B1 inhomogeneity corrected CEST MRI based on direct saturation removed omega plot model at 5T.

PURPOSE: CEST can image macromolecules/compounds via detecting chemical exchange between labile protons and bulk water. B1 field inhomogeneity impairs CEST quantification. Conventional B1 inhomogeneity correction methods depend on interpolation algorithms, B1 choices, acquisition number or calibration curves, making reliable correction challenging. This study proposed a novel B1 inhomogeneity correction method based on a direct saturation (DS) removed omega plot model. METHODS: Four healthy volunteers underwent B1 field mapping and CEST imaging under four nominal B1 levels of 0.75, 1.0, 1.5, and 2.0 µT at 5T. DS was resolved using a multi-pool Lorentzian model and removed from respective Z spectrum. Residual spectral signals were used to construct the omega plot as a linear function of 1/ B 1 2 $$ {B}_1^2 $$ , from which corrected signals at nominal B1 levels were calculated. Routine asymmetry analysis was conducted to quantify amide proton transfer (APT) effect. Its distribution across white matter was compared before and after B1 inhomogeneity correction and also with the conventional interpolation approach. RESULTS: B1 inhomogeneity yielded conspicuous artifact on APT images. Such artifact was mitigated by the proposed method. Homogeneous APT maps were shown with SD consistently smaller than that before B1 inhomogeneity correction and the interpolation method. Moreover, B1 inhomogeneity correction from two and four CEST acquisitions yielded similar results, superior over the interpolation method that derived inconsistent APT contrasts among different B1 choices. CONCLUSION: The proposed method enables reliable B1 inhomogeneity correction from at least two CEST acquisitions, providing an effective way to improve quantitative CEST MRI.

pH Mapping of Gliomas Using Quantitative Chemical Exchange Saturation Transfer MRI: Quasi-Steady-State, Spillover-, and MT-Corrected Omega Plot Analysis.

BACKGROUND: Quantitative in-situ pH mapping of gliomas is important for therapeutic interventions, given its significant association with tumor progression, invasion, and metastasis. Although chemical exchange saturation transfer (CEST) offers a noninvasive way for pH imaging based on the pH-dependent exchange rate (ksw ), the reliable quantification of ksw in glioma remains constrained due to technical challenges. PURPOSE: To quantify the pH of gliomas by measuring the proton exchange rate through optimized omega plot analysis. STUDY TYPE: Prospective. PHANTOMS/ANIMAL MODEL/SUBJECTS: Creatine and murine brain lysates phantoms, six rats with glioma xenograft model, and three patients with World Health Organization grade 2-4 gliomas. FIELD STRENGTH/SEQUENCE: 11.7 T, 7.0 T, CEST imaging, T2 -weighted (T2 W) imaging, and T1 -mapping. ASSESSMENT: Omega plot analysis, quasi-steady-state (QUASS) analysis, multi-pool Lorentzian fitting, amine and amide concentration-independent detection, pH enhanced method with the combination of amide and guanidyl (pHenh ), and magnetization transfer ratio (MTR) were utilized for pH metric quantification. The clinical outcomes were determined through radiologic follow-up and histopathological analysis. STATISTICAL TESTS: Mann-Whitney U test was performed to compare glioma with normal tissue, and Pearson's correlation analysis was used to assess the relationship between ksw and other parameters. RESULTS: In vitro experiments reveal that the determined ksw at 2 ppm increases exponentially with pH (creatine phantoms: ksw = 106 + 0.147 × 10(pH-4.198) ; lysates: ksw = 185.1 + 0.101 × 10(pH-3.914) ). Omega plot analysis exhibits a linear correlation between 1/MTRRex and 1/ω1 2 in the glioma xenografts (R2 > 0.98) and glioma patients (R2 > 0.99). The exchange rate in the rat glioma decreases compared to the contralateral normal tissue (349.46 ± 30.40 s-1 vs. 403.54 ± 51.01 s-1 , P = 0.025), while keeping independence from changes in concentration (r = 0.5037, P = 0.095). Similar pattern was observed in human data. DATA CONCLUSION: Utilizing QUASS-based, spillover-, and MT-corrected omega plot analysis for the measurement of exchange rates, offers a feasible method for quantifying pH within glioma. LEVEL OF EVIDENCE: NA TECHNICAL EFFICACY: Stage 1.

In vivo pH mapping with omega plot-based quantitative chemical exchange saturation transfer MRI.

PURPOSE: Chemical exchange saturation transfer (CEST) MRI is promising for detecting dilute metabolites and microenvironment properties, which has been increasingly adopted in imaging disorders such as acute stroke and cancer. However, in vivo CEST MRI quantification remains challenging because routine asymmetry analysis (MTRasym ) or Lorentzian decoupling measures a combined effect of the labile proton concentration and its exchange rate. Therefore, our study aimed to quantify amide proton concentration and exchange rate independently in a cardiac arrest-induced global ischemia rat model. METHODS: The amide proton CEST (APT) effect was decoupled from tissue water, macromolecular magnetization transfer, nuclear Overhauser enhancement, guanidinium, and amine protons using the image downsampling expedited adaptive least-squares (IDEAL) fitting algorithm on Z-spectra obtained under multiple RF saturation power levels, before and after global ischemia. Omega plot analysis was applied to determine amide proton concentration and exchange rate simultaneously. RESULTS: Global ischemia induces a significant APT signal drop from intact tissue. Using the modified omega plot analysis, we found that the amide proton exchange rate decreased from 29.6 ± 5.6 to 12.1 ± 1.3 s-1 (P < 0.001), whereas the amide proton concentration showed little change (0.241 ± 0.035% vs. 0.202 ± 0.034%, P = 0.074) following global ischemia. CONCLUSION: Our study determined the labile proton concentration and exchange rate underlying the in vivo APT MRI. The significant change in the exchange rate, but not the concentration of amide proton demonstrated that the pH effect dominates the APT contrast during tissue ischemia.

Quasi-steady-state CEST (QUASS CEST) solution improves the accuracy of CEST quantification: QUASS CEST MRI-based omega plot analysis.

PURPOSE: CEST MRI omega plot quantifies the labile proton fraction ratio (fr ) and exchange rate (ksw ), yet it assumes long RF saturation time (Ts) and relaxation delay (Td). Our study aimed to test if a quasi-steady-state (QUASS) CEST analysis that accounts for the effect of finite Ts and Td could improve the accuracy of CEST MRI quantification. METHODS: We modeled the MRI signal evolution using a typical CEST EPI sequence. The signal relaxes toward its thermal equilibrium following the bulk water relaxation rate during Td, and then toward its CEST steady state following the spin-lock relaxation rate during Ts from which the QUASS CEST effect is derived. Both fr and ksw were solved from simulated conventional apparent CEST and QUASS CEST MRI. We also performed MRI experiments from a Cr-gel phantom under serially varied Ts and Td times from 1.5 to 7.5 s. RESULTS: Simulation showed that, although ksw could be slightly overestimated (3%-15%) for the range of Ts and Td, fr could be substantially underestimated by as much as 67%. In contrast, the QUASS solution provided accurate ksw and fr determination within 2%. The CEST MRI experiments confirmed that the QUASS solution enabled robust quantification of ksw and fr , superior over the omega plot analysis based on the conventional apparent CEST MRI measurements. CONCLUSIONS: The QUASS CEST MRI algorithm corrects the effect of finite Ts and Td times on CEST measurements, thereby allowing robust and accurate CEST quantification.

Quantitative chemical exchange saturation transfer (qCEST) MRI - omega plot analysis of RF-spillover-corrected inverse CEST ratio asymmetry for simultaneous determination of labile proton ratio and exchange rate.

Chemical exchange saturation transfer (CEST) MRI is sensitive to labile proton concentration and exchange rate, thus allowing measurement of dilute CEST agent and microenvironmental properties. However, CEST measurement depends not only on the CEST agent properties but also on the experimental conditions. Quantitative CEST (qCEST) analysis has been proposed to address the limitation of the commonly used simplistic CEST-weighted calculation. Recent research has shown that the concomitant direct RF saturation (spillover) effect can be corrected using an inverse CEST ratio calculation. We postulated that a simplified qCEST analysis is feasible with omega plot analysis of the inverse CEST asymmetry calculation. Specifically, simulations showed that the numerically derived labile proton ratio and exchange rate were in good agreement with input values. In addition, the qCEST analysis was confirmed experimentally in a phantom with concurrent variation in CEST agent concentration and pH. Also, we demonstrated that the derived labile proton ratio increased linearly with creatine concentration (P < 0.01) while the pH-dependent exchange rate followed a dominantly base-catalyzed exchange relationship (P < 0.01). In summary, our study verified that a simplified qCEST analysis can simultaneously determine labile proton ratio and exchange rate in a relatively complex in vitro CEST system.

The Hanes-Woolf linear QUESP method improves the measurements of fast chemical exchange rates with CEST MRI.

PURPOSE: Contrast agents for chemical exchange saturation transfer MRI often require an accurate measurement of the chemical exchange rate. Many analysis methods have been reported that measure chemical exchange rates. Additional analysis methods were derived as part of this study. This report investigated the accuracy and precision of each analysis method. METHODS: Chemical exchange saturation transfer spectra were simulated using the Bloch-McConnell equations modified for chemical exchange. Chemical exchange saturation transfer spectra of iopromide were obtained with a range of saturation times, saturation powers, and concentrations. These simulated and experimental results were used to estimate the chemical exchange rate using the QUESP, QUEST, Omega Plot (LB-QUESP), EH-QUESP, HW-QUESP, LB-Conc, EH-Conc, and HW-Conc methods. RESULTS: Bloch fitting produced the most precise estimates of chemical exchange rates, although substantial expertise and computation time were required to achieve these results. Of the more simplistic analysis methods, the HW-QUESP method produced the most accurate and precise estimates of fast exchange rates. The QUEST and LB-QUESP methods produced the most accurate estimates of slow exchange rates, especially with samples that have short T(1w) relaxation times. CONCLUSIONS: HW-QUESP is a simplistic analysis method that should be used when fast chemical exchange rates need to be estimated from chemical exchange saturation transfer MRI results.

Novel proton exchange rate MRI presents unique contrast in brains of ischemic stroke patients.

BACKGROUND: To map and quantify the proton exchange rate (kex) of brain tissues using improved omega plots in ischemic stroke patients and to investigate whether kex can serve as a potential endogenous surrogate imaging biomarker for detecting the metabolic state and the pathologic changes due to ischemic stroke. NEW METHOD: Three sets of Z-spectra were acquired from seventeen ischemic stroke patients using a spin echo-echo planar imaging sequence with pre-saturation chemical exchange saturation transfer (CEST) pulse at B1 of 1.5, 2.5, and 3.5 µT, respectively. Pixel-wise kex was calculated from improved omega plot of water direct saturation (DS)-removed Z-spectral signals. RESULTS: The derived kex maps can differentiate infarcts from contralateral normal brain tissues with significantly increased signal (893 ±â€¯52 s-1vs. 739 ±â€¯34 s-1, P < 0.001). COMPARISON WITH EXISTING METHOD(S): The kex maps were found to be different from conventional contrasts from diffusion-weighted imaging (DWI), CEST, and semi-solid magnetization transfer (MT) MRI. In brief, kex MRI showed larger lesion areas than DWI with different degrees and different lesion contrast compared to CEST and MT. CONCLUSIONS: In this preliminary translational research, the kex MRI based on DS-removed omega plots has been demonstrated for in vivo imaging of clinical ischemic stroke patients. As a noninvasive and unique MRI contrast, kex MRI at 3 T may serve as a potential surrogate imaging biomarker for the metabolic changes of stroke and help for monitoring the evolution and the treatment of stroke.

In vivo quantification of proton exchange rate in healthy human brains with omega plot.

BACKGROUND: To implement omega plot method for in vivo mapping of proton exchange rates in human brain by taking into account the water direct saturation (DS) effect and multiple saturation transfer exchanging species in vivo. METHODS: Four Z-spectra were collected with chemical exchange saturation transfer (CEST) saturation power =1, 2, 3 & 4 µT. Water DS was estimated by fitting the Z-spectrum to a linear combination of multiple Lorentzian components and its contribution to the signal was subsequently removed. Exchange rate maps were derived by the omega plot, consisting of fitting the inverse of the signal intensity, Mz /(M 0-Mz ), as a function of 1/(γB1)2. RESULTS: The exchange rate values quantified with the DS removed omega plot were significantly higher in the GM region than in the WM region (616±29 vs. 575±20 s-1, P<0.001). Phantom studies confirmed that the exchange rates from DS-removed plots varied linearly with pH (R2=0.998) for the pH range of 6.2 to 7.4, whereas exchange rates from conventional omega plots failed to show such linearity in the entire physiological pH range. CONCLUSIONS: The calculated exchange rate with DS-corrected omega plot is a weighted average for all saturation transfer exchanging proton species which contribute to Z-spectral signal. The healthy brain exchange rate map provided by DS-removed omega plots may serve as a baseline for detecting any pathological changes.

Improving standardization and accuracy of in vivo omega plot exchange parameter determination using rotating-frame model-based fitting of quasi-steady-state Z-spectra.

PURPOSE: Although Ω-plot-driven quantification of in vivo amide exchange properties has been demonstrated, differences in scan parameters may complicate the fidelity of determination. This work systematically evaluated the use of quasi-steady-state (QUASS) Z-spectra reconstruction to standardize in vivo amide exchange quantification across acquisition conditions and further determined it in vivo. METHODS: Simulation and in vivo rodent brain chemical exchange saturation transfer (CEST) data at 4.7 T were fit with and without QUASS reconstruction using both multi-Lorentzian and model-based fitting approaches. pH modulation was accomplished both in simulation and in vivo by inducing global ischemia via cardiac arrest. Amide parameters were determined via Ω-plots and compared across methods. RESULTS: Simulation showed that Ω-plots using multi-Lorentzian fitting could underestimate the exchange rate, with error increasing as conditions diverged from the steady state. In comparison, model-based fitting using QUASS estimated the same exchange rate within 2%. These results aligned with in vivo findings where multi-Lorentzian fitting of native Z-spectra resulted in an exchange rate of 64 ± 13 s-1 (38 ± 16 s-1 after cardiac arrest), whereas model-based fitting of QUASS Z-spectra yielded an exchange rate of 126 ± 25 s-1 (49 ± 13 s-1). CONCLUSION: The model-based fitting of QUASS CEST Z-spectra enables consistent and accurate quantification of exchange parameters through Ω-plot construction by reducing error due to signal overlap and nonequilibrium CEST effects.

Quantitative chemical exchange saturation transfer (qCEST) MRI--RF spillover effect-corrected omega plot for simultaneous determination of labile proton fraction ratio and exchange rate.

Chemical exchange saturation transfer (CEST) MRI is sensitive to dilute proteins and peptides as well as microenvironmental properties. However, the complexity of the CEST MRI effect, which varies with the labile proton content, exchange rate and experimental conditions, underscores the need for developing quantitative CEST (qCEST) analysis. Towards this goal, it has been shown that omega plot is capable of quantifying paramagnetic CEST MRI. However, the use of the omega plot is somewhat limited for diamagnetic CEST (DIACEST) MRI because it is more susceptible to direct radio frequency (RF) saturation (spillover) owing to the relatively small chemical shift. Recently, it has been found that, for dilute DIACEST agents that undergo slow to intermediate chemical exchange, the spillover effect varies little with the labile proton ratio and exchange rate. Therefore, we postulated that the omega plot analysis can be improved if RF spillover effect could be estimated and taken into account. Specifically, simulation showed that both labile proton ratio and exchange rate derived using the spillover effect-corrected omega plot were in good agreement with simulated values. In addition, the modified omega plot was confirmed experimentally, and we showed that the derived labile proton ratio increased linearly with creatine concentration (p < 0.01), with little difference in their exchange rate (p = 0.32). In summary, our study extends the conventional omega plot for quantitative analysis of DIACEST MRI.