Molecular imaging of tumor metabolism: Insight from pyruvate- and glucose-based deuterium MRI studies.

Cancer diagnosis by metabolic MRI proposes to follow the fate of glycolytic precursors such as pyruvate or glucose, and their in vivo conversion into lactate. This study compares the 2H MRI outlooks afforded by these metabolites when targeting a pancreatic cancer model. Exogenously injected [3,3',3″-2H3]-pyruvate was visible only briefly; it generated a deuterated lactate signal throughout the body that faded after ~5 min, showing a minor concentration bias at the rims of the tumors. [6,6'-2H2]-glucose by contrast originated a lactate signal that localized clearly within the tumors, persisting for over an hour. Investigations alternating deuterated and nondeuterated glucose injections revealed correlations between the lactate generation and the glucose available at the tumor, evidencing a continuous and avid glucose consumption generating well-localized lactate signatures as driven by the Warburg effect. This is by contrast to the transient and more promiscuous pyruvate-to-lactate transformation, which seemed subject to transporter and kinetics effects. The consequences of these observations within metabolic MRI are briefly discussed.

Phase-Incremented Steady-State Free Precession as an Alternate Route to High-Resolution NMR.

Pulsed Fourier transform nuclear magnetic resonance (FT-NMR) has reigned supreme in high-resolution, high-field spectroscopy─particularly when targeting complex liquid-state samples involving multiple sharp peaks spread over large spectral bandwidths. It is known, however, that if spectral resolution is not a must, the FT-based approach is not necessarily the optimal route for maximizing NMR sensitivity: if T2 ≈ T1, as often found in solutions, Carr's steady-state free-precession (SSFP) approach can in principle provide a superior signal-to-noise ratio per √(acquisition_time) (SNRt). A rapid train of pulses will then lead to a transverse component that reaches up to 50% of the thermal equilibrium magnetization, provided that pulses are applied at repetition times TR ≪ T2, T1, and that a single suitable offset is involved. It is generally assumed that having to deal with multiple chemical shifts deprives SSFP from its advantages. The present study revisits this assumption by introducing an approach whereby arbitrarily short SSFP-derived free induction decays (FIDs) can deliver high-resolution spectra, without suffering from peak broadenings or phase distortions. To achieve discrimination among nearby frequencies, signals arising from a series of regularly phase-increased excitation pulses are collected. Given SSFP's amplitude and phase sensitivity to the spins' offset, this enables the resolution of sites according to their chemical shift position. In addition, the extreme fold-over associated with SSFP acquisitions is dealt with by a customized discrete FT of the interpulse time-domain signal. Solution-state 13C NMR spectra which compare well with FT-NMR data in terms of sensitivity, bandwidth, and resolution can then be obtained.

High-sensitivity deuterium metabolic MRI differentiates acute pancreatitis from pancreatic cancers in murine models.

Deuterium metabolic imaging (DMI) is a promising tool for investigating a tumor's biology, and eventually contribute in cancer diagnosis and prognosis. In DMI, [6,6'-2H2]-glucose is taken up and metabolized by different tissues, resulting in the formation of HDO but also in an enhanced formation of [3,3'-2H2]-lactate at the tumor site as a result of the Warburg effect. Recent studies have shown DMI's suitability to highlight pancreatic cancer in murine models by [3,3'-2H2]-lactate formation; an important question is whether DMI can also differentiate between these tumors and pancreatitis. This differentiation is critical, as these two diseases are hard to distinguish today radiologically, but have very different prognoses requiring distinctive treatments. Recent studies have shown the limitations that hyperpolarized MRI faces when trying to distinguish these pancreatic diseases by monitoring the [1-13C1]-pyruvate→[1-13C1]-lactate conversion. In this work, we explore DMI's capability to achieve such differentiation. Initial tests used a multi-echo (ME) SSFP sequence, to identify any metabolic differences between tumor and acute pancreatitis models that had been previously elicited very similar [1-13C1]-pyruvate→[1-13C1]-lactate conversion rates. Although ME-SSFP provides approximately 5 times greater signal-to-noise ratio (SNR) than the standard chemical shift imaging (CSI) experiment used in DMI, no lactate signal was observed in the pancreatitis model. To enhance lactate sensitivity further, we developed a new, weighted-average, CSI-SSFP approach for DMI. Weighted-average CSI-SSFP improved DMI's SNR by another factor of 4 over ME-SSFP-a sensitivity enhancement that sufficed to evidence natural abundance 2H fat in abdominal images, something that had escaped the previous approaches even at ultrahigh (15.2 T) MRI fields. Despite these efforts to enhance DMI's sensitivity, no lactate signal could be detected in acute pancreatitis models (n = 10; [3,3'-2H2]-lactate limit of detection < 100 µM; 15.2 T). This leads to the conclusion that pancreatic tumors and acute pancreatitis may be clearly distinguished by DMI, based on their different abilities to generate deuterated lactate.

Deuterium imaging of the Warburg effect at sub-millimolar concentrations by joint processing of the kinetic and spectral dimensions.

Deuterium metabolic imaging (DMI) is a promising molecular MRI approach, which follows the administration of deuterated substrates and their metabolization. [6,6'-2 H2 ]-glucose for instance is preferentially converted in tumors to [3,3'-2 H2 ]-lactate as a result of the Warburg effect, providing a distinct resonance whose mapping using time-resolved spectroscopic imaging can diagnose cancer. The MR detection of low-concentration metabolites such as lactate, however, is challenging. It has been recently shown that multi-echo balanced steady-state free precession (ME-bSSFP) increases the signal-to-noise ratio (SNR) of these experiments approximately threefold over regular chemical shift imaging; the present study examines how DMI's sensitivity can be increased further by advanced processing methods. Some of these, such as compressed sensing multiplicative denoising and block-matching/3D filtering, can be applied to any spectroscopic/imaging methods. Sensitivity-enhancing approaches were also specifically tailored to ME-bSSFP DMI, by relying on priors related to the resonances' positions and to features of the metabolic kinetics. Two new methods are thus proposed that use these constraints for enhancing the sensitivity of both the spectral images and the metabolic kinetics. The ability of these methods to improve DMI is evidenced in pancreatic cancer studies carried at 15.2 T, where suitable implementations of the proposals imparted eightfold or more SNR improvement over the original ME-bSSFP data, at no informational cost. Comparisons with other propositions in the literature are briefly discussed.

Simultaneous acquisition for T2-T2 Exchange and T1-T2 correlation NMR experiments.

The NMR measurements of longitudinal and transverse relaxation times and its multidimensional correlations provide useful information about molecular dynamics. However, these experiments are very time-consuming, and many researchers proposed faster experiments to reduce this issue. This paper presents a new way to simultaneously perform T2-T2 Exchange and T1-T2 correlation experiments by taking the advantage of the storage time and the two steps phase cycling used for running the relaxation exchange experiment. The data corresponding to each step is either summed or subtracted to produce the T2-T2 and T1-T2 data, enhancing the information obtained while maintaining the experiment duration. Comparing the results from this technique with traditional NMR experiments it was possible to validate the method.