Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer with approximately 3,500 new cases each year in the United States. When cancer treatment specifically targets the immature brain, as is the case for children with ALL, treatment efficacy must be balanced against the potential for chronic neurotoxicity. With estimated three-year event-free survival for children with ALL now at approximately 90 percent, increasing attention is directed toward minimizing late neurotoxicity in this particularly vulnerable population. The most common method of CNS prophylaxis for pediatric ALL includes high-dose methotrexate (HDMTX). However, several studies have shown a significant association between HDMTX and neurotoxicity. Thus, treatment-induced neurotoxicity is an important and clinically relevant problem in pediatric oncology. Our own studies have confirmed that leukoencephalopathy can be observed in as many as 75 percent of patients during treatment with HDMTX, even those without seizures or other symptoms of acute neurotoxicity. Our research builds on the hypothesis that leukoencephalopathy resulting from HDMTX spans a continuum of severity that can be probed reliably using noninvasive MR technology. More than 300 children will be treated for ALL on a five-year protocol at our institution with therapy that includes five courses of either 2.5 or 5.0 g/m2 of HDMTX during the induction and consolidation phases. The proposed project will be the first to use quantitative imaging-based measures (hybrid neural network segmentation; T1 and T2 relaxation times) to investigate treatment-induced leukoencephalopathy during therapy in a group of subjects sufficiently large to adequately test the following hypotheses: 1) that leukoencephalopathy early in therapy is predictive of later white matter changes; 2) that leukoencephalopathy during therapy is proportionate to exposure to HDMTX; and 3) that leukoencephalopathy during therapy is predictive of treatment-induced neurocognitive outcome will have a direct impact on the design of future clinical trials for pediatric ALL. The ultimate goal is to use these quantitative MR imaging measures to detect early therapy-induced neurotoxicity, which is potentially reversible through therapy adjustments of other neurobehavioral and pharmacological interventions for individual children.