Biologically Guided Optimization of Test Target Location for Rod-mediated Dark Adaptation in Age-related Macular Degeneration

Owsley, Cynthia; Swain, Thomas A.; McGwin, Gerald; Clark, Mark E.; Kar, Deepayan; Curcio, Christine A.

doi:10.1016/j.xops.2023.100274

Cited by 18 publications

(11 citation statements)

References 63 publications

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“… 7 , 8 Previous and ongoing clinical studies focus predominantly on patients with stable fixation and large stimulus testing (Goldmann V or larger). 25 , 26 The now-devised method offers a fully automated workflow for fundus-controlled dark adaptometry testing for evaluating patients with unstable fixation in a highly localized manner.…”

Section: Discussionmentioning

confidence: 99%

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Establishing Fully-Automated Fundus-Controlled Dark Adaptometry: A Validation and Retest-Reliability Study

Oertli,

Pfau,

Scholl

et al. 2023

Trans. Vis. Sci. Tech.

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Purpose The purpose of this study was to establish and validate a novel fundus-controlled dark-adaptometry method. Methods We developed a custom dark-adaptometry software for the S-MAIA device using the open-perimetry-interface. In the validation-substudy, participants underwent dark-adaptometry testing with a comparator device (MonCvONE, 59% rhodopsin bleach, cyan and red stimuli centered at 2 degrees, 4 degrees, and 6 degrees eccentricity). Following a brief break (approximately 5 minutes), the participants were bleached again and underwent dark-adaptometry testing with the S-MAIA device (same loci). In the retest reliability-substudy, participants were tested twice with the S-MAIA device (same loci as above). Nonlinear curve fitting was applied to extract dark-adaptation curve parameters. Validity and repeatability were summarized in terms of the mean bias and 95% limits of agreement (LoAs). Results In the validation-substudy ( N = 20 participants, median age interquartile range [IQR] 31.5 years [IQR = 25.8, 62.0]), measures of rod-mediated dark-adaptation showed little to no between method differences for the cone-rod-break-time (bias 95% confidence interval [95% CI] of +0.1 minutes [95% CI = −0.6 to 0.8]), rod-intercept-time (−0.23 minutes [95% CI = −1.38 to 0.93]), and S2 slope (−0.01 LogUnits/minutes [95% CI = −0.02 to −0.01]). In the retest reliability-substudy ( N = 10 participants, 32.0 years [95% CI = 27.0, 57.5]), the corresponding LoAs were (cone-rod-break-time) −3.94 to 2.78 minutes, (rod-intercept-time) −4.55 to 3.11 minutes, and (S2 slope [rate-limited component of rod recovery]) −0.03 to 0.03 LogUnits/minutes. The LoAs for the steady-state cone and rod thresholds were −0.28 to 0.33 LogUnits and −0.34 to 0.28 LogUnits. Conclusions The devised fundus-controlled dark-adaptometry method yields valid and reliable results. Translational Relevance Fundus-controlled dark-adaptometry solves the critical need for localized testing of the visual cycle and retinoid transfer in eyes with unstable fixation.

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Section: Discussionmentioning

confidence: 99%

“…free-viewing stimulus presentation). 25 , 26 These free-viewing devices (as opposed to fundus-controlled microperimetry devices) are unsuitable for testing of patients with unstable fixation and assessing small, localized regions of interest in a patient-tailored manner.…”

Section: Introductionmentioning

confidence: 99%

Establishing Fully-Automated Fundus-Controlled Dark Adaptometry: A Validation and Retest-Reliability Study

Oertli,

Pfau,

Scholl

et al. 2023

Trans. Vis. Sci. Tech.

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“…49 Several studies demonstrate that the presence of SDD is associated with markedly delayed RMDA. 48, 50-52 Stage 1 SDD are defined by diffusely distributed granular hyperreflective material between the RPE and the EZ, blurring the boundaries between normally well delineated hyperreflective IZ and RPE lines. Stage 2 and 3 represent the expansion of hyperreflective material accumulation between the RPE and EZ that further distorts band boundaries, with stage 3 SDD protruding upward though the EZ.…”

Section: Discussionmentioning

confidence: 99%

Potential Structural Biomarkers in 3D Images Validated by the First Functional Biomarker for Early Age-Related Macular Degeneration - ALSTAR2 Baseline

Fasih-Ahmad,

Wang,

Mishra

et al. 2023

Preprint

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PurposeWhile intermediate and late age-Related Macular Degeneration (AMD) have been widely investigated, rare studies were focused on the pathophysiologic mechanism of early AMD. Delayed rod-mediated dark adaptation (RMDA) is the first functional biomarker for incident early AMD. The status of outer retinal bands on optical coherence tomography (OCT) may be potential imaging biomarkers and the purpose is to investigate the hypothesis that the integrity of interdigitation zone (IZ) may provide insight into the health of photoreceptors and retinal pigment epithelium (RPE) in early AMD.MethodsWe establish the structure-function relationship between ellipsoid zone (EZ) integrity and RMDA, and IZ integrity and RMDA in a large-scale OCT dataset from eyes with normal aging (n=237), early AMD (n=138), and intermediate AMD (n=101) by utilizing a novel deep-learning-derived algorithm with manual correction when needed to segment the EZ and IZ on OCT B-scans (57,596 B-scans), and utilizing the AdaptDx device to measure RMDA.ResultsOur data demonstrates that slower RMDA is associated with less preserved EZ (r = -0.334; p<0.001) and IZ area (r = -0.591; p<0.001), and decreased IZ thickness (r = -0.434; p<0.001). These associations are not apparent when considering normal eyes alone.ConclusionsThe association with IZ area and RMDA in large-scale data is biologically plausible because retinoid availability and transfer at the interface attributed to IZ is rate-limiting for RMDA. This study supports the hypothesis that the IZ integrity provides insight into the health of photoreceptors and RPE in early AMD and is a potential new imaging biomarker.

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“…2 ). Starting with the article by Haimovici et al, 165 studies of 20 to >500 aged persons with and without early or intermediate AMD 166 – 172 have shown that RMDA is more markedly delayed close to the fovea (3°–5°) than it is at 10° to 12° from the fovea ( Table 4 ). A key finding for the field was that eyes with SDD, which start where rods are abundant, 7 , 173 have particularly poor RMDA.…”

Section: How Rmda Probes the High-risk Areamentioning

confidence: 99%

Age-Related Macular Degeneration, a Mathematically Tractable Disease

Curcio,

Kar,

Owsley

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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A progression sequence for age-related macular degeneration onset may be determinable with consensus neuroanatomical nomenclature augmented by drusen biology and eye-tracked clinical imaging. This narrative review proposes to supplement the Early Treatment of Diabetic Retinopathy Study (sETDRS) grid with a ring to capture high rod densities. Published photoreceptor and retinal pigment epithelium (RPE) densities in flat mounted aged-normal donor eyes were recomputed for sETDRS rings including near-periphery rich in rods and cumulatively for circular fovea-centered regions. Literature was reviewed for tissue-level studies of aging outer retina, population-level epidemiology studies regionally assessing risk, vision studies regionally assessing rod-mediated dark adaptation (RMDA), and impact of atrophy on photopic visual acuity. The 3 mm-diameter xanthophyll-rich macula lutea is rod-dominant and loses rods in aging whereas cone and RPE numbers are relatively stable. Across layers, the largest aging effects are accumulation of lipids prominent in drusen, loss of choriocapillary coverage of Bruch's membrane, and loss of rods. Epidemiology shows maximal risk for drusen-related progression in the central subfield with only one third of this risk level in the inner ring. RMDA studies report greatest slowing at the perimeter of this high-risk area. Vision declines precipitously when the cone-rich central subfield is invaded by geographic atrophy. Lifelong sustenance of foveal cone vision within the macula lutea leads to vulnerability in late adulthood that especially impacts rods at its perimeter. Adherence to an sETDRS grid and outer retinal cell populations within it will help dissect mechanisms, prioritize research, and assist in selecting patients for emerging treatments.

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Biologically Guided Optimization of Test Target Location for Rod-mediated Dark Adaptation in Age-related Macular Degeneration

Cited by 18 publications

References 63 publications

Establishing Fully-Automated Fundus-Controlled Dark Adaptometry: A Validation and Retest-Reliability Study

Establishing Fully-Automated Fundus-Controlled Dark Adaptometry: A Validation and Retest-Reliability Study

Potential Structural Biomarkers in 3D Images Validated by the First Functional Biomarker for Early Age-Related Macular Degeneration - ALSTAR2 Baseline

Age-Related Macular Degeneration, a Mathematically Tractable Disease

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