Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.

中文翻译：

---

小胶质细胞活动的区域去同步化与阿尔茨海默病的认知能力下降有关


小胶质细胞激活是阿尔茨海默病 (AD) 神经病理学的标志之一，但人们对大脑中小胶质细胞区域相互作用的影响知之甚少。我们假设，健康大脑中的小胶质细胞激活是区域同步的，但随着神经退行性疾病的进展，小胶质细胞的激活会出现区域去同步。我们解决了小胶质细胞连接组的存在，并研究了小胶质细胞去同步化作为 AD 生物标志物。为了验证这一概念，我们对小鼠进行了小胶质细胞清除，以测试当小胶质细胞被清除时，18 kDa 易位蛋白 (TSPO)-PET 的区域间相关系数 (ICC) 是否会发生变化。接下来，我们评估了功能失调的小胶质细胞和 AD 病理生理学对小鼠大脑 TSPO-PET ICC 的影响，然后转化为人类 AD 连续体数据集。我们将个性化小胶质细胞去同步指数与认知表现相关联。最后，我们在小鼠中进行了单细胞放射性示踪（scRadiotracing），以确保所测量的去同步化的小胶质细胞来源。小胶质细胞缺失的小鼠在所有脑室中均表现出 ICC 的强烈减少，表明小胶质细胞特异性去同步化。 AD小鼠模型显示小胶质细胞同步性显着降低，这与病理改变的大脑区域中细胞放射性示踪剂摄取的变异性增加有关。 AD连续体中的人类表明，与认知能力下降相关的小胶质细胞同步性的阶段性降低。小鼠 scRadiotracing 表明 TSPO 信号增加归因于小胶质细胞。 在淀粉样蛋白模型中使用小胶质细胞耗尽的小鼠的 TSPO-PET 成像和 scRadiotracing，我们提供了可以评估小鼠大脑中的小胶质细胞连接组的第一个证据。小胶质细胞同步性与 AD 认知能力下降密切相关，可以作为疾病进展的独立个性化生物标志物。