Clinical and Imaging Characteristics Associated with Color Vision Impairment in Lewy Body Disease

Abstract

Background:

Color vision impairment (CVI) has been reported in dementia with Lewy bodies (DLB) and prodromal Lewy body disease (pro-LBD).

Objective:

In order to better characterize the diagnostic value of CVI testing, we compared the prevalence of CVI in patients with with Lewy body disease compared to Alzheimer’s disease (AD), and we examined clinical and imaging characteristics associated with CVI in patients with DLB and suspected pro-LBD.

Methods:

We retrospectively reviewed medical records, dopamine transporter (DaT-SPECT) imaging, and volumetric MRI from patients with AD, DLB, and suspected pro-LBD who underwent an online Farnsworth D-15 color vision test.

Results:

111 patients (62 DLB, 25 pro-LBD, and 24 AD) were included with a median age of 75 years. Newly diagnosed CVI was present in 67% of patients with DLB, 44% of patients with pro-LBD, and 18% of patients with AD. In patients with DLB, CVI was associated with lower Montreal Cognitive Assessment (MoCA) scores and lower sub-scores in visuospatial/executive function, naming, and language. In a multivariable logistic regression model, a diagnosis of DLB or pro-LBD compared to AD, and a lower composite MoCA score in visuospatial/executive function, naming, and language were associated with CVI controlling for age and gender. Among 17 DLB patients who underwent volumetric MRI, patients with CVI (n = 9) demonstrated lower normative volumetric percentiles in the right transverse superior temporal lobe.

Conclusion:

We provide further evidence that CVI can help differentiate DLB from AD, and we suggest that CVI may be an indicator of cognitive decline and disease progression in DLB.

Keywords

Alzheimer’s disease biomarkers color vision Lewy body disease presenile dementia

INTRODUCTION

Patients with dementia with Lewy bodies (DLB) are often deprived of early and adequate treatment due to misdiagnosis as Alzheimer’s disease (AD) [1]. Current diagnostic criteria for DLB focus on the recognition of core features (including fluctuating cognition, visual hallucinations, parkinsonism, and REM sleep behavior disorder [RBD]), as well as a number of supportive features [2]. Despite these prominent and distressing symptoms, some studies report a sensitivity of DLB diagnosis of less than 50% at high-volume academic centers with strong clinical expertise [1]. Identifying features to help differentiate DLB from AD is therefore crucial for improving early and accurate diagnosis of DLB.

Color vision impairment (CVI) is one suggested feature that may help differentiate DLB from AD. Recent studies have indicated that CVI is frequently seen in early-stage synuclein-mediated neurodegenerative disease [3, 4] and may correlate with the severity of clinical symptoms and disease progression in Parkinson’s disease (PD) [5 –7]. We recently reported that CVI may be a biomarker of DLB [8], demonstrating a prevalence similar to core features [2]. Our group and others have similarly indicated that CVI may be prevalent in prodromal Lewy body disease (pro-LBD) [3, 8], and recent prospective evidence suggests that CVI may predict conversion to dementia rather than Parkinsonism in idiopathic RBD [4]. Although diagnostic criteria for pro-LBD continue to evolve, RBD remains the strongest predictor of conversion to DLB [9 –11]. Fluctuating cognition is the least common core symptom in the prodromal phase [9], and other prodromal features such as autonomic dysfunction and hyposmia can be difficult to assess and are less specific [12, 13]. Given growing interest in CVI as a potentially useful biomarker of Lewy body disease, there remains a need to understand its mechanisms and clinical correlates.

In the current study, we sought to compare color vision deficits in patients with DLB, suspected pro-LBD, and AD to gain further insight into the value of CVI testing. Further, in order to assess the clinical correlates and potential mechanisms of CVI in DLB, we sought to uncover clinical and imaging features associated with CVI in patients with Lewy body disease.

METHODS

Patient cohort

After obtaining institutional review board approval, we retrospectively reviewed the medical records of patients who presented to our clinic from 2016 to 2018 with the diagnoses of probable DLB and AD and those with mild cognitive impairment (MCI) suspected to be in the prodromal phase of LBD (pro-LBD). The diagnoses of probable DLB and AD were made according to the clinical criteria of the consortium on DLB [2, 14] and the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for AD [15]. Based on evolving clinical criteria, pro-LBD was defined as a patient with MCI who had RBD and/or parkinsonism without a prior diagnosis of PD or other Parkinson’s plus clinical syndromes and did not meet the diagnostic criteria for PD [9 –12]. Hallucinations were not considered when defining a diagnosis of pro-LBD, as the extent of hallucinations could not be adequately assessed in these patients in a retrospective fashion. About 50% of patients with DLB or pro-LBD had dopamine transporter single-photon emission computed tomography (DaT-SPECT) as part of their diagnostic work-up [16]. Only patients who underwent an online version of the Farnsworth D-15 color vision test at our clinic were included in this study. While a color vision test is not typical in assessing patients in most memory clinics, CVI testing was performed in this memory disorders clinic when time was available in order to improve clinical evaluation and to assess patients’ driving capabilities. An online D-15 color vision test was used because it was simple for patients to understand, could be performed quickly, and provided a binary (CVI versus no CVI) output. Patients in our initial analysis [8] were also included in the current study because a more comprehensive set of clinical and imaging measures were reported in the current study.

Recorded variables

Clinical variables

The following clinical variables were collected for each patient: age at diagnosis, sex, Montreal Cognitive Assessment (MoCA) examination total scores and sub-scores at diagnosis, and binary yes/no indicators for the presence of tremor (action, postural, and resting), rigidity, bradykinesia, postural instability, visual hallucinations, and autonomic disturbances (e.g., orthostatic hypotension). We also recorded a diagnosis of probable REM sleep behavior disorder (pRBD) based on informant response to a validated single screening question: “Have you ever been told, or suspected yourself, that you seem to ‘act out your dreams’ while asleep [for example, punching, flailing your arms in the air, making running movements, etc.]?” [17]. Patients with a remote history of CVI based on patient and caregiver history were excluded from the analysis. The online Farnsworth D-15 color vision test was administered under supervision of a physician (BT). Patients were asked to arrange 15 tiles into an appropriately ordered color spectrum. The test began with one colored tile in the spectrum line with the remaining tiles in the pool of available tiles. Patients were instructed to choose the tile with the color closest to the tile that was already in the spectrum line (in the case of the first selection) or the color closest to the most recently selected tile (in the case of subsequent selections). Color vision impairment was collected as a binary variable according to Farnsworth D-15 results. We also collected confusion index (C-index), which quantifies the degree of color vision loss [18], and the subtype of color vision impairment (protan [red-green, long-wavelength cone defect], deuteran [red-green, medium-wavelength cone defect], and tritan [blue-yellow] defect) [19].

Imaging features

When available, DaT-SPECT and volumetric brain MRI results were collected. DaT-SPECT images were graded by subspecialty-trained nuclear medicine physicians according to established criteria [20]. A normal DaT-SPECT result indicates symmetric tracer uptake bilaterally in the putamen and caudate nuclei. Abnormal grade 1 indicates asymmetric uptake with normal or almost normal putamen activity in one hemisphere and with a more marked reduction in the contralateral putamen. Abnormal grade 2 indicates significant bilateral reduction in putamen uptake with activity confined to the caudate nuclei. Abnormal image grade 3 indicates virtually absent uptake bilaterally affecting both putamen and caudate nuclei. Among patients who underwent volumetric brain MRI, age- and sex-matched normative volumetric percentiles were computed automatically with NeuroQuant (versions 2.0 and 2.3.0) [21, 22]. Left and right volumetric percentiles were recorded separately for 15 distinct cortical regions.

Statistics

All statistics were calculated using Jamovi software (version 1.0). Summary statistics were reported as median values with ranges or interquartile ranges. The Chi-square or Fisher’s exact tests were used for categorical variable comparison, and the Student’s T or Mann-Whitney U tests were used for continuous variable comparison. Based on bivariate analyses, we constructed a multivariable logistic regression model to determine plausible clinical predictors of CVI controlling for age and gender. p-values less than 0.05 were considered statistically significant in this study.

RESULTS

Patient cohort

In total, there were 111 patients included in this study, 47 of whom were also in our initial study [8]. Patients had a median age of 75 years, and 50% were female. Patients were divided into three study groups based on diagnosis: DLB (n = 62); pro-LBD (n = 25); and AD (n = 24) (Table 1). There were no significant differences in age or sex between study groups. Total MoCA scores were significantly lower in patients with DLB compared to patients with pro-LBD (median 16.0 versus 23.0, p < 0.001). There were no significant differences in total MoCA scores between patients with AD versus patients with DLB; however, MoCA sub-scores in orientation were significantly lower in patients with AD compared to patients with DLB (median 3.5 versus 5.0, p = 0.029).

Table 1

Clinical characteristics of patients with mild cognitive impairment and dementia

	All patients (n = 111)	DLB (n = 62)	Pro-LBD (n = 25)	AD (n = 24)	p^a	p^b
Age, median (range)	75 (57–95)	75 (57–88)	75 (67–86)	76 (65–95)	0.966	0.237
Gender, % female	50% (n = 55)	52% (n = 32)	36% (n = 9)	58% (n = 14)	0.187	0.575
MoCA score, median (range)	18 (4–29)	16 (9–27)	23 (18–29)	17 (4–22)	<0.001	0.927
MoCA subscores, median (range)
Visuospatial/executive	2 (0–5)	2 (0–5)	4 (2–5)	2 (0–4)	<0.001	0.116
Naming	3 (0–3)	3 (0–3)	3 (2–3)	2 (1–3)	0.063	0.145
Attention	4 (0–6)	3 (1–6)	6 (3–6)	4.5 (0–6)	<0.001	0.154
Language	2 (0–3)	2 (0–3)	2 (0–3)	2 (0–3)	0.233	0.383
Abstraction	1 (0–2)	1 (0–2)	1 (0–2)	1 (0–2)	0.591	0.888
Delayed recall	0 (0–5)	0 (0–5)	1 (0–5)	0 (0–5)	0.004	0.042
Orientation	5 (0–6)	5 (0–6)	6 (4–6)	3.5 (0–6)	0.004	0.029
History of CVI or blindness	4% (n = 4)	3% (n = 2)	0%	8% (n = 2)
Newly detected CVI	51% (n = 55)	67% (n = 40)	44% (n = 11)	18% (n = 4)	0.052	<0.001
C-index (severity of CVI), median (IQR)	1.62 (1.21–1.97)	1.81 (1.31–2.09)	1.48 (1.21–1.90)	1.29 (1.12–1.45)	0.103	<0.001
Type of CVI	36 Protan	27 Protan	6 Protan	3 Protan
	10 Deuteran	7 Deuteran	3 Deuteran	1 Tritan
	9 Tritan	6 Tritan	2 Tritan

AD, Alzheimer dementia; DLB, dementia with Lewy bodies; pro-LBD, prodromal phase of LBD; IQR, interquartile range; MoCA, Montreal Cognitive Assessment. ^aDLB versus pro-LBD; ^bDLB versus AD.

Color vision testing

Four patients (2 DLB, 2 AD, all male) were identified as having a remote history of CVI from a young age and were excluded from the final analysis. Among 107 remaining patients, we sought to determine the association between diagnosis and CVI. Patients with DLB were significantly more likely to demonstrate CVI compared to patients with AD (67% versus 18%, p < 0.001). CVI was present in 44% of patients with pro-LBD compared to 67% of patients with DLB (p = 0.052). CVI was not associated with sex within individual study groups or in the combined cohort. C-index (a measure of CVI severity) was significantly higher in patients with DLB versus AD (median 1.81 versus 1.29, p < 0.001). C-index was not significantly different in patients with DLB versus pro-LBD (median 1.81 versus 1.48, p = 0.103).

In order to better characterize the diagnostic value of CVI testing, we examined clinical characteristics associated with CVI in patients with DLB and pro-LBD (Table 2). There were no associations between CVI status and the presence of visual hallucinations, Parkinsonian features, pRBD, or autonomic disturbances in either the DLB or pro-LBD study groups. Among patients with DLB, those with CVI had lower total MoCA scores (median 15.0 versus 18.5, p = 0.042) and lower MoCA sub-scores in visuospatial and executive function (median 1.5 versus 2.0, p = 0.046), naming (median 2.0 versus 3.0, p = 0.014), and language (median 1.0 versus 2.0, p = 0.003). Among patients with pro-LBD, total MoCA scores were not significantly different between those with CVI versus without CVI; however, patients with CVI had significantly lower MoCA sub-scores in language (median 1.0 versus 2.5, p = 0.046).

Table 2

Clinical features among patients with DLB and pro-LBD according to CVI status

	DLB (n = 60)		p^a	pro-LBD (n = 25)		p^b
	CVI (n = 40)	No CVI (n = 20)		CVI (n = 11)	No CVI (n = 14)
Demographics
Age, median (range)	75 (57–88)	76 (66–83)	0.875	73 (67–86)	75 (67–85)	0.603
Sex, % female	50% (n = 20)	60% (n = 12)	0.464	18% (n = 2)	50% (n = 7)	0.208
Clinical features
Visual hallucinations	88% (n = 35)	95% (n = 19)	0.653	46% (n = 5)	64% (n = 9)	0.435
Parkinsonian features	80% (n = 16)	78% (n = 31)	1.000	64% (n = 7)	64% (n = 9)	1.000
Probable REM sleep disorder	58% (n = 23)	75% (n = 15)	0.185	64% (n = 7)	71% (n = 10)	1.000
Autonomic disturbances	30% (n = 12)	25% (n = 5)	0.685	9% (n = 1)	14% (n = 2)	1.000
Montreal Cognitive Assessment
MoCA score, median (range)	15 (9–26)	18.5 (9–27)	0.042	22 (19–28)	23 (18–29)	0.978
MoCA subscores, median (range)
Visuospatial/executive	1.5 (0–4)	2 (1–5)	0.046	4 (3–5)	4 (2–5)	0.604
Naming	2 (0–3)	3 (2-3)	0.014	3 (3-3)*	3 (2-3)	NA
Attention	3 (1–6)	4 (1–6)	0.238	5 (3–6)	6 (3–6)	0.721
Language	1 (0–3)	2 (0–3)	0.003	1 (0–2)	2.5 (0–3)	0.046
Abstraction	1 (0–2)	1 (0–2)	0.434	0 (0–2)	1 (0–2)	0.363
Delayed recall	0 (0–4)	0 (0–5)	0.657	1 (0–5)	1.5 (0–5)	0.716
Orientation	5 (0–6)	5 (1–6)	0.689	6 (4–6)	6 (4–6)	0.438

DLB, dementia with Lewy bodies; pro-LBD, prodromal phase of LBD; MoCA, Montreal Cognitive Assessment. ^aCVI versus no CVI, DLB; ^bCVI versus no CVI, pro-LBD. *Violation of the assumptions of the Mann Whitney U test.

Based on significant findings in bivariate analyses, we constructed a multivariable logistic regression model to determine whether a composite MoCA score (comprised of visuospatial/executive function, naming, and language sub-scores) and diagnosis (DLB, pro-LBD, or AD) were significant predictors of CVI status controlling for age and gender. The overall model was statistically significant (χ²(5) = 26.6, p < 0.001) (Table 3). There was no evidence of collinearity as the variance inflation factors for all variable included in the model ranged from 1.01 to 1.22. Compared to a diagnosis of AD, a diagnosis of DLB was associated with a 14-fold increase in the odds of CVI (p < 0.001), and a diagnosis of pro-LBD was associated with a 10-fold increase in the odds of CVI (p = 0.010). Increases in the composite MoCA score were significantly associated with decreased odds of CVI (Odds ratio = 0.72, p = 0.014), indicating that there was a 28% decrease in the odds of CVI per 1 point increase in the composite MoCA score.

Table 3

Multivariable logistic regression model including plausible predictors of CVI

Predictor	Estimate (β)	p	Odds ratio
Age (y)	–0.0005	0.976	0.92
Sex (Male versus female)	0.4482	0.329	1.57
MoCA (Visuospatial-exec, naming, language)	–0.3250	0.014*	0.72
Diagnosis
DLB versus AD	2.6107	<0.001*	13.6
pro-LBD versus AD	2.3504	0.010*	10.5

Note: Estimates represent the log odds of CVI versus no CVI. *Significant at p < 0.05.

Imaging

DaT-SPECT

DaT-SPECT imaging was available for 56% of patients with DLB and 52% of patients with pro-LBD. Striatal dopamine uptake was abnormal in 83% of patients with DLB and 62% of patients with pro-LBD (p = 0.140). CVI was not associated with abnormal DaT-SPECT findings in the combined cohort or in separate DLB or pro-LBD study groups. Overall, 81% of patients with CVI and 70% of patients without CVI demonstrated abnormal striatal dopamine uptake (p = 0.494).

Volumetric MRI

Seventeen patients with DLB had volumetric MRI scans available, 9 of whom had CVI. In Table 4 we compare normative volumetric brain MRI percentiles in patients with DLB between those with CVI versus those without CVI. Compared to patients without CVI, patients with DLB and CVI demonstrated significantly lower volumetric percentiles in the right transverse/superior temporal gyri (median percentile: 6 versus 39, p = 0.021). Brain volumes were not compared within the pro-LBD group due to the small sample size.

Table 4

Comparison of normative volumetric brain MRI percentiles in patients with DLB and CVI (n = 9) versus those without CVI (n = 8)

	Normative percentile, median (IQR)
	Left hemisphere			Right hemisphere
	CVI	No CVI	p^a	CVI	No CVI	p^b
Frontal lobe
Superior frontal	21 (6–49)	52 (23–62)	0.290	19 (7–28)	41 (32–61)	0.083
Lateral orbitofrontal	5 (2–9)	10 (5–23)	0.264	6 (4–12)	14 (6–30)	0.289
Parietal lobe
Superior parietal	37 (23–49)	51 (37–61)	0.481	41 (14–49)	47 (25–67)	0.563
Medial parietal	41 (35–57)	60 (38–87)	0.277	49 (38–62)	65 (38–89)	0.423
Supramarginal	38 (12–50)	60 (37–84)	0.236	45 (27–49)	71 (57–80)	0.102
Inferior parietal	31 (4–47)	54 (36–71)	0.092	36 (13–64)	67 (41–80)	0.067
Temporal lobe
Transverse/superior temporal	25 (11–51)	36 (24–64)	0.630	6 (5–32)	39 (31–60)	0.021
Posterior superior temporal	39 (25–45)	30 (15–45)	0.541	25 (15–49)	57 (36–67)	0.200
Middle temporal	23 (8–39)	39 (13–64)	0.885	15 (3–28)	23 (15–36)	0.334
Inferior temporal	13 (3–19)	17 (6–30)	0.885	12 (7–39)	11 (8–29)	0.736
Fusiform gyrus	51 (16–71)	28 (18–32)	0.178	25 (8–63)	35 (18–43)	0.963
Temporal pole	42 (9–76)	23 (12–47)	0.606	54 (34–56)	27 (11–46)	0.630
Hippocampus	31 (12–44)	32 (20–67)	0.974	32 (17–47)	46 (6–64)	0.872
Occipital lobe
Medial occipital	46 (27–65)	58 (6–70)	1.000	37 (27–56)	46 (16–77)	0.962
Lateral occipital	30 (8–61)	54 (28–69)	0.289	35 (16–76)	48 (31–68)	0.847

DLB, dementia with Lewy bodies; IQR, interquartile range. ^aLeft hemisphere; ^bRight hemisphere.

DISCUSSION

In the present study, we investigated the prevalence of CVI in patients who presented to our clinic with probable DLB, probable AD, and suspected pro-LBD. We subsequently explored the clinical and imaging features associated with CVI in patients with Lewy body disease. Our results recapitulate the finding that CVI is a common feature of DLB, with two-thirds of patients with DLB demonstrating evidence of CVI in our cohort. We also found that CVI was present in a smaller, yet still substantial proportion of patients with suspected pro-LBD, with 44% of pro-LBD patients affected. In line with previous research, our study supports the finding that color vision is impaired in a small fraction of patients with mild to moderate AD, with fewer than 1 out of 5 patients with AD in our cohort affected. While this 20% figure is in accordance with the Farnsworth D-15 failure rate in the elderly population [23], it remains unclear whether a portion of these patients with AD and CVI may also have underlying Lewy body pathology. Pending prospective confirmation, our study supports the idea that online color vision testing is a simple, accessible tool that can help support a diagnosis of DLB over AD.

Recent studies in PD have demonstrated that CVI is correlated with disease progression and severity of motor and cognitive symptoms [5–7 , 24]. Evidence from our cohort supports the idea that CVI may also be associated with disease progression in DLB. First, we demonstrated that the proportion of patients with CVI likely increases with progression from pro-LBD to DLB (from 44% to 67% in our cohort). Second, we found that cognitive decline (as evidenced by lower MoCA sub-scores) was significantly associated with CVI. Additionally, we demonstrated preliminary evidence of focally decreased brain volumes among patients with CVI.

In PD, the question remains whether CVI stems from retinal, neuroanatomical, or cognitive changes. In a recent study, analysis of diffusion tensor imaging from 26 patients with PD demonstrated an association between CVI and white-matter anomalies in the right temporal and parietal portions of the superior longitudinal fasciculus as well as the right fronto-occipital fasciculus, the posterior corpus callosum, and a small portion of the inferior longitudinal fasciculus [25]. The superior longitudinal fasciculus in particular is known to connect regions of the parietal and temporal cortices to the frontal lobe and is thought to play a significant role in conveying information about spatial attention, visuospatial abilities, spatial working memory [26], all of which may be implicated in CVI testing. This is notable given that CVI is related impaired executive function and visuospatial abilities in PD [25] and strongly predicts conversion to dementia as opposed to Parkinsonism in idiopathic RBD [4].

Findings from our sub-group analysis of volumetric MRI data suggest that lower brain volumes in the right transverse/superior temporal gyri are associated with CVI in DLB. While it is unclear if this is a causal relationship, we entertain the hypothesis that atrophy of the right superior temporal lobe may affect visuospatial attention required by the Farnsworth D-15 test and may also underlie lower MoCA sub-scores in visuospatial and executive function seen in patients with CVI in our cohort. Involvement of the right superior temporal lobe in particular may highlight the role of the right temporo-parietal junction in conjunctive feature processing [27], or the simultaneous processing of conjoint differences in color and spatial orientation among the colored tiles in the Farnsworth D-15 test. This is supported by fMRI evidence of predominately visual sub-components of the right temporo-parietal junction that mediate reorientation of attention to task-relevant stimuli, thus playing a critical role in visual attention [28, 29]. Ultimately, a larger sample size of patients with volumetric MRI may provide support for this hypothesis.

Of note, while lower total MoCA scores and sub-scores in visuospatial/executive function were associated with CVI in patients with DLB, similar associations were not seen in patients with pro-LBD, perhaps suggesting that CVI is more closely related to cognitive decline in later stages of disease. Among all cognitive domains, only language deficits were associated with CVI in both the prodromal and dementia stages of disease.

Our study has a number of limitations. First, our results are limited by the retrospective and cross-sectional study design. Future studies should prospectively assess CVI and its relation to disease onset, progression, and clinical heterogeneity. While the Farnsworth 100 hue test would likely allow for more granular results, we suggest that the online Farnsworth D-15 test is a more accessible and convenient test in the clinical setting. We also recognize that our cohort may represent a population of patients with mild to moderate dementia, as patients with more advanced dementia may have been cognitively unable to undergo CVI testing at the time of their initial encounter. However, we suspect that the value of CVI assessment will be in patients in the earlier stage of disease. Additionally, as clinical variables were collected only as binary outcomes, we are limited in our ability to assess the relationship between CVI status and the severity of clinical features. This is notable given a recent study indicating that CVI is a predictor of the severity of hallucinatory symptoms in DLB based on clinician- and questionnaire-derived measures [30]. Lastly, our sub-group analysis of volumetric MRI data was limited due to its small sample size and its omission of a correction for multiple comparisons. To overcome this limitation, future studies should aim to apply post-processing volumetric techniques to routine brain MRIs in a larger sample of patients with DLB who also underwent CVI testing.

In conclusion, we provide further evidence that CVI can help differentiate DLB from AD. We also provide evidence that the presence of CVI may be an indicator of disease progression in Lewy body disease. Pending prospective confirmation, CVI testing may prove to be an accessible tool for enhancing the accuracy of DLB diagnosis and management.

Footnotes

ACKNOWLEDGMENTS

This work was supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke U01 NS100610.

Authors’ disclosures available online ().

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