{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T10:49:26Z","timestamp":1765709366070,"version":"3.48.0"},"reference-count":48,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"unspecified","delay-in-days":3,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/N029941\/1"],"award-info":[{"award-number":["MR\/N029941\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Alzheimer\u2019s Society Project Grant","award":["587 (AS-PG-21-035)"],"award-info":[{"award-number":["587 (AS-PG-21-035)"]}]},{"name":"Optos Plc.","award":["Unrestricted research support"],"award-info":[{"award-number":["Unrestricted research support"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2025,6,23]]},"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>There is a need for early, non-invasive and inexpensive biomarkers for Alzheimer\u2019s disease (AD), which could serve as a proxy measure in prevention and intervention trials that might eventually be suitable for mass screening. People with Down syndrome (DS) are the largest patient group whose condition is associated with a genetically determined increased risk of AD. The REVEAL study aims to examine changes in the structure and function of the eye in individuals with DS compared with those with mild cognitive impairment (MCI) and cognitively healthy control (HC) individuals. REVEAL will also explore whether these changes are connected to inflammatory markers previously associated with AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>\n                      The protocol describes a cross-sectional, non-interventional, single-centre study recruiting three cohorts, including (1) participants with DS (target n=50; age range, 6\u201360 years), (2) participants with MCI (target n=50; age range, 50\u201380 years) and (3) HC participants (target n=50; age range, 50\u201380 years). The primary research objective is to profile retinal, choroidal and lenticular status using a variety of eye imaging modalities and retinal functional testing to determine potential associations with cognitive status. The REVEAL study will also measure and compare established blood markers for AD and proteomic and transcriptomic marker profiles between DS, MCI and HC groups. Between-group differences will be assessed with an independent sample t-test and \u03c7\n                      <jats:sup>2<\/jats:sup>\n                      tests for normally distributed or binary measures, respectively. Multivariate regression analysis will be used to analyse parameters across all three cohorts. Data collection began in October 2023 and is expected to end in October 2025.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The study gained a favourable opinion from Health and Social Care Research Ethics Committee A (REC reference 22\/NI\/0158; approved on 2 December 2022; Amendment 22\/0064 Amend 1, 5 April 2023; Amendment 22\/0064 Amend 2; 23 May 2024; Amendment 22\/0064 Amend 3; 25 June 2024; Amendment 22\/0064 Amend 4; 16 January 2025; Amendment 22.0064 Amend 5; 9 May 2025; Amendment 22.0064 Amend 6; 9 June 2025). The study has also been reviewed and approved by the School of Biomedical Sciences Research Ethics Filter Committee within Ulster University. Findings from the REVEAL study will be presented to academic audiences at international conferences and peer-reviewed publications in targeted high-impact journals after data collection and analysis are complete. Dissemination activities will also include presentations at public events.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2024-098285","type":"journal-article","created":{"date-parts":[[2025,7,5]],"date-time":"2025-07-05T09:45:33Z","timestamp":1751708733000},"page":"e098285","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Investigating the eye in Down syndrome as a window to Alzheimer\u2019s disease: the REVEAL protocol \u2013 a clinical cross-sectional study"],"prefix":"10.1136","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0150-4126","authenticated-orcid":false,"given":"Aoife Mary Louise","family":"Hunter","sequence":"first","affiliation":[{"name":"Centre for Optometry and Vision Science, Biomedical Sciences Research Institute, Ulster University, Coleraine, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3208-8794","authenticated-orcid":false,"given":"Sarah","family":"Atkinson","sequence":"additional","affiliation":[{"name":"Centre for Genomic Medicine, Biomedical Sciences Research Institute, Ulster University, Coleraine, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0170-6809","authenticated-orcid":false,"given":"Elaine","family":"Murray","sequence":"additional","affiliation":[{"name":"Personalised Medical Centre, School of Medicine, Ulster University, Coleraine, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9289-5731","authenticated-orcid":false,"given":"Kathryn","family":"Saunders","sequence":"additional","affiliation":[{"name":"Centre for Optometry and Vision Science, Biomedical Sciences Research Institute, Ulster University, Coleraine, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6265-0381","authenticated-orcid":false,"given":"Tunde","family":"Peto","sequence":"additional","affiliation":[{"name":"Centre for Public Health, School of Medicine Dentistry and Biomedical Science, Queen\u2019s University Belfast, Belfast, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5243-7536","authenticated-orcid":false,"given":"Lajos","family":"Csincsik","sequence":"additional","affiliation":[{"name":"Centre for Public Health, School of Medicine Dentistry and Biomedical Science, Queen\u2019s University Belfast, Belfast, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7329-8194","authenticated-orcid":false,"given":"Jamie","family":"Mitchell","sequence":"additional","affiliation":[{"name":"The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine Dentistry and Biomedical Science, Queen\u2019s University Belfast, Belfast, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"UCL Queen Square Institute of Neurology and UK Dementia Research Institute, University College London, London, UK"},{"name":"Hong Kong Center for Neurodegenerative Diseases, Hong Kong, UK"},{"name":"Wisconsin Alzheimer\u2019s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA"},{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg Sahlgrenska Academy, Gothenburg, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9","family":"Strydom","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry, Psychology & Neuroscience, King\u2019s College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5242-8066","authenticated-orcid":false,"given":"Julie-Anne","family":"Little","sequence":"additional","affiliation":[{"name":"Centre for Optometry and Vision Science, Biomedical Sciences Research Institute, Ulster University, Coleraine, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7467-2174","authenticated-orcid":false,"given":"Imre","family":"Lengyel","sequence":"additional","affiliation":[{"name":"Wellcome-Wolfson Institute for Experimental Medicine, QUB, Belfast, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2025,7,5]]},"reference":[{"key":"2025121402455198000_15.7.e098285.1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(20)32205-4"},{"key":"2025121402455198000_15.7.e098285.2","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2018-024498","article-title":"Deep and Frequent Phenotyping study protocol: an observational study in prodromal Alzheimer\u2019s disease","volume":"9","author":"Koychev","year":"2019","journal-title":"BMJ Open"},{"key":"2025121402455198000_15.7.e098285.3","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12006"},{"key":"2025121402455198000_15.7.e098285.4","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1001\/jamaophthalmol.2022.4845","article-title":"Ocular Biomarkers for Alzheimer Disease Dementia","volume":"141","author":"Costanzo","year":"2023","journal-title":"JAMA Ophthalmol"},{"key":"2025121402455198000_15.7.e098285.5","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-014-7374-z"},{"key":"2025121402455198000_15.7.e098285.6","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.18-25966"},{"key":"2025121402455198000_15.7.e098285.7","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.dadm.2016.09.001","article-title":"Nonvascular retinal imaging markers of preclinical Alzheimer\u2019s disease","volume":"4","author":"Snyder","year":"2016","journal-title":"Alzheimers Dement (Amst)"},{"key":"2025121402455198000_15.7.e098285.8","doi-asserted-by":"crossref","first-page":"3527","DOI":"10.1167\/iovs.19-27135","article-title":"Characterization of Inner Retinal Hyperreflective Alterations in Early Cognitive Impairment on Adaptive Optics Scanning Laser Ophthalmoscopy","volume":"60","author":"Zhang","year":"2019","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2025121402455198000_15.7.e098285.9","doi-asserted-by":"crossref","DOI":"10.1155\/2016\/2898704","article-title":"Choroidal Thickness in Patients with Mild Cognitive Impairment and Alzheimer\u2019s Type Dementia","volume":"2016","author":"Bulut","year":"2016","journal-title":"J Ophthalmol"},{"key":"2025121402455198000_15.7.e098285.10","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0010659","article-title":"Alzheimer\u2019s disease amyloid-beta links lens and brain pathology in Down syndrome","volume":"5","author":"Moncaster","year":"2010","journal-title":"PLoS One"},{"key":"2025121402455198000_15.7.e098285.11","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.exer.2015.03.010","article-title":"A test of lens opacity as an indicator of preclinical Alzheimer Disease","volume":"140","author":"Bei","year":"2015","journal-title":"Exp Eye Res"},{"key":"2025121402455198000_15.7.e098285.12","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1016\/S0140-6736(03)12981-9","article-title":"Cytosolic \u03b2-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer\u2019s disease","volume":"361","author":"Goldstein","year":"2003","journal-title":"The Lancet"},{"key":"2025121402455198000_15.7.e098285.13","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0043728","article-title":"\u03b4-Catenin is genetically and biologically associated with cortical cataract and future Alzheimer-related structural and functional brain changes","volume":"7","author":"Jun","year":"2012","journal-title":"PLoS One"},{"key":"2025121402455198000_15.7.e098285.14","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3983"},{"key":"2025121402455198000_15.7.e098285.15","doi-asserted-by":"publisher","DOI":"10.1016\/0047-6374(88)90041-3"},{"key":"2025121402455198000_15.7.e098285.16","doi-asserted-by":"crossref","first-page":"459","DOI":"10.3233\/JAD-160836","article-title":"Down Syndrome, Partial Trisomy 21, and Absence of Alzheimer\u2019s Disease: The Role of APP","volume":"56","author":"Doran","year":"2017","journal-title":"J Alzheimers Dis"},{"key":"2025121402455198000_15.7.e098285.17","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(20)30689-9"},{"key":"2025121402455198000_15.7.e098285.18","doi-asserted-by":"crossref","DOI":"10.1002\/dad2.12170","article-title":"Increased choroidal thickness in adults with Down syndrome","volume":"13","author":"Csincsik","year":"2021","journal-title":"Alzheimers Dement (Amst)"},{"key":"2025121402455198000_15.7.e098285.19","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-020-66642-1","article-title":"In-vivo anterior segment OCT imaging provides unique insight into cerulean blue-dot opacities and cataracts in Down syndrome","volume":"10","author":"Little","year":"2020","journal-title":"Sci Rep"},{"key":"2025121402455198000_15.7.e098285.20","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/j.dadm.2019.08.007","article-title":"Age-related retinal thickness in Down\u2019s syndrome: A high-risk population for dementia","volume":"11","author":"Walpert","year":"2019","journal-title":"Alzheimers Dement (Amst)"},{"key":"2025121402455198000_15.7.e098285.21","article-title":"The Ophthalmic Manifestations of Down Syndrome","volume":"10","author":"Sun","year":"2023","journal-title":"Children (Basel)"},{"key":"2025121402455198000_15.7.e098285.22","doi-asserted-by":"crossref","unstructured":"Haseeb A , Huynh E , ElSheikh RH , et al . Down syndrome: a review of ocular manifestations. Ophthalmol Eye Dis 2022;14. doi:10.1177\/25158414221101718","DOI":"10.1177\/25158414221101718"},{"key":"2025121402455198000_15.7.e098285.23","doi-asserted-by":"publisher","DOI":"10.1080\/02713683.2019.1597128"},{"key":"2025121402455198000_15.7.e098285.24","doi-asserted-by":"crossref","DOI":"10.1155\/2020\/9726261","article-title":"Ophthalmologic Manifestations and Retinal Findings in Children with Down Syndrome","volume":"2020","author":"Ugurlu","year":"2020","journal-title":"J Ophthalmol"},{"key":"2025121402455198000_15.7.e098285.25","doi-asserted-by":"crossref","DOI":"10.1155\/2020\/6286105","article-title":"Interplay between Oxidative Stress, Inflammation, and Amyloidosis in the Anterior Segment of the Eye; Its Pathological Implications","volume":"2020","author":"Perez-Garmendia","year":"2020","journal-title":"Oxid Med Cell Longev"},{"key":"2025121402455198000_15.7.e098285.26","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1046\/j.1365-2788.2000.00263.x","article-title":"Incidence and course of dementia in people with Down\u2019s syndrome: findings from a population-based study","volume":"44 (Pt 2)","author":"Holland","year":"2000","journal-title":"J Intellect Disabil Res"},{"key":"2025121402455198000_15.7.e098285.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2011.07.011"},{"key":"2025121402455198000_15.7.e098285.28","doi-asserted-by":"crossref","DOI":"10.1002\/dad2.12184","article-title":"Markers of early changes in cognition across cohorts of adults with Down syndrome at risk of Alzheimer\u2019s disease","volume":"13","author":"Aschenbrenner","year":"2021","journal-title":"Alzheimers Dement (Amst)"},{"key":"2025121402455198000_15.7.e098285.29","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.jneumeth.2018.10.025","article-title":"Blood-based biomarkers for Alzheimer\u2019s disease-An update","volume":"319","author":"Zetterberg","year":"2019","journal-title":"J Neurosci Methods"},{"key":"2025121402455198000_15.7.e098285.30","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1348\/014466599162719","article-title":"Neuropsychological assessment of older adults with Down\u2019s syndrome: an epidemiological study using the Cambridge Cognitive Examination (CAMCOG)","volume":"38","author":"Hon","year":"1999","journal-title":"Br J Clin Psychol"},{"key":"2025121402455198000_15.7.e098285.31","doi-asserted-by":"publisher","DOI":"10.1080\/01688638408401233"},{"key":"2025121402455198000_15.7.e098285.32","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-4222(01)00072-5"},{"key":"2025121402455198000_15.7.e098285.33","doi-asserted-by":"crossref","unstructured":"Evenhuis HM . The dementia questionnaire for people with learning disabilities. 2017:43\u201356.","DOI":"10.1007\/978-3-319-61720-6_3"},{"key":"2025121402455198000_15.7.e098285.34","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.149.6.698"},{"key":"2025121402455198000_15.7.e098285.35","doi-asserted-by":"crossref","unstructured":"Kaufman AS , Kaufman NL . Kaufman brief intelligence test. Second ed. Circle Pines, Minnesota: American Guidance Service, 2004.","DOI":"10.1037\/t27706-000"},{"key":"2025121402455198000_15.7.e098285.36","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.2005.53221.x"},{"key":"2025121402455198000_15.7.e098285.37","doi-asserted-by":"publisher","DOI":"10.1017\/S003329170002691X"},{"key":"2025121402455198000_15.7.e098285.38","doi-asserted-by":"crossref","DOI":"10.1002\/dad2.12232","article-title":"Retinal phenotyping of variants of Alzheimer\u2019s disease using ultra-widefield retinal images","volume":"13","author":"Csincsik","year":"2021","journal-title":"Alzheimers Dement (Amst)"},{"key":"2025121402455198000_15.7.e098285.39","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1159\/000487053","article-title":"Peripheral Retinal Imaging Biomarkers for Alzheimer\u2019s Disease: A Pilot Study","volume":"59","author":"Csincsik","year":"2018","journal-title":"Ophthalmic Res"},{"key":"2025121402455198000_15.7.e098285.40","doi-asserted-by":"crossref","DOI":"10.1016\/j.xops.2023.100308","article-title":"Reduced Cone Density Is Associated with Multiple Sclerosis","volume":"3","author":"McIlwaine","year":"2023","journal-title":"Ophthalmol Sci"},{"key":"2025121402455198000_15.7.e098285.41","doi-asserted-by":"crossref","DOI":"10.3390\/ijms24054354","article-title":"Metabolic Syndrome as a Risk Factor for Alzheimer\u2019s Disease: A Focus on Insulin Resistance","volume":"24","author":"Ezkurdia","year":"2023","journal-title":"Int J Mol Sci"},{"key":"2025121402455198000_15.7.e098285.42","doi-asserted-by":"crossref","DOI":"10.3389\/fnins.2020.00670","article-title":"Down Syndrome Is a Metabolic Disease: Altered Insulin Signaling Mediates Peripheral and Brain Dysfunctions","volume":"14","author":"Dierssen","year":"2020","journal-title":"Front Neurosci"},{"key":"2025121402455198000_15.7.e098285.43","doi-asserted-by":"publisher","DOI":"10.4097\/kjae.2013.64.5.402"},{"key":"2025121402455198000_15.7.e098285.44","doi-asserted-by":"publisher","DOI":"10.1080\/09286586.2016.1259636"},{"key":"2025121402455198000_15.7.e098285.45","doi-asserted-by":"publisher","DOI":"10.3109\/09286586.2012.674614"},{"key":"2025121402455198000_15.7.e098285.46","doi-asserted-by":"publisher","DOI":"10.2307\/2533958"},{"key":"2025121402455198000_15.7.e098285.47","doi-asserted-by":"publisher","DOI":"10.3310\/hsdr04110"},{"key":"2025121402455198000_15.7.e098285.48","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-019-0143-7"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2024-098285","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T10:46:03Z","timestamp":1765709163000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2024-098285"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7]]},"references-count":48,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7,5]]},"published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1136\/bmjopen-2024-098285"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2024-098285","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"type":"print","value":"2044-6055"},{"type":"electronic","value":"2044-6055"}],"subject":[],"published":{"date-parts":[[2025,7]]}}}