Calcified Nodules Linked to AMD Progression

Diana Phillips

November 08, 2018

The presence of a specific type of calcified nodule in the retinal drusen of patients with age-related macular degeneration (AMD) is associated with a more than sixfold increased risk for late-stage progression of the disease, a study has shown.

In a cohort of patients with AMD, progression to advanced AMD was observed in those who had histological and imaging evidence of sprawling patterns of polycrystalline hydroxyapatite (HAP) nodules in the extracellular deposits that accumulate in the retina, Anna C.S. Tan, MD, Vitreous Retina Macula Consultants of New York, New York City, and colleagues report in a research article published online November 7 in Science Translational Medicine.

Although previous research has linked the reflective pattern called heterogeneous internal reflectivity within drusen (HIRD) with progression to advanced AMD, this is the first study to identify the composition of the nodules that appears to indicate worsening of the sight-robbing disease. The findings may offer insight into the development of more targeted therapeutic approaches, the authors write.

To investigate early events or changes associated with a worse disease course in AMD, the investigators used a combination of clinical, histopathologic, and molecular imaging techniques across two cohorts of patients with AMD and drusen.

In the first cohort of 17 patients, the investigators used multimodal clinical imaging of 97 HIRD in 21 eyes to define optical coherence tomography (OCT) "signatures" that predict an increased risk for progression in eyes with intermediate AMD. They then sought to replicate the progression risk findings in a 12-month longitudinal observation study comprising 138 patients (mean age, 80.2 years) with intermediate AMD and sequential OCT data.

In the second cohort of patients with intermediate AMD, OCT evidence of at least one HIRD was observed in 62 (45%) of 138 eyes, and 55 (40%) of the eyes progressed to advanced AMD, defined as neovascular AMD or geographic atrophy over 12 months, including 33 that progressed to geographic atrophy only, 14 that progressed to choroidal neovascularization only, and eight that progressed to both. Regression analyses demonstrated significant independent associations between HIRD and progression to advanced AMD at 12 months (odds ratio, 6.36; 95% CI, 2.99 - 13.53; P < .001). The authors note that the findings suggest HIRD might have prognostic value for neovascular AMD and geographic atrophy.

The investigators correlated the imaging characteristics with histology of eyes from deceased donors with AMD and generated a possible four-stage pathway for druse progression to HIRD, beginning with the accumulation of druse under an intact retinal pigment epithelium (RPE), progressing to nodular formation, focal loss of RPE to complete loss of RPE overlying the nodule-filled druse.

Using microscopy and other imaging techniques, the researchers determined that HIRD nodules are made up of "sprawling polycrystalline HAP nodules distinctly different from the restricted sized spherules in drusen," which are also found in the retinas of patients with AMD.

While the spherules appear small and refractile on color fundus photography (CFP) and reflective on OCT, the HIRD nodules "are large, refractile on CFP, and nonreflective on OCT, a difference that is possibly due to the nodules' rough surface and size," the authors write, noting that the nodules are hyporeflective in the posterior eye.

The authors suggest that additional future directions should include extending the clinical observations in the current study to other patient cohorts and the identification of imaging signatures before calcification.

In addition, previous research has linked the preferential formation of a magnesium-substituted calcium phosphate over HAP to acidic pH and increased magnesium-to-calcium ratio. For this reason, the authors advocate exploring whether local and systemic calcium and magnesium regulation may be targets for AMD treatment and prevention.

Finally, in light of the association between HAP nodules and AMD progression, the researchers suggest that multimodal clinical imaging to determine the composition of macular calcifications may help to direct therapeutic strategies and outcome measures in AMD.

The research was supported by the Bill Brown Charitable Trust Senior Research Fellowship, Moorfields Eye Hospital Special Trustees, and European Union Horizon 2020 research and innovation program. The authors have disclosed various relationships with Hoffman LaRoche, Genentech, Bayer HealthCare, Optovue, ThromboGenics, Ohr Pharmaceutical, Heidelberg Engineering Alcon, Novartis, Roche, Optos, Carl Zeiss Meditec, CenterVue, Allergan, and Iconic.

Sci Transl Med. Published online November 7, 2018. Abstract

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