In vivo quantitative PET/MR imaging of gene expression in Parkinson's Disease

Objectives 6-[18F]fluoro-L-m-tyrosine (FMT) PET has been used previously as an imaging method to quantify the level of transgene expression in clinical trial of an adeno-associated virus serotype 2 - aromatic L-amino acid decarboxylase (AAV2-AADC) gene therapy for Parkinson’s Disease (PD). In this study we examined if L-6-[ 18F]fluoro-3,4-dihydroxyphenylalanine (FDOPA) PET could be used to detect AADC gene expression after gene transfer in PD patients.

Methods Dynamic multiframe PET (4×60s, 3×120s, 3×180s, 11×300 s) was acquired while T1-, T2- weighted, and diffusion tensor MR images were acquired simultaneously. The T2-weighted axial MR images were registered to the MNI template, and the same transformation matrix was applied to the PET images. Volumes of interest (VOIs) for cerebellum (as a reference) and putamen were created as part of a general atlas based on the template. In addition, additional VOIs were manually drawn for the specific area of putamen that received the AAV2-AADC infusion when the intraoperative MRI, during the gene transfer, was available.

Results In this dose escalation P-1b trial, five PD patients received low dose (7.5×10¹¹ vector genomes) of AAV2-AADC. Baseline FDOPA-PET/MRI was performed for all five, and for two of the five patients, post-therapy FDOPA-PET/MRI (at 4-6 months after the gene transfer) was performed. When the atlas-based VOIs were used, K_{i_ref}=0.0074±0.0017 min^-1 for baseline scans, and 0.0099±0.0019 min^-1 for post-therapy scans. When the AADC infusion sites were used as target VOIs, K_{i_ref}=0.0056±0.0023 min^-1 for baseline scans (n=3), and 0.0093±0.0012 min^-1 for post-therapy scans (n=2).

Conclusions Similar to FMT-PET, FDOPA-PET/MRI provides a quantitative metric to measure the levels of transgene expression in the ongoing AAV2-AADC gene therapy trial in parkinsonian patients.