Axonal Degeneration in Multiple Sclerosis: The Histopathological Evidence

Multiple Sclerosis As A Neuronal Disease

Volumn , Issue , 2005, Pages 165-184

  Peterson, John W ^a   Kidd, Grahame J ^a   Trapp, Bruce D ^a  

^a LERNER RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 84882550256     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1016/B978-012738761-1/50013-4     Document Type: Chapter

References (144)

1. S.K. Agrawal and M.G. Fehlings (1996) Mechanisms of secondary injury to spinal cord axons in vitro: Role of Na+, Na(+)−K(+)-ATPase. the Na(+)−H+ exchanger, and the Na(+)−Ca2+ exchanger. J. Neurosci. 16 545-552.
2. N.A. al Abdulla and L.J. Martin (2002) Projection neurons and interneurons in the lateral geniculate nucleus undergo distinct forms of degeneration ranging from retrograde and transsynaptic apoptosis to transient atrophy after cortical ablation in rat. Neuroscience 115 7-14.
3. N.A. al Abdulla, C. Portera-Cailliau and L.J. Martin (1998) Occipital cortex ablation in adult rat causes retrograde neuronal death in the lateral geniculate nucleus that resembles apoptosis. Neuroscience 86 191-209.
4. A. Alcazar, I. Regidor, J. Masjuan, M. Salinas and J.C. Alvarez-Cermeno (2000) Axonal damage induced by cerebrospinal fluid from patients with relapsing-remitting multiple sclerosis. J. Neuroimmunol. 104 58-67.
5. A. Ames III (2000) CNS energy metabolism as related to function. Brain Res Brain Res Rev. 34 42-68.
6. D.L. Arnold (1999) Magnetic resonance spectroscopy: imaging axonal damage in MS. J Neuroimmunol. 98 2-6.
7. H. Babbe, A. Roerts, A. Waisman, H. Lassmann, N. Goebels, R. Hohlfeld, M. Friese, R. Schroder, M. Deckert, S. Schmidt, R. Ravid and K. Rajewsky (2000) 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. J. Exp. Med. 192 393-404.
8. D. Barnes, P.M. Munro, B.D. Youl, J.W. Prines and W.I. McDonald (1991) The longstanding MS lesion A quantitative MRI and electron microscopic study. Brain 114 1271-1280.
9. W.W. Beatty, R.H. Paul, S.L. Wilbanks, K.A. Hames, C.R. Blanco and D.E. Goodkin (1995) Identifying multiple sclerosis patients with mild or global cognitive impairment using the Screening Examination for Cognitive Impairment (SEFCI). Neurology 45 718-723.
10. A. Bitsch, J. Schuchardt, S. Bunkowski, T. Kuhlmann and W. Bruck (2000) Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 123 1174-1183.
11. C. Bjartma, G. Kidd, S. Mork, R. Rudick and B.D. Trapp (2000) Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol. 48 893-901.
12. C. Bjartmar and B.D. Trapp (2001) Axonal and neuronal degeneration in multiple sclerosis mechanisms and functional consequences. Curr. Opin. Neurol. 14 271-278.
13. C. Bjartmar and B.D. Trapp (2003) Axonal degeneration and progressive neurologic disability in multiple sclerosis. Neurotax Res. 5 157-164.
14. C. Bjartmar, J.R. Wujek and B.D. Trapp (2003) Axonal loss in the pathology of MS: Consequences for understanding the progressive phase of the disease. J. Neurol. Sci. 206 165-171.
15. C. Bjartmar, X. Yin and B.D. Trapp (1999) Axonal pathology in myelin disorders. J. Neurocytol. 28 383-395.
16. M. Blinkenberg, K. Rune, C.V. Jensen, M. Ravnborg, S. Kyllingsbaek, S. Holm, O.B. Paulson and P.S. Sorensen (2000) Cortical cerebral metabolism correlates with MR1 lesion load and cognitive dysfunction in MS. Neurology 54 558-564.
17. K. Blinzinger and G. Kreutzberg (1968) Displacement of synaptic terminals from regenerating motor neurons by microglial cells. Z. Zellforsch. Mikrosk. Anat. 85 145-157.
18. L. Bö, T.N. Dawson, S. Wesselingh, S. Mörk, S. Choi, P.A. Kong, D. Hanley and B.D. Trapp (1994) Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. Ann. Neurol. 36 778-786.
19. L. Bo, C.A. Vedeler, H. Nyland, B.D. Trapp and S.J. Mork (2003) Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Multiple Sclerosis 9 323-331.
20. L. Bo, C.A. Vedeler, H.IU. Nyland, B.D. Trapp and S.J. Mork (2003) Subpial demylination in the cerebral cortex of multiple sclerosis patients. J. Neuropathol. Exp. Neurol. 62 723-732.
21. M.B. Bornstein and S.H. Appel (1965) Tissue culture studies of demyelination. Ann. N.Y. Acad. Sci. 122 280-286.
22. H. Bostock and T.A. Sears (1978) The intermodal axon membrane: Electrical excitability and continuous conduction in segmental demyelination. Ann. N.Y. Acad. Sci. 122 280-286.
23. H. Bostock and T.A. Sears (1978) The intemodal axon membrane: Electrical excitability and continuous conduction in segmental demyelinational. J. Physiol. 280 273-301.
24. W.G. Bradley (1987) Recent views on amyotrophic lateral sclerosis with emphasis on electrophysiological studies. Muscle Nerve 10 490-502.
25. J.C. Breitner (1996) The role of anti-inflammatory drugs in the prevention and treatment of Alzheimer's disease. Annu. Rev. Med. 47 401-411.
26. H. Brinkmeier, P. Aulkemeryr, K.H. Wollinsky and R. Rudel (2000) An endogenous pentapeptide acting as a sodium channel blocker in inflammatory autoimmune disorders of the central nervous system. Nat. Med. 6 808-811.
27. A. Brown, D.E. McFarlin and C.S. Raine (1982) The chronologic neuropathology of relapsing experimental allergic encephalomyelitis in the mouse. Lab. Invest. 46 171-185.
28. B. Brownell and J.T. Hughes (1962) Distribution of plaques in the cerebrum in multiple seclerosis. J. Neurol Neurosurg. Psychiatry 25 315-320.
29. W. Bruck and C. Stadelmann (2003) Inflammation and degeneration in multiple sclerosis. Neurol. Sci. 24(Suppl. 5), S265-S267.
30. C.K. Combs, D.E. Johnson, J.C. Karlo, S.B. Cannady and G.E. Landreth (2000) Inflammatory mechanisms in Alzheimer's disease: Inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPAR gamma agonis. J Neurosci. 20 558-567.
31. C. Confavreux, S. Vukusic, T. Moreau and P. Adeleine (2000) Relapses and progression of disability in multiple sclerosis. N. Engl. J. Med. 343 1430-1438.
32. M.J. Craner, B.C. Hains, A.C. Lo, J.A. Black and S.G. Waxman (2004) Co-localization of sodium channel Nav 1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE. Brain 127 294-303.
33. M.J. Craner, A.C. Lo, J.A. Black and S.G. Waxman (2003) Abnormal sodium channel distribution in optic nerve axons in a model of inflammatory demyelination. Brain 126 1552-1561.
34. N. De Stefano, L. Guidi, M.L. Stromillo, M.L. Bartolozzi and A. Federico (2003) Imaging neuronal and axonal degeneration in multiple sclerosis. Neurol. Sci. 24(Suppl. 5), S283-S286.
35. N. De Stefano, P.M. Matthews and D.L. Arnold (1995) Reversible decreases in N-acetylaspartate after acute brain injury. Magn. Reson. Med. 34 721-727.
36. N. De Stefano, P.M. Matthews, L. Fu, S. Narayanan, J. Stanley, G.S. Francis, J.P. Antel and D.L. Arnold (1998) Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain 121 1469-1477.
37. N. Evangelou, D. Konz, M.M. Esiri, S. Smith, J. Palace and P.M. Matthews (2001) Size-selective neuronal changes in the anterior optic pathways suggest a differential susceptibility to injury in multiple sclerosis. Brain 124 1813-1820.
38. P.A. Felts, T.A. Baker and K.J. Smith (1997) Conduction in segmentally demyelinated mammalian central axons. J. Neurosci. 17 7267-7277.
39. B. Ferguson, M.K. Matyszak, M.M. Esiri and V.H. Perry (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120 393-399.
40. M. Filippi (2001) Multiple sclerosis: a white matter disease with associated gray matter damage. J. Neurol. Sci. 185 3-4.
41. M. Filippi, D.W. Paty, L. Kappos, F. Barkhof, D.A. Compston, A.J. Thompson, G.J. Zhao, C.M. Wiles, W.I. McDonald and D.H. Miller (1995) Correlations between changes in disability and T2-weighted brain MRI activity in multiple sclerosis: a follow-up study. neurology 45 255-260.
42. R.E. Foster, C.C. Whalen and S.G. Waxman (1980) Reorganization of the axon membrane in demyelinated peripheral nerve fibers: morphological evidence. Science 210 661-663.
43. P. Ganter, C. Prince and M.M. Esiri (1999) Spinal cord axonal loss in multiple sclerosis: A post-mortem study. Neuropathol. Appl. Neurobiol. 25 459-467.
44. J.Y. Garbern, D.A. Yool, G.J. Moore, I.B. Wilds, M.W. Faulk, M. Klugmann, K.A. Nave, E.A. Sistermans, M.S. van der Knaap, T.D. Bird, M.E. Shy, J.A. Kamholz and I.R. Griffiths (2002) Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain 125 551-561.
45. J. Gehrmann, R.B. Banati, M.L. Cuzner, G.W. Kreutzberg and J. Newcombe (1995) Amyloid precursor protein (APP) expression in multiple sclerosis lesions. Glia 15 141-151.
46. J.J. Geurts, G. Wolswijk, L. Bo, P. van der Valk, C.H. Polman, D. Troost and E. Aronica (2003) Altered expression patterns of group I and II metabotropic glutamate receptors in multiple sclerosis. Brain 126 1755-1766.
47. S.D. Ginsberg and L.J. Martin (2002) Axonal transection in adult rat brain induces transsynaptic apoptosis and persistent atrophy of target neurons. J. Neurotrauma 19 99-109.
48. F. Giuliani, C.G. Goodyer, J.P. Antel and V.W. Yong (2003) Vulnerability of human neurons to T cell-mediated cytotoxicity. J. Immunol. 171 368-379.
49. O. Gonen, I. Catalaa, J.S. Babb, Y. Ge, L.J. Mannon, D.L. Kolson and R.I. Grossman (2000) Total brain N-acetylaspartate: a new measure of disease load in MS. Neurology 54 15-19.
50. F. Gonzalez-Scarano and G. Baltuch (1999) Microglia as mediators of inflammatory and degenerative diseases. Annu. Rev. Neurosci. 22 219-240.
51. M.B. Graeber, W.J. STreit and G.W. Kreutzberg (1988) Axotomy of the rat facial nerve leads to increased CR3 complement receptor expression by activated microglial cells. J. Neurosci. Res. 21 18-24.
52. U. Graumann, R. Reynolds, A.J. Steck and N. Schaeren-Wienmers (2003) Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult. Brain Pathol. 13 554-573.
53. J.G. Greenfield and L.S. King (1936) Observations on the histopathology of the cerebral lesions in disseminated sclerosis. Brain 59 445-458.
54. I. Griffiths, M. Klugmann, T. Anderson, D. Yool, C. Thomson, M.H. Schwab, A. Schneider, F. Zimmermann, M. McCulloch, N. Nadon and K.-A. Nave (1998) Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280 1610-1613.
55. C. Hafer-Macko, S.-T. Hsieh, C.Y. Li, T.W. Ho and K.A. Sheikh (1996) Acute motor axonal neuropathy: an antibody-mediated attack on axolemma. Ann. Neurol. 40 635-644.
56. S. Haga, K. Akai and T. Ishii (1989) Demonstration of microglial cells in and around senile (neuritic) plaques in the Alzheimer brain. An immunohistochemical study using a novel monoclonal antibody. Acta Neuropathol. 77 569-575.
57. B.C. Hains, J.A. Black and S.G. Waxman (2003) Primary cortical motor neurons undergo apoptosis after axotomizing spinal cord injury. J. Comp. Neurol. 462 328-341.
58. J.O. Harris, J.A. Frank, N. Patronas, D.E. McFarlin and H.F. McFarland (1991) Serial gadolinium-enhanced magnetic resonance imaging scans in patients with early, relapsing-remitting multiple sclerosis: implications for clinical trials and natural history. Ann. Neurol. 29 548-555.
59. W.F. Hickey (1991) Migration of hematogenous cells through the blood-brain barrier and the initiation of CNS inflammation. Brain Pathol. 1 97-105.
60. T.W. Ho, G.M. McKhann and J.W. Griffin (1998) Human autoimmune neuropathies. Annu. Rev. Neurosci. 21 187-226.
61. R. Hohlfeld (1997) Biotechnological agents for the immunotherapy of multiple sclerosis. Principles, problems and perspectives (invited review). Brain 120 865-916.
62. E.S. Huseby, D. Liggitt, T. Brabb, B. Schnabel, C. Ohlen and J. Goverman (2001) A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis. J. Exp. Med. 194 669-676.
63. S.J. Khoury, C.R. Guttmann, E.J. Orav, R. Kikinis, F.A. Jolesz and H.L. Weiner (2000) Changes in activated T cells in the blood correlate with disease activity in multiple sclerosis. Arch. Neurol. 57 1183-1189.
64. D. Kidd, F. Barkhof, R. McConnell, P.R. Algra, I.V. Allen and T. Revesz (1999) Cortical lesions in multiple sclerosis. Brain 122 17-26.
65. M. Klugmann, M.H. Schwab, A. Puhlhofer, A. Schneider, F. Zimmermann, I.R. Griffiths and K.A. Nave (1997) Assembly of CNS myelin in the absence of proteolipid protein. Neuron 18 59-70.
66. B. Kornek and H. Lassmann (1999) Axonal pathology in multiple sclerosis. A historical note. Brain Pathol. 9 651-656.
67. B. Kornek, M.K. Storch, J. Bauer, A. Djamshidian, R. Weissert, E. Wallstroem, A. Stefferl, F. Zimprich, T. Olsson, C. Linington, M. Schmidbauer and H. Lassmann (2001) Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis. Brain 124 1114-1124.
68. B. Kornek, M.K. Storch, R. Weissert, E. Wallstroem, A. Stefferl, T. Olsson, C. Linington, M. Schmidbauer and H. Lassmann (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am. J. Pathol. 157 267-276.
69. T. Koudriavtseva, A.J. Thompson, M. Fiorelli, C. Gasperini, S. Bastianello, A. Bozzao, A. Paolillo, A. Pisani, S. Galgani and C. Pozzilli (1997) Gadolinium enhanced MRI predicts clinical and MRI disease activity in relapsing-remitting multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 62 285-287.
70. C. Lappe-Siefke, S. Goebbels, M. Gravel, E. Nicksch, J. Lee, P.E. Braun, I.R. Griffiths and K.A. Nave (2003) Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat. Genet. 33 366-374.
71. H. Lassmann (2003) Hypoxia-like tissue injury as a component of multiple sclerosis lesions. J. Neurol. Sci. 206 187-191.
72. H. Lassmann, F. Zimprich, K. Rossler and K. Vass (1991) Inflammation in the nervous system. Basic mechanisms and immunological concepts. Rev. Neurol. 147 763-781.
73. L.L. Leppanen and P.K. Stys (1997) Ion transport and membrane potential in CNS myelinated axons. II: Effects of metabolic inhibition. J. Neurophysiol. 78 2095-2107.
74. C. Li, M.B. Tropak, R. Gerial, S. Clapoff, W. Abramow-Newerly, B. Trapp, A. Peterson and J. Roder (1994) Myelination in the absence of myelin-associated glycoprotein. Nature 369 747-750.
75. S. Li, Q. Jiang and P.K. Stys (2000) Important role of reverse (Na(+)−Ca(2+) exchange in spinal cord white matter injury at physiological temperature. J. Neurophysiol. 84 1116-1119.
76. K.G. Lloyd (1977) CNS compensation to dopamine neuron loss in Parkinson's disease. Adv. Exp. Med. Biol. 90 255-266.
77. D. Lo, L. Feng, L. Li, M.J. Carson, M. Crowley, M. Pauza, A. Nguyen and C.R. Reilly (1999) Integrating innate and adaptive immunity in the whole animal. Immunol. Rev. 169 225-239.
78. N.A. Losseff, L. Wang, H.M. Lai, D.S. Yoo, M.L. Gawne-Cain, W.I. McDonald, D.H. Miller and A.J. Thompson (1996) Progressive cerebral atrophy in multiple sclerosis. A serial MRI study. Brain 119 2009-2019.
79. N.A. Losseff and D.H. Miller (1998) Measures of brain and spinal cord atrophy in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry. May 64(Suppl), S102-S105.
80. G. Lovas, N. Szilagyi, K. Majtenyi, M. Palkovits and S. Komoly (2000) Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain 123 308-317.
81. F. Lu, M. Selak, J. O'Connor, S. Croul, C. Lorenzana, C. Butunoi and B. Kalman (2000) Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis. J. Neurol. Sci. 177 95-103.
82. C. Lucchinetti, W. Bruck, J. Parisi, B. Scheithauer, M. Rodriguez and H. Lassman (2000) Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Ann. Neurol. 47 707-717.
83. C.E. Lumsden (1970) The neuropathology of multiple sclerosis. PJ Vinken, GW Bruyn,(Eds) Handbook of Clinical Neurology Amsterdam: Elsevier Science 217-309.
84. J.N. Lycke, J.E. Karlsson, O. Andersen and L.E. Rosengren (1998) Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 64 402-404.
85. G. Mancardi, B. Hart, L. Roccataglianta, H. Brok, D. Giunti, R. Bontrop, L. Massacesi, E. Capello and A. Uccelli (2001) Demyelination and axonal damage in a non-human primate model of multiple sclerosis. J. Neurol. Sci. 184 41-49.
86. P.M. Matthews, N. De Stefano, S. Narayanan, G.S. Francis, J.S. Wolinsky, J.P. Antel and D.L. Arnold (1998) Putting magnetic resonance spectroscopy studies in context: axonal damage and disability in multiple sclerosis. Semin Neurol. 18 327-336.
87. H.F. McFarland, J.A. Frank, P.S. Albert, M.E. Smith, R. Martin, J.O. Harris, N. Patronas, H. Maloni and D.E. McFarlin (1992) Using gadolinium-enhanced magnetic resonance imaging lesions to monitor disease activity in multiple sclerosis. Ann. Neurol. 32 758-766.
88. P.L. McGeer, T. Kawamata, D.G. Walker, H. Akiyama, I. Tooyama and E.G. McGeer (1992) Microglia in degenerative neurological disease. Glia 7 84-92.
89. I. Medana, M.A. Martinic, H. Wekerle and H. Neumann (2001) Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am. J. Pathol. 159 809-815.
90. I. Mews, M. Bergmann, S. Bunkowski, F. Gullotta and W. Bruck (1998) Oligodendrocyte and axon pathology in clinically silent multiple sclerosis lesions. Multiple Sclerosis 4 55-62.
91. R. Meyer, R. Weissert, R. Diem, M.K. Storch, K.L. de Graaf, B. Kramer and M. Bahr (2001) Acute neuronal apoptosis in a rat model of multiple sclerosis. J. Neurosci. 21 6214-6220.
92. D.H. Miller, F. Barkhof, J.A. Frank, G.J. Parker and A.J. Thompson (2002) Measurement of atrophy in multiple sclerosis: Pathological basis, methodological aspects and clinical relevance. Brain 125 1676-1695.
93. D.H. Miller, F. Barkhof and J.J. Nauta (1993) Gadolinium enhancement increases the sensitivity of MRI in detecting disease activity in multiple sclerosis. Brain 116(Pt 5), 1077-1094.
94. A. Mochizuki, J.W. Peterson, E.J. Mufson and B.D. Trapp (1996) Amyloid load and neural elements in Alzheimer's disease and nondemented individuals with high amyloid plaque density. Exp. Neurol. 142 89-102.
95. P.A. Narayana, T.J. Doyle, D. Lai and J.S. Wolinsky (1998) Serial proton magnetic resonance spectroscopic imaging, contrast-enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis. Ann. Neurol. 43 56-71.
96. J.H. Noseworthy, C. Lucchinetti, M. Rodriguez and B.G. Weinshenker (2000) Multiple sclerosis. N. Engl. J. Med. 343 938-952.
97. C.W. Olanow and W.G. Tatton (1999) Etiology and pathogenesis of Parkinson's disease. Annu. Rev. Neurosci. 22 123-144.
98. P. Pantano, G.D. Iannetti, F. Caramia, C. Maineno, S. Di Legge, L. Bozzao, C. Pozzilli and G.L. Lenzi (2002) Cortical motor reorganization after a single clinical attack of multiple sclerosis. Brain 125 1607-1615.
99. A.M. Parry, R.B. Scott, J. Palace, S. Smith and P.M. Matthews (2003) Potentially adaptive functional changes in cognitive processing for patients with multiple sclerosis and their acute modulation by rivastig-mine. Brain 126 2750-2760.
100. V.H. Perry, P.B. Andersson and S. Gordon (1993) Macrophages and inflammation in the central nervous system [Review]. TINS 16 268-273.
101. G. Peters (1968) Multiple Sclerosis. Pathology of the Nervous System New York: McGraw-Hill
102. J.W. Peterson, L. Bo, S. Mork, A. Chang and B.D. Trapp (2001) Transected neurites, apoptotic neurons and reduced inflammation in cortical MS lesions. Ann. Neurol. 50 389-400.
103. D. Piani, K. Frei, K.Q. Do, M. Cuenod and A. Fontana (1991) Murine brain macrophages induced NMDA receptor mediated neurotoxicity in vitro by secreting glutamate. Neurosci. Lett. 133 159-162.
104. D. Pitt, P. Werner and C.S. Raine (2000) Glutamate excitotoxicity in a model of multiple sclerosis. Nat. Med. 6 67-70.
105. H.C. Powell and R.R. Myers (1996) The axon in Guillain-Barre syndrome: Immune target or innocent bystander? Editorial. Ann. Neurol. 39(1), 4-5.
106. J. Prineas (2001) Pathology of multiple sclerosis. S. Cook (Eds) Handbook of Multiple Sclerosis Basel, NY: Marcel Dekker 289-324.
107. J.W. Prineas, E.E. Kwon, E.S. Cho, L.R. Sharer, M.H. Barnett, E.L. Oleszak, B. Hoffman and B.P. Morgan (2001) Immunopathology of secondary-progressive multiple sclerosis. Ann. Neurol. 50 646-657.
108. T.J. Putnam (1936) Studies in multiple sclerosis. Arch. Neurol. Psychiatry 35 1289-1308.
109. C.S. Raine, B. Cannella, S.L. Hauser and C.P. Genain (1999) Demyelination in primate autoimmune encephalomyelitis and acute multiple sclerosis lesions: A case for antigen-specific antibody mediation. Ann. Neurol. 46 144-160.
110. C.S. Raine and A.H. Cross (1989) Axonal dystrophy as a consequence of long-term demyelination. Lab. Invest. 60 714-725.
111. S.M. Rao, G.J. Leo, L. Bernardin and F. Unverzagt (1991) Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology 41 685-691.
112. J.A. Rawes, V.P. Calabrese, O.A. Khan and G.H. DeVries (1997) Antibodies to the axolemma-enriched fraction in the cerebrospinal fluid and serum of patients with multiple sclerosis and other neurological diseases. Multiple Sclerosis 3 363-369.
113. H. Reddy, S. Narayanan, R. Arnoutelis, M. Jenkinson, J. Antel, P.M. Matthews and D.L. Arnold (2000) Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis. Brain 123(Pt 11), 2314-2320.
114. M.A. Rocca, D.M. Mezzapesa, A. Falini, A. Ghezzi, V. Martinelli, G. Scotti, G. Comi and M. Filippi (2003) Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis. Neuroimage 18 847-855.
115. R.A. Rudick, J.A. Cohen, B. Weinstock-Guttman, R.P. Kinkel and R.M. Ransohoff (1997) Management of multiple sclerosis. N. Engl. J. Med. 337 1604-1611.
116. R.A. Rudick, E. Fisher, J.C. Lee, J. Simon and L. Jacobs (1999) Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology 53 1698-1704.
117. R.A. Rudick, A. Goodman, R.M. Herndon and H.S. Panitch (1999) Selecting relapsing remitting multiple sclerosis patients for treatment: The case for early treatment. J. Neuroimmunol. 98 22-28.
118. S. Scherer (1999) Axonal pathology in demyelinating diseases. Ann. Neurol. 45 6-7.
119. R. Sharma, P.A. Naryana and J.S. Wolinsky (2001) Grey matter abnormalities in multiple sclerosis: Proton magnetic resonance spectroscopic imaging. Multiple Sclerosis 7 221-226.
120. J.H. Simon, L.D. Jacobs, M. Campion, K. Wende, N. Simonian, D.L. Cookfair, R.A. Rudick, R.M. Herdon, J.R. Richert, A.M. Salazar, J.J. Alam, J.S. Fischer, D.E. Goodkin, C.V. Granger, M. Lajaunie, A.L. Martens-Davidson, M. Meyer, J. Sheeder, K. Choi, A.L. Scherzinger, D.M. Bartoszak, D.N. Bourdette, J. Braiman, C.M. Brownscheidle and R.H. Whitham (1998) Magnetic resonance studies of intramuscular interferon beta-1 a for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group. Ann. Neurol. 43 79-87.
121. J.H. Simon, L.D. Jacobs, M.K. Campion, R.A. Rudick, D.L. Cookfair, R.M. Herndon, J.R. Richert, A.M. Salazar, J.S. Fischer, D.E. Goodkin, N. Simonian, M. Lajaunie, D.E. Miller, K. Wende, A. Martens-Davidson, R.P. Kinkel, F.E. Munschauer III and C.M. Brownscheidle (1999) A longitudinal study of brain atrophy in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology 53 139-148.
122. C. Skulina, S. Schmidt, K. Dornmair, H. Babbe, A. Roers, K. Rajewsky, H. Wekerle, R. Hohlfeld and N. Goebels (2004) Multiple sclerosis: brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid and blood. Proc. Natl. Acad. Sci. U. S. A. 101 2428-2433.
123. K.J. Smith and H. Lassmann (2002) The role of nitric oxide in multiple sclerosis. Lancet Neurology 1 232-241.
124. R.A. Sobel, J.M. Greer and V.K. Kuchroo (1994) Minireview: Autoimmune responses to myelin proteolipid protein. Neurochem. Res. 19 915-921.
125. T.A. Springer (1994) Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm. Cell 76 301-314.
126. V.L. Stevenson and D.H. Miller (1999) Magnetic resonance imaging in the monitoring of disease progression in multiple sclerosis. Multiple Sclerosis 5 268-272.
127. W.J. Streit, S.A. Walter and N.A. Pennell (1999) Reactive microgliosis. Prog. Neurobiol. 57 563-581.
128. P.K. Stys, S.G. Waxman and B.R. Ransom (1992) Ionic mechanisms of anoxic injury in mammalian CNS white, matter: role of Na+ channels and Na(+)-Ca2+exchanger. J. Neurosci. 12 430-439.
129. B.D. Trapp, J. Peterson, R.M. Ransohoff, R. Rudick, S. Mork and L. Bo (1998) Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338 278-285.
130. B.D. Trapp, R.M. Ransohoff, E. Fisher and R.A. Rudick (1999) Neurodegeneration in multiple sclerosis: Relationship to neurological disability. The Neuroscientist 5 48-57.
131. B.D. Trapp, R. Ransohoff and R. Rudick (1999) Axonal pathology in multiple sclerosis: relationship to neurological disability. Current Opinion Neurology 12 295-302.
132. J.H. van Waesberghe, W. Kamphorst, C.J. De Groot, M.A. van Walderveen, J.A. Castelijins, R. Ravid, G.J. Nijeholt, P.C.H. van der Valk, A.J. Thompson and F. Barkhof (1999) Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability. Ann. Neurol. 46 747-754.
133. U.H. von Andrian and C.R. Mackay (2000) T-cell function and migration. Two sides of the same coin. N. Engl. J. Med. 343 1020-1034.
134. H.Y. Wang, M. Matsui and T. Saida (2002) Immunological disturbances in the central nervous system linked to MRI findings in multiple sclerosis. J. Neuroimmunol. 125 149-154.
135. S.G. Waxman (1998) Demyelinating diseases—new pathological insights, new therapeutic targets. N. Engl. J. Med. 338 323-325.
136. S.G. Waxman (2001) Acquired channelopathies in nerve injury and MS. Neurology 56 1621-1627.
137. H.L. Weiner, C.R. Guttmann, S.J. Khoury, E.J. Orav, M.J. Hohol, R. Kikinis and F.A. Jolesz (2000) Serial magnetic resonance imaging in multiple sclerosis: correlation with attacks, disability, and disease stage. J. Neuroimmunol. 104 164-173.
138. B.G. Weinshenker (1996) Epidemiology of multiple sclerosis. Neurol. Clin. 14 291-308.
139. B.G. Weinshenker, B. Bass, G.P. Rice, J. Noseworth, W. Carriere, J. Baskerville and G.C. Ebers (1989) The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 112 133-146.
140. P. Werner, D. Pitt and C.S. Raine (2001) Multiple sclerosis: Altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage. Ann. Neurol. 50 169-180.
141. J.R. Wujek, C. Bjartmar, E. Richer, R.M. Ransohoff, M. Yu, V.K. Tuohy and B.D. Trapp (2002) Axon loss in the spinal cord determines permanent neurological disability in an animal model of multiple sclerosis. J. Neuropathol. Exp. Neurol. 61 23-32.
142. X. Yin, T.O. Crawford, J.W. Griffin, P.-H. Tu, V.M.Y. Lee, C. Li, J. Roder and B.D. Trapp (1998) Myelin-associated glycoprotein is a myelin signal that modulates the caliber to myelinated axons. J. Neurosci. 18 1953-1962.
143. M. Yu, A. Nishiyama, B.D. Trapp and V.K. Tuohy (1996) Interferon-beta inhibits progression of relapsing-remitting experimental autoimmue encephalomyelitis. J. Neuroimmunol. 64 91-100.
144. R. Zivadinov and M. Zorzon (2002) Is gadolinium enhancement predictive of the development of brain atrophy in multiple sclerosis? A review of the literature. J. Neuroimag. 12 302-309.