{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:41:50Z","timestamp":1789393310740,"version":"build-2803163510"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Blood-derived extracellular vesicles (EVs) from neurons and astrocytes carrying Alzheimer\u2019s disease (AD) biomarkers can predict progression from mild cognitive impairment (MCI) to AD; however, their potential in saliva remains largely unexplored. Saliva-derived extracellular vesicles (sEVs) represent a promising non-invasive biomarker source for AD and other age-related dementias (ADRD), but progress has been limited by a lack of standardized protocols for saliva collection, storage, and central nervous system (CNS)-derived EV isolation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study had two primary objectives: (1) to optimize enrichment of CNS cell-specific sEVs from the same individuals, and (2) to evaluate the impact of cellular origin and storage temperature (room temperature, 4\u00b0C, \u221220\u00b0C) on the stability and quantification of AD-related biomarkers and inflammatory cytokines. Saliva was collected via passive drool from participants in the Nathan Shock Healthy Aging Study (mean age 71.3 years; n = 15). EVs of neuronal, astrocytic, microglial, and oligodendrocyte origin were isolated using ExoQuick-TC precipitation followed by magnetic bead immunocapture. Executive function and attention were assessed using the NIH Toolbox Cognition Battery. Biomarkers were quantified using high-sensitivity immunoassays (MSD, SIMOA Qunaterix).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Astrocyte-derived EVs demonstrated significant enrichment of key AD biomarkers, including A\u03b240, A\u03b242, and total tau. Phosphorylated tau (p-tau217) was largely undetectable across all fractions. TDP-43 was most abundant in EV-depleted saliva, while inflammatory cytokines were broadly distributed across all fractions. Storage temperature did not consistently alter biomarker levels; however, \u221220\u00b0C storage yielded optimal biomarker quantification. Importantly, lower levels of inflammatory cytokines (IFN-\u03b3, IL-10, and IL-6) in EV-depleted saliva were associated with better working memory performance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study provides proof-of-concept validation for the characterization and comparison of multiple CNS-derived salivary EV fractions within the same individuals. The findings support saliva as a feasible, non-invasive matrix for assessing neurodegenerative and neuroinflammatory biomarkers. Establishing a standardized methodology for salivary EV isolation and storage lays the groundwork for future longitudinal studies aimed at diagnosing and predicting AD progression using saliva-based biomarkers.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2026.1765229","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T06:43:54Z","timestamp":1774248234000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Pre-analytical characterization of CNS-derived extracellular vesicles from human saliva: effect of room temperature and cellular origin"],"prefix":"10.3389","volume":"20","author":[{"given":"Luciano M.","family":"Licatini","sequence":"first","affiliation":[{"name":"Alzheimer\u2019s Therapeutic Research Institute - Neuroscience Translational Research Division, Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California","place":["San Diego, CA, United States"]},{"name":"University of California San Diego","place":["San Diego, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi M.","family":"Licatini","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Therapeutic Research Institute - Neuroscience Translational Research Division, Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California","place":["San Diego, CA, United States"]},{"name":"San Diego State University","place":["San Diego, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadi A.","family":"Haddadin","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Therapeutic Research Institute - Neuroscience Translational Research Division, Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California","place":["San Diego, CA, United States"]},{"name":"University of California San Diego","place":["San Diego, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace C.","family":"Conklin","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Therapeutic Research Institute - Neuroscience Translational Research Division, Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California","place":["San Diego, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"AmanPreet","family":"Badhwar","sequence":"additional","affiliation":[{"name":"Multiomics Investigation of Neurodegenerative Diseases (MIND) Lab, Centre de Recherche de l\u2019Institut Universitaire de G\u00e9riatrie de Montr\u00e9al (CRIUGM)","place":["Montreal, QC, Canada"]},{"name":"Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal","place":["Montreal, QC, Canada"]},{"name":"Institute of Biomedical Engineering, University of Montreal","place":["Montreal, QC, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floyd M.","family":"Sarsoza","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Therapeutic Research Institute - Neuroscience Translational Research Division, Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California","place":["San Diego, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonal","family":"Sukreet","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Therapeutic Research Institute - Neuroscience Translational Research Division, Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California","place":["San Diego, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charisse N.","family":"Winston","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Therapeutic Research Institute - Neuroscience Translational Research Division, Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California","place":["San Diego, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1016\/j.bbi.2019.07.020","article-title":"Inflammatory biomarkers and brain health indicators in children with overweight and obesity: the ActiveBrains project","volume":"81","author":"Adelantado-Renau","year":"2019","journal-title":"Brain Behav. 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