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}
}
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}
}
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}
}
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}
}
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}
}
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}
}
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}
}
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}
}
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}
}
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}
}
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}
}
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}
}