This educational presentation will give a description of the technical aspects of Chemical Exchange Saturation Transfer (CEST) MRI.
CEST MRI is a technology that can detect low (millimolar) concentrations of natural non-metallic magnetic marker molecules through the presence of groups with exchangeable protons, such as hydroxyls (OH), amides (NH) and amines (NH2) (van Zijl and Yadav 2011). These protons interact with the water protons detected in MRI through physical exchange, generally referred to in the field as ”chemical exchange”. When placed in a magnetic field, protons in different chemical environments have a specific MR frequency. Many exchangeable solute protons resonate at a frequency different from the bulk water protons. In CEST-MRI the presence of these metabolites are detected by selectively irradiating with radiofrequency (RF) waves at the appropriate resonance frequency of their exchangeable protons until their signals are saturated and disappear. This saturation is subsequently transferred to bulk water when solute and water protons exchange (exchange rate ksw) and the water signal becomes slightly saturated. Because the water pool is much larger than the saturated solute proton pool, each exchanging saturated solute proton is replaced by a nonsaturated water proton, which is then again saturated. If the solute protons have a sufficiently fast exchange rate (ms range) and the duration of the RF irradiation (saturation time tsat) is sufficiently long (s range), a substantial enhancement of this saturation effect occurs, which eventually becomes visible on the water signal, allowing such low-concentration solutes to be imaged. These frequency-dependent saturation effects are visualized by plotting the ratio of the water signal during saturation (Ssat) and without saturation (S0) as a function of saturation frequency. This gives what has been named a Z-spectrum (Bryant 1996) When saturating the water resonance itself, all signal disappears, which is called direct saturation (DS). All Z-spectra are characterized by a symmetric direct saturation (DS) around the water frequency and some additional signal drops at the exchangeable proton frequency. Thus, even though water signal changes are detected, chemical specificity is retained. Direct saturation may interfere with detection of CEST effects, which is generally addressed by employing the symmetry of the DS through a so-called magnetization transfer ratio (MTR) asymmetry analysis with respect to the water frequency. This process is characterized by subtracting right (−Δω) and left (Δω) signal intensity ratios:
𝑀𝑇𝑅asym(Δ𝜔) = [𝑆sat(−Δ𝜔) − 𝑆sat(Δ𝜔)] /𝑆0 [1]
in which Δω is the frequency difference with water. This analysis inherently assumes independent contributions of solute and water protons, which need not be the case, but it has worked well in first approximation for many applications. Asymmetry analysis also is based on an inherent assumption of symmetry of non-CEST contributions around the water signal, which may not always be true, especially in vivo, where there are contributions of magnetization transfer contrast (MTC) of semi-solid tissue components.
CEST agents can be divided into the following classes: diamagnetic CEST (diaCEST), paramagnetic CEST (paraCEST), and hyperpolarized CEST (hyperCEST). Here we will mainly focus on diaCEST.
DiaCEST can be performed with either endogenous or exogenous solutes. The most commonly used endogenous diaCEST method is Amide Proton Transfer Weighted (APTw) imaging (For a recent review, Zhou et al. 2019). This method has shown promising results in the detection of acute ischemia, tumour grading and to distinguish between radiation necrosis and recurrence in tumors patients. Other examples of endogenous diaCEST methods that are being used by multiple research groups are gagCEST for the glycosaminoglycans detection mainly in cartilage (Ling et al. 2008, Singh et al. 2012), glycoCEST for the detection glycogen (van Zijl et al. 2007), and gluCEST for detection of glutamate, a neurotransmitter in the brain, that may be used as application for Alzheimer's disease and epilepsy (Cai et al. 2012, Haris et al. 2013).
Current exogenous diaCEST applications in humans are based on agents that are already approved for other purposes. One example is glucoCEST where glucose or one of its analogues is injected as a contrast agent in order to get information from the microvasculature in e.g tumours (Chan et al. 2012, Walker-Samuel et al. 2013, Xu et al. 2015).
Bryant RG. The dynamics of water-protein interactions. Annu. Rev. Biophys. Biomol. Struct. 1996:25:29–53.
Cai K, Haris M, Singh A, Kogan F, Greenberg JH, Hariharan H, Detre JA, Reddy R. Magnetic resonance imaging of glutamate. Nat Med. 2012 Jan 22;18(2):302-6.
Chan KW, McMahon MT, Kato Y, Liu G, Bulte JW, Bhujwalla ZM, Artemov D, van Zijl PC. Natural D-glucose as a biodegradable MRI contrast agent for detecting cancer. Magn Reson Med. 2012 Dec;68(6):1764-73
Haris M, Nath K, Cai K, Singh A, Crescenzi R, Kogan F, Verma G, Reddy S, Hariharan H, Melhem ER, Reddy R. Imaging of glutamate neurotransmitter alterations in Alzheimer's disease. NMR Biomed. 2013 Apr;26(4):386-91.
Forsen S, Hoffman RA. Study of moderately rapid chemical exchange reactions by means of nuclear magnetic double resonance. J. Chem. Phys. 1963:39:2892–2901.
Ling W, Regatte RR, Navon G, Jerschow A. Assessment of glycosaminoglycan concentration in vivo by chemical exchange-dependent saturation transfer (gagCEST). Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2266-70.
Singh A, Haris M, Cai K, Kassey VB, Kogan F, Reddy D, Hariharan H, Reddy R. Chemical exchange saturation transfer magnetic resonance imaging of human knee cartilage at 3 T and 7 T. Magn Reson Med. 2012 Aug;68(2):588-94.
van Zijl PC, Jones CK, Ren J, Malloy CR, Sherry AD. MRI detection of glycogen in vivo by using chemical exchange saturation transfer imaging (glycoCEST). Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4359-64.
van Zijl PC, Yadav NN. Chemical exchange saturation transfer (CEST): what is in a name and what isn't? Magn Reson Med. 2011 Apr;65(4):927-48. doi: 10.1002/mrm.22761
Walker-Samuel S, Ramasawmy R, Torrealdea F, Rega M, Rajkumar V, Johnson SP, Richardson S, Gonçalves M, Parkes HG, Arstad E, Thomas DL, Pedley RB, Lythgoe MF, Golay X. In vivo imaging of glucose uptake and metabolism in tumors. Nat Med. 2013 Aug;19(8):1067-72.
Ward KM, Balaban RS. Determination of pH using water protons and chemical exchange dependent saturation transfer (CEST). Magn Reson Med. 2000 Nov;44(5):799-802.
Xu X, Yadav NN, Knutsson L, Hua J, Kalyani R, Hall E, Laterra J, Blakeley J, Strowd R, Pomper M, Barker P, Chan K, Liu G, McMahon MT, Stevens RD, van Zijl PC. Dynamic Glucose-Enhanced (DGE) MRI: Translation to Human Scanning and First Results in Glioma Patients. Tomography. 2015 Dec;1(2):105-114.
Zhou J, Heo HY, Knutsson L, van Zijl PCM, Jiang S. APT-weighted MRI: Techniques, current neuro applications, and challenging issues. J Magn Reson Imaging. 2019 Jan 20. doi: 10.1002/jmri.26645