Neurotherapeutics

, Volume 10, Issue 1, pp 111–123

Neuroinflammatory Imaging Biomarkers: Relevance to Multiple Sclerosis and its Therapy

Review

Abstract

Magnetic resonance imaging is an established tool in the management of multiple sclerosis (MS). Loss of blood brain barrier integrity assessed by gadolinium (Gd) enhancement is the current standard marker of MS activity. To explore the complex cascade of the inflammatory events, other magnetic resonance imaging, but also positron emission tomographic markers reviewed in this article are being developed to address active neuroinflammation with increased sensitivity and specificity. Alternative magnetic resonance contrast agents, positron emission tomographic tracers and imaging techniques could be more sensitive than Gd to early blood brain barrier alteration, and they could assess the inflammatory cell recruitment and/or the associated edema accumulation. These markers of active neuroinflammation, although some of them are limited to experimental studies, could find great relevance to complete Gd information and thereby increase our understanding of acute lesion pathophysiology and its noninvasive follow-up, especially to monitor treatment efficacy. Furthermore, such accurate markers of inflammation combined with those of neurodegeneration hold promise to provide a more complete picture of MS, which will be of great benefit for future therapeutic strategies.

Keywords

Multiple sclerosis Inflammation Imaging biomarkers Blood brain barrier Contrast agent Edema 

Supplementary material

13311_2012_155_MOESM1_ESM.pdf (510 kb)
ESM 1(PDF 510 kb)

References

  1. 1.
    Filippi M, Rocca MA. MR imaging of multiple sclerosis. Radiology 2011;259:659-681.PubMedCrossRefGoogle Scholar
  2. 2.
    Bakshi R, Thompson AJ, Rocca MA, et al. MRI in multiple sclerosis: current status and future prospects. Lancet Neurol 2008;7:615-625.PubMedCrossRefGoogle Scholar
  3. 3.
    Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69:292-302.PubMedCrossRefGoogle Scholar
  4. 4.
    Miller DH, Altmann DR, Chard DT. Advances in imaging to support the development of novel therapies for multiple sclerosis. Clin Pharmacol Ther 2012;91:621-634.PubMedCrossRefGoogle Scholar
  5. 5.
    Barkhof F, Calabresi PA, Miller DH, Reingold SC. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol 2009;5:256-266.PubMedCrossRefGoogle Scholar
  6. 6.
    Lovblad KO, Anzalone N, Dorfler A, et al. MR imaging in multiple sclerosis: review and recommendations for current practice. AJNR Am J Neuroradiol 2010;31:983-989.PubMedCrossRefGoogle Scholar
  7. 7.
    Frohman EM, Racke MK , Raine CS. Multiple sclerosis — the plaque and its pathogenesis. N Engl J Med 2006;354:942-955.PubMedCrossRefGoogle Scholar
  8. 8.
    Waubant E. Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis. Dis Markers 2006;22:235-244.PubMedGoogle Scholar
  9. 9.
    Yednock TA, Cannon C, Fritz LC, et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 1992;356:63-66.PubMedCrossRefGoogle Scholar
  10. 10.
    Minagar A, Alexander JS. Blood-brain barrier disruption in multiple sclerosis. Mult Scler 2003;9:540-549.PubMedCrossRefGoogle Scholar
  11. 11.
    Yeung D, Manias JL, Stewart DJ, Nag S. Decreased junctional adhesion molecule-A expression during blood-brain barrier breakdown. Acta Neuropathol 2008;115:635-642.PubMedCrossRefGoogle Scholar
  12. 12.
    Nag S, Venugopalan R, Stewart DJ. Increased caveolin-1 expression precedes decreased expression of occludin and claudin-5 during blood-brain barrier breakdown. Acta Neuropathol 2007;114:459-469.PubMedCrossRefGoogle Scholar
  13. 13.
    Hawkins CP, Munro PM, MacKenzie F, et al. Duration and selectivity of blood-brain barrier breakdown in chronic relapsing experimental allergic encephalomyelitis studied by gadolinium-DTPA and protein markers. Brain 1990;113(pt 2):365-378.PubMedCrossRefGoogle Scholar
  14. 14.
    Soon D, Tozer DJ, Altmann DR, Tofts PS, Miller DH. Quantification of subtle blood-brain barrier disruption in non-enhancing lesions in multiple sclerosis: a study of disease and lesion subtypes. Mult Scler 2007;13:884-894.PubMedCrossRefGoogle Scholar
  15. 15.
    Bradl M, Lassmann H. Progressive multiple sclerosis. Semin Immunopathol 2009;31:455-465.PubMedCrossRefGoogle Scholar
  16. 16.
    Leech S, Kirk J, Plumb J, McQuaid S. Persistent endothelial abnormalities and blood-brain barrier leak in primary and secondary progressive multiple sclerosis. Neuropathol Appl Neurobiol 2007;33:86-98.PubMedCrossRefGoogle Scholar
  17. 17.
    Misselwitz B, Platzek J, Weinmann HJ. Early MR lymphography with gadofluorine M in rabbits. Radiology 2004;231:682-688.PubMedCrossRefGoogle Scholar
  18. 18.
    Meding J, Urich M, Licha K, et al. Magnetic resonance imaging of atherosclerosis by targeting extracellular matrix deposition with Gadofluorine M. Contrast Media Mol Imaging 2007;2:120-129.PubMedCrossRefGoogle Scholar
  19. 19.
    Bendszus M, Ladewig G, Jestaedt L, et al. Gadofluorine M enhancement allows more sensitive detection of inflammatory CNS lesions than T2-w imaging: a quantitative MRI study. Brain 2008;131:2341-2352.PubMedCrossRefGoogle Scholar
  20. 20.
    Corot C, Robert P, Idee JM, Port M. Recent advances in iron oxide nanocrystal technology for medical imaging. Adv Drug Deliv Rev 2006;58:1471-1504.PubMedCrossRefGoogle Scholar
  21. 21.
    Weinstein JS, Varallyay CG, Dosa E, et al. Superparamagnetic iron oxide nanoparticles: diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology and central nervous system inflammatory pathologies, a review. J Cereb Blood Flow Metab 2010;30:15-35.PubMedCrossRefGoogle Scholar
  22. 22.
    Wuerfel J, Tysiak E, Prozorovski T, et al. Mouse model mimics multiple sclerosis in the clinico-radiological paradox. Eur J Neurosci 2007;26:190-198.PubMedCrossRefGoogle Scholar
  23. 23.
    Tysiak E, Asbach P, Aktas O, et al. Beyond blood brain barrier breakdown — in vivo detection of occult neuroinflammatory foci by magnetic nanoparticles in high field MRI. J Neuroinflammation 2009;6:20.PubMedCrossRefGoogle Scholar
  24. 24.
    Grenier N, Brader P. Principles and basic concepts of molecular imaging. Pediatr Radiol 2011;41:144-160.PubMedCrossRefGoogle Scholar
  25. 25.
    Sibson NR, Blamire AM, Bernades-Silva M, et al. MRI detection of early endothelial activation in brain inflammation. Magn Reson Med 2004;51:248-252.PubMedCrossRefGoogle Scholar
  26. 26.
    Nahrendorf M, Jaffer FA, Kelly KA, et al. Noninvasive vascular cell adhesion molecule-1 imaging identifies inflammatory activation of cells in atherosclerosis. Circulation 2006;114:1504-1511.PubMedCrossRefGoogle Scholar
  27. 27.
    Tsourkas A, Shinde-Patil VR, Kelly KA, et al. In vivo imaging of activated endothelium using an anti-VCAM-1 magnetooptical probe. Bioconjug Chem 2005;16:576-581.PubMedCrossRefGoogle Scholar
  28. 28.
    Schneider C, Schuetz G , Zollner TM. Acute neuroinflammation in Lewis rats — a model for acute multiple sclerosis relapses. J Neuroimmunol 2009;213:84-90.PubMedCrossRefGoogle Scholar
  29. 29.
    Shapiro EM, Skrtic S, Sharer K, et al. MRI detection of single particles for cellular imaging. Proc Natl Acad Sci U S A 2004;101:10901-10906.PubMedCrossRefGoogle Scholar
  30. 30.
    Yang Y, Yanasak N, Schumacher A , Hu TC. Temporal and noninvasive monitoring of inflammatory-cell infiltration to myocardial infarction sites using micrometer-sized iron oxide particles. Magn Reson Med 2010;63:33-40.PubMedGoogle Scholar
  31. 31.
    McAteer MA, Sibson NR, von Zur Muhlen C, et al. In vivo magnetic resonance imaging of acute brain inflammation using microparticles of iron oxide. Nat Med 2007;13:1253-1258.PubMedCrossRefGoogle Scholar
  32. 32.
    Serres S, Anthony DC, Jiang Y, et al. Systemic inflammatory response reactivates immune-mediated lesions in rat brain. J Neurosci 2009;29:4820-4828.PubMedCrossRefGoogle Scholar
  33. 33.
    Serres S, Mardiguian S, Campbell SJ, et al. VCAM-1-targeted magnetic resonance imaging reveals subclinical disease in a mouse model of multiple sclerosis. Faseb J 2011;25:4415-4422.PubMedCrossRefGoogle Scholar
  34. 34.
    Man S, Ubogu EE, Ransohoff RM. Inflammatory cell migration into the central nervous system: a few new twists on an old tale. Brain Pathol 2007;17:243-250.PubMedCrossRefGoogle Scholar
  35. 35.
    Carman CV, Springer TA. Trans-cellular migration: cell-cell contacts get intimate. Curr Opin Cell Biol 2008;b20:533-540.CrossRefGoogle Scholar
  36. 36.
    Wolburg H, Wolburg-Buchholz K, Engelhardt B. Diapedesis of mononuclear cells across cerebral venules during experimental autoimmune encephalomyelitis leaves tight junctions intact. Acta Neuropathol 2005;109:181-190.PubMedCrossRefGoogle Scholar
  37. 37.
    Petry KG, Boiziau C, Dousset V, Brochet B. Magnetic resonance imaging of human brain macrophage infiltration. Neurotherapeutics 2007;4:434-442.PubMedCrossRefGoogle Scholar
  38. 38.
    Beckmann N, Cannet C, Babin AL, et al. In vivo visualization of macrophage infiltration and activity in inflammation using magnetic resonance imaging. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2009;1:272-298.PubMedCrossRefGoogle Scholar
  39. 39.
    Bendszus M, Stoll G. Caught in the act: in vivo mapping of macrophage infiltration in nerve injury by magnetic resonance imaging. J Neurosci 2003;23:10892-10896.PubMedGoogle Scholar
  40. 40.
    Engberink RD, Blezer EL, Hoff EI, et al. MRI of monocyte infiltration in an animal model of neuroinflammation using SPIO-labeled monocytes or free USPIO. J Cereb Blood Flow Metab 2008;28:841-851.CrossRefGoogle Scholar
  41. 41.
    Oude Engberink RD, Blezer EL, Dijkstra CD, et al. Dynamics and fate of USPIO in the central nervous system in experimental autoimmune encephalomyelitis. NMR Biomed 2010;23:1087-1096.PubMedCrossRefGoogle Scholar
  42. 42.
    Anderson SA, Shukaliak-Quandt J, Jordan EK, et al. Magnetic resonance imaging of labeled T-cells in a mouse model of multiple sclerosis. Ann Neurol 2004;55:654-659.PubMedCrossRefGoogle Scholar
  43. 43.
    Stoll G, Bendszus M. Imaging of inflammation in the peripheral and central nervous system by magnetic resonance imaging. Neuroscience 2009;158:1151-1160.PubMedCrossRefGoogle Scholar
  44. 44.
    Dousset V, Delalande C, Ballarino L, et al. In vivo macrophage activity imaging in the central nervous system detected by magnetic resonance. Magn Reson Med 1999;41:329-333.PubMedCrossRefGoogle Scholar
  45. 45.
    Floris S, Blezer EL, Schreibelt G, et al. Blood-brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis: a quantitative MRI study. Brain 2004;127:616-627.PubMedCrossRefGoogle Scholar
  46. 46.
    Dousset V, Ballarino L, Delalande C, et al. Comparison of ultrasmall particles of iron oxide (USPIO)-enhanced T2-weighted, conventional T2-weighted, and gadolinium-enhanced T1-weighted MR images in rats with experimental autoimmune encephalomyelitis. AJNR Am J Neuroradiol 1999;20:223-227.PubMedGoogle Scholar
  47. 47.
    Rausch M, Hiestand P, Baumann D, Cannet C, Rudin M. MRI-based monitoring of inflammation and tissue damage in acute and chronic relapsing EAE. Magn Reson Med 2003;50:309-314.PubMedCrossRefGoogle Scholar
  48. 48.
    Chin CL, Pai M, Bousquet PF, et al. Distinct spatiotemporal pattern of CNS lesions revealed by USPIO-enhanced MRI in MOG-induced EAE rats implicates the involvement of spino-olivocerebellar pathways. J Neuroimmunol 2009;211:49-55.PubMedCrossRefGoogle Scholar
  49. 49.
    Baeten K, Hendriks JJ, Hellings N, et al. Visualisation of the kinetics of macrophage infiltration during experimental autoimmune encephalomyelitis by magnetic resonance imaging. J Neuroimmunol 2008;195:1-6.PubMedCrossRefGoogle Scholar
  50. 50.
    Ladewig G, Jestaedt L, Misselwitz B, et al. Spatial diversity of blood-brain barrier alteration and macrophage invasion in experimental autoimmune encephalomyelitis: a comparative MRI study. Exp Neurol 2009;220:207-211.PubMedCrossRefGoogle Scholar
  51. 51.
    Dousset V, Brochet B, Deloire MS, et al. MR imaging of relapsing multiple sclerosis patients using ultra-small-particle iron oxide and compared with gadolinium. AJNR Am J Neuroradiol 2006;27:1000-1005.PubMedGoogle Scholar
  52. 52.
    Vellinga MM, Oude Engberink RD, Seewann A, et al. Pluriformity of inflammation in multiple sclerosis shown by ultra-small iron oxide particle enhancement. Brain 2008;131:800-807.Google Scholar
  53. 53.
    Tourdias T, Roggerone S, Filippi M, et al. Assessment of disease activity in multiple sclerosis phenotypes with combined gadolinium- and superparamagnetic iron oxide-enhanced MR imaging. Radiology 2012;264:225-233.PubMedCrossRefGoogle Scholar
  54. 54.
    Lassmann H, Bruck W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol 2007;17:210-218.PubMedCrossRefGoogle Scholar
  55. 55.
    Vellinga MM, Vrenken H, Hulst HE, et al. Use of ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced MRI to demonstrate diffuse inflammation in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) patients: an exploratory study. J Magn Reson Imaging 2009;29:774-779.PubMedCrossRefGoogle Scholar
  56. 56.
    Martin R, McFarland HF. Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis. Crit Rev Clin Lab Sci 1995;c32:121-182.CrossRefGoogle Scholar
  57. 57.
    Brochet B, Deloire MS, Touil T, et al. Early macrophage MRI of inflammatory lesions predicts lesion severity and disease development in relapsing EAE. Neuroimage 2006;32:266-274.PubMedCrossRefGoogle Scholar
  58. 58.
    Bradley PP, Christensen RD, Rothstein G. Cellular and extracellular myeloperoxidase in pyogenic inflammation. Blood 1982;60:618-622.PubMedGoogle Scholar
  59. 59.
    Chen JW, Querol Sans M, Bogdanov A Jr., Weissleder R. Imaging of myeloperoxidase in mice by using novel amplifiable paramagnetic substrates. Radiology 2006;240:473-481.PubMedCrossRefGoogle Scholar
  60. 60.
    Rodriguez E, Nilges M, Weissleder R, Chen JW. Activatable magnetic resonance imaging agents for myeloperoxidase sensing: mechanism of activation, stability, and toxicity. J Am Chem Soc 2010;132:168-177.PubMedCrossRefGoogle Scholar
  61. 61.
    Chen JW, Breckwoldt MO, Aikawa E, Chiang G, Weissleder R. Myeloperoxidase-targeted imaging of active inflammatory lesions in murine experimental autoimmune encephalomyelitis. Brain 2008;131:1123-1133.PubMedCrossRefGoogle Scholar
  62. 62.
    Stoll G, Basse-Lusebrink T, Weise G, Jakob P. Visualization of inflammation using (19) F-magnetic resonance imaging and perfluorocarbons. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2012;4:438-447.PubMedCrossRefGoogle Scholar
  63. 63.
    Janjic JM , Ahrens ET. Fluorine-containing nanoemulsions for MRI cell tracking. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2009;1:492-501.PubMedCrossRefGoogle Scholar
  64. 64.
    Flogel U, Ding Z, Hardung H, et al. In vivo monitoring of inflammation after cardiac and cerebral ischemia by fluorine magnetic resonance imaging. Circulation 2008;118:140-148.PubMedCrossRefGoogle Scholar
  65. 65.
    Bulte JW. Hot spot MRI emerges from the background. Nat Biotechnol 2005;23:945-946.PubMedCrossRefGoogle Scholar
  66. 66.
    Weise G, Basse-Luesebrink TC, Wessig C, Jakob PM, Stoll G. In vivo imaging of inflammation in the peripheral nervous system by (19)F MRI. Exp Neurol 2011;229:494-501.PubMedCrossRefGoogle Scholar
  67. 67.
    Weise G, Basse-Lusebrink TC, Kleinschnitz C, et al. In vivo imaging of stepwise vessel occlusion in cerebral photothrombosis of mice by 19F MRI. PLoS One 2011;6:e28143.PubMedCrossRefGoogle Scholar
  68. 68.
    Wang Y, Wang Q, Haldar JP, et al. Quantification of increased cellularity during inflammatory demyelination. Brain 2011;134:3590-3601.PubMedCrossRefGoogle Scholar
  69. 69.
    Denic A, Johnson AJ, Bieber AJ, et al. The relevance of animal models in multiple sclerosis research. Pathophysiology 2011;18:21-29.PubMedCrossRefGoogle Scholar
  70. 70.
    Hammond KE, Metcalf M, Carvajal L, et al. Quantitative in vivo magnetic resonance imaging of multiple sclerosis at 7 Tesla with sensitivity to iron. Ann Neurol 2008;64:707-713.PubMedCrossRefGoogle Scholar
  71. 71.
    Bagnato F, Hametner S, Yao B, et al. Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla. Brain 2011;134:3602-3615.PubMedCrossRefGoogle Scholar
  72. 72.
    Bian W, Harter K, Hammond-Rosenbluth KE, et al. A serial in vivo 7T magnetic resonance phase imaging study of white matter lesions in multiple sclerosis. Mult Scler 2012. doi:10.1177/1352458512447870
  73. 73.
    Banati RB. Visualising microglial activation in vivo. Glia 2002;40:206-217.PubMedCrossRefGoogle Scholar
  74. 74.
    Venneti S, Lopresti BJ, Wiley CA. Molecular imaging of microglia/macrophages in the brain. Glia 2012. doi:10.1002/glia.22357
  75. 75.
    Banati RB, Newcombe J, Gunn RN, et al. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain 2000;123(pt 11):2321-2337.PubMedCrossRefGoogle Scholar
  76. 76.
    Debruyne JC, Versijpt J, Van Laere KJ, et al. PET visualization of microglia in multiple sclerosis patients using [11C]PK11195. Eur J Neurol 2003;10:257-264.PubMedCrossRefGoogle Scholar
  77. 77.
    Versijpt J, Debruyne JC, Van Laere KJ, et al. Microglial imaging with positron emission tomography and atrophy measurements with magnetic resonance imaging in multiple sclerosis: a correlative study. Mult Scler 2005;11:127-134.PubMedCrossRefGoogle Scholar
  78. 78.
    Politis M, Giannetti P, Su P, et al. Increased PK11195 PET binding in the cortex of patients with MS correlates with disability. Neurology 2012;79:523-530.PubMedCrossRefGoogle Scholar
  79. 79.
    Chauveau F, Boutin H, Van Camp N, Dolle F, Tavitian B. Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers. Eur J Nucl Med Mol Imaging 2008;35:2304-2319.PubMedCrossRefGoogle Scholar
  80. 80.
    Kiferle L, Politis M, Muraro PA, Piccini P. Positron emission tomography imaging in multiple sclerosis-current status and future applications. Eur J Neurol 2011;18:226-231.PubMedCrossRefGoogle Scholar
  81. 81.
    Abourbeh G, Theze B, Maroy R, et al. Imaging microglial/macrophage activation in spinal cords of experimental autoimmune encephalomyelitis rats by positron emission tomography using the mitochondrial 18 kDa translocator protein radioligand [(1)(8)F]DPA-714. J Neurosci 2012;32:5728-5736.PubMedCrossRefGoogle Scholar
  82. 82.
    Nag S, Manias JL, Stewart DJ. Pathology and new players in the pathogenesis of brain edema. Acta Neuropathol 2009;118:197-217.PubMedCrossRefGoogle Scholar
  83. 83.
    cLucchinetti CF, Gavrilova RH, Metz I, et al. Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis. Brain 2008;131:1759-1775.Google Scholar
  84. 84.
    Tait MJ, Saadoun S, Bell BA, Papadopoulos MC. Water movements in the brain: role of aquaporins. Trends Neurosci 2008;31:37-43.PubMedCrossRefGoogle Scholar
  85. 85.
    Saadoun S , Papadopoulos MC. Aquaporin-4 in brain and spinal cord oedema. Neuroscience 2010;168:1036-1046.PubMedCrossRefGoogle Scholar
  86. 86.
    Tourdias T, Mori N, Dragonu I, et al. Differential aquaporin 4 expression during edema build-up and resolution phases of brain inflammation. J Neuroinflammation 2011;8:143.PubMedCrossRefGoogle Scholar
  87. 87.
    Saadoun S, Papadopoulos MC, Watanabe H, et al. Involvement of aquaporin-4 in astroglial cell migration and glial scar formation. J Cell Sci 2005;118:5691-5698.PubMedCrossRefGoogle Scholar
  88. 88.
    Auguste KI, Jin S, Uchida K, et al. Greatly impaired migration of implanted aquaporin-4-deficient astroglial cells in mouse brain toward a site of injury. Faseb J 2007;21:108-116.PubMedCrossRefGoogle Scholar
  89. 89.
    Li L, Zhang H , Verkman AS. Greatly attenuated experimental autoimmune encephalomyelitis in aquaporin-4 knockout mice. BMC Neurosci 2009;10:94.PubMedCrossRefGoogle Scholar
  90. 90.
    Li L, Zhang H, Varrin-Doyer M, Zamvil SS, Verkman AS. Proinflammatory role of aquaporin-4 in autoimmune neuroinflammation. Faseb J 2011;25:1556-1566.PubMedCrossRefGoogle Scholar
  91. 91.
    Ratelade J, Verkman AS. Neuromyelitis optica: Aquaporin-4 based pathogenesis mechanisms and new therapies. Int J Biochem Cell Biol 2012;44:1519-30.Google Scholar
  92. 92.
    Shinohara RT, Goldsmith J, Mateen FJ, Crainiceanu C, Reich DS. Predicting breakdown of the blood-brain barrier in multiple sclerosis without contrast agents. AJNR Am J Neuroradiol 2012;33:1586-90.Google Scholar
  93. 93.
    Ropele S, Langkammer C, Enzinger C, Fuchs S, Fazekas F. Relaxation time mapping in multiple sclerosis. Expert Rev Neurother 2011;11:441-450.PubMedCrossRefGoogle Scholar
  94. 94.
    Laule C, Vavasour IM, Moore GR, et al. Water content and myelin water fraction in multiple sclerosis. A T2 relaxation study. J Neurol 2004;251:284-293.PubMedCrossRefGoogle Scholar
  95. 95.
    Vavasour IM, Laule C, Li DK, et al. Longitudinal changes in myelin water fraction in two MS patients with active disease. J Neurol Sci 2009;276:49-53.PubMedCrossRefGoogle Scholar
  96. 96.
    MacKay AL, Vavasour IM, Rauscher A, et al. MR relaxation in multiple sclerosis. Neuroimaging Clin N Am 2009;19:1-26.PubMedCrossRefGoogle Scholar
  97. 97.
    Le Bihan D. Looking into the functional architecture of the brain with diffusion MRI. Nat Rev Neurosci 2003;4:469-480.PubMedCrossRefGoogle Scholar
  98. 98.
    Tievsky AL, Ptak T, Farkas J. Investigation of apparent diffusion coefficient and diffusion tensor anisotrophy in acute and chronic multiple sclerosis lesions. AJNR Am J Neuroradiol 1999;20:1491-1499.PubMedGoogle Scholar
  99. 99.
    Le Bihan D. The "wet mind": water and functional neuroimaging. Phys Med Biol 2007;52:R57-R90.PubMedCrossRefGoogle Scholar
  100. 100.
    Balashov KE, Lindzen E. Acute demyelinating lesions with restricted diffusion in multiple sclerosis. Mult Scler 2012. doi:10.1177/1352458512445407
  101. 101.
    Lucchinetti C, Bruck W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000;47:707-717.PubMedCrossRefGoogle Scholar
  102. 102.
    Lassmann H. Hypoxia-like tissue injury as a component of multiple sclerosis lesions. J Neurol Sci 2003;206:187-191.PubMedCrossRefGoogle Scholar
  103. 103.
    Tourdias T, Hiba B, Raffard G, et al. Adapted focal experimental autoimmune encephalomyelitis to allow MRI exploration of multiple sclerosis features. Exp Neurol 2011;230:248-257.PubMedCrossRefGoogle Scholar
  104. 104.
    Papadopoulos MC, Verkman AS. Potential utility of aquaporin modulators for therapy of brain disorders. Prog Brain Res 2008;170:589-601.PubMedCrossRefGoogle Scholar
  105. 105.
    Tourdias T, Dragonu I, Fushimi Y, et al. Aquaporin 4 correlates with apparent diffusion coefficient and hydrocephalus severity in the rat brain: a combined MRI-histological study. Neuroimage 2009;47:659-666.PubMedCrossRefGoogle Scholar
  106. 106.
    Badaut J, Ashwal S, Adami A, et al. Brain water mobility decreases after astrocytic aquaporin-4 inhibition using RNA interference. J Cereb Blood Flow Metab 2011;31:819-31.Google Scholar
  107. 107.
    Rovira A, Swanton J, Tintore M, et al. A single, early magnetic resonance imaging study in the diagnosis of multiple sclerosis. Arch Neurol 2009;66:587-592.PubMedCrossRefGoogle Scholar
  108. 108.
    Kappos L, Freedman MS, Polman CH, et al. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet 2007; 370:389-397.PubMedCrossRefGoogle Scholar
  109. 109.
    Trojano M, Pellegrini F, Fuiani A, et al. New natural history of interferon-beta-treated relapsing multiple sclerosis. Ann Neurol 2007;61:300-306.PubMedCrossRefGoogle Scholar
  110. 110.
    Yong VW. Differential mechanisms of action of interferon-beta and glatiramer aetate in MS. Neurology 2002;59:802-808.PubMedCrossRefGoogle Scholar
  111. 111.
    Gaitan MI, Shea CD, Evangelou IE, et al. Evolution of the blood-brain barrier in newly forming multiple sclerosis lesions. Ann Neurol 2011;70:22-29.PubMedCrossRefGoogle Scholar
  112. 112.
    Wuerfel E, Infante-Duarte C, Glumm R, Wuerfel JT. Gadofluorine M-enhanced MRI shows involvement of circumventricular organs in neuroinflammation. J Neuroinflammation 2010;7:70.PubMedCrossRefGoogle Scholar
  113. 113.
    Compston A. Making progress on the natural history of multiple sclerosis. Brain 2006;129:561-563.PubMedCrossRefGoogle Scholar
  114. 114.
    Bonzano L, Roccatagliata L, Mancardi GL, Sormani MP. Gadolinium-enhancing or active T2 magnetic resonance imaging lesions in multiple sclerosis clinical trials? Mult Scler 2009;15:1043-1047.PubMedCrossRefGoogle Scholar
  115. 115.
    Smith JJ, Sorensen AG, Thrall JH. Biomarkers in imaging: realizing radiology's future. Radiology 2003;227:633-638.PubMedCrossRefGoogle Scholar
  116. 116.
    Sormani MP, Bonzano L, Roccatagliata L, et al. Magnetic resonance imaging as a potential surrogate for relapses in multiple sclerosis: a meta-analytic approach. Ann Neurol 2009;65:268-275.PubMedCrossRefGoogle Scholar
  117. 117.
    Sormani MP, Bonzano L, Roccatagliata L, et al. Surrogate endpoints for EDSS worsening in multiple sclerosis. A meta-analytic approach. Neurology 2010;75:302-309.PubMedCrossRefGoogle Scholar
  118. 118.
    Sormani MP, Filippi M, De Stefano N, Ebers G, Daumer M. MRI as an outcome in multiple sclerosis clinical trials. Neurology 2009;73:1932-1933.PubMedCrossRefGoogle Scholar
  119. 119.
    Daumer M, Neuhaus A, Morrissey S, Hintzen R , Ebers GC. MRI as an outcome in multiple sclerosis clinical trials. Neurology 2009;72:705-711.PubMedCrossRefGoogle Scholar
  120. 120.
    Held U, Heigenhauser L, Shang C, Kappos L, Polman C. Predictors of relapse rate in MS clinical trials. Neurology 2005;65:1769-1773.PubMedCrossRefGoogle Scholar
  121. 121.
    Deloire MS, Touil T, Brochet B, et al. Macrophage brain infiltration in experimental autoimmune encephalomyelitis is not completely compromised by suppressed T-cell invasion: in vivo magnetic resonance imaging illustration in effective anti-VLA-4 antibody treatment. Mult Scler 2004;10:540-548.PubMedCrossRefGoogle Scholar
  122. 122.
    Rausch M, Hiestand P, Foster CA, et al. Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: clinical implications for ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging. J Magn Reson Imaging 2004;20:16-24.PubMedCrossRefGoogle Scholar
  123. 123.
    Forghani R, Wojtkiewicz GR, Zhang Y, et al. Demyelinating diseases: myeloperoxidase as an imaging biomarker and therapeutic target. Radiology 2012;263:451-460.PubMedCrossRefGoogle Scholar
  124. 124.
    Wiendl H, Toyka KV, Rieckmann P, et al. Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations. J Neurol 2008;255:1449-1463.PubMedCrossRefGoogle Scholar
  125. 125.
    Ros PR, Freeny PC, Harms SE, et al. Hepatic MR imaging with ferumoxides: a multicenter clinical trial of the safety and efficacy in the detection of focal hepatic lesions. Radiology 1995;196:481-488.PubMedGoogle Scholar
  126. 126.
    Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 2003;348:2491-2499.PubMedCrossRefGoogle Scholar
  127. 127.
    Bernd H, De Kerviler E, Gaillard S, Bonnemain B. Safety and tolerability of ultrasmall superparamagnetic iron oxide contrast agent: comprehensive analysis of a clinical development program. Invest Radiol 2009;44:336-342.PubMedCrossRefGoogle Scholar
  128. 128.
    Hsiao JK, Chu HH, Wang YH, et al. Macrophage physiological function after superparamagnetic iron oxide labeling. NMR Biomed 2008;21:820-829.PubMedCrossRefGoogle Scholar
  129. 129.
    Schafer R, Ayturan M, Bantleon R, et al. The use of clinically approved small particles of iron oxide (SPIO) for labeling of mesenchymal stem cells aggravates clinical symptoms in experimental autoimmune encephalomyelitis and influences their in vivo distribution. Cell Transplant 2008;17:923-941.PubMedCrossRefGoogle Scholar
  130. 130.
    Levine SM, Chakrabarty A. The role of iron in the pathogenesis of experimental allergic encephalomyelitis and multiple sclerosis. Ann N Y Acad Sci 2004;1012:252-266.PubMedCrossRefGoogle Scholar
  131. 131.
    Riess JG. Perfluorocarbon-based oxygen delivery. Artif Cells Blood Substit Immobil Biotechnol 2006;34:567-580.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2012

Authors and Affiliations

  1. 1.INSERM Unit 1049 Neuroinflammation, Imagerie et Thérapie de la Sclérose en PlaquesUniversité de BordeauxBordeauxFrance
  2. 2.CHU de Bordeaux, Service de Neuroimagerie Diagnostique et ThérapeutiqueBordeauxFrance

Personalised recommendations