Discipline of Psychiatry, School of Medicine & Trinity College Institute of Neuroscience, Laboratory of Neuroimaging & Biomarker Research, Trinity College, University of Dublin, The Adelaide and Meath Hospital Incorporating The National Children's Hospital, Tallaght, Dublin, Ireland.
Exp Gerontol. 2010 Jan;45(1):30-40. doi: 10.1016/j.exger.2009.10.010. Epub 2009 Oct 22.
Advances in our understanding of tau-mediated neurodegeneration in Alzheimer's disease (AD) are moving this disease pathway to center stage for the development of biomarkers and disease modifying drug discovery efforts. Immunoassays were developed detecting total (t-tau) and tau phosphorylated at specific epitopes (p-tauX) in cerebrospinal fluid (CSF), methods to analyse tau in blood are at the experimental beginning. Clinical research consistently demonstrated CSF t- and p-tau increased in AD compared to controls. Measuring these tau species proved informative for classifying AD from relevant differential diagnoses. Tau phosphorylated at threonine 231 (p-tau231) differentiated between AD and frontotemporal dementia, tau phosphorylated at serine 181 (p-tau181) enhanced classification between AD and dementia with Lewy bodies. T- and p-tau are considered "core" AD biomarkers that have been successfully validated by controlled large-scale multi-center studies. Tau biomarkers are implemented in clinical trials to reflect biological activity, mechanisms of action of compounds, support enrichment of target populations, provide endpoints for proof-of-concept and confirmatory trials on disease modification. World-wide quality control initiatives are underway to set required methodological and protocol standards. Discussions with regulatory authorities gain momentum defining the role of tau biomarkers for trial designs and how they may be further qualified for surrogate marker status.
我们对阿尔茨海默病（AD）中 tau 介导的神经退行性变的理解的进展正在将该疾病途径推向开发生物标志物和疾病修饰药物发现的中心舞台。免疫测定法被开发用于检测脑脊液（CSF）中总 tau（t-tau）和在特定表位磷酸化的 tau（p-tauX），分析血液中 tau 的方法仍处于实验阶段。临床研究一致表明，与对照组相比，AD 患者的 CSF t- 和 p-tau 增加。测量这些 tau 物种被证明有助于将 AD 与相关鉴别诊断区分开来。在 AD 和额颞叶痴呆之间，tau 在苏氨酸 231 处磷酸化（p-tau231）有所区分，tau 在丝氨酸 181 处磷酸化（p-tau181）增强了 AD 与路易体痴呆之间的分类。T-和 p-tau 被认为是“核心”AD 生物标志物，已通过受控的大型多中心研究成功验证。tau 生物标志物已在临床试验中实施，以反映化合物的生物学活性和作用机制，支持目标人群的富集，提供概念验证和确认性试验的终点，以证实疾病修饰。正在进行全球范围内的质量控制计划，以制定所需的方法学和方案标准。与监管机构的讨论正在加紧确定 tau 生物标志物在试验设计中的作用，以及它们如何进一步有资格作为替代标志物。
