different genotypes at the acute (1 day) and subacute (7 day) phase after TBI. In this study, we found that deletion of GCPII reduced glutamate production, excitotoxicity, and neuronal damage and improved cognitive function, but GCPIII deletion had no significant neuroprotective effect. Additionally, there was no significant difference in the neuroprotective effect between the combination of GCPII and GCPIII deletion and GCPII deletion alone. These results suggest that GCPII inhibition may be a therapeutic option for TBI, and that GCPIII may not act as a complementary enzyme to GCPII in this context.

Examining the long-term effects of traumatic brain injury on fear extinction in male rats.

There is a strong association between traumatic brain injuries (TBIs) and the development of psychiatric disorders, including post-traumatic stress disorder (PTSD). Exposure-based therapy is a first-line intervention for individuals who suffer from PTSD and other anxiety-related disorders; however, up to 50% of individuals with PTSD do not respond well to this approach. Fear extinction, a core mechanism underlying exposure-based therapy, is a procedure in which a repeated presentation of a conditioned stimulus in the absence of an unconditioned stimulus leads to a decrease in fear expression, and is a useful tool to better understand exposure-based therapy. Identifying predictors of extinction would be useful in developing alternative treatments for the non-responders. We recently found that CO2 reactivity predicts extinction phenotypes in rats, likely through the activation of orexin receptors in the lateral hypothalamus. While studies have reported mixed results in extinction of fear after TBI, none have examined the long-term durability of this phenotype in the more chronically injured brain. Here we tested the hypothesis that TBI results in a long-term deficit in fear extinction, and that CO2 reactivity would be predictive of this extinction phenotype. Isoflurane-anesthetized adult male rats received TBI (n = 59) (produced by a controlled cortical impactor) or sham surgery (n = 29). One month post-injury or sham surgery, rats underwent a CO2 or air challenge, followed by fear conditioning, extinction, and fear expression testing. TBI rats exposed to CO2 (TBI-CO2) showed no difference during extinction or fear expression relative to shams exposed to CO2 (sham-CO2). However, TBI-CO2 rats, showed significantly better fear expression than TBI rats exposed to air (TBI-air). In contrast to previous findings, we observed no relationship between CO2 reactivity and post-extinction fear expression in either the sham or TBI rats. However, compared to the previously observed naïve sample, we observed more variability in post-extinction fear expression but a very similar distribution of CO2 reactivity in the current sample. Isoflurane anesthesia may lead to interoceptive threat habituation, possibly via action on orexin receptors in the lateral hypothalamus, and may interact with CO2 exposure, resulting in enhanced extinction. Future work will directly test this possibility.

Synaptamide Ameliorates Hippocampal Neurodegeneration and Glial Activation in Mice with Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major concern for public health worldwide, affecting 55 million people and being the leading cause of death and disability. To improve the outcomes and effectiveness of treatment for these patients, we conducted a study on the potential therapeutic use of N-docosahexaenoylethanolamine (synaptamide) in mice using the weight-drop injury (WDI) TBI model. Our study focused on exploring synaptamide's effects on neurodegeneration processes and changes in neuronal and glial plasticity. Our findings showed that synaptamide could prevent TBI-associated working memory decline and neurodegenerative changes in the hippocampus, and it could alleviate decreased adult hippocampal neurogenesis. Furthermore, synaptamide regulated the production of astro- and microglial markers during TBI, promoting the anti-inflammatory transformation of the microglial phenotype. Additional effects of synaptamide in TBI include stimulating antioxidant and antiapoptotic defense, leading to the downregulation of the Bad pro-apoptotic marker. Our data suggest that synaptamide has promising potential as a therapeutic agent to prevent the long-term neurodegenerative consequences of TBI and improve the quality of life.