Cholinesterase Inhibitor Treatment Research Articles

Brain Age Is Associated with Cognitive Outcomes of Cholinesterase Inhibitor Treatment in Patients with Mild Cognitive Impairment.

The effect of cholinesterase inhibitor (ChEI) on mild cognitive impairment (MCI) is controversial. Brain age has been shown to predict Alzheimer's disease conversion from MCI. The study aimed to show that brain age is related to cognitive outcomes of ChEI treatment in MCI. Brain MRI, the Clinical Dementia Rating (CDR) and Mini-Mental State Exam (MMSE) scores were retrospectively retrieved from a ChEI treatment database. Patients who presented baseline CDR of 0.5 and received ChEI treatment for at least 2 years were selected. Patients with stationary or improved cognition as verified by the CDR and MMSE were categorized to the ChEI-responsive group, and those with worsened cognition were assigned to the ChEI-unresponsive group. A gray matter brain age model was built with a machine learning algorithm by training T1-weighted MRI data of 362 healthy participants. The model was applied to each patient to compute predicted age difference (PAD), i.e. the difference between brain age and chronological age. The PADs were compared between the two groups. 58 patients were found to fit the ChEI-responsive criteria in the patient data, and 58 matched patients that fit the ChEI-unresponsive criteria were compared. ChEI-unresponsive patients showed significantly larger PAD than ChEI-responsive patients (8.44±8.78 years versus 3.87±9.02 years, p = 0.0067). Gray matter brain age is associated with cognitive outcomes after 2 years of ChEI treatment in patients with the CDR of 0.5. It might facilitate the clinical trials of novel therapeutics for MCI.

Cholinesterase inhibitors are associated with reduced mortality in patients with Alzheimer's disease and previous myocardial infarction.

Cholinesterase inhibitors (ChEIs) are the first-line symptomatic pharmacologic treatment for patients with mild-to-moderate Alzheimer's disease (AD). Although the target organ for this group of drugs is the brain, inhibition of the enzyme may affect cardiac function through vagotonic and anti-inflammatory effects. To assess the impact of ChEIs on outcomes in patients with AD who have experienced myocardial infarction (MI) prior to the AD diagnosis. Patients who had experienced MI before they were diagnosed with AD or Alzheimer's mixed dementia between 2008 and 2018 were identified from the Swedish Dementia Registry (SveDem, www.svedem.se), which was linked to the National Patient Registry to obtain data on MI and mortality. Cox proportional hazards regression model among a propensity score-matched dataset was performed to assess the association between ChEI treatment and clinical outcomes. Of 3198 patients with previous MI and a diagnosis of AD or mixed dementia, 1705 (53%) were on treatment with ChEIs. Patients treated with ChEIs were more likely to be younger and have a better overall cardiovascular (CV) risk profile. The incidence rate of all-cause death (per 1000 patient-years) in the propensity-matched cohort of 1016 ChEI users and 1016 non-users was 168.6 in patients on treatment with ChEIs compared with 190.7 in patients not on treatment with ChEIs. In this propensity-matched cohort, treatment with ChEIs was associated with a significantly lower risk of all-cause death (adjusted hazard ratio 0.81, 95% confidence interval 0.71-0.92) and a greater reduction with higher doses of ChEIs. While in the unadjusted analysis, ChEIs were associated with a lower risk of both CV and non-CV death, only the association with non-CV death remained significant after accounting for baseline differences. Treatment with ChEIs was associated with a significantly reduced risk of all-cause death, driven by lower rates of non-CV death in a nationwide cohort of patients with previous MI and a diagnosis of AD or mixed dementia. These associations were greater with higher ChEI doses. We assessed the association between cholinesterase inhibitors (ChEIs) and clinical outcomes in a nationwide cohort of patients with previous myocardial infarction (MI) and a diagnosis of Alzheimer's disease (AD) or mixed dementi. In propensity-matched analysis, treatment with ChEIs was associated with a 19% reduction in all-cause death driven by non-cardiovascular death. The reduction in all-cause death was greater with the higher doses of ChEIs.

How to Use Percentiles to Better Understand Standardized Mean Difference (SMD) as a Measure of Effect Size.

The standardized mean difference (SMD) is the difference between the means of a variable, expressed not in its original unit but in the unit of standard deviation (SD). SMDs of 0.2, 0.5, and 0.8 are conventionally considered to be small, medium, and large, respectively. The reader, however, obtains no real world understanding of an SMD from these adjectives. This article suggests a solution: SMDs and their 95% confidence intervals can be better understood if they are converted into percentile scores. The procedure is explained, step by step, with reference to a meta-analysis that found that cholinesterase inhibitors (ChEIs) significantly attenuated delusions and hallucinations in Alzheimer disease and Parkinson disease with SMDs that ranged from -0.08 to -0.14. After conversion of these SMDs to percentile scores, the reader is shown that the average patient in the ChEI treatment arms would have improved by just 3 to 7 percentile places relative to the average patient in the placebo arms. So, whereas the findings were statistically significant, they would perhaps be so small as to be clinically unobservable in the average patient. All that the reader needs to do to convert an SMD into a percentile score is to locate a table that presents area under the normal curve, understand how the table presents what it does, look up the SMD value in the table, and obtain the percentile score from the value in the table. The entire procedure is very easily understood and takes less than a minute, starting from locating the table through an online search to obtaining the percentile score for the SMD.

Cholinesterase Inhibitors for Delusions and Hallucinations in Alzheimer Disease and Parkinson Disease: Questionably Significant Benefits.

Delusions and hallucinations are common in Alzheimer disease (AD) and Parkinson disease (PD), especially in the later stages of illness. Antipsychotic drugs are effective in treating these psychotic symptoms but are associated with an increased risk of serious adverse events, including mortality. There is therefore a need to explore other treatment approaches. In this context, a recent individual patient data meta-analysis of 17 randomized controlled trials (RCTs) conducted in AD (12 RCTs) and PD (5 RCTs) found that the cholinesterase inhibitor (ChEI) drugs donepezil, rivastigmine, and galantamine attenuated the severity of both delusions and hallucinations in both AD and PD. Most of these trials were 24 weeks in duration. The effect sizes, expressed as standardized mean differences (SMDs), were, however, small, lying in the -0.08 to -0.14 range. These values are so small as to be perhaps clinically insignificant. When analyses were restricted to data from patients who actually had delusions and hallucinations at baseline, all effect sizes became larger, lying in the -0.13 to -0.39 range; however, after correcting for multiple hypothesis testing, only the finding for delusions in PD remained statistically significant. The meta-analysis did not provide information on what the best doses were, how long it took for improvement to become evident, and what proportion of patients showed remission from psychotic symptoms. Whereas the signal identified in this meta-analysis merits examination in appropriately designed RCTs, the findings of the meta-analysis may not much change current treatment strategies because patients with dementia would probably anyway receive a ChEI. Therefore, if psychotic symptoms persist for 24 weeks despite optimally dosed ChEI treatment, and if behavioral and psychosocial interventions do not help, clinicians may need to consider the potential benefits vs risks of other drugs, such as atypical antipsychotics and pimavanserin, in a shared decision-making process.

Cholinesterase Inhibitors for Treatment of Psychotic Symptoms in Alzheimer Disease and Parkinson Disease

Psychotic symptoms greatly increase the burden of disease for people with neurodegenerative disorders and their caregivers. Cholinesterase inhibitors (ChEIs) may be effective treatment for psychotic symptoms in these disorders. Previous trials only evaluated neuropsychiatric symptoms as a secondary and an overall outcome, potentially blurring the outcomes noted with ChEI use specifically for psychotic symptoms. To quantitatively assess the use of ChEIs for treatment of individual neuropsychiatric symptoms, specifically hallucinations and delusions, in patients with Alzheimer disease (AD), Parkinson disease (PD), and dementia with Lewy bodies (DLB). A systematic search was performed in PubMed (MEDLINE), Embase, and PsychInfo, without year restrictions. Additional eligible studies were retrieved from reference lists. The final search cutoff date was April 21, 2022. Studies were selected if they presented the results of placebo-controlled randomized clinical trials, including at least 1 donepezil, rivastigmine, or galantamine treatment arm in patients with AD, PD, or DLB; if they applied at least 1 neuropsychiatric measure including hallucinations and/or delusions; and if a full-text version of the study was available in the English language. Study selection was performed and checked by multiple reviewers. Original research data were requested on eligible studies. A 2-stage meta-analysis was then performed, using random-effects models. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed for extracting data and assessing the data quality and validity. Data extraction was checked by a second reviewer. Primary outcomes were hallucinations and delusions; secondary outcomes included all other individual neuropsychiatric subdomains as well as the total neuropsychiatric score. In total, 34 eligible randomized clinical trials were selected. Individual participant data on 6649 individuals (3830 [62.6%] women; mean [SD] age, 75.0 [8.2] years) were obtained from 17 trials (AD: n = 12; PD: n = 5; individual participant data were not available for DLB). An association with ChEI treatment was shown in the AD subgroup for delusions (-0.08; 95% CI, -0.14 to -0.03; P = .006) and hallucinations (-0.09; 95% CI, -0.14 to -0.04; P = .003) and in the PD subgroup for delusions (-0.14; 95% CI, -0.26 to -0.01; P = .04) and hallucinations (-0.08, 95% CI -0.13 to -0.03; P = .01). The results of this individual participant data meta-analysis suggest that ChEI treatment improves psychotic symptoms in patients with AD and PD with small effect sizes.

CD34+ progenitor cells as diagnostic and therapeutic targets in Alzheimer's disease.

CD34+ progenitor cells as diagnostic and therapeutic targets in Alzheimer's disease.

Plasma Myeloperoxidase as a Potential Biomarker of Patient Response to Anti-Dementia Treatment in Alzheimer's Disease.

Myeloperoxidase (MPO), a neutrophil-derived pro-inflammatory protein, co-localizes with amyloid-β (Aβ) plaques in Alzheimer's disease (AD). Anti-dementia treatment may facilitate efflux of Aβ and associated plaque proteins from the brain to the peripheral circulation, therefore providing potential biomarkers for the monitoring of donor response to drug treatment. We investigated the diagnostic utility of MPO as a biomarker of AD, and how anti-dementia treatment alters plasma MPO concentration. Thirty-two AD patients were recruited, and plasma collected pre-drug administration (baseline), and 1- and 6-months post-treatment. All patients received cholinesterase inhibitors (ChEIs). At baseline and 6 months, patients underwent neuropsychological assessment. Forty-nine elderly healthy individuals with normal cognitive status served as controls. Plasma MPO concentration was measured by ELISA. AD drug naïve patients had similar plasma MPO concentration to their control counterparts (p > 0.05). Baseline MPO levels positively correlated with Neuropsychiatric Inventory score (r = 0.5080; p = 0.011) and carer distress (r = 0.5022; p = 0.012). Following 1-month ChEI treatment, 84.4% of AD patients exhibited increased plasma MPO levels (p < 0.001), which decreased at 6 months (p < 0.001). MPO concentration at 1 month was greatest in AD patients whose memory deteriorated during the study period (p = 0.028), and for AD patients with deterioration in Cornell assessment score (p = 0.044). Whereas baseline MPO levels did not differentiate between healthy and AD populations, baseline MPO positively correlated with initial Neuropsychiatric Inventory evaluation. Post-treatment, transient MPO upregulation in ChEI-treated patients may reflect worse therapeutic outcome. Further studies are required to assess the potential of plasma MPO as an AD therapeutic biomarker.

Cholinesterase Inhibitors Response Might Be Related to Right Hippocampal Functional Connectivity in Mild Alzheimer's Disease.

Background: The response to cholinesterase inhibitors (ChEIs) treatment is variable in patients with Alzheimer's disease (AD). Patients and physicians would benefit if these drugs could be targeted at those most likely to respond in a clinical setting. Therefore, this study aimed to evaluate the ability of cerebrospinal fluid (CSF) AD biomarkers, hippocampal volumes, and Default Mode Network functional connectivity to predict clinical response to ChEIs treatment in mild AD. Methods: We followed up on 39 mild AD patients using ChEIs at therapeutic doses. All subjects underwent clinical evaluation, neuropsychological assessment, magnetic resonance imaging examination, and CSF biomarkers quantification at the first assessment. The Mini-Mental Status Examination (MMSE) was used to measure the global cognitive status before and after the follow-up. "Responders" were considered as those who have remained stable or improved the MMSE score between evaluations and "Nonresponders" as those who have worsened the MMSE score. We performed univariate and multivariate logistic regressions to predict the clinical response from each biomarker. Results: About 35.89% of patients were classified as "Responders" to ChEIs treatment after the follow-up. The multivariate model with measures of Right Hippocampus (RHIPPO), adjusted for gender and interval between assessments, was significant (odds ratio: 1.09 [95% confidence interval, 1.00-1.19], p = 0.0392). This model achieved an accuracy of 77.60%. Conclusion: Our findings suggest that the functional connectivity of RHIPPO might be an early imaging biomarker to predict clinical response to ChEIs drugs in mild AD. Impact statement The functional connectivity of the right hippocampus showed a direct relationship with the clinical response to cholinesterase inhibitors (ChEIs) treatment in patients with mild Alzheimer's disease. Transposing our findings to clinical settings could allow physicians to prescribe ChEIs for patients for whom treatment would be most beneficial.

Effect of Cholinesterase Inhibitors on Mortality in Patients With Dementia: A Systematic Review of Randomized and Nonrandomized Trials.

Cholinesterase inhibitors (ChEIs) have cardiovascular effects in addition to their neurologic activity and might alter mortality. We wanted to know whether treatment with ChEIs modifies mortality in patients with dementia. We searched PubMed, Embase, Cochrane CENTRAL, ClinicalTrials.gov, and ICRTP, from their inception to November 2021, and screened bibliographies of reviews, guidelines, and included studies. We included randomized controlled trials (RCTs) and nonrandomized controlled studies at lower risk of bias comparing ChEI treatment with placebo or usual treatment, for 6 months or longer, in patients with dementia of any type. Two investigators independently assessed studies for inclusion, assessed their risk of bias, and extracted data using predefined forms. Any discordance between investigators was solved by discussion and consensus. Data on all-cause and cardiovascular mortality, measured as either crude death rates or multivariate adjusted hazard ratios (HRs), were pooled using a random-effect model. Information size achieved was assessed using trial sequential analysis (TSA). We followed Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Twenty-four studies (12 RCTs, 12 cohorts, mean follow-up 6-120 months), cumulating 79,153 patients with Alzheimer (13 studies), Parkinson (1), vascular (1), or any type (9) dementia, fulfilled inclusion criteria. Pooled all-cause mortality in control patients was 15.1 per 100 person-years. Treatment with ChEIs was associated with lower all-cause mortality (unadjusted risk ratio [RR] 0.74, 95% CI 0.66-0.84; adjusted HR 0.77, 95% CI 0.70-0.84, moderate-quality to high-quality evidence). This result was consistent between randomized and nonrandomized studies and in several sensitivity analyses. No difference appeared between subgroups by type of dementia, age, individual drug, or dementia severity. Less data were available for cardiovascular mortality (3 RCTs, 2 cohorts, 9,182 patients, low-quality to moderate-quality evidence), which was also lower in patients treated with ChEIs (unadjusted RR 0.61, 95% CI 0.40-0.93, adjusted HR 0.47, 95% CI 0.32-0.68). In TSA analysis, the results for all-cause mortality were conclusive but not those for cardiovascular mortality. There is moderate-quality to high-quality evidence of a consistent association between long-term treatment with ChEIs and a reduction in all-cause mortality in patients with dementia. These findings may influence decisions to prescribe ChEIs in those patients. This systematic review was registered in the PROSPERO international prospective register of systematic reviews with the number CRD42021254458 (June 11, 2021).

Poststroke Cognitive Impairment: A Longitudinal Follow-Up and Pre/Poststroke Mini-Mental State Examination Comparison.

Poststroke cognitive impairment (PSCI) is a prevalent cause of disability in people with stroke. PSCI results from either lesion-dependent loss of cognitive function or augmentation of Alzheimer's pathology due to vascular insufficiency. The lack of prestroke cognitive assessments limits the clear understanding of the impact of PSCI on cognition. The present study aims to make a direct comparison of longitudinal cognitive assessment results to clarify the impact of ischemic stroke on PSCI and assess the cognitive decline in PSCI compared to people with Alzheimer's disease (AD). All study participants had their Mini-Mental State Examination (MMSE) at the chronic poststroke stage (≥6 months after stroke), which was compared with prestroke or acute poststroke (<6 months after stroke) MMSE to investigate the two aspects of PSCI. A group of patients with AD was used to reference the speed of neurodegenerative cognitive deterioration. Repeated measures analysis of variance was used to compare the longitudinal change of MMSE. MMSE score between acute and chronic poststroke revealed a 1.8 ± 6.49 decline per year (n=76), which was not significantly different from the AD patients who underwent cholinesterase inhibitors treatment (-1.11 ± 2.61, p=0.35, n=232). MMSE score between prestroke and chronic poststroke (n=33) revealed a significant decline (-6.52 ± 6.86, p < 0.001). In addition, their cognitive deterioration was significantly associated with sex, age, and stroke over the white matter or basal ganglia. Ischemic stroke substantially affects cognition with an average six-point drop in MMSE. The rate of cognitive decline in PSCI was similar to AD, and those with white matter or basal ganglia infarct were at greater risk of PSCI.

Drug cost optimization of cholinesterase inhibitor therapy in advanced dementia: Results of a prospective study of discontinuation

Purpose: To investigate the effect of discontinuing treatment with cholinesterase inhibitors (ChEIs) on drug costs in patients with advanced dementia.&#x0D; Methods: Severe dementia patients receiving ChEI treatment for over 12 months (n = 43) aged over 65 years (mean age = 82.6 ± 7.5 years) were recruited from 8 nursing homes located in Alicante, Spain. ChEI treatment was discontinued in 23 patients. Here, we report the results from a cost-minimization analysis to evaluate the drug costs with a follow-up period of three months. The drug costs were prospectively analyzed based on drug acquisition costs.&#x0D; Results: At the end of the follow-up, the mean monthly drug costs were €52.68 ± 22.48 in the discontinuation group and €122.54 ± 44.74 in the continuation group - a significant difference of means of -€69.86 (95 % CI, -91.24 to -48.48; p = 0.000). The monthly drug cost reduction for the ChEI discontinuation group was €1,533.35.&#x0D; Conclusion: ChEI discontinuation appears to be a possible option for minimizing treatment costs in institutionalized patients with advanced dementia.

Longitudinal atrophy in prodromal dementia with Lewy bodies points to cholinergic degeneration.

Mild cognitive impairment with the core clinical features of dementia with Lewy bodies is recognized as a prodromal stage of dementia with Lewy bodies. Although grey matter atrophy has been demonstrated in prodromal dementia with Lewy bodies, longitudinal rates of atrophy during progression to probable dementia with Lewy bodies are unknown. We investigated the regional patterns of cross-sectional and longitudinal rates of grey matter atrophy in prodromal dementia with Lewy bodies, including those who progressed to probable dementia with Lewy bodies. Patients with mild cognitive impairment with at least one core clinical feature of dementia with Lewy bodies (mean age = 70.5; 95% male), who were enrolled in the Mayo Clinic Alzheimer’s Disease Research Center and followed for at least two clinical evaluations and MRI examinations, were included (n = 56). A cognitively unimpaired control group (n = 112) was matched 2:1 to the patients with mild cognitive impairment by age and sex. Patients either remained stable (n = 28) or progressed to probable dementia with Lewy bodies (n = 28) during a similar follow-up period and pathologic confirmation was available in a subset of cases (n = 18). Cross-sectional and longitudinal rates of grey matter atrophy were assessed using voxel-based and atlas-based region of interest analyses. At baseline, prodromal dementia with Lewy bodies was characterized by atrophy in the nucleus basalis of Meynert both in those who remained stable and those who progressed to probable dementia with Lewy bodies (P < 0.05 false discovery rate corrected). Increase in longitudinal grey matter atrophy rates were widespread, with greatest rates of atrophy observed in the enthorhinal and parahippocampal cortices, temporoparietal association cortices, thalamus and the basal ganglia, in mild cognitive impairment patients who progressed to probable dementia with Lewy bodies at follow-up (P < 0.05 false discovery rate corrected). Rates of inferior temporal atrophy were associated with greater rates of worsening on the clinical dementia rating–sum of boxes. Seventeen of the 18 (94%) autopsied cases had Lewy body disease. Results show that atrophy in the nucleus basalis of Meynert is a feature of prodromal dementia with Lewy bodies regardless of proximity to progression to probable dementia with Lewy bodies. Longitudinally, grey matter atrophy progresses in regions with significant cholinergic innervation, in alignment with clinical disease progression, with widespread and accelerated rates of atrophy in patients who progress to probable dementia with Lewy bodies. Given the prominent neurodegeneration in the cholinergic system, patients with prodromal dementia with Lewy bodies may be candidates for cholinesterase inhibitor treatment.

Childhood autoimmune myasthenia gravis in Senegal

ObjectiveThe purpose of this study was to describe epidemiological, clinical, electrophysiological and biological features of autoimmune Myasthenia Gravis in a cohort of Senegalese children. Materials and MethodsThe medical records of patients diagnosed with autoimmune Myasthenia Gravis at the Neurological Department of Fann National Teaching Hospital and National Children's Hospital Albert Royer were reviewed from May 2005 to January 2020. ResultsThirty-six patients (12 boys and 24 girls) were enrolled with age ranging from 17 months to 16 years. 31 children were of prepubertal age and 5 children of pubertal age. 23 patients (63.9%) presented an ocular form, 13 patients (36.1%) had generalized myasthenia gravis. Electroneuromyography showed a 10-70% decrement in all patients. Serum level tests of acetylcholine receptors antibodies were positive in 22 patients (65.2%). Chest CT scan found thymoma in 3 patients. All the patients received cholinesterase inhibitor treatment and corticosteroids in addition for 14 of them. The median follow up was 20.25 months. The evolution was marked by a complete remission in 9 patients myasthenic in the prepubertal period, with a mean follow-up time of 31.57 months (range 27 to 42 months) and the death of 6 patients by myasthenic crisis after a follow-up of 31.16 months on average (range 3 to 48 months). ConclusionIn our context, myasthenia in children is more likely to be of prepubertal age. Therapeutic education is essential for optimal patient management.

Racial/ethnic disparities in new and persistent cholinesterase inhibitors treatment in Alzheimer’s disease

AbstractBackgroundRacial/ethnic minorities are less likely to use anti‐dementia medications and less likely to participate in dementia studies. It is unclear if treatment disparities remain in those who participate in longitudinal research at Alzheimer’s Disease Centers (ADCs).MethodsData were drawn from the National Alzheimer's Coordinating Center Uniform Data Set (9/2005‐11/2019). Baseline inclusion criteria: ≥65yo, etiology of AD, and CDR&lt;3. Sample included Non‐Hispanic white, Non‐Hispanic Black, or Hispanic participants with ≥1 follow‐up. Main outcomes: (1) any new Acetylcholinesterase (AChEI) treatment during follow‐up, (2) persistence of treatment measured by proportion of follow‐up visits reporting AChEI use, categorized into: intermittent (&lt;50% follow‐ups), persistent (≥50% follow‐ups), and always treated. Differences by race/ethnicity were estimated using logistic or ordered logistic regression models, controlling for participant clinical and demographic variables.ResultsSample included 5,866 white, 918 Black, and 608 Hispanic participants. Compare to the treated, those who were untreated at baseline were older, more likely to be female, lived alone, more likely to have AD (vs. MCI), with better clinical profiles (better CDR, FAQ, NPIQ, MMSE, lower rate of hypertension and diabetes). Among baseline untreated, average age=77.1±7.0, 55% female, education=14.7±3.8 years, MMSE=24.4±4.7. 51% AD. The proportion of participants with CDR=0.5, 1, 2 was 66%, 25%, and 6% respectively. 47% were referred by a clinical professional. Average follow‐up=3.9±2.2 years. 83% had a spouse/partner or child as co‐participant. Etiology remained AD for 85% of follow‐up visits. Any new AChEI treatment during follow‐up was lower among Blacks (33.7%) and Hispanics (41.4%) compared to whites (45.8%) (p&lt;0.001). After controlling for participant characteristics, adjusted odds of any new AChEI treatment remained lower for Blacks (OR=0.707±0.068) and Hispanics (OR=0.813±0.083, both p&lt;0.05) compared to whites. Unadjusted differences in persistence of treatment were not statistically significant (13.6% intermittent, 28,8% persistence, 57.6% always treated). However, adjusted differences in persistence of treatment was significantly lower for Blacks (OR=0.827±0.090) and Hispanics (OR=0.785±0.081, both p&lt;0.05) compared to whites.ConclusionRacial/ethnic minorities had lower rates of AChEI treatment at study enrollment. Disparities in AChEI treatment persisted even though individuals were followed in ADCs over time and remained significant after adjusting for clinical and demographic variables.

Cholinesterase inhibitors for gait, balance, and fall in Parkinson disease: a meta-analysis

Gait disturbance and imbalance are the major symptoms of Parkinson disease (PD), with fall being the most undesirable consequence. However, few effective evidence-based treatments are available for alleviating these symptoms and preventing falls. Cholinesterase inhibitors (ChEIs) are a well-established treatment for PD dementia with possible impacts on gait, balance, and fall reduction. The present study involved a meta-analysis of randomized controlled trials (RCTs) to investigate the effects of ChEIs on gait, balance, and fall in patients with PD. We searched for studies using the PubMed, Embase, and Web of Science databases. The major outcomes were effects on gait parameters, balance, and fall. This study was registered with PROSPERO (CRD42021254733). Five RCTs were included in the present meta-analysis. ChEIs did not significantly increase gait speed in PD patients (mean difference [MD]: 0.03 m/s, 95% confidence interval [CI]: −0.02 to 0.07, p = 0.29). However, ChEI treatment significantly decreased step or stride variability during the single task (standard MD: −0.43, 95% CI = −0.79 to −0.06, p = 0.02). Regarding fall and balance, trending but nonsignificant beneficial effects were observed with ChEI treatment. In conclusion, although ChEI treatment did not significantly improve gait speed and reduce fall, it can significantly reduce step or stride variability. Considering that gait disorder is a challenging issue in patients with PD and that ChEIs are generally tolerable, the present meta-analysis may provide more evidence for the benefit of ChEIs on PD gait disturbance as an alternative treatment consideration.

Imagine that: cholinesterase inhibitor treatment of complex visual hallucinations of unknown aetiology

ABSTRACT Introduction: Our objective is to highlight the value of the neurophenomenological classification of complex visual hallucinations (VHs). This approach enabled the authors to successfully treat VHs of uncertain aetiology with cholinesterase inhibitors because the content of the hallucinations suggested dysfunction in cholinergic modulated networks. Methods: We utilise the single case report to describe the nature and content of chronic VHs experienced by a 49-year-old woman following a prolonged admission to ITU. Despite extensive investigation, no clear cause was identified for these hallucinations and the patient did not respond to rationalisation of medications or trials of antipsychotics. We therefore adopted the neurophenomenological approach to classifying and treating her VHs. Results: After several years of distressing visual hallucinations, a course of Rivastigmine was trialed despite no evidence suggestive of a Parkinsonian syndrome. Nevertheless, the patient reported a dose-effect response with significant reduction in the frequency and intensity of her hallucinations, almost to complete resolution. Conclusions: At present there is limited evidence about the medical management of visual hallucinations. This case report suggests that cholinesterase inhibitors may be of benefit, even in the absence of clear parkinsonsian features, if the form and content of the VHs suggest dysfunction in cholinergic modulated attentional networks.

Pre-Stroke Cholinesterase Inhibitor Treatment Is Beneficially Associated with Functional Outcome in Patients with Acute Ischemic Stroke and Pre-Stroke Dementia: The Fukuoka Stroke Registry

Introduction: Pre-stroke dementia is significantly associated with poor stroke outcome. Cholinesterase inhibitors (ChEIs) might reduce the risk of stroke in patients with dementia. However, the association between pre-stroke ChEI treatment and stroke outcome remains unresolved. Therefore, we aimed to determine this association in patients with acute ischemic stroke and pre-stroke dementia. Methods: We enrolled 805 patients with pre-stroke dementia among 13,167 with ischemic stroke within 7 days of onset who were registered in the Fukuoka Stroke Registry between June 2007 and May 2019 and were independent in basic activities of daily living (ADLs) before admission. Primary and secondary study outcomes were poor functional outcome (modified Rankin Scale [mRS] score: 3–6) at 3 months after stroke onset and neurological deterioration (≥2-point increase in the NIH Stroke Scale [NIHSS] during hospitalization), respectively. Logistic regression analysis was used to evaluate associations between pre-stroke ChEI treatment and study outcomes. To improve covariate imbalance, we further conducted a propensity score (PS)-matched cohort study. Results: Among the participants, 212 (26.3%) had pre-stroke ChEI treatment. Treatment was negatively associated with poor functional outcome (odds ratio: 0.68 [95% confidence interval: 0.46–0.99]) and neurological deterioration (0.52 [0.31–0.88]) after adjusting for potential confounding factors. In the PS-matched cohort study, the same trends were observed between pre-stroke ChEI treatment and poor functional outcome (0.61 [0.40–0.92]) and between the treatment and neurological deterioration (0.47 [0.25–0.86]). Conclusions: Our findings suggest that pre-stroke ChEI treatment is associated with reduced risks for poor functional outcome and neurological deterioration after acute ischemic stroke in patients with pre-stroke dementia who are independent in basic ADLs before the onset of stroke.

The Association Between the Use of Cholinesterase Inhibitors and Cardiovascular Events Among Older Patients With Alzheimer Disease

ObjectiveTo evaluate the association between the use of cholinesterase inhibitors (ChEIs) and incident cardiovascular events (CVEs) among older patients with Alzheimer disease (AD). Patients and MethodsThis retrospective cohort study was conducted with a new-user design and active-comparator design. The data source was the 2005–2014 Full Population file from the Health and Welfare Database in Taiwan. Patients were included if they were aged 50 years or older and had been diagnosed with AD between January 1, 2006, and December 31, 2010. The association between ChEI use and the risk of CVEs was investigated in patients with AD. Among the ChEI users, the risk of CVEs was further compared between patients with different cumulative doses and different ChEI treatment strategies. The propensity score method, which included matching and inverse probability of treatment weighting, was used to balance the potential confounders. A Cox proportional hazards model with competing risks was used to estimate the hazard ratio of CVEs. ResultsThe study included 6070 patients with AD. After covariate adjustment, ChEI users had a significantly lower risk of CVEs than nonusers (hazard ratio, 0.57; 95% CI, 0.51 to 0.62). Among ChEI users, patients with a high cumulative dose had a significantly lower risk of CVEs than those with a low cumulative dose (hazard ratio, 0.82; 95% CI, 0.70 to 0.96). ConclusionThe use of ChEIs was associated with a decreased risk of incident CVEs among patients with AD. The cardioprotective effect of ChEIs showed a dose-response relationship.

Odor identification impairment and cholinesterase inhibitor treatment in Alzheimer's disease.

IntroductionThis study evaluated acute change in odor identification following atropine nasal spray challenge, and 8‐week change in odor identification ability, as a predictor of long‐term improvement in patients with mild to moderate Alzheimer's disease (AD) who received open‐label cholinesterase inhibitor treatment.MethodsIn patients with clinical AD, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Patients were then treated with donepezil for 52 weeks.ResultsIn 21 study participants, acute atropine‐induced decrease in UPSIT was not associated with change in the Alzheimer's Disease Assessment Scale ‐ Cognitive Subscale (ADAS‐Cog) or Selective Reminding Test (SRT). Decline in odor identification performance from baseline to week 8 was indicative of a future decline in cognitive performance over 52 weeks.DiscussionChange in odor identification with atropine challenge is not a useful predictor of treatment response to cholinesterase inhibitors. Short‐term change in odor identification performance needs further investigation as a potential predictor of cognitive improvement with cholinesterase inhibitor treatment.

Discontinuation of cholinesterase inhibitor treatment in institutionalised patients with advanced dementia

ObjectiveTo evaluate the impact of discontinuation of treatment with cholinesterase inhibitors (ChEIs) on cognitive, behavioural and functional outcomes in patients with severe dementia.MethodsA prospective observational study in which the prescribing...