Repetitive Concussive Brain Injury Research Articles

Early Blood-Brain Barrier Impairment as a Pathological Hallmark in a Novel Model of Closed-Head Concussive Brain Injury (CBI) in Mice.

Concussion, caused by a rotational acceleration/deceleration injury mild enough to avoid structural brain damage, is insufficiently captured in recent preclinical models, hampering the relation of pathophysiological findings on the cellular level to functional and behavioral deficits. We here describe a novel model of unrestrained, single vs. repetitive concussive brain injury (CBI) in male C56Bl/6j mice. Longitudinal behavioral assessments were conducted for up to seven days afterward, alongside the evaluation of structural cerebral integrity by in vivo magnetic resonance imaging (MRI, 9.4 T), and validated ex vivo by histology. Blood-brain barrier (BBB) integrity was analyzed by means of fluorescent dextran- as well as immunoglobulin G (IgG) extravasation, and neuroinflammatory processes were characterized both in vivo by positron emission tomography (PET) using [18F]DPA-714 and ex vivo using immunohistochemistry. While a single CBI resulted in a defined, subacute neuropsychiatric phenotype, longitudinal cognitive testing revealed a marked decrease in spatial cognition, most pronounced in mice subjected to CBI at high frequency (every 48 h). Functional deficits were correlated to a parallel disruption of the BBB, (R2 = 0.29, p < 0.01), even detectable by a significant increase in hippocampal uptake of [18F]DPA-714, which was not due to activation of microglia, as confirmed immunohistochemically. Featuring a mild but widespread disruption of the BBB without evidence of macroscopic damage, this model induces a characteristic neuro-psychiatric phenotype that correlates to the degree of BBB disruption. Based on these findings, the BBB may function as both a biomarker of CBI severity and as a potential treatment target to improve recovery from concussion.

Chronic Neurobehavioral Sex Differences in a Murine Model of Repetitive Concussive Brain Injury.

Traumatic brain injury (TBI) resulting from repeated head trauma is frequently characterized by diffuse axonal injury and long-term motor, cognitive and neuropsychiatric symptoms. Given the delay, often decades, between repeated head traumas and the presentation of symptoms in TBI patients, animal models of repeated injuries should be studied longitudinally to properly assess the longer-term effects of multiple concussive injuries on functional outcomes. In this study, male and cycling female C57BL/6J mice underwent repeated (three) concussive brain injuries (rCBI) delivered via a Leica ImpactOne cortical impact device and were assessed chronically on motor (open field and rotarod), cognitive (y-maze and active place avoidance), and neuropsychiatric (marble-burying, elevated zero maze and tail suspension) tests. Motor deficits were significant on the rotarod on the day following the injuries, and slight impairment remained for up to 6 months. All mice that sustained rCBI had significant cognitive deficits on the active place avoidance test and showed greater agitation (less immobility) in the tail suspension test. Only injured male mice were significantly hyperactive in the open field, and had increased time spent in the open quadrants of the elevated zero maze. One year after the injuries, mice of both sexes exhibited persistent pathological changes by the presence of Prussian blue staining (indication of prior microbleeds), primarily in the cortex at the site of the injury, and increased GFAP staining in the perilesional cortex and axonal tracts (corpus callosum and optic tracts). These data demonstrate that a pathological phenotype with motor, cognitive, and neuropsychiatric symptoms can be observed in an animal model of rCBI for at least one year post-injury, providing a pre-clinical setting for the study of the link between multiple brain injuries and neurodegenerative disorders. Furthermore, this is the first study to include both sexes in a pre-clinical long-term rCBI model, and female mice are less impaired functionally than males.

Cognitive performance of male and female C57BL/6J mice after repetitive concussive brain injuries

In contact sports, repetitive concussive brain injury (rCBI) is the prevalent form of head injury seen in athletes. The need for effective treatment is urgent as rCBI has been associated with a host of cognitive, behavioral and neurological complaints. There has been a growing trend in the use of female animals in pre-clinical research, but few studies have investigated possible sex differences following rCBI. The goal of the current study was to determine any differences between male and female C57BL/6J mice on assessments of learning and memory after repetitive concussive injury. Following rCBI by impact to the scalp, male mice exhibited longer righting reflexes during acute recovery. In both sexes, there were no evident histopathological changes observed in the underlying cerebral cortex or hippocampus. Reactive astrogliosis was elevated in the corpus callosum and optic tract, and astrogliosis was slightly less in the optic tract of female mice. rCBI mice exhibited impairment during the learning phase of the Morris water maze (MWM), but female mice, in comparison to male mice, were observed to have superior spatial memory during standard MWM probe trials. Female mice were overall more active, evidenced by greater distances traveled in the y-maze and greater swim speeds in the MWM. The results of this study demonstrate sex differences in cognitive performance following rCBI and support previous research suggesting the neuroprotective role of sex in brain injury.

Chronic Traumatic Encephalopathy in a National Football League Player

We present the results of the autopsy of a retired professional football player that revealed neuropathological changes consistent with long-term repetitive concussive brain injury. This case draws attention to the need for further studies in the cohort of retired National Football League players to elucidate the neuropathological sequelae of repeated mild traumatic brain injury in professional football. The patient's premortem medical history included symptoms of cognitive impairment, a mood disorder, and parkinsonian symptoms. There was no family history of Alzheimer's disease or any other head trauma outside football. A complete autopsy with a comprehensive neuropathological examination was performed on the retired National Football League player approximately 12 years after retirement. He died suddenly as a result of coronary atherosclerotic disease. Studies included determination of apolipoprotein E genotype. Autopsy confirmed the presence of coronary atherosclerotic disease with dilated cardiomyopathy. The brain demonstrated no cortical atrophy, cortical contusion, hemorrhage, or infarcts. The substantia nigra revealed mild pallor with mild dropout of pigmented neurons. There was mild neuronal dropout in the frontal, parietal, and temporal neocortex. Chronic traumatic encephalopathy was evident with many diffuse amyloid plaques as well as sparse neurofibrillary tangles and tau-positive neuritic threads in neocortical areas. There were no neurofibrillary tangles or neuropil threads in the hippocampus or entorhinal cortex. Lewy bodies were absent. The apolipoprotein E genotype was E3/E3. This case highlights potential long-term neurodegenerative outcomes in retired professional National Football League players subjected to repeated mild traumatic brain injury. The prevalence and pathoetiological mechanisms of these possible adverse long-term outcomes and their relation to duration of years of playing football have not been sufficiently studied. We recommend comprehensive clinical and forensic approaches to understand and further elucidate this emergent professional sport hazard.

Temporal Window of Vulnerability to Repetitive Experimental Concussive Brain Injury

Repetitive concussive brain injury (CBI) is associated with cognitive alterations and increased risk of neurodegenerative disease. To evaluate the temporal window during which the concussed brain remains vulnerable to a second concussion, anesthetized mice were subjected to either sham injury or single or repetitive CBI (either 3, 5, or 7 days apart) using a clinically relevant model of CBI. Cognitive, vestibular, and sensorimotor function (balance and coordination) were evaluated, and postmortem histological analyses were performed to detect neuronal degeneration, cytoskeletal proteolysis, and axonal injury. No cognitive deficits were observed in sham-injured animals or those concussed once. Mice subjected to a second concussion within 3 or 5 days exhibited significantly impaired cognitive function compared with either sham-injured animals (P < 0.05) or mice receiving a single concussion (P < 0.01). No cognitive deficits were observed when the interconcussion interval was extended to 7 days, suggestive of a transient vulnerability of the brain during the first 5 days after an initial concussion. Although all concussed mice showed transient motor deficits, vestibulomotor dysfunction was more pronounced in the group that sustained two concussions 3 days apart (P < 0.01 compared with all other groups). Although scattered degenerating neurons, evidence of cytoskeletal damage, and axonal injury were detected in selective brain regions between 72 hours and 1 week after injury in all animals sustaining a single concussion, the occurrence of a second concussion 3 days later resulted in significantly greater traumatic axonal injury (P < 0.05) than that resulting from a single CBI. These data suggest that a single concussion is associated with behavioral dysfunction and subcellular alterations that may contribute to a transiently vulnerable state during which a second concussion within 3 to 5 days can lead to exacerbated and more prolonged axonal damage and greater behavioral dysfunction.

Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury

The authors wish to make a correction to the article entitled ‘Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury’ published in J. Neurochem.90, pp. 758–764. The description of the sham-operated animals is not correct. The sham animals described in the cited paper were part of a previously published paper (Uryu et al., J. Neurosci.22, pp. 446–454). The last sentence of the section Animals and Surgical Procedure should have been: ‘The data for sham-treated animals was taken from those published in J. Neurosci.22, pp. 446–454, with permission of the Society for Neuroscience.’ The authors apologize for the mistake and the inconvenience that it has created.