The effect of age-related macular degeneration on cognitive test performance

The reliable assessment of cognitive functioning is critical to the study of brain-behaviour relationships. Yet conditions that are synchronous which ageing, including visual decline, are easily overlooked when interpreting cognitive test scores. The purpose of this study was to demonstrate the negative consequences of visual impairments on cognitive tests performance. Moderate to severe levels of age-related macular degeneration were simulated, with a set of goggles, in a sample of twenty-four normally sighted participants while they completed two cognitive tasks: a vision-dependent reaction time task and a vision-independent verbal fluency test. Performance on the reaction time task significantly decreased (p < 0.001) in the simulated age-related macular degeneration condition, by as much as 25 percentile ranks. In contrast, performance on the verbal fluency test were not statistically different between the simulated and normal vision conditions (p = 0.78). The findings highlight the importance of considering visual functioning when assessing cognitive function. When vision is not accounted for, low test scores may inaccurately indicate poor cognition. Such false attributions may have significant ramification for diagnosis and research on cognitive functioning.


Methods
Participants. An a priori power calculation was conducted to estimate the required number of participants for a larger study investigating the effects of simulated AMD on anxiety and stress levels in everyday activities (not reported here). Using G*Power 12 , it was estimated that a minimum of 13 participants were required to provide sufficient power (0.90), at a significance level of α = 0.05, to detect a large effect. A large effect could increase the practical significance of the findings. The estimate was based upon an AMD simulation study which was similar in nature to the larger study conducted 13 . All eligible participants that signed up during the advertisement period (between July and September 2020) were tested. Data were only analysed after data collection was completed.
Twenty-four normal-to-corrected sighted (best corrected visual acuity of greater > 6/18) participants (19 women) aged 18-60 (Mean = 27.1, SD = 9.7) completed the experiment. They were English speakers, and had no history of visual impairment, anxiety disorders, psychiatric disorders, or cognitive impairment. Participants were recruited at the University of South Australia (UniSA) and via the UniSA online research participation system, and informed consent was obtained from all. The study was approved by the UniSA Human Research Ethics Committee (Ethics Protocol 202889); and it was conducted in accordance with the Declaration of Helsinki, and the Australian National Statement on Ethical Conduct in Human Research guidelines.
Apparatus and materials. The visual effect of AMD was induced with enhanced Fork in the Road Macular Degeneration simulator goggles 14 . The severity was manipulated to reflect moderate to severe AMD-visual acuity 6/18 to 3/60 respectively 15 . The goggles were enhanced by the addition of two layers of 20 mm diameter circular Bangerter occlusion foils of 0.1 LogUnit (resulting in 20/200 or 6/60 vision), positioned in the central inner region of each lens. These enhancements were calibrated by a neuro-ophthalmologist to ensure the simulator resulted in a reduction in best corrected visual acuity to 6/60 and created a 10° central scotoma monocularly in each eye. The visual acuity was verified using Snellen linear acuity at 6 m and the scotoma was confirmed with a Zeiss Humphry 24-2 automated visual field analyser (see Fig. 1; Carl Zeiss Meditec, Inc. Jena, Germany). To ensure the results were not confounded by the goggle frames (e.g., restricted peripheral vision), identical goggles with clear lenses were worn in the normal vision condition. If required, participants wore prescription glasses under the goggles.
Cognition was assessed via a vision-dependent Reaction Time Task (RTI) 16 and a vision-independent Verbal Fluency Test (VFT) 17 . The tests were chosen as they are suitable for assessing cognition in aging, clinical populations (e.g., Alzheimer's) [18][19][20][21] . The RTI [choice], from the Cambridge Neuropsychological Test Automated Battery (CANTAB) 16 , assesses mental and motor response speeds. Participants pressed a button on the screen, after which a yellow dot appeared in one of five circle locations. Participants were instructed to move their finger from the button to the yellow dot, as quickly and accurately as possible. Mental responses reflected the times taken for participants to identify the yellow dot location and release the button. Motor responses were the times taken for participants to move from the button to the yellow dot.
The VFT appraises semantic and phonemic fluency 17 . Participants had sixty seconds to generate as many different words (excluding names, places, and repeated words with different endings), starting with the letter F or S. The VFT was conducted as a control task, because unlike the RTI, it does not require vision for completion. Statistical analysis. We conducted separate 2 (visual condition: normal or simulated AMD) × 2 (order: normal or simulated AMD vision first) repeated measures ANOVA using jamovi 22 for the mental and motor responses in the RTI, and the VFT. The TOSTER module 23,24 in jamovi with equivalence bounds of ± 0.5 Cohen's d z and an alpha of 0.05 was used to test for equivalence between the two vision conditions in the case of non-significant results in the above analyses.
To further quantify the impact of AMD on cognitive performance, the cNORMJ module 25 in jamovi estimated T-scores based on the results of the normal vision condition. Using an inverted ranking order, a quartic polynomial regression modelled the relationship between raw and norm scores. A norm table for normal vision was compiled based on the model, and changes in percentile ranks for the simulated AMD condition was calculated.

Results
For the RTI, mental response times significantly increased in the simulated AMD condition (381.98, SD = 29.90 ms) compared to the normal vision condition (359.02, SD = 28.04 ms; see

Discussion
Our findings provide a compelling demonstration of how visual impairments may significantly impact performance on cognitive tasks that rely on vision. The RTI was compromised due to the AMD simulation, yet the VFT remained unaffected. To put the findings into the context of standardized scores, the mean mental response time for the simulated AMD condition in the RTI was approximately 25 percentile ranks lower than in the normal vision condition. Being scored in the 25th percentile instead of the 50th percentile, as in our study, is a significant reminder to researchers that the added interference due to vision loss deserves attention and should not be easily discounted 26 .
Even though cognitive tests are just one aspect of the diagnostic process, the inaccurate scoring of cognitive performance could still contribute towards the misdiagnosis of cognitive related problems, including mild cognitive impairment (MCI) or dementia. In this event, subsequent issues can arise. For example, a mistaken diagnosis of dementia may precipitate unnecessary changes to a person's living, working, financial or social circumstances 27 . Furthermore, the diagnosis of MCI can trigger psychological problems (e.g., depression and anxiety) due to the stigma of cognitive impairment 28 . For people with AMD, who are already experiencing www.nature.com/scientificreports/ physical and psychological issues due to vision loss 6,29 , the multitude of repercussions that inaccurate cognitive assessments causes are an unneeded additional burden. It only takes the incorporation of simple precautionary measures in order to make allowances for the potential impact of AMD. For example, screening participants with mobile vision charts (e.g., Snellen) 30 prior to participation, or administering vision-friendly variations of standard cognitive assessments (e.g., blind MOCA) 31 . While our findings specifically relate to AMD, the differences between normal and simulated conditions corroborate previous studies using paper-and-pencil tests under low visual acuity or cataract simulations 10,11,32 . The findings also align with studies assessing cognition in older clinical populations, indicating that this problem is systematic across a range of visual impairments 33,34 .
It is currently unclear whether these simulations lead to an over-or underestimation of the true impact of visual impairments on test performance, but there are reports that the severity of AMD health effects are underestimated with lenses that simulate AMD 35 . While the true impact of AMD on cognitive test scores remains to be established, it is clear that not controlling for vision can adversely affect the results and can have broader implications for the health of visually impaired people.

Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.