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Design for the Next Trials of Neurodegeneration

  • P. Soelbergs Sørensen
Part of the Topics in Neuroscience book series (TOPNEURO)

Abstract

During the past decade, several new medications have become available for the treatment of multiple sclerosis (MS). The main effect of these therapies, whether they are immunomodulatory or immunosuppressive types of treatment, has been their strong impact on the inflammatory component of the MS disease process. These anti-inflammatory therapies have, with various degrees of success, suppressed signs of inflammation as detected by magnetic resonance imaging (MRI) and have reduced the incidence of the clinical correlate to inflammation, i.e., the acute relapses [1, 2, 3, 4, 5, 6, 7], although they have had little effect on disease progression caused by permanent demyelination and axonal loss. Hence, it has been hypothesized that there are two different disease mechanisms at work in patients with MS: inflammation and neurodegeneration. The neurodegenerative disease process has been associated with the progressive phases of MS, either primary progressive (PP) MS or secondary progressive (SP) MS, during which the disease activity is thought to be driven by degenerative rather than inflammatory processes. However, recent studies have emphasized the presence of axonal damage early in the course of the disease [8], a fact that was already known by Charcot, as shown in his seminal studies of MS [9]. According to one theory, both inflammatory and degenerative disease processes are present from the onset of the disease and proceed independently; with inflammation being most prominent in the early phases of the disease, whereas neurodegeneration dominates during the later stages [10]. On the other hand, there are arguments for inflammation being the culprit for both acute relapses and disease progression [11, 12, 13]. Recent studies have indeed shown that inflammation is also prominent in patients with PPMS and SPMS, although this inflammation is thought to be compartmentalized within the CNS and is independent of the activation of T-cells in the peripheral bloodstream [14]. This low-burning, widespread inflammation is thought to be mediated by activated microglia that interact with T-and B-cells from infiltrates in the meninges and in the perivascular spaces, causing demyelination and axonal injury in plaques as well as diffusely in the white and gray matter of the brain [15, 16].

Keywords

Multiple Sclerosis Expand Disability Status Scale Diffusion Tensor Magnetic Resonance Imaging Secondary Progressive Multiple Sclerosis Brain Parenchymal Fraction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Comi G, Filippi M, Wolinsky JS (2001) European/Canadian multicenter, doubleblind, 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 49:290–297PubMedCrossRefGoogle Scholar
  2. 2.
    Hartung HP, Gonsette R, Konig N et al (2002) Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 360:2018–2025PubMedCrossRefGoogle Scholar
  3. 3.
    Jacobs LD, Cookfair DL, Rudick RA et al (1996) Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 39:285–294PubMedCrossRefGoogle Scholar
  4. 4.
    Johnson KP, Brooks BR, Cohen JA 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 45:1268–1276PubMedGoogle Scholar
  5. 5.
    PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group (1998) Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 352:1498–1504CrossRefGoogle Scholar
  6. 6.
    IFN*b 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 43:655–661Google Scholar
  7. 7.
    IFN*b Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group (1995) Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 45:1277–1285Google Scholar
  8. 8.
    Trapp BD, Peterson J, Ransohoff RM et al (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285PubMedCrossRefGoogle Scholar
  9. 9.
    Charcot JM (1868) Histologie de la sclerose en plaque. Gazette Hopital (Paris) 41, 554–566Google Scholar
  10. 10.
    Prineas JW, Kwon EE, Cho ES et al (2001) Immunopathology of secondary-progressive multiple sclerosis. Ann Neurol 50:646–657PubMedCrossRefGoogle Scholar
  11. 11.
    Bruck W, Stadelmann C (2003) Inflammation and degeneration in multiple sclerosis. Neurol Sci 24 (Suppl 5):S265–S267Google Scholar
  12. 12.
    Bruck W (2005) The pathology of multiple sclerosis is the result of focal inflammatory demyelination with axonal damage. J Neurol 252 (Suppl 5):V3–V9Google Scholar
  13. 13.
    Lassmann H (1998) Neuropathology in multiple sclerosis: new concepts. Mult Scler 4:93–98PubMedGoogle Scholar
  14. 14.
    Kutzelnigg A, Lucchinetti CF, Stadelmann C et al (2005) Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128:2705–2712PubMedCrossRefGoogle Scholar
  15. 15.
    Prineas JW (1979) Multiple sclerosis: presence of lymphatic capillaries and lymphoid tissue in the brain and spinal cord. Science 203:1123–1125PubMedCrossRefGoogle Scholar
  16. 16.
    Serafini B, Rosicarelli B, Magliozzi R et al (2004) Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 14:164–174PubMedCrossRefGoogle Scholar
  17. 17.
    Kappos L, Moeri D, Radue EW et al (1999) Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis. Gadolinium MRI Meta-analysis Group. Lancet 353:964–969PubMedCrossRefGoogle Scholar
  18. 18.
    Miller DH, Barkhof F, Frank JA et al (2002) Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 125:1676–1695PubMedCrossRefGoogle Scholar
  19. 19.
    Barkhof F, van Waesberghe JH, Filippi Metal(2001)T(1) hypoin tense lesions in secondary progressive multiple sclerosis: effect of interferon beta-1b treatment. Brain 124:1396–1402Google Scholar
  20. 20.
    van Walderveen MA, Kamphorst W, Scheltens P et al (1998) Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. Neurology 50:1282–1288PubMedGoogle Scholar
  21. 21.
    van Walderveen MA, Barkhof F, Pouwels PJ et al (1999) Neuronal damage in Tlhypointense multiple sclerosis lesions demonstrated in vivo using proton magnetic resonance spectroscopy. Ann Neurol 46:79–87PubMedCrossRefGoogle Scholar
  22. 22.
    Leary SM, Miller DH, Stevenson VL et al (2003) Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial. Neurology 60:44–51PubMedGoogle Scholar
  23. 23.
    European Study Group on Interferon beta-1b in Secondary Progressive MS (1998) Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. Lancet 352:1491–1497CrossRefGoogle Scholar
  24. 24.
    Hommes OR, Sorensen PS, Fazekas F et al (2004) Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet 364:1149–1156PubMedCrossRefGoogle Scholar
  25. 25.
    Panitch H, Miller A, Paty D, Weinshenker B (2004) Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology 63:1788–1795PubMedGoogle Scholar
  26. 26.
    SPECTRIMS (2001) Randomized controlled trial of interferon-beta-1a in secondary progressive MS: clinical results. Neurology 56:1496–1504Google Scholar
  27. 27.
    Rovaris M, Filippi M (1999) Magnetic resonance techniques to monitor disease evolution and treatment trial outcomes in multiple sclerosis. Curr Opin Neurol 12:337–344PubMedCrossRefGoogle Scholar
  28. 28.
    van Walderveen MA, Barkhof F, Hommes OR et al (1995) Correlating MRI and clinical disease activity in multiple sclerosis: relevance of hypointense lesions on short-TR/short-TE (T1-weighted) spin-echo images. Neurology 45:1684–1690PubMedGoogle Scholar
  29. 29.
    Filippi M, Rovaris M, Rocca MA et al (2001) Glatiramer acetate reduces the proportion of new MS lesions evolving into “black holes”. Neurology 57:731–733PubMedGoogle Scholar
  30. 30.
    Dalton CM, Miszkiel KA, Barker GJ et al (2004) Effect of natalizumab on conversion of gadolinium enhancing lesions to T1 hypointense lesions in relapsing multiple sclerosis. J Neurol 251:407–413PubMedCrossRefGoogle Scholar
  31. 31.
    Rudick RA, Fisher E, Lee JC et al (1999) Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology 53:1698–1704PubMedGoogle Scholar
  32. 32.
    Rao AB, Richert N, Howard T et al (2002) Methylprednisolone effect on brain volume and enhancing lesions in MS before and during IFNbeta-1b. Neurology 59:688–694PubMedGoogle Scholar
  33. 33.
    Zivadinov R, Bakshi R (2004) Role of MRI in multiple sclerosis. I. Inflammation and lesions. Front Biosci 9:665–683PubMedCrossRefGoogle Scholar
  34. 34.
    Filippi M, Rocca MA, Comi G (2003) The use of quantitative magnetic-resonance-based techniques to monitor the evolution of multiple sclerosis. Lancet Neurol 2:337–346PubMedCrossRefGoogle Scholar
  35. 35.
    Agosta F, Rovaris M, Pagani E et al (2006) Magnetization transfer MRI metrics predict the accumulation of disability 8 years later in patients with multiple sclerosis. Brain 129:2620–2627PubMedCrossRefGoogle Scholar
  36. 36.
    Cercignani M, Bozzali M, Iannucci G et al (2001) Magnetisation transfer ratio and mean diffusivity of normal appearing white and grey matter from patients with multiple sclerosis. J Neurol Neurosurg Psychiat 70:311–317PubMedCrossRefGoogle Scholar
  37. 37.
    Rovaris M, Agosta F, Sormani MP et al (2003) Conventional and magnetization transfer MRI predictors of clinical multiple sclerosis evolution: a medium-term follow-up study. Brain 126:2323–2332PubMedCrossRefGoogle Scholar
  38. 38.
    Fazekas F, Sorensen PS, Filippi M et al (2005) MRI results from the European Study on Intravenous Immunoglobulin in Secondary Progressive Multiple Sclerosis (ESIMS). Mult Scler 11:433–440PubMedCrossRefGoogle Scholar
  39. 39.
    Richert ND, Ostuni JL, Bash CN et al (2001) Interferon beta-1b and intravenous methylprednisolone promote lesion recovery in multiple sclerosis. Mult Scler 7:49–58PubMedGoogle Scholar
  40. 40.
    Inglese M, van Waesberghe JH, Rovaris M et al (2003) The effect of interferon beta1b on quantities derived from MT MRI in secondary progressive MS. Neurology 60:853–860PubMedGoogle Scholar
  41. 41.
    Rovaris M, Bozzali M, Iannucci G et al (2002) Assessment of normal-appearing white and gray matter in patients with primary progressive multiple sclerosis: a diffusiontensor magnetic resonance imaging study. Arch Neurol 59:1406–1412PubMedCrossRefGoogle Scholar
  42. 42.
    Schmierer K, Altmann DR, Kassim N et al (2004) Progressive change in primary progressive multiple sclerosis normal-appearing white matter: a serial diffusion magnetic resonance imaging study. Mult Scler 10:182–187PubMedCrossRefGoogle Scholar
  43. 43.
    Davie CA, Hawkins CP, Barker GJ et al (1994) Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions. Brain 117:49–58PubMedCrossRefGoogle Scholar
  44. 44.
    Davie CA, Barker GJ, Thompson AJ et al (1997) 1H magnetic resonance spectroscopy of chronic cerebral white matter lesions and normal appearing white matter in multiple sclerosis. J Neurol Neurosurg Psychiat 63:736–742PubMedGoogle Scholar
  45. 45.
    Narayana PA, Doyle TJ, Lai D, Wolinsky JS (1998) Serial proton magnetic resonance spectroscopic imaging, contrast-enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis. Ann Neurol 43:56–71PubMedCrossRefGoogle Scholar
  46. 46.
    Brex PA, Gomez-Anson B, Parker GJ et al (1999) Proton MR spectroscopy in clinically isolated syndromes suggestive of multiple sclerosis. J Neurol Sci 166:16–22PubMedCrossRefGoogle Scholar
  47. 47.
    Cucurella MG, Rovira A, Rio J et al (2000) Proton magnetic resonance spectroscopy in primary and secondary progressive multiple sclerosis. NMR Biomed 13:57–63PubMedCrossRefGoogle Scholar
  48. 48.
    De Stefano N, Narayanan S, Francis GS et al (2001) Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol 58:65–70PubMedCrossRefGoogle Scholar
  49. 49.
    Mathiesen HK, Jonsson A, Tscherning T et al (2006) Correlation of global N-acetyl aspartate with cognitive impairment in multiple sclerosis. Arch Neurol 63:533–536PubMedCrossRefGoogle Scholar
  50. 50.
    Narayanan S, De Stefano N, Francis GS et al (2001) Axonal metabolic recovery in multiple sclerosis patients treated with interferon *b-lb. J Neurol 248:979–986PubMedCrossRefGoogle Scholar
  51. 51.
    Sarchielli P, Presciutti O, Tarducci R et al (1998) 1H-MRS in patients with multiple sclerosis undergoing treatment with interferon beta-1a: results of a preliminary study. J Neurol Neurosurg Psychiat 64:204–212PubMedCrossRefGoogle Scholar
  52. 52.
    Parry A, Corkill R, Blamire AM et al (2003) Beta-interferon treatment does not always slow the progression of axonal injury in multiple sclerosis. J Neurol 250:171–178PubMedCrossRefGoogle Scholar
  53. 53.
    Rocca MA, Falini A, Colombo B et al (2002) Adaptive functional changes in the cerebral cortex of patients with nondisabling multiple sclerosis correlate with the extent of brain structural damage. Ann Neurol 51:330–339PubMedCrossRefGoogle Scholar
  54. 54.
    Lee M, Reddy H, Johansen-Berg H et al (2000) The motor cortex shows adaptive functional changes to brain injury from multiple sclerosis. Ann Neurol 47:606–613PubMedCrossRefGoogle Scholar
  55. 55.
    Reddy H, Narayanan S, Woolrich M et al (2002) Functional brain reorganization for hand movement in patients with multiple sclerosis: defining distinct effects of injury and disability. Brain 125:2646–2657PubMedCrossRefGoogle Scholar
  56. 56.
    Blinkenberg M, Rune K, Jensen CV et al (2000) Cortical cerebral metabolism correlates with MRI lesion load and cognitive dysfunction in MS. Neurology 54:558–564PubMedGoogle Scholar
  57. 57.
    Blinkenberg M, Jensen CV, Holm S et al (1999) A longitudinal study of cerebral glucose metabolism, MRI, and disability in patients with MS. Neurology 53:149–153PubMedGoogle Scholar
  58. 58.
    Comi G, Filippi M (2005) Clinical trials in multiple sclerosis: methodological issues. Curr Opin Neurol 18:245–252PubMedCrossRefGoogle Scholar
  59. 59.
    Goodin DS (2004) Disease-modifying therapy in MS: a critical review of the literature. Part I. Analysis of clinical trial errors. J Neurol 251 (Suppl 5):V3–V11Google Scholar
  60. 60.
    Roxburgh RH, Seaman SR, Masterman T et al (2005) Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology 64:1144–1151PubMedGoogle Scholar
  61. 61.
    Molyneux PD, Kappos L, Polman C et al (2000) The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis. European Study Group on Interferon beta-1b in Secondary Progressive Multiple Sclerosis. Brain 123:2256–2263PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2007

Authors and Affiliations

  • P. Soelbergs Sørensen
    • 1
  1. 1.Danish Multiple Sclerosis Research Center Department of NeurologyCopenhaguen University HospitalCopenhaguenDenmark

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