CNS Drugs

, Volume 33, Issue 11, pp 1073–1086 | Cite as

Targeting Iron Dyshomeostasis for Treatment of Neurodegenerative Disorders

  • Niels BergslandEmail author
  • Eleonora Tavazzi
  • Ferdinand Schweser
  • Dejan Jakimovski
  • Jesper Hagemeier
  • Michael G. Dwyer
  • Robert Zivadinov
Leading Article


While iron has an important role in the normal functioning of the brain owing to its involvement in several physiological processes, dyshomeostasis has been found in many neurodegenerative disorders, as evidenced by both histopathological and imaging studies. Although the exact causes have remained elusive, the fact that altered iron levels have been found in disparate diseases suggests that iron may contribute to their development and/or progression. As such, the processes involved in iron dyshomeostasis may represent novel therapeutic targets. There are, however, many questions about the exact interplay between neurodegeneration and altered iron homeostasis. Some insight can be gained by considering the parallels with respect to what occurs in healthy aging, which is also characterized by increased iron throughout many regions in the brain along with progressive neurodegeneration. Nevertheless, the exact mechanisms of iron-mediated damage are likely disease specific to a certain degree, given that iron plays a crucial role in many disparate biological processes, which are not always affected in the same way across different neurodegenerative disorders. Moreover, it is not even entirely clear yet whether iron actually has a causative role in all of the diseases where altered iron levels have been noted. For example, there is strong evidence of iron dyshomeostasis leading to neurodegeneration in Parkinson’s disease, but there is still some question as to whether changes in iron levels are merely an epiphenomenon in multiple sclerosis. Recent advances in neuroimaging now offer the possibility to detect and monitor iron levels in vivo, which allows for an improved understanding of both the temporal and spatial dynamics of iron changes and associated neurodegeneration compared to post-mortem studies. In this regard, iron-based imaging will likely play an important role in the development of therapeutic approaches aimed at addressing altered iron dynamics in neurodegenerative diseases. Currently, the bulk of such therapies have focused on chelating excess iron. Although there is some evidence that these treatment options may yield some benefit, they are not without their own limitations. They are generally effective at reducing brain iron levels, as assessed by imaging, but clinical benefits are more modest. New drugs that specifically target iron-related pathological processes may offer the possibility to prevent, or at the least, slow down irreversible neurodegeneration, which represents an unmet therapeutic target.


Compliance with Ethical Standards


This work was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health, under award Number UL1TR001412. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of interest

Niels Bergsland, Eleonora Tavazzi, Dejan Jakimovski, and Jesper Hagemeier have no conflicts of interest that are directly relevant to the content of this article. Ferdinand Schweser has received personal compensation from Toshiba Canada Medical Systems Limited, Canon Medical Systems Corporation Japan, and Goodwin Procter LLP for speaking and consultant fees. He received financial support for research activities from SynchroPET Inc. and travel sponsorship from GE Healthcare and SynchroPET Inc. Michael G. Dwyer has received consultant fees from Claret Medical and research grant support from Novartis. Robert Zivadinov has received personal compensation from EMD Serono, Genzyme-Sanofi, Novartis, and Celgene for speaking and consultant fees. He received financial support for research activities from Genzyme-Sanofi, Celgene, Novartis, Mapi Pharma, V-WAVE Medical, and Protembis.


  1. 1.
    Masaldan S, Bush AI, Devos D, Rolland AS, Moreau C. Striking while the iron is hot: iron metabolism and ferroptosis in neurodegeneration. Free Radic Biol Med. 2019;133:221–33. Scholar
  2. 2.
    Nnah IC, Wessling-Resnick M. Brain iron homeostasis: a focus on microglial iron. Pharmaceuticals (Basel). 2018;11(4):E129. Scholar
  3. 3.
    Hagemeier J, Geurts JJ, Zivadinov R. Brain iron accumulation in aging and neurodegenerative disorders. Expert Rev Neurother. 2012;12(12):1467–80. Scholar
  4. 4.
    Atamna H, Frey WH 2nd. A role for heme in Alzheimer’s disease: heme binds amyloid beta and has altered metabolism. Proc Natl Acad Sci USA. 2004;101(30):11153–8. Scholar
  5. 5.
    Zucca FA, Segura-Aguilar J, Ferrari E, Munoz P, Paris I, Sulzer D, et al. Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson’s disease. Prog Neurobiol. 2017;155:96–119. Scholar
  6. 6.
    Zivadinov R, Heininen-Brown M, Schirda CV, Poloni GU, Bergsland N, Magnano CR, et al. Abnormal subcortical deep-gray matter susceptibility-weighted imaging filtered phase measurements in patients with multiple sclerosis: a case–control study. Neuroimage. 2012;59(1):331–9. Scholar
  7. 7.
    Levi S, Tiranti V. Neurodegeneration with brain iron accumulation disorders: valuable models aimed at understanding the pathogenesis of iron deposition. Pharmaceuticals (Basel). 2019;12(1):E27. Scholar
  8. 8.
    Haacke EM, Liu S, Buch S, Zheng W, Wu D, Ye Y. Quantitative susceptibility mapping: current status and future directions. Magn Reson Imaging. 2015;33(1):1–25. Scholar
  9. 9.
    Schweser F, Deistung A, Lehr BW, Reichenbach JR. Quantitative imaging of intrinsic magnetic tissue properties using MRI signal phase: an approach to in vivo brain iron metabolism? Neuroimage. 2011;54(4):2789–807. Scholar
  10. 10.
    Wang Y, Spincemaille P, Liu Z, Dimov A, Deh K, Li J, et al. Clinical quantitative susceptibility mapping (QSM): Biometal imaging and its emerging roles in patient care. J Magn Reson Imaging. 2017;46(4):951–71. Scholar
  11. 11.
    Du G, Lewis MM, Sica C, He L, Connor JR, Kong L, et al. Distinct progression pattern of susceptibility MRI in the substantia nigra of Parkinson’s patients. Mov Disord. 2018;33(9):1423–31. Scholar
  12. 12.
    Zivadinov R, Tavazzi E, Bergsland N, Hagemeier J, Lin F, Dwyer MG, et al. Brain iron at quantitative MRI is associated with disability in multiple sclerosis. Radiology. 2018;289(2):487–96. Scholar
  13. 13.
    Ayton S, Wang Y, Diouf I, Schneider JA, Brockman J, Morris MC, et al. Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology. Mol Psychiatry. 2019. Scholar
  14. 14.
    Nunez MT, Chana-Cuevas P. New perspectives in iron chelation therapy for the treatment of neurodegenerative diseases. Pharmaceuticals (Basel). 2018;11(4):E109. Scholar
  15. 15.
    Dusek P, Schneider SA, Aaseth J. Iron chelation in the treatment of neurodegenerative diseases. J Trace Elem Med Biol. 2016;38:81–92. Scholar
  16. 16.
    Lobel U, Schweser F, Nickel M, Deistung A, Grosse R, Hagel C, et al. Brain iron quantification by MRI in mitochondrial membrane protein-associated neurodegeneration under iron-chelating therapy. Ann Clin Transl Neurol. 2014;1(12):1041–6. Scholar
  17. 17.
    Leitner DF, Connor JR. Functional roles of transferrin in the brain. Biochim Biophys Acta. 2012;1820(3):393–402. Scholar
  18. 18.
    Chiou B, Neal EH, Bowman AB, Lippmann ES, Simpson IA, Connor JR. Endothelial cells are critical regulators of iron transport in a model of the human blood-brain barrier. J Cereb Blood Flow Metab. 2018. Scholar
  19. 19.
    Chiou B, Connor JR. Emerging and dynamic biomedical uses of ferritin. Pharmaceuticals (Basel). 2018;11(4):E124. Scholar
  20. 20.
    Singh N, Haldar S, Tripathi AK, Horback K, Wong J, Sharma D, et al. Brain iron homeostasis: from molecular mechanisms to clinical significance and therapeutic opportunities. Antioxid Redox Signal. 2014;20(8):1324–63. Scholar
  21. 21.
    Lane DJ, Merlot AM, Huang ML, Bae DH, Jansson PJ, Sahni S, et al. Cellular iron uptake, trafficking and metabolism: key molecules and mechanisms and their roles in disease. Biochim Biophys Acta. 2015;1853(5):1130–44. Scholar
  22. 22.
    Carocci A, Catalano A, Sinicropi MS, Genchi G. Oxidative stress and neurodegeneration: the involvement of iron. Biometals. 2018;31(5):715–35. Scholar
  23. 23.
    Horowitz MP, Greenamyre JT. Mitochondrial iron metabolism and its role in neurodegeneration. J Alzheimers Dis. 2010;20(Suppl. 2):S551–68. Scholar
  24. 24.
    Zhang C. Essential functions of iron-requiring proteins in DNA replication, repair and cell cycle control. Protein Cell. 2014;5(10):750–60. Scholar
  25. 25.
    Reinert A, Morawski M, Seeger J, Arendt T, Reinert T. Iron concentrations in neurons and glial cells with estimates on ferritin concentrations. BMC Neurosci. 2019;20(1):25. Scholar
  26. 26.
    Ndayisaba A, Kaindlstorfer C, Wenning GK. Iron in neurodegeneration: cause or consequence? Front Neurosci. 2019;13:180. Scholar
  27. 27.
    Farrall AJ, Wardlaw JM. Blood-brain barrier: ageing and microvascular disease: systematic review and meta-analysis. Neurobiol Aging. 2009;30(3):337–52. Scholar
  28. 28.
    Lopes Pinheiro MA, Kooij G, Mizee MR, Kamermans A, Enzmann G, Lyck R, et al. Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke. Biochim Biophys Acta. 2016;1862(3):461–71. Scholar
  29. 29.
    Conde JR, Streit WJ. Microglia in the aging brain. J Neuropathol Exp Neurol. 2006;65(3):199–203. Scholar
  30. 30.
    Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 2014;13(10):1045–60. Scholar
  31. 31.
    Sfera A, Bullock K, Price A, Inderias L, Osorio C. Ferrosenescence: the iron age of neurodegeneration? Mech Ageing Dev. 2018;174:63–75. Scholar
  32. 32.
    Vanni S, Colini Baldeschi A, Zattoni M, Legname G. Brain aging: a Ianus-faced player between health and neurodegeneration. J Neurosci Res. 2019. Scholar
  33. 33.
    Gozzelino R. The pathophysiology of heme in the brain. Curr Alzheimer Res. 2016;13(2):174–84.CrossRefGoogle Scholar
  34. 34.
    Hallgren B, Sourander P. The effect of age on the non-haemin iron in the human brain. J Neurochem. 1958;3(1):41–51.CrossRefGoogle Scholar
  35. 35.
    Bartzokis G, Beckson M, Hance DB, Marx P, Foster JA, Marder SR. MR evaluation of age-related increase of brain iron in young adult and older normal males. Magn Reson Imaging. 1997;15(1):29–35.CrossRefGoogle Scholar
  36. 36.
    Connor JR, Menzies SL, St Martin SM, Mufson EJ. Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains. J Neurosci Res. 1990;27(4):595–611. Scholar
  37. 37.
    Zecca L, Stroppolo A, Gatti A, Tampellini D, Toscani M, Gallorini M, et al. The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. Proc Natl Acad Sci USA. 2004;101(26):9843–8. Scholar
  38. 38.
    Wyss-Coray T. Ageing, neurodegeneration and brain rejuvenation. Nature. 2016;539(7628):180–6. Scholar
  39. 39.
    Elobeid A, Libard S, Leino M, Popova SN, Alafuzoff I. Altered proteins in the aging brain. J Neuropathol Exp Neurol. 2016;75(4):316–25. Scholar
  40. 40.
    Bresgen N, Eckl PM. Oxidative stress and the homeodynamics of iron metabolism. Biomolecules. 2015;5(2):808–47. Scholar
  41. 41.
    Sindrilaru A, Peters T, Wieschalka S, Baican C, Baican A, Peter H, et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Investig. 2011;121(3):985–97. Scholar
  42. 42.
    Everett J, Cespedes E, Shelford LR, Exley C, Collingwood JF, Dobson J, et al. Ferrous iron formation following the co-aggregation of ferric iron and the Alzheimer’s disease peptide beta-amyloid (1–42). J R Soc Interface. 2014;11(95):20140165. Scholar
  43. 43.
    Yamamoto A, Shin RW, Hasegawa K, Naiki H, Sato H, Yoshimasu F, et al. Iron (III) induces aggregation of hyperphosphorylated tau and its reduction to iron (II) reverses the aggregation: implications in the formation of neurofibrillary tangles of Alzheimer’s disease. J Neurochem. 2002;82(5):1137–47. Scholar
  44. 44.
    Sofic E, Riederer P, Heinsen H, Beckmann H, Reynolds GP, Hebenstreit G, et al. Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm. 1988;74(3):199–205.CrossRefGoogle Scholar
  45. 45.
    Connor JR, Menzies SL, St Martin SM, Mufson EJ. A histochemical study of iron, transferrin, and ferritin in Alzheimer’s diseased brains. J Neurosci Res. 1992;31(1):75–83. Scholar
  46. 46.
    Jellinger K, Paulus W, Grundke-Iqbal I, Riederer P, Youdim MB. Brain iron and ferritin in Parkinson’s and Alzheimer’s diseases. J Neural Transm Park Dis Dement Sect. 1990;2(4):327–40.CrossRefGoogle Scholar
  47. 47.
    Hentze MW, Caughman SW, Rouault TA, Barriocanal JG, Dancis A, Harford JB, et al. Identification of the iron-responsive element for the translational regulation of human ferritin mRNA. Science. 1987;238(4833):1570–3.CrossRefGoogle Scholar
  48. 48.
    Lane CA, Hardy J, Schott JM. Alzheimer’s disease. Eur J Neurol. 2018;25(1):59–70. Scholar
  49. 49.
    Calderon-Garciduenas AL, Duyckaerts C. Alzheimer disease. Handb Clin Neurol. 2017;145:325–37. Scholar
  50. 50.
    Bjorklund G, Aaseth J, Dadar M, Chirumbolo S. Molecular targets in Alzheimer’s disease. Mol Neurobiol. 2019. Scholar
  51. 51.
    McCarthy RC, Park YH, Kosman DJ. sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin. EMBO Rep. 2014;15(7):809–15. Scholar
  52. 52.
    Belaidi AA, Gunn AP, Wong BX, Ayton S, Appukuttan AT, Roberts BR, et al. Marked age-related changes in brain iron homeostasis in amyloid protein precursor knockout mice. Neurotherapeutics. 2018;15(4):1055–62. Scholar
  53. 53.
    Chuang JY, Lee CW, Shih YH, Yang T, Yu L, Kuo YM. Interactions between amyloid-beta and hemoglobin: implications for amyloid plaque formation in Alzheimer’s disease. PLoS One. 2012;7(3):e33120. Scholar
  54. 54.
    Wu CW, Liao PC, Yu L, Wang ST, Chen ST, Wu CM, et al. Hemoglobin promotes Abeta oligomer formation and localizes in neurons and amyloid deposits. Neurobiol Dis. 2004;17(3):367–77. Scholar
  55. 55.
    de la Torre JC. Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol. 2004;3(3):184–90. Scholar
  56. 56.
    Peters DG, Connor JR, Meadowcroft MD. The relationship between iron dyshomeostasis and amyloidogenesis in Alzheimer’s disease: two sides of the same coin. Neurobiol Dis. 2015;81:49–65. Scholar
  57. 57.
    Hallgren B, Sourander P. The non-haemin iron in the cerebral cortex in Alzheimer’s disease. J Neurochem. 1960;5:307–10.CrossRefGoogle Scholar
  58. 58.
    Ayton S, Fazlollahi A, Bourgeat P, Raniga P, Ng A, Lim YY, et al. Cerebral quantitative susceptibility mapping predicts amyloid-beta-related cognitive decline. Brain. 2017;140(8):2112–9. Scholar
  59. 59.
    Ding B, Chen KM, Ling HW, Sun F, Li X, Wan T, et al. Correlation of iron in the hippocampus with MMSE in patients with Alzheimer’s disease. J Magn Reson Imaging. 2009;29(4):793–8. Scholar
  60. 60.
    Kozlov S, Afonin A, Evsyukov I, Bondarenko A. Alzheimer’s disease: as it was in the beginning. Rev Neurosci. 2017;28(8):825–43. Scholar
  61. 61.
    Kaur D, Peng J, Chinta SJ, Rajagopalan S, Di Monte DA, Cherny RA, et al. Increased murine neonatal iron intake results in Parkinson-like neurodegeneration with age. Neurobiol Aging. 2007;28(6):907–13. Scholar
  62. 62.
    Kaur D, Yantiri F, Rajagopalan S, Kumar J, Mo JQ, Boonplueang R, et al. Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson’s disease. Neuron. 2003;37(6):899–909.CrossRefGoogle Scholar
  63. 63.
    Bjorklund G, Hofer T, Nurchi VM, Aaseth J. Iron and other metals in the pathogenesis of Parkinson’s disease: toxic effects and possible detoxification. J Inorg Biochem. 2019;199:110717. Scholar
  64. 64.
    Dusek P, Roos PM, Litwin T, Schneider SA, Flaten TP, Aaseth J. The neurotoxicity of iron, copper and manganese in Parkinson’s and Wilson’s diseases. J Trace Elem Med Biol. 2015;31:193–203. Scholar
  65. 65.
    Dexter DT, Wells FR, Agid F, Agid Y, Lees AJ, Jenner P, et al. Increased nigral iron content in postmortem parkinsonian brain. Lancet. 1987;2(8569):1219–20.CrossRefGoogle Scholar
  66. 66.
    Acosta-Cabronero J, Cardenas-Blanco A, Betts MJ, Butryn M, Valdes-Herrera JP, Galazky I, et al. The whole-brain pattern of magnetic susceptibility perturbations in Parkinson’s disease. Brain. 2017;140(1):118–31. Scholar
  67. 67.
    Gorell JM, Ordidge RJ, Brown GG, Deniau JC, Buderer NM, Helpern JA. Increased iron-related MRI contrast in the substantia nigra in Parkinson’s disease. Neurology. 1995;45(6):1138–43.CrossRefGoogle Scholar
  68. 68.
    Bartzokis G, Cummings JL, Markham CH, Marmarelis PZ, Treciokas LJ, Tishler TA, et al. MRI evaluation of brain iron in earlier- and later-onset Parkinson’s disease and normal subjects. Magn Reson Imaging. 1999;17(2):213–22.CrossRefGoogle Scholar
  69. 69.
    Becker G, Berg D. Neuroimaging in basal ganglia disorders: perspectives for transcranial ultrasound. Mov Disord. 2001;16(1):23–32.CrossRefGoogle Scholar
  70. 70.
    Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res. 2004;318(1):121–34. Scholar
  71. 71.
    Moreau C, Duce JA, Rascol O, Devedjian JC, Berg D, Dexter D, et al. Iron as a therapeutic target for Parkinson’s disease. Mov Disord. 2018;33(4):568–74. Scholar
  72. 72.
    Hare DJ, Double KL. Iron and dopamine: a toxic couple. Brain. 2016;139(Pt 4):1026–35. Scholar
  73. 73.
    Zucca FA, Bellei C, Giannelli S, Terreni MR, Gallorini M, Rizzio E, et al. Neuromelanin and iron in human locus coeruleus and substantia nigra during aging: consequences for neuronal vulnerability. J Neural Transm (Vienna). 2006;113(6):757–67. Scholar
  74. 74.
    Duce JA, Wong BX, Durham H, Devedjian JC, Smith DP, Devos D. Post translational changes to alpha-synuclein control iron and dopamine trafficking; a concept for neuron vulnerability in Parkinson’s disease. Mol Neurodegener. 2017;12(1):45. Scholar
  75. 75.
    Chau KY, Ching HL, Schapira AH, Cooper JM. Relationship between alpha synuclein phosphorylation, proteasomal inhibition and cell death: relevance to Parkinson’s disease pathogenesis. J Neurochem. 2009;110(3):1005–13. Scholar
  76. 76.
    Li WJ, Jiang H, Song N, Xie JX. Dose- and time-dependent alpha-synuclein aggregation induced by ferric iron in SK-N-SH cells. Neurosci Bull. 2010;26(3):205–10.CrossRefGoogle Scholar
  77. 77.
    Stuber C, Pitt D, Wang Y. Iron in multiple sclerosis and its noninvasive imaging with quantitative susceptibility mapping. Int J Mol Sci. 2016;17(1):E100. Scholar
  78. 78.
    Mehta V, Pei W, Yang G, Li S, Swamy E, Boster A, et al. Iron is a sensitive biomarker for inflammation in multiple sclerosis lesions. PLoS One. 2013;8(3):e57573. Scholar
  79. 79.
    Chen W, Gauthier SA, Gupta A, Comunale J, Liu T, Wang S, et al. Quantitative susceptibility mapping of multiple sclerosis lesions at various ages. Radiology. 2014;271(1):183–92. Scholar
  80. 80.
    Hametner S, Wimmer I, Haider L, Pfeifenbring S, Bruck W, Lassmann H. Iron and neurodegeneration in the multiple sclerosis brain. Ann Neurol. 2013;74(6):848–61. Scholar
  81. 81.
    Popescu BF, Frischer JM, Webb SM, Tham M, Adiele RC, Robinson CA, et al. Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions. Acta Neuropathol. 2017;134(1):45–64. Scholar
  82. 82.
    Moller HE, Bossoni L, Connor JR, Crichton RR, Does MD, Ward RJ, et al. Iron, myelin, and the brain: neuroimaging meets neurobiology. Trends Neurosci. 2019;42(6):384–401. Scholar
  83. 83.
    Peferoen L, Kipp M, van der Valk P, van Noort JM, Amor S. Oligodendrocyte-microglia cross-talk in the central nervous system. Immunology. 2014;141(3):302–13. Scholar
  84. 84.
    Bergsland N, Agostini S, Lagana MM, Mancuso R, Mendozzi L, Tavazzi E, et al. Serum iron concentration is associated with subcortical deep gray matter iron levels in multiple sclerosis patients. Neuroreport. 2017;28(11):645–8. Scholar
  85. 85.
    Burgetova A, Seidl Z, Krasensky J, Horakova D, Vaneckova M. Multiple sclerosis and the accumulation of iron in the basal ganglia: quantitative assessment of brain iron using MRI t(2) relaxometry. Eur Neurol. 2010;63(3):136–43. Scholar
  86. 86.
    Rudko DA, Solovey I, Gati JS, Kremenchutzky M, Menon RS. Multiple sclerosis: improved identification of disease-relevant changes in gray and white matter by using susceptibility-based MR imaging. Radiology. 2014;272(3):851–64. Scholar
  87. 87.
    Schweser F, RaffainiDuarteMartins AL, Hagemeier J, Lin F, Hanspach J, Weinstock-Guttman B, et al. Mapping of thalamic magnetic susceptibility in multiple sclerosis indicates decreasing iron with disease duration: a proposed mechanistic relationship between inflammation and oligodendrocyte vitality. Neuroimage. 2018;167:438–52. Scholar
  88. 88.
    Bergsland N, Schweser F, Dwyer MG, Weinstock-Guttman B, Benedict RHB, Zivadinov R. Thalamic white matter in multiple sclerosis: a combined diffusion-tensor imaging and quantitative susceptibility mapping study. Hum Brain Mapp. 2018;39(10):4007–17. Scholar
  89. 89.
    Zivadinov R, Ramasamy DP, Benedict RR, Polak P, Hagemeier J, Magnano C, et al. Cerebral microbleeds in multiple sclerosis evaluated on susceptibility-weighted images and quantitative susceptibility maps: a case–control study. Radiology. 2016;281(3):884–95. Scholar
  90. 90.
    Hayflick SJ, Kurian MA, Hogarth P. Neurodegeneration with brain iron accumulation. Handb Clin Neurol. 2018;147:293–305. Scholar
  91. 91.
    Kruer MC. The neuropathology of neurodegeneration with brain iron accumulation. Int Rev Neurobiol. 2013;110:165–94. Scholar
  92. 92.
    Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KH, et al. Genetic, clinical, and radiographic delineation of Hallervorden–Spatz syndrome. N Engl J Med. 2003;348(1):33–40. Scholar
  93. 93.
    Fiorito V, Chiabrando D, Tolosano E. Mitochondrial targeting in neurodegeneration: a heme perspective. Pharmaceuticals (Basel). 2018;11(3):E87. Scholar
  94. 94.
    Bergsland N, Zivadinov R, Schweser F, Hagemeier J, Lichter D, Guttuso T. Ventral posterior substantia nigra iron increases over 3 years in Parkinson’s disease. Mov Disord. 2019;34(7):1006–13.CrossRefGoogle Scholar
  95. 95.
    Hagemeier J, Zivadinov R, Dwyer MG, Polak P, Bergsland N, Weinstock-Guttman B, et al. Changes of deep gray matter magnetic susceptibility over 2 years in multiple sclerosis and healthy control brain. Neuroimage Clin. 2018;18:1007–16. Scholar
  96. 96.
    Hernandez-Torres E, Wiggermann V, Machan L, Sadovnick AD, Li DKB, Traboulsee A, et al. Increased mean R2* in the deep gray matter of multiple sclerosis patients: have we been measuring atrophy? J Magn Reson Imaging. 2019;50(1):201–8. Scholar
  97. 97.
    Hagemeier J, Dwyer M, Bergsland N, Weinstock-Guttman B, Zivadinov R, Schweser F. Loss of brain iron is linked to disability in multiple sclerosis: the difference between concentration and mass of iron (P5.2-011). Neurology. 2019;92(15 Suppl.):P.52-011.Google Scholar
  98. 98.
    Hametner S, Endmayr V, Deistung A, Palmrich P, Prihoda M, Haimburger E, et al. The influence of brain iron and myelin on magnetic susceptibility and effective transverse relaxation: a biochemical and histological validation study. Neuroimage. 2018;179:117–33. Scholar
  99. 99.
    Bagnato F, Hametner S, Boyd E, Endmayr V, Shi Y, Ikonomidou V, et al. Untangling the R2* contrast in multiple sclerosis: a combined MRI-histology study at 7.0 Tesla. PLoS One. 2018;13(3):e0193839. Scholar
  100. 100.
    Elkady AM, Cobzas D, Sun H, Blevins G, Wilman AH. Discriminative analysis of regional evolution of iron and myelin/calcium in deep gray matter of multiple sclerosis and healthy subjects. J Magn Reson Imaging. 2018. Scholar
  101. 101.
    Elkady AM, Cobzas D, Sun H, Seres P, Blevins G, Wilman AH. Five year iron changes in relapsing-remitting multiple sclerosis deep gray matter compared to healthy controls. Mult Scler Relat Disord. 2019;33:107–15. Scholar
  102. 102.
    Dietrich O, Levin J, Ahmadi SA, Plate A, Reiser MF, Botzel K, et al. MR imaging differentiation of Fe(2+) and Fe(3+) based on relaxation and magnetic susceptibility properties. Neuroradiology. 2017;59(4):403–9. Scholar
  103. 103.
    Batista-Nascimento L, Pimentel C, Menezes RA, Rodrigues-Pousada C. Iron and neurodegeneration: from cellular homeostasis to disease. Oxid Med Cell Longev. 2012;2012:128647. Scholar
  104. 104.
    Mills E, Dong XP, Wang F, Xu H. Mechanisms of brain iron transport: insight into neurodegeneration and CNS disorders. Future Med Chem. 2010;2(1):51–64.CrossRefGoogle Scholar
  105. 105.
    Qian ZM, Shen X. Brain iron transport and neurodegeneration. Trends Mol Med. 2001;7(3):103–8.CrossRefGoogle Scholar
  106. 106.
    Hagemeier J, Weinstock-Guttman B, Bergsland N, Heininen-Brown M, Carl E, Kennedy C, et al. Iron deposition on SWI-filtered phase in the subcortical deep gray matter of patients with clinically isolated syndrome may precede structure-specific atrophy. AJNR Am J Neuroradiol. 2012;33(8):1596–601. Scholar
  107. 107.
    Al-Radaideh AM, Wharton SJ, Lim SY, Tench CR, Morgan PS, Bowtell RW, et al. Increased iron accumulation occurs in the earliest stages of demyelinating disease: an ultra-high field susceptibility mapping study in clinically isolated syndrome. Mult Scler. 2013;19(7):896–903. Scholar
  108. 108.
    Wyss-Coray T, Rogers J. Inflammation in Alzheimer disease: a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med. 2012;2(1):a006346. Scholar
  109. 109.
    Tufekci KU, Meuwissen R, Genc S, Genc K. Inflammation in Parkinson’s disease. Adv Protein Chem Struct Biol. 2012;88:69–132. Scholar
  110. 110.
    Sanai SA, Saini V, Benedict RH, Zivadinov R, Teter BE, Ramanathan M, et al. Aging and multiple sclerosis. Mult Scler. 2016;22(6):717–25. Scholar
  111. 111.
    Devos D, Moreau C, Devedjian JC, Kluza J, Petrault M, Laloux C, et al. Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid Redox Signal. 2014;21(2):195–210. Scholar
  112. 112.
    Martin-Bastida A, Ward RJ, Newbould R, Piccini P, Sharp D, Kabba C, et al. Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease. Sci Rep. 2017;7(1):1398. Scholar
  113. 113.
    Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–72. Scholar
  114. 114.
    Genoud S, Roberts BR, Gunn AP, Halliday GM, Lewis SJG, Ball HJ, et al. Subcellular compartmentalisation of copper, iron, manganese, and zinc in the Parkinson’s disease brain. Metallomics. 2017;9(10):1447–55. Scholar
  115. 115.
    Kordower JH, Olanow CW, Dodiya HB, Chu Y, Beach TG, Adler CH, et al. Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain. 2013;136(Pt 8):2419–31. Scholar
  116. 116.
    Aaseth J, Dusek P, Roos PM. Prevention of progression in Parkinson’s disease. Biometals. 2018;31(5):737–47. Scholar
  117. 117.
    Erbas O, Cinar BP, Solmaz V, Cavusoglu T, Ates U. The neuroprotective effect of erythropoietin on experimental Parkinson model in rats. Neuropeptides. 2015;49:1–5. Scholar
  118. 118.
    Jang W, Park J, Shin KJ, Kim JS, Kim JS, Youn J, et al. Safety and efficacy of recombinant human erythropoietin treatment of non-motor symptoms in Parkinson’s disease. J Neurol Sci. 2014;337(1–2):47–54. Scholar
  119. 119.
    Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol. 2003;60(12):1685–91. Scholar
  120. 120.
    Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2008;7(9):779–86. Scholar
  121. 121.
    Lynch SG, Peters K, LeVine SM. Desferrioxamine in chronic progressive multiple sclerosis: a pilot study. Mult Scler. 1996;2(3):157–60. Scholar
  122. 122.
    Lynch SG, Fonseca T, LeVine SM. A multiple course trial of desferrioxamine in chronic progressive multiple sclerosis. Cell Mol Biol (Noisy-le-grand). 2000;46(4):865–9.Google Scholar
  123. 123.
    Sweeney ME, Slusser JG, Lynch SG, Benedict SH, Garcia SL, Rues L, et al. Deferiprone modulates in vitro responses by peripheral blood T cells from control and relapsing-remitting multiple sclerosis subjects. Int Immunopharmacol. 2011;11(11):1796–801. Scholar
  124. 124.
    Mitchell KM, Dotson AL, Cool KM, Chakrabarty A, Benedict SH, LeVine SM. Deferiprone, an orally deliverable iron chelator, ameliorates experimental autoimmune encephalomyelitis. Mult Scler. 2007;13(9):1118–26. Scholar
  125. 125.
    Lindner U, Schuppan D, Schleithoff L, Habeck JO, Grodde T, Kirchhof K, et al. Aceruloplasminaemia: a family with a novel mutation and long-term therapy with deferasirox. Horm Metab Res. 2015;47(4):303–8. Scholar
  126. 126.
    Mariani R, Arosio C, Pelucchi S, Grisoli M, Piga A, Trombini P, et al. Iron chelation therapy in aceruloplasminaemia: study of a patient with a novel missense mutation. Gut. 2004;53(5):756–8.CrossRefGoogle Scholar
  127. 127.
    Fasano A, Colosimo C, Miyajima H, Tonali PA, Re TJ, Bentivoglio AR. Aceruloplasminemia: a novel mutation in a family with marked phenotypic variability. Mov Disord. 2008;23(5):751–5. Scholar
  128. 128.
    Abbruzzese G, Cossu G, Balocco M, Marchese R, Murgia D, Melis M, et al. A pilot trial of deferiprone for neurodegeneration with brain iron accumulation. Haematologica. 2011;96(11):1708–11. Scholar
  129. 129.
    Cossu G, Abbruzzese G, Matta G, Murgia D, Melis M, Ricchi V, et al. Efficacy and safety of deferiprone for the treatment of pantothenate kinase-associated neurodegeneration (PKAN) and neurodegeneration with brain iron accumulation (NBIA): results from a four years follow-up. Parkinsonism Relat Disord. 2014;20(6):651–4. Scholar
  130. 130.
    Gao HM, Liu B, Zhang W, Hong JS. Novel anti-inflammatory therapy for Parkinson’s disease. Trends Pharmacol Sci. 2003;24(8):395–401. Scholar
  131. 131.
    Reksidler AB, Lima MM, Zanata SM, Machado HB, da Cunha C, Andreatini R, et al. The COX-2 inhibitor parecoxib produces neuroprotective effects in MPTP-lesioned rats. Eur J Pharmacol. 2007;560(2–3):163–75. Scholar
  132. 132.
    Quintero EM, Willis L, Singleton R, Harris N, Huang P, Bhat N, et al. Behavioral and morphological effects of minocycline in the 6-hydroxydopamine rat model of Parkinson’s disease. Brain Res. 2006;1093(1):198–207. Scholar
  133. 133.
    Wu HM, Tzeng NS, Qian L, Wei SJ, Hu X, Chen SH, et al. Novel neuroprotective mechanisms of memantine: increase in neurotrophic factor release from astroglia and anti-inflammation by preventing microglial activation. Neuropsychopharmacology. 2009;34(10):2344–57. Scholar
  134. 134.
    Kubera M, Maes M, Budziszewska B, Basta-Kaim A, Leskiewicz M, Grygier B, et al. Inhibitory effects of amantadine on the production of pro-inflammatory cytokines by stimulated in vitro human blood. Pharmacol Rep. 2009;61(6):1105–12.CrossRefGoogle Scholar
  135. 135.
    Rees K, Stowe R, Patel S, Ives N, Breen K, Clarke CE, et al. Non-steroidal anti-inflammatory drugs as disease-modifying agents for Parkinson’s disease: evidence from observational studies. Cochrane Database Syst Rev. 2011;11:CD008454. Scholar
  136. 136.
    Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA. 2003;289(21):2819–26. Scholar
  137. 137.
    Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Ciccarelli O. Multiple sclerosis. Lancet. 2018;391(10130):1622–36. Scholar
  138. 138.
    Foote AK, Blakemore WF. Inflammation stimulates remyelination in areas of chronic demyelination. Brain. 2005;128(Pt 3):528–39. Scholar
  139. 139.
    Sochocka M, Diniz BS, Leszek J. Inflammatory response in the CNS: friend or foe? Mol Neurobiol. 2017;54(10):8071–89. Scholar
  140. 140.
    Pfefferbaum A, Adalsteinsson E, Rohlfing T, Sullivan EV. MRI estimates of brain iron concentration in normal aging: comparison of field-dependent (FDRI) and phase (SWI) methods. Neuroimage. 2009;47(2):493–500. Scholar
  141. 141.
    Bartzokis G, Lu PH, Tishler TA, Peters DG, Kosenko A, Barrall KA, et al. Prevalent iron metabolism gene variants associated with increased brain ferritin iron in healthy older men. J Alzheimers Dis. 2010;20(1):333–41. Scholar
  142. 142.
    Jensen JH, Chandra R, Ramani A, Lu H, Johnson G, Lee SP, et al. Magnetic field correlation imaging. Magn Reson Med. 2006;55(6):1350–61. Scholar
  143. 143.
    Ge Y, Jensen JH, Lu H, Helpern JA, Miles L, Inglese M, et al. Quantitative assessment of iron accumulation in the deep gray matter of multiple sclerosis by magnetic field correlation imaging. AJNR Am J Neuroradiol. 2007;28(9):1639–44. Scholar
  144. 144.
    Dumas EM, Versluis MJ, van den Bogaard SJ, van Osch MJ, Hart EP, van Roon-Mom WM, et al. Elevated brain iron is independent from atrophy in Huntington’s disease. Neuroimage. 2012;61(3):558–64. Scholar
  145. 145.
    Wang Y, Butros SR, Shuai X, Dai Y, Chen C, Liu M, et al. Different iron-deposition patterns of multiple system atrophy with predominant parkinsonism and idiopathetic Parkinson diseases demonstrated by phase-corrected susceptibility-weighted imaging. AJNR Am J Neuroradiol. 2012;33(2):266–73. Scholar
  146. 146.
    Langkammer C, Schweser F, Krebs N, Deistung A, Goessler W, Scheurer E, et al. Quantitative susceptibility mapping (QSM) as a means to measure brain iron? A post mortem validation study. Neuroimage. 2012;62(3):1593–9. Scholar
  147. 147.
    Hagemeier J, Ramanathan M, Schweser F, Dwyer MG, Lin F, Bergsland N, et al. Iron-related gene variants and brain iron in multiple sclerosis and healthy individuals. Neuroimage Clin. 2018;17:530–40. Scholar
  148. 148.
    House MJ, St Pierre TG, Kowdley KV, Montine T, Connor J, Beard J, et al. Correlation of proton transverse relaxation rates (R2) with iron concentrations in postmortem brain tissue from Alzheimer’s disease patients. Magn Reson Med. 2007;57(1):172–80. Scholar
  149. 149.
    Hasan KM, Walimuni IS, Kramer LA, Narayana PA. Human brain iron mapping using atlas-based T2 relaxometry. Magn Reson Med. 2012;67(3):731–9. Scholar
  150. 150.
    Khalil M, Langkammer C, Pichler A, Pinter D, Gattringer T, Bachmaier G, et al. Dynamics of brain iron levels in multiple sclerosis: a longitudinal 3T MRI study. Neurology. 2015;84(24):2396–402. Scholar
  151. 151.
    Ulla M, Bonny JM, Ouchchane L, Rieu I, Claise B, Durif F. Is R2* a new MRI biomarker for the progression of Parkinson’s disease? A longitudinal follow-up. PLoS One. 2013;8(3):e57904. Scholar
  152. 152.
    Langkammer C, Ropele S, Pirpamer L, Fazekas F, Schmidt R. MRI for iron mapping in Alzheimer’s disease. Neurodegener Dis. 2014;13(2–3):189–91. Scholar
  153. 153.
    Akter M, Hirai T, Hiai Y, Kitajima M, Komi M, Murakami R, et al. Detection of hemorrhagic hypointense foci in the brain on susceptibility-weighted imaging clinical and phantom studies. Acad Radiol. 2007;14(9):1011–9. Scholar
  154. 154.
    Tjoa CW, Benedict RH, Weinstock-Guttman B, Fabiano AJ, Bakshi R. MRI T2 hypointensity of the dentate nucleus is related to ambulatory impairment in multiple sclerosis. J Neurol Sci. 2005;234(1–2):17–24. Scholar
  155. 155.
    Bakshi R, Benedict RH, Bermel RA, Caruthers SD, Puli SR, Tjoa CW, et al. T2 hypointensity in the deep gray matter of patients with multiple sclerosis: a quantitative magnetic resonance imaging study. Arch Neurol. 2002;59(1):62–8.CrossRefGoogle Scholar
  156. 156.
    Lopez-Sendon Moreno JL, Alonso-Canovas A, Buisan Catevilla J, Garcia Barragan N, Corral Corral I, de Felipe Mimbrera A, et al. Substantia nigra echogenicity predicts response to drug withdrawal in suspected drug-induced parkinsonism. Mov Disord Clin Pract. 2016;3(3):268–74. Scholar
  157. 157.
    Liman J, Wellmer A, Rostasy K, Bahr M, Kermer P. Transcranial ultrasound in neurodegeneration with brain iron accumulation (NBIA). Eur J Paediatr Neurol. 2012;16(2):175–8. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical SciencesUniversity at Buffalo, State University of New YorkBuffaloUSA
  2. 2.Center for Biomedical Imaging, Clinical and Translational Science InstituteUniversity at Buffalo, State University of New YorkBuffaloUSA

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