Amino Acid Metabolism in Multiple Sclerosis: Analyzing Plasma and Cerebrospinal Fluid Profiles for Biomarker Discovery and Pathophysiological Insights

Sümeyra Kaplan; Burhanettin Çiğdem; Şeyda Figül Gökçe; Hayrettin Yavuz; Halef Okan Dogan

doi:10.17776/csj.1790961

Amino Acid Metabolism in Multiple Sclerosis: Analyzing Plasma and Cerebrospinal Fluid Profiles for Biomarker Discovery and Pathophysiological Insights

Abstract

Multiple sclerosis (MS) is a neuroinflammatory disease associated with involving metabolic disruptions. Although amino acid metabolism is linked to MS pathophysiology, its role remains unclear. This study investigates alterations in amino acid profiles to identify potential biomarkers for MS. Plasma and cerebrospinal fluid (CSF) samples were collected from MS patients and individuals with pseudotumor cerebri (PTC) as controls. Amino acid concentrations were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Compared to controls, MS patients exhibited lower plasma tyrosine levels and higher CSF hydroxylysine and ornithine levels. CSF 3-aminoisobutyric acid and valine correlated positively with lymphocyte/monocyte counts, while CSF β-alanine exhibited inverse correlations. Additionally, CSF β-alanine, homocitrulline, and citrulline were associated with CSF protein levels. Expanded Disability Status Scale (EDSS) scores were associated with plasma isoleucine, methionine, citrulline, and threonine—no CSF amino acids correlated with EDSS. Pathway analysis identified significant disruptions in phenylalanine-tyrosine-tryptophan biosynthesis, arginine biosynthesis, and ubiquinone pathway. Altered amino acid metabolism plays a critical role in MS pathogenesis. The observed correlations between immune cell counts and specific amino acids highlight their involvement in immune activation and neuroinflammation, suggesting that targeting specific molecular networks may offer therapeutic potential

Keywords

References

[1] Filippi, M., Bar-Or, A., Piehl, F., Preziosa, P., Solari, A., Vukusic, S., & Rocca, M. A. (2018). Multiple sclerosis. Nature Reviews Disease Primers, 4(1), 43. https://doi.org/10.1038/s41572-018-0041-4
[2] Dendrou, C. A., Fugger, L., & Friese, M. A. (2015). Immunopathology of multiple sclerosis. Nature Reviews Immunology, 15(9), 545–558. https://doi.org/10.1038/nri3871
[3] Li, R., Patterson, K. R., & Bar-Or, A. (2018). Reassessing B cell contributions in multiple sclerosis. Nature Immunology, 19(7), 696–707. https://doi.org/10.1038/s41590-018-0135-x
[4] Coles, A. J., & Compston, D. A. S. (2001). Multiple sclerosis: Ethics, outcome variables and clinical scales. In R. J. Guiloff (Ed.), Clinical trials in neurology (pp. 415–424). Springer. https://doi.org/10.1007/978-1-4471-3787-0_30
[5] Bhargava, P., & Anthony, D. C. (2020). Metabolomics in multiple sclerosis disease course and progression. Multiple Sclerosis Journal, 26(5), 591–598. https://doi.org/10.1177/1352458519876020
[6] Bhargava, P., & Calabresi, P. A. (2016). Metabolomics in multiple sclerosis. Multiple Sclerosis Journal, 22(4), 451–460. https://doi.org/10.1177/1352458515622827
[7] Amorini, A. M., Petzold, A., Tavazzi, B., Eikelenboom, J., Keir, G., Belli, A., Giovannoni, G., Di Pietro, V., Polman, C., D'Urso, S., Vagnozzi, R., Uitdehaag, B., & Lazzarino, G. (2009). Increase of uric acid and purine compounds in biological fluids of multiple sclerosis patients. Clinical Biochemistry, 42(10-11), 1001–1006. https://doi.org/10.1016/j.clinbiochem.2009.03.020
[8] Wu, G. (2013). Functional amino acids in nutrition and health. Amino Acids, 45, 407–411. https://doi.org/10.1007/s00726-013-1500-6

[9] Pashaei, S., Yarani, R., Mohammadi, P., & Aleagha, M. S. E. (2022). The potential roles of amino acids and their major derivatives in the management of multiple sclerosis. Amino Acids, 54(6), 841–858. https://doi.org/10.1007/s00726-022-03162-4
[10] Židó, M., Kačer, D., Valeš, K., Zimová, D., & Štětkářová, I. (2023). Metabolomics of cerebrospinal fluid amino and fatty acids in early stages of multiple sclerosis. International Journal of Molecular Sciences, 24(22), 16271. https://doi.org/10.3390/ijms242216271
[11] Fitzgerald, K. C., Smith, M. D., Kim, S., Sotirchos, E. S., Kornberg, M. D., Douglas, M., Nourbakhsh, B., Graves, J., Rattan, R., Poisson, L., Cerghet, M., Mowry, E. M., Waubant, E., Giri, S., Calabresi, P. A., & Bhargava, P. (2021). Multi-omic evaluation of metabolic alterations in multiple sclerosis identifies shifts in aromatic amino acid metabolism. Cell Reports Medicine, 2(10), 100424. https://doi.org/10.1016/j.xcrm.2021.100424
[12] Adamczyk, B., & Adamczyk-Sowa, M. (2016). New insights into the role of oxidative stress mechanisms in the pathophysiology and treatment of multiple sclerosis. Oxidative Medicine and Cellular Longevity, 2016, 1973834. https://doi.org/10.1155/2016/1973834
[13] Cocco, E., Murgia, F., Lorefice, L., Barberini, L., Poddighe, S., Frau, J., Fenu, G., Coghe, G., Murru, M. R., Murru, R., Carratore, F. D., Atzori, L., & Marrosu, M. G. (2015). (1)H-NMR analysis provides a metabolomic profile of patients with multiple sclerosis. Neuroimmunology & Neuroinflammation, 2(3), e185. https://doi.org/10.1212/NXI.0000000000000185
[14] Gebregiworgis, T., Nielsen, H. H., Massilamany, C., Gangaplara, A., Reddy, J., Illes, Z., & Powers, R. (2016). A urinary metabolic signature for multiple sclerosis and neuromyelitis optica. Journal of Proteome Research, 15(2), 659–666. https://doi.org/10.1021/acs.jproteome.5b01111
[15] Noga, M. J., Dane, A., Shi, S., Attali, A., Aken, H., Suidgeest, E., Tuinstra, T., Muilwijk, B., Coulier, L., Luider, T., Reijmers, T. H., Vreeken, R. J., & Hankemeier, T. (2012). Metabolomics of cerebrospinal fluid reveals changes in the central nervous system metabolism in a rat model of multiple sclerosis. Metabolomics, 8(2), 253–263. https://doi.org/10.1007/s11306-011-0306-3
[16] Kasakin, M. F., Rogachev, A. D., Predtechenskaya, E. V., Zaigraev, V. J., Koval, V. V., & Pokrovsky, A. G. (2020). Changes in amino acid and acylcarnitine plasma profiles for distinguishing patients with multiple sclerosis from healthy controls. Multiple Sclerosis International, 2020, 9010937. https://doi.org/10.1155/2020/9010937
[17] Rajda, C., Galla, Z., Polyák, H., Maróti, Z., Babarczy, K., Pukoli, D., & Vécsei, L. (2020). Cerebrospinal fluid neurofilament light chain is associated with kynurenine pathway metabolite changes in multiple sclerosis. International Journal of Molecular Sciences, 21(8), 2665. https://doi.org/10.3390/ijms21082665
[18] Bagheri, S., Haddadi, R., Saki, S., Kourosh-Arami, M., Rashno, M., Mojaver, A., & Komaki, A. (2023). Neuroprotective effects of coenzyme Q10 on neurological diseases: A review article. Frontiers in Neuroscience, 17, 1188839. https://doi.org/10.3389/fnins.2023.1188839
[19] Khalilian, B., Madadi, S., Fattahi, N., & Abouhamzeh, B. (2021). Coenzyme Q10 enhances remyelination and regulate inflammation effects of cuprizone in corpus callosum of chronic model of multiple sclerosis. Journal of Molecular Histology, 52(1), 125–134. https://doi.org/10.1007/s10735-020-09929-x
[20] Moccia, M., Capacchione, A., Lanzillo, R., Carbone, F., Micillo, T., Matarese, G., Palladino, R., & Morra, B. V. (2019). Sample size for oxidative stress and inflammation when treating multiple sclerosis with interferon-β1a and coenzyme Q10. Brain Sciences, 9(10), 259. https://doi.org/10.3390/brainsci9100259
[21] Sanoobar, M., Dehghan, P., Khalili, M., Azimi, A., & Seifar, F. (2016). Coenzyme Q10 as a treatment for fatigue and depression in multiple sclerosis patients: A double blind randomized clinical trial. Nutritional Neuroscience, 19(3), 138–143. https://doi.org/10.1179/1476830515Y.0000000002
[22] Stefely, J. A., & Pagliarini, D. J. (2017). Biochemistry of mitochondrial coenzyme Q biosynthesis. Trends in Biochemical Sciences, 42(10), 824–843. https://doi.org/10.1016/j.tibs.2017.06.008
[23] Murgia, F., Lorefice, L., Poddighe, S., Fenu, G., Secci, M. A., Marrosu, M. G., Cocco, E., & Atzori, L. (2020). Multi-platform characterization of cerebrospinal fluid and serum metabolome of patients affected by relapsing–remitting and primary progressive multiple sclerosis. Journal of Clinical Medicine, 9(3), 863. https://doi.org/10.3390/jcm9030863
[24] Poddighe, S., Murgia, F., Lorefice, L., Liggi, S., Cocco, E., Marrosu, M. G., & Atzori, L. (2017). Metabolomic analysis identifies altered metabolic pathways in Multiple Sclerosis. The International Journal of Biochemistry & Cell Biology, 93, 148–155. https://doi.org/10.1016/j.biocel.2017.07.004
[25] Onmaz, D. E., Isık, S. M. T., Abusoglu, S., Ekmekci, A. H., Sivrikaya, A., Abusoglu, G., Ozturk, S., Aydemir, H. Y., & Unlu, A. (2021). Serum ADMA levels were positively correlated with EDSS scores in patients with multiple sclerosis. Journal of Neuroimmunology, 353, 577497. https://doi.org/10.1016/j.jneuroim.2021.577497
[26] Ljubisavljevic, S., Stojanovic, I., Pavlovic, R., Sokolovic, D., Pavlovic, D., Cvetkovic, T., & Stevanovic, I. (2012). Modulation of nitric oxide synthase by arginase and methylated arginines during the acute phase of experimental multiple sclerosis. Journal of the Neurological Sciences, 318(1-2), 106–111. https://doi.org/10.1016/j.jns.2012.03.015
[27] Sisalli, M. J., Notte, S. D., Secondo, A., Ventra, C., Annunziato, L., & Scorziello, A. (2022). L-ornithine L-aspartate restores mitochondrial function and modulates intracellular calcium homeostasis in Parkinson’s disease models. Cells, 11(18), 2909. https://doi.org/10.3390/cells11182909
[28] Ortiz, G. G., Pacheco-Moisés, F. P., Macías-Islas, M. Á., Flores-Alvarado, L. J., Mireles-Ramírez, M. A., González-Renovato, E. D., Hernández-Navarro, V. E., Sánchez-López, A. L., & Alatorre-Jiménez, M. A. (2014). Role of the blood–brain barrier in multiple sclerosis. Archives of Medical Research, 45(8), 687–697. https://doi.org/10.1016/j.arcmed.2014.11.013
[29] Fischer, M. T., Sharma, R., Lim, J. L., Haider, L., Frischer, J. M., Drexhage, J., Mahad, D., Bradl, M., Horssen, J., & Lassmann, H. (2012). NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain, 135(3), 886–899. https://doi.org/10.1093/brain/aws012
[30] Luissint, A. C., Artus, C., Glacial, F., Ganeshamoorthy, K., & Couraud, P. O. (2012). Tight junctions at the blood brain barrier: Physiological architecture and disease-associated dysregulation. Fluids and Barriers of the CNS, 9(1), 23. https://doi.org/10.1186/2045-8118-9-23
[31] Murakami, T., & Furuse, M. (2010). The impact of taurine-and beta-alanine-supplemented diets on behavioral and neurochemical parameters in mice: Antidepressant versus anxiolytic-like effects. Amino Acids, 39(2), 427–434. https://doi.org/10.1007/s00726-009-0458-x
[32] Wang, C., Peng, Y., Zhang, Y., Xu, J., Jiang, S., Wang, L., & Yin, Y. (2023). The biological functions and metabolic pathways of valine in swine. Journal of Animal Science and Biotechnology, 14(1), 135. https://doi.org/10.1186/s40104-023-00927-z
[33] Liaqat, U., Ditta, Y., Naveed, S., King, A., Pasha, T., Ullah, S., & Majeed, K. A. (2022). Effects of L-valine in layer diets containing 0.72% isoleucine. PLoS ONE, 17(4), e0258250. https://doi.org/10.1371/journal.pone.0258250
[34] Vignoli, A., Paciotti, S., Tenori, L., Eusebi, P., Biscetti, L., Chiasserini, D., Scheltens, P., Turano, P., Teunissen, C., & Luchinat, C. (2020). Fingerprinting Alzheimer’s disease by 1H nuclear magnetic resonance spectroscopy of cerebrospinal fluid. Journal of Proteome Research, 19(4), 1696–1705. https://doi.org/10.1021/acs.jproteome.9b00850
[35] Xiong, Y. I., Therriault, J., Ren, S. J., Jing, X. J., Zhang, H., & Alzheimer's Disease Neuroimaging Initiative. (2022). The associations of serum valine with mild cognitive impairment and Alzheimer’s disease. Aging Clinical and Experimental Research, 34(8), 1807–1817. https://doi.org/10.1007/s40520-022-02120-0
[36] Lorefice, L., Murgia, F., Fenu, G., Frau, J., Coghe, G., Murru, M. R., Tranquilli, S., Visconti, A., Marrosu, M. G., Atzori, L., & Cocco, E. (2019). Assessing the metabolomic profile of multiple sclerosis patients treated with interferon beta 1a by 1H-NMR spectroscopy. Neurotherapeutics, 16(3), 797–807. https://doi.org/10.1007/s13311-019-00721-8
[37] Pukoli, D., & Vécsei, L. (2025). Kynurenines and mitochondrial disturbances in multiple sclerosis. International Journal of Molecular Sciences, 26(11), 5098. https://doi.org/10.3390/ijms26115098
[38] Tremlett, H., & Waubant, E. (2018). The gut microbiota and pediatric multiple sclerosis: Recent findings. Neurotherapeutics, 15(1), 102–108. https://doi.org/10.1007/s13311-017-0574-3
[39] Ferreira, B., Mendes, F., Osorio, N., Caseiro, A., Gabriel, A., & Valado, A. (2013). Glutathione in multiple sclerosis. British Journal of Biomedical Science, 70(2), 75–79. https://doi.org/10.1080/09674845.2013.11669939

Details

Primary Language

English

Subjects

Medical Biochemistry and Metabolomics (Other)

Journal Section

Research Article

Authors

Sümeyra Kaplan
0000-0002-6470-8783
Türkiye

Burhanettin Çiğdem ^*
0000-0003-4941-9497
Türkiye

Şeyda Figül Gökçe
0000-0002-2719-0428
Türkiye

Hayrettin Yavuz
0000-0001-5190-7022
United States

Halef Okan Dogan
0000-0001-8738-0760
Türkiye

Publication Date

February 27, 2026

Submission Date

September 25, 2025

Acceptance Date

February 3, 2026

Published in Issue

Year 2026 Volume: 47 Number: 1

DOI

https://doi.org/10.17776/csj.1790961

IZ

https://izlik.org/JA66MS73TA

Cite

RIS / Bibtex

APA

Kaplan, S., Çiğdem, B., Gökçe, Ş. F., Yavuz, H., & Dogan, H. O. (2026). Amino Acid Metabolism in Multiple Sclerosis: Analyzing Plasma and Cerebrospinal Fluid Profiles for Biomarker Discovery and Pathophysiological Insights. Cumhuriyet Science Journal, 47(1), 44-54. https://doi.org/10.17776/csj.1790961