Brain Advance Access originally published online on February 1, 2008
Brain 2008 131(3):800-807; doi:10.1093/brain/awn009
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Pluriformity of inflammation in multiple sclerosis shown by ultra-small iron oxide particle enhancement
1Department of Neurology, 2Department of Cell Biology and Immunology, MS Centre Amsterdam, VU University Medical Centre, Amsterdam, 3Image Sciences Institute, University Medical Center, Utrecht, The Netherlands, 4Department of Physics and Medical Technology, 5Department of Radiology, MS Centre Amsterdam, VU University Medical Centre, Amsterdam, 6Department of Diagnostic Imaging, Bayer Schering Pharma, Berlin, Germany, 7Department of Pathology, MS Centre Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands
Correspondence to: Machteld M Vellinga, VU University Medical Center, Department of Neurology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands E-mail: m.vellinga{at}vumc.nl
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.
Key Words: MS; USPIO; cellular imaging; MRI; lesional patterns
Abbreviations: BBB, blood-brain barrier; BW, body weight; EAE, experimental allergic encephalomyelitis; EDSS, expanded disability status scale; Gd, gadolinium-diethylene-triamine pentaacetic- acid (Gd-DTPA); Gd+, Gd-DTPA-positive; Gd–, Gd-DTPA-negative; nm, nanometre; PB, Prussian blue; PBMC, peripheral blood mononuclear cells; PD, proton density; ROI, region of interest; ROS, reactive oxygen species; T1-w, T1-weighted; T2(*)-w, T2(*)-weighted gradient echo; TR, repetition time; TE, echo time; USPIO, ultra-small superparamagnetic particles of iron oxide; USPIO+, USPIO-positive; USPIO–, USPIO-negative
Received July 20, 2007. Revised December 31, 2007. Accepted January 10, 2008.