Quantitative multiparametric MRI assessment of glioma response to radiotherapy in a rat model

Abstract

Background: The inability of structural MRI to accurately measure tumor response to therapy complicates care management for patients with gliomas. The purpose of this study was to assess the potential of several noninvasive functional and molecular MRI biomarkers for the assessment of glioma response to radiotherapy.

Methods: Fourteen U87 tumor-bearing rats were irradiated using a small-animal radiation research platform (40 or 20 Gy), and 6 rats were used as controls. MRI was performed on a 4.7 T animal scanner, preradiation treatment, as well as at 3, 6, 9, and 14 days postradiation. Image features of the tumors, as well as tumor volumes and animal survival, were quantitatively compared.

Results: Structural MRI showed that all irradiated tumors still grew in size during the initial days postradiation. The apparent diffusion coefficient (ADC) values of tumors increased significantly postradiation (40 and 20 Gy), except at day 3 postradiation, compared with preradiation. The tumor blood flow decreased significantly postradiation (40 and 20 Gy), but the relative blood flow (tumor vs contralateral) did not show a significant change at most time points postradiation. The amide proton transfer weighted (APTw) signals of the tumor decreased significantly at all time points postradiation (40 Gy), and also at day 9 postradiation (20 Gy). The blood flow and APTw maps demonstrated tumor features that were similar to those seen on gadolinium-enhanced T1-weighted images.

Conclusions: Tumor ADC, blood flow, and APTw were all useful imaging biomarkers by which to predict glioma response to radiotherapy. The APTw signal was most promising for early response assessment in this model.

Keywords: APT imaging; glioma; multiparametric MRI; radiotherapy; response assessment.

Fig. 1.

(A–C) T₂w MRI features acquired at the different time points (preradiation and at 3, 6, and 9 days postradiation) for 3 different rats. (A) Eleven days post-implantation, 40 Gy; (B) 12 days post-implantation, 20 Gy; (C) 13 days post-implantation, without radiation. The irradiated tumors were still growing in size during the initial days postradiation. (D) Tumor volumes as measured by T₂w MRI at the different time points (preradiation and at 3, 6, and 9 d postradiation). The statistical significance of the difference compared with preradiation: *P < .05, **P < .01, ***P < .001.

Fig. 2.

Plots of Kaplan–Meier survival curves as a function of post-implantation days for 3 different groups (40 Gy, n = 6; 20 Gy, n = 4; 0 Gy, n = 6). The rats were observed daily until 90 days post-implantation. Both the 40-Gy and 20-Gy irradiation groups survived longer than the nonirradiated control group (P < .001 and P = .033, respectively).

Fig. 3.

Changes in T₂w, T₁, T₂, ADC, blood flow, MTR, and APTw images acquired at the different time points (preradiation and at 3, 6, and 9 d postradiation) for a rat with a U87MG glioma. The display windows are T₁ (0.5–2 s), T₂ (0–100 ms), ADC (0–2 × 10⁻⁹ m²/s), blood flow (0–200 mL/100 g/min), MTR at 2 kHz (0%–50% of the bulk water signal intensity), and APTw (−10% to 10% of the bulk water signal intensity).

Fig. 4.

Quantitative analysis of multiparametric MRI signal intensities at the different time points (preradiation and at 3, 6, 9, and 14 days postradiation) for the irradiated tumors (40 Gy) and the contralateral normal brain tissue (n = 10). The statistical significance of the difference compared with preradiation: *P < .05, **P < .01, ***P < .001, not marked = not significant.

Fig. 5.

Quantitative analysis of relative MRI signal intensities in the tumor, with respect to contralateral normal brain tissue, after therapy (preradiation and at 3, 6, 9, and 14 days postradiation) for the 40-Gy irradiation group (n = 10). The relative T₁, T₂, ADC, and APTw intensities were defined as tumor value – contralateral value, and the relative blood flow and MTR intensities were defined as tumor value/contralateral value. The statistical significance of the difference compared with preradiation: *P < .05, **P < .01, ***P < .001, not marked = not significant.

Fig. 6.

Quantitative analysis of multiparametric MRI signal intensities at the different time points (preradiation and at 3, 6, and 9 days postradiation) for 3 different groups (40 Gy, n = 10; 20 Gy, n = 4; 0 Gy, n = 6). The statistical significance of the difference compared with preradiation: *P < .05, **P < .01, ***P < .001, not marked = not significant.

Fig. 7.

Histogram analysis of T₂, T₁, ADC, blood flow, MTR at 2 kHz, and APTw intensities obtained at different time points (preradiation and at 3, 6, 9, and 14 days postradiation) for a U87MG glioma in a rat. It seems that the ADC histograms demonstrated a right shift, while the blood flow and APT histograms demonstrated a consistent left shift after therapy.

Fig. 8.

Comparison of the MRI features of the T₂w image, Gd-T₁w image, ADC map, blood flow map, and APTw map at the different time points with different doses postradiation. The display windows are ADC (0–2 × 10⁻⁹ m²/s), blood flow (0–200 mL/100 g/min), and APT (−10% to 10% of the bulk water signal intensity).

Fig. 9.

T₂w and APTw images (A and C) and high-magnification (40×) H&E-stained images (B and D) of a treated rat and an untreated rat. The H&E image (B) shows coagulative necrosis and vacuolation changes in the irradiated tumor at 3 days postradiation.