The association of white matter (WM) lesions and grey matter (GM) atrophy is a feature in relapsing‐remitting multiple sclerosis (RRMS). The spatiotemporal distribution pattern of WM lesions, their relations to regional GM changes and the underlying dynamics are unclear. Here we combined parametric and non‐parametric voxel‐based morphometry (VBM) to clarify these issues. MRI data from RRMS patients with progressive (PLV, n = 45) and non‐progressive WM lesion volumes (NPLV, n = 44) followed up for 12 months were analysed. Cross‐sectionally, the spatial WM lesion distribution was compared using lesion probability maps (LPMs). Longitudinally, WM lesions and GM volumes were studied using FSL‐VBM and SPM5‐VBM, respectively. WM lesions clustered around the lateral ventricles and in the centrum semiovale with a more widespread pattern in the PLV than in the NPLV group. The maximum local probabilities were similar in both groups and higher for T2 lesions (PLV: 27%, NPLV: 25%) than for T1 lesions (PLV: 15%, NPLV 14%). Significant WM lesion changes accompanied by cortical GM volume reductions occured in the corpus callosum and optic radiations ( P = 0.01 corrected), and more liberally tested (uncorrected P < 0.01) in the inferior fronto‐occipital and longitudinal fasciculi, and corona radiata in the PLV group. Not any WM or GM changes were found in the NPLV group. In the PLV group, WM lesion distribution and development in fibres, was associated with regional GM volume loss. The different spatiotemporal distribution patterns of patients with progressive compared to patients with non‐progressive WM lesions suggest differences in the dynamics of pathogenesis. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

Prevention of global gray matter (GM) volume changes in multiple sclerosis (MS) are an objective in clinical trials, but the effect of immunomodulatory medication on regional GM atrophy progression is unclear. MRIs from 86 patients with relapsing-remitting MS (RRMS) followed up for 24 months were analyzed using voxel-based morphometry. An analysis of covariance model (cluster threshold, corrected p<0.05) was used to compare GM volumes between baseline and follow-up while stratified by immunomodulatory medication (IM): Interferone INF-beta-1a (n=34), INF-beta-1b (n=16), glatiramer acetate (GA) (n=15), and no-immunomodulatory treatment (n=21). In the INF-beta-1a/1b group (n=50), significant GM volume reductions were observed during follow-up in fronto-temporal, cingulate and cerebellar cortical brain regions, without significant differences between the INF-beta-1a and INF-beta-1b patients. In the GA group and in unmedicated patients, no significant regional GM volume reductions were observed. In contrast to GA, INF-beta-1a/1b treatment was associated with GM volume reductions in hippocampal/parahippocampal and anterior ungulate cortex. This is the first longitudinal study investigating the effects of IMs on GM in RRMS. Results suggest differences in the dynamics of regional GM volume atrophy in differentially treated or untreated RRMS patients. (C) 2010 Elsevier B.V. All rights reserved.

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.

Prinomide tromethamine, a nonsteroidal antiinflammatory drug, was orally administered at doses of 250, 500, and 1000 mg every 12 hr for 28 days to healthy male volunteers. The pharmacokinetic behavior of prinomide and its primary plasma metabolite displayed nonlinear characteristics, while those of free prinomide and its metabolite were dose proportional. The nonlinear pharmacokinetic behavior of total prinomide and p-hydroxy metabolite was found to be caused by both saturable and mutually dependent competitive Langmuir-type plasma protein binding between prinomide and its p-hydroxy metabolite. The extent of the protein interaction displayed at steady state was due to the extensive accumulation of the p-hydroxy metabolite. While ligand–protein interactions are known for xenobiotic competitors, the characteristic behavior of prinomide is the first known example to be reported for a competitive protein interaction between a xenobiotic and its own in vivo generated metabolite. The findings of this study may have implications regarding the disposition of other extensively bound nonsteroidal antiinflammatory drugs with long-lived metabolites.