Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions

Popescu, Bogdan F.; Frischer, Josa M.; Webb, Samuel M.; Tham, Mylyne; Adiele, Reginald C.; Robinson, Christopher A.; Fitz-Gibbon, Patrick D.; Weigand, Stephen D.; Metz, Imke; Nehzati, Susan; George, Graham N.; Pickering, Ingrid J.; Bruck, Wolfgang; Hametner, Simon; Lassmann, Hans; Parisi, Joseph E.; Yong, Guo; Lucchinetti, Claudia F.

doi:10.1007/s00401-017-1696-8

Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions

Journal Article · Wed Mar 22 00:00:00 EDT 2017 · Acta Neuropathologica

DOI:https://doi.org/10.1007/s00401-017-1696-8· OSTI ID:1372893

Popescu, Bogdan F. ^[1]; Frischer, Josa M. ^[2]; Webb, Samuel M. ^[3]; Tham, Mylyne ^[1]; Adiele, Reginald C. ^[1]; Robinson, Christopher A. ^[1]; Fitz-Gibbon, Patrick D. ^[4]; Weigand, Stephen D. ^[4]; Metz, Imke ^[5]; Nehzati, Susan ^[1]; George, Graham N. ^[1]; Pickering, Ingrid J. ^[1]; Bruck, Wolfgang ^[5]; Hametner, Simon ^[6]; Lassmann, Hans ^[6]; Parisi, Joseph E. ^[4]; Yong, Guo ^[4]; Lucchinetti, Claudia F. ^[4]

Univ. of Saskatchewan, Saskatoon (Canada)
Medical Univ. Vienna, Vienna (Austria)
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Mayo Clinic, Rochester, MN (United States)
Univ. of Gottingen, Gottingen (Germany)
Medical Univ. of Vienna, Vienna (Austria)

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) in which oligodendrocytes, the CNS cells that stain most robustly for iron and myelin are the targets of injury. Metals are essential for normal CNS functioning, and metal imbalances have been linked to demyelination and neurodegeneration. Using a multidisciplinary approach involving synchrotron techniques, iron histochemistry and immunohistochemistry, we compared the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing and periplaque white matter, and assessed the involvement of these metals in MS lesion pathogenesis. We found that the distribution of iron and zinc is heterogeneous in MS plaques, and with few remarkable exceptions they do not accumulate in chronic MS lesions. We show that brain iron tends to decrease with increasing age and disease duration of MS patients; reactive astrocytes organized in large astrogliotic areas in a subset of smoldering and inactive plaques accumulate iron and safely store it in ferritin; a subset of smoldering lesions do not contain a rim of iron-loaded macrophages/microglia; and the iron content of shadow plaques varies with the stage of remyelination. Zinc in MS lesions was generally decreased, paralleling myelin loss. Iron accumulates concentrically in a subset of chronic inactive lesions suggesting that not all iron rims around MS lesions equate with smoldering plaques. Furthermore, upon degeneration of iron-loaded microglia/macrophages, astrocytes may form an additional protective barrier that may prevent iron-induced oxidative damage.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Lab., Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), High Energy Physics (HEP) (SC-25)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1372893

Journal Information:: Acta Neuropathologica, Journal Name: Acta Neuropathologica Journal Issue: 1 Vol. 134; ISSN 0001-6322

Publisher:: SpringerCopyright Statement

Country of Publication:: United States

Language:: English

References (87)

Imaging Cortical Lesions in Multiple Sclerosis With Ultra–High-Field Magnetic Resonance Imaging Pitt, David; Boster, Aaron; Pei, Wei Archives of Neurology, Vol. 67, Issue 7 https://doi.org/10.1001/archneurol.2010.148	journal	July 2010
New diagnostic criteria for multiple sclerosis: Guidelines for research protocols Poser, Charles M.; Paty, Donald W.; Scheinberg, Labe Annals of Neurology, Vol. 13, Issue 3 https://doi.org/10.1002/ana.410130302	journal	March 1983
Cytokine toxicity to oligodendrocyte precursors is mediated by iron Zhang, Xuesheng; Haaf, Michael; Todorich, Bozho Glia, Vol. 52, Issue 3 https://doi.org/10.1002/glia.20235	journal	January 2005
Cellular iron status influences the functional relationship between microglia and oligodendrocytes Zhang, X.; Surguladze, N.; Slagle-Webb, B. Glia, Vol. 54, Issue 8 https://doi.org/10.1002/glia.20416	journal	January 2006
Iron homeostasis in astrocytes and microglia is differentially regulated by TNF-α and TGF-β1 Rathore, Khizr I.; Redensek, Adriana; David, Samuel Glia, Vol. 60, Issue 5 https://doi.org/10.1002/glia.22303	journal	February 2012
Brain iron detected by SWI high pass filtered phase calibrated with synchrotron X-ray fluorescence Hopp, Karla; Popescu, Bogdan F. Gh.; McCrea, Richard P. E. Journal of Magnetic Resonance Imaging, Vol. 31, Issue 6 https://doi.org/10.1002/jmri.22201	journal	May 2010
Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains Connor, J. R.; Menzies, S. L.; Martin, S. M. St. Journal of Neuroscience Research, Vol. 27, Issue 4 https://doi.org/10.1002/jnr.490270421	journal	December 1990
Studies on haemosiderin and ferritin from iron-loaded rat liver Andrews, Simon C.; Brady, Madeleine C.; Treffry, Amyra Biology of Metals, Vol. 1, Issue 1 https://doi.org/10.1007/bf01128015	journal	January 1988
Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration Finazzi, Dario; Arosio, Paolo Archives of Toxicology, Vol. 88, Issue 10 https://doi.org/10.1007/s00204-014-1329-0	journal	August 2014
Extended haplotype analysis in the HLA complex reveals an increased frequency of the HFE-C282Y mutation in individuals with multiple sclerosis Rubio, Justin P.; Tubridy, Niall; Bahlo, Melanie Human Genetics, Vol. 114, Issue 6 https://doi.org/10.1007/s00439-004-1095-9	journal	May 2004
The effect of formalin fixation on the levels of brain transition metals in archived samples Schrag, Matthew; Dickson, April; Jiffry, Arshad BioMetals, Vol. 23, Issue 6 https://doi.org/10.1007/s10534-010-9359-4	journal	June 2010
Myelin Breakdown and Iron Changes in Huntington’s Disease: Pathogenesis and Treatment Implications Bartzokis, George; Lu, Po H.; Tishler, Todd A. Neurochemical Research, Vol. 32, Issue 10 https://doi.org/10.1007/s11064-007-9352-7	journal	May 2007
The Pivotal Role of Astrocytes in the Metabolism of Iron in the Brain Dringen, Ralf; Bishop, Glenda M.; Koeppe, Maico Neurochemical Research, Vol. 32, Issue 11 https://doi.org/10.1007/s11064-007-9375-0	journal	June 2007
Neuronal Hemoglobin Expression and Its Relevance to Multiple Sclerosis Neuropathology Brown, Nolan; Alkhayer, Kholoud; Clements, Robert Journal of Molecular Neuroscience, Vol. 59, Issue 1 https://doi.org/10.1007/s12031-015-0711-6	journal	January 2016
Iron, Copper, and Zinc Distribution of the Cerebellum Popescu, Bogdan F. Gh.; Robinson, Christopher A.; Rajput, Alex The Cerebellum, Vol. 8, Issue 2 https://doi.org/10.1007/s12311-008-0091-3	journal	January 2009
Synchrotron X-ray Fluorescence Reveals Abnormal Metal Distributions in Brain and Spinal Cord in Spinocerebellar Ataxia: A Case Report Popescu, Bogdan F. Gh.; Robinson, Christopher A.; Chapman, L. Dean The Cerebellum, Vol. 8, Issue 3 https://doi.org/10.1007/s12311-009-0102-z	journal	March 2009
Iron levels in polarized macrophages: Regulation of immunity and autoimmunity Recalcati, Stefania; Locati, Massimo; Gammella, Elena Autoimmunity Reviews, Vol. 11, Issue 12 https://doi.org/10.1016/j.autrev.2012.03.003	journal	October 2012
Iron uptake in quiescent and inflammation-activated astrocytes: A potentially neuroprotective control of iron burden Pelizzoni, Ilaria; Zacchetti, Daniele; Campanella, Alessandro Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Vol. 1832, Issue 8 https://doi.org/10.1016/j.bbadis.2013.04.007	journal	August 2013
Expression of the iron transporter ferroportin in synaptic vesicles and the blood–brain barrier Wu, Laura Jui-chen; Leenders, A. G. Miriam; Cooperman, Sharon Brain Research, Vol. 1001, Issue 1-2 https://doi.org/10.1016/j.brainres.2003.10.066	journal	March 2004
Iron is essential for oligodendrocyte genesis following intraspinal macrophage activation Schonberg, David L.; McTigue, Dana M. Experimental Neurology, Vol. 218, Issue 1 https://doi.org/10.1016/j.expneurol.2009.04.005	journal	July 2009
The chemical form of mitochondrial iron in Friedreich’s ataxia Popescu, Bogdan F. Gh.; Pickering, Ingrid J.; George, Graham N. Journal of Inorganic Biochemistry, Vol. 101, Issue 6 https://doi.org/10.1016/j.jinorgbio.2007.03.004	journal	June 2007
Visualizing iron in multiple sclerosis Bagnato, Francesca; Hametner, Simon; Welch, Edward Brian Magnetic Resonance Imaging, Vol. 31, Issue 3 https://doi.org/10.1016/j.mri.2012.11.011	journal	April 2013
Iron depletion induced by bloodletting and followed by rhEPO administration as a therapeutic strategy in progressive multiple sclerosis: A pilot, open-label study with neurophysiological measurements Créange, A.; Lefaucheur, J. -P.; Balleyguier, M. -O. Neurophysiologie Clinique/Clinical Neurophysiology, Vol. 43, Issue 5-6 https://doi.org/10.1016/j.neucli.2013.09.004	journal	December 2013
Measuring iron in the brain using quantitative susceptibility mapping and X-ray fluorescence imaging Zheng, Weili; Nichol, Helen; Liu, Saifeng NeuroImage, Vol. 78 https://doi.org/10.1016/j.neuroimage.2013.04.022	journal	September 2013
The emerging roles of somatic globins in cardiovascular redox biology and beyond Rahaman, Mizanur M.; Straub, Adam C. Redox Biology, Vol. 1, Issue 1 https://doi.org/10.1016/j.redox.2013.08.001	journal	January 2013
Ferritin, transferrin and iron concentrations in the cerebrospinal fluid of multiple sclerosis patients LeVine, Steven M.; Lynch, Sharon G.; Ou, Ching-Nan Brain Research, Vol. 821, Issue 2 https://doi.org/10.1016/s0006-8993(98)01360-2	journal	March 1999
Sulfur K-edge X-ray absorption spectroscopy for determining the chemical speciation of sulfur in biological systems Pickering, Ingrid J.; Prince, Roger C.; Divers, Thomas FEBS Letters, Vol. 441, Issue 1 https://doi.org/10.1016/s0014-5793(98)01402-1	journal	December 1998
Distribution of transferrin and ferritin binding in normal and multiple sclerotic human brains Hulet, S. W.; Powers, S.; Connor, J. R. Journal of the Neurological Sciences, Vol. 165, Issue 1 https://doi.org/10.1016/s0022-510x(99)00077-5	journal	May 1999
Does the haemosiderin iron core determine its potential for chelation and the development of iron-induced tissue damage? Ward, Roberta J.; Legssyer, Rachida; Henry, Christophe Journal of Inorganic Biochemistry, Vol. 79, Issue 1-4 https://doi.org/10.1016/s0162-0134(99)00237-8	journal	April 2000
The effect of histological processing on the form of iron in iron-loaded human tissues Chua-anusorn, Wanida; Webb, John; J. Macey, David Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Vol. 1360, Issue 3 https://doi.org/10.1016/s0925-4439(97)00009-4	journal	May 1997
Elemental and Chemically Specific X-ray Fluorescence Imaging of Biological Systems Pushie, M. Jake; Pickering, Ingrid J.; Korbas, Malgorzata Chemical Reviews, Vol. 114, Issue 17 https://doi.org/10.1021/cr4007297	journal	January 2014
Iron, brain ageing and neurodegenerative disorders Zecca, Luigi; Youdim, Moussa B. H.; Riederer, Peter Nature Reviews Neuroscience, Vol. 5, Issue 11 https://doi.org/10.1038/nrn1537	journal	November 2004
Iron in multiple sclerosis: roles in neurodegeneration and repair Stephenson, Erin; Nathoo, Nabeela; Mahjoub, Yasamin Nature Reviews Neurology, Vol. 10, Issue 8 https://doi.org/10.1038/nrneurol.2014.118	journal	July 2014
The receptor kinase SRF3 coordinates iron-level and flagellin dependent defense and growth responses in plants Platre, Matthieu Pierre; Satbhai, Santosh B.; Brent, Lukas Nature Communications, Vol. 13, Issue 1 https://doi.org/10.1038/s41467-022-32167-6	journal	August 2022
Chemical alterations to murine brain tissue induced by formalin fixation: implications for biospectroscopic imaging and mapping studies of disease pathogenesis Hackett, Mark J.; McQuillan, James A.; El-Assaad, Fatima The Analyst, Vol. 136, Issue 14 https://doi.org/10.1039/c0an00269k	journal	January 2011
Iron Chelation and Multiple Sclerosis Weigel, Kelsey J.; Lynch, Sharon G.; LeVine, Steven M. ASN Neuro, Vol. 6, Issue 1 https://doi.org/10.1042/an20130037	journal	December 2013
Iron release from haemosiderin and ferritin by therapeutic and physiological chelators O'Connell, M. J.; Ward, R. J.; Baum, H. Biochemical Journal, Vol. 260, Issue 3 https://doi.org/10.1042/bj2600903	journal	June 1989
Astrocyte characterization in the multiple sclerosis glial scar Holley, J. E.; Gveric, D.; Newcombe, J. Neuropathology and Applied Neurobiology, Vol. 29, Issue 5 https://doi.org/10.1046/j.1365-2990.2003.00491.x	journal	October 2003
Inflammatory Cortical Demyelination in Early Multiple Sclerosis Lucchinetti, Claudia F.; Popescu, Bogdan F. G.; Bunyan, Reem F. New England Journal of Medicine, Vol. 365, Issue 23 https://doi.org/10.1056/nejmoa1100648	journal	December 2011
A Novel Glycosylphosphatidylinositol-anchored Form of Ceruloplasmin Is Expressed by Mammalian Astrocytes Patel, Bharatkumar N.; David, Samuel Journal of Biological Chemistry, Vol. 272, Issue 32 https://doi.org/10.1074/jbc.272.32.20185	journal	August 1997
Pathological relationships involving iron and myelin may constitute a shared mechanism linking various rare and common brain diseases Heidari, Moones; Gerami, Sam H.; Bassett, Brianna Rare Diseases, Vol. 4, Issue 1 https://doi.org/10.1080/21675511.2016.1198458	journal	January 2016
Cortical lesions in multiple sclerosis Kidd, D.; Barkhof, F.; McConnell, R. Brain, Vol. 122, Issue 1 https://doi.org/10.1093/brain/122.1.17	journal	January 1999
The relation between inflammation and neurodegeneration in multiple sclerosis brains Frischer, Josa M.; Bramow, Stephan; Dal-Bianco, Assunta Brain, Vol. 132, Issue 5 https://doi.org/10.1093/brain/awp070	journal	March 2009
Zinc Ions Stabilise the Association of Basic Protein with Brain Myelin Membranes Earl, Christopher; Chantry, Andrew; Mohammad, Nazar Journal of Neurochemistry, Vol. 51, Issue 3 https://doi.org/10.1111/j.1471-4159.1988.tb01803.x	journal	September 1988
Copper and Iron Disorders of the Brain Madsen, Erik; Gitlin, Jonathan D. Annual Review of Neuroscience, Vol. 30, Issue 1 https://doi.org/10.1146/annurev.neuro.30.051606.094232	journal	July 2007
Multiple sclerosis masquerading as Alzheimer-type dementia: Clinical, radiological and pathological findings Tobin, Wo; Popescu, Bf; Lowe, V. Multiple Sclerosis Journal, Vol. 22, Issue 5 https://doi.org/10.1177/1352458515604382	journal	October 2015
Remyelination in multiple sclerosis Lassmann, Hans; Brück, Wolfgang; Lucchinetti, Claudia Multiple Sclerosis Journal, Vol. 3, Issue 2 https://doi.org/10.1177/135245859700300213	journal	April 1997
Astrocytes acquire resistance to iron-dependent oxidative stress upon proinflammatory activation Macco, Romina; Pelizzoni, Ilaria; Consonni, Alessandra Journal of Neuroinflammation, Vol. 10, Issue 1 https://doi.org/10.1186/1742-2094-10-130	journal	October 2013
Serum elements and oxidative status in clinically isolated syndromes: Imbalance and predictivity Ristori, G.; Brescianini, S.; Pino, A. Neurology, Vol. 76, Issue 6 https://doi.org/10.1212/wnl.0b013e31820af7de	journal	February 2011
Iron Is a Sensitive Biomarker for Inflammation in Multiple Sclerosis Lesions Mehta, Veela; Pei, Wei; Yang, Grant PLoS ONE, Vol. 8, Issue 3 https://doi.org/10.1371/journal.pone.0057573	journal	March 2013
7 Tesla Magnetic Resonance Imaging to Detect Cortical Pathology in Multiple Sclerosis Yao, Bing; Hametner, Simon; van Gelderen, Peter PLoS ONE, Vol. 9, Issue 10 https://doi.org/10.1371/journal.pone.0108863	journal	October 2014
Iron Efflux from Astrocytes Plays a Role in Remyelination Schulz, K.; Kroner, A.; David, S. Journal of Neuroscience, Vol. 32, Issue 14 https://doi.org/10.1523/jneurosci.5328-11.2012	journal	April 2012
Pro-Inflammatory S100A8 and S100A9 Proteins: Self-Assembly into Multifunctional Native and Amyloid Complexes Vogl, Thomas; Gharibyan, Anna L.; Morozova-Roche, Ludmilla A. International Journal of Molecular Sciences, Vol. 13, Issue 3 https://doi.org/10.3390/ijms13032893	journal	March 2012
Relationship of iron to oligondendrocytes and myelination Connor, James R.; Menzies, Sharon L. Glia, Vol. 17, Issue 2 https://doi.org/10.1002/(SICI)1098-1136(199606)17:2<83::AID-GLIA1>3.0.CO;2-7	journal	June 1996
Recommended diagnostic criteria for multiple sclerosis: Guidelines from the international panel on the diagnosis of multiple sclerosis McDonald, W. Ian; Compston, Alistair; Edan, Gilles Annals of Neurology, Vol. 50, Issue 1 https://doi.org/10.1002/ana.1032	journal	January 2001
Iron and neurodegeneration in the multiple sclerosis brain: Iron in the MS Brain Hametner, Simon; Wimmer, Isabella; Haider, Lukas Annals of Neurology, Vol. 74, Issue 6 https://doi.org/10.1002/ana.23974	journal	October 2013
Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque: Dynamic Nature of MS Plaque Frischer, Josa M.; Weigand, Stephen D.; Guo, Yong Annals of Neurology, Vol. 78, Issue 5 https://doi.org/10.1002/ana.24497	journal	August 2015
Oligodendrocytes and myelination: The role of iron Todorich, Bozho; Pasquini, Juana M.; Garcia, Corina I. Glia, Vol. 57, Issue 5 https://doi.org/10.1002/glia.20784	journal	April 2009
Cytochemical techniques for zinc and heavy metals localization in nerve cells: Cytochemical Localization of Zinc in Neurons López-García, Carlos; Varea, Emilio; Palop, Jorge J. Microscopy Research and Technique, Vol. 56, Issue 5 https://doi.org/10.1002/jemt.10037	journal	February 2002
Studies on haemosiderin and ferritin from iron-loaded rat liver Andrews, Simon C.; Brady, Madeleine C.; Treffry, Amyra Biology of Metals, Vol. 1, Issue 1 https://doi.org/10.1007/BF01128015	journal	January 1988
Biochemical studies of the iron cores and polypeptide shells of haemosiderin isolated from patients with primary or secondary haemochromatosis Ward, Roberta J.; O'Connell, Martin J.; Dickson, Dominic P. E. Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 993, Issue 1 https://doi.org/10.1016/0304-4165(89)90153-0	journal	October 1989
Ferritin, transferrin and iron concentrations in the cerebrospinal fluid of multiple sclerosis patients LeVine, Steven M.; Lynch, Sharon G.; Ou, Ching-Nan Brain Research, Vol. 821, Issue 2 https://doi.org/10.1016/S0006-8993(98)01360-2	journal	March 1999
Sulfur K-edge X-ray absorption spectroscopy for determining the chemical speciation of sulfur in biological systems Pickering, Ingrid J.; Prince, Roger C.; Divers, Thomas FEBS Letters, Vol. 441, Issue 1 https://doi.org/10.1016/S0014-5793(98)01402-1	journal	December 1998
Distribution of transferrin and ferritin binding in normal and multiple sclerotic human brains Hulet, S. W.; Powers, S.; Connor, J. R. Journal of the Neurological Sciences, Vol. 165, Issue 1 https://doi.org/10.1016/S0022-510X(99)00077-5	journal	May 1999
Neurobiology of Zinc and Zinc-Containing Neurons Frederickson, Christopher J. International Review of Neurobiology https://doi.org/10.1016/S0074-7742(08)60279-2	book	January 1989
Remyelination in multiple sclerosis Piaton, Gabrièle; Williams, Anna; Seilhean, Danielle Progress in Brain Research https://doi.org/10.1016/S0079-6123(09)17530-1	book	January 2009
Does the haemosiderin iron core determine its potential for chelation and the development of iron-induced tissue damage? Ward, Roberta J.; Legssyer, Rachida; Henry, Christophe Journal of Inorganic Biochemistry, Vol. 79, Issue 1-4 https://doi.org/10.1016/S0162-0134(99)00237-8	journal	April 2000
Transition metal complexes with the thiosemicarbazide-based ligands—III. Synthesis, physico-chemical properties and voltammetric characterization of some FeIII complexes with ter- and quadridentate S-methylisothiosemicarbazide derivatives Leovac, Vukadin M.; Jovanović, Ljiljana S.; Bjelica, Luka J. Polyhedron, Vol. 8, Issue 2 https://doi.org/10.1016/S0277-5387(00)86494-3	journal	January 1989
The effect of histological processing on the form of iron in iron-loaded human tissues Chua-anusorn, Wanida; Webb, John; J. Macey, David Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Vol. 1360, Issue 3 https://doi.org/10.1016/S0925-4439(97)00009-4	journal	May 1997
Diagnostic Value of Quantitative Hepatic Copper Determination in Patients With Wilson’s Disease Ferenci, Peter; Steindl-Munda, Petra; Vogel, Wolfgang Clinical Gastroenterology and Hepatology, Vol. 3, Issue 8 https://doi.org/10.1016/S1542-3565(05)00181-3	journal	August 2005
Imaging of stroke: a comparison between X-ray fluorescence and magnetic resonance imaging methods Zheng, Weili; Haacke, E. Mark; Webb, Samuel M. Magnetic Resonance Imaging, Vol. 30, Issue 10 https://doi.org/10.1016/j.mri.2012.04.011	journal	December 2012
Data Analysis Using Regression and Multilevel/Hierarchical Models Gelman, Andrew; Hill, Jennifer https://doi.org/10.1017/CBO9780511790942	book	January 2006
Myelin Basic Protein Is a Zinc-Binding Protein in Brain: Possible Role in Myelin Compaction Tsang, D.; Tsang, Y. S.; Ho, W. K. K. Neurochemical Research, Vol. 22, Issue 7, p. 811-819 https://doi.org/10.1023/A:1022031825923	journal	January 1997
Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features Heidari, M.; Johnstone, D. M.; Bassett, B. Molecular Psychiatry, Vol. 21, Issue 11 https://doi.org/10.1038/mp.2015.192	journal	January 2016
Iron Chelation and Multiple Sclerosis Weigel, Kelsey J.; Lynch, Sharon G.; LeVine, Steven M. ASN Neuro, Vol. 6, Issue 1 https://doi.org/10.1042/AN20130037	journal	December 2013
Inflammatory Cortical Demyelination in Early Multiple Sclerosis Lucchinetti, Claudia F.; Popescu, Bogdan F. G.; Bunyan, Reem F. New England Journal of Medicine, Vol. 365, Issue 23 https://doi.org/10.1056/NEJMoa1100648	journal	December 2011
The MicroAnalysis Toolkit: X-ray Fluorescence Image Processing Software Webb, S. M.; McNulty, Ian; Eyberger, Catherine THE 10TH INTERNATIONAL CONFERENCE ON X-RAY MICROSCOPY, AIP Conference Proceedings https://doi.org/10.1063/1.3625338	conference	January 2011
Mapping metals in Parkinson's and normal brain using rapid-scanning x-ray fluorescence Gh Popescu, Bogdan F.; George, Martin J.; Bergmann, Uwe Physics in Medicine and Biology, Vol. 54, Issue 3 https://doi.org/10.1088/0031-9155/54/3/012	journal	January 2009
Essential and toxic element concentrations in fresh and formalin-fixed human autopsy tissues Bush, V. J.; Moyer, T. P.; Batts, K. P. Clinical Chemistry, Vol. 41, Issue 2 https://doi.org/10.1093/clinchem/41.2.284	journal	February 1995
Mapping Brain Metals to Evaluate Therapies for Neurodegenerative Disease: Mapping Brain Metals to Evaluate Therapies for Neurodegenerative Disease Gh Popescu, Bogdan Florin; Nichol, Helen CNS Neuroscience & Therapeutics, Vol. 17, Issue 4 https://doi.org/10.1111/j.1755-5949.2010.00149.x	journal	June 2010
Persistent 7-tesla phase rim predicts poor outcome in new multiple sclerosis patient lesions Absinta, Martina; Sati, Pascal; Schindler, Matthew Journal of Clinical Investigation, Vol. 126, Issue 7 https://doi.org/10.1172/JCI86198	journal	June 2016
CNS demyelination associated with copper deficiency and hyperzincemia Prodan, C. I.; Holland, N. R.; Wisdom, P. J. Neurology, Vol. 59, Issue 9 https://doi.org/10.1212/01.WNL.0000032497.30439.F6	journal	November 2002
Serum elements and oxidative status in clinically isolated syndromes: Imbalance and predictivity Ristori, G.; Brescianini, S.; Pino, A. Neurology, Vol. 76, Issue 6 https://doi.org/10.1212/WNL.0b013e31820af7de	journal	February 2011
Defining the clinical course of multiple sclerosis: Results of an international survey Lublin, F. D.; Reingold, S. C. Neurology, Vol. 46, Issue 4 https://doi.org/10.1212/WNL.46.4.907	journal	April 1996
Effect of Silicate Species on the Transformation of Ferrihydrite into Goethite and Hematite in Alkaline Media Cornell, R. M. Clays and Clay Minerals, Vol. 35, Issue 1 https://doi.org/10.1346/CCMN.1987.0350103	journal	January 1987
Iron Efflux from Astrocytes Plays a Role in Remyelination Schulz, K.; Kroner, A.; David, S. Journal of Neuroscience, Vol. 32, Issue 14 https://doi.org/10.1523/JNEUROSCI.5328-11.2012	journal	April 2012
Nonheme-iron histochemistry for light and electron microscopy: a historical, theoretical and technical review Meguro, Reiko; Asano, Yoshiya; Odagiri, Saori Archives of Histology and Cytology, Vol. 70, Issue 1 https://doi.org/10.1679/aohc.70.1	journal	January 2007

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Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis Elliott, Colm; Belachew, Shibeshih; Wolinsky, Jerry S. Brain, Vol. 142, Issue 9 https://doi.org/10.1093/brain/awz212	journal	August 2019
Multiplexed imaging of immune cells in staged multiple sclerosis lesions by mass cytometry Ramaglia, Valeria; Sheikh-Mohamed, Salma; Legg, Karen eLife https://doi.org/10.1101/638015	posted_content	May 2019
Iron related changes in MS lesions and their validity to characterize MS lesion types and dynamics with Ultra‐high field magnetic resonance imaging Hametner, Simon; Dal Bianco, Assunta; Trattnig, Siegfried Brain Pathology, Vol. 28, Issue 5 https://doi.org/10.1111/bpa.12643	journal	December 2017
Linking Cigarette Smoking/Tobacco Exposure and Cluster Headache: A Pathogenesis Theory Rozen, Todd D. Headache: The Journal of Head and Face Pain, Vol. 58, Issue 7 https://doi.org/10.1111/head.13338	journal	July 2018
Slowly expanding/evolving lesions as a magnetic resonance imaging marker of chronic active multiple sclerosis lesions Elliott, Colm; Wolinsky, Jerry S.; Hauser, Stephen L. Multiple Sclerosis Journal, Vol. 25, Issue 14 https://doi.org/10.1177/1352458518814117	journal	December 2018
Evaluation of the ‘ring sign’ and the ‘core sign’ as a magnetic resonance imaging marker of disease activity and progression in clinically isolated syndrome and early multiple sclerosis Blindenbacher, Nelly; Brunner, Eveline; Asseyer, Susanna Multiple Sclerosis Journal - Experimental, Translational and Clinical, Vol. 6, Issue 1 https://doi.org/10.1177/2055217320915480	journal	January 2020
Longitudinal study of multiple sclerosis lesions using ultra-high field (7T) multiparametric MR imaging Chawla, Sanjeev; Kister, Ilya; Sinnecker, Tim PLOS ONE, Vol. 13, Issue 9 https://doi.org/10.1371/journal.pone.0202918	journal	September 2018
Evaluation of the ‘ring sign’ and the ‘core sign’ as a magnetic resonance imaging marker of disease activity and progression in clinically isolated syndrome and early multiple sclerosis Blindenbacher, Nelly; Brunner, Eveline; Asseyer, Susanna Charité - Universitätsmedizin Berlin https://doi.org/10.17169/refubium-27538	text	January 2020
Zinc Signals and Immunity Maywald, Martina; Weßels, Inga; Rink, Lothar RWTH Aachen University https://doi.org/10.18154/rwth-2017-10705	text	January 2017
Zinc as a Gatekeeper of Immune Function Wessels, Inga; Maywald, Martina; Rink, Lothar RWTH Aachen University https://doi.org/10.18154/rwth-2018-221110	text	January 2017
The Intracellular Free Zinc Level Is Vital for Treg Function and a Feasible Tool to Discriminate between Treg and Activated Th Cells Maywald, Martina; Wang, Fudi; Rink, Lothar RWTH Aachen University https://doi.org/10.18154/rwth-conv-236961	text	January 2018
Identification of Chronic Active Multiple Sclerosis Lesions on 3T MRI Absinta, M.; Sati, P.; Fechner, A. American Journal of Neuroradiology, Vol. 39, Issue 7 https://doi.org/10.3174/ajnr.a5660	journal	May 2018
Significance and In Vivo Detection of Iron-Laden Microglia in White Matter Multiple Sclerosis Lesions Gillen, Kelly M.; Mubarak, Mayyan; Nguyen, Thanh D. Frontiers in Immunology, Vol. 9 https://doi.org/10.3389/fimmu.2018.00255	journal	February 2018

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Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions

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