Altered Outer Retinal Structure, Electrophysiology and Visual Perception in Parkinson's Disease

Abstract

Background: Visual biomarkers of Parkinson's disease (PD) are attractive as the retina is an outpouching of the brain. Although inner retinal neurodegeneration in PD is well-established this has overlap with other neurodegenerative diseases and thus outer retinal (photoreceptor) measures warrant further investigation.

Objective: To examine in a cross-sectional study whether clinically implementable measures targeting outer retinal function and structure can differentiate PD from healthy ageing and whether these are sensitive to intraday levodopa (L-DOPA) dosing.

Methods: Centre-surround perceptual contrast suppression, macular visual field sensitivity, colour discrimination, light-adapted electroretinography and optical coherence tomography (OCT) were tested in PD participants (n = 16) and controls (n = 21). Electroretinography and OCT were conducted before and after midday L-DOPA in PD participants, or repeated after ∼2 hours in controls.

Results: PD participants had decreased center-surround contrast suppression (p < 0.01), reduced macular visual field sensitivity (p < 0.05), color vision impairment (p < 0.01) photoreceptor dysfunction (a-wave, p < 0.01) and photoreceptor neurodegeneration (outer nuclear layer thinning, p < 0.05), relative to controls. Effect size comparison between inner and outer retinal parameters showed that photoreceptor metrics were similarly robust in differentiating the PD group from age-matched controls as inner retinal changes. Electroretinography and OCT were unaffected by L-DOPA treatment or time.

Conclusions: We show that outer retinal outcomes of photoreceptoral dysfunction (decreased cone function and impaired color vision) and degeneration (i.e., outer nuclear layer thinning) were equivalent to inner retinal metrics at differentiating PD from healthy age-matched adults. These findings suggest outer retinal metrics may serve as useful biomarkers for PD.

Keywords: Color vision; center-surround suppression; electroretinography; optical coherence tomography; retina.

Fig. 1

Study Experimental Design. PD, Parkinson’s disease; OCT, optical coherence tomography; ERG, electroretinography; L-DOPA, levodopa. The timeline of each visit depicts L-DOPA status of Parkinson’s disease participants during visual assessments.

Fig. 2

Example stimuli used in the visuo-perceptual tasks. A) Two circularly windowed grating stimuli oriented at 90° to determine contrast matching thresholds (when the two stimuli appeared perceptually of the same contrast) for the no surround task. B) The center-surround stimulus (left) and center-only stimulus (right) to measure the effect of perceptual surround suppression. C) Locations and size of the 0.43° radius stimuli used to measure macular visual field sensitivity at discrete locations within the central (2°) visual field, while the participant fixated on the central fixation cross. The touchscreen buttons (3.4×3.4 or 5×5 deg of visual angle) are indicated by the grey squares at the bottom corners of the screen which observers tapped to register their response.

Fig. 3

Example macular OCT scan. A) A macular volume scan with an Early Treatment Diabetic Retinopathy Study [ETDRS] grid overlaid for retinal layer thickness profile analysis. B) Corresponding cross section [green line on panel A] illustrating the automatic segmentation of retinal layers: retinal nerve fiber layer, RNFL; ganglion cell inner plexiform layer, GCIPL; inner nuclear layer, INL; outer plexiform layer, OPL; outer nuclear layer, ONL and total retinal thickness, TRT. TRT is a measurement that spans from the inner limiting membrane (ILM) to the outer limiting membrane (OLM). Scale bar, 200μm.

Fig. 4

Comparison of visual perceptual measures and color vision performance between control and Parkinson’s disease participants. Perceived contrast (%) for the no surround task (A) and center-surround task (B), macular visual field sensitivity (C, decibels, dB) and FM-100 colour vision (CV) total test error scores (D, arbitrary unit, AU). Parkinson’s disease (PD) participants exhibited dysfunctional center surround contrast perception, reduced macular visual field (VF) sensitivity and poorer diffuse color discrimination (as indicated by higher test error scores) when compared to control participants. Grey data dots denote control group data and purple data dots denote PD group data. All data shown, mean±SEM; *p < 0.05 for PD effect on unpaired Student’s t-test analyses; grey shaded area, 95% CI of control group mean.

Fig. 5

Comparison of inner and outer retinal layer thicknesses and function between control and Parkinson’s disease participants before L-DOPA treatment (i.e., first OCT/ERG measurement of both groups). Raw macular thickness values of the: ganglion cell inner plexiform layer, mGCIPL (A); inner nuclear layer, mINL (B) and outer nuclear layer, mONL (C) as measured by optical coherence tomography (OCT). Light-adapted electroretinogram (ERG) photopic negative response (PhNR, D), b-wave (E) and a-wave (F) amplitudes, respectively. Thinning in the mONL and smaller a-wave and b-wave amplitudes were observed in Parkinson’s disease (PD) participants compared to control participants. Grey data dots denote control group data and purple data dots denote Parkinson’s disease group data. All data shown, mean±SEM; *p < 0.05 and/or **p < 0.01 for PD effect on unpaired Student’s t-test analyses; grey shaded area, 95% CI of control group mean.

Fig. 6

Comparison of inner and outer retinal layer thicknesses and function across time, prior to and after L-DOPA treatment. Raw macular thickness values of the: ganglion cell inner plexiform layer, mGCIPL (A); inner nuclear layer, mINL (B) and outer nuclear layer, mONL (C) as measured by optical coherence tomography (OCT). Light-adapted electroretinogram (ERG) photopic negative response (PhNR, D), b-wave (E) and a-wave (F) amplitudes, respectively. No interaction effects were found in any of these OCT or ERG parameters. Grey bars denote control group data and purple bars denote Parkinson’s disease group data. All data shown, mean±SEM, analyzed by two-way repeated measures analysis of variance (ANOVA) or mixed-effects model.

Fig. 7

Magnitude of inter-group effects across different key parameters in Parkinson’s disease participants. Z-scores were calculated relative to the control group using pooled standard deviation across both groups. Negative z-scores indicate Parkinson’s disease participants had smaller ERG amplitudes (a-wave, b-wave), thinner retinal layer thickness (mONL, mGCIPL), poorer color vision (CV, FM-100 test error score, TES), weaker center surround perceptual contrast suppression and reduced macular visual field sensitivity relative to the control group mean. Error bars are the 95% confidence limits of the mean.