Objective/Rationale:
Transgenic pre-clinical models are instrumental to investigate mutation-induced abnormalities at the bio-chemical, cellular level in a manner not possible in humans. In humans, non-invasive functional brain imaging provides information on disease and mutation-induced abnormalities at a macroscopic, neurochemical level. We will develop functional imaging for pre-clinical models similar to that performed in humans to provide (i) a better understanding of the relation between LRRK2 mutations and Parkinson’s disease and (ii) an identification of a possible target for early diagnosis and disease modifying therapies.
Project Description:
Parkinson’s disease is characterized by the lack of the neurotransmitter dopamine due to neuronal degeneration. In-vivo human and ex-vivo pre-clinical models studies suggest that a possible early signature of the LRRK2 mutation-related Parkinson’s disease is an alteration in the mechanisms related to the release of dopamine from the neuronal terminals. Positron Emission Tomography (PET) is an imaging technique used to investigate in-vivo the integrity of the dopamine producing neurons. In humans it can also provide information on dopamine release mechanisms. We plan to develop imaging protocols that would allow to perform similar measures in transgenic pre-clinical models to provide a set of observables common to transgenic pre-clinical models and humans.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This project will provide a link between basic science studies in pre-clinical models and manifestation of the LRRK2 mutation-related Parkinson’s disease in humans. The common observables will allow us to assess the relevance of the transgenic pre-clinical models models to human disease. If similar outcomes are observed, the pre-clinical models models can be used with confidence in unraveling mutation-related neuronal abnormalities and identify early mutation-related alterations to provide a target for potential disease-modifying therapies. The non-invasive aspect of imaging will allow longitudinal studies thus providing a tool to assess the efficacy of novel therapies in pre-clinical models and humans.
Anticipated Outcome:
The methodology developed as part of this project will provide an essential tool to validate pre-clinical LRRK2 mutation models and confirm that abnormalities in dopamine release are an early biomarker of LRRK2 mutation associated Parkinsonism. The identification of a reliable biomarker will help to reliably diagnose the disease and will provide an invaluable tool to both design highly targeted novel therapies and assess their efficacy.