The serum proteome and exosome characteristics of cognitive impairment in the Post Acute COVID-19 Syndrome: lasting dysregulation of metabolism, coagulation and immune pathways

The serum proteome and exosome characteristics of cognitive impairment in the Post Acute COVID-19 Syndrome: lasting dysregulation of metabolism, coagulation and immune pathways | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The serum proteome and exosome characteristics of cognitive impairment in the Post Acute COVID-19 Syndrome: lasting dysregulation of metabolism, coagulation and immune pathways George Vavougios, Eirini Karamichali, Dimitrios Mysiris, Vasileios Stavrou, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8040648/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Cognitive impairment following COVID-19 hospitalization is a commonly observed symptom, though its biological correlates remain unclear. The objective of this study was to investigate serum proteomes and circulating extracellular vesicles (EVs), including exosomes, for the purpose of uncovering differences between cognitively impaired and cognitively intact participants, at a minimum of two months following hospitalization for COVID-19. Methods: Consecutive adult participants were enrolled from the COVID-19 outpatient clinic after hospitalization for COVID-19 and during their initial follow-up visit. Data gathered included demographic information, medical and patient histories, neurocognitive and affective assessments, as well as biochemical evaluations aimed at identifying reversible cognitive impairment. Serum samples collected were subsequently analyzed for proteomic profiles and characteristics of circulating EVs. Results: The study recruited 67 consecutive patients. After propensity score matching for age, gender, education, and disease severity, 31 cognitively impaired participants were matched with 31 cognitively intact participants. Twenty-five proteins, including A2M, PZP, and PXLDC2 were determined as differentially abundant between groups. Enrichment analysis identified protein-protein interaction networks related to immune function, coagulation, and lipid metabolism. Enriched cellular components involved the presence of blood nanoparticles, including exosomes. The latter find was corroborated by observed differences in measurements of circulating vesicular and exosomeal content between the groups. Discussion: We report on differentially abundant proteins between cognitively impaired and cognitively intact individuals with a history of COVID-19 hospitalization, and provide a role for prolonged immune, metabolic and coagulation defects, along with perturbed EV communication. The identified proteins and pathways have been previously linked to amnestic mild cognitive impairment and Alzheimer’s disease (AD), suggesting potential pathophysiological interactions. Cognitive impairment Long COVID COVID-19 infection exosomes extracellular vesicles complement coagulation proteomics metabolism Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8040648","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":540576662,"identity":"32046030-c421-422a-b4b1-9c132b3c697e","order_by":0,"name":"George Vavougios","email":"data:image/png;base64,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","orcid":"","institution":"","correspondingAuthor":true,"prefix":"","firstName":"George","middleName":"","lastName":"Vavougios","suffix":""},{"id":540576663,"identity":"f0aa77f8-2714-4517-8e47-a5225ae07b92","order_by":1,"name":"Eirini Karamichali","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Eirini","middleName":"","lastName":"Karamichali","suffix":""},{"id":540576664,"identity":"875d464f-52c0-497d-a730-5cb239b9f2a5","order_by":2,"name":"Dimitrios Mysiris","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Dimitrios","middleName":"","lastName":"Mysiris","suffix":""},{"id":540576665,"identity":"95317453-1b01-4d79-ab79-2743299fcb0f","order_by":3,"name":"Vasileios Stavrou","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Vasileios","middleName":"","lastName":"Stavrou","suffix":""},{"id":540576666,"identity":"1677b65d-c580-4ddd-b13b-1b0611904d9f","order_by":4,"name":"Sri Ranjani Ganji","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Sri","middleName":"Ranjani","lastName":"Ganji","suffix":""},{"id":540576667,"identity":"20d67d23-17bd-43a0-b0ef-7305107e0029","order_by":5,"name":"Olga Papaggeli","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Olga","middleName":"","lastName":"Papaggeli","suffix":""},{"id":540576668,"identity":"780e108b-5ee4-462b-8a64-aa7e4f977eeb","order_by":6,"name":"Stylianos Boutlas","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Stylianos","middleName":"","lastName":"Boutlas","suffix":""},{"id":540576669,"identity":"2619725b-4825-4d67-971d-3ac673030d0a","order_by":7,"name":"Sofia Mazi","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Sofia","middleName":"","lastName":"Mazi","suffix":""},{"id":540576670,"identity":"289c9b57-f595-4e4b-9c65-9a2f6b87cedc","order_by":8,"name":"Glykeria Tsirimona","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Glykeria","middleName":"","lastName":"Tsirimona","suffix":""},{"id":540576671,"identity":"c46bcedd-026b-4a7d-a21a-71015fda939d","order_by":9,"name":"Ilias E. 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The objective of this study was to investigate serum proteomes and circulating extracellular vesicles (EVs), including exosomes, for the purpose of uncovering differences between cognitively impaired and cognitively intact participants, at a minimum of two months following hospitalization for COVID-19.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Consecutive adult participants were enrolled from the COVID-19 outpatient clinic after hospitalization for COVID-19 and during their initial follow-up visit. Data gathered included demographic information, medical and patient histories, neurocognitive and affective assessments, as well as biochemical evaluations aimed at identifying reversible cognitive impairment. Serum samples collected were subsequently analyzed for proteomic profiles and characteristics of circulating EVs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e The study recruited 67 consecutive patients. After propensity score matching for age, gender, education, and disease severity, 31 cognitively impaired participants were matched with 31 cognitively intact participants. Twenty-five proteins, including A2M, PZP, and PXLDC2 were determined as differentially abundant between groups. Enrichment analysis identified protein-protein interaction networks related to immune function, coagulation, and lipid metabolism. Enriched cellular components involved the presence of blood nanoparticles, including exosomes. The latter find was corroborated by observed differences in measurements of circulating vesicular and exosomeal content between the groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion:\u003c/strong\u003e We report on differentially abundant proteins between cognitively impaired and cognitively intact individuals with a history of COVID-19 hospitalization, and provide a role for prolonged immune, metabolic and coagulation defects, along with perturbed EV communication. The identified proteins and pathways have been previously linked to amnestic mild cognitive impairment and Alzheimer’s disease (AD), suggesting potential pathophysiological interactions.\u003c/p\u003e","manuscriptTitle":"The serum proteome and exosome characteristics of cognitive impairment in the Post Acute COVID-19 Syndrome: lasting dysregulation of metabolism, coagulation and immune pathways","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-06 09:02:31","doi":"10.21203/rs.3.rs-8040648/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2fbfc7df-02a6-41f8-bafc-9be97c347d33","owner":[],"postedDate":"November 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-06T09:02:31+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-06 09:02:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8040648","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8040648","identity":"rs-8040648","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}