Introduction: In recent years, APT imaging has been intensively studied and its clinical value has been established in evaluating brain tumor, based on which FDA has approved its commercial use in brain tumors [1-3]. With the wide clinical use, the question was raised that whether and how much Gadolinium-based (Gd-based) agent in clinical dosage has impact on the APT effect. In theory, the magnetization transfer ratio asymmetry analysis (MTRasym) is T1 dependent, hence residual Gd in post-contrast imaging may affect the presence of the CEST imaging [4]. However, two recent studies have reported quite the contradictory results in terms of potential impact of Gd has on the APT effect [4,5]. Hence, the purpose of this study is to verify the possible impact of gadolinium contrast agent on amide-proton-transfer weighted (APTw) MRI, and to quantify to what extent the contrast agents alter the APT effect. Materials and Methods: A phantom was made by mixing a gradient of 24 dosages of Gd-based contrast agent with 10 mL pure egg white (EW) in each tube, with reference to the clinical dosage (fig.1). Six patients with brain tumor had undergone routine clinical brain MR scan, in which APT-weighted imaging and T1 mapping was added before and after the administration of Gd. MRI study was performed on a 3T MR scanner (Discovery MR 750w, General Electric Healthcare, Waukesha, WI) using a 8-channel head and neck coil. Chemical shift-selective fat suppression and single-shot fast spin echo (FSE) readout were used (4 radiofrequency saturation pulses with duration of 500 ms for each pulse and without inter-pulse delay, RF saturation power B1 of 2 μT, TR = 6189 ms with minimum TE, slice thickness = 4 mm, field of view = 12×12 cm2, matrix size = 96×96). In addition to an unsaturated scan, 69 CEST-weighted images with frequency offsets of -7 to 7 ppm in 0.5 ppm increments were acquired. To correct B0 inhomogeneity, a water saturation shift referencing (WASSR) map was collected with B1 of 0.5 μT (frequency offsets including ±240, ±192, ±144, ±96, ±48 and 0 Hz). On an in-house MATLAB platform, APT values were calculated and measured for each tube of the phantom, and different regions of interest (ROIs) of the brain, including peripheral edema, tumor area, white matter (WM) and gray matter (GM). Similarity between the pre-contrast and post-contrast APT map was quantified using cosine similarity. Paired student t-test was used to evaluate the pixel-wise difference in the APT values between the same ROI of pre-contrast and post-contrast APT maps. Results and Discussions: The results of ex vivo experiment show that the three scans have a high consistency (ICC = 0.998), suggesting the satisfactory reproducibility of APT sequence in our study. Along with the increase of the MRI contrast agent concentration, the average APT value of each tube in the phantom shows a downward trend. When the added Gd content is less than 1 μL, the average value of APT remains relatively stable and fluctuates around 12% (ranging from 11.61% to 13.42%) (fig.2). However, when the Gd content added exceeds 1 μL, the APT value of the egg white considerably dropped. Until the added Gd content reaches about 20 μL, the decline rate of APT value gradually stabilizes and maintains at about 2% (ranging from 1.88% to 2.13%) (fig.3). Therefore, the in vitro experiment demonstrated the definite impact of Gd on APT effect that the APT signal dropped along with the increased concentration of Gd. As reported, the asymmetry analysis of the magnetization transfer ratio is closely related to the T1 effect[4,6], and the T1 relaxation time of the tissue is shortened after the injection of Gd, both of which might explain the clear impact of Gd on APT asymmetry signal. The results of in vivo experiments showed that for the entire brain tissue (n = 6), brain gray matter and white matter (n = 5) and enhanced tumor lesions (n = 7) (fig.4), the pixel-wise APT value of each corresponding ROI showed significant changes (P < 0.05) between before and after the contrast agent enhancement. For non-enhanced tumor lesions (n = 3), the APT value did not change significantly (P > 0.05) between before and after enhancement. In the edema area surrounding the tumor lesion (n = 2), compared with the counterpart before enhancement, the APT value was significantly reduced after enhancement (P < 0.05) (fig.5). The results of this study showed that the APT value of the tumor lesions with enhancement has significant changes, while most of the non-enhanced areas of the tumor have no significant changes. This finding is consistent with the result of in vitro study that Gd could have an obvious impact on APT signal by considerably shorten the T1 relaxation time in tumor tissue. Conclusion: Both in vitro phantom study and in vivo study demonstrated the significant impact of Gd-based contrast agent on APT effect, especially for highly enhanced brain tumor, suggesting that it should be avoided to perform APT weighted imaging after contrast enhanced imaging in clinical setting.

Acknowledgements

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References

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