Monday, June 1, 2015

Circadian Dysfunction in Parkinson's Disease

Sleep disturbances and circadian rhythm dysfunction are common features of Parkinson’s, Alzheimer’s and Huntington’s diseases. These symptoms adversely affect quality of life. Yet the mechanisms of sleep and circadian disruption in neurodegenerative diseases are not well understood. Aleksandar Videnovic, MD, a neurologist at Massachusetts General Hospital and director of the new Program in Sleep, Circadian Biology and Neurodegeneration, is investigating the pathophysiology of such sleep-wake disturbances.

Patients with Parkinson’s disease (PD) in particular exhibit diurnal fluctuations of motor and nonmotor symptoms, in conjunction with sleep dysfunction, which suggests a role of the circadian system in the modulation of these symptoms. Impaired circadian function in PD is suspected to underlie not only the dysregulation of the sleep-wake cycle but also autonomic, cognitive, psychiatric and motor symptoms of the disease. Investigations into the mechanisms of circadian dysfunction may help researchers understand the progress of neurodegeneration in PD and possibly uncover novel approaches to treatment.

Melatonin and Parkinson’s Disease

Melatonin and Parkinson’s Disease
Parkinson’s patients demonstrate significantly reduced serum melatonin secretion as compared with controls (A), with conspicuously lower amplitude of melatonin rhythmicity in PD patients expressing excessive daytime sleepiness (EDS), (B). Circadian time is measured as time since awakening.
Source: Aleksandar Videnovic, MD

Disruption of Circadian Rhythms in Parkinson's Disease

In a study published in JAMA Neurology (1) in April 2014, funded by a National Institute of Neurological Disorders and Stroke Mentored Patient-Oriented Research Career Development Award (K23 NS072283), Dr. Videnovic and his colleagues studied the alteration of circadian system in Parkinson’s disease (2). Serum melatonin secretion over a 24-hour period provides a reliable marker of endogenous circadian rhythmicity, so Dr. Videnovic and his colleagues monitored serum melatonin levels at 30-minute intervals in patients with Parkinson’s disease, taking 50 samples from each subject. Melatonin secretion proved to be severely blunted in patients with Parkinson’s disease compared with controls, with Parkinson’s patients who expressed excessive daytime sleepiness showing a markedly lower amplitude of melatonin rhythm. These findings were consistent with an assumption that circadian regulation is associated with PD and raise intriguing questions about the mechanisms underlying the blunted rhythm.

Dr. Videnovic’s work doesn’t show whether this impairment of circadian rhythmicity is a cause or consequence of Parkinson’s disease, but his team will investigate causation in future research. Instead, research is now focusing on what happens to the function of the circadian system as the disease progresses. Upcoming investigations will test interventions, such as bright light therapy and timed applications of melatonin, that target circadian function, attempting to improve the sleep-wake cycle disturbances and explore whether such interventions have any effect on the underlying neurological disease process.

Circadian Dysfunction and Parkinson’s Disease

Circadian Dysfunction and Parkinson’s Disease
The circadian system is managed by a collection of brain cells known as the suprachiasmatic nucleus, which is influenced by exogenic factors such as light, food and physical activity. Many characteristic symptoms of Parkinson’s manifest as defects in the circadian system. Patients are often sleepy during the daytime, and characteristic motor symptoms fluctuate throughout the day.
Source: Aleksandar Videnovic, MD

REM Sleep Behavior Disorder (RBD): An Early Indicator of Neurodegeneration

REM sleep behavior disorder (RBD) is a sleep disorder, increasingly linked to an ongoing synuclein-related neurodegeneration. Symptoms of RBD include abnormal vocalizations and movement behaviors during sleep. RBD is thought to be a prodromal stage of PD, preceding the expression of cardinal motor symptoms. Patients with PD can also exhibit freezing of gait (FOG), a symptom that emerges from neuroanatomical changes in the brain stem that include the pedunculopontine nucleus and locus coeruleus. These same anatomical regions have been implicated in RBD.

Dr. Videnovic and his colleagues looked at another aspect of this connection in a study funded by the Michael J. Fox Foundation for Parkinson’s Research. The study, published in Neurology (3) in September 2013, looked at several groups of patients: one group with PD and FOG, a group with PD that did not have FOG, and another group with RBD and no diagnosis of PD (as well as matched controls). The team saw a marked difference in tonic muscle activity during REM sleep between the PD patients with and without FOG. Patients with PD and FOG and the group with RBD, however, had similar tonic muscle activity patterns during REM sleep. These latter groups also showed similar amounts of tonic EMG activity during REM sleep.

Dr. Videnovic and his team raise the possibility that the commonalities in sleep dysfunction between the RBD and PD with FOG groups might reflect an overlap in the circuits that control muscle activity during REM sleep and FOG. Their data led them to hypothesize that the presence of excessive tonic EMG activity during REM sleep may predict development of PD with FOG, and that the pathophysiologic mechanisms that mediate FOG in PD share a common set of neurodegenerative changes that underlie the tonic muscle activity during REM sleep that is found in RBD.

While this is an initial, cross-sectional study, Dr. Videnovic and his colleagues at the Program in Sleep, Circadian Biology and Neurodegeneration hope to recruit more patients with RBD for a longitudinal study that will look more closely at the connections between RBD and FOG, in the hope of identifying additional markers in sleep patterns and via brain imaging that predict the development of FOG in Parkinson’s disease.


(1)Videnovic, Aleksandar, Charleston Noble, Kathryn J Reid, Jie Peng, Fred W Turek, Angelica Marconi, Alfred W Rademaker, et al. "Circadian Melatonin Rhythm and Excessive Daytime Sleepiness in Parkinson’s Disease." JAMA Neurology, vol. 71, no. 4 (April 2014): 463-9.

(2) Videnovic, Aleksandar, Alpar S Lazar, Roger A Barker and Sebastiaan Overeem. "The Clocks That Time Us: Circadian Rhythms in Neurodegenerative Disorders." Nature Reviews Neurology, vol. 10, no. 12 (December 2014): 683-693.

(3) Videnovic, Aleksandar, Clare Marlin, Laila Alibiglou, Peggy J Planetta, David E Vaillancourt, and Colum D MacKinnon. "Increased REM Sleep Without Atonia in Parkinson Disease Patients With Freezing of Gait." Neurology, vol. 81, no. 12 (September 2013): 1030-5.


  • Aleksandar Videnovic, MD
    Director, Program on Sleep
    Circadian Biology and Neurodegeneration
    Massachusetts General Hospital

This article first appeared in the Spring 2015 issue of Advances at Mass General

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