J. J. Le Jeune

In vivo quantitative microimaging of rat spinal cord at 7T.

In vivo T2, ADC, and MT properties of the GM and WM of the rat spinal cord were measured at 7T in the cervical region. The GM T2, T2GM = 43.2 ± 1.0 msec is significantly reduced compared to the WM T2, T2WM = 57.0 ± 1.6 msec. Diffusion is anisotropic for both GM and WM, with a larger ADC value along the cord axis (ADCGM// = 1.05 ± 0.09 10−9 m2sec−1 and ADCWM// = 1.85 ± 0.18 10−9 m2sec−1) than perpendicular to this plane (ADCGM⊥ ∼ 0.50 * 10−9 m2sec−1 and ADCWM⊥ ∼ 0.18 * 10−9 m2sec−1). The MT properties do not significantly differ between the WM and the GM, but allow one to distinguish the thin CSF layer from the WM. DWI with the sensitizing gradient perpendicular to the cord axis leads to the best contrast between GM and WM in the cervical region. Magn Reson Med 44:893–898, 2000.

Biodistribution of dual radiolabeled lipidic nanocapsules in the rat using scintigraphy and γ counting

The aim of the present work was to study the biodistribution of a radiolabeled lipidic nanocapsule formulation after intravenous administration in rat by scintigraphy and gamma counting. This formulation is expected to be used as anticancer agent delivery devices and as transfection complexes. For this purpose, 99mTc-oxine was incorporated in the lipidic core, while 125I labeled tensioactive shell of the nanocapsule. First, in vitro stability of radiolabeled nanocapsules was evaluated by dialysis against distilled water and size measurements. Second, the nanocapsule biodistribution was followed after intravenous administration for 3 h by dynamic scintigraphic acquisition and up to 24 h by determining the gamma activity in blood and tissues. Radiolabeling was efficient and stable in vitro. After intravenous injection blood radioactivity decreased with an early half disappearance time of about 45 min for both radioisotopes. Liver and intestine radioactivities raised up to 24 h. The relatively long remanence in blood of the tracers which is probably due to the presence of PEG at the nanocarrier surface seems promising for the use of these solvent free lipidic nanocapsules as carrier of lipophilic drugs.

Early detection of liposome brain localization in rat experimental allergic encephalomyelitis.

Abstract Blood-brain barrier (BBB) permeability increases prior to the development of clinical signs in early-stage multiple sclerosis (MS). Detection of subtle changes would thus be helpful for diagnostic purposes and rapid therapeutic decisions before new episodes. Since multiple sclerosis and experimental allergic encephalomyelitis (EAE) have numerous common features, in particular BBB-permeability characteristics, and since we have previously shown that BBB localization is disturbed by tumors, embolism, and mannitol injection, we investigated BBB-liposome permeability in an EAE rat model. Twenty young male Lewis rats received a single intradermal inoculation of guinea-pig spinal cord. The effect of the Freund’s adjuvant and spinal cord alone on brain permeability were also assessed. In order to compare solution permeability and liposome localization, radioactive liposomes and, 1 h later, 99mTc-DTPA were injected intravenously. Scintigraphic acquisitions were obtained to follow the biodistribution of radioactivity in the whole body. Each rat was subjected to a first examination before inoculation and then every two days until completion and may be considered as its own control. EAE induced a previously unreported increase in global-body permeability, probably due to inflammation. Liposome brain localization and brain/heart ratio were significantly different between normal animals and those with early-stage EAE (before appearance of clinical signs) and distinguished between different disease stages in clinically patent EAE. The index of disease progression was modified earlier than with 99mTc-DTPA injection. One explanation may be particle pick-up by circulating macrophages, which cross the BBB during this pathology. For clinical applications, experiments must be confirmed on models more reliable for human multiple sclerosis.

Characterization and detection of experimental rat gliomas using magnetic resonance imaging

Two different experimental rat brain tumours (F98 glioma and 9L glioma) were characterized using T1 and T2, apparent diffusion coefficient (ADC) and magnetization transfer ratio (MTR). Even though both tumours appeared homogenous at the early stage of growth, significant differences were measured for all parametric images between tumours and normal brain tissue. Irrespective of the sequence used, tumour lesion/normal parenchyma contrast for the non-infiltrative 9L was twice that of the infiltrative F98 glioma. The use of spin preparation via an inversion pulse in a fast spin echo sequence increases contrast by a factor of 20–30.

Investigation of blood-brain barrier permeability to magnetite-dextran nanoparticles (MD3) after osmotic disruption in rats

The permeability of experimentally disrupted blood-brain barrier (BBB) to superparamagnetic nanoparticles (MD3) was studied in rats. BBB opening was induced by intracarotid injection of mannitol. One hundred eighty rats were used for the study. Rats were examined at two time points, 30 minutes and 12 hours after intracarotid mannitol injection. Different preparations intravenously injected 30 minutes before rat sacrifice were used for characterization of BBB disruption. BBB integrity was determined with99mTc-diethylenetriamine pentaacetic acid (DTPA) and99mTc-albumin. Iron oxide-glucose particles (12-nm mean diameter),99mTc-labeled lecithin-cholesterol liposomes of three different sizes (50, 100, and 200 nm), and polyethylene glycol (PEG)-coated99mTc liposomes (50 nm) were used for investigations of the dependence of BBB permeability on particle system size or surface. Magnetite-dextran nanoparticles (MD3) were evaluated as superparamagnetic contrast agent to monitor with magnetic resonance imaging (MRI) the BBB breakdown.In vitro T1 and T2 relaxation times of the brain tissue were measured at 40 MHz and 37°C, and T2-weighted MR images were acquired at 0.5 T. After intracarotid mannitol infusion, as expected, the BBB breakdown was immediate and temporary as judged by soluble molecule diffusion. MD3 nanoparticles crossed the BBB 12 hours after intravenous mannitol injection, at a time when brain permeability for molecules or small particles returns to normal. Magnetite crystals were found in cytoplasmic vesicles of glial cells. On MRI, signal intensity decreased after injection of MD3, even 12 hours after mannitol injection. This particularity could be useful in the study of focal pathological lesions accompanied by BBB permeability modifications. In such conditions, superparamagnetic particle contrast agents could be caught by the BBB, allowing the observation of impaired BBB areas without detectable cellular lesions.

Susceptibility gradient quantization by MRI signal response mapping (SIRMA) to dephaser

PURPOSE Susceptibility effects are a very efficient source of contrast in magnetic resonance imaging. However, detection is hampered by the fact the induced contrast is negative. In this work, the SIgnal Response MApping (SIRMA) to dephaser method is proposed to map susceptibility gradient to improve visualization. METHODS In conventional gradient echo acquisitions, the echo formation of susceptibility affected spins is shifted in k-space, the shift being proportional to the susceptibility gradient. Susceptibility gradients map can be produced by measuring this induced shifts. The SIRMA method measures these shifts from a series of dephased images collected with additional incremental dephasers. These additional dephasers correspond either to a slice refocusing gradient offset or to a reconstruction window off-centering. The signal intensity profile as a function of the additional dephaser was determined on a pixel-by-pixel basis from the ensemble of dephased images. Susceptibility affected voxels presented a signal response profile maximum shifted compared to nonaffected voxels ones. Shift magnitude and sign were measured for each pixel to determine susceptibility gradients and produce a susceptibility gradient map. RESULTS In vitro experiments demonstrated the ability of the method to map gradient inhomogeneities induced by a cylinder. Quantization accuracy was evaluated comparing SIRMA images and simulations performed on the well-characterized air filled cylinder model. Performances of the SIRMA method, evaluated in vitro on cylinders filled with various superparamagnetic iron oxide SPIO concentrations, showed limited influence of acquisition parameters. Robustness of the method was then assessed in vivo after an infusion of SPIO-loaded nanocapsules into the rat brain using a convection-enhanced drug delivery approach. The region of massive susceptibility gradient induced by the SPIO-loaded nanocapsules was clearly delineated on SIRMA maps and images were compared to T2* weighted images, Susceptibility Gradient Map (SGM), and histological Perls staining slice. The potential for quantitative evaluation of SPIO distribution volume was demonstrated. CONCLUSIONS The proposed method is a promising technique for a wide range of applications especially in molecular or cellular imaging with respect to its quantitative nature and its computational simplicity.

Prenatal evaluation of kidney function in mice using dynamic contrast-enhanced magnetic resonance imaging

Glomerular differentiation starts as soon as embryonic stage 12 in mice and suggests that kidneys may be functional at this stage. Dynamic contrast-enhanced magnetic resonance microscopy, a noninvasive imaging technique, was used to assess renal function establishment in utero. Indeed, in adults (n=3), an intravenous injection of gadolinium-DOTA induced in a first step a massive and rapid drop in kidney signal intensity followed, in a second step, by a drop in bladder signal intensity. The delay in signal changes between kidney and bladder reflected glomerular filtration. Pregnant mice underwent anatomical and dynamic contrast-enhanced magnetic resonance microscopy on postcoital days 12–13 (n=2), 13–14 (n=1), 14–15 (n=3), 15–16 (n=2), 16–17 (n=3), 17–18 (n=3), and 18–19 (n=1). Kidneys and bladder were unambiguously depicted prior to contrast agent injection on stage 15–16 embryos. Contrast agent injection allowed kidney, detection as early as stage 12–13 but not bladder. Kinetics of signal changes demonstrated that glomerular filtration is established at embryonic stage 15–16 in mice. Thus, anatomical and dynamic contrast-enhanced magnetic resonance microscopy may be a powerful noninvasive method for in vivo prenatal developmental and functional studies.

In vitro and in vivo evaluation of superparamagnetic iron oxide nanoparticles coated by bisphosphonates: the effects of electrical charge and molecule length.

Physicochemical coating properties are often considered to be determining factors for in vivo characteristics of superparamagnetic iron oxide nanoparticles, used as contrast agent in Magnetic Resonance Imaging (MRI). To investigate the electrical charge (modified by zero, one or two ammonium groups) and the molecule length (3, 5 or 7 methylene chains) effects of bisphosphonate-type coatings, we assessed the complement activation, in vivo plasma and tissue relaxation time alterations of intravenously injected small iron oxide nanoparticles (<25 nm) on male healthy Wistar rats. The presence of ammonium groups induces a weak activation of the complement whatever the size and the concentration of particles, whereas hydroxyethylenebisphosphonate (HEBP)-coated particles are poor complement activators only at the lowest concentration. In vivo, HEBP-coated nanoparticles have the greatest prolonged relaxation time effects, despite their higher negative electrical charge, contrary to two ammonium bearing coatings. No significant differences were observed between mono-ammonium molecular coatings.

Model based and iconic multimodal registration to merge gated cardiac PET, CT and MR sequences

In this paper, we present a multimodal registration method applied to gated positron emission tomography (PET), X-ray Computed Tomography (CT) and Magnetic Resonance (MR) cardiac images. CT images acquired on the same device as the PET ones are used as link to merge anatomical MR images and functional PET images. The registration process is divided in two steps: a 3D structure registration and a grey-levels registration. This approach enables global to local transformations. The structure registration uses a 3D biventricular heart model initialized on CT and MR data to define a rigid transform. This global registration is then refined with a grey-levels step based on mutual information and free form deformations. To improve endocardium registration, we propose a composite PET-CT image to find the optimal transformation on MR image. We also take into account the temporal problematic of heart motion by initializing the searched transformation, at a current frame, with the composition of a monomodal transformation (representing the heart motion between the previous and current frames) and a multimodal one (representing the spatial transformation between the two images at the previous frame).