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. Author manuscript; available in PMC: 2021 Sep 1.
Published in final edited form as: Graefes Arch Clin Exp Ophthalmol. 2020 Jun 2;258(9):1931–1940. doi: 10.1007/s00417-020-04774-w

Subtype-differentiated impacts of subretinal drusenoid deposits on photoreceptors revealed by adaptive optics scanning laser ophthalmoscopy

Xiaoyu Xu 1,2, Xiaolin Wang 1, SriniVas R Sadda 1, Yuhua Zhang 1,*
PMCID: PMC7442725  NIHMSID: NIHMS1600290  PMID: 32488329

Abstract

Purpose:

To examine the structure of photoreceptors surrounding two subtypes of subretinal drusenoid deposits (SDD), namely, dot and ribbon SDD, using multimodal imaging including adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SD-OCT).

Methods:

Twenty-six eyes of 13 patients with age-related macular degeneration (AMD) and SDD and 16 eyes of 8 subjects in normal chorioretinal health were studied. SDD presence, stage, and subtype were determined using color fundus photographs, infrared reflectance, autofluorescence imaging, and SD-OCT. SDD and surrounding photoreceptors were imaged using AOSLO. The structure of cone photoreceptors and SDD were examined at the baseline and at 2-year follow-up studies in 6 patients.

Results:

Dot SDD were identified in 18 eyes of 9 patients and coexisting dot and ribbon SDD were observed in 8 eyes of 4 patients. While a characteristic photoreceptor mosaic was clearly revealed by AOSLO in the area unaffected by lesions in those eyes with dot-only SDD, in unaffected areas adjacent to retinal regions with predominantly ribbon SDD, photoreceptors could no longer be visualized.

Conclusion:

The invisibility of the photoreceptor mosaic in unaffected areas adjacent to retinal regions with predominantly ribbon SDD suggests degeneration in the outer segment and the interdigitation zone, which impairs the waveguiding ability of the photoreceptors. Our study implies possible differentiation of disease outcome and functional impact in different types of SDD.

Keywords: age-related macular degeneration, subretinal drusenoid deposits, dot, ribbon, photoreceptor, imaging, adaptive optics scanning laser ophthalmoscopy

INTRODUCTION

Our knowledge of age-related macular degeneration (AMD) is expanded by recognition of subretinal drusenoid deposits (SDD), originally called reticular pseudodrusen.[1] In comparison to AMD’s classical hall-marker lesion, namely drusen [2], SDD are located in the subretinal space, thus they have more direct impact on photoreceptors’ structure and function than drusen. Clinical studies have found that SDD are highly associated with progression to neovascularization (NV) and geographic atrophy (GA). [3–6] SDD have been recognized as a major precursor to AMD-related vision loss and confer risk for AMD progression independently from drusen.[1,7] The disparate location of SDD compared with that of classic drusen would suggest there may be different processes leading to late stage AMD. Recently, Spaide reported outer retinal atrophy (ORA) featuring photoreceptor degeneration after SDD regression and suggested that ORA was a distinct form of late AMD different from GA and NV.[8]

SDD have been characterized with a number of different morphologic types by multimodal imaging. Lee and co-workers classified SDD into 3 patterns (discrete, branching, and confluent) based on color fundus photography (CFP).[9] Suzuki and Spaide characterized 3 subtypes: dot (similar to the discrete pattern of Lee et al), ribbon (similar to the branching or confluent pattern of Lee et al), and midperipheral, using multimodal imaging including CFP, near infrared reflectance (IR) scanning laser ophthalmoscopy (SLO) and spectral domain optical coherence tomography (SD-OCT) [10]. Meanwhile, Lee and Ham defined 2 subtypes of SDD according to the presence of hyper- or hypo-autofluorescence. [11] Based on their appearance on SLO and OCT, Steinberg and co-workers classified SDD into ‘dot’, ‘target’, ‘ribbon’ ‘spike’ and ‘wave’ phenotypes. [12] Zhou and co-workers characterized SDD into dot, reticular (equivalent to Suzuki’s ribbon form), and confluent forms. They reported that dot SDD were independently associated with the development of neovascular AMD and the confluent form SDD were independently associated with the development of GA. [13] Regardless of the differences in these classification methods, SDD’s phenotypic variability suggests potentially different etiological events that lead to the extracellular material accumulation and variable pathological processes that confer risk for progression to late AMD.

While prominent pathological consequences of SDD involve the retinal pigment epithelium (RPE) and the choriocapillaris, [2] it is the degeneration, dysfunction, and death of photoreceptors that ultimately translates to vision loss. Thus, characterizing the structure and optical properties of the photoreceptors in areas affected by different types of SDD can provide new insights into the mechanism by which SDD cause photoreceptor degeneration. In previous studies, we have examined the photoreceptor structure alterations of dot SDD associated with different lesion stages and over the lesion’s life cycle using high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) and SD-OCT. In the present study, we examine the photoreceptor structure in the area affected by ribbon SDD using AOSLO and multimodal imaging and assess the impact of ribbon SDD on photoreceptors in comparison to that of dot SDD.

METHODS

This study followed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Boards at the University of Alabama at Birmingham and the University of California - Los Angeles. Written informed consent was obtained from all participants after the nature and possible consequences of the study were explained. The study complied with the Health Insurance Portability and Accountability Act of 1996.

Subjects and data collection

Study patients diagnosed with AMD and age-matched subjects in normal chorioretinal health were recruited from the clinical research registry of the Department of Ophthalmology and Visual Sciences of the University of Alabama at Birmingham and through the Retina Service between October 2010 and January 2017.[14] AMD presence and severity were further assessed using color fundus photographs and the Age-Related Eye Disease Study 2 (AREDS2) scale [15] for AMD by a masked, experienced grader. Participants in normal macular health met the criteria for AREDS grade 1 in both eyes, and had no clinically significant cataract, with best-corrected visual acuity of 20/25 or better. Exclusion criteria were diabetes, malignant hypertension, high myopia, retinal vascular occlusions, retinal detachment, central serous chorioretinopathy, any retinal dystrophy, glaucoma and any optic nerve disorders, past vitreoretinal surgery including laser treatment and photodynamic therapy, and refractive errors beyond ±6 D spherical and ±3 D cylinder. All subjects were white and non-Hispanic.

Clinical demographic data included sex, age, and best-corrected visual acuity (BCVA). The BCVA was measured using the Electronic Visual Acuity protocol and expressed in logarithm of the minimum angle of resolution (logMAR). [16] Multimode imaging included: stereoscopic 45° and 30° CFP (FF450 Plus fundus camera, Carl Zeiss Meditec, Dublin, California), en face 30 ° × 30 ° IR SLO (λ= 830 nm), autofluorescence (AF; excitation, 488 nm; emission > 600 nm), and SD-OCT (97 – 127 B-scans across a 20° × 20° of the macula using the enhanced depth imaging mode). IR, AF and SD-OCT images were acquired using the Heidelberg Spectralis system (Heidelberg Engineering, Heidelberg, Germany). A custom developed research AOSLO [17,18,14] was performed to image the photoreceptors in the macula. Images of various retinal locations were manually aligned on a cell-to-cell basis to create a continuous montage (Photoshop CC; Adobe Systems, Mountain View, California). Color fundus photographs were magnified and registered to the AOSLO montage by using retinal vessels and capillaries as landmarks.

Image grading

SDD presence was determined in at least two en face imaging modalities (CFP, IR, FAF) and on cross-sectional SD-OCT. [19,11,9] The stage of SDD was scored with a SD-OCT based 3-stage grading system as previously reported. [20] The phenotypic subtype of SDD was classified into dot or ribbon form. The eyes were categorized into 2 groups: those with exclusively dot SDD, and those with mixed dot and ribbon SDD. In 8 eyes of 4 subjects with the mixed phenotype, the ribbon lesions were found preferentially locating in the vicinity of the retinal vascular arcades, whereas dot lesions were more prevalent towards the central retina. Dot SDD appear as yellow-white dots on CFP, discrete hyporeflective dots with a target pattern on IR imaging, discrete hypoautofluorescent dots against a mild hyperautofluorescent background on AF imaging, and discrete subretinal accumulations with sharp peaks on SD-OCT B-scans. Ribbon SDD can be identified as interlacing yellow-white ribbons or confluent lesions on CFP, faint hyporeflective ribbons on IR imaging, interlacing hypoautofluorescent lesions on AF imaging, and broad accumulations of subretinal materials with contiguous elevation of overlying photoreceptor ellipsoid zone (EZ) on SD-OCT B-scans. [10] The presence, stage, and subtype of SDD for each subject were assessed by 2 masked authors (X.X. and X.W.). Any discrepancy was adjudicated by a senior author (Y.Z.).

Statistical Analysis

Data analysis was performed using the SPSS (Version 25.0, SPSS Inc, Chicago, IL). The Shapiro-Wilk test was applied to test data normality. The independent-samples Mann-Whitney U test was used to compare the BCVA between the group with advanced AMD and the group with non-advanced AMD, and between the subjects with exclusively dot SDD and those with mixed dot and ribbon lesions. Age and sex differences between the group with dot only SDD and the group with mixed lesions were assessed using independent-samples t test, and Fisher’s exact test, respectively. A p-value < 0.05 was considered statistically significant.

RESULTS

Thirteen patients (6 males and 7 females) aged 75.5 ± 7.3 years (range from 60 to 85 years, median 76 years), and 8 control subjects (4 males and 4 females) aged 73.5 ± 3.9 years (range from 65 to 77 years, median 75 years) were included in this study. Of 26 eyes of the 13 patients, 10 eyes of 6 patients were found with choroidal neovascularization (CNV), 2 eyes of 1 patient had central GA. The mean BCVA of eyes with advanced AMD (CNV and central GA, total 12 eyes of 7 patients) was 0.56 ± 0.71 (LogMAR), whereas the mean BCVA of eyes without advanced AMD (14 eyes of 8 patients) was 0.19 ± 0.17 (LogMAR) (p = 0.193). Seventeen eyes had both SDD and drusen, and 9 eyes had SDD only. Six eyes of 3 patients had only stage 1–2 SDD, and 20 eyes of 10 patients had stage 3 SDD. Eighteen eyes of 9 patients had exclusively dot SDD and 8 eyes of 4 patients showed mixed dot and ribbon SDD. The mean BCVA of the 16 eyes of the 8 control subjects was 0.08 ± 0.10 (LogMAR). The characteristics of the study patients are in Table 1. Six patients including 4 with predominantly dot-SDD and 2 with predominantly ribbon SDD returned for annual follow-up study [21,22]. However, the 2 subjects with predominantly ribbon SDD came back once only, 2 -years later after the baseline investigation.

Table 1.

Study patient characteristics

Number of eyes Age (years) Sex (male/female) BCVA (LogMAR)
Dot-predominant 18 73.7 ± 7.9 6/3 0.43 ± 0.60
Combined ribbon and dot 8 79.5 ± 3.9 0/4 0.21 ± 0.20
p-value / 0.197 0.049 0.495
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SDD: subretinal drusenoid deposits; BCVA: best-corrected visual acuity; LogMAR: logarithm of the minimum angle of resolution. Values are presented as mean ± standard deviation.

High resolution imaging revealed distinctive disruption of photoreceptor structure by SDD. As a reference for the normal cone photoreceptor structure, Figure 1 shows multimodal images of the macula taken in a 65-year-old normal subject. SD-OCT renders clear and well-aligned outer retinal bands indicating well maintained photoreceptor sub-cellular structure (Figures 1d & e), which is corroborated by high resolution AOSLO that discloses a clear contiguous mosaic of the photoreceptors, which are presumably cones (Figure 1f). In eyes with exclusively dot SDD (Figure 2), the EZ band was interrupted by stage 3 SDD, whereas in the unaffected region or in areas between lesions, the EZ remained discernible and continuous (Figures 2d & 2e). On AOSLO, stage 3 dot SDD featured a hyporeflective annular zone consisting of indistinct photoreceptors surrounding a reflective core that is attributable to the lesion material. Outside of the hyporeflective annulus, photoreceptors show a clear packing mosaic of hyper-reflective cells (Figure 2f). These mosaics remained visible at the follow-up visit, while the SDD progressing (Figure 2g). We examined the SDD structure and the surrounding photoreceptor mosaic in 131 lesions of this form to confirm the consistency of this finding.

Fig. 1.

Fig. 1

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Multimodal imaging of a 65-year-old subject in normal chorioretinal health. (a). Color fundus photograph. (b). Infrared reflectance. (c). Autofluorescence. (d). Spectral domain optical coherence tomography (SD-OCT) B-scan taken along the green line in panel (b). (e). The enlargement of the yellow box in panel (d) discloses characteristic outer retinal bands: external limiting membrane (ELM), ellipsoid zone (EZ), interdigitation zone (IZ), and retinal pigment epithelium (RPE). (f). Adaptive optics scanning laser ophthalmoscopy (AOSLO) of the retinal area in the yellow box in panel (b) discloses a clear mosaic of the cone photoreceptors (hyperreflective dots). Hyporeflective bands are shadows of overlying retinal capillaries.

Fig. 2.

Fig. 2

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Multimodal imaging of dot form subretinal drusenoid deposit (SDD). The patient was a 73-year-old male diagnosed with non-neovascular age-related macular degeneration and with dot-only SDD in this eye. Multimodal images were obtained at baseline visit (07/03/2013, panels (a, b, c, d, and f), and at the follow-up of 25 months (08/26/2015, panels e and g). The best-corrected visual acuity was 20/25 at baseline and remained stable during the follow-up period. (a). Color fundus photograph (CFP). (b). Infrared (IR) reflectance. (c). Autofluorescence (AF). (d). A B-scan of Spectral domain optical coherence tomography (SD-OCT) taken along the green line in panel b. (f). Adaptive optics scanning laser ophthalmoscopy (AOSLO) of the retina in the white box in panel b at the baseline. (e & g ) The SD-OCT B-scan and the AOSLO of the same retinal area shown in panels (d & f) at the follow-up, respectively. Dot SDD manifest as discrete white or yellowish spots on CFP (a), hypereflective cores with hyporeflective rings on IR (b), and discrete hypo-autofluorescent spots on AF image (c). SD-OCT B-scans show that the ellipsoid zone (EZ) band was discernible in areas between SDD and the underlying interdigitation zone (IZ) was preserved at both baseline and at the follow-up (panels d & e). The AOSLO images reveals a clear, characteristic cone photoreceptor mosaic surrounding the dot SDD (f & g), despite progression of the SDD. Yellow and aqua arrowheads indicate two typical dot SDD in multimodal imaging. Scale bar in panel c also applies to panels (a & b). Scale bar in panel (e) also applies to panel d, and scale bar in panel g applies to panel f.

In eyes containing both ribbon and dot SDD (Figures 3 & 4), the EZ bands in the lesion area on SD-OCT manifested more extensive undulation (Figures 3d & 3f) than those in eyes with exclusively dot SDD. On AOSLO, the characteristic appearance of stage-3 dot SDD could still be observed. However, photoreceptors adjacent to the lesions were no longer visible, as shown in images taken at both baseline and at the follow-up visit (Figures 3d - 3g). SD-OCT also disclosed a distinctive structural difference in the interdigitation zone (IZ). In eyes with exclusively dot SDD, the IZ was relatively well defined or preserved in areas not affected by the lesions, whereas in eyes with mixed dot and ribbon SDD, the IZ was indistinguishable across a broad retinal region.

Fig. 3.

Fig. 3

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Multimodal imaging of mixed dot and ribbon subretinal drusenoid deposit (SDD). These images were taken from the left eye of a 78-year-old patient who was diagnosed with bilateral non-neovascular age-related macular degeneration. The baseline imaging (panels (a) to (e)) was performed on 08/01/2013, and the follow-up study of 24 months (panels (f) to (g)) was on 08/05/2015. The best-corrected visual acuity was 20/70 at baseline and remained stable during the follow-up period. (a) Color fundus photography (CFP). (b) Infrared (IR) reflectance. (c) Autofluorescence (AF). Ribbon SDD manifest as broad ribbons of yellowish material composing an interlocking network on CFP (a), faint hyporeflective ribbon-like lesions on IR (b), well defined hypo-autofluorescent ribbons on AF (c). (d) The baseline B-scan of spectral domain optical coherence tomography (SD-OCT) B-scan taken along the green line in panel (b). (e) The baseline adaptive optics scanning laser ophthalmoscopy (AOSLO) of the retinal area indicated by the aqua box in panel (b). (g) The follow-up SD-OCT B-scan of the same location shown in panel (d). (g) The follow-up AOSLO of same retinal areas shown in panel (e). SD-OCT B-scans disclose that ribbon SDD form broad, diffuse and rounded elevations between the ellipsoid zone (EZ) band and the band of retinal pigment epithelium. While EZ is discernable over the SDD, the interdigitation zone (IZ) is indistinctive. On AOSLO, the characteristic appearance of stage-3 dot SDD (yellow arrowheads in panels (e and g) could still be visualized in the area mixed with ribbon SDD, but photoreceptor mosaic in the area with ribbon SDD that is adjacent to stage 3 dot SDD was no longer visible both at the baseline and at the follow-up. Scale bar in panel (c) applies to panels (a - c), Scale bar in panel (f) also applies to panel (d), and panel (e) uses the scale bar in panel (g).

Fig. 4.

Fig. 4

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Adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SD-OCT) of 2 subjects with mixed dot and ribbon subretinal drusenoid deposits (SDD). (a, c, d). Multimodal images of the fellow eye of the subject whose left eye shown in Fig. 3. The best-corrected visual acuity (BCVA) in this eye was 20/50. (b, e, f). Multiimodal images taken in the left eye of a 76-year-old patient with bilateral non-neovascular age-related macular degeneration (AMD). The BCVA was 20/25. (a, b). Color fundus photographs. (c). The SD-OCT B-scan taken along the green line in panel (a). (d). High-resolution AOSLO image of the retinal area indicted by the yellow box in panel (a). (e). The SDOCT B-scan taken along the green line in panel (b). (f) AOSLO image of the retinal area indicted by the white box in panel (b). In these cases, no visible photoreceptor mosaic adjacent to the retinal region of predominantly ribbon SDD (left portion of AOSLO images) can be observed. Notably, characteristic photoreceptor mosaic is visible adjacent to the dot SDD (right portion of AOSLO images). Scale bar in panel (e) also applies to panel (c). Panel (d) has the same scale as that of panel (f).

DISCUSSION

In this study, we observed loss of visibility of photoreceptors on the AOSLO in the retinae containing ribbon SDD in comparison to eyes with exclusively dot SDD. This finding suggests that different types of SDD may affect surrounding photoreceptors in different ways or to different extents.

The loss of visibility of photoreceptors surrounding ribbon SDD on AOSLO is unlikely to be due to a deficiency in the imaging. First, this phenomenon was detected in all regions adjacent to ribbon SDD in 8 eyes with predominant ribbon SDD areas, at both the baseline and at the follow-up. Second, while photoreceptors could not be visualized in regions adjacent to these ribbon lesion, photoreceptor mosaics could be clearly seen in the same eye (with both ribbon and dot SDD) when images were obtained in regions adjacent to dot SDD (Figures 3 & 4). Third, the invisibility of the photoreceptor mosaic in area with predominant ribbon SDD is unlikely to be related to poor imaging quality due to subject fatigue or dryness of the eye, as the subjects were instructed to rest and relax frequently to avoid these potential adverse effects.

Photoreceptor visibility on AOSLO reflects the normality of the cells’ spatial positioning and optical wave-guiding property thus it has important clinical significance. In a healthy retina, photoreceptors pack tightly in a cellular matrix with their normal orientation toward the pupil center, allowing for the AOSLO rendering a clear mosaic of the photoreceptors’ inner segments across the retina (Figure 1). Previous studies with AOSLO revealed that photoreceptor reflectivity was qualitatively reduced by stage 1 dot SDD and greatly reduced by stage 2 lesions. [14,21,23] A large dark area with indistinct photoreceptors in an AOSLO image, such as the hyporeflective annulus around the stage 3 dot SDD, implies that photoreceptors are misaligned, degenerate, and/or missing outer or inner segments. A deflected photoreceptor is neither ableto funnel incident light into the inner and outer segments nor able to reflect light back toward the AOSLO’s detector, resulting in undetectability of these cones. Waveguiding is an important optical property of the photoreceptor and is critical for producing the image of the cones on the AOSLO. [24] The waveguiding ability of a photoreceptor is mainly formed by its outer segment. If the outer segment is disrupted, light for imaging will be reduced or absent. [25] In the retinal regions with predominantly ribbon SDD, SD-OCT revealed reduced or loss of reflectivity of the EZ and IZ, indicating alterations in photoreceptors’ outer segments, which contributes a substantial portion of the reflectance of the cones. Studies of other chorioretinal disorders have also demonstrated that cone visibility on AOSLO is closely related to the status of the EZ and IZ on SD-OCT. [26,27]

SDD are now recognized biomicroscopic features of chorioretinal degeneration. They are not only a risk factor for late AMD but also cause retinal dysfunction directly. This assertion has been supported by studies which found that photopic sensitivity in regions of SDD were significantly reduced, as evaluated by microperimetry. [28,29] Photoreceptors may be victims of SDD progression and be reporters of the health of their support system. The optical property of the photoreceptors reflects the status of the cell structure. As a fundamental premise - normal function of the photoreceptors depends on sound structure of individual cells and surrounding matrix. Thus, one can infer the function of photoreceptors overlying SDD by studying their optical properties. The loss of visibility of photoreceptors around ribbon SDD on AOSLO is a clear indication of altered outer segment optical properties. Of note, although the EZ showed greater undulation on SD-OCT with accumulation of ribbon SDD, it remained well defined and continuous over most of these lesions (Figures 3 & 4). The change in the optical property of the outer segments could also be attributed to some biochemical toxicity or other physical impairment caused by the extracellular subretinal drusenoid material.

The etiology of SDD is not well understood. It may involve malfunction of RPE phagocytosis and derangement in photoreceptor outer segment shedding. The ribbon form appears to indicate a more diffuse accumulation of the extracellular material in the subretinal space than the dot form. This difference may represent different types of dysfunction and potentially different risks for development of specific subtypes of advanced AMD [10]. Zhou et al found that eyes with dot pseudodrusen had approximately a 3-fold increased risk for developing nAMD, whereas eyes with confluent pseudodrusen had a 4-fold higher risk for developing GA.[30]

The disrupted optical property of the photoreceptors as suggested by the imaging visibility associated with different types of SDD may have relevance to important disease outcomes. During progression, both dot and ribbon SDD can become confluent. The ribbon SDD may impose a broad and heavier lesion load on the affected region that one could theorize may have greater propensity for toxicity to the photoreceptors and the RPE, thereby leading to GA development. A similar process may be occurring with vitelliform deposits, which can also be associated with SDD and can progress to GA. [31] Vitelliform deposits, although not traditionally associated with AMD, were frequently (20%) observed in a cohort of patients with pure SDD and were prone to collapse overtime, resulting in atrophy. [31] In contrast, when dot SDD regress, with loss of the superjacent retinal architecture, outer retinal atrophy is commonly observed, [8,21,32] and is followed by a decrease in choroidal thickness. [33–36] This may be associated with choriocapillaris non-perfusion and ischemia, [36–39] which could promote subsequent neovascularization. However, eyes with ribbon SDD may be even “sicker” and may have more diffuse choriocapillaris abnormalities in comparison to eyes with dot SDD. Consequently, they are not even able to mount a CNV response. This hypothesis may be tested in future OCT angiography studies.

There are several limitations to our study that should be considered when assessing our findings. First, our sample size was relatively small. Although we evaluated many locations within the same eye to confirm the consistency of our findings, there is obviously a correlation bias within the same eye. Second, functional assays like microperimetry or multifocal electroretinography were not performed in these participants, making it difficult to reach definite conclusions regarding functional impact of different types of SDD in this specific cohort. Third, only a small subgroup of the subjects were evaluated in follow-up studies over a short period (2 years) due to lack of availability of the participants. To fully understand and interpret the natural history of the two types of SDD, longitudinal follow-up in more subjects over a longer period of time is warranted in a future study.

The strength of this study is the combination of AOSLO (for imaging the en face structure) and SD-OCT (for imaging the cross-sectional structure) that allowed for a high resolution examination of photoreceptor impairment at the cellular level. Repeated imaging through longitudinal follow-up suggests the disruption in IZ may also be the underlying causative mechanism accounting for the invisibility of the photoreceptors (on AOSLO) in retinal regions with predominantly ribbon SDD.

In summary, the differential appearance of photoreceptors surrounding ribbon and dot SDD on high resolution AOSLO supports the contention that specific phenotypes of SDD in eyes with AMD may have different prognostic and functional implications.

Acknowledgments:

This project was supported by NIH R01EY024378. X. Xu is supported by funding from National Natural Science Foundation of China (81800879), Fundamental Research Funds of the State Key Laboratory of Ophthalmology, China (2018KF04 & 2017QN05) and Natural Science Foundation of Guangdong Province (2017A030310372).

Funding: This project was supported by NIH R01EY024378. X. Xu is supported by funding from National Natural Science Foundation of China (81800879), Fundamental Research Funds of the State Key Laboratory of Ophthalmology, China (2018KF04 & 2017QN05) and Natural Science Foundation of Guangdong Province (2017A030310372).

Footnotes

Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of a an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.

Conflicts of interest: X. Xu, X. Wang, and Y. Zhang report no conflicts of interests. S. R. Sadda receives research funding from Allergan, Carl Zeiss Meditec, Genentech, Optos and Topcon. S. R. Sadda is a consultant for Allergan, Centervue, Genentech, Heidelberg, Iconic, Novartis, Optos, Oxurion.

Ethics approval: This study followed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Boards at the University of Alabama at Birmingham (UAB IRB-141024002 & UAB IRB-100928002) and the University of California - Los Angeles (UCLA IRB-19–000011).

Consent to participate: Written informed consent for participating in the study was obtained from participants after the nature and possible consequences of the study were explained.

Consent for publication: Written informed consent for publication was obtained from all participants.

Availability of data and material: Data and materials are available upon request.

Code availability: Not applicable.

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