Downfield‐NOE‐suppressed amide‐CEST‐MRI at 7 Tesla provides a unique contrast in human glioblastoma

Abstract

Purpose: The chemical exchange saturation transfer (CEST) effect observed in brain tissue in vivo at the frequency offset 3.5 ppm downfield of water was assigned to amide protons of the protein backbone. Obeying a base-catalyzed exchange process such an amide-CEST effect would correlate with intracellular pH and protein concentration, correlations that are highly interesting for cancer diagnosis. However, recent experiments suggested that, besides the known aliphatic relayednuclear Overhauser effect (rNOE) upfield of water, an additional downfield rNOE is apparent in vivo resonating as well around þ3.5 ppm. In this study, we present further evidence for the underlying downfield-rNOE signal, and we propose a first method that suppresses the downfield-rNOE contribution to the amide-CEST contrast. Thus, an isolated amide-CEST effect depending mainly on amide proton concentration and pH is generated. Methods: The isolation of the exchange mediated amide proton effect was investigated in protein model-solutions and tissue lysates and successfully applied to in vivo CEST images of 11 glioblastoma patients. Results: Comparison with gadolinium contrast enhancing longitudinal relaxation time-weighted images revealed that the downfield-rNOE-suppressed amide-CEST contrast forms a unique contrast that delineates tumor regions and show remarkable overlap with the gadolinium contrast enhancement. Conclusion: Thus, suppression of the downfield rNOE contribution might be the important step to yield the amide proton CEST contrast originally aimed at.

Improving the detection sensitivity of pH‐weighted amide proton transfer MRI in acute stroke patients using extrapolated semisolid magnetization transfer reference signals

“…Therefore, the absolute MTR asym (3.5ppm) signal intensity as well as the contrast of the ischemic stroke is reduced by the upfield NOE signals and the use of the asymmetry metric reduces the sensitivity of APT signals in ischemic stroke imaging. It should be mentioned that, contrary to our findings and the basic evidence from studies on cells and tissue (53) and high resolution NMR studies of proteins (56, 57), others have not found a change of relayed-NOE signals following acute stroke (29, 58, 59). The most likely explanation of this is a difference in saturation power B 1 , leading to very different contributions of fast and slow exchanging protons to the Z-spectrum (60).…”

Enhancing sensitivity of pH-weighted MRI with combination of amide and guanidyl CEST

“…Besides the guanidyl protons, there are other possible contributions to the endogenous CEST signal at 2.0 ppm, such as from the aromatic NOE from mobile proteins as suggested by our group and others (Jin and Kim, 2013; Zaiss et al, 2017), and amide of glutamine (Mori et al, 1998). Since NOE effects are insensitive to pH {Jin, 2013 #2715}, and amide has opposite pH-contrast with guanidyl with our selection of saturation powers, we expect that the pH-contrast at 2.0 ppm should be mostly from the guanidyl protons.…”

Diagnostic performance between contrast enhancement, proton MR spectroscopy, and amide proton transfer imaging in patients with brain tumors

“…Some authors implied or demonstrated that the background MT asymmetry or NOE effects are negligible at 3T, while others argue that MT asymmetry is more significant than the APT effect even at 3T . According to the recent researches with ultrahigh‐field MRI, NOE imaging has the potential to delineate portions with high cellularity, or BBB disruption in glioma, without contrast agents . MT contrast in the brain tumor has been reported to be decreased compared with white matter, and correlate with nuclear density .…”