MRI–clinical correlations in the primary progressive course of MS: new insights into the disease pathophysiology from the application of magnetization transfer, diffusion tensor, and functional MRI

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Abstract

Despite patients with primary progressive multiple sclerosis (PPMS) experience a progressive disease course from onset, the burden and activity of lesions on conventional magnetic resonance imaging (MRI) scans of the brain are lower than in all other main clinical phenotypes of MS. This review outlines the major contributions given by magnetization transfer MRI, diffusion tensor MRI and functional MRI to the understanding of the pathophysiology of PPMS and provides evidence that, at least, three factors might explain this clinical/MRI discrepancy: (a) the presence of a diffuse tissue damage at a microscopic level; (b) a prevalent involvement of the cervical cord, and (c) an impairment of the adaptive capacity of the cortex to limit the functional consequences of subcortical structural damage.

Introduction

Patients with primary progressive multiple sclerosis (PPMS) represent a subgroup of patients with clinical and magnetic resonance (MR) imaging (MRI) characteristics which differ from those of patients with relapsing–remitting (RR) MS and secondary progressive (SP) MS [1], [2]. Despite patients with PPMS experience a progressive disease course from onset, the burden and activity of lesions on their T2-weighted and gadolinium-enhanced brain MRI scans are, on average, lower than in all other main clinical phenotypes of MS [3], [4], [5], [6], [7], [8]. That the pathology of lesions in PPMS is characterized by a predominant loss of myelin and axons with only mild inflammatory components [9] can explain, at least partially, the relative paucity of conventional MRI-detectable activity [4], [5]. However, differently from the case of other disease phenotypes, in PPMS patients the correlation between MRI abnormalities and clinical disease severity is not significantly ameliorated when measuring the load of brain T1-hypointense lesions [7], [8], which are thought to reflect areas where severe tissue disruption has occurred [10]. Three factors might explain the discrepancy between brain MRI and clinical findings in PPMS. First, the presence of diffuse tissue damage at a microscopic level [11]. Second, a prevalent involvement of the cervical cord [6], [7], which might also explain the disproportion between the severity of locomotor disability and the less pronounced impairment of other functional systems [1]. Third, an impairment of the adaptive capacity of the cortex to limit the functional consequences of subcortical structural damage [12], [13].

Magnetization transfer MRI (MT MRI) [14] and diffusion tensor MRI (DT MRI) [15] can provide metrics reflecting the extent of tissue damage with increased pathological specificity over conventional MRI. In addition, they enable us to quantify the severity of tissue pathology affecting the normal-appearing white (NAWM) and gray (NAGM) matter beyond the resolution of conventional MRI. Functional MRI (fMRI) holds substantial promise to elucidate the mechanisms of cortical adaptive reorganization following MS injury [12], [13], [16], [17], [18] and, as a consequence, opens new perspectives for the monitoring of the mechanisms underlying recovery or maintenance of functions in the presence of irreversible tissue damage. This review outlines the major contributions given by MT MRI, DT MRI and fMRI to the understanding of the pathophysiology of PPMS.

Section snippets

Basic principles of MT MRI, DT MRI, and fMRI

MT MRI provides an index, named MT ratio (MTR), which reflects the efficiency of the magnetization exchange between protons in tissue water (relatively free) and those bound to the macromolecules [14]. Such an exchange depends upon the relative concentrations of the two pools of protons and on their efficiency of interaction. Although, in MS, low MTR values may be caused either by a reduction in the integrity of macromolecular matrix reflecting damage to the myelin or to the axonal membrane [19]

Brain MT MRI studies of PPMS

The first report of MT MRI findings in PPMS was that from Gass et al. [45], who studied 43 MS cases, of whom 10 were affected by PPMS, using a ROI analysis of T2-visible lesions and NAWM. The average lesion MTR was lower in PPMS patients than in subjects with small vessel disease, but no difference was found between PPMS and other MS clinical phenotypes. A significant, inverse correlation between lesion MTR and expanded disability status scale (EDSS) [46] scores was found for SPMS, but not for

Cervical cord MT MRI studies of PPMS

The technical difficulties in the acquisition of MT MRI scans from the cervical cord have recently been overcome and it is now feasible to obtain good-quality MTR maps from slabs of either sagittal or axial slices covering the entire cervical cord [38]. Cervical cord MTR histogram-derived metrics well differentiate MS patients from normal controls [38], [58], [59]. However, when RRMS patients are considered in isolation, cord MTR histogram characteristics are similar to those from healthy

DT MRI studies of PPMS

In the last few years, an increasing number of DT MRI studies have been conducted in MS [26], [27], [28], [29], [30], [31], [32], [33], [35], [61]. However, only few of these studies included PPMS patients [27], [28], [31], [35]. Droogan et al. [31] compared the DT MRI characteristics of 35 MS patients with various clinical phenotypes (nine patients were affected by PPMS). In this study, brain coverage was limited to four to six central slices and a ROI-based analysis of MS lesions and NAWM was

fMRI studies of PPMS

Our group has recently conducted two fMRI studies of patients with PPMS [67], [68] to investigate the potential for cortical reorganization in limiting the functional consequences of subcortical structural damage in these patients. Clearly, knowing to which extent cortical reorganization occurs in PPMS and whether it has an adaptive role might be rewarding in terms of improving our understanding of the pathophysiology of progressive disability in MS and in terms of planning treatment strategies

Conclusions

Several cross-sectional studies, using MT MRI and DT MRI, have consistently demonstrated that brain NAWM and NAGM are damaged in patients with PPMS. MT MRI studies of the cervical cord indicate that, whereas brain MS pathology may have different patterns in PPMS and SPMS, cord damage plays an important role in determining the irreversible accumulation of MS disability, independent of the way this occurs. fMRI studies showed that cortical functional changes do occur in patients with PPMS, and

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