Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson's disease: an in vivo11C-BU99008 PET study.
Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson's disease: an in vivo11C-BU99008 PET study.
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DOI：
10.1093/brain/awz260
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发表时间：
2019-08
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通讯作者：
H. Wilson;G. Dervenoulas;G. Pagano;R. Tyacke;Sotirios Polychronis;J. Myers;R. Gunn;E. Rabiner;D. Nutt;M. Politis
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作者：
H. Wilson;G. Dervenoulas;G. Pagano;R. Tyacke;Sotirios Polychronis;J. Myers;R. Gunn;E. Rabiner;D. Nutt;M. Politis
星形胶质细胞是调节神经炎症和维持脑内稳态的多功能细胞。在帕金森病患者死后，星形胶质细胞α-突触核蛋白阳性细胞质积聚，因此星形胶质细胞可能在帕金森病的发生和发展中起重要作用。咪唑啉2结合位点在皮质、海马、基底神经节和脑干中的活化星形胶质细胞上表达;因此，通过测量咪唑啉2结合位点水平，我们可以间接评估帕金森病患者的星形胶质细胞增生。在这里，我们的目的是评估帕金森病患者体内星形胶质细胞活化的作用，使用11 C-BU 99008 PET，一种新型的放射性配体，具有高特异性和选择性的咪唑啉2结合位点。22例帕金森病患者和14例健康对照受试者接受了3 T MRI和120 min 11 C-BU 99008 PET扫描，使用具有代谢物校正动脉血浆输入函数的双组织房室模型估计分布容积（VT）。帕金森病患者根据疾病分期分为早期（n = 8）和中度/晚期（n = 14）组。在早期帕金森病中，与健康对照组相比，在额叶（P = 0.022）、颞叶（P = 0.02）、顶叶（P = 0.026）和枕叶（P = 0.047）皮质区域观察到11 C-BU 99008 VT摄取增加。在早期帕金森病患者中，脑干中观察到最大的11 C-BU 99008 VT增加（52%; P = 0.018）。在中度/晚期帕金森病患者中，观察到11 C-BU 99008 VT在额叶和颞叶的丢失。（P = 0.002），时间（P < 0.001），顶叶（P = 0.039），枕叶（P = 0.024），（P < 0.001）皮质;尾状核皮质下区与健康对照组比较，脑皮质（P <0.001）、壳核（P <0.001）、丘脑（P < 0.001）、脑干（P = 0.018）的神经元数量明显减少。在帕金森病患者中，皮质区、纹状体、丘脑和脑干的11 C-BU 99008 VT丢失与疾病持续时间较长（P < 0.05）和疾病负担评分较高（采用运动障碍协会统一帕金森病评定量表测量）相关（P < 0.05）。在中度/晚期帕金森病患者亚组中，额叶（r = 0.79; P = 0.001）、颞叶（r = 0.74; P = 0.002）和顶叶（r = 0.89; P < 0.001）皮质11 C-BU 99008 VT丢失与整体认知功能障碍相关。这项研究表明，在体内的作用，星形胶质细胞在帕金森氏病的开始和进展。在帕金森病早期观察到的反应性星形胶质细胞可能反映了神经保护性代偿机制和对α-突触核蛋白积聚的促炎性上调。然而，随着疾病的进展和显著的神经变性的发生，星形胶质细胞失去了它们的反应功能，并且皮质中的这种丧失在认知障碍的发展中具有临床相关性。
Astroglia are multifunctional cells that regulate neuroinflammation and maintain homeostasis within the brain. Astroglial α-synuclein-positive cytoplasmic accumulations have been shown post-mortem in patients with Parkinson's disease and therefore astroglia may play an important role in the initiation and progression of Parkinson's disease. Imidazoline 2 binding sites are expressed on activated astroglia in the cortex, hippocampus, basal ganglia and brainstem; therefore, by measuring imidazoline 2 binding site levels we can indirectly evaluate astrogliosis in patients with Parkinson's disease. Here, we aimed to evaluate the role of astroglia activation in vivo in patients with Parkinson's disease using 11C-BU99008 PET, a novel radioligand with high specificity and selectivity for imidazoline 2 binding sites. Twenty-two patients with Parkinson's disease and 14 healthy control subjects underwent 3 T MRI and a 120-min 11C-BU99008 PET scan with volume of distribution (VT) estimated using a two-tissue compartmental model with a metabolite corrected arterial plasma input function. Parkinson's disease patients were stratified into early (n = 8) and moderate/advanced (n = 14) groups according to disease stage. In early Parkinson's disease, increased 11C-BU99008 VT uptake was observed in frontal (P = 0.022), temporal (P = 0.02), parietal (P = 0.026) and occipital (P = 0.047) cortical regions compared with healthy controls. The greatest 11C-BU99008 VT increase in patients with early Parkinson's disease was observed in the brainstem (52%; P = 0.018). In patients with moderate/advanced Parkinson's disease, loss of 11C-BU99008 VT was observed across frontal (P = 0.002), temporal (P < 0.001), parietal (P = 0.039), occipital (P = 0.024), and insula (P < 0.001) cortices; and in the subcortical regions of caudate (P < 0.001), putamen (P < 0.001) and thalamus (P < 0.001); and in the brainstem (P = 0.018) compared with healthy controls. In patients with Parkinson's disease, loss of 11C-BU99008 VT in cortical regions, striatum, thalamus and brainstem correlated with longer disease duration (P < 0.05) and higher disease burden scores, measured with Movement Disorder Society Unified Parkinson's Disease Rating Scale (P < 0.05). In the subgroup of patients with moderate/advanced Parkinson's disease, loss of 11C-BU99008 VT in the frontal (r = 0.79; P = 0.001), temporal (r = 0.74; P = 0.002) and parietal (r = 0.89; P < 0.001) cortex correlated with global cognitive impairment. This study demonstrates in vivo the role of astroglia in the initiation and progression of Parkinson's disease. Reactive astroglia observed early in Parkinson's disease could reflect a neuroprotective compensatory mechanisms and pro-inflammatory upregulation in response to α-synuclein accumulation. However, as the disease progresses and significant neurodegeneration occurs, astroglia lose their reactive function and such loss in the cortex has clinical relevance in the development of cognitive impairment.