Abstract P3-08-01: Cognitive impairment and cortical network dysfunction following chemotherapy

Abstract

Abstract A common complaint of cancer patients is the experience of cognitive difficulty during and after chemotherapy. However, the mechanisms through which this occurs are still unknown. We hypothesized that chemotherapy-induced cognitive impairment may result from dysfunction in large-scale brain networks, particularly those involved in attentional control. These networks are evident when measuring task-based brain activity during attention-demanding tasks, but can also be studied using resting state functional connectivity magnetic resonance imaging (rs-fcMRI). In rs-fcMRI, connectivity between brain regions is measured using data collected while participants lie awake in the magnet with their eyes open, but performing no task. It reliably distinguishes known sensory, motor, and executive networks based on connectivity patterns. These data complement information about structural (white matter) connectivity obtained using diffusion tensor imaging (DTI). Here we report a case-control study of women with a history of triple negative breast cancer (BrCa) who completed standard adjuvant chemotherapy within two years of study entry. The cases (n = 15) were defined as women who reported cognitive impairment by the Cognitive Failures Questionnaire and controls (n = 13) were women who did not report cognitive impairment. All participants eligible for MRI investigation underwent rs-fcMRI and DTI on a Siemens 3T TIM Trio scanner. DTI parameters measured included Fractional Anisotropy (FA), Mean Diffusivity (MD), Radial Diffusivity (RD), and Axial Diffusivity. The study was conducted in its entirety at Washington University in St. Louis School of Medicine. Institutional review board approval was obtained prior to recruitment. The mean age of cases was 53.1 years and controls 51.6 years; all were diagnosed with invasive ductal or lobular BrCa. For each participant, we extracted the timecourse of brain activity for regions of interest in frontoparietal and cingularopercular control systems, measured indirectly via blood oxygenation level dependent (BOLD) contrast, from the MRI scans, and additional regions of interest distributed across the brain. We excluded scans that showed motion artifact. Pairwise connectivity was calculated using Pearson correlation between all regions of interest; we also used these regions in seed-based analyses. We compared the strength of rs-fcMRI-defined network connections between the two groups and used nonparametric permutation tests to calculate statistical significance. We found significant changes within several regions of the frontoparietal attention network, such that patients reporting greater cognitive difficulty showed weaker neural connectivity. In addition, DTI analyses revealed different patterns of anatomical connectivity between groups, including reduced FA (p<0.03) and increased MD and RD (p<0.02), both of which have been shown to be signatures of brain change in demyelinating disease. Together our results suggest that standard therapeutic levels of chemotherapy for BrCa patients may result in structural and functional connectivity alterations in the brain networks supporting executive attention, which in turn may be a contributing factor in cognitive difficulty. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-08-01.