Sleep and circadian rhythm regulation in early Parkinson disease

Abstract

Importance: Sleep disturbances are recognized as a common nonmotor complaint in Parkinson disease but their etiology is poorly understood.

Objective: To define the sleep and circadian phenotype of patients with early-stage Parkinson disease.

Design, setting, and participants: Initial assessment of sleep characteristics in a large population-representative incident Parkinson disease cohort (N=239) at the University of Cambridge, England, followed by further comprehensive case-control sleep assessments in a subgroup of these patients (n=30) and matched controls (n=15).

Main outcomes and measures: Sleep diagnoses and sleep architecture based on polysomnography studies, actigraphy assessment, and 24-hour analyses of serum cortisol, melatonin, and peripheral clock gene expression (Bmal1, Per2, and Rev-Erbα).

Results: Subjective sleep complaints were present in almost half of newly diagnosed patients and correlated significantly with poorer quality of life. Patients with Parkinson disease exhibited increased sleep latency (P = .04), reduced sleep efficiency (P = .008), and reduced rapid eye movement sleep (P = .02). In addition, there was a sustained elevation of serum cortisol levels, reduced circulating melatonin levels, and altered Bmal1 expression in patients with Parkinson disease compared with controls.

Conclusions and relevance: Sleep dysfunction seen in early Parkinson disease may reflect a more fundamental pathology in the molecular clock underlying circadian rhythms.

Figure 1. Twenty-Four-Hour Melatonin and Cortisol Rhythms in Patients With Parkinson Disease (PD) vs Controls

These graphs show the mean (SEM) serum melatonin and cortisol concentrations at each time point. In healthy individuals, melatonin levels typically rise in the late evening while cortisol levels peak in the early morning. A, Significant group effect on melatonin concentration on repeated-measures 2-way analysis of variance and lack of a statistically significant time-dependent variation in melatonin concentration over the 24-hour sampling period. Patients with PD also had a reduced area under the curve and a reduced melatonin nadir. There were individual missing melatonin data points in 6 patients with PD (1.1% of total data set) and 1 control (0.4% of total dataset). B, Significant group effect on cortisol concentration on repeated-measures 2-way analysis of variance. Patients with PD also had an increased acrophase, increased amplitude, and increased area under the curve. There were individual missing cortisol data points in 7 patients with PD (1.3% of total data set) and 4 controls (1.6% of total data set).

Figure 2. Twenty-Four-Hour Clock Gene Expression in Patients With Parkinson Disease (PD) vs Controls

These graphs show the mean (SEM) normalized gene expression levels for the 3 clock genes studied at each time point in peripheral blood mononuclear cells. We sought to investigate whether patients with PD exhibited the same peripheral clock gene expressions oscillations as one would expect in healthy individuals. Loss of the time-dependent variation in Bmal1 was seen in patients with PD over the 24-hour period (A), together with higher expression of Per2 and RevErbα at 4 AM (B and C, respectively). There were individual missing data points in 2 patients with PD (0.8%) and no controls.