Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
Mol Psychiatry. 2018 Feb;23(2):323-334. doi: 10.1038/mp.2016.248. Epub 2017 Jan 17.
Positron emission tomography (PET) imaging with radiotracers that target translocator protein 18 kDa (TSPO) has become a popular approach to assess putative neuroinflammatory processes and associated microglia activation in psychotic illnesses. It remains unclear, however, whether TSPO imaging can accurately capture low-grade inflammatory processes such as those present in schizophrenia and related disorders. Therefore, we evaluated the validity of TSPO as a disease-relevant marker of inflammation using a translational approach, which combined neurodevelopmental and neurodegenerative mouse models with PET imaging in patients with recent-onset schizophrenia and matched controls. Using an infection-mediated neurodevelopmental mouse model, we show that schizophrenia-relevant behavioral abnormalities and increased inflammatory cytokine expression are associated with reduced prefrontal TSPO levels. On the other hand, TSPO was markedly upregulated in a mouse model of acute neurodegeneration and reactive gliosis, which was induced by intrahippocampal injection of kainic acid. In both models, the changes in TSPO levels were not restricted to microglia but emerged in various cell types, including microglia, astrocytes and vascular endothelial cells. Human PET imaging using the second-generation TSPO radiotracer [C]DPA-713 revealed a strong trend towards reduced TSPO binding in the middle frontal gyrus of patients with recent-onset schizophrenia, who were previously shown to display increased levels of inflammatory cytokines in peripheral and central tissues. Together, our findings challenge the common assumption that central low-grade inflammation in schizophrenia is mirrored by increased TSPO expression or ligand binding. Our study further underscores the need to interpret altered TSPO binding in schizophrenia with caution, especially when measures of TSPO are not complemented with other markers of inflammation. Unless more selective microglial markers are available for PET imaging, quantification of cytokines and other inflammatory biomarkers, along with their molecular signaling pathways, may be more accurate in attempts to characterize inflammatory profiles in schizophrenia and other mental disorders that lack robust reactive gliosis.
正电子发射断层扫描（PET）成像技术使用放射性示踪剂靶向 18kDa 转位蛋白（TSPO），已成为评估精神疾病中假定的神经炎症过程和相关小胶质细胞激活的一种流行方法。然而，TSPO 成像是否能准确捕捉到精神分裂症和相关疾病中存在的低水平炎症过程尚不清楚。因此，我们采用转化方法评估 TSPO 作为炎症相关疾病标志物的有效性，该方法结合了神经发育和神经退行性小鼠模型以及伴有首发精神分裂症和匹配对照的患者的 PET 成像。我们使用感染介导的神经发育小鼠模型表明，与精神分裂症相关的行为异常和炎症细胞因子表达增加与前额叶 TSPO 水平降低有关。另一方面，在海马内注射海人酸诱导的急性神经退行性和反应性神经胶质增生的小鼠模型中，TSPO 明显上调。在这两种模型中，TSPO 水平的变化不仅限于小胶质细胞，而且出现在各种细胞类型中，包括小胶质细胞、星形胶质细胞和血管内皮细胞。使用第二代 TSPO 放射性示踪剂 [C]DPA-713 的人类 PET 成像显示，在以前显示外周和中枢组织中炎症细胞因子水平升高的首发精神分裂症患者的中额回中，TSPO 结合呈现出明显的下降趋势。总的来说，我们的研究结果挑战了一个常见的假设，即精神分裂症中的中枢低度炎症与 TSPO 表达或配体结合增加相对应。我们的研究进一步强调需要谨慎解释精神分裂症中改变的 TSPO 结合，尤其是当 TSPO 的测量方法没有与其他炎症标志物相结合时。除非有更具选择性的小胶质细胞标志物可用于 PET 成像，否则定量分析细胞因子和其他炎症生物标志物及其分子信号通路可能更能准确地描述精神分裂症和其他缺乏活跃神经胶质增生的精神障碍中的炎症特征。
