Journal of Neurology

, Volume 252, Supplement 5, pp v16–v24

MRI evidence for multiple sclerosis as a diffuse disease of the central nervous system

Article

Abstract

The classical view of MS as a chronic inflammatory demyelinating disease leading to the formation of focal central nervous system (CNS) white matter (WM) lesions has been recently challenged by pathological studies and by the extensive application of modern MRI-based techniques. There is now overwhelming evidence supporting the following statements:

• MS causes widespread tissue damage in the normal-appearing white matter (NAWM) of the brain and spinal cord, whose extent and severity is more strictly associated to the clinical manifestations of the disease than the extent of focal pathology. Discrete, macroscopic lesions are just the tip of the iceberg of MS pathology.

• Grey matter (GM) damage is a consistent feature of all MS phenotypes, which is progressive from the start of the relapsing-remitting phase of the disease. As is the case for WM, GM damage is also a mixture of focal lesions and diffuse pathology. High-field strength MR scanners are improving our ability to image focal GM lesions and modern MR-based techniques are enabling us to quantify in vivo the extent and severity of GM pathology, which have been shown to correlate only moderately with the amount ofWM changes. At least part of GM pathology in MS is not secondary to retrograde degeneration of fibers traversing WM lesions.

• The neurodegenerative component of the disease is not a late phenomenon and it is not completely driven by inflammatory demyelination. In fact, neurodegeneration occurs very early in the course of MS and the correlation between MRI measures of inflammation and neurodegeneration is weak in all disease phases. The interplay of inflammation and neurodegeneration is a complex and still poorly understood phenomenon. At least part of MS-related neurodegeneration is not directly driven by Wallerian degeneration.

• Functional cortical changes can be seen in virtually all MS patients and are likely to play a central role in the ability of the MS brain to respond to tissue injury and, hence, limit the functional consequences of structural damage. MS disability is not just the result of tissue destruction but rather a balance between tissue destruction, tissue repair and adaptive cortical reorganization.

All of this calls for the concept of MS as a focal, inflammatory demyelinating, WM disease to be reexamined and to start viewing MS as a diffuse CNS disease with an important neurodegenerative component. This is central for identifying novel and effective treatment strategies.

Key words

multiple sclerosis normal-appearing white matter grey matter neurodegeneration cortical adaptation 

References

  1. 1.
    Adalsteinsson E, Langer-Gould A, Homer RJ, et al. (2003) Gray Matter N-Acetyl Aspartate Deficits in Secondary Progressive but Not Relapsing-Remitting Multiple Sclerosis. Am J Neuroradiol 24:1941–1945PubMedGoogle Scholar
  2. 2.
    Allen IV, McKeown SR (1979) A histological, histochemical and biochemical study of the macroscopically normal white matter in multiple sclerosis. J Neurol Sci 41:81–91CrossRefPubMedGoogle Scholar
  3. 3.
    Audoin B, Ranjeva JP, Duong MV, et al. (2004) Voxel-based analysis of MTR images: a method to locate gray matter abnormalities in patients at the earliest stage of multiple sclerosis. J Magn Reson Imaging 20:765–771CrossRefPubMedGoogle Scholar
  4. 4.
    Bjartmar C, Kinkel RP, Kidd G, et al. (2001) Axonal loss in normal-appearing white matter in a patient with acute MS. Neurology 57:1248–1252PubMedGoogle Scholar
  5. 5.
    Bonneville F, Moriarty DM, Li BS, et al. (2002) Whole-brain N-acetylaspartate concentration: correlation with T2-weighted lesion volume and expanded disability status scale score in cases of relapsing-remitting multiple sclerosis. Am J Neuroradiol 23:371–375PubMedGoogle Scholar
  6. 6.
    Bozzali M, Cercignani M, Sormani MP, et al. (2002) Quantification of brain gray matter damage in different MS phenotypes by use of diffusion tensor MR imaging. Am J Neuroradiol 23:985–988PubMedGoogle Scholar
  7. 7.
    Caramia F, Pantano P, Di Legge S, et al. (2002) A longitudinal study of MR diffusion changes in normal appearing white matter of patients with early multiple sclerosis. Magn Reson Imaging 20:383–388CrossRefPubMedGoogle Scholar
  8. 8.
    Castriota Scanderbeg A, Tomaiuolo F, Sabatini U, et al. (2000) Demyelinating plaques in relapsing-remitting and secondary-progressive multiple sclerosis: assessment with diffusion MR imaging. Am J Neuroradiol 21:862–868PubMedGoogle Scholar
  9. 9.
    Cercignani M, Bozzali M, Iannucci G, et al. (2001) Magnetisation transfer ratio and mean diffusivity of normalappearing white and grey matter from patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 70:311–317CrossRefPubMedGoogle Scholar
  10. 10.
    Cercignani M, Iannucci G, Rocca MA, et al. (2000) Pathologic damage in MS assessed by diffusion-weighted and magnetization transfer MRI. Neurology 54:1139–1144PubMedGoogle Scholar
  11. 11.
    Cercignani M, Inglese M, Pagani E, et al. (2001) Mean diffusivity and fractional anisotropy histograms of patients with multiple sclerosis. Am J Neuroradiol 22:952–958PubMedGoogle Scholar
  12. 12.
    Chard DT, Griffin CM, McLean MA, et al. (2002) Brain metabolite changes in cortical gray and normal-appearing white matter in clinically early relapsing-remitting multiple sclerosis. Brain 125:2342–2352CrossRefPubMedGoogle Scholar
  13. 13.
    Ciccarelli O, Werring DJ, Barker GJ, et al. (2003) A study of the mechanisms of normal-appearing white matter damage in multiple sclerosis using diffusion tensor imaging-evidence ofWallerian degeneration. J Neurol 250:287–292CrossRefPubMedGoogle Scholar
  14. 14.
    Ciccarelli O, Werring DJ, Wheeler-Kingshott CA, et al. (2001) Investigation of MS normal-appearing brain using diffusion tensor MRI with clinical correlations. Neurology 56:926–933PubMedGoogle Scholar
  15. 15.
    Cifelli A, Arridge M, Jezzard P, et al. (2002) Thalamic neurodegeneration in multiple sclerosis. Ann Neurol 52:650–653CrossRefPubMedGoogle Scholar
  16. 16.
    Codella M, Rocca MA, Colombo B, et al. (2002) Cerebral gray matter pathology and fatigue in patients with multiple sclerosis: a preliminary study. J Neurol Sci 194:71–74CrossRefPubMedGoogle Scholar
  17. 17.
    Coles AJ, Wing MG, Molyneux P, et al. (1999) Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 46:296–304Google Scholar
  18. 18.
    Comi G, Filippi M, Barkhof F, et al. (2001) Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 357:1576–1582CrossRefPubMedGoogle Scholar
  19. 19.
    Comi G, Filippi M, Wolinsky JS, and the European/Canadian Glatiramer Acetate Study Group (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. Ann Neurol 49:290–297CrossRefPubMedGoogle Scholar
  20. 20.
    Davie CA, Barker GJ,W ebb S, et al. (1995) Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss. Brain 118:1583–1592PubMedGoogle Scholar
  21. 21.
    De Stefano N, Matthews PM, Fu L, et al. (1998) Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain 121:1469–1477CrossRefPubMedGoogle Scholar
  22. 22.
    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 58:65–70CrossRefPubMedGoogle Scholar
  23. 23.
    De Stefano N, Narayanan S, Francis SJ, et al. (2002) Diffuse axonal and tissue injury in patients with multiple sclerosis with low cerebral lesion load and no disability. Arch Neurol 59:1565–1571CrossRefPubMedGoogle Scholar
  24. 24.
    Dehmeshki J, Chard DT, Leary SM, et al. (2003) The normal appearing gray matter in primary progressive multiple sclerosis: a magnetisation transfer imaging study. J Neurol 250:67–74CrossRefPubMedGoogle Scholar
  25. 25.
    Dehmeshki J, Ruto AC, Arridge S, et al. (2001) Analysis of MTR histograms in multiple sclerosis using principal components and multiple discriminant analysis. Magn Reson Med 46:600–609CrossRefPubMedGoogle Scholar
  26. 26.
    Droogan AG, Clark CA, Werring DJ, et al. (1999) Comparison of multiple sclerosis clinical subgroups using navigated spin echo diffusion-weighted imaging. Magn Reson Imaging 17:653–661CrossRefPubMedGoogle Scholar
  27. 27.
    Evangelou N, Esiri MM, Smith S, et al. (2000) Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann Neurol 47:391–395CrossRefPubMedGoogle Scholar
  28. 28.
    Fabiano AJ, Sharma J, Weinstock-Guttman B, et al. (2003) Thalamic involvement in multiple sclerosis: a diffusion-weighted magnetic resonance imaging study. J Neuroimaging 13:307–314CrossRefPubMedGoogle Scholar
  29. 29.
    Filippi M, Inglese M (2001) Overview of diffusion-weighted magnetic resonance studies in multiple sclerosis. J Neurol Sci 186:S37-S43CrossRefPubMedGoogle Scholar
  30. 30.
    Filippi M, Rocca MA (2003) Disturbed function and plasticity in multiple sclerosis as gleaned from functional magnetic resonance imaging. Curr Opin Neurol 16:275–282Google Scholar
  31. 31.
    Filippi M, Arnold DL, Comi G (2001) Magnetic resonance spectroscopy in multiple sclerosis. Springer, MilanGoogle Scholar
  32. 32.
    Filippi M, Bozzali M, Rovaris M, et al. (2003) Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis. Brain 126:433–437CrossRefPubMedGoogle Scholar
  33. 33.
    Filippi M, Campi A, Dousset V, et al. (1995) A magnetisation transfer imaging study of normal-appearing white matter in multiple sclerosis. Neurology 45:478–482PubMedGoogle Scholar
  34. 34.
    Filippi M, Cercignani M, Inglese M, et al. (2001) Diffusion tensor magnetic resonance imaging in multiple sclerosis. Neurology 56:304–311PubMedGoogle Scholar
  35. 35.
    Filippi M, Grossman RI, Comi G (1999) Magnetisation transfer in multiple sclerosis. Neurology 53(Suppl 3)Google Scholar
  36. 36.
    Filippi M, Iannucci G, Cercignani M, et al. (2000) A quantitative study of water diffusion in multiple sclerosis lesions and normal-appearing white matter using echo-planar imaging. Arch Neurol 57:1017–1021CrossRefPubMedGoogle Scholar
  37. 37.
    Filippi M, Iannucci G, Tortorella C, et al. (1999) Comparison of MS clinical phenotypes using conventional and magnetization transfer MRI. Neurology 52:588–594PubMedGoogle Scholar
  38. 38.
    Filippi M, Inglese M, Rovaris M, et al. (2000) Magnetization transfer imaging to monitor the evolution of MS: a 1-year follow-up study. Neurology 55:940–946PubMedGoogle Scholar
  39. 39.
    Filippi M, Rocca MA, Colombo B, et al. (2002) Functional magnetic resonance imaging correlates of fatigue in multiple sclerosis. NeuroImage 15:559–567CrossRefPubMedGoogle Scholar
  40. 40.
    Filippi M, Rocca MA, Falini A, et al. (2002) Correlations between structural CNS damage and functional MRI changes in primary progressive MS. NeuroImage 15:537–546CrossRefPubMedGoogle Scholar
  41. 41.
    Filippi M, Rocca MA, Mezzapesa DM, et al. (2004) A functional MRI study of cortical activations associated with object manipulation in patients with MS. NeuroImage 21:1147–1154CrossRefPubMedGoogle Scholar
  42. 42.
    Filippi M, Rocca MA, Mezzapesa DM, et al. (2004) Simple and complex movement-associated functional MRI changes in patients at presentation with clinically isolated syndromes suggestive of MS. Human Brain Mapping 21:108–117CrossRefPubMedGoogle Scholar
  43. 43.
    Filippi M, Rovaris M, Iannucci G, et al. (2000) Whole brain volume changes in patients with progressive MS treated with cladribine. Neurology 55:1714–1718PubMedGoogle Scholar
  44. 44.
    Filippi M, Rovaris M, Inglese M, et al. (2004) Reduced brain tissue loss during randomized study of interferon beta-1a in patients at presentation with syndromes suggestive of multiple sclerosis. Lancet 364:1489–1496CrossRefPubMedGoogle Scholar
  45. 45.
    Filippi M, Tortorella C, Rovaris M, et al. (2000) Changes in the normal appearing brain tissue and cognitive impairment in multiple sclerosis. J Neurol Neurosurg Psychiatry 68:157–161CrossRefPubMedGoogle Scholar
  46. 46.
    Fu L, Matthews PM, De Stefano N, et al. (1998) Imaging axonal damage of normal-appearing white matter in multiple sclerosis. Brain 121:103–113CrossRefPubMedGoogle Scholar
  47. 47.
    Gadea M, Martinez-Bisbal MC, Marti-Bonmati L, et al. (2004) Spectroscopic axonal damage of the right locus coeruleus relates to selective attention impairment in early stage relapsing-remitting multiple sclerosis. Brain 127:89–98CrossRefPubMedGoogle Scholar
  48. 48.
    Gallo A, Rovaris M, Riva R, et al. (2005) Diffusion-tensor magnetic resonance imaging detects normalappearing white matter damage unrelated to short-term disease activity in patients at the earliest clinical stage of multiple sclerosis. Arch Neurol 62:803–808CrossRefPubMedGoogle Scholar
  49. 49.
    Ge Y, Grossman RI, Babb JS, et al. (2003) Dirty-appearing white matter in multiple sclerosis: volumetric MR imaging and magnetization transfer ratio histogram analysis. Am J Neuroradiol 24:1935–1940PubMedGoogle Scholar
  50. 50.
    Ge Y, Grossman RI, Udupa JK, et al. (2001) Magnetization transfer ratio histogram analysis of gray matter in relapsing-remitting multiple sclerosis. Am J Neuroradiol 22:470–475PubMedGoogle Scholar
  51. 51.
    Ge Y, Grossman RI, Udupa JK, et al. (2002) Magnetization transfer ratio histogram analysis of normal-appearing gray matter and normal-appearing white matter in multiple sclerosis. J Comput Assist Tomogr 26:62–68CrossRefPubMedGoogle Scholar
  52. 52.
    Gonen O, Catalaa I, Babb JS, et al. (2000) Total brain N-acetylaspartate. A new measure of disease load in MS. Neurology 54:15–19PubMedGoogle Scholar
  53. 53.
    Gonen O, Viswanathan AK, Catalaa I, et al. (1998) Total brain N-acetylaspartate concentration in normal, age-grouped females: quantitation with non-echo proton NMR spectroscopy. Magn Reson Med 40:684–689PubMedGoogle Scholar
  54. 54.
    Griffin CM, Chard DT, Ciccarelli O, et al. (2001) Diffusion tensor imaging in early relapsing-remitting multiple sclerosis. Mult Scler 7:290–297CrossRefPubMedGoogle Scholar
  55. 55.
    Hillary FG, Chiaravalloti ND, Ricker JH, et al. (2003) An investigation of working memory rehearsal in multiple sclerosis using fMRI. J Clin Exp Neuropsychol 25:965–978PubMedGoogle Scholar
  56. 56.
    Horsfield MA, Lai M, Webb SL, et al. (1996) Apparent diffusion coefficients in benign and secondary progressive multiple sclerosis by nuclear magnetic resonance. Magn Reson Med 36:393–400PubMedGoogle Scholar
  57. 57.
    Iannucci G, Minicucci L, Rodegher M, et al. (1999) Correlations between clinical and MRI involvement in multiple sclerosis: assessment using T1, T2 and MT histograms. J Neurol Sci 171:121–129CrossRefPubMedGoogle Scholar
  58. 58.
    Iannucci G, Rovaris M, Giacomotti L, et al. (2001) Correlation of multiple sclerosis measures derived from T2-weighted, T1-weighted, magnetization transfer, and diffusion tensor MR imaging. Am J Neuroradiol 22:1462–1467PubMedGoogle Scholar
  59. 59.
    Iannucci G, Tortorella C, Rovaris M, et al. (2000) Prognostic value of MR and magnetization transfer imaging findings in patients with clinically isolated syndromes suggestive of multiple sclerosis at presentation. Am J Neuroradiol 21:1034–1038PubMedGoogle Scholar
  60. 60.
    Inglese M, Benedetti B, Filippi M (2005) The relation between MRI measures of inflammation and neurodegeneration in multiple sclerosis. J Neurol Sci 15:15–19CrossRefGoogle Scholar
  61. 61.
    Inglese M, Ge Y, Filippi M, et al. (2004) Indirect evidence for early widespread gray matter involvement in relapsing-remitting multiple sclerosis. NeuroImage 21:1825–1829CrossRefPubMedGoogle Scholar
  62. 62.
    Inglese M, Ghezzi A, Bianchi S, et al. (2002) Irreversible disability and tissue loss in multiple sclerosis: a conventional and magnetization transfer magnetic resonance imaging study of the optic nerves. Arch Neurol 59:250–255CrossRefPubMedGoogle Scholar
  63. 63.
    Inglese M, Li BS, Rusinek H, et al. (2003) Diffusely elevated cerebral choline and creatine in relapsing-remitting multiple sclerosis. Magn Reson Med 50:190–195CrossRefPubMedGoogle Scholar
  64. 64.
    Inglese M, Mancardi GL, Pagani E, et al. (2004) Brain tissue loss occurs after suppression of enhancement in patients with multiple sclerosis treated with autologous hematopoietic stem cell transplantation. J Neurol Neurosurg Psychiatry 75:643–644PubMedGoogle Scholar
  65. 65.
    Kalkers NF, Hintzen RQ, van Waesberghe JH, et al. (2001) Magnetization transfer histogram parameters reflect all dimensions of MS pathology, including atrophy. J Neurol Sci 184:155–162CrossRefPubMedGoogle Scholar
  66. 66.
    Kapeller P, Brex PA, Chard D, et al. (2002) Quantitative 1H-MRS imaging 14 years after presenting with a clinically isolated syndrome suggestive of multiple sclerosis. Mult Scler 8:207–210CrossRefPubMedGoogle Scholar
  67. 67.
    Kapeller P, McLean MA, Griffin CM, et al. (2001) Preliminary evidence for neuronal damage in cortical grey matter and normal appearing white matter in short duration relapsing-remitting multiple sclerosis: a quantitative MR spectroscopic imaging study. J Neurol 248:131–138CrossRefPubMedGoogle Scholar
  68. 68.
    Kidd D, Barkhof F, McConnell R, et al. (1999) Cortical lesions in multiple sclerosis. Brain 122:17–26CrossRefPubMedGoogle Scholar
  69. 69.
    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 47:606–613CrossRefPubMedGoogle Scholar
  70. 70.
    Lee MA, Blamire AM, Pendlebury S, et al. (2000) Axonal injury or loss in the internal capsule and motor impairment in multiple sclerosis. Arch Neurol 57:65–70CrossRefPubMedGoogle Scholar
  71. 71.
    Li DKB, Paty DW, the UBC MS/MRI Analysis Research Group, and the PRISMS Study Group (1998) Magnetic resonance imaging results of PRISMS trial: a randomized, doubleblind, placebo-controlled study of interferon-beta 1a in relapsing-remitting multiple sclerosis. Ann Neurol 46:197–206CrossRefGoogle Scholar
  72. 72.
    Loevner LA, Grossman RI, Cohen JA, et al. (1995) Microscopic disease in normal-appearing white matter on conventional MR images in patients with multiple sclerosis: assessment with magnetisation-transfer measurements. Radiology 196:511–515PubMedGoogle Scholar
  73. 73.
    Lumdsen CE (1970) The neuropathology of multiple sclerosis. In: Vinken PJ, Bruyn GW (eds) Handbook of clinical neurology.Vol 9 North-Holland, Amsterdam, pp 217–309Google Scholar
  74. 74.
    Mainero C, Caramia F, Pozzilli C, et al. (2004) fMRI evidence of brain reorganization during attention and memory tasks in multiple sclerosis. NeuroImage 21:858–867CrossRefPubMedGoogle Scholar
  75. 75.
    Mancardi GL, Saccardi R, Filippi M, et al. (2001) Autologous hematopoietic stem cell transplantation suppresses Gd-enhanced MRI activity in MS. Neurology 57:62–68Google Scholar
  76. 76.
    McDonald WI, Compston A, Edan G, et al. (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127Google Scholar
  77. 77.
    Mezzapesa DM, Rocca MA, Falini A, et al. (2004) A preliminary diffusion tensor and magnetization transfer magnetic resonance imaging study of early-onset multiple sclerosis. Arch Neurol 61:366–368CrossRefPubMedGoogle Scholar
  78. 78.
    Miller DH, Barkhof F, Frank JA, et al. (2002) Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 125:1676–1695CrossRefPubMedGoogle Scholar
  79. 79.
    Molyneux PD, Barker GJ, Barkhof F, et al. (2001) Clinical-MRI correlations in a European trial of interferon beta-1b in secondary progressive MS. Neurology 57:2191–2197PubMedGoogle Scholar
  80. 80.
    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. Brain 123:2256–2263CrossRefPubMedGoogle Scholar
  81. 81.
    Nusbaum AO, Tang CY, Wei TC, et al. (2000) Whole-brain diffusion MR histograms differ between MS subtypes. Neurology 54:1421–1426PubMedGoogle Scholar
  82. 82.
    Oreja-Guevara C, Rovaris M, Iannucci G, et al. (2005) Progressive gray matter damage in patients with relapsing remitting MS: a longitudinal diffusion tensor MRI study. Arch Neurol 62:578–584CrossRefPubMedGoogle Scholar
  83. 83.
    Pagani E, Filippi M, Rocca MA, Horsfield MA (2005) A method for obtaining tract-specific diffusion tensor MRI measurements in the presence of disease: application to patients with clinically isolated syndromes suggestive of multiple sclerosis. NeuroImage 26:258–265CrossRefPubMedGoogle Scholar
  84. 84.
    Pantano P, Iannetti GD, Caramia F, et al. (2002) Cortical motor reorganization after a single clinical attack of multiple sclerosis Brain 125:1607–1615CrossRefPubMedGoogle Scholar
  85. 85.
    Pantano P, Mainero C, Iannetti GD, et al. (2002) Contribution of corticospinal tract damage to cortical motor reorganization after a single clinical attack of multiple sclerosis. NeuroImage 17:1837–1843CrossRefPubMedGoogle Scholar
  86. 86.
    Paolillo A, Coles AJ, Molyneux PD, et al. (1999) Quantitative MRI in patients with secondary progressive MS treated with monoclonal antibody Campath-1H. Neurology 53:751–757PubMedGoogle Scholar
  87. 87.
    Parry AM, Scott RB, Palace J, et al. (2003) Potentially adaptive functional changes in cognitive processing for patients with multiple sclerosis and their acute modulation by rivastigmine. Brain 126:2750–2760CrossRefPubMedGoogle Scholar
  88. 88.
    Peterson JW, Bo L, Mork S, et al. (2001) Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50:389–400Google Scholar
  89. 89.
    Reddy H, Narayanan S, Arnoutelis R, et al. (2000) Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis. Brain 123:2314–2320CrossRefPubMedGoogle Scholar
  90. 90.
    Reddy H, Narayanan S, Matthews PM, et al. (2000) Relating axonal injury to functional recovery in MS. Neurology 54:236–239PubMedGoogle Scholar
  91. 91.
    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 125:2646–2657CrossRefPubMedGoogle Scholar
  92. 92.
    Rice GPA, for the Cladribine Clinical Study Group, Filippi M, Comi G, for the Cladribine MRI Study Group (2000) Cladribine and progressive MS. Clinical and MRI outcomes of a multicenter controlled trial. Neurology 54:1145–1155PubMedGoogle Scholar
  93. 93.
    Rocca MA, Cercignani M, Iannucci G, et al. (2000) Weekly diffusion-weighted imaging of normal-appearing white matter in MS. Neurology 55:882–884PubMedGoogle Scholar
  94. 94.
    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 51:330–339CrossRefPubMedGoogle Scholar
  95. 95.
    Rocca MA, Gallo A, Colombo B, et al. (2004) Pyramidal tract lesions and movement-associated cortical recruitment in patients with MS. NeuroImage 23:141–147CrossRefPubMedGoogle Scholar
  96. 96.
    Rocca MA, Gavazzi C, Mezzapesa DM, et al. (2003) A functional MRI study of patients with secondary progressive multiple sclerosis. NeuroImage 19:1770–1777CrossRefPubMedGoogle Scholar
  97. 97.
    Rocca MA, Matthews PM, Caputo D, et al. (2002) Evidence for widespread movement-associated functional MRI changes in patients with PPMS. Neurology 58:866–872PubMedGoogle Scholar
  98. 98.
    Rocca MA, Mezzapesa DM, Falini A, et al. (2003) Evidence for axonal pathology and adaptive cortical reorganisation in patients at presentation with clinically isolated syndromes suggestive of MS. NeuroImage 18:847–855CrossRefPubMedGoogle Scholar
  99. 99.
    Rocca MA, Mezzapesa DM, Ghezzi A, et al. (2003) Cord damage elicits brain functional reorganization after a single episode of myelitis. Neurology 61:1078–1085PubMedGoogle Scholar
  100. 100.
    Rocca MA, Mezzapesa DM, Ghezzi A, et al. (2005) A widespread pattern of cortical activations in patients at presentation with CIS is associated with evolution to definite MS. Am J Neuroradiol 26:1136–1139PubMedGoogle Scholar
  101. 101.
    Rocca MA, Pagani E, Ghezzi A, et al. (2003) Functional cortical changes in patients with multiple sclerosis and nonspecific findings on conventional magnetic resonance imaging scans of the brain. NeuroImage 19:826–836CrossRefPubMedGoogle Scholar
  102. 102.
    Rombouts SA, Lazeron RH, Scheltens P, et al. (1998) Visual activation patterns in patients with optic neuritis: an fMRI pilot study. Neurology 50:1896–1899PubMedGoogle Scholar
  103. 103.
    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 126:2323–2332CrossRefPubMedGoogle Scholar
  104. 104.
    Rovaris M, Bozzali M, Iannucci G, et al. (2002) Assessment of normal-appearing white and gray matter in patients with primary progressive multiple sclerosis. Arch Neurol 59:1406–1412CrossRefPubMedGoogle Scholar
  105. 105.
    Rovaris M, Bozzali M, Santuccio G, et al. (2001) In vivo assessment of the brain and cervical cord pathology of patients with primary progressive multiple sclerosis. Brain 124:2540–2549CrossRefPubMedGoogle Scholar
  106. 106.
    Rovaris M, Comi G, Rocca MA, et al. (2001) Short-term brain volume change in relapsing-remitting multiple sclerosis. Effect of glatiramer acetate and implications. Brain 124:1803–1812CrossRefPubMedGoogle Scholar
  107. 107.
    Rovaris M, Filippi M (1999) Magnetic resonance techniques to monitor disease evolution and treatment trial outcomes in multiple sclerosis. Curr Opin Neurol 12:337–344CrossRefPubMedGoogle Scholar
  108. 108.
    Rovaris M, Filippi M, Falautano M, et al. (1998) Relation between MR abnormalities and patterns of cognitive impairment in multiple sclerosis. Neurology 50:1601–1608PubMedGoogle Scholar
  109. 109.
    Rovaris M, Filippi M, Minicucci L, et al. (2000) Cortical/subcortical disease burden and cognitive impairment in multiple sclerosis. Am J Neuroradiol 21:402–408PubMedGoogle Scholar
  110. 110.
    Rovaris M, Gallo A, Falini A, et al. (2005) Axonal injury and overall tissue loss are not related in primary progressive multiple sclerosis. Arch Neurol 62:898–902CrossRefPubMedGoogle Scholar
  111. 111.
    Rovaris M, Gallo A, Valsasina P, et al. (2005) Short-term accrual of gray matter pathology in patients with progressive multiple sclerosis: an in vivo study using diffusion tensor MRI. NeuroImage 15:1139–1146CrossRefGoogle Scholar
  112. 112.
    Rovaris M, Iannucci G, Falautano M, et al. (2002) Cognitive dysfunction in patients with mildly disabling relapsing-remitting multiple sclerosis: an exploratory study with diffusion tensor MR imaging. J Neurol Sci 195:103–109CrossRefPubMedGoogle Scholar
  113. 113.
    Santos AC, Narayanan S, De Stefano N, et al. (2002) Magnetization transfer can predict clinical evolution in patients with multiple sclerosis. J Neurol 249:662–668CrossRefPubMedGoogle Scholar
  114. 114.
    Sarchielli P, Presciutti O, Pelliccioli GP, et al. (1999) Absolute quantification of brain metabolites by proton magnetic resonance spectroscopy in normal-appearing white matter of multiple sclerosis patients. Brain 122:513–521CrossRefPubMedGoogle Scholar
  115. 115.
    Sarchielli P, Presciutti O, Tarducci R, et al. (2002) Localized [1] H magnetic resonance spectroscopy in mainly cortical gray matter of patients with multiple sclerosis. J Neurol 249:902–910CrossRefPubMedGoogle Scholar
  116. 116.
    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 10:182–187CrossRefPubMedGoogle Scholar
  117. 117.
    Sharma R, Narayana PA, Wolinsky JS (2001) Gray matter abnormalities in multiple sclerosis: proton magnetic resonance spectroscopic imaging. Mult Scler 7:221–226CrossRefPubMedGoogle Scholar
  118. 118.
    Staffen W, Mair A, Zauner H, et al. (2002) Cognitive function and fMRI in patients with multiple sclerosis: evidence for compensatory cortical activation during an attention task. Brain 156:1275–1282CrossRefGoogle Scholar
  119. 119.
    Suhy J, Rooney WD, Goodkin DE, et al. (2000) 1H-MRSI comparison of white matter and lesions in primary progressive and relapsing-remitting MS. Mult Scler 6:148–155CrossRefPubMedGoogle Scholar
  120. 120.
    Tartaglia MC, Narayanan S, Francis SJ, et al. (2004) The relationship between diffuse axonal damage and fatigue in multiple sclerosis. Arch Neurol 61:201–207CrossRefPubMedGoogle Scholar
  121. 121.
    Tortorella C, Viti B, Bozzali M, et al. (2000) A magnetization transfer histogram study of normal-appearing brain tissue in MS. Neurology 54:186–193CrossRefPubMedGoogle Scholar
  122. 122.
    Traboulsee A, Dehmeshki J, Brex PA, et al. (2002) Normal-appearing brain tissue MTR histograms in clinically isolated syndromes suggestive of MS. Neurology 59:126–128PubMedGoogle Scholar
  123. 123.
    Traboulsee A, Dehmeshki J, Peters KR, et al. (2003) Disability in multiple sclerosis is related to normal appearing brain tissue MTR histogram abnormalities. Mult Scler 9:566–573CrossRefPubMedGoogle Scholar
  124. 124.
    Trapp BD, Peterson J, Ransohoff RM, et al. (1998) Axonal transaction in the lesions of multiple sclerosis. N Engl J Med 338:278–285CrossRefPubMedGoogle Scholar
  125. 125.
    Valsasina P, Rocca MA, Agosta F, et al. (2005) Mean diffusivity and fractional anisotropy histogram analysis of the cervical cord in MS patients. NeuroImage 26:822–828CrossRefPubMedGoogle Scholar
  126. 126.
    van Buchem MA, Grossman RI, Armstrong C et al. (1998) Correlation of volumetric magnetization transfer imaging with clinical data in MS. Neurology 50:1609–1617PubMedGoogle Scholar
  127. 127.
    Werring DJ, Brassat D, Droogan AG, et al. (2000) The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosis. A serial diffusion MRI study. Brain 123:1667–1676CrossRefPubMedGoogle Scholar
  128. 128.
    Werring DJ, Bullmore ET, Toosy AT, et al. (2000) Recovery from optic neuritis is associated with a change in the distribution of cerebral response to visual stimulation: a functional magnetic resonance imaging study. J Neurol Neurosurg Psychiatry 68:441–449CrossRefPubMedGoogle Scholar
  129. 129.
    Werring DJ, Clark CA, Barker GJ, et al. (1999) Diffusion tensor imaging of lesions and normal-appearing white matter in multiple sclerosis. Neurology 52:1626–1632PubMedGoogle Scholar
  130. 130.
    Wilson M, Tench CR, Morgan PS, et al. (2003) Pyramidal tract mapping by diffusion tensor magnetic resonance imaging in multiple sclerosis: improving correlations with disability. J Neurol Neurosurg Psychiatry 74:203–207CrossRefPubMedGoogle Scholar
  131. 131.
    Wylezinska M, Cifelli A, Jezzard P, et al. (2003) Thalamic neurodegeneration in relapsing-remitting multiple sclerosis. Neurology 60:1949–1954PubMedGoogle Scholar

Copyright information

© Steinkopff-Verlag 2005

Authors and Affiliations

  1. 1.Neuroimaging Research Unit, Dept. of Neurology Scientific Institute and University Ospedale San RaffaeleMilanItaly

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