Serum-derived exosomes promote CD8+ T cells to overexpress PD-1, affecting the prognosis of hypopharyngeal carcinoma.

BACKGROUND: Hypopharyngeal cancer (HPC) is associated with a poor prognosis and a high recurrence rate. Immune escape is one of the reasons for the poor prognosis of malignant tumors. Programmed cell death ligand 1 (PD-L1) and programmed cell death-1 (PD-1) have been shown to play important roles in immune escape. However, the role of PD-1/PD-L1 in HPC remains unclear. In this experiment, we investigated the effect of exosomes from HPC patient serum on CD8+ T cell function and PD-1/PD-L1 expression and, thus, on prognosis. We hope to provide guidance for the identification of new targets for HPC immunotherapy. METHODS: PD-1 and CD8 expression in 71 HPC tissues and 16 paracarcinoma tissues was detected by immunohistochemistry. Concurrently, the clinicopathological data of the patients were obtained to conduct correlation analysis. Exosomes were isolated from serum and then identified by Western blotting (WB), transmission electron microscopy (TEM), and nanoparticle tracking analysis (NTA). Flow cytometry was used to assess the activity of CD8+ T cells after exosome stimulation. The effects of exosomes on the ability of CD8+ T cells to kill FaDu cells were assessed by CCK-8 assay. The expression of IL-10 and TGF-ß1 was measured by enzyme-linked immunosorbent assay (ELISA). PD-L1 expression in HPC tissue samples was evaluated by immunohistochemistry, and the relationship between PD-1/PD-L1 expression and prognosis was investigated with patient specimens. RESULTS: PD-1 expression was significantly upregulated on CD8+ T cells in tumor tissues compared with those in normal tissues. The overall survival (OS) and disease-free survival (DFS) of PD-1-overexpressing patients were decreased. Serum exosomes from patients can elevate PD-1 expression on CD8+ T cells and suppress their killing capacity and secretory function. The rate of positive PD-L1 expression was increased in HPC tissues compared with paracancerous tissues. The DFS and OS of the PD-1(+)-PD-L1(+) group were significantly lower than those of the PD-1(-)-PD-L1(-) group. CONCLUSION: Our findings indicate that serum exosomes from HPC patients can inhibit CD8+ T cell function and that the PD-1-PD-L1 pathway plays an important role in the immune escape of HPC. Exosomes combined with immunotherapy may guide the treatment of patients with advanced disease in the future.

Cerebrospinal Fluid Biomarkers in Dementia Patients with Cerebral Amyloid Angiopathy.

OBJECTIVE: To study the changes of biomarkers in cerebrospinal fluid (CSF) in cerebral amyloid angiopathy (CAA) dementia and Alzheimer(')s disease. METHODS: Levels of amyloid protein ß (Aß42, Aß40) and phosphorylated Tau-protein (P-tau) in CSF and ratio of Aß42/Aß40 were tested in 5 cases with CAA dementia and 20 cases with Alzheimer's disease collected at Peking Union Medical College Hospital from December 2001 to March 2011. RESULTS: The levels of Aß42, Aß40, and P-tau in CSF and ratio of Aß42/Aß40 were (660.4 ± 265.2) ng/L, (7111.0 ± 1033.4) ng/L, (71.8 ± 51.5) ng/L, and 0.077 ± 0.033, respectively in CAA dementia and (663.6 ± 365.6) ng/L, (5115.0 ± 2931.1) ng/L, (47.7 ± 38.8) ng/L, and 0.192 ± 0.140, respectively in Alzheimer's disease patients. There were no statistically significant differences between CAA dementia and Alzheimer's disease in terms of these CSF biomarkers (all P>0.05). CONCLUSION: Measurements of CSF biomarkers may not be helpful in differential diagnosis of CAA and Alzheimer's disease.

Increased cysteinyl-tRNA synthetase drives neuroinflammation in Alzheimer's disease.

BACKGROUND: Microglia-mediated neuroinflammation in Alzheimer's disease (AD) is not only a response to pathophysiological events, but also plays a causative role in neurodegeneration. Cytoplasmic cysteinyl-tRNA synthetase (CARS) is considered to be a stimulant for immune responses to diseases; however, it remains unknown whether CARS is involved in the pathogenesis of AD. METHODS: Postmortem human temporal cortical tissues at different Braak stages and AD patient-derived serum samples were used to investigate the changes of CARS levels in AD by immunocytochemical staining, real-time PCR, western blotting and ELISA. After that, C57BL/6J and APP/PS1 transgenic mice and BV-2 cell line were used to explore the role of CARS protein in memory and neuroinflammation, as well as the underlying mechanisms. Finally, the associations of morphological features among CARS protein, microglia and dense-core plaques were examined by immunocytochemical staining. RESULTS: A positive correlation was found between aging and the intensity of CARS immunoreactivity in the temporal cortex. Both protein and mRNA levels of CARS were increased in the temporal cortex of AD patients. Immunocytochemical staining revealed increased CARS immunoreactivity in neurons of the temporal cortex in AD patients. Moreover, overexpression of CARS in hippocampal neurons induced and aggravated cognitive dysfunction in C57BL/6J and APP/PS1 mice, respectively, accompanied by activation of microglia and the TLR2/MyD88 signaling pathway as well as upregulation of proinflammatory cytokines. In vitro experiments showed that CARS treatment facilitated the production of proinflammatory cytokines and the activation of the TLR2/MyD88 signaling pathway of BV-2 cells. The accumulation of CARS protein occurred within dense-core Aß plaques accompanied by recruitment of ameboid microglia. Significant upregulation of TLR2/MyD88 proteins was also observed in the temporal cortex of AD. CONCLUSIONS: The findings suggest that the neuronal CARS drives neuroinflammation and induces memory deficits, which might be involved in the pathogenesis of AD.

Blood-based CNS regionally and neuronally enriched extracellular vesicles carrying pTau217 for Alzheimer's disease diagnosis and differential diagnosis.

Accurate differential diagnosis among various dementias is crucial for effective treatment of Alzheimer's disease (AD). The study began with searching for novel blood-based neuronal extracellular vesicles (EVs) that are more enriched in the brain regions vulnerable to AD development and progression. With extensive proteomic profiling, GABRD and GPR162 were identified as novel brain regionally enriched plasma EVs markers. The performance of GABRD and GPR162, along with the AD molecule pTau217, was tested using the self-developed and optimized nanoflow cytometry-based technology, which not only detected the positive ratio of EVs but also concurrently presented the corresponding particle size of the EVs, in discovery (n = 310) and validation (n = 213) cohorts. Plasma GABRD+- or GPR162+-carrying pTau217-EVs were significantly reduced in AD compared with healthy control (HC). Additionally, the size distribution of GABRD+- and GPR162+-carrying pTau217-EVs were significantly different between AD and non-AD dementia (NAD). An integrative model, combining age, the number and corresponding size of the distribution of GABRD+- or GPR162+-carrying pTau217-EVs, accurately and sensitively discriminated AD from HC [discovery cohort, area under the curve (AUC) = 0.96; validation cohort, AUC = 0.93] and effectively differentiated AD from NAD (discovery cohort, AUC = 0.91; validation cohort, AUC = 0.90). This study showed that brain regionally enriched neuronal EVs carrying pTau217 in plasma may serve as a robust diagnostic and differential diagnostic tool in both clinical practice and trials for AD.

A Cysteinyl-tRNA Synthetase Mutation Causes Novel Autosomal-Dominant Inheritance of a Parkinsonism/Spinocerebellar-Ataxia Complex.

This study aimed to identify possible pathogenic genes in a 90-member family with a rare combination of multiple neurodegenerative disease phenotypes, which has not been depicted by the known neurodegenerative disease. We performed physical and neurological examinations with International Rating Scales to assess signs of ataxia, Parkinsonism, and cognitive function, as well as brain magnetic resonance imaging scans with seven sequences. We searched for co-segregations of abnormal repeat-expansion loci, pathogenic variants in known spinocerebellar ataxia-related genes, and novel rare mutations via whole-genome sequencing and linkage analysis. A rare co-segregating missense mutation in the CARS gene was validated by Sanger sequencing and the aminoacylation activity of mutant CARS was measured by spectrophotometric assay. This pedigree presented novel late-onset core characteristics including cerebellar ataxia, Parkinsonism, and pyramidal signs in all nine affected members. Brain magnetic resonance imaging showed cerebellar/pons atrophy, pontine-midline linear hyperintensity, decreased rCBF in the bilateral basal ganglia and cerebellar dentate nucleus, and hypo-intensities of the cerebellar dentate nuclei, basal ganglia, mesencephalic red nuclei, and substantia nigra, all of which suggested neurodegeneration. Whole-genome sequencing identified a novel pathogenic heterozygous mutation (E795V) in the CARS gene, meanwhile, exhibited none of the known repeat-expansions or point mutations in pathogenic genes. Remarkably, this CARS mutation causes a 20% decrease in aminoacylation activity to charge tRNACys with L-cysteine in protein synthesis compared with that of the wild type. All family members carrying a heterozygous mutation CARS (E795V) had the same clinical manifestations and neuropathological changes of Parkinsonism and spinocerebellar-ataxia. These findings identify novel pathogenesis of Parkinsonism-spinocerebellar ataxia and provide insights into its genetic architecture.

[Correlation between Apolipoprotein E polymorphism and age at onset of Alzheimer's disease in a Chinese Han population].

OBJECTIVE: To investigate the correlation between the ApoE genotype and age at onset in a cohort of hospital-based AD patients of Han population in China. METHODS: All cases were consecutive probable AD patients from the Memory and Cognitive Impairment Clinic of Peking Union Medical College Hospital from 1999 to 2010. They were all Han ethnicity. They were divided into two groups according to age at onset (AAO): early onset AD (EOAD, AAO < 65 years) and late onset AD (LOAD, AAO ≥ 65 years). DNA was extracted and ApoE was genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. The linkage between ApoE polymorphism and AAO of AD were analyzed by one-way ANOVA. RESULTS: AAO of all cases (n = 495) was (69 ± 10) years, of EOAD (n = 149) was (58 ± 5) years and of LOAD (n = 346) was (74 ± 6) years. ApoEε4(+) genotypes were not associated with AAO of EOAD [ε4-/-: (57 ± 5) years, n = 90; ε4+/-: (59 ± 5) years, n = 50; ε4+/+: (59 ± 5) years, n = 9; F = 0.99, P = 0.38], while they were significantly associated with AAO of LOAD [ε4-/-: ( 75 ± 6) years, n = 189; ε4+/-: (73 ± 6) years, n = 138; ε4+/+: (71 ± 5) years, n = 19; F = 6.51, P = 0.002]. As for all ApoE genotypes, AAO of LOAD reduced gradually in a way as follows: ε2/3 > ε3/3 > ε3/4 > ε2/4 > ε4/4. There was great correlation between AAO and ApoE polymorphism in LOAD without dementia family history, whereas no correlation in LOAD with dementia family history. CONCLUSION: ApoE genotypes carrying at least one ε4 allele maybe significantly lower AAO of LOAD in a dose-dependent manner whereas no such correlation in LOAD with dementia family history.

[Validity of complex figure test in differentiation of Alzheimer's disease from non-dementia].

OBJECTIVE: To assess the validity of Complex Figure Test(CFT)in differentiating Alzheimer's disease(AD)from non-dementia. METHODS: Using CFT,we tested 183 AD patients(AD group),1283 cognitively intact individuals(normal control group),and 134 individuals suffered from other diseases that could be easily confused with dementia(confused control group). RESULTS: The CFT score was 38.7±0.2 in the normal control group,35.3±0.8 in confused control group,23.7±0.8 in mild AD group,and 13.2±1.1 in moderate AD group after adjusted for educational level,age,and sex(all P<0.05).With the 5(th) percentage of the overall score as cutoff point,this tool showed a sensitivity of 73.8% and a specificity of 93.8% in differentiating AD from non-dementia. CONCLUSION: CFT is a sensitive and specific tool in the differentiation of AD from non-dementia.

A 14 bp indel variation in the NCX1 gene modulates the age at onset in late-onset Alzheimer's disease.

Calcium homeostasis is critical to amyloid beta precursor protein (APP) processing. Na(+)/Ca(2+) exchanger (NCX) proteins play an important role in maintaining intracellular Na(+) and Ca(2+) homeostasis in the brain under physiological and pathological conditions. We sequenced a hyper-variable region in intron 2 of the Na(+)/Ca(2+) exchanger 1 gene (NCX1), and investigated whether insertion/deletion variations in this region are associated with the occurrence for Alzheimer's disease (AD). Examining 413 AD patients and 361 healthy controls, we identified 3 insertion/deletion polymorphisms. No significant differences of the allele and genotype frequencies were observed between the AD cases and the controls for any of the three polymorphisms. However, among the AD patients whose age at onset (AAO) was 65 years or older (n = 299), carriers of a 14 bp insertion showed a lower average AAO (ins/ins and ins/del vs. del/del, 72.49 ± 5.17 vs. 74.28 ± 5.79, p = 0.016). It suggested that this 14 bp insertion/deletion polymorphism might modulate AAO in late-onset AD patients.

Validity of auditory verbal learning test in diagnosis of Alzheimer's disease.

OBJECTIVE: To assess the validity of World Health Organization-University of California-Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT) in the diagnosis of Alzheimer's disease (AD). METHODS: Using WHO-UCLA AVLT, we assessed 183 AD patients (AD group),1283 subjects with normal cognitive status (normal control group), and 134 individuals suffered from other diseases easy to be confused with AD (confused control group). RESULTS: The AVLT score was 40.9∓0.3 in normal control group, 30.7∓0.9 in confused control group, 16.6∓1.0 in mild AD group, and 10.2∓1.2 in moderate AD group after adjustment for educational level, age, sex, and rural/urban residence (all P<0.05). With the 5th percentage of the overall score as the cutoff point, this tool showed a sensitivity of 86.3% and a specificity of 93.3%. CONCLUSION: WHO-UCLA CVLT is highly sensitive and specific in the diagnosis of AD.

[Clinical features and treatment of dementia with Lewy bodies].

OBJECTIVE: To investigate the clinical, neuropsychological, neuroimaging features and treatment of dementia with Lewy bodies (DLB). METHODS: The clinical, neuropsychological, neuroimaging and therapeutic features of 33 DLB patients were retrospectively analyzed. RESULTS: There were 25 males and 8 females. The mean course from onset to diagnosis was 3.3 years. Sleep disorder, depression, anxiety and constipation were present at 1 - 10 years prior to DLB onset in 10 patients. Memory impairment (52%) and parkinsonism (21%) were initial symptoms. The mean duration from memory impairment to presence of parkinsonism was 17 months. Pattern of extrapyramidal signs showed bilateral, symmetry and axial muscles bias as postural instability and facial impassivity, tremor was less in DLB. Hallucination (70%), sleep disorder (63%), apathy (56%) and delusion (52%) were the major behavioral and psychological symptoms. Hallucination occurred within a mean of 15 months after presence of initial symptoms. Cognition impairment progressed rapidly in half of patients. Neuropsychological tests of mild patients revealed visuospatial dysfunction and relatively preservation of memory. Severe impairment of all domains of cognition was noticed in moderate-severe patients. MRI (magnetic resonance imaging) revealed the preservation of hippocampal structures. And PET (positron emission tomography) showed hypometabolism of occipital lobe. Cholinesterase inhibitors could improve cognitive impairment and behavioral symptoms in a large majority of patients. CONCLUSION: Neuronal dysfunction may be present at an early stage of DLB. Early presence of hallucination, a high prevalence of sleep disorders, axial rigidity and hypometabolism of occipital lobe on PET may help to distinguish DLB from other types of dementia.

Characteristics and clinical significance of polyploid giant cancer cells in laryngeal carcinoma.

OBJECTIVES: We aimed to construct an induction system for polyploid giant cancer cells (PGCCs), as well as to investigate PGCC features and clinical significance. METHODS: A laryngeal neoplasm-PGCC induction system was constructed using paclitaxel liposomes (PTX). We used western blots to compare expression of epithelial-mesenchymal transition-related proteins, stem cell interrelated proteins, and cyclin-associated proteins. We then measured PGCC count in tissue samples of patients with laryngeal neoplasms and analyzed its relationship with prognosis. Statistical significance was determined using t-tests. RESULTS: PTX successfully induced PGCCs. Western blotting showed that CyclinB1, CDC25C, CDK1, E-cadherin, and EIF-4A expression decreased in PGCCs compared with normal cancer cells, whereas vimentin and CD133 expression increased. Number of PGCCs in laryngeal cancer tissues and overall survival time were inversely correlated (P < .05). CONCLUSIONS: PTX successfully induces PGCC formation in laryngeal carcinoma, which may be the cause of poor prognosis in patients with laryngeal cancer.Level of Evidence: 4.

Discontinuation Rate of Newly Prescribed Donepezil in Alzheimer's Disease Patients in Asia.

BACKGROUND AND PURPOSE: The rate of donepezil discontinuation and the underlying reasons for discontinuation in Asian patients with Alzheimer's disease (AD) are currently unknown. We aimed to determine the treatment discontinuation rates in AD patients who had newly been prescribed donepezil in routine clinical practice in Asia. METHODS: This 1-year observational study involved 38 institutions in seven Asian countries, and it evaluated 398 participants aged 50-90 years with a diagnosis of probable AD and on newly prescribed donepezil monotherapy. The primary endpoint was the rate of donepezil discontinuation over 1 year. Secondary endpoints included the reason for discontinuation, treatment duration, changes in cognitive function over the 1-year study period, and compliance as assessed using a clinician rating scale (CRS) and visual analog scale (VAS). RESULTS: Donepezil was discontinued in 83 (20.9%) patients, most commonly due to an adverse event (43.4%). The mean treatment duration was 103.67 days in patients who discontinued. Among patients whose cognitive function was assessed at baseline and 1 year, there were no significant changes in scores on the Mini-Mental State Examination, Montreal Cognitive Assessment, and Trail-Making Test-Black and White scores, whereas the Clinical Dementia Rating score increased significantly (p<0.001). Treatment compliance at 1 year was 96.8% (306/316) on the CRS and 92.6±14.1% (mean±standard deviation) on the VAS. CONCLUSIONS: In patients on newly prescribed donepezil, the primary reason for discontinuation was an adverse event. Cognitive assessments revealed no significant worsening at 1 year, indicating that continuous donepezil treatment contributes to the maintenance of cognitive function.

Association analysis of CbetaS 844ins68 and MTHFD1 G1958A polymorphisms with Alzheimer's disease in Chinese.

Folate deficiency and elevated plasma homocysteine play important roles in pathogenesis of Alzheimer's disease (AD). The aim of this study was to test the association of folate metabolism-related genes, cystathionine beta-synthase gene (CbetaS) and 5, 10-methylenetetrahydrofolate dehydrogenase gene (MTHFD1), with sporadic AD. The CbetaS 844ins68 polymorphism was determined by PCR and the MTHFD1 G1958A single nucleotide polymorphism (rs2236225) by PCR-RFLP. No significant difference of allele and genotype contributions of the CbetaS polymorphism between AD cases and controls was detected, before and after stratification by APOE epsilon4-carrying status, age/age at onset and genders. No significant difference of allele and genotype contributions of the MTHFD1 polymorphism between AD cases and controls was detected in total samples. When stratified by age/at onset age, we found that A allele and AA genotype frequencies in cases were higher than in controls and the differences were close to significant [A vs. G, P = 0.032, Odds ratio (OR) 1.642, 95% CI 1.040-2.591; AA + GA vs. GG, P = 0.068, OR 1.665, 95% CI 0.961-2.885; AA vs. GG, P = 0.059, OR 3.458, 95% CI 0.894-13.369] in <65 years groups, which suggested that the MTHFD1 G1958A A allele might be a weak risk factor for early onset AD although it needs further confirmation.

Relationship between birth head circumference and adulthood quality of life in Chinese people.

AIM: To determine the relationship between birth size and later QOL for Chinese people. METHODS: Birth data of 1074 subjects were obtained from obstetric birth records of Peking Union Medical College Hospital. All subjects are interviewed face to face with the 36-Item Short-Form Health Survey scale by trained investigators. Linear regression model was used to analyse the relationship between QOL and birth head circumference of the subjects after adjusting for the childhood and adulthood characteristics. The relationship was described with regression coefficients (B) and its 95% confidence interval (CI). RESULTS: The mean weighted score of QOL was 88.1 ± 9.1, ranging from 76.8 to 100. Larger birth head circumference meant higher adulthood QOL total score (P= 0.001). After controlling the adulthood confounders, as compared to larger head circumference (≥33 cm), small (<31 cm) and medium head circumferences (31-33 cm) meant lower adulthood QOL scores (B=-2.356, P= 0.005 and B=-1.645, P= 0.014, respectively). The increase of head circumference by 1 cm was associated with 0.480 (95% CI: 0.141, 0.820) increase of QOL score after adjusting adulthood confounders (P= 0.006). CONCLUSIONS: This study validated the relationship between birth head circumference and QOL in later life. Smaller head circumference at birth could predict worse adulthood QOL at above 50 years old.

Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors.

Despite mortality due to communicable diseases, poverty, and human conflicts, dementia incidence is destined to increase in the developing world in tandem with the ageing population. Current data from developing countries suggest that age-adjusted dementia prevalence estimates in 65 year olds are high (>or=5%) in certain Asian and Latin American countries, but consistently low (1-3%) in India and sub-Saharan Africa; Alzheimer's disease accounts for 60% whereas vascular dementia accounts for approximately 30% of the prevalence. Early-onset familial forms of dementia with single-gene defects occur in Latin America, Asia, and Africa. Illiteracy remains a risk factor for dementia. The APOE epsilon4 allele does not influence dementia progression in sub-Saharan Africans. Vascular factors, such as hypertension and type 2 diabetes, are likely to increase the burden of dementia. Use of traditional diets and medicinal plant extracts might aid prevention and treatment. Dementia costs in developing countries are estimated to be US$73 billion yearly, but care demands social protection, which seems scarce in these regions.

Association of NAD(P)H:quinone oxidoreductase 1 polymorphism and Alzheimer's disease in Chinese.

Several lines of evidence support a role of oxidative stress in the pathology of Alzheimer's disease (AD). NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyzes the two-electron reduction of quinones, preventing their participation in redox cycling and subsequent generation of reactive oxygen species. We examined association between the NQO1 C609T gene polymorphism and sporadic AD in a Chinese population comprising 311 AD patients and 330 controls. Our results showed a higher T-allele frequency in the AD cases compared with the controls. The difference was close to but did not reach statistically significant level [p = 0.059; odds ratio (OR) T versus C = 1.236; 95% confidence interval (95% CI), 0.992-1.540]. A significantly low C/C genotype frequency in the AD cases compared with the controls was detected (p = 0.025; OR C/C versus C/T + T/T = 0.674; 95% CI, 1.049-2.098) and APOE epsilon4 status analysis revealed significant difference in the APOE epsilon4 non-carriers (p = 0.036; OR = 0.633; 95% CI, 1.027-2.427). In the > or =65 years samples, significantly low C/C frequency in the AD cases in comparison with the controls was observed in the APOE epsilon4 non-carriers (p = 0.045; OR = 0.595; 95% CI, 1.010-2.794). These results indicated that the C/C genotype had a possible protective effect against AD development, and the T allele might be a weak risk factor for late onset AD.

Association analysis of methionine synthase gene 2756 A>G polymorphism and Alzheimer disease in a Chinese population.

Homocysteine has been identified to be associated with Alzheimer disease (AD) and methionine synthase (MS) is one of the enzymes involved in homocysteine metabolism. Confused data were reported on the association between the MS 2756 A>G polymorphism and AD. To determine if this polymorphism could affect the occurrence of AD, we investigated the association between the MS 2756 A>G polymorphism and AD risk in 353 sporadic AD patients and 346 controls in a Chinese Han population. No significant differences of allele and genotype distributions between the AD cases and the controls were observed in the total samples, neither when the samples were stratified by age/age at onset and gender. When the samples were stratified by APOE epsilon4 status, a trend of A allele and AA genotype over-representation in the AD patients in comparison with the controls was observed, but it was not statistically significant (for the alleles, A versus G OR=1.549, 95% CI 0.920-2.609, p=0.098; for the genotypes, AA versus AG+GG OR=1.485, 95% CI 0.861-2.560, p=0.153). Similar trend was observed in the APOE epsilon4 non-carrier samples of the >or=65 year subgroups and it was not statistically significant too (for the alleles, A versus G OR=1.682, 95% CI 0.901-3.140, p=0.099, for the genotypes, AA versus AG+GG OR=1.690, 95% CI 0.884-3.232, p=0.110). Our data did not reveal significant association between the MS 2756 A>G polymorphism and AD development. However, a weak effect of the A allele on developing AD could not be completely excluded.

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.

[The application of Montreal cognitive assessment in urban Chinese residents of Beijing].

OBJECTIVE: To study the distribution of Montreal cognitive assessment (MoCA) scores in terms of age and educational level in Chinese residents aged 50 years and over and to offer a benchmark for a cutoff score. METHODS: A total of 281 residents aged 50 years or older was drawn randomly in the urban areas of Beijing, including 215 healthy elderly controls (NC) and 66 patients meeting the clinical criteria of mild cognitive impairment (MCI). The final scores for MoCA were given in the form of mean percentage distributions specific for age, sex and educational level so as to compare the validity of MMSE mini-mental state examination and MoCA in detecting MCI. By a fitting multiple regression model the influence of the factors on MMSE and MoCA was assessed. RESULTS: Using a cutoff score of 26, MMSE had a sensitivity of 24.2% to detect MCI, whereas MoCA detected 92.4% of the MCI subjects. We found a bivariate correlation between MoCA scores and both the factors of age and educational level (P < 0.001). CONCLUSIONS: MoCA is a brief cognitive screening tool with high sensitivity and specificity for detecting MCI as currently conceptualized in patients performing normally on MMSE. Our adjustment in the cutoff scores would improve the detection of MCI and Alzheimer's disease by reducing the number of false negatives. MoCA scores should be used to identify current cognitive difficulties but not to make formal diagnoses.

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.