What do we know about the macular pigment in AMD: the past, the present, and the future

Abstract

Carotenoids are lipophilic isoprenoid pigments with a common C₄₀H₅₆ core chemical structure that are naturally synthesized by many plants, algae, bacteria, and fungi. Humans and animals cannot synthesize carotenoids de novo and must obtain them solely through dietary sources. Among the more than 750 carotenoids in nature, only lutein, zeaxanthin, meso-zeaxanthin, and their oxidative metabolites selectively accumulate in the foveal region of the retina where they are collectively referred to as the macular pigment (MP) of the macula lutea. MP serves an ocular protective role through its ability to filter phototoxic blue light radiation and also via its antioxidant activity. These properties have led to the hypothesis that carotenoids may protect against the development of age-related macular degeneration (AMD), the most common cause of blindness in the aged population >60 years old. Epidemiological studies have supported this by showing that patients with lower concentrations of serum carotenoids and macular pigment optical density (MPOD) measurements are at a higher risk of developing AMD. Conversely, nutritional supplementation and diets rich in lutein and zeaxanthin readily impact MP concentrations and reduce the risk of progression to advanced AMD, and the AREDS2 supplement formulation containing 10 mg of lutein and 2 mg of zeaxanthin is the standard-of-care recommendation for individuals at risk for visual loss from advanced AMD. This article reviews the rich history of research on the MP dating back to the 1700s and outlines their potential for further therapeutic improvements for AMD in the future.

Fig.1

Structure of macular carotenoids. Lutein, zeaxanthin, and meso-zeaxanthin are the three carotenoids present in the primate macula. They are structural isomers with the same molecular formula C₄₀H₅₆O₂

Fig. 2

Topography of the macular pigment, schematically showing the distribution of the yellow macular pigment across the retina: horizontally (top) and vertically (bottom)

Fig. 3

Absorption spectra of lutein (red) and zeaxanthin (blue) in olive oil. A mixture of lutein plus zeaxanthin (dashed black line) closely approximates the absorption spectrum of the macular pigment in the living human eye

Fig.4

The retinal distribution of macular pigment binding proteins. a GSTP1 labeling of foveal cones in the macula of a 3-year-old monkey. This montage shows strongest labeling by antibody against GSTP1 (red) over the myoid and ellipsoid regions of cones identified by monoclonal antibody (7G6, green). b A low-magnification view of a near-foveal retina section in which N-62 StAR (red) identifies StARD3, an anti-cone arrestin monoclonal antibody (7G6, green) identifies monkey cones. Images courtesy of Dr. Jeanne M. Frederick

Fig. 5

Possible pathway for MP carotenoid uptake, transport, and accumulation in the human retina. Choroicapillaris (CH); Bruch’s membrane (BM); Retinal pigment epithelium (RPE); Inner segments (IS); Outer plexiform layer (OPL); Inner plexiform layer (IPL), (►) Retinal transport pathway

Fig. 6

Fundus images of A, normal macula; B, macula with confluent soft drusen C, macula with dry AMD; D, macula with wet AMD

Fig. 7

Macular pigment readout from an unsupplemented normal control obtained by dual wavelength autofluorescence imaging on a Heidelberg Spectralis. a Macular pigment tracing at 0.5° (red line), 2° (blue line), and 9° (green line). b Autofluorescent image showing the fovea and the degrees (0.5°, red; 2°, blue; 9°, green) from the center of the macula lutea