Janssen Daalen Jules M, Gerritsen Aranka, Gerritse Gijs, Gouman Jan, Meijerink Hannie, Rietdijk Leny E, Darweesh Sirwan K L
Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Department of Neurology, Center of Expertise for Parkinson & Movement Disorders, 6525 GA Nijmegen, The Netherlands.
Dutch Parkinson's Patient Association, P.O. Box 46, 3980 CA Bunnik, The Netherlands.
Brain Sci. 2024 Apr 3;14(4):358. doi: 10.3390/brainsci14040358.
Parkinson's disease (PD) has a long, heterogeneous, pre-diagnostic phase, during which pathology insidiously accumulates. Increasing evidence suggests that environmental and lifestyle factors in early life contribute to disease risk and progression. Thanks to the extensive study of this pre-diagnostic phase, the first prevention trials of PD are being designed. However, the highly heterogenous evolution of the disease across the life course is not yet sufficiently taken into account. This could hamper clinical trial success in the advent of biological disease definitions. In an interdisciplinary patient-clinician study group, we discussed how an approach that incorporates the lifetime evolution of PD may benefit the design of disease-modifying trials by impacting population, target and outcome selection. We argue that the timepoint of exposure to risk and protective factors plays a critical role in PD subtypes, influencing population selection. In addition, recent developments in differential disease mechanisms, aided by biological disease definitions, could impact optimal treatment targets. Finally, multimodal biomarker panels using this lifetime approach will likely be most sensitive as progression markers for more personalized trials. We believe that the lifetime evolution of PD should be considered in the design of clinical trials, and that such initiatives could benefit from more patient-clinician partnerships.
帕金森病（PD）有一个漫长、异质性的诊断前阶段，在此期间病理变化悄然累积。越来越多的证据表明，早年的环境和生活方式因素会影响疾病风险和进展。由于对这一诊断前阶段进行了广泛研究，目前正在设计首批帕金森病预防试验。然而，该疾病在整个生命过程中的高度异质性演变尚未得到充分考虑。在出现生物学疾病定义的情况下，这可能会阻碍临床试验的成功。在一个跨学科的患者-临床医生研究小组中，我们讨论了一种纳入帕金森病终生演变过程的方法如何通过影响人群、靶点和结局选择，从而有益于疾病修饰试验的设计。我们认为，接触风险和保护因素的时间点在帕金森病亚型中起着关键作用，会影响人群选择。此外，借助生物学疾病定义，疾病差异机制方面的最新进展可能会影响最佳治疗靶点。最后，采用这种终生方法的多模式生物标志物组合可能作为更个性化试验的进展标志物最为敏感。我们认为，在临床试验设计中应考虑帕金森病的终生演变，而且此类举措可能会受益于更多的患者-临床医生合作关系。
