Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe-University, Frankfurt, Heinrich-Hoffmann-Str. 10, 60528 Frankfurt, Germany.
Prog Neurobiol. 2011 Dec;95(4):579-93. doi: 10.1016/j.pneurobio.2010.11.005. Epub 2010 Dec 2.
The development of disease-modifying treatments for Alzheimer's disease requires innovative trials with large numbers of subjects and long observation periods. The use of blood, cerebrospinal fluid or neuroimaging biomarkers is critical for the demonstration of disease-modifying therapy effects on the brain. Suitable biomarkers are those which reflect the progression of AD related molecular mechanisms and neuropathology, including amyloidogenic processing and aggregation, hyperphosphorylation, accumulation of tau and neurofibrillary tangles, progressive functional, metabolic and structural decline, leading to neurodegeneration, loss of brain tissue and cognitive symptoms. Biomarkers should be used throughout clinical trial phases I-III of AD drug development. They can be used to enhance inclusion and exclusion criteria, or as baseline predictors to increase the statistical power of trials. Validated and qualified biomarkers may be used as outcome measures to detect treatment effects in pivotal clinical trials. Finally, biomarkers can be used to identify adverse effects. Questions regarding which biomarkers should be used in clinical trials, and how, are currently far from resolved. The Oxford Task Force continues and expands the work of our previous international expert task forces on disease-modifying trials and on endpoints for Alzheimer's disease clinical trials. The aim of this initiative was to bring together a selected number of key international opinion leaders and experts from academia, regulatory agencies and industry to condense the current knowledge and state of the art regarding the best use of biological markers in Alzheimer's disease therapy trials and to propose practical recommendations for the planning of future AD trials.
开发治疗阿尔茨海默病的疾病修饰疗法需要进行创新性的临床试验，涉及大量的受试者和长期的观察期。使用血液、脑脊液或神经影像学生物标志物对于证明疾病修饰疗法对大脑的影响至关重要。合适的生物标志物是那些能够反映 AD 相关分子机制和神经病理学进展的标志物，包括淀粉样蛋白加工和聚集、过度磷酸化、tau 和神经原纤维缠结的积累、进行性的功能、代谢和结构下降，导致神经退行性变、脑组织丧失和认知症状。生物标志物应在 AD 药物开发的临床试验 I-III 期全程使用。它们可以用于增强纳入和排除标准，或者作为基线预测指标，以增加试验的统计学效力。经过验证和合格的生物标志物可用作终点指标，以检测关键临床试验中的治疗效果。最后，生物标志物可用于识别不良反应。关于应在临床试验中使用哪些生物标志物以及如何使用这些标志物的问题，目前仍远未得到解决。牛津工作组延续并扩展了我们之前关于疾病修饰试验和阿尔茨海默病临床试验终点的国际专家工作组的工作。该倡议的目的是汇集来自学术界、监管机构和行业的少数选定的国际意见领袖和专家，总结在阿尔茨海默病治疗试验中最佳使用生物标志物的现有知识和最新技术，并为未来 AD 试验的规划提出切实可行的建议。
