Philippe Choquet

Xenon-129 MR imaging and spectroscopy of rat brain using arterial delivery of hyperpolarized xenon in a lipid emulsion.

Hyperpolarized 129Xe dissolved in a lipid emulsion constitutes an NMR tracer that can be injected into the blood stream, enabling blood‐flow measurement and perfusion imaging. A small volume (0.15 ml) of this tracer was injected in 1.5 s in rat carotid and 129Xe MR spectra and images were acquired at 2.35 T to evaluate the potential of this approach for cerebral studies. Xenon spectra consistently showed two resonances, at 194.5 ppm and 199.0 ppm relative to the gas peak. The signal‐to‐noise ratio (SNR) obtained for the two peaks was sufficient (ranging from 12 to 90) to follow their time courses. 2D transverse‐projection xenon images were obtained with an in‐plane resolution of 900 μm per pixel (SNR range 8–15). Histological analysis revealed no brain damage except in two rats that had received three injections. Magn Reson Med 46:208–212, 2001.

Magnetic resonance elastography compared with rotational rheometry for in vitro brain tissue viscoelasticity measurement

Magnetic resonance elastography (MRE) is an increasingly used method for non-invasive determination of tissue stiffness. MRE has shown its ability to measure in vivo elasticity or viscoelasticity depending on the chosen rheological model. However, few data exist on quantitative comparison of MRE with reference mechanical measurement techniques. MRE has only been validated on soft homogeneous gels under both Hookean elasticity and linear viscoelasticity assumptions, but comparison studies are lacking concerning viscoelastic properties of complex heterogeneous tissues. In this context, the present study aims at comparing an MRE-based method combined with a wave equation inversion algorithm to rotational rheometry. For this purpose, experiments are performed on in vitro porcine brain tissue. The dynamic behavior of shear storage (G- and loss (G′) moduli obtained by both rheometry and MRE at different frequency ranges is similar to that of linear viscoelastic properties of brain tissue found in other studies. This continuity between rheometry and MRE results consolidates the quantitative nature of values found by MRE in terms of viscoelastic parameters of soft heterogeneous tissues. Based on these results, the limits of MRE in terms of frequency range are also discussed.

SPECT Low-Field MRI System for Small-Animal Imaging

Localization of regions with increased uptake of radiotracer in small-animal SPECT is greatly facilitated when using coregistration with anatomic images of the same animal. As MRI has several advantages compared with CT (soft-tissue contrast and lack of ionizing radiation) we developed a SPECT/low-field MRI hybrid device for small-animal imaging. Methods: A small-animal single-pinhole γ-camera (pinhole, 1.5 mm in diameter and 12 cm in focal length) adjacent to a dedicated low-field (0.1 T) small MR imager (imaging volume, 10 × 10 × 6 cm3) was used. The animal was placed in a warmed nonmagnetic polymethyl methacrylate imaging cell for MR acquisition, which was followed immediately by SPECT after translation of the imaging cell from one modality to the other. 3-Dimensional T1-weighted sequences were used for MRI. Phantom studies enabled verification of a low attenuation (10%) for 99mTc and 201Tl and a very slight increase in Compton scattering due to the radiofrequency coil and polymethyl methacrylate imaging cell. Results: SPECT/MRI data acquisition and image coregistration of selected examples using different radiotracers for lungs, kidneys, and brain were obtained in 3 nude mice with isotropic spatial resolutions of 0.5 × 0.5 × 0.5 mm3 for MRI and 1 × 1 × 1 mm3 for SPECT. The total acquisition time for combined SPECT and MRI lasted 1 h 45 min. Conclusion: A low-magnetic-field strength of 0.1 T is a simple and useful solution for a small-animal dual-imaging device combining pinhole SPECT with the adjacent MR imager.

In vivo 129Xe NMR in rat brain during intra-arterial injection of hyperpolarized 129Xe dissolved in a lipid emulsion

Hyperpolarized 129Xe was dissolved in a lipid emulsion and administered to anaesthetized rats by manual injections into the carotid (approximately 1-1.5 mL in a maximum time of 30 s). During injection, 129Xe NMR brain spectra at 2.35 T were recorded over 51 s, with a repetition time of 253 ms. Two peaks assigned to dissolved 129Xe were observed (the larger at 194 +/- 1 ppm assigned to intravascular xenon and the smaller at 199 +/- 1 ppm to xenon dissolved in the brain tissue). Their kinetics revealed a rapid intensity increase, followed by a plateau (approximately 15 s duration) and then a decrease over 5 s. This behaviour was attributed to combined influences of the T1 relaxation of the tracer, of radiofrequency sampling, and of the tracer perfusion rate in rat brain. Similar kinetics were observed in experiments carried out on a simple micro-vessel phantom. An identical experimental set-up was used to acquire a series of 2D projection 129Xe images on the phantom and the rat brain.

Towards thrombosis-targeted zeolite nanoparticles for laser-polarized 129Xe MRI

The synthesis and functionalisation of zeolite nanoparticles designed for laser-polarized 129Xe NMR experiments in solution are described. These nanoparticles were functionalized by using original synthesis pathways through semicarbazide COCHO chemistry in order to ensure anchoring of a peptide for targeting biological receptors and attachment of PEG chains for in vivo experiments. Results demonstrated that accessibility of the dissolved noble gas to the micropores was maintained after functionalization. γ Scintigraphy with 111In linked to the zeolite particles has been investigated in order to follow the behaviour of the zeolite nanoparticles in mice. These preliminary 111In scintigraphy experiments showed the localization of the nanoparticles after injection in mice and their biodistribution, as a first proof-of-concept towards in vivo129Xe MRI.

Pinhole SPECT imaging: compact projection/backprojection operator for efficient algebraic reconstruction

We describe the efficient algebraic reconstruction (EAR) method, which applies to cone-beam tomographic reconstruction problems with a circular symmetry. Three independant steps/stages are presented, which use two symmetries and a factorization of the point spread functions (PSFs), each reducing computing times and eventually storage in memory or hard drive. In the case of pinhole single photon emission computed tomography (SPECT), we show how the EAR method can incorporate most of the physical and geometrical effects which change the PSF compared to the Dirac function assumed in analytical methods, thus showing improvements on reconstructed images. We also compare results obtained by the EAR method with a cubic grid implementation of an algebraic method and modeling of the PSF and we show that there is no significant loss of quality, despite the use of a noncubic grid for voxels in the EAR method. Data from a phantom, reconstructed with the EAR method, demonstrate 1.08-mm spatial tomographic resolution despite the use of a 1.5-mm pinhole SPECT device and several applications in rat and mouse imaging are shown. Finally, we discuss the conditions of application of the method when symmetries are broken, by considering the different parameters of the calibration and nonsymmetric physical effects such as attenuation.

Global and regional cerebral blood flow measurements using NMR of injected hyperpolarized xenon-129

RATIONALE AND OBJECTIVES Xenon is an inert gas characterized by a nuclear halfspin and a high solubility in lipids. It appears to diffuse freely in biological tissues and, in particular, through the blood-brain barrier. Spin-exchange with optically pumped rubidiu mvapo rincrease sth enuclea rpolarizatio no f 129 Xe gas by several orders of magnitude above the polarization at thermal equilibrium, resulting in “hyperpolarized” (HP) xenon. HP xenon can be used as a magnetic resonance (MR) tracer because of its NMR-enhanced sensitivity combined with its high solubility. This HP tracer is a potential exogenous NMR probe for cerebral imaging studies. The purpose of this paper is to describe the preparation of this HP tracer and to demonstrate that it can be used in NMR for absolute cerebral perfusion measurements.

Method to determine in vivo the relaxation time T1 of hyperpolarized xenon in rat brain.

The magnetic polarization of the stable 129Xe isotope may be enhanced dramatically by means of optical techniques and, in principle, hyperpolarized 129Xe MRI should allow quantitative mapping of cerebral blood flow with better spatial resolution than scintigraphic techniques. A parameter necessary for this quantitation, and not previously known, is the longitudinal relaxation time (T  1tissue ) of 129Xe in brain tissue in vivo: a method for determining this is reported. The time course of the MR signal in the brain during arterial injection of hyperpolarized 129Xe in a lipid emulsion was analyzed using an extended two‐compartment model. The model uses experimentally determined values of the RF flip angle and the T1 of 129Xe in the lipid emulsion. Measurements on rats, in vivo, at 2.35 T gave T  1tissue = 3.6 ± 2.1 sec (±SD, n = 6). This method enables quantitative mapping of cerebral blood flow. Magn Reson Med 49:1014–1018, 2003.

Increasing the oxygen load by treatment with myo-inositol trispyrophosphate reduces growth of colon cancer and modulates the intestine homeobox gene Cdx2

Preventing tumor neovascularisation is one of the strategies recently developed to limit the dissemination of cancer cells and apparition of metastases. Although these approaches could improve the existing treatments, a number of unexpected negative effects have been reported, mainly linked to the hypoxic condition and the subsequent induction of the pro-oncogenic hypoxia inducible factor(s) resulting from cancer cells’ oxygen starvation. Here, we checked in vivo on colon cancer cells an alternative approach. It is based on treatment with myo-inositol trispyrophosphate (ITPP), a molecule that leads to increased oxygenation of tumors. We provide evidence that ITPP increases the survival of mice in a model of carcinomatosis of human colon cancer cells implanted into the peritoneal cavity. ITPP also reduced the growth of subcutaneous colon cancer cells xenografted in nu/nu mice. In the subcutaneous tumors, ITPP stimulated the expression of the homeobox gene Cdx2 that is crucial for intestinal differentiation and that also has an anti-tumoral function. On this basis, human colon cancer cells were cultured in vitro in hypoxic conditions. Hypoxia was shown to decrease the level of Cdx2 protein, mRNA and the activity of the Cdx2 promoter. This decline was unrelated to the activation of HIF1α and HIF2α by hypoxia. However, it resulted from the activation of a phosphatidylinositol 3-kinases-like mitogen-activated protein kinase pathway, as assessed by the fact that LY294002 and U0126 restored high Cdx2 expression in hypoxia. Corroborating these results, U0126 recapitulated the increase of Cdx2 triggered by ITPP in subcutaneous colon tumor xenografts. The present study provides evidence that a chemical compound that increases oxygen pressure can antagonize the hypoxic setting and reduce the growth of human colon tumors implanted in nu/nu mice.

Dynamic viscoelastic shear properties of soft matter by magnetic resonance elastography using a low-field dedicated system

A magnetic resonance elastography (MRE) based method that consists in measuring dynamic viscoelastic parameters of soft matter by analysis of propagating shear waves at different frequencies is proposed. Dynamic shear tests were performed on soft gels with a dedicated magnetic resonance imaging system at low field (0.1T) and were compared with results obtained with a mechanical rotational rheometer. Storage and loss moduli were plotted against frequency with both methods and good agreement was found between their results in the shared frequency range. Therefore, it is shown that the described method could be a reliable and accessible tool for three-dimensional dynamic mechanical analysis on soft matter able to overcome dynamic range, sample dimensions and directional limitations of mechanical rheometers. Advantages and limits of the method are discussed.