From the The Florey Institute of Neuroscience and Mental Health (L.C.B., D.F., K.J.B.); Health & Biosecurity Flagship (V.D.), The Australian eHealth Research Centre, The Commonwealth Scientific and Industrial Research Organisation; Department of Psychiatry (V.L.V.), University of Pittsburgh, PA; Department of Neurology (S.X.), Austin Health, Melbourne; The University of Melbourne (D.F.); Department of Molecular Imaging and Therapy (C.R.), Austin Health, Melbourne, Australia.
Neurology. 2023 Nov 27;101(22):e2314-e2324. doi: 10.1212/WNL.0000000000207748.
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 F-AV-133 VMAT2 PET is sensitive enough to monitor and quantify disease progression over a 2-year window.
F-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 test, Sniffin' Sticks, and Hospital Anxiety and Depression Score.
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.
Over a 2-year period, F-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.
This study provides Class IV evidence that VMAT2 PET can detect patients with Parkinson disease and quantify progression over a 2-year window.
帕金森病（PD）中可用的验证性生物标志物十分有限，这极大地限制了我们监测疾病进展的能力，进而也无法衡量疾病修饰治疗的效果。影像生物标志物，如囊泡单胺转运体 2（VMAT2）PET，能够提高诊断准确性，并检测与前驱期 PD 相关的早期神经退行性改变。本研究旨在评估 F-AV-133 VMAT2 PET 是否足够灵敏，能够在 2 年的窗口期内监测和量化疾病进展。
对 PD 伴 REM 睡眠行为障碍（RBD）和神经对照组（NC）的参与者进行 F-AV-133 PET 扫描。所有参与者在大约 26 个月后进行两次扫描。使用初级视觉皮层参考区域计算区域示踪剂保留率，并表示为标准摄取值比。感兴趣的区域包括尾状核、前壳核和后壳核。在扫描时，参与者接受了临床评估，包括 UPDRS 测试、Sniffin' Sticks 和医院焦虑抑郁量表。
在 26 个月的时间间隔内，与 NC（n = 12）相比，PD 患者（n = 26）的所有 3 个区域的 PET 信号均明显下降，这与 VMAT2 水平下降和持续神经退行性变一致。影像学轨迹计算表明，PD 中的神经退行性变发生在大约 33 年[置信区间：27.2-39.5]内，在后壳核中，大约有 10.5 年[置信区间：9.1-11.3]的变性是在 VMAT2 PET 扫描可检测到之前发生的，然后再经过大约 6.5 年[置信区间：1.6-12.7]才出现症状，再经过大约 3 年[置信区间：0.3-8.7]才出现临床诊断。
在 2 年的时间内，F-AV-133 VMAT2 PET 能够检测到 PD 患者黑质纹状体变性的进展，它代表了一种能够识别处于 PD 进展风险中的个体的敏感工具，而目前使用临床检测结果还无法识别这些个体。轨迹模型提出，在临床诊断之前，有大约 20 年的黑质纹状体变性。这些数据表明，VMAT2 PET 提供了一种敏感的方法来监测 PD 的神经退行性进展，这对 PD 的诊断有影响，进而对临床试验的患者分层和监测也有影响。
本研究提供了 IV 级证据，表明 VMAT2 PET 可以检测出帕金森病患者，并在 2 年的时间窗口内定量疾病进展。
