Acetylcholinesterase Inhibitor Therapy Research Articles

Galantamine Reduces Blood Pressure and Renal Injury in Female Angiotensin II-induced Hypertensive Mice

Inflammation is a known culprit in the development and progression of hypertension. The autoimmune disease, systemic lupus erythematosus (SLE), is an important model of hypertension in the setting of chronic kidney inflammation. We have shown that administration of an acetylcholinesterase inhibitor, galantamine, attenuates the hypertension, kidney inflammation, and kidney injury in female SLE mice by activating the vagally-mediated cholinergic anti-inflammatory pathway. Although SLE hypertension represents a specific population of patients, we hypothesized that galantamine would have similar anti-inflammatory effects in the angiotensin II (AngII)-induced hypertensive mouse, which more commonly models essential hypertension. Female C57BL/6 mice were implanted with minipumps at 9 weeks of age for subcutaneous delivery of either AngII (1000 ng/kg/min) or saline (controls), and galantamine hydrobromide (4 mg/kg/day) or vehicle, for 21 days. At 12 weeks, carotid catheters were implanted and mean arterial pressure (MAP) was measured in conscious mice for two consecutive days. Mice were then euthanized, and kidneys collected. Markers of kidney inflammation and injury, including interleukin (IL)-6 and kidney injury molecule (KIM)-1, were measured by ELISA and normalized to total kidney protein. MAP (mmHg) was higher in AngII-treated mice compared to controls (174±4 vs. 133±3; n=4-5, p=0.0023). Galantamine lowered MAP in AngII mice (157±8; n=7, p=0.2567) without altering MAP in controls (133±4; n=5, p=0.9999). Renal IL-6 (pg/μg) was not different between AngII and control mice (0.004±0.0001 vs. 0.005±0.0006; p=0.6685). Although galantamine lowered IL-6 in both groups, it was only significant in controls (0.003±0.0002; p=0.0134) and not AngII mice (0.003±0.0003; p=0.4677). Renal cortical KIM-1 (pg/μg) trended higher in AngII mice compared to controls (2.53±0.50 vs 0.63±0.16; p=0.0741). Galantamine lowered KIM-1 in AngII mice (1.18±0.39, p=0.2064), but not controls (1.45 ± 0.59; p=0.6285). In summary, galantamine protected female mice from hypertension and renal injury in a model of AngII hypertension. This suggests that acetylcholinesterase inhibitor therapy may be effective in patients with hypertension. Studies funded by NIH R01HL153703 and K01HL139859 for KWM. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

ACT‐AD: Fosgonimeton in mild‐to‐moderate Alzheimer’s disease – first results of a randomized, placebo‐controlled, 26‐week Phase 2 proof‐of‐concept trial

AbstractBackgroundFosgonimeton (ATH‐1017) is a positive modulator of HGF/MET, a key neurotrophic pathway impaired in Alzheimer’s disease (AD). Neuronal MET expression is decreased in the cortex and hippocampus, which may contribute to synaptic loss, neurodegeneration, and functional decline. ACT‐AD seeks to replicate and extend the previously shown improvement of event‐related potential (ERP) P300 latency in AD patients demonstrated in an 8‐day randomized, placebo‐controlled, double‐blind Phase 1 trial. ERP P300 latency is a noninvasive, objective, quantitative biomarker of cognitive performance without learning effects.MethodACT‐AD is a Phase 2, 26‐week, randomized, double‐blind, placebo‐controlled, parallel group trial in patients with a clinical diagnosis of mild to moderate AD. Patients enrolled were aged 55‐85 years, had a mini‐mental state examination (MMSE) score of 14‐24, a Clinical Dementia Rating global score of 1 or 2 at screening, a syndromal clinical diagnosis of probable AD according to McKhann et al. (Alzheimers Dement. 2011), and were treatment‐naïve or receiving stable acetylcholinesterase inhibitor therapy. Patients were randomized (1:1:1) to placebo or fosgonimeton at doses of 40 or 70 mg, administered subcutaneously once daily. The trial is powered for the primary endpoint, change in ERP P300 latency. Secondary endpoints include ADAS‐Cog11, ADCS‐CGIC and ADCS‐ADL23. The relationship of ERP P300 latency with cognition, memory and executive function, as well as pharmacokinetics, and safety will also be analyzed.ResultIn total, 77 patients with mild to moderate AD were randomized, with a mean (SD) age of 71.4 (7.3) years, 50.6% female, and mean (SD) baseline MMSE score of 19.5 (3.1). ApoE4 carriers made up 56% of the population, with 42% as noncarriers and 2% unknown.ConclusionThe double‐blind period of ACT‐AD is ongoing and estimated to complete in May 2022, with results available in June 2022. First analyses will be presented at the annual 2022 AAIC congress.This study is sponsored by Athira Pharma, registered at Clinicaltrials.gov: NCT04491006, and supported by a grant from the National Institute on Aging of the National Institutes of Health under Award Number R01AG06268.

Role of Pharmacogenomics in Individualizing Treatment for Alzheimer's Disease.

The development of Alzheimer's disease therapeutics has been challenging, with 99% of clinical trials failing to find a significant difference between drug and placebo. While the quest continues for more effective treatments, there is emerging evidence that pharmacogenetic considerations are important factors in regard to metabolism, efficacy, and toxicity of drugs. Currently, there are five US Food and Drug Administration-approved drugs for the treatment of Alzheimer's disease; three acetylcholinesterase inhibitors, memantine, and aducanumab. Introducing a limited genetic panel consisting of APOE4, CYP2D6*10, and BChE*K would optimize acetylcholinesterase inhibitor therapy, facilitate immunotherapy risk assessment, and inform an amyloid-related imaging abnormality surveillance schedule. In view of the genetic heterogeneity of Alzheimer's disease identified in genome-wide association studies, pharmacogenetics is expected to play an increasing role in mechanism-specific treatment strategies and personalized medicine.

The combination of acetylcholinesterase inhibitor therapy and high‐frequency repetitive transcranial magnetic stimulation in Alzheimer’s disease: A preliminary fMRI study

AbstractBackgroundBasal forebrain (BF) cholinergic dysfunction is one of the characteristics in Alzheimer’s disease (AD). Acetylcholinesterase inhibitors (AChEI) are approved drus currently used for the clinical treatment of AD. However, drug therapy has considerable side effects, and not everyone can benefit from it. Previous studies have shown that repetitive transcranial magnetic stimulation (rTMS) can improve cognitive function in patients with AD. Therefore, we aimed to determine the effect of cholinergic treatment on BF functional brain networks using functional connectivity (FC) analysis, and investigate whether donepezil therapy combined with rTMS is superior to monotherapy of AD.MethodThirty AD patients received ten sessions of 10Hz high frequency rTMS (HF‐rTMS) at 110% of the motor threshold on the left dorsolateral prefrontal cortex (DLPFC) and the left lateral parietal cortex (combination therapy group, n=15) or sham stimulation (drug treatment group, n=15), added to their donepezil treatment (5mg/d), in a randomized double‐blind design. Fifteen untreated and age, gender and years of education matched AD patients served as control group. The resting‐state FC of BF was calculated using a seed‐based approach. Spearman correlation with false discovery rate (FDR) correction was used to investigate the relationship between clinical and cognitive tests scores and FC values.ResultCompared to control group, the combination therapy group showed BF seed‐based FC enhancement in the bilateral posterior cingulate cortex (PCC), superior parietal lobule, left hippocampus, precuneus, and cerebellum. Drug treatment patients showed increased BF‐related FC in the bilateral PCC, and left hippocampus, and cerebellum. In addition, combination therapy group patients had significantly higher BF seed‐based FC in the left PCC and precuneus than drug treatment patients. Moreover, these brain regions are mainly concentrated in the default mode network (DMN).ConclusionOur results indicate that the levels of functional connectivity between the BF and the DMN is significantly higher in the combination therapy group than that in the other groups, and which is positively correlated with improvements in MMSE and ADL. HF‐rTMS over the left DLPFC and the left lateral parietal cortex is an add‐on strategy of clinical significance in combination with donepezil in patients with AD.

Congenital myasthenic syndrome in China: genetic and myopathological characterization

ObjectiveWe aimed to summarize the clinical, genetic, and myopathological features of a cohort of Chinese patients with congenital myasthenic syndrome, and follow up on therapeutic outcomes.MethodsThe clinical spectrum, mutational frequency of genes, and pathological diagnostic clues of various subtypes of patients with congenital myasthenic syndrome were summarized. Therapeutic effects were followed up.ResultsThirty‐five patients from 29 families were recruited. Ten genes were identified: GFPT1 (27.6%), AGRN (17.2%), CHRNE (17.2%), COLQ (13.8%), GMPPB (6.9%), CHAT, CHRNA1, DOK7, COG7, and SLC25A1 (3.4% each, respectively). Sole limb‐girdle weakness was found in patients with AGRN (1/8) and GFPT1 (7/8) mutations, whereas distal weakness was all observed in patients with AGRN (6/8) mutations. Tubular aggregates were only found in patients with GFPT1 mutations (5/6). The patients with GMPPB mutations (2/2) had decreased alpha‐dystroglycan. Acetylcholinesterase inhibitor therapy resulted in no response or worsened symptoms in patients with COLQ mutations, a diverse response in patients with AGRN mutations, and a good response in patients with other subtypes. Albuterol therapy was effective or harmless in most subtypes. Therapy effects became attenuated with long‐term use in patients with COLQ or AGRN mutations.InterpretationThe genetic distribution of congenital myasthenic syndrome in China is distinct from that of other ethnic origins. The appearance of distal weakness, selective limb‐girdle myasthenic syndrome, tubular aggregates, and decreased alpha‐dystroglycan were indicative of the specific subtypes. Based on the follow‐up findings, we suggest cautious evaluation of the long‐term efficacy of therapeutic agents in congenital myasthenic syndrome.

Selective Vulnerability of the Nucleus Basalis of Meynert Among Neuropathologic Subtypes of Alzheimer Disease

Corticolimbic patterns of neurofibrillary tangle (NFT) accumulation define neuropathologic subtypes of Alzheimer disease (AD), which underlie the clinical heterogeneity observed antemortem. The cholinergic system, which is the target of acetylcholinesterase inhibitor therapy, is selectively vulnerable in AD. To investigate the major source of cholinergic innervation, the nucleus basalis of Meynert (nbM), in order to determine whether there is differential involvement of NFT accumulation or neuronal loss among AD subtypes. In this cross-sectional study, retrospective abstraction of clinical records and quantitative assessment of NFTs and neuron counts in the nbM was completed in January 2019 at the Mayo Clinic using the Florida Autopsied Multi-Ethnic (FLAME) cohort, which had been accessioned from 1991 until 2015. The FLAME cohort is derived from the deeded autopsy program funded throughout the State of Florida's memory disorder clinic referral services. Of the 2809 consecutively accessioned FLAME cohort, 1464 were identified as neuropathologically diagnosed AD cases and nondemented normal controls available for clinicopathologic assessment. Quantification of NFTs and neuronal density in the anterior nbM was performed blinded to neuropathologic groupings. Demographic and clinical characteristics, including cognitive decline measured using the Mini-Mental State Examination score (range, 0-30), were evaluated. The anterior nbM was investigated quantitatively for neuronal loss and NFT accumulation. In total, 1361 AD subtypes and 103 nondemented controls were assessed. The median (interquartile range) age at death was 72 (66-80) years in hippocampal sparing (HpSp) AD, 81 (76-86) years in typical AD, and 86 (82-90) years in limbic predominant AD. The median (interquartile range) count per 0.125 mm2 of thioflavin S-positive NFTs was highest in the nbM of HpSp AD (14 [9-20]; n = 163), lower in typical AD (10 [5-16]; n = 937), and lowest in limbic predominant AD (8 [5-11], n = 163) (P < .001). The median (interquartile range) neuronal density per millimeters squared was lowest in HpSp AD cases (22 [17-28]; n = 148), higher in typical AD (25 [19-30]; n = 727), and highest in limbic predominant AD (26 [19-32]; n = 127) (P = .002). Multivariable regression modeling of clinical and demographic variables was performed to assess overlap in NFT accumulation and neuronal density differences among AD subtypes. Higher NFT accumulation in the nbM was associated with younger age at onset for HpSp AD (β, -1.5; 95% CI, -2.9 to -0.15; P = .03) and typical AD (β, -3.2; 95% CI, -3.9 to -2.4; P < .001). In addition, higher NFT accumulation in the nbM of typical AD cases was associated with female sex (β, 2.5; 95% CI, 1.4-3.5; P < .001), apolipoprotein E ε4 allele (β, 1.3; 95% CI, 0.15-2.5; P = .03), and lower Mini-Mental State Examination scores (β, -1.8; 95% CI, -3.2 to -0.31; P = .02). Demographic and clinical progression variables were not associated with NFT accumulation in the nbM of limbic predominant AD cases. These data provide supportive evidence that NFT accumulation in the nbM may underlie more widespread and severe cholinergic deficits in young-onset AD, in particular in patients with HpSp AD. Moreover, these findings underscore the importance of considering age at onset, sex, and apolipoprotein E genotype when assessing outcomes in AD.

Novel compound heterozygous GFPT1 mutations in a family with limb-girdle myasthenia with tubular aggregates

Limb-girdle myasthenia with tubular aggregates, a subtype of congenital myasthenic syndrome, is an extremely rare autosomal recessive genetic disease characterized by prominent limb-girdle weakness and good response to acetylcholinesterase inhibitor therapy. Herein, we reported two novel mutations of GFPT1 gene in a Chinese pedigree. Two siblings presented with fatigue, weakness of limb-girdle and decrement of the muscle action potential with repetitive nerve stimulation. Thus, myasthenia gravis was initially suspected, but anti-AChR antibodies were negative. Two novel missense mutations (p.Lys154Asn and p.Asn363Ser) in GFPT1 were identified through genetic testing conducted on 167 well-established genes associated with muscular diseases by targeted high throughput sequencing. Both mutations have not been recorded in the dsSNP database, Exome Aggregation Consortium database and 1000 Genomes Project database. The mutation sites were co-segregated with the phenotype and conserved between the different species. The mutations were not found in the 200 unrelated normal controls. Muscle biopsies revealed tubular aggregates, in accordance with previous reports with GFPT1 mutations. Subsequently, dramatic improvement in strength occurred following anti-cholinesterase therapy. Our study will be helpful for the diagnosis and treatment for Limb-girdle myasthenia with tubular aggregates.

Effects of Acetylcholinesterase Inhibitors on Nutritional Status in Elderly Patients with Dementia: A 6-month Follow-up Study.

Nutritional status is one of the factors that affects disease progression, morbidity and mortality in elderly patients with dementia. The present study aimed to evaluate the effect of acetylcholinesterase inhibitor (AchEI) therapy on nutritional status and food intake in the elderly. Newly diagnosed patients with dementia, who underwent comprehensive geriatric assessment (CGA) and were followed at regular intervals, were retrospectively evaluated. A total of 116 patients, who began to receive AchEI therapy and completed 6-month follow-up period under this treatment, were enrolled in the study. Socio-demographic characteristics and data on comorbidity, polypharmacy, cognitive function, depression, activities of daily living and nutritional status (weight, Body Mass Index (BMI), Mini Nutritional Assessment (MNA)-Short Form) were recorded. The mean age of the patients was 78.0±8.9 years. There was no significant difference between baseline and 6-month BMI, weight and MNA scores of dementia patients who received AchEI therapy (p>0.05). With regard to the relation between changes in BMI, weight and MNA on the 6th month versus baseline, and donepezil, rivastigmine and galantamine therapies, no difference was determined (p>0.05). However, no worsening in food intake was observed (kappa: 0.377). When the effects of each AchEI on food intake were compared, food intake in rivastigmine treated patients was not decreased as much as it was in galantamine or donepezil treated patients (p<0.05). AchEI therapy has no unfavorable effect on nutritional status or weight in elderly patients with different types of dementia, but it seems that food intake is better in those treated by rivastigmine patch.

Effects of acetylcholinesterase inhibitors on nutritional status in elderly patients with dementia: A 6-month follow-up study

Nutritional status is one of the factors that affects disease progression, morbidity and mortality in elderly patients with dementia. The present study aimed to evaluate the effect of acetylcholinesterase inhibitor (AchEI) therapy on nutritional status and food intake in the elderly. Newly diagnosed patients with dementia, who underwent comprehensive geriatric assessment (CGA) and were followed at regular intervals, were retrospectively evaluated. A total of 116 patients, who began to receive AchEI therapy and completed 6-month follow-up period under this treatment, were enrolled in the study. Socio-demographic characteristics and data on comorbidity, polypharmacy, cognitive function, depression, activities of daily living and nutritional status (weight, Body Mass Index (BMI), Mini Nutritional Assessment (MNA)-Short Form) were recorded. The mean age of the patients was 78.0±8.9 years. There was no significant difference between baseline and 6-month BMI, weight and MNA scores of dementia patients who received AchEI therapy (p>0.05). With regard to the relation between changes in BMI, weight and MNA on the 6th month versus baseline, and donepezil, rivastigmine and galantamine therapies, no difference was determined (p>0.05). However, no worsening in food intake was observed (kappa: 0.377). When the effects of each AchEI on food intake were compared, food intake in rivastigmine treated patients was not decreased as much as it was in galantamine or donepezil treated patients (p<0.05). AchEI therapy has no unfavorable effect on nutritional status or weight in elderly patients with different types of dementia, but it seems that food intake is better in those treated by rivastigmine patch.

Simple Smell Test May Predict Donepezil Response

Simple Smell Test May Predict Donepezil Response

Antidementia drug use among community-dwelling individuals with Alzheimer’s disease in Finland

The objective of this study was to investigate the prevalence of acetylcholinesterase inhibitor (AChEI) and memantine use, duration of treatment, concomitant use of these drugs, and factors associated with the discontinuation of AChEI therapy during 2006–2009. We utilized data from a nationwide sample of community-dwelling individuals with a clinically verified Alzheimer’s disease diagnosed during the year 2005 (n=6858) as a part of the MEDALZ-2005 study. During the 4-year follow-up, 84% used AChEI and 47% used memantine. Altogether, 22% of the sample used both drugs concomitantly. The median duration of the first AChEI use period was 860 (interquartile range 295–1458) days and 1103 (interquartile range 489–1487) days for the total duration of AChEI use. Although 20% of the AChEI users discontinued the use during the first year, over half of them restarted later. The risk of discontinuation was higher for rivastigmine [hazard ratio 1.34 (confidence interval 1.22–1.48)] and galantamine users [hazard ratio 1.23 (confidence interval 1.15–1.37)] compared with donepezil users in the adjusted model. In conclusion, median time for AChEI use was over 3 years and every fifth Alzheimer’s disease patient used AChEI and memantine concomitantly during the follow-up. The low rate of discontinuation is consistent with the Finnish Care Guideline but in contrast to the results reported from many other countries.

Duration of therapy with acetylcholinesterase inhibitors in patients with mild-to-moderate Alzheimer's disease as reported in the literature.

To review the literature regarding the treatment duration of acetylcholinesterase inhibitor (AChEI) therapy for mild-to-moderate Alzheimer's disease (AD) patients. A literature search was performed using MEDLINE/PubMed, Embase, International Pharmaceutical Abstracts, and Clinical Key (all through May 31, 2013) with the search terms Alzheimer's disease, cholinesterase inhibitors, dementia, treatment and duration, with limits to human, clinical, and observational trials, and English studies; no limits were placed on publication dates. Based on the study selection, 40 studies were identified. The criteria for studies reviewed focused on the duration of AChEIs in patients with mild or moderate AD for a minimum of one year. Based on the selection criteria, five studies were reviewed. These studies evaluated the cognitive efficacy of AChEI after "long-term" (1.5 years) treatment in the clinical trial with follow-up noted in the observational studies of a maximum of "greater than 3 years" (up to 7 years). Cognitive decline was measured by changes in Mini-Mental State Exam scores or Alzheimer's Disease Assessment Scale scores. There were no studies identified that suggested an optimal duration of AChEI therapy for AD patients. Based on the trials reviewed, the duration for AChEI use is very patient-specific; therefore, risk versus benefit of therapy needs to be evaluated regularly in AD patients. The maximum mean duration of follow-up in the clinical study analyzed here was only 1.5 years and observational studies with follow-up "greater than 3 years." Further long-term research is needed.

Duration of Therapy with Acetylcholinesterase Inhibitors in Patients with Mild-to-Moderate Alzheimer's Disease as Reported in the Literature

To review the literature regarding the treatment duration of acetylcholinesterase inhibitor (AChEI) therapy for mild-to-moderate Alzheimer's disease (AD) patients.A literature search was performed using MEDLINE/PubMed, Embase, International Pharmaceutical Abstracts, and Clinical Key (all through May 31, 2013) with the search terms Alzheimer's disease, cholinesterase inhibitors, dementia, treatment and duration, with limits to human, clinical, and observational trials, and English studies; no limits were placed on publication dates.Based on the study selection, 40 studies were identified. The criteria for studies reviewed focused on the duration of AChEIs in patients with mild or moderate AD for a minimum of one year.Based on the selection criteria, five studies were reviewed. These studies evaluated the cognitive efficacy of AChEI after "long-term" (1.5 years) treatment in the clinical trial with follow-up noted in the observational studies of a maximum of "greater than 3 years" (up to 7 years). Cognitive decline was measured by changes in Mini-Mental State Exam scores or Alzheimer's Disease Assessment Scale scores. There were no studies identified that suggested an optimal duration of AChEI therapy for AD patients.Based on the trials reviewed, the duration for AChEI use is very patient-specific; therefore, risk versus benefit of therapy needs to be evaluated regularly in AD patients. The maximum mean duration of follow-up in the clinical study analyzed here was only 1.5 years and observational studies with follow-up "greater than 3 years." Further long-term research is needed.

Exploring sleep‐related outcomes in patients with mild to moderate Alzheimer's disease initiating acetylcholinesterase inhibitor therapy: the Morpheus survey

Exploring sleep‐related outcomes in patients with mild to moderate Alzheimer's disease initiating acetylcholinesterase inhibitor therapy: the Morpheus survey

Memantine and cholinesterase inhibitor combination therapy for Alzheimer's disease: a systematic review

BackgroundMemantine is licensed for moderate-to-severe Alzheimer's disease (AD). National Institute for Clinical Excellence (NICE) guidance does not recommend the use of memantine in combination with cholinesterase inhibitors (acetylcholinesterase inhibitor (AChEI))....

Modeling Alzheimer's disease progression using the disease system analysis approach

A novel mechanistic model based on a disease system analysis paradigm was developed to explore the role of homeostatic mechanisms involved in Alzheimer's disease (AD) progression. We used longitudinal AD Assessment Scale-cognitive subscale (ADAS-cog) scores from 926 subjects with AD on stable acetylcholinesterase inhibitor therapy randomized to placebo treatment in two 54-week clinical trials. Alternative mechanistic models were evaluated by assuming that the rate of change of ADAS-cog over time was jointly regulated by a process characterizing the deterioration of ADAS-cog and by a process associated with a compensatory regulatory response. The model based on a time-varying deterioration rate of ADAS-cog performed better than the model based on a time-varying homeostatic control. The covariate analysis indicated that baseline Mini-Mental State Examination score, education, age, and apolipoprotein ɛ4 genotype had a significant effect on the level and shape of the trajectories of the mean model predicted ADAS-cog change from baseline.

Acetylcholinesterase Inhibitor and N-Methyl-D-Aspartic Acid Receptor Antagonist Use among Hospice Enrollees with a Primary Diagnosis of Dementia

To describe acetylcholinesterase inhibitor (AChEI) and memantine use among persons over the age of 65 admitted to hospice with a primary diagnosis of dementia and identify patient and hospice program characteristics associated with the use of these agents. Retrospective, cross-sectional study. Administrative database of a national hospice pharmacy provider. A total of 10,065 persons with end-stage dementia admitted to one of 441 U.S. hospices in 2004. The frequency of AChEI and memantine use was determined and utilized as the unit of analysis for bivariate and multivariate comparisons with patient and hospice program characteristics. Twenty-one percent (2148/10,065) of patients were prescribed AChEI and/or memantine therapy at the time of hospice enrollment. Of these, 49.5% were prescribed donepezil. Odds of receiving AChEI and/or memantine therapy were less likely if the patient was female, (odds ratio [OR] 0.68, 0.62-0.76), died while enrolled in hospice (OR 0.75, 0.67-0.85), received care at home (0.80, 0.71-0.89), or had a hospice length of stay (LOS) less than 7 days (0.53, 0.45-0.62). Patients who had a LOS of at least 60 days were significantly more likely to have received such therapies (OR 1.41 [1.24-1.60] for 61-180 days and 1.33 [1.15-1.54] for over 180 days). A notable number of hospice enrollees with a primary diagnosis of dementia were prescribed AChEI and/or NMDA receptor antagonist therapy. Studies are needed to better define the role of these agents as well as the impact of medication discontinuation in persons with end-stage dementia.

Effect of ApoE Genotype on Response to Donepezil in Patients with Alzheimer’s Disease

Background/Aims: The possible influence of apolipoprotein E (ApoE) genotype on the response to acetylcholinesterase inhibitor therapy in patients with Alzheimer’s disease (AD) remains a matter of controversy. In order to address this issue, we investigated the effects of ApoE genotype on the clinical response to donepezil in patients with mild to moderate AD. Methods: An open study was carried out in 51 patients with probable AD who were treated with 5–10 mg of donepezil per day for 48 weeks. Results: Eighteen (35.3%) of the 51 patients had 1 or 2 ApoE Ε4 alleles. ApoE Ε4 carriers with AD showed a mean 1.1-point increase from the baseline score of 23.9 on the 70-point Alzheimer’s Disease Assessment Scale-Cognitive Component at 48 weeks, while the ApoE Ε4 noncarrier group showed a 3.1-point increase from the baseline score of 22.5 (p = 0.03). The ApoE Ε4 carrier group exhibited a mean 0.13-point worsening from the baseline score of 0.97 on the Korean Instrumental Activities of Daily Living at 48 weeks, while the ApoE Ε4 noncarrier group exhibited a 0.17-point worsening from the baseline score of 0.64 (p = 0.05). Conclusion: AD patients who carry the ApoE Ε4 allele may respond more favorably to donepezil than Ε4 noncarriers.

Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (COLQ) cause synaptic basal-lamina associated CMS with end-plate AChE deficiency. Here we present the clinical and molecular genetic findings of 22 COLQ-mutant CMS patients, carrying a total of 20 different COLQ mutations, 11 of them had not previously been reported. Typically, patients with esterase deficiency suffer from a severe, progressive weakness with onset at birth or in early infancy. In addition, patients with a late onset showing a mild course of disease are described. AChE inhibitor therapy, beneficial for other forms of CMS, is of no effect in cases of esterase deficiency. The large cohort of COLQ patients studied here enabled us to define additional clinical presentations associated with COLQ mutations that differ from the 'classical' phenotypes: several patients with disease onset at birth or in early infancy presented an unexpected, mild disease course without significant progression of weakness. Moreover, many patients had clinical features reminiscent of limb-girdle CMS with mutations in the recently discovered DOK7 gene, including sparing of eye movements and a predominantly proximal muscle weakness. There was no long-term objective benefit from esterase inhibitors treatment in COLQ patients. Surprisingly, a short-term beneficial effect was observed in four patients and a Tensilon test was positive in two. Treatment with ephedrine was efficient in all five cases where it was administered. The variability of phenotypes caused by COLQ mutations, the divergence from the previously published classical clinical features and an initial positive response to esterase inhibitors in some patients may obscure AChE deficiency as the molecular cause of the disease and delay the start of appropriate therapy. Moreover, overlap with other CMS subtypes and potentially absence of a repetitive compound muscle action potential should be considered in the diagnosis of COLQ-mutated patients.

G.P.3 08 Novel mutations in the CHRNB1 gene in three patients affected by a congenital myasthenic syndrome

Mutations of the nicotinic acetylcholine receptor (AChR) cause congenital myasthenic syndromes (CMS) by leading either to endplate AChR deficiency or to altered kinetic properties. Mutations in the alpha, beta and delta subunits of the AChR are less frequent than mutations of the epsilon subunit and often associated with a severe phenotype. So far, only five mutations of the gene encoding the beta subunit (CHRNB1) have been published. Here we present three CMS patients out of two families with mutations in the CHRNB1 gene. Two patients of Serbian origin, mother and daughter, presented with mild myasthenic syndromes in their late twenties. In each case, symptoms appeared during a pregnancy. At a neurological examination, mild ptosis and weakness of facial and upper extremities muscles were noted. A clear decremental response to repetitive nerve stimulation was obtained; repeated prostigmine tests did not show any clear improvement of the symptoms. The third patient, a girl currently 3 years of age, presented with an early-onset CMS associated with muscle hypotonia at birth, respiratory and feeding difficulties in the first weeks of life. Later on, apneic episodes occurred several times, especially during infections. At the age of 2 years, a CMS was diagnosed and acetylcholinesterase inhibitor therapy was started, which was only partially effective. By direct sequencing of the CHRNB1 gene we identified a heterozygous missense mutation (T265S) in the two Serbian patients. This mutation alters a conserved residue of the pore-forming second transmembrane region of the AChR beta subunit. In the third patient we identified two compound heterozygous mutations of the CHRNB1 gene: a nonsense mutation, Y149X, and a missense mutation, R220C. The arginine at position 220 in the extracellular domain of the beta subunit is highly conserved among species and AChR subunits. CHRNB1 mutations shall be considered as a rare cause of CMS. The pathogenic mechanisms of the mutations presented here remain to be investigated.