Discussion

In this retrospective study, we applied novel MPOD analysis tools enabling spatially resolved, topographic assessment of MP in MacTel. Both qualitative visualization and quantitative topographic analyses demonstrated significant differences across disease stages. The spatial pattern of MP loss mirrors the known spatiotemporal predilection of MacTel pathology, with pathologic changes occurring first temporally to the fovea.28 Macular pigment optical density en face maps revealed a preserved nasal–inferior “MP bridge” as a feature in intermediate to advanced disease stages. Preserved MPOD within the temporal inner ETDRS subfield was associated with a lower likelihood of disease progression.

The depletion of Müller glia plays a major role in MacTel. Lutein and Z are lipophilic and partition into cellular membranes.6,7 In healthy eyes, they are concentrated at the foveal center, defined as the area where cone photoreceptors and Müller glia are at their highest spatial densities,29 including the outer nuclear layer, with extensions into plexiform and nerve fiber layer.9,30, 31, 32 The relative contribution to total MP by Müller glia and photoreceptors in the foveola remains to be determined. As reviewed,10,11 the Müller glia hypothesis is supported by evidence from human eyes: loss of clinically detectable MP and histologically detectable Müller glia markers in donor eyes with MacTel, the detection of Müller glia markers and MP in surgically excised lamellar hole epiretinal membrane, and Müller glia abundance in the macula lutea, especially in retinal layers with high xanthophyll signal.28,29,33,34 Therefore, it appears reasonable to use MPOD as a surrogate marker for Müller glia.

Müller cells contribute to structural stabilization of the neurosensory retina, regulate metabolic exchange, and protect against oxidative stress, as well as provide neurotrophic support to photoreceptors.35,36 Additionally, MPOD correlates with photoreceptor density and structural integrity,37 and regions with preserved MP appear to exhibit slower photoreceptor degeneration.15

In MacTel, Helb et al5 described an initial MP depletion in the temporal parafoveal region, while Zeimer et al38 reported central pigment loss accompanied by perifoveal redistribution. Fundus autofluorescence studies by Wong et al39 further demonstrated that a mild increase in central autofluorescence may represent one of the earliest imaging signs of MacTel, even before other clinical or angiographic abnormalities become apparent. Esposti et al17 compared MPOD values of different disease stages, classified per the Gass and Blodi staging system,9 and did not find significant differences. However, their sample size was small, with the number of eyes per disease group ranging from 4 (stages 1 and 5) to 17 (stages 3 and 4). Chin et al16, investigating a small sample (n = 12) using heterochromatic flicker photometry for MPOD assessment, did not find differences between MacTel eyes in stages 1 and 2 compared to controls, but significant differences when comparing eyes staged 3 and 4 to controls. Müller et al15 described three qualitative MPOD distribution patterns and linked them to differences in EZ loss progression. Our research adds a quantitative component to these findings, showing that MPOD alterations indicate risk for disease progression. As preserved MP may reflect locally maintained Müller cell integrity, our findings support the hypothesis that localized preservation of MP may indicate a more stable retinal microenvironment and reduced susceptibility to disease progression in MacTel.

Our observations may, thus, have potential therapeutic implications. Current treatment strategies for MacTel, including the recently approved neuroprotective approaches,4 aim to slow disease progression rather than restore atrophic retinal structure. Consequently, therapeutic intervention may be most effective at stages when retinal architecture is still partially preserved. Regions with preserved MPOD may therefore represent retinal areas where the underlying cellular microenvironment remains sufficiently intact to respond to neuroprotective interventions. While partial recovery of the EZ has been reported in some cases,40,41 restoration of MP has not been demonstrated to date. This suggests that once MP is depleted, the associated cellular structures, particularly Müller cells, may already be irreversibly compromised. Consistent with this interpretation, previous studies have shown that after oral supplementation with lutein and Z, an increase in MP was detected only in retinal areas where pigment was present at baseline, whereas no increase was observed in regions where MP was already absent.38 Taken together, these findings support the hypothesis that early therapeutic intervention, before complete MP loss, may offer the greatest potential to modulate disease progression. Spatially resolved MPOD mapping may help to identify disease stages in which neuroprotective therapies could be most effective.

We observed a paradoxical association of superior outer MPOD with disease progression. However, this finding is likely of limited relevance. The ETDRS outer ring corresponds to an eccentricity of approximately 3 to 6 mm (≈9–19°), which lies largely outside the characteristic MacTel area typically described at approximately 4–7° eccentricity.28 As a result, the outer ETDRS sectors encompass retinal areas that are most likely spatially too large and too peripheral to adequately capture focal MP redistribution characteristic of MacTel. In addition, MPOD outside the central subfield and inner ETDRS ring is generally low, and differences may be statistically significant, yet clinically irrelevant. Consistent with this finding, the spatial MPOD maps (Fig 2) revealed no relevant alterations within the outer ring across different disease stages. The lack of consistent associations in the outer ETDRS subfields, therefore, underscores the strong regional specificity of MacTel-related MP alterations.

The MPOD maps presented in Figure 2 show a bridge of relatively preserved MPOD inferonasally inside the MacTel area. As discussed, structural alterations in MacTel occur first temporally to the fovea. To the best of the authors' knowledge, this is the first described pathologic finding that does not follow this typical distribution. However, hemispherical differences have been recognized in healthy maculae: Cellular populations and the retinal vasculature are generally denser in the superior compared to the inferior retina, which may render it more vulnerable to early neurodegenerative changes than the inferior hemisphere.19,42, 43, 44

Several limitations should be considered. First, no correction for lens status was applied, which may have influenced autofluorescence-based MPOD measurements. Second, the follow-up period was relatively short, limiting the ability to evaluate the impact of MPOD distribution on disease progression. Third, the presented study does not investigate the association between topographical MPOD, structural, and vascular metrics, which is warranted in future research.

Strengths of this study include the application of a novel, validated, and spatially resolved MPOD analysis approach and the large study cohort, allowing a detailed assessment of MP distribution across multiple disease stages.

In conclusion, we describe distinct disease stage-specific MPOD distribution maps and identify the prognostic relevance of quantitatively measured MPOD. Our results may help identify eyes that benefit most from neuroprotective treatment strategies before irreversible vision loss occurs. Future research should further investigate the relation between quantitative MPOD, structural, and microvascular changes to further elucidate drivers of MacTel pathology.