Re: Zekavat et al.: Photoreceptor layer thinning is an early biomarker for age-related macular degeneration: epidemiological and genetic evidence from UK Biobank OCT data (Ophthalmology. 2022;129:694–707)

Abstract

Zekavat et al1Zekavat S.M. Sekimitsu S. Ye Y. et al.Photoreceptor layer thinning is an early biomarker for age-related macular degeneration: epidemiologic and genetic evidence from UK Biobank OCT data.Ophthalmology. 2022; 129: 694-707Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar conducted a cohort study in the UK and reported that 10 years of data proving photoreceptor segment thinning precedes retinal pigment epithelium and Bruch’s membrane complex thickening by decades, and is the retinal layer most strongly predictive of future age-related macular degeneration (AMD) risk. We congratulate the authors on a careful trial with important results. However, we would like to offer an alternative explanation. As proposed by Zekavat et al,1Zekavat S.M. Sekimitsu S. Ye Y. et al.Photoreceptor layer thinning is an early biomarker for age-related macular degeneration: epidemiologic and genetic evidence from UK Biobank OCT data.Ophthalmology. 2022; 129: 694-707Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar photoreceptor segment thinning was observed throughout the lifespan of the individuals analyzed. A study by Curcio et al2Curcio C.A. McGwin Jr., G. Sadda S.R. et al.Functionally validated imaging endpoints in the Alabama Study on Early Age-related Macular Degeneration 2 (ALSTAR2): design and methods.BMC Ophthalmol. 2020; 20: 196Crossref PubMed Scopus (19) Google Scholar showed that, in healthy retinal aging, cones seem to be resilient—any possible loss of cone photoreceptors is too small to be distinguishable from the large interindividual differences in cone density. The resilience of cones is a factor that limits our understanding of the transition between healthy retinal cone function in aging and early AMD. A study by Baraas et al3Baraas R.C. Horjen Å. Gilson S.J. et al.The relationship between perifoveal L-cone isolating visual acuity and cone photoreceptor spacing-understanding the transition between healthy aging and early AMD.Front Aging Neurosci. 2021; 13732287Crossref PubMed Scopus (1) Google Scholar showed that the transition between healthy aging of cone structures and changes in cone structures secondary to early AMD relates to outer segment (OS) shortening. There was a significant correlation between age and photoreceptor inner segment (IS) length, but not between age and photoreceptor OS length at 5° eccentricity. There was a significant difference in OS length at 5° eccentricity between early AMD and healthy controls aged ≥ 50 years. There was no significant difference in IS length between early AMD and healthy controls aged ≥ 50 years. Because the loss of function in healthy controls cannot be explained by loss of cones or changes in OS length, the most parsimonious explanation is that it is related to IS shortening. Thus, it may be that the combined effect of normal age-related IS shortening and the OS shortening associated with early AMD together explain the significant loss of L-cone function observed in those with early AMD and a medium-to-high risk of progression. This finding indicates that the transition between healthy aging and early AMD seems to be related mainly to structural changes in the OS length at 5° eccentricity. Photoreceptor Layer Thinning Is an Early Biomarker for Age-Related Macular Degeneration: Epidemiologic and Genetic Evidence from UK Biobank OCT DataOphthalmologyVol. 129Issue 6PreviewDespite widespread use of OCT, an early-stage imaging biomarker for age-related macular degeneration (AMD) has not been identified. Pathophysiologically, the timing of drusen accumulation in relationship to photoreceptor degeneration in AMD remains unclear, as are the inherited genetic variants contributing to these processes. Herein, we jointly analyzed OCT, electronic health record data, and genomic data to characterize the time sequence of changes in retinal layer thicknesses in AMD, as well as epidemiologic and genetic associations between retinal layer thicknesses and AMD. Full-Text PDF ReplyOphthalmologyPreviewWe thank Dr Liu et al for their correspondence and have performed new analyses to distinguish inner and outer segment (IS, OS) associations with aging and with incident AMD in response. Full-Text PDF