Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
Neuroimage. 2012 Oct 15;63(1):232-9. doi: 10.1016/j.neuroimage.2012.06.055. Epub 2012 Jul 6.
Microglia play an essential role in many brain diseases. Microglia are activated by local tissue damage or inflammation, but systemic inflammation can also activate microglia. An important clinical question is whether the effects of systemic inflammation on microglia mediate the deleterious effects of systemic inflammation in diseases such as Alzheimer's dementia, multiple sclerosis, and stroke. Positron Emission Tomography (PET) imaging with ligands that bind to Translocator Protein (TSPO) can be used to detect activated microglia. The aim of this study was to evaluate whether the effect of systemic inflammation on microglia could be measured with PET imaging in nonhuman primates, using the TSPO ligand [(11)C]PBR28.
Six female baboons (Papio anubis) were scanned before and at 1h and/or 4h and/or 22 h after intravenous administration of E. coli lipopolysaccharide (LPS; 0.1mg/kg), which induces systemic inflammation. Regional time-activity data from regions of interest (ROIs) were fitted to the two-tissue compartmental model, using the metabolite-corrected arterial plasma curve as input function. Total volume of distribution (V(T)) of [(11)C]PBR28 was used as a measure of total ligand binding. The primary outcome was change in V(T) from baseline. Serum levels of tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) were used to assess correlations between systemic inflammation and microglial activation. In one baboon, immunohistochemistry was used to identify cells expressing TSPO.
LPS administration increased [(11)C]PBR28 binding (F(3,6)=5.1, p=.043) with a 29 ± 16% increase at 1h (n=4) and a 62 ± 34% increase at 4h (n=3) post-LPS. There was a positive correlation between serum IL-1β and IL-6 levels and the increase in [(11)C]PBR28 binding. TSPO immunoreactivity occurred almost exclusively in microglia and rarely in astrocytes.
In the nonhuman-primate brain, LPS-induced systemic inflammation produces a robust increase in the level of TSPO that is readily detected with [(11)C]PBR28 PET. The effect of LPS on [(11)C]PBR28 binding is likely mediated by inflammatory cytokines. Activation of microglia may be a mechanism through which systemic inflammatory processes influence the course of diseases such as Alzheimer's, multiple sclerosis, and possibly depression.
本研究旨在评估使用 TSPO 配体 [(11)C]PBR28 是否可以通过正电子发射断层扫描 (PET) 成像在非人类灵长类动物中测量系统性炎症对小胶质细胞的影响。
6 只雌性狒狒 (Papio anubis) 在静脉注射大肠杆菌脂多糖 (LPS; 0.1mg/kg) 前以及注射后 1h 和/或 4h 和/或 22h 进行扫描，LPS 可诱导全身性炎症。使用校正代谢的动脉血浆曲线作为输入函数，对感兴趣区域 (ROI) 的区域时间活性数据进行拟合，以二室模型拟合。[(11)C]PBR28 的总分布容积 (V(T)) 用作总配体结合的测量值。主要结果是从基线变化的 V(T)。肿瘤坏死因子-α (TNFα)、白细胞介素-1β (IL-1β)、白细胞介素-6 (IL-6) 和白细胞介素-8 (IL-8) 的血清水平用于评估系统性炎症与小胶质细胞激活之间的相关性。在一只狒狒中，使用免疫组织化学鉴定表达 TSPO 的细胞。
LPS 给药增加了 [(11)C]PBR28 结合 (F(3,6)=5.1，p=.043)，在 LPS 后 1h 增加了 29±16% (n=4)，在 LPS 后 4h 增加了 62±34% (n=3)。血清 IL-1β 和 IL-6 水平与 [(11)C]PBR28 结合的增加呈正相关。TSPO 免疫反应性几乎仅发生在小胶质细胞中，很少发生在星形胶质细胞中。
在非人类灵长类动物大脑中，LPS 诱导的全身性炎症会导致 TSPO 水平大幅增加，这很容易通过 [(11)C]PBR28 PET 检测到。LPS 对 [(11)C]PBR28 结合的影响可能是由炎症细胞因子介导的。小胶质细胞的激活可能是系统性炎症过程影响阿尔茨海默病、多发性硬化症等疾病病程的一种机制，也可能是抑郁症的一种机制。
