TWIN study: biomarkers in the eye and Alzheimer’s disease

TWIN study: A longitudinal study investigating biomarkers in the eye and Alzheimer’s disease

The TWIN study aims to provide inside in parameters or biomarkers that can lead to preclinical Alzheimer’s disease development.  Patients included in this longitudinal study are monozygotic twins who are cognitively normal and have been screened for amyloid status via MRI, PET scans or limbal puncture. In addition to various blood and physical examinations, various ocular examinations have also been performed including slit lamp examination, fundus photography, Ocular Coherence Tomography (OCT) and Ocular Coherence Tomography-Angiography (OCT-A).

The baseline and first follow up results of these ocular parameters have already been analyzed and published.^2-8 The results for the second follow up are undergoing analysis for publication at the moment (delay due to COVID) and will form a part of this PhD thesis. An amendment is currently being written up for the third follow up. For the third follow up, the Optina hyperspectral retinal camera and the Optos widefield camera will be added to the patient’s imaging regime alongside the OCT, and OCT-A.

Aims and objectives

The aim of this PhD study is to investigate changes in previously described retinal biomarkers over time as well as to explore potential retinal biomarkers by comparing amyloid positive and negative patients in preclinical Alzheimer’s disease. The research questions which we wish to address are divided into 5 areas based on the following biomarkers:

 

Retinal layer thickness changes over time in preclinical Alzheimer’s disease

Numerous studies have reported a connection between retinal nerve fiber layer thinning and macular volume loss in the retina in patients with Alzheimer’s disease using OCT. The Heidelberg Spectralis ocular coherence tomography is the only ocular modality at our department of Ophthalmology which has been used at baseline and all 3 follow ups. The two research questions we wish to address are:

• Is there a difference between the retinal layer thickness measurements between amyloid positive preclinical AD patients and amyloid negative controls using the OCT scan?
• Is there a difference in the change of the retinal layer thicknesses between amyloid positive preclinical AD patients and amyloid negative controls using the OCT scan over the last six years?

Changes in foveal avascular zone, vessel density and perfusion density over time in preclinical Alzheimer’s disease

To date, only two observational case studies have explored in vivo preclinical Alzheimer’s disease biomarkers using the Cirrus 5000 OCT-A device. Van de Kreeke et al reported a significantly higher vessel density in the inner and outer macular and ONH rings amongst amyloid beta positive patients and no significant difference in the foveal avascular zone, however O’Bryhim et al observed an enlarged foveal avascular zone amongst amyloid positive patients and a diminished vessel density. We wish to further examine these observations during a follow up two years later using OCT-A by posing the following question:

• Are there any changes in the retinal vessel parameters between amyloid positive, preclinical AD patients and amyloid negative controls on the OCT-A device between the first and second follow ups?

Changes in vessel density, perfusion density and foveal avascular zone between amyloid positive and amyloid negative subjects on a new swept source OCT-A device

During the third follow up, vessel density, perfusion density and foveal avascular zone will be studied using another type of OCT-A, the Zeiss Plexelite. The advantages of this device compared to the Cirrus 5000 OCT-A are a deeper penetration of tissue, higher speed of scanning and larger area of scanning which potentially could increase imaging quality of these biomarkers. Analysis of these scans will be used to answer the same question:

• Is there a difference between amyloid positive pre-clinical AD and amyloid negative control patients in the outcome of Vessel Density, Perfusion Density, and FAZ?

Changes in retinal vessel parameters over time in preclinical Alzheimer’s disease

Three studies have shown changes in several retinal vascular parameters in Alzheimer’s disease. This thesis will also examine seven retinal vascular parameters (central retinal artery equivalent, central retinal vein equivalent, arteriole-venular ratio, fractal dimension of the arteriolar network, fractal dimension of the venular network, curvature tortuosity of the arterioles and curvature tortuosity of the venules) to answer the following question:

• Are there any changes in retinal vascular parameters over time between healthy and preclinical Alzheimer disease patients?

Cerebral amyloid status via changes in retinal signals in preclinical Alzheimer’s disease

Recently a novel ocular modality has been developed by Optina diagnostics which has shown promise in displaying an association between cerebral amyloid levels and a change in retinal signal by scanning the retina using a metabolic hyperspectral retinal camera. This device was recently obtained by our department of Ophthalmology and will be used in the third follow up cohort of patients to analyze the following question:

• Can images made with a hyperspectral retinal camera provide insight into cerebral amyloid status and are these reliable predictors of preclinical Alzheimer’s disease?

Hard peripheral drusen and vascular parameters in preclinical Alzheimer’s disease

The Optos widefield camera is another novel device which has been implicated as a potential diagnostic tool to determine biomarkers of Alzheimer’s disease. Two studies have shown a positive correlation between hard peripheral drusen and changes in the vasculature beyond the posterior pole in preclinical Alzheimer’s disease. We will therefore also examine this device to explore the following question:

• Can the Optos widefield camera detect evidence of preclinical Alzheimer’s disease? More specifically is there a link between hard peripheral drusen and/or vascular parameters and Alzheimer’s disease in the preclinical stage?

 

Promotores

Prof.dr. Ruth van Nispen, Prof.dr. Stevie Tan, Dr. Frank Verbraak, Dr. Femke Bouwman, Dr. Pieter-Jelle Visser