RPE-contiguous Hyperreflective Foci Associated with Visual Function

In this study, hyperreflective foci contiguous with the RPE were substantially more frequent and numerous in intermediate AMD than in early AMD or normal aging and clustered at the foveal center. Their presence and higher burden were independently associated with worse BCVA, low-luminance VA, contrast sensitivity and scotopic sensitivity. This heatmap from the study shows the topographic rpeHRF distribution, with rings representing the central subfield, inner and outer rings of the ETDRS grid. rpeHRF were most concentrated within the central subfield, followed by the inner and outer rings. Photo: Goerdt L, et al. Am J Ophthalmol. March 2026. Click image to enlarge. Treatments for age-related macular degeneration (AMD) largely target late-stage disease, leaving an unmet need in early and intermediate stages. To help identify high-risk eyes for earlier intervention, the multicenter MACUSTAR study set out to test whether hyperreflective foci contiguous with the retinal pigment epithelium (rpeHRF)—an OCT feature thought to precede intraretinal migration and linked to future atrophy—correlate with key functional deficits such as contrast sensitivity and rod-mediated dark adaptation. The findings, recently published in the American Journal of Ophthalmology, revealed an independent association between rpeHRF and impaired visual function, positioning this structural finding as a practical prognostic biomarker for future clinical trials.The MACUSTAR study, conducted across 20 sites in seven European countries, comprised 673 eyes from 673 participants (mean age: 71.7; 66.4% female), categorized as normal aging (n=56), early AMD (n=34) and intermediate AMD (n=583). Participants underwent a comprehensive panel of tests; functional testing included best-corrected and low-luminance visual acuity (BCVA, LLVA) using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, Pelli-Robson contrast sensitivity, mesopic/scotopic microperimetry and rod‑mediated dark adaptation at 12°. Using custom software, the researchers quantified rpeHRF on each patient’s B-scan, then used several methods of analysis to determine associations between rpeHRF burden and visual function.The data showed that rpeHRF prevalence and burden rose with disease stage, present in 5.4% of normal eyes, 17.6% of early AMD eyes and 48.0% of intermediate AMD eyes. Mean counts increased from 0.16 ±0.85 (normal) to 0.33 ±0.96 (early AMD) and 1.61 ±2.49 (intermediate AMD).All structural biomarkers measured in the study, shown in the table below, indicated a stronger disease load in intermediate AMD eyes with rpeHRF.Structural metricNormal agingEarly AMDIntermediate AMDPresence of subretinal drusenoid deposits0.0%11.8%26.9%Intraretinal hyperreflective foci area (mm2)Not available0.0310.111Retinal pigment epithelium-drusen complex volume (mm3)Not available0.00070.013 Eyes with intermediate AMD also scored worse in all but one visual function test (rod‑mediated dark adaptation), though the authors point out that fewer data points were available for this metric compared to other visual functions. Those findings were as follows:Functional vision metricNormal agingEarly AMDIntermediate AMDBCVA-0.040.010.03LLVA0.140.190.24Contrast sensitivity1.711.631.55Mesopic microperimetry (dB)2.202.632.79Scotopic microperimetry (dB)2.312.903.12Rod-mediated dark adaptation (rod intercept time in minutes)4.248.237.65 “Our findings confirm our hypothesis of rpeHRF presence and count being associated with visual function impairment,” the researchers wrote in their paper. They explained that while the multifactorial pathophysiology of AMD has yet to be fully understood, “RPE cells are thought to experience progressive dysfunction and eventually epithelial-mesenchymal transition,” which likely occurs “at the origin of the RPE cells’ migration toward the inner retina, where they can be identified as intraretinal hyperreflective foci.” This process may begin before the cells leave the monolayer, they noted, “which indicates that rpeHRF formation may be a very early biomarker for RPE pathology.”The researchers also observed that rpeHRF cluster most densely at the foveal center and thin out with increasing eccentricity, paralleling the cone photoreceptor topography of the human retina. “This distribution pattern is shared by other AMD-related findings, such as sub-RPE drusen, choriocapillaris flow deficits and large hypertransmission defects,” they noted, the latter of which were identified in 4.8% of intermediate AMD eyes in this study.Collectively, the authors note that these findings support rpeHRF as a potential prognostic biomarker and enrichment factor for clinical trials. “Ongoing longitudinal analyses focus on rpeHRF’s prognostic value for intermediate AMD progression to late-stage disease manifestations and will further clarify rpeHRF’s presumed migration pattern toward intraretinal vessels located in the inner ring of the ETDRS grid,” they concluded.Click here for the journal source. Goerdt L, Basten V, Terheyden JH, et al. Hyperreflective foci contiguous with the RPE associate with visual function in aging, early and intermediate AMD: MACUSTAR study report. Am J Ophthalmol. March 23, 2026. [Epub ahead of print].  This article was developed by the editorial staff in conjunction with experts in the field. In the process, AI may have been among the editorial tools used to meet the goals of human editors, who approved all content.