Institute of Experimental Neurology

San Raffaele Cimena, Italy

Institute of Experimental Neurology

San Raffaele Cimena, Italy
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Agosta F.,Institute of Experimental Neurology | Scola E.,Vita-Salute San Raffaele University | Canu E.,Institute of Experimental Neurology | Marcone A.,San Raffaele Turro Hospital | And 11 more authors.
Cerebral Cortex | Year: 2012

White matter (WM) tract damage was assessed in patients with the behavioral variant frontotemporal dementia (bvFTD) and the 3 primary progressive aphasia (PPA) variants and compared with the corresponding brain atrophy patterns. Thirteen bvFTD and 20 PPA patients were studied. Tract-based spatial statistics and voxel-based morphometry were used. Patients with bvFTD showed widespread diffusion tensor magnetic resonance imaging (DT MRI) abnormalities affecting most of the WM bilaterally. In PPA patients, WM damage was more focal and varied across the 3 syndromes: left frontotemporoparietal in nonfluent, left frontotemporal in semantic, and left frontoparietal in logopenic patients. In each syndrome, DT MRI changes extended beyond the topography of gray matter loss. Left uncinate damage was the best predictor of frontotemporal lobar degeneration diagnosis versus controls. DT MRI measures of the anterior corpus callosum and left superior longitudinal fasciculus differentiated bvFTD from nonfluent cases. The best predictors of semantic PPA compared with both bvFTD and nonfluent cases were diffusivity abnormalities of the left uncinate and inferior longitudinal fasciculus. This study provides insights into the similarities and differences of WM damage in bvFTD and PPA variants. DT MRI metrics hold promise to serve as early markers of WM integrity loss that only at a later stage may be detectable by volumetric measures. © The Author 2011. Published by Oxford University Press. All rights reserved.


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 | Valsasina P.,Institute of Experimental Neurology | Misci P.,Institute of Experimental Neurology | Falini A.,Vita-Salute San Raffaele University | Filippi M.,Institute of Experimental Neurology
Neurology | Year: 2012

Objectives: Given that multiple sclerosis (MS) hits diffusely the brain hemispheres, we hypothesized that this should result in a distributed pattern of functional connectivity (FC) abnormalities. To this aim, we assessed, using resting-state (RS) fMRI, intrinsic FC and functional network connectivity (FNC) of brain large-scale neuronal networks from 85 patients with relapsing-remitting MS (RRMS) and 40 matched controls. Methods: Independent component analysis was used to analyze RS fMRI data. Intrinsic FC of each cluster of each RS network (RSN) was compared between controls and patients (analysis of variance adjusted for age, gender, and gray matter volume). The FNC toolbox was used to assess interactions among RSNs. Results: Compared to controls, patients with RRMS experienced a decreased RS FC in regions of the salience (SN), executive control (ECN), working memory (WMN), default mode (DMN), sensorimotor, and visual networks. They also had an increased RS FC in regions of the ECN and auditory RSN. Decreased RS FC was significantly correlated with disability and T2 lesion volumes. In patients with RRMS, when compared to controls, FNC analysis showed that the ECN had an increased connectivity with the SN and a decreased connectivity with the DMN. An abnormal connectivity between the WMNs and sensory networks was also found. Conclusions: Functional abnormalities within and between large-scale neuronal networks occur in patients with RRMS and are related to the extent of T2 lesions and the severity of disability. Longitudinal studies should ascertain whether such functional abnormalities confer a systematic vulnerability to disease progression or, conversely, protect against the onset of clinical deficits. Copyright © 2012 by AAN Enterprises, Inc.


Valsasina P.,Institute of Experimental Neurology | Rocca M.A.,Institute of Experimental Neurology | Rocca M.A.,San Raffaele Scientific Institute | Absinta M.,Institute of Experimental Neurology | And 7 more authors.
Human Brain Mapping | Year: 2012

Objective: Aim of this study was to compare tactile-associated cervical cord fMRI activity between primary progressive (PP) and secondary progressive (SP) MS patients and to investigate whether cord recruitment was associated with structural brain and cord damage. Experimental Design: Cervical cord fMRI during a tactile stimulation of the right hand was acquired from 17 healthy controls, 18 SPMS patients, and 16 PPMS patients. Average fMRI activity and its topographical distribution in cord sectors (left vs. right, posterior vs. anterior) were assessed. Correlations between cord recruitment and structural cord and brain MRI were estimated. Principal Observations: Progressive MS patients showed an increased cord recruitment compared with controls (P = 0.003). Despite a similar structural cord damage, cord activity was increased in SPMS compared to PPMS patients (P = 0.05). Regional analysis showed a non-lateralized pattern of cord recruitment in MS patients. Compared to PPMS, SPMS patients had grey matter (GM) atrophy in several cortical and subcortical regions. In SPMS patients, atrophy of the left postcentral gyrus was correlated with cord activity (r = -0.48, P = 0.04). Conclusions: Patients with progressive MS had an over-recruitment of the cervical cord, which was more pronounced in SPMS than PPMS, despite similar cord structural damage. The alteration of the complex modulation of spinal cord interneurons possibly due to a loss of supratentorial inhibition secondary to brain injury might contribute to explain the observed functional cord abnormalities. © 2011 Wiley Periodicals, 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.


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.


Rossi S.,NeuroLogica | Rossi S.,Santa Lucia Foundation | Furlan R.,Institute of Experimental Neurology | De Chiara V.,NeuroLogica | And 17 more authors.
Annals of Neurology | Year: 2012

Objective: The frequency of inflammatory episodes in the early stages of multiple sclerosis (MS) has been correlated with late neurodegeneration, but the mechanism by which inflammation gives rise to delayed neuronal damage is unknown. Increased activity of the neurotransmitter glutamate is thought to play a role in the inflammation-driven neurodegenerative process of MS, and therefore we tested whether inflammatory cytokines released during acute MS attacks have the property of enhancing glutamate-mediated transmission and excitotoxicity in central neurons. Methods: We compared the effect of cerebrospinal fluid (CSF) from active and quiescent MS patients on glutamate-mediated excitatory postsynaptic currents (EPSCs) and excitotoxic damage in rodent brain slices. We also measured CSF concentrations of tumor necrosis factor-α, of interleukin-1β (IL-1β), and of IL-1 receptor antagonist (IL-1ra), and correlated cytokine levels with cortical excitability assessed in MS patients by means of paired-pulse transcranial magnetic stimulation (TMS). Results: CSF from MS patients with enhanced brain lesions at magnetic resonance imaging was able to increase spontaneous EPSC frequency and glutamate-mediated neuronal swelling in vitro, through a mechanism dependent on enhanced IL-1β signaling and increased glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor stimulation. Furthermore, IL-1β/IL-1ra ratio was significantly higher in the CSF of active MS subjects, and correlated with intracortical facilitation, an accredited TMS measure of glutamate transmission. Finally, we identified for the first time transient receptor potential vanilloid 1 channels as essential intermediates for the synaptic action of IL-1β on central glutamatergic synapses. Interpretation: Our results provide compelling evidence of the synaptic mechanism linking inflammation and excitotoxic neurodegeneration in MS. Copyright © 2011 American Neurological Association.


Agosta F.,Neuroimaging Research Unit | Sala S.,Neuroimaging Research Unit | Sala S.,University of Milan Bicocca | Valsasina P.,Neuroimaging Research Unit | And 11 more authors.
Neurology | Year: 2013

Objective: To investigate whether brain functional network connectivity is disrupted in patients with the behavioral variant of frontotemporal dementia (bvFTD). Methods: Graph theoretical analysis was applied to resting state functionalMRI data from18 patients with probable bvFTDand 50 healthy individuals. Functional connectivity between 90 cortical and subcortical brain regions was estimated using bivariate correlation analysis and thresholded to construct a set of undirected graphs. Correlations between network properties and cognitive variables were tested. Results: Global topologic organization of the functional brain network in bvFTD was significantly disrupted as indicated by reduced mean network degree, clustering coefficient, and global efficiency and increased characteristic path length and assortativity relative to normal subjects. Compared to controls, bvFTD data showed retention of major "hub" regions in the medial parietal, temporal, and occipital lobes, but cortical hubs were not noted in the frontal lobes. Medial and dorsal frontal regions, left caudate nucleus, left insular cortices, and some regions of the temporal, parietal, and occipital lobes showed decreased nodal centrality. BvFTD patients showed the greatest decrease in inter-regional connectivity between the frontal and occipital regions, and the insular cortices and occipital, temporal, subcortical, and frontal regions. In bvFTD, altered global network properties correlated with executive dysfunction. Conclusions: Global and local functional networks are altered in bvFTD, suggesting a loss of efficiency in information exchange between both distant and close brain areas. Altered brain regions are located in structures that are closely associated with neuropathologic changes in bvFTD. Aberrant topology of the functional brain networks in bvFTD appears to underlie cognitive deficits in these patients. © 2013 American Academy of Neurology.


Rocca M.A.,Institute of Experimental Neurology | Parisi L.,Institute of Experimental Neurology | Pagani E.,Institute of Experimental Neurology | Copetti M.,Biostatistics Unit | And 5 more authors.
Radiology | Year: 2014

Purpose: To use magnetic resonance (MR) imaging and advanced analysis to assess the role of lesions in normal-appearing white matter (NAWM) and gray matter (GM) damage, global versus regional damage, and atrophy versus microstructural abnormalities in the pathogenesis of fatigue in multiple sclerosis (MS).Materials and Methods: Local ethics committee approval and written informed consent were obtained. Dual-echo, double inversion-recovery, high-resolution T1-weighted and diffusion-tensor (DT) MR was performed in 31 fatigued patients, 32 nonfatigued patients, and 35 control subjects. Global and regional atrophy and DT MR measures of damage to lesions, NAWM, and GM were compared (analysis of variance).Results: Lesional, atrophy, and DT MR measures of global damage to brain, white matter (WM), and GM did not differ between fatigued and nonfatigued patients. Compared with nonfatigued patients and control subjects, fatigued patients experienced atrophy of the right side of the accumbens (mean volume±standard deviation, 0.37 mL±0.09 in control subjects; 0.39 mL±0.1 in nonfatigued patients; and 0.33 mL±0.09 in fatigued patients), right inferior temporal gyrus (ITG) (Montreal Neurological Institute [MNI] coordinates: 51, 251, 211; t value, 4.83), left superior frontal gyrus (MNI coordinates: 210, 49, 24; t value, 3.40), and forceps major (MNI coordinates: 11, 291, 18; t value, 3.37). They also had lower fractional anisotropy (FA) of forceps major (MNI coordinates: 217, 278, 6), left inferior fronto-occipital fasciculus (MNI coordinates: 225, 2, 211), and right anterior thalamic radiation (ATR) (MNI coordinates: 11, 2, 26) (P < .05, corrected). More lesions were found at T2-weighted imaging in fatigued patients. Multivariable model was used to identify right ITG atrophy (odds ratio, 0.83; 95% confidence interval [CI]: 0.82, 0.97; P = .009) and right ATR FA (odds ratio, 0.74; 95% CI: 0.61, 0.90; P = .003) as covariates independently associated with fatigue (C statistic, 0.85).Conclusion: Damage to strategic brain WM and GM regions, in terms of microstructural abnormalities and atrophy, contributes to pathogenesis of fatigue in MS, whereas global lesional, WM, and GM damage does not seem to have a role. © RSNA, 2014.


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.

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