Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An understanding of the basic pathophysiology and molecular mechanisms of Alzheimer's disease is essential to effective treatment of the disease. Despite multiple hypotheses related to the development and progression of Alzheimer's disease, no unifying theory is currently available. Inflammation, oxidation stress, estrogen hormone status, pathways for production of beta-amyloid42, apolipoprotein E state, cholinergic neuron depletion, and head injury are all possible contributors and therefore provide points of intervention or potential intervention in the development and progression of Alzheimer's disease. Thus, this article reviews current therapeutic modalities, including estrogen replacement therapy, Ginkgo biloba, and the two cholinesterase inhibitors approved in the United States, tacrine and donepezil.
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PMID:Treatment options for Alzheimer's disease. 1073 May 6

Increased butyrylcholinesterase (BChE) activity has been reported to be associated with the formation of amyloid plaques and neurofibrillary tangles and may consequently be involved in the pathogenesis of Alzheimer disease (AD). Because the catalytic activity of BChE-K variant is reduced by one-third compared with non-variant, we speculated that BChE-K variant has a protective effect on AD. However, Lehmann et al. [1997] reported a synergistic effect between the genes for BChE-K variant and apolipoprotein E (ApoE) epsilon 4, which increases the risk for late onset AD. In the present study, we tested 89 Chinese AD patients and 101 Chinese controls and found no evidence of association between BCHE-K and AD of either early or late onset (age > 65 years). No evidence of a synergistic effect was found between the BCHE-K variant and APOE epsilon 4 in this study. Our data suggest that BChE-K variant has no modifying effect on the pathogenesis of AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:167-169, 2000.
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PMID:No association between butyrylcholinesterase K-variant and Alzheimer disease in Chinese. 1089 90

Alzheimer's disease (AD) and Parkinson's disease (PD) are genetically heterogeneous. Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) genes may modify the risk of these disorders. We investigated whether common polymorphisms present in these genes operate as risk factors for AD and PD in Finnish subjects, independently or in concert with the apolipoprotein E epsilon4 allele (APOE epsilon4). Eighty late onset sporadic AD patients, 53 PD patients (34 of whom had concomitant AD pathology), and 67 control subjects were genotyped for the insertion (I)/deletion (D) polymorphism of DCP1 and the K variant of BCHE. In logistic regression analysis, the DCP1 *I allele in combination with APOE epsilon4 significantly increased the risk of AD (OR 30.0, 95% CI 7.3-123.7), compared to subjects carrying neither of the alleles. Similar analysis showed that the risk of AD was significantly increased in subjects carrying both the BCHE wild type (*WT/*WT) genotype and epsilon4 (OR 9.9, 95% CI 2.9-33.8), compared to those without this BCHE genotype and epsilon4. Further, the risk of PD with AD pathology was significantly increased for carriers of DCP1 *I and epsilon4 (OR 8.0, 95% CI 2.1-31.1). We thus conclude that, in Finns, interaction between DCP1 *I and epsilon4 increases the risk of AD as well as of PD with coexisting Alzheimer pathology, which underlines the importance of the DCP1 I/D polymorphism in the development of Alzheimer neuropathology, whereas the wild type BCHE genotype in combination with epsilon4 had a combined effect with regard to the risk of AD.
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PMID:Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) gene interactions with the apolipoprotein E epsilon4 allele as risk factors in Alzheimer's disease and in Parkinson's disease with coexisting Alzheimer pathology. 1101 54

A proportion of Alzheimer's disease (AD) patients treated for several months with cholinesterase (ChE) inhibitors have shown some favorable response on cognition, but the characteristics of the responders are still unclear. This study attempts to identify the characteristics of individuals with a positive behavioral response after a double-blind randomized administration of a single oral dose of tacrine (40 mg) and placebo to AD patients. Furthermore, the relationship between single-dose and long-term responders are examined. Twenty-four mildly to very mildly demented AD patients participated in the study. They all fulfilled the diagnosis of probable AD according to NINCDS-ADRDA criteria. Active treatment (tacrine 40 mg) and placebo was administered in random order on 2 consecutive days, and the effects were evaluated within 2 h using neuropsychological tests (assessing visuospatial ability, episodic memory and attention), registration of EEG activity and measurement of red blood cells (RBC) acetylcholinesterase (AChE), ChE activity and concentrations of tacrine and its metabolites in plasma. Results demonstrated significant improvement, tacrine compared to placebo, in measures of attention, but not in episodic memory or visuospatial ability. A single-dose response was therefore defined in terms of improvement in attention. The tacrine plasma concentration (pcTHA) showed a positively skewed distribution (mean +/- SD: 10.5 +/- 11.8, range: 1.0-51.8 ng/ml). There were no significant differences between single-dose responders compared to nonresponders in pcTHA, metabolites of tacrine, inhibition of AChE in RBC, tau levels in CSF, AChE activity in CSF or plasma and demographic variables. However, single-dose responders showed a higher right frontal alpha/theta ratio on EEG and had lower glucose metabolism in the parietal-temporal association cortex at baseline. In addition, the frequency of apolipoprotein E (APOE) epsilon 4 alleles was higher in responders. Interestingly, the single-dose response was related to the long-term response, although not significantly, which probably was due to lack of power. To conclude, the present study identified single-dose responders in terms of improved attentional performance associated with a relatively higher alpha/theta activity in the right frontal regions of the brain measured on EEG and predominance of APOE epsilon 4 allele.
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PMID:Responder characteristics to a single oral dose of cholinesterase inhibitor: a double-blind placebo-controlled study with tacrine in Alzheimer patients. 1112 38

Hypertriglyceridaemia is a risk factor for cardiovascular disease in patients suffering from Type II diabetes mellitus, and is due to enhanced synthesis and/or impaired clearance of triacylglycerol-rich lipoproteins. In the present study we investigated whether pseudocholinesterase (PChE) activity could serve as a marker for the rate of triacylglycerol synthesis in these patients. Patients were stratified according to their apolipoprotein E (apoE) phenotype, i.e. E3E2, E3E3 or E3E4. In study I, the relationship between PChE activity and serum triacylglycerols was investigated in 224 insulin-treated patients with Type II diabetes. In study II, which had a cross-over design, PChE activity was measured in 45 dyslipidaemic, insulin-treated patients with Type II diabetes that were treated with bezafibrate or pravastatin. In study I, PChE activity was correlated positively with serum triacylglycerol concentrations, but did not differ significantly between apoE phenotypes. The strongest relationship was found in the E3E4 group (r=0.50; P=0.001), the phenotype for which hypertriglyceridaemia is expected to be the result of increased triacylglycerol synthesis. In a stepwise multiple regression analysis, serum triacylglycerol concentrations were found to be the strongest predictor of PChE activity in the E3E4 group. In study II, PChE activity decreased as a result of bezafibrate treatment in all three apoE groups. The decrease in PChE activity with bezafibrate treatment paralleled the decrease in serum triacylglycerol concentrations in the apoE subgroups. Pravastatin treatment did not significantly affect PChE activity. Thus the present study suggests an association between PChE activity and the rate of triacylglycerol synthesis. Measurement of PChE activity may therefore be a useful tool in the choice of drug for treatment of hypertriglyceridaemia in patients with Type II diabetes.
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PMID:Is pseudocholinesterase activity related to markers of triacylglycerol synthesis in Type II diabetes mellitus? 1141 Jan 11

Alzheimer disease (AD) is characterized pathologically by cholinergic deficits, amyloid plaques, neurofibrillary tangles, gliosis, and neuronal and synaptic loss. The primary therapeutic approach that has arisen from the pathological analysis of AD brain has been cholinergic augmentation by cholinesterase inhibitors, which modestly improve cognitive function. Research on the underlying pathophysiological dysfunction have focussed on AD-specific processes such as amyloid precursor protein, tau, and cerebral apolipoprotein E metabolism, and more general neurodegenerative processes such as inflammation, oxidation, excitotoxicity, and apoptosis. Rational neuroprotective approaches have led to recent trials of estrogen, antioxidant and anti-inflammatory medications in AD, and to the development of anti-amyloid strategies for delaying progression or preventing development of AD.
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PMID:Alzheimer disease therapeutics. 1158 22

To investigate the possible involvement of the butyrylcholinesterase (BCHE) K variant and transferrin (TF) C2 variant in the manifestation of Alzheimer's disease (AD), we analyzed the BCHE, TF and apolipoprotein E (APOE) genotypes of 164 sporadic AD patients and 239 normal elderly controls. The frequencies of the BCHE K and TF C2 did not differ between the AD patients and controls (P > 0.1). The occurrence of the APOE epsilon4 did not influence the distribution of the BCHE K and TF C2 variants (P > 0.1). No linkage disequilibrium between the BCHE K and TF C2 was observed either in both the AD patients and controls (P > 0.1). In conclusion, neither the BCHE K nor the TF C2 confers a risk for AD.
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PMID:Neither the butyrylcholinesterase K variant nor transferrin C2 variant confers a risk for Alzheimer's disease in Koreans. 1172 18

In late-onset Alzheimer's disease, there is a puzzling inconsistency between the findings of case-control studies of most proposed risk genes, except apolipoprotein E epsilon4. This inconsistency may stem from the failure to define the genetic and non-genetic interactions that affect the disease association of each particular susceptibility gene. Such interactions will limit the influence of the gene to a 'relevant subset' of vulnerable people. The relevant subsets for many risk genes will be narrow, compared to that of apolipoprotein E epsilon4. Studies may therefore miss the association or even suggest that a risk gene is protective. In these circumstances, the precise composition of a cohort is critical and defining the relevant subset is crucial. We illustrate how such definition may be achieved through meta-analysis. We take as an example the butyrylcholinesterase K variant, whose association with Alzheimer's disease may now be provisionally defined. This analysis leads to the identification of a potentially high-risk group: over 75 year old male carriers of both apolipoprotein E epsilon4 and butyrylcholinesterase K variant.
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PMID:Using meta-analysis to explain the diversity of results in genetic studies of late-onset Alzheimer's disease and to identify high-risk subgroups. 1173 93

In a cross-sectional study of outpatients diagnosed with dementia of the Alzheimer type who had been treated with a broad variety of drugs supposed to improve cognition or to delay cognitive decline, we have investigated the effects of abruptly discontinuing therapy on cognition. Termination of therapy with any cholinesterase inhibitor was associated with a cognitive decline during the following 6-7 weeks which was significantly more pronounced than that experienced by patients who had received nootropic drugs or calcium channel blockers (3.41 vs. 1.17 points on the ADAS-Cog scale; -1.14 vs. -0.06 points on the MMSE scale). This effect was not modified by gender, apolipoprotein E genotype, or the extent of ventricular enlargement on CT scans. Its magnitude was comparable to the cognitive response observed in published clinical trials when cholinesterase therapy commenced, and also with the data obtained during a 6-week placebo washout phase.
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PMID:Cognitive relapse after discontinuation of drug therapy in Alzheimer's disease: cholinesterase inhibitors versus nootropics. 1176 31

The incidence, distribution and chemical composition of amyloid-beta (A beta) peptide-positive deposits were investigated in the lower primate species common marmoset (Callithrix jacchus). No A beta deposits were observed in the brains of 7 marmosets below 7 years of age. In 15 marmosets above 7 years, 60% displayed cortical A beta-immunoreactive plaques, 80% had A beta deposited in intracortical vessels and 87% displayed A beta deposits in meningeal vessels. The cerebral cortex of the oldest animal (15 years) contained a substantial density of deposits. A beta-immunoreactive plaques were found predominantly in association cortical zones followed by a lower density in paralimbic cortical areas. Deposits within vessels were most frequent in occipital cortex. A beta40 was found primarily in vascular deposits, while A beta42 was present in plaques. Approximately 20% of plaques and most vascular deposits displayed thioflavin S staining, indicative of the presence of fibrillar A beta. Varying proportions of A beta deposits contained acetylcholinesterase or butyrylcholinesterase activities and apolipoprotein E and alpha1-antichymotrypsin immunoreactivity. A few plaques contained immunoreactivity for amyloid precursor protein in swollen neurites. However, no abnormally phosphorylated tau immunoreactivity was present in these neurites. Survival analysis in a colony of marmosets indicated that only 6% of animals can be expected to survive beyond 7 years of age. These results indicate that the aged marmoset brain displays A beta deposits with a distribution and chemical composition similar to those found in the human. These similarities suggest that the aged marmoset may be a useful lower primate model for the study of the pathological effects of A beta. However, the relatively small number of animals which can be expected to reach old age severely limits the utility of this species as a model of A beta deposition.
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PMID:Amyloid-beta deposits in the cerebral cortex of the aged common marmoset (Callithrix jacchus): incidence and chemical composition. 1183 47


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