Biomarkers of Multiple Sclerosis – Current Options and Future Perspectives

Czech version

Authors: J. Piťha
Authors‘ workplace: Neurologické oddělení, Krajská zdravotní, a. s. – Nemocnice Teplice o. z.
Published in: Cesk Slov Neurol N 2015; 78/111(3): 269-273
Category: Review Article

Overview

Multiple sclerosis is a chronic disease of the central nervous system of unknown etiology with manifestations of autoimmune inflammation and neurodegeneration. The disease is heterogeneous with an unpredictable outcome. The course of the disease can be monitored with clinical parameters as well as pathological changes on magnetic resonance imaging. Even though the effects of newly introduced drugs are known from clinical trials, it is not possible to predict their efficacy in a specific patient. Therefore, efforts have intensified over the recent years to identify laboratory markers that would as reliably as possible answer questions on subclinical disease activity, its progression and would facilitate therapeutic decisions based personalized medicine.

Key words.
multiple sclerosis – therapy – biomarkers

The author declare he has no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Sources

1. Havrdová E et al. Roztroušená skleróza. Praha: Mladá fronta 2013.

2. Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol 2012; 8(11): 647– 656. doi: 10.1038/ nrneurol.2012.168.

3. Gourraud PA, Harbo HF, Hauser SL, Baranzini SE. The genetics of multiple sclerosis: an up‑ to‑ date review. Immunol Rev 2012; 248(1): 87– 103. doi: 10.1111/ j.1600‑ 065X.2012.01134.x.

4. Ascherio A. Environmental factors in multiple sclerosis. Expert Rev Neurother 2013; 13 (Suppl 12): 3– 9. doi: 10.1586/ 14737175.2013.865866.

5. Shirani A, Zhao Y, Karim ME, Evans C, Kingwell E, van der Kop ML et al. Association between use of interferon beta and progression of disability in patients with relapsing – remitting multiple sclerosis. JAMA 2012; 308(3): 247– 256. doi: 10.1001/ jama.2012.7625.

6. Lucchinetti CF, Bruck W, Rodriguez M, Lassmann H. Distinct patterns of multiple sclerosis pathology indicates heterogenity on pathogenesis. Brain Pathol 1996; 6(3): 259– 274.

7. Harris VK, Sadiq SA. Disease biomarkers in multiple sclerosis: potential for use in therapeutic decision making. Mol Diagn Ther 2009; 13(4): 225– 244. doi: 10.2165/ 11313470‑ 000000000‑ 00000.

8. Rudick RA, Lee JC, Simon J, Ransohoff RM, Fisher E. Defining interferon beta response status in multiple sclerosis patients. Ann Neurol 2004; 56(4): 548– 555.

9. Sorensen PS, Koch‑ Henriksen N, Ross C, Clemmesen KM, Bendtzen K. Appearance and disappearance of neutralizing antibodies during interferon‑beta therapy. Neurology 2005; 65(1): 33– 39.

10. Bertolotto A, Deisenhammer F, Gallo P, Solberg Sorensen P. Immunogenicity of interferon beta: differences among products. J Neurol 2004; 251 (Suppl 2): II15– II24.

11. Calabresi PA, Giovannoni G, Confavreux C, Galetta SL, Havrdova E, Hutchinson M et al. The incidence and signifikance of anti‑natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology 2007; 69(14): 1391– 1403.

12. Oliver B, Fernandez O, Orpez T, Alvarenga MP, Pinto‑ Medel MJ, Guerrero M et al. Kinetics and incidence of anti‑natalizumab antibodies in multiple sclerosis patients on treatment for 18 months. Mult Scler 2011; 17(3): 368– 371.

13. Sorensen PS, Jensen PE, Haghikia A, Lundkvist M, Vedeler C, Sellebjerg F et al. Occurrence of antibodies against natalizumab in relapsing multiple sclerosis patients treated with natalizumab. Mult Scler 2011; 17(9): 1074– 1078. doi: 10.1177/ 1352458511404271.

14. Vennegoor A, Rispens T, Strijbis EM, Seewann A, Uitdehaag BM, Balk LJ et al. Clinical relevance of serum natalizumab concentration and anti‑natalizumab antibodies in multiple sclerosis. Mult Scler 2013; 19(5): 593– 600. doi: 10.1177/ 1352458512460604.

15. Mori K, Emoto M, Inaba M. Fetuin‑A: a multifunctional protein. Recent Pat Endocr Metab Immune Drug Discov 2011; 5(2): 124– 146.

16. Saunders NR, Habgood MD, Ward RA, Reynolds ML. Origin and fate of fetuin‑containing neurons in the developing neocortex of the fetal sheep. Anat Embryol (Berl) 1992; 186(5): 477– 486.

17. Harris VK, Diamanduros A, Good P, Zakin E, Chalivendra V, Sadiq SA. Bri2– 23 is a potential cerebrospinal fluid biomarker in multiple sclerosis. Neurobiol Dis 2010; 40(1): 331– 339. doi: 10.1016/ j.nbd.2010.06.007.

18. Harris VK, Donelan N, Yan QJ, Clark K, Touray A, Rammal M et al. Cerebrospinal fluid fetuin‑A is a biomarker of active multiple sclerosis. Mult Scler 2013; 19(11): 1462– 1472. doi: 10.1177/ 1352458513477923.

19. Defer G, Mariotte D, Derache N, Toutirais O, Legros H, Cauquelin B et al. CD49d expression as a promising biomarker to monitor natalizumab efficacy. J Neurol Sci 2012; 314(1– 2): 138– 142. doi: 10.1016/ j.jns.2011.10.005.

20. Bartosik‑ Psujek H, Psujek M, Jaworski J, Stelmasiak Z. Total tau and S100b proteins in different types of multiple sclerosis and during immunosuppressive treatment with mitoxantrone. Acta Neurol Scand 2011; 123(4): 252– 256. doi: 10.1111/ j.1600‑ 0404.2010.01393.x.

21. Lehmensiek V, Süssmuth SD, Tauscher G, Brettschneider J, Felk S, Gillardon F et al. Cerebrospinal fluid proteome profile in multiple sclerosis. Mult Scler 2007; 13(7): 840– 849.

22. Tumani H, Lehmensiek V, Rau D, Guttmann I, Tauscher G, Mogel H et al. CSF proteome analysis in clinically isolated syndrome (CIS): candidate markers for conversion to definite multiple sclerosis. Neurosci Lett 2009; 452(2): 214– 217. doi: 10.1016/ j.neulet.2009.01.057.

23. Tumani H, Lehmensiek V, Rau D, Guttmann I, Tauscher G, Mogel H et al. CSF proteome analysis in clinically isolated syndrome (CIS): candidate markers for conversion to definite multiple sclerosis. Neurosci Lett 2009; 452(2): 214– 217. doi: 10.1016/ j.neulet.2009.01.057.

24. Chabas D, Baranzini SE, Mitchell D, Bernard CC, Rittling SR, Denhardt DT et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 2001; 294(5547): 1731– 1735.

25. Shimizu Y, Ota K, Ikeguchi R, Kubo S, Kabasawa C, Uchiyama S. Plasma osteopontin levels are associated with disease aktivity in the patients with multiple sclerosis and neuromyelitis optica. J Neuroimmunol 2013; 263(1– 2): 148– 151. doi: 10.1016/ j.jneuroim.2013.07.005.

26. Kivisäkk P, Healy BC, Francois K, Gandhi R, Gholipour T, Egorova S et al. Evaluation of circulating osteopontin levels in an unselected cohort of patients with multiple sclerosis: relevance for biomarker development. Mult Scler 2014; 20(4): 438– 444. doi: 10.1177/ 1352458513503052.

27. Runia TF, Meurs MV, Nasserinejad K, Hintzen RQ. No evidence for an association of osteopontin plasma levels with disease activity in multiple sclerosis. Mult Scler 2014; 20(12): 1670– 1671. doi: 10.1177/ 1352458514528765.

28. Chowdhury SA, Lin J, Sadiq SA. Specificity and correlation with disease activity of cerebrospinal fluid osteopontin levels in patients with multiple sclerosis. Arch Neurol 2008; 65(2): 232– 235. doi: 10.1001/ archneurol.2007.33.

29. Szalardy L, Zadori D, Simu M, Bencsik K, Vecsei L, Klivenyi P. Evaluating biomarkers of neuronal degeneration and neuroinflammation in CSF of patients with multiple sclerosis‑ osteopontin as a potential marker of clinical severity. J Neurol Sci 2013; 331(1– 2): 38– 42. doi: 10.1016/ j.jns.2013.04.024.

30. Khademi M, Bornsen L, Rafatnia F, Andersson M, Brundin L, Piehl F et al. The effects of natalizumab on inflammatory mediators in multiple sclerosis: prospects for treatment‑ sensitive biomarkers. Eur J Neurol 2009; 16(4): 528– 536. doi: 10.1111/ j.1468‑ 1331.2009.02532.x.

31. Kapural M, Krizanac‑ Bengez Lj, Barnett G, Perl J, Masaryk T, Apollo D. Serum S‑ 100beta as a possible marker of blood‑ brain barrier disruption. Brain Res 2002; 940(1– 2): 102– 104.

32. Muller AM, Jun E, Conlon H, Sadiq SA. Cerebrospinal hepatocyte growth factor levels correlate negatively with disease activity in multiple sclerosis. J Neuroimmunol 2012; 251(1– 2): 80– 86. doi: 10.1016/ j.jneuroim.2012.06.008.

33. Wang P, Xie K, Wang C, Bi J. Oxidative stress induced by lipid peroxidation is related with inflammation of demyelination and neurodegeneration in multiple sclerosis. Eur Neurol 2014; 72(3– 4): 249– 254. doi: 10.1159/ 000363515.

34. Miller E, Mrowicka M, Saluk‑ Juszczak J, Ireneusz M. The level of isoprostanes as a non‑invasive marker for in vivo lipid peroxidation in secondary progressive multiple sclerosis. Neurochem Res 2011; 36(6):1012– 1016. doi: 10.1007/ s11064‑ 011‑ 0442‑ 1.

35. Mir F, Lee D, Ray H, Sadiq SA. CSF isoprostane levels are a biomarker of oxidative stress in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2014; 1(2): e21. doi: 10.1212/ NXI.0000000000000021.

36. Sellebjerg F, Bornsen L, Khademi M, Krakauer M, Olsson T, Frederiksen JL et al. Increased cerebrospinal fluid concentrations of the chemokine CXCL13 in active MS. Neurology 2009; 73(23): 2003– 2010. doi: 10.1212/ WNL.0b013e3181c5b457.

37. Alvarez E, Piccio L, Mikesell RJ, Klawiter EC, Parks BJ, Naismith RT et al. CXCL13 is a biomarker of inflammation in multiple sclerosis, neuromyelitis optica and other neurological conditions. Mult Scler 2013; 19(9): 1204– 1208. doi: 10.1177/ 1352458512473362.

38. Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M et al. Meningeal B‑ cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 2007; 130(4): 1089– 1104.

39. Brettschneider J, Czerwoniak A, Senel M, Fang L, Kassubek J, Pinkhardt E et al. The chemokine CXCL13 is a prognostic marker in clinically isolated syndrome (CIS). PLoS One 2010; 5(8): e11986. doi: 10.1371/ journal.pone.0011986.

40. Axelsson M, Mattsson N, Malmestrom C, Zetterberg H, Lycke J. The influence of disease duration, clinical course, and immunosuppressive therapy on the synthesis of intrathecal oligoclonal IgG bands in multiple sclerosis. J Neuroimmunol 2013; 264(1– 2): 100– 105. doi: 10.1016/ j.jneuroim.2013.09.003.

41. Ferraro D, Simone AM, Bedin R, Galli V, Vitetta F, Federzoni L et al. Cerebrospinal fluid oligoclonal IgM bands predict early conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome. J Neuroimmunol 2013; 257(1– 2): 76– 81. doi: 10.1016/ j.jneuroim.2013.01.011.

42. Naismith RT, Piccio L, Lyons JA, Lauber J, Tutlam NT, Parks BJ et al. Rituximab add‑ on therapy for breakthrough relapsingmultiple sclerosis: a 52‑week phase II trial. Neurology 2010; 74(23): 1860– 1867. doi: 10.1212/ WNL.0b013e3181e24373.

43. Petzold A. Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss. J Neurol Sci 2005; 233(1– 2): 183– 198.

44. Kuhle J, Leppert D, Petzold A, Regeniter A, Schindler C, Mehling M et al. Neurofilament heavy chain in CSF correlates with relapses and disability in multiple sclerosis. Neurology 2011; 76(14): 1206– 1213. doi: 10.1212/ WNL.0b013e31821432ff.

45. Salzer J, Svenningsson A, Sundström P. Neurofilament light as a prognostic marker in multiple sclerosis. Mult Scler 2010; 16(3): 287– 292. doi: 10.1177/ 1352458509359725.

46. Khalil M, Enzinger C, Langkammer C, Ropele S, Mader A, Trentini A et al. CSF neurofilament and N‑ acetylaspartate related brain changes in clinically isolated syndrome. Mult Scler 2013; 19(4): 436– 442. doi: 10.1177/ 1352458512458010.

47. Teunissen CE, Khalil M. Neurofilaments as biomarkers in multiple sclerosis. Mult Scler 2012; 18(5): 552– 556. doi: 10.1177/ 1352458512443092.

48. Colucci M, Roccatagliata L, Capello E, Narciso E, Latronico N, Tabaton M et al. The 14- 3- 3 protein in multiple sclerosis: a marker of disease severity. Mult Scler 2004; 10(5): 477– 481.

49. Gunnarsson M, Malmestrom C, Axelsson M, Sundstrom P, Dahle C, Vrethem M et al. Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab. Ann Neurol 2011; 69(1): 83– 89. doi: 10.1002/ ana.22247.

50. Axelsson M, Malmestrom C, Gunnarsson M, Zetterberg H, Sundstrom P, Lycke J et al. Immunosuppressive therapy reduces axonal damage in progressive multiple sclerosis. Mult Scler 2014; 20(1): 43– 50. doi: 10.1177/ 1352458513490544.

51. Bartos A, Fialova L, Soukupova J, Kukal J, Malbohan I, Pitha J. Antibodies against light neurofilaments in multiple sclerosis patients. Acta Neurol Scand 2007; 116(2): 100– 107.

52. Bartos A, Fialova L, Soukupova J, Kukal J, Malbohan I, Pitha J. Elevated intrathecal antibodies against the medium neurofilament subunit in multiple sclerosis. J Neurol 2007; 254(1): 20– 25.

53. Lee CG, Da Silva CA, Dela Cruz CS, Ahangari F, Ma B, Kang MJ et al. Role of chitin and chitinase/ chitinase‑like proteins in inflammation, tissue remodeling and injury. Ann Rev Physiol 2011; 73: 479– 501. doi: 10.1146/ annurev‑ physiol‑ 012110‑ 142250.

54. Comabella M, Fernandez M, Martin R, Rivera‑ Vallve S, Borras E, Chiva C et al. Cerebrospinal fluid chitinase 3‑like 1 levels are associated with conversion to multiple sclerosis. Brain 2010; 133(4): 1082– 1093. doi: 10.1093/ brain/ awq035.

55. Modvig S, Degn M, Horwitz H, Cramer SP, Larsson HB, Wanscher B et al. Relationship between cerebrospinal fluid biomarkers for inflammation, demyelination and neurodegeneration in acute optic neuritis. PLoS One 2013; 8(10): e77163. doi: 10.1371/ journal.pone.0077163.

56. Thouvenot E, Hinsinger G, Galeotti N, Nabholz N, Urbach S, Rigau V et al. Chitinase 3‑like 1 and chitinase 3‑like 2 as diagnostic and prognostic biomarkers of multiple sclerosis. Philadelphia: American Academy of Neurology Annual Meeting 2014.

57. Malmeström C, Axelsson M, Lycke J, Zetterberg H, Blennow K, Olsson B. CSF levels of YKL‑ 40 are increased in MS and replaces with immunosuppressive treatment. J Neuroimmunol 2014; 269(1– 2): 87– 89. doi: 10.1016/ j.jneuroim.2014.02.004.

58. Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I et al. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N Engl J Med 2003; 349(2): 139– 145.

59. Nakashima I, Fujinoki M, Fujihara K, Kawamura T, Nishimura T, Nakamura M et al. Alteration of cystatin C in the cerebrospinal fluid of multiple sclerosis. Ann Neurol 2007; 62(2): 197– 200.

60. Sladkova V, Mareš J, Lubenova B, Zapletalova J, Stejskal D, Hlustik P 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.

61. Hansson SF, Simonsen AH, Zetterberg H, Andersen O, Haghighi S, Fagerberg I et al. Cystatin C in cerebrospinal fluid and multiple sclerosis. Ann Neurol 2007; 62(2): 193– 196.

62. Gurevich M, Tuller T, Rubinstein U, Or‑ Bach R, Achiron A. Prediction of acute multiple sclerosis relapses by transcription levels of peripheral blood cells. BMC Med Genomics 2009; 2: 46. doi: 10.1186/ 1755‑ 8794‑ 2‑ 46.

63. Ratzer R, Sondergaard H, Christensen JR, Bornsen L, Borup R, Sorensen P et al. Gene expression analysis of relapsing – remitting, primary progressive and secondary progressive multiple sclerosis. Mult Scler 2013; 19(14): 1841– 1848. doi: 10.1177/ 1352458513500553.

64. Bustamante MF, Fissolo N, Rio J, Espejo C, Costa C, Mansilla MJ et al. Implication of the Toll‑like receptor 4 pathway in the response to interferon‑beta in multiple sclerosis. Ann Neurol 2011; 70(4): 634– 645. doi: 10.1002/ ana.22511.

65. Baranzini SE, Madireddy LR, Cromer A, D‘Antonio M, Lehr L, Beelke M et al. Prognostic biomarkers of IFNb therapy in multiple sclerosis patients. Mult Scler 2014 Nov 12. pii: 1352458514555786.

66. Parnell GP, Gatt PN, McKay FC, Schibeci S, Krupa M, Powell JE et al. Ribosomal protein S6 mRNA is a biomarker upregulated in multiple sclerosis, downregulated by interferon treatment, and affected by season. Mult Scler 2014; 20(6): 675– 685. doi: 10.1177/ 1352458513507819.

67. Verderio C, Muzio L, Turola E, Bergami A, Novellino L, Ruffini F et al. Myeloid microvesicles are a marker and therapeutic target for neuroinflammation. Ann Neurol 2012; 72(4): 610– 624. doi: 10.1002/ana.23627.