BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) leading to the loss of myelin and axons. Diagnosis is based on clinical findings, MRI, and analysis of cerebrospinal fluid (CSF). CSF is an ultrafiltrate of plasma and reflects inflammatory processes in the CNS. The aim of this study was to perform metabolomics analysis of CSF in patients after the first attack of MS and healthy controls and try to find new specific analytes for MS including those potentially predicting disease activities at the onset. METHODS: We collected CSF from 19 patients (16 females, aged 19-55 years) after the first attack of clinical symptoms who fulfilled revised McDonald criteria of MS and CSF of 19 controls (16 females, aged 19-50 years). Analyses of CSF samples were provided using the high-performance liquid chromatography system coupled with a mass spectrometer with a high-resolution detector (TripleTOF 5600, AB Sciex, Canada). RESULTS: Approximately 130 selected analytes were identified, and 30 of them were verified. During the targeted analysis, a significant decrease in arginine and histidine and a less significant decrease in the levels of asparagine, leucine/isoleucine, and tryptophan, together with a significant increase of palmitic acid in the patient group, were found. CONCLUSION: We observed significant differences in amino and fatty acids in the CSF of newly diagnosed patients with MS in comparison with controls. The most significant changes were observed in levels of arginine, histidine, and palmitic acid that may predict inflammatory disease activity. Further studies are necessary to support these findings as potential biomarkers of MS.

Department of Neurology 3rd Faculty of Medicine Charles University Prague Czechia

Department of Neurology Faculty Hospital Královské Vinohrady Prague Czechia

Institute of Physiology Academy of Sciences of the Czech Republic Prague Czechia

National Institute of Mental Health Klecany Czechia

Zobrazit více v PubMed

Weiner HL. Multiple sclerosis is an inflammatory T-cell-mediated autoimmune disease. Arch Neurol. (2004) 61:1613–5. 10.1001/archneur.61.10.1613 PubMed DOI

Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis. N Engl J Med. (2018) 378:169–80. 10.1056/NEJMra1401483 PubMed DOI PMC

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. (1983) 33:1444–52. 10.1212/WNL.33.11.1444 PubMed DOI

Hauser SL, Chan JR, Oksenberg JR. Multiple sclerosis: prospects and promise: multiple sclerosis. Ann Neurol. (2013) 74:317–27. 10.1002/ana.24009 PubMed DOI

Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. . Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. (2018) 17:162–73. 10.1016/S1474-4422(17)30470-2 PubMed DOI

Sylvestre DA, Slupsky CM, Aviv RI, Swardfager W, Taha AY. Untargeted metabolomic analysis of plasma from relapsing-remitting multiple sclerosis patients reveals changes in metabolites associated with structural changes in brain. Brain Res. (2020) 1732:146589. 10.1016/j.brainres.2019.146589 PubMed DOI

Park SJ, Jeong IH, Kong BS, Lee J-E, Kim KH, Lee DY, et al. . Disease type- and status-specific alteration of CSF metabolome coordinated with clinical parameters in inflammatory demyelinating diseases of CNS. PLoS ONE. (2016) 11:e0166277. 10.1371/journal.pone.0166277 PubMed DOI PMC

Kasakin MF, Rogachev AD, Predtechenskaya EV, Zaigraev VJ, Koval VV, Pokrovsky AG. Targeted metabolomics approach for identification of relapsing-remitting multiple sclerosis markers and evaluation of diagnostic models. Medchemcomm. (2019) 10:1803–9. 10.1039/C9MD00253G PubMed DOI PMC

Reinke SN, Broadhurst DL, Sykes BD, Baker GB, Catz I, Warren KG, et al. . Metabolomic profiling in multiple sclerosis: insights into biomarkers and pathogenesis. Mult Scler. (2014) 20:1396–400. 10.1177/1352458513516528 PubMed DOI

Fitzgerald KC, Smith MD, Kim S, Sotirchos ES, Kornberg MD, Douglas M, et al. . Multi-omic evaluation of metabolic alterations in multiple sclerosis identifies shifts in aromatic amino acid metabolism. Cell Rep Med. (2021) 2:100424. 10.1016/j.xcrm.2021.100424 PubMed DOI PMC

Nogueras L, Gonzalo H, Jové M, Sol J, Gil-Sanchez A, Hervás JV, et al. . Lipid profile of cerebrospinal fluid in multiple sclerosis patients: a potential tool for diagnosis. Sci Rep. (2019) 9:11313. 10.1038/s41598-019-47906-x PubMed DOI PMC

Gonzalo H, Brieva L, Tatzber F, Jové M, Cacabelos D, Cassanyé A, et al. . Lipidome analysis in multiple sclerosis reveals protein lipoxidative damage as a potential pathogenic mechanism. J Neurochem. (2012) 123:622–34. 10.1111/j.1471-4159.2012.07934.x PubMed DOI

Oliveira EML de, Montani DA, Oliveira-Silva D, Rodrigues-Oliveira AF, Matas SL de A, Fernandes GBP, et al. . Multiple sclerosis has a distinct lipid signature in plasma and cerebrospinal fluid. Arq Neuropsiquiatr. (2019) 77:696–704. 10.1590/0004-282x20190122 PubMed DOI

Pieragostino D, D'Alessandro M, di Ioia M, Rossi C, Zucchelli M, Urbani A, et al. . An integrated metabolomics approach for the research of new cerebrospinal fluid biomarkers of multiple sclerosis. Mol Biosyst. (2015) 11:1563–72. 10.1039/C4MB00700J PubMed DOI

Sinclair AJ, Viant MR, Ball AK, Burdon MA, Walker EA, Stewart PM, et al. . NMR-based metabolomic analysis of cerebrospinal fluid and serum in neurological diseases - a diagnostic tool? NMR Biomed. (2009) 23:123–32. 10.1002/nbm.1428 PubMed DOI

Sarchielli P, Greco L, Floridi A, Floridi A, Gallai V. Excitatory amino acids and multiple sclerosis: evidence from cerebrospinal fluid: evidence from cerebrospinal fluid. Arch Neurol. (2003) 60:1082–8. 10.1001/archneur.60.8.1082 PubMed DOI

Poddighe S, Murgia F, Lorefice L, Liggi S, Cocco E, Marrosu MG, et al. . Metabolomic analysis identifies altered metabolic pathways in multiple sclerosis. Int J Biochem Cell Biol. (2017) 93:148–55. 10.1016/j.biocel.2017.07.004 PubMed DOI

Srinivasan R, Sailasuta N, Hurd R, Nelson S, Pelletier D. Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T. Brain. (2005) 128:1016–25. 10.1093/brain/awh467 PubMed DOI

Cocco E, Murgia F, Lorefice L, Barberini L, Poddighe S, Frau J, et al. . H-NMR analysis provides a metabolomic profile of patients with multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. (2016) 3:e185. 10.1212/NXI.0000000000000185 PubMed DOI PMC

Podlecka-Pietowska A, Kacka A, Zakrzewska-Pniewska B, Nojszewska M, Zieminska E, Chalimoniuk M, et al. . Altered cerebrospinal fluid concentrations of hydrophobic and hydrophilic compounds in early stages of multiple sclerosis-metabolic profile analyses. J Mol Neurosci. (2019) 69:94–105. 10.1007/s12031-019-01336-6 PubMed DOI PMC

Teunissen C, Menge T, Altintas A, Álvarez-Cermeño JC, Bertolotto A, Berven FS, et al. . Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis. Mult Scler. (2013) 19:1802–9. 10.1177/1352458513488232 PubMed DOI

Levi I, Gurevich M, Perlman G, Magalashvili D, Menascu S, Bar N, et al. . Potential role of indolelactate and butyrate in multiple sclerosis revealed by integrated microbiome-metabolome analysis. Cell Rep Med. (2021) 2:100246. 10.1016/j.xcrm.2021.100246 PubMed DOI PMC

Li P, Yin Y-L, Li D, Woo Kim S, Wu G. Amino acids and immune function. Br J Nutr. (2007) 98:237–52. 10.1017/S000711450769936X PubMed DOI

Smith KJ, Lassmann H. The role of nitric oxide in multiple sclerosis. Lancet Neurol. (2002) 1:232–41. 10.1016/S1474-4422(02)00102-3 PubMed DOI

Koprowski H, Zheng YM, Heber-Katz E, Fraser N, Rorke L, Fu ZF, et al. . In vivo expression of inducible nitric oxide synthase in experimentally induced neurologic diseases. Proc Natl Acad Sci USA. (1993) 90:3024–7. 10.1073/pnas.90.7.3024 PubMed DOI PMC

Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: structure, function and inhibition. Biochem J. (2001) 357:593. 10.1042/bj3570593 PubMed DOI PMC

Encinas JM, Manganas L, Enikolopov G. Nitric oxide and multiple sclerosis. Curr Neurol Neurosci Rep. (2005) 5:232–8. 10.1007/s11910-005-0051-y PubMed DOI

Jadidi-Niaragh F, Mirshafiey A. Histamine and histamine receptors in pathogenesis and treatment of multiple sclerosis. Neuropharmacology. (2010) 59:180–9. 10.1016/j.neuropharm.2010.05.005 PubMed DOI

Molnár G, Moldován J. Histamine content of the cerebrospinal fluid in multiple sclerosis. A preliminary communication. Acta Med Acad Sci Hung. (1966) 22:271–4. PubMed

Tuomisto L, Kilpeläinen H, Riekkinen P. Histamine and histamine-N-methyltransferase in the CSF of patients with multiple sclerosis. Agents Actions. (1983) 13:255–7. 10.1007/BF01967346 PubMed DOI

Kallweit U, Aritake K, Bassetti CL, Blumenthal S, Hayaishi O, Linnebank M, et al. . Elevated CSF histamine levels in multiple sclerosis patients. Fluids Barriers CNS. (2013) 10:19. 10.1186/2045-8118-10-19 PubMed DOI PMC

Hinzman JM, Thomas TC, Burmeister JJ, Quintero JE, Huettl P, Pomerleau F, et al. . Diffuse brain injury elevates tonic glutamate levels and potassium-evoked glutamate release in discrete brain regions at two days post-injury: an enzyme-based microelectrode array study. J Neurotrauma. (2010) 27:889–99. 10.1089/neu.2009.1238 PubMed DOI PMC

Andersen SL, Briggs FBS, Winnike JH, Natanzon Y, Maichle S, Knagge KJ, et al. . Metabolome-based signature of disease pathology in MS. Mult Scler Relat Disord. (2019) 31:12–21. 10.1016/j.msard.2019.03.006 PubMed DOI PMC

Morell P, Quarles RH. The Myelin Sheath. Philadelphia, PA: Lippincott-Raven; (1999).

Metabolomics of Cerebrospinal Fluid Amino and Fatty Acids in Early Stages of Multiple Sclerosis