Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, UK.
Neuroimage. 2012 Feb 1;59(3):2007-16. doi: 10.1016/j.neuroimage.2011.10.060. Epub 2011 Oct 25.
Post-stroke microglial activation (MA) may have both neurotoxic and pro-repair effects, particularly in the salvaged penumbra. Mapping MA in vivo is therefore an important goal. 11C-PK11195, a ligand for the 18 kDa translocator protein, is the reference radioligand for MA imaging, but a correlation between the regional distributions of in vivo tracer binding and post mortem MA after stroke, as assessed with PET and immunohistochemistry, respectively, has not been demonstrated so far. Here we performed 11C-PK11195 microPET in a rat model previously shown to induce extensive cortical MA, and determined the correlation between 11C-PK11195 and immunostaining with the CD11 antibody OX42, so as to verify the presence of activated microglia, in a template of PET-resolution size regions-of-interest (ROIs) spanning the whole affected hemisphere.
Adult spontaneously hypertensive rats underwent 45 min distal middle cerebral artery occlusion and 11C-PK11195 PET at Days 2 and 14 after stroke according to a longitudinal design. Following perfusion-fixation at Day 14, brains were removed and coronally cut for OX42 staining. 11C-PK11195 binding potential (BPND) parametric maps were generated, and in each rat both BP(ND) and OX42 (intensity×extent score) were obtained in the same set of 44 ROIs extracted from a cytoarchitectonic atlas to cover the whole hemisphere. Correlations were computed across the 44 ROIs both within and across subjects.
Significant BPND increases were observed in both the infarct and surrounding areas in all rats at day 14; less strong but still significant increases were present at day 2. There were highly significant (all p<0.001) positive correlations, both within- and across-subjects, between day 14 BPND values and OX42 scores.
The correlation between Day 14 11C-PK11195 and OX42 across the affected hemisphere from the same brain regions and animals further supports the validity of 11C-PK11195 as an in vivo imaging marker of MA following stroke. The finding of statistically significant increases in 11C-PK11195 as early as 48 h after stroke is novel. These results have implications for mapping MA after stroke, with potential therapeutic applications.
中风后小胶质细胞激活（MA）可能具有神经毒性和促进修复的双重作用，尤其是在挽救的半影区。因此，对体内 MA 进行成像描绘是一个重要的目标。11C-PK11195 是一种 18 kDa 转位蛋白的配体，是 MA 成像的参考放射性配体，但迄今为止，尚未证明 PET 和免疫组织化学评估的中风后活体示踪剂结合的区域分布与死后 MA 之间存在相关性。在此，我们在以前证明可诱导广泛皮质 MA 的大鼠模型中进行了 11C-PK11195 微 PET 研究，并确定了 11C-PK11195 与 OX42 抗体免疫染色之间的相关性，以便在横跨整个受累半球的 PET 分辨率大小的感兴趣区（ROI）模板中验证活化的小胶质细胞的存在。
成年自发性高血压大鼠接受 45 分钟远端大脑中动脉闭塞，并根据纵向设计在中风后第 2 天和第 14 天进行 11C-PK11195 PET。在第 14 天进行灌注固定后，取出大脑并进行冠状面 OX42 染色。生成 11C-PK11195 结合势（BPND）参数图，并在同一组 44 个 ROI 中获得每个大鼠的 BP（ND）和 OX42（强度×范围评分），这些 ROI 从细胞构筑学图谱中提取出来，以覆盖整个半球。在跨主体的 44 个 ROI 内和跨主体内均进行相关性计算。
在所有大鼠中，第 14 天梗塞区和周围区域均观察到 BPND 显著增加；在第 2 天也观察到较弱但仍具有显著意义的增加。在跨主体内和跨主体内，第 14 天 BPND 值与 OX42 评分之间存在高度显著的（均 p<0.001）正相关。
在同一大脑区域和动物的受累半球上，第 14 天 11C-PK11195 和 OX42 之间的相关性进一步支持 11C-PK11195 作为中风后 MA 的体内成像标志物的有效性。在中风后 48 小时内即可检测到 11C-PK11195 统计学上的显著增加是新颖的发现。这些结果对中风后 MA 进行描绘具有影响，具有潜在的治疗应用价值。
