Lesion-Centered Functional Trajectories Reveal Early Retinal Sensitivity Decline in Intermediate Age-Related Macular Degeneration: PINNACLE Study Report 15.

PURPOSE: To characterize lesion-centered functional decline in intermediate age-related macular degeneration, including measurement variability, spatial vulnerability, predetection functional changes, and lesion-specific sensitivity trajectories.

DESIGN

Longitudinal analysis of microperimetry from the prospective, multicenter PINNACLE study (NCT06682455).

PARTICIPANTS

Overall, 264 participants contributing 422 eyes were included. Focal event analyses included 338 optical coherence tomography-defined events from 131 eyes of 113 participants.

METHODS

Participants underwent mesopic microperimetry using a standard 24-point grid. Optical coherence tomography-defined events triggered lesion-centered 5-point testing. Repeatability was assessed using linear mixed-effects models. Lesion-centered sensitivity trajectories were estimated using spatiotemporal generalized additive mixed models incorporating measured postdetection focal-grid data and spatially interpolated predetection standard-grid data. A secondary piecewise linear mixed-effects model quantified changes before and after event detection.

MAIN OUTCOME MEASURES: Point-wise microperimetry repeatability, sensitivity loss of ≥7 dB, relative and absolute scotoma, and model-estimated lesion-centered sensitivity trajectories.

RESULTS

The point-wise coefficient of repeatability was 7.61 dB (95% confidence interval [CI], 7.58-7.64) for standard-grid testing and 13.00 dB (95% CI, 12.76-13.21) for lesion-centered testing. The 338 events comprised 240 ellipsoid zone/interdigitation zone (EZ/IZ) loss events, 85 drusen-collapse events, and 13 subretinal-fluid events. Within 2 years, the risk of sensitivity loss of ≥7 dB was lower at parafoveal (hazard ratio, 0.66; 95% CI, 0.51-0.84) and perifoveal locations (hazard ratio, 0.68; 95% CI, 0.53-0.87) than at foveal locations. Model-estimated sensitivity at EZ/IZ loss sites declined before detection by 0.57 dB/y (95% CI, 0.25-0.89 dB/y) and continued after detection, reaching 0.94 dB/y (95% CI, 0.55-1.34 dB/y) during the late postdetection period. Drusen-collapse sites showed no clear longitudinal decline. Subretinal-fluid events showed an immediate loss of 2.18 dB (95% CI, 0.84-3.53), followed by early decline and possible later improvement. Matched control locations remained stable.

CONCLUSIONS

Localized functional decline in intermediate age-related macular degeneration is characterized by measurement variability, central spatial vulnerability, and lesion-specific trajectories. Model-estimated sensitivity decline was most evident at sites of EZ/IZ loss. These findings support structurally and spatially informed microperimetry endpoints while highlighting substantial measurement variability.