Epigenetic Associations of Brain-Derived Neurotrophic Factor (BDNF) and Neurobehavioral Recovery From Pediatric TBI

Research Objectives: To evaluate BDNF DNA methylation (DNAm) as a potential biomarker of neurobehavioral recovery in children with complicated mild to severe TBI.

Design: Observational, prospective, longitudinal consecutive cohort study.

Setting: UPMC Children's Hospital of Pittsburgh (CHP).

Participants: Consecutive cohort of 208 children (3–18 years) hospitalized overnight at CHP with complicated mild to severe TBI (n=144, Glasgow Coma Scale of 3-12 or 13-15 with abnormal neuroimaging) and orthopedic injury controls (OI, n=65). Patients with spinal cord injury, prior TBI requiring overnight hospitalization, neurological disorder, or psychiatric disorder requiring hospitalization were excluded. A subsample of participants had neurobehavioral outcomes at 6- and 12-months post-injury.

Interventions: Not applicable.

Main Outcome Measures: DNA was extracted from acute blood samples (mean+SD, 20.4+8.16 hours post-injury). BDNF DNAm of 5 CpG sites across exons I and IV were measured via pyrosequencing. Cognitive function (NIH Toolbox-Cognitive Battery) and caregiver-reports of emotional/behavioral, executive, and adaptive functions were assessed. Associations between DNAm and injury group (TBI vs. OI) were determined using logistic regression, adjusting for age and sex. Associations between acute BDNF DNAm and neurobehavioral measures were determined using linear regression, adjusting for age, sex, and injury severity.

Results: BDNF was hypomethylated in children with TBI at two sites (Odds Ratio [95% CI], exon I site 2: 0.39 [0.17, 0.91], p=0.03; exon IV site 2: 0.52 [0.27, 0.98], p=0.04) and marginally hypermethylated at a third site (exon I site 1: 2.23 [0.98-5.09], p=0.055). Higher DNAm at exon 1 sites 1 and 3 were significantly associated with lower crystallized cognition (β [95% CI], 5.47 [-9.48, -1.46], p=0.009), and lower total cognition (β: -7.13 [-12.61, -1.64], p=0.01), respectively, at 6 months in children with TBI but not OI (n=53 TBI, n=15 OI). Lower DNAm at exon I site 2 was associated with greater adaptive function at 12 months (β: 13.33 [4.14, 22.52], p=0.005) in TBI but not OI (n=85 TBI, n=34 OI).

Conclusions: BDNF DNAm has potential as a biomarker of neurobehavioral recovery over the first year post-injury. Further exploration with greater sample sizes is required.

Author(s) Disclosures: None.