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Investigating Plasma Amino Acids for Differentiating Individuals with Autism Spectrum Disorder and Typically Developing Peers.

ABSTRACT: Background:Plasma amino acid measurements have been extensively investigated in individuals with autism spectrum disorder (ASD). Results thus far have been inconclusive as studies generally disagree on which amino acids are different in individuals with ASD versus their typically developing (TD) peers, due in part to methodological limitations of several studies. Method:This paper investigates plasma amino acids in children and adults with ASD using data from Arizona State University's Comprehensive Nutritional and Dietary Intervention Study. Measurements from 64 individuals with ASD and 49 TD controls were analyzed using univariate and multivariate statistical techniques. Results:Univariate analysis indicated increased median levels of glutamate (+21%, p=0.014) and serine (+8%, p=0.043), and increased mean levels of hydroxyproline (+17%, p=0.018) for the ASD cohort, although these differences were insignificant after correcting for multiple comparisons. A multivariate approach was used to classify study participants into ASD/TD cohorts using Fisher discriminant analysis (FDA) and its nonlinear extension, kernel Fisher discriminant analysis (KFDA). Model fitting with FDA using all available measurements produced Type I and Type II errors of 27.0% and 27.8%, respectively. KFDA was most effective when using hydroxyproline, leucine, and threonine as inputs; however, leave-one-out cross-validation with this nonlinear model only resulted in 70.3% sensitivity and 77.6% specificity. Conclusions:The finding of elevated glutamate in ASD is in agreement with several other studies. Overall, however, these results suggest that plasma amino acid measurements are of limited use for purposes of ASD classification, which may explain some of the inconsistencies in results presented in the literature.

SUBMITTER: Vargason T

PROVIDER: S-EPMC5903290 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Investigating Plasma Amino Acids for Differentiating Individuals with Autism Spectrum Disorder and Typically Developing Peers.

Vargason Troy T Kruger Uwe U McGuinness Deborah L DL Adams James B JB Geis Elizabeth E Gehn Eva E Coleman Devon D Hahn Juergen J

Research in autism spectrum disorders 20180330

<h4>Background</h4>Plasma amino acid measurements have been extensively investigated in individuals with autism spectrum disorder (ASD). Results thus far have been inconclusive as studies generally disagree on which amino acids are different in individuals with ASD versus their typically developing (TD) peers, due in part to methodological limitations of several studies.<h4>Method</h4>This paper investigates plasma amino acids in children and adults with ASD using data from Arizona State Univers ...[more]

PMID: 29682004

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Project description:BackgroundAberrant brain connectivity, especially with long-distance underconnectivity, has been recognized as a candidate pathophysiology of autism spectrum disorders. However, a number of diffusion tensor imaging studies investigating people with autism spectrum disorders have yielded inconsistent results.MethodsTo test the long-distance underconnectivity hypothesis, we performed a systematic review and meta-analysis of diffusion tensor imaging studies in subjects with autism spectrum disorder. Diffusion tensor imaging studies comparing individuals with autism spectrum disorders with typically developing individuals were searched using MEDLINE, Web of Science and EMBASE from 1980 through 1 August 2012. Standardized mean differences were calculated as an effect size of the tracts.ResultsA comprehensive literature search identified 25 relevant diffusion tensor imaging studies comparing autism spectrum disorders and typical development with regions-of-interest methods. Among these, 14 studies examining regions of interest with suprathreshold sample sizes were included in the meta-analysis. A random-effects model demonstrated significant fractional anisotropy reductions in the corpus callosum (P = 0.023, n = 387 (autism spectrum disorders/typically developing individuals: 208/179)), left uncinate fasciculus (P = 0.011, n = 242 (117/125)), and left superior longitudinal fasciculus (P = 0.016, n = 182 (96/86)), and significant increases of mean diffusivity in the corpus callosum (P = 0.006, n = 254 (129/125)) and superior longitudinal fasciculus bilaterally (P = 0.031 and 0.011, left and right, respectively, n = 109 (51/58)), in subjects with autism spectrum disorders compared with typically developing individuals with no significant publication bias.ConclusionThe current meta-analysis of diffusion tensor imaging studies in subjects with autism spectrum disorders emphasizes important roles of the superior longitudinal fasciculus, uncinate fasciculus, and corpus callosum in the pathophysiology of autism spectrum disorders and supports the long-distance underconnectivity hypothesis.

Project description:Autism spectrum disorders (ASD) affect 1% of children. Although there is no cure, early diagnosis and behavioral intervention can relieve the symptoms. The clinical heterogeneity of ASD has created a need for improved sensitive and specific laboratory diagnostic methods. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based analysis of the metabolome has shown great potential to uncover biomarkers for complex diseases such as ASD. Here, we used a two-step discovery-validation approach to identify potential novel metabolic biomarkers for ASD. Urine samples from 57 children with ASD and 81 matched children with typical development (TD) were analyzed by LS-MS/MS to assess differences in urinary amino acids and their metabolites (referred to as UAA indicators). A total of 63 UAA indicators were identified, of which 21 were present at significantly different levels in the urine of ASD children compared with TD children. Of these 21, the concentrations of 19 and 10 were higher and lower, respectively, in the urine of ASD children compared with TD children. Using support vector machine modeling and receiver operating characteristic curve analysis, we identified a panel of 7 UAA indicators that discriminated between the samples from ASD and TD children (lysine, 2-aminoisobutyric acid, 5-hydroxytryptamine, proline, aspartate, arginine/ornithine, and 4-hydroxyproline). Among the significantly changed pathways in ASD children were the ornithine/urea cycle (decreased levels of the excitatory amino acid aspartate [p = 2.15 × 10-10] and increased arginine/ornithine [p = 5.21 × 10-9]), tryptophan metabolism (increased levels of inhibitory 5-hydroxytryptamine p = 3.62 × 10-9), the methionine cycle (increased methionine sulfoxide [p = 1.46 × 10-10] and decreased homocysteine [p = 2.73 × 10-7]), and lysine metabolism (reduced lysine [p = 7.8 × 10-9], α-aminoadipic acid [p = 1.16 × 10-9], and 5-aminovaleric acid [p = 1.05 × 10-5]). Collectively, the data presented here identify a possible imbalance between excitatory and inhibitory amino acid metabolism in ASD children. The significantly altered UAA indicators could therefore be potential diagnostic biomarkers for ASD.

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Investigating Plasma Amino Acids for Differentiating Individuals with Autism Spectrum Disorder and Typically Developing Peers.

Publications

Investigating Plasma Amino Acids for Differentiating Individuals with Autism Spectrum Disorder and Typically Developing Peers.

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