Description of the condition
Dementia is a syndrome characterised by disturbances of multiple cognitive domains, including memory, orientation, thinking and behaviour. Most cases of dementia are due to progressive, degenerative disease of the brain. There were estimated to be 24 million people with dementia in the world in 2001, and this is predicted to rise to 42.3 million in 2020, and to 81.1 million by 2040 (Ballard 2011; Ferri 2005). Dementia due to Alzheimer's disease (AD) is the most common (Cacabelos 2008), accounting for 50% to 70% of the cases, followed by vascular dementia (30% to 40%) and mixed Alzheimer's/vascular cases (15% to 20%). Lewy body dementia (LBD) and Parkinson's disease dementia (PDD) together account for 5% to 10% of dementia cases (Mollenhauer 2010). There are also various rarer dementias due to other neurodegenerative disease. These include frontotemporal dementias (FTDs), Huntington's disease (HD), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), dementia in multiple sclerosis (MS) and progressive supranuclear palsy (PSP).
Frontotemporal dementias (FTDs) are a group of disorders with a variety of underlying pathologies, characterised by a progressive decline in behaviour or language associated with degeneration of frontal and anterior temporal lobes. Some FTDs are familial disorders associated with single gene mutation. The prevalence of FTD in population-based studies has varied between 2.7 per 100,000 inhabitants in the Netherlands to 17.6 per 100,000 inhabitants in Northern Italy (Premi 2012). Behavioural variant frontotemporal dementia (bvFTD) is the most common clinical presentation, with prominent personality changes and impaired social behaviour. The most common symptoms of cognitive decline are poor judgement, inattentiveness and distractibility, loss of planning ability and disorganisation (Rabinovici 2010).
Huntington's Disease (HD) is a hereditary neurodegenerative disorder caused by an expansion of a repeating CAG triplet series in the Huntingdon gene. It is characterised by chorea, behavioural and psychiatric manifestations and cognitive dysfunction. The worldwide service-based prevalence of HD, based on a meta-analysis (including 13 studies), was 2.71 per 100,000 (95% confidence interval (CI) 1.55 to 4.72) (Pringsheim 2012). The cognitive and behavioural symptoms and signs of HD have been shown to be evident at least 15 years prior to the time at which motor diagnosis is typically given (Paulsen 2011). Thus, the cognitive and behavioural impairments have been growing in prominence in HD diagnosis and treatment.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single-gene disorder (mutation in NOTCH3) directly affecting the cerebral small blood vessels. The main clinical manifestations of CADASIL are migraine, recurrent stroke or stepwise deterioration of motor ability and subcortical ischaemic vascular dementia. Estimates of the population prevalence of CADASIL vary from 1.98 per 100,000 in West Scotland to 4.10 per 100,000 in North-East England (Narayan 2012; Razvi 2005). Cognitive deficits can be found in about 60% of people with CADASIL. Typically these are frontal-lobe cognitive deficits, including problems with executive function, working memory, and verbal fluency (Choi 2010; Fukutake 2011). As the disease progresses, people begin to show cognitive deficits typical of subcortical vascular dementia (Choi 2010).
Multiple sclerosis (MS) is a chronic inflammatory neurological condition characterised by focal and diffuse neurodegeneration and demyelination throughout the central nervous system (CNS). Depending on the extent and location of damage in the CNS, people with MS may experience a wide variety of symptoms, including motor, cognitive, and neuropsychiatric problems (Chiaravalloti 2008). MS affects more than 600,000 people in the United States and more than 2 million people worldwide, and 40% to 65% of these people experience some degree of cognitive impairment (Rahn 2012). MS detrimentally affects various aspects of cognitive functioning, including attention, information processing efficiency, executive functioning, processing speed and long-term memory. Processing speed, visual learning and memory seem to be most commonly affected (Chiaravalloti 2008).
Progressive supraneuclear palsy (PSP) is a neurodegenerative disease which falls in the general class of tauopathies. It classically presents with early postural instability and falls; a peculiar wide-based, slow and unsteady gait; Parkinsonism characterised by axial more than limb rigidity and by symmetrical limb involvement; early dysarthria and dysphagia; and early cognitive and behavioural frontal lobe-type disturbances (Boeve 2012; Litvan 2001). The prevalence of PSP ranges from 3.1 to 6.5 per 100,000 in the United Kingdom (Hoppitt 2011). The age-standardised incidence of PSP in Sweden (2004 to 2007) is 1.2 (95% CI 0.4 to 2.6) per 100,000 (Linder 2010).
Description of the intervention
The first cholinesterase inhibitors were introduced into clinical practice in 1993 and the three currently licensed cholinesterase inhibitors - donepezil, rivastigmine and galantamine - are now considered to be the first-line medicines for dementia due to AD. They are usually recommended for dementia of mild to moderate severity. Cholinesterase inhibitors inhibit the enzyme acetylcholinesterase which breaks down acetylcholine (a neurotransmitter in the peripheral and central nervous systems). The cholinergic system is known to play an important role in cognition.
Donepezil is a selective reversible inhibitor of acetylcholinesterase. It is given orally, usually starting at a dose of 5 mg per day, increased after several weeks to 10 mg per day. Rivastigmine is an inhibitor of both acetylcholinesterase and butylcholinesterase. It can be administered orally or transdermally. Rivastigmine treatment is initiated at 1.5 mg twice daily, and is increased gradually over weeks to 6 mg twice daily. Galantamine can stimulate nicotinic acetylcholine receptors as well as inhibiting cholinesterase activity. It is administered orally in once- or twice-daily formulations. Galantamine treatment is usually initiated at 8 mg daily, and can be increased gradually up to 24 mg daily (Lanctôt 2009). Side effects of all the cholinesterase inhibitors include gastrointestinal symptoms, including nausea, diarrhoea and vomiting, as well as leg cramps, abnormal dreams, dizziness and weight loss (Hansen 2008; Tayeb 2012).
There is evidence for the efficacy of cholinesterase inhibitors in dementias due to conditions other than AD. These medications significantly improved the global assessment, cognitive function, behavioural disturbance and activities of daily living in people with dementia or cognitive impairment in Parkinson's disease (Rolinski 2012). They are also reported to produce small cognitive improvements in people with vascular dementia (Baskys 2012) and vascular cognitive impairment (Levine 2011). Based on these findings, cholinesterase inhibitors have also been used in the treatment of rarer dementias.
How the intervention might work
The cholinesterase inhibitors are thought to work primarily by preventing the breakdown of acetylcholine and hence boosting cholinergic neurotransmission in forebrain regions (Tayeb 2012).
CADASIL is a genetic form of subcortical ischaemic vascular dementia. Several recent studies have suggested that subcortical ischaemic lesions disrupt cholinergic pathways. Hence, cholinergic deficits may play a role in the dementia of CADASIL (Keverne 2007; Mesulam 2003). Reductions in cerebrospinal fluid (CSF) markers of cholinergic activity, which may reflect reductions in global brain cholinergic activity, have been found in MS, possibly due to disruption of cholinergic pathways by demyelination and axonal transection (Ruberg 1987). Depletions of postsynaptic cholinoreceptors have been found in the temporal cortex of people with FTD (Odawara 2003). Cholinergic neurons may also be indirectly affected in other neurodegenerative conditions associated with cognitive decline and dementia, including HD (Cubo 2006) and PSP (Litvan 2001). The cholinesterase inhibitors may therefore have an impact on cognitive impairment in these rarer dementias.
Why it is important to do this review
Cognitive impairment is one of the major causes of disability in those neurological conditions in which it occurs, resulting in a serious burden for individuals and their carers (Nunnemann 2012; Rahn 2012). In the United States, the estimated yearly monetary cost per person attributable to dementia was USD 41,000 to USD 56,000 in 2010 (Hurd 2013). It is therefore important to evaluate the treatment of the rarer dementias. Some studies have suggested that cholinesterase inhibitors might be associated with improved cognition in people with rarer dementias, but there are conflicting reports in the literature. A systematic review to focus on the efficacy of cholinesterase inhibitors is therefore needed for rarer dementias.
The objectives of this review are to evaluate:
- The efficacy of cholinesterase inhibitors for the treatment of cognitive impairment or dementia in neurological conditions associated with rarer dementias;
- The adverse effects of cholinesterase inhibitors in these conditions.
Criteria for considering studies for this review
Types of studies
We will include randomised double-blind controlled trials assessing the efficacy of treatment with currently marketed cholinesterase inhibitors in neurological conditions associated with rarer dementias.
Types of participants
Participants will be of any age and either gender with the following conditions: frontotemporal dementias (FTDs), Huntington's disease (HD), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADACIL), multiple sclerosis (MS), and progressive supranuclear palsy (PSP). The diagnostic criteria for these conditions should be globally accepted, such as Lund–Manchester criteria (Brun 1994; Neary 1998) or recent consensus criteria (Rascovsky 2011) for FTD; genetically-confirmed and/or positive family history, and clinical motor disorders for HD; genetic or biopsy diagnosis for CADASIL; clinical research criteria for MS (Poser 1983) and PSP (Litvan 1996). Participants may have any level of cognitive function at inclusion.
Types of interventions
- Cholinesterase inhibitors versus placebo.
- Cholinesterase inhibitors versus no intervention.
- Cholinesterase inhibitors plus other therapy (or therapies) versus placebo plus same other therapy (or therapies).
- Cholinesterase inhibitors plus other therapy (or therapies) versus other therapy (or therapies).
Cholinesterase inhibitors may be given at any dose for any duration. The currently marketed cholinesterase inhibitors are galantamine, donepezil and rivastigmine.
Types of outcome measures
The outcomes may be measured at different time points from baseline: short-term (three months or less), medium-term (more than three to 12 months) and long-term (more than12 months). We will analyse the outcome measures according to the time grouping.
- Cognition (measured by psychometric tests, including tests of single cognitive domains as well as multidomain scales and neuropsychological test batteries).
- Clinical global impression of change (measured by scales or by the physician's or participant's self-reported impression of any change).
- Global severity of dementia.
- Activities of daily living (measured by scales such as Alzheimer's Disease Co-operative Study-Activities of Daily Living Scale).
- Adverse effects.
- Caregiver burden.
- Behavioural disturbance and/or neuropsychiatric symptoms.
- Dependency (such as institutionalisation).
- Tolerability (all drop-outs, and those due to adverse drug reactions)
Search methods for identification of studies
We will search ALOIS (www.medicine.ox.ac.uk/alois): the Cochrane Dementia and Cognitive Improvement Group’s (CDCIG) Specialised Register. The search terms used will be: Frontal lobe dementia, Primary Progressive Aphasia, Huntington's disease, CADASIL, Multiple Sclerosis, Progressive Supranuclear Palsy, Motor Neurone Disease, Amyotrophic Lateral Sclerosis, combined with terms for the interventions (galantamine, donepezil, rivastigmine).
ALOIS is maintained by the CDCIG Trials Search Co-ordinator and contains dementia and cognitive improvement studies identified from the following:
- Monthly searches of a number of major healthcare databases: MEDLINE, EMBASE, CINAHL, PsycINFO and LILACS.
- Monthly searches of a number of trial registers: meta-Register of Controlled Trials; Umin (Japan's Trial Register); ICTRP/WHO portal (which covers ClinicalTrials.gov; Internation Standard Randomised Controlled Trial Number (ISRCTN) register; Chinese Clinical Trials Register; German Clinical Trials Register; Australian and New Zealand Clinical Trials Registry (ANZCTR); Iranian Registry of Clinical Trials and the Netherlands National Trials Regsiter, plus others).
- Quarterly search of the Cochrane Central Register of Controlled Trials (CENTRAL).
- 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.
Additional separate searches will be run in many of the above sources to ensure that the most up-to-date results are retrieved. The search strategy that will be used 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 identified citations for additional trials. We will contact the first author of identified trials for additional references and unpublished data.
We will check the US Food and Drug Administration website (FDA) for more information.
We will send e-mails to the manufacturers of the marketed cholinesterase inhibitors requesting any unpublished trial data.
Data collection and analysis
Selection of studies
Two review authors (Li and Zhou) will conduct a screening stage based on the title and abstract before retrieving the papers. Both review authors will independently read the abstract and methods sections of the papers to select the trials for inclusion in this review. Both review authors will independently assess all the references to identify potentially relevant trials. We will resolve any disagreement regarding differences in opinion by discussion and refer to the third author (Birong Dong) if there are unresolved differences.
Data extraction and management
Two review authors (Li and Zhou) will independently extract data for the trials including study characteristics, methods, interventions, participant demographic characteristics, enrolment criteria, outcomes, adverse effects, and number and reasons for drop-out. We will resolve any disagreements through discussion or by consulting the third review author.
For binary data, we will record the number in each treatment group and the number experiencing the outcome of interest. In some cases it may be necessary, due to variation in the way response to treatment is measured, to record outcomes as 'clinical improvement' versus 'no clinical improvement', regardless of the scales used by the authors. For continuous data, we will extract the mean change from baseline, the standard deviation of the mean change, and the number of participants for each treatment group in individual studies. Where changes from baseline are not reported, we will extract the mean, standard deviation and the number of participants in each treatment group at each time point, if available. If the studies use different measurement scales for the same outcome, we will calculate standardised mean differences. For cross-over trials, we will only extract data from the first treatment period.
Assessment of risk of bias in included studies
Two review authors (Li and Zhou) will independently assess studies for quality according to the Cochrane 'Risk of bias' tool described in the Cochrane Handbook (Chapter 8). The following criteria will form the main evaluation of methodological quality.
- Generation of random sequence.
- Concealment of allocation schedule.
- Blinding of: clinician (person delivering treatment) to treatment allocation; participant to treatment allocation; outcome assessor to treatment allocation.
- The proportion of included randomised participants in the main analysis, noting particularly where more than 20% are 'lost to follow-up'. We will also report the proportion of differing levels of losses to follow-up affecting the validity of the results for different outcomes to different degrees.
- All the study's prespecified outcomes and all expected outcomes of interest to the review have been reported.
For each criterion, we will make a judgement of low, high or unclear risk of bias. We will record the judgment and supporting evidence in a study-linked table and discuss it in the text of the review where relevant.
We will also evaluate other problems that could put the study at risk of bias, including possible conflicts of interest and demographic bias.
We will use the quality assessment to explore differences in the results of studies as part of any investigations of heterogeneity or in sensitivity analyses to explore the robustness of summary estimates.
Measures of treatment effect
For binary outcomes, we will use the risk ratio (RR) to measure treatment effect, with a 95% confidence interval (CI). We will express continuous data as mean difference (MD) or standardised mean difference (SMD), if different scales have been used.
Unit of analysis issues
We do not anticipate finding cluster-randomised trials for this review. We will only use first-period data from cross-over trials. We will take care to avoid double-counting of participants where there are multiple interventions in the same trial.
Dealing with missing data
Where there are missing data, we will attempt to seek the necessary information from the study authors. A 'worst-case' scenario analysis of the main outcome may be used in the event of missing data that cannot be obtained. The analysis in that case will assume that those participants who were lost to follow-up in the treatment group had the worse outcome, and that the participants lost to follow-up in the control group had the better outcome.
Assessment of heterogeneity
For pooled effects, we will calculate the I² statistic. An I² value greater than 40% will be taken to mean significant heterogeneity (Cochrane Handbook; Higgins 2003). Where there is evidence of significant heterogeneity of treatment effect between trials, we will use subgroup analysis to explore possible reasons for the heterogeneity.
Assessment of reporting biases
We will use funnel plots to test for publication bias, provided that ten studies or more contribute to the outcome meta-analysed. If the funnel plot shows an asymmetrical appearance, we will distinguish the possible cause of asymmetry and interpret its findings carefully.
We will analyse studies of the different neurological conditions separately. We will combine data in a meta-analysis using Review Manager 5, provided they are of sufficient quality and are from studies which are sufficiently similar clinically. We will use a fixed-effect method where we judge that all studies in the analysis are estimating the same intervention effect. Where we judge there to be significant clinical or methodological diversity, we will use a random effects model.
Subgroup analysis and investigation of heterogeneity
If there are sufficient data, we plan to undertake subgroup analyses for age, sex, severity of dementia, dosages and duration of treatment.
We plan to perform a sensitivity analysis to test the robustness of the results to the choice of model by comparing the results of a fixed-effect model with a random-effects model.
Sponsored by the Chinese Cochrane Center. We wish to acknowledge the consumer editor.
Appendix 1. MEDLINE search strategy
Last assessed as up-to-date: 25 July 2013.
Contributions of authors
All correspondence: Ying Li and Birong Dong
Drafting of review versions: Ying li, Shan Hai and Yan Zhou
Search for trials: Cochrane Dementai and Cognitive Improvement Group
Obtaining copies of trial reports: Ying Li and Yan Zhou
Selection of trials for inclusion/exclusion: Ying Li, Yan Zhou and Birong Dong
Extraction of data: Ying Li and Yan Zhou
Entry of data: Ying Li and Zou Jian
Interpretation of data analyses: Zhou Yan and Birong Dong
Declarations of interest
Sources of support
- Chinese Cochrane Centre, China.
- No sources of support supplied