Chemotherapy & Cognition in Older breast Cancer Patients

描述(申请人提供)：本申请的目的是研究辅助化疗对老年乳腺癌患者认知功能的影响。虽然大剂量化疗可能会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。这是正在接受治疗的女性中的一种常见症状，俗称为“化疗障碍”。它是影响生活质量(QOL)的重要因素。这个问题在老年女性中可能尤其值得注意，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疾病。到目前为止，这个问题还没有在老年女性中进行研究，而且对接受化疗的女性认知障碍的自然病史一般知之甚少。我们建议评估这种现象的流行率和性质，以及它在18个月间隔中的发展轨迹。我们还将测试有关风险因素和病因学的假设。我们假设，由于血脑屏障(BBB)轻度受损，患有损害脑血管系统疾病(如糖尿病、高血压)的女性可能特别危险。此外，我们还将间接评估一种假说，即促炎细胞因子在脑毛细血管内皮细胞层的渗透可能会通过在脑白质，特别是脑室周围产生炎症状态来损害认知。我们建议以重复测量设计研究四组女性--接受辅助治疗的老年癌症女性，拒绝接受辅助治疗的老年癌症女性，接受辅助治疗的45-60岁乳腺癌女性，以及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，特别关注经常与白质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(每组n=25)的一个子样本进行磁共振成像，以测量受影响白质的体积。最后，我们将抽血测定某些性激素(特别是雌激素)的水平，并测定外周血促炎症细胞因子白介素1和白介素6(IL-1和IL-6)和肿瘤坏死因子α(TNF-α)的水平。这一结果可能对辅助化疗的决策具有重要意义，将进一步描述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.