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Background: Drusen are extracellular lesions characteristic of aging and age-related maculopathy, a major retinal disease of the elderly. We determined the relative proportions of lipids and proteins in drusen capped with retinal pigment epithelium (RPE) and in RPE isolated from non-macular regions of 36 human retinas with grossly normal maculas obtained ,6 hr after death. Methodology/Principal Findings: Druse pellets were examined by light and electron microscopy. Component proteins were extracted using novel methods for preserved tissues, separated, subjected to tryptic digestion and LC-MS(MS)2 analysis using an ion trap mass spectrometer, and identified with reference to databases. Lipid classes were separated using thin layer chromatography and quantified by densitometry. Major druse components were esterified cholesterol (EC), phosphatidylcholine (PC), and protein (37.5±13.7, 36.9±12.9, and 43.0±11.5 ng/druse, respectively). Lipid-containing particles (median diameter, 77 nm) occupied 37-44% of druse volume. Major proteins include vitronectin, complement component 9, apoE, and clusterin, previously seen in drusen, and ATP synthase subunit b, scavenger receptor B2, and retinol dehydrogenase 5, previously seen in RPE. Drusen and RPE had similar protein profiles, with higher intensities and greater variability in drusen. C8, part of the complement membrane attack complex, was localized in drusen by immunofluorescence. Conclusions/Significance: At least 40% of druse content is comprised by lipids dominated by EC and PC, 2 components that are potentially accounted for by just one pathway, the secretion of lipoproteins by RPE. Manipulating genes encoding apolipoprotein pathways would be a fruitful approach to producing drusen with high EC content in laboratory animals. Therapies that directly mitigate drusen should prepare for the substantial volume of neutral lipids. The catalog of major druse proteins is nearing completion. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

The bigmouth buffalo (Ictiobus cyprinellus) is an iconic freshwater fish native to North America that is in decline. Recent studies have revealed bigmouth buffalo exhibit a slow pace of life, yet demographic information on bigmouth buffalo outside of North Dakota and Minnesota is lacking. We used otoliths to investigate population demographics of bigmouth buffalo in Canada, and also monitored bigmouth buffalo spawning frequency and reproductive success in the wild. From a sample of 52 fish collected during 2018–2021 we found bigmouth buffalo from the Qu'Appelle system more than 125 years old. Only 13 year classes ranging from 1894–1997 were evident with one year class since 1948, indicating recruitment has been episodic. During the past decade (2013–2022) bigmouth buffalo have spawned only once (May 2013) in Buffalo Pound Lake. This spawning effort culminated in recruitment failure because the water-level recession rate was too rapid. Our findings indicate that bigmouth buffalo spawning attempts as well as recruitment occur within a narrow range of water-level fluctuations that may rarely occur, which is enabled by their supercentenarian lifespan, and has direct implications for the conservation of this species. [ABSTRACT FROM AUTHOR]

This initial methods study presents the initial immunohistochemical and transcriptomic changes in the optic nerve head and retina from three research-consented brain-dead organ donors following prolonged and transient intraocular pressure (IOP) elevation. In this initial study, research-consented brain-dead organ donors were exposed to unilateral elevation of IOP for 7.5 h (Donor 1), 30 h (Donor 2), and 1 h (Donor 3) prior to organ procurement. Optic nerve tissue and retinal tissue was obtained following organ procurement for immunohistological and transcriptomic analysis. Optic nerve sections in Donor 1 exposed to 7.5-hours of unilateral sub-ischemic IOP elevation demonstrated higher levels of protein expression of the astrocytic marker, glial fibrillary acidic protein (GFAP), within the lamina cribrosa with greatest expression inferior temporally in the treated eye compared to control. Spatial transcriptomic analysis performed on optic nerve head tissues from Donor 2 exposed to 30 h of unilateral IOP elevation demonstrated differential transcription of mRNA across laminar and scleral regions. Immunohistochemistry of retinal sections from Donor 2 exhibited higher GFAP and IBA1 expression in the treated eye compared with control, but this was not observed in Donor 3, which was exposed to only 1-hour of IOP elevation. While there were no differences in GFAP protein expression in the retina following the 1-hour IOP elevation in Donor 3, there were higher levels of transcription of GFAP in the inner nuclear layer, and CD44 in the retinal ganglion cell layer, indicative of astrocytic and Müller glial reactivity as well as an early inflammatory response, respectively. We found that transcriptomic differences can be observed across treated and control eyes following unilateral elevation of IOP in brain dead organ donors. The continued development of this model affords the unique opportunity to define the acute mechanotranscriptomic response of the optic nerve head, evaluate the injury and repair mechanisms in the retina in response to IOP elevation, and enable correlation of in vivo imaging and functional testing with ex vivo cellular responses for the first time in the living human eye. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • In the brain-dead organ donor eye, the inner retina is selectively impacted by acute and prolonged increases in intraocular pressure similar to small animal models of acute intraocular pressure elevation used to study the cellular and molecular response of the optic nerve and retina. [ABSTRACT FROM AUTHOR]

PURPOSE: To describe the microscopic structure of photoreceptors impacted by subretinal drusenoid deposits, also called pseudodrusen, an extracellular lesion associated with age-related macular degeneration (AMD), using adaptive optics scanning laser ophthalmoscopy (AOSLO). DESIGN: Observational case series. METHODS: We recruited 53 patients with AMD and 10 age-similar subjects who had normal retinal health. All subjects underwent color fundus photography, infrared reflectance, red-free reflectance, autofluorescence, and spectral-domain optical coherence tomography (OCT). Subretinal drusenoid deposits were classified by a 3- stage OCT-based grading system. Lesions and surrounding photoreceptors were examined by AOSLO. RESULTS: Subretinal drusenoid deposits were found in 26 eyes of 13 patients with AMD and imaged by AOSLO and spectral-domain OCT in 18 eyes (n = 342 lesions). Spectral-domain OCT showed subretinal drusenoid deposits as highly reflective material accumulated internal to the retinal pigment epithelium. AOSLO revealed that photoreceptor reflectivity was qualitatively reduced by stage 1 subretinal drusenoid deposits and was greatly reduced by stage 2. AOSLO presented a distinct structure in stage 3, a hyporeflective annulus consisting of deflected, degenerated or absent photoreceptors. A central core with a reflectivity superficially resembling photoreceptors is formed by the lesion material itself. A hyporeflective gap in the photoreceptor ellipsoid zone on either side of this core shown in spectral-domain OCT corresponded to the hyporeflective annulus seen by AOSLO. CONCLUSIONS: AOSLO and multimodal imaging of subretinal drusenoid deposits indicate solid, space-filling lesions in the subretinal space. Associated retinal reflectivity changes are related to lesion stages and are consistent with perturbations to photoreceptors, as suggested by histology. [ABSTRACT FROM AUTHOR]

Purpose: Both retinal changes and age-related macular degeneration (AMD) have been shown to be associated with Alzheimer's disease and related dementias (ADRD). In AMD, the outer retina is impacted significantly and early, but little is known about its association with cognition or changes in brain morphometry. This study investigates the relationship between retinal and brain morphometry in older adults with early and intermediate AMD., Design: Cross-sectional study., Methods: Adults ≥70 years with normal, early, and intermediate AMD were recruited from Callahan Eye Hospital Clinics at the University of Alabama at Birmingham. Participants underwent cognitive testing, optical coherence tomography, and magnetic resonance imaging. Associations of retinal layer thickness with brain volume and thickness of specific brain regions were evaluated utilizing multivariable linear regression. The relevance of retinal thickness variables in brain volumetrics was quantified using least absolute shrinkage and selection operator regression models. Correlations between demographic variables, cognitive scores, and brain morphometry were evaluated., Results: Participants with thinner outer retina had significantly smaller hippocampus (β = 0.019, P = .022), lower occipital cortex regions of interest (occipital ROIs) thickness (β = 5.68, P = .020), and lower cortical thickness in ADRD-related brain regions (β = 7.72, P = .006). People with thinner total retina had significantly lower occipital ROIs (β = 3.19, P = .009) and ADRD-related brain region (β = 3.94, P = .005) thickness. Outer retinal thickness in the outer Early Treatment of Diabetic Retinopathy Study ring was the most frequently reported retinal variable associated with brain morphometry on least absolute shrinkage and selection operator regression. Total gray matter volume showed positive correlations with education (Pearson's r = 0.30, P = .022)., Conclusions: In older adults with normal retinal aging and early and intermediate AMD, thinner outer retina had specific associations with brain regions primarily involved in vision and cognition, such as lower hippocampal volume and lower thickness of the occipital ROIs and brain regions known to show early structural changes in dementia., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The bigmouth buffalo Ictiobus cyprinellus (Catostomidae) is a freshwater fish native to North America that is known for its longevity. During the 1970s, the bigmouth buffalo was recorded as declining in Canada, Minnesota, and North Dakota and became a protected species in Canada. In the USA, population declines are exacerbated by wasteful recreational bowfishing, lack of fisheries management, and overall lack of knowledge. However, recent studies have revealed the exceptional lifespan of bigmouth buffalo, their negligible senescence, slow growth, delayed maturity, and episodic recruitment. Yet little is known about the spawning phenology of bigmouth buffalo, nor their age demographics in east central Minnesota. In this 2021-2023 study of bigmouth buffalo from Rice Lake National Wildlife Refuge we found that 99.7% (389 of 390) of the extant population hatched prior to 1972 despite annual spawning in Rice Lake. Moreover, recruitment success declined significantly since water control measures were established (1953). We found males arrive to spawning grounds with females but depart later, that both the midpoint and duration of spawn significantly vary across years, and that more massive females of the same age range invest disproportionately more in ovaries. Extensive post-spawn seining revealed bigmouth buffalo young-of-the-year in low numbers, but by mid-to-late summer they were no longer evident having likely succumbed to predation. Overall, these findings thoroughly reveal one of the oldest populations of vertebrate currently known (median age of 79 years as of 2024) and expose the stark vulnerability of a bigmouth buffalo population for which substantial recruitment has not occurred for more than six decades. Multiple lines of evidence indicate that the long-lived bigmouth buffalo is vulnerable, that a precautionary approach is immediately needed, and that the unlimited and unregulated kill-fishery be closed., (© 2024. The Author(s).)

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.

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.

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.

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.

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., (© 2024 S. Karger AG, Basel.)

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.

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., (© 2023 Published by Elsevier Inc. on behalf of American Academy of Ophthalmology.)

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 [R s ] = 0.49; P < 0.0001). These correlations were significant ( P  < 0.0001) but lower in normal (R s  = 0.37) than early and intermediate AMD (R s  = 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., (© 2022 Published by Elsevier Inc. on behalf of American Academy of Ophthalmology.)