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.