Abstract
Clinical studies indicate that up to 70% of patients with cancer who receive chemotherapy experience cognitive impairment. The present study used a prospective longitudinal design to assess short- and long-term effects of commonly used anticancer drugs on cognitive performance in a mouse model. Normal mice received three weekly injections of a combination of methotrexate + 5-fluorouracil (CHEMO group) or an equal volume of saline (SAL group). Cognitive tests, measuring different aspects of learning and memory, were administered before treatment, immediately after treatment, and three months later. Structural MRI scanning was conducted at each stage of cognitive testing. The CHEMO group exhibited deficits on cognitive tasks acquired pretreatment [spatial memory, nonmatching-to-sample (NMTS) learning, and delayed NMTS], as well as impaired new learning on two tasks (conditional associative learning, discrimination learning) introduced posttreatment. Consistent with clinical evidence, cognitive deficits were pronounced on tests that are sensitive to hippocampal and frontal lobe dysfunction, but the CHEMO group's poor performance on the discrimination learning problem suggests that impairment is more widespread than previously thought. Cognitive deficits persisted for at least three months after treatment but some recovery was noted, particularly on tests thought to be under frontal lobe control. The MRI tests did not detect brain changes that could be attributed to treatment. Chemotherapeutic agents can have adverse effects on information acquired pretreatment as well as new learning and memory and, despite some recovery, impairment is long lasting.
Highlights
Clinical studies indicate that up to 70% of patients with cancer who receive adjuvant chemotherapy experience cognitive impairment [1,2,3]
Consistent with clinical evidence, cognitive deficits were pronounced on tests that are sensitive to hippocampal and frontal lobe dysfunction, but the CHEMO group’s poor performance on the discrimination learning problem suggests that impairment is more widespread than previously thought
The mice were monitored for possible side effects related to drug treatment but, except for a small amount of hair loss in about 25% of the mice that received chemotherapy, none was detected
Summary
Clinical studies indicate that up to 70% of patients with cancer who receive adjuvant chemotherapy experience cognitive impairment [1,2,3]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). The adverse effects of anticancer drugs on cognition have been confirmed in animals and the deficits are often similar to those observed in patients [4,5,6,7,8,9]. The congruence of data from animal models points to the biologic basis of the problem and argues against the notion that such effects are psychosocial in nature, resulting from the challenges of coping with a serious disease and difficult treatment
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