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Current Concepts in the Neuropathology and Pathogenesis of Multiple Sclerosis

Published online by Cambridge University Press:  02 December 2014

G.R. Wayne Moore*
Affiliation:
Department of Pathology and Laboratory Medicine, University of British Columbia, Division of Neuropathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.
*
Room 5450, Blusson Spinal Cord Centre, ICORD (International Collaboration on Repair Discoveries), 818 West 10th Avenue, Vancouver, British Columbia, V5Z 1M9, Canada.
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Abstract:

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Multiple sclerosis (MS) has been classically regarded as an inflammatory demyelinating disease of the central nervous system. In recent years, the classification and pathogenesis of the disease have become controversial, particularly with respect to whether an individual patient demonstrates a single or multiple pathogenetic mechanisms in the establishment of the focal plaque of MS. It is also becoming increasingly apparent that there is a significant neurodegenerative component in the disease, involving not only plaques but the non-plaque parenchyma as well. Magnetic resonance imaging, together with histopathologic studies, will continue to shed light on the pathogenesis of these focal and diffuse abnormalities in MS.

Résumé:

RÉSUMÉ:

La sclérose en plaques (SP) est considérée comme une maladie démyélinisante inflammatoire du système nerveux central. Au cours des dernières années, la classification et la pathogenèse de la maladie ont fait l'objet de controverses, particulièrement en ce qui concerne la présence d'un ou de plusieurs mécanismes pathogènes dans la formation de la plaque focale de la SP. Il est de plus en plus évident qu'il existe une composante neurodégénérative significative dans cette maladie, impliquant non seulement les plaques mais aussi le parenchyme exempt de plaques. L'IRM a contribué et, conjointement avec les études anatomopathologiques, continuera à élucider la pathogenèse de ces anomalies focales et diffuses dans la SP.

Type
Research Article
Copyright
Copyright © Canadian Neurological Sciences Federation 2010

References

1. Carswell, R. Pathological anatomy. Ilustrations of the elementary forms of disease. London: Longman, Orme, Brown, Green and Longman; 1838.Google Scholar
2. Cruveilhier, J. Anatomie pathologique du corps humain; descriptions avec figures lithographieεs et coloriees; des diverses alterations morbides dont le corps humain est susceptible. Paris: JB Balliere; 18291842.Google Scholar
3. Dawson, JW. The histology of multiple sclerosis. Trans R Soc Edin Reproduced by the Montreal Neurological Institute, Montreal, 1973. 1916;50:517–40 (with plates).Google Scholar
4. Compston, A, Lassmann, H, McDonald, WI. The story of multiple sclerosis. In: Compston, A, Confavreux, C, Lassmann, H, et al, Editors. McAlpine’s multiple sclerosis, 4th edition. Philadelphia: Churchill Livingstone Elsevier; 2006. p. 368.Google Scholar
5. Lassman, H, Wekerle, H. The pathology of multiple sclerosis. In: Compston, A, Confavreux, C, Lassman, H, et al, Editors. McAlpine’s multiple sclerosis, 4th edition. Philadelphia: Churchill Livingstone Elsevier; 2006. p. 557–99.Google Scholar
6. Sobel, RA, Moore, GRW. Demyelinating diseases. In: Love, S, Louis, DN, Ellison, DW, Editors. London: Hodder Arnold; 2008. p. 1513–608.Google Scholar
7. Ludwin, SK, Raine, CS. The neuropathology of multiple sclerosis. In: Raine, CS, McFarland, HF, Hohlfeld, R, editors. Multiple SclerosisAcomprehensive text. Philadelphia: Saunders Elsevier; 2008. p. 151–7.Google Scholar
8. Prineas, JW, Connell, F. The fine structure of chronically active multiple sclerosis plaques. Neurology. 1978;28(9 (Part 2)): 6875.Google Scholar
9. Lampert, PW. Fine stucture of the demyelinating process. In: Hallpike, JF, Adams, CWM, Tourtellotte, WW, editors. Multiple sclerosis: pathology, diagnosis and management. Baltimore: Williams and Wilkins; 1983. p. 2946.Google Scholar
10. Frohman, EM, Racke, MK, Raine, CS. Multiple sclerosis--the plaque and its pathogenesis. N Engl J Med. 2006 Mar 2;354(9):942–55.Google Scholar
11. Raine, CS, Scheinberg, L, Waltz, JM. Multiple sclerosis. Oligodendrocyte survival and proliferation in an active established lesion. Lab Invest. 1981 Dec;45(6):534–46.Google Scholar
12. Franklin, RJ, Ffrench-Constant, C. Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci. 2008 Nov;9(11):839–55.Google Scholar
13. Prineas, JW, Kwon, EE, Cho, ES, et al. Continual breakdown and regeneration of myelin in progressive multiple sclerosis plaques. Ann N Y Acad Sci. 1984;436:1132.Google Scholar
14. Ferguson, B, Matyszak, MK, Esiri, MM, et al. Axonal damage in acute multiple sclerosis lesions. Brain. 1997 Mar;120 (Pt 3): 393–9.Google Scholar
15. Trapp, BD, Peterson, J, Ransohoff, RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998 Jan 29;338 (5):278–85.Google Scholar
16. Raine, CS. Demyelinating Disease. In Textbook of Neuropathology. 3rd Edition. Baltimore:Williams & Wilkins, pp 627714. 3rd ed. Baltimore: Williams & Wilkins 1997.Google Scholar
17. Marburg, O. Die sogenannte “akute multiple sklerose” (Encephalomyelitis periaxialis scleroticans). Jahrbucher fur Psychiatrie und Neurologie. 1906;27:213312.Google Scholar
18. Moore, GRW. Neuropathology and pathophysiology of the multiple sclerosis lesion. In: Paty, DW, Ebers, GC, editors. Multiple sclerosis. Philadelphia: F.A. Davis; 1998. p. 257327.Google Scholar
19. Prineas, JW. The neuropathology of multiple sclerosis. In: Koetsier, JC, editor. Handbook of clinical neurology, Volume 3 (47). Amsterdam: Elsevier; 1985. p. 213–57.Google Scholar
20. Prineas, JW. Pathology of multiple sclerosis. In: Cook, SD, editor. Handbook of multiple sclerosis. New York: Marcel Decker; 1990. p. 187218.Google Scholar
21. Prineas, JW, Wright, RG. Macrophages, lymphocytes and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab Invest. 1978(38):409–21.Google Scholar
22. Prineas, JW, Barnard, RO, Revesz, T, et al. Multiple sclerosis. Pathology of recurrent lesions. Brain. 1993 Jun;116 (Pt 3): 681–93.Google Scholar
23. Sanders, V, Conrad, AJ, Tourtellotte, WW. On classification of postmortem multiple sclerosis plaques for neuroscientists. J Neuroimmunol. 1993 Jul;46(1–2):207–16.Google Scholar
24. Bo, L, Mork, S, Kong, PA, et al. Detection of MHC class II-antigens on macrophages and microglia, but not on astrocytes and endothelia in active multiple sclerosis lesions. J Neuroimmunol. 1994 May;51(2):135–46.Google Scholar
25. Lucchinetti, C, Bruck, W, Parisi, J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000 Jun;47(6):707–17.Google Scholar
26. Lucchinetti, CF, Parisi, J, Bruck, W. The pathology of multiple sclerosis. Neurol Clin. 2005 Feb;23(1):77105, vi.Google Scholar
27. Keegan, M, Konig, F, McClelland, R, et al. Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange. Lancet. 2005 Aug 13–19;366 (9485):579–82.Google Scholar
28. Bruck, W, Neubert, K, Berger, T, et al. Clinical, radiological, immunological and pathological findings in inflammatory CNS demyelination--possible markers for an antibody-mediated process. Mult Scler. 2001 Jun;7(3):173–7.Google Scholar
29. Mahad, D, Ziabreva, I, Lassmann, H, et al. Mitochondrial defects in acute multiple sclerosis lesions. Brain. 2008 Jul;131(Pt 7): 1722–35.Google Scholar
30. Stadelmann, C, Ludwin, S, Tabira, T, et al. Tissue preconditioning may explain concentric lesions in Balo’s type of multiple sclerosis. Brain. 2005 May;128(Pt 5):979–87.Google Scholar
31. Barnett, MH, Prineas, JW. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol. 2004 Apr;55(4):458–68.Google Scholar
32. Lucchinetti, CF, Bruck, W, Lassmann, H. Evidence for pathogenic heterogeneity in multiple sclerosis (letter). Ann Neurol. 2004;56 (2):308.Google Scholar
33. Pender, MP. Oliogodendrocyte apopotosis before immune attack in multiple sclerosis? (letter). Ann Neurol 2005;57(1):158.Google Scholar
34. Prineas, JW, Barnett, MH. Reply (letter). Ann Neurol. 2005;57 (158159).Google Scholar
35. Barnett, MH, Parratt, JD, Cho, ES, et al. Immunoglobulins and complement in postmortem multiple sclerosis tissue. Ann Neurol. 2009 Jan;65(1):3246.Google Scholar
36. Breij, EC, Brink, BP, Veerhuis, R, et al. Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann Neurol. 2008 Jan;63(1):1625.Google Scholar
37. Raine, CS. Multiple sclerosis: classification revisited reveals homogeneity and recapitulation. Ann Neurol. 2008 Jan;63(1): 13.Google Scholar
38. Esiri, MM. MS: is it one disease? Int MS J. 2009 Jun;16(2):3941.Google Scholar
39. Stewart, WA, Hall, LD, Berry, K, et al. Correlation between NMR scan and brain slice data in multiple sclerosis. Lancet. 1984 (ii):412.Google Scholar
40. Paty, DW, Moore, GRW. Magnetic resonance imaging changes as living pathology in multiple sclerosis In: Paty, DW, Ebers, GC, editors. Multiple Sclerosis. Philadelphia: F.A. Davis; 1998. p. 328–69.Google Scholar
41. Moore, GR. MRI-clinical correlations: more than inflammation alone-what can MRI contribute to improve the understanding of pathological processes in MS? J Neurol Sci. 2003 Feb 15;206(2): 175–9.Google Scholar
42. van Walderveen, MA, Kamphorst, W, Scheltens, P, et al. Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. Neurology. 1998 May;50 (5):1282–8.Google Scholar
43. Bitsch, A, Kuhlmann, T, Stadelmann, C, et al. A longitudinal MRI study of histopathologically defined hypointense multiple sclerosis lesions. Ann Neurol. 2001 Jun;49(6):793–6.Google Scholar
44. Katz, D, Taubenberger, JK, Cannella, B, et al. Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis. Ann Neurol. 1993 Nov;34(5): 661–9.Google Scholar
45. Ludwin, SK, Henry, JM, McFarland, HF. Vascular proliferation and angiogenesis in MS: clinical and pathogenetic implications (abstract). J Neuropathol Exp Neurol. 2001;60:505.Google Scholar
46. Sajja, BR, Wolinsky, JS, Narayana, PA. Proton magnetic resonance spectroscopy in multiple sclerosis. Neuroimaging Clin N Am. 2009 Feb;19(1):4558.Google Scholar
47. Bjartmar, C, Battistuta, J, Terada, N, et al. N-acetylaspartate is an axon-specific marker of mature white matter in vivo: a biochemical and immunohistochemical study on the rat optic nerve. Ann Neurol. 2002 Jan;51(1):51–8.Google Scholar
48. Arnold, DL, Matthews, PM, Francis, GS, et al. Proton magnetic resonance spectroscopic imaging for metabolic characterization of demyelinating plaques. Ann Neurol. 1992 Mar;31(3):235–41.Google Scholar
49. Narayana, PA, Doyle, TJ, Lai, D, et al. Serial proton magnetic resonance spectroscopic imaging, contrast-enhanced magnetic resonance imaging, and quantitative lesion volumetry in multipl sclerosis. Ann Neurol. 1998 Jan;43(1):5671.Google Scholar
50. Bitsch, A, Bruhn, H, Vougioukas, V, et al. Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy. AJNR Am J Neuroradiol. 1999 Oct;20(9):1619–27.Google Scholar
51. Brex, PA, Parker, GJ, Leary, SM, et al. Lesion heterogeneity in multiple sclerosis: a study of the relations between appearances on T1 weighted images, T1 relaxation times, and metabolite concentrations. J Neurol Neurosurg Psychiatry. 2000 May;68(5): 627–32.Google Scholar
52. Helms, G, Stawiarz, L, Kivisakk, P, et al. Regression analysis of metabolite concentrations estimated from localized proton MR spectra of active and chronic multiple sclerosis lesions. Magn Reson Med. 2000 Jan;43(1):102–10.Google Scholar
53. Husted, CA, Goodin, DS, Hugg, JW, et al. Biochemical alterations in multiple sclerosis lesions and normal-appearing white matter detected by in vivo 31P and 1H spectroscopic imaging. Ann Neurol. 1994 Aug;36(2):157–65.Google Scholar
54. Schmierer, K, Scaravilli, F, Altmann, DR, et al. Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain. Ann Neurol. 2004 Sep;56(3):407–15.Google Scholar
55. Schmierer, K, Wheeler-Kingshott, CA, Tozer, DJ, et al. Quantitative magnetic resonance of postmortem multiple sclerosis brain before and after fixation. Magn Reson Med. 2008 Feb;59(2): 268–77.Google Scholar
56. van Waesberghe, JH, Kamphorst, W, De Groot, CJ, et al. Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability. Ann Neurol. 1999 Nov;46 (5):747–54.Google Scholar
57. Fisher, E, Chang, A, Fox, RJ, et al. Imaging correlates of axonal swelling in chronic multiple sclerosis brains. Ann Neurol. 2007 Sep;62(3):219–28.Google Scholar
58. Rovaris, M, Gass, A, Bammer, R, et al. Diffusion MRI in multiple sclerosis. Neurology. 2005 Nov 22;65(10):1526–32.CrossRefGoogle ScholarPubMed
59. Schmierer, K, Wheeler-Kingshott, CA, Boulby, PA, et al. Diffusion tensor imaging of post mortem multiple sclerosis brain. Neuroimage. 2007 Apr 1;35(2):467–77.Google Scholar
60. MacKay, A, Whittall, K, Adler, J, et al. In vivo visualization of myelin water in brain by magnetic resonance. Magn Reson Med. 1994 Jun;31(6):673–7.Google Scholar
61. Moore, GR, Leung, E, MacKay, AL, et al. A pathology-MRI study of the short-T2 component in formalin-fixed multiple sclerosis brain. Neurology. 2000 Nov 28;55(10):1506–10.Google Scholar
62. Laule, C, Leung, E, Lis, DK, et al. Myelin water imaging in multiple sclerosis: quantitative correlations with histopathology. Mult Scler. 2006 Dec;12(6):747–53.Google Scholar
63. Vavasour, IM, Laule, C, Li, DK, et al. Longitudinal changes in myelin water fraction in two MS patients with active disease. J Neurol Sci. 2009 Jan 15;276(1–2):4953.Google Scholar
64. Nesbit, GM, Forbes, GS, Scheithauer, BW, et al. Multiple sclerosis: histopathologic and MR and/or CT correlation in 37 cases at biopsy and three cases at autopsy. Radiology. 1991 Aug;180(2): 467–74.Google Scholar
65. Bruck, W, Bitsch, A, Kolenda, H, et al. Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol. 1997 Nov; 42(5):783–93.Google Scholar
66. Karaarslan, E, Altintas, A, Senol, U, et al. Balo’s concentric sclerosis: clinical and radiologic features of five cases. AJNR Am J Neuroradiol. 2001 Aug;22(7):1362–7.Google Scholar
67. Kidd, D, Barkhof, F, McConnell, R, et al. Cortical lesions in multiple sclerosis. Brain. 1999 Jan;122 (Pt 1):1726.Google Scholar
68. Geurts, JJ, Bo, L, Pouwels, PJ, et al. Cortical lesions in multiple sclerosis: combined postmortem MR imaging and histopathology. AJNR Am J Neuroradiol. 2005 Mar;26(3):572–7.Google ScholarPubMed
69. Peterson, JW, Bo, L, Mork, S, et al. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol. 2001 Sep;50(3):389400.Google Scholar
70. Roosendaal, SD, Moraal, B, Pouwels, PJ, et al. Accumulation of cortical lesions in MS: relation with cognitive impairment. Mult Scler. 2009 Jun;15(6):708–14.Google Scholar
71. Kutzelnigg, A, Lassmann, H. Cortical demyelination in multiple sclerosis: a substrate for cognitive deficits? J Neurol Sci. 2006 Jun 15;245(1–2):123–6.Google Scholar
72. Wegner, C, Esiri, MM, Chance, SA, et al. Neocortical neuronal, synaptic, and glial loss in multiple sclerosis. Neurology. 2006 Sep 26;67(6):960–7.Google Scholar
73. Bo, L, Vedeler, CA, Nyland, H, et al. Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult Scler. 2003 Aug;9(4):323–31.Google Scholar
74. Bo, L, Vedeler, CA, Nyland, HI, et al. Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol. 2003 Jul;62(7):723–32.Google Scholar
75. Roemer, S, Stadelmann, C, Bruck, W, et al. Cortical demyelination is present in early multiple sclerosis (abstract). Neurology. 2006 March;66 (Suppl 2)(5):A93–4.Google Scholar
76. Kangarlu, A, Bourekas, EC, Ray-Chaudhury, A, et al. Cerebral cortical lesions in multiple sclerosis detected by MR imaging at 8 Tesla. AJNR Am J Neuroradiol. 2007 Feb;28(2):262–6.Google Scholar
77. Huitinga, I, De Groot, CJ, Van der Valk, P, et al. Hypothalamic lesions in multiple sclerosis. J Neuropathol Exp Neurol. 2001 Dec;60 (12):1208–18.Google Scholar
78. Vercellino, M, Masera, S, Lorenzatti, M, et al. Demyelination, inflammation, and neurodegeneration in multiple sclerosis deep gray matter. J Neuropathol Exp Neurol. 2009 May;68(5): 489502.Google Scholar
79. Allen, IV, Glover, G, Anderson, R. Abnormalities in the macroscopically normal white matter in cases of mild or spinal multiple sclerosis (MS). Acta Neuropathol Suppl (Berl). 1981;7: 176–8.Google Scholar
80. Allen, IV, McKeown, SR. A histological, histochemical and biochemical study of the macroscopically normal white matter in multiple sclerosis. J Neurol Sci. 1979 Mar;41(1):8191.Google Scholar
81. Kutzelnigg, A, Lucchinetti, CF, Stadelmann, C, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005 Nov;128(Pt 11):2705–12.Google Scholar
82. Allen, IV, McQuaid, S, Mirakhur, M, et al. Pathological abnormalities in the normal-appearing white matter in multiple sclerosis. Neurol Sci. 2001 Apr;22(2):141–4.Google Scholar
83. Gobin, SJ, Montagne, L, Van Zutphen, M, et al. Upregulation of transcription factors controlling MHC expression in multiple sclerosis lesions. Glia. 2001 Oct;36(1):6877.Google Scholar
84. Arstila, AU, Riekkinen, P, Rinne, UK, et al. Studies on the pathogenesis of multiple sclerosis. Participation of lysosomes on demyelination in the central nervous system white matter outside plaques. Eur Neurol. 1973;9(1):120.Google Scholar
85. Riekkinen, PJ, Rinne, UK, Arstila, AU. Neurochemical and morphological studies on demyelination in multiple sclerosis with special reference to etiological aspects. Z Neurol. 1972;203(2):91104.Google Scholar
86. Rinne, UK, Riekkinen, PJ, Arstila, AU. Biochemical and electron microscopic alterations in the white matter outside demyelinated plaques in multiple sclerosis. . In: Lubowitz, U, editor. Progress in Multiple Sclerosis. New York: Academic Press; 1972. p. 7698.Google Scholar
87. Lindberg, RL, De Groot, CJ, Montagne, L, et al. The expression profile of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in lesions and normal appearing white matter of multiple sclerosis. Brain. 2001 Sep;124(Pt 9):1743–53.Google Scholar
88. Sobel, RA, Ahmed, AS. White matter extracellular matrix chondroitin sulfate/dermatan sulfate proteoglycans in multiple sclerosis. J Neuropathol Exp Neurol. 2001 Dec;60(12): 1198–207.Google Scholar
89. Plumb, J, McQuaid, S, Mirakhur, M, Kirk, J. Abnormal endothelial tight junctions in active lesions and normal-appearing white matter in multiple sclerosis. Brain Pathol. 2002 Apr;12(2): 154–69.Google Scholar
90. Kirk, J, Plumb, J, Mirakhur, M, et al. Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination. J Pathol. 2003 Oct;201(2):319–27.Google Scholar
91. Evangelou, N, Esiri, MM, Smith, S, et al. Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann Neurol. 2000 Mar;47(3):391–5.Google Scholar
92. Evangelou, N, Konz, D, Esiri, MM, et al. Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis. Brain. 2000 Sep; 123 (Pt 9):1845–9.Google Scholar
93. De Stefano, N, Narayanan, S, Francis, SJ, et al. Diffuse axonal and tissue injury in patients with multiple sclerosis with low cerebral lesion load and no disability. Arch Neurol. 2002 Oct;59(10): 1565–71.Google Scholar
94. Miller, DH, Thompson, AJ, Filippi, M. Magnetic resonance studies of abnormalities in the normal appearing white matter and grey matter in multiple sclerosis. J Neurol. 2003 Dec;250(12): 1407–19.Google Scholar
95. Narayana, PA, Wolinsky, JS, Rao, SB, et al. Multicentre proton magnetic resonance spectroscopy imaging of primary progressive multiple sclerosis. Mult Scler. 2004 Jun;10 Suppl 1:S73–8.Google Scholar
96. Inglese, M, Li, BS, Rusinek, H, et al. Diffusely elevated cerebral choline and creatine in relapsing-remitting multiple sclerosis. Magn Reson Med. 2003 Jul;50(1):190–5.Google Scholar
97. Fernando, KT, McLean, MA, Chard, DT, et al. Elevated white matter myo-inositol in clinically isolated syndromes suggestive of multiple sclerosis. Brain. 2004 Jun;127(Pt 6):1361–9.Google Scholar
98. Ropele, S, Fazekas, F. Magnetization transfer MR imaging in multiple sclerosis. Neuroimaging Clin N Am. 2009 Feb;19(1): 2736.Google Scholar
99. Werring, DJ, Clark, CA, Droogan, AG, et al. Water diffusion is elevated in widespread regions of normal-appearing white matter in multiple sclerosis and correlates with diffusion in focal lesions. Mult Scler. 2001 Apr;7(2):83–9.Google Scholar
100. Guo, AC, Jewells, VL, Provenzale, JM. Analysis of normal-appearing white matter in multiple sclerosis: comparison of diffusion tensor MR imaging and magnetization transfer imaging. AJNR Am J Neuroradiol. 2001 Nov-Dec;22(10):1893–900.Google Scholar
101. van Walderveen, MA, van Schijndel, RA, Pouwels, PJ, et al. Multislice T1 relaxation time measurements in the brain using IR-EPI: reproducibility, normal values, and histogram analysis in patients with multiple sclerosis. J Magn Reson Imaging. 2003 Dec;18(6):656–64.Google Scholar
102. Traboulsee, A, Dehmeshki, J, Peters, KR, et al. Disability in multiple sclerosis is related to normal appearing brain tissue MTR histogram abnormalities. Mult Scler. 2003 Dec;9(6):566–73.Google Scholar
103. Bakshi, R, Benedict, RH, Bermel, RA, et al. T2 hypointensity in the deep gray matter of patients with multiple sclerosis: a quantitative magnetic resonance imaging study. Arch Neurol. 2002 Jan;59(1):62–8.Google Scholar
104. Cifelli, A, Arridge, M, Jezzard, P, et al. Thalamic neurodegeneration in multiple sclerosis. Ann Neurol. 2002 Nov;52(5):650–3.Google Scholar
105. Zhao, GJ, Li, DKB, Cheng, Y, et al. MRI dirty-appearing white matter in MS (abstract). Neurology. 2000;54 (suppl 3):A121.Google Scholar
106. Seewann, A, Vrenken, H, van der Valk, P, et al. Diffusely abnormal white matter in chronic multiple sclerosis: imaging and histopathologic analysis. Arch Neurol. 2009 May;66(5):601–9.Google Scholar
107. Vos, CM, Geurts, JJ, Montagne, L, et al. Blood-brain barrier alterations in both focal and diffuse abnormalities on postmortem MRI in multiple sclerosis. Neurobiol Dis. 2005 Dec; 20(3):953–60.Google Scholar
108. Segarra, JM. Histological and histochemical staining methods: A selection In: Teduchi, CG, editor. Neuropathology Methods and Diagnosis. Boston: Little, Brown and Company; 1970. p. 233–69.Google Scholar
109. Moore, GR, Laule, C, Mackay, A, et al. Dirty-appearing white matter in multiple sclerosis: preliminary observations of myelin phospholipid and axonal loss. J Neurol. 2008 Nov;255(11):1802–11, discussion 12.Google Scholar
110. Laule, C, Kozlowski, P, Leung, E, et al. Myelin water imaging of multiple sclerosis at 7 T: correlations with histopathology. Neuroimage. 2008 May 1;40(4):1575–80.Google Scholar
111. Filippi, M, Rocca, MA, Martino, G, et al. Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis. Ann Neurol. 1998 Jun;43(6):809–14.Google Scholar
112. Laule, C, Vavasour, IM, Whittall, KP, et al. Evolution of focal and diffuse magnetisation transfer abnormalities in multiple sclerosis. J Neurol. 2003 Aug;250(8):924–31.Google Scholar
113. Wuerfel, J, Bellmann-Strobl, J, Brunecker, P, et al. Changes in cerebral perfusion precede plaque formation in multiple sclerosis: a longitudinal perfusion MRI study. Brain. 2004 Jan; 127(Pt 1):111–9.Google Scholar
114. Werring, DJ, Brassat, D, Droogan, AG, et al. The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosis: a serial diffusion MRI study. Brain. 2000 Aug;123 (Pt 8):1667–76.Google Scholar
115. Tartaglia, MC, Narayanan, S, De Stefano, N, et al. Choline is increased in pre-lesional normal appearing white matter in multiple sclerosis. J Neurol. 2002 Oct;249(10):1382–90.Google Scholar