Linking physiology and demographics, non-ocular pathology and pharmaceutical drug use to standard OCT measures of the inner retina: The PPP project.

PURPOSE: To assess the associations between physiology and demographics, non-ocular pathology and pharmaceutical drug use against peri-papillary retinal nerve fibre layer thickness (pRNFL T) and other optical coherence tomography (OCT) inner retinal measures in normal, healthy eyes. METHODS: A retrospective, cross-sectional study of 705 consecutive participants with bilateral normal, healthy optic nerves and maculae. PRNFL Ts, vertical cup/disc ratio (CDR), cup volume and macular ganglion cell layer-inner plexiform layer (GCL-IPL) Ts were extracted from Cirrus OCT scans, then regressed against predictor variables of participants' physiology and demographics (eye laterality, refraction, intraocular pressure [IOP], age, sex, race/ethnicity, etc.) and non-ocular pathology and pharmaceutical drug use according to the World Health Organisation classifications. Associations were assessed for statistical significance (p < 0.05) and clinical significance (|ß| > 95% limits of agreement for repeated measures). RESULTS: A multitude of non-ocular pathology and pharmaceutical drug use were statistically and clinically significantly associated with deviations in standard OCT inner retinal measures, exceeding the magnitude of other factors such as age, IOP and race/ethnicity. Thinner inner retina and larger optic nerve cup measures were linked to use of systemic corticosteroids, sex hormones/modulators, presence of vasomotor/allergic rhinitis and other diseases and drugs (up to -29.3 [-49.88, -8.72] µm pRNFL T, 0.31 [0.07, 0.54] vertical CDR, 0.29 [0.03, 0.54] mm3 cup volume and -10.18 [-16.62, -3.74] µm macular GCL-IPL T; all p < 0.05). Thicker inner retina and smaller optic nerve cup measures were diffusely associated with use of antineoplastic agents, presence of liver or urinary diseases and other diseases and drugs (up to 67.12 [64.92, 69.31] µm pRNFL T, -0.31 [-0.53, -0.09] vertical CDR, -0.06 [-0.11, 0] mm3 cup volume and 28.84 [14.51, 43.17] µm macular GCL-IPL T; all p < 0.05). CONCLUSION: There are a multitude of systemic diseases and drugs associated with altered OCT inner retinal measures, with magnitudes far exceeding those of other factors such as age, IOP and race/ethnicity. These systemic factors should at least be considered during OCT assessments to ensure precise interpretation of normal versus pathological inner retinal health.

Retinal sensitivity changes in early/intermediate AMD: a systematic review and meta-analysis of visual field testing under mesopic and scotopic lighting.

Visual fields under mesopic and scotopic lighting are increasingly being used for macular functional assessment. This review evaluates its statistical significance and clinical relevance, and the optimal testing protocol for early/intermediate age-related macular degeneration (AMD). PubMed and Embase were searched from inception to 14/05/2022. All quality assessments were performed according to GRADE guidelines. The primary outcome was global mean sensitivity (MS), further meta-analysed by: AMD classification scheme, device, test pattern, mesopic/scotopic lighting, stimuli size/chromaticity, pupil dilation, testing radius (area), background luminance, adaptation time, AMD severity, reticular pseudodrusen presence, and follow-up visit. From 1489 studies screened, 42 observational study results contributed to the primary meta-analysis. Supported by moderate GRADE certainty of the evidence, global MS was significantly reduced across all devices under mesopic and scotopic lighting with large effect size (-0.9 [-1.04, -0.75] Hedge's g, P < 0.0001). The device (P < 0.01) and lighting (P < 0.05) used were the only modifiable factors affecting global MS, whereby the mesopic MP-1 and MAIA produced the largest effect sizes and exceeded test-retest variabilities. Global MS was significantly affected by AMD severity (intermediate versus early AMD; -0.58 [-0.88, -0.29] Hedge's g or -2.55 [3.62, -1.47] MAIA-dB) and at follow-up visit (versus baseline; -0.62 [-0.84, -0.41] Hedge's g or -1.61[-2.69, -0.54] MAIA-dB). Magnitudes of retinal sensitivity changes in early/intermediate AMD are clinically relevant for the MP-1 and MAIA devices under mesopic lighting within the central 10° radius. Other factors including pupil dilation and dark adaptation did not significantly affect global MS in early/intermediate AMD.

OCTA Signal Quality Augmentation Using the Isometric Handgrip Test to Maximize Vascular Flow (SQUEEZE): A Randomized Crossover Trial.

Purpose: To determine if performing the isometric handgrip test (IHGT) can augment optical coherence tomography angiography (OCTA) vascular signal quality in eyes with macular abnormalities. Methods: A randomized, single-blinded crossover trial was conducted including 36 participants with macular abnormalities, randomized to undergo OCTA with or without the IHGT, then crossed over to the alternate "intervention" after 1 minute. The primary outcome was OCTA signal quality after 1 minute of squeezing at 50% maximum grip strength. Secondary outcomes were other measures of vascular flow and systemic blood pressure (BP), also regressed against person- and eye-level covariables. Results: Primary analysis of OCTA signal quality with versus without the IHGT was nonsignificant (P = 0.73). Nested analyses showed that the IHGT resulted in increased OCTA B-scan retinal vascular flow signal (2.95 [-1.64 to 7.55] Δ%, P < 0.05) and increased systolic BP, diastolic BP, pulse pressure, and mean arterial pressure (4.94 [0.41 to 9.47] to 12.38 [8.01 to 16.75] mm Hg, P < 0.05). OCTA signal quality and en face vessel density and perfusion changes were associated with sex, refraction, race/ethnicity, and right-hand IHGT use (P < 0.05). Greater increases in systolic and diastolic BP and mean arterial pressure were generally associated with right-hand IHGT use and greater maximum grip strength (P < 0.09). Conclusions: The IHGT can temporarily increase OCTA B-scan retinal vascular flow signal in participants with macular abnormalities. IHGT-induced changes to systemic BP appear to be linked to absolute (rather than relative) grip strength, implying that the IHGT may be ineffective with low grip strength. Further research in larger populations is warranted. Translational Relevance: This study provides early validation that the IHGT may augment OCTA output, which may lead to improved noninvasive detection of pathologic vascular changes.

Spatial Analysis Reveals Vascular Changes in Retinal and Choroidal Vessel Perfusion in Intermediate AMD With Reticular Pseudodrusen.

Purpose: To examine the effect of reticular pseudodrusen (RPD) on retinal and choroidal vessel perfusion (VP) topography in intermediate age-related macular degeneration (iAMD) using refined spatial analyses. Methods: This was a retrospective cross-sectional study of 120 individuals with 30 iAMDRPD, 60 iAMDno_RPD, and 30 normal eyes, propensity-score matched by age, sex, and presence of cardiovascular-related disease. VP of the superficial and deep retinal and choriocapillaris vascular slabs was assessed from 6 × 6-mm optical coherence tomography angiography (OCTA) scans divided into 126 × 126 grids, with adjustment for various person- and eye-level factors. Grid-wise VP differences (%) among the groups were spatially assessed according to analyses based on the Early Treatment for Diabetic Retinopathy Study (ETDRS), eccentricity (µm), and degree (°). Results: VP was significantly decreased between iAMDRPD and iAMDno_RPD, across all vascular slabs in various ETDRS sectors (up to -2.16%; 95% confidence interval, -2.99 to -1.34; P < 0.05). Eccentricity analyses revealed more complex patterns: a bisegmented relationship where VP in iAMDRPD eyes decreased linearly toward 1000 µm then returned toward similar values as iAMDno_RPD, plateauing around 2000 µm in the superficial and 3000 µm in the deep retina (R2 = 0.57-0.9; P < 0.001). Degree-based analysis further showed that the greatest VP differences in iAMDRPD eyes were commonly located superiorly and nasally across all vascular slabs (P < 0.05). Conclusions: RPD appears to compound the vascular impact of iAMD, displaying complex spatial patterns beyond the ETDRS sectors. This highlights the importance of considering spatial delineations for future work regarding the role of RPD and vascular dysfunction.

Retinal vessel diameters in intermediate age-related macular degeneration using en face optical coherence tomography.

CLINICAL RELEVANCE: Clinical assessment of age-related macular degeneration (AMD) relies on biomarkers that do not necessarily reflect the contributions of vascular dysfunction. Validation of clinically accessible methods of measuring retinal vascular integrity could provide a more holistic understanding of AMD-related changes to facilitate appropriate care. BACKGROUND: There is conflicting evidence if retinal vessel calibre is significantly altered in the early stages of AMD. This study examined the outer and inner diameters of first order retinal vessels in intermediate AMD eyes using en face optical coherence tomography (OCT). METHODS: Retinal en face (6 × 6 mm) OCT images were examined in a single eye of participants with intermediate AMD (n = 46) versus normal macula (n = 43) for arterioles (all identifiable) and venules (40/46 and 39/43 identifiable). All participants were aged ≥50 years without diabetes mellitus, hypertension, or other systemic vascular disease. RESULTS: Intra- and inter-grader agreement was good-to-excellent for all en face OCT measurements of arteriole and venule diameters (intraclass correlation coefficient = 0.87 to 0.99). Arteriolar outer diameters (82.3 ± 19.8 µm vs 73.8 ± 16.1 µm; p < 0.05) and inner diameters (35.1 ± 8.4 µm vs 31.5 ± 8.1 µm; p < 0.05) were significantly greater in AMD eyes compared to normal eyes. Venular inner diameter was significantly greater (43.1 ± 9.5 µm vs 39.2 ± 10.1 µm; p < 0.05), but outer diameter remained unchanged (p = 0.17) in AMD eyes compared to normal eyes. CONCLUSION: Arteriolar dilation and altered venular inner diameter were observed in intermediate AMD eyes. These results support further investigation of vascular contributions to AMD in the early stages of disease, possibly using the en face OCT imaging modality.

RPE Curvature Can Screen for Early and Intermediate AMD.

Purpose: Diagnosing AMD early optimizes clinical management. However, current diagnostic accuracy is limited by the subjectivity of qualitative diagnostic measures used in clinical practice. This study tests if RPE curvature could be an accurate, quantitative measure for AMD diagnosis. Methods: Consecutive patients without AMD or normal aging changes (n = 111), with normal aging changes (n = 107), early AMD (n = 102) and intermediate AMD (n = 114) were recruited. RPE curvature was calculated based on the sinuosity method of measuring river curvature in environmental science. RPE and Bruch's membrane were manually segmented from optical coherence tomography B-scans and then their lengths automatically extracted using customized MATLAB code. RPE sinuosity was calculated as a ratio of RPE to Bruch's membrane length. Diagnostic accuracy was determined from area under the receiver operator characteristic curve (aROC). Results: RPE sinuosity of foveal B-scans could distinguish any eyes with AMD (early or intermediate) from those without AMD (non-AMD or eyes with normal aging changes) with acceptable diagnostic accuracy (aROC = 0.775). Similarly, RPE sinuosity could identify intermediate AMD from all other groups (aROC = 0.871) and distinguish between early and intermediate AMD (aROC = 0.737). RPE sinuosity was significantly associated with known AMD lesions: reticular pseudodrusen (P < 0.0001) and drusen volume (P < 0.0001), but not physiological variables such as age, sex, and ethnicity. Conclusions: RPE sinuosity is a simple, robust, quantitative biomarker that is amenable to automation and could enhance screening of AMD.

OCT Prognostic Biomarkers for Progression to Late Age-related Macular Degeneration: A Systematic Review and Meta-analysis.

TOPIC: To evaluate which OCT prognostic biomarkers best predict the risk of progression from early/intermediate to late age-related macular degeneration (AMD). CLINICAL RELEVANCE: Among > 100 OCT prognostic biomarkers for AMD, it is unclear which are the most relevant for clinicians and researchers to focus on. This review evaluated which OCT biomarkers confer the greatest magnitude of prediction for progression to late AMD. METHODS: Study protocol was registered on PROSPERO (CRD42023400166). PubMed and Embase were searched from inception to March 2, 2023, and eligible studies assessed following the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The primary outcome was any quantified risk of progression from treatment-naive early/intermediate AMD to late AMD, including hazard ratios (HRs), odds ratios (ORs), and standardized mean differences (at baseline, between eyes with versus without progression), subgrouped by each OCT biomarker. Further meta-analyses were subgrouped by progression to geographic atrophy or neovascularization. RESULTS: A total of 114 quantified OCT prognostic biomarkers were identified. With high GRADE certainty of evidence, the greatest magnitudes of prediction to late AMD belonged to: external limiting membrane abnormality (OR, 15.42 [7.63, 31.17]), ellipsoid zone abnormality (OR, 10.8 [4.58, 25.46]), interdigitation zone abnormality (OR, 7.68 [2.57, 23]), concurrent large drusen and reticular pseudodrusen (HR, 6.73 [1.35, 33.65], hyporeflective drusen cores (HR, 2.48 [1.8, 3.4]; OR 1.85 [1.29, 2.66]), intraretinal hyperreflective foci (IHRF; HR, 2.16 [0.92, 5.07]; OR 5.08 [3.26, 7.92]), and large drusen (HR, 2.01 [1.35, 2.99]); OR, 1.98 [1.27, 3.08]). There was greater risk of geographic atrophy for IHRF and hyporeflective drusen cores (P < 0.05), and neovascularization for ellipsoid zone abnormality (P < 0.05). Other OCT biomarkers such as drusenoid pigment epithelium detachment, shallow irregular retinal pigment epithelium elevations, and nascent geographic atrophy exhibited large magnitudes of risk but required further studies for validation. CONCLUSION: This review synthesizes the 6 most relevant OCT prognostic biomarkers for AMD with greater predictive ability than large drusen alone, for clinicians and researchers to focus on. Further study is required to validate other biomarkers with less than high certainty of evidence, and assess how the copresence of biomarkers may affect risks. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Spatial Cluster Patterns of Retinal Sensitivity Loss in Intermediate Age-Related Macular Degeneration Features.

Purpose: To examine spatial patterns of retinal sensitivity loss in the three key features of intermediate age-related macular degeneration (iAMD). Methods: One-hundred individuals (53 iAMD, 47 normal) underwent 10-2 mesopic microperimetry testing in one eye. Pointwise sensitivities (dB) were corrected for age, sex, iAMD status, and co-presence of co-localized key iAMD features: drusen load, pigmentary abnormalities, and reticular pseudodrusen (RPD). Clusters (labeled by ranks of magnitude C-2, C-1, C0) were derived from pointwise sensitivities and then assessed by quadrants and eccentricity/rings. Results: Two clusters of decreased sensitivities were evident in iAMD versus normal: C-2, -1.67 dB (95% CI (confidence intervals), -2.36 to -0.98; P < 0.0001); C-1, -0.93 dB (95% CI, -1.5 to -0.36; P < 0.01). One cluster of decreased sensitivity was independently associated each with increased drusen load (13.57 µm increase per -1 dB; P < 0.0001), pigmentary abnormalities (C-1: -2.23 dB; 95% CI, -3.36 to -1.1; P < 0.01), and RPD (C-1: -1.07 dB; 95% CI, -2 to -0.14; P < 0.01). Sensitivity loss in iAMD was biased toward the superior and central macula (P = 0.16 to <0.0001), aligning with structural distributions of features. However, sensitivity loss associated with drusen load also extended to the peripheral macula (P < 0.0001) with paracentral sparing, which was discordant with the central distribution of drusen. Conclusions: Drusen load, pigmentary abnormalities, and RPD are associated with patterns of retinal sensitivity loss commonly demonstrating superior and central bias. Results highlighted that a clinical focus on these three key iAMD features using structural measures alone does not capture the complex, spatial extent of vision-related functional impairment in iAMD. Translational Relevance: Defining the spatial patterns of retinal sensitivity loss in iAMD can facilitate a targeted visual field protocol for iAMD assessment.

Derivation of human retinal cell densities using high-density, spatially localized optical coherence tomography data from the human retina.

This study sought to identify demographic variations in retinal thickness measurements from optical coherence tomography (OCT), to enable the calculation of cell density parameters across the neural layers of the healthy human macula. From macular OCTs (n = 247), ganglion cell (GCL), inner nuclear (INL), and inner segment-outer segment (ISOS) layer measurements were extracted using a customized high-density grid. Variations with age, sex, ethnicity, and refractive error were assessed with multiple linear regression analyses, with age-related distributions further assessed using hierarchical cluster analysis and regression models. Models were tested on a naïve healthy cohort (n = 40) with Mann-Whitney tests to determine generalizability. Quantitative cell density data were calculated from histological data from previous human studies. Eccentricity-dependent variations in OCT retinal thickness closely resemble topographic cell density maps from human histological studies. Age was consistently identified as significantly impacting retinal thickness (p = .0006, .0007, and .003 for GCL, INL and ISOS), with gender affecting ISOS only (p < .0001). Regression models demonstrated that age-related changes in the GCL and INL begin in the 30th decade and were linear for the ISOS. Model testing revealed significant differences in INL and ISOS thickness (p = .0008 and .0001; however, differences fell within the OCT's axial resolution. Qualitative comparisons show close alignment between OCT and histological cell densities when using unique, high-resolution OCT data, and correction for demographics-related variability. Overall, this study describes a process to calculate in vivo cell density from OCT for all neural layers of the human retina, providing a framework for basic science and clinical investigations.

Reticular Pseudodrusen Are Associated With More Advanced Para-Central Photoreceptor Degeneration in Intermediate Age-Related Macular Degeneration.

Purpose: The purpose of this study was to examine retinal topographical differences between intermediate age-related macular degeneration (iAMD) with reticular pseudodrusen (RPD) versus iAMD without RPD, using high-density optical coherence tomography (OCT) cluster analysis. Methods: Single eyes from 153 individuals (51 with iAMD+RPD, 51 with iAMD, and 51 healthy) were propensity-score matched by age, sex, and refraction. High-density OCT grid-wise (60 × 60 grids, each approximately 0.01 mm2 area) thicknesses were custom-extracted from macular cube scans, then compared between iAMD+RPD and iAMD eyes with correction for confounding factors. These "differences (µm)" were clustered and results de-convoluted to reveal mean difference (95% confidence interval [CI]) and topography of the inner retina (retinal nerve fiber, ganglion cell, inner plexiform, and inner nuclear layers) and outer retina (outer plexiform/Henle's fiber/outer nuclear layers, inner and outer segments, and retinal pigment epithelium-to-Bruch's membrane [RPE-BM]). Differences were also converted to Z-scores using normal data. Results: In iAMD+RPD compared to iAMD eyes, the inner retina was thicker (up to +5.89 [95% CI = +2.44 to +9.35] µm, P < 0.0001 to 0.05), the outer para-central retina was thinner (up to -3.21 [95% CI = -5.39 to -1.03] µm, P < 0.01 to 0.001), and the RPE-BM was thicker (+3.38 [95% CI = +1.05 to +5.71] µm, P < 0.05). The majority of effect sizes (Z-scores) were large (-3.13 to +1.91). Conclusions: OCT retinal topography differed across all retinal layers between iAMD eyes with versus without RPD. Greater para-central photoreceptor thinning in RPD eyes was suggestive of more advanced degeneration, whereas the significance of inner retinal thickening was unclear. In the future, quantitative evaluation of photoreceptor thicknesses may help clinicians monitor the potential deleterious effects of RPD on retinal integrity.

High-Density Optical Coherence Tomography Analysis Provides Insights Into Early/Intermediate Age-Related Macular Degeneration Retinal Layer Changes.

Purpose: To topographically map all of the thickness differences in individual retinal layers between early/intermediate age-related macular degeneration (AMDearly/AMDint) and normal eyes and to determine interlayer relationships. Methods: Ninety-six AMDtotal (48 AMDearly and 48 AMDint) and 96 normal eyes from 192 participants were propensity-score matched by age, sex, and refraction. Retrospective optical coherence tomography (OCT) macular cube scans were acquired, and high-density (60 × 60 0.01-mm2) grid thicknesses were custom extracted for comparison between AMDtotal and normal eyes corrected for confounding. Resultant "normal differences" underwent cluster, interlayer correlation, and dose-response analyses for the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer + Henle's fiber layer (ONL+HFL), inner and outer segment (IS/OS) thickness, and retinal pigment epithelium (RPE) to Bruch's membrane (BM) thickness. Results: AMDtotal inner retinal clusters demonstrated extensively thinned RNFL, GCL, IPL, and paracentral INL and thickened INL elsewhere, with normal difference means ranging from -8.13 µm (95% confidence interval [CI], -11.12 to -5.13) to 1.58 µm (95% CI, 1.07-2.09) (P < 0.0001 to P < 0.05). Outer retinal clusters displayed thinned paracentral OPL/ONL+HFL, central IS/OS, and peripheral RPE-BM and thickened central RPE-BM, with means ranging from -1.31 µm (95% CI, -2.06 to -0.55) to 2.99 µm (95% CI, 0.97-5.01] (P < 0.0001 to P <0.05). Effect sizes (-2.56 to 9.93 SD), cluster sizes, and eccentricity effects varied. All interlayer correlations were negligible to moderate regardless of AMD severity. Only the RPE-BM was partly thicker with greater AMD severity (up to 5.44 µm; 95% CI, 4.88-6.00; P < 0.01). Conclusions: From the early stage, AMD eyes demonstrate thickness differences compared to normal with unique topographies across all retinal layers. Poor interlayer correlations highlight that the outer retina inadequately reflects complete retinal health. The clinical importance of OCT assessment across all individual retinal layers in early/intermediate AMD requires further investigation.

Should clinical automated perimetry be considered for routine functional assessment of early/intermediate age-related macular degeneration (AMD)? A systematic review of current literature.

PURPOSE: There is growing interest in functional testing for early/intermediate age-related macular degeneration (iAMD). However, systematic evaluation of existing clinical functional tests is lacking. This systematic review examines evidence for using clinical automated perimetry in routine assessment of early/iAMD. RECENT FINDINGS: PubMed, Web of Science Core Collection, and Embase were searched from inception to October 2020 to answer, is there evidence of visual field defects in early/iAMD, and if so, are early/iAMD visual field defects linked to real-world patient outcomes? Articles using clinical automated perimetry (commercially accessible and non-modified devices/protocols) were included. Microperimetry was excluded as this has yet to be incorporated into clinical guidelines. The primary outcome was global visual field indices including mean deviation (MD), pattern standard deviation (PSD), mean sensitivity (MS) and frequency of defects. The secondary outcome was any real-world patient outcome including quality of life and/or activities of daily living indices. Twenty-six studies were eligible for inclusion and all studies were observational. There was consistent evidence of worsened MD, PSD, MS and frequency of defects for early/iAMD compared to normal eyes under photopic, low-photopic and scotopic conditions. Meta-analysis of studies using standard automated perimetry (SAP) under photopic conditions revealed worsened MD (-1.52dB [-2.27, -0.78 dB]) and MS (-1.47dB [-2, -0.94 dB]) in early/iAMD compared to normal eyes, representing large statistical effect sizes but non-clinically meaningful reductions. There was insufficient data for meta-analyses regarding other clinical automated perimetry protocols. Only one study assessed a real-world patient outcome (on-road driving performance), with no significant link to visual field outcomes in early/iAMD. SUMMARY: Significant reduction of global visual field indices is present in early/iAMD, but not clinically meaningful using SAP under photopic conditions. Translational relevance of visual field outcomes to patient outcomes in early/iAMD remains unclear. Thus, SAP under photopic conditions is unlikely to be useful for routine assessment of early/iAMD.

Location-Specific Thickness Patterns in Intermediate Age-Related Macular Degeneration Reveals Anatomical Differences in Multiple Retinal Layers.

Purpose: To examine individual retinal layers' location-specific patterns of thicknesses in intermediate age-related macular degeneration (iAMD) using optical coherence tomography (OCT). Methods: OCT macular cube scans were retrospectively acquired from 84 iAMD eyes of 84 participants and 84 normal eyes of 84 participants propensity-score matched on age, sex, and spherical equivalent refraction. Thicknesses of the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer + Henle's fiber layer (ONL+HFL), inner- and outer-segment layers (IS/OS), and retinal pigment epithelium to Bruch's membrane (RPE-BM) were calculated across an 8 × 8 grid (total 24° × 24° area). Location-specific analysis was performed using cluster(normal) and grid(iAMD)-to-cluster(normal) comparisons. Results: In iAMD versus normal eyes, the central RPE-BM was thickened (mean difference ± SEM up to 27.45% ± 7.48%, P < 0.001; up to 7.6 SD-from-normal), whereas there was thinned outer (OPL, ONL+HFL, and non-central RPE-BM, up to -6.76% ± 2.47%, P < 0.001; up to -1.6 SD-from-normal) and inner retina (GCL and IPL, up to -4.83% ± 1.56%, P < 0.01; up to -1.7 SD-from-normal) with eccentricity-based effects. Interlayer correlations were greater against the ONL+HFL (mean |r| ± SEM 0.19 ± 0.03, P = 0.14 to < 0.0001) than the RPE-BM (0.09 ± 0, P = 0.72 to < 0.0001). Conclusions: Location-specific analysis suggests altered retinal anatomy between iAMD and normal eyes. These data could direct clinical diagnosis and monitoring of AMD toward targeted locations.

Radial Peripapillary Capillary Plexus Sparing and Underlying Retinal Vascular Impairment in Intermediate Age-Related Macular Degeneration.

Purpose: To examine location-specific retinal vascular changes in intermediate age-related macular degeneration (iAMD) using age-matched, high-density en face optical coherence tomography angiography (OCTA) cluster analysis. Methods: En face OCTA images of the 6 × 6 mm macular area were retrospectively acquired from 60 iAMD eyes and 60 age-matched normal eyes and then subdivided into 126 × 126 (47.62 × 47.62 µm) grids within the superficial and deep vascular complex. Grid-wise vessel perfusion (VP) were compared between iAMD and normal eyes from the corresponding 10-yearly age cohort, forming difference plots. Difference plots were further separated by normative topographical map spatial clusters (C1-6), derived from normaldatabase eyes (n = 236, 20-81 years old). Results: Overall difference plots showed decreased VP in the superficial (-12.19%) and deep vascular complex (-6.44%) of iAMD compared to normal eyes (P < 0.0001 both comparisons). Cluster-based difference plots highlighted nonuniform changes in the superficial vascular complex, with sparing of VP at the nasal macula (corresponding to the radial peripapillary capillary plexus) versus decreased VP toward the temporal macula and foveal avascular zone (FAZ) (C1-6 all comparisons P < 0.0001, except C1 vs. C2P > 0.99 and C4 vs. C5P = 0.11). The deep vascular complex displayed diffusely decreased VP, greater at the FAZ (P < 0.0001). Conclusions: High-density en face OCTA cluster analysis suggests relative sparing of the radial peripapillary capillary plexus and impairment of underlying retinal vasculature, supporting potential anterograde transsynaptic degeneration in iAMD. These location-specific data may better guide future diagnostic and management protocol of iAMD.

Modelling normal age-related changes in individual retinal layers using location-specific OCT analysis.

Current descriptions of retinal thickness across normal age cohorts are mostly limited to global analyses, thus overlooking spatial variation across the retina and limiting spatial analyses of retinal and optic nerve disease. This retrospective cross-sectional study uses location-specific cluster analysis of 8 × 8 macular average grid-wise thicknesses to quantify topographical patterns and rates of normal, age-related changes in all individual retinal layers of 253 eyes of 253 participants across various age cohorts (n = 23-69 eyes per decade). Most retinal layers had concentric spatial cluster patterns except the retinal nerve fibre layer (RNFL) which displayed a nasal, asymmetric radial pattern. Age-related thickness decline mostly occurred after the late 4th decade, described by quadratic regression models. The ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), and outer nuclear layer + Henle's fibre layer (ONL+HFL) were significantly associated with age (p < 0.0001 to < 0.05), demonstrating similar rates of thickness decline (mean pooled slope = - 0.07 µm/year), while the IS/OS had lesser mean pooled thickness slopes for all clusters (- 0.04 µm/year). The RNFL, OPL, and RPE exhibited no significant age-related thickness change, and the RNFL were significantly associated with sex. Analysis using spatial clusters compared to the ETDRS sectors revealed more extensive spatial definition and less variability in the former method. These spatially defined, clustered normative data and age-correction functions provide an accessible method of retinal thickness analysis with more spatial detail and less variability than the ETDRS sectors, potentially aiding the diagnosis and monitoring of retinal and optic nerve disease.

Macula Ganglion Cell Thickness Changes Display Location-Specific Variation Patterns in Intermediate Age-Related Macular Degeneration.

Purpose: The purpose of this study was to examine changes in the ganglion cell layer (GCL) of individuals with intermediate age-related macular degeneration (AMD) using grid-wise analysis for macular optical coherence tomography (OCT) volume scans. We also aim to validate the use of age-correction functions for GCL thickness in diseased eyes. Methods: OCT macular cube scans covering 30° × 25° were acquired using Spectralis spectral-domain OCT for 87 eyes with intermediate AMD, 77 age-matched normal eyes, and 254 non-age-matched normal eyes. The thickness of the ganglion cell layer (GCL) was defined after segmentation at 60 locations across an 8 × 8 grid centered on the fovea, where each grid location covered 0.74 mm2 (approximately 3° × 3°) within the macula. Each GCL location of normal eyes (n = 77) were assigned to a specific iso-ganglion cell density cluster in the macula, based on patterns of age-related GCL thickness loss. Analyses were then performed comparing AMD GCL grid-wise data against corresponding spatial clusters, and significant AMD GCL thickness changes were denoted as values outside the 95% distribution limits. Results: Analysis of GCL thickness changes revealed significant differences between spatial clusters, with thinning toward the fovea, and thickening toward the peripheral macula. The direction of GCL thickness changes in AMD were associated more so with thickening than thinning in all analyses. Results were corroborated by the application of GCL thickness age-correction functions. Conclusions: GCL thickness changed significantly and nonuniformly within the macula of intermediate AMD eyes. Further characterization of these changes is critical to improve diagnoses and monitoring of GCL-altering pathologies.

Vascular Changes in Intermediate Age-Related Macular Degeneration Quantified Using Optical Coherence Tomography Angiography.

PURPOSE: To examine changes in retinal vasculature and ganglion cell layer (GCL) thickness in intermediate age-related macular degeneration (AMD) using optical coherence tomography angiography (OCTA). METHODS: Zeiss Cirrus Angioplex OCTA 6 × 6 mm scans and a macula 512 × 128 cube scans of the central retina were taken of 63 eyes with intermediate AMD and 51 control eyes. For OCTA scans, the superficial and deep capillary plexus were automatically segmented and vascular density quantified as total number of pixels contributing to the blood flow signal detectable by OCTA. Images were then skeletonized and vessel length, diameter index, morphology, and branching complexity determined. Foveal avascular zone (FAZ) characteristics and GCL thickness were extracted from in-built Angioplex software. RESULTS: Vascular density was significantly reduced in the superficial capillary plexus of AMD eyes compared with normal eyes, particularly in the superior quadrant (42.4% ± 1.6% vs. 43.2% ± 1.4%; P < 0.05). A nonsignificant reduction was also seen in the deep capillary plexus (P = 0.06). Total vessel length and average vessel diameter were all significantly decreased in AMD eyes suggesting density changes were related to decreased vessel number and caliber. Vascular complexity and number of branch points was significantly decreased in the deep capillary plexus (P < 0.05) suggesting loss or significantly reduced flow of vessels. Average GCL thickness was also significantly reduced in the AMD eyes (P < 0.05). No significant changes in FAZ parameters were observed in AMD eyes. CONCLUSIONS: This study suggests intermediate AMD affects both the quantity and morphology of inner retinal vasculature and may be associated with changes in inner retinal structure. This work builds upon the notion that AMD pathogenesis may extends beyond the outer retina. TRANSLATIONAL RELEVANCE: Better understanding of retinal vascular changes in AMD can provide insights in the development of treatment and prevention protocols for these diseases.