Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Apr 30;4(4):38.
doi: 10.1186/gm337.

Multi-platform Characterization of the Human Cerebrospinal Fluid Metabolome: A Comprehensive and Quantitative Update

Affiliations
Free PMC article

Multi-platform Characterization of the Human Cerebrospinal Fluid Metabolome: A Comprehensive and Quantitative Update

Rupasri Mandal et al. Genome Med. .
Free PMC article

Abstract

Background: Human cerebral spinal fluid (CSF) is known to be a rich source of small molecule biomarkers for neurological and neurodegenerative diseases. In 2007, we conducted a comprehensive metabolomic study and performed a detailed literature review on metabolites that could be detected (via metabolomics or other techniques) in CSF. A total of 308 detectable metabolites were identified, of which only 23% were shown to be routinely identifiable or quantifiable with the metabolomics technologies available at that time. The continuing advancement in analytical technologies along with the growing interest in CSF metabolomics has led us to re-visit the human CSF metabolome and to re-assess both its size and the level of coverage than can be achieved with today's technologies.

Methods: We used five analytical platforms, including nuclear magnetic resonance (NMR), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), direct flow injection-mass spectrometry (DFI-MS/MS) and inductively coupled plasma-mass spectrometry (ICP-MS) to perform quantitative metabolomics on multiple human CSF samples. This experimental work was complemented with an extensive literature review to acquire additional information on reported CSF compounds, their concentrations and their disease associations.

Results: NMR, GC-MS and LC-MS methods allowed the identification and quantification of 70 CSF metabolites (as previously reported). DFI-MS/MS allowed the quantification of 78 metabolites (6 acylcarnitines, 13 amino acids, hexose, 42 phosphatidylcholines, 2 lyso-phosphatidylcholines and 14 sphingolipids), while ICP-MS provided quantitative results for 33 metal ions in CSF. Literature analysis led to the identification of 57 more metabolites. In total, 476 compounds have now been confirmed to exist in human CSF.

Conclusions: The use of improved metabolomic and other analytical techniques has led to a 54% increase in the known size of the human CSF metabolome over the past 5 years. Commonly available metabolomic methods, when combined, can now routinely identify and quantify 36% of the 'detectable' human CSF metabolome. Our experimental works measured 78 new metabolites that, as per our knowledge, have not been reported to be present in human CSF. An updated CSF metabolome database containing the complete set of 476 human CSF compounds, their concentrations, related literature references and links to their known disease associations is freely available at the CSF metabolome database.

Figures

Figure 1
Figure 1
Typical 500 MHz 1H-NMR spectrum of human cerebrospinal fluid. Numbers indicate the following metabolites: 1, DSS; 2, imidazole; 3, 2-hydroxybutyric acid; 4, 2-hydroxyisovaleric acid; 5, 2-oxoisovaleric acid; 6, 3-hydroxybutyric acid; 7, 3-hydroxyisobutyric acid; 8, 3-hydroxyisovaleric acid; 9, acetic acid; 10, acetoacetic acid; 11, acetone; 12, L-glutamine; 13, pyruvic acid; 14, L-glutamic acid; 15, citric acid; 16, creatinine; 17, creatine; 18, D-glucose; 19, L-lactic acid; 20, myo-inositol; 21, D-fructose; 22, formic acid; 23, L-histidine; 24, L-tyrosine; 25, methanol; 26, glycerol.
Figure 2
Figure 2
Typical GC-MS total ion chromatogram spectrum of human cerebrospinal fluid. Numbers indicate the following metabolites: 1, L-lactic acid; 2, oxalic acid; 3, L-alanine; 4, glycine; 5, L-valine; 6, urea; 7, glycerol; 8, L-serine; 9, L-threonine/pyroglutamic acid; 10, L-glutamine; 11, L-phenylalanine; 12, ribitol; 13, L-glutamic acid; 14, citric acid; 15, D-fructose; 16, D-glucose; 17, D-galactose; 18, L-lysine; 19, mannitol; 20, L-tyrosine; 21, myo-inositol.
Figure 3
Figure 3
Typical direct flow injection (DFI) spectra of human cerebrospinal fluid. (a) negative mode, MRM (15 pairs); (b) positive mode, MRM (175 pairs).

Similar articles

  • Translational Metabolomics of Head Injury: Exploring Dysfunctional Cerebral Metabolism with Ex Vivo NMR Spectroscopy-Based Metabolite Quantification.
    Wolahan SM, Hirt D, Glenn TC. Wolahan SM, et al. In: Kobeissy FH, editor. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press/Taylor & Francis; 2015. Chapter 25. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. 2015. PMID: 26269925 Free Books & Documents. Review.
  • The human urine metabolome.
    Bouatra S, Aziat F, Mandal R, Guo AC, Wilson MR, Knox C, Bjorndahl TC, Krishnamurthy R, Saleem F, Liu P, Dame ZT, Poelzer J, Huynh J, Yallou FS, Psychogios N, Dong E, Bogumil R, Roehring C, Wishart DS. Bouatra S, et al. PLoS One. 2013 Sep 4;8(9):e73076. doi: 10.1371/journal.pone.0073076. eCollection 2013. PLoS One. 2013. PMID: 24023812 Free PMC article.
  • The human serum metabolome.
    Psychogios N, Hau DD, Peng J, Guo AC, Mandal R, Bouatra S, Sinelnikov I, Krishnamurthy R, Eisner R, Gautam B, Young N, Xia J, Knox C, Dong E, Huang P, Hollander Z, Pedersen TL, Smith SR, Bamforth F, Greiner R, McManus B, Newman JW, Goodfriend T, Wishart DS. Psychogios N, et al. PLoS One. 2011 Feb 16;6(2):e16957. doi: 10.1371/journal.pone.0016957. PLoS One. 2011. PMID: 21359215 Free PMC article.
  • The human cerebrospinal fluid metabolome.
    Wishart DS, Lewis MJ, Morrissey JA, Flegel MD, Jeroncic K, Xiong Y, Cheng D, Eisner R, Gautam B, Tzur D, Sawhney S, Bamforth F, Greiner R, Li L. Wishart DS, et al. J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Aug 15;871(2):164-73. doi: 10.1016/j.jchromb.2008.05.001. Epub 2008 May 8. J Chromatogr B Analyt Technol Biomed Life Sci. 2008. PMID: 18502700
  • Beyond the paradigm: Combining mass spectrometry and nuclear magnetic resonance for metabolomics.
    Marshall DD, Powers R. Marshall DD, et al. Prog Nucl Magn Reson Spectrosc. 2017 May;100:1-16. doi: 10.1016/j.pnmrs.2017.01.001. Epub 2017 Jan 11. Prog Nucl Magn Reson Spectrosc. 2017. PMID: 28552170 Free PMC article. Review.
See all similar articles

Cited by 39 articles

See all "Cited by" articles

References

    1. Wishart DS, Tzur D, Knox C, Eisner R, Guo AC, Young N, Cheng D, Jewell K, Arndt D, Sawhney S, Fung C, Nikolai L, Lewis M, Coutouly MA, Forsythe I, Tang P, Shrivastava S, Jeroncic K, Stothard P, Amegbey G, Block D, Hau DD, Wagner J, Miniaci J, Clements M, Gebremedhin M, Guo N, Zhang Y, Duggan GE, Macinnis GD. et al. HMDB: the Human Metabolome Database. Nucleic Acids Res. 2007;35(Database issue):D521–6. - PMC - PubMed
    1. Wishart DS, Lewis MJ, Morrissey JA, Flegel MD, Jeroncic K, Xiong Y, Cheng D, Eisner R, Gautam B, Tzur D, Sawhney S, Bamforth F, Greiner R and Li L. The human cerebrospinal fluid metabolome. J Chrom B. 2008;871:164–173. doi: 10.1016/j.jchromb.2008.05.001. - DOI - PubMed
    1. Hoffmann G, Meier-Augenstein W, Stockler S, Surtees R, Rating D, Nyhan W. Physiology and pathophysiology of organic acids in cerebrospinal fluid. J Inherit Metab Dis. 1993;16:648–669. doi: 10.1007/BF00711898. - DOI - PubMed
    1. Toczylowska B, Chalimoniuk M, Wodowska M, Mayzner-Zawadzka E. Changes in concentration of cerebrospinal fluid components in patients with traumatic brain injury. Brain Res. 2006;1104:183–189. doi: 10.1016/j.brainres.2006.05.057. - DOI - PubMed
    1. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 2006;5:228–234. doi: 10.1016/S1474-4422(06)70355-6. - DOI - PubMed

LinkOut - more resources

Feedback