Chemical exchange saturation transfer (CEST) is a contrast mechanism exploiting exchange-based magnetization transfer (MT) between solute and water protons. CEST effects compete with direct water saturation and conventional MT processes and generally can only be quantified through an asymmetry analysis of the water saturation spectrum (Z-spectrum) with respect to the water frequency, a process that is exquisitely sensitive to magnetic field inhomogeneities. Here, it is shown that direct water saturation imaging allows measurement of the absolute water frequency in each voxel, allowing proper centering of Z-spectra on a voxel-by-voxel basis independent of spatial B 0 field variations. Optimal acquisition parameters for this "water saturation shift referencing" or "WASSR" approach were estimated using Monte Carlo simulations and later confirmed experimentally. The optimal ratio of the WASSR sweep width to the linewidth of the direct saturation curve was found to be 3.3-4.0, requiring a sampling of 16-32 points. The frequency error was smaller than 1 Hz at signal to noise ratios of 40 or higher. The WASSR method was applied to study glycogen, where the chemical shift difference between the hydroxyl (OH) protons and bulk water protons at 3T is so small (0.75-1.25 ppm) that the CEST spectrum is inconclusive without proper referencing.

Amide proton transfer (APT) imaging is a type of chemical exchange-dependent saturation transfer (CEST) magnetic resonance imaging (MRI) in which amide protons of endogenous mobile proteins and peptides in tissue are detected. Initial studies have shown promising results for distinguishing tumor from surrounding brain in patients, but these data were hampered by magnetic field inhomogeneity and a low signal-to-noise ratio (SNR). Here a practical six-offset APT data acquisition scheme is presented that, together with a separately acquired CEST spectrum, can provide B 0 -inhomogeneity corrected human brain APT images of sufficient SNR within a clinically relevant time frame. Data from nine brain tumor patients at 3T shows that APT intensities were significantly higher in the tumor core, as assigned by gadolinium-enhancement, than in contralateral normal-appearing white matter ( Recent progress in the field of proteomics (1-3) has shown that the biological characteristics of human gliomas and other cancers are defined by numerous proteins, and that the pathologic distinctions between normal and malignant tissues can be identified at the level of protein expression. Using in vivo proton MRS, Howe et al. (4) showed that the MRS-detectable mobile macromolecular proton concentration is higher in human brain tumors than in normal white matter (WM), and increases with tumor grade. These advances have prompted much interest in visualizing the protein content of tumors in vivo in MRI.Chemical exchange-dependent saturation transfer (CEST) has recently emerged as a new contrast mechanism for MRI (5-7) in the field of cellular and molecular imaging. This technique, which is a type of magnetization transfer (MT)imaging (8), has now evolved into several different variants as new CEST contrast agents (diamagnetic and paramagnetic) and approaches have been designed (9 -22). In one of these, dubbed amide proton transfer (APT) imaging (9 -13,23-25), endogenous cytosolic proteins and peptides are detected through saturation of the amide protons in the peptide bonds. Similar to the results of Howe et al. (4), this unique amide proton-based MRI contrast mechanism has shown promise for imaging the increase in protein and peptide content in brain tumors in animals (11), as well as in an initial study in human brain tumor patients (23). However, these preliminary human studies were confounded by a low signal-to-noise ratio (SNR; the APT effect is only a few percent of the water signal) and by local field inhomogeneity. The high sensitivity of APT to field inhomogeneity is due to the inherent approach in CEST-type imaging, where water saturation is measured as a function of transmitter frequency, producing the "z-spectra" (26) or CEST spectra (5). Such spectra are dominated by large direct water saturation around the water frequency at about 4.7 ppm in the proton spectrum and other saturation effects, such as conventional MT based on semisolid tissue structures (8). The effects of the saturation transfer of exchangeable protons to water ...

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