No dependable biomarker signal
The review’s main finding is straightforward: a single circulating BDNF measurement did not reliably separate children with cerebral palsy, non-syndromic intellectual disability or Down syndrome from comparison groups. Across five comparisons from four studies, the pooled standardized difference was 0.46, but the 95% confidence interval ran from -0.44 to 1.35 and the result was not statistically significant, with p = 0.32. In ordinary terms, the combined data were compatible with lower BDNF, little difference or higher BDNF, rather than a settled pattern.
The review asked two related questions: whether BDNF differs between affected and unaffected children, and whether it changes with cognitive impairment severity among affected children. The authors say current evidence does not support circulating BDNF as a reliable biomarker, meaning a biological measurement used for screening, diagnosis or severity assessment, and they do not recommend it for those purposes in these populations.
What the review combined
To assemble the evidence, researchers identified 340 records, screened 280 titles and abstracts, examined 29 full texts and included seven studies. The studies involved children or adolescents with cerebral palsy, non-syndromic intellectual disability or Down syndrome. They measured circulating BDNF in serum, plasma or eluates from archived dried blood spots, using healthy or typically developing controls where available and internal severity comparisons otherwise. The review followed PRISMA 2020 and used an a priori protocol prepared before data extraction, but it was not registered in a public registry.
All seven studies contributed data from at least 547 participants, but the main numerical synthesis was much smaller: five comparisons, four studies and 322 unique participants. The review used Hedges’ g, a standardized way to express the difference between groups, and a random-effects model that allows results to vary across studies. One shared control group contained 54 participants and was split into 27 per comparison so the same children were not counted twice.
The studies did not agree
The individual studies did not point in one consistent direction. The review found very high between-study heterogeneity, with I-squared at 92.6%. Within the intellectual-disability group, one study reported significantly lower BDNF while two reported significantly higher BDNF. That conflict makes a single pooled number difficult to treat as a stable feature of the diagnosis.
An alternative analysis using a more conservative method kept the estimate at 0.46 but widened the 95% confidence interval to -0.80 to 1.71. Its 95% prediction interval, which reflects the range of effects that could appear in a new comparable study, stretched from -2.95 to 3.87. Adding a Down syndrome dataset digitized from a graph produced a pooled effect of 0.54, with a confidence interval from -0.25 to 1.33 and I-squared of 91.0%. The review judged that this did not change the overall conclusion.
Severity remained unresolved
The severity results could not be pooled into a single estimate. A positive correlation of 0.424, with p = 0.001, came from a combined case-control sample, so it mixed the question of being affected with the question of severity within an affected group. In the cerebral palsy analysis, based on 150 children, the severity gradient was negligible: F(4,145) = 0.04, with eta-squared of 0.001 and an approximate correlation of 0.03. The intellectual-disability gradient, based on 45 children, was not detectable after adjusting for age.
A cautious conclusion
The review rated the certainty of the evidence as very low. Four of five GRADE domains were downgraded, and the five-comparison pool was too small for publication bias to be assessed formally. Taken together with the high inconsistency between studies, those limits leave substantial uncertainty around the pooled estimate.
The authors conclude that current evidence does not support circulating BDNF as a reliable case-control or severity biomarker in children with cerebral palsy, intellectual disability or Down syndrome. They do not recommend it for screening, diagnosis or severity stratification. For the populations studied, a single circulating BDNF measurement therefore cannot currently support those judgments reliably.
Paper data and sources
Original title: Circulating BDNF in pediatric neurodevelopmental disorders: a meta-analysis of case–control differences and cognitive severity
Authors: Tayyare B, Yuksel B, Eryılmaz N
Journal/Repository: Frontiers in neurology
Status: Peer-reviewed
First online: 2026-10-08
DOI: Not available
Original paper · Full text