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Reliable and accurate biomarkers for iRBD detection and the prediction of phenoconversion are in urgent need. This study aimed to investigate whether \u03b1\u2010Synuclein (\u03b1\u2010Syn) species in plasma neuron\u2010derived extracellular vesicles (NDEVs) could differentiate between iRBD patients and healthy controls (HCs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Nanoscale flow cytometry was used to detect \u03b1\u2010Syn\u2010containing NDEVs in plasma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 54 iRBD patients and 53 HCs were recruited. The concentrations of total \u03b1\u2010Syn, \u03b1\u2010Syn aggregates, and phosphorylated \u03b1\u2010Syn at Ser129 (pS129)\u2010containing NDEVs in plasma of iRBD individuals were significantly higher than those in HCs (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001 for all). In distinguishing between iRBD and HCs, the area under the receiver operating characteristic (ROC) curve (AUC) for an integrative model incorporating the levels of \u03b1\u2010Syn, pS129, and \u03b1\u2010Syn aggregate\u2010containing NDEVs in plasma was 0.965. This model achieved a sensitivity of 94.3% and a specificity of 88.9%. In iRBD group, the concentrations of \u03b1\u2010Syn aggregate\u2010containing NDEVs exhibited a negative correlation with Sniffin\u2019 Sticks olfactory scores (<jats:italic>r<\/jats:italic>\u2009=\u2009\u22120.351, <jats:italic>p<\/jats:italic>\u2009=\u20090.039). Smokers with iRBD exhibited lower levels of \u03b1\u2010Syn aggregates and pS129\u2010containing NDEVs in plasma compared to nonsmokers (<jats:italic>p<\/jats:italic><jats:sub>\u03b1\u2010Syn aggregates<\/jats:sub>\u2009=\u20090.014; <jats:italic>p<\/jats:italic><jats:sub>pS129<\/jats:sub>\u2009=\u20090.003).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>The current study demonstrated that the levels of total \u03b1\u2010Syn, \u03b1\u2010Syn aggregates, and pS129\u2010containing NDEVs in the plasma of individuals with iRBD were significantly higher compared to HCs. The levels of \u03b1\u2010Syn species\u2010containing NDEVs in plasma may serve as biomarkers for iRBD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.52200","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T11:29:00Z","timestamp":1726658940000},"page":"2891-2903","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["\u03b1\u2010Synuclein species in plasma neuron\u2010derived extracellular vesicles as biomarkers for <scp>iRBD<\/scp>"],"prefix":"10.1002","volume":"11","author":[{"given":"Xuemei","family":"Wang","sequence":"first","affiliation":[{"name":"Center for Movement Disorders, Department of Neurology Beijing Tiantan Hospital, Capital Medical University  Beijing China"},{"name":"China National Clinical Research Center for Neurological Diseases Beijing Tiantan Hospital, Capital Medical University  Beijing 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