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Asymptomatic patients with head trauma often fly under the radar of clinicians. Without proper treatment and diagnosis, they can suffer more long-term injuries over time. Two studies zeroed in on undetected brain traumas, leveraging blood biomarkers such as glial fibrillary acidic protein (GFAP) to flag concussion.

One of the studies, published in BMJ Paediatrics Open, utilized two serum biomarkers, GFAP and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) to hunt for an often silent type of head trauma, the subconcussive injury. “These are people who experience head trauma without symptoms of concussion,” said Linda Papa, MD, lead author of the study and an emergency medicine physician at Orlando Health. “They may be classified as having ‘no injury,’ or they may represent milder forms of concussion that do not elicit the typical signs or symptoms associated with concussion and are referred to as ‘subconcussive’ injuries.” 

Subconcussive trauma has been of particular concern in military personnel and  athletes, “as repetitive subconcussive impacts have the potential for long-term deleterious effects,” Papa told CLN Stat. The Food and Drug Administration had approved tests for GFAP and UCH-L1 to detect abnormalities on CT scan in adults with mild to moderate traumatic brain injury. “However, they have not been approved to detect concussion, and they have not been approved for use in children,” she added. The study’s aim was to raise awareness about elevations of these biomarkers in subconcussive trauma and milder forms of brain injury in patients of all ages and different injury types.

Researchers analyzed GFAP and UCH-L1 levels in 712 adult and pediatric patients of all ages, grouped into three cohorts: concussion; head trauma without overt signs of concussion (head trauma control); and body trauma without head trauma or concussion. According to Papa, “this is a very unique comparison because it describes gradients of injury from no head trauma (no concussion), to head trauma without symptoms (subconcussion), to head trauma with symptoms (concussion).”

Among all three groups, the researchers found small but significant elevations in both GFAP and UCH-L1 levels. Those in the concussion group had much higher GFAP concentrations than the subjects in the body trauma and control group. Overall, GFAP outperformed UCH-L1 in detecting concussion among children and adults. “GFAP levels in the blood increased after head trauma but were not elevated after body trauma, making it very specific to brain injury,” Papa explained. UCH-L1 levels were higher than GFAP in patients with nonconcussive trauma. This was especially true in the pediatric patients.

The findings may inform the development of a standard blood test for this type of injury. However, the researchers called for additional studies to verify their findings. “Next steps will include examining these patients over time to see how they recover from their injuries and validating these results in a larger group of patients, particularly children and youth,” said Papa.

Another study in The Lancet Neurology was able to successfully identify traumatic brain injury (TBI) in patients with normal CT scans. “Our earlier research has shown that even in the best trauma centers, patients with TBI are not getting the care they need,” Geoffrey Manley, MD, PhD, senior author of the study, professor of neurosurgery at University of California-San Francisco (UCSF) and a member of the Weill Institutes for Neurosciences, said in a statement. "Now we know that many of these patients with TBI are not even getting a diagnosis."

Manley and his research team tracked 450 patients suspected of TBI who had normal CT scans. Most of these patients had either experienced a fall or a traffic accident. Using a portable blood analyzer by Abbott Laboratories, the i-STAT Alinity, they measured blood samples for GFAP within 24 hours of the accident, later confirming the results with magnetic resonance imaging (MRI).

Among the 450 patients, 27% or 120 had an MRI that tested positive for TBI. In a comparative assessment, the researchers discovered that the average protein value of these patients’ blood samples was nearly 52% and 31.6% higher than levels in the two control groups, healthy patients and orthopedic injury patients who had normal MRI findings. “The protein was elevated even in patients with normal MRIs, suggesting that this test may be sensitive to injury undetectable by MRI,” according to the statement from UCSF.

Blood-based biomarkers represent the next step in diagnosing and treating TBI, said Manley. “We are finding that not only are they more sensitive than [computed tomography] in identifying TBI, but they may be more accurate than the current standard of MRI.” One biomarker assay, the Banyan Brain Trauma Indicator, has promise in predicting mild TBI. In a 2018 study, the test “yielded a sensitivity of 97.6% and an NPV of 99.6% for identifying traumatic injuries on head CT scan … It also produced more positive results than did CT scan, suggesting that the GFAP and UCH-L1 proteins may be detecting injuries CT scans are missing,” CLN Stat reported.