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Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model.
Sci Transl Med. 2012 May 16; 4(134):134ra60
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26 Jun 2012
Jean Charchaflieh
F1000 Anesthesiology & Pain Management
Yale University School of Medicine,
New Haven, CT, USA.
F1000 Anesthesiology & Pain Management
Yale University School of Medicine,
New Haven, CT, USA.
New Finding
DOI: 10.3410/f.717348020.792703130
I found this article interesting because it studies two clinically important and related phenomena: concussion-induced chronic traumatic encephalopathy (CI-CTE) and blast-induced traumatic brain injury (BI-TBI), through a translational method that combines clinical and neuropathologic observation with...Continue reading
I found this article interesting because it studies two clinically important and related phenomena: concussion-induced chronic traumatic encephalopathy (CI-CTE) and blast-induced traumatic brain injury (BI-TBI), through a translational method that combines clinical and neuropathologic observation with animal experimentation to examine the relationship between the mechanism of injury, neuropathologic findings and neurobehavioral sequelae.
The authors presented a clinical and neuropathologic description of four military veterans with BI-TBI, four athletes with CI-CTE and four matching controls who died from similar causes but did not have either BI-TBI or CI-CTE.
The authors also presented a mouse model of blast neurotrauma to examine the linkage between blast exposure, neuropathologic findings and neurobehavioral sequelae.
Clinical manifestations in the four cases of (BI-TBI) included daily headaches, depression, anxiety, irritability, aggression, anger, rage, and impaired concentration, attention, sleep, memory, word finding, executive function and psychomotor speed. Similar symptoms have been found in athletes with CI-CTE. Two of the four patients with BI-TBI and two of the four with CI-CTE died of suicide.
Neuropathologic findings of BI-TBI and CI-CTE were characteristic of these disorders, absent in the matched controls and different from those due to age-related neurodegenerative disorders, Alzheimer's disease and frontotemporal dementia. Characteristic neuropathologic findings included cortical perivascular tau-immunoreactive neurofibrillary tangles (NFTs) and glial tangles, plus subcortical axonal injury, astrocytosis and perivascular microglial nodules.
Animal experimentation included delivering a gas blast (equivalent in scale to explosion of an improvised explosive device [IED]) to mice held in a tube that allowed free movement of head and cervical spine. Gas blast injury in mice produced neuropathology findings and neurobehavioral sequelae characteristic of BI-TBI and CI-CTE. Neuropathology findings included tau protein hyperphosphorylation, myelinated axonopathy, microvascular damage, chronic neuroinflammation, and neurodegeneration. Neurobehavioral sequelae included slowed axonal conduction, reduced activity-dependent long-term synaptic plasticity, and impaired spatial learning and memory.
The animal experiments provided mechanistic insight into BI-TBI and CI-CTE by showing that head immobilization (prevention of acceleration) during blast exposure eliminated blast-related impairments in hippocampus-dependent learning acquisition and restored blast-related memory deficits to normal levels.
With BI-TBI affecting about 20% of the 2.3 million deployed U.S. military personnel, this study provides an important neuropathologic correlation for clinical findings, introduces an animal experimental model and suggests a mechanistic insight that might be useful in injury prevention.
The authors presented a clinical and neuropathologic description of four military veterans with BI-TBI, four athletes with CI-CTE and four matching controls who died from similar causes but did not have either BI-TBI or CI-CTE.
The authors also presented a mouse model of blast neurotrauma to examine the linkage between blast exposure, neuropathologic findings and neurobehavioral sequelae.
Clinical manifestations in the four cases of (BI-TBI) included daily headaches, depression, anxiety, irritability, aggression, anger, rage, and impaired concentration, attention, sleep, memory, word finding, executive function and psychomotor speed. Similar symptoms have been found in athletes with CI-CTE. Two of the four patients with BI-TBI and two of the four with CI-CTE died of suicide.
Neuropathologic findings of BI-TBI and CI-CTE were characteristic of these disorders, absent in the matched controls and different from those due to age-related neurodegenerative disorders, Alzheimer's disease and frontotemporal dementia. Characteristic neuropathologic findings included cortical perivascular tau-immunoreactive neurofibrillary tangles (NFTs) and glial tangles, plus subcortical axonal injury, astrocytosis and perivascular microglial nodules.
Animal experimentation included delivering a gas blast (equivalent in scale to explosion of an improvised explosive device [IED]) to mice held in a tube that allowed free movement of head and cervical spine. Gas blast injury in mice produced neuropathology findings and neurobehavioral sequelae characteristic of BI-TBI and CI-CTE. Neuropathology findings included tau protein hyperphosphorylation, myelinated axonopathy, microvascular damage, chronic neuroinflammation, and neurodegeneration. Neurobehavioral sequelae included slowed axonal conduction, reduced activity-dependent long-term synaptic plasticity, and impaired spatial learning and memory.
The animal experiments provided mechanistic insight into BI-TBI and CI-CTE by showing that head immobilization (prevention of acceleration) during blast exposure eliminated blast-related impairments in hippocampus-dependent learning acquisition and restored blast-related memory deficits to normal levels.
With BI-TBI affecting about 20% of the 2.3 million deployed U.S. military personnel, this study provides an important neuropathologic correlation for clinical findings, introduces an animal experimental model and suggests a mechanistic insight that might be useful in injury prevention.
Disclosures
None declared
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Charchaflieh J: F1000Prime Recommendation of [Goldstein LE et al., Sci Transl Med 2012, 4(134):134ra60]. In F1000Prime, 26 Jun 2012; DOI: 10.3410/f.717348020.792703130. F1000Prime.com/717348020#eval792703130
F1000Prime Recommendations, Dissents and Comments for [Goldstein LE et al., Sci Transl Med 2012, 4(134):134ra60]. In F1000Prime, 24 May 2013; F1000Prime.com/717348020
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Blast exposure is associated with traumatic brain injury (TBI), neuropsychiatric symptoms, and long-term cognitive disability. We examined a case series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury. We found evidence of chronic traumatic encephalopathy (CTE), a tau protein-linked neurodegenerative disease, that was similar to the CTE neuropathology observed in young amateur American football players and a professional wrestler with histories of concussive injuries. We developed a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage. Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shock waves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning and memory deficits. The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These results identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory.
DOI: 10.1126/scitranslmed.3003716
PMID: 22593173
