Chronic neuropathological and neurobehavioral changes in a repetitive mild traumatic brain injury model

Mouzon, Benoit; Bachmeier, Corbin; Ferro, Austin; Ojo, J. Villegas-del; Crynen, Gogce; Acker, Christopher M.; Davies, Peter; Mullan, Michael; Stewart, William; Crawford, Fiona

doi:10.1002/ana.24064

Cited by 287 publications

(360 citation statements)

References 54 publications

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“…The same brain regions were devoid of PHF1‐ and MC1‐positive neurons regardless of the injury status (data not shown). Consistent with our previous observation of lack of increased A β 40 or tau phosphorylation at 12 months post single and r‐mTBI/anesthesia,13 the analysis of Low‐Tau ELISAs at the 24 month time point showed no TBI‐dependent increase in cortical or hippocampal soluble p‐tau pSer‐202 (CP13), pThr‐231 (RZ3), and pSer‐396/404 (PHF1) ( P > 0.05) (Fig. 6D).…”

Section: Resultssupporting

confidence: 93%

“…From a neuropathological perspective, the 24‐month post injury data were consistent with our observations at earlier timepoints 13, 19. Mice exposed to repetitive injury displayed evidence of ongoing microgliosis localized to the CC.…”

Section: Discussionsupporting

confidence: 87%

“…Moreover, our interinjury interval was 48 h, which is similar to our previous work,13, 19 a temporal window during which the mouse brain is known to be vulnerable to subsequent injuries21 in order to mimic human situations (combat or sports) in which additional injuries are sustained prior to full recovery from the previous injury. At the end of the procedure, each animal was removed from the stereotaxic table and allowed to recover on a heating pad and, upon becoming ambulatory, was returned to its home cage.…”

Section: Methodsmentioning

confidence: 82%

“…APP immunoreactive axonal swellings were quantified from the caudal to the dorsal area of the body of the CC. Using ImageJ software, the average thickness of the corpus callosum was calculated as previously described 13. A total of five slides per animal were averaged for each immunohistochemical analysis.…”

Section: Methodsmentioning

confidence: 99%

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Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

Mouzon

Bachmeier

Ojo

et al. 2017

Ann Clin Transl Neurol

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ObjectiveExposure to repetitive concussion, or mild traumatic brain injury (mTBI), has been linked with increased risk of long‐term neurodegenerative changes, specifically chronic traumatic encephalopathy (CTE). To date, preclinical studies largely have focused on the immediate aftermath of mTBI, with no literature on the lifelong consequences of mTBI in these models. This study provides the first account of lifelong neurobehavioral and histological consequences of repetitive mTBI providing unique insight into the constellation of evolving and ongoing pathologies with late survival.MethodsMale C57BL/6J mice (aged 2–3 months) were exposed to either single or repetitive mild TBI or sham procedure. Thereafter, animals were monitored and assessed at 24 months post last injury for measures of motor coordination, learning deficits, cognitive function, and anxiety‐like behavior prior to euthanasia and preparation of the brains for detailed neuropathological and protein biochemical studies.ResultsAt 24 months survival animals exposed to r‐mTBI showed clear evidence of learning and working memory impairment with a lack of spatial memory and vestibule‐motor vestibulomotor deficits compared to sham animals. Associated with these late behavioral deficits there was evidence of ongoing axonal degeneration and neuroinflammation in subcortical white matter tracts. Notably, these changes were also observed after a single mTBI, albeit to a lesser degree than repetitive mTBI.InterpretationIn this context, our current data demonstrate, for the first time, that rather than an acute, time limited event, mild TBI can precipitate a lifelong degenerative process. These data therefore suggest that successful treatment strategies should consider both the acute and chronic nature of mTBI.

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Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 87%

Section: Methodsmentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

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Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

Mouzon

Bachmeier

Ojo

et al. 2017

Ann Clin Transl Neurol

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“…Several rodent models of rmCHI have been reported from two, three, five TBIs to 16 or 42 impacts at different intervals or frequencies. 23,24,[30][31][32][33][34][35][36][37] In the present study, we chose a mouse model of rmCHI with three impacts at an interval of 24 hours, as reported previously. 5,23,24 As shown in our results, our model displayed mild brain trauma with low NSS scores and the absence of intracranial hemorrhage and convulsions.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Monoacylglycerol Lipase Prevents Chronic Traumatic Encephalopathy-like Neuropathology in a Mouse Model of Repetitive Mild Closed Head Injury

Zhang

Teng

Song

et al. 2015

J Cereb Blood Flow Metab

102

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Emerging evidence suggests that the risk of developing chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease, is significantly increased in military personnel and contact sports players who have been exposed to repetitive trauma brain injury (TBI). Unfortunately there are no effective medications currently available for prevention and treatment of CTE. Here we demonstrate that inhibition of monoacylglycerol lipase (MAGL), the key enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, significantly reduced CTE-like neuropathologic changes in a mouse model of repetitive mild closed head injury (rmCHI). Inhibition of 2-AG metabolism promoted neurologic recovery following rmCHI and reduced proinflammatory cytokines, astroglial reactivity, expression of amyloid precursor protein and the enzymes that make Aβ, as well as formation of Aβ. Importantly, neurodegeneration, TDP-43 protein aggregation, and tau phosphorylation, which are the neuropathologic hallmarks of CTE, were significantly suppressed by MAGL inactivation. Furthermore, alterations in expression of glutamate receptor subunits and impairments in basal synaptic transmission, long-term synaptic plasticity, and spatial learning and memory were recovered by inhibition of 2-AG metabolism in animals exposed to rmCHI. Our results suggest that MAGL inhibition, which boosts 2-AG and reduces 2-AG metabolites prostaglandins in the brain, may lead to a new therapy for CTE.

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Peripheral Total Tau in Military Personnel Who Sustain Traumatic Brain Injuries During Deployment

et al. 2015

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IMPORTANCE Approximately one-third of military personnel who deploy for combat operations sustain 1 or more traumatic brain injuries (TBIs), which increases the risk for chronic symptoms of postconcussive disorder, posttraumatic stress disorder, and depression and for the development of chronic traumatic encephalopathy. Elevated concentrations of tau are observed in blood shortly following a TBI, but, to our knowledge, the role of tau elevations in blood in the onset and maintenance of chronic symptoms after TBI has not been investigated.OBJECTIVES To assess peripheral tau levels in military personnel exposed to TBI and to examine the relationship between chronic neurological symptoms and tau elevations. DESIGN, SETTING, AND PARTICIPANTSObservational assessment from September 2012 to August 2014 of US military personnel at the Madigan Army Medical Center who had been deployed within the previous 18 months. Plasma total tau concentrations were measured using a novel ultrasensitive single-molecule enzyme-linked immunosorbent assay. Classification of participants with and without self-reported TBI was made using the Warrior Administered Retrospective Casualty Assessment Tool. Self-reported symptoms of postconcussive disorder, posttraumatic stress disorder, and depression were determined by the Neurobehavioral Symptom Inventory, the Posttraumatic Stress Disorder Checklist Military Version, and the Quick Inventory of Depressive Symptomatology, respectively. Group differences in tau concentrations were determined through analysis of variance models, and area under the receiver operating characteristic curve determined the sensitivity and specificity of tau concentrations in predicting TBI and chronic symptoms. Seventy participants with self-reported TBI on the Warrior Administered Retrospective Casualty Assessment Tool and 28 control participants with no TBI exposure were included. MAIN OUTCOMES AND MEASURES Concentration of total tau in peripheral blood.RESULTS Concentrations of plasma tau were significantly elevated in the 70 participants with self-reported TBI compared with the 28 controls (mean [SD], 1.13 [0.78] vs 0.63 [0.48] pg/mL, respectively; F 1,97 = 4.97; P = .03). Within the self-reported TBI cases, plasma total tau concentrations were significantly associated with having a medical record of TBI compared with self-reported TBI only (mean [SD], 1.57 [0.92] vs 0.85 [0.52] pg/mL, respectively; F 1,69 = 6.15; P = .02) as well as reporting the occurrence of 3 of more TBIs during deployment compared with fewer than 3 TBIs (mean [SD], 1.52 [0.82] vs 0.82 [0.60] pg/mL, respectively; F 1,69 = 8.57; P = .008). The severity of total postconcussive symptoms correlated with total tau concentrations in the self-reported TBI group (r = 0.37; P = .003). CONCLUSIONS AND RELEVANCEMilitary personnel who report multiple TBIs have long-term elevations in total tau concentration. The total tau concentration relates to symptoms of postconcussive disorder.

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Chronic neuropathological and neurobehavioral changes in a repetitive mild traumatic brain injury model

Cited by 287 publications

References 54 publications

Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

Inhibition of Monoacylglycerol Lipase Prevents Chronic Traumatic Encephalopathy-like Neuropathology in a Mouse Model of Repetitive Mild Closed Head Injury

Peripheral Total Tau in Military Personnel Who Sustain Traumatic Brain Injuries During Deployment

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