Alterations in brain structure and function in breast cancer survivors: effect of post-chemotherapy interval and relation to oxidative DNA damage

Abstract

Neuroimaging studies have begun to uncover the neural substrates of cancer and treatment-related cognitive dysfunction, but the time course of these changes in the years following chemotherapy is unclear. This study analyzed multimodality 3T MRI scans to examine the structural and functional effects of chemotherapy and post-chemotherapy interval (PCI) in a cohort of breast cancer survivors (BCS; n = 24; PCI mean 6, range 3-10 y) relative to age- and education-matched healthy controls (HC; n = 23). Assessments included voxel-based morphometry for gray matter density (GMD) and fMRI for activation profile during a 3-back working memory task. The relationships between brain regions associated with PCI and neuropsychological performance, self-reported cognition, and oxidative and direct DNA damage as measured in peripheral lymphocytes were assessed in secondary analyses. PCI was positively associated with GMD and activation on fMRI in the right anterior frontal region (Brodmann Areas 9 and 10) independent of participant age. GMD in this region was also positively correlated with global neuropsychological function. Memory dysfunction, cognitive complaints, and oxidative DNA damages were increased in BCS compared with HC. Imaging results indicated lower fMRI activation in several regions in the BCS group. BCS also had lower GMD than HC in several regions, and in these regions, GMD was inversely related to oxidative DNA damage and learning and memory neuropsychological domain scores. This is the first study to show structural and functional effects of PCI and to relate oxidative DNA damage to brain alterations in BCS. The relationship between neuroimaging and cognitive function indicates the potential clinical relevance of these findings. The relationship with oxidative DNA damage provides a mechanistic clue warranting further investigation.

Figure 1

Functional and structural overlap in the right anterior middle frontal gyrus, in which gray matter density (red) was positively correlated with post-chemotherapy interval. Working memory-related activation (blue) was negatively correlated with post-chemotherapy interval (voxelwise p uncorrected = 0.001, cluster size=10 for both modalities)

Figure 2

In breast cancer survivors (BCS), the average of neuropsychological domain z-scores vs. mean gray matter density in right middle and superior frontal gyri (Brodmann Areas 9, 10)

Figure 3

Oxidative DNA damage in breast cancer survivors (BCS) as measured by Comet assay of peripheral lymphocytes vs. mean gray matter density (GMD) of clusters in which BCS showed relatively decreased GMD compared to healthy controls (HC)