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

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• 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. WHAT THIS STUDY ADDS• 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. 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. METHODSData 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. RESULTSTremor 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. CONCLUSIONSThis analysis indicates that tremor progresses more slowly than other cardinal features and that PIGD is less treatment respon...

Item Response Theory as an Efficient Tool to Describe a Heterogeneous Clinical Rating Scale in De Novo Idiopathic Parkinson’s Disease Patients

“…The choice of three latent variables corroborates the literature (9,13,14). In Parkinson disease clinical trials, the initiation time of PD medications is closely related to the rate of disease progression.…”

“…When analyzed independently, tremor items have been shown to progress more slowly than all other motor features (9,13,14). Non-motor symptoms occur a decade before the other symptoms (16).…”

“…The existing therapies (carbidopa-levodopa, dopamine agonists, monoamine oxidase B inhibitors, catechol-O-methyltransferase inhibitors, anticholinergics and amantadine) have symptomatic effects and, for some of them, disease modifying effects (8,9). With a high number of failures in PD clinical trials and among the several challenges in the field of the neurological diseases, questions have been raised concerning the sensitivity and the accuracy of the clinical endpoint (9,10).…”

An improved approach for prediction of Parkinson's disease using machine learning techniques

“…Many people are aware of the motor symptoms as they can be visually perceived by human beings. These symptoms are also called as cardinal symptoms, these include resting tremor, slowness of movement (bradykinesia), postural instability (balance problems) and rigidity [2]. It is now established that there exists a timespan in which the non-motor symptoms can be observed.…”

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“…Traditionally, analyses of PD trials are performed using the composite score, e.g., Btotal^UPDRS score (sum of parts I, II, and III). However, occasionally, only a portion(s) of the rating scale (e.g., only the motor component of UPDRS scale), dependent on the specific range of disease severity of the patient cohort (3,4), may be used. The ranges in the resulting scores may therefore vary greatly, making the comparability across the rating scales difficult and leveraging/integration of knowledge from multiple sources cumbersome.…”