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: 7649468
• 负责人: HEATHER M CONKLIN
• 金额: $ 18.9万
• 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/7649468
• 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; Outcome; Parents; Participant; Patients; Performance; Persons; Prefrontal Cortex; Process; Quality of life; Questionnaires; 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; meetings; memory process; memory recognition; methionylmethionine; neurotoxicity; novel; processing speed; programs; public health relevance; 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）：接受治疗的脑肿瘤的儿童始终证明，全球认知功能的度量下降，包括智力功能，这些功能与学术失败，高失业率和生活质量降低有关。最近的研究表明，特定功能领域的损害包括注意力，工作记忆和处理速度可能是这些全球下降的近端贡献者。治疗后认知变化的规范改进对于识别脆弱的神经途径和制定有针对性的干预措施至关重要。工作记忆（在线维护和操纵信息的能力）是在这方面进行调查的理想系统，因为它是一种支持许多更高级别认知技能的能力（行为和神经解剖学上）。此外，已经证明工作记忆取决于发育中长期发育的额叶区域，脑白质的增加延伸到生命的第三个十年。鉴于接受脑肿瘤治疗的儿童与预期的发育成熟相反，白质显着丧失，因此工作记忆可能尤其容易受到治疗效果的影响。神经递质多巴胺对于前额叶皮层介导的功能至关重要。 Catechol O-甲基转移酶（COMT）基因的MET多态性可导致前额叶多巴胺的可用性，与健康儿童的工作记忆表现更好有关。因此，COMT MET多态性可能是针对用于脑肿瘤治疗的儿童工作记忆缺陷的出现的弹性因素。在拟议的研究中，儿童脑肿瘤幸存者，实体瘤控制（没有中枢神经系统指导疗法的史）和同学控制措施将完成认知技能的实验室措施（例如，工作记忆，识别记忆和智商），而父母则完成评估儿童执行功能的问卷。将收集颊（脸颊）样品以进行DNA提取。研究目的包括：使用新型实验室测量（特定目标1）评估儿童脑肿瘤幸存者的工作记忆性能和健康的兄弟姐妹（特定目标1），研究COMT基因的多态性与工作记忆表现的多态性与工作记忆表现（特定目标2）之间的关系（特定目标）以及评估工作记忆和父母报告的相关性与儿童执行功能的相关性（特定）。假设：1。儿童脑肿瘤幸存者的表现将比实体肿瘤和工作记忆任务的同级控制差，2。工作记忆任务的表现将与IQ相关，3。具有COMT MET/MET Genotype的儿童在工作记忆任务上的表现更好，而实验室工作记忆测量将与父母报告的执行功能相关。拟议的研究可能有助于隔离与癌症治疗相关的认知缺陷的基本原因，并有助于发现行为和药理干预措施的目标，以改善癌症幸存者的认知功能。公共卫生相关性：在CNS定向治疗儿童癌症后，认知变化的规格更大，对于隔离脆弱的神经途径并发展有针对性的认知干预措施至关重要。识别弹性因素针对认知功能障碍的出现可以改善预后，指导基于个性化认知风险的神经毒性的治疗方法的选择，并为新型的行为和药理干预打开大门。

项目成果

Computerized assessment of cognitive late effects among adolescent brain tumor survivors.

• DOI: 10.1007/s11060-013-1123-5
• 发表时间: 2013-06
• 期刊: JOURNAL OF NEURO-ONCOLOGY
• 影响因子: 3.9
• 作者: Conklin, Heather M.;Ashford, Jason M.;Di Pinto, Marcos;Vaughan, Christopher G.;Gioia, Gerard A.;Merchant, Thomas E.;Ogg, Robert J.;Santana, Victor;Wu, Shengjie
• 通讯作者: Wu, Shengjie

Working memory performance among childhood brain tumor survivors.

• DOI: 10.1017/s1355617712000793
• 发表时间: 2012-11
• 期刊: JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY
• 影响因子: 2.6
• 作者: Conklin, Heather M.;Ashford, Jason M.;Howarth, Robyn A.;Merchant, Thomas E.;Ogg, Robert J.;Santana, Victor M.;Reddick, Wilburn E.;Wu, Shengjie;Xiong, Xiaoping
• 通讯作者: Xiong, Xiaoping

Executive dysfunction is associated with poorer health-related quality of life in pediatric brain tumor survivors.

• DOI: 10.1007/s11060-016-2113-1
• 发表时间: 2016-06
• 期刊: Journal of neuro-oncology
• 影响因子: 3.9
• 作者: Netson KL;Ashford JM;Skinner T;Carty L;Wu S;Merchant TE;Conklin HM
• 通讯作者: Conklin HM

Adaptive functioning of childhood brain tumor survivors following conformal radiation therapy.

• DOI: 10.1007/s11060-014-1420-7
• 发表时间: 2014-05
• 期刊: JOURNAL OF NEURO-ONCOLOGY
• 影响因子: 3.9
• 作者: Ashford, Jason M.;Netson, Kelli L.;Clark, Kellie N.;Merchant, Thomas E.;Santana, Victor M.;Wu, Shengjie;Conklin, Heather M.
• 通讯作者: Conklin, Heather M.

The relationship between working memory and cerebral white matter volume in survivors of childhood brain tumors treated with conformal radiation therapy.

• DOI: 10.1007/s11060-014-1476-4
• 发表时间: 2014-08
• 期刊: JOURNAL OF NEURO-ONCOLOGY
• 影响因子: 3.9
• 作者: Jacola, Lisa M.;Ashford, Jason M.;Reddick, Wilburn E.;Glass, John O.;Ogg, Robert J.;Merchant, Thomas E.;Conklin, Heather M.
• 通讯作者: Conklin, Heather M.