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ZAARAOUI Wafaa

Ph.D. - Senior Researcher/Chargée de Recherche CNRS

wafaa.zaaraoui@univ-amu.fr
tel : +33 4 91 38 84 66
Key Words
- Brain MRI
- Sodium MRI
- Neurodegeneration
- Neurosciences
- Multiple Sclerosis

Current Research Interest and projects

Wafaa Zaaraoui obtained her PhD in Biophysics from the University of Bordeaux in 2007. She trained under the supervision of Professors Franconi and Dousset, specialising in MR physics and neuroscientific applications. She pursued further studies in MR spectroscopy in the team of Professor Gonen at New York University. She is currently senior researcher at the Centre for Magnetic Resonance in Biology and Medicine at CNRS Aix-Marseille University, France. Her work focuses on the development of neuroimaging techniques to act as markers and provide insight into neurodegenerative processes, particularly in multiple sclerosis. She has spearheaded the development of quantitative MR techniques, currently focussed on x-nuclei contrasts such as sodium MRI. She is the principal investigator of a project to develop new strategies to quantify neurodegeneration via intra-cellular brain sodium concentrations using ultra-high field MRI in humans.

Publications

2017

Journal Article


  • 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. “Increased total sodium concentration in gray matter better explains cognition than atrophy in MS.”. Neurology [En ligne]. 17 January 2017. Vol. 88, n°3, p. 289-295. Disponible sur : < http://dx.doi.org/10.1212/WNL.0000000000003511 > (consulté le 18 August 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.

  • RIDLEY B., MARCHI A., WIRSICH J., SOULIER E., CONFORT-GOUNY S., SCHAD L., BARTOLOMEI F., RANJEVA J. - P., GUYE M., ZAARAOUI W. “Brain sodium MRI in human epilepsy: Disturbances of ionic homeostasis reflect the organization of pathological regions.”. NeuroImage [En ligne]. 7 June 2017. Vol. 157, p. 173-183. Disponible sur : < http://dx.doi.org/10.1016/j.neuroimage.2017.06.011 > (consulté le no date)
    Résumé : In light of technical advancements supporting exploration of MR signals other than (1)H, sodium ((23)Na) has received attention as a marker of ionic homeostasis and cell viability. Here, we evaluate for the first time the possibility that (23)Na-MRI is sensitive to pathological processes occurring in human epilepsy. A normative sample of 27 controls was used to normalize regions of interest (ROIs) from 1424 unique brain locales on quantitative (23)Na-MRI and high-resolution (1)H-MPRAGE images. ROIs were based on intracerebral electrodes in ten patients undergoing epileptic network mapping. The stereo-EEG gold standard was used to define regions as belonging to primarily epileptogenic, secondarily irritative and to non-involved regions. Estimates of total sodium concentration (TSC) on (23)Na-MRI and cerebrospinal fluid (CSF) on (1)H imaging were extracted for each patient ROI, and normalized against the same region in controls. ROIs with disproportionate CSF contributions (ZCSF≥1.96) were excluded. TSC levels were found to be elevated in patients relative to controls except in one patient, who suffered non-convulsive seizures during the scan, in whom we found reduced TSC levels. In the remaining patients, an ANOVA (F1100= 12.37, p<0.0001) revealed a highly significant effect of clinically-defined zones (F1100= 11.13, p<0.0001), with higher normalized TSC in the epileptogenic zone relative to both secondarily irritative (F1100= 11, p=0.0009) and non-involved regions (F1100= 17.8, p<0.0001). We provide the first non-invasive, in vivo evidence of a chronic TSC elevation alongside ZCSF levels within the normative range, associated with the epileptogenic region even during the interictal period in human epilepsy, and the possibility of reduced TSC levels due to seizure. In line with modified homeostatic mechanisms in epilepsy - including altered mechanisms underlying ionic gating, clearance and exchange - we provide the first indication of (23)Na-MRI as an assay of altered sodium concentrations occurring in epilepsy associated with the organization of clinically relevant divisions of pathological cortex.
    Mots-clés : Cortical localisation, crmbm, epilepsy, Epilepsy surgery, Intracranial EEG, Ionic imaging, snc, Sodium MRI.

2016

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. “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) [En ligne]. 1 August 2016. Disponible sur : < http://dx.doi.org/10.1177/1352458516661640 > (consulté le no date)
    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.
    Mots-clés : connectivity, crmbm, intermittent theta burst stimulation, Multiple Sclerosis, primary motor cortex, resting state fMRI, snc, spasticity.

  • 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. “Hypoperfusion of the thalamus is associated with disability in relapsing remitting multiple sclerosis.”. Journal of Neuroradiology. Journal De Neuroradiologie [En ligne]. 16 November 2016. Disponible sur : < http://dx.doi.org/10.1016/j.neurad.2016.10.001 > (consulté le no date)
    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.
    Mots-clés : Atrophy, crmbm, Disability, Multiple Sclerosis, perfusion, Pseudo-continuous arterial spin labeling, snc, Thalamus.

  • DONADIEU M., LE FUR Y., LECOCQ A., MAUDSLEY A. A., GHERIB S., SOULIER E., CONFORT-GOUNY S., PARIOLLAUD F., RANJEVA M. - P., PELLETIER J., GUYE M., ZAARAOUI W., AUDOIN B., RANJEVA J. - P. “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 [En ligne]. August 2016. Vol. 44, n°2, p. 411-419. Disponible sur : < http://dx.doi.org/10.1002/jmri.25139 > (consulté le no date)
    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. “Depletion of brain functional connectivity enhancement leads to disability progression in multiple sclerosis: A longitudinal resting-state fMRI study.”. Multiple Sclerosis (Houndmills, Basingstoke, England) [En ligne]. November 2016. Vol. 22, n°13, p. 1695-1708. Disponible sur : < http://dx.doi.org/10.1177/1352458516628657 > (consulté le no date)
    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.

2015

Journal Article

  • 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. “Ultra-small superparamagnetic iron oxide enhancement is associated with higher loss of brain tissue structure in clinically isolated syndrome.”. Multiple Sclerosis (Houndmills, Basingstoke, England) [En ligne]. 9 October 2015. Disponible sur : < http://dx.doi.org/10.1177/1352458515607649 > (consulté le no date)
    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


  • MAAROUF A., AUDOIN B., KONSTANDIN S., RICO A., SOULIER E., REUTER F., TROTER A. L., CONFORT-GOUNY S., COZZONE P. J., GUYE M., SCHAD L. R., PELLETIER J., RANJEVA J. - P., ZAARAOUI W. “Topography of brain sodium accumulation in progressive multiple sclerosis.”. Magnetic Resonance Materials in Physics, Biology and Medicine [En ligne]. 1 February 2014. Vol. 27, n°1, p. 53-62. Disponible sur : < http://dx.doi.org/10.1007/s10334-013-0396-1 > (consulté le 30 October 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.

2013

Journal Article


  • INGLESE M., OESINGMANN N., ZAARAOUI W., RANJEVA J. P., FLEYSHER L. “Sodium imaging as a marker of tissue injury in patients with multiple sclerosis.”. Multiple Sclerosis and Related Disorders [En ligne]. October 2013. Vol. 2, n°4, p. 263-269. Disponible sur : < http://dx.doi.org/10.1016/j.msard.2013.03.009 > (consulté le 10 July 2013)
    Résumé : Abstract Recent studies have suggested that intra-axonal sodium accumulation contribute to axonal degeneration in patients with MS. Advances in MRI hardware and software allow acquisition of brain sodium signal in vivo. This review begins with a summary of the experimental evidence for impairment of sodium homeostasis in MS. Then, MRI methods for sodium acquisition are reviewed and the application of the techniques in patients with MS is discussed. Sodium imaging and ultra-high field MRI have the potential to provide tissue-specific markers of neurodegeneration in MS.
    Mots-clés : crmbm, Multiple Sclerosis, Multiple-quantum filtering, Sodium imaging, Ultra-high magnetic field.
  • MOLL N., REUTER F., ZAARAOUI W., RICO A., MALIKOVA I., CRESPY L., FAIVRE A., LOUNDOU A., AUQUIER P., COZZONE P., RANJEVA J. P., AUDOIN B., PELLETIER J. “T2 Lesion Load Influences Cognitive Impairment at the Early Phase of MS.”. Neurology. 12 February 2013. Vol. 80,.

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 P. J., RANJEVA J. - P., PELLETIER J., BOUCRAUT J., AUDOIN B. “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) [En ligne]. May 2012. Vol. 18, n°5, p. 587-591. Disponible sur : < http://dx.doi.org/10.1177/1352458511424589 > (consulté le no date)
    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 P. J., PELLETIER J., RANJEVA J. - P., AUDOIN B. “Assessing brain connectivity at rest is clinically relevant in early multiple sclerosis.”. Multiple sclerosis (Houndmills, Basingstoke, England) [En ligne]. September 2012. Vol. 18, n°9, p. 1251-1258. Disponible sur : < http://dx.doi.org/10.1177/1352458511435930 > (consulté le no date)
    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 P. J., PELLETIER J., RANJEVA J. - P., AUDOIN B. “Voxelwise analysis of conventional magnetic resonance imaging to predict future disability in early relapsing-remitting multiple sclerosis.”. Multiple sclerosis (Houndmills, Basingstoke, England) [En ligne]. November 2012. Vol. 18, n°11, p. 1585-1591. Disponible sur : < http://dx.doi.org/10.1177/1352458512442991 > (consulté le no date)
    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 A. M., RICO A., MALIKOVA I., SOULIER E., VIOUT P., CONFORT-GOUNY S., COZZONE P. J., PELLETIER J., SCHAD L. R., RANJEVA J. - P. “Distribution of brain sodium accumulation correlates with disability in multiple sclerosis: a cross-sectional 23Na MR imaging study.”. Radiology [En ligne]. September 2012. Vol. 264, n°3, p. 859-867. Disponible sur : < http://dx.doi.org/10.1148/radiol.12112680 > (consulté le no date)
    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 P. J., PELLETIER J., RANJEVA J. - P., AUDOIN B. “Prevalence of grey matter pathology in early multiple sclerosis assessed by magnetization transfer ratio imaging.”. PloS one [En ligne]. 2011. Vol. 6, n°9, p. e24969. Disponible sur : < http://dx.doi.org/10.1371/journal.pone.0024969 > (consulté le no date)
    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 P. J., RANJEVA J. - P., PELLETIER J., AUDOIN B. “Cognitive impairment at the onset of multiple sclerosis: relationship to lesion location.”. Multiple sclerosis (Houndmills, Basingstoke, England) [En ligne]. June 2011. Vol. 17, n°6, p. 755-758. Disponible sur : < http://dx.doi.org/10.1177/1352458511398265 > (consulté le no date)
    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. “Frequency of cognitive impairment dramatically increases during the first 5 years of multiple sclerosis.”. Journal of neurology, neurosurgery, and psychiatry [En ligne]. October 2011. Vol. 82, n°10, p. 1157-1159. Disponible sur : < http://dx.doi.org/10.1136/jnnp.2010.213744 > (consulté le no date)
    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 P. J., PELLETIER J., RANJEVA J. - P., AUDOIN B. “Motor cortical reorganization is present after a single attack of multiple sclerosis devoid of cortico-spinal dysfunction.”. Magma (New York, N.Y.) [En ligne]. April 2011. Vol. 24, n°2, p. 77-84. Disponible sur : < http://dx.doi.org/10.1007/s10334-010-0232-9 > (consulté le no date)
    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 P. J., PELLETIER J., RANJEVA J. - P., KAPHAN E., AUDOIN B. “In vivo quantification of brain injury in adult Niemann-Pick Disease Type C.”. Molecular genetics and metabolism [En ligne]. June 2011. Vol. 103, n°2, p. 138-141. Disponible sur : < http://dx.doi.org/10.1016/j.ymgme.2011.02.013 > (consulté le no date)
    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 P. J., PELLETIER J., RANJEVA J. - P., AUDOIN B. “Occurrence of neuronal dysfunction during the first 5 years of multiple sclerosis is associated with cognitive deterioration.”. Journal of neurology [En ligne]. May 2011. Vol. 258, n°5, p. 811-819. Disponible sur : < http://dx.doi.org/10.1007/s00415-010-5845-4 > (consulté le no date)
    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 P. J., PELLETIER J., RANJEVA J. - P. “Atrophy mainly affects the limbic system and the deep grey matter at the first stage of multiple sclerosis.”. Journal of neurology, neurosurgery, and psychiatry [En ligne]. June 2010. Vol. 81, n°6, p. 690-695. Disponible sur : < http://dx.doi.org/10.1136/jnnp.2009.188748 > (consulté le no date)
    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 P. J., PELLETIER J., RANJEVA J. - P., AUDOIN B. “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 [En ligne]. August 2010. Vol. 32, n°2, p. 424-428. Disponible sur : < http://dx.doi.org/10.1002/jmri.22265 > (consulté le no date)
    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 P. J., PELLETIER J., RANJEVA J. - P. “Unfolding the long-term pathophysiological processes following an acute inflammatory demyelinating lesion of multiple sclerosis.”. Magnetic resonance imaging [En ligne]. May 2010. Vol. 28, n°4, p. 477-486. Disponible sur : < http://dx.doi.org/10.1016/j.mri.2009.12.011 > (consulté le no date)
    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.
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