Microglia-PET as a surrogate marker for post-stroke neuroinflammation

本项目旨在了解人类缺血性脑卒中后小胶质细胞激活与功能预后之间的关系。纵向ICARUS研究包括一系列TSPO- PET和MR成像，以揭示皮质或皮质下病变患者的小胶质细胞激活特征。小胶质细胞的激活将与血液中的炎症标志物和中风的结果相关。我们假设1)急性卒中患者亚群出现明显的小胶质细胞激活，2)小胶质细胞广泛激活的患者更有可能出现不良预后，3)这些患者更有可能从免疫干预中受益。正在进行的ICARUS研究解决了前两个假设，并将通过制定使用TSPO PET选择合适患者的标准，为未来的免疫干预试验做准备。ICARUS将：(1)确定人类中风后小胶质细胞激活的特征和决定因素；(2)将小胶质细胞的激活与血液中的炎症标志物联系起来；(3)将小胶质细胞激活与梗死演变、继发性神经变性和卒中结局相关；(4)制定未来免疫干预试验的患者选择标准。为了能够直接比较人类和实验中风中的小胶质细胞激活，我们进一步在三种不同的实验中风模型中进行小胶质细胞pet。该方法将通过与免疫组织化学金标准实验的相关性来验证TSPO PET示踪信号的特异性。此外，我们将在实验小鼠模型中使用一种新的靶向单氨基氧化酶B的PET示踪剂，以探索这种成像生物标志物在卒中反应性星形细胞病中的潜力。

This project aims to understand the relationship between microglia activation and functional outcome after ischemic stroke in humans. The longitudinal ICARUS study involves serial TSPO- PET and MR imaging to uncover the characteristics of microglia activation in patients with cortical or sub-cortical lesions. Microglial activation will be correlated to inflammatory markers in blood and to stroke outcome. We hypothesise i) that a subpopulation of patients with acute stroke develop prominent microglial activation, ii) that patients with extensive microglial activation are more likely to have poor outcome and iii) that these patients will be more likely to benefit from immune interventions. The ongoing ICARUS study addresses the first two hypotheses and will prepare for a future immune intervention trial by developing criteria for the selection of suitable patients using TSPO PET. ICARUS will: (1) define the characteristics and determinants of microglial activation after human stroke; (2) correlate microglial activation with inflammatory markers in blood; (3) correlate microglial activation with infarct evolution, secondary neurodegeneration, and stroke outcome; and (4) develop criteria for patient selection for future immune intervention trials. To enable a direct comparison of microglial activation in human and experimental stroke we are further perform microglia-PET in three different experimental stroke models. This approach will validate specificity of the TSPO PET tracer signal by correlation with immunohistochemistry gold standard experiments. Furthermore, we will use a novel PET tracer targeting monoaminoxidase B in the experimental mouse models to explore the potential of this imaging biomarker for reactive astrocytosis in stroke.