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Professor Emeritus of Biophysics
Faculty of Medicine, Aix-Marseille University
tel : +33 4 91 32 48 06

Biographical Note

  • Patrick J. Cozzone is Professor Emeritus of Biophysics at the Faculty of Medicine, Aix-Marseille University (AMU) and a honorary member of the Academic Institute of France (Paris) where he held the chair of Biophysics from 1998 to 2008. He holds a PhD in Organic Chemistry (Marseille), a "Doctorat ès-Sciences" in Biochemistry (Marseille) and a MBA (University of Chicago). He has previously held research/faculty positions at Stanford University (Pharmacology Department of the School of Medicine and Stanford Magnetic Resonance Laboratory), the Universities of Tunis and Sfax and the Pasteur Institute in Tunis (Tunisia) and the Institute of Biological Chemistry in Marseille. He is the founder (1986) and was director of the Centre de Résonance Magnétique Biologique et Médicale (CRMBM) until 2012.
  • P. J. Cozzone is the south of France coordinator of the French Life Imaging initiative to develop multimodal in vivo bioimaging. He is the Principal Investigator of the ultra high field MRI 7T-AMI Equipex project which has received funding for installing in the spring of 2014 a 7T MRI system at CRMBM.
  • P. J. Cozzone has co-authored over 400 peer-reviewed papers and directed 40 PhD theses. He has served in several French research agencies (CNRS, INRA, ANR, etc.) and international organizations, was an adviser to the French Minister of Research, has presided ESMRMB, and is currently a member of the IUPAB Executive Committee and the Editor-in-chief of MAGMA.
  • P.J. Cozzone is a Laureate of the French Academy of Sciences (1981), the recipient of the 1998 European Magnetic Resonance Forum Award in Basic Sciences, a fellow of ISMRM (2007), and a member of the Academy of Sciences, Literature and Arts, Marseille (2011). He was knighted in the French national order of the Legion of Honor in 2013.

Recents Publications


Journal Article

  • Bernard, M, Maixent, J-M, Gerbi, A, Lan, C, Cozzone, PJ, Pieroni, G, Armand, M & Coste, TC 2016, “Dietary docosahexaenoic acid-enriched glycerophospholipids exert cardioprotective effects in ouabain-treated rats via physiological and metabolic changes”, Food & Function, vol. 7, no. 2, p. 798-804.
    Résumé : Docosahexaenoic acid (DHA) might prevent heart failure or optimise drug treatments by improving cardiac contraction. We investigated whether DHA-enriched avian glycerophospholipids (GPL-DHA) exert cardioprotection in ouabain-treated rats after 4 weeks of dietary supplementation with 10, 35 or 60 mg DHA per kg body weight versus none (DHA10, DHA35, DHA60 and control groups, respectively). The contractile responsiveness to different doses of ouabain (10(-7) to 10(-4) M), ouabain intoxication (at 3 × 10(-4) M), and relative variations in cardiac energy metabolism were determined using (31)P NMR in isolated perfused rat hearts. The fatty acid composition of cardiac membranes was analysed by gas chromatography. DHA accretion in the heart was dose-dependent (+8%, +30% and +45% for DHA10, DHA35 and DHA60, respectively). The cardiac phosphocreatine content significantly increased at the baseline in DHA35 (+45%) and DHA60 groups (+85%), and at the different doses of ouabain in the DHA60 group (+73% to 98%). The maximum positive inotropy achieved at 10(-4) M ouabain was significantly increased in all DHA groups versus control (+150%, +122.5% and +135% for DHA10, DHA35 and DHA60, respectively), and ouabain intoxication was delayed. The increase in myocardial phosphocreatine content and the improved efficacy of ouabain on myocardial contraction without toxicity suggest the potential of GPL-DHA as a dietary supplement or ingredient for functional food, and possibly as a co-treatment with digitalis drugs in humans.
    Mots-clés : crmbm, snc.

  • Layec, G, Bringard, A, LE Fur, Y, Micallef, J-P, Vilmen, C, Perrey, S, Cozzone, PJ & Bendahan, D 2016, “Mitochondrial Coupling and Contractile Efficiency in Humans with High and Low V˙O2peaks”, Medicine and Science in Sports and Exercise, vol. 48, no. 5, p. 811-821.
    Résumé : INTRODUCTION: Endurance training elicits tremendous adaptations of the mitochondrial energetic capacity. Yet, the effects of training or physical fitness on mitochondrial efficiency during exercise are still unclear. Accordingly, the purpose of the present study was to examine in vivo the differences in mitochondrial efficiency and ATP cost of contraction during exercise in two groups of adults differing in their aerobic capacity. METHOD: We simultaneously assessed the ATP synthesis and O2 fluxes with P-magnetic resonance spectroscopy and pulmonary gas exchange measurements in seven endurance-trained (ET, V˙O2max: 67 ± 8 mL·min·kg) and seven recreationally active (RA, V˙O2max: 43 ± 7 mL·min·kg) subjects during 6 min of dynamic moderate-intensity knee extension. RESULTS: The ATP cost of dynamic contraction was not significantly different between ET and RA (P > 0.05). Similarly, end-exercise O2 consumption was not significantly different between groups (ET: 848 ± 155 mL·min and RA: 760 ± 131 mL·min, P > 0.05). During the recovery period, the PCr offset time constant was significantly faster in ET compared with RA (ET: 32 ± 8 s and RA: 43 ± 10 s, P < 0.05), thus indicating an increased mitochondrial capacity for ATP synthesis in the quadriceps of ET. In contrast, the estimated mitochondrial efficiency during exercise was not significantly different (P/O, ET: 2.0 ± 1.0 and RA: 1.8 ± 0.4, P > 0.05). Consequently, the higher mitochondrial capacity for ATP synthesis in ET likely originated from an elevated mitochondrial volume density, mitochondria-specific respiratory capacity, and/or slower postexercise inactivation of oxidative phosphorylation by the parallel activation mechanism. CONCLUSION: Together, these findings reveal that 1) mitochondrial and contractile efficiencies are unaltered by several years of endurance training in young adults, and 2) the training-induced improvement in mitochondrial energetic capacity appears to be independent from changes in mitochondrial coupling.
    Mots-clés : crmbm, msk.

  • Lutz, NW, Banerjee, P, Wilson, BJ, Ma, J, Cozzone, PJ & Frank, MH 2016, “Expression of Cell-Surface Marker ABCB5 Causes Characteristic Modifications of Glucose, Amino Acid and Phospholipid Metabolism in the G3361 Melanoma-Initiating Cell Line”, PloS One, vol. 11, no. 8, p. e0161803.
    Résumé : We present a pilot study aimed at determining the effects of expression of ATP-binding cassette member B5 (ABCB5), a previously described marker for melanoma-initiating cells, on cellular metabolism. Metabolic profiles for two groups of human G3361 melanoma cells were compared, i.e. wildtype melanoma cells with intact ABCB5 expression (ABCB5-WT) and corresponding melanoma cell variants with inhibited ABCB5 expression, through shRNA-mediated gene knockdown (ABCB5-KD). A comprehensive metabolomic analysis was performed by using proton and phosphorus NMR spectroscopy of cell extracts to examine water-soluble metabolites and lipids. Parametric and non-parametric statistical analysis of absolute and relative metabolite levels yielded significant differences for compounds involved in glucose, amino acid and phospholipid (PL) metabolism. By contrast, energy metabolism was virtually unaffected by ABCB5 expression. The sum of water-soluble metabolites per total protein was 17% higher in ABCB5-WT vs. ABCB5-KD G3361 variants, but no difference was found for the sum of PLs. Enhanced abundance was particularly pronounced for lactate (+ 23%) and alanine (+ 26%), suggesting an increase in glycolysis and potentially glutaminolysis. Increases in PL degradation products, glycerophosphocholine and glycerophosphoethanolamine (+ 85 and 123%, respectively), and redistributions within the PL pool suggested enhanced membrane PL turnover as a consequence of ABCB5 expression. The possibility of glycolysis modulation by an ABCB5-dependent IL1β-mediated mechanism was supported by functional studies employing monoclonal antibody (mAb)-dependent ABCB5 protein inhibition in wildtype G3361 melanoma cells. Our metabolomic results suggest that the underlying biochemical pathways may offer targets for melanoma therapy, potentially in combination with other treatment forms.
    Mots-clés : crmbm.

  • Sdika, M, Tonson, A, Le Fur, Y, Cozzone, PJ & Bendahan, D 2016, “Multi-atlas-based fully automatic segmentation of individual muscles in rat leg”, Magma (New York, N.Y.), vol. 29, no. 2, p. 223-235.
    Résumé : OBJECTIVE: To quantify individual muscle volume in rat leg MR images using a fully automatic multi-atlas-based segmentation method. MATERIALS AND METHODS: We optimized a multi-atlas-based segmentation method to take into account the voxel anisotropy of numbers of MRI acquisition protocols. We mainly tested an image upsampling process along Z and a constraint on the nonlinear deformation in the XY plane. We also evaluated a weighted vote procedure and an original implementation of an artificial atlas addition. Using this approach, we measured gastrocnemius and plantaris muscle volumes and compared the results with manual segmentation. The method reliability for volume quantification was evaluated using the relative overlap index. RESULTS: The most accurate segmentation was obtained using a nonlinear registration constrained in the XY plane by zeroing the Z component of the displacement and a weighted vote procedure for both muscles regardless of the number of atlases. The performance of the automatic segmentation and the corresponding volume quantification outperformed the interoperator variability using a minimum of three original atlases. CONCLUSION: We demonstrated the reliability of a multi-atlas segmentation approach for the automatic segmentation and volume quantification of individual muscles in rat leg and found that constraining the registration in plane significantly improved the results.
    Mots-clés : Anisotropy, crmbm, Magnetic Resonance Imaging, msk, Multi-atlas, rat, Reproducibility of Results, Segmentation, skeletal muscle.


Journal Article

  • Girard, OM, Prevost, VH, Varma, G, Cozzone, PJ, Alsop, DC & Duhamel, G 2015, “Magnetization transfer from inhomogeneously broadened lines (ihMT): Experimental optimization of saturation parameters for human brain imaging at 1.5 Tesla”, Magnetic Resonance in Medicine, vol. 73, no. 6, p. 2111-2121.
    Résumé : PURPOSE: Recently a new MR endogenous contrast mechanism was reported. It allows specifically imaging the magnetization transfer (MT) effect arising from inhomogeneously broadened components of the NMR spectrum, and was hence dubbed ihMT. Such unique NMR lineshape properties are presumably occurring in myelin because of its specifically ordered, multilayered sheath structure. Here, optimization of a pulsed ihMT preparation module is presented to provide guidance for future studies and improve the understanding of underlying contrast mechanisms. METHODS: This study was performed at 1.5 Tesla on healthy volunteers. A pulsed ihMT preparation was implemented in combination with a HASTE readout module. The pulse width, interpulse repetition time, total saturation duration and RF saturation power were considered for optimization of the ihMT sensitivity and contrast. RESULTS: An optimal configuration of the preparation module was derived, leading to 10% ihMT signal in internal capsule (relative to unsaturated data) and around 200% signal increase relative to gray matter, i.e., approximately 10-fold superior contrast compared with conventional MT ratios, measured under similar experimental conditions. CONCLUSION: Overall the ihMT sequence was robust, sensitive and very specific for white matter. These findings suggest great potential for assessing brain myelination and for better characterization of myelin related disorders. Magn Reson Med 73:2111-2121, 2015. © 2014 Wiley Periodicals, Inc.
    Mots-clés : crmbm, ihMT, inhomogeneously broadened lines, Magnetization transfer, myelin, snc, specificity, White Matter.

  • Jubeau, M, LE Fur, Y, Duhamel, G, Wegrzyk, J, Confort-Gouny, S, Vilmen, C, Cozzone, PJ, Mattei, JP, Bendahan, D & Gondin, J 2015, “Localized metabolic and t2 changes induced by voluntary and evoked contractions”, Medicine and Science in Sports and Exercise, vol. 47, no. 5, p. 921-930.
    Résumé : PURPOSE: This study compared the metabolic and activation changes induced by electrically evoked (neuromuscular electrical stimulation (NMES)) and voluntary (VOL) contractions performed at the same submaximal intensity using P chemical shift imaging (CSI) and T2 mapping investigations. METHODS: Fifteen healthy subjects were asked to perform both NMES and VOL protocols with the knee extensors (i.e., 232 isometric contractions at 30% of maximal force) inside a 3-T scanner for two experimental sessions. During the first session, metabolic variations, i.e., phosphocreatine (PCr), inorganic phosphate (Pi), and pH, were recorded using localized P CSI. During a second session, T2 maps of the knee extensors were obtained at rest and immediately after each exercise. Voxels of interest were selected from the directly stimulated vastus lateralis and from the nondirectly stimulated rectus femoris/vastus intermedius muscles. RESULTS: PCr depletion recorded throughout the NMES session was significantly larger in the vastus lateralis as compared with the rectus femoris/vastus intermedius muscles for both conditions (VOL and NMES). A higher occurrence of Pi splitting and a greater acidosis was found during NMES as compared with VOL exercise, illustrating the heterogeneous activation of both slow and fast muscle fibers. T2 changes were greater after NMES as compared with VOL for both muscles but were not necessarily related to the localized metabolic demand. CONCLUSION: We provided direct evidence that the metabolic demand was strongly related to both the exercise modality and the site of stimulation. On the basis of the occurrence of Pi splitting, we suggested that NMES can activate fast muscle fibers even at low force levels.
    Mots-clés : crmbm, msk.

  • Layec, G, Bringard, A, Le Fur, Y, Micallef, J-P, Vilmen, C, Perrey, S, Cozzone, PJ & Bendahan, D 2015, “Opposite effects of hyperoxia on mitochondrial and contractile efficiency in human quadriceps muscles”, American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, vol. 308, no. 8, p. R724-733.
    Résumé : Exercise efficiency is an important determinant of exercise capacity. However, little is known about the physiological factors that can modulate muscle efficiency during exercise. We examined whether improved O2 availability would 1) impair mitochondrial efficiency and shift the energy production toward aerobic ATP synthesis and 2) reduce the ATP cost of dynamic contraction owing to an improved neuromuscular efficiency, such that 3) whole body O2 cost would remain unchanged. We used (31)P-magnetic resonance spectroscopy, surface electromyography, and pulmonary O2 consumption (V̇o2p) measurements in eight active subjects during 6 min of dynamic knee-extension exercise under different fractions of inspired O2 (FiO2 , 0.21 in normoxia and 1.0 in hyperoxia). V̇o2p (755 ± 111 ml/min in normoxia and 799 ± 188 ml/min in hyperoxia, P > 0.05) and O2 cost (P > 0.05) were not significantly different between normoxia and hyperoxia. In contrast, the total ATP synthesis rate and the ATP cost of dynamic contraction were significantly lower in hyperoxia than normoxia (P < 0.05). As a result, the ratio of the rate of oxidative ATP synthesis from the quadriceps to V̇o2p was lower in hyperoxia than normoxia but did not reach statistical significance (16 ± 3 mM/ml in normoxia and 12 ± 5 mM/ml in hyperoxia, P = 0.07). Together, these findings reveal dynamic and independent regulations of mitochondrial and contractile efficiency as a consequence of O2 availability in young active individuals. Furthermore, muscle efficiency appears to be already optimized in normoxia and is unlikely to contribute to the well-established improvement in exercise capacity induced by hyperoxia.
    Mots-clés : 31P-magnetic resonance spectroscopy, Adenosine Triphosphate, Adult, Bicycling, crmbm, Electromyography, Energy Metabolism, Exercise, Exercise Tolerance, Female, Humans, Hydrogen-Ion Concentration, Hyperoxia, Isometric Contraction, Lung, Magnetic Resonance Spectroscopy, Male, Mitochondria, Mitochondria, Muscle, msk, muscle efficiency, Muscle energetics, Muscle Fatigue, Muscle Strength, O2 availability, Oxygen Consumption, Quadriceps Muscle, Time Factors.

  • Le Fur, Y & Cozzone, PJ 2015, “Hemi-spectrum substitution after water signal fitting (HESWAF): an improvement of the modulus post-processing of MR spectra”, Magma (New York, N.Y.), vol. 28, no. 1, p. 67-85.
    Résumé : OBJECTIVE: In a previous study, we have shown that modulus post-processing is a simple and efficient tool to both phase correct and frequency align magnetic resonance (MR) spectra automatically. Furthermore, this technique also eliminates sidebands and phase distortions. The advantages of the modulus technique have been illustrated in several applications to brain proton MR spectroscopy. Two possible drawbacks have also been pointed out. The first one is the theoretical decrease in signal-to-noise ratio (SNR) by a factor up to √2 when comparing the spectrum obtained after modulus versus conventional post-processing. The second pitfall results from the symmetrization of the spectrum induced by modulus post-processing, since any resonance or artifact located at the left of the water resonance is duplicated at the right of the water resonance, thus contaminating the region of the spectrum containing the resonances of interest. Herein, we propose a strategy in order to eliminate these two limitations. MATERIALS AND METHODS: Concerning the SNR issue, two complementary approaches are presented here. The first is based on the application of modulus post-processing before spatial apodization, and the second consists in substituting the left half of the spectrum by the fit of the water resonance before applying modulus post-processing. The symmetrization induced by modulus post-processing then combines the right half of the original spectrum containing the resonances of interest with the left half of the water fit, free of noise and artifacts. Consequently, the SNR is improved when compared to modulus post-processing alone. As a bonus, any artifact or resonance present in the left half of the original spectrum is removed. This solves the second limitation. RESULTS: After validation of the technique on simulations, we demonstrated that this improvement of the modulus technique is significantly advantageous for both in vitro and in vivo applications. CONCLUSION: By improving the SNR of the spectra and eliminating eventual contaminations, the new strategies proposed here confer an additional competitive advantage to the modulus post-processing technique.
    Mots-clés : crmbm, snc.

  • Lecocq, A, Le Fur, Y, Amadon, A, Vignaud, A, Cozzone, PJ, Guye, M & Ranjeva, J-P 2015, “Fast water concentration mapping to normalize (1)H MR spectroscopic imaging”, Magma (New York, N.Y.), vol. 28, no. 1, p. 87-100.
    Résumé : OBJECT: To propose a fast and robust acquisition and post-processing pipeline that is time-compatible with clinical explorations to obtain a proton density (ρ) map used as a reference for metabolic map normalization. This allows inter-subject and inter-group comparisons of magnetic resonance spectroscopic imaging (MRSI) data and longitudinal follow-up for single subjects. MATERIALS AND METHODS: A multi-echo T 2 (*) mapping sequence, the XEP sequence for B 1 (+) -mapping and Driven Equilibrium Single Pulse Observation of T 1-an optimized variable flip angle method for T 1 mapping used for both B 1 (-) -mapping and M 0 calculation-were used to determine correction factors leading to quantitative water proton density maps at 3T. Normalized metabolite maps were obtained on a phantom and nine healthy volunteers. To show the potential use of this technique at the individual level, we also explored one patient with low-grade glioma. RESULTS: Accurate ρ maps were obtained both on phantom and volunteers. After signal normalization with the generated ρ maps, metabolic concentrations determined by the present method differed from theory by <7 % in the phantom and were in agreement with data from the literature for the healthy controls. Using these normalized metabolic values, it was possible to demonstrate in the patient with brain glioma, metabolic abnormalities in normalized N-acetyl aspartate, choline and creatine levels; illustrating the potential for direct use of this technique in clinical studies. CONCLUSION: The proposed combination of sequences provides a robust ρ map that can be used to normalize metabolic maps in clinical MRSI studies.
    Mots-clés : crmbm, snc.

  • Lecocq, A, Le Fur, Y, Maudsley, AA, Le Troter, A, Sheriff, S, Sabati, M, Donadieu, M, Confort-Gouny, S, Cozzone, PJ, Guye, M & Ranjeva, J-P 2015, “Whole-brain quantitative mapping of metabolites using short echo three-dimensional proton MRSI”, Journal of magnetic resonance imaging: JMRI, vol. 42, no. 2, p. 280-289.
    Résumé : BACKGROUND: To improve the extent over which whole brain quantitative three-dimensional (3D) magnetic resonance spectroscopic imaging (MRSI) maps can be obtained and be used to explore brain metabolism in a population of healthy volunteers. METHODS: Two short echo time (20 ms) acquisitions of 3D echo planar spectroscopic imaging at two orientations, one in the anterior commissure-posterior commissure (AC-PC) plane and the second tilted in the AC-PC +15° plane were obtained at 3 Tesla in a group of 10 healthy volunteers. B1 (+) , B1 (-) , and B0 correction procedures and normalization of metabolite signals with quantitative water proton density measurements were performed. A combination of the two spatially normalized 3D-MRSI, using a weighted mean based on the pixel wise standard deviation metabolic maps of each orientation obtained from the whole group, provided metabolite maps for each subject allowing regional metabolic profiles of all parcels of the automated anatomical labeling (AAL) atlas to be obtained. RESULTS: The combined metabolite maps derived from the two acquisitions reduced the regional intersubject variance. The numbers of AAL regions showing N-acetyl aspartate (NAA) SD/Mean ratios lower than 30% increased from 17 in the AC-PC orientation and 41 in the AC-PC+15° orientation, to a value of 76 regions of 116 for the combined NAA maps. Quantitatively, regional differences in absolute metabolite concentrations (mM) over the whole brain were depicted such as in the GM of frontal lobes (cNAA  = 10.03 + 1.71; cCho  = 1.78 ± 0.55; cCr  = 7.29 ± 1.69; cmIns  = 5.30 ± 2.67) and in cerebellum (cNAA  = 5.28 ± 1.77; cCho  = 1.60 ± 0.41; cCr  = 6.95 ± 2.15; cmIns  = 3.60 ± 0.74). CONCLUSION: A double-angulation acquisition enables improved metabolic characterization over a wide volume of the brain. J. Magn. Reson. Imaging 2015;42:280-289.
    Mots-clés : crmbm, snc.

  • Prevost, VH, Girard, OM, Callot, V, Cozzone, PJ & Duhamel, G 2015, “Fast imaging strategies for mouse kidney perfusion measurement with pseudocontinuous arterial spin labeling (pCASL) at ultra high magnetic field (11.75 tesla)”, Journal of Magnetic Resonance Imaging, vol. 42, no. 4, p. 999-1008, viewed 5October,2015, .
    Résumé : Background To derive an adapted protocol at ultra high magnetic field for mouse kidney perfusion measurements using pCASL in combination with three widely available fast imaging readouts: segmented SE EPI (sSE EPI), RARE, and TrueFISP. Methods pCASL sSE EPI, pCASL RARE, and pCASL TrueFISP were used for the acquisition of mouse kidney perfusion images in the axial and coronal planes at 11.75T. Results were compared in terms of perfusion sensitivity, signal-to-noise ratio (SNR), blood flow values, intrasession and intersession repeatability, and image quality (subjectively classified into three grades: good, satisfactory, and unacceptable). Results Renal cortex perfusion measurements were performed within 2 min with pCASL RARE/pCASL TrueFISP and 4 min with pCASL sSE EPI. In an axial direction, SNR values of 6.6/5.6/2.8, perfusion sensitivity values of 16.1 ± 3.7/13.6 ± 2.4/13.4 ± 1.0 %, blood flow values of 679 ± 149/466 ± 111/572 ± 46 mL/100 g/min and in-ROI variations values of 192/161/181 mL/100 g/min were obtained with pCASL sSE EPI/pCASL RARE/pCASL TrueFISP. Highest SNR per unit of time (1.8) and highest intra/intersession reliability (92.9% and 95.1%) were obtained with pCASL RARE, which additionally presented highly reproducible satisfactory image quality. In coronal plane, significantly lower SNR, perfusion sensitivity and perfusion values were obtained for all techniques compared with that in the axial plane (P < 0.05) due to magnetization saturation effects. Conclusion pCASL RARE demonstrated more advantages for longitudinal preclinical kidney perfusion studies at ultra high magnetic field. J. Magn. Reson. Imaging 2015;42:999–1008.
    Mots-clés : crmbm, high magnetic field, mouse kidney, Perfusion, pseudocontinuous ASL, RBF, snc.


Journal Article

  • Desrois, M, Piccardo, A, Zogheib, E, Dalmasso, C, Lan, C, Fourré, D, Cozzone, PJ, Caus, T & Bernard, M 2014, “Heart donation after cardiac death: preliminary study on an isolated, perfused Swine heart after 20 minutes of normothermic ischemia”, Transplantation Proceedings, vol. 46, no. 10, p. 3314-3318.
    Résumé : BACKGROUND: We measured the functional and metabolic status of hearts submitted to normothermic ischemia before preservation through the use of an ex vivo pig heart model to assess the feasibility of donation after cardiac death (DCD) in heart transplantation. METHODS: Ten pigs were separated into 2 groups: control (n = 6, brain-dead group) and DCD (n = 4, heart donation after cardiac death). In the control group, hearts were excised 20 minutes after the brachiocephalic trunk cross-clamping and were immediately reperfused. In DCD, hearts were excised 20 minutes after exsanguination and asphyxia, stored in the Centre de Résonance Magnétique Biologique et Médicale (CRMBM) solution for 2 hours, and then were reperfused. Cardioplegic arrest was induced with the use of 1 L of CRMBM solution (4°C) and the heart was reperfused for 60 minutes through the use of an ex vivo perfusion system in Langendorff mode with normothermic autologous blood. During reperfusion, functional parameters were analyzed. Biochemical assays were performed in myocardial effluents and freeze-clamped hearts. RESULTS: No electromechanical activity was found in DCD compared with control. Creatine kinase (CK) was higher at 2 minutes of reperfusion in DCD versus control (P = .005). Adenosine triphosphate was lower in DCD versus control (P = .0019). Malondialdehyde, an oxidative stress index, was present only in DCD. The nitric oxide (NO) pathway was impaired in DCD versus control, with lower eNOS expression (P < .0001) and total nitrate concentration content (P = .04). CONCLUSIONS: We reported no cardiac functional and metabolic recovery in the DCD group after normothermic ischemia and reperfusion, which indicates that a single immersion of the cardiac graft during storage does not provide an optimal protection. New strategies in heart preservation are necessary for recruiting heart donation after cardiac death.
    Mots-clés : crmbm.

  • Desrois, M, Kober, F, Lan, C, Dalmasso, C, Cole, M, Clarke, K, Cozzone, PJ & Bernard, M 2014, “Effect of isoproterenol on myocardial perfusion, function, energy metabolism and nitric oxide pathway in the rat heart – a longitudinal MR study”, NMR in Biomedicine, vol. 27, no. 5, p. 529-538, viewed 20February,2014, .
    Résumé : The chronic administration of the β-adrenoreceptor agonist isoproterenol (IsoP) is used in animals to study the mechanisms of cardiac hypertrophy and failure associated with a sustained increase in circulating catecholamines. Time-dependent changes in myocardial blood flow (MBF), morphological and functional parameters were assessed in rats in vivo using multimodal cardiac MRI. Energy metabolism, oxidative stress and the nitric oxide (NO) pathway were evaluated in isolated perfused rat hearts following 7 days of treatment. Male Wistar rats were infused for 7 days with IsoP or vehicle using osmotic pumps. Cine-MRI and arterial spin labeling were used to determine left ventricular morphology, function and MBF at days 1, 2 and 7 after pump implantation. Isolated hearts were then perfused, and high-energy phosphate compounds and intracellular pH were followed using 31P MRS with simultaneous measurement of contractile function. Total creatine and malondialdehyde (MDA) contents were measured by high-performance liquid chromatography. The NO pathway was evaluated by NO synthase isoform expression and total nitrate concentration (NOx). In IsoP-treated rats, left ventricular mass was increased at day 1 and maintained. Wall thickness was increased with a peak at day 2 and a tendency to return to baseline values at day 7. MBF was markedly increased at day 1 and returned to normal values between days 1 and 2. The rate–pressure product and phosphocreatine/adenosine triphosphate ratio in perfused hearts were reduced. MDA, endothelial NO synthase expression and NOx were increased. Sustained high cardiac function and normal MBF after 24 h of IsoP infusion indicate imbalance between functional demand and blood flow, leading to morphological changes. After 1 week, cardiac hypertrophy and decreased function were associated with impaired phosphocreatine, increased oxidative stress and up-regulation of the NO pathway. These results provide supplemental information on the evolution of the different contributing factors leading to morphological and functional changes in this model of cardiac hypertrophy and failure. Copyright © 2014 John Wiley & Sons, Ltd.
    Mots-clés : cine-MRI, crmbm, Function, Heart, isoproterenol, Metabolism, nitric oxide pathway, Perfusion, rat.

  • Duhamel, G, Prevost, V, Girard, OM, Callot, V & Cozzone, PJ 2014, “High-resolution mouse kidney perfusion imaging by pseudo-continuous arterial spin labeling at 11.75T”, Magnetic Resonance in Medicine, vol. 71, no. 3, p. 1186-1196, viewed 29October,2014, .
    Résumé : Purpose Quantitative measure of blood flow provides important information regarding renal function, nephropathies and viability of kidney transplantation. Therefore, a method that would allow quantitative and reliable assessment of the renal microvascular perfusion would be very valuable. Arterial spin labeling Magnetic Resonance Imaging has started to be widely used for human studies. For rodents though, despite the increasing number of transgenic mouse models, renal perfusion Magnetic Resonance Imaging has been only sparsely reported. This study investigated the use of FAIR (flow-sensitive alternating inversion recovery) and pseudo-continuous arterial spin labeling (pCASL) for mouse renal blood flow measurements. Methods FAIR and pCASL were compared in terms of sensitivity, absolute quantification, reproducibility and flexibility of implementation. Multislice and coronal imaging were also investigated. Studies were performed at 11.75 T with volumic transmitter/receiver radiofrequency coils and fast imaging. Results pCASL demonstrated better experimental flexibility and higher sensitivity compared to FAIR (> +20%). Renal blood flow values in the range of 550–750 mL/100 g/min for the cortex and of 140–230 mL/100 g/min for the medulla, consistent with literature data, were measured. Conclusion pCASL was successfully applied at very high field for mouse renal blood flow measurements, demonstrating high sensitivity, flexibility and multislice imaging capability. pCASL may be considered as a method of choice for mouse kidney perfusion studies. Magn Reson Med 71:1186–1196, 2014. © 2013 Wiley Periodicals, Inc.
    Mots-clés : crmbm, high magnetic field, mouse kidney, Perfusion, pseudo-continuous ASL, RBF.

  • Gineste, C, Ottenheijm, C, Le Fur, Y, Banzet, S, Pecchi, E, Vilmen, C, Cozzone, PJ, Koulmann, N, Hardeman, EC, Bendahan, D & Gondin, J 2014, “Alterations at the cross-bridge level are associated with a paradoxical gain of muscle function in vivo in a mouse model of nemaline myopathy”, PloS One, vol. 9, no. 9, p. e109066.
    Résumé : Nemaline myopathy is the most common disease entity among non-dystrophic skeletal muscle congenital diseases. The first disease causing mutation (Met9Arg) was identified in the gene encoding α-tropomyosinslow gene (TPM3). Considering the conflicting findings of the previous studies on the transgenic (Tg) mice carrying the TPM3Met9Arg mutation, we investigated carefully the effect of the Met9Arg mutation in 8-9 month-old Tg(TPM3)Met9Arg mice on muscle function using a multiscale methodological approach including skinned muscle fibers analysis and in vivo investigations by magnetic resonance imaging and 31-phosphorus magnetic resonance spectroscopy. While in vitro maximal force production was reduced in Tg(TPM3)Met9Arg mice as compared to controls, in vivo measurements revealed an improved mechanical performance in the transgenic mice as compared to the former. The reduced in vitro muscle force might be related to alterations occuring at the cross-bridges level with muscle-specific underlying mechanisms. In vivo muscle improvement was not associated with any changes in either muscle volume or energy metabolism. Our findings indicate that TPM3(Met9Arg) mutation leads to a mild muscle weakness in vitro related to an alteration at the cross-bridges level and a paradoxical gain of muscle function in vivo. These results clearly point out that in vitro alterations are muscle-dependent and do not necessarily translate into similar changes in vivo.
    Mots-clés : crmbm.

  • Gondin, J, Vilmen, C, Cozzone, PJ, Bendahan, D & Duhamel, G 2014, “High-field (11.75T) multimodal MR imaging of exercising hindlimb mouse muscles using a non-invasive combined stimulation and force measurement device”, NMR in biomedicine, vol. 27, no. 8, p. 870-879.
    Résumé : We have designed and constructed an experimental set-up allowing electrical stimulation of hindlimb mouse muscles and the corresponding force measurements at high-field (11.75T). We performed high-resolution multimodal MRI (including T2 -weighted imaging, angiography and diffusion) and analysed the corresponding MRI changes in response to a stimulation protocol. Mice were tested twice over a 1-week period to investigate the reliability of mechanical measurements and T2 changes associated with the stimulation protocol. Additionally, angiographic images were obtained before and immediately after the stimulation protocol. Finally, multislice diffusion imaging was performed before, during and immediately after the stimulation session. Apparent diffusion coefficient (ADC) maps were calculated on the basis of diffusion weighted images (DWI). Both force production and T2 values were highly reproducible as illustrated by the low coefficient of variation (<8%) and high intraclass correlation coefficient (≥0.75) values. Maximum intensity projection angiographic images clearly showed a strong vascular effect resulting from the stimulation protocol. Although a motion sensitive imaging sequence was used (echo planar imaging) and in spite of the strong muscle contractions, motion artifacts were minimal for DWI recorded under exercising conditions, thereby underlining the robustness of the measurements. Mean ADC values increased under exercising conditions and were higher during the recovery period as compared with the corresponding control values. The proposed experimental approach demonstrates accurate high-field multimodal MRI muscle investigations at a preclinical level which is of interest for monitoring the severity and/or the progression of neuromuscular diseases but also for assessing the efficacy of potential therapeutic interventions.
    Mots-clés : crmbm.

  • Grapperon, A-M, Verschueren, A, Duclos, Y, Confort-Gouny, S, Soulier, E, Loundou, AD, Guye, M, Cozzone, PJ, Pouget, J, Ranjeva, J-P & Attarian, S 2014, “Association between structural and functional corticospinal involvement in amyotrophic lateral sclerosis assessed by diffusion tensor MRI and triple stimulation technique”, Muscle & Nerve, vol. 49, no. 4, p. 551-557, viewed 29October,2014, .
    Résumé : Introduction: We investigated the functional and structural integrity of the corticospinal tract (CST) using diffusion tensor imaging (DTI) and the triple stimulation technique (TST) in patients with amyotrophic lateral sclerosis (ALS). Methods: Fourteen patients with ALS, 13 healthy controls (HCs), and 6 patients with lower motor neuron (LMN) syndrome underwent DTI and TST. Results: The mean diffusivity was higher in ALS patients than HCs (P < 0.01). The TST ratio was lower in ALS patients compared with HCs (P < 0.001) and in LMN patients compared with HCs (P < 0.05). The increase in the mean diffusivity was correlated with the decrease in the TST ratio (P < 0.01). Conclusions: Significant correlations exist between the DTI and TST results, indicating both structural and functional involvement of the CST in patients with ALS. Muscle Nerve 49:551–557, 2014
    Mots-clés : Adult, Aged, Amyotrophic Lateral Sclerosis, brain MRI, Diffusion Magnetic Resonance Imaging, diffusion tensor imaging, Female, Humans, Male, Middle Aged, Pyramidal Tracts, Transcranial Magnetic Stimulation, triple stimulation technique.

  • Le Fur, Y & Cozzone, PJ 2014, “FID modulus: a simple and efficient technique to phase and align MR spectra”, Magnetic Resonance Materials in Physics, Biology and Medicine, vol. 27, no. 2, p. 131-148, viewed 29October,2014, .
    Résumé : Object The post-processing of MR spectroscopic data requires several steps more or less easy to automate, including the phase correction and the chemical shift assignment. First, since the absolute phase is unknown, one of the difficulties the MR spectroscopist has to face is the determination of the correct phase correction. When only a few spectra have to be processed, this is usually performed manually. However, this correction needs to be automated as soon as a large number of spectra is involved, like in the case of phase coherent averaging or when the signals collected with phased array coils have to be combined. A second post-processing requirement is the frequency axis assignment. In standard mono-voxel MR spectroscopy, this can also be easily performed manually, by simply assigning a frequency value to a well-known resonance (e.g. the water or NAA resonance in the case of brain spectroscopy). However, when the correction of a frequency shift is required before averaging a large amount of spectra (due to B 0 spatial inhomogeneities in chemical shift imaging, or resulting from motion for example), this post-processing definitely needs to be performed automatically. Materials and methods Zero-order phase and frequency shift of a MR spectrum are linked respectively to zero-order and first-order phase variations in the corresponding free induction decay (FID) signal. One of the simplest ways to remove the phase component of a signal is to calculate the modulus of this signal: this approach is the basis of the correction technique presented here. Results We show that selecting the modulus of the FID allows, under certain conditions that are detailed, to automatically phase correct and frequency align the spectra. This correction technique can be for example applied to the summation of signals acquired from combined phased array coils, to phase coherent averaging and to B 0 shift correction. Conclusion We demonstrate that working on the modulus of the FID signal is a simple and efficient way to both phase correct and frequency align MR spectra automatically. This approach is particularly well suited to brain proton MR spectroscopy.
    Mots-clés : Biomedical Engineering, Computer Appl. in Life Sciences, crmbm, Free induction decay, Frequency assignment, Health Informatics, Imaging / Radiology, Modulus, MR spectroscopy, Phase correction, Post-processing, Solid State Physics.

  • Lutz, NW, Béraud, E & Cozzone, PJ 2014, “Metabolomic Analysis of Rat Brain by High Resolution Nuclear Magnetic Resonance Spectroscopy of Tissue Extracts”, Journal of Visualized Experiments, no. 91, p. e51829, viewed 7January,2015, .

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

  • Ratel, S, Tonson, A, Cozzone, PJ & Bendahan, D 2014, “The rate of PCr resynthesis is not a reliable index of skeletal muscle oxidative capacity”, European Journal of Applied Physiology, vol. 114, no. 1, p. 217-218, viewed 29October,2014, .
    Résumé : Dear Editor,We have read with much interest the paper recently published by Kappenstein et al. (2013) regarding changes in phosphocreatine concentration in skeletal muscle of children and adults during high-intensity intermittent exercise. Although the results of this investigation are of potential interest, we are actually concerned about the utilization of the time constant of PCr recovery (τPCr) as a simple index of mitochondrial function and the corresponding interpretation regarding borderline differences in τPCr values between children and adults.In their paper, Kappenstein et al. (2013) reported lower τPCr values in children, which became statistically significant when the smallest and highest values were eliminated. Although the authors mentioned that the borderline difference in τPCr values between children and adults might be attributed to a temporary inhibition of oxidative phosphorylation in adults during the early post-exercise recovery period, they did not take into accou ...
    Mots-clés : crmbm, Human Physiology, Occupational Medicine/Industrial Medicine, Sports Medicine.


Conference Paper
  • Leporq, B, Le Troter, A, Le Fur, Y, Salort-Campana, E, Cozzone, P, Beuf, O & Bendahan, D 2013, “Combination of a Fat Volume Fraction Quantification Method with a Dedicated Automatic Segmentation Algorithm for Simultaneous Measurement of Infiltrated Fatty Tissue Fraction and Muscle Relaxation Times.”, in, Salt Lake City, Utah, USA.
    Résumé : Due to its sensitivity to key processes in the diseased muscle such oedema, inflammation and fatty infiltration, MRI is emerging as a suitable quantitative method which could provide reliable surrogate markers of disease severity and progression. This work investigates the feasibility of a method to distinguish IMAT and SCAT, (ii) to measure muscle relaxation times (T1 andT2*) and to quantify the infiltrated fatty tissue fraction (IFTF) simultaneously. Our approach includes a magnitude-based fat volume fraction quantification method based on multiple-echo multiple angle acquisition with a dedicated automatic segmentation algorithm.
Journal Article

  • Capron, T, Troalen, T, Cozzone, PJ, Bernard, M & Kober, F 2013, “Cine-ASL: a steady-pulsed arterial spin labeling method for myocardial perfusion mapping in mice. Part II. Theoretical model and sensitivity optimization”, Magnetic Resonance in Medicine, vol. 70, no. 5, p. 1399-1408.
    Résumé : In small rodent myocardial perfusion studies, the most widely used method is based on Look-Locker measurements of the magnetization recovery after FAIR preparation, which bears limitations regarding acquisition efficiency due to the pulsed arterial spin labeling nature of the sequence. To improve efficiency, this two-article set proposes a new steady-pulsed arterial spin labeling scheme using a cine readout incorporating one tagging pulse per heart cycle. In this part, we derive a theoretical description of the magnetization time evolution in such a scheme. The combination of steady-pulsed labeling and cine readout drives tissue magnetization into a stationary regime that explicitly depends on perfusion. In comparison with dedicated experiments on the mouse heart, the model is discussed and validated for perfusion quantification. The model predicts that in this regime, signal is independent of irregular dynamics occurring during acquisition, such as heart rate variations or arterial input function. Optimization of the sequence offers the possibility to increase the signal to noise ratio by efficient signal averaging. The sensitivity of this new method is shown to be more than three times larger than previously used techniques.
    Mots-clés : crmbm.

  • Fellah, S, Caudal, D, De Paula, AM, Dory-Lautrec, P, Figarella-Branger, D, Chinot, O, Metellus, P, Cozzone, PJ, Confort-Gouny, S, Ghattas, B, Callot, V & Girard, N 2013, “Multimodal MR imaging (diffusion, perfusion, and spectroscopy): is it possible to distinguish oligodendroglial tumor grade and 1p/19q codeletion in the pretherapeutic diagnosis?”, AJNR. American journal of neuroradiology, vol. 34, no. 7, p. 1326-1333.
    Résumé : BACKGROUND AND PURPOSE: Pretherapeutic determination of tumor grade and genotype in grade II and III oligodendroglial tumors is clinically important but is still challenging. Tumor grade and 1p/19q status are currently the 2 most important factors in therapeutic decision making for patients with these tumors. Histopathology and cMRI studies are still limited in some cases. In the present study, we were interested in determining whether the combination of PWI, DWI, and MR spectroscopy could help distinguish oligodendroglial tumors according to their histopathologic grade and genotype. MATERIALS AND METHODS: We retrospectively reviewed 50 adult patients with grade II and III oligodendrogliomas and oligoastrocytomas who had DWI, PWI, and MR spectroscopy at short and long TE data and known 1p/19q status. Univariate analyses and multivariate random forest models were performed to determine which criteria could differentiate between grades and genotypes. RESULTS: ADC, rCBV, rCBF, and rK2 were significantly different between grade II and III oligodendroglial tumors. DWI, PWI, and MR spectroscopy showed no significant difference between tumors with and without 1p/19q loss. Separation between tumor grades and genotypes with cMRI alone showed 31% and 48% misclassification rates, respectively. Multimodal MR imaging helps to determine tumor grade and 1p/19q genotype more accurately (misclassification rates of 17% and 40%, respectively). CONCLUSIONS: Although multimodal investigation of oligodendroglial tumors has a lower contribution to 1p/19q genotyping compared with cMRI alone, it greatly improves the accuracy of grading of these neoplasms. Use of multimodal MR imaging could thus provide valuable information that may assist clinicians in patient preoperative management and treatment decision making.
    Mots-clés : Adolescent, Adult, Aged, Aged, 80 and over, Astrocytoma, Brain Neoplasms, Cerebral Cortex, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 19, Contrast Media, crmbm, Diagnosis, Differential, Diffusion Magnetic Resonance Imaging, Female, Frontal Lobe, Genotype, Humans, Image Enhancement, Image Processing, Computer-Assisted, Magnetic Resonance Angiography, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Male, Middle Aged, Neoplasm Grading, Oligodendroglioma, Retrospective Studies, Sequence Deletion, Temporal Lobe, Young Adult.

  • Gineste, C, De Winter, JM, Kohl, C, Witt, CC, Giannesini, B, Brohm, K, Le Fur, Y, Gretz, N, Vilmen, C, Pecchi, E, Jubeau, M, Cozzone, PJ, Stienen, GJM, Granzier, H, Labeit, S, Ottenheijm, CAC, Bendahan, D & Gondin, J 2013, “In vivo and in vitro investigations of heterozygous nebulin knock-out mice disclose a mild skeletal muscle phenotype”, Neuromuscular disorders: NMD, vol. 23, no. 4, p. 357-369.
    Résumé : Nemaline myopathy is the most common congenital skeletal muscle disease, and mutations in the nebulin gene account for 50% of all cases. Recent studies suggest that the disease severity might be related to the nebulin expression levels. Considering that mutations in the nebulin gene are typically recessive, one would expect that a single functional nebulin allele would maintain nebulin protein expression which would result in preserved skeletal muscle function. We investigated skeletal muscle function of heterozygous nebulin knock-out (i.e., nebulin(+/-)) mice using a multidisciplinary approach including protein and gene expression analysis and combined in vivo and in vitro force measurements. Skeletal muscle anatomy and energy metabolism were studied strictly non-invasively using magnetic resonance imaging and 31P-magnetic resonance spectroscopy. Maximal force production was reduced by around 16% in isolated muscle of nebulin(+/-) mice while in vivo force generating capacity was preserved. Muscle weakness was associated with a shift toward a slower proteomic phenotype, but was not related to nebulin protein deficiency or to an impaired energy metabolism. Further studies would be warranted in order to determine the mechanisms leading to a mild skeletal muscle phenotype resulting from the expression of a single nebulin allele.
    Mots-clés : Animals, crmbm, Disease Models, Animal, Gene Expression, Heterozygote, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Male, Mice, Mice, Knockout, Muscle Proteins, Muscle Strength, Muscle Weakness, Muscle, Skeletal, Mutation, Myopathies, Nemaline, Phenotype, Severity of Illness Index.
    Note Note
    The following values have no corresponding Zotero field:<br />Author Address: Aix-Marseille Universite, CRMBM, 13005 Marseille, France; CNRS, Centre de Resonance Magnetique Biologique et Medicale (CRMBM), 13005 Marseille, France.<br />C2 - Muscle <br />ET - 2013/02/05<br />
    Note Note
    <p>Gineste, C<br/>De Winter, J M<br/>Kohl, C<br/>Witt, C C<br/>Giannesini, B<br/>Brohm, K<br/>Le Fur, Y<br/>Gretz, N<br/>Vilmen, C<br/>Pecchi, E<br/>Jubeau, M<br/>Cozzone, P J<br/>Stienen, G J M<br/>Granzier, H<br/>Labeit, S<br/>Ottenheijm, C A C<br/>Bendahan, D<br/>Gondin, J<br/>England<br/>Neuromuscular disorders : NMD<br/>Neuromuscul Disord. 2013 Apr;23(4):357-69. doi: 10.1016/j.nmd.2012.12.011. Epub 2013 Feb 1.</p>

  • Gineste, C, Duhamel, G, Le Fur, Y, Vilmen, C, Cozzone, PJ, Nowak, KJ, Bendahan, D & Gondin, J 2013, “Multimodal MRI and (31)P-MRS Investigations of the ACTA1(Asp286Gly) Mouse Model of Nemaline Myopathy Provide Evidence of Impaired In Vivo Muscle Function, Altered Muscle Structure and Disturbed Energy Metabolism”, PloS one, vol. 8, no. 8, p. e72294.
    Résumé : Nemaline myopathy (NM), the most common non-dystrophic congenital disease of skeletal muscle, can be caused by mutations in the skeletal muscle α-actin gene (ACTA1) (~25% of all NM cases and up to 50% of severe forms of NM). Muscle function of the recently generated transgenic mouse model carrying the human Asp286Gly mutation in the ACTA1 gene (Tg(ACTA1)(Asp286Gly)) has been mainly investigated in vitro. Therefore, we aimed at providing a comprehensive picture of the in vivo hindlimb muscle function of Tg(ACTA1)(Asp286Gly) mice by combining strictly noninvasive investigations. Skeletal muscle anatomy (hindlimb muscles, intramuscular fat volumes) and microstructure were studied using multimodal magnetic resonance imaging (Dixon, T2, Diffusion Tensor Imaging [DTI]). Energy metabolism was studied using 31-phosphorus Magnetic Resonance Spectroscopy ((31)P-MRS). Skeletal muscle contractile performance was investigated while applying a force-frequency protocol (1-150 Hz) and a fatigue protocol (6 min-1.7 Hz). Tg(ACTA1)(Asp286Gly) mice showed a mild muscle weakness as illustrated by the reduction of both absolute (30%) and specific (15%) maximal force production. Dixon MRI did not show discernable fatty infiltration in Tg(ACTA1)(Asp286Gly) mice indicating that this mouse model does not reproduce human MRI findings. Increased T2 values were observed in Tg(ACTA1)(Asp286Gly) mice and might reflect the occurrence of muscle degeneration/regeneration process. Interestingly, T2 values were linearly related to muscle weakness. DTI experiments indicated lower λ2 and λ3 values in Tg(ACTA1)(Asp286Gly) mice, which might be associated to muscle atrophy and/or the presence of histological anomalies. Finally (31)P-MRS investigations illustrated an increased anaerobic energy cost of contraction in Tg(ACTA1)(Asp286Gly) mice, which might be ascribed to contractile and non-contractile processes. Overall, we provide a unique set of information about the anatomic, metabolic and functional consequences of the Asp286Gly mutation that might be considered as relevant biomarkers for monitoring the severity and/or the progression of NM and for assessing the efficacy of potential therapeutic interventions.
    Mots-clés : crmbm.

  • Gineste, C, Le Fur, Y, Vilmen, C, Le Troter, A, Pecchi, E, Cozzone, PJ, Hardeman, EC, Bendahan, D & Gondin, J 2013, “Combined MRI and (31)P-MRS Investigations of the ACTA1(H40Y) Mouse Model of Nemaline Myopathy Show Impaired Muscle Function and Altered Energy Metabolism”, PloS one, vol. 8, no. 4, p. e61517.
    Résumé : Nemaline myopathy (NM) is the most common disease entity among non-dystrophic skeletal muscle congenital diseases. Mutations in the skeletal muscle α-actin gene (ACTA1) account for ∼25% of all NM cases and are the most frequent cause of severe forms of NM. So far, the mechanisms underlying muscle weakness in NM patients remain unclear. Additionally, recent Magnetic Resonance Imaging (MRI) studies reported a progressive fatty infiltration of skeletal muscle with a specific muscle involvement in patients with ACTA1 mutations. We investigated strictly noninvasively the gastrocnemius muscle function of a mouse model carrying a mutation in the ACTA1 gene (H40Y). Skeletal muscle anatomy (hindlimb muscles and fat volumes) and energy metabolism were studied using MRI and (31)Phosphorus magnetic resonance spectroscopy. Skeletal muscle contractile performance was investigated while applying a force-frequency protocol (from 1-150 Hz) and a fatigue protocol (80 stimuli at 40 Hz). H40Y mice showed a reduction of both absolute (-40%) and specific (-25%) maximal force production as compared to controls. Interestingly, muscle weakness was associated with an improved resistance to fatigue (+40%) and an increased energy cost. On the contrary, the force frequency relationship was not modified in H40Y mice and the extent of fatty infiltration was minor and not different from the WT group. We concluded that the H40Y mouse model does not reproduce human MRI findings but shows a severe muscle weakness which might be related to an alteration of intrinsic muscular properties. The increased energy cost in H40Y mice might be related to either an impaired mitochondrial function or an alteration at the cross-bridges level. Overall, we provided a unique set of anatomic, metabolic and functional biomarkers that might be relevant for monitoring the progression of NM disease but also for assessing the efficacy of potential therapeutic interventions at a preclinical level.
    Mots-clés : Actins, Animals, crmbm, Energy Metabolism, Female, Magnetic Resonance Imaging, Mice, Mice, Mutant Strains, Muscle, Skeletal, Myopathies, Nemaline.

  • Layec, G, Malucelli, E, Le Fur, Y, Manners, D, Yashiro, K, Testa, C, Cozzone, PJ, Iotti, S & Bendahan, D 2013, “Effects of exercise-induced intracellular acidosis on the phosphocreatine recovery kinetics: a 31P MRS study in three muscle groups in humans”, NMR in Biomedicine, vol. 26, no. 11, p. 1403-1411, viewed 29October,2014, .
    Résumé : Little is known about the metabolic differences that exist among different muscle groups within the same subjects. Therefore, we used 31P-magnetic resonance spectroscopy (31P-MRS) to investigate muscle oxidative capacity and the potential effects of pH on PCr recovery kinetics between muscles of different phenotypes (quadriceps (Q), finger (FF) and plantar flexors (PF)) in the same cohort of 16 untrained adults. The estimated muscle oxidative capacity was lower in Q (29 ± 12 mM min-1, CVinter-subject = 42%) as compared with PF (46 ± 20 mM min-1, CVinter-subject = 44%) and tended to be higher in FF (43 ± 35 mM min-1, CVinter-subject = 80%). The coefficient of variation (CV) of oxidative capacity between muscles within the group was 59 ± 24%. PCr recovery time constant was correlated with end-exercise pH in Q (p < 0.01), FF (p < 0.05) and PF (p <0.05) as well as proton efflux rate in FF (p < 0.01), PF (p < 0.01) and Q (p = 0.12). We also observed a steeper slope of the relationship between end-exercise acidosis and PCr recovery kinetics in FF compared with either PF or Q muscles. Overall, this study supports the concept of skeletal muscle heterogeneity by revealing a comparable inter- and intra-individual variability in oxidative capacity across three skeletal muscles in untrained individuals. These findings also indicate that the sensitivity of mitochondrial respiration to the inhibition associated with cytosolic acidosis is greater in the finger flexor muscles compared with locomotor muscles, which might be related to differences in permeability in the mitochondrial membrane and, to some extent, to proton efflux rates. Copyright © 2013 John Wiley & Sons, Ltd.
    Mots-clés : crmbm, Exercise, Magnetic Resonance Spectroscopy, mitochondrial function, muscle acidosis, muscle oxidative capacity, skeletal muscle.
    Attachment Full Text PDF 264.9 kb (source)

  • Lutz, NW, Fernandez, C, Pellissier, J-F, Cozzone, PJ & Béraud, E 2013, “Cerebral biochemical pathways in experimental autoimmune encephalomyelitis and adjuvant arthritis: a comparative metabolomic study”, PloS one, vol. 8, no. 2, p. e56101.
    Résumé : Many diseases, including brain disorders, are associated with perturbations of tissue metabolism. However, an often overlooked issue is the impact that inflammations outside the brain may have on brain metabolism. Our main goal was to study similarities and differences between brain metabolite profiles of animals suffering from experimental autoimmune encephalomyelitis (EAE) and adjuvant arthritis (AA) in Lewis rat models. Our principal objective was the determination of molecular protagonists involved in the metabolism underlying these diseases. EAE was induced by intraplantar injection of complete Freund's adjuvant (CFA) and spinal-cord homogenate (SC-H), whereas AA was induced by CFA only. Naive rats served as controls (n = 9 for each group). Two weeks after inoculation, animals were sacrificed, and brains were removed and processed for metabolomic analysis by NMR spectroscopy or for immunohistochemistry. Interestingly, both inflammatory diseases caused similar, though not identical, changes in metabolites involved in regulation of brain cell size and membrane production: among the osmolytes, taurine and the neuronal marker, N-acetylaspartate, were decreased, and the astrocyte marker, myo-inositol, slightly increased in both inoculated groups compared with controls. Also ethanolamine-containing phospholipids, sources of inflammatory agents, and several glycolytic metabolites were increased in both inoculated groups. By contrast, the amino acids, aspartate and isoleucine, were less concentrated in CFA/SC-H and control vs. CFA rats. Our results suggest that inflammatory brain metabolite profiles may indicate the existence of either cerebral (EAE) or extra-cerebral (AA) inflammation. These inflammatory processes may act through distinct pathways that converge toward similar brain metabolic profiles. Our findings open new avenues for future studies aimed at demonstrating whether brain metabolic effects provoked by AA are pain/stress-mediated and/or due to the presence of systemic proinflammatory molecules. Regardless of the nature of these mechanisms, our findings may be of interest for future clinical studies, e.g. by in-vivo magnetic resonance spectroscopy.
    Mots-clés : Animals, Arthritis, Experimental, Brain, crmbm, Encephalomyelitis, Autoimmune, Experimental, Female, Freund's Adjuvant, Metabolic Networks and Pathways, Metabolomics, Phospholipids, Rats, Rats, Inbred Lew, Spinal cord, Water.

  • Lutz, NW, Fur, YL, Chiche, J, Pouysségur, J & Cozzone, PJ 2013, “Quantitative In Vivo Characterization of Intracellular and Extracellular pH Profiles in Heterogeneous Tumors: A Novel Method Enabling Multiparametric pH Analysis”, Cancer Research, vol. 73, no. 15, p. 4616-4628, viewed 6January,2015, .
    Résumé : Acid production and transport are currently being studied to identify new targets for efficient cancer treatment, as subpopulations of tumor cells frequently escape conventional therapy owing to their particularly acidic tumor microenvironment. Heterogeneity in intracellular and extracellular tumor pH (pHi, pHe) has been reported, but none of the methods currently available for measuring tissue pH provides quantitative parameters characterizing pH distribution profiles in tissues. To this intent, we present here a multiparametric, noninvasive approach based on in vivo 31P nuclear magnetic resonance (NMR) spectroscopy and its application to mouse tumor xenografts. First, localized 31P NMR spectrum signals of pHi and pHe reporter molecules [inorganic phosphate (Pi) and 3-aminopropylphosphonate (3-APP), respectively] were transformed into pH curves using established algorithms. Although Pi is an endogenous compound, 3-APP had to be injected intraperitoneally. Then, we developed algorithms for the calculation of six to eight quantitative pH parameters from the digital points of each pH curve obtained. For this purpose, each pH distribution profile was approximated as a histogram, and intensities were corrected for the nonlinearity between chemical-shift and pH. Cancer Res; 73(15); 4616–28. ©2013 AACR
    Mots-clés : Animals, Cricetinae, crmbm, Hydrogen-Ion Concentration, Magnetic Resonance Spectroscopy, Mice, Neoplasms, Experimental, Xenograft Model Antitumor Assays.
    Attachment Full Text PDF 2.1 Mb (source)
    Attachment Full Text PDF 2.1 Mb (source)
  • Moll, N, Reuter, F, Zaaraoui, W, Rico, A, Malikova, I, Crespy, L, Faivre, A, Loundou, A, Auquier, P, Cozzone, P, Ranjeva, JP, Audoin, B & Pelletier, J 2013, “T2 Lesion Load Influences Cognitive Impairment at the Early Phase of MS”, Neurology, vol. 80.

  • Tachrount, M, Duhamel, G, Laurin, J, Marqueste, T, de Paula, AM, Decherchi, P, Cozzone, PJ & Callot, V 2013, “In vivo short TE localized (1) H MR spectroscopy of mouse cervical spinal cord at very high magnetic field (11.75 T)”, Magnetic resonance in medicine, vol. 69, no. 5, p. 1226-1232.
    Résumé : MR spectroscopy allows a noninvasive assessment of metabolic information in healthy and pathological central nervous system. Whereas MR spectroscopy has been extensively applied in the brain, only few spectroscopic studies of the spinal cord (SC) have been performed so far. For mice, due to additional technical challenges, in vivo (1) H SC MRS has not yet been reported. In this work, the feasibility of short echo time localized proton magnetic resonance spectroscopy using Point RESolved Spectroscopy sequence for the examination of mouse cervical SC at 11.75 T is presented. Several optimizations were performed to improve the static field homogeneity, to reduce physiological motion effects and lipid contaminations arising from SC surrounding tissues, and to provide a careful metabolic quantification. Satisfactory spectrum quality was obtained. The described protocol allowed reliable quantification of five metabolites in the cervical SC. The mean reproducibility regarding the quantification of tNAA, tCr and tCho was ≥ 80%, > 70% for mI and > 55% for Glu, whereas the intersubject variabilities were ≤ 21%. The application of this protocol to transgenic mouse models in pathological conditions such as SC injury or neurodegenerative diseases may thus provide complementary information to MRI and increase our understanding of such pathologies. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.
    Mots-clés : Algorithms, Animals, Cervical Vertebrae, crmbm, Magnetic Resonance Spectroscopy, Male, Mice, Mice, Inbred C57BL, Protons, Reproducibility of Results, Sensitivity and Specificity, Spinal cord, Tissue Distribution.

  • Troalen, T, Capron, T, Cozzone, PJ, Bernard, M & Kober, F 2013, “Cine-ASL: a steady-pulsed arterial spin labeling method for myocardial perfusion mapping in mice. Part I. Experimental study”, Magnetic Resonance in Medicine, vol. 70, no. 5, p. 1389-1398.
    Résumé : Arterial spin labeling has been developed and used for the quantitative and completely noninvasive assessment of myocardial perfusion in vivo. Here we propose a novel arterial spin labeling method called cine-ASL, which is based on an electrocardiogram-gated steady-pulsed labeling approach combined with simultaneous readout over the cardiac cycle using cine-fast low-angle shot. This method led to shorter acquisition times than the previously used Look-Locker flow-sensitive alternating inversion recovery gradient-echo technique while preserving spatial resolution and robustness with respect to cardiac motion. High resolution perfusion mapping (in-plane resolution = 195 μm × 391 μm) was carried out with both techniques at 4.7 T in a group of 14 healthy mice. Mean perfusion values were 5.0 ± 0.8 mL g(-1) min(-1) with cine-ASL and 5.9 ± 1.4 mL g(-1) min(-1) with Look-Locker flow-sensitive alternating inversion recovery. In one animal, physiological stress was induced with higher anesthetic concentration to evaluate the response of both methods under vasodilation. Global myocardial perfusion increased from 5.6 to 16.0 mL g(-1) min(-1) with cine-ASL and from 6.3 to 18.7 mL g(-1) min(-1) with Look-Locker flow-sensitive alternating inversion recovery. Although this original scheme requires a separate T1 measurement to be fully quantitative, it improves arterial spin labeling sensitivity while maintaining compatibility with motion constraints in cardiac MRI in small rodents.
    Mots-clés : crmbm.


Book Section
Journal Article

  • Barbeau, EJ, Didic, M, Joubert, S, Guedj, E, Koric, L, Felician, O, Ranjeva, J-P, Cozzone, P & Ceccaldi, M 2012, “Extent and neural basis of semantic memory impairment in mild cognitive impairment”, Journal of Alzheimer's disease: JAD, vol. 28, no. 4, p. 823-837.
    Résumé : An increasing number of studies indicate that semantic memory is impaired in mild cognitive impairment (MCI). However, the extent and the neural basis of this impairment remain unknown. The aim of the present study was: 1) to evaluate whether all or only a subset of semantic domains are impaired in MCI patients; and 2) to assess the neural substrate of the semantic impairment in MCI patients using voxel-based analysis of MR grey matter density and SPECT perfusion. 29 predominantly amnestic MCI patients and 29 matched control subjects participated in this study. All subjects underwent a full neuropsychological assessment, along with a battery of five tests evaluating different domains of semantic memory. A semantic memory composite Z-score was established on the basis of this battery and was correlated with MRI grey matter density and SPECT perfusion measures. MCI patients were found to have significantly impaired performance across all semantic tasks, in addition to their anterograde memory deficit. Moreover, no temporal gradient was found for famous faces or famous public events and knowledge for the most remote decades was also impaired. Neuroimaging analyses revealed correlations between semantic knowledge and perirhinal/entorhinal areas as well as the anterior hippocampus. Therefore, the deficits in the realm of semantic memory in patients with MCI is more widespread than previously thought and related to dysfunction of brain areas beyond the limbic-diencephalic system involved in episodic memory. The severity of the semantic impairment may indicate a decline of semantic memory that began many years before the patients first consulted.
    Mots-clés : Aged, Aged, 80 and over, Case-Control Studies, Cerebral Cortex, Female, Follow-Up Studies, Humans, Longitudinal Studies, Male, Memory Disorders, Memory, Long-Term, Middle Aged, Mild cognitive impairment, Neuropsychological Tests, Photic Stimulation, Semantics.

  • Bartoli, MA, Kober, F, Cozzone, P, Thompson, RW, Alessi, MC & Bernard, M 2012, “In vivo assessment of murine elastase-induced abdominal aortic aneurysm with high resolution magnetic resonance imaging”, European journal of vascular and endovascular surgery: the official journal of the European Society for Vascular Surgery, vol. 44, no. 5, p. 475-481.
    Résumé : OBJECTIVES: There are, to date, no published non-invasive or longitudinal studies performed in mice to measure aortic diameter and wall thickness in an elastase-induced abdominal aortic aneurysm. This MRI study at 11.75 T aimed at evaluating the reliability of longitudinal in vivo aortic diameter and wall thickness measurements in this particular model. METHODS: Adult male C57BL/6 mice underwent transient elastase or heat-inactivated elastase perfusion (controls). Aortic dilatation was measured before, during and immediately after elastase perfusion, and again 14 days after, with a calibrated ocular grid. MRI was performed just before initial surgery and at day 14 before harvest using an 11.75 T MR microscopy imager. RESULTS: Aortic diameter was significantly greater in elastase-perfused mice compared to controls as measured by optic grid (1.150 ± 0.153 mm vs 0.939 ± 0.07 mm, P = 0.038) and according to MRI measurement of the outer diameter on spin echo images (1.203 ± 0.105 mm vs 1070 ± 0.048 mm, P = 0.0067). Aortic wall thickness was found to be significantly increased in elastase-perfused mice at day 14. CONCLUSIONS: This study demonstrates in the mouse elastase-induced aneurysm model that characterization of aneurysm development by its inner and outer vessel diameter and vessel wall thickness can be carried out longitudinally using high resolution MRI without significant mortality.
    Mots-clés : AAA, Animals, Aorta, Abdominal, Aortic Aneurysm, Abdominal, crmbm, Dilatation, Pathologic, Disease Models, Animal, High resolution MRI, Magnetic Resonance Imaging, Male, Mice, Mice, Inbred C57BL, Murine elastase-induced abdominal aortic aneurysm, Pancreatic Elastase, Time Factors.

  • Bun, S-S, Kober, F, Jacquier, A, Espinosa, L, Kalifa, J, Bonzi, M-F, Kopp, F, Lalevee, N, Zaffran, S, Deharo, J-C, Cozzone, PJ & Bernard, M 2012, “Value of in vivo T2 measurement for myocardial fibrosis assessment in diabetic mice at 11.75 T”, Investigative radiology, vol. 47, no. 5, p. 319-323.
    Résumé : OBJECTIVE: The aim of the study was to assess the value of in vivo T2 measurements to noninvasively quantify myocardial fibrosis in diabetic mice at 11.75 T. Diabetic cardiomyopathy is characterized by extracellular matrix alteration and microcirculation impairment. These conditions might provide electrical heterogeneity, which is a substrate for arrhythmogenesis. T1 mapping has been proposed to quantify diffuse myocardial fibrosis in cardiac diseases but has several limitations. T2 measurement may represent an alternative for fibrosis quantification at high magnetic field. MATERIALS AND METHODS: A magnetic resonance imaging protocol including in vivo T2 measurements at 11.75 T was performed in 9 male C57BL/6J mice after 8 weeks of streptozotocin-induced diabetes and in 9 control mice. Programmed ventricular stimulation was performed in both groups. T2 measurements were compared with histologic quantification of fibrosis using picrosirius red staining. RESULTS: Myocardial T2 was significantly lower in diabetic mice (13.8 ± 2.8 ms) than in controls (18.9 ± 2.3 ms, P < 0.001). There was a good correlation between T2 and fibrosis area obtained by histopathology (R = 0.947, P < 0.001). During programmed ventricular stimulation, 3 nonsustained ventricular tachycardias were induced in diabetic mice versus none in the control group. CONCLUSIONS: The in vivo T2 relaxation time strongly correlated with myocardial fibrosis area assessed with histologic staining in diabetic mice.
    Mots-clés : Animals, crmbm, Diabetes Mellitus, Experimental, Endomyocardial Fibrosis, Magnetic Resonance Imaging, Male, Mice, Mice, Inbred C57BL, Reproducibility of Results, Sensitivity and Specificity, Streptozocin.
    Note Note
    The following values have no corresponding Zotero field:<br/>Author Address: Centre de Resonance Magnetique Biologique et Medicale-UMR 6612 CNRS, Universite de la Mediterranee, Faculte de Medecine, Marseille, France.<br/>ET - 2012/04/11<br/>
    Note Note
    <p>Bun, Sok-Sithikun <br />Kober, Frank <br />Jacquier, Alexis <br />Espinosa, Leon <br />Kalifa, Jerome <br />Bonzi, Marie-France <br />Kopp, Francis <br />Lalevee, Nathalie <br />Zaffran, Stephane <br />Deharo, Jean-Claude <br />Cozzone, Patrick J <br />Bernard, Monique <br />Research Support, Non-U.S. Gov't <br />United States <br />Investigative radiology <br />Invest Radiol. 2012 May;47(5):319-23. doi: 10.1097/RLI.0b013e318243e062.</p>

  • Chiche, J, Le Fur, Y, Vilmen, C, Frassineti, F, Daniel, L, Halestrap, AP, Cozzone, PJ, Pouysségur, J & Lutz, NW 2012, “In vivo pH in metabolic-defective Ras-transformed fibroblast tumors: key role of the monocarboxylate transporter, MCT4, for inducing an alkaline intracellular pH”, International journal of cancer. Journal international du cancer, vol. 130, no. 7, p. 1511-1520.
    Résumé : We present an investigation of tumor pH regulation, designed to support a new anticancer therapy concept that we had previously proposed. Our study uses a tumor model of ras-transformed hamster fibroblasts, CCL39, xenografted in the thighs of nude mice. We demonstrate, for the first time, that genetic modifications of specific mechanisms of proton production and/or proton transport result in distinct, reproducible changes in intracellular and extracellular tumor pH that can be detected and quantified noninvasively in vivo, simultaneously with determinations of tumor energetic status and necrosis in the same experiment. The CCL39 variants used were deficient in the sodium/proton exchanger, NHE-1, and/or in the monocarboxylate transporter, MCT4; further, variants were deficient in glycolysis or respiration. MCT4 expression markedly increased the gradient between intracellular and extracellular pH from 0.14 to 0.43 when compared to CCL39 wild-type tumors not expressing MCT4. The other genetic modifications studied produced smaller but significant increases in intracellular and decreases in extracellular pH. In general, increased pH gradients were paralleled by increased tumor growth performance and diminished necrotic regions, and 50% of the CCL39 variant expressing neither MCT4 nor NHE-1, but possessing full genetic capacity for glycolysis and oxidative phosphorylation, underwent regression before reaching a 1-cm diameter. Except for CCL39 wild-type tumors, no significant HIF-1α expression was detected. Our in vivo results support a multipronged approach to tumor treatment based on minimizing intracellular pH by targeting several proton production and proton transport processes, among which the very efficient MCT4 proton/lactate co-transport deserves particular attention.
    Mots-clés : Animals, Cell Line, Tumor, Cell Transformation, Neoplastic, Cricetinae, crmbm, Fibroblasts, Genes, ras, Glycolysis, Hydrogen-Ion Concentration, Hypoxia-Inducible Factor 1, alpha Subunit, Ion Exchange, Ion Transport, Mice, Mice, Nude, Monocarboxylic Acid Transporters, Muscle Proteins, Mutation, Necrosis, Oxidative Phosphorylation, Phospholipids, Protons, Sodium-Hydrogen Antiporter.

  • Duhamel, G, Callot, V, Tachrount, M, Alsop, DC & Cozzone, PJ 2012, “Pseudo-continuous arterial spin labeling at very high magnetic field (11.75 T) for high-resolution mouse brain perfusion imaging”, Magnetic resonance in medicine, vol. 67, no. 5, p. 1225-1236.
    Résumé : With the increasing number of transgenic mouse models of human brain diseases, there is a need for a sensitive method that allows assessing quantitative whole brain perfusion within a reasonable scan time. Arterial spin labeling (ASL), an MRI technique that permits the noninvasive quantification of cerebral blood flow, has been used to assess rodents brain perfusion. For mice, the reported experiments performed with continuous or pulsed ASL were challenged by poor multislice capability, limited sensitivity, or quantification issues. Here, the recently proposed pseudo-continuous ASL strategy, which has shown great promise for human studies, was investigated for mouse brain perfusion imaging at 11.75 T. Pseudo-continuous ASL was experimentally optimized and compared with a standard flow-sensitive alternating inversion recovery sequence for sensitivity, robustness, absolute quantification, and multislice imaging capability. A sensitivity gain up to 40% and clear advantages for multislice imaging are obtained with pseudo-continuous ASL.
    Mots-clés : Algorithms, Animals, Blood Flow Velocity, Brain, Cerebrovascular Circulation, crmbm, Image Enhancement, Image Interpretation, Computer-Assisted, Magnetic Resonance Angiography, Male, Mice, Mice, Inbred C57BL, Models, Animal, Reproducibility of Results, Sensitivity and Specificity, Spin Labels.

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

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

  • 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.

  • Gaborit, B, Kober, F, Jacquier, A, Moro, PJ, Flavian, A, Quilici, J, Cuisset, T, Simeoni, U, Cozzone, P, Alessi, M-C, Clément, K, Bernard, M & Dutour, A 2012, “Epicardial fat volume is associated with coronary microvascular response in healthy subjects: a pilot study”, Obesity (Silver Spring, Md.), vol. 20, no. 6, p. 1200-1205.
    Résumé : Epicardial fat (EF) is an active ectopic fat depot, which has been associated with coronary atherosclerosis, and which could early influence endothelial function. We thus investigated the relationship between EF and endothelium-dependent vasoreactivity of the coronary microcirculation, in highly selected healthy volunteers. Myocardial blood flow (MBF) was determined by measuring coronary sinus flow with velocity-encoded cine magnetic resonance imaging (MRI) at 3T. We measured MBF at baseline and in response to sympathetic stimulation by cold pressor testing (CPT) in 30 healthy volunteers with normal left ventricular (LV) function (age 22 ± 4 years, BMI = 21.3 ± 2.8 kg/m(2)). EF volume was volumetrically assessed by manual delineation on short-axis views. CPT was applied by immersing one foot in ice water for 4 min. Mean EF volume was 56 ± 26 ml and mean LV mass 100 ± 28 g. CPT significantly increased heart rate (HR) by 32 ± 19%, systolic blood pressure by 14 ± 10%, and rate-pressure product by 45 ± 25%, P < 0.0001. The increase in HR, reflecting sympathetic stimulation, was not influenced by sex, age or EF volume. CPT induced a decrease in coronary vascular resistance (135 ± 72 vs. 100 ± 42 mm, P = 0.0006), and a significant increase in MBF (0.81 ± 0.37 vs. 1.24 ± 0.56 ml.min(-1).g(-1), P < 0.0001). Interestingly, we found a significant negative correlation between EF volume and ΔMBF (r= - 0.40, P = 0.03), which remained significant after adjusting for ΔHR. ΔMBF was also associated with adiponectin (r = 0.41, P = 0.046), but not with waist circumference, BMI, C-reactive protein, lipid or glycemic parameters. In multivariate analysis, adiponectin and EF volume remained both independently associated with ΔMBF. A high EF amount is associated with a lower coronary microvascular response, suggesting that EF could early influence endothelial function.
    Mots-clés : Adolescent, Adult, Blood pressure, Cold Temperature, Coronary Artery Disease, Coronary Circulation, Coronary Vessels, crmbm, Endothelium, Vascular, Female, Humans, Male, Microcirculation, Pilot Projects, Reproducibility of Results, Ventricular Function, Left, Young Adult.

  • Garcia, C, Lutz, NW, Confort-Gouny, S, Cozzone, PJ, Armand, M & Bernard, M 2012, “Phospholipid fingerprints of milk from different mammalians determined by 31P NMR: towards specific interest in human health”, Food Chemistry, vol. 135, no. 3, p. 1777-1783.
    Résumé : Our objective was to identify and quantify phospholipids in milk from different species (human HM, cow CoM, camel CaM, and mare MM) using an optimised (31)P NMR spectroscopy procedure. The phospholipid fingerprints were species-specific with a broader variety of classes found in HM and MM; HM and CaM were richer in sphingomyelin (78.3 and 117.5μg/ml) and plasmalogens (27.3 and 24μg/ml), possibly important for infant development. Total phospholipid content was higher in CaM (0.503mM) and lower in MM (0.101mM) compared to HM (0.324mM) or CoM (0.265mM). Our optimised method showed good sensitivity, high resolution, and easy sample preparation with minimal loss of target molecules. It is suitable for determining the accurate composition of a large number of bioactive phospholipids with putative health benefits, including plasmalogens, and should aid in selecting appropriate ingredient sources for infant milk substitutes or fortifiers, and for functional foods dedicated to adults.
    Mots-clés : Animals, Camels, crmbm, Humans, Magnetic Resonance Spectroscopy, Milk, Milk, Human, Phospholipids.

  • Laigle, C, Confort-Gouny, S, Le Fur, Y, Cozzone, PJ & Viola, A 2012, “Deletion of TRAAK potassium channel affects brain metabolism and protects against ischemia”, PloS one, vol. 7, no. 12, p. e53266.
    Résumé : Cerebral stroke is a worldwide leading cause of disability. The two-pore domain K⁺ channels identified as background channels are involved in many functions in brain under physiological and pathological conditions. We addressed the hypothesis that TRAAK, a mechano-gated and lipid-sensitive two-pore domain K⁺ channel, is involved in the pathophysiology of brain ischemia. We studied the effects of TRAAK deletion on brain morphology and metabolism under physiological conditions, and during temporary focal cerebral ischemia in Traak⁻/⁻ mice using a combination of in vivo magnetic resonance imaging (MRI) techniques and multinuclear magnetic resonance spectroscopy (MRS) methods. We provide the first in vivo evidence establishing a link between TRAAK and neurometabolism. Under physiological conditions, Traak⁻/⁻ mice showed a particular metabolic phenotype characterized by higher levels of taurine and myo-inositol than Traak⁺/⁺ mice. Upon ischemia, Traak⁻/⁻ mice had a smaller infarcted volume, with lower contribution of cellular edema than Traak⁺/⁺ mice. Moreover, brain microcirculation was less damaged, and brain metabolism and pH were preserved. Our results show that expression of TRAAK strongly influences tissue levels of organic osmolytes. Traak⁻/⁻ mice resilience to cellular edema under ischemia appears related to their physiologically high levels of myo-inositol and of taurine, an aminoacid involved in the modulation of mitochondrial activity and cell death. The beneficial effects of TRAAK deletion designate this channel as a promising pharmacological target for the treatment against stroke.
    Mots-clés : Animals, Brain, crmbm, Cytoprotection, Energy Metabolism, Female, Gene Deletion, Hypoxia-Ischemia, Brain, Infarction, Middle Cerebral Artery, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Potassium Channels.

  • Layec, G, Bringard, A, Yashiro, K, Le Fur, Y, Vilmen, C, Micallef, J-P, Perrey, S, Cozzone, PJ & Bendahan, D 2012, “The slow components of phosphocreatine and pulmonary oxygen uptake can be dissociated during heavy exercise according to training status”, Experimental physiology, vol. 97, no. 8, p. 955-969.
    Résumé : To better understand the mechanisms underlying the pulmonary O(2) uptake (V(O(2P))) slow component during high-intensity exercise, we used (31)P magnetic resonance spectroscopy, gas exchange, surface electromyography and near-infrared spectroscopy measurements to examine the potential relationship between the slow components of V(O(2P)) and phosphocreatine (PCr), muscle recruitment and tissue oxygenation in endurance-trained athletes and sedentary subjects. Specifically, six endurance-trained and seven sedentary subjects performed a dynamic high-intensity exercise protocol during 6 min at an exercise intensity corresponding to 35-40% of knee-extensor maximal voluntary contraction. The slow component of V(O(2P))(117 ± 60 ml min(-1), i.e. 20 ± 10% of the total response) was associated with a paradoxical PCr resynthesis in endurance-trained athletes (-0.90 ± 1.27 mm, i.e. -12 ± 16% of the total response). Meanwhile, oxygenated haemoglobin increased throughout the second part of exercise and was significantly higher at the end of exercise compared with the value at 120 s (P < 0.05), whereas the integrated EMG was not significantly changed throughout exercise. In sedentary subjects, a slow component was simultaneously observed for V(O(2P)) and [PCr] time-dependent changes (208 ± 14 ml min(-1), i.e. 38 ± 18% of the total V(O(2P))response, and 1.82 ± 1.39 mm, i.e. 16 ± 13% of the total [PCr] response), but the corresponding absolute or relative amplitudes were not correlated. The integrated EMG was significantly increased throughout exercise in sedentary subjects. Taken together, our results challenge the hypothesis of a mechanistic link between [PCr] and V(O(2P)) slow components and demonstrate that, as a result of a tighter metabolic control and increased O(2) availability, the [PCr] slow component can be minimized in endurance-trained athletes while the V(O(2P)) slow component occurs.
    Mots-clés : Adult, crmbm, Electromyography, Exercise, Female, Humans, Knee, Magnetic Resonance Spectroscopy, Male, Muscle Contraction, Muscle, Skeletal, Oxygen Consumption, Phosphocreatine, Physical Endurance, Pulmonary Gas Exchange, Sedentary Lifestyle, Young Adult.

  • Ratel, S, Martin, V, Tonson, A, Cozzone, PJ & Bendahan, D 2012, “Skeletal muscle mitochondrial function cannot be properly inferred from PCr resynthesis without taking pH changes into account”, Magnetic resonance imaging, vol. 30, no. 10, p. 1542-1543.
    Mots-clés : crmbm, Female, Humans, Hypothyroidism, Magnetic Resonance Spectroscopy, Male, Muscle, Skeletal, Phosphocreatine.

  • Ratel, S, Martin, V, Tonson, A, Cozzone, PJ & Bendahan, D 2012, “Can we simply infer mitochondrial function from PCr resynthesis after exercise in skeletal muscle?”, Pediatric research, vol. 72, no. 2, p. 221.
    Mots-clés : crmbm, Cystic Fibrosis, Energy Metabolism, Exercise, Female, Humans, Kartagener Syndrome, Male, Muscle, Skeletal.

  • Simões, RV, Ortega-Martorell, S, Delgado-Goñi, T, Le Fur, Y, Pumarola, M, Candiota, AP, Martín, J, Stoyanova, R, Cozzone, PJ, Julià-Sapé, M & Arús, C 2012, “Improving the classification of brain tumors in mice with perturbation enhanced (PE)-MRSI”, Integrative biology: quantitative biosciences from nano to macro, vol. 4, no. 2, p. 183-191.
    Résumé : Classifiers based on statistical pattern recognition analysis of MRSI data are becoming important tools for the non-invasive diagnosis of human brain tumors. Here we investigate the potential interest of perturbation-enhanced MRSI (PE-MRSI), in this case acute hyperglycemia, for improving the discrimination between mouse brain MRS patterns of glioblastoma multiforme (GBM), oligodendroglioma (ODG), and non-tumor brain parenchyma (NT). Six GBM-bearing mice and three ODG-bearing mice were scanned at 7 Tesla by PRESS-MRSI with 12 and 136 ms echo-time, during euglycemia (Eug) and also during induced acute hyperglycemia (Hyp), generating altogether four datasets per animal (echo time + glycemic condition): 12Eug, 136Eug, 12Hyp, and 136Hyp. For classifier development all spectral vectors (spv) selected from the MRSI matrix were unit length normalized (UL2) and used either as a training set (76 GBM spv, four mice; 70 ODG spv, two mice; 54 NT spv) or as an independent testing set (61 GBM spv, two mice; 31 ODG, one mouse; 23 NT spv). All Fisher's LDA classifiers obtained were evaluated as far as their descriptive performance-correctly classified cases of the training set (bootstrapping)-and predictive accuracy-balanced error rate of independent testing set classification. MRSI-based classifiers at 12Hyp were consistently more efficient in separating GBM, ODG, and NT regions, with overall accuracies always >80% and up to 95-96%; remaining classifiers were within the 48-85% range. This was also confirmed by user-independent selection of training and testing sets, using leave-one-out (LOO). This highlights the potential interest of perturbation-enhanced MRSI protocols for improving the non-invasive characterization of preclinical brain tumors.
    Mots-clés : Animals, Blood Glucose, Brain Neoplasms, Female, Glioblastoma, Histocytochemistry, Hyperglycemia, Magnetic Resonance Spectroscopy, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Oligodendroglioma, Pattern Recognition, Automated.

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

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