Glial Activation and Glucose Metabolism in a Transgenic Amyloid Mouse Model: A Triple-Tracer PET Study
Glial Activation and Glucose Metabolism in a Transgenic Amyloid Mouse Model: A Triple-Tracer PET Study
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DOI：
10.2967/jnumed.115.167858
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发表时间：
2016-06-01
影响因子：
9.3
通讯作者：
Rominger, Axel
中科院分区：
文献类型：
--
作者：
Brendel, Matthias;Probst, Federico;Rominger, Axel
阿尔茨海默病（AD）模型的小动物PET淀粉样蛋白成像提供了跟踪淀粉样蛋白形成和脑能量代谢的可能性。由于小胶质细胞激活被认为与阿尔茨海默病病理有关，我们进行了一项三示踪小动物PET研究，以评估转基因阿尔茨海默病小鼠模型中小胶质细胞激活和葡萄糖代谢与淀粉样斑块负荷的关系。方法：采用小动物PET检测各组不同年龄的PS2APP和C57BL/6野生型小鼠。我们用F-18-GE180获得了90分钟的动态发射数据，用于成像活化的小胶质细胞（18-kD转运蛋白配体[TSPO]），用F-18-FDG获得了30至60分钟的静态记录，用于能量代谢，用F-18-florbetaben记录淀粉样变性。通过自动非线性空间归一化对PET数据进行最优融合，计算出suv。对于新型TSPO示踪剂F-18-GE180，我们在建立合适的参考区域后计算了分布体积比。TSPO抗血清免疫组织化学分析、甲氧基- x04纤维（β -淀粉样蛋白）染色和离体放射自显影作为最终金标准评估。结果：注射后60-90 min的SUVR定量分析了F-18-GE180，与整个记录计算的分布体积比和使用白质参考区具有良好的相关性。与年龄匹配的野生型相比，PS2APP小鼠F-18-GE180 SUVR在5月龄时略有升高（+9%,P < 0.01），在16月龄时明显升高（+25%,P < 0.001）。在这一年龄范围内，小动物PET发现的小胶质细胞激活与淀粉样蛋白负荷呈正相关（R = 0.85, P < 0.001），与代谢呈正相关（R = 0.61, P < 0.005）。免疫组织化学和放射自显像结果证实了体内小动物PET数据。结论：在建立的阿尔茨海默氏症小鼠模型中，我们发现了年龄依赖性小胶质细胞激活的证据。这种激活与淀粉样蛋白负荷呈正相关，暗示了PS2APP AD小鼠模型中淀粉样变性和炎症之间的关系。
Amyloid imaging by small-animal PET in models of Alzheimer disease (AD) offers the possibility to track amyloidogenesis and brain energy metabolism. Because microglial activation is thought to contribute to AD pathology, we undertook a triple-tracer small animal PET study to assess microglial activation and glucose metabolism in association with amyloid plaque load in a transgenic AD mouse model. Methods: Groups of PS2APP and C57BL/6 wild type mice of various ages were examined by small-animal PET. We acquired 90-min dynamic emission data with F-18-GE180 for imaging activated microglia (18-kD translocator protein ligand [TSPO]) and static 30- to 60-min recordings with F-18-FDG for energy metabolism and F-18-florbetaben for amyloidosis. Optimal fusion of PET data was obtained through automatic nonlinear spatial normalization, and SUVRs were calculated. For the novel TSPO tracer F-18-GE180, we then calculated distribution volume ratios after establishing a suitable reference region. lmmuno-histochemical analyses with TSPO antisera, methoxy-X04 staining for fibrillary (beta-amyloid, and ex vivo autoradiography served as terminal gold standard assessments. Results: SUVR at 60-90 min after injection gave robust quantitation of F-18-GE180, which correlated well with distribution volume ratios calculated from the entire recording and using a white matter reference region. Relative to age-matched wild-type, F-18-GE180 SUVR was slightly elevated in PS2APP mice at 5 mo (+9%; P < 0.01) and distinctly increased at 16 mo (+25%; P < 0.001). Over this age range, there was a high positive correlation between small-animal PET findings of microglial activation with amyloid load (R = 0.85; P < 0.001) and likewise with metabolism (R = 0.61; P < 0.005). Immunohistochemical and autoradiographic findings confirmed the in vivo small-animal PET data. Conclusion: In this first triple-tracer small-animal PET in a well-established AD mouse model, we found evidence for age-dependent microglial activation. This activation, correlating positively with the amyloid load, implies a relationship between amyloidosis and inflammation in the PS2APP AD mouse model.