Perfusion assessment with bolus differentiation: a technique applicable to hyperpolarized tracers.

A new technique for assessing tissue blood flow using hyperpolarized tracers, based on the fact that the magnetization of a hyperpolarized substance can be destroyed permanently, is described. Assessments of blood flow with this technique are inherently insensitive to arterial delay and dispersion, and allow for quantification of the transit time and dispersion in the arteries that supply the investigated tissue. Renal cortical blood flow was studied in six rabbits using a 13C-labeled compound (2-hydroxyethylacrylate) that was polarized by the parahydrogen-induced polarization (PHIP) technique. The renal cortical blood flow was estimated to be 5.7/5.4 +/- 1.6/1.3 ml/min per milliliter of tissue (mean +/- SD, right/left kidney), and the mean transit time and dispersion in the renal arteries were determined to be 1.47/1.42 +/- 0.07/0.07 s and 1.78/1.93 +/- 0.40/0.42 s2, respectively.

Cerebral perfusion assessment by bolus tracking using hyperpolarized 13C.

Cerebral perfusion was assessed with 13C MRI in a rat model after intravenous injections of the 13C-labeled compound bis-1,1-(hydroxymethyl)-1-13C-cyclopropane-D8 in aqueous solutions hyperpolarized by dynamic nuclear polarization (DNP). Since the tracer acted as a direct signal source, several of the problems associated with techniques based on traditional dynamic susceptibility contrast (DSC) MRI contrast agents were avoided. Maps of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) were calculated. The MTT was determined to be 2.8 +/- 0.8 sec. However, arterial partial-volume effects in the animal model prevented accurate absolute quantification of CBF and CBV. It was demonstrated that depolarization of the hyperpolarized 13C tracer via relaxation and the imaging sequence had little influence on CBF assessment when the time resolution of the imaging sequence was short compared to the MTT. However, CBV and MTT were increasingly underestimated as MTT or the depolarization rate increased if depolarization was not taken into account. With a modified bolus-tracking theory depolarization could be compensated for, assuming that the depolarization rate was known. Three separate compensation methods were investigated experimentally and by numerical simulations.

Molecular imaging using hyperpolarized 13C.

MRI provides unsurpassed soft tissue contrast, but the inherent low sensitivity of this modality has limited the clinical use to imaging of water protons. With hyperpolarization techniques, the signal from a given number of nuclear spins can be raised more than 100 000 times. The strong signal enhancement enables imaging of nuclei other than protons, e.g. (13)C and (15)N, and their molecular distribution in vivo can be visualized in a clinically relevant time window. This article reviews different hyperpolarization techniques and some of the many application areas. As an example, experiments are presented where hyperpolarized (13)C nuclei have been injected into rabbits, followed by rapid (13)C MRI with high spatial resolution (scan time <1 s and 1.0 mm in-plane resolution). The high degree of polarization thus enabled mapping of the molecular distribution within various organs, a few seconds after injection. The hyperpolarized (13)C MRI technique allows a selective identification of the molecules that give rise to the MR signal, offering direct molecular imaging.

Gradient echo imaging of flowing hyperpolarized nuclei: theory and phantom studies on 129Xe dissolved in ethanol.

The influence of flip angle and flow velocity on the signal intensity achieved when imaging a hyperpolarized substance with a spoiled gradient echo sequence was investigated. The study was performed both theoretically and experimentally using hyperpolarized xenon dissolved in ethanol. Analytical expressions regarding the optimal flip angle with respect to signal and the corresponding signal level are presented and comparisons with thermally polarized substances are made. Both experimentally and theoretically, the optimal flip angle was found to increase with increasing flow velocity. Numerical calculations showed that the velocity dependence of the signal differs between the cases of hyperpolarized and thermally polarized substances.

Echo-planar MR imaging of dissolved hyperpolarized 129Xe.

PURPOSE: The feasibility of hyperpolarized 129Xe for fast MR angiography (MRA) was evaluated using the echo-planar imaging (EPI) technique. MATERIAL AND METHODS: Hyperpolarized Xe gas was dissolved in ethanol, a carrier agent with high solubility for Xe (Ostwald solubility coefficient 2.5) and long relaxation times. The dissolved Xe was injected as a bolus into a flow phantom where the mean flow velocity was 15 cm/s. Ultrafast EPI images with 44 ms scan time were acquired of the flowing bolus and the signal-to-noise ratios (SNR) were measured. RESULTS: The relaxation times of hyperpolarized Xe in ethanol were measured to T1=160+/-11 s and T2 approximately 20 s. The resulting images of the flowing liquid were of reasonable quality and had an SNR of about 70. CONCLUSION: Based on the SNR of the obtained Xe EPI images, it was estimated that rapid in vivo MRA with 129Xe may be feasible, provided that an efficient, biologically acceptable carrier for Xe can be found and polarization levels of more than 25% can be achieved in isotopically enriched 129Xe.

Parahydrogen-induced polarization in imaging: subsecond (13)C angiography.

High nuclear spin polarization of (13)C was reached in organic molecules. Enhancements of up to 10(4), compared to thermal polarization at 1.5 T, were achieved using the parahydrogen-induced polarization technique in combination with a field cycling method. While parahydrogen has no net polarization, it has a high spin order, which is retained when hydrogen is incorporated into another molecule by a chemical reaction. By subjecting this molecule to a sudden change of the external magnetic field, the spin order is transferred into net polarization. A (13)C angiogram of an animal was generated in less than a second. Magn Reson Med 46:1-5, 2001.

Dynamic in vivo oxymetry using overhauser enhanced MR imaging.

A noninvasive method for in vivo measurement of the oxygen concentration has been developed. By introducing a novel contrast medium (CM) based on a single electron substance, it is possible to enhance the proton signal through the Overhauser effect. A low-field magnetic resonance scanner is used to image the proton nuclei of the object. The electron spin transition of the CM is saturated using rf irradiation. As a consequence, the nuclear polarization becomes enhanced through dipole-dipole interaction. The signal enhancement is a function of rf power and of the EPR line width of the substance, which is influenced by the oxygen concentration. The maximum in vivo enhancement has been measured to 60. Image data, generated with different scanning parameters, is used in a postprocessing method to generate images showing pO(2) and the contrast medium concentration, respectively. The mathematical foundation of the postprocessing algorithm is outlined. The results from phantom experiments and animal experiments, in which the oxygen content of the inspired gas was varied, are presented. The potential for human imaging is discussed. J. Magn. Reson. Imaging 2000;12:929-938.

EPR and DNP properties of certain novel single electron contrast agents intended for oximetric imaging.

Parameters of relevance to oximetry with Overhauser magnetic resonance imaging (OMRI) have been measured for three single electron contrast agents of the triphenylmethyl type. The single electron contrast agents are stable and water soluble. Magnetic resonance properties of the agents have been examined with electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR), and dynamic nuclear polarization (DNP) at 9.5 mT in water, isotonic saline, plasma, and blood at 23 and 37 degreesC. The relaxivities of the agents are about 0.2-0.4 mM-1s-1 and the DNP enhancements extrapolate close to the dipolar limit. The agents have a single, narrow EPR line, which is analyzed as a Voigt function. The linewidth is measured as a function of the agent concentration and the oxygen concentration. The concentration broadenings are about 1-3 microT/mM and the Lorentzian linewidths at infinite dilution are less than 1 microT in water at room temperature. The longitudinal electron spin relaxation rate is calculated from the DNP enhancement curves. The oxygen broadening in water is about 50 microT/mM O2 at 37 degreesC. These agents have good properties for oximetry with OMRI.

Overhauser-enhanced MR imaging (OMRI).

PURPOSE: To evaluate a new single-electron contrast agent for Overhauser-enhanced MR imaging. The contrast agents that are currently available give enhancement factors that are too low to make the technique a valid option for routine clinical use. MATERIAL AND METHODS: MR images were generated directly following the injection of the substance into rats. The MR scanner was operated at a main magnetic field of 0.01 T and equipped with a separate rf-transmitter tuned to the electron paramagnetic resonance frequency of the contrast agent. RESULTS: As expected, the images generated show a high level of enhancement in areas where the contrast agent was present, and a maximum enhancement of 60 times the normal proton signal was obtained in the vascular area. The signal-to-noise ratios in the images were superior to those previously attained. CONCLUSION: The new contrast agent makes it possible to generate MR images with both morphological and functional information at 0.01 T. The signal-to-noise ratios found in the generated images were of the same order as, or better than, those obtained with the standard clinical routine.

Urine profiles and kidney histology after ionic and nonionic radiologic and magnetic resonance contrast media in rats with cisplatin nephropathy.

RATIONALE AND OBJECTIVES: The nephrotoxic drug cisplatin has been used successfully in treating some cancers. Patients with suspected carcinoma frequently undergo examinations with contrast media. We examined whether ionic and nonionic radiologic and magnetic resonance contrast media would have any effect on cisplatin nephropathy in rats. METHODS: Urine and serum profiles were monitored for 24 days after intravenous (i.v.) injections of saline, diatrizoate, iohexol, gadopentetate dimeglumine, and gadodiamide in high doses (4.59 mmol/kg body weight) in rats that received a weekly intraperitoneal (i.p.) injection of cisplatin (1 mg/kg) for 10 weeks. There were 10 rats in each group. Another 10 rats injected with both i.p. and i.v. saline served as control subjects. After euthanization, rats' kidneys were removed for examination by light microscopy and electron microscopy. RESULTS: Light and electron microscopy showed severe morphologic changes, including tubular dilatation, atrophy, and necrosis induced by cisplatin; however, the contrast media did not induce any additional morphologic changes. Gadopentetate dimeglumine, diatrizoate, and iohexol significantly increased (3-20 times) albuminuria compared with i.v. saline in cisplatin nephropathy, whereas gadodiamide did not. Albuminuria was highest after diatrizoate injection. All four contrast media caused an immediate and transient significant increase in the excretion of the brush border enzymes alkaline phosphatase and gamma-glutamyltransferase (125-500 times) and the cytoplasmatic enzymes alanine aminopeptidase and lactate dehydrogenase (16-100 times). Compared with saline, the ionic agents significantly increased the excretion of both glucose (two times) and sodium (three to five times), whereas the nonionic agents did not. CONCLUSION: High doses of radiologic and magnetic resonance contrast agents cause temporary dysfunction in rats with cisplatin nephropathy. Gadodiamide caused the least dysfunction and diatrizoate the most.

Renal effects of iodixanol in experimental animals.

The effects of the new nonionic dimeric hexa-iodinated contrast media (CM) iodixanol on renal function and morphology were investigated in 7 independent studies in rats, rabbits and monkeys and compared with other iodinated CM. No significant effect on serum creatinine levels was seen at doses up to and including 5 g I/kg in rats and 10.5 g I/kg in rabbits. An immediate and transient increase in proteinuria was found in rabbits when 10.5 g I/kg was administered as a bolus, and when 12.5 g I/kg was administered as a slow infusion in a comparative study with several CM. Increased serum elimination half-life was shown by measuring serum iodine concentrations after the infusion of 12.5 g I/kg. The effect of a high dose of iodixanol on proteinuria and elimination half-life were in this study in the same range as those of the monomeric nonionic CM, but less pronounced than those of the monomeric ionic CM. Reduced renal capacity was induced in male rats by performing unilateral nephrectomy 4 weeks before i.v. injection of iodixanol or iopamidol (2g I/kg). The administration of CM did not affect renal function monitored as serum concentrations of creatinine and urea. The vacuolation of renal proximal tubular cells and kidney iodine retention were investigated in rats 48 hours after administration of different doses of iodixanol or iotrolan. The no-effect level for vacuolation was 0.5 g I/kg for both CM. Iodine retention was higher in male than females rats, and was higher for iodixanol than iotrolan at the 2 highest dose levels (3 and 5 g I/kg). No difference in iodine retention was found at the other dose levels (0.25-1g I/kg). The reversibility of renal proximal tubular vacuolation after administration of iodixanol was studied in male rats (1.2 g I/kg) and monkeys (1.2 and 3.6 g I/kg). The vacuolation was more pronounced in rats than in monkeys. Vacuolation was completely reversed in all rats 3 weeks after dosing, and 2 of 3 monkeys 3 days after a dose of 1.2 g I/kg. The degree of vacuolation evident in renal percutaneous biopsy specimens from monkeys 14 days after i.v. administration of iodixanol at a dose of 3.5 g I/kg was not significantly different to that in control animals. In conclusion, iodixanol affected renal function to the same degree as did the nonionic monomeric and dimeric comparative media, but to a lesser degree than the ionic monomers. The degree of renal proximal tubular cell vacuolation induced by iodixanol seems to be species-dependent, being less pronounced and more quickly reversed in monkeys than rats.

Adverse reactions in myelography.

An attempt was made to assess the usefulness of using animal models to predict the neural tolerability in man of iodinated contrast media (CM) in general, and of the new nonionic dimer iodixanol in particular. For this purpose, the results from 6 animal experiments evaluating excitative and depressive effects of subarachnoidally injected CM in nonanesthetized rabbits were compared with the results from 22 randomized double-blind clinical trials dealing with post-myelographic adverse reactions. Comparisons were made as regards the nonionic monomers metrizamide, iohexol, and iopamidol, and the dimer iotrolan. The results seem to justify the conclusion that the convulsive effects of CM can be reliably predicted from animal experiments. The animal model cannot be used to predict specific types of nonconclusive adverse reactions in man, but reflects well the differences in frequencies of minor reactions following clinical myelography with different nonionic CM. In general, the neural tolerability of iodixanol may be expected to be better than that of the nonionic monomers and approximately equal to that of iotrolan.

Urine profiles and kidney histology after intravenous injection of ionic and nonionic radiologic and magnetic resonance contrast media in normal rats.

RATIONALE AND OBJECTIVES: Previous studies showed that both high-osmolality and low-osmolality iodinated contrast media cause temporary albuminuria and enzymuria (presence of enzymes in urine) in normal rats. Whether the same is true with ionic high-osmolality and nonionic low-osmolality magnetic resonance (MR) contrast media is unknown. We studied urine profiles and histology after intravenous injection of four types of contrast media in rats with normal kidneys. METHODS: Urine profiles were monitored 4, 24, 48, and 72 hr after intravenous injection of saline, diatrizoate, iohexol, gadopentetate dimeglumine, and gadodiamide (4.59 mmol/kg of body weight) in normal rats. Each group included 20 male rats. After sacrifice, both kidneys were removed for examination by light microscopy (LM) and electron microscopy (EM). RESULTS: All four contrast agents caused a temporary (< 22 hr) increase in the excretion of albumin (2-5 times) and of cytoplasmic (30-100 times) and brush border (10-100 times) renal enzymes when compared with saline. The degree of albuminuria correlated well (r = 0.90) with the osmolality of the injected media, whereas the increased level of enzymuria was unrelated to the osmolality. No major differences in the enzymuric effects of the four agents were noted. LM revealed vacuoles in all kidneys exposed to radiologic contrast media but not in kidneys exposed to MR contrast media or saline. Slight vacuolation was revealed by EM after the use of MR contrast media, and significant vacuolation was evident via EM after the use of radiologic contrast media. No difference between ionic and nonionic media within each drug group was detected by either LM or EM. CONCLUSIONS: Transient renal effects are induced by both ionic and nonionic high-osmolality and low-osmolality radiologic and MR contrast media in normal rats. Both osmotic (e.g., albuminuria) and chemotoxic (e.g., enzymuria) mechanisms seem to be involved. From a morphologic point of view, the chemotoxic mechanisms seem to be of major importance.

A comparison between IEEC, a new biodegradable particulate contrast medium, and iohexol in a tumor model of computed tomography imaging of the liver.

RATIONALE AND OBJECTIVES: Higher contrast between normal and pathologic tissues in the liver may enable detection of smaller lesions in computed tomography (CT). This can be obtained using a liver-specific contrast medium. The authors evaluate a new agent, IEEC (1'-Ethyloxycarbonyloxy)-ethyl-5-acetylamino-3-(N-methyl-acetylami no)-2,4,6- triiodo-benzenecarboxylate), in an animal model, as a potential contrast agent for CT scanning of the liver. The IEEC particulate contrast medium used is based on a prodrug ester design of metrizoic acid and accumulates rapidly in the liver. The particles are quickly degraded into well-known metabolites and excreted from the body. METHODS: Two groups of rabbits were inoculated with VX2-carcinoma directly into the liver by laparotomy. Computed tomography imaging studies were carried out 9 and 11 days after the inoculation. The investigation was designed as a crossover study. The first group was imaged both as controls (without contrast medium) and with the particulate contrast medium on the 9th day and with iohexol on the 11th day. The second group was imaged with iohexol on the 9th day and as controls, and with the particulate contrast medium on the 11th day. The contrast medium was administered in a dose of 100 mgI/kg. Iohexol was administered in a dose of 570 mgI/kg according to a standard clinical scheme in use at a radiology department for dynamic CT. Changes in normal liver/lesion contrast and the conspicuity of tumors were assessed. On completion of imaging studies on day 11, all animals were killed. The liver was removed and evaluated for the presence of tumors. RESULTS: At macroscopic inspection, all rabbits were found to have tumors ranging from 2 to 14 mm in diameter. The size and location of the tumors corresponded well with the CT images. In the images where the particulate contrast medium was used, the attenuation in the normal liver parenchyma and the contrast between normal liver and lesion was significantly higher compared with the images where iohexol was used or the controls. For all tumor sizes, the lesion detection capability with the particulate contrast medium was significantly higher compared with iohexol (P < .005) and controls (P < .05). CONCLUSIONS: VX2-carcinoma in rabbit liver is a useful model for studying the efficacy of contrast media in CT imaging. The particulate contrast medium IEEC improved visualization of liver tumors.

Urine profiles and kidney histologic findings after intravenous injection of mannitol and iohexol in the degeneration phase of gentamicin nephropathy in rats.

RATIONALE AND OBJECTIVES: Previous studies have shown that iodinated contrast media may cause further renal dysfunction in tubulointerstitial nephropathy induced by gentamicin. The current investigation was undertaken to study whether the dysfunction after intravenous injection of a low-osmolar contrast medium is due to a chemotoxic and/or an osmotic effect. METHODS: Urine profiles were followed for 3 or 9 days after intravenous injection of saline, mannitol, and varying dosages of iohexol (1, 2.5, 5, and 10 mL/kg body weight (BW); 350 mg I/mL) in 60 rats, in which intramuscular injection of 40 mg/kg BW gentamicin had been administered daily nine times. A seventh group of 10 rats was given 20 mg/kg BW gentamicin and 5 mL/kg BW of 350 mg I/mL iohexol. Another 10 rats injected with saline served as controls. RESULTS: Both mannitol and iohexol increased the excretion of albumin and the enzyme N-acetyl-B-D-glucosaminidase (NAG) temporarily; the effect was independent of the dose of iohexol. There was a dose-dependent effect on the transient increase in excretion of the enzymes lactate dehydrogenase (LDH), gamma glutamyltransferase (GGT), and alkaline phosphatase (ALK); mannitol did not increase the excretion of these enzymes. In the group given 20 mg/kg BW gentamicin, only the dose-dependent effects of iohexol were seen. Neither various plasma components nor light/electron microscopy showed any changes that could solely be related to the contrast medium. CONCLUSIONS: Iohexol produces transient renal effects in gentamicin nephropathy, which may be due to both chemotoxic and osmotic mechanisms.

MRI simulation using the k-space formalism.

An MRI simulation method, together with a corresponding computer program, using the k-space formalism has been developed. It uses a FFT algorithm to generate the ideal NMR signal from a user defined object. The k-space trajectory given by a pulse sequence is calculated. And it is used to select elements from the ideal NMR signal. This selection of elements mimic the sampling of the signal in an actual MRI experiment. During the sampling procedure changes in signal amplitude due to relaxation and excitation are introduced as well as signal phase changes due to movement or flow. Artifacts due to stimulated echoes and transversal magnetization that propagate through several repetition periods are also handled. The usefulness of the method is demonstrated by calculations using standard spin-echo sequence as well as modifications introduced in order to generate angiographical images and flow phase images. Further more a fast pulse sequence, echo planar imaging (EPI), is also simulated. The method is faster than previously presented ones. It is capable of generating images (128 x 128 matrix), including more than eight different T1 and T2 combinations, in less than 3 min on a standard 386/387 type IBM compatible PC.

Early effect of gadopentetate and iodinated contrast media on rabbit kidneys.

RATIONALE AND OBJECTIVES: The authors compared the physiologic and nephrotoxic effects of the magnetic resonance imaging contrast medium gadopentetate with two conventional radiographic contrast media. METHODS: Rabbits were injected intravenously with one of the following solutions: 1) gadopentetate (0.1 M); 2) iohexol (300 mg I/mL); 3) metrizoate (300 mg I/mL); and 4) NaCl (0.9%). Blood samples were taken before and 5, 15, 45, 90, and 180 minutes after injection of the solutions and were analyzed for creatinine, aldosterone, and contrast media levels. Urine was sampled before and 1, 2.5, and 5 hours after injection of the solutions, and creatinine, leucine amino peptidase (LAP), alkaline phosphatase (ALP), gamma glutaryl transferase (GGT), and N-acetyl beta-D-glucosaminidase (NAG) activities were quantified. RESULTS: Contrast media clearance was similar for gadopentetate, iohexol, and metrizoate. Plasma aldosterone was significantly higher in the two groups injected with iodinated contrast agents compared with the gadopentetate and saline groups in the 3-hour samples. During the 5 hours after injection, the excretion of brushborder enzymes LAP, ALP, and gamma GT was significantly higher for all contrast media compared with pre-contrast values and 0.9% NaCl controls. NAG, a lysosomal enzyme from tubular cells, showed a significant increase compared with pre-contrast values for all contrast media. CONCLUSIONS: Intravenous injection of gadopentetate in rabbits showed nephrotoxicity of the same order as that of conventional iodinated contrast media.