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 cell loss in a variety of diseases. Whether sleep problems affect the progression of PD is currently unknown. In our study we will use imaging markers of the "glymphatic" system function and follow patients across the stages of PD to see if these markers indeed predict faster decline of motor and cognitive symptoms, which has been suggested by findings in our preliminary studies. In addition to the problems of chronic sleep problems on PD, our model of fluctuations also suggests that PD patients are also vulnerable to acute insults to their sleep, which have been proposed to trigger cognitive symptoms such as fluctuations. Therefore, we will also investigate the impact of acute sleep deprivation on PD, using cognitive testing, scalp electrical recordings and neuroimaging. Together, the findings of these studies will show the importance of treating and targeting sleep as both a symptomatic therapy (to address cognitive symptoms in later PD) and even as a way of slowing down the progression of PD.

In the short term we would expect that this will raise awareness among patients and physicians of the importance of addressing and optimizing sleep issues in clinic, but in the long term (5-10 years) may also open a pathway for new modes of preventing decline in PD, such as through multidisciplinary intervention trials aimed at improving sleep in PD, or the development and use of novel agents focused on improving glymphatic clearance.