title: In vivo neuroimaging and behavioral correlates in a rat model of chemotherapy-induced cognitive dysfunction.
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 decreased18F-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.
authors.affiliation: Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA. Robert.Barry@mgh.Harvard.edu.|Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA. Robert.Barry@mgh.Harvard.edu.|Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA. Robert.Barry@mgh.Harvard.edu.|Department of Radiology, Harvard Medical School, Boston, MA, USA. Robert.Barry@mgh.Harvard.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Barry
authors.affiliation: Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Nellie E
authors.initials: NE
authors.lastname: Byun
authors.affiliation: Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: M Noor
authors.initials: MN
authors.lastname: Tantawy
authors.affiliation: Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Chase A
authors.initials: CA
authors.lastname: Mackey
authors.affiliation: Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: George H
authors.initials: GH
authors.lastname: Wilson
authors.affiliation: Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA.|Neuroscience Program, Vanderbilt University, Nashville, TN, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Stark
authors.affiliation: Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA.|Neuroscience Program, Vanderbilt University, Nashville, TN, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Flom
authors.affiliation: Division of Animal Care, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Gee
authors.affiliation: Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.|Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: C Chad
authors.initials: CC
authors.lastname: Quarles
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects*; D001931:Brain Mapping; D060825:Cognitive Dysfunction / Q000139:chemically induced* / Q000000981:diagnostic imaging* / Q000523:psychology; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity*; D005239:Fear / Q000187:drug effects; D005260:Female; D019788:Fluorodeoxyglucose F18; D008279:Magnetic Resonance Imaging; D059906:Neuroimaging; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects; D014057:Tomography, X-Ray Computed
chemical_list: D000970:Antineoplastic Agents; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D004317:Doxorubicin
keywords: Chemobrain; Chemotherapy; Chemotherapy-induced cognitive dysfunction; Contextual fear conditioning; Doxorubicin; Neurobehavioral testing; Neuroimaging; Novel object recognition; [18F]fluorodeoxyglucose positron emission tomography