Rodríguez-Chinchilla Tatiana, Quiroga-Varela Ana, Molinet-Dronda Francisco, Belloso-Iguerategui Arantzazu, Merino-Galan Leyre, Jimenez-Urbieta Haritz, Gago Belén, Rodriguez-Oroz María Cruz
Neuroscience Area, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain.
Network Center for Biomedical Research in Neurodegenerative Diseases, CIBERNED, Madrid, Spain.
Eur J Nucl Med Mol Imaging. 2020 Oct;47(11):2602-2612. doi: 10.1007/s00259-020-04772-4. Epub 2020 Mar 23.
To study the feasibility of the in vivo [F]-DPA-714 TSPO positron emission tomography (PET) to detect glial activation in a rat model of progressive parkinsonism induced by viral-mediated overexpression of A53T mutated human α-synuclein (hα-syn) in the substantia nigra pars compacta (SNpc).
We conducted a cross-sectional study in a model of progressive parkinsonism. Bilateral intranigral injections with 2/9 adeno-associated viral vectors encoding either hα-syn (AAV-hα-syn) or green fluorescent protein (AAV-GFP) were performed in rats (n = 60). In vivo [F]-DPA-714 PET imaging was performed at different time points after inoculation (p.i.) of the viral vector (24 and 72 h and 1, 2, 3, and 16 weeks). Images were analyzed to compute values of binding potential (BP) in the SNpc and striatum using a volume of interest (VOI) analysis. Immunohistochemistry of markers of dopaminergic degeneration (tyrosine hydroxylase (TH)), microglia (Iba-1), and astrocytes (GFAP) was carried out. Binding potential (BP) of [F]-DPA-714 PET in the in vivo PET study was correlated with post-mortem histological markers.
In the SNpc of AAV-hα-syn rats, there was higher in vivo [F]-DPA-714 BP (p < 0.05) and increased number of post-mortem Iba-1 cells (p < 0.05) from second week p.i. onwards, which were highly correlated (p < 0.05) between each other. These findings antedated the nigral reduction of TH cells that occurs since third week p.i. (p < 0.01). In addition, the [F]-DPA-714 BP was inversely correlated (p < 0.05) with the TH cells. In contrast, GFAP cells only increased at 16 weeks p.i. and did not correlate with the in vivo results. In the striatum, no changes in the number of Iba-1 and GFAP cells were observed, but an increment in the [F]-DPA-714 BP was found at 16 weeks p.i.
Our study showed that in vivo PET study with [F]-DPA-714 is a selective and reliable biomarker of microglial activation and could be used to study preclinical stages of Parkinson's disease (PD) and to monitor the progression of the disease.
研究体内[¹⁸F]-DPA-714转运蛋白18 kDa（TSPO）正电子发射断层扫描（PET）检测黑质致密部（SNpc）中病毒介导的A53T突变型人α-突触核蛋白（hα-syn）过表达诱导的进行性帕金森病大鼠模型中神经胶质细胞激活的可行性。
我们在进行性帕金森病模型中开展了一项横断面研究。对大鼠（n = 60）双侧黑质内注射编码hα-syn（腺相关病毒-hα-syn，AAV-hα-syn）或绿色荧光蛋白（腺相关病毒-GFP，AAV-GFP）的2/9型腺相关病毒载体。在接种病毒载体后不同时间点（接种后24小时和72小时以及1、2、3和16周）进行体内[¹⁸F]-DPA-714 PET成像。使用感兴趣区（VOI）分析对图像进行分析，以计算SNpc和纹状体中的结合潜能（BP）值。进行多巴胺能神经元变性标志物（酪氨酸羟化酶（TH））、小胶质细胞（离子钙接头蛋白1，Iba-1）和星形胶质细胞（胶质纤维酸性蛋白，GFAP）的免疫组织化学检测。体内PET研究中[¹⁸F]-DPA-714 PET的结合潜能（BP）与死后组织学标志物相关。
在AAV-hα-syn大鼠的SNpc中，从接种后第二周起，体内[¹⁸F]-DPA-714 BP较高（p < 0.05），死后Iba-1细胞数量增加（p < 0.05），两者之间高度相关（p < 0.05）。这些发现早于接种后第三周开始出现的TH细胞黑质减少（p < 0.01）。此外，[¹⁸F]-DPA-714 BP与TH细胞呈负相关（p < 0.05）。相比之下，GFAP细胞仅在接种后16周增加，且与体内结果不相关。在纹状体中，未观察到Iba-1和GFAP细胞数量的变化，但在接种后16周发现[¹⁸F]-DPA-714 BP增加。
我们的研究表明，体内[¹⁸F]-DPA-714 PET研究是小胶质细胞激活的一种选择性和可靠的生物标志物，可用于研究帕金森病（PD）的临床前期阶段并监测疾病进展。
