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在认知功能（包括智力功能）的总体指标上一直表现出下降，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障碍可能是导致这些全球性下降的更近端因素。改善治疗后认知变化的规范对于识别脆弱的神经通路和制定有针对性的干预措施至关重要。工作记忆（在线维护和处理信息的能力）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），支持许多更高层次的认知技能。此外，工作记忆已经被证明依赖于额叶脑区，这些脑区在发育中被延长，大脑白色物质的增加一直延伸到生命的第三个十年。考虑到接受脑肿瘤治疗的儿童表现出白色物质的显著损失，与预期的发育成熟相反，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层介导的功能至关重要。儿茶酚O-甲基转移酶（COMT）基因的Met多态性导致前额多巴胺的更大可用性，与健康儿童更好的工作记忆表现相关。因此，COMT Met多态性可能是一个弹性因素，可以防止脑肿瘤治疗儿童出现工作记忆缺陷。在拟议的研究中，儿童脑肿瘤幸存者、实体瘤对照（无CNS导向治疗史）和兄弟姐妹对照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），同时他们的父母完成一份评估儿童执行功能的问卷。将采集颊部（脸颊）样本用于DNA提取。研究目的包括：使用新的实验室测量（具体目标1）评估儿童期脑肿瘤幸存者相对于实体瘤幸存者和健康同胞的工作记忆表现，调查COMT基因多态性与工作记忆表现之间的关系（具体目标2），以及评估工作记忆的实验室测量与儿童执行功能的父母报告测量之间的关联（具体目标3）。假设：1.儿童期脑肿瘤幸存者在工作记忆任务中的表现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，3。具有COMT Met/Met基因型的儿童在工作记忆任务中表现更好，实验室工作记忆测量将与执行功能的父母报告测量相关。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理干预的目标，以改善癌症幸存者的认知功能。公共卫生相关性：CNS定向治疗儿童癌症后更详细的认知变化对于隔离脆弱的神经通路和开发有针对性的认知干预措施至关重要。针对认知功能障碍的出现识别弹性因素可以改善诊断，指导基于个体化认知风险的神经毒性不同的治疗选择，并为新型行为和药理学干预打开大门。