Nuclear Overhauser enhancement (NOE) imaging in the human brain at 7T

Abstract

Chemical exchange saturation transfer (CEST) is a magnetization transfer (MT) technique to indirectly detect pools of exchangeable protons through the water signal. CEST MRI has focused predominantly on signals from exchangeable protons downfield (higher frequency) from water in the CEST spectrum. Low power radiofrequency (RF) pulses can slowly saturate protons with minimal interference of conventional semi-solid based MT contrast (MTC). When doing so, saturation-transfer signals are revealed upfield from water, which is the frequency range of non-exchangeable aliphatic and olefinic protons. The visibility of such signals indicates the presence of a relayed transfer mechanism to the water signal, while their finite width reflects that these signals are likely due to mobile solutes. It is shown here in protein phantoms and the human brain that these signals build up slower than conventional CEST, at a rate typical for intramolecular nuclear Overhauser enhancement (NOE) effects in mobile macromolecules such as proteins/peptides and lipids. These NOE-based saturation transfer signals show a pH dependence, suggesting that this process is the inverse of the well-known exchange-relayed NOEs in high resolution NMR protein studies, thus an relayed-NOE CEST process. When studying 6 normal volunteers with a low-power pulsed CEST approach, the relayed-NOE CEST effect was about twice as large as the CEST effects downfield and larger in white matter than gray matter. This NOE contrast upfield from water provides a way to study mobile macromolecules in tissue. First data on a tumor patient show reduction in both relayed NOE and CEST amide proton signals leading to an increase in magnetization transfer ratio asymmetry, providing insight into previously reported amide proton transfer (APT) effects in tumors.

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

“…Two distinct saturation transfer (ST) effects apparent in vivo are attributed to protons of mobile proteins: at 3.5 ppm the backbone amide signals with their base catalyzed proton transfer (APT) and at -3.5 ppm the nuclear Overhauser enhancement (NOE) mediated aliphatic proton magnetization transfer (so called exchangerelayed NOE or relayed-NOE (rNOE) ST) (8,9). For these protein ST effects, several interesting correlations have been shown that might play a role in vivo and especially in pathologies: dependence on intracellular pH (5,(10)(11)(12)(13), protein concentration (8,13), or protein folding (14,15) and aggregation states (16). Already, the use for brain tumor detection (6,(17)(18)(19)(20), grading (21), and possible differentiation of tumor recurrence and radiation necrosis (22) has been shown to be feasible by proteinbased saturation transfer MRI.…”

Proton Chemical Exchange Saturation Transfer (CEST) MRS and MRI

“…This method was demonstrated by Liu et al 119 for some paraCEST agents in phantoms and by Jones et al 71,72 in vivo in the human brain (Figure 7b and d). In Figure 13, the upfield LD spectrum of the right posterior lobe in human brain is compared with 1 H MRS data from the same region.…”

“…Only at very low B 1 field does the fine structure of the mobile components become visible above a broader MTC residual. 72 Recent data 73 using a pulse sequence that can remove the MTC component have confirmed that these rNOE-CEST effects in the brain are of equivalent magnitude in gray matter (GM) and white matter (WM), while the myelin-based MTC is dominant for WM. Evidence from the WEX spectra indicate that the rNOE effects originate from the mobile MM baseline in 1 H MRS.…”

“…While agreement is evident for a number of resonances, it was later concluded that a broader component from residual MTC was still present in the LD data, causing enhancement of WM in LD-based images. 71,72 Around the same time, Zaiss et al 120 theoretically demonstrated the possibility of estimating and removing DS and MTC contributions with Lorentzian fitting when the weak-saturation pulse condition is applicable. In a related approach, CEST effects have also been filtered from other MTC and DS effects by using time-domain analysis in an approach known as time-domain removal of irrelevant magnetization (TRIM).…”

Amide Proton Transfer Imaging in Clinics: Basic Concepts and Current and Future Use in Brain Tumors and Stroke

“…Therefore, pulsed saturation approaches are commonly used in clinical MRI scanners, wherein a train of saturation RF pulses is used with crusher gradients. Alternatively, one or multiple short saturation RF pulses are inserted into the two-dimensional or three-dimensional (3D) gradient-echo (22,23), segmented echo-planar imaging (24,25), turbo spin-echo (19,26,27) or gradient-and spin-echo image readout (12,18). This leads to accumulation of the saturation effect for slowly exchanging species, e.g., amide protons, due to a relatively short imaging TR, which is much less than the relaxation time (T1) of tissue.…”