Concussion Biomarker Useful Up to 7 Days After Injury

May 04, 2016

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."

GFAP Most Accurate

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."

She explained that at present diagnosis of concussion is based on rather crude and subjective measures.

"We mainly just use symptoms, but these are self-reported by patients who may not be reliable. Some patients may have a CT [computed tomography] scan but often patients with a normal CT scan will have long-term symptoms, such as problems with concentration, memory, sleep and anxiety," she said.

"We need to try and identify better the patients who are going to have long-term problems. At the moment they can be left in an abyss not knowing what is wrong with them."

Dr Papa said that diagnostic tests based on these markers were at a late stage of development and could be available for routine clinical use in 2 years. "They are very attractive as we don't have many tools at our disposal to diagnose concussion at present. They will help us determine if a patient has concussion and also select out those who need more intervention such as those with brain lesions or those needing neurosurgery. It is very exciting."

Study Has "Many Strengths"

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.

"So for these reasons this study will boost confidence in the reliability of these biomarkers," Dr Bogoslovsky told Medscape Medical News.

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.

During the course of 1 week, GFAP demonstrated a diagnostic range of areas under the curve for detecting mild to moderate TBI of 0.73 to 0.94, and UCH-L1 demonstrated a diagnostic range of 0.30 to 0.67.

For detecting intracranial lesions on CT, the diagnostic ranges of areas under the curve were 0.80 to 0.97 for GFAP and 0.31 to 0.77 for UCH-L1. For distinguishing patients with and without a neurosurgical intervention, the range for GFAP was 0.91 to 1.00, and the range for UCH-L1 was 0.50 to 0.92.

"This study has important clinical implications for when these TBI biomarkers should be used by health care professionals after trauma," the authors conclude. "It appears…that GFAP has a consistent ability to detect MMTBI [mild to moderate TBI] and detect traumatic intracranial lesions on CT over 7 days after injury, whereas the ability of UCH-L1 seems to be more limited to the earliest time points after injury."

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.

This study was supported by an award from the National Institute of Neurological Disorders and Stroke (Dr Papa, principal investigator). Dr Papa reported being an unpaid scientific consultant for Banyan Biomarkers Inc but reported not receiving stocks or royalties from the company and reported not benefiting financially from this publication. Disclosures for coauthors appear in the paper. Dr Bogoslovsky and Dr Diaz-Arrastia have disclosed no relevant financial relationships.

JAMA Neurol. Published online March 28, 2016. Abstract Editorial

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