Principal Investigator

Catherine M.
Bender
Awardee Organization

University Of Pittsburgh At Pittsburgh
United States

Fiscal Year
2020
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Influence of Exercise on Neurocognitive Function in Breast Cancer

Nearly 61% of women with breast cancer experience a decline in cognitive function with adjuvant therapy. We found declines in attention and working memory with aromatase inhibitor (AI) therapy in women with breast cancer and poorer executive function compared to healthy controls. Multiple biological mechanisms likely underlie this cognitive decline including estrogen (E2) reduction and cytokine dysregulation. AI therapy provides near complete E2 withdrawal and we found that lower E2 levels were related to poorer psychomotor efficiency, attention and executive function with breast cancer therapy. Increases in pro- inflammatory cytokines occur with cancer and persist up to 5 years post-treatment. We found that higher IL-6 levels are related to poorer executive function and reduced gray matter volume. The effect of AIs on cognitive function may also be mediated by symptoms experienced by women with breast cancer including fatigue, sleep problems, depression and anxiety. A promising method for improving cognitive and brain function in older adults is moderate intensity aerobic exercise. Our neuroimaging studies have shown that only modest amounts of aerobic exercise increase hippocampal volume and modify intrinsic connectivity and task-related functional dynamics in the prefrontal cortex and hippocampus. We also found that exercise reduces pro- inflammatory cytokines that are directly linked to hippocampal size and memory formation. Exercise also reduces depression and anxiety and the severity of fatigue and sleep problems in women with breast cancer. We propose a clinical trial in which post-menopausal women with early stage breast cancer are randomized to receive a 6-month, moderate-intensity aerobic exercise intervention or usual care. We will examine whether a well-controlled and monitored site-based exercise intervention, initiated before AI therapy, improves cognitive function and explore whether neuroimaging metrics of brain health, pro-inflammatory biomarkers (IL-6, CRP, TNF-α), and symptoms (fatigue, sleep problems, depression, anxiety) mediate the effects of exercise on cognitive function. Furthermore, we will explore whether the magnitude of the improvements in cognitive function are modified by E2. The specific aims include: 1) Compared to usual care, examine whether the 6-month exercise intervention improves cognitive function over the first six months of AI therapy in postmenopausal women with early stage breast cancer. 2) Compared to usual care, examine the direct effects of exercise on neuroimaging metrics of brain health including regional gray matter volume, white matter architecture and functional dynamics of the brain and pro-inflammatory biomarkers (IL-6 and CRP as primary outcomes; TNF-α as secondary) and explore the direct effects of exercise on symptoms (fatigue, sleep problems, depression, anxiety). 3) Compared to usual care, explore whether the effects of exercise on cognitive function are mediated by neuroimaging metrics of cognitive function, pro-inflammatory cytokines and symptoms and moderated by E2.

Publications

  • Smagula SF, Karim HT, Rangarajan A, Santos FP, Wood SC, Santini T, Jakicic JM, Reynolds CF 3rd, Cameron JL, Vallejo AN, Butters MA, Rosano C, Ibrahim TS, Erickson KI, Aizenstein HJ. Association of Hippocampal Substructure Resting-State Functional Connectivity with Memory Performance in Older Adults. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 2018 Jun;26(6):690-699. Epub 2018 Mar 13. PMID: 29628321
  • Oberlin LE, Waiwood AM, Cumming TB, Marsland AL, Bernhardt J, Erickson KI. Effects of Physical Activity on Poststroke Cognitive Function: A Meta-Analysis of Randomized Controlled Trials. Stroke. 2017 Nov;48(11):3093-3100. Epub 2017 Sep 20. PMID: 28931620
  • Gujral S, McAuley E, Oberlin LE, Kramer AF, Erickson KI. Role of Brain Structure in Predicting Adherence to a Physical Activity Regimen. Psychosomatic medicine. 2018 Jan;80(1):69-77. PMID: 28914724
  • Erickson KI, Donofry SD, Sewell KR, Brown BM, Stillman CM. Cognitive Aging and the Promise of Physical Activity. Annual review of clinical psychology. 2022 May 9;18:417-442. Epub 2022 Jan 19. PMID: 35044793
  • Gentry AL, Erickson KI, Sereika SM, Casillo FE, Crisafio ME, Donahue PT, Grove GA, Marsland AL, Watt JC, Bender CM. Protocol for Exercise Program in Cancer and Cognition (EPICC): A randomized controlled trial of the effects of aerobic exercise on cognitive function in postmenopausal women with breast cancer receiving aromatase inhibitor therapy. Contemporary clinical trials. 2018 Apr;67:109-115. Epub 2018 Mar 6. PMID: 29501739
  • Donofry SD, Stillman CM, Hanson JL, Sheridan M, Sun S, Loucks EB, Erickson KI. Promoting brain health through physical activity among adults exposed to early life adversity: Potential mechanisms and theoretical framework. Neuroscience and biobehavioral reviews. 2021 Dec;131:688-703. Epub 2021 Oct 5. PMID: 34624365
  • Gujral S, Aizenstein H, Reynolds CF 3rd, Butters MA, Grove G, Karp JF, Erickson KI. Exercise for Depression: A Feasibility Trial Exploring Neural Mechanisms. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 2019 Jun;27(6):611-616. Epub 2019 Jan 17. PMID: 30797651
  • Stillman CM, Esteban-Cornejo I, Brown B, Bender CM, Erickson KI. Effects of Exercise on Brain and Cognition Across Age Groups and Health States. Trends in neurosciences. 2020 Jul;43(7):533-543. Epub 2020 May 11. PMID: 32409017
  • Lesnovskaya A, Ripperger HS, Donofry SD, Drake JA, Wan L, Poniatowski A, Donahue PT, Crisafio ME, Gilmore AD, Richards EA, Grove G, Gentry AL, Sereika SM, Bender CM, Erickson KI. Cardiorespiratory fitness is associated with hippocampal resting state connectivity in women newly diagnosed with breast cancer. Frontiers in Cognition. 2023;2. Epub 2023 Aug 3. PMID: 37744285
  • Bender CM, Sereika SM, Gentry AL, Duquette JE, Casillo FE, Marsland A, Brufsky AM, Evans S, Gorantla VC, Grahovac TL, McAuliffe PF, Steiman JG, Zhu Y, Erickson KI. Physical activity, cardiorespiratory fitness, and cognitive function in postmenopausal women with breast cancer. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2021 Jul;29(7):3743-3752. Epub 2020 Nov 19. PMID: 33210238
  • Wagner MA, Erickson KI, Bender CM, Conley YP. The Influence of Physical Activity and Epigenomics On Cognitive Function and Brain Health in Breast Cancer. Frontiers in aging neuroscience. 2020 May 8;12:123. doi: 10.3389/fnagi.2020.00123. eCollection 2020. PMID: 32457596

Clinical Trials

Study Name Clinical Trial ID
Exercise Program in Cancer and Cognition NCT02793921