Analysis of chemical exchange saturation transfer contributions from brain metabolites to the Z-spectra at various field strengths and pH

Khlebnikov, Vitaliy; Kemp, Wybe J. M. van der; Hoogduin, Hans; Klomp, Dennis W. J.; Prompers, Jeanine J.

doi:10.1038/s41598-018-37295-y

Cited by 52 publications

(89 citation statements)

References 54 publications

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“…This dominant base‐catalyzed and weak buffer‐catalyzed proton exchange was also reported previously 46 . The published exchange rate of Cr guanidinium protons at pH = 7 and body temperature ranged from 810 s −1 to 1190 s −1 41,46 . Our predicted values of exchange rates were smaller than the values reported by other groups, although within the same order of magnitude.…”

Section: Discussionsupporting

confidence: 80%

Influence of phosphate concentration on amine, amide, and hydroxyl CEST contrast

Yao

Wang

Ellingson

2020

Magnetic Resonance in Med

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Purpose To evaluate the influence of phosphate on amine, amide, and hydroxyl CEST contrast using Bloch‐McConnell simulations applied to physical phantom data. Methods Phantom solutions of 4 representative metabolites with exchangeable protons—glycine (α‐amine protons), Cr (η‐amine protons), egg white protein (amide protons), and glucose (hydroxyl protons)—were prepared at different pH levels (5.6 to 8.9) and phosphate concentrations (5 to 80 mM). CEST images of the phantom were collected with CEST‐EPI sequence at 3 tesla. The CEST data were then fitted to full Bloch‐McConnell equation simulations to estimate the exchange rate constants. With the fitted parameters, simulations were performed to evaluate the intracellular and extracellular contributions of CEST signals in normal brain tissue and brain tumors, as well as in dynamic glucose‐enhanced experiments. Results The exchange rates of α‐amine and hydroxyl protons were found to be highly dependent on both pH and phosphate concentrations, whereas the exchange rates of η‐amine and amide protons were pH‐dependent, albeit not catalyzed by phosphate. With phosphate being predominantly intracellular, CEST contrast of α‐amine exhibited a higher sensitivity to changes in the extracellular microenvironment. Simulations of dynamic glucose‐enhanced signals demonstrated that the contrast between normal and tumor tissue was mostly due to the extracellular CEST effect. Conclusion The proton exchange rates in some metabolites can be greatly catalyzed by the presence of phosphate at physiological concentrations, which substantially alters the CEST contrast. Catalytic agents should be considered as confounding factors in future CEST‐MRI research. This new dimension may also benefit the development of novel phosphate‐sensitive imaging methods.

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Section: Discussionsupporting

confidence: 80%

Influence of phosphate concentration on amine, amide, and hydroxyl CEST contrast

Yao

Wang

Ellingson

2020

Magnetic Resonance in Med

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“…Also, the relative B 1 in the tumor area is approximately 50–60% (see below), resulting in approximately 0.5 μT average effective B 1 in the tumor. Considering this B 1 , the main contributor to the measured signal is APT (approximately 90%), which makes the contribution of fast‐exchanging protons highly unlikely. A more likely explanation for the decrease of APT with increasing pH would be the decreasing cellularity (PE/Pi) with pH.…”

Section: Discussionmentioning

confidence: 99%

Contradiction between amide‐CEST signal and pH in breast cancer explained with metabolic MRI

et al. 2019

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Purpose Metabolic MRI is a noninvasive technique that can give new insights into understanding cancer metabolism and finding biomarkers to evaluate or monitor treatment plans. Using this technique, a previous study has shown an increase in pH during neoadjuvant chemotherapy (NAC) treatment, while recent observation in a different study showed a reduced amide proton transfer (APT) signal during NAC treatment (negative relation). These findings are counterintuitive, given the known intrinsic positive relation of APT signal to pH. Methods In this study we combined APT MRI and 31P‐MRSI measurements to unravel the relation between the APT signal and pH in breast cancer. Twenty‐two breast cancer patients were scanned with a 7 T MRI before and after the first cycle of NAC treatment. pH was determined by the chemical shift of inorganic phosphate (Pi). Results While APT signals have a positive relation to pH and amide content, we observed a direct negative linear correlation between APT signals and pH in breast tumors in vivo. Conclusions As differentiation of cancer stages was confirmed by observation of a linear correlation between cell proliferation marker PE/Pi (phosphoethanolamine over inorganic phosphate) and pH in the tumor, our data demonstrates that the concentration of mobile proteins likely supersedes the contribution of the exchange rate to the APT signal.

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“…16 However, quite limited studies focus on which solutes should be included in a multi-pool model for each tissue. 23 The other widely used type of approaches is fitting the ΔZ values to a simplified analytical model. 24 A series of ΔZ values are acquired using different saturation powers or saturation times and then, fitted to an analytical equation.…”

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confidence: 99%

Quantifying the fractional concentrations and exchange rates of small‐linewidth CEST agents using the QUCESOP method under multi‐solute conditions in MRI signals

Wang

Chen

et al. 2020

Magnetic Resonance in Med

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To develop a novel method for quantifying the fractional concentration (f b) and the exchange rate (k b) of a specific small-linewidth chemical exchange saturation transfer (CEST) solute in the presence of other unknown CEST solutes. Theory and Methods: A simplified R 1ρ model was proposed assuming a small linewidth of the specific solute and a linear approximation of the other solutes' contribution to R 1ρ. Two modes of CEST data acquisition, using various saturation offsets and various saturation powers, were used. The f b and k b of the specific solute could be fitted using the proposed model. In MRI experiments, using either singlesolute or multi-solute phantoms with various creatine concentrations and pHs, the f b and k b values of creatine were calculated for each phantom; the f b and k b values of phosphocreatine in rats' skeletal muscles were also evaluated. Results: The fitted f b value of creatine from the phantoms were in excellent agreement. The fitted k b value of creatine from the phantoms coincides with that from the literature, as do the f b and k b values of phosphocreatine in skeletal muscles. Conclusion: The proposed approach enables us to quantify the f b and k b values of a specific small-linewidth solute in the presence of other unknown solutes. K E Y W O R D S CEST, chemical exchange saturation transfer, creatine, multiple solutes, phosphocreatine, quantitative CEST analysis 1 | INTRODUCTION Chemical exchange saturation transfer (CEST) has the potential to characterize low-concentration solutes with labile, exchangeable protons in an NMR/MRI field. 1-6 The CEST technique provides contrast on the basis of the chemical-exchange (CE) parameters (ie, the fractional concentration f b , exchange rate k b , transverse relaxation time R 2b , and spectral offset) of specific CEST solute(s). The f b of various solutes are given more attention in relevant studies. 7-11 The k b of some solutes are also widely studied, as the microenvironmental properties (eg, pH) could be indirectly reflected. 12-14 How to cite this article: Wang Y, Chen J-F, Li P, Gao J-H. Quantifying the fractional concentrations and exchange rates of small-linewidth CEST agents using the QUCESOP method under multi-solute conditions in MRI signals.

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Analysis of chemical exchange saturation transfer contributions from brain metabolites to the Z-spectra at various field strengths and pH

Cited by 52 publications

References 54 publications

Influence of phosphate concentration on amine, amide, and hydroxyl CEST contrast

Influence of phosphate concentration on amine, amide, and hydroxyl CEST contrast

Contradiction between amide‐CEST signal and pH in breast cancer explained with metabolic MRI

Quantifying the fractional concentrations and exchange rates of small‐linewidth CEST agents using the QUCESOP method under multi‐solute conditions in MRI signals

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