{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T15:50:50Z","timestamp":1780069850944,"version":"3.54.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T00:00:00Z","timestamp":1667433600000},"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><jats:title>Objectives<\/jats:title><jats:p>To evaluate the predictive clinical role of neurofilament light chain (NfL), amyloid-\u03b2 (A\u03b2), glial fibrillary acidic protein (GFAP), and phosphorylated tau at threonine 181 (p-tau181) proteins in human aqueous humor (AH) and quantify the retinal macular microvascular parameters by optical coherence tomography angiography (OCTA) as early diagnostic markers of Alzheimer\u2019s disease (AD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This prospective, single-site, cross-sectional, cohort study enrolled 55 participants, including 38 patients with neovascular age-related macular degeneration (nAMD) and 17 individuals with senile cataracts. The single-molecule array platform was used to quantitatively measure the levels of AH NfL, A\u03b240, A\u03b242, GFAP, and p-tau181 proteins in AH. The mini-mental state examination (MMSE) score was used to assess the global cognitive function. OCTA scan with 6\u2009\u00d7\u20096\u2009mm macular area was used to quantify the retinal thickness and microvascular densities of superficial retinal capillary plexuses and deep retinal capillary plexuses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>NfL, A\u03b240, A\u03b242, GFAP, and p-tau181 were detected in all AH samples by Simoa platform. Individuals with cataract had higher concentrations of NfL and p-tau181 but lower A\u03b240 and A\u03b242 and similar GFAP compared to those with nAMD. Lower MMSE scores showed a negative correlation with NfL concentration of AH not only in the nAMD group (<jats:italic>p<\/jats:italic>\u2009=\u20090.043), but also in the cataract group (<jats:italic>p<\/jats:italic>\u2009=\u20090.032). However, the MMSE scores were not associated with the levels of A\u03b240, A\u03b242, GFAP, or p-Tau181. Further analysis found that the A\u03b240 and A\u03b242 concentrations showed a strong positive correlation (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.0001). In addition, the NfL concentration showed a mild positive correlation with that of GFAP in the cataract group (<jats:italic>p<\/jats:italic>\u2009=\u20090.021). Although it has not reached statistical significance, there was a correlation between the levels of NfL and A\u03b242 in the nAMD group (<jats:italic>p<\/jats:italic>\u2009=\u20090.051). Moreover, the macular superficial vessel density values had a negative correlation with the concentration of NfL (<jats:italic>p<\/jats:italic>\u2009=\u20090.004) but a positive correlation with MMSE scores (<jats:italic>p<\/jats:italic>\u2009=\u20090.045). The macular deep vessel density values were negatively correlated with the concentration of p-tau181 (<jats:italic>p<\/jats:italic>\u2009=\u20090.031) and positively correlated with MMSE scores (<jats:italic>p<\/jats:italic>\u2009=\u20090.020).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The examination of AD-related biomarkers in human AH and OCTA may improve the ocular-based AD detection methods and contribute to forestalling the progression of preclinical AD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2022.1027705","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T13:41:11Z","timestamp":1667482871000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Association of cognitive function with Neurofilament light chain in the aqueous humor of human eye"],"prefix":"10.3389","volume":"14","author":[{"given":"Jianhao","family":"Bai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongqi","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minli","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yawen","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,3]]},"reference":[{"key":"ref1","article-title":"Alzheimers Dement","year":"2022"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"503293","DOI":"10.4061\/2011\/503293","article-title":"Diagnostic utility of CSF tau and A\u03b2(42) in dementia: a meta-analysis","volume":"2011","author":"Agarwal","year":"2011","journal-title":"Int. J. Alzheimers Dis."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"7290","DOI":"10.3390\/ijms21197290","article-title":"Retinal degeneration and Alzheimer's disease: an evolving link","volume":"21","author":"Ashok","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1001\/archophthalmol.2009.30","article-title":"Early age-related macular degeneration, cognitive function, and dementia: the cardiovascular health study","volume":"127","author":"Baker","year":"2009","journal-title":"Arch. Ophthalmol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1111\/joim.12816","article-title":"Biomarkers for Alzheimer\u2019s disease: current status and prospects for the future","volume":"284","author":"Blennow","year":"2018","journal-title":"J. Intern. Med."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"8538573","DOI":"10.1155\/2018\/8538573","article-title":"Ocular manifestations of Alzheimer's and other neurodegenerative diseases: the Prospect of the eye as a tool for the early diagnosis of Alzheimer's disease","volume":"2018","author":"Colligris","year":"2018","journal-title":"J. Ophthalmol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1136\/jnnp-2018-320106","article-title":"Neurofilament light chain as a biomarker in neurological disorders","volume":"90","author":"Gaetani","year":"2019","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"89","DOI":"10.2174\/1567205018666210414113634","article-title":"Retinal changes in transgenic mouse models of Alzheimer's disease","volume":"18","author":"Guo","year":"2021","journal-title":"Curr. Alzheimer Res."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.exer.2014.10.012","article-title":"Iron increases APP translation and amyloid-beta production in the retina","volume":"129","author":"Guo","year":"2014","journal-title":"Exp. Eye Res."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"165","DOI":"10.3233\/jad-170534","article-title":"Subtle cognitive impairment and Alzheimer's disease-type pathological changes in cerebrospinal fluid are common among neurologically healthy subjects","volume":"62","author":"Haapalinna","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1016\/j.jalz.2017.11.015","article-title":"Alzheimer's disease biomarker-guided diagnostic workflow using the added value of six combined cerebrospinal fluid candidates: A\u03b2(1-42), total-tau, phosphorylated-tau, NFL, neurogranin, and YKL-40","volume":"14","author":"Hampel","year":"2018","journal-title":"Alzheimers Dement."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.neuro.2017.03.006","article-title":"Risk factors associated with the onset and progression of Alzheimer's disease: a systematic review of the evidence","volume":"61","author":"Hersi","year":"2017","journal-title":"Neurotoxicology"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1038\/s41392-022-00974-4","article-title":"Microbiota in health and diseases","volume":"7","author":"Hou","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/s41582-019-0244-7","article-title":"Ageing as a risk factor for neurodegenerative disease","volume":"15","author":"Hou","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1442","DOI":"10.1002\/alz.12313","article-title":"Ophthalmic conditions associated with dementia risk: the cardiovascular health study","volume":"17","author":"Hwang","year":"2021","journal-title":"Alzheimers Dement."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1038\/s41591-020-0755-1","article-title":"Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia","volume":"26","author":"Janelidze","year":"2020","journal-title":"Nat. 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Aging Neurosci."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s12886-015-0060-9","article-title":"Visual signs and symptoms in patients with the visual variant of Alzheimer disease","volume":"15","author":"Kaeser","year":"2015","journal-title":"BMC Ophthalmol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1159\/000313985","article-title":"Genistein blunts the negative effect of ischaemia to the retina caused by an elevation of intraocular pressure","volume":"45","author":"Kamalden","year":"2011","journal-title":"Ophthalmic Res."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1177\/1533317513520214","article-title":"Detection of amyloid \u03b2 signature in the lens and its correlation in the brain to aid in the diagnosis of Alzheimer's disease","volume":"30","author":"Kerbage","year":"2015","journal-title":"Am. J. Alzheimers Dis. Other Dement."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1655","DOI":"10.1515\/cclm-2015-1195","article-title":"Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa","volume":"54","author":"Kuhle","year":"2016","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.jalz.2018.06.2856","article-title":"Associations between recent and established ophthalmic conditions and risk of Alzheimer's disease","volume":"15","author":"Lee","year":"2019","journal-title":"Alzheimers Dement."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"61","DOI":"10.3238\/arztebl.2016.0061","article-title":"The differential diagnosis and treatment of atypical parkinsonism","volume":"113","author":"Levin","year":"2016","journal-title":"Dtsch. Arztebl. Int."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"314","DOI":"10.3760\/cma.j.issn.0412-4081.2017.04.016","article-title":"Correlation between Alzheimer disease and cataract","volume":"53","author":"Liu","year":"2017","journal-title":"Zhonghua Yan Ke Za Zhi"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nrneurol.2012.227","article-title":"The retina as a window to the brain-from eye research to CNS disorders","volume":"9","author":"London","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"971","DOI":"10.2174\/1570159x16666171206144045","article-title":"Glaucoma and Alzheimer disease: one age-related neurodegenerative disease of the brain","volume":"16","author":"Mancino","year":"2018","journal-title":"Curr. Neuropharmacol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"2394","DOI":"10.3390\/cells10092394","article-title":"Ocular neurodegenerative diseases: interconnection between retina and cortical areas","volume":"10","author":"Marchesi","year":"2021","journal-title":"Cells"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1001\/jamaneurol.2016.6117","article-title":"Association of Plasma Neurofilament Light with Neurodegeneration in patients with Alzheimer disease","volume":"74","author":"Mattsson","year":"2017","journal-title":"JAMA Neurol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.freeradbiomed.2004.10.023","article-title":"Mice transgenic for Alzheimer disease beta-amyloid develop lens cataracts that are rescued by antioxidant treatment","volume":"38","author":"Melov","year":"2005","journal-title":"Free Radic. Biol. Med."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1177\/1352458515599074","article-title":"Cerebrospinal fluid neurofilament light chain levels predict visual outcome after optic neuritis","volume":"22","author":"Modvig","year":"2016","journal-title":"Mult. Scler."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1021\/cn500242z","article-title":"Hyperspectral imaging signatures detect amyloidopathy in Alzheimer's mouse retina well before onset of cognitive decline","volume":"6","author":"More","year":"2015","journal-title":"ACS Chem. Neurosci."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1001\/jamaophthalmol.2018.3556","article-title":"Association of Preclinical Alzheimer disease with optical coherence tomographic angiography findings","volume":"136","author":"O'Bryhim","year":"2018","journal-title":"JAMA Ophthalmol"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.preteyeres.2011.02.004","article-title":"Parallel findings in age-related macular degeneration and Alzheimer's disease","volume":"30","author":"Ohno-Matsui","year":"2011","journal-title":"Prog. Retin. Eye Res."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/s1474-4422(16)00070-3","article-title":"CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis","volume":"15","author":"Olsson","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1001\/jamaneurol.2018.3746","article-title":"Association of Cerebrospinal Fluid Neurofilament Light Protein Levels with Cognition in patients with dementia, motor neuron disease, and movement disorders","volume":"76","author":"Olsson","year":"2019","journal-title":"JAMA Neurol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1566","DOI":"10.1007\/s00415-018-9028-z","article-title":"Ocular amyloid imaging at the crossroad of Alzheimer's disease and age-related macular degeneration: implications for diagnosis and therapy","volume":"266","author":"Ong","year":"2019","journal-title":"J. Neurol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"889","DOI":"10.3233\/jad-180240","article-title":"Distribution of cerebrospinal fluid biomarker profiles in patients explored for cognitive disorders","volume":"64","author":"Paquet","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.3233\/jad-2010-100210","article-title":"Differential accumulation of secreted AbetaPP metabolites in ocular fluids","volume":"20","author":"Prakasam","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"3222","DOI":"10.1038\/s41598-017-03397-2","article-title":"Amyloid \u03b2 peptides overexpression in retinal pigment epithelial cells via AAV-mediated gene transfer mimics AMD-like pathology in mice","volume":"7","author":"Prasad","year":"2017","journal-title":"Sci. Rep."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"Cd008345","DOI":"10.1002\/14651858.CD008345.pub2","article-title":"Case management approaches to home support for people with dementia","volume":"1","author":"Reilly","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"e0220535","DOI":"10.1371\/journal.pone.0220535","article-title":"Changes in visual function and retinal structure in the progression of Alzheimer's disease","volume":"14","author":"Salobrar-Garc\u00eda","year":"2019","journal-title":"PLoS One"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/j.exer.2006.03.007","article-title":"Intravitreal injection of endothelin-1 caused optic nerve damage following to ocular hypoperfusion in rabbits","volume":"83","author":"Sasaoka","year":"2006","journal-title":"Exp. Eye Res."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s40942-019-0157-z","article-title":"Anterior chamber paracentesis during intravitreal injections in observational trials: effectiveness and safety and effects","volume":"5","author":"Saxena","year":"2019","journal-title":"Int. J. Retina Vitreous"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1212\/WNL.0b013e31823ed0f0","article-title":"Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort","volume":"78","author":"Schoonenboom","year":"2012","journal-title":"Neurology"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/s1350-9462(00)00024-0","article-title":"Development of retinal ganglion cell structure and function","volume":"20","author":"Sernagor","year":"2001","journal-title":"Prog. Retin. Eye Res."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/mp.2016.251","article-title":"Beta-amyloid sequelae in the eye: a critical review on its diagnostic significance and clinical relevance in Alzheimer's disease","volume":"22","author":"Shah","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s12929-019-0524-y","article-title":"Alzheimer's disease: risk factors and potentially protective measures","volume":"26","author":"Silva","year":"2019","journal-title":"J. Biomed. Sci."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1186\/s13195-020-00677-4","article-title":"Neurofilament light chain in the vitreous humor of the eye","volume":"12","author":"Subramanian","year":"2020","journal-title":"Alzheimers Res. Ther."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.brainres.2004.04.023","article-title":"Alterations in neurofilament light in optic nerve in rat kainate and monkey ocular hypertension models","volume":"1013","author":"Taniguchi","year":"2004","journal-title":"Brain Res."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1097\/01.wad.0000191420.61260.a8","article-title":"The role of biomarkers in clinical trials for Alzheimer disease","volume":"20","author":"Thal","year":"2006","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"2327","DOI":"10.1016\/j.ophtha.2015.07.033","article-title":"Age-related macular degeneration and risk of degenerative dementia among the elderly in Taiwan: a population-based cohort study","volume":"122","author":"Tsai","year":"2015","journal-title":"Ophthalmology"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1167\/iovs.13-12888","article-title":"Ocular changes in TgF344-AD rat model of Alzheimer's disease","volume":"55","author":"Tsai","year":"2014","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1111\/ceo.12872","article-title":"Emerging ocular biomarkers of Alzheimer disease","volume":"45","author":"van Wijngaarden","year":"2017","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/j.jcjo.2014.03.009","article-title":"Survey of intravitreal injection techniques and treatment protocols among retina specialists in Canada","volume":"49","author":"Xing","year":"2014","journal-title":"Can. J. Ophthalmol."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.diabres.2016.10.024","article-title":"An updated meta-analysis of cohort studies: diabetes and risk of Alzheimer's disease","volume":"124","author":"Zhang","year":"2017","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1080\/08820538.2021.1883679","article-title":"Highly expressed amyloid Beta-42 of aqueous humor in patients with Neovascular macular degeneration","volume":"36","author":"Zhu","year":"2021","journal-title":"Semin. Ophthalmol."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2022.1027705\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T13:41:27Z","timestamp":1667482887000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2022.1027705\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,3]]},"references-count":57,"alternative-id":["10.3389\/fnagi.2022.1027705"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2022.1027705","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,3]]},"article-number":"1027705"}}