Sven Månsson

Molecular imaging with endogenous substances

Dynamic nuclear polarization has enabled hyperpolarization of nuclei such as 13C and 15N in endogenous substances. The resulting high nuclear polarization makes it possible to perform subsecond 13C MRI. By using the dynamic nuclear polarization hyperpolarization technique, 10% polarization was obtained in an aqueous solution of 100 mM 13C-labeled urea, ready for injection. The in vivo T1 relaxation time of 13C in the urea solution was determined to 20 ± 2 s. Due to the long relaxation time, it is possible to use the hyperpolarized substance for medical imaging. A series of high-resolution (≈1-mm) magnetic resonance images were acquired, each with a scan time of 240 ms, 0-5 s after an i.v. injection of the hyperpolarized aqueous [13C]urea solution in a rat. The results show that it is possible to perform 13C angiography with a signal-to-noise ratio of ≈275 in ≈0.25 s. Perfusion studies with endogenous substances may allow higher spatial and/or temporal resolution than is possible with current proton imaging techniques.

Cardiac metabolism measured noninvasively by hyperpolarized (13)C MRI.

Pyruvate is included in the energy production of the heart muscle and is metabolized into lactate, alanine, and CO2 in equilibrium with HCO  3− . The aim of this study was to evaluate the feasibility of using 13C 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 13C chemical shift imaging following intravenous injection of 1‐13C pyruvate. 13C 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 1‐13C‐pyruvate is feasible. The changes in concentrations of the metabolites within a minute after injection can be detected and metabolic maps constructed. Magn Reson Med 59:1005–1013, 2008.

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.

Quantitative measurement of regional lung ventilation using 3He MRI.

A new strategy for a quantitative measurement of regional pulmonary ventilation using hyperpolarized helium‐3 (3He) MRI has been developed. The method employs the build‐up of the signal intensity after a variable number of 3He breaths. A mathematical model of the signal dynamics is presented, from which the local ventilation, defined as the fraction of gas exchanged per breath within a given volume, is calculated. The model was used to create ventilation maps of coronal slices of guinea pig lungs. Ventilation values very close to 1 were found in the trachea and the major airways. In the lung parenchyma, regions adjacent to the hilum showed values of 0.6–0.8, whereas 0.2–0.4 was measured in peripheral regions. Monte Carlo simulations were used to investigate the accuracy of the method and its limitations. The simulations revealed that, at presently attainable signal‐to‐noise ratios, the ventilation parameter can be determined with a relative uncertainty of <5% over a wide range of values. Magn Reson Med 48:223–232, 2002.

Hyperpolarized 13C MR angiography using trueFISP.

A 13C‐enriched water‐soluble compound (bis‐1,1‐(hydroxymethyl)‐1‐13C‐cyclopropane‐D8), with a 13C‐concentration of approximately 200 mM, was hyperpolarized to ∼15% using dynamic nuclear polarization, and then used as a contrast medium (CM) for contrast‐enhanced magnetic resonance angiography (CE‐MRA). The long relaxation times (in vitro: T1 ≈ 82 s, T2 ≈ 18 s; in vivo: T1 ≈ 38 s, T2 ≈ 1.3 s) are ideal for steady‐state free precession (SSFP) imaging with a true fast imaging and steady precession (trueFISP) pulse sequence. It was shown both theoretically and experimentally that the optimal flip angle was 180°. CE‐MRA was performed in four anesthetized live rats after intravenous injection of 3 ml CM. The angiograms covered the thoracic/abdominal region in two of the animals, and the head‐neck region in the other two. Fifteen consecutive images were acquired in each experiment, with a flip‐back pulse at the end of each image acquisition. In the angiograms, the vena cava (SNR ≈ 240), aorta, renal arteries, carotid arteries (SNR ≈ 75), jugular veins, and several other vessels were visible. The SNR in the cardiac region was 500. Magnetization was preserved from one image acquisition to the next using the flip‐back technique (SNRcardiac ≈ 10 in the 15th image). Magn Reson Med 50:256–262, 2003.

Characterization of diffusing capacity and perfusion of the rat lung in a lipopolysaccaride disease model using hyperpolarized 129Xe

The ability to quantify pulmonary diffusing capacity and perfusion using dynamic hyperpolarized 129Xe NMR spectroscopy is demonstrated. A model of alveolar gas exchange was developed, which, in conjunction with 129Xe NMR, enables quantification of average alveolar wall thickness, pulmonary perfusion, capillary diffusion length, and mean transit time. The technique was employed to compare a group of naïve rats (n = 10) with a group of rats with acute inflammatory lung injury (n = 10), caused by instillation of lipopolysaccaride (LPS). The measured structural and perfusion‐related parameters were in agreement with reported values from studies using non‐NMR methods. Significant differences between the groups were found in total diffusion length (control 8.5 ± 0.5 μm, LPS 9.9 ± 0.6 μm, P < 0.001), in capillary diffusion length (control 2.9 ± 0.4 μm, LPS 3.9 ± 1.0 μm, P < 0.05), and in pulmonary hematocrit (control 0.55 ± 0.06, LPS 0.43 ± 0.08, P < 0.01), whereas no differences were observed in alveolar wall thickness, pulmonary perfusion, and mean transit time. These results demonstrate the ability of the method to distinguish two main aspects of lung function, namely, diffusing capacity and pulmonary perfusion. Magn Reson Med 50:1170–1179, 2003.

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. Magn Reson Med 51:464–472, 2004.

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. Magn Reson Med 52:1043–1051, 2004.

Determining 'true' glomerular filtration rate in healthy adults using infusion of inulin and comparing it with values obtained using other clearance techniques or prediction equations.

Objective. To determine ‘true’ glomerular filtration rate (GFR) in healthy adults as renal clearance following infusion of inulin, and compare that result with those obtained using other markers and clearance techniques and with estimations of GFR using creatinine-based prediction equations. Material and methods. Twenty healthy volunteers (11 females) with a median age of 27 years (range 19–36 years) received bolus doses of inulin and iohexol i.v. and 16 blood samples were taken after injection. Then, inulin and iohexol were infused to give stable plasma concentrations and blood and urine samples were collected. Residual bladder volume was estimated using ultrasound scanning. Plasma and urine concentrations of inulin and iohexol were determined using chromatography and resorcinol methods, respectively. Different methods of GFR determination were compared as well as four formulae for GFR estimation based on serum creatinine. Results. ‘True’ GFR, i.e. renal clearance of inulin during its infusion, was a median of 117 ml/min/1.73 m2 (inter-quartile range 106–129 ml/min/1.73 m2). Similar values of GFR were obtained with renal clearance of iohexol during its infusion and also with plasma (body) clearance of inulin or iohexol following bolus injections and using 16 or five plasma samples. Endogenous creatinine clearance was higher (p<0.001) than true GFR (median 23 ml/min/1.73 m2). Plasma clearance of iohexol and inulin based on their concentrations in four blood samples underestimated their renal clearance considerably. All four creatinine-based formulae markedly underestimated renal inulin clearance. Conclusions. Plasma and renal clearance of iohexol and inulin were similar in healthy adults. Underestimation of GFR was noted when plasma clearance of iohexol and inulin was based on four but not five or more blood samples. Some prediction equations underestimate true GFR to such an extent that caution must be taken when using them to evaluate normal or high GFR values.

Fast multiecho balanced SSFP metabolite mapping of 1H and hyperpolarized 13C compounds

ObjectTo investigate the feasibility of multiecho balanced steady-state free precession (bSSFP)-based fast chemical shift mapping hyperpolarized 13C metabolites. The overall goal was to reduce total imaging time and to increase spatial resolution compared to common chemical shift imaging (CSI).Materials and methodsA multiecho bSSFP sequence in combination with an iterative reconstruction algorithm was implemented. 1H experiments were performed on phantoms and on a human volunteer in order to investigate the feasibility of the method on a system with metabolite maps that are known beforehand. 13C experiments were performed in vivo on pigs, where CSI images were acquired also for comparison.ResultsChemical shift images of three and four distinct 1H resonance frequencies as well as chemical shift images of up to five hyperpolarized 13C metabolites were successfully obtained.ConclusionFast metabolite mapping based on multiecho balanced SSFP in combination with an iterative reconstruction approach could successfully separate several 1H resonances and hyperpolarized 13C metabolites.