Progression of motor and nonmotor features of Parkinson's disease and their response to treatment

Abstract

Aims: (i) To describe the progression of the cardinal features of Parkinson's disease (PD); (ii) to investigate whether baseline PD subtypes explain disease progression; and (iii) to quantify the symptomatic and disease-modifying effects of anti-parkinsonian treatments.

Methods: Data were available for 795 PD subjects, initially untreated, followed for up to 8 years. Cardinal features [tremor, rigidity, bradykinesia, and postural instability and gait disorder (PIGD)] were derived from the total unified Parkinson's disease rating scale (total UPDRS), cognitive status from the mini-mental status exam score (MMSE) and depression status from the Hamilton depression scale (HAM-D). Analysis was performed using a nonlinear mixed effects approach with an asymptotic model for natural disease progression. Treatment effects (i.e. symptomatic and disease modifying) were evaluated by describing changes in the natural history model parameters.

Results: Tremor progressed more slowly (half-time of 3.9 years) than all other motor features (half-time 2-3 years). The MMSE progression was negligible, while HAM-D progressed with a half-time of 5 years. Levodopa had marked symptomatic effects on all features, but low potency for effect on PIGD (ED₅₀ of 1237 mg day⁻¹ compared with 7-24 mg day⁻¹ for other motor and nonmotor features). Other anti-parkinsonian treatments had much smaller symptomatic effects. All treatments had disease-modifying effects on the cardinal features of PD. Baseline PD subtypes only explained small differences in disease progression.

Conclusions: This analysis indicates that tremor progresses more slowly than other cardinal features and that PIGD is less treatment responsive in early PD patients. There was no evidence of baseline PD subtypes as a clinically useful predictor of disease progression rate. Anti-parkinsonian treatments have symptomatic and disease-modifying effects on all major features of PD.

© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Figures

Figure 1

Observed time courses (open triangles) of total Unified Parkinson's Disease Rating Scale (UPDRS) and subscales and nonmotor features for two individuals to illustrate the symptomatic and disease-modifying effects of anti-parkinsonian treatments. Individual predicted scores are shown as continuous lines; treatment dosages are normalized to 300 mg day−1 for levodopa (dotted lines), 10 mg day−1 selegiline (short dashed-dotted lines) and 1.25 mg day−1 pergolide (long dashed-dotted lines). Subject ID no. 4 was tremor-dominant subtype [tremor/postural instability and gait disorder (PIGD) ratio of 3.5] and subject ID no. 10 was indeterminate subtype at study entry (ratio of 1.3). Both converted to PIGD-dominant subtype at the end of the study (ratio of 0.5 for both)

Figure 2

Visual predictive check (VPC) for total UPDRS showing observations and observed percentiles (a), prediction-corrected (PRED-corrected) VPC without dropouts (b) and with dropouts (c), and simulated adaptive treatment with dropouts (uncorrected; d). Median (continuous lines) and 90% prediction intervals (dashed lines) of the observed (continuous lines with filled circles) and simulated data are shown. The 90% confidence intervals for the median and the prediction intervals are shown in the plot as shaded bands

Figure 3

Visual predictive checks for other disease status variables (lines and symbols similar to Figure 2)

Figure 3

Visual predictive checks for other disease status variables (lines and symbols similar to Figure 2)

Figure 3

Visual predictive checks for other disease status variables (lines and symbols similar to Figure 2)

Figure 4

Predicted natural disease progress (continuous lines) and symptomatic and disease-modifying effects starting at year 2 of levodopa (dotted lines) and combination of levodopa and selegiline (dashed lines) on disease progress curves (y-axes are scaled to maximal possible score of the respective features)

Figure 5

Median ratio of tremor/PIGD over 8 years, illustrating the transition from tremor-dominant to PIGD-dominant subtypes in the study cohort