Friday, June 10, 2016

Biomarkers of brain injury in concussion

The promise of a blood test to identify patients with concussion and differentiate which patients may have more severe or persistent injuries looks closer to becoming a reality with the publication of a new large-scale study of two biomarkers of brain injury.

The study, published online in JAMA Neurology on March 28, was conducted by a group led by Linda Papa, MD, Orlando Regional Medical Center, Florida.

In their study of almost 600 trauma patients, 55% of whom had a mild or moderate traumatic brain injury (TBI), they showed that serum levels of two biomarkers — glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1) — correlated with degree of brain injury, with GFAP being the more reliable of the two.

GFAP is a protein expressed almost exclusively in astrocytes and UCH-L1 is found in neurons.

"In a head injury, the astrocytes and neurons are damaged so these proteins leak out and small amounts enter the blood stream," Dr Papa explained to Medscape Medical News. "We used assays that can detect minute amounts of these proteins in the serum."

The study was also the first to have looked in detail at the time course of the rise in these biomarkers in mild TBI, and it showed that while UCH-L1 was useful early on (in the first day or two after injury), GFAP was a more accurate indicator of diagnostic accuracy at all time points and continued to predict brain injury severity up to 7 days after impact. 

"This is really helpful in giving us a window for when we can do the test," she said. "The results with GFAP are particularly exciting. It seems to be able to detect problems several days post injury. This is very useful because in many instances patients may not come in right away."

She noted that for very early brain injury, use of the two biomarkers together was a little better than GFAT alone, "but we are not sure if the difference is worth the extra work in doing two tests."…

In an editorial accompanying the publication, Tanya Bogoslovsky, MD, and Ramon Diaz-Arrastia, MD, Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences, Rockville, Maryland, describe the current study as a "substantial step toward validation and ultimate clinical usefulness of 2 candidate diagnostic biomarkers of mTBI [mild TBI]."

They say the study has many strengths, including large sample size, allowing subgroup analysis; multiple blood sampling, allowing time profiles of the biomarkers to be tracked; a unique control group of patients who had experienced trauma but did not have concussion, thus capturing the setting in which a blood test for TBI biomarkers would be used clinically; and rigorous assessments of patients with mild TBI by both emergency department physicians and specialists confirming the accuracy of classification of the enrolled patients…

For the study, 584 adult trauma patients, 55% of whom had mild to moderate TBI and the remaining 45% had trauma without TBI, had blood samples taken within 4 hours of injury and at 19 additional time points up to 7 days after injury.

Results showed that both GFAP and UCH-L1 were detectible within 1 hour of injury. GFAP peaked at 20 hours after injury and slowly declined over 72 hours, whereas UCH-L1 rose rapidly and peaked at 8 hours after injury and then declined rapidly over 48 hours…

They note that both biomarkers have an excellent value for predicting neurosurgical intervention early after injury and UCH-L1 performed best within 16 hours of injury. They point out that determining whether a patient will require a neurosurgical intervention is most important within 24 hours after injury to allow decisions such as transferring a patient to a trauma center or admitting for observation.

In the context of developing a point-of-care test, the researchers suggest that the early and rapid rise of UCH-L1 could be used to detect TBI immediately at the scene of injury in settings such as in the ambulance, on the playing field, or on the battlefield, whereas the profile of GFAP makes it a favorable biomarker to use in both the acute and subacute phases of injury.


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