Brain Biomarkers of Cognitive and Mood Changes Related to Aromatase Inhibitor Use

与芳香酶抑制剂使用相关的认知和情绪变化的大脑生物标志物

• 批准号: 9032606
• 负责人: John D. Merriman
• 金额: $ 9.51万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032606
• 关键词: Adverse effects; Age; Amygdaloid structure; Anxiety; Aromatase Inhibitors; Basic Science; Biological Markers; Brain; Brain imaging; Brain region; Breast; Breast Cancer therapy; Cancer Survivorship; Clinical; Cognitive; Communication; Control Groups; Cytokine Gene; Data; Deterioration; Diffusion Magnetic Resonance Imaging; Discipline; Discipline of Nursing; Education; Environment; Estrogen Antagonists; Fostering; Foundations; Functional Magnetic Resonance Imaging; Funding; Future; Gene Expression; Genes; Genetic; Genetic Variation; Goals; Hippocampus (Brain); Hormone Receptor; Image; Individual; Individual Differences; Inflammation; Inflammatory; International; Intervention; Intervention Studies; Laboratories; Learning; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Medical center; Memory; Mentors; Methods; Moods; Nature; Neuraxis; Neurons; Neuropsychological Tests; Neuropsychology; Nursing Societies; Oncologic Nursing; Oncology Nurse; Oxidative Stress; Parents; Patient Self-Report; Peripheral; Phase; Pilot Projects; Postmenopause; Prefrontal Cortex; Reporting; Research; Research Training; Resources; Rest; Risk; Risk Factors; Role; Sample Size; Sampling; School Nursing; Secure; Severities; Short-Term Memory; Structure; Symptoms; Techniques; Testing; Training; Universities; Variant; Verbal Learning; Woman; Work; anastrozole; breast surgery; cancer diagnosis; cancer therapy; career; cognitive ability; cognitive change; cognitive function; comparison group; cytokine; depressive symptoms; executive function; experience; improved; interest; intervention effect; malignant breast neoplasm; modifiable risk; neuroimaging; neuropsychological; post-doctoral training; pre-doctoral; prevent; programs; public health relevance; relating to nervous system; skills; success; tau Proteins; visual learning; white matter

 DESCRIPTION (provided by applicant): Aromatase inhibitor (AI) therapy is the standard anti-estrogen treatment for postmenopausal women with hormone receptor-positive breast cancer. Among the potential side effects of AI therapy is poorer cognitive function. Studies using objective neuropsychological tests found subtle deteriorations in cognitive domains including verbal and visual learning and memory-as well as concentration, working memory, and executive function. However, two trials found no objective cognitive changes. Although women with breast cancer may report that they experience poorer cognitive abilities, these self-reported cognitive changes often do not correlate with scores on objective tests. Neuroimaging techniques may help explain inconsistent relationships between cancer therapy and cognitive changes by describing underlying alterations in brain function and structure. Functional magnetic resonance imaging (fMRI) evaluates brain activation during tasks. Diffusion tensor imaging (DTI) evaluates the extent and integrity of white matter connections. Together, fMRI and DTI evaluate brain function and structure. Alterations in brain function and structure (i.e., brain alterations) may explain disparate findings using subjective and objective measures of cognitive function. The proposed mentored K99 study leverages the mentor's R01 (CA107408), which is evaluating the neuropsychological effects of AI therapy. This application leverages the pilot study to add a crucial long-term imaging assessment, describe resting state functional connectivity (fcMRI) between neural regions, augment sample size, and build capacity to evaluate inter-individual differences in peripheral inflammation using gene expression techniques early in the R00-phase study. The purposes of the K99 study are to describe long-term relationships between AI therapy and brain alterations, and to explore relationships between brain alterations and cognitive and mood changes. Two groups will be studied: a sample of women evaluated 18 months after the initiation of AI therapy for breast cancer and a comparison group of age- and education-matched women without breast cancer. The primary aim of the K99 study is to (1) describe trajectories of alterations in brain function and structure during AI therapy. The exploratory, hypothesis-generating aim of the K99 study, using the same sample, is to (2a) describe long-term relationships between brain alterations and cognitive changes, and (2b) describe long-term relationships of mood changes with cognitive changes and brain alterations. The R00 study first will explicate the risk profile for brain alterations duing AI therapy with analyses of inter-individual differences in expression of inflammatory genes. Then, it will evaluate the effect of an intervention targeted at improving modifiable risk factors or brain alterations underlying cognitive and mood changes. Clinical and academic experiences led the applicant to focus his research on understanding inter-individual differences in cognitive changes after a diagnosis of cancer and on developing targeted interventions to prevent or alleviate cognitive changes. Pre-doctoral training provided a foundational understanding of subjective assessment and the role of genetic variation in inter-individual variability in cognitiv changes. However, two important pieces were missing that are necessary to build the applicant's program of research: (1) objective neuropsychological testing and neuroimaging methods must be incorporated into his research, and (2) these methods must be integrated with past training in genetics and subjective symptom assessment. The applicant currently lacks the expertise to direct an independent program of research that integrates his past training with new skills in neuroimaging, neuropsychology, and gene expression methods that are necessary to launch an independent research career. The K99 training plan was carefully developed with his mentoring team to fill these gaps. The University of Pittsburgh and University of Pittsburgh Medical Center (UPMC) provide the ideal environment for the applicant to integrate training and research in these multiple disciplines. The mentoring team includes experts in each of these disciplines who are committed to the applicant's success and future independent research career. The primary facilities and resources available (i.e., University of Pittsburgh School of Nursing, UPMC Magnetic Resonance Research Center, Mood and Brain Laboratory, Nursing Basic Science Laboratory) are known nationally and internationally for their outstanding environments. The applicant is completing the first year as a postdoctoral scholar. Training in cancer survivorship research (T32NR011972) with his mentor, Dr. Catherine Bender, is focused on the addition of brain imaging into his emerging program of research. Among other accomplishments in this first year, the applicant secured funding from the Oncology Nursing Society-Sigma Theta Tau International Foundation for Nursing for a pilot study using imaging to evaluate brain function and structure early during AI therapy. The K99 will leverage the pilot study, provide the necessary training in new methods, and integrate his pre-doctoral and postdoctoral training into a coordinated program of research that will begin with the R00 phase. Ultimately, the integrated program of research fostered by the K99/R00 has the potential to uncover biomarkers of alterations in brain function and structure, which could explain inter-individual differences in cognitive changes during cancer therapy and provide targeted intervention to prevent or alleviate these changes.

 描述（由申请方提供）：芳香化酶抑制剂（AI）治疗是激素受体阳性乳腺癌绝经后女性的标准抗雌激素治疗。AI疗法的潜在副作用之一是认知功能较差。使用客观神经心理学测试的研究发现，包括语言和视觉学习和记忆在内的认知领域以及注意力、工作记忆和执行功能都出现了微妙的退化。然而，两项试验没有发现客观的认知变化。虽然乳腺癌患者可能会报告他们的认知能力较差，但这些自我报告的认知变化通常与客观测试的分数无关。神经影像学技术可以通过描述大脑功能和结构的潜在变化来帮助解释癌症治疗和认知变化之间不一致的关系。功能性磁共振成像（fMRI）评估任务期间的大脑激活。扩散张量成像（DTI）评价白色物质连接的范围和完整性。fMRI和DTI共同评估大脑功能和结构。大脑功能和结构的改变（即，大脑改变）可以解释使用认知功能的主观和客观测量的不同发现。拟议的指导K99研究利用了导师的R 01（CA 107408），该研究正在评估AI治疗的神经心理学影响。该应用程序利用试点研究增加了一项重要的长期成像评估，描述了神经区域之间的静息状态功能连接（fcMRI），增加了样本量，并建立了在R 00阶段研究早期使用基因表达技术评估外周炎症个体间差异的能力。K99研究的目的是描述AI治疗与大脑改变之间的长期关系，并探索大脑改变与认知和情绪变化之间的关系。将研究两组：一组妇女在开始乳腺癌AI治疗后18个月进行评估，另一组妇女在年龄和教育程度上相匹配，但没有乳腺癌。K99研究的主要目的是（1）描述大脑功能和结构变化的轨迹 在人工智能治疗期间。K99研究的探索性假设生成目的是使用相同的样本，（2a）描述大脑变化和认知变化之间的长期关系，（2b）描述情绪变化与认知变化和大脑变化之间的长期关系。R 00研究首先将通过分析炎症基因表达的个体间差异来阐明AI治疗期间大脑改变的风险特征。然后，它将评估针对改善可改变的风险因素或认知和情绪变化的大脑改变的干预措施的效果。临床和学术经验使申请人将研究重点放在了解癌症诊断后认知变化的个体间差异，以及制定有针对性的干预措施以预防或缓解认知变化。博士前培训提供了对主观评估和遗传变异在认知变化中个体间变异性中的作用的基本理解。然而，缺少了两个重要的部分，这是建立申请人的研究计划所必需的：（1）客观的神经心理学测试和神经影像学方法必须纳入他的研究，（2）这些方法必须与过去的遗传学和主观症状评估培训相结合。申请人目前缺乏指导独立研究计划的专业知识，该计划将他过去的培训与神经影像学，神经心理学和基因表达方法的新技能相结合，这些技能是开展独立研究生涯所必需的。K99培训计划是与他的指导团队一起精心制定的，以填补这些空白。匹兹堡大学和匹兹堡大学医学中心（UPMC）为申请人提供了理想的环境，以整合这些多学科的培训和研究。指导团队包括这些学科的专家，他们致力于申请人的成功和未来的独立研究事业。可用的主要设施和资源（即，匹兹堡大学护理学院，UPMC磁共振研究中心，情绪和大脑实验室，护理基础科学实验室）以其出色的环境而闻名于国内和国际。申请人正在完成作为博士后学者的第一年。在癌症生存研究（T32 NR 011972）与他的导师，凯瑟琳本德博士的培训，重点是增加脑成像到他的新兴研究计划。在第一年的其他成就中，申请人获得了肿瘤护理学会-Sigma Theta Tau国际护理基金会的资助，用于在AI治疗期间使用成像来评估大脑功能和结构的试点研究。K99将利用试点研究，提供新方法的必要培训，并将他的博士前和博士后培训整合到一个协调的研究计划中，该计划将从R 00阶段开始。最终，由K99/R 00培养的综合研究计划有可能发现大脑功能和结构改变的生物标志物，这可以解释癌症治疗期间认知变化的个体间差异，并提供有针对性的干预措施来预防或缓解这些变化。