Between 40-70% of children treated for acute lymphoblastic leukemia (ALL) on contemporary protocols exhibit measurable deficits in cognitive functioning, which negatively impacts school and occupational performance, and diminishes quality of life. However, the specific processing deficits contributing to poor cognitive functioning in survivors of childhood ALL and the implications for ongoing brain development are poorly understood. The goal of this project is to characterize treatment-related effects on brain functions (Aim 1), identify abnormal patterns of neural connectivity (Aim 2), and assess chronic effects of chemotherapy treatment on the development of cognitive skills (Aim 3) in childhood survivors. We achieve these aims by using a combination of behavioral, electrophysiological, and neuroimaging measures to demonstrate effects on neurocognitive function, brain activity and brain development following chemotherapy compared to healthy, matched controls. Our study is designed to identify the relative contributions of sensory processes, memory, and attentional mechanisms, and cortical-maturation delays to poor performance on standardized tests of cognition function. Our approach will lead to the development of a powerful set of tools for identifying children with persistent treatment-related changes in cognitive functioning due to exposure to toxic therapy. Results will differentiate the level at which processing deficits occur (Aims 1 and 2), and longitudinally assess cognitive development (Aim 3) and the associated development in brain function and pathways in survivors of childhood ALL. This contribution is significant because defining the loci of neurocognitive dysfunction caused by ALL treatment would guide the development of novel preventive, treatment, and intervention strategies.
This project has relevance for public health because results will provide a more precise understanding of the long-term effects of chemotherapy on the developing brain, and shed light on the pathophysiology of chemotherapy-induced cognitive dysfunction, thus laying the foundation to improve the therapeutic index of cancer therapy by guiding clinical trials of protective interventions aimed at reducing the permanent burdens of curative treatment for leukemia.
