Journal of neurotrauma
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Journal of neurotrauma · Dec 2019
Randomized Controlled TrialCopenhagen Head Injury Ciclosporin (CHIC) study: A phase IIa safety, pharmacokinetics and biomarker study of ciclosporin in severe head injury patients.
Traumatic brain injury (TBI) contributes to almost one third of all trauma-related deaths, and those that survive often suffer from long-term physical and cognitive deficits. Ciclosporin (cyclosporine, cyclosporin A) has shown promising neuroprotective properties in pre-clinical TBI models. The Copenhagen Head Injury Ciclosporin (CHIC) study was initiated to establish the safety profile and pharmacokinetics of ciclosporin in patients with severe TBI, using a novel parenteral lipid emulsion formulation. ⋯ The four biomarkers, glial fibrillary acidic protein, neurofilament light, tau, and ubiquitin carboxy-terminal hydrolase L1, showed consistent trends to decrease during the 5-day treatment period, whereas the samples taken on the days after the treatment period showed higher values in the majority of patients. In conclusion, ciclosporin, as administered in this study, is safe and well tolerated. The study confirmed that ciclosporin is able to pass the blood-brain barrier in a TBI population and provided an initial biomarker-based signal of efficacy.
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Journal of neurotrauma · Dec 2019
Controlled Clinical TrialChange in headache suffering and predictors of headache following mild traumatic brain injury. A population based, controlled, longitudinal study with 12 months follow-up.
Headache attributed to traumatic injury to the head (HAIH) is claimed to be the most common sequela following mild traumatic brain injury (MTBI), but epidemiological evidence is scarce. We explored whether patients with MTBI had an increase in headache suffering following injury compared with controls. We also studied predictors of headache. ⋯ Predictors for persistent HAIH were prior MTBI, being injured under the influence of alcohol, and acute HAIH. Patients who experience HAIH during the first 3 months post-injury have a good chance to improve before 12 months post-injury. Female sex, imaging findings on CT or MRI, prior MTBI, and being injured under the influence of alcohol may predict exacerbation of headache.
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Journal of neurotrauma · Dec 2019
Multimodal Signatures of Tau Pathology, Neuronal Fiber Integrity, and Functional Connectivity in Traumatic Brain Injury.
[18F]AV-1451 (aka 18F-Flortaucipir, [18F]T807) was developed for positron-emission tomography (PET) imaging of paired helical filaments of hyperphosphorylated tau, which are of interest in a range of neuropathologies, including traumatic brain injury (TBI). Magnetic resonance imaging (MRI) techniques like diffusion tensor imaging (DTI) and resting state functional connectivity assess structural and functional characteristics of the brain, complementing the molecular information that can be obtained by PET. The goal herein was to explore the utility of such multi-modal imaging in a case series based on a population of TBI subjects. ⋯ Functional MRI results exhibited an increase in functional connectivity, particularly among local connections, in the areas where tau aggregates were more prevalent. In a case series of a diverse group of TBI subjects, brain regions with elevated tau burden exhibited increased functional connectivity as well as decreased white matter integrity. These findings portray molecular, microstructural, and functional corollaries of TBI that spatially coincide and can be measured in the living human brain using noninvasive neuroimaging techniques.
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Journal of neurotrauma · Dec 2019
Hypertension exacerbates cerebrovascular oxidative stress induced by mild traumatic brain injury: protective effects of the mitochondria-targeted antioxidative peptide SS-31.
Traumatic brain injury (TBI) induces cerebrovascular oxidative stress, which is associated with neurovascular uncoupling, autoregulatory dysfunction, and persisting cognitive decline in both pre-clinical models and patients. However, single mild TBI (mTBI), the most frequent form of brain trauma, increases cerebral generation of reactive oxygen species (ROS) only transiently. We hypothesized that comorbid conditions might exacerbate long-term ROS generation in cerebral arteries after mTBI. ⋯ We found that mTBI induced a significant increase in long-term cytoplasmic and mitochondrial O2- production in MCAs of SHRs and increased expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit Nox4, which were reversed to the normal level by treating the animals with the cell-permeable, mitochondria-targeted antioxidant peptide SS-31 (5.7 mg kg-1 day-1, i.p.). Persistent mTBI-induced oxidative stress in MCAs of SHRs was significantly decreased by inhibiting vascular NADPH oxidase (apocyinin). We propose that hypertension- and mTBI-induced cerebrovascular oxidative stress likely lead to persistent dysregulation of cerebral blood flow (CBF) and cognitive dysfunction, which might be reversed by SS-31 treatment.
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Journal of neurotrauma · Dec 2019
Tranexamic acid influences the immune response, but not bacterial clearance in a model of post-traumatic brain injury pneumonia.
The antifibrinolytic agent, tranexamic acid (TXA), an inhibitor of plasmin formation, currently is evaluated to reduce bleeding in various conditions, including traumatic brain injury (TBI). Because plasmin is implicated in inflammation and immunity, we investigated the effects of plasmin inhibition on the immune response after TBI in the presence or absence of induced pneumonia. Wild-type mice treated with vehicle or TXA or mice deficient in plasminogen (plg-/-) underwent TBI using the controlled cortical impact model. ⋯ Similarly, in wild type mice, treatment with TXA did not impact on the ability of mice to counteract pneumonia after TBI. Administration of TXA after TBI and subsequent pneumonia, however, altered the number and surface marker expression of several myeloid and lymphoid cell populations, consistent with enhanced immune activation at the 72 h time point. This investigation confirms the immune-modulatory properties of TXA, thereby highlighting its effects unrelated to inhibition of fibrinolysis.