The diagnostic value of Metabolic Hyperspectral Imaging of the Retina in Alzheimer's disease (MHIRA).

The human brain and retina both arise from the diencephalon during embryonic
development and possess many similarities in terms of cellular structure and
function. As such, there are a number of potential ocular manifestations, that
may mirror Alzheimer*s disease (AD) hallmark pathology in the brain, increasing
interest in imaging the retina as a potential biomarker for AD.
Recently, spectral changes were reported in Alzheimer*s mice relative to
age-matched wild-type mice ex vivo and in vivo using reflectance hyperspectral
retinal images. A similar trend was observed in human brain and retina tissue
post mortem. These results support the idea that hyperspectral retinal imaging
could be used to identify signs of AD without an extraneous labeling agent.
The MHRC makes it possible to identify and quantify specific biomolecules in
the retina, thus paving the way for metabolic imaging of the fundus. The ocular
fundus image acquisition time is a few seconds. Hence, this technique permits
direct, non-invasive and inexpensive evaluation of the retina without
radiation. We aim to evaluate the MHRC in a large group of subjects to
determine whether imaging of the retina with the MHRC may be used to predict
cerebral amyloid-β status, with acceptable accuracy, using amyloid PET status
for validation.

Primarily, to investigate the diagnostic accuracy of the MHRC for predicting
cerebral amyloid pathology (as measured with amyloid PET as a reference).

Secondarily, we will relate the MHRC scans to:
1. Syndrome diagnosis (subjective cognitive complaints, mild cognitive
impairment (MCI) or dementia) and established AD biomarkers in CSF on brain MRI
as well as cognitive performance.
2. (Widefield) fundus photography and Optical Coherence Tomography (OCT).
3. Possible AD biomarkers as measured in tear fluid.

This is an observational, prospective monocenter study. Patients will undergo a
general ophthalmological consultation comprising ophthalmological history,
intraocular pressure and refraction/visual acuity measurement. Based on the
data of this prescreening patients will be in- or excluded.
The study comprises of 1 visit that takes place at the outpatient ophthalmology
department of the AUMC, location VUmc with a duration of approximately 90
minutes.
Participants who are considered eligible after prescreening will undergo
imaging with the MHRC, OCT(-A) (Heidelberg Engineering, Heidelberg, Germany and
Zeiss Plexelite), and wide field fundus photography (Optos). In addition, tear
fluid will be collected from both eyes.
Participants recruited from the AMYPAD-DPMS study (METc 2018.37) will undergo
their study visit subsequently to the neuropsychological examination at the
clinical visit of the AMYPAD-DPMS study at 6 months, ±14 days or at the
clinical visit at 13 months ±4 weeks.

Nature and extent of the burden and risks associated with participation,
benefit and group relatedness (if applicable):
The study visit at Amsterdam University Medical Center (AUMC), location Vrije
Universiteit Medical Center (VUmc) will take approximately 90 minutes,
including a general ophthalmological examination, Optical Coherence Tomography
(-Angiography) (OCT-(A)), (wide-field) fundus photography and MHRC imaging. In
addition tearfluid from both eyes will be collected. In order to enhance
imaging quality, participants will undergo pupil mydriasis achieved by
tropicamide 0,5%, causing temporary photophobia and blurred view. These
procedures are medical routine procedures; therefore, the risks are negligible.
The MHRC visible light exposure is below recommended exposure limits, therefore
the risks are negligible.


Benefits and risks assessment, group relatedness:
Incapacitated participants will not be included in this study. All participants
have to be mentally competent, i.e. MMSE >= 17. All participants undergo an
ophthalmological consultation free of charge. There are no other direct
benefits for participants in this study, besides that the results obtained
could lead to a simpler and less invasive method for diagnosing AD in the
future.

In order to enhance imaging quality, participants will undergo pupil mydriasis
achieved by tropicamide 0.5%. This is a standard procedure in ophthalmological
clinical practice. Pupil mydriasis may cause transient photophobia and blurred
view for several hours. Therefore, we advise participants not to drive after
this examination. Mydriasis using tropicamide 0.5% can precipitate acute angle
closure glaucoma in a very small proportion of cases (0.03%)24,25. Each
participant will undergo ophthalmological screening to reduce this risk to be
negligible and will be monitored during mydriasis. In the rare case of acute
angle closure glaucoma participants will receive standard care following
international glaucoma guidelines26.
The MHRC is a research device and thus does not have a CE-marking yet.
Nevertheless, the MHRC meets all the safety requirements (see IMDD). The method
of obtaining images and the light intensity during the procedure is comparable
with the conventional fundus camera. The MHRC uses visible light exposure to
the eye, and the power of the monochromatic light source has been calculated
and found to be below the recommended exposure limits of the *American National
Standard for safe use of lasers*1 We therefore expect the risks to patients
undergoing measurements to be negligible.
The measurement of vision, intraocular pressure, fundus photography and OCT(-A)
are non-invasive measurements and are all standard procedures in
ophthalmological clinical practice. Risks or side effects have not been
described and are not expected from these tests. Tears are sampled using paper
Schirmer strips that are gently placed behind the lower eyelid. This procedure
is not considered uncomfortable. In some cases, insertion of the paper strip
causes reflex tearing (excessive tearing similar to tearing in reaction to
foreign body, smoke or onions).
In conclusion, risks associated with participation in the MHIRA-study are
negligible.