Children surviving some types of cancer, particularly acute lymphoblastic leukemia (ALL) and brain tumors, have an increased incidence of learning impairments compared to their healthy peers in the general population. These impairments, for which there is no known effective treatment, are of sufficient severity to inhibit normal academic achievement, vocational attainment, and quality of life. Previous investigations have suggested a model in which treatment-induced lesions of the brain, especially in the white matter, are an underlying cause of learning difficulties that are frequently manifested as deficits in the ability to sustain attention. The goal of this research proposal is to test the validity of this model by defining the neuroanatomic substrates of problems with attention and learning and by assessing the behavioral response of these problems to pharmacological intervention. To accomplish this goal, quantitative magnetic resonance imaging (qMRI) of the brain and neuropsychological testing will be conducted on 625 participating children treated for ALL or malignant brain tumors at 3 pediatric cancer centers. It is hypothesized that volumes of normal white matter in patients will be: a) significantly reduced compared to healthy peers, b) directly associated with the intensity of their central nervous system treatment, and c) positively correlated with their performance on measures of sustained attention and learning. A second study hypothesis is that methylphenidate will be effective in reducing their problems with attention and learning. This hypothesis will be tested with 200 children selected from the larger screened sample on the basis of objective problems with sustained attention and learning with regard to: (a) immediate (1-1/2 hr) behavioral benefits in our laboratory and (b) short-term (3 week) benefits at home and school in randomized, placebo-controlled, crossover designs, and then (c) long-term (12 month) maintenance benefits at home and school. The results of these studies will have a potentially important impact on childhood cancer by reducing the cognitive morbidities of cancer and cancer treatment and by furthering our knowledge of their biological basis.
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