Calcifications identified as risk factors in macular degeneration

Calcified nodules in the retina are associated with progression to late stages of age-related macular degeneration (AMD), researchers say.

The finding could lead to better understanding of the way the disease develops and perhaps to new treatments, according to an international team of researchers.

“Our research revealed that early changes in the back of the eye can lead to the build-up of hard mineral deposits, made of calcium and phosphate that may incorporate other types of trace metals, like magnesium," said Imre Lengyel, of Queen's University in Belfast, United Kingdom, in a prepared statement. "The build-up of these mineral deposits are an indicator of irreversible damage of the retina.”

Imre and colleagues from Queen’s University, the University of Alabama in Birmingham in the United States and other centres, as well as UK material scientists and US clinical ophthalmology practices published their finding in Science Translational Medicine.

Drusen are extracellular deposits containing lipids, minerals and proteins. They accumulate between the basal lamina of the retinal pigment epithelium (RPE) and Bruch’s membrane (BrM).

Previous research has suggest that the appearance of heterogeneous internal reflectivity within drusen (HIRD) on optical coherence tomography (OCT) images indicates an increased risk of progression to advanced AMD.

To see whether these findings could be used in the prognosis of advanced AMD, they analyzed 138 eyes from 138 patients (mean age, 80.2 years), with intermediate AMD and sequential OCT data, for the presence of HIRD on dense-volume OCT scans.

They found evidence of at least one HIRD in 62 (45%) eyes. Fifty-five (40%) progressed to advanced AMD (defined as neovascular AMD or geographic atrophy) within the next 12 months. Of these, 33 progressed to geographic atrophy only, 14 progressed to choroidal neovascularization (CNV) only, and 8 progressed to both atrophy and CNV.

The researchers determined that HIRD were significantly and independently associated with progression to advanced AMD at 12 months with an odds ratio of 6.36 (95% confidence interval, 2.99 to 13.53; P < 0.001).

In an independent cohort, they used multimodal imaging to demonstrate that progression to AMD is associated with increasing degeneration of the RPE overlying HIRD. And in a morphological analysis of clinically imaged cadaveric human eye samples, they found that that HIRD was formed by multilobular nodules.

The nodules were composed of hydroxyapatite and differed from spherules and BrM plaques. They also found other refractile features in the retinas of patients with AMD, suggesting that hydroxyapatite nodules may indicate progression to advanced AMD.

They propose that multimodal clinical imaging, used to determine the composition of macular calcifications, may help to direct therapeutic strategies and outcome measures in AMD.

In the next stages of their research, the team hope to extend these clinical observations to other patient cohorts, identification of imaging signatures before calcification, and exploring whether local and systemic Ca2+ and Mg2+ regulation are targets for AMD treatment and prevention.

“By fully understanding the causes behind the changing environment in which these large, damaging nodules grow, we could design new ways to intervene with their growth earlier in the disease process than is currently possible," said Christine Curcio from the University of Alabama.

“Identification of these risks associated with disease progression in the eye, especially in the retina, could become a diagnostic tool for monitoring the progression of retinal degeneration. This allows ophthalmologists to counsel their patients more wisely and also allow us to think about slowing or halting the progression of disease, earlier in its course.”

The team will aim to help determine new treatment options for patients, which could be as simple as modification of diet, said Jayakrishna Ambati, of the University of Virginia in Charlottesville, the United States. "The research will also allow ophthalmologists to advise their patients about prognosis more fully, based on the details found in their clinical imaging."