RB-01A PRECLINICAL MODEL OF TRANSIENT EARLY-DELAYED RADIATION EFFECTS FOLLOWING WHOLE BRAIN IRRADIATION IN THE ADULT RAT

BACKGROUND: Whole brain radiotherapy is a common for metastatic brain cancer. While it prolongs survival, it causes transient early-delayed cognitive deficits termed “beamo” brain. We describe a dose-escalation study that demonstrates a potential preclinical animal model of this clinical phenomenon. METHODS: 3-month old Fisher rats were given a single fraction of 0, 10, 20, or 30G Gray (Gy) whole brain irradiation. The open-field exploration task and the elevated plus maze were performed at 4 months post-irradiation. Declarative memory was tested by novel object recognition at 4- and 7-months post-irradiation. Magnetic resonance imaging, including diffusion tensor imaging (DTI) and spectroscopy (MRS), was obtained at baseline, 4-, and 7-months post-irradiation in controls, 20Gy and 30Gy groups. RESULTS: At 4 months post-irradiation, no differences were found between the groups in either the open-field exploration or the elevated plus maze. There was no difference in novel object recognition between 10Gy and sham controls at 4 months post-irradiation. However, both 20Gy (p = 0.02) and 30Gy (p < 0.02) animals demonstrated memory deficits at this early time-point compared to controls. At 7 months post-irradiation, the 20Gy group performed similar to controls and 10Gy; however, the 30Gy animals (p = 0.01) persisted in their memory impairment. MRS demonstrated increased choline in the corpus callosum in 20Gy (p = 0.08) and in 30Gy (p = 0.01) at 4 months, but normalized by 7 months in all groups. Fractional anisotropy was significantly decreased in the hippocampus of 20Gy (p = 0.02) and 30Gy (p = 0.0002) animals by 7 months, but not before. CONCLUSION: 3-month old rats given 20Gy single whole brain radiation demonstrated transient cognitive impairment similar to that observed in adult patients receiving whole brain irradiation for metastatic disease and may correlate with increased levels of choline in the hippocampus. This may be a promising model in which to test potential therapies for “beamo” brain.