USPIO-positive MS lesions are associated with greater tissue damage than gadolinium-positive-only lesions during 3-year follow-up

Abstract

Background:

Identifying in vivo the processes that determine lesion severity in multiple sclerosis (MS) remains a challenge.

Objectives:

To describe the dynamics of ultrasmall superparamagnetic iron oxide (USPIO) enhancement in MS lesions and the relationship between USPIO enhancement and microstructural changes over 3 years.

Methods:

Lesion development was assessed at baseline, Months 3, 6, and 9, using magnetic resonance imaging (MRI) with gadolinium and USPIO. Microstructural changes were assessed at baseline, Months 3, 6, 9, 12, 18, 24, and 36, using relaxometry, magnetization transfer, and diffusion-weighted imaging.

Results:

We included 15 patients with clinically isolated syndrome. In the 52 MRI scans acquired with USPIO, 22 lesions were USPIO and gadolinium positive, and 44 were USPIO negative but gadolinium positive. Lesions no longer exhibited sustained USPIO enhancement 3 months later. At baseline, lesions that were both USPIO and gadolinium positive had lower magnetization transfer ratio values (common language effect size = 0.84, p = 0.0005) and lower fractional anisotropy values (0.83, p = 0.001) than gadolinium-positive-only lesions. USPIO-positive lesions remained associated with greater damage than gadolinium-positive-only lesions throughout the 3-year follow-up.

Conclusion:

USPIO enhancement, mainly reflecting monocyte infiltration, is transient and is associated with persistent tissue damage after 3 years.

Keywords

Multiple sclerosis clinically isolated syndrome magnetic resonance imaging diffusion tensor imaging magnetization transfer imaging USPIO gadolinium

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References

Frischer

Weigand

Guo

et al . Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol 2015; 78(5): 710–721.

Mottershead

Schmierer

Clemence

et al . High field MRI correlates of myelin content and axonal density in multiple sclerosis. J Neurol 2003; 250: 1293–1301.

Schmierer

Scaravilli

Altmann

et al . Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain. Ann Neurol 2004; 56: 407–415.

Filippi

Rocca

Barkhof

Association between pathological and MRI findings in multiple sclerosis. Lancet Neurol 2012; 11: 349–360.

Ciccarelli

Barkhof

Bodini

et al . Pathogenesis of multiple sclerosis: Insights from molecular and metabolic imaging. Lancet Neurol 2014; 13: 807–822.

Floris

Blezer

Schreibelt

et al . Blood-brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis. Brain 2004; 127: 616–627.

Ajami

Bennett

Krieger

et al . Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 2011; 14(9): 1142–1149.

Rausch

Hiestand

Baumann

et al . MRI-based monitoring of inflammation and tissue damage in acute and chronic relapsing EAE. Magn Reson Med 2003; 50: 309–314.

Berger

Hiestand

Kindler-Baumann

et al . Analysis of lesion development during acute inflammation and remission in a rat model of experimental autoimmune encephalomyelitis by visualization of macrophage infiltration, demyelination and blood-brain barrier damage. NMR Biomed 2006; 19: 101–107.

10.

Brochet

Deloire

Touil

et al . Early macrophage MRI of inflammatory lesions predicts lesion severity and disease development in relapsing EAE. Neuroimage 2006; 32: 266–274.

11.

Corot

Robert

Idee

et al . Recent advances in iron oxide nanocrystal technology for medical imaging. Adv Drug Deliver Rev 2006; 58: 1471–1504.

12.

Maarouf

Ferré

Zaaraoui

et al . Ultra-small superparamagnetic iron oxide enhancement is associated with higher loss of brain tissue structure in clinically isolated syndrome. Mult Scler 2016; 22(8): 1032–1039.

13.

Crimi

Commowick

Maarouf

et al . Predictive value of imaging markers at multiple sclerosis disease onset based on gadolinium- and USPIO-enhanced MRI and machine learning. PLoS ONE 2014; 9(4): e93024.

14.

Polman

Reingold

Edan

et al . Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann Neurol 2005; 58(6): 840–846.

15.

Commowick

Wiest-Daesslé

Prima

Automated diffeomorphic registration of anatomical structures with rigid parts: Application to dynamic cervical MRI. Med Image Comput Comput Assist Interv 2012; 15: 163–170.

16.

Commowick

Wiest-Daesslé

Prima

Block-matching strategies for rigid registration of multimodal medical images. In: 9th IEEE international symposium on biomedical imaging (ISBI), Barcelona, 2–5 May 2012, pp. 700–703. New York: IEEE.

17.

Boulby

Rugg–Gunn

The transverse relaxation time. In: Paul

(ed.) Quantitative MRI of the brain: Measuring changes caused by disease. Hoboken, NJ: John Wiley & Sons; 2004; pp. 143–201.

18.

Wheeler-Kingshott

Barker

Steens

et al . The diffusion of water. In: Quantitative MRI of the brain: Measuring changes caused by disease. Hoboken, NJ: John Wiley & Sons; 2004; pp. 203–256.

19.

Dousset

Brochet

Deloire

et al . MR imaging of relapsing multiple sclerosis patients using ultra-small-particle iron oxide and compared with gadolinium. AJNR Am J Neuroradiol 2006; 27: 1000–1005.

20.

Vellinga

Oude Engberink

Seewann

et al . Pluriformity of inflammation in multiple sclerosis shown by ultra-small iron oxide particle enhancement. Brain 2008; 131(3): 800–807.

21.

Tourdias

Roggerone

Filippi

et al . Assessment of disease activity in multiple sclerosis phenotypes with combined gadolinium- and superparamagnetic iron oxide-enhanced MR imaging. Radiology 2012; 264(1): 225–233.

22.

Vellinga

Vrenken

Hulst

et al . Use of ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced MRI to demonstrate diffuse inflammation in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) patients: An exploratory study. J Magn Reson Imaging 2009; 29(4): 774–779.

23.

Tourdias

Dousset

Neuroinflammatory imaging biomarkers: Relevance to multiple sclerosis and its therapy. Neurotherapeutics 2013; 10: 111–123.

24.

Kirschbaum

Sonner

Zeller

et al . In vivo nanoparticle imaging of innate immune cells can serve as a marker of disease severity in a model of multiple sclerosis. Proc Natl Acad Sci U S A 2016; 113(46): 13227–13232.

25.

Bruck

Sommermeier

Bergmann

et al . Macrophages in multiple sclerosis. Immunobiology 1996; 195: 588–600.

26.

Kotter

Setzu

Sim

et al . Macrophage depletion impairs oligodendrocyte remyelination following lysolecithin-induced demyelination. Glia 2001; 35: 204–212.

27.

Oude Engberink

Blezer

Dijkstra

et al . Dynamics and fate of USPIO in the central nervous system in experimental autoimmune encephalomyelitis. NMR Biomed 2010; 23(9): 1087–1096.

28.

Pirko

Johnson

Ciric

et al . In vivo magnetic resonance imaging of immune cells in the central nervous system with superparamagnetic antibodies. FASEB J 2004; 18: 179–182.

29.

Engberink

Van Der Pol

Walczak

et al . Magnetic resonance imaging of monocytes labeled with ultrasmall superparamagnetic particles of iron oxide using magnetoelectroporation in an animal model of multiple sclerosis. Mol Imaging 2010; 9: 268–277.

30.

Prineas

Kwon

Cho

et al . Immunopathology of secondary-progressive multiple sclerosis. Ann Neurol 2001; 50: 646–657.

31.

Farrell

Hamilton

Dósa

et al . Using iron oxide nanoparticles to diagnose CNS inflammatory diseases and PCNSL. Neurology 2013; 1681(3): 256–263.

32.

Hasan

Chalouhi

Jabbour

et al . Early change in ferumoxytol-enhanced magnetic resonance imaging signal suggests unstable human cerebral aneurysm: A pilot study. Stroke 2012; 43: 3258–3265.

33.

https://clinicaltrials.gov/ct2/show/NCT01973517

34.

Zhang

Gauthier

Gupta

et al . Longitudinal change in magnetic susceptibility of new enhanced multiple sclerosis (MS) lesions measured on serial quantitative susceptibility mapping (QSM). J Magn Reson Imaging 2016; 44: 426–432.

35.

Wisnieff

Ramanan

Olesik

et al . Quantitative susceptibility mapping (QSM) of white matter multiple sclerosis lesions: Interpreting positive susceptibility and the presence of iron. Magn Reson Med 2014; 74: 564–570.

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