Clinical Traumatic Brain Injury Research Articles

Exploratory assessment of the effect of systemic administration of soluble glycoprotein 130 on cognitive performance and chemokine levels in a mouse model of experimental traumatic brain injury

Uncontrolled neuroinflammation mediates traumatic brain injury (TBI) pathology and impairs recovery. Interleukin-6 (IL-6), a pleiotropic inflammatory regulator, is associated with poor clinical TBI outcomes. IL-6 operates via classical-signaling through membrane-bound IL-6 receptor (IL-6R) and trans-signaling through soluble IL-6 receptor (s)IL-6R. IL-6 trans-signaling specifically contributes to neuropathology, making it a potential precision therapeutic TBI target. Soluble glycoprotein 130 (sgp130) prevents IL-6 trans-signaling, sparing classical signaling, thus is a possible treatment. Mice received either controlled cortical impact (CCI) (6.0 ± 0.2 m/s; 2 mm; 50-60ms) or sham procedures. Vehicle (VEH) or sgp130-Fc was subcutaneously administered to sham (VEH or 1 µg) and CCI (VEH, 0.25 µg or 1 µg) mice on days 1, 4, 7, 10 and 13 post-surgery to assess effects on cognition [Morris Water Maze (MWM)] and ipsilateral hemisphere IL-6 related biomarkers (day 21 post-surgery). CCI + sgp130-Fc groups (0.25 µg and 1 µg) were combined for analysis given similar behavior/biomarker outcomes. CCI + VEH mice had longer latencies and path lengths to the platform and increased peripheral zone time versus Sham + VEH and Sham + sgp130-Fc mice, suggesting injury-induced impairments in learning and anxiety. CCI + sgp130-Fc mice had shorter platform latencies and path lengths and had decreased peripheral zone time, indicating a therapeutic benefit of sgp130-Fc after injury on learning and anxiety. Interestingly, Sham + sgp130-Fc mice had shorter platform latencies, path lengths and peripheral zone times than Sham + VEH mice, suggesting a beneficial effect of sgp130-Fc, independent of injury. CCI + VEH mice had increased brain IL-6 and decreased sgp130 levels versus Sham + VEH and Sham + sgp130-Fc mice. There was no treatment effect on IL-6, sIL6-R or sgp130 in Sham + VEH versus Sham + sgp130-Fc mice. There was also no treatment effect on IL-6 in CCI + VEH versus CCI + sgp130-Fc mice. However, CCI + sgp130-Fc mice had increased sIL-6R and sgp130 versus CCI + VEH mice, demonstrating sgp130-Fc treatment effects on brain biomarkers. Inflammatory chemokines (MIP-1β, IP-10, MIG) were increased in CCI + VEH mice versus Sham + VEH and Sham + sgp130-Fc mice. However, CCI + sgp130-Fc mice had decreased chemokine levels versus CCI + VEH mice. IL-6 positively correlated, while sgp130 negatively correlated, with chemokine levels. Overall, we found that systemic sgp130-Fc treatment after CCI improved learning, decreased anxiety and reduced CCI-induced brain chemokines. Future studies will explore sex-specific dosing and treatment mechanisms for sgp130-Fc therapy.

TREM2 alleviates white matter injury after traumatic brain injury in mice might be mediated by regulation of DHCR24/LXR pathway in microglia.

White matter injury (WMI) is an important pathological process after traumatic brain injury (TBI). The correlation between white matter functions and the myeloid cells expressing triggering receptor-2 (TREM2) has been convincingly demonstrated. Moreover, a recent study revealed that microglial sterol metabolism is crucial for early remyelination after demyelinating diseases. However, the potential roles of TREM2 expression and microglial sterol metabolism in WMI after TBI have not yet been explored. Controlled cortical injury was induced in both wild-type (WT) and TREM2 depletion (TREM2 KO) mice to simulate clinical TBI. COG1410 was used to upregulate TREM2, while PLX5622 and GSK2033 were used to deplete microglia and inhibit the liver X receptor (LXR), respectively. Immunofluorescence, Luxol fast blue staining, magnetic resonance imaging, transmission electron microscopy, and oil red O staining were employed to assess WMI after TBI. Neurological behaviour tests and electrophysiological recordings were utilized to evaluate cognitive functions following TBI. Microglial cell sorting and transcriptomic sequencing were utilized to identify alterations in microglial sterol metabolism-related genes, while western blot was conducted to validate the findings. TREM2 expressed highest at 3 days post-TBI and was predominantly localized to microglial cells within the white matter. Depletion of TREM2 worsened aberrant neurological behaviours, and this phenomenon was mediated by the exacerbation of WMI, reduced renewal of oligodendrocytes, and impaired phagocytosis ability of microglia after TBI. Subsequently, the upregulation of TREM2 alleviated WMI, promoted oligodendrocyte regeneration, and ultimately facilitated the recovery of neurological behaviours after TBI. Finally, the expression of DHCR24 increased in TREM2 KO mice after TBI. Interestingly, TREM2 inhibited DHCR24 and upregulated members of the LXR pathway. Moreover, LXR inhibition could partially reverse the effects of TREM2 upregulation on electrophysiological activities. We demonstrate that TREM2 has the potential to alleviate WMI following TBI, possibly through the DHCR24/LXR pathway in microglia.

Diffusion tensor imaging and plasma immunological biomarker panel in a rat traumatic brain injury (TBI) model and in human clinical TBI.

Neuroinflammatory reactions play a significant role in the pathology and long-term consequences of traumatic brain injury (TBI) and may mediate salutogenic processes that white matter integrity. This study aimed to investigate the relationship between inflammatory markers and white matter integrity following TBI in both a rat TBI model and clinical TBI cases. In the rat model, blood samples were collected following a controlled cortical impact (CCI) to assess a panel of inflammatory markers; MR-based diffusion tensor imaging (DTI) was employed to evaluate white matter integrity 60 days post-injury. 15 clinical TBI patients were similarly assessed for a panel of inflammatory markers and DTI post-intensive care unit discharge. Blood samples from healthy controls were used for comparison of the inflammatory markers. Time-dependent elevations in immunological markers were observed in TBI rats, with a correlation to preserved fractional anisotropy (FA) in white matter. Specifically, TBI-induced increased plasma levels of IL-1β, IL-6, G-CSF, CCL3, CCL5, and TNF-α were associated with higher white matter integrity, as measured by FA. Clinical cases had similar findings: elevated inflammatory markers (relative to controls) were associated with preservation of FA in vulnerable white matter regions. Inflammatory markers in post-TBI plasma samples are ambivalent with respect to prediction of favourable outcome versus a progression to more pervasive pathology and morbidity.

Insights from Rodent Models for Improving Bench-to-Bedside Translation in Traumatic Brain Injury.

Road accidents, domestic falls, and persons associated with sports and military services exhibited the concussion or contusion type of traumatic brain injury (TBI) that resulted in chronic traumatic encephalopathy. In some instances, these complex neurological aberrations pose severe brain damage and devastating long-term neurological sequelae. Several preclinical (rat and mouse) TBI models simulate the clinical TBI endophenotypes. Moreover, many investigational neuroprotective candidates showed promising effects in these models; however, the therapeutic success of these screening candidates has been discouraging at various stages of clinical trials. Thus, a correct selection of screening model that recapitulates the clinical neurobiology and endophenotypes of concussion or contusion is essential. Herein, we summarize the advantages and caveats of different preclinical models adopted for TBI research. We suggest that an accurate selection of experimental TBI models may improve the translational viability of the investigational entity.

Connecting cellular mechanisms and extracellular vesicle cargo in traumatic brain injury.

Traumatic brain injury is followed by a cascade of dynamic and complex events occurring at the cellular level. These events include: diffuse axonal injury, neuronal cell death, blood-brain barrier break down, glial activation and neuroinflammation, edema, ischemia, vascular injury, energy failure, and peripheral immune cell infiltration. The timing of these events post injury has been linked to injury severity and functional outcome. Extracellular vesicles are membrane bound secretory vesicles that contain markers and cargo pertaining to their cell of origin and can cross the blood-brain barrier. These qualities make extracellular vesicles intriguing candidates for a liquid biopsy into the pathophysiologic changes occurring at the cellular level post traumatic brain injury. Herein, we review the most commonly reported cargo changes in extracellular vesicles from clinical traumatic brain injury samples. We then use knowledge from animal and in vitro models to help infer what these changes may indicate regrading cellular responses post traumatic brain injury. Future research should prioritize labeling extracellular vesicles with markers for distinct cell types across a range of timepoints post traumatic brain injury.

Modeling the Inflammatory Response of Traumatic Brain Injury Using Human Induced Pluripotent Stem Cell Derived Microglia.

The neuroinflammatory response after traumatic brain injury (TBI) is implicated as a key mediator of secondary injury in both the acute and chronic periods after primary injury. Microglia are the key innate immune cell in the central nervous system, responding to injury with the release of cytokines and chemokines. In this context, we aimed to characterize the downstream cytokine response of human induced pluripotent stem cell (iPSC)-derived microglia when stimulated with five separate cytokines identified after human TBI. The iPSC-derived microglia were exposed to interleukin (IL)-1β, IL-4, IL-6, IL-10, and tumor necrosis factor (TNF) in the concentration ranges identified in clinical TBI studies. The downstream cytokine response was measured against a panel of 37 separate cytokines over a 72h time-course. The secretome revealed concentration-, time- and combined concentration and time-dependent downstream responses. TNF appeared to be the strongest inducer of downstream cytokine changes (51), followed by IL-1β (26) and IL-4 (19). IL-10 (11) and IL-6 (10) produced fewer responses. We also compare these responses with our previous studies of iPSC-derived neuronal and astrocyte cultures and the in vivo human TBI cytokine response. Notably, we found microglial culture to induce both a wider range of downstream cytokine responses and a greater fold change in concentration for those downstream responses, compared with astrocyte and neuronal cultures. In summary, we present a dataset for human microglial cytokine responses specific to the secretome found in the clinical context of TBI. This reductionist approach complements our previous datasets for astrocyte and neuronal responses and will provide a platform to enable future studies to unravel the complex neuroinflammatory network activated after TBI.

Potential Biomarkers in Experimental Animal Models for Traumatic Brain Injury.

Traumatic brain injury (TBI) is a complex and multifaceted disorder that has become a significant public health concern worldwide due to its contribution to mortality and morbidity. This condition encompasses a spectrum of injuries, including axonal damage, contusions, edema, and hemorrhage. Unfortunately, specific effective therapeutic interventions to improve patient outcomes following TBI are currently lacking. Various experimental animal models have been developed to mimic TBI and evaluate potential therapeutic agents to address this issue. These models are designed to recapitulate different biomarkers and mechanisms involved in TBI. However, due to the heterogeneous nature of clinical TBI, no single experimental animal model can effectively mimic all aspects of human TBI. Accurate emulation of clinical TBI mechanisms is also tricky due to ethical considerations. Therefore, the continued study of TBI mechanisms and biomarkers, of the duration and severity of brain injury, treatment strategies, and animal model optimization is necessary. This review focuses on the pathophysiology of TBI, available experimental TBI animal models, and the range of biomarkers and detection methods for TBI. Overall, this review highlights the need for further research to improve patient outcomes and reduce the global burden of TBI.

The Glasgow Coma Scale: A disconnect between medical documentation and traumatic brain injury litigation in the United States.

Traumatic brain injuries are consistently difficult to objectively measure. This creates significant challenges for medical and legal practitioners who each apply the Glasgow Coma Scale-based traumatic brain injury severity classifications of "mild", "moderate" and "severe". It can be difficult to medically define an often-subjective traumatic brain injury, where the law requires objective evidence of injuries. This descriptive review aims to elucidate the intended purpose of the Glasgow Coma Scale in traumatic brain injury assessment by doctors and attorneys. We highlight two different Glasgow Coma Scale uses, demonstrating a disconnect between the clinical traumatic brain injury adjectival classifications used in medicine and law. The Glasgow Coma Scale-based adjectival traumatic brain injury classifications create a diagnostic label which can affect a patient long after their initial medical assessment, representing a de facto diagnosis to the legal profession which may affect a patient's potential legal financial recovery.

Sensitivity of outcome instruments in a priori selected patient groups after traumatic brain injury: Results from the CENTER-TBI study.

Traumatic brain injury (TBI) can negatively impact patients' lives on many dimensions. Multiple instruments are available for evaluating TBI outcomes, but it is still unclear which instruments are the most sensitive for that purpose. This study examines the sensitivity of nine outcome instruments in terms of their ability to discriminate within and between specific patient groups, selected a priori as identified from the literature, at three different time points within a year after TBI (i.e., 3, 6, and 12 months post injury). The sensitivity of the instruments to sociodemographic (sex, age, education), premorbid (psychological health status), and injury-related (clinical care pathways, TBI and extracranial injury severity) factors was assessed by means of cross-sectional multivariate Wei-Lachin analyses. The Glasgow Outcome Scale Extended (GOSE)-the standard in the field of TBI for measuring functional recovery-demonstrated the highest sensitivity in most group comparisons. However, as single functional scale, it may not be able to reflect the multidimensional nature of the outcome. Therefore, the GOSE was used as a reference for further sensitivity analyses on more specific outcome scales, addressing further potential deficits following TBI. The physical component summary score (PCS) of the generic health-related quality of life (HRQOL) instruments (SF-36v2/-12v2) and the TBI-specific HRQOL instruments (QOLIBRI/-OS) were most sensitive in distinguishing recovery after TBI across all time points and patient groups, followed by the RPQ assessing post-concussion symptoms and the PHQ-9 measuring depression. The SF-36v2/-12v2 mental component summary score and the GAD-7 measuring anxiety were less sensitive in several group comparisons. The assessment of the functional recovery status combined with generic HRQOL (the PCS of the SF-12v2), disease-specific HRQOL (QOLIBRI-OS), and post-concussion symptoms (RPQ) can provide a sensitive, comprehensive, yet time-efficient evaluation of the health status of individuals after TBI in different patient groups.

Traumatic Brain Injury in a Well: A Modular Three-Dimensional Printed Tool for Inducing Traumatic Brain Injury In vitro.

Traumatic brain injury (TBI) is a major health problem that affects millions of persons worldwide every year among all age groups, mainly young children, and elderly persons. It is the leading cause of death for children under the age of 16 and is highly correlated with a variety of neuronal disorders, such as epilepsy, and neurodegenerative disease, such as Alzheimer's disease or amyotrophic lateral sclerosis. Over the past few decades, our comprehension of the molecular pathway of TBI has improved, yet despite being a major public health issue, there is currently no U.S. Food and Drug Administration-approved treatment for TBI, and a gap remains between these advances and their application to the clinical treatment of TBI. One of the major hurdles for pushing TBI research forward is the accessibility of TBI models and tools. Most of the TBI models require costume-made, complex, and expensive equipment, which often requires special knowledge to operate. In this study, we present a modular, three-dimensional printed TBI induction device, which induces, by the pulse of a pressure shock, a TBI-like injury on any standard cell-culture tool. Moreover, we demonstrate that our device can be used on multiple systems and cell types and can induce repetitive TBIs, which is very common in clinical TBI. Further, we demonstrate that our platform can recapitulate the hallmarks of TBI, which include cell death, decrease in neuronal functionality, axonal swelling (for neurons), and increase permeability (for endothelium). In addition, in view of the continued discussion on the need, benefits, and ethics of the use of animals in scientific research, this in vitro, high-throughput platform will make TBI research more accessible to other labs that prefer to avoid the use of animals yet are interested in this field. We believe that this will enable us to push the field forward and facilitate/accelerate the availability of novel treatments.

Pramipexole alleviates traumatic brain injury in rats through inhibiting necroptosis

Traumatic brain injury (TBI) has high morbidity, mortality and disability. Cell death runs through its occurrence and development. Necroptosis is a recently discovered mode of cell death. Its mechanism still has not been fully resolved. Studies which researcher published before showed that: pramipexole could play a neuroprotective role by inducing hypothermia; receptor interacting protein 1 (RIP1) could play a neuroprotective role by regulating necroptosis. On this basis, we carried out the experiments and it was observed that we could establish a hypothermia model of SD rats safely and effectively via pramipexole. Meanwhile, necroptosis and expression of RIP1 and its related proteins did change. As a result, the prognosis of TBI rats did improve. In brief, we found that pramipexole could play a protective role after TBI by inhibiting necroptosis. We hope our investigation would provide new theoretical basis to improve the outcome of clinical TBI patients.

Obstructive sleep apnea is associated with worse cognitive outcomes in acute moderate-to-severe traumatic brain injury: A TBI Model Systems study

ObjectiveTo examine the relationship between polysomnography-classified obstructive sleep apnea (OSA) severity and cognitive performance in acute moderate-to-severe traumatic brain injury (TBI). MethodThis was a cross-sectional, secondary analysis leveraging data from a clinical trial (NCT03033901) and TBI Model Systems. Sixty participants (mean age = 50 ± 18y, 72% male, 67% white) with moderate-to-severe TBI from five civilian rehabilitation hospitals were assessed at one-month post-injury. Participants underwent Level 1 polysomnography. OSA severity was classified as mild, moderate, and severe using the Apnea-Hypopnea Index (AHI). Associations between OSA metrics of hypoxemia (nadir and total time spent below 90%) and AHI with cognition were examined. Cognition was assessed with the Brief Test of Adult Cognition by Telephone (BTACT), which is comprised of six subtests assessing verbal memory, attention/working memory, processing speed, language, and executive function. ResultsOver three-quarters of this acute TBI sample (76.7%) were diagnosed with OSA (no OSA n = 14; mild OSA n = 19; moderate/severe OSA n = 27). After adjustment for age, gender, and education, those with OSA had worse processing speed, working memory, and executive functioning compared to those without OSA. Compared to those with moderate/severe OSA, those with mild OSA had worse working memory and executive function. ConclusionsOSA is highly prevalent during acute stages of TBI recovery, and even in mild cases is related to poorer cognitive performance, particularly in the domains of attention/working memory and executive functioning. Our results support the incorporation of OSA diagnostic tools and interventions into routine clinical care in rehabilitation settings.

Cerebral metabolic derangements following traumatic brain injury.

Purpose of reviewOutcome following traumatic brain injury (TBI) remains variable, and derangements in cerebral metabolism are a common finding in patients with poor outcome. This review compares our understanding of cerebral metabolism in health with derangements seen following TBI.Recent findingsIschemia is common within the first 24 h of injury and inconsistently detected by bedside monitoring. Metabolic derangements can also result from tissue hypoxia in the absence of ischemic reductions in blood flow due to microvascular ischemia and mitochondrial dysfunction. Glucose delivery across the injured brain is dependent on blood glucose and regional cerebral blood flow, and is an important contributor to derangements in glucose metabolism. Alternative energy substrates such as lactate, ketone bodies and succinate that may support mitochondrial function, and can be utilized when glucose availability is low, have been studied following TBI but require further investigation.SummaryMitochondrial dysfunction and the use of alternative energy substrates are potential therapeutic targets, but improved understanding of the causes, impact and significance of metabolic derangements in clinical TBI are needed. Maintaining adequate oxygen and glucose delivery across the injured brain may accelerate the recovery of mitochondrial function and cerebral energy metabolism and remain important management targets.

Electroacupuncture improves TBI dysfunction by targeting HDAC overexpression and BDNF-associated Akt/GSK-3β signaling.

BackgroundAcupuncture or electroacupuncture (EA) appears to be a potential treatment in acute clinical traumatic brain injury (TBI); however, it remains uncertain whether acupuncture affects post-TBI histone deacetylase (HDAC) expression or impacts other biochemical/neurobiological events.Materials and methodsWe used behavioral testing, Western blot, and immunohistochemistry analysis to evaluate the cellular and molecular effects of EA at LI4 and LI11 in both weight drop-impact acceleration (WD)- and controlled cortical impact (CCI)-induced TBI models.ResultsBoth WD- and CCI-induced TBI caused behavioral dysfunction, increased cortical levels of HDAC1 and HDAC3 isoforms, activated microglia and astrocytes, and decreased cortical levels of BDNF as well as its downstream mediators phosphorylated-Akt and phosphorylated-GSK-3β. Application of EA reversed motor, sensorimotor, and learning/memory deficits. EA also restored overexpression of HDAC1 and HDAC3, and recovered downregulation of BDNF-associated signaling in the cortex of TBI mice.ConclusionThe results strongly suggest that acupuncture has multiple benefits against TBI-associated adverse behavioral and biochemical effects and that the underlying mechanisms are likely mediated by targeting HDAC overexpression and aberrant BDNF-associated Akt/GSK-3 signaling.

National Institutes of Health Clinical Research Funding and All-Cause In-Hospital Traumatic Brain Injury-Related Mortality.

IntroductionHigher federal research funding levels may improve patient outcomes. We examined this relationship between traumatic brain injury (TBI) funding and all-cause in-hospital TBI-related mortality.MethodsUsing an ecological series analysis, we examined the linear trend in both clinical TBI research funding in year 2000 United States dollars ($) (National Institutes of Health [NIH] RePORTER) and in-hospital isolated TBI mortality among patients aged 15 and older (National Trauma Data Bank [NTDB], TBI-related ICD-9 or ICD-10 code, abbreviated head injury score >2 and body region score <2 with ICU admission) between 2007-2015 with data from centers contributing all years of data for the study period. Linear regression was used to assess the relationship between mortality rate and total funding, lagged one to three years, both overall and within ten-year age groups.ResultsThe mean annual NIH-TBI research funding was $64.36 million (lowest: 2008; $48.79 million, highest: 2015; $71.42 million). 192,597 encounters of patients 15 years and older, predominantly male (67.5%) and with polytrauma (59.9%), were included. There was no statistically significant reduction in in-hospital TBI-related mortality (14.15% in 2007 to 13.36% in 2015) for the cohort overall, but the mortality rate decreased for patients over 55 years. The greatest mortality reduction occurred in patients 85 years and older (-62.35, 95% CI -92.45-32.25), followed by patients 75-84 years (-44.41, 95% CI -61.72, -27.09), patients 65-74 years (-47.60, 95% CI -67.39, -27.81), and patients 55-64 years of age (-15.15, 95% CI -27.59, -2.72). During the study period, annual NIH funding for TBI varied from the lowest level of $48.79 million (in 2007) to the highest level of $77.34.43 million (in 2005). There was no association between funding in the previous three years and the in-hospital TBI-related mortality rate.ConclusionThis study found a variable pattern in NIH funding for clinical TBI research and a contemporaneous reduction in moderate-severe TBI-related deaths only for those aged 55 years and older, but no association between funding and mortality.

What are the predictors of TOMM failure in clinical TBI populations? A retrospective analysis.

To determine base rates of invalid performance on the Test of Memory Malingering (TOMM) in patients with traumatic brain injury (TBI) undertaking rehabilitation who were referred for clinical assessment, and the factors contributing to TOMM failure. Retrospective file review of consecutive TBI referrals for neuropsychological assessment over seven years. TOMM failure was conventionally defined as performance <45/50 on Trial 2 or Retention Trial. Demographic, injury, financial compensation, occupational, and medical variables were collected. Four hundred and ninety one TBI cases (Median age = 40 years [IQR = 26-52], 79% male, 82%severe TBI) were identified. Overall, 48 cases (9.78%) failed the TOMM. Logistic regression analyses revealed that use of an interpreter during the assessment (adjusted odds ratio [aOR] = 8.25, 95%CI = 3.96-17.18), outpatient setting (aOR = 4.80, 95%CI = 1.87-12.31) and post-injury psychological distress (aOR = 2.77, 95%CI = 1.35-5.70) were significant multivariate predictors of TOMM failure. The TOMM failure rate for interpreter cases was 49% (21/43) in the outpatient setting vs. 7% (2/30) in the inpatient setting. By comparison, 9% (21/230) of non-interpreter outpatient cases failed the TOMM vs. 2% (4/188) of inpatient cases. TOMM failure very rarely occurs in clinical assessment of TBI patients in the inpatient rehabilitation setting. It is more common in the outpatient setting, particularly in non-English-speaking people requiring an interpreter. The findings reinforce the importance of routinely administering stand-alone performance validity tests in assessments of clinical TBI populations, particularly in outpatient settings, to ensure that neuropsychological test results can be interpreted with a high degree of confidence.

Plasma Neurofilament Light and Glial Fibrillary Acidic Protein Levels over Thirty Days in a Porcine Model of Traumatic Brain Injury.

To establish the clinical relevance of porcine model of traumatic brain injury (TBI) using the plasma biomarkers of injury with diffusion tensor imaging (DTI) over 30 days, we performed a randomized, blinded, pre-clinical trial using Yorkshire pigs weighing 7-10 kg. Twelve pigs were subjected to Sham injury (n = 5) by skin incision or TBI (n = 7) by controlled cortical impact. Blood samples were collected before the injury, then at approximately 5-day intervals until 30 days. Both groups also had DTI at 24 h and at 30 days after injury. Plasma samples were isolated and single molecule array (Simoa) was performed for glial fibrillary acidic protein (GFAP) and neurofilament light (NFL) levels. Afterwards, brain tissue samples were stained for β-APP. DTI showed fractional anisotropy (FA) decrease in the right corona radiata (ipsilateral to injury), contralateral corona radiata, and anterior corpus callosum at 1 day. At 30 days, ipsilateral corona radiata showed decreased FA. Pigs with TBI also had increase in GFAP and NFL at 1-5 days after injury. Significant difference between Sham and TBI animals continued up to 20 days. Linear regression showed significant negative correlation between ipsilateral corona radiata FA and both NFL and GFAP levels at 1 day. To further validate the degree of axonal injury found in DTI, β-APP immunohistochemistry was performed on a perilesional tissue as well as corona radiata bilaterally. Variable degree of staining was found in ipsilateral corona radiata. Porcine model of TBI replicates the acute increase in plasma biomarkers seen in clinical TBI. Further, long term white matter injury is confirmed in the areas such as the splenium and corona radiata. However, future study stratifying severe and mild TBI, as well as comparison with other subtypes of TBI such as diffuse axonal injury, may be warranted.

Brain-Derived Neurotrophic Factor and Nerve Growth Factor Therapeutics for Brain Injury: The Current Translational Challenges in Preclinical and Clinical Research.

Ischemic stroke and traumatic brain injury (TBI) are among the leading causes of death and disability worldwide with impairments ranging from mild to severe. Many therapies are aimed at improving functional and cognitive recovery by targeting neural repair but have encountered issues involving efficacy and drug delivery. As a result, therapeutic options for patients are sparse. Neurotrophic factors are one of the key mediators of neural plasticity and functional recovery. Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) serve as potential therapeutic options to increase neural repair and recovery as they promote neuroprotection and regeneration. BDNF and NGF have demonstrated the ability to improve functional recovery in preclinical and to a lesser extent clinical studies. Direct and indirect methods to increase levels of neurotrophic factors in animal models have been successful in improving postinjury outcome measures. However, the translation of these studies into clinical trials has been limited. Preclinical experiments have largely failed to result in significant impacts in clinical research. This review will focus on the administration of these neurotrophic factors in preclinical and clinical stroke and TBI and the challenges in translating these therapies from the bench to the clinic.

Factors Associated With High and Low Life Satisfaction 10 Years After Traumatic Brain Injury

ObjectiveTo identify correlates of life satisfaction at 10 years after moderate to severe traumatic brain injury (TBI) using an extreme phenotyping approach. DesignEffect sizes were calculated in this observational cohort study to estimate relationships of 10-year postinjury extremely high, extremely low, and moderate life satisfaction with (1) pre-injury demographics, injury-related factors, and functional characteristics at inpatient rehabilitation admission and discharge; and (2) postinjury demographics and clinical and functional measures at 10 years postinjury. SettingMulticenter longitudinal database study. ParticipantsPeople identified from the National Institute on Disability, Independent Living, and Rehabilitation Research TBI Database with life satisfaction data at 10 years post TBI (N=4800). InterventionsNot applicable. Main Outcome MeasureSatisfaction With Life Scale. ResultsAlthough few pre-injury factors or clinical and functional factors shortly after injury were associated with 10-year life satisfaction groups, the following 10-year postinjury factors were associated with extremely high vs extremely low life satisfaction group membership: greater independent functioning, less disability, more frequent community participation, being employed, and having fewer depressive and anxiety symptoms. Those with extremely high life satisfaction were distinctly different from those with moderate and extremely low satisfaction. Extremely high life satisfaction was underrepresented among non-Hispanic Black persons relative to non-Hispanic White persons. Relationships between life satisfaction and independent functioning, disability, and participation were attenuated among non-Hispanic Black persons. ConclusionsExtreme phenotyping analysis complements existing knowledge regarding life satisfaction after moderate to severe TBI and may inform acute and postacute clinical service delivery by comparing extremely high and extremely low life satisfaction subgroups. Findings suggest little association among personal, clinical, and functional characteristics early post TBI and life satisfaction 10 years later. Contemporaneous correlates of extremely high life satisfaction exist at 10 years post TBI, although the positive relationship of these variables to life satisfaction may be attenuated for non-Hispanic Black persons.

Patient-Reported Problem Areas in Chronic Traumatic Brain Injury.

The aims of this study were to (1) assess self-reported main problem areas reported by patients with traumatic brain injury (TBI) and their family members in the chronic phase, and (2) compare the self-prioritized problems with difficulties captured by questionnaires and neuropsychological screening through linking to the International Classification of Functioning, Disability and Health (ICF). Outpatient clinic at the Oslo University Hospital, Norway. In total, 120 patients with TBI were recruited, of whom, 78 had a participating family member. Eligibility criteria were a clinical TBI diagnosis with verified intracranial injury, living at home, aged 18 to 72 years, 2 years or more postinjury, and experiencing perceived TBI-related difficulties, reduced physical and mental health, or difficulties with participation in everyday life. Patients with severe psychiatric or neurological disorders or inability to participate in goal-setting processes were excluded. Cross-sectional. Target Outcomes, that is, 3 main TBI-related problem areas reported by patients and family members, collected in a semistructured interview; standardized questionnaires of TBI-related symptoms, anxiety, depression, functioning, and health-related quality of life; neuropsychological screening battery. Target Outcomes were related to cognitive, physical, emotional, and social difficulties. Target Outcomes were linked to 12 chapters and 112 distinct categories in the ICF, while standardized measures only covered 10 chapters and 28 categories. Some aspects of post-TBI adjustment were found to be insufficiently covered by the ICF classification, such as identity issues, lack of meaningful activities, and feeling lonely. The Target Outcomes approach is a useful assessment method in a population with chronic TBI. The standardized questionnaires capture the spectrum of problems, whereas the Target Outcomes approach captures the prioritized individual problems hindering everyday life after TBI. While the standardized measures are an irreplaceable part of the assessment, Target Outcomes ensures patient involvement and may help clinicians better tailor relevant rehabilitation efforts.