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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