Mild Brain Trauma Could Have Links to Alzheimer’s

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BETHESDA, MD—It was two years ago that Ira Katz, MD, PhD, then chief of VA’s mental health services, told researchers at the VISN 20 Mental Illness Research, Education, and Clinical Center (MIRECC) in Portland, OR, that they should begin focusing some of their research on TBI. It was an edict that confused Elaine Peskind, MD, a geriatric psychiatrist who has spent the last 20 years becoming an expert on Alzheimer’s disease and other neurodegenerative disorders.

“At first, I didn’t get it,” she admitted during her keynote address at the 3rd annual Trauma Spectrum Conference held at NIH last month. Trained as a psychiatrist, Peskind thought that this was a rehab problem, not a mental health problem.

At the time, Peskind, the MIRECC’s associate research director, was conducting research at nearby Joint Base Lewis McChord on PTSD. She would be giving her study participants instructions or setting up new appointments and many of them would take out notepads and begin meticulously writing down her instructions. They told her that if they did not write it down, they could very easily forget. Peskind realized that not only did many of her PTSD patients have a mild TBI, but also that mTBI presented very much like the early stages of a neurodegenerative disorder.

Alzheimer’s and mTBI

Currently, over 2 million American servicemembers, guards, and reservists have been deployed; with 800,000 having deployed more than once. “The estimate of those returned with mTBI due to blast exposure has varied from 9% of officially diagnosed TBI to 20%, and I think it will ultimately be higher than that,” Peskind said. Improvements in body armor and battlefield medicine have altered the ratio of wounded-to-killed from the four-to-one that was seen in the first Gulf War to the current 10 to one ratio in OEF/OIF.

“We see a lot more soldiers surviving blast exposure,” Peskind said. “And we see multiple deployments. In OEF/OIF, we see soldiers deployed up to five times.”

Looking at one Stryker brigade—1st Stryker Brigade (Lancers), 25th Infantry Division—which operated in Mosul, Iraq over a 12-month period in 2004 to 2005, Peskind was able to quantify the number of blasts a group of soldiers could be exposed to over a relatively short amount of time. During that year, the brigade experienced 3,056 enemy attacks, 1,336 IEDs, 1,513 fire attacks, and 84 suicide vehicle-borne IEDs.

The question—and one that has resulted in “lively controversy” among researchers—is what is the etiology, course, and treatment of persistent somatic, cognitive, and behavioral symptoms in OEF/OIF veterans following an mTBI? While the research is admittedly still in its infancy, Peskind is convinced that these chronic post-concussive symptoms reflect real, but relatively subtle, persistent brain damage.

The Effects of mTBI on the Brain

Sports medicine has recognized for years that multiple concussions can lead to neurodegenerative disorders later in life. It is common to see boxers develop problems as they age, and research is finding neurofibrillary tangles in the brains of football players much younger than would be expected in people who had not experienced repetitive head trauma. But exactly what multiple blast exposures are doing to soldiers remains unknown.

Peskind set out to discover whether persistent symptoms following mTBI reflected structural or functional changes in a patient’s brain. She began recruiting a group of 35 male OIF veterans with blast-induced mTBI, all of whom had experienced a single blast severe enough to cause some change in mental status, such as loss of consciousness, and most of whom had persistent blast-concussive symptoms. She also recruited a smaller group of non-concussed OIF veterans who had been deployed, but had no blast exposure, as well as a civilian control group.

“This has been the easiest study I ever recruited for,” Peskind said. “We maintain a waiting list of veterans with blast exposure who want to be in the study. What’s been harder to find are veterans who have not had a blast exposure.”

The study participants were subjected to a neurological exam, neuropsychological testing, as well as a battery of brain scans, with the results being compared between the groups. While there was some variability in the neurological exams, there was no group difference between blast-exposed and non-blast-exposed veterans.

However, the neuroimaging found a number of differences in brain function between the groups. Veterans with mTBI showed significant hypometabolism compared to the civilian controls in a number of areas in the brain. That finding was reported online in NeuroImage in April 2010. “Since then we now have a group of non-blast exposed controls,” Peskind said. “Comparing those OIF controls to civilian controls, we found similar effects in the cerebellum and the pons. Just being in military service appears to cause some brain changes.”

But when researchers compared the mTBI group to the OIF controls, there were still significant differences in glucose metabolism in the posterior cingulate and biparietal lobes. They also found hypometabolism in the medial temporal lobe and the thalamus in mTBI versus civilian. Controlling for effects from PTSD found that changes in brain metabolism were not the result of PTSD.

“Hypometabolism was found for both blast-exposed and non-blast-exposed veterans in the cerebellum and pons, and we are really just speculating here on what the causes might be,” Peskind said. “But among our thoughts are that there may have been pre-military vulnerabilities. Also, it might be due to the military lifestyle, including other head trauma.”

There is also hyperthermia caused by the environment to consider. In Iraq, it is 130 degrees outside and there is no air conditioning inside a Stryker, where soldiers are packed in together in full armor.

Future Research

While much of the research is still incomplete, it is apparent that there are distinct changes in brain structure in servicemembers who experience mTBI, Peskind explained. Diffuse tensor imaging shows white matter disintegrity in a number of brain areas. CRI tests suggest alterations in myelin structure in white matter tracks known to be vulnerable to damage in diffuse axonal injury. The latter might be distinct enough and consistent enough to have potential as a tool in diagnosing mTBI.

Better diagnostic techniques are just one of many tools that need to be developed to better treat and understand the effects of mTBI.

“Structural imaging modalities are starting to provide a coherent picture of diffuse axonal injury with corresponding hypometabolism of glucose in brain injuries,” Peskind said. “The pattern of functional deficits is reminiscent of very early changes seen in Alzheimer’s. But, please, caution is needed. We need more data. We need more analysis.”

Longitudinal follow-up studies are essential. “We have to know what the long-term risk for these veterans is,” she said. “Additional study groups are also needed. We have not had a single subject yet who has PTSD but not mTBI.”

Peskind’s group is also currently creating their own mouse model of repetitive blast concussion.

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