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Parkinson's Disease Mechanisms and Treatments / Sleep and Related Disorders · Journal article
npj Parkinson S Disease · September 8, 2026
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This is a protocol document for a planned prospective cohort study investigating the association between circadian syndrome (a multi-system dysfunction combining sleep disruption, metabolic abnormalities, hormonal imbalance, and mood disorder) and incident Parkinson's disease using UK Biobank data. No results are presented; the document sets out the rationale and planned approach to address the gap that existing studies lack longitudinal data and do not examine circadian syndrome as an integrated construct.
Prospective population-based cohort study. UK Biobank participants; specific eligibility criteria not stated in protocol. Intervention: Circadian syndrome (defined as multi-system dysfunction including sleep-wake cycle disturbances, metabolic abnormalities, hormonal imbalances, and emotional disorders) and its individual components. Compared with: Absence of circadian syndrome or varying levels of circadian syndrome exposure; genetic susceptibility groups (for interaction analysis). UK Biobank.
Approximately 80% of PD patients exhibit circadian rhythm disruption symptoms during early disease stages Circadian syndrome incorporates short sleep duration (<6 hours/day) and depressive symptoms alongside metabolic syndrome components In 2019, over 8.5 million individuals were affected by PD globally, resulting in 5.8 million disability-adjusted life years
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If completed as planned, this study could identify circadian syndrome as a modifiable risk factor for Parkinson's disease and support early prevention strategies targeting circadian regulation. However, no clinical implications can be drawn until results are reported.
This is a protocol or background document describing a planned prospective cohort study using UK Biobank data to investigate circadian syndrome and Parkinson's disease incidence; no results are reported, making it a prospective study design statement rather than evidence of an effect.
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If completed as planned, this study could identify circadian syndrome as a modifiable risk factor for Parkinson's disease and support early prevention strategies targeting circadian regulation. However, no clinical implications can be drawn until results are reported.
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Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the abnormal aggregation of misfolded α-synuclein protein into Lewy bodies 1,2.With global population aging, the burden of PD have risen rapidly. Current estimates suggest that in 2019 over 8.5 million individuals were affected by PD, resulting in 5.8 million disability adjusted life years3. Clinical diagnosis of PD primarily relies on motor features including bradykinesia, tremor and rigidity4. However, non-motor features such as cognitive impairment, sleep disorders, and depression often precede motor deficits5 and have been incorporated into the Parkinson and Movement Disorder Society prodromal diagnostic criteria6, with prodromal features increasing PD incidence. Notably, approximately 80% of PD patients exhibit circadian rhythm disruption symptoms during early disease stages, including rapid eye movement sleep behavior disorder, excessive daytime sleepiness, and abnormal melatonin secretion rhythms7. Despite the circadian variation in motor features and the high prevalence of sleep disturbances in PD patients8 suggest that circadian rhythm disruption may play a critical role in the disease progression, researches on the circadian rhythm in PD remains relatively limited. Circadian syndrome (CircS), defined as multi-system dysfunction caused by circadian disruption, including sleep-wake cycle disturbances, metabolic abnormalities, hormonal imbalances, and emotional disorders9, has been proposed as a comprehensive pathological concept. Compared to traditional metabolic syndrome (MetS), which is characterized by central obesity, elevated blood pressure, hyperglycemia, elevated triglycerides, and reduced high-density lipoprotein cholesterol (HDL-C), CircS incorporates short sleep duration (< 6 h/day) and depressive symptoms alongside MetS components, offering a more precise reflection of the harmful effects of modern lifestyles on circadian-metabolism-neural networks10. CircS is an important driver of multiple chronic diseases11–13, which may serve as a predictor of PD. Nonetheless, existing studies typically focus on single circadian markers14, overlooking the synergistic effects of CircS as an integrated syndrome. And most studies focus on MetS, while the association between CircS and PD remains limited. Moreover, the majority of these studies are cross-sectional design and lacking longitudinal data, which restricts the inference of causality15. Genetic factors are crucial in PD pathogenesis, with PD resulting from interaction of genetic and environmental factors16. Notably, the joint impact of genetic susceptibility and CircS on PD incidence remains unknown. To address these gaps, this study will use data from the UK Biobank, a large prospective population-based cohort, to investigate the longitudinal association between CircS and PD incidence. We aim to explore the effects of CircS and its individual components on PD risk, while investigating interaction between CircS and genetic susceptibility. This work is expected to provide potential targets for early PD prevention and offer a scientific basis for interventions focused on circadian regulation. References: 1 Wilson EN, Umans J, Swarovski MS, et al. Parkinson’s disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction. npj Parkinsons Dis 2025; 11: 1–13. 2 Schulz-Schaeffer WJ. The synaptic pathology of α-synuclein aggregation in dementia with lewy bodies, parkinson’s disease and parkinson’s disease dementia. Acta Neuropathol 2010; 120: 131–43. 3 Parkinson-disease. https://www.who.int/zh/news-room/fact-sheets/detail/parkinson-disease (accessed April 28, 2025). 4 Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for parkinson’s disease. Movement Disorders 2015; 30: 1591–601. 5 Simon DK, Tanner CM, Brundin P. Parkinson disease epidemiology, pathology, genetics and pathophysiology. Clin Geriatr Med 2020; 36: 1–12. 6 Berg D, Postuma RB, Adler CH, et al. MDS research criteria for prodromal parkinson’s disease. Movement Disorders 2015; 30: 1600–11. 7 Chahine LM, Amara AW, Videnovic A. A systematic review of the literature on disorders of sleep and wakefulness in parkinson’s disease from 2005 to 2015. Sleep Medicine Reviews 2017; 35: 33–50. 8 Leng Y, Musiek ES, Hu K, Cappuccio FP, Yaffe K. Association between circadian rhythms and neurodegenerative diseases. Lancet Neurol 2019; 18: 307–18. 9 Akbar Z, Shi Z. Unfavorable mealtime, meal skipping, and shiftwork are associated with circadian syndrome in adults participating in NHANES 2005-2016. Nutrients 2024; 16: 1581. 10 Zimmet P, Alberti KGMM, Stern N, et al. The circadian syndrome: Is the metabolic syndrome and much more! J Intern Med 2019; 286: 181–91. 11 Shi Z, Stern N, Liu J, et al. The circadian syndrome is a predictor for cognition impairment in middle-aged adults: Comparison with the metabolic syndrome. Diabetes Metab Res Rev 2024; 40: e3827. 12 Shi Z, Tuomilehto J, Kronfeld-Schor N, et al. The circadian syndrome predicts cardiovascular disease better than metabolic syndrome in Chinese adults. J Intern Med 2021; 289: 851–60. 13 Xiao Y, Yin S, Wang J, et al. A positive association between the prevalence of circadian syndrome and overactive bladder in united states adults. Front Public Health 2023; 11: 1137191. 14 Sleep disorders in the elderly: A growing challenge - gulia - 2018 - psychogeriatrics - wiley online library. https://onlinelibrary.wiley.com/doi/10.1111/psyg.12319 (accessed May 7, 2025). 15 Gros P, Videnovic A. Overview of sleep and circadian rhythm disorders in parkinson disease. Clin Geriatr Med 2020; 36: 119–30. 16 Kalia LV, Lang AE. Parkinson’s disease. The Lancet 2015; 386: 896–912.
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