Association of salivary microRNA changes with prolonged concussion symptoms

Jeremiah J. Johnson, Andrea Loeffert, Jennifer Stokes, Robert Olympia, Harry Bramley, Steven Hicks

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

IMPORTANCE Approximately one-third of children who experience a concussion develop prolonged concussion symptoms. To our knowledge, there are currently no objective or easily administered tests for predicting prolonged concussion symptoms. Several studies have identified alterations in epigenetic molecules known as microRNAs (miRNAs) following traumatic brain injury. No studies have examined whether miRNA expression can detect prolonged concussion symptoms. OBJECTIVE To evaluate the efficacy of salivary miRNAs for identifying children with concussion who are at risk for prolonged symptoms. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study at the Penn State Medical Center observed 52 patients aged 7 to 21 years presenting for evaluation of concussion within 14 days of initial head injury, with follow-up at 4 and 8 weeks. EXPOSURES All patients had a clinical diagnosis of concussion. MAIN OUTCOMES AND MEASURES Salivary miRNA expressionwas measured at the time of initial clinical presentation in all patients. Patients with a Sport Concussion Assessment Tool (SCAT3) symptom score of 5 or greater on self-report or parent report 4 weeks after injury were designated as having prolonged symptoms. RESULTS Of the 52 included participants, 22 (42%) were female, and the mean (SD) age was 14 (3) years. Participants were split into the prolonged symptom group (n = 30) and acute symptom group (n = 22). Concentrations of 15 salivary miRNAs spatially differentiated prolonged and acute symptom groups on partial least squares discriminant analysis and demonstrated functional relationships with neuronal regulatory pathways. Levels of 5 miRNAs (miR-320c-1, miR-133a-5p, miR-769-5p, let-7a-3p, and miR-1307-3p) accurately identified patients with prolonged symptoms on logistic regression (area under the curve, 0.856; 95%CI, 0.822-0.890). This accuracy exceeded accuracy of symptom burden on child (area under the curve, 0.649; 95%CI, 0.388-0.887) or parent (area under the curve, 0.562; 95%CI, 0.219-0.734) SCAT3 score. Levels of 3 miRNAs were associated with specific symptoms 4 weeks after injury; miR-320c-1 was associated with memory difficulty (R, 0.55; false detection rate, 0.02), miR-629 was associated with headaches (R, 0.47; false detection rate, 0.04), and let-7b-5p was associated with fatigue (R, 0.45; false detection rate, 0.04). CONCLUSIONS AND RELEVANCE Salivary miRNA levels may identify the duration and character of concussion symptoms. This could reduce parental anxiety and improve care by providing a tool for concussion management. Further validation of this approach is needed.

Original languageEnglish (US)
Pages (from-to)65-73
Number of pages9
JournalJAMA Pediatrics
Volume172
Issue number1
DOIs
StatePublished - Jan 1 2018

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MicroRNAs
Area Under Curve
Wounds and Injuries
Discriminant Analysis
Least-Squares Analysis
Craniocerebral Trauma
Epigenomics
Self Report
Sports
Fatigue
Headache
Cohort Studies
Anxiety
Logistic Models
Prospective Studies

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health

Cite this

Johnson, Jeremiah J. ; Loeffert, Andrea ; Stokes, Jennifer ; Olympia, Robert ; Bramley, Harry ; Hicks, Steven. / Association of salivary microRNA changes with prolonged concussion symptoms. In: JAMA Pediatrics. 2018 ; Vol. 172, No. 1. pp. 65-73.
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abstract = "IMPORTANCE Approximately one-third of children who experience a concussion develop prolonged concussion symptoms. To our knowledge, there are currently no objective or easily administered tests for predicting prolonged concussion symptoms. Several studies have identified alterations in epigenetic molecules known as microRNAs (miRNAs) following traumatic brain injury. No studies have examined whether miRNA expression can detect prolonged concussion symptoms. OBJECTIVE To evaluate the efficacy of salivary miRNAs for identifying children with concussion who are at risk for prolonged symptoms. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study at the Penn State Medical Center observed 52 patients aged 7 to 21 years presenting for evaluation of concussion within 14 days of initial head injury, with follow-up at 4 and 8 weeks. EXPOSURES All patients had a clinical diagnosis of concussion. MAIN OUTCOMES AND MEASURES Salivary miRNA expressionwas measured at the time of initial clinical presentation in all patients. Patients with a Sport Concussion Assessment Tool (SCAT3) symptom score of 5 or greater on self-report or parent report 4 weeks after injury were designated as having prolonged symptoms. RESULTS Of the 52 included participants, 22 (42{\%}) were female, and the mean (SD) age was 14 (3) years. Participants were split into the prolonged symptom group (n = 30) and acute symptom group (n = 22). Concentrations of 15 salivary miRNAs spatially differentiated prolonged and acute symptom groups on partial least squares discriminant analysis and demonstrated functional relationships with neuronal regulatory pathways. Levels of 5 miRNAs (miR-320c-1, miR-133a-5p, miR-769-5p, let-7a-3p, and miR-1307-3p) accurately identified patients with prolonged symptoms on logistic regression (area under the curve, 0.856; 95{\%}CI, 0.822-0.890). This accuracy exceeded accuracy of symptom burden on child (area under the curve, 0.649; 95{\%}CI, 0.388-0.887) or parent (area under the curve, 0.562; 95{\%}CI, 0.219-0.734) SCAT3 score. Levels of 3 miRNAs were associated with specific symptoms 4 weeks after injury; miR-320c-1 was associated with memory difficulty (R, 0.55; false detection rate, 0.02), miR-629 was associated with headaches (R, 0.47; false detection rate, 0.04), and let-7b-5p was associated with fatigue (R, 0.45; false detection rate, 0.04). CONCLUSIONS AND RELEVANCE Salivary miRNA levels may identify the duration and character of concussion symptoms. This could reduce parental anxiety and improve care by providing a tool for concussion management. Further validation of this approach is needed.",
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Association of salivary microRNA changes with prolonged concussion symptoms. / Johnson, Jeremiah J.; Loeffert, Andrea; Stokes, Jennifer; Olympia, Robert; Bramley, Harry; Hicks, Steven.

In: JAMA Pediatrics, Vol. 172, No. 1, 01.01.2018, p. 65-73.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Association of salivary microRNA changes with prolonged concussion symptoms

AU - Johnson, Jeremiah J.

AU - Loeffert, Andrea

AU - Stokes, Jennifer

AU - Olympia, Robert

AU - Bramley, Harry

AU - Hicks, Steven

PY - 2018/1/1

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N2 - IMPORTANCE Approximately one-third of children who experience a concussion develop prolonged concussion symptoms. To our knowledge, there are currently no objective or easily administered tests for predicting prolonged concussion symptoms. Several studies have identified alterations in epigenetic molecules known as microRNAs (miRNAs) following traumatic brain injury. No studies have examined whether miRNA expression can detect prolonged concussion symptoms. OBJECTIVE To evaluate the efficacy of salivary miRNAs for identifying children with concussion who are at risk for prolonged symptoms. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study at the Penn State Medical Center observed 52 patients aged 7 to 21 years presenting for evaluation of concussion within 14 days of initial head injury, with follow-up at 4 and 8 weeks. EXPOSURES All patients had a clinical diagnosis of concussion. MAIN OUTCOMES AND MEASURES Salivary miRNA expressionwas measured at the time of initial clinical presentation in all patients. Patients with a Sport Concussion Assessment Tool (SCAT3) symptom score of 5 or greater on self-report or parent report 4 weeks after injury were designated as having prolonged symptoms. RESULTS Of the 52 included participants, 22 (42%) were female, and the mean (SD) age was 14 (3) years. Participants were split into the prolonged symptom group (n = 30) and acute symptom group (n = 22). Concentrations of 15 salivary miRNAs spatially differentiated prolonged and acute symptom groups on partial least squares discriminant analysis and demonstrated functional relationships with neuronal regulatory pathways. Levels of 5 miRNAs (miR-320c-1, miR-133a-5p, miR-769-5p, let-7a-3p, and miR-1307-3p) accurately identified patients with prolonged symptoms on logistic regression (area under the curve, 0.856; 95%CI, 0.822-0.890). This accuracy exceeded accuracy of symptom burden on child (area under the curve, 0.649; 95%CI, 0.388-0.887) or parent (area under the curve, 0.562; 95%CI, 0.219-0.734) SCAT3 score. Levels of 3 miRNAs were associated with specific symptoms 4 weeks after injury; miR-320c-1 was associated with memory difficulty (R, 0.55; false detection rate, 0.02), miR-629 was associated with headaches (R, 0.47; false detection rate, 0.04), and let-7b-5p was associated with fatigue (R, 0.45; false detection rate, 0.04). CONCLUSIONS AND RELEVANCE Salivary miRNA levels may identify the duration and character of concussion symptoms. This could reduce parental anxiety and improve care by providing a tool for concussion management. Further validation of this approach is needed.

AB - IMPORTANCE Approximately one-third of children who experience a concussion develop prolonged concussion symptoms. To our knowledge, there are currently no objective or easily administered tests for predicting prolonged concussion symptoms. Several studies have identified alterations in epigenetic molecules known as microRNAs (miRNAs) following traumatic brain injury. No studies have examined whether miRNA expression can detect prolonged concussion symptoms. OBJECTIVE To evaluate the efficacy of salivary miRNAs for identifying children with concussion who are at risk for prolonged symptoms. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study at the Penn State Medical Center observed 52 patients aged 7 to 21 years presenting for evaluation of concussion within 14 days of initial head injury, with follow-up at 4 and 8 weeks. EXPOSURES All patients had a clinical diagnosis of concussion. MAIN OUTCOMES AND MEASURES Salivary miRNA expressionwas measured at the time of initial clinical presentation in all patients. Patients with a Sport Concussion Assessment Tool (SCAT3) symptom score of 5 or greater on self-report or parent report 4 weeks after injury were designated as having prolonged symptoms. RESULTS Of the 52 included participants, 22 (42%) were female, and the mean (SD) age was 14 (3) years. Participants were split into the prolonged symptom group (n = 30) and acute symptom group (n = 22). Concentrations of 15 salivary miRNAs spatially differentiated prolonged and acute symptom groups on partial least squares discriminant analysis and demonstrated functional relationships with neuronal regulatory pathways. Levels of 5 miRNAs (miR-320c-1, miR-133a-5p, miR-769-5p, let-7a-3p, and miR-1307-3p) accurately identified patients with prolonged symptoms on logistic regression (area under the curve, 0.856; 95%CI, 0.822-0.890). This accuracy exceeded accuracy of symptom burden on child (area under the curve, 0.649; 95%CI, 0.388-0.887) or parent (area under the curve, 0.562; 95%CI, 0.219-0.734) SCAT3 score. Levels of 3 miRNAs were associated with specific symptoms 4 weeks after injury; miR-320c-1 was associated with memory difficulty (R, 0.55; false detection rate, 0.02), miR-629 was associated with headaches (R, 0.47; false detection rate, 0.04), and let-7b-5p was associated with fatigue (R, 0.45; false detection rate, 0.04). CONCLUSIONS AND RELEVANCE Salivary miRNA levels may identify the duration and character of concussion symptoms. This could reduce parental anxiety and improve care by providing a tool for concussion management. Further validation of this approach is needed.

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