Molecular Mechanisms of Chemotherapy-Induced Cognitive Decline
Karen Hubbard, PhD and Tim A. Ahles, PhD
Chemotherapy-induced changes in cognitive performance and brain structure and function have been demonstrated; however, there have been few studies either in humans or animals that detail specific cellular or molecular alterations underlying this cognitive decline, or where in the brain such changes might occur. Ahles and Saykin have proposed that cognitive changes associated with chemotherapy are related to DNA damage and cellular senescence. Chemotherapeutic agents used clinically often generate DNA damage to induce programmed cell death or senescence to reduced tumor growth. This DNA damage may induce pre-mature cellular senescence and presents a dilemma, as exposed normal cells may be induced to undergo premature cellular senescence in a similar manner. The primary goal of this translational, pilot study is to assess the impact of chemotherapy by measuring the alteration in gene expression by DNA damage induced pre-mature senescence in the brain of a rodent model system. We will then extend these studies to assess changes in gene expression in human blood cells isolated from patients at the end of their chemotherapy. Our hypothesis is that chemotherapeutics induce changes in gene expression in the brain that contribute to cognitive impairment. The specific aims are 1) to determine the areas specifically affected in rat brains following treatment of chemotherapeutic agents, and 2) to determine the effects of chemotherapy on specific neuronal and immuno-gene expression changes in humans. We will also explore the relationships between the markers of cell senescence and cognitive changes in the rodent (measured by performance in the Morris Water Maze) and in breast cancer patients (measured by neuropsychological assessment and fMRI). This proof of concept study represents the first step in achieving our long-term goals of understanding the interactions between cognition , carcinogenesis and aging and molecular mechanisms of chemotherapy induced cognitive change and the development of targeted interventions designed to prevent or reduce the cognitive impact of chemotherapy.