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

项目摘要 癌症相关认知障碍（CRCI）是一种令人烦恼的副作用，降低了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博士的国家癌症研究所资助的全国范围内， 队列研究中，45%的乳腺癌患者报告化疗后有临床意义（URCC 10055; N=945）;这是迄今为止规模最大的CRCI研究之一，也是我们在社区中了解到的唯一一项研究 肿瘤诊所CRCI也可能长期存在;然而，纳入化疗前 需要时间点来清楚地阐明CRCI的长期轨迹。在URCC 10055中，Janelsins博士和 同事们使用了两个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，对前额叶皮层功能障碍敏感， 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）快速 视觉处理测试（RVP）-持续注意力测试，对顶叶和额叶敏感 功能障碍通过DMS和RVP测试，乳腺癌患者的发病率显著下降， 与年龄匹配的对照组相比，在化疗前至化疗后6个月接受辅助化疗 在同一时间进行评估（N=943）。相比之下，标准的神经心理学测试并没有揭示出 在这个时间点的显著差异表明，它们可能缺乏评估长期下降的敏感性。 我们还提出了初步的数据，炎症途径可能与较低的DMS评分。基于 根据我们的临床前数据和其他文献，我们还将增加一个新的学习测试，以精确地解决 海马功能，配对相关学习（PAL）测试。我们的目标是进行一次 长期CRCI在视觉工作记忆（DMS; 主要目标（目标1a）、持续注意力（RVP;目标1b）和新学习（PAL;目标1c） 与对照组相比，乳腺癌患者化疗后，评估导致 认知功能下降，并评估长期CRCI与这些措施对日常功能的影响（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URCC 10055收集新的7年和9年 450名乳腺癌患者（幸存者）和300名对照组的数据。这些时间点正好与 评估纵向、长期CRCI的文献，这些是资助期间可用的时间点 期为了评估长期纵向CRCI，我们还将利用现有的URCC 10055数据 （化疗前、化疗后和6个月随访）。这一提议将填补这一领域的关键空白 在我们对CRCI从化疗前的纵向长期效应的理解中， 影响，并影响整体的日常运作。这些认知测量可以提供实用的CRCI- 在忙碌的肿瘤诊所中使用特定的筛查方法，并为未来的机制和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.