Prospective outcome of rapid eye movement sleep behaviour disorder: psychiatric disorders as a potential early marker of Parkinson's disease
- Yun Kwok Wing1,
- Shirley Xin Li1,
- Vincent Mok2,
- Siu Ping Lam1,
- Joshua Tsoh1,
- Anne Chan2,
- Mandy Wai Man Yu1,
- Christine Y K Lau2,
- Jihui Zhang1,
- Crover Kwok Wah Ho1
- 1Department of Psychiatry, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
- 2Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
- Correspondence to Dr Yun-Kwok Wing, Professor, Director of Sleep Assessment Unit, Department of Psychiatry, Shatin hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China;
Contributors All the authors made substantial contributions to the intellectual content of the manuscript: Y-KW and SXL contributed to the conception and design of the study, analysis and interpretation of the data, and manuscript preparation. VM, S-PL, JT and AC contributed to the conception and design of the study, interpretation of the data and critical revision of the manuscript. MW-MY and CYKL contributed to the acquisition of data and critical revision of the manuscript. JZ contributed to the interpretation of the data and critical revision of the manuscript. CKWH contributed to the design of the study and critical revision of the manuscript.
- Received 20 August 2011
- Revised 29 November 2011
- Accepted 2 December 2011
- Published Online First 16 January 2012
- REM sleep behaviour disorder
- early clinical marker
- Parkinson's disease
- psychiatric disorders
- neurodegenerative disorders
- sleep disorders
Increasing evidence suggests that rapid eye movement sleep behaviour disorder (RBD) is a heralding feature associated with evolving α-synucleinopathy-related neurodegenerative disorders.1–4 Several neurobiological markers such as olfactory abnormality were associated with the development of neurodegenerative disorders in ‘idiopathic’ RBD (iRBD) patients.5 On the other hand, pre-morbid psychiatric disorders were suggested as an important but often neglected preclinical marker of Parkinson's disease (PD),6 and its role is unclear in iRBD patients. The current study aimed to provide a quantitative risk estimate of neurodegenerative outcome, and to investigate the role of psychiatric disorders in predicting future neurodegenerative disorders in a prospective cohort of Hong Kong Chinese iRBD patients.
Ninety-one iRBD patients (82.4% men) (recruited during 1994–2009) were prospectively followed-up with routine clinical assessments in our sleep centre for a mean duration of 5.6 years (SD 3.3).1 An additional research-based follow-up protocol has been implemented since 2008, which included neuropsychiatric examinations as conducted by the research neurologists and psychiatrists. The mean age of onset of RBD symptoms and of diagnosis of RBD in the study cohort was 60.0 (SD 12.7) and 65.5 years (SD 9.9), respectively. Twenty patients (22%) had only regular follow-up at the sleep clinic (Sleep Clinic Group) and 71 patients (78.0%) completed a research-based follow-up protocol in addition to their regular sleep clinic attendance (Research Group). There was no significant difference in gender, age of onset and age at diagnosis of RBD, and history of psychiatric disorder(s) between the two groups. During the follow-up period, five patients died without any neurodegenerative disease; three patients emigrated out of Hong Kong. About 29% of the study cohort (n=26) had a history of psychiatric disorders (depression (21), anxiety disorders (3), alcohol dependence/abuse (2)), and 9 patients were on antidepressant medications during baseline polysomnographic assessment.
Of the study cohort (n=91), 8 subjects developed PD and 11 subjects developed dementia (Alzheimer's disease (8), dementia with Lewy bodies (1), vascular dementia (2)). There was no clinical evidence of Parkinsonian features in those patients who were diagnosed with Alzheimer's disease. There was no significant difference in gender, age of onset and age at diagnosis of RBD, comorbidity of other sleep disorders (eg, obstructive sleep apnoea) and lifestyle (eg, smoking status) between the patients who did and did not develop the neurodegenerative conditions. Patients with neurodegenerative disorders had a longer follow-up duration than those who did not develop the condition (8.6 (2.8) years vs 4.8 (3.0) years, p<0.001). In addition, mild cognitive impairment (as defined by Clinical Dementia Rating=0.5) was found in 3 out of 8 (38.5%) PD patients and was evident in 28% of the rest of disease-free subjects (n=25) during the last follow-up assessment.
The estimated 5-year and 9-year risks of any neurodegenerative disorder for the overall study cohort were 8.5% and 38.1%, respectively (figure 1A). In the research group, the estimated 5-year and 9-year risks of any neurodegenerative disorder were relatively higher (9.2% and 52.6%, respectively). Subjects in the research group had slightly shorter survival duration (mean: 8.2 (95% CI 7.5 to 8.9) years) as compared with those with sleep clinic-only attendance (mean: 9.6 (95% CI 8.7 to 10.4) years) (p<0.05, log-rank test).
The overall prevalence of psychiatric disorders was 31.6% in the iRBD patients who developed neurodegenerative disorders. Only 1 out of 9 iRBD patients (11.1%) who developed dementia had premorbid depression, whereas five out of eight iRBD patients (5/8, 62.5%) had a history of psychiatric disorder prior to the diagnosis of PD (p=0.05). Among the RBD patients with a psychiatric disorder who developed PD, their psychiatric diagnosis were all made before the RBD diagnosis (mean duration=4.1 years, SD 4.2; range: 0.1–8.1 years). Presence of premorbid psychiatric disorders was associated with an increased risk of PD after adjusting for gender, age at RBD diagnosis and smoking status (HR 7.0, 95% CI 1.3 to 38.3) (figure 1B).
In line with other populations,2–4 a heightened risk of future neurodegenerative disorders was demonstrated in our iRBD patients over a long-term follow-up (9-year risk: 38.1%), which may suggest a universal mechanism for the underlying pathophysiological progression of RBD across different ethnicities.1 However, compared with other studies, our study had a relatively lower 5-year risk estimate (8.5% vs 17.7–45% in other cohort studies),2–4 which might be partly related to our stringent study criterion that defined a disease status by clinically confirmed diagnosis of PD or dementia, instead of the onset of symptoms as reported by patients. In addition, our study revealed that psychiatric disorders, particularly depression, was a significant risk factor in predicting PD in iRBD patients, which may lend a further support to the role of psychiatric disorders in predicting the emergence of PD-related pathologies. Although the pathophysiological mechanism remains unclear, the reduction of monoamines activities may suggest a shared biological mechanism mediating PD and psychiatric disorders.7 Our findings may provide preliminary evidence to support a link between premorbid psychiatric disorders and future PD in iRBD patients, but it remains inconclusive whether psychiatric disorders alone, or its presence exerted a synergistic effect on the risk of neurodegeneration. Despite a comparative timeline of the diagnosis of psychiatric disorders, iRBD and PD, it is still difficult to provide a detailed delineation on the exact onset of diseases and how they interactively progressed. In addition, the current study was limited by a relatively modest sample size and a clinical diagnosis without further ancillary investigations (eg, neuroimaging) to confirm the underlying pathology. In this regard, future prospective research with more rigorous measurements in a much larger scale and additional recruitment of non-RBD controls is needed.
In parallel with current research, there have been increasing reports of RBD features in psychiatric populations.8 Although antidepressants were suggested as a potential culprit, emerging evidence suggested that residual RBD features persisted even after the discontinuation of psychotropic medications.9 Given our preliminary finding of psychiatric disorders as a possible early neurodegenerative marker in iRBD patients, further research is needed to determine whether this group of RBD patients in the psychiatric populations may also be at risk of predisposition to future neurodegeneration.
Funding This work was supported by General Research Fund grant (CUHK 476610) of Research Grants Council, Hong Kong SAR, China.
Competing interests None.
Patient consent Obtained.
Ethics approval Ethics approval was provided by Joint CUHK-NTEC Clinical Research Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The corresponding author declares that all the authors have agreed to the condition regarding data sharing stated in the authorship agreement form.