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Loss\u2010of\u2010function mutations in progranulin (<jats:italic>GRN<\/jats:italic>) are a major cause of frontotemporal dementia (FTD), and brains from <jats:italic>GRN<\/jats:italic> carriers with FTD (FTD\u2010<jats:italic>GRN<\/jats:italic>) exhibit signs of lysosomal dysfunction. Lysosomal dysfunction may induce compensatory increases in secretion of exosomes, EVs secreted from the endolysosomal system, so we hypothesized that progranulin insufficiency would increase EV levels in the brain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed levels and protein contents of brain EVs from <jats:italic>Grn<jats:sup>\u2013\/\u2013<\/jats:sup><\/jats:italic> mice, which model the lysosomal abnormalities of FTD\u2010<jats:italic>GRN<\/jats:italic> patients. We then measured brain EVs in FTD\u2010<jats:italic>GRN<\/jats:italic> patients. To assess the relationship of EVs with symptomatic disease, we measured plasma EVs in presymptomatic and symptomatic <jats:italic>GRN<\/jats:italic> mutation carriers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Grn<jats:sup>\u2013\/\u2013<\/jats:sup><\/jats:italic> mice had elevated brain EV levels and altered EV protein contents relative to wild\u2010type mice. These changes were age\u2010dependent, occurring only after the emergence of pathology in <jats:italic>Grn<jats:sup>\u2013\/\u2013<\/jats:sup><\/jats:italic> mice. FTD\u2010<jats:italic>GRN<\/jats:italic> patients (n\u00a0=\u00a013) had elevated brain EV levels relative to controls (n\u00a0=\u00a05). Symptomatic (n\u00a0=\u00a012), but not presymptomatic (n\u00a0=\u00a07), <jats:italic>GRN<\/jats:italic> carriers had elevated plasma EV levels relative to controls (n\u00a0=\u00a08).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These data show that symptomatic FTD\u2010<jats:italic>GRN<\/jats:italic> patients have elevated levels of brain and plasma EVs, and that this effect is modeled in the brain of <jats:italic>Grn<jats:sup>\u2013\/\u2013<\/jats:sup><\/jats:italic> mice after the onset of pathology. This increase in EVs could influence FTD disease progression, and provides further support for EVs as potential FTD biomarkers.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51242","type":"journal-article","created":{"date-parts":[[2020,11,16]],"date-time":"2020-11-16T14:23:21Z","timestamp":1605536601000},"page":"2433-2449","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Elevated levels of extracellular vesicles in progranulin\u2010deficient mice and FTD\u2010<i>GRN<\/i> Patients"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4706-9411","authenticated-orcid":false,"given":"Andrew E.","family":"Arrant","sequence":"first","affiliation":[{"name":"Departments of Neurology and Neurobiology Center for Neurodegeneration and Experimental Therapeutics Alzheimer\u2019s Disease Center Evelyn F. 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