Children treated for brain tumors consistently demonstrate declines on global measures of cognitive functioning, including intellectual functioning, which are associated with academic failure, high unemployment rates and a reduced quality of life. Recent research suggests that impairments in specific areas of functioning including attention, working memory and processing speed may be more proximal contributors to these global declines. Improved specification of cognitive changes following treatment is crucial for identifying vulnerable neural pathways and developing targeted interventions. Working memory (the ability to maintain and manipulate information on-line) is an ideal system to investigate in this regard as it is a well defined ability (behaviorally and neuroanatomically) that supports many higher level cognitive skills. Further, working memory has been shown to depend on frontal brain areas that are protracted in development, with increases in cerebral white matter extending into the third decade of life. Given that children treated for brain tumors demonstrate a significant loss of white matter, in contrast to expected developmental maturation, working memory may be particularly vulnerable to treatment effects. The neurotransmitter dopamine is critically important for functions mediated by the prefrontal cortex. The Met polymorphism of the catechol O-methyltransferase (COMT) gene, which results in greater availability of prefrontal dopamine, is associated with better working memory performance in healthy children. Therefore, the COMT Met polymorphism may serve as a resiliency factor against the emergence of working memory deficits in children treated for brain tumors. In the proposed study, childhood brain tumor survivors, solid tumor controls (with no history of CNS-directed therapy) and sibling controls will complete laboratory measures of cognitive skills (e.g., working memory, recognition memory and IQ) while their parents complete a questionnaire assessing childhood executive functions. Buccal (cheek) samples will be gathered for DNA extraction.
Study aims i nclude: assessing working memory performance of childhood brain tumor survivors relative to solid tumor survivors and healthy siblings using novel laboratory measures (Specific Aim 1), investigating the relationship between polymorphisms of the COMT gene and working memory performance (Specific Aim 2) and evaluating the association between laboratory measures of working memory and parent report measures of child executive functioning (Specific Aim 3). It is hypothesized that: 1. childhood brain tumor survivors will perform worse than solid tumor and sibling controls on working memory tasks, 2. working memory task performance will correlate with IQ, 3. children with the COMT Met/Met genotype will perform better on working memory tasks and 4. laboratory working memory measures will correlate with parent report measures of executive functioning. The proposed research may assist in isolating the fundamental causes underlying cognitive deficits associated with cancer therapy and aid in the discovery of targets for behavioral and pharmacological interventions to improve cognitive function in cancer survivors.
Greater specification of cognitive changes following CNS-directed treatment for childhood cancer is imperative for isolating vulnerable neural pathways and developing targeted cognitive interventions. Identification of resiliency factors against the emergence of cognitive dysfunction can improve prognostication, guide selection of treatments that vary in neurotoxicity based on individualized cognitive risk and open the door for novel behavioral and pharmacological interventions.
