Using ¹⁸F-AV-133 VMAT2 PET Imaging to Monitor Progressive Nigrostriatal Degeneration in Parkinson Disease

BackgroundThere are limited validated biomarkers in Parkinson's disease (PD) which substantially hinders the ability to monitor disease progression and consequently measure the efficacy of disease-modifying treatments. Imaging biomarkers, such as VMAT2 PET, enable enhanced diagnostic accuracy, and detect early neurodegenerative changes associated with prodromal PD. This study sought to assess whether F-18-AV-133 VMAT2 PET is sensitive enough to monitor and quantify disease progression over a two-year window.Methods F-18-AV-133 PET scans were performed on participants with PD and REM sleep behavior disorder (RBD) and neurological controls (NC). All participants were scanned twice similar to 26 months apart. Regional tracer retention was calculated with a primary visual cortex reference region and expressed as the standard uptake volume ratio. Regions of interest included caudate, anterior and posterior putamen. At the time of scanning participants underwent clinical evaluation including UPDRSMOTOR test, Sniffin' Sticks, and Hospital Anxiety and Depression Score.Results Over the 26-month interval a significant decline in PET signal was observed in all three regions in participants with PD (N=26) and in the posterior putamen in participants with RBD (N=11) compared to NC (N=12), consistent with a decrease in VMAT2 level and ongoing neurodegeneration. Imaging trajectory calculations suggest the neurodegeneration in PD occurs over similar to 33 years [CI: 27.2, 39.5], with similar to 10.5 years [CI: 9.1-11.3] of degeneration in the posterior putamen before it becomes detectable on a VMAT2 PET scan, a further similar to 6.5 years [CI: 1.6,12.7] until symptom onset, and a further similar to 3 years [CI: 0.3,8.7] until clinical diagnosis.Discussion Over a two-year period, F-18-AV-133 VMAT2 PET was able to detect progression of nigrostriatal degeneration in participants with PD and represents a sensitive tool to identify individuals at risk of progression to PD, which are currently lacking using clinical readouts. Trajectory models propose that there is nigrostriatal degeneration occurring for 20 years before clinical diagnosis. These data demonstrate that VMAT2 PET provides a sensitive measure to monitor neurodegenerative progression of PD which has implications for PD diagnostics and subsequently clinical trial patient stratification and monitoring.Classification of evidenceThis study provides Class IV evidence that VMAT2 PET can detect patients with Parkinson Disease and quantify progression over a two-year window.