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PELLETIER Jean

MD PhD
Professor in Neurology (CNU 49.01)
Department of Neurology, Timone University Hospital (APHM)
Medical School of Marseille, Neurosciences (AMU)
jean.pelletier@ap-hm.fr
tel : +33 4 91 38 59 41
fax : +33 4 91 38 62 56
Key Words
- Multiple sclerosis
- CNS demyelinating diseases
- MRI, neuropsychology
- quality of life, neuroinflammation
- neurobiology, genetics

Current Research Interest and projects

I am heading the Department of Neurology of the Timone University Hospital and the team “multiple sclerosis and CNS demyelinating” diseases of the laboratory CRMBM. The activity of the team is focused on MS and CNS demyelinating diseases. We aim at characterizing clinical and functional consequences of MS progression from the very first stage (clinically isolated syndrome (CIS)) and along the disease courses, by using innovative in vivo and non-invasive MR parameters and others non invasive approaches (electrophysiology, experimental neuropsychology). Projects
- Morphological, structural, metabolic, functional, clinical, neuropsychological and quality of life status long term follow-up patients with clinically isolated syndromes suggestive of multiple sclerosis
- Evaluation of brain plasticity efficiency in cognitive and motor systems of patients with early multiple sclerosis using repetitive transcranial magnetic stimulation (rTMS) and fMRI
- In vivo study of axonal degeneration in multiple sclerosis using cerebral sodium (23Na) Magnetic Resonance Imaging
- Modulation of the effects of TWEAK on the blood brain barrier: a new therapeutic approach to multiple sclerosis

Publications

2018

Journal Article

  • Durozard, P, Maarouf, A, Boutiere, C, Ruet, A, Brochet, B, Vukusic, S, Carra-Dalliere, C, Labauge, P, Mathey, G, Debouverie, M, Papeix, C, Maillart, E, Lubetzki, C, Bensa, C, Gout, O, Giannesini, C, Stankoff, B, Ciron, J, Brassat, D, Pelletier, J, Rico Lamy, A, Audoin, B & SFSEP and OFSEP groups, 2018, “Efficacy of rituximab in refractory RRMS”, Multiple Sclerosis (Houndmills, Basingstoke, England), p. 1352458518772748.
    Résumé : OBJECTIVE: To investigate the efficacy of rituximab as rescue therapy in patients with relapsing-remitting multiple sclerosis (RRMS) and persistent disease activity confirmed by magnetic resonance imaging (MRI) despite immunosuppressive disease-modifying therapy (DMT). METHODS: In this observational nationwide retrospective multicenter study, we first identified 351 off-label rituximab-treated patients through a cohort of 15,984 RRMS patients. In this group, we identified patients with disease activity prior to rituximab confirmed by MRI (one or more new T2 lesion and/or gadolinium-enhancing lesion) despite immunosuppressive DMT (fingolimod, natalizumab, or mitoxantrone) with a follow-up after rituximab initiation longer than 6 months. Outcome data were collected from the French Observatory of Multiple Sclerosis (OFSEP) register and medical charts. RESULTS: A total of 50 patients were identified. Median rituximab treatment duration was 1.1 (0.5-6.4) year. Mean annualized relapse rate significantly decreased from 0.8 during last immunosuppressive DMT to 0.18 after rituximab ( p < 0.0001). While 72% of patients showed gadolinium-enhancing lesions on the last MRI performed during last immunosuppressive DMT, 8% of them showed gadolinium-enhancing lesions on the first MRI performed 6.1 (range 1.4-18.4) months after rituximab ( p < 0.0001). CONCLUSION: This study provides level IV evidence that rituximab reduces clinical and MRI disease activity in patients with active RRMS despite immunosuppressive DMT.
    Mots-clés : disease-modifying therapies, Multiple sclerosis, relapsing/remitting, second-line treatment, snc, treatment response.

  • Tourbah, A, Gout, O, Vighetto, A, Deburghgraeve, V, Pelletier, J, Papeix, C, Lebrun-Frenay, C, Labauge, P, Brassat, D, Toosy, A, Laplaud, D-A, Outteryck, O, Moreau, T, Debouverie, M, Clavelou, P, Heinzlef, O, De Sèze, J, Defer, G, Sedel, F & Arndt, C 2018, “MD1003 (High-Dose Pharmaceutical-Grade Biotin) for the Treatment of Chronic Visual Loss Related to Optic Neuritis in Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Study”, CNS drugs.
    Résumé : BACKGROUND: Chronic visual loss is a disabling feature in patients with multiple sclerosis (MS). It was recently shown that MD1003 (high-dose pharmaceutical-grade biotin or hdPB) may improve disability in patients with progressive MS. OBJECTIVE: The aim of this study was to evaluate whether MD1003 improves vision compared with placebo in MS patients with chronic visual loss. METHODS: The MS-ON was a 6-month, randomized, double-blind, placebo-controlled study with a 6-month open-label extension phase. Adult patients with MS-related chronic visual loss of at least one eye [visual acuity (VA) below 0.5 decimal chart] were randomized 2:1 to oral MD1003 300 mg/day or placebo. The selected eye had to show worsening of VA within the past 3 years following either acute optic neuritis (AON) or slowly progressive optic neuropathy (PON). The primary endpoint was the mean change from baseline to month 6 in VA measured in logarithm of the minimum angle of resolution (logMAR) at 100% contrast of the selected eye. Visually evoked potentials, visual field, retinal nerve fiber layer (RNFL) thickness, and health outcomes were also assessed. RESULTS: Ninety-three patients received MD1003 (n = 65) or placebo (n = 28). The study did not meet its primary endpoint, as the mean change in the primary endpoint was nonsignificantly larger (p = 0.66) with MD1003 (- 0.061 logMAR, + 3.1 letters) than with placebo (- 0.036 logMAR, + 1.8 letters). Pre-planned subgroup analyses showed that 100% contrast VA improved by a mean of + 2.8 letters (- 0.058 logMAR) with MD1003 and worsened by - 1.5 letters (+ 0.029 logMAR) with placebo (p = 0.45) in the subgroup of patients with PON. MD1003-treated patients also had nonsignificant improvement in logMAR at 5% contrast and in RNFL thickness and health outcome scores when compared with placebo-treated patients. There was no superiority of MD1003 vs placebo in patients with AON. The safety profile of MD1003 was similar to that of placebo. CONCLUSIONS: MD1003 did not significantly improve VA compared with placebo in patients with MS experiencing chronic visual loss. An interesting trend favoring MD1003 was observed in the subgroup of patients with PON. Treatment was overall well tolerated. TRIAL REGISTRATION: EudraCT identifier 2013-002112-27. ClinicalTrials.gov Identifier: NCT02220244 FUNDING: MedDay Pharmaceuticals.
    Mots-clés : snc.

2017

Journal Article

  • Boutière, C, Rey, C, Zaaraoui, W, Le Troter, A, Rico, A, Crespy, L, Achard, S, Reuter, F, Pariollaud, F, Wirsich, J, Asquinazi, P, Confort-Gouny, S, Soulier, E, Guye, M, Pelletier, J, Ranjeva, J-P & Audoin, B 2017, “Improvement of spasticity following intermittent theta burst stimulation in multiple sclerosis is associated with modulation of resting-state functional connectivity of the primary motor cortices”, Multiple Sclerosis (Houndmills, Basingstoke, England), vol. 23, no. 6, p. 855-863.
    Résumé : BACKGROUND: Intermittent theta burst stimulation (iTBS) of the primary motor cortex improves transiently lower limbs spasticity in multiple sclerosis (MS). However, the cerebral mechanisms underlying this effect have never been investigated. OBJECTIVE: To assess whether modulation of spasticity induced by iTBS is underlined by functional reorganization of the primary motor cortices. METHODS: A total of 17 patients with MS suffering from lower limbs spasticity were randomized to receive real iTBS or sham iTBS during the first half of a 5-week indoor rehabilitation programme. Spasticity was assessed using the Modified Ashworth Scale and the Visual Analogue Scale at baseline, after the stimulation session and at the end of the rehabilitation programme. Resting-state functional magnetic resonance imaging (fMRI) was performed at the three time points, and brain functional networks topology was analysed using graph-theoretical approach. RESULTS: At the end of stimulation, improvement of spasticity was greater in real iTBS group than in sham iTBS group ( p = 0.026). iTBS had a significant effect on the balance of the connectivity degree between the stimulated and the homologous primary motor cortex ( p = 0.005). Changes in inter-hemispheric balance were correlated with improvement of spasticity (rho = 0.56, p = 0.015). CONCLUSION: This longitudinal resting-state fMRI study evidences that functional reorganization of the primary motor cortices may underlie the effect of iTBS on spasticity in MS.

  • Doche, E, Lecocq, A, Maarouf, A, Duhamel, G, Soulier, E, Confort-Gouny, S, Rico, A, Guye, M, Audoin, B, Pelletier, J, Ranjeva, J-P & Zaaraoui, W 2017, “Hypoperfusion of the thalamus is associated with disability in relapsing remitting multiple sclerosis”, Journal of Neuroradiology. Journal De Neuroradiologie, vol. 44, no. 2, p. 158-164.
    Résumé : BACKGROUND: While gray matter (GM) perfusion abnormalities have been evidenced in multiple sclerosis (MS) patients, the relationships with disability still remain unclear. Considering that atrophy is known to impact on perfusion, we aimed to assess perfusion abnormalities in GM of MS patients, outside atrophic regions and investigate relationships with disability. METHODS: Brain perfusion of 23 relapsing remitting MS patients and 16 matched healthy subjects were assessed at 3T using the pseudo-continuous arterial spin labeling magnetic resonance imaging technique. In order to locate potential GM perfusion abnormalities in regions spared by atrophy, we combined voxelwise comparisons of GM cerebral blood flow (CBF) maps (cortex and deep GM) (P<0.005, FWE-corrected) and voxel-based-morphometry analysis (P<0.005, FDR-corrected) to exclude atrophic regions. Disability was assessed using the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite score (MSFC). RESULTS: In patients, significant GM hypoperfusion outside atrophic regions was depicted only in bilateral thalami. No other cluster was found to be hypoperfused compared to controls. Perfusion of thalami was correlated to MSFC (P=0.011, rho=0.523). A trend of correlation was found between perfusion of thalami and EDSS (P=0.061, rho=-0.396). CONCLUSION: In relapsing remitting MS, perfusion abnormalities in thalamic regions contribute to disability. These findings suggest that functional impairments of thalami, representing a major brain hub, may disturb various cerebral functions even before structural damage.

  • Donadieu, M, Le Fur, Y, Maarouf, A, Gherib, S, Ridley, B, Pini, L, Rapacchi, S, Confort-Gouny, S, Guye, M, Schad, LR, Maudsley, AA, Pelletier, J, Audoin, B, Zaaraoui, W & Ranjeva, J-P 2017, “Metabolic counterparts of sodium accumulation in multiple sclerosis: A whole brain (23)Na-MRI and fast (1)H-MRSI study”, Multiple Sclerosis (Houndmills, Basingstoke, England), p. 1352458517736146.
    Résumé : BACKGROUND: Increase of brain total sodium concentrations (TSC) is present in multiple sclerosis (MS), but its pathological involvement has not been assessed yet. OBJECTIVE: To determine in vivo the metabolic counterpart of brain sodium accumulation. MATERIALS/METHODS: Whole brain (23)Na-MR imaging and 3D-(1)H-EPSI data were collected in 21 relapsing-remitting multiple sclerosis (RRMS) patients and 20 volunteers. Metabolites and sodium levels were extracted from several regions of grey matter (GM), normal-appearing white matter (NAWM) and white matter (WM) T2 lesions. Metabolic and ionic levels expressed as Z-scores have been averaged over the different compartments and used to explain sodium accumulations through stepwise regression models. RESULTS: MS patients showed significant (23)Na accumulations with lower choline and glutamate-glutamine (Glx) levels in GM; (23)Na accumulations with lower N-acetyl aspartate (NAA), Glx levels and higher Myo-Inositol (m-Ins) in NAWM; and higher (23)Na, m-Ins levels with lower NAA in WM T2 lesions. Regression models showed associations of TSC increase with reduced NAA in GM, NAWM and T2 lesions, as well as higher total-creatine, and smaller decrease of m-Ins in T2 lesions. GM Glx levels were associated with clinical scores. CONCLUSION: Increase of TSC in RRMS is mainly related to neuronal mitochondrial dysfunction while dysfunction of neuro-glial interactions within GM is linked to clinical scores.
    Mots-clés : 23Na-MRI, crmbm, demyelination, MRSI, Multiple sclerosis, neurodegeneration, snc, stepwise regression.

  • Fissolo, N, Pignolet, B, Matute-Blanch, C, Triviño, JC, Miró, B, Mota, M, Perez-Hoyos, S, Sanchez, A, Vermersch, P, Ruet, A, de Sèze, J, Labauge, P, Vukusic, S, Papeix, C, Almoyna, L, Tourbah, A, Clavelou, P, Moreau, T, Pelletier, J, Lebrun-Frenay, C, Montalban, X, Brassat, D, Comabella, M & Biomarkers and Response to Natalizumab for Multiple Sclerosis Treatment (BIONAT), Best EScalation Treatment in Multiple Sclerosis (BEST-MS), and the Société Francophone de la Sclérose En Plaques (SFSEP) Network, 2017, “Matrix metalloproteinase 9 is decreased in natalizumab-treated multiple sclerosis patients at risk for progressive multifocal leukoencephalopathy”, Annals of Neurology, vol. 82, no. 2, p. 186-195.
    Résumé : OBJECTIVE: To identify biomarkers associated with the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab (NTZ). METHODS: Relapsing-remitting MS patients who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr) were included in the study. Cryopreserved peripheral blood mononuclear cells and serum samples collected at baseline, at 1- and 2-year treated time points, and during PML were analyzed for gene expression by RNA sequencing and for serum protein levels by Luminex and enzyme-linked immunosorbent assays, respectively. RESULTS: Among top differentially expressed genes in the RNA sequencing between pre-PML and NTZ-ctr patients, pathway analysis revealed a high representation of genes belonging to the following categories: proangiogenic factors (MMP9, VEGFA), chemokines (CXCL1, CXCL5, IL8, CCL2), cytokines (IL1B, IFNG), and plasminogen- and coagulation-related molecules (SERPINB2, PLAU, PLAUR, TFPI, THBD). Serum protein levels for these candidates were measured in a 2-step manner in a screening cohort and a validation cohort of pre-PML and NTZ-ctr patients. Only matrix metalloproteinase 9 (MMP9) was validated; in pre-PML patients, MMP9 protein levels were significantly reduced at baseline compared with NTZ-ctr patients, and levels remained lower at later time points during NTZ treatment. INTERPRETATION: The results from this study suggest that the proangiogenic factor MMP9 may play a role as a biomarker associated with the development of PML in MS patients treated with NTZ. Ann Neurol 2017;82:186-195.
    Mots-clés : Biomarkers, Blood Proteins, Gene Expression, Humans, Immunologic Factors, Leukoencephalopathy, Progressive Multifocal, Matrix Metalloproteinase 9, Multiple Sclerosis, Relapsing-Remitting, Natalizumab, snc, Vascular Endothelial Growth Factor A.


  • Maarouf, A, Audoin, B, Pariollaud, F, Gherib, S, Rico, A, Soulier, E, Confort-Gouny, S, Guye, M, Schad, L, Pelletier, J, Ranjeva, J-P & Zaaraoui, W 2017, “Increased total sodium concentration in gray matter better explains cognition than atrophy in MS”, Neurology, vol. 88, no. 3, p. 289-295, viewed 18August,2017, .
    Résumé : Objective: To investigate whether brain total sodium accumulation assessed by 23Na MRI is associated with cognitive deficit in relapsing-remitting multiple sclerosis (RRMS). Methods: Eighty-nine participants were enrolled in the study (58 patients with RRMS with a disease duration ≤10 years and 31 matched healthy controls). Patients were classified as cognitively impaired if they failed at least 2 tasks on the Brief Repeatable Battery. MRI was performed at 3T using 23Na MRI to obtain total sodium concentration (TSC) in the different brain compartments (lesions, normal-appearing white matter [NAWM], gray matter [GM]) and 1H- magnetization-prepared rapid gradient echo to assess GM atrophy (GM fraction). Results: The mean disease duration was 3.1 years and the median Expanded Disability Status Scale score was 1 (range 0–4.5). Thirty-seven patients were classified as cognitively preserved and 21 as cognitively impaired. TSC was increased in GM and NAWM in cognitively impaired patients compared to cognitively preserved patients and healthy controls. Voxel-wise analysis demonstrated that sodium accumulation was mainly located in the neocortex in cognitively impaired patients. Regression analysis evidenced than the 2 best independent predictors of cognitive impairment were GM TSC and age. Receiver operating characteristic analyses demonstrated that sensitivity and specificity of the GM TSC to classify patients according to their cognitive status were 76% and 71%, respectively. Conclusions: This study provides 2 main findings. (1) In RRMS, total sodium accumulation in the GM is better associated with cognitive impairment than GM atrophy; and (2) total sodium accumulation in patients with cognitive impairment is mainly located in the neocortex.
    Mots-clés : crmbm, snc.

  • Wybrecht, D, Reuter, F, Pariollaud, F, Zaaraoui, W, Le Troter, A, Rico, A, Confort-Gouny, S, Soulier, E, Guye, M, Maarouf, A, Ranjeva, J-P, Pelletier, J & Audoin, B 2017, “New brain lesions with no impact on physical disability can impact cognition in early multiple sclerosis: A ten-year longitudinal study”, PloS One, vol. 12, no. 11, p. e0184650.
    Résumé : OBJECTIVE: In early multiple sclerosis, although brain T2 lesions accrual are hallmark of the disease, only weak correlations were found between T2 lesions accrual and EDSS progression, the disability scale commonly used in multiple sclerosis studies. This may be related to the very poor sensitivity of EDSS to cognitive dysfunctions that may occur and progress from the first stage of the disease. In the present study, we aimed to demonstrate that cognitive deficits progress during the first ten years of MS and are significantly impacted by new T2 lesions. METHODS: EDSS and extensive neuropsychological battery (22 measures) exploring memory, attention/speed of information processing and executive functions were assessed at baseline, Year 1 and Year 10 in 26 patients enrolled after their first clinical attack. To limit the bias of test-retest effect, only measures obtained at Year 1 and Year 10 were reported in the analysis. Raw scores of patients were transformed into z-scores using published normative data when available or scores of matched controls. Lesion probability mapping was used to assess the potential relationships between T2 lesions accumulation, cognitive decline and EDSS progression (P<0.05, FWE-corrected). RESULTS: At Year 1, 27% of patients showed attention/speed of information processing deficits, 11.5% executive dysfunction and 11.5% memory impairment. During the follow-up, frequency and severity of executive dysfunction increased (from 11.5% of patients at Year 1 to 42% at Year 10, p<0.01) while no significant changes were evidenced for the other cognitive domains. Median EDSS increased from 0.5 [range: 0-3] at Year 1 to 2.5 [range: 0-6.5] at Year 10 (p<0.001). During the ten-year follow-up, lesions accumulation in the left cerebellum and semi-ovale centers was associated with EDSS progression. In contrast, most lesions accumulation in the frontal, parietal and temporal lobes were associated with cognitive decline but had no effect on EDSS progression. CONCLUSION: The present study provides strong evidence that clinically silent T2 lesions impact cognition in early MS. In daily practice, early prevention of T2 lesions accrual may be useful to limit cognitive decline.
    Mots-clés : crmbm, snc.

2016

Journal Article

  • Barbin, L, Rousseau, C, Jousset, N, Casey, R, Debouverie, M, Vukusic, S, De Sèze, J, Brassat, D, Wiertlewski, S, Brochet, B, Pelletier, J, Vermersch, P, Edan, G, Lebrun-Frenay, C, Clavelou, P, Thouvenot, E, Camdessanché, J-P, Tourbah, A, Stankoff, B, Al Khedr, A, Cabre, P, Papeix, C, Berger, E, Heinzlef, O, Debroucker, T, Moreau, T, Gout, O, Bourre, B, Créange, A, Labauge, P, Magy, L, Defer, G, Foucher, Y, Laplaud, DA & CFSEP and OFSEP groups, 2016, “Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study”, Neurology, vol. 86, no. 8, p. 771-778.
    Résumé : OBJECTIVE: To compare natalizumab and fingolimod on both clinical and MRI outcomes in patients with relapsing-remitting multiple sclerosis (RRMS) from 27 multiple sclerosis centers participating in the French follow-up cohort Observatoire of Multiple Sclerosis. METHODS: Patients with RRMS included in the study were aged from 18 to 65 years with an Expanded Disability Status Scale score of 0-5.5 and an available brain MRI performed within the year before treatment initiation. The data were collected for 326 patients treated with natalizumab and 303 with fingolimod. The statistical analysis was performed using 2 different methods: logistic regression and propensity scores (inverse probability treatment weighting). RESULTS: The confounder-adjusted proportion of patients with at least one relapse within the first and second year of treatment was lower in natalizumab-treated patients compared to the fingolimod group (21.1% vs 30.4% at first year, p = 0.0092; and 30.9% vs 41.7% at second year, p = 0.0059) and supported the trend observed in nonadjusted analysis (21.2% vs 27.1% at 1 year, p = 0.0775). Such statistically significant associations were also observed for gadolinium (Gd)-enhancing lesions and new T2 lesions at both 1 year (Gd-enhancing lesions: 9.3% vs 29.8%, p < 0.0001; new T2 lesions: 10.6% vs 29.6%, p < 0.0001) and 2 years (Gd-enhancing lesions: 9.1% vs 22.1%, p = 0.0025; new T2 lesions: 16.9% vs 34.1%, p = 0.0010) post treatment initiation. CONCLUSION: Taken together, these results suggest the superiority of natalizumab over fingolimod to prevent relapses and new T2 and Gd-enhancing lesions at 1 and 2 years. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with RRMS, natalizumab decreases the proportion of patients with at least one relapse within the first year of treatment compared to fingolimod.
    Mots-clés : Adult, Cohort Studies, Female, Fingolimod Hydrochloride, Follow-Up Studies, France, Humans, Immunologic Factors, Immunosuppressive Agents, Male, Multiple sclerosis, Natalizumab, Treatment Outcome.

  • Cohen, JA, Khatri, B, Barkhof, F, Comi, G, Hartung, H-P, Montalban, X, Pelletier, J, Stites, T, Ritter, S, von Rosenstiel, P, Tomic, D, Kappos, L & TRANSFORMS (TRial Assessing injectable interferoN vS. FTY720 Oral in RRMS) Study Group, 2016, “Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomised TRANSFORMS study”, Journal of Neurology, Neurosurgery, and Psychiatry, vol. 87, no. 5, p. 468-475.
    Résumé : OBJECTIVE: The 12-month (M), phase 3, double-blind, randomised TRANSFORMS study demonstrated significant benefits of fingolimod 0.5 or 1.25 mg over interferon β-1a (IFNβ-1a) in patients with relapsing-remitting multiple sclerosis. We report the results of long-term (up to 4.5 years) extension of TRANSFORMS. METHODS: Patients randomised to fingolimod (0.5/1.25 mg) in the core phase continued the same dose (continuous-fingolimod) in the extension, whereas those on IFNβ-1a were re-randomised (1:1) to fingolimod (IFN-switch; IFN: 0.5/1.25 mg). Outcomes included annualised relapse rate (ARR), confirmed disability progression and MRI measures. Results are presented here for the continuous-fingolimod 0.5 mg and pooled IFN-switch groups. RESULTS: Of the 1027 patients who entered the extension, 772 (75.2%) completed the study. From baseline to the end of the study (EOS), ARR in patients on continuous-fingolimod 0.5 mg was significantly lower than in the IFN-switch group (M0-EOS: 0.17 vs 0.27). After switching to fingolimod (M0-12 vs M13-EOS), patients initially treated with IFN had a 50% reduction in ARR (0.40 vs 0.20), reduced MRI activity and a lower rate of brain volume loss. In a post hoc analysis, the proportion of IFN-switch patients with no evidence of disease activity increased by approximately 50% in the first year after switching to fingolimod treatment (44.3% to 66.0%). The safety profile was consistent with that observed in the core phase. CONCLUSIONS: These results support a continued effect of long-term fingolimod therapy in maintaining a low rate of disease activity and sustained improved efficacy after switching from IFNβ-1a to fingolimod. CLINICAL TRIAL REGISTRATION NO: NCT00340834.
    Mots-clés : snc.

  • Donadieu, M, Le Fur, Y, Lecocq, A, Maudsley, AA, Gherib, S, Soulier, E, Confort-Gouny, S, Pariollaud, F, Ranjeva, M-P, Pelletier, J, Guye, M, Zaaraoui, W, Audoin, B & Ranjeva, J-P 2016, “Metabolic voxel-based analysis of the complete human brain using fast 3D-MRSI: Proof of concept in multiple sclerosis”, Journal of magnetic resonance imaging: JMRI, vol. 44, no. 2, p. 411-419.
    Résumé : PURPOSE: To detect local metabolic abnormalities over the complete human brain in multiple sclerosis (MS) patients, we used optimized fast volumic echo planar spectroscopic imaging (3D-EPSI). MATERIALS AND METHODS: Weighted mean combination of two 3D-EPSI covering the whole brain acquired at 3T in AC-PC and AC-PC+15° axial planes was performed to obtain high-quality metabolite maps for five metabolites: N-acetyl aspartate (NAA), glutamate+glutamine (Glx), choline (Cho), myo-inositol (m-Ins), and creatine+phosphocreatine (tCr). After spatial normalization, maps from 19 patients suffering from relapsing-remitting MS were compared to 19 matched controls using statistical mapping analyses to determine the topography of metabolic abnormalities. Probabilistic white matter (WM) T2 lesion maps and gray matter (GM) atrophy maps were also generated. RESULTS: Two-group analysis of variance (ANOVA) (SPM8, P < 0.005, false discovery rate [FDR]-corrected P < 0.05 at the cluster level with age and sex as confounding covariates) comparing patients and controls matched for age and sex showed clusters of abnormal metabolite levels with 1) decreased NAA (around -15%) and Glx (around 20%) predominantly in GM within prefrontal cortices, motor cortices, bilateral thalami, and mesial temporal cortices in line with neuronal/neuro-astrocytic dysfunction; 2) increased m-Ins (around + 20%) inside WM T2 lesions and in the normal-appearing WM of temporal-occipital lobes, suggesting glial activation. CONCLUSION: We demonstrate the ability to noninvasively map over the complete brain-from vertex to cerebellum-with a validated sequence, the metabolic abnormalities associated with MS, for characterizing the topography of pathological processes affecting widespread areas of WM and GM and its functional impact. J. Magn. Reson. Imaging 2016;44:411-419.
    Mots-clés : crmbm, Inflammation, Multiple sclerosis, neurodegeneration, proton magnetic resonance spectroscopic imaging, snc, statistical mapping analysis, whole brain.

  • Faivre, A, Robinet, E, Guye, M, Rousseau, C, Maarouf, A, Le Troter, A, Zaaraoui, W, Rico, A, Crespy, L, Soulier, E, Confort-Gouny, S, Pelletier, J, Achard, S, Ranjeva, J-P & Audoin, B 2016, “Depletion of brain functional connectivity enhancement leads to disability progression in multiple sclerosis: A longitudinal resting-state fMRI study”, Multiple Sclerosis (Houndmills, Basingstoke, England), vol. 22, no. 13, p. 1695-1708.
    Résumé : BACKGROUND: The compensatory effect of brain functional connectivity enhancement in relapsing-remitting multiple sclerosis (RRMS) remains controversial. OBJECTIVE: To characterize the relationships between brain functional connectivity changes and disability progression in RRMS. METHODS: Long-range connectivity, short-range connectivity, and density of connections were assessed using graph theoretical analysis of resting-state functional magnetic resonance imaging (fMRI) data acquired in 38 RRMS patients (disease duration: 120 ± 32 months) and 24 controls. All subjects were explored at baseline and all patients and six controls 2 years later. RESULTS: At baseline, levels of long-range and short-range brain functional connectivity were higher in patients compared to controls. During the follow-up, decrease in connections' density was inversely correlated with disability progression. Post-hoc analysis evidenced differential evolution of brain functional connectivity metrics in patients according to their level of disability at baseline: while patients with lowest disability at baseline experienced an increase in all connectivity metrics during the follow-up, patients with higher disability at baseline showed a decrease in the connectivity metrics. In these patients, decrease in the connectivity metrics was associated with disability progression. CONCLUSION: The study provides two main findings: (1) brain functional connectivity enhancement decreases during the disease course after reaching a maximal level, and (2) decrease in brain functional connectivity enhancement participates in disability progression.
    Mots-clés : crmbm, cvs, Disability, Functional connectivity, Functional MRI, graph theory, Multiple sclerosis.

  • Kappos, L, Edan, G, Freedman, MS, Montalbán, X, Hartung, H-P, Hemmer, B, Fox, EJ, Barkhof, F, Schippling, S, Schulze, A, Pleimes, D, Pohl, C, Sandbrink, R, Suarez, G, Wicklein, E-M & BENEFIT Study Group, 2016, “The 11-year long-term follow-up study from the randomized BENEFIT CIS trial”, Neurology, vol. 87, no. 10, p. 978-987.
    Résumé : OBJECTIVE: To assess outcomes for patients treated with interferon beta-1b immediately after clinically isolated syndrome (CIS) or after a short delay. METHODS: Participants in BENEFIT (Betaferon/Betaseron in Newly Emerging MS for Initial Treatment) were randomly assigned to receive interferon beta-1b (early treatment) or placebo (delayed treatment). After conversion to clinically definite multiple sclerosis (CDMS) or 2 years, patients on placebo could switch to interferon beta-1b or another treatment. Eleven years after randomization, patients were reassessed. RESULTS: Two hundred seventy-eight (59.4%) of the original 468 patients (71.3% of those eligible at participating sites) were enrolled (early: 167 [57.2%]; delayed: 111 [63.1%]). After 11 years, risk of CDMS remained lower in the early-treatment arm compared with the delayed-treatment arm (p = 0.0012), with longer time to first relapse (median [Q1, Q3] days: 1,888 [540, not reached] vs 931 [253, 3,296]; p = 0.0005) and lower overall annualized relapse rate (0.21 vs 0.26; p = 0.0018). Only 25 patients (5.9%, overall; early, 4.5%; delayed, 8.3%) converted to secondary progressive multiple sclerosis. Expanded Disability Status Scale scores remained low and stable, with no difference between treatment arms (median [Q1, Q3]: 2.0 [1.0, 3.0]). The early-treatment group had better Paced Auditory Serial Addition Task-3 total scores (p = 0.0070). Employment rates remained high, and health resource utilization tended to be low in both groups. MRI metrics did not differ between groups. CONCLUSIONS: Although the delay in treatment was relatively short, several clinical outcomes favored earlier treatment. Along with low rates of disability and disease progression in both groups, this supports the value of treatment at CIS. CLINICALTRIALSGOV IDENTIFIER: NCT01795872. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that early compared to delayed treatment prolongs time to CDMS in CIS after 11 years.
    Mots-clés : Adjuvants, Immunologic, Adult, Cross-Sectional Studies, Demyelinating Diseases, Disability Evaluation, Double-Blind Method, Female, Follow-Up Studies, Humans, Interferon beta-1b, Kaplan-Meier Estimate, Male, Recurrence, Time-to-Treatment, Treatment Outcome, Young Adult.

  • Lublin, F, Miller, DH, Freedman, MS, Cree, BAC, Wolinsky, JS, Weiner, H, Lubetzki, C, Hartung, H-P, Montalban, X, Uitdehaag, BMJ, Merschhemke, M, Li, B, Putzki, N, Liu, FC, Häring, DA, Kappos, L & INFORMS study investigators, 2016, “Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial”, Lancet (London, England), vol. 387, no. 10023, p. 1075-1084.
    Résumé : BACKGROUND: No treatments have been approved for primary progressive multiple sclerosis. Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is effective in relapse-onset multiple sclerosis, but has not been assessed in primary progressive multiple sclerosis. We assessed the safety and efficacy of fingolimod in patients with primary progressive multiple sclerosis. METHODS: In INFORMS, a multicentre, double-blind, placebo-controlled parallel-group study, patients with primary progressive multiple sclerosis recruited across 148 centres in 18 countries were randomly allocated (1:1) with computer-generated blocks to receive oral fingolimod or placebo for at least 36 months and a maximum of 5 years. Patients were initially assigned to fingolimod 1·25 mg per day or placebo (cohort 1); however, after a protocol amendment on Nov 19, 2009, patients were switched in a masked manner to fingolimod 0·5 mg, whereas those on placebo continued on matching placebo. From then onwards, patients were assigned to receive fingolimod 0·5 mg/day or placebo (cohort 2). Key inclusion criteria were age 25-65 years, clinical diagnosis of primary progressive multiple sclerosis, 1 year or more of disease progression, and two of the following criteria: positive brain MRI; positive spinal cord MRI; or positive cerebrospinal fluid. Additional eligibility criteria included disease duration of 2-10 years and objective evidence of disability progression in the previous 2 years. Patients and study investigators were masked to group assignment. We used a novel primary composite endpoint based on change from baseline in Expanded Disability Status Scale (EDSS), 25' Timed-Walk Test, or Nine-Hole Peg Test to assess time to 3-month confirmed disability progression in study participants treated for at least 3 years. All randomised patients took at least one dose of study drug. The primary efficacy analysis included all patients in cohort 2 and those assigned to placebo in cohort 1. The safety analysis included all patients in cohorts 1 and 2. This study is registered with ClinicalTrials.gov, number NCT00731692. The study is now closed. FINDINGS: 970 patients were randomly assigned between Sept 3, 2008, and Aug 30, 2011 (147 to fingolimod 1·25 mg and 133 to placebo in cohort 1; 336 to fingolimod 0·5 mg and 354 to placebo in cohort 2). The efficacy analysis set (n=823) consisted of 336 patients randomly allocated to fingolimod 0·5 mg and 487 to placebo. Baseline characteristics were similar across groups and representative of a primary progressive multiple sclerosis population (48% women, mean age 48·5 years [SD 8·4], mean EDSS 4·67 [SD 1·03], 87% free of gadolinium-enhancing lesions). By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively, resulting in Kaplan-Meier estimates of 77·2% (95% CI 71·87-82·51) of patients in the fingolimod group versus 80·3% (73·31-87·25) of patients in the placebo group (risk reduction 5·05%; hazard ratio 0·95, 95% CI 0·80-1·12; p=0·544). Safety results were generally consistent with those of studies of fingolimod in patients with relapse-onset multiple sclerosis. Lymphopenia occurred in 19 (6%) patients in the fingolimod group versus none in the placebo group, bradycardia in five (1%) versus one (<1%), and first-degree atrioventricular block in three (1%) versus six (1%). Serious adverse events occurred in 84 (25%) patients in the fingolimod group and 117 (24%) in the placebo group, including macular oedema in six (2%) versus six (1%), and basal-cell carcinoma in 14 (4%) versus nine (2%). INTERPRETATION: The anti-inflammatory effects of fingolimod did not slow disease progression in primary progressive multiple sclerosis. Therapeutic strategies for primary progressive multiple sclerosis might need different approaches to those used for relapse-onset multiple sclerosis. FUNDING: Novartis Pharma AG.
    Mots-clés : Administration, Oral, Adolescent, Adult, Aged, Disease Progression, Dose-Response Relationship, Drug, Double-Blind Method, Female, Fingolimod Hydrochloride, Humans, Immunosuppressive Agents, Male, Middle Aged, Multiple Sclerosis, Chronic Progressive, snc, Treatment Outcome, Young Adult.

  • Michel, P, Baumstarck, K, Ghattas, B, Pelletier, J, Loundou, A, Boucekine, M, Auquier, P & Boyer, L 2016, “A Multidimensional Computerized Adaptive Short-Form Quality of Life Questionnaire Developed and Validated for Multiple Sclerosis: The MusiQoL-MCAT”, Medicine, vol. 95, no. 14, p. e3068.
    Résumé : The aim was to develop a multidimensional computerized adaptive short-form questionnaire, the MusiQoL-MCAT, from a fixed-length QoL questionnaire for multiple sclerosis.A total of 1992 patients were enrolled in this international cross-sectional study. The development of the MusiQoL-MCAT was based on the assessment of between-items MIRT model fit followed by real-data simulations. The MCAT algorithm was based on Bayesian maximum a posteriori estimation of latent traits and Kullback-Leibler information item selection. We examined several simulations based on a fixed number of items. Accuracy was assessed using correlations (r) between initial IRT scores and MCAT scores. Precision was assessed using the standard error measurement (SEM) and the root mean square error (RMSE).The multidimensional graded response model was used to estimate item parameters and IRT scores. Among the MCAT simulations, the 16-item version of the MusiQoL-MCAT was selected because the accuracy and precision became stable with 16 items with satisfactory levels (r ≥ 0.9, SEM ≤ 0.55, and RMSE ≤ 0.3). External validity of the MusiQoL-MCAT was satisfactory.The MusiQoL-MCAT presents satisfactory properties and can individually tailor QoL assessment to each patient, making it less burdensome to patients and better adapted for use in clinical practice.
    Mots-clés : snc.

  • Tourbah, A, Lebrun-Frenay, C, Edan, G, Clanet, M, Papeix, C, Vukusic, S, De Sèze, J, Debouverie, M, Gout, O, Clavelou, P, Defer, G, Laplaud, D-A, Moreau, T, Labauge, P, Brochet, B, Sedel, F, Pelletier, J & MS-SPI study group, 2016, “MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study”, Multiple Sclerosis (Houndmills, Basingstoke, England), vol. 22, no. 13, p. 1719-1731.
    Résumé : BACKGROUND: Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study. OBJECTIVE: To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study. METHODS: Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5-7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of ⩾1 point (⩾0.5 for EDSS 6-7) or a ⩾20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits. RESULTS: A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo. CONCLUSION: MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated.
    Mots-clés : clinical trial, disability progression, high-dose biotin, MD1003, Multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, snc.

2015

Journal Article

  • Baumstarck, K, Pelletier, J, Boucekine, M, Auquier, P & MusiQoL study group, 2015, “Predictors of quality of life in patients with relapsing-remitting multiple sclerosis: A 2-year longitudinal study”, Revue Neurologique, vol. 171, no. 2, p. 173-180.
    Résumé : INTRODUCTION: Knowledge of which factors are determinant of quality of life (QoL) in patients with multiple scleroris (MS) would assist clinicians in choosing the most appropriate interventions. The aim of this study was to determine the contribution of sociodemographic and clinical factors in the predicting QoL in a 2-year cohort of patients with relapsing-remitting MS (RR-MS). METHODS: The study had a multi-center, multi-regional, and longitudinal design. Main inclusion criteria were: patient with a RR-MS subtype (McDonald criteria) and an Expanded Disability Status Scale (EDSS) score lower than 7.0. Sociodemographic (age, gender, education level, marital and employment status) and clinical (disability, disease duration, relapse) data were recorded. The QoL was assessed using the MusiQoL (disease-specific) and SF-36 (generic) questionnaires. Each patient was investigated at baseline and 24 months post-inclusion (ClinicalTrials.gov identifier: NCT00702065). RESULTS: Five hundred and twenty-six patients were enrolled in the present study. The 24-month MusiQoL index score was significantly inversely correlated with the disease duration. Baseline EDSS score impacted in both 'physical-like' and 'psychological-like' dimensions. At least one relapse during the follow-up period was associated with lower physical scores. Occupational status and marital status were associated with 24-month scores of MusiQoL and SF-36. CONCLUSION: After adjusting for disability and relapse occurrence, sociodemographics (age, marital status, and occupational status) and baseline QoL scores were also independent QoL predictors in MS patients. Special attention should be given to subgroups to ensure optimal management.
    Mots-clés : snc.


  • Caucheteux, N, Maarouf, A, Genevray, M, Leray, E, Deschamps, R, Chaunu, MP, Daelman, L, Ferré, JC, Gout, O, Pelletier, J, Pierot, L, Edan, G & Tourbah, A 2015, “Criteria improving multiple sclerosis diagnosis at the first MRI”, Journal of Neurology, vol. 262, no. 4, p. 979-987, viewed 3June,2016, .
    Résumé : The introduction of the McDonald criteria has enabled earlier diagnosis of multiple sclerosis (MS). However, even with the 2010 revised criteria, nearly 50 % of patients remain classified as “possible MS” following the first MRI. The present study aimed to demonstrate that time to MS diagnosis could be shorter than 2010 revised criteria, and established after a single early MRI in most patients with the association of the symptomatic lesion and at least one suggestive asymptomatic lesion. We also evaluated the short-term predictive capacity of an individual suggestive lesion on disease activity. We analyzed initial MRI results from 146 patients with MS from a multicenter retrospective study. Visualization of the symptomatic lesion was used as a primary criterion. Secondary criteria included one suggestive lesion (SL) aspect or topography on MRI, or one non-specific lesion associated with positive CSF. The proposed criteria led to a positive diagnosis of MS in 100 % of cases, from information available from the time of the first MRI for 145 patients (99.3 %). At least one SL was observed for 143 patients (97.9 %), and positive CSF for the 3 others. Compared to the McDonald criteria, the proposed criteria had 100 % sensitivity, with a significantly shorter mean time to reach a positive diagnosis. Furthermore, the simultaneous presence of corpus callosum, temporal horn, and ovoid lesions was associated with radiological or clinical activity after a year of follow-up. The proposed diagnostic criteria are easy to apply, have a good sensitivity, and allow an earlier diagnosis than the 2010 McDonald criteria. Nevertheless, prospective studies are needed to establish specificity and to confirm these findings.
    Mots-clés : Diagnosis, Multiple sclerosis, Neurology, Neuroradiology, Neurosciences, Prognosis, Relapsing-remitting, snc.

  • Kuhle, J, Disanto, G, Dobson, R, Adiutori, R, Bianchi, L, Topping, J, Bestwick, JP, Meier, U-C, Marta, M, Dalla Costa, G, Runia, T, Evdoshenko, E, Lazareva, N, Thouvenot, E, Iaffaldano, P, Direnzo, V, Khademi, M, Piehl, F, Comabella, M, Sombekke, M, Killestein, J, Hegen, H, Rauch, S, D'Alfonso, S, Alvarez-Cermeño, JC, Kleinová, P, Horáková, D, Roesler, R, Lauda, F, Llufriu, S, Avsar, T, Uygunoglu, U, Altintas, A, Saip, S, Menge, T, Rajda, C, Bergamaschi, R, Moll, N, Khalil, M, Marignier, R, Dujmovic, I, Larsson, H, Malmestrom, C, Scarpini, E, Fenoglio, C, Wergeland, S, Laroni, A, Annibali, V, Romano, S, Martínez, AD, Carra, A, Salvetti, M, Uccelli, A, Torkildsen, Ø, Myhr, KM, Galimberti, D, Rejdak, K, Lycke, J, Frederiksen, JL, Drulovic, J, Confavreux, C, Brassat, D, Enzinger, C, Fuchs, S, Bosca, I, Pelletier, J, Picard, C, Colombo, E, Franciotta, D, Derfuss, T, Lindberg, R, Yaldizli, Ö, Vécsei, L, Kieseier, BC, Hartung, HP, Villoslada, P, Siva, A, Saiz, A, Tumani, H, Havrdová, E, Villar, LM, Leone, M, Barizzone, N, Deisenhammer, F, Teunissen, C, Montalban, X, Tintoré, M, Olsson, T, Trojano, M, Lehmann, S, Castelnovo, G, Lapin, S, Hintzen, R, Kappos, L, Furlan, R, Martinelli, V, Comi, G, Ramagopalan, SV & Giovannoni, G 2015, “Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study”, Multiple Sclerosis (Houndmills, Basingstoke, England), vol. 21, no. 8, p. 1013-1024.
    Résumé : BACKGROUND AND OBJECTIVE: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. METHODS: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. RESULTS: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. CONCLUSIONS: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.
    Mots-clés : Adult, Clinically definite multiple sclerosis (CDMS), clinically isolated syndrome (CIS), Cohort Studies, Disease Progression, Epstein-Barr nuclear antigen 1 (EBNA-1), Female, Follow-Up Studies, Humans, Immunoglobulin G, Magnetic Resonance Imaging, Male, Multiple sclerosis, Nuclear Proteins, Oligoclonal Bands, oligoclonal bands (OCBs), Predictive Value of Tests, Prognosis, Risk Assessment, serum 25-hydroxyvitamin D3 (25-OH-D), snc, Survival Analysis, Vitamin D.

  • Maarouf, A, Ferré, J-C, Zaaraoui, W, Le Troter, A, Bannier, E, Berry, I, Guye, M, Pierot, L, Barillot, C, Pelletier, J, Tourbah, A, Edan, G, Audoin, B & Ranjeva, J-P 2015, “Ultra-small superparamagnetic iron oxide enhancement is associated with higher loss of brain tissue structure in clinically isolated syndrome”, Multiple Sclerosis (Houndmills, Basingstoke, England).
    Résumé : BACKGROUND: Macrophages are important components of inflammatory processes in multiple sclerosis, closely linked to axonal loss, and can now be observed in vivo using ultra-small superparamagnetic iron oxide (USPIO). In the present 1-year longitudinal study, we aimed to determine the prevalence and the impact on tissue injury of macrophage infiltration in patients after the first clinical event of multiple sclerosis. METHODS: Thirty-five patients, 32 years mean age, were imaged in a mean of 66 days after their first event using conventional magnetic resonance imaging, gadolinium (Gd) to probe blood-brain barrier integrity, USPIO to study macrophage infiltration and magnetization transfer ratio (MTR) to assess tissue structure integrity. Statistics were performed using two-group repeated-measures ANOVA. Any patient received treatment at baseline. RESULTS: At baseline, patients showed 17 USPIO-positive lesions reflecting infiltration of macrophages present from the onset. This infiltration was associated with local higher loss of tissue structure as emphasized by significant lower MTRnorm values (p<0.03) in USPIO(+)/Gd(+) lesions (n=16; MTRnormUSPIO(+)/Gd(+)=0.78 at baseline, MTRnormUSPIO(+)/Gd(+)=0.81 at M12) relative to USPIO(-)/Gd(+) lesions (n=67; MTRnormUSPIO(-)/Gd(+)=0.82 at baseline, MTRnormUSPIO(-)/Gd(+)=0.85 at M12). No interaction in MTR values was observed during the 12 months follow-up (lesion type × time). CONCLUSION: Infiltration of activated macrophages evidenced by USPIO enhancement, is present at the onset of multiple sclerosis and is associated with higher and persistent local loss of tissue structure. Macrophage infiltration affects more tissue structure while tissue recovery during the following year has a similar pattern for USPIO and Gd-enhanced lesions, leading to relative higher persistent local loss of tissue structure in lesions showing USPIO enhancement at baseline.
    Mots-clés : clinically isolated syndrome, crmbm, macrophage, MRI, Multiple sclerosis, snc, USPIO.

2014

Journal Article

  • Calabresi, PA, Kieseier, BC, Arnold, DL, Balcer, LJ, Boyko, A, Pelletier, J, Liu, S, Zhu, Y, Seddighzadeh, A, Hung, S, Deykin, A & ADVANCE Study Investigators, 2014, “Pegylated interferon β-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study”, The Lancet. Neurology, vol. 13, no. 7, p. 657-665.
    Résumé : BACKGROUND: Subcutaneous pegylated interferon (peginterferon) beta-1a is being developed for treatment of relapsing multiple sclerosis, with less frequent dosing than currently available first-line injectable treatments. We assessed the safety and efficacy of peginterferon beta-1a after 48 weeks of treatment in the placebo-controlled phase of the ADVANCE trial, a study of patients with relapsing-remitting multiple sclerosis. METHODS: We did this 2-year, double-blind, parallel group, phase 3 study, with a placebo-controlled design for the first 48 weeks, at 183 sites in 26 countries. Patients with relapsing-remitting multiple sclerosis (age 18-65 years, with Expanded Disability Status Scale score ≤5) were randomly assigned (1:1:1) via an interactive voice response or web system, and stratified by site, to placebo or subcutaneous peginterferon beta-1a 125 μg once every 2 weeks or every 4 weeks. The primary endpoint was annualised relapse rate at 48 weeks. This trial is registered with ClinicalTrials.gov, number NCT00906399. FINDINGS: We screened 1936 patients and enrolled 1516, of whom 1512 were randomly assigned (500 to placebo, 512 to peginterferon every 2 weeks, 500 to peginterferon every 4 weeks); 1332 (88%) patients completed 48 weeks of treatment. Adjusted annualised relapse rates were 0·397 (95% CI 0·328-0·481) in the placebo group versus 0·256 (0·206-0·318) in the every 2 weeks group and 0·288 (0·234-0·355) in the every 4 weeks group (rate ratio for every 2 weeks group 0·644, 95% CI 0·500-0·831, p=0·0007; rate ratio for the every 4 weeks group 0·725, 95% CI 0·565-0·930, p=0·0114). 417 (83%) patients taking placebo, 481 (94%) patients taking peginterferon every 2 weeks, and 472 (94%) patients taking peginterferon every 4 weeks reported adverse events including relapses. The most common adverse events associated with peginterferon beta-1a were injection site reactions, influenza-like symptoms, pyrexia, and headache. 76 (15%) patients taking placebo, 55 (11%) patients taking study drug every 2 weeks, and 71 (14%) patients taking study drug every 4 weeks reported serious adverse events; relapse, pneumonia, and urinary tract infection were the most common. INTERPRETATION: After 48 weeks, peginterferon beta-1a significantly reduced relapse rate compared with placebo. The drug might be an effective treatment for relapsing-remitting multiple sclerosis with less frequent administration than available treatments. FUNDING: Biogen Idec.
    Mots-clés : Adjuvants, Immunologic, Adult, Double-Blind Method, Female, Humans, Interferon-beta, Male, Middle Aged, Multiple Sclerosis, Relapsing-Remitting, Polyethylene Glycols, Treatment Outcome.

  • Khatri, BO, Pelletier, J, Kappos, L, Hartung, H-P, Comi, G, Barkhof, F, von Rosenstiel, P, Meng, X, Grinspan, A, Hashmonay, R, Cohen, JA & TRANSFORMS Study Group, 2014, “Effect of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod vs. interferon β-1a intramuscular: Subgroup analyses of the Trial Assessing Injectable Interferon vs. Fingolimod Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS)”, Multiple Sclerosis and Related Disorders, vol. 3, no. 3, p. 355-363.
    Résumé : BACKGROUND: Fingolimod demonstrated superior efficacy compared with interferon β-1a intramuscular in relapsing multiple sclerosis. The impact of treatment history on fingolimod efficacy is unknown. OBJECTIVES: This post-hoc analysis of phase 3 TRANSFORMS data compared the efficacy and safety of fingolimod and interferon β-1a intramuscular among patient subgroups defined by prior treatment history. METHODS: Annualized relapse rate and safety of once-daily oral fingolimod 0.5mg, 1.25mg, or once-weekly interferon β-1a 30μg intramuscular for 12 months were analyzed in 1292 patients with relapsing multiple sclerosis according to prior disease-modifying therapy, reason for prior disease-modifying therapy discontinuation (adverse events or unsatisfactory therapeutic effect), and prior disease-modifying therapy duration. RESULTS: Compared with interferon β-1a intramuscular, fingolimod 0.5mg significantly reduced annualized relapse rate in patients who were treatment naive, received prior interferon-β treatment, discontinued prior disease-modifying therapy for unsatisfactory therapeutic effect, or had prior disease-modifying therapy duration of ≥1 year (P≤0.05, all comparisons). Similar trends were observed in patients with prior glatiramer acetate treatment. Significant reductions were also seen with fingolimod 1.25mg for treatment-naive and prior interferon-β-treated patients. CONCLUSIONS: This analysis demonstrates superiority of fingolimod over interferon β-1a intramuscular regardless of prior (interferon-β) treatment and prior treatment efficacy and duration. ClinicalTrials.gov identifier: NCT00340834.


  • Maarouf, A, Audoin, B, Konstandin, S, Rico, A, Soulier, E, Reuter, F, Troter, AL, Confort-Gouny, S, Cozzone, PJ, Guye, M, Schad, LR, Pelletier, J, Ranjeva, J-P & Zaaraoui, W 2014, “Topography of brain sodium accumulation in progressive multiple sclerosis”, Magnetic Resonance Materials in Physics, Biology and Medicine, vol. 27, no. 1, p. 53-62, viewed 30October,2014, .
    Résumé : Object Sodium accumulation is involved in neuronal injury occurring in multiple sclerosis (MS). We aimed to assess sodium accumulation in progressive MS, known to suffer from severe neuronal injury. Materials and methods 3D-23Na-MRI was obtained on a 3T-MR-scanner in 20 progressive MS patients [11 primary-progressive (PPMS) and nine secondary-progressive (SPMS)] and 15 controls. Total sodium concentrations (TSC) within grey matter (GM), normal-appearing white matter (WM) and lesions were extracted. Statistical mapping analyses of TSC abnormalities were also performed. Results Progressive MS patients presented higher GM–TSC values (48.8 ± 3.1 mmol/l wet tissue vol, p < 0.001) and T2lesions-TSC values (50.9 ± 2.2 mmol/l wet tissue vol, p = 0.01) compared to GM and WM of controls. Statistical mapping analysis showed TSC increases in PPMS patients confined to motor and somatosensory cortices, prefrontal cortices, pons and cerebellum. In SPMS, TSC increases were associated with areas involving: primary motor, premotor and somatosensory cortices; prefrontal, cingulate and visual cortices; the corpus callosum, thalami, brainstem and cerebellum. Anterior prefrontal and premotor cortices TSC were correlated with disability. Conclusion Sodium accumulation is present in progressive MS patients, more restricted to the motor system in PPMS and more widespread in SPMS. Local brain sodium accumulation appears as a promising marker to monitor patients with progressive MS.
    Mots-clés : Adult, Aged, Biomedical Engineering, Brain, Brain Mapping, Case-Control Studies, Computer Appl. in Life Sciences, crmbm, Disability, Female, Grey matter, Health Informatics, Humans, Imaging / Radiology, Magnetic Resonance Imaging, Male, Middle Aged, MRI, Multiple sclerosis, Nerve Fibers, Myelinated, Neurons, Progressive multiple sclerosis, Sodium, Solid State Physics.

  • Michel, P, Baumstarck, K, Boyer, L, Fernandez, O, Flachenecker, P, Pelletier, J, Loundou, A, Ghattas, B, Auquier, P & on behalf of the MusiQoL Study Group, 2014, “Defining Quality of Life Levels to Enhance Clinical Interpretation in Multiple Sclerosis: Application of a Novel Clustering Method”, Medical Care.
    Résumé : BACKGROUND:: To enhance the use of quality of life (QoL) measures in clinical practice, it is pertinent to help clinicians interpret QoL scores. OBJECTIVE:: The aim of this study was to define clusters of QoL levels from a specific questionnaire (MusiQoL) for multiple sclerosis (MS) patients using a new method of interpretable clustering based on unsupervised binary trees and to test the validity regarding clinical and functional outcomes. METHODS:: In this international, multicenter, cross-sectional study, patients with MS were classified using a hierarchical top-down method of Clustering using Unsupervised Binary Trees. The clustering tree was built using the 9 dimension scores of the MusiQoL in 2 stages, growing and tree reduction (pruning and joining). A 3-group structure was considered, as follows: "high," "moderate," and "low" QoL levels. Clinical and QoL data were compared between the 3 clusters. RESULTS:: A total of 1361 patients were analyzed: 87 were classified with "low," 1173 with "moderate," and 101 with "high" QoL levels. The clustering showed satisfactory properties, including repeatability (using bootstrap) and discriminancy (using factor analysis). The 3 clusters consistently differentiated patients based on sociodemographic and clinical characteristics, and the QoL scores were assessed using a generic questionnaire, ensuring the clinical validity of the clustering. CONCLUSIONS:: The study suggests that Clustering using Unsupervised Binary Trees is an original, innovative, and relevant classification method to define clusters of QoL levels in MS patients.

2012

Journal Article

  • Durante, L, Zaaraoui, W, Rico, A, Crespy, L, Wybrecht, D, Faivre, A, Reuter, F, Malikova, I, Pommier, G, Confort-Gouny, S, Cozzone, PJ, Ranjeva, J-P, Pelletier, J, Boucraut, J & Audoin, B 2012, “Intrathecal synthesis of IgM measured after a first demyelinating event suggestive of multiple sclerosis is associated with subsequent MRI brain lesion accrual”, Multiple sclerosis (Houndmills, Basingstoke, England), vol. 18, no. 5, p. 587-591.
    Résumé : BACKGROUND: Previous studies have demonstrated that intrathecal synthesis of IgM is observed in multiple sclerosis (MS) and correlates with a worse disease course. These results suggest that IgM participates in the formation of MS lesions. OBJECTIVE: The aim of the present study was to assess the potential association between the level of intrathecal synthesis of IgM measured after a clinically isolated syndrome (CIS) and the subsequent formation of brain lesions. METHODS: Fifty seven patients with a CIS and a high risk developing MS were enrolled in a longitudinal study. Examination of cerebrospinal fluid was performed after the CIS and included measures of intrathecal IgM and IgG synthesis. Patients were assessed with the same 1.5 Tesla magnetic resonance imaging (MRI) system at baseline and after a mean follow-up period of 49 months (range 36-60). Spearman Rank correlation was used to assess the potential correlations between levels of intrathecal immunoglobulin synthesis and MRI data. RESULTS: The level of intrathecal IgM synthesis was correlated with the number of gadolinium-enhancing lesions at baseline (p = 0.01) and with accrual of brain lesions during the follow-up period (p = 0.02). By taking into account brain sub-regions, we demonstrated that the level of intrathecal IgM synthesis was only correlated with the increased number of lesions in the periventricular regions (p = 0.004). The level of intrathecal IgG synthesis was not correlated with any MRI data. CONCLUSION: The present longitudinal study demonstrates that the level of intrathecal IgM synthesis measured after a CIS is associated with subsequent lesion accrual during the first years of MS. This result emphasizes the involvement of IgM in plaque formation.
    Mots-clés : Adult, Brain, Contrast Media, crmbm, Demyelinating Diseases, Disease Progression, Female, France, Humans, Immunoglobulin M, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Multiple sclerosis, Predictive Value of Tests, Severity of Illness Index, Time Factors, Young Adult.

  • Faivre, A, Rico, A, Zaaraoui, W, Crespy, L, Reuter, F, Wybrecht, D, Soulier, E, Malikova, I, Confort-Gouny, S, Cozzone, PJ, Pelletier, J, Ranjeva, J-P & Audoin, B 2012, “Assessing brain connectivity at rest is clinically relevant in early multiple sclerosis”, Multiple sclerosis (Houndmills, Basingstoke, England), vol. 18, no. 9, p. 1251-1258.
    Résumé : OBJECTIVE: The present study aims to determine the clinical counterpart of brain resting-state networks reorganization recently evidenced in early multiple sclerosis. METHODS: Thirteen patients with early relapsing-remitting multiple sclerosis and 14 matched healthy controls were included in a resting state functional MRI study performed at 3 T. Data were analyzed using group spatial Independent Component Analysis using concatenation approach (FSL 4.1.3) and double regression analyses (SPM5) to extract local and global levels of connectivity inside various resting state networks (RSNs). Differences in global levels of connectivity of each network between patients and controls were assessed using Mann-Whitney U-test. In patients, relationship between clinical data (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite Score - MSFC) and global RSN connectivity were assessed using Spearman rank correlation. RESULTS: Independent component analysis provided eight consistent neuronal networks involved in motor, sensory and cognitive processes. For seven RSNs, the global level of connectivity was significantly increased in patients compared with controls. No significant decrease in RSN connectivity was found in early multiple sclerosis patients. MSFC values were negatively correlated with increased RSN connectivity within the dorsal frontoparietal network (r = -0.811, p = 0.001), the right ventral frontoparietal network (r = - 0.587, p = 0.045) and the prefronto-insular network (r = -0.615, p = 0.033). CONCLUSIONS: This study demonstrates that resting state networks reorganization is strongly associated with disability in early multiple sclerosis. These findings suggest that resting state functional MRI may represent a promising surrogate marker of disease burden.
    Mots-clés : Adult, Analysis of Variance, Brain, Brain Mapping, Case-Control Studies, Cognition, crmbm, Disability Evaluation, Female, Humans, Magnetic Resonance Imaging, Male, Motor Activity, Multiple Sclerosis, Relapsing-Remitting, Nerve Net, Neuropsychological Tests, Predictive Value of Tests, Prognosis, Regression Analysis, Rest, Sensation, Severity of Illness Index, Young Adult.

  • Wybrecht, D, Reuter, F, Zaaraoui, W, Faivre, A, Crespy, L, Rico, A, Malikova, I, Confort-Gouny, S, Soulier, E, Cozzone, PJ, Pelletier, J, Ranjeva, J-P & Audoin, B 2012, “Voxelwise analysis of conventional magnetic resonance imaging to predict future disability in early relapsing-remitting multiple sclerosis”, Multiple sclerosis (Houndmills, Basingstoke, England), vol. 18, no. 11, p. 1585-1591.
    Résumé : BACKGROUND: The ability of conventional magnetic resonance imaging (MRI) to predict subsequent physical disability and cognitive deterioration after a clinically isolated syndrome (CIS) is weak. OBJECTIVES: We aimed to investigate whether conventional MRI changes over 1 year could predict cognitive and physical disability 5 years later in CIS. We performed analyses using a global approach (T(2) lesion load, number of T(2) lesions), but also a topographic approach. METHODS: This study included 38 patients with a CIS. At inclusion, 10 out of 38 patients fulfilled the 2010 revised McDonald's criteria for the diagnosis of multiple sclerosis. Expanded Disability Status Scale (EDSS) evaluation was performed at baseline, year 1 and year 5, and cognitive evaluation at baseline and year 5. T(2)-weighted MRI was performed at baseline and year 1. We used voxelwise analysis to analyse the predictive value of lesions location for subsequent disability. RESULTS: Using the global approach, no correlation was found between MRI and clinical data. The occurrence or growth of new lesions in the brainstem was correlated with EDSS changes over the 5 years of follow-up. The occurrence or growth of new lesions in cerebellum, thalami, corpus callosum and frontal lobes over 1 year was correlated with cognitive impairment at 5 years. CONCLUSION: The assessment of lesion location at the first stage of multiple sclerosis may be of value to predict future clinical disability.
    Mots-clés : crmbm.

  • Zaaraoui, W, Konstandin, S, Audoin, B, Nagel, AM, Rico, A, Malikova, I, Soulier, E, Viout, P, Confort-Gouny, S, Cozzone, PJ, Pelletier, J, Schad, LR & Ranjeva, J-P 2012, “Distribution of brain sodium accumulation correlates with disability in multiple sclerosis: a cross-sectional 23Na MR imaging study”, Radiology, vol. 264, no. 3, p. 859-867.
    Résumé : PURPOSE: To quantify brain sodium accumulations and characterize for the first time the spatial location of sodium abnormalities at different stages of relapsing-remitting (RR) multiple sclerosis (MS) by using sodium 23 ((23)Na) magnetic resonance (MR) imaging. MATERIALS AND METHODS: This study was approved by the local committee on ethics, and written informed consent was obtained from all participants. Three-dimensional (23)Na MR imaging data were obtained with a 3.0-T unit in two groups of patients with RR MS-14 with early RR MS (disease duration <5 years) and 12 with advanced RR MS (disease duration >5 years)-and 15 control subjects. Quantitative assessment of total sodium concentration (TSC) levels within compartments (MS lesions, white matter [WM], and gray matter [GM]) as well as statistical mapping analyses of TSC abnormalities were performed. RESULTS: TSC was increased inside demyelinating lesions in both groups of patients, whereas increased TSC was observed in normal-appearing WM and GM only in those with advanced RR MS. In patients, increased TSC inside GM was correlated with disability (as determined with the Expanded Disability Status Scale [EDSS] score; P = .046, corrected) and lesion load at T2-weighted imaging (P = .003, corrected) but not with disease duration (P = .089, corrected). Statistical mapping analysis showed confined TSC increases inside the brainstem, cerebellum, and temporal poles in early RR MS and widespread TSC increases that affected the entire brain in advanced RR MS. EDSS score correlated with TSC increases inside motor networks. CONCLUSION: TSC accumulation dramatically increases in the advanced stage of RR MS, especially in the normal-appearing brain tissues, concomitant with disability. Brain sodium MR imaging may help monitor the occurrence of tissue injury and disability.
    Mots-clés : Adult, Area Under Curve, Brain, crmbm, Disability Evaluation, Female, Humans, Image Enhancement, Image Interpretation, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, Relapsing-Remitting, Regression Analysis, Sodium, Statistics, Nonparametric.

2011

Journal Article

  • Crespy, L, Zaaraoui, W, Lemaire, M, Rico, A, Faivre, A, Reuter, F, Malikova, I, Confort-Gouny, S, Cozzone, PJ, Pelletier, J, Ranjeva, J-P & Audoin, B 2011, “Prevalence of grey matter pathology in early multiple sclerosis assessed by magnetization transfer ratio imaging”, PloS one, vol. 6, no. 9, p. e24969.
    Résumé : The aim of the study was to assess the prevalence, the distribution and the impact on disability of grey matter (GM) pathology in early multiple sclerosis. Eighty-eight patients with a clinically isolated syndrome with a high risk developing multiple sclerosis were included in the study. Forty-four healthy controls constituted the normative population. An optimized statistical mapping analysis was performed to compare each subject's GM Magnetization Transfer Ratio (MTR) imaging maps with those of the whole group of controls. The statistical threshold of significant GM MTR decrease was determined as the maximum p value (p<0.05 FDR) for which no significant cluster survived when comparing each control to the whole control population. Using this threshold, 51% of patients showed GM abnormalities compared to controls. Locally, 37% of patients presented abnormalities inside the limbic cortex, 34% in the temporal cortex, 32% in the deep grey matter, 30% in the cerebellum, 30% in the frontal cortex, 26% in the occipital cortex and 19% in the parietal cortex. Stepwise regression analysis evidenced significant association (p = 0.002) between EDSS and both GM pathology (p = 0.028) and T2 white matter lesions load (p = 0.019). In the present study, we evidenced that individual analysis of GM MTR map allowed demonstrating that GM pathology is highly heterogeneous across patients at the early stage of MS and partly underlies irreversible disability.
    Mots-clés : Adolescent, Adult, Brain, Brain Mapping, Case-Control Studies, crmbm, Diagnostic Imaging, Disease Progression, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Middle Aged, Multiple sclerosis, Young Adult.

  • Reuter, F, Zaaraoui, W, Crespy, L, Faivre, A, Rico, A, Malikova, I, Confort-Gouny, S, Cozzone, PJ, Ranjeva, J-P, Pelletier, J & Audoin, B 2011, “Cognitive impairment at the onset of multiple sclerosis: relationship to lesion location”, Multiple sclerosis (Houndmills, Basingstoke, England), vol. 17, no. 6, p. 755-758.
    Résumé : The impact of lesion location on cognitive functioning was assessed in a group of 97 patients with a clinically isolated syndrome. Using the Brief Repeatable Battery, we evidenced that 24% of patients showed at least one abnormal test, 20% at least two and 15% at least three. Verbal learning performances were inversely associated with presence of lesions in Broca's area, in the right frontal lobe and in the splenium while spatial learning performances were inversely correlated to the presence of lesions in the deep white matter. No associations were evidenced between lesion location and performance of tasks exploring attention and executive functions.
    Mots-clés : Adult, Attention, Brain, Case-Control Studies, Cognition, Cognition Disorders, crmbm, Demyelinating Diseases, Disability Evaluation, Executive Function, Female, France, Humans, Magnetic Resonance Imaging, Male, Memory, Multiple sclerosis, Neuropsychological Tests, Prevalence, Spinal cord, Verbal Learning, Young Adult.

  • Reuter, F, Zaaraoui, W, Crespy, L, Faivre, A, Rico, A, Malikova, I, Soulier, E, Viout, P, Ranjeva, J-P, Pelletier, J & Audoin, B 2011, “Frequency of cognitive impairment dramatically increases during the first 5 years of multiple sclerosis”, Journal of neurology, neurosurgery, and psychiatry, vol. 82, no. 10, p. 1157-1159.
    Résumé : Previous studies have demonstrated that cognitive impairment is already present in patients suffering from a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). However, little is known about the course of cognitive impairment after the occurrence of a CIS. In order to characterise the early evolution of cognitive impairment, the authors assessed during a 5-year follow-up period a group of 24 CIS patients with high risk of developing MS. Longitudinal neuropsychological assessment was performed at two time points (baseline and year 5) in patients and controls (baseline and year 1). At year 5, 54% of patients showed cognitive impairment against 29% at baseline. Multiple regression models showed that patients with a higher T(2) lesion load at baseline had a higher cognitive impairment at year 5. This longitudinal study performed in CIS patients showed that the frequency of cognitive impairment increases dramatically during the first 5 years following a CIS and that the cognitive status at year 5 was predictable by conventional MRI parameters recorded at baseline.
    Mots-clés : Adult, Brain, Cognition Disorders, crmbm, Demyelinating Diseases, Disability Evaluation, Disease Progression, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Multiple sclerosis, Neuropsychological Tests, Oligoclonal Bands, Risk Factors, Spinal cord.

  • Rico, A, Zaaraoui, W, Franques, J, Attarian, S, Reuter, F, Malikova, I, Confort-Gouny, S, Soulier, E, Pouget, J, Cozzone, PJ, Pelletier, J, Ranjeva, J-P & Audoin, B 2011, “Motor cortical reorganization is present after a single attack of multiple sclerosis devoid of cortico-spinal dysfunction”, Magma (New York, N.Y.), vol. 24, no. 2, p. 77-84.
    Résumé : OBJECT: While occurrence of motor cortical reorganization has been clearly demonstrated in patients with multiple sclerosis (MS), it is not yet clear whether this cortical reorganization constitutes a response to cortico-spinal lesions or to more diffuse damage affecting the neuronal network involved in motor act preparation, or both. We proposed to investigate the changes in the activation pattern during a simple motor task devoid of cortico-spinal dysfunction occurring in patients with clinically isolated syndrome (CIS) suggestive of MS. MATERIALS AND METHODS: Among 15 right-handed CIS patients, we selected eight patients with a preserved central motor pathway established by motor evoked potentials. Ten healthy right-handed gender- and age-matched volunteers were also included. After morphological MRI, subjects performed calibrated conjugated finger flexion and extension movements during fMRI acquisition. RESULTS: In CIS patients, simple movements of the non-dominant hand induced recruitment of the anterior cingulate cortex (BA32) usually involved in complex motor movements. This reorganization was correlated with the diffuse brain tissue damage (brain T₂ lesion load). CONCLUSION: These results suggest that at least part of the cortical reorganization observed during very simple tasks in the earliest stage of MS occurs whether or not the efferent pathways are intact.
    Mots-clés : Adult, Brain Mapping, crmbm, Demyelinating Diseases, Evoked Potentials, Motor, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Motor Activity, Motor Cortex, Multiple sclerosis, Pyramidal Tracts, Young Adult.

  • Zaaraoui, W, Crespy, L, Rico, A, Faivre, A, Soulier, E, Confort-Gouny, S, Cozzone, PJ, Pelletier, J, Ranjeva, J-P, Kaphan, E & Audoin, B 2011, “In vivo quantification of brain injury in adult Niemann-Pick Disease Type C”, Molecular genetics and metabolism, vol. 103, no. 2, p. 138-141.
    Résumé : Development of surrogate markers is necessary to assess the potential efficacy of new therapeutics in Niemann-Pick Disease Type C (NP-C). In the present study, magnetization transfer ratio (MTR) imaging, a quantitative MRI imaging technique sensitive to subtle brain microstructural changes, was applied in two patients suffering from adult NP-C. Statistical mapping analysis was performed to compare each patient's MTR maps with those of a group of 34 healthy controls to quantify and localize the extent of brain injury of each patient. Using this method, pathological changes were evidenced in the cerebellum, the thalami and the lenticular nuclei in both patients and also in the fronto-temporal cortices in the patient with the worse functional deficit. In addition, white matter changes were located in the midbrain, the cerebellum and the fronto-temporal lobes in the patient with the higher level of disability and in only one limited periventricular white matter region in the other patient. A 6-month follow-up was performed in the patient with the lower functional deficit and evidenced significant extension of grey matter (GM) and white matter (WM) injuries during the following period (14% of increased injury for GM and 53% for WM). This study demonstrates that significant brain injury related to clinical deficit can be assessed in vivo in adult NP-C using MTR imaging. Although preliminary, these findings suggest that MTR imaging may be a relevant candidate for the development of biomarker in NP-C.
    Mots-clés : Adult, Biological Markers, Brain Injuries, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Niemann-Pick Disease, Type C, Young Adult.

  • Zaaraoui, W, Reuter, F, Rico, A, Faivre, A, Crespy, L, Malikova, I, Soulier, E, Viout, P, Le Fur, Y, Confort-Gouny, S, Cozzone, PJ, Pelletier, J, Ranjeva, J-P & Audoin, B 2011, “Occurrence of neuronal dysfunction during the first 5 years of multiple sclerosis is associated with cognitive deterioration”, Journal of neurology, vol. 258, no. 5, p. 811-819.
    Résumé : Brain neuronal injury is present in patients suffering from multiple sclerosis (MS) from the earliest stage of the disease; however, the functional counterpart of early neuronal injury is largely unknown. The goal of this study was to assess the potential impact of early neuronal dysfunction affecting white matter (WM), grey matter (GM), or the cerebellum on cognitive deterioration and/or EDSS progression during the first 5 years of MS. Magnetic resonance spectroscopic (MRS) examinations and neuropsychological assessments were performed in 23 patients included after the first clinical attack of MS and 24 healthy controls. The same protocol was performed in patients after a follow-up of 5 years. Metabolic neuronal function was assessed in WM (splenium of corpus callosum), GM (dorsal posterior cingulate cortex), and the cerebellum by evaluating N-acetylaspartate (NAA) levels. During follow-up, 39% of patients showed cognitive deterioration and 43% showed a deterioration in their EDSS. Patients with cognitive deterioration had greater NAA level reductions during follow-up in the cerebellum (p = 0.003) and WM (p = 0.02) compared to patients without cognitive deterioration. In addition, patients with cognitive deterioration had higher progression of T2 lesion load (T2LL) during the follow-up period compared to patients without cognitive deterioration (p = 0.03). No differences between patients with and without EDSS progression in terms of NAA levels or T2LL were observed. The present longitudinal study found evidence that, during the first 5 years of MS, cognitive deterioration is associated with the progression of neuronal dysfunction and tissue injury as assessed by MRS and T2LL, respectively.
    Mots-clés : Adult, Aspartic Acid, Cognition Disorders, crmbm, Disease Progression, Female, Humans, Magnetic Resonance Spectroscopy, Male, Multiple sclerosis, Neurons, Neuropsychological Tests, Young Adult.

2010

Journal Article

  • Audoin, B, Zaaraoui, W, Reuter, F, Rico, A, Malikova, I, Confort-Gouny, S, Cozzone, PJ, Pelletier, J & Ranjeva, J-P 2010, “Atrophy mainly affects the limbic system and the deep grey matter at the first stage of multiple sclerosis”, Journal of neurology, neurosurgery, and psychiatry, vol. 81, no. 6, p. 690-695.
    Résumé : BACKGROUND: The existence of grey matter (GM) atrophy right after the first clinical event suggestive of multiple sclerosis (MS) remains controversial. The aim of this study was therefore to establish whether regional GM atrophy is already present in the earliest stage of MS assessing regional GM atrophy in a large group of patients. METHODS: Sixty-two patients with a clinically isolated syndrome (CIS) were examined on a 1.5 T MR imager within 6 months after their first clinical events. A group of 37 matched healthy control subjects were also included in the study. An optimised voxel-based morphometry (VBM) method customised for MS was applied on volumetric T(1)-weighted images. The functional status of patients was assessed using the Expanded Disability Status Scale (EDSS) and the Brief Repeatable Battery. RESULTS: VBM analysis (p<0.005, familywise error corrected) on patients versus control subjects showed the presence of significant focal GM atrophy in patients involving the bilateral insula, the bilateral orbitofrontal cortices, the bilateral internal and inferior temporal regions, the posterior cingulate cortex, the bilateral thalami, the bilateral caudate nuclei, the bilateral lenticular nuclei and the bilateral cerebellum. EDSS was slightly correlated (rho=-0.37 p=0.0027) with the atrophy of the right cerebellum. No correlations have been evidenced between the cognitive status of patients and the regional GM atrophy. CONCLUSION: The present study performed on a large group of CIS patients demonstrated that regional GM atrophy is present right after the first clinical event of multiple sclerosis and mainly affects the deep GM and the limbic system.
    Mots-clés : Adult, Amygdala, Atrophy, Cerebral Cortex, crmbm, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Multiple sclerosis, Severity of Illness Index, Young Adult.

  • Jure, L, Zaaraoui, W, Rousseau, C, Reuter, F, Rico, A, Malikova, I, Confort-Gouny, S, Cozzone, PJ, Pelletier, J, Ranjeva, J-P & Audoin, B 2010, “Individual voxel-based analysis of brain magnetization transfer maps shows great variability of gray matter injury in the first stage of multiple sclerosis”, Journal of magnetic resonance imaging: JMRI, vol. 32, no. 2, p. 424-428.
    Résumé : In multiple sclerosis (MS), it seems likely that the variability of the long-term disability might be partly due to the variability of the early gray matter (GM) injury. In the present study, we assessed the variability of GM injury in early MS, using a method designed to determine individual pathological GM patterns. Eighteen patients presenting with a clinically isolated syndrome and 24 healthy matched control subjects were included in this study. Patients were explored using a 1.5 Tesla MR scanner (Magnetom Vision Plus; Siemens). Brain MR protocol included magnetization transfer ratio imaging (MTR). Statistical mapping analyses were performed to compare each subject's GM MTR maps with those of the whole group of control subjects (SPM5). The statistical threshold was taken to be the maximum P value showing no significant cluster when any control individual was compared with the whole control population. GM abnormalities were observed in 83% of the patients, ranging in size from 0.3 to 125 cm(3). Among the patients with GM abnormalities, 87% had abnormalities located in the temporal cortex, 80% in the frontal cortex, 80% in the limbic cortex, 73% in the posterior fossa, 53% in the deep GM, 47% in the parietal cortex, and 47% in the occipital cortex. Individual statistical mapping of MTR data, which gives a quantitative assessment of individual GM lesions, demonstrates great variability of grey matter injury in the first stage of multiple sclerosis.
    Mots-clés : Adolescent, Adult, Brain, Brain Mapping, Case-Control Studies, crmbm, Diagnostic Imaging, Disease Progression, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Multiple sclerosis, Reproducibility of Results.

  • Zaaraoui, W, Rico, A, Audoin, B, Reuter, F, Malikova, I, Soulier, E, Viout, P, Le Fur, Y, Confort-Gouny, S, Cozzone, PJ, Pelletier, J & Ranjeva, J-P 2010, “Unfolding the long-term pathophysiological processes following an acute inflammatory demyelinating lesion of multiple sclerosis”, Magnetic resonance imaging, vol. 28, no. 4, p. 477-486.
    Résumé : BACKGROUND: Acute symptomatic inflammation is a main feature of multiple sclerosis but pathophysiological processes underlying total or partial recovery are poorly understood. OBJECTIVE: To characterize in vivo these processes at molecular, structural and functional levels using multimodal MR methods. METHODS: A neuroimaging 3-year follow-up (Weeks 0, 3, 11, 29, 59 and 169) was conducted on a 41-year-old woman presenting at baseline with a large acute demyelinating lesion of multiple sclerosis. Conventional magnetic resonance imaging (MRI), magnetization transfer imaging, diffusion-weighted imaging, functional MRI and magnetic resonance spectroscopy were conducted at 1.5 T. RESULTS: Patient presenting with subacute left hemiplegia recovered progressively (expended disability status scale 7 to 5.5). The MR exploration demonstrated structural functional and metabolic impairments at baseline. Despite restoration of the blood brain barrier integrity, high lactate levels persisted for several weeks concomitant with glial activation. Slow and progressive structural and metabolic restorations occurred from baseline to W169 (lesion volume -64%; apparent diffusion coefficient -14.7%, magnetization transfer ratio +14%, choline -51%, lipids -78%, N-acetylaspartate +77%) while functionality of the motor system recovered. CONCLUSIONS: Multimodal MRI/MRS evidenced long-term dynamics recovery processes involving tissue repair, glial activation, recovery of neuronal function and functional systems. This may impact on customized rehabilitation strategies generally focused on the first months following the onset of symptoms.
    Mots-clés : Acute Disease, Adult, Brain, Female, Humans, Inflammation, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Multiple sclerosis.

2009

Journal Article
  • Pelletier, J, Audoin, B, Reuter, F & Ranjeva, J 2009, “Plasticity in MS: from Functional Imaging to Rehabilitation”, International MS journal / MS Forum, vol. 16, no. 1, p. 26-31.
    Résumé : One of the main characteristics of multiple sclerosis (MS) is the existence of a "clinico-radiological paradox". The discrepancies observed between the clinical and radiological findings might be partly attributable to lack of specificity of the imaging measures, but also to functional reorganization mechanisms occurring at both the brain and spinal cord levels. These neuroplastic processes might provide a means of delaying the clinical expression of some functional symptoms. Functional MRI (fMRI) methods provide a useful means of determining whether functional reorganization mechanisms of this kind are at work. It has been established, for example, that these neuroplastic mechanisms occur right from the start of the disease and may contribute to reducing the expression of the symptoms resulting from pathological tissue damage. This functional reorganization may therefore constitute an important adaptive mechanism during the early stages of the disease. One potential practical application of the findings made on these neuroplastic processes is likely to be the development of specific rehabilitation methods, which can be used to enhance these reactive mechanisms in order to maintain MS patients functional abilities, and other specifically targeted approaches will also predictably be developed.
    Mots-clés : crmbm.

  • Reuter, F, Audoin, B, Rico, A, Malikova, I, Ranjeva, J-P & Pelletier, J 2009, “[Cognitive impairment]”, Revue neurologique, vol. 165 Suppl 4, p. S113-122.
    Résumé : Cognitive impairment is common in multiple sclerosis (MS), occurring at all stages of the disease, even at the earliest, and can be a major source of disability, social impairment, and impoverished quality of life. Cognitive dysfunction is mainly focused on working memory, conceptual reasoning, verbal fluency, speed of information processing, attention and executive function. Measures of information-processing speed appear to be the most robust and sensitive markers of cognitive impairment in MS patients. Cognitive testing in MS patients is complex and cognitive screening tests are time- and cost-saving test instruments. A comprehensive and sensitive cognitive test procedure should be administered to detect cognitive dysfunction, and recent studies demonstrate that single, predominantly speed-related cognitive tests may be superior to extensive and time-consuming test batteries in screening cognitive decline. Additional clinical factors, including disease course, fatigue, and affective disturbance, can impact the degree of MS-related cognitive impairment. Despite weak correlation with disease duration and physical disability status, the degree of cognitive impairment in MS has been related to the extent of topographically specific neuronal tissue damage and loss. Numerous studies have applied conventional and quantitative magnetic resonance imaging (MRI) techniques to correlate the profile and degree of cognitive impairment with various MRI-detectable abnormalities. The burden of MRI-visible lesions does not fully account for the degree of MS-related cognitive impairment. Nonconventional MRI findings suggest the extent of subtle tissue damage in normal-appearing white and grey matter to correlate best with the severity of cognitive impairment in MS patients. Structural MRI approaches have recently been extended by functional MRI studies scrutinizing the brain's ability for adaptive functional reorganization in the presence of widespread tissue damage. Cognitive impairment in MS seems to be not simply the result of tissue destruction, but also a balance between tissue destruction, tissue repair, and adaptive functional reorganization. These findings highlight the need to screen for cognitive deficits in MS patients to conduct potential cognitive rehabilitation intervention.
    Mots-clés : Cognition Disorders, crmbm, Disease Progression, Humans, Multiple sclerosis, Psychomotor Performance.

  • Reuter, F, Del Cul, A, Malikova, I, Naccache, L, Confort-Gouny, S, Cohen, L, Cherif, AA, Cozzone, PJ, Pelletier, J, Ranjeva, J-P, Dehaene, S & Audoin, B 2009, “White matter damage impairs access to consciousness in multiple sclerosis”, NeuroImage, vol. 44, no. 2, p. 590-599.
    Résumé : Global neuronal workspace theory predicts that damage to long-distance white matter (WM) tracts should impair access to consciousness during the perception of brief stimuli. To address this issue, we studied visual backward masking in 18 patients at the very first clinical stage of multiple sclerosis (MS), a neurological disease characterized by extensive WM damage, and in 18 matched healthy subjects. In our masking paradigm, the visibility of a digit stimulus increases non-linearly as a function of the interval duration between this target and a subsequent mask. In order to characterize quantitatively, for each subject, the transition between non-conscious and conscious perception of the stimulus, we used non-linear regression to fit a sigmoid curve to objective performance and subjective visibility reports as a function of target-mask delay. The delay corresponding to the inflexion point of the sigmoid, where visibility suddenly increases, was termed the "non-linear transition threshold" and used as a summary measure of masking efficiency. Objective and subjective non-linear transition thresholds were highly correlated across subjects in both groups, and were higher in patients compared to controls. In patients, variations in the non-linear transition threshold were inversely correlated to the Magnetization transfer ratio (MTR) values inside the right dorsolateral prefrontal WM, the right occipito-frontal fasciculus and the left cerebellum. This study provides clinical evidence of a relationship between impairments of conscious access and integrity of large WM bundles, particularly involving prefrontal cortex, as predicted by global neuronal workspace theory.
    Mots-clés : Adolescent, Adult, Cognition, Cognition Disorders, Consciousness, crmbm, Demyelinating Diseases, Female, Humans, Male, Middle Aged, Multiple sclerosis, Nerve Fibers, Myelinated, Perceptual Masking, Visual Perception, Young Adult.

2008

Journal Article

  • Audoin, B, Reuter, F, Duong, MVA, Malikova, I, Confort-Gouny, S, Cherif, AA, Cozzone, PJ, Pelletier, J & Ranjeva, JP 2008, “Efficiency of cognitive control recruitment in the very early stage of multiple sclerosis: a one-year fMRI follow-up study”, Multiple sclerosis (Houndmills, Basingstoke, England), vol. 14, no. 6, p. 786-792.
    Résumé : Functional magnetic resonance imaging (FMRI) studies have established that patients with multiple sclerosis show stronger activation in the lateral prefrontal cortices (LPFC) than healthy control subjects during effortful cognitive tasks. The aim of the present study was to assess the impact of these activation changes on cognitive performances. In addition to 19 controls, who were tested at a single time-point to define a standard pattern of fMRI activation during the performance of the Paced Auditory Serial Addition Task (PASAT), 13 patients with clinically isolated syndrome underwent a longitudinal fMRI examination while performing the PASAT at the beginning of the study (M0) and one year later (M12). Relative to the M0 scores, PASAT performances improved in eight patients (group A) and either decreased (n = 4) or remained unchanged (n = 1) (group B) in five patients at M12. Random effect analyses (SPM2; Wellcome Institute, London, England) were performed to compare intra-group time-related effects on brain activation (paired t-test between M0 and M12), and inter-group differences were also compared between the two groups of patients (analysis of covariance with PASAT performances as the covariate). Relative to group B, group A showed larger increase in activation between M0 and M12 in the right LPFC. In the whole group of patients, interaction analyses showed that the differences in the PASAT scores between M0 and M12 were correlated with the differences in activation observed in the right LPFC. This longitudinal study shows that in patients with early multiple sclerosis, the increased levels of activation in the right LPFC was associated with improved individual working memory and processing speed performances.
    Mots-clés : Adaptation, Physiological, Adult, Cognition, crmbm, Early Diagnosis, Female, Follow-Up Studies, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Memory, Short-Term, Multiple sclerosis, Neuropsychological Tests, Prefrontal Cortex.
  • Pelletier, J, Audoin, B, Reuter, F, Malikova, I, Rico, A, Chérif, AA, Ranjeva, J-P & Cozzone, P 2008, “[Cerebral plasticity and multiple sclerosis: data from functional imaging]”, Revue neurologique, vol. 164 Spec No 2, p. F147-153.
    Mots-clés : Brain, Brain Chemistry, crmbm, Humans, Magnetic Resonance Imaging, Multiple sclerosis, Neuronal Plasticity.

2007

Journal Article
  • Audoin, B, Ibarrola, D, Malikova, I, Soulier, E, Confort-Gouny, S, Duong, MVA, Reuter, F, Viout, P, Ali-Chérif, A, Cozzone, PJ, Pelletier, J & Ranjeva, JP 2007, “Onset and underpinnings of white matter atrophy at the very early stage of multiple sclerosis--a two-year longitudinal MRI/MRSI study of corpus callosum”, Multiple sclerosis (Houndmills, Basingstoke, England), vol. 13, no. 1, p. 41-51.
    Résumé : BACKGROUND: Atrophy of corpus callosum (CC), a white matter structure linking the two hemispheres, is commonly observed in multiple sclerosis (MS). However, the occurrence and processes leading to this alteration are not yet determined. GOAL AND METHODS: To better characterize the onset and progression of CC atrophy from the early stage of MS, we performed a two-year follow-up magnetic resonance imaging/magnetic resonance spectroscopic imaging (MRI/MRSI) exploration of CC in 24 patients with clinically isolated syndrome. These patients were explored using the same protocol at month (M)6, M12 and M24. MRI/MRSI techniques were applied to measure CC volume, and relative concentrations of N-acetylaspartate (NAA), creatine/phosphocreatine (Cr) and choline-containing compounds (Cho). A group of matched controls was also explored. RESULTS: Atrophy of CC, not present at baseline, was observed at M12 and progressed over the second year (M24). At baseline, a decrease in relative NAA level was observed in the anterior and posterior body of CC, with normalization during the follow-up period. In the anterior body, an increase in relative Cho level was observed, with normalization at M6. Normal relative Cr levels were observed at all time points in all sub-regions. The rate of CC atrophy was correlated with the change in the Expanded Disability Status Scale (EDSS) during the follow-up period. CONCLUSION: These results suggest that CC atrophy appears over a period of one year after the first acute inflammatory episode, and that this atrophy is accompanied, especially in the anterior body of CC, by a normalization of the relative Cho levels, marker of acute inflammation, and NAA levels, marker of neuronal dysfunction and/or loss.
    Mots-clés : Adult, Age of Onset, Atrophy, Corpus Callosum, crmbm, Disability Evaluation, Disease Progression, Early Diagnosis, Female, Follow-Up Studies, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Male, Multiple sclerosis, Nerve Fibers, Myelinated.

  • Audoin, B, Guye, M, Reuter, F, Au Duong, M-V, Confort-Gouny, S, Malikova, I, Soulier, E, Viout, P, Chérif, AA, Cozzone, PJ, Pelletier, J & Ranjeva, J-P 2007, “Structure of WM bundles constituting the working memory system in early multiple sclerosis: a quantitative DTI tractography study”, NeuroImage, vol. 36, no. 4, p. 1324-1330.
    Résumé : Working memory impairment is frequently observed in patients with early multiple sclerosis (MS). MRI and functional MRI studies have shown that working memory impairment is mostly due to diffuse white matter (WM) damage affecting the connectivity between distant cortical areas. However, working memory deficits in early MS patients can be either completely or partly masked by compensatory functional plasticity. It seems likely that concomitantly with the WM bundle injury resulting from pathological processes, the functional plasticity present in early MS patients may be accompanied by reactive structural WM plasticity. This structural plasticity may effectively compensate for connectivity disturbances and/or contribute to functional brain reorganization. The diffusion characteristics of WM bundles involved in working memory were assessed here by performing quantitative diffusion tensor imaging (DTI) tractography on 24 patients with early relapsing-remitting MS and 15 healthy control subjects. The DTI tractography findings showed that WM connections constituting the executive system of working memory were structurally impaired (the fractional anisotropy was lower than normal and the mean diffusivity, higher than normal). A significantly larger number of connections between the left and right thalami was concurrently observed in the MS patients than in the control subjects, which suggests that the WM is endowed with reactive structural plasticity.
    Mots-clés : Adult, Anisotropy, Brain Mapping, Cerebral Cortex, crmbm, Diagnosis, Differential, Diffusion Magnetic Resonance Imaging, Dominance, Cerebral, Female, Gyrus Cinguli, Humans, Image Processing, Computer-Assisted, Male, Memory, Short-Term, Multiple sclerosis, Nerve Fibers, Myelinated, Nerve Net, Neuronal Plasticity, Software, Thalamus.

  • Lutz, NW, Viola, A, Malikova, I, Confort-Gouny, S, Audoin, B, Ranjeva, J-P, Pelletier, J & Cozzone, PJ 2007, “Inflammatory multiple-sclerosis plaques generate characteristic metabolic profiles in cerebrospinal fluid”, PloS one, vol. 2, no. 7, p. e595.
    Résumé : BACKGROUND: Multiple sclerosis (MS), an inflammatory disease of the central nervous system, manifests itself in numerous forms and stages. A number of brain metabolic alterations have been reported for MS patients vs. control subjects. However, metabolite profiles of cerebrospinal fluid (CSF) are not consistent among the published MS studies, most probably due to variations in the patient cohorts studied. We undertook the first investigation of highly homogeneous MS patient cohorts to determine characteristic effects of inflammatory MS plaques on the CSF metabolome, including only patients with clinically isolated syndrome (CIS) with or without inflammatory brain plaques, and controls. METHODOLOGY/PRINCIPAL FINDINGS: CSF obtained by lumbar puncture was analyzed by proton magnetic resonance spectroscopy. 27 metabolites were quantified. Differences between groups of control subjects (n = 10), CIS patients with (n = 21) and without (n = 12) inflammatory plaques were evaluated by univariate statistics and principal component analysis (PCA). Seven metabolites showed statistically significant inter-group differences (p<0.05). Interestingly, a significant increase in beta-hydroxyisobutyrate (BHIB) was detected in CIS with vs. without active plaques, but not when comparing either CIS group with control subjects. Moreover, a significant correlation was found, for the first time, between CSF lactate concentration and the number of inflammatory MS brain plaques. In contrast, fructose concentrations were equally enhanced in CIS with or without active plaques. PCA based on all 27 metabolites yielded group-specific clusters. CONCLUSIONS/SIGNIFICANCE: CSF metabolic profiles suggest a close link between MS plaque activity in CIS patients on the one hand and organic-acid metabolism on the other. Our detection of increased BHIB levels points to a hitherto unsuspected role for this compound in MS with active plaques, and serves as a basis for further investigation. The metabolic effects described in our study are crucial elements in the explanation of biochemical mechanisms involved in specific MS manifestations.
    Mots-clés : Adult, Amino Acids, Brain, Creatinine, crmbm, Female, Fructose, Glucose, Hemolytic Plaque Technique, Humans, Inflammation, Male, Middle Aged, Multiple sclerosis, Syndrome.

  • Lutz, NW, Viola, A, Malikova, I, Confort-Gouny, S, Ranjeva, J-P, Pelletier, J & Cozzone, PJ 2007, “A branched-chain organic acid linked to multiple sclerosis: first identification by NMR spectroscopy of CSF”, Biochemical and biophysical research communications, vol. 354, no. 1, p. 160-164.
    Résumé : (1)H NMR spectroscopy of cerebrospinal fluid (CSF) is currently being used to study metabolic profiles characteristic of distinct multiple sclerosis (MS) manifestations. For select MS patient groups, we have previously detected significantly increased concentrations of several identified metabolites and one unidentified compound. We now present, for the first time, the identification of the latter molecule, beta-hydroxyisobutyrate (BHIB). A combination of dedicated 1D and 2D (1)H NMR experiments was employed for signal assignment. To our knowledge, BHIB has not previously been identified in (1)H NMR spectra of biofluids or biological tissues. Our assignment suggests new biochemical pathways involved in specific MS pathologies.
    Mots-clés : Acids, Biological Markers, crmbm, Humans, Hydroxybutyrates, Magnetic Resonance Spectroscopy, Multiple sclerosis, Organic Chemicals, Protons.
  • Pelletier, J, Audoin, B & Ranjeva, JP 2007, “[Future of non conventional MR techniques in MS]”, Revue neurologique, vol. 163, no. 6-7, p. 663-666.
    Résumé : Although conventional magnetic resonance imaging (MRI) is used for diagnosing multiple sclerosis (MS) and monitoring disease activity and course, the correlation between conventional MRI data and clinical findings remains weak. This "clinical-MRI paradox" could be partly due to the lack of MRI specificity related to the heterogeneous pathological substrates of MS and to its inability to quantify the extent of damage in the normal-appearing tissue. Recently, non-conventional MRI techniques, including magnetization transfer MRI, diffusion tensor MRI, and proton MR spectroscopy have been applied to improve our understanding of the pathophysiology of MS. These techniques may provide information about structural and biochemical changes occurring within and outside macroscopic MS lesions (inflammation, demyelination, axonal loss), in particular in the normal-appearing white and grey matter. These techniques could also significantly improve our ability to monitor inflammatory demyelination and axonal injury. In the same way, functional MRI gives us the potential substrate to assess the mechanisms of adaptive cortical reorganization, which may limit the irreversible consequences of MS tissue injury.
    Mots-clés : Animals, Axons, Brain Chemistry, crmbm, Demyelinating Diseases, Humans, Inflammation, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Multiple sclerosis, Neurodegenerative Diseases.

  • Reuter, F, Del Cul, A, Audoin, B, Malikova, I, Naccache, L, Ranjeva, JP, Lyon-Caen, O, Ali Chérif, A, Cohen, L, Dehaene, S & Pelletier, J 2007, “Intact subliminal processing and delayed conscious access in multiple sclerosis”, Neuropsychologia, vol. 45, no. 12, p. 2683-2691.
    Résumé : Periventricular white matter damage affecting large bundles connecting distant cortical areas may constitute the main neuronal mechanism for the deficit of controlled information processing observed in patients with early multiple sclerosis (MS). Visual backward masking has been demonstrated to affect late stages of conscious perception involving long-range interactions between visual perceptual areas and higher level integrative cortices while leaving intact early feed-forward visual processing and even complex processing such as object recognition or semantic processing. We therefore hypothesized that patients with early MS would have an elevated masking threshold, because of an impairment of conscious perception whereas subliminal processing of masked stimuli would be preserved. Twenty-two patients with early MS and 22 normal controls performed two backward-masking experiments. We used Arabic digits as stimuli and varied quasi-continuously the temporal interval with a subsequent mask, thus allowing us to progressively "unmask" the stimuli. We finely quantified the visibility of the masked stimuli using both objective and subjective measures, thus obtaining accurate estimates of the threshold duration for access to consciousness. We also studied the priming effect caused by the variably masked numbers on a comparison task performed on a subsequently presented and highly visible target number. The threshold for access to consciousness of masked stimuli was elevated in MS patients compared to controls, whereas non-conscious processing of these stimuli, as measured by priming, was preserved. These findings suggest that conscious access to masked stimuli depends on the integrity of large-scale cortical integrative processes, which involve long-distance white matter projections, and are impaired due to diffuse demyelinating injury in patients with early MS.
    Mots-clés : Adolescent, Adult, Consciousness, crmbm, Cues, Female, Humans, Male, Middle Aged, Multiple Sclerosis, Relapsing-Remitting, Perceptual Masking, Photic Stimulation, Psychomotor Performance, Reaction Time, Reading, Subliminal Stimulation.

  • Van Au Duong, M, Audoin, B, Le Fur, Y, Confort-Gouny, S, Malikova, I, Soulier, E, Viout, P, Ali-Cherif, A, Pelletier, J, Cozzone, PJ & Ranjeva, J-P 2007, “Relationships between gray matter metabolic abnormalities and white matter inflammation in patients at the very early stage of MS : a MRSI study”, Journal of neurology, vol. 254, no. 7, p. 914-923.
    Résumé : Proton magnetic resonance spectroscopic imaging ((1)H-MRSI) was used to study metabolic abnormalities inside the gray matter (GM) during or distant to white matter (WM) inflammatory processes reflected by T(1) gadolinium-enhancing lesions in patients at the very early stage of multiple sclerosis (MS). The spectroscopic examination was performed in the axial plane using a home-designed acquisition-weighted, hamming shape, 2D-SE pulse sequence (TE = 135 ms; TR = 1,600 ms). Bilateral thalami and the medial occipital cortex were explored in 35 patients (15 with and 20 without T(1)-Gd enhancing lesions) with clinically isolated syndrome suggestive of MS and in 30 controls. The mean duration since the first presenting symptom was 9.1 (+/-6.7) months. The two groups of patients (with or without T(1) Gd-enhancing lesions) did not differ in terms of time elapsed since the first clinical onset and T(2) lesion load. The spatial contamination of surrounding WM tissues was obtained in each GM region by determining the tissue component in the ROI from GM and WM probability maps smoothed with the point spread function of the MRSI acquisition. Contribution of WM signal was important (60%) inside thalami while the region centered on the medial occipital cortex was well representative of GM metabolism (>70%). Comparisons of relative metabolite levels (ratios of each metabolite over the sum of all metabolites) between all patients and controls showed significant decrease in relative N-acetyl aspartate (NAA) levels, increase in relative choline-containing compounds (Cho) levels and no change in relative creatine/phosphocreatine levels inside the three ROIs. Decrease in relative NAA levels and increase in relative Cho levels were found in patients with inflammatory activity, while no metabolic alterations were present in patients without T(1) Gd-enhancing lesions. These results suggest that abnormalities in GM metabolism observed in patients at the very early stage of MS are mainly related to neuronal dysfunction occurring during acute inflammatory processes.
    Mots-clés : Adult, Analysis of Variance, Aspartic Acid, Brain Mapping, Case-Control Studies, Choline, crmbm, Female, Humans, Magnetic Resonance Spectroscopy, Male, Multiple sclerosis, Occipital Lobe, Protons, Thalamus.

2006

Journal Article

  • Audoin, B, Au Duong, MV, Malikova, I, Confort-Gouny, S, Ibarrola, D, Cozzone, PJ, Pelletier, J & Ranjeva, J-P 2006, “Functional magnetic resonance imaging and cognition at the very early stage of MS”, Journal of the neurological sciences, vol. 245, no. 1-2, p. 87-91.
    Résumé : Dysfunction of high controlled information processing is present in patients with multiple sclerosis (MS) right at the beginning of the disease. One hypothesis is that disruption of communication inside large-scale cortical networks, occurring as a consequence of white matter damage, may constitute the anatomical substrate of cognitive impairment at the very early stage of MS. Disturbance of interregional synchronization might be the main pathogenic factor in controlled information processing deficiency in early MS. Preliminary functional MRI studies (fMRI) have provided important clues to corroborate the connectivity hypotheses. First, brain connectivity assessed by fMRI has brought new data about the influence of diffuse white matter damage on connectivity efficiency inside large-scale networks. These studies have suggested that connectivity disturbances occur inside the working memory network in patients at the very early stage of MS and appear related to the extent of structural white matter damage. Also, fMRI studies have suggested that patients may partially compensate for connectivity impairment by a greater cognitive control. Such a compensatory mechanism could limit the determinant functional impact of diffuse white matter damage on high controlled information processing.
    Mots-clés : Age of Onset, Brain Mapping, Cerebral Cortex, Cognition, crmbm, Humans, Magnetic Resonance Imaging, Memory, Short-Term, Multiple sclerosis, Oxygen.

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