· Chemical Exchange Saturation Transfer: The physical/chemical effect and how to measure it

· Endogenous contrasts and applications

· Exogenous contrasts and applications

Researchers, clinicians and basic scientists, who want to learn about this very versatile new technology.

Upon completion of this course, participants should be able to:

· Get a glimpse of fundamental concepts and methods used in CEST MRI

· Learn about the state-of-the-art applications, and the ones closest to ‘clinical practice’.

· Understand the power of potentially important new contrast agents and the challenges necessary to bring those to the clinics.

What is Chemical Exchange Saturation Transfer? What are its boundary conditions and its limits? The purpose of this presentation will be to show what are the general characteristics of this versatile, albeit difficult MRI method to understand.In vivo CEST-based imaging is a variant of magnetization transfer (MT) imaging (1), in which the selective saturation of the magnetization of amide protons is detected indirectly through chemical exchange with bulk water protons. Selective irradiation is possible because there are composite proton resonance between 1ppm and 4ppm downfield from the water resonance. Among the most widely assessed exchangeable proton groups are amide protons, exchanging with bulk water at a rate of about 30 times per second, amine groups, exchanging at a rate of 1000-2000 Hz, and finally hydroxyl groups, exchanging at rates of 2000 Hz and above. Such exchange rates falls within the slow to intermediate exchange rate on the NMR time scale (2). Finally, NOE effects, thought to originate from protons in the aliphatic region, 3 to 5 ppm upfield from water can also lead to a detectable exchange of protons. Even though the underlying mechanisms are not fully understood, the effect is considered to be initially mediated by the cross relaxation via dipole-dipole interaction of the backbone protons in medium-size molecules. Most of these exchangeable proton pools are small (mM concentration range), but continuous saturation leads to a measurable decrease by a few percent of the large water signal due to a sensitivity enhancement mechanism. Indeed, by continuously saturating protons at the right off-resonance frequency, and letting them exchanging with the surrounding bulk water, one would achieve complete saturation of the latter, without the counterbalancing effect from the spin-lattice relaxation of the water T1. Note that this off-resonance saturation can be performed either in a continuous or pseudo-continuous mode. In humans, pulsed methods have been generally used (e.g. (3)), analogous to the pulsed MT techniques used in clinical MT imaging. In general, a CEST image is calculated based either on the subtraction of a single off-resonance pulse up-field and down-field from the water line, or as the integral under the curve created by the subtraction of both parts of the Z spectrum, obtained by continuous sweep of the off- resonance saturation frequency across typically ± 5-10 ppm around the water peak (2). Many imaging pulse sequences and post-processing methods have been developed to measure and assess the CEST effects, and it is beyond this syllabus to describe them all in details. Suffice to say that most of the necessary information can be found in two very good review papers: (2) for the CEST effect in general and (4) for a review on image processing methods. The main applications of most CEST methods have been for the assessment of pH changes, as the exchange rate of most of the above-mentioned moieties is based-catalyzed (2). As such, some of the most important uses of this method have been in stroke (5, 6) using endogenous CEST contrast (i.e. looking at changes in the signal from amide protons due to an acidification of the tissue) and the imaging of pH in tumours using exogenous contrast agents such as iopamidol (7). In addition, some of the early work has also been focusing on the use of the amide proton signal mainly for the assessment of tumour aggressiveness based on the increased protein turnover from high-metabolic cancerous cells (3, 8, 9). Finally, a whole series of applications based on the amide and hydroxyl groups have been demonstrated, from glutamate (10) to glucose (11, 12). Some of its advantages and issues will also be highlighted in this presentation.CEST and its variants are very versatile and possibly very useful techniques, but, as often at the early stages of development of novel MRI techniques, currently suffer from a lack of harmonization in both sequences and processing techniques. In addition, there are remaining issues and ongoing debates on the source of some of the endogenous CEST applications, and much more work is needed before quantification of the exchangeable pool is possible.