Acetylcholinesterase Inhibitor Treatment Research Articles

Effects of strategic white matter hyperintensities of cholinergic pathways on basal forebrain volume in patients with amyloid-negative neurocognitive disorders

BackgroundThe cholinergic neurotransmitter system is crucial to cognitive function, with the basal forebrain (BF) being particularly susceptible to Alzheimer’s disease (AD) pathology. However, the interaction of white matter hyperintensities (WMH) in cholinergic pathways and BF atrophy without amyloid pathology remains poorly understood.MethodsWe enrolled patients who underwent neuropsychological tests, magnetic resonance imaging, and 18F-florbetaben positron emission tomography due to cognitive impairment at the teaching university hospital from 2015 to 2022. Among these, we selected patients with negative amyloid scans and additionally excluded those with Parkinson’s dementia that may be accompanied by BF atrophy. The WMH burden of cholinergic pathways was quantified by the Cholinergic Pathways Hyperintensities Scale (CHIPS) score, and categorized into tertile groups because the CHIPS score did not meet normal distribution. Segmentation of the BF on volumetric T1-weighted MRI was performed using FreeSurfer, then was normalized for total intracranial volume. Multivariable regression analysis was performed to investigate the association between BF volumes and CHIPS scores.ResultsA total of 187 patients were enrolled. The median CHIPS score was 12 [IQR 5.0; 24.0]. The BF volume of the highest CHIPS tertile group (mean ± SD, 3.51 ± 0.49, CHIPSt3) was significantly decreased than those of the lower CHIPS tertile groups (3.75 ± 0.53, CHIPSt2; 3.83 ± 0.53, CHIPSt1; P = 0.02). In the univariable regression analysis, factors showing significant associations with the BF volume were the CHIPSt3 group, age, female, education, diabetes mellitus, smoking, previous stroke history, periventricular WMH, and cerebral microbleeds. In multivariable regression analysis, the CHIPSt3 group (standardized beta [βstd] = -0.25, P = 0.01), female (βstd = 0.20, P = 0.04), and diabetes mellitus (βstd = -0.22, P < 0.01) showed a significant association with the BF volume. Sensitivity analyses showed a negative correlation between CHIPS score and normalized BF volume, regardless of WMH severity.ConclusionsWe identified a significant correlation between strategic WMH burden in the cholinergic pathway and BF atrophy independently of amyloid positivity and WMH severity. These results suggest a mechanism of cholinergic neuronal loss through the dying-back phenomenon and provide a rationale that strategic WMH assessment may help identify target groups that may benefit from acetylcholinesterase inhibitor treatment.

White matter hyperintensities in cholinergic pathways may predict poorer responsiveness to acetylcholinesterase inhibitor treatment for Alzheimer's disease.

Acetylcholinesterase inhibitor (AChEI) drug regimens are the mainstay treatment options for patients with Alzheimer's disease (AD). Herein, We examined the association between clinical response to AChEI and white matter hyperintensities on magnetic resonance imaging (MRI) scan at baseline. Between 2020 and 2021, we recruited 101 individuals with a clinical diagnosis of probable AD. Each participant underwent complete neuropsychological testing and 3T (Telsa) brain magnetic resonance imaging. Responsiveness to AChEI, as assessed after 12 months, was designated as less than two points of regression in Mini-Mental State Examination scores (MMSE) and stable clinical dementia rating scale. We also evaluated MRI images by examining scores on the Cholinergic Pathways Hyperintensities Scale (CHIPS), Fazekas scale, and medial temporal atrophy (MTA) scale. In our cohort, 52 patients (51.4%) were classified as responders. We observed significantly higher CHIPS scores in the nonresponder group (21.1 ± 12.9 vs. 14.9 ± 9.2, P = 0.007). Age at baseline, education level, sex, Clinical Dementia Rating sum of boxes scores, and three neuroimaging parameters were tested in regression models. Only CHIPS scores predicted clinical response to AChEI treatment. WMHs in the cholinergic pathways, not diffuse white matter lesions or hippocampal atrophy, correlated with poorer responsiveness to AChEI treatment. Therefore, further investigation into the role of the cholinergic pathway in AD is warranted.

Association of acetylcholinesterase inhibitor and memantine treatment with cognitive function in patients with clinical dementia syndrome with and without post‐mortem Alzheimer pathology

AbstractBackgroundAcetylcholinesterase inhibitors (AchE‐I) and memantine are licensed and recommended for the treatment of dementia of Alzheimer type (DAT). Between 10 and 20 % of patients with DAT, however, do not have Alzheimer’s disease (AD) pathology. It remains unclear, if these patients also benefit from treatment. This project aims to examine the association of AchE‐I and memantine use with cognitive function in patients with DAT with and without evidence of AD pathology at autopsy.MethodThis study is based on The National Alzheimer‘s Coordinating Center‐Uniform Data Set (NACC‐UDS). Inclusion of participants for this analysis was based on the following criteria: 1) Diagnosis of DAT, 2) information on the extent of AD‐neuropathological change at autopsy (ABC score high/intermediate/low/not), 3) follow‐up time ≥ 6 months, 4) ≥ 2 Mini‐Mental State Examinations (MMSE) during follow‐up.Result1483 participants with 3.8 ± 1.7 visits met inclusion criteria. Of these, 1009 participants showed an ABC score of “high”, 265 of “intermediate” and 209 of “low/not”. Use of AD‐medication was more common in participants with pronounced AD pathology (ABC score “high”: 89 %, “intermediate”: 66 %, “low/not”: 53 %). Follow‐up time was 41 ± 23 months in participants with medication compared to 36 ± 24 months in participants without medication. In the group of participants with an ABC score of “high” and “intermediate”, those with treatment showed a baseline MMSE score of 23 ± 5 and a decline of 8 ± 6 points, while those without treatment scored 26 ± 4 at baseline with a decline of 4 ± 6 points. In the cohort of participants with an ABC score of “low” and “not”, both groups with and without medication showed a baseline MMSE score of 26 ± 4 points with a decline in those with medication of 6 ± 6 points and of 3 ± 4 points in those without medication.ConclusionThe present descriptive analysis does not provide evidence for a clear association of treatment with AD medication and the presence of AD pathology in patients with DAT. Modelling analyses including covariates will be presented.

Pharmaco-fUS in cognitive impairment: Lessons from a preclinical model.

There is an urgent need to understand and reverse cognitive impairment. The lack of appropriate animal models combined with the limited knowledge of pathophysiological mechanisms makes the development of new cognition-enhancing drugs complex. Scopolamine is a pharmacologic agent which impairs cognition and functional imaging in a wide range of animal species, similarly to what is seen in cognitive impairment in humans. In this study, using a functional ultrasound (fUS) neuroimaging technique, we monitored the impact of donepezil (DPZ), a potent acetylcholinesterase inhibitor and first-line treatment in patients with mild to moderate Alzheimer's disease, in a scopolamine-induced mouse model. We demonstrated that despite its low impact on the cerebral blood volume (CBV) signal, scopolamine injection produced an overall decrease in functional connectivity between various brain areas. In addition, we revealed that DPZ induced a strong decrease in CBV signal without causing a difference in functional connectivity. Finally, our work highlighted that DPZ counteracted the impact of scopolamine on functional connectivity changes and confirmed the interest of using pharmaco-fUS imaging on cognitive disorders, both in frequent and rare neurological disorders.

Normalized Theta but Increased Gamma Activity after Acetylcholinesterase Inhibitor Treatment in Alzheimer's Disease: Preliminary qEEG Study.

Acetylcholinesterase inhibitors (AChE-I) are the core treatment of mild to severe Alzheimer's disease (AD). However, the efficacy of AChE-I treatment on electroencephalography (EEG) and cognition remains unclear. We aimed to investigate the EEG power and coherence changes, in addition to neuropsychological performance, following a one-year treatment. Nine de-novo AD patients and demographically-matched healthy controls (HC) were included. After baseline assessments, all AD participants started cholinergic therapy. We found that baseline and follow-up gamma power analyzes were similar between groups. Yet, within the AD group after AChE-I intake, individuals with AD displayed higher gamma power compared to their baselines (P < .039). Also, baseline gamma coherence analysis showed lower values in the AD than in HC (P < .048), while these differences disappeared with increased gamma values of AD patients at the follow-up. Within the AD group after AChE-I intake, individuals with AD displayed higher theta and alpha coherence compared to their baselines (all, P < .039). These increased results within the AD group may result from a subclinical epileptiform activity. Even though AChE-I is associated with lower mortality, our results showed a significant effect on EEG power yet can increase the subclinical epileptiform activity. It is essential to be conscious of the seizure risk that treatment may cause.

Racial/ethnic disparities in initiation and persistent use of anti-dementia medications.

Racial/ethnic disparities in anti-dementia medications use in longitudinally followed research participants are unclear. The study included initially untreated participants followed in National Alzheimer's Coordinating Center Uniform Data Set who were ≥65 at baseline with Alzheimer's disease dementia. Outcomes for acetylcholinesterase inhibitor (AChEI) treatment included (1) any new AChEI treatment during follow-up, and (2) persistence of treatment during follow-up categorized into: intermittent treatment (<50% follow-ups reporting treatment), persistent (≥50% follow-ups), and always treated. Outcomes for memantine treatment were similarly constructed. Controlling for participant characteristics, Black and Hispanic participants remained less likely than White participants to report any new AChEI or memantine treatment during follow-up. Among those who reported new treatment during follow-up, both Black and Hispanic participants were less likely than White participants to be persistently treated with AChEI and memantine. Substantial racial/ethnic treatment disparities remain in controlled settings of longitudinal research in which participants have access to dementia experts, suggesting wider disparities in the larger community.

Factors associated with slow progression of cognitive impairment following first dementia diagnosis.

To investigate the extent to which slow progression of dementia after diagnosis might be predicted from routine longitudinal healthcare data, in order to clarify characteristics of people who experience this outcome. A retrospective observational study was conducted using data from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre Case Register. This study included all patients receiving a first dementia diagnosis between 2006 and 2017, restricted to those with a baseline Mini-Mental State Examination (MMSE) score within 6 months of initial diagnosis of dementia and at least one MMSE score after 3 years post-diagnosis. Slow progression was defined as a change in MMSE score of -1, 0 or an increase at the follow-up point. This group was compared to the remainder with an MMSE decline of -2 or more. Overall, 682 patients with slow progression were compared to 1045 with faster progression. In the confounder-adjusted multivariate logistic regression model, slow progression was more likely in younger patients (age 65-74 years; odds ratio: 1.18; 95% confidence intervals: 1.04-1.37), males (1.24; 1.01-1.53), those with moderate or severe dementia according to MMSE, patients with mixed-type dementia (2.06; 1.11-3.82) compared to Alzheimer's disease and less likely in those receiving acetylcholinesterase inhibitor (AChEI) treatment (0.57; 0.46-0.71). Slow dementia progression after diagnosis was common in patients with mixed Alzheimer's and vascular dementia, younger age, males and non-receipt of AChEIs, possibly suggesting non-Alzheimer pathologies and clarifying such predictors is important, as there is currently very limited information on which to base prognosis estimates in post-diagnosis counselling.

Comparison of Mini Mental Score Examination, Quantitative Electroencephalography and Cerebrospinal Fluid Biomarkers in Clinical Practice Examining Dementia

Background: A new method to measure the cholinergic status with quantitative electroencephalography (qEEG) to distinguish healthy from early dementia patients and identify responders of Acetylcholinesterase inhibitor treatment. The objective is to evaluate cognition via Mini Mental Score Examination (MMSE) at baseline and follow-up examination after approximately 2 years for patients with suspected dementia and comparison with the predictive baseline values for (qEEG) and Cerebro-spinal fluid (Csf) biomarkers. If qEEG predicts the cognitive decline best, a noninvasive and inexpensive method is offering the possibility to start Acetylcholinesterase inhibitor treatment early in the dementia disease course. Methods: The average power of four qEEG epochs with eyes closed (E.Cl.) and open eyes (E.O.), and the ratio of E.O. / E.Cl. (Vigilance-index), and average peak frequency of E.Cl. epochs, calculated. The Csf parameters; total-Tau, phospho-Tau, and Amyloid β-42 analyzed. The correlation between the number of pathological MMSE-scores and pathological values of baseline biomarkers evaluated. Results: The Spearman rank correlation between MMSE revealed no linear relation for the examined biomarkers. When comparison of pathological values for MMSE at follow up after approximately 2 years the sensitivity to identify from the baseline values for qEEG and Csf biomarkers, found Vigilanceindex to have the highest sensitivity (1.0) then total-Tau (0.5) and the rest parameters lower, lowest for the combination of Csf parameters (0,09) to predict cognitive decline. The specificity for the baseline Vigilance-index was (0.87) and for total-Tau (0.39) and lower for the other parameters at the follow-up examination. Conclusion: Vigilance-index best reflects the cognitive decline after two years in early dementia disease, by measuring cholinergic deficit, compared to Csf biomarkers to measure total-Tau, phospho-Tau, and Amyloid β-42.

Congenital myasthenic syndrome caused by novel COL13A1 mutations

Collagen XIII is a non-fibrillar transmembrane collagen which has been long recognized for its critical role in synaptic maturation of the neuromuscular junction. More recently, biallelic COL13A1 loss-of-function mutations were identified in three patients with congenital myasthenic syndrome (CMS), a rare inherited condition with defective neuromuscular transmission, causing abnormal fatigability and fluctuating muscle weakness and often successfully treated with acetylcholinesterase inhibitors. Here we report six additional CMS patients from three unrelated families with previously unreported homozygous COL13A1 loss-of-function mutations (p.Tyr216*, p.Glu543fs and p.Thr629fs). The phenotype of our cases was similar to the previously reported patients including respiratory distress and severe dysphagia at birth that often resolved or improved in the first days or weeks of life. All individuals had prominent eyelid ptosis with only minor ophthalmoparesis as well as generalized muscle weakness, predominantly affecting facial, bulbar, respiratory and axial muscles. Response to acetylcholinesterase inhibitor treatment was generally negative while salbutamol proved beneficial. Our data further support the causality of COL13A1 variants for CMS and suggest that this type of CMS might be clinically homogenous and requires alternative pharmacological therapy.

Comparison of Cholinergic Status with Quantitative EEG in Healthy Subjects and Patients Suspected of Dementia

Introduction: Objective is to evaluate quantitative electroencephalography (qEEG) variables to distinguish healthy subjects from patients who investigated for dementia and, to assess also at follow-up examination if acetylcholinesterase inhibitor (AChEI) treatment or not influenced the qEEG.

COMPARISON OF CHOLINERGIC STATUS EVALUATED VIA QUANTITATIVE EEG PARAMETERS IN NORMAL SUBJECTS AND PATIENTS SUSPECTED OF DEMENTIA

This study evaluated quantitative electroencephalography (QEEG) variables to distinguish normal subjects from patients who were being investigated for dementia and followed-up with or without acetylcholinesterase inhibitor (AChEI) treatment. Means from 4 EEG epochs obtained with eyes closed (E.Cl.) 80 sec. per epoch or eyes open (E.O.) 25 sec. per epoch, the peak frequency with eyes closed and the vigilance index (ratio of E.O./E.Cl. mean power) were calculated. A normal group and a group suspected of having primary dementia were followed after 10±4 with or 11±4 months without AChEI treatment. Student's t tests compared the means and standard deviations and the extent of changes between the baseline and follow-up assessments. Based on earlier studies when cholinergic and anticholinergic drugs tested in humans, demonstrates the anticholinergic effect on EEG by reducing power of basic rhythm (Alfa-rhythm) and increase power when eyes are open, why vigilance index reflects the anticholinergic effect on the EEG. When the normal group were compared with those of the suspected dementia group at baseline, all variables were significantly altered. The vigilance index and power of the E.O. increased, the peak frequency and E.Cl. power was reduced (Fig 1). At follow-up, the vigilance index and E.O. power of the untreated group increased (p = 0.06, respectively 0.07) compared to AChEI treated group (p = 0.46 respectively 0.43). The ratio of the change compared to baseline was unchanged for the vigilance-index (1.0) for the AchEI treated, while increased (1.15) in the untreated group. For E.O power reduced (0.69) for the treated and increased (1.43) for the treated group. The treated group exhibited a higher proportion of patients with a decreased or unchanged vigilance index and fewer patients with an increased vigilance index than the untreated patients (Fig. 2). The examined variables. A (left) Normal EEG with four epochs superimposed n the graphs. B (right) shows an examination of a patient at baseline (above) under E.CI. and E.O. conditions and follow-up (tower) in B. The patient did not receive AChEI treatment. Thus, the power ratio value of the E.O./E.CI. (vigilance index) increased at follow-up. Comparison of the vigilance index at the follow-up EEG of patients who were treated with or without AChEI after the baseline EEG. The treated group exhibited a higher proportion of patients with a decreased or unchanged vigilance index and fewer patients with an increased vigilance index compared to untreated patients. These data support the hypothesis that acetylcholine levels further reduction halts or even increases in patients treated with AChEI. The increased vigilance index in AChEI treated group suggests that these patients did not respond to the treatment at this follow-up visit (non-responders). The vigilance index reflects the cholinergic status, and it was clearly increased in the early dementia group and at follow-up for those not treated with AChEI, but was not changed in the treated patients. The vigilance index may be used to assess cholinergic deficits in patients with dementia and evaluate the effects of AChEI treatment.

Parkinson's disease psychosis: presentation, diagnosis and management.

Parkinson's disease is a neurodegenerative disorder characterized by motor and nonmotor symptoms. Psychosis is a common feature of Parkinson's disease. Parkinson's disease psychosis (PDP) encompasses minor phenomena (illusions, passage hallucinations and presence hallucinations), visual and nonvisual hallucinations and delusions. PDP is associated with reduced function and quality of life. The initial management approach should focus on identification and treatment of any contributory medical factors, reduction or discontinuation of medications with potential to induce or worsen psychosis, nonpharmacological strategies and consideration of acetylcholinesterase inhibitor treatment in the setting of dementia. Pimavanserin, quetiapine and clozapine may all be considered for use in PDP. In this review, we discuss the presentation, diagnosis and management of PDP.

Associations of acetylcholinesterase inhibitor treatment with reduced mortality in Alzheimer's disease: a retrospective survival analysis

dementia is increasingly recognised as life-limiting condition. Although the benefits of acetylcholinesterase inhibitors (AChEIs) on cognition and function are well established, their effect on survival is less clear. to investigate associations between AChEI prescription and mortality in patients with Alzheimer's dementia (AD) in a naturalistic setting, using detailed baseline data on cognition, functioning, and mental and physical wellbeing. we used a large mental healthcare database in South London, linked to Hospital Episode Statistics and Office for National Statistics mortality data, to assemble a retrospective cohort. We conducted a survival analysis adjusting for a wide range of potential confounders using propensity scores to reduce the impact of confounding by indication. of 2,464 patients with AD, 1,261 were prescribed AChEIs. We detected a strong association between AChEI receipt and lower mortality (hazard ratio = 0.57; 95% CI 0.51-0.64). This remained significant after controlling for a broad range of potential confounders including psychotropic co-prescription, symptom severity, functional status and hospital admissions (hazard ratio = 0.77; 95% CI 0.67-0.87). in a large cohort of patients with AD, AChEI prescription was associated with reduced risk of death by more than 20% in adjusted models. This has implications for individual care planning and service development.

Rivastigmine reduces postoperative delirium in elderly patients

Elderly patients with cognitive impairment who received a rivastigmine patch in the period 3 days before to 7 days after hip surgery experienced less incidence and severity of postoperative delirium than patients who did not receive the acetylcholinesterase inhibitor treatment, a new study has found. No rivastigmine‐related complications occurred during surgery, the researchers added.

Sex differences in Alzheimer's disease and other dementias

The Lancet Neurology Commission1 draws attention to the dramatically increasing personal, societal, and economic costs of Alzheimer’s disease (AD) and associated dementias, and provides a call to action for an innovative research response to develop prevention and treatment strategies. The Commission also emphasises that the symptoms and course of dementias necessitate long-term care, thus requiring outcome assessments that include both patients’ health status and the viability of health-care systems. We assert that, integrated within the portfolio of research proposed by the Commission, a focus on the effect of sex on AD and other dementias is essential to ensure progress in understanding, treatment, and prevention of these disorders. AD and other dementias disproportionately affect women. The Commission affirms that, for most regions of the world, the occurrence of AD and other dementias is higher in women than in men, particularly in the most elderly, and that women provide most caregiving for people with dementia.1 However, beyond statistics showing the greater burden of dementias for women, empirical data about sex differences and emerging sex-specific findings in dementias can guide and inform the scientific approach to these illnesses for the benefit of both women and men. Brain development and adult brain structure, function, and biochemistry differ by sex.2 These sex differences in the brain are initiated through sex-determining genes and fetal hormonal programming. Such differences have important implications for brain-based disease risk and for clinical and investigational approaches. For example, with regard to genetic findings, the results of a large prospective cohort study published in 2015 confirmed previous case–control reports that women who are positive for the e4 allele of the apolipoprotein E gene (APOE e4) are at greater risk of developing AD than are men with this allele,3 and they demonstrate more severe behavioural disinhibition.4 As pointed out in these investigations, the inconsistency of past findings about this allele could be attributable specifically to investigators overlooking the APOE-e4-by-sex interaction, resulting in missed opportunities to enhance understanding of the genetic underpinnings of AD.3 Testing for the effects of numerous other genes implicated in dementias by sex, rather than pooling data for both sexes, would likewise speed efforts to discern new directions for personalised treatment and management.5 In terms of localised brain changes and brain function, reports suggest that women diagnosed with AD experience a faster progression of hippocampal atrophy than do men,6 whereas men might be more likely to progress to AD in the presence of severe periventricular white matter hyperintensities and reduced global cognitive performance.7 Women and men also have different clinical presentations, in that men show more aggressive behaviours, more comorbidity, and higher mortality than women; women tend to have more affective symptoms and disability but longer survival times.8 These presentations might indicate different neuropathologies and certainly necessitate different management strategies to serve men and women with dementia. From the perspective of treatment, emerging evidence also points to the possibility that sex-specific genetic and hormonal factors contribute to variance in clinical efficacy. For example, the improved response to acetylcholinesterase inhibitor treatment in women with AD was attributed to variants of the oestrogen receptor α gene (ESR1).9 In addition to differences in genetic or brain-based vulnerabilities, broader societal factors also have roles in the risk, course, and outcome of dementias. Perhaps the most salient examples are education and occupation levels, both of which have repeatedly been shown to affect the risk of dementia and for which substantial inequalities have existed between the sexes in previous generations.5 A host of behavioural and lifestyle choices, including diet, exercise, and tobacco and alcohol use, also affect vascular risk factors and the degree of disability in individuals with dementia. In brief, an individual’s behaviours and experiences over the lifespan affect the brain, and many of these factors vary by sex. Sex differences, extending from genetic to psychosocial domains, are relevant to productive and reproducible research, and they signal urgent priorities for public health planning. For example, almost all countries are facing the same demographic evolution in which women are diversifying their roles while carrying the heavier burden of caregiving. The availability of resources differs substantially across countries, yet the needs of a growing population of people with dementias cannot be met by public and social-care sectors alone, prompting important questions about the role of women in future caregiving.1 Advances have been made in various fields, from cardiology to addiction medicine, by analysing the effects of sex on outcomes.10 The Lancet Neurology Commission provides a timely opportunity to embrace this approach in the research agenda for AD and other dementias.

Acetylcholinesterase inhibitor treatment for myasthenia gravis.

In myasthenia gravis, antibody-mediated blockade of acetylcholine receptors at the neuromuscular junction abolishes the naturally occurring 'safety factor' of synaptic transmission. Acetylcholinesterase inhibitors provide temporary symptomatic treatment of muscle weakness but there is controversy about their long-term efficacy, dosage and side effects. This is the second update of a review published in The Cochrane Library Issue 2, 2011. To evaluate the efficacy of acetylcholinesterase inhibitors in all forms of myasthenia gravis. On 8 July 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE and EMBASE for randomised controlled trials and quasi-randomised controlled trials regarding usage of acetylcholinesterase inhibitors in myasthenia gravis. Two authors scanned the articles for any study eligible for inclusion. We also contacted the authors and known experts in the field to identify additional published or unpublished data and searched clinical trials registries for ongoing trials. The types of studies were randomised or quasi-randomised trials. Participants were myasthenia gravis patients diagnosed by an internationally accepted definition. The intervention was treatment with any form of acetylcholinesterase inhibitor. Types of outcome measures Primary outcome measureImprovement in the presenting symptoms within one to 14 days of the start of treatment. Secondary outcome measures(1) Improvement in the presenting symptoms more than 14 days after the start of treatment.(2) Change in impairment measured by a recognised and preferably validated scale, such as the quantitative myasthenia gravis score, within one to 14 days and more than 14 days after the start of treatment.(3) Myasthenia Gravis Association of America post-intervention status more than 14 days after start of treatment.(4) Adverse events including muscarinic side effects. One author (MMM) extracted the data, which were checked by a second author. We contacted study authors for extra information and collected data on adverse effects from the trials. We did not find any large randomised or quasi-randomised trials of acetylcholinesterase inhibitors in generalised myasthenia gravis either for the first version of this review or this update. One cross-over randomised trial using intranasal neostigmine in a total of 10 participants was only available as an abstract. It included three participants with ocular myasthenia gravis and seven with generalised myasthenia gravis. Symptoms of myasthenia gravis (measured as improvement in at least one muscle function) improved in nine of the 10 participants after the two-week neostigmine treatment phase. No participant improved after the placebo phase. Lack of detail in the report meant that the risk of bias was unclear. Adverse events were minor. Except for one small and inconclusive trial of intranasal neostigmine, no other randomised controlled trials have been conducted on the use of acetylcholinesterase inhibitors in myasthenia gravis. The response to acetylcholinesterase inhibitors in observational studies is so clear that a randomised controlled trial depriving participants in a placebo arm of treatment would be difficult to justify.

Is memantine + acetylcholinesterase inhibitor treatment superior to either therapy alone in Alzheimer's disease?

Alzheimer's disease is the most common form of dementia in the elderly. Currently, there is no established standard treatment for this disease; therefore, the treatment of Alzheimer's disease will be a major challenge for physicians in the next decade in order to ameliorate quality of life of patients and reduce the costs for the communities.

Cholinergic neuromuscular hypersensitivity in musk antibody positive myasthenia gravis

Background: The patients with MuSK antibody (MuSK-Ab) positive myasthenia gravis (MG) show distinct responses to acetylcholinesterase inhibitor (AChEI), such as less effective therapeutic response to AChEI and more frequent nicotinic side effects and negative result of diagnostic AChEI test. Some MuSK-Ab positive MG patients experience overt worsening after AChEI treatment. In addition, the compound muscle action potential with extradischarges (CMAP-EDs), elecrophysiologic feature of cholinergic neuromuscular hyperactivity, may develop in the MuSK-Ab positive MG patients with usual therapeutic dose of AChEI.

Rivastigmine is associated with restoration of left frontal brain activity in Parkinson's disease

The objective of this study was to investigate how acetylcholinesterase inhibitor (ChEI) treatment affects brain function in Parkinson's disease (PD). Twelve patients with PD and either dementia or mild cognitive impairment underwent task-free functional magnetic resonance imaging before and after 3 months of ChEI treatment and were compared with 15 age- and sex-matched neurologically healthy controls. Regional spontaneous brain activity was measured using the fractional amplitude of low-frequency fluctuations. At baseline, patients showed reduced spontaneous brain activity in regions important for motor control (eg, caudate, supplementary motor area, precentral gyrus, thalamus), attention and executive functions (eg, lateral prefrontal cortex), and episodic memory (eg, precuneus, angular gyrus, hippocampus). After treatment, the patients showed a similar but less extensive pattern of reduced spontaneous brain activity relative to controls. Spontaneous brain activity deficits in the left premotor cortex, inferior frontal gyrus, and supplementary motor area were restored such that the activity was increased posttreatment compared with baseline and was no longer different from controls. Treatment-related increases in left premotor and inferior frontal cortex spontaneous brain activity correlated with parallel reaction time improvement on a test of controlled attention. PD patients with cognitive impairment show numerous regions of decreased spontaneous brain function compared with controls, and rivastigmine is associated with performance-related normalization in the left frontal cortex function.

Cholinergic enhancement of functional networks in older adults with mild cognitive impairment

The importance of the cholinergic system for cognitive function has been well documented in animal and human studies. The objective of this study was to elucidate the cognitive and functional connectivity changes associated with enhanced acetylcholine levels. We hypothesized that older adults with mild memory deficits would show behavioral and functional network enhancements with an acetylcholinesterase inhibitor treatment (donepezil) when compared to a placebo control group. We conducted a 3-month, double-blind, placebo-controlled study on the effects of donepezil in 27 older adults with mild memory deficits. Participants completed a delayed recognition memory task. Functional magnetic resonance imaging (fMRI) scans were collected at baseline prior to treatment and at 3-month follow-up while subjects were on a 10mg daily dose of donepezil or placebo. Donepezil treatment significantly enhanced the response time for face and scene memory probes when compared to the placebo group. A group-by-visit interaction was identified for the functional network connectivity of the left fusiform face area (FFA) with the hippocampus and inferior frontal junction, such that the treatment group showed increased connectivity over time when compared to the placebo group. Additionally, the enhanced functional network connectivity of the FFA and hippocampus significantly predicted memory response time at 3-month follow-up in the treatment group. These findings suggest that increased cholinergic transmission improves goal-directed neural processing and cognitive ability and may serve to facilitate communication across functionally-connected attention and memory networks. Longitudinal fMRI is a useful method for elucidating the neural changes associated with pharmacological modulation and is a potential tool for monitoring intervention efficacy in clinical trials.