Sleep and circadian rhythms in α‐synucleinopathies—Perspectives for disease modification

The global north is facing an unprecedented rise in the prevalence of neurodegenerative diseases. The increasing incidence of Parkinson's disease is being referred to as a pandemic. The reason for the enormous increase is only partly understood. Lifestyle factors are known to play a role, but they alone cannot account for the surge. One factor that—although being recognized as important—has not been explored in detail so far is the influence of circadian rhythms. Sleep and circadian rhythm disruption are known as key factors in neurodegeneration, and their occurrence during early disease stages suggests a causal role in the pathogenesis. Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) has been identified as a prodromal state of α‐synucleinopathies, such as Parkinson's disease, Lewy body dementia, and multiple system atrophy offering a window for insights into the early development of these diseases. Even though REM sleep is the sleep state most pronounced, driven and modulated by the circadian timing system, specific circadian abnormalities have not been described in iRBD. Novel experimental and clinical approaches exploiting the molecular circuitry underlying circadian timekeeping hold promise to disentangle some of the pathophysiologic mechanisms of α‐synucleinopathies. In this review, we summarize current knowledge on sleep and circadian rhythm disruptions in α‐synucleinopathies with an emphasis on molecular aspects and therapeutic potentials. These insights might contribute to our understanding of the pathogenesis of neurodegenerative diseases and may allow therapeutic interventions addressing the disturbed circadian system at the early stage of disease.


| INTRODUCTION
A dramatic increase in the prevalence of neurodegenerative diseases 1,2 has led to a global endeavor to better understand the factors that influence their pathophysiology. The fastest growing neurological disorder is the αsynucleinopathy Parkinson's disease (PD) (Figure 1) with a projected prevalence in extent of a pandemic. 3,4 Longevity, increasing industrialization and several lifestyle factors have been shown to contribute to this pandemic but cannot account for the whole scenario. One factor significantly influenced by lifestyle, which little attention has been attributed to so far is circadian rhythmicity. This is astonishing as "the circadian clock is involved in every piece of human physiology; it covers everything from emotion to endocrinology to metabolism." 5 In 2017, the Nobel prize for physiology or medicine was awarded for discoveries on the mechanistic basis of circadian rhythms.
Circadian clocks are found throughout all kingdoms of life. In mammals, ubiquitous cellular clocks are organized in a hierarchical network coordinated by a pacemaker residing in the hypothalamic suprachiasmatic nuclei (SCN) and reset by external time cues such as the daily light-dark cycle. 6 At the molecular level, two transcription factors-Circadian locomotor output cycles kaput (CLOCK) and Brain and muscle ARNT-like 1 (BMAL1)drive transcription of three period (Per1-3) and two cryptochrome (Cry1/2) genes during the day. 7 PER/CRY protein complexes accumulate in the nucleus during the night and repress CLOCK/BMAL1-mediated transcription, and thus, their own biosynthesis. Toward the end of the night, PER/CRY complexes are degraded, and the circadian cycle starts anew. Posttranslational modifications determine amplitude and period of the circadian cycle, and clock-controlled output genes temporally coordinate physiological processes in a tissue-specific manner. It is estimated that 5%-10% of transcribed genes in any tissue show a circadian pattern of activation. 8 The title of an editorial to a special issue on circadian rhythms in neurodegeneration stated provocatively in 2017 that "circadian rhythms are everywhere-except in neurodegenerative disorders". 9 Already more than 30 years ago, it was documented that patients with neurodegenerative disorders show disturbed sleep and flattened circadian rhythms on behavioral, hormonal, and electrophysiological levels. 10 In patients with Alzheimer's, neuropathological changes suggested that circadian pacemaker neurons in the suprachiasmatic nucleus (SCN) are structurally intact, but functionally silenced. In 1991, Dick Swaab coined the principle of "use it or lose it" regarding neuronal plasticity of SCN neurons. 11 Since then, a substantial number of well-designed studies have shown beneficial effects of two major synchronizers of the clock system, light and melatonin, on symptoms of neurodegenerative disorders. [12][13][14] Lately, the glymphatic system was shown to wash out both misfolded tau and synuclein from the brain during sleep, 15-17 a process which is modulated by the circadian system, too. 18 For αsynucleinopathies-PD, Lewy body dementia (LBD) and multiple system atrophy (MSA)-specific disturbances of sleep and circadian rhythms characterize some of the disease-specific peculiarities. Idiopathic REM sleep behavior disorder (iRBD) is recognized as a prodromal state of αsynucleinopathies. [19][20][21] Therapies using light in patients with PD and melatonin in patients with iRBD have shown beneficial effects. 13,14,22 Still, the mechanisms behind this are poorly understood. F I G U R E 1 Estimated and projected prevalence of Parkinson's disease 3,4 is much higher than to be expected from the projected growth of world population alone (UN World Population Prospects 2019).
In the series of review articles quoted above, 9 prominent authors dealt with circadian aspects of neurodegeneration and the complex effects of light and melatonin with a focus on clinical aspects. The words "molecular" or "gene" cannot be found in any of these papers. Needless to say, it is time to finally translate the wealth of existing basic circadian knowledge into clinical practice. The aim of this review is to summarize the current knowledge of circadian and sleep-related factors in αsynucleinopathies. It covers rhythm phenotypes in PD animal models, summarizes behavioral, pharmacological, electrophysiological, and molecular evidence of rhythm disruption in human patients, and devises circadian treatment strategies. In the conclusion, we discuss unmet needs and possible future research directions to target this debilitating disease.

| Circadian and sleep phenotypes in rodent models of PD
Circadian rhythm and sleep disturbances are important facets of non-motor symptoms of PD, and often arise prior to the presentation of typical motor deficits. Rodent models used to understand the mechanisms of and develop potential therapies for PD should therefore also mimic dysfunctions in circadian rhythms and sleep-particularly in view of developing circadian rhythm-facing therapeutic treatments. The different neurotoxin-, seeding-and genetics-based rodent models of PD fulfill these requirements to very various extents ( Figure 2).

| 6-OHDA neurotoxin model
When injected into the brain, 6-hydroxydopamine (6-OHDA), a structural analogue of dopamine and noradrenaline, undergoes rapid toxic autoxidation events in catecholaminergic neurons. As with most neurotoxinbased models, the acute effect of the 6-OHDA model is an imperfect fit of the progressive degeneration seen in PD patients; Lewy bodies are not present in this model. 23 Regarding circadian rhythms, 6-OHDA-lesioned rats show dampening and phase advances of heart rate and temperature rhythms. 24,25 Similarly, locomotor activity rhythms are dampened but not shifted. 26 In constant light conditions, free-running periods are increased in 6-OHDA-lesioned rats relative to sham controls. These findings have since been supported by a multitude of publications in both bilateral and unilateral lesioned rat and mouse models. 24,27,28 Unilateral 6-OHDA lesion selectively blunts PER2 protein expression in the ipsilateral dorsal striatum but not the SCN. 29 Further, striatal mRNA levels of BMAL1, PER2, and CLOCK are significantly decreased in these rats together with increased acetylation of BMAL1 protein. 30 Previous research indicates that changes in striatal neurons that develop after 6-OHDA lesions can be reversed with dopamine receptor agonist treatment. 31 Interestingly, such treatments, specifically systemic injections of quinpirole (dopamine receptor 2/3 agonist) at ZT01, were later shown to successfully restore rhythmic PER2 protein expression in the 6-OHDA-lesioned dorsal striatum. 29 Regarding the effect of 6-OHDA lesions on sleep in this model, it was observed that total NREM and REM sleep duration is decreased during the light phase and increased during the dark, which aligns with REM sleep deterioration in PD. 32 F I G U R E 2 Motor and non-motor phenotypes in rodent PD models. Pharmacological and genetic rodent models of PD present different aspects of the human PD pathology. While model development has traditionally focused on motor symptoms and histological phenotypes, non-motor symptoms-and circadian rhythms and sleep phenotypes in particular-have gained increasing interest in recent years. For abbreviations of rodent models, see main text.

| MPTP neurotoxin model
Acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration produces rapid cell death in dopaminergic SNpc neurons. More recently, though, chronic low MPTP infusions are used to better replicate the progression of PD. 33 In both paradigms, PD-like alterations in motor movement are observed. 34 Again, Lewy body formation is lacking, and circadian dysfunction typically associated with PD is poorly reflected in this model. 35 Endogenous free-running rhythms, entrainment, and SCN clock gene expression remain intact in both the chronic and acute MPTP models. 36 Moreover, MPTP rats do not display a sleep disruption phenotype like that of PD patients. 37 However, MPTP is also commonly used to study PD in non-human primates. Here, it was shown that MPTP administration can lead to circadian and sleep disturbances, such as insomnia, delayed sleep onset, sleep fragmentation and increased wakefulness. 38 Interestingly, pathological beta oscillations, a hallmark of PD, during NREM was associated with sleep disturbances. This provides first evidence that specific biomarkers of circadian disturbances can be quantified in PD that may aid the future development of new therapeutic approaches.

| Rotenone neurotoxin model
The pesticiderotenonehas neurotoxic activity due to its inhibitory effect on mitochondrial respiratory complex I. While its mechanism of toxicity is not neuron-typespecific, the neurotoxic effects are predominantly dopamine neuron-selective. 39 Rotenone treatment in rats dampens body temperature and sleep/wake rhythms. 40 This is accompanied by an amplitude reduction in the expression of circadian clock genes, such as Per1/2, Cry1/2, and Bmal1. 41 Moreover, rotenone-treated rats develop similar progressive sleep disturbances as PD patients with increases in slow-wave sleep and REM sleep during the active phase and decreases in the rest phase. 42

| α-Synuclein transgenic models
αsynuclein is the key component of PD intracellular inclusions, and mutations in the SNCA gene (which encodes αsynuclein) can cause autosomal-dominant PD, 43,44 which led to the development of SNCA-targeting transgenic mouse models. 45 Masliah and colleagues developed a PD model in which loss of dopaminergic neurons and subsequent motor deficits are induced by overexpressing αsynuclein (referred to as αsynuclein overexpressing, or ASO). 45 ASO show progressive age-dependent deficits in wheel-running rhythms, such as reduced active-phase activity and greater fragmentation. However, PER2 expression in the SCN does not differ in these mice and no evidence was found that the photic response of the circadian system is compromised. 46 Interestingly, energy expenditure, oxygen consumption, and respiratory exchange ratio rhythms are significantly dampened in ASO mice. 47 They also show increased NREM sleep during their quiescent phase and decreased REM sleep across rest and active phases with marked alterations in EEG power spectra. 48 2.6 | VMAT2, MitoPark, Cycad,

LRRK2, and other models
Genetic suppression of vesicular monoamine transporter 2 protein levels in the VMAT2 model results in striatal dopamine loss, motor deficits, αsynuclein accumulation, and progressive nigral dopaminergic cell loss. 49 Little is known about the non-motor symptoms of this model so far, but age-dependent shorter latency to behavioral sleep has been reported. 50 More recently, new data emerged showing that VMAT2 mice at 5 months have altered vigilant states, with increased wake, decreased NREM and REM sleep during the first half of the active phase but no significant changes in the corresponding spectrograms except for REM sleep. 51 Sleep parameters during the resting (light) phase remained unaltered. Existing reports show that this transgenic PD model develops an increased αsynuclein burden 49,51,52 with age. Interestingly, chronic treatment with sodium oxybate, primarily used to reduce excessive daytime sleepiness and cataplexy in narcolepsy, 53 and which also enhances slow-wave sleep, 51,54,55 can reduce prefrontocortical αsynuclein neuropathology in slow-wave sleep enhanced aged VMAT2 mice. 51 Additional broadly promising results, although gender specific, were obtained using the familial human ASO transgenic mouse model. 51 Dopaminergic neuronspecific deletion of the mitochondrial transcription factor A-encoding gene results in progressive midbrain dopaminergic neuron degeneration and αsynuclein aggregates in the MitoPark model. 56 These mice also show PD-like impairments in the circadian control of sleep-wake cycles regarding amplitude and fragmentation levels. 57 In rats, consumption of Cycas micronesica (cycad) seeds may lead to neurodegeneration with characteristics of PD such as αsynuclein aggregates in dopaminergic and noradrenergic neurons. 58 These rats exhibit increased REM and NREM sleep and less wakefulness during the active period. 59 Several other chemical and genetic models of PD have been introduced such as paraquat injection, genetic modulation of LRRK2, PINK1, PRKN, and DJ-1, or the preformed fibrils (PFF) seeding model. 60 For some of these, circadian rhythm and/or sleep alterations have been described in non-vertebrate animal models, but studies in rodents have so far only focused on PD motor and cognitive symptoms.

| Closing remark
Utilizing preclinical models has significant potential to advance the understanding of the interplay of PD with the circadian system and sleep, especially when coordinated with clinical studies. 61,62 Preclinical investigations allow for tight control of environmental factors, circadian phenotyping at the behavioral, physiological, and genetic levels, and relative ease of longitudinal analysis and assessment of pharmacological, environmental, and behavioral interventions that would be highly challenging in human studies. In chronobiology research, the use of animal models will be essential as it has led to important translation to human health knowledge in the past; for example, the fundamental work on the genetics of the circadian clock in fruit flies led to the understanding of the molecular basis of familiar circadian rhythm sleep disorders. 63 As such, there is growing interest in the use and further development of animal models for investigating sleep and circadian function in PD (

SYNUC LEI NOP ATH IES -IRBD
iRBD is recognized not only as the most reliable prognostic biomarker for the development of αsynucleinopathies, but to also represent the ongoing neurodegenerative process itself, indicating a prodromal state for clinical αsynucleinopathies. [19][20][21] As such, iRBD offers an early window into the pathophysiologic process and an opportunity for early-state disease-modifying treatment.
Except for impaired REM sleep associated atonia, other sleep characteristics and neurophysiological circadian rhythms seem to be not pathologically altered in the early stages of αsynucleinopathies. Rather, during this period, total sleep time and slow-wave sleep seem to be prolonged, suggesting a supernormal sleep as compared with healthy subjects. 64 Maybe even more puzzling, a higher awakening index was associated with a reduced risk of developing PD later. 64 So does a longer total sleep time really indicate circadian rhythm or sleep improvement? Sleep length is determined early in adulthood, and on an individual level, varies between 5 and 10 hours for an average night accompanied by proper daytime functioning. 65 Counterintuitively, until now, specific markers have not been able to differentiate good-from impairedquality sleep of equal length. Functions of sleep such as memory consolidation, learning, metabolic coordination, or immune system restoration remain technically difficult to assess. As a result, in the sleep community, sleep and circadian abnormalities are not considered critical factors in the pathophysiology of early αsynucleinopathies.
Interestingly, both major groups of neurodegenerative disorders, tau-and αsynucleinopathies, are accompanied by changes in REM sleep. Whereas patients with tauopathies show a pronounced reduction in the quantity of REM sleep, 66 patients with αsynucleinopathies show impaired REM sleep quality indicated by RSWA. This may indicate a basic role for REM sleep in the pathophysiology of neurodegeneration. Possibly, the increase in total sleep time in patients with αsynucleinopathies indicates a compensating mechanism of a yet unknown origin. A first-rank candidate could be a disturbed orchestration of circadian rhythms leading to uncoordinated neurophysiological processes predominantly affecting REM sleep. 9,67,68 Recent reports suggest the circadian timing system to be involved in the pathology of αsynucleinopathies, 69 and chronobiotic treatments such as melatonin in iRBD 13,22,67 have shown beneficial effects. On the other hand, the underlying neurophysiology remains largely unknown. During REM sleep, vivid dreams occur. The REM sleepspecific atonia of voluntary muscles prevents healthy subjects from becoming aware of dream content and acting out of dreams. The loss of REM sleep atonia in patients with iRBD is the hallmark of the disease. 19 Patients start to vocalize, perform complex behaviors, and not rarely shout, fight and even jump out of bed or hit and choke their bed partners. REM sleep is the sleep stage strongest modulated by the circadian system. 70-72 REM sleep amount, REM latency (time from falling asleep until occurrence of first REM sleep episode), REM polarity (distribution of REM sleep episode length over the night), and REM density (amount of phasic eye movements within REM sleep episodes) all have a circadian component. Nevertheless, in patients with iRBD, none of these parameters seems to be altered. No evidence of a shifted circadian phase such as higher proportion of late or early chronotypes has been reported, yet. Only patients with early signs of PD show a reduced rhythmicity of day-night activity variation. 69 A strong hint toward a possible involvement of the circadian system comes from the positive effects of treatment with melatonin when it is used as a chronobiotic. 13,22,67,73 Although melatonin is recommended as one of two level-B therapies in the treatment of RBDs, 74 reports in the literature are controversial. Two recent placebo-controlled trials using melatonin in iRBD did not show positive effects. 75,76 In contrast, our data, including a large retrospective observation and a small randomized controlled trial, do show a pronounced positive effect. The discrepancy between results point to the specific mode of action of melatonin as a chronobiotic 77 rather than as a hypnotic. In this context, it is important to note that melatonin is conventionally prescribed as a sleeping aid, to be administered after dinner or 1-2 hours prior to bedtime. Patients and physicians expect (from the first night of administration) hypnotic properties from the "sleeping-aid" melatonin such as an increase of sleep time, faster sleep onset or a reduction of wake-after-sleep onset. Instead, administration of melatonin in a chronobiotic protocol, in which patients are asked to administer melatonin always at the same clock time-ideally adjusted for chronotype-exerts gradual effects, emerging after days or even weeks. They may even involve shortened sleep times, but improvement of daytime functioning is observed due to better sleep quality. 13,22,67 Besides having a myriad of other effects, 78,79 exogenous melatonin has two distinct chronobiotic properties: (i) it resets internal circadian phase according to a phase response curve and may, thus, be used in jetlag or to adjust late chronotypes to social time schedules. 80 In line with this, no phase shifting or sleep facilitating effects were reported when melatonin was administered in the evening to healthy subjects. 80,81 Somewhat surprisingly, the preferred time for melatonin administration in our chronobiotic iRBD protocol is precisely in this time period, around 10-11 pm. This is not contradictory. (ii) Crucial in the context of iRBD, however, seems to be a second, yet under-appreciated chronobiotic effect of melatonin, its darkness promoting property. 77,82 Administered during its endogenous rise in the evening, melatonin does not shift circadian phase, but may strengthen the coordination of nightly circadian factors, with consequences such as promoting wake-related activities in nocturnal species and sleep-related activities in diurnal species such as REM sleep in humans. [70][71][72]83 The timing of impulses to this system seems decisive for resynchronization, and once established, needs to be kept always at the same clock time. 13,22,77,80,83 In contrast, administering melatonin at any other time induces phase shifts resulting in a desynchrony of internal rhythms. 80,84,85

ATH IES
Much more than in the respective prodromal stages, the importance of circadian rhythms is increasingly recognized in full-blown neurodegenerative disorders. In PD, on the one hand, disruption of structure and function of the circadian system contributing to the symptomatology, and on the other hand, the disruption itself contributing to the risk of disease manifestation and progression of the neurodegenerative process are being discussed. Although the scarce neuropathological studies available detected Lewy pathology (i.e., Lewy bodies and Lewy neurites, the major pathological hallmark of PD) only in single cases in the SCN pacemaker and the pineal gland (a major relay center of the SCN and the production site of melatonin), 86 the widespread neuropathological changes associated with PD interfere and disturb the signaling networks aligned and coordinated by these structures. 87 Besides the triad of classical motor symptomsbradykinesia, rigidity and resting tremor-the symptomatology of PD encompasses a variety of non-motor symptoms including disruption of the sleep-wake cycle, autonomic dysfunction, cognitive impairment, psychiatric manifestations and sensory deficits, with many of them exhibiting diurnal fluctuations throughout the disease course. 88,89 Disturbances of the sleep-wake cycle are particularly relevant as they may manifest as RBD (see above) or excessive daytime sleepiness years before the diagnosis can be made according to the classical motor symptoms. Moreover, sleep deprivation, a frequent consecutive problem of disturbances of the sleep-wake cycle, may also contribute to the neurodegenerative process in PD. One reason may be that clearance of waste proteins via the glymphatic system during the night is constrained, demonstrated in a studythat identified a 36% increase in αsynuclein (the central protein in the pathogenesis of PD) in the cerebrospinal fluid (CSF) of healthy individuals after one night of sleep deprivation. 16 Similarly, the finding of a higher degree of Lewy body pathology and substantia nigra cell loss postmortem in a large cohort of older adults without PD, but with the presence of sleep fragmentation, points to a contribution of disturbances of the sleep-wake cycle to PD pathology. And in fact, this contribution indeed seems to manifest as increased risk for PD: in the ancillary sleep study of the longitudinal cohort Osteoporotic Fractures in Men Study (MrOS), comprising more than 2900 men, lower circadian rhythmicity was indeed associated with higher risk of incident PD. 69 Importantly, dopamine metabolism and circadian homeostasis have a strong bidirectional relationship. This is especially relevant as this neurotransmitter is seen as modulator of circadian rhythms, 90 rendering an effect of dopaminergic medication on circadian rhythms highly likely. Although a study comparing PD patients and controls did not find a significant difference in the concentration of the melatonin metabolite 6-sulfatoxymelatonin, a clear relationship between the levodopa equivalent dose patients were taking for their individual medication and this metabolite could be established. 91 This effect, however, needs to be further explored.
Other lines of evidence of a relation of PD and circadian rhythms can be derived from the expression of clock genes. Especially regarding one of the core clock genes, BMAL1, striking abnormalities have been found in PD patients including (i) a significant lower expression in the 12-hour night period when compared with controls, with expression levels correlating with the severity of motor symptoms and quality of sleep, 92 (ii) a reduction in timedependent variation of in BMAL1 expression, 93 and (iii) an association of a BMAL1 variant and the risk for the tremor-dominant subtype of PD. 94 Also changes in the expression of the clock genes such as PER2 and NR1D1 have been reported. 93 This dysregulation in clock genes may on the one hand influence pathophysiology, on the other hand, alter symptomatology. Still, the causal relation needs to be further explored.
In the future, more insight will be gained through technological innovations in symptom tracking, both in the motor and non-motor domain. Wearables and digital health applications are currently emerging that can track medication intake and rhythmic fluctuations of symptoms and side-effects. 95 Circadian data can also be obtained directly from the human brain with clinical brain computer interfaces for deep brain stimulation (DBS). 96 DBS is a neurosurgical treatment, for which electrodes are implanted into the basal ganglia and electrical stimulation is applied with robust therapeutic efficacy. 97 The newest generation of deep brain stimulation now allows for recording invasive brain activity, such as beta activity that was described for the MPTP non-human primate model above, over months across the circadian cycle. 98 In the future, tracking beta activity for real-time treatment adaptation, while accounting for sleep/wake cycles 99

| CONCLUSIONS
Circadian rhythm and sleep disturbances frequently precede cognitive decline and motor dysfunction in patients with αsynucleinopathies. Thus, they have been postulated as risk factors or predictors for dementia and Parkinsonism. On the other hand, the neural circuits that regulate sleep and circadian rhythms are vulnerable to neurodegeneration and brain damage, so both sleep abnormalities and disrupted circadian rhythms may also be consequences of these diseases. Uncovering the fundamentals of this bidirectional relationship may provide opportunities to identify targets for prevention and treatment of these debilitating diseases.
Even though neuropathologic examinations, behavioral patterns, and therapeutic effects suggest involvement of the circadian system in αsynucleinopathies, the underlying mechanisms are poorly understood. Possibly, new perspectives including circadian molecular F I G U R E 3 Increasing deterioration of circadian rhythms and sleep-wake cycle during a-synucleinopathy progression. Healthy circadian rhythms and sleep-wake cycle in humans are characterized by consolidated night sleep, functional REM and N-REM architecture, and synchronized high-amplitude clock rhythms. iRBD is characterized by dysfunctional REM sleep while sleep consolidation is preserved. It remains unclear to which extent molecular clock rhythms are affected in this prodromal stage. In mature a-synucleinopathies such as PD, sleep becomes increasingly fragmented, both REM sleep dysfunction and decreased N-REM sleep are observed. Circadian rhythm disruption is reflected in dampened and misaligned clock rhythms. circuitryand for examplemachine learning for neurophysiologic mechanisms may broaden our view. In this review, we primarily focused on existing evidence of disturbed circadian rhythmicity on the molecular level as a cause or symptom of prodromal and clinical αsynucleinopathies. Future work may want to consider to apply controlled conditions like the forced desynchrony or constant routine protocols to patients with αsynucleinopathies to disentangle the influence of (i) homeostatic sleep-wake cycle versus circadian rhythmicity and (ii) central versus peripheral circadian rhythms on pathophysiologic mechanisms. Insights derived from circadian phenotypes of αsynucleinopathies should foster development of disease-modifying treatments at the earliest disease stage possible-iRBD. Such early treatment seems desperately needed as it would prevent disease development and counteract the irreversible loss of neuronal structures that precedes even the earliest stages of PD by years. Out-acting of dreams is experienced by some 1-2% of the population over 60 years of age. 100 Looking into the internet, one finds profound statements indicating an ongoing neurodegeneration toward Parkinson's disease and Lewy body dementia. Not many insights into one's individual future exist that are more distressing. 101 Moreover, the globally increasing prevalence of PD urges a call to action. 3 This action should incorporate as many lifestyle factors as possible and if needed their adaption, as in disrupted circadian rhythmicity.