{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T20:56:22Z","timestamp":1792443382792,"version":"4.5.0"},"reference-count":54,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,30]],"date-time":"2022-01-30T00:00:00Z","timestamp":1643500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RF-2016-02361492"],"award-info":[{"award-number":["RF-2016-02361492"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["Ricerca Corrente"],"award-info":[{"award-number":["Ricerca Corrente"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cutting-edge research suggests endosomal\/immune dysregulation in GRN\/C9orf72-associated frontotemporal lobar degeneration (FTLD). In this retrospective study, we investigated plasma small extracellular vesicles (sEVs) and complement proteins in 172 subjects (40 Sporadic FTLD, 40 Intermediate\/Pathological C9orf72 expansion carriers, and 49 Heterozygous\/Homozygous GRN mutation carriers, 43 controls). Plasma sEVs (concentration, size) were analyzed by nanoparticle tracking analysis; plasma and sEVs C1q, C4, C3 proteins were quantified by multiplex assay. We demonstrated that genetic\/sporadic FTLD share lower sEV concentrations and higher sEV sizes. The diagnostic performance of the two most predictive variables (sEV concentration\/size ratio) was high (AUC = 0.91, sensitivity 85.3%, specificity 81.4%). C1q, C4, and C3 cargo per sEV is increased in genetic and sporadic FTLD. C4 (cargo per sEV, total sEV concentration) is increased in Sporadic FTLD and reduced in GRN+ Homozygous, suggesting its specific unbalance compared with Heterozygous cases. C3 plasma level was increased in genetic vs. sporadic FTLD. Looking at complement protein compartmentalization, in control subjects, the C3 and C4 sEV concentrations were roughly half that in respect to those measured in plasma; interestingly, this compartmentalization was altered in different ways in patients. These results suggest sEVs and complement proteins as potential therapeutic targets to mitigate neurodegeneration in FTLD.<\/jats:p>","DOI":"10.3390\/cells11030488","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T01:46:08Z","timestamp":1643593568000},"page":"488","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Plasma Small Extracellular Vesicles with Complement Alterations in GRN\/C9orf72 and Sporadic Frontotemporal Lobar Degeneration"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6162-252X","authenticated-orcid":false,"given":"Sonia","family":"Bellini","sequence":"first","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8618-4282","authenticated-orcid":false,"given":"Claudia","family":"Saraceno","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2836-8141","authenticated-orcid":false,"given":"Luisa","family":"Benussi","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Squitti","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Cimini","sequence":"additional","affiliation":[{"name":"Unit of Neurology V\u2014Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Ricci","sequence":"additional","affiliation":[{"name":"Unit of Neurology V\u2014Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5385-761X","authenticated-orcid":false,"given":"Laura","family":"Canafoglia","sequence":"additional","affiliation":[{"name":"Integrated Diagnostics for Epilepsy, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1125-6779","authenticated-orcid":false,"given":"Cinzia","family":"Coppola","sequence":"additional","affiliation":[{"name":"Department of Advanced Medical and Surgical Sciences, University of Campania \u201cL. Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianfranco","family":"Puoti","sequence":"additional","affiliation":[{"name":"Department of Advanced Medical and Surgical Sciences, University of Campania \u201cL. Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarissa","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Service of Statistics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8292-6434","authenticated-orcid":false,"given":"Antonio","family":"Longobardi","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6621-8729","authenticated-orcid":false,"given":"Roland","family":"Nicsanu","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Lombardi","sequence":"additional","affiliation":[{"name":"CNR Institute of Neuroscience, 20129 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3984-8888","authenticated-orcid":false,"given":"Giulia","family":"D\u2019Arrigo","sequence":"additional","affiliation":[{"name":"CNR Institute of Neuroscience, 20129 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Verderio","sequence":"additional","affiliation":[{"name":"CNR Institute of Neuroscience, 20129 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliano","family":"Binetti","sequence":"additional","affiliation":[{"name":"MAC-Memory Clinic and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6680-2725","authenticated-orcid":false,"given":"Giacomina","family":"Rossi","sequence":"additional","affiliation":[{"name":"Unit of Neurology V\u2014Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7691-1957","authenticated-orcid":false,"given":"Roberta","family":"Ghidoni","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1212\/WNL.58.11.1615","article-title":"The prevalence of frontotemporal dementia","volume":"58","author":"Ratnavalli","year":"2002","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1016\/S0140-6736(15)00461-4","article-title":"Frontotemporal dementia","volume":"386","author":"Bang","year":"2015","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00401-009-0612-2","article-title":"Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: An update","volume":"119","author":"Mackenzie","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1212\/WNL.0b013e3181bf997a","article-title":"The heritability and genetics of frontotemporal lobar degeneration","volume":"73","author":"Rohrer","year":"2009","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1001\/jamaneurol.2013.3956","article-title":"Development and validation of pedigree classification criteria for frontotemporal lobar degeneration","volume":"70","author":"Wood","year":"2013","journal-title":"JAMA Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"753","DOI":"10.3233\/JAD-170661","article-title":"The Heritability of Frontotemporal Lobar Degeneration: Validation of Pedigree Classification Criteria in a Northern Italy Cohort","volume":"61","author":"Fostinelli","year":"2018","journal-title":"J. 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