Sex and race differences of cerebrospinal fluid metabolites in healthy individuals

Abstract

Introduction

Analyses of cerebrospinal fluid (CSF) metabolites in large, healthy samples have been limited and potential demographic moderators of brain metabolism are largely unknown.

Objective

Our objective in this study was to examine sex and race differences in 33 CSF metabolites within a sample of 129 healthy individuals (37 African American women, 29 white women, 38 African American men, and 25 white men).

Methods

CSF metabolites were measured with a targeted electrochemistry-based metabolomics platform. Sex and race differences were quantified with both univariate and multivariate analyses. Type I error was controlled for by using a Bonferroni adjustment (0.05/33 = .0015).

Results

Multivariate Canonical Variate Analysis (CVA) of the 33 metabolites showed correct classification of sex at an average rate of 80.6% and correct classification of race at an average rate of 88.4%. Univariate analyses revealed that men had significantly higher concentrations of cysteine (p < 0.0001), uric acid (p < 0.0001), and N-acetylserotonin (p = 0.049), while women had significantly higher concentrations of 5-hydroxyindoleacetic acid (5-HIAA) (p = 0.001). African American participants had significantly higher concentrations of 3-hydroxykynurenine (p = 0.018), while white participants had significantly higher concentrations of kynurenine (p < 0.0001), indoleacetic acid (p < 0.0001), xanthine (p = 0.001), alpha-tocopherol (p = 0.007), cysteine (p = 0.029), melatonin (p = 0.036), and 7-methylxanthine (p = 0.037). After the Bonferroni adjustment, the effects for cysteine, uric acid, and 5-HIAA were still significant from the analysis of sex differences and kynurenine and indoleacetic acid were still significant from the analysis of race differences.

Conclusion

Several of the metabolites assayed in this study have been associated with mental health disorders and neurological diseases. Our data provide some novel information regarding normal variations by sex and race in CSF metabolite levels within the tryptophan, tyrosine and purine pathways, which may help to enhance our understanding of mechanisms underlying sex and race differences and potentially prove useful in the future treatment of disease.

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Fig. 1

Data availability

The metabolomics data reported in this study is available upon request to the corresponding author, Anastasia Georgiades.

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Funding

The research in this manuscript was funded by the NHLBI Grant Number P01-HL036587.

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Authors

Contributions

ZWR took the lead in writing the manuscript, conducted the statistical univariate analyses and created figures and tables. NM and SS derived the multivariate models analyses of the data, provided the figures and tables for the multivariate analyses and contributed to the interpretation of the results and the writing of the manuscript. SHB contributed to the outline of the paper, interpretation of the results and the writing of the manuscript. CMK contributed to the design of the original study, supervised the univariate analyses write-up and provided interpretation of the results, and gave feedback on the manuscript. WRM was responsible for the metabolomics platform analyses, supervision of the multivariate analyses and provided interpretation of the data. MAB reviewed the statistical analyses and provided feedback on the results. SAM aided in the metabolomics platform analyses and interpretation the multivariate analyses. ICS contributed to the design of the study and provided feedback on the results. RK-D contributed to the design of the metabolomics analyses and the interpretation of the data. ECS contributed to the design of the original study and provided feedback on the results. RBW was responsible for the design of the study and overall supervision the work. KG collected the CSF samples and provided feedback on the results. MS-S collected the CSF samples and provided feedback on the results. AG was in charge of overall direction and planning of the manuscript. She also supervised the interpretation of the data and provided feedback on the results. All authors contributed to the final manuscript.

Corresponding author

Correspondence to Anastasia Georgiades.

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Conflict of interest

Redford Williams holds a U.S. patent on the use of 5HTTLPR L allele as a marker of increased cardiovascular disease risk. The remaining authors have nothing to disclose.

Ethical approval

The study was approved by the Duke University Medical Center Institutional Review Board.

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Reavis, Z.W., Mirjankar, N., Sarangi, S. et al. Sex and race differences of cerebrospinal fluid metabolites in healthy individuals. Metabolomics 17, 13 (2021). https://doi.org/10.1007/s11306-020-01757-0

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Keywords

  • Sex
  • Race
  • Cerebrospinal fluid
  • Monoamine metabolites
  • 5-Hydroxyindoleacetic acid
  • Kynurenine
  • Tryptophan pathway
  • Tyrosine pathway
  • Purine pathway
  • Central nervous system