{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T10:27:15Z","timestamp":1787308035309,"version":"build-2736575974"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SingHealth Fund -NNI Fund under its Eco-system of Dementia Care programme","award":["SHF(U)\/23\/GC-2C\/002(EC)"],"award-info":[{"award-number":["SHF(U)\/23\/GC-2C\/002(EC)"]}]},{"name":"SingHealth Fund -NNI Fund under its Eco-system of Dementia Care programme","award":["SHF(U)\/22\/GC5C\/007(EC)"],"award-info":[{"award-number":["SHF(U)\/22\/GC5C\/007(EC)"]}]},{"name":"Singapore\u2019s National Medical Research Council NMRC Centre Grant Programme Category 2","award":["NMRC\/CG2\/005a\/2022NNI"],"award-info":[{"award-number":["NMRC\/CG2\/005a\/2022NNI"]}]}],"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>Disturbances in brain fluid homeostasis are increasingly implicated in neurodegeneration. Imaging measures of structural alterations of the choroid plexus (CP) and impaired glymphatic transport have each been associated with cognitive decline, yet their potential interaction in humans remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We investigated the relationship between CP volume, glymphatic diffusion, and cognitive performance in 100 memory clinic patients. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) was used as an imaging proxy of glymphatic diffusion, and CP volume and WMH volume were derived from structural MRI using FastSurfer segmentation. Multivariable linear regression models examined associations between CP volume, ALPS index, and global cognitive performance measured by the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). Models were adjusted for age, sex, education, APOE \u03b54 status, WMH burden and plasma phosphorylated tau (pTau217). Interaction terms tested whether CP structure and glymphatic diffusion jointly influenced cognition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Larger CP volume was associated with lower ALPS index after adjustment for demographic and molecular covariates (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u202f=\u202f\u2212282.19,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.015). CP volume and ALPS index were not independently associated with MoCA scores; however, a significant interaction between CP volume and ALPS index was observed (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u202f=\u202f\u221213,299.09,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.036). The association between CP volume and cognitive performance depended on DTI-ALPS, such that larger CP volumes were associated with poorer MoCA scores at higher ALPS values, whereas CP volume showed little association with cognition at lower ALPS values. This interaction improved model fit compared with main-effects models (\n                      <jats:italic>\n                        R\n                        <jats:sup>2<\/jats:sup>\n                      <\/jats:italic>\n                      \u202f=\u202f0.31). The findings remained significant after adjusting for CSF volume and were replicated using MMSE as the outcome. Plasma pTau217 levels were strongly associated with worse cognition but did not significantly modify the CP-ALPS interaction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>CP enlargement is associated with glymphatic diffusion, and its relationship with cognitive performance varies across DTI-ALPS index values. These findings suggest that interactions between CSF regulatory systems may correlate with cognitive performance in a state-dependent manner. Notably, higher ALPS values in individuals with enlarged CP may reflect compensatory or altered perivascular fluid dynamics rather than preserved glymphatic function, highlighting the complexity of interpreting diffusion-based markers of brain clearance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1883244","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:39:48Z","timestamp":1785130788000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Choroid plexus enlargement is negatively associated with cognitive performance in a DTI-ALPS\u2013dependent manner"],"prefix":"10.3389","volume":"18","author":[{"given":"Nicole I. Y. Z.","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Welton","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute","place":["Singapore, Singapore"]},{"name":"Neuroscience Academic Clinical Programme, Duke NUS Medical School","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi Jayne","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyed Ehsan","family":"Saffari","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elenor","family":"Morgenroth","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J. Y.","family":"Foo","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi Rou","family":"Kwok","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu Chin","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui Jin","family":"Chiew","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kok Pin","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute","place":["Singapore, Singapore"]},{"name":"Neuroscience Academic Clinical Programme, Duke NUS Medical School","place":["Singapore, Singapore"]},{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon K. S.","family":"Ting","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute","place":["Singapore, Singapore"]},{"name":"Neuroscience Academic Clinical Programme, Duke NUS Medical School","place":["Singapore, Singapore"]},{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumeet","family":"Kumar","sequence":"additional","affiliation":[{"name":"Neuroscience Academic Clinical Programme, Duke NUS Medical School","place":["Singapore, Singapore"]},{"name":"Department of Neuroradiology, National Neuroscience Institute","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Keong","sequence":"additional","affiliation":[{"name":"Neuroscience Academic Clinical Programme, Duke NUS Medical School","place":["Singapore, Singapore"]},{"name":"Department of Neurosurgery, National Neuroscience Institute, Singapore General Hospital","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adeline S. L.","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Neuroscience Institute","place":["Singapore, Singapore"]},{"name":"Neuroscience Academic Clinical Programme, Duke NUS Medical School","place":["Singapore, Singapore"]},{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"102926","DOI":"10.1016\/j.nicl.2021.102926","article-title":"Choroid plexus enlargement is associated with neuroinflammation and reduction of blood brain barrier permeability in depression","volume":"33","author":"Althubaity","year":"2022","journal-title":"Neuroimage Clin"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"101","DOI":"10.3389\/fnana.2017.00101","article-title":"The paravascular pathway for brain waste clearance: current understanding, significance and controversy","volume":"11","author":"Bacyinski","year":"2017","journal-title":"Front. Neuroanat."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1847","DOI":"10.1152\/physrev.00004.2013","article-title":"Cerebrospinal fluid secretion by the choroid plexus","volume":"93","author":"Damkier","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1038\/s41392-024-01997-9","article-title":"Beyond borders: the choroid plexus-immune communication during neuroinflammation","volume":"9","author":"Dumas","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2384","DOI":"10.1093\/brain\/awaf033","article-title":"Plasma phosphorylated tau217 strongly associates with memory deficits in the Alzheimer\u2019s disease spectrum","volume":"148","author":"Fern\u00e1ndez Arias","year":"2025","journal-title":"Brain"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"e213676","DOI":"10.1212\/WNL.0000000000213676","article-title":"Associations between changes in levels of phosphorylated tau and severity of cognitive impairment in early Alzheimer disease","volume":"104","author":"Gonzalez-Ortiz","year":"2025","journal-title":"Neurology"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"2576","DOI":"10.1093\/brain\/awaa179","article-title":"Impaired glymphatic function and clearance of tau in an Alzheimer\u2019s disease model","volume":"143","author":"Harrison","year":"2020","journal-title":"Brain"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"117012","DOI":"10.1016\/j.neuroimage.2020.117012","article-title":"FastSurfer - a fast and accurate deep learning based neuroimaging pipeline","volume":"219","author":"Henschel","year":"2020","journal-title":"NeuroImage"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1002\/ana.26516","article-title":"Magnetic resonance images implicate that glymphatic alterations mediate cognitive dysfunction in Alzheimer disease","volume":"93","author":"Hsu","year":"2023","journal-title":"Ann. Neurol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"3251","DOI":"10.1002\/alz.13789","article-title":"Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer\u2019s disease","volume":"20","author":"Huang","year":"2024","journal-title":"Alzheimers Dement."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"2583","DOI":"10.1007\/s11064-015-1581-6","article-title":"The Glymphatic system \u2013 a beginner\u2019s guide","volume":"40","author":"Jessen","year":"2015","journal-title":"Neurochem. Res."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.jcm.2016.02.012","article-title":"A guideline of selecting and reporting Intraclass correlation coefficients for reliability research","volume":"15","author":"Koo","year":"2016","journal-title":"J. Chiropr. Med."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1177\/13872877261426578","article-title":"Choroid plexus-glymphatic axis disruption in Alzheimer\u2019s disease: cerebrospinal fluid expansion as a mediator of metabolic dysfunction and cognitive decline","volume":"110","author":"Lv","year":"2026","journal-title":"J. Alzheimer's Dis"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1001\/jamaneurol.2025.4721","article-title":"Plasma phosphorylated tau 217 and amyloid burden in older adults without cognitive impairment: a Meta-analysis","volume":"83","author":"Malek-Ahmadi","year":"2026","journal-title":"JAMA Neurol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.nbd.2016.05.015","article-title":"Suppression of glymphatic fluid transport in a mouse model of Alzheimer\u2019s disease","volume":"93","author":"Peng","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"e200414","DOI":"10.1212\/NXI.0000000000200414","article-title":"Glymphatic system may mediate the relation between choroid plexus and brain damage in multiple sclerosis","volume":"12","author":"Preziosa","year":"2025","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"102588","DOI":"10.1016\/j.coi.2025.102588","article-title":"The choroid plexus in inflammatory and degenerative diseases of the central nervous system","volume":"95","author":"Reynolds","year":"2025","journal-title":"Curr. Opin. Immunol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"121705","DOI":"10.1016\/j.neuroimage.2026.121705","article-title":"ALPS index and choroid plexus volume as indirect MRI biomarkers of glymphatic function for predicting cognitive decline in Parkinson\u2019s disease","volume":"326","author":"Ruan","year":"2026","journal-title":"NeuroImage"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1186\/s13195-025-01842-3","article-title":"Evaluation and interpretation of DTI-ALPS, a proposed surrogate marker for glymphatic clearance, in a large population-based sample","volume":"17","author":"Satpathi","year":"2025","journal-title":"Alzheimer's Res. Ther."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s12987-020-00196-2","article-title":"Choroid plexus and the blood-cerebrospinal fluid barrier in disease","volume":"17","author":"Sol\u00e1r","year":"2020","journal-title":"Fluids Barriers CNS"},{"key":"ref22","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-026-02008-5","article-title":"Evaluating the real-world performance of plasma pTau217 and pTau181 in a southeast Asian tertiary memory clinic","volume":"18","author":"Tan","year":"2026","journal-title":"Alzheimer's Res. Ther."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"P241","DOI":"10.1016\/j.jalz.2016.06.429","article-title":"Higher peripheral TREM2 mRNA expression levels are related to cognitive deficits and hippocampal atrophy in Alzheimer\u2019s disease and amnestic MCI","volume":"12","author":"Tan","year":"2016","journal-title":"Alzheimers Dement."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"268","DOI":"10.2463\/mrms.rev.2023-0175","article-title":"Diffusion tensor image analysis ALong the perivascular space (DTI-ALPS): revisiting the meaning and significance of the method","volume":"23","author":"Taoka","year":"2024","journal-title":"Magn. Reson. Med. Sci."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/nrneurol.2015.119","article-title":"Clearance systems in the brain-implications for Alzheimer disease","volume":"11","author":"Tarasoff-Conway","year":"2015","journal-title":"Nat. Rev. Neurol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"116137","DOI":"10.1016\/j.neuroimage.2019.116137","article-title":"MRtrix3: a fast, flexible and open software framework for medical image processing and visualisation","volume":"202","author":"Tournier","year":"2019","journal-title":"NeuroImage"},{"key":"ref27","doi-asserted-by":"publisher","DOI":"10.3390\/cells11050919","article-title":"Waste clearance in the brain and Neuroinflammation: a novel perspective on biomarker and drug target discovery in Alzheimer\u2019s disease","volume":"11","author":"Uchida","year":"2022","journal-title":"Cells"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"5297","DOI":"10.1007\/s00330-023-10572-9","article-title":"Choroid plexus enlargement in mild cognitive impairment on MRI: a large cohort study","volume":"34","author":"Umemura","year":"2024","journal-title":"Eur. Radiol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"4946","DOI":"10.1016\/j.cell.2024.07.002","article-title":"The choroid plexus synergizes with immune cells during neuroinflammation","volume":"187","author":"Xu","year":"2024","journal-title":"Cell"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"bhae265","DOI":"10.1093\/cercor\/bhae265","article-title":"Glymphatic dysfunction mediates the influence of choroid plexus enlargement on information processing speed in patients with white matter hyperintensities","volume":"34","author":"Xu","year":"2024","journal-title":"Cereb. Cortex"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"3587","DOI":"10.1007\/s00234-025-03761-4","article-title":"The relationship between choroid plexus volume, DTI-ALPS index, kidney function, and amyloid pathology in alzheimer\u2019s disease","volume":"67","author":"Yu","year":"2025","journal-title":"Neuroradiology"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"e70810","DOI":"10.1002\/cns.70810","article-title":"Glymphatic system dysfunction in central nervous system diseases","volume":"32","author":"Zahran","year":"2026","journal-title":"CNS Neurosci. Ther."}],"updated-by":[{"DOI":"10.3389\/fnagi.2026.1951916","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000}}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2026.1883244\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T10:00:18Z","timestamp":1787306418000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2026.1883244\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":32,"alternative-id":["10.3389\/fnagi.2026.1883244"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2026.1883244","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]},"article-number":"1883244"}}