One of the most critical needs, Dr. Korley says, is to distinguish between acute and chronic elevations in both biomarkers. In addition to the elderly, some patients with brain injuries may have baseline elevations as well. It’s possible that clinicians will find utility in doing serial measurements, as with cardiac troponins; if so, the markers might also be useful for monitoring patient recovery and for understanding response to therapeutic agents.
Dr. Gherasim agrees that there might be usefulness in thinking about the troponin experience. “For nonspecific elevations of the biomarkers due to chronic conditions, it may be important to have serial testing similar to troponin, at zero, one-hour, and two-hour intervals,” she says. “We are definitely interested in working with the clinical teams to see if a series of biomarker testing could be useful.”
Ideally, a better understanding of the markers will also help refine patient selection for clinical trials. Current inclusion criteria include the Glasgow Coma Scale, but as Dr. Korley notes, that can be affected by things such as intoxication (a not-uncommon factor in trauma patients).
GFAP and UCH-L1 are paired in current assays, though whether that ultimately is the most useful approach—like putting twins in separate or the same classrooms—is a matter of debate.
Some observers have suggested that GFAP might be the more useful of the two and raise questions about what UCH-L1 adds to the picture. “The verdict is still out,” says Dr. Korley. “We found that UCH-L1 did not add a whole lot to GFAP.”
But that’s not a final answer. UCH-L1 theoretically rises earlier than GFAP—in very early presenters, it may provide information while GFAP levels appear normal. In clinical practice, however, by the time injury occurs and the patient presents to the ED and blood is drawn, several hours may have elapsed, making the advantage of UCH-L1 less obvious, Dr. Korley says. Nevertheless, they plan to keep using UCH-L1 unless sufficient data accumulate to suggest it’s not useful, “on the off chance that you have an early presenter with elevated values.”
Another potential downside of UCH-L1, says Dr. Korley, is that he and colleagues have observed that it’s elevated in multisystem trauma, thus limiting its specificity for traumatic intracranial hemorrhage. That might be another reason not to include it on a testing panel, but again, they lack sufficient data to decide whether they can safely drop the marker.
Dr. Gherasim weighs in with her own observations. Given the biomarkers’ apparently complementary kinetics, it might make sense to offer them both. “But there are a number of companies that are pursuing a GFAP-only test.” As Dr. Korley and others look at the diagnostic accuracy of GFAP alone, as well as GFAP and UCH-L1, she says, “It would be important to know the value of each biomarker in terms of sensitivity as well as specificity, and whether certain populations or conditions might benefit from using both biomarkers as opposed to relying on a single one.” Likewise, such information would be valuable if the biomarkers are used in serial measurements. “It would be interesting to see the value of each biomarker in different clinical scenarios as we get more data.”
In the meantime, the work continues. Michigan Medicine recently received a grant from the former Department of Defense to expand its work to six additional sites. The aim of this effort, called the PIONEER studies (Prospective Implementation of Novel Evidence-based Biomarkers for Evaluating Traumatic Brain Injury), is to demonstrate test utility across multiple sites, “which would be strong evidence to encourage the field that we’re headed in the right direction, and that these tests are worth adopting universally,” says Dr. Korley.
Karen Titus is CAP TODAY contributing editor and co-managing editor.