Ratiometric analysis in hyperpolarized NMR (I): test of the two‐site exchange model and the quantification of reaction rate constants

Li, Lin Z.; Kadlececk, Stephen; Xu, He N.; Daye, Dania; Pullinger, Benjamin; Profka, Harrilla; Chodosh, Lewis A.; Rizi, Rahim R.

doi:10.1002/nbm.2953

Cited by 17 publications

(27 citation statements)

References 18 publications

(47 reference statements)

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“…All NMR experiments were performed with a 1.1-cm or 1.4-cm 1 H/ 13 C dual-tuned home-made surface coil in a 9.4-T Varian vertical bore NMR spectrometer as previously described (32, 33). The tumor-bearing mice were anesthetized by administering oxygen doped with 1% isofluorane while the body temperature was maintained at ~35.0±2.5 °C with heated air.…”

Section: Methodsmentioning

confidence: 99%

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Is Higher Lactate an Indicator of Tumor Metastatic Risk? A Pilot MRS Study Using Hyperpolarized 13C-Pyruvate

Kadlececk

Profka

et al. 2014

Academic Radiology

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Rationale and Objectives Cancer cells generate more lactate than normal cells under aerobic and hypoxic conditions – exhibiting the so-called Warburg effect. However, the relationship between the Warburg effect and tumor metastatic potential remains controversial. We intend to investigate whether the higher lactate reflects higher tumor metastatic potential. Materials and Methods We employed hyperpolarized 13C-pyruvate magnetic resonance spectroscopy (MRS) to compare lactate 13C-labeling in vivo in breast cancer mouse xenografts of highly metastatic (MDA-MB-231) and relatively indolent (MCF-7) human cell lines. We obtained the kinetic parameters of the lactate dehydrogenase (LDH)-catalyzed reaction by three methods of analysis including the differential equation (DE) fit, q-ratio (qR) fit, and ratio fit (RF) methods. Results Consistent results from the three methods showed that the highly metastatic breast tumors exhibited a smaller apparent forward rate constant (k+ = 0.060 ± .004 s−1) than the relatively indolent tumors (k+ = 0.097 ± .013 s−1). The RF fit generates the highest statistical significance for the difference (p=0.02). No significant difference is found for the reverse rate constant. Conclusion The result indicates that the less metastatic breast tumors may produce more lactate than the highly metastatic ones from the injected 13C-pyruvate, and supports the viewpoint that breast tumor metastatic risk is not necessarily associated with the high levels of glycolysis and lactate production. More studies are needed to confirm whether and how much the measured apparent rate constants are affected by the membrane transporter activity and whether they are primarily determined by the LDH activity or not.

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Section: Methodsmentioning

confidence: 99%

“…the reaction rate constants of the lactate dehydrogenase-catalyzed reaction as described by Li et al (32, 33). The principles of the analysis are briefly summarized as follows.…”

Section: Methodsmentioning

confidence: 99%

Is Higher Lactate an Indicator of Tumor Metastatic Risk? A Pilot MRS Study Using Hyperpolarized 13C-Pyruvate

Kadlececk

Profka

et al. 2014

Academic Radiology

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“…[15][16][17][18] Whereas HP-pyruvate has made real-time magnetic resonance-based detection of cellular aerobic glycolysis possible, quantification methods are not well established. [19][20][21][22][23][24][25] Researchers have proposed many methods of quantification ranging from determining the ratios of metabolite signals 21 to use of multicompartment pharmacokinetic models. 19,25,26 Some acquisition and modeling techniques intend to obtain sequence-independent results, 21 whereas others have sequence parameters designed to ensure the most efficient use of the signal-to-noise ratio (SNR).…”

Section: Introductionmentioning

confidence: 99%

“…[19][20][21][22][23][24][25] Researchers have proposed many methods of quantification ranging from determining the ratios of metabolite signals 21 to use of multicompartment pharmacokinetic models. 19,25,26 Some acquisition and modeling techniques intend to obtain sequence-independent results, 21 whereas others have sequence parameters designed to ensure the most efficient use of the signal-to-noise ratio (SNR). 27 The effects of different acquisition strategies and sequence parameters on the accuracy of such quantitative metrics remain unclear.…”

Section: Introductionmentioning

confidence: 99%

A novel perfused Bloch–McConnell simulator for analyzing the accuracy of dynamic hyperpolarized MRS

et al. 2016

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Purpose: Magnetic resonance spectroscopy of hyperpolarized agents allows real-time detection of metabolism in vivo. However, the nonrenewable nature of these signals necessitates data acquisitions that differ significantly from conventional magnetic resonance imaging. Signal evolution is permanently altered by the data acquisition scheme, potentially leading to sequence parameter-dependent bias in quantification. The authors have developed a novel simulation environment to characterize the effects of sequence parameters on magnetic resonance spectroscopy-based chemical exchange measurements using hyperpolarized pyruvate. Methods: Conventional Bloch-McConnell equations were coupled with a pharmacokinetic model for perfusion to allow realistic simulation of in vivo dynamic hyperpolarized signal evolution. In this study, simulations were conducted to explore effects of excitation angle and repetition time on the observed signal and subsequent parametric analysis. Both high and low apparent exchange rates were modeled under assumption of both perfused and closed systems. Bias due to sampling strategy bias was subsequently tested in vivo. Results: Simulation of dynamic magnetic resonance spectroscopy studies using hyperpolarized pyruvate demonstrated that for closed systems, accurate measurement of the apparent exchange rate was possible over a wide range of sequence parameters. This was true for both high and low apparent exchange rates, although a low exchange rate was associated with larger errors when excitation angles were high. When effects of perfusion were included to account for pyruvate delivery, a more restricted range of settings led to accurate quantification of exchange rates. Perfusion alleviated some of the errors seen at high excitation angles for low exchange rates. Residuals from parametric analysis did not generally correlate with fit accuracy, implying that the quality of the analysis model was not a major driver of error. Animal studies acquired with sequence parameters that are predicted to impart bias showed a significant under estimation of exchange rates (P < 0.035) compared to parameter combinations that are not expected to bias measurements. Conclusions: The authors' results suggest that great care must be taken when measuring dynamic processes by magnetic resonance spectroscopy of hyperpolarized substrates. When comparing apparent exchange rates, choice of sequence parameters will affect the results. Bias introduced by parameters of more advanced acquisition and reconstruction schemes will likely increase compared to the relatively simple dynamic spectroscopy methods tested herein. The modified Bloch-McConnell equations the authors describe will be crucial tools for characterizing and optimizing the performance of these more advanced techniques. C

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“…The accurate determination of reaction rate constants remains a challenge. The first-order rate constants of LDH reaction have been quantified in tissues by modeling the signal time courses of hyperpolarized 13 C-labeled pyruvate and lactate (3)(4)(5)(6)(7). Nevertheless, the rate constant quantification suffers from inaccuracy for the following reasons:  Both intracellular and extracellular 13 C-labeled pyruvate contributes to the detected HP-NMR signal, but it is the intracellular pyruvate that is coupled to the LDH reaction in the cell.…”

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confidence: 99%

A pre-tracer approach for improving the accuracy of metabolic measurements by hyperpolarized nuclear magnetic resonance

2016

Quant. Imaging Med. Surg.

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Hyperpolarized nuclear magnetic resonance (HP-NMR) can probe the reaction kinetics of metabolic enzymes in vivo (1), and the translation of this technology into human patients based on the most commonly used tracer 13 C-pyruvate has been initiated in recent years (2). Currently the metabolite signal ratios are used as indicators for biological processes in healthy and diseased status. For example, to probe the reaction of lactate dehydrogenase (LDH) with hyperpolarized 13 C-pyruvate, the peak, mean, or integrated (area-undercurve) signal ratios of 13 C-lactate to 13 C-pyruvate are used to differentiate tumor and normal tissues, and to evaluate treatment response (3-5). However, these ratios do not have clearly defined biochemical meaning, and it is desirable to quantify the reaction rate constants. The accurate determination of reaction rate constants remains a challenge. The first-order rate constants of LDH reaction have been quantified in tissues by modeling the signal time courses of hyperpolarized 13 C-labeled pyruvate and lactate (3-7). Nevertheless, the rate constant quantification suffers from inaccuracy for the following reasons:  Both intracellular and extracellular 13 C-labeled pyruvate contributes to the detected HP-NMR signal, but it is the intracellular pyruvate that is coupled to the LDH reaction in the cell. The extracellular space (ECS) volume fraction varies with tissue and physiological state, being about 20% in brain and up to 70% in tumor (8,9). A significant increase in the lactate/pyruvate ratio when using hyperpolarized [1-13 C]alanine compared to hyperpolarized [1-13 C]pyruvate have been reported in rats (10). This results support the significant contribution to HP-NMR signals by extracellular pyruvate that does not involve in LDH reaction directly. The modeling of hyperpolarized pyruvate signals without differentiating signals from intracellular and ECS will underestimate the reaction rate constant for the conversion of pyruvate to lactate. This underestimation is expected to be particularly severe for some perfused organ studies using non-selective radiofrequency pulses for signal acquisition (5);  The transport of tracer from blood to interstitial space, and then through cell membrane to intracellular space complicates the mathematical modeling of enzyme kinetics. The rate constants determined for LDH by the two-site exchange modeling are really apparent rate constants, depending on the speeds of these transport processes (11). To determine the kinetic constants of an intracellular enzyme in vivo more accurately by HP-NMR, here I propose a simple pre-tracer approach to remove the complexities caused by extracellular metabolite signals and transport processes. Generally speaking, a hyperpolarized isotopelabeled pre-tracer (A), once it enters the space of interest (e.g., inside the cell), will be converted to the tracer of interest (B) via a local chemical reaction (e.g., by an intracellular enzyme E 1 ) ( Figure 1A). The tracer B will then be converted into additional metabolites of ...

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Ratiometric analysis in hyperpolarized NMR (I): test of the two‐site exchange model and the quantification of reaction rate constants

Cited by 17 publications

References 18 publications

Is Higher Lactate an Indicator of Tumor Metastatic Risk? A Pilot MRS Study Using Hyperpolarized 13C-Pyruvate

Is Higher Lactate an Indicator of Tumor Metastatic Risk? A Pilot MRS Study Using Hyperpolarized 13C-Pyruvate

A novel perfused Bloch–McConnell simulator for analyzing the accuracy of dynamic hyperpolarized MRS

A pre-tracer approach for improving the accuracy of metabolic measurements by hyperpolarized nuclear magnetic resonance

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