|Ahead of print publication
Role of sleep and sleep disorders on motor and nonmotor features of Parkinson's Disease
Bektas Korkmaz1, Büşra Yıldız2, Gülçin Benbir Şenel3, Derya Karadeniz3
1 Department of Neurology, Division of Clinical Neurophysiology, Diskapı Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
2 Department of Neurology, Gaziosmanpasa Training and Research Hospital, Istanbul, Turkey
3 Department of Neurology, Division of Clinical Neurophysiology, Cerrahpasa Faculty of Medicine, Istanbul University Cerrahpasa, Istanbul, Turkey
|Date of Submission||23-May-2020|
|Date of Decision||24-Jun-2020|
|Date of Acceptance||10-Sep-2020|
|Date of Web Publication||20-Jan-2021|
Department of Neurology, Division of Clinical Neurophysiology, Diskapı Yildirim Beyazit Training and Research Hospital, Ankara
Source of Support: None, Conflict of Interest: None
Purpose of the Study: Sleep problems are frequently encountered in Parkinson's disease (PD), including sleep fragmentation, rapid eye movement (REM) sleep behavior disorder (RBD), excessive daytime sleepiness, and sleep-disordered breathing. In this study, we aimed to examine the relationship between sleep structure and sleep disorders on motor and nonmotor symptoms of PD. Basic Procedures: Seventy-three consecutive patients diagnosed as having PD based on the United Kingdom Brain Bank Criteria were prospectively enrolled. Detailed histories of PD-related symptoms, sleep anamnesis, subjective evaluation of nocturnal sleep, and daytime sleepiness were made. All participants underwent one-night video-polysomnography (PSG) and multiple sleep latency test (MSLT) in a sleep laboratory. Main Findings: A significant correlation was present between female sex and RLS (P = 0.009). Age and body mass index showed no significant correlations with PD-related parameters including Unified Parkinson's Disease Rating Scale (UPDRS) scores and PSG parameters. RLS or RBD showed no significant correlation with PD-related variables. Among PSG parameters, higher REM sleep percentages showed a statistically significant correlation with increased scores of UPDRS part III (P = 0.007). A statistically significant negative correlation was present between apnea–hypopnea index and PD duration (P = 0.005), and the presence of obstructive sleep apnea syndrome (OSAS) was statistically significantly correlated with lower scores of UPDRS part II (P = 0.050). The mean sleep latency in MSLT decreased as the dose of dopaminergic treatment increased (P = 0.016). Principal Conclusions: Our study demonstrated that changes in sleep structure and sleep-related disorders observed in PD could be attributed to intrinsic disease-related properties. The presence of changes in sleep structure as higher REM sleep percentages and sleep-related disorders such as OSAS show correlations with the severity of PD.
Keywords: Parkinson's disease, sleep disorders, sleep, Unified Parkinson's Disease Rating Scale
|How to cite this URL:|
Korkmaz B, Yıldız B, Şenel GB, Karadeniz D. Role of sleep and sleep disorders on motor and nonmotor features of Parkinson's Disease. Neurol Sci Neurophysiol [Epub ahead of print] [cited 2021 Feb 26]. Available from: http://www.nsnjournal.org/preprintarticle.asp?id=307509
| Introduction|| |
Parkinson's disease (PD) is the second-most common neurodegenerative disease following Alzheimer's disease, affecting about 2% of the population aged over 65 years. The main features of PD are of motor symptoms including resting tremor, rigidity, bradykinesia, and, at later stages, postural instability., Nevertheless, nonmotor symptoms such as sleep disturbances or psychiatric disorders are commonly associated with PD, and even develop before motor problems in the prodromal stage., Sleep-related disturbances are common in PD, varying between 40% and 80% in different studies., Among these, sleep fragmentation and rapid eye movement (REM) sleep-related disturbances are most commonly encountered.,,, The relationship between PD and restless legs syndrome (RLS) or obstructive sleep apnea syndrome (OSAS), however, is not well understood.,, On the other hand, the higher incidence of these sleep disorders in patients with PD compared with the general population points to a common pathophysiologic basis. Excessive daytime sleepiness is also frequently reported in patients with PD; although a positive correlation was demonstrated between excessive daytime sleepiness and disease duration or severity, dopaminergic treatments or other therapies used as sedative-hypnotic agents may also be related to excessive daytime sleepiness.,
The relationship between PD and sleep disorders is bidirectional. The structure of sleep is disturbed in PD secondary to disease-related factors, and the risk of developing sleep disorders is increased in PD. On the other hand, disturbed nocturnal sleep or sleep-related disorders associated with PD exert negative influences on disease course.,, Changes and disturbances in sleep structure were found to correlate with a decline in cognition and development of PD-dementia. In particular, the decrease in deep non-REM sleep stage was related to PD progression, due to loss of protective function of slow delta wave sleep in beta-amyloid plaque formation via glymphatic clearance system., In light of these data, we aimed to study sleep structure and sleep disorders in patients with PD through clinical and polysomnographic evaluations, and to analyze their effects on motor and nonmotor symptoms of PD.
| Methods|| |
In our study, we prospectively examined all patients with the diagnosis of PD based on the United Kingdom Brain Bank Criteria, who were admitted to our sleep and disorders unit for 2 years. Inclusion criteria involved the diagnosis of idiopathic PD and willingness to participate. The exclusion criteria were set as follows: juvenile PD; PD of genetic basis; Parkinson-plus syndromes or parkinsonism; use of drugs or substances that might affect sleep structure, such as sedative-hypnotics or serotonin/noradrenaline reuptake inhibitors; cognitive decline severe enough not to cooperate; and unwillingness to participate. This study was approved by the local ethics committee.
The clinical evaluation of all patients was made by one neurology specialist (BK), and clinical anamnesis of movement and sleep disorders was taken in detail. Neurologic examination findings, together with the clinical history, were used to complete the Unified PD Rating Scale, and to determine the Hoehn and Yahr (H and Y) staging. Patients were instructed to use their medications regularly at the scheduled time. During scoring, the “best ON periods” of the patients were taken into consideration. The subjective evaluation of nocturnal sleep quality was tested by using the Pittsburgh Sleep Quality Index (PSQI) (5 points or more indicate poor quality of sleep), and a subjective evaluation of excessive daytime sleepiness was made using the Epworth Sleepiness Scale (ESS), which is positive if the ESS score is ≥10 points. All patients underwent one-night polysomnography (PSG) in the sleep laboratory (American Academy of Sleep Medicine type 1), by which an objective evaluation of nocturnal sleep structure was made. PSG recordings were made based on international criteria, including frontal, central, and occipital electroencephalography (EEG) placed according to the 10–20 system, right and left-sided electrooculography (EOG), superficial chin and bilateral tibialis anterior electromyography (EMG), electrocardiography (ECG), oronasal thermistor, nasal pressure sensor, thoraco-abdominal movement belts, pulse-oxymetry, oxygen saturation, and synchronized video recordings. The following parameters were obtained from PSG recordings: total recording time, total sleep time, sleep latency (SL), REM-SL, sleep efficiency (SE), duration and percentages of wakefulness and sleep stages (N1, N2, N3, and R), apnea–hypopnea index (AHI), respiratory effort-related arousal index (RERAI), mean and minimum oxygen saturation, and index of periodic leg movements in sleep (PLMSI). Using these data and clinical anamnesis, diagnoses of sleep disorders were made according to the International Classification of Sleep Disorders. The diagnosis of OSAS was made if respiratory disturbance index (RDI; AHI plus RERAI) was >5/h in the presence of clinical symptomatology and/or associated risk factors, or if RDI was >15/h. In the diagnosis of RLS and REM sleep behavior disorder (RBD), guidelines in the international classification of sleep disorders were also used.
Multiple SL tests (MSLTs) were performed during the day after PSG recording to objectively analyze excessive daytime sleepiness. During MSLT, frontal, central, and occipital EEG, right and left-sided EOG, superficial chin EMG, and ECG were monitored. Four naps with 2-h intervals were performed for 20 min (15 min after sleep onset). The evaluation of PSG and MSLT was made by a Turkish and European Sleep Expert (GBS.) who was blinded to the clinical data of the patients.
The statistical analysis of our study was made using the Statistical Package for the Social Sciences (SPSS) 18.0 program (IBM Corp, Armonk, NY). The Chi-square test was used for nominal parameters, the Mann–Whitney U-test for nonparametric variables, and the Kruskal–Wallis test for parametric variables. Correlation analysis was performed using Pearson's correlation analysis, logistic regression, and analysis of variance tests. Statistical significance was set as P ≤ 0.05.
| Results|| |
A total of 73 patients with PD were included in our study, of which the majority were males (n = 53, 72.6%). The mean age of the patients on admission was calculated as 64.0 ± 9.6 years, and the mean PD duration was 5.5 ± 5.6 years. The mean H and Y staging was 2.0 ± 0.7 (varying between Stages 1 and 3). The mean Unified Parkinson's Disease Rating Scale (UPDRS) score was calculated as 4.2 ± 3.6 points for UPDRS part I, 9.6 ± 5.5 points for UPDRS part II, 18.0 ± 11.7 points for UPDRS part III, and 4.5 ± 4.9 points for UPDRS part IV. The mean body mass index (BMI) was 29.4 ± 5.1 kg/m2. Sixty-one patients (83.6%) had nocturia, 42 (57.5%) of whom had nocturia three times or more per night.
The mean ESS score was 7.6 ± 4.6 points; twenty patients (27.4%) had excessive daytime sleepiness. The mean PSQI score was 7.8 ± 4.2 points; 42 (57.5%) patients had subjective poor quality of sleep. PSG parameters are summarized in [Table 1]. Sixty-one patients (83.6%) were diagnosed as having OSAS; of these, 49 (67.1%) patients had an AHI >15/h. Twenty-seven (37.0%) patients had a PLMSI >15/h, and 21 (28.7%) patients were diagnosed as having periodic leg movement disorder. RLS was present in 26 (35.6%) patients. REM sleep without atonia (RSWA) was detected in 32 (43.8%) patients, and REM RBD was diagnosed in 29 (39.7%) patients. The mean SL in MSLT was 8.3 ± 5.4 min; 38 patients (52.0%) had a mean SL <8 min, and seven patients (9.6%) had more than two sleep-onset REM episodes in MSLT. Only one patient (1.4%) was described as having cataplexy.
|Table 1: Polysomnographic parameters of the study population based on Hoehn and Yahr staging|
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Role of demographic factors in Parkinson's disease and sleep
Among the demographic parameters, sex showed no significant correlations with PD-related parameters such as PD duration or UPDRS scores. Regarding sleep parameters, a statistically significant correlation was observed between female sex and RLS (P = 0.009). Subjective daytime sleepiness as measured using ESS was more common in males than in females (P = 0.053). Subjective poor nocturnal sleep quality showed no difference between the sexes in patients with PD (P = 0.567). Of the PSG parameters, REM SL was longer in females (214.2 ± 124.6 min vs. 145.2 ± 85.7 min, P = 0.057), the percentage of N1 sleep was higher in males (9.3 ± 5.6% vs. 6.8 ± 3.1%, P = 0.046), and N3 sleep was lower in males (17.9 ± 10.3% vs. 14.0 ± 9.8%, P = 0.087). The AHI was also higher in males, though the difference was not statistically significant (32.3 ± 22.8/h vs. 22.6 ± 20.4/h, P = 0.073). Higher AHI was correlated with lower SE (P = 0.047), as expected. Although OSAS was diagnosed in 71.7% of males and 55.0% of females, this difference also failed to reach a statistically significant level (P = 0.180). RBD was present in 43.4% of males and 30.0% of females (P = 0.071). Age on admission did not significantly correlate with OSAS or RSWA or RBD. The mean SL in MSLT was shorter in males, though not statistically significant (6.1 ± 5.0 min vs. 10.6 ± 5.2 min, P = 0.060).
In the correlation analysis, no significant correlations were demonstrated between age on admission and PD-related parameters such as disease duration, UPDRS scores or dopaminergic treatment, and PSG parameters. The mean percentage of slow delta sleep (deep NREM, N3) decreased with increasing age (P = 0.063). AHI positively correlated with increasing age (P = 0.064). There were also no correlations between BMI and PD-related variables. The AHI increased as BMI increased (P = 0.114). Nevertheless, none of these reached statistical significance.
Increased disease duration, as one might expect, was statistically significantly correlated with higher UPDRS part II (P = 0.022) and part III scores (P = 0.055). However, PD duration and UPDRS part I showed no statistically significant correlation (P = 0.161).
Role of sleep and disorders in Parkinson's disease
Disease duration and subjective sleep parameters, including ESS or PSQI scores, showed no statistically significant correlation (P = 0.093 and P = 0.071, respectively). ESS scores increased as scores of UPDRS part II increased (P = 0.052). The mean PSQI scores revealed no correlations with UPDRS scores. The presence of RLS, similarly, showed no significant correlation with disease-related parameters including PD duration, or UPDRS scores.
In the analysis of PD duration and PSG parameters, although a trend for higher wakefulness (P = 0.096), lower percentages of slow-wave sleep (P = 0.441), and REM sleep (P = 0.757) was observed with increasing PD duration, none were statistically significant. On the other hand, a statistically significant negative correlation was found between AHI and PD duration (P = 0.005). On the other hand, no correlation between AHI and H and Y staging or UPDRS scores was present. The presence of RBD also increased with increased disease duration, but not statistically significantly (P = 0.097). The presence of RLS was not found to correlate with PD duration (P = 0.176).
Among the PSG parameters, objective measures of sleep structure, we observed that lower SE (P = 0.077) and higher percentages of wakefulness (P = 0.069) were correlated with higher scores of UPDRS part I. REM sleep percentages showed a statistically significant positive correlation with scores of UPDRS part III (P = 0.007). The presence of OSAS was correlated with lower scores of UPDRS part II (P = 0.050), but no correlation was present between OSAS and scores of UPDRS part I (P = 0.179), part III (P = 0.665), or part IV (P = 0.683) [Figure 1]. The mean UPDRS part II scores were 8.2 + 5.3 points and 11.9 + 5.2 points in patients with PD with and without OSAS, respectively (P = 0.048). PLMSI showed a positive correlation with scores of UPDRS part III (P = 0.089) but failed to reach statistical significance. All other PSG parameters failed to show any correlation with UPDRS scores. PSG parameters were not significantly associated with H and Y staging [Table 1].
|Figure 1: Unified Parkinson's Disease Rating Scale scores in patients with Parkinson's Disease with or without obstructive sleep apnea syndrome; (i) scores of Unified Parkinson's Disease Rating Scale part I, (ii) scores of Unified Parkinson's Disease Rating Scale part II, (iii) scores of Unified Parkinson's Disease Rating Scale part III, and (iv) scores of Unified Parkinson's Disease Rating Scale part IV|
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In MSLT measurements, mean SL showed no correlation with PD-related parameters including disease duration or UPDRS scores, except for dopaminergic treatment. The mean SL decreased with an increased dose of dopaminergic treatment (P = 0.016).
| Discussion|| |
To summarize the remarkable findings of our study, a significant correlation was present between female sex and RLS, but there was no correlation with PD duration. Age and BMI showed no significant correlations with PD-related parameters such as disease duration, UPDRS scores or dopaminergic treatment, and PSG parameters. The presence of RLS or RBD showed no significant correlation with PD-related variables. Subjective daytime sleepiness was much more common in the male sex, and higher ESS scores were highly correlated with higher scores of UPDRS part II. Among the PSG parameters, higher REM sleep percentages showed a significant correlation with increased scores of UPDRS part III. A significant negative correlation was present between AHI and PD duration, and the presence of OSAS was significantly correlated with lower scores of UPDRS part II. Of the MSLT measurements, the mean SL decreased as the dose of dopaminergic treatment increased.
The relationship between PD and sleep has been well demonstrated. Although it was first thought that the beneficial effects of sleep were derived from the dopaminergic synthesis and storage during sleep, further studies have proven that the benefit is beyond this hypothesis, emphasizing the role of quality of sleep., Studies have especially pointed out the role of REM sleep deprivation, upon which a dopaminergic receptor binding was increased and associated with better performance in motor functions in PD. Although there are conflicting results, our study supported this hypothesis that higher REM sleep percentages were significantly correlated with increased scores of UPDRS part III. Although increased REM sleep duration may indirectly reflect depressive symptomatology, it would not be wise to perform chronic REM sleep restriction for possible adverse effects in the long term such as psychosis or delirium; these data may be carefully evaluated in patients with PD with increased REM sleep periods, as observed in depression. In this regard, it will be of crucial importance to treat depression and normalize the effects of depression on sleep structure to obtain better motor functioning in patients with PD. On the other hand, the significant correlation with UPDRS part III indicates a more severe motor involvement and worse dopaminergic dysregulation. The loss of dopamine may result in a loss of control over REM sleep because the dopaminergic system plays a crucial role both in PD and sleep–wake cycle regulation.
A recent retrospective study reported that higher percentages of slow-wave sleep were associated with slower motor progression in patients with PD, being especially prominent in axial progression. The authors concluded that slow-wave sleep might be related to a more benign PD course because sleep fragmentation was recently associated with the pathophysiology of PD. In our study, we observed no correlation with deep NREM sleep stage and PD-duration or UPDRS scores. Although we observed a trend for increased wakefulness with increasing PD duration, and decreased SE correlated with higher scores of UPDRS part I, these correlations did not reach a statistically significant level. Disturbed nocturnal sleep as measured using the PSQI was reported to be associated with higher UPDRS scores, though no objective evaluations with PSG were made. In this study, we observed no significant correlation between PSQI and UPDRS scores. PD-related factors may also be responsible for poor-quality nocturnal sleep, such as motor fluctuations or nocturia. The worsening effect of nocturia was reported on both subjective and objective poor sleep quality. In contrast, our findings failed to show a correlation between nocturia and subjective or objective sleep parameters. On the other hand, nocturia constitutes one of the clinical symptomatologies of OSAS.,, Beyond a common neuro-anatomic basis shared between PD and sleep, associated sleep disorders may also be responsible for poor quality sleep and sleep fragmentation.
The association of PD and sleep-related disorders has mainly focused on REM-RBD, which is an important prodromal feature of neurodegeneration.,, Other sleep disorders, such as OSAS,, or RLS,, have been increasingly reported in the literature in recent years. The involvement of extra-nigral brain regions in PD, especially the brainstem, may provide biologic and clinical confirmation for the increased risk of sleep-related disorders. Furthermore, improvements in upper airway obstruction and obstructive-type respiratory abnormalities were revealed upon treatment with levodopa. By contrast, a recent meta-analysis on this comorbidity between PD and OSAS reported that patients with PD might not carry an increased risk for sleep-related breathing disorders in terms of pathophysiologic basis. In addition, the long-term impact of OSAS on motor symptomatology of PD and cognitive functions was not concluded due to a paucity of data, warranting further investigation.
A very recent meta-analysis evaluating 12 studies and 93,332 patients showed that OSAS was an independent risk factor for PD, and PD was not a risk factor for OSAS. The risk for the emergence of PD was calculated as 1.59 times higher in patients with OSAS compared with controls. No significant difference was reported between the sexes. Contrary to OSAS in the general population, OSAS in patients with PD was previously shown to be independent of known risk factors such as sex, advanced age, or BMI., This difference was explained through the hypothesis that the increased risk for OSAS was probably associated with motor incoordination and autonomic dysfunction in patients with PD. However, PD-related factors including PD duration, disease severity, or dopaminergic treatment were also shown not to be correlated with OSAS. In parallel to data in the literature, sex, age, and BMI failed to show a significant correlation with AHI or OSAS in our study. Moreover, the possible effects of sleep apnea on motor functions of PD await exploration. Although it was suggested that sleep structure and sleep-related disorders were only poorly predicted by clinical PD-related characteristics, a positive correlation was reported between poor sleep quality and disease severity evaluated using H and Y staging. Here, we demonstrated a significant correlation between lower AHI and higher PD duration. Moreover, the presence of OSAS was significantly correlated with lower scores of UPDRS part II, which includes symptoms occurring late during PD course, such as swallowing, postural instability, and freezing. These data should be confirmed by larger studies for better explanation. We may assume that because OSAS is an independent risk factor for PD via oxidative stress and neuro-inflammation, patients with PD with a lower AHI may have a milder course with longer disease duration. Another hypothesis may be that the regular intake of medications in patients with PD with longer disease duration may have at least partially neutralized the OSAS-related effects.
The relationship between PD and RLS is complicated; although a shared pathophysiology via dopaminergic and iron metabolism was suggested to at least play a part in the comorbidity, some differences in the course of the disease were also reported., A recent study demonstrated that the presence of RLS in PD was associated with worse nonmotor symptoms including depression and autonomic functions. More interestingly, the authors also reported that the H and Y stage was lower in patients PD with RLS before disease onset. In our study, however, no significant correlation was observed between the presence of RLS and PD-related clinical features, such as PD duration, and the H and Y stage and UPDRS scores.
As mentioned above, RBD is a well-defined sleep disorder in patients with neurodegenerative disorders and PD.,, RBD, together with some other biomarkers, was identified as a prodromal determinant of PD, largely because of the importance of nonmotor features in PD in terms of enlightening pathophysiology and/or guiding protective approaches with an early diagnosis. Although the role of RBD has already been proven as a significant prodromal clinical marker for the development of PD, further disease-related changes in sleep structure or medication-induced influences were not demonstrated in the early stages of PD. In our study, RBD showed no significant correlation with PD-related variables, such as disease duration or severity of disease as measured using H and Y staging and UPDRS scores. In this context, the authors hypothesize that these sleep-related symptoms might constitute integral PD-related features.
Finally, excessive daytime sleepiness is another manifestation commonly encountered in patients with PD. Excessive daytime sleepiness may develop due to multiple factors, including disease-related intrinsic properties such as disease duration or severity, effects of medications, and sleep disturbances. Increased daytime sleepiness was reported to correlate with advanced H and Y stage, daily dopaminergic dose, or use of dopaminergic agonists.,, Contrary to expectations, OSAS was not related with excessive daytime sleepiness in patients with PD., Given these differences, genetic predisposition or ethnicity-specific factors may determine the emergence of excessive daytime sleepiness. In this study, the main determinant of excessive daytime sleepiness was observed as the total daily dose of dopaminergic treatment. On the other hand, we found that excessive daytime sleepiness was not correlated with PD duration, H and Y stages, or UPDRS scores. Nevertheless, a weak correlation was present between subjective daytime sleepiness and higher scores of UPDRS part II.
| Conclusion|| |
Our study demonstrated that changes in sleep structure and sleep-related disorders, which are commonly encountered in patients with PD, might be attributed to intrinsic disease-related properties, rather than demographic characteristics. We also found that the presence of some changes in sleep structure such as REM sleep percentages and the presence of sleep-related disorders such as OSAS showed significant correlations with the severity of PD, as demonstrated through UPDRS scores.
Nevertheless, we should mention the limitations of our study. First, this study is cross-sectional in nature, not longitudinal, thus a cause-and-effect relationship could not be precisely known. Among the important determinants of nonmotor features of PD and sleep structure, psychiatric investigation, evaluation of depressive symptomatology, and cognitive status could not be made. Furthermore, many sleep-related parameters showed borderline significance with PD-related characteristics; a study with a larger population and longitudinal design would better delineate sleep-related determinants of motor and nonmotor features of PD.
Financial support and sponsorship
Our study was funded by the Department of Neurology, Faculty of Medicine, Istanbul University Cerrahpasa.
Conflicts of interest
There are no conflicts of interest.
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