Purpose In pediatric cancer survivors treated with whole-brain irradiation (WBI), long-term cognitive deficits and morbidity develop that are poorly understood and for which there is no treatment. We describe similar cognitive defects in juvenile WBI rats and correlate them with alterations in diffusion tensor imaging and magnetic resonance spectroscopy (MRS) during brain development. Methods and Materials Juvenile Fischer rats received clinically relevant fractionated doses of WBI or a high-dose exposure. Diffusion tensor imaging and MRS were performed at the time of WBI and during the subacute (3-month) and late (6-month) phases, before behavioral testing. Results Fractional anisotropy in the splenium of the corpus callosum increased steadily over the study period, reflecting brain development. WBI did not alter the subacute response, but thereafter there was no further increase in fractional anisotropy, especially in the high-dose group. Similarly, the ratios of various MRS metabolites to creatine increased over the study period, and in general, the most significant changes after WBI were during the late phase and with the higher dose. The most dramatic changes observed were in glutamine-creatine ratios that failed to increase normally between 3 and 6 months after either radiation dose. WBI did not affect the ambulatory response to novel open field testing in the subacute phase, but locomotor habituation was impaired and anxiety-like behaviors increased. As for cognitive measures, the most dramatic impairments were in novel object recognition late after either dose of WBI. Conclusions The developing brains of juvenile rats given clinically relevant fractionated doses of WBI show few abnormalities in the subacute phase but marked late cognitive alterations that may be linked with perturbed MRS signals measured in the corpus callosum. This pathomimetic phenotype of clinically relevant cranial irradiation effects may be useful for modeling, mechanistic evaluations, and testing of mitigation approaches.

No abstract

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 ¼ 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 ¼ 0.01) persisted in their memory impairment. MRS demonstrated increased choline in the corpus callosum in 20Gy (p ¼ 0.08) and in 30Gy (p ¼ 0.01) at 4 months, but normalized by 7 months in all groups. Fractional anisotropy was significantly decreased in the hippocampus of 20Gy (p ¼ 0.02) and 30Gy (p ¼ 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.