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Abstract

Sleep is involved in regulating many aspects of the body, including cell function, physical activity, and disease. Neurodegenerative diseases are often preceded by sleep disturbance. This disturbance is not just a non-motor symptom but also an important risk factor for developing the disease. It is now understood that the glymphatic system plays important physiological functions in the human body: maintaining the balance of interstitial fluid and clearing waste products from metabolism or death in the brain. Glymphatic system dysfunction contributes to the progression of neurodegenerative diseases. Importantly, sleep is involved in regulating the glymphatic system, which affects the clearance of pathological proteins in the brain, and may be an important pathway affecting the progression of neurodegenerative diseases. Here, we review recent advances in sleep disturbances and the glymphatic system in health and Parkinson’s disease, hoping to identify potentially targetable avenues for future research and treatment of Parkinson’s disease.

Keywords

Sleep, Parkinson’s disease, neurodegeneration, glymphatic system, α-synuclein

INTRODUCTION

Parkinson’s disease (PD) has emerged as a prominent neurodegenerative disorder, exhibiting a marked increase in prevalence^[1]. PD is characterized by the pathological aggregation of α-Synuclein(α-Syn) into Lewy bodies and subsequent loss of dopaminergic neurons, resulting in a cascade of motor and non-motor symptoms^[2]. Motor symptoms include resting tremors, dystonia, bradykinesia, and postural gait disturbances^[3], while non-motor symptoms such as sleep disturbances, hyperalgesia, hyposmia, cognitive deficits, anxiety, depression, constipation, and other autonomic symptoms (including orthostatic hypotension, urinary urgency, and erectile dysfunction) significantly decrease patients’ health-related quality of life and well-being^[4,5]. Among these, sleep disturbances stand out as the most prevalent non-motor symptom, typically manifesting as insomnia^[6], rapid eye movement sleep behavior disorder (RBD)^[7], excessive daytime sleepiness (EDS), and restless legs syndrome (RLS), affecting over half of PD patients, significantly impairing their quality of life, and imposing a substantial economic burden on society^[6]. Importantly, sleep disturbances can emerge early in the prodromal disease phase and worsen as PD progresses, which are not merely regarded as a consequence of PD but also may contribute to disease progression^[8,9]. Among them, the pathological progress of RBD and PD is the most close. The Oxford Discovery Cohort Study^[10] found faster progression of motor, mood, and cognitive symptoms in PD patients combined with possible RBD (pRBD), confirming a more aggressive PD subtype identifiable at baseline. Additionally, numerous basic science studies support a correlation between sleep and neurodegenerative disease progression at the pathophysiological level^[11], and have revealed a strong bidirectional relationship between sleep disruption and increased amyloid-beta (Aβ) deposition, as well as higher levels of α-Syn in the brain’s extracellular fluid and cerebrospinal fluid^[12–17]. Collectively, these findings strongly suggest a close relationship between sleep disturbances and neurodegenerative disease, and understanding the impact of sleep disturbance on PD remains an urgent avenue for further investigation.

The glymphatic system is regulated by the sleep-wake cycle, facilitating the efficient removal of accumulated waste from the brain by allowing the flow of interstitial and cerebrospinal fluid through perivascular pathways, with significantly greater efficiency at night than during the day. Aging is a well-established risk factor for glymphatic system dysfunction^[18,19], which may explain the particular relevance of this system to neurodegenerative diseases affecting older populations^[20]. Numerous studies have demonstrated the involvement of the glymphatic system in the clearance and spread of pathogenic proteins tau^[21], amyloid-β^[22–25], and α-Syn^[26–28], which provides a new direction for exploring the pathogenesis of neurodegenerative diseases characterized by abnormal protein deposition in the brain. PD is known to be primarily caused by protein homeostasis imbalance. Under normal physiological conditions, α-Syn is a physiologically benign, soluble monomer consisting of 140 amino acids^[29]. However, pathological conditions can trigger α-Syn oligomerization or polymerization, leading to the formation of cytotoxic aggregates with a β-lamellar structure. If the abnormally folded proteins are not efficiently cleared, this can result in the accumulation of α-Syn both inside and outside cells, along with the intercellular spread of pathological α-Syn, which contributes to dopaminergic neuron death^[30,31]. Among these, the extracellular pathological proteins are more likely to be cleared through the glymphatic system^[25]. Clinical studies have already confirmed damage to the glymphatic system in PD^[32,33], strongly suggesting that glymphatic system dysfunction may be one of the important pathogenic mechanisms of PD.

Interestingly, the glymphatic system, responsible for clearing waste products from the brain, is also physiologically regulated by sleep. Fluid transport within this system exhibits a daily rhythm, with enhanced activity during sleep and reduced activity during wakefulness^[34]. Consistently, several studies have identified strong associations between glymphatic dysfunction and sleep disturbances^[35], especially in aging individuals and those suffering from age-related neurodegenerative diseases. Furthermore, similar to amyloid-β, α-Syn in the brain’s extracellular fluid and cerebrospinal fluid are higher during wakefulness compared to sleep^[17]. Moreover, α-Syn levels can be further exacerbated by sleep disruption^[36]. These findings collectively suggest a complex interplay between sleep, the glymphatic system, and neurodegeneration^[37]. Therefore, this article focuses on the link between sleep disturbances and the glymphatic system in neurodegeneration, especially regarding the clearance of pathological proteins, aiming to provide new research avenues for the pathogenesis and neuroprotection of PD.

SLEEP AND PARKINSON’S DISEASE

Sleep is a fundamental biological process essential for health, driven by different electrophysiological rhythms within the brain^[38]. Sleep and wakefulness are two distinct functional states governed by the circadian rhythm^[39,40]. While wakefulness allows us to perform a variety of physical and cognitive tasks, sleep serves critical restorative functions. It replenishes energy and physical strength, enhances immunity, promotes growth and development, improves learning and memory abilities, and helps to stabilize emotions^[41]. With advancing age, sleep patterns exhibit a progressive disruption. In addition, growing evidence suggests that sleep disorders may even precede the onset of some neurodegenerative diseases, and abnormal sleep patterns can worsen their progression^[42], including PD.

Severe sleep disturbances have been documented in PD^[11,43], such as insomnia, EDS, RBD, and RLS, which can manifest in the early stages of PD. Insomnia, characterized by difficulty falling asleep, staying asleep, or early awakening, and generally poor sleep quality, is one of the most common non-motor symptoms in PD patients, significantly impacting their quality of life^[44,45]. EDS refers to the inability to maintain a state of wakefulness and alertness during the day, often leading to unintentionally falling asleep at inappropriate times almost daily for at least 3 months. EDS is prevalent in PD patients, affecting approximately 20%-60% of individuals^[46,47], and can worsen their quality of life and increase their risk of injury^[48]. RBD is characterized by vivid or unpleasant dreams and intense body movements that may lead to acting out dreams and potential injury. Existing research suggests that RBD can be a precursor to neurodegenerative diseases characterized by α-Syn deposition, including PD, dementia with Lewy bodies, or multiple system atrophy^[49,50].

Longitudinal studies indicate that most patients will gradually develop symptoms of PD or cognitive impairments over time^[51]. A prospective study followed a group of patients with idiopathic RBD; after decades, the majority (82%) were ultimately diagnosed with a neurodegenerative disease characterized by α-Syn deposition^[52]. RLS is a common sensorimotor disorder where patients experience unpleasant sensations in their legs at rest, typically relieved by movement. A recent meta-analysis showed a significantly higher prevalence of RLS in PD patients compared to healthy controls (2.86 times higher). Treated PD patients exhibited a prevalence of 15%, while non-medicated patients showed an 11% prevalence^[53]. However, another research suggests no causal or genetic link between RLS and PD^[54]. Additionally, research suggests that sleep disturbances in PD, including more disrupted sleep patterns, reduced slow wave sleep (SWS), and rapid eye movement sleep, may contribute to cognitive decline and memory consolidation difficulties. A study demonstrated that PD patients taking dopaminergic medications showed improvement in working memory after sleep. Notably, the degree of improvement correlated with the amount of SWS^[55]. In conclusion, strong evidence suggests a close link between sleep disturbances and the development of PD.

Basic scientific research also confirms that PD model mice exhibit sleep disturbances and disrupted circadian rhythms^[56]. Interfering with sleep or circadian rhythms significantly exacerbates pathological protein deposition, excessive neuroinflammation, dopaminergic neuronal loss in the substantia nigra, and motor impairments in PD model mice^[57–59]. However, while circadian rhythms and sleep disorders are strongly linked to the progression of neurodegenerative diseases, the specific mechanisms underlying this connection remain poorly understood. It is well known that the sleep-wake cycle plays a crucial regulatory role in the glymphatic system^[60]. Intriguingly, growing interest has emerged regarding the function of the glymphatic system in central nervous system diseases, which plays an important role in the removal of metabolic waste, including pathological proteins^[23,61]. Taken together, this all suggests that the glymphatic system may serve as a potential bridge between sleep and neurodegenerative diseases^[17].

GLYMPHATIC SYSTEM AND SLEEP

Sleep is a crucial human life activity, accounting for about one-third of our lifespan, and plays a significant role in maintaining overall health. Despite the recognized importance of sleep, its complex effects on the body are not yet fully understood. The glymphatic system, a recently discovered waste clearance pathway in the brain, plays a critical role in maintaining metabolic balance and brain health by removing metabolic byproducts. Notably, the glymphatic system is primarily active during sleep and exhibits a close link to the regulation of circadian rhythms^[60].

The lymphatic network, a low-pressure, unidirectional flow system found throughout the vertebrate body, removes interstitial fluid (ISF) formed by capillary filtrate and plays a role in tissue immune surveillance^[62]. In the brain, however, there is a lack of parenchymal lymphatic vessels. Until 2012, Iliff et al.^[63] observed the flow pathway of a fluorescent CSF tracer injected into the cerebral space of mice using a two-photon laser scanning microscope. For the first time, they visualized the active and directional flow of CSF into brain cell spaces to remove waste products, a system they termed the glymphatic system. The anatomical foundation of the glymphatic system is the perivascular space. This space arises from the extension of the soft meninges that accompany penetrating arteries and draining veins into and out of the brain parenchyma. It is surrounded by a barrier formed by the adherent astrocyte endfeet^[64]. Within the brain tissue, this space is filled with an extracellular matrix rich in type IV collagen and laminin, secreted by pericytes and fibroblasts. Platelet-derived growth factor β (PDGF-β) secreted by endothelial cells recruits pericytes, which in turn induce high expression of aquaporin 4 (AQP4) water channels in the endfeet of neighboring astrocytes^[65]. CSF travels along the surface of cerebral arteries and the perivascular spaces of penetrating arterioles. It enters the brain parenchyma through the space between astrocyte endfeet or via aquaporin-4 (AQP4), facilitating CSF-ISF exchange, as well as solute and metabolite transport. Finally, convective flow carries CSF and ISF to the venous perivascular spaces, ultimately draining them out of the brain. This process maintains the stability of extracellular ions and fluids^[66].