Repetitive Brain Injury Research Articles

Abstract 2149 Cell-specific differential gene expression analysis by snRNA-seq after repetitive weaponry-type blast-induced traumatic brain injury

Abstract 2149 Cell-specific differential gene expression analysis by snRNA-seq after repetitive weaponry-type blast-induced traumatic brain injury

Dementia in football/soccer players: professional resistance to a new cause of neurodegenerative disease

Football is popular world wide, and in the U.S. the sport is known as soccer. This game consists of two teams of eleven players using a spherical ball. Dementia, a tragic progressive neurodegenerative disease has been recognised in boxing for over a century, and this paper explores its emergence in football. Heading the ball is a feature of the game, producing repetitive subconcussive brain injuries. Dementia in football/soccer only emerged at the end of the 20th century in Scotland. The author had been alerted to the issue in 1981; his observational study, including some neuropathological findings, of 14 players was eventually published in 2017. This was the first study in the world to show a link between football and the development of dementia. The difficulties of getting the results published, including the vulnerability of the brain to repetitive subconcussive injuries, are described and the resistance to the idea is explored. These include the conservative nature of the medical profession, the rigidity of Evidence Based Medicine and the role of Paul McCrory. These negative attitudes delayed the development of a more enlightened dementia management and prevention strategy in football.

Chronic traumatic encephalopathy pathology in a large population‐based study.

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease predominantly found in former athletes and associated with repetitive brain injury (TBI). Despite the increased number of studies, several questions about prevalence and risk factors for CTE in the general population remain unknown.Methodto investigate the presence of CTE pathology in a population‐based clinicopathological cohort, we analyzed brain sections immunostained with tau antibody (AT8) of 1151 individuals over 30 years of age with previous neuropathological assessment. The presence of CTE pathology was evaluated according to the current neuropathological consensus criteria. Demographic and clinical data were collected through interviews with a next‐of‐kin. All cases are from the Biobank for Aging Studies of the University of São Paulo University. Internationally accepted criteria were used to diagnose and stage the brain tissue pathologies.ResultOnly 7 cases (0.6%) met neuropathological criteria for CTE, contrasting with the high frequency of aging‐related tau astrocyte pathology (ARTAG) (50%) The mean age of death was 73.4 12.5 and only one individual were female. Presence of co‐pathologies was observed in all cases, being the most frequent comorbidity AD‐type pathology, followed by argyrophilic grain disease. Dementia was present in 43%, meanwhile 57% had some degree of neuropsychiatric symptoms (NPS). The most frequent NPS was depression, followed by anxiety. The history of sport practice was complete only for two cases. Both played soccer, however only one semi‐professionally.ConclusionThe low frequency of CTE pathology corroborate findings from other studies that CTE is not a frequent finding in population‐based samples. The overlapping between CTE and ARTAG may contribute with the misclassification of ARTAG as CTE.

Repeated mild closed head injury in neonatal rats results in sustained cognitive deficits associated with chronic microglial activation and neurodegeneration.

Abusive head trauma in infants is a consequence of multiple episodes of abuse and results in axonal injury, brain atrophy, and chronic cognitive deficits. Anesthetized 11-day-old rats, neurologically equivalent to infants, were subjected to 1 impact/day to the intact skull for 3 successive days. Repeated, but not single impact(s) resulted in spatial learning deficits (p < 0.05 compared to sham-injured animals) up to 5 weeks postinjury. In the first week following single or repetitive brain injury, axonal and neuronal degeneration, and microglial activation were observed in the cortex, white matter, thalamus, and subiculum; the extent of the histopathologic damage was significantly greater in the repetitive-injured animals compared to single-injured animals. At 40 days postinjury, loss of cortical, white matter and hippocampal tissue was evident only in the repetitive-injured animals, along with evidence of microglial activation in the white matter tracts and thalamus. Axonal injury and neurodegeneration were evident in the thalamus up to 40 days postinjury in the repetitive-injured rats. These data demonstrate that while single closed head injury in the neonate rat is associated with pathologic alterations in the acute post-traumatic period, repetitive closed head injury results in sustained behavioral and pathologic deficits reminiscent of infants with abusive head trauma.

Repetitive mild traumatic brain injury induces hippocampal neural immune signaling linked to astrocyte reactivity

AbstractBackgroundRepeated mild traumatic brain injuries (mTBIs) sustained within a “window of vulnerability” can lead to a cumulative severity of outcomes such as memory impairment, depression, and long‐term development of amyloid beta (Aβ) pathology and neurofibrillary tangles. We previously reported that acute increases in neural immune signaling within the MAPK pathway and expression of pro‐inflammatory cytokines were associated with low cerebral blood flow (CBF) and worse long‐term spatial learning and memory in a weight‐drop mouse model of repetitive mTBI. We hypothesized that an increasing number of injuries would lead to an increase in neural immune signaling, pathological markers, and glial activation in the hippocampus.MethodFemale 3xTg mice at 3‐4mo of age were subjected to 1x, 3x, or 5x weight‐drop closed head injuries (CHI) spaced once‐daily. Animals were sacrificed and brains harvested at 30min, 4h, 24h, or 1‐month after the final CHI (n = 7‐10/time point/injury group). 32 cytokines, 10 MAPK phospho‐proteins, Aβ42, Aβ40, phospho‐tau (pThr181), and total tau were measured by Luminex in hippocampal tissues. GFAP was measured by ELISA. CBF was non‐invasively measured immediately prior to sacrifice.ResultWe observed a steady increase in both total tau and phospho‐tau and a trend of increased GFAP in the hippocampus after repeated injuries. We then identified groups of cytokines and MAPK phospho‐proteins which co‐vary with either GFAP or phospho‐tau. GFAP‐associated cytokines showed a rapid acute increase after injury then a return to basal levels by 24h, while GFAP‐associated MAPK dynamics changed with repeated injury. Cytokines and MAPK phospho‐proteins showed a notably high degree of cross‐correlation 4h after repeated injury, when GFAP levels were at their highest. Multivariate analysis revealed that high levels of GFAP were associated with low CBF while increased phospho‐tau in the frontal cortex was associated with high CBF.ConclusionTogether, our data indicate an increase in hippocampal neural immune signaling and astrocyte reactivity after repetitive brain injury. Immune signaling changes may be causally linked to spatial learning and memory deficits after repetitive mTBI.

Repetitive mild traumatic brain injuries in children of abuse

Repetitive mild traumatic brain injuries in children of abuse

PRMT7 can prevent neurovascular uncoupling, blood-brain barrier permeability, and mitochondrial dysfunction in repetitive and mild traumatic brain injury

Mild traumatic brain injury (TBI) comprises the largest percentage of TBI-related injuries, with pathophysiological and functional deficits that persist in a subset of TBI patients. In our three-hit paradigm of repetitive and mild traumatic brain injury (rmTBI), we observed neurovascular uncoupling via decreased red blood cell velocity, microvessel diameter, and leukocyte rolling velocity 3 days post-rmTBI via intra-vital two-photon laser scanning microscopy. Furthermore, our data suggest increased blood-brain barrier (BBB) permeability (leakage), with corresponding decrease in junctional protein expression post-rmTBI. Mitochondrial oxygen consumption rates (measured via Seahorse XFe24) were also altered 3 days post-rmTBI, along with disrupted mitochondrial dynamics of fission and fusion. Overall, these pathophysiological findings correlated with decreased protein arginine methyltransferase 7 (PRMT7) protein levels and activity post-rmTBI. Here, we increased PRMT7 levels in vivo to assess the role of the neurovasculature and mitochondria post-rmTBI. In vivo overexpression of PRMT7 using a neuronal specific AAV vector led to restoration of neurovascular coupling, prevented BBB leakage, and promoted mitochondrial respiration, altogether to suggest a protective and functional role of PRMT7 in rmTBI.

A role for protein arginine methyltransferase 7 in repetitive and mild traumatic brain injury

Mild traumatic brain injury affects the largest proportion of individuals in the United States and world-wide. Pre-clinical studies of repetitive and mild traumatic brain injury (rmTBI) have been limited in their ability to recapitulate human pathology (i.e. diffuse rotational injury). We used the closed-head impact model of engineered rotation acceleration (CHIMERA) to simulate rotational injury observed in patients and to study the pathological outcomes post-rmTBI using C57BL/6J mice. Enhanced cytokine production was observed in both the cortex and hippocampus to suggest neuroinflammation. Furthermore, microglia were assessed via enhanced iba1 protein levels and morphological changes using immunofluorescence. In addition, LC/MS analyses revealed excess glutamate production, as well as diffuse axonal injury via Bielschowsky's silver stain kit. Moreover, the heterogeneous nature of rmTBI has made it challenging to identify drug therapies that address rmTBI, therefore we sought to identify novel targets in the concurrent rmTBI pathology. The pathophysiological findings correlated with a time-dependent decrease in protein arginine methyltransferase 7 (PRMT7) protein expression and activity post-rmTBI along with dysregulation of PRMT upstream mediators s-adenosylmethionine and methionine adenosyltransferase 2 (MAT2) in vivo. In addition, inhibition of the upstream mediator MAT2A using the HT22 hippocampal neuronal cell line suggest a mechanistic role for PRMT7 via MAT2A in vitro. Collectively, we have identified PRMT7 as a novel target in rmTBI pathology in vivo and a mechanistic link between PRMT7 and upstream mediator MAT2A in vitro.

Effects of Vitamin D and Memantine on Repetitive Mild Traumatic Brain Injury via mTOR, TRPM2, and GABA Expression Levels on Juvenile Rats.

To investigate the effects of vitamin D and memantine on the healing process in juvenile rats with repetitive brain injury (rTBI) and to elucidate the mechanisms underlying these potential therapeutic effects. Juvenile rats were randomly allocated into seven groups, with eight rats per group: sham-operated (Group I), trauma (Group II), memantine supplementation (10 mg/kg) pre-trauma (Group III), vitamin D supplementation (5 µg/kg) pre-trauma (Group IV), vitamin D supplementation post-trauma (Group V), memantine and vitamin D supplementation post-trauma (Group VI), and vitamin D supplementation pre- and post-trauma with post-trauma memantine supplementation (Group VII). A modified repeated weight drop model was employed to induce rTBI. Brain tissues and blood samples were collected for analysis. Expressions of the mammalian target of rapamycin (mTOR), temporary receptor potential (TRPM2), and GABA receptors were assessed via immunohistochemistry. Levels of 8-hydroxy-2-deoxyguanine (8-OHdG) were determined using high-performance liquid chromatography (HPLC). Matrix metalloproteinases -2 and -9, tissue inhibitors of metalloproteinases-1 and-2, and NADPH oxidation-4 levels were determined using commercially available enzyme-linked immunosorbent Test kits. Immunohistochemistry analyses were performed on the brain cortex and hippocampus. The levels of 8OHdG/106dG, MMP-2, MMP-9, TIMP-1, -TIMP2, and NOX-4 were significantly higher in the trauma group than in the other groups. No difference was found between the control and Pre Vit D+Mem+Post Vit D groups regarding 8OHdG/106dG, MMP-2, -9 and NOX-4 levels. Normalized expressions of mTOR and TRPM2 were observed in Groups VI and VII. Conversely, GABA expression levels decreased in Group II, with the most pronounced therapeutic effects observed in Group VII. Memantine and vitamin D positively affected rTBI when used alone. Their combined use exhibited greater therapeutic outcomes. These effects are mediated by mTOR mRNA, TRPM2 mRNA, and GABA mRNA expressions.

The pathological progression of repetitive and mild traumatic brain injury in mice

Traumatic brain injury (TBI) is defined as an impact to the head by an external force that causes brain alterations and subsequent long‐term functional deficits. TBI contributes to an economic burden of $17 billion USD annually and is a leading cause of death and disability for individuals under 45. The severity of TBI varies from mild to severe with repetitive and mild (rm) TBI, and accounts for the highest percentage of TBI‐cases, leading to long‐term cognitive impairment. There are no current treatment(s) for repetitive and mild TBI, therefore, we sought to identify novel signaling molecules/pathways that could contribute to TBI.We employed a clinically relevant (non‐surgical) closed‐head impact model of engineered rotational acceleration (CHIMERA) that allows free rotation of the head upon impact generated from an air‐compressed piston. Our data suggest a novel role for PRMT7 (protein arginine methyltransferases) in the disease progression as indicated by the temporal decrease in protein expression post‐rmTBI. Our central hypothesis is that the loss of PRMT7, due to repetitive and mild TBI, mediates excitotoxicity, increased cellular death, disturbed mitochondrial dynamics and contributes to behavioral deficits. PRMTs are novel targets that catalyze the methylation of arginine residues (a constitutive post‐translational modification) involved in transcription, translation, receptor trafficking, and protein stability. There are currently 11 known PRMT isoforms (PRMT1‐11), with PRMT7 gene deletion in human patients causing neurological deficits such as intellectual disability, microcephaly, and brachydactyly, along with hyperexcitability and impaired social behaviors in murine in vivo models.We assessed diffuse axonal injury in our model of mild and repetitive TBI (via CHIMERA) to suggest enhanced silver deposition (dark stained regions) throughout the brain, similar to human pathology. Next, we measured PRMT7 protein levels that were decreased in the cortex and hippocampus 7‐days post‐rmTBI. Relative PRMT7 mRNA (via real‐time qPCR) was enhanced in the cortex 1‐day post‐rmTBI. Using LC‐MS, we measured excitatory neurotransmitters to suggest that glutamate was enhanced in the hippocampus 3‐day post‐rmTBI. In addition, mitochondrial fission and fusion was assessed by measuring DRP1 and OPA1 and our results indicated increased polarization towards fission as indicated by significant increase of DRP1 protein expression 1,3,7 days post rmTBI. Furthermore, mitochondrial oxygen consumption rates were analyzed via Seahorse XF analyzer and indicated dynamic changes in ATP‐linked respiration and maximal respiration 1 and 3 days post‐rmTBI. Finally, learning, working memory, and locomotor skills were significantly impaired as indicated by decreased alternation ratios via T‐maze, novel object recognition, and rotarod assessment. Overall, our results suggest that PRMT7 can mediate neuronal hyperexcitability, altered mitochondrial dynamics and can affect functional outcomes post‐rmTBI.

Study on the Cumulative Effect of Acute Repetitive Traumatic Brain Injury: An Experimental Animal Research

&lt;div class="section abstract"&gt;&lt;div class="htmlview paragraph"&gt;Acute repetitive traumatic brain injury (rTBI) can occur in a pedestrian collision when the head hits the vehicle and the ground twice, as well as in a serial rear-ended collision in a very short period. This study established an animal model of acute rTBI to investigate the cumulative effects of repetitive brain injury under different combinations of impact levels. 117 adult male Sprague–Dawley (SD) rats (190±20g) were divided into control, single impact, and repeated impact groups, with the single impact group was divided into three subgroups of mild, moderate, and severe. And the repeated impact group was divided into nine subgroups by combining mild, moderate, and severe. The kinematic response parameters of the rat’s head were captured by a high-speed camera and acceleration sensors. Modified neurological severity score (mNSS) was performed at 6h after final injury, and the severity of injury was quantified using the abbreviated injury scale (AIS). The results showed that cumulative effects of rTBI were not simply linearly superimposed and there was a clear threshold of injury. As a conclusion, an animal model of acute rTBI was successfully established, and the cumulative effects of acute rTBI were preliminarily discussed, which can provide a reference for the biomechanical mechanism and protection of brain injury in road traffic accidents.&lt;/div&gt;&lt;/div&gt;

The neurological risks of playing association football.

SummaryAims:The present study aims to provide a narrative review of the literature surrounding concussion and head injury in football and its clarity in evaluating the risk of long-term neurological disease.Findings:Epidemiological studies have shown correlations between participation in professional football and increased incidence of neurodegenerative disease and there have been reports of chronic traumatic encephalopathy (CTE) in the brains of former players in autopsy. These findings have been assumed by some to be the result of repetitive brain injury from head injuries and/or from heading the ball over a player's career. Data linking increased heading exposure with dementia is conflicting, and studies are limited by the reliance on retrospection and undocumented reports of concussion. It remains unclear whether CTE is unique to sportsmen or a variant of dementia pathology endemic in the population.Conclusions:Although logically appealing, there is no current evidence that heading is the cause of neurodegeneration amongst footballers and risks should be balanced by the protective mental and physical benefits of the sport. Physicians have an important role in providing balanced views in this emotive and controversial area.

Severe Suicidality in Athletes with Chronic Traumatic Encephalopathy: A Case Series and Overview on Putative Ethiopathogenetic Mechanisms

Chronic traumatic encephalopathy (CTE) results from repetitive brain injuries and is a common neurotraumatic sequela in contact sports. CTE is often accompanied by neuropsychiatric symptoms, which could escalate to suicidal ideation (SI) and suicidal behaviour (SB). Nevertheless, fairly limited emphasis about the association between suicidality and CTE exists in medical literature. Here, we report two cases of retired professional athletes in high contact sports (boxing and ice hockey) who have developed similar clinical trajectories characterized by progressive neuropsychiatric symptoms compatible with a CTE diagnosis and subsequent SB in its severe forms (medical serious suicide attempt (SA) and completed suicide). In addition to the description of outlining clinical, neuropsychological, neuroimaging, and differential diagnosis elements related to these cases, we also hypothesized some mechanisms that might augment the suicide risk in CTE. They include those related to neurobiological (neuroanatomic/neuroinflammatory) dysfunctions as well as those pertaining to psychiatry and psychosocial maladaptation to neurotraumas and retirement from professional competitive activity. Findings described here can provide clinical pictures to improve the identification of patients with CTE and also potential mechanistic insights to refine the knowledge of eventual severe SB development, which might enable its earlier prevention.

Enrichment of Phosphorylated Tau (Thr181) and Functionally Interacting Molecules in Chronic Traumatic Encephalopathy Brain-derived Extracellular Vesicles.

Chronic Traumatic Encephalopathy (CTE) is a tauopathy that affects individuals with a history of mild repetitive brain injury. The initial neuropathologic changes of CTE include perivascular deposition of phosphorylated microtubule-associated protein tau (p-tau). Extracellular vesicles (EVs) are known to carry pathogenic molecules, such as tau in Alzheimer’s disease and CTE suggesting their contribution in pathogenesis. We therefore examined the protein composition of EVs separated from CTE and an age-matched control brain tissues by tandem mass tag -mass spectrometry. The reporter ion intensity was used to quantify the identified molecules. A total of 516 common proteins were identified among three sets of experiments. Weighted protein co-expression network analysis identified 18 unique modules of co-expressed proteins. Two modules were significantly correlated with total tau (t-tau) and p-tau protein in the isolated EVs and enriched in cellular components and biological processes for synaptic vesicle secretion and multivesicular body-plasma membrane fusion. The p-tau (Thr181) level is significantly higher in CTE EVs compared to control EVs and can distinguish the two groups with 73.6% accuracy. A combination of t-tau or p-tau (Thr181) with SNAP-25, PLXNA4 or UBA1, enhanced the accuracy to 96.3, 93.8 and 93.8%, respectively. Bioinformatic protein-protein interaction analysis revealed the functional interaction of SNAP-25 and PLXNA4 with tau, suggesting their interaction in CTE EVs. These data indicate the future application of identified EV proteins for monitoring the CTE risk assessments and understanding the EV-mediated disease progression mechanism.

Top Ten Reasons Why All Athletes Need to have Neuropsychological Testing

Currently, we are more and more aware of head injuries, concussion and the risks and dangers of athletes being exposed to long term risk and injury.Twenty years or so ago, coaches relied on side line assessment to decide as to whether an athlete who“has had his/her bells rung” should return to play. Currently however, there is much more sophisticated sideline assessment (such as Impact) and other laptop instruments. There are many, many reasons why athletes should undergo pre-and post-test assessment as well as sideline assessment. These will be summarily discussed. These issues have also been discussed by:Arginteanu (2019) and others have clearly specified the need to be concerned and observant regardingthe concept of return to play and even return to the classroom. Hernandez, Giordano, Goubran, Parivash, Grant, Zeineh and Camarillo (2019) have discussed sports related concussions and Corman, Adame, Tsa, Ruston, Beaumont, Kamrath, Liu, Posteher, Tremblayand van Raalt, (2019) have published on sports related concussions. Rose, Yeates, Nguyen, McCarthy, Ercole, Pizzimenti, (2019)have written on youth tackle football. Engleman (2013) writing in The Rotarian pp 27-30 suggests that “youth football leagues should require coaches and encourage all parents, to take the “Heads IUP” training course available at www.cdc.gov. The web site of the U.S. Centers for Disease Control and Prevention” There is much concern about CTE (Chronic traumatic encephalopathy- which is a progressive degenerative disease of the brain. This is usually discerned in individuals who have some type of history of repetitive brain trauma or injury. This could include soccer, basketball, baseball, softball (at least many players DO wear helmets) and wrestling (in terms of wrestling, players do wear protective devices for their ears, but still may suffer concussions and head injuries. Shaughnessy and Laman (2012) have provided an excellent review of evidence based intervention and treatment/rehabilitation of traumatic brain injury. This was published in the Research Journal in Organizational Psychology and Educational Studies and is a serious review of the literature in this realm.

Sex differences in cued fear responses and parvalbumin cell density in the hippocampus following repetitive concussive brain injuries in C57BL/6J mice.

There is strong evidence to suggest a link between repeated head trauma and cognitive and emotional disorders, and Repetitive concussive brain injuries (rCBI) may also be a risk factor for depression and anxiety disorders. Animal models of brain injury afford the opportunity for controlled study of the effects of injury on functional outcomes. In this study, male and cycling female C57BL/6J mice sustained rCBI (3x) at 24-hr intervals and were tested in a context and cued fear conditioning paradigm, open field (OF), elevated zero maze and tail suspension test. All mice with rCBI showed less freezing behavior than sham control mice during the fear conditioning context test. Injured male, but not female mice also froze less in response to the auditory cue (tone). Injured mice were hyperactive in an OF environment and spent more time in the open quadrants of the elevated zero maze, suggesting decreased anxiety, but there were no differences between injured mice and sham-controls in depressive-like activity on the tail suspension test. Pathologically, injured mice showed increased astrogliosis in the injured cortex and white matter tracts (optic tracts and corpus callosum). There were no changes in the number of parvalbumin-positive interneurons in the cortex or amygdala, but injured male mice had fewer parvalbumin-positive neurons in the hippocampus. Parvalbumin-reactive interneurons of the hippocampus have been previously demonstrated to be involved in hippocampal-cortical interactions required for memory consolidation, and it is possible memory changes in the fear-conditioning paradigm following rCBI are the result of more subtle imbalances in excitation and inhibition both within the amygdala and hippocampus, and between more widespread brain regions that are injured following a diffuse brain injury.

A Novel and Translational Rat Model of Concussion Combining Force and Rotation with In Vivo Cerebral Microdialysis.

Persistent cognitive and motor symptoms are known consequences of concussions/mild traumatic brain injury (mTBIs) that can be partly attributable to altered neurotransmission. Indeed, cerebral microdialysis studies in rodents have demonstrated an excessive extracellular glutamate release in the hippocampus within the first 10 min following trauma. Microdialysis offers the clear advantage of in vivo neurotransmitter continuous sampling while not having to sacrifice the animal. In addition to the aforementioned technique, a closed head injury model that exerts rapid acceleration and deceleration of the head and torso is needed, as such a factor is not available in many other animal models. The Wayne State weight-drop model mimics this essential component of human craniocerebral trauma, allowing the induction of an impact on the head of an unrestrained rodent with a falling weight. Our novel and translational rat model combines cerebral microdialysis with the Wayne State weight-drop model to study, in lightly anesthetized and unrestrained adult rats, the acute changes in extracellular neurotransmitter levels following concussion. In this protocol, the microdialysis probe was inserted inside the hippocampus as region of interest, and was left inserted in the brain at impact. There is a high density of terminals and receptors in the hippocampus, making it a relevant region to document altered neurotransmission following concussion. When applied to adult Sprague-Dawley rats, our combined model induced increases in hippocampal extracellular glutamate concentrations within the first 10 min, consistent with the previously reported post-concussion symptomology. This combined weight-drop model provides a reliable tool for researchers to study early therapeutic responses to concussions in addition to repetitive brain injury, since this protocol induces a closed-head mild trauma.

Traumatic Brain Injury-related voiding dysfunction in mice is caused by damage to rostral pathways, altering inputs to the reflex pathways

Brain degeneration, including that caused by traumatic brain injury (TBI) often leads to severe bladder dysfunction, including incontinence and lower urinary tract symptoms; with the causes remaining unknown. Male C57BL/6J mice underwent repetitive moderate brain injury (rmdTBI) or sham injury, then mice received either cis P-tau monoclonal antibody (cis mAb), which prevents brain degeneration in TBI mice, or control (IgG). Void spot assays revealed age-dependent incontinence in IgG controls 8 months after injury, while cis mAb treated or sham mice showed no dysfunction. No obvious bladder pathology occurred in any group. Urodynamic cystometry in conscious mice revealed overactive bladder, reduced maximal voiding pressures and incontinence in IgG control, but not sham or cis mAb treated mice. Hyperphosphorylated tau deposition and neural tangle-like pathology occurred in cortical and hippocampal regions only of IgG control mice accompanied with post-traumatic neuroinflammation and was not seen in midbrain and hindbrain regions associated with bladder filling and voiding reflex arcs. In this model of brain degeneration bladder dysfunction results from rostral, and not hindbrain damage, indicating that rostral brain inputs are required for normal bladder functioning. Detailed analysis of the functioning of neural circuits controlling bladder function in TBI should lead to insights into how brain degeneration leads to bladder dysfunction, as well as novel strategies to treat these disorders.

Definition, Quantification, and Utility of Biomarkers of Repetitive Brain Injury in Predicting Concussion and Other Long-Term Injury Risks in Patients With Atrial Fibrillation (Concussion AF)

Definition, Quantification, and Utility of Biomarkers of Repetitive Brain Injury in Predicting Concussion and Other Long-Term Injury Risks in Patients With Atrial Fibrillation (Concussion AF)

Repetitive Concussive and Subconcussive Injury in a Human Tau Mouse Model Results in Chronic Cognitive Dysfunction and Disruption of White Matter Tracts, But Not Tau Pathology.

Due to the unmet need for a means to study chronic traumatic encephalopathy (CTE) in vivo, there have been numerous efforts to develop an animal model of this progressive tauopathy. However, there is currently no consensus in the field on an injury model that consistently reproduces the neuropathological and behavioral features of CTE. We have implemented a repetitive Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) injury paradigm in human transgenic (hTau) mice. Animals were subjected to daily subconcussive or concussive injuries for 20 days and tested acutely, 3 months, and 12 months post-injury for deficits in social behavior, anxiety, spatial learning and memory, and depressive behavior. Animals also were assessed for chronic tau pathology, astrogliosis, and white matter degeneration. Repetitive concussive injury caused acute deficits in Morris water maze performance, including reduced swimming speed and increased distance to the platform during visible and hidden platform phases that persisted during the subacute and chronic time-points following injury. We found evidence of white matter disruption in animals injured with subconcussive and concussive injuries, with the most severe disruption occurring in the repetitive concussive injury group. Severity of white matter disruption in the corpus callosum was moderately correlated with swimming speed, while white matter disruption in the fimbria showed weak but significant correlation with worse performance during probe trial. There was no evidence of tau pathology or astrogliosis in sham or injured animals. In summary, we show that repetitive brain injury produces persistent behavioral abnormalities as late as 1 year post-injury that may be related to chronic white matter disruption, although the relationship with CTE remains to be determined.