Journal of neurotrauma最新文献

Biomaterial-based neural cell transplantation has displayed promise in regenerative medicine. E-cadherin and N-cadherin are cell-cell adhesion proteins with important roles in neuronal maturity. Therefore, cell culture on Petri dishes coated with a fusion protein combining the human E-cadherin or N-cadherin extracellular domain with an immunoglobulin G Fc region chimeric antibody (E-cad-Fc and N-cad-Fc) can regulate cell maturity through the process of neuronal differentiation in stem cells. This study explored the efficacy of dental pulp-derived induced neural cells (DPiNCs), which were cultured in dishes coated with cell-recognizing E-cadherin-Fc chimeric antibody (E-cad NCs) or N-cadherin-Fc chimeric antibody (N-cad NCs), in promoting neural regeneration in a traumatic brain injury (TBI) model. In vitro, DPiNCs featured axon-like projections with positive GFAP expression, weak positivity for DCX and βIII-tubulin, and positivity for MAP2 and vascular endothelial growth factor, indicating that the cell population included a mixture of mature and immature neurons. E-cad NCs exhibited staining for DCX and βIII-tubulin but reduced MAP2 staining, indicating immaturity. N-cad NCs displayed weaker DCX and βIII-tubulin staining but increased MAP2 staining, indicating maturity. In an oxygen-glucose deprivation/reoxygenation model, which simulates secondary brain injury, E-cad NC cells maintained higher βIII-tubulin and DCX expression and extended axons, denoting resistance to hypoxic stress. N-cad NCs displayed stronger MAP2 staining and axon extension, indicating resilience and maturity. In vivo, TBI model mice were transplanted with each cell type. Regarding motor function, the wire hang test revealed a significant improvement in the E-cad NC group with the other cell groups and sham group on day 28 post-transplantation. Additionally, in the cylinder test (right paw drags), a significant improvement was noted in the E-cad NC group compared with the DPiNC and sham groups from day 14 to day 28 post-transplantation. The E-cad NC group exhibited the highest rate of improvement on the Revised Neurobehavioral Severity Scale. Dual immunostaining on day 28 confirmed that the number of surviving transplanted cells was higher in the N-cad NC group than in the DPiNC group. Our study demonstrated the potential of cadherin-modified DPiNCs in TBI treatment, suggesting that controlling cell maturity through cadherin expression can significantly improve outcomes by promoting cell survival, integration, and neural regeneration. This study offers promising insights into regenerative medicine for acute-phase TBI, but further research is needed to clarify the long-term efficacy and the mechanisms underlying cell integration and neural network reconstruction.

Neuroimaging technologies such as computed tomography and magnetic resonance imaging (MRI) have been widely adopted in the clinical diagnosis and management of traumatic brain injury (TBI), particularly at the more acute and severe levels of injury. Additionally, a number of advanced applications of MRI have been employed in TBI-related clinical research with great promise, and researchers have used these techniques to better understand the underlying mechanisms, progression of secondary injury and tissue perturbation over time, and relation of focal and diffuse injury to outcome. However, the acquisition and analysis time, the cost of these and other imaging modalities, and the need for specialized expertise have represented historical barriers in extending these tools in clinical practice. While group studies are important in detecting patterns, heterogeneity among patient presentation and limited sample sizes from which to compare individual-level data to well-developed normative data have also played a role in the limited translatability of imaging to wider clinical application. Fortunately, the field of TBI has benefited from increased public and scientific awareness of the prevalence and impact of TBI, particularly related to recent military conflicts and sport-related concussion. This awareness parallels an increase in federal funding in the United States and other countries allocated to investigation in these areas. In 2025, funding for TBI research in the United States is less certain due to the changing administrative priorities, so we hope this article can highlight the incredible productivity of the TBI neuroimaging research community. In this article, we summarize funding and publication trends since the mainstream adoption of imaging in TBI to elucidate evolving trends and priorities in the application of different techniques and patient populations. A total of 4872 articles over 82 years are categorized. We also review recent and ongoing efforts to advance the field through promoting reproducibility, data sharing, big data analytic methods, and team science. Finally, we discuss international collaborative efforts to combine and harmonize neuroimaging, cognitive, and clinical data, both prospectively and retrospectively. Each of these represents unique, but related, efforts that facilitate closing gaps between the use of advanced imaging solely as a research tool and the use of it in clinical diagnosis, prognosis, and treatment planning and monitoring.

Neuronal apoptosis suppression and efficient apoptotic cell clearance are crucial for preventing secondary spinal cord injury (SCI). The immunoreceptor CD300a is a phosphatidylserine receptor expressed on myeloid cells that modulates secondary neuronal damage by regulating efferocytosis. CD300a blockade has previously enhanced efferocytosis and improved neurological deficits in an ischemic stroke mouse model. However, the mechanisms and roles of CD300a in acute SCI remain unclear. Therefore, we evaluated the effects of CD300a regulation on acute SCI. First, an SCI model was created in CD300a-deficient mice and compared with that in wild-type mice. Second, we compared the effects of treating wild-type mice with anti-CD300a or control antibodies. The effects were evaluated over 6 weeks by analyzing behavioral outcomes using the Basso Mouse Scale and injured spinal cord tissue. Damage-associated molecular patterns (DAMPs) were evaluated in the acute phase, and oligodendrocyte apoptosis was assessed in the subacute phase of SCI to assess the effects of CD300a on inflammation and secondary injury. CD300a-deficient mice exhibited improved motor function, a reduced lesion area, and an increased residual myelin area. Immunohistochemical staining revealed reduced scarring and more surviving neurons. CD300a-deficient mice exhibited decreased extracellular DAMPs and oligodendrocyte apoptosis in the acute and subacute phases, respectively. The antibody-treated group also exhibited improved motor function, reduced lesion area, and increased residual myelin. These findings suggest that CD300a regulation mitigates SCI by suppressing DAMP release and apoptosis, thereby contributing to reduced tissue damage and functional recovery. These findings highlight CD300a regulation as a potentially effective treatment for acute SCI.

Neuroinflammation is known to contribute to worse patient outcomes following severe traumatic brain injury (TBI). Specifically, complement activation as part of the innate immune response has been explored in animal models and post-mortem human tissue. However, it has not been well-characterized in a substantial clinical cohort. We aimed to investigate the complement cascade, specifically focusing on the lectin pathway initiators, in patients with TBI compared with healthy controls. We describe temporal profiles of complement proteins, and investigate their association with outcome, and clinical variables following TBI. Plasma blood samples collected from 64 patients with TBI (on days 1-7, 42, and 365) and 17 healthy controls (single samples) were analyzed for 10 complement proteins using single and multiplexing protein assays. We quantified initiator (MBL, MASP2, ficolin3), effector (C4b, C2, factor D, factor I), and downstream (C5, C5a, C5b9) complement proteins. Clinical variables included injury severity score, Glasgow Coma Scale motor score, pupil reactivity, and Glasgow Outcome Scale Extended at 6 months post-injury. 7 out of 10 measured complement proteins had median concentrations that were significantly different in patients with TBI compared with healthy controls (all p values < 0.05). Ficolin3, an initiator, was particularly lower in TBI versus controls (0.22 vs. 1.84 ng/mL, p < 0.001), and consistently lower over time, showing depressed levels even 1 year post-injury (p < 0.001). Initiators MBL and MASP2, effector C2 and downstream proteins C5, C5a, and factor I demonstrate a steady rise in the first week post-injury, and are consistently elevated compared with control levels. Patients with unfavorable outcome had higher levels of C4b, C5, and factor I, with C5 demonstrating this trend over time (OR: 1.53 [1.52-1.53], p value < 0.001), and showing additional prognostic benefit over and above IMPACT clinical outcome predictors. This study characterized the complement cascade in human TBI with high temporal resolution in initiator, effector, and downstream proteins. Seven out of the 10 measured proteins were significantly different in patients with TBI compared with healthy controls. Notably, C5 has an independent and robust association with outcome in both univariate and linear mixed regression, where a higher C5 concentration was associated with unfavorable outcome 6 months post-injury. Further investigation is required to explore the potential of complement as a therapeutic target in TBI.

To identify, categorize, and rank the predictors of walking recovery in patients with traumatic spinal cord injury (SCI). We prospectively registered (CRD42023443454) this review and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed, Embase, Cochrane, and Web of Science until July 2025. We assessed study eligibility, extracted data, appraised study quality using the Quality In Prognostic Studies, and evaluated the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation. We meta-analyzed adjusted effect estimates within the same stratification when data from two or more studies were available; when meta-analysis was not appropriate, we presented the results qualitatively. Fifty-four studies met the inclusion criteria. Study quality levels were rated as poor (3 [5.6%] of 54 studies), fair (40 [70%]), and good (11 [20.4%]) quality. Predictor variables were classified into five categories: (1) sociodemographic factors, (2) injury-related factors, (3) magnetic resonance imaging parameters, (4) serum/cerebrospinal fluid (CSF) biomarkers, and (5) treatment-related factors. American Spinal Injury Association Impairment Scale (AIS) and neurological level of injury (NLI) were found to be the most significant predictors of walking recovery (odds ratio [OR] = 3.70; 95% confidence interval [CI]: 2.86-4.79; p = 0.001; I² = 2%; high certainty) and (OR = 2.81; 95% CI: 1.54-5.14; p = 0.008; I² = 0%; moderate certainty), respectively. Patients with diabetes were less likely to regain ambulatory ability after SCI (OR = 0.64, 95% CI: 0.42-0.98; p = 0.038; I² = 0.0%; moderate certainty). Other widely studied predictors, such as age and timing of surgery, showed inconsistent results across cutoffs. In conclusion, the initial severity of injury (AIS and NLI) was the strongest predictor of walking recovery, indicating that patients with less severe impairment at admission had a higher probability of walking recovery.

Traumatic brain injury (TBI) frequently results in long-term cognitive deficits due to traumatic axonal injury and disruption of structural brain connectivity. Computerized cognitive remediation (CCR) has shown promise for improving cognitive outcomes in chronic TBI; however, diffusion imaging studies evaluating its effectiveness have often relied on tensor-based metrics that are limited in their ability to detect subtle treatment-related changes. This study used correlational tractography, a diffusion magnetic resonance imaging (dMRI) connectometry method sensitive to localized, fiber-specific changes, to investigate the effects of CCR on white matter microstructure in adults with chronic TBI and to further examine the relationship between white matter changes and improvements in cognitive function. Seventeen adults with chronic mild to severe TBI were assigned to an experimental group (n = 10), who received 40 hours of CCR over 14 weeks, or a nonintervention control group (n = 7). All participants underwent dMRI scans and cognitive assessments at pre- and postintervention visits. Correlational tractography was used to assess differences in longitudinal change of normalized quantitative anisotropy (QA), a tensor-free metric associated with axonal density and plasticity, across whole-brain white matter between CCR and nonintervention control groups. Following the intervention period, increased QA was observed in the CCR group, relative to the nonintervention control group, and changes in QA in the CCR group were related to improvements on objective measures of processing speed, attention, and working memory. These results provide preliminary evidence that CCR may promote white matter plasticity in relation to improved cognitive function in individuals with chronic TBI. Furthermore, by leveraging QA and correlational tractography, we were able to detect regionally specific changes that may have been overlooked using traditional tensor-derived diffusion metrics or tract-averaged approaches. Overall, our findings support the potential of CCR as a scalable intervention to facilitate structural and functional plasticity in adults with chronic TBI.

Although the younger age of first exposure (AFE) to American football has not been associated with neurodegenerative pathology, AFE has been associated with clinical symptoms. However, the literature is mixed. We examined the association between AFE to football and clinical outcomes before and after age 60 at death, to isolate the potential role of decreased neuropathological resilience in older age. This study included 677 deceased male football players who donated their brains to the Understanding Neurologic Injury and Traumatic Encephalopathy Brain Bank. Informants completed modified scales assessing cognition, function, behavior, and neuropsychiatric features with dementia adjudicated through consensus conferences. Regressions tested the association between AFE and dementia, chronic traumatic encephalopathy (CTE) pathology, and each scale, adjusted for multiple testing. Analyses were stratified by age 60, adjusting for age at death, duration of play, and neuropathology. Most donors (mean age = 60.9, standard deviation = 19.8) played college or professional football (n = 509, 76%). CTE was the most prevalent neuropathology (n = 471, 70%). AFE was not associated with neurodegenerative disease pathology. Among those older than 60 at death, younger AFE was associated with cognitive composite score impairment (odds ratio: 0.897, 95% confidence interval [CI]: 0.814-0.988, p = 0.027) and worse cognitive (beta: 0.04, 95% CI: 0.01-0.069, p = 0.009), neurobehavioral (beta: 0.032, 95% CI: 0.002-0.062, p = 0.035), and neuropsychiatric (beta: 0.032, 95% CI: 0.00-0.064, p = 0.048) composite scores. Younger AFE was only associated with worse informant-reported clinical outcomes in older deceased football players, independent of neurodegeneration. Our findings offer a potential explanation for the mixed literature on AFE and clinical outcomes. The effects of AFE may only manifest in older adults when cognitive reserve is depleted, neuropathological resilience is reduced, or age-related vulnerabilities interact with prior head injury exposure, worsening clinical outcomes.

In this prospective longitudinal multiple-cohort study, we investigated mental health outcomes in patients with traumatic brain injury (TBI) or Orthotrauma (fracture excluding head/neck) using data from six University of California civilian healthcare settings between 2013 and 2022. Trauma cohorts were propensity matched 1:1 by age, race and ethnicity, sex, site, insurance coverage, area deprivation index, and number of visits within the year preceding injury diagnosis in the health record (index), then propensity matched to unexposed individuals. International Statistical Classification of Diseases, Tenth Revision, Clinical Modification codes identified patients and study mental health outcomes (depression, anxiety, post-traumatic stress or PTSD, suicidality, bipolar disorder, schizophrenia). Cox proportional hazard models generated hazard ratios (HR) from 1 year pre- to 7 years post-index for 3 groups: TBI vs unexposed, Orthotrauma vs unexposed, and TBI vs Orthotrauma. Analyses included patients with pre-index mental health outcomes and were adjusted for documented suicide attempt. Age and sex stratifications were explored. Results included 174,384 patients (99,356 female [57.0%]; 10,584 Black [6.1%]), including 43,596 each in TBI and Orthotrauma cohorts and 87,192 unexposed (all median [IQR] age, 57.0 [42.0-70.0] years). Compared to Orthotrauma, TBI affected post-index HRs most strongly for PTSD (HR range 1.75-2.59 through Year 6, pre-index 1.74-1.84) and suicidality (HR range 2.34-6.17 through Year 7, pre-index 1.51-1.95) with particularly elevated suicidality risk within 6-12 months of index. Mental health diagnoses served as precursors to and consequences of TBI. Patients with traumatic injuries should be screened and treated for mental health conditions. Etiologic studies are urgently needed.

An acute subdural hematoma (ASDH) is the most common focal injury in traumatic brain injury (TBI) and a major cause of death and morbidity worldwide. The decision to perform neurosurgical evacuation of the ASDH is complex. The Brain Trauma Foundation (BTF) issued guidelines in 2006, recommending evacuation for ASDHs >1 cm or with >5 mm midline shift regardless of patients' Glasgow Coma Scale (GCS) score, and in cases of neurological deterioration, abnormal pupillary reaction, or high intracranial pressure (ICP). Despite their global recognition, the evidence supporting these guidelines is weak. This study assesses adherence to BTF guidelines in a European cohort and determines the effect on mortality and functional outcomes. Data from the prospective observational Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study were analyzed. Patients presenting after a TBI with an ASDH on the initial computed tomography scan across 65 trauma centers in Europe and Israel between 2014 and 2018 were included. Patients with concomitant epidural hematoma were excluded. Adherence to BTF guidelines for ASDH surgery and ICP monitoring was assessed, including subgroup analyses based on age and TBI severity. Multivariable logistic regression models examined the association between guideline adherence and outcomes, adjusting for prespecified confounders. Among 985 patients with traumatic ASDH, overall guideline adherence was 74% (n = 724), with higher adherence to conservative treatment (95% [n = 533]) compared with surgical recommendations (45% [n = 191]). Adherence varied by age and TBI severity, being lower in elderly and severely injured patients. ICP monitoring adherence in comatose patients was 63% (n = 240). Adherence to surgical ASDH guidelines was not significantly associated with in-hospital mortality (odds ratio [OR]: 0.72 [0.43-1.2]) or 6-month functional outcome (OR: 0.73 [0.47-1.1]). Overall adherence to BTF guidelines for surgical ASDH management was low. The current surgical thresholds do not align with clinical practice. Elderly patients and those with severe TBI were less likely to be treated per guidelines. Incorporating patient age, GCS and hematoma volume into the guidelines may enhance their relevance and adherence in clinical practice.