Aromatase inhibitors (AIs) are drugs that inhibit estrogen synthesis and that are prescribed to prevent the recurrence of estrogen responsive breast cancers. However, AIs, such as the commonly prescribed Letrozole (LET), are associated with severe side-effects that further burden the quality of life, including insomnia, hot flashes, depressive symptoms and cognitive deficits. The precise mechanisms by which AIs may give rise to these CNS symptoms remain unclear and difficult to study in humans, as control for individual differences in disease severity, treatment history and experienced stress is lacking. Furthermore, AI treatment is recommended for 3 to 5 years, yet little is known about the effects of long-term AI use on the brain and behavior, especially with regards to age-related cognitive decline and Alzheimer's disease (AD) risk. We propose to develop a primate model for AI-induced CNS effects to advance our knowledge in this area and facilitate the design of novel therapeutics. This application uses the marmoset (Callithrix jacchus), a small primate with a brain architecture, sleep patterns, cognitive abilities, emotional responses and thermoregulation patterns that are comparable to those of humans (1) to study the effects of chronic LET use on the brain and behavior and (2) to test whether DHED, a prodrug that delivers E2 selectively to the brain, can effectively and safely prevent LET-associated adverse effects. To achieve these aims, middle-aged male and female marmosets treated with LET, LET + DHED or Vehicle for 3 years will be studied longitudinally for changes in sleep/wake patterns, cognitive performance, emotional regulation, and thermoregulation. The monkeys will be outfitted with an activity monitor for sleep/wake patterns analysis. Cognitive function will be assessed via an automated computerized battery. Thermal imaging will be used to measure changes in facial skin temperature during a thermal challenge. Emotional regulation will be assessed by measuring heart rate variability and facial skin temperature in monkeys viewing emotional and neutral videos. Following these in vivo behavioral assessments, analyses of brain tissues from underlying brain regions (hypothalamus, hippocampus, prefrontal cortex, locus coeruleus) will be carried out to quantify gene expression of selected genes, tauopathies, ?-amyloid deposition and neuronal excitability. The results will have important translational applications for AI-treated patients by (1) characterizing the effects of AIs on multiple neural and behavioral outcomes; (2) determining whether long-term estrogen suppression promotes the development of an AD-like phenotype and (3) whether providing the brain with an alternate source of estrogen can counteract the adverse effects of AIs on the brain and behavior.

Public Health Relevance

Breast cancer patients using aromatase inhibitors (AIs) as an adjuvant therapy often report severe side effects, including hot flashes, cognitive impairment, insomnia and mood changes. Despite long-term use in humans, little is known about the long-term effects of AIs on brain function. This proposal uses a primate model to understand how AIs affect the brain and behavior and to test whether a drug that delivers estrogens exclusively to the brain can safely alleviate these deficits.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Horowitz, Todd S
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University of Massachusetts Amherst
Schools of Arts and Sciences
United States
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