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'The clocks that time us'—circadian rhythms in neurodegenerative disorders

Key Points

  • Sleep and circadian disruption are common in Alzheimer disease, Parkinson disease and Huntington disease

  • Symptoms of circadian disruption range from subjective sleep complaints and alterations of sleep timing to severe disruptions in rest–activity cycles and sleep architecture

  • Behavioural, physiological and molecular markers of circadian system function suggest progressive deterioration of circadian rhythmicity as the disease progresses

  • The relationship between circadian dysfunction and neurodegenerative processes might be bidirectional: circadian dysfunction might exacerbate the disease processes

  • Behavioural or pharmaceutical interventions that target sleep–wake cycles might reverse circadian disruption

Abstract

Circadian rhythms are physiological and behavioural cycles generated by an endogenous biological clock, the suprachiasmatic nucleus. The circadian system influences the majority of physiological processes, including sleep–wake homeostasis. Impaired sleep and alertness are common symptoms of neurodegenerative disorders, and circadian dysfunction might exacerbate the disease process. The pathophysiology of sleep–wake disturbances in these disorders remains largely unknown, and is presumably multifactorial. Circadian rhythm dysfunction is often observed in patients with Alzheimer disease, in whom it has a major impact on quality of life and represents one of the most important factors leading to institutionalization of patients. Similarly, sleep and circadian problems represent common nonmotor features of Parkinson disease and Huntington disease. Clinical studies and experiments in animal models of neurodegenerative disorders have revealed the progressive nature of circadian dysfunction throughout the course of neurodegeneration, and suggest strategies for the restoration of circadian rhythmicity involving behavioural and pharmacological interventions that target the sleep–wake cycle. In this Review, we discuss the role of the circadian system in the regulation of the sleep–wake cycle, and outline the implications of disrupted circadian timekeeping in neurodegenerative diseases.

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Figure 1: A simplified scheme of the circadian system.
Figure 2: Molecular organization of the circadian system.

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Acknowledgements

A.V. has received research grant support from the NIH (K23 NS072283). A.S.L. has received research grant support from the CHDI Foundation (RG50786). R.A.B. has received research grant support from the CHDI Foundation (RG50786), Evelyn Trust (RG66030), Butterfield Trust (RG68592), and the NIHR Biomedical Research Centre and Biomedical Research Unit Award to Addenbrooke's Hospital/University of Cambridge (RG68592). S.O. has received research grant support from the Netherlands Organization for Scientific Research (grant no. 016.116.371).

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A.V., A.S.L. and S.O. researched data for the article. All authors provided substantial contributions to discussion of the content, wrote the article and reviewed and/or edited the manuscript before and after submission.

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Videnovic, A., Lazar, A., Barker, R. et al. 'The clocks that time us'—circadian rhythms in neurodegenerative disorders. Nat Rev Neurol 10, 683–693 (2014). https://doi.org/10.1038/nrneurol.2014.206

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