ArticlesEffect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study
Introduction
The term mild cognitive impairment (MCI) has emerged as a nosological construct that describes a cognitive state associated with ageing that is abnormal yet not diagnosable as dementia.1 Although proposed criteria and definitions of MCI are still evolving, the most commonly used definition of MCI specifies the following criteria: both subjective and objective impairments in memory, preserved overall cognitive function outside memory, and normal basic activities of daily living.2 This MCI phenotype has been consistently reported to carry an increased risk of progression or conversion to Alzheimer's disease (AD) or dementia.3, 4 The annual rates of progression from MCI to AD or dementia of this clinical phenotype have generally been reported to be 10–15% per year.4, 5, 6 This identification of MCI as a risk state for progression to AD or dementia holds the potential to allow testing of early treatment interventions that might improve cognitive symptoms, slow the rate of symptom progression towards dementia, and even delay the time to diagnosis or prevent AD or dementia.
Pharmacological treatment of the cholinergic dysfunction of AD with cholinesterase inhibitors has been the most widely used for mild and moderate stages of AD, with symptomatic efficacy shown for up to 1 year in placebo-controlled randomised clinical trials.7 Cholinergic abnormalities have been detected in early AD stages,8, 9, 10, 11 including abnormalities in other markers of the cholinergic system, such as signal transduction,12 p75 neurotrophin receptor concentrations,13 and beta-amyloid peptides.14 These abnormalities have triggered interest in investigating the effect of cholinesterase inhibitors on progression to AD and cognitive function in patients with MCI.15, 16, 17, 18
Our aims were to investigate whether rivastigmine delays the time to progression to AD in patients with MCI, and whether rivastigmine benefits cognitive function in patients with MCI.
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Patients
A total of 1526 patients were screened for the study. All patients were identified at entry to have MCI operationally defined by having cognitive symptoms, a global clinical dementia rating (CDR) stage of 0·5,19 and a score of less than 9 on the New York University delayed paragraph recall test.20 There was no specification of the onset or course of the presenting cognitive symptoms of MCI. Patients were excluded if they met either the AD diagnostic criteria of the Diagnostic and Statistical
Results
The baseline characteristics of the InDDEx study population are summarised in table 1. Figure 1 shows the flow of patients through the study. Of the 1526 patients screened for this study, 374 (24%) were screening failures, and 134 (9%) were still in active screening when the study was closed to further randomisation. The randomised groups did not differ in demographic characteristics or in their mean baseline scores. Of the full study sample, 500 patients (49·1%) participated in the APOE
Discussion
MCI has been recognised as an at-risk state for progression to dementia, particularly AD. Rates of progression are 10–15% per year in studies of up to 5 years or longer.2, 5, 6 As a result, MCI is a potentially compelling target for therapeutic intervention. To delay the time to develop AD could have significant clinical, economic, and social consequences.
The InDDEx study investigated the effect of rivastigmine over 3–4 years on the rate of progression from MCI to AD, in addition to the effects
References (57)
- et al.
Mild cognitive impairment
Am J Geriatr Psychiatry
(2005) - et al.
Beta-amyloid peptides as direct cholinergic neuromodulators: a missing link?
Trends Neurosci
(1998) - et al.
Mini-mental state. A practical method for grading the cognitive state of patients for the clinician
J Psychiatr Res
(1975) Apolipoprotein E, cholesterol transport and synthesis in sporadic Alzheimer's disease
Neurobiol Aging
(2005)- et al.
Mild cognitive impairment: clinical characterization and outcome
Arch Neurol
(1999) - et al.
Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials
Arch Neurol
(2004) - et al.
Current concepts in mild cognitive impairment
Arch Neurol
(2001) - et al.
Vascular risk factors, incidence of MCI, and rates of progression to dementia
Neurology
(2004) - et al.
Incidence and outcome of mild cognitive impairment in a population-based prospective cohort
Neurology
(2002) - et al.
A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD
Neurology
(2001)
The cholinergic deficit coincides with Abeta deposition at the earliest histopathologic stages of Alzheimer disease
J Neuropathol Exp Neurol
Imaging of nicotinic and muscarinic receptors in Alzheimer's disease: effect of tacrine treatment
Dement Geriatr Cogn Disord
Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial
Arch Neurol
Butyrylcholinesterase in the normal and Alzheimer brain
Mitogen-activated protein kinase-dependent and protein kinase C-dependent pathways link the m1 muscarinic receptor to beta-amyloid precursor protein secretion
J Neurochem
Loss of nucleus basalis neurons containing trkA immunoreactivity in individuals with mild cognitive impairment and early Alzheimer's disease
J Comp Neurol
Vitamin E and donepezil for the treatment of mild cognitive impairment
N Engl J Med
Study synopsis: a randomized double-blind, placebo-controlled trial to evaluate the efficacy and safety of galantamine in subjects with mild cognitive impairment (MCI) clinically at risk for development of clinically probable Alzheimer's disease. (Protocol No. GAL-INT-11)
Study synopsis: a randomized double-blind, placebo-controlled trial to evaluate the efficacy and safety of galantamine in subjects with mild cognitive impairment (MCI) clinically at risk for development of clinically probable Alzheimer's Disease (Protocol No. GAL-INT-18)
Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial
Neurology
The Clinical Dementia Rating (CDR): current version and scoring rules
Neurology
Neuropsychological prediction of decline to dementia in nondemented elderly
J Geriatr Psychiatry Neurol
Diagnostic and statistical manual of mental disorders
Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease
Neurology
Development of a rating scale for primary depressive illness
Br J Soc Clin Psychol
Recommendations guiding physicians in biomedical research involving human subjects
JAMA
Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale that broaden its scope. The Alzheimer's Disease Cooperative Study
Alzheimer Dis Assoc Disord
Wechsler Adult Intelligence Scale—third edition
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