Changes In Imaging And Cognition In Juveniles Rats After Whole Brain Irradiation

Publication date: Available online 16 June 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Robert J. Brown, Brandon J. Jun, Jesse D. Cushman, Christine Nguyen, Adam H. Beighley, Johnny Blanchard, Kei Iwamoto, Dorthe Schaue, Neil G. Harris, James D. Jentsch, Stefan Bluml, William H. McBride
PurposePediatric cancer survivors treated with whole brain irradiation (WBI) develop long-term cognitive deficits and morbidity 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 (DTI) and magnetic resonance spectroscopy (MRS) during brain development.MethodsJuvenile Fischer rats received clinically relevant fractionated doses of WBI, or a high dose exposure. DTI and MRS were performed at the time of WBI and during the subacute (3-mo) and late (6-mo) phases, prior to behavioral testing.ResultsFractional anisotropy (FA) 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 FA, 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.ConclusionsThe developing brains of juvenile rats given clinically relevant fractionated doses of WBI demonstrate 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 mitigation approaches.

Teaser

Few animal models of whole brain irradiation take into account young age and dose fractionation. We present both imaging and behavioral data following clinically relevant fractionated whole brain irradiation in juvenile rats pathomimetic to those observed in survivors of pediatric brain tumors including development of early prefrontal dysfunction and late memory deficits that correlate with developmental imaging abnormalities.


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