Elsevier

NeuroImage

Volume 45, Issue 1, March 2009, Pages 60-67
NeuroImage

Association of regional gray matter volume loss and progression of white matter lesions in multiple sclerosis — A longitudinal voxel-based morphometry study

https://doi.org/10.1016/j.neuroimage.2008.10.006Get rights and content

Abstract

Previous studies have established regional gray matter (GM) volume loss in multiple sclerosis (MS) but the relationship between development of white matter (WM) lesions and changes of regional GM volumes is unclear. The present study addresses this issue by means of voxel-based morphometry (VBM).

T1-weighted three-dimensional magnetic resonance imaging (MRI) data from MS patients followed up for 12 months were analyzed using VBM. An analysis of covariance model assessed with cluster size inference (all corrected for multiple comparisons, p < 0.01) was used to compare GM volumes between baseline and follow-up while controlling for age, gender, and disease duration. Lesion burden, i.e. volumes of T1 hypointense and T2 hyperintense lesions and the number of new T2 lesions at year one, was also determined.

Comparing all MS patients (n = 211) longitudinally, GM volume remained unchanged during one year-follow-up. Focusing on patients with relapsing remitting MS (RRMS) (n = 151), significant cortical GM volume reductions between baseline and follow-up scans were found in the anterior and posterior cingulate, the temporal cortex, and cerebellum. Within the RRMS group, those patients with increasing T2 and T1 lesion burden (n = 45) showed additional GM volume loss during follow-up in the frontal and parietal cortex, and precuneus. In contrast, patients lacking an increase in WM lesion burden (n = 44) did not show any significant GM changes.

The present study suggests that the progression of regional GM volume reductions is associated with WM lesion progression and occurs predominantly in fronto-temporal cortical areas.

Introduction

Progressive brain atrophy is a well-known feature of MS and is considered as a marker of irreversible tissue damage of both GM and WM (Miller et al., 2002, Pirko et al., 2007). Quantitative MRI indicates 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., 2004) and is more related to physical disability and cognitive impairment (Amato et al., 2004, Chard et al., 2002, Dalton et al., 2004, De Stefano et al., 2003, Ge et al., 2001, Quarantelli et al., 2003, Sailer et al., 2003, Sanfilipo et al., 2005Sanfilipo et al., 2006, Tiberio et al., 2005) than T2- and T1-lesion volumes.

Neuroimaging studies indicate a correlation between global GM volume and WM lesion load (Chard et al., 2002, De Stefano et al., 2003, Ge et al., 2001, Sanfilipo et al., 2005). Less is known, however, about the mutual relationship of regional volume changes in GM and WM. Cross-sectional attempts to correlate regional GM atrophy with WM lesion measures have revealed conflicting results, ranging from no (Morgen et al., 2006, Prinster et al., 2006) to moderate correlation (Charil et al., 2007, Sailer et al., 2003). To date, there are only two longitudinal studies relating regional GM volume changes to WM lesions. A positive correlation between T2 lesion burden and thalamic volume reduction at baseline has been shown in patients with primary progressive MS (PPMS) using VBM (Sepulcre et al., 2006). Another recent publication based on a rather small cohort of 20 patients with RRMS reported a positive correlation between changes in T2 and T1 lesion volumes and ventricular enlargement (Pagani et al., 2005). It remains elusive whether these observed regional GM volume changes are the consequence of ongoing tissue destruction in WM lesions, e.g. axonal transection and retrograde neurodegeneration (Chard et al., 2002, Evangelou et al., 2000), or whether they occur independently.

The aim of the present study was to clarify the relationship between the development of WM lesions and 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). Firstly, we assessed the longitudinal trajectory in 211 MS patients during a follow-up period of one year. Secondly, we focused on patients with established RRMS and finally on subgroups of patients with a) increasing T2- as well as T1-lesion burden and b) without increasing WM lesion burden.

On the basis of previous longitudinal MRI studies of MS (Table 1), we predicted that the development of GM volume loss in MS is associated with the development of WM lesion burden. In particular, we hypothesized that regional GM volume reductions occur predominantly in patients with increasing WM lesion volumes. Our second hypothesis was that patients with both increasing T1- and T2 lesion burden would show volumetric GM reductions that are qualitatively similar but even more pronounced.

Section snippets

Patients

We examined pairs of MRI data from 211 patients of the case-controlled study for genotype-phenotype associations in MS (GeneMSA; GSK, UK) with the diagnosis of MS (McDonald et al., 2001) (147 women, 64 men; mean age at baseline, 44.0 years; SD 11.0 years). Patients with clinically isolated syndromes (CIS) were also included if they fulfilled 3 of 4 Barkhof criteria for dissemination in space as application of McDonald criteria (McDonald et al., 2001). The total sample of 211 patients comprised

Sample characteristics

The mean inter-scan interval of all MS subjects was 12.6 (0.9) months, with a total of 211 subjects scanned twice. The main sample characteristics are listed in Table 2. Of the 151 patients with RRMS, 45 subjects with ‘progressive’ WM lesions did not differ significantly from the 44 RRMS subjects with ‘non-progressive’ WM lesions with respect to ethnicity, gender, mean inter-scan interval, expanded disability status scale (EDSS) scores, medication, and lesion load neither at baseline nor at

Discussion

In MS, brain atrophy occurs almost 10 times faster than in healthy subjects (Fox et al., 2000, Ge et al., 2000, Kalkers et al., 2002, Rudick et al., 1999, Zivadinov et al., 2001) and it is viewed as the result of extensive demyelination and axonal loss in both WM and GM (Pirko et al., 2007). By measuring decreases in global cortical volumes (De Stefano et al., 2003), thickness (Chen et al., 2004, Sailer et al., 2003), or by means of VBM (Audoin et al., 2006, Morgen et al., 2006, Prinster et

Conclusion

This is the first longitudinal voxel-based morphometry study that has examined the relationship between development of white matter lesions and changes of regional GM volumes in a large sample of patients with RRMS. The results suggest that cortical regional GM volume reductions are directly associated with increasing white matter lesion volumes and occur predominantly in fronto-temporal areas. Long-term follow-up imaging studies should clarify the clinical significance of these associations.

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