Plasma and CSF Candidate Biomarkers of Neonatal Encephalopathy Severity and Neurodevelopmental Outcomes

Objectives To identify candidate biomarkers in both plasma and cerebrospinal fluid (CSF) that are associated with neonatal encephalopathy severity measured by encephalopathy grade, seizures, brain injury by magnetic resonance imaging (MRI), and neurodevelopmental outcomes at 15-30 months. Study design A retrospective cohort study of plasma (N=155, day of life 0-1) and CSF (n=30, day of life 0-7) from neonates with NE and healthy term neonates (N=30, ≥36 weeks’ gestation) was conducted. We measured CNS necrosis (glial fibrillary acidic protein [GFAP], neurogranin [NRGN], Tau), inflammatory (IL-6, IL-8, IL-10), and trophic (brain-derived neurotrophic factor [BDNF], vascular endothelial growth factor [VEGF]) proteins. Clinical outcomes were Sarnat scores of encephalopathy, seizures, MRI scores, and Bayley Scales of Infant and Toddler Development III (Bayley-III) at 15-30 months. Results Plasma NRGN, Tau, IL-6, IL-8, and IL-10 were higher, whereas BDNF and VEGF were lower in NE versus controls. In plasma, Tau, GFAP, and NRGN were directly and BDNF inversely associated with encephalopathy grade. IL-6 was inversely related to seizures. Tau was directly related to MRI abnormalities. Tau was inversely associated with Bayley-III cognitive and motor outcomes. In CSF, NRGN was inversely associated with cognitive, motor, and language measures. GFAP, IL-6, and IL-10 were inversely related to cognitive and motor outcomes. IL-8 was inversely related to motor outcomes. CSF candidate biomarkers showed no significant relationships with encephalopathy grade, seizures, or MRI abnormalities. Conclusions Plasma candidate biomarkers predicted encephalopathy severity, seizures, MRI abnormalities, and neurodevelopmental outcomes at 15-30 months.