Metabolic Mapping to Measure Retinal Metabolism

Background. Alterations in retinal metabolism are associated with blinding conditions and
vision loss. We propose to apply a non-invasive in vivo retinal imaging system to
investigate key physiologic processes affecting retinal metabolism. The imaging system is
designed to quantify and characterize the topology of retinal metabolism in 3-dimensional
space across 40--130 picosecond time periods and allows dynamic measurement of
physiologically relevant events.

Objectives. The primary objectives of our study are to: (1) evaluate the utility of this
system in a clinical setting; and (2) examine variation in retinal metabolism within retinal
cell subtypes under environmental conditions optimized to support this metabolism. The
working hypothesis of our first objective is that the imaging system will be easily and
efficiently implemented in a clinical setting and will yield stable and repeatable results.
The working hypothesis for our second objective is that people with or at high risk for
progression to sight threatening retinal disease will exhibit different metabolic profiles
than an age- and sex-matched disease-free comparison group. Their peers with less severe
disease may exhibit differences with severe diseased and non-diseased groups. The long-term
goal of the project is to address the following research questions: Are metabolic profiles
generated by the imaging system effective for determining presence and severity of retinal
diseases?; and if so, are these metabolic profiles useful in identifying people at risk for
progression to sight threatening forms of retinal diseases?

Study Population. We will first apply the systems in 3 groups of 10 people exhibiting a
range of severity in retinal diseases that influence retinal metabolism; these diseases are:
age-related macular degeneration (AMD); diabetic retinopathy (DR); and von-Hippel-Lindau
(VHL) disease.

Design. Cross-sectional sampling design. If the system yields accurate, stable, and
repeatable results it will be applied in longitudinal studies to evaluate prognostic utility
for estimating the risk of progression to sight-threatening AMD, DR, or VHL disease.

Outcome Measures. The magnitude and 3-D topographic profile of fluorescence anisotropy
values across physiologically meaningful time periods for a 20 degree field centered on the
macula. Fluorescence anisotropy of our system provides a measure of retinal metabolism.

- INCLUSION CRITERIA:

GENERAL INCLUSION CRITERIA:

1. Ability and willingness to provide informed consent.

2. Presence of a natural lens in the study eye(s).

3. Media clarity, pupillary dilation, and cooperation sufficient to perform
measurements.

4. All participants will have the ability to read with at least 1 eye

AMD-SPECIFIC INCLUSION CRITERIA:

Participants will range from those with no AMD and little or no drusen in either eye
through end stage AMD (geographic atrophic, retinal pigment epithelial detachment, or
other signs of neovascular/exudative disease) in one eye. Participants will be classified
with the AREDS System for Classifying Age-Related Macular Degeneration and will exhibit a
range of severities of AMD with at least half exhibiting unilateral advanced AMD
(geographic atrophy or neovascular AMD) and half at high risk of progression. Inclusion
criteria are as follows:

1. A diagnosis of AMD. We will use AREDS criteria and diagnostic scales for the
definition of AMD.

2. Men and women aged 60 years or older. Children are not included because AMD (by
definition) is a disease afflicting adults.

3. Eligible participants may have no evidence of AMD with little or no drusen in either
eye, or may have any stage of AMD through end stage (geographic atrophic, retinal
pigment epithelial detachment, or other signs of neovascular/exudative disease) in
one eye.

DR-SPECIFIC INCLUSION CRITERIA:

1. People with DR will be classified with the modified ETDRS scale; participants will
have a range of severities of DR, with at least half classified in the severe
non-proliferative DR category (SNPDR). Efforts will be made to recruit people with
unilateral SNPDR.

2. Participants will be men and women aged 18 years or older with diagnosis of diabetes
mellitus (type 1 or type 2). Any one of the following will be considered sufficient
evidence that diabetes is present:

- Current regular use of insulin for the treatment of diabetes.

- Current regular use of oral antihyperglycemia agents for the treatment of
diabetes.

- Documented diabetes by ADA guidelines.

VHL-SPECIFIC INCLUSION CRITERIA:

1. Participants will be men and women aged 18 years or older with a genetic confirmation
of VHL-disease.

2. People with VHL disease exhibit a range of retinal lesions from none to severe.

EXCLUSION CRITERIA:

GENERAL EXCLUSION CRITERIA:

1. Cataract surgery in the study eye.

2. Glaucoma with evidence of optic nerve damage.

3. Chronic requirement for any systemic or ocular medication for other eye diseases
other than AMD, DR, or VHL-disease.

4. Presence of implanted medical devices that may be affected by electromagnetic
frequency (EMF) emissions. Although our equipment is CE or UL rated for EMF emissions
it would be prudent to exclude people with implanted pacemakers, neural stimulators,
and insulin pumps.

5. Arrhythmia as indicated in medical records, as this may result in instability in
measurements.

6. History of seizures. The scanning mechanism of the system operates at 12 Hz, which
may induce a seizure (n.b. a 12Hz scan rate is used in the Heidelberg HRTII and HRA).

7. Presence of chronic obstructive pulmonary disease (COPD) or other lung disease that
might make breathing 100% O2 unsafe.

8. Ocular disease (other than AMD, DR, or VHL) that confounds assessment of the retina.
These include but are not limited to central serous choroidopathy, optic atrophy,
retinal vein occlusion, active uveitis, significant explained or unexplained visual
field loss, or any other type of retinopathy or retinal degeneration.

9. Vitreous hemorrhage.

10. History of renal failure requiring dialysis or renal transplant.

11. Existing condition that in the opinion of the investigator would preclude
participation in the study (e.g., unstable medical status including blood pressure
and glycemic control).