Using adaptive optics to assess hyporeflective clump speed and size in age-related macular degeneration in the PINNACLE Study. (PINNACLE Study Report 6)

Christopher Holmes¹, Dimitrios Kazantzis², Syed Ahmer Raza², Naomi Wijesingha², Thomas Rp Taylor³, Ahmed Hagag^{2

4

5}, Sophie Riedl⁶, Julia Mai⁶, Daniel Rueckert⁷, Hrvoje Bogunović⁶, Hendrik Scholl^{8

9}, Ursula Schmidt-Erfurth⁶, Lars Fritsche¹⁰, Andrew Lotery^#¹¹, Sobha Sivaprasad^#^{12

13}

Affiliations

¹ NIHR Moorfields Clinical Research Facility, Moorfields Eye Hospital NHS Foundation Trust, London, UK. christopher.holmes11@nhs.net.
² NIHR Moorfields Clinical Research Facility, Moorfields Eye Hospital NHS Foundation Trust, London, UK.
³ University of Southampton, Faculty of Medicine, Southampton, UK.
⁴ University College London Institute of Ophthalmology, London, UK.
⁵ Boehringer Ingelheim Limited, Bracknell, UK.
⁶ Medical University of Vienna, Vienna, Austria.
⁷ Imperial College London, London, UK.
⁸ Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland.
⁹ Department of Ophthalmology, University of Basel, Basel, Switzerland.
¹⁰ University of Michigan, Ann Arbor, MI, USA.
¹¹ University of Southampton, Faculty of Medicine, Southampton, UK. a.j.lotery@soton.ac.uk.
¹² NIHR Moorfields Clinical Research Facility, Moorfields Eye Hospital NHS Foundation Trust, London, UK. sobha.sivaprasad@nhs.net.
¹³ University College London Institute of Ophthalmology, London, UK. sobha.sivaprasad@nhs.net.

^# Contributed equally.

PMID: 40908402
DOI: 10.1038/s41433-025-03951-7

Using adaptive optics to assess hyporeflective clump speed and size in age-related macular degeneration in the PINNACLE Study. (PINNACLE Study Report 6)

Christopher Holmes et al. Eye (Lond). 2025.

. 2025 Sep 4.

doi: 10.1038/s41433-025-03951-7. Online ahead of print.

Authors

Affiliations

¹ NIHR Moorfields Clinical Research Facility, Moorfields Eye Hospital NHS Foundation Trust, London, UK. christopher.holmes11@nhs.net.
² NIHR Moorfields Clinical Research Facility, Moorfields Eye Hospital NHS Foundation Trust, London, UK.
³ University of Southampton, Faculty of Medicine, Southampton, UK.
⁴ University College London Institute of Ophthalmology, London, UK.
⁵ Boehringer Ingelheim Limited, Bracknell, UK.
⁶ Medical University of Vienna, Vienna, Austria.
⁷ Imperial College London, London, UK.
⁸ Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland.
⁹ Department of Ophthalmology, University of Basel, Basel, Switzerland.
¹⁰ University of Michigan, Ann Arbor, MI, USA.
¹¹ University of Southampton, Faculty of Medicine, Southampton, UK. a.j.lotery@soton.ac.uk.
¹² NIHR Moorfields Clinical Research Facility, Moorfields Eye Hospital NHS Foundation Trust, London, UK. sobha.sivaprasad@nhs.net.
¹³ University College London Institute of Ophthalmology, London, UK. sobha.sivaprasad@nhs.net.

^# Contributed equally.

PMID: 40908402
DOI: 10.1038/s41433-025-03951-7

Abstract

Background/objectives: Hyporeflective clumps (HRC) are a common finding in adaptive optics ophthalmoscopy (AOO) of age-related macular degeneration (AMD). They appear on optical coherence tomography (OCT) as hyperreflective foci (HRF) or abutting the retinal pigment epithelium (RPE) layer as RPE thickening. The cellular origin of HRF is debated between migrated RPE cells and mononuclear phagocytes (MP). Microglial cells are MP known to migrate at 0.02 µm/s, but RPE migration speed is unknown. Phenotyping HRCs by migration speed and size may improve our understanding of HRFs.

Methods: Patients with non-neovascular AMD were imaged with the RTX1 retinal camera (Imagine Eyes, Orsey, France). Pairs of AOO images taken 1-3 h apart were centred on areas with multiple HRCs and compared to identify mobile HRCs. Macular OCT scans were performed immediately after initial AOO.

Results: A total of 21 pairs of images from 14 eyes of 12 patients were of adequate quality to assess HRCs. There were 411 measurable HRCs, with a mean diameter of 15.9 ± 6.0 µm. The HRCs were larger in images of atrophy (p < 0.001). Within the timeframe assessed, most HRCs remained static, but mobile HRCs were not uncommon and migrated up to 0.015 µm/s. HRFs on OCT corresponding to mobile HRCs on AOO appeared adjacent to the RPE or in the interdigitation zone.

Conclusion: AOO can detect HRC movement in AMD in images captured a mean of 105.5 min apart. HRC size and movement speed are consistent with microglial cells, but may also represent RPE cells. HRCs appear larger in images of atrophy.

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Conflict of interest statement

Competing interests: The authors do not have any conflict of interest related to this project. A Hagag is an employee of Boehringer Ingelheim. Dr Rueckert is co-founder of, and holds personal financial interest in, IXICO PLC. Dr Bogunovic receives funding from Apellis, Heidelberg Engineering, and Retinsight. He has received financial compensation from Apellis and Bayer. Dr. Scholl is a member of the Scientific Advisory Board of Astellas, Boehringer Ingelheim, Gyroscope/Novartis, Janssen, Okuvision, and Third Rock Ventures. He is a consultant for Gerson Lehrman Group, Guidepoint Global, and Tenpoint Therapeutics. He is a member of a Data Monitoring and Safety Board/Committee for Belite Bio, ReNeuron Group Plc/Ora Inc., Roche, and member of a Steering Committee for Novo Nordisk. He is a co-director of the Institute of Molecular and Clinical Ophthalmology Basel (IOB), which receives funding from the University of Basel, the University Hospital Basel, Novartis, and the government of Basel-Stadt. Dr. Schmidt-Erfurth receives grant support from Apellis, Genentech, Kodiak, Novartis, RetInSight, and Roche and is a consultant for Apellis, AbbVie, Aviceda, Boehringer Ingelheim, Heidelberg Engineering, Novartis, Stealth Biotherapeutics, and Topcon. Dr. Lotery is a consultant for Gyroscope/Novartis, Eyebio, Complement Therapeutics, Allergan, Apellis, and Tarsus Pharmaceuticals. Dr. Sivaprasad has received grant funding from Bayer, Novartis, AbbVie, Roche, Boehringer Ingelheim, Optos, and is a consultant for Bayer, Novartis, AbbVie, Roche, Boehringer Ingelheim, Optos, EyeBiotech, Biogen, Amgen, Kriya Therapeutics, Ocular Therapeutix, OcuTerra, Janssen, Stealth Biotherapeutics, Sanofi, and Apellis. She is a member of the Data Monitoring and Safety Board/Committee for Bayer and a member of the Steering Committee for Novo Nordisk. She is a member of the Data Monitoring and Safety Board/Committee for Bayer and a member of the Steering Committee for Novo Nordisk. She is the Editor in Chief of EYE. No other disclosures were reported. No conflicts related to this project.

References

1. Ferris FL 3rd, Wilkinson CP, Bird A, Chakravarthy U, Chew E, et al. Clinical classification of age-related macular degeneration. Ophthalmology. 2013;120:844–51. - DOI - PubMed
1. Khanifar AA, Koreishi AF, Izatt JA, Toth CA. Drusen ultrastructure imaging with spectral domain optical coherence tomography in age-related macular degeneration. Ophthalmology. 2008;115:1883–90. - DOI - PubMed
1. Paques M, Meimon S, Rossant F, Rosenbaum D, Mrejen S, Sennlaub F, et al. Adaptive optics ophthalmoscopy: application to age-related macular degeneration and vascular diseases. Prog Retin Eye Res. 2018;66:1–16. - DOI - PubMed
1. Zanzottera EC, Messinger JD, Ach T, Smith RT, Curcio CA. Subducted and melanotic cells in advanced age-related macular degeneration are derived from retinal pigment epithelium. Investig Ophthalmol Vis Sci. 2015;56:3269–78. - DOI
1. Paques M, Simonutti M, Augustin S, Goupille O, El Mathari B, Sahel J-A. In vivo observation of the locomotion of microglial cells in the retina. Glia. 2010;58:1663–8. - DOI - PubMed

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Using adaptive optics to assess hyporeflective clump speed and size in age-related macular degeneration in the PINNACLE Study. (PINNACLE Study Report 6)

Affiliations

Using adaptive optics to assess hyporeflective clump speed and size in age-related macular degeneration in the PINNACLE Study. (PINNACLE Study Report 6)

Authors

Affiliations

Abstract

Conflict of interest statement

References

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