Journal of Neurology

, Volume 253, Issue 2, pp 224–230 | Cite as

Metabolite changes in early relapsing–remitting multiple sclerosis

A two year follow–up study
  • M. Tiberio
  • D. T. Chard
  • D. R. Altmann
  • G. Davies
  • C. M. Griffin
  • M. A. McLean
  • W. Rashid
  • J. Sastre–Garriga
  • A. J. Thompson
  • D. H. Miller


Previous in vivo proton magnetic resonance spectroscopic imaging (1H–MRSI) studies have found reduced levels of N–acetyl–aspartate (NAA) in multiple sclerosis (MS) lesions, the surrounding normal–appearing white matter (NAWM) and cortical grey matter (CGM), suggesting neuronal and axonal dysfunction and loss. Other metabolites, such as myoinositol (Ins), creatine (Cr), choline (Cho), and glutamate plus glutamine (Glx), can also be quantified by 1H–MRSI, and studies have indicated that concentrations of these metabolites may also be altered in MS. Relatively little is known about the time course of such metabolite changes. This preliminary study aimed to characterise changes in total NAA (tNAA, the sum of NAA and N–acetyl–aspartyl–glutamate), Cr, Cho, Ins and Glx concentrations in NAWM and in CGM, and their relationship with clinical outcome, in subjects with clinically early relapsing–remitting MS (RRMS). Twenty RRMS subjects and 10 healthy control subjects underwent 1H–MRSI examinations yearly for two years. Using the LCModel, tNAA, Cr, Cho, Ins and Glx concentrations were estimated both in NAWM and CGM.At baseline, the concentration of tNAA was significantly reduced in the NAWM of the MS patients compared to the control group (–7%, p = 0.003), as well as in the CGM (–8.7%, p = 0.009). NAWM tNAA concentrations tended to recover from baseline, but otherwise tissue metabolite profiles did not significantly change in the MS subjects, or relatively between MS and healthy control subjects. While neuronal and axonal damage is apparent from the early clinical stages of MS, this study suggests that initially it may be partly reversible. Compared with other MR imaging measures, serial 1H–MRSI may be relatively less sensitive to progressive pathological tissue changes in early RRMS.

Key words

multiple sclerosis early relapsing–remitting proton magnetic resonance spectroscopic imaging brain metabolites axonal damage 


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  1. 1.
    Arnold DL, Matthews PM, Francis G, Antel J (1990) Proton magnetic resonance spectroscopy of human brain in vivo in the evaluation of multiple sclerosis: assessment of the load of disease. Magn Reson Med 14:154–159PubMedGoogle Scholar
  2. 2.
    Baltagi H (1995) Econometric analysis of panel data. New York: John Wiley and SonsGoogle Scholar
  3. 3.
    Bitsch A, Bruhn H, Vougioukas V, Stringaris A, Lassmann H, Frahm J, Bruck W (1999) Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative MR spectroscopy. Am J Neuroradiol 20:1619–1627PubMedGoogle Scholar
  4. 4.
    Bjartmar C, Kidd G, Mörk S, Rudick R, Trapp BD (2000) Neurological disability correlates with spinal cord axonal loss and reduced N–acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol 48:893–901CrossRefPubMedGoogle Scholar
  5. 5.
    Bjartmar C, Battistuta J, Terada N, Dupree E, Trapp BD (2002) 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 51:51–58CrossRefPubMedGoogle Scholar
  6. 6.
    Casanova B, Martínez–Bisbal MC, Valero C, Celda B, Marti–Bonmati L, Pascual A, Landente L, Coret F (2003) Evidence of Wallerian degeneration in normal appearing white matter in the early stages of relapsing–remitting multiple sclerosis: a HMRS study. J Neurol 250:22–28CrossRefPubMedGoogle Scholar
  7. 7.
    Chard DT, Griffin CM, Parker GJ, Kapoor R, Thompson AJ, Miller DH (2002) Brain atrophy in clinically early relapsing–remitting multiple sclerosis. Brain 125:327–337PubMedGoogle Scholar
  8. 8.
    Chard DT, Griffin CM, McLean MA, Kapeller P, Kapoor R, Thompson AJ, Miller DH (2002) Brain metabolite changes in cortical grey and normalappearing white matter in clinically early relapsing–remitting multiple sclerosis. Brain 125:2342–2352PubMedGoogle Scholar
  9. 9.
    Chard DT, Parker GJ, Griffin CM, Thompson AJ, Miller DH (2002) The reproducibility and sensitivity of brain tissue volume measurements derived from an SPM–based segmentation methodology. J Magn Reson Imaging 15:259–267PubMedGoogle Scholar
  10. 10.
    Chard DT, McLean MA, Parker GJ, MacManus DG, Miller DH (2002) Reproducibility of in vivo metabolite quantification with proton magnetic resonance spectroscopic imaging. J Magn Reson Imaging 15:219–225PubMedGoogle Scholar
  11. 11.
    Dalton CM, Chard DT, Davies GR, Miszkiel A, Altmann DR, Fernando K, Plant GT, Thompson AJ, Miller DH (2004) Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes. Brain 127:1101–1107CrossRefPubMedGoogle Scholar
  12. 12.
    Dautry C, Vaufrey F, Brouillet E, Bizat N, Henry PG, Conde F, Bloch G, Hantraye P (2000) Early N–acetylaspartate depletion is a marker of neuronal dysfunction in rats and primates chronically treated with the mitochondrial toxin 3–nitropropionic acid. J Cereb Blood Flow Metab 20:789–799PubMedGoogle Scholar
  13. 13.
    Davie CA, Hawkins CP, Barker GJ, Brennan A, Tofts PS, Miller DH, Mc– Donald WI (1994) Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions. Brain 117:49–58PubMedGoogle Scholar
  14. 14.
    Davies GR, Altmann DR, Hadjiprocopis A, Rashid W, Chard DT, Griffin CM, Tofts PS, Barker GJ, Kapoor R, Thompson AJ, Miller DH (2005) Increasing normal–appearing grey and white matter magnetisation transfer ratio abnormality in early relapsingremitting multiple sclerosis. J Neurol 18Google Scholar
  15. 15.
    De Stefano N, Matthews PM, Arnold DL (1995) Reversible decreases in Nacetylaspartate after acute brain injury. Magn Reson Med 34:721–727PubMedGoogle Scholar
  16. 16.
    De Stefano N, Matthews PM, Fu L, Narayanan S, Stanley J, Francis GS, Antel JP, Arnold DL (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
  17. 17.
    De Stefano N, Narayanan S, Francis GS, Arnaoutelis R, Tartaglia MC, Antel JP, Matthews PM, Arnold DL (2001) Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol 58:65–70CrossRefPubMedGoogle Scholar
  18. 18.
    De Stefano N, Narayanan S, Francis SJ, Smith S, Mortilla M, Tartaglia MC, Bartolozzi ML, Guidi L, Federico A, Arnold DL (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
  19. 19.
    Degaonkar MN, Khubchandhani M, Dhawan JK, Jayasundar R, Jagannathan NR (2002) Sequential proton MRS study of brain metabolite changes monitored during a complete pathological cycle of demyelination and remyelination in a lysophosphatidyl choline (LCP)–induced experimental demyelinating lesion model. NMR Biomed 15:293–300CrossRefPubMedGoogle Scholar
  20. 20.
    Fernando KT, McLean MA, Chard DT, MacManus DG, Dalton CM, Miszkiel KA, Gordon RM, Plant GT, Thompson AJ, Miller DH (2004) Elevated white matter myo–inositol in clinically isolated syndromes suggestive of multiple sclerosis. Brain 127:1361–1369CrossRefPubMedGoogle Scholar
  21. 21.
    Fisher JS, Jak AJ, Kniker JE, Rudick RA, Cutter G (1999) Administration and scoring manual for the multiple sclerosis functional composite measure (MSFC). New York: DemosGoogle Scholar
  22. 22.
    Fu L, Matthews PM, De Stefano N, Worsley KJ, Narayanan S, Francis GS, Antel JP, Wolfson C, Arnold DL (1998) Imaging axonal damage of normalappearing white matter in multiple sclerosis. Brain 121:103–113CrossRefPubMedGoogle Scholar
  23. 23.
    Grimaud J, Lai M, Thorpe J, Adeleine P, Wang L, Barker GJ, Plummer DL, Tofts PS, McDonald WI, Miller DH (1996) Quantification of MRI lesion load in multiple sclerosis: a comparison of three computer–assisted techniques. Magn Reson Imaging 14:495–505PubMedGoogle Scholar
  24. 24.
    Helms G (2001) Volume correction for edema in single–volume proton MR spectroscopy of contrast–enhancing multiple sclerosis lesions. Magn Reson Med 46:256–263PubMedGoogle Scholar
  25. 25.
    Kapeller P, McLean MA, Griffin CM, Chard D, Parker GJ, Barker GJ, Thompson AJ, Miller DH (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
  26. 26.
    Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452PubMedGoogle Scholar
  27. 27.
    Mader I, Roser W, Kappos L, Hagberg G, Seelig J, Radue EW, Steinbrich W (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(7):1220–1227PubMedGoogle Scholar
  28. 28.
    Matthews PM, Francis G, Antel J, Arnold DL (1991) Proton magnetic resonance spectroscopy for metabolic characterization of plaques in multiple sclerosis. Neurology 41:1251–1256PubMedGoogle Scholar
  29. 29.
    McLean MA, Woermann FG, Barker GJ, Duncan JS (2000) Quantitative analysis of short echo time 1H–MRSI of cerebral gray and white matter. Magn Reson Med 44:401–411CrossRefPubMedGoogle Scholar
  30. 30.
    Peterson JW, Bø L, Mork S, Chang A, Trapp BD (2001) Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50:389–400CrossRefPubMedGoogle Scholar
  31. 31.
    Plummer DL (1992) Dispimage: a display and analysis tool for medical images. Rev Neuroradiol 5:489–495Google Scholar
  32. 32.
    Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13:227–231PubMedGoogle Scholar
  33. 33.
    Provencher SW (1993) Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30:672–679PubMedGoogle Scholar
  34. 34.
    Rao SM, Leo GJ, Bernardin L, Unverzagt F (1991) Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology 41:685–691PubMedGoogle Scholar
  35. 35.
    Sarchielli P, Presciutti O, Pelliccioli GP, Tarducci R, Gobbi G, Chiarini P, Alberti A, Vicinanza F, Gallai V (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
  36. 36.
    Sarchielli P, Presciutti O, Tarducci R, Gobbi G, Alberti A, Pelliccioli GP, Chiarini P, Gallai V (2002) Localized (1)H magnetic resonance spectroscopy in mainly cortical gray matter of patients with multiple sclerosis. J Neurol 249:902–910CrossRefPubMedGoogle Scholar
  37. 37.
    Sastre–Garriga J, Ingle GT, Chard DT, Ramiò–Torrenta Lí McLean MA, Miller DH, Thompson AJ (2005) Metabolite changes in normal–appearing gray and white matter are linked with disability in early primary progressive multiple sclerosis. Arch Neurol 62:569–573PubMedGoogle Scholar
  38. 38.
    Tiberio M, Chard DT, Altmann DR, Davies G, Griffin CM, Rashid W, Sastre–Garriga J, Thompson AJ, Miller DH (2005) Gray and white matter volume changes in early RRMS. A 2– year longitudinal study. Neurology 64:1001–1007PubMedGoogle Scholar

Copyright information

© Steinkopff-Verlag 2005

Authors and Affiliations

  • M. Tiberio
    • 1
    • 3
  • D. T. Chard
    • 1
  • D. R. Altmann
    • 1
    • 4
  • G. Davies
    • 1
  • C. M. Griffin
    • 1
  • M. A. McLean
    • 5
  • W. Rashid
    • 1
  • J. Sastre–Garriga
    • 2
  • A. J. Thompson
    • 2
  • D. H. Miller
    • 1
  1. 1.NMR Research GroupInstitute of NeurologyLondon WC1N 3BGUK
  2. 2.NMR Research Unit, Department of Headache, Brain Injury and RehabilitationInstitute of Neurology, University College LondonLondon WC1N 3BGUK
  3. 3.Department of Neurological and Psychiatric SciencesUniversity of PaduaPaduaItaly
  4. 4.Department of Medical StatisticsSchool of Hygiene and Tropical Medicine, University College LondonLondon WC1N 3BGUK
  5. 5.Department of Clinical and Experimental EpilepsyInstitute of Neurology, University College LondonLondon WC1N 3BGUK

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