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Metabolomics

, Volume 1, Issue 2, pp 101–108 | Cite as

Metabolomic analysis and signatures in motor neuron disease

  • Steve Rozen
  • Merit E. Cudkowicz
  • Mikhail Bogdanov
  • Wayne R. Matson
  • Bruce S. Kristal
  • Chris Beecher
  • Scott Harrison
  • Paul Vouros
  • Jimmy Flarakos
  • Karen Vigneau-Callahan
  • Theodore D. Matson
  • Kristyn M. Newhall
  • M. Flint Beal
  • Robert H. BrownJr.
  • Rima Kaddurah-Daouk
Article

Motor neuron diseases (MND) are a heterogeneous group of disorders that includes amyotrophic lateral sclerosis (ALS) and result in death of motor neurons. These diseases may produce characteristic perturbations of the metabolome, the collection of small-molecules (metabolites) present in a cell, tissue, or organism. To test this hypothesis, we used high performance liquid chromatography followed by electrochemical detection to profile blood plasma from 28 patients with MND and 30 healthy controls. Of 317 metabolites, 50 were elevated in MND patients and more than 70 were decreased (p<0.05). Among the compounds elevated, 12 were associated with the drug Riluzole. In a subsequent study of 19 subjects with MND who were not taking Riluzole and 33 healthy control subjects, six compounds were significantly elevated in MND, while the number of compounds with decreased concentration was similar to study 1. Our data also revealed a distinctive signature of highly correlated metabolites in a set of four patients, three of whom had lower motor neuron (LMN) disease. In both datasets we were able to separate MND patients from controls using multivariate regression techniques. These results suggest that metabolomic studies can be used to ascertain metabolic signatures of disease in a non-invasive fashion. Elucidation of the structures of signature molecules in ALS and other forms of MND should provide insight into aberrant biochemical pathways and may provide diagnostic markers and targets for drug design.

KEY WORDS

amyotrophic lateral sclerosis motor neuron disease coulometric array metabolic profiling 

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References

  1. Beal, M., Ferrante, R., Browne, S., Matthews, R., Kowall, N., Brown, R. 1997Increased 3-Nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosisAnn. Neurol42644654CrossRefPubMedGoogle Scholar
  2. Bensimon, G., Lacomblez, L., Meininger, V. 1994A controlled trial of Riluzole in amyotrophic lateral sclerosisN. Engl. J. Med330585591CrossRefPubMedGoogle Scholar
  3. Beuche, W., Yushchenko, M., Mader, M., Maliszewska, M., Felgenhauer, K., Weber, F. 2000Matrix metalloproteinase-9 is elevated in serum of patients with amyotrophic lateral sclerosisNeuroreport1134193422PubMedGoogle Scholar
  4. Bogdanov, M., Brown, R.H., Matson, W., Smart, R., Hayden, D., O’Donnell, H., Flint Beal, M., Cudkowicz, M. 2000Increased oxidative damage to DNA in ALS patientsFree Radic. Biol. Med29652658CrossRefPubMedGoogle Scholar
  5. Brindle, J., Antti, H., Holmes, E., Traner, G., Nicholson, J., Bethell, H., Clarke, S., Schofield, P., McKilling, E., Mosedale, D., Grainer, D. 2002Rapid and non-invasive diagnosis of the presence and severity of coronary hear disease using 1H-NMR-based metabonomicsNat. Med814391444CrossRefPubMedGoogle Scholar
  6. Brindle, J., Nicholson, J., Schofield, P., Grainger, D., Holmes, E. 2003Application of chemometrics to 1H NMR spectroscopic data to investigate a relationship between human serum metabolic profiles and hypertensionAnalyst1283236CrossRefPubMedGoogle Scholar
  7. Camu, W., Billiard, M., Baldy-Moulinier, M. 1993Fasting plasma and CSF amino acid levels in amyotrophic lateral sclerosis: a subtype analysisActa Neurol. Scand885155PubMedGoogle Scholar
  8. Cleveland, D., Rothstein, J. 2001From Charcot to Lou Gehrig: Deciphering selective motor neuron death in ALSNat. Rev. Neurosci2806819CrossRefPubMedGoogle Scholar
  9. Eriksson, L., Johansson, E., Kettaneh-Wold, N., Wold, S. 2001Multi and Megavariate Analysis: Principles and ApplicationsUmetricsUmeaGoogle Scholar
  10. Golub, T.R., Slonim, D.K., Tamayo, P., Huard, C., Gaasenbeek, M., Mesirov, J.P., Coller, H., Loh, M.L., Downing, J.R., Caligiuri, M.A., Bloomfield, C.D., Lander, E.S. 1999Molecular classification of cancer: class discovery and class prediction by gene expression monitoringScience286531537Google Scholar
  11. Hadano, S., Hand, C., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R., Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D., Kwiatkowski, T., Hosler, B., Sagie, T., Skaung, J., Nasir, J., Brown, R.J., Scherer, S., Rouleau, G., Hayden, M., Ikeda, J. 2001A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2Nat. Genet29166173CrossRefPubMedGoogle Scholar
  12. Harrigan, G.G.Goodacre, R. eds. 2003Metabolic Profiling: Its Role in Biomarker Discovery and Gene Function AnalysisKluwer Academic PublishersBostonGoogle Scholar
  13. Kell, D.B. 2004Metabolomics and system biology: making sense of the soupCurr. Opin. Microbiol7296307CrossRefPubMedGoogle Scholar
  14. Kennedy, R., Lee, Y., Roy, B., Redd, C., Lippman, R. 1997Solving Data Mining Problems Through Pattern RecognitionPrentice Hall PTRIndianapolisGoogle Scholar
  15. Kristal, B., Vigneeau-Callahan, K., Matson, W. 1998Simultaneous analysis of the majority of low-molecular weight, redox-active compounds from mitochondriaAnal Biochem2631825CrossRefPubMedGoogle Scholar
  16. Kristal, B.S., Vigneau-Callahan, K., Matson, W.R. 2002Simultaneous analysis of multiple redox-active metabolites from biological matricesMeth. Mol. Biol186185194Google Scholar
  17. Kurtzke, J., Kurland, L. 1989The epidemiology of neurologic diseaseJoynt, R. eds. Clinical NeurologyJ.B. LippincotPhiladelphia143Google Scholar
  18. Lacomblez, L., Bensimon, G., Leigh, P., Guillett, P., Meininger, V. 1996Dose-ranging study of riluzole in amyotrophic lateral sclerosisLancet34714251431PubMedGoogle Scholar
  19. Lambrechts, D., Storkebaum, E., Morimoto, M., Del-Favero, J., Desmet, F., Marklund, S., S.W. and et al. (2003). VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat. Genet. 34, 383–394Google Scholar
  20. Lilienfeld, D.E., Chan, E., Ehland, J., Godbold, J., Landrigan, P.J., Marsh, G., Perl, D.P. 1989Rising mortality from motoneuron disease in the USA, 1962–84Lancet1710713CrossRefPubMedGoogle Scholar
  21. Lindon, J.C., Holmes, E., Nicholson, J.K. 2004Metabolomics and its role in drug development and disease diagnosisExpert Rev. Mo. Diagn4189199CrossRefGoogle Scholar
  22. Manley, B. 1994Multivariate Statistical Methods: A Primer2CRC PressBoca RatonGoogle Scholar
  23. Matson, W., Langials, P., Volicer, L., Gamache, P., Bird, E., Mark, K. 1984N-electrode three dimensional liquid chromatography with electrochemical detection for determination of neurotransmittersClin. Chem3014771488PubMedGoogle Scholar
  24. McGuire, V., Longstreth, W., Koepsell, T., Belle, G. 1996Incidence of ALS in three counties in western Washington stateNeurology47571573PubMedGoogle Scholar
  25. Milbury, P. (1997). CEAS generation of large multiparameter databases for determining categorical process involvement of biomolecules, Coulometric Array Detectors for HPLC, V.S.P. International Science, Utrecht, the Netherlands, pp. 125–141Google Scholar
  26. Mitsumoto, H., Chad, D., Pioro, E. 1998Amyotrophic Lateral SclerosisOxford PressNew YorkGoogle Scholar
  27. Nicholson, J. K., Wilson, I. D. 2003Understanding ‘global’ systems biology: metabonomics and the continuum of metabolismNat. Rev. Drug Discov2668676CrossRefPubMedGoogle Scholar
  28. Puls, I., Jonnakuty, C., LaMonte, B., Holzbaur, E., Tokito, M., Mann, E., Floeter, M., Bidus, K., Drayna, D., Oh, S., Brown, R., Ludlow, C., Fischbeck, K. 2003Mutant dynactin in motor neuron diseaseNat. Genet33455456CrossRefPubMedGoogle Scholar
  29. Rosen, D., Siddique, T., Patterson, D., Figlewicz, D., Sapp, E., Hentati, A., Donaldson, D., Goto, J., O’Reagan, J., Deng, H. 1993Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosisNature3625962CrossRefPubMedGoogle Scholar
  30. Rothstein, J., Tsai, G., Kuncl, R., et al. (1990). Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann. Neurol. 28, 18–25Google Scholar
  31. Rowland, L., Shneider, N. 2001Amyotrophic lateral sclerosisN Engl. J. Med34416881700CrossRefPubMedGoogle Scholar
  32. Shi, H., Vigneau-Callahan, K., Matson, W., Kristal, B. 2002Attention to relative response across sequential electrodes improves quantitation of coulometric arrayAnal. Biochem302239245CrossRefPubMedGoogle Scholar
  33. Simpson, E., Henkel, J., Henry, Y., Smith, R., Appel, S. 2003Elevated levels of 4-HNE in the sera of patients wtih amyotrophic lateral sclerosisNeurology60A242Google Scholar
  34. Smith, R., Henry, Y., Mattson, M., Appel, S. 1998Presence of 4-hydroxynonenal in cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosisAnn. Neurol44696699CrossRefPubMedGoogle Scholar
  35. Greef, J., Stroobant, P., Heijden, R. 2004The role of analytical sciences in medical systems biologyCurr. Opin. Chem. Biol8559565CrossRefPubMedGoogle Scholar
  36. Vigneau-Callahan, K., Shestopalov, A., Milbury, P., Matson, W., Kristal, B. 2001Characterization of diet-dependent metabolic serotypes: I. Analytical and biological variability issuesJ Nutr131924S932SPubMedGoogle Scholar
  37. Yang, Y., Hentati, A., Deng, H., Dabbagh, O., Sasaki, T., Hirano, M., Hung, W., Ouahchi, K., Yan, J., Azim, A., Cole, N., Gascon, G., Yagmour, A., Ben-Hamida, M., Pericak-Vance, M., Hentati, F., Siddique, T. 2001The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosisNat. Genet29160165CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Steve Rozen
    • 1
    • 2
  • Merit E. Cudkowicz
    • 3
  • Mikhail Bogdanov
    • 4
  • Wayne R. Matson
    • 5
  • Bruce S. Kristal
    • 4
    • 6
  • Chris Beecher
    • 1
  • Scott Harrison
    • 1
  • Paul Vouros
    • 7
  • Jimmy Flarakos
    • 7
  • Karen Vigneau-Callahan
    • 5
  • Theodore D. Matson
    • 8
  • Kristyn M. Newhall
    • 3
  • M. Flint Beal
    • 4
  • Robert H. BrownJr.
    • 9
  • Rima Kaddurah-Daouk
    • 1
  1. 1.Metabolon Inc.
  2. 2.Whitehead Inst. for Biomedical ResearchCambridge
  3. 3.MGH, Neurology Clinical Trial UnitCharlestown
  4. 4.Weill Medical College of Cornell UniversityNew York
  5. 5.ESA, Inc.Chelmsford
  6. 6.Dementia Research ServiceBurke Medical Research InstituteWhite Plains
  7. 7.Department of Chemistry and Barnett InstituteNortheastern UniversityBoston
  8. 8.Department of ChemistryUniversity of ChicagoChicago
  9. 9.MGH, NeurologyCharlestown

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