CoChat
Sign Up
Cited by 63Circadian rhythm and melatoninParkinson's Disease Mechanisms and TreatmentsSleep and Work-Related Fatigue

Circadian dysregulation in Parkinson's disease

Open access
Videnovic, Aleksandar, Golombek, Diego·2017·Neurobiology of Sleep and Circadian Rhythms
DOI 10.1016/j.nbscr.2016.11.001PMC PMC5509072
Open this paper in CoChat — free accountOpen PDF

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder that affects over one million individuals in the US alone. PD is characterized by a plethora of motor and non-motor manifestations, resulting from a progressive degeneration of dopaminergic neurons and disbalance of several other neurotransmitters. A growing body of evidence points to significant alterations of the circadian system in PD. This is not surprising given the pivotal role that dopamine plays in circadian regulation as well as the role of circadian influences in dopamine metabolism. In this review we present basic and clinical investigations that examined the function of the circadian system in PD.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes evidence that circadian function is disrupted in Parkinson’s disease, with bidirectional links between dopamine and the circadian system. It covers animal models and clinical findings including altered rest-activity rhythms, melatonin/cortisol/clock gene profiles, and light therapy effects, while noting most human studies lack rigorous circadian protocols.

Key findings

  • Dopamine and the circadian system interact bidirectionally: striatal dopamine shows daily rhythms with nocturnal peaks in mice, clock genes and dopamine-related genes/receptors show 24-h variation, and SCN lesions or constant light disrupt dopamine and tyrosine hydroxylase rhythms.
  • Animal PD models show circadian and sleep disruption: MPTP-treated primates have significant sleep-wake disruption and REM sleep deregulation; 6-OHDA rats show severe sleep deficits and circadian disruption partially reversible by L-DOPA; α-synuclein transgenic mice show fragmented locomotor rhythms and altered SCN firing; VMAT2-deficient mice show reduced sleep-wake amplitude and dampened circadian rhythms.
  • Clinical PD findings include flattened diurnal activity rhythms and reduced nighttime quiescence on actigraphy, independent of dopaminergic medications. Melatonin studies report prolonged phase angle of entrainment in medicated PD patients, decreased melatonin amplitude in moderate PD, and lower melatonin amplitude in PD patients with excessive daytime sleepiness; Breen et al. found elevated cortisol and reduced melatonin in 30 early PD patients versus 15 matched controls, and Bmal1 was lower at night in 17 PD patients versus 16 controls and correlated with UPDRS severity.
  • Light therapy studies report benefits: a case series of 12 PD patients given 1000–1500 lux for 60–90 minutes before habitual bedtime over two weeks improved sleep onset latency, sleep continuity, mood, and motor symptoms, allowing dopamine replacement reduction in half; a controlled trial of 36 PD patients randomized to 7500 lux versus 950 lux for 30 minutes in the morning over two weeks showed improved UPDRS part I and II scores and modest improvements in mood and daytime sleepiness. Higher latitudes were associated with up to 56% increased PD incidence.

Methods

  • Narrative review of basic and clinical investigations examining circadian system function in Parkinson’s disease.
  • Sources include animal models (e.g., MPTP, 6-OHDA, α-synuclein, VMAT2, rotenone, MitoPark) and human studies of actigraphy, melatonin, cortisol, clock genes, and light therapy.
  • Main analysis is qualitative synthesis; no systematic search strategy, inclusion criteria, or quantitative meta-analysis is stated.

Limitations

  • The paper states that circadian rhythms have not been systematically studied in PD, that most studies did not employ rigorous circadian protocols controlling exogenous stimuli, and that light therapy studies are limited by small size, short duration, and suboptimal design. It also notes that conducting circadian studies in PD is limited by symptom burden and patient frailty.
  • Evident from the text: this is a narrative review without a stated systematic search or quantitative synthesis, and the cited evidence base is heterogeneous across animal models and small clinical samples.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.nbscr.2016.11.001

Cites

104 of 104 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 87 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    A growing body of evidence points to significant alterations of the circadian system in Parkinson's disease.

    “A growing body of evidence points to significant alterations of the circadian system in PD.”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning

    Basic investigations collectively provide support for alterations of the circadian system in Parkinson's disease.

    “Collectively, these basic investigations provide a support for alterations of circadian system in PD.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Prominent changes in 24-hour rhythms of heart rate and blood pressure have been repeatedly reported in Parkinson's disease.

    “Similar to motor function, prominent changes in 24-hour rhythms of heart rate and blood pressure have been repeatedly reported in PD.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Haapaniemi et al., 2001 source

      Not checked in the free run.

    • cites Kallio et al., 2000 source

      Not checked in the free run.

    • cites Kallio et al., 2004 source

      Not checked in the free run.

  • Premisecitation

    Many symptoms and signs associated with Parkinson's disease demonstrate diurnal variations in intensity and frequency.

    “Many symptoms and signs associated with PD demonstrate diurnal variations in its intensity and frequency.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bonuccelli et al., 2000 source

      Not checked in the free run.

    • cites Nutt et al., 1989 source

      Not checked in the free run.

    • cites van Hilten et al., 1993

      Not checked in the free run.

  • Premisecitation

    Circadian and sleep misalignment likely influence the neurodegenerative process itself.

    “Of note, circadian and sleep misalignment likely influence the neurodegenerative process itself (Ju et al., 2014, Mamelak, 1997, Morton et al., 2005).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Ju et al., 2014

      Not checked in the free run.

    • cites Mamelak, 1997 source

      Not checked in the free run.

    • cites Morton et al., 2005 source

      Not checked in the free run.

  • May combine two claims. 15
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Premisecitation

    α-synuclein transgenic mice exhibit fragmented rhythms of locomotor activity, as well as changes in firing rate in the suprachiasmatic nuclei (SCN).

    “α-synuclein transgenic mice exhibit fragmented rhythms of locomotor activity, as well as changes in firing rate in the suprachiasmatic nuclei (SCN), the site of the mammalian main circadian clock (Kudo et al., 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kudo et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Studies employing actigraphy in the Parkinson's disease population revealed flattening of diurnal activity rhythms and reduced quiescence during night.

    “Studies that employed actigraphy in the PD population revealed flattening of the diurnal activity rhythms and reduced quiescence during night (Piccini et al., 1991, Placidi et al., 2008).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Piccini et al., 1991

      Not checked in the free run.

    • cites Placidi et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Circadian changes have been documented in rotenone-induced neurodegeneration in rats, including alterations in serotonergic transmission and circadian expression of clock genes; both parameters partially recover with melatonin administration.

    “Circadian changes have been documented in rotenone-induced neurodegeneration in rats, including alterations in serotonergic transmission and circadian expression of clock genes; both parameters partially recover with melatonin administration (Mattam and Jagota, 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mattam and Jagota, 2015

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Dopamine plays a pivotal role in circadian regulation and circadian influences play a role in dopamine metabolism.

    “This is not surprising given the pivotal role that dopamine plays in circadian regulation as well as the role of circadian influences in dopamine metabolism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The amplitude of the circadian rhythm of dopamine appears to be highest in the morning around 10am, and that of homovanillic acid in the afternoon around 2pm.

    “For example, the amplitude of the circadian rhythm of dopamine appears to be highest in the morning around 10am, and that of homovanillic acid in the afternoon, around 2pm (Poceta et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Poceta et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced amplitude of the rest-activity cycle is present in both de novo and more advanced Parkinson's disease patients, and appears to be independent of the intake of dopaminergic medications.

    “This reduced amplitude of the rest-activity cycle is present in both de novo and more advanced patients, and appears to be independent of the intake of dopaminergic medications (Piccini et al., 1991, Placidi et al., 2008, van Hilten et al., 1994, van Hilten et al., 1993, van Hilten et al., 1993).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Piccini et al., 1991

      Not checked in the free run.

    • cites Placidi et al., 2008 source

      Not checked in the free run.

    • cites van Hilten et al., 1994 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Diurnal variation in dopamine and some of its metabolites has been reported for many years.

    “indeed, diurnal variation in dopamine and some of its metabolites has been reported for many years (Kafka et al., 1986).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kafka et al., 1986 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Studies report reversal of the normal diurnal rhythm of blood pressure with increased diurnal variability of blood pressure and elevations of overnight blood pressure, along with loss of diurnal heart rate variability and a disappearance of the sympathetic morning peak in Parkinson's disease.

    “These studies report reversal of the normal diurnal rhythm of BP with increased diurnal variability of BP and elevations of overnight BP along with loss of diurnal HR variability and a disappearance of the sympathetic morning peak (Haapaniemi et al., 2001, Kallio et al., 2000, Kallio et al., 2004, Mastrocola et al., 1999).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Haapaniemi et al., 2001 source

      Not checked in the free run.

    • cites Kallio et al., 2000 source

      Not checked in the free run.

    • cites Kallio et al., 2004 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clock genes exhibit periodic variations in striatal structures and could be related to rhythms in the expression of dopamine-related genes.

    “Clock genes also exhibit periodic variations in striatal structures (Bussi et al., 2014, Li et al., 2009, Natsubori et al., 2014), and could be related to rhythms in the expression of dopamine-related genes (Shumay et al., 2012).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bussi et al., 2014 source

      Not checked in the free run.

    • cites Li et al., 2009

      Not checked in the free run.

    • cites Natsubori et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rhythmic dopaminergic activity can be controlled by the circadian clock and, in turn, might also regulate the activity of the clock itself.

    “Indeed, rhythmic dopaminergic activity can be controlled by the circadian clock and, in turn, might also regulate the activity of the clock itself (Mendoza and Challet, 2014, Sleipness et al., 2007).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Mendoza and Challet, 2014

      Not checked in the free run.

    • cites Sleipness et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In that case series, beneficial effects on sleep emerged within two to three days after commencing light therapy and lasted for several days after discontinuation.

    “Beneficial effects on sleep emerged within two to three days after commencing LT, and lasted for several days after discontinuation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Willis and Turner, 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    While Parkinson's disease patients exhibit a preserved circadian rhythm of cortisol, the amount of cortisol secreted is elevated in early PD.

    “While PD patients exhibit a preserved circadian rhythm of cortisol, the amount of cortsiol secreted is elevated in early PD (Breen et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Breen et al., 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Activation of the SCN has been hypothesized as one of the mechanisms of bright environmental light effects on mood, sleep and circadian rhythms.

    “Activation of the SCN has been hypothesized as one of the mechanisms of bright environmental light effects on mood, sleep and circadian rhythms (McEnany and Lee, 2005, Riemersma-van der Lek et al., 2008).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites McEnany and Lee, 2005

      Not checked in the free run.

    • cites Riemersma-van der Lek et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two studies reported increasing incidence of Parkinson's disease, as much as 56%, with higher latitudes, where the yearly net exposure to light is significantly lower.

    “Two studies reported increasing incidence of PD, as much as 56%, with higher latitudes, where the yearly net exposure to light is significantly lower (de Pedro Cuesta, 1987, de Pedro-Cuesta and Stawiarz, 1991).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites de Pedro Cuesta, 1987

      Not checked in the free run.

    • cites de Pedro-Cuesta and Stawiarz, 1991

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Parkinson's disease patients had elevated cortisol levels and reduced melatonin levels.

    “PD patients had elevated cortisol levels and reduced melatonin levels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Breen et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In an open-label study of 120 PD patients prescribed bright light therapy 4000-6000 lux for 60 minutes before habitual bedtime and followed for a few months to eight years, patients with good compliance achieved improvements in mood, anxiety, and tests of motor function.

    “Patients with good compliance achieved improvements in mood, anxiety, and tests of motor function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Willis et al., 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    To date, several studies have been published on light therapy in Parkinson's disease.

    “To date, several studies have been published on LT in PD (Paus et al., 2007, Willis and Turner, 2007, Willis et al., 2012).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Paus et al., 2007 source

      Not checked in the free run.

    • cites Willis and Turner, 2007

      Not checked in the free run.

    • cites Willis et al., 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Differences in timing of light therapy in studies to date may explain its variable effects on specific outcomes.

    “Differences in timing of LT in studies performed to date may explain its variable effects on specific outcomes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These studies demonstrate beneficial effects of bright light therapy on sleep, mood, and non-motor function in PD.

    “These studies demonstrate beneficial effects of bright LT on sleep, mood and non-motor function in PD.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Limitations of conducting circadian studies in PD patients are substantial because of the burden of PD symptoms and frailty of PD patients.

    “Limitations of conducting such circadian studies in PD patients are substantial, given the burden of PD symptoms and frailty of PD patients.”
    Quote in the paperSubstantial claim
20 of 20

  • The paper relies on this without support.

    The role of the circadian system in Parkinson's disease has not been systematically studied to date.

    “The role of the circadian system in PD has not been systematically studied to date.”
    “Circadian rhythms have not been systematically studied in PD patients.”

  • The paper relies on this without support.

    Studies centered on alterations of circadian rhythmicity and applications of potential circadian-based interventions in animal models of Parkinson's disease are scarce.

    “Studied that centered on alterations of circadian rhythmicity and applications of potential circadian-based interventions in animal models of PD are scarce.”

  • The paper relies on this without support.

    Dopamine is a major regulator of the circadian system.

    “since dopamine represents a major regulator of the circadian system”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Compared with healthy aged people, individuals with AD or PD show considerably lower melatonin rhythm amplitudes and excessive sleepiness, as well as other sleep-wake cycle disturbances, such as later sleep onsets.

    “Compared with healthy aged people, individuals with AD or PD show considerably lower melatonin rhythm amplitudes and excessive sleepiness, as well as other sleep–wake cycle disturbances, such as later sleep onsets254–258.”

    From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [254]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Mouse circadian finding attributed to an unrelated human study

    Minor

    The text attributes disrupted oscillations in α-synuclein transgenic mice to "Willison et al. (Fliers et al., 1985)." The cited reference lists Fliers and colleagues and describes human neurons in aging and senile dementia, not transgenic mice.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. de Pedro Cuesta, 1987, Studies on the prevalence of paralysis agitans by tracer methodology, Acta Neurol. Scand., 1

Cited by

Sorted by citations

Related

Authors
Videnovic, A., & Golombek, D.
Affiliations
National University of Quilmes (AR)
ORCID
Golombek, Diego
Venue
Neurobiology of Sleep and Circadian Rhythms
Publisher
Elsevier BV
Published
2017-01
Volume
2
Pages
53-58
ISSN
2451-9944 (ISSN-L)
DOI
10.1016/j.nbscr.2016.11.001
PMC
PMC5509072
OpenAlex
W2551225567
Semantic Scholar
54574c2546b0396ce904e67be76557bbb2d8fb65
Cited by
63
References
104
Citations by year
2026: 4 · 2025: 8 · 2024: 9 · 2023: 6 · 2022: 5 · 2021: 9 · 2020: 11 · 2019: 5 · 2018: 6
FWCI
2.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Sleep and Circadian Rhythms (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Americanae (AECID Library) (publishedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-nd)
Funders
National Institutes of Health (K23 NS072283)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
Keywords
Parkinson's disease, circadian rhythm, circadian dysfunction, circadian system, dopamine, dopaminergic neurons, dopamine metabolism, non-motor symptoms, neurodegeneration

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review