Accuracy in the quantification of chemical exchange saturation transfer (CEST) and relayed nuclear Overhauser enhancement (rNOE) saturation transfer effects

Abstract

Accurate quantification of chemical exchange saturation transfer (CEST) effects, including dipole-dipole mediated relayed nuclear Overhauser enhancements (rNOE) saturation transfer, is important for applications and studies of molecular concentration and transfer rate (and thereby pH or temperature). Although several quantification methods, such as Lorentzian difference (LD) analysis, multiple-pool Lorentzian fits, and the three-point method, have been extensively used in several preclinical and clinical applications, the accuracy of these methods has not been evaluated. Here we simulated multiple-pool Z-spectra containing the pools that contribute to the main CEST and rNOE saturation transfer signals in brain, and numerically fit them using the different methods, and then compared their derived CEST metrics with the known solute concentrations and exchange rates. Our results show that the LD analysis overestimates contributions from amide proton transfer (APT) and intermediate exchanging amine protons; the three-point method significantly underestimates both APT and rNOE saturation transfer at −3.5 ppm (NOE(−3.5)). In contrast, the multiple-pool Lorentzian fit is more accurate than the other two methods, but only at lower irradiation powers (< 1 μT at 9.4 T) within the range of our simulations. At higher irradiation powers, this method is also inaccurate because of the presence of a fast exchanging CEST signal that has a non-Lorentzian lineshape. Quantitative parameters derived from in vivo images of rodent brain tumor obtained using an irradiation power of 1 μT were also compared. Our results demonstrate that all three quantification methods show similar contrasts between tumor and contralateral normal tissue for both APT and the NOE(−3.5). However, the quantified values of the three methods are significantly different. Our work provides insight into the fitting accuracy obtainable in a complex tissue model and provides guidelines for evaluating other newly developed quantification methods.

Measurement of APT using a combined CERT-AREX approach with varying duty cycles

“…6g (p=0.38) and Fig. 7h support the previous results (11,30,33) that tumor/contralateral MTR asym contrast in a simple tumor model may be driven by T 1 , semi-solid MT, and rNOE, and not amide differences. Note that there have been differences in the CEST literature (6,30) concerning the relative protein (and hence amide) concentration in tumors.…”

“…Commonly, an asymmetry analysis (comparing images obtained from offset frequencies symmetric about the water resonance) is used to quantify the APT contrast. Although this works well in phantom studies, there are several factors in vivo that confound this approach, including effects of tissue relaxation, semi-solid magnetization transfer (MT), MT asymmetry, relayed nuclear overhauser enhancements (rNOE) from aliphatic protons, and contributions from other nearby exchanging protons such as amines (7–11). The relative magnitudes of these depend on the irradiation power level.…”

Spin‐lock imaging of early tissue pH changes in ischemic rat brain

“…Here we performed correlations between spin-locking parameters and the normalized MTR asym to compare their changes over time. The method used to measure MTR asym can be influenced by relayed nuclear overhauser enhancement (rNOE), MT, and MT asymmetry effects (32,33). As a result, the normalized MTR asym images are inhomogeneous and their values are negative in both lesions and contralateral normal tissues.…”

“…In addition, some protons, e.g. fast exchanging amine protons, do not produce Lorentzian lineshapes and their effects coalesce with the water peak, which causes errors in multiple-pool Lorentzian fitting (33). Specially designed pulsed saturation schemes e.g.…”

“…However, optimizing APT sequence parameters in vivo is challenging due to overlapping signals from other exchanging pools. For example, the irradiation power may be limited by nearby amines which are more significant at higher powers and contaminate APT signals (33). The inhomogeneous ΔR 1ρ and the normalized MTR asym signals in some rat brains in baseline measurements may be caused by inhomogeneous B 1 fields to which both methods are sensitive.…”