Cholinesterase inhibitors for mild cognitive impairment
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy, safety and tolerability of cholinesterase inhibitors for mild cognitive impairment in adults.
Background
Description of the condition
Mild cognitive impairment describes a condition in a group of people who complain of memory problems but do not meet the diagnostic criteria for dementia. Specifically they show some deficits on cognitive testing but do not demonstrate significant impairment of their day‐to‐day functioning (Petersen 1999). It is a syndrome with an uncertain status: “... whether mild cognitive impairment remains a discrete syndrome, part of a continuum with normal ageing, or the early expression of various forms of progressive neurological problems that have yet to manifest themselves fully remains an uncertain and controversial area which is often the subject of heated debate” (O'Brien 2008).
Despite its controversial status and the lack of strict consensus regarding the diagnosis (Petersen 1999; Winblad 2004), the syndrome does seem to be reliably diagnosable and may be a high‐risk state for the development of dementia (O'Brien 2008; Winblad 2004). Estimates of conversion vary greatly, with between 1% and 25% of people with mild cognitive impairment (or analogous conditions) converting to dementia per year (Dawe 1992) and between 11% and 33% developing dementia within two years (Ritchie 2004). However, the prognosis is heterogeneous; some patients remain the same and some even improve so that they no longer meet the criteria for the syndrome.
If mild cognitive impairment is indeed a precursor or 'high‐risk state' for dementia and even, as has been suggested, if there were a more specific link between amnestic mild cognitive impairment and Alzheimer's disease (Petersen 2006), the amount of interest in mild cognitive impairment as a therapeutic target is understandable. Since the majority of the progression of dementia is irreversible, it would be a great advance with significant public health implications if one could target those at risk and delay or even prevent the onset of frank dementia.
Description of the intervention
Cholinesterase inhibitors are usually taken orally once daily, although other preparations, such as transdermal patches, are available. They act by inhibiting the enzyme acetylcholinesterase which degrades acetylcholine, a major neurotransmitter. This has the effect of enhancing the cholinergic function of the brain.
How the intervention might work
The efficacy of cholinesterase inhibition on the progression of mild and moderate Alzheimer’s disease is well‐established (Birks 2006a; Birks 2006b; Birks 2009; Loy 2006). Similarly, amnestic mild cognitive impairment is thought to be characterised by a central cholinergic deficit (Gauthier 2006). Given the progression of mild cognitive impairment to dementia (and amnestic mild cognitive impairment to Alzheimer's disease) and the cholinergic deficit in both disorders, it has been suggested that cholinesterase inhibitors might slow this process of progression
Why it is important to do this review
Epidemiological studies worldwide have found the prevalence of mild cognitive impairment to be between 3% and 19% of the older population (Ritchie 2004). Given that the UK is estimated to have an over‐65 population of 9.7 million people (Office for National Statistics 2006), potentially 1.8 million people in the UK could have mild cognitive impairment. Given the above estimates, this equates to approximately 100,000 to 300,000 people progressing to dementia each year. Rates of progression from amnestic mild cognitive impairment to Alzheimer’s disease have been found to be even higher.
In view of the various controversies and competing pressures mentioned above it is important that evidence regarding the efficacy and safety of cholinesterase inhibitors in mild cognitive impairment is systematically and carefully reviewed to provide the "... necessary scrutiny... in an even‐handed manner" (Graham 2006).
A systematic review (Raschetti 2007) found that "... use of [cholinesterase inhibitors] in MCI was not associated with any delay in the onset of AD or dementia." They also highlighted the side effect profile of these medications and the difficulties of defining mild cognitive impairment as an entity. This review would seek to build on the work of this systematic review, applying Cochrane methodology to randomised controlled trials published before Raschetti 2007 and in the five years since their literature search.
Objectives
To assess the efficacy, safety and tolerability of cholinesterase inhibitors for mild cognitive impairment in adults.
Methods
Criteria for considering studies for this review
Types of studies
Randomised, double‐blind, placebo‐controlled trials.
Types of participants
Adults with mild cognitive impairment as defined by each study but in line with the generally accepted criteria of a subjective memory complaint and relatively preserved daily functioning (Petersen 1999).
Types of interventions
Cholinesterase inhibitors of all types, at all doses, and in any formulation for a minimum of one month. We will specify no maximum duration of treatment.
Types of outcome measures
Primary outcomes
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Progression to dementia, either in general or specific sub‐types: Alzheimer's disease defined by the NINCDS‐ARDRA criteria (McKhann 1984); vascular dementia defined by consensus criteria (Roman 1993); or dementia with Lewy bodies defined by consensus criteria (McKeith 2005), measured at the time points of 12, 24 and 36 months. DSM‐IV or ICD‐10 criteria for the dementia syndrome in general or specific sub‐types will also be acceptable. Cognition will have been measured with standardised cognitive tests.
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Side effects, including gastro‐intestinal and cardiac.
Secondary outcomes
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Change in cognitive test scores.
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Mortality.
Search methods for identification of studies
Electronic searches
We will search ALOIS (www.medicine.ox.ac.uk/alois): the Cochrane Dementia and Cognitive Improvement Group’s (CDCIG) Specialised Register. We will search for all treatment of mild cognitive impairment studies in which any of the following interventions have been used: donepezil, rivastigmine, galantamineand tacrine. ALOIS is maintained by the Trials Search Co‐ordinator for CDCIG and contains dementia and cognitive impairment studies identified from the following.
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Monthly searches of a number of major healthcare databases: MEDLINE, EMBASE, CINAHL, PsycINFO and Lilacs.
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Monthly searches of a number of trial registers: metaRegister of Controlled Trials (mRCT); Umin Japan Trial Register; ICTRP/WHO portal (which covers ClinicalTrials.gov; ISRCTN; Chinese Clinical Trials Register; German Clinical Trials Register; Iranian Registry of Clinical Trials and the Netherlands National Trials Register, plus others).
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Quarterly searches of The Cochrane Library’s Central Register of Controlled Trials (CENTRAL).
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Six‐monthly searches of a number of grey literature sources: ISI Web of Knowledge Conference Proceedings; Index to Theses; Australasian Digital Theses.
To view a list of all sources searched for ALOIS see About ALOIS on the ALOIS website.
We will run additional separate searches in many of the above sources to ensure that the most up‐to‐date results are retrieved. The search strategy that we use for the retrieval of reports of trials from MEDLINE (via the Ovid SP platform) can be seen in Appendix 1.
Searching other resources
We will search reference lists of relevant studies for additional trials.
Data collection and analysis
We will include relevant publications based on the title of the publication and its abstract. In the presence of any suggestion that an article could be relevant, we will retrieve it for further assessment.
Selection of studies
Two review authors (TR, JM) will independently select trials for relevance using the criteria defined in the current Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011).
Data extraction and management
We will extract data regarding the primary and secondary outcomes from the published reports. TR and JM will extract data independently using a data extraction form. We will settle any disagreement over inclusion or exclusion of trials, risk of bias or data extraction by discussion. The data to be extracted will be the number of patients progressing to dementia at the time points of 12, 24 and 36 months. We will also collect information about drug side effects and the secondary outcomes listed above.
Assessment of risk of bias in included studies
We will comment on the methodological quality of trials. Specifically, TR and JM will undertake assessment of the risk of bias of the included trials independently in accordance with the current Cochrane Handbook for Systematic Reviews of Interventions.
We will use the Cochrane 'Risk of bias' tool in RevMan 5.1 (RevMan 2011).
Measures of treatment effect
We will express the treatment effects as risk ratios (RR) for dichotomous outcomes.
Unit of analysis issues
The individual will be the unit of analysis.
Dealing with missing data
We will deal with missing data in accordance with the current Cochrane Handbook for Systematic Reviews of Interventions. We will contact the original publication author(s) wherever possible. Where assumptions need to be made regarding missing data we will make these explicit and conduct sensitivity analyses.
Assessment of heterogeneity
We will assess heterogeneity by forest plot and Chi² test.
Assessment of reporting biases
We will assess reporting bias by funnel plot.
Data synthesis
We will use RevMan 5.1 to perform meta‐analysis if studies are sufficiently similar to allow this.
Subgroup analysis and investigation of heterogeneity
The only subgroup analysis that could potentially be conducted would be the comparison of different sub‐types of mild cognitive impairment, although it is unlikely that studies will have been sufficiently detailed to allow this.
Sensitivity analysis
If a sufficient number of trials are found, we will perform sensitivity analyses to test the robustness of the evidence. We will exclude the trials of low quality (high risk of bias) in sensitivity analyses.
