Visual cycle metabolites: Cause of AMD?

September 1, 2016

Article

Oxidative stress stemming from a growing accumulation of visual cycle adducts may play an important role in the pathogenesis of AMD, suggest new findings.

Reviewed by Janet R. Sparrow, MD

New York-Evidence to date suggests that age-related macular degeneration (AMD) is a multifactorial disease.

However, new findings suggest that oxidative stress stemming from a growing accumulation of visual cycle adducts may play an important role in the pathogenesis of AMD, said Janet R. Sparrow, MD.

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“There are a number of genes that have been implicated in AMD and there are likely multiple modifiable environmental factors at work,” said Dr. Sparrow, Anthony Donn Professor of Ophthalmic Science, Columbia University, New York.

But the disease process probably also involves photo reactive fluorescent compounds that are produced inadvertently by the visual cycle and are deposited secondarily into the retinal pigment epithelium (RPE). Other changes in photoreceptor cells and in the choroid occur secondary to the dysfunction in RPE cells, she noted.

At least 34 different genetic loci have been associated with AMD, Dr. Sparrow noted.

Nongenetic risk factors include age, smoking, nutrition, and sunlight. And while patients may not be able to reduce genetic risk factors for AMD or increasing age, they can take such positive steps as smoking cessation, appropriate nutrition that is high in antioxidative compounds, and sun protection, such as sunglasses.

The protective effects of smoking cessation, increased intake of antioxidants, and sunglasses all play roles in reducing oxidative stress in the visual system, particularly in RPEs.

All cells are subject to oxidative stress, she said, but the visual system appears to be particularly vulnerable.

Visual cycle adducts

The visual cycle produces adducts, bisretinoid fluorophores that accumulate in RPE cells as the lipofuscin of the cells. The yellow-orange fluorescence emitted from lipofuscin is a prominent feature of aging RPE cells.

These fluorophores are best known to ophthalmologists as the source of fundus autofluoresence. This 488-nm peak can be imaged by confocal scanning laser ophthalmoscopy using short wavelength excitation.

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“Fundus autofluorescence is recorded every day in retinal clinics because it serves as a marker for disease,” Dr. Sparrow said. “The fluorescent properties and spatial distributions of fundus autofluorescence change depending on the disease and the progression.

“By understanding what these compounds are and how they behave, we also improve the interpretation of fundus autofluorescence images and approaches to quantifying fundus autofluorescence,” she said.

Visual cycle adducts form as a result of reactions of vitamin A aldehyde during the visual retinoid cycle. These adducts are byproducts of the visual cycle and serve no functional purpose.

More importantly, in terms of AMD, fluorophores are toxic and the eye has no mechanism to remove these compounds. They accumulate over time and contribute to oxidative stress that can lead to chronic disease.

“AMD is likely a disease that builds up over years,” Dr. Sparrow said. “Over how many years, we don’t know.

“The building evidence that lifetime light exposure may play a role in the pathogenesis of AMD supports the idea that visual adducts and their photo reactivity are important players,” she said. “And you immediately think of very easy preventative or protective actions like wearing sun glasses and reducing sun exposure.”

There is growing evidence to support several lines of reasoning leading to the conclusion that visual adducts play a role in AMD.

Accumulation with age

The first is that they accumulate with age. As fluorophores accumulate in RPE cells, fundus autofluoresence intensity increases. The pathogenesis of AMD is thought to begin in RPE cells and the underlying Bruch’s membrane.

Evidence for the toxicity of fluorophores can be seen in recessive Stargardt’s disease where the accumulation of these compounds in abundance is responsible for RPE cell death at an early age.

It is known that visual cycle adducts are photo reactive, she continued. It is thought that this light sensitivity and reactivity accounts for the toxic effects on RPE cells. Photo oxidation leads to degradation and fragmentation into a mixture of reactive aldehydes and dicarbonyls.

These small reactive molecules produced by photo degradation react with and damage proteins. Proteins that have been modified by dicarbonyls can be detected in drusen deposits in Bruchs membrane, a well-known risk factor for AMD.

The dicarbonyls released from photo-degraded visual cycle adducts also cross-link proteins. Cross-linked collagen is a recognized feature of the aging Bruch’s membrane.

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The photo oxidative processes that are initiated by visual cycle adducts could be one of the processes that explain why increased antioxidant intake, either through dietary changes or by supplementation, appears to protect against progression to late AMD. The same photo oxidative process could provide a mechanism for the observed relationship between AMD and lifetime light exposure.

“Visual cycle adducts likely contribute to AMD within the framework of other factors,” Dr. Sparrow said. “They are not the sole cause, but they appear to be contributors to the pathogenesis of AMD.”

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Janet R. Sparrow, MD

E: jrs88@cumc.columbia.edu

This article was adapted from Dr. Sparrow’s presentation during Retina Subspecialty Day at the 2015 meeting of the American Academy of Ophthalmology. Dr. Sparrow did not indicate any proprietary interest in the subject matter.