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.
