Metabolic Interventions for Sleep, Anesthesia-related Neurocognitive Disorders and Alzheimer's Disease

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ABSTRACT This objective of this research is to develop metabolic interventions to improve sleep quality and anesthesia safety in the elderly and eventually to treat neurodegenerative diseases like Alzheimer's disease. The aging brain has many changes including mitochondrial dysfunction, insulin resistance and decreased neurotransmitter release leading to poor sleep quality and more complications with general anesthesia. The ability of the brain to use glucose declines with age but the brain's ability to use ketones as fuel remains. Ketone bodies are produced naturally from the breakdown of fatty acids and become a major fuel source for the brain during times of starvation, exercise and high-fat, low-carbohydrate diets. The ketone bodies acetoacetate and beta-hydroxybutyrate not only provide energy to the brain but also have potent signaling and anti-inflammatory effects. The activation of inflammatory pathways, such as nuclear factor kappa B, are thought to be one mechanism through which sleep disturbance and dementia are linked as well as post-operative delirium and post-operative cognitive dysfunction. The inflammatory response is also tightly correlated with the onset and clinical course of Alzheimer's disease and disruptions in sleep are an early biomarker of Alzheimer's disease. Sleep quality declines with normal age as well, losing restorative slow and delta power and becoming more fragmented. Therefore, targeting brain energy usage by providing ketones could be one strategy for improving sleep quality in aged animals. In addition, the aged population is more susceptible to general anesthesia. Less anesthesia is needed to anesthetize older people and they are more likely to develop post-operative cognitive dysfunction. The energy substrate and anti-inflammatory effects of ketones could be neuroprotective during anesthesia in the aged brain. Taken together, these ideas give rise to novel strategies that address the dysfunctional neuronal metabolic-immune interactions in the aged brain by increasing ketones that could lead to improved sleep quality (AIM 1) and safer delivery of general anesthesia (AIM 2) to the elderly. These innovative strategies to improve brain health in the aged population have the potential for broad impact as many brain diseases have components of metabolic dysregulation including epilepsy, Alzheimer's disease, Parkinson's disease, autism, anxiety, depression and glioblastoma.