Ojo, J O; Mouzon, B C; Crawford, F
Repetitive head trauma, chronic traumatic encephalopathy and tau: Challenges in translating from mice to men Journal Article
In: Experimental Neurology, vol. 275, pp. 389–404, 2016.
Abstract | Links | BibTeX | Tags: amyloid beta protein, animal, Animal models, Animals, Astroglial tangles, Brain Injury, cell activation, Chronic, complication, Concussion, Craniocerebral Trauma, CTE, diffuse axonal injury, disease duration, disease model, Disease Models, genetic predisposition, gliosis, head injury, hippocampus, human, Humans, lifestyle modification, lithium, metabolism, Mice, microglia, minocycline, mouse, nervous system inflammation, Neurobehaviour, Neurofibrillary tangles, neuropathology, nonhuman, pathogenesis, pathology, priority journal, procedures, protein aggregation, protein analysis, protein blood level, protein cleavage, Repetitive TBI, Review, sex difference, stress activated protein kinase inhibitor, Systematic Review, Tau, tau protein, tau Proteins, Transgenic mice, Translational Medical Research, translational research, traumatic brain injury, trends
@article{Ojo2016,
title = {Repetitive head trauma, chronic traumatic encephalopathy and tau: Challenges in translating from mice to men},
author = {Ojo, J O and Mouzon, B C and Crawford, F},
doi = {10.1016/j.expneurol.2015.06.003},
year = {2016},
date = {2016-01-01},
journal = {Experimental Neurology},
volume = {275},
pages = {389--404},
abstract = {Chronic traumatic encephalopathy (CTE) is a neurological and psychiatric condition marked by preferential perivascular foci of neurofibrillary and glial tangles (composed of hyperphosphorylated-tau proteins) in the depths of the sulci. Recent retrospective case series published over the last decade on athletes and military personnel have added considerably to our clinical and histopathological knowledge of CTE. This has marked a vital turning point in the traumatic brain injury (TBI) field, raising public awareness of the potential long-term effects of mild and moderate repetitive TBI, which has been recognized as one of the major risk factors associated with CTE. Although these human studies have been informative, their retrospective design carries certain inherent limitations that should be cautiously interpreted. In particular, the current overriding issue in the CTE literature remains confusing in regard to appropriate definitions of terminology, variability in individual pathologies and the potential case selection bias in autopsy based studies. There are currently no epidemiological or prospective studies on CTE. Controlled preclinical studies in animals therefore provide an alternative means for specifically interrogating aspects of CTE pathogenesis. In this article, we review the current literature and discuss difficulties and challenges of developing in-vivo TBI experimental paradigms to explore the link between repetitive head trauma and tau-dependent changes. We provide our current opinion list of recommended features to consider for successfully modeling CTE in animals to better understand the pathobiology and develop therapeutics and diagnostics, and critical factors, which might influence outcome. We finally discuss the possible directions of future experimental research in the repetitive TBI/CTE field. © 2015 Elsevier Inc..},
keywords = {amyloid beta protein, animal, Animal models, Animals, Astroglial tangles, Brain Injury, cell activation, Chronic, complication, Concussion, Craniocerebral Trauma, CTE, diffuse axonal injury, disease duration, disease model, Disease Models, genetic predisposition, gliosis, head injury, hippocampus, human, Humans, lifestyle modification, lithium, metabolism, Mice, microglia, minocycline, mouse, nervous system inflammation, Neurobehaviour, Neurofibrillary tangles, neuropathology, nonhuman, pathogenesis, pathology, priority journal, procedures, protein aggregation, protein analysis, protein blood level, protein cleavage, Repetitive TBI, Review, sex difference, stress activated protein kinase inhibitor, Systematic Review, Tau, tau protein, tau Proteins, Transgenic mice, Translational Medical Research, translational research, traumatic brain injury, trends},
pubstate = {published},
tppubtype = {article}
}
Mollayeva, T; Mollayeva, S; Colantonio, A
The Risk of Sleep Disorder Among Persons with Mild Traumatic Brain Injury Journal Article
In: Current Neurology & Neuroscience Reports, vol. 16, no. 6, pp. 55, 2016.
Abstract | BibTeX | Tags: *Brain Concussion/co [Complications], *Sleep Wake Disorders/et [Etiology], Animals, Brain Concussion/pa [Pathology], Brain/pa [Pathology], Humans, Risk Factors, Sleep Wake Disorders/ge [Genetics], wakefulness
@article{Mollayeva2016,
title = {The Risk of Sleep Disorder Among Persons with Mild Traumatic Brain Injury},
author = {Mollayeva, T and Mollayeva, S and Colantonio, A},
year = {2016},
date = {2016-01-01},
journal = {Current Neurology \& Neuroscience Reports},
volume = {16},
number = {6},
pages = {55},
abstract = {Sleep disorders and mild traumatic brain injury (mTBI) are among the most commonly occurring neurological problems clinicians encounter simultaneously. Each can cause the other, and both share common predisposing factors. An important question that remains to be addressed is whether high-risk groups can be defined. We observed an accumulation of considerable knowledge on sleep dysfunction in mTBI in recently published works. The results highlight sleep disturbances in mTBI as the product of diverse internal and external influences, acting on a genetically determined substrate. This may partially explain the clinical heterogeneity of mTBI, pointing to the importance of establishing an accurate history on the onset and course of a specific sleep disorder in the early stages post-mTBI in the individual patient. Such an approach will aid not only diagnosis and treatment but may also lead to identification of disorders whose symptoms mimic those of TBI and thereby direct the most suitable treatment and management.},
keywords = {*Brain Concussion/co [Complications], *Sleep Wake Disorders/et [Etiology], Animals, Brain Concussion/pa [Pathology], Brain/pa [Pathology], Humans, Risk Factors, Sleep Wake Disorders/ge [Genetics], wakefulness},
pubstate = {published},
tppubtype = {article}
}
Lucke-Wold, B P; Turner, R C; Logsdon, A F; Nguyen, L; Bailes, J E; Lee, J M; Robson, M J; Omalu, B I; Huber, J D; Rosen, C L
Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy Journal Article
In: Journal of Neurosurgery, vol. 124, no. 3, pp. 687–702, 2016.
Abstract | BibTeX | Tags: *Blast Injuries/px [Psychology], *Brain Injury, *Endoplasmic Reticulum Stress/ph [Physiology], *Football/in [Injuries], *Wrestling/in [Injuries], adult, animal, Animals, Blast Injuries/et [Etiology], Blast Injuries/pa [Pathology], Brain Injury, Chronic/et [Etiology], Chronic/pa [Pathology], Chronic/px [Psychology], Disease Models, Humans, Male, Rats, Sprague-Dawley
@article{Lucke-Wold2016,
title = {Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy},
author = {Lucke-Wold, B P and Turner, R C and Logsdon, A F and Nguyen, L and Bailes, J E and Lee, J M and Robson, M J and Omalu, B I and Huber, J D and Rosen, C L},
year = {2016},
date = {2016-01-01},
journal = {Journal of Neurosurgery},
volume = {124},
number = {3},
pages = {687--702},
abstract = {OBJECTIVE: Chronic traumatic encephalopathy is a progressive neurodegenerative disease characterized by neurofibrillary tau tangles following repetitive neurotrauma. The underlying mechanism linking traumatic brain injury to chronic traumatic encephalopathy has not been elucidated. The authors investigate the role of endoplasmic reticulum stress as a link between acute neurotrauma and chronic neurodegeneration. METHODS: The authors used pharmacological, biochemical, and behavioral tools to assess the role of endoplasmic reticulum stress in linking acute repetitive traumatic brain injury to the development of chronic neurodegeneration. Data from the authors' clinically relevant and validated rodent blast model were compared with those obtained from postmortem human chronic traumatic encephalopathy specimens from a National Football League player and World Wrestling Entertainment wrestler. RESULTS: The results demonstrated strong correlation of endoplasmic reticulum stress activation with subsequent tau hyperphosphorylation. Various endoplasmic reticulum stress markers were increased in human chronic traumatic encephalopathy specimens, and the endoplasmic reticulum stress response was associated with an increase in the tau kinase, glycogen synthase kinase-3beta. Docosahexaenoic acid, an endoplasmic reticulum stress inhibitor, improved cognitive performance in the rat model 3 weeks after repetitive blast exposure. The data showed that docosahexaenoic acid administration substantially reduced tau hyperphosphorylation (t = 4.111, p \< 0.05), improved cognition (t = 6.532, p \< 0.001), and inhibited C/EBP homology protein activation (t = 5.631, p \< 0.01). Additionally the data showed, for the first time, that endoplasmic reticulum stress is involved in the pathophysiology of chronic traumatic encephalopathy. CONCLUSIONS: Docosahexaenoic acid therefore warrants further investigation as a potential therapeutic agent for the prevention of chronic traumatic encephalopathy.},
keywords = {*Blast Injuries/px [Psychology], *Brain Injury, *Endoplasmic Reticulum Stress/ph [Physiology], *Football/in [Injuries], *Wrestling/in [Injuries], adult, animal, Animals, Blast Injuries/et [Etiology], Blast Injuries/pa [Pathology], Brain Injury, Chronic/et [Etiology], Chronic/pa [Pathology], Chronic/px [Psychology], Disease Models, Humans, Male, Rats, Sprague-Dawley},
pubstate = {published},
tppubtype = {article}
}
Faden, A I; Loane, D J
Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation? Journal Article
In: Neurotherapeutics, vol. 12, no. 1, pp. 143–150, 2015.
Abstract | BibTeX | Tags: *Alzheimer Disease/et [Etiology], *Brain Injuries/co [Complications], *Brain Injury, *Encephalitis/et [Etiology], *Nerve Degeneration/et [Etiology], Alzheimer Disease/pa [Pathology], Animals, Brain Injury, Chronic/et [Etiology], Chronic/pa [Pathology], Encephalitis/pa [Pathology], Humans, Nerve Degeneration/pa [Pathology]
@article{Faden2015,
title = {Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation?},
author = {Faden, A I and Loane, D J},
year = {2015},
date = {2015-01-01},
journal = {Neurotherapeutics},
volume = {12},
number = {1},
pages = {143--150},
abstract = {It has long been suggested that prior traumatic brain injury (TBI) increases the subsequent incidence of chronic neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis. Among these, the association with Alzheimer disease has the strongest support. There is also a long-recognized association between repeated concussive insults and progressive cognitive decline or other neuropsychiatric abnormalities. The latter was first described in boxers as dementia pugilistica, and has received widespread recent attention in contact sports such as professional American football. The term chronic traumatic encephalopathy was coined to attempt to define a "specific" entity marked by neurobehavioral changes and the extensive deposition of phosphorylated tau protein. Nearly lost in the discussions of post-traumatic neurodegeneration after traumatic brain injury has been the role of sustained neuroinflammation, even though this association has been well established pathologically since the 1950s, and is strongly supported by subsequent preclinical and clinical studies. Manifested by extensive microglial and astroglial activation, such chronic traumatic brain inflammation may be the most important cause of post-traumatic neurodegeneration in terms of prevalence. Critically, emerging preclinical studies indicate that persistent neuroinflammation and associated neurodegeneration may be treatable long after the initiating insult(s).},
keywords = {*Alzheimer Disease/et [Etiology], *Brain Injuries/co [Complications], *Brain Injury, *Encephalitis/et [Etiology], *Nerve Degeneration/et [Etiology], Alzheimer Disease/pa [Pathology], Animals, Brain Injury, Chronic/et [Etiology], Chronic/pa [Pathology], Encephalitis/pa [Pathology], Humans, Nerve Degeneration/pa [Pathology]},
pubstate = {published},
tppubtype = {article}
}
Jin, Y; Bouyer, J; Haas, C; Fischer, I
Evaluation of the anatomical and functional consequences of repetitive mild cervical contusion using a model of spinal concussion Journal Article
In: Experimental Neurology, vol. 271, pp. 175–188, 2015.
Abstract | BibTeX | Tags: *Gait Disorders, *Spinal Cord Injuries/co [Complications], *Spinal Cord Injuries/pa [Pathology], *Spinal Cord/pa [Pathology], 0 (Antigens, 0 (Ectodysplasins), 0 (Glial Fibrillary Acidic Protein), ANALYSIS of variance, animal, Animals, Antigens, CD31), CD31/me [Metabolism], Contusions/co [Complications], Disease Models, EC 2-7-11-13 (Protein Kinase C), Ectodysplasins/me [Metabolism], Exploratory Behavior/ph [Physiology], Female, Glial Fibrillary Acidic Protein/me [Metabolism], Muscle Strength/ph [Physiology], Neurologic/et [Etiology], PAIN measurement, Protein Kinase C/me [Metabolism], Rats, Spinal Cord Injuries/et [Etiology], Spinal Cord/me [Metabolism], Sprague-Dawley
@article{Jin2015,
title = {Evaluation of the anatomical and functional consequences of repetitive mild cervical contusion using a model of spinal concussion},
author = {Jin, Y and Bouyer, J and Haas, C and Fischer, I},
year = {2015},
date = {2015-01-01},
journal = {Experimental Neurology},
volume = {271},
pages = {175--188},
abstract = {Spinal cord concussion is characterized by a transient loss of motor and sensory function that generally resolves without permanent deficits. Spinal cord concussions usually occur during vehicular accidents, falls, and sport activity, but unlike brain concussions, have received much less attention despite the potential for repeated injury leading to permanent neurological sequelae. Consequently, there is no consensus regarding decisions related to return to play following an episode of spinal concussion, nor an understanding of the short- and long-term consequences of repeated injury. Importantly, there are no models of spinal concussion to study the anatomical and functional sequelae of single or repeated injury. We have developed a new model of spinal cord concussion focusing on the anatomical and behavioral outcomes of single and repeated injury. Rats received a very mild (50 kdyn, IH impactor) spinal contusion at C5 and were separated into two groups three weeks after the initial injury--C1, which received a second, sham surgery, and C2, which received a second contusion at the same site. To track motor function and recovery, animals received weekly behavioral tests--BBB, CatWalkTM, cylinder, and Von Frey. Analysis of locomotor activity by BBB demonstrated that rats rapidly recovered, regaining near-normal function by one week after the first and second injury, which was confirmed using the more detailed CatWalkTM analysis. The cylinder test showed that a single contusion did not induce significant deficits of the affected limb, but that repeated injury resulted in significant alteration in paw preference, with animals favoring the unaffected limb. Intriguingly, Von Frey analysis demonstrated an increased sensitivity in the contralateral hindlimb in the C2 group vs. the C1 group. Anatomical analyses revealed that while the lesion volume of both groups was minimal, the area of spared white matter in the C2 group was significantly reduced 1 and 2mm rostral to the lesion epicenter. Reactive astrocytes were present in both groups, with the majority found at the lesion epicenter in the C1 group, whereas the C2 group demonstrated increased reactive astrocytes extending 1mm caudal to the lesion epicenter. Macrophages accumulated within the injured, dorsal and ipsilateral spinal cord, with significant increases at 2 and 3mm rostral to the epicenter in the C2 group. Our model is designed to represent the clinical presentation of spinal cord concussion, and highlight the susceptibility and functional sequelae of repeated injury. Future experiments will examine the temporal and spatial windows of vulnerability for repeated injuries.Copyright © 2015. Published by Elsevier Inc.},
keywords = {*Gait Disorders, *Spinal Cord Injuries/co [Complications], *Spinal Cord Injuries/pa [Pathology], *Spinal Cord/pa [Pathology], 0 (Antigens, 0 (Ectodysplasins), 0 (Glial Fibrillary Acidic Protein), ANALYSIS of variance, animal, Animals, Antigens, CD31), CD31/me [Metabolism], Contusions/co [Complications], Disease Models, EC 2-7-11-13 (Protein Kinase C), Ectodysplasins/me [Metabolism], Exploratory Behavior/ph [Physiology], Female, Glial Fibrillary Acidic Protein/me [Metabolism], Muscle Strength/ph [Physiology], Neurologic/et [Etiology], PAIN measurement, Protein Kinase C/me [Metabolism], Rats, Spinal Cord Injuries/et [Etiology], Spinal Cord/me [Metabolism], Sprague-Dawley},
pubstate = {published},
tppubtype = {article}
}
Lucke-Wold, B P; Naser, Z J; Logsdon, A F; Turner, R C; Smith, K E; Robson, M J; Bailes, J E; Lee, J M; Rosen, C L; Huber, J D
Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury Journal Article
In: Translational Research: The Journal Of Laboratory & Clinical Medicine, vol. 166, no. 6, pp. 509–528.e1, 2015.
Abstract | BibTeX | Tags: *Blast Injuries/pa [Pathology], *Brain Injuries/pa [Pathology], *NADPH Oxidase/me [Metabolism], *Oxidative Stress, 73Y7P0K73Y (Thioctic Acid), Animals, Apoptosis, Blast Injuries/en [Enzymology], Blast Injuries/me [Metabolism], Brain Injuries/en [Enzymology], Brain Injuries/me [Metabolism], EC 1-6-3-1 (NADPH Oxidase), Male, Rats, Sprague-Dawley, Thioctic Acid/pd [Pharmacology]
@article{Lucke-Wold2015,
title = {Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury},
author = {Lucke-Wold, B P and Naser, Z J and Logsdon, A F and Turner, R C and Smith, K E and Robson, M J and Bailes, J E and Lee, J M and Rosen, C L and Huber, J D},
year = {2015},
date = {2015-01-01},
journal = {Translational Research: The Journal Of Laboratory \& Clinical Medicine},
volume = {166},
number = {6},
pages = {509--528.e1},
abstract = {A total of 1.7 million traumatic brain injuries (TBIs) occur each year in the United States, but available pharmacologic options for the treatment of acute neurotrauma are limited. Oxidative stress is an important secondary mechanism of injury that can lead to neuronal apoptosis and subsequent behavioral changes. Using a clinically relevant and validated rodent blast model, we investigated how nicotinamide adenine dinucleotide phosphate oxidase (Nox) expression and associated oxidative stress contribute to cellular apoptosis after single and repeat blast injuries. Nox4 forms a complex with p22phox after injury, forming free radicals at neuronal membranes. Using immunohistochemical-staining methods, we found a visible increase in Nox4 after single blast injury in Sprague Dawley rats. Interestingly, Nox4 was also increased in postmortem human samples obtained from athletes diagnosed with chronic traumatic encephalopathy. Nox4 activity correlated with an increase in superoxide formation. Alpha-lipoic acid, an oxidative stress inhibitor, prevented the development of superoxide acutely and increased antiapoptotic markers B-cell lymphoma 2 (t = 3.079, P \< 0.05) and heme oxygenase 1 (t = 8.169, P \< 0.001) after single blast. Subacutely, alpha-lipoic acid treatment reduced proapoptotic markers Bax (t = 4.483, P \< 0.05), caspase 12 (t = 6.157, P \< 0.001), and caspase 3 (t = 4.573, P \< 0.01) after repetitive blast, and reduced tau hyperphosphorylation indicated by decreased CP-13 and paired helical filament staining. Alpha-lipoic acid ameliorated impulsive-like behavior 7 days after repetitive blast injury (t = 3.573, P \< 0.05) compared with blast exposed animals without treatment. TBI can cause debilitating symptoms and psychiatric disorders. Oxidative stress is an ideal target for neuropharmacologic intervention, and alpha-lipoic acid warrants further investigation as a therapeutic for prevention of chronic neurodegeneration. Copyright © 2015 Elsevier Inc. All rights reserved.},
keywords = {*Blast Injuries/pa [Pathology], *Brain Injuries/pa [Pathology], *NADPH Oxidase/me [Metabolism], *Oxidative Stress, 73Y7P0K73Y (Thioctic Acid), Animals, Apoptosis, Blast Injuries/en [Enzymology], Blast Injuries/me [Metabolism], Brain Injuries/en [Enzymology], Brain Injuries/me [Metabolism], EC 1-6-3-1 (NADPH Oxidase), Male, Rats, Sprague-Dawley, Thioctic Acid/pd [Pharmacology]},
pubstate = {published},
tppubtype = {article}
}
Grafman, J; Salazar, A M
The ebb and flow of traumatic brain injury research Journal Article
In: Handbook of Clinical Neurology, vol. 128, pp. 795–802, 2015.
Abstract | BibTeX | Tags: *Biomedical Research/mt [Methods], *Biomedical Research/td [Trends], *Brain Injuries/th [Therapy], Animals, Humans
@article{Grafman2015,
title = {The ebb and flow of traumatic brain injury research},
author = {Grafman, J and Salazar, A M},
year = {2015},
date = {2015-01-01},
journal = {Handbook of Clinical Neurology},
volume = {128},
pages = {795--802},
abstract = {The purpose of this chapter is to summarize some key topics discussed in this volume and describe trends suggesting the direction of future traumatic brain injury (TBI) research. Interest in, and funding for, TBI has ebbed and flowed with the public awareness of injury risk from combat, sports, or everyday life. Advances in acute resuscitation, emergency response systems, and early management have had a major impact on survival after TBI, while recent research has emphasized underlying genetic substrates and the molecular mechanisms of brain injury, repair, and neuroplasticity. This in turn impacts not only on primary and secondary neuroprotection strategies for minimizing injury, but also on the other critical remaining challenge, that of identification and validation of optimal strategies for physical and cognitive TBI rehabilitation. New information also highlights long-term degenerative conditions associated with earlier TBI and mediated by a signature cascade of abnormal molecular processes. Thus, TBI has emerged as a recognized significant public health risk with both immediate and lifelong repercussions. The linkage of a TBI to late-life neurodegenerative diseases, the observation of persistent pathologic processes including neuroinflammation and accumulation of tau protein, as well as individual differences in the genetic predisposition for brain repair and plasticity should lead to meaningful translational research with a significant impact on the efficacy and cost-efficiency of acute and chronic treatment for TBI survivors. Copyright © 2015 Elsevier B.V. All rights reserved.},
keywords = {*Biomedical Research/mt [Methods], *Biomedical Research/td [Trends], *Brain Injuries/th [Therapy], Animals, Humans},
pubstate = {published},
tppubtype = {article}
}
Levin, B; Bhardwaj, A
Chronic traumatic encephalopathy: A critical appraisal Journal Article
In: Neurocritical Care, vol. 20, no. 2, pp. 334–344, 2014.
Abstract | Links | BibTeX | Tags: accident, alcohol consumption, amnesia, amyloid plaque, animal, Animals, Athletic Injuries, autopsy, behavior change, Brain Injury, Chronic, Chronic traumatic encephalopathy, Chronic Traumatic Encephalopathy Dementia, complication, Diffusion Tensor Imaging, disease course, Encephalopathy, functional magnetic resonance imaging, histopathology, human, Humans, longitudinal study, Male, Neurodegenerative, Neurodegenerative Diseases, nonhuman, NUCLEAR magnetic resonance spectroscopy, Parkinsonism, pathogenesis, pathology, Pathophysiology, Prevalence, priority journal, Pugilistic, Review, risk factor, Risk Factors, sport injury, suicide, Systematic Review, traumatic brain injury, violence
@article{Levin2014,
title = {Chronic traumatic encephalopathy: A critical appraisal},
author = {Levin, B and Bhardwaj, A},
url = {http://www.scopus.com/inward/record.url?eid=2-s2.0-84896549537\&partnerID=40\&md5=138104db42f7ca99527a78bb9c821f59},
doi = {10.1007/s12028-013-9931-1},
year = {2014},
date = {2014-01-01},
journal = {Neurocritical Care},
volume = {20},
number = {2},
pages = {334--344},
abstract = {Chronic traumatic encephalopathy (CTE) formerly known as dementia pugilistica is a long-term neurodegenerative disorder associated with repeated subconcussive head injuries in high-contact sports. We reviewed the existing literature on CTE and examined epidemiological trends, risk factors, and its temporal progression, and proposed the underlying pathophysiological mechanisms that may provide unique insights to clinicians with an in-depth understanding of the disease to aid in the diagnosis and prevention, and provide future perspectives for research via search of Medline and Cochrane databases as well as manual review of bibliographies from selected articles and monographs. The prevalence of CTE in recent years is on the rise and almost exclusively affects men, with pathologic signs characterized by progressive memory loss, behavioral changes, and violent tendencies with some patients demonstrating Parkinsonian-like symptoms and signs. Many patients with CTE die following suicide, accident, or complications of drug or alcohol use. Postmortem pathologic analysis is characterized by neurofibrillary tangles and A$beta$ plaques in 50 % of cases. Currently, there are no ante-mortem diagnostic criteria, but modern imaging techniques such as functional magnetic resonance (MR) imaging, MR spectroscopy, and diffusion tension imaging hold promise for delineating the future diagnostic criteria. Further long-term longitudinal studies are warranted to investigate risk factors that will enhance understanding of the disease progression and its pathogenesis. © 2013 Springer Science+Business Media.},
keywords = {accident, alcohol consumption, amnesia, amyloid plaque, animal, Animals, Athletic Injuries, autopsy, behavior change, Brain Injury, Chronic, Chronic traumatic encephalopathy, Chronic Traumatic Encephalopathy Dementia, complication, Diffusion Tensor Imaging, disease course, Encephalopathy, functional magnetic resonance imaging, histopathology, human, Humans, longitudinal study, Male, Neurodegenerative, Neurodegenerative Diseases, nonhuman, NUCLEAR magnetic resonance spectroscopy, Parkinsonism, pathogenesis, pathology, Pathophysiology, Prevalence, priority journal, Pugilistic, Review, risk factor, Risk Factors, sport injury, suicide, Systematic Review, traumatic brain injury, violence},
pubstate = {published},
tppubtype = {article}
}
Kiraly, M; Kiraly, S J
Traumatic brain injury and delayed sequelae: a review--traumatic brain injury and mild traumatic brain injury (concussion) are precursors to later-onset brain disorders, including early-onset dementia Journal Article
In: TheScientificWorldJournal, vol. 7, pp. 1768–1776, 2007.
Abstract | BibTeX | Tags: *Brain Injuries/co [Complications], *Brain Injuries/pp [Physiopathology], *Brain/pp [Physiopathology], *Dementia/et [Etiology], *Dementia/pp [Physiopathology], *Models, Animals, Humans, Neurological
@article{Kiraly2007,
title = {Traumatic brain injury and delayed sequelae: a review--traumatic brain injury and mild traumatic brain injury (concussion) are precursors to later-onset brain disorders, including early-onset dementia},
author = {Kiraly, M and Kiraly, S J},
year = {2007},
date = {2007-01-01},
journal = {TheScientificWorldJournal},
volume = {7},
pages = {1768--1776},
abstract = {Brain injuries are too common. Most people are unaware of the incidence of and horrendous consequences of traumatic brain injury (TBI) and mild traumatic brain injury (MTBI). Research and the advent of sophisticated imaging have led to progression in the understanding of brain pathophysiology following TBI. Seminal evidence from animal and human experiments demonstrate links between TBI and the subsequent onset of premature, psychiatric syndromes and neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Objectives of this summary are, therefore, to instill appreciation regarding the importance of brain injury prevention, diagnosis, and treatment, and to increase awareness regarding the long-term delayed consequences following TBI. [References: 88]},
keywords = {*Brain Injuries/co [Complications], *Brain Injuries/pp [Physiopathology], *Brain/pp [Physiopathology], *Dementia/et [Etiology], *Dementia/pp [Physiopathology], *Models, Animals, Humans, Neurological},
pubstate = {published},
tppubtype = {article}
}
Hamberger, A; Huang, Y L; Zhu, H; Bao, F; Ding, M; Blennow, K; Olsson, A; Hansson, H A; Viano, D; Haglid, K G
Redistribution of neurofilaments and accumulation of beta-amyloid protein after brain injury by rotational acceleration of the head Journal Article
In: Journal of Neurotrauma, vol. 20, no. 2, pp. 169–178, 2003.
Abstract | BibTeX | Tags: *Amyloid beta-Peptides/me [Metabolism], *Brain Injuries/me [Metabolism], *Brain/me [Metabolism], *Neurofilament Proteins/me [Metabolism], 0 (Amyloid beta-Peptides), 0 (neurofilament protein L), 0 (Neurofilament Proteins), 108688-71-7 (neurofilament protein H), Acceleration, Animals, Brain Injuries/et [Etiology], immunohistochemistry, Phosphorylation, Rabbits, Rotation, Tissue Distribution
@article{Hamberger2003,
title = {Redistribution of neurofilaments and accumulation of beta-amyloid protein after brain injury by rotational acceleration of the head},
author = {Hamberger, A and Huang, Y L and Zhu, H and Bao, F and Ding, M and Blennow, K and Olsson, A and Hansson, H A and Viano, D and Haglid, K G},
year = {2003},
date = {2003-01-01},
journal = {Journal of Neurotrauma},
volume = {20},
number = {2},
pages = {169--178},
abstract = {Rotational acceleration of the head, as occurs in falls, car crashes, and sport injuries, may result in diffuse brain damage, with acute and chronic neurological and psychiatric symptoms. The present study addresses the effects of rotational trauma on the neuronal cytoskeleton, which stabilizes perikaryal, dendritic and axonal shape and function. The study focuses upon the distribution of (1) the phosphorylated form of the heavy neurofilament subunit, (2) the light neurofilament subunit, and (3) beta-amyloid, a marker for brain injury. While normally restricted to axons, the phosphorylated heavy neurofilament subunits were drastically decreased in the axons after rotational trauma. Instead, they accumulated in the neuronal perikarya, normally devoid of the phosphorylated subunit. This alteration was seen, not only in the cerebral cortex, but also in the hippocampus, the cervical spinal cord, the cerebellum, the cranial nerves and the pyramidal tract. The distribution of the light subunit of neurofilaments was also altered post trauma. Only a weak beta-amyloid immunoreactivity was detected in the brains of control animals. Promptly after the trauma, a large number of beta-amyloid positive neurons appeared. Intensely co-localized immunoreactivity for the light subunit of neurofilaments and of beta-amyloid was seen 3 days after the rotational trauma axons of in the subcortical white matter and in the granule cell layer of the dentate gyrus as well as in neurons of the hypoglossal nucleus. The reported alterations in the central nervous system neurons are similar to those in the human brain after closed head injury and in chronic degenerative diseases. Regions of importance for social behavior, memory and body movement were affected.},
keywords = {*Amyloid beta-Peptides/me [Metabolism], *Brain Injuries/me [Metabolism], *Brain/me [Metabolism], *Neurofilament Proteins/me [Metabolism], 0 (Amyloid beta-Peptides), 0 (neurofilament protein L), 0 (Neurofilament Proteins), 108688-71-7 (neurofilament protein H), Acceleration, Animals, Brain Injuries/et [Etiology], immunohistochemistry, Phosphorylation, Rabbits, Rotation, Tissue Distribution},
pubstate = {published},
tppubtype = {article}
}
King, A I
Fundamentals of impact biomechanics: Part I--Biomechanics of the head, neck, and thorax Journal Article
In: Annual Review of Biomedical Engineering, vol. 2, pp. 55–81, 2000.
Abstract | BibTeX | Tags: *Biomechanical Phenomena, *Craniocerebral Trauma/pp [Physiopathology], *Neck Injuries/pp [Physiopathology], *Thoracic Injuries/pp [Physiopathology], Animals, Biomedical Engineering, Brain Injuries/pp [Physiopathology], Humans
@article{King2000,
title = {Fundamentals of impact biomechanics: Part I--Biomechanics of the head, neck, and thorax},
author = {King, A I},
year = {2000},
date = {2000-01-01},
journal = {Annual Review of Biomedical Engineering},
volume = {2},
pages = {55--81},
abstract = {This is the first of two chapters dealing with some 60 years of accumulated knowledge in the field of impact biomechanics. The regions covered in this first chapter are the head, neck, and thorax. The next chapter will discuss the abdomen, pelvis, and the lower extremities. Although the principal thrust of the research has been toward the mitigation of injuries sustained by automotive crash victims, the results of this research have applications in aircraft safety, contact sports, and protection of military personnel and civilians from intentional injury, such as in the use of nonlethal weapons. The reader should be keenly aware of the wide variation in human response and tolerance data in the cited results. This is due primarily to the large biological variation among humans and to the effects of aging. Average values are useful in design but cannot be applied to individuals. [References: 94]},
keywords = {*Biomechanical Phenomena, *Craniocerebral Trauma/pp [Physiopathology], *Neck Injuries/pp [Physiopathology], *Thoracic Injuries/pp [Physiopathology], Animals, Biomedical Engineering, Brain Injuries/pp [Physiopathology], Humans},
pubstate = {published},
tppubtype = {article}
}
Ojo, J O; Mouzon, B C; Crawford, F
Repetitive head trauma, chronic traumatic encephalopathy and tau: Challenges in translating from mice to men Journal Article
In: Experimental Neurology, vol. 275, pp. 389–404, 2016.
@article{Ojo2016,
title = {Repetitive head trauma, chronic traumatic encephalopathy and tau: Challenges in translating from mice to men},
author = {Ojo, J O and Mouzon, B C and Crawford, F},
doi = {10.1016/j.expneurol.2015.06.003},
year = {2016},
date = {2016-01-01},
journal = {Experimental Neurology},
volume = {275},
pages = {389--404},
abstract = {Chronic traumatic encephalopathy (CTE) is a neurological and psychiatric condition marked by preferential perivascular foci of neurofibrillary and glial tangles (composed of hyperphosphorylated-tau proteins) in the depths of the sulci. Recent retrospective case series published over the last decade on athletes and military personnel have added considerably to our clinical and histopathological knowledge of CTE. This has marked a vital turning point in the traumatic brain injury (TBI) field, raising public awareness of the potential long-term effects of mild and moderate repetitive TBI, which has been recognized as one of the major risk factors associated with CTE. Although these human studies have been informative, their retrospective design carries certain inherent limitations that should be cautiously interpreted. In particular, the current overriding issue in the CTE literature remains confusing in regard to appropriate definitions of terminology, variability in individual pathologies and the potential case selection bias in autopsy based studies. There are currently no epidemiological or prospective studies on CTE. Controlled preclinical studies in animals therefore provide an alternative means for specifically interrogating aspects of CTE pathogenesis. In this article, we review the current literature and discuss difficulties and challenges of developing in-vivo TBI experimental paradigms to explore the link between repetitive head trauma and tau-dependent changes. We provide our current opinion list of recommended features to consider for successfully modeling CTE in animals to better understand the pathobiology and develop therapeutics and diagnostics, and critical factors, which might influence outcome. We finally discuss the possible directions of future experimental research in the repetitive TBI/CTE field. © 2015 Elsevier Inc..},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Mollayeva, T; Mollayeva, S; Colantonio, A
The Risk of Sleep Disorder Among Persons with Mild Traumatic Brain Injury Journal Article
In: Current Neurology & Neuroscience Reports, vol. 16, no. 6, pp. 55, 2016.
@article{Mollayeva2016,
title = {The Risk of Sleep Disorder Among Persons with Mild Traumatic Brain Injury},
author = {Mollayeva, T and Mollayeva, S and Colantonio, A},
year = {2016},
date = {2016-01-01},
journal = {Current Neurology \& Neuroscience Reports},
volume = {16},
number = {6},
pages = {55},
abstract = {Sleep disorders and mild traumatic brain injury (mTBI) are among the most commonly occurring neurological problems clinicians encounter simultaneously. Each can cause the other, and both share common predisposing factors. An important question that remains to be addressed is whether high-risk groups can be defined. We observed an accumulation of considerable knowledge on sleep dysfunction in mTBI in recently published works. The results highlight sleep disturbances in mTBI as the product of diverse internal and external influences, acting on a genetically determined substrate. This may partially explain the clinical heterogeneity of mTBI, pointing to the importance of establishing an accurate history on the onset and course of a specific sleep disorder in the early stages post-mTBI in the individual patient. Such an approach will aid not only diagnosis and treatment but may also lead to identification of disorders whose symptoms mimic those of TBI and thereby direct the most suitable treatment and management.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Lucke-Wold, B P; Turner, R C; Logsdon, A F; Nguyen, L; Bailes, J E; Lee, J M; Robson, M J; Omalu, B I; Huber, J D; Rosen, C L
Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy Journal Article
In: Journal of Neurosurgery, vol. 124, no. 3, pp. 687–702, 2016.
@article{Lucke-Wold2016,
title = {Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy},
author = {Lucke-Wold, B P and Turner, R C and Logsdon, A F and Nguyen, L and Bailes, J E and Lee, J M and Robson, M J and Omalu, B I and Huber, J D and Rosen, C L},
year = {2016},
date = {2016-01-01},
journal = {Journal of Neurosurgery},
volume = {124},
number = {3},
pages = {687--702},
abstract = {OBJECTIVE: Chronic traumatic encephalopathy is a progressive neurodegenerative disease characterized by neurofibrillary tau tangles following repetitive neurotrauma. The underlying mechanism linking traumatic brain injury to chronic traumatic encephalopathy has not been elucidated. The authors investigate the role of endoplasmic reticulum stress as a link between acute neurotrauma and chronic neurodegeneration. METHODS: The authors used pharmacological, biochemical, and behavioral tools to assess the role of endoplasmic reticulum stress in linking acute repetitive traumatic brain injury to the development of chronic neurodegeneration. Data from the authors' clinically relevant and validated rodent blast model were compared with those obtained from postmortem human chronic traumatic encephalopathy specimens from a National Football League player and World Wrestling Entertainment wrestler. RESULTS: The results demonstrated strong correlation of endoplasmic reticulum stress activation with subsequent tau hyperphosphorylation. Various endoplasmic reticulum stress markers were increased in human chronic traumatic encephalopathy specimens, and the endoplasmic reticulum stress response was associated with an increase in the tau kinase, glycogen synthase kinase-3beta. Docosahexaenoic acid, an endoplasmic reticulum stress inhibitor, improved cognitive performance in the rat model 3 weeks after repetitive blast exposure. The data showed that docosahexaenoic acid administration substantially reduced tau hyperphosphorylation (t = 4.111, p \< 0.05), improved cognition (t = 6.532, p \< 0.001), and inhibited C/EBP homology protein activation (t = 5.631, p \< 0.01). Additionally the data showed, for the first time, that endoplasmic reticulum stress is involved in the pathophysiology of chronic traumatic encephalopathy. CONCLUSIONS: Docosahexaenoic acid therefore warrants further investigation as a potential therapeutic agent for the prevention of chronic traumatic encephalopathy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Faden, A I; Loane, D J
Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation? Journal Article
In: Neurotherapeutics, vol. 12, no. 1, pp. 143–150, 2015.
@article{Faden2015,
title = {Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation?},
author = {Faden, A I and Loane, D J},
year = {2015},
date = {2015-01-01},
journal = {Neurotherapeutics},
volume = {12},
number = {1},
pages = {143--150},
abstract = {It has long been suggested that prior traumatic brain injury (TBI) increases the subsequent incidence of chronic neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis. Among these, the association with Alzheimer disease has the strongest support. There is also a long-recognized association between repeated concussive insults and progressive cognitive decline or other neuropsychiatric abnormalities. The latter was first described in boxers as dementia pugilistica, and has received widespread recent attention in contact sports such as professional American football. The term chronic traumatic encephalopathy was coined to attempt to define a "specific" entity marked by neurobehavioral changes and the extensive deposition of phosphorylated tau protein. Nearly lost in the discussions of post-traumatic neurodegeneration after traumatic brain injury has been the role of sustained neuroinflammation, even though this association has been well established pathologically since the 1950s, and is strongly supported by subsequent preclinical and clinical studies. Manifested by extensive microglial and astroglial activation, such chronic traumatic brain inflammation may be the most important cause of post-traumatic neurodegeneration in terms of prevalence. Critically, emerging preclinical studies indicate that persistent neuroinflammation and associated neurodegeneration may be treatable long after the initiating insult(s).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Jin, Y; Bouyer, J; Haas, C; Fischer, I
Evaluation of the anatomical and functional consequences of repetitive mild cervical contusion using a model of spinal concussion Journal Article
In: Experimental Neurology, vol. 271, pp. 175–188, 2015.
@article{Jin2015,
title = {Evaluation of the anatomical and functional consequences of repetitive mild cervical contusion using a model of spinal concussion},
author = {Jin, Y and Bouyer, J and Haas, C and Fischer, I},
year = {2015},
date = {2015-01-01},
journal = {Experimental Neurology},
volume = {271},
pages = {175--188},
abstract = {Spinal cord concussion is characterized by a transient loss of motor and sensory function that generally resolves without permanent deficits. Spinal cord concussions usually occur during vehicular accidents, falls, and sport activity, but unlike brain concussions, have received much less attention despite the potential for repeated injury leading to permanent neurological sequelae. Consequently, there is no consensus regarding decisions related to return to play following an episode of spinal concussion, nor an understanding of the short- and long-term consequences of repeated injury. Importantly, there are no models of spinal concussion to study the anatomical and functional sequelae of single or repeated injury. We have developed a new model of spinal cord concussion focusing on the anatomical and behavioral outcomes of single and repeated injury. Rats received a very mild (50 kdyn, IH impactor) spinal contusion at C5 and were separated into two groups three weeks after the initial injury--C1, which received a second, sham surgery, and C2, which received a second contusion at the same site. To track motor function and recovery, animals received weekly behavioral tests--BBB, CatWalkTM, cylinder, and Von Frey. Analysis of locomotor activity by BBB demonstrated that rats rapidly recovered, regaining near-normal function by one week after the first and second injury, which was confirmed using the more detailed CatWalkTM analysis. The cylinder test showed that a single contusion did not induce significant deficits of the affected limb, but that repeated injury resulted in significant alteration in paw preference, with animals favoring the unaffected limb. Intriguingly, Von Frey analysis demonstrated an increased sensitivity in the contralateral hindlimb in the C2 group vs. the C1 group. Anatomical analyses revealed that while the lesion volume of both groups was minimal, the area of spared white matter in the C2 group was significantly reduced 1 and 2mm rostral to the lesion epicenter. Reactive astrocytes were present in both groups, with the majority found at the lesion epicenter in the C1 group, whereas the C2 group demonstrated increased reactive astrocytes extending 1mm caudal to the lesion epicenter. Macrophages accumulated within the injured, dorsal and ipsilateral spinal cord, with significant increases at 2 and 3mm rostral to the epicenter in the C2 group. Our model is designed to represent the clinical presentation of spinal cord concussion, and highlight the susceptibility and functional sequelae of repeated injury. Future experiments will examine the temporal and spatial windows of vulnerability for repeated injuries.Copyright © 2015. Published by Elsevier Inc.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Lucke-Wold, B P; Naser, Z J; Logsdon, A F; Turner, R C; Smith, K E; Robson, M J; Bailes, J E; Lee, J M; Rosen, C L; Huber, J D
Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury Journal Article
In: Translational Research: The Journal Of Laboratory & Clinical Medicine, vol. 166, no. 6, pp. 509–528.e1, 2015.
@article{Lucke-Wold2015,
title = {Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury},
author = {Lucke-Wold, B P and Naser, Z J and Logsdon, A F and Turner, R C and Smith, K E and Robson, M J and Bailes, J E and Lee, J M and Rosen, C L and Huber, J D},
year = {2015},
date = {2015-01-01},
journal = {Translational Research: The Journal Of Laboratory \& Clinical Medicine},
volume = {166},
number = {6},
pages = {509--528.e1},
abstract = {A total of 1.7 million traumatic brain injuries (TBIs) occur each year in the United States, but available pharmacologic options for the treatment of acute neurotrauma are limited. Oxidative stress is an important secondary mechanism of injury that can lead to neuronal apoptosis and subsequent behavioral changes. Using a clinically relevant and validated rodent blast model, we investigated how nicotinamide adenine dinucleotide phosphate oxidase (Nox) expression and associated oxidative stress contribute to cellular apoptosis after single and repeat blast injuries. Nox4 forms a complex with p22phox after injury, forming free radicals at neuronal membranes. Using immunohistochemical-staining methods, we found a visible increase in Nox4 after single blast injury in Sprague Dawley rats. Interestingly, Nox4 was also increased in postmortem human samples obtained from athletes diagnosed with chronic traumatic encephalopathy. Nox4 activity correlated with an increase in superoxide formation. Alpha-lipoic acid, an oxidative stress inhibitor, prevented the development of superoxide acutely and increased antiapoptotic markers B-cell lymphoma 2 (t = 3.079, P \< 0.05) and heme oxygenase 1 (t = 8.169, P \< 0.001) after single blast. Subacutely, alpha-lipoic acid treatment reduced proapoptotic markers Bax (t = 4.483, P \< 0.05), caspase 12 (t = 6.157, P \< 0.001), and caspase 3 (t = 4.573, P \< 0.01) after repetitive blast, and reduced tau hyperphosphorylation indicated by decreased CP-13 and paired helical filament staining. Alpha-lipoic acid ameliorated impulsive-like behavior 7 days after repetitive blast injury (t = 3.573, P \< 0.05) compared with blast exposed animals without treatment. TBI can cause debilitating symptoms and psychiatric disorders. Oxidative stress is an ideal target for neuropharmacologic intervention, and alpha-lipoic acid warrants further investigation as a therapeutic for prevention of chronic neurodegeneration. Copyright © 2015 Elsevier Inc. All rights reserved.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Grafman, J; Salazar, A M
The ebb and flow of traumatic brain injury research Journal Article
In: Handbook of Clinical Neurology, vol. 128, pp. 795–802, 2015.
@article{Grafman2015,
title = {The ebb and flow of traumatic brain injury research},
author = {Grafman, J and Salazar, A M},
year = {2015},
date = {2015-01-01},
journal = {Handbook of Clinical Neurology},
volume = {128},
pages = {795--802},
abstract = {The purpose of this chapter is to summarize some key topics discussed in this volume and describe trends suggesting the direction of future traumatic brain injury (TBI) research. Interest in, and funding for, TBI has ebbed and flowed with the public awareness of injury risk from combat, sports, or everyday life. Advances in acute resuscitation, emergency response systems, and early management have had a major impact on survival after TBI, while recent research has emphasized underlying genetic substrates and the molecular mechanisms of brain injury, repair, and neuroplasticity. This in turn impacts not only on primary and secondary neuroprotection strategies for minimizing injury, but also on the other critical remaining challenge, that of identification and validation of optimal strategies for physical and cognitive TBI rehabilitation. New information also highlights long-term degenerative conditions associated with earlier TBI and mediated by a signature cascade of abnormal molecular processes. Thus, TBI has emerged as a recognized significant public health risk with both immediate and lifelong repercussions. The linkage of a TBI to late-life neurodegenerative diseases, the observation of persistent pathologic processes including neuroinflammation and accumulation of tau protein, as well as individual differences in the genetic predisposition for brain repair and plasticity should lead to meaningful translational research with a significant impact on the efficacy and cost-efficiency of acute and chronic treatment for TBI survivors. Copyright © 2015 Elsevier B.V. All rights reserved.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Levin, B; Bhardwaj, A
Chronic traumatic encephalopathy: A critical appraisal Journal Article
In: Neurocritical Care, vol. 20, no. 2, pp. 334–344, 2014.
@article{Levin2014,
title = {Chronic traumatic encephalopathy: A critical appraisal},
author = {Levin, B and Bhardwaj, A},
url = {http://www.scopus.com/inward/record.url?eid=2-s2.0-84896549537\&partnerID=40\&md5=138104db42f7ca99527a78bb9c821f59},
doi = {10.1007/s12028-013-9931-1},
year = {2014},
date = {2014-01-01},
journal = {Neurocritical Care},
volume = {20},
number = {2},
pages = {334--344},
abstract = {Chronic traumatic encephalopathy (CTE) formerly known as dementia pugilistica is a long-term neurodegenerative disorder associated with repeated subconcussive head injuries in high-contact sports. We reviewed the existing literature on CTE and examined epidemiological trends, risk factors, and its temporal progression, and proposed the underlying pathophysiological mechanisms that may provide unique insights to clinicians with an in-depth understanding of the disease to aid in the diagnosis and prevention, and provide future perspectives for research via search of Medline and Cochrane databases as well as manual review of bibliographies from selected articles and monographs. The prevalence of CTE in recent years is on the rise and almost exclusively affects men, with pathologic signs characterized by progressive memory loss, behavioral changes, and violent tendencies with some patients demonstrating Parkinsonian-like symptoms and signs. Many patients with CTE die following suicide, accident, or complications of drug or alcohol use. Postmortem pathologic analysis is characterized by neurofibrillary tangles and A$beta$ plaques in 50 % of cases. Currently, there are no ante-mortem diagnostic criteria, but modern imaging techniques such as functional magnetic resonance (MR) imaging, MR spectroscopy, and diffusion tension imaging hold promise for delineating the future diagnostic criteria. Further long-term longitudinal studies are warranted to investigate risk factors that will enhance understanding of the disease progression and its pathogenesis. © 2013 Springer Science+Business Media.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Kiraly, M; Kiraly, S J
Traumatic brain injury and delayed sequelae: a review--traumatic brain injury and mild traumatic brain injury (concussion) are precursors to later-onset brain disorders, including early-onset dementia Journal Article
In: TheScientificWorldJournal, vol. 7, pp. 1768–1776, 2007.
@article{Kiraly2007,
title = {Traumatic brain injury and delayed sequelae: a review--traumatic brain injury and mild traumatic brain injury (concussion) are precursors to later-onset brain disorders, including early-onset dementia},
author = {Kiraly, M and Kiraly, S J},
year = {2007},
date = {2007-01-01},
journal = {TheScientificWorldJournal},
volume = {7},
pages = {1768--1776},
abstract = {Brain injuries are too common. Most people are unaware of the incidence of and horrendous consequences of traumatic brain injury (TBI) and mild traumatic brain injury (MTBI). Research and the advent of sophisticated imaging have led to progression in the understanding of brain pathophysiology following TBI. Seminal evidence from animal and human experiments demonstrate links between TBI and the subsequent onset of premature, psychiatric syndromes and neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Objectives of this summary are, therefore, to instill appreciation regarding the importance of brain injury prevention, diagnosis, and treatment, and to increase awareness regarding the long-term delayed consequences following TBI. [References: 88]},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Hamberger, A; Huang, Y L; Zhu, H; Bao, F; Ding, M; Blennow, K; Olsson, A; Hansson, H A; Viano, D; Haglid, K G
Redistribution of neurofilaments and accumulation of beta-amyloid protein after brain injury by rotational acceleration of the head Journal Article
In: Journal of Neurotrauma, vol. 20, no. 2, pp. 169–178, 2003.
@article{Hamberger2003,
title = {Redistribution of neurofilaments and accumulation of beta-amyloid protein after brain injury by rotational acceleration of the head},
author = {Hamberger, A and Huang, Y L and Zhu, H and Bao, F and Ding, M and Blennow, K and Olsson, A and Hansson, H A and Viano, D and Haglid, K G},
year = {2003},
date = {2003-01-01},
journal = {Journal of Neurotrauma},
volume = {20},
number = {2},
pages = {169--178},
abstract = {Rotational acceleration of the head, as occurs in falls, car crashes, and sport injuries, may result in diffuse brain damage, with acute and chronic neurological and psychiatric symptoms. The present study addresses the effects of rotational trauma on the neuronal cytoskeleton, which stabilizes perikaryal, dendritic and axonal shape and function. The study focuses upon the distribution of (1) the phosphorylated form of the heavy neurofilament subunit, (2) the light neurofilament subunit, and (3) beta-amyloid, a marker for brain injury. While normally restricted to axons, the phosphorylated heavy neurofilament subunits were drastically decreased in the axons after rotational trauma. Instead, they accumulated in the neuronal perikarya, normally devoid of the phosphorylated subunit. This alteration was seen, not only in the cerebral cortex, but also in the hippocampus, the cervical spinal cord, the cerebellum, the cranial nerves and the pyramidal tract. The distribution of the light subunit of neurofilaments was also altered post trauma. Only a weak beta-amyloid immunoreactivity was detected in the brains of control animals. Promptly after the trauma, a large number of beta-amyloid positive neurons appeared. Intensely co-localized immunoreactivity for the light subunit of neurofilaments and of beta-amyloid was seen 3 days after the rotational trauma axons of in the subcortical white matter and in the granule cell layer of the dentate gyrus as well as in neurons of the hypoglossal nucleus. The reported alterations in the central nervous system neurons are similar to those in the human brain after closed head injury and in chronic degenerative diseases. Regions of importance for social behavior, memory and body movement were affected.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
King, A I
Fundamentals of impact biomechanics: Part I--Biomechanics of the head, neck, and thorax Journal Article
In: Annual Review of Biomedical Engineering, vol. 2, pp. 55–81, 2000.
@article{King2000,
title = {Fundamentals of impact biomechanics: Part I--Biomechanics of the head, neck, and thorax},
author = {King, A I},
year = {2000},
date = {2000-01-01},
journal = {Annual Review of Biomedical Engineering},
volume = {2},
pages = {55--81},
abstract = {This is the first of two chapters dealing with some 60 years of accumulated knowledge in the field of impact biomechanics. The regions covered in this first chapter are the head, neck, and thorax. The next chapter will discuss the abdomen, pelvis, and the lower extremities. Although the principal thrust of the research has been toward the mitigation of injuries sustained by automotive crash victims, the results of this research have applications in aircraft safety, contact sports, and protection of military personnel and civilians from intentional injury, such as in the use of nonlethal weapons. The reader should be keenly aware of the wide variation in human response and tolerance data in the cited results. This is due primarily to the large biological variation among humans and to the effects of aging. Average values are useful in design but cannot be applied to individuals. [References: 94]},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Ojo, J O; Mouzon, B C; Crawford, F
Repetitive head trauma, chronic traumatic encephalopathy and tau: Challenges in translating from mice to men Journal Article
In: Experimental Neurology, vol. 275, pp. 389–404, 2016.
Abstract | Links | BibTeX | Tags: amyloid beta protein, animal, Animal models, Animals, Astroglial tangles, Brain Injury, cell activation, Chronic, complication, Concussion, Craniocerebral Trauma, CTE, diffuse axonal injury, disease duration, disease model, Disease Models, genetic predisposition, gliosis, head injury, hippocampus, human, Humans, lifestyle modification, lithium, metabolism, Mice, microglia, minocycline, mouse, nervous system inflammation, Neurobehaviour, Neurofibrillary tangles, neuropathology, nonhuman, pathogenesis, pathology, priority journal, procedures, protein aggregation, protein analysis, protein blood level, protein cleavage, Repetitive TBI, Review, sex difference, stress activated protein kinase inhibitor, Systematic Review, Tau, tau protein, tau Proteins, Transgenic mice, Translational Medical Research, translational research, traumatic brain injury, trends
@article{Ojo2016,
title = {Repetitive head trauma, chronic traumatic encephalopathy and tau: Challenges in translating from mice to men},
author = {Ojo, J O and Mouzon, B C and Crawford, F},
doi = {10.1016/j.expneurol.2015.06.003},
year = {2016},
date = {2016-01-01},
journal = {Experimental Neurology},
volume = {275},
pages = {389--404},
abstract = {Chronic traumatic encephalopathy (CTE) is a neurological and psychiatric condition marked by preferential perivascular foci of neurofibrillary and glial tangles (composed of hyperphosphorylated-tau proteins) in the depths of the sulci. Recent retrospective case series published over the last decade on athletes and military personnel have added considerably to our clinical and histopathological knowledge of CTE. This has marked a vital turning point in the traumatic brain injury (TBI) field, raising public awareness of the potential long-term effects of mild and moderate repetitive TBI, which has been recognized as one of the major risk factors associated with CTE. Although these human studies have been informative, their retrospective design carries certain inherent limitations that should be cautiously interpreted. In particular, the current overriding issue in the CTE literature remains confusing in regard to appropriate definitions of terminology, variability in individual pathologies and the potential case selection bias in autopsy based studies. There are currently no epidemiological or prospective studies on CTE. Controlled preclinical studies in animals therefore provide an alternative means for specifically interrogating aspects of CTE pathogenesis. In this article, we review the current literature and discuss difficulties and challenges of developing in-vivo TBI experimental paradigms to explore the link between repetitive head trauma and tau-dependent changes. We provide our current opinion list of recommended features to consider for successfully modeling CTE in animals to better understand the pathobiology and develop therapeutics and diagnostics, and critical factors, which might influence outcome. We finally discuss the possible directions of future experimental research in the repetitive TBI/CTE field. © 2015 Elsevier Inc..},
keywords = {amyloid beta protein, animal, Animal models, Animals, Astroglial tangles, Brain Injury, cell activation, Chronic, complication, Concussion, Craniocerebral Trauma, CTE, diffuse axonal injury, disease duration, disease model, Disease Models, genetic predisposition, gliosis, head injury, hippocampus, human, Humans, lifestyle modification, lithium, metabolism, Mice, microglia, minocycline, mouse, nervous system inflammation, Neurobehaviour, Neurofibrillary tangles, neuropathology, nonhuman, pathogenesis, pathology, priority journal, procedures, protein aggregation, protein analysis, protein blood level, protein cleavage, Repetitive TBI, Review, sex difference, stress activated protein kinase inhibitor, Systematic Review, Tau, tau protein, tau Proteins, Transgenic mice, Translational Medical Research, translational research, traumatic brain injury, trends},
pubstate = {published},
tppubtype = {article}
}
Mollayeva, T; Mollayeva, S; Colantonio, A
The Risk of Sleep Disorder Among Persons with Mild Traumatic Brain Injury Journal Article
In: Current Neurology & Neuroscience Reports, vol. 16, no. 6, pp. 55, 2016.
Abstract | BibTeX | Tags: *Brain Concussion/co [Complications], *Sleep Wake Disorders/et [Etiology], Animals, Brain Concussion/pa [Pathology], Brain/pa [Pathology], Humans, Risk Factors, Sleep Wake Disorders/ge [Genetics], wakefulness
@article{Mollayeva2016,
title = {The Risk of Sleep Disorder Among Persons with Mild Traumatic Brain Injury},
author = {Mollayeva, T and Mollayeva, S and Colantonio, A},
year = {2016},
date = {2016-01-01},
journal = {Current Neurology \& Neuroscience Reports},
volume = {16},
number = {6},
pages = {55},
abstract = {Sleep disorders and mild traumatic brain injury (mTBI) are among the most commonly occurring neurological problems clinicians encounter simultaneously. Each can cause the other, and both share common predisposing factors. An important question that remains to be addressed is whether high-risk groups can be defined. We observed an accumulation of considerable knowledge on sleep dysfunction in mTBI in recently published works. The results highlight sleep disturbances in mTBI as the product of diverse internal and external influences, acting on a genetically determined substrate. This may partially explain the clinical heterogeneity of mTBI, pointing to the importance of establishing an accurate history on the onset and course of a specific sleep disorder in the early stages post-mTBI in the individual patient. Such an approach will aid not only diagnosis and treatment but may also lead to identification of disorders whose symptoms mimic those of TBI and thereby direct the most suitable treatment and management.},
keywords = {*Brain Concussion/co [Complications], *Sleep Wake Disorders/et [Etiology], Animals, Brain Concussion/pa [Pathology], Brain/pa [Pathology], Humans, Risk Factors, Sleep Wake Disorders/ge [Genetics], wakefulness},
pubstate = {published},
tppubtype = {article}
}
Lucke-Wold, B P; Turner, R C; Logsdon, A F; Nguyen, L; Bailes, J E; Lee, J M; Robson, M J; Omalu, B I; Huber, J D; Rosen, C L
Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy Journal Article
In: Journal of Neurosurgery, vol. 124, no. 3, pp. 687–702, 2016.
Abstract | BibTeX | Tags: *Blast Injuries/px [Psychology], *Brain Injury, *Endoplasmic Reticulum Stress/ph [Physiology], *Football/in [Injuries], *Wrestling/in [Injuries], adult, animal, Animals, Blast Injuries/et [Etiology], Blast Injuries/pa [Pathology], Brain Injury, Chronic/et [Etiology], Chronic/pa [Pathology], Chronic/px [Psychology], Disease Models, Humans, Male, Rats, Sprague-Dawley
@article{Lucke-Wold2016,
title = {Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy},
author = {Lucke-Wold, B P and Turner, R C and Logsdon, A F and Nguyen, L and Bailes, J E and Lee, J M and Robson, M J and Omalu, B I and Huber, J D and Rosen, C L},
year = {2016},
date = {2016-01-01},
journal = {Journal of Neurosurgery},
volume = {124},
number = {3},
pages = {687--702},
abstract = {OBJECTIVE: Chronic traumatic encephalopathy is a progressive neurodegenerative disease characterized by neurofibrillary tau tangles following repetitive neurotrauma. The underlying mechanism linking traumatic brain injury to chronic traumatic encephalopathy has not been elucidated. The authors investigate the role of endoplasmic reticulum stress as a link between acute neurotrauma and chronic neurodegeneration. METHODS: The authors used pharmacological, biochemical, and behavioral tools to assess the role of endoplasmic reticulum stress in linking acute repetitive traumatic brain injury to the development of chronic neurodegeneration. Data from the authors' clinically relevant and validated rodent blast model were compared with those obtained from postmortem human chronic traumatic encephalopathy specimens from a National Football League player and World Wrestling Entertainment wrestler. RESULTS: The results demonstrated strong correlation of endoplasmic reticulum stress activation with subsequent tau hyperphosphorylation. Various endoplasmic reticulum stress markers were increased in human chronic traumatic encephalopathy specimens, and the endoplasmic reticulum stress response was associated with an increase in the tau kinase, glycogen synthase kinase-3beta. Docosahexaenoic acid, an endoplasmic reticulum stress inhibitor, improved cognitive performance in the rat model 3 weeks after repetitive blast exposure. The data showed that docosahexaenoic acid administration substantially reduced tau hyperphosphorylation (t = 4.111, p \< 0.05), improved cognition (t = 6.532, p \< 0.001), and inhibited C/EBP homology protein activation (t = 5.631, p \< 0.01). Additionally the data showed, for the first time, that endoplasmic reticulum stress is involved in the pathophysiology of chronic traumatic encephalopathy. CONCLUSIONS: Docosahexaenoic acid therefore warrants further investigation as a potential therapeutic agent for the prevention of chronic traumatic encephalopathy.},
keywords = {*Blast Injuries/px [Psychology], *Brain Injury, *Endoplasmic Reticulum Stress/ph [Physiology], *Football/in [Injuries], *Wrestling/in [Injuries], adult, animal, Animals, Blast Injuries/et [Etiology], Blast Injuries/pa [Pathology], Brain Injury, Chronic/et [Etiology], Chronic/pa [Pathology], Chronic/px [Psychology], Disease Models, Humans, Male, Rats, Sprague-Dawley},
pubstate = {published},
tppubtype = {article}
}
Faden, A I; Loane, D J
Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation? Journal Article
In: Neurotherapeutics, vol. 12, no. 1, pp. 143–150, 2015.
Abstract | BibTeX | Tags: *Alzheimer Disease/et [Etiology], *Brain Injuries/co [Complications], *Brain Injury, *Encephalitis/et [Etiology], *Nerve Degeneration/et [Etiology], Alzheimer Disease/pa [Pathology], Animals, Brain Injury, Chronic/et [Etiology], Chronic/pa [Pathology], Encephalitis/pa [Pathology], Humans, Nerve Degeneration/pa [Pathology]
@article{Faden2015,
title = {Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation?},
author = {Faden, A I and Loane, D J},
year = {2015},
date = {2015-01-01},
journal = {Neurotherapeutics},
volume = {12},
number = {1},
pages = {143--150},
abstract = {It has long been suggested that prior traumatic brain injury (TBI) increases the subsequent incidence of chronic neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis. Among these, the association with Alzheimer disease has the strongest support. There is also a long-recognized association between repeated concussive insults and progressive cognitive decline or other neuropsychiatric abnormalities. The latter was first described in boxers as dementia pugilistica, and has received widespread recent attention in contact sports such as professional American football. The term chronic traumatic encephalopathy was coined to attempt to define a "specific" entity marked by neurobehavioral changes and the extensive deposition of phosphorylated tau protein. Nearly lost in the discussions of post-traumatic neurodegeneration after traumatic brain injury has been the role of sustained neuroinflammation, even though this association has been well established pathologically since the 1950s, and is strongly supported by subsequent preclinical and clinical studies. Manifested by extensive microglial and astroglial activation, such chronic traumatic brain inflammation may be the most important cause of post-traumatic neurodegeneration in terms of prevalence. Critically, emerging preclinical studies indicate that persistent neuroinflammation and associated neurodegeneration may be treatable long after the initiating insult(s).},
keywords = {*Alzheimer Disease/et [Etiology], *Brain Injuries/co [Complications], *Brain Injury, *Encephalitis/et [Etiology], *Nerve Degeneration/et [Etiology], Alzheimer Disease/pa [Pathology], Animals, Brain Injury, Chronic/et [Etiology], Chronic/pa [Pathology], Encephalitis/pa [Pathology], Humans, Nerve Degeneration/pa [Pathology]},
pubstate = {published},
tppubtype = {article}
}
Jin, Y; Bouyer, J; Haas, C; Fischer, I
Evaluation of the anatomical and functional consequences of repetitive mild cervical contusion using a model of spinal concussion Journal Article
In: Experimental Neurology, vol. 271, pp. 175–188, 2015.
Abstract | BibTeX | Tags: *Gait Disorders, *Spinal Cord Injuries/co [Complications], *Spinal Cord Injuries/pa [Pathology], *Spinal Cord/pa [Pathology], 0 (Antigens, 0 (Ectodysplasins), 0 (Glial Fibrillary Acidic Protein), ANALYSIS of variance, animal, Animals, Antigens, CD31), CD31/me [Metabolism], Contusions/co [Complications], Disease Models, EC 2-7-11-13 (Protein Kinase C), Ectodysplasins/me [Metabolism], Exploratory Behavior/ph [Physiology], Female, Glial Fibrillary Acidic Protein/me [Metabolism], Muscle Strength/ph [Physiology], Neurologic/et [Etiology], PAIN measurement, Protein Kinase C/me [Metabolism], Rats, Spinal Cord Injuries/et [Etiology], Spinal Cord/me [Metabolism], Sprague-Dawley
@article{Jin2015,
title = {Evaluation of the anatomical and functional consequences of repetitive mild cervical contusion using a model of spinal concussion},
author = {Jin, Y and Bouyer, J and Haas, C and Fischer, I},
year = {2015},
date = {2015-01-01},
journal = {Experimental Neurology},
volume = {271},
pages = {175--188},
abstract = {Spinal cord concussion is characterized by a transient loss of motor and sensory function that generally resolves without permanent deficits. Spinal cord concussions usually occur during vehicular accidents, falls, and sport activity, but unlike brain concussions, have received much less attention despite the potential for repeated injury leading to permanent neurological sequelae. Consequently, there is no consensus regarding decisions related to return to play following an episode of spinal concussion, nor an understanding of the short- and long-term consequences of repeated injury. Importantly, there are no models of spinal concussion to study the anatomical and functional sequelae of single or repeated injury. We have developed a new model of spinal cord concussion focusing on the anatomical and behavioral outcomes of single and repeated injury. Rats received a very mild (50 kdyn, IH impactor) spinal contusion at C5 and were separated into two groups three weeks after the initial injury--C1, which received a second, sham surgery, and C2, which received a second contusion at the same site. To track motor function and recovery, animals received weekly behavioral tests--BBB, CatWalkTM, cylinder, and Von Frey. Analysis of locomotor activity by BBB demonstrated that rats rapidly recovered, regaining near-normal function by one week after the first and second injury, which was confirmed using the more detailed CatWalkTM analysis. The cylinder test showed that a single contusion did not induce significant deficits of the affected limb, but that repeated injury resulted in significant alteration in paw preference, with animals favoring the unaffected limb. Intriguingly, Von Frey analysis demonstrated an increased sensitivity in the contralateral hindlimb in the C2 group vs. the C1 group. Anatomical analyses revealed that while the lesion volume of both groups was minimal, the area of spared white matter in the C2 group was significantly reduced 1 and 2mm rostral to the lesion epicenter. Reactive astrocytes were present in both groups, with the majority found at the lesion epicenter in the C1 group, whereas the C2 group demonstrated increased reactive astrocytes extending 1mm caudal to the lesion epicenter. Macrophages accumulated within the injured, dorsal and ipsilateral spinal cord, with significant increases at 2 and 3mm rostral to the epicenter in the C2 group. Our model is designed to represent the clinical presentation of spinal cord concussion, and highlight the susceptibility and functional sequelae of repeated injury. Future experiments will examine the temporal and spatial windows of vulnerability for repeated injuries.Copyright © 2015. Published by Elsevier Inc.},
keywords = {*Gait Disorders, *Spinal Cord Injuries/co [Complications], *Spinal Cord Injuries/pa [Pathology], *Spinal Cord/pa [Pathology], 0 (Antigens, 0 (Ectodysplasins), 0 (Glial Fibrillary Acidic Protein), ANALYSIS of variance, animal, Animals, Antigens, CD31), CD31/me [Metabolism], Contusions/co [Complications], Disease Models, EC 2-7-11-13 (Protein Kinase C), Ectodysplasins/me [Metabolism], Exploratory Behavior/ph [Physiology], Female, Glial Fibrillary Acidic Protein/me [Metabolism], Muscle Strength/ph [Physiology], Neurologic/et [Etiology], PAIN measurement, Protein Kinase C/me [Metabolism], Rats, Spinal Cord Injuries/et [Etiology], Spinal Cord/me [Metabolism], Sprague-Dawley},
pubstate = {published},
tppubtype = {article}
}
Lucke-Wold, B P; Naser, Z J; Logsdon, A F; Turner, R C; Smith, K E; Robson, M J; Bailes, J E; Lee, J M; Rosen, C L; Huber, J D
Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury Journal Article
In: Translational Research: The Journal Of Laboratory & Clinical Medicine, vol. 166, no. 6, pp. 509–528.e1, 2015.
Abstract | BibTeX | Tags: *Blast Injuries/pa [Pathology], *Brain Injuries/pa [Pathology], *NADPH Oxidase/me [Metabolism], *Oxidative Stress, 73Y7P0K73Y (Thioctic Acid), Animals, Apoptosis, Blast Injuries/en [Enzymology], Blast Injuries/me [Metabolism], Brain Injuries/en [Enzymology], Brain Injuries/me [Metabolism], EC 1-6-3-1 (NADPH Oxidase), Male, Rats, Sprague-Dawley, Thioctic Acid/pd [Pharmacology]
@article{Lucke-Wold2015,
title = {Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury},
author = {Lucke-Wold, B P and Naser, Z J and Logsdon, A F and Turner, R C and Smith, K E and Robson, M J and Bailes, J E and Lee, J M and Rosen, C L and Huber, J D},
year = {2015},
date = {2015-01-01},
journal = {Translational Research: The Journal Of Laboratory \& Clinical Medicine},
volume = {166},
number = {6},
pages = {509--528.e1},
abstract = {A total of 1.7 million traumatic brain injuries (TBIs) occur each year in the United States, but available pharmacologic options for the treatment of acute neurotrauma are limited. Oxidative stress is an important secondary mechanism of injury that can lead to neuronal apoptosis and subsequent behavioral changes. Using a clinically relevant and validated rodent blast model, we investigated how nicotinamide adenine dinucleotide phosphate oxidase (Nox) expression and associated oxidative stress contribute to cellular apoptosis after single and repeat blast injuries. Nox4 forms a complex with p22phox after injury, forming free radicals at neuronal membranes. Using immunohistochemical-staining methods, we found a visible increase in Nox4 after single blast injury in Sprague Dawley rats. Interestingly, Nox4 was also increased in postmortem human samples obtained from athletes diagnosed with chronic traumatic encephalopathy. Nox4 activity correlated with an increase in superoxide formation. Alpha-lipoic acid, an oxidative stress inhibitor, prevented the development of superoxide acutely and increased antiapoptotic markers B-cell lymphoma 2 (t = 3.079, P \< 0.05) and heme oxygenase 1 (t = 8.169, P \< 0.001) after single blast. Subacutely, alpha-lipoic acid treatment reduced proapoptotic markers Bax (t = 4.483, P \< 0.05), caspase 12 (t = 6.157, P \< 0.001), and caspase 3 (t = 4.573, P \< 0.01) after repetitive blast, and reduced tau hyperphosphorylation indicated by decreased CP-13 and paired helical filament staining. Alpha-lipoic acid ameliorated impulsive-like behavior 7 days after repetitive blast injury (t = 3.573, P \< 0.05) compared with blast exposed animals without treatment. TBI can cause debilitating symptoms and psychiatric disorders. Oxidative stress is an ideal target for neuropharmacologic intervention, and alpha-lipoic acid warrants further investigation as a therapeutic for prevention of chronic neurodegeneration. Copyright © 2015 Elsevier Inc. All rights reserved.},
keywords = {*Blast Injuries/pa [Pathology], *Brain Injuries/pa [Pathology], *NADPH Oxidase/me [Metabolism], *Oxidative Stress, 73Y7P0K73Y (Thioctic Acid), Animals, Apoptosis, Blast Injuries/en [Enzymology], Blast Injuries/me [Metabolism], Brain Injuries/en [Enzymology], Brain Injuries/me [Metabolism], EC 1-6-3-1 (NADPH Oxidase), Male, Rats, Sprague-Dawley, Thioctic Acid/pd [Pharmacology]},
pubstate = {published},
tppubtype = {article}
}
Grafman, J; Salazar, A M
The ebb and flow of traumatic brain injury research Journal Article
In: Handbook of Clinical Neurology, vol. 128, pp. 795–802, 2015.
Abstract | BibTeX | Tags: *Biomedical Research/mt [Methods], *Biomedical Research/td [Trends], *Brain Injuries/th [Therapy], Animals, Humans
@article{Grafman2015,
title = {The ebb and flow of traumatic brain injury research},
author = {Grafman, J and Salazar, A M},
year = {2015},
date = {2015-01-01},
journal = {Handbook of Clinical Neurology},
volume = {128},
pages = {795--802},
abstract = {The purpose of this chapter is to summarize some key topics discussed in this volume and describe trends suggesting the direction of future traumatic brain injury (TBI) research. Interest in, and funding for, TBI has ebbed and flowed with the public awareness of injury risk from combat, sports, or everyday life. Advances in acute resuscitation, emergency response systems, and early management have had a major impact on survival after TBI, while recent research has emphasized underlying genetic substrates and the molecular mechanisms of brain injury, repair, and neuroplasticity. This in turn impacts not only on primary and secondary neuroprotection strategies for minimizing injury, but also on the other critical remaining challenge, that of identification and validation of optimal strategies for physical and cognitive TBI rehabilitation. New information also highlights long-term degenerative conditions associated with earlier TBI and mediated by a signature cascade of abnormal molecular processes. Thus, TBI has emerged as a recognized significant public health risk with both immediate and lifelong repercussions. The linkage of a TBI to late-life neurodegenerative diseases, the observation of persistent pathologic processes including neuroinflammation and accumulation of tau protein, as well as individual differences in the genetic predisposition for brain repair and plasticity should lead to meaningful translational research with a significant impact on the efficacy and cost-efficiency of acute and chronic treatment for TBI survivors. Copyright © 2015 Elsevier B.V. All rights reserved.},
keywords = {*Biomedical Research/mt [Methods], *Biomedical Research/td [Trends], *Brain Injuries/th [Therapy], Animals, Humans},
pubstate = {published},
tppubtype = {article}
}
Levin, B; Bhardwaj, A
Chronic traumatic encephalopathy: A critical appraisal Journal Article
In: Neurocritical Care, vol. 20, no. 2, pp. 334–344, 2014.
Abstract | Links | BibTeX | Tags: accident, alcohol consumption, amnesia, amyloid plaque, animal, Animals, Athletic Injuries, autopsy, behavior change, Brain Injury, Chronic, Chronic traumatic encephalopathy, Chronic Traumatic Encephalopathy Dementia, complication, Diffusion Tensor Imaging, disease course, Encephalopathy, functional magnetic resonance imaging, histopathology, human, Humans, longitudinal study, Male, Neurodegenerative, Neurodegenerative Diseases, nonhuman, NUCLEAR magnetic resonance spectroscopy, Parkinsonism, pathogenesis, pathology, Pathophysiology, Prevalence, priority journal, Pugilistic, Review, risk factor, Risk Factors, sport injury, suicide, Systematic Review, traumatic brain injury, violence
@article{Levin2014,
title = {Chronic traumatic encephalopathy: A critical appraisal},
author = {Levin, B and Bhardwaj, A},
url = {http://www.scopus.com/inward/record.url?eid=2-s2.0-84896549537\&partnerID=40\&md5=138104db42f7ca99527a78bb9c821f59},
doi = {10.1007/s12028-013-9931-1},
year = {2014},
date = {2014-01-01},
journal = {Neurocritical Care},
volume = {20},
number = {2},
pages = {334--344},
abstract = {Chronic traumatic encephalopathy (CTE) formerly known as dementia pugilistica is a long-term neurodegenerative disorder associated with repeated subconcussive head injuries in high-contact sports. We reviewed the existing literature on CTE and examined epidemiological trends, risk factors, and its temporal progression, and proposed the underlying pathophysiological mechanisms that may provide unique insights to clinicians with an in-depth understanding of the disease to aid in the diagnosis and prevention, and provide future perspectives for research via search of Medline and Cochrane databases as well as manual review of bibliographies from selected articles and monographs. The prevalence of CTE in recent years is on the rise and almost exclusively affects men, with pathologic signs characterized by progressive memory loss, behavioral changes, and violent tendencies with some patients demonstrating Parkinsonian-like symptoms and signs. Many patients with CTE die following suicide, accident, or complications of drug or alcohol use. Postmortem pathologic analysis is characterized by neurofibrillary tangles and A$beta$ plaques in 50 % of cases. Currently, there are no ante-mortem diagnostic criteria, but modern imaging techniques such as functional magnetic resonance (MR) imaging, MR spectroscopy, and diffusion tension imaging hold promise for delineating the future diagnostic criteria. Further long-term longitudinal studies are warranted to investigate risk factors that will enhance understanding of the disease progression and its pathogenesis. © 2013 Springer Science+Business Media.},
keywords = {accident, alcohol consumption, amnesia, amyloid plaque, animal, Animals, Athletic Injuries, autopsy, behavior change, Brain Injury, Chronic, Chronic traumatic encephalopathy, Chronic Traumatic Encephalopathy Dementia, complication, Diffusion Tensor Imaging, disease course, Encephalopathy, functional magnetic resonance imaging, histopathology, human, Humans, longitudinal study, Male, Neurodegenerative, Neurodegenerative Diseases, nonhuman, NUCLEAR magnetic resonance spectroscopy, Parkinsonism, pathogenesis, pathology, Pathophysiology, Prevalence, priority journal, Pugilistic, Review, risk factor, Risk Factors, sport injury, suicide, Systematic Review, traumatic brain injury, violence},
pubstate = {published},
tppubtype = {article}
}
Kiraly, M; Kiraly, S J
Traumatic brain injury and delayed sequelae: a review--traumatic brain injury and mild traumatic brain injury (concussion) are precursors to later-onset brain disorders, including early-onset dementia Journal Article
In: TheScientificWorldJournal, vol. 7, pp. 1768–1776, 2007.
Abstract | BibTeX | Tags: *Brain Injuries/co [Complications], *Brain Injuries/pp [Physiopathology], *Brain/pp [Physiopathology], *Dementia/et [Etiology], *Dementia/pp [Physiopathology], *Models, Animals, Humans, Neurological
@article{Kiraly2007,
title = {Traumatic brain injury and delayed sequelae: a review--traumatic brain injury and mild traumatic brain injury (concussion) are precursors to later-onset brain disorders, including early-onset dementia},
author = {Kiraly, M and Kiraly, S J},
year = {2007},
date = {2007-01-01},
journal = {TheScientificWorldJournal},
volume = {7},
pages = {1768--1776},
abstract = {Brain injuries are too common. Most people are unaware of the incidence of and horrendous consequences of traumatic brain injury (TBI) and mild traumatic brain injury (MTBI). Research and the advent of sophisticated imaging have led to progression in the understanding of brain pathophysiology following TBI. Seminal evidence from animal and human experiments demonstrate links between TBI and the subsequent onset of premature, psychiatric syndromes and neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Objectives of this summary are, therefore, to instill appreciation regarding the importance of brain injury prevention, diagnosis, and treatment, and to increase awareness regarding the long-term delayed consequences following TBI. [References: 88]},
keywords = {*Brain Injuries/co [Complications], *Brain Injuries/pp [Physiopathology], *Brain/pp [Physiopathology], *Dementia/et [Etiology], *Dementia/pp [Physiopathology], *Models, Animals, Humans, Neurological},
pubstate = {published},
tppubtype = {article}
}
Hamberger, A; Huang, Y L; Zhu, H; Bao, F; Ding, M; Blennow, K; Olsson, A; Hansson, H A; Viano, D; Haglid, K G
Redistribution of neurofilaments and accumulation of beta-amyloid protein after brain injury by rotational acceleration of the head Journal Article
In: Journal of Neurotrauma, vol. 20, no. 2, pp. 169–178, 2003.
Abstract | BibTeX | Tags: *Amyloid beta-Peptides/me [Metabolism], *Brain Injuries/me [Metabolism], *Brain/me [Metabolism], *Neurofilament Proteins/me [Metabolism], 0 (Amyloid beta-Peptides), 0 (neurofilament protein L), 0 (Neurofilament Proteins), 108688-71-7 (neurofilament protein H), Acceleration, Animals, Brain Injuries/et [Etiology], immunohistochemistry, Phosphorylation, Rabbits, Rotation, Tissue Distribution
@article{Hamberger2003,
title = {Redistribution of neurofilaments and accumulation of beta-amyloid protein after brain injury by rotational acceleration of the head},
author = {Hamberger, A and Huang, Y L and Zhu, H and Bao, F and Ding, M and Blennow, K and Olsson, A and Hansson, H A and Viano, D and Haglid, K G},
year = {2003},
date = {2003-01-01},
journal = {Journal of Neurotrauma},
volume = {20},
number = {2},
pages = {169--178},
abstract = {Rotational acceleration of the head, as occurs in falls, car crashes, and sport injuries, may result in diffuse brain damage, with acute and chronic neurological and psychiatric symptoms. The present study addresses the effects of rotational trauma on the neuronal cytoskeleton, which stabilizes perikaryal, dendritic and axonal shape and function. The study focuses upon the distribution of (1) the phosphorylated form of the heavy neurofilament subunit, (2) the light neurofilament subunit, and (3) beta-amyloid, a marker for brain injury. While normally restricted to axons, the phosphorylated heavy neurofilament subunits were drastically decreased in the axons after rotational trauma. Instead, they accumulated in the neuronal perikarya, normally devoid of the phosphorylated subunit. This alteration was seen, not only in the cerebral cortex, but also in the hippocampus, the cervical spinal cord, the cerebellum, the cranial nerves and the pyramidal tract. The distribution of the light subunit of neurofilaments was also altered post trauma. Only a weak beta-amyloid immunoreactivity was detected in the brains of control animals. Promptly after the trauma, a large number of beta-amyloid positive neurons appeared. Intensely co-localized immunoreactivity for the light subunit of neurofilaments and of beta-amyloid was seen 3 days after the rotational trauma axons of in the subcortical white matter and in the granule cell layer of the dentate gyrus as well as in neurons of the hypoglossal nucleus. The reported alterations in the central nervous system neurons are similar to those in the human brain after closed head injury and in chronic degenerative diseases. Regions of importance for social behavior, memory and body movement were affected.},
keywords = {*Amyloid beta-Peptides/me [Metabolism], *Brain Injuries/me [Metabolism], *Brain/me [Metabolism], *Neurofilament Proteins/me [Metabolism], 0 (Amyloid beta-Peptides), 0 (neurofilament protein L), 0 (Neurofilament Proteins), 108688-71-7 (neurofilament protein H), Acceleration, Animals, Brain Injuries/et [Etiology], immunohistochemistry, Phosphorylation, Rabbits, Rotation, Tissue Distribution},
pubstate = {published},
tppubtype = {article}
}
King, A I
Fundamentals of impact biomechanics: Part I--Biomechanics of the head, neck, and thorax Journal Article
In: Annual Review of Biomedical Engineering, vol. 2, pp. 55–81, 2000.
Abstract | BibTeX | Tags: *Biomechanical Phenomena, *Craniocerebral Trauma/pp [Physiopathology], *Neck Injuries/pp [Physiopathology], *Thoracic Injuries/pp [Physiopathology], Animals, Biomedical Engineering, Brain Injuries/pp [Physiopathology], Humans
@article{King2000,
title = {Fundamentals of impact biomechanics: Part I--Biomechanics of the head, neck, and thorax},
author = {King, A I},
year = {2000},
date = {2000-01-01},
journal = {Annual Review of Biomedical Engineering},
volume = {2},
pages = {55--81},
abstract = {This is the first of two chapters dealing with some 60 years of accumulated knowledge in the field of impact biomechanics. The regions covered in this first chapter are the head, neck, and thorax. The next chapter will discuss the abdomen, pelvis, and the lower extremities. Although the principal thrust of the research has been toward the mitigation of injuries sustained by automotive crash victims, the results of this research have applications in aircraft safety, contact sports, and protection of military personnel and civilians from intentional injury, such as in the use of nonlethal weapons. The reader should be keenly aware of the wide variation in human response and tolerance data in the cited results. This is due primarily to the large biological variation among humans and to the effects of aging. Average values are useful in design but cannot be applied to individuals. [References: 94]},
keywords = {*Biomechanical Phenomena, *Craniocerebral Trauma/pp [Physiopathology], *Neck Injuries/pp [Physiopathology], *Thoracic Injuries/pp [Physiopathology], Animals, Biomedical Engineering, Brain Injuries/pp [Physiopathology], Humans},
pubstate = {published},
tppubtype = {article}
}