Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Mov Disord. 2023 Jun;38(6):978-989. doi: 10.1002/mds.29395. Epub 2023 Apr 6.
Severe reduced synaptic density was observed in spinocerebellar ataxia (SCA) in postmortem neuropathology, but in vivo assessment of synaptic loss remains challenging. OBJECTIVE SPINOCEREBELLAR ATAXIA TYPE 3: The objective of this study was to assess in vivo synaptic loss and its clinical correlates in spinocerebellar ataxia type 3 (SCA3) patients by synaptic vesicle glycoprotein 2A (SV2A)-positron emission tomography (PET) imaging.
We recruited 74 SCA3 individuals including preataxic and ataxic stages and divided into two cohorts. All participants received SV2A-PET imaging using F-SynVesT-1 for synaptic density assessment. Specifically, cohort 1 received standard PET procedure and quantified neurofilament light chain (NfL), and cohort 2 received simplified PET procedure for exploratory purpose. Bivariate correlation was performed between synaptic loss and clinical as well as genetic assessments.
In cohort 1, significant reductions of synaptic density were observed in cerebellum and brainstem in SCA3 ataxia stage compared to preataxic stage and controls. Vermis was found significantly involved in preataxic stage compared to controls. Receiver operating characteristic (ROC) curves highlighted SV2A of vermis, pons, and medulla differentiating preataxic stage from ataxic stage, and SV2A combined with NfL improved the performance. Synaptic density was significantly negatively correlated with disease severity in cerebellum and brainstem (International Co-operative Ataxia Rating Scale: ρ ranging from -0.467 to -0.667, P ≤ 0.002; Scale of Assessment and Rating of Ataxia: ρ ranging from -0.465 to -0.586, P ≤ 0.002). SV2A reduction tendency of cerebellum and brainstem identified in cohort 1 was observed in cohort 2 with simplified PET procedure.
We first identified in vivo synaptic loss was related to disease severity of SCA3, suggesting SV2A PET could be a promising clinical biomarker for disease progression of SCA3. © 2023 International Parkinson and Movement Disorder Society.
在脊髓小脑共济失调（SCA）的尸检神经病理学中观察到严重的突触密度降低，但突触丢失的体内评估仍然具有挑战性。
本研究旨在通过突触小泡糖蛋白 2A（SV2A）-正电子发射断层扫描（PET）成像评估脊髓小脑共济失调 3 型（SCA3）患者的体内突触丢失及其临床相关性。
我们招募了 74 名 SCA3 个体，包括前共济失调和共济失调阶段，并分为两个队列。所有参与者均接受使用 F-SynVesT-1 进行的 SV2A-PET 成像，以评估突触密度。具体来说，队列 1 接受了标准的 PET 程序，并量化了神经丝轻链（NfL），而队列 2 则为探索目的接受了简化的 PET 程序。在队列 1 中，与前共济失调阶段和对照组相比，SCA3 共济失调阶段的小脑和脑干中观察到突触密度显著降低。与对照组相比，发现小脑蚓部在前共济失调阶段明显受累。受试者工作特征（ROC）曲线突出了小脑蚓部、脑桥和延髓的 SV2A 可以区分前共济失调阶段和共济失调阶段，并且 SV2A 与 NfL 相结合可以提高性能。在小脑和脑干中，突触密度与疾病严重程度呈显著负相关（国际合作共济失调评分量表：ρ 范围从-0.467 到-0.667，P≤0.002；共济失调评估和评分量表：ρ 范围从-0.465 到-0.586，P≤0.002）。在简化 PET 程序的队列 2 中观察到队列 1 中观察到的小脑和脑干的 SV2A 减少趋势。
我们首次发现体内突触丢失与 SCA3 的疾病严重程度相关，提示 SV2A PET 可能是 SCA3 疾病进展的有前途的临床生物标志物。
