Neurological Insights into Sleep Disorders in Parkinson's Disease

Abstract

Parkinson's disease (PD) is a common multidimensional neurological disorder characterized by motor and non-motor features and is more prevalent in the elderly. Sleep disorders and cognitive disturbances are also significant characteristics of PD. Sleep is an important physiological process for normal human cognition and physical functioning. Sleep deprivation negatively impacts human physical, mental, and behavioral functions. Sleep disturbances include problems falling asleep, disturbances occurring during sleep, abnormal movements during sleep, insufficient sleep, and excessive sleep. The most recognizable and known sleep disorders, such as rapid-eye-movement behavior disorder (RBD), insomnia, excessive daytime sleepiness (EDS), restless legs syndrome (RLS), sleep-related breathing disorders (SRBDs), and circadian-rhythm-related sleep-wake disorders (CRSWDs), have been associated with PD. RBD and associated emotional disorders are common non-motor symptoms of PD. In individuals, sleep disorders and cognitive impairment are important prognostic factors for predicting progressing neurodegeneration and developing dementia conditions in PD. Studies have focused on RBD and its associated neurological changes and functional deficits in PD patients. Other risks, such as cognitive decline, anxiety, and depression, are related to RBD. Sleep-disorder diagnosis is challenging, especially in identifying the essential factors that disturb the sleep-wake cycle and the co-existence of other concomitant sleep issues, motor symptoms, and breathing disorders. Focusing on sleep patterns and their disturbances, including genetic and other neurochemical changes, helps us to better understand the central causes of sleep alterations and cognitive functions in PD patients. Relations between α-synuclein aggregation in the brain and gender differences in sleep disorders have been reported. The existing correlation between sleep disorders and levels of α-synuclein in the cerebrospinal fluid indicates the risk of progression of synucleinopathies. Multidirectional approaches are required to correlate sleep disorders and neuropsychiatric symptoms and diagnose sensitive biomarkers for neurodegeneration. The evaluation of sleep pattern disturbances and cognitive impairment may aid in the development of novel and effective treatments for PD.

Keywords: Parkinson’s disease; circadian rhythm; excessive daytime sleepiness; insomnia; rapid eye movement; sleep disorders; sleep-related breathing disorders.

Figure 1

The illustration describes various sleep disorders associated with Parkinson’s disease and their causes and neurological changes. EDS: excessive daytime sleeping; DA: dopamine; REM: rapid eye movement; RBD: REM sleep behavior disorder; OSA: obstructive sleep apnea; RLS: restless legs syndrome; SWD: sleep–wake disorder; CLOCK: circadian locomotor output cycles kaput. (Figure created using BioRender.com; accessed on 27 June 2023).

Figure 2

(A) Obstructive sleep apnea (OSA): The episodic breathing session and repeated obstructions in the upper airway worsen nocturnal respiration and sleep. OSA produces irregular respiratory patterns, hypoventilation, nocturnal worsened respiration, and oxidative stress due to the resaturation and desaturation of oxygen levels, and produces damage to dopaminergic neurons. (B) Restless legs syndrome (RLS): Hypo-functioning of dopamine signaling due to reduced dopamine subtype 2 receptor (D2R) expression in the CNS. Reduced peripheral blood flow causes peripheral hypoxia, which leads to urges to move legs and causes defects in neurological sensorimotor functions. (Figure created using BioRender.com; accessed on 27 June 2023).

Figure 3

Schematic diagram showing key components of physiological and neurological changes in sleep disorders. (A) Excessive daytime sleeping (EDS): EDS occurs due to damage to the ascending arousal system (AAS), degeneration of hypothalamic orexin neurons, dopaminergic dysfunction, and increased dopaminergic therapy (DT) dosage. PD patients with EDS show changes in the AAS, including neurotransmitter systems like dopamine–ventral periaqueductal gray matter (vPAG), orexin–lateral hypothalamus, serotonin–raphe, noradrenaline–locus coeruleus (LC), histamine–tuberomammillary nucleus (TMN), acetylcholine, GABA–basal forebrain (BF). (B) Insomnia: Lesions in the regulatory sleep regions of the brain, like substantia nigra (SN), ventral tegmental area (VTA), and LC, cause disturbances in the sleep–wake cycle. (C). REM sleep behavior disorder (RBD): A common parasomnia due to loss of skeletal muscle atonia, changes in the brain stem regions controlling motor movements during REM sleep, or any impairment in the excitatory and inhibitory neural circuits; overactivation of the ascending reticular activating system (ARAS) causes abnormal motor behavior and dream enactments in REM sleep. (Figure created using BioRender.com; accessed on 27 June 2023).

Figure 4

Circadian-rhythm sleep–wake disorders (CRSWDs): The SCN is the master clock that regulates circadian rhythm and signals. When light enters the retinal hypothalamic (RH) tract and reaches the SCN within the hypothalamus, the SCN signals the pineal gland to turn off melatonin production. Light-induced dopamine release or dopamine therapy-induced dopaminergic stimulation alters circadian-rhythm amplitudes, and mutations in circadian regulating genes cause changes in circadian-phase shift. (Figure created using BioRender.com; accessed on 27 June 2023).

Figure 5

Summary chart representing types of non-pharmacological and pharmacological treatment methods for PD-associated sleep disorders. (Figure created using BioRender.com; accessed on 2 August 2023).