PROJECT SUMMARY Childhood acute lymphoblastic leukemia (ALL) was uniformly fatal prior to the 1960s. Survival rates today approach 95%, making ALL one of medicine's great success stories. As the number of survivors across the US has increased, the focus of research has shifted to life after cancer. Research in ALL survivors has highlighted problems in executive functions, representing mental functions governed by the frontal lobes. Most patients will be cured prior to entering kindergarten, meaning that these neurocognitive problems potentially create a lifetime burden. Indeed, research in long-term survivors of ALL show that neurocognitive difficulties affect scholastic and vocational success, creating a profound and long-lasting burden on quality of life. While survivorship issues are well-documented, research in young patients undergoing treatment is lagging. Our plan to assess neurodevelopmental changes in patients during treatment will help pinpoint the timing and extent of neurotoxic exposures in children treated for ALL, providing tangible opportunities to implement strategies of remediation and prevention. The overall objective of this proposal is to identify markers of altered neurocognitive development in ALL patients. We recently piloted a prospective study where young ALL patients completed neurocognitive evaluations and non-sedated neuroimaging on two occasions occurring at a 6-month interval. Preliminary outcomes highlighted the importance of evaluating growth trajectories in gaining insights into the etiology of neurocognitive morbidity. In our pilot study decrements in executive functions (EF) were observed. We also observed that frontal white matter growth was substantially slower in ALL patients relative to peers. And finally, increased concentrations of neurofilament light, which is a marker of axonal damage, was associated with a slower rate of change in frontal white matter volume in ALL patients. Based on our groundwork results, we propose to evaluate early markers of abnormal neurodevelopmental trajectories in ALL patients undergoing active treatment. We will employ a longitudinal design where newly diagnosed ALL patients between the ages of 3-6 years old (n=30) will be compared to controls (n=30). Leveraging the power of a within-subject design, participants will be assessed on three occasions occurring at major treatment milestones (180 observations total). Using validated cognitive neuroscience paradigms, we will identify changes in discrete aspects of executive function for aim 1. Non-sedated structural and functional neuroimaging will be used for the work proposed under aim 2 to evaluate changes in brain volume, connectivity, and metabolism. Lastly, we will utilize ultrasensitive digital assays for quantifying neurochemical markers of brain injury in ALL patients. Results from this work will have impactful implications for understanding early neurodevelopmental changes in children undergoing treatment for ALL, providin...