Working Memory Performance among Childhood Brain Tumor Survivors

儿童脑肿瘤幸存者的工作记忆表现

• 批准号: 7522371
• 负责人: HEATHER M CONKLIN
• 金额: $ 22.68万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7522371
• 关键词: Academic achievement; Address; Alleles; Area; Attention; Behavior; Behavioral; Brain; Brain Neoplasms; Brain region; Cancer Survivor; Catechol O-Methyltransferase; Cerebrum; Cheek structure; Child; Childhood; Childhood Brain Neoplasm; Cognitive; Cognitive deficits; Conformal Radiotherapy; Control Groups; Controlled Study; DNA; Development; Dopamine; Equipment and supply inventories; Evaluation; Failure; Functional disorder; Genetic Polymorphism; Genotype; Goals; Government; Grant; Impaired cognition; Impairment; Individual; Intervention; Laboratories; Life; Longitudinal Studies; Malignant Childhood Neoplasm; Measures; Mediating; Memory; Memory impairment; Methyltransferase Gene; Neural Pathways; Neurotransmitters; Numbers; Outcome; Parents; Participant; Patients; Performance; Persons; Prefrontal Cortex; Process; Public Health; Purpose; Quality of life; Questionnaires; Rate; Recording of previous events; Relative (related person); Reporting; Research; Risk; Saint Jude Children' s Research Hospital; Sampling; Secondary to; Selection for Treatments; Short-Term Memory; Siblings; Solid Neoplasm; Survivors; System; Task Performances; Unemployment; base; cancer therapy; cognitive change; cognitive function; computerized; executive function; improved; memory process; memory recognition; methionylmethionine; neurotoxicity; novel; processing speed; programs; skills; treatment effect; valylvaline; white matter

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.

描述（由申请人提供）：接受脑肿瘤治疗的儿童的认知功能（包括智力功能）的整体指标持续下降，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，注意力、工作记忆和处理速度等特定功能领域的损伤可能是导致这些全球衰退的更直接原因。改善治疗后认知变化的规范对于识别脆弱的神经通路和制定有针对性的干预措施至关重要。工作记忆（在线维护和操作信息的能力）是在这方面进行研究的理想系统，因为它是一种明确定义的能力（行为学和神经解剖学），支持许多更高水平的认知技能。此外，工作记忆已被证明取决于长期发育的额脑区域，大脑白质的增加会持续到生命的第三个十年。鉴于接受脑肿瘤治疗的儿童表现出白质的显着损失，与预期的发育成熟相比，工作记忆可能特别容易受到治疗效果的影响。神经递质多巴胺对于前额皮质介导的功能至关重要。儿茶酚 O-甲基转移酶 (COMT) 基因的 Met 多态性导致前额叶多巴胺的可用性更高，与健康儿童更好的工作记忆表现相关。因此，COMT Met 多态性可能作为针对脑肿瘤治疗儿童出现工作记忆缺陷的弹性因素。在拟议的研究中，儿童脑肿瘤幸存者、实体瘤对照（没有中枢神经系统定向治疗史）和兄弟姐妹对照将完成认知技能（例如工作记忆、识别记忆和智商）的实验室测量，而他们的父母则完成问卷评估儿童执行功能。将收集颊（脸颊）样本进行 DNA 提取。研究目的包括：使用新颖的实验室测量方法评估儿童脑肿瘤幸存者相对于实体瘤幸存者和健康兄弟姐妹的工作记忆表现（具体目标 1），研究 COMT 基因多态性与工作记忆表现之间的关系（具体目标 2）以及评估实验室工作记忆测量与家长报告的儿童执行功能测量之间的关联（具体目标 3）。假设： 1. 儿童脑肿瘤幸存者在工作记忆任务上的表现将比实体瘤和兄弟姐妹对照差， 2. 工作记忆任务的表现将与智商相关， 3. 具有 COMT Met/Met 基因型的儿童将在以下方面表现更好4. 工作记忆任务和实验室工作记忆测量将与家长报告的执行功能测量相关联。拟议的研究可能有助于找出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：对于儿童癌症中枢神经系统定向治疗后的认知变化进行更详细的说明对于隔离脆弱的神经通路和制定有针对性的认知干预措施至关重要。识别针对认知功能障碍出现的弹性因素可以改善预后，指导根据个体认知风险选择不同神经毒性的治疗方法，并为新的行为和药物干预措施打开大门。