Primary brain tumors are the most common solid tumors and the leading cause of death from childhood cancer. In the era of molecular targeted therapy, greater than 60% of children with brain tumors are expected to become long-term survivors. Survival however is not without morbidity, with the majority of patients suffering from neurocognitive deficits that directly impact their educational attainment and work employment. Despite molecular tailored treatment regimens, radiation therapy remains a mainstay of cancer treatment in children with brain tumors and is considered the single most important risk factor for neurocognitive dysfunction. Radiation therapy leads to cellular injury that accelerates iron deposition in the brain. MR imaging with quantitative susceptibility mapping (QSM) is changing the landscape of neurodegenerative diseases such as Parkinson’s, where iron has been recently identified as a biomarker for disease burden as well as a target for disease therapy in the form of chelation therapy. Similar to patients with neurodegenerative disorders, our preliminary MR imaging data with QSM demonstrates accelerated iron deposition in our patients with brain tumors that received cranial radiation therapy (CRT). The purpose of this pilot study is to collect novel imaging and neuropsychological data in pediatric brain tumor survivors, exploring the continuum of short and long term effects of radiation therapy in order to investigate the direct association between radiation injury to the brain, iron accumulation and cognitive deficits. Our central hypothesis is that CRT in pediatric brain tumor survivors results in higher accumulation of iron in the brain (as quantified in vivo by QSM) as compared to patients without history of CRT, with increased brain iron independently correlating with worsening neurocognitive function. In this context, we advance the following specific aims: Specific Aim 1: To determine if cranial radiation therapy affects iron accumulation in the brain in a cross- sectional cohort of pediatric patients with posterior fossa tumors. Specific Aim 2: To explore the correlation between iron deposition and neuropsychological dysfunction in children with posterior fossa tumors. Currently, there is a disconnect between neuro-oncologists and their priority of curing the disease and prolonging survival versus neuropsychologists and their attempts of identifying and managing sequel of radiation induced neurocognitive deficits in survivors. Should this exploratory study provide evidence for the direct association between radiation injury to the brain, iron accumulation and cognitive dysfunction, this disconnect can potentially be bridged. This will ultimately lead to early identification of high-risk patients with radiation-induced injury and the implementation of risk-adaptive cancer therapy as well as the exploration of neuro-protective treatment options, such as iron chelation therapy, to reduce neurocognitive deficits in these patients throughout their lifespan.

Project Narrative This exploratory study is intended to investigate, for the first time, the link between iron deposition, cranial radiation therapy, and neurocognitive deficits in pediatric brain tumor survivors using a quantifiable imaging biomarker. This will help improve our understanding of the underlying timeline and mechanisms of radiation injury to the brain and inform neuro-protective treatments that will reduce neurocognitive deficits throughout the lifespan of the survivors.