Methods

This prospective clinical observational study adhered to the tenets of the Declaration of Helsinki and was conducted in compliance with the Health Insurance Portability and Accountability Act. The institutional review board at Oregon Health and Science University approved the study, and written informed consent was obtained from each participant.

The criteria for GA patient inclusion were age of 50+ years and diagnosis of GA secondary to AMD in at least 1 eye. GA was defined as sharply demarcated atrophic lesions of at least 175 μm with increased visibility of choroidal vessels. The diagnosis of GA was confirmed by both hypoautofluorescence on fundus autofluorescence (FAF) imaging and on OCT scans (Spectralis, Heidelberg, Germany) demonstrating congruent loss of photoreceptors and RPE and hypertransmission of OCT signal into the choroid. A group of age-matched healthy participants was included as control subjects. The criteria for controls inclusion were an age of at least 50 years old, no history of retinal diseases, corrected visual acuity ≥20/20, IOP (IOP) <21 mm Hg and the absence of any abnormalities on clinical fundus examination and OCT. The exclusion criteria for both GA and control groups included a history of diabetes mellitus, choroidal or retinal neovascularization, previous intraocular surgery except for cataract surgery, any other macular disease such as epiretinal membrane or vitreomacular traction syndrome, refractive error greater than −6 or +3 diopters and media opacities that precluded a high-quality OCTA scan.

All participants underwent a comprehensive ocular examination, including early treatment of diabetic retinopathy study (ETDRS) visual acuity testing, IOP, axial length measurement (IOL master 500, Carl Zeiss Meditec, Dublin, California), dilated fundus examination, fundus photography (model FF450 plus, Carl Zeiss Meditec), OCTA, FAF (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany), structural OCT, as well as a systemic blood pressure measurement. The mean arterial pressure (MAP) was calculated as the diastolic blood pressure plus one-third of the difference between the diastolic blood pressure and the systolic blood pressure. The ocular perfusion pressure was determined by subtracting the IOP from the two-thirds of MAP.

OCTA was obtained after pupil dilation by using a commercially available spectral-domain instrument (RTVue XR Avanti; Optovue, Inc., Fremont, California), with a center wavelength of 840 nm and an axial scan rate of 70 kHz. The 3- × 3-mm scans centered on the fovea were acquired. The commercial version of a split-spectrum amplitude decorrelation angiography algorithm was used to detect blood flow by comparing consecutive B-scans at the same location. Each scan set consisted of 1 vertical-priority raster and 1 horizontal-priority raster scan. The AngioVue (Phoenix, Arizona) software uses an orthogonal registration algorithm to register the 2 perpendicular raster volumes to produce a merged 3-dimensional (3D) OCT angiogram. The merged volumetric angiograms were then exported for customized processing using COOL-ART software (New York City, New York). Scans were excluded if images were out of focus, significant motion artifacts were detected, or signal strength index was less than 55.

A semiautomated algorithm based on a directional graph search segmented the volumes. ^, Segmentations were then reviewed and manually adjusted to ensure accuracy. Retinal layer thickness measurements were defined by the whole retinal layer, from the internal limiting membrane to the inner surface of RPE; and by the whole nerve fiber layer (NFL), from the internal limiting membrane to the outer surface of the NFL; and by the ganglion cell complex (GCC), consisting of both the ganglion cell layer and the inner plexiform layer (IPL), from the outer surface of the NFL to the inner surface of inner nuclear layer (INL); and by the inner nuclear layer, from inner surface of the INL to the outer surface of the INL; and by the outer plexiform layer (OPL), from the outer surface of the INL to the inner surface of the outer nuclear layer (ONL); and by photoreceptor thickness, from the inner surface of the ONL to the inner surface of the RPE. Retinal vessel density was defined as the proportion of vessel area with blood flow over the total area measured. Reflectance-compensated vessel densities were calculated on projection-resolved superficial vascular complex (SVC), intermediate capillary plexus (ICP), and deep capillary plexus (DCP). ^{, ,} The central 0.6-mm diameter area centered on the fovea was excluded to limit the effect of foveal avascular zone on vessel density measurement. An en face OCT reflectance map was used to identify areas of GA.

Retinal vessel densities were calculated within GA regions, within the GA rim region (500 μm rim around GA), and in the non-GA regions that included regions outside of the GA rim area. For eyes with multiple GA regions, a mean vessel density of all GA regions or rim area was calculated by dividing the sum of vessel area within GA region or rim area by the total GA area or total rim area. Because GA locations varied among individuals and because vessel density varied by location within the macula, fractional vessel density deviation maps were calculated normalized to the average vessel density map in the normal control group. The normalized vessel deviation was defined as the value from the eye under evaluation minus the normal average and then divided by the normal average. Thus, the reduction of vessel density within GA rims could be calculated by averaging the normalized vessel density deviation in the rim area. The analytical areas were centered on the foveal avascular zone and adjusted for transverse optical magnification calculated according to the axial length of each eye. The pixel coordinate was used to match the location when comparing GA region, GA rim, and non-GA region to corresponding areas of normal average maps.

Statistical analysis was conducted using SPSS version 25.0 (IBM, Armonk, New York) for Windows (Microsoft, Redmond, Washington). Descriptive statistics included mean, standard deviation (SD), and range, and percentages were presented where appropriate. The Shapiro-Wilk test was used to test normality of data distribution of age, axial length, retinal layer thickness, and vessel density. An independent sample t test was used to compare age, axial length, retinal thickness, and vessel density on each individual plexus between eyes with GA and healthy normal eyes. Pearson correlation was used to analyze the correlation between extent of vessel density reduction and GA size, and the correlation between vessel densities and retinal layer thicknesses. A 1-sample t test was used to determine whether the normalized deviation was significantly different from zero within the GA region and GA rims and outside the GA rim region. All P values were 2-sided and considered statistically significant if the value was less than 0.05. Bonferroni correction was applied when doing multiple comparisons.

Results

One eye each of 10 GA patients (7 women) and 10 normal healthy controls (7 women) were included. The mean ages were 81.3 ± 9.3 (range, 66–95 years) and 76.3 ± 4.2 years (range, 73–85 years) for GA and control groups, respectively ( P = 0.14). The axial length was not significantly different between GA and control eyes (24.02 ± 0.63 mm vs. 24.63 ± 0.85 mm, respectively; P = 0.09). The systolic arterial blood pressure, diastolic blood pressure, IOP, and calculated ocular perfusion pressure were similar between the 2 groups. On the 3- × 3-mm OCTA scan area, GA lesion was multifocal in 9 of 10 eyes and monofocal in 1 of 10 eyes. The mean atrophic area was 1.84 ± 1.00 mm ² (range, 0.72–4.35 mm ² ) on 3- × 3-mm en face OCT scans. Table 1 summarizes the clinical characteristics of the participants.

The mean retinal vessel densities were significantly lower in GA eyes than in normal controls in SVC (54.8 ± 2.4% vs. 60.8 ± 3.1%, respectively; P < 0.001), ICP (34.0 ± 1.5% vs. 37.3 ± 1.7%, respectively; P < 0.001), and DCP (24.4 ± 2.3% vs. 28.0 ± 2.3%, respectively; P = 0.002). The DCP in eyes with GA had the greatest reduction (13%) of retinal vessel density compared to the DCP of normal controls, followed by the SVC (10%) and ICP (9%). The GA size was not significantly associated with the extent of vessel density reduction in SVC ( P = 0.24), ICP ( P = 0.31), or DCP ( P = 0.59).

Quantitative analysis using normalized deviation compared the retinal vessel density in GA regions, GA rim regions, and non-GA regions to similar macular locations in control eyes ( Table 2 ). The retinal vessel density within the GA region was significantly lower in SVC, ICP, and DCP. Retinal vessel density in the GA rim region decreased in only the SVC and ICP but not in the DCP. The non-GA region did not deviate from normal controls. The GA region had the greatest reduction in retinal vessel density ( Figure ).

Table 2

Retinal Vessel Density in Eyes with Geographic Atrophy and Age-Matched Controls

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