Short-term accrual of gray matter pathology in patients with progressive multiple sclerosis: an in vivo study using diffusion tensor MRI
Introduction
Patients with primary progressive (PP) multiple sclerosis (MS) experience accumulation of irreversible neurological disability since the onset of the disease, without an initial period of clinical relapses and remissions (Thompson et al., 1997). Conversely, when the progression of disability begins after a purely relapsing-remitting course, which may have lasted several years, the disease course is named secondary progressive (SP) (Lublin et al., 1996). Although it is likely that diffuse axonal loss and persistent demyelination may play a role in increasing the clinical impact of MS-related damage, the pathological mechanisms underlying the progressive course of MS remain, at least partially, unclear (Noseworthy et al., 2000).
Conventional MRI has given a relevant contribution to the in vivo monitoring of MS evolution, by allowing us to detect signs of disease activity and increasing lesion burden over time with a greater sensitivity than the patients' assessment on a solely clinical ground (Miller et al., 1993). However, conventional MRI aspects are poorly correlated with MS clinical progression and have a limited prognostic value for the short- and long-term disease outcome (Brex et al., 2002, Losseff et al., 1996, Molyneux et al., 2001, Rovaris et al., 2003b). Quantitative MR-based techniques, able to provide a more accurate in vivo estimation of MS pathology, may overcome some of the limitations of conventional MRI (Filippi and Grossman, 2002). Among these techniques, diffusion tensor (DT) MRI allows the quantitative measurement of different aspects of tissue microstructure, obtained by exploiting the properties of water diffusion in the brain (Basser et al., 1994, Le Bihan et al., 1986, Le Bihan et al., 1991). The diffusion coefficient of biological tissues, which is influenced by their various components, including cell membranes and organelles, is always lower than the diffusion coefficient in free water and, for this reason, is named apparent diffusion coefficient (ADC). Since some cellular structures are aligned on the scale of an image pixel, the measurement of diffusion is also dependent on the direction in which diffusion is measured. As a consequence, diffusion measurements can give information about the size, shape, orientation, and geometry of tissues. A measure of diffusion which is independent of the orientation of structures is provided by the mean diffusivity (MD), the average of the ADCs measured in three orthogonal directions. A full characterization of diffusion can be obtained in terms of a tensor, a 3 × 3 matrix which accounts for the correlation existing between molecular displacement along orthogonal directions. From the tensor, it is possible to derive MD, equal to the one third of its trace, and some other dimensionless indexes of anisotropy. One of the most used is the fractional anisotropy (FA). The pathological elements of MS can alter the permeability or geometry of structural barriers to water diffusion in the brain, thus typically causing increased MD and decreased FA values (Hajnal et al., 1991). Since “inflammatory” changes and gliosis can potentially restrict water molecular motion, myelin and axonal loss seem to be the most likely contributors to MS-related DT MRI abnormalities (Mottershead et al., 2003). Using histogram analysis (Cercignani et al., 2001b), the DT MRI characteristics of large portions of the brain, as well as of the gray and white matter (WM) compartments, can be investigated. In MS, those pixels corresponding to T2-visible lesions can be excluded from the analysis, thus allowing a selective assessment of the normal-appearing white (NAWM) and gray matter (NAGM) to be performed in isolation (Cercignani et al., 2001a).
To the best of our knowledge, no longitudinal DT MRI studies have been conducted in patients with progressive MS yet. The present study was therefore performed to assess the value of DT MRI for the in vivo assessment of the short-term accumulation of NAWM and NAGM damage in patients with PP and SP MS, with the ultimate aim to investigate whether DT MRI-derived metrics may reliably serve as paraclinical measures of outcome to monitor the evolution of progressive MS.
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Patients
All patients were selected from the populations attending the outpatient MS clinics of the participating institutions. The disease course was classified as PP or SP according to international criteria (Lublin et al., 1996, Thompson et al., 2000). Other neurological conditions were always carefully excluded by performing the appropriate investigations, including cerebrospinal fluid (CSF) examination in all patients (Thompson et al., 2000). At study entry and follow-up, patients underwent a
Healthy volunteers
No abnormalities were detected on the brain MRI scans from controls, both at baseline and at follow-up. The mean values of PBVC, average WM and GM MD, and average WM FA are reported in Table 1. The observed PBVC was not significantly different from zero (P = 0.23). No significant differences between baseline and follow-up values were found for any DT MRI histogram-derived quantity (P values were 0.272, 0.834, and 0.904, respectively).
Patients
At follow-up, median EDSS scores were 6.0 (range: 3.0–7.5)
Discussion
DT MRI studies of MS have provided important pieces of information about the pathological heterogeneity of MRI-visible lesions (Castriota-Scanderbeg et al., 2000, Cercignani et al., 2000, Filippi et al., 2000a, Werring et al., 2000) and have confirmed that progressive worsening of NAWM damage can be detected in areas where new lesions will subsequently appear (Rocca et al., 2000, Werring et al., 2000). Moreover, by using MD and FA histograms where T2-visible lesions are masked, a comprehensive
Acknowledgment
This study was in part supported by a grant from the “Fondazione Italiana Sclerosi Multipla” (FISM, Genoa, Italy).
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