Subtle outer retinal and choroidal alterations in patients at high risk of progression to AMD

doi:10.21203/rs.3.rs-3304913/v1

AIM

To explore the changes in the microstructure and blood supply of the outer retina in eyes at high risk of progression to age–related macular degeneration (AMD).

METHODS

Forty-seven patients of unilateral neovascular AMD (nAMD) were enrolled, twenty-two of the healthy contralateral eyes were considered at high risk of progression to AMD (Group1), the other twenty-five eyes were of dry AMD (Group2). Fifty healthy subjects (50 eyes) were enrolled as control. Swept-source optical coherence tomography equipped with angiovue was used to obtain three-dimensional retinal thickness maps, microvascular images of the superficial and deep retinal capillary plexuses (SCP and DCP) around the macula and choroid vessel index (CVI). Quantitative analyze was automatically calculated by inbuilt algorithm in the SS-OCT.

RESULTS

Compared to the controls, the densities of the SCP and DCP tend to decrease in Group2 without significance in all regions (P > 0.05). However, the CVI of patients in S and T regions was significantly decrease compared to the controls (P < 0.05). The outer retinal thickness of the Group1 trend to be increased without significance compared to the controls, while the Group2 in the C, S and T regions were significantly decreased compared to the controls and Group1. Meanwhile, compared to the controls, the thickness of total retina and choroid of the Group2 were significantly decreased (P < 0.05). The outer retinal thickness was significantly correlated to choroidal thickness in AMD patients.

CONCLUSION

Significantly thinning of outer retina and choroid were observed in patients with dry AMD. For eyes at high risk of progression to AMD, the outer retinal thickness trend to be increased while the choroidal thickness and CVI trend to be decreased. SS-OCT might be useful in evaluating the microstructural and blood supply disorders of the outer retinal layers in healthy eyes of unilateral nAMD patients, which might be a quantitative approach to identify the earliest progression of AMD.

AMD

outer retina

choroidal thickness

outer retina

optical coherence tomography

Age–related macular degeneration (AMD) was the third cause of blindness worldwide and the prevalence increased with age. [1, 2] The patients of AMD in China was concentrated in 85–89 age, the number of which increased from 1.201 billion in 1990 to 2.665 billion in 2015, while the number of early AMD increased to 2.091 billion. [3] AMD is the result of complex multi-factors including metabolic, environmental, functional and genetic factors. It was common for the death of retinal pigment epithelial (RPE) cells, choroidal endothelial cells (CECs) and photoreceptor cells in advanced AMD. Loss of CECs is one of the earliest detectable events in AMD, which may be the initial point for progression to the advanced stages of AMD as choriocapillaris was the metabolic supports of outer retina. [4, 5] Lipofuscin and cell debris of photoreceptor cells can normally be expelled by RPE and then cleared by capillaries in pathological conditions. The previous studies found that the onset site of AMD is Bruch's membrane (BM).[6] When RPE cell function is abnormal, permeability change of BM lead to the gradually accumulate of lipofuscin and cell debris between RPE and BM to form drusen, [7] which is related to the thickening and calcification of BM collagen layer. It has also been observed that the atrophy of the choroidal layer in AMD patients further reduces the clearance of extracellular substances, thus leading to the formation of drusen. [8] Initially, abnormal blood vessels which coexist with subretinal fluid accumulation may appear before degeneration and the formation of a disk scar.[8, 9] As a result, irreversible and permanent loss of vision acuity eventually cause by neovascular AMD.

At present, the study of early AMD mainly includes morphological changes of outer retina in macular area, drusen and choroid.[4] The main methods include fundus photograph, optical coherence tomography (OCT), fundus spontaneous fluorescence image and indocyanine green angiography (ICGA). Besides, OCT equipped angiography (OCTA) is a non-invasive instrument possessing an advantage to quantify the microvascular a characteristics of retina and choroid.[10]

Early AMD is usually asymptomatic, although RPE mottling and extracellular lipofuscin deposits between RPE cells and Bruch’s membrane can be clinically detected in the posterior pole.[6] Some studies found that there was significantly different in retinal layers between patients with early AMD and normal people,[11] while others hold the opposite attitude.[12] However, there are not so much studies about the changes of retinal vascular and structure in early AMD, which need to be further explored.

At the same time, the disease stage of contralateral eye has a significant influence on the occurrence and development of AMD. AMD usually develops in both eyes, and the more severe the stage is in the contralateral eye, the faster the disease progresses in the study eye as described in a 20-year follow-up study (AREDS 5-step scale).[13, 14] As reported in large sample clinical studies, 72.4% of patients with unilateral advanced AMD still have good vision in the opposite eye, and the probability of severe vision loss in the opposite eye is 2–30% per year. [13] Nichole Joachim et al. found in 5-year follow-up that greater proportion of unilateral AMD progressed to bilateral AMD, which was more obvious in unilateral advanced AMD. The incidence of AMD within 5 years in healthy eyes was 2.4–3.5 times for unilateral AMD higher than those without AMD. [15] Therefore, in this study, the contralateral healthy eye of unilateral nAMD (AREDS 5-step classification) [14] was considered at high risk of progression to AMD (Group1). The changes of fundus structure, microvascular and visual function in Group1 were observed to seek possible biological markers for early identification of the occurrence of AMD. Timely intervention and treatment will delay the course of AMD and avoid irreversible vision loss.[16]

Patients

Patients of retrospective selection with a diagnosis of nAMD were identified by an ophthalmologist following the international ARM epidemiological study group grading system,[17] and the contralateral eye without any treatment of each patient was evaluate in detail. Patients with AMD were graded by ophthalmologist according to the description (0) a , No signs ; b , Few hard drusen (<63 μm) ; (1) a , Soft distinct (>63 μm) ; b , Pigment irregularities only (no soft drusen) ; (2) a , Soft indistinct drusen (>125 μm) ; b , Soft distinct drusen (>63 μm) and pigment irregularities ; (3) Soft indistinct drusen (>125 μm) and pigment irregularities ; (4) a, GA; b, CNV; c, GA and CNV [17]. Patients were retrospectively select from the Zhejiang Provincial People's Hospital, China from May 2022 to May 2023. Inclusion criteria were: (1) stable foveal fixation, and (2) spherical equivalent (SE) refractive error between −5.00 and +5.00 diopters.

Exclusion criteria were: (1) established any retinal or choroidal disease, (2) presence of any drusen-like deposits, atrophy, or retinal detachment on indirect ophthalmology or swept - source optical coherence tomography (SS-OCT) examination; (3) ocular trauma or surgery, (4) systemic disorders with ocular involvement such as diabetes and hypertension.

The study was performed in accordance with the tenets of the Declaration of Helsinki and the Institutional Review Board/Ethics Committee of Zhejiang Provincial People‘s Hospital approved the study protocol. Age- and sex-matched control subjects were recruited from workers at the Zhejiang Provincial People’s Hospital.

Evaluations and Measurements

Clinical Examinations

All subjects underwent comprehensive clinical examinations, including spherical equivalent refractive and best corrected visual acuity (BCVA), intraocular pressure (IOP) measurement (Kowa applanation tonometer HA-2; Kowa Company Ltd. Tokyo, Japan), slit-lamp biomicroscopy, and ophthalmoscopy. In addition, the fundus photography was performed with a 200-degree ultrawide field color fundus photographs (Optos PLC, Dunfermline, Scotland, UK).

Image Acquisition Protocol and Analysis

All the subjects were imaged by a commercial SS-OCT device (VG200; SVision Imaging, Ltd., Luoyang, China) which was equipped with angiovue for OCT-A. The swept-source (SS) OCT has a central wavelength of 1,050 nm. The 6×6mm scan patterns centering on the fovea were conducted in this study. Images with a high signal strength index (> 6) were further evaluated.

Inbuilt algorithm in the SS-OCT was used to segment and measure the thickness of the (1) NFL, (2) GCL+IPL, (3) INL, (4) outer retina(include outer plexiform layer (OPL), Henle fiber layer and outer nuclear layer (HFL+ONL), the myoid and ellipsoid zone (MEZ), photoreceptor outer segments (OS),and interdigitation zone + retinal pigment epithelium (IZ+RPE)), and (5)choroid (Fig. 1, B). And there were manual corrections within SS-OCT used to adjust segmentation errors. For analysis, the macular thickness map was divided into a 1-mm diameter circle centered over the fovea and a total annular zone (TAZ) surrounded by a concentric ring 0.5 - 1.5 mm from the fovea. The areas of the central circle and the TAZ were then divided into five regions including the central (C) and the superior, temporal, inferior, and nasal regions (S, T, I, and N, respectively) (Fig. 1, A).

Parameters of OCTA from the inner circle were automatically calculated in the parafoveal regions include superior (S), temporal (T), inferior (I), and nasal (N) regions of the 3-mm diameter circular zone after excluding the foveal avascular zone (FAZ), while the outer circle were excluded because of an incomplete edge in the 6×6mm scanning area (Fig. 1, C and D). Vessel density is a metrics used to describe the percentage of area occupied by blood vessels in a 2D retina projection image. The projection image is acquired by projecting a 3D angiography volume data onto a 2D imaging plane, sometimes also called an en face image. The presence of blood vessel is directly indicated by angiography signal. An algorithm is designed to separate the foreground (blood vessel) pixels from background (non-vessel tissue) pixels, by properly segmenting the image from the perspective of angiography signal strength. Then the ratio of blood vessel pixels as a percentage of all pixels is computed within a pre-defined window size. Microvasculature parameters included the superficial capillary plexus (SCP), deep capillary plexus (DCP) from a 6 × 6mm scan pattern. The SCP was defined as the microvasculature between the base of the retinal nerve fiber layer (RNFL) to the junction between the inner plexiform layer (IPL) and inner nuclear layer (INL) (Fig. 1, F), DCP was defined as the microvasculature between the INL/OPL junction to 25 μm below it (Fig. 1, G). The OCTA parameter was also described in previous study.[10] The choroid vessel index (CVI) is defined as the ratio of the volume of Haller’s and Sattler’s layers to the volume of the choroid (Fig. 1, H), which was automatically measured by an artificial intelligence-based algorithm that identifies Haller’s and Sattler’s layers on B-scans and reconstructs 3D graphic maps of the medium-diameter and large-diameter choroidal vessel layers.

Statistical Analysis

All data were calculated as means ± standard deviations and analyzed with SPSS software (version 22.0; SPSS, Inc., Chicago, IL, USA). The spherical equivalent (SE) of refraction error was calculated as the spherical dioptric power plus one-half of the cylindrical dioptric power. Differences of gender among the groups were determined by the x²test. One-way analysis of variance (ANOVA) was used to compare the differences among the groups, and post hoc procedures were used to compare differences between the two groups. P values of < 0.05 were considered statistically significant.

In total, 47 patients with nAMD in unilateral eye were included in our study (Fig. 2, C and E). According to the stage of the contralateral eye, there were 22 healthy eyes considered at high risk of progression to AMD as Group1 (Fig. 2, B), 25 eyes of dry AMD as Group2 (Fig. 2, D). And 50 healthy subjects (50 eyes) were enrolled as control group meanwhile. There were no significant differences in the age, gender, SE, and IOP among the three groups (P = 0.153 ~ 0.954, Table 1), except BCVA (P = 0.003). Raw OCT images in the Control, Group1 and Group2 eyes were presented in Figure 3. In eyes with dry AMD, the out retina and choroid was evidently thinner.

Table 1. Basic characteristics of the subjects

	Control	Group1	Group2	P Value
N (Eyes)	50 (50)	22 (22)	25 (25)	-
Gender (F:M)	23:27	10:12	12:13	0.919
Age, years	63.3 ± 8.7	65.8± 10.6	66.6 ± 10.8	0.153
SE, diopters	-0.31 ± 2.3	-0.37 ± 1.8	-0.16 ± 1.6	0.954
BCVA, LogMAR	0.02 ± 0.07	0.05 ± 0.12	0.12 ± 0.16	0.003
IOP, mmHg	14.9 ± 3.3	15.3 ± 2.4	15.2 ± 2.7	0.841

F, female; M, male; SE, spherical equivalent; BCVA, best corrected visual acuity; IOP, intraocular pressure.

P values for differences among the three groups were determined by one-way ANOVA (except for sex, where the P value was determined by ). Bold P-value represents < 0.05.

Compared to the controls, the densities of the SCP and DCP tend to decrease in Group2 without significance in all regions (P > 0.05). However, the CVI of patients in S and T regions was significantly decrease compared to the controls (P< 0.05, Table 2).

Table 2. The retinal capillary density (%) and choroid vessel index (CVI) among the three groups

Layers	Regions	Control	Group1	Group2	P
DCP	S	52.6 ± 5.1	52.7 ± 5.1	49.2 ± 8.4	0.175
	T	52.4 ± 4.1	52.2 ± 5.2	48.5 ± 10.0	0.209
	I	52.4 ± 4.5	50.9 ± 6.8	52.1 ± 5.5	0.582
	N	51.9 ± 5.2	52.3 ± 5.0	49.0 ± 11.3	0.227
SCP	S	44.7 ± 5.4	44.9 ± 10.4	40.4 ± 8.9	0.114
	T	36.2 ± 4.7	36.8 ± 8.4	33.0 ± 8.0	0.180
	I	45.1 ± 6.3	44.0 ± 11.9	41.8 ± 9.0	0.288
	N	39.3 ± 5.6	39.7 ± 10.8	35.9 ± 9.7	0.288
CVI	C	0.41 ± 0.06	0.40 ± 0.07	0.39 ± 0.05	0.521
	S	0.41 ± 0.06	0.40 ± 0.09	0.36 ± 0.03	0.009
	T	0.40 ± 0.06	0.36 ± 0.05	0.37± 0.04	0.020
	I	0.41 ± 0.05	0.39 ± 0.07	0.38 ± 0.03	0.265
	N	0.43 ± 0.05	0.41 ± 0.12	0.41 ± 0.03	0.355

SCP, superficial capillary plexus; DCP, deep capillary plexus; CVI, choroid vessel index; S, superior region; T, temporal region; I, inferior region; N, nasal region. P, the differences among the three groups. Bold P-value represents < 0.05.

There was no significant difference of the inner retinal thicknesses among the three groups (P > 0.05). The outer retinal thickness of the Group1 trend to be increased without significance compared to the controls, while the Group2 in the C, S and T regions were significantly decreased compared to the controls (P = 0.048, 0.004 and 0.003, respectively) and Group1 (P = 0.004, 0.005 and 0.014, respectively) (Table 3). Meanwhile, compared to the controls, the total retinal thickness of the Group2 in the S (P = 0.034), T (P = 0.021) and I (P = 0.024) regions were decreased (Table 3). Compared to the controls, the choroidal thicknesses of the Group1 trend to be decreased without significance, while the Group2 were decreased in almost all regions (P = 0.001 ~ 0.022, Table 3) except for the T. The outer retinal thickness was significantly correlated to choroidal thickness in AMD patients (Fig. 4).

Table 3. The thickness (μm) of retina and choroid among the three groups

Layers	Regions	Control	Group1	Group2	P*	P⁺	P^#	P
Inner retina	C	62.4 ± 13.7	68.9 ± 10.4	66.9 ± 10.0	0.375	0.928	0.396	0.627
	S	167.2 ± 11.4	165.3 ± 9.7	162.8 ± 15.0	0.497	0.094	0.419	0.242
	T	147.7 ± 10.4	147.1 ± 12.1	143.9 ± 13.4	0.914	0.072	0.160	0.176
	I	163.3 ± 8.8	166.7 ± 9.4	158.3 ± 14.4	0.831	0.077	0.196	0.194
	N	157.4 ± 8.9	160.5 ± 11.4	154.6 ± 15.0	0.815	0.463	0.420	0.680
Outer retina	C	186.4 ± 14.1	191.1 ± 10.3	178.3 ± 14.8	0.145	0.048	0.004	0.015
	S	170.4 ± 10.1	171.7 ± 8.1	159.5 ± 14.5	0.621	0.004	0.005	0.006
	T	173.4 ± 9.3	174.7 ± 8.0	162.6 ± 12.3	0.878	0.003	0.014	0.012
	I	166.3 ± 11.1	166.6 ± 5.2	158.8 ± 9.2	0.786	0.138	0.142	0.247
	N	175.6 ± 9.7	178.6 ± 7.3	170.8 ± 8.5	0.486	0.347	0166	0.375
Total retina	C	249.1 ± 25.5	268.1 ± 22.5	245.0± 17.7	0.072	0.999	0.116	0.165
	S	336.8 ± 18.5	338.1 ± 16.6	322.4± 20.3	0.996	0.034	0.078	0.083
	T	321.1 ± 18.2	323.6 ± 12.9	307.8 ± 15.6	0.985	0.021	0.052	0.049
	I	330.1 ± 19.8	334.6 ± 10.4	317.1 ± 14.2	0.737	0.024	0.031	0.044
	N	332.9 ± 17.3	341.0 ± 15.4	326.3 ± 17.2	0.406	0.302	0.116	0.284
Choroid	C	347.4 ± 89.5	316.4 ± 66.9	286.8± 83.3	0.157	0.011	0.280	0.031
	S	348.1 ± 88.9	330.5 ± 65.4	294.1± 83.0	0.416	0.022	0.181	0.072
	T	345.0 ± 95.5	321.1 ± 64.2	298.7 ± 72.5	0.283	0.056	0.421	0.136
	I	340.5 ± 98.1	318.4 ± 78.5	272.5 ± 86.7	0.356	0.001	0.128	0.034
	N	328.8 ± 93.1	301.9 ± 73.9	266.1 ± 88.1	0.244	0.013	0.215	0.040

C, central region; S, superior region; T, temporal region; I, inferior region; N, nasal region. P*, control versus Group1; P⁺, control versus Group2; P^#, Group1 versus Group2; P, the differences among the three groups. Bold P-value represents < 0.05.

The present study investigated the microstructure around the macula in the patients with dry AMD and the earlier stage using SS-OCT. We found that the total retina tended to be thickening in Group1 and thinning in Group2, which was more evident in outer retina. The microvascular densities of SCP and DCP have the same trend. However, the choroidal thickness and CVI have decreasing gradient among the controls, Group1 and Group2. In addition, the outer retinal thickness was significantly correlated to choroidal thickness in AMD patients.

There was no doubt that the early AMD began with the imbalances within the photoreceptor/RPE/choriocapillaris/choroid system as most previous reports describe.[2, 18] At length, drusen and other sub-RPE deposits (basal laminar deposit and basal linear deposit, also referred to as diffuse drusen) are diagnostic and predictive of AMD.[18] Therefore, the thickening of outer retina might be ascribed to the accumulation of metabolic wastes within photoreceptor and RPE in the eyes of Group1. And the thinning of retina of the early AMD was detected in previous study along with apoptosis of RPE.[19] However, the choroid was significantly thinning even in the eyes of Group1. Actually, the vascular density of the choriocapillaris tend to be decreased in early AMD in a previous study of cell biology.[20] As the main blood supply of outer retina, the choroid seemed to be impaired earlier than retina itself. It was consistent with previous research that the loss of endothelial cells of the choriocapillaris is one of the earliest detectable events in AMD. [5] At the same time, the significant correlation between outer retinal thickness and choroidal thickness in AMD patients in our study was also a strong piece of evidence. In the meanwhile, using the OCT-A, we found that the retinal microvascular density in both SCP and DCP tend to increase in Group1 without significance compared to the controls, as the same as the inner retina. We suggest that the impairment in the RCP and inner retina occurring in the advanced stage of AMD.

In the current study, there are still some limitations. Firstly, we did not describe the exact layer of out retina, which was more sensitive of macular degeneration. Secondly, we used a simple choroidal thickness to react the blood supply of outer retina. Further study should describe all four layers of choroid. Lastly, a longitudinal study with a larger sample size is needed to confirm retinal and choroidal changes from subclinical to clinical AMD.

In conclusion, the choroidal thickness in patient without clinical diagnosed AMD (stage 0, Group1) was evidently decreased. However, the outer retinal thickness and microvascular density of inner retina tend to be increasing, which might be a compensatory change. It indicated that impaired choroid might promote changes in the outer retinal microstructure, resulting in a risk of progression into fully developed AMD, which will be demonstrated in a future longitudinal study. SS-OCT might be useful in evaluating the microstructural and blood supply disorders of the outer retinal layers in eyes at high risk of progression to AMD, which may contribute a quantitative approach to the earlier diagnosis and risk assessment of AMD.

Ethics approval and consent to participate.

The study was approved by the Institutional Review Board/Ethics Committee of Zhejiang Provincial People‘s Hospital. The data are anonymous, and the requirement for informed consent was therefore waived by the Institutional Review Board/Ethics Committee of Zhejiang Provincial People’s Hospital.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed in our study are available from the corresponding author on reasonable request.

Competing interests

The authors have no proprietary interest in any materials or methods described within this article.

Funding

Not applicable.

Authors' contributions

Design of the study (XW, MW); Conduct of the study, data collection, analysis and interpretation (LB, HL, HY); Manuscript preparation and review (XW, MW, LB, HL).

Acknowledgement

None.

Proprietary interests: The authors have no proprietary interest in any materials or methods described within this article.

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No competing interests reported.

Subtle outer retinal and choroidal alterations in patients at high risk of progression to AMD

Status:

Version 1

Abstract

AIM

METHODS

RESULTS

CONCLUSION

Figures

Introduction

Methods

Results

Discussion

Declarations

References

Additional Declarations

Status:

Version 1