Metabolomika cerebrospinálneho likvoru pomocou magnetickej rezonančnej spektroskopie u pacientov so sclerosis multiplex, s klinicky izolovaným syndrómom, inými zápalovými ochoreniami mozgu a u zdravých kontrol

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Autoři: E. Baranovičová ¹; D. Čierny ²; P. Hnilicova ¹; J. Lehotský ^1,3; R. Murín ³; Š. Sivák ⁴; E. Kurča ⁴; L. Plicová ²; E. Kantorová ⁴
Působiště autorů: BioMedical Center BioMed, Division, of Neurosciences, Jessenius Faculty, of Medicine, Comenius University in, Bratislava, Martin, Slovakia ¹; Department of Clinical Biochemistry, Jessenius Faculty of Medicine, Comenius University in Bratislava and, University Hospital Martin, Slovakia ²; Department of Medical Biochemistry, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia ³; Clinic of Neurology, Jessenius Faculty, of Medicine, Comenius University, in Bratislava and University Hospital, Martin, Slovakia ⁴
Vyšlo v časopise: Cesk Slov Neurol N 2020; 83/116(3): 315-322
Kategorie: Původní práce
doi: https://doi.org/10.14735/amcsnn2020315

Souhrn

Cieľ: Včasné rozpoznanie sclerosis multiplex (SM) pomáha začať liečbu pacientov skôr, a tak oddialiť progresiu ochorenia. Urobili sme analýzu metabolitov cerebro-spinálneho likvoru (cerebrospinal fluid; CSF), s cieľom zistiť prediktory včas, a tak oddialiť SM.

Metódy: Do štúdie bolo zaradených 56 jedincov s podozrením na SM, pred začatím akejkoľvek liečby. Z nich bolo 28 diagnostikovaných ako definitívna SM, u 17 pacientov sme zistili klinicky izolovaný syndróm (clinically isolated syndrome; CIS) podľa McDonaldových kritérií z roku 2010, v 11 prípadoch sa jednalo o iné demyelinizačné ochorenie CNS (DEM). Kontrolnú skupinu (CON) tvorili 29 jedinci, ktorí nemali dokázané žiadne ochorenie CNS. Na meranie metabolitov CSF bola použitá protonová nukleárna magnetická rezonančná spektroskopia.

Výsledky: Glutamín, ktorý koreloval s Expanded Disability Status Scale (EDSS), bol jediným metabolitom, ktorý dokázal odlíšiť CIS, SM, DEM a CON. Valín, leucín, isoleucín, znížené u CIS a SM v porovnaní s CON, sa neodlišovali od DEM. Hladiny citrátu v CSF špecifikovali SM a CIS oproti DEM, ale nepomohli v rozlíšení CIS a SM. Citrát ukazoval signifikantné korelácie s vekom, dľžkou trvania ochorenia a EDSS u SM pacientov. Acetát, aceton, pyruvát, formát, histidin v CSF neboli signifikantnými prediktormi SM alebo CIS, hoci korelovali s niektorými vybranými premennými.

Záver: Táto práca ukazuje prediktívnu úlohu glutamínu v CSF v stanovení diagnózy SM od jej včasných štádií, vypichujúc tak dôležitú úlohu glutamát/glutamínového cyklu v patogenéze SM. Ďalší potenciálny prediktor SM bol citrát. Ďalšie metabolity neboli identifikované ako senzitívne CSF markery SM.

Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do biomedicínských časopisů.

Klíčová slova:

cerebro-spinálny likvor – metabolomika – jednoprotonová nukleárna magnetická rezonančná spektroskopia (1H-NMRS) – sclerosis multiplex – klinicky izolovaný syndrom – zápalové demyelizačné ochorenia mozgu

Zdroje

1. Levin MC, Douglas JN, Meyers L et al. Neurodegeneration in multiple sclerosis involves multiple pathogenic mechanisms. Degener Neurol Neuromuscul Dis 2014: 4; 49–63. doi: 10.2147/DNND.S54391.

2. Štourač P. Imunologická léčba roztroušené sklerózy mozkomíšní v klinických a zobrazovacích parametrech. Cesk Slov Neurol N 2012; 75/108 (4): 404–410.

3. Polman CH, Reingold SC, Banwell B et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69 (2): 292–302. doi: 10.1002/ana.22366.

4. Deisenhammer F, Zetterberg H, Fitzner B et al. The cerebrospinal fluid in multiple sclerosis. Front Immunol 2019; 10: 726. doi: 10.3389/fimmu.2019.00726.

5. Hnilicová P, Kantorová E, Poláček H et al. Altered hypothalamic metabolism in early multiple sclerosis – MR spectroscopy study. J Neurol Sci 2019; 407: 116458. doi: 10.1016/j.jns.2019.116458.

6. Sladkova V, Mareš J, Lubenova B et al. Degenerative and inflammatory markers in the cerebrospinal fluid of multiple sclerosis patients with relapsing-remitting course of disease and after clinical isolated syndrome. Neurol Res 2011 33 (4): 415–420. doi: 10.1179/016164110X12816242542535.

7. Lutz NW, Viola A, Malikova I et al. Inflammatory multiple sclerosis plaques generate characteristic metabolic profiles in cerebrospinal fluid. PLos One 2007; 2 (7): e595. doi: 10.1371/journal.pone.0000595.

8. French CD, Wiloughby RE, Wong Sj et al. NMR metabolomics of cerebrospinal fluid differentiates inflammatory diseases of the central nervous system. PLOS Negl Trop Dis 2018; 12 (12): e0007045. doi: 10.1371/journal.pntd.0007045.

9. Kim HH, Jeong IH, Hyun JS et al. Metabolomic profiling of CSF in multiple sclerosis and neuromyelitis optica spectrum disorder by nuclear magnetic resonance. PLoS One 2017; 12 (7): e0181758. doi: 10.1371/journal.pone.0181758.

10. Aasly J, Garseth M, Sonnewald U et al. Cerebrospinal fluid lactate and glutamine are reduced in multiple sclerosis. Acta Neurol Scand 1997; 95 (1): 9–12. doi: 10.1111/j.1600-0404.1997.tb00060.x.

11. Herman S, Åkerfeldt T, Spjuth O et al. Biochemical differences in cerebrospinal fluid between secondary progressive and relapsing-remitting multiple sclerosis. Cells 2019; 8 (2): 84. doi: 10.3390/cells8020084.

12. Cruz T, Balayssac S, Gilard V et al. 1H NMR Analysis of cerebrospinal fluid from Alzheimer’s disease patients: an example of a possible misinterpretation due to non- adjustment of pH. Metabolites 2014; 4 (1): 114–128. doi: 10.3390/metabo4010115.

13. Lutz NW, Cozzone PJ. Metabolomic profiling in multiple sclerosis and other disorders by quantitative analysis of cerebrospinal fluid using nuclear magnetic resonance spectroscopy. Curr Pharm Biotechnol 2011; 12 (7): 1016–1025. doi: 10.2174/138920111795909122.

14. Barkhof F, Filippi M, Miller D et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997; 120 (Pt 11): 2059–2069. doi: 10.1093/brain/120.11.2059.

15. Albrecht J, Sonnewald U, Waagepetersen HS et al. Glutamine in the central nervous system: function and dysfunction. Front Biosci 2007; 12: 332–343. doi: 10.2741/2067.

16. Meldrum BS. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr 2000; 130 (4S Suppl): 1007S–1015S. doi: 10.1093/jn/130.4.1007S.

17. Barkhatova VP, Zavalishin IA, Askarova LS et al. Changes in neurotransmitters in multiple sclerosis. Neurosci Behav Physiol 1998: 28 (4): 341–344. doi: 10.1007/ BF02464784.

18. Sarchielli P, Greco L, Floridi A et al. Excitatory amino acids and multiple sclerosis: evidence from cerebrospinal fluid. Arch Neurol 2003; 60 (8): 1082–1088. doi: 10.1001/archneur.60.8.1082.

19. Hawkins RA, O‘Kane RL, Vina JR. Structure of the blood–brain barrier and its role in the trans-port of amino acids. J Nutr 2006; 136 (1 Suppl): 218S–226S. doi: 10.1093/jn/136.1.218S.

20. Lee WJ, Hawkins RA, Vina JR et al. Glutamine transport by the blood-brain barrier: a possible mechanism for nitrogen removal. Am J Physiol 1998; 274 (4): C1101–C1104. doi: 10.1152/ajpcell.1998.274.4.C1101.

21. Xu GY, McAdoo DJ, Hughes MG et al. Considerations in the determination by microdialysis of resting extracellular amino acid concentrations and release upon spinal cord injury. Neuroscience 1998; 86 (3): 1011–1021. doi: 10.1016/s0306-4522 (98) 00063-3.

22. Wang Y, Zhu M, Han J et al. Blood brain barrier perrmeability could be a biomarker to predict severity of neuromyelitis optica spectrum disorders: a retrospective analysis. Front Neurol 2018; 9: 648. doi: 10.3389/fneur.2018.00648.

23. Carr EL, Kelman A, Wu GS et al. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J Immunol 2010; 185 (2): 1037–1044. doi: 10.4049/jimmunol.0903586.

24. Zhou Y, Danboll NC. Glutamate as a neurotransmitter in the healthy brain. J Neural Transm (Vienna) 2014; 121 (8): 799–817. doi: 10.1007/s00702-014-1180-8.

25. Prineas J. Pathology of the early lesion in multiple sclerosis. Hum Pathol 1975; 6 (5): 531–554. doi: 10.1016/s0046-8177 (75) 80040-2.

26. Medera C, Vargas-Lopes C, Brandai CO et al. Elevated glutamate and glutamine levels in the cerebrospinal fluid of patients with probable alzheimer‘s disease and depression. Front Psychiatry 2018; 9: 561. doi: 10.3389/fpsyt.2018.00561.

27. Camu W, Biliard M, Maldy-Moulinier M. Fasting plasma and CSF amino acid levels in amyotrophic lateral sclerosis: a subtype analysis. Acta Neurol Scand 1993; 88 (1): 51–55. doi: 10.1111/j.1600-0404.1993.tb04186.x.

28. Yudkoff M. Interactions in the metabolism of glutamate and the branched-chain amino acids and ketoccids in the CNS. Neurochem Res 2017; 42 (1): 10–18. doi: 10.1007/s11064-016-2057-z.

29. Murin R, Mohammadi G, Leibfritz D et al. Glial metabolism of isoleucine. Neurochem Res 2009; 34 (7): 1195–1203. doi: 10.1007/s11064-008-9895-2.

30. Murin R, Hamprecht B. Metabolic and regulatory roles of leucine in neural cells. NeurochemRes 2008; 33 (2): 279–284. doi: 10.1007/s11064-007-9444-4.

31. Dienel GA. Brain lactate metabolism: the discoveries and the controversies. J Cereb Blood Flow Metab 2012; 32 (7): 1107–1138. doi: 10.1038/jcbfm.2011.175.

32. De Simone R, Vissicchio F, Mingarelli C et al. Branched-chain amino acids influence the immune properties of microglial cells and their responsiveness to pro-inflammatory signals. Biochim Biophys Acta 2013; 1832 (5): 650–659. doi: 10.1016/j.bbadis.2013.02.001.

33. O’Brien JS, Sampson EL. Fatty acid and fatty aldehyde composition of the major brain lipids in normal human gray matter, white matter, and myelin. J Lipid Res 1965; 6 (4): 545–551.

34. Sonnewald U, Westrgaard N, Unsgard G et al. First direct demonstration of a preferential release of citrate from astrocytes using [13C] NMR spectroscopy of cultured neurons and astrocytes. Neurosci Lett 1991; 128 (2): 235–239. doi: 10.1016/0304-3940 (91) 90268-x.

35. Westergaard N, Sonnewald U, Unsgard G et al. Uptake, release, and metabolism of citrate in neurons and astrocytes in primary cultures. J Neurochem 1994; 62 (5): 1727–1733. doi: 10.1046/j.1471-4159.1994.62051727.x.

36. Westergaard N, Banke T, Sonnewald U et al. Citrate modulates the regulation by Zn2+ of N-methyl-D-aspartate receptor-mediated channel current and neurotransmitter release. Proc Natl Acad Sci U S A 1995; 92 (8): 3367–3370. doi: 10.1073/pnas.92.8.3367.

37. Westergaard N, Waagepetersen HS, Belhage B et al.Citrate, a ubiquitous key metabolite with regulatory function in the CNS. Neurochem Res 2017; 42 (6): 1583–1588. doi: 10.1007/s11064-016-2159-7.

38. Reinkee SN, Broadhurst DI, Sykes BD et al. Metabolomic profiling in multiple sclerosis: insights into biomarkers and pathogenesis. Mult Scler J 2014; 20 (10): 1396–1400. doi: 10.1177/1352458513516528.

39. Simone IL, Federico F, Trojano M et al. High resolution proton MR spectroscopy of cerebrospinal fluid in MS patients. Comparison with biochemical changes in demyelinating plaques. J Neurol Sci 1996; 144 (1–2): 182–190. doi: 10.1016/s0022-510x (96) 00224-9.

40. Cocco E, Murgia F, Lorefice L et.al. 1H-NMR analysis provides a metabolomic profile of patients with multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2015; 3 (1): e185. doi: 10.1212/NXI.0000000000000185.

41. Mao P, Reddy PH. Is multiple sclerosis a mitochondrial disease? Biochim Biophys Acta 2010; 1802 (1): 66–79. doi: 10.1016/j.bbadis.2009.07.002.

42. Kallweit U, Aritake K, Bassetti CL et al. Elevated CSF histamine levels in multiple sclerosis patients. Fluids Barriers CNS 2013; 10: 19. doi: 10.1186/2045-8118-10-19.

43. Tuomisto L, Kilpelainen H, Riekkinen P. Histamine and histamine-N-methyltransferase in the CSF of patients with multiple sclerosis. Agents Actions 1983; 13 (2–3): 255–257. doi: 10.1007/BF01967346.

44. Polyzoidis S, Koletsa T, Panagiotidou S et al. Mast cells in meningiomas and brain inflammation. J Neuroinflammation 2015; 12: 170. doi: 10.1186/s12974-015-0388-3.

45. Sinclair AJ, Viant MR, Ball AK et al. NMR-based metabolomic analysis of cerebrospinal fluid and serum in neurological diseases – a diagnostic tool? NMR Biomed 2010; 23 (2): 123–132. doi: 10.1002/nbm.1428.

46. Ronowska A, Szutowicz A, Bielarczyk H et al. The regulatory effects of acetyl- CoA distribution in the healthy and diseased brain. Front Cell Neurosci 2018; 12: 169. doi: 10.3389/fncel.2018.00169.

47. Ariyannur PS, Moffett JR, Madhavarao CN et al. Nuclear-cytoplasmic localization of acetyl coenzyme a synthetase-1 in the rat brain. J Comp Neurol 2011; 518 (15): 2952–2977. doi: 10.1002/cne.22373.

48. Van Veldhoven PP. Biochemistry and genetics of inherited disorders of peroxisomal fatty acids metabolism. J Lipid Res 2010; 51 (10): 2863–2895. doi: 10.1194/jlr.R005959.

49. Bao XR, Ong SE, Goldberger O et al. Mitochondrial dysfunction remodels one- carbon metabolism in human cells. Elife 2016; 5: e10575. doi: 10.7554/eLife.10575.

50. Nicklas WJ, Clarke DD, Berl S. Decarboxylation studies of glutamate, gltamine and aspartate from brain labeled with [1-14C] acetate, [L-U-14C] aspartate and [L-U- 14C glutamate]. J Neurochem 1969: 16 (4): 549–558. doi: 10.1111/j.1471-4159.1969.tb06854.x.

51. Badar-Goffer RS, Bachelard HS, Morris PG. Cerebral metabolism of acetate and glucose studied by 13C-n. m.r. spectroscopy. A technique for investigating metabolic compartmentation in the brain. Biochem J 1990; 266 (1): 133–139. doi: 10.1042/bj2660133.

52. Hawkins RA. The blood-brain barrier and glutamate. Am J Clin Nutr 2009; 90 (3): 867S–874S. doi: 10.3945/ajcn.2009.27462BB.

53. Waagepetersen HS, Sonnewald U, Larsson OM et al.A possible role of alanine for ammonia transfer between astrocytes and glutamatergic neurons. J Neurochem 2000; 75 (2): 471–479. doi: 10.1046/j.1471-4159.2000.0750471.x.

54. Zwingmann C, Richter-Landsberg C, Brand A et al.NMR spectroscopic study on the metabolic fate of [3- (13) C]alanine in astrocytes, neurons, and cocultures: implications for glianeuron interactions in neurotransmitter metabolism. Glia 2000; 32 (3): 286–303. doi: 10.1002/1098-1136 (200012) 32: 3<286:: aid-glia80>3.0.co; 2-p.

55. Jiang T, Cadenas E. Astrocytic metabolic and inflammatory changes as a function of age. Aging cell 2014; 13 (6): 1059–1067. doi: 10.1111/acel.12268.

56. Markianos M, Koutsis G, Evangelopoulos ME et al. Relationship of CSF neurotransmitter metabolitte levels to disease severity and disability in multiple sclerosis. J Neurochem 2009; 108 (1): 158–164. doi: 10.1111/j.1471-4159.2008.05750.x.