CogState Ltd, Melbourne, Victoria, Australia.
Int Psychogeriatr. 2011 Nov;23(9):1376-85. doi: 10.1017/S1041610211000354. Epub 2011 Apr 11.
Ideally putative disease-modifying therapies for Alzheimer's disease (AD) should be tested in patients who have minimal morbidity. Current barriers to such trials in early disease include the lack of disease-specific early biomarkers, insensitivity of quantitative cognitive outcome measures, and expensive trial designs requiring large sample sizes and long duration. This paper describes principles and progress towards a novel trial design that overcomes these problems, utilizing wide-scale cognitive performance screening to define pre-trial cognitive decline trajectories which can serve as trial outcome measures to assess AD disease-modifying efficacy.
Theoretical principles important for the detection of intra-individual cognitive decline and a practical example are described.
Serial evaluations of community-based volunteers demonstrate how a screening tool method to detect subtle cognitive decline can predict in vivo amyloid pathology as a trigger for etiological evaluation. Trajectories of decline appear consistent over at least two years, suggesting they could be used as a trial inclusion criterion and ameliorable outcome measure together with other AD biomarkers. Informative trial durations could be 6-12 months, or extend to incorporate staggered random withdrawal or start designs, with as few as 20 individuals per treatment arm.
This trial methodology offers significant advantages over current AD trial designs, including treatment at earlier stages of disease, shorter trial duration, obviation of informed consent difficulties, smaller sample sizes, reduced cost and--given adequate screening programs--sufficient subjects for multiple simultaneous trials. Importantly, it allows the rapid evaluation of putative treatments that may only be efficacious in pre-dementia states.
理想情况下，用于治疗阿尔茨海默病（AD）的潜在疗法应在患病风险最小的患者中进行测试。目前，早期疾病中此类试验面临的障碍包括缺乏特定于疾病的早期生物标志物、定量认知结果测量的不敏感性以及需要大样本量和长期试验设计的昂贵试验设计。本文介绍了一种克服这些问题的新型试验设计的原则和进展，利用广泛的认知表现筛查来定义术前认知下降轨迹，这些轨迹可用作评估 AD 疾病修饰疗效的试验结果测量。
描述了用于检测个体内认知下降的重要理论原则和一个实际示例。
对基于社区的志愿者的连续评估表明，如何使用筛查工具方法来检测细微的认知下降可以预测体内淀粉样蛋白病理学作为病因评估的触发因素。下降轨迹似乎至少在两年内保持一致，表明它们可以用作试验纳入标准，并与其他 AD 生物标志物一起作为可改善的结果测量。信息丰富的试验持续时间可以是 6-12 个月，或者扩展为纳入交错随机退出或起始设计，每个治疗组只需 20 名个体。
与当前的 AD 试验设计相比，这种试验方法具有明显的优势，包括在疾病的早期阶段进行治疗、缩短试验持续时间、避免知情同意困难、减少样本量、降低成本——如果有足够的筛查计划——可用于多个同时进行的试验。重要的是，它允许快速评估可能仅在痴呆前状态有效治疗。
