Metabolomic biomarkers for childhood executive function
The relationship between higher circulating leucine level with poorer cognitive regulation may be determined by genetic factors and may not be easily amenable to dietary interventions.
Early-life plasma metabolites have been associated with childhood cognitive functions such as IQ, but few studies have investigated the molecular biomarkers for specific executive function (EF) skills, which is a set of higher-level cognitive skills responsible for goal-directed behaviours. We aimed to characterise the prospective associations between metabolome and multiple domains of EF using a bidirectional design. In addition, it remains an open question as to how early nutritional environments and metabolism are linked to EF.
This study was conducted within a longitudinal birth cohort, the Growing Up in Singapore Towards healthy Outcomes (GUSTO). Circulating levels of 165 metabolites were quantified using a nuclear magnetic resonance based metabolomics platform (n = 457 (∼6yrs) and n = 524 (∼8yrs)). Parent-reported EF was available for 495 children (∼7yrs).
Higher leucine level (∼6yrs) was associated with poorer EF (∼7yrs, Initiate and Working Memory subscales). EF (∼7yrs) was not associated with leucine (∼8yrs). Importantly, we found weak evidence for associations of dietary factors (∼5yrs) with leucine (∼6yrs) and EF (∼7yrs). Amongst those with less strongly genetically influenced leucine, the inverse association between leucine and cognitive regulation were weaker among those with higher BMI.
Taken together, our metabolomics analysis found an association between higher circulating leucine level with poorer EF, especially cognitive regulation. Effect sizes attenuated after accounting for earlier general EF score suggested that the observed association may be determined by factors in earlier life. Our further investigation showed that this relationship may be determined by genetic factors and may not be easily amenable to dietary interventions. Causal mediation analysis suggested a relatively lower circulating leucine level, leucine-BMI interaction may counteract the harmful effect of leucine on cognitive regulation. While the role of leucine on neurodevelopment is supported by biological evidence, suggesting our findings may be relevant to risk prediction and drive further research into mechanisms, future investigation with a larger sample size should be considered for validation.
For more details, see Huang J, et al. Investigation of metabolomic biomarkers for childhood executive function and the role of genetic and dietary factors: The GUSTO cohort. eBioMedicine. 2022.
For more details, see Huang J, et al. Investigation of metabolomic biomarkers for childhood executive function and the role of genetic and dietary factors: The GUSTO cohort. eBioMedicine. 2022.