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Journal Article

  • Ridley, B, Nagel, AM, Bydder, M, Maarouf, A, Stellmann, J-P, Gherib, S, Verneuil, J, Viout, P, Guye, M, Ranjeva, J-P & Zaaraoui, W 2018, “Distribution of brain sodium long and short relaxation times and concentrations: a multi-echo ultra-high field23Na MRI study”, Scientific Reports, vol. 8, no. 1, p. 4357.
    Résumé : Sodium (23Na) MRI proffers the possibility of novel information for neurological research but also particular challenges. Uncertainty can arise in in vivo23Na estimates from signal losses given the rapidity of T2* decay due to biexponential relaxation with both short (T2*short) and long (T2*long) components. We build on previous work by characterising the decay curve directly via multi-echo imaging at 7 T in 13 controls with the requisite number, distribution and range to assess the distribution of both in vivo T2*shortand T2*longand in variation between grey and white matter, and subregions. By modelling the relationship between signal and reference concentration and applying it to in vivo23Na-MRI signal,23Na concentrations and apparent transverse relaxation times of different brain regions were measured for the first time. Relaxation components and concentrations differed substantially between regions of differing tissue composition, suggesting sensitivity of multi-echo23Na-MRI toward features of tissue composition. As such, these results raise the prospect of multi-echo23Na-MRI as an adjunct source of information on biochemical mechanisms in both physiological and pathophysiological states.
    Mots-clés : crmbm, snc.


Journal Article

  • Wirsich, J, Rey, M, Guye, M, Bénar, C, Lanteaume, L, Ridley, B, Confort-Gouny, S, Cassé-Perrot, C, Soulier, E, Viout, P, Rouby, F, Lefebvre, M-N, Audebert, C, Truillet, R, Jouve, E, Payoux, P, Bartrés-Faz, D, Bordet, R, Richardson, JC, Babiloni, C, Rossini, PM, Micallef, J, Blin, O, Ranjeva, J-P & Pharmacog Consortium, 2017, “Brain Networks are Independently Modulated by Donepezil, Sleep, and Sleep Deprivation”, Brain Topography.
    Résumé : Resting-state connectivity has been widely studied in the healthy and pathological brain. Less well-characterized are the brain networks altered during pharmacological interventions and their possible interaction with vigilance. In the hopes of finding new biomarkers which can be used to identify cortical activity and cognitive processes linked to the effects of drugs to treat neurodegenerative diseases such as Alzheimer's disease, the analysis of networks altered by medication would be particularly interesting. Eleven healthy subjects were recruited in the context of the European Innovative Medicines Initiative 'PharmaCog'. Each underwent five sessions of simultaneous EEG-fMRI in order to investigate the effects of donepezil and memantine before and after sleep deprivation (SD). The SD approach has been previously proposed as a model for cognitive impairment in healthy subjects. By applying network based statistics (NBS), we observed altered brain networks significantly linked to donepezil intake and sleep deprivation. Taking into account the sleep stages extracted from the EEG data we revealed that a network linked to sleep is interacting with sleep deprivation but not with medication intake. We successfully extracted the functional resting-state networks modified by donepezil intake, sleep and SD. We observed donepezil induced whole brain connectivity alterations forming a network separated from the changes induced by sleep and SD, a result which shows the utility of this approach to check for the validity of pharmacological resting-state analysis of the tested medications without the need of taking into account the subject specific vigilance.
    Mots-clés : Donepezil, EEG-fMRI, Functional connectivity, Memantine, Sleep, snc.


Journal Article

  • Rapetti-Mauss, R, Lacoste, C, Picard, V, Guitton, C, Lombard, E, Loosveld, M, Nivaggioni, V, Dasilva, N, Salgado, D, Desvignes, J-P, Béroud, C, Viout, P, Bernard, M, Soriani, O, Vinti, H, Lacroze, V, Feneant-Thibault, M, Thuret, I, Guizouarn, H & Badens, C 2015, “A mutation in the Gardos channel is associated with hereditary xerocytosis”, Blood, vol. 126, no. 11, p. 1273-1280.
    Résumé : The Gardos channel is a Ca(2+)-sensitive, intermediate conductance, potassium selective channel expressed in several tissues including erythrocytes and pancreas. In normal erythrocytes, it is involved in cell volume modification. Here, we report the identification of a dominantly inherited mutation in the Gardos channel in 2 unrelated families and its association with chronic hemolysis and dehydrated cells, also referred to as hereditary xerocytosis (HX). The affected individuals present chronic anemia that varies in severity. Their red cells exhibit a panel of various shape abnormalities such as elliptocytes, hemighosts, schizocytes, and very rare stomatocytic cells. The missense mutation concerns a highly conserved residue among species, located in the region interacting with Calmodulin and responsible for the channel opening and the K(+) efflux. Using 2-microelectrode experiments on Xenopus oocytes and patch-clamp electrophysiology on HEK293 cells, we demonstrated that the mutated channel exhibits a higher activity and a higher Ca(2+) sensitivity compared with the wild-type (WT) channel. The mutated channel remains sensitive to inhibition suggesting that treatment of this type of HX by a specific inhibitor of the Gardos channel could be considered. The identification of a KCNN4 mutation associated with chronic hemolysis constitutes the first report of a human disease caused by a defect of the Gardos channel.
    Mots-clés : Adult, Amino Acid Sequence, Anemia, Hemolytic, Congenital, Animals, Child, Preschool, cvs, Erythrocytes, Abnormal, Female, Genes, Dominant, HEK293 Cells, Humans, Hydrops Fetalis, In Vitro Techniques, Infant, Infant, Newborn, Intermediate-Conductance Calcium-Activated Potassium Channels, Male, Models, Molecular, Molecular Sequence Data, Mutant Proteins, Mutation, Missense, Oocytes, Osmotic Fragility, Patch-Clamp Techniques, Pedigree, Pregnancy, Recombinant Proteins, Sequence Homology, Amino Acid, Xenopus laevis.


Journal Article

  • Fellah, S, Callot, V, Viout, P, Confort-Gouny, S, Scavarda, D, Dory-Lautrec, P, Figarella-Branger, D, Cozzone, PJ & Girard, N 2012, “Epileptogenic brain lesions in children: the added-value of combined diffusion imaging and proton MR spectroscopy to the presurgical differential diagnosis”, Child's nervous system: ChNS: official journal of the International Society for Pediatric Neurosurgery, vol. 28, no. 2, p. 273-282.
    Résumé : PURPOSE: Focal cortical dysplasia (FCD), dysembryoplastic neuroepithelial tumors (DNTs), and gangliogliomas (GGs) share many clinical features, and the presurgical differential diagnosis of these lesions using conventional magnetic resonance imaging (MRI) is challenging in some cases. The purpose of this work was thus to evaluate the capacity of diffusion-weighted imaging (DWI) and proton magnetic resonance spectroscopy (MRS) to distinguish each lesion from the others. METHODS: Seventeen children (mean age 9.0 ± 4.7 years), who had been referred for epilepsy associated with a brain tumor and operated, were selected. Preoperative MRI examinations were performed on a 1.5 T system and included anatomical images [T2-weighted, fluid-attenuated inversion recovery (FLAIR) and T1 pre- and post-injection images] as well as DWI and MRS [echo time (TE) = 30 and 135 ms]. Apparent diffusion coefficient (ADC) values were calculated in the lesion and healthy control. MRS relative quantification consisted in normalizing each metabolite by the sum (S) of all metabolites (S(TE=135 ms) = NAA+Cr+Cho; S(TE=30 ms) = NAA+Cr+Cho+Glx+mI). Univariate and multivariate analyses were performed in order to determine which criteria could differentiate the different epileptogenic brain lesions. RESULTS: When taken alone, none of the MRI parameters was able to distinguish each disease from the others. Conventional MRI failed classifying two patients. When adding ADC to the linear discriminant analysis (LDA), one patient was still misclassified. Complete separation of the three groups was possible when combining conventional MRI, diffusion, and MRS either at long or short TE. CONCLUSION: This study shows the added-value of multimodal MRI and MRS in the presurgical diagnosis of epileptogenic brain lesions in children.
    Mots-clés : Adolescent, Brain Diseases, Brain Neoplasms, Child, Child, Preschool, crmbm, Diagnosis, Differential, Diffusion Magnetic Resonance Imaging, Epilepsy, Humans, Infant, Magnetic Resonance Spectroscopy, Malformations of Cortical Development, Malformations of Cortical Development, Group I, Protons.

  • 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.


Journal Article

  • 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.

  • Viola, A, Confort-Gouny, S, Schneider, JF, Le Fur, Y, Viout, P, Chapon, F, Pineau, S, Cozzone, PJ & Girard, N 2011, “Is brain maturation comparable in fetuses and premature neonates at term equivalent age?”, AJNR. American journal of neuroradiology, vol. 32, no. 8, p. 1451-1458.
    Résumé : BACKGROUND AND PURPOSE: Improved knowledge of brain maturation in fetuses and premature neonates is crucial for the early detection of pathologies and would help determine whether MR data from the premature brain might be used to evaluate fetal maturation. Using diffusion-weighted MR imaging and (1)H-MR spectroscopy, we compared cerebral microstructure and metabolism in normal in utero fetuses imaged near term and premature neonates imaged at term equivalent. MATERIALS AND METHODS: Forty-eight subjects were investigated: 24 in utero fetuses (mean gestational age, 37 ± 1 weeks) and 24 premature neonates (mean postconceptional age, 37 ± 1 weeks). ADC values were measured in cerebellum, pons, white matter, brain stem, basal ganglia, and thalamus. MR spectroscopy was performed in deep white matter. RESULTS: Mean ADC values from fetuses and premature neonates were comparable except for the pons and the parietal white matter. ADC values were lower in the pons of premature neonates, whereas greater values were found in their parietal white matter compared with fetuses. Proton MR spectroscopy showed higher levels of NAA/H(2)O, Glx/H(2)O, tCr/H(2)O, and mIns/H(2)O in premature neonates compared with fetuses. CONCLUSIONS: Our study provides evidence of subtle anomalies in the parietal white matter of healthy premature neonates. In addition, the reduced ADC values in the pons together with the increased levels of NAA/H(2)O, tCr/H(2)O, and Glx/H(2)O in the centrum semiovale suggest a more advanced maturation in some white matter regions. Our results indicate that MR data from the premature brain are not appropriate for the assessment of the fetal brain maturation.
    Mots-clés : Brain, crmbm, Fetal Organ Maturity, Fetus, Gestational Age, Humans, Infant, Newborn, Infant, Premature, Term Birth.

  • 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.


Journal Article

  • 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.


Journal Article

  • Combaz, X, Girard, N, Scavarda, D, Chapon, F, Pineau, S, Levrier, O, Viout, P & Confort-Gouny, S 2008, “[Imaging of brain tumors in children]”, Journal of Neuroradiology. Journal De Neuroradiologie, vol. 35, no. 5, p. 261-267.
    Résumé : Few studies exist in the literature on pediatric brain tumors examined with advances MRI techniques. The aim of this review is to try to find out some specific tissular characteristics of the main cerebral tumors encountered in children, especially through diffusion imaging, perfusion imaging and proton magnetic resonance spectroscopy (MRS). However, hemispheric cerebral tumors are not as common as in the adult population.
    Mots-clés : Brain, Brain Neoplasms, Child, Child, Preschool, Contrast Media, crmbm, Humans, Infant, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy.

  • Rousseau, MC, Confort-Gouny, S, Catala, A, Graperon, J, Blaya, J, Soulier, E, Viout, P, Galanaud, D, Le Fur, Y, Cozzone, PJ & Ranjeva, JP 2008, “A MRS-MRI-fMRI exploration of the brain. Impact of long-lasting persistent vegetative state”, Brain injury: [BI], vol. 22, no. 2, p. 123-134.
    Résumé : BACKGROUND: The persistent vegetative state (PVS) is a devastating medical condition characterized by preserved wakefulness contrasting with absent voluntary interaction with the environment. However, very little is known about the actual degree of perception in these patients and the extent of progressive brain injury induced by very prolonged unawareness. METHODS: The authors have conducted a 2-year longitudinal study using a multimodal MRI-MRSI-fMRI protocol in four patients in long-lasting PVS (over 3 years at inclusion) characterized by various brain injuries. RESULTS: Although one subject showed initially preserved local brain metabolism and brain activity related to primary perception suggesting the presence of potential residual brain plasticity even in this critical stage, none of the four patients recovered to consciousness during the 2 years of the protocol. Moreover, significant deterioration of parameters related to brain atrophy, metabolism and functional excitability of primary cortices was observed in all patients during the follow-up. CONCLUSIONS: Heterogeneity of brain injury, consequences of long term minimal brain activity and potential factors that prevent recovery to consciousness are discussed.
    Mots-clés : Adolescent, Adult, Brain Injuries, Coma, crmbm, Decision Making, Evoked Potentials, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Persistent Vegetative State, Somatosensory Cortex.


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.

  • Schneider, JF, Confort-Gouny, S, Le Fur, Y, Viout, P, Bennathan, M, Chapon, F, Fogliarini, C, Cozzone, P & Girard, N 2007, “Diffusion-weighted imaging in normal fetal brain maturation”, European radiology, vol. 17, no. 9, p. 2422-2429.
    Résumé : Diffusion-weighted imaging (DWI) provides information about tissue maturation not seen on conventional magnetic resonance imaging. The aim of this study is to analyze the evolution over time of the apparent diffusion coefficient (ADC) of normal fetal brain in utero. DWI was performed on 78 fetuses, ranging from 23 to 37 gestational weeks (GW). All children showed at follow-up a normal neurological evaluation. ADC values were obtained in the deep white matter (DWM) of the centrum semiovale, the frontal, parietal, occipital and temporal lobe, in the cerebellar hemisphere, the brainstem, the basal ganglia (BG) and the thalamus. Mean ADC values in supratentorial DWM areas (1.68 +/- 0.05 mm(2)/s) were higher compared with the cerebellar hemisphere (1.25 +/- 0.06 mm(2)/s) and lowest in the pons (1.11 +/- 0.05 mm(2)/s). Thalamus and BG showed intermediate values (1.25 +/- 0.04 mm(2)/s). Brainstem, cerebellar hemisphere and thalamus showed a linear negative correlation with gestational age. Supratentorial areas revealed an increase in ADC values, followed by a decrease after the 30th GW. This study provides a normative data set that allows insights in the normal fetal brain maturation in utero, which has not yet been observed in previous studies on premature babies.
    Mots-clés : Analysis of Variance, Brain, Brain Mapping, crmbm, Diffusion Magnetic Resonance Imaging, Female, Gestational Age, Humans, Pregnancy, Retrospective Studies.

  • Schneider, JF, Confort-Gouny, S, Viola, A, Le Fur, Y, Viout, P, Bennathan, M, Chapon, F, Figarella-Branger, D, Cozzone, P & Girard, N 2007, “Multiparametric differentiation of posterior fossa tumors in children using diffusion-weighted imaging and short echo-time 1H-MR spectroscopy”, Journal of magnetic resonance imaging: JMRI, vol. 26, no. 6, p. 1390-1398.
    Résumé : PURPOSE: To assess the combined value of diffusion-weighted imaging (DWI) and proton magnetic resonance spectroscopy (1H-MRS) in differentiating medulloblastoma, ependymoma, pilocytic astrocytoma, and infiltrating glioma in a pediatric population. MATERIALS AND METHODS: A total of 17 children with untreated posterior fossa tumors (seven medulloblastoma, four infiltrating glioma, two ependymoma, and four pilocytic astrocytoma), were investigated with conventional MRI, DWI, and MRS using a single-voxel technique. Within the nonnecrotic tumor core, apparent diffusion coefficient (ADC) values using a standardized region of interest (ROI) were retrieved. Quantification of water signal and analysis of metabolite signals from MRS measurements in the same tumorous area were reviewed using multivariant linear discriminant analysis. RESULTS: Combination of ADC values and metabolites, which were normalized using water as an internal standard, allowed discrimination between the four tumor groups with a likelihood below 1 x 10(-9). Positive predictive value was 1 in all cases. Tumors could not be discriminated when using metabolite ratios or ADC values alone, nor could they be differentiated using creatine (Cr) as an internal reference even in combination with ADC values. CONCLUSION: Linear discriminant analysis using DWI and MRS using water as internal reference, fully discriminates the four most frequent posterior fossa tumors in children.
    Mots-clés : Adolescent, Astrocytoma, Brain Neoplasms, Child, Child, Preschool, Cranial Fossa, Posterior, crmbm, Diagnosis, Differential, Diffusion Magnetic Resonance Imaging, Discriminant Analysis, Ependymoma, Female, Glioma, Humans, Infant, Magnetic Resonance Spectroscopy, Male, Medulloblastoma, Retrospective Studies, Statistics, Nonparametric.

  • Schneider, JF, Viola, A, Confort-Gouny, S, Ayunts, K, Le Fur, Y, Viout, P, Bennathan, M, Chapon, F, Figarella-Branger, D, Cozzone, P & Girard, N 2007, “Infratentorial pediatric brain tumors: the value of new imaging modalities”, Journal of neuroradiology. Journal de neuroradiologie, vol. 34, no. 1, p. 49-58.
    Résumé : The correct assessment of the four most frequent infratentorial brain tumors in children (medulloblastoma, ependymoma, pilocytic astrocytoma and infiltrating glioma) has always been problematic. They are known to often resemble one another on conventional magnetic resonance (MR) imaging. We tested the hypothesis whether the combined strength of diffusion-weighted imaging (DWI) and proton MR spectroscopy (MRS) could help differentiate these tumors. Seventeen children with untreated posterior fossa tumors were investigated between January 2005 and January 2006 with conventional MR imaging and combined DWI and MR spectroscopy using a single-voxel technique at short and long echo time (TE) of 30 ms and 135 ms respectively. Apparent diffusion coefficient (ADC) values were retrieved after regions of interest were manually positioned within non necrotic tumor core. Water signal was quantified and metabolite signals were compared and analyzed using linear discriminant analysis. When a combination of ADC values and normalized metabolites was used, all tumors could be discriminated against one other. This could only be achieved when metabolites were normalized using water as an internal standard. They could not be discriminated when using metabolite ratios or ADC values alone, nor could they be differentiated using creatine (Cr) as an internal reference even in combination with ADC values. In conclusion, linear discriminant analysis and multiparametric combination of DWI and MRS, although not replacing histology, fully discriminates the four most frequent posterior fossa tumors in children, but metabolites have to be normalized using water and not Cr signal as an internal reference.
    Mots-clés : Adolescent, Child, Child, Preschool, crmbm, Diffusion Magnetic Resonance Imaging, Female, Glioma, Humans, Infratentorial Neoplasms, Magnetic Resonance Spectroscopy, Male, Reproducibility of Results, Retrospective Studies.

  • 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.


Journal Article

  • Girard, N, Fogliarini, C, Viola, A, Confort-Gouny, S, Fur, YL, Viout, P, Chapon, F, Levrier, O & Cozzone, P 2006, “MRS of normal and impaired fetal brain development”, European journal of radiology, vol. 57, no. 2, p. 217-225.
    Résumé : Cerebral maturation in the human fetal brain was investigated by in utero localized proton magnetic resonance spectroscopy (MRS). Spectra were acquired on a clinical MR system operating at 1.5 T. Body phased array coils (four coils) were used in combination with spinal coils (two coils). The size of the nominal volume of interest (VOI) was 4.5 cm(3) (20 mm x 15 mm x 15 mm). The MRS acquisitions were performed using a spin echo sequence at short and long echo times (TE = 30 ms and 135 ms) with a VOI located within the cerebral hemisphere at the level of the centrum semiovale. A significant reduction in myo-inositol and choline and an increase in N-acetylaspartate were observed with progressive age. The normal MR spectroscopy data reported here will help to determine whether brain metabolism is altered, especially when subtle anatomic changes are observed on conventional images. Some examples of impaired fetal brain development studied by MRS are illustrated.
    Mots-clés : aging, Aspartic Acid, Brain, Choline, Creatine, crmbm, Female, Fetal Development, Fetus, gamma-Aminobutyric Acid, Humans, Inositol, Linear Models, Magnetic Resonance Spectroscopy, Taurine.

  • Girard, N, Gouny, SC, Viola, A, Le Fur, Y, Viout, P, Chaumoitre, K, D'Ercole, C, Gire, C, Figarella-Branger, D & Cozzone, PJ 2006, “Assessment of normal fetal brain maturation in utero by proton magnetic resonance spectroscopy”, Magnetic resonance in medicine: official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine, vol. 56, no. 4, p. 768-775.
    Résumé : Cerebral maturation in the normal human fetal brain was investigated by in utero localized proton MR spectroscopy ((1)H MRS). Fifty-eight subjects at 22-39 weeks of gestational age (GA) were explored. A combination of anterior body phased-array coils (four elements) and posterior spinal coils (two to three elements) was used. Four sequences were performed (point-resolved spectroscopy (PRESS) sequence with short and long TEs (30 and 135 ms), with and without water saturation). A significant reduction in myo-inositol (myo-Ins) and choline (Cho) levels, and an increase in N-acetylaspartate (NAA) and creatine (Cr) content were observed with progressing age. A new finding is the detection of NAA as early as 22 weeks of GA. This result is probably related to the fact that oligodendrocytes (whether mature or not) express NAA, as demonstrated by in vitro studies. Cho and myo-inositol were the predominant resonances from 22 to 30 weeks and decreased gradually, probably reflecting the variations in substrate needed for membrane synthesis and myelination. The normal MRS data for the second trimester of gestation (when fetal MRI is usually performed) reported here can help determine whether brain metabolism is altered or not, especially when subtle anatomic changes are observed on conventional images.
    Mots-clés : aging, Algorithms, Aspartic Acid, Brain, Brain Chemistry, crmbm, Female, Fetal Development, Gestational Age, Humans, Linear Models, Magnetic Resonance Spectroscopy, Pregnancy.

  • Ranjeva, J-P, Audoin, B, Au Duong, MV, Confort-Gouny, S, Malikova, I, Viout, P, Soulier, E, Pelletier, J & Cozzone, PJ 2006, “Structural and functional surrogates of cognitive impairment at the very early stage of multiple sclerosis”, Journal of the neurological sciences, vol. 245, no. 1-2, p. 161-167.
    Résumé : Following our previous reports based on parametric MRI methods (T(2)-weighted MRI, statistical mapping analysis of magnetization transfer ratio images and functional MRI) applied to a population of 18 patients with clinically isolated syndrome suggestive of multiple sclerosis, we have reviewed the possible structural and functional surrogates of MS that could explain the subtle cognitive impairment related to attention and working memory deficits evaluated with paced auditory serial addition test (PASAT). We propose that the brain substrates underlying cognitive impairment observed at the very early stage of MS are multifactorial. Several components could influence PASAT performances in patients: i) the extent of diffuse white matter damage, ii) the location of visible and non visible lesions, iii) the connectivity efficiency between distant brain functional areas involved in working memory processes and iv) the cortical reorganization. Nevertheless, individually, each of these parameters may have few influences on PASAT performance in patients. Using a multiregression model built with independent MR parameters, a very good evaluation of PASAT scores has been obtained in this limited number of patients explaining 90% of the variance. In conclusion, the different aspects of tissue and functional pathological brain underpinnings must be accounted to monitor accurately new therapeutic strategies for the treatment of early cognitive deficits related to MS.
    Mots-clés : Adult, Attention, Brain, Cognition Disorders, crmbm, Female, Humans, Magnetic Resonance Imaging, Male, Memory, Short-Term, Multiple sclerosis.


Journal Article

  • Audoin, B, Au Duong, MV, Ranjeva, J-P, Ibarrola, D, Malikova, I, Confort-Gouny, S, Soulier, E, Viout, P, Ali-Chérif, A, Pelletier, J & Cozzone, PJ 2005, “Magnetic resonance study of the influence of tissue damage and cortical reorganization on PASAT performance at the earliest stage of multiple sclerosis”, Human brain mapping, vol. 24, no. 3, p. 216-228.
    Résumé : We sought to determine the influence of tissue damage and the potential impact of cortical reorganization on the performance to the Paced Auditory Serial Addition Test (PASAT) in patients at the earliest stage of multiple sclerosis (MS). Magnetization transfer ratio (MTR) imaging and functional magnetic resonance imaging (fMRI) experiments using PASAT as paradigm were carried out in 18 patients with clinically isolated syndrome suggestive of MS (CISSMS) compared to 18 controls. MTR histogram analyses showed structural abnormalities in patients involving the normal-appearing white matter (NAWM) but also the gray matter (GM). Mean PASAT scores were significantly lower in the group of patients taken as a whole, and were correlated with the mean NAWM MTR value. No correlation was observed between PASAT scores and GM MTR. However, in the subgroup of patients with normal PASAT performance (n = 9), fMRI showed larger activations in bilateral Brodmann area 45 (BA45) and right BA44 compared to that in controls (n = 18). In these areas with potentially compensatory reorganization, the whole group of patients (n = 18) showed significantly greater activation than controls (n = 18). Activation in the right BA45 was inversely correlated with the mean NAWM MTR and the peak position of GM MTR histograms of patients. This study indicates that even at the earliest stage of MS, cortical reorganization is present inside the executive system of working memory and could tend to limit the determinant functional impact of NAWM injury on the execution of the PASAT.
    Mots-clés : Adult, Brain Mapping, Cerebral Cortex, crmbm, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Multiple sclerosis, Neuropsychological Tests.
  • Ranjeva, J-P, Audoin, B, Au Duong, MV, Duong, MVA, Ibarrola, D, Confort-Gouny, S, Malikova, I, Soulier, E, Viout, P, Ali-Chérif, A, Pelletier, J & Cozzone, P 2005, “Local tissue damage assessed with statistical mapping analysis of brain magnetization transfer ratio: relationship with functional status of patients in the earliest stage of multiple sclerosis”, AJNR. American journal of neuroradiology, vol. 26, no. 1, p. 119-127.
    Résumé : BACKGROUND AND PURPOSE: In the early stage of Multiple Sclerosis (MS), conventional MR imaging parameters such as T2 lesion load fail to explain the clinical status of patients. In the present work, we aimed to determine the ability of magnification transfer imaging to better reflect the relationship between local tissue damage and functional status of MS patients. METHODS: We performed a comparative statistical mapping analysis on brain tissue magnetization transfer ratio (MTR) data measured in 18 patients with clinically isolated syndrome suggestive of MS (CISSMS) and 18 matched control subjects. RESULTS: In the patients with CISSMS, a pattern of significant low MTR values was observed in the white matter, corpus callosum, bilateral occipitofrontal fascicles, right fornix, right parietal white matter, external capsule, right superior longitudinal fasciculus (SLF), right inferior longitudinal fasciculus, optica radiata, parietal white matter, right cingulum, gray matter, bilateral thalamus, bilateral caudate, right insula, and left Brodmann area (BA) 8. No correlation was found between local MTR decrease and Expanded Disability Status Scale score. Significant correlations between MTR and MS Functional Composite scores (Spearman rank test, P <.05) were observed in the left BA40, right SLF, right frontal white matter, splenium, and anterior corpus callosum. Local MTR values correlated with Paced Auditory Serial Addition Test scores in the left BA40, right BA4, right SLF, and splenium. CONCLUSION: Statistical mapping analysis of brain MTR data provides valuable information on the relationship between the location of brain tissue damage and its functional impact in patients with MS, even in the earliest stage of the disease.
    Mots-clés : Activities of Daily Living, Adult, Brain, Cerebral Cortex, crmbm, Disability Evaluation, Dominance, Cerebral, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Multiple Sclerosis, Relapsing-Remitting, Neurologic Examination, Numerical Analysis, Computer-Assisted, Perforant Pathway, Sickness Impact Profile, Statistics as Topic.


Journal Article

  • Audoin, B, Ranjeva, J-P, Au Duong, MV, Ibarrola, D, Malikova, I, Confort-Gouny, S, Soulier, E, Viout, P, Ali-Chérif, A, Pelletier, J & Cozzone, PJ 2004, “Voxel-based analysis of MTR images: a method to locate gray matter abnormalities in patients at the earliest stage of multiple sclerosis”, Journal of magnetic resonance imaging: JMRI, vol. 20, no. 5, p. 765-771.
    Résumé : PURPOSE: To determine whether voxel-based analysis of magnetization transfer ratio (MTR) maps can provide evidence of a coherent pattern of gray matter (GM) macroscopic and microscopic tissue damage in patients at the earliest stage of multiple sclerosis (MS). MATERIALS AND METHODS: We acquired GM MTR maps in 18 patients with clinically isolated syndrome suggestive of MS (CISSMS), and 18 sex- and age-matched healthy controls. We evaluated the clinical status of the patients using the MS functional composite score and the expanded disability status scale. A two-sample t-test (P <0.0001, k=20, uncorrected for height threshold) was used to compare GM MTR maps from patients and controls on a voxel-by-voxel basis. We then extracted data from regions with t-values above the statistical threshold to verify the significance of differences using a nonparametric Mann-Whitney U-test. RESULTS: A between-groups comparison of GM maps revealed large abnormalities in the basal ganglia, including the bilateral thalamus, bilateral lenticular nucleus, bilateral head of caudate, and protuberance, and smaller abnormalities in the right insula, right BA 4, and left BA 40. The MTR measured in the left caudate and right insula was inversely correlated with duration following the first clinical event. CONCLUSION: These results suggest that although MS is a multifocal demyelinating disease that affects white matter (WM), a pattern of tissue damage is present inside the GM involving predominantly basal ganglia at the earliest stage of the disease.
    Mots-clés : Adult, Brain, Brain Mapping, crmbm, Disease Progression, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Multiple sclerosis, Reference Values, Statistics, Nonparametric.

  • Viola, A, Nicoli, F, Denis, B, Confort-Gouny, S, Le Fur, Y, Ranjeva, J-P, Viout, P & Cozzone, PJ 2004, “High cerebral scyllo-inositol: a new marker of brain metabolism disturbances induced by chronic alcoholism”, Magma (New York, N.Y.), vol. 17, no. 1, p. 47-61.
    Résumé : Cerebral metabolic changes that concur to motor and/or cognitive disorders in actively drinking alcoholics are not well established. We tested the hypothesis that chronic alcoholics exhibit profound alterations in the cerebral metabolism of scyllo-inositol. Brain metabolism was explored in nine actively drinking and 11 recently detoxified chronic alcoholics by in vivo brain (1)H-MRS and in vitro(1)H-MRS of blood serum and cerebrospinal fluid. The cohort was composed of individuals with acute, subacute or chronic encephalopathy or without any clinical encephalopathy. Chronic alcoholism is associated with a hitherto unrecognized accumulation of brain scyllo-inositol. Our results suggest that scyllo-inositol is produced within the central nervous system and shows a diffuse but heterogenous distribution in brain where it can persist several weeks after detoxification. Its highest levels were observed in subjects with a clinically symptomatic alcohol-related encephalopathy. When detected, brain scyllo-inositol takes part in a metabolic encephalopathy since it is associated with reduced N-acetylaspartate and increased creatine. High levels of cerebral scyllo-inositol are correlated with altered glial and neuronal metabolism. Our findings suggest that the accumulation of scyllo-inositol may precede and take part in the development of symptomatic alcoholic metabolic encephalopathy.
    Mots-clés : Adult, Aged, Alcohol Drinking, Alcoholism, Biological Markers, Brain, Brain Chemistry, Brain Diseases, Metabolic, Central Nervous System, Cohort Studies, crmbm, Female, Humans, Inositol, Magnetic Resonance Spectroscopy, Male, Middle Aged, Models, Biological, Time Factors.


Journal Article
  • Galanaud, D, Nicoli, F, Le Fur, Y, Guye, M, Ranjeva, J-P, Confort-Gouny, S, Viout, P, Soulier, E & Cozzone, PJ 2003, “Multimodal magnetic resonance imaging of the central nervous system”, Biochimie, vol. 85, no. 9, p. 905-914.
    Résumé : The physiological and biochemical properties of the diseased brain that can be explored with magnetic resonance imaging (MRI) are increasing. Progress in MR-based technology affords a large panel of MRI sequences that explore different phenomena and, thus, provide complementary informations. The diagnostic accuracy of MRI is improved by the combination of all MR modalities. However, this abundance of data requires an efficient multiparametric analysis to fully achieve the goal of the multimodal strategy. We will discuss the potential impact of this advanced MRI analysis in the clinical management and the therapeutical strategies of the most common brain pathologies (intracranial tumors, multiple sclerosis, stroke, epilepsy and dementia). This non-invasive approach is of utmost importance since it already improves the diagnosis and the therapeutic choice in the management of several central nervous system diseases.
    Mots-clés : Central Nervous System Diseases, Humans, Nuclear Magnetic Resonance, Biomolecular.

  • Galanaud, D, Chinot, O, Nicoli, F, Confort-Gouny, S, Le Fur, Y, Barrie-Attarian, M, Ranjeva, J-P, Fuentès, S, Viout, P, Figarella-Branger, D & Cozzone, PJ 2003, “Use of proton magnetic resonance spectroscopy of the brain to differentiate gliomatosis cerebri from low-grade glioma”, Journal of neurosurgery, vol. 98, no. 2, p. 269-276.
    Résumé : OBJECT: Gliomatosis cerebri (GC), a rare entity characterized by a widespread infiltration of brain by tumor, lacks objective and quantitative diagnostic criteria. Single-voxel spectroscopy and chemical shift imaging (two-dimensional proton magnetic resonance [MR] spectroscopy) were performed using both short (20- or 22-msec) and long (135-msec) echo times in nine patients suffering from GC, nine patients with low-grade gliomas (LGGs), and 25 healthy volunteers to establish the precise metabolic pattern of this uncommon brain neoplasm. METHODS: The gliomatosis infiltration was characterized by markedly elevated levels of creatine-phosphocreatine (Cr) and mvo-inositol (Ins), a reduced level of N-acetyl aspartate (NAA), and a moderately elevated level of choline-containing compounds (Cho). This pattern differs strikingly from LGGs, which are characterized by elevated levels of Cho and Ins, markedly reduced levels of NAA, and low-to-normal Cr concentrations. Although the distinction between GC and LGG, based on histological and MR imaging criteria, is a matter of debate, MR spectroscopy produces valuable information for the differentiation between these two entities and, hence, the choice of therapeutic strategy. It also provides new insight into the pathophysiology of GC because elevated Cr and Ins levels may be related to proliferation of glial elements or, more probably, activation of normal glia. Elevated levels of Cho reflect cellular proliferation and reduced NAA corresponds to reversible neuronal injury and/or focal invasion by the tumor process. CONCLUSIONS: Owing to the unfavorable clinical outcome associated with GC compared with that associated with LGG, the findings of this study illustrate the diagnostic and prognostic value of proton MR spectroscopy in the characterization of infiltrating gliomas.
    Mots-clés : Adolescent, Adult, Aged, Brain, Brain Neoplasms, Diagnosis, Differential, Female, Glioma, Humans, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Male, Middle Aged, Neoplasms, Neuroepithelial, Prospective Studies, Sensitivity and Specificity, Time Factors.
  • Ranjeva, JP, Pelletier, J, Confort-Gouny, S, Ibarrola, D, Audoin, B, Le Fur, Y, Viout, P, Chérif, AA & Cozzone, PJ 2003, “MRI/MRS of corpus callosum in patients with clinically isolated syndrome suggestive of multiple sclerosis”, Multiple sclerosis (Houndmills, Basingstoke, England), vol. 9, no. 6, p. 554-565.
    Résumé : Atrophy of corpus callosum (CC) related to axonal loss has previously been observed in patients at the early stage of clinically definite multiple sclerosis (CDMS). Atrophy increases with the progression of the disease. Nevertheless, no data concerning the onset of atrophy of CC are currently available. The purpose of this study is to determine if damage in callosal tissue was present at the earliest stage of MS, in a subgroup of patients presenting with a clinically isolated syndrome suggestive of MS (CISSMS), fulfilling the dissemination in space criteria according to McDonald. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) techniques were applied to measure CC volume, magnetization transfer ratio (MTR), mean diffusivity (MD), N-acetyl aspartate/choline-containing compounds (NAA/Cho) ratio, N-acetyl aspartate/total creatine (NAA/Cr) ratio and Cho/Cr ratio inside the CC of 46 CISSMS patients and 24 sex- and age-matched controls. No atrophy of CC was observed in the CISSMS group. CC of patients was characterized by decreased MTR and increased MD. No change in the NAA/Cr ratio was observed while the NAA/Cho ratio decreased and Cho/Cr ratio increased in the splenium and the central anterior part of CC. These abnormalities were present in patients with, but also without, macroscopic lesions inside the CC. Our results indicate that diffuse structural and metabolic changes, which may be interpreted as representing predominantly myelin pathology, occur in the CC at the earliest stage of MS before any atrophy is detected.
    Mots-clés : Adult, Corpus Callosum, Diffusion Magnetic Resonance Imaging, Female, Humans, Magnetic Resonance Spectroscopy, Male, Multiple sclerosis, Nerve Fibers.


Journal Article
  • Galanaud, D, Nicoli, F, Le Fur, Y, Roche, P, Confort-Gouny, S, Dufour, H, Ranjeva, J-P, Peragut, J-C, Viout, P & Cozzone, PJ 2002, “[Contribution of magnetic resonance spectrometry to the diagnosis of intracranial tumors]”, Annales de médecine interne, vol. 153, no. 8, p. 491-498.
    Résumé : Magnetic resonance spectroscopy (MRS) is a method enabling the analysis of the tissue metabolic content. It may offer a more accurate diagnosis of the intracranial tumors than conventional MRI sequences. MRS of normal brain parenchyma displays 4 main metabolites: N-acetyl aspartate (neuronal marker), creatine (cellular density marker), choline (membrane activity marker) and myoinositol (glial marker); pathological processes lead to variations of the level of these metabolites and/or the appearance of abnormal metabolites (lactate), following different patterns according to pathological process involved: glioma, meningioma, metastasis, bacterial or toxoplasmic abscess, radionecrosis. The potential clinical use of this method includes positive, differential and etiological diagnosis of tumors, determination of the level of malignancy of gliomas, screening for tumor recurrence following treatment. Our laboratory has been performing MR spectroscopic explorations of brain tumors for many years. Based on this experience, we show how MRS can be routinely performed in the clinical setting, what are its limitations and potential, and what kind of information can be supplied to the clinician.
    Mots-clés : Aspartic Acid, Biological Markers, Brain Abscess, Brain Neoplasms, Choline, Computer Graphics, Creatine, Diagnosis, Differential, Glioma, Humans, Inositol, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Meningioma, Sensitivity and Specificity.

  • Viola, A, Chabrol, B, Nicoli, F, Confort-Gouny, S, Viout, P & Cozzone, PJ 2002, “Magnetic resonance spectroscopy study of glycine pathways in nonketotic hyperglycinemia”, Pediatric research, vol. 52, no. 2, p. 292-300.
    Résumé : Nonketotic hyperglycinemia is a life-threatening disorder in neonates characterized by a deficiency of the glycine cleavage system. We report on four cases of the neonatal form of the disease, which were investigated by in vitro(1)H magnetic resonance spectroscopy of blood and cerebrospinal fluid, and in vivo(1)H magnetic resonance spectroscopy of brain. The existence of glycine disposal pathways leading to an increase in lactate in fluids and creatine in fluids and brain was demonstrated. This is the first observation of elevated creatine in brain in nonketotic hyperglycinemia. A recurrent decrease of glutamine and citrate was observed in cerebrospinal fluid, which might be related to abnormal glutamine metabolism in brain. Finally, the cerebral N-acetylaspartate to myo-inositol-glycine ratio was identified as a prognostic indicator of the disease.
    Mots-clés : Aspartic Acid, Brain, Child, Preschool, Dextromethorphan, Excitatory Amino Acid Antagonists, Female, Glycine, Humans, Hyperglycinemia, Nonketotic, Infant, Inositol, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Male, Prognosis, Sodium Benzoate.


Journal Article
  • Galanaud, D, Le Fur, Y, Nicoli, F, Denis, B, Confort-Gouny, S, Ranjeva, JP, Viout, P, Pelletier, J & Cozzone, PJ 2001, “Regional metabolite levels of the normal posterior fossa studied by proton chemical shift imaging”, Magma (New York, N.Y.), vol. 13, no. 2, p. 127-133.
    Résumé : MR spectroscopy of the posterior fossa is pitted with numerous technical difficulties. It is, however, of great clinical interest in the study of the degenerative diseases and tumors of this area. We have developed a method to perform 2D CSI of this area, by using a sagittal slice and a careful positioning of outer volume saturation. We performed this acquisition in 30 healthy volunteers to determine the normal metabolic ratios in five voxels of this area (mesencephalon, pons, medulla oblongata, vermis, cerebellar white matter). The main technical difficulty was magnetic field inhomogeneity in the lower brainstem generated by dental alloys. However, 88% of the voxels were of sufficient quality to be analyzed. The statistically significant regional variations were a higher NAA/Cr ratio in the pons than in the medulla oblongata, higher Cho/Cr in the pons than in the mesencephalon and higher Cho/Cr in the cerebellar white matter than in the vermis. We conclude that 2D CSI of the brainstem, although technically delicate can be performed in most patients.
    Mots-clés : Brain, Brain Stem, Humans, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Protons, Software.


Journal Article
  • Maillet, S, Vion-Dury, J, Confort-Gouny, S, Nicoli, F, Lutz, NW, Viout, P & Cozzone, PJ 1998, “Experimental protocol for clinical analysis of cerebrospinal fluid by high resolution proton magnetic resonance spectroscopy”, Brain research. Brain research protocols, vol. 3, no. 2, p. 123-134.
    Résumé : High resolution magnetic resonance spectroscopy (MRS) of cerebrospinal fluid (CSF) is a non-destructive analytical method which allows rapid and simultaneous detection of molecules involved in intermediary and oxidative metabolic pathways. We developed a protocol suitable for routine MRS analysis of lyophilized CSF samples. This procedure guarantees sample integrity, from CSF collection to spectrum acquisition. MRS analysis of blood serum was included in our protocol as a complementary method to CSF analysis. This protocol can contribute to establish MRS of CSF as a new analytical tool to better understand the metabolic processes involved in neurological diseases.
    Mots-clés : Adult, Aged, Brain, Brain Chemistry, Cerebrospinal Fluid, Cerebrospinal Fluid Proteins, Energy Metabolism, Female, Humans, Magnetic Resonance Spectroscopy, Male, Middle Aged, Oxidation-Reduction.


Journal Article
  • Kriat, M, Vion-Dury, J, Confort-Gouny, S, Favre, R, Viout, P, Sciaky, M, Sari, H & Cozzone, PJ 1993, “Analysis of plasma lipids by NMR spectroscopy: application to modifications induced by malignant tumors”, Journal of lipid research, vol. 34, no. 6, p. 1009-1019.
    Résumé : Lipid extracts of plasma were studied by 31P and 1H NMR spectroscopy at 9.4 T. Signals recorded on lipid mixtures were assigned to different lipid classes using a data base built with two-dimensional 1H COSY spectra of seven standard lipids. Signals unique to glycerophospholipids, sphingolipids, and triacylglycerols were identified. 31P and 1H NMR spectroscopy was used to study qualitative and quantitative modifications induced in plasma by malignant tumors. The results show a significant increase in triglyceride/phospholipid ratio and a concomitant decrease of total phospholipids in patients with cancer. In order to check for the possible presence of particular lipids such as glycolipids in these patients, 1H COSY spectra were recorded on the intact plasma and on extracts of plasma lipids in patients with cancer and in healthy subjects. Only in one case of ovarian cancer, a cross-peak at 1.35 and 4.15 ppm, corresponding to fucose residue in glycolipids, was detected.
    Mots-clés : Databases, Factual, Female, Humans, Lipids, Magnetic Resonance Spectroscopy, Male, Molecular Structure, neoplasms.
  • Vion-Dury, J, Favre, R, Sciaky, M, Kriat, M, Confort-Gouny, S, Harlé, JR, Grazziani, N, Viout, P, Grisoli, F & Cozzone, PJ 1993, “Graphic-aided study of metabolic modifications of plasma in cancer using proton magnetic resonance spectroscopy”, NMR in biomedicine, vol. 6, no. 1, p. 58-65.
    Résumé : Proton high-resolution MRS of human plasma allows the rapid detection, on the same spectrum, of many compounds originating from different metabolic pathways. In this paper, we illustrate the modifications of the plasma metabolic profiles recorded by proton NMR spectroscopy in different classes of cancers. These modifications can be easily monitored with graphic aids such as 'star plots' which define for each type of cancer a particular pattern describing the most altered metabolic pathways. By using 'star plots' three types of metabolic patterns have been distinguished: (i) the 'inflammatory' pattern characterized by an increase of glycosylated moieties of glycoproteins; (ii) a 'lipid modified' pattern, characterized by various modifications occurring mainly in the lipid moieties detected by MRS; and (iii) a pattern which is often observed in sarcomas and mainly characterized by an alteration in the N-acetyl glucosamine/N-acetyl neuraminic acid ratio. This study demonstrates the ability of proton MRS of plasma to rapidly detect the occurrence of metabolic modifications brought about by cancer evolution or therapy.
    Mots-clés : Acetylglucosamine, Head and Neck Neoplasms, Humans, Lipids, Magnetic Resonance Spectroscopy, neoplasms, Protons, Sensitivity and Specificity, Sialic Acids, Skin Neoplasms, Spectrum Analysis.


Journal Article
  • Kriat, M, Confort-Gouny, S, Vion-Dury, J, Sciaky, M, Viout, P & Cozzone, PJ 1992, “Quantitation of metabolites in human blood serum by proton magnetic resonance spectroscopy. A comparative study of the use of formate and TSP as concentration standards”, NMR in biomedicine, vol. 5, no. 4, p. 179-184.
    Résumé : Formate has been evaluated as an alternative standard to quantitate human serum metabolites in 1H NMR spin-echo spectra. The comparison between added formate and 3-(trimethylsilyl) 3,3,3,3-tetradeutero-propionic acid (TSP) shows that, unlike TSP, formate does not interact with serum macromolecules. Transverse and longitudinal proton relaxation times have been measured on several serum metabolites, in the presence of ammonium chloride. With the exception of glucose, values of metabolite concentrations derived from Hahn spin-echo spectra recorded on serum containing 15.4 mM exogenous formate as a standard, are in excellent agreement with the results of biochemical and chromatographic assays, after correction for differential relaxation effects. This approach can be readily used for quantitation of metabolites from blood serum (and eventually other physiological fluids) in normal and in pathological situations not involving disorders of endogenous formate metabolism.
    Mots-clés : Ammonium Chloride, Blood Chemical Analysis, Chromatography, High Pressure Liquid, Formates, Humans, Magnetic Resonance Spectroscopy, Propionates, Quality Control, Trimethylsilyl Compounds.
  • Kriat, M, Confort-Gouny, S, Vion-Dury, J, Viout, P & Cozzone, PJ 1992, “Two-dimensional 1H NMR spectroscopy of normal and pathological human plasma: complete water suppression and further assignment of resonances”, Biochimie, vol. 74, no. 9-10, p. 913-918.
    Résumé : Two-dimensional J-resolved and correlated 1H NMR spectra with complete water suppression have been obtained to further characterize a metabolic pattern for normal and pathological human plasma samples. 1H COSY spectra have been recorded on plasma from 12 patients with cancer in order to check for the possible presence of fucose. Our results show that there is no evidence for the presence of fucosylated lipids in the plasma of these patients.
    Mots-clés : Fucose, Humans, Hyperlipidemias, Magnetic Resonance Spectroscopy, neoplasms, Plasma, Protons, Reference Values, Water.
  • Mouly-Bandini, A, Vion-Dury, J, Sciaky, M, Viout, P, Confort-Gouny, S, Mesana, T, Goudard, A, Monties, JR & Cozzone, PJ 1992, “[Plasma glycosylated residues demonstrated by proton NMR spectroscopy. Value in the detection of heart graft rejection]”, Presse Médicale (Paris, France: 1983), vol. 21, no. 41, p. 2003-2004.
    Résumé : In conjunction with biopsy and Doppler studies, we analysed by high resolution proton NMR spectroscopy the blood plasma of 22 heart transplant recipients. There was a significant variation in the glycosylated residues of proteins with the development of acute cardiac rejection. A more extensive study is underway to assess the sensitivity and specificity of this approach for the early diagnosis of acute cardiac rejection.
    Mots-clés : Acetylglucosamine, Graft Rejection, Heart Transplantation, Humans, Magnetic Resonance Spectroscopy, Sialic Acids.
  • Vion-Dury, J, Mouly-Bandini, A, Viout, P, Sciaky, M, Confort-Gouny, S, Montiès, JR & Cozzone, P 1992, “Early detection of heart transplant rejection using cardiac echography combined with the assay of glycosylated residues in plasma by proton NMR spectroscopy”, Comptes rendus de l'Académie des sciences. Série III, Sciences de la vie, vol. 315, no. 12, p. 479-484.
    Résumé : Early diagnosis of acute cardiac graft rejection by non-invasive methods is required for medical, organizational, psychological and economic reasons. We have monitored 18 heart recipients over a period of 2.5 years using endomyocardial biopsies (EMB), cardiac Doppler-echography (CDE) and proton NMR spectroscopy assay of plasma glycosylated residues. Diastolic parameters of CDE and assay of the glycosylated residues by NMR spectroscopy respectively detect 42 and 45% of the acute low grade (mild or moderate) histological rejections. The combination of the two methods allows the detection of 65% of rejections. The strategy combining plasma NMR spectroscopy and echography is pertinent to the non-invasive detection of acute cardiac rejections with low histological grade.
    Mots-clés : Adult, Aged, Echocardiography, Doppler, Female, Follow-Up Studies, Glycosylation, Graft Rejection, Heart Transplantation, Humans, Magnetic Resonance Spectroscopy, Male, Middle Aged, Sensitivity and Specificity.
  • Vion-Dury, J, Nicoli, F, Torri, G, Torri, J, Kriat, M, Sciaky, M, Davin, A, Viout, P, Confort-Gouny, S & Cozzone, PJ 1992, “High resolution NMR spectroscopy of physiological fluids: from metabolism to physiology”, Biochimie, vol. 74, no. 9-10, p. 801-807.
    Résumé : High resolution NMR spectroscopy of physiological fluids provides quantitative, qualitative and dynamic information on the metabolic status of the interstitial and plasma compartments under a variety of pathophysiological conditions. The simultaneous detection and quantitation by NMR spectroscopy of numerous compounds of the intermediary metabolism offers a new insight in the understanding of the milieu intérieur. NMR spectroscopy of physiological fluids offers a unique way to define and monitor the global metabolic homeostasis in humans. The development of this analytical approach is still limited by the scarcity of pluridisciplinary teams able to fully exploit the wealth of information present on the NMR spectrum of a fluid. While application in pharmacology and toxicology is already established, the main areas of current development are cancer, hereditary metabolic disorders, organ transplantation and neurological diseases.
    Mots-clés : Body Fluids, Cerebrospinal Fluid, Glycosylation, Homeostasis, Humans, Magnetic Resonance Spectroscopy.


Journal Article
  • Kriat, M, Vion-Dury, J, Fayre, R, Maraninchi, D, Harlé, JR, Confort-Gouny, S, Sciaky, M, Fontanarava, E, Viout, P & Cozzone, PJ 1991, “Variations of plasma sialic acid and N-acetylglucosamine levels in cancer, inflammatory diseases and bone marrow transplantation: a proton NMR spectroscopy study”, Biochimie, vol. 73, no. 1, p. 99-104.
    Résumé : Proton NMR spectroscopy allows the detection in plasma of resonances arising from N-acetyl-glucosamine (NAG) and N-acetyl-neuraminic acid (NANA) which have been shown to be borne by acute phase glycoproteins. These resonances can be identified using 2 different protocols of spectrum acquisition detecting different physical states in the global pool of glycoproteins, ie mobile and less mobile moieties of glycosylated chains. In this study we demonstrate that NMR spectroscopy allows a precise monitoring of the variations of glycosylated residues in cancers, inflammatory processes and bone marrow transplantation. The most important findings are that: i), the distribution of glycosylated residues varies with the origin of the cancerous tissue; ii), the level of these residues is a function of tumor development; iii), the concentrations in NAG and NANA are well correlated with the standard biological parameters of acute phase and leucocyte activation. Proton NMR spectroscopy of glycosylated residues in plasma may offer a new means of monitoring sialic acid in cancer and other pathological conditions.
    Mots-clés : Acetylglucosamine, Alanine, Bone Marrow Transplantation, Humans, Inflammation, Longitudinal Studies, Magnetic Resonance Spectroscopy, N-Acetylneuraminic Acid, neoplasms, Sialic Acids, Time Factors.
  • Pont, H, Vion-Dury, J, Kriat, M, Mouly-Bandini, A, Sciaky, M, Viout, P, Confort-Gouny, S, Messana, T, Goudart, M & Montiès, JR 1991, “NMR spectroscopy of plasma during acute--rejection of transplanted hearts”, Lancet, vol. 337, no. 8744, p. 792-793.
    Mots-clés : Acetylglucosamine, Acute Disease, echocardiography, Graft Rejection, Heart Transplantation, Humans, Magnetic Resonance Spectroscopy, Monitoring, Physiologic, Sialic Acids.
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