• disease progression;
  • levodopa;
  • motor subscales;
  • Parkinson's disease;
  • pharmacodynamics;
  • selegiline


• There is marked variability among patients with Parkinson's disease (PD) in the rate of progression of status (severity) assessed with a global functional score (Unified Parkinson's Disease Rating Scale; UPDRS). It has been hypothesized that there are distinct PD subtypes with different rates of progression.

• Previous studies attempted to quantify the rates of progression for tremor-dominant and postural instability and gait disorder (PIGD)-dominant subtypes using only baseline clinical features.


• We used a nonlinear mixed effects modelling approach to describe the time course of the four cardinal features of PD before and during anti-parkinsonian treatment.

• Tremor-dominant and PIGD-dominant subtypes appear to be different stages of the disease rather than persistent attributes in individual patients and do not explain variability in progression among patients. Tremor progresses more slowly than other cardinal features with and without drug treatment. Postural instability and gait disorder is much less sensitive to the symptomatic effects of levodopa than the other cardinal features.

• We have extended the finding that anti-parkinsonian treatments have symptomatic and disease-modifying effects on overall function and demonstrate similar effects on each of the four cardinal features of PD.


(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.


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.


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.


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.