Monitoring of 30 marker candidates in early Parkinson disease as progression markers

Abstract

Objective: This was a longitudinal single-center cohort study to comprehensively explore multimodal progression markers for Parkinson disease (PD) in patients with recently diagnosed PD (n = 123) and age-matched, neurologically healthy controls (HC; n = 106).

Methods: Thirty tests at baseline and after 24 months covered nonmotor symptoms (NMS), cognitive function, and REM sleep behavior disorder (RBD) by polysomnography (PSG), voxel-based morphometry (VBM) of the brain by MRI, and CSF markers. Linear mixed-effect models were used to estimate differences of rates of change and to provide standardized effect sizes (d) with 95% confidence intervals (CI).

Results: A composite panel of 10 informative markers was identified. Significant relative worsening (PD vs HC) was seen with the following markers: the Unified Parkinson's Disease Rating Scale I (d 0.39; CI 0.09-0.70), the Autonomic Scale for Outcomes in Parkinson's Disease (d 0.25; CI 0.06-0.46), the Epworth Sleepiness Scale (d 0.47; CI 0.24-0.71), the RBD Screening Questionnaire (d 0.44; CI 0.25-0.64), and RBD by PSG (d 0.37; CI 0.19-0.55) as well as VBM units of cortical gray matter (d -0.2; CI -0.3 to -0.09) and hippocampus (d -0.15; CI -0.27 to -0.03). Markers with a relative improvement included the Nonmotor Symptom (Severity) Scale (d -0.19; CI -0.36 to -0.02) and 2 depression scales (Beck Depression Inventory d -0.18; CI -0.36 to 0; Montgomery-Åsberg Depression Rating Scale d -0.26; CI -0.47 to -0.04). Unexpectedly, cognitive measures and select laboratory markers were not significantly changed in PD vs HC participants.

Conclusions: Current CSF biomarkers and cognitive scales do not represent useful progression markers. However, sleep and imaging measures, and to some extent NMS, assessed using adequate scales, may be more informative markers to quantify progression.

Figure 1. Longitudinal changes in nonmotor symptoms (NMS), impaired quality of life (QoL), and depression

Estimated means and 95% confidence intervals of Movement Disorder Society–Unified Parkinson's Disease Rating Scale I (MDS-UPDRS I) (A), NMS Questionnaire (NMSQuest) (B), NMS Severity Scale (NMSS) (C), Scopa-AUT (D), QoL measure (PDQ-39) (E), and the depression scales: Beck Depression Inventory (BDI) (F) and Montgomery-Åsberg Depression Rating Scale (MADRS) (G) at baseline (BL) and 2-year follow-up (24FU). Blue line represents healthy controls (HC); red line represents participants with Parkinson disease (PD). *Significant change in PD vs HC (p < 0.05).

Figure 2. Longitudinal changes in sleep parameters

Estimated means and 95% confidence intervals of the Parkinson's Disease Sleepiness Scale (PDSS-2) (A), Epworth Sleepiness Scale (ESS) (B), REM Sleep Behavior Disorder by Questionnaire (RBD-SQ) (C), and by video-supported polysomnography (PSG) (D), at baseline (BL) and 2-year follow-up (24FU). Blue line represents healthy controls (HC); red line represents participants with Parkinson disease (PD). *Significant change in PD vs HC (p < 0.05).

Figure 3. Longitudinal changes in 1.5T volumetric MRI

Estimated means and 95% confidence intervals of voxel-based morphometry (VBM) in total gray matter volume (GMV) (A) and hippocampal volume (HCV) (B) at baseline (BL) and 2-year follow-up (24FU). Blue line represents healthy controls (HC); red line represents participants with Parkinson disease (PD). *Significant change in PD vs HC (p < 0.05). (C) Example of gray matter segmentation in 3 orthogonal cutplanes. For the analysis, native space maps were summed to generate an absolute volume per class and subject. (D) Example of smoothed gray matter maps (in Montreal Neurological Institute space) shown with the a priori defined hippocampal analysis region overlaid in red. Within this region, the mean average gray matter probability was calculated yielding one average value of hippocampal gray matter per subject.