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Neuronally derived extracellular vesicles (NDEVs) have been suggested as a peripheral substrate providing insights on the central nervous system pathology. Here, we assessed the accuracy of NDEV neurofilament light chain (Nf-L) levels in discriminating between PD and rET patients. Thirty-three PD and 13 rET patients and 30 healthy controls (HC) were consecutively enrolled in the study. NDEVs were obtained from serum through size exclusion chromatography followed by immunocapture based on L1CAM expression. NDEV Nf-L levels were quantified by ELISA on Ella Platform. Receiver operator characteristic (ROC) analysis was performed to investigate the NDEV Nf-L classification performance. Associations between NDEV Nf-L and demographical or clinical variables were investigated with Spearman\u2019s method. NDEV Nf-L levels were significantly higher in PD compared to rET patients and HC, and achieved an excellent classification performance in distinguishing PD from both rET and HC (AUC: 0.902 and 0.987, respectively). No differences were observed between rET and HC. A significant negative association between NDEV Nf-L and sex was detected in rET patients. Our pilot study suggests that NDEV Nf-L might be a useful blood-derived biomarker helping the differential diagnosis between PD and rET patients. Future studies are needed to validate these findings in larger independent cohorts.<\/jats:p>","DOI":"10.1007\/s12035-025-05285-7","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T08:35:58Z","timestamp":1762850158000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Neurofilament Light Chain from Neuronally Derived Extracellular Vesicles in Differentiating Parkinson\u2019s Disease from Essential Tremor with Resting Tremor"],"prefix":"10.1007","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2187-9176","authenticated-orcid":false,"given":"Selena","family":"Mimmi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7811-2083","authenticated-orcid":false,"given":"Costanza Maria","family":"Cristiani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7439-3973","authenticated-orcid":false,"given":"Mariagrazia","family":"Talarico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5077-0845","authenticated-orcid":false,"given":"Anna Maria","family":"Tolomeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8145-3623","authenticated-orcid":false,"given":"Elvira Immacolata","family":"Parrotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3239-3745","authenticated-orcid":false,"given":"Luana","family":"Scaramuzzino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8334-0005","authenticated-orcid":false,"given":"Valentina","family":"Crapella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9023-710X","authenticated-orcid":false,"given":"Elisabetta","family":"Pingitore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3565-7817","authenticated-orcid":false,"given":"Enrico","family":"Iaccino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6313-1866","authenticated-orcid":false,"given":"Giovanni","family":"Cuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2001-957X","authenticated-orcid":false,"given":"Aldo","family":"Quattrone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2071-2083","authenticated-orcid":false,"given":"Andrea","family":"Quattrone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,11]]},"reference":[{"issue":"6","key":"5285_CR1","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1586\/ern.12.49","volume":"12","author":"MA Thenganatt","year":"2012","unstructured":"Thenganatt MA, Louis ED (2012) Distinguishing essential tremor from Parkinson\u2019s disease: bedside tests and laboratory evaluations. 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Written informed consent was obtained from all enrolled patients, both for study participation and data publication.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval and Consent to Participate"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interest"}}],"article-number":"24"}}