Multiple sclerosis: an immune or neurodegenerative disorder?

Multiple sclerosis (MS) is an inflammatory-mediated demyelinating disease of the human central nervous system. The clinical disease course is variable, usually starts with reversible episodes of neurological disability in the third or fourth decade of life, and transforms into a disease of continuous and irreversible neurological decline by the sixth or seventh decade. We review data that support neurodegeneration as the major cause of irreversible neurological disability in MS patients. We question whether inflammatory demyelination is primary or secondary in the disease process and discuss the challenges of elucidating the cause of MS and developing therapies that will delay or prevent the irreversible and progressive neurological decline that most MS patients endure.

[1]  T. Rivers,et al.  OBSERVATIONS ON ATTEMPTS TO PRODUCE ACUTE DISSEMINATED ENCEPHALOMYELITIS IN MONKEYS , 1933, The Journal of experimental medicine.

[2]  T. J. Putnam STUDIES IN MULTIPLE SCLEROSIS: VII. SIMILARITIES BETWEEN SOME FORMS OF ENCEPHALOMYELITIS AND MULTIPLE SCLEROSIS , 1936 .

[3]  L. S. King,et al.  OBSERVATIONS ON THE HISTOPATHOLOGY OF THE CEREBRAL LESIONS IN DISSEMINATED SCLEROSIS , 1936 .

[4]  H. Shiraki,et al.  A CONTRIBUTION TO THE CLASSIFICATION AND THE PATHOGENESIS OF DEMYLELINATING EXCEPHALOMYELITIS WITH SPECIAL REFERENCE TO THE CENTIRM, NERVOOS SYSTEM LESIONS CAUSED BY PREVENTIVE INOCULATION AGAINST RABIES , 1957, Journal of neuropathology and experimental neurology.

[5]  B. Brownell,et al.  The distribution of plaques in the cerebrum in multiple sclerosis , 1962, Journal of neurology, neurosurgery, and psychiatry.

[6]  T A Sears,et al.  The internodal axon membrane: electrical excitability and continuous conduction in segmental demyelination. , 1978, The Journal of physiology.

[7]  D. Price,et al.  Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Sylvie M. de Waegh,et al.  Altered slow axonal transport and regeneration in a myelin-deficient mutant mouse: the trembler as an in vivo model for Schwann cell-axon interactions , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[9]  Stephen M. Rao,et al.  Cognitive dysfunction in multiple sclerosis. , 1991, Neurology.

[10]  E. Warrington,et al.  Cognitive abnormalities in multiple sclerosis: a psychometric and MRI study , 1991, Psychological Medicine.

[11]  G. Mckhann,et al.  Clinical and electrophysiological aspects of acute paralytic disease of children and young adults in northern China , 1991, The Lancet.

[12]  F. Barkhof,et al.  Relapsing-remitting multiple sclerosis: sequential enhanced MR imaging vs clinical findings in determining disease activity. , 1992, AJR. American journal of roentgenology.

[13]  S G Waxman,et al.  Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na(+)-Ca2+ exchanger , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  F. Sánchez‐Madrid,et al.  Prevention of experimental autoimmune encephalomyelitis by antibodies against α4βl integrin , 1992, Nature.

[15]  L. J. McDonald,et al.  Stimulation by nitric oxide of an NAD linkage to glyceraldehyde-3-phosphate dehydrogenase. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[16]  D. Paty,et al.  Interferon beta‐1b is effective in relapsing‐remitting multiple sclerosis , 1993, Neurology.

[17]  F. Barkhof,et al.  Gadolinium enhancement increases the sensitivity of MRI in detecting disease activity in multiple sclerosis. , 1993, Brain : a journal of neurology.

[18]  J. Roder,et al.  Myelination in the absence of myelin-associated glycoprotein , 1994, Nature.

[19]  D. Hanley,et al.  Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains , 1994, Annals of neurology.

[20]  P. Matthews,et al.  Use of proton magnetic resonance spectroscopy for monitoring disease progression in multiple sclerosis , 1994, Annals of neurology.

[21]  S. Lipton,et al.  Excitatory amino acids as a final common pathway for neurologic disorders. , 1994, The New England journal of medicine.

[22]  R. Paul,et al.  Identifying multiple sclerosis patients with mild or global cognitive impairment using the Screening Examination for Cognitive Impairment (SEFCI) , 1995, Neurology.

[23]  G. Mckhann,et al.  Guillain-Barré syndrome in northern China. The spectrum of neuropathological changes in clinically defined cases. , 1995, Brain : a journal of neurology.

[24]  M. Blaser,et al.  Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. , 1995, Brain : a journal of neurology.

[25]  P M Matthews,et al.  Assessment of lesion pathology in multiple sclerosis using quantitative MRI morphometry and magnetic resonance spectroscopy. , 1996, Brain : a journal of neurology.

[26]  R. Nixon,et al.  Oligodendroglia Regulate the Regional Expansion of Axon Caliber and Local Accumulation of Neurofilaments during Development Independently of Myelin Formation , 1996, The Journal of Neuroscience.

[27]  C. Granger,et al.  Intramuscular interferon beta‐1a for disease progression in relapsing multiple sclerosis , 1996, Annals of neurology.

[28]  B. Weinshenker,et al.  Epidemiology of multiple sclerosis. , 1996, Neurologic clinics.

[29]  K. Nave,et al.  Assembly of CNS Myelin in the Absence of Proteolipid Protein , 1997, Neuron.

[30]  R. Hohlfeld,et al.  Biotechnological agents for the immunotherapy of multiple sclerosis. Principles, problems and perspectives. , 1997, Brain : a journal of neurology.

[31]  Kenneth J. Smith,et al.  Conduction in Segmentally Demyelinated Mammalian Central Axons , 1997, The Journal of Neuroscience.

[32]  V. Perry,et al.  Axonal damage in acute multiple sclerosis lesions. , 1997, Brain : a journal of neurology.

[33]  Jeanelle Sheeder,et al.  Magnetic resonance studies of intramuscular interferon β–1a for relapsing multiple sclerosis , 1998 .

[34]  K. Nave,et al.  Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. , 1998, Science.

[35]  E. Mignot,et al.  Genetic and familial aspects of narcolepsy , 1998, Neurology.

[36]  P M Matthews,et al.  Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. , 1998, Brain : a journal of neurology.

[37]  M Filippi,et al.  Magnetization transfer changes in the normal appering white matter precede the appearance of enhancing lesions in patients with multiple sclerosis , 1998, Annals of neurology.

[38]  Ludwig Kappos,et al.  Placebo-controlled multicentre randomised trial of interferon β-1b in treatment of secondary progressive multiple sclerosis , 1998, The Lancet.

[39]  G. Mckhann,et al.  Molecular Mimicry in Guillain‐Barré Syndrome a , 1998, Annals of the New York Academy of Sciences.

[40]  R. Rudick,et al.  Axonal transection in the lesions of multiple sclerosis. , 1998, The New England journal of medicine.

[41]  G. Ebers,et al.  Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis , 1998, The Lancet.

[42]  Virginia M. Y. Lee,et al.  Myelin-Associated Glycoprotein Is a Myelin Signal that Modulates the Caliber of Myelinated Axons , 1998, The Journal of Neuroscience.

[43]  J. Haines,et al.  Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group. , 1998, Human molecular genetics.

[44]  F. Barkhof,et al.  Cortical lesions in multiple sclerosis. , 1999, Brain : a journal of neurology.

[45]  T. Saido,et al.  A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[46]  R. Herndon,et al.  Selecting relapsing remitting multiple sclerosis patients for treatment: the case for early treatment , 1999, Journal of Neuroimmunology.

[47]  H. Lassmann,et al.  Axonal Pathology in Multiple Sclerosis. A Historical Note , 1999, Brain pathology.

[48]  R. Rudick,et al.  Neurodegeneration in Multiple Sclerosis: Relationship to Neurological Disability , 1999 .

[49]  Ganter,et al.  Spinal cord axonal loss in multiple sclerosis: a post‐mortem study , 1999, Neuropathology and applied neurobiology.

[50]  Bruce D. Trapp,et al.  Axonal pathology in myelin disorders , 1999, Journal of neurocytology.

[51]  R. Herndon,et al.  A longitudinal study of brain atrophy in relapsing multiple sclerosis , 1999, Neurology.

[52]  J Foong,et al.  Correlates of executive function in multiple sclerosis: the use of magnetic resonance spectroscopy as an index of focal pathology. , 1999, The Journal of neuropsychiatry and clinical neurosciences.

[53]  R. Rudick,et al.  Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS , 1999, Neurology.

[54]  Virginia M. Y. Lee,et al.  Formation of Compact Myelin Is Required for Maturation of the Axonal Cytoskeleton , 1999, The Journal of Neuroscience.

[55]  Hans Lassmann,et al.  Clonal Expansions of Cd8+ T Cells Dominate the T Cell Infiltrate in Active Multiple Sclerosis Lesions as Shown by Micromanipulation and Single Cell Polymerase Chain Reaction , 2000, The Journal of experimental medicine.

[56]  L. Turski,et al.  Autoimmune encephalomyelitis ameliorated by AMPA antagonists , 2000, Nature Medicine.

[57]  M. Palkovits,et al.  Axonal changes in chronic demyelinated cervical spinal cord plaques. , 2000, Brain : a journal of neurology.

[58]  A. Sadovnick,et al.  Conjugal multiple sclerosis: Population‐based prevalence and recurrence risks in offspring , 2000, Annals of neurology.

[59]  H. Lassmann,et al.  Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. , 2000, The American journal of pathology.

[60]  Shuxin Li,et al.  Mechanisms of Ionotropic Glutamate Receptor-Mediated Excitotoxicity in Isolated Spinal Cord White Matter , 2000, The Journal of Neuroscience.

[61]  P M Matthews,et al.  Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis. , 2000, Brain : a journal of neurology.

[62]  P. Stys,et al.  Important role of reverse Na(+)-Ca(2+) exchange in spinal cord white matter injury at physiological temperature. , 2000, Journal of neurophysiology.

[63]  J. Parisi,et al.  Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination , 2000, Annals of neurology.

[64]  R. Rudick,et al.  Neurological disability correlates with spinal cord axonal loss and reduced N‐acetyl aspartate in chronic multiple sclerosis patients , 2000, Annals of neurology.

[65]  D. Pitt,et al.  Glutamate excitotoxicity in a model of multiple sclerosis , 2000, Nature Medicine.

[66]  A. Compston,et al.  Recommended diagnostic criteria for multiple sclerosis: Guidelines from the international panel on the diagnosis of multiple sclerosis , 2001, Annals of neurology.

[67]  B. Trapp,et al.  Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions , 2001, Annals of neurology.

[68]  J. Goverman,et al.  A Pathogenic Role for Myelin-Specific Cd8+ T Cells in a Model for Multiple Sclerosis , 2001, The Journal of experimental medicine.

[69]  M. Goldberg,et al.  AMPA/Kainate Receptor Activation Mediates Hypoxic Oligodendrocyte Death and Axonal Injury in Cerebral White Matter , 2001, The Journal of Neuroscience.

[70]  J S Wolinsky,et al.  Grey matter abnormalities in multiple sclerosis: proton magnetic resonance spectroscopic imaging , 2001, Multiple sclerosis.

[71]  H. Neumann,et al.  Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. , 2001, The American journal of pathology.

[72]  A. Pérez-Samartín,et al.  The link between excitotoxic oligodendroglial death and demyelinating diseases , 2001, Trends in Neurosciences.

[73]  Massimo Filippi,et al.  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 , 2001, Annals of neurology.

[74]  Ponnada A Narayana,et al.  United States open-label glatiramer acetate extension trial for relapsing multiple sclerosis: MRI and clinical correlates , 2001 .

[75]  G. Rosati,et al.  The prevalence of multiple sclerosis in the world: an update , 2001, Neurological Sciences.

[76]  C. Brosnan,et al.  Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. , 2001, The American journal of pathology.

[77]  C. Farina,et al.  Mechanisms of action of glatiramer acetate in multiple sclerosis , 2001, Neurology.

[78]  R. Kinkel,et al.  Axonal loss in normal-appearing white matter in a patient with acute MS , 2001, Neurology.

[79]  Lawrence Steinman,et al.  Multiple sclerosis: a two-stage disease , 2001, Nature Immunology.

[80]  S. Waxman,et al.  Nitric oxide blocks fast, slow, and persistent Na+ channels in C-type DRG neurons by S-nitrosylation. , 2002, Journal of neurophysiology.

[81]  H. Lassmann,et al.  The role of nitric oxide in multiple sclerosis , 2002, The Lancet Neurology.

[82]  David H. Miller,et al.  Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. , 2002, Brain : a journal of neurology.

[83]  Gian Domenico Iannetti,et al.  Cortical motor reorganization after a single clinical attack of multiple sclerosis. , 2002, Brain : a journal of neurology.

[84]  V. Borutaite,et al.  Serial Review: Nitric Oxide in Mitochondria Guest Editors: Christoph Richter and Matthias Schweizer NITRIC OXIDE INHIBITION OF MITOCHONDRIAL RESPIRATION AND ITS ROLE IN CELL DEATH , 2002 .

[85]  K. Nave,et al.  Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination , 2003, Nature Genetics.

[86]  Hans Lassmann,et al.  Hypoxia-like tissue injury as a component of multiple sclerosis lesions , 2002, Journal of the Neurological Sciences.

[87]  Stephen Smith,et al.  Potentially adaptive functional changes in cognitive processing for patients with multiple sclerosis and their acute modulation by rivastigmine. , 2003, Brain : a journal of neurology.

[88]  P. Muriel,et al.  Insights into the mechanism of erythrocyte Na+/K+‐ATPase inhibition by nitric oxide and peroxynitrite anion , 2003, Journal of applied toxicology : JAT.

[89]  Yves Dauvilliers,et al.  Pharmacogenomics in the treatment of narcolepsy. , 2003, Pharmacogenomics.

[90]  Giuseppe Scotti,et al.  Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis , 2003, NeuroImage.

[91]  B. Ransom,et al.  Functional Hemichannels in Astrocytes: A Novel Mechanism of Glutamate Release , 2003, The Journal of Neuroscience.

[92]  B. Trapp,et al.  Subpial Demyelination in the Cerebral Cortex of Multiple Sclerosis Patients , 2003, Journal of neuropathology and experimental neurology.

[93]  D. Busija,et al.  Opening of Mitochondrial ATP-Sensitive Potassium Channels Is a Trigger of 3-Nitropropionic Acid–Induced Tolerance to Transient Focal Cerebral Ischemia in Rats , 2003, Stroke.

[94]  L. Turski,et al.  Multiple Sclerosis and Glutamate , 2003, Annals of the New York Academy of Sciences.

[95]  B D Trapp,et al.  Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration , 2003, Multiple sclerosis.

[96]  Silke Schmidt,et al.  Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. , 2004, American journal of human genetics.

[97]  B. Trapp,et al.  Structure of the Myelinated Axon , 2004 .

[98]  T. Vollmer,et al.  Randomized multicenter trial of natalizumab in acute MS relapses , 2004, Neurology.

[99]  S. Elkabes,et al.  Beneficial effect of erythropoietin on experimental allergic encephalomyelitis , 2004, Annals of neurology.

[100]  Vladimir Parpura,et al.  Mechanisms of glutamate release from astrocytes: gap junction “hemichannels”, purinergic receptors and exocytotic release , 2004, Neurochemistry International.

[101]  H. Lassmann Experimental Autoimmune Encephalomyelitis , 2004 .

[102]  D. Attwell,et al.  NMDA receptors are expressed in oligodendrocytes and activated in ischaemia , 2005, Nature.

[103]  K. Tyler,et al.  Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. , 2005, The New England journal of medicine.

[104]  Daniel Pelletier,et al.  Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T. , 2005, Brain : a journal of neurology.

[105]  Hans Lassmann,et al.  Cortical lesions and brain atrophy in MS , 2005, Journal of the Neurological Sciences.

[106]  S. Reingold,et al.  Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria” , 2005, Annals of neurology.

[107]  B. Trapp,et al.  12 – Axonal Degeneration in Multiple Sclerosis: The Histopathological Evidence , 2005 .

[108]  M. Salter,et al.  NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury , 2005, Nature.

[109]  S. Vukusic,et al.  Natural history of multiple sclerosis: a unifying concept. , 2006, Brain : a journal of neurology.

[110]  J. Baskerville,et al.  The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. , 2006, Brain : a journal of neurology.

[111]  Chiara Romualdi,et al.  Cortical atrophy is relevant in multiple sclerosis at clinical onset , 2007, Journal of Neurology.

[112]  A. Compston Making progress on the natural history of multiple sclerosis. , 2006, Brain : a journal of neurology.

[113]  S. Vukusic,et al.  Age at disability milestones in multiple sclerosis. , 2006, Brain : a journal of neurology.

[114]  S. Hauser,et al.  The Neurobiology of Multiple Sclerosis: Genes, Inflammation, and Neurodegeneration , 2006, Neuron.

[115]  B. Trapp,et al.  NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia , 2006, Nature.

[116]  R. Rudick,et al.  Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients , 2006, Annals of neurology.

[117]  Ludwig Kappos,et al.  A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. , 2006, The New England journal of medicine.

[118]  C. Matute,et al.  Glutamate‐mediated glial injury: Mechanisms and clinical importance , 2006, Glia.

[119]  D. Kirschner,et al.  Evolution of a neuroprotective function of central nervous system myelin , 2006, The Journal of cell biology.

[120]  Neurogenesis in the chronic lesions of multiple sclerosis: 120.4 , 2007 .

[121]  Alan C. Evans,et al.  Focal cortical atrophy in multiple sclerosis: Relation to lesion load and disability , 2007, NeuroImage.

[122]  Rohit Bakshi,et al.  Gray matter involvement in multiple sclerosis , 2007, Neurology.

[123]  S. Gabriel,et al.  Risk alleles for multiple sclerosis identified by a genomewide study. , 2007, The New England journal of medicine.

[124]  Dieter Vaitl,et al.  Distinct mechanisms of altered brain activation in patients with multiple sclerosis , 2007, NeuroImage.

[125]  Elizabeth Fisher,et al.  Imaging correlates of axonal swelling in chronic multiple sclerosis brains , 2007, Annals of neurology.

[126]  Silke Schmidt,et al.  Interleukin 7 receptor α chain ( IL7R ) shows allelic and functional association with multiple sclerosis , 2007, Nature Genetics.

[127]  M. Karamouzis,et al.  Selective modulation of the erythropoietic and tissue-protective effects of erythropoietin: time to reach the full therapeutic potential of erythropoietin. , 2007, Biochimica et biophysica acta.

[128]  H. Harbo,et al.  Variation in interleukin 7 receptor α chain (IL7R) influences risk of multiple sclerosis , 2007, Nature Genetics.

[129]  R. Rudick,et al.  Imaging correlates of decreased axonal Na+/K+ ATPase in chronic multiple sclerosis lesions , 2008, Annals of neurology.

[130]  Klaus-Armin Nave,et al.  Axon-glial signaling and the glial support of axon function. , 2008, Annual review of neuroscience.