Galantamine plasma concentration and cognitive response in Alzheimer’s disease

Background Galantamine has been approved for the treatment of Alzheimer’s disease (AD). However, there are few studies which have reported the association between cognitive responses and galantamine plasma concentration. The aim of this study was to determine the correlation between galantamine plasma concentration and the subsequent cognitive response following treatment in AD patients. Methods AD sufferers who continuously took 8 mg/d galantamine for at least 6 months without previous exposure to other kinds of AChEI such as donepezil, rivastigmine, or memantine were included in this cohort study. The assessments included the Mini Mental Status Examination (MMSE), Clinical Dementia Rating Scale (CDR) and the Cognitive Assessment Screening Instrument (CASI). Each subdomain of the CASI assessment was conducted at baseline and after 6 months of galantamine. The plasma concentrations of galantamine were measured by capillary electrophoresis after 6 months of the treatment. Logistic regression was performed to adjust for age, gender, apolipoprotein E ε4 genotype status, and baseline score to investigate the association between galantamine plasma concentrations and the cognitive response. Results The total sample consisted of 33 clinically diagnosed AD patients taking galantamine 8 mg/d for 6 months. There was no linear correlation between galantamine concentration and cognitive response in patients. However, 22 patients were responsive to the treatment in the long-term memory domain. In CASI subset domain, concentration improved during the 6 months follow up. Conclusions In the limited samples study, galantamine mostly benefitted the cognitive domain of long-term memory. The benefits were not related to the galantamine plasma concentration. Objective intra-individual evaluation of therapeutic response should be encouraged

Bcl-2–Modifying Factor Induces Renal Proximal Tubular Cell Apoptosis in Diabetic Mice

This study investigated the mechanisms underlying tubular apoptosis in diabetes by identifying proapoptotic genes that are differentially upregulated by reactive oxygen species in renal proximal tubular cells (RPTCs) in models of diabetes. Total RNAs isolated from renal proximal tubules (RPTs) of 20-week-old heterozygous db/m+, db/db, and db/db catalase (CAT)-transgenic (Tg) mice were used for DNA chip microarray analysis. Real-time quantitative PCR assays, immunohistochemistry, and mice rendered diabetic with streptozotocin were used to validate the proapoptotic gene expression in RPTs. Cultured rat RPTCs were used to confirm the apoptotic activity and regulation of proapoptotic gene expression. Additionally, studies in kidney tissues from patients with and without diabetes were used to confirm enhanced proapoptotic gene expression in RPTs. Bcl-2–modifying factor (Bmf) was differentially upregulated (P < 0.01) in RPTs of db/db mice compared with db/m+ and db/db CAT-Tg mice and in RPTs of streptozotocin-induced diabetic mice in which insulin reversed this finding. In vitro, Bmf cDNA overexpression in rat RPTCs coimmunoprecipated with Bcl-2, enhanced caspase-3 activity, and promoted apoptosis. High glucose (25 mmol/L) induced Bmf mRNA expression in RPTCs, whereas rotenone, catalase, diphenylene iodinium, and apocynin decreased it. Knockdown of Bmf with small interfering RNA reduced high glucose–induced apoptosis in RPTCs. More important, enhanced Bmf expression was detected in RPTs of kidneys from patients with diabetes. These data demonstrate differential upregulation of Bmf in diabetic RPTs and suggest a potential role for Bmf in regulating RPTC apoptosis and tubular atrophy in diabetes

The G-217a Variant of the Angiotensinogen Gene Affects Basal Transcription and Is Associated with Hypertension in a Taiwanese Population

SUMMARY: OBJECTIVE Polymorphisms of the angiotensinogen (AGT ) gene, especially in the promoter region, are in linkage concordance and are associated with hypertension. In this study, we examined the role of AGT promoter polymorphisms, including G-217A, A-6G and M235T variants, and their promoter function in essential hypertension in Taiwanese populations .DESIGN An association study was conducted to assess the genotype distribution between hypertensive patients and normotensive subjects. We also used a transient transfection assay to examine basal transcriptional activity of G-217A and A-6G variants in a mammalian cell system.METHODS Hypertensive subjects (390) and normotensive controls (388) of Taiwanese ethnicity were genotyped for the AGT G-217A, A-6G and M235T variants. Promoter activity was studied by cloning the promoter region (-614 to +41 bp) of AGT into the pSEAP2-Basic reporter vector and performing a transient transfection assay in HuH7 and HepG2 cells.RESULTS The G-217A variant of the AGT gene was significantly associated with hypertension (P = 0.0047), but the A-6G and M235T polymorphisms were not (P = 0.17 and P = 0.33, respectively). Furthermore, the recessive model of homozygous genotype (-217AA) conferred a high risk for hypertension (odds ratio 3.64) in this population. The -217A variant expressed higher transcriptional activity than -217 G in vitro.CONCLUSIONS Our study showed a significant association between the -217A variant of the AGT gene and hypertension. This variant plays a functional role in basal transcription of AGT, and may confer a risk for hypertension in Taiwanese populations

Three Single-Nucleotide Polymorphisms of the Angiotensinogen Gene and Susceptibility to Hypertension: Single Locus Genotype Vs. Haplotype Analysis

Although some single polymorphism analyses of the angiotensinogen (AGT) gene have been found to be associated with hypertension, the results are still inconsistent. The objectives of this study are to evaluate the association of the genotype and haplotype distributions of three single- nucleotide polymorphisms (SNPs) (G-217A, A-6G, and M235T) in the AGT gene with hypertension. In a sample of 461 hypertensive and 327 normotensive patients in Taiwan, we found that -217AA and -6GG homozygotes conferred independently an increased risk to hypertension (P = 0.008 and P = 0.037, respectively), as illustrated by their significant associations with hypertension in both single SNP and pair-wise SNPs analyses. Meanwhile, a very weak linkage disequilibrium was found between the G -17A and the A-6G polymorphisms in terms of r(2) (< 0.05). On the basis of likelihood ratio test, only the set of haplotypes that constituted the A-6G and the M235T polymorphisms was associated with hypertension (χ(2) = 20.91, P = 0.0008) , which was mainly due to the increased frequency of the recombinant haplotypes (-6A &EQUIV; 235M and -6G &EQUIV; 235 T), and a pathophysiological role in the predisposition to hypertension was hence indicated. In functional assays, the promoter activities of the haplotypes -217A &EQUIV; -6A and- 217G &EQUIV; -6G were significantly higher than the most common haplotype -217G &EQUIV; -6A. These results highlight the necessity of a thorough analysis of all reported variants of a candidate gene in the elucidation of genetic susceptibility to a complex disease like hypertension, even when the variants are in the same haplotype block

Particle swarm optimization algorithm for analyzing SNP-SNP interaction of renin-angiotensin system genes against hypertension

Most non-significant individual single nucleotide polymorphisms (SNPs) were undiscovered in hypertension association studies. Their possible SNP-SNP interactions were usually ignored and leaded to missing heritability. In present study, we proposed a particle swarm optimization (PSO) algorithm to analyze the SNP-SNP interaction associated with hypertension. Genotype dataset of eight SNPs of renin-angiotensin system genes for 130 non-hypertension and 313 hypertension subjects were included. Without SNP-SNP interaction, most individual SNPs were non-significant difference between the hypertension and non-hypertension groups. For SNP-SNP interaction, PSO can select the SNP combinations involving different SNP numbers, namely the best SNP barcodes, to show the maximum frequency difference between non-hypertension and hypertension groups. After computation, the best PSO-generated SNP barcodes were dominant in non-hypertension in terms of the occurrences of frequency differences between non-hypertension and hypertension groups. The OR values of the best SNP barcodes involving 2-8 SNPs were 0.705-0.334, suggesting that these SNP barcodes were protective against hypertension. In conclusion, this study demonstrated that non-significant SNPs may generate the joint effect in association study. Our proposed PSO algorithm is effective to identify the best protective SNP barcodes against hypertension

Galantamine plasma concentration and cognitive response in Alzheimer's disease

Background Galantamine has been approved for the treatment of Alzheimer's disease (AD). However, there are few studies which have reported the association between cognitive responses and galantamine plasma concentration. The aim of this study was to determine the correlation between galantamine plasma concentration and the subsequent cognitive response following treatment in AD patients. Methods ADsufferers who continuously took 8 mg/d galantamine for at least 6 months without previous exposure to other kinds of AChEI such as donepezil, rivastigmine, or memantine were included in this cohort study. The assessments included the Mini Mental Status Examination (MMSE), Clinical Dementia Rating Scale (CDR) and the Cognitive Assessment Screening Instrument (CASI). Each subdomain of the CASI assessment was conducted at baseline and after 6 months of galantamine. The plasma concentrations of galantamine were measured by capillary electrophoresis after 6 months of the treatment. Logistic regression was performed to adjust for age, gender, apolipoprotein E epsilon 4 genotype status, and baseline score to investigate the association between galantamine plasma concentrations and the cognitive response. Results The total sample consisted of 33 clinically diagnosed AD patients taking galantamine 8 mg/d for 6 months. There was no linear correlation between galantamine concentration and cognitive response in patients. However, 22 patients were responsive to the treatment in the long-term memory domain. In CASI subset domain, concentration improved during the 6 months follow up. Conclusions In the limited samples study, galantamine mostly benefitted the cognitive domain of long-term memory. The benefits were not related to the galantamine plasma concentration. Objective intra-individual evaluation of therapeutic response should be encouraged

High Order Gene-Gene Interactions in Eight Single Nucleotide Polymorphisms of Renin-Angiotensin System Genes for Hypertension Association Study

Several single nucleotide polymorphisms (SNPs) of renin-angiotensin system (RAS) genes are associated with hypertension (HT) but most of them are focusing on single locus effects. Here, we introduce an unbalanced function based on multifactor dimensionality reduction (MDR) for multiloci genotypes to detect high order gene-gene (SNP-SNP) interaction in unbalanced cases and controls of HT data. Eight SNPs of three RAS genes (angiotensinogen, AGT; angiotensin-converting enzyme, ACE; angiotensin II type 1 receptor, AT1R) in HT and non-HT subjects were included that showed no significant genotype differences. In 2- to 6-locus models of the SNP-SNP interaction, the SNPs of AGT and ACE genes were associated with hypertension (bootstrapping odds ratio [Boot-OR] = 1.972~3.785; 95%, confidence interval (CI) 1.26~6.21; P<0.005). In 7- and 8-locus model, SNP A1166C of AT1R gene is joined to improve the maximum Boot-OR values of 4.050 to 4.483; CI = 2.49 to 7.29; P<1.63E−08. In conclusion, the epistasis networks are identified by eight SNP-SNP interaction models. AGT, ACE, and AT1R genes have overall effects with susceptibility to hypertension, where the SNPs of ACE have a mainly hypertension-associated effect and show an interacting effect to SNPs of AGT and AT1R genes

Alterations of the Neuroinflammatory Markers IL-6 and TRAIL in Alzheimer's Disease

Objective: We aimed to identify biomarkers of Alzheimer's disease (AD) in order to improve diagnostic accuracy at mild stage. Methods: AD patients aged >50 years were included in the disease group. We evaluated the relationship between potential blood and cerebrospinal fluid inflammatory biomarkers, cognitive status, temporal lobe atrophy and disease severity. Inflammatory biomarkers including interleukin 6 (IL-6), IL-18, fractalkine and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) levels were measured. APOE genotypes were determined. Results: We enrolled 41 subjects in the disease group and 40 subjects in the normal control group. The majority (88.9%) of subjects in the disease group had mild AD. Elevated levels of plasma IL-6 and decreased levels of plasma TRAIL in the disease group were noted. Plasma levels of IL-6 and TRAIL were significantly correlated with their cerebrospinal fluid levels. Conclusion: Plasma IL-6 and TRAIL were identified as potential biomarkers of AD at an early stage

Factors affecting therapeutic response to Rivastigmine in Alzheimer's disease patients in Taiwan

Rivastigmine has been widely used in mild-to-moderate Alzheimer's disease (AD), but the therapeutic response rate varies from 20 to 60%. A dose-dependent effect has been suggested, but the plasma concentration of rivastigmine and its metabolite, NAP 226-90, were not measured in previous studies. The influencing factors of therapeutic response are complicated and discordant in various studies among different ethnic groups. Hence, we analyzed the therapeutic responses of rivastigmine, measured by neuropsychological assessments, among 63 clinically diagnosed AD patients taking a daily dosage of 6–9 mg in relation to their plasma concentration of rivastigmine and NAP 226-90, apolipoprotein E (APOE) genotype and demographic characteristics. Our reports revealed that 41.3% of recruited AD patients had improvement in cognition, measured by Mini-Mental Status Examination (MMSE), and 63.5% in global status, by Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score. In cognition, the clinically improving group had a significantly higher rivastigmine concentration [p = 0.049, odds ratio (OR) = 1.029, 95%CI = 1.000–1.058], lower initial MMSE score (p = 0.010, OR = 0.708, 95%CI = 0.546–0.920), and lower initial CDR-SB score (p = 0.003, OR = 0.552, 95%CI = 0.372–0.817). The patients with APOE ε4 allele had worsening cognition (p = 0.037, OR = 3.870, 95%CI = 1.082–13.840). In global status, only higher education (p = 0.043, OR = 1.222, 95%CI = 1.007–1.484) was significantly associated with clinical improvement. In conclusion, high concentrations of rivastigmine may benefit cognitive function of AD patients, especially in APOE ε4 (−) carriers