Translational Neuroscience Approaches to Cancer-Related Cognitive Impairment: Measurement, Mechanisms, and Function

癌症相关认知障碍的转化神经科学方法：测量、机制和功能

• 批准号: 10222614
• 负责人: Michelle C Janelsins
• 金额: $ 51.53万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10222614
• 关键词: Address; Adjuvant Chemotherapy; Age; Awareness; Biological Process; Breast Cancer Patient; CCL2 gene; CCR5 gene; Clinic; Clinical; Cognition; Cognitive; Cognitive deficits; Community Clinical Oncology Program; Cyclophosphamide; Data; Delayed Memory; Evaluable Disease; Exhibits; Functional disorder; Funding; Future; Gender; Hippocampus (Brain); Immune; Impaired cognition; Inflammation; Inflammatory; Intervention Trial; Learning; Link; Literature; Long-Term Effects; Longitudinal Studies; Measurement; Measures; Mediating; Methods; Modeling; Neuropsychological Tests; Neuropsychology; Oncology; Paired-Associate Learning; Parietal Lobe; Pathway interactions; Patient Self-Report; Patients; Performance; Physical activity; Prefrontal Cortex; Prospective Studies; Prospective cohort study; Public Health; Reporting; Research Design; Rodent; Role; Sampling; Short-Term Memory; Survivors; TNF gene; TNFRSF1A gene; TNFRSF1B gene; Testing; Time; Vision; Visual; base; cancer-related cognitive impairment; chemobrain; chemotherapy; classical conditioning; clinically significant; cognitive function; cognitive neuroscience; cohort; daily functioning; experience; follow-up; frontal lobe; frontal lobe function; innovation; instrumental activity of daily living; intercellular cell adhesion molecule; malignant breast neoplasm; mouse model; novel; pre-clinical; psychologic; screening; side effect; sustained attention; translational neuroscience; visual processing

PROJECT SUMMARY Cancer-related cognitive impairment (CRCI) is a troublesome side effect reducing overall daily functioning for many breast cancer patients undergoing chemotherapy. In Dr. Janelsins’ NCI-funded nationwide, prospective cohort study, 45% of breast cancer patients report clinically significant post-chemotherapy (URCC10055; N=945); this is one of the largest studies of CRCI to date and the only one we are aware of in community oncology clinics. CRCI may also persist long-term; however, large studies incorporating pre-chemotherapy time-points are needed to clearly elucidate long-term trajectories of CRCI. In URCC10055, Dr. Janelsins and colleagues used two tests that address specific cognitive functions: 1) the Delayed Match to Sample (DMS) task—a visual working memory test with sensitivity to the prefrontal cortex dysfunction and with analogous features to the delayed spatial alternation test used in her CRCI mouse model, and 2) the Rapid Visual Processing Test (RVP)—a sustained attention test with sensitivity to parietal and frontal lobe dysfunction. With both the DMS and RVP tests, there was a significant decline in breast cancer patients receiving adjuvant chemotherapy from pre- to 6 months post-chemotherapy compared to age-matched controls assessed at the same times (N=943). By comparison, the standard neuropsychological tests did not reveal significant differences at this time-point suggesting they may lack sensitivity for assessing long-term decline. We also present preliminary data that the inflammatory pathways may be related to lower DMS scores. Based on our preclinical data, and literature of others, we will also add a new learning test to precisely address hippocampal function, the Paired Associated Learning (PAL) test. Our aims are to conduct a comprehensive assessment of long-term CRCI in specific cognitive functions of visual working memory (DMS; primary aim; Aim 1a), sustained attention (RVP; Aim 1b) and new learning (PAL; Aim 1c) at 7 and 9 years post-chemotherapy in breast cancer patients compared to controls, assessing specific factors leading to cognitive decline, and to assess the impact of long-term CRCI with these measures on daily function (Aim 2), inflammation (Aim 3), and relationship to other cognitive measures (standard neuropsychological, self-report; Aim 4). In order to address these innovative aims, we will leverage URCC10055 to collect new 7- and 9-year data on 450 breast cancer patients (survivors) and 300 controls. These time-points coincide with gaps in the literature in evaluating longitudinal, long-term CRCI and these are the time-points available during the funding period. In order to evaluate long-term longitudinal CRCI, we will also leverage the existing URCC10055 data (pre-chemotherapy, post-chemotherapy, and 6 months follow-up). This proposal will fill critical gaps in the field in our understanding of longitudinal long-term effects of CRCI from prior to chemotherapy, biologic processes involved, and impact on overall daily functioning. These cognitive measures could provide practical yet CRCI- specific screening methods in busy oncology clinics and inform future mechanistic and CRCI intervention trials.

项目概要 癌症相关认知障碍 (CRCI) 是一种令人烦恼的副作用，会降低患者的整体日常功能 Janelsins 博士在全国范围内资助的前瞻性乳腺癌患者中进行了研究。 队列研究中，45% 的乳腺癌患者报告化疗后出现临床意义（URCC10055； N=945)；这是迄今为止规模最大的 CRCI 研究之一，也是我们在社区中所知的唯一一项研究 肿瘤诊所也可能长期持续；然而，大型研究纳入了化疗前的治疗。 Janelsins 博士和 URCC10055 需要时间点来清楚地阐明 CRCI 的长期轨迹。 同事们使用了两项针对特定认知功能的测试：1）延迟匹配样本 （DMS）任务——视觉工作记忆测试，对前额皮质功能障碍敏感，并具有 与她的 CRCI 小鼠模型中使用的延迟空间交替测试类似的特征，以及 2) Rapid 视觉处理测试（RVP）——一种对顶叶和额叶敏感的持续注意力测试 通过 DMS 和 RVP 测试，乳腺癌患者的功能障碍显着下降。 与年龄匹配的对照组相比，从化疗前至化疗后 6 个月接受辅助化疗 相比之下，标准神经心理学测试没有揭示。 这个时间点的显着差异表明他们可能缺乏评估长期下降的敏感性。 我们还提供了初步数据，表明炎症途径可能与较低的 DMS 评分有关。 根据我们的临床前数据和其他文献，我们还将添加一个新的学习测试来精确解决 海马功能，配对关联学习（PAL）测试我们的目标是进行一项。 视觉工作记忆特定认知功能的长期CRCI综合评估（DMS； 7 岁和 9 岁时的主要目标；目标 1a)、持续注意力（RVP；目标 1b）和新学习（PAL；目标 1c） 将乳腺癌患者化疗后与对照组进行比较，评估导致乳腺癌患者化疗后的具体因素 认知能力下降，并通过这些措施评估长期 CRCI 对日常功能的影响（目标 2）， 炎症（目标 3）以及与其他认知测量的关系（标准神经心理学、自我报告； 目标 4)。为了实现这些创新目标，我们将利用 URCC10055 收集新的 7 年和 9 年期数据。 这些时间点与 450 名乳腺癌患者（幸存者）和 300 名对照者的数据一致。 评估纵向、长期 CRCI 的文献，这些是资助期间可用的时间点 为了评估长期纵向 CRCI，我们还将利用现有的 URCC10055 数据。 （化疗前、化疗后和 6 个月的随访）。该提案将填补该领域的关键空白。 在我们对化疗前 CRCI 的纵向长期影响的理解中，生物过程 这些认知测量可以提供实用且 CRCI- 的参与和对整体日常功能的影响。 繁忙的肿瘤诊所的具体筛查方法，并为未来的机制和 CRCI 干预试验提供信息。