Sodium MRI of multiple sclerosis

Abstract

Multiple sclerosis (MS) is the most common cause of non-traumatic disability in young adults. The mechanisms underlying neurodegeneration and disease progression are poorly understood, in part as a result of the lack of non-invasive methods to measure and monitor neurodegeneration in vivo. Sodium MRI is a topic of increasing interest in MS research as it allows the metabolic characterization of brain tissue in vivo, and integration with the structural information provided by (1)H MRI, helping in the exploration of pathogenetic mechanisms and possibly offering insights into disease progression and monitoring of treatment outcomes. We present an up-to-date review of the sodium MRI application in MS organized into four main sections: (i) biological and pathogenetic role of sodium; (ii) brief overview of sodium imaging techniques; (iii) results of sodium MRI application in clinical studies; and (iv) future perspectives.

Keywords: axonal degeneration; multiple sclerosis; sodium MRI.

Fig. 1

Role of ²³Na channels in the axon degeneration cascade. Mitochondrial damage determines energy failure, with ATP deprivation and loss of function of Na/K ATPase. Consequent loss of ionic transmembrane gradient activates Nav1.6 channels producing a sustained ²³Na influx and reversing the operation of the Na/Ca exchanger. Further ²⁰Ca release into the axoplasm occurs from injured mitochondria and intracellular stores, triggered by inositol 1,4,5-trisphosphate receptors and ryanodine receptors, stimulate by increased intracellular ²³Na concentrations. Elevated intracellular levels of ²⁰Ca activate downstream proteolytic cascade, which produce axonal injury. Reproduced from Waxman 2006 by permission of Elsevier Ltd.

Fig. 2

Altered axonal expression of ²³Na channels in MS. Sections of postmortem spinal cord white matter from control (A and B) and MS (C–L) patients, immunostained to show Nav1.6 (red), Nav1.2 (red), Caspr (integral constituent of paranodal junctions-green), and neurofilaments (blue). In control white matter (A) and in normal-appearing white matter in MS tissue (C), Nav1.6 is localized at nodes of Ranvier whereas Nav1.2 is not detectable (B and D). Within MS plaques, continuous Nav1.6 (E) and Nav1.2 (F) immunostaining are present; in some instances bounded by Caspr (G-H). Colocalization of Nav1.6 (I) and Nav1.2 (J) with neurofilament immunostaining (K and L; blue) confirms the axonal identity of these profiles. Reproduced from Craner et al.2004 Copyright (2004) National Academy of Sciences, U.S.A.

Fig. 3

Selected brain axial proton density (A), T1-weighted (B), ²³Na images (C) and corresponding TSC map (D) from an MS patient. The arrow indicates a hypointense periventricular lesion (B) that shows a higher TSC value. The color bar represents the TSC values (mM). Reproduced by Inglese et al. 2010 by permission of Oxford University Press.

Fig. 4

Global ²³Na concentration across MS phenotypes. Raw ²³Na images in ²³Na space (top), tissue ²³Na maps with CSF partial volume correction (middle) and T2-weighted images (bottom) registered to the T1 volumetric scan in controls (A) and patients with MS (B-C-D). Increased ²³Na is seen in relapsing remitting- MS patients lesions (B) and, more extensively, in lesions and normal appearing white matter of secondary- (C) and primary- (D) progressive MS patients. Reproduced from Paling et al.2013 by permission of Oxford University Press.

Fig. 5

Statistical mapping of TSC increases in secondary progressive MS patients relative to controls (A) and in primary progressive MS patients relative to controls (B). In order to reduce CSF contamination grey matter, normal appearing white matter and T2 lesion masks were applied onto the co-registered quantitative sodium concentration maps to obtain TSC distribution maps of each compartment for each patient. Reproduced from Maarouf et al. 2013 by permission of Springer Ltd.

Fig. 6

ISC and ISVF quantification. ISC map (a) and ISVF map (b) derived from MRI measurements of a healthy young 27-year-old male. ISCs of the grey matter and white matter regions are relatively uniform, while ISVF for white matter is higher than for grey matter, consistently with previous findings obtained with invasive methods in animals or ex vivo human brain tissue. Reproduced from Fleysher et al. 2013 by permission of John Wiley & Sons, Ltd.