Chemotherapy & Cognition in Older breast Cancer Patients

描述（由申请人提供）：本申请的目的是研究辅助化疗对老年乳腺癌女性认知功能的影响。虽然高剂量化疗可能损害认知已经有一段时间了，但越来越多的文献表明，标准剂量化疗会损害认知的某些方面。这是接受治疗的妇女中常见的主诉，通俗地称为“化学性脑出血”。“这是影响生活质量（QOL）的重要因素。这个问题在老年妇女中可能特别值得注意，她们可能已经有一些继发于衰老过程本身的认知障碍，或者可能影响认知的各种共病医学疾病。迄今为止，这个问题还没有在老年妇女中进行过研究，而且对于接受化疗的妇女中认知障碍的自然史也知之甚少。我们建议评估这一现象的普遍性和性质，以及其在18个月间隔内的轨迹。我们还将测试有关风险因素和病因学的假设。我们假设患有损害脑血管系统疾病的女性（例如，糖尿病、高血压）由于血脑屏障（BBB）的轻度损伤而可能尤其处于危险之中。此外，我们将间接评估这一假设，即促炎细胞因子渗透穿过脑毛细血管中的内皮细胞层，可能通过在白色物质中产生炎性状态而损害认知，特别是室周。我们建议在重复测量设计中研究四组妇女--接受辅助治疗的老年癌症妇女、拒绝辅助治疗的老年癌症妇女、接受辅助治疗的45-60岁乳腺癌妇女和一组年龄和教育程度匹配的健康对照组。我们将在基线（治疗前）以及基线后6个月和12个月进行认知评估，特别关注经常与白色疾病相关的认知能力（例如，工作记忆、注意力、执行功能）。我们还建议在每个时间点对每组的子样本（每组n = 25）进行磁共振成像，以测量受影响的白色物质的体积。最后，我们将抽血测量某些性类固醇（特别是雌激素）的水平，并测定外周促炎细胞因子白细胞介素-1和白细胞介素-6（IL-1和IL-6）以及肿瘤坏死因子α（TNF-α）的水平。这些结果可能对辅助化疗的决策具有重要意义，将进一步阐明这一问题的范围和性质，并可能为神经保护干预提供有用的数据。

DESCRIPTION (provided by applicant): The purpose of this application is to study the effects of adjuvant chemotherapy on cognitive functioning among older women with breast cancer. Although it has appeared for some time that high dose chemotherapy may impair cognition, there is a growing literature that suggests that certain aspects of cognition are impaired by standard-dose chemotherapy. This is a common complaint among women undergoing treatment, and is colloquially referred to as "chemobrain." It is a significant factor affecting quality of life (QOL). The problem may be especially noteworthy among older women, who already may have some cognitive impairment secondary to the aging process itself, or to various comorbid medical disorders that could affect cognition. The issue has not been studied to date in older women, and little is known about the natural history of cognitive impairment among women on chemotherapy generally. We propose to assess the prevalence and nature of this phenomenon, and its trajectory over an 18-month interval. We also will test hypotheses regarding risk factors and etiology. We hypothesize that women with disorders that compromise cerebral vasculature (e.g., diabetes, hypertension) may be especially at risk, due to a mild impairment of the blood-brain barrier (BBB). In addition, we will indirectly assess the hypothesis that the infiltration of pro-inflammatory cytokines across the endothelial cell layer in brain capillaries may impair cognition by producing an inflammatory condition in the white matter, especially periventricularly. We propose to study four groups of women in a repeated-measures design-older women with cancer on adjuvant therapy, older women with cancer who decline adjuvant therapy, women aged 45-60 with breast cancer on adjuvant therapy, and a group of age- and education-matched healthy control subjects. We will conduct cognitive assessments at baseline (prior to treatment), and at 6 and 12 months after baseline, focusing in particular on cognitive abilities frequently associated with white matter disease (e.g., working memory, attention, executive functioning). We also propose to conduct magnetic resonance imaging on a subsample of each group (n = 25 per group) at each timepoint in order to measure the volume of affected white matter. Finally, we will draw blood to measure the level of certain sex steroids (estrogens in particular), and for the determination of level of peripheral pro-inflammatory eytokines Interleukin-1 and Interleukin-6 (IL-1 and IL-6), and Tumor Necrosis Factor alpha (TNF-alpha). The results could have important implications for decision-making about adjuvant chemotherapy, will further delineate the scope and nature of this problem, and could provide data useful in neuroprotective interventions.