Introduction

Multiple sclerosis (MS) is the most common chronic inflammatory-demyelinating disease affecting the central nervous system (CNS) of young adults in the western countries, leading, in the majority of cases, to severe and irreversible clinical disability (1). Since its clinical introduction, conventional magnetic resonance imaging (cMRI-dual-echo and postcontrast Tl-weighted scans) has greatly improved our ability to diagnose MS and to monitor its evolution, either natural or modified by treatment (Fig. 1) (2). cMRI-derived measures have indeed shown several advantages over clinical assessment, including their more objective nature and increased sensitivity to MS-related changes. Nevertheless, the magnitude of the relationship between cMRI measures of disease activity or burden and the clinical manifestations of the disease is weak (3,4). This necessarily limits the role of cMRI for the understanding of MS pathophysiology and monitoring of experimental treatment.

Several factors are likely to be responsible for this clinical/MRI discrepancy. First, dual-echo imaging lacks specificity with regard to the heterogeneous pathological substrates of individual lesions (3), and, as a consequence, does not allow an accurate quantification of tissue damage. Specifically, edema, inflammation, demye-lination, remyelination, gliosis, and axonal loss (5), all lead to a similar appearance of hyperintensity on dual-echo images. This is a major issue now that there is compelling evidence that: (i) inflammatory-demyelination is not enough to explain "fixed" neurological deficits in MS (6); (ii) irreversible axonal damage does occur in inflammed MS lesions (7,8); and (iii) irreversible axonal loss is the main contributor to the clinical manifestations of the disease and to its clinical worsening over time (4,6). Second, T2-weighted images do not delineate tissue damage occurring in the normal-appearing white matter (NAWM), which usually represents a large portion of the brain tissue from MS patients and which is known to be damaged in these patients (9). Postmortem studies have shown subtle changes in the NAWM from

Figure 1 Axial proton density-weighted (A), T2-weighted (B), and postcontrast (Gd DTPA, 0.1 mmol/kg) Tl-weighted (C) magnetic resonance images of the brain from a patient with multiple sclerosis. In (A) and (B), multiple hyperintense lesions, suggestive of multifocal white matter pathology, are visible. In (C), some of these lesions are contrast enhanced, indicating the presence of a local blood-brain barrier disruption. Abbreviation: Gd, gadolinium.

Figure 1 Axial proton density-weighted (A), T2-weighted (B), and postcontrast (Gd DTPA, 0.1 mmol/kg) Tl-weighted (C) magnetic resonance images of the brain from a patient with multiple sclerosis. In (A) and (B), multiple hyperintense lesions, suggestive of multifocal white matter pathology, are visible. In (C), some of these lesions are contrast enhanced, indicating the presence of a local blood-brain barrier disruption. Abbreviation: Gd, gadolinium.

MS patients, which not only include diffuse astrocytic hyperplasia, patchy edema, and perivascular cellular infiltration, but also axonal damage (10-12). Finally, dual-echo imaging does not provide an accurate picture of gray matter (GM) damage, which several pathological studies have shown to be prominent in MS

(13-15) and which is likely to be associated to some clinical manifestations of the disease, such as cognitive impairment and fatigue.

These limitations of dual-echo imaging are only partially overcome by the use of postcontrast Tl-weighted scans. Gadolinium (Gd)-enhanced Tl-weighted images allow one to distinguish active from inactive lesions (Fig. 1) (16,17), because enhancement occurs as a result of increased blood-brain barrier (BBB) permeability (18) and corresponds to areas with ongoing inflammation (19). However, the activity of the lesions as demonstrated on postcontrast T1-weighted imaging still does not provide information on tissue damage. Chronically hypointense areas on T1-weighted images (Fig. 2) correspond to areas where severe tissue disruption has occurred (20), and their extent is correlated with the clinical severity of the disease and its evolution over time (21,22). Still, measuring the extent of T1 hypointense lesions may not correspond to the severity of intrinsic lesion pathology and provides no information about NAWM and GM damage. Recently, several nonconventional MRI techniques have been developed and applied in an attempt to improve our understanding of the evolution of MS (23). These techniques, including magnetization transfer (MT) MRI, diffusion-weighted (DW) MRI, and proton MR spec-troscopy (1H-MRS), can provide quantitative information of MS micro- and macroscopic lesion burden with a higher pathological specificity to the most destructive aspects of MS (i.e., severe demyelination and axonal loss) than cMRI. In addition, their application in longitudinal studies may improve our ability to monitor reparative mechanisms, such as resolution of edema, remyelination, reactive gliosis,

Figure 2 Axial proton density-weighted (A) and T1-weighted (B) magnetic resonance images of the brain from a patient with a secondary progressive form of multiple sclerosis. In (A), multiple hyperintense lesions are visible with a predominant involvement of the periventricular regions. In (B), some of these lesions are hypointense (''black holes''), indicating that marked tissue destruction (demyelination and axonal loss) has occurred.

Figure 2 Axial proton density-weighted (A) and T1-weighted (B) magnetic resonance images of the brain from a patient with a secondary progressive form of multiple sclerosis. In (A), multiple hyperintense lesions are visible with a predominant involvement of the periventricular regions. In (B), some of these lesions are hypointense (''black holes''), indicating that marked tissue destruction (demyelination and axonal loss) has occurred.

and recovery from sublethal axonal injury. Finally, functional MRI (fMRI) holds substantial promise to define the role of adaptive cortical reorganization with the potential to limit the clinical consequences of irreversible MS tissue damage. The present chapter outlines the major contributions obtained by the application of cMRI and modern, quantitative MR-based techniques to the diagnosis of MS and to the understanding of the factors leading to the accumulation of irreversible disability. The main results obtained from the application of MR technology to monitor MS clinical trials are also discussed. These paragraphs are preceded by a brief review of the basic aspects of nonconventional MRI techniques to provide an adequate background to those readers who are not MRI specialists.

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