Working Memory Performance among Childhood Brain Tumor Survivors

描述(由申请人提供)：接受脑瘤治疗的儿童在包括智力功能在内的全球认知功能指标上持续下降，这与学业失败、高失业率和生活质量下降有关。最近的研究表明，包括注意力、工作记忆和处理速度在内的特定功能领域的损害可能是导致这些全球衰退的更接近的因素。改善治疗后认知变化的规范对于识别脆弱的神经通路和开发有针对性的干预措施至关重要。工作记忆(在线维护和操纵信息的能力)是研究这方面的理想系统，因为它是一种定义明确的能力(行为和神经解剖学)，支持许多更高水平的认知技能。此外，工作记忆已被证明依赖于大脑额叶区域的长期发育，大脑白质的增加延续到生命的第三个十年。鉴于接受脑瘤治疗的儿童表现出脑白质的显著丧失，与预期的发育成熟形成对比，工作记忆可能特别容易受到治疗效果的影响。神经递质多巴胺对前额叶皮质调节的功能至关重要。儿茶酚O-甲基转移酶(COMT)基因的Met多态导致前额叶多巴胺的更高利用率，与健康儿童更好的工作记忆表现有关。因此，COMT Met多态可能是脑肿瘤治疗儿童出现工作记忆缺陷的弹性因子。在这项拟议的研究中，儿童脑瘤幸存者、实体肿瘤对照组(没有中枢神经系统指导治疗的病史)和兄弟姐妹对照组将完成认知技能的实验室测量(例如，工作记忆、识别记忆和智商)，而他们的父母则完成一份评估儿童执行功能的问卷。口腔(脸颊)样本将被采集用于DNA提取。研究目标包括：使用新的实验室测量方法(特定目标1)评估儿童脑瘤幸存者相对于实体肿瘤幸存者和健康兄弟姐妹的工作记忆表现(特定目标3)，调查COMT基因多态与工作记忆表现之间的关系(特定目标2)，以及评估实验室工作记忆测量与儿童执行功能家长报告测量之间的关系(特定目标3)。假设：1.儿童脑瘤幸存者在工作记忆任务上的表现比实体瘤和兄弟姐妹对照差，2.工作记忆任务表现与智商相关，3.COMT Met/Met基因儿童在工作记忆任务上表现更好，4.实验室工作记忆测量与父母报告的执行功能测量相关。这项拟议的研究可能有助于分离与癌症治疗相关的认知缺陷的根本原因，并有助于发现行为和药物干预的目标，以改善癌症幸存者的认知功能。公共卫生相关性：对于分离脆弱的神经通路和开发有针对性的认知干预措施，更详细地说明儿童癌症中枢神经系统治疗后的认知变化是必要的。识别针对认知功能障碍出现的弹性因素可以改善预后，根据个性化的认知风险指导神经毒性不同的治疗方法的选择，并为新的行为和药物干预打开大门。

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.