Retinal biomarkers of prodromal Parkinson disease

PROJECT SUMMARY/ABSTRACT
At present, the diagnosis of Parkinson disease (PD) relies on clinical manifestation of motor signs which
appear only after substantial loss of brain neurons. This diagnostic delay limits the opportunity for early
intervention strategies and hampers the ability to study early PD pathophysiology. The proposed research aims
to shift this paradigm by identifying and refining novel retinal biomarkers of PD that present in the prodromal
stage, years before hallmark motor dysfunction. By focusing on translationally relevant, non-invasive retinal
structure and function assays, and established motor assays, this study uses a longitudinal approach to define
the onset and progression of PD-associated retinal disease in relation to PD-associated brain disease. The
central hypothesis of this work is that quantifiable retinal pathology exists during prodromal-stage disease in a
PD mouse model, which is recapitulated in the prodrome of human PD. To test this hypothesis, this project has
two specific aims. In Aim 1, this work will identify features of retinal pathology in prodromal PD in a mouse
model of PD using in vivo assays of retinal structure and function: adaptive optics scanning laser
ophthalmoscopy (AOSLO), optical coherence tomography (OCT), electroretinography (ERG), optomotor reflex
(OMR), combined with assays of motor function (pole and cylinder tests). In vivo assays will be compared with
retinal and brain tissue pathology using immunohistochemistry, cell death assays, and electron microscopy.
This innovative approach utilizes phenotypic definitions of retinal prodrome and motor clinical PD, rather than
relying on fixed timepoints which accounts for disease progression heterogeneity in individuals, enhancing the
translatability of findings to humans. In Aim 2, this work will identify in vivo retinal biomarkers of prodromal PD
in humans, applying survival analysis of human subjects with OCT images from the UK Biobank who later are
diagnosed with PD and comparing both inner and outer retina layer thicknesses measured via OCT with
healthy matched control subjects. This fellowship includes a comprehensive training plan at the University of
Wisconsin-Madison with complementary sponsor Dr. Freya Mowat (veterinary ophthalmologist clinician-
scientist with expertise in animal models of retinal neurodegeneration) and cosponsor Dr. Michelle Ciucci
(speech-language pathologist clinician-scientist with expertise in PD), with supportive collaborations within the
Wisconsin Advanced Imaging of Visual Systems (WAIVS) lab and the Wisconsin Reading Center. The proposal
and training plan is designed to enhance the physician fellow’s ophthalmology and neuroscience research
skills through applied research and education in advanced imaging, medical statistics, clinical study design,
and research ethics. This comprehensive training and research endeavor aims to equip the fellow with the
necessary skills to emerge as an independent clinician-scientist investigator in vision research, with a project
that promises significant public health impact through the potential for early, non-invasive PD detection.

Grant Number: 1F32EY037178-01
NIH Institute/Center: NIH
Principal Investigator: David Barnett