Cited by 351Advanced MRI Techniques and ApplicationsMultiple Sclerosis Research StudiesNeurological diseases and metabolism

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Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla

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Bagnato, F., Hametner, S., Yao, B., van Gelderen, P., Merkle, H., Cantor, F. K., Lassmann, H., Duyn, J. H.·2011·Brain

DOI 10.1093/brain/awr278PMC PMC3235560

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Abstract

Previous authors have shown that the transverse relaxivity R(2)* and frequency shifts that characterize gradient echo signal decay in magnetic resonance imaging are closely associated with the distribution of iron and myelin in the brain's white matter. In multiple sclerosis, iron accumulation in brain tissue may reflect a multiplicity of pathological processes. Hence, iron may have the unique potential to serve as an in vivo magnetic resonance imaging tracer of disease pathology. To investigate the ability of iron in tracking multiple sclerosis-induced pathology by magnetic resonance imaging, we performed qualitative histopathological analysis of white matter lesions and normal-appearing white matter regions with variable appearance on gradient echo magnetic resonance imaging at 7 Tesla. The samples used for this study derive from two patients with multiple sclerosis and one non-multiple sclerosis donor. Magnetic resonance images were acquired using a whole body 7 Tesla magnetic resonance imaging scanner equipped with a 24-channel receive-only array designed for tissue imaging. A 3D multi-gradient echo sequence was obtained and quantitative R(2)* and phase maps were reconstructed. Immunohistochemical stainings for myelin and oligodendrocytes, microglia and macrophages, ferritin and ferritin light polypeptide were performed on 3- to 5-µm thick paraffin sections. Iron was detected with Perl's staining and 3,3'-diaminobenzidine-tetrahydrochloride enhanced Turnbull blue staining. In multiple sclerosis tissue, iron presence invariably matched with an increase in R(2)*. Conversely, R(2)* increase was not always associated with the presence of iron on histochemical staining. We interpret this finding as the effect of embedding, sectioning and staining procedures. These processes likely affected the histopathological analysis results but not the magnetic resonance imaging that was obtained before tissue manipulations. Several cellular sources of iron were identified. These sources included oligodendrocytes in normal-appearing white matter and activated macrophages/microglia at the edges of white matter lesions. Additionally, in white matter lesions, iron precipitation in aggregates typical of microbleeds was shown by the Perl's staining. Our combined imaging and pathological study shows that multi-gradient echo magnetic resonance imaging is a sensitive technique for the identification of iron in the brain tissue of patients with multiple sclerosis. However, magnetic resonance imaging-identified iron does not necessarily reflect pathology and may also be seen in apparently normal tissue. Iron identification by multi-gradient echo magnetic resonance imaging in diseased tissues can shed light on the pathological processes when coupled with topographical information and patient disease history.

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Authors: Bagnato, F., Hametner, S., Yao, B., van Gelderen, P., Merkle, H., Cantor, F. K., Lassmann, H., & Duyn, J. H.
Affiliations: National Institutes of Health (US)
Medical University of Vienna (AT)
ORCID: Bagnato, F.
Hametner, S.
Yao, B.
Lassmann, H.
Venue: Brain
Publisher: Oxford University Press (OUP)
Published: 2011-12-01
Volume: 134
Issue: 12
Pages: 3602-3615
ISSN: 0006-8950 (ISSN-L)
1460-2156
DOI: 10.1093/brain/awr278
PMC: PMC3235560
OpenAlex: W2154189431
Cited by: 351
References: 65
Citations by year: 2026: 14 · 2025: 19 · 2024: 29 · 2023: 33 · 2022: 32 · 2021: 25 · 2020: 22 · 2019: 18 · 2018: 18 · 2017: 22 · 2016: 35 · 2015: 24 · 2014: 28 · 2013: 19 · 2012: 13
FWCI: 14.67
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Brain (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
HighWire Press Open Archive (submittedVersion)
Funders: National Institutes of Health
Topics: Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
Keywords: multiple sclerosis, iron accumulation, r2 relaxivity, gradient echo MRI, 7T MRI, white matter lesions, normal-appearing white matter, ferritin, oligodendrocytes, microglia, macrophages, microbleeds, myelin
MeSH terms: Brain, Humans, Image Processing, Computer-Assisted, Iron, Magnetic Resonance Imaging, Multiple Sclerosis, Myelin Sheath, Nerve Fibers, Myelinated

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Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla

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