Amide proton transfer imaging of 9L gliosarcoma and human glioblastoma xenografts

Abstract

Amide proton transfer (APT) imaging is a variant of magnetization transfer (MT) imaging, in which the contrast is determined by a change in water intensity due to chemical exchange with saturated amide protons of endogenous mobile proteins and peptides. In this study, eight Fisher 344 rats implanted with 9L gliosarcoma cells and six nude rats implanted with human glioblastoma cells were imaged at 4.7 T. There were increased signal intensities in tumors in the APT-weighted images. The contrast of APT imaging between the tumor and contralateral brain tissue was about 3.9% in water intensity (1.49 +/- 0.66% vs -2.36 +/- 0.19%) for the more uniformly hypercellular 9L brain tumors, and it was reduced to 1.6% (-1.18 +/- 0.60% vs -2.77 +/- 0.42%) for the human glioblastoma xenografts that contained hypocellular zones of necrosis. The preliminary results show that the APT technique at the protein level may provide a unique MRI contrast for the characterization of brain tumors.

Figure 1

Z-spectra (A, B), MTR_asym spectra (C, D), and MTR_asym-difference spectra (E, F) for the 9L brain tumors (left column, 12 days post-implantation, n = 6) and the human glioblastoma brain tumors (right column, 7 weeks post-implantation, n = 2). The data from the same post-implantation days were averaged. The offsets of ±6 ppm were excluded in the display. Tumor: open circles; contralateral normal brain tissue: solid circles. MTR_asym difference = MTR_asym(tumor) − MTR_asym(normal). The APT effects are visible at the offset of 3.5 ppm in the z-spectra and MTR_asym spectra. The effect is stronger in tumor than in the contralateral normal-appearing region.

Figure 2

MR images and histology for the 9L gliosarcoma tumor model in a Fisher 344 rat (12 days post-implantation). The tumor is visible in all of the MR images, as confirmed by histology. The APT-weighted image appears to distinguish a small, likely edematous region (arrow) from tumor. The blue dotted line on the APT-weighted image defined a tumor ROI for quantitative analysis.

Figure 3

MR images and histology for the human glioblastoma brain tumor model in a nude rat (7 weeks post-implantation). The hyperintense (T₂, T₁, ADC) or hypointense (MTR) regions on several conventional MR images are larger than that on the APT-weighted image. The APT-weighted image is able to separate the likely edematous part (arrow) from tumor, and its hyperintensity profile is in good correspondence with histology. The blue dotted line on the APT-weighted image defined a tumor ROI for quantitative analysis.

Figure 4

Photomicrographs of hematoxylin and eosin stained sections of orthotopic human glioblastoma (A, C) and 9L gliosarcoma (B, D). Prominent hypocellular, eosinophilic zones of necrosis (N) are evident within the deeper regions of the human glioblastoma tumors and absent within the 9L gliosarcoma model. White arrows (C) indicate pseudopalisades that surround the necrosis. Bars equal 1 mm (A, B) and 0.5 mm (C, D).