In Vivo Detection of Age- and Disease-Related Increases in Neuroinflammation by 18F-GE180 TSPO MicroPET Imaging in Wild-Type and Alzheimer's Transgenic Mice
In Vivo Detection of Age- and Disease-Related Increases in Neuroinflammation by 18F-GE180 TSPO MicroPET Imaging in Wild-Type and Alzheimer's Transgenic Mice
复制标题
DOI：
10.1523/jneurosci.0996-15.2015
复制
发表时间：
2015-11-25
影响因子：
5.3
通讯作者：
Lemere, Cynthia A.
中科院分区：
文献类型：
--
作者：
Liu, Bin;Le, Kevin X.;Lemere, Cynthia A.
阿尔茨海默病(AD)是导致痴呆症的最常见原因。神经炎症在AD的发病机制中起着重要作用。18 kDa转位蛋白(TSPO)的配体是激活的小胶质细胞的标志，已被用作正电子发射断层扫描(PET)示踪剂，以反映人类和小鼠模型的神经炎症。在这里，我们使用新型TSPO靶向PET示踪剂F-18-GE180(氟曲拉胺)来研究年轻和老年WT和APP/PS1dE9转基因(TG)小鼠神经炎症的差异。体内PET扫描显示，与年轻的TG小鼠和所有的WT小鼠相比，WTT和TG小鼠的全脑摄取F-18-GE180明显随年龄的增加而增加，老年TG小鼠的全脑摄取(峰值摄取和滞留)显著增加。同样，通过MRI联合注册，老年WT>；年轻WT>；年轻WT；小鼠的海马区F-18-GE180结合潜力最高到最低。体外PET和放射自显影分析进一步证实了我们在体内的PET结果：F-18-GE180在海马区和皮质中的增强摄取和特异性结合(SUV75%)在老年TG小鼠中最高，其次是老年WT小鼠，年轻TG小鼠，最后是年轻WT小鼠。体内冷示踪剂竞争研究证实了F-18-GE180的特异性。我们还检测了4个月大的WT鼠的F-18-GE180代谢物，发现尽管总放射性在2小时内下降，但在剩余的放射性中，类似90%是由亲本F-18-GE180引起的。总之，F-18-GE180正电子发射计算机断层扫描可能有助于对AD进展和治疗过程中的神经炎症进行纵向监测。
Alzheimer's disease (AD) is the most common cause of dementia. Neuroinflammation appears to play an important role in AD pathogenesis. Ligands of the 18 kDa translocator protein (TSPO), a marker for activated microglia, have been used as positron emission tomography (PET) tracers to reflect neuroinflammation in humans and mouse models. Here, we used the novel TSPO-targeted PET tracer F-18-GE180 (flutriciclamide) to investigate differences in neuroinflammation between young and old WT and APP/PS1dE9 transgenic (Tg) mice. In vivo PET scans revealed an overt age-dependent elevation in whole-brain uptake of F-18-GE180 in bothWTand Tg mice, and a significant increase in whole-brain uptake of F-18-GE180 (peak-uptake and retention) in old Tg mice compared with young Tg mice and all WT mice. Similarly, the F-18-GE180 binding potential in hippocampus was highest to lowest in old Tg > old WT > young Tg > young WT mice using MRI coregistration. Ex vivo PET and autoradiography analysis further confirmed our in vivo PET results: enhanced uptake and specific binding (SUV75%) of F-18-GE180 in hippocampus and cortex was highest in old Tg mice followed by old WT, young Tg, and finally youngWTmice. F-18-GE180 specificity was confirmed by an in vivo cold tracer competition study. Wealso examined F-18-GE180 metabolites in 4-month-oldWTmice and found that, although total radioactivity declined over 2 h, of the remaining radioactivity, similar to 90% was due to parent F-18-GE180. In conclusion, F-18-GE180 PET scans may be useful for longitudinal monitoring of neuroinflammation during AD progression and treatment.