Brain iron accumulation in aging and neurodegenerative disorders

Expert Review of Neurotherapeutics

Volumn 12, Issue 12, 2012, Pages 1467-1480

  Hagemeier, Jesper ^a   Geurts, Jeroen J G ^b   Zivadinov, Robert ^a  

^a UNIVERSITY AT BUFFALO   (United States)

^b VU UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

aging; Alzheimer's disease; iron deposition; multiple sclerosis; neurodegenerative disorders; oxidative stress; Parkinson's disease

Indexed keywords

CLIOQUINOL; DEFERASIROX; DEFERIPRONE; DEFEROXAMINE; FREE RADICAL; IRON; METAL ION; REACTIVE OXYGEN METABOLITE;

AGING; ALZHEIMER DISEASE; CAENORHABDITIS ELEGANS; DROSOPHILA MELANOGASTER; ENVIRONMENTAL FACTOR; HEREDITY; HOMEOSTASIS; HUMAN; IN VIVO STUDY; IRON DEPLETION; MULTIPLE SCLEROSIS; NEURODEGENERATION WITH BRAIN IRON ACCUMULATION; NEUROIMAGING; NEUROTOXICITY; NON INVASIVE PROCEDURE; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; OXIDATIVE STRESS; PARKINSON DISEASE; PROTEIN AGGREGATION; REVIEW; SEX DIFFERENCE; SUSCEPTIBILITY WEIGHTED IMAGING;

AGING; BRAIN; BRAIN CHEMISTRY; HUMANS; IRON; NEURODEGENERATIVE DISEASES;

EID: 84871075551     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/ern.12.128     Document Type: Review

References (196)

1. Beard JL, Connor JR. Iron status and neural functioning. Annu. Rev. Nutr. 23, 41-58 (2003). (Pubitemid 37059715)
2. Hallgren B, Sourander P. The effect of age on the non-haemin iron in the human brain. J. Neurochem. 3(1), 41-51 (1958).
3. Dröge W, Schipper HM. Oxidative stress and aberrant signaling in aging and cognitive decline. Aging Cell 6(3), 361-370 (2007). (Pubitemid 46785141)
4. Gerlach M, Ben-Shachar D, Riederer P, Youdim MB. Altered brain metabolism of iron as a cause of neurodegenerative diseases? J. Neurochem. 63(3), 793-807 (1994). (Pubitemid 24266591)
5. Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR. Iron, brain ageing and neurodegenerative disorders. Nat. Rev. Neurosci. 5(11), 863-873 (2004). (Pubitemid 39482155)
6. Beard J. Iron deficiency alters brain development and functioning. J. Nutr. 133(5 Suppl. 1), 1468S-1472S (2003). (Pubitemid 36548728)
7. Beard JL, Connor JR, Jones BC. Iron in the brain. Nutr. Rev. 51(6), 157-170 (1993). (Pubitemid 23247807)
8. Harrison PM, Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation. Biochim. Biophys. Acta 1275(3), 161-203 (1996). (Pubitemid 26248989)
9. Mims MP, Prchal JT. Divalent metal transporter 1. Hematology 10(4), 339-345 (2005). (Pubitemid 41801131)
10. Anderson GJ, Vulpe CD. Mammalian iron transport. Cell. Mol. Life Sci. 66(20), 3241-3261 (2009).
11. Andrews NC. Iron homeostasis: insights from genetics and animal models. Nat. Rev. Genet. 1(3), 208-217 (2000).
12. Crichton RR, Dexter DT, Ward RJ. Brain iron metabolism and its perturbation in neurological diseases. J. Neural Transm. 118(3), 301-314 (2011).
13. Harris ZL, Durley AP, Man TK, Gitlin JD. Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc. Natl Acad. Sci. USA 96(19), 10812-10817 (1999). (Pubitemid 29442226)
14. Texel SJ, Camandola S, Ladenheim B et al. Ceruloplasmin deficiency results in an anxiety phenotype involving deficits in hippocampal iron, serotonin, and BDNF. J. Neurochem. 120(1), 125-134 (2012).
15. Kidane TZ, Sauble E, Linder MC. Release of iron from ferritin requires lysosomal activity. Am. J. Physiol., Cell Physiol. 291(3), C445-C455 (2006). (Pubitemid 44343627)
16. Terman A, Kurz T. Lysosomal iron, iron chelation and cell death. Antioxid. Redox Signal. doi:10.1089/ars.2012.4885 (2012) (Epub ahead of print).
17. Nemeth E, Tuttle MS, Powelson J et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306(5704), 2090-2093 (2004). (Pubitemid 40007660)
18. Crichton RR, Wilmet S, Legssyer R, Ward RJ. Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells. J. Inorg. Biochem. 91(1), 9-18 (2002). (Pubitemid 34727756)
19. Moos T, Skjoerringe T, Gosk S, Morgan EH. Brain capillary endothelial cells mediate iron transport into the brain by segregating iron from transferrin without the involvement of divalent metal transporter 1. J. Neurochem. 98(6), 1946-1958 (2006). (Pubitemid 44298257)
20. Morgan EH, Moos T. Mechanism and developmental changes in iron transport across the blood-brain barrier. Dev. Neurosci. 24(2-3), 106-113 (2002). (Pubitemid 36151440)
21. Moos T, Rosengren Nielsen T, Skjørringe T, Morgan EH. Iron trafficking inside the brain. J. Neurochem. 103(5), 1730-1740 (2007). (Pubitemid 350126643)
22. Youdim MB, Ben-Shachar D, Yehuda S. Putative biological mechanisms of the effect of iron deficiency on brain biochemistry and behavior. Am. J. Clin. Nutr. 50(Suppl. 3), 607-615; discussion 615. (1989).
23. Connor JR, Ponnuru P, Wang XS, Patton SM, Allen RP, Earley CJ. Profile of altered brain iron acquisition in restless legs syndrome. Brain 134(Pt 4), 959-968 (2011).
24. Rouault TA, Zhang DL, Jeong SY. Brain iron homeostasis, the choroid plexus, and localization of iron transport proteins. Metab. Brain Dis. 24(4), 673-684 (2009).
25. Xu J, Marzetti E, Seo AY, Kim JS, Prolla TA, Leeuwenburgh C. The emerging role of iron dyshomeostasis in the mitochondrial decay of aging. Mech. Ageing Dev. 131(7-8), 487-493 (2010).
26. Andersen JK. Oxidative stress in neurodegeneration: cause or consequence? Nat. Med. 10(Suppl.), S18-S25 (2004). (Pubitemid 38901863)
27. Halliwell B. Reactive oxygen species and the central nervous system. J. Neurochem. 59(5), 1609-1623 (1992).
28. Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease. Toxicology 283(2-3), 65-87 (2011).
29. Liang LP, Jarrett SG, Patel M. Chelation of mitochondrial iron prevents seizureinduced mitochondrial dysfunction and neuronal injury. J. Neurosci. 28(45), 11550-11556 (2008).
30. Millerot-Serrurot E, Bertrand N, Mossiat C et al. Temporal changes in free iron levels after brain ischemia Relevance to the timing of iron chelation therapy in stroke. Neurochem. Int. 52(8), 1442-1448 (2008).
31. Bains JS, Shaw CA. Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death. Brain Res. Brain Res. Rev. 25(3), 335-358 (1997). (Pubitemid 28071452)
32. Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants, and the degenerative diseases of aging. Proc. Natl Acad. Sci. USA 90(17), 7915-7922 (1993). (Pubitemid 23260825)
33. Atwood CS, Obrenovich ME, Liu T et al. Amyloid-β: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-β. Brain Res. Brain Res. Rev. 43(1), 1-16 (2003). (Pubitemid 37130077)
34. Kontush A. Amyloid-β: an antioxidant that becomes a pro-oxidant and critically contributes to Alzheimer's disease. Free Radic. Biol. Med. 31(9), 1120-1131 (2001). (Pubitemid 33000134)
35. Smith MA, Casadesus G, Joseph JA, Perry G. Amyloid-β and tau serve antioxidant functions in the aging and Alzheimer brain. Free Radic. Biol. Med. 33(9), 1194-1199 (2002). (Pubitemid 35246587)
36. Koeppen AH. The history of iron in the brain. J. Neurol. Sci. 134(Suppl.), 1-9 (1995).
37. 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 15(1), 29-35 (1997). (Pubitemid 27143746)
38. 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. 27(4), 595-611 (1990).
39. Connor JR, Snyder BS, Arosio P, Loeffler DA, LeWitt P. A quantitative analysis of isoferritins in select regions of aged, parkinsonian, and Alzheimer's diseased brains. J. Neurochem. 65(2), 717-724 (1995).
40. Zecca L, Gallorini M, Schünemann V et al. 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(6), 1766-1773 (2001). (Pubitemid 32221116)
41. Hirose W, Ikematsu K, Tsuda R. Ageassociated increases in heme oxygenase-1 and ferritin immunoreactivity in the autopsied brain. Leg. Med. 5(Suppl. 1), 360-366 (2003).
42. Maines MD. Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. FASEB J. 2(10), 2557-2568 (1988).
43. Schipper HM, Song W, Zukor H, Hascalovici JR, Zeligman D. Heme oxygenase-1 and neurodegeneration: expanding frontiers of engagement. J. Neurochem. 110(2), 469-485 (2009).
44. Bartzokis G, Marder SR. Magnetic resonance imaging evaluation of brain iron levels. Biol. Psychiatry 38(2), 133-135 (1995).
45. Bartzokis G, Mintz J, Sultzer D et al. In vivo MR evaluation of age-related increases in brain iron. AJNR Am. J. Neuroradiol. 15(6), 1129-1138 (1994). (Pubitemid 24184373)
46. Thomas LO, Boyko OB, Anthony DC, Burger PC. MR detection of brain iron. AJNR Am. J. Neuroradiol. 14(5), 1043-1048 (1993). (Pubitemid 23281331)
47. Aoki S, Okada Y, Nishimura K et al. Normal deposition of brain iron in childhood and adolescence: MR imaging at 1.5 T. Radiology 172(2), 381-385 (1989). (Pubitemid 19184873)
48. Aquino D, Bizzi A, Grisoli M et al. Age-related iron deposition in the basal ganglia: quantitative analysis in healthy subjects. Radiology 252(1), 165-172 (2009).
49. Cherubini A, Péran P, Caltagirone C, Sabatini U, Spalletta G. Aging of subcortical nuclei: microstructural, mineralization and atrophy modifications measured in vivo using MRI. Neuroimage 48(1), 29-36 (2009).
50. Martin WR, Ye FQ, Allen PS. Increasing striatal iron content associated with normal aging. Mov. Disord. 13(2), 281-286 (1998). (Pubitemid 28127804)
51. Péran P, Cherubini A, Luccichenti G et al. Volume and iron content in basal ganglia and thalamus. Hum. Brain Mapp. 30(8), 2667-2675 (2009).
52. Bilgic B, Pfefferbaum A, Rohlfing T, Sullivan EV, Adalsteinsson E. MRI estimates of brain iron concentration in normal aging using quantitative susceptibility mapping. Neuroimage 59(3), 2625-2635 (2012).
53. 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 47(2), 493-500 (2009).
54. Xu X, Wang Q, Zhang M. Age, gender, and hemispheric differences in iron deposition in the human brain: an in vivo MRI study. Neuroimage 40(1), 35-42 (2008).
55. Antharam V, Collingwood JF, Bullivant JP et al. High field magnetic resonance microscopy of the human hippocampus in Alzheimer's disease: quantitative imaging and correlation with iron. Neuroimage 59(2), 1249-1260 (2012).
56. Bagnato F, Hametner S, Yao B et al. Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla. Brain 134(Pt 12), 3602-3615 (2011).
57. Lotfipour AK, Wharton S, Schwarz ST et al. High resolution magnetic susceptibility mapping of the substantia nigra in Parkinson's disease. J. Magn. Reson. Imaging 35(1), 48-55 (2012).
58. Penke L, Valdés Hernandéz MC, Maniega SM et al. Brain iron deposits are associated with general cognitive ability and cognitive aging. Neurobiol. Aging 33(3), 510-517.e2 (2012).
59. Sullivan EV, Adalsteinsson E, Rohlfing T, Pfefferbaum A. Relevance of iron deposition in deep gray matter brain structures to cognitive and motor performance in healthy elderly men and women: exploratory findings. Brain Imaging Behav. 3(2), 167-175 (2009).
60. Harman D. Free radical theory of aging. Mutat. Res. 275(3-6), 257-266 (1992).
61. Lee CK, Klopp RG, Weindruch R, Prolla TA. Gene expression profile of aging and its retardation by caloric restriction. Science 285(5432), 1390-1393 (1999). (Pubitemid 29411668)
62. Kennedy BK, Steffen KK, Kaeberlein M. Ruminations on dietary restriction and aging. Cell. Mol. Life Sci. 64(11), 1323-1328 (2007). (Pubitemid 46889228)
63. Mair W, Dillin A. Aging and survival: the genetics of life span extension by dietary restriction. Annu. Rev. Biochem. 77, 727-754 (2008).
64. Masoro EJ. Caloric restriction and aging: an update. Exp. Gerontol. 35(3), 299-305 (2000). (Pubitemid 30314687)
65. Sharma PK, Mittal N, Deswal S, Roy N. Calorie restriction up-regulates iron and copper transport genes in Saccharomyces cerevisiae. Mol. Biosyst. 7(2), 394-402 (2011).
66. Bonilla E, Medina-Leendertz S, Díaz S. Extension of life span and stress resistance of Drosophila melanogaster by long-term supplementation with melatonin. Exp. Gerontol. 37(5), 629-638 (2002). (Pubitemid 34224108)
67. Melov S, Ravenscroft J, Malik S et al. Extension of life-span with superoxide dismutase/catalase mimetics. Science 289(5484), 1567-1569 (2000).
68. Massie HR, Aiello VR, Williams TR. Inhibition of iron absorption prolongs the life span of Drosophila. Mech. Ageing Dev. 67(3), 227-237 (1993).
69. Gakh O, Park S, Liu G et al. Mitochondrial iron detoxification is a primary function of frataxin that limits oxidative damage and preserves cell longevity. Hum. Mol. Genet. 15(3), 467-479 (2006). (Pubitemid 43159898)
70. Lapointe J, Hekimi S. When a theory of aging ages badly. Cell. Mol. Life Sci. 67(1), 1-8 (2010).
71. Whitfield JB, Treloar S, Zhu G, Powell LW, Martin NG. Relative importance of female-specific and non-female-specific effects on variation in iron stores between women. Br. J. Haematol. 120(5), 860-866 (2003). (Pubitemid 36315112)
72. Milman N. Serum ferritin in Danes: studies of iron status from infancy to old age, during blood donation and pregnancy. Int. J. Hematol. 63(2), 103-135 (1996). (Pubitemid 26084888)
73. Zacharski LR, Ornstein DL, Woloshin S, Schwartz LM. Association of age, sex, and race with body iron stores in adults: analysis of NHANES III data. Am. Heart J. 140(1), 98-104 (2000). (Pubitemid 30471247)
74. Bartzokis G, Tishler TA, Lu PH et al. Brain ferritin iron may influence age-and gender-related risks of neurodegeneration. Neurobiol. Aging 28(3), 414-423 (2007). (Pubitemid 46177391)
75. Haaxma CA, Bloem BR, Borm GF et al. Gender differences in Parkinson's disease. J. Neurol. Neurosurg. Psychiatr. 78(8), 819-824 (2007). (Pubitemid 47204585)
76. Bartzokis G, Tishler TA, Shin IS, Lu PH, Cummings JL. Brain ferritin iron as a risk factor for age at onset in neurodegenerative diseases. Ann. NY Acad. Sci. 1012, 224-236 (2004). (Pubitemid 38453528)
77. Bartzokis G, Lu PH, Tishler TA et al. Prevalent iron metabolism gene variants associated with increased brain ferritin iron in healthy older men. J. Alzheimers Dis. 20(1), 333-341 (2010).
78. Tishler TA, Raven EP, Lu PH, Altshuler LL, Bartzokis G. Premenopausal hysterectomy is associated with increased brain ferritin iron. Neurobiol. Aging 33(9), 1950-1958 (2012).
79. Sazawal S, Black RE, Ramsan M et al. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet 367(9505), 133-143 (2006). (Pubitemid 43077129)
80. WHO. Conclusions and recommendations of the WHO consultation on prevention and control of iron deficiency in infants and young children in malaria-endemic areas. Food Nutr. Bull. 28, 621-627 (2007).
81. Mursu J, Robien K, Harnack LJ, Park K, Jacobs DR Jr. Dietary supplements and mortality rate in older women: the Iowa Women's Health Study. Arch. Intern. Med. 171(18), 1625-1633 (2011).
82. Polla AS, Polla LL, Polla BS. Iron as the malignant spirit in successful ageing. Ageing Res. Rev. 2(1), 25-37 (2003). (Pubitemid 37443916)
83. Bissett DL, McBride JF. Synergistic topical photoprotection by a combination of the iron chelator 2-furildioxime and sunscreen. J. Am. Acad. Dermatol. 35(4), 546-549 (1996). (Pubitemid 26427054)
84. Bissett DL, Chatterjee R, Hannon DP. Chronic ultraviolet radiation-induced increase in skin iron and the photoprotective effect of topically applied iron chelators. Photochem. Photobiol. 54(2), 215-223 (1991).
85. Bissett DL, Oelrich DM, Hannon DP. Evaluation of a topical iron chelator in animals and in human beings: short-term photoprotection by 2-furildioxime. J. Am. Acad. Dermatol. 31(4), 572-578 (1994). (Pubitemid 24309772)
86. Tuomainen TP, Kontula K, Nyyssönen K, Lakka TA, Heliö T, Salonen JT. Increased risk of acute myocardial infarction in carriers of the hemochromatosis gene Cys282Tyr mutation: a prospective cohort study in men in eastern Finland. Circulation 100(12), 1274-1279 (1999). (Pubitemid 29440118)
87. Roest M, van der Schouw YT, de Valk B et al. Heterozygosity for a hereditary hemochromatosis gene is associated with cardiovascular death in women. Circulation 100(12), 1268-1273 (1999). (Pubitemid 29440117)
88. Allen KJ, Gurrin LC, Constantine CC et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N. Engl. J. Med. 358(3), 221-230 (2008).
89. Nandar W, Connor JR. HFE gene variants affect iron in the brain. J. Nutr. 141(4), S729-S739 (2011).
90. Ristic S, Lovrecic L, Brajenovic-Milic B et al. Mutations in the hemochromatosis gene (HFE) and multiple sclerosis. Neurosci. Lett. 383(3), 301-304 (2005). (Pubitemid 40805574)
91. Rubio JP, Bahlo M, Tubridy N et al. Extended haplotype analysis in the HLA complex reveals an increased frequency of the HFE-C282Y mutation in individuals with multiple sclerosis. Hum. Genet. 114(6), 573-580 (2004). (Pubitemid 39010854)
92. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch. Neurol. 60(8), 1119-1122 (2003). (Pubitemid 36975801)
93. Plassman BL, Langa KM, Fisher GG et al. Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology 29(1-2), 125-132 (2007). (Pubitemid 350191430)
94. Kester MI, Scheltens P. Dementia: the bare essentials. Pract. Neurol. 9(4), 241-251 (2009).
95. Jack CR Jr, Petersen RC, Xu YC et al. Medial temporal atrophy on MRI in normal aging and very mild Alzheimer's disease. Neurology 49(3), 786-794 (1997). (Pubitemid 27428023)
96. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297(5580), 353-356 (2002). (Pubitemid 34790756)
97. Kang J, Lemaire HG, Unterbeck A et al. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325(6106), 733-736 (1987). (Pubitemid 17054046)
98. Nunan J, Small DH. Regulation of APP cleavage by α-, β-and γ-secretases. FEBS Lett. 483(1), 6-10 (2000).
99. Small DH, McLean CA. Alzheimer's disease and the amyloid β protein: What is the role of amyloid? J. Neurochem. 73(2), 443-449 (1999). (Pubitemid 29339815)
100. Yan Y, Wang C. Aβ42 is more rigid than Aβ40 at the C terminus: implications for Aβ aggregation and toxicity. J. Mol. Biol. 364(5), 853-862 (2006). (Pubitemid 44765041)
101. Maynard CJ, Bush AI, Masters CL, Cappai R, Li QX. Metals and amyloid-β in Alzheimer's disease. Int. J. Exp. Pathol. 86(3), 147-159 (2005).
102. Klein WL, Krafft GA, Finch CE. Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci. 24(4), 219-224 (2001). (Pubitemid 32204378)
103. Bush AI, Tanzi RE. Therapeutics for Alzheimer's disease based on the metal hypothesis. Neurotherapeutics 5(3), 421-432 (2008). (Pubitemid 351952485)
104. Duce JA, Tsatsanis A, Cater MA et al. Iron-export ferroxidase activity of ß-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 142(6), 857-867 (2010).
105. Connor JR, Snyder BS, Beard JL, Fine RE, Mufson EJ. Regional distribution of iron and iron-regulatory proteins in the brain in aging and Alzheimer's disease. J. Neurosci. Res. 31(2), 327-335 (1992).
106. LeVine SM. Iron deposits in multiple sclerosis and Alzheimer's disease brains. Brain Res. 760(1-2), 298-303 (1997). (Pubitemid 27304170)
107. Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR. Copper, iron and zinc in Alzheimer's disease senile plaques. J. Neurol. Sci. 158(1), 47-52 (1998). (Pubitemid 28277534)
108. Schrag M, Mueller C, Oyoyo U, Smith MA, Kirsch WM. Iron, zinc and copper in the Alzheimer's disease brain: a quantitative meta-analysis. Some insight on the influence of citation bias on scientific opinion. Prog. Neurobiol. 94(3), 296-306 (2011).
109. Miller LM, Wang Q, Telivala TP, Smith RJ, Lanzirotti A, Miklossy J. Synchrotronbased infrared and X-ray imaging shows focalized accumulation of Cu and Zn co-localized with β-amyloid deposits in Alzheimer's disease. J. Struct. Biol. 155(1), 30-37 (2006). (Pubitemid 43867313)
110. Rottkamp CA, Raina AK, Zhu X et al. Redox-active iron mediates amyloid-β toxicity. Free Radic. Biol. Med. 30(4), 447-450 (2001). (Pubitemid 32155543)
111. Honda K, Casadesus G, Petersen RB, Perry G, Smith MA. Oxidative stress and redox-active iron in Alzheimer's disease. Ann. NY Acad. Sci. 1012, 179-182 (2004). (Pubitemid 38453525)
112. Bishop GM, Robinson SR, Liu Q, Perry G, Atwood CS, Smith MA. Iron: a pathological mediator of Alzheimer disease? Dev. Neurosci. 24(2-3), 184-187 (2002). (Pubitemid 36151449)
113. Atwood CS, Robinson SR, Smith MA. Amyloid-β: redox-metal chelator and antioxidant. J. Alzheimers Dis. 4(3), 203-214 (2002).
114. Yan SD, Yan SF, Chen X et al. Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid β-peptide. Nat. Med. 1(7), 693-699 (1995).
115. Castellani RJ, Lee HG, Perry G, Smith MA. Antioxidant protection and neurodegenerative disease: the role of amyloid-β and tau. Am. J. Alzheimers. Dis. Other Demen. 21(2), 126-130 (2006).
116. Tamagno E, Guglielmotto M, Aragno M et al. Oxidative stress activates a positive feedback between the γ-and β-secretase cleavages of the β-amyloid precursor protein. J. Neurochem. 104(3), 683-695 (2008).
117. Bartzokis G, Sultzer D, Mintz J et al. In vivo evaluation of brain iron in Alzheimer's disease and normal subjects using MRI. Biol. Psychiatry 35(7), 480-487 (1994). (Pubitemid 24122331)
118. Bartzokis G, Sultzer D, Cummings J et al. In vivo evaluation of brain iron in Alzheimer disease using magnetic resonance imaging. Arch. Gen. Psychiatry 57(1), 47-53 (2000). (Pubitemid 30035658)
119. Bartzokis G, Tishler TA. MRI evaluation of basal ganglia ferritin iron and neurotoxicity in Alzheimer's and Huntingon's disease. Cell. Mol. Biol. (Noisy-le-grand) 46(4), 821-833 (2000).
120. House MJ, St Pierre TG, Foster JK, Martins RN, Clarnette R. Quantitative MR imaging R2 relaxometry in elderly participants reporting memory loss. AJNR Am. J. Neuroradiol. 27(2), 430-439 (2006). (Pubitemid 44897857)
121. Smith MA, Zhu X, Tabaton M et al. Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment. J. Alzheimers Dis. 19(1), 363-372 (2010).
122. Leskovjan AC, Kretlow A, Lanzirotti A, Barrea R, Vogt S, Miller LM. Increased brain iron coincides with early plaque formation in a mouse model of Alzheimer's disease. Neuroimage 55(1), 32-38 (2011).
123. Ling HW, Ding B, Wang T, Zhang H, Chen KM. Could iron accumulation be an etiology of the white matter change in Alzheimer's disease: using phase imaging to detect white matter iron deposition based on diffusion tensor imaging. Dement. Geriatr. Cogn. Disord. 31(4), 300-308 (2011).
124. van Rensburg SJ, Carstens ME, Potocnik FC, Aucamp AK, Taljaard JJ. Increased frequency of the transferrin C2 subtype in Alzheimer's disease. Neuroreport 4(11), 1269-1271 (1993). (Pubitemid 23289210)
125. Namekata K, Imagawa M, Terashi A, Ohta S, Oyama F, Ihara Y. Association of transferrin C2 allele with late-onset Alzheimer's disease. Hum. Genet. 101(2), 126-129 (1997). (Pubitemid 28014718)
126. Moalem S, Percy ME, Andrews DF et al. Are hereditary hemochromatosis mutations involved in Alzheimer disease? Am. J. Med. Genet. 93(1), 58-66 (2000). (Pubitemid 30350273)
127. Sampietro M, Caputo L, Casatta A et al. The hemochromatosis gene affects the age of onset of sporadic Alzheimer's disease. Neurobiol. Aging 22(4), 563-568 (2001). (Pubitemid 32607740)
128. Alizadeh BZ, Njajou OT, Millán MR, Hofman A, Breteler MM, van Duijn CM. HFE variants, APOE and Alzheimer's disease: findings from the population-based Rotterdam study. Neurobiol. Aging 30(2), 330-332 (2009).
129. Lin M, Zhao L, Fan J et al. Association between HFE polymorphisms and susceptibility to Alzheimer's disease: a meta-analysis of 22 studies including 4,365 cases and 8,652 controls. Mol. Biol. Rep. 39(3), 3089-3095 (2012).
130. Sian-Hülsmann J, Mandel S, Youdim MB, Riederer P. The relevance of iron in the pathogenesis of Parkinson's disease. J. Neurochem. 118(6), 939-957 (2011).
131. Dexter DT, Carayon A, Javoy-Agid F et al. Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114 (Pt 4), 1953-1975 (1991).
132. Morawski M, Meinecke C, Reinert T et al. Determination of trace elements in the human substantia nigra. Nucl. Instrum. Methods B 231(1-4), 224-228 (2005).
133. Jin L, Wang J, Jin H et al. Nigral iron deposition occurs across motor phenotypes of Parkinson's disease. Eur. J. Neurol. 19(7), 969-976 (2012).
134. 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 45(6), 1138-1143 (1995).
135. Atasoy HT, Nuyan O, Tunc T, Yorubulut M, Unal AE, Inan LE. T2-weighted MRI in Parkinson's disease; substantia nigra pars compacta hypointensity correlates with the clinical scores. Neurol. India 52(3), 332-337 (2004). (Pubitemid 39430186)
136. Wallis LI, Paley MN, Graham JM et al. MRI assessment of basal ganglia iron deposition in Parkinson's disease. J. Magn. Reson. Imaging 28(5), 1061-1067 (2008).
137. Martin WR, Wieler M, Gee M. Midbrain iron content in early Parkinson disease: a potential biomarker of disease status. Neurology 70(16 Pt 2), 1411-1417 (2008). (Pubitemid 351521933)
138. Du G, Lewis MM, Styner M et al. Combined R2* and diffusion tensor imaging changes in the substantia nigra in Parkinson's disease. Mov. Disord. 26(9), 1627-1632 (2011).
139. Zucca FA, Bellei C, Giannelli S et al. Neuromelanin and iron in human locus coeruleus and substantia nigra during aging: consequences for neuronal vulnerability. J. Neural Transm. 113(6), 757-767 (2006). (Pubitemid 43847169)
140. Aime S, Bergamasco B, Casu M et al. Isolation and 13C-NMR characterization of an insoluble proteinaceous fraction from substantia nigra of patients with Parkinson's disease. Mov. Disord. 15(5), 977-981 (2000).
141. Shamoto-Nagai M, Maruyama W, Yi H et al. Neuromelanin induces oxidative stress in mitochondria through release of iron: mechanism behind the inhibition of 26S proteasome. J. Neural Transm. 113(5), 633-644 (2006). (Pubitemid 43673603)
142. Friedman A, Galazka-Friedman J, Koziorowski D. Iron as a cause of Parkinson disease-a myth or a well established hypothesis? Parkinsonism Relat. Disord. 15(Suppl. 3), S212-S214 (2009).
143. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. Proc. Natl Acad. Sci. USA 95(11), 6469-6473 (1998). (Pubitemid 28249037)
144. Chandra S, Gallardo G, Fernández-Chacón R, Schlüter OM, Südhof TC. α-Synuclein cooperates with CSPα in preventing neurodegeneration. Cell 123(3), 383-396 (2005). (Pubitemid 41546670)
145. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. α-synuclein in Lewy bodies. Nature 388(6645), 839-840 (1997).
146. Lee HG, Zhu X, Takeda A, Perry G, Smith MA. Emerging evidence for the neuroprotective role of α-synuclein. Exp. Neurol. 200(1), 1-7 (2006). (Pubitemid 44080768)
147. Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B. The A53T α-synuclein mutation increases irondependent aggregation and toxicity. J. Neurosci. 20(16), 6048-6054 (2000). (Pubitemid 30658398)
148. Hashimoto M, Takeda A, Hsu LJ, Takenouchi T, Masliah E. Role of cytochrome c as a stimulator of α-synuclein aggregation in Lewy body disease. J. Biol. Chem. 274(41), 28849-28852 (1999).
149. Riederer P, Sofic E, Rausch WD et al. Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J. Neurochem. 52(2), 515-520 (1989). (Pubitemid 19037617)
150. Dexter DT, Sian J, Jenner P, Marsden CD. Implications of alterations in trace element levels in brain in Parkinson's disease and other neurological disorders affecting the basal ganglia. Adv. Neurol. 60, 273-281 (1993).
151. Khalil M, Teunissen C, Langkammer C. Iron and neurodegeneration in multiple sclerosis. Mult. Scler. Int. 2011, 606807 (2011).
152. Pirko I, Lucchinetti CF, Sriram S, Bakshi R. Gray matter involvement in multiple sclerosis. Neurology 68(9), 634-642 (2007). (Pubitemid 46667808)
153. Zivadinov R, Heininen-Brown M, Schirda CV et al. Abnormal subcortical deep-gray matter susceptibility-weighted imaging filtered phase measurements in patients with multiple sclerosis: a case-control study. Neuroimage 59(1), 331-339 (2012).
154. Bakshi R, Dmochowski J, Shaikh ZA, Jacobs L. Gray matter T2 hypointensity is related to plaques and atrophy in the brains of multiple sclerosis patients. J. Neurol. Sci. 185(1), 19-26 (2001). (Pubitemid 32215497)
155. Neema M, Arora A, Healy BC et al. Deep gray matter involvement on brain MRI scans is associated with clinical progression in multiple sclerosis. J. Neuroimaging 19(1), 3-8 (2009).
156. 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. 234(1-2), 17-24 (2005). (Pubitemid 40910338)
157. Brass SD, Benedict RH, Weinstock-Guttman B, Munschauer F, Bakshi R. Cognitive impairment is associated with subcortical magnetic resonance imaging grey matter T2 hypointensity in multiple sclerosis. Mult. Scler. 12(4), 437-444 (2006). (Pubitemid 44132584)
158. Hagemeier J, Weinstock-Guttman B, Bergsland N et al. Iron deposition on SWI-filtered phase in the subcortical deep gray matter of patients with clinically isolated syndrome may precede structurespecific atrophy. AJNR Am. J. Neuroradiol. 33(8), 1596-1601 (2012).
159. Ceccarelli A, Rocca MA, Neema M et al. Deep gray matter T2 hypointensity is present in patients with clinically isolated syndromes suggestive of multiple sclerosis. Mult. Scler. 16(1), 39-44 (2010).
160. Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat. Genet. 28(4), 345-349 (2001). (Pubitemid 32702423)
161. Miyajima H, Takahashi Y, Kono S. Aceruloplasminemia, an inherited disorder of iron metabolism. Biometals 16(1), 205-213 (2003). (Pubitemid 36140230)
162. Chinnery PF, Crompton DE, Birchall D et al. Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation. Brain 130(Pt 1), 110-119 (2007). (Pubitemid 46026227)
163. Koutnikova H, Campuzano V, Foury F, Dollé P, Cazzalini O, Koenig M. Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nat. Genet. 16(4), 345-351 (1997). (Pubitemid 27323298)
164. Schneider SA, Hardy J, Bhatia KP. Syndromes of neurodegeneration with brain iron accumulation (NBIA): an update on clinical presentations, histological and genetic underpinnings, and treatment considerations. Mov. Disord. 27(1), 42-53 (2012).
165. Ke Y, Qian ZM. Brain iron metabolism: neurobiology and neurochemistry. Prog. Neurobiol. 83(3), 149-173 (2007). (Pubitemid 47484044)
166. Gregory A, Hayflick SJ. Genetics of neurodegeneration with brain iron accumulation. Curr. Neurol. Neurosci. Rep. 11(3), 254-261 (2011).
167. Miyajima H, Adachi J, Tatsuno Y et al. Increased very long-chain fatty
168. Kenche VB, Barnham KJ. Alzheimer's disease & metals: therapeutic opportunities. Br. J. Pharmacol. 163(2), 211-219 (2011).
169. Prass K, Ruscher K, Karsch M et al. Desferrioxamine induces delayed tolerance against cerebral ischemia in vivo and in vitro. J. Cereb. Blood Flow Metab. 22(5), 520-525 (2002). (Pubitemid 34477773)
170. Crapper McLachlan DR, Dalton AJ, Kruck TP et al. Intramuscular desferrioxamine in patients with Alzheimer's disease. Lancet 337(8753), 1304-1308 (1991).
171. Cherny RA, Atwood CS, Xilinas ME et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 30(3), 665-676 (2001). (Pubitemid 32607332)
172. Ritchie CW, Bush AI, Mackinnon A et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer disease: a pilot Phase 2 clinical trial. Arch. Neurol. 60(12), 1685-1691 (2003). (Pubitemid 37521621)
173. Adlard PA, Cherny RA, Finkelstein DI et al. Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Aβ. Neuron 59(1), 43-55 (2008). (Pubitemid 351905863)
174. Faux NG, Ritchie CW, Gunn A et al. PBT2 rapidly improves cognition in Alzheimer's Disease: additional Phase II analyses. J. Alzheimers Dis. 20(2), 509-516 (2010).
175. Lannfelt L, Blennow K, Zetterberg H et al.; PBT2-201-EURO study group. Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer's disease: a Phase IIa, doubleblind, randomised, placebo-controlled trial. Lancet Neurol. 7(9), 779-786 (2008).
176. Crouch PJ, Savva MS, Hung LW et al. The Alzheimer's therapeutic PBT2 promotes amyloid-ß degradation and GSK3 phosphorylation via a metal chaperone activity. J. Neurochem. 119(1), 220-230 (2011).
177. Perez CA, Tong Y, Guo M. Iron chelators as potential therapeutic agents for Parkinson's disease. Curr. Bioact. Compd. 4(3), 150-158 (2008).
178. Ben-Shachar D, Eshel G, Finberg JP, Youdim MB. The iron chelator desferrioxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J. Neurochem. 56(4), 1441-1444 (1991). (Pubitemid 21902069)
179. Jiang H, Luan Z, Wang J, Xie J. Neuroprotective effects of iron chelator Desferal on dopaminergic neurons in the substantia nigra of rats with iron-overload. Neurochem. Int. 49(6), 605-609 (2006). (Pubitemid 44528090)
180. Pedchenko TV, LeVine SM. Desferrioxamine suppresses experimental allergic encephalomyelitis induced by MBP in SJL mice. J. Neuroimmunol. 84(2), 188-197 (1998). (Pubitemid 28248405)
181. Mitchell KM, Dotson AL, Cool KM, Chakrabarty A, Benedict SH, LeVine SM. Deferiprone, an orally deliverable iron chelator, ameliorates experimental autoimmune encephalomyelitis. Mult. Scler. 13(9), 1118-1126 (2007). (Pubitemid 351541415)
182. Lynch SG, Fonseca T, LeVine SM. A multiple course trial of desferrioxamine in chronic progressive multiple sclerosis. Cell. Mol. Biol. (Noisy-le-grand) 46(4), 865-869 (2000).
183. Kaur D, Yantiri F, Rajagopalan S et al. Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease. Neuron 37(6), 899-909 (2003). (Pubitemid 36398297)
184. Wilson RB. Therapeutic developments in Friedreich ataxia. J. Child Neurol. 27(9), 1212-1216 (2012).
185. Dexter DT, Statton SA, Whitmore C et al. Clinically available iron chelators induce neuroprotection in the 6-OHDA model of Parkinson's disease after peripheral administration. J. Neural Transm. 118(2), 223-231 (2011).
186. Leed MG, Wolkow N, Pham DM, Daniel CL, Dunaief JL, Franz KJ. Prochelators triggered by hydrogen peroxide provide hexadentate iron coordination to impede oxidative stress. J. Inorg. Biochem. 105(9), 1161-1172 (2011).
187. Wei Y, Guo M. Hydrogen peroxide triggered prochelator activation, subsequent metal chelation, and attenuation of the fenton reaction. Angew. Chem. Int. Ed. Engl. 46(25), 4722-4725 (2007). (Pubitemid 46997471)
188. Mercer LD, Kelly BL, Horne MK, Beart PM. Dietary polyphenols protect dopamine neurons from oxidative insults and apoptosis: investigations in primary rat mesencephalic cultures. Biochem. Pharmacol. 69(2), 339-345 (2005). (Pubitemid 41556580)
189. Scalbert A, Williamson G. Dietary intake and bioavailability of polyphenols. J. Nutr. 130(8S Suppl.), S2073S-S2085 (2000).
190. Mandel SA, Amit T, Weinreb O, Youdim MB. Understanding the broad-spectrum neuroprotective action profile of green tea polyphenols in aging and neurodegenerative diseases. J. Alzheimers Dis. 25(2), 187-208 (2011).
191. Rahman I, Biswas SK, Kirkham PA. Regulation of inflammation and redox signaling by dietary polyphenols. Biochem. Pharmacol. 72(11), 1439-1452 (2006). (Pubitemid 44666744)
192. Sun AY, Simonyi A, Sun GY. The 'French Paradox' and beyond: neuroprotective effects of polyphenols. Free Radic. Biol. Med. 32(4), 314-318 (2002). (Pubitemid 34159085)
193. Scapagnini G, Caruso C, Calabrese V. Therapeutic potential of dietary polyphenols against brain ageing and neurodegenerative disorders. Adv. Exp. Med. Biol. 698, 27-35 (2010).
194. Levites Y, Weinreb O, Maor G, Youdim MB, Mandel S. Green tea polyphenol (-)-epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-induced dopaminergic neurodegeneration. J. Neurochem. 78(5), 1073-1082 (2001). (Pubitemid 32823156)
195. Joseph JA, Shukitt-Hale B, Denisova NA et al. Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J. Neurosci. 19(18), 8114-8121 (1999). (Pubitemid 30225807)
196. Reznichenko L, Kalfon L, Amit T, Youdim MB, Mandel SA. Low dosage of rasagiline and epigallocatechin gallate synergistically restored the nigrostriatal axis in MPTP-induced parkinsonism. Neurodegener. Dis. 7(4), 219-231 (2010).