Intersection of Sleep Disorders and Parkinson Disease: Unveiling the Bidirectional Relationship

Abstract

Background

Patients with Parkinson's Disease (PD) frequently exhibit non‐motor symptoms, particularly sleep disturbances. Sleep disorders in PD patients are intricately linked to the pathogenesis and progression of PD itself, exacerbating neurodegenerative processes and worsening patient quality of life.

Objectives

This review underscores the significance of sleep disorders in PD, highlighting their prevalence, impact on disease progression, and the bidirectional relationship between sleep disruption and neurodegeneration. It aims to enhance clinician awareness for better diagnosis and management of sleep‐related comorbidities in PD.

Methods

A comprehensive literature search was conducted in PubMed and Scopus using key terms such as “sleep disorders”, “Parkinson's disease”, “REM sleep behavior disorder”, “restless legs syndrome”, “insomnia”, “obstructive sleep apnea”, “excessive daytime sleepiness”, “circadian rhythm disorders”, “sleep and neurodegeneration”.

Results

Sleep disorders are prevalent in PD affecting up to 90% of patients. Conditions such as insomnia, REM sleep behavior disorder, restless legs syndrome, obstructive sleep apnea, excessive daytime sleepiness, and circadian rhythm disorders are commonly reported. These disorders are linked to multifactorial biological mechanisms and are associated with more severe disease phenotypes. Of note, several evidence shows that sleep abnormalities may contribute to neuroinflammation and neurodegeneration, further accelerating the disease course.

Conclusions

Sleep disturbances are critical non‐motor symptoms in PD. Early diagnosis and tailored management of sleep disorders are essential for improving clinical outcomes and potentially offering neuroprotective benefits.

It is now well established that almost all patients with Parkinson's Disease (PD) suffer from non‐motor symptoms, not only as an epiphenomenon of the underlying disease but mainly as a factor directly linked to the pathogenesis of the disorder itself and further contributing to the progression of the movement disorders and/or to the underlying neurodegenerative condition.

Among non‐motor symptoms, sleep disorders are the most prevalent and up to 90% of patients have sleep disturbances, even in the early stages of the disease. Sleep disorders may antedate the motor phenotype and highly affect patients’ quality of life. Moreover, mounting evidence supports the notion that sleep loss promotes accumulation of misfolded proteins ¹ , ² and circadian rhythm dysfunction trigger a neuroinflammatory reaction and degeneration of the nigral‐dopaminergic system.

Given the long period of preclinical PD, sleep disturbances are hypothesized to be either markers for PD pathology, related to the involvement of extranigral structures and/ or a mechanism modulating increased risk of alpha‐synuclein spreading (ie, acting with a bidirectional relationship).

Considering the bidirectional relationship between neurodegeneration and sleep disruption and the mounting evidence supporting the neuroprotective role of sleep, awareness of this link and investigation of sleep complaints is mandatory in our patients to ameliorate quality of life but also to promote neuroprotection.

In this review we will highlight all the corollarial of sleep disorders reported in PD, particularly focusing on new evidence linking sleep disorder and PD to the same neurodegenerative/functional processes, highlighting the bidirectional links between sleep disruption and neurodegeneration.

Methods

We conducted a comprehensive literature search in PubMed and Scopus, covering articles published up to June 2024. Key search terms included “sleep disorders”, “Parkinson's disease”, “REM sleep behavior disorder”, “restless legs syndrome”, “insomnia”, “obstructive sleep apnea”, “excessive daytime sleepiness”, “circadian rhythm disorders”, “sleep and neurodegeneration”. Boolean operators (AND, OR) were used to refine the search results and ensure the inclusion of relevant studies.

The selection criteria for articles included original research studies, review articles, and meta‐analyses published in peer‐reviewed journals. Studies were selected based on their relevance to the topics of interest, with an emphasis on those providing insights into the relationship between sleep and PD.

The review process involved screening titles and abstracts, followed by full‐text assessment of relevant studies. Data extraction focused on study design, methods of sleep assessment, key findings, and proposed mechanisms linking sleep and PD.

Results

Sleep Disorders in PD

Among sleep disorders in PD, insomnia is one of the most common, affecting up to 44% of patients, and correlating with longer disease duration, higher daily levodopa doses, and more severe depression. ³ Sleep maintenance insomnia and objective alterations (namely, total sleep time, sleep latency, sleep efficiency and wake after sleep onset, as well as percentages of sleep stages, sleep fragmentation and microstructure alterations) found in polysomnography (PSG) may also be iatrogenic, associated with dopamine agonists, while levodopa seems to have positive effects on sleep architecture, improving sleep efficiency by reducing sleep latency and wake after sleep onset. ⁴

REM Sleep Behavior Disorder (RBD) affects up to 46% of PD patients, correlating with older age, lower education level, longer disease duration, higher daily levodopa dose, and more severe motor, autonomic, and neuropsychiatric manifestations. ³ Moreover, patients with PD associated with RBD experience more widespread degeneration and a faster disease progression. ³

It has also been demonstrated that violent and aggressive dreams are more common in patients with RBD and PD (especially in men) compared to PD without RBD. ⁵ However, recall bias related to nocturnal awakening due to RBD episodes may be involved in the reported differences in dream content. Non‐REM parasomnias and overlap parasomnias have also been described in PD. ⁴

Also the prevalence of Restless Legs Syndrome (RLS) appears to be higher in PD compared to the general population. ⁶ , ⁷ Different dopaminergic pathways might be involved, pointing at different therapeutic approaches. ^{8 , 9} The pathogenetic link between PD and RLS is unknown, also considering that the etiopathogenesis of RLS itself is still under study. ¹⁰ A recent meta‐analysis suggests that neurotransmitter systems other than the dopaminergic one are involved in PD‐RLS etiology. ¹¹

Prevalence of nocturnal respiratory disturbances (both obstructive and central apneas) in PD ranges from 20 to 70%, being higher than in the general population. ¹² The presence of obstructive sleep apnea (OSA) negatively impacts quality of life of PD patients, potentially affecting sleepiness and pharmacological management. ¹²

Excessive daytime sleepiness (EDS) is found in 35% of PD patients. ³ It might be one of the earliest non‐motor symptoms in PD, further aggravated by the introduction of the treatment for motor symptoms, and particularly by dopamine‐agonist. ⁴ Large case studies have recently shown that, in the early stage of PD, EDS correlates with a faster cognitive decline, a higher likelihood of RBD, autonomic dysfunction, depression, and anxiety. ¹³

Circadian rhythm alterations are another major issue linked to alterations of dopaminergic circuits, alterations of the hypothalamic suprachiasmatic nucleus (SCN), ¹⁴ abnormal expression of circadian genes and proteins ¹⁵ and to the involvement of the NLRP3 inflammasome. ¹⁵ , ¹⁶

Table 1 shows relevant tools and exams suggested for the main sleep complaints in patients with PD.

TABLE 1.

Relevant tools and exams for the main sleep complaints in patients with PD.

Sleep disorders	First level examination (to be always performed)	Second level examination (not always needed, but useful)	Third level examination (only in selected cases)
EDS	Medical history and physical examination	Actigraphy	PSG (if RLS, PLMS, RBD, or Circadian Rhythm Disorder is suspected)
	Sleep history and diary	Home nocturnal cardio‐respiratory monitoring (if OSAS is suspected)	Multiple Sleep Latency Test and/or Maintenance of Wakefulness Test
	EDS quantification through standardized scales (eg, Epworth Sleepiness Scale)	Electroencephalography
Insomnia	Medical history and physical examination	Actigraphy	PSG (if other primary sleep disorders are suspected)
	Sleep history and diary	Home nocturnal cardio‐respiratory monitoring (if OSAS is suspected)
	Insomnia Severity Index, Pittsburgh Sleep Quality Index, and other standardized scales	Psychiatric consultation (if depression or other psychiatric disorders are suspected)
Sleep‐related breathing disorder	Medical history and physical examination	Home nocturnal cardio‐respiratory monitoring	PSG (if unclear, doubtful, or other sleep disorders)
	Sleep history and diary, bed partner report	Cardiological, pneumological, and ENT evaluation	Arterial blood gas test (in case of central or mixed apnea syndrome)
	Epworth Sleepiness Scale, Berlin questionnaire, STOP‐BANG questionnaire, and other standardized scales	Neurocognitive assessment (if cognitive deficit is suspected)
RLS and/or PLMS	Medical history and physical examination	Actigraphy	Other medical consultations (to exclude any secondary form)
	Sleep history and diary, bed partner report	PSG (if PLMS or if other sleep disorders are suspected)
	International RLS Study Group Rating Scale
	Iron and other routine blood tests
RBD	Medical history and physical examination		Brainstem reflexes study
	Sleep history and diary, bed partner report
	RBD validated questionnaires PSG mandatory for documenting REM sleep without atonia (ideally, with video recording)
Circadian rhythm sleep disorder	Medical history and physical examination	Body temperature patterns, dim‐light melatonin onset	PSG (if other primary sleep disorders are suspected)
	Sleep history and diary	Actigraphy
	Questionnaires for typical bedtime, sleep duration and latency, waking up instances

Abbreviations: Excessive Daytime Sleepiness, EDS; Obstructive Sleep Apnea Syndrome, OSAS; Polysomnography, PSG; Ear‐Nose‐Throat, ENT; Restless Legs Syndrome, RLS; Periodic Limb Movements during Sleep, PLMS; Parkinson's Disease, PD; REM Sleep Behavior Disorder, RBD; Magnetic Resonance Imaging, MRI.

Figure 1 shows recommended approaches for the management of the main sleep disorders in PD.

Figure 1.

Management of common sleep disorders in PD.

Prodromal Phase of PD: Evidence Linking Sleep Disorders to PD

Relationship between Specific Sleep Disorders and Prodromal Phase of PD

Sleep disorders in PD may represent a prodromal phase of the disease; specifically, considering that pathological processes and neurodegeneration begin long before the cardinal motor symptoms develop, their identification and correct management may help with early diagnosis, improving therapeutic approaches and prognosis. ¹⁷ With the exception of RBD, clinical and epidemiological data on the possibility that other sleep disorders (RLS, periodic limb movements (PLMS) during sleep, EDS, OSA) may represent a prodromal phase of PD are lacking and conflicting, although all these disorders are notoriously associated with more severe PD phenotypes and are more frequent in this disease than in the general population ¹⁸ ; to better clarify these aspects, genetics could provide important assistance. ¹⁸ Regarding RBD, approximately 50% of patients convert to a parkinsonian disorder within a decade, and considering longer times, 81–90% develop a neurodegenerative disease; moreover, RBD predicts a non‐tremor‐predominant subtype, gait freezing, and an aggressive clinical course. ¹⁹

Sleep Disorders as Premorbid Biomarkers

In the prodromal phase, genetic, pathological, and imaging markers, as well as motor and non‐motor symptoms, could define PD subtypes and be used to identify individuals who are more likely to develop phenoconversion in a shorter time. ¹⁷ Regarding sleep disorders, RBD carries the highest positive predictive values for impending alpha‐synucleinopathy, and great efforts have been made in order to find the best prognostic markers in terms of time‐to‐conversion and subtypes of conversion. ²⁰ The study of RBD can also provide important insights into the progression of PD, as demonstrated in a recent study conducted on a very large sample of 1160 RBD patients (mean follow‐up of 3.3 ± 2.2 years), where motor variables tended to progress more rapidly, while cognitive, olfactory, and autonomic variables showed a modest progression. ²¹ Other study groups have also emphasized that the onset of RBD may accelerate the motor progression of PD ²² and that the course of cholinergic dysfunction in RBD may play a role in PD progression. ²³

Multiple biomarkers have been highlighted so far, with different sensitivities and specificities in disease evolution: neurophysiological, neuroimaging, biological fluid, and motor, cognitive, olfactory, and autonomic function assessments, as well as tissue biopsies and genetic tests. ²⁰ The quantification of REM sleep without atonia (RSWA), both visually and automatically, ²⁴ is one of the key diagnostic and prognostic factors in predicting different types of alpha‐synucleinopathy. ²⁵

Bidirectional Relationship between Sleep Disorders and PD

Current Evidence and Proposed Pathomechanisms

As said, sleep disorders in PD are pleiomorphic and of multifactorial origin. ²⁶ Both dopaminergic and non‐dopaminergic degeneration can disrupt sleep–wake and circadian rhythm in PD. ²⁷ Furthermore, neuroinflammation, impaired glymphatic clearance, blood–brain barrier disruption, endoplasmic reticulum stress, defect of autophagy, nocturnal brain deoxygenation, gut‐brain axis dysfunction, and peripheral inflammatory processes, among others, are known to exacerbate neurodegenerative pathology and can contribute to sleep problems in PD, often in combination. ²⁸ , ²⁹ Also at clinical level, nocturnal motor symptoms (such as hypokinesia or dystonia), non‐motor symptoms (such as nocturia or pain), psychiatric comorbidities (such as depression or anxiety), and sleep problems other than insomnia (such as OSAS, RLS, and PLMS) significantly impair sleep in these patients, as well as the effect of some medications for PD. ³⁰ Altogether, these pathophysiological and clinical observations suggest that sleep disturbances may clearly be a consequence of PD.

One example is degeneration of the brainstem centers due to underline pathology affecting the respiratory centers and loop gain mechanism, ³¹ leading to nocturnal apneas. ³² Chronic intermittent hypoxia related to sleep apnea and associated oxidative stress, further contributes to a worse neurodegenerative process. ³³ In this regard, it has been also reported that OSAS can contribute to reduced striatal dopamine transporter availability in PD, possibly leading to dopaminergic neuronal degeneration and impairing the clearance of α‐synuclein. ³⁴

Recent studies have also further investigated the impact of sleep disturbances on the susceptibility to develop PD or to causally contribute to its progression. A large retrospective longitudinal cohort study revealed that non‐apnoea sleep disorders, especially insomnia, were associated with a significantly higher risk of PD; of note, those with chronic insomnia lasting for more than 3 months had the greatest risk. ³⁵ In a larger cohort of adults with non‐apnoea sleep disorders without PD compared to a control cohort, non‐apnoea sleep disorders were found to be an independent risk factor for PD, also after multivariate adjustment. ²⁹ Another large long‐term prospective population‐based study demonstrated that subjectively poorer sleep quality and shorter sleep duration were associated with an increased risk of parkinsonism within the first 2 years, which attenuated during follow‐up. ³⁶ This is in line with a large registry‐based study showing increases in insomnia 2 years but not 5 or 10 years before diagnosis of PD. ³⁷ However, although these studies suggest that sleep disturbances were prodromal or early manifestations of PD, they cannot exclude the possibility that sleep disturbances may have merely accelerated an underlying PD pathology in vulnerable individuals.

Apart from epidemiological studies using subjective assessment, it has been demonstrated that greater sleep fragmentation measured by actigraphy in older adults without a clinical diagnosis of PD was associated with higher risk of subclinical PD pathology, such as the presence of Lewy bodies and substantia nigra neuronal loss. ³⁸ Importantly, these associations were independent of any medical and psychiatric comorbidity, including cognitive impairment. Furthermore, in a retrospective longitudinal study in PD patients who underwent PSG followed over an average period of 4.6 years, lower accumulated power of slow wave sleep (SWS) was associated with faster progression, especially axial motor symptoms. ³⁹ Overall, this demonstrated the association between impaired sleep and increased risk for PD onset or progression.

An intriguing interpretation may lie on the evidence that early PD pathology might affect the sleep regulatory circuit or circadian rhythm, which is a hypothesis well established in the case of RBD and, based on the clinic‐epidemiological studies described above, likely also in the case of insomnia. ²⁹ , ⁴⁰ An alternative explanation is that sleep disturbances accelerate the onset and progression of PD. However, these two mechanisms should not be viewed as mutually exclusive, as they may perpetuate a vicious cycle in which sleep disturbances are caused by PD pathology, which in turn accelerate PD symptoms, but with the opposite that can be also true.

Contributions from Preclinical Studies

Mouse models of PD are particularly useful in this context, since the core mechanisms underlying the sleep–wake cycle and its regulation are shared between humans and mice. ⁴¹ A recent study demonstrated that the administration of sodium oxybate enhanced SWS and reduced the accumulation of aggregated a‐syn in the mouse brain, although no major symptomatic effects were observed. ⁴²

Another approach considered the homeostatic regulation of protein quality, referred to as proteostasis, which is vital for human health. Proteostasis is maintained via the coordination of multiple intra‐ and extracellular systems that regulate protein synthesis, folding, disaggregation, and degradation/clearance. Impaired proteostasis and the subsequent accumulation of misfolded or aggregation‐prone neurotoxic proteins, including a‐syn in PD, are common pathomechanisms that underlie neurodegenerative diseases. ⁴³ Also in sleep disturbances, various intra‐ and extracellular mechanisms may contribute to impaired proteostasis. For instance, sustained wakefulness activates the unfolded protein response pathway, which is one of the key mechanisms protecting cells from the accumulation of neurotoxic proteins. ⁴⁴ , ⁴⁵ Aging impairs this protective response against insufficient sleep, favoring the activation of the pro‐apoptotic signaling pathways. ⁴⁶ Interestingly, a sustained wakefulness due to sleep restriction raises the extracellular soluble level of a‐syn in the interstitial fluid and in the CSF, a phenomenon observed both in mice and in humans. ¹ , ⁴⁷ , ⁴⁸

Animal studies provide insightful hints also in delineating the role of neuroinflammation in PD and its relationship with sleep disorders. In a mouse model of PD, ligating deep cervical lymph nodes decreased meningeal lymphatic drainage and aggravated a‐syn pathology and motor impairment. ⁴⁹ More recently, it has been shown that meningeal lymphatic drainage was significantly decreased in patients with PD. ⁵⁰ However, also the decrease in intracellular a‐syn degradation, in addition to the decrease in extracellular a‐syn clearance, contributed to the aggravation of a‐syn pathology and motor phenotype in PD mice subjected to meningeal lymphatic drainage blockage. ⁴⁹ Consequently, additional studies exploring the interplay between sleep and both intra‐ and extracellular a‐syn dynamics are necessary to comprehensively understand the causal relationship between sleep disturbances and PD, also considering a new study that questioned the notion of the increased brain clearance during sleep. ⁵¹

PD and Sleep Disorders: Risk Factor, Progression Factor, or both?

Research on the contribution of neuroinflammation to the dopamine neuron loss in PD and of extracellular clearance pathways, especially including the glymphatic system, is emerging. Briefly, extracellular a‐syn induces an inflammatory response, which can lead to neural cell death and inhibition of neurogenesis; on the other hand, the glymphatic system normally functions towards the removal of extracellular brain solutes during sleep, ⁵² although this notion has been recently questioned. ⁵¹ Therefore, sleep alteration may act as a risk factor for PD but also as a factor for its progression or worse course compared to good sleepers. ³²

In recent years, Uchihara and Giasson proposed a multifocal PD pathology hypothesis based on the observation that PD pathology initially appears in multiple neuronal groups without transsynaptic connections and then spreads into selective but variable neuroanatomical structures. ⁵³ In this context, sleep might serve as a preventive target in either pattern or stage of PD progression. In those patients with PD pathology in the brain regions regulating sleep–wake or circadian rhythms, sleep disturbances caused by PD pathology may accelerate PD progression. Conversely, in other patients sleep disturbances caused by aging may accelerate PD progression both in the brain and from the peripheral autonomic nervous system into the brain because sleep disturbances evoke the systemic immune response and metabolic stress, both of which contribute to PD pathology. ⁵⁴ , ⁵⁵ The RBD, which is a strong predictor of neurodegeneration, representing a degenerative disorder itself, ²¹ , ⁵⁶ , ⁵⁷ supports this hypothesis: the prodromal presence of RBD is associated with a more severe motor and non‐motor PD subtype, thus implying a significant disease‐modifying effect of this parasomnia on PD. ⁵⁸

At the same time, sleep disturbances may be viewed as a progression factor for PD. ³² For instance, it is known that episodic sleep disturbances (such as RBD) arise from the impairment of neural circuit regulating the balance between inhibitory and excitatory neuronal populations, as also confirmed by recent transcranial magnetic stimulation (TMS) studies. ⁵⁹ , ⁶⁰ As neural circuits may predict the pattern of a‐syn propagation in the nervous system, the impairment of such networks is of high relevance for PD pathophysiology. ⁶¹ A recent study aimed to examine the bidirectional causal relationships of multiple sleep‐related phenotypes with PD using a two‐sample Mendelian randomization method. Although there was insufficient evidence to support the causal effect of sleep‐related phenotypes on risk and age at the onset of PD, the results indicated that a later onset age of PD was related to the frequent occurrence of insomnia, also after the adjustment for multiple testing. The authors concluded that insomnia‐associated single nucleotide polymorphisms were more frequent in later onset PD compared to earlier onset patients. ⁶¹

Finally, additional mechanisms have been recently proposed. Among them, it is known that PD symptoms develop in response to disruption of not only dopaminergic pathways but also other neurotransmitters, including gamma‐aminobutyric acid (GABA). ⁶² GABA has a neuroprotective effect against PD neuropathology by protecting dopaminergic neurons in the substantia nigra pars compacta. Accordingly, the degeneration of GABAergic fibers is linked with a greater loss of dopaminergic neurons and a more sever progression of both motor and non‐motor PD symptoms, including sleep disorders and cognitive dysfunction. Indeed, GABA is necessary also for normal sleep, thus a deregulation of GABAergic neurotransmission in PD might be the potential cause of sleep disorders in these patients. ⁶³ At the same time, however, sleep disorders worsen GABA neurotransmission, which aggravates PD. Nevertheless, the mechanistic role of GABA in the neurobiology of PD is not fully elucidated, although a bidirectional relationship between the PD pathogenesis and sleep disorders due to GABA deregulation is likely to occur. ⁶⁴

Sleep and Neuroprotection in PD

Novel molecules with different mechanisms of action and potentially better safety profiles may offer more suitable therapeutic opportunities than in the past, also with potential neuroprotective purposes. ⁶⁵ , ⁶⁶ Among them, orexin is a neuropeptide that plays a role in the pathogenesis of PD, also exerting neuroprotective properties in dopaminergic neurons. In PD neuropathology, degeneration of orexinergic neurons in the hypothalamus has been reported, although this begins after the loss of dopaminergic neurons. Nevertheless, reduced activity of orexinergic neurons has been linked to the development and progression of both motor and non‐motor symptoms in PD, including sleep disorders. However, considering that the number of orexinergic neurons is decreased in patients with PD ⁶⁷ , ⁶⁸ and that orexin administration partly ameliorates non‐motor symptoms in a mouse model of PD, ⁶⁹ the potential effect of drugs acting on orexinergic transmission needs to be explored in humans yet.

Melatonin has a wide range of regulatory effects, such as synchronizing circadian rhythm, is expected to be a potential new circadian treatment target of sleep disorders in PD, and ongoing clinical trials seem to confirm its therapeutic effects. ⁷⁰ Mechanistically, melatonin plays antioxidant, anti‐inflammatory, anti‐excitotoxity, anti‐synaptic dysfunction, and anti‐apoptotic activities. In addition, it attenuates the effects of genetic variation in the clock genes Baml1 and Per1, thus favoring the circadian rhythm. However, the specific mechanisms of action and a systematic use of melatonin in PD patients require further investigations. ⁷¹ Tight collaboration between clinicians and researchers will contribute to the understanding of the bidirectional relationship between sleep and PD and help develop new disease modifying agents.

Lastly, along with melatonin, other feasible and well‐tolerated strategies, such as sleep hygiene, light therapy, or both, may be effective in improving the quality of nighttime sleep, although to date it is unknown whether such interventions may also be effective in slowing neurodegeneration.

Summary of Evidence and Critical Considerations

Based on these considerations, the potential effect of sleep alterations on the neurodegenerative process underlying PD seems clear. However, it should be kept in mind that PD is an umbrella term encompassing multiple phenotypes, which share some symptoms, mainly the motor ones. Therefore, sleep disorders may play different roles depending on the affected cellular metabolic or signaling pathways involved. In some phenotypes, sleep disorders can be primarily a consequence of neurodegeneration of controlling centers, whereas in others it may substantially contribute to the neurodegenerative process, eg, by inducing neuroinflammation. In this complex but also intriguing scenario, it is crucial to identify specific pathways that might be affected by sleep disorders, eventually resulting in neurodegeneration.

Although the most recognized degenerative process in PD is the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), ⁷² pathological cascades common to many neuron subgroups may cause sleep disturbances and contribute to widespread neurodegeneration. Namely, degeneration of the hypothalamus or the brainstem likely precede midbrain dopaminergic loss and may result in some sleep disturbances, such as insomnia, sleep‐breathing disorders, and RBD, as early premotor signs of PD. ⁷² , ⁷³ In particular, the hypothalamus exerts a strong influence on sleep, with many sleep‐promoting nuclei and neurotransmitters arising from this region, including the sleep‐active neurons of the ventrolateral and median preoptic areas. ⁷⁴ , ⁷⁵ These hypothalamic regions, along with melanin‐concentrating hormone neurons, ⁷⁶ have been experimentally demonstrated to promote sleep; indeed, the pathology‐induced lesion of these areas is involved in PD‐related insomnia and other sleep disturbances.

Loss of normal homeostatic patterns of sleep may contribute to neurodegeneration in PD. ²⁶ Accordingly, a loss of orexin‐containing neurons, that parallels PD disease stages, has been reported ⁶⁸ and decreases in cerebrospinal fluid concentrations of orexin correlated with increased objective sleepiness. ⁷⁷ This compromised wake‐promoting system may contribute to EDS and disrupted nocturnal sleep in PD, especially in advanced stages. Noradrenergic neurons of the locus coeruleus ⁷⁸ , ⁷⁹ are prominently and progressively lost, potentially contributing to loss of daytime vigilance, eventually leading to EDS typically observed in PD patients. ⁸⁰ Additionally, the posterior hypothalamic regions involved in wakefulness, such as the histaminergic tuberomamillary nucleus, are also damaged. ⁸¹

It has also been demonstrated that basal ganglia themselves exert a direct control over sleep and wakefulness. Briefly, 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. ⁸² Simultaneous electrophysiological recordings from the GPe and cortical pyramidal neurons depict a strong relationship between the “inactive” deflections of EEG slow‐wave activity (SWA) and GPe firing. ⁸³ 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. ⁸³

Lastly, mounting evidence highlights the impact of circadian rhythms disruption on neurodegeneration. Indeed, most neurodegenerative diseases, including not only PD but also Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, present with some degree of circadian dysfunction. ²⁶ On the other hand, melatonin secretion is phase‐advanced and blunted in PD and may be related to disease progression or dopaminergic therapy. ⁸⁴ , ⁸⁵ A significant contribution also comes from the glymphatic system dysfunction, which is believed to remove extracellular brain solutes during sleep. Accordingly, the strong correlation between quality of sleep and glymphatic efficiency implicates the sleep disruption as a potential pathogenic factor in the development and progression of PD. ⁵²

To summarize, sleep changes may serve as markers to identify patients in the preclinical stage of different neurodegenerative disorders, including PD. A recently proposed hypothetical model postulated that specific sleep abnormalities, when noted to increase in severity beyond that expected for age, might be a surrogate index of pathophysiological processes underlying neurodegeneration. ⁸¹ This provides a clinical strategy for screening patients in the preclinical stage of PD, thus possibly allowing prevention or delay in the onset and/or progression of symptoms and testing therapeutic trials with a potential neuroprotective action.

Conclusions

Sleep disorders are by far the most common non‐motor symptoms in PD. Of note, sleep abnormalities may antedate the motor phenotype likely because of the involvement of the sleep networks by the same underlined neuropathological processes. This is particularly important not only because prodromal sleep disorders can offer a privileged window to study the natural history of the disease but also a time‐window to intervene with neuroprotective strategies. In this regard, there is mounting evidence stressing the pivotal role of sleep disruption in accelerating neurodegeneration and this has been particularly studied in PD where sleep disturbances caused by PD pathology itself further trigger a dangerous circle that may accelerate neurodegenerative processes and PD progression. With the worsening of the disease, sleep disorders become even more severe due to the motor disorder itself but also to the overlap with additional non motor symptoms and to the use of medications. In this scenario, sleep disorders significantly affect the quality of life of the patients. It is therefore pivotal to recognize and make a proper differential diagnosis of sleep complaints in our patients aiming at offering a precocious treatment which should be patient tailored.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.

E.A.: 1A, 1B, 1C, 3A, 3B

G.L.: 1B, 1C, 3A, 3B

M.P.M.: 1B, 1C, 3A, 3B

G.P.M.: 1B, 1C, 3A, 3B

G.P.: 1B, 1C, 3B

L.F.S.: 1B, 1C, 3B

R.F.: 1B, 1C, 3B

M.T.: 1A, 1B, 1C, 3B

Disclosures

Ethical Compliance Statement: The authors confirm that neither the approval of an institutional review board nor patient consent was required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the previous 12 months: The authors declare that there are no additional disclosures to report.

Data Availability Statement

na.