18 May 2012

Since soldiers stumbled out of World War I with panic attacks, nightmares, and other signs of shell shock, debate has raged over the nature of this trauma: Is it purely psychological, or are physical brain changes to blame? Research in the May 16 Science Translational Medicine convincingly supports the latter. Scientists at Boston University School of Medicine, Massachusetts, report that brains of blast-exposed military veterans pathologically resemble those of athletes who develop a tau-linked neurodegenerative disorder from repetitive head injuries. “Whether on a ball field in suburban Massachusetts or on the battlefield in Afghanistan, as far as the physics is concerned, it’s the same story,” said first author Lee Goldstein, who led the study with senior investigator Ann McKee of BU and the Veterans Affairs Boston Healthcare System and collaborators elsewhere. Rotational acceleration causes the head to swivel, and in normal mice subjected to a single blast, the “bobblehead effect” induces tau pathology, neurodegeneration, and learning and memory deficits resembling chronic traumatic encephalopathy (CTE). In this blast neurotrauma model, holding the head still during the blast reduced cognitive losses. Having a mouse model that recapitulates key aspects of CTE is a big step forward, experts say, as it enables experiments toward diagnosis and therapy development that were not previously possible.

Some 10 to 20 percent of U.S. military personnel deployed to Iraq and Afghanistan have suffered traumatic brain injuries (TBIs), many from exposure to explosive blasts (Wilk et al., 2010; see also U.S. Department of Defense numbers). People with blast-related injury present with symptoms similar to the ones reported by athletes who are later diagnosed with CTE, a tauopathy associated primarily with repeated concussions. Yet in a recent case study, scientists also found CTE pathology in the brain of a blast-exposed Iraqi war veteran (Omalu et al., 2011), suggesting that blast trauma and sports-related head injuries may share biomechanical underpinnings.

In the current paper, McKee and colleagues analyzed a case series of four postmortem brains from U.S. military veterans with blast exposure and/or concussive injury. They compared these with two other groups (four brains each): young athletes who suffered repeated head blows playing football or wrestling, and normal controls who died young with no blast exposure or concussive injury. In all, the group has analyzed some 60 cases of CTE due to different causes thus far.

The veteran and athlete brains showed pure tauopathy (i.e., no amyloid plaques), and were pathologically indistinguishable from each other. Both had pronounced neurofibrillary and glial tangles with phosphorylated tau, as well as distorted axons, activated microglia, and other CTE-like pathology—none of which appeared in the control brains. The findings were “readily differentiated from neuropathology associated with Alzheimer’s disease, frontotemporal dementia, and other age-related neurodegenerative disorders,” the authors wrote.

Still, the case series was small and cannot determine causality. “It’s like looking at the last frame of a movie and trying to figure out the plot line,” Goldstein said. “We’re looking at pathology years after the trauma has occurred.” Further complicating matters, many veterans also played contact sports, and could have whacked their heads in fights or car accidents. “You could do a hundred cases and not get around that,” Goldstein said.

This overlap prompted the researchers to develop a blast neurotrauma model. Lab mice do not play football or go to war, and have no prior head trauma. “They are a completely clean group,” Goldstein said. His team subjected 2.5-month-old mice to a single blast calculated to simulate what soldiers experience in the military setting, about 5.8 kilograms of TNT at 5.5 meters. Analyzed two weeks later, the mouse brains had no gross abnormalities or evidence of concussion. However, the researchers did find CTE-like tau pathology and neurodegeneration, as well as disrupted synaptic long-term potentiation and problems with learning and memory that lasted at least a month. “We were floored. We weren’t expecting this,” Goldstein said. “We were just using these mice to calibrate the gas tube in our blast study, thinking we would need multiple blasts and/or human tau transgenic mice to see tau pathology.”

In separate experiments measuring intracerebral pressure changes and head movements in mice during blast exposure, it appeared that blast-induced head acceleration, not the pressure wave itself, was the likely mechanism leading to brain injury and CTE. To test that idea, the researchers immobilized the animals’ heads during a single blast exposure, and found this could largely restore blast-induced cognitive deficits.

“This paper is a real tour de force. It’s an absolutely huge advance to the field,” said Elaine Peskind of the VA Puget Sound Health Care System and the University of Washington, Seattle. Using neuroimaging to study the brains of blast-exposed Iraq veterans, Peskind and colleagues have found they have lower glucose metabolism, poor structural integrity, and functional brain changes resembling those in early mild cognitive impairment (see ARF related news story). Her lab is also collecting cerebrospinal fluid data on these veterans.

Nigel Cairns of Washington University School of Medicine, St. Louis, Missouri, heard some of the new data presented at a recent symposium on military risk factors for AD. “The blast model is quite sound,” he told Alzforum. “From the pathology point of view, the lesions are comparable to those seen in human disease.” He noted minor differences—for example, tau aggregating less in blast-exposed mice than in people with CTE.

Scientists are working on other mouse models of TBI, too. In the May 9 Journal of Neuroscience, Kimberle Jacobs and colleagues at Virginia Commonwealth University, Richmond, use a yellow fluorescent protein (YFP)-expressing mouse to study electrophysiological consequences of TBI in neurons within living cortical slices. Other TBI animal models took the stage at a recent Keystone symposium on chronic encephalopathies (see ARF related conference story).

Meanwhile, new research published online May 16 in Neurology strengthens the idea that repeated head impacts can harm cognition. In a prospective cohort study, Thomas McAllister of Dartmouth Medical School in Lebanon, New Hampshire, and colleagues compared 214 college football and ice hockey players with 45 college athletes in non-contact sports. The results suggest that a single season of head impacts—measured by helmets with incorporated accelerometers—impairs learning in some athletes.

“These studies are coming together,” Cairns said. “If the head is exposed to trauma in a number of different settings, the sequelae are likely to be similar.” (See ARF Webinar.)

Genetics may also play a role, as suggested in a Science Translational Medicine editorial accompanying the paper on CTE in blast-exposed military veterans. There, Sam Gandy of Mount Sinai School of Medicine, New York, and Steven DeKosky of the University of Virginia School of Medicine, Charlottesville, highlight ApoE4 as a potential risk factor for CTE. However, among the CTE cases analyzed thus far at Boston University, ApoE genotype does not seem to influence CTE severity, Goldstein told ARF.

Does CTE pathology resulting from head trauma predispose people to Alzheimer’s disease? The blast neurotrauma mouse model could help address the question. The current study looked at relatively young (2.5-month-old) mice. If, however, the researchers found amyloid plaques a year later, “that would be a clear indication that head trauma accelerates development of AD,” Cairns said. Further clues could come through a joint project by the U.S. Department of Defense (DoD) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Under the initiative, 210 U.S. military veterans will be analyzed using ADNI protocols for brain amyloid imaging and Aβ and tau CSF biomarker analysis. Recruitment is slated to begin this fall, said lead investigator Michael Weiner of the University of California, San Francisco (see also Weiner comment on related editorial).

Ironically, while CTE pathology lacks a defining component of Alzheimer’s disease—amyloid plaques—the neuroanatomist who first described shell shock syndrome in World War I veterans was none other than that disease’s eponymous father, Alois Alzheimer, in his article Der Krieg und die Nerven: Breslau, Verlag von Preuf & Jünger, 1915 (see ARF related news story).

One future question this new research raises in some researchers’ minds is whether some cases of PTSD, for example, among veterans, might represent a prodromal form of CTE. PTSD is a clinical diagnosis, CTE primarily a pathological one, though that is beginning to change.—Esther Landhuis

Comments

- Henrik Zetterberg
  University of Gothenburg
- Posted: 18 May 2012
- Paper: Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model.
This is a very interesting paper demonstrating that the neuropathology seen in some soldiers exposed to blast overpressure with clinical symptoms suggesting chronic traumatic brain injury is very similar to that of athletes with repetitive concussive head injuries. Importantly, a carefully calibrated mouse model was developed in which it was shown that blast overpressure per se does not injure the brain; instead, it is the head movement induced by the blast that causes the brain trauma. This is well known to any boxer: Make the head on your opponent accelerate in an uncontrolled manner and you will have a good chance of winning the bout on a knockout. The mouse model will be very useful for finding strategies to prevent a progressive tauopathy from developing after brain trauma.

View all comments by Henrik Zetterberg

- Eric Nauman
  Purdue University
- Posted: 18 May 2012
- Paper: Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model.
The study is very interesting, and there are a few groups that are obtaining similar results with their animal models.

There has been a big controversy about the relevance of head impact studies to military trauma. There is a large group that assumes that the physics of blast waves is completely unrelated to head impacts of the type received during car accidents, playing football, falling on the ice, and the like. This study provides a good argument that they are, in fact, similar injury mechanisms. Effectively, the blast wave passes through the skull and brain, but it isn't until the blast wind causes a shock to the head that you get the damaging relative motion between the brain and the skull. It does not take a lot of displacement to cause an injury; a rapid acceleration is sufficient.

There are some possible issues to consider. The skull of a mouse will not impede the blast wave very much, but we know that pig skulls alter the blast wave considerably. Human skulls are going to be somewhere in between, and we don't necessarily know what effect that might have. It is also likely that a large enough blast wave will just liquefy most of the internal organs. Having said that, I think these results provide pretty convincing evidence that the physics of head trauma are dominated by the impulse delivered to the head.

Lastly, I think the fact that there seem to be similar mechanisms involved in military and sports head traumas provides circumstantial evidence that PTSD and CTE are related, but there is the potential for a number of other factors to be involved in PTSD. One of the most important things we can do to help soldiers and athletes is to find ways to detect the damage early and localize it to specific structures in the brain. This would enable clinicians to develop treatments specific to a given patient. Because of this study, I think we are much closer to reaching that goal.

View all comments by Eric Nauman

- Rudy Tanzi
  Massachusetts General Hospital
- Posted: 18 May 2012
- Paper: APOE {varepsilon}4 Status and Traumatic Brain Injury on the Gridiron or the Battlefield.
Given what Lee Goldstein, Ann McKee, and colleagues observed in the brains of blast victims and athletes who suffered severe concussions in our recent study, we need to be much more cognizant of how to protect our military and those playing violent contact sports from head trauma. Knowing you are ApoE4 postive may be a start toward increased vigilance in these activities. But those who do not carry the ApoE4 allele must still be equally concerned with protecting themselves from head injury to avoid downstream risk for CTE and dementia.

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- Douglas Galasko
  University of California, San Diego
- Posted: 18 May 2012
- Paper: APOE {varepsilon}4 Status and Traumatic Brain Injury on the Gridiron or the Battlefield.
The editorial makes several important points. Perhaps the most important is that we need a much larger database to understand risks that transform TBI into CTE and its various clinical expressions among people at risk due to sports, war, or other situations. A long-term investment in studying cohorts prospectively could provide appropriate information for counseling and risk assessment. Initiatives such as lifetime TBI diaries among athletes, amateur and professional, in sports that are associated with increased risk of TBI, would be extremely valuable. Some of the expense could be deferred by piggy-backing these studies onto existing cohort studies, but specific funding for registries or cohort studies would be worth considering.

The editorial highlights ApoE4 as a risk factor for CTE. The data from which this conclusion is drawn are limited: For example, reference 4 in the editorial is a study of 30 boxers, and should be viewed as preliminary.

Many studies of ApoE have come from major TBI and its outcomes. For example, Ponsford et al., 2011, was an Australian study of TBI in more than 600 adults. It reported no association between initial severity of clinical deficits from TBI and ApoE4, but an association between worse longer-term recovery and ApoE4. Follow-up of this cohort was not long enough to consider the long-term risk of CTE and its consequences.

Alexander et al., 2007, followed 123 adults with severe TBI for up to 24 months and documented a slower recovery rate for people with an ApoE4 allele, controlling for other potential predictors. It is tempting to extrapolate from the data on severe TBI about the additional influence of ApoE, but the questions raised by milder TBI and CTE may not be identical.

More data are needed to inform and develop public health policy, particularly regarding sensitive issues that surround genetic testing and disclosure. As an inverse of advising people who are ApoE4 carriers to consider avoiding contact sports with higher risk of TBI, would the knowledge that one lacks an ApoE4 allele give a false sense of security to other athletes? Reducing the risk of TBI, regardless of ApoE genotype, is an imperative of further research related to CTE.

References:

Ponsford J, McLaren A, Schönberger M, Burke R, Rudzki D, Olver J, Ponsford M. The association between apolipoprotein E and traumatic brain injury severity and functional outcome in a rehabilitation sample. J Neurotrauma. 2011 Sep;28(9):1683-92. PubMed.

Alexander S, Kerr ME, Kim Y, Kamboh MI, Beers SR, Conley YP. Apolipoprotein E4 allele presence and functional outcome after severe traumatic brain injury. J Neurotrauma. 2007 May;24(5):790-7. PubMed.

View all comments by Douglas Galasko

- Michael Weiner
  San Francisco Veterans Affairs Medical Center
- Posted: 18 May 2012
- Paper: APOE {varepsilon}4 Status and Traumatic Brain Injury on the Gridiron or the Battlefield.
The editorial by Drs. Gandy and DeKosky very appropriately raises concerns about the effects of traumatic brain injury to produce chronic traumatic encephalopathy and as a long-term risk factor for Alzheimer's disease. Furthermore, the editorial raises questions concerning the role of ApoE4 as an added or interactive risk factor for future brain damage. Recently, the ADNI team was funded by the Department of Defense to begin a study of the effects of traumatic brain injury and post-traumatic stress disorder on Alzheimer's disease in veterans using imaging and biomarkers in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We will enroll 210 Vietnam War veterans (70 in each group) who: 1) have a documented history of moderate to severe concussion, 2) documented post-traumatic stress disorder, or 3) healthy controls and study them with the identical clinical, cognitive, MRI, PET, and CSF biomarkers as subjects in ADNI2. Of course, ApoE4 testing, GWAS, or even whole-genome sequencing will also be performed on DNA from these subjects. We expect that the results of this study will provide new insights into the relationship of TBI and PTSD to the development of cognitive decline, Alzheimer's disease, and dementia.

Millions of Americans have served in the Armed Forces, many of whom have been subjected to exposures such as TBI and PTSD that may increase their risk for dementia. The Veterans Administration runs the largest single healthcare system in the U.S. In my view, considering the magnitude, prevalence, and severity of Alzheimer's disease in veterans, the DOD and VA have not provided sufficient funding for research concerning Alzheimer's disease.

Therefore, this very important editorial further raises awareness and concerns about several important issues. Hopefully, this will result in new research and additional funding, which will lead to improved diagnostic methods and treatments to prevent cognitive decline and dementia.

View all comments by Michael Weiner