Reduced hippocampal volume and verbal memory performance associated with interleukin-6 and tumor necrosis factor-alpha levels in chemotherapy-treated breast cancer survivors

Abstract

Many survivors of breast cancer show significant cognitive impairments, including memory deficits. Inflammation induced by chemotherapy may contribute to hippocampal changes that underlie these deficits. In this cross-sectional study, we measured bilateral hippocampal volumes from high-resolution magnetic resonance images in 42 chemotherapy-treated breast cancer survivors and 35 healthy female controls. Patients with breast cancer were, on average, 4.8 ± 3.4 years off-therapy. In a subset of these participants (20 breast cancer, 23 controls), we quantified serum cytokine levels. Left hippocampal volumes and memory performance were significantly reduced and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFα) concentrations were significantly elevated in the breast cancer group compared to controls. In the breast cancer group, lower left hippocampal volume was associated with higher levels of TNFα and lower levels of IL-6 with a significant interaction between these two cytokines suggesting a potential modulatory effect of IL-6 on TNFα. Verbal memory performance was associated with cytokine levels and left hippocampal volume in both groups. These findings provide evidence of altered hippocampal volume and verbal memory difficulties following breast cancer chemotherapy that may be mediated by TNFα and IL-6.

Fig. 1

Illustration of hippocampal delineation using Freesurfer (http://surfer.nmr.mgh.harvard.edu/). The image is shown in radiologic convention where the left hippocampus is shown on the right side of the image and right hippocampus is shown on the left.

Fig. 2

In breast cancer survivors, (A) lower peripheral interleukin-6 (IL-6) and higher tumor necrosis factor-alpha (TNFα) levels were associated with lower left hippocampal (LHIP) volume. (B) Interactions between cytokines and left hippocampal volume were associated with reduced performance on the Hopkins Verbal Learning Test (HVLT).