Imaging of amide proton transfer and nuclear Overhauser enhancement in ischemic stroke with corrections for competing effects

Abstract

Chemical exchange saturation transfer (CEST) potentially provides the ability to detect small solute pools through indirect measurements of attenuated water signals. However, CEST effects may be diluted by various competing effects, such as non-specific magnetization transfer (MT) and asymmetric MT effects, water longitudinal relaxation (T1 ) and direct water saturation (radiofrequency spillover). In the current study, CEST images were acquired in rats following ischemic stroke and analyzed by comparing the reciprocals of the CEST signals at three different saturation offsets. This combined approach corrects the above competing effects and provides a more robust signal metric sensitive specifically to the proton exchange rate constant. The corrected amide proton transfer (APT) data show greater differences between the ischemic and contralateral (non-ischemic) hemispheres. By contrast, corrected nuclear Overhauser enhancements (NOEs) around -3.5 ppm from water change over time in both hemispheres, indicating whole-brain changes that have not been reported previously. This study may help us to better understand the contrast mechanisms of APT and NOE imaging in ischemic stroke, and may also establish a framework for future stroke measurements using CEST imaging with spillover, MT and T1 corrections.

Keywords: amide proton transfer (APT); apparent exchange-dependent relaxation (AREX); chemical exchange saturation transfer (CEST); ischemia; nuclear Overhauser enhancement (NOE); stroke.

Figure 1

Illustration of Z^*_ref and Z_lab for APT (a) and NOE (b) quantification. The blue circles represent the measured data, from which Z_lab (red squares) were obtained using a spline interpolation. The spline interpolation of the points (ppm) 2.7, 3, 4.2, and 4.5 provided Z^*_ref (black asterisks) for APT quantification, and the spline interpolation of the points (ppm) −5.75, −5, −2 and −1.25 for NOE quantification.

Figure 2

Temporal evolution of R₂, R₁, PSR, ADC, APT*(1.8 µT), AREX*(APT, 1.8 µT), NOE*(1.2 µT), and AREX*(NOE, 1.2 µT) maps acquired from a representative rat. Parametric maps are acquired at time points shown at the bottom. −0.5 h represents the baseline time point before MCAO. The conventional R₂R₁ and ADC maps show visible changes immediately after stroke. The R₁ map at 3 h shows the ROIs of the ischemic hemisphere (white) and the contralateral hemisphere (black).

Figure 3

Time-dependent values of R₂ (a), ADC (b), PSR (c) and R₁ (d) for the ischemic hemisphere (red squares), the contralateral hemisphere (blue circles) and the healthy controls (magenta triangles). Data are presented as mean ± s.d. (n=6). Statistical significances between pre- and post-MCAO were evaluated using the Wilcoxon rank-sum test (*P<0.01 for the ischemic hemisphere and ⁺P<0.01 for the contralateral hemisphere).

Figure 4

APT* (a) and AREX*(APT) (b) as a function of B₁ for the ischemic hemisphere (red squares) and the contralateral hemisphere (blue circles) at each time point. Data are presented as mean ± s.d. (n=6).

Figure 5

NOE* (a) and AREX*(NOE) (b) as a function of B₁ for the ischemic hemisphere (red squares) and the contralateral hemisphere (blue circles) at each time point. Data are presented as mean ± s.d. (n=6).

Figure 6

Time-dependent values of APT*(1.8 µT) (a), AREX*(APT, 1.8 µT) (b), NOE*(1.2 µT) (c) and AREX*(NOE, 1.2 µT) (d) for the ischemic hemisphere (red squares), the contralateral hemisphere (blue circles) and the healthy controls (magenta triangles). Data are presented as mean ± s.d. (n=6). Statistical significances between pre- and post-MCAO were evaluated using the Wilcoxon rank-sum test (*P<0.01 for the ischemic hemisphere and ⁺P<0.01 for the contralateral hemisphere).