University of California, San Francisco San Francisco, CA, United States
A. Oyewole1, J. Yang2, M. Lee2, Y. Sei2, J. Sims2, P. Bisoyi1, K. Nakamura2, and J. L. Nakamura3; 1University of California, San Francisco, San Francisco, CA, 2Gladstone Institute for Neurological Disease, San Francisco, CA, 3Department of Radiation Oncology, University of California San Francisco, San Francisco, CA
Purpose/Objective(s): Cognitive changes are a serious complication that can occur after brain radiotherapy. Not all patients develop this complication and it is challenging to estimate precisely the risks and their magnitude. Nonetheless, there is a need to better understand which individuals are more susceptible to develop strategies to preserve their function. The apolipoprotein E type 4 allele (APOEe4) APOE4 is the most prevalent genetic risk factor for Alzheimer Disease. Limited clinical data suggest that APOE4 is associated with worse cognitive function after whole brain radiotherapy, but do not address whether APOE genotype increases the incidence or severity of cognitive decline from brain radiotherapy. We hypothesized that APOE genotype influences memory function after a subtherapeutic dose of whole brain irradiation in male and female mice. Materials/
Methods: Age-matched female and male mice engineered with either human APOE3 or APOE4 gene knocked-in were randomized to no treatment or whole brain irradiation (0 Gy or 5 Gy x 2), then evaluated with longitudinal neurobehavioral tests of learning, memory, pain threshold and anxiety. We performed immunohistochemical analyses of mouse brain sections at 1 month and at 4 months post-radiation to quantify extracellular amyloid beta plaques and other neuropathologic hallmarks associated with neurodegeneration. Results: Neurobehavioral testing identified significant sex and genotype-dependent changes in memory and anxiety measures developing longitudinally in irradiated mice. At baseline (unirradiated), APOE4 mice (male and female) performed worse on multiple memory measures. However in irradiated mice, both sex and genotype each independently impacted multiple neurobehavioral function tests and also interacted with each other to significantly influence the timing and magnitude of changes in memory function. ApoE4 significantly impacted the toxicity of radiation in a sex-dependent manner. Neuropathologic analyses including amyloid beta plaque deposition and ApoE levels are ongoing. Conclusion: After brain irradiation of relatively moderate dose, neurobehavioral performance including memory are impacted in a genotype and sex-dependent manner and dynamically over time. In addition to suggesting important sex-dependent differences in memory vulnerability, these data point to new opportunities for personalizing care for patients receiving brain irradiation. Memory preservation after brain irradiation may be more accurately prognosticated to identify at-risk individuals, develop more refined radiotherapeutic strategies and windows of opportunity for mitigative approaches. Prospective clinical trials are needed to better define these relationships, which could influence dosimetry constraints and radiotherapy approaches.
