Promising Outcomes of Original Grant:
The goals of the original grant were to develop PET (a non invasive imaging technique used in the study of human Parkinson’s disease ) –derived measures of dopamine kinetics for pre-clinical models, since impaired dopaminergic neurotransmission has been shown to be a key feature of LRRK2 mutations-related Parkinsonism. We succeeded to measure dopamine uptake and turnover in unilaterally 6-hydroxydopamine lesioned pre-clinical models using the radiotracer 18F-fluorodopa (FD). These were, to our knowledge, the first measurements of their kind. The quantitative accuracy of the data was confirmed by comparing FD results to those obtained with a PET marker of vesicular transporter density, previously validated against post-mortem data.
Objectives for Supplemental Investigation:
We will be using the newly developed imaging techniques to investigate longitudinally, in-vivo, dopamine kinetics in (i) antisense oligonucleotide (ASO) induced LRRK2 knockdown pre-clinical models to investigate LRRK2 function in-vivo, (ii) transgenic pre-clinical models with the G2019S mutation to investigate the effects of the mutation on dopaminergic neurotransmission. Imaging data will be complemented by behavioral observation, microdialysis and post-mortem measures, such as electrophysiology, and will be compared to similar imaging studies in humans. The common imaging observables between pre-clinical models and humans will provide a means (i) of validating the pre-clinical models and (ii) of vertically integrating basic science studies in pre-clinical models and manifestation of the LRRK2 mutation-related Parkinson’s disease (PD) in humans to achieve a better understanding of both LRRK2 function and relations between LRRK2 mutations and Parkinsonism.
Importance of This Research for the Development of a New PD Therapy:
If imaging data show similar outcomes between the pre-clinical models and human LRRK2-associated PD, the pre-clinical 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 facilitate a common readout between pre-clinical models and humans in the short and long term assessment of the efficacy of potential neuroprotective therapies, thus facilitating transitions of novel agents from pre-clinical model testing to human use. Results will provide guidance when identifying the optimum, simplest and most easily available imaging protocols when investigating larger populations.