Monitoring plaque inflammation in atherosclerotic rabbits with an iron oxide (P904) and (18)F-FDG using a combined PET/MR scanner.

PURPOSE: The aim of this study was to compare the ability of (18)F-FDG PET and iron contrast-enhanced MRI with a novel USPIO (P904) to assess change in plaque inflammation induced by atorvastatin and dietary change in a rabbit model of atherosclerosis using a combined PET/MR scanner. MATERIALS AND METHODS: Atherosclerotic rabbits underwent USPIO-enhanced MRI and (18)F-FDG PET in PET/MR hybrid system at baseline and were then randomly divided into a progression group (high cholesterol diet) and a regression group (chow diet and atorvastatin). Each group was scanned again 6 months after baseline imaging. R2* (i.e. 1/T2*) values were calculated pre/post P904 injection. (18)F-FDG PET data were analyzed by averaging the mean Standard Uptake Value (SUVmean) over the abdominal aorta. The in vivo imaging was then correlated with matched histological sections stained for macrophages. RESULTS: (18)F-FDG PET showed strong FDG uptake in the abdominal aorta and P904 injection revealed an increase in R2* values in the aortic wall at baseline. At 6 months, SUVmean values measured in the regression group showed a significant decrease from baseline (p = 0.015). In comparison, progression group values remained constant (p = 0.681). R2* values showed a similar decreasing trend in the regression group suggesting less USPIO uptake in the aortic wall. Correlations between SUVmean or Change in R2* value and macrophages density (RAM-11 staining) were good (R(2) = 0.778 and 0.707 respectively). CONCLUSION: This experimental study confirms the possibility to combine two functional imaging modalities to assess changes in the inflammation of atherosclerotic plaques. (18)F-FDG-PET seems to be more sensitive than USPIO P904 to detect early changes in plaque inflammation.

Magnetic resonance imaging of ruptured plaques in the rabbit with ultrasmall superparamagnetic particles of iron oxide.

BACKGROUND: Magnetic resonance imaging (MRI) enhanced with ultrasmall superparamagnetic particles of iron oxide (USPIO) has previously been evaluated in hyperlipidemic rabbits. The aim of this study was therefore to compare USPIO in ruptured and non-ruptured arteries in an atherosclerotic rabbit model. METHODS: Atherosclerotic-like lesions were induced by the combination of endothelial abrasion and high-cholesterol diet in iliac rabbit arteries (n = 16). Rupture of atherosclerotic lesions was realized by oversized balloon angioplasty in one iliac artery, whereas the contralateral artery was used as control. USPIO (ferumoxtran-10: 1 mmol Fe/kg) was administered immediately (n = 10) or 28 days (n = 6) after injury. MRI and histological analysis were performed 7 and 35 days after injury and in control arteries. RESULTS: In vivo MRI analysis showed extended susceptibility artifact with transluminal signal loss in all ruptured arteries 7 days after injury. In contrast, hyposignal was reduced 35 days following injury (i.e. after healing), and absent in non-ruptured arteries. Similarly, histological analysis of iron uptake was significantly increased 7 days after injury compared to healed-ruptured and control arteries. CONCLUSIONS: Accumulation ofUSPIO is significantly increased in ruptured as compared to non-ruptured arteries in the atherosclerotic rabbit model.

Distribution of gadomelitol in a human breast tumor model in mice.

The study evaluates the tumor distribution of the rapid clearance blood pool agent (RCBPA) gadomelitol, in a breast tumor model. Different techniques were used : (1) tissue gadolinium concentrations measured by inductively coupled plasma atomic emission spectroscopy (ICP-AES), (2) whole body quantitative autoradiography using radiolabeled [153Gd] gadomelitol and (3) dynamic contrast-enhanced MRI with compartmental analysis. An accumulation of gadomelitol in tumors compared to muscle was observed 30 min and 3 h post injection (p.i.). Thirty minutes p.i., the gadomelitol tumor distribution evaluated by autoradiography showed a marked difference between the rim and the center, whereas both areas showed comparable concentrations after 3 h. Using dynamic contrast-enhanced MRI, three phases could be observed during the 1 hour observation period: (1) rapid tumor uptake within the first few minutes post-injection (2) a progressive increase in tumor signal enhancement over 10 min and (3) a steady-state phase. Average +/- SD (n=5) transendothelial permeability K(PS) and the fractional blood volume fBV were 12.2+/-1.6 microl/min(-1)/g and 5.4+/-0.2% respectively. Due to its slow extravasation and high tumor residence time, gadomelitol may potentially be useful to improve characterization between benign versus malignant tumors using dynamic MRI.

Mice deficient in cellular glutathione peroxidase show increased vulnerability to malonate, 3-nitropropionic acid, and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine.

Glutathione peroxidase (GSHPx) is a critical intracellular enzyme involved in detoxification of hydrogen peroxide (H(2)O(2)) to water. In the present study we examined the susceptibility of mice with a disruption of the glutathione peroxidase gene to the neurotoxic effects of malonate, 3-nitropropionic acid (3-NP), and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Glutathione peroxidase knock-out mice showed no evidence of neuropathological or behavioral abnormalities at 2-3 months of age. Intrastriatal injections of malonate resulted in a significant twofold increase in lesion volume in homozygote GSHPx knock-out mice as compared to both heterozygote GSHPx knock-out and wild-type control mice. Malonate-induced increases in conversion of salicylate to 2,3- and 2, 5-dihydroxybenzoic acid, an index of hydroxyl radical generation, were greater in homozygote GSHPx knock-out mice as compared with both heterozygote GSHPx knock-out and wild-type control mice. Administration of MPTP resulted in significantly greater depletions of dopamine, 3,4-dihydroxybenzoic acid, and homovanillic acid in GSHPx knock-out mice than those seen in wild-type control mice. Striatal 3-nitrotyrosine (3-NT) concentrations after MPTP were significantly increased in GSHPx knock-out mice as compared with wild-type control mice. Systemic 3-NP administration resulted in significantly greater striatal damage and increases in 3-NT in GSHPx knock-out mice as compared to wild-type control mice. The present results indicate that a knock-out of GSHPx may be adequately compensated under nonstressed conditions, but that after administration of mitochondrial toxins GSHPx plays an important role in detoxifying increases in oxygen radicals.