1 Neurology Imaging Unit, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
1 Neurology Imaging Unit, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK 2 Department of Nuclear Medicine, Aarhus University, Denmark.
Brain. 2015 Dec;138(Pt 12):3685-98. doi: 10.1093/brain/awv288. Epub 2015 Oct 27.
Amyloid deposition, tangle formation, neuroinflammation and neuronal dysfunction are pathological processes involved in Alzheimer's disease. However, the relative role of these processes in driving disease progression is still unclear. The aim of this positron emission tomography study was to: (i) investigate longitudinal changes of microglial activation, amyloid and glucose metabolism; and (ii) assess the temporospatial relationship between these three processes in Alzheimer's disease. A group of eight patients with a diagnosis of Alzheimer's disease (66 ± 4.8 years) and 14 healthy controls (65 ± 5.5 years) underwent T1 and T2 magnetic resonance imaging, along with (11)C-(R)-PK11195, (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose positron emission tomography scans for microglial activation, amyloid deposition and glucose metabolism. All patients were followed-up with repeated magnetic resonance imaging and three positron emission tomography scans after 16 months. Parametric maps were interrogated using region of interest analysis, Statistical Parametric Mapping, and between-group correlation analysis at voxel-level using Biological Parametric Mapping. At baseline, patients with Alzheimer's disease showed significantly increased microglial activation compared to the control subjects. During follow-up, for the first time, we found that while there is a progressive reduction of glucose metabolism, there was a longitudinal increase of microglial activation in the majority of the patients with Alzheimer's disease. Voxel-wise correlation analysis revealed that microglial activation in patients with Alzheimer's disease was positively correlated with amyloid deposition and inversely correlated with regional cerebral metabolic rate at voxel level over time. Even though one of the limitations of this study is the lack of longitudinal follow-up of healthy control subjects, this study demonstrates that there is persistent neuroinflammation throughout the Alzheimer's disease process with associated synaptic dysfunction and reduced glucose metabolism. Voxel-wise correlation analysis suggests that neuroinflammation is associated with localized amyloid deposition and glucose metabolism over time, however, the level of inflammation could also occur independently of amyloid pathology, especially in the later stages of Alzheimer's disease.
淀粉样蛋白沉积、缠结形成、神经炎症和神经元功能障碍是阿尔茨海默病涉及的病理过程。然而，这些过程在驱动疾病进展中的相对作用仍不清楚。本正电子发射断层扫描研究的目的是：（i）研究小胶质细胞激活、淀粉样蛋白和葡萄糖代谢的纵向变化；（ii）评估阿尔茨海默病中这三个过程的时空关系。一组 8 名被诊断为阿尔茨海默病的患者（66±4.8 岁）和 14 名健康对照者（65±5.5 岁）接受了 T1 和 T2 磁共振成像，以及（11）C-（R）-PK11195、（11）C-Pittsburgh 化合物 B 和（18）F-氟脱氧葡萄糖正电子发射断层扫描，以检测小胶质细胞激活、淀粉样蛋白沉积和葡萄糖代谢。所有患者在 16 个月后进行了重复磁共振成像和三次正电子发射断层扫描随访。使用感兴趣区域分析、统计参数映射和基于生物参数映射的体素水平组间相关分析，对参数图进行了研究。在基线时，与对照组相比，阿尔茨海默病患者的小胶质细胞激活明显增加。在随访期间，我们首次发现，虽然葡萄糖代谢呈进行性降低，但大多数阿尔茨海默病患者的小胶质细胞激活呈纵向增加。体素水平的相关分析显示，阿尔茨海默病患者的小胶质细胞激活与淀粉样蛋白沉积呈正相关，与区域脑代谢率呈负相关。尽管本研究的局限性之一是缺乏对健康对照组的纵向随访，但本研究表明，在阿尔茨海默病过程中存在持续的神经炎症，伴有突触功能障碍和葡萄糖代谢降低。体素水平的相关分析表明，神经炎症与淀粉样蛋白沉积和葡萄糖代谢随时间的变化有关，但炎症水平也可能独立于淀粉样蛋白病理学发生，尤其是在阿尔茨海默病的后期。
