COORDINATEUR SCIENTIFIQUE: Norbert Nighogossian, PUPH, Chef de Service de Neurologie au HCL

Membres du Projet: Equipe 1: Y. Berthezène. Equipe 2: C. Frindel, D. Rousseau. 

I. Contexte socio-économique: L'accident Vasculaire Cérébral (AVC) est une des causes les plus fréquentes de décès dans le monde. L'AVC ischémique, qui résulte de l'occlusion d'une artère cérébrale, représente 88 % des cas d'AVC. A ce jour, le seul traitement efficace pour l'AVC ischémique est la thérapie par reperfusion. Néanmoins, seulement un faible pourcentage de patients victimes d'AVC sont admissibles à ce traitement, en raison d’une fenêtre thérapeutique étroite (4,5 heures). Pour mieux comprendre et exploiter les mécanismes mis en jeu dans l'ischémie cérébrale focale, et proposer de nouvelles stratégies thérapeutiques, les phénomènes moléculaires doivent être étudiés grâce à des modèles expériementaux.

II. Lien avec les Equipements et Investissements d'avenir: Equipex LILI (plateforme PET-MR plateforme), LabEX Primes.

III. Objectifs du projet:  L'objectif du groupe AVC est le développement et la validation de techniques d'imagerie moléculaire afin d'étudier la physiopathologie de l'ischémie cérébrale et d'évaluer de nouvelles stratégies neuroprotectrices. Les principaux domaines d'expertise de l'équipe sont les suivants :

• Des modèles animaux d'ischémie cérébrale
• Imagerie de l'AVC
• Les agents de contraste / imagerie moléculaire
• Les données de post-traitement et la quantification
• Conception de bobines RMN et micro- bobines implantables

IV. Les moyens du projets:

Dernier Worshop interne: le ???? 2016. Programme et présentations powerpoints accessibles aux membres actifs du Projet sur l'intranet de CREATIS au lien suivant: En savoir plus...

Les Partenaires industriels: Guerbet (Contrast agents evaluation in the brain), SANOFI (New neuroprotective treatment evaluation)

V. Les Publications 2016 du Projet AVC:

1. MRI prediction of stroke outcome : Hermitte L, Cho TH, Ozenne B, Nighoghossian N, Mikkelsen IK, Ribe L, Baron JC, Ostergaard L, Derex L, Hjort N, Fiehler J, Pedraza S, Hermier M, Maucort-Boulch D, Berthezène Y. Very Low Cerebral Blood Volume Predicts Parenchymal Hematoma in Acute Ischemic Stroke. Stroke;44(8):2318-2320, 2013.

2. Investigation of USPIO-enhanced MRI to study neuroinflammation: Desestret V, Brisset JC, Devillard E, Moucharrafie S, Nataf S, Honnorat J, Nighoghossian N, Berthezène Y, and Wiart M. Early stage investigations of USPIO-induced signal changes after focal cerebral ischemia in mice. Stroke, 40:1834-1841, 2009

3. Inverse problem in perfusion weighted imaging : C. Frindel, M. Robini, D. Rousseau. A 3-D Spatio-Temporal Deconvolution Approach for MR Perfusion in the Brain. Medical Image Analysis (MEDIA), 2013 (accepted).

VI. Collaborations :

• Belgium: Sabine Van Huffel, Leuven University, Leuven MR Spectroscopy processing and classification methods
• Canada: Douglas L. Arnold, Mc Gill University, Montreal, Quebec
• Danemark: Leif Oestergaard , Aarhus University, Aarhus MRI prediction of stroke outcome Danemark Thomas Vorup-Jensen, Interdisciplinary Nanoscience Center, Aarhus Molecular imaging of neuro-inflammation: molecular targeting Germany Götz Thomalla, UKE, Hamburg MRI prediction of stroke outcome
• United-States: Charles R.G. Guttmann, Boston MRI characterization in Multiple Sclerosis
• France: Michel Lagarde, Laboratoire de Recherche en Cardiovasculaire, Métabolisme, Diabétologie et Nutrition (CarMeN, U1060 Inserm), Lyon Novel engineered polyunsaturated acid as a treatment of cerebral ischemia
• France: Serge Nataf, Centre de Recherche en Neurosciences de Lyon (CRNL, UMR CNRS 5292, UMR_S 1028 Inserm), Lyon Molecular imaging of neuro-inflammation: cell imaging and therapy
• France: Christiane Charriaut-Marlangue, Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes au cerveau en développement (U676 Inserm), Paris Post-conditioning as a treatment of cerebral ischemia
• France: Stéphane Parola, Laboratoire de Chimie de l’ENS Lyon (UMR CNRS 5182), Lyon Molecular imaging of neuro-inflammation: contrast agents
• France: Emmanuelle Canet-Soulas, Laboratoire de Recherche en Cardiovasculaire, Métabolisme, Diabétologie et Nutrition (CarMeN, U1060 Inserm), Lyon Molecular imaging of neuro-inflammation: non-human primate models
• France: Patrick Poulichet, Laboratoire ESYCOM, ESIEE Paris Portable NMR system: Modeling, Design and optimization Tunisia Cherif Dridi, Monastir University of sciences NMR microsystems for biomedical applications
• Vietnam: Pham Huy Hoang and Phan Dinh HUAN, Ho Chi Minh University of Technology Ho Chi Minh Polytechnic Institute Portable NMR system: Modeling, Design and optimization USA Youssef Zaim Wadghiri, NYU School of Medicine Center for Biomedical Imaging Development of Coils and Microcoils: NMR applications on animals models of Alzheimer

VII. Highlights

1. Dual mapping of iron oxides in the mouse brain (MRI and SR-PCT) Marinescu M, Chabrol A, Langer M, Durand A, Olivier C, et al. Synchrotron Radiation Micro-Computed Tomography as a new method to detect iron oxide nanoparticles in the brain. Molecular Imaging & Biology, 2013

We have pioneered the development of an innovative Magnetic Resonance Imaging (MRI) method devoted to the analysis of neuroinflammation following cerebral ischemia, based on the in vivo magnetic labelling of phagocytic cells with ultrasmall superparamagnetic particles of iron oxide (USPIO-enhanced MRI) in mice. We have shown that monitoring of the effect of minocycline, an anti-inflammatory treatment, can be achieved using this approach. Limitations of USPIO-enhanced MRI, however, lie in the difficulty of interpreting MR signal changes. For example, determining the precise topography of labeled cells on MR images is hampered by the low spatial resolution (100x100-µm in plane with 1000-µm slice thickness) compared to phagocytic cells size (40-µm) and by the “blooming” effect (the local magnetic field created by labeled cells extending well beyond the actual cell radius). We therefore used in-line Synchrotron Radiation X-ray Phase Computed Tomography (SR-PCT) as a new method of visualizing USPIO distribution into the whole brain of mice with cerebral ischemia (Figure 1). SR-PCT images displayed brain anatomy as clearly as histology as well as the marked cells at an isotropic spatial resolution of 8-µm. Figure 1- USPIO distribution in the brain of a mouse with focal cerebral ischemia A) Pre- and B) post-contrast T2-weighted MRI. The lesion can be seen as a hyperintense region before USPIO injection (arrow). The hypointense signal that appears in the lesion 48h post-injection is caused by USPIO presence in the brain. C) SR-PCT image of the same mouse with hyperintense areas (arrowheads) appearing either as: D) a diffuse signal or E) bright spots. These hyperintense areas reflect USPIO distribution in the lesion. The difference in appearance arises from the difference in compartmentalization (interstitial vs. intracellular). F) 3D reconstruction of hyperintense area distribution (light blue)

VIII. Perspectives

Concerning the “stroke” program, new developments will be oriented towards new kind of hybrid nanoparticles (NP) that tricks the brain blood barrier (BBB) into guiding the probe into the brain and combines: 1) optical probes for intravital microscopy, 2) magnetic properties for magnetic resonance imaging (MRI) and 3) radio opacity phase-contrast X-ray computed tomography. Specifically, Stéphane Parola with the LC ENS (UMR 5182, Lyon) propose to build a NP targeted at the integrin Mac-1 (CD11b/CD18 or alpha M/beta 2) to assess neuroinflammation non-invasively, based on luminescent conjugated polythiophenes (LCP), an agent that has been shown to have capacity to cross the BBB. LCPs will be attached to magnetic NP consisting of a mineral core (gadolinium-based compound) and an organic shell (PEG chains). These NPs can also be coated with gold nanoshells to enhance opacifying properties. Targeting of Mac-1 will be achieved by grafting a fibrinopeptide at the surface of the NP. The biological and imaging properties of the obtained NPs will be fully characterized in collaboration with the Grenoble intravital microscopy platform (France Life Imaging, located at the Grenoble Institute of Neuroscience (GIN) INSERM U836 and Clinatec). Proof-of-concept of molecular imaging of Mac-1 expression will then be established in a model of transient middle cerebral artery occlusion in wild type and Mac-1 null mice.