July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Clinical and nano-analytical imaging identify calcified nodules as progression markers for age-related macular degeneration
Author Affiliations & Notes
  • Anna CS Tan
    Vitreous Retina Macula Consultants of New York, New York, New York, United States
    Singapore Eye Research Institute, Singapore, Singapore
  • Matthew Pilgrim
    UCL Institute of Ophthalmology, London, United Kingdom
  • Sarah Fearn
    Department of Materials, Imperial College London, London, United Kingdom
  • Sergio Bertazzo
    Department of Medical Physics & Biomedical Engineering, Imperial College London, London, United Kingdom
  • Elena Tsolaki
    Department of Medical Physics & Biomedical Engineering, Imperial College London, London, United Kingdom
  • Alexander P Morrell
    Material Physics, Aston University, Birmingham, United Kingdom
  • Miaoling Li
    Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Jerry Messinger
    Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Rosa Dolz-Marco
    Vitreous Retina Macula Consultants of New York, New York, New York, United States
  • Jianqin Lei
    Doheny Eye Institute, Los Angeles, California, United States
  • Muneeswar Gupta Nittala
    Doheny Eye Institute, Los Angeles, California, United States
  • Srinivas R. Sadda
    Doheny Eye Institute, Los Angeles, California, United States
    Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
  • Imre Lengyel
    UCL Institute of Ophthalmology, London, United Kingdom
    Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom
  • K Bailey Freund
    Vitreous Retina Macula Consultants of New York, New York, New York, United States
  • Christine A Curcio
    Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Footnotes
    Commercial Relationships   Anna Tan, None; Matthew Pilgrim, None; Sarah Fearn, None; Sergio Bertazzo, None; Elena Tsolaki, None; Alexander Morrell, None; Miaoling Li, Hoffman LaRoche (F); Jerry Messinger, None; Rosa Dolz-Marco, Alcon (F), Genentech (F), Heidelberg Engineering (F), Novartis (F), Roche (F); Jianqin Lei, None; Muneeswar Nittala, None; Srinivas Sadda, Allergan (F), Allergan (C), Carl Zeiss Meditech (C), Centervue (C), Genentech (C), Genetech (F), Heidelberg Engineering (C), Iconic (C), Novartis (C), Ophthotech (C), Optos (F), Optos (C), Thrombogenics (C), Topcon (R); Imre Lengyel, Optos (F); K Bailey Freund, Bayer Healthcare (C), Genetech (C), Heidelberg Engineering (C), Optos (C), Optovue (C); Christine Curcio, Heidelberg Engineering (F), Hoffman LaRoche (F)
  • Footnotes
    Support  The study was supported by the Macula Foundation Inc., New York, NY. Dr. Curcio’s research and the Project MACULA website has been supported by NIH grant R01EY06019, EyeSight Foundation of Alabama, International Retinal Research Foundation, Edward N. and Della L. Thome Foundation, the Arnold and Mabel Beckman Initiative for Macular Research, and Research to Prevent Blindness.
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 2433. doi:
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    • Get Citation

      Anna CS Tan, Matthew Pilgrim, Sarah Fearn, Sergio Bertazzo, Elena Tsolaki, Alexander P Morrell, Miaoling Li, Jerry Messinger, Rosa Dolz-Marco, Jianqin Lei, Muneeswar Gupta Nittala, Srinivas R. Sadda, Imre Lengyel, K Bailey Freund, Christine A Curcio; Clinical and nano-analytical imaging identify calcified nodules as progression markers for age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2433.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Heterogeneous internal reflectivity within drusen (HIRD) is an optical coherence tomography (OCT) biomarker associated with progression to late age-related macular degeneration (AMD). Multilobular refractile nodules (5-20 µm) in drusen contain phosphates. To test whether nodules contain calcium in a specific mineralization state that might account for HIRD, we sought a longitudinal, multimodal imaging clinical description and molecular/physical differentiation from small reflective hydroxyapatite (HAP) spherules and Bruch’s membrane plaques.

Methods : Two clinical cohorts were followed for 1 and 6 years, respectively. Human donor eye tissues were subject to in vivo and ex vivo OCT, other multi-modal imaging modalities, histology, and several nano-analytical imaging techniques from material sciences.

Results : HIRD are associated with hypoautofluorescence of overlying retinal pigment epithelium (RPE) and 4-fold increased risk of progression to geographic atrophy at 1 year through stages outlined below (Figure 1). Histology of clinically imaged eyes linked HIRD to nodules. By energy dispersive x-ray spectroscopy, time of flight secondary ion mass spectrometry and specific histochemistry, and transmission electron microscopy with selected area electron diffraction, respectively, we found that 1) nodules, spherules, and plaques contain calcium and phosphate, and uniquely, nodules lack magnesium; 2) HAP is the major nodule constituent; 3) nodules are polycrystalline HAP, spherules diffracts as single crystal whitlockite, and plaques are HAP of amorphous crystallinity.

Conclusions : Nodules signify risk by association with the agonal state of the RPE (Figure 1). They may form due to a shift in extracellular magnesium-calcium balance and lowering of environmental pH as RPE degenerates. Results highlight the role of RPE in outer retinal mineral regulation and the potential of clinical imaging for molecular discovery.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

 

<!--StartFragment-->Figure 1: Multi-modal imaging representing the different stages of progression of a calcified nodule and HAP spherule as seen in different patients on color fundus photo (CFP) (far left), fundus autofluorescence (FAF) (middle left), near infra-red (NIR) (middle right) and optical coherence tomography (OCT) (far right). <!--EndFragment-->

<!--StartFragment-->Figure 1: Multi-modal imaging representing the different stages of progression of a calcified nodule and HAP spherule as seen in different patients on color fundus photo (CFP) (far left), fundus autofluorescence (FAF) (middle left), near infra-red (NIR) (middle right) and optical coherence tomography (OCT) (far right). <!--EndFragment-->

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