Research ReportEffect of immunomodulatory medication on regional gray matter loss in relapsing–remitting multiple sclerosis—A longitudinal MRI study
Introduction
Progressive brain atrophy is a well-known feature of MS and is considered as a marker of irreversible tissue damage of both gray matter (GM) and white matter (WM) (Miller et al., 2002, Pirko et al., 2007). Quantitative MRI studies demonstrated that GM atrophy develops faster than WM atrophy (Chard et al., 2004), occurs in the earliest stages of the disease (Chard et al., 2002, Chard et al., 2004, Dalton et al., 2004a) and is related to physical disability, cognitive impairment and quality of life (Chard et al., 2002, Tiberio et al., 2005). Longitudinal neuroimaging studies relating GM volume changes to WM lesions suggested a positive correlation between progressive WM lesion load and GM volume reductions in patients with primary progressive MS (PPMS) (Sepulcre et al., 2006) and in RRMS patients (Pagani et al., 2005).
We showed in a recent longitudinal voxel-based morphometry (VBM) study (Bendfeldt et al., 2009) of 151 patients with RRMS significant cortical GM volume reductions in the cingulate, the temporal cortex, and cerebellum during 1-year follow-up. The data suggest that progression of regional GM volume reductions might be, at least partly, associated with WM lesion progression. It remains elusive whether these GM volume changes are the consequence of ongoing tissue destruction in WM lesions (Chard et al., 2002, Evangelou et al., 2000) or whether they occur independently. Although all patient groups matched well regarding immunomodulatory treatment, the different drugs used in these previous studies might have influenced regional GM volume atrophy differentially. The introduction of immunomodulatory medication (IM) made a significant impact on treatment of patients with MS as they have been demonstrated effective and tolerable (Rudick and Polman, 2009). Whereas there is clear evidence demonstrating their impact on disease activity measured by clinical and MRI parameters, their impact on regional GM atrophy in particular remains unclear. The aim of the present study was to investigate the potential effects of IMs on regional GM volume loss by means of VBM (Ashburner and Friston, 2000). By surveying the whole brain, VBM provides a non-biased measure of regional differences in GM volumes (Ashburner and Friston, 2000).
On the basis of previous MRI studies of MS investigating the impact of immunomodulatory medications on global gray matter (Tiberio et al., 2005, Zivadinov et al., 2007), we predicted that the development of regional GM volume loss in RRMS is not only associated with the development of WM lesion burden, but also modulated by medication. Our main hypothesis was that in patients with established disease and long-term treatment, immunomodulatory medication would inhibit regional GM volume loss in specific cortical areas prone to atrophy (Battaglini et al., 2009, Bendfeldt et al., 2010, Bendfeldt et al., 2009, Charil et al., 2007, Morgen et al., 2006, Prinster et al., 2006). Based on the only longitudinal study that explicitly investigated the effects of immunomodulatory medication on the global gray matter (Zivadinov et al., 2007), we hypothesized differential effects of treatment or non-treatment on regional GM volume changes in fronto-temporal and cingulate brain regions critically involved in MS.
Section snippets
Sample characteristics
The mean inter-scan interval of all RRMS subjects was 742 days, with a total of 86 patients with RRMS scanned twice. The main sample characteristics are listed in Table 1.
The groups of patients receiving INF-β-1a/b (n = 50) and GA (n = 15) did not differ with respect to age, gender, change of expanded disability status scale (EDSS) scores, and mean inter-scan interval neither at baseline nor at follow-up. Significant differences, however, occurred in disease duration (p = 0.007), global GMV (p < 0.001),
Discussion
To the best of our knowledge, this is the first study to investigate the effect of IMs on regional GM atrophy progression in patients with RRMS. In the present study, we sought to discriminate between the impact of immunomodulatory medication and disease-related effects of itself on the longitudinal atrophy of WM lesions and GM volume changes in a sample of 86 RRMS patients with established disease. We aimed to extend the findings of our prior longitudinal MRI studies (Bendfeldt et al., 2009b)
Patients
In a post-hoc analysis, we examined pairs of MRI data from 86 patients of the ‘Case-controlled study for genotype–phenotype associations in MS’ (GeneMSA; GSK, UK) with the diagnosis of RRMS (McDonald et al., 2001) (66 women, 20 men). Of the 86 patients with RRMS, 65 received IM (INF-β-1a/b: n = 50, whereas 34 received INF-β-1a and 16 INF-β-1b; GA: n = 15) and 21 were free of IM. At baseline scan, patients were on IM for at least 1 year. During follow-up, 23 patients had received corticosteroid
Acknowledgments
We would like to thank the Head of GSK Clinical Imaging Centre, Professor Paul Matthews. We also like to acknowledge Peter Schaerli, Danilo Marzetti, Petra Huber, and Markus Colussi for their expert technical assistance.
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