MicroRNAs (miRNAs) may serve as biomarkers of concussion with prolonged symptoms, according to results of a prospective cohort study published online November 20 in JAMA Pediatrics.
More than 80% of concussions follow mild traumatic brain injuries (mTBIs). For one-third of children, symptoms of concussion persist beyond 2 weeks. A tool to predict children at elevated risk for prolonged concussion symptoms (PCS), other than questionnaires to identify clinical risk scores, would be valuable in referring appropriate patients to specialists.
The study identified five specific microRNAs that might function as a biomarker of PCS.
MicroRNAs are 21- or 22-base-long RNA molecules that block the translation of specific (complementary in sequence) mRNA transcripts into protein. They have been described as “dimmer switches” that fine-tune gene expression.
Several studies have shown that miRNA levels are altered in the circulation of adults after a TBI, reflecting changes in their levels in cerebrospinal fluid during the critical first 24 hours. The levels vary with injury severity.
Studies using miRNAs as biomarkers so far have focused on adults. In the new investigation, Jeremiah J. Johnson, MA, BS, from the Department of Pediatrics at Penn State College of Medicine, Hershey, and colleagues used the Sport Concussion Assessment Tool (SCAT3) to evaluate the prognostic value of salivary miRNA levels as a more objective biomarker of PCS in children. SCAT3 assesses 20 symptoms. The researchers recently reported identification of 6 dysregulated miRNAs in CSF of 60 children with mTBI.
In the new study, the researchers measured levels of salivary miRNAs in 52 patients, aged 7 to 21 years, at the time of diagnosis with mTBI (within 14 days of initial head injury) and at 4 and 8 weeks. A self-reported SCAT3 score of at least 5, or parent report 4 weeks after injury, indicated prolonged symptoms. Participants were classified in the prolonged symptom group (n = 30) and the acute symptom group (n = 22).
Causes of injury were participation in sports (42%) or motor vehicle collision (15%). Nearly half (24 [46%]) of the patients had a previous concussion. At the time of injury, the most commonly reported symptoms were amnesia (25 participants [48%]) and loss of consciousness (14 participants [27%]).
The researchers evaluated 15 miRNAs that differed the most in levels between acute concussion cases and PCS. Two of the miRNAs were also on the list of 6 that the group previously published, and another five were detected in other investigations. The 15 miRNAs fell into three groups on the basis of function, targeting 2429 genes in total. The specific functions involved migration and repair of neurons and synaptic signaling.
“Concentrations of 5 miRNAs determined PCS status in 42 of 50 participants, an accuracy of more than 85%,” the researchers write.
Three miRNAs displayed a positive association with specific complaints: miR-320c-1 to “I have problems remembering what people tell me” (R, 0.55; false detection rate [FDR], 0.02), miR-629 to “I have headaches” (R, 0.47; FDR, 0.04), and let-7b-5p to “I get tired a lot” (R, 0.45; FDR, 0.04).
“In this cohort of 52 children, the classification accuracy of salivary miRNA exceeds that of symptom burden and the modified PCS risk score,” the researchers conclude. The ability to identify children at higher risk for prolonged symptoms can prepare parents and help in determining when it is safe to return to school and athletic activities.
In an accompanying editorial, William P. Meehan III, MD, and Rebekah Mannix, MD, MPH, from Boston Children’s Hospital, point out that the small sample size limited detecting the effect of potential confounding factors, such as the apparent higher risk for prolonged symptoms among girls and users of nonsteroidal antiinflammatory medications and lower risk for children with sports-related injuries or loss of consciousness. The study also lacked baseline measures of miRNA levels, so this metric may mark susceptibility to PCS, rather than cause the condition.
“Still, this work represents an advance in the science of sport-related concussions. The findings are promising, representing potential biomarkers for the diagnosis, recovery, and prognostic assessment of a sport-related concussion,” Dr Meehan and Dr Mannix write. A salivary test would be easy to administer in several types of settings to a pediatric population. They conclude, “The use of salivary microRNA in this study is both novel and clinically relevant…. If validated in larger, multisite clinical trials, using this salivary microRNA panel to diagnose and manage concussions could be a major advancement to the field.”
Dr Hicks is a coinventor of microRNA biomarkers in disorders of the CNS licensed to Quadrant Biosciences, for which he consults and holds shares. The remaining authors and editorialists have disclosed no relevant financial relationships.
JAMA Peds. Published online November 20, 2017. Abstract
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