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Age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is the leading cause of legal blindness in the industrialized world. AMD is characterized by accumulation of extracellular deposits, namely drusen, along with progressive degeneration of photoreceptors and adjacent tissues. AMD is a multifactorial disease encompassing a complex interplay between ageing, environmental risk factors and genetic susceptibility. Chronic inflammation, lipid deposition, oxidative stress and impaired extracellular matrix maintenance are strongly implicated in AMD pathogenesis. However, the exact interactions of pathophysiological events that culminate in drusen formation and the associated degeneration processes remain to be elucidated. Despite tremendous advances in clinical care and in unravelling pathophysiological mechanisms, the unmet medical need related to AMD remains substantial. Although there have been major breakthroughs in the treatment of exudative AMD, no efficacious treatment is yet available to prevent progressive irreversible photoreceptor degeneration, which leads to central vision loss. Compelling progress in high-resolution retinal imaging has enabled refined phenotyping of AMD in vivo. These insights, in combination with clinicopathological and genetic correlations, have underscored the heterogeneity of AMD. Hence, our current understanding promotes the view that AMD represents a disease spectrum comprising distinct phenotypes with different mechanisms of pathogenesis. Hence, tailoring therapeutics to specific phenotypes and stages may, in the future, be the key to preventing irreversible vision loss.

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Fig. 1: Manifestations of AMD.
Fig. 2: Annual incidence of AMD by 5-year age groups.
Fig. 3: Manifestations of AMD as observed on colour fundus photography.
Fig. 4: Subretinal drusenoid deposits.
Fig. 5: Model of AMD pathogenesis.
Fig. 6: High-resolution OCT scans showing different stages of AMD.
Fig. 7: Therapeutic effect of anti-VEGF treatment on exudative MNV.
Fig. 8: Differential enlargement rates of GA.
Fig. 9: Exudative macular neovascularization in AMD.
Fig. 10: Non-exudative macular neovascularization.

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Acknowledgements

M.F. and S.S.-V. were in part supported by National Institutes of Health Core Grant (EY014800), and an Unrestricted Grant from Research to Prevent Blindness, New York, NY, to the Department of Ophthalmology & Visual Sciences, University of Utah and the German Research Foundation (DFG) grant FL 658/4-1 and FL 658/4-2.

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Authors

Contributions

Introduction (E.Y.C., U.C., R.H.G., and M.F.); Epidemiology (C.C.K., U.C., R.H.G., T.D.L.K., M.F. and E.Y.C.); Mechanisms/pathophysiology (T.D.L.K., W.T.W., M.F., U.C., R.H.G., E.Y.C. and S.S.-V.); Diagnosis, screening and prevention (M.F., S.S.-V., U.C., E.Y.C. and R.H.G.); Management (R.H.G., U.C., E.Y.C. and M.F.); Quality of life (U.C.); Outlook (E.Y.C., U.C., R.H.G. and M.F.); Overview of Primer (E.Y.C., U.C., R.H.G. and M.F.).

Corresponding authors

Correspondence to Monika Fleckenstein or Emily Y. Chew.

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Competing interests

M.F. reports grants from Heidelberg Engineering, Genentech/Roche, Novartis and Optos; and personal fees from Bayer, Heidelberg Engineering, Genentech/Roche and Novartis; and non-financial support from Heidelberg Engineering, Optos and Zeiss Meditech, outside the submitted work. In addition, M.F. has a patent, US20140303013 A1, pending. R.H.G serves on the advisory boards of Apellis, Bayer, Genentech/Roche and Novartis. U.C. reports personal fees from Apellis, Alimera, Boehringer Ingelheim, Iveric Bio, Novartis, and Roche. S.S.-V. reports grants from Acucela/Kubota Vision, grants and personal fees from Allergan, personal fees from Bayer, non-financial support from Carl Zeiss MediTec, non-financial support from Centervue, personal fees from Gailmedix, personal fees and non-financial support from Heidelberg Engineering, grants from Katairo, grants and personal fees from Novartis, grants and personal fees from Roche, personal fees from Oxurion, grants and personal fees from Bioeq/Formycon, personal fees from Apellis, grants from SparingVision, grants from Pixium, outside the submitted work. E.Y.C., T.D.L.K and W.T.W. are co-inventors on a patent application (‘Methods and systems for predicting rates of progression of age-related macular degeneration’). W.T.W. is a current employee at Janssen Research and Development. C.C.K. declares no competing interests.

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Nature Reviews Disease Primers thanks C. Curcio, C. Delcourt and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Macula

An area in the centre of the retina, which harbours the area of sharpest vision.

Drusen

Focal deposits located between the retinal pigment epithelium (RPE)–basal lamina and the subRPE space (the inner collagenous layer of Bruch’s membrane).

Subretinal drusenoid deposit

(SDD). A drusen-like deposit located between the apical aspect of the retinal pigment epithelium and the subretinal space. SDD on optical coherence tomography correlates with the ‘reticular pseudodrusen’ pattern, described in en face imaging modalities.

Choriocapillaris

The innermost layer of the choroidal vasculature.

Scotoma

An area of partial or complete vision loss in the visual field.

Macular neovascularization

(MNV). Denotes neovascular disease in the macula from many causes. In AMD, neovascularization may start from the choroid (also termed choroidal neovascularization (CNV)) or in the outer retina.

Basal linear deposits

(BLinD). Thin layer of drusen material usually continuous with drusen.

Lutein and zeaxanthin

Two types of xanthophyll carotenoids in the retina.

Linkage disequilibrium

Non-random association of alleles at different loci.

Lead variant

The most associated variant for the lead trait at a given locus.

Trickling GA

Subtype of geographic atrophy (GA) with rapid enlargement and phenotypic features, such as extensive subretinal drusenoid deposits, deposition of subRPE material and a thin choroid.

Microangiopathy

A disease of small blood vessels.

Basal laminar deposits

(BLamD). Focal deposits located between the retinal pigment epithelium and its basement membrane.

Lipofuscin

Autofluorescent material that accumulates progressively over time in lysosomes of post-mitotic cells such as the retinal pigment epithelium.

Malondialdehyde

A product of lipid oxidation and a marker of oxidative stress.

Central visual field defect

Area of partial or complete vision loss in the central visual field.

Visual acuity

A point measure that reflects function in a small area of the retina, the fovea. It is a reproducible metric and used widely both in clinical practice and in research.

Hard exudates

Lipid molecules that accumulate within the retina from the abnormally leaky blood vessels.

Mediterranean diet

A diet comprising a well-balanced combination of foods with high consumption of plant foods (such as fruits, vegetables and cereals), moderate consumption of fish and wine, low consumption of dairy products and meat, and monounsaturated fat as the primary fat source.

Alternate Mediterranean diet (aMeDi) score

A scoring system that ranges from 0 to 9, with higher scores indicating a higher adherence to the diet. Alternate part refers to a variation in the diet that is most typical of the Mediterranean diet found in Europe.

Intravitreal injection

A procedure to administer, typically, a drug, directly into the vitreous cavity of the eye.

Pro re nata

Latin for ‘as needed’ or ‘as the circumstances arise’. In the context of AMD, this term is used for a ‘reactive’ treatment strategy for exudative neovascular AMD; treatment is given on monthly review only when disease activity is noted.

Lampalizumab

A selective complement factor D inhibitor.

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Fleckenstein, M., Keenan, T.D.L., Guymer, R.H. et al. Age-related macular degeneration. Nat Rev Dis Primers 7, 31 (2021). https://doi.org/10.1038/s41572-021-00265-2

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