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Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla
Open accessAbstract
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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“However, degeneration of cells in the brain also result in the deposition of iron in the extracellular space, which then induces waves of oxidative stress (via Fenton chemistry) in these brain regions (Craelius et al., 1982; Bagnato et al., 2011).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Bagnato et al., 2011
In the citing paper
“In-vivo and post-mortem investigations suggest focal iron accumulation in the white matter in multiple sclerosis160,161,206 and focal iron accumulation in the cortex in amyotrophic lateral sclerosis207 co-localise with microglia (appendix).160,207”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [160]
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Cites
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Cited by
Sorted by citations
The role of iron in brain ageing and neurodegenerative disorders
Ward, R. J., Zucca, F. A., Duyn, J. H., Crichton, R. R., & Zecca, L. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70117-6 · Cited by 1,819
Pathological mechanisms in progressive multiple sclerosis
Mahad, D., Trapp, B. D., & Lassmann, H. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70256-x · Cited by 1,198
Progressive multiple sclerosis: pathology and pathogenesis
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Quantitative susceptibility mapping (QSM): Decoding MRI data for a tissue magnetic biomarker
Wang, Y., & Liu, T. (2015) · Magnetic Resonance in Medicine · doi:10.1002/mrm.25358 · Cited by 878
A lymphocyte–microglia–astrocyte axis in chronic active multiple sclerosis
Absinta, M., Maric, D., Gharagozloo, M., Garton, T., Smith, M. D., Jin, J., Fitzgerald, K. C., Song, A., Liu, P., Lin, J.-P., et al. (2021) · Nature · doi:10.1038/s41586-021-03892-7 · Cited by 768
Metadata
- 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)
- 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
- 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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