@article{f9b35cc7c86248b09eedc21b29bac1ed,
title = "Iron Heterogeneity in Early Active Multiple Sclerosis Lesions",
abstract = "Objective: Multiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disease. Iron distribution is altered in MS patients' brains, suggesting iron liberation within active lesions amplifies demyelination and neurodegeneration. Whether the amount and distribution of iron are similar or different among different MS immunopatterns is currently unknown. Methods: We used synchrotron X-ray fluorescence imaging, histology, and immunohistochemistry to compare the iron quantity and distribution between immunopattern II and III early active MS lesions. We analyzed archival autopsy and biopsy tissue from 21 MS patients. Results: Immunopattern II early active lesions contain 64% more iron (95% confidence interval [CI] = 17–127%, p = 0.004) than immunopattern III lesions, and 30% more iron than the surrounding periplaque white matter (95% CI = 3–64%, p = 0.03). Iron in immunopattern III lesions is 28% lower than in the periplaque white matter (95% CI = −40 to −14%, p < 0.001). When normalizing the iron content of early active lesions to that of surrounding periplaque white matter, the ratio is significantly higher in immunopattern II (p < 0.001). Microfocused X-ray fluorescence imaging shows that iron in immunopattern II lesions localizes to macrophages, whereas macrophages in immunopattern III lesions contain little iron. Interpretation: Iron distribution and content are heterogeneous in early active MS lesions. Iron accumulates in macrophages in immunopattern II, but not immunopattern III lesions. This heterogeneity in the two most common MS immunopatterns may be explained by different macrophage polarization, origin, or different demyelination mechanisms, and paves the way for developing new or using existing iron-sensitive magnetic resonance imaging techniques to differentiate among immunopatterns in the general nonbiopsied MS patient population. ANN NEUROL 2021;89:498–510.",
author = "Mylyne Tham and Frischer, {Josa M.} and Weigand, {Stephen D.} and Fitz-Gibbon, {Patrick D.} and Webb, {Samuel M.} and Yong Guo and Adiele, {Reginald C.} and Robinson, {Christopher A.} and Wolfgang Br{\"u}ck and Hans Lassmann and Furber, {Kendra L.} and Pushie, {M. Jake} and Parisi, {Joseph E.} and Lucchinetti, {Claudia F.} and Popescu, {Bogdan F.}",
note = "Funding Information: This study was funded by the Canada Research Chairs Program (to B.F.P.), the Saskatchewan Health Research Foundation (to B.F.P.), Biogen Idec (to B.F.P. and C.F.L.), and the National Institute of Neurological Disorders and Stroke (NINDS), NIH (to C.F.L.). M.T. and R.C.A. were Fellows of the Canadian Institutes of Health Research Training grant in Health Research Using Synchrotron Techniques (CIHR-THRUST). M.T. was supported by a College of Medicine Graduate Scholarship, University of Saskatchewan and a Saskatchewan Innovation and Opportunity Scholarship, Government of Saskatchewan. J.M.F. was supported by the Austrian Science Fund (FWF Project J3508-B24) while conducting parts of this work. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the NIH National Institute of General Medical Sciences (NIGMS; including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIGMS or NIH. We thank A. Givens and P. Ziemer for their expert technical assistance, and the Department of Pathology and Laboratory Medicine, Saskatoon Health Region, Saskatoon, Canada for retrieval of some of the tissue blocks used in this study. Funding Information: This study was funded by the Canada Research Chairs Program (to B.F.P.), the Saskatchewan Health Research Foundation (to B.F.P.), Biogen Idec (to B.F.P. and C.F.L.), and the National Institute of Neurological Disorders and Stroke (NINDS), NIH (to C.F.L.). M.T. and R.C.A. were Fellows of the Canadian Institutes of Health Research Training grant in Health Research Using Synchrotron Techniques (CIHR‐THRUST). M.T. was supported by a College of Medicine Graduate Scholarship, University of Saskatchewan and a Saskatchewan Innovation and Opportunity Scholarship, Government of Saskatchewan. J.M.F. was supported by the Austrian Science Fund (FWF Project J3508‐B24) while conducting parts of this work. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE‐AC02‐76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the NIH National Institute of General Medical Sciences (NIGMS; including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIGMS or NIH. Publisher Copyright: {\textcopyright} 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.",
year = "2021",
month = mar,
doi = "10.1002/ana.25974",
language = "English (US)",
volume = "89",
pages = "498--510",
journal = "Annals of neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "3",
}