Exploring Cholinergic Changes and their Associations with Sleep Alterations in the Lewy Body Disease Spectrum: New Biomarkers and Therapeutic Targets

About This Grant

Abstract Cholinergic brain activity plays a crucial role in regulating sleep, particularly Rapid Eye Movement (REM) sleep, as demonstrated in animal studies. How these findings translate to humans remains insufficiently explored. Understanding the neurobiology of sleep in humans is critical, as sleep dysregulation is closely linked to neurodegeneration, making sleep a promising therapeutic target. REM sleep behavior disorder (RBD), an early sign of Parkinson’s disease (PD) and Dementia with Lewy Bodies—collectively known as Lewy Body Disorders (LBD) —often appears decades before diagnosis, where it is referred to as isolated RBD. Cholinergic changes also emerge early in LBD, possibly starting in isolated RBD phase. These changes extend beyond the typical decline in cholinergic activity and can include compensatory mechanisms, such as increased activity of the vesicular acetylcholine transporter. We hypothesize that changes in cholinergic neurotransmission, whether increases or decreases, can affect the tonic and phasic availability of acetylcholine. Changes in tonic and phasic availability of acetylcholine, in turn, may disrupt the sleep-wake cycle, leading to REM sleep disturbances such as RBD among others. Our preliminary findings in patients with PD support this hypothesis. We observed cholinergic changes using the selective brain PET radiotracer [18F]-FEOBV, which binds to the vesicular acetylcholine transporter, and self-reported measures of RBD symptoms and excessive daytime sleepiness. Wearable at-home sleep recording devices, such as the Sleep Profiler™, provide a patient-friendly method for quantifying sleep architecture and its alterations with performance comparable to traditional in-lab polysomnography. These technologies enable more ecological investigations of sleep biomarkers. The main aim of this study is to investigate the relationship between cholinergic brain changes and sleep, moving beyond qualitative, questionnaire-based measures in patients with PD (K99) and isolated RBD (R00). We will do that by using advanced imaging techniques ([18F]-FEOBV PET) and wearable sleep recording devices (Sleep Profiler™). During the K99 phase, we will focus on patients with PD, examining the association between cholinergic changes and REM (Aim 1) and non-REM sleep alterations (Aim 2). Building on the skills acquired during the K99 (sleep recording analyses and neurobiology of sleep), I will transition to the independent R00 phase to investigate cholinergic changes in a newly recruited cohort of patients with isolated RBD. I will explore how these changes relate to sleep architecture and clinical progression (one-year follow-up). This research can provide valuable insights into how the cholinergic system contributes to sleep disturbances, potentially paving the way for novel cholinergic modulation treatments that target sleep to protect brain health in isolated RBD and LBD. It may also validate the use of wearable sleep devices for at-home monitoring of cholinergic system changes. The findings in this study will inform the design of future research on molecular mechanisms linked to sleep disturbances and neurodegeneration.