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Multiple Sclerosis International
Volume 2011 (2011), Article ID 606807, 6 pages
http://dx.doi.org/10.1155/2011/606807
Review Article

Iron and Neurodegeneration in Multiple Sclerosis

1Department of Neurology, Medical University of Graz, A-8036 Graz, Austria
2NUBIN, Department of Clinical Chemistry, VU University Medical Center, 1007MB Amsterdam, The Netherlands

Received 31 October 2010; Revised 26 December 2010; Accepted 2 January 2011

Academic Editor: Jeroen J. G. Geurts

Copyright © 2011 Michael Khalil et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. D. B. Kell, “Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson's, Huntington's, Alzheimer's, prions, bactericides, chemical toxicology and others as examples,” Archives of Toxicology, vol. 84, no. 11, pp. 825–889, 2010. View at Publisher · View at Google Scholar
  2. D. B. Kell, “Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases,” BMC Medical Genomics, vol. 2, article 2, 2009. View at Publisher · View at Google Scholar · View at Scopus
  3. L. Zecca, M. B. H. Youdim, P. Riederer, J. R. Connor, and R. R. Crichton, “Iron, brain ageing and neurodegenerative disorders,” Nature Reviews Neuroscience, vol. 5, no. 11, pp. 863–873, 2004. View at Publisher · View at Google Scholar · View at Scopus
  4. B. Hallgren and P. Sourander, “The effect of age on the non-haemin iron in the human brain,” Journal of Neurochemistry, vol. 3, pp. 41–51, 1958.
  5. J. Stankiewicz, S. S. Panter, M. Neema, A. Arora, C. E. Batt, and R. Bakshi, “Iron in chronic brain disorders: imaging and neurotherapeutic implications,” Neurotherapeutics, vol. 4, no. 3, pp. 371–386, 2007. View at Publisher · View at Google Scholar · View at Scopus
  6. B. Drayer, P. Burger, and B. Hurwitz, “Reduced signal intensity on MR images of thalamus and putamen in multiple sclerosis: increased iron content?” American Journal of Roentgenology, vol. 149, no. 2, pp. 357–363, 1987. View at Scopus
  7. J. Grimaud, J. Millar, J. W. Thorpe, I. F. Moseley, W. I. McDonald, and D. H. Miller, “Signal intensity on MRI of basal ganglia in multiple sclerosis,” Journal of Neurology Neurosurgery and Psychiatry, vol. 59, no. 3, pp. 306–308, 1995. View at Scopus
  8. R. Bakshi, R. H. B. Benedict, R. A. Bermel et al., “T2 hypointensity in the deep gray matter of patients with multiple sclerosis: a quantitative magnetic resonance imaging study,” Archives of Neurology, vol. 59, no. 1, pp. 62–68, 2002. View at Scopus
  9. R. Bakshi, Z. A. Shaikh, and V. Janardhan, “MRI T2 shortening ('black T2') in multiple sclerosis: frequency, location, and clinical correlation,” NeuroReport, vol. 11, no. 1, pp. 15–21, 2000. View at Scopus
  10. C. W. Tjoa, R. H. B. Benedict, B. Weinstock-Guttman, A. J. Fabiano, and R. Bakshi, “MRI T2 hypointensity of the dentate nucleus is related to ambulatory impairment in multiple sclerosis,” Journal of the Neurological Sciences, vol. 234, no. 1-2, pp. 17–24, 2005. View at Publisher · View at Google Scholar · View at Scopus
  11. Y. Zhang, R. K. Zabad, X. Wei, L. M. Metz, M. D. Hill, and J. R. Mitchell, “Deep grey matter "black T2" on 3 tesla magnetic resonance imaging correlates with disability in multiple sclerosis,” Multiple Sclerosis, vol. 13, no. 7, pp. 880–883, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. Y. Zhang, L. M. Metz, V. W. Yong, and J. R. Mitchell, “3 T deep gray matter T2 hypointensity correlates with disability over time in stable relapsing-remitting multiple sclerosis: a 3-year pilot study,” Journal of the Neurological Sciences, vol. 297, no. 1-2, pp. 76–81, 2010. View at Publisher · View at Google Scholar
  13. A. Ceccarelli, M. Filippi, M. Neema et al., “T2 hypointensity in the deep gray matter of patients with benign multiple sclerosis,” Multiple Sclerosis, vol. 15, no. 6, pp. 678–686, 2009. View at Publisher · View at Google Scholar · View at Scopus
  14. S. D. Brass, R. H. B. Benedict, B. Weinstock-Guttman, F. Munschauer, and R. Bakshi, “Cognitive impairment is associated with subcortical magnetic resonance imaging grey matter T2 hypointensity in multiple sclerosis,” Multiple Sclerosis, vol. 12, no. 4, pp. 437–444, 2006. View at Publisher · View at Google Scholar · View at Scopus
  15. M. Neema, A. Arora, B. C. Healy et al., “Deep gray matter involvement on brain MRI scans is associated with clinical progression in multiple sclerosis,” Journal of Neuroimaging, vol. 19, no. 1, pp. 3–8, 2009. View at Publisher · View at Google Scholar · View at Scopus
  16. R. A. Bermel, S. R. Puli, R. A. Rudick et al., “Prediction of longitudinal brain atrophy in multiple sclerosis by gray matter magnetic resonance imaging T2 hypointensity,” Archives of Neurology, vol. 62, no. 9, pp. 1371–1376, 2005. View at Publisher · View at Google Scholar · View at Scopus
  17. A. Ceccarelli, M. A. Rocca, M. Neema et al., “Deep gray matter T2 hypointensity is present in patients with clinically isolated syndromes suggestive of multiple sclerosis,” Multiple Sclerosis, vol. 16, no. 1, pp. 39–44, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. E. M. Haacke, N. Y. C. Cheng, M. J. House et al., “Imaging iron stores in the brain using magnetic resonance imaging,” Magnetic Resonance Imaging, vol. 23, no. 1, pp. 1–25, 2005. View at Publisher · View at Google Scholar · View at Scopus
  19. A. L. MacKay, I. M. Vavasour, A. Rauscher et al., “MR relaxation in multiple sclerosis,” Neuroimaging Clinics of North America, vol. 19, no. 1, pp. 1–26, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. M. Khalil, C. Enzinger, C. Langkammer et al., “Quantitative assessment of brain iron by R(2) relaxometry in patients with clinically isolated syndrome and relapsing-remitting multiple sclerosis,” Multiple Sclerosis, vol. 15, no. 9, pp. 1048–1054, 2009. View at Publisher · View at Google Scholar · View at Scopus
  21. R. J. Ogg, J. W. Langston, E. M. Haacke, R. G. Steen, and J. S. Taylor, “The correlation between phase shifts in gradient-echo MR images and regional brain iron concentration,” Magnetic Resonance Imaging, vol. 17, no. 8, pp. 1141–1148, 1999. View at Publisher · View at Google Scholar · View at Scopus
  22. K. E. Hammond, M. Metcalf, L. Carvajal et al., “Quantitative in vivo magnetic resonance imaging of multiple sclerosis at 7 Tesla with sensitivity to iron,” Annals of Neurology, vol. 64, no. 6, pp. 707–713, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. Y. Ge, J. H. Jensen, H. Lu et al., “Quantitative assessment of iron accumulation in the deep gray matter of multiple sclerosis by magnetic field correlation imaging,” American Journal of Neuroradiology, vol. 28, no. 9, pp. 1639–1644, 2007. View at Publisher · View at Google Scholar · View at Scopus
  24. S. A. Smith, J. W. M. Bulte, and P. C. M. Van Zijl, “Direct saturation MRI: theory and application to imaging brain iron,” Magnetic Resonance in Medicine, vol. 62, no. 2, pp. 384–393, 2009. View at Publisher · View at Google Scholar · View at Scopus
  25. E. M. Haacke, Y. Xu, Y. C. N. Cheng, and J. R. Reichenbach, “Susceptibility weighted imaging (SWI),” Magnetic Resonance in Medicine, vol. 52, no. 3, pp. 612–618, 2004. View at Publisher · View at Google Scholar · View at Scopus
  26. J. R. Reichenbach, M. Barth, E. M. Haacke, M. Klarhöfer, W. A. Kaiser, and E. Moser, “High-resolution MR venography at 3.0 Tesla,” Journal of Computer Assisted Tomography, vol. 24, no. 6, pp. 949–957, 2000. View at Publisher · View at Google Scholar · View at Scopus
  27. A. Deistung, A. Rauscher, J. Sedlacik, J. Stadler, S. Witoszynskyj, and J. R. Reichenbach, “Susceptibility weighted imaging at ultra high magnetic field strengths: theoretical considerations and experimental results,” Magnetic Resonance in Medicine, vol. 60, no. 5, pp. 1155–1168, 2008. View at Publisher · View at Google Scholar · View at Scopus
  28. L. De Rochefort, R. Brown, M. R. Prince, and YI. Wang, “Quantitative MR susceptibility mapping using piece-wise constant regularized inversion of the magnetic field,” Magnetic Resonance in Medicine, vol. 60, no. 4, pp. 1003–1009, 2008. View at Publisher · View at Google Scholar · View at Scopus
  29. F. Schweser, A. Deistung, B. W. Lehr, and J. R. Reichenbach, “Quantitative imaging of intrinsic magnetic tissue properties using MRI signal phase: an approach to in vivo brain iron metabolism?” NeuroImage, vol. 54, no. 4, pp. 2789–2807, 2011. View at Publisher · View at Google Scholar
  30. J. F. Schenck, “The role of magnetic susceptibility in magnetic resonance imaging: MRI magnetic compatibility of the first and second kinds,” Medical Physics, vol. 23, no. 6, pp. 815–850, 1996. View at Publisher · View at Google Scholar · View at Scopus
  31. D. Aquino, A. Bizzi, M. Grisoli et al., “Age-related iron deposition in the basal ganglia: quantitative analysis in healthy subjects,” Radiology, vol. 252, no. 1, pp. 165–172, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. K. Hopp, B. F. GH. Popescu, R. P. E. McCrea et al., “Brain iron detected by SWI high pass filtered phase calibrated with synchrotron X-ray fluorescence,” Journal of Magnetic Resonance Imaging, vol. 31, no. 6, pp. 1346–1354, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. C. Langkammer, N. Krebs, W. Goessler et al., “Quantitative MR imaging of brain iron: a postmortem validation study,” Radiology, vol. 257, no. 2, pp. 455–462, 2010. View at Publisher · View at Google Scholar
  34. R. Bakshi, J. Dmochowski, Z. A. Shaikh, and L. Jacobs, “Gray matter T2 hypointensity is related to plaques and atrophy in the brains of multiple sclerosis patients,” Journal of the Neurological Sciences, vol. 185, no. 1, pp. 19–26, 2001. View at Publisher · View at Google Scholar · View at Scopus
  35. V. Janardhan, S. Suri, and R. Bakshi, “Multiple sclerosis: hyperintense lesions in the brain on nonenhanced T1 -weighted MR images evidenced as areas of T1 shortening,” Radiology, vol. 244, no. 3, pp. 823–831, 2007. View at Publisher · View at Google Scholar · View at Scopus
  36. E. M. Haacke, M. Makki, Y. Ge et al., “Characterizing iron deposition in multiple sclerosis lesions using susceptibility weighted imaging,” Journal of Magnetic Resonance Imaging, vol. 29, no. 3, pp. 537–544, 2009. View at Publisher · View at Google Scholar · View at Scopus
  37. M. Fukunaga, T. Q. Li, P. Van Gelderen et al., “Layer-specific variation of iron content in cerebral cortex as a source of MRI contrast,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 8, pp. 3834–3839, 2010. View at Publisher · View at Google Scholar · View at Scopus
  38. P. Zamboni, R. Galeotti, E. Menegatti et al., “Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 80, no. 4, pp. 392–399, 2009. View at Publisher · View at Google Scholar · View at Scopus
  39. E. M. Haacke, J. Garbern, Y. Miao, C. Habib, and M. Liu, “Iron stores and cerebral veins in MS studied by susceptibility weighted imaging,” International Angiology, vol. 29, no. 2, pp. 149–157, 2010. View at Scopus
  40. R. Zivadinov, C. Schirda, M. G. Dwyer et al., “Chronic cerebrospinal venous insufficiency and iron deposition on susceptibility-weighted imaging in patients with multiple sclerosis: a pilot case-control study,” International Angiology, vol. 29, no. 2, pp. 158–175, 2010. View at Scopus
  41. P. Zamboni, “The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis,” Journal of the Royal Society of Medicine, vol. 99, no. 11, pp. 589–593, 2006. View at Scopus
  42. A. V. Singh and P. Zamboni, “Anomalous venous blood flow and iron deposition in multiple sclerosis,” Journal of Cerebral Blood Flow and Metabolism, vol. 29, no. 12, pp. 1867–1878, 2009. View at Publisher · View at Google Scholar · View at Scopus
  43. O. Khan, M. Filippi, M. S. Freedman et al., “Chronic cerebrospinal venous insufficiency and multiple sclerosis,” Annals of Neurology, vol. 67, no. 3, pp. 286–290, 2010. View at Publisher · View at Google Scholar · View at Scopus
  44. M. P. Wattjes, B. W. van Oosten, W. L. de Graaf et al., “No association of abnormal cranial venous drainage with multiple sclerosis: a magnetic resonance venography and flow-quantification study,” Journal of Neurology, Neurosurgery and Psychiatry, 2010. Epub ahead of print. View at Publisher · View at Google Scholar
  45. F. Doepp, F. Paul, J. M. Valdueza, K. Schmierer, and S. J. Schreiber, “No cerebrocervical venous congestion in patients with multiple sclerosis,” Annals of Neurology, vol. 68, no. 2, pp. 173–183, 2010. View at Publisher · View at Google Scholar
  46. V. Worthington, J. Killestein, M. J. Eikelenboom et al., “Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency,” Neurology, vol. 75, no. 18, pp. 1617–1622, 2010. View at Publisher · View at Google Scholar
  47. P. Sundström, A. Wåhlin, K. Ambarki, R. Birgander, A. Eklund, and J. Malm, “Venous and cerebrospinal fluid flow in multiple sclerosis: a case-control study,” Annals of Neurology, vol. 68, no. 2, pp. 255–259, 2010. View at Publisher · View at Google Scholar
  48. A. P. D. Henderson, M. H. Barnett, J. D. E. Parratt, and J. W. Prineas, “Multiple sclerosis: distribution of inflammatory cells in newly forming lesions,” Annals of Neurology, vol. 66, no. 6, pp. 739–753, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. B. D. Trapp, J. Peterson, R. M. Ransohoff, R. Rudick, S. Mörk, and L. Bö, “Axonal transection in the lesions of multiple sclerosis,” New England Journal of Medicine, vol. 338, no. 5, pp. 278–285, 1998. View at Publisher · View at Google Scholar · View at Scopus
  50. E. C. Tallantyre, L. Bø, O. Al-Rawashdeh et al., “Greater loss of axons in primary progressive multiple sclerosis plaques compared to secondary progressive disease,” Brain, vol. 132, no. 5, pp. 1190–1199, 2009. View at Publisher · View at Google Scholar · View at Scopus
  51. J. M. Frischer, S. Bramow, A. Dal-Bianco et al., “The relation between inflammation and neurodegeneration in multiple sclerosis brains,” Brain, vol. 132, no. 5, pp. 1175–1189, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. L. Bø, C. A. Vedeler, H. Nyland, B. D. Trapp, and S. J. Mørk, “Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration,” Multiple Sclerosis, vol. 9, no. 4, pp. 323–331, 2003. View at Publisher · View at Google Scholar · View at Scopus
  53. T. Moos, “Brain iron homeostasis,” Danish Medical Bulletin, vol. 49, pp. 279–301, 2002.
  54. J. R. Connor, S. L. Menzies, S. M. ST. Martin, and E. J. Mufson, “Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains,” Journal of Neuroscience Research, vol. 27, no. 4, pp. 595–611, 1990. View at Publisher · View at Google Scholar · View at Scopus
  55. W. Craelius, M. W. Migdal, C. P. Luessenhop, A. Sugar, and I. Mihalakis, “Iron deposits surrounding multiple sclerosis plaques,” Archives of Pathology and Laboratory Medicine, vol. 106, no. 8, pp. 397–399, 1982. View at Scopus
  56. S. M. Levine, “Iron deposits in multiple sclerosis and Alzheimer's disease brains,” Brain Research, vol. 760, no. 1-2, pp. 298–303, 1997. View at Publisher · View at Google Scholar · View at Scopus
  57. A. Petzold, M. J. Eikelenboom, D. Gveric et al., “Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations,” Brain, vol. 125, no. 7, pp. 1462–1473, 2002. View at Scopus
  58. K. Mehindate, D. J. Sahlas, D. Frankel et al., “Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis,” Journal of Neurochemistry, vol. 77, no. 5, pp. 1386–1395, 2001. View at Publisher · View at Google Scholar · View at Scopus
  59. T. Moos, T. R. Nielsen, T. Skjørringe, and E. H. Morgan, “Iron trafficking inside the brain,” Journal of Neurochemistry, vol. 103, no. 5, pp. 1730–1740, 2007. View at Publisher · View at Google Scholar · View at Scopus
  60. YA. Ke and Z. M. Qian, “Brain iron metabolism: neurobiology and neurochemistry,” Progress in Neurobiology, vol. 83, no. 3, pp. 149–173, 2007. View at Publisher · View at Google Scholar · View at Scopus
  61. S. A. Schneider, J. Hardy, and K. P. Bhatia, “Iron accumulation in syndromes of neurodegeneration with brain iron accumulation 1 and 2: causative or consequential?” Journal of Neurology, Neurosurgery and Psychiatry, vol. 80, no. 6, pp. 589–590, 2009. View at Publisher · View at Google Scholar · View at Scopus
  62. B. Halliwell, “Oxidative stress and neurodegeneration: where are we now?” Journal of Neurochemistry, vol. 97, no. 6, pp. 1634–1658, 2006. View at Publisher · View at Google Scholar · View at Scopus
  63. J. M. C. Gutteridge, “Iron and oxygen radicals in brain,” Annals of Neurology, vol. 32, pp. S16–S21, 1992. View at Scopus
  64. G. A. Salvador, “Iron in neuronal function and dysfunction,” BioFactors, vol. 36, no. 2, pp. 103–110, 2010. View at Publisher · View at Google Scholar · View at Scopus
  65. S. M. LeVine, S. G. Lynch, C. N. Ou, M. J. Wulser, E. Tam, and N. Boo, “Ferritin, transferrin and iron concentrations in the cerebrospinal fluid of multiple sclerosis patients,” Brain Research, vol. 821, no. 2, pp. 511–515, 1999. View at Publisher · View at Google Scholar · View at Scopus
  66. E. T. Lim, D. Grant, M. Pashenkov et al., “Cerebrospinal fluid levels of brain specific proteins in optic neuritis,” Multiple Sclerosis, vol. 10, no. 3, pp. 261–265, 2004. View at Publisher · View at Google Scholar · View at Scopus
  67. K. Rejdak, A. Petzold, Z. Stelmasiak, and G. Giovannoni, “Cerebrospinal fluid brain specific proteins in relation to nitric oxide metabolites during relapse of multiple sclerosis,” Multiple Sclerosis, vol. 14, no. 1, pp. 59–66, 2008. View at Publisher · View at Google Scholar · View at Scopus
  68. C. Sfagos, A. C. Makis, A. Chaidos et al., “Serum ferritin, transferrin and soluble transferrin receptor levels in multiple sclerosis patients,” Multiple Sclerosis, vol. 11, no. 3, pp. 272–275, 2005. View at Publisher · View at Google Scholar · View at Scopus
  69. N. Abo-Krysha and L. Rashed, “The role of iron dysregulation in the pathogenesis of multiple sclerosis: an Egyptian study,” Multiple Sclerosis, vol. 14, no. 5, pp. 602–608, 2008. View at Publisher · View at Google Scholar · View at Scopus
  70. R. Van Toorn, J. F. Schoeman, R. Solomons, M. A. Rensburg, and S. J. Van Rensburg, “Iron status in children with recurrent episodes of tumefactive cerebral demyelination,” Journal of Child Neurology, vol. 25, no. 11, pp. 1401–1407, 2010. View at Publisher · View at Google Scholar
  71. D. R. Richardson, “Novel chelators for central nervous system disorders that involve alterations in the metabolism of iron and other metal ions,” Annals of the New York Academy of Sciences, vol. 1012, pp. 326–341, 2004. View at Publisher · View at Google Scholar · View at Scopus
  72. S. M. LeVine and A. Chakrabarty, “The role of iron in the pathogenesis of experimental allergic encephalomyelitis and multiple sclerosis,” Annals of the New York Academy of Sciences, vol. 1012, pp. 252–266, 2004. View at Publisher · View at Google Scholar · View at Scopus
  73. M. Whitnall and D. R. Richardson, “Iron: a new target for pharmacological intervention in neurodegenerative diseases,” Seminars in Pediatric Neurology, vol. 13, no. 3, pp. 186–197, 2006. View at Publisher · View at Google Scholar · View at Scopus
  74. T. V. Pedchenko and S. M. Levine, “Desferrioxamine suppresses experimental allergic encephalomyelitis induced by MBP in SJL mice,” Journal of Neuroimmunology, vol. 84, no. 2, pp. 188–197, 1998. View at Publisher · View at Google Scholar · View at Scopus
  75. K. M. Mitchell, A. L. Dotson, K. M. Cool, A. Chakrabarty, S. H. Benedict, and S. M. LeVine, “Deferiprone, an orally deliverable iron chelator, ameliorates experimental autoimmune encephalomyelitis,” Multiple Sclerosis, vol. 13, no. 9, pp. 1118–1126, 2007. View at Publisher · View at Google Scholar · View at Scopus
  76. S. G. Lynch, T. Fonseca, and S. M. Levine, “A multiple course trial of desferrioxamine in chronic progressive multiple sclerosis,” Cellular and Molecular Biology, vol. 46, no. 4, pp. 865–869, 2000. View at Scopus