Cholinesterase Inhibitors In Patients Research Articles

Testing Van Gool’s Hypothesis: A Method to Predict Side Effects of Cholinesterase Inhibitors in Patients with Cellular Degenerative and Vascular Dementia

This study investigates a method to predict medical outcome of cholinesterase inhibitors in patients with Alzheimer’s disease (AD) and vascular dementia (VaD). Van Gool predicts that patients with cholinergic deficit symptoms will benefit from treatment whereas patients without will experience side effects because of overstimulation of the cholinergic system. We predicted that AD and VaD patients with a longer RT experience fewer side effects than patients with a faster response and that VaD patients have a longer RT than AD patients. A number of 71 patients with AD or VaD diagnosis were included. A sustained attention task was administered, as well as the MMSE and a questionnaire about side effects. Results indicated that VaD patients with a longer RT reported fewer side effects. Furthermore, patients with VaD had a longer RT than patients with AD. MMSE was negatively correlated with RT in the VaD group. Thus, the performance on the attention task seems associated with suffering from side effects and thus tends to predict medical outcome in VaD, but not in AD. Perhaps this attention task was not sensitive enough to measure cholinergic deficit symptoms in AD patients. Furthermore, different doses of medication might confound the effect for the AD group.

Effect of APOE and CHRNA7 genotypes on the cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease.

The loss of cholinergic transmission is considered to be an important cause of Alzheimer's disease (AD). Treatment with acetyl cholinesterase inhibitors (ChEIs) shows benefits; however, great heterogeneity has been observed in patient responses. We evaluated apolipoprotein E (APOE) and α7 nicotinic receptor (CHRNA7) single-nucleotide polymorphisms (SNPs) and associated these SNPs with pharmacological responses to ChEIs in a Brazilian population with AD. We studied 177 outpatients using ChEIs, and they were classified as responders and nonresponders according to variation in Mini-Mental State Examination (MMSE) status. The analysis of APOE genotypes showed that patients with the ε4 allele had a worse response than those without the ε4 allele. We observed an association between the CHRNA7 T allele and a better response to treatment with ChEIs in patients with mild AD (MMSE ≥ 20). The SNP rs6494223 of CHRNA7 as well as APOEε4 could be useful for understanding the response to ChEI treatment in patients with AD.

The effect of APOE ε4 allele on cholinesterase inhibitors in patients with Alzheimer disease: evaluation of the feasibility of resting state functional connectivity magnetic resonance imaging.

This work is to determine whether apolipoprotein E (APOE) genotype modulates the effect of cholinesterase inhibitor (ChEI) treatment on resting state functional connectivity magnetic resonance imaging (rs-fcMRI) in patients with Alzheimer disease (AD). We retrospectively studied very mild and mild AD participants who were treated (N=25) or untreated (N=19) with ChEIs with respect to rs-fcMRI measure of 5 resting state networks (RSNs): default mode, dorsal attention (DAN), control (CON), salience (SAL), and sensory motor. For each network, a composite score was computed as the mean of Pearson correlations between pairwise time courses extracted from areas comprising this network. The composite scores were analyzed as a function of ChEI treatment and APOE ε4 allele. Across all participants, significant interactions between ChEI treatment and APOE ε4 allele were observed for all 5 RSNs. Within APOE ε4 carriers, significantly greater composite scores were observed in the DAN, CON, and SAL for treated compared with untreated participants. Within APOE ε4 noncarriers, treated and untreated participants did not have significantly different composite scores for all RSNs. These data suggest that APOE genotype affects the response to ChEI using rs-fcMRI. Rs-fcMRI may be useful for assessing the therapeutic effect of medications in AD clinical trials.

Cholinesterase inhibitors for co-morbid Alzhemer’s disease dementia and schizophrenia: Systematic review and meta-analysis

Cholinergic dysfunction is common to Alzheimer’s dementia and Schizophrenia. The objective of this study is to undertake a systematic review and meta-analysis of the literature on the cognitive and clinical effects of cholinesterase inhibitors administered to patients with schizophrenia and co-morbid Alzheimer’s disease dementia. A literature search of the MEDLINE, CINAHL, PubMed, PsycINFO, EMBASE, AMED, BNI, HMIC and Health Business Elite databases has been performed (up to January 2013) to investigate the use of cholinesterase inhibitors in patients with schizophrenia and dementia. The terms “schizophrenia”, “dementia”, “rivastigmine”, “donepezil”, “galantamine” and “cognitive deficit” have been searched, with a restriction for English language. Five published studies including 1 RCT have been included for the qualitative review. Treatments include Donepezil 5 mg and 10 mg as well as Rivastigmine 9 mg. The numbers of participants vary from 2 incase report to20 inthe RCT. Only 1 study qualifies for meta-analysis. There is a very limited evidence on the efficacy and safety of using acetylcholinesterase inhibitors in the management of dementia co-morbid with schizophrenia. The only randomised controlled study shows lack of evidence in terms of efficacy in using cholinesterase inhibitors in the management of dementia with schizophrenia. Future research projects will have to look at an adequate sample size to explore treatment on various cognitive and noncognitive domains and the sample should be selected by using definitive and internationally acceptable diagnostic criteria.

Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson's disease dementia and cognitive impairment in Parkinson's disease

Previous Cochrane reviews have considered the use of cholinesterase inhibitors in both Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). The clinical features of DLB and PDD have much in common and are distinguished primarily on the basis of whether or not parkinsonism precedes dementia by more than a year. Patients with both conditions have particularly severe deficits in cortical levels of the neurotransmitter acetylcholine. Therefore, blocking its breakdown using cholinesterase inhibitors may lead to clinical improvement. To assess the efficacy, safety and tolerability of cholinesterase inhibitors in dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), and cognitive impairment in Parkinson's disease falling short of dementia (CIND-PD) (considered as separate phenomena and also grouped together as Lewy body disease). The trials were identified from a search of ALOIS, the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group (on 30 August 2011) using the search terms Lewy, Parkinson, PDD, DLB, LBD. This register consists of records from major healthcare databases (MEDLINE, EMBASE, PsycINFO, CINAHL) and many ongoing trial databases and is updated regularly.Reference lists of relevant studies were searched for additional trials. Randomised, double-blind, placebo-controlled trials assessing the efficacy of treatment with cholinesterase inhibitors in DLB, PDD and cognitive impairment in Parkinson's disease (CIND-PD). Data were extracted from published reports by one review author (MR). The data for each 'condition' (that is DLB, PDD or CIND-PD) were considered separately and, where possible, also pooled together. Statistical analysis was conducted using Review Manager version 5.0. Six trials met the inclusion criteria for this review, in which a total of 1236 participants were randomised. Four of the trials were of a parallel group design and two cross-over trials were included. Four of the trials included participants with a diagnosis of Parkinson's disease with dementia (Aarsland 2002a; Dubois 2007; Emre 2004; Ravina 2005), of which Dubois 2007 remains unpublished. Leroi 2004 included patients with cognitive impairment and Parkinson's disease (both with and without dementia). Patients with dementia with Lewy bodies (DLB) were included in only one of the trials (McKeith 2000).For global assessment, three trials comparing cholinesterase inhibitor treatment to placebo in PDD (Aarsland 2002a; Emre 2004; Ravina 2005) reported a difference in the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) score of -0.38, favouring the cholinesterase inhibitors (95% CI -0.56 to -0.24, P < 0.0001).For cognitive function, a pooled estimate of the effect of cholinesterase inhibitors on cognitive function measures was consistent with the presence of a therapeutic benefit (standardised mean difference (SMD) -0.34, 95% CI -0.46 to -0.23, P < 0.00001). There was evidence of a positive effect of cholinesterase inhibitors on the Mini-Mental State Examination (MMSE) in patients with PDD (WMD 1.09, 95% CI 0.45 to 1.73, P = 0.0008) and in the single PDD and CIND-PD trial (WMD 1.05, 95% CI 0.42 to 1.68, P = 0.01) but not in the single DLB trial.For behavioural disturbance, analysis of the pooled continuous data relating to behavioural disturbance rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.36 to -0.04, P = 0.01).For activities of daily living, combined data for the ADCS and the Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.38 to -0.02, P = 0.03).For safety and tolerability, those taking a cholinesterase inhibitor were more likely to experience an adverse event (318/452 versus 668/842; odds ratio (OR) 1.64, 95% CI 1.26 to 2.15, P = 0.0003) and to drop out (128/465 versus 45/279; OR 1.94, 95% CI 1.33 to 2.84, P = 0.0006). Adverse events were more common amongst those taking rivastigmine (357/421 versus 173/240; OR 2.28, 95% CI 1.53 to 3.38, P < 0.0001) but not those taking donepezil (311/421 versus 145/212; OR 1.24, 95% CI 0.86 to 1.80, P = 0.25). Parkinsonian symptoms in particular tremor (64/739 versus 12/352; OR 2.71, 95% CI 1.44 to 5.09, P = 0.002), but not falls (P = 0.39), were reported more commonly in the treatment group but this did not have a significant impact on the UPDRS (total and motor) scores (P = 0.71). Fewer deaths occurred in the treatment group than in the placebo group (4/465 versus 9/279; OR 0.28, 95% CI 0.09 to 0.84, P = 0.03). The currently available evidence supports the use of cholinesterase inhibitors in patients with PDD, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales. The effect in DLB remains unclear. There is no current disaggregated evidence to support their use in CIND-PD.

Impact of geriatric comorbidity and polypharmacy on cholinesterase inhibitors prescribing in dementia.

BackgroundAlthough most guidelines recommend the use of cholinesterase inhibitors (ChEIs) for mild to moderate Alzheimer's Disease, only a small proportion of affected patients receive these drugs. We aimed to study if geriatric comorbidity and polypharmacy influence the prescription of ChEIs in patients with dementia in Germany.MethodsWe used claims data of 1,848 incident patients with dementia aged 65 years and older. Inclusion criteria were first outpatient diagnoses for dementia in at least three of four consecutive quarters (incidence year). Our dependent variable was the prescription of at least one ChEI in the incidence year. Main independent variables were polypharmacy (defined as the number of prescribed medications categorized into quartiles) and measures of geriatric comorbidity (levels of care dependency and 14 symptom complexes characterizing geriatric patients). Data were analyzed by multivariate logistic regression.ResultsOn average, patients were 78.7 years old (47.6% female) and received 9.7 different medications (interquartile range: 6-13). 44.4% were assigned to one of three care levels and virtually all patients (92.0%) had at least one symptom complex characterizing geriatric patients. 13.0% received at least one ChEI within the incidence year. Patients not assigned to the highest care level were more likely to receive a prescription (e.g., no level of care dependency vs. level 3: adjusted Odds Ratio [OR]: 5.35; 95% CI: 1.61-17.81). The chance decreased with increasing numbers of symptoms characterizing geriatric patients (e.g., 0 vs. 5+ geriatric complexes: OR: 4.23; 95% CI: 2.06-8.69). The overall number of prescribed medications had no influence on ChEI prescription and a significant effect of age could only be found in the univariate analysis. Living in a rural compared to an urban environment and contacts to neurologists or psychiatrists were associated with a significant increase in the likelihood of receiving ChEIs in the multivariate analysis.ConclusionsIt seems that not age as such but the overall clinical condition of a patient including care dependency and geriatric comorbidities influences the process of decision making on prescription of ChEIs.

Mania After Administration of Cholinesterase Inhibitors in Patients With Dementia and Comorbid Bipolar Disorder

1Department of Geriatric Psychiatry, Salus gGmbH Psychiatric Clinic, Bernburg, Germany 2Department for Old Age Psychiatry, Psychiatric Clinic, Stavanger University Hospital, Stavanger, Norway [email protected]

Clinical Efficacy of Aniracetam, Either as Monotherapy or Combined with Cholinesterase Inhibitors, in Patients with Cognitive Impairment: A Comparative Open Study*

Dementia constitutes an increasingly prevalent cognitive disorder with serious socioeconomic implications. In the present study, we aimed to evaluate the efficacy of aniracetam, either as monotherapy or combined with cholinesterase inhibitors (ChEIs), in terms of several neuropsychological parameters, in a considerable number of patients with dementia. In our prospective, open-label study, we enrolled a total of 276 patients (mean age 71 ± 8 years, 95 males) with cognitive disorders. Our study population comprised four groups: no treatment group (n = 75), aniracetam monotherapy group (n = 58), ChEIs monotherapy group (n = 68), and group of combined treatment (n = 68). Patients were examined with validated neuropsychological tests at baseline, 3, 6, and 12 months of treatment. In patients treated with aniracetam, all studied parameters were adequately maintained at 6 and 12 months, while emotional state was significantly improved at 3 months. In patients treated with ChEIs, we observed a significant cognitive deterioration at 12 months. The comparison between aniracetam and ChEIs in patients with relatively mild dementia (15 ≤ MMSE ≤ 25) revealed a significantly better cognitive performance with aniracetam at 6 months and improved functionality at 3 months. Comparing aniracetam monotherapy with combined treatment in the same population, aniracetam performed better in the cognitive scale at 6 months, and displayed a notable tendency for enhanced mood at 12 months and improved functionality at 6 months. Our findings indicate that aniracetam (a nootropic compound with glutamatergic activity and neuroprotective potential) is a promising option for patients with cognitive deficit of mild severity. It preserved all neuropsychological parameters for at least 12 months, and seemed to exert a favorable effect on emotional stability of demented patients.

Cardio‐vascular safety of acetyl cholinesterase inhibitors in patients suffering from Alzheimer's disease; factors that predict poor tolerability

Cardio‐vascular safety of acetyl cholinesterase inhibitors in patients suffering from Alzheimer's disease; factors that predict poor tolerability

Cholinesterase Inhibitors as Adjunctive Therapy in Patients with Schizophrenia and Schizoaffective Disorder

Cognitive deficits have been described in patients with schizophrenia from the first descriptions of dementia praecox to current concepts of cognitive dysmetria. Nevertheless, little is known about how to deal with them. In Alzheimer disease, cholinergic deficit is found and cholinesterase inhibitors have been used to delay the progression of memory and cognitive dysfunction. Several lines of evidence suggest that the cholinergic system may be disrupted in schizophrenia. To evaluate cognitive and clinical effects of adjunctive cholinesterase inhibitors in patients with schizophrenia and schizoaffective disorder. We conducted a literature search on PubMed and EMBASE (up to December 2008) for articles that investigated adjunctive cholinesterase inhibitors in patients with schizophrenia. The terms 'schizophrenia', 'acetylcholinesterase inhibitors', 'rivastigmine', 'donepezil', 'galantamine' and 'cognitive deficit' were searched with restriction for English language and without a year limit. All articles that presented original data from randomized, double-blind, placebo-controlled trials with donepezil, rivastigmine or galantamine in patients with schizophrenia or schizoaffective disorder were included in the meta-analysis. Studies were excluded for the following reasons: (i) case study/letter/correspondence/review; (ii) animal study; (iii) molecular/genetic investigation; and (iv) inclusion of patients with schizophrenia and co-morbid dementia. Few appropriate data for meta-analysis were found because of the large heterogeneity of the assessment instruments used. Nevertheless, effects of cholinesterase inhibitors in some cognitive domains (executive function, memory and language), psychopathology (using the Positive and Negative Syndrome Scale) and extrapyramidal symptoms could be analysed. Six open-label and 24 double-blind studies were found. In five open-label studies there was an improvement in memory, attention and executive functions. Thirteen double-blind studies (four with rivastigmine, six with donepezil and three with galantamine) contributed to the meta-analysis. Significant improvement was found in this analysis for memory and the Trail Making test part A. The reviewed studies suggest that specific cognitive deficits (memory, and the motor speed and attention part of executive function) of patients with schizophrenia and schizoaffective disorder are responsive to rivastigmine, donepezil and galantamine as adjunctive therapy. Confirmatory studies are needed to determine the clinical utility of this treatment strategy.

Carotid Intima-Media Thickness as a Predictor of Response to Cholinesterase Inhibitors in Alzheimerʼs Disease

Cholinesterase inhibitors are modestly effective in treating patients with Alzheimer's disease. However, there may be important inter-individual variations ranging from no improvement at all to significant improvement and long periods of stabilization. Carotid atherosclerosis is associated with cognitive decline in elderly people. The objective of this study was to investigate whether carotid intima-media thickness (IMT) predicts response to cholinesterase inhibitors in Alzheimer's disease. A series of 54 patients with mild to moderate Alzheimer's disease were enrolled consecutively in an open-label trial. At baseline, all patients were assessed on the following clinical scales: Mini-Mental State Examination, Clinical Dementia Rating, the Hachinski Ischemic Scale, Blessed Dementia Rating Scale, Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Neuropsychiatric Inventory (NPI) and a daily-living activities scale (Disability Assessment for Dementia [DAD]). Investigations included magnetic resonance imaging of the brain and a colour echo-Doppler scan of the carotid arteries to measure the maximum IMT. Patients were then commenced on galantamine treatment for 6 months, after which scores on the ADAS-cog, NPI and DAD scales were reassessed. A total of 50 patients completed the study. Their mean age was 77.78 years (SD 6.51 years); 34 patients were female. Galantamine treatment decreased the mean NPI score from 17.68 to 13.86 points, but this difference was not statistically significant (p=0.07). On the ADAS-cog scale, a modest and nonsignificant mean difference of -0.4 points (p=0.7) was observed. A weak (correlation coefficient r=0.4) but significant correlation between IMT and changes in clinical scale score was found, with low carotid IMT being shown to be a predictor of response on both the ADAS-cog (p=0.003) and NPI (p=0.006) scales; these findings were corroborated in multivariate analysis. For men, the correlation was stronger (r=0.7 and 0.8 for the ADAS-cog and NPI scales, respectively). Although the magnitude of effect was moderate, carotid IMT could be a significant predictor of clinical response to cholinesterase inhibitors in patients with Alzheimer's disease.

An Observational Study of the Needs and Quality of Life Amongst Patients in the Treatment of Alzheimers Dementia with Cholinesterase Inhibitors

Alzheimer's dementia is one of the most commost mental health disorders associated with aging. In its earlier stages sufferers live independently but gradually rely increasingly on loved ones or formal carers for support as the illness progresses. Its treatment involves both medical and social care. This study assesses the impact of outpatients' care and cholinesterase inhibitors in patients being treated for Alzheimer's dementia. The needs and quality of life of patients attending an outpatients dementia care service were assessed using the Camberwell Assessment of Need for the Elderly (CANE) and Quality of Life in Alzheimer's Disease: Patient and Caregiver report. Other tools used were the Problems Checklist and Carer Strain, the Minimental State Examination (MMSE) and a proforma to obtain sociodemographic details. All patients who had informal care were assessed using the questionnaires. 104 patients were seen of whom 34 were new and 70 were follow-up patients. 43 patients lived alone while the rest lived with their spouses or other relatives such as children. There was reduction in the number of CANE unmet needs and increased combined Quality of Life in Alzheimer's Dementia scores in the first three months amongst the newly referred patients. The findings suggest that outpatients' dementia care and prescribing of cholinesterase inhibitors helped to meet the needs of patients and improve patients' quality of life in first three months.

Standardized low-resolution brain electromagnetic tomography (sLORETA) in the prediction of response to cholinesterase inhibitors in patients with Alzheimer's disease

Materials and methods Resting EEG was recorded in 20 mild to moderate AD patients (mean age= 75.04 years; 13 women and 7 men; MMSE 15-24) before and after 6 months and 2 years on ChEI (donepezil, rivastigmine, galantamine) treatment. Based on changes of MMSE scores after 2 years follow-up, 11 patients were classified as Non-responders (decrease of MMSE > 2) and 9 patients as Responders (decrease of MMSE < 2). The localization of the differences in activity between two groups (at baseline) and within groups (baseline vs. 6 months) was assessed by voxel-by-voxel ttests of the sLORETA images of the log-transformed computed current density power in seven frequency bands.

Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL

Cholinergic deficits might contribute to vascular cognitive impairment. Trials of cholinesterase inhibitors in patients with vascular dementia are difficult because of heterogeneous disease mechanisms and overlap between vascular and Alzheimer's disease (AD) pathology in the age-group recruited. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a genetic form of subcortical ischaemic vascular dementia. It represents a homogeneous disease process, and because of CADASIL's early onset, comorbid AD pathology is rare. We did a multicentre, 18-week, placebo-controlled, double-blind, randomised parallel-group trial to determine whether the cholinesterase inhibitor donepezil improves cognition in patients with CADASIL. 168 patients with CADASIL (mean age 54.8 years) were assigned to 10 mg donepezil per day (n=86) or placebo (n=82) by a computer-generated randomisation protocol. Inclusion criteria included a mini-mental state examination (MMSE) score of 10-27 or a trail making test (TMT) B time score at least 1.5 SD below the mean, after adjustment for age and education. The primary endpoint was change from baseline in the score on the vascular AD assessment scale cognitive subscale (V-ADAS-cog) at 18 weeks. Secondary endpoints included scores on the ADAS-cog, MMSE, TMT A time and B time, Stroop, executive interview-25 (EXIT25), CLOX, disability assessment for dementia, and sum of boxes of the clinical dementia rating scale. Analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00103948. 161 patients were analysed. There was no significant difference between donepezil (n=84) and placebo (n=77) in the primary endpoint. The least-squares mean change from baseline score was -0.81 (SE 0.59) in the placebo group and -0.85 (SE 0.57) in the donepezil group (p=0.956). There was a significant treatment effect favouring donepezil on the following secondary outcomes: TMT B time (p=0.023), TMT A time (p=0.015), and EXIT25 (p=0.022). Ten donepezil-treated patients discontinued treatment due to adverse events compared to seven placebo-treated patients. Donepezil had no effect on the primary endpoint, the V-ADAS-cog score in CADASIL patients with cognitive impairment. Improvements were noted on several measures of executive function, but the clinical relevance of these findings is not clear. Our findings may have implications for future trial design in subcortical vascular cognitive impairment.

Cholinergic balance in dementia with Lewy bodies: reversible worsening of Parkinsonism at rivastigmine dosage modulation

We describe a patient with probable dementia with Lewy bodies (DLB) whose Parkinsonism worsened after administration of rivastigmine within the therapeutic dose range. Some extrapyramidal signs (EPS) then reversed to pre-treatment level after rivastigmine dose reduction. We draw attention to the need of EPS monitoring during titration of cholinesterase inhibitors in patients with DLB. This is the first report to our knowledge of iatrogenic worsening of Parkinsonism which was successfully managed by dose reduction.

A randomised double‐blind placebo‐controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer's disease

(1) to assess the effect of 1 mg folic acid supplementation of cholinesterase inhibitors (ChI) in a 6 month double-blind placebo-controlled study of patients with Alzheimer's Disease (AD) and (2) to assess whether outcome measures were affected by changes in homocysteine levels. Fifty-seven consecutive outpatients with probable AD were treated concurrently with a ChI and either folic acid or placebo. None had conditions or medication known to interfere with folate metabolism. Fasting folate and homocysteine levels were measured prior to commencing ChI and 6 months later. Response was categorised using criteria of the National Institute of Clinical Excellence (NICE). Twelve males and 29 females completed treatment (mean age 76.27 SD 6.23 years, Mini-Mental State Examination (MMSE) 23.49 SD 3.53, baseline homocysteine 18.39 SD 4.62 micromoles per litre). 23 received folic acid and 18 placebo. There were no significant baseline differences or use of individual ChI between the two arms. After 6 months a significant difference was seen in the change from baseline in combined Instrumental Activities of Daily Living and Social Behaviour scores between arms (folate+1.50 (SD 5.32) vs placebo -2.29 (SD 6.16) (p=0.03) but not change in MMSE scores. Sixteen of 23 subjects receiving folic acid and 7/18 placebo subjects were classified as NICE responders (p=0.05). This pilot double blind study suggests that response to ChI in patients with AD may be improved by the use of folic acid. The relationship between any change in homocysteine levels and response to treatment is discussed.

Treatment Guidelines for Alzheimer's Disease

Current treatment guidelines for Alzheimer's disease (AD) do not reflect more recently collected data on therapeutic outcomes other than cognitive function and memory, and this has led to a limited understanding of the value of drug therapy in AD. To evaluate the need to revise treatment guidelines for AD, to review data that have become available since the publication of current guidelines, and to communicate how existing guidelines and relevant new data can be valuable to the primary care provider who assesses and treats patients with AD. A MEDLINE search was conducted to identify existing treatment guidelines using the MeSH headings Alzheimer disease-drug therapy AND practice guidelines. The alternative terms treatment guidelines, practice parameter, and practice recommendation were also searched in conjunction with the MeSH term Alzheimer disease-drug therapy. Additionally, MEDLINE was searched using the term dementia and publication type "practice guideline." All searches were limited to articles published within the last 10 years, in English. A total of 116 articles were identified by these searches. Additional publications were identified by manually searching the reference lists of these articles and of published clinical trials of AD therapies. Current AD treatment guidelines and clinical trial results for AD treatment options were extracted, reviewed, and summarized to meet the objectives of this article. Current guidelines support the use of cholinesterase inhibitors in patients with mild to moderate AD. More recent clinical research indicates that cholinesterase inhibitor treatment provides effectiveness across a wide range of dementia severity and multiple symptom domains. These medications also significantly decrease caregiver burden and may lower the risk for nursing home placement. The expanding literature on AD medications suggests that treatment guidelines need to be reexamined. Recent data emphasize preservation of abilities and delay of adverse outcomes in AD patients rather than short-term improvements in cognitive test scores. Treatment appears to provide the greatest benefit when it is initiated early in the course of the disease and maintained over the long term. Revised treatment guidelines should address newer medications and more recent outcomes considerations, as well as provide guidance on how long to continue and when to discontinue pharmacotherapy for AD.

Effect of cerebral white matter changes on clinical response to cholinesterase inhibitors in dementia

Background:Cerebral white matter changes (WMC) represent cerebrovascular disease (CVD) and are common in dementia. Cholinesterase inhibitors (ChEIs) are effective in Alzheimer's Disease (AD) with or without CVD, and in Dementia with Lewy Bodies/Parkinson's Disease Dementia (DLB/PDD). Predictors of treatment response are controversial.Objective:To investigate the effect of WMC severity on response to ChEIs in dementia.Method:CT or MRI brain scans were rated for WMC severity in 243 patients taking ChEIs for dementia. Raters were blind to patients' clinical risk factors, dementia subtype and course of illness. Effects of WMC severity on rates of decline in cognition, function and behaviour were analysed for 140 patients treated for nine months or longer. Analysis was performed for this group as a whole and within diagnostic subgroups AD and DLB/PDD. The main outcome measure was rate of change in Mini Mental State Examination (MMSE) score. Secondary measures were rates of change in scores on the Cambridge Cognitive Examination (CAMCOG), Instrumental Activities of Daily Living (IADL) and Clifton Assessment Procedures for the Elderly – Behaviour Rating Scale (CAPE-BRS).Results:There was no significant correlation between severity of WMC and any specified outcome variable for the cohort as a whole or for patients with AD. In patients with DLB/PDD, higher WMC scores were associated with more rapid cognitive decline.Conclusions:Increased WMC severity does not predict response to ChEIs in AD, but may weaken response to ChEIs in patients with DLB/PDD.

Is pharmacotherapy feasible for mild cognitive impairment?

AbstractThe feasibility of pharmacotherapy with cholinesterase inhibitors, which have been approved as the treatment agent for Alzheimer's disease (AD), for mild cognitive impairment (MCI) is discussed together with the results of previous studies. The clinical trials of cholinesterase inhibitors in patients with early or mild AD are reviewed first, because some cases of MCI may be regarded as cases of very early‐stage AD or very mild AD. Clinical trials for MCI treatment are then analyzed, although only preliminary results of data analysis have been reported. In addition, the methodological issues in the clinical trials for MCI treatment are discussed. The author points out that there should be focus on the observation period of trials, patient inclusion and exclusion criteria and subtypes of MCI, and that the suitability of cognitive measurements need to be further discussed.

Pharmacological treatment of behavioural problems in dementia

Dementia is commonly associated with distressing behavioural problems that warrant intervention. A general medical assessment of the patient is needed before assessing whether specific treatment is required. Both non-pharmacological and pharmacological interventions can be considered. The best available evidence is for the use of low-dose antipsychotic medication in patients with agitated or aggressive behaviour with or without associated psychotic symptoms. There is less evidence to support the use of antidepressants, anticonvulsants and cholinesterase inhibitors in patients whose dementia is complicated by behavioural problems. When psychotropic medication is prescribed to people with dementia, it should be regularly reviewed with a view to stopping it or assessing the patient after a trial off the medication.