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Are changes in the retinal nerve fiber layer (RNFL) associated with current or future cognitive function in a large community cohort of healthy participants?
In this community-based cohort study of more than 500 000 UK residents aged 40 to 69 years who received optical coherence tomography measurements of RNFL thickness and cognitive testing, there was a significant association between RNFL thickness and cognitive function at baseline. Furthermore, those with a thinner RNFL were twice as likely to experience cognitive decline over 3 years.
A thinner RNFL is associated with worse current cognitive function and may have a role in screening those at risk of future cognitive decline.
Identifing potential screening tests for future cognitive decline is a priority for developing treatments for and the prevention of dementia.
To examine the potential of retinal nerve fiber layer (RNFL) thickness measurement in identifying those at greater risk of cognitive decline in a large community cohort of healthy people.
Design, Setting, and Participants
UK Biobank is a prospective, multicenter, community-based study of UK residents aged 40 to 69 years at enrollment who underwent baseline retinal optical coherence tomography imaging, a physical examination, and a questionnaire. The pilot study phase was conducted from March 2006 to June 2006, and the main cohort underwent examination for baseline measures from April 2007 to October 2010. Four basic cognitive tests were performed at baseline, which were then repeated in a subset of participants approximately 3 years later. We analyzed eyes with high-quality optical coherence tomography images, excluding those with eye disease or vision loss, a history of ocular or neurological disease, or diabetes. We explored associations between RNFL thickness and cognitive function using multivariable logistic regression modeling to control for demographic as well as physiologic and ocular variation.
Main Outcomes and Measures
Odds ratios (ORs) for cognitive performance in the lowest fifth percentile in at least 2 of 4 cognitive tests at baseline, or worsening results on at least 1 cognitive test at follow-up. These analyses were adjusted for age, sex, race/ethnicity, height, refraction, intraocular pressure, education, and socioeconomic status.
A total of 32 038 people were included at baseline testing, for whom the mean age was 56.0 years and of whom 17 172 (53.6%) were women. A thinner RNFL was associated with worse cognitive performance on baseline assessment. A multivariable regression controlling for potential confounders showed that those in the thinnest quintile of RNFL were 11% more likely to fail at least 1 cognitive test (95% CI, 2.0%-2.1%; P = .01). Follow-up cognitive tests were performed for 1251 participants (3.9%). Participants with an RNFL thickness in the 2 thinnest quintiles were almost twice as likely to have at least 1 test score be worse at follow-up cognitive testing (quintile 1: OR, 1.92; 95% CI, 1.29-2.85; P < .001; quintile 2: OR, 2.08; 95% CI, 1.40-3.08; P < .001).
Conclusions and Relevance
A thinner RNFL is associated with worse cognitive function in individuals without a neurodegenerative disease as well as greater likelihood of future cognitive decline. This preclinical observation has implications for future research, prevention, and treatment of dementia.
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Accepted for Publication: April 27, 2018.
Corresponding Author: Paul J. Foster, PhD, UCL Institute of Ophthalmology, 11-43 Bath St, London EC1V 9EL, England (firstname.lastname@example.org).
Published Online: June 25, 2018. doi:10.1001/jamaneurol.2018.1578
Author Contributions: Dr Ko had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Patel and Foster contributed equally to the authorship of this article.
Concept and design: Ko, Gallacher, Khaw, Reisman, Foster, Patel.
Acquisition, analysis, or interpretation of data: Ko, Muthy, Gallacher, Sudlow, Rees, Yang, Keane, Petzold, Reisman, Strouthidis, Foster, Patel.
Drafting of the manuscript: Ko, Muthy, Gallacher, Rees, Yang, Foster, Patel.
Critical revision of the manuscript for important intellectual content: Ko, Muthy, Gallacher, Sudlow, Rees, Keane, Petzold, Khaw, Reisman, Strouthidis, Foster, Patel.
Statistical analysis: Ko, Gallacher, Rees, Reisman, Foster.
Obtained funding: Ko, Sudlow, Khaw, Foster, Patel.
Administrative, technical, or material support: Ko, Muthy, Sudlow, Rees, Keane, Khaw, Reisman, Foster.
Supervision: Petzold, Reisman, Strouthidis, Foster, Patel.
Conflict of Interest Disclosures: Dr Ko receives grant support from University College of London (UCL). Ms Muthy receives personal fees from UCL. Prof Sudlow is chief scientist at UK Biobank. Prof Rees receives grant support from Wellcome Trust and personal fees from Google DeepMind. Dr Yang and Mr Reisman are employed by Topcon Medical Systems Inc. Dr Keane receives personal fees from Allergan, Topcon, Heidelberg Engineering, Haag-Streit, Novartis, Bayer, Optos, and DeepMind as well as grant support from a Clinician Scientist award (CS-2014-14-023) from the National Institute for Health Research (NIHR). Dr Petzold receives personal fees and grant support from Novartis and is a member of the steering committee of the Optical Coherence Tomography Trial in Multiple Sclerosis (OCTiMS), which is sponsored by Novartis and for which he has not received honoraria Prof Foster receives personal fees from Allergan, Carl Zeiss, Google/DeepMind, and Santen; grant support from Alcon, and support from the Richard Desmond Charitable Trust, via Fight for Sight, London. Dr Patel receives grant support from Topcon Medical Systems Inc. Prof Khaw is supported in part by the Helen Hamlyn Trust. No other disclosures are reported.
Funding/Support: This analysis was supported by the Eranda Foundation via the International Glaucoma Association in the design and conduct of the study. The UCL Overseas Research Scholarship and Graduate Research Scholarship programs provided scholarship support for Dr Ko. Ms Muthy, Drs Strouthidis and Patel and Profs Khaw and Foster received salary support from the NIHR Biomedical Research Centres at Moorfields Eye Hospital NHS Foundation Trust. Dr Foster received support from the Richard Desmond Charitable Trust via Fight for Sight, London. UK Biobank Eye and Vision Consortium is supported by grants from Moorfields Eye Charity, the NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, and the UCL Institute of Ophthalmology and the Alcon Research Institute.
Role of the Funder/Sponsor: No funders had a direct role in the collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; nor in the decision to submit the manuscript for publication.
UK Biobank Eye & Vision Consortium: The UK Biobank Eye & Vision Consortium members are Tariq Aslam, PhD, Manchester University, Sarah A. Barman, PhD, Kingston University, Jenny H. Barrett, PhD, University of Leeds, Paul Bishop, PhD, Manchester University, Peter Blows, BSc, NIHR Biomedical Research Centre, Catey Bunce, DSc, King’s College London, Roxana O. Carare, PhD, University of Southampton, Usha Chakravarthy, FRCOphth, Queens University Belfast, Michelle Chan, FRCOphth, NIHR Biomedical Research Centre, Sharon Y.L. Chua, PhD, NIHR Biomedical Research Centre, David P. Crabb, PhD, UCL, Philippa M. Cumberland, MSc, UCL Great Ormond Street Institute of Child Health, Alexander Day, PhD, NIHR Biomedical Research Centre, Parul Desai, PhD, NIHR Biomedical Research Centre, Bal Dhillon, FRCOphth, University of Edinburgh, Andrew D. Dick, FRCOphth, University of Bristol, Cathy Egan, FRCOphth, NIHR Biomedical Research Centre, Sarah Ennis, PhD, University of Southampton, Paul Foster, PhD, NIHR Biomedical Research Centre, Marcus Fruttiger, PhD, NIHR Biomedical Research Centre, John E.J. Gallacher, PhD, University of Oxford, David F. GARWAY-HEATH FRCOphth- NIHR Biomedical Research Centre, Jane Gibson, PhD, University of Southampton, Dan Gore, FRCOphth, NIHR Biomedical Research Centre, Jeremy A. Guggenheim, PhD, Cardiff University, Chris J. Hammond, FRCOphth, King's College London, Alison Hardcastle, PhD, NIHR Biomedical Research Centre, Simon P. Harding, MD, University of Liverpool, Ruth E. Hogg, PhD, Queens University Belfast, Pirro Hysi, PhD, King's College London, Pearse A. Keane, MD, NIHR Biomedical Research Centre, Sir Peng T. Khaw, PhD, NIHR Biomedical Research Centre, Anthony P. Khawaja, DPhil, NIHR Biomedical Research Centre, Gerassimos Lascaratos, PhD, NIHR Biomedical Research Centre, Andrew J. Lotery, MD, University of Southampton, Tom Macgillivray, PhD, University of Edinburgh, Sarah Mackie, PhD, University of Leeds, Keith Martin, FRCOphth, University of Cambridge, Michelle McGaughey, Queen’s University Belfast, Bernadette McGuinness, PhD, Queen’s University Belfast, Gareth J. McKay, PhD, Queen's University Belfast, Martin McKibbin, FRCOphth, Leeds Teaching HospitalsNHS Trust, Danny Mitry, PhD, NIHR Biomedical Research Centre, Tony Moore, FRCOphth, NIHR Biomedical Research Centre, James E. Morgan, DPhil, Cardiff University, Zaynah A. Muthy, BSc, NIHR Biomedical Research Centre, Eoin O’Sullivan, MD, King's College Hospital NHS Foundation Trust, Chris G. Owen, PhD, University of London, Praveen Patel, FRCOphth, NIHR Biomedical Research Centre, Euan Paterson, BSc, Queens University Belfast, Tunde Peto, PhD, Queen's University Belfast, Axel Petzold, PhD, UCL, Jugnoo S. Rahi, PhD, UCL Great Ormond Street Institute of Child Health, Alicja R. Rudnikca, PhD, University of London, Jay Self, PhD, University of Southampton, Sobha Sivaprasad, FRCOphth, NIHR Biomedical Research Centre, David Steel, FRCOphth, Newcastle University, Irene Stratton, MSc, Gloucestershire HospitalsNHS Foundation Trust, Nicholas Strouthidis, PhD, NIHR Biomedical Research Centre, Cathie Sudlow, DPhil, University of Edinburgh, Dhanes Thomas, FRCOphth, NIHR Biomedical Research Centre, Emanuele Trucco, PhD, University of Dundee, Adnan Tufail, FRCOphth, NIHR Biomedical Research Centre, Veronique Vitart, PhD, University of Edinburgh, Stephen A. Vernon, DM, Nottingham University HospitalsNHS Trust, Ananth C. Viswanathan, FRCOphth, NIHR Biomedical Research Centre, Cathy Williams, PhD, University of Bristol, Katie Williams, PhD, King's College London, Jayne V. Woodside, MRCOphth, PhD, Queen's University Belfast, Max M. Yates, PhD, University of East Anglia, Jennifer Yip, PhD, University of Cambridge, and Yalin Zheng, PhD, University of Liverpool.
Disclaimer: The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health.
Additional Contributions: We thank the UK Department of Health for providing financial support through an award from the NIHR to Moorfields Eye Hospital NHS Foundation Trust and the UCL Institute of Ophthalmology for a Biomedical Research Centre for Ophthalmology. We also thank Kay-Tee Khaw, PhD, University of Cambridge, for providing analytic advice. No individuals were compensated for their contributions.
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