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Genetics traumatic brain injury

Ethan A Winkler, John K Yue, Adam R Ferguson, Nancy R Temkin, Murray B Stein, Jason Barber, Esther L Yuh, Sourabh Sharma, Gabriela G Satris, Thomas W McAllister, Jonathan Rosand, Marco D Sorani, Hester F Lingsma, Phiroz E Tarapore, Esteban G Burchard, Donglei Hu, Celeste Eng, Kevin K W Wang, Pratik Mukherjee, David O Okonkwo, Ramon Diaz-Arrastia, Geoffrey T Manley
Mild traumatic brain injury (mTBI) results in variable clinical trajectories and outcomes. The source of variability remains unclear, but may involve genetic variations, such as single nucleotide polymorphisms (SNPs). A SNP in catechol-o-methyltransferase (COMT) is suggested to influence development of post-traumatic stress disorder (PTSD), but its role in TBI remains unclear. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val(158)Met polymorphism is associated with PTSD and global functional outcome as measured by the PTSD Checklist - Civilian Version and Glasgow Outcome Scale Extended (GOSE), respectively...
October 18, 2016: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
Sandro M Krieg, Raimund Trabold, Nikolaus Plesnila
Arginine-vasopressin (AVP) V1 receptors are known to mediate brain edema formation after traumatic brain injury (TBI). So far, however, AVP V1 receptors were only inhibited by genetic deletion or prior to trauma. Therefore the current study aimed to determine the therapeutic window of AVP V1 receptors anatomization after TBI. Male C57BL/6 mice (n=7 per group) were subjected to controlled cortical impact (CCI) and 500 ng of a selective peptide V1 receptor antagonist (V1880) were applied by intracerebroventricular injection 5 min, 1, 3, and 6 hours thereafter...
October 20, 2016: Journal of Neurotrauma
Rebeccah J Katzenberger, Barry Ganetzky, David A Wassarman
Outcomes of traumatic brain injury (TBI) vary because of differences in primary and secondary injuries. Primary injuries occur at the time of a traumatic event, whereas secondary injuries occur later as a result of cellular and molecular events activated in the brain and other tissues by primary injuries. We used a Drosophila melanogaster TBI model to investigate secondary injuries that cause acute mortality. By analyzing percent mortality within 24 hours of primary injuries, we previously found that age at the time of primary injuries and diet afterward affect the severity of secondary injuries...
October 17, 2016: G3: Genes—Genomes—Genetics
Emilio Russo, Rita Citraro, Andrew Constanti, Antonio Leo, Annika Lüttjohann, Gilles van Luijtelaar, Giovambattista De Sarro
The WAG/Rij rat model has recently gathered attention as a suitable animal model of absence epileptogenesis. This latter term has a broad definition encompassing any possible cause that determines the development of spontaneous seizures; however, most of, if not all, preclinical knowledge on epileptogenesis is confined to the study of post-brain insult models such as traumatic brain injury or post-status epilepticus models. WAG/Rij rats, but also synapsin 2 knockout, Kv7 current-deficient mice represent the first examples of genetic models where an efficacious antiepileptogenic treatment (ethosuximide) was started before seizure onset...
September 26, 2016: Neuroscience and Biobehavioral Reviews
Ruchira M Jha, Ava M Puccio, David O Okonkwo, Benjamin E Zusman, Seo-Young Park, Jessica Wallisch, Philip E Empey, Lori A Shutter, Robert S B Clark, Patrick M Kochanek, Yvette P Conley
OBJECTIVE: Cerebral edema (CE) in traumatic brain injury (TBI) is the consequence of multiple underlying mechanisms and is associated with unfavorable outcomes. Genetic variability in these pathways likely explains some of the clinical heterogeneity observed in edema development. A role for sulfonylurea receptor-1 (Sur1) in CE is supported. However, there are no prior studies examining the effect of genetic variability in the Sur1 gene (ABCC8) on the development of CE. We hypothesize that ABCC8 single nucleotide polymorphisms (SNPs) are predictive of CE...
September 27, 2016: Neurocritical Care
Sandy R Shultz, Stuart J McDonald, Cole Vonder Haar, Alicia Meconi, Robert Vink, Paul van Donkelaar, Chand Taneja, Grant L Iverson, Brian R Christie
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...
September 19, 2016: Neuroscience and Biobehavioral Reviews
Victoria McCutcheon, Eugene Park, Elaine Liu, Pooya Sobhe Bidari, Jahan Tavakkoli, Xiao-Yan Wen, Andrew J Baker
Traumatic brain injury (TBI) is a leading cause of death and morbidity in industrialized countries with considerable associated healthcare costs. The cost and time associated with preclinical development of TBI therapeutics is lengthy and expensive with a poor track record of successful translation to the clinic. The zebrafish is an emerging model organism in research with unique technical and genomic strengths in the study of disease and development. Its high degree of genetic homology and cell signaling pathways relative to mammalian species and amenability to high and medium throughput assays has potential to accelerate the rate of therapeutic drug identification...
September 20, 2016: Journal of Neurotrauma
Joshua Kamins, Christopher C Giza
Concussion is increasingly recognized as a major public health issue. Most patients will return to baseline and experience full recovery, although a subset experiences persistent symptoms. Newer animal models and imaging studies are beginning to demonstrate that metabolic and neurovascular resolution may actually take longer than symptomatic recovery. Repeat traumatic brain injury within the metabolic window of dysfunction may result in worsened symptoms and prolonged recovery. The true risk for second impact syndrome appears to be small, and development of cerebral edema after a mild impact may be related to genetic risks rather than serial impacts...
October 2016: Neurosurgery Clinics of North America
Melissa J McGinn, John T Povlishock
This article provides a concise overview, at the structural and functional level, of those changes evoked by traumatic brain injury across the spectrum of the disease. Using data derived from animals and humans, the pathogenesis of focal versus diffuse brain damage is presented for consideration of its overall implications for morbidity. Emphasis is placed on contusion and its potential expansion in concert with diffuse changes primarily assessed at the axonal level. Concomitant involvement of neuroexcitation and its role in global and focal metabolic changes is considered...
October 2016: Neurosurgery Clinics of North America
Gustav Folmer Genét, Peter Bentzer, Sisse Rye Ostrowski, Pär Ingemar Johansson
Traumatic brain injury and hemorrhagic shock is associated with blood-brain barrier (BBB) breakdown and edema formation. Recent animal studies have shown that fresh frozen plasma (FFP) resuscitation reduces brain swelling and improves endothelial function compared to isotonic NaCl (NS). The aim of this study was to investigate whether pooled and pathogen-reduced plasma (OctaplasLG(®) [OCTA]; Octapharma, Stockholm, Sweden) was comparable to FFP with regard to effects on brain water content, BBB permeability, and plasma biomarkers of endothelial glycocalyx shedding and cell damage...
October 13, 2016: Journal of Neurotrauma
Fushun Wang, Xiaowei Wang, Lee A Shapiro, Maria L Cotrina, Weimin Liu, Ernest W Wang, Simeng Gu, Wei Wang, Xiaosheng He, Maiken Nedergaard, Jason H Huang
Traumatic brain injury (TBI) is not only a leading cause for morbidity and mortality in young adults (Bruns and Hauser, Epilepsia 44(Suppl 10):210, 2003), but also a leading cause of seizures. Understanding the seizure-inducing mechanisms of TBI is of the utmost importance, because these seizures are often resistant to traditional first- and second-line anti-seizure treatments. The early post-traumatic seizures, in turn, are a contributing factor to ongoing neuropathology, and it is critically important to control these seizures...
September 1, 2016: Brain Structure & Function
Eric P Ratliff, Ayeh Barekat, Marta M Lipinski, Kim D Finley
Drosophila models have been successfully used to identify many genetic components that affect neurodegenerative disorders. Recently, there has been a growing interest in identifying innate and environmental factors that influence the individual outcomes following traumatic brain injury (TBI). This includes both severe TBI and more subtle, mild TBI (mTBI), which is common in people playing contact sports. Autophagy, as a clearance pathway, exerts protective effects in multiple neurological disease models. In a recent publication, we highlighted the development of a novel repetitive mTBI system using Drosophila, which recapitulates several phenotypes associated with trauma in mammalian models...
August 25, 2016: Autophagy
Amir Sariaslan, David J Sharp, Brian M D'Onofrio, Henrik Larsson, Seena Fazel
BACKGROUND: Traumatic brain injury (TBI) is the leading cause of disability and mortality in children and young adults worldwide. It remains unclear, however, how TBI in childhood and adolescence is associated with adult mortality, psychiatric morbidity, and social outcomes. METHODS AND FINDINGS: In a Swedish birth cohort between 1973 and 1985 of 1,143,470 individuals, we identified all those who had sustained at least one TBI (n = 104,290 or 9.1%) up to age 25 y and their unaffected siblings (n = 68,268) using patient registers...
August 2016: PLoS Medicine
Zhongqi Li, Diana Oganesyan, Rachael Mooney, Xianfang Rong, Matthew J Christensen, David Shahmanyan, Patrick M Perrigue, Joseph Benetatos, Lusine Tsaturyan, Soraya Aramburo, Alexander J Annala, Yang Lu, Joseph Najbauer, Xiwei Wu, Michael E Barish, David L Brody, Karen S Aboody, Margarita Gutova
Pre-clinical studies indicate that neural stem cells (NSCs) can limit or reverse CNS damage through direct cell replacement, promotion of regeneration, or delivery of therapeutic agents. Immortalized NSC lines are in growing demand due to the inherent limitations of adult patient-derived NSCs, including availability, expandability, potential for genetic modifications, and costs. Here, we describe the generation and characterization of a new human fetal NSC line, immortalized by transduction with L-MYC (LM-NSC008) that in vitro displays both self-renewal and multipotent differentiation into neurons, oligodendrocytes, and astrocytes...
September 13, 2016: Stem Cell Reports
Shaobin Wang, Brandi Reeves, Erica M Sparkenbaugh, Janice Russell, Zbigniew Soltys, Hua Zhang, James E Faber, Nigel S Key, Daniel Kirchhofer, D Neil Granger, Nigel Mackman, Rafal Pawlinski
Within the CNS, a dysregulated hemostatic response contributes to both hemorrhagic and ischemic strokes. Tissue factor (TF), the primary initiator of the extrinsic coagulation cascade, plays an essential role in hemostasis and also contributes to thrombosis. Using both genetic and pharmacologic approaches, we characterized the contribution of neuroectodermal (NE) cell TF to the pathophysiology of stroke. We used mice with various levels of TF expression and found that astrocyte TF activity reduced to ~5% of WT levels was still sufficient to maintain hemostasis after hemorrhagic stroke but was also low enough to attenuate inflammation, reduce damage to the blood-brain barrier, and improve outcomes following ischemic stroke...
July 21, 2016: JCI Insight
Alexander V Glushakov, Rodrigo A Arias, Emanuela Tolosano, Sylvain Doré
Cerebral hemorrhages are common features of traumatic brain injury (TBI) and their presence is associated with chronic disabilities. Recent clinical and experimental evidence suggests that haptoglobin (Hp), an endogenous hemoglobin-binding protein most abundant in blood plasma, is involved in the intrinsic molecular defensive mechanism, though its role in TBI is poorly understood. The aim of this study was to investigate the effects of Hp deletion on the anatomical and behavioral outcomes in the controlled cortical impact model using wildtype (WT) C57BL/6 mice and genetically modified mice lacking the Hp gene (Hp(-∕-)) in two age cohorts [2-4 mo-old (young adult) and 7-8 mo-old (older adult)]...
2016: Frontiers in Molecular Biosciences
Renato Polimanti, Chia-Yen Chen, Robert J Ursano, Steven G Heeringa, Sonia Jain, Ronald C Kessler, Matthew K Nock, Jordan Smoller, Xiaoying Sun, Joel Gelernter, Murray B Stein
Traumatic brain injury (TBI) contributes to the increased rates of suicide and post-traumatic stress disorder in military personnel and veterans; and it is also associated with the risk of neurodegenerative and psychiatric disorders. A cross-phenotype high-resolution polygenic risk score (PRS) analysis of persistent post-concussive symptoms (PCS) was conducted in 845 U.S. Army soldiers who sustained TBI during their deployment. We used a prospective longitudinal survey of three Brigade Combat Teams to assess deployment-acquired TBI and persistent physical, cognitive, and emotional PCS...
July 20, 2016: Journal of Neurotrauma
Fenella Jane Kirkham
Pediatric neurology relies on ultrasound, computed tomography (CT), and magnetic resonance (MR) imaging. CT prevails in acute neurologic presentations, including traumatic brain injury (TBI), nontraumatic coma, stroke, and status epilepticus, because of easy availability, with images of diagnostic quality, e.g., to exclude hemorrhage, usually completed quickly enough to avoid sedation. Concerns over the risks of ionizing radiation mean re-imaging and higher-dose procedures, e.g., arteriography and venography, require justification...
2016: Handbook of Clinical Neurology
Amir Sariaslan, Paul Lichtenstein, Henrik Larsson, Seena Fazel
IMPORTANCE: Absolute and relative risks of violence are increased in patients with psychotic disorders, but the contribution of triggers for violent acts to these risks is uncertain. OBJECTIVE: To examine whether a range of triggers for violent acts are associated with risks of violence in patients diagnosed with psychotic disorders and in individuals without a psychiatric diagnosis. DESIGN, SETTING, AND PARTICIPANTS: Using a sample of all individuals born in Sweden between 1958 and 1988 (N = 3 123 724), we identified patients in the National Patient Register who were diagnosed with schizophrenia spectrum disorders (n = 34 903) and bipolar disorder (n = 29 692), as well as unaffected controls (n = 2 763 012)...
August 1, 2016: JAMA Psychiatry
Chong-Chi Chiu, Yi-En Liao, Ling-Yu Yang, Jing-Ya Wang, David Tweedie, Hanuma K Karnati, Nigel H Greig, Jia-Yi Wang
Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide. Neuroinflammation is prominent in the short and long-term consequences of neuronal injuries that occur after TBI. Neuroinflammation involves the activation of glia, including microglia and astrocytes, to release inflammatory mediators within the brain, and the subsequent recruitment of peripheral immune cells. Various animal models of TBI have been developed that have proved valuable to elucidate the pathophysiology of the disorder and to assess the safety and efficacy of novel therapies prior to clinical trials...
July 2, 2016: Journal of Neuroscience Methods
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