A phase II randomized trial of sodium oligomannate in Alzheimer's dementia.

BACKGROUND: Sodium oligomannate (GV-971), a marine-derived oligosaccharide, is a novel agent that may improve cognition in AD patients. METHODS: The 24-week multicenter, randomized, double-blind, placebo parallel controlled clinical trial was conducted in AD in China between 24 October 2011 and 10 July 2013. The study included a 4-week screening/washout period, followed by a 24-week treatment period. Patients were randomized in a 1:1:1 ratio to receive GV-971 900 mg, 600 mg, or placebo capsule in treatment period, respectively. The primary outcome was cognitive improvement as assessed by changes in Alzheimer's Disease Assessment Scale-cognitive subscale 12-item (ADAS-cog12) scores from baseline to week 24. The secondary efficacy outcomes included CIBIC-Plus, ADCS-ADL, and NPI at 24 weeks after treatment compared with baseline. A subgroup study was assessment of the change in cerebral glucose metabolism by fluorodeoxyglucose positron emission tomography measurements. RESULTS: Comparing with the placebo group (n = 83, change - 1.45), the ADAS-cog12 score change in the GV-971 600-mg group (n = 76) was - 1.39 (p = 0.89) and the GV-971 900-mg group (n = 83) was - 2.58 (p = 0.30). The treatment responders according to CIBIC-Plus assessment were significantly higher in the GV-971 900-mg group than the placebo group (92.77% vs. 79.52%, p < 0.05). The GV-971 900-mg subgroup showed a lower decline of cerebral metabolic rate for glucose than the placebo subgroup at the left precuneus, right posterior cingulate, bilateral hippocampus, and bilateral inferior orbital frontal at uncorrected p = 0.05. The respective rates of treatment-related AEs were 5.9%, 14.3%, and 3.5%. CONCLUSIONS: GV-971 was safe and well tolerated. GV-971 900 mg was chosen for phase III clinical study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01453569 . Registered on October 18, 2011.

Efficacy of cognitive behavioural therapy with medication for patients with obsessive-compulsive disorder: A multicentre randomised controlled trial in China.

BACKGROUND: Meta-analyses support the efficacy of cognitive behavioural therapy (CBT) for obsessive-compulsive disorder (OCD) in Western cultures. However, there are no adequately powered multicentre studies in China. This study aimed to compare the effectiveness of treatment with CBT combined with medication and medication alone in OCD patients in China. METHODS: OCD patients (N = 167) were recruited from outpatient clinics at three large tertiary psychiatric hospitals and one general hospital in China. Participants were randomly allocated to receive either CBT combined with medication (n = 92) or medication alone (n = 75) for a 24-week treatment period. Participants' symptoms and social functioning were assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Hamilton Anxiety Rating Scale (HAM-A), Global Assessment of Functioning (GAF) and Clinical Global Impression Scale for Severity (CGI-S) at 0, 4, 8, 12 and 24 weeks, and the effectiveness of the two treatments compared using linear mixed-effects models. RESULTS: At 24 weeks, both groups showed large within-group effects in all measures. Significantly more patients receiving combined therapy than medication alone had a decrease in symptom severity of at least 35% (based on Y-BOCS total score). The CGI-S and GAF scores decreased in both groups, and significant differences were found between the groups. LIMITATIONS: Study limitations included lack of consideration of medication types and dosages, and the absence of a CBT-only arm. CONCLUSIONS: CBT combined with medication may be effective in alleviating symptoms and social functioning impairment associated with OCD, and is more effective than medication alone in China, particularly for the treatment of compulsive behaviours.

Incidence of dementia and subtypes: A cohort study in four regions in China.

INTRODUCTION: There is a dearth of literature on the incidence of dementia in China. METHODS: Using a stratified, multistage, cluster-sampling method, 16,921 nondemented participants ≥55 years were recruited from four regional centers in China in 1997 and followed up to 4.5 years. Cases were identified through a three-step protocol, according to standardized criteria for dementia, Alzheimer's dementia (AD), and vascular dementia (VaD). RESULTS: The crude incidence in persons ≥65 years was 12.1/1000 person-years for dementia, 8.2/1000 person-years for AD, and 3.1/1000 person-years for VaD. After adjusting for sociodemographic factors, older age and lower education were associated with a higher risk of incident dementia, AD and VaD; regional difference was associated mainly with incidence of VaD (north vs. south: hazard ratio [HR] = 3.59); modestly with AD (east vs. west: HR = 1.55). DISCUSSION: The incidence of dementia in Chinese population is comparable with that in Europe and United States.

Effectiveness and safety of generic memantine hydrochloride manufactured in China in the treatment of moderate to severe Alzheimer's disease: a multicenter, double-blind randomized controlled trial.

BACKGROUND: Memantine hydrochloride is a N-methyl-D-aspartate (NMDA) antagonist that may be useful in the treatment of Alzheimer's disease. AIM: Compare the efficacy and safety of generic memantine hydrochloride produced in China to that of the imported proprietary version of the medication (Ebixa) in the treatment of moderate to severe Alzheimer's disease (AD). METHODS: In this multicenter, double-blind randomized controlled trial 229 patients with moderate to severe AD were randomly assigned to a 16-week trial of either the generic preparation or the proprietary preparation of memantine hydrochloride. All participants were assessed at baseline and at 4, 8, 12 and 16 weeks after enrolment. The primary outcome variable was the Alzheimer Disease Assessment Scale-cognition (ADAS-Cog) score. Secondary outcomes were scores in the Mini-Mental State Examination (MMSE), the Activities of Daily Living (ADL) scale and the Clinical Global Impression (CGI) scale. RESULTS: Sample sizes for the safety set (SS) analysis, full analysis set (FAS) and per protocol set (PPS) analysis were 112, 109 and 103 in the generic medication group, and 111, 107 and 101 in the proprietary medication group, respectively. The ADAS-Cog and ADL total scores at the end of weeks 4, 8, 12, and 16 decreased significantly compared with baseline for both groups (p<0.001) and the MMSE total scores at the end of weeks 4, 8, 12, and 16 increased significantly compared with baseline for both groups (p<0.001). There were no significant differences in ADAS-Cog total scores, ADL total scores and level of improvement based on the CGI scores between the two groups at any of the follow-up assessments. The occurrence of adverse events was 20.5% in the generic medication group and 27.0% in the proprietary medication group; this difference was not statistically significant (χ (2)=1.30, p=0.255). CONCLUSION: There are no significant differences in the effectiveness or safety between memantine that is generically produced in China and imported proprietary memantine in the treatment of individuals with moderate and severe AD during the first 16 weeks of treatment.

An intronic CYP46A1 polymorphism is associated with Alzheimer disease in a Chinese Han population.

Excess cholesterol is removed from the brain via hydroxylation mediated by cholesterol 24S-hydroxylase (CYP46), which is a mechanism of maintaining cholesterol homeostasis in the brain. The CYP46A1 gene has been suggested as a genetic risk factor for sporadic late-onset Alzheimer's disease (AD). In this report, we analyzed an intronic CYP46A1 single nucleotide polymorphism (SNP) in 508 sporadic AD patients and 549 controls in a Chinese Han population. Our results indicated that the distribution of CYP46A1 SNP rs754203 genotypes was significantly different in AD patients compared to controls (χ(2) = 6.59, P = 0.037). The frequency of at least one of CYP46A1 T allele (C/T or T/T) was higher in AD patients compared to controls (χ(2) = 6.58, P = 0.01). The age- and sex-adjusted odds ratio for the risk of AD in carriers of CYP46A1 T allele (C/T + T/T) was 1.69 (95 % confidence interval, 1.12-2.56). We conclude that this intronic polymorphism in CYP46A1 gene is associated with AD in a Chinese Han population, and the CYP46A1 T allele might be a risk factor for AD.

Genetic association between low-density lipoprotein receptor-related protein gene polymorphisms and Alzheimer's disease in Chinese Han population.

Alzheimer's disease (AD) is the most common neurodegenerative disorders in the elderly. Low-density lipoprotein receptor-related protein (LRP), as a receptor of apolipoprotein E (APOE), APP, and alpha2 macroglobulin (alpha2-M), keeps the balance between degeneration and production of beta-amyloid protein (Abeta) clearance. Its gene had been defined as a candidate gene for AD, but the results were not universal. Total 496 AD patients and 478 controls were recruited in Chinese Han population and real-time PCR was used to detect the polymorphism of LRP C766T. Multiple logistic regression, Chi-square test and survival analysis were performed to explore the association. The distribution of LRP genotypes and alleles was significantly different between cases and controls, and T allele could reduce the risk for developing AD (OR of CT genotype: 0.57; 95% CI: 0.38-0.85, rho=0.003; OR of T allele: 0.57; 95% CI: 0.39-0.83, rho=0.003). TT genotype carriers had 5 years later for developing AD compared with CC genotype carriers, but survival analysis did not conform this (LRP TT vs. CT and CC log rank chi(2)=2.71, rho=0.26). The distribution of LRP C766T genotypes and alleles was different among different severity stratified by MMSE yet (rho=0.26). Our data suggested that the polymorphism of LRP C766T was strongly associated with AD and T allele might be a protective factor for AD in Chinese Han population.

Lack of association between the BDNF gene Val66Met polymorphism and Alzheimer disease in a Chinese Han population.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by excessive neuronal loss in specific regions of the brain. Among the areas most severely affected are the basal forebrain cholinergic neurons and their projection regions, the hippocampus and the cortex. Several lines of evidence have made brain-derived neurotrophic factor (BDNF) an important candidate gene conferring risk for AD. Recently, several reports investigated the association between a single nucleotide polymorphism (Val66Met, rs6265) of the BDNF gene and AD but yielded ambiguous results. To figure out the association of this single nucleotide polymorphism in the BDNF gene with sporadic AD in a Chinese Han population, we analyzed 513 patients with AD and 575 controls for the genetic association studies. Our results indicated that the distribution of the BDNF genotypes and alleles did not differ significantly. Similar results were observed when the AD and control groups were stratified by age/age at onset and sex. Our data also showed that in the Chinese Han population, the frequencies of the BDNF Met allele (46.5%) and Val allele (53.5%) were significantly different from ethnic groups from Italy, Japan and the USA. The present data revealed no significant effect of the genotypes on the age at onset for developing AD, and no significant association between the genotypes and the severity of the disease.

Gln192Arg polymorphism in paraoxonase 1 gene is associated with Alzheimer disease in a Chinese Han ethnic population.

BACKGROUND: Oxidative stress such as low-density lipoprotein (LDL) oxidation is thought to be an important mechanism in Alzheimer's disease (AD). Paraoxonase 1 (PON1), an enzyme located on high-density lipoprotein, can prevent LDL from oxidation to some extent. It is also a potent cholinesterase inhibitor and an arylesterase, combating organophosphate poisoning and metabolization of environmental neurotoxins which might be responsible for neurodegeneration with aging. We evaluated the association of Gln192Arg polymorphism in the PON1 gene with AD in a Chinese Han ethnic population. METHODS: Patients and age-matched controls were recruited from outpatient clinics and a population-based epidemiological survey, respectively. Gln192Arg polymorphism in the PON1 gene was detected by allele-specific PCR technique in 521 patients with AD and 578 healthy controls. RESULTS: The presence of at least one of PON1 R alleles (Q/R or R/R) was lower in AD patients than in the controls (82.7% vs 87.4%; chi(2) = 4.68, P = 0.03). PON1 gene R allele frequency was lower in AD patients than in the controls (60.7% vs 64.7%; chi(2) = 3.85, P = 0.05). One-way ANOVA showed that PON1 genotype had no effect on the age of onset for developing AD. Logistic regression analysis demonstrated the age and sex-adjusted odds ratio (OR) for the risk of AD in PON1 of PON1 R allele carriers was 0.71 (P = 0.044, 95% CI, 0.51 - 0.99). CONCLUSION: Our results indicate that Gln192Arg polymorphism in the PON1 gene is associated with AD, and PON1 R allele might be a protective factor for AD in a Chinese Han ethnic population.

[Paraoxonase 1 gene Gln192Arg polymorphism in and Alzheimer disease].

OBJECTIVE: The aim of this study was to evaluate the association of Gln192Arg polymorphism in paraoxonase 1 (PON1) gene with Alzheimer's disease (AD) in Chinese Han population. METHODS: Gln192Arg polymorphism in PON1 gene was detected with real-time PCR (RT-PCR) technique in 521 patients with AD and 578 healthy controls. RESULTS: The presence of at least one of PON1 R allele (Q/R or R/R) was lower in AD patients as compared with the controls (82.7% vs 87.4%; chi(2) = 4.68, P = 0.03). PON1 gene R allele frequency was lower in AD patients as compared with the controls (60.7% vs 64.7%; chi(2) = 3.85, P = 0.05). One-Way ANOVA showed that PON1 genotype had no effect on the age of onset of AD. Logistic regression analysis demonstrated that the age and sex-adjusted OR for the risk of AD in PON1 R allele carriers was 0.71 (P = 0.044, 95% CI = 0.51 - 0.99). CONCLUSION: Our results indicate that Gln192Arg polymorphism in PON1 gene is associated with AD and PON1 R allele might be a protective factor for AD in Chinese Han population.

The Fas gene A-670G polymorphism is not associated with sporadic Alzheimer disease in a Chinese Han population.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by excessive neuronal loss, intracellular neurofibrillary tangles and extracellular deposition of amyloid beta-peptide (Abeta). The Fas antigen is a cell surface receptor-mediating cell apoptosis. Several lines of evidence have made Fas/Fas ligand induced apoptosis play an important role in the pathogenesis of AD. Moreover, the Fas gene is located on chromosome 10q24.1, a region of linkage to late-onset AD. Several reports have investigated the association between a single nucleotide polymorphism (SNP) that is located at position -670 of Fas gene and AD, but yielded ambiguous results. To figure out the association of this SNP with sporadic AD in Chinese Han population, we have analyzed 509 patients with AD and 561 controls for the genetic association studies. Our results indicate that the distribution of the Fas genotypes (chi(2) = 0.66, P = 0.72) and alleles (chi(2) = 0.70, P = 0.40) did not differ significantly. The similar results were observed when AD and control groups were stratified by age/age at onset and sex (P > 0.10). The present data revealed no significant effect of the genotypes on the age of onset for developing AD, and no significant association between the genotypes and the severity of the disease.

The APOC3 SstI polymorphism is weakly associated with sporadic Alzheimer's disease in a Chinese population.

In order to clarify the relationship of apolipoprotein CIII (APOC3) polymorphism and sporadic Alzheimer's disease (AD) in Chinese, 165 sporadic AD patients and 174 age-matched elderly individuals were genotyped for the APOC3 SstI and apolipoprotein E (APOE) HhaI polymorphisms. As the result, the APOC3 3017G allele was found to be associated with AD in APOE epsilon4 allele noncarriers (chi2=4.433, P=0.035), and the risk estimate of allele C versus G resulted in an OR of 1.56 (95% CI: 1.03-2.37), although in total no significant differences of allelic or genotypic frequencies between patients and controls were found. Assessment of interaction between APOE epsilon4 and APOC3 3017G status presented an adjusted odds ratio of 0.62 (95% CI: 0.37-1.03) with a borderline significant P-value (P=0.066). Therefore, we conclude that the rare APOC3 G allele may offer some protection against the development of sporadic AD in APOE epsilon4 noncarriers in Chinese.

Mutation screening and association study of the neprilysin gene in sporadic Alzheimer's disease in Chinese persons.

Neprilysin has been reported to be a major beta-amyloid peptide (Abeta)-degrading enzyme. The decreased expression and activity of it may contribute to the development of Alzheimer's disease by promoting the accumulation of Abeta. We used denaturing high-performance liquid chromatography to screen the neprilysin gene (NEP) for single nucleotide polymorphisms (SNPs) in 257 Chinese sporadic Alzheimer's disease patients and 242 cognitive normal controls. As a result, eight novel and one known SNP were identified. Three of them, -204G-->C in the promoter region, IVS17-294C-->T, and IVS22+36C-->A showed a significant association with Alzheimer's disease (p = .006,.017, and.003, respectively). Subsequent haplotype analysis provided further evidence of the association (global p < .0001 for the three SNPs mentioned above, and global p < .01 for the eight SNPs with rare allele frequency > 1%). These findings indicate that genetic variations within or extremely close to NEP might influence the susceptibility to Alzheimer's disease in Chinese persons.

[No evidence for genetic association between alpha-2 macroglobulin I1000V polymorphism and sporadic Alzheimer's disease in two independent Chinese populations].

OBJECTIVE: Alpha-2 macroglobulin (alpha2M) is a proteinase inhibitor found in association with senile plaques in Alzheimer's disease (AD). Also alpha2M has been implicated in several pathophysiological processes in AD. In view of the recent contradictory reports on the relationship between AD and a common polymorphism I1000V in A2M gene, the present authors studied a relatively large sample, determined the genotype of the I1000V polymorphism in A2M gene in sporadic AD patients and age-matched controls with normal cognition, and examined the possible association of the polymorphism with AD. METHODS: Genotypes of A2M and apolipoprotein E (apoE) were detected by polymerase chain reaction combined with restriction fragment length polymorphism in 257 patients and 242 controls in Guangzhou, and 112 patients and 113 controls in Chengdu. RESULTS: The 1000Val allele frequencies in the merged AD and control groups were 7.7% and 8.7%, respectively. The differences of allelic and genotypic frequencies between the patients and control subjects were not statistically significant, even after stratification by apoE epsilon4 status or by age-of-onset of the disease. CONCLUSION: The results of this study revealed no association between the I1000V polymorphism of A2M and Chinese sporadic AD in Guangzhou and Chengdu.

[Gln192Arg polymorphism of the paraoxonase-1 gene is not associated with Alzheimer's disease in Chinese].

OBJECTIVE: To explore the relationship between paraoxonase-1 (PON1) gene Gln192Arg polymorphism and sporadic Alzheimer's disease (AD) in Chinese. METHODS: A total of 165 AD patients and 174 age-matched control subjects were enrolled in this study for examination of PON1 Gln192Arg and apolipoprotein E gene polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The distribution of PON1 allelic and genotypic frequencies did not significantly differ between AD patients and the control subjects, even after the stratification by ApoE-epsilon4 status. CONCLUSION: Gln192Arg polymorphism of the PON1 gene is not associated with sporadic AD in Chinese.

Possible association between Cys311Ser polymorphism of paraoxonase 2 gene and late-onset Alzheimer's disease in Chinese.

The common polymorphism at codon 311 (C311S) of paraoxonase 2 gene (PON2) was investigated in 165 patients with sporadic late-onset Alzheimer's disease (LOAD) and 174 controls in Chinese. The PON2*C allele frequency was significantly increased in the patients as compared with controls. However, no significant difference was observed after stratification of apolipoprotein E (ApoE) epsilon4 allele. These results suggested that the PON2 polymorphism might be a risk factor for LOAD independent of ApoE epsilon4 status in Chinese.

The 1239G/C polymorphism in exon 5 of BACE1 gene may be associated with sporadic Alzheimer's disease in Chinese Hans.

Beta-site amyloid-precursor protein cleaving enzyme (BACE1) is a candidate risk factor for Alzheimer's disease (AD) because of involving in generating beta-amyloid peptide, which is thought to play a central role in the pathogenesis of the disease. A single nucleotide polymorphism 1239G/C in exon 5 of BACE1 gene and a weak association between this polymorphism and AD in Caucasian APOEepsilon4 allele carriers has been reported. To examine possible association of the polymorphism with sporadic AD, two Chinese Han cohorts including 257 patients and 242 age-matched controls in Guangzhou and 112 patients and 113 controls in Chengdu were genotyped using PCR-RFLP techniques. The frequency of the C allele in controls of both cohorts was 0.65, which was higher than that in Caucasian populations [0.39 by Nowotny et al. 2001: Neuroport 12:1799-1802; 0.44 by Nicolaou et al. 2001: Neurogenetics 3:203-206]. There was a significant excess of C allele among the patients in both cohorts (Guangzhou, 0.71 vs. 0.65, chi(2) = 5.20, P = 0.02; Chengdu, 0.74 vs. 0.65, chi(2) = 4.36, P = 0.04). The CC genotype was found to be associated with AD (Guangzhou cohort, OR = 1.56, 95% CI = 1.09-2.23; Chengdu cohort, OR = 1.74, 95% CI = 1.03-2.95; combined sample: OR = 1.61, 95% CI = 1.20-2.17). The association remained in non-APOE epsilon4 allele carriers when all subjects were divided on the basis of the APOEepsilon4 status. Our findings suggest that the 1239G/C polymorphism in exon 5 of BACE1 gene may be associated with sporadic AD in Chinese Hans.