Study Extends Traumatic Brain Pathology to Blast-Exposed Veterans

Evidence of chronic traumatic encephalopathy has been found in autopsies of four blast-exposed veterans of the Iraq and Afghanistan wars, signaling a potential overlap of the clinical signs and symptoms of the neurodegenerative disease observed in some athletes with a history of multiple concussions.

But the case-control study’s small sample size – four veterans, four athletes with multiple concussions, and four controls without a history of head injury, blast exposure, or neurological disease – and additional history of civilian concussions in the four veterans leaves the specificity of the findings for blast-related trauma under question until further studies can be conducted.

"The injuries that we could see in the military personnel looked identical to what we’d seen in athletes," suggesting that blast exposure created the same basic injury in the brain as does concussion, Dr. Ann C. McKee, senior author of the study, said in an interview. But military personnel usually have a long history of multiple confounding injuries, including prior concussions and getting thrown against something during a blast, which makes it nearly "impossible to dissect blast from concussion in the human condition," said Dr. McKee, codirector of the Center for the Study of Traumatic Encephalopathy at Boston University. The study is the first case series of military service personnel with blast-related injuries who have been examined for chronic traumatic encephalopathy (CTE).

Blast exposure could be confirmed in three of the four military veterans. One of the veterans had had multiple concussions as a civilian and in combat, but was never exposed to a blast. One of the veterans with blast exposure had no history of a previous concussive injury. Three of the four veterans also had been diagnosed with posttraumatic stress disorder. All four experienced similar symptoms, including headaches, irritability, difficulty sleeping and concentrating, memory loss, depression, and persistent anxiety (Sci. Transl. Med. 2012 May 16 [doi:10.1126/scitranslmed.3003716]).

In the veterans, the investigators observed CTE-linked neuropathology characterized by perivascular foci of tau-immunoreactive neurofibrillary tangles and glial tangles with prominence in the sulcal depths of the inferior frontal, dorsolateral frontal, parietal, and temporal cortices. These findings were indistinguishable from those seen in the four athletes.

"I think that this is an important contribution in that it tells us that there are individuals who’ve been in uniform, been deployed, been exposed to what you’re exposed to on the battlefield, who develop CTE. I’m somewhat cautious about laying the blame to blast exposure here based on their data, but it underlines the idea that we have a ... significant ‘tau problem’ in the military, and that needs to be studied further," Dr. Daniel P. Perl said in an interview. He is director of the neuropathology core at the Uniformed Services University of the Health Sciences’ Center for Neuroscience and Regenerative Medicine in Bethesda, Md. He also is director of Military Brain Injury Studies at the university.

Dr. McKee and lead author Dr. Lee E. Goldstein and their associates also tried to tease out the components of a pure blast injury by creating a mouse model in which they found evidence for some of the features of CTE only 2 weeks after a single exposure to blast-force winds. The investigators constructed a compressed gas blast tube that delivered a blast with a static pressure profile that is comparable to common improved explosive devices and is within the range of typical explosives, blast conditions, and standoff distances associated with military blast injury. Anesthetized, wild-type strain of mice were restrained but left free to move their heads during the experiment, in which a single blast traveling 336 miles per hour violently shook their heads. After 2 weeks, these mice had many of the same injuries seen in humans with CTE, including the accumulation of phosphorylated tau protein, axonal injury, and disruption of the integrity of the blood-brain barrier surrounding vessels in the brain, as well as behavioral and memory deficits. However, none of the mice had mature neurofibrillary tangles in the cortex or hippocampus.

Dr. Perl called the use of wild-type mice "a little unusual" because they are not known to develop neurofibrillary tangles. "It is difficult to conclude that this is CTE because it is a progressive neurodegenerative disease with tau accumulation," he said. Pathological changes at only 2 weeks without any signs of disease progression are too early for researchers to be able to know that it is CTE, he added.

When Dr. McKee and her associates performed the same experiment with mice whose heads were immobilized, the restraint prevented learning and memory deficits from occurring, which is "consistent with a common injury mechanism involving oscillating head acceleration-deceleration cycles that lead to pathogenic shearing strain imposed on the cranial contents," they wrote.

The lack of neurobehavioral sequelae following the blast exposure with a head restraint may have implications for the design of helmets that help to keep the head stationary, she said.

The next goal is to identify CTE in living humans, Dr. McKee said. Her group is now analyzing cerebrospinal fluid for tau protein and conducting neuroimaging in a cohort of recent veterans of the Iraq and Afghanistan conflicts.

Dr. Perl and his colleagues at the Uniformed Services University of the Health Sciences have recently established the first brain tissue repository that is specifically designed to support research on the effects of traumatic brain injury suffered by military service members. It is supported by a multiyear grant from the U.S. Army Medical Research and Materiel Command.

The study was supported by various grants from the National Institutes of Health, the National Science Foundation, Cure Alzheimer’s Fund, the Department of Veterans Affairs, the Department of Defense, the Migraine Research Foundation, the March of Dimes Foundation, and the National Football League. One author is a science advisory board member of Immunotrex Biologics, but other authors reported having no competing interests.

Evidence of chronic traumatic encephalopathy has been found in autopsies of four blast-exposed veterans of the Iraq and Afghanistan wars, signaling a potential overlap of the clinical signs and symptoms of the neurodegenerative disease observed in some athletes with a history of multiple concussions.

But the case-control study’s small sample size – four veterans, four athletes with multiple concussions, and four controls without a history of head injury, blast exposure, or neurological disease – and additional history of civilian concussions in the four veterans leaves the specificity of the findings for blast-related trauma under question until further studies can be conducted.

"The injuries that we could see in the military personnel looked identical to what we’d seen in athletes," suggesting that blast exposure created the same basic injury in the brain as does concussion, Dr. Ann C. McKee, senior author of the study, said in an interview. But military personnel usually have a long history of multiple confounding injuries, including prior concussions and getting thrown against something during a blast, which makes it nearly "impossible to dissect blast from concussion in the human condition," said Dr. McKee, codirector of the Center for the Study of Traumatic Encephalopathy at Boston University. The study is the first case series of military service personnel with blast-related injuries who have been examined for chronic traumatic encephalopathy (CTE).

Blast exposure could be confirmed in three of the four military veterans. One of the veterans had had multiple concussions as a civilian and in combat, but was never exposed to a blast. One of the veterans with blast exposure had no history of a previous concussive injury. Three of the four veterans also had been diagnosed with posttraumatic stress disorder. All four experienced similar symptoms, including headaches, irritability, difficulty sleeping and concentrating, memory loss, depression, and persistent anxiety (Sci. Transl. Med. 2012 May 16 [doi:10.1126/scitranslmed.3003716]).

In the veterans, the investigators observed CTE-linked neuropathology characterized by perivascular foci of tau-immunoreactive neurofibrillary tangles and glial tangles with prominence in the sulcal depths of the inferior frontal, dorsolateral frontal, parietal, and temporal cortices. These findings were indistinguishable from those seen in the four athletes.

"I think that this is an important contribution in that it tells us that there are individuals who’ve been in uniform, been deployed, been exposed to what you’re exposed to on the battlefield, who develop CTE. I’m somewhat cautious about laying the blame to blast exposure here based on their data, but it underlines the idea that we have a ... significant ‘tau problem’ in the military, and that needs to be studied further," Dr. Daniel P. Perl said in an interview. He is director of the neuropathology core at the Uniformed Services University of the Health Sciences’ Center for Neuroscience and Regenerative Medicine in Bethesda, Md. He also is director of Military Brain Injury Studies at the university.

Dr. McKee and lead author Dr. Lee E. Goldstein and their associates also tried to tease out the components of a pure blast injury by creating a mouse model in which they found evidence for some of the features of CTE only 2 weeks after a single exposure to blast-force winds. The investigators constructed a compressed gas blast tube that delivered a blast with a static pressure profile that is comparable to common improved explosive devices and is within the range of typical explosives, blast conditions, and standoff distances associated with military blast injury. Anesthetized, wild-type strain of mice were restrained but left free to move their heads during the experiment, in which a single blast traveling 336 miles per hour violently shook their heads. After 2 weeks, these mice had many of the same injuries seen in humans with CTE, including the accumulation of phosphorylated tau protein, axonal injury, and disruption of the integrity of the blood-brain barrier surrounding vessels in the brain, as well as behavioral and memory deficits. However, none of the mice had mature neurofibrillary tangles in the cortex or hippocampus.

Dr. Perl called the use of wild-type mice "a little unusual" because they are not known to develop neurofibrillary tangles. "It is difficult to conclude that this is CTE because it is a progressive neurodegenerative disease with tau accumulation," he said. Pathological changes at only 2 weeks without any signs of disease progression are too early for researchers to be able to know that it is CTE, he added.

When Dr. McKee and her associates performed the same experiment with mice whose heads were immobilized, the restraint prevented learning and memory deficits from occurring, which is "consistent with a common injury mechanism involving oscillating head acceleration-deceleration cycles that lead to pathogenic shearing strain imposed on the cranial contents," they wrote.

The lack of neurobehavioral sequelae following the blast exposure with a head restraint may have implications for the design of helmets that help to keep the head stationary, she said.

The next goal is to identify CTE in living humans, Dr. McKee said. Her group is now analyzing cerebrospinal fluid for tau protein and conducting neuroimaging in a cohort of recent veterans of the Iraq and Afghanistan conflicts.

Dr. Perl and his colleagues at the Uniformed Services University of the Health Sciences have recently established the first brain tissue repository that is specifically designed to support research on the effects of traumatic brain injury suffered by military service members. It is supported by a multiyear grant from the U.S. Army Medical Research and Materiel Command.

The study was supported by various grants from the National Institutes of Health, the National Science Foundation, Cure Alzheimer’s Fund, the Department of Veterans Affairs, the Department of Defense, the Migraine Research Foundation, the March of Dimes Foundation, and the National Football League. One author is a science advisory board member of Immunotrex Biologics, but other authors reported having no competing interests.

Evidence of chronic traumatic encephalopathy has been found in autopsies of four blast-exposed veterans of the Iraq and Afghanistan wars, signaling a potential overlap of the clinical signs and symptoms of the neurodegenerative disease observed in some athletes with a history of multiple concussions.

But the case-control study’s small sample size – four veterans, four athletes with multiple concussions, and four controls without a history of head injury, blast exposure, or neurological disease – and additional history of civilian concussions in the four veterans leaves the specificity of the findings for blast-related trauma under question until further studies can be conducted.

"The injuries that we could see in the military personnel looked identical to what we’d seen in athletes," suggesting that blast exposure created the same basic injury in the brain as does concussion, Dr. Ann C. McKee, senior author of the study, said in an interview. But military personnel usually have a long history of multiple confounding injuries, including prior concussions and getting thrown against something during a blast, which makes it nearly "impossible to dissect blast from concussion in the human condition," said Dr. McKee, codirector of the Center for the Study of Traumatic Encephalopathy at Boston University. The study is the first case series of military service personnel with blast-related injuries who have been examined for chronic traumatic encephalopathy (CTE).

Blast exposure could be confirmed in three of the four military veterans. One of the veterans had had multiple concussions as a civilian and in combat, but was never exposed to a blast. One of the veterans with blast exposure had no history of a previous concussive injury. Three of the four veterans also had been diagnosed with posttraumatic stress disorder. All four experienced similar symptoms, including headaches, irritability, difficulty sleeping and concentrating, memory loss, depression, and persistent anxiety (Sci. Transl. Med. 2012 May 16 [doi:10.1126/scitranslmed.3003716]).

In the veterans, the investigators observed CTE-linked neuropathology characterized by perivascular foci of tau-immunoreactive neurofibrillary tangles and glial tangles with prominence in the sulcal depths of the inferior frontal, dorsolateral frontal, parietal, and temporal cortices. These findings were indistinguishable from those seen in the four athletes.

"I think that this is an important contribution in that it tells us that there are individuals who’ve been in uniform, been deployed, been exposed to what you’re exposed to on the battlefield, who develop CTE. I’m somewhat cautious about laying the blame to blast exposure here based on their data, but it underlines the idea that we have a ... significant ‘tau problem’ in the military, and that needs to be studied further," Dr. Daniel P. Perl said in an interview. He is director of the neuropathology core at the Uniformed Services University of the Health Sciences’ Center for Neuroscience and Regenerative Medicine in Bethesda, Md. He also is director of Military Brain Injury Studies at the university.

Dr. McKee and lead author Dr. Lee E. Goldstein and their associates also tried to tease out the components of a pure blast injury by creating a mouse model in which they found evidence for some of the features of CTE only 2 weeks after a single exposure to blast-force winds. The investigators constructed a compressed gas blast tube that delivered a blast with a static pressure profile that is comparable to common improved explosive devices and is within the range of typical explosives, blast conditions, and standoff distances associated with military blast injury. Anesthetized, wild-type strain of mice were restrained but left free to move their heads during the experiment, in which a single blast traveling 336 miles per hour violently shook their heads. After 2 weeks, these mice had many of the same injuries seen in humans with CTE, including the accumulation of phosphorylated tau protein, axonal injury, and disruption of the integrity of the blood-brain barrier surrounding vessels in the brain, as well as behavioral and memory deficits. However, none of the mice had mature neurofibrillary tangles in the cortex or hippocampus.

Dr. Perl called the use of wild-type mice "a little unusual" because they are not known to develop neurofibrillary tangles. "It is difficult to conclude that this is CTE because it is a progressive neurodegenerative disease with tau accumulation," he said. Pathological changes at only 2 weeks without any signs of disease progression are too early for researchers to be able to know that it is CTE, he added.

When Dr. McKee and her associates performed the same experiment with mice whose heads were immobilized, the restraint prevented learning and memory deficits from occurring, which is "consistent with a common injury mechanism involving oscillating head acceleration-deceleration cycles that lead to pathogenic shearing strain imposed on the cranial contents," they wrote.

The lack of neurobehavioral sequelae following the blast exposure with a head restraint may have implications for the design of helmets that help to keep the head stationary, she said.

The next goal is to identify CTE in living humans, Dr. McKee said. Her group is now analyzing cerebrospinal fluid for tau protein and conducting neuroimaging in a cohort of recent veterans of the Iraq and Afghanistan conflicts.

Dr. Perl and his colleagues at the Uniformed Services University of the Health Sciences have recently established the first brain tissue repository that is specifically designed to support research on the effects of traumatic brain injury suffered by military service members. It is supported by a multiyear grant from the U.S. Army Medical Research and Materiel Command.

The study was supported by various grants from the National Institutes of Health, the National Science Foundation, Cure Alzheimer’s Fund, the Department of Veterans Affairs, the Department of Defense, the Migraine Research Foundation, the March of Dimes Foundation, and the National Football League. One author is a science advisory board member of Immunotrex Biologics, but other authors reported having no competing interests.