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The research, led by researchers at the Georgetown University Medical Center (GUMC) and published in Neurotoxicity research, concludes the findings of another study conducted by GUMC, published Oct. 3, which revealed that a subgroup of breast cancer patients with long-lasting cognitive deficits also presented the APOE4 gene. Cancer survivors often report difficulties with memory and this study, published in the Journal of Clinical Oncology (JCO), was the first major American study on cognition in elderly patients with breast cancer and the first to focus on the cause of memory difficulties, among other problems.
Although the JCO study did not examine the specific type of chemotherapy used in patients treated for metastatic breast cancer, the study in mice focused on a single drug, doxorubicin, commonly used to treat cancer.
"These two studies have taken completely different approaches, but they tell the same story, which is a real asset," says G. William Rebeck, Ph.D., a professor in GUMC's Department of Neuroscience and lead author on Neurotoxicity research study.
"The data on the mice are very clear: APOE4 is working with doxorubicin to produce significant changes in the cortex and hippocampus and to significantly impede learning," he said. .
"Given the good functioning of this mouse model, we believe that we can now methodically test chemotherapy drugs, one by one, and see what effects these drugs may produce in the brain." We could also test agents to prevent cognitive decline in cancer patients with APOE4., "says Rebeck.
"This type of direct studies can not be done in humans, our mouse models could provide valuable information on the most effective drugs for individual patients," he says.
Rebeck, a neuroscientist, began working on this project several years ago when Jeanne Mandelblatt, MD, MD, MPH, came to see Rebeck. Mandelblatt, who led the JCO study, asked himself at the beginning of the study whether APOE4 could be a culprit of the cognitive problems that some of the patients in his study had. Rebeck is well known for his work on the connection between APOE4 and Alzheimer's disease.
They discussed the potential impact of chemotherapy on brain function in APOE4-positive patients, which led Rebeck to test a mouse model of human APOE3 (the most common variant) and of 39; APOE4. These mice lack the mouse APOE gene (which is different from that of humans) and instead express one of two human APOE alleles.
While the APOE3 and APOE4 chemotherapy-treated mice had brain changes, compared to a control group of doxorubicin-free knock-in mice, the difference was more severe in the APOE4-treated mice. These mice also exhibited a significant impairment of the functioning of the learning tasks.
Rebeck can not say why chemotherapy and APOE4 can work together to affect brain function, but "good hypotheses" are that the combination increases inflammation at the periphery of the brain that accelerates aging – and that aging is linked to the development of Alzheimer's disease – or that APOE4 inhibits normal growth of new neurons in the brain that helps replace damaged neurons.
"Our group is delighted to be able to provide information to our colleagues who are studying cancer," he said. "We hope to collaborate a lot on these issues in the future."
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The first major study details cognitive outcomes in elderly patients with breast cancer
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