CNS Drugs

, Volume 28, Issue 2, pp 147–156

Clinical Relevance of Brain Volume Measures in Multiple Sclerosis

  • Nicola De Stefano
  • Laura Airas
  • Nikolaos Grigoriadis
  • Heinrich P. Mattle
  • Jonathan O’Riordan
  • Celia Oreja-Guevara
  • Finn Sellebjerg
  • Bruno Stankoff
  • Agata Walczak
  • Heinz Wiendl
  • Bernd C. Kieseier
Review Article

Abstract

Multiple sclerosis (MS) is a chronic disease with an inflammatory and neurodegenerative pathology. Axonal loss and neurodegeneration occurs early in the disease course and may lead to irreversible neurological impairment. Changes in brain volume, observed from the earliest stage of MS and proceeding throughout the disease course, may be an accurate measure of neurodegeneration and tissue damage. There are a number of magnetic resonance imaging-based methods for determining global or regional brain volume, including cross-sectional (e.g. brain parenchymal fraction) and longitudinal techniques (e.g. SIENA [Structural Image Evaluation using Normalization of Atrophy]). Although these methods are sensitive and reproducible, caution must be exercised when interpreting brain volume data, as numerous factors (e.g. pseudoatrophy) may have a confounding effect on measurements, especially in a disease with complex pathological substrates such as MS. Brain volume loss has been correlated with disability progression and cognitive impairment in MS, with the loss of grey matter volume more closely correlated with clinical measures than loss of white matter volume. Preventing brain volume loss may therefore have important clinical implications affecting treatment decisions, with several clinical trials now demonstrating an effect of disease-modifying treatments (DMTs) on reducing brain volume loss. In clinical practice, it may therefore be important to consider the potential impact of a therapy on reducing the rate of brain volume loss. This article reviews the measurement of brain volume in clinical trials and practice, the effect of DMTs on brain volume change across trials and the clinical relevance of brain volume loss in MS.

References

  1. 1.
    Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359:1221–31.PubMedCrossRefGoogle Scholar
  2. 2.
    Dutta R, Trapp BD. Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog Neurobiol. 2011;93:1–12.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Young CA. Factors predisposing to the development of multiple sclerosis. QJM. 2011;104:383–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Siffrin V, Vogt J, Radbruch H, et al. Multiple sclerosis—candidate mechanisms underlying CNS atrophy. Trends Neurosci. 2010;33:202–10.PubMedCrossRefGoogle Scholar
  5. 5.
    Bar-Or A. The immunology of multiple sclerosis. Semin Neurol. 2008;28:29–45.PubMedCrossRefGoogle Scholar
  6. 6.
    Barten LJ, Allington DR, Procacci KA, et al. New approaches in the management of multiple sclerosis. Drug Des Devel Ther. 2010;4:343–66.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Filippi M, Rocca MA, Barkhof F, et al. Association between pathological and MRI findings in multiple sclerosis. Lancet Neurol. 2012;11:349–60.PubMedCrossRefGoogle Scholar
  8. 8.
    Filippi M, Rocca M. Preventing brain atrophy should be the gold standard of effective theraphy in MS (after the first year of treatment): no. Mult Scler. 2013;19:1005–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Rudick RA, Fisher E. Preventing brain atrophy should be the gold standard of effective therapy in MS (after the first year of treatment): yes. Mult Scler. 2013;19:1003–4.PubMedCrossRefGoogle Scholar
  10. 10.
    Arnold D, De Stefano N. Preventing brain atrophy should be the gold standard of effective therapy in multiple sclerosis (after the first year of treatment): commentary. Mult Scler. 2013;19:1007–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Barkhof F, Calabresi PA, Miller DH, et al. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol. 2009;5:256–66.PubMedCrossRefGoogle Scholar
  12. 12.
    Zivadinov R, Bakshi R. Central nervous system atrophy and clinical status in multiple sclerosis. J Neuroimaging. 2004;14(3 Suppl.):27S–35S.PubMedCrossRefGoogle Scholar
  13. 13.
    Bermel RA, Bakshi R. The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol. 2006;5:158–70.PubMedCrossRefGoogle Scholar
  14. 14.
    Giorgio A, Battaglini M, Smith SM, et al. Brain atrophy assessment in multiple sclerosis: importance and limitations. Neuroimaging Clin N Am. 2008;18:675–86.PubMedCrossRefGoogle Scholar
  15. 15.
    Zipp F. A new window in multiple sclerosis pathology: non-conventional quantitative magnetic resonance imaging outcomes. J Neurol Sci. 2009;287(Suppl 1):S24–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Enzinger C, Fazekas F, Matthews PM, et al. Risk factors for progression of brain atrophy in aging: six-year follow-up of normal subjects. Neurology. 2005;64:1704–11.PubMedCrossRefGoogle Scholar
  17. 17.
    Zivadinov R, Weinstock-Guttman B, Hashmi K, et al. Smoking is associated with increased lesion volumes and brain atrophy in multiple sclerosis. Neurology. 2009;73:504–10.PubMedCrossRefGoogle Scholar
  18. 18.
    Durand-Dubief F, Belaroussi B, Armspach JP, et al. Reliability of longitudinal brain volume loss measurements between 2 sites in patients with multiple sclerosis: comparison of 7 quantification techniques. Am J Neuroradiol. 2012;33:1918–24.PubMedCrossRefGoogle Scholar
  19. 19.
    Rudick RA, Fisher E, Lee JC, et al. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology. 1999;53:1698–704.PubMedCrossRefGoogle Scholar
  20. 20.
    Filippi M, Rovaris M, Inglese M, et al. Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:1489–96.PubMedCrossRefGoogle Scholar
  21. 21.
    Kappos L, Freedman MS, Polman CH, et al. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 2009;8:987–97.PubMedCrossRefGoogle Scholar
  22. 22.
    Molyneux PD, Kappos L, Polman C, et al. The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis. European Study Group on Interferon beta-1b in secondary progressive multiple sclerosis. Brain. 2000;123(Pt 11):2256–63.PubMedCrossRefGoogle Scholar
  23. 23.
    Sormani MP, Rovaris M, Valsasina P, et al. Measurement error of two different techniques for brain atrophy assessment in multiple sclerosis. Neurology. 2004;62:1432–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Comi G, Martinelli V, Rodegher M, et al. Effects of early treatment with glatiramer acetate in patients with clinically isolated syndrome. Mult Scler. 2013;19:1074–83.PubMedCrossRefGoogle Scholar
  25. 25.
    Vidal-Jordana A, Sastre-Garriga J, Pérez-Miralles F, et al. Early brain pseudoatrophy while on natalizumab therapy is due to white matter volume changes. Mult Scler. 2013;19:1175–81.PubMedCrossRefGoogle Scholar
  26. 26.
    Miller DH, Soon D, Fernando KT, et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology. 2007;68:1390–401.PubMedCrossRefGoogle Scholar
  27. 27.
    Barkhof F, Hulst HE, Drulovic J, et al. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010;74:1033–40.PubMedCrossRefGoogle Scholar
  28. 28.
    Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387–401.PubMedCrossRefGoogle Scholar
  29. 29.
    O’Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365:1293–303.PubMedCrossRefGoogle Scholar
  30. 30.
    Comi G, Jeffery D, Kappos L, et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366:1000–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Filippi M, Rocca MA, Pagani E, et al. Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage. J Neurol Neurosurg Psychiatry. Epub 12 Sep 2013.Google Scholar
  32. 32.
    Vollmer TL, Soelberg Sorensen P, Arnold DL, et al. A placebo-controlled and active comparator phase III trial (BRAVO) for relapsing–remitting multiple sclerosis. ECTRIMS 2011. Abstract P148.Google Scholar
  33. 33.
    Arnold DL, Gold R, Kappos L, et al. Effects of BG-12 on magnetic resonance imaging outcomes in the DEFINE study. CMSC 2012. Poster DX21.Google Scholar
  34. 34.
    Miller D, Fox RJ, Phillips JT, et al. Effects of BG-12 on magnetic resonance imaging outcomes in CONFIRM (Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis), a randomized, placebo-controlled, phase 3 study. ENS 2012. O259.Google Scholar
  35. 35.
    O’Connor P, Filippi M, Arnason B, et al. 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol. 2009;8:889–97.PubMedCrossRefGoogle Scholar
  36. 36.
    Hardmeier M, Wagenpfeil S, Freitag P, et al. Rate of brain atrophy in relapsing MS decreases during treatment with IFN beta-1a. Neurology. 2005;64:236–40.PubMedCrossRefGoogle Scholar
  37. 37.
    Borges IT, Shea CD, Ohayon J, et al. The effect of daclizumab on brain atrophy in relapsing-remitting multiple sclerosis. Mult Scler Relat Disord. 2013;2:133–40.PubMedCrossRefGoogle Scholar
  38. 38.
    Bendfeldt K, Egger H, Nichols TE, et al. Effect of immunomodulatory medication on regional gray matter loss in relapsing-remitting multiple sclerosis—a longitudinal MRI study. Brain Res. 2010;1325:174–82.PubMedCrossRefGoogle Scholar
  39. 39.
    Khan O, Bao F, Shah M, et al. Effect of disease-modifying therapies on brain volume in relapsing-remitting multiple sclerosis: results of a five-year brain MRI study. J Neurol Sci. 2012;312:7–12.PubMedCrossRefGoogle Scholar
  40. 40.
    Portaccio E, Stromillo ML, Goretti B, et al. Natalizumab may reduce cognitive changes and brain atrophy rate in relapsing-remitting multiple sclerosis: a prospective, non-randomized pilot study. Eur J Neurol. 2013;20:986–90.PubMedCrossRefGoogle Scholar
  41. 41.
    CAMMS223 Trial Investigators, Coles AJ, Compston DA, et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008;359:1786–801.Google Scholar
  42. 42.
    Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380:1829–39.PubMedCrossRefGoogle Scholar
  43. 43.
    Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380:1819–28.PubMedCrossRefGoogle Scholar
  44. 44.
    Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–15.PubMedCrossRefGoogle Scholar
  45. 45.
    Takao H, Hayashi N, Ohtomo K. A longitudinal study of brain volume changes in normal aging. Eur J Radiol. 2012;81:2801–4.PubMedCrossRefGoogle Scholar
  46. 46.
    Sidaros A, Skimminge A, Liptrot MG, et al. Long-term global and regional brain volume changes following severe traumatic brain injury: a longitudinal study with clinical correlates. Neuroimage. 2009;44:1–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Scahill RI, Frost C, Jenkins R, et al. A longitudinal study of brain volume changes in normal aging using serial registered magnetic resonance imaging. Arch Neurol. 2003;60:989–94.PubMedCrossRefGoogle Scholar
  48. 48.
    Hedman AM, van Haren NE, Schnack HG, et al. Human brain changes across the life span: a review of 56 longitudinal magnetic resonance imaging studies. Hum Brain Mapp. 2012;33:1987–2002.PubMedCrossRefGoogle Scholar
  49. 49.
    Giorgio A, Stromillo ML, Bartolozzi ML, et al. Ten-year brain atrophy and disability changes in multiple sclerosis. AAN 2012. Poster P065.Google Scholar
  50. 50.
    De Stefano N, Giorgio A, Battaglini M, et al. Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology. 2010;74:1868–76.PubMedCrossRefGoogle Scholar
  51. 51.
    Fisher E, Lee JC, Nakamura K, et al. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol. 2008;64:255–65.PubMedCrossRefGoogle Scholar
  52. 52.
    Simon JH. Brain atrophy in multiple sclerosis: what we know and would like to know. Mult Scler. 2006;12:679–87.PubMedCrossRefGoogle Scholar
  53. 53.
    Minneboo A, Jasperse B, Barkhof F, et al. Predicting short-term disability progression in early multiple sclerosis: added value of MRI parameters. J Neurol Neurosurg Psychiatry. 2008;79:917–23.PubMedCrossRefGoogle Scholar
  54. 54.
    Amato MP, Portaccio E, Goretti B, et al. Association of neocortical volume changes with cognitive deterioration in relapsing-remitting multiple sclerosis. Arch Neurol. 2007;64:1157–61.PubMedCrossRefGoogle Scholar
  55. 55.
    Fisniku LK, Altmann DR, Cercignani M, et al. Magnetization transfer ratio abnormalities reflect clinically relevant grey matter damage in multiple sclerosis. Mult Scler. 2009;15:668–77.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Filippi M, Rocca MA. MR imaging of multiple sclerosis. Radiology. 2011;259:659–81.PubMedCrossRefGoogle Scholar
  57. 57.
    Zivadinov R, Havrdová E, Bergsland N, et al. Thalamic atrophy is associated with development of clinically definite multiple sclerosis. Radiology. 2013;268:831–41.PubMedCrossRefGoogle Scholar
  58. 58.
    Popescu V, Agosta F, Hulst HE, et al. Brain atrophy and lesion load predict long term disability in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013;84:1082–91.PubMedCrossRefGoogle Scholar
  59. 59.
    Zivadinov R, Bergsland N, Dolezal O, et al. Evolution of cortical and thalamus atrophy and disability progression in early relapsing-remitting MS during 5 years. Am J Neuroradiol. 2013;34:1931–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Fisniku LK, Chard DT, Jackson JS, et al. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol. 2008;64:247–54.PubMedCrossRefGoogle Scholar
  61. 61.
    Sanfilipo MP, Benedict RH, Sharma J, et al. The relationship between whole brain volume and disability in multiple sclerosis: a comparison of normalized gray vs. white matter with misclassification correction. Neuroimage. 2005;26:1068–77.PubMedCrossRefGoogle Scholar
  62. 62.
    Fisher E, Rudick RA, Cutter G, et al. Relationship between brain atrophy and disability: an 8-year follow-up study of multiple sclerosis patients. Mult Scler. 2000;6:373–7.PubMedGoogle Scholar
  63. 63.
    Shiee N, Bazin PL, Zackowski KM, et al. Revisiting brain atrophy and its relationship to disability in multiple sclerosis. PLoS One. 2012;7:e37049.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Lansley J, Mataix-Cols D, Grau M, et al. Localized grey matter atrophy in multiple sclerosis: a meta-analysis of voxel-based morphometry studies and associations with functional disability. Neurosci Biobehav Rev. 2013;37:819–30.PubMedCrossRefGoogle Scholar
  65. 65.
    Zivadinov R, Tekwe C, Bergsland N, et al. Bimonthly evolution of cortical atrophy in early relapsing–remitting multiple sclerosis over 2 years: a longitudinal study. Mult Scler Int. 2013;2013:231345.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Fisher E, Rudick RA, Simon JH, et al. Eight-year follow-up study of brain atrophy in patients with MS. Neurology. 2002;59:1412–20.PubMedCrossRefGoogle Scholar
  67. 67.
    Brex PA, Jenkins R, Fox NC, et al. Detection of ventricular enlargement in patients at the earliest clinical stage of MS. Neurology. 2000;54:1689–91.PubMedCrossRefGoogle Scholar
  68. 68.
    Dalton CM, Brex PA, Jenkins R, et al. Progressive ventricular enlargement in patients with clinically isolated syndromes is associated with the early development of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2002;73:141–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Pérez-Miralles F, Sastre-Garriga J, Tintoré M, et al. Clinical impact of early brain atrophy in clinically isolated syndromes. Mult Scler. 2013;19:1878–86.PubMedCrossRefGoogle Scholar
  70. 70.
    Ingle GT, Stevenson VL, Miller DH, et al. Two-year follow-up study of primary and transitional progressive multiple sclerosis. Mult Scler. 2002;8:108–14.PubMedCrossRefGoogle Scholar
  71. 71.
    Rudick RA, Fisher E, Lee JC, et al. Brain atrophy in relapsing multiple sclerosis: relationship to relapses, EDSS, and treatment with interferon beta-1a. Mult Scler. 2000;6:365–72.PubMedGoogle Scholar
  72. 72.
    Lavorgna L, Bonavita S, Ippolito D, et al. Clinical and magnetic resonance imaging predictors of disease progression in multiple sclerosis: a nine-year follow-up study. Mult Scler. Epub 9 Jul 2013.Google Scholar
  73. 73.
    Kearney H, Rocca M, Valsasina P, et al. Magnetic resonance imaging correlates of physical disability in relapse onset multiple sclerosis of long disease duration. Mult Scler. 2014;20:72–80.PubMedCrossRefGoogle Scholar
  74. 74.
    Rocca MA, Valsasina P, Damjanovic D, et al. Voxel-wise mapping of cervical cord damage in multiple sclerosis patients with different clinical phenotypes. J Neurol Neurosurg Psychiatry. 2013;84:35–41.PubMedCrossRefGoogle Scholar
  75. 75.
    Lukas C, Sombekke MH, Bellenberg B, et al. Relevance of spinal cord abnormalities to clinical disability in multiple sclerosis: MR imaging findings in a large cohort of patients. Radiology. 2013;269:542–52.PubMedCrossRefGoogle Scholar
  76. 76.
    Valsasina P, Rocca MA, Horsfield MA, et al. Regional cervical cord atrophy and disability in multiple sclerosis: a voxel-based analysis. Radiology. 2013;266:853–61.PubMedCrossRefGoogle Scholar
  77. 77.
    Lukas C, Minneboo A, de Groot V, et al. Early central atrophy rate predicts 5 year clinical outcome in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2010;81:1351–6.PubMedCrossRefGoogle Scholar
  78. 78.
    Horakova D, Dwyer MG, Havrdova E, et al. Gray matter atrophy and disability progression in patients with early relapsing-remitting multiple sclerosis: a 5-year longitudinal study. J Neurol Sci. 2009;282:112–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Rocca MA, Mesaros S, Pagani E, et al. Thalamic damage and long-term progression of disability in multiple sclerosis. Radiology. 2010;257:463–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Filippi M, Preziosa P, Copetti M, et al. Gray matter damage predicts the accumulation of disability 13 years later in MS. Neurology. 2013;81:1759–67.PubMedCrossRefGoogle Scholar
  81. 81.
    Covey TJ, Zivadinov R, Shucard JL, et al. Information processing speed, neural efficiency, and working memory performance in multiple sclerosis: differential relationships with structural magnetic resonance imaging. J Clin Exp Neuropsychol. 2011;33:1129–45.PubMedCrossRefGoogle Scholar
  82. 82.
    Nocentini U, Bozzali M, Spanó B, et al. Exploration of the relationships between regional grey matter atrophy and cognition in multiple sclerosis. Brain Imaging Behav. Epub 15 May 2012.Google Scholar
  83. 83.
    Benedict RH, Hulst HE, Bergsland N, et al. Clinical significance of atrophy and white matter mean diffusivity within the thalamus of multiple sclerosis patients. Mult Scler. 2013;19:1478–84.PubMedCrossRefGoogle Scholar
  84. 84.
    Deloire MS, Ruet A, Hamel D, et al. MRI predictors of cognitive outcome in early multiple sclerosis. Neurology. 2011;76:1161–7.PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Calabrese M, Rinaldi F, Grossi P, et al. Cortical pathology and cognitive impairment in multiple sclerosis. Expert Rev Neurother. 2011;11:425–32.PubMedCrossRefGoogle Scholar
  86. 86.
    Sicotte NL, Kern KC, Giesser BS, et al. Regional hippocampal atrophy in multiple sclerosis. Brain. 2008;131:1134–41.PubMedCrossRefGoogle Scholar
  87. 87.
    Amato MP, Bartolozzi ML, Zipoli V, et al. Neocortical volume decrease in relapsing-remitting MS patients with mild cognitive impairment. Neurology. 2004;63:89–93.PubMedCrossRefGoogle Scholar
  88. 88.
    Hulst HE, Steenwijk MD, Versteeg A, et al. Cognitive impairment in MS: impact of white matter integrity, gray matter volume, and lesions. Neurology. 2013;80:1025–32.PubMedCrossRefGoogle Scholar
  89. 89.
    Rossi F, Giorgio A, Battaglini M, et al. Relevance of brain lesion location to cognition in relapsing multiple sclerosis. PLoS One. 2012;7:e44826.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Kapoor R, Furby J, Hayton T, et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol. 2010;9:681–8.PubMedCrossRefGoogle Scholar
  91. 91.
    Zivadinov R, Reder AT, Filippi M, et al. Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis. Neurology. 2008;71:136–44.PubMedCrossRefGoogle Scholar
  92. 92.
    Gauthier SA, Berger AM, Liptak Z, et al. Rate of brain atrophy in benign vs early multiple sclerosis. Arch Neurol. 2009;66:234–7.PubMedCrossRefGoogle Scholar
  93. 93.
    Romero JR, Vasan RS, Beiser AS, et al. Association of matrix metalloproteinases with MRI indices of brain ischemia and aging. Neurobiol Aging. 2010;31:2128–35.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Bernal F, Elias B, Hartung HP, et al. Regulation of matrix metalloproteinases and their inhibitors by interferon-beta: a longitudinal study in multiple sclerosis patients. Mult Scler. 2009;15:721–7.PubMedCrossRefGoogle Scholar
  95. 95.
    Debette S, Seshadri S, Beiser A, et al. Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline. Neurology. 2011;77:461–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Sumowski JF, Rocca MA, Leavitt VM, et al. Brain reserve and cognitive reserve in multiple sclerosis: what you’ve got and how you use it. Neurology. 2013;80:2186–93.PubMedCrossRefGoogle Scholar
  97. 97.
    Amato MP, Razzolini L, Goretti B, et al. Cognitive reserve and cortical atrophy in multiple sclerosis: a longitudinal study. Neurology. 2013;80:1728–33.PubMedCrossRefGoogle Scholar
  98. 98.
    Feinstein A, Lapshin H, O’Connor P, et al. Sub-threshold cognitive impairment in multiple sclerosis: the association with cognitive reserve. J Neurol. 2013;260:2256–61.PubMedCrossRefGoogle Scholar
  99. 99.
    Booth AJ, Rodgers JD, Schwartz CE, et al. Active cognitive reserve influences the regional atrophy to cognition link in multiple sclerosis. J Int Neuropsychol Soc. 2013;19:1128–33.PubMedCrossRefGoogle Scholar
  100. 100.
    Zivadinov R. Steroids and brain atrophy in multiple sclerosis. J Neurol Sci. 2005;233:73–81.PubMedCrossRefGoogle Scholar
  101. 101.
    Barkhof F, Simon JH, Fazekas F, et al. MRI monitoring of immunomodulation in relapse-onset multiple sclerosis trials. Nat Rev Neurol. 2011;8:13–21.PubMedCrossRefGoogle Scholar
  102. 102.
    Sormani MP, Arnold DL, De Stefano N. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann Neurol. Epub 5 Sep 2013.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Nicola De Stefano
    • 1
  • Laura Airas
    • 2
  • Nikolaos Grigoriadis
    • 3
  • Heinrich P. Mattle
    • 4
  • Jonathan O’Riordan
    • 5
  • Celia Oreja-Guevara
    • 6
  • Finn Sellebjerg
    • 7
  • Bruno Stankoff
    • 8
  • Agata Walczak
    • 9
  • Heinz Wiendl
    • 10
  • Bernd C. Kieseier
    • 11
  1. 1.Department of Medicine, Surgery and NeuroscienceUniversity of SienaSienaItaly
  2. 2.Department of NeurologyTurku University HospitalTurkuFinland
  3. 3.B’ Department of Neurology, Laboratory of Experimental Neurology and Neuroimmunology, AHEPA University HospitalAristotle University of ThessalonikiMacedoniaGreece
  4. 4.Department of Neurology, InselspitalUniversity of BernBernSwitzerland
  5. 5.Department of Neurology, Ninewells Hospital and Medical SchoolUniversity of DundeeTaysideUK
  6. 6.Department of NeurologyUniversity Hospital San Carlos, IdISCCMadridSpain
  7. 7.Danish Multiple Sclerosis Center, Department of NeurologyCopenhagen University Hospital, RigshospitaletCopenhagenDenmark
  8. 8.Centre d’Investigation Clinique, AP-HPHôpital Pitié-Salpêtrière-UPMCParisFrance
  9. 9.Katedra i Klinika NeurologiiUniwersytet Medyczny w ŁodziLodzPoland
  10. 10.Department of NeurologyUniversity of Münster Albert-Schweitzer-Campus 1MünsterGermany
  11. 11.Department of NeurologyHeinrich-Heine-UniversityDüsseldorfGermany

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