Effect of physical exercise on the hippocampus and global grey matter volume in breast cancer patients: A randomized controlled trial (PAM study)

E. W. Koevoets, M. I. Geerlings, E. M. Monninkhof, R. Mandl, L. Witlox, E. van der Wall, M. M. Stuiver, G. S. Sonke, M. J. Velthuis, J. J. Jobsen, J. van der Palen, M. E.M.M. Bos, E. Göker, M. B.E. Menke-Pluijmers, D. W. Sommeijer, A. M. May, Annebeth W. Haringhuizen, Wim A. van der Steeg, Frederiek Terheggen, Charlotte Blanken-PeetersHarold Fliervoet, Margrethe S. Schlooz-Vries, Tanja G. Frakking, Marc W.A. van Tilburg, Corina Oldenhuis, Maartje F. Sier, Carmen C. van der Pol, Lidwine W. Tick, Nel A. van Holsteijn, M. B. de Ruiter, S. B. Schagen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Background: Physical exercise in cancer patients is a promising intervention to improve cognition and increase brain volume, including hippocampal volume. We investigated whether a 6-month exercise intervention primarily impacts total hippocampal volume and additionally hippocampal subfield volumes, cortical thickness and grey matter volume in previously physically inactive breast cancer patients. Furthermore, we evaluated associations with verbal memory. Methods: Chemotherapy-exposed breast cancer patients (stage I-III, 2–4 years post diagnosis) with cognitive problems were included and randomized in an exercise intervention (n = 70, age = 52.5 ± 9.0 years) or control group (n = 72, age = 53.2 ± 8.6 years). The intervention consisted of 2x1 hours/week of supervised aerobic and strength training and 2x1 hours/week Nordic or power walking. At baseline and at 6-month follow-up, volumetric brain measures were derived from 3D T1-weighted 3T magnetic resonance imaging scans, including hippocampal (subfield) volume (FreeSurfer), cortical thickness (CAT12), and grey matter volume (voxel-based morphometry CAT12). Physical fitness was measured with a cardiopulmonary exercise test. Memory functioning was measured with the Hopkins Verbal Learning Test-Revised (HVLT-R total recall) and Wordlist Learning of an online cognitive test battery, the Amsterdam Cognition Scan (ACS Wordlist Learning). An explorative analysis was conducted in highly fatigued patients (score of ≥ 39 on the symptom scale ‘fatigue’ of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire), as previous research in this dataset has shown that the intervention improved cognition only in these patients. Results: Multiple regression analyses and voxel-based morphometry revealed no significant intervention effects on brain volume, although at baseline increased physical fitness was significantly related to larger brain volume (e.g., total hippocampal volume: R = 0.32, B = 21.7 mm3, 95 % CI = 3.0 – 40.4). Subgroup analyses showed an intervention effect in highly fatigued patients. Unexpectedly, these patients had significant reductions in hippocampal volume, compared to the control group (e.g., total hippocampal volume: B = −52.3 mm3, 95 % CI = −100.3 – −4.4)), which was related to improved memory functioning (HVLT-R total recall: B = −0.022, 95 % CI = −0.039 – −0.005; ACS Wordlist Learning: B = −0.039, 95 % CI = −0.062 – −0.015). Conclusions: No exercise intervention effects were found on hippocampal volume, hippocampal subfield volumes, cortical thickness or grey matter volume for the entire intervention group. Contrary to what we expected, in highly fatigued patients a reduction in hippocampal volume was found after the intervention, which was related to improved memory functioning. These results suggest that physical fitness may benefit cognition in specific groups and stress the importance of further research into the biological basis of this finding.

Original languageEnglish
Article number103292
JournalNeuroImage: Clinical
Publication statusPublished - Jan 2023

Bibliographical note

Funding Information:
This work was supported by KWF kankerbestrijding [grant number UU 2015-7954 ]. We acknowledge the following departments of the UMCU who have collected and stored data: laboratory, data management, the radiology department, and the department of rehabilitation. We would like to thank Theo Witkamp for visually inspecting the MRI scans for incidental findings, and our sports medicine specialists Esther Schoots and Anne-Marie Boelens-Quist for guiding the physical fitness tests. Special thanks to all participants for their continuous effort, physiotherapists and Nordic walking instructors for supervising training sessions, and all interns and research assistants, in particular Beatrix Vogelaar and Judith Meurs, for their help in gathering data. Additionally, we would like to thank the members of the PAM study group: Annebeth W Haringhuizen, Wim A van der Steeg, Frederiek Terheggen, Charlotte Blanken-Peeters, Harold Fliervoet, Margrethe S Schlooz-Vries, Tanja G Frakking, Marc WA van Tilburg, Corina Oldenhuis, Maartje F Sier, Carmen C van der Pol, Lidwine W Tick and Nel A van Holsteijn.

Publisher Copyright:
© 2022 The Authors


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