Purpose

The purpose of this work was to explore the impact of slice profile effects on apparent diffusion coefficient (ADC) mapping of hyperpolarized (HP) substrates.

Methods

Slice profile effects were simulated using a Gaussian radiofrequency (RF) pulse with a variety of flip angle schedules and b-value ordering schemes. A long T₁ water phantom was used to validate the simulation results, and ADC mapping of HP [¹³ C,¹⁵ N₂ ]urea was performed on the murine liver to assess these effects in vivo.

Results

Slice profile effects result in excess signal after repeated RF pulses, causing bias in HP measurements. The largest error occurs for metabolites with small ADCs, resulting in up to 10-fold overestimation for metabolites that are in more-restricted environments. A mixed b-value scheme substantially reduces this bias, whereas scaling the slice-select gradient can mitigate it completely. In vivo, the liver ADC of hyperpolarized [¹³ C,¹⁵ N₂ ]urea is nearly 70% lower (0.99 ± 0.22 vs 1.69 ± 0.21 × 10^-3 mm² /s) when slice-select gradient scaling is used.

Conclusion

Slice profile effects can lead to bias in HP ADC measurements. A mixed b-value ordering scheme can reduce this bias compared to sequential b-value ordering. Slice-select gradient scaling can also correct for this deviation, minimizing bias and providing more-precise ADC measurements of HP substrates. Magn Reson Med 78:1087-1092, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Purpose

To develop a compressed sensing (CS) acceleration method with a high spectral bandwidth exploiting the spatial-spectral sparsity of MR spectroscopic imaging (MRSI).

Methods

Accelerations were achieved using blip gradients during the readout to perform nonoverlapped and stochastically delayed random walks in kx -ky -t space, combined with block-Hankel matrix completion for efficient reconstruction. Both retrospective and prospective CS accelerations were applied to (13) C MRSI experiments, including in vivo rodent brain and liver studies with administrations of hyperpolarized [1-(13) C] pyruvate at 7.0 Tesla (T) and [2-(13) C] dihydroxyacetone at 3.0 T, respectively.

Results

In retrospective undersampling experiments using in vivo 7.0 T data, the proposed method preserved spectral, spatial, and dynamic fidelities with R(2) ≥ 0.96 and ≥ 0.87 for pyruvate and lactate signals, respectively, 750-Hz spectral separation, and up to 6.6-fold accelerations. In prospective in vivo experiments, with 3.8-fold acceleration, the proposed method exhibited excellent spatial localization of metabolites and peak recovery for pyruvate and lactate at 7.0 T as well as for dihydroxyacetone and its metabolic products with a 4.5-kHz spectral span (140 ppm at 3.0 T).

Conclusions

This study demonstrated the feasibility of a new CS approach to accelerate high spectral bandwidth MRSI experiments. Magn Reson Med 76:369-379, 2016. © 2016 Wiley Periodicals, Inc.

Purpose

Hyperpolarized ¹³ C MRI is a powerful tool for studying metabolism, but can lack tissue specificity. Gadoxetate is a gadolinium-based MRI contrast agent that is selectively taken into hepatocytes. The goal of this project was to investigate whether gadoxetate can be used to selectively suppress the hyperpolarized signal arising from hepatocytes, which could in future studies be applied to generate specificity for signal from abnormal cell types.

Methods

Baseline gadoxetate uptake kinetics were measured using T₁ -weighted contrast enhanced imaging. Relaxivity of gadoxetate was measured for [1-¹³ C]pyruvate, [1-¹³ C]lactate, and [1-¹³ C]alanine. Four healthy rats were imaged with hyperpolarized [1-¹³ C]pyruvate using a three-dimensional (3D) MRSI sequence prior to and 15 min following administration of gadoxetate. The lactate:pyruvate ratio and alanine:pyruvate ratios were measured in liver and kidney.

Results

Overall, the hyperpolarized signal decreased approximately 60% as a result of pre-injection of gadoxetate. In liver, the lactate:pyruvate and alanine:pyruvate ratios decreased 42% and 78%, respectively (P < 0.05) following gadoxetate administration. In kidneys, these ratios did not change significantly. Relaxivity of gadoxetate for [1-¹³ C]alanine was 12.6 times higher than relaxivity of gadoxetate for [1-¹³ C]pyruvate, explaining the greater selective relaxation effect on alanine.

Conclusions

The liver-specific gadolinium contrast-agent gadoxetate can selectively suppress normal hepatocyte contributions to hyperpolarized ¹³ C MRI signals. Magn Reson Med 77:2356-2363, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Purpose

The purpose of this study was to investigate the hyperpolarized ketone body ¹³ C-acetoacetate (AcAc) and its conversion to ¹³ C-β-hydroxybutyrate (βOHB) in vivo, catalyzed by β-hydroxybutyrate dehydrogenase (BDH), as a novel direct marker of mitochondrial redox state.

Methods

[1,3-¹³ C₂ ]AcAc was synthesized by hydrolysis of the ethyl ester, and hyperpolarized via dissolution DNP. Cold storage under basic conditions resulted in sufficient chemical stability for use in hyperpolarized (HP) MRI studies. Polarizations and relaxation times of HP [1,3-¹³ C₂ ]AcAc were measured in a clinical 3T MRI scanner, and 8 rats were scanned by dynamic HP ¹³ C MR spectroscopy of a slab through the kidneys. Four rats were scanned after acute treatment with high dose metformin (125 mg/kg, intravenous), which is known to modulate mitochondrial redox via inhibition of mitochondrial complex I. An additional metformin-treated rat was scanned by abdominal 2D CSI (8 mm × 8 mm).

Results

Polarizations of 7 ± 1% and 7 ± 3%, and T₁ relaxation times of 58 ± 5 s and 52 ± 3 s, were attained at the C₁ and C₃ positions, respectively. Rapid conversion of HP AcAc to βOHB was detected in rat kidney in vivo, via the C₁ label. The product HP βOHB was resolved from closely resonating acetate. Conversion to βOHB was also detected via 2D CSI, in both kidney as well as liver regions. Metformin treatment resulted in a significant increase (40%, P = 0.01) of conversion of HP AcAc to βOHB.

Conclusion

Rapid conversion of HP AcAc to βOHB was observed in rat kidney in vivo and is a promising new non-invasive marker of mitochondrial redox state. Magn Reson Med 79:1862-1869, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Purpose

To compare the apparent diffusion coefficient (ADC) of hyperpolarized (HP) [¹³ C,¹⁵ N]urea to the ADC of endogenous water in healthy and fibrotic mouse liver.

Materials and methods

ADC measurements for water and [¹³ C]urea were made in agarose phantoms at 14.1T. Next, the ADC of water and injected HP [¹³ C,¹⁵ N]urea were measured in eight CD1 mouse livers before and after induction of liver fibrosis using CCl₄ . Liver fibrosis was quantified pathologically using the modified Brunt fibrosis score and compared to the measured ADC of water and urea.

Results

In cell-free phantoms with 12.5% agarose, water ADC was nearly twice the ADC of urea (1.93 × 10^-3 mm² /s vs. 1.00 × 10^-3 mm² /s). The mean ADC values of water and [¹³ C,¹⁵ N]urea in healthy mouse liver (±SD) were nearly identical [(0.75 ± 0.11) × 10^-3 mm² /s and (0.75 ± 0.22) × 10^-3 mm² /s, respectively]. Mean water and [¹³ C,¹⁵ N]urea ADC values in fibrotic liver (±SD) were (0.84 ± 0.22) × 10^-3 mm² /s and (0.75 ± 0.15) × 10^-3 mm² /s, respectively. Neither water nor urea ADCs were statistically different in the fibrotic livers compared to baseline (P = 0.14 and P = 0.99, respectively). Water and urea ADCs were positively correlated at baseline (R²  = 0.52 and P = 0.045) but not in fibrotic livers (R²  = 0.23 and P = 0.23).

Conclusion

ADC of injected hyperpolarized urea in healthy liver reflects a smaller change as compared to free solution than ADC of water. This may reflect differences in cellular compartmentalization of the two compounds. No significant change in ADC of either water or urea were observed in relatively mild stages of liver fibrosis.

Level of evidence

1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:141-151.

Purpose

To develop a specialized multislice, single-acquisition approach to detect the metabolites of hyperpolarized (HP) [2-¹³ C]dihydroxyacetone (DHAc) to probe gluconeogenesis in vivo, which have a broad 144 ppm spectral range (∼4.6 kHz at 3T). A novel multiband radio-frequency (RF) excitation pulse was designed for independent flip angle control over five to six spectral-spatial (SPSP) excitation bands, each corrected for chemical shift misregistration effects.

Methods

Specialized multiband SPSP RF pulses were designed, tested, and applied to investigate HP [2-¹³ C]DHAc metabolism in kidney and liver of fasted rats with dynamic ¹³ C-MR spectroscopy and an optimal flip angle scheme. For comparison, experiments were also performed with narrow-band slice-selective RF pulses and a sequential change of the frequency offset to cover the five frequency bands of interest.

Results

The SPSP pulses provided a controllable spectral profile free of baseline distortion with improved signal to noise of the metabolite peaks, allowing for quantification of the metabolic products. We observed organ-specific differences in DHAc metabolism. There was two to five times more [2-¹³ C]phosphoenolpyruvate and about 19 times more [2-¹³ C]glycerol 3-phosphate in the liver than in the kidney.

Conclusion

A multiband SPSP RF pulse covering a spectral range over 144 ppm enabled in vivo characterization of HP [2-¹³ C]DHAc metabolism in rat liver and kidney. Magn Reson Med 77:1419-1428, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Zero- to ultralow-field (ZULF) nuclear magnetic resonance (NMR) is an emerging tool for precision chemical analysis. In this work, we study dynamic processes and investigate the influence of chemical exchange on ZULF NMR J-spectra. We develop a computational approach that allows quantitative calculation of J-spectra in the presence of chemical exchange and apply it to study aqueous solutions of [¹⁵N]ammonium (¹⁵N[Formula: see text]) as a model system. We show that pH-dependent chemical exchange substantially affects the J-spectra and, in some cases, can lead to degradation and complete disappearance of the spectral features. To demonstrate potential applications of ZULF NMR for chemistry and biomedicine, we show a ZULF NMR spectrum of [2-¹³C]pyruvic acid hyperpolarized via dissolution dynamic nuclear polarization (dDNP). We foresee applications of affordable and scalable ZULF NMR coupled with hyperpolarization to study chemical exchange phenomena in vivo and in situations where high-field NMR detection is not possible to implement.

Purpose

The purpose of this study was to characterize tissue-specific alterations in metabolism of hyperpolarized (HP) gluconeogenic precursors ¹³ C-lactate and ¹³ C-pyruvate by rat liver and kidneys under conditions of fasting or insulin-deprived diabetes.

Methods

Seven normal rats were studied by MR spectroscopic imaging of both HP ¹³ C-lactate and ¹³ C-pyruvate in both normal fed and 24 h fasting states, and seven additional rats were scanned after induction of diabetes by streptozotocin (STZ) with insulin withdrawal. Phosphoenolpyruvate carboxykinase (PEPCK) expression levels were also measured in liver and kidney tissues of the STZ-treated rats.

Results

Multiple sets of significant signal modulations were detected, with graded intensity in general between fasting and diabetic states. An approximate two-fold reduction in the ratio of ¹³ C-bicarbonate to total ¹³ C signal was observed in both organs in fasting. The ratio of HP lactate-to-alanine was markedly altered, ranging from a liver-specific 54% increase in fasting, to increases of 69% and 92% in liver and kidney, respectively, in diabetes. Diabetes resulted in a 40% increase in renal lactate signal. STZ resulted in 5.86-fold and 2.73-fold increases in PEPCK expression in liver and kidney, respectively.

Conclusion

MRI of HP ¹³ C gluconeogenic precursors may advance diabetes research by clarifying organ-specific roles in abnormal diabetic metabolism. Magn Reson Med 77:1429-1437, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Purpose

To investigate acute changes in glucose metabolism in liver and kidneys in vivo after a bolus injection of either fructose or glucose, using hyperpolarized [2-¹³ C]dihydroxyacetone.

Methods

Spatially registered, dynamic, multislice MR spectroscopy was acquired for the metabolic products of [2-¹³ C]dihydroxyacetone in liver and kidneys. Metabolism was probed in 13 fasted rats at three time points: 0, 70, and 140 min. At 60 min, rats were injected intravenously with fructose (n = 5) or glucose (n = 4) at 0.8 g/kg to initiate acute response. Controls (n = 4) did not receive a carbohydrate challenge.

Results

Ten minutes after fructose infusion, levels of [2-¹³ C]phosphoenolpyruvate and [2-¹³ C]glycerol-3-phosphate halved in liver: 51% (P = 0.0010) and 47% (P = 0.0001) of baseline, respectively. Seventy minutes later, levels returned to baseline. The glucose challenge did not alter the signals significantly, nor did repeated administration of the dihydroxyacetone imaging bolus. In kidneys, no statistically significant changes were detected after sugar infusion other than a 20% increase of the glycerol-3-phosphate signal between 10 and 80 min after fructose injection (P = 0.0028).

Conclusion

Hyperpolarized [2-¹³ C]dihydroxyacetone detects a real-time, transient metabolic response of the liver to an acute fructose challenge. Observed effects possibly include ATP depletion and changes in the unlabeled pool sizes of glycolytic intermediates. Magn Reson Med 77:65-73, 2017. © 2016 International Society for Magnetic Resonance in Medicine.