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

Abstract

Background and objectives: There are limited validated biomarkers in Parkinson disease (PD) which substantially hinders the ability to monitor disease progression and consequently measure the efficacy of disease-modifying treatments. Imaging biomarkers, such as vesicular monoamine transporter type 2 (VMAT2) PET, enable enhanced diagnostic accuracy and detect early neurodegenerative changes associated with prodromal PD. This study sought to assess whether ¹⁸F-AV-133 VMAT2 PET is sensitive enough to monitor and quantify disease progression over a 2-year window.

Methods: ¹⁸F-AV-133 PET scans were performed on participants with PD and REM sleep behavior disorder (RBD) and neurologic controls (NC). All participants were scanned twice ∼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 UPDRS_MOTOR 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 3 regions in participants with PD (N = 26) compared with NC (N = 12), consistent with a decrease in VMAT2 level and ongoing neurodegeneration. Imaging trajectory calculations suggest that the neurodegeneration in PD occurs over ∼33 years [CI: 27.2-39.5], with ∼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 ∼6.5 years [CI: 1.6-12.7] until symptom onset, and a further ∼3 years [CI: 0.3-8.7] until clinical diagnosis.

Discussion: Over a 2-year period, ¹⁸F-AV-133 VMAT2 PET was able to detect progression of nigrostriatal degeneration in participants with PD, and it 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 evidence: This study provides Class IV evidence that VMAT2 PET can detect patients with Parkinson disease and quantify progression over a 2-year window.

Figure 1. VMAT2 18F-AV-133 SUVR in the REM Sleep Behavior Disorder and Parkinson Disease Brain

(A) Baseline posterior and anterior putamen and caudate SUVR levels and (B) follow-up posterior and anterior putamen and caudate SUVR levels. (C) Average VMAT2 scans for the neurologic control (NC), REM sleep behavior disorder (RBD), and Parkinson disease (PD) groups. The bottom row displays the difference in means of the NC and RBD and of NC and PD. Boxplot horizontal lines represent the median and whiskers reflect minimum and maximum values. Δ: difference in means, SUVR = standardized uptake value ratio. *p < 0.05, **p < 0.01, ***p < 0.001 ****p < 0.0001.

Figure 2. VMAT2 18F-AV-133 SUVR Annual Change in the REM Sleep Behavior Disorder and Parkinson Disease Brain

(A) Annual change in the posterior and anterior putamen and caudate of all groups. Boxplot horizontal lines represent the median and whiskers represent minimum and maximum values. (B) Annual SUVR change as a function of the baseline SUVR in the posterior putamen, anterior putamen, and caudate. Data are presented as scatter plots. A second-order polynomial was fitted to the data and displayed as a black curve with confidence intervals in gray. RBD data points are overlaid on curves. Dotted line represents neurologic control (NC) mean. PD = Parkinson disease; RBD = REM sleep behavior disorder; SUVR = standardized uptake value ratio. *p < 0.05, ***p < 0.001, ****p < 0.0001.

Figure 3. Standardized VMAT2 18F-AV-133 SUVR Plots and Trajectory Curves Along the Parkinson Disease Continuum

Boxplot horizontal lines represent the median, whiskers reflect minimum and maximum values, and plus sign represents the mean. Perforated red line represents the average point of clinical diagnosis (time 0), perforated green line represents the average point of motor symptom onset, and shaded portion represents CI. Calculations for posterior putamen are based on individual hemispheres; posterior putamen: NC N = 13, RBD N = 18, and PD N = 52; anterior putamen: NC N = 8, RBD N = 16, and PD N = 44; and caudate: NC N = 14, RBD N = 16, and PD N = 42. NC = neurologic control; PD = Parkinson disease; RBD = REM sleep behavior disorder; SUVR = standardized uptake value ratio.