Evaluation of Progression Markers in the Premotor Phase of Parkinson's Disease: The Progression Markers in the Premotor Phase Study

Abstract

Background: The clinical diagnosis of Parkinson's disease (PD) is proposed to be too late for the application of beneficial neuroprotective treatment. Thus, it is important to identify and follow individuals at risk for PD in order to gain knowledge about the prodromal course of the disease. Substantia nigra hyperechogenicity (SN+) has been confirmed as a risk factor for PD and appears promising as a predictor of PD, particularly in combination with other putative PD markers. We present the design and initial data of a 2-year longitudinal investigation of subjects proposed to be at high risk of developing PD (HR_PD), compared to early PD patients and control subjects. The aim of the presented study is to monitor progression of the neurodegenerative process to motor PD. Methods: In total, 40 HR_PD, 16 PD and 41 control individuals were recruited. The HR_PD subjects had SN+ and additionally either 1 cardinal PD motor sign or 2 further risk (e.g. positive family history) or prodromal markers (e.g. hyposmia). In this cohort, motor function, olfaction, mood and blood markers will be evaluated every 6 months, complemented by a comprehensive clinical, imaging and electrophysiological assessment. Results: PD, HR_PD and control subjects did not differ significantly regarding age, but the HR_PD group consisted mainly of males (72.5% of HR_PD subjects vs. 43.9% of controls; p = 0.013). Mean disease duration in PD patients was 31 months (range 15-56). HR_PD subjects were predominantly recruited according to the occurrence of slight motor signs (HR_PD 77.5%, PD 100%, p = 0.05; controls 0%, HR_PD vs. controls, p < 0.017). The Unified Parkinson's Disease Rating Scale motor score (mean, range) indicated that the HR_PD group (4, 0-12) had values between those of controls (0, 0-2; p < 0.017) and PD subjects (26, 9-55; p < 0.017). Among nonmotor symptoms, hyposmia was more common in both HR_PD (47.5%) and PD subjects (75%) than in controls (5.1%; p < 0.017 for both comparisons). Conclusions: Here, we describe the recruitment of a highly enriched-risk cohort and a promising study design to assess progression to motor PD. Whether the HR_PD group indeed suffers from early, PD-specific neurodegeneration remains to be verified in the ongoing follow-up examinations.