How biological clocks are affected in Parkinson’s disease patients
Parkinson’s disease is a neurodegenerative disorder characterized by the death of neurons. The disease progresses with the death of dopaminergic neurons located in in the pars compacta of the substantia nigra (SNpc), located in the midbrain. The substantia nigra is located within the basal ganglia, which is responsible for the motor control pathway. Along the course of the disease, neurons die in the olfactory bulb, locus coeruleus, vagus nerve, and cortex. One of the hallmarks of Parkinson’s disease is Lewy Bodies, which are aggregates of misfolded α-synuclein protein. These misfolded protein aggregates occur due to mutations in the SNCA gene, among others.(1) The Lewy bodies can spread from the brain to the spinal cord and peripheral nervous system.
Due to the fact that the neurodegeneration is in the basal ganglia but also affects all different parts of the cortex, there are motor and non-motor symptoms. Motor symptoms include dyskinesia, tremors, rigidity, bradykinesia, and dystonia. These symptoms can proceed to other functional motor impairments in speech and swallowing.(2)
Non-motor features, often originating from the regions of damage, include psychosis, dementia, hyposmia, pain, fatigue, excessive sleepiness, and altered circadian rhythms.(3) Many of the nonmotor pathologies occur prior to the onset of motor symptoms, in what is known as the prodromal phase. The onset of many prodromal symptoms have been studied to predict later diagnosis of Parkinson’s, providing a period of time during which preventative steps or medical treatments could be started.
The development of Parkinson’s is multifactorial, but genetics plays a huge role. In addition to SNCA which produces α-synuclein, LRRK2, parkin, and GBA gene mutations are all heavily associated with Parkinson’s development.(1,4) As is the case with many neurodegenerative diseases, there is no ultimate cure. The current popular treatments include drugs that increase dopamine levels or are dopamine receptor agonists.
Rhythmic States and Impacts of Disruption
Issues related to sleep and circadian rhythms fall within the category of nonmotor symptoms in Parkinson’s disease. There are distinct sleep, fatigue, and hormone patterns expected of normal and healthy patients, which differ from those of Parkinson’s disease.
Sleep is one particular rhythm that is different in Parkinson’s patients. Healthy patients typically feel most sleepy during the night hours, and complete their daily commitments in work and at home during the day. They feel most productive during the day, and recharge at night. Most Parkinson’s patients have abnormalities in their sleep rhythms, with 64% self-reporting at least one sleep problem. Insomnia, REM behavior disorder, excessive daytime sleepiness, and restless leg syndrome are a few of these problems, and they compromise patients’ quality of life.(5) While they may occur before the onset of Parkinson’s, the sleep conditions typically worsen as Parkinson’s advances in patients.
Insomnia is a diagnosis characterized by recurrent difficulty going to sleep, or staying asleep. Parkinson’s patients tend to show symptoms of this by having many more awakenings during the night than control patients.(6) Questionnaires have shown that Parkinson’s patients suffer from severely disrupted sleep during the night, even if they do not have a formal diagnosis of insomnia. Correlations have also been identified between insomnia severity and nonmotor symptom severity, including fatigue and depression.(7)
The most common parasomnia in Parkinson’s patients is REM Sleep Behavior Disorder (RBD), which typically involves acting out dreams during the night, and engagement of muscle tone during REM sleep. A typical REM sleep cycle involves active blocking of muscle activity and muscle twitches, so this activity can be dangerous and disturbing for patients. RBD has been studied to have the most predictive value in identifying risk for Parkinson’s development, and most patients with idiopathic RBD have shown to be in the prodromal phase of a Lewy Body Disorder. Many nonmotor symptoms of Parkinson’s patients are thus evident in patients with RBD even before disease onset — they tend to have sympathetic and parasympathetic dysfunction, reduced sense of smell, a slowed EEG activity.(8) The slowed EEG activity indicates that PD patients with RBD may be losing cortical neurons even earlier than PD patients without RBD.
About one third of PD patients have RBD episodes every week, and they tend to wake up in the night to perform activities in their daily diurnal routine, such as singing or cooking. RBD’s etiology is still not completely understood, but in Parkinson’s it seems to originate from a lesion in the subceruleus nucleus of the brain. Lesions in the cat and rat equivalents of the subceruleus nucleus that descend through the pons and medulla have shown to result in loss of muscle atonia during sleep, similar to RBD.(9) Imaging has shown that Parkinson’s patients with RBD have less dopamine-responding transporters in the striatum of their brains.
Excessive daytime sleepiness (EDS) is a functionally impairing disturbance of the sleep-wake cycle in patients. In patients with EDS, a great difference in process S and process C persists during the day, and sleepiness does not wear off. In PD patients, EDS increases the frequency of patients getting into automobile accidents by over 75%. EDS is another symptom that, like RBD, can predict disease onset in the prodromal phases. In a longitudinal study of men, it was found that those with EDS were over 3 times more likely to develop PD. Men with PD and EDS also demonstrated higher levels of napping, insomnia, grogginess, and nocturnal awakening than men with just PD (Figure 1).(10)
Most PD patients with EDS can fall asleep extremely fast — in one study patients fell asleep in about 5 minutes every 3 hours, and 41% fell into REM many times. More frequent daytime sleepiness in these patients is correlated with more advanced stages of Parkinson’s. Although strong levels of daytime sleepiness can be triggered by insomnia or other sleep disturbances during the night, many PD patients are sleepier during the day even if they sleep longer during the night.(10) The mechanisms of EDS development in PD patients seem to involve molecular interactions with the drugs that patients take. For many, the dopamine agonists trigger daytime sleepiness and have a sedative effect.
Restless leg syndrome (RLS) is a condition in which patients have an urge to be moving their legs during periods of rest. This typically starts or worsens in the night. Restless leg syndrome is caused by the dopaminergic dysfunction in PD, which is confirmed by the fact that dopaminergic drugs can improve RLS symptoms in patients. Those with RLS seem to have a higher risk of developing PD than those without PD. The incidence and severity of RLS also appears to increase as PD advances in stages.(11) PD patients with RLS have a higher incidence of several nonmotor symptoms of PD, such as fatigue, depression, and sympathetic dysfunction.
Circadian Rhythms and Hormones
PD patients have abnormalities in several of their circadian rhythms, but is important to recognize the confounding effects of pharmacological therapies that patients may be on. In addition, all of the circadian differences noted between PD and control patients are in peripheral clock outputs, and not central clock measures because brain tissue in living patients cannot be obtained.
Urination and urine production is a circadian rhythm that is typically more active during the day and less active during the evening. Many patients with PD have an abnormal alteration in this rhythm with the presence of nocturia, or a higher than normal need to urinate in the night. It is a very common urinary symptom in patients, and increases with age and PD disease severity.(12)
In addition to the EDS condition mentioned earlier, PD patients generally seem to engage in more activity than controls at night and reduced activity during the day. Over the course of each day, patients endure a deterioration in motor performance and activity, independent of the timing of their levodopa or drug therapy.(10)
One of the prevalent nonmotor symptoms in PD patients is autonomic system dysfunction, and this seems to follow a circadian rhythm. Typical humans endure a mild reduction in blood pressure during the night, and a mild increase after eating meals. All PD patients in one study conversely showed hypertension during the night, and hypotension after meals. In addition to this, patients had a reduced cardiovascular low frequency power to high frequency power ratio than controls during the day and night.(12)
One important area affected in PD due to neurodegeneration is contrast sensitivity in the visual system. In an experiment with rats, it was shown that there was a circadian rhythm of dopamine synthesis in the retina that induces a contrast sensitivity rhythm. This rhythm seems to be altered in PD patients, as they have impaired contrast sensitivity compared to matched controls at all hours of the day.(12)
Endocrine rhythms are an easily measurable way to analyze the differences between PD and healthy patients. Melatonin is a hormone that is important for timing sleep and wake, typically spiking during the evening. Several studies have investigated melatonin concentrations over a constant interval to generate curves for patients and controls. They found blunted melatonin peaks in PD patients compared to controls, and additional blunting for PD patients with EDS (Figure 2).(13)
PD patients also have continuously high levels of serum cortisol, a hormone that plays a role in arousal and anticipation of anxious or stressful events.(14) This occurs because patients tend to have fewer pulses with more release per pulse than controls. Body temperature rhythms are also disturbed in PD patients. In one study, Parkinson’s patients had a lower nocturnal body temperature than controls, but the reduction from their diurnal average temperature was also lower than controls.(12)
Clock genes, and Peripheral and Central Clocks
Due to the host of circadian abnormalities in Parkinson’s which collectively worsen over time, a term called chronodegeneration has been used to characterize it. In order to study the etiology of these different rhythm and sleep disruptions, studies have been conducted regarding clock genes. SCN and cortical rhythms which represent the central clock are not possible to measure in living humans, so most experiments study gene rhythmicity in peripheral clocks in skin or blood tissues. This was solidified after experiments showed that clock genes had circadian rhythms of expression in blood cells and could be a way to evaluate the robustness of the circadian clock. The mechanisms and changes in the SCN due to PD are thus being interpreted via rhythms that are outside the central clock. It is also clear that the research in this area is sparse and requires more work before it can help in the realm of therapy.
Most studies evaluating clock genes looked at expression of Bmal, Per, Clock, and supplementary genes such as Rev-Erbα. Bmal and Clock are genes that influence expression of Per and Cry amongst others, which when phosphorylated engage in a feedback loop with Bmal and Clock. These genes have idiosyncratic peaks in expression and circadian rhythms of expression. One study that reported gene expression relative to control β-actin found that in PD there was not a circadian variation in Bmal expression as seen in healthy controls. With regard to Per2 and Rev-Erba, PD patients had increased expression at 4 am but otherwise normal rhythms.(14)
Two other studies that evaluated clock gene expression in leukocytes found that Bmal expression was lower in PD patients, and that Bmal levels decreased as Parkinson’s severity increased.(15) One leading hypothesis for the alteration of Bmal expression was altered patterns of methylation of clock genes in PD, although a study investigating this showed that most clock genes are not methylated to begin with, except for the NPAS2 promoter.(16) Another explanation for this related to the idea that dopamine interacts with the Bmal and Clock circuit, and thus loss of dopaminergic neurons damages the SCN and central clock mechanism.(17) Scientists are also beginning to investigate that that the sleep disruptions in PD can possibly accelerate changes in clock gene expression.
The separation of roles of peripheral and central clocks and how they affect PD is still being elucidated. The experimental limitations in alive human subjects will make it challenging to find out what changes in the central clock exist. At this point, it seems that the sleep disturbances in PD are due to changes in the neural circuits with degenerating dopaminergic neurons. Disjunction between the pyramidal and extrapyramidal tracts are hypothesized to cause the different sleep disorders that PD patients tend to have. The reduced output of hormonal circuits like melatonin are thought to be governed by SCN disruption. An experiment with mice indicated that heightened expression of α-synuclein associated with a slower SCN firing weakens the potential for communication between the central and peripheral clocks.(18)
Therapy and Pharmacology
Through the symptoms of PD patients and their comorbidities, it is clear that PD is a circadian rhythm disorder, meaning that the internal circadian rhythm is not appropriately entrained to the light-dark cycle. An important area in PD therapy that relates to circadian rhythms is chronopharmacology. Several drugs and dopaminergic agonists currently exist for PD patients to take in order to alleviate their symptoms, but they are best used or administered at specific times. In PD patients, the absorption of levodopa is much faster if taken while seated and during the day than lying down at night. This is considered in the current timing of administration of medication for patients.(19)
The mechanisms behind some PD drugs’ interactions are based on altering circadian rhythms and their coordination. Dopaminergic treatment has shown to result in increased melatonin levels, as well as a delay in sleep onset with regard to the evening melatonin peak. This study suggests that dopaminergic therapy may be uncoupling process C and process S in order to help the endogenous system reset and re-entrain to light and dark. Sleep onset is even more disrupted than baseline in PD at first but is eventually alleviated, so the endogenous circadian system gradually resets.(20)
Light is independently being studied for treatment in PD, given that it is the main means of entrainment in the SCN, and can help promote alertness. Studies have shown that light therapy in PD patients can improve EDS symptoms, recurrent awakenings during the night, and capacity to fall asleep easily.(21) In addition to studies evaluating nonmotor activity, others have shown that light therapy can help the motor symptoms of PD.(22)
Aside from usage to alleviate symptoms in PD patients, light waves have emerged as an avenue for stopping disease onset or progression. Low levels of near infrared light (NIr) have shown neuroprotective effects that can slow the death of neurons. With NIr the capacity to slow down neuronal death is achieved by restoring energy production in cells. This has been shown in vitro to increase neuron ATP levels and mitochondrial transport. In vivo models have shown that NIr can help prevent future neuron death and help damaged neurons recover.(23)
Chronotherapeutics, as they have been frequently referred to, are important to continue study with regard to Parkinson’s. They rely on managing stimuli and mechanisms that occur daily and regularly, so they do not have to involve the pharmaceutical market. They also do not require large swaths of time or excessive human and financial resources, which continue to be limitations in the study of PD.
The future of circadian rhythm-related therapy for Parkinson’s is twofold. One area of research that shows promise is encouragement of positive sleeping habits, despite the discouragement that comes with frequent disturbances every night. Education about the importance of lying on a bed for anything other than sleep, stopping screen time much earlier than bed time, and support from families can all help in this. While it might not help PD motor symptoms, any improvement in the capacity to rest at night and regain some energy during the day can act in a positive feedback loop and improve most sources of nonmotor symptom discomfort for patients. A second novel area is that is just starting to be explored in PD is how to combat seasonal variation in symptoms throughout the year. PD nonmotor symptoms are much worse in winter than summer, when there is more light. These worsening symptoms need to be accommodated by altering medication dosages and providing emotional support.(24)
Chronotherapeutics will prove to be especially important in diseases like PD that are known to have major circadian disruptions. Perhaps the timing of administration of future treatments will affect the speed of clock realignment and mitigation of symptoms in patients.
Figure 1: Incidence of sleep-related symptoms in PD patients and controls
(Abbott et al. 2005)
Figure 2: Melatonin Peaks in PD patients and Controls
(Videnovic et al. 2014)
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