Parkinson’s disease (PD) is the second most common neurodegenerative disease, afflicting about 1% of people over 65 years old and 4–5% of people over 85 years old (Lang and Lozano, 1998a, Lang and Lozano, 1998b). At presentation, the major clinical features include the asymmetric onset of bradykinesia, rigidity, rest tremor and disturbances in balance. PD is a multifactorial disease in which various genetic and non-genetic factors contribute to the disease course (Poewe et al., 2017). Although genetic factors are difficult to modify following birth, non-genetic factors are modifiable and may serve as preventive or therapeutic targets. Of such non-genetic biomarkers, sleep changes have attracted attention as a particularly strong candidate (Suzuki, 2021). In fact, sleep disturbances are highly prevalent among patients with PD and often appear from the early-phase disease or prodromal stages (Lima, 2013).

While sleep disturbances have only recently been recognized in PD and other movement disorders, such frequent afflictions were originally reported in James Parkinson’s initial description of the disorder: “…the sleep becomes much disturbed. The tremulous motion of the limbs occurs during sleep, and augments until they awaken the patient, and frequently with much agitation and alarm” (Parkinson, 1817). These sleep disturbances primarily include insomnia, abnormal movements during sleep (e.g., periodic limb movements—PLM, rapid-eye-movement sleep behavior disorders—RBD) and excessive daytime sleepiness (De Cock, Vidailhet, & Arnulf, 2008). These disturbances have an important impact on the patient’s quality of life, increasing the risk of self or bed-partner injuries (due to RBD/PLM) and/or the risk of driving or machinery accidents (due to the excessive daytime sleepiness). They may precede the cardinal motor features of the disease by many years, and therefore may serve as early biomarkers of the premotor phase of PD (Abbott et al., 2005, Postuma and Montplaisir, 2006).

Essentially, a decrease in rapid eye-movement sleep, non-REM (NREM) sleep and slow wave sleep (SWS), in particular, as shown to occur in PD, may also result in reduced clearance of brain waste promoting the accumulation of intracellular α-synuclein aggregates (Kim, Kågedal, & Halliday, 2014). It is important to note that the relative impact of the clearance of abnormal proteins by the glymphatic system during sleep in PD remains unclear (Sundaram, Hughes, & Peterson, 2019). Nonetheless, α-synuclein, similar to amyloid-β, has been found present in the brain extracellular fluid and cerebrospinal fluid at higher concentrations during wakefulness than during sleep (Nedergaard & Goldman, 2020) and higher even after sleep disruption (Holth, Fritschi, & Wang, 2019). This suggests that the sleep deficits observed in PD in the short term may exacerbate symptoms and in the long term accelerate pathology and contribute to disease progression.

The pattern and sequence of these prodromal symptoms may provide important information on the disease onset and its mechanisms. In the early 2000s, Braak and colleagues established the basis of a stereotypic and chronological progression of Lewy bodies appearance, which received wide acceptance in the literature (Braak et al., 2003, Braak et al., 2003). Accordingly, considering this Braak’ staging scheme, lesions in stages 1–2 are thought to be essentially responsible for prodromal symptoms. In fact, stage 1 includes the dorsal nucleus of the vagus nerve (DMV) that innervates the gastrointestinal tract and the olfactory bulb, which may be responsible, roughly, for constipation and olfactory dysfunction (hyposmia or even anosmia), respectively. Constipation is one of the main and most frequent autonomic dysfunctions of PD, and a case–control study showed that constipation can occur more than 20 years before the onset of motor symptoms (Savica et al., 2009). In the pathological analysis, α-synuclein was found to be accumulated in the DMV and enteric nervous system (Braak, de Vos, Bohl, & Del Tredici, 2006). In the gastrointestinal tract, α-synuclein pathology is stronger in the rostral part than that in the caudal part (Beach et al., 2010). Olfactory disturbance is observed in more than 90% of sporadic PD patients and appears at least several years before the motor onset (Doty, 2012). In accordance with this clinical observation, α-synuclein aggregates are observed in the olfactory tract, even in early-stage PD patients (Braak et al., 2003, Braak et al., 2003). The number of tyrosine hydroxylase immunoreactive [(TH)-ir] cells in the olfactory bulb is markedly increased, and it has been speculated that the inhibition of olfactory transmission by DA may be responsible for the olfactory disturbance in PD (Huisman, Uylings, & Hoogland, 2004). Besides, in animal models of PD it has been reported that dopamine produced by periglomerular TH-ir neurons and the bulbar dopaminergic D2 receptors are essential participants in olfactory discrimination processes (Rodrigues et al., 2014, Noseda and Lima, 2022). Additionally, a direct association between the periglomerular neurons and depressive-like behaviors has been described (Ilkiw et al., 2019). Consequently, these changes may have a direct impact on the prodromal abnormalities found in patients with PD.

Sleep disturbances are primarily observed during the occurrence of stage 2, which includes the observations of lesions within the raphe nuclei, gigantocellular reticular nucleus of the medulla oblongata, and the locus coeruleus in the pontine tegmentum (Braak et al., 2003, Braak et al., 2003, Jellinger, 2015). Furthermore, these disturbances are secondarily promoted by nocturnal manifestations of the disease and by the side effects of pharmacological treatment and also overlap with independent, age-related sleep disturbances (Lima, 2013). In general, sleep disturbances in PD negatively impact the patients’ quality of life, and they are contributing factors for earlier institutionalization and higher caregiver burden. Nearly all PD patients have sleep disturbances, especially RBD, insomnia, excessive daytime sleepiness, and their rates increase during the course of the PD and are related to its rapid progression (De Pablo-Fernandez et al., 2019, Chahine et al., 2017). Typically, the whole plethora of PD manifestations, including bradykinesia and akinesia, are achieved during and after the degeneration of dopaminergic neurons within the substantia nigra pars compacta (SNpc), corresponding to Braak’s stage 3, leading to a subsequent reduction of dopaminergic input to the dorsal striatum. Moreover, there is a degeneration of neurons of essential brainstem nuclei (LC, raphe nuclei, dorsal motor nucleus of the vagus), cortical neurons (particularly within the cingulate gyrus and the entorhinal cortex), the nucleus basalis of Meynert and of preganglionic sympathetic and parasympathetic neurons (Braak et al., 2003, Braak et al., 2003).

As noted in Chapter 1 of this book, the specific mechanisms of these sleep disturbances are far from being fully understood, likely due to the multiple variables (e.g., age, medication, depression, anxiety, cognitive decline, etc.). Therefore, animal and mathematical/computational models may improve our knowledge of both the pathophysiology of sleep alterations in PD in general and of the role of dopaminergic lesions, in particular. Hence in this chapter, we will discuss the current evidence addressing the links between sleep dysfunctions in PD, focusing most closely on those data from animal and mathematical/computational models, as well as in human-based studies that explore the electrophysiological and molecular mechanisms by which PD and sleep may be intertwined, whether as predictors or consequences of the disease. A comprehensive understanding and overview of the relationship between sleep regulation and PD is needed to guide future research in the field as well as facilitate the clinical management of the disease.