Ultra-small superparamagnetic iron oxide enhancement is associated with higher loss of brain tissue structure in clinically isolated syndrome

Abstract

Background:

Macrophages are important components of inflammatory processes in multiple sclerosis, closely linked to axonal loss, and can now be observed in vivo using ultra-small superparamagnetic iron oxide (USPIO). In the present 1-year longitudinal study, we aimed to determine the prevalence and the impact on tissue injury of macrophage infiltration in patients after the first clinical event of multiple sclerosis.

Methods:

Thirty-five patients, 32 years mean age, were imaged in a mean of 66 days after their first event using conventional magnetic resonance imaging, gadolinium (Gd) to probe blood–brain barrier integrity, USPIO to study macrophage infiltration and magnetization transfer ratio (MTR) to assess tissue structure integrity. Statistics were performed using two-group repeated-measures ANOVA. Any patient received treatment at baseline.

Results:

At baseline, patients showed 17 USPIO-positive lesions reflecting infiltration of macrophages present from the onset. This infiltration was associated with local higher loss of tissue structure as emphasized by significant lower MTR_norm values (p<0.03) in USPIO⁺/Gd⁺ lesions (n=16; MTR_normUSPIO⁺/Gd⁺=0.78 at baseline, MTR_normUSPIO⁺/Gd⁺=0.81 at M12) relative to USPIO^-/Gd⁺ lesions (n=67; MTR_normUSPIO^-/Gd⁺=0.82 at baseline, MTR_normUSPIO^–/Gd⁺=0.85 at M12). No interaction in MTR values was observed during the 12 months follow-up (lesion type × time).

Conclusion:

Infiltration of activated macrophages evidenced by USPIO enhancement, is present at the onset of multiple sclerosis and is associated with higher and persistent local loss of tissue structure. Macrophage infiltration affects more tissue structure while tissue recovery during the following year has a similar pattern for USPIO and Gd-enhanced lesions, leading to relative higher persistent local loss of tissue structure in lesions showing USPIO enhancement at baseline.

Keywords

Multiple sclerosis clinically isolated syndrome MRI USPIO macrophage

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References

Bitsch

Schuchardt

Bunkowski

. Acute axonal injury in multiple sclerosis: Correlation with demyelination and inflammation. Brain 2000; 123: 1174–1183.

Trapp

Peterson

Ransohoff

. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338: 278–285.

Aboul-Enein

Weiser

Höftberger

. Transient axonal injury in the absence of demyelination: A correlate of clinical disease in acute experimental autoimmune encephalomyelitis. Acta Neuropathol (Berl) 2006; 111: 539–547.

Redford

Kapoor

Smith

. Nitric oxide donors reversibly block axonal conduction: Demyelinated axons are especially susceptible. Brain 1997; 120: 2149–2157.

Smith

Kapoor

Hall

. Electrically active axons degenerate when exposed to nitric oxide. Ann Neurol 2001; 49: 470–476.

Lassmann

. Axonal and neuronal pathology in multiple sclerosis: What have we learnt from animal models. Exp Neurol 2010; 225: 2–8.

Kornek

Lassmann

. Axonal pathology in multiple sclerosis. A historical note. Brain Pathol 1999; 9: 651–656.

Trapp

Ransohoff

Rudick

. Axonal pathology in multiple sclerosis: Relationship to neurologic disability. Curr Opin Neurol 1999; 12: 295–302.

Grossman

Braffman

Brorson

. Multiple sclerosis: Serial study of gadolinium-enhanced MR imaging. Radiology 1988; 169: 117–122.

10.

Waubant

. Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis. Dis Markers 2006; 22: 235–244.

11.

Tourdias

Dousset

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

12.

Dousset

Ballarino

Delalande

. Comparison of ultrasmall particles of iron oxide (USPIO)-enhanced T2-weighted, conventional T2-weighted, and gadolinium-enhanced T1-weighted MR images in rats with experimental autoimmune encephalomyelitis. Am J Neuroradiol 1999; 20: 223–227.

13.

Floris

Blezer

ELA

Schreibelt

. Blood–brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis: A quantitative MRI study. Brain 2004; 127: 616–627.

14.

Brochet

Deloire

MSA

Touil

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

15.

Vellinga

Oude Engberink

Seewann

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

16.

Dousset

Brochet

Deloire

MSA

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

17.

Tourdias

Roggerone

Filippi

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

18.

Vellinga

Vrenken

Hulst

. 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: 774–779.

19.

Rausch

Hiestand

Baumann

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

20.

Yang

Feng

Yin

. Comparison of USPIO-enhanced MRI and Gd-DTPA enhancement during the subacute stage of focal cerebral ischemia in rats. Acta Radiol 2014; 55: 864–873.

21.

Polman

Reingold

Edan

. Diagnostic criteria for multiple sclerosis: 2005 revisions to the ‘McDonald Criteria’. Ann Neurol 2005; 58: 840–846.

22.

Maarouf

Audoin

Konstandin

. Topography of brain sodium accumulation in progressive multiple sclerosis. Magma N Y N 2014; 27: 53–62.

23.

Crespy

Zaaraoui

Lemaire

. Prevalence of grey matter pathology in early multiple sclerosis assessed by magnetization transfer ratio imaging. PloS One 2011; 6: e24969.

24.

Moore

Weissleder

Bogdanov

. Uptake of dextran-coated monocrystalline iron oxides in tumor cells and macrophages. J Magn Reson Imaging 1997; 7: 1140–1145.

25.

Weissleder

Elizondo

Wittenberg

. Ultrasmall superparamagnetic iron oxide: An intravenous contrast agent for assessing lymph nodes with MR imaging. Radiology 1990; 175: 494–498.

26.

Oude Engberink

Blezer

ELA

Dijkstra

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

27.

Lucchinetti

Bruck

Parisi

. Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Ann Neurol 2000; 47: 707–717.

28.

Fang

Vazquez-Torres

. Nitric oxide production by human macrophages: There’s NO doubt about it. Am J Physiol Lung Cell Mol Physiol 2002; 282: L941–L943.

29.

Waxman

. Axonal conduction and injury in multiple sclerosis: The role of sodium channels. Nat Rev Neurosci 2006; 7: 932–941.

30.

Audoin

Guye

Reuter

. Structure of WM bundles constituting the working memory system in early multiple sclerosis: A quantitative DTI tractography study. NeuroImage 2007; 36: 1324–1330.

31.

Jurcoane

Wagner

Schmidt

. Within-lesion differences in quantitative MRI parameters predict contrast enhancement in multiple sclerosis. J Magn Reson Imaging 2013; 38: 1454–1461.

32.

Silver

Barker

MacManus

. Magnetisation transfer ratio of normal brain white matter: A normative database spanning four decades of life. J Neurol Neurosurg Psychiatry 1997; 62: 223–228.