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Researchers ID CTE in Blast-injured Veterans; Mouse Model Points to Head Acceleration

Shaw, Gina

doi: 10.1097/01.NT.0000415801.49576.a9
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Using a blast neurotrauma mouse model, investigators at Boston University compared the brains of deceased veterans who sustained blast injuries during service to findings from healthy controls and young athletes with histories of concussion. Exposure to blast injury in veterans can lead to chronic traumatic encephalopathy similar to that sustained by professional athletes exposed to frequent concussions, they suggest.

A complex new paper from a team of researchers at Boston University (BU) School of Medicine and other centers combines pathological analysis of the brains of deceased veterans who sustained blast injury during their service with studies of mice exposed to blast neurotrauma. The study authors suggest that exposure to blast injury in these veterans can lead to chronic traumatic encephalopathy (CTE) similar to that sustained by professional football players and other athletes exposed to frequent concussions.

The paper, which appeared in Science Translational Medicine in May, is not the first paper to feature a blast neurotrauma mouse model, nor is it the first to find CTE in a blast-injured war veteran. (The first article on CTE in a veteran — an Iraqi war veteran who committed suicide — was published last year in Neurosurgical Focus by forensic neuropathologist and co-founder of the Brain Injury Research Institute Bennet Omalu, MD, MPH.)

But the study is unique in juxtaposing the human pathology with the biomechanical and kinematic findings from the mouse model.

In the neuropathological analysis portion of the study, the researchers reported on a case series of four military veterans with a mean age of 32.3 years with known exposure to blast or concussive injury, and compared their findings with another four-case series of brains from young amateur football players and a professional wrestler with histories of repetitive concussive injury (mean age 20.8 years), as well as four normal control subjects of comparable ages (mean age 20.5) and no known exposure to blasts or concussive injuries.



The brains of all four veterans revealed “CTE-linked neuropathology characterized by perivascular foci of tau-immunoreactive neurofibrillary tangles (NFTs) and glial tangles in the inferior frontal, dorsolateral frontal, parietal, and temporal cortices,” the researchers wrote. The pathology was largely similar to CTE findings in the brains of the four young athletes studied, consistent with previous CTE findings. Such findings are readily differentiated from neuropathologies associated with Alzheimer's and other neurodegenerative disorders. By contrast, the brains of the four control subjects showed no signs of CTE.

That alone would seem to suggest that combat-related blast injuries, although different in many ways — including type of force and frequency of occurrence — from sports-related injuries, can also result in the type of CTE seen in athletes. But there are confounding factors — notably, the blast injuries were not the veterans' only potential exposure to brain damage. For example, one of the veterans also sustained a concussion in a car accident as a child; another had played high school football and sustained multiple concussions in fistfights; and a third sustained at least three non-combat concussions in bike accidents and football games. The fourth veteran had no history of concussive injury other than two separate IED blast exposures, five years apart.

The researchers also noted differences in the way the CTE “behaved” between the veterans with blast injuries and the athletes. “In athletes, the disease tends to start cortically, at the depths of the sulci, where the cortical ribbon dies, particularly at the lateral part of the superior frontal lobe,” said one of the study's lead authors, Ann McKee, MD, co-director of the Center for the Study of Traumatic Encephalopathy at Boston University.

Dr. McKee also directs the Neuropathology Service for the New England Veterans Administration Medical Centers and the Brain Banks for the Boston University Alzheimer's Disease Center, Center for the Study of Traumatic Encephalopathy, Framingham Heart Study, and Centenarian Study. She began to develop an interest in the question of CTE among blast-injured veterans in 2009.

“I do all the general autopsies in the greater Boston area, and I noticed that the first veteran of the Iraq-Afghanistan wars whose brain I analyzed had the same neuropathological alterations in his brain as in CTE. And he had been exposed to a blast injury,” she said. “That piqued my interest. I spent a lot of time over the next four years trying to get more cases, and out of 28 veterans that I looked at serially, I found CTE in three. That suggested about an 11 percent incidence of CTE in veterans.”

But comparing CTE in veterans exposed to blast injury with CTE in athletes who've sustained multiple concussions is controversial — because concussion and blast injury are very different. “The prevailing theory in the literature has been that there's a ‘water hammer’ effect from the blast waves, related to the increase in thoracic pressure from the pressure wave coming up through the chest,” said Dr. McKee.

So study co-author Lee E. Goldstein, MD, PhD, associate professor of psychiatry, neurology, ophthalmology, pathology and laboratory medicine & biomedical engineering at BU's Alzheimer's Disease Center, spent nearly two years developing a blast neurotrauma mouse model that could potentially elucidate the precise mechanism of any brain damage. (One of the reasons the study lists 35 co-authors is that a vast range of expertise was required to address the many possible questions about the precision of the model.)

The team chose to avoid standard concussion models in the mouse, because many such models produce a lesion in the brain. “We didn't want that,” said Dr. McKee. “We wanted something that looked invisible, because the real feature of the trauma produced in the brain that gives rise to the impact of blast injury is that there's no hemorrhaging. The brain looks fine grossly and on CT/MRI scans. It's the signature invisible wound of war.”



So Dr. Goldstein and his team produced a blast tube that exerted sufficient, but not excessive, force (about 336 miles per hour, to be precise). All the mice exposed to the blast injury survived, and were not noticeably impaired. But within two weeks, at the microscopic level, the researchers were able to detect a phosphorylated tau proteinopathy similar to that found in CTE. “We saw a lot of axonal injury in the mouse, and we really saw it best ultrastructurally using an electron microscope,” said Dr. McKee. “We could also see alterations of the astrocytes around the vessels.”

And the mice, of course, had not been in fistfights or played high school football; the only concussive impact they had been exposed to was in the blast tube.

The mice also showed impairments in cognitive and spatial memory. “The brain didn't respond properly a few weeks and even a month after injury,” said Christopher Giza, MD, associate professor of pediatric neurology and neurosurgery at the David Geffen School of Medicine at UCLA and a member of its Brain Injury Research Center. “That's pretty good evidence in a mouse model that you can have a single blast injury with 100 percent survival that still yields lasting damage,” said Dr. Giza, who was not connected with the study.

The researchers also sought to settle the question of the exact mechanism by which a blast wave inflicts such brain damage. When the mice had their heads immobilized during the blast, memory and learning deficits did not follow, and the proteinopathies were not seen at the microscopic level. That seems to disprove the “water hammer” theory, Dr. Giza said. “The rat had some pretty violent head movements in the pressure wave, and they did not detect pressure rising up through the chest. But if the head didn't move, the pressure wave didn't seem to cause too much damage. That does suggest that the violent movement of the head, rather than the pressure transmitted from the abdomen, may be the impetus for injury.”

But it's hard to scale up from a mouse to a human. “The biomechanical differences are quite profound,” said Dr. Giza. “The mouse brain is tiny, has very little white matter and fewer wires connecting the parts of the brain, and it doesn't have the folds of the human brain. Further, the mouse has much less musculature to restrain head movement. But does this ‘bobblehead’ effect that happens in the mouse occur in human blast exposure or concussion? It seems like it would be much less severe in humans.”

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“This is a big step forward, but there's still a lot more to do,” agreed Steven DeKosky, MD, dean of the University of Virginia School of Medicine, and a noted CTE researcher whose editorial on apolipoprotein E4(APOE4) status and TBI appears in the same edition of Science Translational Medicine. That editorial suggests that the APOE4 allele may pose an added risk factor for CTE. “We still need more research, in both animal models and in autopsies, to determine whether it's the blast injury alone that does this damage, or is it the blast plus the concussive damage that happens when the head hits something.”

Dr. DeKosky pointed out that the cases of CTE in athletes are from individuals who have, for the most part, experienced repeated head traumas — not just concussions, but the “bell ringing” that can happen in game after game as players are tackled with enormous force. “We don't necessarily know how frequently some of the veterans have been exposed to these forces. Suppose they've been near, but not actually in, the local area where the blast wave comes through? There is also the complication of PTSD, which veterans may have but athletes may not. We don't yet know whether the kinds of things we see in football players are comparable to what plays out with head injuries in a war zone.”

Ultimately, said Dr. DeKosky, greater numbers of well-studied cases are needed. “If we collect a large enough number of autopsies and more data from mouse models, eventually, a pattern will emerge. It's important to note that not everybody who suffers head trauma ends up with a permanent deficit or CTE. We need to identify why some people are more resistant to it than others.”

Dr. McKee believes that identifying the underlying mechanisms and pathologies of CTE early on will be important to both veterans and athletes. Her team is now also assessing the value of CSF testing for tau levels and neuroimaging using PET scanning in efforts to identify biomarkers for CTE. “If we can test drugs and therapies in the mouse model that could reverse tau accumulation or interrupt its spread from focal spots in the nervous system to much larger regions, we could make a huge impact on the suffering of these individuals.”

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• Goldstein LE, Fisher AM, AC McKee, et al. Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model. Science Transl Med 2012; 4(134):134ra60.
    • Omalu B, Hammers JL, Fitzsimmons RP, et al. Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide. Neurosurg Focus 2011; 31(5):E3.
      ©2012 American Academy of Neurology