Ophthalmic Imaging in HCHWA-D

Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is a rare
autosomal dominant disease with repeated intracerebral hemorrhage and cognitive
decline caused by a single base mutation at codon 693 of the amyloid precursor
protein (APP) gene. This mutation leads to extensive amyloid deposition in the
meningocortical arterioles. Levy et al. described this disease in several
families who are originally from the Dutch beach villages Katwijk and
Scheveningen. These cerebral amyloid deposits in HCHWA-D consist of amyloid
beta (Aβ), which links up with other cerebral β-amyloidosis as Alzheimer*s
disease (AD) and sporadic cerebral amyloid angiopathy (sCAA).
It is hypothesized that HCHWA-D patients, like patients with Alzheimer disease,
undergo a prolonged presymptomatic period where histological changes are
progressively accumulating without overt signs and symptoms such as
intracerebral hemorrhage or vascular cognitive impairment. Detecting early
non-invasive markers in apparently presymptomatic carriers would be a major
step towards identifying the effects of cerebrovascular amyloid deposition in
this stage of the disease and is important to future research in
disease-modifying therapy for HCHWA-D (also called Dutch-type hereditary CAA)
and other amyloidosis such as sCAA and AD.
One could suggest that if the cerebral vessels are affected, retinal vessels
may also show abnormalities. Anatomically and developmentally, the retina is
known as an extension of the central nervous system. There are only a few
articles published about retinopathy in patients with cerebral amyloidosis.
Furthermore, retinal abnormalities have been reported in patients with
neurodegenerative diseases like AD. These studies suggest that AD is
accompanied by loss of retinal ganglion cells and therefore retinal
abnormalities could be demonstrated. The Aβ and APP gens are expressed in
retina at the level of the ganglion cell layer (GCL) and retinal nerve fiber
layer (RNFL). A generalized reduction of the peripapillary RNFL thickness in
patients with AD has been reported. In addition, a reduced total macular volume
was shown in patients met AD that correlated with the severity of the disease.
These findings were visualized by optical coherence tomography (OCT), which is
a non-invasive imaging test that uses back-reflected infrared light to take
cross-section pictures of the retina. The OCT is frequently used for detecting
age related macular degeneration (AMD), which is a leading cause of severe
central visual acuity loss in one or both eyes in people over 50 years of age.
In AMD, amyloid depositions can be found in the macular region which relate to
the atrophy of the retinal pigment layer.
So far, no studies with OCT (as a marker of thickness of the GCL and RNFL and
macular region) in combination with fundus imaging have been performed in
patients with HCHWA-D. Since both AD and HCHWA-D are related to Aβ deposition
and APP gene, we suggest that in HCHWA-D patients also retinal abnormalities
will be found.

To detect ophthalmic differences between patients and controles.
To detect (early) changes in the retina in (pre)symptomatic HCHWA-D disease
carriers, in order to find a *biomarker* for disease stage and progression.

We will perform an observational cross-sectional diagnostic study in HCHWA-D
mutation carriers versus age and sex matched control subjects. The study will
take place at the Leiden University Medical Center (LUMC).

Ophthalmic examination will be performed in all subjects, including:
• Visual acuity test
• Intraocular pressure
• Slit lamp examination
• Fundoscopy
• Fundus photography
• OCT-scan

Mydriasis is required for fundoscopy and fundus photography. Therefore
mydriatic and cycloplegic eye drops (Tropicamide 0.5% eye drops and
Phenylephrine hydrochloride 5.0% eye drops) will be given to all subjects. It
takes approximately 15 to 20 minutes prior for these eye drops to have maximum
effect and dilate the pupil. These eye drops have a duration of effect of
approximately 5 to 8 hours.

The fundus photographs will be assessed according to classification of diabetic
retinopathy. The OCT scans will be evaluated according to the classification of
AMD described by Ferris the 3rd en colleagues.

The total duration of all the tests will be approximately 1.5 hour.

For the ophthalmological tests the pupils will be dilated, which temporarily
gives a slightly decreased vision and/or mild to moderate photofobia for 5-8
hours.