Retinal Abnormalities as Biomarker of Disease Progression and Early Diagnosis of Parkinson Disease

The retina is actually brain tissue and is considered part of the central nervous system
(CNS). It is the only part of the CNS that can be visualized directly and non-invasively.
There is already a body of evidence that retinal neurons accumulate alpha-synuclein and
degenerate in Parkinson disease (PD). Whether retinal imaging could be useful as an objective
biomarker to track disease progression and response to disease-modifying treatments in
patients with PD is not known.

While there are a variety of imaging techniques available (e.g., PET, SPECT, MRI), none of
them has emerged as a fully reliable method to accurately measure clinical progression in PD.

The structure of the retina can be studied easily in vivo using spectral domain high
definition optical coherence tomography (OCT), a non-invasive imaging technique with a
resolution of ~1 microns (0.001 mm). OCT quantifies the thickness of the different retinal
layers. The primary aim of this proposal is to determine whether OCT is a reliable clinical
measure that can objectively measure clinical progression in PD.

Our group has shown recently that OCT can be used as a means to measure progressive neuronal
loss in the retina in patients with a synucleinopathy closely related to PD (multiple system
atrophy, MSA). In MSA, retinal degeneration was closely associated with disease severity and
progressively worsened overtime in a predictable fashion, sufficient for biostatistical
modeling. We now want to find out if this is also true in PD.

There is a panel of non-motor clinical features that increase the risk of developing PD. We
propose to measure retinal nerve fiber density in these patients considering them as
"pre-motor" PD and follow their clinical evolution overtime. If OCT proves useful as a means
to identify pre-motor PD, such a result would present an important therapeutic window to
intervene with disease modifying drugs and to prevent the development of CNS deficits.

We plan to determine whether retinal morphology can be correlated with visual function using
complementary measures of visual electrophysiology techniques, including pattern
electroretinogram (PERG) and photopic negative response (PhNR). These techniques have been
used in patients with PD and other synucleinopathies, and do map closely to retinal function
abnormalities. But, there is little data describing how these functional measure of the
retina progression over time in PD.

We hypothesize that patients with PD have specific patterns of damage in retinal structure
and function, that this pattern can be identified in the premotor phase, We believe that OCT
can be used as an objective biomarker of premotor diagnosis and disease progression.

INNOVATION:

The structure of the retina presents an ideal opportunity to image the CNS overtime with OCT.
As a widely available clinical technique that correlates closely with functional measures of
visual electrophysiology, OCT is being increasingly used in multiple sclerosis and other
neurodegenerative disorders. If successful, this work may provide a significant tool for the
diagnosis of PD in the pre-motor phase and could be used as a clinical outcome measure in
disease-modifying trials. To achieve these objectives, we will take advantage of the
infrastructure used in the ongoing NIH-funded Natural History of Autonomic Disorders study
(ClnicalTrials.gov: NCT01799915), which prospectively follows patients with synucleinopathies
with standardized neurological measures overtime. The proposal will provide measures of
retinal structure in conjunction with measures of disease severity in a group of patients
with well-defined PD. By measuring retinal structure in a group of patients considered high
risk for developing PD (namely REM sleep behavior disorder -RBD, and isolated autonomic
failure) we will determine the usefulness of OCT as a mean to identify PD in the premotor
phase.

Inclusion Criteria:

Subjects with PD, MSA and DLB that fulfill current diagnostic criteria.

- Subjects with RBD that have polysomnography-confirmed diagnosis showing evidence of
lack of muscle atonia and dream enacting behaviors during REM sleep.

- Subjects with isolated autonomic failure (i.e., no motor deficits) that have evidence
of neurogenic orthostatic hypotension and other features of autonomic failure without
clinical evidence of cognitive impairment.

- Control subjects with no history of neurological or ophthalmological disorders.

Exclusion Criteria:

- Subjects with glaucoma, retinopathy, or significant media opacification (e.g.,
cataracts).

- Subjects with a history of eye surgery or eye trauma

- Inability to comply with the requirements of the study