Effect of physical exercise on white matter microstructure in chemotherapy-treated breast cancer patients: a randomized controlled trial (PAM study)

Abstract

Physical exercise is a promising intervention to improve brain white matter integrity. In the PAM study, exercise intervention effects on white matter integrity were investigated in breast cancer patients. Chemotherapy-treated breast cancer patients with cognitive problems were randomized 2-4 years post-diagnosis to an exercise (n = 91) or control group (n = 90). The 6-month exercise intervention consisted of four hours/week of aerobic and resistance training. White matter integrity was measured at baseline and 6-month follow-up with fractional anisotropy (FA) and mean diffusivity (MD), which were derived from magnetic resonance diffusion tensor imaging (DTI). Both DTI metrics were analyzed whole brain and voxel-wise with a modified tract based spatial statistics (TBSS) procedure. Other measurements included cognition and physical fitness. Exercise effects were analyzed with multiple regression analyses. An explorative analysis was conducted in highly fatigued patients. DTI scans were available for 69 patients of the intervention (age = 52.3 ± 8.9yrs.) and 72 patients of the control group (age = 53.2 ± 8.6yrs.). Whole brain and voxel-wise analyses revealed no significant intervention effects on FA and MD. In highly fatigued patients (exercise: n = 32; control: n = 24), significant clusters of decreased FA post-intervention were observed in the left inferior and superior longitudinal fasciculus. Mean FA in these clusters was not predictive of cognition. A 6-month exercise intervention did not affect white matter integrity in chemotherapy-treated breast cancer patients. However, in highly fatigued breast cancer patients a significant FA decrease was observed post-intervention. The direction of these results is unexpected, and more research is needed to further understand these results.

Keywords: Breast cancer; Cognition; Exercise; Fatigue; White matter.

Fig. 1

Flowchart of inclusion and randomization procedures of the Physical Activity and Memory (PAM) study patients. *Information through social media, pamphlets, and by word of mouth. **During the last months of the PAM study, a lockdown during the COVID-19 pandemic impacted study procedures. Patients were unable to visit the hospital for research purposes, resulting in missing MRI scans (n = 19) and cardiopulmonary exercise tests (n = 13). Additionally, we had to modify the exercise program to be home-based (n = 7), providing them with exercise materials such as dumbbells and a stationary bike

Fig. 2

Significant clusters for fractional anisotropy decline for highly fatigued patients in the intervention compared to the control group