Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
Knoebel Institute for Healthy Aging (KIHA), University of Denver, Denver, CO, USA.
Mol Neurodegener. 2020 Nov 23;15(1):68. doi: 10.1186/s13024-020-00414-3.
Tau pathology is a major age-related event in Down syndrome with Alzheimer's disease (DS-AD). Although recently, several different Tau PET tracers have been developed as biomarkers for AD, these tracers showed different binding properties in Alzheimer disease and other non-AD tauopathies. They have not been yet investigated in tissue obtained postmortem for DS-AD cases. Here, we evaluated the binding characteristics of two Tau PET tracers (H-MK6240 and H-THK5117) and one amyloid (H-PIB) ligand in the medial frontal gyrus (MFG) and hippocampus (HIPP) in tissue from adults with DS-AD and DS cases with mild cognitive impairment (MCI) compared to sporadic AD.
Tau and amyloid autoradiography were performed on paraffin-embedded sections. To confirm respective ligand targets, adjacent sections were immunoreacted for phospho-Tau (AT8) and stained for amyloid staining using Amylo-Glo.
The two Tau tracers showed a significant correlation with each other and with AT8, suggesting that both tracers were binding to Tau deposits. H-MK6240 Tau binding correlated with AT8 immunostaining but to a lesser degree than the H-THK5117 tracer, suggesting differences in binding sites between the two Tau tracers. H-THK5117, H-MK6240 and H-PIB displayed dense laminar binding in the HIPP and MFG in adult DS brains. A regional difference in Tau binding between adult DS and AD was observed suggesting differential regional Tau deposition in adult DS compared to AD, with higher THK binding density in the MFG in adult with DS compared to AD. No significant correlation was found between H-PIB and Amylo-Glo staining in adult DS brains suggesting that the amyloid PIB tracer binds to additional sites.
This study provides new insights into the regional binding distribution of a first-generation and a second-generation Tau tracer in limbic and neocortical regions in adults with DS, as well as regional differences in Tau binding in adult with DS vs. those with AD. These findings provide new information about the binding properties of two Tau radiotracers for the detection of Tau pathology in adults with DS in vivo and provide valuable data regarding Tau vs. amyloid binding in adult DS compared to AD.
在唐氏综合征伴阿尔茨海默病（DS-AD）中，tau 病理学是与年龄相关的主要事件。尽管最近已经开发出几种不同的 Tau PET 示踪剂作为 AD 的生物标志物，但这些示踪剂在 AD 和其他非 AD tau 病中的结合特性不同。它们尚未在 DS-AD 病例的死后组织中进行研究。在这里，我们评估了两种 Tau PET 示踪剂（H-MK6240 和 H-THK5117）和一种淀粉样蛋白（H-PIB）配体在 DS-AD 成人和 DS 伴有轻度认知障碍（MCI）患者的内侧额回（MFG）和海马（HIPP）中的结合特征，与散发性 AD 相比。
对石蜡包埋切片进行 Tau 和淀粉样蛋白放射自显影。为了确认各自的配体靶标，用磷酸化 Tau（AT8）进行相邻切片的免疫反应，并使用 Amylo-Glo 对淀粉样蛋白染色进行染色。
两种 Tau 示踪剂彼此之间以及与 AT8 之间存在显著相关性，表明这两种示踪剂均与 Tau 沉积物结合。H-MK6240 Tau 结合与 AT8 免疫染色相关，但程度低于 H-THK5117 示踪剂，表明两种 Tau 示踪剂之间的结合部位存在差异。H-THK5117、H-MK6240 和 H-PIB 在成人 DS 大脑的 HIPP 和 MFG 中显示出密集的层状结合。在成人 DS 和 AD 之间观察到 Tau 结合的区域差异，表明与 AD 相比，成人 DS 中 Tau 沉积存在差异，与 AD 相比，成人 DS 中 MFG 中的 THK 结合密度更高。在成人 DS 大脑中，未发现 H-PIB 与 Amylo-Glo 染色之间存在显著相关性，表明淀粉样蛋白 PIB 示踪剂结合到其他部位。
本研究为在成人 DS 中，第一代和第二代 Tau 示踪剂在边缘和新皮质区域的区域结合分布以及成人 DS 中 Tau 结合的区域差异提供了新的见解，与 AD 相比。这些发现为在成人 DS 中体内检测 Tau 病理学的两种 Tau 放射性示踪剂的结合特性提供了新的信息，并提供了有关 Tau 与淀粉样蛋白结合的有价值的数据，与 AD 相比，在成人 DS 中。
