Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia, Canada.
Department of Translational Neuroscience, Michigan State University, Grand Rapids, Michigan, USA.
Mov Disord. 2022 Aug;37(8):1739-1748. doi: 10.1002/mds.29051. Epub 2022 May 7.
Positron emission tomography (PET) imaging in early Parkinson's disease (PD) subjects reveals that increased dopamine (DA) turnover and reduced dopamine transporter (DAT) density precede decreases in DA synthesis and storage. The rat α-synuclein preformed fibril (α-syn PFF) model provides a platform to investigate DA dynamics during multiple stages of α-syn inclusion-triggered nigrostriatal degeneration.
We investigated multiple aspects of in vivo dopaminergic deficits longitudinally and similarities to human PD using translational PET imaging readouts.
Longitudinal imaging was performed every 2 months in PFF and control rats for 7 months. [ F]-Fluoro-3,4-dihydroxyphenyl-L-alanine (FDOPA) imaging was performed to investigate DA synthesis and storage (K ) and DA turnover, estimated by its inverse, the effective distribution volume ratio (EDVR). C-Methylphenidate (MP) was used to estimate DAT density (BP ).
Early DA turnover increases and DAT binding decreases were observed in the ipsilateral striatum of PFF rats, progressing longitudinally. EDVR decreased 26%, 38%, and 47%, and BP decreased 36%, 50%, and 65% at the 2-, 4-, and 6-month time points, respectively, compared to ipsilateral control striatum. In contrast, deficits in DA synthesis and storage were not observed in the ipsilateral striatum of PFF rats compared to control injections and were relatively preserved up to 6 months (K decreased 20% at 6 months).
The relative preservation of DA synthesis and storage compared to robust progressive deficits in DAT density and increases in DA turnover in the rat α-syn PFF model display remarkable face validity to dopaminergic alterations in human PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
正电子发射断层扫描（PET）在早期帕金森病（PD）患者中的成像显示，多巴胺（DA）周转率增加和多巴胺转运体（DAT）密度降低先于 DA 合成和储存减少。大鼠 α-突触核蛋白原纤维（α-syn PFF）模型提供了一个平台，可在α-syn 包含物触发黑质纹状体变性的多个阶段研究 DA 动力学。
我们使用转化型 PET 成像读数来纵向研究和比较活体多巴胺能缺陷，以模拟人类 PD。
在 7 个月的时间里，每 2 个月对 PFF 和对照大鼠进行一次纵向成像。使用 [ F]-氟-3,4-二羟基苯丙氨酸（FDOPA）成像来研究 DA 合成和储存（K）和 DA 周转率，通过其逆效，有效分布容积比（EDVR）来估计。C-甲基苯丙胺（MP）用于估计 DAT 密度（BP）。
在 PFF 大鼠的同侧纹状体中观察到早期 DA 周转率增加和 DAT 结合减少，且呈纵向进展。与同侧对照纹状体相比，EDVR 在 2、4 和 6 个月时分别降低了 26%、38%和 47%，BP 在 2、4 和 6 个月时分别降低了 36%、50%和 65%。相比之下，在 PFF 大鼠的同侧纹状体中没有观察到 DA 合成和储存的缺陷，与对照注射相比，直到 6 个月时相对保存（6 个月时 K 降低了 20%）。
与大鼠 α-syn PFF 模型中 DAT 密度的明显进行性缺陷和 DA 周转率的增加相比，DA 合成和储存的相对保存显示出对人类 PD 中多巴胺能改变的显著相似性。
