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KOBER Frank

Ph.D. - CNRS Research Director

frank.kober@univ-amu.fr
tel : +33 4 91 32 48 02
Key Words
- MR Physics, MR Methods, Arterial Spin Labeling, MR Spectroscopy
- Chemical Shift Imaging, CMR, Cardiovascular Magnetic Resonance
- Myocardial Perfusion, Cerebral Blood Flow

Current Research Interest and projects

- Arterial Spin Labeling in heart and brain
- Small Animal MRI and MRS
- Coronary Flow Reserve
- Phosphorus MRS

Publications

2016

Journal Article

  • ABDESSELAM I., DUTOUR A., KOBER F., ANCEL P., BEGE T., DARMON P., LESAVRE N., BERNARD M., GABORIT B. “Time Course of Change in Ectopic Fat Stores After Bariatric Surgery.”. Journal of the American College of Cardiology [En ligne]. 2016. Vol. 67, n°1, p. 117-119. Disponible sur : < http://dx.doi.org/10.1016/j.jacc.2015.10.052 > (consulté le no date)

  • BRICQ S., FRANDON J., BERNARD M., GUYE M., FINAS M., MARCADET L., MIQUEROL L., KOBER F., HABIB G., FAGRET D., JACQUIER A., LALANDE A. “Semiautomatic detection of myocardial contours in order to investigate normal values of the left ventricular trabeculated mass using MRI.”. Journal of magnetic resonance imaging: JMRI [En ligne]. 2016. Vol. 43, n°6, p. 1398-1406. Disponible sur : < http://dx.doi.org/10.1002/jmri.25113 > (consulté le no date)
    Résumé : PURPOSE: To propose, assess, and validate a semiautomatic method allowing rapid and reproducible measurement of trabeculated and compacted left ventricular (LV) masses from cardiac magnetic resonance imaging (MRI). MATERIALS AND METHODS: We developed a method to automatically detect noncompacted, endocardial, and epicardial contours. Papillary muscles were segmented using semiautomatic thresholding and were included in the compacted mass. Blood was removed from trabeculae using the same threshold tool. Trabeculated, compacted masses and ratio of noncompacted to compacted (NC:C) masses were computed. Preclinical validation was performed on four transgenic mice with hypertrabeculation of the LV (high-resolution cine imaging, 11.75T). Then analysis was performed on normal cine-MRI examinations (steady-state free precession [SSFP] sequences, 1.5T or 3T) obtained from 60 healthy participants (mean age 49 ± 16 years) with 10 men and 10 women for each of the following age groups: [20,39], [40,59], and [60,79]. Interobserver and interexamination segmentation reproducibility was assessed by using Bland-Altman analysis and by computing the correlation coefficient. RESULTS: In normal participants, noncompacted and compacted masses were 6.29 ± 2.03 g/m(2) and 62.17 ± 11.32 g/m(2) , respectively. The NC:C mass ratio was 10.26 ± 3.27%. Correlation between the two observers was from 0.85 for NC:C ratio to 0.99 for end-diastolic volume (P < 10(-5) ). The bias between the two observers was -1.06 ± 1.02 g/m(2) for trabeculated mass, -1.41 ± 2.78 g/m(2) for compacted mass, and -1.51 ± 1.77% for NC:C ratio. CONCLUSION: We propose a semiautomatic method based on region growing, active contours, and thresholding to calculate the NC:C mass ratio. This method is highly reproducible and might help in the diagnosis of LV noncompaction cardiomyopathy. J. Magn. Reson. Imaging 2016;43:1398-1406.
    Mots-clés : cardiovascular magnetic resonance imaging, crmbm, left ventricle, noncompaction, papillary muscles, trabeculae.

  • DUTOUR A., ABDESSELAM I., ANCEL P., KOBER F., MRAD G., DARMON P., RONSIN O., PRADEL V., LESAVRE N., MARTIN J. C., JACQUIER A., LEFUR Y., BERNARD M., GABORIT B. “Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy.”. Diabetes, Obesity & Metabolism [En ligne]. 2016. Vol. 18, n°9, p. 882-891. Disponible sur : < http://dx.doi.org/10.1111/dom.12680 > (consulté le no date)
    Résumé : AIM: To conduct a prospective randomized trial to investigate the effect of glucagon-like peptide-1 (GLP-1) analogues on ectopic fat stores. METHODS: A total of 44 obese subjects with type 2 diabetes uncontrolled on oral antidiabetic drugs were randomly assigned to receive exenatide or reference treatment according to French guidelines. Epicardial adipose tissue (EAT), myocardial triglyceride content (MTGC), hepatic triglyceride content (HTGC) and pancreatic triglyceride content (PTGC) were assessed 45 min after a standardized meal with 3T magnetic resonance imaging and proton magnetic resonance spectroscopy before and after 26 weeks of treatment. RESULTS: The study population had a mean glycated haemoglobin (HbA1c) level of 7.5 ± 0.2% and a mean body mass index of 36.1 ± 1.1 kg/m(2) . Ninety five percent had hepatic steatosis at baseline (HTGC ≥ 5.6%). Exenatide and reference treatment led to a similar improvement in HbA1c (-0.7 ± 0.3% vs. -0.7 ± 0.4%; p = 0.29), whereas significant weight loss was observed only in the exenatide group (-5.5 ± 1.2 kg vs. -0.2 ± 0.8 kg; p = 0.001 for the difference between groups). Exenatide induced a significant reduction in EAT (-8.8 ± 2.1%) and HTGC (-23.8 ± 9.5%), compared with the reference treatment (EAT: -1.2 ± 1.6%, p = 0.003; HTGC: +12.5 ± 9.6%, p = 0.007). No significant difference was observed in other ectopic fat stores, PTGC or MTGC. In the group treated with exenatide, reductions in liver fat and EAT were not associated with homeostatic model assessment of insulin resistance index, adiponectin, HbA1c or fructosamin change, but were significantly related to weight loss (r = 0.47, p = 0.03, and r = 0.50, p = 0.018, respectively). CONCLUSION: Our data indicate that exenatide is an effective treatment to reduce liver fat content and epicardial fat in obese patients with type 2 diabetes, and these effects are mainly weight loss dependent.
    Mots-clés : crmbm, epicardial adipose tissue, glucagon-like peptide 1 receptor agonist, hepatic triglyceride content, Magnetic Resonance Imaging, magnetic-resonance imaging, myocardial triglyceride content, Obesity, pancreatic triglyceride content, Proton Magnetic Resonance Spectroscopy, proton magnetic-resonance spectroscopy, type 2 diabetes.

  • ENGBLOM H., TUFVESSON J., JABLONOWSKI R., CARLSSON M., ALETRAS A. H., HOFFMANN P., JACQUIER A., KOBER F., METZLER B., ERLINGE D., ATAR D., ARHEDEN H., HEIBERG E. “A new automatic algorithm for quantification of myocardial infarction imaged by late gadolinium enhancement cardiovascular magnetic resonance: experimental validation and comparison to expert delineations in multi-center, multi-vendor patient data.”. Journal of Cardiovascular Magnetic Resonance: Official Journal of the Society for Cardiovascular Magnetic Resonance [En ligne]. 2016. Vol. 18, n°1, p. 27. Disponible sur : < http://dx.doi.org/10.1186/s12968-016-0242-5 > (consulté le no date)
    Résumé : BACKGROUND: Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) using magnitude inversion recovery (IR) or phase sensitive inversion recovery (PSIR) has become clinical standard for assessment of myocardial infarction (MI). However, there is no clinical standard for quantification of MI even though multiple methods have been proposed. Simple thresholds have yielded varying results and advanced algorithms have only been validated in single center studies. Therefore, the aim of this study was to develop an automatic algorithm for MI quantification in IR and PSIR LGE images and to validate the new algorithm experimentally and compare it to expert delineations in multi-center, multi-vendor patient data. METHODS: The new automatic algorithm, EWA (Expectation Maximization, weighted intensity, a priori information), was implemented using an intensity threshold by Expectation Maximization (EM) and a weighted summation to account for partial volume effects. The EWA algorithm was validated in-vivo against triphenyltetrazolium-chloride (TTC) staining (n = 7 pigs with paired IR and PSIR images) and against ex-vivo high resolution T1-weighted images (n = 23 IR and n = 13 PSIR images). The EWA algorithm was also compared to expert delineation in 124 patients from multi-center, multi-vendor clinical trials 2-6 days following first time ST-elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI) (n = 124 IR and n = 49 PSIR images). RESULTS: Infarct size by the EWA algorithm in vivo in pigs showed a bias to ex-vivo TTC of -1 ± 4%LVM (R = 0.84) in IR and -2 ± 3%LVM (R = 0.92) in PSIR images and a bias to ex-vivo T1-weighted images of 0 ± 4%LVM (R = 0.94) in IR and 0 ± 5%LVM (R = 0.79) in PSIR images. In multi-center patient studies, infarct size by the EWA algorithm showed a bias to expert delineation of -2 ± 6 %LVM (R = 0.81) in IR images (n = 124) and 0 ± 5%LVM (R = 0.89) in PSIR images (n = 49). CONCLUSIONS: The EWA algorithm was validated experimentally and in patient data with a low bias in both IR and PSIR LGE images. Thus, the use of EM and a weighted intensity as in the EWA algorithm, may serve as a clinical standard for the quantification of myocardial infarction in LGE CMR images. CLINICAL TRIAL REGISTRATION: CHILL-MI: NCT01379261 . MITOCARE: NCT01374321 .
    Mots-clés : Automatic quantification algorithm, Expectation maximization, Experimental validation, LGE CMR, Multi-center patient data.

  • KOBER F., JAO T., TROALEN T., NAYAK K. S. “Myocardial arterial spin labeling.”. Journal of Cardiovascular Magnetic Resonance: Official Journal of the Society for Cardiovascular Magnetic Resonance [En ligne]. 2016. Vol. 18, n°1, p. 22. Disponible sur : < http://dx.doi.org/10.1186/s12968-016-0235-4 > (consulté le no date)
    Résumé : Arterial spin labeling (ASL) is a cardiovascular magnetic resonance (CMR) technique for mapping regional myocardial blood flow. It does not require any contrast agents, is compatible with stress testing, and can be performed repeatedly or even continuously. ASL-CMR has been performed with great success in small-animals, but sensitivity to date has been poor in large animals and humans and remains an active area of research. This review paper summarizes the development of ASL-CMR techniques, current state-of-the-art imaging methods, the latest findings from pre-clinical and clinical studies, and future directions. We also explain how successful developments in brain ASL and small-animal ASL-CMR have helped to inform developments in large animal and human ASL-CMR.
    Mots-clés : arterial spin labeling, Cardiovascular magnetic resonance, crmbm, Ischemic heart disease, myocardial perfusion.

  • NIENDORF T., BARTH M., KOBER F., TRATTNIG S. “From ultrahigh to extreme field magnetic resonance: where physics, biology and medicine meet.”. Magma (New York, N.Y.) [En ligne]. 2016. Vol. 29, n°3, p. 309-311. Disponible sur : < http://dx.doi.org/10.1007/s10334-016-0564-1 > (consulté le no date)

2015

Book Section


  • BERNARD M., KOBER F., CAUS T. “Assessing Cardiac Transplant Viability with MRS.”. In : eMagRes [En ligne]. [s.l.] : John Wiley & Sons, Ltd, 2015. Disponible sur : < http://onlinelibrary.wiley.com/doi/10.1002/9780470034590.emrstm1447/abstract >ISBN : 978-0-470-03459-0.
    Résumé : Heart transplantation remains the treatment of choice for severe heart failure and end-stage cardiac disease. In a context of organ shortage and increasing inclusion of marginal donors, it is important to safely use the available grafts but without overestimating myocardial injury, which could result in discarding viable grafts. The development of biomarkers to assess cardiac graft viability before transplantation is thus of major interest. An important indicator of graft quality is given by high-energy phosphate compound concentrations that can be assessed noninvasively using 31P magnetic resonance spectroscopy. This method is also of use in assessing graft viability after transplantation when cardiac allograft vasculopathy can develop, which is associated with diffuse perfusion defects that potentially affect energy metabolism.
    Mots-clés : 31P MRS, cardiac, cardiac allograft vasculopathy, crmbm, early graft failure, graft viability, transplantation.
Journal Article


  • ABDESSELAM I., PEPINO P., TROALEN T., MACIA M., ANCEL P., MASI B., FOURNY N., GABORIT B., GIANNESINI B., KOBER F., DUTOUR A., BERNARD M. “Time course of cardiometabolic alterations in a high fat high sucrose diet mice model and improvement after GLP-1 analog treatment using multimodal cardiovascular magnetic resonance.”. Journal of Cardiovascular Magnetic Resonance [En ligne]. 06 November 2015. Vol. 17, n°1, p. 95. Disponible sur : < http://dx.doi.org/10.1186/s12968-015-0198-x >
    Résumé : Cardiovascular complications of obesity and diabetes are major health problems. Assessing their development, their link with ectopic fat deposition and their flexibility with therapeutic intervention is essential. The aim of this study was to longitudinally investigate cardiac alterations and ectopic fat accumulation associated with diet-induced obesity using multimodal cardiovascular magnetic resonance (CMR) in mice. The second objective was to monitor cardiac response to exendin-4 (GLP-1 receptor agonist).
    Mots-clés : Cardiovascular magnetic resonance, crmbm, Diabetes, DIO mice model, Longitudinal study, Obesity, Proton-magnetic resonance spectroscopy.


  • CAPRON T., TROALEN T., ROBERT B., JACQUIER A., BERNARD M., KOBER F. “Myocardial perfusion assessment in humans using steady-pulsed arterial spin labeling.”. Magnetic Resonance in Medicine [En ligne]. 2015. Vol. 74, n°4, p. 990-998. Disponible sur : < http://dx.doi.org/10.1002/mrm.25479 >
    Résumé : Purpose Although arterial spin labeling (ASL) has become a routinely performed method in the rodent heart, its application to the human heart remains challenged by low tissue blood flow and cardiac and respiratory motion. We hypothesized that an alternative steady-pulsed ASL (spASL) method would provide more efficient perfusion signal averaging by driving the tissue magnetization into a perfusion-dependent steady state. Methods We evaluated the feasibility of spASL in the human heart by combining pulsed labeling in the aortic root with a balanced steady state free precession sequence. The spASL scheme was applied to 13 subjects under free breathing. Breathing motion was addressed using retrospective image exclusion based on a contour-based cross-correlation algorithm. Results The measured signal with spASL was due to labeled blood. We found that the perfusion signal was larger than that obtained with the earlier flow-sensitive alternating inversion recovery (FAIR) method. Averaged myocardial blood flow (MBF) over four myocardial regions was 1.28 ± 0.36 mL·g−1·min−1. Conclusion spASL was able to quantify MBF in healthy subjects under free breathing. Because quantification with ASL is more direct than with first-pass perfusion MRI, it appears particularly suited for pathologies with diffuse microvascular alterations, MBF reserve, and follow-up studies. Magn Reson Med 74:990–998, 2015. © 2014 Wiley Periodicals, Inc.
    Mots-clés : arterial spin labeling, Blood flow, cine-ASL, crmbm, myocardial perfusion, steady state, steady-pulsed.

  • GABORIT B., ABDESSELAM I., KOBER F., JACQUIER A., RONSIN O., EMUNGANIA O., LESAVRE N., ALESSI M. - C., MARTIN J. C., BERNARD M., DUTOUR A. “Ectopic fat storage in the pancreas using 1H-MRS: importance of diabetic status and modulation with bariatric surgery-induced weight loss.”. International Journal of Obesity (2005) [En ligne]. 2015. Vol. 39, n°3, p. 480-487. Disponible sur : < http://dx.doi.org/10.1038/ijo.2014.126 > (consulté le no date)
    Résumé : OBJECTIVES: Recent literature suggests that ectopic fat deposition in the pancreas may contribute to endocrine and exocrine organ dysfunction, such as type 2 diabetes (T2D), pancreatitis or pancreatic cancer. The aim of this study was to determine factors associated with pancreatic triglyceride content (PTGC), and to investigate the impact of bariatric surgery on ectopic fat pads, pancreatic fat (PTGC) and hepatic fat (HTGC). SUBJECTS: In all, 45 subjects (13 lean, 13 obese nondiabetics and 19 T2D, matched for age and gender) underwent 1H-magnetic resonance spectroscopy, computed tomography of the visceral abdominal fat, metabolic and lipidomic analysis, including insulin-resistance homeostasis model assessment (HOMA-IR), insulin-secretion homeostasis model assessment (HOMA-B) and plasma fatty-acid composition. Twenty obese subjects were reassessed 6 months after the bariatric surgery. RESULTS: PTGC was significantly higher in type 2 diabetic subjects (23.8±3.2%) compared with obese (14.0±3.3; P=0.03) and lean subjects (7.5±0.9%; P=0.0002). PTGC remained significantly associated with T2D after adjusting for age and sex (β=0.47; P=0.004) or even after adjusting for waist circumference, triglycerides and HOMA-IR (β=0.32; P=0.04). T2D, C18:1n-9 (oleic acid), uric acid, triglycerides and plasminogen activator inhibitor-1 were the five more important parameters involved in PTGC prediction (explained 80% of PTGC variance). Bariatric surgery induced a huge reduction of both HTGC (-51.2±7.9%) and PTGC (-43.8±7.0%) reaching lean levels, whereas body mass index remained greatly elevated. An improvement of insulin resistance HOMA-IR and no change in HOMA-B were observed after bariatric surgery. The PTGC or HTGC losses were not correlated, suggesting tissue-specific mobilization of these ectopic fat stores. CONCLUSION: Pancreatic fat increased with T2D and drastically decreased after the bariatric surgery. This suggests that decreased PTGC may contribute to improved beta cell function seen after the bariatric surgery. Further, long-term interventional studies are warranted to examine this hypothesis and to determine the degree to which ectopic fat mobilization may mediate the improvement in endocrine and exocrine pancreatic functions.
    Mots-clés : crmbm.

  • MLIH M., HOST L., MARTIN S., NIEDERHOFFER N., MONASSIER L., TERRAND J., MESSADDEQ N., RADKE M., GOTTHARDT M., BRUBAN V., KOBER F., BERNARD M., CANET-SOULAS E., ABT-JIJON F., BOUCHER P., MATZ R. L. “The Src Homology and Collagen A (ShcA) Adaptor Protein Is Required for the Spatial Organization of the Costamere/Z-disk Network during Heart Development.”. The Journal of Biological Chemistry [En ligne]. 2015. Vol. 290, n°4, p. 2419-2430. Disponible sur : < http://dx.doi.org/10.1074/jbc.M114.597377 > (consulté le no date)
    Résumé : Src homology and collagen A (ShcA) is an adaptor protein that binds to tyrosine kinase receptors. Its germ line deletion is embryonic lethal with abnormal cardiovascular system formation, and its role in cardiovascular development is unknown. To investigate its functional role in cardiovascular development in mice, ShcA was deleted in cardiomyocytes and vascular smooth muscle cells by crossing ShcA flox mice with SM22a-Cre transgenic mice. Conditional mutant mice developed signs of severe dilated cardiomyopathy, myocardial infarctions, and premature death. No evidence of a vascular contribution to the phenotype was observed. Histological analysis of the heart revealed aberrant sarcomeric Z-disk and M-band structures, and misalignments of T-tubules with Z-disks. We find that not only the ErbB3/Neuregulin signaling pathway but also the baroreceptor reflex response, which have been functionally associated, are altered in the mutant mice. We further demonstrate that ShcA interacts with Caveolin-1 and the costameric protein plasma membrane Ca(2+)/calmodulin-dependent ATPase (PMCA), and that its deletion leads to abnormal dystrophin signaling. Collectively, these results demonstrate that ShcA interacts with crucial proteins and pathways that link Z-disk and costamere.
    Mots-clés : crmbm.

2014

Journal Article

  • BERNARD M., JACQUIER A., KOBER F. “Cardiovascular magnetic resonance in ischemic heart disease.”. Future Cardiology [En ligne]. 2014. Vol. 10, n°4, p. 487-496. Disponible sur : < http://dx.doi.org/10.2217/fca.14.39 > (consulté le no date)
    Résumé : Ischemic heart disease is the major cause of death in developed countries. Recently, cardiovascular magnetic resonance (CMR) has appeared as a powerful technique for diagnosis and prognosis of ischemia, as well as for postischemic therapy follow-up. The objective of this chapter is to provide an overview of the role of CMR in assessing ischemic myocardium. It reviews the most recent studies in this field and includes CMR parameters that are already well established in the clinical setting as well as promising or emerging parameters in clinical use.
    Mots-clés : crmbm.


  • DESROIS M., KOBER F., LAN C., DALMASSO C., COLE M., CLARKE K., COZZONE P. J., BERNARD M. “Effect of isoproterenol on myocardial perfusion, function, energy metabolism and nitric oxide pathway in the rat heart – a longitudinal MR study.”. NMR in Biomedicine [En ligne]. 2014. Vol. 27, n°5, p. 529-538. Disponible sur : < http://dx.doi.org/10.1002/nbm.3088 >
    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.


  • KOBER F., TROALEN T., BERNARD M. “Recent Developments in Small Animal Cardiovascular MRI.”. Current Cardiovascular Imaging Reports [En ligne]. 2014. Vol. 7, n°2, p. 1-10. Disponible sur : < http://dx.doi.org/10.1007/s12410-013-9249-6 >
    Résumé : This review is intended to give a comprehensive overview over new cardiovascular magnetic resonance (CMR) method developments and refinements dedicated to the fully non-invasive in vivo exploration of the rodent heart. Unlike other cardiovascular imaging techniques, CMR techniques exist in many modalities giving access to parameters characterizing morphology, global and regional function, blood flow, myocardial structure, cell damage, metabolism and other molecular processes in mouse and rat models of human disease. But even in healthy animals, small animal CMR techniques can help exploring general physiological and biochemical mechanisms in vivo. New magnetic resonance imaging methods and imaging protocols are actively being developed by the entire CMR community with the goal of widening the spectrum of observable and measurable myocardial properties. This report also includes a selection of application studies using recent CMR methodology in this field. Beyond giving new insights into pathophysiologic processes, these studies underline the growing usefulness of CMR in a small animal research context.
    Mots-clés : arterial spin labeling, Cardiology, Cardiovascular magnetic resonance, crmbm, Diagnostic Radiology, Flow, Function, Imaging / Radiology, Interventional Radiology, Mouse, MRI, Nuclear Medicine, perfusion, Rodent, Self-gating, T1 mapping, T2 mapping, T2* mapping, Ultrasound.

  • ODELIN G., FAURE E., KOBER F., MAUREL-ZAFFRAN C., THÉRON A., COULPIER F., GUILLET B., BERNARD M., AVIERINOS J. - F., CHARNAY P., TOPILKO P., ZAFFRAN S. “Loss of Krox20 results in aortic valve regurgitation and impaired transcriptional activation of fibrillar collagen genes.”. Cardiovascular Research [En ligne]. 2014. Vol. 104, n°3, p. 443-455. Disponible sur : < http://dx.doi.org/10.1093/cvr/cvu233 > (consulté le no date)
    Résumé : AIMS: Heart valve maturation is achieved by the organization of extracellular matrix (ECM) and the distribution of valvular interstitial cells. However, the factors that regulate matrix components required for valvular structure and function are unknown. Based on the discovery of its specific expression in cardiac valves, we aimed to uncover the role of Krox20 (Egr-2) during valve development and disease. METHODS AND RESULTS: Using series of mouse genetic tools, we demonstrated that loss of function of Krox20 caused significant hyperplasia of the semilunar valves, while atrioventricular valves appeared normal. This defect was associated with an increase in valvular interstitial cell number and ECM volume. Echo Doppler analysis revealed that adult mutant mice had aortic insufficiency. Defective aortic valves (AoVs) in Krox20(-/-) mice had features of human AoV disease, including excess of proteoglycan deposition and reduction of collagen fibres. Furthermore, examination of diseased human AoVs revealed decreased expression of KROX20. To identify downstream targets of Krox20, we examined expression of fibrillar collagens in the AoV leaflets at different stages in the mouse. We found significant down-regulation of Col1a1, Col1a2, and Col3a1 in the semilunar valves of Krox20 mutant mice. Utilizing in vitro and in vivo experiments, we demonstrated that Col1a1 and Col3a1 are direct targets of Krox20 activation in interstitial cells of the AoV. CONCLUSION: This study identifies a previously unknown function of Krox20 during heart valve development. These results indicate that Krox20-mediated activation of fibrillar Col1a1 and Col3a1 genes is crucial to avoid postnatal degeneration of the AoV leaflets.

  • PIN-BARRE C., LAURIN J., FELIX M. - S., PERTICI V., KOBER F., MARQUESTE T., MATARAZZO V., MUSCATELLI-BOSSY F., TEMPRADO J. - J., BRISSWALTER J., DECHERCHI P. “Acute neuromuscular adaptation at the spinal level following middle cerebral artery occlusion-reperfusion in the rat.”. PloS one [En ligne]. 2014. Vol. 9, n°2, p. e89953. Disponible sur : < http://dx.doi.org/10.1371/journal.pone.0089953 > (consulté le no date)
    Résumé : The purpose of the study was to highlight the acute motor reflex adaptation and to deepen functional deficits following a middle cerebral artery occlusion-reperfusion (MCAO-r). Thirty-six Sprague-Dawley rats were included in this study. The middle cerebral artery occlusion (MCAO; 120 min) was performed on 16 rats studied at 1 and 7 days, respectively (MCAO-D1 and MCAO-D7, n = 8 for each group). The other animals were divided into 3 groups: SHAM-D1 (n = 6), SHAM-D7 (n = 6) and Control (n = 8). Rats performed 4 behavioral tests (the elevated body swing test, the beam balance test, the ladder-climbing test and the forelimb grip force) before the surgery and daily after MCAO-r. H-reflex on triceps brachii was measured before and after isometric exercise. Infarction size and cerebral edema were respectively assessed by histological (Cresyl violet) and MRI measurements at the same time points than H-reflex recordings. Animals with cerebral ischemia showed persistent functional deficits during the first week post-MCAO-r. H-reflex was not decreased in response to isometric exercise one day after the cerebral ischemia contrary to the other groups. The motor reflex regulation was recovered 7 days post-MCAO-r. This result reflects an acute sensorimotor adaptation at the spinal level after MCAO-r.


  • TROALEN T., CAPRON T., BERNARD M., KOBER F. “In vivo characterization of rodent cyclic myocardial perfusion variation at rest and during adenosine-induced stress using cine-ASL cardiovascular magnetic resonance.”. Journal of Cardiovascular Magnetic Resonance [En ligne]. 18 February 2014. Vol. 16, n°1, p. 18. Disponible sur : < http://dx.doi.org/10.1186/1532-429X-16-18 >
    Résumé : Assessment of cyclic myocardial blood flow (MBF) variations can be an interesting addition to the characterization of microvascular function and its alterations. To date, totally non-invasive in vivo methods with this capability are still lacking. As an original technique, a cine arterial spin labeling (ASL) cardiovascular magnetic resonance approach is demonstrated to be able to produce dynamic MBF maps across the cardiac cycle in rats.
    Mots-clés : crmbm.

2013

Journal Article

  • CAPRON T., TROALEN T., COZZONE P. J., BERNARD M., KOBER F. “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 [En ligne]. 2013. Vol. 70, n°5, p. 1399-1408. Disponible sur : < http://dx.doi.org/10.1002/mrm.24588 > (consulté le no date)
    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.

  • TROALEN T., CAPRON T., COZZONE P. J., BERNARD M., KOBER F. “Cine-ASL: a steady-pulsed arterial spin labeling method for myocardial perfusion mapping in mice. Part I. Experimental study.”. Magnetic Resonance in Medicine [En ligne]. 2013. Vol. 70, n°5, p. 1389-1398. Disponible sur : < http://dx.doi.org/10.1002/mrm.24565 > (consulté le no date)
    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.

2012

Journal Article

  • BARTOLI M. A., KOBER F., COZZONE P., THOMPSON R. W., ALESSI M. C., BERNARD M. “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 [En ligne]. 2012. Vol. 44, n°5, p. 475-481. Disponible sur : < http://dx.doi.org/10.1016/j.ejvs.2012.08.002 > (consulté le no date)
    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 P. J., BERNARD M. “Value of in vivo T2 measurement for myocardial fibrosis assessment in diabetic mice at 11.75 T.”. Investigative radiology [En ligne]. 2012. Vol. 47, n°5, p. 319-323. Disponible sur : < http://dx.doi.org/10.1097/RLI.0b013e318243e062 > (consulté le no date)
    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.

  • FLAVIAN A., CARTA F., THUNY F., BERNARD M., KOBER F., MOULIN G., VAROQUAUX A., JACQUIER A. “Cardiac MRI in the diagnosis of complications of myocardial infarction.”. Diagnostic and interventional imaging [En ligne]. 2012. Vol. 93, n°7-8, p. 578-585. Disponible sur : < http://dx.doi.org/10.1016/j.diii.2012.05.012 > (consulté le no date)
    Résumé : The improvement in revascularization techniques and medicine treatment during infarction has substantially reduced mortality during the acute phase of this condition. Since the advent of kinetic sequences and the concomitant development of gadolinium chelates and delayed enhancement sequences, cardiac MRI has become the second-line reference examination for ischemic heart disease. The technique of delayed enhancement with the inversion recovery sequence performed after injection has been validated for numerous indications in ischemic disease. Delayed enhancement sequences make it possible in particular to look for "no-reflow" areas (microvascular obstructions), to quantify the infarction area, and to assess prognosis. MRI also allows us to define the area at risk, that is, the area with edema, and to look for and assess the mechanical complications of the infarction. The aim of this review is to summarize current knowledge about: the pharmacokinetic principles that regulate myocardial enhancement; the different sequences available to acquire delayed enhancement images, and; the value of cardiac MRI in the diagnosis of complications of myocardial infarction.
    Mots-clés : Cardiac Imaging Techniques, crmbm, Heart Diseases, Humans, Magnetic Resonance Imaging, Myocardial Infarction.

  • GABORIT B., KOBER F., JACQUIER A., MORO P. J., CUISSET T., BOULLU S., DADOUN F., ALESSI M. - C., MORANGE P., CLéMENT K., BERNARD M., DUTOUR A. “Assessment of epicardial fat volume and myocardial triglyceride content in severely obese subjects: relationship to metabolic profile, cardiac function and visceral fat.”. International journal of obesity (2005) [En ligne]. 2012. Vol. 36, n°3, p. 422-430. Disponible sur : < http://dx.doi.org/10.1038/ijo.2011.117 > (consulté le no date)
    Résumé : OBJECTIVE: To assess epicardial fat volume (EFV), myocardial TG content (MTGC) and metabolic profile in severely obese patients, and to determine whether ectopic fat depots are linked to metabolic disorders or myocardial function. RESEARCH DESIGN AND METHODS: Sixty-three subjects with normal LV function and no coronary artery disease, including 33 lean (BMI: 21.4 ± 2.0 kg m(-2)) and 30 obese (BMI: 41.8 ± 6 kg m(-2)) patients, underwent 3-T cardiovascular MRI, and anthropometric, biological and visceral abdominal fat (VAT) assessments. EFV was measured by short-axis slice imaging and myocardial (intra-myocellular) TG content was measured by proton magnetic resonance spectroscopy. RESULTS: EFV and MTGC were positively correlated (r=0.52, P<0.0001), and were both strongly correlated with age, BMI, waist circumference and VAT, but not with severity of obesity. EFV and MTGC were significantly higher in obese patients than in lean controls (141 ± 18 versus 79 ± 7 ml, P=0.0001; 1.0 ± 0.1 versus 0.6 ± 0.1%, P=0.01, respectively), but some differences were found between the two cardiac depots: EFV was higher in diabetic obese subjects as compared with that in non-diabetic obese subjects (213 ± 34 versus 141 ± 18 ml, P=0.03), and was correlated with parameters of glucose tolerance (fasting plasma glucose, insulin and HOMA-IR), whereas MTGC was not. EFV and MTGC were both associated with parameters of lipid profile or inflammation (TGs, CRP). Remarkably, this was VAT-dependent, as only VAT remained independently associated with metabolic parameters (P<0.01). Concerning myocardial function, MTGC was the only parameter independently associated with stroke volume (β=-0.38, P=0.01), suggesting an impact of cardiac steatosis in cardiac function. CONCLUSIONS: These data show that VAT dominates the relationship between EFV, MTGC and metabolic measures, and uncover specific partitioning of cardiac ectopic lipid deposition.
    Mots-clés : Adult, crmbm, Diabetes Mellitus, Type 2, Female, Humans, Intra-Abdominal Fat, Lipid Metabolism, Magnetic Resonance Spectroscopy, Male, Metabolome, Obesity, Morbid, Pericardium, Triglycerides, Ventricular Dysfunction, Left.
  • GABORIT B., JACQUIER A., KOBER F., ABDESSELAM I., CUISSET T., BOULLU-CIOCCA S., EMUNGANIA O., ALESSI M. C., CLEMENT K., BERNARD M., DUTOUR A. “Bariatric surgery induces an improvement of left ventricular function and differential effects on cardiac ectopic fat deposition.”. Fundamental & Clinical Pharmacology. 2012. Vol. 26, p. 3-4.

  • GABORIT B., JACQUIER A., KOBER F., ABDESSELAM I., CUISSET T., BOULLU-CIOCCA S., EMUNGANIA O., ALESSI M. - C., CLéMENT K., BERNARD M., DUTOUR A. “Effects of bariatric surgery on cardiac ectopic fat: lesser decrease in epicardial fat compared to visceral fat loss and no change in myocardial triglyceride content.”. Journal of the American College of Cardiology [En ligne]. 2012. Vol. 60, n°15, p. 1381-1389. Disponible sur : < http://dx.doi.org/10.1016/j.jacc.2012.06.016 > (consulté le no date)
    Résumé : OBJECTIVES: This study investigated the effect of bariatric surgery (BS)-induced weight loss on cardiac ectopic fat using 3T magnetic resonance imaging in morbid obesity. BACKGROUND: Heart disease is one of the leading causes of mortality and morbidity in obese patients. Deposition of cardiac ectopic fat has been related to increased heart risk. Whether sustained weight loss can modulate epicardial fat or myocardial fat is unknown. METHODS: Twenty-three morbidly obese patients underwent 1H-magnetic resonance spectroscopy to determine myocardial triglyceride content (MTGC), magnetic resonance imaging to assess epicardial fat volume (EFV), cardiac function, and computed tomography visceral abdominal fat (VAF) measurements at baseline and 6 months after BS. RESULTS: The BS reduced body mass index significantly, from 43.1±4.5 kg/m2 to 32.3±4.0 kg/m2, subcutaneous fat from 649±162 cm2 to 442±127 cm2, VAF from 190±83 cm2 to 107±44 cm2, and EFV from 137±37 ml to 98±25 ml (all p<0.0001). There was no significant change in MTGC: 1.03±0.2% versus 1.1±0.2% (p=0.85). A significant reduction in left ventricular mass (118±24 g vs. 101±18 g) and cardiac output (7.1±1.6 l/min vs. 5.4±1.0 l/min) was observed and was statistically associated with weight loss (p<0.05). The loss in EFV was limited (-27±11%) compared to VAF diminution (-40±19%). The EFV variation was not correlated with percentage of body mass index or VAF loss (p=0.007). The ratio of %EFV to %VAF loss decreased with sleep apnea syndrome (1.34±0.3 vs. 0.52±0.08, p<0.05). CONCLUSIONS: Six-month BS modulates differently cardiac ectopic fat deposition, with a significant decrease in epicardial fat and no change in myocardial fat. Epicardial fat volume loss was limited in patients with sleep apnea. (Impact of Bariatric Surgery on Epicardial Adipose Tissue and on Myocardial Function; NCT01284816).
    Mots-clés : Adult, Bariatric Surgery, Body Mass Index, crmbm, Female, Follow-Up Studies, Heart Diseases, Humans, Intra-Abdominal Fat, Lipid Metabolism, Magnetic Resonance Imaging, Cine, Magnetic Resonance Spectroscopy, Male, Myocardium, Obesity, Morbid, Pericardium, Retrospective Studies, Risk Factors, Tomography, X-Ray Computed, Triglycerides.

  • GABORIT B., KOBER F., JACQUIER A., MORO P. J., FLAVIAN A., QUILICI J., CUISSET T., SIMEONI U., COZZONE P., ALESSI M. - C., CLÉMENT K., BERNARD M., DUTOUR A. “Epicardial fat volume is associated with coronary microvascular response in healthy subjects: a pilot study.”. Obesity (Silver Spring, Md.) [En ligne]. 2012. Vol. 20, n°6, p. 1200-1205. Disponible sur : < http://dx.doi.org/10.1038/oby.2011.283 > (consulté le no date)
    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 Hg.ml(-1).min.g, 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.


  • KOBER F., BERNARD M., TROALEN T., CAPRON T. “Cardiovascular Magnetic Resonance of Myocardial Structure, Function, and Perfusion in Mouse and Rat Models.”. Current Cardiovascular Imaging Reports [En ligne]. 2012. Vol. 5, n°2, p. 109-115. Disponible sur : < http://dx.doi.org/10.1007/s12410-012-9122-z >
    Résumé : This review summarizes small-animal cardiovascular magnetic resonance (CMR) techniques that are being actively developed at present. Taking into account with few exceptions only literature of the past 2 years it shows that small-animal CMR has become an important and versatile analysis tool in many biomedical studies. The relatively complex signal formation and detection in magnetic resonance offers numerous ways of creating and modulating image contrast as a function of the specific needs. Although most new small-animal CMR developments are done within the scientific MR community, the MR manufacturers have readily contributed in making these techniques robust and available for routine application studies. Unlike other cardiovascular imaging techniques, CMR is used in many facets to assess morphology, global and regional function, blood flow, myocardial structure, cell damage, metabolism, and other molecular processes for studying mouse and rat models of human disease as well as general biochemical mechanisms in vivo.
    Mots-clés : Cardiology, Cardiovascular magnetic resonance, crmbm, Diagnostic Radiology, Function, Imaging / Radiology, Interventional Radiology, Late-enhancement, MRI, Nuclear Medicine, perfusion, Self-gating, T1-mapping, Ultrasound.

  • POISNEL G., HÉRARD A. - S., EL TANNIR EL TAYARA N., BOURRIN E., VOLK A., KOBER F., DELATOUR B., DELZESCAUX T., DEBEIR T., ROONEY T., BENAVIDES J., HANTRAYE P., DHENAIN M. “Increased regional cerebral glucose uptake in an APP/PS1 model of Alzheimer's disease.”. Neurobiology of aging [En ligne]. 2012. Vol. 33, n°9, p. 1995-2005. Disponible sur : < http://dx.doi.org/10.1016/j.neurobiolaging.2011.09.026 > (consulté le no date)
    Résumé : Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is characterized by the invariant cerebral accumulation of β-amyloid peptide. This event occurs early in the disease process. In humans, [18F]-fluoro-2-deoxy-D-glucose ([18F]-FDG) positron emission tomography (PET) is largely used to follow-up in vivo cerebral glucose utilization (CGU) and brain metabolism modifications associated with the Alzheimer's disease pathology. Here, [18F]-FDG positron emission tomography was used to study age-related changes of cerebral glucose utilization under resting conditions in 3-, 6-, and 12-month-old APP(SweLon)/PS1(M146L), a mouse model of amyloidosis. We showed an age-dependent increase of glucose uptake in several brain regions of APP/PS1 mice but not in control animals and a higher [18F]-FDG uptake in the cortex and the hippocampus of 12-month-old APP/PS1 mice as compared with age-matched control mice. We then developed a method of 3-D microscopic autoradiography to evaluate glucose uptake at the level of amyloid plaques and showed an increased glucose uptake close to the plaques rather than in amyloid-free cerebral tissues. These data suggest a macroscopic and microscopic reorganization of glucose uptake in relation to cerebral amyloidosis.
    Mots-clés : Alzheimer Disease, Amyloid beta-Protein Precursor, Analysis of Variance, Animals, Calcium-Binding Proteins, Cerebral Cortex, Cerebrovascular Circulation, Disease Models, Animal, Fluorodeoxyglucose F18, Glial Fibrillary Acidic Protein, Glucose, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microfilament Proteins, Positron-Emission Tomography, Presenilin-1.

2011

Book Section
  • CALLOT V., DUHAMEL G., KOBER F. “Spinal cord - MR of rodent models.”. In : Methods in molecular biology (Clifton, N.J.). [s.l.] : [s.n.], 2011. p. 355-383.
    Résumé : Different MR techniques, such as relaxation times, diffusion, perfusion, and spectroscopy have been employed to study rodent spinal cord. In this chapter, a description of these methods is given, along with examples of normal metrics that can be derived from the MR acquisitions, as well as examples of applications to pathology.
    Mots-clés : Animals, crmbm, Diffusion Magnetic Resonance Imaging, Mice, Rats, Rodentia, Spinal Cord.


  • HYACINTHE J. - N., KOBER F., VIALLON M. “Imagerie par résonance magnétique dynamique.”. In : Imagerie dynamique cardiaque et thoracique [En ligne]. Paris : Hermes Science Publications, 2011. p. 99-192. Disponible sur : < http://www.lavoisier.fr/livre/medecine/imagerie-dynamique-cardiaque-et-thoracique/clarysse/descriptif-9782746225299 > (consulté le no date)ISBN : 978-2-7462-2529-9.
  • KOBER F., DUHAMEL G., CALLOT V. “Cerebral perfusion MRI in mice.”. In : Methods in molecular biology (Clifton, N.J.). [s.l.] : [s.n.], 2011. p. 117-138.
    Résumé : Perfusion MRI is a tool to assess the spatial distribution of microvascular blood flow. Arterial spin labeling (ASL) is shown here to be advantageous for quantification of cerebral microvascular blood flow (CBF) in rodents. This technique is today ready for assessment of a variety of murine models of human pathology including those associated with diffuse microvascular dysfunction. This chapter provides an introduction to the principles of CBF measurements by MRI along with a short overview over applications in which these measurements were found useful. The basics of commonly employed specific arterial spin-labeling techniques are described and theory is outlined in order to give the reader the ability to set up adequate post-processing tools. Three typical MR protocols for pulsed ASL on two different MRI systems are described in detail along with all necessary sequence parameters and technical requirements. The importance of the different parameters entering theory is discussed. Particular steps for animal preparation and maintenance during the experiment are given, since CBF regulation is sensitive to a number of experimental physiological parameters and influenced mainly by anesthesia and body temperature.
    Mots-clés : Anesthesia, Animals, Cerebrovascular Circulation, crmbm, Magnetic Resonance Imaging, Mice.
Journal Article

  • FAURE A., VERRET L., BOZON B., EL TANNIR EL TAYARA N., LY M., KOBER F., DHENAIN M., RAMPON C., DELATOUR B. “Impaired neurogenesis, neuronal loss, and brain functional deficits in the APPxPS1-Ki mouse model of Alzheimer's disease.”. Neurobiology of aging [En ligne]. 2011. Vol. 32, n°3, p. 407-418. Disponible sur : < http://dx.doi.org/10.1016/j.neurobiolaging.2009.03.009 > (consulté le no date)
    Résumé : Amyloid-β peptide species accumulating in the brain of patients with Alzheimer's disease are assumed to have a neurotoxic action and hence to be key actors in the physiopathology of this neurodegenerative disease. We have studied a new mouse mutant (APPxPS1-Ki) line developing both early-onset brain amyloid-β deposition and, in contrast to most of transgenic models, subsequent neuronal loss. In 6-month-old mice, we observed cell layer atrophies in the hippocampus, together with a dramatic decrease in neurogenesis and a reduced brain blood perfusion as measured in vivo by magnetic resonance imaging. In these mice, neurological impairments and spatial hippocampal dependent memory deficits were also substantiated and worsened with aging. We described here a phenotype of APPxPS1-Ki mice that summarizes several neuroanatomical alterations and functional deficits evocative of the human pathology. Such a transgenic model that displays strong face validity might be highly beneficial to future research on AD physiopathogeny and therapeutics.
    Mots-clés : Age Factors, Aging, Alzheimer Disease, Amyloid, Amyloid beta-Protein Precursor, Analysis of Variance, Animals, Animals, Genetically Modified, Anxiety, Brain, Cognition Disorders, Disease Models, Animal, Humans, Magnetic Resonance Imaging, Mice, Motor Activity, Movement Disorders, Mutation, Neurogenesis, Neurologic Examination, Presenilin-1.

  • JACQUIER A., KOBER F., BUN S., GIORGI R., COZZONE P. J., BERNARD M. “Quantification of myocardial blood flow and flow reserve in rats using arterial spin labeling MRI: comparison with a fluorescent microsphere technique.”. NMR in biomedicine [En ligne]. 2011. Vol. 24, n°9, p. 1047-1053. Disponible sur : < http://dx.doi.org/10.1002/nbm.1645 > (consulté le no date)
    Résumé : To quantify noninvasively myocardial blood flow (MBF) and MBF reserve in isoflurane-anesthetized rats using the Look-Locker flow-alternating inversion recovery gradient-echo arterial spin labeling technique (LLFAIRGE-ASL), and to compare the results with the fluorescent microsphere (FM) technique. Male Wistar rats (weight = 200-240 g, n = 21) were anesthetized with 2.0% isoflurane. Hemodynamic parameters were recorded. In seven rats, MBF was assessed on a Bruker Biospec 4.7T MR system using an ECG- and respiration-gated LLFAIRGE-ASL (pixel size = 234 × 468µm(2) , TE = 1.52ms) at rest and during adenosine infusion (140 µg/kg/min). A mixture of 200 000 FM was injected into a second group of rats at rest and during adenosine infusion (n = 7 each), under similar physiologic conditions. Hearts and skeletal muscle samples were processed for fluorescence spectroscopy. Two-tailed unpaired, paired Student's t-test and ANOVA were used to compare groups. MBF measured with LLFAIRGE-ASL was 5.2 ± 1.0 mL/g/min at rest and 13.3 ± 3.0 mL/g/min during adenosine infusion. Results obtained with fluorescent microspheres yielded 5.9 ± 2.3 mL/g/min (nonsignificant vs. LLFAIRGE-ASL, p = 0.9) at rest and 13.1 ± 2.1 mL/g/min (nonsignificant vs. LLFAIRGE-ASL, p = 0.4) during adenosine infusion. Myocardial blood flow reserve measured using LLFAIRGE-ASL and FM were not significantly different (2.5 ± 0.6 vs. 2.4 ± 0.9, respectively; p = 0.8). Hemodynamic parameters during the experiments were not different between the groups. The myocardial blood flow reserve determined under isoflurane anesthesia was 2.5 ± 0.6, which was not different from the value obtained with FM. LLFAIRGE-ASL provided MBF maps with high spatial resolution in rats under isoflurane anesthesia. LLFAIRGE-ASL is a noninvasive measure to assess myocardial blood flow reserve and provides an interesting tool for cardiovascular research.
    Mots-clés : Adenosine, Animals, Arteries, Coronary Circulation, crmbm, Fluorescence, Heart, Heart Ventricles, Hemodynamics, Magnetic Resonance Imaging, Magnetic Resonance Imaging, Cine, Male, Microspheres, Myocardium, Rats, Rats, Sprague-Dawley, Spin Labels, Ventricular Function.

  • MORO P. - J., FLAVIAN A., JACQUIER A., KOBER F., QUILICI J., GABORIT B., BONNET J. - L., MOULIN G., COZZONE P. J., BERNARD M. “Gender differences in response to cold pressor test assessed with velocity-encoded cardiovascular magnetic resonance of the coronary sinus.”. Journal of cardiovascular magnetic resonance: official journal of the Society for Cardiovascular Magnetic Resonance [En ligne]. 2011. Vol. 13, p. 54. Disponible sur : < http://dx.doi.org/10.1186/1532-429X-13-54 > (consulté le no date)
    Résumé : BACKGROUND: Gender-specific differences in cardiovascular risk are well known, and current evidence supports an existing role of endothelium in these differences. The purpose of this study was to assess non invasively coronary endothelial function in male and female young volunteers by myocardial blood flow (MBF) measurement using coronary sinus (CS) flow quantification by velocity encoded cine cardiovascular magnetic resonance (CMR) at rest and during cold pressor test (CPT). METHODS: Twenty-four healthy volunteers (12 men, 12 women) underwent CMR in a 3 Tesla MR imager. Coronary sinus flow was measured at rest and during CPT using non breath-hold velocity encoded phase contrast cine-CMR. Myocardial function and morphology were acquired using a cine steady-state free precession sequence. RESULTS: At baseline, mean MBF was 0.63 ± 0.23 mL·g⁻¹·min⁻¹ in men and 0.79 ± 0.21 mL·g⁻¹·min⁻¹ in women. During CPT, the rate pressure product in men significantly increased by 49 ± 36% (p < 0.0001) and in women by 52 ± 22% (p < 0.0001). MBF increased significantly in both men and women by 0.22 ± 0.19 mL·g⁻¹·min⁻¹ (p = 0.0022) and by 0.73 ± 0.43 mL·g⁻¹·min⁻¹ (p = 0.0001), respectively. The increase in MBF was significantly higher in women than in men (p = 0.0012). CONCLUSION: CMR coronary sinus flow quantification for measuring myocardial blood flow revealed a higher response of MBF to CPT in women than in men. This finding may reflect gender differences in endothelial-dependent vasodilatation in these young subjects. This non invasive rest/stress protocol may become helpful to study endothelial function in normal physiology and in physiopathology.
    Mots-clés : Adolescent, Adult, Blood Flow Velocity, Blood Pressure, Cold Temperature, Coronary Circulation, Coronary Sinus, crmbm, Endothelium, Vascular, Female, France, Hand, Heart Rate, Humans, Immersion, Magnetic Resonance Imaging, Cine, Male, Myocardial Perfusion Imaging, Observer Variation, Predictive Value of Tests, Reproducibility of Results, Sex Factors, Ventricular Function, Left, Young Adult.

2010

Journal Article

  • CALLOT V., DUHAMEL G., LE FUR Y., DECHERCHI P., MARQUESTE T., KOBER F., COZZONE P. J. “Echo planar diffusion tensor imaging of the mouse spinal cord at thoracic and lumbar levels: A feasibility study.”. Magnetic resonance in medicine [En ligne]. 2010. Vol. 63, n°4, p. 1125-1134. Disponible sur : < http://dx.doi.org/10.1002/mrm.22301 > (consulté le no date)
    Résumé : Diffusion tensor imaging is increasingly used for probing spinal cord (SC) pathologies, especially in mouse models of human diseases. However, diffusion tensor imaging series requires a long acquisition time and mouse experiments rarely use rapid imaging techniques such as echo planar imaging. A recent preliminary study demonstrated the feasibility and robustness of the echo planar imaging sequence for mouse cervical SC diffusion tensor imaging investigations. The feasibility of echo planar imaging at thoracic and lumbar levels, however, remained unknown due to bulk motion, field inhomogeneities, and off-centering of the SC in the axial plane. In the present study, the feasibility and the robustness of an echo planar imaging-based diffusion tensor imaging sequence for mouse thoracic and lumbar SC investigations is demonstrated. Quantitative and accurate diffusion tensor imaging metrics, as well as high spatially resolved images, have been obtained. This successful demonstration may open new perspectives in the field of mouse SC imaging. Echo planar imaging is used in several imaging modalities, such as relaxometry or perfusion, and may prove to be very attractive for multimodal MR investigations to acquire a more detailed characterization of the SC tissue.
    Mots-clés : Analysis of Variance, Animals, crmbm, Diffusion Magnetic Resonance Imaging, Echo-Planar Imaging, Feasibility Studies, Image Processing, Computer-Assisted, Lumbar Vertebrae, Male, Mice, Sensitivity and Specificity, Spinal Cord, Thoracic Vertebrae.

  • GROS D., THéVENIAU-RUISSY M., BERNARD M., CALMELS T., KOBER F., SöHL G., WILLECKE K., NARGEOT J., JONGSMA H. J., MANGONI M. E. “Connexin 30 is expressed in the mouse sino-atrial node and modulates heart rate.”. Cardiovascular research [En ligne]. 2010. Vol. 85, n°1, p. 45-55. Disponible sur : < http://dx.doi.org/10.1093/cvr/cvp280 > (consulté le no date)
    Résumé : AIMS: This study aimed at characterizing expression and the functional role of the Gjb6 gene, encoding for connexin 30 (Cx30) protein, in the adult mouse heart. METHODS AND RESULTS: The expression of the Gjb6 gene in the mouse heart was investigated by RT-PCR and sequencing of amplified cDNA fragments. The sites of Gjb6 expression were identified in the adult heart using transgenic mice with reporter genes (Cx30(LacZ/LacZ) and Cx30(LacZ/LacZ)/Cx40(EGFP/EGFP) mice), as well as anti-HCN4 (hyperpolarization activated cyclic nucleotide-gated potassium channel 4) or anti-connexin antibodies. Cine-magnetic resonance imaging and telemetric ECG recordings were used to evaluate the impact of Cx30 deficiency on cardiac physiology. Gjb6 was shown to be expressed in the sinoatrial (SA) node of the adult mouse heart. Eighty from 100 nuclei on average were LacZ-positive in the SA node of Cx30(LacZ/LacZ) mice. No significant LacZ expression was seen in other cardiac tissues. Cx30 protein was identified in low abundance in the SA node of wild-type mice, as indicated by immunofluorescence experiments. Telemetric ECG recordings indicated that Cx30-deficient mice displayed a mean daily heart rate (HR) that was 9% faster than that measured in control mice (572 +/- 38 b.p.m. vs. 524 +/- 23, P < 0.05). This moderate tachycardia was still observed after inhibition of the autonomic nervous system, demonstrating that Cx30 deficiency resulted in changes in the intrinsic electrical properties of the SA node. Consistent with this hypothesis, Cx30(LacZ/LacZ) displayed a significant reduction of SDNN (standard deviation of the interbeat interval) compared with control mice. Increase of both the cardiac index (20%) and the end-diastolic volume to body weight ratio (16%) with no deficiency in ejection fraction or stroke volume were observed in mutant mice. An increase in cardiac index was interpreted as being a direct consequence of high HR, whereas large end-diastolic volume may be an indirect consequence of prolonged high HR. CONCLUSION: Cx30 is functionally expressed, in low abundance, in the SA node of the adult mouse heart where it participates in HR regulation.
    Mots-clés : Animals, Connexins, crmbm, Electrocardiography, Female, Heart Rate, Male, Mice, Mice, Inbred C57BL, Myocardium, Rats, Wistar, Ventricular Remodeling.

  • LE FUR Y., NICOLI F., GUYE M., CONFORT-GOUNY S., COZZONE P. J., KOBER F. “Grid-free interactive and automated data processing for MR chemical shift imaging data.”. Magnetic Resonance Materials in Physics, Biology and Medicine [En ligne]. 2010. Vol. 23, n°1, p. 23-30. Disponible sur : < http://dx.doi.org/10.1007/s10334-009-0186-y > (consulté le no date)
    Résumé : PURPOSE: Today's available chemical shift imaging (CSI) analysis tools are based on Fourier transform of the entire data set prior to interactive display. This strategy is associated with limitations particularly when arbitrary voxel positions within a 3D spatial volume are needed by the user. In this work, we propose and demonstrate a processing-resource-efficient alternative strategy for both interactive and automated CSI data processing up to three spatial dimensions. METHODS: This approach uses real-time voxel-shift by first-order phase manipulation as a basis and therefore allows grid-free voxel positioning within the 3D volume. The corresponding spectrum is extracted from the 4D data (3D spatial/1D spectral) at each time a voxel position is selected. The spatial response function and hence the exact voxel size and shape are calculated in parallel including the same processing parameters. Using this mechanism sequentially along with AMARES time-domain modeling, we also implemented automated quantitative and B (0)-insensitive metabolite mapping. RESULTS: Metabolite maps of N-acetyl aspartate, choline and creatine were generated using (1)H-CSI data from the brain of healthy volunteers and patients with tumor and epilepsy. (31)P-3D-CSI of the heart of a healthy volunteer is also shown. CONCLUSION: The calculated metabolite maps demonstrate good stability and accuracy of the algorithm in all situations tested. The suggested algorithm constitutes therefore an attractive alternative to existing CSI processing strategies.
    Mots-clés : Aspartic Acid, Automatic Data Processing, Brain, Brain Mapping, Brain Neoplasms, Case-Control Studies, Choline, Creatine, crmbm, Epilepsy, Fourier Analysis, Humans, Imaging, Three-Dimensional, Magnetic Resonance Imaging, Reproducibility of Results, Sensitivity and Specificity.

2009

Journal Article

  • DUHAMEL G., CALLOT V., DECHERCHI P., LE FUR Y., MARQUESTE T., COZZONE P. J., KOBER F. “Mouse lumbar and cervical spinal cord blood flow measurements by arterial spin labeling: sensitivity optimization and first application.”. Magnetic Resonance in Medicine [En ligne]. 2009. Vol. 62, n°2, p. 430-439. Disponible sur : < http://dx.doi.org/10.1002/mrm.22015 > (consulté le no date)
    Résumé : In spinal cord injuries (SCI), tissue edema and consequent ischemia play an important role in neuronal damage. The assessment of quantitative spinal cord blood flow (SCBF) would be very valuable to help in understanding SCI pathophysiology. SCBF has previously been measured in animals with invasive techniques such as hydrogen clearance or labeled microspheres. A recent preliminary study also demonstrated the feasibility of assessing cervical SCBF by MRI with arterial spin labeling (ASL). However, due to bulk motion and field inhomogeneities, the feasibility of perfusion MRI at lower levels of the SC (thoracic, lumbar) remained an open question. In the present study, absolute SCBF measurements were carried out at both the cervical C3 and lumbar L1 levels of mouse SC using an adapted presaturated flow-sensitive alternating inversion recovery (presat-FAIR) ASL technique at 11.75T. Quantitative SCBF maps (resolution of 133 x 133 microm(2)) showed significantly lower gray matter (GM) perfusion values at the L1 level as compared to the C3 level (6% and 11% for the ventral and dorsal horns and 8% for total GM). The presat-FAIR technique was then successfully applied to a mouse model of hemisection performed at the L1 level, illustrating the potential of ASL to help in SC pathology characterization.
    Mots-clés : Animals, Arteries, Blood Flow Velocity, Cervical Vertebrae, crmbm, Image Enhancement, Information Storage and Retrieval, Lumbar Vertebrae, Magnetic Resonance Angiography, Male, Mice, Mice, Inbred C57BL, Reproducibility of Results, Rheology, Sensitivity and Specificity, Spin Labels, Spinal Cord.

2008

Journal Article

  • CALLOT V., DUHAMEL G., COZZONE P. J., KOBER F. “Short-scan-time multi-slice diffusion MRI of the mouse cervical spinal cord using echo planar imaging.”. NMR in biomedicine [En ligne]. 2008. Vol. 21, n°8, p. 868-877. Disponible sur : < http://dx.doi.org/10.1002/nbm.1274 > (consulté le no date)
    Résumé : Mouse spinal cord (SC) diffusion-weighted imaging (DWI) provides important information on tissue morphology and structural changes that may occur during pathologies such as multiple sclerosis or SC injury. The acquisition scheme of the commonly used DWI techniques is based on conventional spin-echo encoding, which is time-consuming. The purpose of this work was to investigate whether the use of echo planar imaging (EPI) would provide good-quality diffusion MR images of mouse SC, as well as accurate measurements of diffusion-derived metrics, and thus enable diffusion tensor imaging (DTI) and highly resolved DWI within reasonable scan times. A four-shot diffusion-weighted spin-echo EPI (SE-EPI) sequence was evaluated at 11.75 T on a group of healthy mice (n = 10). SE-EPI-derived apparent diffusion coefficients of gray and white matter were compared with those obtained using a conventional spin-echo sequence (c-SE) to validate the accuracy of the method. To take advantage of the reduction in acquisition time offered by the EPI sequence, multi-slice DTI acquisitions were performed covering the cervical segments (six slices, six diffusion-encoding directions, three b values) within 30 min (vs 2 h for c-SE). From these measurements, fractional anisotropy and mean diffusivities were calculated, and fiber tracking along the C1 to C6 cervical segments was performed. In addition, high-resolution images (74 x 94 microm(2)) were acquired within 5 min per direction. Clear delineation of gray and white matter and identical apparent diffusion coefficient values were obtained, with a threefold reduction in acquisition time compared with c-SE. While overcoming the difficulties associated with high spatially and temporally resolved DTI measurements, the present SE-EPI approach permitted identification of reliable quantitative parameters with a reproducibility compatible with the detection of pathologies. The SE-EPI method may be particularly valuable when multiple sets of images from the SC are needed, in cases of rapidly evolving conditions, to decrease the duration of anesthesia or to improve MR exploration by including additional MR measurements.
    Mots-clés : Anatomy, Cross-Sectional, Animals, Cervical Vertebrae, crmbm, Diffusion Magnetic Resonance Imaging, Echo-Planar Imaging, Image Enhancement, Image Interpretation, Computer-Assisted, Male, Mice, Mice, Inbred C57BL, Spinal Cord.

  • DUHAMEL G., CALLOT V., COZZONE P. J., KOBER F. “Spinal cord blood flow measurement by arterial spin labeling.”. Magnetic Resonance in Medicine [En ligne]. 2008. Vol. 59, n°4, p. 846-854. Disponible sur : < http://dx.doi.org/10.1002/mrm.21567 > (consulté le no date)
    Résumé : The assessment of spinal cord (SC) hemodynamics, and especially SC blood flow (SCBF), plays a key role in the pathophysiological description and understanding of many SC diseases such as ischemia, or spinal cord injury. SCBF has been previously measured in animals with invasive techniques such as autoradiography or labeled microspheres; no MR technique, however, has been proposed so far. The possibility of quantitatively measuring SCBF in mice using MRI was investigated using a presaturated FAIR (flow-sensitive alternating inversion recovery) arterial spin labeling (ASL) technique. SCBF measurements were performed at the cervical level of the mouse as well as on the brain so as to use cerebral blood flow (CBF) values as internal references. With a spatial resolution of 133 x 133 microm(2) for the SCBF maps, absolute regional perfusion values could be measured within the different structures of the SC (gray matter, white matter, and cerebrospinal fluid area). Similar perfusion values were found in SC gray matter (330+/-90 mL/100g/min) and in brain (295+/-22 mL/100g/min for thalamus). This result, in agreement with SCBF/CBF measurements performed with non-MR techniques, opens new perspectives for noninvasive longitudinal and in vivo animal studies. Application to human experiments may also be possible.
    Mots-clés : Animals, Blood Flow Velocity, crmbm, Image Interpretation, Computer-Assisted, Magnetic Resonance Imaging, Male, Mice, Mice, Inbred C57BL, Microcirculation, Spin Labels, Spinal Cord.

  • KOBER F., DUHAMEL G., COZZONE P. J. “Experimental comparison of four FAIR arterial spin labeling techniques for quantification of mouse cerebral blood flow at 4.7 T.”. NMR in biomedicine [En ligne]. 2008. Vol. 21, n°8, p. 781-792. Disponible sur : < http://dx.doi.org/10.1002/nbm.1253 > (consulté le no date)
    Résumé : Pulsed arterial spin labeling (ASL) is an attractive and robust method for quantification of rodent cerebral blood flow (CBF) in particular, although there is a need for sensitivity optimization. Look-Locker flow-sensitive alternating inversion recovery (FAIR) echo planar imaging (EPI) (LLFAIREPI) was expected to be a likely candidate for assessing sensitivity, although it has not yet been applied to rodents. In this study, the performance of two FAIR techniques and two Look-Locker FAIR techniques were compared in mouse brain at 4.7 T. FAIR-EPI (single inversion time, FAIREPI-1TI), FAIR-EPI (eight inversion times, FAIREPI-8TI), LLFAIREPI and Look-Locker FAIR gradient echo (LLFAIRGE) sequences were implemented with equal spatial resolution and equal FAIR preparation modules. Measurements were carried out sequentially on the brain in 10 healthy mice, and quantitative CBF maps were obtained after different acquisition times up to 23 min. All methods gave similar group variability in CBF. Especially at shorter acquisition times, LLFAIREPI gave lower relative variations in CBF within selected brain regions than the other techniques at the same acquisition time. The Look-Locker techniques, however, overestimated CBF compared with classical FAIR-EPI, which was attributed to bulk flow in arterioles and T(2) effects. The image quality with LLFAIREPI was less reproducible within the group. Both FAIREPI-1TI and LLFAIREPI appear to be good candidates for serial rapid measurement of CBF, but LLFAIREPI has the additional advantage that apparent T(1) can be measured simultaneously with CBF.
    Mots-clés : Animals, Cerebral Arteries, Cerebrovascular Circulation, crmbm, Image Interpretation, Computer-Assisted, Magnetic Resonance Angiography, Male, Mice, Mice, Inbred C57BL, Reproducibility of Results, Rheology, Sensitivity and Specificity, Spin Labels.

2007

Journal Article

  • KOBER F., CANAULT M., PEIRETTI F., MUELLER C., KOPP F., ALESSI M. - C., COZZONE P. J., NALBONE G., BERNARD M. “MRI follow-up of TNF-dependent differential progression of atherosclerotic wall-thickening in mouse aortic arch from early to advanced stages.”. Atherosclerosis [En ligne]. 2007. Vol. 195, n°2, p. e93-99. Disponible sur : < http://dx.doi.org/10.1016/j.atherosclerosis.2007.06.015 > (consulté le no date)
    Résumé : OBJECTIVES: An optimized, longitudinal in vivo magnetic resonance vessel wall-imaging protocol was evaluated regarding its capability of detecting differences in the time-dependent atherosclerotic lesion progression in the aortic arch between ApoE(-/-) and double-deficient ApoE(-/-)/TNF(-/-) mice at comparatively early plaque development stages. MATERIALS AND METHODS: Seven ApoE(-/-) and seven ApoE(-/-)/TNF(-/-) female mice underwent MRI at 11.75 teslas at four stages up to 26 weeks of age. A double-gated spin-echo MRI sequence was used with careful perpendicular slice positioning to visualize the vessel wall of the ascending aortic arch. RESULTS: Wall-thickness progression measured with MRI was significant at 11 weeks of age in ApoE(-/-) mice, but only at 26 weeks in ApoE(-/-)/TNF(-/-) mice. A significant correlation was found between MRI wall-thickness and lesion area determined on histology. CONCLUSION: MRI was shown to be sensitive enough to reveal subtle genetically-induced differences in lesion progression at ages earlier than 25 weeks.
    Mots-clés : Animals, Aorta, Thoracic, Apolipoproteins E, Atherosclerosis, crmbm, Disease Models, Animal, Disease Progression, Echo-Planar Imaging, Female, Mice, Mice, Knockout, Sensitivity and Specificity, Tumor Necrosis Factor-alpha.

  • PENET M. - F., KOBER F., CONFORT-GOUNY S., LE FUR Y., DALMASSO C., COLTEL N., LIPRANDI A., GULIAN J. - M., GRAU G. E., COZZONE P. J., VIOLA A. “Magnetic resonance spectroscopy reveals an impaired brain metabolic profile in mice resistant to cerebral malaria infected with Plasmodium berghei ANKA.”. The Journal of Biological Chemistry [En ligne]. 2007. Vol. 282, n°19, p. 14505-14514. Disponible sur : < http://dx.doi.org/10.1074/jbc.M608035200 > (consulté le no date)
    Résumé : Malaria is a major cause of morbidity and mortality with an annual death toll exceeding one million. Severe malaria is a complex multisystem disorder, including one or more of the following complications: cerebral malaria, anemia, acidosis, jaundice, respiratory distress, renal insufficiency, coagulation anomalies, and hyperparasitemia. Using a combined in vivo/in vitro metabolic-based approach, we investigated the putative pathogenic effects of Plasmodium berghei ANKA on brain, in a mouse strain developing malaria but resistant to cerebral malaria. The purpose was to determine whether the infection could cause a brain dysfunction distinct from the classic cerebral syndrome. Mice resistant to cerebral malaria were infected with P. berghei ANKA and explored during both the symptomless and the severe stage of the disease by using in vivo brain magnetic resonance imaging and spectroscopy. The infected mice did not present the lesional and metabolic hallmarks of cerebral malaria. However, brain dysfunction caused by anemia, parasite burden, and hepatic damage was evidenced. We report an increase in cerebral blood flow, a process allowing temporary maintenance of oxygen supply to brain despite anemia. Besides, we document metabolic anomalies affecting choline-derived compounds, myo-inositol, glutamine, glycine, and alanine. The choline decrease appears related to parasite proliferation. Glutamine, myo-inositol, glycine, and alanine variations together indicate a hepatic encephalopathy, a finding in agreement with the liver damage detected in mice, which is also a feature of the human disease. These results reveal the vulnerability of brain to malaria infection at the severe stage of the disease even in the absence of cerebral malaria.
    Mots-clés : Alanine, Anemia, Animals, Brain, Brain Diseases, Brain Edema, Brain Ischemia, Cell Proliferation, Cerebrovascular Circulation, crmbm, Female, Liver, Magnetic Resonance Spectroscopy, Malaria, Cerebral, Mice, Mice, Inbred BALB C, Plasmodium berghei.

2006

Journal Article

  • CAUS T., KOBER F., MARIN P., MOULY-BANDINI A., QUILICI J., MÉTRAS D., COZZONE P. J., BERNARD M. “Non-invasive diagnostic of cardiac allograft vasculopathy by 31P magnetic resonance chemical shift imaging.”. European Journal of Cardio-Thoracic Surgery: Official Journal of the European Association for Cardio-Thoracic Surgery [En ligne]. 2006. Vol. 29, n°1, p. 45-49. Disponible sur : < http://dx.doi.org/10.1016/j.ejcts.2005.10.038 > (consulté le no date)
    Résumé : BACKGROUND: Coronary angiography is still the gold standard for the diagnosis of cardiac allograft vasculopathy (CAV) for which alternative non-invasive diagnostic approaches are currently investigated. In this study, we assessed whether 31P magnetic resonance chemical shift imaging can diagnose CAV by studying variations in cardiac high-energy phosphates in a population of adult heart transplant recipients. METHODS AND RESULTS: CAV was defined by coronary angiography as the presence of diffuse coronary irregularities with significant concentric narrowing on epicardial or distal coronary arteries. Eight patients with CAV (group A), and 18 patients without CAV (group B) were included in this study and compared to nine healthy volunteers (group C). Patients and volunteers underwent 31P three-dimensional chemical shift imaging to determine the ratio of phosphocreatine (PCr) and adenosine tri-phosphate (ATP). PCr/ATP was significantly lower in group A (1.51+/-0.50) than in groups B and C (1.98+/-0.53 (p=0.003) and 2.14+/-0.31 (p=0.001)), respectively. Time from transplant, number of episodes of acute rejection, and left ventricular ejection fraction (LVEF) were not significantly different between patient groups. A PCr/ATP value of 1.59 was the optimal cut-off value to predict CAV (specificity and sensitivity of 100% and 72%, respectively). CONCLUSION: Clinically, in vivo 31P chemical shift imaging is a promising, non-invasive method to detect the potential modifications of high-energy phosphates related to CAV and to better screen indications for coronary angiograms. This may be relevant for coronary angiography follow-up and adjustments of immunotherapy regimen.
    Mots-clés : Adenosine Triphosphate, Adult, Coronary Disease, Coronary Vessels, crmbm, Female, Graft Rejection, Heart Transplantation, Humans, Magnetic Resonance Spectroscopy, Male, Phosphates, Phosphocreatine, Phosphorus Isotopes, Stroke Volume, Time Factors.

2005

Journal Article

  • CAUS T., KOBER F., MOULY-BANDINI A., RIBERI A., MÉTRAS D. R., COZZONE P. J., BERNARD M. “31P MRS of heart grafts provides metabolic markers of early dysfunction.”. European Journal of Cardio-Thoracic Surgery: Official Journal of the European Association for Cardio-Thoracic Surgery [En ligne]. 2005. Vol. 28, n°4, p. 576-580. Disponible sur : < http://dx.doi.org/10.1016/j.ejcts.2005.07.009 > (consulté le no date)
    Résumé : OBJECTIVE: Early graft failure (EGF) is a life-threatening event still accounting for a significant percentage of early deaths after heart transplantation. We tested whether selected metabolic markers, including high-energy phosphate concentrations measured ex vivo in pre-transplant heart grafts by (31)P magnetic resonance spectroscopy (MRS) are related with early post-transplant outcome. METHODS: During a 3-year period, 26 heart grafts harvested in the vicinity of the transplantation centre were studied. Evaluation of transplantability was done conventionally. (31)P MRS was performed ex vivo approximately 60min after aortic cross-clamp to quantify ATP, P(i) and PCr concentration ratios. A MRS-score was defined as a combination of intracellular pH (pHi) and the PCr/P(i) ratio. EGF was defined as the need to abnormally extend circulatory support or to use more than two inotropes before weaning the patient from CPB after transplantation. The grafts were attributed to three groups as follows: A1, transplanted with uneventful outcome (n=14); A2, transplanted with subsequent EGF (n=3) and B, not suitable for transplantation (n=9). RESULTS: Significant differences between groups existed for the following metabolic markers: PCr/ATP (P=0.013), PCr/P(i) (P=0.0004), pHi (P=0.0016) and MRS-score (P=0.0001). The sensitivity, specificity and positive likelihood ratio for EGF with a MRS-score<or=1.95 were, respectively, 100%, 86% and 7. CONCLUSIONS: In the setting of this study, post-transplant outcome was related to the pre-transplant MRS-score of grafts evaluated ex vivo. This result might help to more securely use grafts from marginal donors.
    Mots-clés : Adenosine Triphosphate, Biomarkers, crmbm, Delayed Graft Function, Heart, Heart Transplantation, Humans, Magnetic Resonance Spectroscopy, Middle Aged, Phosphocreatine, Phosphorus Isotopes, Pilot Projects, Predictive Value of Tests.

  • ILTIS I., KOBER F., DALMASSO C., COZZONE P. J., BERNARD M. “Noninvasive characterization of myocardial blood flow in diabetic, hypertensive, and diabetic-hypertensive rats using spin-labeling MRI.”. Microcirculation (New York, N.Y.: 1994) [En ligne]. 2005. Vol. 12, n°8, p. 607-614. Disponible sur : < http://dx.doi.org/10.1080/10739680500301607 > (consulté le no date)
    Résumé : OBJECTIVE: Microvascular alterations in the diabetic and hypertensive heart are likely to contribute to heart failure. In this work, myocardial blood flow and left ventricular function were measured in vivo in diabetic, hypertensive, and diabetic-hypertensive rats using MRI methods. METHODS: An 8-week-duration type 1 diabetes was induced by streptozotocin (STZ) in 8 Wistar-Kyoto (WKY) rats (STZ) and in 11 spontaneously hypertensive (SHR) rats (STZ-SHR). Fourteen WKY and 12 SHR served as control and hypertensive groups. Myocardial blood flow quantification was performed using an arterial spin-labeling MRI method. Left ventricular morphology and function were assessed during the same experiment using cine-MRI. RESULTS: Respective myocardial blood flow values for each group were 6.4 +/- 1.1 (WKY), 6.0 +/- 1.9 (STZ), 5.5 +/- 1.3 (SHR), and 4.3 +/- 0.9 mL. g(-1). min(-1) (STZ-SHR). Myocardial blood flow was significantly decreased in STZ-SHR rats compared with the other groups (p <.05, STZ-SHR vs. all groups). Cine-MRI showed morphological alterations in all pathological groups. No alteration of the ejection fraction was observed in the pathological groups. CONCLUSION: Myocardial blood flow is altered in vivo before any sign of heart failure when rats have type 1 diabetes and hypertension simultaneously. When only one of the pathologies occurs, MBF does not vary significantly.
    Mots-clés : Animals, Blood Flow Velocity, Coronary Circulation, crmbm, Diabetes Mellitus, Experimental, Heart Failure, Hypertension, Magnetic Resonance Angiography, Rats, Rats, Inbred SHR, Rats, Inbred WKY, Spin Labels.

  • ILTIS I., KOBER F., DALMASSO C., LAN C., COZZONE P. J., BERNARD M. “In vivo assessment of myocardial blood flow in rat heart using magnetic resonance imaging: effect of anesthesia.”. Journal of magnetic resonance imaging: JMRI [En ligne]. 2005. Vol. 22, n°2, p. 242-247. Disponible sur : < http://dx.doi.org/10.1002/jmri.20352 > (consulté le no date)
    Résumé : PURPOSE: To assess the influence of isoflurane and pentobarbital anesthesia and the carrier gases on myocardial blood flow (MBF) in the rat heart in vivo. MATERIALS AND METHODS: MBF was quantified in vivo using arterial spin-labeling (ASL) magnetic resonance imaging (MRI). Left ventricular (LV) function was estimated during the same experiment using cine-MRI. Thirty-four male Wistar-Kyoto rats were divided in four groups, one anesthetized with isoflurane in oxygen:nitrous oxide mix (ISO), the three others with intraperitoneal pentobarbital, and breathing either room air (PB), oxygen:nitrous oxide (PB + N(2)O), or oxygen:nitrogen (PB + N(2)). RESULTS: MBF was significantly higher in the ISO and PB + N(2)O groups vs. PB and in ISO vs. PB + N(2), with the following respective MBF values: ISO, 5.9 +/- 1.1; PB, 4.0 +/- 0.8; PB + N(2)O, 5.1 +/- 1.4; and PB + N(2), 4.6 +/- 0.8 mL/g/minute, mean +/- SD. Ejection fractions were reduced by 10% in PB and PB + N(2)O rats vs. ISO rats. Cardiac output (CO) and index (CI) were 25 to 30% lower in all rats anesthetized with pentobarbital than with isoflurane. CONCLUSION: Isoflurane and nitrous oxide induce a higher MBF than pentobarbital. Isoflurane also induces a higher ejection fraction in healthy rats.
    Mots-clés : Anesthesia, Inhalation, Anesthetics, Inhalation, Animals, Coronary Circulation, crmbm, Disease Models, Animal, Female, Hemodynamics, Isoflurane, Magnetic Resonance Angiography, Magnetic Resonance Imaging, Cine, Male, Myocardium, Nitrous Oxide, Pentobarbital, Rats, Rats, Wistar, Sensitivity and Specificity, Stroke Volume.
  • ILTIS I., KOBER F., DESROIS M., DALMASSO C., LAN C., PORTHA B., COZZONE P. J., BERNARD M. “Defective myocardial blood flow and altered function of the left ventricle in type 2 diabetic rats: a noninvasive in vivo study using perfusion and cine magnetic resonance imaging.”. Investigative Radiology. 2005. Vol. 40, n°1, p. 19-26.
    Résumé : OBJECTIVE: In type 2 diabetes mellitus, cardiovascular complications are related to microvascular abnormalities. In this work, we aimed at characterizing in vivo myocardial blood flow and left ventricular function of the Goto-Kakizaki (GK) rat as a nonobese model of type 2 diabetes. MATERIALS AND METHODS: We performed arterial spin labeling magnetic resonance imaging (MRI) for myocardial blood flow quantification and cine MRI for functional evaluation in free-breathing isoflurane-anesthetized animals. RESULTS: Myocardial blood flow was altered in adult female GK rats compared with age-matched female Wistar rats (4.7 +/- 1.6 vs. 7.1 +/- 1.2 mL/g/min respectively, P = 0.0022). Ejection fraction was decreased in GK compared with Wistar rats (64 +/- 7 vs. 78 +/- 8% respectively, P <0.005), mainly as a result of a loss in left ventricular longitudinal contraction. CONCLUSIONS: Adult female GK rats have defective myocardial blood flow associated with altered left ventricular function. This multiparametric MRI approach in the GK rat is of particular interest for the study of type 2 diabetic cardiomyopathy.
    Mots-clés : Animals, Coronary Circulation, crmbm, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Female, Magnetic Resonance Imaging, Cine, Rats, Rats, Wistar, Ventricular Dysfunction, Left.

  • KOBER F., ILTIS I., COZZONE P. J., BERNARD M. “Myocardial blood flow mapping in mice using high-resolution spin labeling magnetic resonance imaging: influence of ketamine/xylazine and isoflurane anesthesia.”. Magnetic Resonance in Medicine [En ligne]. 2005. Vol. 53, n°3, p. 601-606. Disponible sur : < http://dx.doi.org/10.1002/mrm.20373 > (consulté le no date)
    Résumé : Genetically modified mouse models of many human diseases reflecting cardiovascular alterations are currently available. To date, little information on absolute myocardial perfusion in mice is found in the literature. High-resolution quantitative myocardial blood flow maps (in-plane resolution 156 x 312 mum(2), slice thickness 1.5 mm) have been obtained noninvasively within 25 min at 4.7 T in 30 freely breathing C57/Bl6J mice using electrocardiogram- and respiration-gated spin labeling magnetic resonance imaging (MRI). Regional myocardial blood flow measurements were carried out, and the effects of isoflurane at two different concentrations and ketamine/xylazine anesthesia were assessed. The mean blood flow value in the left ventricular myocardium was 6.0 +/- 1.9 mL g(-1) min(-1) under ketamine/xylazine and 6.9 +/- 1.7 mL g(-1) min(-1) (group average +/- SD) under isoflurane (1.25%). Under the influence of higher isoflurane concentration (2.00%), myocardial blood flow increased dramatically to 16.9 +/- 1.8 mL g(-1)min(-1) with no significant change in heart rate. This work illustrates the feasibility of noninvasive quantitative myocardial perfusion mapping in mice using MRI. The study of the influence of anesthesia shows that myocardial blood flow is highly sensitive to isoflurane concentration. The method employed offers a noninvasive approach to longitudinal studies of murine models of cardiac disease.
    Mots-clés : Adrenergic alpha-Agonists, Analysis of Variance, Anesthetics, Dissociative, Anesthetics, Inhalation, Animals, Coronary Circulation, crmbm, Image Processing, Computer-Assisted, Isoflurane, Ketamine, Magnetic Resonance Imaging, Male, Mice, Spin Labels, Xylazine.

  • PENET M. - F., VIOLA A., CONFORT-GOUNY S., LE FUR Y., DUHAMEL G., KOBER F., IBARROLA D., IZQUIERDO M., COLTEL N., GHARIB B., GRAU G. E., COZZONE P. J. “Imaging experimental cerebral malaria in vivo: significant role of ischemic brain edema.”. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience [En ligne]. 2005. Vol. 25, n°32, p. 7352-7358. Disponible sur : < http://dx.doi.org/10.1523/JNEUROSCI.1002-05.2005 > (consulté le no date)
    Résumé : The first in vivo magnetic resonance study of experimental cerebral malaria is presented. Cerebral involvement is a lethal complication of malaria. To explore the brain of susceptible mice infected with Plasmodium berghei ANKA, multimodal magnetic resonance techniques were applied (imaging, diffusion, perfusion, angiography, spectroscopy). They reveal vascular damage including blood-brain barrier disruption and hemorrhages attributable to inflammatory processes. We provide the first in vivo demonstration for blood-brain barrier breakdown in cerebral malaria. Major edema formation as well as reduced brain perfusion was detected and is accompanied by an ischemic metabolic profile with reduction of high-energy phosphates and elevated brain lactate. In addition, angiography supplies compelling evidence for major hemodynamics dysfunction. Actually, edema further worsens ischemia by compressing cerebral arteries, which subsequently leads to a collapse of the blood flow that ultimately represents the cause of death. These findings demonstrate the coexistence of inflammatory and ischemic lesions and prove the preponderant role of edema in the fatal outcome of experimental cerebral malaria. They improve our understanding of the pathogenesis of cerebral malaria and may provide the necessary noninvasive surrogate markers for quantitative monitoring of treatment.
    Mots-clés : Animals, Blood-Brain Barrier, Brain, Brain Edema, Brain Ischemia, Cerebral Hemorrhage, Cerebrovascular Circulation, crmbm, Female, Magnetic Resonance Angiography, Magnetic Resonance Imaging, Malaria, Cerebral, Mice, Mice, Inbred CBA, Neurons.

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