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Targeted metabolomics highlights perturbed metabolism in the brain of autism spectrum disorder sufferers

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Abstract

Introduction

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by deficiencies in social interactions and communication, combined with restricted and repetitive behavioral issues.

Objectives

As little is known about the etiopathophysiology of ASD and early diagnosis is relatively subjective, we aim to employ a targeted, fully quantitative metabolomics approach to biochemically profile post-mortem human brain with the overall goal of identifying metabolic pathways that may have been perturbed as a result of the disease while uncovering potential central diagnostic biomarkers.

Methods

Using a combination of 1H NMR and DI/LC–MS/MS we quantitatively profiled the metabolome of the posterolateral cerebellum from post-mortem human brain harvested from people who suffered with ASD (n = 11) and compared them with age-matched controls (n = 10).

Results

We accurately identified and quantified 203 metabolites in post-mortem brain extracts and performed a metabolite set enrichment analyses identifying 3 metabolic pathways as significantly perturbed (p < 0.05). These include Pyrimidine, Ubiquinone and Vitamin K metabolism. Further, using a variety of machine-based learning algorithms, we identified a panel of central biomarkers (9-hexadecenoylcarnitine (C16:1) and the phosphatidylcholine PC ae C36:1) capable of discriminating between ASD and controls with an AUC = 0.855 with a sensitivity and specificity equal to 0.80 and 0.818, respectively.

Conclusion

For the first time, we report the use of a multi-platform metabolomics approach to biochemically profile brain from people with ASD and report several metabolic pathways which are perturbed in the diseased brain of ASD sufferers. Further, we identified a panel of biomarkers capable of distinguishing ASD from control brains. We believe that these central biomarkers may be useful for diagnosing ASD in more accessible biomatrices.

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Data availability

The 1H NMR spectroscopy and mass spectrometry metabolomics data have been deposited to the MetaboLights. Archive (https://www.ebi.ac.uk/metabolights/mysubmissions?status=PRIVATE) via the MetaboLights partner repository with the data set MTBL960.

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Acknowledgements

We would like to thank the NICHD Brain and Tissue Bank for Developmental Disorder ad NICH Contract #HHSN275200900011C, Ref. No. N01-HD-9-0011 for supplying the tissue used herein. In addition, this work was partly funded by the generous contribution made by the Fred A. & Barbara M. Erb Foundation.

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Authors and Affiliations

  1. Oakland University-William Beaumont School of Medicine, Rochester, MI, 48309, USA

    Stewart F. Graham, Onur Turkoglu, Ali Yilmaz, Zafer Ugur & Ray O. Bahado-Singh

  2. Research Institute, Metabolomics Division, Beaumont Health, Royal Oak, MI, 48073, USA

    Stewart F. Graham, Ali Yilmaz & Zafer Ugur

  3. Wayne State University, Civil and Environmental Engineering, Detroit, MI, USA

    Ilyas Ustun

  4. Department of Biological and Computing Sciences, University of Alberta, Edmonton, AB, Canada

    Trent Bjorndhal, BeomSoo Han, Rupa Mandal & David Wishart

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  1. Stewart F. Graham
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  2. Onur Turkoglu
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  3. Ali Yilmaz
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  10. Ray O. Bahado-Singh
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Contributions

Designing research studies (SFG, ROB-S), conducting experiments (AY, TB, RM, ZU), statistical analysis (BH, IU), analyzing data (SFG, BH, IU, AY), and writing the manuscript (All authors contributed to the writing of the manuscript).

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Correspondence to Stewart F. Graham.

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The authors have no conflicts of interest to declare.

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This study was performed in accordance with the 1964 Helsinki declaration and its later amendments, and ethical approval was obtained from the Beaumont Institutional Review Board (IRB# 2014-142).

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11306_2020_1685_MOESM3_ESM.docx

Supplementary file3 (DOCX 15 kb) Table S1. Clinical and demographic information of patient and control groups. The donor highlighted in Bold was excluded from the study.

Supplementary file4 (DOCX 13 kb) Table S2. The results of the demographic comparisons between ASD and control brains.

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Graham, S.F., Turkoglu, O., Yilmaz, A. et al. Targeted metabolomics highlights perturbed metabolism in the brain of autism spectrum disorder sufferers. Metabolomics 16, 59 (2020). https://doi.org/10.1007/s11306-020-01685-z

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