An Exploratory Study to Investigate the Utility of Clinical Screening for Neurodegenerative Disease in Age-Related Eye Disease Research

Background: Unrecognized neurodegenerative diseases (NDD) in age-related eye disease research studies have the potential to confound vision-specific quality of life and retinal optical coherence tomography (OCT) outcome measures. The aim of this exploratory study was to investigate relationships between NDD screening tools and visual outcome measures in a small cohort of controls from the Colorado Age-Related Macular Degeneration Registry (CO-AMD), to consider the utility of future studies. Methods: Twenty-nine controls from the CO-AMD were screened using the Montreal Cognitive Assessment (MoCA), a Colorado Parkinsonian Checklist, and the Lewy Body Composite Risk Score. Univariate and multivariable linear regression modeling was used to assess associations between screening tools and the National Eye Institute Visual Function Questionnaire-25 (VFQ-25) and macular OCT outcome measures, and t tests were used to evaluate outcome measure differences between those with normal vs abnormal MoCA scores. Results: One patient withdrew. The average age was 72.8 years, and 68% were female patients. Ten participants (36%) had abnormal MoCA scores, and their VFQ-25 scores were only 1 point less and not statistically different than those with normal MoCA scores. Macular OCT volumes and thicknesses for retinal nerve fiber layer (RNFL) and retinal ganglion cell layer were consistently and moderately lower for those with abnormal MoCA scores, and a positive association between MoCA and macular RNFL volume was observed, although differences and regression were not significant. Parkinson screening tests were abnormal for only 4 participants and were not associated with OCT or VFQ-25 measures by regression modeling. Conclusions: Given the degree and direction of observed differences, further investigation is warranted regarding the relationship between cognitive screening tools and macular OCT measures in age-related eye disease research, but future investigations regarding the relationship between NDD screening tools and VFQ-25 seem unwarranted.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD An Exploratory Study to Investigate the Utility of Clinical Screening for Neurodegenerative Disease in Age-Related Eye Disease Research Victoria S. Pelak, MD, Yosbelkys Martin Paez, MD, Jennifer L. Patnaik, PhD, Samantha K. Holden, MD, MS, Prem S. Subramanian, MD, PhD, Marc T. Mathias, MD, Naresh Mandava, MD, Anne M. Lynch, MB, BCh, BAO, MSPH Background: Unrecognized neurodegenerative diseases (NDD) in age-related eye disease research studies have the potential to confound vision-specific quality of life and retinal optical coherence tomography (OCT) outcome measures. The aim of this exploratory study was to investigate relationships between NDD screening tools and visual outcome measures in a small cohort of controls from the Colorado Age-Related Macular Degeneration Registry (COAMD), to consider the utility of future studies. Methods: Twenty-nine controls from the CO-AMD were screened using the Montreal Cognitive Assessment (MoCA), a Colorado Parkinsonian Checklist, and the Lewy Body Composite Risk Score. Univariate and multivariable linear regression modeling was used to assess associations between screening tools and the National Eye Institute Visual Function Questionnaire-25 (VFQ-25) and macular OCT Departments of Neurology (VSP, YMP, SKH, PSS), Ophthalmology (VSP, YMP, JLP, PSS, MTM, NM, AML), and Neurosurgery (PSS), University of Colorado School of Medicine, Aurora, Colorado; and Department of Surgery (PSS), Division of Ophthalmology, Uniformed Services University of the Health Sciences, Bethesda, Maryland. Fight for Sight-North American Neuro-Ophthalmology Society Research Award, and the AMD Registry supported by the Frederic C. Hamilton Macular Degeneration Center, an unrestricted grant to the Department of Ophthalmology from Research to Prevent Blindness, Inc, and the Colorado Clinical and Translational Sciences Institute (CCSTI-UL1 TR002535) with the Development and Informatics Service Center (DISC) from NIH/NCRR. V. S. Pelak: none; Y. M. Paez: none; J. L. Patnaik: none; S. K. Holden: none; P. S. Subramanian: Consultant-Horizon Therapeutics, GenSight Biologics, Invex Therapeutics, Viridian Therapeutics and Research Support-Horizon Therapeutics, GenSight Biologics, and Santhera Pharmaceuticals; M. T. Mathias: none; N. Mandava: none; and A. M. Lynch: none. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Victoria S. Pelak, MD, 12631 East 17th Avenue, Mail Stop B185, Aurora, CO 80045; E-mail: Victoria.Pelak@ CUAnschutz.edu 346 outcome measures, and t tests were used to evaluate outcome measure differences between those with normal vs abnormal MoCA scores. Results: One patient withdrew. The average age was 72.8 years, and 68% were female patients. Ten participants (36%) had abnormal MoCA scores, and their VFQ-25 scores were only 1 point less and not statistically different than those with normal MoCA scores. Macular OCT volumes and thicknesses for retinal nerve fiber layer (RNFL) and retinal ganglion cell layer were consistently and moderately lower for those with abnormal MoCA scores, and a positive association between MoCA and macular RNFL volume was observed, although differences and regression were not significant. Parkinson screening tests were abnormal for only 4 participants and were not associated with OCT or VFQ-25 measures by regression modeling. Conclusions: Given the degree and direction of observed differences, further investigation is warranted regarding the relationship between cognitive screening tools and macular OCT measures in age-related eye disease research, but future investigations regarding the relationship between NDD screening tools and VFQ-25 seem unwarranted. Journal of Neuro-Ophthalmology 2022;42:346–352 doi: 10.1097/WNO.0000000000001550 © 2022 by North American Neuro-Ophthalmology Society A ge-related neurodegenerative diseases (NDD) that lead to dementia, such as Alzheimer disease, Parkinson disease (PD), and dementia with Lewy bodies, result in retinal degeneration and brain-related visual dysfunction (1–4). These diseases have in common long predementia stages, which include a preclinical stage and a mild cognitive impairment (MCI) stage, and affected individuals can harbor pathological brain changes for at least 2 decades and retinal changes for up to 1 decade or more before dementia onset (5–7). In the late 1980s, Sadun et al found evidence for loss and degeneration of retinal ganglion cell bodies and axons in postmortem histopathological studies of retinas Pelak et al: J Neuro-Ophthalmol 2022; 42: 346-352 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution from persons with neuropathological evidence of Alzheimer disease but not in age-matched controls (2). Over the past 2 decades, retinal optical coherence tomography (OCT) of the macula and the circumpapillary regions reveal that the inner retinal loss and macular retinal volume and thickness loss can be demonstrated during life in the dementia and MCI stages and potentially in preclinical stages (3,6). These findings are consequential to age-related eye disease studies because NDD are common, and people in the early stages are often not recognized or diagnosed until the late stages of dementia (8). For instance, it is estimated that 28%–38% of people older than 65 years are in the predementia or dementia stages of NDD, and only 20%– 50% of cases of dementia are diagnosed and documented by primary care providers, with a much smaller proportion identified in the predementia stages (8,9). NDD manifestations are frequently mistaken for normal aging, although thorough neurologic and cognitive evaluations and retinal OCT can detect clinicopathological changes (2,5,10). Cortical and subcortical visual pathways are also selectively vulnerable to NDD, and higher-order visual brain dysfunction occurs while normal visual acuity is maintained, and functional ability is strongly correlated with visuospatial function and semantic memory more than any other cognitive domain in early Alzheimer disease (11). Vision-specific quality of life measures, such as the National Eye Institute Visual Functional Questionnaire-25 (VFQ-25), assess everyday activities that depend on higher-order visual processing (e.g., reading and driving) and are compromised in people with PD and other parkinsonian syndromes (12). These data suggest that undiagnosed NDD could impact vision-specific quality of life measures used in age-related eye disease research, but this has not been previously investigated. It is unknown whether screening for undiagnosed NDD or cognitive impairment as a potential confounder in agerelated eye disease research is necessary. Thus, the objective of this cross-sectional, single-center exploratory study was to investigate the relationship between NDD screening tools and VFQ-25 and retinal OCT measures in healthy controls without known NDD or cognitive impairment in an agerelated macular degeneration registry and to use these data to determine the utility of larger, follow-up studies. METHODS Participants After approval from the Colorado Multiple Institutional Review Board, healthy controls from the Colorado AgeRelated Macular Degeneration (CO-AMD) Registry at the University of Colorado, described in detail elsewhere (13), were screened, and those meeting inclusion and exclusion criteria were invited to participate. Inclusion criteria included enrollment in the CO-AMD Registry as a control subject (cataract surgery patients without AMD) and age between Pelak et al: J Neuro-Ophthalmol 2022; 42: 346-352 60 and 75 years. Exclusion criteria included dense cataract precluding optical imaging of the retina, decrease in visual acuity because of pre-existing retinal disease, history of panretinal photocoagulation for diabetic retinopathy, history of branch or central retinal vein occlusion, previous ocular inflammatory disease, moderate or severe glaucoma or other known optic neuropathy, active cancer, previous diagnosis of NDD, known history of cognitive impairment or dementia, poor health or gravely ill, or status as a prisoner or on probation. None of the participants had cognitive complaints. Participants were recruited between October 2019 and February 2020. Study data were collected and managed using REDCap (Research Electronic Data Capture) tools. Macular Optical Coherence Tomography Imaging All participants underwent spectral-domain optical coherence tomography (SD-OCT) using the Heidelberg Spectralis, software version 6.6.2 (Heidelberg Engineering GmbH, Heidelberg, Germany). Right and left eye macular SD-OCT scanning with scan fixation on the fovea was performed by trained ophthalmic technicians at the UCHealth Sue AnschutzRodgers Eye Center (Department of Ophthalmology, University of Colorado School of Medicine). Automated segmentation techniques were used for macular retinal ganglion cell layer (RGCL) thickness and volume measures. Manual segmentation of the macular retinal nerve fiber layer (RNFL) was performed by 1 author (Y.M.P.). Postscan quality control included review of all retinal images by a vitreoretinal ophthalmologist and segmentation and signal quality review by an ophthalmologytrained neuro-ophthalmologist and a neurology-trained neuroophthalmologist (P.S.S. and V.S.P.). Quality control reviewers were blinded to NDD screening results. Neurological and Cognitive Screening Participants had 1 study visit with the following procedures performed by a board-certified neurologist and neuroophthalmology fellow (Y.M.P.): neurologic and neuroophthalmic examinations; the VFQ-25 (completed at the visit if the initial VFQ-25 from the CO-AMD Registry was older than 6 months or if cataract extraction occurred after the initial VFQ-25); the Montreal Cognitive Assessment (MoCA) Version 7.0; the Colorado Parkinsonian Checklist (CPC— described below); and the Lewy Body Composite Risk Score (LBCRS) (14). Clinically relevant findings (e.g., abnormal examination or abnormal MoCA scores) were shared with participants, who were given the option for findings to be shared with their primary care provider. The MoCA was chosen because it was designed to capture MCI and is more sensitive and specific than the Mini-Mental Status Examination for MCI and Alzheimer disease (15). It has a positive predictive value of 98% and a negative predictive value of 89% for Alzheimer disease, and scores have empirical validation compared with the gold standard, formal 347 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution neuropsychological testing (16). A score of $26 of 30 is considered normal (15). The LBCRS (see Supplemental Digital Content 1, Table, http://links.lww.com/WNO/A564) has a maximum score of 10 points, and 3 or more points is considered high risk of Lewy body dementia (14). For this study, we created a CPC (see Supplemental Digital Content 2, Table, http://links.lww.com/WNO/A565) (maximum 11 points) to pilot the checklist as a method to standardize the assessment for features of PD and parkinsonism and to enumerate diagnostic criteria from the Movement Disorder Society’s diagnostic criteria for PD (17). LBCRS), and all others had a score of zero on the CPC. LBCRS screening noted rapid eye movement (REM) sleep behavior disorder (n = 1), orthostasis (n = 1), bradykinesia (n = 1), and excessive daytime drowsiness (n = 1). Of note, the participant with bradykinesia scored 1 point for small handwriting on the CPC questionnaire; the other 2 participants scored 1 on the CPC for orthostasis and 1 for REM sleep behavior disorder, overlapping with the LBCRS. The mean total score for the VFQ-25 for all participants was 95.2 ± 4.3 (Table 1). The average macular OCT measurements for right eyes and left eyes are shown in Table 2. Statistical Analysis National Eye Institute Visual Function Questionnaire-25 and Macular Inner Retinal Optical Coherence Tomography Measures Descriptive statistics included basic frequencies for categorical variables, and mean values, SDs, medians, and ranges were used for continuous variables. Univariate and multivariable linear regression modeling was used to assess associations between the explanatory variables that included the neurologic and cognitive screening measures (i.e., MoCA, LBCRS, and CPC) and the following outcome variables: VFQ-25; VFQ-25 subscales (for driving, near activities, and peripheral vision) and VFQ-25 question #7 because it assesses the ease of finding objects on a crowded shelf, which is commonly reported by those with posterior cortical dysfunction, and macular OCT measures were chosen based on previously established relationships between macular OCT and NDD, including macular OCT volume for RNFL and RGCL, and macular OCT thicknesses for RNFL and RGCL using the Early Treatment of Diabetic Retinopathy Study OCT macular grid. Univariate and multivariable linear regression (age- and gender-adjusted) revealed that VFQ-25 total was not associated (P . 0.05) with MoCA, CPC, or LBCRS. The VFQ-25 subscales and question #7 were also not associated with MoCA, CPC, or LBCRS (P . 0.05). Associations between macular inner retinal OCT measures and MoCA using univariate and multivariable analyses were not significant. However, the positive association between MoCA scores and right eye macular OCT RNFL volume, as noted TABLE 1. Demographic factors and questionnaire summary measures, total = 28 participants n (%) Demographics RESULTS Twenty-nine participants were recruited, and 1 patient withdrew because of discomfort with cognitive testing. Twenty-four right eye and 20 left eye macular OCT scans were eligible for analysis, and OCT studies were completed within an average of 17 months before neurologic and cognitive screening. There was agreement by retina and neuro-ophthalmology experts regarding the quality review of OCT measures, which eliminated 4 right eye scans and 8 left eye scans because of lack of complete data for the outer ring or evidence of asymptomatic macular traction, and in 1 eye, evidence of an asymptomatic macular hole. The average age for participants was 72.8 ± 3.9 years with 19 female patients (67.9%) (Table 1). The mean MoCA score was 26.5 (median 28; range 20–30). Criterion for cognitive impairment (MoCA score ,26/30) was met for 10/28 (36%) participants, and none had MoCA scores within the dementia range (i.e., ,20). Examples of incorrect figure copy and clock drawing, completed for the MoCA by participants scoring ,26/30, are shown in Figure l. Four participants had a score of one on the LBCRS, and all others had a score of zero. Similarly, 3 participants had a score of 1 on the CPC (and each with 1 point on the 348 Gender Male Female Age (yrs) Mean (SD) 9 (32.1%) 19 (67.9%) 72.8 (3.9) NDD Screening Tests Montreal Cognitive Assessment Mean (SD) Median (range) Colorado Parkinsonism Sign and Symptom Checklist Mean (SD) Median (range) Score of 1 Lewy Body Composite Risk Score Mean (SD) Median (range) Score of 1 26.5 (3.0) 28.0 (20–30) 0.11 (0.31) 0 (0–1) 3 (10.7%) 0.14 (0.36) 0 (0–1) 4 (14.3%) National Eye Institute Visual Function Questionnaire-25 VFQ-25 composite score Mean (SD) Median (range) 95.2 (4.3) 96.9 (80.8–100) Pelak et al: J Neuro-Ophthalmol 2022; 42: 346-352 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution had abnormal cognitive testing in the range of MCI, despite no known history of MCI or NDD and no cognitive complaints. These findings are consistent with investigations of the general population, revealing 28%–38% of people older than 65 years harbor unrecognized clinical manifestations of NDD (5,8,9). The withdrawal of 1 participant highlights the delicate nature of cognitive screening in healthy subjects. We adjusted our script to participants to emphasize that cognitive testing can be challenging, and this approach will be important for future studies. National Eye Institute Visual Function Questionnaire-25 FIG. 1. Drawings from 4 participants. Clock drawings (from the Montreal Cognitive Assessment or MoCA) by 2 participants with MoCA scores of 24 points (A) and 20 points (B) of a total possible 30 points. Cube copy test drawings (from the MoCA) by 2 other participants with MoCA scores of 24 (C) and 20 (D). in Figure 2, reached near statistical significance (P = 0.06). Associations between macular OCT measures and LBCRS were not significant using univariate analysis or multivariable analysis (P . 0.05), and none of the macular OCT measures revealed significant associations with the CPC by univariate or multivariable analyses (P . 0.05). Abnormal Montreal Cognitive Assessment Versus Normal Montreal Cognitive Assessment Average VFQ-25 scores for those with normal MoCA scores (n = 18) was approximately 1 point higher than for those with abnormal scores (n = 10), but this was not statistically significant (95.5 ± 3.7 vs 94.6 ± 5.5, respectively, P . 0.05). Macular OCT RNFL volumes and inner and outer ring RNFL thicknesses were lower for each eye for those with abnormal MoCA scores compared with those with normal scores (Table 3), although not statistically significant. Except for left eye RGCL volumes and left eye outer ring RGCL thickness, macular RGCL volume and thicknesses for each eye were also lower in those with abnormal MoCA scores (Table 3). CONCLUSIONS In this exploratory study of participants from a healthy control group in the CO-AMD Registry, 36% of participants Pelak et al: J Neuro-Ophthalmol 2022; 42: 346-352 Drawings by 4 participants with abnormal cognitive testing demonstrated that significant visuospatial impairment can be revealed (Fig. 1) in people without previously diagnosed MCI or NDD and with no cognitive complaints. Despite these findings, the VFQ-25, and its subscales for driving, near activities, peripheral vision, and question #7 were not associated with MoCA scores. Those with impairment on the MoCA had scores 1 point less on the VFQ-25 compared with those without cognitive impairment, which was not statistically significant. To detect a two-point difference on VFQ-25 composite scores between any 2 groups, 1,568 participants per group are required (18). Because these exploratory data revealed only a 1-point difference VFQ-25 scores, the VFQ25 is unlikely to be impacted by unrecognized cognitive impairment alone unless study group sizes are very large. Interestingly, VFQ-25 seems not to capture vision-specific changes in quality of life in participants with abnormal screening MoCA scores even when visuospatial dysfunction is present. A lack of insight (i.e., anosognosia) for decreased visual brain functioning could have contributed to these findings, particularly because participants had no cognitive complaints. LBCRS and CPC were also not associated with VFQ-25. Given that previous studies revealed decreased VFQ-25 in those with PD and other parkinsonian conditions (12), the lack of an association for those with parkinsonian findings could be due to the unexpected low prevalence of positive screening for parkinsonian signs and symptoms. In summary, further exploration of the impact of undetected cognitive impairment or NDD on VFQ-25 scores in age-related eye disease research seems to be unwarranted. Macular Optical Coherence Tomography Those with cognitive impairment had macular inner retina OCT volumes and thickness measures 3%–7% below those without impairment, for all but left eye RGCL volume and left eye RGCL outer ring thickness. Although differences were not significant between these small groups, we calculated a sample size for future studies. Assuming a power of 80%, an alpha of 5%, and prevalence of cognitive impairment of 33%, the estimated total sample size to detect a significance difference is 133 patients. If a future larger study supports these exploratory findings, then this range 349 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Spectral-domain optical coherence tomography measures for the right and left eye macula Average Macular Right Average Macular Left Average Macular Right Average Macular Left Eye RNFL Eye RNFL Eye RGCL Eye RGCL N N N N Mean (SD) Mean (SD) Mean (SD) Mean (SD) OCT volume (mm3) OCT central (mm) OCT nasal inner (mm) OCT nasal outer (mm) OCT superior inner (mm) OCT superior outer (mm) OCT temporal inner (mm) OCT temporal outer (mm) OCT inferior outer (mm) OCT inferior inner (mm) 20 1.0 (0.13) 24 14.1 (2.7) 24 22.7 (2.7) 24 53.9 (10.1) 24 26.9 (3.2) 22 39.7 (5.6) 24 18.2 (1.7) 24 21.1 (1.6) 24 26.3 (3.0) 20 40.2 (7.5) 18 1.0 (0.12) 20 13.7 (2.1) 20 22.4 (2.4) 20 52.8 (8.5) 20 26.6 (3.0) 19 39.9 (5.3) 20 18.0 (1.9) 20 21.1 (1.6) 20 25.8 (2.7) 19 38.9 (7.3) 20 1.0 (0.10) 24 16.2 (4.5) 24 49.8 (4.1) 24 34.0 (3.7) 24 50.3 (4.0) 22 35.2 (4.0) 24 46.0 (4.9) 24 33.9 (4.0) 24 50.0 (4.5) 20 33.6 (3.1) 18 1.1 (0.10) 20 16.2 (4.4) 20 50.0 (4.4) 20 34.4 (3.7) 20 48.8 (8.0) 19 35.4 (4.2) 20 46.4 (4.3) 20 33.8 (3.5) 20 49.4 (4.1) 19 34.4 (4.1) OCT, optical coherence tomography; RGC, retinal ganglion cell layer; RNFL, retinal nerve fiber layer. of differences in OCT inner retinal measures is consistent with the data available for studies of MCI cohorts vs controls (19). Once again, when determining whether screening for NDD or cognitive impairment is necessary for age- related eye disease research, sample size and group characteristics (e.g., age and disease associations with NDD) must be considered. Given the growing data revealing retinal thinning in a variety of age-related NDD and dementing FIG. 2. Regression of macular OCT retinal nerve fiber layer volume for right eyes and Montreal Cognitive Assessment (MoCA) scores. 350 Pelak et al: J Neuro-Ophthalmol 2022; 42: 346-352 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Comparison of VFQ-25, OCT RNFL volume, and OCT inner and outer ring thickness measures for those with Montreal Cognitive Assessment (MoCA) scores less than 26 and greater than or equal to 26 Measures VFQ-25 Patient totals Mean (SD) Median Macular OCT volume mm3 Eye and patient totals Mean (SD) Right eye RNFL Left eye RNFL Right eye RGCL Left eye RGCL Macular OCT inner ring thickness mm Eye and patient totals Mean (SD) Right eye RNFL Left eye RNFL Right eye RGCL Left eye RGCL Macular OCT outer ring thickness mm Eye and patient totals Mean (SD) Right eye RNFL Left eye RNFL Right eye RGCL Left eye RGCL MoCA ,26/30 MoCA $26/30 t test P 10 94.6 (5.5) 96.0 18 95.5 (3.7) 96.9 — 0.61 0.85 RE 6/LE 6 RE 14/LE 12 — 0.94 0.94 0.99 1.06 (0.14) (0.13) (0.07) (0.13) RE 8/LE 7 90.0 88.6 189.1 190.9 (8.3) (8.1) (17.9) (18.2) RE 6/LE 6 148.0 150.0 130.7 139.7 (23.7) (23.8) (11.5) (19.5) 1.01 0.99 1.06 1.06 (0.12) (0.12) (0.09) (0.09) RE 16/LE 13 96.2 95.1 199.7 196.7 (8.5) (8.2) (15.3) (16.8) RE 14/LE 12 159.6 155.7 137.3 137.2 (21.4) (20.4) (14.1) (13.0) 0.23 0.49 0.17 1.00 — 0.10 0.11 0.15 0.48 — 0.30 0.61 0.32 0.76 LE, left eye; RE, right eye. illnesses, we believe these results suggest that further investigation is warranted to understand whether MoCA screening will be important to control for undiagnosed cognitive impairment on retinal OCT measures within age-related eye disease cohorts. A major limitation of our exploratory study is the small sample size. However, the prevalence of abnormal cognitive screening in age-related eye disease research cohorts was not previously investigated before this study, and visual outcome measures for those screened for NDD or cognitive impairment were also not previously investigated. For these reasons, the study provides data that allowed for calculation of sample sizes for future studies related to OCT measures and determine that VFQ-25 differences are unlikely to yield important differences in future studies with groups ,1,600. Another limitation is the lack of inclusion of an eye disease study group (i.e., those with AMD), which is particularly important, given the higher rate of dementia associated with AMD (20). Future studies should incorporate the use of a cognitive screening measures for the visually impaired, and inclusion of blood-based biomarkers such as beta-amyloid and tau is worth considering in future studies if sensitivity and reliability improve. In summary, further investigations with a larger cohort using sample sizes from the estimates noted and inclusion Pelak et al: J Neuro-Ophthalmol 2022; 42: 346-352 of those with age-related eye disease will be necessary to confirm the potential associations between cognitive testing and macular OCT measures, but further investigations do not seem warranted for the VFQ-25 outcome measure. Ultimately, future studies could discern whether it is necessary to screen for unrecognized cognitive impairment as a confounder in age-related eye disease research. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: V. S. Pelak; Y. M. Paez, J. L. Patnaik; and A. M. Lynch; b. Acquisition of data: V. S. Pelak; Y. M. Paez, J. L. Patnaik; and A. 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