Circadian Expression of Clock Genes in Parkinson’s Disease - Implications for Disrupted Sleep and Daytime Sleepiness (S19.008)

Abstract

OBJECTIVE 1) To examine circadian rhythms of clock genes Per1,2,3, and Bmal1 in whole blood in participants with Parkinson’s Disease (PD); 2) to examine relationship between clock gene expression and disease severity, sleep quality and daytime sleepiness in PD. BACKGROUND Alterations of the circadian system may be one mechanism leading to disrupted sleep/wake cycles in PD. This hypothesis is supported by recent reports of impaired circadian secretion of melatonin, an endogenous marker of circadian rhythmicity, in PD. Clock genes, molecular markers of circadian timekeeping, have not been studied in PD patients with sleep dysfunction. METHODS Twenty PD participants on dopaminergic therapy, 10M/10F, age 63.2±1.8 yrs, average PD duration of 6.7±1.4 yrs, total UPDRS score 34.1±2.1, participated in this study. Real-time reverse transcription PCR was used to measure transcript levels of clock genes every 2 hours over a 24-hour period under modified constant routine conditions. Additional measures included metrics of sleep and alertness. RESULTS A significant variability of gene expression levels and acrophases was observed. A definitive acrophase was observed for each clock gene in all participants. Amplitudes of gene expressions did not correlate with PD severity or sleep metrics. Acrophases (i.e., timing or phase) of Per1,2 were advanced and of Bmal1 were delayed when compared to published data in healthy controls. The phase delay of Bmal1 was positively correlated with daytime sleepiness. The phase of Per1,2,3 and Bmal1 was significantly different in participants with various levels of daytime somnolence and sleep quality. CONCLUSIONS Core circadian clock genes express circadian oscillations in PD. The phase and amplitude of these clock genes may affect physiology in PD. The phase of Bmal1 is associated with daytime sleepiness in PD. Further longitudinal studies employing larger cohorts of PD participants are needed to better define interactions between molecular circadian markers and sleep/wake regulation in PD.

Disclosure: Dr. Videnovic has received personal compensation for activities with Acorda Therapeutics and Wilson's Therapeutics. Dr. Videnovic has received research support from PhotoPharmics. Dr. Marconi has nothing to disclose. Dr. Zee has received personal compensation for activities with Vanda, Merck & Co., Inc., and Jazz Pharmaceuticals as a consultant. Dr. Zee holds stock and/or stock options in Teva Neuroscience. Dr. Zee has received research support from Jazz Pharmaceutica Dr. Klerman has nothing to disclose. Dr. Turek has nothing to disclose.