By Stephen Spotswood
BETHESDA, MD — A number of drugs have been shown to have neuroprotective benefits in animal models of TBI. When studies have moved on to human subjects, however, most have had poor results.
Ramon Diaz-Arrastia, MD, PhD
Researchers say they believe part of the problem is a too-limited understanding of the pathophysiology of TBI in humans. While rat models of diseases are designed to be as homogenous as possible from subject to subject, the injury in humans is anything but.
What is needed is not only a better understanding of the injury but better ways of imaging it and accurate biomarkers for researchers to use to predict outcome and help direct treatment, according to Ramon Diaz-Arrastia, MD, PhD, director of clinical research at the Center for Neuroscience and Regenerative Medicine at the Uniformed Services University of the Health Sciences (USUHS) in Bethesda, MD.
TBI historically has been “the poor stepchild” of neurology and neurosciences, Diaz-Arrastia told an audience of fellow researchers on the campuses of NIH.
What he meant by that remark is that, until injured troops began returning from Iraq and Afghanistan, serious effort had not gone into diagnosing, understanding and treating TBI — particularly mild TBI — even though millions of Americans, military and civilian, suffer from its effects.
According to Diaz-Arrastia, 5.3 million Americans are living with disabilities resulting from TBI, which is the single most common cause of death and permanent disability in people under 45. Yet, the seriousness of TBI in returning servicemembers caught DoD by surprise, he said.
“The concern was that [blast-related TBI] is a new type of injury — something that had never been seen before. I’m not sure that’s true. I think TBI is something that’s been in every conflict since we were still in caves. And mTBI was there as well, but no one paid attention to it because there were much more severe injuries,” he pointed out.
Now, everyone is paying attention to it, especially NIH and DoD, which have entered intense partnerships to better understand the injury.
Diaz-Arrastia says he is especially interested in the heterogeneous nature of TBI injuries. One patient’s TBI does not look like another’s, which might have profound implications for treatment.
“What might work with one type of injury may not work on another,” he added..
Each TBI is a complex combination of endophenotypes involving inflammation, vascular injury, ischemia, glucose levels and other aspects of the patient’s health. Magnetic resonance imaging (MRI) is one way to identify those endophenotypes.
Prior to being recruited by USUHS, Diaz-Arrastia had been director of the North Texas TBI Research Center at the University of Texas Southwestern Medical Center in Dallas. While there, he and his colleagues made considerable inroads into better imaging traumatic brain injuries.
The long-term goal is to compare imaging with outcome and identify biomarkers that have a correlation to a patient’s future health and recovery.
One diagnostic technique with great potential is quantitative volumetric analysis, Diaz-Arrastia said.
“It’s been known for some time that cerebral atrophy is a consequence of TBI, especially severe TBI. [In Dallas], we were able to make an association between lesions seen during a first scan and changes in brain volume over the first six months,” he said.
This indicates that lesions which can be measured in the acute scan are highly associated with the eventual degree of brain atrophy when the patients return for follow-up.
“Brain atrophy is a very good biomarker for outcome and highly associated with disability,” Diaz-Arrastia said, citing the following statistics:
- In patients with no atrophy, 10% can expect some disability, with 3% having severe disability.
- In patients with 5% atrophy, 37% have disability, with 15% having severe.
- In patients with 10% atrophy, 76% have disability, and 48% have severe disability.
Researchers at NIH and other federal agencies are developing more-sensitive methods of looking at atrophy, because not all structures in the brain show the same degree of atrophy in TBI patients; the amygdala, thalamus and hippocampus tend to show higher degrees of atrophy, while the caudate and cerebellum show relatively little.
“Regional brain atrophy is attractive as a candidate surrogate biomarker,” Diaz-Arrastia said. “A patient’s functional outcome after TBI is affected by so many things that are not dependent on the biology of the injury or repair. [Outcomes] can be affected by premorbid education and premorbid personality factors and the social economic status of the family. And they’re really confounders. On the other hand, brain atrophy — particularly regional brain atrophy — is closer to the biology of the injury and the biology of whatever therapy you may want to be testing.”
Another promising technique is the use of diffusion tensor imaging (DTI), by which researchers can look at axonal injury, which is believed to be a very important mechanism affecting patient outcome, post-TBI. Looking at DTIs in TBI patients, it’s clear that axonal degeneration goes on for several months after the initial injury, Diaz-Arrastia said.
The big challenge with DTI is that there is too much information to easily process it all. Sophisticated statistical analysis is needed.
Another technique under development is using hypercapnia — increasing carbon dioxide in the blood, which triggers a reflex causing an increase in breathing and access to oxygen — as a stimulus to dilate blood vessels. Using it in combination with MRI can help assess cerebral vascular reactivity.
Reactivity decreases in Alzheimer’s patients, and researchers say they believe it likewise will be decreased in TBI patients.
“This is important, because there are a number of drugs that are postulated to stimulate angiogenesis [the growth of new blood vessels],” Diaz-Arrastia said. “These are the same drugs that have been found to work in rodent models of TBI. In principle, they may be exerting a neuroprotective effect by stimulating angiogenesis.”
One long-approved compound with potential is erythropoietin. “It’s one of the compounds that has the largest track record of efficacy in TBI,” Diaz-Arrastia said. “There’s a lot of animal evidence that it’s a neuroprotectant.”
Diaz-Arrastia is helping develop a phase 2 study using MRI volumetrics as the primary outcome method for assessing erythropoietin’s efficacy.
Another pilot study he is helping to develop will look at sildenafil (marketed as Viagra) and its potential to improve cerebral vascular reactivity. “It potentates signaling of nitric oxide — the major endothelial-dependent vasodilator in the brain,” Diaz-Arrastia said. “There’s animal evidence that it’s neuroprotective.”
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