Coughlin David, Irwin David J
Frontotemporal Dementia Center (FTDC), University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
University of Pennsylvania Perelman School of Medicine, Hospital of the University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA, 19104, USA.
Curr Neurol Neurosci Rep. 2017 Sep;17(9):72. doi: 10.1007/s11910-017-0779-1.
Tauopathies represent a spectrum of incurable and progressive age-associated neurodegenerative diseases that currently are diagnosed definitively only at autopsy. Few clinical diagnoses, such as classic Richardson's syndrome of progressive supranuclear palsy, are specific for underlying tauopathy and no clinical syndrome is fully sensitive to reliably identify all forms of clinically manifest tauopathy. Thus, a major unmet need for the development and implementation of tau-targeted therapies is precise antemortem diagnosis. This article reviews new and emerging diagnostic therapies for tauopathies including novel imaging techniques and biomarkers and also reviews recent tau therapeutics.
Building evidence from animal and cell models suggests that prion-like misfolding and propagation of pathogenic tau proteins between brain cells are central to the neurodegenerative process. These rapidly growing developments build rationale and motivation for the development of therapeutics targeting this mechanism through altering phosphorylation and other post-translational modifications of the tau protein, blocking aggregation and spread using small molecular compounds or immunotherapy and reducing or silencing expression of the MAPT tau gene. New clinical criteria, CSF, MRI, and PET biomarkers will aid in identifying tauopathies earlier and more accurately which will aid in selection for new clinical trials which focus on a variety of agents including immunotherapy and gene silencing.
Tau蛋白病是一系列无法治愈且呈进行性发展的与年龄相关的神经退行性疾病,目前只有在尸检时才能明确诊断。很少有临床诊断,如进行性核上性麻痹的经典理查森综合征,对潜在的tau蛋白病具有特异性,而且没有一种临床综合征对可靠识别所有形式的临床显性tau蛋白病完全敏感。因此,开发和实施针对tau蛋白的疗法的一个主要未满足需求是精确的生前诊断。本文综述了tau蛋白病的新兴诊断疗法,包括新型成像技术和生物标志物,还综述了近期的tau蛋白治疗方法。
来自动物和细胞模型的越来越多的证据表明,致病性tau蛋白在脑细胞之间的朊病毒样错误折叠和传播是神经退行性过程的核心。这些快速发展为通过改变tau蛋白的磷酸化和其他翻译后修饰、使用小分子化合物或免疫疗法阻断聚集和传播以及降低或沉默MAPT tau基因的表达来开发针对这一机制的治疗方法提供了理论依据和动力。新的临床标准、脑脊液、磁共振成像和正电子发射断层扫描生物标志物将有助于更早、更准确地识别tau蛋白病,这将有助于选择针对包括免疫疗法和基因沉默在内的多种药物的新临床试验。