Parkinson’s disease (PD) is a neurodegenerative disease characterized by bradykinesia, rigidity, tremor, impaired balance, and non-motor symptoms such as cognitive dysfunction, sleep disturbance, autonomic system dysfunctions, pain, and mood disorders. These symptoms exhibit diurnal oscillations, so increasing attention has been paid to circadian rhythms in PD patients.

The sleep-wake cycle in PD is profoundly disrupted in both motor and non-motor symptoms [1]. The pathophysiological mechanisms are not yet clear, several evidence have shown reciprocal interactions between dopamine (DA) system and circadian rhythms. Dopamine receptor system may mediate psychostimulant-induced changes in clock gene expression [2]. On the other hand, circadian-associated genes (e.g. Clock) regulate the expression and phosphorylation of tyrosine hydroxylase that the ratelimiting enzyme in dopamine synthesis [3]. Moreover, production of melatonin, that is regulator of the sleep-wake cycle, by the pineal gland is regulated by a circadian-related heteromerization of adrenergic and dopamine receptors [4].

Neuroanatomical sites of circadian disruption in PD may be along the afferent pathways to the suprachiasmatic nucleus (SCN), within the SCN itself, or within the downstream peripheral efferents of the SCN [5]. In an alpha-synuclein overexpressing transgenic mouse study, the peak/trough expression of the clock gene PERIOD2 was normal in the SCN; however, the daytime firing rate of SCN neurons was reduced in the mutant mice [6].

Mechanisms underlying circadian fluctuations of symptoms and signs of PD remain unknown. This review summarizes the existing research on the circadian rhythms in PD especially endogenous markers, clinical symptoms, and available treatment options.

Circadian rhythms are physiological and behavioral cycles with a periodicity of approximately 24 hours, generated by the endogenous biological clock in the SCN, and can be characterized by analyzing well-established endogenous circadian markers such as melatonin and cortisol [7].

Initial studies about melatonin revealed no significant differences in the amplitude of the melatonin rhythm and its phase advance relative to healthy controls [8,9]. Later studies investigated melatonin levels in different stages of PD with or without levodopa treatment. One found that the plasma melatonin level phase is more advanced in patients receiving a dopaminergic treatment compared with untreated PD patients [10]. And the dopaminergic treatment also increases the secretion of melatonin (measured by salivary melatonin) and induces delayed sleep onset, suggesting dopaminergic therapy in PD results in an uncoupling of circadian and sleep regulation [11]. On the other hand, some studies reported reduced melatonin production and blunted melatonin rhythm in PD patients, especially with excessive daytime sleepiness [12,13].

Cortisol, another marker of circadian function, is also impaired in PD patients. Cortisol secretion is dominated by the hypothalamic-pituitary-adrenal (HPA) axis, which receives the circadian flow from the hypothalamic paraventricular nucleus. So the secretory rhythm of cortisol could be regarded as a sensitive marker of circadian function [14]. Breen et al. [12] examined cortisol levels in 30 patients with early PD, there was an elevated total serum cortisol level and half of the patients had arrhythmic cortisol profiles but with no phase shifting. Moreover, salivary diurnal cortisol level is not affected by L-dope treatment, duration, and severity of PD [15]. In an animal study, neuroendocrine abnormality of the HPA was investigated in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated dogs as a model of PD. The concentrations of plasma cortisol increased by 60% after MPTP treatment, and circadian rhythm of plasma cortisol concentration was observed. This implied that the HPA axis is modulated by the circadian rhythm and dopamine function [16].

Although these investigations suggest modifications of circadian rhythmicity in PD, results are to be interpreted with caution due to small sample sizes and study designs that reflect influences of both endogenous circadian and exogenous (e.g., light exposure, physical activity, meals, social schedules) rhythms on PD [5].

Exposure to bright light can reset the human circadian pacemaker, which controls daily variations in physiologic, behavioral, and cognitive function [38]. Light is the most important and potent stimulus to “zeitgebers” which makes circadian rhythms synchronized with the solar day. Also, exposure to light could increase retinal dopamine activity [39]. So, there were several studies using light to treatment in a variety of sleep and neuropsychiatric conditions including circadian rhythm disorders, seasonal affective disorder, and dementia [40,41]. Paus et al. [42] examined effects of bright light therapy on motor symptoms, depression, and sleep in PD in a randomized placebo-controlled double-blind study in 36 PD patients. In the results, light therapy led to significant improvement of depression, tremor, and other motor symptoms. Another exploratory study also examined the effects of bright light in PD, and documented significant improvements in depression, bradykinesia, rigidity, and dyskinesias [43]. Currently, the available pharmacological and lifestyle-based therapeutic interventions for circadian alterations have at best modest impact on the symptoms with little or no effect on the intrinsic neuropathology [44-46]. Therefore, further validation studies including larger cohorts and employing objective outcome measures are needed.

Increasing evidence suggest disruptions of the circadian system in PD, and these circadian impairments likely contribute to the progressive deterioration of the clinical signs and symptoms. From this review, we could understand about melatonin, cortisol as the circadian system markers, clinical symptoms, and bright light therapy as a treatment option. A major question which arises is whether circadian disruption is a causal factor for PD pathogenesis or a consequence of PD progression. Further systematic longitudinal investigations are needed to examine more thoroughly neuronal network underlying the generation of circadian rhythms. It will make us could develop mechanism-based therapies for circadian disruption and shed new insights about the neurodegenerative process of PD itself.