Global Brain Proton MR Spectroscopy in MS

  • O. Gonen
  • R. I. Grossman
Part of the Topics in Neuroscience book series (TOPNEURO)


Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, affecting nearly 350 000 Americans, 100 000 Britons, and over 2 million people worldwide. It is the leading cause of nontraumatic neurological disability in young and middle-aged adults [1]. Roughly 85% of MS patients, two-thirds of whom are women, experience acute symptoms over short (weeks) periods, followed by variable, unpredictable lengths (months to years) of partial or complete remission, entering the relapsing-remitting (RR) stage. These cycles continue, leading to accumulating clinical disability from incomplete remissions. After 10 years, 50% will enter the secondary progressive phase of the disease [2]. This progression entails chronic clinical deterioration, increasing motor, sensory, and cognitive deficits, but not a significant reduction of life expectancy [2].


Multiple Sclerosis Expand Disability Status Scale Axonal Loss Expand Disability Status Scale Score Multiple Scle 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hauser SL (1994) Multiple sclerosis and other demyelinating diseases. In: Isselbacher KJ, Wilson JD, Martin JB, Fauci AS, Kasper DL (eds) Harrison’s principles of internal medicine. McGraw-Hill, New York, pp 2287–2295Google Scholar
  2. 2.
    Weinshenker BG (1994) Natural history of multiple sclerosis. Ann Neurol 36: S6 - S11PubMedCrossRefGoogle Scholar
  3. 3.
    McFarland HF, Barkhof F, Antel J, Miller DH (2002) The role of MRI as a surrogate outcome measure in multiple sclerosis. Mult Scler 8: 40–51PubMedGoogle Scholar
  4. 4.
    Filippi M (2001) Linking structural, metabolic and functional changes in multiple sclerosis. Eur J Neurol 8: 291–297PubMedCrossRefGoogle Scholar
  5. 5.
    Miki Y, Grossman RI, Udupa JK et al (1999) Differences between relapsing-remitting and chronic progressive multiple sclerosis as determined with quantitative MR imaging. Radiology 210: 769–774PubMedGoogle Scholar
  6. 6.
    Allen IV, McKeown SR (1979) A histological, histochemical and biochemical study of the macroscopically normal white matter in multiple sclerosis. J Neurol Sci 41: 81–91PubMedCrossRefGoogle Scholar
  7. 7.
    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
  8. 8.
    Arnold DL, De Stefano N, Narayanan S, Matthews PM (2001) Axonal injury and disability in multiple sclerosis: magnetic resonance spectroscopy as a measure of dynamic pathological change in white matter. In: Filippi M, Arnold D, Comi G (eds) Magnetic resonance spectroscopy in multiple sclerosis. Springer, Milan, pp 61–67Google Scholar
  9. 9.
    Miller DH, Grossman RI, Reingold SC, McFarland HF (1998) The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain 121: 3–24.PubMedCrossRefGoogle Scholar
  10. 10.
    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
  11. 11.
    Narayana PA, Doyle TJ, Lai D, Wolinsky JS (1998) Serial proton magnetic resonance spectroscopic imaging, contrast-enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis. Ann Neurol 43: 56–71PubMedCrossRefGoogle Scholar
  12. 12.
    Filippi M, Rocca MA, Martino G et al (1998) Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis. Ann Neurol 43: 809–814PubMedCrossRefGoogle Scholar
  13. 13.
    Rocca MA, Cercignani M, lannucci G et al (2000) Weekly diffusion-weighted imaging of normal-appearing white matter in MS. Neurology 55: 882–884PubMedGoogle Scholar
  14. 14.
    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 magnetization-transfer measurements. Radiology 196: 511–515PubMedGoogle Scholar
  15. 15.
    Davie CA, Barker GJ, Thompson AJ et al (1997) H-1 magnetic resonance spectroscopy of chronic cerebral white matter lesions and normal appearing white matter in multiple sclerosis. J Neurol Neurosurg Psychiatry 63: 736–742PubMedCrossRefGoogle Scholar
  16. 16.
    Fu L, Matthews PM, De Stefano N et al (1998) Imaging axonal damage of normal-appearing white matter in multiple sclerosis. Brain 121: 103–113PubMedCrossRefGoogle Scholar
  17. 17.
    Tortorella C, Viti B, Bozzali M et al (2000) A magnetization transfer histogram study of normal-appearing brain tissue in MS. Neurology 54: 186–193PubMedGoogle Scholar
  18. 18.
    De Stefano N, Matthews PM, Fu LQ 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: 1469–1477PubMedCrossRefGoogle Scholar
  19. 19.
    Nusbaum AO, Lu D, Tang CY, Atlas SW (2000) Quantitative diffusion measurements in focal multiple sclerosis lesions: correlations with appearance on TI-weighted MR images. AJR Am J Roentgenol 175: 821–825PubMedGoogle Scholar
  20. 20.
    Rovaris M, Filippi M, Minicucci L et al (2000) Cortical/sub cortical disease burden and cognitive impairment in patients with multiple sclerosis. AJNR Am J Neuroradiol 21: 402–408PubMedGoogle Scholar
  21. 21.
    Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120: 393–399PubMedCrossRefGoogle Scholar
  22. 22.
    Lexa FJ, Grossman RI, Rosenquist AC (1994) MR of wallerian degeneration in the feline visual system: characterization by magnetization transfer rate with histopathologic correlation. AJNR Am J Neuroradiol 15: 201–212PubMedGoogle Scholar
  23. 23.
    Narayanan S, Fu L, Pioro E et al (1997) Imaging of axonal damage in multiple sclerosis: Spatial distribution of magnetic resonance imaging lesions. Ann Neurol 41: 385–391PubMedCrossRefGoogle Scholar
  24. 24.
    De Stefano N, Narayanan S, Matthews PM et al (1999) In vivo evidence for axonal dysfunction remote from focal cerebral demyelination of the type seen in multiple sclerosis. Brain 122: 1933–1939PubMedCrossRefGoogle Scholar
  25. 25.
    Moffett JR, Namboodiri MA, Cangro CB, Neale JH (1991) Immunohistochemical localization of N-acetylaspartate in rat brain. Neuroreport 2: 131–134PubMedCrossRefGoogle Scholar
  26. 26.
    Simmons ML, Frondoza CG, Coyle JT (1991) Immunocytochemical localization of Nacetyl-aspartate with monoclonal antibodies. Neuroscience 45: 37–45PubMedCrossRefGoogle Scholar
  27. 27.
    Clark JB (1998) N-acetylaspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev Neurosci 20: 271–276PubMedCrossRefGoogle Scholar
  28. 28.
    Davie CA, Hawkins CP, Barker GJ et al (1994) Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions. Brain 117: 49–58PubMedCrossRefGoogle Scholar
  29. 29.
    De Stefano N, Narayanan S, Mortilla M et al (2000) Imaging axonal damage in multiple sclerosis by means of MR spectroscopy. Neurol Sci 21: S883–887PubMedCrossRefGoogle Scholar
  30. 30.
    Trapp BD, Peterson J, Ransohoff RM et al (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338: 278–285PubMedCrossRefGoogle Scholar
  31. 31.
    Bjartmar C, Kidd G, Mork S et al (2000) Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol 48: 893–901PubMedCrossRefGoogle Scholar
  32. 32.
    Matthews PM, Arnold DL (2001) Magnetic resonance imaging of multiple sclerosis: new insights linking pathology to clinical evolution. Curr Opin Neurol 14: 279–287PubMedCrossRefGoogle Scholar
  33. 33.
    Gonen O, Grossman RI (2001) New magnetic resonance spectroscopy strategies. In: Filippi M, Arnold D, Comi G (eds) Magnetic resonance spectroscopy in multiple sclerosis. Springer, Milan, pp 97–112Google Scholar
  34. 34.
    Gonen 0, 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: 684–689PubMedCrossRefGoogle Scholar
  35. 35.
    Sadovnick AD (2001) To treat or not to treat the person with clinical multiple sclerosis–a dilemma. Neurol Sci 22: 205–207PubMedCrossRefGoogle Scholar
  36. 36.
    Schwid SR, Bever CT (2001) The cost of delaying treatment in multiple sclerosis. What is lost is not regained. Neurology 56: 1620PubMedGoogle Scholar
  37. 37.
    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: 1576–1582PubMedCrossRefGoogle Scholar
  38. 38.
    Goodkin DE (2000) Interferon beta-lb in secondary progressive MS: clinical and MRI results of a 3-year randomized controlled trial. Neurology 54: 6Google Scholar
  39. 39.
    Jacobs LD, Cookfair DL, Rudick RA et al (1996) Intramuscular interferon beta-1 alpha for disease progression in relapsing multiple sclerosis. Ann Neurol 39: 285–294PubMedCrossRefGoogle Scholar
  40. 40.
    Johnson KP, Brooks BR, Cohen JA et al (1995) Copolymer-1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis–results of a phase-III multicenter, double-blind, placebo-controlled trial. Neurology 45: 1268–1276PubMedGoogle Scholar
  41. 41.
    Compston A (1999) Interferon beta in multiple sclerosis–Reply. Lancet 354: 512–513CrossRefGoogle Scholar
  42. 42.
    NIH (1993) Multiple sclerosis. National Institutes of Health, Bethesda, Md, pp 8–11. (NIH Guide)Google Scholar
  43. 43.
    Hartung HP (2000) NICE and drugs for multiple sclerosis. Lancet 356: 1114–1114PubMedCrossRefGoogle Scholar
  44. 44.
    Willoughby E, Paty D (1998) Scales for rating impariment in multiple sclerosis: a critique. Neurology 38: 1793–1798Google Scholar
  45. 45.
    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
  46. 46.
    Krupp LB, Elkins LE (2000) Fatigue and declines in cognitive functioning in multiple sclerosis. Neurology 55: 934–939PubMedGoogle Scholar
  47. 47.
    Tas MW, Barkhol F, van Walderveen MAA, Polman CH et al (1995) The effect of gadolinium on the sensitivity and specificity of MR in the initial diagnosis of multiple sclerosis. AJNR Am J Neuroradiol 16: 259–264PubMedGoogle Scholar
  48. 48.
    Jacobs LD, Kaba SE, Miller CM et al (1997) Correlation of clinical, magnetic resonance imaging, and cerebrospinal fluid findings in optic neuritis. Ann Neurol 41: 392–398PubMedCrossRefGoogle Scholar
  49. 49.
    Fazekas F, Barkhof F, Filippi M et al (1999) The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis. Neurology 53: 448–456PubMedGoogle Scholar
  50. 50.
    Filippi M, Horsfield MA, Toffs PS et al (1995) Quantitative assessment of MRI lesion load in monitoring the evolution of multiple sclerosis. Brain 118: 1601–1612PubMedCrossRefGoogle Scholar
  51. 51.
    Udupa JK, Samarasekera S (1996) Fuzzy connectedness and object definition: theory, algorithms, and applications in image segmentation. Graph Models Image Process 58: 246–261CrossRefGoogle Scholar
  52. 52.
    Ge Y, Grossman RI, Udupa JK et al (1999) Longitudinal quantitative analysis of brain atrophy in relapsing-remitting and secondary-progressive multiple sclerosis. Radiology 214: 665–670Google Scholar
  53. 53.
    De Stefano N, Matthews PM, Antel JP et al (1995) Chemical pathology of acute demyelinating lesions and its correlation with disability. Ann Neurology 38: 901–909CrossRefGoogle Scholar
  54. 54.
    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: 6570Google Scholar
  55. 55.
    Arnold DL, Riess GT, Matthews PM et al (1994) Use of proton magnetic resonance spectroscopy for monitoring disease progression in multiple sclerosis. Ann Neurol 36: 76–82PubMedCrossRefGoogle Scholar
  56. 56.
    Taylor DL, Davis SE, Obrenovitch TP et al (1995) Investigation into the role of N-acetylaspartate in cerebral osmoregulation. J Neurochem 65: 275–281PubMedCrossRefGoogle Scholar
  57. 57.
    Ebers GC, Yee IM, Sadovnick AD, Duquette P (2000) Conjugal multiple sclerosis: population-based prevalence and recurrence risks in offspring. Canadian Collaborative Study Group. Ann Neurol 48: 927–931PubMedCrossRefGoogle Scholar
  58. 58.
    Sadovnick AD, Yee IM, Ebers GC (2000) Factors influencing sib risks for multiple sclerosis. Clin Genet 58: 431–435PubMedCrossRefGoogle Scholar
  59. 59.
    Dyment DA, Willer CJ, Scott B et al (2001) Genetic susceptibility to MS: a second stage analysis in Canadian MS families. Neurogenetics 3: 145–151PubMedCrossRefGoogle Scholar
  60. 60.
    Dyment DA, Cader MZ, Willer CJ et al (2002) A multigenerational family with multiple sclerosis. Brain 125: 1474–1482PubMedCrossRefGoogle Scholar
  61. 61.
    Fox NC, Miller DH, Thompson AJ (2000) Progressive cerebral atrophy in MS: a serial study using registered, volumetric MRI–reply. Neurology 55: 1243–1243Google Scholar
  62. 62.
    Rudick RA, Fisher E, Lee JC et al (1999) Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Neurology 53: 1698–1704PubMedGoogle Scholar
  63. 63.
    Scott TF, Schramke CJ, Novero J, Chieffe C (2000) Short-term prognosis in early relapsing-remitting multiple sclerosis. Neurology 55: 689–693PubMedGoogle Scholar
  64. 64.
    Rogatko A, Litwin S (1996) Phase II studies: which is worse, false positive or false negative? J Natl Cancer Inst 88: 462PubMedGoogle Scholar
  65. 65.
    Sormani MP, Miller DH, Comi G et al (2001) Clinical trials of multiple sclerosis monitored with enhanced MRI: new sample size calculations based on large data sets. J Neurol Neurosurg Psychiatry 70: 494–499PubMedCrossRefGoogle Scholar
  66. 66.
    Duquette P, Despault L, Knobler RL et al (1995) Interferon beta-lb in the treatment of multiple sclerosis–final outcome of the randomized controlled trial. Neurology 45: 1277–1285Google Scholar
  67. 67.
    Forbes RB, Lees A, Waugh N, Swingler RJ (1999) Population based cost utility study of interferon beta-lb in secondary progressive multiple sclerosis. Br Med J 319: 1529–1533CrossRefGoogle Scholar
  68. 68.
    Bitsch A, Bruhn H, Vougioukas V et al (1999) Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy. AJNR Am J Neuroradiol 20: 1619–1627PubMedGoogle Scholar
  69. 69.
    Arnold DL, Matthews PM, Francis G, Antel J (1990) Proton magnetic resonance spectroscopy of human brain in vivo in the evaluations of multiple sclerosis: assessment of the load of disease. Magn Reson Med 14: 154–159PubMedCrossRefGoogle Scholar
  70. 70.
    Arnold DL, De Stefano N, Matthews PM, Trapp BD (2001) N-acetylaspartate: usefulness as an indicator of viable neuronal tissue. Ann Neurol 50:823; discussion 824–825Google Scholar
  71. 71.
    Husted CA, Goodin DS, Hugg JW et al (1994) Biochemical alterations in multiple sclerosis lesions and normal-appearing white matter detected by in vivo 31P and 1H spectroscopic imaging. Ann Neurol 36: 157–165PubMedCrossRefGoogle Scholar
  72. 72.
    Tourbah A, Stievenart JL, Iba-Zizen MT et al (1996) In vivo localized proton NMR spectroscopy of normal appearing white matter in patients with multiple sclerosis. J Neuroradiol 23: 49–55PubMedGoogle Scholar
  73. 73.
    Rooney WD, Goodkin DE, Schuff N et al (1997) 1H MRSI of normal appearing white matter in multiple sclerosis. Mult Scler 3:231–237Google Scholar
  74. 74.
    Sarchielli P, Presciutti 0, 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: 513–521PubMedCrossRefGoogle Scholar
  75. 75.
    Suhy J, Rooney WD, Goodkin DE et al (2000) H-1 MRSI comparison of white matter and lesions in primary progressive and relapsing-remitting MS. Mult Scler 6: 148–155PubMedGoogle Scholar
  76. 76.
    Urenjak J, Williams SR, Gadian DG, Noble M (1993) Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 13: 981–989PubMedGoogle Scholar
  77. 77.
    Gonen O, Murdoch JB, Stoyanova R, Goelman G (1998) 3D multivoxel proton spectroscopy of human brain using a hybrid of 8th-order Hadamard encoding with 2D-chemical shift imaging. Magn Reson Med 39:34–40Google Scholar
  78. 78.
    Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46: 907–911PubMedGoogle Scholar
  79. 79.
    Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33: 1444–1452PubMedGoogle Scholar
  80. 80.
    Hu J, Javaid T, Arias-Mendoza F et al (1995) A fast, reliable, automatic shimming procedure using 1H chemical-shift-imaging spectroscopy. J Magn Reson B 108: 213–219PubMedCrossRefGoogle Scholar
  81. 81.
    Soher BJ, Young K, Govindaraju V, Maudsley AA (1998) Automated spectral analysis III: application to in vivo proton MR spectroscopy and spectroscopic imaging. Magn Reson Med 40: 822–831PubMedCrossRefGoogle Scholar
  82. 82.
    Soher BJ, van Zijl PCM, Duyn JH, Barker PB (1996) Quantitative proton MR spectroscopic imaging of the human brain. Magn Reson Med 35: 356–363PubMedCrossRefGoogle Scholar
  83. 83.
    Christiansen P, Tofts P, Larsson HB et al (1993) The concentration of N-acetyl aspartate, creatine + phosphocreatine, and choline in different parts of the brain in adulthood and senium. Magn Reson Imaging 11: 799–806PubMedCrossRefGoogle Scholar
  84. 84.
    Duyn JH, Gillen J, Sobering G et al (1993) Multisection proton MR spectroscopic imaging of the brain. Radiology 188: 277–282PubMedGoogle Scholar
  85. 85.
    Ge Y, Grossman RI, Udupa JK et al (2001) Brain atrophy in relapsing-remitting multiple sclerosis: fractional volumetric analysis of gray matter and white matter. Radiology 220: 606–610PubMedCrossRefGoogle Scholar
  86. 86.
    Hutchinson M, Rusinek H, Nenov VI et al (1997) Segmentation analysis in functional MRI: activation sensitivity and gray-matter specificity of RARE and FLASH. J Magn Reson Imaging 7: 361–364PubMedCrossRefGoogle Scholar
  87. 87.
    Fox NC, Jenkins R, Leary SM et al (2000) Progressive cerebral atrophy in MS–a serial study using registered, volumetric MRI. Neurology 54: 807–812PubMedGoogle Scholar
  88. 88.
    Mcllwain H, Bachelard H (1985) Biochemistry and central nervous system. Churchill Livingstone, Edinburgh, pp 282–335Google Scholar
  89. 89.
    Arnold DL, Matthews PM, Francis GS et al (1992) Proton magnetic resonance spectroscopic imaging for metabolic characterization of demyelinating plaques. Ann Neurol 31: 235–241PubMedCrossRefGoogle Scholar
  90. 90.
    Brenner RE, Munro PMG, Williams SCR et al (1993) The proton NMR spectrum in acute EAE: the significance of the change in the Cho:Cr ratio. Magn Reson Med 29: 737–745PubMedCrossRefGoogle Scholar
  91. 91.
    Miller BL (1991) A review of chemical issues in 1H NMR spectroscopy: N-acetyl-Laspartate, creatine and choline. NMR Biomed 4: 47–52PubMedCrossRefGoogle Scholar
  92. 92.
    Mader I, Roser W, Kappos L et al (2000) Serial proton MR spectroscopy of contrast-enhancing multiple sclerosis plaques: absolute metabolic values over 2 years during a clinical pharmacological study. AJNR Am J Neuroradiol 21: 1220–1227PubMedGoogle Scholar
  93. 93.
    Pan JW, Hetherington HP, Vaughan JT et al (1996) Evaluation of multiple sclerosis by ‘H spectroscopy imaging at 4.1 T. Magn Reson Med 36: 72–77PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia, Milano 2003

Authors and Affiliations

  • O. Gonen
  • R. I. Grossman

There are no affiliations available

Personalised recommendations