From Dreams to Degeneration: Sleep-Wake Disturbances as a Target for Novel Biomarkers and Therapies for Patients with Parkinson s Disease
Abstract
Sleep-wake disturbances are among the most prevalent and distressing non-motor features of Parkinson s disease (PD), associated with reduced quality of life and increased caregiver stress. Sleep problems in PD include broken sleep, excessive daytime sleepiness, insomnia, and Rapid Eye Movement Sleep behaviour disorder (RBD) -- a disorder in which subjects will lose the normal paralysis in sleep and begin to act out their dreams. Interestingly, sleep disturbances can occur early in PD and even precede the movement symptoms by decades, and, as in the case of RBD, have become the strongest clinical indicator that someone will develop PD. These observations suggest that sleep disruption is intimately linked with the pathology underlying PD. Unfortunately, the mechanisms and biology underlying sleep disturbances in PD are poorly understood. The proposed work tries to address this gap, motivated by the core hypothesis that understanding the biology of sleep-wake dysfunction in PD may help us find better treatments for sleep problems and also provide clues to understanding and even preventing the progression of the disease itself. Recent advances from animal models have improved our understanding of the neurotransmitters and circuitry responsible for sleep and wakefulness. Recently, we applied these concepts to a model explaining a disabling symptom seen in advanced stages of PD known as cognitive fluctuations wherein patients experience profound swings in their attention and levels of alertness between days and sometimes also within a single day. We proposed that this arises from pathology affecting key parts of the sleep-wake circuitry, producing a transient sleep-like state during wake. This was supported by findings from a recent imaging study. We also predicted that the same pathology will also result in a range of other subtle sleep-related changes that can be detected in patients with PD as the disease progresses, such as the amount of slow waves that occur in sleep and intrude into wakefulness, and other characteristic changes seen in the brain waves recorded during sleep. This serves as the starting point of our first aim of the proposed work, in which we will look for these characteristic changes or signatures of disruption of sleep-wake circuitry using a combination of high-resolution scalp recordings and neuroimaging methods in patient groups representing the spectrum of PD, including patients with isolated RBD who have yet to develop PD, patients with early PD, and patients with PD and dementia (PDD). By comparing across the groups and healthy controls, we hope to find signatures that may be used as biomarkers to track progression of PD and potentially predict the development of cognitive problems like fluctuations. In parallel, as part of our second aim we will use brain samples donated by patients with PD to directly investigate the pathology affecting key areas of the brain regulating sleep and wake across patients with PD and PD dementia. We will understand which regions are affected at different stages of PD compared to controls and will relate these to sleep-related symptoms and fluctuations reported whilst alive. Understanding which populations of cells and their neurotransmitters are affected and at what stage of the disease they are affected may help us understand the biology of sleep disorders in PD, as well as make decisions about which existing medications may be useful to use to treat these symptoms and offer suggestions for new medication targets. The final aim of the proposed study explores how sleep disturbances can impact PD and its symptoms. One of the many vital functions of sleep is the clearance of abnormal proteins from the brain at night, which occurs via a recently discovered drainage pathway known as the glymphatic system. Therefore, it has been hypothesized that sleep problems may interfere with the clearance of these proteins and worsen the progression of brain
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310849
Entities
People
- Elie Matar
Organizations
- United States Army
- University of Sydney