Abstract

IntroductionDespite widespread use of second-generation cholinesterase inhibitors for the symptomatic treatment of Alzheimer’s disease (AD), little is known about the long term effects of cholinergic treatment on global cognitive function and potential specific effects in different cognitive domains. The objectives of this study were to determine the association between cholinergic treatment and global cognitive function over one and two years in a cohort of patients with mild or moderate AD and identify potential differences in domain-specific cognitive outcomes within this cohort.MethodsA cohort of patients meeting the revised National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for mild or moderate AD, including patients both on treatment with a cholinesterase inhibitor and untreated controls (treated = 65, untreated = 65), were recruited from the Cognitive Neurology Clinic at Sunnybrook Health Sciences Centre, as part of the Sunnybrook Dementia Study. Patients were followed for one to two years and underwent standardized neuropsychological assessments to evaluate global and domain-specific cognitive function. Associations between cholinesterase inhibitor use and global and domain-specific cognitive outcome measures at one and two years of follow-up were estimated using mixed model linear regression, adjusting for age, education, and baseline mini mental state examination (MMSE).ResultsAt one year, treated patients showed significantly less decline in global cognitive function, and treatment and time effects across tests of executive and visuospatial function. At two years, there was a significant trend towards less decline in global cognition for treated patients. Moreover, treated patients showed significant treatment and time effects across tests of executive functioning, memory, and visuospatial function.ConclusionsThe present study offers two important contributions to knowledge of the effectiveness of cholinesterase inhibitor treatment in patients with mild-moderate AD: 1) that second-generation cholinesterase inhibitors demonstrate long-term effectiveness for reducing global cognitive decline over one to two years of follow-up, and 2) that decline in function for cognitive domains, including executive function, memory, and visuospatial skill that are primarily mediated by frontal networks and by the cholinergic system, rather than memory, may be slowed by treatment targeting the cholinergic system.

Highlights

  • Despite widespread use of second-generation cholinesterase inhibitors for the symptomatic treatment of Alzheimer’s disease (AD), little is known about the long term effects of cholinergic treatment on global cognitive function and potential specific effects in different cognitive domains

  • Secondary analyses indicated that performance on tasks requiring the domains of executive function, memory, visuospatial attention, and visuoconstructive skill differed either between groups or over time in this cohort, suggesting that, in addition to memory, other specific cognitive domains may be selectively responsive to long-term cholinesterase treatment in mild to moderate AD patients

  • The findings of the present study are consistent with data from previous 6-month pivotal clinical trials and provide further evidence to support the benefit of cholinesterase inhibitor (ChEI) treatment for global cognitive function in patients with mild–moderate AD

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Summary

Introduction

Despite widespread use of second-generation cholinesterase inhibitors for the symptomatic treatment of Alzheimer’s disease (AD), little is known about the long term effects of cholinergic treatment on global cognitive function and potential specific effects in different cognitive domains. The objectives of this study were to determine the association between cholinergic treatment and global cognitive function over one and two years in a cohort of patients with mild or moderate AD and identify potential differences in domain-specific cognitive outcomes within this cohort. Most clinical trials have only examined patients over shorter term periods of follow-up, so the duration of treatment effects have not been well characterized [14,15] The reasons for this are related primarily to the disease process itself: it is difficult to conduct symptomatic treatment studies in a relentlessly progressive neurodegenerative disorder such as AD over time periods longer than 6 months within the context of a clinical trial because, given the efficacy shown with ChEIs, longer term placebo groups may no longer be considered ethical. Longer follow-up periods of up to 18 months are being pursued in trials with disease-modifying potential, with the experimental treatment being added on to stable approved symptomatic therapy

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