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.

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.

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.

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.

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.

Rotigotine transdermal patch in Chinese patients with advanced Parkinson's disease: A randomized, double-blind, placebo-controlled pivotal study.

INTRODUCTION: Rotigotine was demonstrated to be efficacious and well-tolerated in three placebo-controlled studies (CLEOPATRA-PD/PREFER/SP921) of patients with advanced-stage Parkinson's disease (PD), most of whom were Caucasian. This multicenter phase 3 study (SP1037; NCT01646255) was the first to investigate the efficacy and safety of rotigotine in Chinese patients with advanced-stage PD. METHODS: Chinese patients with PD, inadequately controlled on levodopa (stable dose ≥200 mg/day), with ≥2.5 h/day "off" time, and Hoehn & Yahr stage 2-4, were randomized 1:1 to receive transdermal rotigotine or placebo, titrated over ≤7 weeks, maintained at optimal/maximum dose (4-16 mg/24 h) for 12 weeks. Primary efficacy variable: mean change in absolute "off" time (according to patient diaries) from baseline to end of maintenance. Safety variables included adverse events (AEs) and discontinuations due to AEs. RESULTS: 346 patients were randomized and 89.9% completed the study (87.8% placebo; 92.0% rotigotine). All were Chinese (58.7% male; mean ± SD age: 62.2 ± 8.9 years; mean ± SD time since PD diagnosis: 6.62 ± 3.70 years). Rotigotine significantly reduced "off" time vs placebo (LS mean [95% CI] treatment difference: -1.20 h/day [-1.83, -0.57]; p = 0.0002), and resulted in more responders (≥30% decrease in "off" time: 36.9% placebo; 48.8% rotigotine; p = 0.0269). AEs were reported for 86 (50.0%) placebo- and 103 (59.2%) rotigotine-treated patients; 15 discontinued due to AEs (placebo 7; rotigotine 8). The most common AEs (≥5%) were dizziness, nausea, pruritus, and dyskinesia. CONCLUSIONS: Rotigotine was efficacious in Chinese patients with advanced-stage PD as add-on therapy to levodopa, significantly reducing "off" time vs placebo; the treatment difference was similar to that observed in previous studies of mainly Caucasian patients. Rotigotine was generally well-tolerated and had a similar AE profile to those observed in previous studies.

Rotigotine transdermal patch in Chinese patients with early Parkinson's disease: A randomized, double-blind, placebo-controlled pivotal study.

INTRODUCTION: Two phase3 studies (SP512; SP513) involving mostly Caucasian patients showed that rotigotine (≤8 mg/24 h) was efficacious and welltolerated in early-stage Parkinson's disease (PD). We report results from a phase 3 study (SP0914/NCT01646268) investigating rotigotine in Chinese patients with early-stage PD. METHODS: Patients were randomized 1:1 to rotigotine or placebo, titrated over 1-4 weeks, maintained at optimal/maximum dose (≤8 mg/24 h) for 24 weeks. Primary efficacy variable: change in Unified Parkinson's Disease Rating Scale (UPDRS) II + III total score from Baseline to End-of-Maintenance. Secondary variables: UPDRS II + III responders (≥20% decrease in UPDRS II + III) and changes in UPDRS II (activities of daily living [ADL]) and III (motor examination) subscores. RESULTS: Of 247 patients randomized, 113/124 (91.1%) rotigotine- and 107/123 (87.0%) placebo-treated patients completed the study. PATIENTS: mean (SD) age: 59.4 (10.2) years; time since PD diagnosis: 1.01 (1.22) years, 60.7% male. Rotigotine significantly improved UPDRS II + III total score (change from Baseline LSmean [95%CI] treatment difference, -4.82 [-7.18 to -2.45]; P < 0.0001). UPDRS II + III responder rates were higher with rotigotine (42.3% vs 22.3%; P = 0.0006). UPDRS II and III subscores improved with rotigotine (both subscores: P < 0.0005 vs. placebo). Most frequent adverse events (AEs): nausea (8.9% rotigotine, 3.3% placebo), dizziness (8.1%, 5.7%), pruritus (8.1%, 4.1%), somnolence (8.1%, 3.3%), erythema (6.5%, 1.6%), and vomiting (5.6%, 1.6%). Thirteen (5.3%) patients discontinued due to AEs (6 rotigotine, 7 placebo). CONCLUSIONS: Rotigotine was efficacious in Chinese patients with early-stage PD, providing benefits to control of ADL and motor function. Rotigotine was generally welltolerated, with similar AEs to those observed in Caucasian patients.

Rivastigmine Patch in Chinese Patients with Probable Alzheimer's disease: A 24-week, Randomized, Double-Blind Parallel-Group Study Comparing Rivastigmine Patch (9.5 mg/24 h) with Capsule (6 mg Twice Daily).

AIMS: To compare the once-daily rivastigmine patch 9.5 mg/24 h (10 cm(2) ) versus twice-daily capsule (12 mg/day) in Chinese patients with probable Alzheimer's disease (AD) (mini-mental state examination [MMSE] scores of 10-20). METHODS: The primary objective was to demonstrate the noninferiority of patch to capsule in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) change from baseline to 24 week. Secondary endpoints included cognition (MMSE), overall clinical response (Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change [ADCS-CGIC]), activities of daily living (Alzheimer's Disease Cooperative Study-Activities of Daily Living [ADCS-ADL]), behavior (Neuropsychiatric Inventory [NPI-12]), and safety. RESULTS: Similar cognitive improvement was observed in both patch (n = 248) and capsule (n = 253) groups. Statistical noninferiority for ADAS-Cog was not established (least-square means difference, 0.1; 95% confidence interval, -1.2; 1.5). Considering all efficacy parameters into account, both treatments showed similar performance at Week 24. Treatment-related adverse events (AEs) were lower for patch (39.7%) compared with capsule (49.8%). Application site pruritus was reported in 10.9% of patients receiving patch; most cases were mild. Gastrointestinal AEs including nausea, vomiting, and diarrhea occurred less frequently in the patch group (15.8% vs. 28.7%). CONCLUSION: Rivastigmine patch 9.5 mg/24 h is effective and well tolerated in Chinese patients with probable AD.

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.

Positive Association Between Type 2 Diabetes Risk Alleles Near CDKAL1 and Reduced Birthweight in Chinese Han Individuals.

BACKGROUND: Fetal insulin hypothesis was proposed that the association between low birth weight and type 2 diabetes is principally genetically mediated. The aim of this study was to investigate whether common variants in genes CDKAL1, HHEX, ADCY5, SRR, PTPRD that predisposed to type 2 diabetes were also associated with reduced birthweight in Chinese Han population. METHODS: Twelve single nucleotide polymorphisms (rs7756992/rs10946398 in CDKAL1, rs1111875 in HHEX, rs391300 in SRR, rs17584499 in PTPRD, rs1170806/rs9883204/rs4678017/rs9881942/rs7641344/rs6777397/rs6226243 in ADCY5) were genotyped in 1174 unrelated individuals born in Peking Union Medical College Hospital from 1921 to 1954 by TaqMan allelic discrimination assays, of which 645 had normal glucose tolerance, 181 had developed type 2 diabetes and 348 impaired glucose regulation. Associations of these 12 genetic variants with birthweight and glucose metabolism in later life were analyzed. RESULTS: Birthweight was inversely associated with CDKAL1-rs10946398 (ß = -41 g [95% confidence interval [CI]: -80, -3], P = 0.034), common variants both associated with increased risk of impaired glucose metabolism and decreased insulin secretion index later in life. After adjusting for sex, gestational weeks, parity and maternal age, the risk allele of CDKAL1-rs7756992 was associated with reduced birthweight (ß = -36 g [95% CI: -72, -0.2], P = 0.048). The risk allele in SRR showed a trend toward a reduction of birthweight (P = 0.085). CONCLUSIONS: This study identified the association between type 2 diabetes risk variants in CDKAL1 and birthweight in Chinese Han individuals, and the carrier of risk allele within SRR had the trend of reduced birthweight. This demonstrates that there is a clear overlap between the genetics of type 2 diabetes and fetal growth, which proposes that lower birth weight and type 2 diabetes may be two phenotypes of one genotype.

Chinese culture permeation in the treatment of Parkinson disease: a cross-sectional study in four regions of China.

BACKGROUND: Little is known about the clinical features and treatment of Chinese patients with Parkinson disease (PD). METHODS: A large cross-sectional survey of clinical features, medication use, and motor complications was conducted in 901 consecutive PD patients, from 42 randomly selected university-affiliated hospitals in four urban economic regions of China, between December 2006 and May 2007. RESULTS: The 901 PD patients had age range 30 to 88, and median disease duration 50 months. Most (737, 81.8%) used L-dopa (median 375 mg/day), and often added low doses of other antiparkinsonian agents. Among L-dopa-treated patients, the prevalence of motor complications was low (dyskinesias: 8.5%; motor fluctuations: 18.6%), even among patients with disease duration ≥11 years (dyskinesias: 18.1%; motor fluctuations: 42.2%). Higher L-dopa use was associated with higher occurrence of dyskinesias (OR 2.44; 95% CI 1.20-5.13) and motor fluctuations (OR 2.48; 95% CI 1.49-4.14). Initiating PD treatment with L-dopa alone (OR 0.46; 95% CI 0.22-0.95) or in combination with other medications (OR 0.41; 95% CI 0.19-0.87) was associated with less dyskinesia than treatment initiated with non-L-dopa medication. CONCLUSIONS: Many Chinese PD patients are treated with low-dose L-dopa and added low-dose antiparkinsonian agents, with a low prevalence of motor complications, which might be influenced by Chinese culture.

[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.

[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 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.

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.

Birth measurements, family history, and environmental factors associated with later-life hypertensive status.

BACKGROUND: This birth cohort study was conducted to investigate the contribution of prenatal and antenatal environmental exposures to later-life hypertensive status. METHODS: Two thousand five hundred and three individuals born in 1921-1954 at the Peking Union Medical College Hospital (PUMCH) were targeted; 2,081 (83.1%) participated. Clinical examinations included an interview, blood pressure (BP) measurements, and laboratory assays. Statistical analyses were performed using ordinal regression models with later-life hypertensive status as the dependent variable. Similar analyses were for subpopulations divided by family history of hypertension. RESULTS: In the 2,081 subjects, 449 were normotensive, 531 were prehypertensive, and 1,101 had hypertension. Three hundred and forty two hypertensive patients were classified as high-risk (BP ≥180/110 mm Hg, or accompanied with diabetes or three well-established cardiovascular risk factors); the other 759 patients were at mid-to-low risks. Lower birth weight (<2,500 g: odds ratio (OR) = 1.67, P = 0.02; 2,500- <3,000 g: OR = 1.64, P < 0.01; 3,000- <3,500 g, OR = 1.40, P = 0.01), family history of hypertension (OR = 1.73, P < 0.01), poor education (OR = 1.76, P < 0.01), and alcoholism (OR = 3.05, P < 0.01) significantly predicted later-life high-risk hypertension. For participants with hypertensive family history (57.7%), the association with birth weight became nonsignificant, but poor education (OR = 2.33, P < 0.01) and alcoholism (OR = 3.10, P = 0.01) remained important. For participants without hypertensive family history (42.3%), the effects of lower birth weight (<2,500 g: OR = 2.26, P = 0.02; 2,500- <3,000 g: OR = 1.91, P = 0.01; 3,000- <3,500 g, OR = 1.78, P = 0.01) and alcoholism (OR = 3.23, P < 0.01) remained significant. CONCLUSION: Low birth weight, low education, alcoholism, and hypertensive family history are linked to later-life hypertensive status. Low birth weight is also partly associated with one's genetic background; whereas the association with education and alcoholism are independent from hypertensive family history.

Epidemiology and clinical phenomenology for Parkinson's disease with pain and fatigue.

We conducted a cross-sectional analysis with 901 Parkinson's disease (PD) patients in China to understand the epidemiological characteristics of PD pain among Chinese patients. In addition, we searched PubMed and the China Hospital Knowledge Database for epidemiological studies of pain and fatigue among PD patients from 1999 to 2011 to understand the prevalence of these symptoms around the world and associated clinical features. The 901 PD cases were recruited from 42 university affiliated hospitals randomly selected from seven provincial capitals across four economic regions of China. We documented motor and non-motor symptoms via clinical examinations and questionnaire surveys. Using logistic regression models, we evaluated factors that were associated with PD pain among these Chinese patients. Of the 901 Chinese patients, 269 (29.9%) had PD-related pain. After adjusting for confounders, only dyskinesias (OR = 2.66) and depression (OR = 2.88) were independently associated with PD pain. The literature search identified a total of 16 eligible studies on PD-pain and 19 on PD fatigue with various tools for symptom assessment. The data suggest a crude prevalence of 33.7% for PD pain in Asia and 79.4% in Northern Europe; the prevalence for PD fatigue was 35.4% in Northern Europe and 59.1% in Western Europe. Interestingly, Northern-European PD patients reported the highest prevalence of pain, but the lowest prevalence of fatigue. These studies suggest that motor complications and depression are likely key predictors for PD pain, while disease severity, depression and sleep disturbance are associated with PD fatigue. More studies with standardized methods would be needed to better understand the prevalence of PD pain and fatigue across various regions of the world.

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.

PEMT G523A (V175M) is associated with sporadic Alzheimer's disease in a Chinese population.

There is evidence that increased concentrations of circulating homocysteine are associated with Alzheimer's disease (AD). Phosphatidylethanolamine N-methyltransferase (PEMT) is an important catalyst involved in the production of homocysteine. We investigated the association of a functional single nucleotide polymorphism (rs7946) in PEMT with sporadic AD risk in a Han Chinese population that included 386 AD patients and 366 controls. PEMT G523A was genotyped by either sequencing or PCR-restriction fragment length polymorphism analysis. The plasma homocysteine concentrations of 210 subjects were determined by high-performance liquid chromatography. Significant higher frequency of the A allele was detected in AD cases than in controls (A vs. G, p = 0.007, OR = 1.482, 95% CI 1.114-1.972). After adjusting for gender, age/age at onset, and APOE ε4 status, logistic analysis showed rs7946 was associated with AD in a dominant model (AA + GA vs. GG, p = 0.007, OR = 1.596, 95% CI 1.138-2.240). When stratified by APOE ε4 status or gender, the significant difference was only observed in the APOE ε4 non-carriers and in the female subjects, respectively. We did not find a relationship of this polymorphism with plasma homocysteine levels. These results suggested that PEMT G523A is associated with AD and that the A allele is an APOE ε4-independent risk factor for AD among Han Chinese women.