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.

Quantitative autofluorescence at AMD's beginnings highlights retinal topography and grading system differences: ALSTAR2 baseline.

PURPOSE: To describe baseline quantitative (short-wavelength) autofluorescence (qAF) findings in a large pseudophakic cohort at age-related macular degeneration (AMD)'s beginnings; to assess qAF8 as an outcome measure and evaluate 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 (e)AMD (N=104, 66), and intermediate (i)AMD (N=82, 122). Groups were compared via mean qAF intensities in a 6°- 8° annulus (qAF8) and maps of differences between observations and 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.

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.

Displacement of the Lamina Cribrosa With Acute Intraocular Pressure Increase in Brain-Dead Organ Donors.

Purpose: To examine deformations of the optic nerve head (ONH) deep tissues in response to acute elevation of intraocular pressure (IOP). Methods: Research-consented brain-dead organ donors underwent imaging by spectral domain optical coherence tomography (OCT). OCT imaging was repeated while the eye was sequentially maintained at manometric pressures of 10, 30, and 50 mm Hg. Radial scans of the ONH were automatically segmented by deep learning and quantified in three dimensions by a custom algorithm. Change in lamina cribrosa (LC) depth and choroidal thickness was correlated with IOP and age by linear mixed-effect models. LC depth was computed against commonly utilized reference planes. Results: Twenty-six eyes from 20 brain-dead organ donors (age range, 22-62 years; median age, 43 years) were imaged and quantified. LC depth measured against a reference plane based on Bruch's membrane (BM), BM opening, and an anterior sclera canal opening plane showed both a reduction and an increase in LC depth with IOP elevation. LC depth universally increased in depth when measured against a sclera reference plane. Choroidal (-0.5222 µm/mm Hg, P < 0.001) and retinal nerve fiber layer thickness (-0.0717 µm/mm Hg, P < 0.001) significantly thinned with increasing IOP. The magnitude of LC depth change with IOP was significantly smaller with increasing age (P < 0.03 for all reference planes). Conclusions: LC depth changes with IOP reduce with age and are significantly affected by the reference plane of choice, which highlights a need for standardizing LC metrics to properly follow progressive remodeling of the loadbearing tissues of the ONH by OCT imaging and for the definition of a reference database.

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.

Choriocapillaris Impairment Is Associated With Delayed Rod-Mediated Dark Adaptation in Age-Related Macular Degeneration.

Purpose: Progress toward treatment and prevention of age-related macular degeneration (AMD) requires imaging end points that relate to vision. We investigated choriocapillaris flow signal deficits (FD%) and visual function in eyes of individuals aged ≥60 years, with and without AMD. Methods: One eye of each participant in the baseline visit of the Alabama Study on Early Age-Related Macular Degeneration 2 (ALSTAR2; NCT04112667) was studied. AMD presence and severity was determined using the Age-Related Eye Disease Study (AREDS) grading system. FD% was quantified using macular spectral domain optical coherence tomography angiography (OCTA) scans. Vision tests included rod-mediated dark adaptation (RMDA), best-corrected visual acuity, and contrast sensitivity (photopic and mesopic), and microperimetric light sensitivity (scotopic, mesopic, and photopic). Presence of subretinal drusenoid deposits (SDD) was determined using multimodal imaging. Results: In 410 study eyes of 410 participants (mean [SD] age = 71.7 years [5.9]), FD% was higher in early AMD (mean [SD] = 54.0% [5.5], N = 122) and intermediate AMD (59.8% [7.4], N = 92), compared to normal (52.1% [5.3], N = 196) eyes. Among visual functions evaluated, RMDA showed the strongest association with FD% (r = 0.35, P < 0.0001), followed by contrast sensitivity (r = -0.22, P < 0.0001). Eyes with SDD had worse FD% (58.3% [7.4], N = 87), compared to eyes without SDD (53.4% [6.0], N = 323, P = < 0.0001). Conclusions: Choriocapillaris FD% were associated with AMD severity and with impaired vision, especially RMDA. Reduced metabolic transport and exchange across the choriocapillaris-Bruch's membrane retinal pigment epithelium (RPE) complex, a causal factor for high-risk soft drusen formation, also may impair photoreceptor sustenance from the circulation. This includes retinoid resupply, essential to dynamic rod function.

Discernibility of the Interdigitation Zone (IZ), a Potential Optical Coherence Tomography (OCT) Biomarker for Visual Dysfunction in Aging.

PURPOSE: Photoreceptor (PR) outer segments, retinal pigment epithelium apical processes, and inter-PR matrix contribute to the interdigitation zone (IZ) of optical coherence tomography (OCT). We hypothesize that this interface degrades over adulthood, in concert with a delay of rod mediated dark adaptation (RMDA). To explore this idea, we determined IZ discernibility and RMDA in younger and older adults. METHODS: For this cross-sectional study, eyes of 20 young (20-30 years) and 40 older (≥60 years) participants with normal maculas according to the AREDS 9-step grading system underwent OCT imaging and RMDA testing at 5° superior to the fovea. Custom FIJI plugins enabled analysis for IZ discernibility at 9 eccentricities in 0.5 mm steps on one single horizontal B-scan through the fovea. Locations with discernible IZ met two criteria: visibility on B-scans and a distinct peak on a longitudinal reflectivity profile. The frequency of sites meeting both criteria was compared between both age groups and correlated with rod intercept time (RIT). RESULTS: The median number of locations with discernible IZ was significantly higher (foveal, 4 vs. 0, p = 0.0099; extra-foveal 6 vs. 0, p < 0.001) in eyes of young (26 ± 3 years) compared to older (73 ± 5 years) participants. For the combined young and older sample, the higher frequency of discernible IZ was correlated with shorter RIT (faster dark adaptation) (rs = -0.56, p < 0.0001). This association was significant within young eyes (rs = -0.54; p = 0.0134) and not within older eyes (rs = -0.29, p = 0.706). CONCLUSIONS: Results suggest that the interface between outer segments and apical processes degrades in normal aging, potentially contributing to delayed rod-mediated dark adaptation. More research is needed to verify an age-related association between IZ discernibility and rod-mediated dark adaptation. If confirmed in a large sample, IZ discernibility might prove to be a valuable biomarker and predictor for visual function in aging.

Compensatory Growth Is Accompanied by Changes in Insulin-Like Growth Factor 1 but Not Markers of Cellular Aging in a Long-Lived Seabird.

AbstractDeveloping organisms often plastically modify growth in response to environmental circumstances, which may be adaptive but is expected to entail long-term costs. However, the mechanisms that mediate these growth adjustments and any associated costs are less well understood. In vertebrates, one mechanism that may be important in this context is the highly conserved signaling factor insulin-like growth factor 1 (IGF-1), which is frequently positively related to postnatal growth and negatively related to longevity. To test this idea, we exposed captive Franklin's gulls (Leucophaeus pipixcan) to a physiologically relevant nutritional stressor by restricting food availability during postnatal development and examined the effects on growth, IGF-1, and two potential biomarkers of cellular and organismal aging (oxidative stress and telomeres). During food restriction, experimental chicks gained body mass more slowly and had lower IGF-1 levels than controls. Following food restriction, experimental chicks underwent compensatory growth, which was accompanied by an increase in IGF-1 levels. Interestingly, however, there were no significant effects of the experimental treatment or of variation in IGF-1 levels on oxidative stress or telomeres. These findings suggest that IGF-1 is responsive to changes in resource availability but is not associated with increased markers of cellular aging during development in this relatively long-lived species.

Macular and Plasma Xanthophylls Are Higher in Age-related Macular Degeneration than in Normal Aging: Alabama Study on Early Age-related Macular Degeneration 2 Baseline.

Purpose: Quantification of retinal xanthophyll carotenoids in eyes with and without age-related macular degeneration (AMD) via macular pigment optical volume (MPOV), a metric for xanthophyll abundance from dual wavelength autofluorescence, plus correlations to plasma levels, could clarify the role of lutein (L) and zeaxanthin (Z) in health, AMD progression, and supplementation strategies. Design: Cross-sectional observational study (NCT04112667). Participants: Adults ≥ 60 years from a comprehensive ophthalmology clinic, with healthy maculas or maculas meeting fundus criteria for early or intermediate AMD. Methods: Macular health and supplement use was assessed by the Age-related Eye Disease Study (AREDS) 9-step scale and self-report, respectively. Macular pigment optical volume was measured from dual wavelength autofluorescence emissions (Spectralis, Heidelberg Engineering). Non-fasting blood draws were assayed for L and Z using high-performance liquid chromatography. Associations among plasma xanthophylls and MPOV were assessed adjusting for age. Main Outcome Measures: Age-related macular degeneration presence and severity, MPOV in fovea-centered regions of radius 2.0° and 9.0°; plasma L and Z (µM/ml). Results: Of 809 eyes from 434 persons (89% aged 60-79, 61% female), 53.3% eyes were normal, 28.2% early AMD, and 18.5% intermediate AMD. Macular pigment optical volume 2° and 9° were similar in phakic and pseudophakic eyes, which were combined for analysis. Macular pigment optical volume 2° and 9° and plasma L and Z were higher in early AMD than normal and higher still in intermediate AMD (P < 0.0001). For all participants, higher plasma L was correlated with higher MPOV 2° (Spearman correlation coefficient [Rs] = 0.49; P < 0.0001). These correlations were significant (P < 0.0001) but lower in normal (Rs = 0.37) than early and intermediate AMD (Rs = 0.52 and 0.51, respectively). Results were similar for MPOV 9°. Plasma Z, MPOV 2°, and MPOV 9° followed this same pattern of associations. Associations were not affected by supplement use or smoking status. Conclusions: A moderate positive correlation of MPOV with plasma L and Z comports with regulated xanthophyll bioavailability and a hypothesized role for xanthophyll transfer in soft drusen biology. An assumption that xanthophylls are low in AMD retina underlies supplementation strategies to reduce progression risk, which our data do not support. Whether higher xanthophyll levels in AMD are due to supplement use cannot be determined in this study.

Biologically Guided Optimization of Test Target Location for Rod-mediated Dark Adaptation in Age-related Macular Degeneration: Alabama Study on Early Age-related Macular Degeneration 2 Baseline.

Purpose: We evaluate the impact of test target location in assessing rod-mediated dark adaptation (RMDA) along the transition from normal aging to intermediate age-related macular degeneration (AMD). We consider whether RMDA slows because the test locations are near mechanisms leading to or resulting from high-risk extracellular deposits. Soft drusen cluster under the fovea and extend to the inner ring of the ETDRS grid where rods are sparse. Subretinal drusenoid deposits (SDDs) appear first in the outer superior subfield of the ETDRS grid where rod photoreceptors are maximal and spread toward the fovea without covering it. Design: Cross-sectional. Participants: Adults ≥ 60 years with normal older maculas, early AMD, or intermediate AMD as defined by the Age-Related Eye Disease Study (AREDS) 9-step and Beckman grading systems. Methods: In 1 eye per participant, RMDA was assessed at 5° and at 12° in the superior retina. Subretinal drusenoid deposit presence was identified with multi-modal imaging. Main Outcome Measures: Rod intercept time (RIT) as a measure of RMDA rate at 5° and 12°. Results: In 438 eyes of 438 persons, RIT was significantly longer (i.e., RMDA is slower) at 5° than at 12° for each AMD severity group. Differences among groups were bigger at 5° than at 12°. At 5°, SDD presence was associated with longer RIT as compared to SDD absence at early and intermediate AMD but not in normal eyes. At 12°, SDD presence was associated with longer RIT in intermediate AMD only, and not in normal or early AMD eyes. Findings were similar in eyes stratified by AREDS 9-step and Beckman systems. Conclusions: We probed RMDA in relation to current models of deposit-driven AMD progression organized around photoreceptor topography. In eyes with SDD, slowed RMDA occurs at 5° where these deposits typically do not appear until later in AMD. Even in eyes lacking detectable SDD, RMDA at 5° is slower than at 12°. The effect at 5° may be attributed to mechanisms associated with the accumulation of soft drusen and precursors under the macula lutea throughout adulthood. These data will facilitate the design of efficient clinical trials for interventions that aim to delay AMD progression.

Retinal electrophysiologic response to IOP elevation in living human eyes.

PURPOSE: The relationships between intraocular pressure (IOP), ocular perfusion pressure (OPP), retinal perfusion, and retinal electrophysiologic responses have been explored experimentally across several animal models. These studies have demonstrated that elevated IOP reduces OPP, and when this reduction in OPP exceeds the autoregulatory capacity of the retina vasculature, retinal perfusion and electrophysiologic responses are reduced. This study aimed to evaluate these interactions for the first time in the living human eye. METHODS: Five eyes from three research-consented brain-dead organ donors underwent optical coherence tomography with angiographic (OCT/A; Spectralis, Heidelberg Engineering) and electroretinographic (ERG, Diagnosys LLC) measurements while IOP was manometrically-elevated stepwise to pressures of 10, 30 and 50 mmHg. Systemic blood pressure (BP) was monitored continuously during testing. Correlation analysis was applied to assess association between ERG and OPP changes. In a single eye, prolonged IOP elevation was induced with viscoelastic injection and serial ERG measurements were obtained. RESULTS: Reductions in inner retinal function defined by photopic ERG were observed with elevation in IOP and concomitant reduction in OPP. Reductions, especially in b-wave, and photopic negative response (PhNR) amplitudes and implicit times were significantly correlated with elevation in IOP and reduction in OPP. There were more appreciable changes in perfusion and functional responses in eyes tested while systemic blood pressure was lower. With prolonged IOP elevation, selective loss of the PhNR response was observed. CONCLUSIONS: In the living human eye, retinal perfusion and inner retinal function are acutely impacted by elevation of IOP, and this impact is related to systemic BP and OPP. This novel approach provides a viable model to study the autoregulatory responses to IOP elevation in the living human eye.

Comparing Rod-Mediated Dark Adaptation in Older Adults before and after Cataract Surgery.

PURPOSE: Studies on age-related macular degeneration often use rod-mediated dark adaptation (RMDA) to evaluate macular functional health, studying eyes with cataract and pseudophakic eyes within the same sample. We examine a poorly understood issue-whether rod intercept time (RIT), a measure of RMDA, changes after cataract surgery and intraocular lens (IOL) insertion as compared to RIT before cataract surgery. Cataract may serve as a filter reducing photo-bleach magnitude prior to surgery, biasing RMDA interpretation. METHODS: A pre-/post-cataract surgery design was used. Persons with nuclear sclerotic and/or cortical cataract per the electronic health record were enrolled. Prior to cataract surgery, visual acuity, RMDA, and the LOCS III classification documenting cataract presence/severity were measured. Thirty days after surgery (mean), visual acuity and RMDA were repeated, followed by fundus photos to document macular health. RESULTS: Twenty-four participants (mean age 72.7 years, standard deviation 5.6) enrolled. All eyes had nuclear sclerotic and nuclear color cataract; 68% had cortical cataract. All IOLs were monofocal with 21 having blue blocking characteristics and 3 had clear IOLs. Most eyes had higher RIT post-surgery (15.6 min, SD 6.7) as compared to pre-surgery (13.7 min, SD 6.4), p = 0.0006, meaning that RMDA was slower post-surgery. Eyes with moderate cataract (<4 on any LOCS III grade) had RIT that increased on average by 0.7 min; those with more advanced cataract (≥4) had RIT that increased by 3.1 min (p = 0.0116). Results were unchanged when clear IOLs were removed from analysis. CONCLUSION: RMDA was significantly slower (RIT was greater) following cataract surgery, with the greatest impact on RIT in older eyes after surgery for more advanced cataract. These findings suggest that persons with more advanced cataract may bias results when evaluating RMDA using RIT.

Impact of the Aging Lens and Posterior Capsular Opacification on Quantitative Autofluorescence Imaging in Age-Related Macular Degeneration.

Purpose: The purpose of this study was to investigate quantitative autofluorescence (qAF8) in patients with and without early or intermediate age-related macular degeneration (AMD); to determine the impact of the aged crystalline lens and posterior capsular opacification (PCO). Methods: In phakic and pseudophakic eyes ≥60 years, AMD status was determined by the Beckman system. PCO presence and severity was extracted from clinical records. qAF8 was calculated using custom FIJI plugins. Differences in qAF8, stratified by lens status, PCO severity, and AMD status, were analyzed using generalized estimating equations. Results: In 210 eyes of 115 individuals (mean age = 75.7 ± 6.6 years), qAF8 was lower in intermediate AMD compared to early AMD (P = 0.05). qAF8 did not differ between phakic and pseudophakic eyes (P = 0.8909). In phakic (n = 83) and pseudophakic (n = 127) eyes considered separately, qAF8 did not differ by AMD status (P = 0.0936 and 0.3494, respectively). Qualitative review of qAF images in phakic eyes illustrated high variability. In pseudophakic eyes, qAF8 did not differ with PCO present versus absent (54.5% vs. 45.5%). Review of implanted intraocular lenses (IOLs) revealed that 43.9% were blue-filter IOLs. Conclusions: qAF8 was not associated with AMD status, up to intermediate AMD, considering only pseudophakic eyes to avoid noisy images in phakic eyes. In pseudophakic eyes, qAF8 was not affected by PCO. Because blue-filter IOLs may reduce levels of exciting light for qAF8, future studies investigating qAF in eyes with different IOL types are needed. Translational Relevance: To reduce variability in observational studies and clinical trials requiring qAF8, pseudophakic participants without blue-filter IOLs or advanced PCO should be preferentially enrolled.

Otoliths suggest lifespans more than 30 years for free-living bowfin Amia calva: Implications for fisheries management in the bowfishing era.

The bowfin Amia calva is an amiid (Amiiformes) relict native to North America. It is the last surviving member of the Halecomorphi, a group of fishes that evolved more than 250 million years ago. Despite the phylogenetic significance of the amiids in vertebrate evolution, little has been published about their age and growth. Recreational bowfin harvest is currently unregulated throughout most of the USA, yet new recreational fisheries are emerging. As such, bowfin are increasingly harvested by sport bowfishing without limit, in addition to their growing commercial harvest for caviar. From 2017 to 2021 we studied a total of 81 bowfin from 11 populations across the east-west gradient of Minnesota within a narrow latitudinal margin (<50 km) of the 46th parallel north. We compared the allometry and translucence of bowfin asteriscus, lapillus and sagittal otoliths and found the lapillus otoliths provide consistent readability for age estimation despite being the smallest of the set. Size-at-age data derived from otoliths indicated that bowfin are sexually dimorphic in asymptotic length and may live up to 33 years, which is 15 years longer than previously estimated in wild populations, but comparable to what has been reported in captivity. Overall, 28% of the otolith-aged fish were estimated as older than the previously reported maximum age for wild bowfin populations. Our findings suggest that the bowfin life history may exhibit slower growth, greater longevity, and more variable recruitment than previously recognized, which sets the stage for more otolith-derived population demographics across their range and age validation study. Our results have direct implications for conservation of bowfin, especially amidst the increasing rates of exploitation during the bowfishing era.

How Vision Is Impaired From Aging to Early and Intermediate Age-Related Macular Degeneration: Insights From ALSTAR2 Baseline.

Purpose: We hypothesize the first visual dysfunction in transitioning to early and intermediate age-related macular degeneration (AMD) is delayed rod-mediated dark adaptation (RMDA), owing to impaired photoreceptor sustenance from the circulation. This analysis from the Alabama Study on Early Age-related Macular Degeneration 2 provides insight on our framework's validity, comparing RMDA and other visual tests among older normal, early, and intermediate AMD eyes. Methods: AMD disease severity was determined via fundus photos using the Age-Related Eye Disease Study nine-step system. Visual functions evaluated were RMDA 5°, acuity, contrast sensitivity (photopic, mesopic), and light sensitivity for a macular grid (scotopic, mesopic, photopic). Presence versus absence of subretinal drusenoid deposits (SDD) was identified through multimodal imaging. Results: One eye from each of 481 persons (mean age, 72 years) was evaluated. All visual functions were significantly worse with increasing AMD disease severity. Using z-scores to standardize visual function measures across groups, the greatest difference in probability density functions between older normal and intermediate AMD was for RMDA. Early and intermediate AMD eyes with SDD present had longer rod intercept times than eyes with SDD absent. SDD absent eyes also exhibited delayed RMDA and wide probability density functions relative to normal eyes. Conclusions: Among the visual functions evaluated, RMDA best discriminates among normal, early AMD, and intermediate AMD eyes. The Alabama Study on Early Age-related Macular Degeneration 2 will evaluate whether AMD's natural history confirms our hypothesis at the 3-year follow-up. Translational Relevance: Results support a sequence of visual function impairments in aging and AMD, suggesting RMDA as a promising outcome for evaluating interventions in early disease.

Spatial Dissociation of Subretinal Drusenoid Deposits and Impaired Scotopic and Mesopic Sensitivity in AMD.

Purpose: Subretinal drusenoid deposits (SDD) first appear in the rod-rich perifovea and can extend to the cone-rich fovea. To refine the spatial relationship of visual dysfunction with SDD burden, we determined the topography of mesopic and scotopic light sensitivity in participants with non-neovascular AMD with and without SDD. Methods: Thirty-three subjects were classified into three groups: normal (n = 9), AMD-Drusen (with drusen and without SDD; n = 12), and AMD-SDD (predominantly SDD; n = 12). Mesopic and scotopic microperimetry were performed using 68 targets within the Early Treatment Diabetic Retinopathy Study grid, including points at 1.7° from the foveal center (rod:cone ratio, 0.35). Age-adjusted linear regression was used to compare mesopic and scotopic light sensitivities across groups. Results: Across the entire Early Treatment Diabetic Retinopathy Study grid and within individual subfields, the three groups differed significantly for mesopic and scotopic light sensitivities (all P < 0.05). The AMD-SDD group exhibited significantly decreased mesopic and scotopic sensitivity versus both the normal and the AMD-Drusen groups (all P < 0.05), while AMD-Drusen and normal eyes did not significantly differ (all P > 0.05). The lowest relative sensitivities were recorded for scotopic light levels, especially in the central subfield, in the AMD-SDD group. Conclusions: SDD-associated decrements in rod-mediated vision can be detected close to the foveola, and these deficits are proportionately worse than functional loss in the rod-rich perifovea. This finding suggests that factors other than the previously hypothesized direct cytotoxicity to photoreceptors and local transport barrier limitations may negatively impact vision. Larger prospective studies are required to confirm these observations.

No evidence of physiological declines with age in an extremely long-lived fish.

Although the pace of senescence varies considerably, the physiological systems that contribute to different patterns of senescence are not well understood, especially in long-lived vertebrates. Long-lived bony fish (i.e., Class Osteichthyes) are a particularly useful model for studies of senescence because they can readily be aged and exhibit some of the longest lifespans among vertebrates. In this study we examined the potential relationship between age and multiple physiological systems including: stress levels, immune function, and telomere length in individuals ranging in age from 2 to 99 years old in bigmouth buffalo (Ictiobus cyprinellus), the oldest known freshwater teleost fish. Contrary to expectation, we did not find any evidence for age-related declines in these physiological systems. Instead, older fish appeared to be less stressed and had greater immunity than younger fish, suggesting age-related improvements rather than declines in these systems. There was no significant effect of age on telomeres, but individuals that may be more stressed had shorter telomeres. Taken together, these findings suggest that bigmouth buffalo exhibit negligible senescence in multiple physiological systems despite living for nearly a century.