A voxel-based morphometry study of grey matter loss in MS patients with different clinical phenotypes Antonia Ceccarelli, a Maria A. Rocca, a,b Elisabetta Pagani, a Bruno Colombo, b Vittorio Martinelli, b Giancarlo Comi, b and Massimo Filippi a,b, ⁎ a Neuroimaging Research Unit, Scientific Institute and University Ospedale San Raffaele, Milan, Italy b Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy Received 19 February 2008; revised 9 April 2008; accepted 11 April 2008 Available online 20 April 2008 To assess regional grey matter (GM) changes in a large cohort of multiple sclerosis (MS) patients with different clinical phenotypes, using voxel- based morphometry (VBM) and their correlation with the extent of global and regional T2 lesion volumes (LV), we acquired conventional MRI scans from 71 MS patients with different clinical phenotypes (26 with relapsing-remitting [RR] MS, 27 with secondary progressive [SP] MS and 18 with primary progressive [PP] MS), 28 patients with a clinically isolated syndrome (CIS) suggestive of MS, and 21 controls. No GM loss was found in CIS patients. Compared to CIS patients, those with RRMS had a significant GM loss in the right pre and postcentral gyri. Compared to RRMS, SPMS patients had a significant GM loss in several regions of the fronto-parieto-temporo-occipital lobes, the cerebellum and superior and inferior colliculus, bilaterally, and deep GM structures. Compared to PPMS, SPMS patients had a significant GM loss in the postcentral gyrus, the cuneus, the middle occipital gyrus, the thalamus, the cerebellum, and the superior and inferior colliculus. In all MS groups, regional GM loss was strongly/moderately correlated with brain T2 LV. In SPMS and PPMS patients, a correlation was found between cortical regional GM loss and T2 LV of the corresponding or adjacent lobes. In MS patients, GM volume loss follows different patterns of regional distribution according to the clinical phenotype of the disease, is likely secondary to the presence and topography of focal WM inflammatory-demyelinating lesions, and is more evident in the progressive forms of the disease. © 2008 Elsevier Inc. All rights reserved. Introduction Brain atrophy is a well-known feature of multiple sclerosis (MS) and affects extensively the white matter (WM) and the grey matter (GM) (Amato et al., 2004; Bermel et al., 2002; Chard et al., 2004; Cifelli et al., 2002; De Stefano et al., 2003; Miller et al., 2002; Pelletier et al., 2003; Sailer et al., 2006; Zivadinov et al., 2004). In this latter tissue compartment, the involvement of both cortical and deep GM structures has been demonstrated by pathologic (Bo et al., 2006; Brownell and Hughes, 1962; Wylezinska et al., 2003) and structural MR (Amato et al., 2004; Bermel et al., 2002; Cifelli et al., 2002, De Stefano et al., 2003; Sailer et al., 2006; Wylezinska et al., 2003) studies. In addition, several studies suggest that, in MS, GM loss might be more prominent than that of WM (Carone et al., 2006; Dalton et al., 2004; Morgen et al., 2006; Quarantelli et al., 2003; Tiberio et al., 2005), probably because inflammatory changes, which are more pronounced in the WM (Bo et al., 2006), might at least partially mask tissue loss in this tissue compartment. Recently, several approaches have been developed to obtain measures of atrophy at a regional level (Benedict et al., 2005; Carone et al., 2006; Locatelli et al., 2004; Pagani et al., 2007; Sailer et al., 2006; Zivadinov et al., 2003) and their application to MS has demonstrated GM loss in several brain regions in patients when compared to healthy controls (Bermel et al., 2002; Cifelli et al., 2002; Dietemann et al., 1988; Evangelou et al., 2000; Locatelli et al., 2004; Zivadinov et al., 2003). Among these approaches, voxel- based morphometry (VBM) holds substantial promise, since it is a fully automated and accurate method that allows comparison of the local “concentrations” of GM between groups of subjects (Ash- burner and Friston, 2000; Good et al., 2001). Using such an ap- proach, previous studies have attempted to define the topographical distribution of GM atrophy in cortical and subcortical structures in MS patients with different disease phenotypes and have shown a reduction of GM density in the thalami in patients with pediatric MS (Mesaros et al., 2008), relapsing-remitting (RR) MS (Audoin et al., 2006) and early primary progressive (PP) MS (Sepulcre et al., 2006). In patients with RRMS, the involvement of several cortical areas has also been described (Audoin et al., 2006; Morgen et al., 2006; Prinster et al., 2006). To the best of our knowledge, no study has compared the distribution of GM loss among patients with the main www.elsevier.com/locate/ynimg NeuroImage 42 (2008) 315 – 322 ⁎ Corresponding author. Neuroimaging Research Unit Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Via Olgettina, 60, 20132 Milan, Italy. Fax: +39 02 26435972. E-mail address: m.filippi@hsr.it (M. Filippi). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2008.04.173