Significant neurobehavioral sequelae of radiotherapy (RT) in children treated for brain tumors is well-documented and is of increasing concern as larger numbers of such children become long-term survivors. Research on long-term outcomes has promoted the development of RT techniques and protocols that attempt to reduce this morbidity. Further understanding of RT late-effects, though, requires improvements in how we characterized radiation delivered to the brain. Recent technical advances in radiation ontology that permit detailed examination of dose heterogeneity throughout the brain offer new possibilities for improving our models of outcome. One index that shows considerable promise is Integral Biologically effective Dose (IBED). IBED combines numerous RT parameters (dose, volume, fractionation, biological effect) into a Single index for the entire brain or for designated volumes/structures. In this proposal we describe a novel approach to studying outcome that improves upon existing research in three ways: (a) the use of IBED as a index of radiation insult, (b) an improved neurobehavioral measurement strategy that focuses on three crucial constructs (Attention, Processing Speed, and Working Memory), and (e) the use of sophisticated, multimodal imaging techniques (MR Volumetrics, Spectroscopy, and Diffusion Imaging) to measure late-effects on brain composition. This prospective study will be conducted at two sites (Cincinnati and Columbus) enrolling and following children for up to four yeas who have been treated for brain tumors. It will address neurobehavioral imaging changes for participants treated with RT compared to those treated without RT (Specific Aim 1), IBED as a predictor of neurobehavioral and imaging changes over time (Specific Aims 2 & 3), and the relationship between neurobehavioral and imaging changes (Specific Aim 4). The results of this study promise to improve our knowledge and prediction of radiation-related late-effects, which in turn will guide further improvements in RT techniques. It will also provide important information about the development of vulnerable neurobehavioral functions, how they might be protected/preserved, and where to focus early interventions to limit functional morbidity.
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