Circulating BDNF in pediatric neurodevelopmental disorders: a meta-analysis of case-control differences and cognitive severity.

BACKGROUND

Brain-derived neurotrophic factor (BDNF) has been proposed as a neuroimmune biomarker of cognitive dysfunction in paediatric neurodevelopmental disorders other than autism spectrum disorder, but two related questions remain poorly characterised: whether circulating BDNF differs between affected and unaffected individuals, and whether it tracks the severity of cognitive impairment within affected populations. This systematic review and meta-analysis addressed both questions in children and adolescents with cerebral palsy (CP), intellectual disability (ID), or Down syndrome (DS).

METHODS

PubMed, Web of Science, Google Scholar, and citation-tracking (snowball) searches identified 340 records. After deduplication and title/abstract screening, 29 records underwent full-text assessment; 7 studies (comprising at least 547 participants) met eligibility criteria. Five comparisons (four studies, five case-control arms, 322 unique participants) reported extractable means and standard deviations and were pooled using Hedges' g in a random-effects (DerSimonian-Laird) model; three additional studies, providing within-group severity-gradient data, were retained for narrative synthesis or sensitivity analysis because of missing healthy-control comparators, non-standard assay platforms, or data reported only in figures.

RESULTS

The case-control comparison yielded a pooled effect size of 0.46 (95% CI: -0.44 to 1.35), which was not statistically significant (z = 1.00, p = 0.32). Heterogeneity was very high (Q = 53.71, df = 4, p < 0.001; I 2 = 92.6%; τ 2 = 0.96). Subgrouping by diagnostic category did not reduce heterogeneity (I 2 = 96.0% within studies of intellectual disability alone). A sensitivity analysis incorporating an additional digitised Down syndrome dataset yielded a consistent conclusion (pooled g = 0.54, 95% CI: -0.25 to 1.33).

CONCLUSION

Current evidence does not support circulating BDNF as a reliable case-control or severity biomarker of cognitive impairment in children with CP, ID, or DS. The direction of association is inconsistent even within the same diagnostic category, likely reflecting methodological heterogeneity (assay platform, age-matching of controls) rather than a genuine, replicable biological signal. Age-matched studies using standardised assay protocols are needed before BDNF can be considered for clinical or research use in this population.