Center for Neurodegenerative Disease Research (CNDR), Institute On Aging and Department of Pathology & Laboratory Medicine, University of Pennsylvania, 3600 Spruce Street, 3 Maloney Building, Philadelphia, PA, 19104-4283, USA.
Tanz Centre for Research in Neurodegenerative Disease (CRND) and Department of Laboratory Medicine and Pathobiology, University of Toronto, 60 Leonard Ave, Krembil Discovery Tower, Toronto, ON, M5T 0S8, Canada.
Acta Neuropathol. 2020 Aug;140(2):99-119. doi: 10.1007/s00401-020-02158-2. Epub 2020 May 7.
Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns.
进行性核上性麻痹（PSP）是一种 4R-tau 病，以神经元、星形胶质细胞和少突胶质细胞中的皮质下病理学为主要特征，与各种临床表型有关。在本项国际研究中，我们探讨了 PSP 病理学是否存在顺序分布模式的问题。我们评估了尸检大脑中不同 PSP 临床亚型的神经元、星形胶质细胞和少突胶质细胞 tau 病理学及其组合的热图和分布模式。我们使用条件概率和逻辑回归来模拟 tau 病理学在不同脑区的顺序分布。在不同的临床亚型中，tau 病理学均匀地优先出现在苍白球黑质路易体（pallido-nigro-luysian axis）的神经元中。然而，临床亚型的区分不仅取决于总 tau 负荷，还取决于大脑区域 tau 病理学的细胞类型（神经元与神经胶质）特异性易损性模式，这表明 tau 病理学的传播具有不同的动力学或特定回路的隔离。对于 Richardson 综合征（n=81），我们识别出组合细胞 tau 病理学参与脑区的六个连续步骤。这可以转化为通过评估丘脑下核、苍白球、纹状体、带有齿状核的小脑以及额回和枕回，对神经病理学诊断的六个阶段。通过强调它们是否表现为尾部（小脑/齿状核）或头部（皮质）优势，或者两者兼有，该系统可应用于进一步的临床亚型。定义 tau 病理学的细胞特异性阶段有助于识别临床前或早期病例，以更好地了解早期发病事件，对理解疾病传播的临床亚型特异性动力学具有启示意义，并为 tau 神经影像学提供分布模式信息。
