Sleep and Circadian Alterations in Parkinson's: Understanding the Source for Smarter Treatment

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Sleep alterations often precede cognitive and motor symptoms in PD and appear during the prodromal phase of the disease.
Sleep alterations often precede cognitive and motor symptoms in PD and appear during the prodromal phase of the disease.

In addition to the hallmark motor symptoms of Parkinson disease (PD), non-motor symptoms have a significant impact on patients' quality of life. Sleep disturbances are among the most common symptoms, with 64% of patients reporting at least one sleep-related disorder in a 2009 multicenter study (n=1072), including insomnia (37%), behavioral sleep disturbances (30%), excessive daytime sleepiness (21%), and restless legs during sleep (15%).1

Sleep alterations often precede cognitive and motor symptoms in PD and appear during the prodromal phase of the disease. “One current hypothesis is that circadian and sleep alterations might indeed trigger and drive neurodegeneration from the earliest phases of disease…. [which] would in turn drive further sleep and circadian alterations, creating a detrimental self-perpetuating cycle,” according to a paper published in  the Journal of Sleep Research.2 This underscores the importance of elucidating disturbances in sleep and circadian rhythms in PD, as this knowledge may ultimately lead to strategies that could modify progression of the disease very early on.

To that end, the investigators conducted a narrative review of relevant studies, including those highlighted below.

  • Sleep architecture. While numerous polysomnographic (PSG) studies have demonstrated altered sleep architecture in patients with PD, there have been conflicting results for several measures across studies. For example, while some investigators reported evidence of reduced REM sleep, longer latency to REM sleep, and more frequent awakenings in patients with PD vs healthy controls, these observations were not supported in other research.2
  • Insomnia is the sleep disorder most frequently reported in PD, with various large studies indicating the presence of sleep disruption in roughly 80% of patients.2
  • Excessive daytime sleepiness (EDS). Findings regarding EDS prevalence in PD vary widely, with estimates ranging from 15% to 76% depending on the assessment tool used; these include questionnaires such as the Epworth Sleepiness Scale and the Karolinska Sleepiness Scale, as well as objective methods such as the Multiple Sleep Latency Test.2 Numerous studies have found an association between increased EDS and the use of dopaminergic medication. This symptom “might also be promoted by… the sedative effects of common drugs used by the PD population, and the alterations in nocturnal sleep and circadian rhythms described in this review,” wrote the researchers. Other research has found evidence for EDS in prodromal PD, including a 2005 study (n=3076) that showed a 3-fold risk for developing PD within 10 years in participants with vs without initial subjective EDS.2
  • REM sleep behavior disorder (RBD) affects an estimated 42% of patients with PD and “seems to be symptomatic in earlier phases of the disease, and associated with older age, male gender, longer disease duration, higher systolic blood pressure and higher frequency of freezing.”2 Patients with idiopathic RBD have an extremely high risk for developing a neurodegenerative disease, especially PD. Research published in 2013 showed that 82% of patients with RBD developed a defined neurodegenerative disorder within 14 years of RBD diagnosis, and PD and Lewy body dementia were the most common of these diagnoses.2 

In postmortem analyses, 94% of patients with co-occurring idiopathic RBD and neurologic disorders could be classified as having a synucleinopathy.3 “No prodromal marker of synucleinopathy has nearly the same predictive power and specificity as has RBD,” noted the review.2 “Crucially, the Movement Disorder Society includes RBD in their research criteria for prodromal PD, to inform the design of disease-modifying and neuroprotective clinical trials.”

Recent findings point to the presence of RBD in PD as a strong risk factor for dementia, with one study showing an odds ratio approaching 50 (OR 49.7, P =.001) at 4.4 years post-baseline.4

Patients with PD are also more likely to have REM sleep without muscle atonia (RSWA) compared with healthy controls. A 2013 magnetic resonance imaging (MRI) study5 showed reduced signal intensity in the locus coeruleus/subcoeruleus in patients with RBD and PD, which correlated with increased RSWA, suggesting that the “coeruleus/subcoeruleus area is affected in PD, and might be directly linked to RSWA and RBD occurrence in PD.”2

  • Restless legs syndrome (RLS). Although it is difficult to assess the prevalence of restless legs syndrome in PD because of overlapping pathophysiology and symptoms, several associations have been noted between the two disorders. Researchers have found an increased prevalence of RLS following PD diagnosis, a higher prevalence of PD in patients with vs without RLS, and a higher relative risk (approximately 1.5) of developing PD within 8 years in patients with severe RLS vs patients without RLS.2,6 The duration of anti-parkinsonian therapy has been identified as the most significant factor contributing to the development of RLS symptoms in PD.2
  • Circadian alterations. Increasing evidence supports the presence of “chronodegeneration” — which refers to a range of circadian alterations associated with neurodegenerative diseases — in patients with PD.2 For example, studies have observed reduced melatonin concentrations and higher cortisol levels in this population. Emerging evidence indicates that CLOCK gene expression may be altered in PD, with particular support for altered expression of core circadian gene BMAL-1 in patients vs heathy controls. It has been proposed that circadian alterations have a significant influence on PD development and progression.

Further investigation is needed to elucidate the direct and indirect effects of anti-parkinsonian drugs on sleep and circadian rhythms, as some data suggests that “dopaminergic treatments in PD might act to uncouple circadian and sleep regulatory mechanisms,” the investigators stated.2 Among other possible mechanisms, dopamine can “act as a clock controller, enhancing the transcription of the CLOCK:BMAL-1 complex via the activation of D2 receptors.”

Neurology Advisor checked in with the following experts for additional discussion about sleep dysfunction in PD: Donn Dexter, MD, FAAN, assistant professor of neurology at the Mayo Clinic College of Medicine and Science in Rochester, Minnesota, and Emmanuel During, MD, director of the Stanford Sleep Movement Disorders & Parasomnia Clinic, and clinical assistant professor of psychiatry and behavioral sciences and of neurology and neurological sciences at Stanford University in California.

Neurology Advisor: What are the mechanisms believed to underlie the links between sleep/circadian alterations and PD? 

Dr Dexter: Complex abnormalities in the noradrenergic, serotonergic, and cholinergic systems likely play a role in the sleep disruption seen in PD. A number of sleep disorders are common in PD, including REM sleep behavior disorder, periodic limb movement disorder, and insomnia. The primary manifestations of PD may adversely affect sleep, and the effects of associated depression or medication adverse events may also play a deleterious role in sleep in these patients. In general, medication provides more benefit than harm regarding sleep in these patients. 

Dr During: Synuclein deposition in PD likely starts outside the brain, possibly in the peripheral nervous system. Before PD pathology reaches the higher central nervous system (CNS) areas, causing tremor and gait difficulty or cognitive symptoms, it infiltrates the brainstem at an early stage of the disease. This brainstem pathology disrupts critical centers involved in generating and regulating sleep and wakefulness, resulting in sleep fragmentation, daytime sleepiness, and dysregulation of normal loss of muscle activity during REM sleep. In addition, Lewy body pathology infiltrates the suprachiasmatic nucleus, disrupting normal melatonin function and blurring the central signal defining day vs night, in patients with PD.

Neurology Advisor: How are these issues addressed in clinical practice?

Dr During: Sleep pattern, quantity, and quality should be systematically evaluated and treated in patients with PD. Further, providers should screen for dream-enactment in this population, as RBD can lead to severe injuries to patients and their partners.

Treatments for insomnia and circadian abnormalities include behavioral measures, use of light, lifestyle modifications — timed light, exercise, sleep hygiene — as well as medications when indicated. Melatonin can be particularly helpful in patients with PD as it can improve sleep pattern and insomnia and may reduce RBD.

Neurology Advisor: What are remaining research needs in this area? 

Dr Dexter: There is much still to learn and new options for treatment are still needed. Research into RBD etiology and effective treatments remain a high priority in my opinion.

Dr During: We need tools to evaluate and predict the risk for injury due to RBD, as well as better drugs to treat this disorder. We also need, for patients with PD experiencing insomnia and the elderly population in general, drugs that are demonstrated to be both effective and safe in the long run, particularly from a cognitive and healthy aging standpoint.

References

  1. Barone P, Antonini A, Colosimo C, et al; PRIAMO Study Group. The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease. Mov Disord. 2009; 24(11):1641-1649.
  2. Mantovani SSmith SSGordon RO'Sullivan JD. An overview of sleep and circadian dysfunction in Parkinson's disease. J Sleep Res. 2018; 27(3):e12673. 
  3. Boeve BF, Silber MH, TJ Ferman, et al. Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder. Sleep Med. 2013; 14(8):754-762.
  4. Anang JBM, Gagnon JF, Bertrand JA, et al. Predictors of dementia in Parkinson disease. A prospective cohort study. Neurology. 2014; 83(14):1253-1260.
  5. Garcia-Lorenzo D, Longo-Dos Santos C, Ewenczyk C, et al. The coeruleus/ subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson's disease. Brain. 2013; 136(7):2120-2129.
  6. Wong JC, Li Y, Schwarzschild MA, Ascherio A, Gao X. Restless legs syndrome: An early clinical feature of Parkinson disease in men. Sleep. 2014; 37(2):369-372.
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