Journal of neurotrauma最新文献

Traumatic spinal cord injury (SCI) increases the risk for skin complications, including the development of decubitus ulcers, that is, pressure sores. The mechanisms by which SCI adversely affects skin health are poorly understood. To better understand how SCI affects the normal progression of wound healing, two mouse models of cutaneous wound healing were used. Mice received a high-level (T3) SCI or sham injury (Lam) over the first week postinjury. Mice received standardized skin wounds on the dorsum below the injury level (punch biopsy or compression/ischemia wounds). Planimetric analysis revealed that wound closure was consistently delayed and impaired after SCI. Subsequent analyses of the expression of genes and proteins responsible for regulating cell migration and recruitment, particularly of neutrophils, were reduced in SCI mice as early as 1 day post-wounding. This impaired chemotactic signaling was associated with a corresponding decrease in neutrophil recruitment to the wounds of SCI mice. At later phases of healing, the expression of inflammatory genes and the accumulation of wound myeloid cells with an elevated capacity for arginine catabolism was enhanced in SCI mice relative to Lam. Overall, data in this report show that impaired wound closure in SCI mice is associated with early and prolonged disruption of the expression of genes and proteins needed to coordinate the sequential progression through all phases of wound healing. Consequently, skin wounds in SCI mice exhibit prolonged inflammation, characteristic of complicated wound healing. Thus, targeting signaling pathways during the inflammatory phase of healing of decubitus ulcers after SCI could improve wound closure and limit further complications.

Traumatic brain injury (TBI) is a leading cause of death and disability. While the Glasgow Coma Scale (GCS) guides initial assessment, single values miss evolving neurological change. In this multicenter ICU cohort integrating NSICU, MIMIC-IV, and eICU databases, we analyzed adults (≥18 years) with TBI who had ≥3 GCS measurements within the first 120 ICU hours. Using 12-hourly measures, latent class growth modeling identified four dynamic GCS trajectories (Stable High, Rapidly Improving, Persistently Moderate, Persistently Low), and we quantified cumulative neurological burden with a mean threshold-based area-under-the-curve (TBM-AUC) summarizing time above prespecified GCS thresholds. Among 3,132 patients, mortality increased monotonically across trajectories, highest in the Persistently Low group (adjusted hazard ratio [HR] 4.95, 95% confidence interval: 3.14-7.81 vs. Stable High). Lower TBM-AUC was strongly associated with mortality; most pronounced at threshold 13 (HR 0.34). Age-stratified analyses showed a trajectory-by-age interaction (p = 0.013), with Persistently Low conferring the greatest risk in both younger and older adults. Adding trajectory class to baseline predictors improved discrimination (AUC: 0.820-0.861, p < 0.001) with consistent gains in integrated discrimination improvement, net reclassification improvement, and median risk score across Boruta-, LASSO-, and best-subset-based models. Dynamic GCS trajectories and TBM-AUC provide prognostic information beyond conventional assessments and may enhance risk stratification and clinical decision-making in neurocritical care; prospective validation is warranted. [Figure: see text].

The long-term sequelae of severe penetrating traumatic brain injury (TBI) include neurological and psychiatric disability, impaired cognitive function, and the development of post-traumatic epilepsy. The present study evaluated the therapeutic effects of intravenous immunoglobin (IVIg), a well-established immunomodulatory treatment, in a controlled cortical impact model of severe TBI in mice. The beneficial effects of IVIg treatment on acute neurological status, motor function, anxiety level, and spatial learning ability were demonstrated by reduced Neurological Severity Scores, increased Rotarod latency and cumulative movement durations in open-field tests, and improved active place avoidance performance. IVIg treatment also significantly reduced brain tissue loss, which was examined using Nissl staining at 16 weeks after TBI. Furthermore, brain microRNAs (miRNAs) were profiled to identify the biological pathways potentially associated with the actions of IVIg treatment using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. To identify potential peripheral biomarkers reflecting the changes in the brain, differentially expressed miRNAs in plasma and brain samples from the same animals were compared. Our immunostaining results showed that IVIg treatment significantly attenuated the upregulation of IL-1β and complement 3 (C3) and altered the activation of microglia and astrocytes. This proof-of-concept study provided strong evidence for the beneficial effects of IVIg treatment in severe penetrating TBI.

Neurogenic bowel (NB) affects roughly 60% of people with a spinal cord injury (SCI), and these patients present with slow colonic transit, constipation, and chronic abdominal pain. The mechanisms by which NB bowel develops are unclear, thereby limiting interventions to being primarily symptom-focused and ineffective. Therefore, the main goal of this study was to identify the mechanisms that initiate and maintain NB after SCI as a critical step to develop evidence-based, novel therapeutic options to prevent NB. In previous studies, the neurogenic inflammatory mediator calcitonin gene-related peptide (CGRP) was identified as a high-priority candidate gene. Therefore, in a midthoracic rodent spinal contusion model that presents with clinically translatable NB-like phenotypes, we conducted intrarectal antagonism of CGRP activity using CGRP_8-37 (compared to vehicle administration) in mice with SCI. This was followed by histological, molecular, and functional (Ca²⁺ imaging) approaches to assess the prevention of previously reported phenotypes of NB. CGRP_8-37 significantly prevented colonic dysmotility and structural defects of the colon (i.e., expanded lymphoid nodules). There was also a prevention of microbial invasion into the colon wall and neuronal hyperresponsiveness to autologous fecal supernatants. These data support the role of CGRP/CGRP as a candidate mechanism for NB after SCI and highlight the potential for novel therapeutic treatments for the prevention of NB.

Traumatic brain injury (TBI) remains a leading global cause of death and disability, disproportionately impacting low- and middle-income countries (LMICs), where neurosurgical resources are often limited. In these settings, foundational gaps in health system infrastructure-such as limited internet access, absence of electronic medical records (EMRs), and lack of standardized protocols-impede timely diagnosis, intervention, and continuity of care. This study evaluates the relationship between health system infrastructure and neurosurgical capacity, intervention delivery, and TBI outcomes across LMICs. We conducted a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines across PubMed, Embase, and Scopus to identify studies examining TBI care and system infrastructure in LMIC institutions. Extracted data were categorized across two primary domains: (1) clinical management and patient outcomes, and (2) implementation of health system components, including EMRs, information and communication technology access, and standardized care protocols. Quantitative analysis incorporated descriptive statistics, chi-square testing, Kruskal-Wallis tests, Glasgow Coma Scale-adjusted linear regression models, and machine learning classifiers to examine associations. Of the LMIC institutions reviewed, only 41% reported the presence of neurosurgical capacity. Implementation of EMRs and standardized protocols was significantly associated with increased neurosurgical capacity (odds ratio [OR] = 1.1, p = 0.06; OR = 1.1, p = 0.03, respectively). Among facilities with operative capacity, the median neurosurgical intervention rate was 28% (interquartile range [IQR]: 3-33%). Policy implementation predicted reduced post-TBI mortality (B = -10.8, p = 0.06; R² = 0.56), with a median institutional mortality rate of 19% (IQR: 8-17%). Machine learning models demonstrated strong discriminatory ability to predict TBI mortality based on neurosurgical capacity and infrastructure metrics (area under the curve = 0.76). These findings highlight the potential for health system infrastructure-particularly EMRs, internet access, and standardized clinical protocols-to improve neurosurgical readiness and reduce preventable mortality following TBI in LMICs. Strategic investment in digital health tools and policy standardization could be a high-yield, scalable approach to closing global neurosurgical care gaps and improving TBI outcomes in resource-limited settings.

The Glasgow Outcome Scale-Extended (GOSE) is the most frequently used outcome measure for traumatic brain injury (TBI) clinical trials. The GOSE may be administered several ways, the choice depending on the purpose of the research. For example, the GOSE can be administered to reflect functional limitations attributed to the overall injury, including extracranial injuries (GOSE-All), or to discount limitations attributed to extracranial injuries (GOSE-TBI). In this investigation, we assessed the effect of using GOSE-All versus GOSE-TBI in clinical trial design. We estimated the impact of the differences in assessment strategy on sample size and power for a clinical trial of an intervention that affects only TBI-related limitations. Inclusion criteria based on TBI severity and extracranial injury severity were examined, as were primary assessments at 2 weeks or 3, 6, or 12 months after injury. Data from 2,288 participants in the prospective observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study were used to simulate the effects. If the trial were analyzed by a Mann-Whitney test comparing GOSE-All scores between treatment groups, sample size would need to increase 8-158% to account for the apparent decreased effect of a treatment that affects only the brain injury. If the sample size were not adjusted, power to detect a treatment effect would decrease from 80% to as low as 41%. If the outcome were dichotomized (favorable=GOSE 8 if including only patients with Glasgow Coma Scale [GCS]=13-15, GOSE 5-8 if GCS = 3-12), the sample size would need to increase 6-165%. The ratios of sample size are largest when the trial population consists of people with milder brain injuries and decrease with time since injury in those with GCS 13-15. It is crucial for researchers, given the aims of their studies, to decide in advance whether the classification of the GOSE should be based on effects attributed to the brain injury, despite the fact that extracranial injuries may not have allowed one to experience the extent of limitation due to the TBI, or all injuries, including extracranial injuries, and to power their studies accordingly. Instructions to the respondent and outcomes examiner need to be clear about what causes of disability are to be included. The assessment method should be accounted for in the power and sample size calculations, clearly indicated in the protocol and publications and documentation accompanying shared data, and emphasized in the training of the outcome examiners so all are collecting the desired information.

Pediatric traumatic brain injury (TBI) triggers biological changes that may differ from those observed in non-brain injuries. Brain-derived neurotrophic factor (BDNF) DNA methylation (DNAm) may serve as a novel, dynamic biomarker of the brain's response and help identify TBI-specific epigenetic patterns relevant to later recovery. Therefore, the purpose of this study was to examine whether BDNF DNAm differed between children with TBI and those with orthopedic injury (OI, comparison group) acutely and over time. Data were derived from the Epigenetic Effects on TBI Recovery study, a prospective, longitudinal cohort study conducted at UPMC Children's Hospital of Pittsburgh. Children aged 3-18 years hospitalized at a minimum of overnight for complicated mild-to-severe TBI or OI without head trauma were enrolled. Exclusion criteria included prior hospitalization for TBI, pre-existing neurological or psychiatric conditions, or sensory or motor impairments precluding study participation. Blood samples were collected during hospitalization (mean = 31.6 h post-injury) and at 6 (mean = 216.9 days) and 12 months (mean = 405.9 days) post-injury. The primary outcome variable was DNAm assessed via pyrosequencing at five quality-controlled CpG sites in the BDNF gene (chromosome 11, Genome Reference Consortium Human Build 38 positions 27722033, 27722036, 27722047, 27701612, and 27701614). The primary exposure was injury type (TBI vs. OI), with severity (measured via Glasgow Coma Scale [GCS]) examined as a secondary exposure within the TBI group. Primary covariates included age, sex, and race; secondary covariates included pubertal status, age-adjusted body mass index, non-head injury severity, socioeconomic status, and psychosocial adversity. The final analysis sample included n = 189 participants with TBI and n = 105 participants with OI. Participants were 66.3% male, 83.2% White, and had a mean age of 10.6 (±4.3) years at the time of enrollment. Acutely, children with TBI showed significantly lower DNAm at three of five sites (3.17-5.83% lower; p = 0.0044 to 6.48E-06) while controlling for age, sex, and race. One site remained significantly lower at 12 months (8.56% lower; p = 0.0045); no significant differences were observed at 6 months. Observed differences remained robust across sensitivity models adjusting for secondary covariates. GCS-measured TBI severity was not associated with DNAm at any time point. These findings suggest that BDNF DNAm differs between children with TBI and those with OI, particularly in the acute period. BDNF DNAm differences may reflect early biological responses that are specific to TBI.

Traumatic brain injury (TBI) is a neurological disease that seriously endangers human life and has a poor prognosis. In particular, neuroinflammation during secondary injury after TBI affects the course of TBI, and interleukin-33 (IL-33) plays an important regulatory role in neuroinflammation after TBI. Meanwhile, the Yes-associated protein (YAP) can influence the prognosis after TBI. In this study, we explored whether the upregulation of YAP in astrocytes can enhance the protective effect of IL-33 against neuroinflammation after TBI. In the current study, the markers of microglial proinflammatory/anti-inflammatory responses both in vivo and in vitro were assessed after the administration of exogenous IL-33. Adeno-associated virus targeting astrocytes in vivo and lentivirus transfecting astrocytes in vitro were used to overexpress YAP, and the expression and localization of proteins were evaluated by Western blotting and immunofluorescence staining. Chromatin immunoprecipitation-quantitative Polymerase Chain Reaction (qPCR) assays were performed to confirm that YAP transcriptionally regulates the IL33 gene by binding directly to its promoter region. Astegolimab was administered to block Growth Stimulation Express Gene 2 Protein (ST2) receptors in vivo and in vitro. Morris water maze and Y-maze tests were employed to assess cognitive function after TBI. The results demonstrated that the expression levels of both YAP and IL-33 were significantly decreased during the early phase of TBI. Concurrently, the anti-inflammatory marker CD206 in microglia was also markedly reduced in the acute stage post-TBI. Importantly, YAP was found to enhance IL-33 secretion by binding to its gene promoter, thereby activating the IL-33/ST2 signaling pathway. This activation promoted anti-inflammatory responses in microglia, which were mediated through the NF-κB signaling pathway, and ultimately led to improved cognitive function. These beneficial effects were effectively reversed by the administration of astegolimab, confirming the specificity of the YAP/IL-33/ST2 mechanism. Above all, we found that YAP produced by astrocytes regulates microglial anti-inflammatory responses through the IL-33/ST2 pathway, thereby improving cognitive function after TBI.

Given the heterogeneity of traumatic brain injury (TBI), the development of a therapeutic strategy has been difficult despite decades of research. To develop an accurate classification system to guide individualized treatment, new protein biomarkers of TBI have been studied. We explored if different subtypes of TBI have unique biomarker profiles and histological findings using four pig models of TBI: moderate rotational injury (100-110 r/s), mild rotational injury (85-95 r/s), moderate contusional injury (8-9 mm), and mild contusional injury (6-7 mm). Among these groups, we identified unique profile of plasma neurofilament light (NFL) and glial fibrillary acidic protein (GFAP): whereas moderate contusion animals had early peak of NFL (2-3 days) and GFAP (1 day), mild contusion animals had delayed peak of NFL (8 days) and GFAP (3 days). Diffusion tensor imaging analysis found reduced fractional anisotropy in corona radiata for contusional injured animals but rotational injured animals showed no significant changes compared to control animals. Histological analysis showed prominent vascular inflammation and axonal injury in the pericontusional cortex in contusional injured animals. In rotational injured animals, prominent axonal injury was found in perivascular white matter. Future studies for mechanistic underpinning of biomarker changes are needed to establish therapeutic targets, predict severity of injury, and determine clinical trial enrollment and therapeutic response.