Centre for Clinical Epidemiology & Evaluation, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada.
PLoS One. 2013 Oct 18;8(10):e76595. doi: 10.1371/journal.pone.0076595. eCollection 2013.
To date, statistical methods that take into account fully the non-linear, longitudinal and multivariate aspects of clinical data have not been applied to the study of progression in Parkinson's disease (PD). In this paper, we demonstrate the usefulness of such methodology for studying the temporal and spatial aspects of the progression of PD. Extending this methodology further, we also explore the presymptomatic course of this disease.
Longitudinal Positron Emission Tomography (PET) measurements were collected on 78 PD patients, from 4 subregions on each side of the brain, using 3 different radiotracers. Non-linear, multivariate, longitudinal random effects modelling was applied to analyze and interpret these data.
The data showed a non-linear decline in PET measurements, which we modelled successfully by an exponential function depending on two patient-related covariates duration since symptom onset and age at symptom onset. We found that the degree of damage was significantly greater in the posterior putamen than in the anterior putamen throughout the disease. We also found that over the course of the illness, the difference between the less affected and more affected sides of the brain decreased in the anterior putamen. Younger patients had significantly poorer measurements than older patients at the time of symptom onset suggesting more effective compensatory mechanisms delaying the onset of symptoms. Cautious extrapolation showed that disease onset had occurred some 8 to 17 years prior to symptom onset.
Our model provides important biological insights into the pathogenesis of PD, as well as its preclinical aspects. Our methodology can be applied widely to study many other chronic progressive diseases.
迄今为止，尚未将充分考虑临床数据的非线性、纵向和多变量方面的统计方法应用于帕金森病（PD）进展的研究。在本文中，我们展示了这种方法在研究 PD 进展的时间和空间方面的有用性。通过进一步扩展这种方法，我们还探索了这种疾病的无症状期过程。
对 78 名 PD 患者的大脑两侧的 4 个分区使用 3 种不同的示踪剂进行了纵向正电子发射断层扫描（PET）测量。应用非线性、多变量、纵向随机效应建模来分析和解释这些数据。
数据显示 PET 测量值呈非线性下降，我们通过依赖于两个与患者相关的协变量（从症状发作到症状发作的持续时间和年龄）的指数函数成功地对其进行了建模。我们发现，在整个疾病过程中，后壳核的损伤程度明显大于前壳核。我们还发现，在疾病过程中，大脑受影响较轻和较重两侧之间的差异在前壳核中逐渐减小。症状发作时，年轻患者的测量值明显比老年患者差，这表明更有效的代偿机制延迟了症状的发作。谨慎的外推表明，疾病发作发生在症状发作前 8 至 17 年。
我们的模型为 PD 的发病机制及其临床前方面提供了重要的生物学见解。我们的方法可以广泛应用于研究许多其他慢性进行性疾病。
