Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, USA.
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
J Parkinsons Dis. 2023;13(6):899-916. doi: 10.3233/JPD-223433.
Identifying a meaningful progression metric for Parkinson's disease (PD) that reflects heterogeneity remains a challenge.
To assess the frequency and baseline predictors of progression to clinically relevant motor and non-motor PD milestones.
Using data from the Parkinson's Progression Markers Initiative (PPMI) de novo PD cohort, we monitored 25 milestones across six domains ("walking and balance"; "motor complications"; "cognition"; "autonomic dysfunction"; "functional dependence"; "activities of daily living"). Milestones were intended to be severe enough to reflect meaningful disability. We assessed the proportion of participants reaching any milestone; evaluated which occurred most frequently; and conducted a time-to-first-event analysis exploring whether baseline characteristics were associated with progression.
Half of participants reached at least one milestone within five years. Milestones within the cognitive, functional dependence, and autonomic dysfunction domains were reached most often. Among participants who reached a milestone at an annual follow-up visit and remained active in the study, 82% continued to meet criteria for any milestone at one or more subsequent annual visits and 55% did so at the next annual visit. In multivariable analysis, baseline features predicting faster time to reaching a milestone included age (p < 0.0001), greater MDS-UPDRS total scores (p < 0.0001), higher GDS-15 depression scores (p = 0.0341), lower dopamine transporter binding (p = 0.0043), and lower CSF total α-synuclein levels (p = 0.0030). Symptomatic treatment was not significantly associated with reaching a milestone (p = 0.1639).
Clinically relevant milestones occur frequently, even in early PD. Milestones were significantly associated with baseline clinical and biological markers, but not with symptomatic treatment. Further studies are necessary to validate these results, further assess the stability of milestones, and explore translating them into an outcome measure suitable for observational and therapeutic studies.
确定能够反映帕金森病（PD）异质性的有意义的进展指标仍然是一个挑战。
评估进展为临床相关运动和非运动 PD 里程碑的频率和基线预测因素。
利用帕金森进展标志物倡议（PPMI）新发 PD 队列的数据，我们监测了六个领域的 25 个里程碑（“行走和平衡”；“运动并发症”；“认知”；“自主神经功能障碍”；“功能依赖”；“日常生活活动”）。里程碑旨在严重到足以反映有意义的残疾。我们评估了达到任何里程碑的参与者比例；评估了最常发生的里程碑；并进行了首次事件时间分析，以探讨基线特征是否与进展相关。
一半的参与者在五年内达到了至少一个里程碑。认知、功能依赖和自主神经功能障碍领域的里程碑最常达到。在每年随访时达到里程碑并在研究中保持活跃的参与者中，82%在随后的一次或多次年度访问中继续符合任何里程碑的标准，55%在下次年度访问中符合标准。在多变量分析中，预测更快达到里程碑时间的基线特征包括年龄（p<0.0001）、更大的 MDS-UPDRS 总分（p<0.0001）、更高的 GDS-15 抑郁评分（p=0.0341）、更低的多巴胺转运蛋白结合（p=0.0043）和更低的 CSF 总 α-突触核蛋白水平（p=0.0030）。症状性治疗与达到里程碑无显著相关性（p=0.1639）。
即使在早期 PD 中，也经常出现临床相关的里程碑。里程碑与基线临床和生物学标志物显著相关，但与症状性治疗无关。需要进一步的研究来验证这些结果，进一步评估里程碑的稳定性，并探索将其转化为适合观察性和治疗性研究的结局测量。
