Protein epigenetic scores derived in neonatal saliva as biomarkers of childhood cognition

AI Summary

Neonatal salivary DNAm CRP negatively predicts 5-year cognitive ability; effect stronger in infants born at lower gestational ages.
DNAm CD209 is positively associated with 5-year Mullen ELC; 14 additional EpiScores showed nominal associations at 2 and 5 years.
In preterm children, DNAm CCL18 (2-year positive) and DNAm CRP, DNAm CRTAM (5-year negative) remain significant after inflammatory adjustment, supporting biomarker potential.

AI Summary

To evaluate the utility of neonatal protein EpiScores for predicting childhood cognition, we examined associations of DNAm CRP and 42 other saliva-based EpiScores enriched for inflammatory proteins correlated with low gestational age, with cognition in a cohort of 231 children, including 154 preterm children assessed at 2 years and 127 preterm and term-born children assessed at 5 years.

For preterm children, associations of DNAm CCL18 with 2-year cognition (β = 0.182, p = 0.039) and of DNAm CRP (β = -0.318, p = 0.021) and DNAm CRTAM (β = -0.307, p = 0.008) with 5-year cognition remained significant after adjustment for inflammatory exposures.

We demonstrate associations between a range of neonatal salivary EpiScores and childhood cognition, suggesting the clinical value of EpiScores as early life markers of cognitive ability in children at risk of impairment warrants further investigation.

Basic summary

Mol Psychiatry. 2026 Jun 24. doi: 10.1038/s41380-026-03702-4. Online ahead of print.

ABSTRACT

Preterm birth is closely associated with immune dysregulation in early life and subsequent learning and psychiatric disorders, but methods for stratifying infants at risk remain elusive. Protein epigenetic Scores (EpiScores) are DNA methylation (DNAm)-based proxies of circulating proteins and can capture health-related exposures such as chronic inflammation. EpiScore of C-reactive protein (DNAm CRP) is associated with inflammatory burden in early life, atypical brain development following preterm birth and adult cognitive ability. To evaluate the utility of neonatal protein EpiScores for predicting childhood cognition, we examined associations of DNAm CRP and 42 other saliva-based EpiScores enriched for inflammatory proteins correlated with low gestational age, with cognition in a cohort of 231 children, including 154 preterm children assessed at 2 years and 127 preterm and term-born children assessed at 5 years. DNAm CRP was negatively associated with 5-year Mullen Scales of Early Learning Composite (ELC) (β = -0.273, p = 0.002). Association magnitudes were larger for children born earlier (DNAm CRP x gestational age, β_interaction = 0.181). DNAm CD209 was positively associated with 5-year ELC (β = 0.267, adjusted p < 0.005). Fourteen other EpiScores were nominally associated with either 2-year Bayley-III Cognitive composite or 5-year ELC (absolute β range 0.180 to 0.245, p < 0.05). For preterm children, associations of DNAm CCL18 with 2-year cognition (β = 0.182, p = 0.039) and of DNAm CRP (β = -0.318, p = 0.021) and DNAm CRTAM (β = -0.307, p = 0.008) with 5-year cognition remained significant after adjustment for inflammatory exposures. We demonstrate associations between a range of neonatal salivary EpiScores and childhood cognition, suggesting the clinical value of EpiScores as early life markers of cognitive ability in children at risk of impairment warrants further investigation.

PMID:42337013 | DOI:10.1038/s41380-026-03702-4

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