Skip to main content
SpringerLink
Log in

Multiple Sclerosis: Basic and Clinical

  • Chapter
  • First Online:
Neurodegenerative Diseases

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 15))

Abstract

Multiple sclerosis (MS) is the most common neurodegenerative disease affecting young adults in our community. It is a complex disease influenced by gender, genetic and environmental factors. MS is a chronic inflammatory disease of the central nervous system caused by aberrant immune activation resulting in damage to myelin sheaths within the brain and spinal cord and axonal loss. The demyelinating insult initially impairs the speed and efficiency of nerve cell function. In the majority of cases, this is followed by an innate endogenous repair response that can restore the myelin sheath and nerve cell function to relatively normal levels. However over time and with subsequent demyelinating events, this capacity is lost ultimately leading to neural degeneration. The influences that oligodendrocytes and myelin exert upon nerve cells to sustain their health and viability have begun to be identified. While immune-directed therapies can reduce the frequency of relapses and development of new lesions, they have little effect upon remyelination and nerve cell repair. This presents the next big challenge in MS therapeutics; complementing immune targeted therapies with strategies that directly target the primary cause of disability, that of remyelination.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 229.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 299.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ATP:

Adenosine triphosphate

BBB:

Blood brain barrier

B-cell:

B lymphocyte

CD:

Cluster of differentiation

CGRP:

Calcitonin gene related peptide

CI:

Confidence interval

Cnp1:

2′,3′-Cyclic nucleotide phosphodiesterase

Cox10:

Heme A:farnesyltransferase cytochrome C oxidase assembly factor

DHODH:

Dihydroorotate dehydrogenase

DMF:

Dimethyl fumarate

EAE:

Experimental autoimmune encephalomyelitis

EBNA:

Anti-EBV nuclear antigen

EBV:

Epstein-Barr virus

ECTRIMS:

   European committee for treatment and research in MS

EDSS:

Expanded disability status scale

FLAIR:

Fluid-attenuated inversion recovery

GA:

Glatiramer acetate

α-MSH:

Alpha melanocyte stimulating hormone

GAD+:

Gadolinium enhanced

GWAS:

Genome-wide association studies

HLA:

Human leukocyte antigen

HSCT:

Haematopoietic stem cell therapy

IFN-β:

Interferon beta

IgG:

Immunoglobulin G

JC virus:

John Cunningham virus

LINGO-1:

Leucine-rich repeat and Ig-containing Nogo receptor interacting protein-1

MCT:

Monocarboxylate transporter

MHC:

Major histocompatibility complex

MOG:

Myelin oligodendrocyte glycoprotein

MRI:

Magnetic resonance imaging

MS:

Multiple sclerosis

MyRF:

Myelin gene regulatory factor

NEDA:

No evidence of disease activity

NF-κβ:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NK cells:

Natural killer cells

Nrf-2:

Nuclear factor erythroid 2-related factor 2

OPERA:

A clinical trial into the efficacy of ocrelizumab in RRMS and SPMS

ORATORIO:

A clinical trial into the efficacy of ocrelizumab in PPMS

Plp1:

Proteo-lipid protein 1

PML:

Progressive multifocal leukoencephalopathy

PPMS:

Primary progressive MS

RR:

Risk ratio

RRMS:

Relapsing-remitting MS

SNPs:

Single nucleotide polymorphisms

SPMS:

Secondary progressive MS

T1:

Longitudinal relaxation time

T-cell:

T-lymphocyte

T-reg:

Regulatory T cell

TEMSO:

Teriflunomide Multiple Sclerosis Oral

Th:

T helper, subsets of T-cells

UVR:

Ultraviolet radiation

VCAM1:

Vascular cell adhesion molecule-1

VLA-4:

Very late antigen-4, alpha 4 integrin

References

  1. Orton SM, Herrera BM, Yee IM, Valdar W, Ramagopalan SV, Sadovnick AD et al (2006) Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol 5(11):932–936

    Article  PubMed  Google Scholar 

  2. Multiple Sclerosis International Federation (2015) Atlas of MS: mapping multiple sclerosis around the world. Available from http://www.msif.org/about-us/advocacy/atlas/atlas-of-ms/. Accessed 6 Sept 2015

  3. Patani R, Balaratnam M, Vora A, Reynolds R (2007) Remyelination can be extensive in multiple sclerosis despite a long disease course. Neuropathol Appl Neurobiol 33(3):277–287

    Article  CAS  PubMed  Google Scholar 

  4. Patrikios P, Stadelmann C, Kutzelnigg A, Rauschka H, Schmidbauer M, Laursen H et al (2006) Remyelination is extensive in a subset of multiple sclerosis patients. Brain 129(Pt 12):3165–3172

    Article  PubMed  Google Scholar 

  5. Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis—the plaque and its pathogenesis. N Engl J Med 354(9):942–955

    Article  CAS  PubMed  Google Scholar 

  6. Lassmann H, Bruck W, Lucchinetti CF (2007) The immunopathology of multiple sclerosis: an overview. Brain Pathol 17(2):210–218

    Article  PubMed  Google Scholar 

  7. GF W, Alvarez E (2011) The immunopathophysiology of multiple sclerosis. Neurol Clin 29(2):257–278

    Article  Google Scholar 

  8. Prineas JW, Kwon EE, Cho ES, Sharer LR, Barnett MH, Oleszak EL et al (2001) Immunopathology of secondary-progressive multiple sclerosis. Ann Neurol 50(5):646–657

    Article  CAS  PubMed  Google Scholar 

  9. Amato MP, Portaccio E, Goretti B, Zipoli V, Battaglini M, Bartolozzi ML et al (2007) Association of neocortical volume changes with cognitive deterioration in relapsing-remitting multiple sclerosis. Arch Neurol 64(8):1157–1161

    Article  PubMed  Google Scholar 

  10. Brink BP, Veerhuis R, Breij EC, van der Valk P, Dijkstra CD, Bo L (2005) The pathology of multiple sclerosis is location-dependent: no significant complement activation is detected in purely cortical lesions. J Neuropathol Exp Neurol 64(2):147–155

    Article  CAS  PubMed  Google Scholar 

  11. Peterson JW, Bo L, Mork S, Chang A, Trapp BD (2001) Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50(3):389–400

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  13. Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F (2004) Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 14(2):164–174

    Article  PubMed  Google Scholar 

  14. Lovato L, Willis SN, Rodig SJ, Caron T, Almendinger SE, Howell OW et al (2011) Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis. Brain 134(Pt 2):534–541

    Article  PubMed  PubMed Central  Google Scholar 

  15. Allen IV, McQuaid S, Mirakhur M, Nevin G (2001) Pathological abnormalities in the normal-appearing white matter in multiple sclerosis. Neurol Sci 22(2):141–144

    Article  CAS  PubMed  Google Scholar 

  16. Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M et al (2005) Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128(Pt 11):2705–2712

    Article  PubMed  Google Scholar 

  17. O’Gorman C, Lin R, Stankovich J, Broadley SA (2013) Modelling genetic susceptibility to multiple sclerosis with family data. Neuroepidemiology 40(1):1–12

    Article  PubMed  Google Scholar 

  18. International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium, Sawcer S, Hellenthal G, Pirinen M, Spencer CC et al (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476(7359):214–219

    Article  CAS  Google Scholar 

  19. Patsopoulos NA, Barcellos LF, Hintzen RQ, Schaefer C, van Duijn CM, Noble JA et al (2013) Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects. PLoS Genet 9(11):e1003926

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Sawcer S, Franklin RJ, Ban M (2014) Multiple sclerosis genetics. Lancet Neurol 13(7):700–709

    Article  CAS  PubMed  Google Scholar 

  21. International Multiple Sclerosis Genetics Consortium, Beecham AH, Patsopoulos NA, Xifara DK, Davis MF, Kemppinen A et al (2013) Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 45(11):1353–1360

    Article  CAS  Google Scholar 

  22. Simpson S Jr, Blizzard L, Otahal P, Van der Mei I, Taylor B (2011) Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry 82(10):1132–1141

    Article  PubMed  Google Scholar 

  23. McLeod JG, Hammond SR, Kurtzke JF (2011) Migration and multiple sclerosis in immigrants to Australia from United Kingdom and Ireland: a reassessment. I. Risk of MS by age at immigration. J Neurol 258(6):1140–1149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mokry LE, Ross S, Ahmad OS, Forgetta V, Smith GD, Leong A, et al. (2015) Vitamin D and risk of multiple sclerosis: a mendelian randomization study. PLoS Med 12(8):e1001866

    Google Scholar 

  25. Kuhle J, Disanto G, Dobson R, Adiutori R, Bianchi L, Topping J et al (2015) Conversion from clinically isolated syndrome to multiple sclerosis: a large multicentre study. Mult Scler 21(8):1013–1024

    Article  CAS  PubMed  Google Scholar 

  26. Simpson S Jr, Taylor B, Blizzard L, Ponsonby AL, Pittas F, Tremlett H et al (2010) Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol 68(2):193–203

    CAS  PubMed  Google Scholar 

  27. Mowry EM, Waubant E, McCulloch CE, Okuda DT, Evangelista AA, Lincoln RR et al (2012) Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol 72(2):234–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Thouvenot E, Orsini M, Daures JP, Camu W (2015) Vitamin D is associated with degree of disability in patients with fully ambulatory relapsing-remitting multiple sclerosis. Eur J Neurol 22(3):564–569

    Article  CAS  PubMed  Google Scholar 

  29. Ramagopalan SV, Dyment DA, Cader MZ, Morrison KM, Disanto G, Morahan JM et al (2011) Rare variants in the CYP27B1 gene are associated with multiple sclerosis. Ann Neurol 70(6):881–886

    Article  CAS  PubMed  Google Scholar 

  30. Peelen E, Knippenberg S, Muris AH, Thewissen M, Smolders J, Tervaert JW et al (2011) Effects of vitamin D on the peripheral adaptive immune system: a review. Autoimmun Rev 10(12):733–743

    Article  CAS  PubMed  Google Scholar 

  31. Pozuelo-Moyano B, Benito-Leon J, Mitchell AJ, Hernandez-Gallego J (2013) A systematic review of randomized, double-blind, placebo-controlled trials examining the clinical efficacy of vitamin D in multiple sclerosis. Neuroepidemiology 40(3):147–153

    Article  PubMed  Google Scholar 

  32. Lucas RM, Ponsonby AL, Dear K, Valery PC, Pender MP, Taylor BV et al (2011) Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology 76(6):540–548

    Article  CAS  PubMed  Google Scholar 

  33. Lucas RM, Ponsonby AL (2006) Considering the potential benefits as well as adverse effects of sun exposure: can all the potential benefits be provided by oral vitamin D supplementation? Prog Biophys Mol Biol 92(1):140–149

    Article  CAS  PubMed  Google Scholar 

  34. Ponsonby AL, Lucas RM, van der Mei IA (2005) UVR, vitamin D and three autoimmune diseases–multiple sclerosis, type 1 diabetes, rheumatoid arthritis. Photochem Photobiol 81(6):1267–1275

    Article  CAS  PubMed  Google Scholar 

  35. Seiffert K, Granstein RD (2002) Neuropeptides and neuroendocrine hormones in ultraviolet radiation-induced immunosuppression. Methods 28(1):97–103

    Article  CAS  PubMed  Google Scholar 

  36. Maestroni GJ (2001) The immunotherapeutic potential of melatonin. Expert Opin Investig Drugs 10(3):467–476

    Article  CAS  PubMed  Google Scholar 

  37. Hart PH, Gorman S, Finlay-Jones JJ (2011) Modulation of the immune system by UV radiation: more than just the effects of vitamin D? Nat Rev Immunol 11(9):584–596

    Article  CAS  PubMed  Google Scholar 

  38. Registry AaNZCT (2014) In patients with Clinically Isolated Syndrome, can narrow band UVB therapy decrease the risk of developing Multiple Sclerosis over the 12 months from their first demyelinating event? Available from www.anzctr.org.au/ACTRN12614000185662.aspx

  39. Ascherio A, Munger KL (2007) Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol 61(4):288–299

    Article  PubMed  Google Scholar 

  40. Thacker EL, Mirzaei F, Ascherio A (2006) Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann Neurol 59(3):499–503

    Article  PubMed  Google Scholar 

  41. Munger KL, Levin LI, O’Reilly EJ, Falk KI, Ascherio A (2011) Anti-Epstein-Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel. Mult Scler 17(10):1185–1193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lunemann JD, Munz C (2009) EBV in MS: guilty by association? Trends Immunol 30(6):243–248

    Article  PubMed  CAS  Google Scholar 

  43. Pender MP, Csurhes PA, Pfluger CM, Burrows SR (2014) Deficiency of CD8+ effector memory T cells is an early and persistent feature of multiple sclerosis. Mult Scler 20(14):1825–1832

    Article  PubMed  PubMed Central  Google Scholar 

  44. Pender MP (2011) The essential role of Epstein-Barr virus in the pathogenesis of multiple sclerosis. Neuroscientist 17(4):351–367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wingerchuk DM (2012) Smoking: effects on multiple sclerosis susceptibility and disease progression. Ther Adv Neurol Disord 5(1):13–22

    Article  PubMed  PubMed Central  Google Scholar 

  46. Ramanujam R, Hedstrom AK, Manouchehrinia A, Alfredsson L, Olsson T, Bottai M et al (2015) Effect of smoking cessation on multiple sclerosis prognosis. JAMA Neurol 72(10):1117–1123

    Article  PubMed  Google Scholar 

  47. Munger KL, Bentzen J, Laursen B, Stenager E, Koch-Henriksen N, Sorensen TI et al (2013) Childhood body mass index and multiple sclerosis risk: a long-term cohort study. Mult Scler 19(10):1323–1329

    Article  PubMed  PubMed Central  Google Scholar 

  48. Munger KL, Chitnis T, Ascherio A (2009) Body size and risk of MS in two cohorts of US women. Neurology 73(19):1543–1550

    Article  PubMed  PubMed Central  Google Scholar 

  49. Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA et al (2013) Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496(7446):518–522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Farez MF, Fiol MP, Gaitan MI, Quintana FJ, Correale J (2015) Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry 86(1):26–31

    Article  PubMed  Google Scholar 

  51. Campbell AW (2014) Autoimmunity and the gut. Autoimmune Dis 2014:152428

    PubMed  PubMed Central  Google Scholar 

  52. Wang Y, Kasper LH (2014) The role of microbiome in central nervous system disorders. Brain Behav Immun 38:1–12

    Article  PubMed  CAS  Google Scholar 

  53. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD et al (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International panel on the diagnosis of multiple sclerosis. Ann Neurol 50(1):121–127

    Article  CAS  PubMed  Google Scholar 

  54. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M et al (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69(2):292–302

    Article  PubMed  PubMed Central  Google Scholar 

  55. Confavreux C, Vukusic S (2006) Natural history of multiple sclerosis: a unifying concept. Brain 129(Pt 3):606–616

    Article  PubMed  Google Scholar 

  56. Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J et al (1989) The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 112(Pt 1):133–146

    Article  PubMed  Google Scholar 

  57. Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sorensen PS, Thompson AJ et al (2014) Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 83(3):278–286

    Article  PubMed  PubMed Central  Google Scholar 

  58. Bergamaschi R (2007) Prognostic factors in multiple sclerosis. Int Rev Neurobiol 79:423–447

    Article  PubMed  Google Scholar 

  59. Degenhardt A, Ramagopalan SV, Scalfari A, Ebers GC (2009) Clinical prognostic factors in multiple sclerosis: a natural history review. Nat Rev Neurol 5(12):672–682

    Article  PubMed  Google Scholar 

  60. Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33(11):1444–1452

    Article  CAS  PubMed  Google Scholar 

  61. De Stefano N, Airas L, Grigoriadis N, Mattle HP, O’Riordan J, Oreja-Guevara C et al (2014) Clinical relevance of brain volume measures in multiple sclerosis. CNS Drugs 28(2):147–156

    Article  PubMed  Google Scholar 

  62. Chard DT, Griffin CM, Parker GJ, Kapoor R, Thompson AJ, Miller DH (2002) Brain atrophy in clinically early relapsing-remitting multiple sclerosis. Brain 125(Pt 2):327–337

    Article  CAS  PubMed  Google Scholar 

  63. Horakova D, Kalincik T, Dusankova JB, Dolezal O (2012) Clinical correlates of grey matter pathology in multiple sclerosis. BMC Neurol 12:10

    Article  PubMed  PubMed Central  Google Scholar 

  64. Fisniku LK, Chard DT, Jackson JS, Anderson VM, Altmann DR, Miszkiel KA et al (2008) Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol 64(3):247–254

    Article  PubMed  Google Scholar 

  65. Paty DW, Li DK (1993) Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI study group and the IFNB multiple sclerosis study group. Neurology 43(4):662–667

    Article  CAS  PubMed  Google Scholar 

  66. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM et al (1996) Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The multiple sclerosis collaborative research group (MSCRG). Ann Neurol 39(3):285–294

    Article  CAS  PubMed  Google Scholar 

  67. Ebers GC (1998) PRISMS (prevention of relapses and disability by interferon β-1a subcutaneously in multiple sclerosis) study group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 352(9139):1498–1504

    Google Scholar 

  68. The IFNB Multiple sclerosis study group (1993) Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43(4):655–661

    Google Scholar 

  69. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP et al (1995) Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The copolymer 1 multiple sclerosis study group. Neurology 45(7):1268–1276

    Article  CAS  PubMed  Google Scholar 

  70. Comi G, Filippi M, Wolinsky JS (2001) European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging--measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer acetate study group. Ann Neurol 49(3):290–297

    Article  CAS  PubMed  Google Scholar 

  71. Comi G, Martinelli V, Rodegher M, Moiola L, Bajenaru O, Carra A et al (2009) Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet 374(9700):1503–1511

    Article  CAS  PubMed  Google Scholar 

  72. Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH et al (2006) Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 67(7):1242–1249

    Article  CAS  PubMed  Google Scholar 

  73. Kozovska ME, Hong J, Zang YC, Li S, Rivera VM, Killian JM et al (1999) Interferon beta induces T-helper 2 immune deviation in MS. Neurology 53(8):1692–1697

    Article  CAS  PubMed  Google Scholar 

  74. Liu Z, Pelfrey CM, Cotleur A, Lee JC, Rudick RA (2001) Immunomodulatory effects of interferon beta-1a in multiple sclerosis. J Neuroimmunol 112(1–2):153–162

    Article  CAS  PubMed  Google Scholar 

  75. Ozenci V, Kouwenhoven M, Huang YM, Xiao B, Kivisakk P, Fredrikson S et al (1999) Multiple sclerosis: levels of interleukin-10-secreting blood mononuclear cells are low in untreated patients but augmented during interferon-beta-1b treatment. Scand J Immunol 49(5):554–561

    Article  CAS  PubMed  Google Scholar 

  76. Zhang L, Yuan S, Cheng G, Guo B (2011) Type I IFN promotes IL-10 production from T cells to suppress Th17 cells and Th17-associated autoimmune inflammation. PLoS One 6(12):e28432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kieseier BC (2011) The mechanism of action of interferon-beta in relapsing multiple sclerosis. CNS Drugs 25(6):491–502

    Article  CAS  PubMed  Google Scholar 

  78. Vandenbark AA, Huan J, Agotsch M, La Tocha D, Goelz S, Offner H et al (2009) Interferon-beta-1a treatment increases CD56bright natural killer cells and CD4+CD25+ Foxp3 expression in subjects with multiple sclerosis. J Neuroimmunol 215(1–2):125–128

    Article  CAS  PubMed  Google Scholar 

  79. de Andres C, Aristimuno C, de Las Heras V, Martinez-Gines ML, Bartolome M, Arroyo R et al (2007) Interferon beta-1a therapy enhances CD4+ regulatory T-cell function: an ex vivo and in vitro longitudinal study in relapsing-remitting multiple sclerosis. J Neuroimmunol 182(1–2):204–211

    Article  PubMed  CAS  Google Scholar 

  80. Korporal M, Haas J, Balint B, Fritzsching B, Schwarz A, Moeller S et al (2008) Interferon beta-induced restoration of regulatory T-cell function in multiple sclerosis is prompted by an increase in newly generated naive regulatory T cells. Arch Neurol 65(11):1434–1439

    Article  PubMed  Google Scholar 

  81. Boutros T, Croze E, Yong VW (1997) Interferon-beta is a potent promoter of nerve growth factor production by astrocytes. J Neurochem 69(3):939–946

    Article  CAS  PubMed  Google Scholar 

  82. Biernacki K, Antel JP, Blain M, Narayanan S, Arnold DL, Prat A (2005) Interferon beta promotes nerve growth factor secretion early in the course of multiple sclerosis. Arch Neurol 62(4):563–568

    Article  PubMed  Google Scholar 

  83. Ramgolam VS, Sha Y, Marcus KL, Choudhary N, Troiani L, Chopra M et al (2011) B cells as a therapeutic target for IFN-beta in relapsing-remitting multiple sclerosis. J Immunol 186(7):4518–4526

    Article  CAS  PubMed  Google Scholar 

  84. Teitelbaum D, Meshorer A, Hirshfeld T, Arnon R, Sela M (1971) Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur J Immunol 1(4):242–248

    Article  CAS  PubMed  Google Scholar 

  85. Kala M, Miravalle A, Vollmer T (2011) Recent insights into the mechanism of action of glatiramer acetate. J Neuroimmunol 235(1–2):9–17

    Article  CAS  PubMed  Google Scholar 

  86. Vieira PL, Heystek HC, Wormmeester J, Wierenga EA, Kapsenberg ML (2003) Glatiramer acetate (copolymer-1, copaxone) promotes Th2 cell development and increased IL-10 production through modulation of dendritic cells. J Immunol 170(9):4483–4488

    Article  CAS  PubMed  Google Scholar 

  87. Aharoni R, Eilam R, Stock A, Vainshtein A, Shezen E, Gal H et al (2010) Glatiramer acetate reduces Th-17 inflammation and induces regulatory T-cells in the CNS of mice with relapsing-remitting or chronic EAE. J Neuroimmunol 225(1–2):100–111

    Article  CAS  PubMed  Google Scholar 

  88. Lalive PH, Neuhaus O, Benkhoucha M, Burger D, Hohlfeld R, Zamvil SS et al (2011) Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action. CNS Drugs 25(5):401–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Arnon R, Aharoni R (2004) Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications. Proc Natl Acad Sci U S A 101(Suppl 2):14593–14598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Sarchielli P, Zaffaroni M, Floridi A, Greco L, Candeliere A, Mattioni A et al (2007) Production of brain-derived neurotrophic factor by mononuclear cells of patients with multiple sclerosis treated with glatiramer acetate, interferon-beta 1a, and high doses of immunoglobulins. Mult Scler 13(3):313–331

    Article  CAS  PubMed  Google Scholar 

  91. Aharoni R, Eilam R, Domev H, Labunskay G, Sela M, Arnon R (2005) The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice. Proc Natl Acad Sci U S A 102(52):19045–19050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH et al (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354(9):899–910

    Article  CAS  PubMed  Google Scholar 

  93. Pucci E, Giuliani G, Solari A, Simi S, Minozzi S, Di Pietrantonj C et al (2011) Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev 10:CD007621

    Google Scholar 

  94. Rice GP, Hartung HP, Calabresi PA (2005) Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology 64(8):1336–1342

    Article  CAS  PubMed  Google Scholar 

  95. Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D (2005) Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 353(4):375–381

    Article  CAS  PubMed  Google Scholar 

  96. Major EO, Ault GS (1995) Progressive multifocal leukoencephalopathy: clinical and laboratory observations on a viral induced demyelinating disease in the immunodeficient patient. Curr Opin Neurol 8(3):184–190

    Article  CAS  PubMed  Google Scholar 

  97. Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A et al (2012) Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 366(20):1870–1880

    Article  CAS  PubMed  Google Scholar 

  98. Plavina T, Subramanyam M, Bloomgren G, Richman S, Pace A, Lee S et al (2014) Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 76(6):802–812

    Article  CAS  PubMed  Google Scholar 

  99. Cohen JA, Chun J (2011) Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis. Ann Neurol 69(5):759–777

    Article  CAS  PubMed  Google Scholar 

  100. Mehling M, Lindberg R, Raulf F, Kuhle J, Hess C, Kappos L et al (2010) Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology 75(5):403–410

    Article  CAS  PubMed  Google Scholar 

  101. Chun J, Brinkmann V (2011) A mechanistically novel, first oral therapy for multiple sclerosis: the development of fingolimod (FTY720, Gilenya). Discov Med 12(64):213–228

    PubMed  PubMed Central  Google Scholar 

  102. Khatri B, Barkhof F, Comi G, Hartung HP, Kappos L, Montalban X et al (2011) Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol 10(6):520–529

    Article  CAS  PubMed  Google Scholar 

  103. Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P et al (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362(5):387–401

    Article  CAS  PubMed  Google Scholar 

  104. Radue EW, O’Connor P, Polman CH, Hohlfeld R, Calabresi P, Selmaj K et al (2012) Impact of fingolimod therapy on magnetic resonance imaging outcomes in patients with multiple sclerosis. Arch Neurol 69(10):1259–1269

    Article  PubMed  Google Scholar 

  105. Novartis Media Release (2014) Novartis provides update on fingolimod Phase III trial in primary progressive MS (PPMS). Available from https://www.novartis.com/news/media-releases/novartis-provides-update-fingolimod-phase-iii-trial-primary-progressive-ms-ppms

  106. U.S. Food and Drug Administration FDA (2015) Drug Safety Communication: FDA warns about cases of rare brain infection with MS drug Gilenya (fingolimod) in two patients with no prior exposure to immunosuppressant drugs. Available from http://www.fda.gov/Drugs/DrugSafety/ucm456919.htm

  107. Van Schependom J, Gielen J, Laton J, Nagels G (2016) Assessing PML risk under immunotherapy: if all you have is a hammer, everything looks like a nail. Mult Scler 22(3):389–392

    Article  PubMed  CAS  Google Scholar 

  108. Altmeyer PJ, Matthes U, Pawlak F, Hoffmann K, Frosch PJ, Ruppert P et al (1994) Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J Am Acad Dermatol 30(6):977–981

    Article  CAS  PubMed  Google Scholar 

  109. Albrecht P, Bouchachia I, Goebels N, Henke N, Hofstetter HH, Issberner A et al (2012) Effects of dimethyl fumarate on neuroprotection and immunomodulation. J Neuroinflammation 9:163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Scannevin RH, Chollate S, Jung MY, Shackett M, Patel H, Bista P et al (2012) Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther 341(1):274–284

    Article  CAS  PubMed  Google Scholar 

  111. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K et al (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 367(12):1098–1107

    Article  CAS  PubMed  Google Scholar 

  112. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M et al (2012) Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 367(12):1087–1097

    Article  CAS  PubMed  Google Scholar 

  113. van Oosten BW, Killestein J, Barkhof F, Polman CH, Wattjes MP (2013) PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med 368(17):1658–1659

    Article  PubMed  CAS  Google Scholar 

  114. Ermis U, Weis J, Schulz JB (2013) PML in a patient treated with fumaric acid. N Engl J Med 368(17):1657–1658

    Article  CAS  PubMed  Google Scholar 

  115. Claussen MC, Korn T (2012) Immune mechanisms of new therapeutic strategies in MS: teriflunomide. Clin Immunol 142(1):49–56

    Article  CAS  PubMed  Google Scholar 

  116. O’Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP et al (2011) Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 365(14):1293–1303

    Article  PubMed  Google Scholar 

  117. Confavreux C, O’Connor P, Comi G, Freedman MS, Miller AE, Olsson TP et al (2014) Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 13(3):247–256

    Article  CAS  PubMed  Google Scholar 

  118. Radue E-W, Sprenger T, Gaetano L, Mueller-Lenke N, Wuerfel J, Wolinsky JS et al (2015) Terifunomide slows brain volume loss in relapsing MS: a SIENA analysis of the TEMSO MRI dataset. 31st Congress of the European Committee for the Treatment and Research in Multiple Sclerosis; Barcelona, Spain. Abstract 229

    Google Scholar 

  119. Gilleece MH, Dexter TM (1993) Effect of Campath-1H antibody on human hematopoietic progenitors in vitro. Blood 82(3):807–812

    CAS  PubMed  Google Scholar 

  120. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ et al (2012) Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 380(9856):1829–1839

    Article  CAS  PubMed  Google Scholar 

  121. Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J et al (2006) The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol 253(1):98–108

    Article  PubMed  Google Scholar 

  122. Gold R, Giovannoni G, Selmaj K, Havrdova E, Montalban X, Radue EW et al (2013) Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet 381(9884):2167–2175

    Article  CAS  PubMed  Google Scholar 

  123. Wynn D, Kaufman M, Montalban X, Vollmer T, Simon J, Elkins J et al (2010) Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol 9(4):381–390

    Article  CAS  PubMed  Google Scholar 

  124. Rose JW, Watt HE, White AT, Carlson NG (2004) Treatment of multiple sclerosis with an anti-interleukin-2 receptor monoclonal antibody. Ann Neurol 56(6):864–867

    Article  CAS  PubMed  Google Scholar 

  125. Kappos L, Wiendl H, Selmaj K, Arnold DL, Havrdova E, Boyko A et al (2015) Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 373(15):1418–1428

    Article  CAS  PubMed  Google Scholar 

  126. Hao J, Campagnolo D, Liu R, Piao W, Shi S, Hu B et al (2011) Interleukin-2/interleukin-2 antibody therapy induces target organ natural killer cells that inhibit central nervous system inflammation. Ann Neurol 69(4):721–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Bielekova B, Howard T, Packer AN, Richert N, Blevins G, Ohayon J et al (2009) Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis. Arch Neurol 66(4):483–489

    Article  PubMed  PubMed Central  Google Scholar 

  128. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ et al (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358(7):676–688

    Article  CAS  PubMed  Google Scholar 

  129. Hawker K, O’Connor P, Freedman MS, Calabresi PA, Antel J, Simon J et al (2009) Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 66(4):460–471

    Article  CAS  PubMed  Google Scholar 

  130. Hauser SL, Comi GC, Hartung H-P, Selmaj K, Traboulsee A, Bar-Or A et al (2015) Efficacy and safety of ocrelizumab in relapsing multiple sclerosis–results of the interferon-beta-1a-controlled, double-blind, Phase III OPERA I and II studies. 31st Congress of the European Committee for the Treatment and Research in Multiple Sclerosis, Barcelona, Spain. Abstract 190

    Google Scholar 

  131. Montalban X, Hemmer B, Rammohan K, Giovannoni G, Seze JD, Bar-Or A et al (2015) Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis—results of the placebo-controlled, double-blind, Phase III ORATORIO study. 31st Congress of the European Committee for the Treatment and Research in Multiple Sclerosis; Barcelona, Spain. Abstract 228

    Google Scholar 

  132. Karussis D, Petrou P, Vourka-Karussis U, Kassis I (2013) Hematopoietic stem cell transplantation in multiple sclerosis. Expert Rev Neurother 13(5):567–578

    Article  CAS  PubMed  Google Scholar 

  133. Reston JT, Uhl S, Treadwell JR, Nash RA, Schoelles K (2011) Autologous hematopoietic cell transplantation for multiple sclerosis: a systematic review. Mult Scler 17(2):204–213

    Article  PubMed  Google Scholar 

  134. Mancardi G, Saccardi R (2008) Autologous haematopoietic stem-cell transplantation in multiple sclerosis. Lancet Neurol 7(7):626–636

    Article  PubMed  Google Scholar 

  135. Radaelli M, Merlini A, Greco R, Sangalli F, Comi G, Ciceri F et al (2014) Autologous bone marrow transplantation for the treatment of multiple sclerosis. Curr Neurol Neurosci Rep 14(9):478

    Article  PubMed  CAS  Google Scholar 

  136. Cohen JA (2013) Mesenchymal stem cell transplantation in multiple sclerosis. J Neurol Sci 333(1–2):43–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Mohyeddin Bonab M, Yazdanbakhsh S, Lotfi J, Alimoghaddom K, Talebian F, Hooshmand F et al (2007) Does mesenchymal stem cell therapy help multiple sclerosis patients? Report of a pilot study. Iran J Immunol 4(1):50–57

    PubMed  Google Scholar 

  138. Yamout B, Hourani R, Salti H, Barada W, El-Hajj T, Al-Kutoubi A et al (2010) Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study. J Neuroimmunol 227(1–2):185–189

    Article  CAS  PubMed  Google Scholar 

  139. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I et al (2010) Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 67(10):1187–1194

    Article  PubMed  PubMed Central  Google Scholar 

  140. U.S. National Institutes of Health (2014) Autologous Mesenchymal Stem Cell (MSC) Transplantation in MS 2014. Available from https://clinicaltrials.gov/ct2/show/NCT00813969

  141. Carrithers MD (2014) Update on disease-modifying treatments for multiple sclerosis. Clin Ther 36(12):1938–1945

    Article  CAS  PubMed  Google Scholar 

  142. Rice CM (2014) Disease modification in multiple sclerosis: an update. Pract Neurol 14(1):6–13

    Article  PubMed  Google Scholar 

  143. U.S. National Institutes of Health (2015) Study to assess the efficacy, safety, tolerability, and pharmacokinetics of BIIB033 in participants with relapsing forms of multiple sclerosis when used concurrently with avonex (SYNERGY). Available from https://clinicaltrials.gov/ct2/show/NCT01864148

  144. Mi S, Hu B, Hahm K, Luo Y, Kam Hui ES, Yuan Q et al (2007) LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat Med 13(10):1228–1233

    Article  CAS  PubMed  Google Scholar 

  145. Mi S, Miller RH, Tang W, Lee X, Hu B, Wu W et al (2009) Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells. Ann Neurol 65(3):304–315

    Article  CAS  PubMed  Google Scholar 

  146. Mi S, Pepinsky RB, Cadavid D (2013) Blocking LINGO-1 as a therapy to promote CNS repair: from concept to the clinic. CNS Drugs 27(7):493–503

    Article  CAS  PubMed  Google Scholar 

  147. Tran JQ, Rana J, Barkhof F, Melamed I, Gevorkyan H, Wattjes MP et al (2014) Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033. Neurol Neuroimmunol Neuroinflamm 1(2):e18

    Article  PubMed  PubMed Central  Google Scholar 

  148. Cadavid D, Balcer LJ, Galetta S, Aktas O, Ziemssen T, Vanopdenbosch L et al (eds) (2015) Efficacy analysis of the anti-LINGO-1 monoclonal antibody BIIB033 in Acute Optic Neuritis: The RENEW Trial Neurology 84(14), supplement P7202. American Academy of Neurology, Washington, DC

    Google Scholar 

  149. Health USNIo (2015) 215ON201 BIIB033 in Acute Optic Neuritis (AON) (RENEW). Available from https://clinicaltrials.gov/ct2/show/NCT01721161

  150. Hagemeier K, Bruck W, Kuhlmann T (2012) Multiple sclerosis—remyelination failure as a cause of disease progression. Histol Histopathol 27(3):277–287

    CAS  PubMed  Google Scholar 

  151. Trapp BD, Nave KA (2008) Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 31:247–269

    Article  CAS  PubMed  Google Scholar 

  152. Ransohoff RM (2012) Animal models of multiple sclerosis: the good, the bad and the bottom line. Nat Neurosci 15(8):1074–1077

    Article  CAS  PubMed  Google Scholar 

  153. van der Star BJ, Vogel DY, Kipp M, Puentes F, Baker D, Amor S (2012) In vitro and in vivo models of multiple sclerosis. CNS Neurol Disord Drug Targets 11(5):570–588

    Article  PubMed  Google Scholar 

  154. Denic A, Johnson AJ, Bieber AJ, Warrington AE, Rodriguez M, Pirko I (2011) The relevance of animal models in multiple sclerosis research. Pathophysiology 18(1):21–29

    Article  CAS  PubMed  Google Scholar 

  155. Kipp M, van der Star B, Vogel DY, Puentes F, van der Valk P, Baker D et al (2012) Experimental in vivo and in vitro models of multiple sclerosis: EAE and beyond. Mult Scler Relat Disord 1(1):15–28

    Article  PubMed  Google Scholar 

  156. Libbey JE, Fujinami RS (2011) Experimental autoimmune encephalomyelitis as a testing paradigm for adjuvants and vaccines. Vaccine 29(17):3356–3362

    Article  CAS  PubMed  Google Scholar 

  157. Steinman L, Zamvil SS (2005) Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis. Trends Immunol 26(11):565–571

    Article  CAS  PubMed  Google Scholar 

  158. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD et al (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523(7560):337–341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Chang A, Tourtellotte WW, Rudick R, Trapp BD (2002) Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 346(3):165–173

    Article  PubMed  Google Scholar 

  160. Franklin RJ (2002) Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci 3(9):705–714

    Article  CAS  PubMed  Google Scholar 

  161. Kuhlmann T, Miron V, Cui Q, Wegner C, Antel J, Bruck W (2008) Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain 131(Pt 7):1749–1758

    Article  CAS  PubMed  Google Scholar 

  162. Wolswijk G (1998) Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci 18(2):601–609

    CAS  PubMed  Google Scholar 

  163. Hall SM (1972) The effect of injections of lysophosphatidyl choline into white matter of the adult mouse spinal cord. J Cell Sci 10(2):535–546

    CAS  PubMed  Google Scholar 

  164. Yajima K, Suzuki K (1979) Demyelination and remyelination in the rat central nervous system following ethidium bromide injection. Lab Invest 41(5):385–392

    CAS  PubMed  Google Scholar 

  165. Blakemore WF (1972) Observations on oligodendrocyte degeneration, the resolution of status spongiosus and remyelination in cuprizone intoxication in mice. J Neurocytol 1(4):413–426

    Article  CAS  PubMed  Google Scholar 

  166. Woodruff RH, Franklin RJ (1999) Demyelination and remyelination of the caudal cerebellar peduncle of adult rats following stereotaxic injections of lysolecithin, ethidium bromide, and complement/anti-galactocerebroside: a comparative study. Glia 25(3):216–228

    Article  CAS  PubMed  Google Scholar 

  167. Huang JK, Jarjour AA, Nait Oumesmar B, Kerninon C, Williams A, Krezel W et al (2011) Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci 14(1):45–53

    Article  CAS  PubMed  Google Scholar 

  168. Norkute A, Hieble A, Braun A, Johann S, Clarner T, Baumgartner W et al (2009) Cuprizone treatment induces demyelination and astrocytosis in the mouse hippocampus. J Neurosci Res 87(6):1343–1355

    Article  CAS  PubMed  Google Scholar 

  169. Pott F, Gingele S, Clarner T, Dang J, Baumgartner W, Beyer C et al (2009) Cuprizone effect on myelination, astrogliosis and microglia attraction in the mouse basal ganglia. Brain Res 1305:137–149

    Article  CAS  PubMed  Google Scholar 

  170. Kipp M, Clarner T, Dang J, Copray S, Beyer C (2009) The cuprizone animal model: new insights into an old story. Acta Neuropathol 118(6):723–736

    Article  PubMed  Google Scholar 

  171. Groebe A, Clarner T, Baumgartner W, Dang J, Beyer C, Kipp M (2009) Cuprizone treatment induces distinct demyelination, astrocytosis, and microglia cell invasion or proliferation in the mouse cerebellum. Cerebellum 8(3):163–174

    Article  CAS  PubMed  Google Scholar 

  172. Matsushima GK, Morell P (2001) The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 11(1):107–116

    Article  CAS  PubMed  Google Scholar 

  173. Stidworthy MF, Genoud S, Suter U, Mantei N, Franklin RJ (2003) Quantifying the early stages of remyelination following cuprizone-induced demyelination. Brain Pathol 13(3):329–339

    Article  PubMed  Google Scholar 

  174. Wu QZ, Yang Q, Cate HS, Kemper D, Binder M, Wang HX et al (2008) MRI identification of the rostral-caudal pattern of pathology within the corpus callosum in the cuprizone mouse model. J Magn Reson Imaging 27(3):446–453

    Article  PubMed  Google Scholar 

  175. Mason JL, Langaman C, Morell P, Suzuki K, Matsushima GK (2001) Episodic demyelination and subsequent remyelination within the murine central nervous system: changes in axonal calibre. Neuropathol Appl Neurobiol 27(1):50–58

    Article  CAS  PubMed  Google Scholar 

  176. Mason JL, Toews A, Hostettler JD, Morell P, Suzuki K, Goldman JE et al (2004) Oligodendrocytes and progenitors become progressively depleted within chronically demyelinated lesions. Am J Pathol 164(5):1673–1682

    Article  PubMed  PubMed Central  Google Scholar 

  177. Serra-de-Oliveira N, Boilesen SN, Prado de Franca Carvalho C, LeSueur-Maluf L, Zollner Rde L, Spadari RC et al (2015) Behavioural changes observed in demyelination model shares similarities with white matter abnormalities in humans. Behav Brain Res 287:265–275

    Article  CAS  PubMed  Google Scholar 

  178. Franco-Pons N, Torrente M, Colomina MT, Vilella E (2007) Behavioral deficits in the cuprizone-induced murine model of demyelination/remyelination. Toxicol Lett 169(3):205–213

    Article  CAS  PubMed  Google Scholar 

  179. Yamamoto S, Gotoh M, Kawamura Y, Yamashina K, Yagishita S, Awaji T et al (2014) Cyclic phosphatidic acid treatment suppress cuprizone-induced demyelination and motor dysfunction in mice. Eur J Pharmacol 741:17–24

    Article  CAS  PubMed  Google Scholar 

  180. Arnett HA, Wang Y, Matsushima GK, Suzuki K, Ting JP (2003) Functional genomic analysis of remyelination reveals importance of inflammation in oligodendrocyte regeneration. J Neurosci 23(30):9824–9832

    CAS  PubMed  Google Scholar 

  181. Marik C, Felts PA, Bauer J, Lassmann H, Smith KJ (2007) Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 130(Pt 11):2800–2815

    Article  PubMed  PubMed Central  Google Scholar 

  182. Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 55(4):458–468

    Article  PubMed  Google Scholar 

  183. Henderson AP, Barnett MH, Parratt JD, Prineas JW (2009) Multiple sclerosis: distribution of inflammatory cells in newly forming lesions. Ann Neurol 66(6):739–753

    Article  PubMed  Google Scholar 

  184. Buch T, Heppner FL, Tertilt C, Heinen TJ, Kremer M, Wunderlich FT et al (2005) A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat Methods 2(6):419–426

    Article  CAS  PubMed  Google Scholar 

  185. Oluich LJ, Stratton JA, Xing YL, Ng SW, Cate HS, Sah P et al (2012) Targeted ablation of oligodendrocytes induces axonal pathology independent of overt demyelination. J Neurosci 32(24):8317–8330

    Article  CAS  PubMed  Google Scholar 

  186. Pohl HB, Porcheri C, Mueggler T, Bachmann LC, Martino G, Riethmacher D et al (2011) Genetically induced adult oligodendrocyte cell death is associated with poor myelin clearance, reduced remyelination, and axonal damage. J Neurosci 31(3):1069–1080

    Article  CAS  PubMed  Google Scholar 

  187. Traka M, Arasi K, Avila RL, Podojil JR, Christakos A, Miller SD et al (2010) A genetic mouse model of adult-onset, pervasive central nervous system demyelination with robust remyelination. Brain 133(10):3017–3029

    Article  PubMed  PubMed Central  Google Scholar 

  188. Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W (2002) Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 125(Pt 10):2202–2212

    Article  PubMed  Google Scholar 

  189. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338(5):278–285

    Article  CAS  PubMed  Google Scholar 

  190. Nikic I, Merkler D, Sorbara C, Brinkoetter M, Kreutzfeldt M, Bareyre FM et al (2011) A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med 17(4):495–499

    Article  CAS  PubMed  Google Scholar 

  191. Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120(Pt 3):393–399

    Article  PubMed  Google Scholar 

  192. Pfeifenbring S, Bunyan RF, Metz I, Rover C, Huppke P, Gartner J et al (2015) Extensive acute axonal damage in pediatric multiple sclerosis lesions. Ann Neurol 77(4):655–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. McCarthy KD, de Vellis J (1980) Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 85(3):890–902

    Article  CAS  PubMed  Google Scholar 

  194. Dugas JC, Emery B (2013) Purification of oligodendrocyte precursor cells from rat cortices by immunopanning. Cold Spring Harb Protoc 2013(8):745–758

    Article  PubMed  Google Scholar 

  195. Emery B, Dugas JC (2013) Purification of oligodendrocyte lineage cells from mouse cortices by immunopanning. Cold Spring Harb Protoc 2013(9):854–868

    Article  PubMed  Google Scholar 

  196. Dugas JC, Emery B (2013) Purification and culture of oligodendrocyte lineage cells. Cold Spring Harb Protoc 2013(9):810–814

    Article  PubMed  Google Scholar 

  197. Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS et al (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28(1):264–278

    Article  CAS  PubMed  Google Scholar 

  198. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34(36):11929–11947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Emery B, Agalliu D, Cahoy JD, Watkins TA, Dugas JC, Mulinyawe SB et al (2009) Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination. Cell 138(1):172–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Moyon S, Dubessy AL, Aigrot MS, Trotter M, Huang JK, Dauphinot L et al (2015) Demyelination causes adult CNS progenitors to revert to an immature state and express immune cues that support their migration. J Neurosci 35(1):4–20

    Article  PubMed  CAS  Google Scholar 

  201. Kleitman N, Wood PM, Bunge RP (1991) Tissue culture methods for the study of myelination. In: Banker G, Goslin K (eds) Culturing nerve cells. MIT Press, Cambridge, MA, pp 337–377

    Google Scholar 

  202. Chan JR, Watkins TA, Cosgaya JM, Zhang C, Chen L, Reichardt LF et al (2004) NGF controls axonal receptivity to myelination by Schwann cells or oligodendrocytes. Neuron 43(2):183–191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Lappe-Siefke C, Goebbels S, Gravel M, Nicksch E, Lee J, Braun PE et al (2003) Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat Genet 33(3):366–374

    Article  CAS  PubMed  Google Scholar 

  204. Griffiths I, Klugmann M, Anderson T, Yool D, Thomson C, Schwab MH et al (1998) Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280(5369):1610–1613

    Article  CAS  PubMed  Google Scholar 

  205. Klugmann M, Schwab MH, Puhlhofer A, Schneider A, Zimmermann F, Griffiths IR et al (1997) Assembly of CNS myelin in the absence of proteolipid protein. Neuron 18(1):59–70

    Article  CAS  PubMed  Google Scholar 

  206. Nave KA (2010) Myelination and support of axonal integrity by glia. Nature 468(7321):244–252

    Article  CAS  PubMed  Google Scholar 

  207. Nave KA (2010) Myelination and the trophic support of long axons. Nat Rev Neurosci 11(4):275–283

    Article  CAS  PubMed  Google Scholar 

  208. Mahad DJ, Ziabreva I, Campbell G, Lax N, White K, Hanson PS et al (2009) Mitochondrial changes within axons in multiple sclerosis. Brain 132(Pt 5):1161–1174

    Article  PubMed  PubMed Central  Google Scholar 

  209. Kiryu-Seo S, Ohno N, Kidd GJ, Komuro H, Trapp BD (2010) Demyelination increases axonal stationary mitochondrial size and the speed of axonal mitochondrial transport. J Neurosci 30(19):6658–6666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Zambonin JL, Zhao C, Ohno N, Campbell GR, Engeham S, Ziabreva I et al (2011) Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis. Brain 134(Pt 7):1901–1913

    Article  PubMed  PubMed Central  Google Scholar 

  211. Funfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J et al (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485(7399):517–521

    PubMed  PubMed Central  Google Scholar 

  212. Fukui H, Diaz F, Garcia S, Moraes CT (2007) Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 104(35):14163–14168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN et al (2012) Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487(7408):443–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Halestrap AP (2013) The SLC16 gene family–structure, role and regulation in health and disease. Mol Asp Med 34(2–3):337–349

    Article  CAS  Google Scholar 

  215. Fruhbeis C, Frohlich D, Kuo WP, Amphornrat J, Thilemann S, Saab AS, et al. (2013) Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol 11(7):e1001604

    Google Scholar 

  216. Smith KJ, Blakemore WF, McDonald WI (1979) Central remyelination restores secure conduction. Nature 280(5721):395–396

    Article  CAS  PubMed  Google Scholar 

  217. Duncan ID, Brower A, Kondo Y, Curlee JF Jr, Schultz RD (2009) Extensive remyelination of the CNS leads to functional recovery. Proc Natl Acad Sci U S A 106(16):6832–6836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Irvine KA, Blakemore WF (2008) Remyelination protects axons from demyelination-associated axon degeneration. Brain 131(Pt 6):1464–1477

    Article  CAS  PubMed  Google Scholar 

  219. Dutta R, Trapp BD (2011) Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog Neurobiol 93(1):1–12

    Article  PubMed  Google Scholar 

  220. Compston A, Coles A (2008) Multiple sclerosis. Lancet 372(9648):1502–1517

    Article  CAS  PubMed  Google Scholar 

  221. Haines JD, Inglese M, Casaccia P (2011) Axonal damage in multiple sclerosis. Mt Sinai J Med 78(2):231–243

    Article  PubMed  PubMed Central  Google Scholar 

  222. Goldschmidt T, Antel J, Konig FB, Bruck W, Kuhlmann T (2009) Remyelination capacity of the MS brain decreases with disease chronicity. Neurology 72(22):1914–1921

    Article  CAS  PubMed  Google Scholar 

  223. Mi S, Miller RH, Lee X, Scott ML, Shulag-Morskaya S, Shao Z et al (2005) LINGO-1 negatively regulates myelination by oligodendrocytes. Nat Neurosci 8(6):745–751

    Article  CAS  PubMed  Google Scholar 

  224. Bengtsson SL, Nagy Z, Skare S, Forsman L, Forssberg H, Ullen F (2005) Extensive piano practicing has regionally specific effects on white matter development. Nat Neurosci 8(9):1148–1150

    Article  CAS  PubMed  Google Scholar 

  225. Imfeld A, Oechslin MS, Meyer M, Loenneker T, Jancke L (2009) White matter plasticity in the corticospinal tract of musicians: a diffusion tensor imaging study. NeuroImage 46(3):600–607

    Article  PubMed  Google Scholar 

  226. Schlegel AA, Rudelson JJ, Tse PU (2012) White matter structure changes as adults learn a second language. J Cogn Neurosci 24(8):1664–1670

    Article  PubMed  Google Scholar 

  227. Scholz J, Klein MC, Behrens TE, Johansen-Berg H (2009) Training induces changes in white-matter architecture. Nat Neurosci 12(11):1370–1371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. McKenzie IA, Ohayon D, Li H, de Faria JP, Emery B, Tohyama K et al (2014) Motor skill learning requires active central myelination. Science 346(6207):318–322

    Article  CAS  PubMed  Google Scholar 

  229. Young KM, Psachoulia K, Tripathi RB, Dunn SJ, Cossell L, Attwell D et al (2013) Oligodendrocyte dynamics in the healthy adult CNS: evidence for myelin remodeling. Neuron 77(5):873–885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Yeung MS, Zdunek S, Bergmann O, Bernard S, Salehpour M, Alkass K et al (2014) Dynamics of oligodendrocyte generation and myelination in the human brain. Cell 159(4):766–774

    Article  CAS  PubMed  Google Scholar 

  231. Tomassy GS, Berger DR, Chen HH, Kasthuri N, Hayworth KJ, Vercelli A et al (2014) Distinct profiles of myelin distribution along single axons of pyramidal neurons in the neocortex. Science 344(6181):319–324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Rivers LE, Young KM, Rizzi M, Jamen F, Psachoulia K, Wade A et al (2008) PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci 11(12):1392–1401

    Article  CAS  PubMed  Google Scholar 

  233. Kang SH, Fukaya M, Yang JK, Rothstein JD, Bergles DE (2010) NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron 68(4):668–681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Psachoulia K, Jamen F, Young KM, Richardson WD (2009) Cell cycle dynamics of NG2 cells in the postnatal and ageing brain. Neuron Glia Biol 5(3–4):57–67

    Article  PubMed  Google Scholar 

  235. Tripathi RB, Rivers LE, Young KM, Jamen F, Richardson WD (2010) NG2 glia generate new oligodendrocytes but few astrocytes in a murine experimental autoimmune encephalomyelitis model of demyelinating disease. J Neurosci 30(48):16383–16390

    Google Scholar 

  236. Zawadzka M, Rivers LE, Fancy SP, Zhao C, Tripathi R, Jamen F et al (2010) CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination. Cell Stem Cell 6(6):578–590

    Article  CAS  PubMed  Google Scholar 

  237. Nait-Oumesmar B, Decker L, Lachapelle F, Avellana-Adalid V, Bachelin C, Baron-Van Evercooren A (1999) Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination. Eur J Neurosci 11(12):4357–4366

    Article  CAS  PubMed  Google Scholar 

  238. Menn B, Garcia-Verdugo JM, Yaschine C, Gonzalez-Perez O, Rowitch D, Alvarez-Buylla A (2006) Origin of oligodendrocytes in the subventricular zone of the adult brain. J Neurosci 26(30):7907–7918

    Article  CAS  PubMed  Google Scholar 

  239. Xing YL, Roth PT, Stratton JA, Chuang BH, Danne J, Ellis SL et al (2014) Adult neural precursor cells from the subventricular zone contribute significantly to oligodendrocyte regeneration and remyelination. J Neurosci 34(42):14128–14146

    Article  PubMed  CAS  Google Scholar 

  240. Brousse B, Magalon K, Durbec P, Cayre M (2015) Region and dynamic specificities of adult neural stem cells and oligodendrocyte precursors in myelin regeneration in the mouse brain. Biol Open 4(8):980–992

    Article  PubMed  PubMed Central  Google Scholar 

  241. Samanta J, Grund EM, Silva HM, Lafaille JJ, Fishell G, Salzer JL (2015) Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination. Nature 526(7573):448–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Powers BE, Sellers DL, Lovelett EA, Cheung W, Aalami SP, Zapertov N et al (2013) Remyelination reporter reveals prolonged refinement of spontaneously regenerated myelin. Proc Natl Acad Sci U S A 110(10):4075–4080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Najm FJ, Madhavan M, Zaremba A, Shick E, Karl RT, Factor DC et al (2015) Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature 522(7555):216–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Deshmukh VA, Tardif V, Lyssiotis CA, Green CC, Kerman B, Kim HJ et al (2013) A regenerative approach to the treatment of multiple sclerosis. Nature 502(7471):327–332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Van der Walt A, Butzkueven H, Kolbe S, Marriott M, Alexandrou E, Gresle M et al (2010) Neuroprotection in multiple sclerosis: a therapeutic challenge for the next decade. Pharmacol Ther 126(1):82–93

    Article  PubMed  CAS  Google Scholar 

  246. Barres BA, Raff MC (1993) Proliferation of oligodendrocyte precursor cells depends on electrical activity in axons. Nature 361(6409):258–260

    Article  CAS  PubMed  Google Scholar 

  247. Demerens C, Stankoff B, Logak M, Anglade P, Allinquant B, Couraud F et al (1996) Induction of myelination in the central nervous system by electrical activity. Proc Natl Acad Sci U S A 93(18):9887–9892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Gibson EM, Purger D, Mount CW, Goldstein AK, Lin GL, Wood LS, et al (2014) Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science 344(6183):1252304

    Google Scholar 

  249. Ishibashi T, Dakin KA, Stevens B, Lee PR, Kozlov SV, Stewart CL et al (2006) Astrocytes promote myelination in response to electrical impulses. Neuron 49(6):823–832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Stevens B, Porta S, Haak LL, Gallo V, Fields RD (2002) Adenosine: a neuron-glial transmitter promoting myelination in the CNS in response to action potentials. Neuron 36(5):855–868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Bergles DE, Roberts JD, Somogyi P, Jahr CE (2000) Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature 405(6783):187–191

    Article  CAS  PubMed  Google Scholar 

  252. Salter MG, Fern R (2005) NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature 438(7071):1167–1171

    Article  CAS  PubMed  Google Scholar 

  253. Karadottir R, Cavelier P, Bergersen LH, Attwell D (2005) NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature 438(7071):1162–1166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Karadottir R, Hamilton NB, Bakiri Y, Attwell D (2008) Spiking and nonspiking classes of oligodendrocyte precursor glia in CNS white matter. Nat Neurosci 11(4):450–456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Gautier HO, Evans KA, Volbracht K, James R, Sitnikov S, Lundgaard I et al (2015) Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors. Nat Commun 6:8518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Lundgaard I, Luzhynskaya A, Stockley JH, Wang Z, Evans KA, Swire M, et al (2013) Neuregulin and BDNF induce a switch to NMDA receptor-dependent myelination by oligodendrocytes. PLoS Biol 11(12):e1001743

    Google Scholar 

  257. Lee S, Chong SY, Tuck SJ, Corey JM, Chan JR (2013) A rapid and reproducible assay for modeling myelination by oligodendrocytes using engineered nanofibers. Nat Protoc 8(4):771–782

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  258. Lee S, Leach MK, Redmond SA, Chong SY, Mellon SH, Tuck SJ et al (2012) A culture system to study oligodendrocyte myelination processes using engineered nanofibers. Nat Methods 9(9):917–922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Rosenberg SS, Kelland EE, Tokar E, De la Torre AR, Chan JR (2008) The geometric and spatial constraints of the microenvironment induce oligodendrocyte differentiation. Proc Natl Acad Sci U S A 105(38):14662–14667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Royal Melbourne Hospital, Parkville, VIC, 3050, Australia

    Katherine Buzzard B.Sc. (Hons.), Ph.D., M.B.B.S.

  2. Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, 3010, Australia

    Wing Hei Chan M.Phil., Trevor Kilpatrick M.B.B.S., Ph.D., F.R.A.C.P. & Simon Murray B.Sc. (Hons.), B.App.Sci., Ph.D.

  3. Melbourne Neuroscience Institute, The University of Melbourne, Parkville, VIC, 3010, Australia

    Trevor Kilpatrick M.B.B.S., Ph.D., F.R.A.C.P.

  4. Multiple Sclerosis Research Division, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3052, Australia

    Trevor Kilpatrick M.B.B.S., Ph.D., F.R.A.C.P. & Simon Murray B.Sc. (Hons.), B.App.Sci., Ph.D.

Authors
  1. Katherine Buzzard B.Sc. (Hons.), Ph.D., M.B.B.S.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wing Hei Chan M.Phil.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Trevor Kilpatrick M.B.B.S., Ph.D., F.R.A.C.P.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simon Murray B.Sc. (Hons.), B.App.Sci., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Simon Murray B.Sc. (Hons.), B.App.Sci., Ph.D. .

Editor information

Editors and Affiliations

  1. University of Melbourne Florey Institute of Neuroscience and Mental Health, Parkville, Australia

    Philip Beart

  2. Pediatrics and Pharmacology Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Michael Robinson

  3. School of Life Sciences Bradford School of Pharmacy, University of Bradford, Bradford, United Kingdom

    Marcus Rattray

  4. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Nicholas J. Maragakis

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Buzzard, K., Chan, W.H., Kilpatrick, T., Murray, S. (2017). Multiple Sclerosis: Basic and Clinical. In: Beart, P., Robinson, M., Rattray, M., Maragakis, N. (eds) Neurodegenerative Diseases. Advances in Neurobiology, vol 15. Springer, Cham. https://doi.org/10.1007/978-3-319-57193-5_8

Download citation

Publish with us

Policies and ethics

Search

Navigation