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1.  Cholinesterase Inhibitors in Mild Cognitive Impairment: A Systematic Review of Randomised Trials 
PLoS Medicine  2007;4(11):e338.
Background
Mild cognitive impairment (MCI) refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs) currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD), in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (donepezil, rivastigmine, and galantamine) in delaying the conversion from MCI to Alzheimer disease or dementia.
Methods and Findings
The terms “donepezil”, “rivastigmine”, “galantamine”, and “mild cognitive impairment” and their variants, synonyms, and acronyms were used as search terms in four electronic databases (MEDLINE, EMBASE, Cochrane, PsycINFO) and three registers: the Cochrane Collaboration Trial Register, Current Controlled Trials, and ClinicalTrials.gov. Published and unpublished studies were included if they were randomized clinical trials published (or described) in English and conducted among persons who had received a diagnosis of MCI and/or abnormal memory function documented by a neuropsychological assessment. A standardized data extraction form was used. The reporting quality was assessed using the Jadad scale. Three published and five unpublished trials met the inclusion criteria (three on donepezil, two on rivastigmine, and three on galantamine). Enrolment criteria differed among the trials, so the study populations were not homogeneous. The duration of the trials ranged from 24 wk to 3 y. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated groups and the placebo groups. The rate of conversion ranged from 13% (over 2 y) to 25% (over 3 y) among treated patients, and from 18% (over 2 y) to 28% (over 3 y) among those in the placebo groups. Only for two studies was it possible to derive point estimates of the relative risk of conversion: 0.85 (95% confidence interval 0.64–1.12), and 0.84 (0.57–1.25). Statistically significant differences emerged for three secondary end points. However, when adjusting for multiple comparisons, only one difference remained significant (i.e., the rate of atrophy in the whole brain).
Conclusions
The use of ChEIs in MCI was not associated with any delay in the onset of AD or dementia. Moreover, the safety profile showed that the risks associated with ChEIs are not negligible. The uncertainty regarding MCI as a clinical entity raises the question as to the scientific validity of these trials.
A systematic review of trials of cholinesterase inhibitors for preventing transition of mild cognitive impairment (MCI) to dementia, conducted by Roberto Raschetti and colleagues, found no difference between treatment and control groups and concluded that uncertainty regarding the definition of MCI casts doubts on the validity of such trials.
Editors' Summary
Background.
Worldwide, more than 24 million people have dementia, a group of brain disorders characterized by an irreversible decline in memory, problem solving, communication, and other “cognitive” functions. The commonest form of dementia is Alzheimer disease (AD). The risk of developing AD increases with age—AD is rare in people younger than 65 but about half of people over 85 years old have it. The earliest symptom of AD is usually difficulty in remembering new information. As the disease progresses, patients may become confused and have problems expressing themselves. Their behavior and personality can also change. In advanced AD, patients need help with daily activities like dressing and eating, and eventually lose their ability to recognize relatives and to communicate. There is no cure for AD but a class of drugs called “cholinesterase inhibitors” can sometimes temporarily slow the worsening of symptoms. Three cholinesterase inhibitors—donepezil, rivastigmine, and galantamine—are currently approved for use in mild-to-moderate AD.
Why Was This Study Done?
Some experts have questioned the efficacy of cholinesterase inhibitors in AD, but other experts and patient support groups have called for these drugs to be given to patients with a condition called mild cognitive impairment (MCI) as well as to those with mild AD. People with MCI have memory problems that are more severe than those normally seen in people of their age but no other symptoms of dementia. They are thought to have an increased risk of developing AD, but it is not known whether everyone with MCI eventually develops AD, and there is no standardized way to diagnose MCI. Despite these uncertainties, several clinical trials have investigated whether cholinesterase inhibitors prevent progression from MCI to AD. In this study, the researchers have assessed whether the results of these trials provide any evidence that cholinesterase inhibitors can prevent MCI progressing to AD.
What Did the Researchers Do and Find?
The researchers conducted a systematic review of the medical literature to find trials that had addressed this issue, which met criteria that they had defined clearly in advance of their search. They identified three published and five unpublished randomized controlled trials (studies in which patients randomly receive the test drug or an inactive placebo) that investigated the effect of cholinesterase inhibitors on the progression of MCI. The researchers obtained the results of six of these trials—four examined the effect of cholinesterase inhibitors on the conversion of MCI to clinically diagnosed AD or dementia (the primary end point); all six examined the effect of the drugs on several secondary end points (for example, individual aspects of cognitive function). None of the drugs produced a statistically significant difference (a difference that is unlikely to have happened by chance) in the probability of progression from MCI to AD. The only statistically significant secondary end point after adjustment for multiple comparisons (when many outcomes are considered, false positive results can occur unless specific mathematical techniques are used to prevent this problem) was a decrease in the rate of brain shrinkage associated with galantamine treatment. More patients treated with cholinesterase inhibitors dropped out of trials because of adverse effects than patients given placebo. Finally, in the one trial that reported all causes of deaths, one participant who received placebo and six who received galantamine died.
What Do These Findings Mean?
These findings suggest that the use of cholinesterase inhibitors is not associated with any delay in the onset of clinically diagnosed AD or dementia in people with MCI. They also show that the use of these drugs has no effect on most surrogate (substitute) indicators of AD but that the risks associated with their use are not negligible. However, because MCI has not yet been clearly defined as a clinical condition that precedes dementia, some (even many) of the patients enrolled into the trials that the researchers assessed may not actually have had MCI. Thus, further clinical trials are needed to clarify whether cholinesterase inhibitors can delay the progression of MCI to dementia, but these additional trials should not be done until the diagnosis of MCI has been standardized.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040338.
An essay by Matthews and colleagues, in the October 2007 issue of PLoS Medicine, discusses how mild cognitive impairment is currently diagnosed
The US Alzheimer's Association provides information about all aspects of Alzheimer disease, including fact sheets on treatments for Alzheimer disease and on mild cognitive impairment
The UK Alzheimer's Society provides information for patients and caregivers on all aspects of dementia, including drug treatments and mild cognitive impairment
The UK charity DIPEx provides short video clips of personal experiences of care givers of people with dementia
doi:10.1371/journal.pmed.0040338
PMCID: PMC2082649  PMID: 18044984
2.  Response to cholinesterase inhibitors affects lifespan in Alzheimer’s disease 
BMC Neurology  2014;14(1):173.
Background
A varying response to cholinesterase inhibitor (ChEI) treatment has been reported among patients with Alzheimer’s disease (AD). Whether the individual-specific response, specific ChEI agent or dose affects mortality is unclear. We aimed to examine the relationship between the 6-month response to ChEI and lifespan.
Methods
Six hundred and eighty-one deceased patients with a clinical AD diagnosis and a Mini-Mental State Examination (MMSE) score of 10–26 at the start of ChEI therapy (baseline) were included in a prospective, observational, multicentre study in clinical practice. At baseline and after 6 months of treatment, the participants were assessed using the MMSE, the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), the Clinician’s Interview-Based Impression of Change (CIBIC), the Instrumental Activities of Daily Living (IADL) scale, and the Physical Self-Maintenance Scale (PSMS). The individuals’ socio-demographic characteristics, ChEI dose, and date of death were recorded. Responses to ChEI and the association of possible risk factors with survival were analysed using general linear models.
Results
A longer lifespan (mean of 0.5 years) was observed among the improved/unchanged patients, as measured by MMSE or CIBIC score, but not by ADAS-cog score, after 6 months of ChEI therapy. In the multivariate models, increased survival time was independently related to a better 6-month response in MMSE, CIBIC, IADL, and PSMS scores, female sex, no antihypertensive/cardiac or antidiabetic therapy, younger age, lower education, milder disease stage at baseline, and higher ChEI dose. Apolipoprotein E genotype did not affect mortality significantly. The patients who received a higher ChEI dose during the first 6 months had a mean lifespan after baseline that was 15 months longer than that of those who received a lower dose.
Conclusions
A better short-term response to ChEI might prolong survival in naturalistic AD patients. In individuals who received and tolerated higher ChEI doses, a longer lifespan can be expected.
doi:10.1186/s12883-014-0173-4
PMCID: PMC4172846  PMID: 25213579
Alzheimer’s disease; Cholinesterase inhibitors; Treatment effect; Life expectancy; Survival; Cognition; Activities of daily living; Predictors; Statistical models
3.  Progression of mild Alzheimer’s disease: knowledge and prediction models required for future treatment strategies 
Introduction
Knowledge of longitudinal progression in mild Alzheimer’s disease (AD) is required for the evaluation of disease-modifying therapies. Our aim was to observe the effects of long-term cholinesterase inhibitor (ChEI) therapy in mild AD patients in a routine clinical setting.
Methods
This was a prospective, open-label, non-randomized, multicenter study of ChEI treatment (donepezil, rivastigmine or galantamine) conducted during clinical practice. The 734 mild AD patients (Mini-Mental State Examination (MMSE) score 20 to 26) were assessed at baseline and then semi-annually over three years. Outcome measures included the MMSE, Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), Clinician’s Interview-Based Impression of Change (CIBIC) and Instrumental Activities of Daily Living (IADL) scale.
Results
After three years of ChEI therapy, 31% (MMSE) and 33% (ADAS-cog) of the patients showed improved/unchanged cognitive ability, 33% showed improved/unchanged global performance and 14% showed improved/unchanged IADL capacity. Higher mean dose of ChEI and lower educational level were both predictors of more positive longitudinal cognitive and functional outcomes. Older participants and those with a better IADL score at baseline exhibited a slower rate of cognitive decline, whereas younger participants and those with higher cognitive status showed more preserved IADL ability over time. Gender and apolipoprotein E (APOE) genotype showed inconsistent results. Prediction models using the abovementioned scales are presented.
Conclusions
In naturalistic mild AD patients, a marked deterioration in IADL compared with cognitive and global long-term outcomes was observed, indicating the importance of functional assessments during the early stages of the disease. The participants’ time on ChEI treatment before inclusion in studies of new therapies might affect their rate of decline and thus the comparisons of changes in scores between various studies. An increased understanding of expected disease progression in different domains and potential predictors of disease progression is essential for assessment of future therapies in AD.
doi:10.1186/alzrt210
PMCID: PMC3978889  PMID: 24099236
4.  Functional response to cholinesterase inhibitor therapy in a naturalistic Alzheimer’s disease cohort 
BMC Neurology  2012;12:134.
Background
Activities of daily living (ADL) are an essential part of the diagnostic criteria for Alzheimer’s disease (AD). A decline in ADL affects independent living and has a strong negative impact on caregiver burden. Functional response to cholinesterase inhibitor (ChEI) treatment and factors that might influence this response in naturalistic AD patients need investigating. The aim of this study was to identify the socio-demographic and clinical factors that affect the functional response after 6 months of ChEI therapy.
Methods
This prospective, non-randomised, multicentre study in a routine clinical setting included 784 AD patients treated with donepezil, rivastigmine or galantamine. At baseline and after 6 months of treatment, patients were assessed using several rating scales, including the Instrumental Activities of Daily Living (IADL) scale, Physical Self-Maintenance Scale (PSMS) and Mini-Mental State Examination (MMSE). Demographic and clinical characteristics were investigated at baseline. The functional response and the relationships of potential predictors were analysed using general linear models.
Results
After 6 months of ChEI treatment, 49% and 74% of patients showed improvement/no change in IADL and in PSMS score, respectively. The improved/unchanged patients exhibited better cognitive status at baseline; regarding improved/unchanged PSMS, patients were younger and used fewer anti-depressants. A more positive functional response to ChEI was observed in younger individuals or among those having the interaction effect of better preserved cognition and lower ADL ability. Patients with fewer concomitant medications or those using NSAIDs/acetylsalicylic acid showed a better PSMS response.
Conclusions
Critical characteristics that may influence the functional response to ChEI in AD were identified. Some predictors differed from those previously shown to affect cognitive response, e.g., lower cognitive ability and older age predicted better cognitive but worse functional response.
doi:10.1186/1471-2377-12-134
PMCID: PMC3534216  PMID: 23126532
Alzheimer’s disease; Activities of daily living; Cholinesterase inhibitors; Treatment effect; Predictors; Statistical models
5.  Predictors of long-term cognitive outcome in Alzheimer's disease 
Introduction
The objective of this study was to describe the longitudinal cognitive outcome in Alzheimer's disease (AD) and analyze factors that affect the outcome, including the impact of different cholinesterase inhibitors (ChEI).
Methods
In an open, three-year, nonrandomized, prospective, multicenter study, 843 patients were treated with donepezil, rivastigmine, or galantamine in a routine clinical setting. At baseline and every six months, patients were assessed using several rating scales, including the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the dose of ChEI was recorded. Sociodemographic and clinical characteristics were investigated. The relationships of these predictors with longitudinal cognitive ability were analyzed using mixed-effects models.
Results
Slower long-term cognitive decline was associated with a higher cognitive ability at baseline or a lower level of education. The improvement in cognitive response after six months of ChEI therapy and a more positive longitudinal outcome were related to a higher mean dose of ChEI, nonsteroidal anti-inflammatory drug (NSAID)/acetylsalicylic acid usage, male gender, older age, and absence of the apolipoprotein E (APOE) ε4 allele. More severe cognitive impairment at baseline also predicted an improved response to ChEI treatment after six months. The type of ChEI agent did not influence the short-term response or the long-term outcome.
Conclusions
In this three-year AD study performed in a routine clinical practice, the response to ChEI treatment and longitudinal cognitive outcome were better in males, older individuals, non-carriers of the APOE ε4 allele, patients treated with NSAIDs/acetylsalicylic acid, and those receiving a higher dose of ChEI, regardless of the drug agent.
doi:10.1186/alzrt85
PMCID: PMC3226278  PMID: 21774798
6.  Treatment With Cholinesterase Inhibitors and Memantine of Patients in the Alzheimer’s Disease Neuroimaging Initiative 
Archives of Neurology  2011;68(1):58-66.
Objectives
To assess the clinical characteristics and course of patients with mild cognitive impairment (MCI) and mild Alzheimer disease (AD) treated with cholinesterase inhibitors (ChEIs) and memantine hydrochloride.
Design
Cohort study.
Setting
The 59 recruiting sites for the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
Participants
Outpatients with MCI and AD in ADNI.
Main Outcome Measures
The AD Assessment Scale–cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR) scale, and Functional Activities Questionnaire (FAQ).
Results
A total of 177 (44.0%) of 402 MCI patients and 159 (84.6%) of 188 mild-AD patients were treated with ChEIs and 11.4% of MCI patients and 45.7% of AD patients with memantine at entry. Mild-cognitive-impairment patients who received ChEIs with or without memantine were more impaired, showed greater decline in scores, and progressed to dementia sooner than patients who did not receive ChEIs. Alzheimer-disease patients who received ChEIs and memantine took them longer, were more functionally impaired, and showed greater decline on the MMSE and CDR (but not on the ADAS-cog or FAQ) than those who received ChEIs only.
Conclusions
Academic physicians frequently prescribe ChEIs and memantine earlier than indicated in the US Food and Drug Administration–approved labeling to patients who are relatively more severely impaired or who are rapidly progressing toward cognitive impairment. The use of these medications in ADNI is associated with clinical decline and may affect the interpretation of clinical trial outcomes.
Study Registration
clinicalTrials.gov Identifier: NCT00106899
doi:10.1001/archneurol.2010.343
PMCID: PMC3259850  PMID: 21220675
7.  Cholinesterase inhibitor use does not significantly influence the ability of 123I‐FP‐CIT imaging to distinguish Alzheimer's disease from dementia with Lewy bodies 
Background
123I‐labelled 2β‐carbomethoxy‐3β‐(4‐iodophenyl)‐N‐(3‐fluoropropyl) nortropane (123I‐FP‐CIT) imaging is a diagnostic tool to help differentiate dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). However, in animals, cholinesterase inhibitors (ChEi) have been reported to reduce radioligand binding to the striatal dopamine transporter. As ChEi are frequently used in people with dementia, it is important to determine whether their use affects 123I‐FP‐CIT uptake in the striatum.
Objective
To clarify whether chronic ChEi therapy modulates striatal dopamine transporter binding measured by 123I‐FP‐CIT in patients with AD, DLB and Parkinson's disease with dementia (PDD).
Design
Cross sectional study in 99 patients with AD (nine on ChEi, 25 not on ChEi), DLB (nine on ChEi, 19 not on ChEi) and PDD (six on ChEi, 31 not on ChEi) comparing 123I‐FP‐CIT striatal binding (caudate, anterior and posterior putamen) in patients receiving compared with those not receiving ChEi, correcting for key clinical variables including diagnosis, age, sex, Mini‐Mental State Examination score, severity of parkinsonism and concurrent antidepressant use.
Results
As previously described, 123I‐FP‐CIT striatal uptake was lower in DLB and PDD subjects compared with those with AD. Median duration of ChEi use was 180 days. 123I‐FP‐CIT uptake was not significantly reduced in subjects receiving ChEi compared those not receiving ChEi (mean percentage reduction: AD 4.3%; DLB 0.7%; PDD 6.1%; p = 0.40). ChEi use did not differentially affect striatal 123FP‐CIT uptake between patient groups (p = 0.83).
Conclusions
Use of ChEi does not significantly influence the ability of 123I‐FP‐CIT imaging to distinguish AD from DLB.
doi:10.1136/jnnp.2006.111666
PMCID: PMC2117542  PMID: 17299017
8.  Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer's disease 
Background: Six cholinesterase inhibitors (ChEIs) have been tested in people with Alzheimer's disease, using methods currently required for regulatory approval. The clinical importance of their treatment effects is controversial.
Objective: To determine whether cholinesterase inhibition produces treatment effects in Alzheimer's disease that are large enough to be clinically detectable.
Methods: Overview analysis of published trials of ChEIs in which the Alzheimer's Disease Assessment Scale—Cognitive Subscale (ADAS-Cog) and a global clinical measure were primary outcomes. Two quantitative summary measures of the treatment effect (Cohen's d and the standardised response mean (SRM)) were calculated and presented as funnel plots. Observed cases analyses and intention to treat (ITT) with the last observation carried forward (LOCF) analyses were compared.
Results: The median Cohen's d effect sizes (ES) using ITT samples with LOCF for the ADAS-Cog were: low dose of a ChEI (n = 8 studies) median ES = 0.15, range = 0.03–0.22; medium dose (n = 13) median ES = 0.23, range = 0.12–0.29; high dose (n = 9) median ES = 0.28, range = 0.01–0.31. In general, the ES were larger when calculated as SRMs (for example, high dose ChEI studies, median SRM = 0.47; range = 0.30–0.63) and highest in the observed cases analyses (for example, high dose median SRM = 0.56, range = 0.35–0.78).
Global clinical scales produced similar estimates of ES (for example, high dose ChEI, ITT/LOCF median Cohen's d = 0.29, range = 0.20–0.47).
Conclusions: ChEIs produce small-moderate effect sizes in clinical trials which are reproducible and demonstrate a dose response. Better descriptions of the patterns of treatment response are needed to guide individual patient decisions about the effectiveness of treatment, but group effects are evident and appear large enough to be clinically detectable.
doi:10.1136/jnnp.2003.029074
PMCID: PMC1763555  PMID: 15090558
9.  Effects of Cholinesterase Inhibitors on Visual Attention in Drivers with Alzheimer’s Disease 
Objective
We conducted a combined observational cohort and case-control study in patients with Alzheimer’s disease (AD) to assess the effects of acetylcholinesterase inhibitor (ChEI) treatment on cognitive functions important for driving.
Methods
Performance of twenty-four outpatients with newly diagnosed (untreated) early stage AD was compared prior to beginning ChEI (Pre-ChEI) and after 3 months of therapy (Post-ChEI) on a set of computerized tests of visual attention and executive function administered under both single-task and dual-task conditions. In order to address the limitation of a lack of an untreated control group in this observational cohort study, performance of thirty-five outpatients with newly diagnosed (untreated) early stage AD (ChEI Non-Users) were also compared to a demographically-matched group of AD patients treated with stable doses of a ChEI (ChEI Users) on these tasks.
Results
Performance was consistently worse under dual-task than single-task conditions regardless of ChEI treatment status. However, ChEI treatment consistently affected specific components of attention within each test across both sets of comparisons: ChEI treatment enhanced simulated driving accuracy, and was associated with significantly better visual search target detection accuracy and response time in both Pre/Post ChEI and Users/Non-Users treatment comparisons. ChEI treatment also improved overall time to complete a set of mazes while not affecting accuracy of completion.
Conclusion
ChEI treatment was associated with improvements in tests of executive function and visual attention. These findings could have important implications for patients who continue to drive in the early stages of AD.
doi:10.1097/JCP.0b013e3181da5406
PMCID: PMC3289132  PMID: 20473058
All cognitive disorders/dementia; Alzheimer’s disease; Cholinesterase inhibitors; Attention; Driving
10.  Memantine combined with an acetyl cholinesterase inhibitor – hope for the future? 
Background
Memantine and cholinesterase inhibitors (ChEI) have distinct pharmacological actions, and interest in the use of combination therapy for Alzheimer’s disease (AD) is increasing.
Objective
To assess the available data on the use of memantine–ChEI combination and to develop evidence-based recommendations.
Method
A systematic literature review with detailed discussion of the current evidence base.
Results
Available data are limited: five studies of which two were randomized, double-blind, placebo-controlled trials. One study indicated that memantine–ChEI combination is not significantly more effective than placebo–ChEI in mild to moderate AD, but data were published in abstract and poster form only. A second study indicated that the memantine–ChEI combination is significantly more effective than placebo–ChEI in moderate to severe AD. The calculated effect sizes of 0.36 on cognition and 0.12 on function, which were the primary outcomes, were small, indicating a clinically minimal effect on cognition and no effect on function. No data are available on whether combination treatment is more effective than memantine monotherapy.
Conclusion
The available data do not justify the use of combination therapy. Future studies should include three arms (memantine–placebo, placebo–ChEI, and memantine–ChEI), be of an adequate size and duration, and use pragmatic measures. Clinicians should have full access to data from any future trials.
PMCID: PMC2671774  PMID: 19412456
memantine; cholinesterase inhibitors; combination; Alzheimer’s disease; randomised control studies; open-label studies
11.  CHRNA7 Polymorphisms and Response to Cholinesterase Inhibitors in Alzheimer's Disease 
PLoS ONE  2013;8(12):e84059.
Background
CHRNA7 encodes the α7 nicotinic acetylcholine receptor subunit, which is important to Alzheimer's disease (AD) pathogenesis and cholinergic neurotransmission. Previously, CHRNA7 polymorphisms have not been related to cholinesterase inhibitors (ChEI) response.
Methods
Mild to moderate AD patients received ChEIs were recruited from the neurology clinics of three teaching hospitals from 2007 to 2010 (n = 204). Nine haplotype-tagging single nucleotide polymorphisms of CHRNA7 were genotyped. Cognitive responders were those showing improvement in the Mini-Mental State Examination score ≧2 between baseline and 6 months after ChEI treatment.
Results
AD women carrying rs8024987 variants [GG+GC vs. CC: adjusted odds ratio (AOR) = 3.62, 95% confidence interval (CI) = 1.47–8.89] and GG haplotype in block1 (AOR = 3.34, 95% CI = 1.38–8.06) had significantly better response to ChEIs (false discovery rate <0.05). These variant carriers using galantamine were 11 times more likely to be responders than female non-carriers using donepezil or rivastigmine.
Conclusion
For the first time, this study found a significant association between CHRNA7 polymorphisms and better ChEI response. If confirmed by further studies, CHRNA7 polymorphisms may aid in predicting ChEI response and refining treatment choice.
doi:10.1371/journal.pone.0084059
PMCID: PMC3877150  PMID: 24391883
12.  Cognitive dysfunctions in schizophrenia: potential benefits of cholinesterase inhibitor adjunctive therapy 
Objective
In schizophrenia, cognitive dysfunctions commonly affect attention, memory and executive function, interfere with functional outcome and remain difficult to treat. Previous studies have implicated the cholinergic system in cognitive functioning. In Alzheimer's disease, cholinergic agonists have shown modest clinical benefits on cognitive and behavioural symptoms. Impaired cholinergic activity might also be involved in schizophrenia. Hence the role of cholinesterase inhibitors (ChEI) as adjunctive therapy is under study. We aimed to review the literature and evaluate the overall effectiveness of ChEI adjunctive therapy for the management of cognitive dysfunctions in schizophrenia.
Methods
We conducted a computer-based search using PubMed (up to February 15, 2006) and ISI Web of Science (conference proceeding abstracts from January 2003 to December 2005) databases. We used the search terms “schizophrenia,” “cognition or memory” and “tacrine or donepezil or rivastigmine or galantamine.” Studies included were critically analyzed for allocation, blindness, duration and study design, demographic data, and clinical and neuropsychological outcome assessments. We excluded studies that involved patients with psychiatric disorders other than schizophrenia-spectrum or if they involved animals or molecular investigations. We also excluded conference proceeding abstracts with no explicit neuropsychological battery and/or results.
Results
Data on ChEI as adjunctive therapy for the cognitive impairments in schizophrenia are sparse and so far derived from small samples and mostly open uncontrolled studies. ChEI's potential in long-term management has barely been documented and remains to be fully explored.
Conclusion
There is insufficient evidence on whether ChEI should be used for the treatment of cognitive dysfunctions in schizophrenia. Nevertheless, further studies with appropriate trial designs and outcome measures in homogenous schizophrenia populations are warranted.
PMCID: PMC1635800  PMID: 17136214
cholinesterase inhibitor; cognition; dementia; donepezil; schizophrenia.
13.  Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease 
Background
Patients using cholinesterase inhibitors (ChEIs) have a delay in nursing home (NH) admission compared with those who were not using the medication. There are no long-term studies of the effects of memantine in combination with ChEIs use in Alzheimer disease (AD). This study was conducted to examine the effects of ChEIs and memantine on time to death and time to NH admission.
Methods
Time to NH admission and death was examined in 943 probable AD patients who had at least a 1-year follow-up evaluation. Of these patients, 140 (14.9%) used both ChEIs and memantine, 387 (45.0%) used only ChEIs, and 416 (40.1%) used neither. The mean (SD) follow-up time was 62.3 (35.8) months. The analysis was conducted with multivariable Cox proportional hazard models controlling for critical covariates (ie, age, education level, gender, severity of the dementia, hypertension, diabetes mellitus, heart disease, psychiatric symptoms and use of psychotropic medications).
Results
Compared with those who never used cognitive enhancers, patients who used ChEIs had a significant delay in NH admission (HR: 0.37, 95% CI 0.27 to 0.49); this effect was significantly augmented with the addition of memantine (HR: 0.29, 95% CI 0.11 to 0.72) (memantine+ChEI vs ChEI alone). ChEIs alone, or in combination with memantine had no significant association on time to death.
Conclusions
This observational study revealed that the addition of the NMDA receptor antagonist memantine to the treatment of AD with ChEI significantly altered the treated history of AD by extending time to nursing home admission.
doi:10.1136/jnnp.2008.158964
PMCID: PMC2823571  PMID: 19204022
14.  Efficacy and Safety of Switching from Oral Cholinesterase Inhibitors to the Rivastigmine Transdermal Patch in Patients with Probable Alzheimer's Disease 
Background and Purpose
The goal of this study was to estimate the efficacy and safety of the rivastigmine transdermal patch in patients with probable Alzheimer's disease (AD) who cannot tolerate or do not respond to oral cholinesterase inhibitors (ChEIs).
Methods
A 24-week, prospective, open-label, single-arm, multicenter study was conducted from June 2009 to June 2010 in patients with probable AD. The enrolled patients had either a poor response or a decline in global function after treatment with oral ChEIs, or they were not able to tolerate treatment with oral ChEIs due to adverse events such as nausea or vomiting. A poor response was defined as a decrease of at least 2 points on the Korean version of the Mini-Mental State Examination (K-MMSE) within the previous 6 months (the decline in global function was determined by the investigator or caregiver). The efficacy of treatment was assessed using a follow-up Clinical Global Impression of Change (CGIC) assessment and K-MMSE conducted after 24 weeks, and safety was measured by the occurrence of adverse events and patient disposition.
Results
In total, 164 patients aged 74.7±7.52 years (mean±SD) and with 5.12±3.64 years of education were included. The study was completed by 70% of the patients (n=116), with 12.2% discontinuing due to adverse events. The most frequently reported adverse events (11%) were skin lesions, such as erythema or itching, followed by gastrointestinal problems (1.2%). Either an improvement or no decline in CGIC scores was reported for 82% of the patients.
Conclusions
The immediate switching of patients from an oral ChEI to the rivastigmine transdermal patch without a washout period was safe and well tolerated by the probable-AD patients in this study.
doi:10.3988/jcn.2011.7.3.137
PMCID: PMC3212599  PMID: 22087207
cholinesterase inhibitors; rivastigmine transdermal patch; efficacy; safety; Alzheimer's disease
15.  A Quick Test of cognitive speed is sensitive in detecting early treatment response in Alzheimer's disease 
Introduction
There is a great need for quick tests that identify treatment response in Alzheimer's disease (AD) to determine who benefits from the treatment. In this study, A Quick Test of cognitive speed (AQT) was compared with the mini-mental state examination (MMSE) in the evaluation of treatment outcome in AD.
Methods
75 patients with mild to moderate AD at a memory clinic were assessed with AQT and the MMSE at a pretreatment visit, at baseline and after 8 weeks of treatment with cholinesterase inhibitors (ChEI) initiated at baseline. Changes in the mean test scores before and after treatment were compared, as well as the number of treatment responders detected by each test, according to a reliable change index (RCI).
Results
After 8 weeks of treatment, the AQT improvement, expressed as a percentage, was significantly greater than that of the MMSE (P = 0.026). According to the RCI, the cut-offs to define a responder were ≥16 seconds improvement on AQT and ≥3 points on the MMSE after 8 weeks. With these cut-offs, both tests falsely classified ≤5% as responders during the pretreatment period. After 8 weeks of treatment, AQT detected significantly more responders than the MMSE (34% compared with 17%; P = 0.024). After 6 months of treatment, the 8-week AQT responders still showed a significantly better treatment response than the AQT nonresponders (22.3 seconds in mean difference; P < 0.001).
Conclusions
AQT detects twice as many treatment responders as the MMSE. It seems that AQT can, already after 8 weeks, identify the AD patients who will continue to benefit from ChEI treatment.
doi:10.1186/alzrt53
PMCID: PMC2983438  PMID: 20950460
16.  Longitudinal Medication Usage in Alzheimer Disease Patients 
This study examined in detail patterns of cholinesterase inhibitors (ChEIs) and memantine use and explored the relationship between patient characteristics and such use. Patients with probable Alzheimer disease AD (n = 201) were recruited from the Predictors Study in 3 academic AD centers and followed from early disease stages for up to 6 years. Random effects logistic regressions were used to examine effects of patient characteristics on ChEIs/memantine use over time. Independent variables included measures of function, cognition, comorbidities, the presence of extrapyramidal signs, psychotic symptoms, age, sex, and patient’s living situation at each interval. Control variables included assessment interval, year of study entry, and site. During a 6-year study period, rate of ChEIs use decreased (80.6% to 73.0%) whereas memantine use increased (2.0% to 45.9%). Random effects logistic regression analyses showed that ChEI use was associated with better function, no psychotic symptoms, and younger age. Memantine use was associated with better function, poorer cognition, living at home, later assessment interval, and later year of study entry. Results suggest that high rate of ChEI use and increasing memantine use over time are consistent with current practice guidelines of initiation of ChEIs in mild-to-moderate AD patients and initiation of memantine in moderate-to-severe patients.
doi:10.1097/WAD.0b013e3181e6a17a
PMCID: PMC3087865  PMID: 20625271
Alzheimer disease; cholinesterase inhibitors; memantine; longitudinal studies
17.  A longitudinal study of risk factors for community-based home help services in Alzheimer’s disease: the influence of cholinesterase inhibitor therapy 
Background
To investigate the long-term effects of cholinesterase inhibitor (ChEI) therapy and the influence of sociodemographic and clinical factors on the use of community-based home help services (HHS) by patients with Alzheimer’s disease (AD).
Methods
This 3-year, prospective, multicenter study included 880 AD patients treated with donepezil, rivastigmine, or galantamine in a routine clinical setting. At baseline and every 6 months, the patients were assessed with several rating scales, including the Mini-Mental State Examination, Instrumental Activities of Daily Living (IADL), and Physical Self-Maintenance Scale. Doses of ChEI and amounts of HHS per week were recorded. Cox regression models were used to predict the time to HHS, and multiple linear regression was used to predict the volume of HHS used.
Results
During the study, 332 patients (38%) used HHS. Factors that both postponed HHS use and predicted lower amounts of HHS were higher doses of ChEIs, better IADL ability, and living with family. Men, younger individuals, and those with a slower IADL decline showed a longer time to HHS, whereas female sex, a lower cognitive status, or more medications at baseline predicted fewer hours of HHS.
Conclusions
Higher doses of ChEI might reduce the use of HHS, possibly reducing the costs of community-based care. Female spouses provide more informal care than do male spouses, so the likelihood of using HHS is greater among women with AD. The “silent group” of more cognitively impaired and frail elderly AD patients receives less HHS, which might precipitate institutionalization.
doi:10.2147/CIA.S40087
PMCID: PMC3610439  PMID: 23682212
cognition; activities of daily living; treatment effect; gender; predictors
18.  Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis 
Background
Cholinesterase inhibitors (ChEIs) are the only drugs marketed for the treatment of Alzheimer's disease. Despite numerous randomized controlled trials, the efficacy and safety of this group of medications has not been quantified. Our objective was to quantitatively summarize data on the efficacy and safety of ChEIs in Alzheimer's disease in a format useful to clinicians.
Methods
We performed a meta-analysis of randomized, double-blind, placebo-controlled, parallel-group trials of currently marketed ChEIs (donepezil, rivastigmine and galantamine), used in therapeutic doses for at least 12 weeks, from which a cognitive outcome was reported. Studies were identified through 3 electronic databases searched to May 2002, pharmaceutical companies and journals. We extracted the proportions of subjects who responded, experienced adverse events, discontinued treatment for any reason or discontinued treatment because of adverse events.
Results
In the 16 identified trials that met the inclusion criteria, 5159 patients were treated with a ChEI and 2795 received a placebo. The pooled mean proportion of global responders to ChEI treatment in excess of that for placebo treatment was 9% (95% confidence interval [95% CI] 6%–12%). The rates of adverse events, dropout for any reason and dropout because of adverse events were also higher among the patients receiving ChEI treatment than among those receiving placebo, the excess proportions being 8% (95% CI 5%–11%), 8% (95% CI 5%–11%) and 7% (95% CI 3%–10%), respectively. The numbers needed to treat for 1 additional patient to benefit were 7 (95% CI 6–9) for stabilization or better, 12 (95% CI 9–16) for minimal improvement or better and 42 (95% CI 26–114) for marked improvement; the number needed to treat for 1 additional patient to experience an adverse event was 12 (95% CI 10–18).
Interpretation
Treatment with ChEIs results in a modest but significant therapeutic effect and modestly but significantly higher rates of adverse events and discontinuation of treatment. The numbers needed to treat to benefit 1 additional patient are small.
PMCID: PMC191283  PMID: 12975222
19.  Cholinesterase Inhibitors and Hospitalization for Bradycardia: A Population-Based Study 
PLoS Medicine  2009;6(9):e1000157.
Laura Park-Wyllie and colleagues examined the health records of more than 1.4 million older adults and show that initiation of cholinesterase inhibitor therapy is associated with a more than doubling of the risk of hospitalization for bradycardia.
Background
Cholinesterase inhibitors are commonly used to treat dementia. These drugs enhance the effects of acetylcholine, and reports suggest they may precipitate bradycardia in some patients. We aimed to examine the association between use of cholinesterase inhibitors and hospitalization for bradycardia.
Methods and Findings
We examined the health care records of more than 1.4 million older adults using a case-time-control design, allowing each individual to serve as his or her own control. Case patients were residents of Ontario, Canada, aged 67 y or older hospitalized for bradycardia between January 1, 2003 and March 31, 2008. Control patients (3∶1) were not hospitalized for bradycardia, and were matched to the corresponding case on age, sex, and a disease risk index. All patients had received cholinesterase inhibitor therapy in the 9 mo preceding the index hospitalization. We identified 1,009 community-dwelling older persons hospitalized for bradycardia within 9 mo of using a cholinesterase inhibitor. Of these, 161 cases informed the matched analysis of discordant pairs. Of these, 17 (11%) required a pacemaker during hospitalization, and six (4%) died prior to discharge. After adjusting for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor (adjusted odds ratio [OR] 2.13, 95% confidence interval [CI] 1.29–3.51). The risk was similar among individuals with pre-existing cardiac disease (adjusted OR 2.25, 95% CI 1.18–4.28) and those receiving negative chronotropic drugs (adjusted OR 2.34, 95% CI 1.16–4.71). We found no such association when we replicated the analysis using proton pump inhibitors as a neutral exposure. Despite hospitalization for bradycardia, more than half of the patients (78 of 138 cases [57%]) who survived to discharge subsequently resumed cholinesterase inhibitor therapy.
Conclusions
Among older patients, initiation of cholinesterase inhibitor therapy was associated with a more than doubling of the risk of hospitalization for bradycardia. Resumption of therapy following discharge was common, suggesting that the cardiovascular toxicity of cholinesterase inhibitors is underappreciated by clinicians.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Alzheimer disease and other forms of dementia principally affect people aged over 65. These conditions result in confusion, long term memory loss, irritability, and mood swings. As the population of developed countries ages, the prevalence of dementia is expected to increase significantly. It is forecast that the proportion of people with dementia in the US will quadruple by 2045.
A common treatment for Alzheimer disease is a class of drug called an acetylcholinesterase inhibitor or cholinesterase inhibitor. These include donepezil (brand name Aricept), rivastigmine (marketed as Exelon and Exelon Patch), and galantamine (branded Razadyne).
The benefit of taking cholinesterase inhibitors is generally small and they cannot reverse the effects of dementia. In about 50% of patients they delay the worsening of symptoms for between six months and a year, although a small number of patients may benefit more. They can have unpleasant side effects, which may include diarrhoea and muscle cramps.
Why Was This Study Done?
Existing evidence is inconclusive on whether cholinesterase inhibitors increase the risk of bradycardia, an abnormally slow resting heart rate of below 60 beats a minute, which can cause fatigue, dizziness, fainting, palpitations, shortness of breath, or death. In this paper, the authors use routinely collected health care data to investigate whether an older person taking a cholinesterase inhibitor is at increased risk of bradycardia.
What Did the Researchers Do and Find?
They began by supposing that cholinesterase inhibitors might induce bradycardia soon after a patient first began to take them. To investigate this, they obtained health care data on 1.4 million patients aged 67 or over in Ontario, Canada. They identified 161 patients who had visited a hospital for bradycardia and who had previously taken a cholinesterase inhibitor only within specific periods of time. They found that 139 had taken a cholinesterase inhibitor within the previous three months compared with 22 who had stopped taking it at least six months before.
They compared these cases with up to three “control” patients who matched each of the initial “case” group of 161 patients by age, sex, and risk of bradycardia on the basis of their general health. None of the 466 controls had visited a hospital for bradycardia by the “index date,” that is, the date of hospitalization of the case patient they matched. The researchers found 349 of the control patients had begun to take a cholinesterase inhibitor in the three months prior to the index date, compared with 117 who had stopped taking it at least six months before. A statistical analysis of these data showed that recent initiation of cholinesterase inhibitors was associated with approximately a doubling of the risk of hospitalization for bradycardia.
The authors repeated their procedure to see whether another class of drug, proton pump inhibitors, had a similar effect. As they had expected, it did not. They repeated the analysis for patients taking into account other drugs that slow the heart rate and found that their increased risk of bradycardia when taking a cholinesterase inhibitor persisted. The increase in risk was also similar in patients with pre-existing heart problems.
The researchers' data also showed that, excluding patients who while in the hospital had a pacemaker fitted to control their heart rate, over half of the patients released from hospital started taking a cholinesterase inhibitor again. Of these, a few returned to hospital with bradycardia within 100 days.
What Do These Findings Mean?
Recent guidelines suggest that doctors should not prescribe cholinesterase inhibitors for dementia patients as a matter of course, but weigh the potential risks and benefits. This paper provides evidence of an additional risk, of which at least some doctors are unaware. It was not possible to compare risk for different cholinesterase inhibitors because most patients took donepezil.
A population-based study like this cannot prove that cholinesterase inhibitors cause bradycardia. The authors used routinely collected data and so did not have information on all relevant risk factors, and thus there remains a possibility of bias due to unmeasured factors. In addition the authors had to make assumptions, for instance that patients took the drugs prescribed for them. They also considered only diagnoses of bradycardia made by a hospital doctor and not those made elsewhere, which means the incidence of bradycardia may have been underestimated. A strength of the study is the use of a case-time-control design, which has the advantage of reducing bias due to the different health conditions and lifestyle of individual patients, and also bias due to factors changing over time.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000157.
Wikipedia contains information on Alzheimer disease (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Information on bradycardia and its causes can be found in Wikipedia (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The UKs National Health Service provides information on dementia, including symptoms, causes, diagnosis, treatment, and prevention
MedlinePlus provides US-based health information (in English and Spanish)
The US National Institute on Aging provides information on health, relevant to older people, including Alzheimer Disease and dementia (in English and Spanish)
The US Alzheimers Association contains useful information on the disease, including on medication
The Public Health Agency of Canada website provides information on senior health (in English and French)
The UK-based Alzheimers Society provides advice on caring for people with dementia
doi:10.1371/journal.pmed.1000157
PMCID: PMC2742897  PMID: 19787032
20.  Long term associations between cholinesterase inhibitors and memantine use and health outcomes among patients with Alzheimer’s disease 
BACKGROUND
Randomized-controlled trials that examine the effects of Cholinesterase inhibitors (ChEI) and memantine on patient outcomes over long periods of time are difficult to conduct. Observational studies based on practice-based populations outside the context of controlled trials and open label extension studies that evaluate the effects of these medications over time are limited.
OBJECTIVES
To examine in an observational study (1) relationships between ChEI and memantine use and functional and cognitive endpoints and mortality in AD patients, (2) relationships between other patient characteristics on these clinical endpoints, and (3) whether effects of the predictors change across time.
DESIGN
Multicenter, natural history study.
SETTING
Three university-based AD centers in the US.
PARTICIPANTS
201 patients diagnosed with probable AD with modified Mini-Mental State Examination scores of 30 or higher at study entry followed annually for 6 years.
MEASUREMENTS
Discrete-time hazard analyses were used to examine relationships between ChEI and memantine use during the previous 6 months reported at each assessment and time to cognitive (Mini-Mental State Examination, MMSE≤10) and functional (Blessed Dementia Rating Scale, BDRS≥10) endpoints and mortality. Analyses controlled for clinical characteristics including baseline cognition, function, and comorbid conditions, and presence of extrapyramidal signs and psychiatric symptoms at each assessment interval. Demographic characteristics included baseline age, sex, education, and living arrangement at each assessment interval.
RESULTS
ChEI use was associated with delayed time in reaching functional endpoint and death. Memantine use was associated with delayed time to death. Different patient characteristics were associated with different clinical endpoints
CONCLUSION
Results suggest long term beneficial effects of ChEI and memantine on patient outcomes. As for all observational cohort study, observed relationships should not be interpreted as causal effects.
doi:10.1016/j.jalz.2012.09.015
PMCID: PMC3633652  PMID: 23332671
Alzheimer’s disease; cholinesterase inhibitors; memantine; outcomes; longitudinal studies
21.  Cholinesterase inhibitors may increase phosphorylated tau in Alzheimer’s disease 
Journal of neurology  2009;256(5):717-720.
Cholinesterase inhibitors (ChEIs) are widely used for the symptomatic treatment of Alzheimer’s disease (AD). In vitro and in animal studies, ChEIs have been shown to influence the processing of Aβ and the phosphorylation of tau, proteins that are the principal constituents of the plaques and neurofibrillary tangles, respectively, in AD brain. However, little is known about the effects of these drugs on Aβ and tau pathology in AD. Using avidin-biotin immunohistochemistry and computer-assisted image analysis, we compared Aβ and tau loads in the frontal and temporal cortices of 72 brains from matched cohorts of AD patients who had or had not received ChEIs. Patients treated with ChEIs had accumulated significantly more phospho-tau in their cerebral cortex than had untreated patients (P = 0.004). Aβ accumulation was reduced but not significantly. These data raise the possibility that increased tau phosphorylation may influence long-term clinical responsiveness to ChEIs.
doi:10.1007/s00415-009-5000-2
PMCID: PMC4120887  PMID: 19240967
Alzheimer’s disease; Cholinesterase inhibitors; Amyloid; Tau; Neuropathology
22.  Medication adherence and tolerability of Alzheimer’s disease medications: study protocol for a randomized controlled trial 
Trials  2013;14:125.
Background
The class of acetylcholinesterase inhibitors (ChEI), including donepezil, rivastigmine, and galantamine, have similar efficacy profiles in patients with mild to moderate Alzheimer’s disease (AD). However, few studies have evaluated adherence to these agents. We sought to prospectively capture the rates and reasons for nonadherence to ChEI and determine factors influencing tolerability and adherence.
Methods/design
We designed a pragmatic randomized clinical trial to evaluate the adherence to ChEIs among older adults with AD. Participants include AD patients receiving care within memory care practices in the greater Indianapolis area. Participants will be followed at 6-week intervals up to 18 weeks to measure the primary outcome of ChEI discontinuation and adherence rates and secondary outcomes of behavioral and psychological symptoms of dementia. The primary outcome will be assessed through two methods, a telephone interview of an informal caregiver and electronic medical record data captured from each healthcare system through a regional health information exchange. The secondary outcome will be measured by the Healthy Aging Brain Care Monitor and the Neuropsychiatric Inventory. In addition, the trial will conduct an exploratory evaluation of the pharmacogenomic signatures for the efficacy and the adverse effect responses to ChEIs. We hypothesized that patient-specific factors, including pharmacogenomics and pharmacokinetic characteristics, may influence the study outcomes.
Discussion
This pragmatic trial will engage a diverse population from multiple memory care practices to evaluate the adherence to and tolerability of ChEIs in a real world setting. Engaging participants from multiple healthcare systems connected through a health information exchange will capture valuable clinical and non-clinical influences on the patterns of utilization and tolerability of a class of medications with a high rate of discontinuation.
Trial Registration
Clinicaltrials.gov: NCT01362686
doi:10.1186/1745-6215-14-125
PMCID: PMC3764973  PMID: 23782591
Dementia; Adherence; Tolerability; Pharmacogenomics
23.  Prolonged cholinergic enrichment influences regional cortical activation in early Alzheimer’s disease 
Neuroimaging studies of cholinesterase inhibitor (ChEI) treatment in Alzheimer’s disease (AD) indicate that the short and long term actions of ChEIs are dissimilar. fMRI studies of the ChEI rivastigmine have focused on its short term action. In this exploratory study the effect of prolonged (20 weeks) rivastigmine treatment on regional brain activity was measured with fMRI in patients with mild AD. Eleven patients with probable AD and nine age-matched controls were assessed with a Pyramids and Palm Trees semantic association and an n-back working memory fMRI paradigm. In the patient group only, the assessment was repeated after 20 weeks of treatment. There was an increase in task-related brain activity after treatment with activations more like those of normal healthy elderly. Behaviorally, however, there were no significant differences between baseline and retest scores, with a range of performance probably reflecting variation in drug efficacy across patients. Variable patient response and drug dynamic/kinetic factors in small patient groups will inevitably bias (either way) the effect size of any relevant drug related changes in activation. Future studies should take drug response into account to provide more insight into the benefits of ChEI drugs at the individual level.
PMCID: PMC2518373  PMID: 18728791
fMRI; rivastigmine; treatment; dementia; Alzheimer’s disease
24.  A randomised pilot study to assess the efficacy of an interactive, multimedia tool of cognitive stimulation in Alzheimer's disease 
Objective
To determine the usefulness of an interactive multimedia internet‐based system (IMIS) for the cognitive stimulation of Alzheimer's disease.
Methods
This is a 24‐week, single‐blind, randomised pilot study conducted on 46 mildly impaired patients suspected of having Alzheimer's disease receiving stable treatment with cholinesterase inhibitors (ChEIs). The patients were divided into three groups: (1) those who received 3 weekly, 20‐min sessions of IMIS in addition to 8 h/day of an integrated psychostimulation program (IPP); (2) those who received only IPP sessions; and (3) those who received only ChEI treatment. The primary outcome measure was the Alzheimer's Disease Assessment Scale‐Cognitive (ADAS‐Cog). Secondary outcome measures were: Mini‐Mental State Examination (MMSE), Syndrom Kurztest, Boston Naming Test, Verbal Fluency, and the Rivermead Behavioral Memory Test story recall subtest.
Results
After 12 weeks, the patients treated with both IMIS and IPP had improved outcome scores on the ADAS‐Cog and MMSE, which was maintained through 24 weeks of follow‐up. The patients treated with IPP alone had better outcome than those treated with ChEIs alone, but the effects were attenuated after 24 weeks. All patients had improved scores in all of the IMIS individual tasks, attaining higher levels of difficulty in all cases.
Conclusion
Although both the IPP and IMIS improved cognition in patients with Alzheimer's disease, the IMIS program provided an improvement above and beyond that seen with IPP alone, which lasted for 24 weeks.
doi:10.1136/jnnp.2005.086074
PMCID: PMC2077529  PMID: 16820420
25.  Validity, Significance, Strengths, Limitations, and Evidentiary Value of Real-World Clinical Data for Combination Therapy in Alzheimer's Disease: Comparison of Efficacy and Effectiveness Studies 
Neuro-Degenerative Diseases  2012;10(1-4):170-174.
Background
Randomized controlled efficacy trials (RCTs), the scientific gold standard, are required for regulatory approval of Alzheimer's disease (AD) interventions, yet provide limited information regarding real-world therapeutic effectiveness. Objective: To compare the nature of evidence regarding the combination of approved AD treatments from RCTs versus long-term observational controlled studies (LTOCs).
Methods
Comparisons of strengths, limitations, and evidence level for monotherapy [cholinesterase inhibitor (ChEI) or memantine] and combination therapy (ChEI + memantine) in RCTs versus LTOCs.
Results
RCTs examined highly selected populations over months. LTOCs collected data across multiple AD stages in large populations over many years. RCTs and LTOCs show similar patterns favoring combination over monotherapy over placebo/no treatment. Long-term combination therapy compared to monotherapy reduced cognitive and functional decline and delayed time to nursing home admission. Persistent treatment was associated with slower decline. While LTOCs used control groups, adjusted for multiple covariates, had higher external validity, and favorable ethical, practical and cost considerations, their limitations included potential selection bias due to lack of placebo comparisons and randomization.
Conclusions
Naturalistic LTOCs provide complementary long-term level II evidence to complement level I evidence from short-term RCTs regarding therapeutic effectiveness in AD that may otherwise be unobtainable. A coordinated strategy/consortium to pool LTOC data from multiple centers to estimate long-term comparative effectiveness, risks/benefits, and costs of AD treatments is needed.
doi:10.1159/000335156
PMCID: PMC3702018  PMID: 22327239
Comparative effectiveness; Evidence grade; Dementia treatment; Donepezil; Galantamine; Rivastigmine; Memantine; Observational trial

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