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PERLES-BARBACARU Teodora-Adriana

MD, PhD - AMU Associate Professor

teodora.perles-barbacaru@univ-amu.fr
tel : +33 4 91 32 48 04

Key Words
- magnetic resonance imaging and spectroscopy
- animal models of brain pathologies
- experimental cerebral malaria

Current research interest and projects

Development and implementation of Magnetic Resonance Imaging (MRI) techniques and their application to the study of pathogenic mechanisms in animal models of brain diseases. We study selected mouse models of brain pathologies using innovative and quantitative in vivo MRI and MRS techniques. Priority is set on the study of a murine model of cerebral malaria, a major cause of morbidity and mortality in the developing world with an estimated human death toll of one million per year. The research project is intended to increase fundamental knowledge on experimental cerebral malaria pathogenesis, to improve the MRI characterization of this disease, and to assess new therapeutic strategies.

Teaching

Neurosciences, Medical Imaging, Nuclear Magnetic Resonance physics, Magnetic Resonance Imaging techniques and their applications

Publications

2015

Journal Article
  • COLLIGNON A., PERLES-BARBACARU A. T., ROBERT S., SILVY F., MARTINEZ E., CRENON I., GERMAIN S., GARCIA S., VIOLA A., LOMBARDO D., MAS E., BéRAUD E. “A pancreatic tumor-specific biomarker characterized in humans and mice as an immunogenic onco-glycoprotein is efficient in dendritic cell vaccination.”. Oncotarget. 2015. Vol. 6, n°27, p. 23462-23479.
    Résumé : Oncofetal fucose-rich glycovariants of the pathological bile salt-dependent lipase (pBSDL) appear during human pancreatic oncogenesis and are detected by themonoclonal antibody J28 (mAbJ28). We aimed to identify murine counterparts onpancreatic ductal adenocarcinoma (PDAC) cells and tissue and investigate the potential of dendritic cells (DC) loaded with this unique pancreatic tumor antigen to promote immunotherapy in preclinical trials. Pathological BSDLs purified from pancreatic juices of patients with PDAC were cleaved to generate glycosylated C-terminal moieties (C-ter) containing mAbJ28-reactive glycoepitopes. Immunoreactivity of the murine PDAC line Panc02 and tumor tissue to mAbJ28 was detected by immunohistochemistry and flow cytometry. C-ter-J28+ immunization promoted Th1-dominated immune responses. In vitro C-ter-J28+-loaded DCskewed CD3+ T-cells toward Th1 polarization. C-ter-J28+-DC-vaccinations selectively enhanced cell immunoreactivity to Panc02, as demonstrated by CD4+- and CD8+-T-cell activation, increased percentages of CD4+- and CD8+-T-cells and NK1.1+ cells expressing granzyme B, and T-cell cytotoxicity. Prophylactic and therapeutic C-ter-J28+-DC-vaccinations reduced ectopic Panc02-tumor growth, provided long-lasting protection from Panc02-tumor development in 100% of micebut not from melanoma, and attenuated progression of orthotopic tumors as revealed by MRI. Thusmurine DC loaded with pancreatic tumor-specific glycoepitope C-ter-J28+ induce efficient anticancer adaptive immunity and represent a potential adjuvant therapy for patients afflicted with PDAC.

  • MASI B., PERLES-BARBACARU T. - A., LAPRIE C., DESSEIN H., BERNARD M., DESSEIN A., VIOLA A. “In Vivo MRI Assessment of Hepatic and Splenic Disease in a Murine Model of Schistosomiasis [corrected].”. PLoS neglected tropical diseases [En ligne]. 2015. Vol. 9, n°9, p. e0004036. Disponible sur : < http://dx.doi.org/10.1371/journal.pntd.0004036 > (consulté le no date)
    Résumé : BACKGROUND: Schistosomiasis (or bilharzia), a major parasitic disease, affects more than 260 million people worldwide. In chronic cases of intestinal schistosomiasis caused by trematodes of the Schistosoma genus, hepatic fibrosis develops as a host immune response to the helminth eggs, followed by potentially lethal portal hypertension. In this study, we characterized hepatic and splenic features of a murine model of intestinal schistosomiasis using in vivo magnetic resonance imaging (MRI) and evaluated the transverse relaxation time T2 as a non-invasive imaging biomarker for monitoring hepatic fibrogenesis. METHODOLOGY/PRINCIPAL FINDINGS: CBA/J mice were imaged at 11.75 T two, six and ten weeks after percutaneous infection with Schistosoma mansoni. In vivo imaging studies were completed with histology at the last two time points. Anatomical MRI allowed detection of typical manifestations of the intestinal disease such as significant hepato- and splenomegaly, and dilation of the portal vein as early as six weeks, with further aggravation at 10 weeks after infection. Liver multifocal lesions observed by MRI in infected animals at 10 weeks post infection corresponded to granulomatous inflammation and intergranulomatous fibrosis with METAVIR scores up to A2F2. While most healthy hepatic tissue showed T2 values below 14 ms, these lesions were characterized by a T2 greater than 16 ms. The area fraction of increased T2 correlated (rS = 0.83) with the area fraction of Sirius Red stained collagen in histological sections. A continuous liver T2* decrease was also measured while brown pigments in macrophages were detected at histology. These findings suggest accumulation of hematin in infected livers. CONCLUSIONS/SIGNIFICANCE: Our multiparametric MRI approach confirms that this murine model replicates hepatic and splenic manifestations of human intestinal schistosomiasis. Quantitative T2 mapping proved sensitive to assess liver fibrogenesis non-invasively and may therefore constitute an objective imaging biomarker for treatment monitoring in diseases involving hepatic fibrosis.
    Mots-clés : crmbm.

  • SARRAF M., PERLES-BARBACARU A. T., NISSOU M. F., VAN DER SANDEN B., BERGER F., LAHRECH H. “Rapid-Steady-State-T1 signal modeling during contrast agent extravasation: toward tumor blood volume quantification without requiring the arterial input function.”. Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine [En ligne]. 2015. Vol. 73, n°3, p. 1005-1014. Disponible sur : < http://dx.doi.org/10.1002/mrm.25218 > (consulté le no date)
    Résumé : PURPOSE: This study demonstrates how to quantify the tumor blood volume fraction (BVf) using the dynamic Rapid-Steady-State-T1 (RSST1 )-MRI method despite contrast agent (CA) leakage and without arterial input function (AIF) determination. METHODS: For vasculature impermeable to CAs, the BVf is directly quantified from the RSST1 signal amplitude. In case of CA extravasation, we propose a two-compartment model to describe the dynamic RSST1 signal increase. We applied the mathematical model in a pilot-study on a RG2-glioma model to compare extravasation of two Gd-based CAs. The BVf quantification using the mathematical model in a C6-glioma model (n = 8) with the clinical CA Gd-DOTA was validated using a ΔR2 *-steady-state MRI method with an USPIO and by immunohistochemical staining of perfused vessels labeled with Hoechst-33342 dye in the same rats. RESULTS: BVf in tumor and in healthy brain tissues (0.034 ± 0.005 and 0.026 ± 0.004, respectively) derived from the dynamic RSST1 signal were confirmed by ΔR2 *-steady-state MRI (0.036 ± 0.003 and 0.027 ± 0.002, respectively, correlation coefficient rS = 0.74) and by histology (0.036 ± 0.003 and 0.025 ± 0.004 respectively, rS = 0.87). CONCLUSION: Straightforward tumor BVf quantification without AIF determination is demonstrated in presence of CA leakage. The method will facilitate angiogenesis assessment in longitudinal neuro-oncologic studies in particular when monitoring the response to antiangiogenic therapies.

2013

Book Section
Journal Article

  • PERLES-BARBACARU A. T., BERGER F., LAHRECH H. “Quantitative rapid steady state T1 magnetic resonance imaging for cerebral blood volume mapping in mice: Lengthened measurement time window with intraperitoneal Gd-DOTA injection.”. Magnetic resonance in medicine: official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine [En ligne]. 2013. Vol. 69, n°5, p. 1451-1456. Disponible sur : < http://dx.doi.org/10.1002/mrm.24365 > (consulté le no date)
    Résumé : This work demonstrates how the rapid steady state T1 MRI technique for cerebral blood volume fraction (BVf) quantification can be used with intraperitoneal Gd-DOTA injections in mice at 4.7 T. The peak signal amplitude after intravenous administration (0.7 mmol/kg) and the steady state signal amplitude reached 15 min after intraperitoneal administration (6 mmol/kg) in the same mice lead to equivalent BVf measures in the order of 0.02 in the brain. The resulting time window for BVf quantification is ≈30 min and allows for cerebral BVf mapping with increased spatial resolution or signal-to-noise ratio, or for monitoring functional BVf changes. A cerebral BVf increase of up to 25% induced by the vasodilator acetazolamide was observed, validating the vascular origin of the signal. The noninvasive and quantitative rapid steady state T1 technique can be used in serial studies to evaluate new drugs or disease models, such as antiangiogenic therapies in tumors.

2012

Book

  • PERLES-BARBACARU T. - A., LAHRECH H. Magnetic Resonance Imaging of the Cerebral Blood Volume: Characterization of Experimental Brain Tumor Neovascularization. [s.l.] : LAP Lambert Academic Publishing, 2012. 452 p.ISBN : 9783659146114.
    Résumé : Cerebral blood volume fraction (CBVf) mapping by magnetic resonance imaging (MRI) can provide information about tumor angiogenesis. The Rapid Steady State T1 (RSST1) MRI method, based on a two-compartment model, intra- and extravascular, and on the longitudinal relaxivity of intravascular contrast agents (CAs), is developed and validated on healthy rats at 2.35 T (CBVf: 2 to 3%) using Gd-DOTA, approved for clinical use, and the experimental CA P760. Gd-ACX and SINEREM are evaluated for their blood pool properties in two rat glioma models C6 and RG2. The CBVf measures in tumor tissue are confirmed by histologic vascular morphometric analysis and were compared with those obtained by a DeltaR2*-based steady state method using the same SINEREM injection. In case of CA extravasation, such as occurs in tumor tissue with Gd-DOTA, the CBVf along with the transfer coefficient (related to the endothelial permeability) were obtained by pharmacokinetic two-compartment analysis of dynamic RSST1 acquisitions. In conclusion, the RSST1 method in conjunction with appropriate CAs can be used for longitudinal angiogenesis studies to quantify the CBVf and the vascular permeability.
Journal Article

  • PERLES-BARBACARU A. T., VAN DER SANDEN B. P. J., FARION R., LAHRECH H. “How stereological analysis of vascular morphology can quantify the blood volume fraction as a marker for tumor vasculature: comparison with magnetic resonance imaging.”. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism [En ligne]. 2012. Vol. 32, n°3, p. 489-501. Disponible sur : < http://dx.doi.org/10.1038/jcbfm.2011.151 > (consulté le no date)
    Résumé : To assess angiogenesis noninvasively in a C6 rat brain tumor model, the rapid-steady-state-T(1) (RSST(1)) magnetic resonance imaging (MRI) method was used for microvascular blood volume fraction (BVf) quantification with a novel contrast agent gadolinium per (3,6 anhydro) α-cyclodextrin (Gd-ACX). In brain tissue contralateral to the tumor, equal BVfs were obtained with Gd-ACX and the clinically approved gadoterate meglumine (Gd-DOTA). Contrary to Gd-DOTA, which leaks out of the tumor vasculature, Gd-ACX was shown to remain vascular in the tumor tissue allowing quantification of the tumor BVf. We sought to confirm the obtained tumor BVf using an independent method: instead of using a 'standard' two-dimensional histologic method, we study here how vascular morphometry combined with a stereological technique can be used for three-dimensional assessment of the vascular volume fraction (V(V)). The V(V) is calculated from the vascular diameter and length density. First, the technique is evaluated on simulated data and the healthy rat brain vasculature and is then applied to the same C6 tumor vasculature previously quantified by RSST(1)-MRI with Gd-ACX. The mean perfused V(V) and the BVf obtained by MRI in tumor regions are practically equal and the technique confirms the spatial heterogeneity revealed by MRI.
    Mots-clés : Animals, Blood Volume, Blood Volume Determination, Brain Mapping, Brain Neoplasms, Cell Line, Tumor, Contrast Media, Glioma, Heterocyclic Compounds, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Microscopy, Fluorescence, Microvessels, Models, Anatomic, Neoplasm Transplantation, Neovascularization, Pathologic, Organometallic Compounds, Rats, Rats, Wistar.

  • PERLES-BARBACARU T. - A., PROCISSI D., DEMYANENKO A. V., JACOBS R. E. “Quantitative pharmacologic MRI in mice.”. NMR in biomedicine [En ligne]. 2012. Vol. 25, n°4, p. 498-505. Disponible sur : < http://dx.doi.org/10.1002/nbm.1760 > (consulté le no date)
    Résumé : Pharmacologic MRI (phMRI) uses functional MRI techniques to provide a noninvasive in vivo measurement of the hemodynamic effects of drugs. The cerebral blood volume change (ΔCBV) serves as a surrogate for neuronal activity via neurovascular coupling mechanisms. By assessing the location and time course of brain activity in mouse mutant studies, phMRI can provide valuable insights into how different behavioral phenotypes are expressed in deferring brain activity response to drug challenge. In this report, we evaluate the utility of three different intravascular ultrasmall superparamagnetic iron oxide (USPIO) contrast agents for phMRI using a gradient-echo technique, with temporal resolution of one min at high magnetic field. The tissue half-life of the USPIOs was studied using a nonlinear detrending model. The three USPIOs are candidates for CBV weighted phMRI experiments, with r(2)/r(1) ratios ≥ 20 and apparent half-lives ≥ 1.5 h at the described doses. An echo-time of about 10 ms or longer results in a functional contrast to noise ratio (fCNR) > 75 after USPIO injection, with negligible decrease between 1.5-2 h. phMRI experiments were conducted at 7 T using cocaine as a psychotropic substance and acetazolamide, a global vasodilator, as a positive control. Cocaine acts as a dopamine-serotonin-norepinephrine reuptake inhibitor, increasing extracellular concentrations of these neurotransmitters, and thus increasing dopaminergic, serotonergic and noradrenergic neurotransmission. phMRI results showed that CBV was reduced in the normal mouse brain after cocaine challenge, with the largest effects in the nucleus accumbens, whereas after acetazolamide, blood volume was increased in both cerebral and extracerebral tissue.
    Mots-clés : Acetazolamide, Animals, Blood Flow Velocity, Blood Volume, Cerebrovascular Circulation, Cocaine, Contrast Media, Dextrans, Female, Magnetic Resonance Imaging, Magnetite Nanoparticles, Mice, Mice, Inbred C57BL, Vasodilator Agents.

2011

Journal Article

  • PERLES-BARBACARU T. - A., PROCISSI D., DEMYANENKO A. V., HALL F. S., UHL G. R., JACOBS R. E. “Quantitative pharmacologic MRI: mapping the cerebral blood volume response to cocaine in dopamine transporter knockout mice.”. NeuroImage [En ligne]. 2011. Vol. 55, n°2, p. 622-628. Disponible sur : < http://dx.doi.org/10.1016/j.neuroimage.2010.12.048 > (consulté le no date)
    Résumé : The use of pharmacologic MRI (phMRI) in mouse models of brain disorders allows noninvasive in vivo assessment of drug-modulated local cerebral blood volume changes (ΔCBV) as one correlate of neuronal and neurovascular activities. In this report, we employed CBV-weighted phMRI to compare cocaine-modulated neuronal activity in dopamine transporter (DAT) knockout (KO) and wild-type mice. Cocaine acts to block the dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT) that clear their respective neurotransmitters from the synapses, helping to terminate cognate neurotransmission. Cocaine consistently reduced CBV, with a similar pattern of regional ΔCBV in brain structures involved in mediating reward in both DAT genotypes. The largest effects (-20% to -30% ΔCBV) were seen in the nucleus accumbens and several cortical regions. Decreasing response amplitudes to cocaine were noted in more posterior components of the cortico-mesolimbic circuit. DAT KO mice had significantly attenuated ΔCBV amplitudes, shortened times to peak response, and reduced response duration in most regions. This study demonstrates that DAT knockout does not abolish the phMRI responses to cocaine, suggesting that adaptations to loss of DAT and/or retained cocaine activity in other monoamine neurotransmitter systems underlie these responses in DAT KO mice.
    Mots-clés : Animals, Cerebral Cortex, Cerebrovascular Circulation, Cocaine, Dopamine Plasma Membrane Transport Proteins, Dopamine Uptake Inhibitors, Female, Magnetic Resonance Imaging, Mice, Mice, Inbred C57BL, Mice, Knockout.

2010

Journal Article

  • ZHANG X., BEARER E. L., PERLES-BARBACARU A. T., JACOBS R. E. “Increased anatomical detail by in vitro MR microscopy with a modified Golgi impregnation method.”. Magnetic resonance in medicine: official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine [En ligne]. 2010. Vol. 63, n°5, p. 1391-1397. Disponible sur : < http://dx.doi.org/10.1002/mrm.22322 > (consulté le no date)
    Résumé : Golgi impregnation is unique in its ability to display the dendritic trees and axons of large numbers of individual neurons by histology. Here we apply magnetic resonance microscopy to visualize the neuroanatomy of animal models by combining histologic fixation chemistry with paramagnetic contrast agents. Although there is some differential uptake of the standard small-molecular-weight contrast agents by different tissue types, detailed discrimination of tissue architecture in MR images does not approach that of standard histology. Our modified Golgi impregnation method significantly increases anatomic detail in magnetic resonance microscopy images. Fixed mouse brains were treated with a solution containing a paramagnetic contrast agent (gadoteridol) and potassium dichromate. Results demonstrate a specific contrast enhancement likely due to diamagnetic hexavalent chromium undergoing tissue specific reduction to paramagnetic trivalent chromium. This new method dramatically improves neuroanatomical contrast compared to conventional fixation, displaying detail approximating that of histologic specimens at low (4x) magnification.
    Mots-clés : Animals, Brain, Contrast Media, Image Enhancement, Magnetic Resonance Imaging, Male, Mice, Mice, Inbred C57BL, Microscopy, Neurons, Silver Staining.

2008

Journal Article

  • LAHRECH H., PERLES-BARBACARU A. - T., AOUS S., LE BAS J. - F., DEBOUZY J. - C., GADELLE A., FRIES P. H. “Cerebral blood volume quantification in a C6 tumor model using gadolinium per (3,6-anhydro) alpha-cyclodextrin as a new magnetic resonance imaging preclinical contrast agent.”. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism [En ligne]. 2008. Vol. 28, n°5, p. 1017-1029. Disponible sur : < http://dx.doi.org/10.1038/sj.jcbfm.9600602 > (consulté le no date)
    Résumé : In magnetic resonance imaging (MRI), cerebral blood volume (CBV) quantification is dependent on the MRI sequence and on the properties of the contrast agents (CAs). By using the rapid steady-state T(1) method, we show the potential of gadolinium per (3,6-anhydro) alpha-cyclodextrin (Gd-ACX), a new MRI paramagnetic CA (inclusion complex of Gd(3+) with per (3,6-anhydro)-alpha-cyclodextrin), for the CBV quantification in the presence of blood-brain barrier lesions. After biocompatibility and relaxivity experiments, in vivo experiments on rats were performed on a C6 tumor model with 0.05 mmol Gd-ACX/kg (<1/10 of the median lethal dose) injected at a 25 mmol/L concentration, inducing neither nephrotoxicity nor hemolysis. On T(1)-weighted images, a signal enhancement of 170% appeared in vessels after injection, but not in the tumor (during the 1 h of observation), in contrast to the 90% signal enhancement obtained with Gd-DOTA (a clinical MRI CA) injected at a T(1) isoefficient dose. This result shows the absence of Gd-ACX extravasation into the tumor tissue and its confinement to the vascular space. Fractional CBV values were found similar to Gd-ACX and Gd-DOTA in healthy brain tissue and in the contralateral hemisphere of tumor-bearing rats, whereas only Gd-ACX was appropriate for CBV quantification in tumor regions.
    Mots-clés : alpha-Cyclodextrins, Animals, Blood Volume, Blood-Brain Barrier, Brain Neoplasms, Cerebrovascular Circulation, Contrast Media, Gadolinium, Glioma, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Mice, Mice, Inbred Strains, Models, Cardiovascular, Organometallic Compounds.

2007

Journal Article

  • PERLES-BARBACARU A. T., LAHRECH H. “A new Magnetic Resonance Imaging method for mapping the cerebral blood volume fraction: the rapid steady-state T1 method.”. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism [En ligne]. 2007. Vol. 27, n°3, p. 618-631. Disponible sur : < http://dx.doi.org/10.1038/sj.jcbfm.9600366 > (consulté le no date)
    Résumé : This paper describes a new rapid steady-state T(1) (RSST(1)) method for mapping the cerebral blood volume fraction (CBVf) by magnetic resonance imaging (MRI). The principle is based on a two-compartment model of the brain (intra- and extravascular), and the effects of paramagnetic contrast agents on the intravascular longitudinal relaxation time T(1). Using appropriate parameters, an Inversion-Recovery-Fast-Low-Angle-Shot sequence acts like a low pass T(1) filter, suppressing signals from tissues with T(1)>TR (TR=repetition time). It was shown in vivo that, exceeding a particular contrast agent dose, the signal reaches its maximum (corresponding to the intravascular equilibrium magnetization), and is maintained for a duration related to the dose. Acquisitions during this steady state divided by an additional measure of the overall (intra- and extravascular) magnetization at thermal equilibrium provides the CBVf. Experiments were performed on healthy rats at 2.35 T using P760 (Gd(3+)-compound from Guerbet Laboratories) and Gd-DOTA. Because of its high longitudinal relaxivity, P760 is more convenient, and was used to show the feasibility of the method. The CBVf in different structures of the rat brain was compared. The average CBVf for the whole brain slice is 3.29%+/-0.69% (n=15). The influence of transendothelial water exchange was quantified and transversal relaxation effects were found negligible in microvasculature. Finally, the sensitivity of the method to CBVf increases under hypercapnia was evaluated (1%/mm Hg PaCO(2)), demonstrating its potential for longitudinal studies and functional MRI. Clinical applications are feasible since equivalent results were obtained with Gd-DOTA.
    Mots-clés : Animals, Brain, Cerebrovascular Circulation, Contrast Media, Heterocyclic Compounds, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Models, Theoretical, Organometallic Compounds, Rats, Rats, Sprague-Dawley.
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