Project Summary/Abstract: Whole brain synaptic density imaging with quantitative positron emission tomography (PET) has demonstrated critical insights into understanding of neurodegenerative disorders and epilepsy, especially in the setting of normal anatomical MRI. We propose to use quantitative whole brain PET with a novel synaptic density tracer to characterize the synaptic density changes in the setting of targeted radiation therapy in rodents and to correlate it to cognitive changes that occur after radiation therapy. While radiation therapy is a life-saving standard of care for treatment of central nervous system (CNS) malignancies in both adults and children, cognitive decline is one of the major complications and has been tied to multifactorial mechanism which includes loss of synapses, white matter damage, endothelial cell damage, and activation of neuroinflammatory markers within the hippocampus and pre-frontal cortex. Hippocampal sparing radiation therapy is the leading approach to preserve cognitive function in patients requiring radiation therapy. Unfortunately, even after hippocampal sparing radiation, over 50% of patients develop debilitating cognitive decline. With increase in long term survival of patients with CNS malignancies, there is a critical need to understand the mechanisms behind radiation induced brain injury, so that therapies can be targeted to prevent post-radiation cognitive decline. Currently there are no established drugs that prevent or treat the sequelae of radiation, nor are there biomarkers to monitor cellular damage. Availability of these could be used to modify treatment protocols prior to the development of severe cognitive decline. Characterization of whole brain dynamic changes in synapses and how they are related to white matter damage have not been evaluated up to now, because tools to study whole brain synaptic density have not been readily available. To characterize the mechanisms behind radiation induced cognitive decline, we will use a novel PET tracer that has been established to measure synaptic density and quantitative PET modeling for quantification of synaptic density in different regions of the human brain. We assembled a team of experts in fields of quantitative PET, rodent quantitative MRI, rodent radiation therapy, rodent neuropathology, and cognitive assessment to determine the time course of synaptic density changes in different regions of the brain and how it relates to pathological assessment of synaptic density, white matter damage, and neuroinflammation. The short term goal of this project is to characterize the hippocampal and extra-hippocampal synaptic density changes in rats after targeted half-brain radiation. The long term goal is to use this model to characterize the molecular mechanisms of radiation therapy induced CNS damage in human patients that must undergo radiation treatments for brain tumors. Completion of this project will characterize a novel non-invasive biomarker of ...