Prodromal Markers of First-degree Relatives of Patients With Psychiatric Disorders Comorbid With RBD

REM sleep behavior disorder (RBD) is a novel REM sleep parasomnia characterized by dream enacting behaviors and sleep-related injuries. Ample evidences have suggested that idiopathic RBD (iRBD) is a precursor of α-synucleinopathy neurodegeneration (e.g. Parkinson's disease, PD) in which dopamine dysfunction is one of the core pathophysiologies. In recent decade, our group has identified a cohort of patients with psychiatric disorders (mainly major depressive disorder, MDD) comorbid with RBD (pRBD). While there was a postulation that RBD symptoms in this psychiatric population may simply be side effects of antidepressant medication (by enhancing REM-sleep related muscle activity), accumulating evidence from case-control and prospective cohort studies suggested that pRBD is only partially explained by antidepressant usage and is better considered as a variant of typical iRBD in terms of comparable clinical presentation with typical iRBD and its close association with neurodegenerative markers. Nonetheless, more evidence is needed to substantiate that pRBD is a distinct diagnostic entity rather than a symptom secondary to antidepressant use. In this study, the investigators will employ genetic epidemiology approach to: 1) determine the familial genetic contribution; 2) search for biomarkers and endophenotypes; and 3) validate the diagnostic entity of a disease.

This proposed study will enrich the limited scientific literature of the potential pathogenesis of pRBD and its relationship with α-synucleinopathy. In addition, the understanding of psychiatric disorders, notably MDD, is often limited by its heterogeneity. Our proposed study will, by determining the familial aggregation of pRBD, help us to identify certain subtype of the psychiatric populations who may likely harbour an underlying neurodegenerative basis. By using a family study design, a number of important aspects with regard to the pathogenesis of pRBD will be answered. First, if first-degree relatives (FDRs) of patients with pRBD have a higher rate of possible RBD or clinical diagnosis of RBD (as confirmed by video-polysomnography) as well as the presence of neurodegenerative diseases when compared with FDRs of controls, it will substantiate the argument that pRBD is not merely a side effect of antidepressants but rather harbouring a familial and genetic predisposition to RBD and, ultimately α-synucleinopathy neurodegeneration. Second, the determination of biomarkers of neurodegeneration among unaffected FDRs of patients with pRBD will also help to identify high-risk individuals for clinical intervention and prevention. Third, the calculation of heritability will help to delineate to which extent the additive genetic contribution is responsible for the variance of pRBD phenotypes. Finally, the findings from this proposed study will be compared with our on-going family study of typical iRBD to determine the extent to which iRBD and pRBD are similar or different to each other in terms of genetic and familial associations.

In this proposed study, the investigators hypothesize that:

• FDRs of patients with pRBD have a higher rate of RBD symptoms and its core features compared with FDRs of controls;
• The unaffected FDRs of patients with pRBD are more likely to exhibit the features associated with prodromal markers of Parkinson's disease compared with FDRs of controls;
• FDRs of patients with pRBD have a higher rate of Parkinson's disease (and other α-synucleinopathy neurodegeneration) compared with FDRs of controls.

Inclusion criteria

• Age- and sex- matched with pRBD proband;
• Without lifetime psychiatric disorder according to Structural Clinical Interview for DSM-IV Disorders (SCID);
• Free of narcolepsy and other neurological diseases;
• Absence of any RBD features as based on RBDQ-HK and v-PSG;
• free of neurodegenerative diseases.

Exclusion criteria

• Not Chinese or aged under 40 years old;
• Refuse to participate in this study;
• without a biological relationship with proband.