The treatment of mild cognitive impairment associated with Parkinson's disease

In Alzheimer’s disease (AD), the term “mild cognitive impairment” (MCI) polarizes opinion, with many researchers now arguing this is a redundant concept, and what is required is a term that accurately and reliably represents the earliest stages of AD. Despite this, MCI associated with Parkinson’s (PD-MCI) has recently been operationalized from a diagnostic perspective and is attracting considerable attention in terms of its clinical impacts, pathophysiology, and management. Parkinson’s disease MCI is common (mean prevalence, 27%; range, 19%-38%), even early in the motor disease course. The clinical profile of PD-MCI is heterogeneous, with a range of cognitive domains affected, almost certainly reflecting different underlying pathophysiologies. Thus, the cognitive deficits could be attributable to Lewy body pathology and represent the earliest stages of dementia associated with Parkinson’s (PDD), but equally well may be attributable to dynamic changes in transmitter networks (eg, dopaminergic projections) or non-PD pathology. As such, defining a patient as having PD-MCI may not necessarily be helpful in predicting prognosis or clinical course. Irrespective of controversy associated with the term MCI, early cognitive impairment in PD, insufficient to merit a diagnosis of PDD, impacts adversely on the patient’s self-perceived health status and quality of life, their ability to undertake activities of daily living, and the strain placed on their caregivers. The trial reported in this issue of Movement Disorders by Mamikonyan and colleagues is therefore both timely and welcome. In this 24-week, randomized, doubleblind, placebo-controlled, crossover single-site study of the rivastigmine transdermal patch, the investigators enrolled 28 subjects and used the Alzheimer’s Disease Cooperative Study—Clinical Global Impression of Change as the primary outcome measure. Because the study predated the publication of the International Parkinson and Movement Disorder society criteria for PDMCI, the authors used the Winblad criteria for MCI, which represent an update of the widely used Petersen MCI criteria. Of study participants, 82.1% (n 5 23) completed both phases on study medication, with no concerns raised regarding tolerability. In terms of efficacy, however, a trend effect was seen only in favor of rivastigmine on the Alzheimer’s Disease Cooperative Study—Clinical Global Impression of Change, whereas a significant effect of the active drug was found on one secondary outcome measure, the Everyday Cognition Battery, and trends in favor of rivastigmine on the PDQ-8 and the State Anxiety Inventory. No benefit was found for the cholinesterase inhibitor on any of the secondary outcome cognitive measures. How should the results from this study be interpreted? In some senses, the work sits between that of Grace and colleagues, who studied the effects of another cholinesterase inhibitor, galantamine, in nondemented people with Parkinson’s, and larger randomized controlled trials of donepezil and rivastigmine in PDD. The former study predated the concept of PD-MCI and set no inclusion criterion in cognitive terms. No benefits were found for galantamine on any neuropsychological measure, but when a post-hoc analysis was performed on a “PD-MCI” subgroup defined on the basis of baseline performance at more than 1 standard deviation below the age-corrected mean on one or more of three measures, the group receiving galantamine appeared to show benefit compared with placebo on the 3MS global cognitive measure. In contrast, a much larger multicenter placebo-controlled randomized controlled study showed significant benefits for rivastigmine capsules in PDD on the Alzheimer’s disease assessment scalecognitive (ADAS-cog) primary outcome measure, and another similarly proportioned multicenter randomized controlled study showed a similar magnitude of effect for donepezil, again in PDD. -----------------------------------------------------------*Correspondence to: David J. Burn, Institute of Neuroscience, and Professor of Movement Disorders Neurology, Henry Wellcome Building, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, e-mail: david.burn@ncl.ac. uk