ABSTRACT
Background
Abnormal color vision and contrast acuity may have significant impact on daily activities.
Objective
Evaluate color visual acuity, at high and low contrast, in Parkinson's disease (PD) and controls using an iPad application.
Methods
Color visual acuity was tested with the Variable Contrast Acuity Chart (King‐Devick Test LLC, Oakbrook Terrace, IL) on an iPad 2 at 40 cms using five colors (red, green, blue, yellow, and black) at low (2.5%) and high (100%) contrast. A numerical score (0–95) was assigned based on the number of correctly identified letters.
Results
Thirty‐six PD (mean ± standard deviation age 68 ± 10 years) and 36 controls (72 ± 11.2 years) were studied. PD disease duration was 6.4 ± 4.6 years; MDS‐UPDRS part II was 11.7 ± 7.0, and part III was 24.5 ± 9.9. After adjusting for age and sex, PD patients had significantly (P < 0.05) lower scores at high (100%) as well as low (2.5%) contrast for all five colors tested (red, green, blue, yellow, and black), except yellow low contrast (2.5%; P = 0.10). The largest effect size (0.88) was with yellow high contrast, and the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy using a cut‐off score of 82 was 31%, 97%, 92%, 58%, and 64%, respectively. No correlation to disease duration was found.
Conclusions
This iPad application may be a simple‐to‐use biomarker for assessing color vision in PD. Further research is needed to determine disease specificity and whether there is a role in monitoring disease progression, treatment response, and identifying prodromal PD.
Keywords: Parkinson's disease, contrast sensitivity, visual acuity, King‐Devick test
Visual dysfunction is a common nonmotor manifestation observed in Parkinson's disease (PD).1 Abnormalities in contrast sensitivity, color vision, visual acuity, eye movements, depth perception, peripheral vision, face and emotion recognition, motion and object perception, and visuospatial construction have been described in PD.1 Normal visual function requires several components, such as color, contrast sensitivity, visual field, visual acuity, etc. High‐contrast visual acuity alone is not a good measure of visual quality.2 The capacity of an individual to function in daily activities, such as walking, driving, employment, etc., gives a better estimate of visual quality, which is dependent on contrast sensitivity.2 Previous studies have shown impaired contrast sensitivity in PD patients.3, 4 This is one of the reasons that some PD patients complain of poor vision despite a normal visual acuity.2
Previous studies of contrast sensitivity used sine‐wave gratings, which lacks reliability, particularly problematic for longitudinal studies.2 The use of a letter chart, such as the Pelli‐Robson contrast sensitivity chart, is more suitable for contrast testing in the clinic, but there can be issues with illumination and reflection from the surface.2 An iPad app was previously used to assess vision contrast acuity.3 That iPad app has now been modified to compare contrast acuity for five different colors (black, blue, yellow, red, and blue) on a white background and was studied in PD and control subjects.
Participants
Subjects
Thirty‐six subjects with PD were recruited from the movement disorders clinic at Mayo Clinic Arizona. Nineteen controls were recruited at Mayo Clinic Arizona, and the remaining 17 controls were tested at the Banner Sun Health Research Institute (BSHRI) as part of the AZSAND (Arizona Study of Aging and Neurodegenerative Disorders).5 All participants signed written informed consent approved by either the Mayo Clinic or Western IRB. The clinical diagnosis of PD was made as previously described.6 Individuals with color blindness, macular degeneration, glaucoma, previous cataract surgery, or dementia were excluded from the study. PD patients were assessed on the same day as vision testing in the practically defined off state (the last dose of PD medications was taken the night before evaluation), and none had had DBS surgery. International Parkinson and Movement Disorder Society (MDS)‐UPDRS (part II and III) was calculated in 30 patients with PD, and UPDRS (part II and III) was calculated in the remaining 6 patients. UPDRS part II and III scores were converted into MDS‐UPDRS part II and III scores based on the formula suggested by Goetz et al.7
Color Vision and Contrast Acuity Testing
Participants viewed the King Devick Variable Color Contrast Sensitivity Chart (VCCSC) on an iPad2 (King‐Devick Test LLC, Oakbrook Terrace, IL) and were allowed to wear corrective lenses. This application can be used only on Apple devices because there is no fluctuation in luminosity and it uses Sloan letters, which is a standard in clinical trials. Visual acuity was tested with both eyes at a comfortable reading distance (approximately 40 cm) for five colors (red, green, black, yellow, and blue) on a white background at two different levels of contrast (2.5% and 100%) (Figure 1). The order of the testing colors was randomized. Direct sunlight was not allowed in the examination room, and the background illumination (white) was set at maximum as previously published.3 The examination was performed with the fluorescent exam room lights on. The iPad application is backlit and does not require any special lighting during testing. The visual acuity score was converted into a numeric score with the maximum score being 95 corresponding to a visual acuity of 20/20. The duration of the test was approximately 10 minutes.
Figure 1.
Variable contrast acuity eye chart at two levels of contrast with two different colors: (A) yellow color at 2.5% contrast, (B) yellow color at 100% contrast, (C) red color at 2.5% contrast, and (D) red color at 100% contrast.
Statistical Analysis
Linear regression adjusted for age at exam and sex was used to compare the visual acuity scores for the five colors at different levels of contrast between the control and PD groups. Cohen's d effect size for each comparison was computed. The false discovery rate (FDR) method was used to control for multiple testing.8 Receiver operating curve analysis was implemented to assess the predictability of yellow 100% contrast score for PD status. The optimum cut‐off point of yellow 100% contrast scores to differentiate PD and control patients was chosen based on Youden's index. Pearson's correlation was calculated between MDS‐UPDRS II and III total score, disease duration, and different color acuity score in the PD group.
Results
A total of 72 subjects, 36 with PD and 36 controls, participated in the study. Demographics are listed in Table 1. There was no difference in age, but there were more females in the control group. Mean disease duration was 6.4 years, H & Y stage 2, MDS‐UPDRS part II 11.7, and MDS‐UPDRS III 24.5. Half (18 of 36) of the PD patients were taking levodopa, 22% were on a dopamine agonist, and 31% were on other medications, such as rasagiline, amantadine, or trihexyphenidyl (Table 1). Wearing off was found in 6% of the PD cases, and 17% had dyskinesias.
Table 1.
Demographics
| Controls (n = 36) | PD (n = 36) | P Value | |
|---|---|---|---|
| Female | 25 (69%) | 14 (39%) | 0.0093 |
| Age (years), mean (SD) | 72.2 (11.2) | 67.8 (10.0) | 0.0843 |
| Disease duration (years), mean (SD) | — | 6.4 (4.6) | — |
| H & Y stage, mean (SD) | — | 2.0 (0.6) | — |
| MDS‐UPDRS part II, mean (SD) | — | 11.7 (7.0) | — |
| MDS‐UPDRS part III, mean (SD) | — | 24.5 (9.9) | — |
| l‐dopa | — | 18 (50%) | — |
| Dopamine agonist | — | 8 (22%) | — |
| Other medications | — | 11 (31%) | — |
SD, standard deviation.
After adjusting for age and sex, PD patients had significantly lower visual acuity scores at high (100%) and low (2.5%) contrast with all colors except yellow color at 2.5% contrast (Table 2). All the results were still significant after controlling for FDR at the 0.05 level except for yellow color at 2.5% contrast. Scores were lower at 2.5% contrast compared to 100% contrast for all colors tested. The biggest effect size, 0.88, was found with the color yellow at 100% contrast. Therefore, yellow color at 100% contrast was chosen to further predict PD and control group. Using the Youden index the optimum cut‐off point of 82 was found to predict PD and controls. That is, patients with a visual acuity score for yellow color at 100% contrast ≤82 are predicted to have PD, and patients with a score > 82 are predicted to be controls. Sensitivity was 30.6%, specificity 97.2%, positive predictive value (PPV) 91.7%, negative predictive value (NPV) 58.3%, and accuracy 63.9% (meaning 63.9% of all PD and controls were correctly identified), for a cut‐off score of 82. Given that the PPV is high (91.7%) and NPV is low (58.3%), if a patient has a visual acuity score of ≤82 for yellow color at 100% contrast, there is very high confidence that this individual has PD. Each color was compared among their testing orders using the analysis of variance method, and no significant difference was found in any of the colors across all their testing orders.
Table 2.
Comparison of the color acuity between PD and Controls adjusting for age and sex
| Variable | PD (n = 36) | Control (n = 36) | Difference (95% CI) | P Value | Effect Size |
|---|---|---|---|---|---|
| Red 2.5% | 60.3 (2.12) | 70.7 (2.12) | –10.4 (–16.6 to –4.2) | 0.0013 | 0.82 |
| Red 100% | 89.6 (0.88) | 93.4 (0.88) | –3.8 (–6.4 to –1.2) | 0.0046 | 0.72 |
| Green 2.5% | 48.8 (2.38) | 60.2 (2.38) | –11.4 (–18.3 to –4.4) | 0.0017 | 0.80 |
| Green 100% | 88.8 (0.81) | 92.7 (0.81) | –3.9 (–6.3 to –1.6) | 0.0015 | 0.81 |
| Blue 2.5% | 54.6 (2.31) | 63.9 (2.31) | –9.2 (–16.0 to –2.5) | 0.0081 | 0.67 |
| Blue 100% | 89.6 (0.82) | 93.5 (0.82) | –3.9 (–6.3 to –1.5) | 0.0019 | 0.79 |
| Yellow 2.5% | 7.3 (1.89) | 12.0 (1.89) | –4.7 (–10.2 to 0.9) | 0.0964 | 0.41 |
| Yellow 100% | 84.3 (1.15) | 90.3 (1.15) | –6.0 (–9.4 to –2.7) | 0.0006 | 0.88 |
| Black 2.5% | 65.8 (1.90) | 73.0 (1.90) | –7.2 (–12.7 to –1.6) | 0.0119 | 0.63 |
| Black 100% | 89.9 (0.93) | 93.4 (0.93) | –3.6 (–6.3 to –0.9) | 0.0108 | 0.64 |
Data are presented as adjusted mean (SE).
CI, confidence interval; SE, standard error.
A negative correlation between MDS‐UPDRS II total score and color acuity was only significant for red at 100% contrast (r = –0.43; P = 0.0090), green at 100% contrast (r = –0.35; P = 0.0342), blue at 100% contrast (r = –0.39; P = 0.0199), yellow at 100% contrast (r = –0.41; P = 0.0125), and black at 2.5% contrast (r = –0.38; P = 0.0225; Table 3). MDS‐UPDRS III total score only negatively correlated with yellow 2.5% color acuity score (r = –0.38; P = 0.0232). There was no significant correlation between disease duration and visual acuity scores for any color (Table 3).
Table 3.
For the 36 subjects with PD the Pearson correlation coefficients for each color and degree of contrast were calculated for MDS‐UPDRS part II, MDS‐UPDRS part III, and PD duration
| Variable | MDS‐UPDRS II | MDS‐UPDRS III | Disease Duration |
|---|---|---|---|
| Red 2.5% | –0.29 (0.0855) | –0.14 (0.4259) | –0.20 (0.2459) |
| Red 100% | –0.43 (0.0090) | –0.12 (0.4938) | –0.22 (0.1973) |
| Green 2.5% | –0.25 (0.1434) | –0.05 (0.7658) | –0.19 (0.2763) |
| Green 100% | –0.35 (0.0342) | 0.06 (0.7442) | –0.11 (0.5334) |
| Blue 2.5% | –0.31 (0.0635) | –0.06 (0.7105) | –0.28 (0.1017) |
| Blue 100% | –0.39 (0.0199) | –0.17 (0.3148) | –0.17 (0.3288) |
| Yellow 2.5% | –0.32 (0.0566) | –0.38 (0.0232) | –0.16 (0.3460) |
| Yellow 100% | –0.41 (0.0125) | 0.02 (0.8908) | –0.17 (0.3130) |
| Black 2.5% | –0.38 (0.0225) | 0.01 (0.9388) | –0.24 (0.1627) |
| Black 100% | –0.16 (0.3450) | 0.09 (0.5888) | –0.03 (0.8823) |
Data presented at r value (P value).
Discussion
This study establishes the usefulness of an iPad visual contrast acuity application using different colors to distinguish between PD and control subjects. Previous studies have used grating charts where correct guessing is possible.9, 10 The Pelli‐Robson chart uses letters and demonstrates a possible learning effect and the test‐retest reliability is low, limiting its usefulness.11, 12 Another test, which uses sine‐wave gratings for contrast sensitivity testing, is Functional Acuity Contrast Test (FACT), but there is a high probability of correct guessing and it has a poor test‐retest reliability.13 A commonly used test for color vision is Farnsworth‐Munsell 100‐Hue, but it requires manual dexterity, is time‐consuming, and depends on the illumination.14 Another disadvantage of the Farnsworth‐Munsell 100‐Hue test is variability in the results with repeated testing.14 An advantage of the King‐Devick visual acuity test is that the letters are arranged randomly and change with every color and at every level of contrast, making learning impossible. Additionally, whereas two contrast levels were tested in this study, 2.5% and 100%, other degrees of contrast can be programmed. The reliability studies were not published, but were completed internally during the development of this application. One limitation is that a decrease in contrast acuity is not specific to PD and can be observed with age, macular degeneration, optic neuritis, etc.2 The decision to study multiple different colors was to determine whether any specific color and contrast level would be more sensitive and specific for PD. All five colors had a reduction in scores at 100% contrast, and all but yellow at 2.5% contrast also differed between groups. Given that there was a significant difference between the visual acuity scores at 100% contrast in both groups, it is possible that this reflects impaired color perception besides contrast sensitivity. Abnormalities in color vision are well known in PD.1 One possible explanation for no significant difference observed for yellow at low contrast could simply be the marked difficulty of seeing a lighter color (yellow) against a white background,15 as evidenced by the extremely low score in the control group (Table 2). In an earlier published study, greatest deficits were found in the tritan axis (blue‐yellow), which may occur because of the involvement of the blue cone system in PD.16 Nevertheless, there are many implications for reduced contrast acuity with different colors, including an overall reduction in PD patient visual quality.1 Contrast sensitivity is required for simple tasks, such as walking or reading, as well as for complex tasks such as driving or recognition of facial emotions.17, 18 It is easier to form memories with color rather than shape or appearance, which is important in day‐to‐day activities.19 Our study showed impairment of visual acuity for high as well as low contrast at a comfortable reading distance, which may require low vision rehabilitation in this population.20
High‐contrast visual acuity has been shown to be impaired in PD patients, but can be normal in the early stages of PD.1, 21, 22 Yet, the present study did not find a significant correlation between disease duration and visual acuity, but the sample size was small. Although some previous studies have shown a greater impairment of contrast sensitivity with increased severity of the disease21, 23 like the current data, some studies have not shown this relationship.9, 23 There was variable negative correlation between certain colors and contrast levels and the MDS‐UPDRS part II score. Again, small sample size may play a role. Similarly, no clear correlations were found with the MDS‐UPDRS part III. A further limitation of this study was the lack of untreated PD cases.
Differentiating PD from controls was then calculated using yellow at 100% contrast given that that had the highest standardized difference. A cut‐off score of 82 was found to show very high specificity, good accuracy, and PPV, but at the cost of low sensitivity. One could consider using this method to differentiate PD from controls. The low level of sensitivity noted in this study is because of the cut‐off score used for analysis. A lower cut‐off score (<82) will improve sensitivity, but decrease specificity. A higher level of specificity helps in ruling out the disease and makes it easier to identify subjects without the disease. One study showed contrast sensitivity and color discrimination as a useful method to distinguish PD from essential tremor,25 although another study showed impairment in drug‐induced parkinsonism.26
Some limitations to the present study have already been discussed. Additionally, this study did not control for the effect of l‐dopa or other dopaminergic treatments.27, 28 The study population was small and included few patients with advanced PD, which may underestimate the degree of impairment in contrast acuity when compared to controls. Although we did not include patients with a diagnosis of dementia, formal neuropsychological testing was not performed to exclude or identify subjects with mild cognitive impairment. Cognitive impairment is associated with impairment of contrast sensitivity as well as color discrimination.29 The study also did not control for drugs that have the potential to cause reduced accommodation leading to blurred vision.30
In summary, the King‐Devick color contrast acuity test is a quick test which can be done in the clinic to look for a reduction in contrast acuity using many colors. The assessment of low contrast acuity should be considered for patients with PD given that it may be important to normal activities of daily living, such as working on a computer, driving, walking, etc. Whether color contrast acuity can be used as a biomarker for prodromal PD, differentiating PD from other disorders, monitoring of disease progression, or assessing response to treatment requires further study.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
C.H.A.: 1A, 1B, 1C, 2C, 3A, 3B
H.V.G.: 1B, 1C, 2C, 3A, 3B
E.D.‐D.: 1C, 3B
S.H.M.: 1C, 3B
T.G.B.: 1B, 3B
N.Z.: 2A, 2B, 3B
Disclosures
Ethical Compliance Statement
We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Both the Mayo Clinic Institutional Review Board and the Western Institutional Review Board approved this study. All subjects signed written informed consent.
Funding Sources and Conflicts of Interest
Supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05‐901, and 1001 to the Arizona Parkinson's Disease Consortium), the Michael J. Fox Foundation for Parkinson's Research, and Mayo Clinic Foundation. The authors report no conflicts of interest.
Financial Disclosures for previous 12 months
T.G. Beach is a consultant for Genentech, Roche Diagnostics, and Prothena Corporation; is a member of an advisory board for Vivid Genomics; and does contracted research for Avid Radiopharmaceuticals, Navidea Biopharmaceuticals, and Aprinoia Therapeutics. C.H. Adler is a consultant for Acadia, Acorda, Adamas, Cynapsus, Jazz, Lundbeck, Merz, Minerva, Neurocrine, and Sunovion. S. Mehta is a consultant for Abbott, Abbvie, Adamas, and Kyowa Kirin.
Acknowledgment
The authors thank Steve Devick and Richard Cronin from the King‐Devick Test LLC for supplying the app used in this study and for helpful comments.
Relevant disclosures and conflicts of interest are listed at the end of this article.
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