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Additionally, the progression and the eventual conversion of prodromal conditions such as REM behavior disorder (RBD) to PD, MSA, or DLB remain challenging to predict. Extracellular vesicles (EVs) are small, membrane-enclosed structures released by cells, playing a vital role in communicating cell-state-specific messages. Due to their ability to cross the blood\u2013brain barrier into the peripheral circulation, measuring biomarkers in blood-isolated speculative CNS enriched EVs has become a popular diagnostic approach. However, replication and independent validation remain challenging in this field. Here, we aimed to evaluate the diagnostic accuracy of speculative CNS-enriched EVs for parkinsonian disorders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a PRISMA-guided systematic review and meta-analysis, covering 18 studies with a total of 1695 patients with PD, 253 with MSA, 21 with DLB, 172 with PSP, 152 with CBS, 189 with RBD, and 1288 HCs, employing either hierarchical bivariate models or univariate models based on study size.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Diagnostic accuracy was moderate for differentiating patients with PD from HCs, but revealed high heterogeneity and significant publication bias, suggesting an inflation of the perceived diagnostic effectiveness. The bias observed indicates that studies with non-significant or lower effect sizes were less likely to be published. Although results for differentiating patients with PD from those with\u00a0MSA or PSP and CBS appeared promising, their validity is limited due to the small number of involved studies coming from the same research group. Despite initial reports, our analyses suggest that using speculative CNS-enriched EV biomarkers may not reliably differentiate patients with MSA from HCs or patients with RBD from HCs, due to their lesser accuracy and substantial variability among the studies, further complicated by substantial publication bias.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings underscore the moderate, yet unreliable diagnostic accuracy of biomarkers in\u00a0speculative CNS-enriched EVs in differentiating parkinsonian disorders, highlighting the presence of substantial heterogeneity and significant publication bias. These observations reinforce the need for larger, more standardized, and unbiased studies to validate the utility of\u00a0these\u00a0biomarkers\u00a0but also\u00a0call\u00a0for the development of better biomarkers for parkinsonian disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-023-12093-3","type":"journal-article","created":{"date-parts":[[2023,12,16]],"date-time":"2023-12-16T10:02:16Z","timestamp":1702720936000},"page":"1680-1706","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Analysis of biomarkers in speculative CNS-enriched extracellular vesicles for parkinsonian disorders: a comprehensive systematic review and diagnostic meta-analysis"],"prefix":"10.1007","volume":"271","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3056-8878","authenticated-orcid":false,"given":"Hash Brown","family":"Taha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksander","family":"Bogoniewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,12,16]]},"reference":[{"key":"12093_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.105185","volume":"148","author":"C Agliardi","year":"2021","unstructured":"Agliardi C, Meloni M, Guerini FR, Zanzottera M, Bolognesi E, Baglio F, Clerici M (2021) Oligomeric \u03b1-Syn and SNARE complex proteins in peripheral extracellular vesicles of neural origin are biomarkers for Parkinson\u2019s disease. 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