Abstract：
Brain inflammation, with an increased density of microglia and macrophages, is an important component of Alzheimer\'s disease (AD) and a potential therapeutic target. However, it is incompletely characterized, particularly in patients whose disease begins before the age of 65 years and, thus, have few co-pathologies. Inflammation has been usefully imaged with translocator protein (TSPO) positron emission tomography (PET), but most inflammation PET tracers cannot image subjects with a low-binder TSPO rs6971 genotype. In an important development, participants with any TSPO genotype can be imaged with a novel tracer, [11C]ER176, that has a high binding potential and a more favorable metabolite profile than other TSPO tracers currently available. We applied [11C]ER176 to detect brain inflammation in mild cognitive impairment (MCI) caused by early-onset AD. Furthermore, we sought to correlate the brain localization of inflammation, volume loss, elevated Aβ and tau. We studied brain inflammation in 25 patients with early-onset amnestic MCI (average age 59 ± 4.5 years, 10 women) and 23 healthy controls (average age 65 ± 6.0 years, 12 women), both groups with a similar proportion of all three TSPO-binding affinities. [11C]ER176 total distribution volume (VT), obtained with an arterial input function, was compared across patients and controls using voxel-wise and region-wise analyses. In addition to inflammation PET, most MCI patients had Aβ (n=23), and tau PET (n=21). For Aβ and tau tracers, standard uptake value ratios (SUVRs) were calculated using cerebellar grey matter as region of reference. Regional correlations among the three tracers were determined. Data were corrected for partial volume effect. Cognitive performance was studied with standard neuropsychological tools. In MCI caused by early-onset AD, there was inflammation in the default network, reaching statistical significance in precuneus and lateral temporal and parietal association cortex bilaterally, and in the right amygdala. Topographically, inflammation co-localized most strongly with tau (r= 0.63 ± 0.24). This correlation was higher than the co-localization of Aβ with tau (r= 0.55±0.25) and of inflammation with Aβ (0.43±0.22). Inflammation co-localized least with atrophy (-0.29±0.26). These regional correlations could be detected in participants with any of the three rs6971 TSPO polymorphisms. Inflammation in AD-related regions correlated with impaired cognitive scores. Our data highlight the importance of inflammation, a potential therapeutic target, in the AD process. Furthermore, they support the notion that, as shown in experimental tissue and animal models, the propagation of tau in humans is associated with brain inflammation.
摘要：
脑部炎症,随着小胶质细胞和巨噬细胞密度的增加，是阿尔茨海默病(AD)的重要组成部分和潜在的治疗靶点。然而,它的特征不完全，特别是在65岁之前开始患病的患者，因此，很少有共病。使用转运蛋白（TSPO）正电子发射断层扫描（PET）对炎症进行了有效成像，但大多数炎症PET示踪剂不能成像低结合TSPOrs6971基因型的受试者。在一个重要的发展中，具有任何TSPO基因型的参与者可以用新型示踪剂成像，[11C]ER176，其具有高结合潜力和比目前可用的其他TSPO示踪剂更有利的代谢物谱。我们应用[11C]ER176检测由早发性AD引起的轻度认知障碍（MCI）的脑炎症。此外，我们试图将炎症的大脑定位联系起来，体积损失,Aβ和tau升高。我们研究了25例早发性遗忘型MCI患者的脑部炎症（平均年龄59±4.5岁，10名女性）和23名健康对照（平均年龄65±6.0岁，12名妇女），两组的所有三种TSPO结合亲和力的比例相似。[11C]ER176总配送量(VT)，用动脉输入函数获得，使用逐体素和逐区域分析对患者和对照组进行比较。除了炎症PET，大多数MCI患者有Aβ（n=23），和tauPET(n=21)。对于Aβ和tau示踪剂，使用小脑灰质作为参考区域计算标准摄取值比率(SUVR).确定了三种示踪剂之间的区域相关性。针对部分体积效应校正数据。使用标准的神经心理学工具研究了认知表现。在由早发性AD引起的MCI中，默认网络中有炎症，在双侧的前叶和外侧颞叶和顶叶关联皮层中达到统计学意义，在右边的杏仁核.从地形上看，炎症与tau共定位最强(r=0.63±0.24)。这种相关性高于Aβ与tau的共定位(r=0.55±0.25)和炎症与Aβ的共定位(0.43±0.22)。炎症与萎缩共同定位最少（-0.29±0.26）。这些区域相关性可以在具有三种rs6971TSPO多态性的参与者中检测到。AD相关区域的炎症与受损的认知评分相关。我们的数据强调了炎症的重要性，潜在的治疗靶点,在AD过程中。此外，他们支持这样的观点，如实验组织和动物模型所示，tau在人类中的传播与大脑炎症有关。
