Department of Psychiatry and Psychotherapy, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany.
German Center for Neurodegenerative Diseases, Munich, Germany.
Ann Neurol. 2022 Nov;92(5):768-781. doi: 10.1002/ana.26465. Epub 2022 Aug 25.
Alzheimer disease (AD) is characterized by amyloid β (Aβ) plaques and neurofibrillary tau tangles, but increasing evidence suggests that neuroinflammation also plays a key role, driven by the activation of microglia. Aβ and tau pathology appear to spread along pathways of highly connected brain regions, but it remains elusive whether microglial activation follows a similar distribution pattern. Here, we assess whether connectivity is associated with microglia activation patterns.
We included 32 Aβ-positive early AD subjects (18 women, 14 men) and 18 Aβ-negative age-matched healthy controls (10 women, 8 men) from the prospective ActiGliA (Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer's Disease) study. All participants underwent microglial activation positron emission tomography (PET) with the third-generation mitochondrial 18 kDa translocator protein (TSPO) ligand [ F]GE-180 and magnetic resonance imaging (MRI) to measure resting-state functional and structural connectivity.
We found that inter-regional covariance in TSPO-PET and standardized uptake value ratio was preferentially distributed along functionally highly connected brain regions, with MRI structural connectivity showing a weaker association with microglial activation. AD patients showed increased TSPO-PET tracer uptake bilaterally in the anterior medial temporal lobe compared to controls, and higher TSPO-PET uptake was associated with cognitive impairment and dementia severity in a disease stage-dependent manner.
Microglial activation distributes preferentially along highly connected brain regions, similar to tau pathology. These findings support the important role of microglia in neurodegeneration, and we speculate that pathology spreads throughout the brain along vulnerable connectivity pathways. ANN NEUROL 2022;92:768-781.
阿尔茨海默病（AD）的特征是淀粉样β（Aβ）斑块和神经原纤维缠结，但越来越多的证据表明，神经炎症也起着关键作用，这是由小胶质细胞的激活驱动的。Aβ和 tau 病理学似乎沿着高度连接的大脑区域的途径传播，但小胶质细胞的激活是否遵循类似的分布模式仍不清楚。在这里，我们评估连通性是否与小胶质细胞激活模式相关。
我们纳入了 32 名 Aβ 阳性的早期 AD 患者（18 名女性，14 名男性）和 18 名年龄匹配的 Aβ 阴性健康对照者（10 名女性，8 名男性），这些参与者均来自前瞻性的 ActiGliA（大脑网络、淀粉样蛋白和衰老及阿尔茨海默病中的小胶质细胞活性）研究。所有参与者均接受了第三代线粒体 18 kDa 转位蛋白（TSPO）配体[ F]GE-180 的正电子发射断层扫描（PET）和磁共振成像（MRI），以测量静息状态下的功能和结构连通性。
我们发现，TSPO-PET 和标准化摄取值比的区域间协方差优先分布在功能上高度连接的大脑区域，而 MRI 结构连通性与小胶质细胞激活的相关性较弱。与对照组相比，AD 患者双侧前内侧颞叶的 TSPO-PET 示踪剂摄取增加，并且 TSPO-PET 摄取量与疾病阶段相关的认知障碍和痴呆严重程度相关。
小胶质细胞的激活优先沿高度连接的大脑区域分布，类似于 tau 病理学。这些发现支持小胶质细胞在神经退行性变中的重要作用，我们推测病理沿着易损的连通性途径在整个大脑中传播。
