{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T06:16:19Z","timestamp":1778220979357,"version":"3.51.4"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"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>Cognitive impairment is a major determinant of disability in Parkinson\u2019s disease (PD), underscoring the need for biomarkers that reflect its underlying pathophysiology. Plasma biomarkers, including phosphorylated tau at threonine 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), are promising candidates, yet their independent predictive value and the pathways by which they relate to cognitive function in PD remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We enrolled 89 PD patients without dementia (37 with normal cognition and 52 with mild cognitive impairment) and 40 healthy controls. Plasma biomarkers were measured using single-molecule array technology. All participants underwent high-resolution structural magnetic resonance imaging and cognitive assessment with the Montreal Cognitive Assessment (MoCA). Hierarchical regression evaluated the independent contribution of each biomarker to MoCA scores. Mediation and moderated mediation analyses were then conducted to test whether atrophy in brain regions of interest mediates the effects of biomarkers on cognitive function and whether these pathways were moderated by cognitive status.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Plasma p-tau181, GFAP, and NfL were each independently associated with worse global cognition. The effects of all three biomarkers were significantly and specifically mediated by atrophy of the entorhinal cortex (ERC), but not by other tested regions. Critically, the mediation pathway for NfL was specifically moderated by cognitive status, being significant only in PD patients with mild cognitive impairment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The associations of plasma p-tau181, GFAP, and NfL on cognitive impairment in PD converges on ERC atrophy. The association between NfL and cognition via ERC atrophy is dynamically potentiated at the mild cognitive impairment stage, positioning NfL as a stage-specific biomarker. An integrative model combining these plasma biomarkers with ERC integrity could enhance risk stratification for cognitive impairment in PD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1791756","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T05:56:17Z","timestamp":1778219777000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Entorhinal cortex atrophy mediates the association of plasma p-tau181, GFAP, and NfL with cognitive impairment in Parkinson\u2019s disease"],"prefix":"10.3389","volume":"18","author":[{"given":"Qiangqiang","family":"Wan","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Wuhan No. 1 Hospital","place":["Wuhan, China"]},{"name":"Engineering Research Center of TCM Protection Technology and New Product Development for the Elderly Brain Health, Ministry of Education, Hubei University of Chinese Medicine","place":["Wuhan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyu","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Neurology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhongwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Shan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gui","family":"Mei","sequence":"additional","affiliation":[{"name":"Department of Neurology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luqi","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lan","family":"Wang","sequence":"additional","affiliation":[{"name":"Hubei Provincial Hospital of Traditional Chinese Medicine","place":["Wuhan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongfen","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Radiology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/s41572-021-00280-3","article-title":"Parkinson disease-associated cognitive impairment.","volume":"7","author":"Aarsland","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"B2","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/S0140-6736(23)01419-8","article-title":"The epidemiology of Parkinson\u2019s disease.","volume":"403","author":"Ben-Shlomo","year":"2024","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1002\/alz.12301","article-title":"Plasma p-tau181, p-tau217, and other blood-based Alzheimer\u2019s disease biomarkers in a multi-ethnic, community study.","volume":"17","author":"Brickman","year":"2021","journal-title":"Alzheimer\u2019s Dement."},{"key":"B4","doi-asserted-by":"publisher","first-page":"6279","DOI":"10.3390\/ijms21176279","article-title":"Interaction between cognitive reserve and biomarkers in Alzheimer disease.","volume":"21","author":"Carapelle","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"281","DOI":"10.4103\/NRR.NRR-D-24-00592","article-title":"Potential biofluid markers for cognitive impairment in Parkinson\u2019s disease.","volume":"21","author":"Chen","year":"2026","journal-title":"Neural Regen. Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1759","DOI":"10.3390\/jcm12051759","article-title":"The protective role of cognitive reserve in mild cognitive impairment: A systematic review.","volume":"12","author":"Corbo","year":"2023","journal-title":"J. Clin. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"283","DOI":"10.3233\/JPD-202166","article-title":"Statistically defined Parkinson\u2019s disease executive and memory cognitive phenotypes: Demographic, behavioral, and structural neuroimaging comparisons.","volume":"11","author":"Crowley","year":"2021","journal-title":"JPD"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1200","DOI":"10.1002\/mds.30181","article-title":"Plasma biomarkers and disease prognosis in mild cognitive impairment with lewy bodies.","volume":"40","author":"Donaghy","year":"2025","journal-title":"Movement Disord."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1002\/alz.12508","article-title":"Plasma p-tau181 shows stronger network association to Alzheimer\u2019s disease dementia than neurofilament light and total tau.","volume":"18","author":"Frank","year":"2022","journal-title":"Alzheimer\u2019s Dement."},{"key":"B10","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s13024-025-00822-3","article-title":"Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer\u2019s disease.","volume":"20","author":"Franzmeier","year":"2025","journal-title":"Mol. Neurodegener."},{"key":"B11","doi-asserted-by":"publisher","first-page":"4270","DOI":"10.1007\/s00415-022-11055-5","article-title":"Plasma neurofilament light chain as a biomarker of Alzheimer\u2019s disease in subjective cognitive decline and mild cognitive impairment.","volume":"269","author":"Giacomucci","year":"2022","journal-title":"J. Neurol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1002\/mds.24938","article-title":"Entorhinal cortex atrophy differentiates Parkinson\u2019s disease patients with and without dementia.","volume":"27","author":"Goldman","year":"2012","journal-title":"Movement Disord."},{"key":"B13","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s13024-024-00750-8","article-title":"Astrocyte reactivity is associated with tau tangle load and cortical thinning in Alzheimer\u2019s disease.","volume":"19","author":"Guo","year":"2024","journal-title":"Mol. Neurodegener."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e14594","DOI":"10.1002\/alz.14594","article-title":"White matter injury, plasma Alzheimer\u2019s disease, and neurodegenerative biomarkers on cognitive decline in community-dwelling older adults: A 10-year longitudinal study.","volume":"21","author":"Hu","year":"2025","journal-title":"Alzheimer\u2019s Dement."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.14336\/AD.2018.1116","article-title":"Entorhinal cortex atrophy in early, drug-naive Parkinson\u2019s disease with mild cognitive impairment.","volume":"10","author":"Jia","year":"2019","journal-title":"Aging Dis."},{"key":"B16","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/s41582-018-0058-z","article-title":"Neurofilaments as biomarkers in neurological disorders.","volume":"14","author":"Khalil","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e70626","DOI":"10.1002\/alz.70626","article-title":"Moderating effects of plasma glial fibrillary acidic protein along the Alzheimer\u2019s disease continuum.","volume":"21","author":"Lee","year":"2025","journal-title":"Alzheimer\u2019s Dement."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e70242","DOI":"10.1002\/alz.70242","article-title":"Relationships between neuropsychiatric symptoms, subtypes of astrocyte activities, and brain pathologies in Alzheimer\u2019s disease and Parkinson\u2019s disease.","volume":"21","author":"Li","year":"2025","journal-title":"Alzheimer\u2019s Dement."},{"key":"B19","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s40035-024-00407-y","article-title":"Overlaps and divergences between tauopathies and synucleinopathies: A duet of neurodegeneration.","volume":"13","author":"Li","year":"2024","journal-title":"Transl. Neurodegener."},{"key":"B20","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1186\/s12974-023-02843-5","article-title":"Cerebrospinal fluid GFAP is a predictive biomarker for conversion to dementia and Alzheimer\u2019s disease-associated biomarkers alterations among de novo Parkinson\u2019s disease patients: A prospective cohort study.","volume":"20","author":"Liu","year":"2023","journal-title":"J. Neuroinflamm."},{"key":"B21","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.neurobiolaging.2017.03.012","article-title":"Longitudinal whole-brain atrophy and ventricular enlargement in nondemented Parkinson\u2019s disease.","volume":"55","author":"Mak","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e16089","DOI":"10.1111\/ene.16089","article-title":"Plasma neurofilament light chain predicts Alzheimer\u2019s disease in patients with subjective cognitive decline and mild cognitive impairment: A cross-sectional and longitudinal study.","volume":"31","author":"Mazzeo","year":"2024","journal-title":"Eur. J. Neurol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/s13195-019-0479-y","article-title":"Concepts for brain aging: Resistance, resilience, reserve, and compensation.","volume":"11","author":"Montine","year":"2019","journal-title":"Alz. Res. Therapy"},{"key":"B24","doi-asserted-by":"publisher","first-page":"8587","DOI":"10.1523\/JNEUROSCI.0679-22.2022","article-title":"Integrity of neuronal size in the entorhinal cortex is a biological substrate of exceptional cognitive aging.","volume":"42","author":"Nassif","year":"2022","journal-title":"J. Neurosci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1358","DOI":"10.1002\/alz.12790","article-title":"Relationship of serum beta-synuclein with blood biomarkers and brain atrophy.","volume":"19","author":"Oeckl","year":"2023","journal-title":"Alzheimer\u2019s Dement."},{"key":"B26","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1002\/alz.13450","article-title":"Astrocyte biomarkers GFAP and YKL-40 mediate early Alzheimer\u2019s disease progression.","volume":"20","author":"Pelkmans","year":"2024","journal-title":"Alzheimer\u2019s Dement."},{"key":"B27","doi-asserted-by":"publisher","first-page":"7537","DOI":"10.1007\/s00415-024-12669-7","article-title":"Plasma NfL, GFAP, amyloid, and p-tau species as Prognostic biomarkers in Parkinson\u2019s disease.","volume":"271","author":"Pilotto","year":"2024","journal-title":"J. Neurol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"709","DOI":"10.4103\/1673-5374.382248","article-title":"Astrocytes dynamically regulate the blood-brain barrier in the healthy brain.","volume":"19","author":"Poci\u016bt\u0117","year":"2024","journal-title":"Neural Regen. Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"8380","DOI":"10.1038\/s41467-023-44192-0","article-title":"Mitochondrial malfunction and atrophy of astrocytes in the aged human cerebral cortex.","volume":"14","author":"Popov","year":"2023","journal-title":"Nat. Commun."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e70381","DOI":"10.1002\/alz.70381","article-title":"Plasma NfL and GFAP for predicting VCI and related brain changes in community and clinical cohorts.","volume":"21","author":"Raghavan","year":"2025","journal-title":"Alzheimer\u2019s Dement."},{"key":"B31","doi-asserted-by":"publisher","first-page":"e213438","DOI":"10.1212\/WNL.0000000000213438","article-title":"Association of plasma biomarkers with longitudinal atrophy and microvascular burden on MRI across neurodegenerative and cerebrovascular diseases.","volume":"104","author":"Sanchez","year":"2025","journal-title":"Neurology"},{"key":"B32","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1002\/mds.27277","article-title":"Parkinson disease with and without Dementia: A prevalence study and future projections.","volume":"33","author":"Savica","year":"2018","journal-title":"Movement Disord."},{"key":"B33","doi-asserted-by":"publisher","first-page":"13169","DOI":"10.3389\/bjbs.2024.13169","article-title":"Neuronal vulnerability of the entorhinal cortex to tau pathology in Alzheimer\u2019s disease.","volume":"81","author":"Zhang","year":"2024","journal-title":"Br. J. Biomed. Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1111\/cns.13188","article-title":"Progressive brain atrophy in Parkinson\u2019s disease patients who convert to mild cognitive impairment.","volume":"26","author":"Zhou","year":"2020","journal-title":"CNS Neurosci. Ther."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2026.1791756\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T05:56:18Z","timestamp":1778219778000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2026.1791756\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,8]]},"references-count":34,"alternative-id":["10.3389\/fnagi.2026.1791756"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2026.1791756","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,8]]},"article-number":"1791756"}}