Bypass the Brain: Deep Cervical Lymphatic-Venous Anastomosis Restores the Default Mode Network in Late-stage Alzheimer's Disease

Bypass the Brain: Deep Cervical Lymphatic-Venous Anastomosis Restores the Default Mode Network in Late-stage Alzheimer's Disease | 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 Article Bypass the Brain: Deep Cervical Lymphatic-Venous Anastomosis Restores the Default Mode Network in Late-stage Alzheimer's Disease Haishuo Xia, Jingyu Chen, Xianfei Yang, Zhiming Zhen, Chenghai Zuo, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7584273/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 The limited efficacy of late-stage Alzheimer’s disease (AD) therapies necessitates exploration of novel therapeutic strategies. Deep cervical lymphatic-venous anastomosis (dcLVA), a microsurgical procedure intended to augment cerebral drainage, represents a promising strategy, yet its efficacy lacks neurobiological evidence. In this longitudinal, single-arm study, 17 patients with moderate-to-severe AD underwent 7-Tesla resting-state functional MRI and neurocognitive assessment at baseline and at 1.52 ± 1.38 months post-dcLVA. Graph-theoretical analyses did not reveal significant reconfiguration of whole-brain network topology. Nevertheless, we observed selectively increased connectivity within the default mode network (DMN), most prominently in temporal regions. Cognitive function measured by mini-mental state examination was improved after dcLVA ( p = 0.024), and was correlated with increased connectivity in bilateral temporal regions. To our knowledge, this study provided the first neuroimaging evidence that controversial dcLVA modulates functional networks in human patients with AD, and highlight DMN connectivity as a quantifiable biomarker for clearance-focused interventions. Health sciences/Diseases/Neurological disorders/Neurodegeneration Biological sciences/Neuroscience/Neural ageing Default mode network glymphatic system functional connectivity lymphatic-venous anastomosis Alzheimer's disease Figures Figure 5 Figure 6 Figure 7 Full Text Additional Declarations The authors declare no competing interests. Supplementary Files SupplementaryMaterials20250910.docx SupplementaryMaterials 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. 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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-7584273","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":536973861,"identity":"7bc0fce2-a40a-4604-a90a-7815b40b5f37","order_by":0,"name":"Haishuo Xia","email":"","orcid":"","institution":"Key Laboratory of Cognition and Personality of Ministry of Education, Faculty of Psychology, Southwest University","correspondingAuthor":false,"prefix":"","firstName":"Haishuo","middleName":"","lastName":"Xia","suffix":""},{"id":536973862,"identity":"248efd4c-fc71-41bb-97da-68df7077d2c7","order_by":1,"name":"Jingyu 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5","display":"","copyAsset":false,"role":"figure","size":537280,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChanges in graph theory parameters for regions within the default mode network before and after treatment. \u003c/strong\u003eEach pair of violin plots depicts pre-treatment (left) and post-treatment (right) data. Only the PC in the bilateral temporal lobes passed FDR correction within the DMN (\u003cem\u003eq\u003c/em\u003e \u0026lt; 0.05); other graph theory metrics showed significance only at an uncorrected \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05 threshold. Furthermore, due to space limitations, detailed results for BC are provided in the Figure S2. PC, Participation Coefficient; DC, Degree Centrality; Ne, Nodal Efficiency; SPL, Shortest Path Length; BC, Betweenness Centrality. Statistical significance: n.s., not significant; \u003csup\u003e*\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05, \u003csup\u003e**\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e\u0026lt;0.01,\u003csup\u003e***\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e\u0026lt;0.001.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7584273/v2/fa81f864daede01f36c67904.png"},{"id":95409535,"identity":"90243bac-2e1c-45f3-ae7f-d3780abe91aa","added_by":"auto","created_at":"2025-11-07 18:28:20","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":596957,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChanges in functional connectivity of DMN regions to other brain regions before and after treatment (FDR-corrected, \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e \u0026lt; 0.05).\u003c/strong\u003e Significant increases in functional connectivity were observed from the bilateral temporal lobes to the limbic, occipital, parietal, and prefrontal cortices. Additionally, increased connectivity was found from the left parahippocampal gyrus to the frontal and occipital lobes, and from the medial prefrontal cortex to the bilateral temporal lobes. Given that parietal lobe connectivity to other brain regions did not show any significantly corrected cortical areas before and after treatment and is thus not presented.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7584273/v2/5f3997ff8731b813c95ccb1b.png"},{"id":95526556,"identity":"5f1f4165-f6bf-4a28-8851-54eba149206a","added_by":"auto","created_at":"2025-11-10 10:07:14","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":259065,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImproved bilateral temporal lobe function correlated with enhanced cognition and ameliorated neuropsychiatric symptoms.\u003c/strong\u003e The x-axis represents the change in graph theory metrics (△: post- minus pre-treatment) for the temporal lobes within the DMN. The y-axis shows the post- minus pre-treatment differences in clinical assessment scores. A higher PC value on the x-axis indicates increased functional integration of DMN regions with other functional networks, while a lower shortest path length value signifies improved global efficiency of DMN regions. Abbreviations: PC, Participation Coefficient. SPL, Shortest Path Length.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7584273/v2/ceafc42f8361c4697afe88b3.png"},{"id":95531605,"identity":"33a5e4a7-0e45-4a2d-b163-0ed6d8e7bde1","added_by":"auto","created_at":"2025-11-10 10:23:25","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1413395,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript20251029.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7584273/v2_covered_d7f29068-b952-4185-8050-c614380c670e.pdf"},{"id":95527461,"identity":"41e1b18e-5827-4766-825a-9b75bf893759","added_by":"auto","created_at":"2025-11-10 10:13:44","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":330847,"visible":true,"origin":"","legend":"SupplementaryMaterials","description":"","filename":"SupplementaryMaterials20250910.docx","url":"https://assets-eu.researchsquare.com/files/rs-7584273/v2/e114e67a33380fbc441b571e.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"Bypass the Brain: Deep Cervical Lymphatic-Venous Anastomosis Restores the Default Mode Network in Late-stage Alzheimer's Disease","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","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":"Default mode network, glymphatic system, functional connectivity, lymphatic-venous anastomosis, Alzheimer's disease","lastPublishedDoi":"10.21203/rs.3.rs-7584273/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7584273/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe limited efficacy of late-stage Alzheimer\u0026rsquo;s disease (AD) therapies necessitates exploration of novel therapeutic strategies. Deep cervical lymphatic-venous anastomosis (dcLVA), a microsurgical procedure intended to augment cerebral drainage, represents a promising strategy, yet its efficacy lacks neurobiological evidence. In this longitudinal, single-arm study, 17 patients with moderate-to-severe AD underwent 7-Tesla resting-state functional MRI and neurocognitive assessment at baseline and at 1.52\u0026thinsp;\u0026plusmn;\u0026thinsp;1.38 months post-dcLVA. Graph-theoretical analyses did not reveal significant reconfiguration of whole-brain network topology. Nevertheless, we observed selectively increased connectivity within the default mode network (DMN), most prominently in temporal regions. Cognitive function measured by mini-mental state examination was improved after dcLVA (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024), and was correlated with increased connectivity in bilateral temporal regions. To our knowledge, this study provided the first neuroimaging evidence that controversial dcLVA modulates functional networks in human patients with AD, and highlight DMN connectivity as a quantifiable biomarker for clearance-focused interventions.\u003c/p\u003e","manuscriptTitle":"Bypass the Brain: Deep Cervical Lymphatic-Venous Anastomosis Restores the Default Mode Network in Late-stage Alzheimer's Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2025-11-07 18:28:15","doi":"10.21203/rs.3.rs-7584273/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":"2025-09-23 07:53:23","doi":"10.21203/rs.3.rs-7584273/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":"60ad3d9a-f698-4995-b88f-828d194dc4b3","owner":[],"postedDate":"November 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":57102558,"name":"Health sciences/Diseases/Neurological disorders/Neurodegeneration"},{"id":57102559,"name":"Biological sciences/Neuroscience/Neural ageing"}],"tags":[],"updatedAt":"2025-10-06T16:34:51+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-07 18:28:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-7584273","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7584273","identity":"rs-7584273","version":["v2"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}