Peripheral inflammation is associated with reduced influx of TSPO PET tracers into the brain: insights from a non-invasive mapping methodology

Peripheral inflammation is associated with reduced influx of TSPO PET tracers into the brain: insights from a non-invasive mapping methodology | 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 Peripheral inflammation is associated with reduced influx of TSPO PET tracers into the brain: insights from a non-invasive mapping methodology Leonardo Barzon, Lucia Maccioni, Manuela Moretto, Alessio Giacomel, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6648321/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Introduction Neuroinflammation is a hallmark of various brain disorders, including neuropsychiatric conditions like major depressive disorder and schizophrenia. Increasing evidence suggests that both peripheral and central inflammation play a critical role in central nervous system dysfunction associated with such disorders. There is evidence, particularly in preclinical models, of a mediating role of the blood-brain barrier in the relationship between peripheral and central immunity. However, this relationship is poorly studied in human cohorts and, importantly, little is known about its effect on the quantification of radioligands used to monitor neuroinflammation in-vivo. Methods A recently developed non-invasive method for estimating the blood-to-brain influx rate constant ( K 1 ) (Maccioni et al., 2024) was applied to TSPO PET imaging, a proposed marker of neuroinflammation. In total, 358 dynamic TSPO PET scans from three different radiotracers ([¹¹C]-PK11195, [¹⁸F]-DPA714, and [¹¹C]-PBR28) were reanalyzed using data from healthy controls, as well as patients with depression and schizophrenia. The relationship between brain-wide K 1 estimates, peripheral inflammatory marker C-reactive protein (CRP), sex, anthropometric measures, and disease states was systematically evaluated. Results A brain-wide negative correlation between peripheral inflammation and K 1 was observed (range: [-0.33, -0.25]). Notably, this association was not influenced by diagnostic labels. Additionally, significant effects of body weight (or body mass index) and sex on K 1 were identified. The findings were consistent at both regional and voxel levels, as well as across the three radiotracers. Imaging transcriptomics analyses revealed that the effect of CRP on K 1 was associated with the expression of genes involved in transport and homeostasis. Discussion The study confirms that increased peripheral inflammation is associated with reduced blood-to-brain transport of TSPO tracers, suggesting a role for blood-brain barrier permeability in the observed effect. This finding supports the emerging model of peripheral-to-central immune interactions via brain barriers by Turkheimer and colleagues (2023). By considering variables such as body mass, sex, and peripheral inflammatory status, this research provides crucial insights into the use of TSPO PET in psychiatry and the interpretability of its findings. Biomedical Engineering Nuclear Medicine & Medical Imaging Psychiatry BBB Inflammation PET Psychiatry TSPO Full Text Additional Declarations The authors declare potential competing interests as follows: Reis Marques, T. has received honoraria for speaking and chairing from Lundbeck, Janssen, Astellas and Viatris and received honoraria to participate in advisory boards organized by Angelini Pharmaceuticals. He is an employee and shareholder of Pasithea Therapeutics. Dr Howes has received research funding from and/or participated in advisory/ speaker meetings organised by Abbvie, Alkermes, Angellini, Autifony, Biogen, BMS (Karuna), Boehringer-Ingelheim, Delix, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Jansenn, Karuna, Lundbeck, Merck, Neumora, Neurocrine, Ono, Ontrack/ Pangea, Otsuka, Sunovion, Teva, Recordati, Roche, Rovi and Viatris/ Mylan. He was previously a part-time employee of Lundbeck A/v. Dr Howes and Dr. Veronese have a patent for the use of dopaminergic imaging. All the other authors do not report any relevant conflict of interest. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants included in the studies. The BIODEP study was approved by the NRES Committee East of England Cambridge Central (REC reference:15/EE/0092) and the UK Administration of Radioactive Substances Advisory Committee. Supplementary Files SupplementaryMaterials.docx Supplementary Materials Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6648321","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":456816134,"identity":"ca296e76-4e58-4708-a35a-f60c4f4b4ac9","order_by":0,"name":"Leonardo Barzon","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABJElEQVRIie3RsWqEMBjA8e8oxCXcrZGI9wongot9GF3MIlK4xVEQvKUPUOhBX6Gla4eUQCb7Bh3uFic7lC4WOtR4cm2JbddC80eIBH/E8AGYTH+w+WE5ASDjDrIKBFi9AKwg0gnSyBzzz0Q3OnFJdCCgyMQxyCrl7vUudIGWzXOXPwKyn+SuBZHNaXkN+04nWDLvvGE+ONK/IHUDiGbM24JYI0eeTf4YSQOCuYgLEvngVaInaUAxiLgi6fRdlm1gvw2EvUCsiF3/QgjuPxhI6sO9IsPOTwQnCXU485FTr2dFLTDCWWJvVyyu+rvwKNHIwhLSbnnoLujmdtblwl1uHiRp8zC+uixv9t2pRj6OG1c8PGoialL8e/ClcY7H4ZpMJtN/7x0zo14+BPVaMAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0003-4517-221X","institution":"Department of Information Engineering, University of Padova, Padova, Italy","correspondingAuthor":true,"prefix":"","firstName":"Leonardo","middleName":"","lastName":"Barzon","suffix":""},{"id":456816135,"identity":"2639a9a2-cfbd-4a22-b71c-2546fdb3d3b5","order_by":1,"name":"Lucia Maccioni","email":"","orcid":"https://orcid.org/0000-0002-6564-2827","institution":"Department of Information Engineering, University of Padova, Padova, Italy","correspondingAuthor":false,"prefix":"","firstName":"Lucia","middleName":"","lastName":"Maccioni","suffix":""},{"id":456816136,"identity":"384a1988-2223-4ba1-a237-26f043193d03","order_by":2,"name":"Manuela Moretto","email":"","orcid":"","institution":"Department of Information Engineering, University of Padova, Padova, Italy","correspondingAuthor":false,"prefix":"","firstName":"Manuela","middleName":"","lastName":"Moretto","suffix":""},{"id":456816137,"identity":"1dd6ab52-6253-4dae-a7c2-b5aef58f2ba7","order_by":3,"name":"Alessio Giacomel","email":"","orcid":"","institution":"Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, UK","correspondingAuthor":false,"prefix":"","firstName":"Alessio","middleName":"","lastName":"Giacomel","suffix":""},{"id":456816138,"identity":"24114f47-5281-416d-8d61-06e0de0feae6","order_by":4,"name":"Julia J. 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He is an employee and shareholder of Pasithea Therapeutics. Dr Howes has received research funding from and/or participated in advisory/ speaker meetings organised by Abbvie, Alkermes, Angellini, Autifony, Biogen, BMS (Karuna), Boehringer-Ingelheim, Delix, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Jansenn, Karuna, Lundbeck, Merck, Neumora, Neurocrine, Ono, Ontrack/ Pangea, Otsuka, Sunovion, Teva, Recordati, Roche, Rovi and Viatris/ Mylan. He was previously a part-time employee of Lundbeck A/v. Dr Howes and Dr. Veronese have a patent for the use of dopaminergic imaging. All the other authors do not report any relevant conflict of interest.\u003c/p\u003e\n\u003cp\u003eAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants included in the studies. The BIODEP study was approved by the NRES Committee East of England Cambridge Central (REC reference:15/EE/0092) and the UK Administration of Radioactive Substances Advisory Committee.\u003c/p\u003e","formattedTitle":"Peripheral inflammation is associated with reduced influx of TSPO PET tracers into the brain: insights from a non-invasive mapping methodology","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University of Padua","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"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},"keywords":"BBB, Inflammation, PET, Psychiatry, TSPO","lastPublishedDoi":"10.21203/rs.3.rs-6648321/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6648321/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cu\u003eIntroduction\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eNeuroinflammation is a hallmark of various brain disorders, including neuropsychiatric conditions like major depressive disorder and schizophrenia. Increasing evidence suggests that both peripheral and central inflammation play a critical role in central nervous system dysfunction associated with such disorders. There is evidence, particularly in preclinical models, of a mediating role of the blood-brain barrier in the relationship between peripheral and central immunity. However, this relationship is poorly studied in human cohorts and, importantly, little is known about its effect on the quantification of radioligands used to monitor neuroinflammation in-vivo.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eMethods\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eA recently developed non-invasive method for estimating the blood-to-brain influx rate constant (\u003cem\u003eK\u003c/em\u003e\u003csub\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sub\u003e) (Maccioni et al., 2024) was applied to TSPO PET imaging, a proposed marker of neuroinflammation. In total, 358 dynamic TSPO PET scans from three different radiotracers ([¹¹C]-PK11195, [¹⁸F]-DPA714, and [¹¹C]-PBR28) were reanalyzed using data from healthy controls, as well as patients with depression and schizophrenia. The relationship between brain-wide \u003cem\u003eK\u003c/em\u003e\u003csub\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sub\u003e estimates, peripheral inflammatory marker C-reactive protein (CRP), sex, anthropometric measures, and disease states was systematically evaluated.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eResults\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eA brain-wide negative correlation between peripheral inflammation and \u003cem\u003eK\u003c/em\u003e\u003csub\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sub\u003e was observed (range: [-0.33, -0.25]). Notably, this association was not influenced by diagnostic labels. Additionally, significant effects of body weight (or body mass index) and sex on \u003cem\u003eK\u003c/em\u003e\u003csub\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sub\u003e were identified. The findings were consistent at both regional and voxel levels, as well as across the three radiotracers. Imaging transcriptomics analyses revealed that the effect of CRP on \u003cem\u003eK\u003c/em\u003e\u003csub\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sub\u003e was associated with the expression of genes involved in transport and homeostasis.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eDiscussion\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe study confirms that increased peripheral inflammation is associated with reduced blood-to-brain transport of TSPO tracers, suggesting a role for blood-brain barrier permeability in the observed effect. This finding supports the emerging model of peripheral-to-central immune interactions via brain barriers by Turkheimer and colleagues (2023). By considering variables such as body mass, sex, and peripheral inflammatory status, this research provides crucial insights into the use of TSPO PET in psychiatry and the interpretability of its findings.\u003c/p\u003e","manuscriptTitle":"Peripheral inflammation is associated with reduced influx of TSPO PET tracers into the brain: insights from a non-invasive mapping methodology","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2025-07-31 18:28:39","doi":"10.21203/rs.3.rs-6648321/v2","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}},{"code":1,"date":"2025-05-15 03:31:25","doi":"10.21203/rs.3.rs-6648321/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":"cef9df57-4353-45c0-b09b-0503ffe39eca","owner":[],"postedDate":"July 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":48552838,"name":"Biomedical Engineering"},{"id":48552839,"name":"Nuclear Medicine \u0026 Medical Imaging"},{"id":48552840,"name":"Psychiatry"}],"tags":[],"updatedAt":"2025-05-15T03:31:25+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-31 18:28:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-6648321","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6648321","identity":"rs-6648321","version":["v2"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}