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Age-Related Eye Disease and Cognitive Function
Journal Pre-proof Age-Related Eye Disease and Cognitive Function: The Search for Mediators Mélanie Varin, MSc, Marie-Jeanne Kergoat, MD, Sylvie Belleville, PhD, Gisele Li, MD, MSc, Jacqueline Rousseau, PhD, Marie-Hélène Roy-Gagnon, PhD, Solmaz Moghadaszadeh, MSc, Ellen E. Freeman, PhD PII:
S0161-6420(19)32111-6
DOI:
https://doi.org/10.1016/j.ophtha.2019.10.004
Reference:
OPHTHA 10952
To appear in:
Ophthalmology
Received Date: 2 July 2019 Revised Date:
30 September 2019
Accepted Date: 2 October 2019
Please cite this article as: Varin M, Kergoat M-J, Belleville S, Li G, Rousseau J, Roy-Gagnon M-H, Moghadaszadeh S, Freeman EE, Age-Related Eye Disease and Cognitive Function: The Search for Mediators, Ophthalmology (2019), doi: https://doi.org/10.1016/j.ophtha.2019.10.004. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Academy of Ophthalmology
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Age-Related Eye Disease and Cognitive Function: The Search for
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Mediators
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Mélanie Varin, MSc1, Marie-Jeanne Kergoat, MD2, Sylvie Belleville, PhD2, Gisele Li, MD,
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MSc3,4, Jacqueline Rousseau, PhD2,5, Marie-Hélène Roy-Gagnon, PhD1, Solmaz
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Moghadaszadeh, MSc3, Ellen E. Freeman, PhD1,3,4,6
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School of Epidemiology and Public Health, University of Ottawa; 2 Centre de Recherche, Institut universitaire de gériatrie de Montréal; 3 Centre de Recherche, Hôpital MaisonneuveRosemont, Montréal; 4 Department of Ophthalmology, Université de Montréal; 5 School of Rehabilitation, Université de Montréal; 6 Ottawa Hospital Research Institute, Ottawa; Canada
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Presented at ARVO Minisymposium, May 2019
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Funded by a grant from the Canadian Institutes of Health Research (MOP 133560)
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Conflict of Interest: No conflicting relationship exists for any author
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Impact Statement 1. We certify that this work is novel 2. The potential impact: Older adults with glaucoma may be at risk for cognitive impairment. 3. This research reports a novel finding on the relationships between glaucoma and three cognitive tests of working memory.
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Corresponding Author: Ellen Freeman, School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada, [email protected], 613-562-5800 x8439
Running Head: Age-Related Eye Disease and Cognitive Function Word Count: 2,507
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ABSTRACT
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Purpose: Age-related eye disease may be associated with cognitive decline but the scientific
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literature has not been consistent. Furthermore, no studies have been able to explain the
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relationship. Our objective was to assess whether older adults with age-related macular
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degeneration (AMD) or glaucoma performed worse on six cognitive tests compared to older
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adults with normal vision, and, if so, to understand why.
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Design: Cross-sectional analysis of hospital-based study (Maisonneuve-Rosemont Hospital
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ophthalmology clinics, Montreal, Canada)
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Subjects, Participants, and Controls: 336 adults ages 65 and older with either AMD,
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glaucoma, or normal vision.
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Methods: Cognition was measured with six cognitive tests administered orally. Activity levels
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were measured using the Victoria Longitudinal Study Activity Lifestyle Questionnaire. Visual
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acuity and visual field were measured. Multiple linear regression was used. Mediation was
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assessed using structural equation modeling.
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Main Outcome Measures: Verbal fluency test animal and letter versions, the digit span forward
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and backward versions, and the logical memory test with immediate and delayed recall
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Results: People with glaucoma had lower scores on three cognitive tests than the group with
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normal vision: the digit span forward and backward tests (β=-0.8, 95% CI -1.5, -0.2 and
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β=-0.7, 95% CI -1.3, -0.1 respectively) and the logical memory test with immediate recall
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(β=-1.3, 95% CI -2.4, -0.2). Activity levels statistically significantly mediated the relationship
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between glaucoma and the digit span forward test (P=0.043, percentage of the total effect
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mediated=17%).
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Conclusions: People with glaucoma had lower scores on cognitive tests that might depend on
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verbal working memory and encoding. If confirmed in longitudinal studies, interventions should
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be developed that are appropriate for a visually impaired population in order to slow this
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cognitive decline.
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Evidence is accumulating that visual impairment due to age-related eye disease is related
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to poorer cognitive function. In particular, studies have found associations between cognitive
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function and early age-related macular degeneration (AMD)1, late AMD2, glaucoma3-5, and
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visual impairment6-9. Brain imaging studies have also found that AMD and glaucoma patients
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have weaker brain functional connectivity compared to controls 10,11. Other studies have not
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found associations between eye disease or vision and cognition12,13.
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There are various hypotheses about why eye disease and cognition may be related 14,15.
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Consistent with the sensory deprivation hypothesis and the disuse hypothesis 14-16, we believe
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that eye disease can cause cognitive decline due to its effect on intervening variables in the
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causal pathway. To our knowledge, no studies have attempted to explain the relationship
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between eye disease and cognitive function by examining potential intervening variables such as
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activity levels. Performing fewer activities in older age can increase the risk of Alzheimer’s
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disease or cognitive impairment 17 18 and the loss of vision late in life may lead to a less active
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lifestyle 19. Besides activity level, other potential intervening variables, also called mediators,
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could include life space and depressive symptoms. Life space, a measure of the spatial extent of
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a person over the last month20, has been found to be associated with both eye disease 21 and
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cognitive function 22, as have depressive symptoms 23,24.
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Our primary objective was to examine the relationship between two common age-related
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eye diseases, AMD and glaucoma, and 6 cognitive outcomes that are valid to use even in
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participants with poor vision because they are orally administered. Our secondary objective was
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to examine whether activity levels, life space, or depressive symptoms act as mediators.
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METHODS
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Study design and population
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Maisonneuve-Rosemont Hospital (Montréal, Québec) ophthalmology clinics from 2016-2018.
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Three groups of people were recruited: 1) those with late stage AMD (geographic atrophy or
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neovascular disease) in both eyes with a better eye visual acuity worse than 20/40 (n=111); 2)
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those with a diagnosis of glaucoma in both eyes with visual field mean deviation worse than or
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equal to -4dB in their better eye, (n=96). Secondary glaucoma was excluded due to concerns that
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the cause of the glaucoma could also affect cognitive function (e.g. trauma); 3) Those with
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normal vision who were not being seen for suspected AMD or glaucoma with visual acuity better
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than 20/40 in both eyes and visual field mean deviation better than -4dB in both eyes (n=129).
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Those in this group had conditions not currently causing visual impairment such as early
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cataract, diabetic retinopathy, posterior vitreous detachment, or ocular hypertension.
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Participants in this hospital-based cross-sectional study were recruited from the
Participants were excluded from the study if they were under 65, if they could not
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respond for themselves, or if they scored less than 10 on the Mini-Mental State Examination
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(MMSE) Blind version. The Blind version of the MMSE omits 8 items that rely on vision and
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has been validated against the original version 25. A score less than 10 on the MMSE Blind
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could indicate some form of dementia, Alzheimer’s disease or cognitive impairment and may
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lead to unreliable self-reported data25,26. Furthermore, people who had received eye surgery in
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the last 2 months were enrolled after a 2 month delay so that their cognition would not be
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affected by their recovery.
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There were 1,010 patients who appeared to meet eligibility criteria from a review of the
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medical records. Of the 1,010 patients, 535 patients accepted our invitation to be in the study
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(53%), 394 refused (39%), and 81 (8%) were not capable of responding for themselves. Of the
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535 who accepted, 336 people met the final eligibility criteria after giving the MMSE and
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measuring their current visual acuity and visual field. Six people were excluded because they
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scored too low on the MMSE. This study received approval from the Ethics Committee at
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Maisonneuve-Rosemont Hospital and was conducted according to the tenets of the Declaration
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of Helsinki. Written informed consent was obtained from each participant.
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Data Collection
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Vision and Eye Disease
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Information on date of diagnosis, type of age-related macular degeneration, type of
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glaucoma, previous treatment for AMD, and number and name(s) of current glaucoma
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medications was acquired from participants’ medical charts. Binocular visual acuity was
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measured using the Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity chart
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at 2 meters. Visual acuity scores were converted to log of the minimum angle of resolution
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(logMAR). Visual field was measured in each eye using the Humphrey Frequency Doubling
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Technology perimeter full-threshold testing27-29. Visual field data were considered unreliable
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and were not used if false positives, false negatives, or fixation losses exceeded 33% of trials. If
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a reliable visual field measure could not be obtained, the most recent visual field data were used
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from the medical chart as measured using the Humphrey SITA-standard 24-2 program. Contrast
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sensitivity was measured in each eye using the Pelli Robson chart at 1 meter 30. The presence of
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a current lens opacity (cataract) was taken from each participant’s medical chart.
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Cognitive Outcomes
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Participants were orally administered six cognitive tests: the one-minute verbal fluency
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test (letter and category versions), the digit span test (forward and backward versions), and the
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logical memory test (immediate and 30-minute delayed recall). The tests took approximately 30
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minutes in total to complete. These tests were chosen because they are valid and reliable
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cognitive tests that are orally administered in their original validated version. All questionnaires
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were interviewer-administered in a face-to-face manner. For the one-minute verbal fluency letter
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test, participants were asked to name as many words as they could that began with the letter p in
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one minute 31,32. For the one-minute verbal fluency category test, participants were asked to
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name as many animals as they could in one minute. These tests measure language and retrieval
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skills. The digit span forward and backward tests were used to assess verbal working memory
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in forward or reverse order. The last cognitive test administered was the logical memory test
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using immediate and 30-minute delayed recall 33. Participants were told a detailed short story
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and were asked to recall the story immediately and again 30 minutes later. This test examines
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verbal memory, encoding, and maintenance. Detailed scoring instructions were available. All
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tests were recorded and were scored by trained personnel.
. Participants were given an increasingly long list of numbers and were asked to repeat the list
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Potential Mediators Activities were measured using the Victoria Longitudinal Study Activity Lifestyle
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Questionnaire 16,34. This questionnaire has 70 items divided into 6 activity categories: physical,
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self-maintenance, social, hobbies and home maintenance, novel information processing, and
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passive information processing. The average frequency of participation over the last 2 years is
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rated on a 9-point scale (never, less than once a year, about once a year, 2 or 3 times a year,
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about once a month, 2 or 3 times a month, about once a week, 2 or 3 times a week, daily). This
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questionnaire showed good test-retest reliability and construct validity34. This questionnaire was
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scored by adding up all the activities that were done at least once per month.
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Depressive symptoms were measured by the Geriatric Depressive Scale Short Form 35
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and life space was measured using the Life Space Assessment 20. Life space is measured on a
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scale of 0 to 120 with higher scores indicating greater independent life space.
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Demographics and Health
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Demographic data such as age, sex, and highest level of education attained were
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collected. The self-report of a physician’s diagnosis of 13 health conditions (e.g., diabetes, heart
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disease, stroke, arthritis, asthma, chronic obstructive pulmonary disorder, hypertension,
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peripheral artery disease, Parkinson’s disease, hearing impairment, depression, back problem,
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hip fracture) was given by participants. Smoking status was obtained through self-report.
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Statistical Analysis To compare the three eye disease groups in preliminary analyses, ANOVA tests were
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used for continuous variables and chi-square tests for categorical variables. The normality of the
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cognitive outcomes was assessed with normal quantile plots. Multiple linear regression analysis
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was utilized to examine the relationship between eye disease and the cognitive outcomes
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adjusting for confounders. Rather than put all 13 comorbid health conditions into the model,
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health conditions were only entered into the model if they had a P-value<0.1 with at least one
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cognitive outcome after adjusting for demographic variables, smoking, and cataract. Diabetes,
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asthma, and hearing impairment had a P-value<0.1 for at least one cognitive outcome.
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Regression analyses were adjusted for covariates such as age, sex, education, diabetes, asthma,
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hearing impairment, , smoking, and cataract because of their potential importance to cognition or
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their association with AMD or glaucoma according to prior literature36. We limited our analyses
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to Caucasian individuals since we did not have enough non-Caucasian people to include them in
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the analysis (n=14).
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To determine whether activity level, life space, or depressive symptoms acted as
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mediators 37 of any relationships, structural equation modeling was used with the maximum
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likelihood with missing values option. Analyses were done in Stata Version 15.0 (College
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Station, Texas).
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RESULTS
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Of the 1,010 patients who we approached to participate in the study, 394 refused (39%).
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Patients who refused did not differ in age or sex from those who agreed to participate and were
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eligible (mean age and sex of participants versus refusers, respectively, 78.1 versus 79.0 years,
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P=0.125 and 58% versus 60% women, P=0.685).
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The three recruitment groups are compared in Table 1. The AMD and glaucoma groups
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were older (P<0.001), more likely to be women (P=0.027), and to have less education (P<0.001)
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than the normal vision group. They also had more depressive symptoms, performed fewer
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activities, and had reduced life space (P<0.001). Furthermore, as expected, the AMD group had
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worse visual acuity and the glaucoma group had worse visual field than the normal vision group
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(P<0.001). Both the AMD and glaucoma groups had worse contrast sensitivity than the normal
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vision group (P<0.001). The average duration of time since AMD diagnosis was 6 years while
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the average duration of time since glaucoma diagnosis was 10 years.
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The means and standard deviations of the cognitive tests are presented by eye disease
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status in Table 2. The scores for the normal vision group were higher than the groups with eye
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disease for all cognitive tests (P<0.001). For example, the AMD group reported three fewer
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words that start with the letter p in one minute, on average, than the normal vision group, while
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the glaucoma group reported just less than 2 fewer words.
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After adjustment for demographic, health, and lifestyle variables, only the glaucoma
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group remained statistically significantly associated with any cognitive outcomes (Table 3).
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Specifically, the glaucoma group had worse digit span forward scores (β=-0.8, 95% CI
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-1.5, -0.2). In other words, on average, the glaucoma group remembered 0.8 fewer digits than
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the normal vision group, after adjustment. The glaucoma group also had worse digit span
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backward scores (β=-0.7, 95% CI -1.3, -0.1), and worse scores on the logical memory test with
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immediate recall (β=-1.3, 95% CI -2.4, -0.2). After adjustment, AMD was not associated with
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any cognitive outcomes although it had borderline statistical significance with the digit span
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backward test (P=0.057). In a sensitivity analysis, we examined whether more severe AMD
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(with visual acuity worse than 20/60) was associated with any of the cognitive outcomes and it
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was not. We also ran a sensitivity analysis to see if the AMD results differed by whether a
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person had neovascular AMD in both eyes, a mix of neovascular AMD in one eye and
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geographic atrophy (GA) in one eye, or GA in both eyes. Those with neovascular AMD in both
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eyes had a lower verbal fluency letter score (β==-1.9, 95% CI -3.7, -0.1). No other statistically
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significant associations were found with AMD type.
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To explain the relationships identified between glaucoma and cognition, we examined
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whether any of the following variables acted as mediators: activity level, life space, or
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depressive symptoms. Activity levels statistically significantly mediated the relationship
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between glaucoma and the digit span forward test. The P-value for the indirect effect was
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0.043and the percentage of the total effect mediated was 17% (Figure 1). The P-values for the
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indirect effect of activity level on the verbal digit span backward test and the logical memory test
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had borderline significance at P=0.073 and P=0.089, respectively. The P-values for the indirect
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effect of life space on the verbal digit span forward test had borderline statistical significant at
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P=0.053 while the P-values for the indirect effect of life space on the verbal digit span backward
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test and the logical memory test were not statistically significant at P=0.113 and P=0.207,
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respectively. The P-values for the indirect effect of depressive symptoms on the verbal digit
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span forward test, the verbal digit span backward test, and the logical memory test were also not
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statistically significant at P=0.194, P=0.351, and P=0.774, respectively.
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We also ran models with visual acuity and visual field without the eye disease indicator
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variables. The results were consistent in that visual field in the better eye (which is primarily
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affected in glaucoma) was statistically significantly associated with the digit span forward
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(P=0.004) and backward tests (P=0.015) and the logical memory test with immediate recall
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(P=0.008) . It was also associated with the verbal fluency category score (P=0.030) and the
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logical memory test with delayed recall (P=0.029). Visual acuity (which is primarily affected in
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AMD) was not related to any cognitive tests. Finally, we ran models with contrast sensitivity
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and visual field without the eye disease variables. Contrast sensitivity was not statistically
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significantly related to any cognitive outcomes.
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DISCUSSION
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We have found for the first time that glaucoma patients have worse scores on three
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cognitive tests that measure verbal memory and verbal working memory, while AMD was not
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associated with any of the cognitive outcomes. Furthermore, activity levels act as a partial
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mediator of the relationship between glaucoma and the digit span forward test while life space
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and depressive symptoms did not act as mediators.
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It is interesting that glaucoma was only related to tests of memory and not the other
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cognitive tests. Working memory involves the storage and manipulation of information over a
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short period of time. In addition to working memory, the immediate recall of a story probably
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also relies on the capacity to process information as the story is being presented. We considered
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a few possible explanations for our results. We found modest evidence to support that reduced
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activity levels explain the relationship between eye disease and cognitive function. Reduced
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activity levels explained a small percentage (17%) of the relationship between glaucoma and the
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digit span forward test. There may be other mediators for which we did not have data that might
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explain more of these relationships such as reading difficulty or anxiety.
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explanation for our findings related to the common cause hypothesis of cognitive aging 15 is that
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elevated intraocular pressure (IOP) itself could affect memory. One study has shown that
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induced IOP elevation in rats was associated with an increase in levels of amyloid beta and
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phosphorylated tau while learning and memory declined 38. It is possible that participants in our
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study had IOP elevations in the past (before initiation of treatment) with residual optic nerve
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damage and possibly chronic changes in amyloid, phosphorylated tau levels, learning, and
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memory. In recent years, glaucoma has been hypothesized to be a neurodegenerative disease 39.
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Retinal ganglion cell injury can lead to trans-synaptic (transneuronal) anterograde degeneration.
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Trans-synaptic degeneration has been shown in various optic neuropathies. It is not clear whether
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the retinal ganglion cell damage seen in glaucoma causes transneuronal neurodegenerative brain
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changes or whether there is a primary central nervous system pathology 39. Although none of
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our participants had cognitive impairment, researchers have noted pathological similarities
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Another possible
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between conditions like glaucoma and Alzheimer’s disease, which affects working memory and
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verbal memory in its prodromal stage 40. These neurodegenerative diseases share features like
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glial reactivity, neuroinflammation, and oxidative stress 41. It is possible that glaucoma and
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neurodegenerative diseases affecting cognition share common biological pathways and share
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common risk factors like age and smoking. However, adjusting for risk factors like age and
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smoking did not diminish the associations between glaucoma and the tests of memory.
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It was surprising that AMD was not related to any of the cognitive tests given prior
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research 1,2,42-44 . However, only three studies had a similar design to ours and can be directly
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compared. First, Rozzini et al compared a late AMD group to a control group and examined a
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variety of cognitive tests 43. They found that AMD was associated with lower letter fluency
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scores but that it was not associated with category fluency scores. Second, Woo et al also
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compared a late AMD group with a control group 44. They found that AMD was associated with
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category fluency but not the digit span forward or backward tests. Finally, the AREDs study did
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not find a relationship between AMD severity and cognitive outcomes like letter fluency,
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category fluency, or the digit span backwards test but they did find associations between visual
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acuity and letter and category fluency 42. The disparate results between our study and these other
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studies may have to do with the use of possibly healthier volunteers recruited from outside the
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clinic in the control population 42,44 or residual confounding for important variables such as age,
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sex, and education 43,44. It is also possible that one must have an eye disease for a certain period
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of time to suffer from its cognitive effects. The average duration of time since AMD diagnosis
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was 6 years in our sample while the average duration of time since glaucoma diagnosis was 10
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years. Perhaps our AMD patients had not experienced visual acuity loss for long enough to have
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experienced cognitive changes. About 70% of our patients had wet AMD while 30% had dry.
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There were slightly lower scores on the verbal fluency letter test for AMD and glaucoma
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patients compared to controls although they were not statistically significant. We had 80%
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power to detect a difference of 1.9 words on the verbal fluency letter test given our sample size
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and the variability of the test. Instead, we saw half of that effect size with a difference of 1 word
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for the glaucoma group and 0.7 words for the AMD group. We would have needed a much
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larger sample size (376 glaucoma patients and 489 people with normal vision) for those more
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modestly sized differences to have been statistically significant.
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Strengths of this study include the involvement of patients with both AMD and glaucoma
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as well as a group with normal vision recruited from the same ophthalmology clinics, the
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measurement of visual acuity and visual field, the examination of potential mediators that were
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tested using structural equation modeling, and the inclusion of multiple cognitive tests that do
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not rely on vision. A limitation of this study is the lack of brain imaging data. To have had that
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data on even just a subset of the sample would have been valuable given previous findings of
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weaker brain functional connectivity in people with AMD and glaucoma 10,11. Another limitation
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is the lack of data on other sensory deprivations like measured hearing or olfactory impairments
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although the self-report of hearing impairment was not related to eye disease in our sample.
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Also, our reference group was being seen for vision problems (e.g. early cataract) that were not
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yet affecting visual acuity, visual field, or contrast sensitivity. However, we cannot be certain
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that this group did not have poorer visual functioning on other vision tests like glare sensitivity
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or motion perception. If our reference group did have vision problems in these other measures,
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this may have diluted our results. Finally, our data were cross-sectional, which precludes our
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ability to examine the temporal relationship of the variables and to more rigorously test
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mediation. Two-year follow-up data will be available in the future.
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To conclude, glaucoma patients had worse scores on three cognitive tests that were
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related to working memory. Further studies should consider longitudinal designs, incorporate
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brain imaging, and measure other sensory deprivations as well as vision problems 45. The
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relevance of this work is that if eye disease does result in cognitive problems, cognitive training
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exercises 46 could be developed that are appropriate and targeted towards people with vision loss.
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Figure 1: Results from a structural equation model showing the direct and indirect effects of glaucoma on the digit span forward test. The indirect effect is the product of -1.98*0.073=-0.15 (SE=0.072). The direct effect is -0.72 (SE=0.305). The total effect is the addition of the direct and indirect effects. The proportion of the total effect mediated= -0.15 / (-0.72-0.15) =0.17
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9. 10.
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13. 14. 15.
16. 17. 18. 19. 20. 21. 22.
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19
Table 1: Descriptive characteristics of the study population Glaucoma Mean (SD) or % n=96 78.1 (7.9)
Normal Vision Mean (SD) or % n=129 72.5 (5.8)
P-value
Age, Years
AMD Mean (SD) or % n=111 83.1 (7.2)
Sex Women
67.6%
56.3%
49.6%
0.027
Education, Years
10.2 (4.2)
11.3 (4.2)
12.8 (4.1)
<0.001
Binocular visual acuity, logMAR
0.6 (0.4)
0.2 (0.2)
0.1 (0.1)
<0.001
Visual field in better eye, MD in dB
-3.3 (3.8)*
-8.5 (6.8)
1.2 (1.9)
<0.001
Log Contrast Sensitivity in Better Eye
1.1 (0.4)
1.4 (0.3)
1.7 (0.2)
<0.001
Cataract
28.4%
28.9%
39.9%
0.165
Smoking Never smoker Former smoker Current smoker
38.1% 52.4% 9.5%
37.8% 54.1% 8.1%
44.9% 48.5% 6.6%
0.739
Diabetes
25%
20%
28%
0.397
Asthma
15.5%
12.6%
14.7%
0.716
34%
31%
29%
0.853
Activity Levels
18.2 (6.2)
22.2 (6.7)
25.8 (5.1)
<0.001
Life Space
48.7 (20.4)
61.0 (23.5)
73.2 (19.6)
<0.001
Hearing Impairment
<0.001
Depressive 3.4 (2.7) 2.7 (2.9) 2.0 (2.0) <0.001 Symptoms MD=mean deviation, dB=decibels, SD=standard deviation, AMD=age-related macular degeneration *38 participants with AMD were missing visual field data.
Table 2: Descriptive statistics for the six cognitive outcomes. Verbal Fluency Letters
Verbal Fluency Category
Digit Span Forward
Digit Span Backward
Immediate Story Recall
Delayed Story Recall
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Eye Disease Group Normal Vision AMD Glaucoma
13.9 (5.2) 11.0 (5.6) 12.1 (5.0)
16.7 (5.2) 13.3 (5.0) 14.6 (5.6)
11.7 (2.0) 10.4 (2.4) 10.4 (2.6)
6.6 (2.3) 5.2 (2.0) 5.6 (2.4)
11.1 (4.1) 8.2 (4.8) 8.6 (4.0)
8.7 (4.5) 6.0 (4.6) 6.6 (3.7)
Possible Range
0-Unlimited
0-Unlimited
0-16
0-14
0-25
0-25
Observed Range
1-27
2-32
3-16
1-13
0-21
0-19
<0.001
<0.001
<0.001
P-value* <0.001 <0.001 <0.001 SD=standard deviation, AMD=age-related macular degeneration * P-value derived from ANOVA test.
Table 3: Multiple linear regression results of relationship between eye diseases and the six cognitive outcomes. Verbal Fluency Letters
Group Normal Vision AMD Glaucoma Age Female Sex Education Smoking Never Former Current Cataract Diabetes Asthma Hearing Impairment
Verbal Fluency Category
Digit Span Forward
β
95% CI
β
95% CI
β
0.0 -0.7 -1.0 -0.1 1.2 0.4
Ref -2.3, 0.8 -2.4, 0.4 -0.2, -0.0 0.0, 2.4 0.3, 0.5
0.0 0.2 -0.2 -0.3 1.0 0.2
Ref -1.3, 1.8 -1.7, 1.2 -0.4, -0.2 -0.2, 2.1 0.1, 0.4
0.0 Ref -0.1 -0.8, 0.6 -0.8 -1.5, -0.2 -0.1 -0.1, -0.0 0.4 -0.1, 0.9 0.2 0.1, 0.2
1.0 0.9 -1.4 -0.3 -1.2 -0.3 -0.8
-0.3, 2.1 -3.6, 0.8 -1.6, 1.0 -2.5, 0.1 -1.8, 1.3 -2.0, 0.5
1.0 -0.1 -0.4 -0.0 -0.5 1.4 0.4
-1.2, 1.1 -2.5, 1.7 -1.3, 1.2 -1.7, 0.8 -0.1, 2.9 -0.8, 1.6
1.0 0.3 0.1 -0.6 -0.2 -0.4 -0.5
AMD=age-related macular degeneration, CI=confidence interval
95% CI
-0.2, 0.9 -0.8, 1.1 -1.1, -0.0 -0.8, 0.3 -1.0, 0.3 -1.0, 0.0
Digit Span Backward
Delayed Story Recall
β
95% CI
β
95% CI
0.0 Ref -0.6 -1.3, 0.0 -0.7 -1.3, -0.1 -0.0 -0.1, 0.0 0.3 -0.2, 0.7 0.2 0.2, 0.3
0.0 -0.4 -1.3 -0.1 0.3 0.3
Ref -1.6, 0.9 -2.4, -0.2 -0.2, -0.1 -0.6, 1.2 0.2, 0.4
0.0 -0.2 -1.0 -0.2 0.3 0.2
Ref -1.5, 1.1 -2.1, 0.2 -0.2, -0.1 -0.6, 1.3 0.1, 0.3
1.0 0.1 1.0 -0.1 -0.3 -0.1 -0.3
1.0 1.0 0.3 -0.9 -0.6 1.9 -0.3
0.1, 1.9 -1.4, 2.0 -1.9, 0.1 -1.6, 0.4 0.6, 3.1 -1.3, 0.6
1.0 0.9 -0.0 -0.9 -0.7 2.3 -0.6
-0.1, 1.9 -1.8, 1.8 -1.9, 0.2 -1.7, 0.4 1.0, 3.6 -1.7, 0.4
β
95% CI
Immediate Story Recall
-0.4, 0.6 0.1, 1.9 -0.6, 0.5 -0.8, 0.3 -0.8, 0.5 -0.8, 0.2
S0161-6420(19)32111-6
DOI:
https://doi.org/10.1016/j.ophtha.2019.10.004
Reference:
OPHTHA 10952
To appear in:
Ophthalmology
Received Date: 2 July 2019 Revised Date:
30 September 2019
Accepted Date: 2 October 2019
Please cite this article as: Varin M, Kergoat M-J, Belleville S, Li G, Rousseau J, Roy-Gagnon M-H, Moghadaszadeh S, Freeman EE, Age-Related Eye Disease and Cognitive Function: The Search for Mediators, Ophthalmology (2019), doi: https://doi.org/10.1016/j.ophtha.2019.10.004. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Academy of Ophthalmology
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2
Age-Related Eye Disease and Cognitive Function: The Search for
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Mediators
4 5
Mélanie Varin, MSc1, Marie-Jeanne Kergoat, MD2, Sylvie Belleville, PhD2, Gisele Li, MD,
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MSc3,4, Jacqueline Rousseau, PhD2,5, Marie-Hélène Roy-Gagnon, PhD1, Solmaz
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Moghadaszadeh, MSc3, Ellen E. Freeman, PhD1,3,4,6
8 9 10 11 12 13
1
School of Epidemiology and Public Health, University of Ottawa; 2 Centre de Recherche, Institut universitaire de gériatrie de Montréal; 3 Centre de Recherche, Hôpital MaisonneuveRosemont, Montréal; 4 Department of Ophthalmology, Université de Montréal; 5 School of Rehabilitation, Université de Montréal; 6 Ottawa Hospital Research Institute, Ottawa; Canada
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Presented at ARVO Minisymposium, May 2019
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Funded by a grant from the Canadian Institutes of Health Research (MOP 133560)
16 17 18 19 20
Conflict of Interest: No conflicting relationship exists for any author
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Impact Statement 1. We certify that this work is novel 2. The potential impact: Older adults with glaucoma may be at risk for cognitive impairment. 3. This research reports a novel finding on the relationships between glaucoma and three cognitive tests of working memory.
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Corresponding Author: Ellen Freeman, School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada, [email protected], 613-562-5800 x8439
Running Head: Age-Related Eye Disease and Cognitive Function Word Count: 2,507
1
ABSTRACT
32 33 34
Purpose: Age-related eye disease may be associated with cognitive decline but the scientific
35
literature has not been consistent. Furthermore, no studies have been able to explain the
36
relationship. Our objective was to assess whether older adults with age-related macular
37
degeneration (AMD) or glaucoma performed worse on six cognitive tests compared to older
38
adults with normal vision, and, if so, to understand why.
39
Design: Cross-sectional analysis of hospital-based study (Maisonneuve-Rosemont Hospital
40
ophthalmology clinics, Montreal, Canada)
41
Subjects, Participants, and Controls: 336 adults ages 65 and older with either AMD,
42
glaucoma, or normal vision.
43
Methods: Cognition was measured with six cognitive tests administered orally. Activity levels
44
were measured using the Victoria Longitudinal Study Activity Lifestyle Questionnaire. Visual
45
acuity and visual field were measured. Multiple linear regression was used. Mediation was
46
assessed using structural equation modeling.
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Main Outcome Measures: Verbal fluency test animal and letter versions, the digit span forward
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and backward versions, and the logical memory test with immediate and delayed recall
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Results: People with glaucoma had lower scores on three cognitive tests than the group with
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normal vision: the digit span forward and backward tests (β=-0.8, 95% CI -1.5, -0.2 and
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β=-0.7, 95% CI -1.3, -0.1 respectively) and the logical memory test with immediate recall
52
(β=-1.3, 95% CI -2.4, -0.2). Activity levels statistically significantly mediated the relationship
53
between glaucoma and the digit span forward test (P=0.043, percentage of the total effect
54
mediated=17%).
2
55
Conclusions: People with glaucoma had lower scores on cognitive tests that might depend on
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verbal working memory and encoding. If confirmed in longitudinal studies, interventions should
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be developed that are appropriate for a visually impaired population in order to slow this
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cognitive decline.
3
59
Evidence is accumulating that visual impairment due to age-related eye disease is related
60
to poorer cognitive function. In particular, studies have found associations between cognitive
61
function and early age-related macular degeneration (AMD)1, late AMD2, glaucoma3-5, and
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visual impairment6-9. Brain imaging studies have also found that AMD and glaucoma patients
63
have weaker brain functional connectivity compared to controls 10,11. Other studies have not
64
found associations between eye disease or vision and cognition12,13.
65
There are various hypotheses about why eye disease and cognition may be related 14,15.
66
Consistent with the sensory deprivation hypothesis and the disuse hypothesis 14-16, we believe
67
that eye disease can cause cognitive decline due to its effect on intervening variables in the
68
causal pathway. To our knowledge, no studies have attempted to explain the relationship
69
between eye disease and cognitive function by examining potential intervening variables such as
70
activity levels. Performing fewer activities in older age can increase the risk of Alzheimer’s
71
disease or cognitive impairment 17 18 and the loss of vision late in life may lead to a less active
72
lifestyle 19. Besides activity level, other potential intervening variables, also called mediators,
73
could include life space and depressive symptoms. Life space, a measure of the spatial extent of
74
a person over the last month20, has been found to be associated with both eye disease 21 and
75
cognitive function 22, as have depressive symptoms 23,24.
76
Our primary objective was to examine the relationship between two common age-related
77
eye diseases, AMD and glaucoma, and 6 cognitive outcomes that are valid to use even in
78
participants with poor vision because they are orally administered. Our secondary objective was
79
to examine whether activity levels, life space, or depressive symptoms act as mediators.
80 81
METHODS
4
82 83 84
Study design and population
85
Maisonneuve-Rosemont Hospital (Montréal, Québec) ophthalmology clinics from 2016-2018.
86
Three groups of people were recruited: 1) those with late stage AMD (geographic atrophy or
87
neovascular disease) in both eyes with a better eye visual acuity worse than 20/40 (n=111); 2)
88
those with a diagnosis of glaucoma in both eyes with visual field mean deviation worse than or
89
equal to -4dB in their better eye, (n=96). Secondary glaucoma was excluded due to concerns that
90
the cause of the glaucoma could also affect cognitive function (e.g. trauma); 3) Those with
91
normal vision who were not being seen for suspected AMD or glaucoma with visual acuity better
92
than 20/40 in both eyes and visual field mean deviation better than -4dB in both eyes (n=129).
93
Those in this group had conditions not currently causing visual impairment such as early
94
cataract, diabetic retinopathy, posterior vitreous detachment, or ocular hypertension.
95
Participants in this hospital-based cross-sectional study were recruited from the
Participants were excluded from the study if they were under 65, if they could not
96
respond for themselves, or if they scored less than 10 on the Mini-Mental State Examination
97
(MMSE) Blind version. The Blind version of the MMSE omits 8 items that rely on vision and
98
has been validated against the original version 25. A score less than 10 on the MMSE Blind
99
could indicate some form of dementia, Alzheimer’s disease or cognitive impairment and may
100
lead to unreliable self-reported data25,26. Furthermore, people who had received eye surgery in
101
the last 2 months were enrolled after a 2 month delay so that their cognition would not be
102
affected by their recovery.
103
There were 1,010 patients who appeared to meet eligibility criteria from a review of the
104
medical records. Of the 1,010 patients, 535 patients accepted our invitation to be in the study
105
(53%), 394 refused (39%), and 81 (8%) were not capable of responding for themselves. Of the
5
106
535 who accepted, 336 people met the final eligibility criteria after giving the MMSE and
107
measuring their current visual acuity and visual field. Six people were excluded because they
108
scored too low on the MMSE. This study received approval from the Ethics Committee at
109
Maisonneuve-Rosemont Hospital and was conducted according to the tenets of the Declaration
110
of Helsinki. Written informed consent was obtained from each participant.
111 112
Data Collection
113
Vision and Eye Disease
114
Information on date of diagnosis, type of age-related macular degeneration, type of
115
glaucoma, previous treatment for AMD, and number and name(s) of current glaucoma
116
medications was acquired from participants’ medical charts. Binocular visual acuity was
117
measured using the Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity chart
118
at 2 meters. Visual acuity scores were converted to log of the minimum angle of resolution
119
(logMAR). Visual field was measured in each eye using the Humphrey Frequency Doubling
120
Technology perimeter full-threshold testing27-29. Visual field data were considered unreliable
121
and were not used if false positives, false negatives, or fixation losses exceeded 33% of trials. If
122
a reliable visual field measure could not be obtained, the most recent visual field data were used
123
from the medical chart as measured using the Humphrey SITA-standard 24-2 program. Contrast
124
sensitivity was measured in each eye using the Pelli Robson chart at 1 meter 30. The presence of
125
a current lens opacity (cataract) was taken from each participant’s medical chart.
126 127
Cognitive Outcomes
6
128
Participants were orally administered six cognitive tests: the one-minute verbal fluency
129
test (letter and category versions), the digit span test (forward and backward versions), and the
130
logical memory test (immediate and 30-minute delayed recall). The tests took approximately 30
131
minutes in total to complete. These tests were chosen because they are valid and reliable
132
cognitive tests that are orally administered in their original validated version. All questionnaires
133
were interviewer-administered in a face-to-face manner. For the one-minute verbal fluency letter
134
test, participants were asked to name as many words as they could that began with the letter p in
135
one minute 31,32. For the one-minute verbal fluency category test, participants were asked to
136
name as many animals as they could in one minute. These tests measure language and retrieval
137
skills. The digit span forward and backward tests were used to assess verbal working memory
138
33
139
in forward or reverse order. The last cognitive test administered was the logical memory test
140
using immediate and 30-minute delayed recall 33. Participants were told a detailed short story
141
and were asked to recall the story immediately and again 30 minutes later. This test examines
142
verbal memory, encoding, and maintenance. Detailed scoring instructions were available. All
143
tests were recorded and were scored by trained personnel.
. Participants were given an increasingly long list of numbers and were asked to repeat the list
144 145 146
Potential Mediators Activities were measured using the Victoria Longitudinal Study Activity Lifestyle
147
Questionnaire 16,34. This questionnaire has 70 items divided into 6 activity categories: physical,
148
self-maintenance, social, hobbies and home maintenance, novel information processing, and
149
passive information processing. The average frequency of participation over the last 2 years is
150
rated on a 9-point scale (never, less than once a year, about once a year, 2 or 3 times a year,
7
151
about once a month, 2 or 3 times a month, about once a week, 2 or 3 times a week, daily). This
152
questionnaire showed good test-retest reliability and construct validity34. This questionnaire was
153
scored by adding up all the activities that were done at least once per month.
154
Depressive symptoms were measured by the Geriatric Depressive Scale Short Form 35
155
and life space was measured using the Life Space Assessment 20. Life space is measured on a
156
scale of 0 to 120 with higher scores indicating greater independent life space.
157 158
Demographics and Health
159
Demographic data such as age, sex, and highest level of education attained were
160
collected. The self-report of a physician’s diagnosis of 13 health conditions (e.g., diabetes, heart
161
disease, stroke, arthritis, asthma, chronic obstructive pulmonary disorder, hypertension,
162
peripheral artery disease, Parkinson’s disease, hearing impairment, depression, back problem,
163
hip fracture) was given by participants. Smoking status was obtained through self-report.
164 165 166
Statistical Analysis To compare the three eye disease groups in preliminary analyses, ANOVA tests were
167
used for continuous variables and chi-square tests for categorical variables. The normality of the
168
cognitive outcomes was assessed with normal quantile plots. Multiple linear regression analysis
169
was utilized to examine the relationship between eye disease and the cognitive outcomes
170
adjusting for confounders. Rather than put all 13 comorbid health conditions into the model,
171
health conditions were only entered into the model if they had a P-value<0.1 with at least one
172
cognitive outcome after adjusting for demographic variables, smoking, and cataract. Diabetes,
173
asthma, and hearing impairment had a P-value<0.1 for at least one cognitive outcome.
8
174
Regression analyses were adjusted for covariates such as age, sex, education, diabetes, asthma,
175
hearing impairment, , smoking, and cataract because of their potential importance to cognition or
176
their association with AMD or glaucoma according to prior literature36. We limited our analyses
177
to Caucasian individuals since we did not have enough non-Caucasian people to include them in
178
the analysis (n=14).
179
To determine whether activity level, life space, or depressive symptoms acted as
180
mediators 37 of any relationships, structural equation modeling was used with the maximum
181
likelihood with missing values option. Analyses were done in Stata Version 15.0 (College
182
Station, Texas).
183 184
RESULTS
185
Of the 1,010 patients who we approached to participate in the study, 394 refused (39%).
186
Patients who refused did not differ in age or sex from those who agreed to participate and were
187
eligible (mean age and sex of participants versus refusers, respectively, 78.1 versus 79.0 years,
188
P=0.125 and 58% versus 60% women, P=0.685).
189
The three recruitment groups are compared in Table 1. The AMD and glaucoma groups
190
were older (P<0.001), more likely to be women (P=0.027), and to have less education (P<0.001)
191
than the normal vision group. They also had more depressive symptoms, performed fewer
192
activities, and had reduced life space (P<0.001). Furthermore, as expected, the AMD group had
193
worse visual acuity and the glaucoma group had worse visual field than the normal vision group
194
(P<0.001). Both the AMD and glaucoma groups had worse contrast sensitivity than the normal
195
vision group (P<0.001). The average duration of time since AMD diagnosis was 6 years while
196
the average duration of time since glaucoma diagnosis was 10 years.
9
197
The means and standard deviations of the cognitive tests are presented by eye disease
198
status in Table 2. The scores for the normal vision group were higher than the groups with eye
199
disease for all cognitive tests (P<0.001). For example, the AMD group reported three fewer
200
words that start with the letter p in one minute, on average, than the normal vision group, while
201
the glaucoma group reported just less than 2 fewer words.
202
After adjustment for demographic, health, and lifestyle variables, only the glaucoma
203
group remained statistically significantly associated with any cognitive outcomes (Table 3).
204
Specifically, the glaucoma group had worse digit span forward scores (β=-0.8, 95% CI
205
-1.5, -0.2). In other words, on average, the glaucoma group remembered 0.8 fewer digits than
206
the normal vision group, after adjustment. The glaucoma group also had worse digit span
207
backward scores (β=-0.7, 95% CI -1.3, -0.1), and worse scores on the logical memory test with
208
immediate recall (β=-1.3, 95% CI -2.4, -0.2). After adjustment, AMD was not associated with
209
any cognitive outcomes although it had borderline statistical significance with the digit span
210
backward test (P=0.057). In a sensitivity analysis, we examined whether more severe AMD
211
(with visual acuity worse than 20/60) was associated with any of the cognitive outcomes and it
212
was not. We also ran a sensitivity analysis to see if the AMD results differed by whether a
213
person had neovascular AMD in both eyes, a mix of neovascular AMD in one eye and
214
geographic atrophy (GA) in one eye, or GA in both eyes. Those with neovascular AMD in both
215
eyes had a lower verbal fluency letter score (β==-1.9, 95% CI -3.7, -0.1). No other statistically
216
significant associations were found with AMD type.
217
To explain the relationships identified between glaucoma and cognition, we examined
218
whether any of the following variables acted as mediators: activity level, life space, or
219
depressive symptoms. Activity levels statistically significantly mediated the relationship
10
220
between glaucoma and the digit span forward test. The P-value for the indirect effect was
221
0.043and the percentage of the total effect mediated was 17% (Figure 1). The P-values for the
222
indirect effect of activity level on the verbal digit span backward test and the logical memory test
223
had borderline significance at P=0.073 and P=0.089, respectively. The P-values for the indirect
224
effect of life space on the verbal digit span forward test had borderline statistical significant at
225
P=0.053 while the P-values for the indirect effect of life space on the verbal digit span backward
226
test and the logical memory test were not statistically significant at P=0.113 and P=0.207,
227
respectively. The P-values for the indirect effect of depressive symptoms on the verbal digit
228
span forward test, the verbal digit span backward test, and the logical memory test were also not
229
statistically significant at P=0.194, P=0.351, and P=0.774, respectively.
230
We also ran models with visual acuity and visual field without the eye disease indicator
231
variables. The results were consistent in that visual field in the better eye (which is primarily
232
affected in glaucoma) was statistically significantly associated with the digit span forward
233
(P=0.004) and backward tests (P=0.015) and the logical memory test with immediate recall
234
(P=0.008) . It was also associated with the verbal fluency category score (P=0.030) and the
235
logical memory test with delayed recall (P=0.029). Visual acuity (which is primarily affected in
236
AMD) was not related to any cognitive tests. Finally, we ran models with contrast sensitivity
237
and visual field without the eye disease variables. Contrast sensitivity was not statistically
238
significantly related to any cognitive outcomes.
239
DISCUSSION
240
We have found for the first time that glaucoma patients have worse scores on three
241
cognitive tests that measure verbal memory and verbal working memory, while AMD was not
242
associated with any of the cognitive outcomes. Furthermore, activity levels act as a partial
11
243
mediator of the relationship between glaucoma and the digit span forward test while life space
244
and depressive symptoms did not act as mediators.
245
It is interesting that glaucoma was only related to tests of memory and not the other
246
cognitive tests. Working memory involves the storage and manipulation of information over a
247
short period of time. In addition to working memory, the immediate recall of a story probably
248
also relies on the capacity to process information as the story is being presented. We considered
249
a few possible explanations for our results. We found modest evidence to support that reduced
250
activity levels explain the relationship between eye disease and cognitive function. Reduced
251
activity levels explained a small percentage (17%) of the relationship between glaucoma and the
252
digit span forward test. There may be other mediators for which we did not have data that might
253
explain more of these relationships such as reading difficulty or anxiety.
254
explanation for our findings related to the common cause hypothesis of cognitive aging 15 is that
255
elevated intraocular pressure (IOP) itself could affect memory. One study has shown that
256
induced IOP elevation in rats was associated with an increase in levels of amyloid beta and
257
phosphorylated tau while learning and memory declined 38. It is possible that participants in our
258
study had IOP elevations in the past (before initiation of treatment) with residual optic nerve
259
damage and possibly chronic changes in amyloid, phosphorylated tau levels, learning, and
260
memory. In recent years, glaucoma has been hypothesized to be a neurodegenerative disease 39.
261
Retinal ganglion cell injury can lead to trans-synaptic (transneuronal) anterograde degeneration.
262
Trans-synaptic degeneration has been shown in various optic neuropathies. It is not clear whether
263
the retinal ganglion cell damage seen in glaucoma causes transneuronal neurodegenerative brain
264
changes or whether there is a primary central nervous system pathology 39. Although none of
265
our participants had cognitive impairment, researchers have noted pathological similarities
12
Another possible
266
between conditions like glaucoma and Alzheimer’s disease, which affects working memory and
267
verbal memory in its prodromal stage 40. These neurodegenerative diseases share features like
268
glial reactivity, neuroinflammation, and oxidative stress 41. It is possible that glaucoma and
269
neurodegenerative diseases affecting cognition share common biological pathways and share
270
common risk factors like age and smoking. However, adjusting for risk factors like age and
271
smoking did not diminish the associations between glaucoma and the tests of memory.
272
It was surprising that AMD was not related to any of the cognitive tests given prior
273
research 1,2,42-44 . However, only three studies had a similar design to ours and can be directly
274
compared. First, Rozzini et al compared a late AMD group to a control group and examined a
275
variety of cognitive tests 43. They found that AMD was associated with lower letter fluency
276
scores but that it was not associated with category fluency scores. Second, Woo et al also
277
compared a late AMD group with a control group 44. They found that AMD was associated with
278
category fluency but not the digit span forward or backward tests. Finally, the AREDs study did
279
not find a relationship between AMD severity and cognitive outcomes like letter fluency,
280
category fluency, or the digit span backwards test but they did find associations between visual
281
acuity and letter and category fluency 42. The disparate results between our study and these other
282
studies may have to do with the use of possibly healthier volunteers recruited from outside the
283
clinic in the control population 42,44 or residual confounding for important variables such as age,
284
sex, and education 43,44. It is also possible that one must have an eye disease for a certain period
285
of time to suffer from its cognitive effects. The average duration of time since AMD diagnosis
286
was 6 years in our sample while the average duration of time since glaucoma diagnosis was 10
287
years. Perhaps our AMD patients had not experienced visual acuity loss for long enough to have
288
experienced cognitive changes. About 70% of our patients had wet AMD while 30% had dry.
13
289
There were slightly lower scores on the verbal fluency letter test for AMD and glaucoma
290
patients compared to controls although they were not statistically significant. We had 80%
291
power to detect a difference of 1.9 words on the verbal fluency letter test given our sample size
292
and the variability of the test. Instead, we saw half of that effect size with a difference of 1 word
293
for the glaucoma group and 0.7 words for the AMD group. We would have needed a much
294
larger sample size (376 glaucoma patients and 489 people with normal vision) for those more
295
modestly sized differences to have been statistically significant.
296
Strengths of this study include the involvement of patients with both AMD and glaucoma
297
as well as a group with normal vision recruited from the same ophthalmology clinics, the
298
measurement of visual acuity and visual field, the examination of potential mediators that were
299
tested using structural equation modeling, and the inclusion of multiple cognitive tests that do
300
not rely on vision. A limitation of this study is the lack of brain imaging data. To have had that
301
data on even just a subset of the sample would have been valuable given previous findings of
302
weaker brain functional connectivity in people with AMD and glaucoma 10,11. Another limitation
303
is the lack of data on other sensory deprivations like measured hearing or olfactory impairments
304
although the self-report of hearing impairment was not related to eye disease in our sample.
305
Also, our reference group was being seen for vision problems (e.g. early cataract) that were not
306
yet affecting visual acuity, visual field, or contrast sensitivity. However, we cannot be certain
307
that this group did not have poorer visual functioning on other vision tests like glare sensitivity
308
or motion perception. If our reference group did have vision problems in these other measures,
309
this may have diluted our results. Finally, our data were cross-sectional, which precludes our
310
ability to examine the temporal relationship of the variables and to more rigorously test
311
mediation. Two-year follow-up data will be available in the future.
14
312
To conclude, glaucoma patients had worse scores on three cognitive tests that were
313
related to working memory. Further studies should consider longitudinal designs, incorporate
314
brain imaging, and measure other sensory deprivations as well as vision problems 45. The
315
relevance of this work is that if eye disease does result in cognitive problems, cognitive training
316
exercises 46 could be developed that are appropriate and targeted towards people with vision loss.
317
15
Figure 1: Results from a structural equation model showing the direct and indirect effects of glaucoma on the digit span forward test. The indirect effect is the product of -1.98*0.073=-0.15 (SE=0.072). The direct effect is -0.72 (SE=0.305). The total effect is the addition of the direct and indirect effects. The proportion of the total effect mediated= -0.15 / (-0.72-0.15) =0.17
16
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19
Table 1: Descriptive characteristics of the study population Glaucoma Mean (SD) or % n=96 78.1 (7.9)
Normal Vision Mean (SD) or % n=129 72.5 (5.8)
P-value
Age, Years
AMD Mean (SD) or % n=111 83.1 (7.2)
Sex Women
67.6%
56.3%
49.6%
0.027
Education, Years
10.2 (4.2)
11.3 (4.2)
12.8 (4.1)
<0.001
Binocular visual acuity, logMAR
0.6 (0.4)
0.2 (0.2)
0.1 (0.1)
<0.001
Visual field in better eye, MD in dB
-3.3 (3.8)*
-8.5 (6.8)
1.2 (1.9)
<0.001
Log Contrast Sensitivity in Better Eye
1.1 (0.4)
1.4 (0.3)
1.7 (0.2)
<0.001
Cataract
28.4%
28.9%
39.9%
0.165
Smoking Never smoker Former smoker Current smoker
38.1% 52.4% 9.5%
37.8% 54.1% 8.1%
44.9% 48.5% 6.6%
0.739
Diabetes
25%
20%
28%
0.397
Asthma
15.5%
12.6%
14.7%
0.716
34%
31%
29%
0.853
Activity Levels
18.2 (6.2)
22.2 (6.7)
25.8 (5.1)
<0.001
Life Space
48.7 (20.4)
61.0 (23.5)
73.2 (19.6)
<0.001
Hearing Impairment
<0.001
Depressive 3.4 (2.7) 2.7 (2.9) 2.0 (2.0) <0.001 Symptoms MD=mean deviation, dB=decibels, SD=standard deviation, AMD=age-related macular degeneration *38 participants with AMD were missing visual field data.
Table 2: Descriptive statistics for the six cognitive outcomes. Verbal Fluency Letters
Verbal Fluency Category
Digit Span Forward
Digit Span Backward
Immediate Story Recall
Delayed Story Recall
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Eye Disease Group Normal Vision AMD Glaucoma
13.9 (5.2) 11.0 (5.6) 12.1 (5.0)
16.7 (5.2) 13.3 (5.0) 14.6 (5.6)
11.7 (2.0) 10.4 (2.4) 10.4 (2.6)
6.6 (2.3) 5.2 (2.0) 5.6 (2.4)
11.1 (4.1) 8.2 (4.8) 8.6 (4.0)
8.7 (4.5) 6.0 (4.6) 6.6 (3.7)
Possible Range
0-Unlimited
0-Unlimited
0-16
0-14
0-25
0-25
Observed Range
1-27
2-32
3-16
1-13
0-21
0-19
<0.001
<0.001
<0.001
P-value* <0.001 <0.001 <0.001 SD=standard deviation, AMD=age-related macular degeneration * P-value derived from ANOVA test.
Table 3: Multiple linear regression results of relationship between eye diseases and the six cognitive outcomes. Verbal Fluency Letters
Group Normal Vision AMD Glaucoma Age Female Sex Education Smoking Never Former Current Cataract Diabetes Asthma Hearing Impairment
Verbal Fluency Category
Digit Span Forward
β
95% CI
β
95% CI
β
0.0 -0.7 -1.0 -0.1 1.2 0.4
Ref -2.3, 0.8 -2.4, 0.4 -0.2, -0.0 0.0, 2.4 0.3, 0.5
0.0 0.2 -0.2 -0.3 1.0 0.2
Ref -1.3, 1.8 -1.7, 1.2 -0.4, -0.2 -0.2, 2.1 0.1, 0.4
0.0 Ref -0.1 -0.8, 0.6 -0.8 -1.5, -0.2 -0.1 -0.1, -0.0 0.4 -0.1, 0.9 0.2 0.1, 0.2
1.0 0.9 -1.4 -0.3 -1.2 -0.3 -0.8
-0.3, 2.1 -3.6, 0.8 -1.6, 1.0 -2.5, 0.1 -1.8, 1.3 -2.0, 0.5
1.0 -0.1 -0.4 -0.0 -0.5 1.4 0.4
-1.2, 1.1 -2.5, 1.7 -1.3, 1.2 -1.7, 0.8 -0.1, 2.9 -0.8, 1.6
1.0 0.3 0.1 -0.6 -0.2 -0.4 -0.5
AMD=age-related macular degeneration, CI=confidence interval
95% CI
-0.2, 0.9 -0.8, 1.1 -1.1, -0.0 -0.8, 0.3 -1.0, 0.3 -1.0, 0.0
Digit Span Backward
Delayed Story Recall
β
95% CI
β
95% CI
0.0 Ref -0.6 -1.3, 0.0 -0.7 -1.3, -0.1 -0.0 -0.1, 0.0 0.3 -0.2, 0.7 0.2 0.2, 0.3
0.0 -0.4 -1.3 -0.1 0.3 0.3
Ref -1.6, 0.9 -2.4, -0.2 -0.2, -0.1 -0.6, 1.2 0.2, 0.4
0.0 -0.2 -1.0 -0.2 0.3 0.2
Ref -1.5, 1.1 -2.1, 0.2 -0.2, -0.1 -0.6, 1.3 0.1, 0.3
1.0 0.1 1.0 -0.1 -0.3 -0.1 -0.3
1.0 1.0 0.3 -0.9 -0.6 1.9 -0.3
0.1, 1.9 -1.4, 2.0 -1.9, 0.1 -1.6, 0.4 0.6, 3.1 -1.3, 0.6
1.0 0.9 -0.0 -0.9 -0.7 2.3 -0.6
-0.1, 1.9 -1.8, 1.8 -1.9, 0.2 -1.7, 0.4 1.0, 3.6 -1.7, 0.4
β
95% CI
Immediate Story Recall
-0.4, 0.6 0.1, 1.9 -0.6, 0.5 -0.8, 0.3 -0.8, 0.5 -0.8, 0.2