Cholinesterase Inhibitors In Dementia Research Articles

Therapeutic use of cannabinoids for the treatment of neurodegenerative disorders: a potential breakthrough.

Respected Editor, Marijuana, also known as cannabis, is a plant-based illicit drug notorious for its recreational purposes. However, in recent years its extracts are being extensively studied for their overall therapeutic effects. Active substances found in marijuana that interact with the endocannabinoid system are known as cannabinoids, the primary examples being 9-tetrahydrocannabinol (9-THC) and Cannabidiol (CBD). These cannabinoids ligand to receptors such as CB1 (found in CNS) and CB2 (found in immune system cells) to prevent the release of neurotransmitters and modulate immune cell migration as well as cytokine release, respectively (1). In recent years, there has been a surge of interest in the neuroprotective potential of marijuana; however, investigators could not make firm conclusions about the effectiveness of these treatments. A comprehensive review by Bahji A et al. (2022) found an evident link between cannabidiol-based products and relief from the motor as well as behavioural and psychological symptoms spanning Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD) (2). Here we discuss the effects of marijuana and its derivatives on the treating significant neurodegenerative disorders. Dronabinol (2.5 mg) seemed to lessen the disordered behaviours as assessed by the Cohen-Mansfield Agitation Inventory in 12 patients of AD (p=0.05) (3). Sherman et al. (2018) reported the association of cannabis administration with weight and pain management in AD patients. The adverse effects are typically well tolerated at the levels supplied, even though cannabis is linked to an increased risk of euphoria, sleepiness and psychosis (1). On the other hand, for HD, nabilone (1 or 2 mg) had a substantial therapeutic benefit in a different 10-week placebo-controlled crossover experiment as determined by the overall motor and chorea score on the Unified Huntington's Disease Rating Scale (UHDRS) (4). Available reviews revealed variable evidence suggesting the clinical benefits of cannabis in treating motor symptoms in patients with PD. A randomized trial found that compared to a placebo, giving a single dosage of 300 mg of CBD successfully decreased tremor amplitude (5). Neurological diseases, including the neurodegenerative diseases, comprise 8.7% of the disease burden in lower- middle- income countries (such as Pakistan) (6). Currently, there is no real cure for neurodegenerative disorders, only symptomatic management, such as dopamine treatment for PD or cholinesterase inhibitors for dementia. Cannabinoids might be the lifeline all neurodegenerative disorder patients have been waiting for. ---Continue

Risk of overactive bladder associated with cholinesterase inhibitors in dementia

Although cholinesterase inhibitors (ChEIs) are the primary treatment for dementia, they are associated with overactive bladder (OAB), necessitating antimuscarinic use. Limited data exist regarding the risk of OAB across individual ChEIs in dementia. This study evaluated the risk of OAB associated with individual ChEIs in older adults with dementia. This was a new user retrospective cohort study using Medicare claims data involving Parts A, B, and D claims dataset from 2013 to 2015. The study included older adults (aged 65 and older) with a diagnosis of dementia using donepezil, galantamine, or rivastigmine. New ChEI claims were identified with a 6-month baseline washout period. Patients with OAB diagnosis or any antimuscarinic or mirabegron use in the baseline period were excluded. The primary outcome of interest was OAB diagnosis or prescription of antimuscarinics or mirabegron within 6 months of ChEI initiation. Multivariable cox proportional hazards regression with propensity scores (PS) as covariates and inverse probability of treatment weighting generated using generalized boosted models was used to assess the risk of OAB among donepezil, galantamine, and rivastigmine users. The study included 524,975 older adults with dementia who were incident users of ChEIs (donepezil 80.72%, rivastigmine 16.41%, galantamine 2.87%). Overall, OAB diagnosis/antimuscarinic/mirabegron prescription was observed in 5.07% of the cohort within 6 months of ChEIs prescription. The Cox regression model with PS as covariate approach found that donepezil use increased the risk of OAB compared to rivastigmine (aHR, 1.13; 95% CI, 1.08-1.28; p < 0.0001). However, there was no differential risk of OAB between galantamine and rivastigmine. The findings were consistent with the generalized boosted models. The study found that the risk of OAB varies across individual ChEIs with an increased risk of OAB with donepezil compared to rivastigmine. The study findings suggest the need to understand and manage medication-related morbidity in older adults with dementia.

Assessing capacity to consent to treatment with cholinesterase inhibitors in dementia using a specific and standardized version of the MacArthur Competence Assessment Tool (MacCAT-T).

The use of assessment tools has been shown to improve the inter-rater reliability of capacity assessments. However, instrument-based capacity assessments of people with dementia face challenges. In dementia research, measuring capacity with instruments like the MacArthur Competence Assessment Tool for Treatment (MacCAT-T) mostly employ hypothetical treatment vignettes that can overwhelm the abstraction capabilities of people with dementia and are thus not always suitable for this target group. The primary aim of this study was to provide a standardized real informed consent paradigm that enables the dementia-specific properties of capacity to consent to treatment in people with dementia to be identified in a real informed consent process that is both externally valid and ethically justifiable. The sample consisted of 53 people with mild to moderate dementia and a group of 133 people without cognitive impairment. Rather than using a hypothetical treatment vignette, we used a standardized version of the MacCAT-T to assess capacity to consent to treatment with cholinesterase inhibitors in people with dementia. Inter-rater reliability, item statistics, and psychometric properties were also investigated. Intraclass correlations (ICCs) (0.951-0.990) indicated high inter-rater reliability of the standardized real informed consent paradigm. In the dementia group, performance on different items of the MacCAT-T varied. Most people with dementia were able to express a treatment choice, and were aware of the need to take a tablet. Further information on the course of the disorder and the benefits and risks of the treatment were less understood, as was comparative reasoning regarding treatment alternatives. The standardized real informed consent paradigm enabled us to detect dementia-specific characteristics of patients' capacity to consent to treatment with cholinesterase inhibitors. In order to determine suitable enhanced consent procedures for this treatment, we recommend the consideration of MacCAT-T results on an item level. People with dementia seem to understand only basic information. Our data indicate that one useful strategy to enhance capacity to consent is to reduce attention and memory demands as far as possible.

Adverse Effects of Cholinesterase Inhibitors in Dementia, According to the Pharmacovigilance Databases of the United-States and Canada.

This survey analyzes two national pharmacovigilance databases in order to determine the major adverse reactions observed with the use of cholinesterase inhibitors in dementia. We conducted a statistical analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) and the Canada Vigilance Adverse Reaction Database (CVARD) concerning the side effects of cholinesterase inhibitors. The statistics calculated for each adverse event were the frequency and the reporting odds ratios (ROR). A total of 9877 and 2247 reports were extracted from the FAERS and CVARD databases, respectively. A disproportionately higher frequency of reports of death as an adverse event for rivastigmine, compared to the other acetylcholinesterase inhibiting drugs, was observed in both the FAERS (ROR = 3.42; CI95% = 2.94–3.98; P<0.0001) and CVARD (ROR = 3.67; CI95% = 1.92–7.00; P = 0.001) databases. While cholinesterase inhibitors remain to be an important therapeutic tool against Alzheimer’s disease, the disproportionate prevalence of fatal outcomes with rivastigmine compared with alternatives should be taken into consideration.

Revisiting choline alphoscerate profile: a new, perspective, role in dementia?

Choline alphoscerate (alpha-glyceryl-phosphorylcholine, alpha-GPC) is a semisynthetic derivative of phosphatidylcholine with central parasympathomimetic action. This action is, on the basis of its use in pathologies, characterized by cognitive deficits of neurodegenerative or vascular nature. In a number of clinical studies, alpha-GPC demonstrated benefit in patients with cognitive dysfunction. In light of the limited therapeutical results obtained in the past decades by the use of cholinesterase inhibitors in dementia, and of the relevance of their side effects in long-lasting therapies, it is desirable to reconsider alpha-GPC in larger carefully controlled studies not only as monotherapy but also in association with cholinesterase inhibitor drugs.

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.

P.5.a.007 Comparative efficacy of cholinesterase inhibitors in dementia associated with Parkinson's disease

P.5.a.007 Comparative efficacy of cholinesterase inhibitors in dementia associated with Parkinson's disease

Sacral Nerve Stimulation for Refractory Overactive Bladder in the Elderly Population

We determined the long-term outcome of sacral nerve stimulation for refractory overactive bladder in the elderly population. We performed a prospective longitudinal study to better characterize the outcome of sacral nerve stimulation in female patients 70 years old or older with refractory overactive bladder. Demographic and perioperative data were recorded. Patients were followed postoperatively for evidence of successful stage conversion, device durability and efficacy, and postoperative complications. Patients were retrospectively compared to a cohort of female patients younger than 70 years with refractory overactive bladder. Statistical analysis was performed. Between July 2001 and February 2008, 19 elderly female patients with refractory overactive bladder underwent stage 1 lead placement. Of the patients 17 (90%) who reported greater than 50% improvement in symptoms based on a 1-week followup voiding log underwent implantable pulse generator placement. No intraoperative or immediate postoperative complications were noted. At a mean followup of 48.5 months 11 patients (65%) had a functional implantable pulse generator with greater than 50% objective improvement over baseline. Compared to matched patients younger than 70 years elderly patients had a similar conversion rate and adverse events but were significantly more likely to undergo device removal (p = 0.018). Based on our experience elderly patients have a high conversion rate, few adverse events, and a high level of device efficacy and durability with sacral nerve stimulation. Although more mature multicenter data are needed, it appears that sacral nerve stimulation in geriatric patients is safe and efficacious, and should be judiciously offered to those with refractory voiding symptoms.

Ginkgo biloba for mild to moderate dementia in a community setting: a pragmatic, randomised, parallel‐group, double‐blind, placebo‐controlled trial

Doubt over the cost-effectiveness of the cholinesterase inhibitors in dementia has renewed interest in alternative treatments such as Ginkgo biloba. We aimed to determine the effectiveness and the safety profile of Ginkgo biloba for treating early stage dementia in a community setting. We conducted a community-based, pragmatic, randomised, double-blind, parallel-group trial where participants were given a standardised extract of Ginkgo biloba (120 mg daily) or a placebo control for 6 months. Our primary outcomes were cognitive functioning (ADAS-Cog) and participant and carer-rated quality of life (QOL-AD). We recruited 176 participants, mainly through general practices. In the ANCOVA model with baseline score as a co-variate (n = 176), Ginkgo did not have a significant effect on outcome at six months on either the ADAS-Cog score (p = 0.392), the participant-rated QOL-AD score (p = 0.787) nor the carer-rated QOL-AD score (p = 0.222). We found no evidence that a standard dose of high purity Ginkgo biloba confers benefit in mild-moderate dementia over 6 months.

‘Ask the Right Questions’ to Reverse Drug Overuse

‘Ask the Right Questions’ to Reverse Drug Overuse

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Cholinesterase inhibitors in dementia: yes, no, or maybe?

Cholinesterase inhibitors in dementia: yes, no, or maybe?

Cerebral white matter changes and rate of progression of dementia during cholinesterase inhibitor treatment: a retrospective cohort study

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 (DLB). Predictors of treatment response are controversial. To investigate the effect of WMC severity on rate of progression of dementia during treatment with ChEIs. 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 9 months or longer. Analysis was performed for this group as a whole and within diagnostic subgroups AD and DLB. 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). There was no significant association between severity of WMC and any specified outcome variable for the cohort as a whole or for patients with AD. In patients with DLB, higher WMC scores were associated with more rapid cognitive decline. Increased WMC severity does not influence clinical response to ChEI treatment in AD, but may hasten deterioration in ChEI-treated patients with DLB.

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.

Cholinesterase inhibitors in dementia with Lewy bodies—a comparative analysis

To compare efficacy of different cholinesterase inhibitors (ChEIs) for treating patients with dementia with Lewy bodies (DLB). Retrospective comparison of three independent clinical studies of ChEI treatment using donepezil, galantamine or rivastigmine in patients with DLB. Data was obtained from open label trials of donepezil and galantamine and a placebo controlled randomized trial of rivastigmine in DLB. Changes in Mini Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI) and United Parkinson's Disease Rating Scale (UPDRS-III) scores were compared between the three treatments at 12 and 20 weeks. All ChEIs significantly improved cognitive and neuropsychiatric measures. Reduction in the total NPI score appeared significantly greater after donepezil treatment. There was no significant increase in UPDRS-III scores. It is unclear to what extent these findings reflect true differences between ChEIs or are due to methodological artefacts of comparing different studies. There is so far no compelling evidence that any one ChEI is better than the other in treating DLB but head to head comparative studies of different ChEIs are warranted to clarify this.

Cholinesterase inhibitors in advanced Dementia with Lewy bodies: increase or stop?

There is little data on stopping cholinesterase inhibitors in Dementia with Lewy bodies (DLB). Equally, it is not known if increasing the dose of cholinesterase inhibitors may help neuropsychiatric symptoms in advanced DLB. We conducted an open label trial with donepezil involving 16 patients with LBD when the dose was reduced and treatment stopped over 4 weeks. Another 7 patients were given a trial of an increased dose of donepezil (15 mg) to resolve rehyphen;emergent neuropsychiatric symptoms. The slow discontinuation protocol was well tolerated in advanced DLB. Five of the seven patients given a trial of a higher dose of donepezil were rated as clinically improved after 12 weeks treatment. Cholinesterase inhibitors can be discontinued slowly in advanced DLB. Increasing the dose of donepezil may be of benefit to some patients with DLB who experience a recurrence in their neuropsychiatric symptoms.

Cholinesterase inhibitors for dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) was first described in 1983, and clinical diagnostic criteria were published in the early to mid 1990s. It has been suggested DLB may account for up to 15-25% of cases of dementia among people aged over 65, although autopsy suggests much lower rates. Characteristic symptoms are dementia, marked fluctuation of cognitive ability, early and persistent visual hallucinations and spontaneous motor features of Parkinsonism. Falls, syncope, transient disturbances of consciousness, neuroleptic sensitivity, and hallucinations in other modalities are also common. This combination of features can be difficult to manage as neuroleptics can make the Parkinsonian and cognitive symptoms worse. There is evidence to suggest that the cholinesterase inhibitors may be beneficial in this disorder; small case series indicate that cholinesterase inhibitors are safe, and will improve both cognitive deficits and neuropsychiatric symptoms in DLB. To assess the use of cholinesterase inhibitors in DLB. The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 25 February 2002 using the terms 'lewy body', 'Lewy bodies' and 'Lewy'. This register contains records from all major health care databases and trial databases and is updated regularly. Randomized, double-blind trials in which treatment with cholinesterase inhibitors was administered and compared with alternative interventions in patients with DLB are included. Two reviewers (TP, RW) independently assessed quality of trials according to criteria described in the Cochrane Collaboration Handbook. Each drug was to be examined separately, and together as a group. We also analysed data by time to outcome measurement; short-term (up to one month), medium term (one month up to six months) and long term (Six months and longer). The primary outcome measures of interest are in the following areas: neuropsychiatric features. i.e. psychiatric symptoms and behavioural disturbances, cognitive function, activities of daily living, global assessments, quality of life, including maintaining role and social functioning, effect on carers, safety as measured by incidence of adverse events and side effects, acceptability of treatment as measured by withdrawal from trials, and by patient/carer assessment, institutionalization and death. There was one included trial (McKeith 2000f) of rivastigmine compared with placebo on 120 patients. Neuropsychiatric InventoryThe 10-item test found no significant difference between the two groups in change of scores from baseline using intention-to-treat (ITT) analysis at 20 weeks and last observation carried forward (LOCF) analysis. The treatment effect was statistically significant in favour of rivastigmine if only observed cases (OC) were analysed (WMD -6.94, 95% CI -11.59 to -2.29, P=0.003). There were similar results for the NPI-4, with only the OC analysis showing a significant superiority of rivastigmine to placebo at 20 weeks (WMD -3.75, 95%CI -6.62 to -0.88, P=0.01).MMSE:Analysis of these results showed no statistically significant difference between the two groups at 20 weeks.CGC-plus:Analysis of the proportion of patients who had no change or became worse found no statistically significant difference between the two groups at 20 weeks for the ITT, LOCK and OC analyses. Adverse Events:The placebo group experienced significantly fewer adverse events than the treatment group (54/59 vs 46/61,OR 3.52, 95%CI 1.19 to 10.43). However, using ITT analysis of 20-week data, there was no significant difference between the two groups when serious adverse events were considered. There were no significant differences in death rates between the two groups at 20 weeks.Drop-out Rates:Analysis of these results showed no difference between the two groups at 20 weeks using ITT analysis. Patients with dementia with Lewy bodies who suffer from behavioural disturbance oS CONCLUSIONS: Patients with dementia with Lewy bodies who suffer from behavioural disturbance or psychiatric problems may benefit from rivastigmine if they tolerate it, but the evidence is weak. Further trials using rivastigmine are needed, as are trials of other cholinesterase inhibitors in dementia with Lewy bodies.

Use of cholinesterase inhibitors in dementia

Alzheimer's disease is the most common cause of dementia in older people, with about half a million people affected in the UK. Its effects are devastating and far-reaching for sufferers, their carers and society in general – the Audit Commission estimated the annual cost of dementia care for 1998–1999 at £6.1 billion (Audit Commission, 2000). There is no cure and it is terminal within 3 to 7 years of diagnosis. Given an estimated doubling of dementia cases over the next 50 years (Melzer et al, 1997), the burden of care is set to increase substantially.