Characterising adaptational dysfunction in age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of visual impairment in the developed world. The prevalence of this disease will continue to increase over the coming decades as the average age of the global population rises. There is consequently an urgent need to develop tests that are sensitive to early visual dysfunction, in order to identify individuals that have a high risk of developing AMD, to identify patients that would benefit from treatment, to assess the outcomes of that treatment and to evaluate emerging treatment strategies. An emerging body of evidence suggests that dark adaptation is a sensitive biomarker for early AMD. Cone dark adaptation is of particular interest to clinicians, as it can identify patients with early AMD in a relatively short recording period. Consequently, this thesis aimed to optimise psychophysical and electrophysiological techniques for the assessment of cone dark adaptation in early AMD, in order to maximise its diagnostic potential. A range of psychophysical methods were shown to be capable of monitoring the rapid changes in threshold that occur during cone dark adaptation. An optimal psychophysical protocol for the assessment of cone dark adaptation in early AMD was developed based on the results of a systematic evaluation of the effect of stimulus parameters and pre-adapting light intensity on the diagnostic potential of cone dark adaptation in early AMD. When compared to the focal cone ERG photostress test, both techniques were shown to be similarly diagnostic for early AMD. In addition, the time constant of cone recovery was shown to be significantly correlated with age, hence the sensitivity and specificity of cone dark adaptation as a biomarker for early macular disease may be further improved by considering these age-related changes. In conclusion, this thesis has confirmed that cone dark adaptation is a sensitive functional biomarker for early AMD. However, as cross-sectional studies are unable to determine the true diagnostic potential of a biomarker, longitudinal investigations are needed to explore the long-term potential of cone dark adaptation and other visual functions as biomarkers for early AMD

Functional Imaging of the Outer Retinal Complex using High Fidelity Imaging Retinal Densitometry

We describe a new technique, high fdelity Imaging Retinal Densitometry (IRD), which probes the functional integrity of the outer retinal complex. We demonstrate the ability of the technique to map visual pigment optical density and synthesis rates in eyes with and without macular disease. A multispectral retinal imaging device obtained precise measurements of retinal refectance over space and time. Data obtained from healthy controls and 5 patients with intermediate AMD, before and after photopigment bleaching, were used to quantify visual pigment metrics. Heat maps were plotted to summarise the topography of rod and cone pigment kinetics and descriptive statistics conducted to highlight diferences between those with and without AMD. Rod and cone visual pigment synthesis rates in those with AMD (v=0.043SD 0.019min−1 and v=0.119SD 0.046min−1, respectively) were approximately half those observed in healthy controls (v=0.079SD 0.024min−1 for rods and v=0.206SD 0.069min−1 for cones). By mapping visual pigment kinetics across the central retina, high fdelity IRD provides a unique insight into outer retinal complex function. This new technique will improve the phenotypic characterisation, diagnosis and treatment monitoring of various ocular pathologies, including AMD

The repeatability of the Goldmann-Weekers adaptometer for measuring cone adaptation

To assess the inter-session repeatability of the Goldmann-Weekers adaptometer for the measurement of cone dark adaptation in a population of healthy subjects. Data were obtained from 31 healthy adults (mean age 21.5 ± 2.5) on 2 days. At each visit, pupils were dilated and a 96% bleach of cone photopigment was administered to the test eye before threshold was monitored continuously for 5 min in the dark using the Goldmann-Weekers adaptometer. A single exponential function was fitted to the threshold recovery data on a least squares basis. The coefficient of repeatability (CoR) was calculated to assess the repeatability of the time constant of recovery (τ), initial threshold and final threshold. Cone dark adaptation functions were successfully recorded from all subjects on both visits. The CoR was 79.48 s for τ, 0.71 log cdm−2 for the initial threshold, and 0.58 log cdm−2 for the final threshold. Paired samples t-tests showed that there were no significant differences between visits for any of the parameters assesed. Although the Goldmann-Weekers adaptometer was capable of monitoring the rapid changes in threshold that occur during cone dark adaptation, the CoR for τ was relatively large compared to the mean recovery time constants (126.48 ± 40.33 and 119.94 ± 33.25 s at the first and second visits, respectively). This indicates that the Goldmann-Weekers adaptometer is unlikely to be a useful instrument to chart changes in an individual’s vision over time

Topography of Cone Dark Adaptation Deficits in Age-Related Maculopathy

Purpose. Despite widespread agreement that dark adaptation is abnormal in age-related maculopathy (ARM), the optimal retinal location for detection of this deficit is unclear. We quantified the diagnostic potential of cone dark adaptation as a function of retinal eccentricity and compared this with the diagnostic potential of the time to the rod-cone-break (RCB). Methods. Cone dark adaptation was monitored after an 80% cone photopigment bleach in 10 subjects with ARM and 10 age-matched controls, using four achromatic annuli (0.5, 2, 7, and 12° radius) centered on the fovea. Threshold recovery data were modeled and the time constant of cone recovery (τ), final cone threshold, and time to RCB were determined. Diagnostic potential was evaluated by constructing receiver operating characteristic curves for these parameters. Results. Cone τ was significantly longer for the ARM group at 2, 7, and 12°. The greatest difference between groups was observed at 12° from fixation. At this location, the mean τ was 3.49 (±2.02) min and 0.64 (±0.38) min for ARM and control subjects, respectively (p = 0.002), and time to RCB was 17.68 (±5.37) min and 9.05 (±2.11) min for ARM and control subjects, respectively (p = 0.001). Correspondingly, receiver operating characteristic curves showed that the diagnostic potential of dark adaptometry is greatest for stimuli presented 12° from fixation; for cone τ, the area under the curve = 0.99 ± 0.02 and for time to RCB, area under the curve = 0.96 ± 0.04. Conclusions. This study has shown cone-mediated dark adaptation to be significantly impaired in ARM. Our results provide compelling evidence in support of the diagnostic potential of cone dark adaptation and the use of annular stimuli at 12°. The observation that cone τ is highly diagnostic at this eccentricity is significant clinically because this parameter may be quantified within a few minutes

Aging and cone dark adaptation

Purpose. Following exposure to a bright light that bleaches a significant portion of photopigment, the eyes take several minutes to regain sensitivity. This slow process, known as dark adaptation, is impaired in patients with age-related macular degeneration and is an important candidate biomarker for this disease. The aim of this study was to evaluate the effect of age on cone dark adaptation. Methods. Data were obtained from 41 healthy adults aged between 20 and 83 years. Pupils were dilated and 96% of cone photopigment was “bleached,” before threshold was monitored continuously for 5 min in the dark, using a 4° diameter achromatic spot centered on the fovea. Threshold recovery data were modeled, and the time constant of cone recovery ([tau]), initial cone thresholds, and final cone thresholds were determined. Regression analysis was used to determine the relationship between age and cone dark adaptation parameters. Results. Cone [tau] increased by 16.4 s/decade of life, indicating a progressive slowing of dark adaptation with increasing age. This change in cone [tau] throughout adulthood was significant (p < 0.0005). There was no significant relationship between increasing age and initial cone threshold (p = 0.84) or final cone threshold (p = 0.82). Conclusions. Our results provide evidence for age-related slowing of cone dark adaptation after a full bleach in healthy adults, which is likely to contribute to visual difficulties when moving from bright to dim photopic light levels. We propose that the sensitivity and specificity of cone [tau] as a biomarker for early age-related macular disease could be improved by taking into account the significant age-related decline in this parameter

Aging and Cone Dark Adaptation

Purpose. Following exposure to a bright light that bleaches a significant portion of photopigment, the eyes take several minutes to regain sensitivity. This slow process, known as dark adaptation, is impaired in patients with age-related macular degeneration and is an important candidate biomarker for this disease. The aim of this study was to evaluate the effect of age on cone dark adaptation. Methods. Data were obtained from 41 healthy adults aged between 20 and 83 years. Pupils were dilated and 96% of cone photopigment was “bleached,” before threshold was monitored continuously for 5 min in the dark, using a 4° diameter achromatic spot centered on the fovea. Threshold recovery data were modeled, and the time constant of cone recovery ([tau]), initial cone thresholds, and final cone thresholds were determined. Regression analysis was used to determine the relationship between age and cone dark adaptation parameters. Results. Cone [tau] increased by 16.4 s/decade of life, indicating a progressive slowing of dark adaptation with increasing age. This change in cone [tau] throughout adulthood was significant (p < 0.0005). There was no significant relationship between increasing age and initial cone threshold (p = 0.84) or final cone threshold (p = 0.82). Conclusions. Our results provide evidence for age-related slowing of cone dark adaptation after a full bleach in healthy adults, which is likely to contribute to visual difficulties when moving from bright to dim photopic light levels. We propose that the sensitivity and specificity of cone [tau] as a biomarker for early age-related macular disease could be improved by taking into account the significant age-related decline in this parameter