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Abstract
Objective To investigate the prevalence and clinical correlates of video polysomnography (vPSG)-confirmed rapid eye movement sleep behaviour disorder (RBD) in patients with major depressive disorder (MDD).
Methods This is a clinic-based two-phase epidemiological study. In phase 1, patients with MDD were screened by a validated questionnaire, RBD Questionnaire-Hong Kong (RBDQ-HK). In phase 2, a subsample of both the screen-positive (RBDQ-HK >20) and screen–negative patients with MDD underwent further clinical and sleep assessment (vPSG) to confirm the diagnosis of RBD (MDD+RBD). Poststratification weighting method was used to estimate the prevalence of MDD+RBD. The total likelihood ratio and the probability of prodromal Parkinson’s disease (PD) were calculated from prodromal markers and risk factors, as per the Movement Disorder Society research criteria.
Results A total of 455 patients with MDD were screened (median age (IQR)=52.66 (15.35) years, 77.58% woman, 43.74% positive). Eighty-one patients underwent vPSG and 12 of them were confirmed MDD+RBD. The prevalence of MDD+RBD was estimated to be 8.77% (95% CI: 4.33% to 16.93%), with possibly male predominance. MDD+RBD were associated with colour vision and olfaction deficit and a higher probability for prodromal PD.
Conclusions Almost 9% of patients with MDD in the psychiatric outpatient clinic has vPSG-confirmed RBD. Comorbid MDD+RBD may represent a subtype of MDD with underlying α-synucleinopathy neurodegeneration. Systematic screening of RBD symptoms and necessity of vPSG confirmation should be highlighted for capturing this MDD subtype with a view to enhance personalised treatment and future neuroprotection to prevent neurodegeneration.
- depression
- sleep disorders
- neuroepidemiology
Data availability statement
Data are available upon reasonable request. The data supporting the findings in this study might be requested from the Li Chiu Kong Sleep Assessment Unit, Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, via the corresponding author of this article.
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Introduction
Depressive disorders, affecting nearly 300 million people globally, has become the third worldwide leading cause of disability.1 The heterogeneity in depression has significant implications for aetiology, treatment responses and long-term outcome. It has been suggested that ‘later-onset’ depression was more likely associated with future risk of neurodegeneration.2 Nonetheless, from both depression and neurodegeneration perspectives, a more specific feature or/and biomarker is needed for the identification and management of this subtype of neurodegeneration-related depression.
Rapid eye movement (REM) sleep behaviour disorder (RBD) is a novel parasomnia characterised by the recurrent dream enactment behaviours leading to repetitive sleep-related vocalisation/motor behaviours and sleep-related injuries (SRI)/violence as accompanied by the loss of muscle atonia in REM sleep (i.e., REM sleep without atonia,RSWA) documented by video-polysomnography (vPSG).3 In particular, over 90% of patients with idiopathic RBD (iRBD) would develop into α-synucleinopathy neurodegeneration, of which the majorities are Parkinson’ disease (PD) and dementia with Lewy bodies (DLB).4 The prevalence of RBD in the general population has been estimated at about 1%.5 On the other hand, RBD features occurring in a psychiatric population, especially in patients with major depressive disorders (MDD), has been reported.6 By using recent 1-year history of SRI as a proxy item for RBD symptoms, the lifetime prevalence of RBD was previously estimated at 5.8% in psychiatric outpatients (6.8% in MDD subgroup).6 However, the genuine prevalence of vPSG-confirmed RBD in the patients with MDD (MDD+RBD) might have been underestimated, as the milder forms of RBD without SRI or those without active SRI in recent 1 year were not taken into consideration.6 Moreover, it remained uncertain on whether the occurrence of RBD in patients with MDD was simply a drug-induced condition as antidepressants especially selective serotonin reuptake inhibitors (SSRIs) may enhance the skeletal muscles tone resulting in RSWA or it might reflect an early phase of neurodegeneration in a subset of patients with MDD.7
With a validated screening questionnaire followed by vPSG confirmation, we conducted this two-phase study to (1) determine the prevalence of MDD+RBD; and (2) investigate the clinical correlates especially the risk of neurodegeneration in patients with MDD+RBD.
Methods
Phase 1: screening of RBD in outpatients with MDD
A consecutive sample of patients with MDD was recruited from July 2016 to November 2017 at the regional outpatient psychiatric clinic affiliated to the university, with the completion of a self-administered questionnaire screening for RBD and other sleep disturbances (online supplemental list 1).
Supplemental material
The inclusion criteria were: (1) age between 18 and 65; (2) diagnosis of MDD based on the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-Ⅳ) criteria. The exclusion criteria included: (1) any documented lifetime or current diagnosis of bipolar disorders, schizophrenia, post-traumatic stress disorder (PTSD) or substance abuse; (2) pre-existing neurological diseases that could account for RBD (e.g., narcolepsy, stroke, neurodegeneration); (3) unable to provide valid informed consent.
RBD Questionnaire-Hong Kong (RBDQ-HK) is a 13-item questionnaire with lifetime and recent 1-year subscales that covers both dream-related and behavioural factors in RBD. Previous validation study suggested a cut-off at 20/21 to diagnose RBD in psychiatric patients.8
Further clinical evaluation
A total of 302 patients agreed for further clinical evaluation, in which, the psychiatric diagnoses were ascertained by the Structured Clinical Interview for DSM-IV Axis I Disorders.9 The severity and atypical symptoms of depression were assessed using the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement (SIGH-ADS) by experienced psychiatrists.10 The patients also completed additional questionnaires related to sleep, lifestyle factors and exposure history (e.g., head injury). Relevant medical information was obtained in a well-established electronic healthcare database.
Phase 2: ascertainment of RBD and prodromal markers assessment
Screen-positive (RBDQ-HK >20) patients were invited to attend the phase 2 study for vPSG assessment in the sleep laboratory, along with a proportion of randomly selected screen-negative patients.
VPSG parameters and RSWA scoring
The vPSG parameters and the scoring method for RSWA were described in detail in our previous studies.11 12 In brief, sleep stages, respiratory events, arousals and movement events were scored according to the American Academy of Sleep Medicine criteria (2012) with the allowance of RSWA.13 Patients were asked to continue their usual medication during the study. In case of prominent apnea/hypopnea events (Apnea-Hypopnea Index ≥15), patients would be invited for a second night vPSG with the titration of continuous positive airway pressure, and their second night vPSG data will be used for scoring. The electromyography (EMG) activity level on the chin muscle in REM sleep was used to determine the severity of RSWA, as chin EMG was suggested to provide the highest phasic EMG activity.14 RSWA scoring was based on a 30-second epoch with the exclusion of the artefacts associated with arousals and respiratory events. A tonic epoch was defined when there is an elevation of EMG amplitude at least twice the background lasting >15 s. Phasic EMG activity, defined by any EMG burst exceeding four times the background that lasts 0.1–5 s, was scored based on 3-second mini epoch. The time of phasic mini epoch or tonic epoch over the whole REM period represent the phasic or tonic EMG level, respectively. Total EMG level is the sum of phasic and tonic EMG level.
Prodromal markers measurements
Risk factors and prodromal markers related to RBD and neurodegeneration were measured across various domains. Autonomic dysfunction symptoms were measured with Scales for Outcomes in Parkinson’s disease-Autonomic dysfunction (SCOPA-AUT) scale,15 and the orthostatic blood pressure change was further measured within 2 min of standing up from the supine position (after 5 min rest). Constipation symptom was suggested by the frequency of bowel opening (≤2/week) or use of laxatives (≥1/week), and the hardness of stool with the Bristol Stool Chart (type 1–2).16 Subtle motor dysfunction was assessed using the Unified Parkinson’s Disease Rating Scale part III by trained personnel who were blind to the diagnosis.17 A locally validated Olfactory Identification Test was used to evaluate the olfaction.18 Farnsworth-Munsell 100-hue test was used to test the colour vision deficit.19 Global cognition was assessed by the Montreal Cognitive Assessment (Hong Kong version).20 To reduce the risk for type 1 error caused by multiple comparisons of prodromal markers and risk factors, the latest Movement Disorder Society (MDS) research criteria was employed to estimate the total likelihood ratio (LR) and probability for prodromal PD.21
Definition of MDD+RBD and non-RBD
The diagnosis of RBD was made according to the International Classification of Sleep Disorders, Third Edition criteria.22 The recurrent dream enactment behavioural symptoms of RBD were clarified by psychiatrists who were experienced in sleep medicine, with the aid of Diagnostic Interview for Sleep Patterns and Disorders23 and cases notes review. As antidepressants may increase EMG activities,24 and in our previous case–control study, the mean total chin EMG level in MDD+RBD and MDD control were 22.7% and 9.9%, respectively,25 we adopted a cut-off of 18% for the total chin EMG level to diagnose MDD+RBD.26 As a result, the vPSG results could be classified into: (1) MDD only (negative clinical RBD symptoms and total chin EMG <18%); (2) probable RBD (positive clinical RBD symptoms but total chin EMG <18%); (3) RSWA (negative clinical RBD symptoms but total chin EMG ≥18%); (4) MDD+RBD (i.e., confirmed RBD, positive clinical RBD symptoms and total EMG ≥18%). To simplify the description, category (1)–(3) were taken together as the non-RBD group.
Data analysis
Sample size estimation
The estimated prevalence of RBD in patients with MDD in our previous survey was 6.8% (p). With 95% CI, a desired marginal error of 0.05(d), and an estimated design effect of 3 (DEFF), the minimum number of patients with MDD would be 293, according to the following formula:
Poststratification weighting
In consideration of the selection strategy in phase 2, we adopted a poststratification strategy in estimating the prevalence of vPSG-confirmed RBD.12 Patients were stratified into four strata according to the screening results and sex. The weight was calculated using the following formula (taking the ‘male with confirmed RBD’ stratum as example):
The weighted prevalence was calculated by the weighted sum of MDD+RBD divided by the total sample with vPSG and presented with the Wilson score 95% CI. We also calculated the weighted prevalence and 95% CI for different sex groups and for probable RBD.
Statistical analysis
The SPSS software (V.26, IBM Corp) and R project (R Foundation for Statistical Computing. URL http://www.R-project.org/) were used to perform the statistical analysis and plotting. The Shapiro-Wilk test and Q–Q plots were used to test the distribution of the continuous data, and the independent t-test or the Mann-Whitney U test was used where appropriate. Categorical variables were compared using χ2 or Fisher’s exact test where applicable. Generalised linear models with link function for linear or binary logistic regression were used to adjust for potential confounders. Among the sample with vPSG, P weighted was also calculated with cases weighted by the weight variable when conducting respective tests in SPSS. A two-tailed p value <0.05 was considered statistically significant for all tests.
Results
Description of the sample in phase 1
Figure 1 shows the flowchart of the study. In phase 1, we approached 751 patients attending psychiatric clinics with depressive complaint, and 504 of them (mean age=49.85 years, 77.0% women, response rate 67.1%) consented to this study. After the diagnostic interview and review of medical records, 48 patients were excluded for having narcolepsy (n=1), stroke (n=1), PTSD (n=16), substance abuse (n=11), bipolar disorder (n=17) and not having lifetime diagnosis of MDD (n=2). One patient was excluded for not completing the RBDQ-HK. The remaining 455 eligible patients with MDD (median age (IQR)=52.66 (15.35) years, 77.58% women) were determined as the whole screen sample. Of them, 302 patients (54.04 (13.12) years, 76.49% women) completed additional questionnaires and clinical interview and was regarded as the description sample. In both the whole screen sample and the description sample, the screen-positive patients were more likely to be men, older at depression onset (age difference around 2 years), had higher suicidal risk, more likely to report SRI and other sleep disturbances, including nightmares, sleep talking and sleepwalking. (table 1 and online supplemental table 1).
Demographic characteristics and self-reported sleep-related disorders in the screen sample of patients recruited in phase 1 (N=455)
Flowchart of the study. MDD, major depressive disorders; PSG, polysomnography; RBD, rapid eye movement sleep behaviour disorder; RBDQ-HK, RBD Questionnaire-Hong Kong; SIGH-ADS, Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement.
Among the description sample (N=302), screen-positive patients consisted of more current smokers (14.39% vs 7.36%) and were more likely to report head injury history (12.23% vs 6.13%), but the difference became non-significant after adjusting for demographics (Padjusted =0.12 and 0.084, respectively). The screen-positive patients also presented with more severe depressive symptoms (Hamilton Depression Rating Scale 17 items score, 12.00 (9.00) vs 10.00 (11.00), Padjusted =0.014), more atypical depressive features (4.00 (4.00) vs 3.00 (4.00), Padjusted =0.038) than their counterpart. Besides, a higher rate of daytime sleepiness (73.38% vs 51.53%, Padjusted =0.001) and probably more insomnia (87.77% vs 74.23%, Padjusted =0.061) were present in the screen-positive patients (online supplemental table 1).
Prevalence of vPSG-confirmed RBD in patients with MDD
A total number of 81 patients (54.08 (12.40) years, 65.43% woman, 51 screen-positive) completed vPSG and neurocognitive assessments in the second phase study. RBD was confirmed in eight men and four women screen-positive patients with MDD (i.e., MDD+RBD, RBD onset age=53 (11) years, three patients reporting RBD onset before starting antidepressants), and the rest 69 patients were classified as non-RBD (including 26 MDD only, 39 probable RBD, 4 isolated RSWA). The weighted prevalence of MDD+RBD was 8.77% (95% CI: 4.33% to 16.93%), with a seemingly male predominance (men vs women: 19.60% (95% CI: 7.49% to 42.33%) vs 5.63% (95% CI: 2.09% to 14.29%)), although it was nearly statistically significant (Pweighted =0.079, table 2). In addition, the weighted prevalence of probable RBD is 38.42% (95% CI: 28.58% to 49.31%), and for isolated RSWA is 7.66% (95% CI: 3.60% to 15.52%).
Clinical and polysomnographic characteristics of patients from phase 2 (classified as MDD+RBD vs non-RBD)
Risk factors associated with MDD+RBD
Among the 81 patients with vPSG assessment, there was no significant difference in the onset age of depression, the severity of depression or the type of antidepressant used between MDD+RBD and non-RBD (table 2 and online supplemental table 2), except that MDD+RBD had a lower body mass index (Pweighted =0.015). As for the RBD symptoms, it was the behavioural (dream enactment) factor (Pweighted =0.022) but not the dream-related factor that differentiated MDD+RBD from non-RBD. We also noted that patients with MDD+RBD were more likely to report sleepwalking than their non-RBD counterparts (41.67% vs 7.25%, Pweighted =0.0073; online supplemental table 2). There was a seemingly higher rate of head injury with loss of consciousness (25.00% vs 7.25%), higher rate of sleep-related eating episodes (25.00% vs 13.04%) and lower rate of diabetes (0 vs 27.54%) in MDD+RBD, although without statistical significance (Pweighted =0.14, 0.065 and 0.19, respectively; online supplemental table 2). As for the vPSG parameters, a possibly lower arousal index (14.55 (13.35) vs 18.60 (12.50), Pweighted =0.055), a possibly higher tonic (%, 6.63 (7.07) vs 0.00 (1.47), Pweighted =0.087) and a significantly higher phasic (%, 19.32 (14.11) vs 5.30 (5.58), Pweighted <0.001) and total (%, 27.21 (16.69) vs 6.05 (7.06), Pweighted <0.001) chin EMG level were found in MDD+RBD (table 2).
Prodromal makers associated with MDD+RBD
Table 3 listed out the prodromal markers of PD according to MDS research criteria for prodromal PD. MDD+RBD group made more errors in the colour vision test (158.00 (60.00) vs 150.00 (93.00), Pweighted =0.023) and scored poorer in the olfaction identification test (4.00 (3.00) vs 5.00 (1.75), Pweighted =0.032). Moreover, patients with MDD+RBD presented a higher total LR for prodromal PD (Pweighted <0.001, figure 2A), and this difference in total LR remained even after excluding the fraction of LR that was contributed by the vPSG-confirmed RBD (Pweighted =0.026, figure 2B). Thus, the probability for prodromal PD (age has been considered in the calculation of probability) was higher in the MDD+RBD group than the non-RBD group (Pweighted <0.001, figure 2C).
Comparison of individual prodromal markers in the patients from phase 2 (classified as MDD+RBD vs. non-RBD)
Pirate plots of the log-total likelihood ratio (LR) and probability of prodromal Parkinson’s disease (PD) among patients with major depressive disorders with and without RBD. (A) Shows the log(total LR) of prodromal PD in the non-RBD and confirmed patients with RBD (median (IQR), 0.23 (0.46) vs 2.91 (1.66), Pweighted <0.001); (B) shows after excluding the LR of confirmed RBD, the log(total LR) of prodromal PD in the non-RBD and confirmed patients with RBD (0.28 (0.56) vs 0.87(1.28), Pweighted =0.026); (C) shows the probability of prodromal PD in the non-RBD and confirmed patients with RBD (%, 0.38 (1.4) vs 82.42 (59.15), Pweighted <0.001). RBD, rapid eye movement sleep behavioural disorder.
Discussion
This two-phase clinical epidemiological study determined the prevalence of vPSG confirmed RBD in MDD (MDD+RBD) with validated screening questionnaire, structured clinical interview for RBD and depressive features, confirmatory vPSG study and comprehensive measurement of risk factors and neurodegenerative markers. The prevalence of MDD+RBD was around 9%, with marginally male predominance. Later onset and more severe depressive symptoms were potential risk factors for the RBD features in MDD. Besides, MDD+RBD harboured prodromal markers of α-synucleinopathy neurodegeneration (colour vision and olfaction deficit) and exhibited a higher total LR and a higher probability for prodromal PD as per the MDS criteria. Overall, it suggested that there is a subtype of MDD which harbours RBD related to the underlying α-synucleinopathy neurodegeneration.
The current estimated prevalence of MDD+RBD was several times higher than that of RBD in the general population,5 which highlighted the susceptibility for RBD in patients with MDD. Nonetheless, this study sample represented the patients with non-remitting depression that requires follow-up in the specialist clinic, which reflected relatively more persistent and deteriorating pathological changes in the brain when compared with the general population. According to the Braak et al staging model, the PD-related pathology progresses caudal-rostrally to the brainstem and affected the Raphe nucleus and coeruleus–subcoeruleus complex, leading to the symptoms of depression (±anxiety) and subsequent RBD (stage 2).27 Previously we found a slightly higher score for anxiety and depression symptoms in patients with psychiatric disorders comorbid with RBD (mostly MDD+RBD) when compared with the psychiatric control (mostly MDD).28 In the current study, more severe depressive symptoms, atypical depressive features, a higher rate of past suicidal attempt and more nightmare symptoms were associated with possible RBD. There remained a possibility that the nightmares and sleep disturbances in RBD could aggravate the severity of depression and suicidality per se,29 but the underlying α-synucleinopathy predisposition in patients with MDD who presented with RBD features may also contribute to a profile of more severe depression with atypical features.
In general, depression onset at an older age was more likely associated with neurodegeneration including PD and dementia.30 A recent cross-sectional study reported that patients with depression onset ≥55 years were associated with both non-motor (e.g., RBD symptoms) and motor prodromal markers of PD and abnormal 123I-ioflupane single photon emission computed tomography (SPECT) findings when compared with healthy control.31 In the current study, we found that patients with MDD who presented with possible RBD were around 2 years older at the onset of depression than those without, although this difference was not statistically significant among the vPSG sample. Nonetheless, these seemingly later-onset MDD together with more deficit in colour vision and olfactory function, a higher risk for prodromal PD (even after excluding the contribution of RBD diagnosis) among those vPSG confirmed patients concurred to the presence of neurodegenerative predisposition in this subgroup MDD+RBD. The findings echoed our previous positron emission tomography (PET) imaging study, in which patients with MDD+RBD presented with a lower striatal presynaptic dopamine uptake level and poorer olfactory function when compared with controls.25 Moreover, around one-third of the patients with MDD+RBD reported RBD onset before the initiation of antidepressants in both studies, and the types of antidepressant were not associated with the occurrence of RBD.25 Collectively, comorbid RBD may highlight a subtype of MDD with underlying α-synucleinopathy, and the role of antidepressants is more likely to unmask the neurodegenerative predisposition in these patients with MDD, although there remained a possibility of antidepressant-induced RBD features (which might be reversible) especially among those with probable RBD in our study.
On the other hand, it remained unclear which subtype of α-synucleinopathy these patients with MDD+RBD will ultimately develop. Previous study suggested that the presence of comorbid depression might predict faster conversion to PD in patients with typical iRBD, although some inconsistent finding was reported.32 33 Indeed, given the current finding that MDD+RBD is associated with worst colour vision performance (suggesting visual processing dysfunction), and that psychiatric-onset presentation could be one of the prodromal phase of DLB,34 it is unclear whether the RBD in the context of MDD might be more suggestive for future risk of DLB. Further studies, for instance, longitudinal follow-up of those patients with MDD +RBD, family-based studies, in vivo neuroimaging studies, as well as α-synuclein pathological studies (e.g., colon biopsy) are warranted to confirm the long-term α-synucleinopathy outcome. From the clinical management of MDD perspective, it would be important to look at whether this presumed neurodegeneration-related subtype of depression, MDD+RBD, would respond better to dopaminergic antidepressants, such as bupropion. Furthermore, the need for early neuroprotection to prevent progression to overt neurodegeneration in this group of patients with MDD+RBD is highly pertinent.
Some risk factors that were initially associated with possible RBD were not ascertained in confirmed RBD, which may likely be related to the limited sample size in the second phase assessment. Nonetheless, there were some robust risk factors found in this study. Head injury, which is recognised as a risk factor for RBD,35 was also likely to be associated with RBD features in the patients with MDD. In addition, the coexistence of self-reported sleepwalking and RBD features in this study might indicate a common sleep instability and arousal disturbance in the depressed patients (the use of both benzodiazepine and z-hypnotics was not increased in the patients with MDD+RBD, online supplemental table 2).6 36 As sleepwalking was suggested to be associated with a phenoconversion of DLB in the clinical cohort of iRBD,37 further outcome study will be needed to investigate whether sleepwalking in patients with MDD+RBD is associated with potential risk for DLB.
Despite merits in the quantification of RBD symptoms in a sufficient sample size of outpatients and the inclusion of both screen-positive and screen-negative results in the vPSG confirmation, this study had several limitations. First, the sample size in phase 2 was only modest, which limited the power to adjust for confounders (e.g., for the comparison of prodromal markers). Second, the frequent presence of nightmare features in MDD may also contribute to the high rate of the false-positive RBD in our study38 and highlight the need for further vPSG confirmation for patients presenting with RBD symptoms. Third, male sex with higher RBDQ-HK scores was over-represented in phase 2, and therefore a poststratification weighting strategy was to balance this disequilibrium. Fourth, our predefined cut-off at 20/21 was previously validated with 27 psychiatric patients with RBD features in sleep clinic,8 but the current positive predictive value (23.53%) of the questionnaire would be deemed to be much lower in view of relatively low prevalence of RBD in the psychiatric population.39 With this consideration, we enrolled patients with mixed screening results into vPSG confirmation. Finally, we did not record the family history of RBD or PD/dementia for this study, considering that there is a confirmed familial-clustered spectrum of α-synucleinopthy in iRBD,12 it would be of interest to investigate whether such features will aggregate in the families of MDD+RBD.
Conclusion
The prevalence of RBD in patients with MDD is much higher than that of the general population. This urges diligent identification of RBD-susceptible patients with MDD, especially for those with later-onset depression, with systematic screening of RBD symptoms, followed by vPSG confirmation. MDD+RBD harbours prodromal markers of α-synucleinopathy and a higher probability for prodromal PD, probably heralding increased risk for future neurodegeneration. Prospective follow-up of these patients with MDD and future planning of neuroprotection to prevent neurodegeneration outcome are warranted.
Data availability statement
Data are available upon reasonable request. The data supporting the findings in this study might be requested from the Li Chiu Kong Sleep Assessment Unit, Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, via the corresponding author of this article.
Ethics statements
Patient consent for publication
Ethics approval
The Joint CUHK-NTEC Clinical Research Ethics Committee approved the study protocol (CREC Ref. No.: 2015.146) and patients had given the written informed consent for participating in this study. The study was conducted in compliance with the Declaration of Helsinki.
Acknowledgments
The authors would like to thank the subjects, research staff and colleagues from the Li Chiu Kong Family Sleep Assessment Unit for the study. The study was supported by RGC-GRF grant (Reference No.: 14117915).
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
JW and SWHC contributed equally.
Presented at The preliminary analysis results were presented in the 13th Symposium of the International REM Sleep Behavior Disorder Study Group (IRBDSG) in Copenhagen, Denmark, 3–5 October 2019.
Contributors JW and SWHC are joint first authors as they contributed equally to this study in data analysis and manuscript drafting. YKW, SPL and JZ conceived the idea for conducting this study and applied for the funding. SPL, NYC, MWMY, JCTT, JWYC, JW, SWHC, MMSC and BH contributed to the subject recruitment and data collection. YKW, YL and JZ supervised the data cleansing and analysis. VM provided his expertise in neurological assessments and clinical referral to neurologists where applicable. All authors critically reviewed this manuscript. All authors gave final approval for the submitted article and take responsibility for the accuracy and integrity of this work. YKW is responsible for the overall content as the guarantor.
Funding This study was supported by the General Research Fund (Reference No.: 14117915) of the Research Grant Council.
Competing interests JW and BH were supported by the Faculty Postdoctoral Fellowship Scheme of the Chinese University of Hong Kong. The University reimbursed their registration fee and airfare for attending international academic conferences in 2019. YL was supported by the Postdoctoral Fellowship in Clinical Neurosciences of the Chinese University of Hong Kong. JWYC received personal fees from Eisai for joining an insomnia expert forum. YKW received personal fees from Eisai for lecture and travel support from Lundbeck HK, which are outside the submitted work.
Provenance and peer review Not commissioned; externally peer reviewed.
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