N-Acetyl-L-Aspartate in Multiple Sclerosis

  • Gerson A. Criste
  • Bruce D. Trapp
Part of the Advances in Experimental Medicine and Biology book series (volume 576)

4. Conclusion

It is well established that axonal pathology is the basis of permanent disability in MS from its earliest stage. The promise of NAA measurement is that, it provides a specific and readily quantifiable index of neuronal and axonal dysfunction or loss. Therefore, monitoring NAA dynamics provides an index of change associated with irreversible stages in the evolution of diffuse MS lesions central to determining disability. Use in the proper context and together with other modern MR techniques, understanding NAA concentration dynamics may enable early forecast of disease course, reflect disease load and so influence treatment decision; improve clinical trial efficiency, and enhance further understanding of this complex disease.


Multiple Sclerosis Expanded Disability Status Scale Axonal Injury Multiple Sclerosis Lesion Axonal Loss 
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.

7. References

  1. 1.
    R. B. Johnston, Multiple Sclerosis: Current Status and Strategies for the Future, (National Academy Press, Washington, D.C., 2001).Google Scholar
  2. 2.
    A. D. Sadovnick, G. C. Ebers, R. W. Wilson, and D. W. Paty, Life expectancy in patients attending multiple sclerosis clinics. Neurology 42, 991–994 (1992).PubMedGoogle Scholar
  3. 3.
    N. Koch-Henriksen, H. Bronnum-Hansen, and E. Stenager, Underlying cause of death in Danish patients with multiple sclerosis: results from the Danish Multiple Sclerosis Registry. J. Neurol. Neurosurg. Psychiatry 65, 56–59 (1998).PubMedGoogle Scholar
  4. 4.
    B. D. Trapp, J. Peterson, R. M. Ransohoff, R. Rudick, S. Mork, and L. Bo, Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338, 278–285 (1998).PubMedCrossRefGoogle Scholar
  5. 5.
    N. De Stefano, P. M. Matthews, L. Fu, S. Narayanan, J. Stanley, G. S. Francis, J. P. Antel, and D. L. Arnold, Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain 121, 1469–1477 (1998).PubMedCrossRefGoogle Scholar
  6. 6.
    C. Bjartmar, X. Yin, and B. D. Trapp, Axonal pathology in myelin disorders. J Neurocytol. 28, 383–395 (1999).PubMedCrossRefGoogle Scholar
  7. 7.
    B. D. Trapp, R. M. Ransohoff, E. Fisher, and R. A. Rudick, Neurodegeneration in multiple sclerosis: Relationship to neurological disability. The Neuroscientist 5, 48–57 (1999).Google Scholar
  8. 8.
    D. L. Arnold, Magnetic resonance spectroscopy: imaging axonal damage in MS. J Neuroimmunol 98[1], 2–6. 1999.CrossRefGoogle Scholar
  9. 9.
    C. Bjartmar and B. D. Trapp, Axonal degeneration and progressive neurologic disability in multiple sclerosis. Neurotox. Res. 5, 157–164 (2003).PubMedCrossRefGoogle Scholar
  10. 10.
    P. M. Matthews, N. De Stefano, S. Narayanan, G. S. Francis, J. S. Wolinsky, J. P. Antel, and D. L. Arnold, Putting magnetic resonance spectroscopy studies in context: axonal damage and disability in multiple sclerosis. Semin. Neurol. 18, 327–336 (1998).PubMedCrossRefGoogle Scholar
  11. 11.
    W. Bruck, A. Bitsch, H. Kolenda, Y. Bruck, M. Stiefel, and H. Lassmann, Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann. Neurol. 42, 783–793 (1997).PubMedCrossRefGoogle Scholar
  12. 12.
    J. W. Peterson, L. Bo, S. Mork, A. Chang, and B. D. Trapp, Transected neurites, apoptotic neurons and reduced inflammation in cortical MS lesions. Ann. Neurol. 50, 389–400 (2001).PubMedCrossRefGoogle Scholar
  13. 13.
    B. Ferguson, M. K. Matyszak, M. M. Esiri, and V. H. Perry, Axonal damage in acute multiple sclerosis lesions. Brain 120, 393–399 (1997).PubMedCrossRefGoogle Scholar
  14. 14.
    E. H. Koo, S. S. Sisodia, D. R. Archer, L. J. Martin, A. Weidemann, K. Beyreuther, P. Fischer, C. L. Masters, and D. L. Price, Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc. Natl. Acad. Sci. USA 87, 1561–1565 (1990).PubMedCrossRefGoogle Scholar
  15. 15.
    B. Kornek, M. K. Storch, R. Weissert, E. Wallstroem, A. Stefferl, T. Olsson, C. Linington, M. Schmidbauer, and H. Lassmann, 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 (2000).PubMedGoogle Scholar
  16. 16.
    R. Hohlfeld, Biotechnological agents for the immunotherapy of multiple sclerosis. Principles, problems and perspectives. Brain 120, 865–916 (1997).PubMedCrossRefGoogle Scholar
  17. 17.
    K. Strigard, P. Larsson, R. Holmdahl, L. Klareskog, and T. Olsson, In vivo monoclonal antibody treatment with Ox19 (anti-rat CD5) causes disease relapse and terminates P2-induced immunospecific tolerance in experimental allergic neuritis. J. Neuroimmunol. 23, 11–18 (1989).PubMedCrossRefGoogle Scholar
  18. 18.
    H. Babbe, A. Roers, A. Waisman, H. Lassmann, N. Goebels, R. Hohlfeld, M. Friese, R. Schroder, M. Deckert, S. Schmidt, R. Ravid, and K. Rajewsky, 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 (2000).PubMedCrossRefGoogle Scholar
  19. 19.
    E. S. Huseby, D. Liggitt, T. Brabb, B. Schnabel, C. Ohlen, and J. Goverman, A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis. J. Exp. Med. 194, 669–676 (2001).PubMedCrossRefGoogle Scholar
  20. 20.
    I. Medana, M. A. Martinic, H. Wekerle, and H. Neumann, Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am. J. Pathol. 159, 809–815 (2001).PubMedGoogle Scholar
  21. 21.
    D. Pitt, P. Werner, and C. S. Raine, Glutamate excitotoxicity in a model of multiple sclerosis. Nat. Med. 6, 67–70 (2000).PubMedCrossRefGoogle Scholar
  22. 22.
    R. Shi and A. R. Blight, Compression injury of mammalian spinal cord in vitro and the dynamics of action potential conduction failure. J Neurophysiol. 76, 1572–1580 (1996).PubMedGoogle Scholar
  23. 23.
    J. R. Wujek, C. Bjartmar, E. Richer, R. M. Ransohoff, M. Yu, V. K. Tuohy, and B. D. Trapp, Axon loss in the spinal cord determines permanent neurological disability in an animal model of multiple sclerosis. J. Neuropathol. Exp. Neurol. 61, 23–32 (2002).PubMedGoogle Scholar
  24. 24.
    C. Bjartmar, G. Kidd, S. Mork, R. Rudick, and B. D. Trapp, Neurological disability correlates with spinal cord axonal loss and reduce N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol 48, 893–901 (2000).PubMedCrossRefGoogle Scholar
  25. 25.
    G. Lovas, N. Szilagyi, K. Majtenyi, M. Palkovits, and S. Komoly, Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain 123, 308–317 (2000).PubMedCrossRefGoogle Scholar
  26. 26.
    S. G. Waxman, Acquired channelopathies in nerve injury and MS. Neurology 56, 1621–1627 (2001).PubMedGoogle Scholar
  27. 27.
    X. Yin, T. O. Crawford, J. W. Griffin, P.-H. Tu, V. M. Y. Lee, C. Li, J. Roder, and B. D. Trapp, Myelinassociated glycoprotein is a myelin signal that modulates the caliber of myelinated axons. J. Neurosci. 18, 1953–1962 (1998).PubMedGoogle Scholar
  28. 28.
    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, Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280, 1610–1613 (1998).PubMedCrossRefGoogle Scholar
  29. 29.
    S. Scherer, Axonal pathology in demyelinating diseases. Ann. Neurol. 45, 6–7 (1999).PubMedCrossRefGoogle Scholar
  30. 30.
    P. Ganter, C. Prince, and M. M. Esiri, Spinal cord axonal loss in multiple sclerosis: a post-mortem study. Neuropathol. Appl. Neurobiol. 25, 459–467 (1999).PubMedCrossRefGoogle Scholar
  31. 31.
    N. Evangelou, M. M. Esiri, S. Smith, J. Palace, and P. M. Matthews, Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann. Neurol. 47, 391–395 (2000).PubMedCrossRefGoogle Scholar
  32. 32.
    C. Bjartmar, R. P. Kinkel, G. Kidd, R. A. Rudick, and B. D. Trapp, Axonal loss in normal-appearing white matter in a patient with acute MS. Neurology 57, 1248–1252 (2001).PubMedGoogle Scholar
  33. 33.
    M. L. Simmons, C. G. Frondoza, and J. T. Coyle, Immunocytochemical localization of N-acetylaspartate with monoclonal antibodies. Neuroscience 45, 37–45 (1991).PubMedCrossRefGoogle Scholar
  34. 34.
    J. Urenjak, S. R. Williams, D. G. Gadian, and M. Noble, Specific expression of N-acetylaspartate in neurons, oligodendrocyte-type-2 astrocyte progenitors, and immature oligodendrocytes in vitro. J. Neurochem. 59, 55–61 (1992).PubMedCrossRefGoogle Scholar
  35. 35.
    J. Urenjak, S. R. Williams, D. G. Gadian, and M. Noble, Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J. Neurosci. 13, 981–989 (1993).PubMedGoogle Scholar
  36. 36.
    K. K. Bhakoo and D. Pearce, In vitro expression of N-acetylaspartate by oligodendrocytes: implications for proton magnetic resonance spectroscopy signal in vivo. J Neurochem 74, 254–262 (2000).PubMedCrossRefGoogle Scholar
  37. 37.
    C. Bjartmar, J. Battistuta, N. Terada, E. Dupree, and B. D. Trapp, 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. 51, 51–58 (2002).PubMedCrossRefGoogle Scholar
  38. 38.
    H. Ueda, J. M. Levine, R. H. Miller, and B. D. Trapp, Rat optic nerve oligodendrocytes develop in the absence of viable retinal ganglion cell axons. J. Cell Biol. 146, 1365–1374 (1999).PubMedCrossRefGoogle Scholar
  39. 39.
    G. Wolswijk, Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J. Neurosci. 18, 601–609 (1998).PubMedGoogle Scholar
  40. 40.
    N. Scolding, R. Franklin, S. Stevens, C.-H. Heldin, A. Compston, and J. Newcombe, Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis. Brain 121, 2221–2228 (1998).PubMedCrossRefGoogle Scholar
  41. 41.
    A. Chang, A. Nishiyama, J. Peterson, J. Prineas, and B. D. Trapp, NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J. Neurosci. 20, 6404–6412 (2000).PubMedGoogle Scholar
  42. 42.
    M. A. van Walderveen, W. Kamphorst, P. Scheltens, J. H. van Waesberghe, R. Ravid, J. Valk, C. H. Polman, and F. Barkhof, Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. Neurology 50, 1282–1288 (1998).PubMedGoogle Scholar
  43. 43.
    J. H. van Waesberghe, W. Kamphorst, C. J. De Groot, M. A. van Walderveen, J. A. Castelijns, R. Ravid, G. J. Nijeholt, d. van, V, C. H. Polman, A. J. Thompson, and F. Barkhof, Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability. Ann. Neurol. 46, 747–754 (1999).PubMedCrossRefGoogle Scholar
  44. 44.
    D. L. Arnold, P. M. Matthews, G. Francis, and J. Antel, Proton magnetic resonance spectroscopy of human brain in vivo in the evaluation of multiple sclerosis: assessment of the load of disease. Magn Reson. Med 14, 154–159 (1990).PubMedGoogle Scholar
  45. 45.
    M. Filippi, C. Tortorella, and M. Rovaris, Magnetic resonance imaging of multiple sclerosis. J Neuroimaging 12, 289–301 (2002).PubMedCrossRefGoogle Scholar
  46. 46.
    A. Bitsch, H. Bruhn, V. Vougioukas, A. Stringaris, H. Lassmann, J. Frahm, and W. Bruck, Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy. AJNR Am. J Neuroradiol. 20, 1619–1627 (1999).PubMedGoogle Scholar
  47. 47.
    A. Falini, G. Calabrese, M. Filippi, D. Origgi, S. Lipari, B. Colombo, G. Comi, and G. Scotti, Benign versus secondary-progressive multiple sclerosis: the potential role of proton MR spectroscopy in defining the nature of disability. AJNR Am. J Neuroradiol. 19, 223–229 (1998).PubMedGoogle Scholar
  48. 48.
    M. Filippi, G. Iannucci, C. Tortorella, L. Minicucci, M. A. Horsfield, B. Colombo, M. P. Sormani, and G. Comi, Comparison of MS clinical phenotypes using conventional and magnetization transfer MRI. neurology 52, 588–594 (1999).PubMedGoogle Scholar
  49. 49.
    D. J. Werring, C. A. Clark, G. J. Barker, A. J. Thompson, and D. H. Miller, Diffusion tensor imaging of lesions and normal-appearing white matter in multiple sclerosis. neurology 52, 1626–1632 (1999).PubMedGoogle Scholar
  50. 50.
    M. Filippi, C. Tortorella, M. Rovaris, M. Bozzali, F. Possa, M. P. Sormani, G. Iannucci, and G. Comi, Changes in the normal appearing brain tissue and cognitive impairment in multiple sclerosis. j neurol neurosurg psychiatry 68, 157–161 (2000).PubMedCrossRefGoogle Scholar
  51. 51.
    A. Cifelli, M. Arridge, P. Jezzard, M. M. Esiri, J. Palace, and P. M. Matthews, Thalamic neurodegeneration in multiple sclerosis. Ann. Neurol. 52, 650–653 (2002).PubMedCrossRefGoogle Scholar
  52. 52.
    P. Kapeller, M. A. McLean, C. M. Griffin, D. Chard, G. J. Parker, G. J. Barker, A. J. Thompson, and D. H. Miller, 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, 131–138 (2001).PubMedCrossRefGoogle Scholar
  53. 53.
    D. T. Chard, C. M. Griffin, M. A. McLean, P. Kapeller, R. Kapoor, A. J. Thompson, and D. H. Miller, Brain metabolite changes in cortical grey and normal-appearing white matter in clinically early relapsing-remitting multiple sclerosis. Brain 125, 2342–2352 (2002).PubMedCrossRefGoogle Scholar
  54. 54.
    N. De Stefano, S. Narayanan, S. J. Francis, S. Smith, M. Mortilla, M. C. Tartaglia, M. L. Bartolozzi, L. Guidi, A. Federico, and D. L. Arnold, Diffuse axonal and tissue injury in patients with multiple sclerosis with low cerebral lesion load and no disability. Arch. Neurol. 59, 1565–1571 (2002).PubMedCrossRefGoogle Scholar
  55. 55.
    O. Gonen, I. Catalaa, J. S. Babb, Y. Ge, L. J. Mannon, D. L. Kolson, and R. I. Grossman, Total brain Nacetylaspartate: a new measure of disease load in MS. Neurology 54, 15–19 (2000).PubMedGoogle Scholar
  56. 56.
    O. Gonen, A. K. Viswanathan, I. Catalaa, J. Babb, J. Udupa, and R. I. Grossman, Total brain Nacetylaspartate concentration in normal, age-grouped females: quantitation with non-echo proton NMR spectroscopy. Magn Reson. Med. 40, 684–689 (1998).PubMedGoogle Scholar
  57. 57.
    O. Gonen, D. M. Moriarty, B. S. Li, J. S. Babb, J. He, J. Listerud, D. Jacobs, C. E. Markowitz, and R. I. Grossman, Relapsing-remitting multiple sclerosis and whole-brain N-acetylaspartate measurement: evidence for different clinical cohorts initial observations. Radiology 225, 261–268 (2002).PubMedGoogle Scholar
  58. 58.
    S. M. de Waegh, V. M. Lee, and S. T. Brady, Local modulation of neurofilament phosphorylation, axonal caliber, and slow axonal transport by myelinating Schwann cells. Cell 68, 451–463 (1992).PubMedCrossRefGoogle Scholar
  59. 59.
    M. Rango, D. Spagnoli, G. Tomei, F. Bamonti, G. Scarlato, and L. Zetta, Central nervous system transsynaptic effects of acute axonal injury: A 1H magnetic resonance spectroscopy study. MRM 33, 595–600 (1995).Google Scholar
  60. 60.
    T. B. Patel and J. B. Clark, Synthesis of N-acetyl-L-aspartate by rat brain mitochondria and its involvement in mitochondrial/cytosolic carbon transport. Biochem. J. 184, 539–546 (1979).PubMedGoogle Scholar
  61. 61.
    M. E. Truckenmiller, M. A. Namboodiri, M. J. Brownstein, and J. H. Neale, N-Acetylation of L-aspartate in the nervous system: differential distribution of a specific enzyme. J. Neurochem. 45, 1658–1662 (1985).PubMedCrossRefGoogle Scholar
  62. 62.
    J. B. Clark, N-acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev. Neurosci. 20, 271–276 (1998).PubMedCrossRefGoogle Scholar
  63. 63.
    N. De Stefano, P. M. Matthews, and D. L. Arnold, Reversible decreases in N-acetylaspartate after acute brain injury. Magn Reson. Med. 34, 721–727 (1995).PubMedGoogle Scholar
  64. 64.
    M. Saragea, M. Clopotaru, M. Sica, A. Vladutiu, T. Negru, and N. Rotaru, Biochemical changes occurring in animals with experimental allergic encephalomyelitis. Med. Pharmacol. Exp. Int. J Exp. Med. 13, 74–80 (1965).PubMedGoogle Scholar
  65. 65.
    R. E. Brenner, P. M. G. Munro, S. C. R. Williams, J. D. Bell, G. J. Barker, C. P. Hawkins, D. N. Landon, and W. I. McDonald, The proton NMR spectrum in acute EAE: The significance of the change in the Cho:Cr ratio. MRM 29, 737–745 (1993).Google Scholar
  66. 66.
    N. De Stefano, P. M. Matthews, and D. L. Arnold, Reversible decreases in N-acetylaspartate after acute brain injury. Magn Reson. Med. 34, 721–727 (1995).PubMedGoogle Scholar
  67. 67.
    C. A. Husted, D. S. Goodin, J. W. Hugg, A. A. Maudsley, J. S. Tsuruda, S. H. de Bie, G. Fein, G. B. Matson, and M. W. Weiner, Biochemical alterations in multiple sclerosis lesions and normal-appearing white matter detected by in vivo 31P and 1H spectroscopic imaging. Ann. Neurol. 36, 157–165 (1994).PubMedCrossRefGoogle Scholar
  68. 68.
    G. Helms, Volume correction for edema in single-volume proton MR spectroscopy of contrast-enhancing multiple sclerosis lesions. Magn Reson. Med. 46, 256–263 (2001).PubMedCrossRefGoogle Scholar
  69. 69.
    R. A. Rudick, E. Fisher, J. C. Lee, J. Simon, and L. Jacobs, Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology 53, 1698–1704 (1999).PubMedGoogle Scholar
  70. 70.
    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, A longitudinal study of brain atrophy in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology 53, 139–148 (1999).PubMedGoogle Scholar
  71. 71.
    N. De Stefano, S. Narayanan, G. S. Francis, R. Arnaoutelis, M. C. Tartaglia, J. P. Antel, P. M. Matthews, and D. L. Arnold, Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch. Neurol. 58, 65–70 (2001).PubMedCrossRefGoogle Scholar
  72. 72.
    P. A. Narayana, J. S. Wolinsky, S. B. Rao, R. He, and M. Mehta, Multicentre proton magnetic resonance spectroscopy imaging of primary progressive multiple sclerosis. Mult. Scler. 10Suppl 1, S73–S78 (2004).PubMedCrossRefGoogle Scholar
  73. 73.
    E. W. Willoughby and D. W. Paty, Scales for rating impairment in multiple sclerosis: a critique. Neurology 38, 1793–1798 (1988).PubMedGoogle Scholar
  74. 74.
    M. Filippi, M. A. Horsfield, P. S. Tofts, F. Barkhof, A. J. Thompson, and D. H. Miller, Quantitative assessment of MRI lesion load in monitoring the evolution of multiple sclerosis. Brain 118, 1601–1612 (1995).PubMedGoogle Scholar
  75. 75.
    M. A. Rocca, D. M. Mezzapesa, A. Falini, A. Ghezzi, V. Martinelli, G. Scotti, G. Comi, and M. Filippi, Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis. Neuroimage. 18, 847–855 (2003).PubMedCrossRefGoogle Scholar
  76. 76.
    P. Pantano, G. D. Iannetti, F. Caramia, C. Mainero, S. Di Legge, L. Bozzao, C. Pozzilli, and G. L. Lenzi, Cortical motor reorganization after a single clinical attack of multiple sclerosis. Brain 125, 1607–1615 (2002).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Gerson A. Criste
  • Bruce D. Trapp
    • 1
  1. 1.Department of Neurosciences, Lerner Research InstituteCleveland Clinic FoundationCleveland

Personalised recommendations