School of Psychology, Vita-Salute San Raffaele University, Milan, Italy.
In Vivo Human Molecular and Structural Neuroimaging Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Ann Clin Transl Neurol. 2020 Sep;7(9):1513-1523. doi: 10.1002/acn3.51112. Epub 2020 Aug 6.
Neuroinflammation is considered a key driver for neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). SOD1 mutations cause about 20% of familial ALS, and related pathology might generate microglial activation triggering neurodegeneration. C-PK11195 is the prototypical and most validated PET radiotracer, targeting the 18-kDa translocator protein which is overexpressed in activated microglia. In this study, we investigated microglia activation in asymptomatic (ASYM) and symptomatic (SYM) SOD1 mutated carriers, by using C-PK11195 and PET imaging.
We included 20 subjects: 4 ASYM-carriers, neurologically normal, 6 SYM-carriers with probable ALS, and 10 healthy controls. A receptor parametric mapping procedure estimated C-PK11195 binding potentials and voxel-wise statistical comparisons were performed at group and single-subject levels.
Both the SYM- and ASYM-carriers showed significant microglia activation in cortical and subcortical structures, with variable patterns at individual level. Clusters of activation were present in occipital and temporal regions, cerebellum, thalamus, and medulla oblongata. Notably, SYM-carriers showed microglia activation also in supplementary and primary motor cortices and in the somatosensory regions.
In vivo neuroinflammation occurred in all SOD1 mutated cases since the presymptomatic stages, as shown by a significant cortical and subcortical microglia activation. The involvement of sensorimotor cortex became evident at the symptomatic disease stage. Although our data indicate the role of in vivo PET imaging for assessing resident microglia in the investigation of SOD1-ALS pathophysiology, further studies are needed to clarify the temporal and spatial dynamics of microglia activation and its relationship with neurodegeneration.
神经炎症被认为是几种神经退行性疾病（包括肌萎缩侧索硬化症（ALS））的关键驱动因素。SOD1 突变导致约 20%的家族性 ALS，相关病理学可能引发小胶质细胞激活，从而触发神经退行性变。C-PK11195 是原型和最有效的正电子发射断层扫描（PET）示踪剂，靶向在激活的小胶质细胞中过度表达的 18kDa 转位蛋白。在这项研究中，我们通过使用 C-PK11195 和 PET 成像来研究无症状（ASYM）和有症状（SYM）SOD1 突变携带者的小胶质细胞激活。
我们纳入了 20 名受试者：4 名 ASYM 携带者，神经正常；6 名 SYM 携带者，可能患有 ALS；10 名健康对照者。采用受体参数映射程序估计 C-PK11195 结合潜力，并在组和个体水平上进行了体素水平的统计比较。
SYM-和 ASYM-携带者在皮质和皮质下结构中均显示出明显的小胶质细胞激活，个体水平上的模式各不相同。激活的簇位于枕叶和颞叶、小脑、丘脑和延髓。值得注意的是，SYM 携带者在补充运动皮质和初级运动皮质以及感觉区域也显示出小胶质细胞激活。
在疾病的无症状阶段，所有 SOD1 突变病例均存在体内神经炎症，表现为皮质和皮质下小胶质细胞的显著激活。在有症状的疾病阶段，感觉运动皮层的参与变得明显。尽管我们的数据表明，体内 PET 成像在评估 SOD1-ALS 病理生理学中的驻留小胶质细胞方面具有作用，但需要进一步的研究来阐明小胶质细胞激活的时间和空间动态及其与神经退行性变的关系。
