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Blood biomarkers are an emerging diagnostic and prognostic tool that reflect a range of neuropathological processes following traumatic brain injury (TBI). Their effectiveness in identifying long-term neuropathological processes after TBI is unclear. Studying biomarkers in the chronic phase is vital because elevated levels in TBI might result from distinct neuropathological mechanisms during acute and chronic phases. Here, we examine plasma biomarkers in the chronic period following TBI and their association with amyloid and tau PET, white matter microarchitecture, brain age and cognition. We recruited participants ≥40 years of age who had suffered a single moderate-severe TBI ≥10 years previously between January 2018 and March 2021. We measured plasma biomarkers using single molecule array technology [ubiquitin C-terminal hydrolase L1 (UCH-L1), neurofilament light (NfL), tau, glial fibrillary acidic protein (GFAP) and phosphorylated tau (P-tau181)]; PET tracers to measure amyloid-β (18F-NAV4694) and tau neurofibrillary tangles (18F-MK6240); MRI to assess white matter microstructure and brain age; and the Rey Auditory Verbal Learning Test to measure verbal-episodic memory. A total of 90 post-TBI participants (73% male; mean = 58.2 years) were recruited on average 22 years (range = 10-33 years) post-injury, and 32 non-TBI control participants (66% male; mean = 57.9 years) were recruited. Plasma UCH-L1 levels were 67% higher {exp(b) = 1.67, P = 0.018, adjusted P = 0.044, 95% confidence interval (CI) [10% to 155%], area under the curve = 0.616} and P-tau181 were 27% higher {exp(b) = 1.24, P = 0.011, adjusted P = 0.044, 95% CI [5% to 46%], area under the curve = 0.632} in TBI participants compared with controls. Amyloid and tau PET were not elevated in TBI participants. Higher concentrations of plasma P-tau181, UCH-L1, GFAP and NfL were significantly associated with worse white matter microstructure but not brain age in TBI participants. For TBI participants, poorer verbal-episodic memory was associated with higher concentration of P-tau181 {short delay: b = -2.17, SE = 1.06, P = 0.043, 95% CI [-4.28, -0.07]; long delay: bP-tau = -2.56, SE = 1.08, P = 0.020, 95% CI [-4.71, -0.41]}, tau {immediate memory: bTau = -6.22, SE = 2.47, P = 0.014, 95% CI [-11.14, -1.30]} and UCH-L1 {immediate memory: bUCH-L1 = -2.14, SE = 1.07, P = 0.048, 95% CI [-4.26, -0.01]}, but was not associated with functional outcome. Elevated plasma markers related to neuronal damage and accumulation of phosphorylated tau suggest the presence of ongoing neuropathology in the chronic phase following a single moderate-severe TBI. Plasma biomarkers were associated with measures of microstructural brain disruption on MRI and disordered cognition, further highlighting their utility as potential objective tools to monitor evolving neuropathology post-TBI., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Traumatic brain injury is a common health problem affecting millions of people each year. BDNF has been investigated in the context of traumatic brain injury due to its crucial role in maintaining brain homeostasis. Val66Met is a functional single-nucleotide polymorphism that results in a valine-to-methionine amino acid substitution at codon 66 in the BDNF prodomain, which ultimately reduces secretion of BDNF. Here, we review experimental animal models as well as clinical studies investigating the role of the Val66Met single-nucleotide polymorphism in traumatic brain injury outcomes, including cognitive function, motor function, neuropsychiatric symptoms, and nociception. We also review studies investigating the role of BDNF on traumatic brain injury pathophysiology as well as circulating BDNF as a biomarker of traumatic brain injury., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Traumatic brain injury (TBI) is a key contributor to global morbidity that lacks effective treatments. Microbial infections are common in TBI patients, and their presence could modify the physiological response to TBI. It is estimated that one-third of the human population is incurably infected with the feline-borne parasite, Toxoplasma gondii, which can invade the central nervous system and result in chronic low-grade neuroinflammation, oxidative stress, and excitotoxicity-all of which are also important pathophysiological processes in TBI. Considering the large number of TBI patients that have a pre-existing T. gondii infection prior to injury, and the potential mechanistic synergies between the conditions, this study investigated how a pre-existing T. gondii infection modified TBI outcomes across acute, sub-acute and chronic recovery in male and female mice. Gene expression analysis of brain tissue found that neuroinflammation and immune cell markers were amplified in the combined T. gondii + TBI setting in both males and females as early as 2-h post-injury. Glutamatergic, neurotoxic, and oxidative stress markers were altered in a sex-specific manner in T. gondii + TBI mice. Structural MRI found that male, but not female, T. gondii + TBI mice had a significantly larger lesion size compared to their uninfected counterparts at 18-weeks post-injury. Similarly, diffusion MRI revealed that T. gondii + TBI mice had exacerbated white matter tract abnormalities, particularly in male mice. These novel findings indicate that a pre-existing T. gondii infection affects the pathophysiological aftermath of TBI in a sex-dependent manner, and may be an important modifier to consider in the care and prognostication of TBI patients., (© 2024. The Author(s).)

Background and Objectives: Blood biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) have recently been Food and Drug Administration approved as predictors of intracranial lesions on CT after mild traumatic brain injury (mTBI). However, most cases with mTBI are CT negative, and no biomarkers are approved to assist diagnosis in these individuals. In this study, we aimed to determine the optimal combination of blood biomarkers to assist mTBI diagnosis in otherwise healthy adults younger than 50 years presenting to an emergency department within 6 hours of injury. To further understand the utility of biomarkers, we assessed how biological sex, presence or absence of loss of consciousness and/or post-traumatic amnesia (LOC/PTA), and delayed presentation affected classification performance., Methods: Blood samples, symptom questionnaires, and cognitive tests were prospectively conducted for participants with mTBI recruited from The Alfred Hospital Level 1 Emergency & Trauma Center and uninjured controls. Follow-up testing was conducted at 7 days. Simoa quantified plasma GFAP, UCH-L1, tau, neurofilament light chain (NfL), interleukin (IL)-6, and IL-1β. Area under the receiver operating characteristic (AUC) analysis assessed classification accuracy for diagnosed mTBI, and logistic regression models identified optimal biomarker combinations., Results: Plasma IL-6 (AUC 0.91, 95% CI 0.86-0.96), GFAP (AUC 0.85, 95% CI 0.78-0.93), and UCH-L1 (AUC 0.79, 95% CI 0.70-0.88) best differentiated mTBI (n = 74) from controls (n = 44) acutely (<6 hours), with NfL (AUC 0.81, 95% CI 0.72-0.90) the only marker to have such utility subacutely (7 days). Biomarker performance was similar between sexes and for participants with and without LOC/PTA, with the exception at 7 days, where GFAP and IL-6 retained some utility in female participants (GFAP: AUC 0.71, 95% CI 0.55-0.88; IL-6: AUC 0.71, 95% CI 0.55-0.87) and in those with LOC/PTA (GFAP: AUC 0.73, 95% CI 0.59-0.86; IL-6: AUC 0.71, 95% CI 0.57-0.84). Acute IL-6 ( R 2 = 0.50, 95% CI 0.34-0.64) outperformed GFAP and UCH-L1 combined ( R 2 = 0.35, 95% CI 0.17-0.50), with the best acute model featuring GFAP and IL-6 ( R 2 = 0.54, 95% CI 0.34-0.68)., Discussion: These findings indicate that adding IL-6 to a panel of brain-specific proteins such as GFAP and UCH-L1 might assist in the acute diagnosis of mTBI in adults younger than 50 years. Multiple markers had high classification accuracy in participants without LOC/PTA. When compared with the best-performing acute markers, subacute measures of plasma NfL resulted in minimal reduction in classification accuracy. Future studies will investigate the optimal time frame over which plasma IL-6 might assist diagnostic decisions and how extracranial trauma affects utility., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Traumatic brain injury (TBI) survivors often experience debilitating consequences. Due to the high impact nature of TBI, patients often experience concomitant peripheral injuries (ie, polytrauma). A common, yet often overlooked, comorbidity of TBI is chronic pain. Therefore, this study investigated how common concomitant peripheral injuries (ie, femoral fracture and muscle crush) can affect long-term behavioral and structural TBI outcomes with a particular focus on nociception. Rats were randomly assigned to 1 of 4 groups: polytrauma (POLY; ie, fracture + muscle crush + TBI), peripheral injury (PERI; ie, fracture + muscle crush + sham TBI), TBI (ie, sham fracture + sham muscle crush + TBI), and sham-injured (SHAM; ie, sham fracture + sham muscle crush + sham TBI). Rats underwent behavioral testing at 3-, 6-, and 11-weeks postinjury, and were then euthanized for postmortem magnetic resonance imaging (MRI). POLY rats had a persisting increase in pain sensitivity compared to all groups on the von Frey test. MRI revealed that POLY rats also had abnormalities in the cortical and subcortical brain structures involved in nociceptive processing. These findings have important implications and provide a foundation for future studies to determine the underlying mechanisms and potential treatment strategies for chronic pain in TBI survivors. PERSPECTIVE: Rats with TBI and concomitant peripheral trauma displayed chronic nociceptive pain and MRI images also revealed damaged brain structures/pathways that are involved in chronic pain development. This study highlights the importance of polytrauma and the affected brain regions for developing chronic pain., (Copyright © 2023 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) and stress are prevalent worldwide and can both result in life-altering health problems. While stress often occurs in the absence of TBI, TBI inherently involves some element of stress. Furthermore, because there is pathophysiological overlap between stress and TBI, it is likely that stress influences TBI outcomes. However, there are temporal complexities in this relationship (e.g., when the stress occurs) that have been understudied despite their potential importance. This paper begins by introducing TBI and stress and highlighting some of their possible synergistic mechanisms including inflammation, excitotoxicity, oxidative stress, hypothalamic-pituitary-adrenal axis dysregulation, and autonomic nervous system dysfunction. We next describe different temporal scenarios involving TBI and stress and review the available literature on this topic. In doing so we find initial evidence that in some contexts stress is a highly influential factor in TBI pathophysiology and recovery, and vice versa. We also identify important knowledge gaps and suggest future research avenues that will increase our understanding of this inherent bidirectional relationship and could one day result in improved patient care., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: TJO declares investigator-initiated research payments and consultancy fees paid to his institution from Eisai, UCB, Supernus, Biogen, ES Therapeutics, Epidarex, LivaNova, and Kinoxis Therapeutics; and payments to his institution for participation on an advisory board from ES Therapeutics and Kinoxis Therapeutics. SRS and SJM declare no competing interests.

Traumatic brain injury (TBI) is a leading cause of morbidity worldwide, with patients often suffering from consequences such as cognitive deficits, social abnormalities, anxiety, depression, pain, and motor dysfunction. Given that these impairments often have a significant impact on the patient's quality of life, a key aim of therapeutic intervention in TBI is to mitigate these effects. Translational strategies to develop such interventions have heavily featured animal models of TBI. To assess the efficacy of interventions in these models, a range of behavioral outcomes are utilized. However, in light of the past translational failures that have plagued the TBI field, the clinical relevance of these preclinical behavioral tests is now being scrutinized. This article will summarize the behavioral consequences of TBI in humans; describe common methods available for testing cognition, social function, motor ability, pain, as well as depression- and anxiety-like behaviors in animal models of TBI; provide an overview of the results from TBI animal model studies that have utilized these methods; and discuss these pre-clinical behavior methods and findings in terms of their relevance to the clinical TBI setting. We conclude that there is translational value in these methods and their related findings, but also suggest strategies and future research to improve the clinical relevance of behavior testing in animal models of TBI.

Traumatic brain injury (TBI) patients often experience post-traumatic infections, especially in the lung. Pulmonary infection is associated with unfavorable outcomes and increased mortality rates in TBI patients; however, our understanding of the underlying mechanisms is poor. Here we used a lateral fluid percussion injury (LFPI) model in rats to investigate whether TBI could lead to spontaneous lung infection. Analysis of bacterial load in lung tissue indicated no occurrence of spontaneous lung infection at 24 h, 48 h, and 7 d following LFPI. This may suggest that exogenous infectious agents play a crucial role in post-TBI infection in patients., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

There is a great clinical need to identify the underlying mechanisms, as well as related biomarkers, and treatment targets, for traumatic brain injury (TBI). Neuroinflammation is a central pathophysiological feature of TBI. NLRP3 inflammasome activity is a necessary component of the innate immune response to tissue damage, and dysregulated inflammasome activity has been implicated in a number of neurological conditions. This paper introduces the NLRP3 inflammasome and its implication in the pathogenesis of neuroinflammatory-related conditions, with a particular focus on TBI. Although its role in TBI has only recently been identified, findings suggest that priming and activation of the NLRP3 inflammasome are upregulated following TBI. Moreover, recent studies utilizing specific NLRP3 inhibitors have provided further evidence that this inflammasome is a major driver of neuroinflammation and neurobehavioral disturbances following TBI. In addition, there is emerging evidence that circulating inflammasome-associated proteins may have utility as diagnostic biomarkers of neuroinflammatory conditions, including TBI. Finally, novel and promising areas of research will be highlighted, including the potential involvement of the NLRP3 inflammasome in mild TBI, how factors such as biological sex may affect NLRP3 activity in TBI, and the use of emerging biomarker platforms. Taken together, this review highlights the exciting potential of the NLRP3 inflammasome as a target for treatments and biomarkers that may ultimately be used to improve TBI management.

Neurological heterotopic ossification (NHO) is characterized by abnormal bone growth in soft tissue and joints in response to injury to the central nervous system. The ectopic bone frequently causes pain, restricts mobility, and decreases the quality of life for those affected. NHO commonly develops in severe traumatic brain injury (TBI) patients, particularly in the presence of concomitant musculoskeletal injuries (i.e. polytrauma). There are currently no animal models that accurately mimic these combinations of injuries, which has limited our understanding of NHO pathobiology, as well as the development of biomarkers and treatments, in TBI patients. In order to address this shortcoming, here we present a novel rat model that combines TBI, femoral fracture, and muscle crush injury. Young adult male Sprague Dawley rats were randomly assigned into three different injury groups: triple sham-injury, peripheral injury only (i.e., sham-TBI + fracture + muscle injury) or triple injury (i.e., TBI + fracture + muscle injury). Evidence of ectopic bone in the injured hind-limb, as confirmed by micro-computed tomography (μCT), was found at 6-weeks post-injury in 70% of triple injury rats, 20% of peripheral injury rats, and 0% of the sham-injured controls. Furthermore, the triple injury rats had higher ectopic bone severity scores than the sham-injured group. This novel model will provide a platform for future studies to identify underlying mechanisms, biomarkers, and develop evidence based pharmacological treatments to combat this debilitating long-term complication of TBI and polytrauma., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) is a leading cause of death and disability, and there are currently no pharmacological treatments known to improve patient outcomes. Unquestionably, contributing toward a lack of effective treatments is the highly complex and heterogenous nature of TBI. In this review, we highlight the recent surge of research that has demonstrated various central interactions with the periphery as a potential major contributor toward this heterogeneity and, in particular, the breadth of research from Australia. We describe the growing evidence of how extracranial factors, such as polytrauma and infection, can significantly alter TBI neuropathology. In addition, we highlight how dysregulation of the autonomic nervous system and the systemic inflammatory response induced by TBI can have profound pathophysiological effects on peripheral organs, such as the heart, lung, gastrointestinal tract, liver, kidney, spleen, and bone. Collectively, this review firmly establishes TBI as a systemic condition. Further, the central and peripheral interactions that can occur after TBI must be further explored and accounted for in the ongoing search for effective treatments.

Primary Objective: This study characterized the acute and chronic effects of tau reduction in traumatic brain injury (TBI)., Research Design: A fluid percussion injury (FPI) or a sham-injury was administered to wild type (WT) or tau knockout (Tau-/-) mice. Mice were assigned to a one-week or twelve-week recovery period before behavioral testing and analysis of brain tissue., Methods and Procedures: Mice were tested on the elevated-plus maze, the Y-maze, and rotarod. The twelve-week recovery mice underwent in vivo MRI. Phosphorylated tau in brain tissue was analyzed post-mortem using western blots., Main Outcomes and Results: FPI mice, regardless of genotype, had abnormalities on the elevated-plus maze (a task to assess anxiety-like behavior) at one-week post-injury. However, after twelve-weeks recovery, the Tau-/- mice that were given an FPI were less anxious and had improved motor function compared to their WT counterparts. MRI analysis found that while all FPI mice had brain damage, the Tau-/- mice had larger hippocampal volumes. The WT+FPI mice also had increased phosphorylated tau compared to WT+sham mice at both the one-week and twelve-week recovery times., Conclusion: These findings suggest that tau may play an important role in some of the consequences of TBI, particularly the long-term functional deficits.

Initial studies suggest that increased age is associated with worse outcomes after traumatic brain injury (TBI), though the pathophysiological mechanisms responsible for this remain unclear. Immunosenescence (i.e., dysregulation of the immune system due to aging) may play a significant role in influencing TBI outcomes. This study therefore examined neurological outcomes and immune response in young-adult (i.e., 10 weeks old) compared to middle-aged (i.e., 1 year old) rats following a TBI (i.e., fluid percussion) or sham-injury. Rats were euthanized at either 24 h or one-week post-injury to analyze immune cell populations in the brain and periphery via flow cytometry, as well as telomere length (i.e., a biomarker of neurological health). Behavioral testing, as well as volumetric and diffusion-weighted MRI, were also performed in the one-week recovery rats to assess for functional deficits and brain damage. Middle-aged rats had worse sensorimotor deficits and shorter telomeres after TBI compared to young rats. Both aging and TBI independently worsened cognitive function and cortical volume. These changes occurred in the presence of fewer total leukocytes, fewer infiltrating myeloid cells, and fewer microglia in the brains of middle-aged TBI rats compared to young rats. These findings indicate that middle-aged rats have worse sensorimotor deficits and shorter telomeres after TBI than young rats, and this may be related to an altered neuroimmune response. Although further studies are required, these findings have important implications for understanding the pathophysiology and optimal treatment strategies in TBI patients across the life span., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, and typically involves a robust immune response. Although a great deal of preclinical research has been conducted to identify an effective treatment, all phase III clinical trials have been unsuccessful to date. These translational shortcomings are in part due to a failure to recognize and account for the heterogeneity of TBI, including how extracranial factors can influence the aftermath of TBI. For example, most preclinical studies have utilized isolated TBI models in young adult males, while clinical trials typically involve highly heterogeneous patient populations (e.g., different mechanisms of injury, a range of ages, presence of polytrauma or infection). This paper will review the current, albeit limited literature related to how TBI is affected by common concomitant immunological stressors. In particular, discussion will focus on whether extracranial trauma (i.e., polytrauma), infection, and age/immunosenescence can influence TBI pathophysiology, and thereby may result in a different brain injury than what would have occurred in an isolated TBI. It is concluded that these immunological stressors are all likely to be TBI modifiers that should be further studied and could impact translational treatment strategies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: There is evidence that treatment with nerve growth factor (NGF) may reduce neuroinflammation and apoptosis after a traumatic brain injury (TBI). NGF is thought to exert its effects via binding to either TrkA or p75 neurotrophin receptors. This study aimed to investigate the effects of a selective TrkA agonist, gambogic amide (GA), on TBI pathology and outcomes in mice following lateral fluid percussion injury., Methods: Male C57BL/6 mice were given either a TBI or sham injury, and then received subcutaneous injections of either 2 mg/kg of GA or vehicle at 1, 24, and 48 h post-injury. Following behavioural studies, mice were euthanized at 72 h post-injury for analysis of neuroinflammatory, apoptotic, and neurite outgrowth markers., Results: Behavioural testing revealed that GA did not mitigate motor deficits after TBI. TBI caused an increase in cortical and hippocampal expression of several markers of neuroinflammation and apoptosis compared to sham groups. GA treatment did not attenuate these increases in expression, possibly contributed to by our finding of TrkA receptor down-regulation post-TBI., Conclusions: These findings suggest that GA treatment may not be suitable for attenuating TBI pathology and improving outcomes.

Traumatic brain injury (TBI) and long bone fracture are common in polytrauma. This injury combination in mice results in elevated levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) and exacerbated neuropathology when compared to isolated-TBI. Here we examined the effect of treatment with an IL-1 receptor antagonist (IL-1ra) in mice given a TBI and a concomitant tibial fracture (i.e., polytrauma). Adult male C57BL/6 mice were given sham-injuries or polytrauma and treated with saline-vehicle or IL-1ra (100mg/kg). Treatments were subcutaneously injected at 1, 6, and 24h, and then once daily for one week post-injury. 7-8 mice/group were euthanized at 48h post-injury. 12-16 mice/group underwent behavioral testing at 12weeks post-injury and MRI at 14weeks post-injury before being euthanized at 16weeks post-injury. At 48h post-injury, markers for activated microglia and astrocytes, as well as neutrophils and edema, were decreased in polytrauma mice treated with IL-1ra compared to polytrauma mice treated with vehicle. At 14weeks post-injury, MRI analysis demonstrated that IL-1ra treatment after polytrauma reduced volumetric loss in the injured cortex and mitigated track-weighted MRI markers for axonal injury. As IL-1ra (Anakinra) is approved for human use, it may represent a promising therapy in polytrauma cases involving TBI and fracture., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) has been suggested to increase the risk of amyotrophic lateral sclerosis (ALS). However, this link remains controversial and as such, here we performed experimental moderate TBI in rats and assessed for the presence of ALS-like pathological and functional abnormalities at both 1 and 12 weeks post-injury. Serial in-vivo magnetic resonance imaging (MRI) demonstrated that rats given a TBI had progressive atrophy of the motor cortices and degeneration of the corticospinal tracts compared with sham-injured rats. Immunofluorescence analyses revealed a progressive reduction in neurons, as well as increased phosphorylated transactive response DNA-binding protein 43 (TDP-43) and cytoplasmic TDP-43, in the motor cortex of rats given a TBI. Rats given a TBI also had fewer spinal cord motor neurons, increased expression of muscle atrophy markers, and altered muscle fiber contractile properties compared with sham-injured rats at 12 weeks, but not 1 week, post-injury. All of these changes occurred in the presence of persisting motor deficits. These findings resemble some of the pathological and functional abnormalities common in ALS and support the notion that TBI can result in a progressive neurodegenerative disease process pathologically bearing similarities to a motor neuron disease., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Mild traumatic brain injury (mTBI) is a common health problem. There is tremendous variability and heterogeneity in human mTBI, including mechanisms of injury, biomechanical forces, injury severity, spatial and temporal pathophysiology, genetic factors, pre-injury vulnerability and resilience factors, and clinical outcomes. Animal models greatly reduce this variability and heterogeneity, and provide a means to study mTBI in a rigorous, controlled, and efficient manner. Rodent models, in particular, are time- and cost-efficient, and they allow researchers to measure morphological, cellular, molecular, and behavioral variables in a single study. However, inter-species differences in anatomy, morphology, metabolism, neurobiology, and lifespan create translational challenges. Although the term "mild" TBI is used often in the pre-clinical literature, clearly defined criteria for mild, moderate, and severe TBI in animal models have not been agreed upon. In this review, we introduce current issues facing the mTBI field, summarize the available research methodologies and previous studies in mTBI animal models, and discuss how a translational research approach may be useful in advancing our understanding and management of mTBI., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: Administration of sodium selenate to rats given traumatic brain injury (TBI) attenuates brain damage and improves long-term behavioural outcomes. We have previously provided evidence that TBI causes bone loss in rats, however the effect of sodium selenate treatment on bone quantity following TBI is unknown., Methods: Rats were randomly assigned into sham injury or fluid percussion injury (FPI) groups and administered saline or sodium selenate for 12 weeks post-injury. Femora were analysed using histomorphometry, peripheral quantitative computed tomography (pQCT) and biomechanical testing., Results: Distal metaphyseal trabecular bone volume fraction of FPI-selenate rats was higher than FPI-vehicle rats (41.8%; p<0.01), however, femora from selenate-treated groups were shorter in length (4.3%; p<0.01) and had increased growth plate width (22.1%; p<0.01), indicating that selenate impaired long bone growth. pQCT analysis demonstrated that distal metaphyseal cortical thickness was decreased in TBI rats compared to shams (11.7%; p<0.05), however selenate treatment to TBI animals offset this reduction (p<0.05). At the midshaft we observed no differences in biomechanical measures., Conclusion: These are the first findings to indicate that mitigating TBI-induced neuropathology may have the added benefit of preventing osteoporosis and associated fracture risk following TBI., Competing Interests: The authors have no conflict of interest.

Few studies have investigated the influence of traumatic brain injury (TBI) on bone homeostasis; however, pathophysiological mechanisms involved in TBI have potential to be detrimental to bone. The current study assessed the effect of experimental TBI in rats on the quantity and quality of two different weight-bearing bones, the femur and humerus. Rats were randomly assigned into either sham or lateral fluid percussion injury (FPI) groups. Open-field testing to assess locomotion was conducted at 1, 4, and 12 weeks post-injury, with the rats killed at 1 and 12 weeks post-injury. Bones were analyzed using peripheral quantitative computed tomography (pQCT), histomorphometric analysis, and three-point bending. pQCT analysis revealed that at 1 and 12 weeks post-injury, the distal metaphyseal region of femora from FPI rats had reduced cortical content (10% decrease at 1 week, 8% decrease at 12 weeks; p < 0.01) and cortical thickness (10% decrease at 1 week, 11% decrease at 12 weeks p < 0.001). There was also a 23% reduction in trabecular bone volume ratio at 1 week post-injury and a 27% reduction at 12 weeks post-injury in FPI rats compared to sham (p < 0.001). There were no differences in bone quantity and mechanical properties of the femoral midshaft between sham and TBI animals. There were no differences in locomotor outcomes, which suggested that post-TBI changes in bone were not attributed to immobility. Taken together, these findings indicate that this rat model of TBI was detrimental to bone and suggests a link between TBI and altered bone remodeling.

Background: Traumatic injuries are physical insults to the body that are prevalent worldwide. Many individuals involved in accidents suffer injuries affecting a number of extremities and organs, otherwise known as multitrauma or polytrauma. Traumatic brain injury is one of the most serious forms of the trauma-induced injuries and is a leading cause of death and long-term disability. Despite over dozens of phase III clinical trials, there are currently no specific treatments known to improve traumatic brain injury outcomes. These failures are in part due to our still poor understanding of the heterogeneous and evolving pathophysiology of traumatic brain injury and how factors such as concomitant extracranial injuries can impact these processes., Main Body: Here, we review the available clinical and pre-clinical studies that have investigated the possible impact of concomitant injuries on traumatic brain injury pathobiology and outcomes. We then list the pathophysiological processes that may interact and affect outcomes and discuss promising areas for future research. Taken together, many of the clinical multitrauma/polytrauma studies discussed in this review suggest that concomitant peripheral injuries may increase the risk of mortality and functional deficits following traumatic brain injury, particularly when severe extracranial injuries are combined with mild to moderate brain injury. In addition, recent animal studies have provided strong evidence that concomitant injuries may increase both peripheral and central inflammatory responses and that structural and functional deficits associated with traumatic brain injury may be exacerbated in multiply injured animals., Conclusions: The findings of this review suggest that concomitant extracranial injuries are capable of modifying the outcomes and pathobiology of traumatic brain injury, in particular neuroinflammation. Though additional studies are needed to further identify the factors and mechanisms involved in central and peripheral injury interactions following multitrauma and polytrauma, concomitant injuries should be recognized and accounted for in future pre-clinical and clinical traumatic brain injury studies.