Extent and Topography of Subretinal Drusenoid Deposits Associate With Rod-Mediated Vision in Aging and AMD: ALSTAR2 Baseline.

Purpose: In AMD, rod-mediated dark adaptation (RMDA) at 5° eccentricity is slower in eyes with subretinal drusenoid deposits (SDDs) than in eyes without. Here we quantified SDD burden using supervised deep learning for comparison to vision and photoreceptor topography. Methods: In persons ≥60 years from the Alabama Study on Early Age-Related Macular Degeneration 2, normal, early AMD, and intermediate AMD eyes were classified by the AREDS nine-step system. A convolutional neural network was trained on 55°-wide near-infrared reflectance images for SDD segmentation. Trained graders annotated ground truth (SDD yes/no). Predicted and true datasets agreed (Dice coefficient, 0.92). Inference was manually proofread using optical coherence tomography. The mean SDD area (mm2) was compared among diagnostic groups (linear regression) and to vision (age-adjusted Spearman correlations). Fundus autofluorescence images were used to mask large vessels in SDD maps. Results: In 428 eyes of 428 persons (normal, 218; early AMD, 120; intermediate AMD, 90), the mean SDD area differed by AMD severity (P < 0.0001): 0.16 ± 0.87 (normal), 2.48 ± 11.23 (early AMD), 11.97 ± 13.33 (intermediate AMD). Greater SDD area was associated with worse RMDA (r = 0.27; P < 0.0001), mesopic (r = -0.13; P = 0.02) and scotopic sensitivity (r = -0.17; P < 0.001). SDD topography peaked at 5° superior, extended beyond the Early Treatment of Diabetic Retinopathy Study grid and optic nerve, then decreased. Conclusions: SDD area is associated with degraded rod-mediated vision. RMDA 5° (superior retina) probes where SDD is maximal, closer to the foveal center than the rod peak at 3 to 6 mm (10.4°-20.8°) superior and the further eccentric peak of rod:cone ratio. Topographic data imply that factors in addition to rod density influence SDD formation.

Choriocapillaris Impairment, Visual Function, and Distance to Fovea in Aging and Age-Related Macular Degeneration: ALSTAR2 Baseline.

Purpose: In aging and early-intermediate age-related macular degeneration (AMD), rod-mediated dark adaptation (RMDA) slows more at 5° superior than at 12°. Using optical coherence tomography angiography (OCTA), we asked whether choriocapillaris flow deficits are related to distance from the fovea. Methods: Persons ≥60 years stratified for AMD via the Age-Related Eye Disease Study's nine-step system underwent RMDA testing. Two adjacent 4.4° × 4.4° choriocapillaris OCTA slabs were centered on the fovea and 12° superior. Flow signal deficits (FD%) in concentric arcs (outer radii in mm, 0.5, 1.5, 2.2, 4.0, and 5.0 superior) were correlated with rod intercept time (RIT) and best-corrected visual acuity (BCVA). Results: In 366 eyes (170 normal, 111 early AMD, 85 intermediate AMD), FD% was significantly worse with greater AMD severity in all regions (overall P < 0.05) and poorest under the fovea (P < 0.0001). In pairwise comparisons, FD% worsened with greater AMD severity (P < 0.05) at distances <2.2 mm. At greater distances, eyes with intermediate, but not early AMD differed from normal eyes. Foveal FD% was more strongly associated with longer RIT at 5° (r = 0.52) than RIT at 12° (r = 0.39) and BCVA (r = 0.21; all P < 0.0001). Choroidal thickness was weakly associated with longer RIT at 5° and 12° (r = 0.10-0.20, P < 0.05) and not associated with AMD severity. Conclusions: Reduced transport across the choriocapillaris-Bruch's membrane-retinal pigment epithelium complex, which contributes to drusen formation under the macula lutea (and fovea), may also reduce retinoid resupply to rods encircling the high-risk area. FD% has potential as a functionally validated imaging biomarker for AMD emergence.

Comparison of Glaucoma Diagnosis by Telemedicine, In-Person Ophthalmologist and Optometrist.

PRECIS: Diagnosis of glaucoma via telemedicine demonstrates moderate agreement with in-person ophthalmologist and optometrist diagnosis, providing evidence that telemedicine is a timely, accurate screening method in settings where an in-person visit may not be feasible. PURPOSE: To compare diagnostic agreement of glaucoma between in-person ophthalmologist (MD), in-person optometrist (OD), and a simulated telemedicine program. PATIENTS AND METHODS: Cross-sectional study of patients with normal optic nerve structural and functional imaging and new patients referred for glaucoma evaluation examined in-person by an MD for glaucoma with a dilated exam and structural and functional optic nerve testing (optical coherence tomography (OCT)), photos, and visual field); examined in person by an OD with a dilated exam and optic nerve testing; and structural and functional optic nerve testing reviewed separately by two ophthalmologists (TMD1, TMD2) with masking of prior MD and OD diagnoses. MAIN OUTCOME MEASURES: Inter-rater agreement between each diagnostic method (MD, OD, TMD1, TMD2) of normal vs. disease (open angle glaucoma, normal tension glaucoma, other type of glaucoma, other optic nerve disorders, ocular hypertension, glaucoma suspect) for each eye was calculated (Cohen's unweighted kappa). RESULTS: A total of 100 patients with median age of 66 years (IQR 59-72), male (40%) and White (62%) were analyzed. There was moderate agreement between MD and telemedicine [TMD1 kappa 0.49 (95% CI 0.37-0.61), TMD2 kappa 0.44 (95% CI 0.32-0.56)] and between MD and OD diagnosis [0.41 (95% CI 0.28-0.54)] and fair-moderate agreement between OD and telemedicine (TMD1 0.46 (95% CI 0.34-0.58), TMD2 0.61 (95% CI 0.50-0.72)]. CONCLUSIONS: The simulated telemedicine approach had comparable levels of agreement in glaucoma diagnosis with in-person fellowship-trained ophthalmologist, presenting a crucial complementary role in screening and increasing access to care, particularly in rural or underserved settings.

Teprotumumab Related Hearing Loss: A Large-Scale Analysis and Review of Voluntarily Reported Patient Complaints to the Food and Drug Administration (FDA).

PURPOSE: Accumulating case reports and series have suggested that teprotumumab may significantly increase the risk of hearing impairment that, in some cases, does not resolve. This study investigates the association between hearing impairment and teprotumumab use. METHODS: A disproportionality analysis was conducted using the United States Food and Drug Administration Adverse Event Reporting System, a publicly accessible database used for postmarketing surveillance and research. All adverse event reports containing the terms "teprotumumab" or "Tepezza" and a similar comparison group from all patients with the same indications for teprotumumab use (e.g., autoimmune thyroiditis, endocrine ophthalmopathy, and hyperthyroidism) but who had not received the drug were selected. Hearing impairment events were identified using the hearing impairment Standardized MedDRA Query. RESULTS: A total of 940 teprotumumab-associated adverse events were identified, including 84 hearing-related adverse events, with the first reported to the Food and Drug Administration in April 2020. A comparison group of 32,794 nonteprotumumab adverse events was identified with 127 hearing-related adverse events reported. Use of teprotumumab in patients with thyroid conditions was associated with a nearly 24-fold (proportional reporting ratio [PRR] 23.6, 95% confidence interval [CI]: 18.1-30.8) increased likelihood of any hearing disorder (p value <0.0001). The association was specifically elevated for a variety of deafness conditions (e.g., bilateral deafness [PRR: 41.9; 95% CI: 12.8-136.9]), Eustachian tube disorders (PRR: 34.9; 95% CI: 4.9-247.4), hypoacusis (PRR: 10.1; 95% CI: 7.6-13.3), and tinnitus (PRR: 8.7; 95% CI: 6.2-12.1). CONCLUSIONS: Patients treated with teprotumumab should receive warnings regarding the increased risk of hearing-related impairments and receive audiometry before, during, and after treatment.

Probing Deposit-Driven Age-Related Macular Degeneration Via Thicknesses of Outer Retinal Bands and Choroid: ALSTAR2 Baseline.

Purpose: We aimed to identify structural differences in normal eyes, early age-related macular degeneration (AMD), and intermediate AMD eyes using optical coherence tomography (OCT) in a well-characterized, large cross-sectional cohort. Methods: Subjects ≥ 60 years with healthy normal eyes, as well as early or intermediate AMD were enrolled in the Alabama Study on Age-related Macular Degeneration 2 (ALSTAR2; NCT04112667). Using Spectralis HRA + OCT2, we obtained macular volumes for each participant. An auto-segmentation software was used to segment six layers and sublayers: photoreceptor inner and outer segments, subretinal drusenoid deposits (SDDs), retinal pigment epithelium + basal lamina (RPE + BL), drusen, and choroid. After manually refining the segmentations of all B-scans, mean thicknesses in whole, central, inner and outer rings of the ETDRS grid were calculated and compared among groups. Results: This study involved 502 patients, 252 were healthy, 147 had early AMD, and 103 had intermediate AMD eyes (per Age-Related Eye Disease Study [AREDS] 9-step). Intermediate AMD eyes exhibited thicker SDD and drusen, thinner photoreceptor inner segments, and RPE compared to healthy and early AMD eyes. They also had thicker photoreceptor outer segments than early AMD eyes. Early AMD eyes had thinner photoreceptor outer segments than normal eyes but a thicker choroid than intermediate AMD eyes. Using the Beckman scale, 42% of the eyes initially classified as early AMD shifted to intermediate AMD, making thickness differences for photoreceptor outer segments and choroid insignificant. Conclusions: With AMD stages, the most consistent structural differences involve appearance of drusen and SDD, followed by RPE + BL thickness, and then thickness of photoreceptor inner and outer segments. Structural changes in the transition from aging to intermediate AMD include alterations in the outer retinal bands, including the appearance of deposits on either side of the RPE.

Outer Retinal Thickness Is Associated With Cognitive Function in Normal Aging to Intermediate Age-Related Macular Degeneration.

Purpose: Research on Alzheimer's disease (AD) and precursor states demonstrates a thinner retinal nerve fiber layer (NFL) compared to age-similar controls. Because AD and age-related macular degeneration (AMD) both impact older adults and share risk factors, we asked if retinal layer thicknesses, including NFL, are associated with cognition in AMD. Methods: Adults ≥ 70 years with normal retinal aging, early AMD, or intermediate AMD per Age-Related Eye Disease Study (AREDS) nine-step grading of color fundus photography were enrolled in a cross-sectional study. Optical coherence tomography (OCT) volumes underwent 11-line segmentation and adjustments by a trained operator. Evaluated thicknesses reflect the vertical organization of retinal neurons and two vascular watersheds: NFL, ganglion cell layer-inner plexiform layer complex (GCL-IPL), inner retina, outer retina (including retinal pigment epithelium-Bruch's membrane), and total retina. Thicknesses were area weighted to achieve mean thickness across the 6-mm-diameter Early Treatment of Diabetic Retinopathy Study (ETDRS) grid. Cognitive status was assessed by the National Institutes of Health Toolbox cognitive battery for fluid and crystallized cognition. Correlations estimated associations between cognition and thicknesses, adjusting for age. Results: Based on 63 subjects (21 per group), thinning of the outer retina was significantly correlated with lower cognition scores (P < 0.05). No other retinal thickness variables were associated with cognition. Conclusions: Only the outer retina (photoreceptors, supporting glia, retinal pigment epithelium, Bruch's membrane) is associated with cognition in aging to intermediate AMD; NFL was not associated with cognition, contrary to AD-associated condition reports. Early and intermediate AMD constitute a retinal disease whose earliest, primary impact is in the outer retina. Our findings hint at a unique impact on the brain from the outer retina in persons with AMD.

Telemedicine Screening for Eye Disorders in Federally Qualified Health Centers: Relationship to Vision-Targeted Health-Related Quality of Life.

Introduction: Federally Qualified Health Centers (FQHCs) play a crucial role as safety-net primary health care clinics in the United States, serving medically underserved areas and populations. However, eye services are rarely offered at FQHCs. We examined how telemedicine-generated ocular diagnoses impacted vision-targeted health-related quality of life at FQHCs in rural Alabama. Methods: We focused on patients who are at risk for glaucoma. Both visual function and retinal imaging were assessed. The telemedicine vision screening protocol performed by a remote ophthalmologist evaluated eyes for glaucoma, diabetic retinopathy, cataract, age-related macular degeneration, and a measurement of habitual visual acuity. The National Eye Institute Visual Function Questionnaire-9 (VFQ-9) was administered. Results: Using stepwise regression, the best-fitting model for predicting VFQ-9 scores incorporated visual acuity 20/40 or worse, a diabetic retinopathy diagnosis, and sociodemographic variables (gender, transportation, insurance type/status, and employment status). Conclusion: Vision-targeted, health-related quality of life in our FQHC settings was related to the visual acuity impairment and the diagnosis of diabetic retinopathy but was also influenced by a variety of sociodemographic factors.

Social Determinants of Health and Glaucoma Screening and Detection in the SIGHT Studies.

PRCIS: Targeted glaucoma screenings in populations with high levels of poverty and high proportions of people who identify as African American or Hispanic/Latino identified a 27% rate of glaucoma and suspected glaucoma, which is 3 times the national average. PURPOSE: To describe the neighborhood-level social risk factors across the 3 SIGHT Study sites and assess potential characteristics of these populations to help other researchers effectively design and implement targeted glaucoma community-based screening and follow-up programs in high-risk groups. METHODS/RESULTS: In 2019, Columbia University, the University of Michigan, and the University of Alabama at Birmingham each received 5 years of CDC funding to test a wide spectrum of targeted telehealth delivery methods to detect glaucoma in community-based health delivery settings among high-risk populations. This collaborative initiative supported innovative strategies to better engage populations most at risk and least likely to have access to eye care to detect and manage glaucoma and other eye diseases in community-based settings. Among the initial 2379 participants enrolled in all 3 SIGHT Studies; 27% screened positive for glaucoma/glaucoma suspect. Of all SIGHT Study participants, 91% were 40 years of age and older, 64% identified as female, 60% identified as African-American, 32% identified as White, 19% identified as Hispanic/Latino, 53% had a high school education or less, 15% had no health insurance, and 38% had Medicaid insurance. Targeted glaucoma screenings in populations with high levels of poverty and high proportions of people who identify as African American or Hispanic/Latino identified a 27% rate of glaucoma and suspected glaucoma, three times the national average. CONCLUSION: These findings were consistent across each of the SIGHT Studies, which are located in 3 geographically distinct US locations in rural Alabama, small urban locations in Michigan, and urban New York City.

Quantitative Autofluorescence at AMD's Beginnings Highlights Retinal Topography and Grading System Differences: ALSTAR2 Baseline.

INTRODUCTION: The aims of the study were to describe baseline quantitative (short-wavelength) autofluorescence (qAF) findings in a large pseudophakic cohort at age-related macular degeneration (AMD)'s beginnings and to assess qAF8 as an outcome measure and evaluate Age-Related Eye Disease Study (AREDS) and Beckman grading systems. METHODS: In the ALSTAR2 baseline cohort (NCT04112667), 346 pseudophakic eyes of 188 persons (74.0 ± 5.5 years) were classified as normal (N = 160 by AREDS, 158 by Beckman), early AMD (eAMD) (N = 104, 66), and intermediate AMD (iAMD) (N = 82, 122). Groups were compared via mean qAF intensities in a 6°-8° annulus (qAF8) and maps of differences between observations and the overall mean, divided by standard deviation (Z-score). RESULTS: qAF8 did not differ significantly among diagnostic groups by either stratification (p = 0.0869 AREDS; p = 0.0569 by Beckman). Notably, 45 eyes considered eAMD by AREDS became iAMD by Beckman. For AREDS-stratified eyes, Z-score maps showed higher centrally located qAF for normal, near the mean in eAMD, and lower values for iAMD. Maps deviated from this pattern for Beckman-stratified eyes. CONCLUSIONS: In a large sample of pseudophakic eyes, qAF8 does not differ overall from normal aging to iAMD but also does not capture the earliest AMD activity in the macula lutea. AREDS classification gives results more consistent with a slow decline in histologic autofluorescence than Beckman classification.

Repeatability of Rod-Mediated Dark Adaptation Testing in Normal Aging and Early and Intermediate Age-Related Macular Degeneration.

PURPOSE: The vulnerability of rod photoreceptors in aging and early and intermediate age-related macular degeneration (AMD) has been well documented. Rod-mediated dark adaptation (RMDA) is a measure of the recovery of light sensitivity in rod photoreceptors following a bright light. Delays in RMDA during early and intermediate AMD have been widely reported. For RMDA's promise as an outcome for trials targeted at early and intermediate AMD to be realized, excellent test-retest reliability, its repeatability, must be established. METHODS: Test-retest performance in a commonly used RMDA test based on the rod intercept time metric (RIT) was evaluated in participants with early and intermediate AMD and with normal retinal aging with testing approximately 2 weeks apart. The test target was placed at 5° eccentricity superior to the foveal center, an area with maximal rod loss in aging and AMD. Disease severity was identified by a trained and masked grader of fundus photographs using both the AREDS 9-step and Beckman classification systems. Bland-Altman plots and intra-class correlation coefficients (ICC) evaluated repeatability. RESULTS: The analysis sample consisted of 37 older adults (mean age 76 years, standard deviation 5), with approximately one-third of the sample in each of three groups - normal aging, early AMD, and intermediate AMD. For the total sample, the ICC was 0.98. For individual AMD groups for both AREDS 9-step and Beckman classifications, the ICCs were also very high ranging from 0.82 to 0.99. CONCLUSION: We demonstrated that RMDA testing using the RIT metric has excellent repeatability when target location is at 5° in studying older adults from normal aging to intermediate AMD, suggesting the reliable use of this functional measure in trials.

Age-Related Macular Degeneration, a Mathematically Tractable Disease.

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.

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

Purpose: Lack of valid end points impedes developing therapeutic strategies for early age-related macular degeneration (AMD). Delayed rod-mediated dark adaptation (RMDA) is the first functional biomarker for incident early AMD. The relationship between RMDA and the status of outer retinal bands on optical coherence tomography (OCT) have not been well defined. This study aims to characterize these relationships in early and intermediate AMD. Methods: Baseline data from 476 participants was assessed including eyes with early AMD (n = 138), intermediate AMD (n = 101), and normal aging (n = 237). Participants underwent volume OCT imaging of the macula and rod intercept time (RIT) was measured. The ellipsoid zone (EZ) and interdigitation zone (IZ) on all OCT B-scans of the volumes were segmented. The area of detectable EZ and IZ, and mean thickness of IZ within the Early Treatment Diabetic Retinopathy Study (ETDRS) grid were computed and associations with RIT were assessed by Spearman's correlation coefficient and age adjusted. Results: Delayed RMDA (longer RIT) was most strongly associated with less preserved IZ area (r = -0.591; P < 0.001), followed by decreased IZ thickness (r = -0.434; P < 0.001), and EZ area (r = -0.334; P < 0.001). This correlation between RIT and IZ integrity was not apparent when considering normal eyes alone within 1.5 mm of the fovea. Conclusions: RMDA is correlated with the status of outer retinal bands in early and intermediate AMD eyes, particularly, the status of the IZ. This correlation is consistent with a previous analysis of only foveal B-scans and is biologically plausible given that retinoid availability, involving transfer at the interface attributed to the IZ, is rate-limiting for RMDA.

Feasibility of Glaucoma Detection Programs for At-Risk Populations Using Existing Health Care Infrastructure.

PRCIS: Targeted glaucoma screening strategies performed within retail care-based clinics and Federally Qualified Health Centers (FQHCs) uncover a high prevalence of glaucoma. OBJECTIVE: To summarize the glaucoma detection and maintenance programs that utilize existing health care infrastructure to promote up-scalable programs. METHODS: Health care infrastructure that already exists may facilitate glaucoma detection. This infrastructure includes retail-based optometry practices and FQHC. Persons who are at risk for glaucoma are disproportionately represented within the patient populations served by much of this infrastructure, thus suggesting that it could be useful for deploying glaucoma screening programs. Glaucoma screening within FQHCs reveals a very high prevalence of glaucoma and related disease in the patients seeking care at these facilities. RESULTS: These telemetric-based care delivery programs have a high patient acceptance. A simulated telemedicine program modeled after a telemedicine program based in Walmart Vision Centers for the diagnosis of glaucoma indicated that there was moderate diagnostic agreement between an ophthalmologist's telemedicine diagnosis and an ophthalmologist's in-person diagnosis. There was also moderate agreement between an optometrist's telemedicine diagnosis and the ophthalmologist's in-person diagnosis. CONCLUSION: Telemetric care delivery programs that capitalize on existing infrastructure within a retail-based care setting or FQHCs may provide a promising setting to cost-effectively screen for glaucoma and other eye diseases that are potentially expandable nationwide.

Alabama Screening and Intervention for Glaucoma and Eye Health through Telemedicine (AL-SIGHT): Baseline Results.

PURPOSE: To describe baseline results of the Alabama Screening and Intervention for Glaucoma and Eye Health through Telemedicine (AL-SIGHT) for patients at federally qualified health centers (FQHCs). Candidates were persons at risk for glaucoma-associated diseases (GAD) based on age, race/ethnicity, current diagnosis of GAD, family history, and diabetes. DESIGN: Baseline screening visit followed by remote diagnosis and referral for follow-up examinations. METHODS: Patients presenting to FQHCs who were at least 18 years of age were enrolled and underwent screening for acuity, autorefraction, intraocular pressure, visual field testing, and fundus imaging. Results were transmitted to an ophthalmologist at University of Alabama at Birmingham for diagnosis who made referrals for follow-up; follow-up attendance was noted. Questionnaires assessed participants' perspectives on screening. Primary outcomes were rates of disease detection, referral for follow-up, follow-up attendance, and participant satisfaction. RESULTS: Of the 500 participants enrolled (mean age 58 years), 45.6% were African American and 51.6% White. Remote diagnostic evaluation of ocular screening by ophthalmologist revealed 30% GAD, 6.8% diabetic retinopathy, 37.6% cataract, 68.4% refractive error, 9.2% other eye conditions. In all, 47.2% of the participants were referred for follow-up examination and for acuity 20/40 or worse or IOP ≥23 mm Hg in one or both eyes. Follow-up examination attendance was 76.7% for those referred. Participants reported being very satisfied with screening (85.8%) and with the convenience of screening in their primary care clinic (92.2%). CONCLUSIONS: The high percentage of patients diagnosed with treatable eye conditions at telemedicine screening suggest these programs in FQHCs can be effective and scalable nationwide. Attendance when referred for follow-up examination was high. Participants welcomed screenings in their communities.

MNREAD Reading Vision in Adults With Glaucoma Under Mesopic and Photopic Conditions.

Purpose: Despite good photopic visual acuity, glaucoma patients report difficulty performing daily activities under dim light such as reading. Here we investigated the impact of mesopic lighting conditions on reading vision of glaucoma patients. Methods: The study design included 39 patients with glaucoma and 40 healthy controls. Reading vision was assessed with MNREAD charts under mesopic (2 cd/m2) and photopic (220 cd/m2) conditions. Four reading indexes: maximum reading speed (MRS), critical print size (CPS), reading acuity (RA), and reading accessibility index (ACC) were obtained from the MNREAD test yielding a plot of reading speed versus print size. Results: Compared to photopic conditions, reading vision of both healthy controls and glaucoma patients significantly decreased under mesopic conditions (P < 0.05). For glaucoma patients (85% with mild or moderate glaucoma), MRS and ACC decreased by six words per minute and 0.1, respectively under mesopic conditions; CPS and RA increased by 0.25 and 0.18 logMAR, respectively. Moreover, under both photopic and mesopic conditions, reading vision of glaucoma patients was significantly worse than that of healthy controls, but the difference was greater under mesopic conditions (P < 0.05) even after controlling for age and visual acuity. Conclusions: Mesopic conditions make reading more challenging for both healthy controls and glaucoma patients. However, reading in dim light appears to be more burdensome for glaucoma patients. Mesopic reading tests mediated by both cone and rod photoreceptor systems likely provide a more sensitive and comprehensive assessment of a patient's reading impairment than testing under photopic conditions.

Volume electron microscopy reveals human retinal mitochondria that align with reflective bands in optical coherence tomography [Invited].

Mitochondria are candidate reflectivity signal sources in optical coherence tomography (OCT) retinal imaging. Here, we use deep-learning-assisted volume electron microscopy of human retina and in vivo imaging to map mitochondria networks in the outer plexiform layer (OPL), where photoreceptors synapse with second-order interneurons. We observed alternating layers of high and low mitochondrial abundance in the anatomical OPL and adjacent inner nuclear layer (INL). Subcellular resolution OCT imaging of human eyes revealed multiple reflective bands that matched the corresponding INL and combined OPL sublayers. Data linking specific mitochondria to defined bands in OCT may help improve clinical diagnosis and the evaluation of mitochondria-targeting therapies.

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

Purpose: While 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. Methods: We 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. Results: Our 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. Conclusions: The 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.

Reading Vision in Adults With Early and Intermediate Age-Related Macular Degeneration Under Mesopic and Photopic Conditions.

Purpose: Reading is involved in various daily activities that operate under a wide range of luminance levels. Rod- and cone-mediated mesopic visual function is known to be impaired even in early/intermediate age-related macular degeneration (AMD). It remains unclear whether and to what extent mesopic reading is impaired in early/intermediate AMD. Here, we assessed differences in reading vision between photopic and mesopic conditions in early/intermediate AMD and compared their performance to those in older adults with normal macular health. Methods: The study included 30 patients with early/intermediate AMD and 30 healthy controls. Reading performance was tested on the MNREAD iPad app under mesopic (2 cd/m2 with a neural-density filter) and photopic (220 cd/m2) conditions. Four reading indices-maximum reading speed (MRS), critical print size (CPS), reading acuity (RA), and reading accessibility index (ACC)-were obtained from the MNREAD test, yielding a function representing reading speed versus print size. Results: Compared to photopic conditions, patients with AMD and healthy controls both exhibited noticeable decreases in reading vision under mesopic conditions (P < 0.001) despite normal photopic visual acuity. This decrease was more pronounced in AMD even after adjusting for age (P < 0.001): Under mesopic conditions, MRS and ACC decreased by 8 words per minute and 0.1, respectively; CPS and RA were enlarged by 0.27 and 0.24 logMAR, respectively. Conclusions: Reading vision deteriorates under mesopic conditions compared to photopic conditions in early/intermediate AMD and is accentuated compared to this difference in healthy controls. Translational Relevance: A mesopic reading test may provide a more sensitive and comprehensive assessment of a patient's reading impairment.