Objectives and Rationale for Study: Alpha-synuclein can be toxic and make neurons sick. Many drugs are currently being developed for Parkinson's disease that are aimed at reducing alpha-synuclein protein levels. What is needed in parallel for the success of these new drugs is to be able to readily measure alpha-synuclein, to show the presence of disease, and to track improvements with treatments. The eye has the potential to provide a window into the brain, and many Parkinson's disease changes can be found in the retina, including alpha-synuclein. This opens the possibility of being able to "see" these protein deposits in a living eye. Retinal imaging photos (hyperspectral imaging) or 3-dimensional imaging (such as optical coherence tomography, OCT) are available or widespread in eyecare clinics. However, for them to be useful in Parkinson's disease we need to determine what aspects of these retinal scans are special to Parkinson's disease processes, and whether they occur with both environmental toxin and genetic risk factors.

By employing laboratory animal studies, we can determine whether specific changes to retinal scans indicate aberrant deposition of toxic alpha-synuclein. Examination in both toxin and genetic models helps us better understand whether they occur via similar biological pathways, informing tailored development of treatments in the future. To show that our system works we will conduct proof-of-principle assessments that monitor improvements in retinal scans and measures of how well the retina works when treated with novel drugs that reduce alpha-synuclein levels. In addition to showing that our testing platform has utility, these studies will help us understand why vison loss occurs in Parkinson's disease and will lay the foundation for new treatments for vision loss in Parkinson's disease.

How Project Relates to Focus Area: This project directly relates to two focus areas. By using animal models to target known genetic and toxin-mediated Parkinson's disease pathways and gaining a deeper understanding of the biology driving retinal biomarkers for PD this project will address "Understand disease heterogeneity to enable precision medicine approaches to PD treatments… Some examples of areas that are encouraged: Data analytics, Digital and other biomarkers, clinical subtyping." By examining whether novel anti-alpha-synuclein drugs shown to be effective for motor symptoms of Parkinson's disease in animal models also work in the eye, the project will address "Basic biology and clinical implications of non-motor symptoms that could lead to the development of new treatments for PD"

Ultimate applicability and impact of research: There is a lack of alternative ways to measure alpha-synuclein protein in Parkinson's disease. The only current confirmation that they are there occurs only after the patient has passed away and brain tissue can be measured. Brain scans are currently not able to image alpha-synuclein. It has been detected in the fluid that surrounds the brain, but this requires an invasive spinal tap, which carries significant risks. As such, laying the building blocks for imaging in the eye is an elegant solution to an important problem in Parkinson's disease research.

In the future, such approaches may also be useful in determining whether a patient is progressing or responding to treatments properly, thereby assisting to develop new medicines for PD. Given vision changes are common early symptoms in Parkinson's disease and toxin exposure, this project will also help us understand whether alpha-synuclein plays a role in eyesight and lays the foundation for developing ways to treat this.

Importantly, by developing PD-specific analyses of retinal scans that are rapid, inexpensive, comfortable, and easily accessible for patients helps fast-track implementation into real-world use. Indeed, these clinical devices are already at your local optometrist's, and many people would have had a retinal scan done if they wear glasses. These attributes help to provide access to everyone, including Veterans, the disabled, older people, and low-socioeconomic communities.