Quantitative mapping of angiogenesis by magnetic resonance imaging

This chapter focuses on MRI techniques for angiogenesis assessment. In particular it describes a newly developed quantitative MRI technique for in vivo blood volume fraction mapping for preclinical and above all for clinical applications in neurooncology. The blood volume fraction is a biomarker for angiogenesis and has proven successful in mapping brain dysfunction and in testing drug efficacy. The described technique is compared with other magnetic resonance imaging techniques currently employed in the preclinical and clinical setting. Therefore, this chapter provides an overview of existing quantitative MRI techniques, briefly explains their basic principle, states their acquisition and postprocessing requirements, and compares their advantages and limits. Quantitative results for blood volume fraction measures in laboratory animals and human subjects are presented and compared. Pitfalls and possibilities in neurooncological applications are pointed out and discussed

Quantitative Mapping of Angiogenesis by Magnetic Resonance Imaging

This chapter focuses on MRI techniques for angiogenesis assessment. In particular it describes a newly developed quantitative MRI technique for in vivo blood volume fraction mapping for preclinical and above all for clinical applications in neurooncology. The blood volume fraction is a biomarker for angiogenesis and has proven successful in mapping brain dysfunction and in testing drug efficacy. The described technique is compared with other magnetic resonance imaging techniques currently employed in the preclinical and clinical setting. Therefore, this chapter provides an overview of existing quantitative MRI techniques, briefly explains their basic principle, states their acquisition and postprocessing requirements, and compares their advantages and limits. Quantitative results for blood volume fraction measures in laboratory animals and human subjects are presented and compared. Pitfalls and possibilities in neurooncological applications are pointed out and discussed

Quantitative pharmacologic MRI: Mapping the cerebral blood volume response to cocaine in dopamine transporter knockout mice

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-typemice. 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 inmediating 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

Quantitative pharmacologic MRI in mice

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

Imagerie par résonance magnétique du volume sanguin pour la caractérisation de la néovascularisation dans les tumeurs expérimentales

La mesure du volume sanguin cérébral (VSC) par Imagerie par Résonance Magnétique (IRM) permet d'étudier l'angiogénèse tumorale. Dans cette thèse, une méthode IRM, dite méthode T1 stationnaire rapide (RSST1) pour quantifier le VSC est proposée. Le principe repose sur les propriétés de la relaxation longitudinale avec des agents de contraste (AC) paramagnétiques intravasculaires et sur un modèle du cerveau bi-compartimentai extra/intravasculaire sans échange d'eau. La méthode a été validée sur des rats sains à 2.35T (VSC: 2 à 3%) et la sensibilité évaluée sous hypercapnie (augmentation du VSC de 1%/mmHg CO2). Pour évaluer l'efficacité d'un traitement antitumoral, des AC ne s'extravasant pas durant la mesure à travers une barrière hématoencéphalique (BHE) lésée sont nécessaires. Deux AC expérimentaux, le Gd-ACX et le SINEREM, ont été étudiés sur deux modèles de rat gliome ca et RG2. Avec le Gd-ACX, les mesures ont été confrontées à une analyse morphométrique de la microvascularisation sur des coupes immuno-histologiques. Les mesures avec le SINEREM ont nécessité le développement d'acquisitions à temps d'écho court et ont été comparées à ceux obtenus par la méthode L\R2* utilisant le même AC. Pour des AC qui s'extravasent (Gd-DOTA admis en clinique), utilisant une analyse pharmacocinétique à deux compartiments, les acquisitions de la méthode RSST1 conduisent à la mesure du VSC et au coefficient de transfert Ktrans lié à la perméabilité de la BHE. En conclusion, la méthode RSST1, méthode quantitative de mesure de VSC, permet avec des AC appropriés, de réaliser des études longitudinales de l'angiogénèse tumorale et d'accéder à la perméabilité vasculaire.Cerebral blood volume fraction (CBVf) mapping by magnetic resonance imaging (MRI) can provide information about the progression of tumor angiogenesis without harmful side-effects. ln this work, a novel MRI method for in vivo CBVf mapping is developed: the Rapid Steady State T1 (RSST1) method. The method is based on a two-compartment model, intra- and extravascular, without water exchange, and on the longitudinal relaxivity of intravascular MRI contrast agents (CAs). This method has been validated on healthy Wistar rats at 2.35 T (CBVf: 2 to 3%) and its sensitivity has been evaluated in a hypercapnia experiment (CBVf increase of 1%/mmHg CO2). ln order to apply this method for monitoring disease evolution or treatment efficacy, CAs are evaluated that do not leak across the blood brain barrier during the measuring time. Two experimental CA, Gd-ACX and SINEREM were used on two rat glioma models ca and RG2. The CBVf measures in tumor tissue obtained with Gd-ACX are confirmed by a histologic vascular morphometric analysis. CBVf mapping with SINEREM necessitates acquisitions with short echo time. The measures were compared with those obtained by a L\R2*-based steady state method using the same SINEREM injection. ln case of CA extravasation, such as occurs in tumor tissue with CAs approved for clinical use, the CBVf along with the transfer coefficient Ktrans (a measure related to the endothelial permeability) were obtained by pharmacokinetic two-compartment analysis of dynamic RSST1 acquisitions.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

IMAGERIE PAR RESONANCE MAGNETIQUE DU VOLUME SANGUIN POUR LA CARACTERISATION DE LA NEOVASCULARISATION DANS LES TUMEURS CEREBRALES EXPERIMENTALES

CEREBRAL BLOOD VOLUME FRACTION (CBVF) MAPPING BY MAGNETIC RESONANCE IMAGING (MRI) CAN PROVIDE INFORMATION ABOUT THE PROGRESSION OF TUMOR ANGIOGENESIS WITHOUT HARMFUL SIDE-EFFECTS. IN THIS WORK, A NOVEL MRI METHOD FOR IN VIVO CBVF MAPPING IS DEVELOPED: THE RAPID STEADY STATE T1 (RSST1) METHOD. THE METHOD IS BASED ON A TWO-COMPARTMENT MODEL, INTRA- AND EXTRAVASCULAR, WITHOUT WATER EXCHANGE, AND ON THE LONGITUDINAL RELAXIVITY OF INTRAVASCULAR MRI CONTRAST AGENTS (CAS). THIS METHOD HAS BEEN VALIDATED ON HEALTHY WISTAR RATS AT 2.35 T (CBVF: 2 TO 3%) AND ITS SENSITIVITY HAS BEEN EVALUATED IN A HYPERCAPNIA EXPERIMENT (CBVF INCREASE OF 1%/MMHG CO2). IN ORDER TO APPLY THIS METHOD FOR MONITORING DISEASE EVOLUTION OR TREATMENT EFFICACY, CAS ARE EVALUATED THAT DO NOT LEAK ACROSS THE BLOOD BRAIN BARRIER DURING THE MEASURING TIME. TWO EXPERIMENTAL CA, GD-ACX AND SINEREM WERE USED ON TWO RAT GLIOMA MODELS C6 AND RG2. THE CBVF MEASURES IN TUMOR TISSUE OBTAINED WITH GD-ACX ARE CONFIRMED BY A HISTOLOGIC VASCULAR MORPHOMETRIC ANALYSIS. CBVF MAPPING WITH SINEREM NECESSITATES ACQUISITIONS WITH SHORT ECHO TIME. THE MEASURES 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 CAS APPROVED FOR CLINICAL USE, THE CBVF ALONG WITH THE TRANSFER COEFFICIENT Κ (A MEASURE 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.LA MESURE DU VOLUME SANGUIN CEREBRAL (VSC) PAR IMAGERIE PAR RESONANCE MAGNETIQUE (IRM) PERMET D'ETUDIER L'ANGIOGENESE TUMORALE. DANS CETTE THESE, UNE METHODE IRM, DITE METHODE T1 STATIONNAIRE RAPIDE (RSST1) POUR QUANTIFIER LE VSC EST PROPOSEE. LE PRINCIPE REPOSE SUR LES PROPRIETES DE LA RELAXATION LONGITUDINALE AVEC DES AGENTS DE CONTRASTE (AC) PARAMAGNETIQUES INTRAVASCULAIRES ET SUR UN MODELE DU CERVEAU BI-COMPARTIMENTAL EXTRA/INTRAVASCULAIRE SANS ECHANGE D'EAU. LA METHODE A ETE VALIDEE SUR DES RATS SAINS A 2.35T (VSC: 2 A 3%) ET LA SENSIBILITE EVALUEE SOUS HYPERCAPNIE (AUGMENTATION DU VSC DE 1%/MMHG CO2). POUR EVALUER L'EFFICACITE D'UN TRAITEMENT ANTITUMORAL, DES AC NE S'EXTRAVASANT PAS DURANT LA MESURE A TRAVERS UNE BARRIERE HEMATOENCEPHALIQUE (BHE) LESEE SONT NECESSAIRES. DEUX AC EXPERIMENTAUX, LE GD-ACX ET LE SINEREM, ONT ETE ETUDIES SUR DEUX MODELES DE RAT GLIOME C6 ET RG2. AVEC LE GD-ACX, LES MESURES ONT ETE CONFRONTEES A UNE ANALYSE MORPHOMETRIQUE DE LA MICROVASCULARISATION SUR DES COUPES IMMUNO-HISTOLOGIQUES. LES MESURES AVEC LE SINEREM ONT NECESSITE LE DEVELOPPEMENT D'ACQUISITIONS A TEMPS D'ECHO COURT ET ONT ETE COMPAREES A CEUX OBTENUS PAR LA METHODE DELTAR2* UTILISANT LE MEME AC. POUR DES AC QUI S'EXTRAVASENT (GD-DOTA ADMIS EN CLINIQUE), UTILISANT UNE ANALYSE PHARMACOCINETIQUE A DEUX COMPARTIMENTS, LES ACQUISITIONS DE LA METHODE RSST1 CONDUISENT A LA MESURE DU VSC ET AU COEFFICIENT DE TRANSFERT Κ LIE A LA PERMEABILITE DE LA BHE. EN CONCLUSION, LA METHODE RSST1, METHODE QUANTITATIVE DE MESURE DE VSC, PERMET AVEC DES AC APPROPRIES, DE REALISER DES ETUDES LONGITUDINALES DE L'ANGIOGENESE TUMORALE ET D'ACCEDER A LA PERMEABILITE VASCULAIRE

In vivo MRI assessment of the pharmacological opening of the blood brain barrier by intraperitoneal mannitol injection in mice.

International audienc

Clinical and preclinical imaging of hepatosplenic schistosomiasis.

International audienceSchistosomiasis, a neglected tropical disease, is a major cause of chronic morbidity and disability, and premature death. The hepatosplenic form of schistosomiasis is characterized by hepatosplenomegaly, liver fibrosis, portal hypertension and oesophageal varices, whose rupture may cause bleeding and death. We review currently available abdominal imaging modalities and describe their basic principles, strengths, weaknesses, and usefulness in the assessment of hepatosplenic schistosomiasis. Advanced imaging methods are presented that could be of interest for hepatosplenic schistosomiasis evaluation by yielding morphological, functional and molecular parameters of disease progression. We also provide a comprehensive view of preclinical imaging studies and current research objectives such as parasite visualisation in hosts, follow-up of host-immune response, and development of non-invasive quantitative methods for liver fibrosis assessment.

Nuclear magnetic resonance spectroscopy and imaging

International audienc

In vivo MRI assessment of the pharmacological opening of the blood brain barrier by intraperitoneal mannitol injection in mice.

International audienc