Reduced Circadian Rhythmicity Associated With Increased Risk of Parkinson Disease

July 9, 2020

Reduced amplitude and/or robustness of the rhythms, rather than disrupted timing, are the most indicative of a subsequent risk of PD, independent of nighttime sleep disturbances.

Yue Leng, MD, PhD

Results from an ancillary sleep study of the longitudinal cohort Osteoporotic Fractures in Men Study (MrOS) revealed that reduced circadian rhythmicity was associated with an increased risk of incident Parkinson disease (PD), suggesting it may represent an important prodromal feature of PD.

The analysis included 2930 men (mean age, 76.3 years [standard deviation (SD), 5.5]), of which 78 (2.3%) developed PD during the 11 years of follow-up. After researchers accounted for all the covariates, they found that the risk of PD increased with decreasing circadian amplitude (odds ratio [OR] per 1-SD decrease, 1.77; 95% CI, 1.30—2.41).

Other factors, such as decreasing mesor, otherwise known as the mean level of activity, (OR per 1-SD decrease, 1.64; 95% CI, 1.22—2.21) and robustness, defined as how closely activity follows a cosine 24-hour pattern, (OR per 1-SD decrease, 1.54; 95% CI, 1.14–2.07) both were associated with an increased risk of PD.

The risk of developing PD increased 3-fold for those in the lowest quartile of amplitude, mesor, or robustness 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). After adjusting for nighttime sleep disturbances and duration in the lowest compared with the highest quartile, the association remained in amplitude (OR, 3.56; 95% CI, 1.68–7.56), mesor (OR, 3.24; 95% CI, 1.52–6.92), and robustness (OR, 3.34; 95% CI, 1.45–7.67).

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Research conducted by Yue Leng, MD, PhD, department of psychiatry, University of California, San Francisco, also revealed that even though the associations were somewhat attenuated, the patterns 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; OR for robustness, 2.33; 95% CI, 1.07–5.07).

A subset analysis of only PD cases confirmed by both physicians diagnosis and PD medication use (n = 58) showed similar results, with more than double the risk of PD observed for those in the lowest quartiles of amplitude (OR, 2.47; 95% 1.12—5.41) and mesor (OR, 2.29; 95% CI, 1.06–4.94) compared with the highest quartiles.

The study, conducted from December 1, 2003, to March 31, 2005, originally had 3049 participants with adequate rest-activity rhythm (RAR) data. Prevalent PD or missing incident data forced 119 to be excluded from the trial, leaving 2930 men included in the analysis.

Leng and colleagues used 20, 4-hour RAR parameters, including amplitude, mesor, robustness, and acrophase, generated by wrist actigraphy-extended cosinor analysis to understand more about the association between RAR and the risk of incident PD. Disruption in circadian activity rhythms is often common with older adults, including those with neurodegenerative disorders, but the association between circadian disruption and PD had not been studied.

“Markers of circadian rhythmicity might be valuable as a prodromal feature to help with the early detection of PD. Future studies are needed to explore underlying mechanisms and to determine whether circadian disruption itself might contribute to the development of PD. If confirmed to be a risk factor for PD, then circadian rhythmicity could be a promising intervention target and will open new opportunities for the prevention and management of PD,” the study authors concluded.

REFERENCE

Leng Y, Blackwell T, Cawthon PM, Ancoli-Israel S, Stone KL, Yaffe K. Association of circadian abnormalities in older adults with an increased risk of developing Parkinson disease. JAMA Neurol. Published online June 15, 2020. doi: 10.1001/jamaneurol.2020.1623.