Insight into the Quantitative Metrics of Chemical Exchange Saturation Transfer (CEST) Imaging
Hye-Young Heo1,2, Dong-Hoon Lee1, Yi Zhang1, Xuna Zhao1, Shanshan Jiang1, and Jinyuan Zhou1,2

1The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States, 2F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States

Synopsis

Amide proton transfer (APT) imaging is a novel chemical exchange saturation transfer (CEST)-based MRI modality that can detect various endogenous mobile proteins and peptides in tissue, such as those in the cytoplasm. The APT quantification results depend on the CEST metrics, which is undesirable. In this study, four CEST metrics: (i) CEST ratio (CESTR), (ii) CESTR normalized with the reference value (CESTRnr), (iii) inverse Z-spectrum-based (MTRRex), and (iv) apparent exchange-related relaxation (AREX), were compared using five-pool Bloch equation-based simulations with varied RF saturation powers and magnetic field strength, and in an in vivo rat tumor study at 4.7 T.

Purpose

CEST imaging is an important molecular MRI technique that allows detection of endogenous, low-concentration biomolecules in tissue. However, CEST quantifications depend on the choice of CEST metric approaches and reference images; thus, care should be taken when doing the quantification of CEST imaging and comparing the measurements in different labs. Herein, we evaluated the reliability of four CEST imaging metrics and potential confounds in tumors at different experimental settings.

Methods

A five-pool proton exchange model (free water, semi-solid, amide, amine, and NOE-related protons) combined with the super-Lorentzian lineshape for semi-solid protons was used for the simulation. Four CEST metrics (CEST ratio or CESTR [1-5], CESTR normalized with the reference value or CESTRnr [6-9], inverse Z-spectrum-based or MTRRex [10], and apparent exchange-related relaxation or AREX [11-13]) were compared. All reference signals (Zref) were taken from the simulated semi-solid MT signal. For the in vivo study, eight glioma-bearing rats were scanned at 4.7 T.

$$(1) CESTR=\frac{S_{ref}-S_{lab}}{S_{0}}=Z_{ref}-Z_{lab}$$

$$(2) CESTR^{nr}=\frac{S_{ref}-S_{lab}}{S_{ref}}=\frac{Z_{ref}-Z_{lab}}{Z_{ref}}$$

$$(3) MTR_{Rex}=\frac{(S_{ref}-S_{lab})S_{0}}{S_{ref}S_{lab}}=\frac{1}{Z_{lab}}-\frac{1} {Z_{ref}}=\frac{Z_{ref}-Z_{lab}}{Z_{ref}Z_{lab}}$$

$$(4) AREX=\frac{MTR_{Rex}}{T_{1w}}=\frac{(S_{ref}-S_{lab})S_{0}}{S_{ref}S_{lab}T_{1w}}=\frac{Z_{ref}-Z_{lab}}{Z_{ref}Z_{lab}}\cdot\frac{1}{T_{1w}}$$

Results and Discussion

The five-pool Bloch equation-based simulation results with six RF saturation power levels of 0.5, 1, 1.5, 2, 2.5, and 3 μT are shown in Fig. 1 (for 4.7 T) and 2 (for 9.4 T). (i) Similar CEST signal features at 3.5 ppm and 2 ppm can be seen with all four CEST metrics when a relatively low RF saturation power (< 1 μT) is applied. (ii) The CEST signals using two inverse metrics (MTRRex and AREX) are dramatically increased (e.g. MTRRex ≈ 43 % and AREX ≈ 30 % at 3.5 ppm, and MTRRex ≈ 132 % and AREX ≈ 95 % at 2 ppm with B1 of 3 μT), while CESTR and CESTRnr metrics stay the same or similar as the RF power increase up to 3 μT. Such a tremendous increase of the inverse metrics occurs due to the inherent error from small denominators, likely resulting in their applications at high RF saturation powers and low clinical B0 field strengths (3 T and 4.7 T) problematic. (iii) The inverse metric signals around the water frequency are not reliable due to denominators approaching zero. These peaks definitely lead to an erroneous result, in particular, for the detection of OH groups (hydroxyl) at 1 ppm and NH2 groups (amine) at 2 ppm, close to the water resonance. (iv) At a high field of 9.4 T, the APT peaks can be relatively well resolved in AREX metrics, as shown in Fig. 2, because of the high spectral resolution compared to 4.7 T, while the AmineCEST peaks is still unreliable at high RF saturation power (> 2 μT).

For the in vivo tumor rat study, quantitative APT signals obtained from these four CEST metrics were assessed at varied saturation power levels (0.5, 0.9, 1.3, 2.1, 3.2, and 4.4 μT) as shown in Fig. 3. The high MTRRex and the AREX peaks can be seen clearly around 1 ppm due to the intrinsic error of the inverse metric, very similar to the result from the Bloch equation-based simulation. As expected, the APT signals of the tumor from CESTRnr and CESTR were significantly higher than those of the normal tissue across all power levels (p < 0.05), while the upfield NOE signals of the tumor from CESTR and CESTRnr were significantly lower than those of the normal tissue across all power levels (p < 0.01) as shown in Fig. 4. Multiple quantitative MRI maps of a tumor-bearing rat are shown in Fig. 5. Remarkably, the tumor was hyperintense on the MTRasym, CESTR, CESTRnr, and MTRRex maps at 3.5 ppm when an RF saturation power of 1.3 μT was applied. On the CESTR, CESTRnr, and MTRRex maps at 2 ppm, the tumor was slightly hyperintense. As reported previously [11-13], the AREX maps at 3.5 and 2 ppm showed no contrast between the tumor and normal tissue.

Conclusions

In this study, we evaluated the reliability of two inverse CEST metrics and compared them with other CEST metrics, using a five-pool Bloch equation-based simulation and the rat tumor experiment at 4.7 T. The choice of CEST metrics must be carefully considered according to RF saturation power levels, B0 field strengths, and specific exchangeable solute protons. MTRRex and AREX may not be used for amine and hydroxyl CEST measurements, particularly, with a relatively higher saturation power level (with the large direct water saturation and semi-solid MT effects). At the clinical field strength (3 T and 4.7 T), CESTR and CESTRnr would be more reliable and valid for APT imaging at the optimal saturation power of 2 μT used currently.

Acknowledgements

No acknowledgement found.

References

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Figures

Simulated five-pool and two-pool Z-spectra, as well as CEST and NOE signals with four CEST metrics at various RF saturation power levels (B1) at a B0 magnetic field strength of 4.7 T.

Simulated five-pool and two-pool Z-spectra, as well as CEST and NOE signals with four CEST metrics at various RF saturation power levels (B1) at a B0 magnetic field strength of 9.4 T.

Average ROI-based experimental data (black dashed lines), extrapolated two-pool MT fitted curves (ZEMR, black solid lines), CEST, and NOE signal features, obtained from normal tissue and from tumor at six RF saturation power levels. Sky-blue solid lines: MTRRex; blue solid lines: AREX; magenta solid lines: CESTRnr; red solid lines: CESTR.

Average APT image intensities and contrasts between the normal tissue and tumor with four CEST metrics at 4.7T. a,b: MTRasym at 3.5 ppm; c,d: CESTR at 3.5 ppm; e,f: CESTRnr at 3.5 ppm; g,h: MTRRex at 3.5 ppm; i,j: AREX at 3.5 ppm.

Multiple MRI parametric maps overlaid on a corresponding EPI image for a representative tumor-bearing rat (45 days post-tumor implantation).



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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