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

项目总结 癌症相关认知障碍(CRCI)是一种麻烦的副作用，会降低患者的整体日常功能 许多正在接受化疗的乳腺癌患者。在Janelsins博士的NCI资助的全国范围内， 队列研究，45%的乳腺癌患者报告化疗后有临床意义(URCC10055； N=945)；这是迄今为止关于CRCI的最大研究之一，也是我们在社区中所知的唯一一项研究 肿瘤科诊所。CRCI也可能长期存在；然而，纳入化疗前的大型研究 需要时间点来清楚地阐明CRCI的长期轨迹。在URCC10055中，Janelsins博士和 同事们使用了两个测试来解决特定的认知功能：1)延迟匹配到样本 (DMS)任务-视觉工作记忆测试，对前额叶皮质功能障碍和 类似于她在CRCI小鼠模型中使用的延迟空间交替测试，以及2)快速 视觉加工测验(RVP)--一种对顶叶和额叶敏感的持续性注意测验 功能障碍。通过DMS和RVP测试，乳腺癌患者的发病率显著下降 化疗前至化疗后6个月接受辅助化疗与年龄匹配的对照组比较 同时评估(N=943)。相比之下，标准的神经心理测试并没有揭示 在这个时间点上的显着差异表明，它们可能缺乏评估长期下滑的敏感性。 我们还提供了初步数据，即炎症途径可能与较低的DMS评分有关。基座 在我们的临床前数据和其他文献的基础上，我们还将添加一个新的学习测试，以准确地解决 海马区功能，配对联想学习(PAL)测试。我们的目标是开展一项 长期CRCI对视觉工作记忆(DMS； 7岁和9岁的主要目标；目标1a)、持续注意力(RVP；目标1b)和新学习(PAL；目标1c) 乳腺癌患者化疗后与对照组的比较，评估导致 认知功能下降，并用这些措施评估长期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年期和9年期 450名乳腺癌患者(幸存者)和300名对照的数据。这些时间点恰好与 评估纵向、长期CRCI的文献，这些是资助期间可用的时间点 句号。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个月随访)。这项提议将填补该领域的重大空白。 在我们对CRCI在化疗前的纵向长期影响的理解中，生物过程 参与其中，并对整体日常运作产生影响。这些认知措施可以提供切实可行的CRCI- 在繁忙的肿瘤科诊所提供具体的筛查方法，并为未来的机械性和CRCI干预试验提供信息。

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.