During the last decades, the effort of establishing satisfactory biomarkers for multiple sclerosis has been proven to be very difficult, due to the clinical and pathophysiological complexities of the disease. Recent knowledge acquired in the domains of genomics-immunogenetics and neuroimmunology, as well as the evolution in neuroimaging, has provided a whole new list of biomarkers. This variety, though, leads inevitably to confusion in the effort of decision making concerning strategic and individualized therapeutics. In this paper, our primary goal is to provide the reader with a list of the most important characteristics that a biomarker must possess in order to be considered as reliable. Additionally, up-to-date biomarkers are further divided into three subgroups, genetic-immunogenetic, laboratorial, and imaging. The most important representatives of each category are presented in the text and for the first time in a summarizing workable table, in a critical way, estimating their diagnostic potential and their efficacy to correlate with phenotypical expression, neuroinflammation, neurodegeneration, disability, and therapeutical response. Special attention is given to the “gold standards” of each category, like HLA-DRB1* polymorphisms, oligoclonal bands, vitamin D, and conventional and nonconventional imaging techniques. Moreover, not adequately established but quite promising, recently characterized biomarkers, like TOB-1 polymorphisms, are further discussed. 1. Introduction Multiple Sclerosis (MS) is the most common reason of neurological disability among young adults. Its clinical course varies greatly, reflecting complexity in pathophysiology. Different mechanisms of inflammation-demyelination, axonal damage-neurodegeneration, gliosis, and remyelination-repair combine together in various degrees (influenced by idiosyncratic factors) to create a unique clinical result for each patient. Identifying those idiosyncratic factors, as well as understanding which mechanism is prominent in each case, is the first step towards a rational therapeutical choice. Thus, guiding research towards distinguishing reliable biomarkers for every independent MS pathogenic factor is of primary importance. An adequate definition of the term “biomarker” would be as follows: “Biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutical intervention” [1]. A biomarker would ideally serve as a “surrogate endpoint” of a clinical outcome, only if it
References
[1]
L. J. Lesko and A. J. Atkinson, “Use of biomarkers and surrogate endpoints in drug development and regulatory decision making: criteria, validation, strategies,” Annual Review of Pharmacology and Toxicology, vol. 41, pp. 347–366, 2001.
[2]
B. Bielekova and R. Martin, “Development of biomarkers in multiple sclerosis,” Brain, vol. 127, no. 7, pp. 1463–1478, 2004.
[3]
H. Tumani, H. P. Hartung, B. Hemmer et al., “Cerebrospinal fluid biomarkers in multiple sclerosis,” Neurobiology of Disease, vol. 35, no. 2, pp. 117–127, 2009.
[4]
G. Giovannoni, A. J. E. Green, and E. J. Thompson, “Are there any body fluid markers of brain atrophy in multiple sclerosis?” Multiple Sclerosis, vol. 4, no. 3, pp. 138–142, 1998.
[5]
D. Slats, J. Claassen, G. J. Lammers, R. J. Melis, M. M. Verbeek, and S. Overeem, “Association between hypocretin-1 and amyloid-beta 42 cerebrospinal fluid levels in Alzheimer’s disease and healthy controls,” Current Alzheimer Research. In press.
[6]
S. P. Grady, S. Nishino, C. A. Czeisler, D. Hepner, and T. E. Scammell, “Diurnal variation in CSF orexin-A in healthy male subjects,” Sleep, vol. 29, no. 3, pp. 295–297, 2006.
[7]
J. S. Poceta, L. Parsons, S. Engelland, and D. F. Kripke, “Circadian rhythm of CSF monoamines and hypocretin-1 in restless legs syndrome and Parkinson's disease,” Sleep Medicine, vol. 10, no. 1, pp. 129–133, 2009.
[8]
J. S. Kennedy, H. E. Gwirtsman, D. E. Schmidt et al., “Serial cerebrospinal fluid tryptophan and 5-hydroxy indoleacetic acid concentrations in healthy human subjects,” Life Sciences, vol. 71, no. 14, pp. 1703–1715, 2002.
[9]
M. G. Perry, J. R. Kirwan, D. S. Jessop, and L. P. Hunt, “Overnight variations in cortisol, interleukin 6, tumour necrosis factor α and other cytokines in people with rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 68, no. 1, pp. 63–68, 2009.
[10]
P. Wipfler, A. Heikkinen, A. Harrer, et al., “Circadian rhythmicity of inflammatory serum parameters: a neglected issue in the search of biomarkers in multiple sclerosis,” Journal of Neurology, vol. 260, no. 1, pp. 221–227, 2013.
[11]
G. Calais, G. Forzy, C. Crinquette et al., “Tear analysis in clinically isolated syndrome as new multiple sclerosis criterion,” Multiple Sclerosis, vol. 16, no. 1, pp. 87–92, 2010.
[12]
A. Minagar, I. Adamashvili, R. E. Kelley, E. Gonzalez-Toledo, J. McLarty, and S. J. Smith, “Saliva soluble HLA as a potential marker of response to interferon-βIa in multiple sclerosis: a preliminary study,” Journal of Neuroinflammation, vol. 4, article 16, 2007.
[13]
H. Link and Y. M. Huang, “Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness,” Journal of Neuroimmunology, vol. 180, no. 1-2, pp. 17–28, 2006.
[14]
A. Sanchez-Pla, F. Reverter, C. Ruiz de Villa, and M. Comabella, “Transcriptomics: mRNA and alternative splicing,” Journal of Neuroimmunology, vol. 248, pp. 23–31, 2012.
[15]
F. Quintana, A. Yeste, H. Weiner, and R. Covacu, “Lipids and lipid-reactive antibodies as biomarkers for multiple sclerosis,” Journal of Neuroimmunology, vol. 248, pp. 53–57, 2012.
[16]
S. E. Baranzini, J. Mudge, J. C. van Velkinburgh et al., “Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis,” Nature, vol. 464, no. 7293, pp. 1351–1356, 2010.
[17]
H. Schmidt, D. Williamson, and A. Ashley-Koch, “HLA-DR15 haplotype and multiple sclerosis: a HuGE review,” American Journal of Epidemiology, vol. 165, no. 10, pp. 1097–1109, 2007.
[18]
J. R. Oksenberg, L. F. Barcellos, B. A. C. Cree et al., “Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans,” American Journal of Human Genetics, vol. 74, no. 1, pp. 160–167, 2004.
[19]
V. P. Bozikas, M. C. Anagnostouli, P. Petrikis et al., “Familial bipolar disorder and multiple sclerosis: a three-generation HLA family study,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 27, no. 5, pp. 835–839, 2003.
[20]
A. S. N. Al-Din, M. El-Khateeb, A. Kurdi et al., “Multiple sclerosis in Arabs in Jordan,” Journal of the Neurological Sciences, vol. 131, no. 2, pp. 144–149, 1995.
[21]
O. J. Kwon, A. Karni, S. Israel et al., “HLA class II susceptibility to multiple sclerosis among Ashkenazi and non-Ashkenazi Jews,” Archives of Neurology, vol. 56, no. 5, pp. 555–560, 1999.
[22]
M. Lincoln, S. Ramagopalan, M. Chao, et al., “Epistasis among HLA-DRB1, HLA-DQA1 and HLA-DQB1 loci determines multiple sclerosis susceptibility,” in Proceedings of the 61st Annual Meeting of the American Academy of Neurology, Seattle, Wash, USA, April-May 2009, abstract IN2-2. 005.
[23]
M. G. Marrosu, C. Sardu, E. Cocco et al., “Bias in parental transmission of the HLA-DR3 allele in Sardinian multiple sclerosis,” Neurology, vol. 63, no. 6, pp. 1084–1086, 2004.
[24]
D. A. Dyment, M. Z. Cader, A. Datta et al., “A first stage genome-wide screen for regions shared identical-by-descent in hutterite families with multiple sclerosis,” American Journal of Medical Genetics Part B, vol. 147B, no. 4, pp. 467–472, 2008.
[25]
M. Minohara, H. Ochi, S. Matsushita, A. Irie, Y. Nishimura, and J. Kira, “Differences between T-cell reactivities to major myelin protein-derived peptides in opticospinal and conventional forms of multiple sclerosis and healthy controls,” Tissue Antigens, vol. 57, no. 5, pp. 447–456, 2001.
[26]
S. Kikuchi, T. Fukazawa, M. Niino et al., “HLA-related subpopulations of MS in Japanese with and without oligoclonal IgG bands. Human leukocyte antigen,” Neurology, vol. 60, no. 4, pp. 647–651, 2003.
[27]
A. Van der Walt, J. Stankovich, M. Bahlo et al., “Heterogeneity at the HLA-DRB1 allelic variation locus does not influence multiple sclerosis disease severity, brain atrophy or cognition,” Multiple Sclerosis, vol. 17, no. 3, pp. 344–352, 2011.
[28]
J. Stankovich, H. Butzkueven, M. Marriott et al., “HLA-DRB1 associations with disease susceptibility and clinical course in Australians with multiple sclerosis,” Tissue Antigens, vol. 74, no. 1, pp. 17–21, 2009.
[29]
I. Cournu-Rebeix, E. Génin, E. Leray et al., “HLA-DRB1*15 allele influences the later course of relapsing remitting multiple sclerosis. HLA-DRB1*15 and the course of multiple sclerosis,” Genes and Immunity, vol. 9, no. 6, pp. 570–574, 2008.
[30]
G. C. DeLuca, S. V. Ramagopalan, B. M. Herrera et al., “An extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 52, pp. 20896–20901, 2007.
[31]
R. Zivadinov, L. Uxa, A. Bratina et al., “HLA-DRB1*1501, -DQB1*0301, -DQB1*0302, -DQB1*0602, and -DQB1*0603 alleles are associated with more severe disease outcome on Mri in patients with multiple sclerosis,” International Review of Neurobiology, vol. 79, pp. 521–535, 2007.
[32]
D. T. Okuda, R. Srinivasan, J. R. Oksenberg et al., “Genotype-phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures,” Brain, vol. 132, no. 1, pp. 250–259, 2009.
[33]
D. Buck, S. Cepok, S. Hoffmann et al., “Influence of the HLA-DRB1 genotype on antibody development to interferon beta in multiple sclerosis,” Archives of Neurology, vol. 68, no. 4, pp. 480–487, 2011.
[34]
International Multiple Sclerosis Genetics Consortium, “Risk alleles for multiple sclerosis identified by a genomewide study,” The New England Journal of Medicine, vol. 357, no. 9, pp. 851–862, 2007.
[35]
M. J. D'Netto, H. Ward, K. M. Morrison et al., “Risk alleles for multiple sclerosis in multiplex families,” Neurology, vol. 72, no. 23, pp. 1984–1988, 2009.
[36]
The International Multiple Sclerosis Genetics Consortium, The Wellcome Trust Case Control Consortium 2, “Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis,” Nature, vol. 476, no. 7359, pp. 214–219, 2011.
[37]
J. C. Corvol, D. Pelletier, R. G. Henry et al., “Abrogation of T cell quiescence characterizes patients at high risk for multiple sclerosis after the initial neurological event,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 33, pp. 11839–11844, 2008.
[38]
H. L. Zhang, J. Wu, and J. Zhu, “The immune-modulatory role of apolipoprotein E with emphasis on multiple sclerosis and experimental autoimmune encephalomyelitis,” Clinical and Developmental Immunology, vol. 2010, Article ID 186813, 10 pages, 2010.
[39]
M. Tintoré, A. Rovira, J. Río et al., “Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis?” Neurology, vol. 70, no. 13, pp. 1079–1083, 2008.
[40]
P. Nilsson, E. M. Larsson, P. Maly-Sundgren, R. Perfekt, and M. Sandberg-Wollheim, “Predicting the outcome of optic neuritis: evaluation of risk factors after 30 years of follow-up,” Journal of Neurology, vol. 252, no. 4, pp. 396–402, 2005.
[41]
G. P. Owens, J. L. Bennett, H. Lassmann et al., “Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid,” Annals of Neurology, vol. 65, no. 6, pp. 639–649, 2009.
[42]
J. Mandrioli, P. Sola, R. Bedin, M. Gambini, and E. Merelli, “A multifactorial prognostic index in multiple sclerosis: cerebrospinal fluid IgM oligoclonal bands and clinical features to predict the evolution of the disease,” Journal of Neurology, vol. 255, no. 7, pp. 1023–1031, 2008.
[43]
R. Schneider, B. Euler, and S. Rauer, “Intrathecal IgM-synthesis does not correlate with the risk of relapse in patients with a primary demyelinating event,” European Journal of Neurology, vol. 14, no. 8, pp. 907–911, 2007.
[44]
L. Villar, N. Garcia-Barragan, M. Espino, et al., “Influence of oligoclonal IgM specificity in multiple sclerosis disease course,” Multiple Sclerosis, vol. 14, pp. 183–187, 2008.
[45]
S. Presslauer, D. Milosavljevic, T. Brücke, P. Bayer, and W. Hübl, “Elevated levels of kappa free light chains in CSF support the diagnosis of multiple sclerosis,” Journal of Neurology, vol. 255, no. 10, pp. 1508–1514, 2008.
[46]
L. M. Villar, M. Espino, L. Costa-Frossard, A. Muriel, J. Jimenez, and J. C. Alvarez-Cermeno, “High levels of cerebrospinal fluid free kappa chains predict conversion to multiple sclerosis,” Clinica Chimica Acta, vol. 413, no. 23-24, pp. 1813–1816, 2012.
[47]
B. Arneth and F. Birklein, “High sensitivity of free lambda and free kappa light chains for detection of intrathecal immunoglobulin synthesis in cerebrospinal fluid,” Acta Neurologica Scandinavica, vol. 119, no. 1, pp. 39–44, 2009.
[48]
J. Brettschneider, H. Tumani, U. Kiechle et al., “IgG antibodies against measles, rubella, and varicella zoster virus predict conversion to multiple sclerosis in clinically isolated syndrome,” PLoS One, vol. 4, no. 11, article e7638, 2009.
[49]
E. Meinl, M. Krumbholz, and R. Hohlfeld, “B lineage cells in the inflammatory central nervous system environment: migration, maintenance, local antibody production, and therapeutic modulation,” Annals of Neurology, vol. 59, no. 6, pp. 880–892, 2006.
[50]
S. Cepok, D. Zhou, R. Srivastava et al., “Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis,” Journal of Clinical Investigation, vol. 115, no. 5, pp. 1352–1360, 2005.
[51]
J. D. Lünemann, N. Edwards, P. A. Muraro et al., “Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis,” Brain, vol. 129, no. 6, pp. 1493–1506, 2006.
[52]
C. Casiraghi, K. Dorovini-Zis, and M. S. Horwitz, “Epstein-Barr virus infection of human brain microvessel endothelial cells: a novel role in multiple sclerosis,” Journal of Neuroimmunology, vol. 230, no. 1-2, pp. 173–177, 2011.
[53]
D. Buljevac, G. Van Doornum, H. Flach, et al., “Epstein-Barr virus and disease activity in multiple sclerosis,” Journal of Neurology, Neurosurgery & Psychiatry, vol. 76, pp. 1377–1381, 2005.
[54]
T. Berger, P. Rubner, F. Schautzer et al., “Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event,” The New England Journal of Medicine, vol. 349, no. 2, pp. 139–145, 2003.
[55]
J. Kuhle, C. Pohl, M. Mehling et al., “Lack of association between antimyelin antibodies and progression to multiple sclerosis,” The New England Journal of Medicine, vol. 356, no. 4, pp. 371–378, 2007.
[56]
T. Menge, P. H. Lalive, H. C. von Büdingen, and C. P. Genain, “Conformational epitopes of myelin oligodendrocyte glycoprotein are targets of potentially pathogenic antibody responses in multiple sclerosis,” Journal of Neuroinflammation, vol. 8, article 161, 2011.
[57]
T. Menge, H. C. von Büdingen, P. H. Lalive, and C. P. Genain, “Relevant antibody subsets against MOG recognize conformational epitopes exclusively exposed in solid-phase ELISA,” European Journal of Immunology, vol. 37, no. 11, pp. 3229–3239, 2007.
[58]
C. J. Hedegaard, N. Chen, F. Sellebjerg et al., “Autoantibodies to myelin basic protein (MBP) in healthy individuals and in patients with multiple sclerosis: a role in regulating cytokine responses to MBP,” Immunology, vol. 128, no. 1, supplement, pp. e451–e461, 2009.
[59]
A. Chan, B. Decard, C. Franke et al., “Serum antibodies to conformational and linear epitopes of myelin oligodendrocyte glycoprotein are not elevated in the preclinical phase of multiple sclerosis,” Multiple Sclerosis, vol. 16, no. 10, pp. 1189–1192, 2010.
[60]
A. A. Belogurov, I. N. Kurkova, A. Friboulet et al., “Recognition and degradation of myelin basic protein peptides by serum autoantibodies: novel biomarker for multiple sclerosis,” Journal of Immunology, vol. 180, no. 2, pp. 1258–1267, 2008.
[61]
K. C. O'Connor, C. Lopez-Amaya, D. Gagne et al., “Anti-myelin antibodies modulate clinical expression of childhood multiple sclerosis,” Journal of Neuroimmunology, vol. 223, no. 1-2, pp. 92–99, 2010.
[62]
F. Brilot, R. C. Dale, R. C. Selter et al., “Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease,” Annals of Neurology, vol. 66, no. 6, pp. 833–842, 2009.
[63]
T. Derfuss and E. Meinl, “Identifying autoantigens in demyelinating diseases: valuable clues to diagnosis and treatment?” Current Opinion in Neurology, vol. 25, no. 3, pp. 231–238, 2012.
[64]
H. J. Willison and C. Linington, “Antibodies to MOG in NMO: a seasoned veteran finds a new role,” Neurology, vol. 79, no. 12, pp. 1198–1199, 2012.
[65]
E. C. Klawiter, L. Piccio, J. A. Lyons, R. Mikesell, K. C. O'Connor, and A. H. Cross, “Elevated intrathecal myelin oligodendrocyte glycoprotein antibodies in multiple sclerosis,” Archives of Neurology, vol. 67, no. 9, pp. 1102–1108, 2010.
[66]
M. C. Kowarik, S. Cepok, J. Sellner, et al., “CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation,” Journal of Neuroinflammation, vol. 9, article 93, 2012.
[67]
F. Sellebjerg, L. B？rnsen, M. Khademi et al., “Increased cerebrospinal fluid concentrations of the chemokine CXCL13 in active MS,” Neurology, vol. 73, no. 23, pp. 2003–2010, 2009.
[68]
D. Miljkovi？, Z. Stanojevi？, M. Momcilovi？, F. Odoardi, A. Flügel, and M. Mostarica-Stojkovi？, “CXCL12 expression within the CNS contributes to the resistance against experimental autoimmune encephalomyelitis in Albino Oxford rats,” Immunobiology, vol. 216, no. 9, pp. 979–987, 2011.
[69]
M. Rentzos, C. Nikolaou, A. Rombos et al., “Effect of treatment with methylprednisolone on the serum levels of IL-12, IL-10 and CCL2 chemokine in patients with multiple sclerosis in relapse,” Clinical Neurology and Neurosurgery, vol. 110, no. 10, pp. 992–996, 2008.
[70]
J. Romme Christensen, L. B？rnsen, D. Hesse, et al., “Cellular sources of dysregulated cytokines in relapsing-remitting multiple sclerosis,” Journal of Neuroinflammation, vol. 9, article 215, 2012.
[71]
Y. C. Chen, X. Yang, L. Miao, et al., “Serum level of interleukin-6 in Chinese patients with multiple sclerosis,” Journal of Neuroinflammation, vol. 249, no. 1-2, pp. 109–111, 2012.
[72]
B. S. Kim, Y. H. Jin, L. Meng, et al., “IL-1 signal affects both protection and pathogenesis of virus-induced chronic CNS demyelinating disease,” Journal of Neuroinflammation, vol. 9, no. 1, article 217, 2012.
[73]
M. N. Karimabad, M. K. Arababadi, E. Hakimizadeh, et al., “Is the IL-10 promoter polymorphism at position -592 associated with immune system-related diseases?” Inflammation. In press.
[74]
R. Schneider, A. N. Mohebiany, I. Ifergan, et al., “B cell-derived IL-15 enhances CD8 T cell cytotoxicity and is increased in multiple sclerosis patients,” The Journal of Immunology, vol. 187, no. 8, pp. 4119–4128, 2011.
[75]
M. Rentzos, C. Cambouri, A. Rombos et al., “IL-15 is elevated in serum and cerebrospinal fluid of patients with multiple sclerosis,” Journal of the Neurological Sciences, vol. 241, no. 1-2, pp. 25–29, 2006.
[76]
M. Li, Y. Li, X. Liu, X. Gao, and Y. Wang, “IL-33 blockade suppresses the development of experimental autoimmune encephalomyelitis in C57BL/6 mice,” Journal of Neuroimmunology, vol. 247, no. 1-2, pp. 25–31, 2012.
[77]
G. Acar, F. Idiman, G. Kirkali et al., “Intrathecal sICAM-1 production in multiple sclerosis correlation with triple dose Gd-DTPA MRI enhancement and IgG index,” Journal of Neurology, vol. 252, no. 2, pp. 146–150, 2005.
[78]
A. Uzawa, M. Mori, S. Masuda, and S. Kuwabara, “Markedly elevated soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1 levels, and blood-brain barrier breakdown in neuromyelitis optica,” Archives of Neurology, vol. 68, no. 7, pp. 913–917, 2011.
[79]
K. Flanagan, K. Fitzgerald, J. Baker, et al., “Laminin-411 is a vascular ligand for MCAM and facilitates TH17 cell entry into the CNS,” PLoS One, vol. 7, no. 7, article e40443, 2012.
[80]
M. Braitch, R. Nunan, G. Niepel, L. J. Edwards, and C. S. Constantinescu, “Increased osteopontin levels in the cerebrospinal fluid of patients with multiple sclerosis,” Archives of Neurology, vol. 65, no. 5, pp. 633–635, 2008.
[81]
W. Sato, A. Tomita, D. Ichikawa, et al., “CCR2+CCR5+ T cells produce matrix metalloproteinase-9 and osteopontin in the pathogenesis of multiple sclerosis,” The Journal of Immunology, vol. 189, no. 10, pp. 5057–5065, 2012.
[82]
Q. Yan, R. Donelan, J. Dinzey, M. Rammal, and S. Sadiq, “Fetuin-A is a biomarker for disease activity and treatment efficacy in multiple sclerosis,” in Proceedings of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS '08), p. 897, Montreal, Canada, 2008.
[83]
E. Iacobaeus, P. Amoudruz, M. Str？m et al., “The expression of VEGF-A is down regulated in peripheral blood mononuclear cells of patients with secondary progressive multiple sclerosis,” PLoS One, vol. 6, no. 5, article e19138, 2011.
[84]
K. I. L？ken-Amsrud, T. Holm？y, S. J. Bakke, et al., “Vitamin D and disease activity in multiple sclerosis before and during interferon-β treatment,” Neurology, vol. 79, no. 3, pp. 267–273, 2012.
[85]
S. V. Ramagopalan, N. J. Maugeri, L. Handunnetthi et al., “Expression of the multiple sclerosis-associated MHC class II allele HLA-DRB1*1501 is regulated by vitamin D,” PLoS Genetics, vol. 5, no. 2, article e1000369, 2009.
[86]
N. Stewart, S. Simpson Jr., I. van der Mei, et al., “Interferon-β and serum 25-hydroxyvitamin D interact to modulate relapse risk in MS,” Neurology, vol. 79, no. 3, pp. 254–260, 2012.
[87]
O. Torkildsen, K. I. L？ken-Amsrud, S. Wergeland, K. M. Myhr, and T. Holm？y, “Fat-soluble vitamins as disease modulators in multiple sclerosis,” Acta Neurologica Scandinavica. Supplement, no. 196, pp. 16–23, 2013.
[88]
M. Anagnostouli, E. Livaniou, J. O. Nyalala et al., “Cerebrospinal fluid levels of biotin in various neurological disorders,” Acta Neurologica Scandinavica, vol. 99, no. 6, pp. 387–392, 1999.
[89]
B. Kuenz, A. Lutterotti, R. Ehling et al., “Cerebrospinal fluid B cells correlate with early brain inflammation in multiple sclerosis,” PLoS One, vol. 3, no. 7, article e2559, 2008.
[90]
A. Corcione, S. Casazza, E. Ferretti et al., “Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 30, pp. 11064–11069, 2004.
[91]
C. Lee-Chang, I. Top, H. Zéphir et al., “Primed status of transitional B cells associated with their presence in the cerebrospinal fluid in early phases of multiple sclerosis,” Clinical Immunology, vol. 139, no. 1, pp. 12–20, 2011.
[92]
C. Lee-Chang, H. Zéphir, I. Top et al., “B-cell subsets up-regulate α4 integrin and accumulate in the cerebrospinal fluid in clinically isolated syndrome suggestive of multiple sclerosis onset,” Neuroscience Letters, vol. 487, no. 3, pp. 273–277, 2011.
[93]
L. Liu, M. K. Callahan, D. Huang, and R. M. Ransohoff, “Chemokine receptor CXCR3: an unexpected enigma,” Current Topics in Developmental Biology, vol. 68, pp. 149–181, 2005.
[94]
B. Broux, K. Pannemans, X. Zhang, et al., “CX3CR1 drives cytotoxic CD4+CD28？ T cells into the brain of multiple sclerosis patients,” Journal of Autoimmunity, vol. 38, no. 1, pp. 10–19, 2012.
[95]
B. Bielekova, M. Catalfamo, S. Reichert-Scrivner et al., “Regulatory natural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 15, pp. 5941–5946, 2006.
[96]
J. Hackenbrock, CD4+ and CD8+ Na？ve T Cell Homeostasis in Primary Progressive Multiple Sclerosis, McGill University, Montreal, Canada, 2008, AAT MR51275.
[97]
F. Marques, S. D. Mesquita, J. C. Sousa, et al., “Lipocalin 2 is present in the EAE brain and is modulated by natalizumab,” Frontiers in Cellular Neuroscience, vol. 6, article 33, 2012.
[98]
J. Bennett, J. Basivireddy, A. Kollar et al., “Blood-brain barrier disruption and enhanced vascular permeability in the multiple sclerosis model EAE,” Journal of Neuroimmunology, vol. 229, no. 1-2, pp. 180–191, 2010.
[99]
J. I. Alvarez, R. Cayrol, and A. Prat, “Disruption of central nervous system barriers in multiple sclerosis,” Biochimica et Biophysica Acta, vol. 1812, no. 2, pp. 252–264, 2011.
[100]
T. G. D'Aversa, E. A. Eugenin, L. Lopez, and J. W. Berman, “Myelin basic protein induces inflammatory mediators from primary human endothelial cells and blood-brain-barrier disruption: implications for the pathogenesis of multiple sclerosis,” Neuropathology and Applied Neurobiology. In press.
[101]
N. Murugesan, D. Paul, Y. Lemire, B. Shrestha, S. Ge, and J. S. Pachter, “Active induction of experimental autoimmune encephalomyelitis by MOG35-55 peptide immunization is associated with differential responses in separate compartments of the choroid plexus,” Fluids Barriers CNS, vol. 9, no. 1, article 15, 2012.
[102]
B. Engelhardt and R. M. Ransohoff, “Capture, crawl, cross: the T cell code to breach the blood-brain barriers,” Trends in Immunology, vol. 33, no. 12, pp. 579–589, 2012.
[103]
Y. Tomizawa, K. Yokoyama, S. Saiki, T. Takahashi, J. Matsuoka, and N. Hattori, “Blood-brain barrier disruption is more severe in neuromyelitis optica than in multiple sclerosis and correlates with clinical disability,” The Journal of International Medical Research, vol. 40, no. 4, pp. 1483–1491, 2012.
[104]
C. Avolio, M. Ruggieri, F. Giuliani et al., “Serum MMP-2 and MMP-9 are elevated in different multiple sclerosis subtypes,” Journal of Neuroimmunology, vol. 136, no. 1-2, pp. 46–53, 2003.
[105]
I. Ifergan, H. Kebir, S. Terouz, et al., “Role of Ninjurin-1 in the migration of myeloid cells to central nervous system inflammatory lesions,” Annals of Neurology, vol. 70, no. 5, pp. 751–763, 2011.
[106]
A. Reijerkerk, K. A. Lakeman, J. A. Drexhage, et al., “Brain endothelial barrier passage by monocytes is controlled by the endothelin system,” Journal of Neurochemistry, vol. 121, no. 5, pp. 730–737, 2012.
[107]
F. Sellebjerg, M. Christiansen, and P. Garred, “MBP, anti-MBP and anti-PLP antibodies, and intrathecal complement activation in multiple sclerosis,” Multiple Sclerosis, vol. 4, no. 3, pp. 127–131, 1998.
[108]
F. Barkhof, S. T. F. M. Frequin, O. R. Hommes et al., “A correlative triad of gadolinium-DTPA MRI, EDSS, and CSF-MBP in relapsing multiple sclerosis patients treated with high-dose intravenous methylprednisolone,” Neurology, vol. 42, no. 1, pp. 63–67, 1992.
[109]
B. Stoevring, O. Vang, and M. Christiansen, “αB-crystallin in cerebrospinal fluid of patients with multiple sclerosis,” Clinica Chimica Acta, vol. 356, no. 1-2, pp. 95–101, 2005.
[110]
J. M. van Noort, M. Bsibsi, W. H. Gerritsen et al., “αB-crystallin is a target for adaptive immune responses and a trigger of innate responses in preactive multiple sclerosis lesions,” Journal of Neuropathology and Experimental Neurology, vol. 69, no. 7, pp. 694–703, 2010.
[111]
K. Rejdak, M. J. Eikelenboom, A. Petzold et al., “CSF nitric oxide metabolites are associated with activity and progression of multiple sclerosis,” Neurology, vol. 63, no. 8, pp. 1439–1445, 2004.
[112]
A. Diestel, O. Aktas, D. Hackel et al., “Activation of microglial poly(ADP-ribose)-polymerase-1 by cholesterol breakdown products during neuroinflammation: a link between demyelination and neuronal damage,” Journal of Experimental Medicine, vol. 198, no. 11, pp. 1729–1740, 2003.
[113]
R. Srinivasan, N. Sailasuta, R. Hurd, S. Nelson, and D. Pelletier, “Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T,” Brain, vol. 128, no. 5, pp. 1016–1025, 2005.
[114]
O. Pampliega, M. Domercq, F. Soria, P. Villoslada, A. Rodriguez-Antiguedad, and C. Matute, “Increased expression of cystine/glutamate antiporter in multiple sclerosis,” Journal of Neuroinflammation, vol. 8, article 63, 2011.
[115]
C. Malmestr？m, S. Haghighi, L. Rosengren, O. Andersen, and J. Lycke, “Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS,” Neurology, vol. 61, no. 12, pp. 1720–1725, 2003.
[116]
M. Gunnarsson, C. Malmestr？m, M. Axelsson et al., “Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab,” Annals of Neurology, vol. 69, no. 1, pp. 83–89, 2011.
[117]
A. Petzold, M. J. Eikelenboom, G. Keir et al., “Axonal damage accumulates in the progressive phase of multiple sclerosis: three year follow up study,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 76, no. 2, pp. 206–211, 2005.
[118]
J. Brettschneider, A. Petzold, A. Junker, and H. Tumani, “Axonal damage markers in the cerebrospinal fluid of patients with clinically isolated syndrome improve predicting conversion to definite multiple sclerosis,” Multiple Sclerosis, vol. 12, no. 2, pp. 143–148, 2006.
[119]
Y. K. Semra, O. A. Seidi, and M. K. Sharief, “Heightened intrathecal release of axonal cytoskeletal proteins in multiple sclerosis is associated with progressive disease and clinical disability,” Journal of Neuroimmunology, vol. 122, no. 1-2, pp. 132–139, 2002.
[120]
F. Mori, S. Rossi, G. Sancesario et al., “Cognitive and cortical plasticity deficits correlate with altered amyloid-β CSF levels in multiple sclerosis,” Neuropsychopharmacology, vol. 36, no. 3, pp. 559–568, 2011.
[121]
C. E. Teunissen, P. C. Dijkstra, and C. Polman, “Biological markers in CSF and blood for axonal degeneration in multiple sclerosis,” Lancet Neurology, vol. 4, no. 1, pp. 32–41, 2005.
[122]
C. Tortorella, M. Ruggieri, E. Di Monte, E. Ceci, P. Iaffaldano, and V. Direnzo, “Serum and CSF N-acetyl aspartate levels differ in multiple sclerosis and neuromyelitis optica,” Neurology, vol. 72, pp. 1322–1329, 2009.
[123]
A. Petzold, M. J. Eikelenboom, D. Gveric et al., “Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations,” Brain, vol. 125, no. 7, pp. 1462–1473, 2002.
[124]
T. Misu, T. Takahashi, I. Nakashima, and K. Fujihara, “Biomarkers in neuromyelitis optica,” Brain Nerve, vol. 64, no. 5, pp. 525–535, 2012.
[125]
T. Misu, R. Takano, K. Fujihara, T. Takahashi, S. Sato, and Y. Itoyama, “Marked increase in cerebrospinal fluid glial fibrillar acidic protein in neuromyelitis optica: an astrocytic damage marker,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 80, no. 5, pp. 575–577, 2009.
[126]
R. Takano, T. Misu, T. Takahashi, S. Sato, K. Fujihara, and Y. Itoyama, “Astrocytic damage is far more severe than demyelination in NMO: a clinical CSF biomarker study,” Neurology, vol. 75, no. 3, pp. 208–216, 2010.
[127]
A. R. Massaro, “Are there indicators of remyelination in blood or CSF of multiple sclerosis patients?” Multiple Sclerosis, vol. 4, no. 3, pp. 228–231, 1998.
[128]
P. Sarchielli, L. Greco, A. Stipa, A. Floridi, and V. Gallai, “Brain-derived neurotrophic factor in patients with multiple sclerosis,” Journal of Neuroimmunology, vol. 132, no. 1-2, pp. 180–188, 2002.
[129]
T. Ziemssen, T. Kümpfel, H. Schneider, W. E. F. Klinkert, O. Neuhaus, and R. Hohlfeld, “Secretion of brain-derived neurotrophic factor by glatiramer acetate-reactive T-helper cell lines: implications for multiple sclerosis therapy,” Journal of the Neurological Sciences, vol. 233, no. 1-2, pp. 109–112, 2005.
[130]
A. Jurewicz, M. Matysiak, C. S. Raine, and K. Selmaj, “Soluble Nogo-A, an inhibitor of axonal regeneration, as a biomarker for multiple sclerosis,” Neurology, vol. 68, no. 4, pp. 283–287, 2007.
[131]
F. Gilli, F. Marnetto, M. Caldano et al., “Biological markers of interferon-beta therapy: comparison among interferon-stimulated genes MxA, TRAIL and XAF-1,” Multiple Sclerosis, vol. 12, no. 1, pp. 47–57, 2006.
[132]
P. Rieckmann, N. Kruse, L. Nagelkerken et al., “Soluble vascular cell adhesion molecule (VCAM) is associated with treatment effects of Interferon beta-1b in patients with Secondary Progressive Multiple Sclerosis,” Journal of Neurology, vol. 252, no. 5, pp. 526–533, 2005.
[133]
R. C. Axtell, C. Raman, and L. Steinman, “Interferon-β exacerbates Th17-mediated inflammatory disease,” Trends in Immunology, vol. 32, no. 6, pp. 272–277, 2011.
[134]
S. E. Bushnell, Z. Zhao, C. C. Stebbins, et al., “Serum IL-17F does not predict poor response to IM IFNβ-1a in relapsing-remitting MS,” Neurology, vol. 79, no. 6, pp. 531–537, 2012.
[135]
P. Wipfler, K. Oppermann, G. Pilz et al., “Adhesion molecules are promising candidates to establish surrogate markers for natalizumab treatment,” Multiple Sclerosis, vol. 17, no. 1, pp. 16–23, 2011.
[136]
K. Mitosek-Szewczyk, Z. Stelmasiak, H. Bartosik-Psujek, and E. Belniak, “Impact of cladribine on soluble adhesion molecules in multiple sclerosis,” Acta Neurologica Scandinavica, vol. 122, no. 6, pp. 409–413, 2010.
[137]
E. Grazioli, R. Zivadinov, B. Weinstock-Guttman et al., “Retinal nerve fiber layer thickness is associated with brain MRI outcomes in multiple sclerosis,” Journal of the Neurological Sciences, vol. 268, no. 1-2, pp. 12–17, 2008.
[138]
R. Herrero, E. Garcia-Martin, C. Almarcegui, et al., “Progressive degeneration of the retinal nerve fiber layer in patients with multiple sclerosis,” Investigative Ophthalmology & Visual Science, vol. 53, no. 13, pp. 8344–8349, 2012.
[139]
R. T. Shinohara, J. Goldsmith, F. J. Mateen, C. Crainiceanu, and D. S. Reich, “Predicting breakdown of the blood-brain barrier in multiple sclerosis without contrast agents,” American Journal of Neuroradiology, vol. 33, no. 8, pp. 1586–1590, 2012.
[140]
P. A. Brex, O. Ciccarelli, J. I. O'Riordan, M. Sailer, A. J. Thompson, and D. H. Miller, “A longitudinal study of abnormalities on MRI and disability from multiple sclerosis,” The New England Journal of Medicine, vol. 346, no. 3, pp. 158–164, 2002.
[141]
P. A. Brex, G. J. M. Parker, S. M. Leary et al., “Lesion heterogeneity in multiple sclerosis: a study of the relations between appearances on T1 weighted images, T1 relaxation times, and metabolite concentrations,” Journal of Neurology Neurosurgery and Psychiatry, vol. 68, no. 5, pp. 627–632, 2000.
[142]
M. A. Sahraian, E. W. Radue, S. Haller, and L. Kappos, “Black holes in multiple sclerosis: definition, evolution, and clinical correlations,” Acta Neurologica Scandinavica, vol. 122, no. 1, pp. 1–8, 2010.
[143]
N. De Stefano, A. Giorgio, M. Battaglini et al., “Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes,” Neurology, vol. 74, no. 23, pp. 1868–1876, 2010.
[144]
E. Fisher, R. A. Rudick, J. H. Simon et al., “Eight-year follow-up study of brain atrophy in patients with MS,” Neurology, vol. 59, no. 9, pp. 1412–1420, 2002.
[145]
E. Fisher, J. C. Lee, K. Nakamura, and R. A. Rudick, “Gray matter atrophy in multiple sclerosis: a longitudinal study,” Annals of Neurology, vol. 64, no. 3, pp. 255–265, 2008.
[146]
C. M. Dalton, D. T. Chard, G. R. Davies et al., “Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes,” Brain, vol. 127, no. 5, pp. 1101–1107, 2004.
[147]
W. Rashid, G. R. Davies, D. T. Chard et al., “Increasing cord atrophy in early relapsing-remitting multiple sclerosis: a 3 year study,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 77, no. 1, pp. 51–55, 2006.
[148]
I. Van Den Elskamp, D. L. Knol, H. Vrenken et al., “Lesional magnetization transfer ratio: a feasible outcome for remyelinating treatment trials in multiple sclerosis,” Multiple Sclerosis, vol. 16, no. 6, pp. 660–669, 2010.
[149]
A. Klistorner, J. Chaganti, R. Garrick, K. Moffat, and C. Yiannikas, “Magnetisation transfer ratio in optic neuritis is associated with axonal loss, but not with demyelination,” NeuroImage, vol. 56, no. 1, pp. 21–26, 2011.
[150]
R. A. Brown, S. Narayanan, and D. L. Arnold, “Segmentation of magnetization transfer ratio lesions for longitudinal analysis of demyelination and remyelination in multiple sclerosis,” NeuroImage, vol. 66, pp. 103–109, 2012.
[151]
M. Bozzali, M. Cercignani, M. P. Sormani, G. Comi, and M. Filippi, “Quantification of brain gray matter damage in different MS phenotypes by use of diffusion tensor MR imaging,” American Journal of Neuroradiology, vol. 23, no. 6, pp. 985–988, 2002.
[152]
M. Wahl, A. Hübers, B. Lauterbach-Soon et al., “Motor callosal disconnection in early relapsing-remitting multiple sclerosis,” Human Brain Mapping, vol. 32, no. 6, pp. 846–855, 2011.
[153]
Y. Liu, P. J. Mitchell, T. J. Kilpatrick, et al., “Diffusion tensor imaging of acute inflammatory lesion evolution in multiple sclerosis,” Journal of Clinical Neuroscience, vol. 19, no. 12, pp. 1689–1694, 2012.
[154]
W. Tian, T. Zhu, J. Zhong et al., “Progressive decline in fractional anisotropy on serial DTI examinations of the corpus callosum: a putative marker of disease activity and progression in SPMS,” Neuroradiology, vol. 54, no. 4, pp. 287–297, 2012.
[155]
D. J. Rigotti, M. Inglese, I. I. Kirov, et al., “Two-year serial whole-brain N-acetyl-L-aspartate in patients with relapsing-remitting multiple sclerosis,” Neurology, vol. 78, no. 18, pp. 1383–1389, 2012.
[156]
E. Hattingen, J. Magerkurth, U. Pilatus, A. Hubers, M. Wahl, and U. Ziemman, “Combined 1H and 31P spectroscopy provides new insights into the pathobiochemistry of brain damage in multiple sclerosis,” NMR in Biomedicine, vol. 24, no. 5, pp. 536–546, 2011.
[157]
I. I. Kirov, A. Tal, J. S. Babb, J. Herbert, and O. Gonen, “Serial proton MR spectroscopy of gray and white matter in relapsing-remitting MS,” Neurology, vol. 80, no. 1, pp. 39–46, 2012.
[158]
E. T. Wood, I. Ronen, A. Techawiboonwong, et al., “Investigating axonal damage in multiple sclerosis by diffusion tensor spectroscopy,” Journal of Neuroscience, vol. 32, no. 19, pp. 6665–6669, 2012.
[159]
U. Oh, M. Fujita, V. N. Ikonomidou et al., “Translocator protein PET imaging for glial activation in multiple sclerosis,” Journal of Neuroimmune Pharmacology, vol. 6, no. 3, pp. 354–361, 2011.
[160]
M. Laron, H. Cheng, B. Zhang, J. S. Schiffman, R. A. Tang, and L. J. Frishman, “Comparison of multifocal visual evoked potential, standard automated perimetry and optical coherence tomography in assessing visual pathway in multiple sclerosis patients,” Multiple Sclerosis, vol. 16, no. 4, pp. 412–426, 2010.
[161]
V. Fernández, J. Valls-Sole, J. L. Relova, et al., “Recommendations for the clinical use of motor evoked potentials in multiple sclerosis,” Neurologia. In press.
[162]
N. Margaritella, L. Mendozzi, M. Garegnani, et al., “Sensory evoked potentials to predict short-term progression of disability in multiple sclerosis,” Neurological Sciences, vol. 33, no. 4, pp. 887–892, 2012.
[163]
S. Gazioglu and C. Boz, “Ocular and cervical vestibular evoked myogenic potentials in multiple sclerosis patients,” Clinical Neurophysiology, vol. 123, no. 9, pp. 1872–1879, 2012.
[164]
N. Margaritella, L. Mendozzi, M. Garegnani, et al., “Exploring the predictive value of the evoked potentials score in MS within an appropriate patient population: a hint for an early identification of benign MS?” BMC Neurology, vol. 12, article 80, 2012.
[165]
R. Schlaeger, M. D'Souza, C. Schindler, L. Grize, L. Kappos, and P. Fuhr, “Combined evoked potentials as markers and predictors of disability in early multiple sclerosis,” Clinical Neurophysiology, vol. 123, no. 2, pp. 406–410, 2012.
[166]
V. Aghamollaii, M. H. Harirchian, A. Modabbernia, M. Ghaffarpour, M. Mousavi, and A. Tafakhori, “Sympathetic skin response (SSR) in multiple sclerosis and clinically isolated syndrome: a case-control study,” Neurophysiologie Clinique, vol. 41, no. 4, pp. 161–171, 2011.
