The Pattern of Retinal Ganglion Cell Loss in OPA1-Related Autosomal Dominant Optic Atrophy Inferred From Temporal, Spatial, and Chromatic Sensitivity Losses

Abstract

Purpose: Progressive retinal ganglion cell (RGC) loss is the pathological hallmark of autosomal dominant optic atrophy (DOA) caused by pathogenic OPA1 mutations. The aim of this study was to conduct an in-depth psychophysical study of the visual losses in DOA and to infer any selective vulnerability of visual pathways subserved by different RGC subtypes.

Methods: We recruited 25 patients carrying pathogenic OPA1 mutations and age-matched healthy individuals. Spatial contrast sensitivity functions (SCSFs) and chromatic contrast sensitivity were quantified, the latter using the Cambridge Colour Test. In 11 patients, long (L) and short (S) wavelength-sensitive cone temporal acuities were measured as a function of target illuminance, and L-cone temporal contrast sensitivity (TCSF) as a function of temporal frequency.

Results: Spatial contrast sensitivity functions were abnormal, with the loss of sensitivity increasing with spatial frequency. Further, the highest L-cone temporal acuity fell on average by 10 Hz and the TCSFs by 0.66 log10 unit. Chromatic thresholds along the protan, deutan, and tritan axes were 8, 9, and 14 times higher than normal, respectively, with losses increasing with age and S-cone temporal acuity showing the most significant age-related decline.

Conclusions: Losses of midget parvocellular, parasol magnocellular, and bistratified koniocellular RGCs could account for the losses of high spatial frequency sensitivity and protan and deutan sensitivities, high temporal frequency sensitivity, and S-cone temporal and tritan sensitivities, respectively. The S-cone-related losses showed a significant deterioration with increasing patient age and could therefore prove useful biomarkers of disease progression in DOA.

Figure 1

L-cone critical flicker fusion. (A, B) L-cone critical flicker frequencies (CFF) measured on a 481-nm background of 8.3 log₁₀ quanta s⁻¹deg⁻² and plotted as a function of the mean log₁₀ radiance of a 650-nm flickering target. (A) Data are plotted as mean ± 1 SEM for each DOA patient indicated with individually colored symbols and as gray symbols for the mean normal observer. (B) The pink symbols denote the mean ± 1 SEM across all DOA patients (except for the lowest two radiances that could be detected only by six and nine patients, respectively), and gray symbols again denote the mean of 15 normal observers (±1 SEM across observers). The Ferry-Porter slopes of mean CFF for DOA and normal observers are indicated by the blue lines. (C) The L-cone CFF frequencies at 8.5 log₁₀ quanta s⁻¹deg⁻² plotted as a function of observer age for normal (gray symbols) and DOA patients (pink symbols). The solid gray and pink lines show the best fits for linear regression for normal and DOA patients, respectively—the dashed lines, the 95% confidence interval for the best-fitting linear regressions.

Figure 2

L-cone modulation sensitivity. Each image shows, for a single DOA patient, the log₁₀ L-cone modulation sensitivities measured using a sinusoidally modulated, 650-nm 4° target with a mean radiance of 10.3 log₁₀ quanta s⁻¹deg⁻² superimposed on a 9°, 481-nm background of 8.3 log₁₀ quanta s⁻¹deg⁻² and plotted as a function temporal frequency colored triangles. (The gray symbols in each image show the mean normal data set for comparison.) The 12th (gray) image shows the mean DOA data (black triangles). The error bars are ±1 SEM either between runs for the individual patients, or between observers for the mean data. In the lower part of the first 11 images, the differences in log₁₀ sensitivity between each DOA patient and the normal mean data (n = 8) are shown as circles. The 12th image shows the differences between the mean data (filled circles). The black curves are the fits of the cubic polynomial model described in Methods.

Figure 3

S-cone critical flicker fusion. (A, B) S-cone critical flicker frequencies (CFF) measured on a 9° 620-nm background of 11.41 log₁₀ quanta s⁻¹deg⁻² plotted as a function of the mean log₁₀ radiance of a 440-nm flickering target. (A) Data are plotted as mean ± 1 SEM for each DOA patient indicated with individually colored symbols and as gray symbols for the mean normal observer. (B) Mean DOA data with ±1 SEM across DOA patients indicated with cyan symbols. The gray symbols denote to the mean normal data again with ±1 SEM across 15 observers. The Ferry-Porter slopes of mean CFF for DOA and normal observers are indicated with blue lines. (C) The S-cone CFF frequencies at 8.5 log₁₀ quanta s⁻¹deg⁻² plotted as a function of observer age, and the best fits for linear regression (solid lines) and 95% confidence intervals (dashed lines), for DOA patients (cyan symbols and lines) and for normal observers (gray symbols and lines).

Figure 4

Achromatic spatial contrast sensitivity functions (SCSFs), expressed as log₁₀ sensitivity as a function of spatial frequency (cycles per degree, cyc/deg—logarithmic axis), are indicated with colored triangles for (A) the 11 individual DOA patients who also participated in the temporal measurements and (B) the 14 individual DOA patients who did not, in separate images together with normal data (inverted gray triangles). The difference in sensitivity between each DOA patient and normal is also indicated in each image by colored circles. The symbols and error bars are mean ± 1 SEM across normal observers, or across repeated runs of individual DOA patients. The black curves are fits of a cubic polynomial model, as described in the text.

Figure 4

Continued.

Figure 5

(A) Mean achromatic spatial contrast sensitivity function (CSF) of 25 DOA (pink triangles) and 15 normal observers (gray triangles) expressed in log₁₀ sensitivity as a function of spatial frequency (cycles per degree, cyc/deg—logarithmic axis). (Extrapolation of the fitted SCSFs to zero sensitivity; that is, sensitivity corresponding to the maximum [100%] sinusoidal contrast, is determined by the spatial frequency at which the SCSFs intersect the horizontal gray dashed line.) The mean sensitivity difference between DOA patients and the mean normal observer is shown as colored circles in the lower image. The symbols and error bars are mean ± 1 SEM within both groups. The black curves are the model fits, as described in the text. (B) Spatial frequency (cyc/deg) at zero sensitivity (logarithmic axis) is plotted as a function of the best-corrected visual acuities (BCVA) of both eyes. The gray line denotes the correlation between the spatial frequency and the visual acuity expressed in logMAR units. The data for DOA patients are presented as a scatter plot, and data for normal observers as a box plot showing median, range (error bars), interquartile range (box), and an outlier (black dots).

Figure 6

The Trivector Cambridge Colour Test. The vector lengths in the protan and deutan (A) and tritan (B) confusion lines expressed in 10⁻⁴ u′v′ units (the CIE 1976 u′v′ color space) as a function of observer age for 23 DOA (colored symbols: upper image, red triangles for protan, inverted green triangles for deutan, and lower image, blue triangles for tritan). Normal observers in both images (small gray diamonds). Solid lines are for the best linear regression and dashed lines for the 95% confidence intervals.

Figure 7

Macular ganglion cell–inner plexiform layer (GCL-IPL) thickness (μm) for 50 eyes of 25 DOA patients (pink symbols) and for 48 healthy eyes (gray symbols) plotted as a function of subject age and including lines for the best fits of linear regression and 95% confidence intervals.