Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1.
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ABSTRACT:
SUBMITTER: Henninger N
PROVIDER: S-EPMC5006226 | biostudies-literature | 2016 Apr
REPOSITORIES: biostudies-literature
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Project description:BackgroundTraumatic brain injury is a major cause of morbidity and mortality worldwide. Ameliorating the neurocognitive and physical deficits that accompany traumatic brain injury would be of substantial benefit, but the mechanisms that underlie them are poorly characterized. This study aimed to use diffusion tensor imaging to relate clinical outcome to the burden of white matter injury.Methodology/principal findingsSixty-eight patients, categorized by the Glasgow Outcome Score, underwent magnetic resonance imaging at a median of 11.8 months (range 6.6 months to 3.7 years) years post injury. Control data were obtained from 36 age-matched healthy volunteers. Mean fractional anisotropy, apparent diffusion coefficient (ADC), and eigenvalues were obtained for regions of interest commonly affected in traumatic brain injury. In a subset of patients where conventional magnetic resonance imaging was completely normal, diffusion tensor imaging was able to detect clear abnormalities. Significant trends of increasing ADC with worse outcome were noted in all regions of interest. In the white matter regions of interest worse clinical outcome corresponded with significant trends of decreasing fractional anisotropy.Conclusions/significanceThis study found that clinical outcome was related to the burden of white matter injury, quantified by diffusivity parameters late after traumatic brain injury. These differences were seen even in patients with the best outcomes and patients in whom conventional magnetic resonance imaging was normal, suggesting that diffusion tensor imaging can detect subtle injury missed by other techniques. An improved in vivo understanding of the pathology of traumatic brain injury, including its distribution and extent, may enhance outcome evaluation and help to provide a mechanistic basis for deficits that remain unexplained by other approaches.
| S-EPMC3087728 | biostudies-literature
Project description:Traumatic brain injury (TBI) causes chronic symptoms and increased risk of neurodegeneration. Axons in white matter tracts, such as the corpus callosum (CC), are critical components of neural circuits and particularly vulnerable to TBI. Treatments are needed to protect axons from traumatic injury and mitigate post-traumatic neurodegeneration. SARM1 protein is a central driver of axon degeneration through a conserved molecular pathway. Sarm1-/- mice with knockout (KO) of the Sarm1 gene enable genetic proof-of-concept testing of the SARM1 pathway as a therapeutic target. We evaluated Sarm1 deletion effects after TBI using a concussive model that causes traumatic axonal injury and progresses to CC atrophy at 10 weeks, indicating post-traumatic neurodegeneration. Sarm1 wild-type (WT) mice developed significant CC atrophy that was reduced in Sarm1 KO mice. Ultrastructural classification of pathology of individual axons, using electron microscopy, demonstrated that Sarm1 KO preserved more intact axons and reduced damaged or demyelinated axons. Longitudinal MRI studies in live mice identified significantly reduced CC volume after TBI in Sarm1 WT mice that was attenuated in Sarm1 KO mice. MR diffusion tensor imaging detected reduced fractional anisotropy in both genotypes while axial diffusivity remained higher in Sarm1 KO mice. Immunohistochemistry revealed significant attenuation of CC atrophy, myelin loss, and neuroinflammation in Sarm1 KO mice after TBI. Functionally, Sarm1 KO mice exhibited beneficial effects in motor learning and sleep behavior. Based on these findings, Sarm1 inactivation can protect axons and white matter tracts to improve translational outcomes associated with CC atrophy and post-traumatic neurodegeneration.
| S-EPMC8130449 | biostudies-literature
Project description:ProblemUninterrupted nighttime sleep is associated with better cognition and functional outcomes in healthy adults, but the relationship between sleep and functional outcome in individuals hospitalized with severe traumatic brain injury (TBI) remains to be clarified.ObjectiveThe aims of this study were to (1) describe nighttime rest-activity variables-wake bouts (counts), total wake time (minutes), and sleep efficiency (SE) (percentage; time asleep/time in bed)-in people on a neuroscience step-down unit (NSDU) post-TBI and (2) describe the association between injury and nighttime rest-activity on post-TBI functional outcome (using Functional Independence Measure [FIM] at discharge from inpatient care).MethodsThis study is a cross-sectional, descriptive pilot study. We recruited participants from the NSDU (n = 17 [age: mean (SD), 63.4 (17.9)]; 82% male, 94% white) who wore wrist actigraphy (source of nighttime rest-activity variables) for up to 5 nights. For injury variables, we used Glasgow Coma Scale (GCS) score and Injury Severity Score (ISS). We used Spearman ρ and regression to measure associations.ResultsGlasgow Coma Scale mean (SD) score was 8.8 (4.9), ISS mean (SD) score was 23.6 (6.7), and FIM mean (SD) score was 48 (14.5). Averages of nighttime rest-activity variables (8 PM-7 AM) were as follows: SE, 73% (SD, 16); wake bouts, 41 counts (SD, 18); total wake time, 74 minutes (SD, 47). Correlations showed significance between FIM and GCS (P = .005) and between SE and GCS (P = .015). GCS was the only statistically significant variable associated with FIM (P = .013); we eliminated other variables from the model as nonsignificant (P > .10). Sleep efficiency and FIM association was nonsignificant (P = .40). In a separate model (ISS, GCS, and SE [dependent variable]), GCS was significant (P = .04), but ISS was not (P = .25).ConclusionPatients with severe TBI on the NSDU have poor actigraphic sleep at night. GCS has a stronger association to functional outcome than nighttime rest-activity variables.
| S-EPMC6788776 | biostudies-literature
Project description:In adult rats, erythropoietin improved outcomes early and late after traumatic brain injury, associated with increased levels of Brain Derived Neurotrophic Factor. Using our model of pediatric traumatic brain injury, controlled cortical impact in 17-day old rats, we previously showed that erythropoietin increased hippocampal neuronal fraction in the first two days after injury. Erythropoietin also decreased activation of caspase3, an apoptotic enzyme modulated by Brain Derived Neurotrophic Factor, and improved Novel Object Recognition testing 14 days after injury. Data on long-term effects of erythropoietin on Brain Derived Neurotrophic Factor expression, histology and cognitive function after developmental traumatic brain injury are lacking. We hypothesized that erythropoietin would increase Brain Derived Neurotrophic Factor and improve long-term object recognition in rat pups after controlled cortical impact, associated with increased neuronal fraction in the hippocampus. METHODS:Rats pups received erythropoietin or vehicle at 1, 24, and 48 h and 7 days after injury or sham surgery followed by histology at 35 days, Novel Object Recognition testing at adulthood, and Brain Derived Neurotrophic Factor measurements early and late after injury. RESULTS:Erythropoietin improved Novel Object Recognition performance and preserved hippocampal volume, but not neuronal fraction, late after injury. CONCLUSIONS:Improved object recognition in erythropoietin treated rats was associated with preserved hippocampal volume late after traumatic brain injury. Erythropoietin is approved to treat various pediatric conditions. Coupled with exciting experimental and clinical studies suggesting it is beneficial after neonatal hypoxic ischemic brain injury, our preliminary findings support further study of erythropoietin use after developmental traumatic brain injury.
| S-EPMC5878733 | biostudies-literature
Project description:Poor outcomes after traumatic brain injury (TBI) are common yet remain difficult to predict. Diffuse axonal injury is important for outcomes, but its assessment remains limited in the clinical setting. Currently, axonal injury is diagnosed based on clinical presentation, visible damage to the white matter or via surrogate markers of axonal injury such as microbleeds. These do not accurately quantify axonal injury leading to misdiagnosis in a proportion of patients. Diffusion tensor imaging provides a quantitative measure of axonal injury in vivo, with fractional anisotropy often used as a proxy for white matter damage. Diffusion imaging has been widely used in TBI but is not routinely applied clinically. This is in part because robust analysis methods to diagnose axonal injury at the individual level have not yet been developed. Here, we present a pipeline for diffusion imaging analysis designed to accurately assess the presence of axonal injury in large white matter tracts in individuals. Average fractional anisotropy is calculated from tracts selected on the basis of high test-retest reliability, good anatomical coverage and their association to cognitive and clinical impairments after TBI. We test our pipeline for common methodological issues such as the impact of varying control sample sizes, focal lesions and age-related changes to demonstrate high specificity, sensitivity and test-retest reliability. We assess 92 patients with moderate-severe TBI in the chronic phase (≥6 months post-injury), 25 patients in the subacute phase (10 days to 6 weeks post-injury) with 6-month follow-up and a large control cohort (n = 103). Evidence of axonal injury is identified in 52% of chronic and 28% of subacute patients. Those classified with axonal injury had significantly poorer cognitive and functional outcomes than those without, a difference not seen for focal lesions or microbleeds. Almost a third of patients with unremarkable standard MRIs had evidence of axonal injury, whilst 40% of patients with visible microbleeds had no diffusion evidence of axonal injury. More diffusion abnormality was seen with greater time since injury, across individuals at various chronic injury times and within individuals between subacute and 6-month scans. We provide evidence that this pipeline can be used to diagnose axonal injury in individual patients at subacute and chronic time points, and that diffusion MRI provides a sensitive and complementary measure when compared to susceptibility weighted imaging, which measures diffuse vascular injury. Guidelines for the implementation of this pipeline in a clinical setting are discussed.
| S-EPMC7880666 | biostudies-literature
Project description:One of the consistent pathologies associated with both clinical and experimental traumatic brain injury is axonal injury, especially following mild traumatic brain injury (or concussive injury). Several lines of experimental evidence have demonstrated a role for NAD+ metabolism in axonal degeneration. One of the enzymes that metabolizes NAD+ in axons is Sarm1 (Sterile Alpha and TIR Motif Containing 1), and its activity is thought to play a key role in axonal degeneration. Using a Sarm1 knock-out mouse, we examined if loss of Sarm1 offers axonal injury protection and improves cognitive outcome after repeated mild closed head injury (rmCHI). Our results indicate that rmCHI caused white matter damage that can be observed in the corpus callosum, cingulum bundle, alveus of the hippocampus, and fimbria of the fornix of wild-type mice. These pathological changes were markedly reduced in injured Sarm1-/- mice. Interestingly, the activation of astrocytes and microglia was also attenuated in the areas with white matter damage, suggesting reduced inflammation. Associated with these improved pathological outcomes, injured Sarm1-/- mice performed significantly better in both motor and cognitive tasks. Taken together, our results suggest that strategies aimed at inhibiting Sarm1 and/or restoring NAD+ levels in injured axons may have therapeutic utility.
| S-EPMC7959192 | biostudies-literature
Project description:OBJECTIVES:Traumatic brain injury triggers multiple cell death pathways, possibly including ferroptosis-a recently described cell death pathway that results from accumulation of 15-lipoxygenase-mediated lipid oxidation products, specifically oxidized phosphatidylethanolamine containing arachidonic or adrenic acid. This study aimed to investigate whether ferroptosis contributed to the pathogenesis of in vitro and in vivo traumatic brain injury, and whether inhibition of 15-lipoxygenase provided neuroprotection. DESIGN:Cell culture study and randomized controlled animal study. SETTING:University research laboratory. SUBJECTS:HT22 neuronal cell line and adult male C57BL/6 mice. INTERVENTIONS:HT22 cells were subjected to pharmacologic induction of ferroptosis or mechanical stretch injury with and without administration of inhibitors of ferroptosis. Mice were subjected to sham or controlled cortical impact injury. Injured mice were randomized to receive vehicle or baicalein (12/15-lipoxygenase inhibitor) at 10-15 minutes postinjury. MEASUREMENTS AND MAIN RESULTS:Pharmacologic inducers of ferroptosis and mechanical stretch injury resulted in cell death that was rescued by prototypical antiferroptotic agents including baicalein. Liquid chromatography tandem-mass spectrometry revealed the abundance of arachidonic/adrenic-phosphatidylethanolamine compared with other arachidonic/adrenic acid-containing phospholipids in the brain. Controlled cortical impact resulted in accumulation of oxidized phosphatidylethanolamine, increased expression of 15-lipoxygenase and acyl-CoA synthetase long-chain family member 4 (enzyme that generates substrate for the esterification of arachidonic/adrenic acid into phosphatidylethanolamine), and depletion of glutathione in the ipsilateral cortex. Postinjury administration of baicalein attenuated oxidation of arachidonic/adrenic acid-containing-phosphatidylethanolamine, decreased the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells in the hippocampus, and improved spatial memory acquisition versus vehicle. CONCLUSIONS:Biomarkers of ferroptotic death were increased after traumatic brain injury. Baicalein decreased ferroptotic phosphatidylethanolamine oxidation and improved outcome after controlled cortical impact, suggesting that 15-lipoxygenase pathway might be a valuable therapeutic target after traumatic brain injury.
| S-EPMC6449247 | biostudies-literature
Project description:Traumatic axonal injury (TAI), thought to be caused by rotational acceleration of the head, is a prevalent neuropathology in traumatic brain injury (TBI). TAI in the optic nerve is a common finding in multiple blunt-force TBI models and hence a great model to study mechanisms and treatments for TAI, especially in view of the compartmentalized anatomy of the visual system. We have previously shown that the somata and the proximal, but not distal, axons of retinal ganglion cells (RGC) respond to DLK/LZK blockade after impact acceleration of the head (IA-TBI). Here, we explored the role of the sterile alpha and TIR-motif containing 1 (SARM1), the key driver of Wallerian degeneration (WD), in the progressive breakdown of distal and proximal segments of the optic nerve following IA-TBI with high-resolution morphological and classical neuropathological approaches. Wild type and Sarm1 knockout (KO) mice received IA-TBI or sham injury and were allowed to survive for 3, 7, 14, and 21 days. Ultrastructural and microscopic analyses revealed that TAI in the optic nerve is characterized by variable involvement of individual axons, ranging from apparent early disconnection of a subpopulation of axons to a range of ongoing axonal and myelin perturbations. Traumatic axonal injury resulted in the degeneration of a population of axons distal and proximal to the injury, along with retrograde death of a subpopulation of RGCs. Quantitative analyses on proximal and distal axons and RGC somata revealed that different neuronal domains exhibit differential vulnerability, with distal axon segments showing more severe degeneration compared with proximal segments and RGC somata. Importantly, we found that Sarm1 KO had a profound effect in the distal optic nerve by suppressing axonal degeneration by up to 50% in the first 2 weeks after IA-TBI, with a continued but lower effect at 3 weeks, while also suppressing microglial activation. Sarm1 KO had no evident effect on the initial traumatic disconnection and did not ameliorate the proximal optic axonopathy or the subsequent attrition of RGCs, indicating that the fate of different axonal segments in the course of TAI may depend on distinct molecular programs within axons.
| S-EPMC10460965 | biostudies-literature
Project description:BackgroundTraumatic brain injury (TBI) is the leading cause of death and disability in children, but effective tools for predicting outcome remain elusive. Although many pediatric patients receive early magnetic resonance imaging (MRI), data on its utility in prognostication are lacking. Diffuse axonal injury (DAI) is a hallmark of TBI detected on early MRI and was shown previously to improve prognostication in adult patients with TBI. In this exploratory study, we investigated whether DAI grade correlates with functional outcome and improves prognostic accuracy when combined with core clinical variables and computed tomography (CT) biomarkers in pediatric patients with moderate-severe TBI (msTBI).MethodsPediatric patients (≤ 19 years) who were admitted to two regional level one trauma centers with a diagnosis of msTBI (Glasgow Coma Scale [GCS] score < 13) between 2011 and 2019 were identified through retrospective chart review. Patients who underwent brain MRI within 30 days of injury and had documented clinical follow-up after discharge were included. Age, pupil reactivity, and initial motor GCS score were collected as part of the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) model. Imaging was reviewed to calculate the Rotterdam score (CT) and DAI grade (MRI) and to evaluate for presence of hypoxic-ischemic injury (MRI). The primary outcome measure was the Pediatric Cerebral Performance Category Scale (PCPCS) score at 6 months after TBI, with favorable outcome defined as PCPCS scores 1-3 and unfavorable outcome defined as PCPCS scores 4-6. The secondary outcome measure was discharge disposition to home versus to an inpatient rehabilitation facility.ResultOf 55 patients included in the study, 45 (82%) had severe TBI. The most common mechanism of injury was motor vehicle collision (71%). Initial head CT scans showed acute hemorrhage in 84% of patients. MRI was acquired a median of 5 days after injury, and hemorrhagic DAI lesions were detected in 87% of patients. Each 1-point increase in DAI grade increased the odds of unfavorable functional outcome by 2.4-fold. When controlling for core IMPACT clinical variables, neither the DAI grade nor the Rotterdam score was independently correlated with outcome and neither significantly improved outcome prediction over the IMPACT model alone.ConclusionsA higher DAI grade on early MRI is associated with worse 6-month functional outcome and with discharge to inpatient rehabilitation in children with acute msTBI in a univariate analysis but does not independently correlate with outcome when controlling for the GCS score. Addition of the DAI grade to the core IMPACT model does not significantly improve prediction of poor neurological outcome. Further study is needed to elucidate the utility of early MRI in children with msTBI.
| S-EPMC8405042 | biostudies-literature
Project description:The current study set out to investigate the dynamic functional connectome in relation to long-term recovery after mild to moderate traumatic brain injury (TBI). Longitudinal resting-state functional MRI data were collected (at 1 and 3?months postinjury) from a prospectively enrolled cohort consisting of 68 patients with TBI (92% mild TBI) and 20 healthy subjects. Patients underwent a neuropsychological assessment at 3?months postinjury. Outcome was measured using the Glasgow Outcome Scale Extended (GOS-E) at 6?months postinjury. The 57 patients who completed the GOS-E were classified as recovered completely (GOS-E = 8; n = 37) or incompletely (GOS-E?<?8; n = 20). Neuropsychological test scores were similar for all groups. Patients with incomplete recovery spent less time in a segregated brain state compared to recovered patients during the second visit. Also, these patients moved less frequently from one meta-state to another as compared to healthy controls and recovered patients. Furthermore, incomplete recovery was associated with disruptions in cyclic state transition patterns, called attractors, during both visits. This study demonstrates that poor long-term functional recovery is associated with alterations in dynamics between brain networks, which becomes more marked as a function of time. These results could be related to psychological processes rather than injury-effects, which is an interesting area for further work. Another natural progression of the current study is to examine whether these dynamic measures can be used to monitor treatment effects.
| S-EPMC7268079 | biostudies-literature