Pluriformity of inflammation in multiple sclerosis shown by ultra-small iron oxide particle enhancement
Abstract
Gadolinium-DTPA (Gd-DTPA) is routinely used as a marker for inflammation in MRI to visualize breakdown of the blood-brain barrier (BBB) in multiple sclerosis. Recent data suggest that ultra-small superparamagnetic particles of iron oxide (USPIO) can be used to visualize cellular infiltration, another aspect of inflammation. This project aimed to compare the novel USPIO particle SHU555C to the longitudinal pattern of Gd-DTPA enhancement in multiple sclerosis. Nineteen relapsing-remitting patients were screened monthly using Gd-enhanced MRI. In case of new enhancing lesions, USPIO were injected and 24 h later, MRI was performed and blood was collected to confirm USPIO loading of circulating monocytes. Lesion development was monitored by 3 monthly Gd-DTPA-enhanced scans and a final scan 7-11 months after injection. USPIO-enhancement was observed as hyperintensity on T1-weighted images, whereas no signal changes were observed on T2-weighted-gradient-echo images. In 14 patients with disease activity, 188 USPIO-positive lesions were seen, 144 of which were Gd-negative. By contrast, there were a total of 59 Gd-positive lesions, 15 of which were USPIO negative. Three patterns of USPIO-enhancement were seen: (i) focal enhancement; (ii) ring-like enhancement and (iii) return to isointensity of a previously hypointense lesion. The latter pattern was most frequently observed for lesions that turned out to be transiently hypointense on follow-up scans, and ring-enhancing lesions were less likely to evolve into black holes at follow-up than lesions without ring-like USPIO-enhancement; we speculate this to be associated with repair. In 4% of the USPIO-positive/Gd negative lesions, USPIO-enhancement preceded Gd-enhancement by 1 month. USPIO-enhancement remained visible for up to 3 months in 1.5% of all USPIO-positive lesions. In 29% of the lesions enhancing with both contrast agents, USPIO-enhancement persisted whereas Gd-enhancement had already resolved. In conclusion, the new nano-particle SHU555C provides complementary information to Gd-enhanced MRI, probably related to monocyte infiltration. The use of USPIO-enhanced MRI is likely to lead to more insight in the pluriformity of inflammation in multiple sclerosis.
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Iron-oxide particles allow in vivo visualization of macrophages but are insensitive to non-phagocytic cells involved in inflammation.
“Iron-oxide particles have been used to allow in vivo visualization of macrophages, but this method is insensitive to non-phagocytic cells involved in inflammation (Vellinga et al., 2008).”
From Quantifying white matter tract diffusion parameters in the presence of increased extra-fiber cellularity and vasogenic edema (2014) · cites this paper as Vellinga et al., 2008
The Introduction (page unavailable) says that phagocytosis of iron-oxide particles by monocytes and macrophages enables visualization of cellular infiltration, supporting the first part of the claim. It does not establish that the method is insensitive to all non-phagocytic inflammatory cells; it also notes a report of particles in astrocytes. (LLM, conf=0.84)
Experimental — accuracy not yet measuredUSPIOs provide insights into the early stages of the inflammatory process preceding gadolinium enhancement.
“The use of USPIOs provide insights into the early stages of the inflammatory process preceding gadolinium enhancement (64).”
From The role of microglia in multiple sclerosis: implications for treatment with Bruton’s tyrosine kinase inhibitors (2025) · cites this paper as [64]
Iron oxide nanoparticles have a key advantage over gadolinium-based contrast agents in MS imaging: they visualize monocyte/macrophage infiltration, which correlates with ongoing demyelination and disease progression.
“In this context, a key advantage of using iron oxide nanoparticles over gadolinium-based contrast agents is the visualization of monocyte/macrophage infiltration by the former, which correlates with ongoing demyelination and is a hallmark of disease progression in MS [175–177].”
From Iron oxide nanoparticles: Diagnostic, therapeutic and theranostic applications (2019) · cites this paper as [176]
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- Authors
- Vellinga, M. M., Oude Engberink, R. D., Seewann, A., Pouwels, P. J. W., Wattjes, M. P., van der Pol, S. M. A., Pering, C., Polman, C. H., de Vries, H. E., Geurts, J. J. G., & Barkhof, F.
- Affiliations
- Utrecht University (NL)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-02-02
- Volume
- 131
- Issue
- 3
- Pages
- 800-807
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2121341823
- Cited by
- 183
- References
- 29
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 7 · 2022: 4 · 2021: 6 · 2020: 1 · 2019: 8 · 2018: 8 · 2017: 9 · 2016: 11 · 2015: 18 · 2014: 14 · 2013: 16 · 2012: 16
- FWCI
- 12.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Vrije Universiteit Amsterdam
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Physical Sciences › Engineering › Biomedical Engineering › Characterization and Applications of Magnetic Nanoparticles
- Keywords
- multiple sclerosis, Gd-DTPA, inflammation, monocyte infiltration, blood-brain barrier disruption, relapsing-remitting multiple sclerosis, lesion enhancement patterns, black holes, lesion repair, contrast-enhanced MRI
- MeSH terms
- Brain, Contrast Media, Dextrans, Female, Follow-Up Studies, Humans, Image Interpretation, Computer-Assisted, Inflammation, Iron, Magnetic Resonance Imaging, Male, Monocytes, Oxides, Gadolinium DTPA, Multiple Sclerosis, Relapsing-Remitting, Ferrosoferric Oxide, Magnetite Nanoparticles
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