Challenges in Parkinson’s Disease Dementia Treatment

Abstract & Commentary

Synopsis: In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson’s disease but also with higher rates of nausea, vomiting, and tremor.

Source: Emre M, et al. Rivastigmine For Dementia Associated With Parkinson’s Disease. N Engl J Med. 2004; 351:2509-2518

This study is a 24-week multicenter, randomized, double blind, placebo-controlled trial of rivastigmine for dementia associated with PD (PD-dementia). 541 patients were enrolled, almost two thirds of whom were men. Subjects had a mean age of 72.7 years, and had a DSMIV diagnosis of dementia due to Parkinson disease. Rivastigmine treatment began at 1.5 mg twice daily, and was slowly adjusted to the highest well-tolerated dose, up to 12 mg/day maximum. The mean dose of rivastigmine was 8.6 mg/day, with 55% taking 9-12 mg/day by 24 weeks. Primary outcome measure was the cognitive subscale of the Alzheimer’s Disease Cooperative Study (ADAS-cog), a 0 to 70-point scale. Seventy-three percent of those taking rivastigmine completed the trial, compared to 82% in the placebo arm. Groups were well matched for baseline ADAS-cog scores, with 23.8 ± -10.2 in the rivastigmine group, and 24.3 ± -10.5 in the placebo group. ADAS-cog scores improved by 2.1 ± -8.2 at 24 weeks, compared with worsening by 0.7 ± -7.5 in the placebo group, a significant between-group difference of 2.9, with P < 0.001. Significant differences were also demonstrated in secondary efficacy variables, addressing activities of daily living, behavior, attention, verbal fluency, and visuospatial skills. Nausea and vomiting were more frequent in the rivastigmine group (29.0% and 16.6%, respectively), compared to placebo (11.2% and 1.7%, respectively). In the rivastigmine group, 5.5% withdrew because of these adverse effects, as compared to only 1.2% in the placebo arm. Increased tremor (rivastigmine: 10.2%; placebo: 3.9%) only accounted for 1.7% of those withdrawing from the rivastigmine group. Only 4.7% of patients taking rivastigmine reported hallucinations, compared to 9.5% in the placebo group.

Commentary

This is the first large, multicenter, clinical trial comparing the cholinesterase inhibitor rivastigmine to placebo in PD dementia. Dementia in those with PD is common; in cross-sectional studies it occurs in approximately 45%. It contributes to functional decline with reduced quality of life and increased morbidity, yet optimal treatment is not well defined. Phenotypically, dementia with PD is quite different from Alzheimer’s disease (AD), with more prominent bradyphrenia and visuospatial deficits, and relatively less memory impairment. Visual hallucinations may occur. Pathology associated with PD-dementia includes widespread Lewy bodies, as well as changes characteristic of Alzheimer disease in some, but a few cases have no such changes, and this heterogeneity presents a challenge. The present study is certainly a step forward in terms of demonstrating benefit of rivastigmine for PD dementia, but unfortunately this benefit proves disappointing in magnitude. One problem is that the ADAS-cog has been specifically designed for AD, and may not provide a true estimate of changes in PD dementia. It is also important to define whether a specific subgroup of patients exists that may derive greater benefit. In the meantime, in the office setting, rivastigmine and other cholinesterase inhibitors may help some individuals, and their use can be guided by clinical response monitored by patient, caregivers and the physician. Claire Henchcliffe