Multifactorial sleep disturbance in Parkinson's disease

Accepted Manuscript Multifactorial Sleep Disturbance in Parkinson’s Disease J.Andrew Albers, Ph.D., Pratap Chand, M.D., A.Michael Anch, Ph.D. PII:

S1389-9457(17)30178-8

DOI:

10.1016/j.sleep.2017.03.026

Reference:

SLEEP 3373

To appear in:

Sleep Medicine

Received Date: 12 January 2017 Revised Date:

24 February 2017

Accepted Date: 1 March 2017

Please cite this article as: Albers JA, Chand P, Anch AM, Multifactorial Sleep Disturbance in Parkinson’s Disease, Sleep Medicine (2017), doi: 10.1016/j.sleep.2017.03.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Albers 1 Title Multifactorial Sleep Disturbance in Parkinson’s Disease

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Authors J Andrew Albers, Ph.D.* a,c Pratap Chand, M.D.a,b A Michael Anch, Ph.D.c

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Affiliations a) Saint Louis University School of Medicine • 1402 South Grand Blvd, St Louis, MO 63104 United States b) Department of Neurology and Psychiatry, Saint Louis University School of Medicine • Monteleone Hall, 1438 South Grand Blvd, St Louis, MO 63104 United States c) Department of Psychology, Saint Louis University College of Arts and Sciences • Morrissey Hall, 3700 Lindell Blvd, St Louis, MO 63108 United States *Corresponding Author. E-mail: [email protected]. Phone: (314) 809-6958.

Conflict of Interest Statement: Dr. Albers and Dr. Anch have received funding from Teva Neuroscience for preclinical research. Dr. Chand has received speaking fees from Teva Neuroscience as well as funding for preclinical research. This research did not receive any specific grant from funding agencies in the public, commercial, or notfor-profit sectors.

Abstract

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Keywords Parkinson's disease, sleep, neurodegeneration, sleep disorder, pharmacology, PD Sleep Model

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder, ranking only behind Alzheimer’s disease and affecting 2% of the population over the age of 65. Pathophysiologically, PD is characterized by selective degeneration of the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and striatal dopamine depletion. Patients may also exhibit mild-to-severe degeneration of other central and peripheral nervous tissues. The most dramatic symptoms of the disease are profound dopamine-responsive motor disturbances, including bradykinesia, akinesia, rigidity, resting tremor, and postural instability. PD patients commonly present with debilitating non-motor symptoms, including cognitive impairment, autonomic nervous system dysfunction, and sleep disturbance. Of these, sleep disturbance is the most consistently reported, and likely represents a disorder integrative of PD-related motor impairment, autonomic nervous system dysfunction, iatrogenic insult, and central neurodegeneration. The pathophysiology of PD may also indirectly disrupt sleep by increasing susceptibility to sleep disorders, including sleep disordered breathing, periodic limb movements, and REM behavior disorder. In this review, we will discuss these systems representing a multifactorial etiology in PD sleep disturbance. 1. Prevalence, Types, and Impact of Sleep Disorders in Parkinson’s Disease Sleep disturbance is a major non-motor complaint of Parkinson’s disease (PD) with extensive impact on patient quality of life. Despite the overwhelming prevalence of this symptom, the impact of PD-related sleep disturbance is often underappreciated in light of the profound motor disorder experienced by this population. Current estimates of PD-related sleep disturbance indicate that up to 98% 1

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of patients exhibit some symptoms of sleep disturbance, often with significant daytime impairment [1]. In fact, certain sleep disturbances, like rapid eye movement sleep behavior disorder (RBD), may be a prodromal symptom of PD, thus prompting a search for sleep-related “biomarkers” of the early, pre-motor stages of the disease [2, 3]. Non-motor symptoms (NMS) of PD, including memory failure, autonomic dysfunction, affective disorders, and sleep disturbance, are the most significant determinant of patient quality of life (QoL) [4], with symptoms of insomnia ranking among the most profoundly detrimental to QoL [5]. Very poor nocturnal sleep may also contribute to excessive daytime sleepiness (EDS), which may precipitate falls [6], impulsive behavior [7], and poor automobile driving performance [8] in this population. Sleep disturbances (including RBD and sleep fragmentation) often worsen with disease progression [9, 10], leading to potentially life-threatening synergies among nocturnal sleep disturbance, daytime sleepiness, disease-related motor impairment, and declines in executive functioning. Sleep disorders are common in PD, and in certain cases, may precede the classic motor manifestation of the disease. These disorders do not operate in isolation from the motor- and central degeneration-related sleep pathology. In fact, there may be significant overlap among the etiologies of seemingly idiopathic disease process-related sleep disturbance and diagnosed sleep disorders in PD. Sleep disorders that are common among PD patients include insomnia, REM behavior disorder (RBD), obstructive sleep apnea (OSA), periodic limb movement disorder (PLMD), restless leg syndrome (RLS), and nocturia [11]. In addition, it should be recognized that PD patients are certainly not excluded from independent development of other common sleep disorders, such as narcolepsy, circadian disorders, shift work-related disorders, and others. Whether or not PD patients are at greater risk for the development of OSA is a contentious issue in PD clinical research. Many prospective studies comparing PD patients to healthy age-matched controls have revealed no increased risk for diagnosis of OSA [12, 13], while other studies contend increased risks of sleep disordered breathing – including OSA – in a PD population [14]. Berlin Questionnaire risk factors predict greater incidence of sleep disordered breathing in PD [15], but overall, the evidence for increased prevalence of OSA in PD populations is lacking. Notably, although PD patients with and without OSA obviously differ in respiratory arousal indices, OSA does not seem to contribute independently to daytime sleepiness within a PD population. REM Behavior Disorder is characterized by vivid dreams and uninhibited, often violent, motor activation during rapid eye movement (REM) sleep. In addition to being highly disruptive of sleep for patients, bed partners, and caregivers, RBD is a putative prodromal sign of future PD diagnosis [16, 17]. RBD may also emerge after the classic motor symptom manifestation of PD, but the presence of RBD at or before the onset of motor symptoms may predict a more rapid decline in motor symptoms relative to their non-RBD peers [10]. The often-prodromal nature of RBD is likely related to the Braak-modeled progression of synucleinopathy from hindbrain regions toward the neocortex, during which the REM- and motor output-controlling pontine neurons become dysfunctional prior to the midbrain and substantia nigra [18]. Predictions of the prodromal interval from RBD onset to motor manifestations of PD or other synucleinopathies range from 4.5-15 years [17, 19], with up to 81% of RBD patients ultimately converting to a synucleinopathy [17]. It is important to differentiate RBD symptoms from confusional arousals, which are also prevalent in Parkinson’s disease and may be similarly described by the patient or bed partner [20]. Restless legs syndrome (RLS) is a disorder that causes an inappropriate urge to move the limbs prior to sleep onset, and most commonly manifests in the lower extremities. Indulging the urge to move the limbs typically allows brief respite from the unpleasant sensation, which returns shortly thereafter. Sleep onset can be dramatically delayed in those suffering from RLS, which is diagnosed at much higher rates in PD patients [21]. Treatment for RLS can include iron supplementation and dopamine agonists. Given that iron supplementation may exert its therapeutic effects through replenishment of iron cofactor for tyrosine hydroxylase or enhancement of D2 receptor binding [22], the combination of the prevalence of RLS in PD and the efficacy of dopamine agonists and iron supplementation may reflect a dopamine deficiency. For the treatment of idiopathic RLS, a primary goal of treatment should be the maintenance of

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ACCEPTED MANUSCRIPT Albers 3 ferritin levels above 50ng/mL. However, the impact of restoring ferritin levels on RLS symptoms in the PD population is currently unknown. 2. Etiology of Parkinson’s Disease Sleep Disruption

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2.1 Motor Impairment

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Nocturnal akinesia is a prime complaint of PD patients treated with short-acting levodopa/carbidopa or dopamine agonists. Patients revert to akinetic and rigid “off” states as dopaminergic medications are metabolized, and without middle-of-the-night re-dosing, may remain profoundly akinetic until the next morning’s dose. Although many of the motor symptoms of PD, including resting tremor and rigidity, seem to be alleviated during sleep, they often do not completely remit. As a result, PD patients report significant motor-related sleep disturbances on the Parkinson’s Disease Sleep Scale (PDSS), including increased frequency of muscle cramps, paresthesias, and painful or uncomfortable limb posture [23]. Minimizing nocturnal akinesia through optimization of dopaminergic therapies seems a viable option to restore sleep quality. Early trials with sustained release levodopa taken before bed demonstrated a marked improvement in nighttime akinesia [24]. Later, the Randomized Evaluation of 24-Hour Coverage: Efficacy of Rotigotine trial (RECOVER) demonstrated both early-morning motor function improvement and subjective improvement in sleep quality using a once-daily transdermal rotigotine patch that provided dopamine agonist coverage [25]. Additionally, post-hoc analysis of RECOVER subjects revealed strong subjective reductions in wake-inducing nocturnal limb pain and immobility [26]. Recently, continuous intestinal infusion of levodopa/carbidopa has also been shown to improve motor symptoms, nocturnal sleep, and daytime functioning relative to prior treatment modality [27, 28]. Taken together, evidence suggests that effective nocturnal dopamine coverage may improve nocturnal motor symptoms, and consequently sleep quality, in PD. Additionally, controlled release levodopa-carbidopa taken before bed seems to improve sleep disordered breathing in the latter half of the night [29]. Deep-brain stimulation (DBS) has become increasingly popular for treatment of parkinsonism. While DBS carries risks as an invasive neurosurgical procedure, patient outcomes are generally positive, and levodopa doses required to control motor symptoms are often reduced [30]. Improvements in sleep quality have been reported for both unilateral [31] and bilateral [32, 33] subthalamic nucleus (STN) DBS, and some evidence suggests that pallidal stimulation may have similar sleep benefit [34]. Finally, PD patients are more susceptible to motoric disorders of sleep, including restless leg syndrome (RLS), periodic limb movement disorder (PLMD), and RBD [35-37]. It has been suggested that the etiology of some of these disorders may lie in midbrain dopamine depletion, as dopamine agonists are effective in treating RLS and PLMD [38], and in one isolated report, can reduce RBD symptoms [39]. However, there is currently insufficient evidence to recommend dopaminergic therapies for RBD in PD patients. Although deficits in nigrostriatal dopamine may explain the underlying pathophysiology of both RLS and PD [40], further research is necessary to determine whether dopamine replacement or agonist therapies are effective in treating the condition. Although sleep quality improvements may parallel motor symptom improvement, it is likely that significant sleep quality improvement must be a product of a “functional mosaic” of corrected deficits. In the sleep functional mosaic, all factors underlying sleep regulation, including motor control, autonomic function, iatrogenic effects, and circadian control, contribute to an analogous composite image of patient sleep quality. As components of the mosaic are damaged, the composite image of sleep quality is gradually degraded. In PD, the damage to the components of the mosaic can be significant, requiring attention to a wide range of insults to sleep quality. While repairing individual components of the mosaic, such as the motor symptoms of PD, may partially ameliorate sleep disturbance, it is apparent that each independent sleep-regulatory component is only an individual piece of the profound sleep disturbance experienced by PD patients. Indeed, significant restoration of sleep quality in PD requires the alteration of

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ACCEPTED MANUSCRIPT Albers 4 multiple sleep-disrupting facets of the disease, including sleep disorders such as insomnia, RLS and RBD, motor and autonomic symptoms, iatrogenic insult, neurological damage, and circadian disorder. 2.2 Autonomic Dysfunction

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In addition to the classic motor symptoms caused by CNS degeneration, PD also results in progressive autonomic nervous system dysfunction, which may affect multiple organ systems and directly or indirectly hinder sleep. In particular, cardiovascular, gastrointestinal, and urinary reflexes are markedly impaired. Sweating, thermoregulation, and saliva production may be dysfunctional. Although the direct contributions of these systems to PD sleep disturbances have not been extensively studied, the impact of autonomic dysfunction can be considered as profoundly sleep-disruptive, and care should be taken to address each component with respect to sleep impact. Cardiac sympathetic denervation is a common finding in PD [41] and has long been proposed as a correlate of disease progression in PD [42], with some focus on the potential diagnostic value of cardiac denervation as a pre-motor facet of the disease [43]. Cardiovascular reflex dysfunction in some PD patients results in orthostatic hypotension [44], which may contribute to falls [45, 46], and delay a necessary rise from bed due to fear of falling. Although it is difficult to draw direct relationships between cardiovascular autonomic dysfunction and sleep disturbance using currently available data, cardiovascular function during sleep may nonetheless prove a diagnostically useful sign for PD. In fact, recent findings suggest that sympathetic control over heart rate is decreased during sleep in PD patients [47], and cardiac autonomic impairment during sleep is highly correlated with PD severity [43]. Gastrointestinal distress may include constipation and defecatory dysfunction [48, 49], contributing to discomfort and unpredictable need to use the bathroom at night. PD patients frequently experience gastroesophageal reflux [50], which is disruptive of sleep, especially when sleeping without head-of-bed elevation [51]. Nocturia is a common non-motor symptom among sufferers of Parkinson’s disease [52] and may contribute to disrupted sleep. Urinary symptoms are likely related to autonomic dysfunction, though some evidence suggests that nigrostriatal dopamine may exert direct control over bladder function [53], leading to lower urinary tract problems in PD. Typical therapeutic strategies, such as using the restroom immediately prior to sleep and restriction of fluids before bed, may reduce the need to urinate at night and prevent incontinence during sleep. Medications should also be carefully evaluated for diuretic effects if incontinence proves detrimental to sleep. Thermoregulation may also be impaired in the Parkinson’s patient, characterized by excessive sweating both with and without a thermal stimulus [54]. Sweating dysregulation is inconsistently responsive [55] or unresponsive [56] to levodopa therapy, suggesting a physiological heterogeneity in the etiology of this symptom. A case report has outlined a patient’s drenching sweats as DBS responsive, suggesting possible CNS, rather than autonomic, etiology [57]. Careful environmental temperature control is key to thermoregulatory comfort. Because autonomic nervous system failure is a highly ubiquitous phenomenon which may present in heterogeneous fashion in PD, careful consideration of each individual patient’s unique symptom profile and symptomatic management could provide helpful information in reducing autonomic failure-induced sleep disturbance. 2.3 Iatrogenic Insult

Pharmacological management of PD is the most common therapeutic modality. Oral levodopa with a dopamine decarboxylase inhibitor, such as carbidopa, is considered the gold standard against which other therapies are compared [58]. Though the introduction and continued investigation of novel pharmacotherapies for PD is a life-saving endeavor, the incredible complexities of sleep neurochemistry and possible sleep-disruptive effects of PD medications must be appreciated in order to maximize the patient’s quality of life. In many cases, sufficient treatment of the motor aspects of the disease is of primary importance, and medication side effects are tolerated. Indeed, pharmacological treatment of the 4

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motor disorder may also improve sleep quality. However, with disease progression and necessary increases in medication dosage, the risk of iatrogenic disturbances of sleep quality may spike dramatically, especially with dopaminergic medications. The role of dopamine in vigilance state control is highly complex and poorly understood. Classic catecholaminergic stimulants, such as amphetamine and cocaine, exert their stimulatory effects through enhancement of dopamine activity, staving off sleepiness and increasing wakefulness [59]. Certain dopaminergic CNS regions, such as the ventral periaqueductal gray (vPAG) [60], ventral tegmental area, nucleus accumbens, and SNpc [61] appear necessary for the maintenance of wakefulness. On the other hand, certain dopamine type-2 receptor (D2R) agonists, such as quinpirole, have dose-dependent effects, which range from sedation and sleepiness at low doses to enhancement of wakefulness at high doses [62, 63]. This effect could be related to activity at D2R auto- and postsynaptic receptors, or may represent differential effects of D2Rs distributed in different brain regions. In fact, dopamine may be a common neurotransmitter to multiple regions that impart unique influences over sleep and wakefulness. Broad dopamine enhancement may ultimately improve vigilance, but this does not preclude the possible necessity of dopamine for sleep induction and maintenance in select regions, including the striatum. This complexity may contribute to the inconsistent effects of antiparkinsonian medications on sleep. Although levodopa coverage at night can improve sleep in PD, this therapeutic avenue is not without significant caveat. At suboptimal brain concentrations, nocturnal akinesia may persist and motor symptoms may disturb sleep. However, at supraoptimal concentrations, levodopa may have stimulant-like effects. Massive overdoses can precipitate insomnia, anorexia, tachycardia, and confusion, similar to other catecholaminergic agents [64]. Even prolonged typical levodopa therapy has been associated with poor sleep quality, especially when administered within four hours of normal bedtime [65]. In these cases, poor sleep quality is typified by elevated wake time after sleep onset. Ongoing or elevated levodopa therapy may also be associated with neuropsychiatric symptoms, which could precipitate sleep disturbance [66]. Given the demonstrated efficacy of optimal nocturnal levodopa therapy, obtaining optimal sleep quality in the levodopa-treated PD patient is likely a balance between efficacious treatment of nocturnal PD symptoms and excessive, wake-promoting levodopa action. Although further research is required, the index between symptom efficacy and sleep disturbance may narrow with disease progression, especially as levodopa dose requirements increase. Dopamine receptor agonists, such as ropinirole and pramipexole, are common in the treatment of several disorders, including PD. The efficacy of dopamine agonists in ameliorating RLS and PLMD symptoms may afford their usage as multipurpose drugs in PD patients presenting with comorbid RLS/PLMD [67], though current lines of evidence suggest that chronic dopaminergic therapy may elicit RLS symptoms in PD patients over time [68-70]. Like all dopaminergic drugs, including levodopa, optimal dosing of the dopamine receptor agonists may improve sleep by improving nocturnal akinesia, rigidity, and discomfort. REM behavior disorder may also respond to dopamine agonists, such as pramipexole, though higher quality evidence is still required [39]. Monoamine oxidase B inhibitors are common adjuvants in the treatment of PD. Although neither selegiline nor rasagiline have been extensively studied in PD in terms of their sleep effects, selegiline decreases REM sleep, increases stage 2 sleep, and increases latency to REM sleep in healthy subjects [71], and is metabolized into amphetamine, which itself may disrupt sleep. Patients with early PD experienced fewer sleep disturbances when treated with rasagiline as compared to pramipexole [72]. As with other medications, it is probable that optimized treatment improves sleep quality, paralleling improvement in certain nocturnal motor symptoms. Table 1 is a brief review of common pharmacological agents in PD and their effects on sleep. -----------------------------------------------------Table 1 Here-------------------------------------------------2.4 Degeneration of Sleep-Related Central Nervous System Regions

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Although the most recognized degenerative process in PD is the loss of SNpc dopaminergic neurons, pathological cascades common to many neuron subgroups cause widespread degeneration and may contribute to insomnia and other sleep disturbances. Degeneration in many areas, such as the olfactory bulbs [73], hypothalamus [74, 75], and brainstem [76], likely precede midbrain dopaminergic degeneration and may result in early signs of PD, such as anosmia and sleep disturbance [76, 77]. The hypothalamus exerts an especially potent influence over sleep, with many sleep-promoting nuclei and neurochemicals emanating from within this region, including sleep-active neurons of the ventrolateral [78, 79] and median preoptic areas [79, 80]. These hypothalamic regions, along with melaninconcentrating hormone (MCH) neurons [81], have been experimentally demonstrated to promote sleep; pathology-induced lesion of these areas is likely involved in PD-related insomnia and sleep disturbance. Loss of normal homeostatic patterns of sleep, due to daytime sleepiness and required naps may contribute to nocturnal sleep disruption. Indeed, a loss of hypocretin-containing neurons that parallels disease stage has been reported [82], and decreases in cerebrospinal fluid concentrations of hypocretin are correlated with increased objective sleepiness [83]. This compromised wake-promoting system may contribute to the excessive daytime sleepiness and disrupted nocturnal sleep found in advanced PD. Noradrenergic neurons of the locus coeruleus [84, 85] are prominently and progressively lost in PD, potentially contributing to loss of daytime vigilance and excessive daytime sleepiness [86]. Posterior hypothalamic regions involved in wakefulness, such as the histaminergic tuberomamillary nucleus (TMN), are also damaged [75]. Loss of normal homeostatic patterns of sleep due to daytime sleepiness and required naps may contribute to nocturnal disruption. Of note, mounting evidence suggests that the basal ganglia may exert direct control over sleep and wakefulness. As illustrated in Figure 1, the GABAergic external segment of the globus pallidus (GPe) projects directly to layer V of the cerebral cortex and appears to be the final output pathway for basal ganglia influence over sleep [87, 88]. Simultaneous electrophysiological recordings from the GPe and cortical pyramidal neurons depict a strong relationship between the “inactive” deflections of EEG slowwave activity (SWA) and GPe firing [89]. Predictably, excitotoxic lesion of the GPe in the rat reduces sleep time by 45% and reduces cortical synchrony [87]. It seems that subpopulations of GABAergic neurons in the GPe are at least partly responsible for the synchronization of cortical neurons during sleep, precipitating SWA and aiding in maintenance of deep sleep. Additionally, lesions of nuclei “upstream” of the GPe (striatum and SNpc) alter sleep patterns, but lesions “downstream” (subthalamic nucleus, internal segment of the globus pallidus, and substantia nigra pars reticulata) do not induce sleep changes [87]. As a D2R ligand and inhibitor of GABAergic striatal projections to the GPe, striatal dopamine from the SNpc may counter-intuitively aid in the maintenance of sleep via disinhibition of the GPe. -----------------------------------------------------Figure 1 Here--------------------------------------------------

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In many ways, PD sleep disturbance parallels experimental lesion of the GPe. Nigrostriatal dopamine depletion results in excessive striatal inhibitory input to the GPe, causing dysfunctional basal ganglia output, GPe hypoactivity, and theoretically, the motor sequelae of the disease [90, 91]. GPe hypoactivity in both lesioned animal models and idiopathic human cases may also underlie an inability to synchronize cortical pyramidal neurons during deep sleep, causing fragmented and unrefreshing sleep. Striatal dopamine replacement, a treatment modality which restores GPe activity in parkinsonism [91, 92], can be effective in treating both motor and sleep symptoms of PD [24, 25, 28], suggesting that the GPe may be an area of focus for sleep disturbance amelioration in PD. As previously mentioned, DBS targeting both the STN [31-33] and GPe [34] has been demonstrated to improve sleep in PD patients. One intriguing hypothesis explaining the efficacy of DBS for amelioration of sleep disturbance in PD is that the restoration of GPe activity may aid in synchronization of cortical pyramidal neurons and preservation of deep sleep. Additionally, stimulation of the pedunculopontine nucleus (PPN) has also been demonstrated to enhance REM sleep in parkinsonian patients [93], possibly owing to its role in behavioral state switching [94]. Given the close functional

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interdependence between the PPN and the basal ganglia [95], it is possible that PPN stimulation may also contribute to this hypothetical explanation of sleep restoration following DBS. One of the greatest challenges to this model lies in discriminating the direct influence of GPe hypoactivity on sleep disturbance from the potentially sleep-disturbing motor symptoms induced by GPe dysfunction. Identification and manipulation of distinct sleep “cortical” and motor “thalamic” GPe projections, thereby influencing sleep without altering basal ganglia motor output, is a necessary step in conclusively establishing this hypothesis. 2.5 Circadian Disorder in Parkinson’s Disease

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Mounting evidence suggests that disruption of circadian rhythms is a common feature of PD sleep disturbance. Indeed, most neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, present with some degree of circadian dysfunction, most commonly as disorders of sleep and wakefulness. In PD, circadian dysfunction potentially manifests itself as motor fluctuations, unpredictable alterations in motor response to levodopa, or cardiovascular anomalies. Melatonin secretion is phase-advanced and blunted in PD relative to age-matched controls, which may be related to both dopaminergic therapy and disease progression [96, 97]. Unfortunately, to date, there are very few systematic studies investigating the presence or significance of circadian dysfunction in PD, despite the fact that circadian processes may underlie sleep and wake disturbances in the disease. Notably, several animal models of PD display desynchronized circadian processes. Mice overexpressing α-synuclein display progressive PD-like motor symptoms alongside an apparent reduction in daylight suprachiasmatic nucleus (SCN) firing rates, indicating a weakening or alteration of circadian patterns [98]. It has not been determined whether SCN dysfunction in this model is a direct effect of αsynuclein aggregation or a secondary effect of dopamine loss or physiological dysfunction as a result of synuclein-mediated neurodegeneration. Clock gene expression is also dysregulated in 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) rodent models of PD [99]. The use of exogenous melatonin and melatonin agonists may be an avenue worth pursuing in the treatment of circadian dysfunction in PD. The ability of melatonin to entrain circadian processes could be harnessed to reduce internal “desynchronization,” which may underlie sleep disturbance in PD. Although extensive research is necessary to determine efficacy (and the efficacy of melatonin even in primary circadian disorders is contested), melatonin remains an intriguing possibility due to its putative neuroprotective and antioxidant effects [100, 101]. Bright-light therapy, which influences melatonin secretion and corrects circadian misalignment, has been shown to restore circadian rhythmicity and improve mood in PD patients [102].

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3. Directions in Treatment of Parkinson’s Disease Sleep Disturbance It is apparent that the mosaic of sleep-disturbing influences in the PD patient far outpaces that of many of their peers. However, there is no specific treatment modality indicated for sleep disturbance in PD. Instead, control of sleep quality in PD is largely relegated to symptom amelioration using sedativehypnotic drugs, which mask sleep disturbance without correcting its PD-related etiology. Progress is hampered by a poor understanding of the extensive underlying physiological, iatrogenic, and psychological issues that cause sleep disturbance in this population, and by the vast interactions among these modules. Indeed, the total mosaic of sleep disturbing effects in PD--once identified--will likely be effectively countered with an equally complex treatment modality. Rational and optimized dopamine replacement may be an efficacious and readily-available pharmacological option in preventing sleep disturbance. Overnight dopamine coverage appears promising in its ability to treat motor and sleep symptoms of PD, but the waning effects of chronic levodopa administration and contribution to painful and unpleasant dyskinesias represent significant shortcomings of this modality. Theoretically, nondopaminergic modalities which may focus on restoration of GPe 7

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activity, facilitation of hypocretin, anterior hypothalamic function, or other potential mechanisms discussed in this review, may offer future therapeutic targets for sleep disturbance in PD. Patient education is vital in reducing negative outcomes associated with PD sleep disturbance. Of note, PD patients are more likely to be involved in at-fault motor vehicle accidents, the risks of which are exacerbated by daytime sleepiness, fatigue, and sudden sleepiness due to nocturnal sleep disturbance. Poor sleep quality also increases risk for affective disorders, which may compound the native increased risk of psychological problems in PD patients. Patients should be appropriately educated in recognizing signs of dangerous sleep deprivation associated with PD, and encouraged to discuss these issues with the clinician if they arise. Insomnia symptoms, especially those related to depression or anxiety, may be ameliorated with certain forms of cognitive-behavioral therapy (CBT). CBT is a well-established therapy for insomnia [103], and at least one longitudinal pilot study has demonstrated the efficacy of CBT in improving subjective sleep quality in PD patients [104]. Furthermore, patient sleep hygiene should be evaluated and adjusted if necessary. All patients with significant sleep disturbance, including those suffering from PD, should be evaluated thoroughly by a sleep specialist, and may include polysomnography if necessary. A systematic approach to sleep disturbance in PD is vital, and comprehensive evaluation can assist the clinician in constructing a “composite image” of the sleep disturbance mosaic, as illustrated in Figure 2. From this point, isolating and treating components of the complex mosaic becomes the primary goal of patient care. Although there is no rigorous treatment regimen for sleep disturbance in PD, further research may identify additional components of the current mosaic of sleep-disturbing PD-related symptoms. Continuous improvements in pharmacological and nonpharmacological management of PD symptoms, neuroprotective strategies to delay disease progression, and symptomatic treatment of sleep disturbance will herald enhancement of quality of life in PD, alongside broad improvement in multiple domains of health, wellness, and independence. Novel advances in targeted treatment of sleep disturbance in PD will undoubtedly rely heavily on an understanding of the complex interactions between motor and autonomic impairment, iatrogenic insult, sleep disorder, and neurological degeneration, highlighting the importance of continued research in this area. -----------------------------------------------------Figure 2 Here-------------------------------------------------References

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Swick, T.J., Parkinson's disease and sleep/wake disturbances. Parkinsons Dis, 2012. 2012: p. 205471. Hansen, I.H., et al., Detection of a sleep disorder predicting Parkinson's disease. Conf Proc IEEE Eng Med Biol Soc, 2013. 2013: p. 5793-5796. Kempfner, J., et al., SLEEP phenomena as an early biomarker for Parkinsonism. Conf Proc IEEE Eng Med Biol Soc, 2013. 2013: p. 5773-5776. Weerkamp, N.J., et al., Nonmotor Symptoms in Nursing Home Residents with Parkinson's Disease: Prevalence and Effect on Quality of Life. J Am Geriatr Soc, 2013. 61(10): p. 1714-1721. Duncan, G.W., et al., Health-related quality of life in early Parkinson's disease: The impact of nonmotor symptoms. Mov Disord, 2013. Spindler, M., et al., Daytime Sleepiness is Associated with Falls in Parkinson's Disease. J Parkinsons Dis, 2013. 3(3): p. 387-91. Scullin, M.K., et al., Sleep and impulsivity in Parkinson's disease. Parkinsonism Relat Disord, 2013. Lachenmayer, L., Parkinson's disease and the ability to drive. J Neurol, 2000. 247 Suppl 4: p. IV/28-30. Goetz, C.G., et al., Hallucinations and sleep disorders in PD: ten-year prospective longitudinal study. Neurology, 2010. 75(20): p. 1773-9.

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11.

Bugalho, P. and M. Viana-Baptista, REM sleep behavior disorder and motor dysfunction in Parkinson's disease - A longitudinal study. Parkinsonism Relat Disord, 2013. Kutscher, S.J., S. Farshidpanah, and D.O. Claassen, Sleep dysfunction and its management in Parkinson's disease. Curr Treat Options Neurol, 2014. 16(8): p. 304. Trotti, L.M. and D.L. Bliwise, No increased risk of obstructive sleep apnea in Parkinson's disease. Mov Disord, 2010. 25(13): p. 2246-9. Nomura, T., et al., Characteristics of obstructive sleep apnea in patients with Parkinson's disease. J Neurol Sci, 2013. 327(1-2): p. 22-4. Maria, B., et al., Sleep breathing disorders in patients with idiopathic Parkinson's disease. Respir Med, 2003. 97(10): p. 1151-7. Chotinaiwattarakul, W., et al., Risk of sleep-disordered breathing in Parkinson's disease. Sleep Breath, 2011. 15(3): p. 471-8. Mahowald, M.W. and C.H. Schenck, REM sleep behaviour disorder: a marker of synucleinopathy. Lancet Neurol, 2013. 12(5): p. 417-9. Schenck, C.H., B.F. Boeve, and M.W. Mahowald, Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder: a 16-year update on a previously reported series. Sleep Med, 2013. 14(8): p. 744-8. Boeve, B.F., Idiopathic REM sleep behaviour disorder in the development of Parkinson's disease. Lancet Neurol, 2013. 12(5): p. 469-82. Postuma, R.B., et al., How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder. Brain, 2012. 135(Pt 6): p. 1860-70. Ratti, P.L., et al., Distinctive features of NREM parasomnia behaviors in parkinson's disease and multiple system atrophy. PLoS One, 2015. 10(3): p. e0120973. Loo, H.V. and E.K. Tan, Case-control study of restless legs syndrome and quality of sleep in Parkinson's disease. J Neurol Sci, 2008. 266(1-2): p. 145-9. Allen, R., Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med, 2004. 5(4): p. 385-91. Chaudhuri, K.R., et al., The Parkinson's disease sleep scale: a new instrument for assessing sleep and nocturnal disability in Parkinson's disease. J Neurol Neurosurg Psychiatry, 2002. 73(6): p. 629-35. Van den Kerchove, M., et al., Sustained-release levodopa in parkinsonian patients with nocturnal disabilities. Acta Neurol Belg, 1993. 93(1): p. 32-9. Trenkwalder, C., et al., Rotigotine effects on early morning motor function and sleep in Parkinson's disease: a double-blind, randomized, placebo-controlled study (RECOVER). Mov Disord, 2011. 26(1): p. 90-9. Ghys, L., et al., Effect of rotigotine on sleep and quality of life in Parkinson's disease patients: post hoc analysis of RECOVER patients who were symptomatic at baseline. Expert Opin Pharmacother, 2011. 12(13): p. 1985-98. Zibetti, M., et al., Sleep improvement with levodopa/carbidopa intestinal gel infusion in Parkinson disease. Acta Neurol Scand, 2013. 127(5): p. e28-32. Fasano, A., et al., Intrajejunal levodopa infusion in advanced Parkinson's disease: long-term effects on motor and non-motor symptoms and impact on patient's and caregiver's quality of life. Eur Rev Med Pharmacol Sci, 2012. 16(1): p. 79-89. Gros, P., et al., Obstructive sleep apnea in Parkinson's disease patients: effect of Sinemet CR taken at bedtime. Sleep Breath, 2016. 20(1): p. 205-12. Sobstyl, M., et al., Quality of life in advanced Parkinson's disease after bilateral subthalamic stimulation: 2 years follow-up study. Clin Neurol Neurosurg, 2014. 124: p. 161-5. Amara, A.W., et al., Unilateral subthalamic nucleus deep brain stimulation improves sleep quality in Parkinson's disease. Parkinsonism Relat Disord, 2012. 18(1): p. 63-8.

AC C

10.

9

ACCEPTED MANUSCRIPT Albers 10

38. 39. 40. 41. 42. 43. 44. 45. 46. 47.

48. 49. 50. 51. 52. 53. 54. 55.

RI PT

37.

SC

36.

M AN U

35.

TE D

34.

EP

33.

Zibetti, M., et al., Motor and nonmotor symptom follow-up in parkinsonian patients after deep brain stimulation of the subthalamic nucleus. Eur Neurol, 2007. 58(4): p. 218-23. Lyons, K.E. and R. Pahwa, Effects of bilateral subthalamic nucleus stimulation on sleep, daytime sleepiness, and early morning dystonia in patients with Parkinson disease. J Neurosurg, 2006. 104(4): p. 502-5. Volkmann, J., et al., Long-term effects of pallidal or subthalamic deep brain stimulation on quality of life in Parkinson's disease. Mov Disord, 2009. 24(8): p. 1154-61. Raggi, A., et al., Sleep disorders in Parkinson's disease: a narrative review of the literature. Rev Neurosci, 2013. 24(3): p. 279-91. Shin, H.Y., et al., Restless legs syndrome in Korean patients with drug-naive Parkinson's disease: a nation-wide study. Parkinsonism Relat Disord, 2013. 19(3): p. 355-8. Svensson, E., et al., Sleep problems in Parkinson's disease: a community-based study in Norway. BMC Neurol, 2012. 12: p. 71. Hening, W.A., et al., An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep, 2004. 27(3): p. 560-83. Sasai, T., Y. Inoue, and M. Matsuura, Effectiveness of pramipexole, a dopamine agonist, on rapid eye movement sleep behavior disorder. Tohoku J Exp Med, 2012. 226(3): p. 177-81. Peeraully, T. and E.K. Tan, Linking restless legs syndrome with Parkinson's disease: clinical, imaging and genetic evidence. Transl Neurodegener, 2012. 1(1): p. 6. Ziemssen, T. and H. Reichmann, Cardiovascular autonomic dysfunction in Parkinson's disease. J Neurol Sci, 2010. 289(1-2): p. 74-80. Meco, G., L. Pratesi, and V. Bonifati, Cardiovascular reflexes and autonomic dysfunction in Parkinson's disease. J Neurol, 1991. 238(4): p. 195-9. Palma, J.A., et al., Cardiac autonomic impairment during sleep is linked with disease severity in Parkinson's disease. Clin Neurophysiol, 2013. 124(6): p. 1163-8. Oka, H., et al., Characteristics of orthostatic hypotension in Parkinson's disease. Brain, 2007. 130(Pt 9): p. 2425-32. Gray, P. and K. Hildebrand, Fall risk factors in Parkinson's disease. J Neurosci Nurs, 2000. 32(4): p. 222-8. Czarkowska, H., et al., Cardiac responses to orthostatic stress deteriorate in Parkinson disease patients who begin to fall. Neurol Neurochir Pol, 2010. 44(4): p. 339-49. Sauvageot, N., M. Vaillant, and N.J. Diederich, Reduced sympathetically driven heart rate variability during sleep in Parkinson's disease: a case-control polysomnography-based study. Mov Disord, 2011. 26(2): p. 234-40. Edwards, L.L., E.M. Quigley, and R.F. Pfeiffer, Gastrointestinal dysfunction in Parkinson's disease: frequency and pathophysiology. Neurology, 1992. 42(4): p. 726-32. Edwards, L.L., et al., Gastrointestinal symptoms in Parkinson's disease. Mov Disord, 1991. 6(2): p. 151-6. Maeda, T., et al., High prevalence of gastroesophageal reflux disease in Parkinson's disease: a questionnaire-based study. Parkinsons Dis, 2013. 2013: p. 742128. Orr, W.C., Reflux events and sleep: are we vulnerable? Curr Gastroenterol Rep, 2006. 8(3): p. 202-7. Bjornara, K.A., E. Dietrichs, and M. Toft, Clinical features associated with sleep disturbances in Parkinson's disease. Clin Neurol Neurosurg, 2014. 124: p. 37-43. Winge, K., et al., Relationship between nigrostriatal dopaminergic degeneration, urinary symptoms, and bladder control in Parkinson's disease. Eur J Neurol, 2005. 12(11): p. 842-50. Turkka, J.T. and V.V. Myllyla, Sweating dysfunction in Parkinson's disease. Eur Neurol, 1987. 26(1): p. 1-7. Sage, J.I. and M.H. Mark, Drenching sweats as an off phenomenon in Parkinson's disease: treatment and relation to plasma levodopa profile. Ann Neurol, 1995. 37(1): p. 120-2.

AC C

32.

10

ACCEPTED MANUSCRIPT Albers 11

62. 63. 64. 65. 66. 67.

68.

69. 70. 71. 72. 73. 74. 75. 76. 77.

78.

RI PT

61.

SC

60.

M AN U

59.

TE D

58.

EP

57.

Pursiainen, V., J. Lyytinen, and E. Pekkonen, Effect of duodenal levodopa infusion on blood pressure and sweating. Acta Neurol Scand, 2012. 126(4): p. e20-4. Sanghera, M.K., et al., Alleviation of drenching sweats following subthalamic deep brain stimulation in a patient with Parkinson's disease--a case report. J Neurol Sci, 2009. 285(1-2): p. 246-9. Pinder, R.M., Drugs for Parkinson's disease: levodopa is still the gold standard. Neuropsychiatr Dis Treat, 2008. 4(1): p. i-ii. Rechtschaffen, A. and L. Maron, The Effect of Amphetamine on the Sleep Cycle. Electroencephalogr Clin Neurophysiol, 1964. 16: p. 438-45. Lu, J., T.C. Jhou, and C.B. Saper, Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter. J Neurosci, 2006. 26(1): p. 193-202. Monti, J.M. and D. Monti, The involvement of dopamine in the modulation of sleep and waking. Sleep Med Rev, 2007. 11(2): p. 113-33. Monti, J.M., H. Jantos, and M. Fernandez, Effects of the selective dopamine D-2 receptor agonist, quinpirole on sleep and wakefulness in the rat. Eur J Pharmacol, 1989. 169(1): p. 61-6. Monti, J.M., et al., Biphasic effects of dopamine D-2 receptor agonists on sleep and wakefulness in the rat. Psychopharmacology (Berl), 1988. 95(3): p. 395-400. Hoehn, M.M. and C.O. Rutledge, Acute overdose with levodopa. Clinical and biochemical consequences. Neurology, 1975. 25(8): p. 792-4. Chahine, L.M., et al., Association between dopaminergic medications and nocturnal sleep in early-stage Parkinson's disease. Parkinsonism & Related Disorders, 2013(0). Nausieda, P.A., et al., Sleep disruption in the course of chronic levodopa therapy: an early feature of the levodopa psychosis. Clin Neuropharmacol, 1982. 5(2): p. 183-94. Walters, A.S., et al., Ropinirole is effective in the treatment of restless legs syndrome. TREAT RLS 2: a 12-week, double-blind, randomized, parallel-group, placebo-controlled study. Mov Disord, 2004. 19(12): p. 1414-23. Elena, M., et al., A prospective study of the cumulative incidence and course of restless legs syndrome in de novo patients with Parkinson's disease during chronic dopaminergic therapy. J Neurol, 2015. Moccia, M., et al., A Four-Year Longitudinal Study on Restless Legs Syndrome in Parkinson Disease. Sleep, 2015. Suzuki, K., et al., Restless Legs Syndrome and Leg Motor Restlessness in Parkinson's Disease. Parkinsons Dis, 2015. 2015: p. 490938. Thornton, C., et al., The effect of deprenyl, a selective monoamine oxidase B inhibitor, on sleep and mood in man. Psychopharmacology (Berl), 1980. 70(2): p. 163-6. Viallet, F., et al., Evaluation of the safety and tolerability of rasagiline in the treatment of the early stages of Parkinson's disease. Curr Med Res Opin, 2013. 29(1): p. 23-31. Pearce, R.K., C.H. Hawkes, and S.E. Daniel, The anterior olfactory nucleus in Parkinson's disease. Mov Disord, 1995. 10(3): p. 283-7. Sandyk, R., R.P. Iacono, and C.R. Bamford, The hypothalamus in Parkinson disease. Ital J Neurol Sci, 1987. 8(3): p. 227-34. Langston, J.W. and L.S. Forno, The hypothalamus in Parkinson disease. Ann Neurol, 1978. 3(2): p. 129-33. Braak, H., et al., Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging, 2003. 24(2): p. 197-211. Halliday, G.M., K. Del Tredici, and H. Braak, Critical appraisal of brain pathology staging related to presymptomatic and symptomatic cases of sporadic Parkinson's disease. J Neural Transm Suppl, 2006(70): p. 99-103. Sherin, J.E., et al., Activation of ventrolateral preoptic neurons during sleep. Science, 1996. 271(5246): p. 216-9.

AC C

56.

11

ACCEPTED MANUSCRIPT Albers 12

85.

86. 87. 88. 89. 90. 91. 92.

93. 94. 95. 96. 97. 98. 99. 100. 101. 102.

RI PT

84.

SC

83.

M AN U

82.

TE D

81.

EP

80.

Gong, H., et al., Activation of c-fos in GABAergic neurones in the preoptic area during sleep and in response to sleep deprivation. J Physiol, 2004. 556(Pt 3): p. 935-46. Suntsova, N., et al., Sleep-waking discharge patterns of median preoptic nucleus neurons in rats. J Physiol, 2002. 543(Pt 2): p. 665-77. Torterolo, P., P. Lagos, and J.M. Monti, Melanin-concentrating hormone: a new sleep factor? Front Neurol, 2011. 2: p. 14. Thannickal, T.C., Y.Y. Lai, and J.M. Siegel, Hypocretin (orexin) cell loss in Parkinson's disease. Brain, 2007. 130(Pt 6): p. 1586-95. Wienecke, M., et al., Progressive dopamine and hypocretin deficiencies in Parkinson's disease: is there an impact on sleep and wakefulness? J Sleep Res, 2012. 21(6): p. 710-7. Ohtsuka, C., et al., Changes in substantia nigra and locus coeruleus in patients with early-stage Parkinson's disease using neuromelanin-sensitive MR imaging. Neurosci Lett, 2013. 541: p. 93-8. Del Tredici, K. and H. Braak, Dysfunction of the locus coeruleus-norepinephrine system and related circuitry in Parkinson's disease-related dementia. J Neurol Neurosurg Psychiatry, 2013. 84(7): p. 774-83. Berridge, C.W., B.E. Schmeichel, and R.A. Espana, Noradrenergic modulation of wakefulness/arousal. Sleep Med Rev, 2012. 16(2): p. 187-97. Qiu, M.H., et al., Basal ganglia control of sleep-wake behavior and cortical activation. Eur J Neurosci, 2010. 31(3): p. 499-507. Vetrivelan, R., et al., Role of Basal Ganglia in sleep-wake regulation: neural circuitry and clinical significance. Front Neuroanat, 2010. 4: p. 145. Mallet, N., et al., Dichotomous organization of the external globus pallidus. Neuron, 2012. 74(6): p. 1075-86. Filion, M. and L. Tremblay, Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res, 1991. 547(1): p. 142-51. Hutchinson, W.D., et al., Effects of apomorphine on globus pallidus neurons in parkinsonian patients. Ann Neurol, 1997. 42(5): p. 767-75. Filion, M., L. Tremblay, and P.J. Bedard, Effects of dopamine agonists on the spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res, 1991. 547(1): p. 152-61. Lim, A.S., et al., Selective enhancement of rapid eye movement sleep by deep brain stimulation of the human pons. Ann Neurol, 2009. 66(1): p. 110-4. Amara, A.W., R.L. Watts, and H.C. Walker, The effects of deep brain stimulation on sleep in Parkinson's disease. Ther Adv Neurol Disord, 2011. 4(1): p. 15-24. Mena-Segovia, J., J.P. Bolam, and P.J. Magill, Pedunculopontine nucleus and basal ganglia: distant relatives or part of the same family? Trends Neurosci, 2004. 27(10): p. 585-8. Bordet, R., et al., Study of circadian melatonin secretion pattern at different stages of Parkinson's disease. Clin Neuropharmacol, 2003. 26(2): p. 65-72. Videnovic, A., et al., Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. JAMA Neurol, 2014. 71(4): p. 463-9. Kudo, T., et al., Circadian dysfunction in a mouse model of Parkinson's disease. Exp Neurol, 2011. 232(1): p. 66-75. Hayashi, A., et al., A disruption mechanism of the molecular clock in a MPTP mouse model of Parkinson's disease. Neuromolecular Med, 2013. 15(2): p. 238-51. Ono, K., et al., Effect of melatonin on alpha-synuclein self-assembly and cytotoxicity. Neurobiol Aging, 2012. 33(9): p. 2172-85. Pandi-Perumal, S.R., et al., Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes. Neurotox Res, 2013. 23(3): p. 267-300. Rutten, S., et al., Bright light therapy in Parkinson's disease: an overview of the background and evidence. Parkinsons Dis, 2012. 2012: p. 767105.

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Trauer, J.M., et al., Cognitive Behavioral Therapy for Chronic Insomnia: A Systematic Review and Meta-analysis. Ann Intern Med, 2015. 163(3): p. 191-204. Yang, H. and M. Petrini, Effect of cognitive behavior therapy on sleep disorder in Parkinson's disease in China: a pilot study. Nurs Health Sci, 2012. 14(4): p. 458-63.

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Figure 1A: A schematic representation of the basal ganglia. The basal ganglia are putative central regulators of sleep maintenance which become dysfunctional in Parkinson’s disease. A potential sleep regulatory circuit is highlighted in red. Figure 1B: A hypothetical model of loss of sleep regulation in PD. Destruction of SNpc neurons induces unchecked inhibition of the GPe by striatopallidal medium spiny neurons, reducing pallidal inhibition of the cortex. Inhibition of the pallidocortical pathway, which provides GABAergic tone to the cortex, may impair sleep maintenance in PD patients. A1: Adenosine Receptor Type 1; A2A: Adenosine Receptor Type 2A; D1: Dopamine Receptor Type 1; D2: Dopamine Receptor Type 2; DA: Dopaminergic nigrostriatal neurons; GABA: Gamma-Aminobutyric Acid; Glu: Glutamate; GPe: Globus Pallidus, External Segment; GPi: Globus Pallidus, Internal Segment; SNpc: Substantia Nigra, Compact Part; SNpr: Substantia Nigra, Reticular Part. →: Glutamatergic or dopaminergic tract; ●: GABAergic tract. Relative activity of each tract is denoted by size and thickness of representative line. Figure 2. A Mosaic Model of Sleep Disturbance in Parkinson’s Disease. Multiple factors must be considered when treating sleep disturbance in PD, including control of motor symptoms, effects of autonomic dysfunction, iatrogenic delay or disruption of sleep, disorders of sleep both related and unrelated to PD, and circadian rhythm disorders. Each of these domains can be evaluated and mitigated through concerted collaboration among sleep specialists, neurologists, occupational therapy, and other providers.

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Table 1. Commonly Used Drugs for the Treatment of Parkinson’s Disease and Their Effects on Sleep

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Mechanism Increases Available Dopamine

Sleep Effects Optimal dosing may improve sleep; Excessive/over dosing precipitates sympathetic activation and sleep disturbance. Subtherapeutic doses may precipitate akinetic disturbances of sleep.

Ropinirole Pramipexole

Dopamine Receptor Agonists

May be useful in treating RLS symptoms. Prolonged use can precipitate RLS symptoms. Possible connection to daytime “sleep attacks” in PD patients.

Selegiline Rasagiline

Monoamine Oxidase Inhibitors Decrease REM sleep. Rasagiline may elicit less sleep disruption than other drugs.

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Table 1. Commonly Used Drugs for the Treatment of Parkinson’s Disease and Their Effects on Sleep

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Article Highlights • Sleep disturbance is a common problem in Parkinson’s disease • Sleep disturbance contributes to poor patient quality of life. • Parkinson’s disease sleep disturbances stem from coexisting system failures. • Motor, autonomic, and central nervous system failure cause sleep disturbance. • Systematic evaluation and management of sleep is vital to patient care.