Advertisement

Pathology and disease mechanisms in different stages of multiple sclerosis

      Abstract

      In this review the differences in pathology and disease mechanisms between early and late stages of multiple sclerosis are discussed. The data suggest that affection of the brain is different, depending on the location of lesions, on the stage of the disease, when lesions arise, and on inter-individual differences between patients. We suggest that in the early stage of the disease new lesions are formed by new waves of inflammatory cells, entering the central nervous system from the circulation and giving rise to focal demyelinated plaques in the white and gray matter. In contrast, at late stages of the disease inflammation decreases, but the susceptibility of the target tissue for neurodegeneration increases. New data suggest that mitochondrial injury, mediated through oxidative injury, is in the center of the pathogenetic events leading to brain damage in multiple sclerosis patients.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Lumsden C.E.
        The neuropathology of multiple sclerosis.
        in: Vinken P.I. Bruyn G.W. Handbook of clinical neurology. 9. Elsevier, New York1970: 217-309
        • Babbe H.
        • Roers A.
        • Waisman A.
        • Lassmann H.
        • Goebels N.
        • Hohlfeld R.
        • et al.
        Clonal expansion of CD8+ T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction.
        J Exp Med. 2000; 192: 393-404
        • Esiri M.M.
        Multiple sclerosis: A quantitative and qualitative study of immunoglobulin-containing cells in the central nervous system.
        Neuropathol Appl Neurobiol. 1980; 6: 9-21
        • Frischer J.M.
        • Bramow S.
        • Dal Bianco A.
        • Lucchinetti C.
        • Rauschka H.
        • Schmidbauer M.
        • et al.
        The relation between inflammation and neurodegeneration in multiple sclerosis.
        Brain. 2009; 132: 1175-1189
        • Hoftberger R.
        • Aboul-Enein F.
        • Brueck W.
        • Lucchinetti C.
        • Rodriguez M.
        • Schmidbauer M.
        • et al.
        Expression of major histocompatibility complex class I molecules on the different cell types in multiple sclerosis lesions.
        Brain Pathol. 2004; 14: 43-50
        • Holman D.W.
        • Klein R.S.
        • Ransohoff R.M.
        The blood brain barrier, chemokines and multiple sclerosis.
        Biochim Biophys Acta. 1812; 2011: 220-230
        • Prineas J.W.
        The neuropathology of multiple sclerosis.
        in: Koetsier J.C. Handbook of Clinical Neurology. 47. Elsevier, New York1985: 337-395
        • Bjartmar C.
        • Kidd G.
        • Mork S.
        • Rudick R.
        • Trapp B.D.
        Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients.
        Ann Neurol. 2000; 48: 893-901
        • Peterson J.W.
        • Bo L.
        • Mork S.
        • Chang A.
        • Trapp B.D.
        Transsected neurites, apoptotic neurons and reduced inflammation in cortical multiple sclerosis lesions.
        Ann Neurol. 2001; 50: 389-400
        • Kutzelnigg A.
        • Lucchinetti C.F.
        • Stadelmann C.
        • Bruck W.
        • Rauschka H.
        • Bergmann M.
        • et al.
        Cortical demyelination and diffuse white matter injury in multiple sclerosis.
        Brain. 2005; 128: 2705-2712
        • Cifelli A.
        • Arridge M.
        • Jezzard P.
        • Esiri M.M.
        • Palace J.
        • Matthews P.M.
        Thalamic neurodegeneration in multiple sclerosis.
        Ann Neurol. 2002; 52: 650-653
        • Gilmore C.P.
        • Geurts J.J.
        • Eveangelou N.
        • Bot J.C.
        • van Schindel R.A.
        • Pouwels P.J.
        • et al.
        Spinal cord grey matter lesions in multiple sclerosis detected by post-mortem high field MR imaging.
        Mult Scler. 2009; 15: 180-188
        • Patrikios P.
        • Stadelmann C.
        • Kutzelnigg A.
        • Rauschka H.
        • Schmidbauer M.
        • Laursen H.
        • et al.
        Remyelination is extensive in a subset of multiple sclerosis patients.
        Brain. 2006; 129: 3165-3172
        • Albert M.
        • Antel J.
        • Brück W.
        • Stadelmann C.
        Extensive cortical remyelination in patients with chronic multiple sclerosis.
        Brain Pathol. 2007; 17: 129-138
        • Kornek B.
        • Storch M.
        • Weissert R.
        • Wallstroem E.
        • Stefferl A.
        • Olsson T.
        • et al.
        Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive and remyelinated lesions.
        Amer J Pathol. 2000; 157: 267-276
        • Prineas J.W.
        • Barnard R.O.
        • Revesz T.
        • Kwon E.E.
        • Sharer L.R.
        • Cho E.S.
        Multiple sclerosis. Pathology of recurrent lesions.
        Brain. 1993; 116: 681-693
        • Bramow S.
        • Frischer J.M.
        • Lassmann H.
        • Koch-Henriksen N.
        • Lucchinetti C.F.
        • Sørensen P.S.
        • et al.
        Demyelination versus remyelination in progressive multiple sclerosis.
        Brain. 2010; 133: 2983-2998
        • Lublin F.D.
        • Reingold S.C.
        Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis.
        Neurology. 1996; 46: 907-911
        • Wiendl H.
        • Hohlfeld R.
        Multiple sclerosis therapeutics: unexpected outcomes clouding undisputed successes.
        Neurology. 2009; 72: 1008-1015
        • Giacomini P.S.
        • Darlington P.J.
        • Bar-Or A.
        Emerging multiple sclerosis disease-modifying therapies.
        Curr Opin Neurol. 2009; 22: 226-232
        • Lucchinetti C.F.
        • Popescu B.F.G.
        • Bunyan R.F.
        • Moll N.M.
        • Roemer S.F.
        • Lassmann H.
        • et al.
        Inflammatory cortical demyelination in early multiple sclerosis.
        N Engl J Med. 2011; 365: 2188-2197
        • Magliozzi R.
        • Howell O.W.
        • Reeves C.
        • Roncaroli F.
        • Nicholas R.
        • Serafini B.
        • et al.
        A gradient of neuronal loss and meningeal inflammation in multiple sclerosis.
        Ann Neurol. 2010; 68: 477-493
        • Magliozzi R.
        • Howell O.
        • Vora A.
        • Serafini B.
        • Nicholas R.
        • Puopolo M.
        • et al.
        Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology.
        Brain. 2007; 130: 1089-1104
        • Hochmeister S.
        • Grundtner R.
        • Bauer J.
        • Engelhardt B.
        • Lyck R.
        • Gordon G.
        • et al.
        Dysferlin is a new marker for leaky brain blood vessels in multiple sclerosis.
        J Neuropathol Exp Neurol. 2006; 65: 855-865
        • Serafini B.
        • Rosicarelli B.
        • Magliozzi R.
        • Stigliano E.
        • Aloisi F.
        Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis.
        Brain Pathol. 2004; 14: 164-174
        • Howell O.W.
        • Reeves C.A.
        • Nicholas R.
        • Carassiti D.
        • Radotra B.
        • Gentleman S.M.
        • et al.
        Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis.
        Brain. 2011; 134: 2755-2771
        • Ozawa K.
        • Suchanek G.
        • Breitschopf H.
        • Brück W.
        • Budka H.
        • Jellinger K.
        • et al.
        Patterns of oligodendroglia pathology in multiple sclerosis.
        Brain. 1994; 117: 1311-1322
        • Brück W.
        • Porada Ph.
        • Poser S.
        • Rieckmann P.
        • Hanefeld F.
        • Kretschmer H.A.
        • et al.
        Monocyte/macrophage differentiation in early multiple sclerosis.
        Ann Neurol. 1995; 38: 788-796
        • Prineas J.W.
        • Kwon E.E.
        • Cho E.S.
        • Sharer L.R.
        • Barnett M.H.
        • Oleszak E.L.
        • et al.
        Immunopathology of secondary-progressive multiple sclerosis.
        Ann Neurol. 2001; 50: 646-657
        • Bo L.
        • Vedeler C.A.
        • Nyland H.I.
        • Trapp B.D.
        • Mork S.J.
        Subpial demyelination in the cerebral cortex of multiple sclerosis patients.
        J Neuropathol Exp Neurol. 2003; 62: 723-732
        • Fischer M.T.
        • Wimmer I.
        • Höftberger R.
        • Gerlach S.
        • Haider L.
        • Zrzavy T.
        • et al.
        Disease-specific molecular events in cortical multiple sclerosis lesions.
        Brain. 2013; ([in press, Electronic publication ahead of print])
        • Moll N.M.
        • Rietsch A.M.
        • Ransohoff A.J.
        • Cossoy M.B.
        • Huang D.
        • Eichler F.S.
        • et al.
        Cortical demyelination in PML and MS: similarities and differences.
        Neurology. 2008; 70: 336-343
        • Choi S.
        • Howell O.W.
        • Carassiti D.
        • Magliozzi R.
        • Gveric D.
        • Muraro P.A.
        • et al.
        Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis.
        Brain. 2012; 135: 2925-2937
        • Kolasinski J.
        • Stagg C.J.
        • Chance S.A.
        • DeLuca G.C.
        • Esiri M.M.
        • Chang E.H.
        • et al.
        A combined post-mortem MRI and quantitative histological study of multiple sclerosis pathology.
        Brain. 2012; 135: 2938-2951
        • Lassmann H.
        Cortical lesions in multiple sclerosis: inflammation versus neurodegeneration.
        Brain. 2012; 135: 2904-2905
        • Evangelou N.
        • Konz D.
        • Esiri M.M.
        • Smith S.
        • Palace J.
        • Matthews P.M.
        Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis.
        Brain. 2000; 123: 1845-1849
        • DeLuca G.C.
        • Williams K.
        • Evangelou N.
        • Ebers G.C.
        • Esiri M.M.
        The contribution of demyelination to axonal loss in multiple sclerosis.
        Brain. 2006; 129: 1507-1516
        • Wegner C.
        • Esiri M.M.
        • Chance S.A.
        • Palace J.
        • Matthews P.M.
        Neocortical neuronal, synaptic, and glial loss in multiple sclerosis.
        Neurology. 2006; 67: 960-967
        • Lucchinetti C.
        • Brück W.
        • Parisi J.
        • Scheithauer B.
        • Rodriguez M.
        • Lassmann H.
        Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination.
        Ann Neurol. 2000; 47: 707-717
        • Lassmann H.
        • van Horssen J.
        The molecular basis of neurodegeneration in multiple sclerosis.
        FEBS Lett. 2011; 585: 3715-3723
        • Mahad D.
        • Ziabreva I.
        • Lassmann H.
        • Turnbull D.
        Mitochondrial defects in acute multiple sclerosis lesions.
        Brain. 2008; 131: 1722-1735
        • Cross A.H.
        • Manning P.T.
        • Keeling R.M.
        • Schmidt R.E.
        • Misko T.P.
        Peroxynitrite formation within the central nervous system in active multiple sclerosis.
        J Neuroimmunol. 1998; 88: 45-56
        • Liu J.S.H.
        • Zhao M.L.
        • Brosnan C.F.
        • Lee S.C.
        Expression of indicible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions.
        Amer J Pathol. 2001; 158: 2057-2066
        • Fischer M.T.
        • Sharma R.
        • Lim J.
        • Haider L.
        • Frischer J.
        • Drexhage J.
        • et al.
        NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury.
        Brain. 2012; 135: 886-899
        • Marik C.
        • Felts P.
        • Bauer J.
        • Lassmann H.
        • Smith K.J.
        Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity?.
        Brain. 2007; 130: 2800-2815
        • Gray E.
        • Thomas T.L.
        • Betmouni S.
        • Scolding N.
        • Love S.
        Elevated myeloperoxidase activity in white matter in multiple sclerosis.
        Neurosci Lett. 2008; 442: 195-198
        • Haider L.
        • Fischer M.T.
        • Frischer J.M.
        • Bauer J.
        • Höftberger R.
        • Botond G.
        • et al.
        Oxidative damage and neurodegeneration in multiple sclerosis lesions.
        Brain. 2011; 134: 1914-1924
        • Hallgren B.
        • Sourander P.
        The effect of age on the non-haemin iron in the human brain.
        J Neurochem. 1958; 3: 41-51
        • Hulet S.W.
        • Powers S.
        • Connor J.R.
        Distribution of transferrin and ferritin binding in normal and multiple sclerotic human brain.
        J Neurol Sci. 1999; 165: 48-55
        • Graf E.
        • Mahoney J.R.
        • Bryant R.G.
        • Eaton J.W.
        Iron-catalyzed hydroxyl radical formation.
        J Biol Chem. 1984; 259: 3620-3624
        • Bagnato F.
        • Hametner S.
        • Yao B.
        • van Gelderen P.
        • Merkle H.
        • Cantor F.K.
        • et al.
        Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla.
        Brain. 2011; 134: 3602-3615
        • Campbell G.R.
        • Ziabreva I.
        • Reeve A.K.
        • Krishnan K.J.
        • Reynolds R.
        • Howell O.
        • et al.
        Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis.
        Ann Neurol. 2011; 69: 481-492