Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy.

Measurements of early tumor responses to therapy have been shown, in some cases, to predict treatment outcome. We show in lymphoma-bearing mice injected intravenously with hyperpolarized [1-(13)C]pyruvate that the lactate dehydrogenase-catalyzed flux of (13)C label between the carboxyl groups of pyruvate and lactate in the tumor can be measured using (13)C magnetic resonance spectroscopy and spectroscopic imaging, and that this flux is inhibited within 24 h of chemotherapy. The reduction in the measured flux after drug treatment and the induction of tumor cell death can be explained by loss of the coenzyme NAD(H) and decreases in concentrations of lactate and enzyme in the tumors. The technique could provide a new way to assess tumor responses to treatment in the clinic.

Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate.

As alterations in tissue pH underlie many pathological processes, the capability to image tissue pH in the clinic could offer new ways of detecting disease and response to treatment. Dynamic nuclear polarization is an emerging technique for substantially increasing the sensitivity of magnetic resonance imaging experiments. Here we show that tissue pH can be imaged in vivo from the ratio of the signal intensities of hyperpolarized bicarbonate (H(13)CO(3)(-)) and (13)CO(2) following intravenous injection of hyperpolarized H(13)CO(3)(-). The technique was demonstrated in a mouse tumour model, which showed that the average tumour interstitial pH was significantly lower than the surrounding tissue. Given that bicarbonate is an endogenous molecule that can be infused in relatively high concentrations into patients, we propose that this technique could be used clinically to image pathological processes that are associated with alterations in tissue pH, such as cancer, ischaemia and inflammation.

Iodixanol 320 results in better renal tolerance and radiodensity than do gadolinium-based contrast media: arteriography in ischemic porcine kidneys.

PURPOSE: To prospectively compare nephrotoxicity and radiodensity of plasma hyperosmotic gadolinium chelates (attenuation-osmotic ratio of 1:1) with those of plasma iso-osmotic iodine-based contrast media (attenuation-osmotic ratio of 3:1 or 6:1) after renal arteriography in ischemic porcine kidneys. MATERIALS AND METHODS: The local animal care committee approved this study. The following contrast media were used: (a) iodixanol (150 mg of iodine per milliliter and 320 mg I/mL, 0.29 osm/kg H(2)O), (b) iopromide (150 mg I/mL, 0.34 osm/kg), (c) 0.5 mol/L gadodiamide (0.78 osm/kg), and (d) 1.0 mol/L gadobutrol (1.6 osm/kg). After left-sided nephrectomy, contrast media (3 mL per kilogram of body weight) were injected (20 mL/min) in a noncrossover design into the right renal artery of pigs during a 10-minute ischemic period. There were eight pigs in each group and one group for each contrast medium. We compared histomorphology, radiographic contrast medium excretion, subjective radiodensity of nephrograms (70 kVp) at the end of injection, and contrast medium plasma half-life elimination times 1-3 hours after injection. Longer elimination times resulted in lower glomerular filtration rates. RESULTS: Gadobutrol caused extensive tubular necrosis and moderate glomerular necrosis; gadodiamide and iopromide, minimal to mild tubular necrosis; and iodixanol, no necrosis. Gadobutrol was the only contrast medium to show no sign of excretion, and its plasma half-life elimination time (median, 1103 minutes; P < .001) was significantly longer than that of other contrast agents. Gadodiamide had a significantly longer plasma half-life elimination time (median, 209 minutes; P = .01) than did iodine-based contrast media (median, 136-142 minutes). The 320 mg I/mL dose of iodixanol had the highest radiodensity, whereas gadodiamide had the lowest radiodensity. The radiodensity of the 320 mg I/mL dose of iodixanol was greater than that of the 150 mg I/mL dose of iodixanol, which was equal to the radiodensities of the 150 mg I/mL dose of iopromide and 1.0 mol/L gadobutrol, which in turn were greater than that of 0.5 mol/L gadodiamide. CONCLUSION: Plasma iso-osmotic iodine-based contrast media used at commercially available concentrations have superior attenuation and nephrotoxic profiles compared with equal volumes of hyperosmotic nonionic 0.5-1.0 mol/L gadolinium-based contrast media when performing renal arteriographic procedures.

Metabolic imaging by hyperpolarized 13C magnetic resonance imaging for in vivo tumor diagnosis.

The "Warburg effect," an elevation in aerobic glycolysis, may be a fundamental property of cancer cells. For cancer diagnosis and treatment, it would be valuable if elevated glycolytic metabolism could be quantified in an image in animals and humans. The pyruvate molecule is at the metabolic crossroad for energy delivery inside the cell, and with a noninvasive measurement of the relative transformation of pyruvate into lactate and alanine within a biologically relevant time frame (seconds), it may be possible to quantify the glycolytic status of the cells. We have examined the metabolism after i.v. injection of hyperpolarized (13)C-pyruvate in rats with implanted P22 tumors. The strongly enhanced nuclear magnetic resonance signal generated by the hyperpolarization techniques allows mapping of pyruvate, lactate, and alanine in a 5 x 5 x 10 mm(3) imaging voxel using a 1.5 T magnetic resonance scanner. The magnetic resonance scanning (chemical shift imaging) was initiated 24 seconds after the pyruvate injection and had a duration of 14 seconds. All implanted tumors showed significantly higher lactate content than the normal tissue. The results indicate that noninvasive quantification of localized Warburg effect may be possible.

3He MRI-based assessment of posture-dependent regional ventilation gradients in rats.

A recently developed method for quantitative assessment of regional lung ventilation was employed for the study of posture-dependent ventilation differences in rats. The measurement employed hyperpolarized (3)He MRI to detect the build-up of the signal intensity after increasing numbers of (3)He breaths, which allowed for computation of a regional ventilation parameter. A group of six anesthetized rats was studied in both supine and prone postures. Three-dimensional maps of the ventilation parameter were obtained with high spatial resolution (voxel volume approximately 2 mm(3)). Vertical (dorsal-ventral) gradients of the ventilation index, defined as the regional ventilation normalized by the average ventilation within the whole lung, were investigated. Variations in the regional distribution of the ventilation parameter, as well as of the ventilation index, could be detected, depending on the posture of the rats. In supine posture, ventilation was elevated in the dependent parts of the lungs, with a linear gradient of the ventilation index of -0.11 +/- 0.03 cm(-1). In prone posture, the distribution of ventilation was more uniform, with a significantly (P < 0.001) smaller gradient of the ventilation index of -0.01 +/- 0.02 cm(-1). It is concluded that the (3)He MRI-based method can detect and quantify regional ventilation gradients in animals as small as the rat and that these gradients depend on prone or supine posture of the animal.

A study of the use of Overhauser enhancement to assist with needle and catheter placement during interventional MRI.

The practicability of using Overhauser enhancement of saline in interventional MRI was investigated. Saline was used as a means of marking the path taken by a fluid-filled cavity, similar to that formed by a needle, catheter, or cannula during interventional MRI procedures. A prototype device was designed and constructed for saturation and propulsion of 0.6 ml of doped liquid. The pertinent Overhauser parameters, such as the obtainable enhancement factor, were measured. Signal enhancement in excess of 10 was demonstrated in practice by acquiring images showing an enhancement of fluid in a catheter tube.

Orally administered manganese with and without ascorbic acid as a liver-specific contrast agent and bowel marker for magnetic resonance imaging: phase I clinical trial assessing efficacy and safety.

OBJECTIVES: The objectives of this clinical trial of orally administered manganese in magnetic resonance imaging (MRI) of the liver were to assess signal enhancements in the liver with and without the addition of an uptake promoter, ascorbic acid, and to evaluate acute safety. MATERIALS AND METHODS: A total of 18 healthy adult males were enrolled in the present trial. Contrast medium: MnCl2, doses: 25, 50, and 100 micromoL/kg bw, respectively, and promoting agent: Ascorbic acid, doses: 50, 100, and 200 micromoL/kg bw, respectively, were used. All imaging was performed on a 1.5 T clinical MRI system. Three pulse-sequences in the abdomen were used: (1) T1-weighted axial gradient-echo (GRE), (2) T1-weighted coronal gradient-echo, and (3) T1-weighted axial spin-echo (SE). Time-points for imaging were precontrast, 1 hour, 2.5, 4, 6, 9, and 24 hours after MnCl2 intake. Safety parameters assessed were clinical examinations and vital signs, including heart rate and blood pressure. Hematology and clinical chemistry were assessed with standard laboratory procedures. RESULTS: All pulse-sequences showed a clear dose-response in liver-enhancement. Temporally, high enhancements in the liver were seen between 2.5 and 6 hours after MnCl2 intake. At the manganese dose 50-micromoL/kg bw, with ascorbic acid and at the dose 100-micromoL/kg bw, both with and without ascorbic acid, the hepatic enhancements were higher than 100% with the GRE pulse-sequence. The promoting effect of ascorbic acid was significant at a manganese-dose of 100-micromoL/kg bw. The contrast media distributed well in the small intestine, delineating intra-abdominal organs well. No serious or unexpected adverse events were encountered. The drug was generally well tolerated, except for minor gastrointestinal adverse events. No significant alteration in hematology or clinical chemistry was seen. CONCLUSIONS: Oral manganese is easy to use, and has few side effects. Besides the liver-specific effect, an additional benefit is the delineation of the intestine.

Cardiac metabolism measured noninvasively by hyperpolarized 13C MRI.

Pyruvate is included in the energy production of the heart muscle and is metabolized into lactate, alanine, and CO(2) in equilibrium with HCO(3) (-). The aim of this study was to evaluate the feasibility of using (13)C hyperpolarization enhanced MRI to monitor pyruvate metabolism in the heart during an ischemic episode. The left circumflex artery of pigs (4 months, male, 29-34 kg) was occluded for 15 or 45 min followed by 2 hr of reperfusion. Pigs were examined by (13)C chemical shift imaging following intravenous injection of 1-(13)C pyruvate. (13)C chemical shift MR imaging was used in order to visualize the local concentrations of the metabolites. After a 15-min occlusion (no infarct) the bicarbonate signal level in the affected area was reduced (25-44%) compared with the normal myocardium. Alanine signal level was normal. After a 45-min occlusion (infarction) the bicarbonate signal was almost absent (0.2-11%) and the alanine signal was reduced (27-51%). Due to image-folding artifacts the data obtained for lactate were inconclusive. These studies demonstrate that cardiac metabolic imaging with hyperpolarized 1-(13)C-pyruvate is feasible. The changes in concentrations of the metabolites within a minute after injection can be detected and metabolic maps constructed.

Passive catheter tracking during interventional MRI using hyperpolarized 13C.

Interventional procedures in MRI can be performed preclinically using active or passive catheter-tracking methods. A novel passive nonproton technique is suggested that uses a catheter filled with a hyperpolarized (13)C contrast agent. A prototype three-lumen catheter was built with two closed lumens containing a flowing hyperpolarized (13)C contrast agent. Entire-length (13)C catheter projection visualization could be performed in vivo with a catheter SNR of approximately 80, one dual projection frame per approximately 700 ms, and an in-plane resolution of 2 x 2 mm(2) while traveling through the aorta of a pig. The traveling path of the (13)C catheter was visualized after back-projection catheter reconstruction and after image fusion with an anatomical offline proton road map. Catheter length visualization was aided by an oblique planar visualization mode. The high catheter signal demonstrated, together with the entire catheter length visualization and high surrounding soft-tissue contrast, warrants further development into a real-time technique.

Hyperpolarized 13C MRI of the pulmonary vasculature and parenchyma.

The study of lung perfusion in normal and diseased subjects is of great interest to physiologists and physicians. In this work we demonstrate the application of a liquid-phase hyperpolarized (HP) carbon-13 ((13)C) tracer to magnetic resonance imaging (MRI) of the pulmonary vasculature and pulmonary perfusion in a porcine model. Our results show that high spatial and temporal resolution images of pulmonary perfusion can be obtained with this contrast technique. Traditionally, pulmonary perfusion measurement techniques have been challenging because of insufficient signal for quantitative functional assessments. The use of polarized (13)C in MRI overcomes this limitation and may lead to a viable clinical method for studying the pulmonary vasculature and perfusion.

Real-time metabolic imaging.

The endogenous substance pyruvate is of major importance to maintain energy homeostasis in the cells and provides a window to several important metabolic processes essential to cell survival. Cell viability is therefore reflected in the metabolism of pyruvate. NMR spectroscopy has until now been the only noninvasive method to gain insight into the fate of pyruvate in the body, but the low NMR sensitivity even at high field strength has only allowed information about steady-state conditions. The medically relevant information about the distribution, localization, and metabolic rate of the substance during the first minute after the injection has not been obtainable. Use of a hyperpolarization technique has enabled 10-15% polarization of (13)C(1) in up to a 0.3 M pyruvate solution. i.v. injection of the solution into rats and pigs allows imaging of the distribution of pyruvate and mapping of its major metabolites lactate and alanine within a time frame of approximately 10 s. Real-time molecular imaging with MRI has become a reality.

Gadolinium contrast media are more nephrotoxic than iodine media. The importance of osmolality in direct renal artery injections.

A study was undertaken of the role of osmotoxicity in gadolinium (Gd) and iodine contrast media (CM) nephrotoxicity in ischemic porcine kidneys. Test solutions: mannitol iso-osmotic to 0.5 M: gadopentetate (1.96 Osm/kg H2O), 0.5 M: gadodiamide (0.78 Osm/kg H2O) and 0.5 M: iohexol (190 mg I/ml, 0.42 Osm/kg H2O). Each solution was injected [3 ml/kg body weight (BW)] into the balloon-occluded (10 min) renal artery of eight left-sided nephrectomized pigs. The plasma half-life of a glomerular filtration rate (GFR) marker was used to compare their effects on GFR 1-3 h post-injection. The median half-lives of the GFR marker after injection of gadopentetate (1,730 min) and mannitol 1.96 Osm/kg H2O (2,782 min) did not differ statistically (P = 0.28), but were significantly longer than after all other solutions (P < 0.001). There was no significant difference (P = 0.06) between gadodiamide (218 min) and mannitol 0.82 Osm/kg H2O (169 min), while there was (P = 0.03) between iohexol (181 min) and mannitol 0.43 Osm/kg H2O (148 min). The difference between gadodiamide and iohexol was significant (P = 0.01). Reduction in GFR, as a marker of nephrotoxicity, induced by gadopentetate correlated with its high osmolality, while the effect of gadodiamide and iohexol may include chemotoxicity. Iohexol molecules were less nephrotoxic than the Gd-CM molecules and contain three-times the number of attenuating atoms per molecule.

MR coronary angiography in pigs with intraarterial injections of a hyperpolarized 13C substance.

A new diagnostic application of a water-soluble contrast medium (CM) based on the hyperpolarization of a 13C substance is introduced. The degree of polarization achieved is >30%, which is about a factor of 10(5) higher than the thermal equilibrium polarization level at 1.5 T. Imaging of hyperpolarized (HP) CM during a cardiac interventional MRI procedure was studied. Catheters were positioned in the left and right coronary arteries of pigs. A coil tuned to 13C was used for nonproton imaging. The HP-13C CM ( approximately 5 ml, 0.5 M, approximately 30% polarization) was injected during projection imaging using a fully balanced steady-state free precession (SSFP) pulse sequence with and without cardiac gating. The contrast agent-filled catheter was clearly visible during the procedure. The coronary arteries were well depicted and the signal-to-noise ratios (SNRs) were in the range of 10-40. The use of HP-13C CM may provide a new diagnostic procedure for interventional MRI.

13C imaging-a new diagnostic platform.

The evolution of magnetic resonance imaging (MRI) has been astounding since the early 1980s, and a broad range of applications has emerged. To date, clinical imaging of nuclei other than protons has been precluded for reasons of sensitivity. However, with the recent development of hyperpolarization techniques, the signal from a given number of nuclei can be increased as much as 100,000 times, sufficient to enable imaging of nonproton nuclei. Technically, imaging of hyperpolarized nuclei offers several unique properties, such as complete lack of background signal and possibility for local and permanent destruction of the signal by means of radio frequency (RF) pulses. These properties allow for improved as well as new techniques within several application areas. Diagnostically, the injected compounds can visualize information about flow, perfusion, excretory function, and metabolic status. In this review article, we explain the concept of hyperpolarization and the techniques to hyperpolarize 13C. An overview of results obtained within angiography, perfusion, and catheter tracking is given, together with a discussion of the particular advantages and limitations. Finally, possible future directions of hyperpolarized 13C MRI are pointed out.

Are gadolinium-based contrast media really safer than iodinated media for digital subtraction angiography in patients with azotemia?

Gadolinium chelates, intended as intravenous contrast media for magnetic resonance imaging, have been regarded as nonnephrotoxic and recommended to replace iodinated contrast media in patients with azotemia who are undergoing digital subtraction angiography (DSA). High intraarterial doses (up to 220 mmol of gadodiamide) have been used, with a 40% incidence of nephropathy. The authors discourage the use of gadolinium for DSA for several reasons. (a) There exist no randomized studies comparing the nephrotoxic effects of gadolinium-based and iodinated media at equal-attenuating concentrations and doses. (b) Gadolinium-based media are hypertonic, a pathogenetic factor in contrast medium-induced nephropathy after renal angiography, with an osmolality two to seven times that of plasma. Iodinated media in concentrations that are equally attenuating with gadolinium-based media can be made isotonic. (c) In vitro measurements indicate that 0.5 mol/L gadolinium chelates are equally attenuating with 60-80 mg iodine per milliliter at the commonly used 70-90-kV range used for DSA. Thus, 50 mL of 0.5 mol/L gadolinium chelate ( approximately 0.3 mmol/kg in an 80-kg person) would be equally attenuating with a dose of 3-4 g of iodine in an iodinated medium (eg, 50 mL iohexol at 60-80 mg I/mL or 10-13 mL at 300 mg I/mL). (d) By combining these data on attenuation and results of toxicity studies in mice, the general toxicity of gadolinium chelates may be six to 25 times higher than that of equal-attenuating doses of iodinated media at 70-kV DSA. Thus, the authors believe that at equal-attenuating doses for DSA, modern iodinated contrast media should result in a lower toxic load on the body than with presently available gadolinium chelates.