Pulse sequence considerations for quantification of pyruvate‐to‐lactate conversion k_PL in hyperpolarized ¹³C imaging

Abstract

Hyperpolarized 13C MRI takes advantage of the unprecedented 50 000‐fold signal‐to‐noise ratio enhancement to interrogate cancer metabolism in patients and animals. It can measure the pyruvate‐to‐lactate conversion rate, kPL, a metabolic biomarker of cancer aggressiveness and progression. Therefore, it is crucial to evaluate kPL reliably. In this study, three sequence components and parameters that modulate kPL estimation were identified and investigated in model simulations and through in vivo animal studies using several specifically designed pulse sequences. These factors included a magnetization spoiling effect due to RF pulses, a crusher gradient‐induced flow suppression, and intrinsic image weightings due to relaxation. Simulation showed that the RF‐induced magnetization spoiling can be substantially improved using an inputless kPL fitting. In vivo studies found a significantly higher apparent kPL with an additional gradient that leads to flow suppression (kPL,FID‐Delay,Crush/kPL,FID‐Delay = 1.37 ± 0.33, P < 0.01, N = 6), which agrees with simulation outcomes (12.5% kPL error with Δv = 40 cm/s), indicating that the gradients predominantly suppressed flowing pyruvate spins. Significantly lower kPL was found using a delayed free induction decay (FID) acquisition versus a minimum‐TE version (kPL,FID‐Delay/kPL,FID = 0.67 ± 0.09, P < 0.01, N = 5), and the lactate peak had broader linewidth than pyruvate (Δωlactate/Δωpyruvate = 1.32 ± 0.07, P < 0.000 01, N = 13). This illustrated that lactate's T2*, shorter than that of pyruvate, can affect calculated kPL values. We also found that an FID sequence yielded significantly lower kPL versus a double spin‐echo sequence that includes spin‐echo spoiling, flow suppression from crusher gradients, and more T2 weighting (kPL,DSE/kPL,FID = 2.40 ± 0.98, P < 0.0001, N = 7). In summary, the pulse sequence, as well as its interaction with pharmacokinetics and the tissue microenvironment, can impact and be optimized for the measurement of kPL. The data acquisition and analysis pipelines can work synergistically to provide more robust and reproducible kPL measures for future preclinical and clinical studies.

Visualizing the effects of lactate dehydrogenase (LDH) inhibition and LDH‐A genetic ablation in breast and lung cancer with hyperpolarized pyruvate NMR

“…The results from this work support the use of hyperpolarized 13 C MR for in vivo, non‐invasive monitoring of the metabolic effects of inhibition of LDH, and more widely in studies relating to modifications to the Warburg effect. The biomarker of metabolism took the form of the lactate‐to‐pyruvate ratio, which provides a surrogate measure relating to cancer aggressiveness and progression, 26,27 and showed a significant reduction in cases of LDH inhibition by the drug GNE140 but remained relatively consistent in the EGFR‐driven lung cancer model following genetic ablation of LDH‐A . Use of hyperpolarized 13 C MR and the lactate‐to‐pyruvate ratio in oncological studies allows interrogation of the metabolic pathways associated with the Warburg effect and aerobic glycolysis that are prominent in cancer cells.…”

Coil profile estimation strategies for parallel imaging with hyperpolarized 13C MRI

“…Besides being sensitive to off‐resonance, the used SPSP pulse was also rather long. A long echo time leads to loss of SNR, but a recent study by Chen et al also found that a long echo time for hyperpolarized experiments can cause errors in the estimated kinetics because of the shorter of lactate compared to pyruvate. Therefore, future improvements should include a better SPSP design and/or IDEAL reconstruction.…”

Acquisition strategies for spatially resolved magnetic resonance detection of hyperpolarized nuclei

“…The effect of individual pulse sequence components and parameters on the quantification of results as imaging biomarkers, e.g. pyruvate-to-lactate conversion rates k pl , has been discussed recently [391]: A profound effect of sequence parameters on k pl was found for the cases of magnetization spoiling by RF pulses, flow suppression by crusher gradients, and intrinsic image weightings due to relaxation. Given the large variety of pulse sequence components used in hyperpolarized MRI, a major challenge for this field will be the standardization of acquisition protocols and data analysis procedures for comparison of results across different sites which, is especially important for the validation of biomarkers in clinical studies.…”