Koga Shunsuke, Ono Maiko, Sahara Naruhiko, Higuchi Makoto, Dickson Dennis W
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
National Institutes for Quantum and Radiological Science and Technology, National Institute of Radiological Sciences, Chiba, Japan.
Mov Disord. 2017 Jun;32(6):884-892. doi: 10.1002/mds.27013. Epub 2017 Apr 25.
The tau PET ligand 2-((1E,3E)-4-(6-([ C]methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol ([ C]PBB3) binds to a wide range of tau pathology; however, binding property of PBB3 to non-tau inclusions remains unknown. To clarify whether [ C]PBB3 binds to α-synuclein pathology, reactivity of PBB3 was assessed by in vitro fluorescence and autoradiographic labeling of brain sections from α-synucleinopathies patients.
Of 10 pure Lewy body disease and 120 multiple system atrophy (MSA) cases in the Mayo Clinic brain bank, we selected 3 Lewy body disease and 4 MSA cases with a range of α-synuclein severity based on the quantitative analysis of α-synuclein burden. PBB3 fluorescence labeling, double or single immunostaining for α-synuclein and phospho-tau, Prussian blue staining, and in vitro autoradiography with [ C]PBB3 were performed for these selected samples.
PBB3 fluorescence labeled various α-synuclein lesions including Lewy bodies, Lewy neurites, spheroids, glial cytoplasmic inclusions, and neuronal cytoplasmic inclusions. Meanwhile, autoradiographic labeling with [ C]PBB3 at 10 nM demonstrated no significant binding in Lewy body disease cases. In contrast, significant autoradiographic binding of [ C]PBB3 to the striatopallidal fibers was found in 2 MSA cases, which had high densities of glial cytoplasmic inclusions without tau or iron deposits in this region.
Given that the maximum concentration of [ C]PBB3 in human PET scans is approximately 10 nM, the present data imply that α-synuclein pathology in Lewy body disease is undetectable by [ C]PBB3-PET, whereas those in a subset of MSA cases with high densities of glial cytoplasmic inclusions could be captured by this radioligand. © 2017 International Parkinson and Movement Disorder Society.
tau正电子发射断层扫描（PET）配体2-((1E,3E)-4-(6-([ C]甲基氨基)吡啶-3-基)丁-1,3-二烯基)苯并[d]噻唑-6-醇([ C]PBB3)可与多种tau病理改变结合；然而，PBB3与非tau包涵体的结合特性尚不清楚。为明确[ C]PBB3是否与α-突触核蛋白病理改变结合，通过对α-突触核蛋白病患者脑切片进行体外荧光和放射自显影标记，评估了PBB3的反应性。
在梅奥诊所脑库的10例纯路易体病和120例多系统萎缩（MSA）病例中，基于对α-突触核蛋白负荷的定量分析，我们选择了3例路易体病和4例MSA病例，其α-突触核蛋白严重程度各不相同。对这些选定的样本进行了PBB3荧光标记、α-突触核蛋白和磷酸化tau的双重或单一免疫染色、普鲁士蓝染色以及用[ C]PBB3进行体外放射自显影。
PBB3荧光标记了各种α-突触核蛋白病变，包括路易小体、路易神经突、球体、胶质细胞胞质包涵体和神经元胞质包涵体。同时，在10 nM浓度下用[ C]PBB3进行放射自显影标记显示，路易体病病例中无明显结合。相反，在2例MSA病例中发现[ C]PBB3与纹状体苍白球纤维有明显的放射自显影结合，这2例病例在该区域有高密度的胶质细胞胞质包涵体，且无tau或铁沉积。
鉴于人类PET扫描中[ C]PBB3的最大浓度约为10 nM，目前的数据表明，[ C]PBB3-PET无法检测出路易体病中的α-突触核蛋白病理改变，而在一部分具有高密度胶质细胞胞质包涵体的MSA病例中，这种放射性配体可以捕捉到α-突触核蛋白病理改变。© 2017国际帕金森病和运动障碍协会。
