Heather M. Conklin, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): 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 include: 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. PUBLIC HEALTH RELEVANCE: 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. [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): Children treated with radiation therapy for brain tumors consistently demonstrate a decline in intellectual functioning that is associated with academic failure and reduced quality of life. Medulloblastoma is the most common malignant brain tumor in children and survival rates approach 80% with current multimodal therapy. With a growing survivor population, efforts to improve long-term cognitive outcomes become imperative. A primary goal of this research program is development of interventions that mitigate the impact of CNS-directed therapies on the quality of life of childhood cancer survivors. While efficacious, pharmacological and therapist- delivered interventions are limited by medical contraindications and availability of local providers. Recent research suggests impairments in attention and working memory (WM; online maintenance and manipulation of information) may be proximal contributors to intellectual declines among brain tumor survivors. A computer- based WM intervention has demonstrated efficacy with individuals with developmental and acquired attention disorders. Improvements have been achieved on measures of attention, WM and executive functions with benefits persisting months after training. Functional neuroimaging (fMRI) conducted before and after WM training suggests neuroplasticity for supporting brain systems. This intervention has recently been shown to be feasible and efficacious for childhood cancer survivors with evidence for associated brain-based changes. It is now crucial to determine whether we can preserve cognitive function by intervening prophylactically, before the emergence of late effects, and combine interventions to optimize outcomes. New research with children with chronic disease indicates aerobic exercise offers cognitive benefits. Further, animal models reveal exercise- related recovery following injury and suggest underlying brain mechanisms (e.g., new nerve cell formation). In the proposed study, we will recruit children treated for newly diagnosed medulloblastoma on a front-line protocol that includes a randomized exercise trial during radiation therapy. Immediately following treatment, we will randomly assign patients to a computerized WM intervention or a time and attention control group (generic social support). Both groups will complete pre- and post-intervention cognitive testing and fMRI. Study aims include: testing the efficacy of a prophylactically administered computerized WM intervention (Specific Aim 1), comparing the cognitive impact of a computerized WM intervention administered in conjunction with an aerobic exercise intervention (Specific Aim 2), and using fMRI to examine neuroplasticity associated with WM training (Specific Aim 3). It is hypothesized that: 1. participants randomized to the WM intervention will demonstrate less WM decline relative to controls, with benefits that are generalizable to higher-order cognitive skills and sustainable over time, 2. participants receiving both aerobic exercise and WM interventions will demonstrate better cognitive outcomes than participants receiving either intervention alone, and 3. participants randomized to the WM intervention will demonstrate meaningful changes in brain activation patterns after WM training.

PROJECT SUMMARY/ABSTRACT Children who receive radiation therapy for brain tumors are at significant risk for cognitive effects of their disease and treatment (e.g., problems with attention, memory and processing speed) that negatively impact quality of life, including reduced academic and social attainment. Low grade gliomas account for 30 to 50% of childhood brain tumors and have high survival rates, with progression-free survival rates approximately 80% on long-term follow-up. With a growing survivor population, efforts to improve long-term cognitive outcomes become imperative. A primary goal of this research program is development of interventions that mitigate the impact of CNS-directed therapies on the quality of life of childhood cancer survivors. The vascular hypothesis of radiation injury suggests that the mechanism of radiation-induced injury is similar to small vessel disease as seen with vascular dementia, prompting interest in treatments for vascular dementia. Randomized placebo- controlled trials have shown memantine (a drug that blocks NMDA receptors for the neurotransmitter glutamate) improves cognition in patients with mild to moderate vascular dementia without concerning side effects. Further, memantine during radiotherapy for brain metastases in adults has been shown to be well tolerated with less cognitive declines over time relative to placebo. Studies with children with Attention Deficit Hyperactivity Disorder or autism spectrum disorders have shown memantine is safe with evidence for improved cognition. Importantly, there are no published studies of memantine in children undergoing treatment for brain tumors. It has become of paramount importance to determine whether we can preserve cognitive function of children treated for cancer by intervening prophylactically, before the emergence of late effects. Accordingly, the specific aims of this study are: 1) To estimate the rate of participation, medication adherence and completion of cognitive assessments in a study of memantine used as a neuroprotective agent in children undergoing radiotherapy for low grade glioma; 2) To estimate the magnitude of change in neurobehavioral outcomes (cognitive, social, quality of life, neurologic) associated with memantine; and 3) To evaluate the frequency and nature of memantine side effects. In order to investigate these aims, we propose to use a randomized, double-blind, placebo-controlled design with children between 6 and 21 years of age scheduled to undergo cranial radiation therapy for a low grade glioma. Participants will be randomized to either memantine (20 mg/d) or a matching placebo. During the 12 week medication phase, participants will receive weekly phone calls to assess medication adherence and side effects. At baseline, 6 weeks (end of radiation therapy) and 12 weeks (end of the memantine medication phase) additional side effect monitoring will take place using laboratory values, physical examination and completion of an ECG. At the same three time points, and one year later, participants will complete laboratory measures of cognitive function and participate in neurologic exams. We will recruit participants until 30 have completed the 12 week assessment time point.