Deficient MWF mapping in multiple sclerosis using 3D whole-brain multi-component relaxation MRI

Abstract

Recent multiple sclerosis (MS) MRI research has highlighted the need to move beyond the lesion-centric view and to develop and validate new MR imaging strategies that quantify the invisible burden of disease in the brain and establish much more sensitive and specific surrogate markers of clinical disability. One of the most promising of such measures is myelin-selective MRI that allows the acquisition of myelin water fraction (MWF) maps, a parameter that is correlated to brain white matter (WM) myelination. The aim of our study was to apply the newest myelin-selective MRI method, multi-component Driven Equilibrium Single Pulse Observation of T1 and T2 (mcDESPOT) in a controlled clinical MS pilot trial. This study was designed to assess the capabilities of this new method to explain differences in disease course and degree of disability in subjects spanning a broad spectrum of MS disease severity. The whole-brain isotropically-resolved 3D acquisition capability of mcDESPOT allowed for the first time the registration of 3D MWF maps to standard space, and consequently a formalized voxel-based analysis of the data. This approach combined with image segmentation further allowed the derivation of new measures of MWF deficiency: total deficient MWF volume (DV) in WM, in WM lesions, in diffusely abnormal white matter and in normal appearing white matter (NAWM). Deficient MWF volume fraction (DVF) was derived from each of these by dividing by the corresponding region volume. Our results confirm that lesion burden does not correlate well with clinical disease activity measured with the extended disability status scale (EDSS) in MS patients. In contrast, our measurements of DVF in NAWM correlated significantly with the EDSS score (R² = 0.37; p < 0.001). The same quantity discriminated clinically isolated syndrome patients from a normal control population (p < 0.001) and discriminated relapsing–remitting from secondary-progressive patients (p < 0.05); hence this new technique may sense early disease-related myelin loss and transitions to progressive disease. Multivariate analysis revealed that global atrophy, mean whole-brain myelin water fraction and white matter atrophy were the three most important image-derived parameters for predicting clinical disability (EDSS). Overall, our results demonstrate that mcDESPOT-defined measurements in NAWM show great promise as imaging markers of global clinical disease activity in MS. Further investigation will determine if this measure can serve as a risk factor for the conversion into definite MS and for the secondary transition into irreversible disease progression.

Introduction

Multiple sclerosis (MS), one of the most common disabling neurological diseases in young adults, is an immune-mediated disease that is poorly understood but is known to involve both demyelination and axonal destruction within the human central nervous system (CNS) (Platten et al., 2005). The pathology findings are heterogeneous but white matter (WM) demyelination is the recognized hallmark of the disease (Lucchinetti et al., 2000).

Conventional T1- and T2-weighted magnetic resonance imaging (MRI) studies reveal focal signal abnormalities, traditionally called lesions or “plaques”, throughout white matter (WM), and less frequently also gray matter (GM), in brain and spinal cord. In fact conventional MRI has revolutionized MS clinical practice (Vellinga et al., 2009), but it does not adequately fulfill the role of a disease biomarker. While MRI derived lesion count and volumetric measures are currently used as paraclinical markers in standardized diagnostic schemes (Polman et al., 2005), the lesion-centric view has been challenged by several studies revealing weak or non-significant correlations (Daumer et al., 2009, Fulton et al., 1999, Zivadinov, 2009). Presently available technologies have failed to meet the critical goal of reflecting MS patient disability status and predicting disease progression (Held et al., 2005, Sormani et al., 2003). When subjected to rigorous statistical analysis, conventional MRI measures appear to offer no more valid endpoint than that already offered by clinical measures of MS disability such as the extended disability status scale (EDSS) and the relapse rate (Daumer et al., 2009).

Newly developed quantitative MRI technologies have shown sensitivity to myelination and axonal integrity. They have been indicative of a process of diffuse myelin damage and axonal loss in MS not restricted to lesion tissue, but throughout the entire CNS parenchyma (Seewann et al., 2009, Vrenken et al., 2010).

Within the battery of newly developed quantitative MRI technologies, magnetization transfer imaging (MTI), (Filippi and Agosta, 2007, Horsfield, 2005) diffusion tensor imaging (DTI), (Schmierer et al., 2007, Song et al., 2003) and relaxation imaging (Karampekios et al., 2005, Papanikolaou et al., 2004) are all thought to provide information related to myelin content. However, measures derived from these approaches are non-specific with regard to demyelination. While quantitative MTI provides an estimate of the macromolecule-bound water fraction, this measure may also reflect other inflammation processes in MS (Gareau et al., 2000, Vavasour et al., 1998). A histological analysis revealed a higher correlation between MTI measures and axonal density than myelin density in MS lesions (van Waesberghe et al., 1999). MTI measures therefore are considered to reflect an overall loss of membrane integrity, including demyelination (Dousset et al., 1995).

For DTI, significant fractional anisotropy is observed even in non-myelinated axonal nerve tissue (Beaulieu, 2002). More importantly, fractional anisotropy is low in regions of crossing fibers independent of myelin content (Oouchi et al., 2007).

With regards to single-component relaxation imaging, while both T1 and T2 relaxation times may be sensitive to myelin content, these are also influenced by additional factors including free water content and the presence of paramagnetic species such as iron.

Currently, T2 multi-component relaxation imaging (MCRI) provides the most established and specific means of quantifying myelin tissue content in vivo. In conventional T2 MCRI, multiple spin-echo images acquired over a range of echo times and multi-exponential data analysis are used to decompose the signal into water pools with a distribution of T2 times. Ultimately, this distribution is separated into main two pools: one intra- and extra-cellular water pool and a second “myelin water” pool, assumed to be trapped between the hydrophobic bilayers of the myelin sheath (Menon and Allen, 1991, Whittall et al., 1997). This is the quantity that links T2 MCRI and the technique that we employ. The myelin water fraction estimate derived this way shows strong correlation with histological assessment of myelin fraction (Laule et al., 2006, MacKay et al., 2009, Webb et al., 2003). For this reason, MCRI has become the de facto standard for non-invasive myelin quantification. Unfortunately, established MCRI methods require lengthy imaging times while providing limited volume coverage. For example, the multi-echo T2 relaxation method requires approximately 25 min to acquire a single slice with a voxel volume of 8.8 mm³ (Madler et al., 2008, Whittall et al., 1997). There have been some recent improvements (Oh et al., 2007), however the volume coverage, spatial resolution, and imaging time characteristics of these methods make high resolution, whole-brain investigations challenging or impossible.

Multi-component driven equilibrium single pulse observation ofT1/T2 (mcDESPOT) is the most recent MCRI technique that allows rapid acquisition of high-resolution whole-brain data which is then processed to yield quantitative two-pool parameters including myelin water fraction maps. Series of spoiled gradient echo (SPGR) and balanced steady-state free precession (bSSFP) scans are each collected over a range of flip angles (FA) at constant repetition times (TR). This data set allows reliable estimation of the relaxation properties of a two-pool model undergoing exchange at every voxel over the whole brain (Deoni et al., 2008b). One of the parameters is the fraction of water in the fast relaxing pool, which we have named the myelin water fraction (MWF) because of its similarity with the one defined by previous MCRI methods (Kolind and Deoni, 2011). We have further hypothesized that MWF derived from mcDESPOT will correlate directly with tissue myelin fraction (Deoni, 2009a, Deoni, 2009b) as have previous measures (Laule et al., 2006, MacKay et al., 2009).

The objectives of our study were (1) to derive MWF maps and a novel MWF-derived quantity that we term deficient MWF volume fraction (DVF) using mcDESPOT acquisitions from a broad spectrum of MS patients, (2) to test the hypothesis that MWF and/or DVF correlate with disability in MS and thus reflect non-lesional MS pathology that may determine disease severity, and (3) to assess the relative contributions of quantitative myelin-specific parameters and brain atrophy measures such as brain parenchymal volume fraction (PVF).

A novel and clearly advantageous feature of the mcDESPOT technique is that it efficiently covers the entire brain, producing isotropic and high quality datasets of the presumed MWF. This allows myelin quantification to be done much more rigorously, for the first time, using standard space approaches which have proven useful for other analyses such as voxel-based morphometry (Mechelli et al., 2005). In this study, we used these tools with mcDESPOT to conduct formalized correlations and group comparisons of myelin water fraction and atrophy measures with clinical disability.