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In vivo neuroimaging and behavioral correlates in a rat model of chemotherapy-induced cognitive dysfunction

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Abstract

Adjuvant chemotherapy has been used for decades to treat cancer, and it is well known that disruptions in cognitive function and memory are common chemotherapeutic adverse effects. However, studies using neuropsychological metrics have also reported group differences in cognitive function and memory before or without chemotherapy, suggesting that complex factors obscure the true etiology of chemotherapy-induced cognitive dysfunction (CICD) in humans. Therefore, to better understand possible mechanisms of CICD, we explored the effects of CICD in rats through cognition testing using novel object recognition (NOR) and contextual fear conditioning (CFC), and through metabolic neuroimaging via [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Cancer-naïve, female Sprague-Dawley rats were administered either saline (1 mL/kg) or doxorubicin (DOX) (1 mg/kg in a volume of 1 mL/kg) weekly for five weeks (total dose = 5 mg/kg), and underwent cognition testing and PET imaging immediately following the treatment regime and 30 days post treatment. We did not observe significant differences with CFC testing post-treatment for either group. However, the chemotherapy group exhibited significantly decreased performance in the NOR test and decreased 18F-FDG uptake only in the prefrontal cortex 30 days post-treatment. These results suggest that long-term impairment within the prefrontal cortex is a plausible mechanism of CICD in this study, suggesting DOX-induced toxicity in the prefrontal cortex at the dose used.

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Acknowledgments

This research was supported by the American Cancer Society (IRG-58-009-51 to C.C.Q.). The authors thank Dr. M. Scott Thompson at the Vanderbilt University Medical Center Oncology Pharmacy; Dr. Randy L. Smith Barrett at the Vanderbilt University School of Medicine Rat Neurobehavioral Core; and Fuxue Xin and Dr. Zou Yue at the Vanderbilt University Institute of Imaging Science Center for Small Animal Imaging. We also acknowledge Mackenzie Whitehurst for her assistance in analyzing the novel object recognition data and Tanner Liddy for his assistance in analyzing the contextual fear conditioning data. Finally, we thank Mrs. Joan M. Gee for asking the question “I wonder what chemotherapy will do to my brain?”; her personal experiences with breast cancer and chemotherapy in 2010 was the motivation for this study.

Author contributions

 Concept and study design: Barry, Byun, Gee, Quarles

Development of methodology: Barry, Byun, Tantawy, Wilson

Acquisition of data: Barry, Byun, Tantawy, Wilson, Gee

Analysis and interpretation of data: Barry, Byun, Tantawy, Mackey, Flom, Stark

Writing, reviewing, and revising manuscript: Barry, Byun, Tantawy, Quarles

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Authors and Affiliations

  1. Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA

    Robert L. Barry, Nellie E. Byun, M. Noor Tantawy, Chase A. Mackey, George H. Wilson III, Adam J. Stark, Michael P. Flom & C. Chad Quarles

  2. Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA

    Robert L. Barry, M. Noor Tantawy & C. Chad Quarles

  3. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA

    Robert L. Barry

  4. Department of Radiology, Harvard Medical School, Boston, MA, USA

    Robert L. Barry

  5. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA

    Nellie E. Byun

  6. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA

    Nellie E. Byun

  7. Neuroscience Program, Vanderbilt University, Nashville, TN, USA

    Adam J. Stark & Michael P. Flom

  8. Division of Animal Care, Vanderbilt University Medical Center, Nashville, TN, USA

    Laura C. Gee

  9. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    C. Chad Quarles

  10. Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA

    C. Chad Quarles

  11. Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA

    C. Chad Quarles

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  1. Robert L. Barry
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  2. Nellie E. Byun
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  4. Chase A. Mackey
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  8. Laura C. Gee
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  9. C. Chad Quarles
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Correspondence to Robert L. Barry.

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Robert L. Barry and Nellie E. Byun contributed equally to this work.

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Barry, R.L., Byun, N.E., Tantawy, M.N. et al. In vivo neuroimaging and behavioral correlates in a rat model of chemotherapy-induced cognitive dysfunction. Brain Imaging and Behavior 12, 87–95 (2018). https://doi.org/10.1007/s11682-017-9674-2

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