{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T22:39:32Z","timestamp":1793054372546,"version":"4.5.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"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. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Klotho is a longevity-associated protein found in membrane-bound and secreted forms, with the latter detectable in blood and cerebrospinal fluid (CSF). Circulating Klotho mainly originates from the kidney, while the choroid plexus (CP) secretes it into the CSF. CP dysfunction is associated with reduced Klotho expression and neurodegeneration and may result in CP enlargement on magnetic resonance imaging (MRI). In this preliminary study, we investigated Klotho levels in neurodegenerative patients and their association with CP enlargement.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>We retrospectively analyzed 40 patients from the IRCCS Ca\u2032 Granda Ospedale Policlinico, Milan, including 32 neurodegenerative patients (Deg) and 8 cognitively normal controls (NonDeg). CSF and serum Klotho levels were measured using an ELISA kit. KL-VS and apolipoprotein E (APOE) genotyping were performed. CP volumes were segmented using ITK-SNAP and normalized to total intracranial volume (TIV), resulting in a measure known as the CP volume fraction (CPVF). A multivariate linear regression analysis was conducted, adjusting for diagnostic group, age, sex, APOE\u03b54, CPVF, and gray matter volume fraction (GMVF).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CSF Klotho levels were significantly lower in Deg patients (mean\u202f=\u202f729\u202fpg.\/mL, SD\u202f=\u202f364) compared to NonDeg individuals (mean\u202f=\u202f1,077\u202fpg.\/mL, SD\u202f=\u202f220) (\n                      <jats:italic>t<\/jats:italic>\n                      =\u202f3.44,\n                      <jats:italic>p<\/jats:italic>\n                      =\u202f0.003). Higher CPVF (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      =\u202f\u22120.34, 95% CI [\u22120.64, \u22120.05],\n                      <jats:italic>p<\/jats:italic>\n                      =\u202f0.023) was independently associated with lower CSF Klotho levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In this preliminary study, we observed a strong association between CSF Klotho levels and CP enlargement. Reduced CSF Klotho levels, due to CP dysfunction, may contribute to neurodegeneration. If confirmed in larger cohorts, this association suggests that CSF Klotho may serve as a biomarker for CP enlargement, possibly reflecting its underlying dysfunction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2025.1688996","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T06:30:17Z","timestamp":1764225017000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Association between Klotho levels in cerebrospinal fluid and choroid plexus enlargement in neurodegeneration"],"prefix":"10.3389","volume":"17","author":[{"given":"Luca","family":"Sacchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Arcaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Bocca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lia","family":"Schmid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Carandini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Ghezzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Pintus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Margherita","family":"Pietroboni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Fenoglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Serpente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Conte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Triulzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Lanzarotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Dolci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Galimberti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Arighi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"e0267298","DOI":"10.1371\/journal.pone.0267298","article-title":"Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of klotho heterozygosity on disease risk","volume":"17","author":"Ali","year":"2022","journal-title":"PLoS One"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e1218","DOI":"10.1212\/WNL.0000000000207600","article-title":"Association of Choroid Plexus Volume with Serum Biomarkers, clinical features, and disease severity in patients with frontotemporal lobar degeneration Spectrum","volume":"101","author":"Assogna","year":"2023","journal-title":"Neurology"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.neurobiolaging.2021.01.008","article-title":"KL\u2217VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE\u22174 carriers","volume":"101","author":"Belloy","year":"2021","journal-title":"Neurobiol. 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Neuroradiol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"3537","DOI":"10.1002\/alz.12970","article-title":"Pathogenesis of Alzheimer\u2019s disease: involvement of the choroid plexus","volume":"19","author":"\u010carna","year":"2023","journal-title":"Alzheimers Dement."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"917","DOI":"10.3390\/genes14040917","article-title":"Interaction between KLOTHO-VS heterozygosity and APOE \u03b54 allele predicts rate of cognitive decline in late-onset Alzheimer\u2019s disease","volume":"14","author":"Chen","year":"2023","journal-title":"Genes"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1927","DOI":"10.1523\/JNEUROSCI.2080-12.2013","article-title":"The antiaging protein klotho enhances oligodendrocyte maturation and myelination of the CNS","volume":"33","author":"Chen","year":"2013","journal-title":"J. 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Nephrol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.3233\/JAD-215719","article-title":"Serum levels of \u03b1-klotho are correlated with cerebrospinal fluid levels and predict measures of cognitive function","volume":"86","author":"Kundu","year":"2022","journal-title":"JAD"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/s41581-018-0078-3","article-title":"The klotho proteins in health and disease","volume":"15","author":"Kuro-o","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/36285","article-title":"Mutation of the mouse klotho gene leads to a syndrome resembling ageing","volume":"390","author":"Kuro-o","year":"1997","journal-title":"Nature"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1002\/ana.26648","article-title":"Choroid plexus enlargement exacerbates White matter hyperintensity growth through glymphatic impairment","volume":"94","author":"Li","year":"2023","journal-title":"Ann. Neurol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"e0143623","DOI":"10.1371\/journal.pone.0143623","article-title":"Secreted and transmembrane \u03b1Klotho isoforms have different Spatio-temporal profiles in the brain during aging and Alzheimer\u2019s disease progression","volume":"10","author":"Mass\u00f3","year":"2015","journal-title":"PLoS One"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1555","DOI":"10.1093\/ckj\/sfad093","article-title":"Is there a role in acute kidney injury for FGF23 and klotho?","volume":"16","author":"Mattinzoli","year":"2023","journal-title":"Clin. Kidney J."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1093\/gerona\/glv163","article-title":"Genetic variants in KLOTHO associate with cognitive function in the oldest old group","volume":"71","author":"Mengel-From","year":"2016","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"3825","DOI":"10.1038\/s41467-021-23755-z","article-title":"KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer\u2019s disease","volume":"12","author":"Neitzel","year":"2021","journal-title":"Nat. Commun."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"931331","DOI":"10.3389\/fragi.2022.931331","article-title":"Pathobiology of the klotho antiaging protein and therapeutic considerations","volume":"3","author":"Prud\u2019homme","year":"2022","journal-title":"Front. 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Disord."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1007\/s12031-019-01345-5","article-title":"Klotho ameliorates cellular inflammation via suppression of cytokine release and upregulation of miR-29a in the PBMCs of diagnosed Alzheimer\u2019s disease patients","volume":"69","author":"Sedighi","year":"2019","journal-title":"J. Mol. Neurosci."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.neulet.2013.10.058","article-title":"Klotho in the cerebrospinal fluid of adults with and without Alzheimer\u2019s disease","volume":"558","author":"Semba","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1093\/gerona\/glv140","article-title":"Plasma klotho and cognitive decline in older adults: findings From the InCHIANTI study","volume":"71","author":"Shardell","year":"2016","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.3233\/JAD-230322","article-title":"Klotho gene expression is decreased in peripheral blood mononuclear cells in patients with Alzheimer\u2019s disease and frontotemporal dementia","volume":"94","author":"Sorrentino","year":"2023","journal-title":"J. Alzheimers Dis."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"51","DOI":"10.3233\/JAD-210181","article-title":"Testing for interactions between APOE and klotho genotypes on cognitive, dementia, and brain imaging metrics in UK biobank","volume":"83","author":"Tank","year":"2021","journal-title":"J. Alzheimers Dis."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1038\/s41398-023-02632-x","article-title":"Relationship of klotho with cognition and dementia: results from the NHANES 2011\u20132014 and mendelian randomization study","volume":"13","author":"Wu","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1007\/s10072-024-07809-w","article-title":"Serum alpha klotho levels in Parkinson\u2019s disease","volume":"46","author":"Yalcin","year":"2024","journal-title":"Neurol. Sci."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1007\/s11682-016-9598-2","article-title":"Systemic klotho is associated with KLOTHO variation and predicts intrinsic cortical connectivity in healthy human aging","volume":"11","author":"Yokoyama","year":"2017","journal-title":"Brain Imaging Behav."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1007\/s12031-019-01356-2","article-title":"Klotho is neuroprotective in the superoxide dismutase (SOD1G93A) mouse model of ALS","volume":"69","author":"Zeldich","year":"2019","journal-title":"J. Mol. Neurosci."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.neurobiolaging.2019.02.003","article-title":"Lentiviral vector\u2013mediated overexpression of klotho in the brain improves Alzheimer\u2019s disease\u2013like pathology and cognitive deficits in mice","volume":"78","author":"Zeng","year":"2019","journal-title":"Neurobiol. Aging"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"e13239","DOI":"10.1111\/acel.13239","article-title":"Klotho overexpression improves amyloid-\u03b2 clearance and cognition in the APP\/PS1 mouse model of Alzheimer\u2019s disease","volume":"19","author":"Zhao","year":"2020","journal-title":"Aging Cell"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"E11388","DOI":"10.1073\/pnas.1808609115","article-title":"Klotho controls the brain\u2013immune system interface in the choroid plexus","volume":"115","author":"Zhu","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"e16388","DOI":"10.1111\/ene.16388","article-title":"Association of elevated cerebrospinal fluid levels of the longevity protein \u03b1-klotho with a delayed onset of cognitive impairment in Parkinson\u2019s disease patients","volume":"31","author":"Zimmermann","year":"2024","journal-title":"Eur. J. Neurol."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1111\/ene.14733","article-title":"The longevity gene klotho and its cerebrospinal fluid protein profiles as a modifier for Parkinson\u2019s disease","volume":"28","author":"Zimmermann","year":"2021","journal-title":"Eur. J. Neurol."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2025.1688996\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T06:30:18Z","timestamp":1764225018000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2025.1688996\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,27]]},"references-count":50,"alternative-id":["10.3389\/fnagi.2025.1688996"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2025.1688996","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,27]]},"article-number":"1688996"}}