A review of optimization and quantification techniques for chemical exchange saturation transfer MRI toward sensitive in vivo imaging

Abstract

Chemical exchange saturation transfer (CEST) MRI is a versatile imaging method that probes the chemical exchange between bulk water and exchangeable protons. CEST imaging indirectly detects dilute labile protons via bulk water signal changes following selective saturation of exchangeable protons, which offers substantial sensitivity enhancement and has sparked numerous biomedical applications. Over the past decade, CEST imaging techniques have rapidly evolved owing to contributions from multiple domains, including the development of CEST mathematical models, innovative contrast agent designs, sensitive data acquisition schemes, efficient field inhomogeneity correction algorithms, and quantitative CEST (qCEST) analysis. The CEST system that underlies the apparent CEST-weighted effect, however, is complex. The experimentally measurable CEST effect depends not only on parameters such as CEST agent concentration, pH and temperature, but also on relaxation rate, magnetic field strength and more importantly, experimental parameters including repetition time, RF irradiation amplitude and scheme, and image readout. Thorough understanding of the underlying CEST system using qCEST analysis may augment the diagnostic capability of conventional imaging. In this review, we provide a concise explanation of CEST acquisition methods and processing algorithms, including their advantages and limitations, for optimization and quantification of CEST MRI experiments.

Keywords: MRI; amide proton transfer; chemical exchange saturatio transfer; quantitative chemical exchange saturatio transfer.

Fig. 1

Plot of T₁ (a) and T₂ (b) as a function of field strength in grey matter (GM). Simulated CEST effect (CESTR) as a function of B₁ irradiation power (c), and the maximal CEST effect for a given field strength (d).

Fig. 2

(a) APTR effect, and (b) MTC and DS as a function of RF saturation strength and duration for a three-compartment model of semisolid macromolecular protons, solute amide protons, and bulk water protons.

Fig. 3

Experimental validation of optimal experimental condition in an in vitro pH CEST phantom. The pH-weighted CEST contrast (ΔCESTR) increases with TR (a), while its contrast-to-noise ratio efficiency (CNR_put) peaks at an intermediate TR (b). Both ΔCESTR (a) and CNR_put (b) increase with RF duty cycle. In addition, ΔCESTR decreases with RF flip angle (a), while CNR_put initially increased with RF flip angle and peaked at about 75° (b).

Fig. 4

Numerically determined optimal B₁ level as a function of field strength and chemical shift. The exchange rate normalized optimal B₁ level approaches unit at high field and chemical shift due to mitigated RF spillover effects.

Fig. 5

(a) Simulated and (b) experimental pulsed-CEST contrast as a function of average power and flip angle of pulsed irradiation at 9.4T with a duty cycle of 50%. Stars represent the experimental results.

Fig. 6

CEST ratio-pH correlation for Yb-DO3A-oAA at 300 MHz magnetic field strength. (a) The % CEST effects of the amide (filled circles) and amine (unfilled circles) of 100 mM Yb-DO3A-oAA were measured at 37 °C using 20 μT saturation power. (b) The log10 of a ratio of CEST showed an excellent correlation with pH (R² = 0.99).

Fig. 7

In vivo demonstration of the LOVARS scheme as applied to the imaging of 9L gliosarcomas in mice. (a) T2-weighted image; (b) B₀ shift map; (c) uncorrected MTR_asym map; (d) LOVARS time domain data (top) with phase (middle) and magnitude (bottom) traces determined through FFT with ROIs as marked in (c); (e) LOVARS phase map calculated using FFT; (f) LOVARS phase map calculated using GLM; (g) thresholded LOVARS imaginary component map.

Fig. 8

(a) Conventional APT contrast is contaminated by (d) spillover and (e) T₁ effects. With correction of spillover by (b) MTR_Rex and correction of T₁ by the (c) AREX evaluation, (f) an absolute pH map can be calculated, which shows (g) significantly higher contrast between the stroke area and normal tissue.