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NMR analysis of the CSF and plasma metabolome of rigorously matched amyotrophic lateral sclerosis, Parkinson’s disease and control subjects

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Abstract

Introduction

Amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) are two severe neurodegenerative disorders for which the disease mechanisms are poorly understood and reliable biomarkers are absent.

Objectives

To identify metabolite biomarkers for ALS and PD, and to gain insights into which metabolic pathways are involved in disease.

Methods

Nuclear magnetic resonance (NMR) metabolomics was utilized to characterize the metabolite profiles of cerebrospinal fluid (CSF) and plasma from individuals in three age, gender, and sampling-date matched groups, comprising 22 ALS, 22 PD and 28 control subjects.

Results

Multivariate analysis of NMR data generated robust discriminatory models for separation of ALS from control subjects. ALS patients showed increased concentrations of several metabolites in both CSF and plasma, these are alanine (CSF fold change = 1.22, p = 0.005), creatine (CSF-fc = 1.17, p = 0.001), glucose (CSF-fc = 1.11, p = 0.036), isoleucine (CSF-fc = 1.24, p = 0.002), and valine (CSF-fc = 1.17, p = 0.014). Additional metabolites in CSF (creatinine, dimethylamine and lactic acid) and plasma (acetic acid, glutamic acid, histidine, leucine, pyruvate and tyrosine) were also important for this discrimination. Similarly, panels of CSF-metabolites that discriminate PD from ALS and control subjects were identified.

Conclusions

The results for the ALS patients suggest an affected creatine/creatinine pathway and an altered branched chain amino acid (BCAA) metabolism, and suggest links to glucose and energy metabolism. Putative metabolic markers specific for ALS (e.g. creatinine and lactic acid) and PD (e.g. 3-hydroxyisovaleric acid and mannose) were identified, while several (e.g. creatine and BCAAs) were shared between ALS and PD, suggesting some overlap in metabolic alterations in these disorders.

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

PD:

Parkinson’s disease

NMR:

Nuclear magnetic resonance

MS:

Mass spectrometry

EDTA:

Ethylenediaminetetraacetic acid

CSF:

Cerebrospinal fluid

CPMG:

Carr-Purcell-Meiboom-Gill

PCA:

Principal component analysis

OPLS:

Orthogonal projection to latent structures

DA:

Discriminant analysis

EP:

Effect projection

CV-ANOVA:

Analysis of variance testing of cross-validated predictive residuals

CNS:

Central nervous system

BCAA:

Branched chain amino acids

References

  • Andersen, P. M., Abrahams, S., Borasio, G. D., de Carvalho, M., Chio, A., Hardiman, O., et al. (2012). EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)–revised report of an EFNS task force. European Journal of Neurology, 19(3), 360–375. doi:10.1111/j.1468-1331.2011.03501.x.

    Article  PubMed  Google Scholar 

  • Aranibar, N., Ott, K. H., Roongta, V., & Mueller, L. (2006). Metabolomic analysis using optimized NMR and statistical methods. Analytical Biochemistry, 355(1), 62–70. doi:10.1016/j.ab.2006.04.014.

    Article  CAS  PubMed  Google Scholar 

  • Averous, J., Lambert-Langlais, S., Carraro, V., Gourbeyre, O., Parry, L., B’Chir, W., et al. (2014). Requirement for lysosomal localization of mTOR for its activation differs between leucine and other amino acids. Cellular Signalling, 26(9), 1918–1927. doi:10.1016/j.cellsig.2014.04.019.

    Article  CAS  PubMed  Google Scholar 

  • Barton, R. H., Waterman, D., Bonner, F. W., Holmes, E., Clarke, R., Procardis, C., et al. (2010). The influence of EDTA and citrate anticoagulant addition to human plasma on information recovery from NMR-based metabolic profiling studies. Molecular BioSystems, 6(1), 215–224. doi:10.1039/b907021d.

    Article  CAS  PubMed  Google Scholar 

  • Beghi, E. (2013). Are professional soccer players at higher risk for ALS? Amyotroph Lateral Scler Frontotemporal Degener, 14(7–8), 501–506. doi:10.3109/21678421.2013.809764.

    Article  CAS  PubMed  Google Scholar 

  • Blasco, H., Corcia, P., Moreau, C., Veau, S., Fournier, C., Vourc’h, P., et al. (2010). 1H-NMR-based metabolomic profiling of CSF in early amyotrophic lateral sclerosis. PLoS ONE, 5(10), e13223. doi:10.1371/journal.pone.0013223.

    Article  PubMed  PubMed Central  Google Scholar 

  • Blasco, H., Corcia, P., Pradat, P. F., Bocca, C., Gordon, P. H., Veyrat-Durebex, C., et al. (2013). Metabolomics in cerebrospinal fluid of patients with amyotrophic lateral sclerosis: an untargeted approach via high-resolution mass spectrometry. Journal of Proteome Research, 12(8), 3746–3754. doi:10.1021/pr400376e.

    Article  CAS  PubMed  Google Scholar 

  • Bouatra, S., Aziat, F., Mandal, R., Guo, A. C., Wilson, M. R., Knox, C., et al. (2013). The human urine metabolome. PLoS ONE, 8(9), e73076. doi:10.1371/journal.pone.0073076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bylesjö, M., Rantalainen, M., Cloarec, O., Nicholson, J. K., Holmes, E., & Trygg, J. (2006). OPLS discriminant analysis: combining the strengths of PLS-DA and SIMCA classification. Journal of Chemometrics, 20(8–10), 341–351. doi:10.1002/cem.1006.

    Article  Google Scholar 

  • Dame, Z. T., Aziat, F., Mandal, R., Krishnamurthy, R., Bouatra, S., Borzouie, S., et al. (2015). The human saliva metabolome. Metabolomics, 11(6), 1864–1883. doi:10.1007/s11306-015-0840-5.

    Article  CAS  Google Scholar 

  • Dunn, W. B., Broadhurst, D. I., Atherton, H. J., Goodacre, R., & Griffin, J. L. (2011). Systems level studies of mammalian metabolomes: the roles of mass spectrometry and nuclear magnetic resonance spectroscopy. Chemical Society Reviews, 40(1), 387–426. doi:10.1039/b906712b.

    Article  CAS  PubMed  Google Scholar 

  • Engelke, U. F., Tangerman, A., Willemsen, M. A., Moskau, D., Loss, S., Mudd, S. H., et al. (2005). Dimethyl sulfone in human cerebrospinal fluid and blood plasma confirmed by one-dimensional (1)H and two-dimensional (1)H-(13)C NMR. NMR in Biomedicine, 18(5), 331–336. doi:10.1002/nbm.966.

    Article  CAS  PubMed  Google Scholar 

  • Eriksson, L., Trygg, J., & Wold, S. (2008). CV-ANOVA for significance testing of PLS and OPLS (R) models. Journal of Chemometrics, 22(11–12), 594–600. doi:10.1002/cem.1187.

    Article  CAS  Google Scholar 

  • Ekhtiari Bidhendi, E., Bergh, J., Zetterström, P., Andersen, P. M., Marklund, S. L., & Brännström, T. (2016). Two superoxide dismutase prion strains transmitting amyotrophic lateral sclerosis. The Journal of Investigation (in press).

  • Fahn, S., Elton, R., & Commitee TUD. (1987). Unified Parkinson’s disease rating scale. In S. Fahn, C. Marsden, D. Calne, & M. Goldstein (Eds.), Recent developments in Parkinson’s disease (pp. 153–163). Florham Park: Macmillan Healthcare Information.

    Google Scholar 

  • Fernstrom, J. D. (2013). Large neutral amino acids: dietary effects on brain neurochemistry and function. Amino Acids, 45(3), 419–430. doi:10.1007/s00726-012-1330-y.

    Article  CAS  PubMed  Google Scholar 

  • Forsberg, K., Jonsson, P. A., Andersen, P. M., Bergemalm, D., Graffmo, K. S., Hultdin, M., et al. (2010). Novel antibodies reveal inclusions containing non-native SOD1 in sporadic ALS patients. PLoS ONE, 5(7), e11552. doi:10.1371/journal.pone.0011552.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gall, W. E., Beebe, K., Lawton, K. A., Adam, K. P., Mitchell, M. W., Nakhle, P. J., et al. (2010). Alpha-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS ONE, 5(5), e10883. doi:10.1371/journal.pone.0010883.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gibb, W. R., & Lees, A. J. (1988). A comparison of clinical and pathological features of young- and old-onset Parkinson’s disease. Neurology, 38(9), 1402–1406.

    Article  CAS  PubMed  Google Scholar 

  • Goedert, M. (2001). Alpha-synuclein and neurodegenerative diseases. Nature Reviews Neuroscience, 2(7), 492–501. doi:10.1038/35081564.

    Article  CAS  PubMed  Google Scholar 

  • Gray, E., Larkin, J. R., Claridge, T. D., Talbot, K., Sibson, N. R., & Turner, M. R. (2015). The longitudinal cerebrospinal fluid metabolomic profile of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener, 16(1–8), 456–463. doi:10.3109/21678421.2015.1053490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holmqvist, S., Chutna, O., Bousset, L., Aldrin-Kirk, P., Li, W., Bjorklund, T., et al. (2014). Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathologica, 128(6), 805–820. doi:10.1007/s00401-014-1343-6.

    Article  PubMed  Google Scholar 

  • Isobe, C., Abe, T., & Terayama, Y. (2010). Decrease in asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in cerebrospinal fluid during elderly aging and in patients with sporadic form of amyotrophic lateral sclerosis. Neurosignals, 18(1), 43–48. doi:10.1159/000312527.

    Article  CAS  PubMed  Google Scholar 

  • Jewell, J. L., Kim, Y. C., Russell, R. C., Yu, F. X., Park, H. W., Plouffe, S. W., et al. (2015). Metabolism differential regulation of mTORC1 by leucine and glutamine. Science, 347(6218), 194–198. doi:10.1126/science.1259472. (New York).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jonsson, P., Wuolikainen, A., Thysell, E., Chorell, E., Stattin, P., Wikström, P., et al. (2015). Constrained randomization and multivariate effect projections improve information extraction and biomarker pattern discovery in metabolomics studies involving dependent samples. Metabolomics, 11(6), 1667–1678. doi:10.1007/s11306-015-0818-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jove, M., Portero-Otin, M., Naudi, A., Ferrer, I., & Pamplona, R. (2014). Metabolomics of human brain aging and age-related neurodegenerative diseases. Journal of Neuropathology and Experimental Neurology, 73(7), 640–657. doi:10.1097/NEN.0000000000000091.

    Article  CAS  PubMed  Google Scholar 

  • Jupin, M., Michiels, P. J., Girard, F. C., Spraul, M., & Wijmenga, S. S. (2013). NMR identification of endogenous metabolites interacting with fatted and non-fatted human serum albumin in blood plasma: fatty acids influence the HSA-metabolite interaction. J Mag Reson, 228, 81–94. (San Diego, Calif: 1997). doi:10.1016/j.jmr.2012.12.010.

    Article  CAS  Google Scholar 

  • Jupin, M., Michiels, P. J., Girard, F. C., Spraul, M., & Wijmenga, S. S. (2014). NMR metabolomics profiling of blood plasma mimics shows that medium- and long-chain fatty acids differently release metabolites from human serum albumin. J Mag Reson, 239, 34–43. (San Diego, Calif: 1997). doi:10.1016/j.jmr.2013.11.019.

    Article  CAS  Google Scholar 

  • Keun, H. C., Ebbels, T. M., Antti, H., Bollard, M. E., Beckonert, O., Schlotterbeck, G., et al. (2002). Analytical reproducibility in (1)H NMR-based metabonomic urinalysis. Chemical Research in Toxicology, 15(11), 1380–1386. doi:10.1021/tx0255774.

    Article  CAS  PubMed  Google Scholar 

  • Kiernan, M. C., Vucic, S., Cheah, B. C., Turner, M. R., Eisen, A., Hardiman, O., et al. (2011). Amyotrophic lateral sclerosis. Lancet, 377(9769), 942–955. doi:10.1016/S0140-6736(10)61156-7.

    Article  CAS  PubMed  Google Scholar 

  • Knowles, T. P. J., Vendruscolo, M., & Dobson, C. M. (2014). The amyloid state and its association with protein misfolding diseases. Nature Reviews Molecular Cell Biology, 15(6), 384–396. doi:10.1038/nrm3810.

    Article  CAS  PubMed  Google Scholar 

  • Kumar, A., Bala, L., Kalita, J., Misra, U. K., Singh, R. L., Khetrapal, C. L., et al. (2010). Metabolomic analysis of serum by (1) H NMR spectroscopy in amyotrophic lateral sclerosis. Clinica Chimica Acta, 411(7–8), 563–567. doi:10.1016/j.cca.2010.01.016.

    Article  CAS  Google Scholar 

  • Lakke, J. P., & Teelken, A. W. (1976). Amino acid abnormalities in cerebrospinal fluid of patients with parkinsonism and extrapyramidal disorders. Neurology, 26(5), 489–493.

    Article  CAS  PubMed  Google Scholar 

  • Lakke, J. P., Teelken, A. W., vd Voet, H., & Wolthers, B. (1987). Amino acid abnormalities in cerebrospinal fluid and blood serum of patients with Parkinson’s disease, other heredodegenerative disorders and head injuries. Advances in Neurology, 45, 243–247.

    CAS  PubMed  Google Scholar 

  • Lang, A. E., & Obeso, J. A. (2004). Challenges in Parkinson’s disease: restoration of the nigrostriatal dopamine system is not enough. Lancet Neurology, 3(5), 309–316. doi:10.1016/S1474-4422(04)00740-9.

    Article  PubMed  Google Scholar 

  • Lawton, K. A., Cudkowicz, M. E., Brown, M. V., Alexander, D., Caffrey, R., Wulff, J. E., et al. (2012). Biochemical alterations associated with ALS. Amyotroph Lateral Scler, 13(1), 110–118. doi:10.3109/17482968.2011.619197.

    Article  CAS  PubMed  Google Scholar 

  • Lawton, K. A., Brown, M. V., Alexander, D., Li, Z., Wulff, J. E., Lawson, R., et al. (2014). Plasma metabolomic biomarker panel to distinguish patients with amyotrophic lateral sclerosis from disease mimics. Amyotroph Lateral Scler Frontotemporal Degener, 15(5–6), 362–370. doi:10.3109/21678421.2014.908311.

    Article  CAS  PubMed  Google Scholar 

  • Lewitt, P. A., Li, J., Lu, M., Beach, T. G., Adler, C. H., Guo, L., et al. (2013). 3-hydroxykynurenine and other Parkinson’s disease biomarkers discovered by metabolomic analysis. Movement Disorders, 28(12), 1653–1660. doi:10.1002/mds.25555.

    Article  CAS  PubMed  Google Scholar 

  • Li, J. V., Ashrafian, H., Bueter, M., Kinross, J., Sands, C., le Roux, C. W., et al. (2011). Metabolic surgery profoundly influences gut microbial-host metabolic cross-talk. Gut, 60(9), 1214–1223. doi:10.1136/gut.2010.234708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin, M. T., & Beal, M. F. (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature, 443(7113), 787–795. doi:10.1038/nature05292.

    Article  CAS  PubMed  Google Scholar 

  • Lindon, J. C., Nicholson, J. K., Holmes, E., Antti, H., Bollard, M. E., Keun, H., et al. (2003). Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project. Toxicology and Applied Pharmacology, 187(3), 137–146. doi:10.1016/S0041-008X(02)00079-0.

    Article  CAS  PubMed  Google Scholar 

  • MacAllister, R. J., Parry, H., Kimoto, M., Ogawa, T., Russell, R. J., Hodson, H., et al. (1996). Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. British Journal of Pharmacology, 119(8), 1533–1540. doi:10.1111/j.1476-5381.1996.tb16069.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mally, J., Szalai, G., & Stone, T. W. (1997). Changes in the concentration of amino acids in serum and cerebrospinal fluid of patients with Parkinson’s disease. Journal of the Neurological Sciences, 151(2), 159–162. doi:10.1016/S0022-510X(97)00119-6.

    Article  CAS  PubMed  Google Scholar 

  • Mandal, R., Guo, A. C., Chaudhary, K. K., Liu, P., Yallou, F. S., Dong, E., et al. (2012). Multi-platform characterization of the human cerebrospinal fluid metabolome: a comprehensive and quantitative update. Genome Med, 4(4), 38. doi:10.1186/gm337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manuel, M., & Heckman, C. J. (2011). Stronger is not always better: could a bodybuilding dietary supplement lead to ALS? Experimental Neurology, 228(1), 5–8. doi:10.1016/j.expneurol.2010.12.007.

    Article  PubMed  PubMed Central  Google Scholar 

  • Menzies, F. M., Fleming, A., & Rubinsztein, D. C. (2015). Compromised autophagy and neurodegenerative diseases. Nature Reviews Neuroscience, 16(6), 345–357. doi:10.1038/nrn3961.

    Article  CAS  PubMed  Google Scholar 

  • Milewski K, Hilgier W, Albrecht J, Zielinska M (2014). The dimethylarginine (ADMA)/nitric oxide pathway in the brain and periphery of rats with thioacetamide-induced acute liver failure: modulation by histidine. http://www.ncbi.nlm.nih.gov/pubmed/25523831.

  • Molina, J. A., Jimenez-Jimenez, F. J., Gomez, P., Vargas, C., Navarro, J. A., Orti-Pareja, M., et al. (1997). Decreased cerebrospinal fluid levels of neutral and basic amino acids in patients with Parkinson’s disease. Journal of the Neurological Sciences, 150(2), 123–127. doi:10.1016/S0022-510X(97)00069-5.

    Article  CAS  PubMed  Google Scholar 

  • Nicholson, J. K., & Lindon, J. C. (2008). Systems biology: metabonomics. Nature, 455(7216), 1054–1056. doi:10.1038/4551054a.

    Article  CAS  PubMed  Google Scholar 

  • Nicholson, J. K., Foxall, P. J. D., Spraul, M., Farrant, R. D., & Lindon, J. C. (1995). 750-Mhz H-1 and H-1-C-13 Nmr-spectroscopy of human blood-plasma. Analytical Chemistry, 67(5), 793–811. doi:10.1021/ac00101a004.

    Article  CAS  PubMed  Google Scholar 

  • Öhman, A., & Forsgren, L. (2015). NMR metabonomics of cerebrospinal fluid distinguishes between Parkinson’s disease and controls. Neuroscience Letters, 594, 36–39. doi:10.1016/j.neulet.2015.03.051.

    Article  PubMed  Google Scholar 

  • Otto, M., Bowser, R., Turner, M., Berry, J., Brettschneider, J., Connor, J., et al. (2012). Roadmap and standard operating procedures for biobanking and discovery of neurochemical markers in ALS. Amyotroph Lateral Scler, 13(1), 1–10. doi:10.3109/17482968.2011.627589.

    Article  PubMed  Google Scholar 

  • Paillisse, C., Lacomblez, L., Dib, M., Bensimon, G., Garcia-Acosta, S., & Meininger, V. (2005). Prognostic factors for survival in amyotrophic lateral sclerosis patients treated with riluzole. Amyotroph Lateral Scler Other Motor Neuron Disord, 6(1), 37–44. doi:10.1080/14660820510027035.

    Article  CAS  PubMed  Google Scholar 

  • Paoli, A., Bianco, A., Damiani, E., & Bosco, G. (2014). Ketogenic diet in neuromuscular and neurodegenerative diseases. Biomed Res Int, 2014, 474296. doi:10.1155/2014/474296.

    Article  PubMed  PubMed Central  Google Scholar 

  • Polymenidou, M., & Cleveland, D. W. (2011). The seeds of neurodegeneration: prion-like spreading in ALS. Cell, 147(3), 498–508. doi:10.1016/j.cell.2011.10.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Psychogios, N., Hau, D. D., Peng, J., Guo, A. C., Mandal, R., Bouatra, S., et al. (2011). The human serum metabolome. PLoS ONE, 6(2), e16957. doi:10.1371/journal.pone.0016957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quinones, M. P., & Kaddurah-Daouk, R. (2009). Metabolomics tools for identifying biomarkers for neuropsychiatric diseases. Neurobiology of Diseases, 35(2), 165–176. doi:10.1016/j.nbd.2009.02.019.

    Article  CAS  Google Scholar 

  • Rajput, A. H., Rozdilsky, B., & Rajput, A. (1991). Accuracy of clinical diagnosis in parkinsonism—a prospective study. Canadian Journal of Neurological Sciences, 18(3), 275–278.

    CAS  PubMed  Google Scholar 

  • Romero, P., Wagg, J., Green, M. L., Kaiser, D., Krummenacker, M., & Karp, P. D. (2005). Computational prediction of human metabolic pathways from the complete human genome. Genome Biology, 6(1), R2. doi:10.1186/gb-2004-6-1-r2.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sharma, V., Ichikawa, M., & Freeze, H. H. (2014). Mannose metabolism: more than meets the eye. Biochem Biophys Res Commun, 453(2), 220–228. doi:10.1016/j.bbrc.2014.06.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shaw, P. J. (2005). Molecular and cellular pathways of neurodegeneration in motor neurone disease. J Neurol Neurosurg Psychiatr, 76(8), 1046–1057. doi:10.1136/jnnp.2004.048652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sinclair, A. J., Viant, M. R., Ball, A. K., Burdon, M. A., Walker, E. A., Stewart, P. M., et al. (2010). NMR-based metabolomic analysis of cerebrospinal fluid and serum in neurological diseases—a diagnostic tool? NMR in Biomedicine, 23(2), 123–132. doi:10.1002/nbm.1428.

    CAS  PubMed  Google Scholar 

  • Smolinska, A., Blanchet, L., Buydens, L. M., & Wijmenga, S. S. (2012a). NMR and pattern recognition methods in metabolomics: from data acquisition to biomarker discovery: a review. Analytica Chimica Acta, 750, 82–97. doi:10.1016/j.aca.2012.05.049.

    Article  CAS  PubMed  Google Scholar 

  • Smolinska, A., Posma, J. M., Blanchet, L., Ampt, K. A., Attali, A., Tuinstra, T., et al. (2012b). Simultaneous analysis of plasma and CSF by NMR and hierarchical models fusion. Analytical and Bioanalytical Chemistry, 403(4), 947–959. doi:10.1007/s00216-012-5871-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stoop, M. P., Coulier, L., Rosenling, T., Shi, S., Smolinska, A. M., Buydens, L., et al. (2010). Quantitative proteomics and metabolomics analysis of normal human cerebrospinal fluid samples. Mol Cell Proteom, 9(9), 2063–2075. doi:10.1074/mcp.M900877-MCP200.

    Article  CAS  Google Scholar 

  • Tachikawa, M., Kasai, Y., Takahashi, M., Fujinawa, J., Kitaichi, K., Terasaki, T., et al. (2008). The blood-cerebrospinal fluid barrier is a major pathway of cerebral creatinine clearance: involvement of transporter-mediated process. Journal of Neurochemistry, 107(2), 432–442. doi:10.1111/j.1471-4159.2008.05641.x.

    Article  CAS  PubMed  Google Scholar 

  • Tandan, R., & Bradley, W. G. (1985). Amyotrophic lateral sclerosis: part 1. Clinical features, pathology, and ethical issues in management. Ann Neurol, 18(3), 271–280. doi:10.1002/ana.410180302.

    Article  CAS  PubMed  Google Scholar 

  • Trupp, M., Jonsson, P., Ohrfelt, A., Zetterberg, H., Obudulu, O., Malm, L., et al. (2014). Metabolite and peptide levels in plasma and CSF differentiating healthy controls from patients with newly diagnosed Parkinson’s disease. J Parkinsons Dis, 4(3), 549–560. doi:10.3233/JPD-140389.

    CAS  PubMed  Google Scholar 

  • Trygg, J., & Wold, S. (2002). Orthogonal projections to latent structures (O-PLS). Journal of Chemometrics, 16(3), 119–128. doi:10.1002/cem.695.

    Article  CAS  Google Scholar 

  • Tsacopoulos, M., & Magistretti, P. J. (1996). Metabolic coupling between glia and neurons. Journal of Neuroscience, 16(3), 877–885.

    CAS  PubMed  Google Scholar 

  • Vallance, P., & Leiper, J. (2004). Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arteriosclerosis, Thrombosis, and Vascular Biology, 24(6), 1023–1030. doi:10.1161/01.ATV.0000128897.54893.26.

    Article  CAS  PubMed  Google Scholar 

  • Van Sande, M., Caers, J., & Lowenthal, A. (1971). Cerebrospinal fluid amino acids in extrapyramidal disorders before and after L-DOPA treatment. Z Neurol, 199(1), 24–29.

    PubMed  Google Scholar 

  • Wade, A. M., & Tucker, H. N. (1998). Antioxidant characteristics of l-histidine 11The work described in this manuscript was partially sponsored and funded by cytos pharmaceuticals, LLC. Journal of Nutritional Biochemistry, 9(6), 308–315. doi:10.1016/s0955-2863(98)00022-9.

    Article  CAS  Google Scholar 

  • Want, E. J., Wilson, I. D., Gika, H., Theodoridis, G., Plumb, R. S., Shockcor, J., et al. (2010). Global metabolic profiling procedures for urine using UPLC-MS. Nature Protocols, 5(6), 1005–1018. doi:10.1038/nprot.2010.50.

    Article  CAS  PubMed  Google Scholar 

  • Wishart, D. S., Lewis, M. J., Morrissey, J. A., Flegel, M. D., Jeroncic, K., Xiong, Y., et al. (2008). The human cerebrospinal fluid metabolome. J Chromatogr B Analyt Technol Biomed Life Sci, 871(2), 164–173. doi:10.1016/j.jchromb.2008.05.001.

    Article  CAS  PubMed  Google Scholar 

  • Wishart, D. S., Jewison, T., Guo, A. C., Wilson, M., Knox, C., Liu, Y., et al. (2013). HMDB 3.0—the human metabolome database in 2013. Nucleic Acids Research, 41, 801–807. doi:10.1093/nar/gks1065. (Database issue).

    Article  Google Scholar 

  • Wuolikainen, A., Moritz, T., Marklund, S. L., Antti, H., & Andersen, P. M. (2011). Disease-related changes in the cerebrospinal fluid metabolome in amyotrophic lateral sclerosis detected by GC/TOFMS. PLoS ONE, 6(4), e17947. doi:10.1371/journal.pone.0017947.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wuolikainen, A., Jonsson, P., Ahnlund, M., Antti, H., Marklund, S. L., Moritz, T., et al. (2016). Multi-platform mass spectrometry analysis of the CSF and plasma metabolomes of rigorously matched amyotrophic lateral sclerosis, Parkinson’s disease and control subjects. Molecular BioSystems, 12(4), 1287–1298. doi:10.1039/c5mb00711a.

    Article  CAS  PubMed  Google Scholar 

  • Wyss, M., & Kaddurah-Daouk, R. (2000). Creatine and creatinine metabolism. Physiological Reviews, 80(3), 1107–1213.

    CAS  PubMed  Google Scholar 

  • Xia, J., Mandal, R., Sinelnikov, I. V., Broadhurst, D., & Wishart, D. S. (2012). MetaboAnalyst 2.0—a comprehensive server for metabolomic data analysis. Nucleic Acids Research, 40(Web Server issue), W127–W133. doi:10.1093/nar/gks374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, A., Sun, H., Wang, P., Han, Y., & Wang, X. (2012). Recent and potential developments of biofluid analyses in metabolomics. J Proteomics, 75(4), 1079–1088. doi:10.1016/j.jprot.2011.10.027.

    Article  CAS  PubMed  Google Scholar 

  • Zhao, Z., Lange, D. J., Voustianiouk, A., MacGrogan, D., Ho, L., Suh, J., et al. (2006). A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis. BMC Neurosci, 7, 29. doi:10.1186/1471-2202-7-29.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We are indebted to the patients who contributed to this study. We are grateful to the Erling-Persson Family Foundation, the Kempe Foundation and Umeå University for support. Dr. Junfang Wu is grateful for a post-doctoral fellowship from the Kempe foundation. Dr. Anna Wuolikainen, Dr. Miles Trupp, Dr. Pär Jonsson and Dr. Anders Öhman are supported by grants from the Erling-Persson Family Foundation. Dr. Peter Andersen has received grants from the Swedish Research Council, the Knut and Alice Wallenberg Foundation, The Bertil Hållsten Brain Research Foundation, The Brain Research Foundation, Swedish Brain Power Consortium, The Ulla-Carin Lindquist Foundation and Neuroförbundet. Dr. Lars Forsgren has received grants from The Swedish Medical Research Council, The Swedish Parkinson Foundation, The Swedish Parkinson’s disease Association, Västerbotten County Council (ALF), and the King Gustaf V’s and Queen Victoria’s Freemason Foundation. Dr. Anders Öhman has received grants from the Parkinson Foundation in Sweden and Insamlingsstiftelsen at Umeå University.

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Authors and Affiliations

  1. Department of Chemistry, Umeå University, 901 87, Umeå, Sweden

    Junfang Wu, Anna Wuolikainen & Pär Jonsson

  2. Department of Pharmacology and Clinical Neuroscience, Umeå University, 901 85, Umeå, Sweden

    Junfang Wu, Miles Trupp, Peter M. Andersen, Lars Forsgren & Anders Öhman

  3. Department of Medical Biosciences, Umeå University, 901 85, Umeå, Sweden

    Stefan L. Marklund

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  1. Junfang Wu
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  2. Anna Wuolikainen
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  3. Miles Trupp
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  4. Pär Jonsson
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  5. Stefan L. Marklund
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  6. Peter M. Andersen
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  7. Lars Forsgren
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  8. Anders Öhman
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Corresponding author

Correspondence to Anders Öhman.

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The authors report no conflicts of interest related to this study.

Ethical approval

This study was carried out in accordance with the Declaration of Helsinki (WMA 1964), with ethical approval from the Medical Ethical Review Board for northern Sweden, Umeå, Sweden.

Informed consent

Written informed consent was obtained from all subjects.

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Wu, J., Wuolikainen, A., Trupp, M. et al. NMR analysis of the CSF and plasma metabolome of rigorously matched amyotrophic lateral sclerosis, Parkinson’s disease and control subjects. Metabolomics 12, 101 (2016). https://doi.org/10.1007/s11306-016-1041-6

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