Olivier Beuf

MRI Monitoring of Neuroinflammation in Mouse Focal Ischemia

Background and Purpose— A growing body of evidence suggests that inflammatory processes are involved in the pathophysiology of stroke. Phagocyte cells, involving resident microglia and infiltrating macrophages, secrete both protective and toxic molecules and thus represent a potential therapeutic target. The aim of the present study was to monitor phagocytic activity after focal cerebral ischemia in mice. Methods— Ultrasmall superparamagnetic particles of iron oxide (USPIO) were intravenously injected after permanent middle cerebral artery occlusion and monitored by high resolution MRI for 72 hours. Results— We here present the first MRI data showing in vivo phagocyte-labeling obtained in mice with focal cerebral ischemia. USPIO-enhanced MRI kinetic analysis disclosed an inflammatory response surrounding the ischemic lesion and in the contralateral hemisphere via the corpus callosum. The imaging data collected during the first 36 hours postinjury suggested a spread of USPIO-related signal from ipsi- to contralateral hemisphere. Imaging data correlated with histochemical analysis showing inflammation remote from the lesion and ingestion of nanoparticles by microglia/macrophages. Conclusions— The present study shows that MR-tracking of phagocyte cells is feasible in mice, which may have critical therapeutic implications given the potential neurotoxicity of activated microglia/macrophages in central nervous system disorders.

Targeted deletion of liver glucose-6 phosphatase mimics glycogen storage disease type 1a including development of multiple adenomas

BACKGROUND AND AIMS Glycogen storage disease type 1a (GSD1a) is an inherited disease caused by a deficiency in the catalytic subunit of the glucose-6 phosphatase enzyme (G6Pase). GSD1a is characterized by hypoglycaemia, hyperlipidemia, and lactic acidosis with associated hepatic (including hepatocellular adenomas), renal, and intestinal disorders. A total G6pc (catalytic subunit of G6Pase) knock-out mouse model has been generated that mimics the human pathology. However, these mice rarely live longer than 3 months and long-term liver pathogenesis cannot be evaluated. Herein, we report the long-term characterization of a liver-specific G6pc knock-out mouse model (L-G6pc(-/-)). METHODS We generated L-G6pc(-/-) mice using an inducible CRE-lox strategy and followed up the development of hepatic tumours using magnetic resonance imaging. RESULTS L-G6pc(-/-) mice are viable and exhibit normoglycemia in the fed state. They develop hyperlipidemia, lactic acidosis, and uricemia during the first month after gene deletion. However, these plasmatic parameters improved after 6 months. L-G6pc(-/-) mice develop hepatomegaly with glycogen accumulation and hepatic steatosis. Using an MRI approach, we could detect hepatic nodules with diameters of less than 1 mm, 9 months after induction of deficiency. Hepatic nodules (1 mm) were detected in 30-40% of L-G6pc(-/-) mice at 12 months. After 18 months, all L-G6pc(-/-) mice developed multiple hepatocellular adenomas of 1-10 mm diameter. CONCLUSIONS This is the first report of a viable animal model of the hepatic pathology of GSD1a, including the late development of hepatocellular adenomas.

Combination of topological parameters and bone volume fraction better predicts the mechanical properties of trabecular bone

Trabecular bone structure may complement bone volume/total volume fraction (BV/TV) in the prediction of the mechanical properties. Nonetheless, the direct in vivo use of information pertaining to trabecular bone structure necessitates some predictive analytical model linking structure measures to mechanical properties. In this context, the purpose of this study was to combine BV/TV and topological parameters so as to better estimate the mechanical properties of trabecular bone. Thirteen trabecular bone mid-sagittal sections were imaged by magnetic resonance (MR) imaging at the resolution of 117 x 117x 300 microm(3). Topological parameters were evaluated in applying the 3D-line skeleton graph analysis (LSGA) technique to the binary MR images. The same images were used to estimate the elastic moduli by finite element analysis (FEA). In addition to the mid-sagittal section, two cylindrical samples were cored from each vertebra along vertical and horizontal directions. Monotonic compression tests were applied to these samples to measure both vertical and horizontal ultimate stresses. BV/TV was found as a strong predictor of the mechanical properties, accounting for 89-94% of the variability of the elastic moduli and for 69-86% of the variability of the ultimate stresses. Topological parameters and BV/TV were combined following two analytical formulations, based on: (1) the normalization of the topological parameters; and on (2) an exponential fit-model. The normalized parameters accounted for 96-98% of the variability of the elastic moduli, and the exponential model accounted for 80-95% of the variability of the ultimate stresses. Such formulations could potentially be used to increase the prediction of the mechanical properties of trabecular bone.

Microgel Iron Oxide Nanoparticles for Tracking Human Fetal Mesenchymal Stem Cells Through Magnetic Resonance Imaging

Stem cell transplantation for regenerative medicine has made significant progress in various injury models, with the development of modalities to track stem cell fate and migration post‐transplantation being currently pursued rigorously. Magnetic resonance imaging (MRI) allows serial high‐resolution in vivo detection of transplanted stem cells labeled with iron oxide particles, but has been hampered by low labeling efficiencies. Here, we describe the use of microgel iron oxide (MGIO) particles of diameters spanning 100‐750 nm for labeling human fetal mesenchymal stem cells (hfMSCs) for MRI tracking. We found that MGIO particle uptake by hfMSCs was size dependent, with 600‐nm MGIO (M600) particles demonstrating three‐ to sixfold higher iron loading than the clinical particle ferucarbotran (33‐263 versus 9.6‐42.0 pg iron/hfMSC; p < .001). Cell labeling with either M600 particles or ferucarbotran did not affect either cellular proliferation or trilineage differentiation into osteoblasts, adipocytes, and chondrocytes, despite differences in gene expression on a genome‐wide microarray analysis. Cell tracking in a rat photothrombotic stroke model using a clinical 1.5‐T MRI scanner demonstrated the migration of labeled hfMSCs from the contralateral cortex to the stroke injury, with M600 particles achieving a five‐ to sevenfold higher sensitivity for MRI detection than ferucarbotran (p < .05). However, model‐related cellular necrosis and acute inflammation limited the survival of hfMSCs beyond 5‐12 days. The use of M600 particles allowed high detection sensitivity with low cellular toxicity to be achieved through a simple incubation protocol, and may thus be useful for cellular tracking using standard clinical MRI scanners. STEM CELLS 2009;27:1921–1931

Transient MR elastography (t-MRE) using ultrasound radiation force: Theory, safety, and initial experiments in vitro

The purpose of our study was to assess the feasibility of using ultrasound radiation force as a safe vibration source for transient MR elastography (t‐MRE). We present a theoretical framework to predict the phase shift of the complex MRE signal, the temperature elevation due to ultrasound, and safety indicators (ISPPA, ISPTA, MI). Next, we report wave images acquired in porcine liver samples in vitro. MR thermometry was used to estimate the temperature elevation induced by ultrasound. Finally, we discuss the implications of our results with regard to the feasibility of using radiation force for t‐MRE in a clinical setting, and a specific echo‐planar imaging (EPI) MRE sequence is proposed. Magn Reson Med 60:871–881, 2008.

Diagnosis of Splanchnic Artery Aneurysms and Pseudoaneurysms, with Special Reference to Contrast Enhanced 3D Magnetic Resonance Angiography: a Review

Splanchnic artery aneurysms are rare. In the past, conventional angiography was the only way to detect them, but today non-invasive techniques are available. Breath-hold contrast-enhanced 3D magnetic resonance angiography has become a routine examination for evaluation of the aorta and its visceral branches. In this article, we briefly discuss the technical aspects of 3D contrast-enhanced magnetic resonance angiography and illustrate various splanchnic artery aneurysms-pseudoaneurysms with their main characteristics.

The use of microgel iron oxide nanoparticles in studies of magnetic resonance relaxation and endothelial progenitor cell labelling.

In vivo tracking of stem cells after transplantation is crucial for understanding cell-fate and therapeutic efficacy. By labelling stem cells with magnetic particles, they can be tracked by Magnetic Resonance Imaging (MRI). We previously demonstrated that microgel iron oxide nanoparticle (MGIO) provide superior tracking sensitivity over commercially available particles. Here, we describe the synthesis of MGIO and report on their morphology, hydrodynamic diameters (87-766 nm), iron oxide weight content (up to 82%) and magnetization characteristics (M(s)=52.9 Am(2)/kg, M(R)=0.061 Am(2)/kg and H(c)=0.672 A/m). Their MR relaxation characteristics are comparable to those of theoretical models and represent the first such correlation between model and real particles of varying diameters. A labelling study of primary endothelial progenitor cells also confirms that MGIO is an efficient label regardless of cell type. The facile synthesis of MGIO makes it a useful tool for the studying of relaxation induced by magnetic particles and cellular tracking by MRI.

Direct Measures of Trabecular Bone Architecture from MR Images

Osteoporosis is a bone disorder involving a decrease in bone mass and changes in the cancellous bone network leading to an increase in fracture risk. Until recently only bone mass and density were routinely assessed in patients, usually measured by dual-energy X-ray absorptiometry (DXA) or by quantitative computed tomography (QCT). Although bone mineral density (BMD) is an important determinant of bone strength, there is strong evidence that architecture of cancellous bone plays a significant role in bone strength and determines its biomechanical properties.1The importance of three-dimensional trabecular bone structure in osteoporosis increases when evaluating the response to therapy, as studies have reported that changes in fracture risk were not mainly attributable to BMD.2The measurement of both bone micro-architecture and BMD may improve the estimation of bone strength. However, the precise relationship between density, structure and mechanical properties is still under investigation.

Significant relaxivity gap between a low-spin and a high-spin iron(II) complex of structural similarity: an attractive off–on system for the potential design of responsive MRI probes

We have identified a pair of structurally similar iron complexes in the oxidation state II that exist in a low-spin and a high-spin electronic spin state in aqueous media, respectively. The low-spin, diamagnetic complex (LS, 1) is mute in MRI while the high-spin, paramagnetic complex (HS, 2) generates considerable contrast in MRI. These results demonstrate that iron(II) complexes, hitherto neglected for contrast enhancement in MRI, have potential for the design of an MRI probe that suffers passage from one state to the other under the influence of a targeted biochemical activity and thus operates in an off–on mode. At 300 MHz (proton resonance frequency at 7 T field strength) and in phosphate buffer, we found a longitudinal relaxivity (r1) of 1.29 mM−1 s−1 for 2 that, in light of the difference in unpaired electrons of the central metal atoms (4 for FeII; 7 for GdIII), comes remarkably close to that of gadolinium(III)–DOTA (2.44 mM−1 s−1), a commercialized MRI contrast agent. Since gadolinium complexes are always paramagnetic and can therefore not be muted in MRI, the here presented Fe(II)-based system offers an alternative strategy to develop responsive MRI probes.

Trabecular Structure Assessment in Lumbar Vertebrae Specimens Using Quantitative Magnetic Resonance Imaging and Relationship with Mechanical Competence

The purpose of this study was to use quantitative magnetic resonance imaging (MRI; high‐resolution [HR] and relaxometry) to assess trabecular bone structure in lumbar vertebrae specimens and to compare these techniques with bone mineral density (BMD) in predicting stress values obtained from mechanical tests. Fourteen vertebral midsagittal sections from lumbar vertebrae L3 were obtained from cadavers (aged 22‐76 years). HR images with a slice thickness of 300 μm and an in‐plane spatial resolution of 117 μm2 × 117 μm2 were obtained. Transverse relaxation time T2′ distribution was measured by using an asymmetric spin‐echo (ASE) sequence. Traditional morphometric measures of bone structure such as apparent trabecular bone fraction (app. BV/TV), apparent trabecular bone number (app. Tb.N), apparent trabecular bone separation (app. Tb.Sp), and apparent trabecular bone thickness (app. Tb.Th) as well as the directional mean intercept length (MIL) were calculated. Additionally, BMD measurements of these sections were obtained by dual‐energy X‐ray absorptiometry (DXA) and biomechanical properties such as directional stress values (to fracture) were determined on adjacent specimens. With the exception of T2′, all morphological parameters correlated very well with age, BMD, and stress values (|R| between 0.79 and 0.92). However, in the direction perpendicular to the magnetic field, T2′ values enhanced the adjusted R2 correlation value with horizontal (M/L) stress values in addition to BMD from 0.70 to 0.91 (p < 0.05).