Quantitative Network Comparisons of REM Sleep Without Atonia Across the α-Synucleinopathy Spectrum: A Systematic Review

Jung-Ick Byun,1 Tae-Won Yang,2– 4 Jun-Sang Sunwoo,5 Won Chul Shin,1,6 Oh-Young Kwon,2,4,7,* Ki-Young Jung8,* 1Department of Neurology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Republic of Korea; 2Department of Neurology, Gyeongsang National University College of Medicine, Jinju, Republic of Korea; 3Department of Neurology, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea; 4Institute of Science, Gyeongsang National University College of Medicine, Jinju, Republic of Korea; 5Department of Neurology, Kangbuk Samsung Hospital, Seoul, Republic of Korea; 6Department of Medicine, AgeTech-service Convergence Major, Kyung Hee University, Seoul, Republic of Korea; 7Department of Neurology, Gyeongsang National University Hospital, Jinju, Republic of Korea; 8Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea*These authors contributed equally to this workCorrespondence: Oh-Young Kwon, Department of Neurology, Gyeongsang National University College of Medicine, 15, Jinjudae-ro 816beon-gil, Jinju, 52727, Republic of Korea, Tel +82-55-750-8288, Email oykwon@gnu.ac.kr Ki-Young Jung, Department of Neurology, Seoul National University Hospital, Neuroscience Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 110-744, Republic of Korea, Tel +82-2-920-6649, Email jungky@snu.ac.krPurpose: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by REM sleep without atonia (RWA) and is regarded as the prodromal stage of α-synucleinopathies, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). RWA is also associated with neurodegeneration driven by α-synucleinopathy. However, the level of RWA across the α-synucleinopathy spectrum remains elusive. We aimed to rate the percentage of RWA across the α-synucleinopathy spectrum, encompassing prodromal and overt phenotypes.Methods: A systematic search was conducted in the PubMed, Embase, Web of Science, and Cochrane Library databases. We included cohort, cross-sectional, and case–control studies comparing the RWA percentage during REM sleep evaluated by tonic chin activity (RWA%-T) or by phasic chin activity (RWA%-P) across the α-synucleinopathy spectrum. Bayesian network meta-analysis was used to combine both direct and indirect evidence regarding the group differences in the RWA%-T and RWA%-P. The surface under the cumulative ranking curve was used to estimate the ranked probability.Results: Fifteen articles met the inclusion criteria. The investigations included 204 iRBD, 295 PD with RBD (PDwtRBD), 187 PD without RBD (PDwoRBD), 42 MSAwtRBD, 9 DLBwtRBD patients, and 246 controls. MSAwtRBD ranked first in RWA%-T, whereas iRBD ranked first in RWA%-P. RWA% in PDwoRBD patients was comparable to that in the controls and was lower than that in PDwtRBD patients.Conclusion: Overt phenotypes such as MSAwtRBD and PDwtRBD ranked high in RWA%-T, whereas iRBD, a prodromal type, ranked highest in RWA%-P. Taken together, our data suggest that the percentage of neurodegeneration in RBD patients may be associated with RWA%-T rather than RWA%-P.Prospero Registration Number: CRD42021276445.Keywords: REM sleep behavior disorder, α-synucleinopathy, REM sleep without atonia, network meta-analysis