Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging
Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging
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DOI：
10.1093/brain/aww017
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发表时间：
2016-04-01
期刊：
影响因子：
14.5
通讯作者：
Sarazin, Marie
中科院分区：
文献类型：
--
作者：
Hamelin, Lorraine;Lagarde, Julien;Sarazin, Marie
虽然新出现的证据表明神经炎症在阿尔茨海默病中起着至关重要的作用，但阿尔茨海默病中小胶质细胞反应的影响仍然是一个争论的问题。我们的目的是研究早期阿尔茨海默病中的小胶质细胞激活及其对临床进展的影响，使用第二代18 kDa转运蛋白正电子发射断层扫描放射性示踪剂与淀粉样蛋白成像，使用匹兹堡化合物B正电子发射断层扫描。我们从IMABio 3研究中招募了96名受试者，64名阿尔茨海默病患者和32名对照，他们都接受了C-11-匹兹堡化合物B和F-18-DPA-714正电子发射断层扫描成像。阿尔茨海默病患者分为前驱阿尔茨海默病（n = 38）和阿尔茨海默病痴呆（n = 26）。考虑到区域萎缩，使用简单的比率法以小脑灰质作为参考组织测量转运蛋白结合。在区域（感兴趣体积）和体素水平上分析图像。转运蛋白基因分型允许所有受试者在高，混合和低亲和力结合剂的分类。将30例高+混合亲和力结合剂的阿尔茨海默病患者在2年随访后分为缓慢下降者（n =10）和快速下降者（n =20）。所有阿尔茨海默病患者的淀粉样蛋白阳性匹兹堡化合物B正电子发射断层扫描。在对照组中，8例具有阳性淀粉样蛋白扫描（n = 6高+混合亲和力结合物），定义为淀粉样变性对照，并单独分析。通过感兴趣的体积和体素比较，18-kDa转运蛋白结合在高亲和力结合剂、混合亲和力结合剂和高+混合亲和力结合剂阿尔茨海默病组中高于对照组，特别是在前驱期，涉及颞顶叶皮质。转运蛋白结合与简易精神状态检查评分和灰质体积以及匹兹堡化合物B结合呈正相关。淀粉样变性对照组显示出比对照组更高的转运蛋白结合，特别是在额叶皮层。我们发现慢下降者比快下降者的转运蛋白结合率更高，匹兹堡化合物B结合率没有差异。小胶质细胞活化出现在阿尔茨海默病的前驱期和可能的临床前阶段，并且似乎在这些早期阶段的疾病的临床进展中起保护作用。小胶质细胞激活的程度在不同的患者之间似乎不同，并且可以解释阿尔茨海默病患者和淀粉样变性对照患者之间转运蛋白结合值的重叠。
While emerging evidence suggests that neuroinflammation plays a crucial role in Alzheimer's disease, the impact of the microglia response in Alzheimer's disease remains a matter of debate. We aimed to study microglial activation in early Alzheimer's disease and its impact on clinical progression using a second-generation 18-kDa translocator protein positron emission tomography radiotracer together with amyloid imaging using Pittsburgh compound B positron emission tomography. We enrolled 96 subjects, 64 patients with Alzheimer's disease and 32 controls, from the IMABio3 study, who had both C-11-Pittsburgh compound B and F-18-DPA-714 positron emission tomography imaging. Patients with Alzheimer's disease were classified as prodromal Alzheimer's disease (n = 38) and Alzheimer's disease dementia (n = 26). Translocator protein-binding was measured using a simple ratio method with cerebellar grey matter as reference tissue, taking into account regional atrophy. Images were analysed at the regional (volume of interest) and at the voxel level. Translocator protein genotyping allowed the classification of all subjects in high, mixed and low affinity binders. Thirty high+mixed affinity binders patients with Alzheimer's disease were dichotomized into slow decliners (n =10) or fast decliners (n =20) after 2 years of follow-up. All patients with Alzheimer's disease had an amyloid positive Pittsburgh compound B positron emission tomography. Among controls, eight had positive amyloid scans (n = 6 high+mixed affinity binders), defined as amyloidosis controls, and were analysed separately. By both volumes of interest and voxel-wise comparison, 18-kDa translocator protein-binding was higher in high affinity binders, mixed affinity binders and high+mixed affinity binders Alzheimer's disease groups compared to controls, especially at the prodromal stage, involving the temporo-parietal cortex. Translocator protein-binding was positively correlated with Mini-Mental State Examination scores and grey matter volume, as well as with Pittsburgh compound B binding. Amyloidosis controls displayed higher translocator protein-binding than controls, especially in the frontal cortex. We found higher translocator protein-binding in slow decliners than fast decliners, with no difference in Pittsburgh compound B binding. Microglial activation appears at the prodromal and possibly at the preclinical stage of Alzheimer's disease, and seems to play a protective role in the clinical progression of the disease at these early stages. The extent of microglial activation appears to differ between patients, and could explain the overlap in translocator protein binding values between patients with Alzheimer's disease and amyloidosis controls.