Development of an MRI-based Imaging Biomarker for the Detection of Alpha-Synuclein in Parkinson's disease

Objective/Rationale:
Parkinson’s disease is associated with accumulation of the protein α-synuclein in the brain, however, it is not currently possible to detect α-synuclein in the brain of Parkinson’s disease patients. This project is aimed at developing a biomarker for the detection of α-synuclein, which will provide early non-invasive diagnosis of Parkinson’s disease and would greatly improve the clinical development of drugs to treat the disease.

Project Description:
In order to be effective for detection of α-synuclein, the biomarker must be able to be imaged on MRI and must pass into the brain after injection into the patient. To accomplish both these goals, a fragment from an antibody that detects alpha-synuclein will be linked to a short protein. This short protein will both facilitate passage of the molecule through the blood-brain-barrier into the brain and will also generate a signal on MRI. To test this new molecule, the antibody-short protein complex, or ‘biomarker,’ will be injected into pre-clinical models that overexpress alpha-synuclein in the brain. After sacrifice, the brains of these pre-clinical models will be sliced and probed for the presence of the biomarker to show that the biomarker crossed through the blood-brain-barrier.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
There is currently no accurate way to diagnose Parkinson’s disease from MRI imaging. Although some biomarkers for Parkinson’s disease exist, these are generally short-lived radioactive compounds that offer limited accessibility to diagnosis for patients who live far from clinical centers. Further, although research has shown that accumulations of alpha-synuclein occur in all Parkinson’s disease patients, there are no biomarkers that detect this protein. The ability to detect aggregated α-synuclein using a non-invasive technique such as non-radioactive MRI imaging will provide early, safe, and readily available diagnoses of Parkinson’s disease.

Anticipated Outcome:
The proposed study is expected to conclusively demonstrate detection of alpha-synuclein in the brain of pre-clinical models using a novel biomarker. If the biomarker is effective in detecting alpha-synuclein in the brain of pre-clinical models, it will demonstrate clinical feasibility of detecting alpha-synuclein using MRI in humans. Further, because there are different forms of alpha-synuclein, it will be possible to use this approach to create biomarkers for other forms of alpha-synuclein. This approach may even become useful for designing biomarkers for other protein targets related to Parkinson’s disease.

This project was supported with a 2014 supplemental grant to continue work outlined above.