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San Raffaele Cimena, Italy

Comi G.,San Raffaele Scientific Institute | Abramsky O.,Hadassah University Hospital | Arbizu T.,University of Barcelona | Boyko A.,Moscow State University | And 6 more authors.
Multiple Sclerosis | Year: 2010

Background: Laquinimod, an oral novel immunomodulator, was shown to reduce MRI-measured disease activity in relapsing-remitting MS (RRMS) patients. Objectives: To determine whether the safety and efficacy profile of laquinimod, as shown in a placebo-controlled 36-week trial (LAQ/5062), is sustained and reproducible. Methods: Two hundred and fifty seven patients entered the extension phase in which MRI was performed at the beginning and at the end of the active extension phase. Clinical assessments were performed at weeks 4, 12 and every 12 weeks thereafter. Results: Two hundred and thirty nine (93%) patients completed the extension phase and 222 (86.3%) had a final scan available. Gadolinium-enhanced (GdE) T1 lesions were significantly reduced for patients switching from placebo to 0.3/ 0.6 mg doses (52%, p = 0.0006). In patients initially randomized to 0.6 mg in LAQ/5062 the reduction of MRI activity observed in the placebo-controlled phase was maintained in the extension. The proportion of GdE-free patients for those who switched from placebo increased from a baseline of 31% to 47% at the end of the extension phase (p = 0.01). The most prominent safety signal was elevations of liver enzymes, reversible in all cases. Conclusions: The good efficacy and the excellent safety and tolerability profiles of laquinimod 0.6 mg/day are confirmed in this extension study. © The Author(s) 2010.

Rocca M.A.,Institute of Experimental Neurology | Valsasina P.,Institute of Experimental Neurology | Absinta M.,Institute of Experimental Neurology | Riccitelli G.,Institute of Experimental Neurology | And 4 more authors.
Neurology | Year: 2010

Objective: This study explores default-mode network (DMN) abnormalities in patients with secondary progressive (SP) and primary progressive (PP) multiple sclerosis (MS) and whether such abnormalities correlate with cognitive impairment and damage to selected white matter (WM) fiber bundles, quantified using diffusion tensor (DT) MRI tractography. Methods: Resting state (RS) functional MRI and DT MRI data were acquired from 33 patients with SPMS, 24 patients with PPMS, and 24 controls. Independent component analysis (ICA) was used to identify the DMN. SPM5 was used to assess within-and between-group activations. Results: Between-group differences in DMN activity were found in the left medial prefrontal cortex (mPFC), left precentral gyrus (PcG), and anterior cingulate cortex (ACC). Compared to controls, patients with SPMS had reduced activity in the mPFC (p = 0.01) and PcG (p = 0.02), while patients with PPMS had reduced activity in the PcG (p = 0.008) and the ACC (p = 0.002). Compared to patients with PPMS, patients with SPMS had increased ACC activity (p = 0.04). Reduction of RS activity in the ACC was more pronounced in cognitively impaired vs cognitively preserved patients with MS (p = 0.02). In patients with MS, DMN abnormalities correlated with the PASAT and word list test scores (r values ranging from 0.35 to 0.45) and DT MRI changes in the corpus callosum and the cingulum (r values ranging from 0.82 to 0.87). Conclusion: These results suggest that a dysfunction of the anterior components of the default-mode network may be among the factors responsible for the accumulation of cognitive deficits in patients with progressive multiple sclerosis. Copyright © 2010 by AAN Enterprises, Inc.

Rocca M.A.,Institute of Experimental Neurology | Horsfield M.A.,University of Leicester | Sala S.,Institute of Experimental Neurology | Copetti M.,Biostatistics Unit | And 9 more authors.
Neurology | Year: 2011

ObjectiveIn this multicenter study, a new semiautomatic method for segmenting the cervical cord from C2 to C5 was used to investigate the correlation between cord atrophy and clinical disability in a large sample of patients with multiple sclerosis (MS). Methods: T2 and 3-dimensional T1-weighted cervical cord scans and dual-echo brain scans were acquired from 143 healthy controls, 22 patients with clinically isolated syndromes (CIS), 101 patients with relapsing-remitting MS (RRMS), 79 patients with secondary progressive MS (SPMS), 58 patients with benign MS (BMS), and 75 patients with primary progressive MS (PPMS) in 3 European centers. Normalized cervical cord cross-sectional area (CSAn) was measured by an active surface cord model. Between-group comparisons were performed using linear mixed-effect models. A nonparametric kernel estimator was used to obtain smoothed plots of CSA along the cervical cord. Results: Cord CSAn was significantly lower in PPMS vs healthy controls, BMS vs RRMS, SPMS vs BMS, and RRMS. From C2 to C5, a net separation and definition of the plots of patients with BMS, PPMS, and SPMS was seen with respect to those of the other study groups. CSAn was correlated with Expanded Disability Status Scale (r = -0.49, p < 0.0001), with a differential effect among disease clinical phenotypes: no association in either CIS or in BMS; association in RRMS (r = -0.30, p = 0.001), SPMS (r = -0.34, p = 0.001), and PPMS (r = -0.27, p = 0.01). Conclusions: Cervical cord atrophy provides a relevant and useful marker for the characterization of clinical heterogeneity of patients with MS. The stability of this measure among different centers supports its use as potential outcome measure to monitor disease progression in multicenter trials. © 2011 by AAN Enterprises, Inc. All rights reserved.

Rocca M.A.,Institute of Experimental Neurology | Filippi M.,Institute of Experimental Neurology
Journal of the Neurological Sciences | Year: 2010

While several studies have assessed the brain patterns of cortical activations following executed and observed movements of the dominant and non-dominant lower limbs in right-handed (RH) subjects, the functional correlates of foot movement in left-handed (LH) subjects have not been investigated, yet. We investigated brain function lateralization during action execution and observation with the dominant and non-dominant feet in 8 left-handers (LH). Thirteen right-handers (RH) were also studied while performing the same tasks with their right-foot. Compared to left-foot movement, during right-foot movement, LH had greater activations of the left primary sensorimotor cortex (SMC) and the right cerebellum. Compared to right-foot movement, during left-foot movement, LH subjects activated areas of the sensorimotor network, the mirror-neurons system (MNS) and the visual network lateralized to the contralateral hemisphere. During right-foot movement no between-group difference was found. LH had a pattern of activations lateralized to the right hemisphere during right-foot observation and to the left hemisphere during left-foot observation. Compared to left-foot observation, during right-foot observation, LH had greater activations of frontal and parietal regions and visual areas. The opposite contrast showed higher activation of the right lateral occipito-temporal cortex in LH during left-foot observation. During right-foot observation, compared to RH, LH had greater activations of the bilateral primary SMC and of MNS and visual system regions. In LH, the performance of simple motor acts with the dominant lower limb might be achieved through a complex adaptation and interaction between different neuronal pathways and the daily-life environment. © 2009 Elsevier B.V. All rights reserved.

Comi G.,University of Milan | Jeffery D.,Advance Neurology and Pain | Kappos L.,University of Basel | Montalban X.,Autonomous University of Barcelona | And 4 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Two proof-of-concept clinical trials have provided evidence that laquinimod reduces disease activity in patients with relapsing-remitting multiple sclerosis. METHODS: We conducted a randomized, double-blind, phase 3 study at 139 sites in 24 countries. A total of 1106 patients with relapsing-remitting multiple sclerosis were randomly assigned in a 1:1 ratio to receive oral laquinimod at a dose of 0.6 mg once daily or placebo for 24 months. The primary end point was the annualized relapse rate during the 24-month period. Secondary end points included confirmed disability progression (defined as an increase in the score on the Expanded Disability Status Scale that was sustained for at least 3 months) and the cumulative number of gadolinium-enhancing lesions and new or enlarging lesions on T 2-weighted magnetic resonance imaging. RESULTS: Treatment with laquinimod as compared with placebo was associated with a modest reduction in the mean (±SE) annualized relapse rate (0.30±0.02 vs. 0.39±0.03, P = 0.002) and with a reduction in the risk of confirmed disability progression (11.1% vs. 15.7%; hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.91; P = 0.01). The mean cumulative numbers of gadolinium-enhancing lesions and new or enlarging lesions on T 2-weighted images were lower for patients receiving laquinimod than for those receiving placebo (1.33±0.14 vs. 2.12±0.22 and 5.03±0.08 vs. 7.14±0.07, respectively; P<0.001 for both comparisons). Transient elevations in alanine aminotransferase levels to greater than three times the upper limit of the normal range were observed in 24 patients receiving laquinimod (5%) and 8 receiving placebo (2%). CONCLUSIONS: In this phase 3 study, oral laquinimod administered once daily slowed the progression of disability and reduced the rate of relapse in patients with relapsing-remitting multiple sclerosis. (Funded by Teva Pharmaceutical Industries; ClinicalTrials.gov number, NCT00509145.) Copyright © 2012 Massachusetts Medical Society.

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