Investigating retinal vascular atrophy as an indicator of brain degeneration in glaucoma

Glaucoma is one of the leading causes of irreversible blindness worldwide. The
traditional view of glaucoma is that of an eye disease in which an elevation of
intraocular pressure (IOP) causes the death of retinal ganglion cells (RGCs)
through mechanical stress, leading to peripheral visual field (VF) defects and
eventually blindness.

Earlier studies suggest that glaucoma is a neurodegenerative brain disease, in
which glaucomatous changes in the retina give rise to degeneration of white and
grey matter in the brain. Numerous MRI studies investigating structural changes
in the brain have shown that neurodegeneration takes place in the entire visual
system in people with glaucoma. One of the objectives of glaucoma research is
to relate this neurodegeneration of the brain to structural and functional
damage at the retinal level. This will give us a more complete overview of the
consequences of glaucoma and potentially may allow us to better predict
progression, and, in the future, even recovery.

Structural damage in the retina is commonly measured using the retinal nerve
fiber layer (RNFL) thickness, which is obtained using an Optical Coherence
Tomography (OCT) scan. An OCT scan is part of standard clinical practice. This
RNFL thickness is reduced in people with glaucoma due to the RGC degeneration.

However, RNFL thickness as a measure of progression of glaucoma stops to be
useful at a certain level due to a floor effect. In advanced glaucoma cases,
the RNFL thickness becomes so thin that further thinning cannot be observed.
Vascular atrophy has been described in several studies as a better indicator of
glaucoma progression than RNFL thickness as it does not show this floor effect.
Based on recent literature, the following metrics for describing structural
damage via vascular atrophy are proposed: perifoveal vessel density (pfVD) and
optic disk flow index (odFI). These changes can be observed using Optical
Coherence Tomography Angiography (OCTA).

In this study, an investigation of vascular atrophy as an indicator of
structural damage to the white matter of people with glaucoma will be
performed. Structural properties of the white matter can be assessed using
diffusion magnetic resonance imaging (dMRI). Fixel-based analysis provides the
most clinically relevant metrics since these directly relate to the structure
of white matter. By comparing the metrics of participants with glaucoma to
those of controls, we can assess white matter changes. We expect that the
changes in people with glaucoma will be reflected by a) structural changes in
the visual system (lower fiber density and fiber cross-section in white
matter), b) lower vessel density, c) lower blood perfusion, d) a correlation
between the structural changes in the brain and vascular atrophy. We expect
this correlation to be higher than between the structural changes in the brain
and the RNFL thickness.

The primary objective of this study is to be able to better assess progression
of visual pathway damage in advanced glaucoma cases in particular. For this,
we will use a unique combination of OCTA and dMRI techniques. In particular, we
aim to relate the retina's vascular information, derived from OCTA, to changes
in the structural properties of the visual white matter in the brain, as
assessed with dMRI. The main question we would like to answer in this study is
*Is there a positive linear relationship between vascular measures in the eye
and structural measures of white matter metrics in the primary visual pathway
of the brain (optic nerve, optic chiasm, optic tract, optic radiation) in
people with primary open angle glaucoma?* Such finding would be clinically
relevant as OCTA is commonly used in clinical practice and is a cheaper and
quicker alternative to MRI to assess structural changes to the visual pathway
in the brain.

The study will be an observational, cross-sectional study with an emphasis on
late disease stage and its association with relevant variables (fixel based
metrics (FD, FC, FDC) and metrics of vasculature (pfVD, odFI, cortical blood
flow). Sex and age will be taken into account in the analysis as potential
confounders. The study will consist of two parts: ophthalmologic examinations
(including an OCTA scan), and a (d)MRI experiment.

There are no direct risks associated with the proposed study. The planned
ophthalmological examination is akin to the standard examination one receives
on a visit to an ophthalmologist, which involves no risks. The MRI scanner that
will be used has a magnetic field strength of 3 Tesla, which is a very common
field strength used extensively in both clinical practice and research. No side
effects have been reported so far from the use of such scanners.