The Impact of Focal Radiation Damage on Whole-brain Development in the Mouse

Radiotherapy is a critical component in treating pediatric brain tumors such as medulloblastoma. Although 5-year survival rates are rising, cognitive late eďŹ ects are frequently seen in survivors that received whole-brain radiotherapy. Importantly, white matter (WM) volumes of survivors are often reduced after receiving radiotherapy. Impairments in both WM and neurogenesis have been implicated in late side eďŹ ects. This work involved the image-guided focal irradiation of WM (anterior commissure or AC), neuronal tissue (olfactory bulbs or OBs), and neurogenesis (subventricular zone or SVZ) in the infant mouse brain and subsequent characterization of developmental outcomes in adulthood using MRI. The results indicate that direct radiation targeting of WM may not be the cause of WM hypersensitivity in development. Importantly, the growth of WM (ie. AC) may depend on radiation targeting of other structures. Overall, this work shows that indirect radiation targeting may be as important in structural outcomes as direct radiation targeting.M.Sc

Altered brain morphology after focal radiation reveals impact of off-target effects: implications for white matter development and neurogenesis

Background: Children with brain tumors treated with cranial radiation therapy (RT) often exhibit cognitive late effects, commonly associated with reduced white matter (WM) volume and decreased neurogenesis. The impact of radiation damage in particular regions or tissues on brain development as a whole has not been elucidated. Methods: We delivered whole-brain or focal radiation (8 Gy single dose) to infant mice. Focal treatments targeted white matter (anterior commissure), neuronal (olfactory bulbs), or neurogenic (subventricular zone) regions. High-resolution ex vivo MRI was used to assess radiation-induced volume differences. Immunohistochemistry for myelin basic protein and doublecortin was performed to assess associated cellular changes within white matter and related to neurogenesis, respectively. Results: Both whole-brain and focal RT in infancy resulted in volume deficits in young adulthood, with whole-brain RT resulting in the largest deficits. RT of the anterior commissure, surprisingly, showed no impact on its volume or on brain development as a whole. In contrast, RT of the olfactory bulbs resulted in off-target volume reduction in the anterior commissure and decreased subventricular zone neurogenesis. RT of the subventricular zone likewise produced volume deficits in both the olfactory bulbs and the anterior commissure. Similar off-target effects were found in the corpus callosum and parietal cortex. Conclusions: Our results demonstrate that radiation damage locally can have important off-target consequences for brain development. These data suggest that WM may be less radiosensitive than volume change alone would indicate and have implications for region-sparing radiation treatments aimed at reducing cognitive late effects.This work was supported by the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, and the Ontario Institute for Cancer Research through funding provided by the government of Ontario