Familial α-synucleinopathy spectrum features in patients with psychiatric REM sleep behaviour disorder.

Background: Rapid eye movement (REM) sleep behaviour disorder (RBD) is one of the earliest and most specific prodromes of the α-synucleinopathies including Parkinson's disease (PD). It remains uncertain whether RBD occurring in the context of psychiatric disorders (psy-RBD), although very common, is merely a benign epiphenomenon of antidepressant treatment, or whether it harbours an underlying α-synucleinopathy. We hypothesised that patients with psy-RBD demonstrate a familial predisposition to an α-synucleinopathy.
Methods: In this case-control-family study, a combination of family history and family study method was used to measure the α-synucleinopathy spectrum features, which included RBD, neurodegenerative prodromal markers and clinical diagnoses of neurodegenerative disorders. We compared the risk of α-synucleinopathy spectrum features in the first-degree relatives (FDRs) of patients with psy-RBD, psychiatric controls and healthy controls.
Results: There was an increase of α-synucleinopathy spectrum features in the psy-RBD-FDRs, including possible and provisional RBD (adjusted HR (aHR)=2.02 and 6.05, respectively), definite RBD (adjusted OR=11.53) and REM-related phasic electromyographic activities, prodromal markers including depression (aHR=4.74) and probable subtle parkinsonism, risk of prodromal PD and clinical diagnosis of PD/dementia (aHR=5.50), as compared with healthy-control-FDRs. When compared with psychiatric-control-FDRs, psy-RBD-FDRs consistently presented with a higher risk for the diagnosis and electromyographic features of RBD, diagnosis of PD/dementia (aHR=3.91) and risk of prodromal PD. In contrast, psychiatric controls only presented with a familial aggregation of depression.
Conclusion: Patients with psy-RBD are familially predisposed to α-synucleinopathy. The occurrence of RBD with major depression may signify a subtype of major depressive disorders with underlying α-synucleinopathy neurodegeneration.
Trial Registration Number: NCT03595475.
Competing Interests: Competing interests: JW: Supported by the Faculty Postdoctoral Fellowship Scheme of the Chinese University of Hong Kong and the International Postdoctoral Exchange Fellowship Program (YJ20220085). She is currently a Principal Investigator, funded by the China Postdoctoral Science Foundation (2022M720913). The Chinese University of Hong Kong reimbursed the airfare and registration fee for attending an international academic conference in 2019. BH: Supported by the Faculty Postdoctoral Fellowship Scheme of the Chinese University of Hong Kong. The Chinese University of Hong Kong reimbursed the airfare and registration fee for attending an international academic conference in 2019. YL: Reported being as Principal Investigator, funded by the Health and Medical Research Fund from Food and Health Bureau, but not related to this manuscript. Received presentation fee from the Chinese Sleep Research Society, but not related to this study. JWYC: Reported grants from General Research Fund of University Grants Committee and Health and Medical Research Fund-Food and Health Bureau, Hong Kong SAR, which are outside of this study, and personal fees for joining an expert panel meeting from Eisai. YKW: Received consultation fee and personal fees from Eisai for lecture, and travel support from Lundbeck HK Limited, which are outside the submitted work. CHS: Received a personal fee from Eisai for a one-time lecture.
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