Combining hyperpolarized 13 C MRI with a liver-specific gadolinium contrast agent for selective assessment of hepatocyte metabolism

Abstract

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.

Keywords: gadoxetate; hyperpolarized carbon; liver; metabolism; pyruvate.

FIG. 1

Timing of hyperpolarized injections used in this work: (a) Timing for slab dynamic imaging; (b) timing for 3D echo planar spectroscopic imaging. All times are relative to gadoxetate injection. Each red box represents a separate hyperpolarized ¹³C-pyruvate injection and acquisition. T₁-weighted images were obtained before and after hyperpolarized ¹³C imaging to confirm gadoxetate arrival.

FIG. 2

Longitudinal relaxation rate, R₁, as a function of gadoxetate concentration for [1-¹³C]pyruvate and its metabolites. The slope of each plot represents the relaxivity of gadoxetate for that compound. All measurements performed at ~25°C dissolved in phosphate-buffered saline. R₁ of pyruvate and lactate were measured at 24 mM through the signal decay of hyperpolarized sample. R₁ of alanine was measured through saturation recovery of a non-hyperpolarized sample at 1.2 M.

FIG. 3

Proton imaging used as an anatomic reference and to confirm the arrival of gadoxetate. (a) Axial steady-state free precession images through the liver. T₁-weighted spoiled gradient echo images acquired (b) before and (c–e) approximately 25 min following administration of gadoxetate. (e) Coronal reformation of the axial data in (c–d). There is expected hyperenhancement of the liver parenchyma relative to the vasculature and muscles. There has been excretion into the common bile duct (arrow), which is characteristic of gadoxetate in the hepatobiliary phase.

FIG. 4

Contrast enhancement dynamics following tail vein injection of gadoxetate into a rat at a dose of 0.1 mmol/kg. ROIs were placed over the liver and the IVC.

FIG. 5

Dynamic experiments from 2-cm slabs placed over the liver and kidney. (a) Slab locations. (b) Summed spectra over all time points for a single animal. Metabolite peaks are labeled as lactate (L), pyruvate hydrate (H), alanine (A), and pyruvate (P). Dotted lines are spectra acquired before gadoxetate administration. Solid lines are spectra acquired 15 min after gadoxetate administration. (c) Dynamic time curves for each metabolite beginning 20 s after injection. All curves are normalized so that the initial pyruvate signal is 1. (d) Scatter plot comparing the percentage change in total lactate and alanine signal (measured as area under the dynamic curve) in the kidney slab and liver slab before and after gadolinium. Each point on the scatter plot corresponds to a different animal. Error bars are standard deviation. *P <0.05.

FIG. 6

Spectra obtained from single voxels placed over the liver (top row) and left kidney (bottom row). The left column shows the location of the voxels overlayed on SSFP anatomic images. Successive columns show spectra obtained before gadoxetate administration and then at various time points after gadoxetate administration. Each spectrum is normalized so that the pyruvate signal is equal to 1. Metabolite peaks are labeled as lactate (L), pyruvate hydrate (H), alanine (A), and pyruvate (P).

FIG. 7

Average metabolite levels measured within an ROI placed over the liver or kidneys. “Post” data were acquired 15 min after injection of gadoxetate. *P<0.05. (a) Lactate/pyruvate ratio; (b) alanine/pyruvate ratio. Error bars are standard deviation (n = 4).