Appleton Johanna, Finn Quentin, Zanotti-Fregonara Paolo, Yu Meixiang, Faridar Alireza, Nakawah Mohammad O, Zarate Carlos, Carrillo Maria C, Dickerson Bradford C, Rabinovici Gil D, Apostolova Liana G, Masdeu Joseph C, Pascual Belen
Nantz National Alzheimer Center, Stanley H. Appel Department of Neurology, Houston Methodist Research Institute, Weill Cornell Medicine, Houston, TX 77030, USA.
Molecular Imaging Branch, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA.
Brain. 2025 Jan 7;148(1):119-132. doi: 10.1093/brain/awae234.
Brain inflammation, with an increased density of microglia and macrophages, is an important component of Alzheimer's disease 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) 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 favourable 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 Alzheimer's disease. Furthermore, we sought to correlate the brain localization of inflammation, volume loss, elevated amyloid-β (Aβ)and tau. We studied brain inflammation in 25 patients with early-onset amnestic MCI (average age 59 ± 4.5 years, 10 female) and 23 healthy controls (average age 65 ± 6.0 years, 12 female), 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 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 Alzheimer's disease, 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 Alzheimer's disease-related regions correlated with impaired cognitive scores. Our data highlight the importance of inflammation, a potential therapeutic target, in the Alzheimer's disease 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.
脑炎症，伴有小胶质细胞和巨噬细胞密度增加，是阿尔茨海默病的重要组成部分，也是一个潜在的治疗靶点。然而，其特征尚未完全明确，尤其是在65岁之前发病且合并症较少的患者中。炎症已通过转运蛋白（TSPO）PET进行有效成像，但大多数炎症PET示踪剂无法对TSPO rs6971基因型结合力低的受试者进行成像。一项重要进展是，任何TSPO基因型的参与者都可以使用新型示踪剂11C-ER176进行成像，该示踪剂具有高结合潜力，且代谢物谱比目前可用的其他TSPO示踪剂更有利。我们应用11C-ER176来检测早发型阿尔茨海默病所致轻度认知障碍（MCI）中的脑炎症。此外，我们试图将炎症的脑定位、体积损失、淀粉样β蛋白（Aβ）升高和tau蛋白进行关联。我们研究了25例早发型遗忘型MCI患者（平均年龄59±4.5岁，10名女性）和23名健康对照者（平均年龄65±6.0岁，12名女性）的脑炎症，两组中三种TSPO结合亲和力的比例相似。使用动脉输入函数获得的11C-ER176总分布容积（VT），通过体素分析和区域分析在患者和对照者之间进行比较。除了炎症PET外，大多数MCI患者还进行了Aβ（n = 2）和tau PET（n = 21）检查。对于Aβ和tau示踪剂，以小脑灰质作为参考区域计算标准摄取值比率。确定了三种示踪剂之间的区域相关性。对数据进行了部分容积效应校正。使用标准神经心理学工具研究认知表现。在早发型阿尔茨海默病所致的MCI中，默认网络存在炎症，在双侧楔前叶、颞叶外侧和顶叶联合皮质以及右侧杏仁核中达到统计学意义。在地形学上，炎症与tau蛋白的共定位最为强烈（r = 0.63±0.24）。这种相关性高于Aβ与tau蛋白的共定位（r = 0.55±0.25）以及炎症与Aβ的共定位（0.43±0.22）。炎症与萎缩的共定位最少（-0.29±0.26）。在具有三种rs6971 TSPO多态性中任何一种的参与者中都可以检测到这些区域相关性。阿尔茨海默病相关区域的炎症与认知评分受损相关。我们的数据突出了炎症这一潜在治疗靶点在阿尔茨海默病进程中的重要性。此外，它们支持了这样一种观点，即如在实验组织和动物模型中所示，tau蛋白在人类中的传播与脑炎症有关。
