Research ArticleRetinal Disease

Calcified nodules in retinal drusen are associated with disease progression in age-related macular degeneration

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Science Translational Medicine  07 Nov 2018:
Vol. 10, Issue 466, eaat4544
DOI: 10.1126/scitranslmed.aat4544

Imaging AMD progression

Age-related macular degeneration (AMD) is the leading cause of vision impairment in older individuals. About 20% of those who develop AMD will progress to vision loss. Reliable methods to identify patients at risk of progression to late stage AMD are lacking. Tan et al. used multimodal imaging, histological analysis and nano-analytical measurements to show that calcified nodules in the retina were associated with AMD progression. The authors found that these nodules were composed of hydroxyapatite and could be distinguished from other types of calcifications. The results suggest that multimodal imaging might help to guide therapeutic approaches and outcome measures in patients at risk of progressing to advanced AMD.


Drusen are lipid-, mineral-, and protein-containing extracellular deposits that accumulate between the basal lamina of the retinal pigment epithelium (RPE) and Bruch’s membrane (BrM) of the human eye. They are a defining feature of age-related macular degeneration (AMD), a common sight-threatening disease of older adults. The appearance of heterogeneous internal reflectivity within drusen (HIRD) on optical coherence tomography (OCT) images has been suggested to indicate an increased risk of progression to advanced AMD. Here, in a cohort of patients with AMD and drusen, we show that HIRD indicated an increased risk of developing advanced AMD within 1 year. Using multimodal imaging in an independent cohort, we demonstrate that progression to AMD was associated with increasing degeneration of the RPE overlying HIRD. Morphological analysis of clinically imaged cadaveric human eye samples revealed that HIRD was formed by multilobular nodules. Nanoanalytical methods showed that nodules were composed of hydroxyapatite and that they differed from spherules and BrM plaques, other refractile features also found in the retinas of patients with AMD. These findings suggest that hydroxyapatite nodules may be indicators of progression to advanced AMD and that using multimodal clinical imaging to determine the composition of macular calcifications may help to direct therapeutic strategies and outcome measures in AMD.

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