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Circulating neuron-derived extracellular vesicles (NDEVs), providing a peripheral window into CNS pathology, might serve as promising biomarkers.<\/jats:p>\n                  <jats:p>A total of 188 participants were recruited from three centres. A discovery cohort [40 PSP patients, 36 PD patients and 31 healthy controls (HCs)] and a multicentre validation cohort (30 PSP patients, 27 PD patients and 24 HCs) were established. NDEVs containing total tau, 4R tau or phosphorylated tau (ptau181, ptau217, ptau231 and ptau396) in plasma samples were analysed using nano-scale flow cytometry. Multivariable logistic regression models were developed in the discovery cohort and strictly validated in the independent cohort using fixed model parameters.<\/jats:p>\n                  <jats:p>In the discovery cohort, the concentrations of tau-, 4R tau-, ptau181- and ptau217-containing NDEVs in PSP patients were significantly higher than those in HCs and PD patients, whereas ptau396-containing NDEVs showed elevation exclusively in PSP compared with HCs (PSP versus HCs: P &amp;lt; 0.001 for tau, P &amp;lt; 0.001 for 4R tau, P &amp;lt; 0.001 for ptau181, P = 0.008 for ptau217, and P = 0.009 for ptau396; PSP versus PD: P &amp;lt; 0.001 for tau, P &amp;lt; 0.001for4R tau, P = 0.029 for ptau181, and P = 0.003 for ptau217). An integrated model incorporating these biomarkers achieved an area under the curve (AUC) of 0.965 (90.0% sensitivity, 96.8% specificity) for distinguishing PSP from HCs and an AUC of 0.963 (87.5% sensitivity, 94.4% specificity) for distinguishing PSP from PD. In the validation cohort, the concentrations of tau-, 4R tau-, ptau181-, ptau217- and ptau396-containing NDEVs in plasma were significantly higher in PSP patients compared with HCs (PSP versus HCs: P &amp;lt; 0.001 for tau, 4R tau and ptau217, P = 0.03 for ptau181, and P = 0.017 for ptau396). Likewise, the concentrations of tau-, 4R tau-, ptau181- and ptau217- were higher in PSP patients than in PD patients (PSP versus PD: P &amp;lt; 0.001 for tau, 4R tau and ptau217, and P = 0.025 for ptau181). The integrated model yielded an AUC of 0.971 for distinguishing PSP from HCs and 0.990 for distinguishing PSP from PD. Notably, in early-stage patients, the integrated model achieved an AUC of 0.987 in differentiating early-stage PSP from PD.<\/jats:p>\n                  <jats:p>These findings indicate that plasma tau-species-containing NDEVs are promising biomarkers for PSP, offering high sensitivity and specificity for distinguishing PSP from both HCs and PD, particularly in early disease stages. Further large-scale, longitudinal studies are warranted to validate these findings fully and explore their role in PSP pathophysiology and progression.<\/jats:p>","DOI":"10.1093\/brain\/awag091","type":"journal-article","created":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T12:47:49Z","timestamp":1772714869000},"source":"Crossref","is-referenced-by-count":1,"title":["Plasma tau-species-positive neuron-derived extracellular vesicles in progressive supranuclear palsy"],"prefix":"10.1093","author":[{"given":"Yuanchu","family":"Zheng","sequence":"first","affiliation":[{"name":"Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University , Beijing 100070 ,","place":["China"]},{"name":"China National Clinical Research Center for Neurological Diseases , Beijing 100070 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huihui","family":"Cai","sequence":"additional","affiliation":[{"name":"Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University , Beijing 100070 ,","place":["China"]},{"name":"China National Clinical Research Center for Neurological Diseases , Beijing 100070 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyi","family":"Kou","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Hospital, National Center of Gerontology, National Clinical Research Center for Gerontology, The Key Laboratory of Geriatrics of NHC, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences , Beijing 100730 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genliang","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University , Beijing 100070 ,","place":["China"]},{"name":"China National Clinical Research Center for Neurological Diseases , Beijing 100070 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanlin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Tianjin Medical University General Hospital , Tianjin 300052 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xijing Hospital of Air Force Military Medical University , Xi\u2019an 710032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingshan","family":"Piao","sequence":"additional","affiliation":[{"name":"Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University , Beijing 100070 ,","place":["China"]},{"name":"China National Clinical Research Center for Neurological Diseases , Beijing 100070 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