Novel plasma metabolite markers of attention-deficit/hyperactivity disorder identified using high-performance chemical isotope labelling-based liquid chromatography-mass spectrometry

Abstract

Objectives

Metabolites are the intermediate and final products of biological processes and ultimately reflect the responses of these processes to genetic regulation and environmental perturbations, including those involved in attention deficit/hyperactivity disorder (ADHD).

Methods

We identified a quantitative profile of plasma metabolites in 58 ADHD patients (mean age 9.0 years, 77.6% males) and 38 healthy control subjects (mean age 10.2 years, 55.3% males) using the high-performance chemical isotope labelling (CIL)-based liquid chromatography-mass spectrometry (LC-MS). Using a volcano plot and orthogonal projections to latent structure-discriminant analysis (OPLS-DA), we determined nine metabolites with differentially expressed levels in ADHD plasma samples.

Results

Compared to the control group, the plasma levels of guanosine, O-phosphoethanolamine, phenyl-leucine, hypoxanthine, 4-aminohippuric acid, 5-hydroxylysine, and L-cystine appeared increased in the ADHD patients, whilegentisic acid and tryptophyl-phenylalanine were down-regulated in the patients with ADHD. We found that the plasma levels of all nine metabolites were able to discriminate the ADHD group from the control group. Levels of O-phosphoethanolamine, 4-aminohippuric acid, 5-hydroxylysine, L-cystine, tryptophyl-phenylalanine, and gentisic acid were significantly correlated with clinical ADHD symptoms.

Conclusions

This study is the first to use the CIL-based LC-MS to profile ADHD plasma metabolites, and we identified nine novel metabolite biomarkers of ADHD.

Keywords:

• ADHD
• metabolomics
• biomarkers
• chemical isotope labelling
• LC-MS

Acknowledgements

The authors would like to thank Prof. Wei-Tsun Soong and Prof. Shur-Fen Gau for granting us the use of the Chinese version of the K-SADS and the SNAP-IV, respectively.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by grants to L.J.W. from Chang Gung Memorial Hospital (CGMH) Research Projects [CMRPG8F1291 and CMRPG8G0711] and grants to C.C.W. from the Ministry of Science and Technology (MOST), Taiwan [MOST 108-2320-B-182-030-MY3] and CGMH, Taiwan CLRPD190018, CLRPD1J0012, and BMRPC77. The work was also supported by the Research Center for Emerging Viral Infections and Molecular Medicine Research Center from Featured Areas Research Center Program within the Framework of Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan and the MOST, Taiwan (MOST 109-2634-F-182-001).