Dynamically altered microglia play an important role in the progression of Alzheimer’s disease (AD). Here, we found a close association of the metabolic reconfiguration of microglia with increased hippocampal glucose uptake on [18F]fluorodeoxyglucose (FDG) PET. We used an AD animal model, 5xFAD, to analyze hippocampal glucose metabolism using both animal FDG PET and ex vivo FDG uptake test. Cells of the hippocampus were isolated to perform single-cell RNA-sequencing (scRNA-seq). The molecular features of cells associated with glucose metabolism were analyzed at a single-cell level. In order to apply our findings to human brain imaging study, brain FDG PET data obtained from the Alzheimer’s Disease Neuroimaging Initiative were analyzed. FDG uptake in the hippocampus was compared according to the diagnosis, AD, mild cognitive impairment, and controls. The correlation analysis between hippocampal FDG uptake and soluble TREM2 in cerebrospinal fluid was performed. In the animal study, 8- and 12-month-old 5xFAD mice showed higher FDG uptake in the hippocampus than wild-type mice. Cellular FDG uptake tests showed that FDG activity in hippocampal microglia was increased in the AD model, while FDG activity in non-microglial cells of the hippocampus was not different between the AD model and wild-type. scRNA-seq data showed that changes in glucose metabolism signatures including glucose transporters, glycolysis and oxidative phosphorylation, mainly occurred in microglia. A subset of microglia with higher glucose transporters with defective glycolysis and oxidative phosphorylation was increased according to disease progression. In the human imaging study, we found a positive association between soluble TREM2 and hippocampal FDG uptake. FDG uptake in the hippocampus at the baseline scan predicted mild cognitive impairment conversion to AD. We identified the reconfiguration of microglial glucose metabolism in the hippocampus of AD, which could be evaluated by FDG PET as a feasible surrogate imaging biomarker for microglia-mediated inflammation.

中文翻译：

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海马葡萄糖摄取作为阿尔茨海默病小胶质细胞代谢变化的替代指标

动态改变的小胶质细胞在阿尔茨海默病 (AD) 的进展中起重要作用。在这里，我们发现小胶质细胞的代谢重构与 [18F] 氟脱氧葡萄糖 (FDG) PET 上海马葡萄糖摄取增加密切相关。我们使用 AD 动物模型 5xFAD，使用动物 FDG PET 和离体 FDG 摄取测试来分析海马葡萄糖代谢。分离海马细胞以进行单细胞 RNA 测序 (scRNA-seq)。在单细胞水平上分析了与葡萄糖代谢相关的细胞的分子特征。为了将我们的研究结果应用于人脑成像研究，我们分析了从阿尔茨海默病神经成像计划获得的大脑 FDG PET 数据。根据诊断、AD、轻度认知障碍、和控制。进行海马FDG摄取与脑脊液可溶性TREM2的相关性分析。在动物研究中，8 个月和 12 个月大的 5xFAD 小鼠在海马中的 FDG 摄取量高于野生型小鼠。细胞 FDG 摄取试验表明，AD 模型中海马小胶质细胞的 FDG 活性增加，而海马非小胶质细胞的 FDG 活性在 AD 模型和野生型之间没有差异。scRNA-seq 数据显示，包括葡萄糖转运蛋白、糖酵解和氧化磷酸化在内的葡萄糖代谢特征的变化主要发生在小胶质细胞中。根据疾病进展，具有较高葡萄糖转运蛋白且糖酵解和氧化磷酸化缺陷的小胶质细胞亚群增加。在人体成像研究中，我们发现可溶性 TREM2 与海马 FDG 摄取呈正相关。基线扫描时海马中的 FDG 摄取预测轻度认知障碍转化为 AD。我们确定了 AD 海马中小胶质细胞葡萄糖代谢的重构，这可以通过 FDG PET 作为小胶质细胞介导炎症的可行替代成像生物标志物进行评估。