Neurochem Res DOI 10.1007/s11064-014-1488-7

OVERVIEW

Are Sleep Disturbances Preclinical Markers of Parkinson’s Disease? Altair B. dos Santos • Kristi A. Kohlmeier George E. Barreto



Received: 14 August 2014 / Revised: 21 November 2014 / Accepted: 24 November 2014 Ó Springer Science+Business Media New York 2014

Abstract Parkinson’s disease (PD) is a neurobehavioral disorder characterized by motor symptoms and signs, and non-motor abnormalities such as olfactory dysfunction, pain, sleep disorders and cognitive impairment. Amongst these alterations, sleep disturbances play an important role in the pathology, but presence of disturbed sleep is not currently considered in diagnosis. However, sleeping problems may precede by many years the classic motor abnormalities of PD and should be clinically evaluated as a potential marker before disease onset. The first disturbance reported with this potential was the disorder REM sleep behaviour and currently several other disturbances have gained importance as potential markers, such as excessive daytime sleepiness, restless legs syndrome and new evidence also points to changes in circadian rhythms. Here we present a brief review of the major evidence indicating that sleep disturbances precede the motor symptoms in PD and neurodegeneration occurs in regions that could underlie these phenomena in order to provide support for the conclusion that disturbances of sleep should be considered as valuable preclinical markers for PD.

A. B. dos Santos Department of Biological Sciences, Universidade Estadual do Sudoeste da Bahia, Vito´ria Da Conquista, Brazil K. A. Kohlmeier Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark e-mail: [email protected] G. E. Barreto (&) Departmento de Nutricio´n y Bioquı´mica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogota´ DC, Colombia e-mail: [email protected]

Keywords Parkinson’s disease  Sleep disturbances  Non-motor signs  Preclinical markers

Introduction While Parkinson’s disease (PD) is a neurobehavioral disorder that has as principal diagnosis criteria, the presence of motor disturbances [1], PD is also characterised by nonmotor symptoms, including heightened experience of pain, increased occurrence of affective disorders, olfactory dysfunction, cognitive impairment and sleep disorders [2, 3] and the presence and severity of these non-motor symptoms as the disease progresses exacerbate the degree of disability of PD patients. Knowledge of the interaction between sleep and PD has been gained from studies examining processes underlying sleep at the biochemical, cellular and systemswide level in PD-diagnosed and preclinical PD patients. Further, improved design of animal models of PD using rodents and non-human primates have greatly assisted in our understanding of the relationship between sleep and this disease. At this time, there is a significant literature comprised of human epidemiological studies, animals model studies across a variety of different species, imaging studies in both animals and humans and post-mortem studies, which have analysed varying manifestations of sleep disorders or neural changes in areas controlling sleep, which precede or co-occur with PD in an attempt to gain understanding of the full range of neurophysiological processes occurring in this disease underlying symptomology. What is clear from these studies is that several neural regions controlling the neurophysiological signs of the different stages of sleep are affected early in this neurodegenerative disease and that disturbances of sleep may precede the classic diagnostic indicator, primarily motor symptoms, common to PD.

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Accordingly, sleep disturbances have been considered for usefulness as preclinical markers of PD prior to onset of motor symptoms. Within the general population, PD is estimated to occur with a prevalence rate of approximately 160 cases per 100,000 individuals [4, 5]. In those suffering from PD, there is a high degree of associated motor, cognitive and psychological disability and the efficacy of currently available pharmacotherapies reduces with time and is associated with unpleasant side effects. Given the high rate of incidence of PD worldwide, the unsatisfactory treatment regime and the impairment imposed by the disease, examination of the underlying mechanisms leading to preclinical sleep abnormalities is justified in hopes that such studies bring a new understanding of the aetiology of the neurophysiology of this disease. In this mini-review, we present the major evidence indicating that sleep disturbances precede the motor symptoms in Parkinson’s disease and the possible explanations for this phenomenon.

Evidence of Sleep Disorders as Preclinical Markers Rapid Eye Movement Sleep Behavior Disorder: First Reliable Evidence

examinations, primarily clinical epidemiological studies, examining this link, and the findings strengthened the conclusion that RBD and PD are tightly associated. It is now recognised that in nearly 40–65 % of cases [10], those with RBD develop alpha-synucleinopathies such as PD and, accordingly, RBD can be considered as a prodromal phase of neurodegenerative diseases, including PD, with the development of the signs and motor symptoms of PD in 16–65 % of individuals occurring between 2 and 13 years following detection of RBD symptomology [6, 11–14]. Interestingly, in a very recently published study, SixelDoring et al. [15] analysed markers of sleep abnormalities in newly-diagnosed, non-medicated PD patients who had not previously presented with sleep complaints, and found abnormal behavioral events in REM sleep, such as the lack of atonia during REM sleep, inappropriate motor movements and involuntary vocalizations. As there is a risk of development of RBD secondary to diagnosis with PD, this finding was not surprising, but does raise the possibility that motor abnormalities associated with REM sleep might have remained undetected in this population for quite some time and, accordingly, motor abnormalities of REM sleep may be present as a prodrome phase in more PD patients than previously recognised. EDS, RLS and Circadian System Alterations

Among the non-motor signs of PD, disturbances of sleep preceding motor dysfunction have become a main focus as a preclinical marker of eventual onset of PD following the intriguing observation that changes in regulation of the sleep and wakefulness cycle may occur years before the onset of PD motor symptoms. This clinical finding was first reported by Schenck et al. [6], and has guided much of the research in this area in the years following its recognition. Schenk et al. [6] observed that in a group of patients diagnosed with the behavioural state disorder known as rapid eye movement (REM) sleep behavior disorder (RBD), surprisingly 38 % of patients were diagnosed as having a parkinsonian syndrome 12, 7 years after RBD diagnosis, and 65 % after, when follow-up was extended by an additional 7-year period. RBD is a motor disorder characterized by aberrant motor activity during the phase of sleep known as REM, which is a state normally characterised by an active inhibition of motor tone [7]. While the reduction of the musculoskeletal atonia during REM sleep in normal individuals can be punctuated by very brief periods of breakthrough motor tone evidenced as jerks or twitches, REM sleep of those with RBD is experienced with an absence of a predominance of motor quiescence, and is instead accompanied by extended periods of motor activity, often of a violent nature [8, 9]. The discovery of the strong association between RBD and eventual development of PD propelled further

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In the search for pre-clinical signs of PD, research of sleep abnormalities associated with human PD has been focused on RBD; however, this focus may have resulted in narrowing the full recognition of the association of PD with other changes in sleep structure and control. PD patients report, in addition to RBD, sleep-associated disorders such as difficulty initiating or maintaining sleep, restless leg syndrome (RLS), parasomnias, excessive daytime somnolence (EDS), abnormal dreams and abnormal regulation of atonia during sleep [16]. Sleep-related symptomology beyond RBD is reported to be present in 60–90 % of PD patients and while these disorders are debilitating in PD patients and therefore warrant investigation in their own right, elucidation of the neural mechanisms leading to their appearance may also give some clues as to the underlying cause of neurodegeneration in PD [1–3, 12, 16–20]. A few clinical studies have investigated the occurrence of sleep and behavioural state disorders other than RBD, such as RLS, EDS and circadian dysfunctions, to determine whether presence of these disorders occurs in patients with non-motor symptoms of PD, but who later present with PD. RLS is a movement disorder characterized by an uncontrollable urge to move the legs, usually accompanied by unpleasant sensations. RLS occurs when in a relaxed state, such as when lying down and trying to fall asleep and, as it is partially or totally relieved by movement, tends to

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preclude afflicted individuals from falling asleep. In addition, sufferers also experience periodic limb movement disorder that disturbs maintenance of a restful sleep. Wong et al. [21] conducted the first prospective study aimed at assessing the risk of developing PD in individuals with RLS, as well as establishing the temporal relationship between the two conditions. Interestingly, this study showed that men with RLS had a higher risk for later PD development in comparison to those without it, suggesting that severe RLS may be an early feature of PD. While sleep is under homeostatic control with a sleep need accumulating during wakefulness, its timing exhibits a circadian rhythmicity suggesting interaction of the homeostatic system with processes involving body clocks. While there are not many studies which were designed to investigate the early changes in circadian rhythms associated with PD, disruption of the circadian system was shown in a transgenic PD mouse model, and circadian alterations preceded evidence of motor dysfunction [22]. The results revealed that the electrical activity of neurons within the suprachiasmatic nuclei (SCN), which is considered the body’s master clock, was already abnormal by the onset of motor symptoms, although the core features of the intrinsic molecular oscillations in the SCN remained functional. Circadian control appears to be altered in human PD, suggesting dysregulation of the body’s clock mechanisms [23]. Disruption of the body’s circadian systems can lead to alterations in metabolism [24], autonomic disorders [25] and memory alterations [26–28]. As alterations in all of these processes have been seen in newly-diagnosed PD patients [29], this raises the possibility that these abnormalities could be present before the onset of motor symptoms even though PD patients may not have complained of circadian-based symptoms prior to PD diagnosis When taken together, evidence found of early abnormalities in the circadian system in animal models of PD, and the presence of circadian disturbances in diagnosed PD patients raises the question as to how long disruptions in these rhythms may precede motor symptoms of PD disease [27]. Further, as nearly 50 % of PD patients experience mild cognitive decline which is most likely predominantly due to cortical lesions, with some subcortical involvement [26, 30] and/or due to cognitive impairment due to PD medications, investigations need to be conducted to examine to what extent PD degeneration of circadian processes exacerbates these cognitive disabilities. Future research designed to study the changes in the mechanisms governing circadian rhythmicity and processes controlled in a circadian fashion are expected to bring a new perspective on our understanding of the neurodegenerative process occurring in PD [27, 28]. As it is present in a range of illnesses and disorders, excessive daytime sleepiness (EDS) which is characterised

by a persistent sleepiness arising from inadequate sleep syndrome, but which can also occur even when adequate night-time rest is achieved, is believed to arise from a multifactorial aetiology and unsurprisingly, it is common in neurodegenerative processes. Many PD patients complain of inability to fall asleep and a reduced sleep efficiency resulting in non-refreshing sleep [23]. It is of note that EDS is not present in all PD patients, but that it can arise in these individuals subsequent to induction of dopamine-based clinical treatments; however, such treatments can also be associated with reductions in self-reports of fatigue [31]. While EDS is often present in PD due to an intrinsic presence or a therapy-induced side effect, there is evidence that it may precede PD. A study of non-PD males, aged between 71 and 93, who presented with EDS, reported a more than threefold higher risk factor for later development of PD in this population [32]. Age-related changes in the brain leading to disturbances in sleep architecture likely play an important role in the development of EDS, however the increased risk of development of PD in EDS patients seen in this study indicates that an interplay between processes underlying EDS and PD, which could include, or be exacerbated by, the altered circadian phenotype seen in many PD patients, exists, and suggests that EDS could serve as a preclinical marker of PD. Studies Using Animal Models Studies using animal models of PD have also detected changes in sleep architecture and motor behavior suggestive of a link between the mechanisms underlying sleep control and PD. When sleep measures were monitored in marmoset monkeys following 2 weeks of sub-chronic treatment with MPTP at doses known to be sufficient to generate a mild PD in this species, high amplitude EMG bouts during REM were found to be associated the most strongly with drug treatment [33]. Motor behaviour during wakefulness was significantly affected, but motor deficits were noted by these authors as being moderate. While the RBD noted in this subchronic MPTP model did not meet the stringent criteria of RBD in humans, it was considered substantial [33]. Therefore, these data suggest that processes underlying RBD are more sensitive to MPTP disruption than those underlying the classic PD waking-state motoric signs, indicating potential usefulness of the subchronic marmoset model in studies of mechanisms underlying appearance of RBD, prior to development of PD clinical motoric signs [33]. Administration of MPTP to rhesus monkeys was found to induce motor symptoms reminiscent of PD, however, changes induced in the structure of sleep such as reductions in REM sleep and EDS occurred prior to the development of abnormal motor control [34]. Long-term follow-up revealed that compensatory recovery from drug treatment was

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associated with a partial restoration of motor behaviour coincident with a partial increase in REM sleep [34, 35]. Taken together, these studies using animal models of PD suggest behavioural changes associated with REM reminiscent to those of RBD in humans and when taken with findings from other studies, indicate that animal models of PD, in addition to their usefulness in treatment strategies for fully developed PD, also provide substrate for studies designed for development of early markers of PD to serve to improve diagnostic ability and in future, recognition of indicators for preventative intervention.

Sleep REM and PPT/LDT Degeneration The different sleep disorders apparent in PD are multifactorial and as they likely arise as a result of brain-wide neurochemical and pathophysiological changes occurring across the entire central nervous system [16, 19], elucidation of crucial alterations in neural regions underlying their appearance is complex. However, given our current understanding regarding how sleep is regulated and controlled, developmental abnormalities induced by PD within a few critical regions involved in sleep and wakefulness and control of motor tone during REM are suggested. As sleep disorders appear to precede the motor deficits of PD by several years, it is likely that degeneration of neurons in regions importantly involved in sleep control precedes occurrence of the well-characterized loss of dopamine-containing cells of the substantia nigra, which leads to the classic motor deficits of PD. One logical neural region involved in sleep control, and shown to degenerate in PD patients is the pontine tegmentum [36]. Within the pontine tegmentum are two distinct nuclei: the pedunculopontine nucleus (PPT) and the laterodorsal tegmental nucleus (LDT). These two brainstem nuclei provide the major cholinergic innervation of rostral and caudal targets and are believed via these projections to control phenomenology of REM sleep [37]; however, while they are defined as cholinergic nuclei, actually the majority of the cellular population of the PPT and LDT are non-cholinergic and likely play a role in functions controlled by the PPT/LDT [38]. Very interestingly, degeneration of cells of the PPT and LDT is present in PD [39, 40]. Morphometric analysis of the PPT of human PD sufferers revealed a loss of nearly 50 % of cells within this region, which is in contrast to findings from similar analysis conducted with brains from those afflicted with Alzheimer’s, which do not show such a heavy loss of cells in this region [40]. Further, studies with postmortem tissue indicated that a substantial loss specifically of cholinergic neurons of the pons occurs in PD [39]. While it appears clear that degeneration of neurons in these nuclei occurs in PD and a substantial proportion of the cholinergic

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neurons are lost, the time-line of this loss and the temporal correlation of loss with motoric signs of PD is unknown. In addition, information regarding loss of non-cholinergic neuronal phenotypes in these nuclei is lacking. In summary, while examinations of the loss of dopamine-containing cells has necessarily driven PD research investigations, following recognition of cholinergic cell loss in this disease, there is growing interest in the clinical effects of loss of cholinergic neurons within the basal forebrain, and loss of cholinergic neurons in the brainstem PPT/LDT and this interest extends to gaining more information regarding loss of other cell types within these nuclei which would be expected to impact on network output. The new emphasis being placed on the role played by degeneration of neurons in these neuronal groups in the symptomology of PD, which is not believed to be due to loss of dopamine-containing substantia nigra cells [36], is expected to result in clarification of their role in PD progression.

Post-mortem Studies and Braak Scheme Post-mortem studies of PD patients indicated a significant loss of cholinergic neurons within the PPT, which was not found in controls [41]. Interestingly, the loss of cholinergic neurons was significantly different from the loss seen in brains from patients with Alzheimer’s, another neurodegenerative disease [41]. Intriguingly, limited data suggests that the degree of loss of these neurons may be associated with the severity of PD symptoms [41]. Based on the spatial appearance within the brain of alpha-synuclein/ ubiquitin complexes known as Lewy Bodies detected with post-mortem immunostaining, Braak et al. [42] developed an elegant method of classifying the stage or severity of pathology of neuronal loss of PD and Alzheimer’s disease. In this scheme, the authors proposed a temporal sequence of development of PD with phases ranging from 1 to 6. In the earliest phases, in which patients are currently considered asymptomatic for PD as they do not exhibit basal ganglia motor deficiencies, Lewy Bodies appear in the pontine and medullary brainstem, with appearance of Lewy Bodies appearing in the substantia nigra at later stages. Accordingly, neurodegeneration of the pontine tegmentum precedes involvement of the dopaminergic neurons of the substantia nigra, providing a mechanistic basis for the clinical observations that disorders in sleep and motor dysfunctions associated with sleep actually precede appearance of dysregulation of motor movement governed by dopaminergic transmission in the basal ganglia [42, 43]. The Braak scheme of staging PD was reviewed and expanded by Boeve et al. [43] to include the modification that REM sleep without atonia (behavioral events in REM sleep) appears in phase 2 and this abnormality can be

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clearly detected upon electroencephalographic measuring. This dysfunction in motor control during REM is considered a precursor of RBD, which has been reported to manifest in phase 2 or 3. While the inclusion of sleep disorders within the Braak staging scheme has been widely supported, some criticism of this inclusion has been presented. For example, post-mortem examination of the brains of aged individuals who lacked neurological signs, found brain synucleinopathy ranging up to Braak stages 4–6 [44]. Nevertheless, the Braak scheme has been very useful for development of hypotheses that can be experimentally tested regarding the relationship between sleep and PD and has had a broad and profound impact on many aspects of current thinking about PD.

RBD and Imaging Studies Imaging studies offer the potential to increase our understanding of the relationship of the appearance of motor behavioural abnormalities in REM sleep and later development of RBD before the classic signs and symptoms of PD emerge. Multiple brain imaging techniques have showed that alterations in brainstem nuclei involved in the control of sleep occurred in patients with PD and RBD [45–47]. Specifically, changes were found in the locus subcoeruleus, which in the rodent is equivalent to the neural structure known as the sublaterodorsalis nucleus. The sublaterodorsalis nucleus has been shown in these species to be importantly involved in atonia, as well as in motor control during REM sleep [46, 48, 49]. Ellmore et al. [50] provided further evidence that nigrocortical nigrostriatal pathways and connectivity in humans are also altered in the disorder of RBD before the onset of motor symptoms. Understanding the causes and symptoms of PD so as to develop better treatment strategies requires a more precise understanding of the progression of neurodegeneration associated with, or preceding clinical indicators, which includes the degeneration present in behavioural state related nuclei, and continuing improvement of imaging techniques offers hope for acquisition of these vital data.

EDS: Biochemical and Cellular Explanations In addition to loss of cholinergic neurons of the PPT/LDT, degeneration of another neuronal group implicated in sleep control has been shown to occur in PD. Post-mortem studies of the brains of PD patients revealed a significant reduction in orexin/hypocretin (Ox/Hcrt)-containing neurons in the lateral hypothalamus [51], which is the only location in which Ox/Hcrt-synthesizing neurons have been

detected [52, 53]. This finding is interesting in light of the role played by these cells in control of behavior. The peptide Ox/Hcrt has been shown to be importantly involved in arousal [54], which was discovered following the observation that loss of these cells leads to the appearance of the sleeping disorder narcolepsy, which is a disease characterised by intrusion of inappropriate bouts of sleep and other signs of dysregulation of control of arousal. Narcolepsy is also characterized by EDS and it has been suggested that the severity of EDS in narcolepsy is correlated with loss of hypothalamic Ox/Hcrt neurons [54]. Interestingly, an inverse correlation was noted in the numbers of Ox/Hcrt-containing neurons with the clinical stage of PD as it was reported that there was a significant reduction in the levels of Ox/Hcrt peptide in cerebrospinal fluid of symptomatic PD patients [55, 56]. Therefore, knowledge of the role of Ox/Hcrt in EDS suggests a mechanistic basis, at least in part, for the occurrence of EDS seen in PD. Although it is currently not understood at which location within the brain the loss of Ox/Hcrt input could lead to development of EDS, a heavy Ox/Hcrt projection is directed to the pontine tegmentum, and loss of this input demonstrated to be excitatory [57], combined with degeneration of the arousal-related brainstem neurons likely contribute to the EDS symptomology associated with PD [27, 32, 58] [33].

Conclusions and Future Perspectives The available data from epidemiological studies demonstrate that sleep disturbances could be exploited as a reliable preclinical marker for PD; however, it is well recognised that these studies have many biases and limitations that may limit their widespread clinical usefulness at this time [59]. Sample sizes in the majority of these studies were small. Further, studies were largely based on cohorts comprised of patients admitted to sleep centers, and therefore, inherently lacked a study design inclusive of individuals drawn from the general population. In addition, the majority of studies have focused on examination of males, leaving unanswered questions regarding the role of gender in sleeping disorders and PD. Therefore, prospective studies with larger sample sizes drawn from the general population and inclusive of a gender-based focus are needed. In addition, as elucidation of changes in neuronal structures is required, imaging techniques for MRI need to be refined, as proposed by Garcia-Lorenzo et al. [47], and applied to longitudinal studies so as to provide more accurate data upon which clear conclusions between the association of PD and aberrations in control of behavioural state can be drawn. The presence of behavioural state disorders in animal models of PD indicates that more

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invasive detailed studies of the relationship of dysfunctioning in brainstem nuclei involved in sleep and arousal and the motor control of sleep can be performed. Increased understanding of the association between PD and behavioural state control will allow us to refine our detection of abnormalities of sleep to facilitate usage of their presence as preclinical markers of PD and offers the possibility of earlier and perhaps more refined drugs and other intervention for both PD and the associated behavioural state disorder. Further, deeper understanding of the neural changes associated with PD in sleep controlling nuclei is expected to advance our determination of the underlying cause of PD, which is necessary if we hope develop a cure for this devastating disease.

References 1. Friedman JH, Millman RP (2008) Sleep disturbances and Parkinson’s disease. CNS Spectr 13:12–17 2. Aarsland D, Zaccai J, Brayne C (2005) A systematic review of prevalence studies of dementia in Parkinson’s disease. Mov Disord 20:1255–1263 3. Chaudhuri KR, Healy DG, Schapira AH (2006) Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol 5:235–245 4. de Lau LM, Giesbergen PC, de Rijk MC, Hofman A, Koudstaal PJ, Breteler MM (2004) Incidence of parkinsonism and Parkinson disease in a general population: the Rotterdam study. Neurology 63:1240–1244 5. Driver JA, Logroscino G, Gaziano JM, Kurth T (2009) Incidence and remaining lifetime risk of Parkinson disease in advanced age. Neurology 72:432–438 6. Schenck CH, Bundlie SR, Mahowald MW (1996) Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology 46:388–393 7. Chase MH (2013) Motor control during sleep and wakefulness: clarifying controversies and resolving paradoxes. Sleep Med Rev 17:299–312 8. Iranzo A, Aparicio J (2009) A lesson from anatomy: focal brain lesions causing REM sleep behavior disorder. Sleep Med 10:9–12 9. Schenck CH, Mahowald MW (2002) REM sleep behavior disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in sleep. Sleep 25:120–138 10. Postuma RB, Gagnon JF, Montplaisir JY (2012) REM sleep behavior disorder: from dreams to neurodegeneration. Neurobiol Dis 46:553–558 11. Fantini ML, Farini E, Ortelli P, Zucconi M, Manconi M, Cappa S, Ferini-Strambi L (2011) Longitudinal study of cognitive function in idiopathic REM sleep behavior disorder. Sleep 34:619–625 12. Postuma RB, Gagnon JF, Vendette M, Montplaisir JY (2009) Idiopathic REM sleep behavior disorder in the transition to degenerative disease. Mov Disord 24:2225–2232 13. Schenck CH, Bundlie SR, Mahowald MW (2003) REM behavior disorder (RBD): delayed emergence of parkinsonism and/or dementia in 65% of older men initially diagnosed with idiopathic RBD, and an analysis of the minimum and maximum tonic and/or phasic electromyographic abnormalities found during REM sleep. Sleep 26:A316

123

14. Tippmann-Peikert M, Olson EJ, Boeve BF, Silber MH (2006) Idiopathic REM sleep behavior disorder: a follow-up of 39 patients. Sleep 29:A272 15. Sixel-Doring F, Trautmann E, Mollenhauer B, Trenkwalder C (2014) Rapid eye movement sleep behavioral events: a new marker for neurodegeneration in early Parkinson disease? Sleep 37:431–438 16. Pal PK, Calne S, Samii A, Fleming JA (1999) A review of normal sleep and its disturbances in Parkinson’s disease. Parkinsonism Relat Disord 5:1–17 17. Arnulf I, Leu S, Oudiette D (2008) Abnormal sleep and sleepiness in Parkinson’s disease. Curr Opin Neurol 21:472–477 18. Brito dos Santos A, Campos S, Ribeiro S, Morales L, Gonzalez J, Trindade J, Barreto G (2013) Relac¸a˜o entre qualidade do sono e func¸o˜es cognitivas em pacientes com doenc¸a de Parkinson. Univ Sci 18:269–281 19. Menza MA, Rosen RC (1995) Sleep in Parkinson’s disease. The role of depression and anxiety. Psychosomatics 36:262–266 20. Trenkwalder C (1998) Sleep dysfunction in Parkinson’s disease. Clin Neurosci 5:107–114 21. Wong JC, Li Y, Schwarzschild MA, Ascherio A, Gao X (2014) Restless legs syndrome: an early clinical feature of Parkinson disease in men. Sleep 37:369–372 22. Willison LD, Kudo T, Loh DH, Kuljis D, Colwell CS (2013) Circadian dysfunction may be a key component of the non-motor symptoms of Parkinson’s disease: insights from a transgenic mouse model. Exp Neurol 243:57–66 23. Breen DP, Vuono R, Nawarathna U, Fisher K, Shneerson JM, Reddy AB, Barker RA (2014) Sleep and circadian rhythm regulation in early Parkinson disease. JAMA Neurol 71:589–595 24. Kallio M, Haapaniemi T, Turkka J, Suominen K, Tolonen U, Sotaniemi K, Heikkila VP, Myllyla V (2000) Heart rate variability in patients with untreated Parkinson’s disease. Eur J Neurol 7:667–672 25. Bray MS, Shaw CA, Moore MW, Garcia RA, Zanquetta MM, Durgan DJ, Jeong WJ, Tsai JY, Bugger H, Zhang D, Rohrwasser A, Rennison JH, Dyck JR, Litwin SE, Hardin PE, Chow CW, Chandler MP, Abel ED, Young ME (2008) Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression. Am J Physiol Heart Circ Physiol 294:H1036–H1047 26. Gerstner JR, Yin JC (2010) Circadian rhythms and memory formation. Nat Rev Neurosci 11:577–588 27. Videnovic A, Golombek D (2013) Circadian and sleep disorders in Parkinson’s disease. Exp Neurol 243:45–56 28. Videnovic A, Lazar AS, Barker RA, Overeem S (2014) ‘The clocks that time us’-circadian rhythms in neurodegenerative disorders. Nat Rev Neurol. doi:10.1038/nrneurol.2014.206 29. Postuma RB, Aarsland D, Barone P, Burn DJ, Hawkes CH, Oertel W, Ziemssen T (2012) Identifying prodromal Parkinson’s disease: pre-motor disorders in Parkinson’s disease. Mov Disord 27:617–626 30. Pace-Schott EF, Spencer RM (2014) Sleep-dependent memory consolidation in healthy aging and mild cognitive impairment. Curr Top Behav Neurosci. doi:10.1007/7854_2014_300 31. de la Riva P, Smith K, Xie SX, Weintraub D (2014) Course of psychiatric symptoms and global cognition in early Parkinson disease. Neurology 83:1096–1103 32. Abbott RD, Ross GW, White LR, Tanner CM, Masaki KH, Nelson JS, Curb JD, Petrovitch H (2005) Excessive daytime sleepiness and subsequent development of Parkinson disease. Neurology 65:1442–1446 33. Verhave PS, Jongsma MJ, Van den Berg RM, Vis JC, Vanwersch RA, Smit AB, Van Someren EJ, Philippens IH (2011) REM sleep behavior disorder in the marmoset MPTP model of early Parkinson disease. Sleep 34:1119–1125

Neurochem Res 34. Barraud Q, Lambrecq V, Forni C, McGuire S, Hill M, Bioulac B, Balzamo E, Bezard E, Tison F, Ghorayeb I (2009) Sleep disorders in Parkinson’s disease: the contribution of the MPTP nonhuman primate model. Exp Neurol 219:574–582 35. Almirall H, Pigarev I, de la Calzada MD, Pigareva M, Herrero MT, Sagales T (1999) Nocturnal sleep structure and temperature slope in MPTP treated monkeys. J Neural Transm 106:1125–1134 36. Muller ML, Bohnen NI (2013) Cholinergic dysfunction in Parkinson’s disease. Curr Neurol Neurosci Rep 13:377 37. Datta S, Maclean RR (2007) Neurobiological mechanisms for the regulation of mammalian sleep-wake behavior: reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence. Neurosci Biobehav Rev 31:775–824 38. Boucetta S, Cisse Y, Mainville L, Morales M, Jones BE (2014) Discharge profiles across the sleep-waking cycle of identified cholinergic, GABAergic, and glutamatergic neurons in the pontomesencephalic tegmentum of the rat. J Neurosci 34:4708–4727 39. Hirsch EC, Graybiel AM, Duyckaerts C, Javoy-Agid F (1987) Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. Proc Natl Acad Sci USA 84:5976–5980 40. Jellinger K (1988) The pedunculopontine nucleus in Parkinson’s disease, progressive supranuclear palsy and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 51:540–543 41. Zweig RM, Jankel WR, Hedreen JC, Mayeux R, Price DL (1989) The pedunculopontine nucleus in Parkinson’s disease. Ann Neurol 26:41–46 42. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211 43. Boeve BF (2013) Idiopathic REM sleep behaviour disorder in the development of Parkinson’s disease. Lancet Neurol 12:469–482 44. Burke RE, Dauer WT, Vonsattel JP (2008) A critical evaluation of the Braak staging scheme for Parkinson’s disease. Ann Neurol 64:485–491 45. Arnulf I, Bonnet AM, Damier P, Bejjani BP, Seilhean D, Derenne JP, Agid Y (2000) Hallucinations, REM sleep, and Parkinson’s disease: a medical hypothesis. Neurology 55:281–288 46. Boeve BF, Silber MH, Saper CB, Ferman TJ, Dickson DW, Parisi JE, Benarroch EE, Ahlskog JE, Smith GE, Caselli RC, TippmanPeikert M, Olson EJ, Lin SC, Young T, Wszolek Z, Schenck CH, Mahowald MW, Castillo PR, Del Tredici K, Braak H (2007) Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain 130:2770–2788 47. Garcia-Lorenzo D, Longo-Dos Santos C, Ewenczyk C, LeuSemenescu S, Gallea C, Quattrocchi G, Pita Lobo P, Poupon C,

48.

49. 50.

51. 52.

53.

54. 55.

56.

57.

58.

59.

Benali H, Arnulf I, Vidailhet M, Lehericy S (2013) The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson’s disease. Brain 136:2120–2129 Boissard R, Gervasoni D, Schmidt MH, Barbagli B, Fort P, Luppi PH (2002) The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study. Eur J Neurosci 16:1959–1973 Lu J, Sherman D, Devor M, Saper CB (2006) A putative flip-flop switch for control of REM sleep. Nature 441:589–594 Ellmore TM, Castriotta RJ, Hendley KL, Aalbers BM, FurrStimming E, Hood AJ, Suescun J, Beurlot MR, Hendley RT, Schiess MC (2013) Altered nigrostriatal and nigrocortical functional connectivity in rapid eye movement sleep behavior disorder. Sleep 36:1885–1892 Thannickal TC, Lai YY, Siegel JM (2007) Hypocretin (orexin) cell loss in Parkinson’s disease. Brain 130:1586–1595 Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:437–451 de Lecea L, Sutcliffe JG (1999) The hypocretins/orexins: novel hypothalamic neuropeptides involved in different physiological systems. Cell Mol Life Sci 56:473–480 Adamantidis A, de Lecea L (2008) Physiological arousal: a role for hypothalamic systems. Cell Mol Life Sci 65:1475–1488 Fronczek R, Overeem S, Lee SY, Hegeman IM, van Pelt J, van Duinen SG, Lammers GJ, Swaab DF (2007) Hypocretin (orexin) loss in Parkinson’s disease. Brain 130:1577–1585 Drouot X, Moutereau S, Nguyen JP, Lefaucheur JP, Creange A, Remy P, Goldenberg F, d’Ortho MP (2003) Low levels of ventricular CSF orexin/hypocretin in advanced PD. Neurology 61:540–543 Burlet S, Tyler CJ, Leonard CS (2002) Direct and indirect excitation of laterodorsal tegmental neurons by hypocretin/orexin peptides: implications for wakefulness and narcolepsy. J Neurosci 22:2862–2872 Gao J, Huang X, Park Y, Hollenbeck A, Blair A, Schatzkin A, Chen H (2011) Daytime napping, nighttime sleeping, and Parkinson disease. Am J Epidemiol 173:1032–1038 Zoccolella S, Savarese M, Lamberti P, Manni R, Pacchetti C, Logroscino G (2011) Sleep disorders and the natural history of Parkinson’s disease: the contribution of epidemiological studies. Sleep Med Rev 15:41–50

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Are sleep disturbances preclinical markers of Parkinson's disease?

Parkinson's disease (PD) is a neurobehavioral disorder characterized by motor symptoms and signs, and non-motor abnormalities such as olfactory dysfun...
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