Alterations in sleep-activity cycles and clock gene expression across the synucleinopathy spectrum

Background Neurodegenerative synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are strongly associated with sleep disturbances. Furthermore, isolated Rapid Eye Movement Sleep Behaviour Disorder (iRBD) is now established as the strongest risk factor for developing PD or DLB, often preceding the clinical diagnosis by several years. Objectives We aimed to investigate sleep/wake cycles and circadian rhythms in patients with early PD and DLB, along with ‘at risk’ prodromal subjects diagnosed with iRBD. Methods Fifteen healthy controls, 20 iRBD, 16 PD and 17 DLB patients within 5 years of diagnosis, underwent assessment. Sleep/wake cycles were evaluated using questionnaires and actigraphy. Salivary and oral mucosa samples were collected every 3 hours to measure melatonin levels and Bmal1 clock gene expression over 24-hours. Results Both subjective and objective measures of sleep/wake cycles demonstrated that the DLB group exhibited the most significant sleep/wake cycle disruption. In the DLB group, no fundamental sine wave could be fitted to the level of melatonin secretion, indicating a severe disruption in the daily rhythm of this hormone. There was a statistically significant pattern of decreasing median Bmal1 amplitude from HC, to iRBD, to PD and then to DLB ( p  = 0.037). Conclusions This work highlights a differential gradient of objective disruption in the daily circadian rhythms from iRBD to established PD and DLB and is the first to directly demonstrate disruption of clock gene expression and melatonin in DLB. The findings support sleep/wake disruption as a marker of neuropathological severity and potentially a novel therapeutic target across the synucleinopathy spectrum.