Department of Neurology, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
Department of Medical Ethics, Philosophy and History of Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
J Neurol. 2021 Feb;268(2):724-733. doi: 10.1007/s00415-020-10162-5. Epub 2020 Aug 18.
Parkinson's disease (PD) research is beginning to focus on early disease modification and prevention. The therapeutic pipeline includes a growing range of pharmacological interventions that could theoretically intervene with the underlying disease process. It is hoped that applying such interventions in a very early stage of the disease pathology, before the onset of motor symptoms or during its early stages, may prevent or delay further disease progression. To identify people in this early disease stage, criteria for 'prodromal PD' have been proposed-describing people with one or more specific features that jointly constitute a variably increased risk of developing clinically manifest PD. Here, we aim to draw lessons from the field of Alzheimer's research, which has followed a similar strategy over the last decade, including the expansion of the disease label to 'prodromal' stages. Importantly, none of the large and costly randomized-controlled trials aiming to slow down or prevent Alzheimer's dementia by targeting the alleged disease pathology, i.e., amyloid-β aggregation, resulted in detectable clinical effects. Lack of sufficiently robust phase 2 trial results before moving to phase 3 studies, suboptimal participant selection, insensitive outcomes, a too narrow target focus, and trial design flaws contributed to this disappointing outcome. We discuss the various similarities between these Alzheimer's and PD approaches, and review the design of prevention or early disease modification trials for both diseases including the potential for immunotherapy. Finally, we offer considerations to optimize the design of such trials in PD, benefiting from the lessons learned in Alzheimer's prevention research.
帕金森病（PD）的研究开始侧重于早期疾病修饰和预防。治疗方案包括越来越多的药理学干预措施，这些措施从理论上可以干预潜在的疾病进程。人们希望在疾病病理的早期阶段，即在运动症状出现之前或早期阶段，应用这些干预措施，以预防或延缓疾病的进一步进展。为了在这个早期疾病阶段识别出患者，已经提出了“前驱期 PD”的标准——描述了具有一个或多个特定特征的人，这些特征共同构成了发展为临床显性 PD 的风险增加。在这里，我们旨在从阿尔茨海默病研究领域吸取经验，该领域在过去十年中采取了类似的策略，包括将疾病标签扩展到“前驱期”阶段。重要的是，没有任何一项旨在通过针对所谓的疾病病理（即淀粉样蛋白-β聚集）来减缓或预防阿尔茨海默病痴呆的大型、昂贵的随机对照试验产生可检测到的临床效果。在进入 3 期研究之前缺乏足够稳健的 2 期试验结果、参与者选择不理想、结果不敏感、目标焦点过于狭窄以及试验设计缺陷导致了这一令人失望的结果。我们讨论了这些阿尔茨海默病和 PD 方法之间的各种相似之处，并回顾了这两种疾病的预防或早期疾病修饰试验的设计，包括免疫疗法的潜力。最后，我们提供了一些考虑因素，以优化 PD 中此类试验的设计，从阿尔茨海默病预防研究中吸取经验教训。
