Water diffusion in a rat glioma during ganciclovir-thymidine kinase gene therapy-induced programmed cell death in vivo:: Correlation with cell density

Purpose: To study the characteristics of diffusion magnetic resonance imaging (MRI) contrast in a rat brain BT4C glioma during progression of ganciclovir (GCV)-thymidine kinase gene therapy-induced programmed cell death (PCD) in vivo. Materials and Methods: The trace of the diffusion tensor (D-av = 1/3TraceD), T-2, and spin density were determined by MRI and the apparent diffusion coefficient (ADC) of water by diffusion nuclear MR (NMR) spectroscopy using largely varying b values and diffusion times (t(D)) at 4.7 T. Cell count and apoptotic cells were quantified by histological means. Results: Decline in cell count was strongly associated with increase in both D, and T-2. Spin density ratio between tumor and contralateral parietal cortex increased with a very similar time course as D-av and T-2, indicating net water gain into the eradicating tumor. Diffusion spectroscopy showed a nonmonoexponential signal decay at all tD values ranging from 14-192 msec. During PCD, the ADC of the component yielding fast diffusion coefficient (D-1), as acquired with t(D) greater than or equal to 47 msec, increased with kinetics similar to those of D-av (t(D) = 4.8 msec). The fractional size of D-1 increased by 10% to 15% throughout the entire t(D) range. Apparent water residence time of the slow diffusion component, D-2, shortened from a value of 38.3 +/- 1.7 msec on day 0 to 33.4 +/- 0.5 msec by day 8. Conclusion: The present results show that reduced cell density and increased water content, leading to altered water microenvironment, are associated with increased water diffusion coefficient in eradicating gliomas as a result of PCD.