Yue Leng1, Terri Blackwell2, Peggy M Cawthon2, Sonia Ancoli-Israel3, Katie L Stone2, Kristine Yaffe4,5,6. 1. Department of Psychiatry, University of California, San Francisco. 2. California Pacific Medical Center Research Institute, California Pacific Medical Center, San Francisco. 3. Department of Psychiatry, University of California, San Diego. 4. Department of Psychiatry, San Francisco Veterans Affairs Medical Center, University of California, San Francisco. 5. Department of Neurology, San Francisco Veterans Affairs Medical Center, University of California, San Francisco. 6. Department of Epidemiology, San Francisco Veterans Affairs Medical Center, University of California, San Francisco.
Abstract
Importance: Disruption in circadian activity rhythms is very common in older adults, particularly among those with neurodegenerative diseases, including Parkinson disease (PD). However, whether circadian disruption could be a prodrome for PD is unclear. Objective: To determine the association between rest-activity rhythm (RAR) and risk of incident PD and to explore whether this association is independent of nighttime sleep disturbances. Design, Setting, and Participants: The ancillary sleep study of the longitudinal cohort Osteoporotic Fractures in Men Study (MrOS) was conducted from December 1, 2003, to March 31, 2005. Of the 3135 community-dwelling men enrolled in the MrOS sleep study, 3049 had technically adequate RAR data; of these, 119 were excluded for having prevalent PD or missing incident data, leaving 2930 men without PD at baseline. Data were analyzed from February 1 through August 31, 2019. Exposures: Twenty four-hour RAR parameters (amplitude, mesor, robustness, and acrophase) generated by wrist actigraphy-extended cosinor analysis. Main Outcomes and Measures: Incident PD based on physician diagnosis. Multivariable logistic regression was used to determine the association between quartiles of RAR parameters and risk of incident PD. Results: Among the 2930 men included in the analysis (mean [SD] age, 76.3 [5.5] years), 78 (2.7%) developed PD during 11 years of follow-up. After accounting for all covariates, the risk of PD increased with decreasing circadian amplitude (strength of the rhythm) (odds ratio [OR] per 1-SD decrease, 1.77; 95% CI, 1.30-2.41), mesor (mean level of activity) (OR per 1-SD decrease, 1.64; 95% CI, 1.22-2.21), or robustness (how closely activity follows a cosine 24-hour pattern) (OR per 1-SD decrease, 1.54; 95% CI, 1.14-2.07) (P < .005 for trend). Those in the lowest quartile of amplitude, mesor, or robustness had approximately 3 times the risk of developing PD compared with those in the highest quartile of amplitude (OR, 3.11; 95% CI, 1.54-6.29), mesor (OR, 3.04; 95% CI, 1.54-6.01), and robustness (OR, 2.65; 95% CI, 1.24-5.66). The association remained after further adjustment for nighttime sleep disturbances and duration in the lowest compared with the highest quartile (OR for amplitude, 3.56 [95% CI, 1.68-7.56]; OR for mesor, 3.24 [95% CI, 1.52-6.92]; and OR for robustness, 3.34 [95% CI, 1.45-7.67]). These associations were somewhat attenuated, but the pattern remained similar after excluding PD cases developed within 2 years after baseline in the lowest compared with the highest quartile (OR for amplitude, 2.40 [95% CI, 1.15-5.00]; OR for mesor, 2.76 [95% CI, 1.35-5.67]; and OR for robustness, 2.33 [95% CI, 1.07-5.07]). Acrophase was not significantly associated with risk of PD. Conclusions and Relevance: In this cohort study, reduced circadian rhythmicity was associated with an increased risk of incident PD, suggesting it may represent an important prodromal feature for PD. Future studies are needed to determine whether circadian disruption could also be a risk factor for PD and whether strategies to improve circadian function affect the risk of PD.
Importance: Disruption in circadian activity rhythms is very common in older adults, particularly among those with neurodegenerative diseases, including Parkinson disease (PD). However, whether circadian disruption could be a prodrome for PD is unclear. Objective: To determine the association between rest-activity rhythm (RAR) and risk of incident PD and to explore whether this association is independent of nighttime sleep disturbances. Design, Setting, and Participants: The ancillary sleep study of the longitudinal cohort Osteoporotic Fractures in Men Study (MrOS) was conducted from December 1, 2003, to March 31, 2005. Of the 3135 community-dwelling men enrolled in the MrOS sleep study, 3049 had technically adequate RAR data; of these, 119 were excluded for having prevalent PD or missing incident data, leaving 2930 men without PD at baseline. Data were analyzed from February 1 through August 31, 2019. Exposures: Twenty four-hour RAR parameters (amplitude, mesor, robustness, and acrophase) generated by wrist actigraphy-extended cosinor analysis. Main Outcomes and Measures: Incident PD based on physician diagnosis. Multivariable logistic regression was used to determine the association between quartiles of RAR parameters and risk of incident PD. Results: Among the 2930 men included in the analysis (mean [SD] age, 76.3 [5.5] years), 78 (2.7%) developed PD during 11 years of follow-up. After accounting for all covariates, the risk of PD increased with decreasing circadian amplitude (strength of the rhythm) (odds ratio [OR] per 1-SD decrease, 1.77; 95% CI, 1.30-2.41), mesor (mean level of activity) (OR per 1-SD decrease, 1.64; 95% CI, 1.22-2.21), or robustness (how closely activity follows a cosine 24-hour pattern) (OR per 1-SD decrease, 1.54; 95% CI, 1.14-2.07) (P < .005 for trend). Those in the lowest quartile of amplitude, mesor, or robustness had approximately 3 times the risk of developing PD compared with those in the highest quartile of amplitude (OR, 3.11; 95% CI, 1.54-6.29), mesor (OR, 3.04; 95% CI, 1.54-6.01), and robustness (OR, 2.65; 95% CI, 1.24-5.66). The association remained after further adjustment for nighttime sleep disturbances and duration in the lowest compared with the highest quartile (OR for amplitude, 3.56 [95% CI, 1.68-7.56]; OR for mesor, 3.24 [95% CI, 1.52-6.92]; and OR for robustness, 3.34 [95% CI, 1.45-7.67]). These associations were somewhat attenuated, but the pattern remained similar after excluding PD cases developed within 2 years after baseline in the lowest compared with the highest quartile (OR for amplitude, 2.40 [95% CI, 1.15-5.00]; OR for mesor, 2.76 [95% CI, 1.35-5.67]; and OR for robustness, 2.33 [95% CI, 1.07-5.07]). Acrophase was not significantly associated with risk of PD. Conclusions and Relevance: In this cohort study, reduced circadian rhythmicity was associated with an increased risk of incident PD, suggesting it may represent an important prodromal feature for PD. Future studies are needed to determine whether circadian disruption could also be a risk factor for PD and whether strategies to improve circadian function affect the risk of PD.