MJFF Imaging Consortium

Initial data from the landmark Parkinson's Progression Markers Initiative (PPMI) showed that AV133 performs better than DAT scan in tracking disease progression and would require fewer subjects to show a change in clinical trials. This project will enroll PPMI prodromal participants to determine if there is an early signal that predicts progression to clinical Parkinson's disease.

AV133 has shown promising results in PPMI as a potential diagnostic and progression marker for PD. Several pharmaceutical companies have expressed interest in using this tracer in clinical trials but, as of now, the tracer can only be produced at a couple of commercial sites. This project will set up several sites so that the tracer is available more broadly for use in Phase I and II clinical trials.

C05-05 is an alpha-synuclein PET tracer developed by Makoto Higuchi (National Institute of Radiological Sciences) that has been tested in a small number of PD volunteers, MSA volunteers, and control participants. The initial data showed a potential signal in the substantia nigra in people with PD. This project will collect additional imaging data in PD and control volunteers to increase the dataset and confirm or refute the previously reported signal in PD.

Increased uptake of DPA-714 has been observed in de novo PD, especially in volunteers with high-affinity binding to TSPO ligands. It is not known how early in the disease the signal appears. This project will enroll PPMI prodromal participants for DPA-714 PET imaging to explore if there is increased binding that is predictive of manifest PD. Additionally, the project will include longitudinal imaging to determine if there is a change over time that could be used to inform clinical trials for anti-inflammatory therapeutic interventions.

This project will continue to use the TSPO PET tracer to image PD volunteers who were previously imaged at The University of Alabama at Birmingham to determine if the signal changes over time. The volunteers were de novo at baseline and increased uptake of DPA-714 was observed in some brain regions. This project will complement the PPMI project that will utilize the same tracer in the earliest stages of PD. Data could potentially be used to determine the sample size required to power a clinical trial for response to an anti-inflammatory therapeutic intervention. This project will also collect arterial blood samples in a small group of PD participants to enable more work on the quantitative modeling of DPA-714.

SV2A has been considered a non-invasive biomarker of synaptic density that can be used for monitoring neurodegenerative diseases. This project will evaluate SV2A across the disease spectrum, including early-stage disease volunteers, to determine if it is useful as a marker of disease and/or disease progression.

SV2C has been found to be involved in the modulation of dopamine release and to be specifically reduced in models of PD and in brain tissue from people with PD. The aim of this project is to develop a PET radioligand for imaging SV2C. The project will include in silico modeling of compounds binding to SV2C, in vitro testing of 3H-labelled compounds using rodent brain homogenates, and autoradiography on non-human brain tissue slices. Ultimately, lead compound(s) showing optimal in vitro properties will be radiolabeled with 11C and examined in vivo with PET in non-human primates.