Candidate mechanisms for chemotherapy-induced neurocognitive deficits in pediatric solid non-CNS tumor patients

儿童实体非中枢神经系统肿瘤患者化疗引起的神经认知缺陷的候选机制

• 批准号: 10285050
• 负责人: Travis E. Baker
• 金额: $ 18.35万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-05 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285050
• 关键词: 17 year old; Address; Adolescence; Adult; Adverse effects; Affect; Aftercare; Age; Area; Arousal; Attention; Awareness; Behavior; Behavioral; Biological Markers; Brain; Cancer Survivor; Carcinoma; Caring; Chemotherapy-Oncologic Procedure; Child; Childhood; Cognition; Cognitive; Cognitive deficits; Corpus striatum structure; Decision Making; Development; Dopamine; Early treatment; Electrophysiology (science); Exhibits; Family; Goals; Impaired cognition; Impairment; Learning; Lymphoblastic Leukemia; Lymphoma; Maintenance; Measurable; Measures; Medical; Modeling; Monitor; Negative Valence; Neuraxis; Neuroblastoma; Neurocognitive; Neurocognitive Deficit; Neurophysiology - biologic function; Patients; Pattern; Pediatric Oncology; Performance; Phenotype; Population; Positive Valence; Prefrontal Cortex; Process; Public Health; Research; Research Domain Criteria; Research Project Grants; Resources; Rewards; Short-Term Memory; Signal Transduction; Social Processes; Solid; Solid Neoplasm; Speed; Structure; Study models; Survival Rate; Survivors; Symptoms; Syndrome; System; Task Performances; Testing; Therapeutic Intervention; Time; Toxicity due to chemotherapy; Update; aged; base; cancer diagnosis; chemobrain; chemotherapeutic agent; chemotherapy; cognitive ability; cognitive control; cognitive function; cognitive system; cost; executive function; flexibility; follow-up; indexing; information processing; insight; memory process; neurotoxic; neurotoxicity; osteosarcoma; processing speed; recruit; relating to nervous system; response; reward processing; sex; therapy development; treatment strategy; virtual

1. Abstract Intensive curative chemotherapy is associated with subacute neurotoxicity, which can adversely affect brain functioning. These adverse treatment sequelae add to the significant lifelong impact on survivors and families, and may entail a measurable cost to societal, medical, and educational systems. To date, converging evidence shows that 40–70% of childhood survivors who have gone through central nervous system (CNS) chemotherapy exhibit deficits in attention, working memory, and information processing speed, deficits believed to be caused by the neurotoxicity of the treatment. While non-CNS solid tumors (NST) collectively account for over one third of cancer diagnoses among children, little is known about the neurotoxic effects of chemotherapy in NST survivors. The overarching goal of this project is to examine the impact of chemotherapy-related neurotoxicity on well-established neural, cognitive, and computational indices of reward processing, cognitive control and working memory in pediatric NST survivors. To achieve our goal, we aim to recruit 30 survivors of childhood NTS (e.g., osteosarcomas, lymphomas, carcinomas, and neuroblastomas) aged 6–17 years old and 30 age-matched typically developing children. The specific aims of this project will be to examine group differences between electrophysiological, behavioral, and computational biomarkers associated with reward responsiveness (Aim 1a), reward valuation (Aim 1b), cognitive control (Aim 2a) and working memory (Aim 2b). Our overarching hypothesis is that chemotherapy for NST alters neural activity and brain structures involved in specific cognitive functions (reward processing, cognitive control, working memory), and we predict that our selected neurocognitive indices of these functions will reveal unique patterns of abnormal neural and computational processes compared to healthy, age- and sex-matched controls. We believe that the diversity in these areas of research, such as engaging multiple neural systems, enables us to address basic, translational, and applied questions, including those at the intersection of the brain, computation, and behavior. Our long-term goal will be to find out whether this cross-cutting research model will aid in the development of a more targeted and efficient chemotherapy treatments for pediatric NST, as well as aftercare for cognitive deficits. By identifying such neurocognitive phenotypes, this research will help develop future research and grant strategies aimed at reducing the adverse effects of chemotherapy as well as tailor therapeutic interventions for the specific cognitive profile of this population.

1.摘要 强化治疗性化疗与亚急性神经毒性有关，可能对大脑产生不利影响 这些不良治疗后遗症增加了对幸存者和家庭的重大终生影响。 并可能给社会、医疗和教育系统带来可衡量的成本。 研究表明，40-70% 的儿童幸存者接受过中枢神经系统 (CNS) 化疗 缺陷表现在注意力、工作记忆和信息处理速度上，据信是由缺陷引起的 而非中枢神经系统实体瘤 (NST) 总共占三分之一以上。 儿童癌症诊断中，对于 NST 化疗的神经毒性作用知之甚少 该项目的首要目标是检查化疗相关神经毒性的影响。 奖励处理、认知控制和奖励处理的完善的神经、认知和计算指标 儿童 NST 幸存者的工作记忆 为了实现我们的目标，我们的目标是招募 30 名儿童 NST 幸存者。 （例如，骨肉瘤、淋巴瘤、癌和神经母细胞瘤）年龄 6-17 岁和 30 岁年龄匹配 该项目的具体目标是检查典型发育儿童之间的群体差异。 与奖赏反应相关的电生理学、行为学和计算生物标志物（Aim 1a）、奖励评估（目标 1b）、认知控制（目标 2a）和工作记忆（目标 2b）。 假设 NST 化疗会改变参与特定认知的神经活动和大脑结构 功能（奖励处理、认知控制、工作记忆），并且我们预测我们选择的 这些功能的神经认知指数将揭示异常神经和计算的独特模式 与健康、年龄和性别匹配的对照相比，我们认为这些领域的多样性。 研究，例如涉及多个神经系统，使我们能够解决基础、转化和应用问题 问题，包括大脑、计算和行为交叉点的问题，我们的长期目标是。 找出这种跨领域研究模型是否有助于开发更有针对性和更有效的 儿童 NST 的化疗以及认知缺陷的术后护理。 神经认知表型，这项研究将有助于制定未来的研究和资助策略 减少化疗的副作用，并针对特定认知量身定制治疗干预措施 该人群的概况。