Novel clinical biomarkers of disease in early stages of age-related macular degeneration

© 2014 Dr. Zhichao WuBackground: The lack of effective disease biomarkers in the early stages of age-related macular degeneration (AMD) is a major impediment to the ability to sensitively identify individuals at risk of progression to the late stages where vision is threatened, and thus also the development and evaluation of novel interventions that aim to slow or prevent such progression. Aims: To investigate and identify potential anatomical and functional biomarkers that can be effectively used for clinical studies in the early stages of AMD. Methods: Functional markers including low luminance visual acuity (LLVA), microperimetry and multifocal electroretinography (mfERG) were examined in participants with the early stages of AMD at cross-section and longitudinally over a 12-month period. Structural measures were then developed via identification on spectral-domain optical coherence tomography (SD-OCT), and their relationship with functional changes was examined. Results: The intrasession test-retest variability of microperimetry was improved by discarding the first examination for participants who had not previously performed microperimetry before, since it was subject to a learning effect. LLVA was on average no more effective than best-corrected visual acuity (BCVA), in detecting functional changes in the early stages of AMD, with microperimetry detecting a greater extent than both acuity measures. The magnitude of measured functional deficit was also greater on microperimetry than mfERG. When examined longitudinally, microperimetry was able to detect subtle functional changes over the 12-month period in intermediate AMD eyes that was not detected by LLVA or BCVA, especially in the parafoveal region. Longitudinal changes on mfERG were insignificant for implicit time and unclear for response amplitudes. In AMD eyes, the relative intensity of the inner-segment ellipsoids (ISe) band on SD-OCT correlated with mfERG implicit time and was reduced compared to control participants. The degree of retinal pigment epithelium (RPE) band elevation and ISe band integrity on SD-OCT were found to be independent predictors of microperimetric retinal sensitivity. In a retrospective, longitudinal analysis, a unique series of features that preceded the development of atrophy on SD-OCT was described as “nascent geographic atrophy (nGA)”. These features were present in a notable percentage of intermediate AMD eyes when examined in a cross-sectional study. The microperimetric retinal sensitivity in areas of nGA were reduced on average compared to surrounding areas of drusen and/or pigmentary abnormalities, but were not consistently the worst performing point in an eye. Conclusions: These findings show that microperimetry can be a potentially useful functional biomarker in the early stages of AMD. The structural parameters determined on SD-OCT can also provide rapidly acquired, more objective biomarkers, some of which correlate with the functional measures. Unique anatomical features detected on SD-OCT that were defined as nGA, appears to be the most specific marker to predict the development of atrophy. These novel clinical biomarkers can now be exploited to better understand the disease severity and progression for eyes with the early stages of AMD, and to improve the evaluation of novel interventions for these stages