Role of Circadian Rhythms and Sleep Disorders in Perioperative Neurocognitive Disorders Trajectories

Massachusetts General Hospital, Boston MA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Perioperative neurocognitive disorders (PND) pose a significant public health problem for patients, leading to detrimental consequences, including increased healthcare costs, functional disability, and long-term cognitive impairment. Understanding its pathogenesis is an area of active research, much of which is focused on the physiological impact of surgery and anesthesia on the central nervous system (CNS). Disruption of circadian rhythms and sleep interferes with biological processes integral to health and the CNS. We observed that patients with sleep disorders have injuries in multiple brain sites that are further exacerbated by surgery. We documented that surgery/anesthesia ignites the underlying brain lesions, leading to an attendant decrease in performance in several cognitive domains. Recent genetic studies point to shared links between sleep and brain health. Whether genetic variations of circadian rhythms and sleep affect PND remains unexamined. My research program will use a multifaceted approach to advance our understanding of perioperative cognitive trajectories, with the goals for the next five years to 1) implement a comprehensive, perioperative neurocognitive assessment program that is accessible to a diversity of populations; 2) gather, analyze, and characterize perioperative sleep/activity abnormalities; 3) identify genetic variants that might play a role in hastening the development of PND. My past and ongoing work incorporates new tools and models to harness and implement technological innovations to understand the mechanisms and risk factors involved in the origins and trajectories of PND. I am well-positioned to lead this research program, with a proven track record, within an excellent institutional environment, and with current and future collaborators positioned to contribute to this program with expertise in genetic studies and circadian phenotyping. Highlights of expected outcomes: 1) collection and analyses of high volumes of comprehensive cognitive data that will provide for the development of prehabilitation programs; 2) causal associations between perioperative sleep disorders and cognitive impairment that will initiate sleep optimization programs and novel therapeutic targets; 3) identification of genetic risk for PND; and 4) discovery of novel mechanisms, pathways, and interactions that may lead to the development of pharmacological interventions. The successful execution of this proposal will produce an innovative framework linking genetic variants with PND and lead to therapeutic strategies that will improve brain health for all populations. In line with the mission of the NIGMS, the goal of this proposal is to lay the research foundation for understanding the interconnected biological processes between PND and sleep, while advancing the diagnosis, treatment, and prevention of these intractable and devastating diseases. Effective prevention strategies for PND will improve the overall health, lifespan, and well-being of surgical patients and communities, help dampen the skyrocketing healthcare costs, and disrupt the cycle of disability and long-term care after surgery.