Association Between Plasma Metabolites and Psychometric Scores Among Children With Developmental Disabilities: Investigating Sex-Differences

Abstract

Background: Developmental disabilities are defined by delays in learning, language, and behavior, yet growing evidence has revealed disturbances in metabolic systems that may also be present. Little is known about whether these metabolic issues contribute to the symptoms or severity of these disabilities, or whether sex plays a role in these associations, given that boys are disproportionately affected by some developmental disabilities. Here we sought to investigate the correlation between psychometric scores, sex, and the plasma metabolome. Methods: The plasma metabolomes of children with autism spectrum disorder (ASD; n = 167), idiopathic developmental delay (i-DD; n = 51), Down syndrome (DS; n = 31), and typically developing controls (TD; n = 193) were investigated using NMR spectroscopy. Spearman rank correlations and multiple linear regression models (adjusted for child's neurodevelopmental diagnosis, child's sex, child's age, child's race/ethnicity, maternal age at child's birth, and parental homeownership) were used to examine the association between plasma metabolites and sex in relation to psychometric measures of cognitive skills, adaptive behavior, and maladaptive behavior in our study population. Results: Higher levels of metabolites involved in cellular energy and mitochondrial function among children with ASD (fumarate and cis-aconitate), DS (lactate), and TD (pyruvate) are associated with poorer cognitive and adaptive subscales. Similarly, higher o-acetylcarnitine associated with deficits in cognitive subscales among all DS cases and TD boys, and carnitine correlated with increased maladaptive behavior among girls with ASD and girls with DS. Among children with DS, elevated myo-inositol, ornithine, and creatine correlated with poorer scores across several subscales. Even among TD cases, elevated 3-hydroxybutyrate correlated with decreased receptive language. In contrast, higher levels of glutamate were associated with better socialization skills among ASD cases. Even after adjusting for the child's neurodevelopmental diagnosis, sex, and other possible confounders, key metabolites including glycolysis metabolites (lactate and pyruvate), ketone bodies (3-hydroxybutyrate and acetoacetate), TCA cycle metabolites (cis-aconitate and fumarate), as well as ornithine were associated with deficits in multiple domains of cognitive function, adaptive skills, and aberrant behaviors. Conclusions: Our results highlight that some plasma metabolites may relate to specific functional subdomains within cognitive, adaptive, and behavioral development with some variation by diagnosis and sex.

Keywords: adaptive behavior; autism spectrum disorder; cognitive scores; down syndrome; maladaptive behavior; metabolites; metabolomics; sex-differences.

Figure 1

Flow chart of the study population.

Figure 2

Spearman correlation heatmap of psychometric scores and plasma metabolites for children with Autism Spectrum disorder (ASD) overall and stratified by sex. Positive associations (blue) identify metabolites where higher plasma concentrations correlated with improvement in psychometric scores, while negative associations (red) identify metabolites where higher plasma concentrations correlated with poorer neurodevelopmental or behavioral scores. For correlation analysis, the inverse scores of ABC subscales were used for ease of comparison with other MSEL and VABS scores. Metabolites that remained significant after FDR correction are shown in green.

Figure 3

Spearman correlation heatmap of psychometric scores and plasma metabolites for children with Down syndrome (DS) overall and stratified by sex. Positive associations (blue) identify metabolites where higher plasma concentrations correlated with improvement in psychometric scores, while negative associations (red) identify metabolites where higher plasma concentrations correlated with poorer neurodevelopmental or behavioral scores. For correlation analysis, the inverse scores of ABC subscales were used for ease of comparison with other MSEL and VABS scores. Metabolites that remained significant after FDR correction are shown in green.

Figure 4

Spearman correlation heatmap of psychometric scores and plasma metabolites for children with idiopathic Developmental Delays (i-DD) overall and stratified by sex. Positive associations (blue) identify metabolites where higher plasma concentrations correlated with improvement in psychometric scores, while negative associations (red) identify metabolites where higher plasma concentrations correlated with poorer neurodevelopmental or behavioral scores. For correlation analysis, the inverse scores of ABC subscales were used for ease of comparison with other MSEL and VABS scores. Metabolites that remained significant after FDR correction are shown in green.

Figure 5

Spearman correlation heatmap of psychometric scores and plasma metabolites for children with typical development (TD) overall and stratified by sex. Positive associations (blue) identify metabolites where higher plasma concentrations correlated with improvement in psychometric scores, while negative associations (red) identify metabolites where higher plasma concentrations correlated with poorer neurodevelopmental or behavioral scores. For correlation analysis, the inverse scores of ABC subscales were used for ease of comparison with other MSEL and VABS scores. Metabolites that remained significant after FDR correction are shown in green.

Figure 6

Metabolic pathways converging glycolysis, tricarboxylic acid cycle (TCA) cycle, and carnitine shuttle. Significant associations between plasma metabolites and psychometric scores are presented with different shapes representing if the association (positive or negative) was seen overall or in a sex-specific manner (circle=Overall, triangle=Males, star=Females) and in which group (yellow=ASD, blue=i-DD, orange=DS, gray=TD).

Figure 7

Overview of the arginine-creatine pathway and arginine metabolism. Significant associations between plasma metabolites and psychometric scores are presented with different shapes representing if the association (positive or negative) was seen overall or in a sex-specific manner (circle=Overall, triangle=Males, star=Females) and in which group (yellow=ASD, blue=i-DD, orange=DS, gray=TD). (mTOR, Mammalian Target of Rapamycin; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine).