Parkinson's Disease and Sleep Disorders

Parkinson's Disease

Parkinson's disease (PD) was first described by James Parkinson, in 1817, he defined it as a series of involuntary tremulous motions, with lessened muscular power, with a propensity to bend the trunk forwards, and to pass from a slow walking to a faster pace, although he considered then senses and intellects weren´t being injured (Parkinson, 1817).

Two hundred years later, most of his clinical observations have remained as a general description of the disease, however, nowadays it is well known that PD in not only a movement disturbance, but a complex disorder which is accompanied by non-motor specific symptoms. Worldwide, the incidence of PD has been estimated to range from 5 to 35 new cases per 100,000 inhabitants per year (Poewe, 2017). And the prevalence rate increases according to age groups, it is estimated that there are 41 cases per 100,000 inhabitants in the age range of 40 to 49 years; 107 cases per 100,000 from 50 to 59 years; 428 cases per 100,000 from 60 to 69 years; 1,087 cases per 100,000 from 70 to 79 years, and 1,903 cases per 100,000 individuals over 80 (Pringsheim, 2014). That is to be expected inasmuch as ageing is the most important risk factor (Delamarre, 2017).

PD is currently the most common movement disturbance and de the second most frequent neurodegenerative disease, right after Alzheimer's disease (Delamarre, 2017). In spite of the fact that the pathogenesis of PD still remains unclear, it has been described that it may be caused by a combination of genetic and environmental factors (Błaszczyk, 2017).

Even though the pathogenesis of PD hasn’t been described, the neuropathological hallmarks are well known; the depigmentation of the substantia nigra pars compacta (SNc), which is now known to be the result of neuronal degeneration in the SNc; which is associated with the presence of Lewy bodies, (Przedborski, 2017), intracytoplasmic inclusion bodies that contain aggregations of the protein α-synuclein. As a result of the degeneration of dopaminergic neurons in the SN, there is a deficit of dopamine in the striatum (Oertel, 2017) which is responsible for the motor impairment.

There are three main clinical manifestations of PD, they correspond to the motor symptoms of the disease: bradykinesia, the most specific manifestation of PD, which is necessary for its characterization; muscle hypertonia and rest tremor (Grabli, 2017).

It has been estimated that the motor symptoms of PD appear when up to 80% of dopaminergic cells in the nigro-striatal system are lost (Seinbjornsdottir, 2016). However, even since PD was first described by James Parkinson, the non-motor symptoms were considered an important part of the disease. He described the presence of sleep disturbance, constipation, dysarthria, dysphonia, dysphagia, urinary incontinence, excessive daytime sleepiness and delirium during the course of the disease (Parkinson, 1817). It is important to recognize that both motor and non-motor symptoms contribute to disability and reduced quality of life in PD.

The treatment of PD, has been focused on motor symptoms therapy, however, it is important to highlight that for most patients the non-motor symptoms will eventually become the most disabling ones (Postuma, 20017), this ones includes the sleep disorders.

Sleep Disorders in PD

The prevalence of sleep disturbances in PD varies in different populations and methodologies; with rates ranging from approximately 40% to 90% (Suzuki, Miyamoto, Miyamoto & Hirata, 2015). The most common among PD patients include insomnia, REM behavior disorder (RBD), obstructive sleep apnea (OSA) and excessive daytime sleepiness (EDS) (Albers, Chand & Anch, 2017).

o Insomnia: It is one of the most common sleep disorders in PD, it may affect up to 60% of patients (Gjerstad, Larsen, Aarsland & Larsen, 2007). According to the American Academy of Sleep Medicine (AASM), insomnia is defined as an impairment that involves initiating sleep, maintaining sleep, early awakenings and poor overall sleep quality (American Academy of Sleep Medicine, 2014). This disorder is more frequently reported as PD progresses, where increased nocturnal symptoms of rigidity, motor fluctuations, and pain can disrupt sleep (Kutscher, Farshidpanah & Claassen 2015).

o REM behavior disorder (RBD): It is characterized by the loss of the normal atonia of REM sleep, which results in an apparent acting out of dream content (Postuma et al., 2012), the overall reported prevalence of RBD symptoms is 23% among patients with newly diagnosed PD (Zhang J, Xu C & Liu J, 2017), however, RBD is considered a clinical non-motor prodromal marker (Berg et al., 2015) (Tekriwal et al., 2017); it has even been reported that up to 90% of people with RBD, diagnosed by polysomnography (PSG), will eventually develop a defined neurodegenerative syndrome, within which, the most frequent is PD (Iranzo et al., 2014). o Obstructive sleep apnea (OSA): It is caused by obstruction of the upper airway, leading to apneas (complete cessations in respiration) or hypopneas (partial decreases in respiration) during sleep (Harmell, 2016). The prevalence rates of OSA in PD ranged from approximately 27% (Cochen et al., 2010) up to 74% (Harmell, 2016) and it has been associated with excessive daytime sleepiness (EDS) and cognitive dysfunction in PD (Mery, 2017). o Excessive daytime sleepiness (EDS): According to de AASM, EDS is defined as the inability to maintain wakefulness and alertness during the major waking episodes of the day, with sleep occurring unintentionally or at inappropriate times almost daily for at least three months (American Academy of Sleep Medicine, 2014). EDS affects up to 60% of patients with PD (Chahine, Amara & Videnovic, 2016) and the rate increases with disease duration and severity of motor symptoms (Amara, et al., 2017).

It is important to consider that, although the aging process is associated with brain degeneration and dysregulation of neurotransmitter secretion that may lead to abnormal sleep-wake cycles (Mao, et al., 2017), it is also known that several factors contribute to these sleep disturbances in PD, such as: pharmacological treatment, anxious and depressive symptomatology, manifestation of motor signs during sleep and, most importantly, the neurodegeneration that occurs during the disease (Diederich & McIntyre, 2012).

Furthermore, the role of Dopamine in circadian dysregulation in PD is also relevant, due to the implication of dopaminergic neurons that emerge from the ventral tegmental area (VTA) and the SNc, major areas of neurodegeneration in PD; these also have connections with the locus coeruleus (LC), pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT) (Monti and Monti, 2007)(Herrera et al., 2017), structures associated with sleep regulation.

It also has been reported that brain structures in this particular areas, DRN, PPT/LDT and LC are affected before SNpc as the disease progresses (Braak et al., 2004), which may explain the presence of sleep disorders as a pre-clinic symptoms.

Genetic Circadian Regulation

Circadian rhythms are cycles generated by the suprachiasmatic nucleus (SCN), the endogenous biological clock (Videnovic, Lazar, Barker & Overeem, 2014), it drives physiological, metabolic and behavioral rhythms (Schuch et al. 2017).

The circadian clock molecular mechanism is regulated by a set of clock genes: CLOCK, ARNTL (BMAL1), three PER genes (PER1, PER2 and PER3), two cryptochrome genes (CRY1 and CRY2), reverse erythroblastosis virus (Rev-erb) and the Retinoic acid receptor-related orphan receptor (Rorα) genes, and their corresponding proteins. It’s known that these specific core clock factors control approximately 10% of all expressed genes of the genome (Videnovic, et al, 2014), and almost all peripheral tissues contain autonomous circadian clocks.

This molecular oscillator consists of a pair of orthologous basic helix–loop–helix PER-ARNT-SIM (bHLH-PAS) transcription factors (CLOCK and BMAL1) form heterodimers that bind to E-box regulatory elements to activate transcription of genes CRY and PER, which accumulate in the cytoplasm and move to the nucleus to bind and inactivate the CLOCK:BMAL1 activators, to repress its transcription (Hardin and Panda, 2013), In addition, Rev-erb and Rorα play a role in maintaining the circle stable (Lowrey and Takahashi, 2011). However, there are many other genes that also have E-box regulatory sequences, so this circadian cycle of expression is involved in many aspects of cellular functions (Mattis and Sehgal, 2016) and determines the circadian periodicity.

It has been reported that several genes oscillate synchronously across diverse organs like liver, kidney, lung, heart, hypothalamus, brainstem, cerebellum, among others (Zhang, et al, 2014); and of these, those found in a continuous circadian synchronization pattern in all tissues are the core Clock genes. However, in spite of the rhythmic transcription regulation of the clock-controlled genes, it has also been described that the expression pattern of CLOCK is nearly constitutive in the SCN in mammals (Schuch J et al., 2017), and this constitutive expression has been observed as well in peripheral tissues (Balmforth et al., 2007).

Moreover, it was reported that these genes oscillated in in blood cells in humans (Fukuya et al., 2007), which indicate the feasibility of using blood to study the characteristics of the molecular clock in human subjects.

Genetic Circadian Regulation and Neurodegeneration

Disruption in sleep and circadian rhythms are common in patients with neurodegenerative diseases, nonetheless, it is important to consider that these affect mainly the elderly, so this can complicate determining if this changes in sleep and circadian patterns are due to de neurodegeneration or the normal aging process (Mattis and Sehgal, 2016); on the other hand there is abounding evidence and literature reports that support the fact that sleep and circadian disruption are, in fact, associated with neurodegenerative diseases. As a matter of fact, circadian and sleep dysregulation may influence the neurodegenerative process itself; a good example of this bidirectional influence among sleep/circadian function and neurodegeneration is Alzheimer's disease (AD), where beta amyloid peptide accumulation is known to disrupt sleep patterns and this dysregulation increases the risk of accumulation of amyloid and the subsequent development of dementia (Ju et al., 2014).

However, there are reports that describe the possible role of circadian clock molecular mechanism in the etiology of neurodegeneration and the development of these diseases. For example, polymorphisms of Bmal1 and Per1 are associated with increased risk of developing PD (Gu et al., 2015). Moreover, clock genes also regulate the expression patterns of other genes straightly implicated in neurocognitive disorders such as AD (Bélange, 2006).

Furthermore, evidence suggests that circadian regulation contributes to neurodegeneration through its involvement in cellular responses to oxidative stress (Hood and Amir, 2017), which has been described as a causal factor of mitochondrial dysfunction and neuronal damage observed in PD and AD. For example, Bmal1 has been associated with the regulation of antioxidant response transcription factors (Lee et al., 2013), additionally Knock Out (KO) animal models of Per1 show differential regulation of the expression of genes involved in detoxification (Jang, 2011).

Genetic Circadian Regulation and Sleep Disorders

Particularly in neurodegenerative diseases where sleep disorders are highly prevalent, there has been studied the association between neurodegeneration, sleep disorders and the regulation of clock genes. For example, REM sleep disturbance and its association with clock genetic regulation has been studied in AD, in this patients it has been reported that Per1 pattern of expression changes during different sleep stages, particularly REM sleep, which reflects the regulatory role of PER1 in the circadian rhythm (Tseng, 2010).

Another member of the Period family genes, Per3, is also associated with sleep architecture, and its regulation after sleep deprivation (Landolt, 2011).

Genetic Circadian Regulation in PD

Particularly in PD, there is evidence that suggests that this core set of clock genes play a significant role in dopamine metabolism, moreover, promoter regions of the dopamine D1A receptor and tyrosine hydroxylase genes include an E-Box element which is the target of the molecular clock (Videnovic and Golombek, 2013), suggesting that the dopamine system is regulated by circadian rhythm. It has been reported that dopamine also regulate the expression of clock genes, through the mediation of light signaling to the retinal circadian clock (Yujnovsky, et al., 2006); since the light is the principal regulator of the circadian clock, it has been reported that dopaminergic activity plays a central role in the mediation of light signaling through the D2 receptor that also induce the expression of certain clock genes.

Animal Models

In the other hand, there has been studies in PD animal models, Si-Yue and cols. work with a murine 6-hydroxydopamine (6-OHDA) PD model, they found that there was difference in the relative expression levels Bmal1 and Per2 among the 6-OHDA group compared with the control and this levels were markedly decreased in the SCN, and interestingly in the Striatum the expression of Clock and Per2 showed a significant reduction; they also included a group where there was administrated L-dopa simultaneously with the 6-OHDA It is also has been reported that the relative expression levels of Bmal1, in PD patients, are significantly reduced than controls during all the circadian pattern and these levels are positive correlated with United Parkinson's Disease Rating Scale (UPDRS) score (Cai, 2010)(Ding, 2011) (Breen, 2014) and these expression may be regulated at an epigenetic level (Lin et al., 2012); moreover, single-nucleotide polymorphisms (SNPs) in these specific set of genes are significantly associated with PD risk (Gu et al., 2015).

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