Iron Oxides in the Human Brain

Iron Oxides: From Nature to Applications

Volumn , Issue , 2016, Pages 143-176

  Collingwood, Joanna F ^a   Telling, Neil D ^b  

^a UNIVERSITY OF WARWICK   (United Kingdom)

^b KEELE UNIVERSITY   (United Kingdom)

Author keywords

Brain; Ferrihydrite; Ferritin; Hemosiderin; Iron; Magnetite; Metabolism; MRI; Nanoparticle; Neurodegeneration

Indexed keywords

BIOMINERALIZATION; HEMATITE; IRON; MAGNETIC RESONANCE IMAGING; MAGNETITE; MAGNETITE NANOPARTICLES; METABOLISM; NANOPARTICLES; PRECIPITATION (CHEMICAL); TISSUE;

CLINICAL TECHNOLOGY; FERRIHYDRITES; FERRITIN; HEMOSIDERIN; IRON OXIDE NANOPARTICLE; LOCAL ENVIRONMENTS; MAGNETITE , MAGHEMITE; NEURODEGENERATION;

BRAIN;

EID: 85017212976     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9783527691395.ch7     Document Type: Chapter

References (171)

1. Cornell, R.M. and Schwertmann, U. (1996) The Iron Oxides, Wiley-VCH Verlag GmbH.
2. Cabantchik, Z.I. (2014) Labile iron in cells and body fluids: physiology, pathology, and pharmacology. Front. Pharmacol., 5, 45.
3. Double, K.L., Dedov, V.N., Fedorow, H., Kettle, E., Halliday, G.M., Garner, B., and Brunk, U.T. (2008) The comparative biology of neuromelanin and lipofuscin in the human brain. Cell. Mol. Life Sci.: CMLS, 65, 1669-1682.
4. Hallgren, B. and Sourander, P. (1958) The effect of age on the non-haemin iron in the human brain. J. Neurochem., 3, 41-51.
5. Connor, J.R., Snyder, B.S., Arosio, P., Loeffler, D.A., and Lewitt, P. (1995) A quantitative analysis of isoferritins in select regions of aged, Parkinsonian, and Alzheimer's diseased brains. J Neurochem., 65, 717-724.
6. Zecca, L., Youdim, M.B.H., Riederer, P., Connor, J.R., and Crichton, R.R. (2004) Iron, brain ageing and neurodegenerative disorders. Nat. Rev. Neurosci., 5, 863-873.
7. Bartzokis, G., Tishler, T.A., Lu, P.H., Villablanca, P., Altshuler, L.L., Carter, M., Huang, D., Edwards, N., and Mintz, J. (2007) Brain ferritin iron may influence age- and gender-related risks of neurodegeneration. Neurobiol. Aging, 28, 414-423.
8. Haacke, E.M., Cheng, N.Y., House, M.J., Liu, Q., Neelavalli, J., Ogg, R.J., Khan, A., Ayaz, M., Kirsch, W., and Obenaus, A. (2005) Imaging iron stores in the brain using magnetic resonance imaging. Magn. Reson. Imaging, 23, 1-25.
9. Harrison, P.M. and Arosio, P. (1996) Ferritins: molecular properties, iron storage function and cellular regulation. Biochim. Biophys. Acta, Bioenerg., 1275, 161-203.
10. Jomova, K., Baros, S., and Valko, M. (2012) Redox active metal-induced oxidative stress in biological systems. Transition Met. Chem., 37, 127-134.
11. Kell, D.B. (2010) 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. Arch. Toxicol., 84, 825-889.
12. Markesbery, W.R. (1997) Oxidative stress hypothesis in Alzheimer's disease. Free Radical Biol. Med., 23, 134-147.
13. Curtis, A.R., Fey, C., Morris, C.M., Bindoff, L.A., Ince, P.G., Chinnery, P.F., Coulthard, A., Jackson, M.J., Jackson, A.P., McHale, D.P., Hay, D., Barker, W.A., Markham, A.F., Bates, D., Curtis, A., and Burn, J. (2001) Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat. Genet., 28, 350-354.
14. Morris, C.M. (2011) Any old iron? Brain, 134, 924-927.
15. Crichton, R.R., Dexter, D.T., and Ward, R.J. (2012) Brain iron metabolism and its perturbation in neurological diseases. J. Neural Transm. (Vienna, Austria: 1996), 118, 301-314.
16. Hare, D., Ayton, S., Bush, A., and Lei, P. (2013) A delicate balance: iron metabolism and diseases of the brain. Front. Aging Neurosci., 5, 34.
17. Rouault, T.A. (2013) Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat. Rev. Neurosci., 14, 551-564.
18. Collingwood, J.F. and Dobson, J. (2008) in Biomedical Nanostructures (eds K.E. Gonsalves, C.L. Laurenein, and C.R. Halberstadt), John Wiley & Sons, Inc., Hoboken, NJ, pp. 455-484.
19. Quintana, C. and Gutierrez, L. (2010) Could a dysfunction of ferritin be a determinant factor in the aetiology of some neurodegenerative diseases? Biochim. Biophys. Acta, 1800, 770-782.
20. Koeppen, A.H., Michael, S.C., Li, D., Chen, Z., Cusack, M.J., Gibson, W.M., Petrocine, S.V., and Qian, J. (2008) The pathology of superficial siderosis of the central nervous system. Acta Neuropathol., 116, 371-382.
21. Tao, Y., Wang, Y., Rogers, J.T., and Wang, F. (2014) Perturbed iron distribution in Alzheimer's disease serum, cerebrospinal fluid, and selected brain regions: a systematic review and meta-analysis. J. Alzheimer's Dis., 42, 679-690.
22. Visanji, N.P., Collingwood, J.F., Finnegan, M.E., Tandon, A., House, E., and Hazrati, L.N. (2013) Iron deficiency in parkinsonism: region-specific iron dysregulation in Parkinson's disease and multiple system atrophy. J. Parkinson's Dis., 3, 523-537.
23. Oakley, A.E., Collingwood, J.F., Dobson, J., Love, G., Perrott, H.R., Edwardson, J.A., Elstner, M., and Morris, C.M. (2007) Individual dopaminergic neurons show raised iron levels in Parkinson disease. Neurology, 68, 1820-1825.
24. Khan, A., Dobson, J.P., and Exley, C. (2006) Redox cycling of iron by AB42. Free Radical Biol. Med., 40, 557-569.
25. Collingwood, J.F., Chong, R.K., Kasama, T., Cervera-Gontard, L., Dunin-Borkowski, R.E., Perry, G., Posfai, M., Siedlak, S.L., Simpson, E.T., Smith, M.A., and Dobson, J.(2008) Three-dimensional tomographic imaging and characterization of iron compounds within Alzheimer's plaque core material. J. Alzheimer's Dis., 14, 235-245.
26. Everett, J., Cespedes, E., Shelford, L.R., Exley, C., Collingwood, J.F., Dobson, J., van der Laan, G., Jenkins, C.A., Arenholz, E., and Telling, N.D. (2014) Evidence of redox-active iron formation following aggregation of ferrihydrite and the Alzheimer's disease peptide beta-amyloid. Inorg. Chem., 53, 2803-2809.
27. Everett, J., Cespedes, E., Shelford, L.R., Exley, C., Collingwood, J.F., Dobson, J., van der Laan, G., Jenkins, C.A., Arenholz, E., and Telling, N.D. (2014) Ferrous iron formation following the co-aggregation of ferric iron and the Alzheimer's disease peptide beta-amyloid (1-42). J. R. Soc. Interface, 11, 20140165.
28. Davies, P., Moualla, D., and Brown, D.R. (2011) Alpha-synuclein is a cellular ferrireductase. PLoS One, 6, e15814.
29. Herynek, V., Wagnerova, D., Malucelli, A., Vymazal, J., Sames, M., and Hajek, M. (2015) Alterations in the basal ganglia in patients with brain tumours may be due to excessive iron deposition. Oncol. Lett., 9, 43-46.
30. Carta, D., Casula, M.F., Corrias, A., Falqui, A., Navarra, G., and Pinna, G. (2009) Structural and magnetic characterization of synthetic ferrihydrite nanoparticles. Mater. Chem. Phys., 113, 349-355.
31. Smith, S.J., Page, K., Kim, H., Campbell, B.J., Boerio-Goates, J., and Woodfield, B.F. (2012) Novel synthesis and structural analysis of ferrihydrite. Inorg. Chem., 51, 6421-6424.
32. Drits, V.A., Sakharov, B.A., Salyn, A.L., and Manceau, A. (1993) Structural model for ferrihydrite. Clay Miner., 28, 185-207.
33. Manceau, A. (2011) Critical evaluation of the revised akdalaite model for ferrihydrite. Am. Mineral., 96, 521-533.
34. Michel, F.M., Barron, V., Torrent, J., Morales, M.P., Serna, C.J., Boily, J.F., Liu, Q., Ambrosini, A., Cismasu, A.C., and Brown, G.E. Jr. (2010) Ordered ferrimagnetic form of ferrihydrite reveals links among structure, composition, and magnetism. Proc. Natl. Acad. Sci. U.S.A., 107, 2787-2792.
35. Michel, F.M., Hosein, H.A., Hausner, D.B., Debnath, S., Parise, J.B., and Strongin, D.R. (2010) Reactivity of ferritin and the structure of ferritin-derived ferrihydrite. Biochim. Biophys. Acta, 1800, 871-885.
36. 3+ in iron phosphate dihydrate, ferrihydrite, haemosiderin and ferritin as revealed by electron energy-loss spectroscopy. Ultramicroscopy, 110, 1020-1032.
37. Finazzi, D. and Arosio, P. (2014) Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration. Arch. Toxicol., 88, 1787-1802.
38. Quintana, C., Cowley, J.M., and Marhic, C. (2004) Electron nanodiffraction and high-resolution electron microscopy studies of the structure and composition of physiological and pathological ferritin. J. Struct. Biol., 147, 166-178.
39. Galvez, N., Fernandez, B., Sanchez, P., Cuesta, R., Ceolin, M., Clemente-Leon, M., Trasobares, S., Lopez-Haro, M., Calvino, J.J., Stephan, O., and Dominguez-Vera, J.M. (2008) Comparative structural and chemical studies of ferritin cores with gradual removal of their iron contents. J. Am. Chem. Soc., 130, 8062-8068.
40. Levi, S., Corsi, B., Bosisio, M., Invernizzi, R., Volz, A., Sanford, D., Arosio, P., and Drysdale, J. (2001) A human mitochondrial ferritin encoded by an intronless gene. J. Biol.Chem., 276, 24437-24440.
41. Popescu, B.F., Pickering, I.J., George, G.N., and Nichol, H. (2007) The chemical form of mitochondrial iron in Friedreich's ataxia. J. Inorg. Biochem., 101, 957-966.
42. Brem, F., Hirt, A.M., Winklhofer, M., Frei, K., Yonekawa, Y., Wieser, H.G., and Dobson, J. (2006) Magnetic iron compounds in the human brain: a comparison of tumour and hippocampal tissue. J. R. Soc. Interface, 3, 833-841.
43. Kornig, A., Winklhofer, M., Baumgartner, J., Gonzalez, T.P., Fratzl, P., and Faivre, D. (2014) Magnetite crystal orientation in magneto-some chains. Adv. Funct. Mater., 24, 3926-3932.
44. Kirschvink, J.L., Kobayashi-Kirschvink, A., and Woodford, B.J. (1992) Magnetite biomineralization in the human brain. Proc. Natl. Acad. Sci. U.S.A., 89, 7683-7687.
45. Schultheiss-Grassi, P.P., Wessiken, R., and Dobson, J. (1999) TEM investigations of biogenic magnetite extracted from the human hippocampus. Biochim. Biophys. Acta, 1426, 212-216.
46. Collingwood, J.F., Mikhaylova, A., Davidson, M., Batich, C., Streit, W.J., Terry, J., and Dobson, J. (2005) In situ characterization and mapping of iron compounds in Alzheimer's disease tissue. J. Alzheimer's Dis., 7, 267-272.
47. Quintana, C., Lancin, M., Marhic, C., Perez, M., Martin-Benito, J., Avila, J., and Carrascosa, J.L. (2000) Initial studies with high resolution TEM and electron energy loss spectroscopy studies of ferritin cores extracted from brains of patients with progressive supranuclear palsy and Alzheimer disease. Cell. Mol. Biol., 46, 807-820.
48. Winklhofer, M. (2010) Magnetoreception. J. R. Soc. Interface, 7 (Suppl. 2), S131-S134.
49. Dobson, J. (2002) Investigation of age-related variations in biogenic magnetite levels in the human hippocampus. Exp. Brain Res, 144, 122-126.
50. Hautot, D., Pankhurst, Q.A., Morris, C.M., Curtis, A., Burn, J., and Dobson, J. (2007) Preliminary observation of elevated levels of nanocrystalline iron oxide in the basal ganglia of neuroferritinopathy patients. Biochim. Biophys. Acta, 1772, 21-25.
51. Quintana, C. (2007) About the presence of hemosiderin in the hippocampus of Alzheimer patients. J. Alzheimer's Dis., 12, 157-160.
52. Borelli, V., Trevisan, E., Vita, F., Bottin, C., Melato, M., Rizzardi, C., and Zabucchi, G. (2012) Peroxidase-like activity of ferruginous bodies isolated by exploiting their magnetic property. J. Toxicol. Environ. Health Part A, 75, 603-623.
53. Melnikova, L., Pospiskova, K., Mitroova, Z., Kopcansky, P., and Safarik, I. (2014) Peroxidase-like activity of magnetoferritin. Microchim. Acta, 181, 295-301.
54. Schultheiss-Grassi, P.P. and Dobson, J. (1999) Magnetic analysis of human brain tissue. Biometals, 12, 67-72.
55. Liu, Q.S., Roberts, A.P., Larrasoana, J.C., Banerjee, S.K., Guyodo, Y., Tauxe, L., and Oldfield, F. (2012) Environmental magnetism: principles and applications. Rev. Geophys., 50.
56. Schwertmann, U. and Murad, E. (1983) Effect of pH on the formation of goethite and hematite from ferrihydrite. Clays Clay Miner., 31, 277-284.
57. Schwertmann, U., Cambier, P., and Murad, E. (1985) Properties of goethites of varying crystallinity. Clays Clay Miner., 33, 369-378.
58. Mackle, P., Garner, C.D., Ward, R.J., and Peters, T.J. (1991) Iron K-edge absorption spectroscopic investigations of the cores of ferritin and haemosiderins. Biochim. Biophys. Acta, Gen. Subj., 1115, 145-150.
59. Ward, R.J., Legssyer, R., Henry, C., and Crichton, R.R. (2000) Does the haemosiderin iron core determine its potential for chelation and the development of iron-induced tissue damage? J. Inorg. Biochem., 79, 311-317.
60. Chua-anusorn, W. and Webb, J. (2000) Infrared spectroscopic studies of nanoscale iron oxide deposits isolated from human thalassemic tissues. J. Inorg. Biochem., 79, 303-309.
61. Mann, S., Wade, V.J., Dickson, D.P., Reid, N.M., Ward, R.J., O'Connell, M., and Peters, T.J. (1988) Structural specificity of haemosiderin iron cores in iron-overload diseases. FEBS Lett., 234, 69-72.
62. Campbell, A.S., Schwertmann, U., and Campbell, P.A. (1997) Formation of cubic phases on heating ferrihydrite. Clay Miner., 32, 615-622.
63. Barron, V. (2012) Critical evaluation of the revised akdalaite model for ferrihydrite-discussion. Am. Mineral., 97, 253-254.
64. Pan, Y., Brown, A., Brydson, R., Warley, A., Li, A., and Powell, J. (2006) Electron beam damage studies of synthetic 6-line ferrihydrite and ferritin molecule cores within a human liver biopsy. Micron, 37, 403-411.
65. Armstrong, R.J., Morrish, A.H., and Sawatzky, G.A. (1966) Mossbauer study of ferric ions in the tetrahedral and octahedral sites of a spinel. Phys. Lett., 23, 414-416.
66. Barron, V., Torrent, J., and de Grave, E. (2003) Hydromaghemite, an intermediate in the hydrothermal transformation of 2-line ferrihydrite into hematite. Am. Mineral., 88, 1679-1688.
67. Hazen, R.M. and Jeanloz, R. (1984) Wustite (Fe[1-x]O): a review of its defect structure and physical properties. Rev. Geophys. Space Phys., 22, 37-46.
68. Pattrick, R.A.D., Van der Laan, G., Henderson, M.B., Kuiper, P., Dudzik, E., and Vaughan, D.J. (2002) Cation site occupancy in spinel ferrites studied by X-ray magnetic circular dichroism: developing a method for minerologists. Eur. J. Mineral., 14, 1095-1102.
69. Guyodo, Y., Sainctavit, P., Arrio, M.A., and Carvallo, C. (2012) X-ray magnetic circular dichroism provides strong evidence for tetrahedral iron in ferrihydrite. Geochem. Geophys. Geosyst., 13.
70. DeBoer, C.B. and Dekkers, M.J. (1998) Thermomagnetic behaviour of haematite and goethite as a function of grain size in various non-saturating magnetic fields. Geophys. J. Int., 133, 541-552.
71. Brooks, R.A., Vymazal, J., Goldfarb, R.B., Bulte, J.W.M., and Aisen, P. (1998) Relaxometry and magnetometry of ferritin. Magn. Reson. Med., 40, 227-235.
72. Chasteen, N.D. and Harrison, P.M. (1999) Mineralization in ferritin: an efficient means of iron storage. J. Struct. Biol., 126, 182-194.
73. Hilty, S., Webb, B., Frankel, R.B., and Watt, G.D. (1994) Iron core formation in horse spleen ferritin: magnetic susceptibility, pH, and compositional studies. J. Inorg. Biochem., 56, 173-185.
74. Byrne, J.M. et al. (2013) Controlled cobalt doping in biogenic magnetite nanoparticles. J. R. Soc. Interface, 10, 20130134.
75. Byrne, J.M. and Coker, V.S. (2014) Biosynthesis of zinc substituted magnetite nanoparticles with enhanced magnetic properties. Adv. Funct. Mater., 24, 2518-2529.
76. Daou, T.J. (2010) Spin canting of maghemite studied by NMR and infield mossbauer spectrometry. J. Phys. Chem C, 114, 8794-8799.
77. Linderoth, S. and Hendriksen, P.V. (1994) On spin-canting in maghemite particles. J. Appl. Phys., 75, 6583-6585.
78. Hautot, D., Pankhurst, Q.A., and Dobson, J. (2005) Superconducting quantum interference device measurements of dilute magnetic materials in biological samples. Rev. Sci. Instrum., 76, 045101.
79. Brem, F., Tiefenauer, L., Fink, A., Dobson, J., and Hirt, A.M. (2006) A mixture of ferritin and magnetite nanoparticles mimics the magnetic properties of human brain tissue. Phys. Rev. B, 73, 224427.
80. St Pierre, T., Webb, J., and Mann, S. (1989) in Biomineralization: Chemical and Biochemical Perspectives (eds S.Mann, J. Webb, and R. Williams), Wiley-VCH Verlag GmbH, Weinheim, pp. 295-344.
81. Papaefthymiou, G.C. (2010) The Mössbauer and magnetic properties of ferritin cores. Biochim. Biophys. Acta, Gen. Subj., 1800, 886-897.
82. Tian, L., Cao, C., and Pan, Y. (2012) The influence of reaction temperature on biomineralization of ferrihydrite cores in human H-ferritin. Biometals, 25, 193-202.
83. Connor, J.R., Ponnuru, P., Wang, X.S., Patton, S.M., Allen, R.P., and Earley, C.J. (2011) Profile of altered brain iron acquisition in restless legs syndrome. Brain, 134, 959-968.
84. Carmona, F., Mendoza, D., Kord, S., Asperti, M., Arosio, P., Atrian, S., Capdevila, M., and Dominguez-Vera, J.M. (2015) Chemically and biologically harmless versus harmful ferritin/copper-metallothionein couples. Chemistry, 21, 808-813.
85. Ayton, S., Faux, N.G., Bush, A.I., and Alzheimer's Disease Neuroimaging Initiative (2015) Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE. Nat. Commun., 6, 6760.
86. Kell, D.B. and Pretorius, E. (2014) Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics, 6, 748-773.
87. Connor, J.R., Snyder, B.S., Beard, J.L., Fine, R.E., and Mufson, E.J. (1992) Regional distribution of iron and iron-regulatory proteins in the brain in aging and Alzheimer's disease. J. Neurosci. Res., 31, 327-335.
88. Dedman, D.J., Treffry, A., Candy, J.M., Taylor, G.A.A., Morris, C.M., Bloxham, C.A., Perry, R.H., Edwardson, J.A., and Harrison, P.M. (1992) Iron and aluminum in relation to brain ferritin in normal individuals and Alzheimer's disease and chronic renal-dialysis patients. Biochem. J., 287, 509-514.
89. Snyder, A.M., Wang, X., Patton, S.M., Arosio, P., Levi, S., Earley, C.J., Allen, R.P., and Connor, J.R. (2009) Mitochondrial ferritin in the substantia nigra in restless legs syndrome. J. Neuropathol. Exp. Neurol., 68, 1193-1199.
90. Gao, G. and Chang, Y.Z. (2014) Mitochondrial ferritin in the regulation of brain iron homeostasis and neurodegenerative diseases. Front. Pharmacol., 5, 19.
91. Campuzano, V., Montermini, L., Moltò, M.D., Pianese, L., Cossée, M., Cavalcanti, F., Monros, E., Rodius, F., Duclos, F., Monticelli, A., Zara, F., Cañizares, J., Koutnikova, H., Bidichandani, S.I., Gellera, C., Brice, A., Trouillas, P., DeMichele, G., Filla, A., DeFrutos, R., Palau, F., Patel, P.I., Di Donato, S., Mandel, J.L., Cocozza, S., Koenig, M., and Pandolfo, M. (1996) Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science, 271, 1423-1427.
92. Anzovino, A., Lane, D.J.R., Huang, M.L.H., and Richardson, D.R. (2014) Fixing frataxin: 'ironing out' the metabolic defect in Friedreich's ataxia. Br. J. Pharmacol., 171, 2174-2190.
93. Dickson, D.P.E., Reid, N.M.K., Mann, S., Wade, V.J., Ward, R.J., and Peters, T.J. (1988) Mössbauer spectroscopy, electron microscopy and electron diffraction studies of the iron cores in various human and animal haemosiderins. Biochim. Biophys. Acta, Protein Struct. Mol. Enzymol., 957, 81-90.
94. O'Connell, M., Halliwell, B., Moorhouse, C.P., Aruoma, O.I., Baum, H., and Peters, T.J. (1986) Formation of hydroxyl radicals in the presence of ferritin and haemosiderin. Is haemosiderin formation a biological protective mechanism? Biochem. J., 234, 727-731.
95. Koorts, A.M. and Viljoen, M. (2007) Ferritin and ferritin isoforms I: structure-function relationships, synthesis, degradation and secretion. Arch. Physiol. Biochem., 113, 30-54.
96. Quintana, C., Bellefqih, S., Laval, J.Y., Guerquin-Kern, J.L., Wu, T.D., Avila, J., Ferrer, I., Arranz, R., and Patino, C. (2006) Study of the localization of iron, ferritin, and hemosiderin in Alzheimer's disease hippocampus by analytical microscopy at the subcellular level. J. Struct. Biol., 153, 42-54.
97. Gotz, M.E., Double, K., Gerlach, M., Youdim, M.B., and Riederer, P. (2004) The relevance of iron in the pathogenesis of Parkinson's disease. Ann. N.Y. Acad. Sci., 1012, 193-208.
98. Zecca, L., Zucca, F.A., Wilms, H., and Sulzer, D. (2003) Neuromelanin of the substantia nigra: a neuronal black hole with protective and toxic characteristics. Trends Neurosci., 26, 578-580.
99. Zucca, F.A., Basso, E., Cupaioli, F.A., Ferrari, E., Sulzer, D., Casella, L., and Zecca, L. (2014) Neuromelanin of the human substantia nigra: an update. Neurotox. Res., 25, 13-23.
100. Zecca, L. and Swartz, H.M. (1993) Total and paramagnetic metals in human substantia nigra and its neuromelanin. J. Neural Transm. Park. Dis. Dement. Sect., 5, 203-213.
101. Zecca, L., Gallorini, M., Schunemann, V., Trautwein, A.X., Gerlach, M., Riederer, P., Vezzoni, P., and Tampellini, D. (2001) Iron, neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: consequences for iron storage and neurodegenerative processes. J. Neurochem., 76, 1766-1773.
102. Kropf, A.J., Bunker, B.A., Eisner, M., Moss, S.C., Zecca, L., Stroppolo, A., and Crippa, P.R. (1998) X-ray absorption fine-structure spectroscopy studies of Fe sites in natural human neuromelanin and synthetic analogues. Biophys. J., 75, 3135-3142.
103. Bolzoni, F., Giraudo, S., Lopiano, L., Bergamasco, B., Fasano, M., and Crippa, P.R. (2002) Magnetic investigations of human mesencephalic neuromelanin. Biochim. Biophys. Acta, 1586, 210-218.
104. Aime, S., Bergamasco, B., Biglino, D., Digilio, G., Fasano, M., Giamello, E., and Lopiano, L. (1997) EPR investigations of the iron domain in neuromelanin. Biochim. Biophys. Acta, 1361, 49-58.
105. Bohic, S., Murphy, K., Paulus, W., Cloetens, P., Salome, M., Susini, J., and Double, K. (2008) Intracellular chemical imaging of the developmental phases of human neuromelanin using synchrotron X-ray microspectroscopy. Anal. Chem., 80, 9557-9566.
106. Lopiano, L., Chiesa, M., Digilio, G., Giraudo, S., Bergamasco, B., Torre, E., and Fasano, M. (2000) Q-band EPR investigations of neuromelanin in control and Parkinson's disease patients. Biochim. Biophys. Acta, 1500, 306-312.
107. Double, K.L., Gerlach, M., Schunemann, V., Trautwein, A.X., Zecca, L., Gallorini, M., Youdim, M.B., Riederer, P., and Ben-Shachar, D. (2003) Iron-binding characteristics of neuromelanin of the human substantia nigra. Biochem. Pharmacol., 66, 489-494.
108. Chwiej, J., Adamek, D., Szczerbowska-Boruchowska, M., Krygowska-Wajs, A., Wojcik, S., Falkenberg, G., Manka, A., and Lankosz, M. (2007) Investigations of differences in iron oxidation state inside single neurons from substantia nigra of Parkinson's disease and control patients using the micro-XANES technique. J. Biol. Inorg. Chem., 12, 204-211.
109. Gerlach, M., Trautwein, A.X., Zecca, L., Youdim, M.B., and Riederer, P. (1995) Mossbauer spectroscopic studies of purified human neuromelanin isolated from the substantia nigra. J. Neurochem., 65, 923-926.
110. Tribl, F., Asan, E., Arzberger, T., Tatschner, T., Langenfeld, E., Meyer, H.E., Bringmann, G., Riederer, P., Gerlach, M., and Marcus, K. (2009) Identification of L-ferritin in neuromelanin granules of the human substantia nigra: a targeted proteomics approach. Mol. Cell. Proteomics, 8, 1832-1838.
111. Drayer, B., Burger, P., Darwin, R., Riederer, S., Herfkens, R., and Johnson, G.A. (1986) MRI of brain iron. Am. J. Roentgenol., 147, 103-110.
112. Smith, M.A., Harris, P.L., Sayre, L.M., and Perry, G. (1997) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc. Natl. Acad. Sci. U.S.A., 94, 9866-9868.
113. Dubiel, S.M., Zablotna-Rypien, B., Mackey, J.B., and Williams, J.M. (1999) Magnetic properties of human liver and brain ferritin. Eur. Biophys. J., 28, 263-267.
114. Jellinger, K., Kienzl, E., Rumpelmair, G., Riederer, P., Stachelberger, H., Ben-Shachar, D., and Youdim, M.B. (1992) Iron-melanin complex in sub-stantia nigra of parkinsonian brains: an X-ray microanalysis. J. Neurochem., 59, 1168-1171.
115. Gossuin, Y., Hautot, D., Muller, R.N., Pankhurst, Q., Dobson, J., Morris, C., Gillis, P., and Collingwood, J. (2005) Looking for biogenic magnetite in brain ferritin using NMR relaxometry. NMR Biomed., 18, 469-472.
116. Becker, J.S., Matusch, A., Palm, C., Salber, D., and Morton, K.A. (2010) Bioimaging of metals in brain tissue by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) and metallomics. Metallomics, 2, 104-111.
117. Wang, H.A., Grolimund, D., Van Loon, L.R., Barmettler, K., Borca, C.N., Aeschlimann, B., and Gunther, D. (2011) Quantitative chemical imaging of element diffusion into heterogeneous media using laser ablation inductively coupled plasma mass spectrometry, synchrotron micro-X-ray fluorescence, and extended X-ray absorption fine structure spectroscopy. Anal. Chem., 83, 6259-6266.
118. Collingwood, J.F. and Davidson, M.R. (2014) The role of iron in neurodegenerative disorders: insights and opportunities with synchrotron light. Front. Pharmacol., 5, 191.
119. Bohic, S., Cotte, M., Salome, M., Fayard, B., Kuehbacher, M., Cloetens, P., Martinez-Criado, G., Tucoulou, R., and Susini, J. (2012) Biomedical applications of the ESRF synchrotron-based microspectroscopy platform. J. Struct. Biol., 177, 248-258.
120. Chwiej, J., Fik-Mazgaj, K., Szczerbowska-Boruchowska, M., Lankosz, M., Ostachowicz, J., Adamek, D., Simionovici, A., and Bohic, S. (2005) Classification of nerve cells from substantia nigra of patients with Parkinson's disease and amyotrophic lateral sclerosis with the use of X-ray fluorescence microscopy and multivariate methods. Anal. Chem., 77, 2895-2900.
121. Koeppen, A.H. (2003) A brief history of brain iron research. J. Neurol. Sci., 207, 95-97.
122. Morris, C.M., Candy, J.M., Oakley, A.E., Bloxham, C.A., and Edwardson, J.A. (1992) Histochemical distribution of non-haem iron in the human brain. Acta Anat., 144, 235-257.
123. Galazka-Friedman, J., Bauminger, E.R., Friedman, A., Barcikowska, M., Hechel, D., and Nowik, I. (1996) Iron in parkinsonian and control substantia nigra - a Mossbauer spectroscopy study. Mov. Disord., 11, 8-16.
124. Dobson, J. and Grassi, P. (1996) Magnetic properties of human hippocampal tissue - evaluation of artefact and contamination sources. Brain Res. Bull., 39, 255-259.
125. Widdrat, M., Kumari, M., Tompa, E., Pósfai, M., Hirt, A.M., and Faivre, D. (2014) Keeping nanoparticles fully functional: long-term storage and alteration of magnetite. ChemPlusChem, 79, 1225-1233.
126. Drits, V., Gorshkov, A.I., Sakharov, B.A., Salyn, A.L., Manseau, A., and Sivtsov, A.B. (1995) Ferrihydrite and its phase transformations during heating in the oxidizing and reducing environments. Lithol. Min. Resour., 1, 68-75.
127. Schenck, J.F. and Zimmerman, E.A. (2004) High-field magnetic resonance imaging of brain iron: birth of a biomarker? NMR Biomed., 17, 433-445.
128. Smith, M.A., Zhu, X., Tabaton, M., Liu, G., McKeel, D.W. Jr., Cohen, M.L., Wang, X., Siedlak, S.L., Dwyer, B.E., Hayashi, T., Nakamura, M., Nunomura, A., and Perry, G. (2010) Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment. J. Alzheimer's Dis., 19, 363-372.
129. House, M.J., StPierre, T.G., Milward, E.A., Bruce, D.G., and Olynyk, J.K. (2010) Relationship between brain R(2) and liver and serum iron concentrations in elderly men. Magn. Reson. Med., 63, 275-281.
130. House, M.J., Pierre, T.G.S., Foster, J.K., Martins, R.N., and Clarnette, R. (2006) Quantitative MR imaging R2 relaxometry in elderly participants reporting memory loss. AJNR. Am. J. Neuroradiol., 27, 430-439.
131. Boddaert, N., Le Quan Sang, K.H., Rotig, A., Leroy-Willig, A., Gallet, S., Brunelle, F., Sidi, D., Thalabard, J.C., Munnich, A., and Cabantchik, Z.I. (2007) Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood, 110, 401-408.
132. Haacke, E.M., Ayaz, M., Khan, A., Manova, E.S., Krishnamurthy, B., Gollapalli, L., Ciulla, C., Kim, I., Petersen, F., and Kirsch, W. (2007) Establishing a baseline phase behavior in magnetic resonance imaging to determine normal vs. abnormal iron content in the brain. J. Magn. Reson. Imaging, 26, 256-264.
133. Raven, E.P., Lu, P.H., Tishler, T.A., Heydari, P., and Bartzokis, G. (2013) Increased iron levels and decreased tissue integrity in hippocampus of Alzheimer's disease detected in vivo with magnetic resonance imaging. J. Alzheimer's Dis., 37, 127-136.
134. Bartzokis, G., Mintz, J., Sultzer, D., Marx, P., Herzberg, J.S., Phelan, C.K., and Marder, S.R. (1994) In vivo MR evaluation of age-related increases in brain iron. AJNR. Am. J. Neuroradiol., 15, 1129-1138.
135. Lorio, S., Lutti, A., Kherif, F., Ruef, A., Dukart, J., Chowdhury, R., Frackowiak, R.S., Ashburner, J., Helms, G., Weiskopf, N., and Draganski, B. (2014) Disentangling in vivo the effects of iron content and atrophy on the ageing human brain. NeuroImage, 103, 280-289.
136. Valdes Hernandez Mdel, C., Maconick, L.C., Tan, E.M., and Wardlaw, J.M. (2012) Identification of mineral deposits in the brain on radiological images: a systematic review. Eur. Radiol., 22, 2371-2381.
137. House, M.J., Pierre, T.G.S., Kowdley, K.V., Montine, T., Connor, J., Beard, J., Berger, J., Siddaiah, N., Shankland, E., and Jin, L.W. (2007) Correlation of proton transverse relaxation rates (R2) with iron concentrations in postmortem brain tissue from Alzheimer's disease patients. Magn. Reson. Med., 57, 172-180.
138. Antharam, V., Collingwood, J.F., Bullivant, J.P., Davidson, M.R., Chandra, S., Mikhaylova, A., Finnegan, M.E., Batich, C., Forder, J.R., and Dobson, J. (2012) High field magnetic resonance microscopy of the human hippocampus in Alzheimer's disease: quantitative imaging and correlation with iron. NeuroImage, 59, 1249-1260.
139. Blazejewska, A.I., Schwarz, S.T., Pitiot, A., Stephenson, M.C., Lowe, J., Bajaj, N., Bowtell, R.W., Auer, D.P., and Gowland, P.A. (2013) Visualization of nigrosome 1 and its loss in PD: pathoanatomical correlation and in vivo 7 T MRI. Neurology, 81, 534-540.
140. Langkammer, C., Schweser, F., Krebs, N., Deistung, A., Goessler, W., Scheurer, E., Sommer, K., Reishofer, G., Yen, K., Fazekas, F., Ropele, S., and Reichenbach, J.R. (2012) Quantitative susceptibility mapping (QSM) as a means to measure brain iron? A post mortem validation study. NeuroImage, 62, 1593-1599.
141. Hopp, K., Popescu, B.F., McCrea, R.P., Harder, S.L., Robinson, C.A., Haacke, M.E., Rajput, A.H., Rajput, A., and Nichol, H. (2010) Brain iron detected by SWI high pass filtered phase calibrated with synchrotron X-ray fluorescence. J. Magn. Reson. Imaging, 31, 1346-1354.
142. Bulte, J.W., Vymazal, J., Brooks, R.A., Pierpaoli, C., and Frank, J.A. (1993) Frequency dependence of MR relaxation times. II. Iron oxides. J. Magn. Reson. Imaging, 3, 641-648.
143. Vymazal, J., Brooks, R.A., Baumgarner, C., Tran, V., Katz, D., Bulte, J.W.M., Bauminger, E.R., and DiChiro, G. (1996) The relation between brain iron and NMR relaxation times: an in vitro study. Magn. Reson. Med., 35, 56-61.
144. Vymazal, J., Urgosik, D., and Bulte, J.W. (2000) Differentiation between hemosiderin- and ferritin-bound brain iron using nuclear magnetic resonance and magnetic resonance imaging. Cell. Mol. Biol., 46, 835-842.
145. Hocq, A., Luhmer, M., Saussez, S., Louryan, S., Gillis, P., and Gossuin, Y. (2014) Effect of magnetic field and iron content on NMR proton relaxation of liver, spleen and brain tissues. Contrast Media Mol. Imaging, 10, 144-152.
146. Gossuin, Y., Burtea, C., Monseux, A., Toubeau, G., Roch, A., Muller, R.N., and Gillis, P. (2004) Ferritin-induced relaxation in tissues: an in vitro study. J. Magn. Reson. Imaging, 20, 690-696.
147. Schweser, F., Deistung, A., Lehr, B.W., and Reichenbach, J.R. (2011) Quantitative imaging of intrinsic magnetic tissue properties using MRI signal phase: an approach to in vivo brain iron metabolism? NeuroImage, 54, 2789-2807.
148. Jensen, J.H., Szulc, K., Hu, C., Ramani, A., Lu, H., Xuan, L., Falangola, M.F., Chandra, R., Knopp, E.A., Schenck, J., Zimmerman, E.A., and Helpern, J.A. (2009) Magnetic field correlation as a measure of iron-generated magnetic field inhomogeneities in the brain. Magn.Reson.Med., 61, 481-485.
149. Berg, D. (2006) In vivo detection of iron and neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage. J. Neural Transm., 113, 775-780.
150. Becker, G. and Berg, D. (2001) Neuroimaging in basal ganglia disorders: perspectives for transcranial ultrasound. Mov. Disord., 16, 23-32.
151. Godau, J., Klose, U., Di Santo, A., Schweitzer, K., and Berg, D. (2008) Multiregional brain iron deficiency in restless legs syndrome. Mov. Disord., 23, 1184-1187.
152. Gutierrez, L., Costo, R., Gruttner, C., Westphal, F., Gehrke, N., Heinke, D., Fornara, A., Pankhurst, Q.A., Johansson, C., Veintemillas-Verdaguer, S., and Morales, M.P. (2015) Synthesis methods to prepare single- and multi-core iron oxide nanoparticles for biomedical applications. Dalton Trans., 44, 2943-2952.
153. Lin, M.M., Kim do, K., El Haj, A.J., and Dobson, J. (2008) Development of superparamagnetic iron oxide nanoparticles (SPIONS) for translation to clinical applications. IEEE Trans. Nanobiosci., 7, 298-305.
154. Krishnan, K.M. (2010) Biomedical nanomagnetics: a spin through possibilities in imaging, diagnostics, and therapy. IEEE Trans. Magn., 46, 2523-2558.
155. Krol, S. (2012) Challenges in drug deliverytothebrain:natureisagainst us. J. Controlled Release, 164, 145-155.
156. Hanini, A., Schmitt, A., Kacem, K., Chau, F., Ammar, S., and Gavard, J. (2011) Evaluation of iron oxide nanoparticle biocompatibility. Int. J. Nanomed., 6, 787-794.
157. Chen, Z., Yin, J.J., Zhou, Y.T., Zhang, Y., Song, L., Song, M., Hu, S., and Gu, N. (2012) Dual enzyme-like activities of iron oxide nanoparticles and their implication for diminishing cytotoxicity. ACS Nano, 6, 4001-4012.
158. 4 nanoparticles combined with daunorubicin for rat brain in vivo. J. Biomed. Nanotechnol., 8, 417-423.
159. Pankhurst, Q.A., Connolly, J., Jones, S.K., and Dobson, J. (2003) Applications of magnetic nanoparticles in biomedicine. J.Phys.D:Appl.Phys., 36, R167-R181.
160. Neuwelt, E.A., Varallyay, P., Bago, A.G., Muldoon, L.L., Nesbit, G., and Nixon, R. (2004) Imaging of iron oxide nanoparticles by MR and light microscopy in patients with malignant brain tumours. Neuropathol. Appl. Neurobiol., 30, 456-471.
161. Zhu, J.H., Zhou, L.F., and Xing Wu, F.G. (2006) Tracking neural stem cells in patients with brain trauma. N. Engl. J. Med., 355, 2376-2378.
162. Alexiou, C., Arnold, W., Klein, R.J., Parak, F.G., Hulin, P., Bergemann, C., Erhardt, W., Wagenpfeil, S., and Lubbe, A.S. (2000) Locoregional cancer treatment with magnetic drug targeting. Cancer Res., 60, 6641-6648.
163. DeVries, H.E., Kuiper, J., DeBoer, A.G., VanBerkel, T.J.C., and Breimer, D.D. (1997) The blood-brain barrier in neuroinflammatory diseases. Pharmacol. Rev, 49, 143-155.
164. Cheng, K.K., Chan, P.S., Fan, S.J., Kwan, S.M., Yeung, K.L., Wang, Y.X.J., Chow, A.H.L., Wu, E.X., and Baum, L. (2015) Curcumin-conjugated magnetic nanoparticles for detecting amyloid plaques in Alzheimer's disease mice using magnetic resonance imaging (MRI). Biomaterials, 44, 155-172.
165. Hergt, R., Dutz, S., Muller, R., and Zeisberger, M. (2006) Magnetic particle hyperthermia: nanoparticle magnetism and materials development for cancer therapy. J. Phys.: Condens. Matter, 18, S2919-S2934.
166. Cavaliere, R., Ciocatto, E.C., Giovanella, B.C., Heidelberger, C., Johnson, R.O., Margottini, M., Mondovi, B., Moricca, G., and Rossi-Fanelli, A. (1967) Selective heat sensitivity of cancer cells. Biochemical and clinical studies. Cancer, 20, 1351-1381.
167. Maier-Hauff, K., Ulrich, F., Nestler, D., Niehoff, H., Wust, P., Thiesen, B., Orawa, H., Budach, V., and Jordan, A. (2011) Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme. J. Neuro-Oncol., 103, 317-324.
168. Zhang, E., Kircher, M.F., Koch, M., Eliasson, L., Goldberg, S.N., and Renstrom, E. (2014) Dynamic magnetic fields remote-control apoptosis via nanoparticle rotation. ACS Nano, 8, 3192-3201.
169. Pennell, D.J., Porter, J.B., Piga, A., Lai, Y.R., El-Beshlawy, A., Elalfy, M., Yesilipek, A., Kilinc, Y., Habr, D., Musallam, K.M., Shen, J., Aydinok, Y., and Cordelia Study Investigators (2015) Sustained improvements in myocardial T2* over 2 years in severely iron-overloaded patients with beta thalassemia major treated with deferasirox or deferoxamine. Am. J. Hematol., 90, 91-96.
170. Abbruzzese, G., Cossu, G., Balocco, M., Marchese, R., Murgia, D., Melis, M., Galanello, R., Barella, S., Matta, G., Ruffinengo, U., Bonuccelli, U., and Forni, G.L. (2011) A pilot trial of deferiprone for neurodegeneration with brain iron accumulation. Haematologica, 96, 1708-1711.
171. Devos, D., Moreau, C., Devedjian, J.C., Kluza, J., Petrault, M., Laloux, C., Jonneaux, A., Ryckewaert, G., Garcon, G., Rouaix, N., Duhamel, A., Jissendi, P., Dujardin, K., Auger, F., Ravasi, L., Hopes, L., Grolez, G., Firdaus, W., Sablonniere, B., Strubi-Vuillaume, I., Zahr, N., Destee, A., Corvol, J.C., Poltl, D., Leist, M., Rose, C., Defebvre, L., Marchetti, P., Cabantchik, Z.I., and Bordet, R. (2014) Targeting chelatable iron as a therapeutic modality in Parkinson's disease. Antioxid. Redox Signaling, 21, 195-21