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.
