Manganese-Enhanced MRI in Patients with Multiple Sclerosis

Abstract

BACKGROUND AND PURPOSE: Cellular uptake of the manganese ion, when administered as a contrast agent for MR imaging, can noninvasively highlight cellular activity and disease processes in both animals and humans. The purpose of this study was to explore the enhancement profile of manganese in patients with multiple sclerosis. MATERIALS AND METHODS: Mangafodipir is a manganese chelate that was clinically approved for MR imaging of liver lesions. We present a case series of 6 adults with multiple sclerosis who were scanned at baseline with gadolinium, then injected with mangafodipir, and followed at variable time points thereafter. RESULTS: Fourteen new lesions formed during or shortly before the study, of which 10 demonstrated manganese enhancement of varying intensity, timing, and spatial pattern. One gadolinium-enhancing extra-axial mass, presumably a meningioma, also demonstrated enhancement with manganese. Most interesting, manganese enhancement was detected in lesions that formed in the days after mangafodipir injection, and this enhancement persisted for several weeks, consistent with contrast coming from intracellular uptake of manganese. Some lesions demonstrated a diffuse pattern of manganese enhancement in an area larger than that of both gadolinium enhancement and T2-FLAIR signal abnormality. CONCLUSIONS: This work demonstrates the first use of a manganese-based contrast agent to enhance MS lesions on MR imaging. Multiple sclerosis lesions were enhanced with a temporal and spatial profile distinct from that of gadolinium. Further experiments are necessary to uncover the mechanism of manganese contrast enhancement as well as cell-specific uptake.

Longitudinal manganese‐enhanced magnetic resonance imaging of neural projections and activity

“…However, mangafodipir may release uncomplexed Mn(II) ion in regions of neural activity for uptake into active brain regions in human 90 . Mangafodipir safely identified plaques in human multiple sclerosis 91 . Application of MEMRI to nonbrain tissue, such as non‐CNS organs in mouse, 347 cardiac muscle in human, 134,348 and diagnoses for cancer, 131,132,349 as well as others mentioned in Section 5.1, are emerging.…”

“…90 Mangafodipir safely identified plaques in human multiple sclerosis. 91 Application of MEMRI to nonbrain tissue, such as non-CNS organs in mouse, 347 cardiac muscle in human, 134,348 and diagnoses for cancer, 131,132,349 as well as others mentioned in Section 5.1, are emerging. Analogies of brain-wide activity using functional atlases to compare rodent networks with human networks obtained by fMRI are more likely than invasive techniques such as high-density electrode arrays or optogenetic manipulations to lead to translation of mechanistic knowledge from preclinical to human disease states.…”

“…89 Very recently, mangafodipir demonstrated success for imaging normal human brain 90 and for detection of lesions in humans with multiple sclerosis. 91 We emphasize that a safe dose of unchelated MnCl 2 for humans has not yet been determined.…”

“…Teslascan), Mn(II) in a complex with dipyridoxyl diphosphate (DPDP)) although FDA‐approved in 2003 for MRI in humans, was originally not commercially successful, despite showing usefulness in retinal imaging in rats 89 . Very recently, mangafodipir demonstrated success for imaging normal human brain 90 and for detection of lesions in humans with multiple sclerosis 91 . We emphasize that a safe dose of unchelated MnCl 2 for humans has not yet been determined.…”

From pathology to MRI and back: Clinically relevant biomarkers of multiple sclerosis lesions

“…The centripetal DCE pattern, seen only in a percentage of new lesions, temporally follows the centrifugal pattern, but not vice versa ( Gaitán et al, 2011 ). Interestingly, a recent study using an intravenous manganese-based contrast agent, mangafodipir, found that manganese ions enable visualization of acute white matter lesions and their surrounding white matter, with persistent enhancement for an extended period relative to gadolinium-based contrast material ( Suto et al, 2020 ). This persistent enhancement is thought to be due to the intracellular uptake of manganese ions released from mangafodipir, compared to the gadolinium agents, which are restricted to the interstitial and intravascular compartments.…”