Non-invasive quantitative retinal imaging as potential biomarker in healthy volunteers and patients with degenerative diseases of the brain and the eye

The retina, an integral part of the central nervous system, plays an essential
role in visual perception but also serves as a window into the systemic and
neurological health of an individual. Recent evidence suggests that imaging of
the retinal oxygenation and metabolism may be valuable for the early detection
and monitoring of degenerative diseases of the brain and the eye.
The most common neurodegenerative diseases are Alzheimer*s and Parkinson*s
disease. These conditions are characterized by specific protein accumulations
in the brain with corresponding changes detectable in the retina using optical
coherence tomography (OCT). Hadoux et al. have demonstrated that non-invasive
retinal imaging using light scattering and absorption maps can discriminate
between individuals with and without moderate-high brain beta-amyloid.
Alzheimer*s disease is marked by the accumulation of beta-amyloid protein.
While Parkinson*s disease involves the loss of dopaminergic neurons along with
observable thinning of the retinal nerve fiber layer (RNFL), the main
misfolding protein is phosphorylated alpha-synuclein and aggregates of this
protein occur inside neurons in the border of the ganglion cell, inner nuclear
and plexiform layers of the retina. All these retinal changes may reflect
neurodegeneration in the brain, offering a non-invasive method for early
detection and monitoring of these diseases.
Imaging of retinal metabolism and oxygenation may also provide insight in the
pathophysiology of many retinal diseases. In diabetic retinopathy changes occur
due to chronic hyperglycaemia, leading to narrowed retinal arteries, reduced
blood flow, and eventually to more progressive retinal ischaemia. Imaging
modalities like fluorescein angiography and OCT-angiography cannot reliably
detect early changes, unlike retinal oximetry, in order to predict progression
towards proliferative diabetic retinopathy. Characterization of retinal oxygen
saturation and retinal carotenoid concentrations also serves as early biomarker
in age-related macular degeneration, in which hypoxia may be an early indicator
of progression of dry age-related macular degeneration towards wet age-related
macular degeneration. In glaucoma, a chronic optic neuropathy associated with
progressive thinning of the RNFL, damage is also associated with reduced tissue
oxygenation.
The Netherlands Organization for Applied Scientific Research (TNO) has
developed a novel multispectral fundus camera that aims to visualize the tissue
oxygenation, biochemical composition as well as structural changes in the
retina. The technology, based on multicolour spatial frequency domain imaging
(mc-SFDI), yields quantitative maps of scattering (related to tissue structure
and proteins such as amyloid-beta and alpha-synuclein aggregates) and
absorption (related to the absolute concentrations of absorbing molecules such
as oxy- and deoxyhemoglobin and carotenoids) at up to 16 preselected
wavelengths. It is hypothesized that the combination of structural, functional
and molecular imaging of the retina using mc-SFDI will enable early disease
diagnosis, monitoring of disease progression, and eventually monitoring of
longitudinal clinical treatment efficacy.
The eye offers a unique transparent window for non-invasive imaging of the
retina, not only assessing its complex structure but also as a biomarker tool
for broader physiological changes in the early detection and management of both
retinal and neurodegenerative diseases. In this study, we aim to find
differences in scattering and absorption properties in the retina between
healthy volunteers and patients with degenerative diseases of the brain and the
eye, which may provide further insight into these diseases.

The general objective is to validate a new non-invasive retinal imaging tool
that allows the identification of relevant biomarkers in the retina in
degenerative diseases of the brain and the eye by scattering and absorption
properties.

This is a phase 0 pilot study to evaluate a novel mc-SFDI fundus camera in
healthy volunteers and patients with degenerative diseases of the brain and
eye. The ultimate goal of this study is to identify relevant retinal biomarkers
that may contribute to early diagnosis or assessment of treatment effects in
the future. A reliable and practical biomarker is expected to differentiate
between healthy volunteers and participants with degenerative eye and/or brain
diseases and demonstrate repeatability within a single day and across multiple
days.

The study will be conducted at two sites. Participants will be screened up to
28 days before the start of the study, including an ocular examination. For the
actual mc-SFDI assessment of the retina, patients with retinal disease will
only be evaluated at the Rotterdam Eye Hospital, with assessments limited to
one eye in principle.

Healthy volunteers, patients with Alzheimer*s disease, and patients with
Parkinson*s disease will be evaluated at CHDR. Healthy volunteers and patients
with Parkinson*s disease will visit CHDR for a first study visit involving two
mc-SFDI assessments, followed by a second visit with only one mc-SFDI
assessment. Alzheimer*s disease patients will visit CHDR only once, for one
mc-SFDI assessment.

No investigational medicinal product will be administered during the study. To
improve the quality of retinal imaging, tropicamide 0.5% eyedrops (up to two
drops per eye) will be administered to dilate the subjects' pupils. To evaluate
both the camera and the biomarkers it generates, comparisons will be made
between the different study populations, and inter- and intra-subject
variability will be assessed. No follow-up visits are planned.

It is not expected that the medical device (a retinal imaging device) will
cause any direct harm through the mechanism of action. The acquisition will be
performed by medically trained personnel in a safe and monitored environment.
Also, the personnel will make sure that the properties of the device will be
considered safe (e.g. the intensity of the light will be adjusted to make sure
it is well tolerated by the participants).
Tropicamide 0.5% eyedrops to dilate the pupil of subjects will be administered
to improve quality of the retinal imaging. Tropicamide is an ocular
parasympatholytic, which is being regularly used in routine clinical care for
ophthalmological fundus examination and considered safe. The most common
complaint (1-10%) after administration is a burning sensation directly after
administration. Subjects will experience blurred vision in the dilated eye for
2-4 hours after administration, maximum effect is seen 15-30 minutes after
instillation. A dilated pupil can be visible for up to 8 hours after
administration. Very rarely (<1%) convulsions, dry mouth, tachycardia,
palpitations, dysuria, hallucinations and ataxia can occur. Therefore, these
eye droplets will be administered under medical supervision.
The use of topical mydriatics including tropicamide is considered safe during
the pregnancy as the systemic absorption and toxicity is expected to be low.
However, pregnant females will not be allowed in the study, and will be
assessed using a urine pregnancy test.
Participants of the study do not benefit from participating in this study.