Objective: To explore the natural history of Parkinson’s disease (PD) accounting for the effect of symptomatic treatments on progression by modeling the time course of MDS-UPDRS clinical endpoints and DaT-SPECT dopaminergic signal decline.

Background: The Parkinson’s Progressive Markers Initiative (PPMI) data from 401 individuals with a newly diagnosed idiopathic PD confirmed by a positive DaT-SPECT and for a follow-up of 10 years was used.

Method: We quantified the natural progression of MDS-UPDRS part I (non-motor symptoms), part II (motor symptoms and impact on function), part III (motor signs) off and of DaT-SPECT striatal binding ratios in the putamen. A mixed-effect modeling approach was used to account for the inter-individual variability in the parameters of disease progression. For each individual, the levodopa equivalent daily dosage (LEDD) regimen was integrated within a disease progression model of MDS-UPDRS parts. Goodness-of-fit plots and precision of parameter estimates were used as measures of model accuracy.

Results: A logistic growth model was the best model to fit the parts I, II, and III scores with estimated progression of 0.9, 1.3, and 2.6 absolute points per year respectively. The results indicate that higher amount of symptomatic therapy (LEDD), is associated with slower progression of parts II and III with estimated magnitude of effect of 0.4 and 1.0 points per daily median LEDD respectively. For part I, a higher amount of symptomatic therapy was associated with faster progression of MDS-UPDRS score with an increase of 0.3 points per daily median LEDD (Figure 1). The DaT-SPECT data were fitted with an exponential decay with time for 50% reduction from baseline of 7.5 years. There was a low level of correlation between the variability of the progression parameters of part II and part I as well as of part II and part III (r-squared 0.16 and 0.13 respectively). The variability in the decline of DaT-SPECT was not correlated to the progression of MDS-UPDRS scores (Figure 2).

Conclusion: The natural progression of part III is the fastest, followed by part II, part I. The amount of symptomatic therapy influences the progression of part I, II, and III. Correlations between inter-individual variability of progression parameters support the concept that MDS-UPDRS part III progression could precede the progression of MDS-UPDRS part II.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/modeling-parkinsons-disease-progression-accounting-for-the-effect-of-symptomatic-treatments-in-the-parkinsons-progression-markers-initiative-study/