Skip to main content
SpringerLink
Log in

Metabolomic analysis and signatures in motor neuron disease

  • Published:
Metabolomics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • M. Beal R. Ferrante S. Browne R. Matthews N. Kowall R. Brown (1997) ArticleTitleIncreased 3-Nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis Ann. Neurol 42 644–654 Occurrence Handle10.1002/ana.410420416 Occurrence Handle9382477

    Article  PubMed  Google Scholar 

  • G. Bensimon L. Lacomblez V. Meininger (1994) ArticleTitleA controlled trial of Riluzole in amyotrophic lateral sclerosis N. Engl. J. Med 330 585–591 Occurrence Handle10.1056/NEJM199403033300901 Occurrence Handle8302340

    Article  PubMed  Google Scholar 

  • W. Beuche M. Yushchenko M. Mader M. Maliszewska K. Felgenhauer F. Weber (2000) ArticleTitleMatrix metalloproteinase-9 is elevated in serum of patients with amyotrophic lateral sclerosis Neuroreport 11 3419–3422 Occurrence Handle11095490

    PubMed  Google Scholar 

  • M. Bogdanov R.H. Brown W. Matson R. Smart D. Hayden H. O’Donnell M. Flint Beal M. Cudkowicz (2000) ArticleTitleIncreased oxidative damage to DNA in ALS patients Free Radic. Biol. Med 29 652–658 Occurrence Handle10.1016/S0891-5849(00)00349-X Occurrence Handle11033417

    Article  PubMed  Google Scholar 

  • J. Brindle H. Antti E. Holmes G. Traner J. Nicholson H. Bethell S. Clarke P. Schofield E. McKilling D. Mosedale D. Grainer (2002) ArticleTitleRapid and non-invasive diagnosis of the presence and severity of coronary hear disease using 1H-NMR-based metabonomics Nat. Med 8 1439–1444 Occurrence Handle10.1038/nm802 Occurrence Handle12447357

    Article  PubMed  Google Scholar 

  • J. Brindle J. Nicholson P. Schofield D. Grainger E. Holmes (2003) ArticleTitleApplication of chemometrics to 1H NMR spectroscopic data to investigate a relationship between human serum metabolic profiles and hypertension Analyst 128 32–36 Occurrence Handle10.1039/b209155k Occurrence Handle12572799

    Article  PubMed  Google Scholar 

  • W. Camu M. Billiard M. Baldy-Moulinier (1993) ArticleTitleFasting plasma and CSF amino acid levels in amyotrophic lateral sclerosis: a subtype analysis Acta Neurol. Scand 88 51–55 Occurrence Handle8372631

    PubMed  Google Scholar 

  • D. Cleveland J. Rothstein (2001) ArticleTitleFrom Charcot to Lou Gehrig: Deciphering selective motor neuron death in ALS Nat. Rev. Neurosci 2 806–819 Occurrence Handle10.1038/35097565 Occurrence Handle11715057

    Article  PubMed  Google Scholar 

  • L. Eriksson E. Johansson N. Kettaneh-Wold S. Wold (2001) Multi and Megavariate Analysis: Principles and Applications Umetrics Umea

    Google Scholar 

  • T.R. Golub D.K. Slonim P. Tamayo C. Huard M. Gaasenbeek J.P. Mesirov H. Coller M.L. Loh J.R. Downing M.A. Caligiuri C.D. Bloomfield E.S. Lander (1999) ArticleTitleMolecular classification of cancer: class discovery and class prediction by gene expression monitoring Science 286 531–537

    Google Scholar 

  • S. Hadano C. Hand H. Osuga Y. Yanagisawa A. Otomo R. Devon N. Miyamoto J. Showguchi-Miyata Y. Okada R. Singaraja D. Figlewicz T. Kwiatkowski B. Hosler T. Sagie J. Skaung J. Nasir R.J. Brown S. Scherer G. Rouleau M. Hayden J. Ikeda (2001) ArticleTitleA gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2 Nat. Genet 29 166–173 Occurrence Handle10.1038/ng1001-166 Occurrence Handle11586298

    Article  PubMed  Google Scholar 

  • G.G. Harrigan R. Goodacre (Eds) (2003) Metabolic Profiling: Its Role in Biomarker Discovery and Gene Function Analysis Kluwer Academic Publishers Boston

    Google Scholar 

  • D.B. Kell (2004) ArticleTitleMetabolomics and system biology: making sense of the soup Curr. Opin. Microbiol 7 296–307 Occurrence Handle10.1016/j.mib.2004.04.012 Occurrence Handle15196499

    Article  PubMed  Google Scholar 

  • R. Kennedy Y. Lee B. Roy Particlevan C. Redd R. Lippman (1997) Solving Data Mining Problems Through Pattern Recognition Prentice Hall PTR Indianapolis

    Google Scholar 

  • B. Kristal K. Vigneeau-Callahan W. Matson (1998) ArticleTitleSimultaneous analysis of the majority of low-molecular weight, redox-active compounds from mitochondria Anal Biochem 263 18–25 Occurrence Handle10.1006/abio.1998.2831 Occurrence Handle9750137

    Article  PubMed  Google Scholar 

  • B.S. Kristal K. Vigneau-Callahan W.R. Matson (2002) ArticleTitleSimultaneous analysis of multiple redox-active metabolites from biological matrices Meth. Mol. Biol 186 185–194

    Google Scholar 

  • J. Kurtzke L. Kurland (1989) The epidemiology of neurologic disease R. Joynt (Eds) Clinical Neurology J.B. Lippincot Philadelphia 1–43

    Google Scholar 

  • L. Lacomblez G. Bensimon P. Leigh P. Guillett V. Meininger (1996) ArticleTitleDose-ranging study of riluzole in amyotrophic lateral sclerosis Lancet 347 1425–1431 Occurrence Handle8676624

    PubMed  Google Scholar 

  • 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, 383–394

  • D.E. Lilienfeld E. Chan J. Ehland J. Godbold P.J. Landrigan G. Marsh D.P. Perl (1989) ArticleTitleRising mortality from motoneuron disease in the USA, 1962–84 Lancet 1 710–713 Occurrence Handle10.1016/S0140-6736(89)92218-6 Occurrence Handle2564517

    Article  PubMed  Google Scholar 

  • J.C. Lindon E. Holmes J.K. Nicholson (2004) ArticleTitleMetabolomics and its role in drug development and disease diagnosis Expert Rev. Mo. Diagn 4 189–199 Occurrence Handle10.1586/14737159.4.2.189

    Article  Google Scholar 

  • B. Manley (1994) Multivariate Statistical Methods: A Primer EditionNumber2 CRC Press Boca Raton

    Google Scholar 

  • W. Matson P. Langials L. Volicer P. Gamache E. Bird K. Mark (1984) ArticleTitleN-electrode three dimensional liquid chromatography with electrochemical detection for determination of neurotransmitters Clin. Chem 30 1477–1488 Occurrence Handle6147209

    PubMed  Google Scholar 

  • V. McGuire W. Longstreth T. Koepsell G. Belle Particlevan (1996) ArticleTitleIncidence of ALS in three counties in western Washington state Neurology 47 571–573 Occurrence Handle8757041

    PubMed  Google Scholar 

  • 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. 125–141

  • H. Mitsumoto D. Chad E. Pioro (1998) Amyotrophic Lateral Sclerosis Oxford Press New York

    Google Scholar 

  • J. K. Nicholson I. D. Wilson (2003) ArticleTitleUnderstanding ‘global’ systems biology: metabonomics and the continuum of metabolism Nat. Rev. Drug Discov 2 668–676 Occurrence Handle10.1038/nrd1157 Occurrence Handle12904817

    Article  PubMed  Google Scholar 

  • I. Puls C. Jonnakuty B. LaMonte E. Holzbaur M. Tokito E. Mann M. Floeter K. Bidus D. Drayna S. Oh R. Brown C. Ludlow K. Fischbeck (2003) ArticleTitleMutant dynactin in motor neuron disease Nat. Genet 33 455–456 Occurrence Handle10.1038/ng1123 Occurrence Handle12627231

    Article  PubMed  Google Scholar 

  • D. Rosen T. Siddique D. Patterson D. Figlewicz E. Sapp A. Hentati D. Donaldson J. Goto J. O’Reagan H. Deng (1993) ArticleTitleMutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis Nature 362 59–62 Occurrence Handle10.1038/362059a0 Occurrence Handle8446170

    Article  PubMed  Google Scholar 

  • Rothstein, J., Tsai, G., Kuncl, R., et al. (1990). Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann. Neurol. 28, 18–25

    Google Scholar 

  • L. Rowland N. Shneider (2001) ArticleTitleAmyotrophic lateral sclerosis N Engl. J. Med 344 1688–1700 Occurrence Handle10.1056/NEJM200105313442207 Occurrence Handle11386269

    Article  PubMed  Google Scholar 

  • H. Shi K. Vigneau-Callahan W. Matson B. Kristal (2002) ArticleTitleAttention to relative response across sequential electrodes improves quantitation of coulometric array Anal. Biochem 302 239–245 Occurrence Handle10.1006/abio.2001.5568 Occurrence Handle11878803

    Article  PubMed  Google Scholar 

  • E. Simpson J. Henkel Y. Henry R. Smith S. Appel (2003) ArticleTitleElevated levels of 4-HNE in the sera of patients wtih amyotrophic lateral sclerosis Neurology 60 A242

    Google Scholar 

  • R. Smith Y. Henry M. Mattson S. Appel (1998) ArticleTitlePresence of 4-hydroxynonenal in cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis Ann. Neurol 44 696–699 Occurrence Handle10.1002/ana.410440419 Occurrence Handle9778272

    Article  PubMed  Google Scholar 

  • J. Greef Particlevan der P. Stroobant R. Heijden Particlevan der (2004) ArticleTitleThe role of analytical sciences in medical systems biology Curr. Opin. Chem. Biol 8 559–565 Occurrence Handle10.1016/j.cbpa.2004.08.013 Occurrence Handle15450501

    Article  PubMed  Google Scholar 

  • K. Vigneau-Callahan A. Shestopalov P. Milbury W. Matson B. Kristal (2001) ArticleTitleCharacterization of diet-dependent metabolic serotypes: I. Analytical and biological variability issues J Nutr 131 924S–932S Occurrence Handle11238787

    PubMed  Google Scholar 

  • Y. Yang A. Hentati H. Deng O. Dabbagh T. Sasaki M. Hirano W. Hung K. Ouahchi J. Yan A. Azim N. Cole G. Gascon A. Yagmour M. Ben-Hamida M. Pericak-Vance F. Hentati T. Siddique (2001) ArticleTitleThe gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis Nat. Genet 29 160–165 Occurrence Handle10.1038/ng1001-160 Occurrence Handle11586297

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Metabolon Inc., 800 Capitola Dr., Research Triangle Park, NC, 27709

    Steve Rozen, Chris Beecher, Scott Harrison & Rima Kaddurah-Daouk

  2. Whitehead Inst. for Biomedical Research, 9 Cambridge Center, Cambridge, MA, 02142

    Steve Rozen

  3. MGH, Neurology Clinical Trial Unit, Charlestown Navy Yard, Building 149, 13th St., Charlestown, MA, 02129

    Merit E. Cudkowicz & Kristyn M. Newhall

  4. Weill Medical College of Cornell University, 525 East 68 St., New York, NY, 10021

    Mikhail Bogdanov, Bruce S. Kristal & M. Flint Beal

  5. ESA, Inc., 22 Alpha Rd., Chelmsford, MA, 01824

    Wayne R. Matson & Karen Vigneau-Callahan

  6. Dementia Research Service, Burke Medical Research Institute, 785 Mamaroneck Ave., White Plains, NY, 10605

    Bruce S. Kristal

  7. Department of Chemistry and Barnett Institute, Northeastern University, Boston, MA, 02115

    Paul Vouros & Jimmy Flarakos

  8. Department of Chemistry, University of Chicago, 5735 S. Ellis Ave., Chicago, IL, 60637

    Theodore D. Matson

  9. MGH, Neurology, MGH East, Charlestown Navy Yard, Building 114, 13th St., Charlestown, MA, 02129

    Robert H. Brown Jr.

Authors
  1. Steve Rozen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Merit E. Cudkowicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mikhail Bogdanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wayne R. Matson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bruce S. Kristal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chris Beecher
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Scott Harrison
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Paul Vouros
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jimmy Flarakos
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Karen Vigneau-Callahan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Theodore D. Matson
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kristyn M. Newhall
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M. Flint Beal
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Robert H. Brown Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Rima Kaddurah-Daouk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rima Kaddurah-Daouk.

Additional information

†S.R., M.E.C. and M.B. contributed equally to this work. W.R.M. and B.S.K. contributed equally to this work. S.R., M.B., W.R.M., B.S.K., C.B., S.H., P.V., M.F.B., and R.K-D. have financial interests in Metabolon Inc., a company engaged in metabolic profiling. ††Electronic supporting figures, tables and datasets are available at the Journal’s website.

*To whom corrsepondence should be addressed.E-mail: kaddu001@mc.duke.eduCurrent address: Duke University Medical Center, Department of Psychiatry, P.O. Box 3950, Durham, NC 27710.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rozen, S., Cudkowicz, M.E., Bogdanov, M. et al. Metabolomic analysis and signatures in motor neuron disease. Metabolomics 1, 101–108 (2005). https://doi.org/10.1007/s11306-005-4810-1

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11306-005-4810-1

KEY WORDS

Search

Navigation