Laser speckle flowgraphy as early indicator of microvasculopathy in radiation-induced cognitive decline

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PROJECT SUMMARY/ABSTRACT This supplemental proposal is an extension of our parent R01 to identify the mediators of radiation-induced vision loss and to develop effective mechanism-based therapies. In the parent project, we are investigating the time course, mechanism and mitigation of retinal microvasculopathy as a driver of radiation-induced neural degeneration and functional loss to facilitate earlier detection, prevention and treatment of radiation-associated retinal damage. Here, we propose that radiation therapy (RT)-induced dementia is driven by the same microvascular processes and molecular mechanisms as within the retina and that retinal laser speckle flowgraphy (LSFG) can be used as an early detection strategy. Importantly, Vascular Cognitive Impairment/Dementia is listed under “Related Dementias” under the “NIH Coding definitions for Alzheimer's disease and its related Dementias”. Thus, the research proposed herein is directly relevant to NOT-AG-20-034. Radiation-induced cognitive impairment occurs in up to 90% of adult survivors of brain tumors. Many adverse side effects of RT have been attributed to damage of microvascular endothelium that is initiated by excessive production of reactive oxygen species and mitochondrial injury during RT and leads to endothelial dysfunction and loss of capillaries over a period of years. However, similar to vision loss after RT, the concept that microangiopathy is a driver of radiation-related dementia has not been conclusively established. This is in part because early indicators of microvascular endothelial dysfunction that predict later cognitive decline have yet to be established. In our parent R01, we are using laser speckle flowgraphy (LSFG) as a novel non- invasive modality to detect early RT-induced microangiopathy. Here, we propose to deploy the experimental approaches and genetic models of our parent R01 to analyze cerebral structure and function. The objectives of the proposed project are to facilitate earlier detection and treatment of RT-associated dementia. Specifically, we expect to develop non-invasive tests in mice for the early detection of RT-induced injury based on altered blood flow and determine whether early endothelial dysfunction is predictive of a subsequent reduction in capillary density and neuronal dysfunction. We also anticipate identifying the molecular mechanism of radiation-induced endothelial dysfunction and its impact on cognitive impairment. As in the parent R01, the application of LSFG will enable us to identify early “radiation endotheliopathy” before capillary loss, and to test molecular mechanisms to ultimately develop novel therapies. Our central hypothesis is that post-radiation endothelial dysfunction is driven by mitochondrial oxidative stress and is predictive of the severity of subsequent capillary dropout and neuronal damage. Capitalizing on our imaging protocols, we will (1) establish whether early impairment of the microvascular endothelial function predicts microvessel dropout and neuronal dysfunction after RT and (2) test whether selective inhibition of mitoROS production in endothelium prevents the early reduction of blood flow and loss of capillaries after RT.