Alzheimer Disease: Li H

Li H, Wolfe MS, Selkoe DJ. · Biology Department, Brookhaven National Laboratory, Upton, NY 11973-5000, USA. · Structure. · Pubmed #19278647 No free full text.

Abstract: Gamma-Secretase is an intramembrane protease complex that mediates the Notch signaling pathway and the production of amyloid beta-proteins. As such, this enzyme has emerged as an important target for development of novel therapeutics for Alzheimer disease and cancer. Great progress has been made in the identification and characterization of the membrane complex and its biological functions. One major challenge now is to illuminate the structure of this fascinating and important protease at atomic resolution. Here, we review recent progress on biochemical and biophysical probing of the structure of the four-component complex and discuss obstacles and potential pathways toward elucidating its detailed structure.

Li H. · Pharmaceutical Department of Wuhan Bioengineering Institute, Wuhan 430415, China. · Zhongguo Zhong Yao Za Zhi. · Pubmed #19149245 No free full text.

Abstract: Review the research and development status that acupuncture and Chinese medicine are treating Alzheimer disease (AD) for recent year. From pathogenesy of AD view explain the interventional effects and mechanisms of traditional Chinese medicine on Alzheimer disease. Summarize the main species of Chinese medicine compound and components playing roles. Prefer that traditional Chinese medicine has multiple effects and this will be the development direction of it on Alzheimer disease.

Yao J, Li H. · Institute of Basic Research, Chinese Academy of Medical Sciences, School OF Basic Medicine, Peking Union Medical College, Beijing 100005, China. · Zhonghua Yu Fang Yi Xue Za Zhi. · Pubmed #15368678 No free full text.

This publication has no abstract.

Jacobs AH, Li H, Winkeler A, Hilker R, Knoess C, Rüger A, Galldiks N, Schaller B, Sobesky J, Kracht L, Monfared P, Klein M, Vollmar S, Bauer B, Wagner R, Graf R, Wienhard K, Herholz K, Heiss WD. · Laboratory for Gene Therapy and Molecular Imaging, Max-Planck-Institute for Neurological Research, Gleuelerstrasse 50, 50931, Cologne, Germany. · Eur J Nucl Med Mol Imaging. · Pubmed #12764552 No free full text.

Abstract: Positron emission tomography (PET) allows non-invasive assessment of physiological, metabolic and molecular processes in humans and animals in vivo. Advances in detector technology have led to a considerable improvement in the spatial resolution of PET (1-2 mm), enabling for the first time investigations in small experimental animals such as mice. With the developments in radiochemistry and tracer technology, a variety of endogenously expressed and exogenously introduced genes can be analysed by PET. This opens up the exciting and rapidly evolving field of molecular imaging, aiming at the non-invasive localisation of a biological process of interest in normal and diseased cells in animal models and humans in vivo. The main and most intriguing advantage of molecular imaging is the kinetic analysis of a given molecular event in the same experimental subject over time. This will allow non-invasive characterisation and "phenotyping" of animal models of human disease at various disease stages, under certain pathophysiological stimuli and after therapeutic intervention. The potential broad applications of imaging molecular events in vivo lie in the study of cell biology, biochemistry, gene/protein function and regulation, signal transduction, transcriptional regulation and characterisation of transgenic animals. Most importantly, molecular imaging will have great implications for the identification of potential molecular therapeutic targets, in the development of new treatment strategies, and in their successful implementation into clinical application. Here, the potential impact of molecular imaging by PET in applications in neuroscience research with a special focus on neurodegeneration and neuro-oncology is reviewed.

Gebicke-Haerter PJ, Spleiss O, Ren LQ, Li H, Dichmann S, Norgauer J, Boddeke HW. · Department of Psychiatry, University of Freiburg, Hauptstr. 8, D-79104 Freiburg, Germany. · Prog Brain Res. · Pubmed #11545017 No free full text.

This publication has no abstract.

Yan JH, Rountree S, Massman P, Doody RS, Li H. · Department of Kinesiology, California State University at East Bay, 25800 Carlos Bee Boulevard, Hayward, CA 94542-3062, USA. · J Psychiatr Res. · Pubmed #18280503 No free full text.

Abstract: Sensory-motor dysfunctions are often associated with Alzheimer's disease (AD) or mild cognitive impairment (MCI). This study suggests that deterioration in fine motor control and coordination characterizes sensory-motor deficiencies of AD and MCI. Nine patients with a clinical diagnosis of probable AD, 9 amnestic MCI subjects and 10 cognitively normal controls performed four types of handwriting movement on a digitizer. Movement time and smoothness were analyzed between the groups and across the movement patterns. Kinematic profiles were also compared among the groups. AD and MCI patients demonstrated slower, less smooth, less coordinated, and less consistent handwriting movements than their healthy counterparts. The theoretical relevance and practical implications of fine motor tasks, such as these movements involved in handwriting, are discussed relative to the deteriorated sensory-motor system of AD and MCI patients.

Li H, Borinskaya S, Yoshimura K, Kal'ina N, Marusin A, Stepanov VA, Qin Z, Khaliq S, Lee MY, Yang Y, Mohyuddin A, Gurwitz D, Mehdi SQ, Rogaev E, Jin L, Yankovsky NK, Kidd JR, Kidd KK. · Department of Genetics, School of Medicine, Yale University, New Haven, CT 06520-8005, USA. · Ann Hum Genet. · Pubmed #19456322 No free full text.

Abstract: Mitochondrial aldehyde dehydrogenase (ALDH2) is one of the most important enzymes in human alcohol metabolism. The oriental ALDH2*504Lys variant functions as a dominant negative, greatly reducing activity in heterozygotes and abolishing activity in homozygotes. This allele is associated with serious disorders such as alcohol liver disease, late onset Alzheimer disease, colorectal cancer, and esophageal cancer, and is best known for protection against alcoholism. Many hundreds of papers in various languages have been published on this variant, providing allele frequency data for many different populations. To develop a highly refined global geographic distribution of ALDH2*504Lys, we have collected new data on 4,091 individuals from 86 population samples and assembled published data on a total of 80,691 individuals from 366 population samples. The allele is essentially absent in all parts of the world except East Asia. The ALDH2*504Lys allele has its highest frequency in Southeast China, and occurs in most areas of China, Japan, Korea, Mongolia, and Indochina with frequencies gradually declining radially from Southeast China. As the indigenous populations in South China have much lower frequencies than the southern Han migrants from Central China, we conclude that ALDH2*504Lys was carried by Han Chinese as they spread throughout East Asia. Esophageal cancer, with its highest incidence in East Asia, may be associated with ALDH2*504Lys because of a toxic effect of increased acetaldehyde in the tissue where ingested ethanol has its highest concentration. While the distributions of esophageal cancer and ALDH2*504Lys do not precisely correlate, that does not disprove the hypothesis. In general the study of fine scale geographic distributions of ALDH2*504Lys and diseases may help in understanding the multiple relationships among genes, diseases, environments, and cultures.

Lopez OL, Mackell JA, Sun Y, Kassalow LM, Xu Y, McRae T, Li H. · Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA. · J Natl Med Assoc. · Pubmed #19024233 links to  free full text

Abstract: BACKGROUND: Hispanics represent 10% of the U.S. population and are the fastest growing group. Studies show a higher prevalence and incidence of Alzheimer's disease (AD) in Hispanics than in the non-Hispanic white population, with an earlier age of onset. Among the currently estimated 200,000 Hispanics with AD, a significant number remain undiagnosed and untreated, and Hispanic participation in AD clinical trials has been historically low. This study evaluated the efficacy and safety of donepezil hydrochloride (donepezil) in Hispanics with mild-to-moderate AD. METHODS: In this multicenter, open-label, 12-week study conducted in the United States, subjects were Hispanic men or women aged > or =50 years with a diagnosis of mild-to-moderate AD (DSMV-IV and NINCDS/ADRDA criteria), with Mini-Mental State Examination (MMSE) scores of 10-26 (inclusive) at screening. Subjects were treated with donepezil 5 mg/day for 6 weeks followed by 10 mg/day for 6 weeks. Clinical evaluation was performed at baseline, week 6 and week 12. Cognitive improvement was measured using the MMSE, Fuld Object Memory Evaluation (FOME) and Symbol Digit Modality Test (SDMT). Behavioral symptoms and associated caregiver distress were assessed with the Neuropsychiatric Inventory (NPI). RESULTS: One-hundred-six patients with mild-to-moderate AD (mean age 68.6 years) were enrolled (intent to treat, n=97); most chose to have assessments conducted in Spanish. With 12 weeks of treatment, subjects showed statistically significant improvement from baseline on MMSE (P<0.0001), FOME retrieval (P=0.0042), FOME repeated retrieval (P=0.0020) and SDMT correct scores (P<0.0001). The NPI subdomain "apathy/indifference" showed statistically significant improvement (P=0.0010).The NPI Caregiver Distress scale (NPI-D) total score was statistically significantly improved (P=0.0500), suggesting a positive impact on relieving caregivers' burden associated with patient behavior. Most patients tolerated the treatment well, with only 2 discontinuing because of adverse events. The most common (>5%) adverse events were insomnia (9.5%), dizziness (7.6%), diarrhea (5.7%) and nausea (5.7%). CONCLUSION: The cognitive improvement and safety results from this study were consistent with those reported for donepezil in the general population. Increased awareness of AD in the Hispanic population will help more Hispanics with AD to benefit from early diagnosis and effective treatment.

Fradinger EA, Monien BH, Urbanc B, Lomakin A, Tan M, Li H, Spring SM, Condron MM, Cruz L, Xie CW, Benedek GB, Bitan G. · Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. · Proc Natl Acad Sci U S A. · Pubmed #18779585 links to  free full text

Abstract: Alzheimer's disease (AD) is an age-related disorder that threatens to become an epidemic as the world population ages. Neurotoxic oligomers of Abeta42 are believed to be the main cause of AD; therefore, disruption of Abeta oligomerization is a promising approach for developing therapeutics for AD. Formation of Abeta42 oligomers is mediated by intermolecular interactions in which the C terminus plays a central role. We hypothesized that peptides derived from the C terminus of Abeta42 may get incorporated into oligomers of Abeta42, disrupt their structure, and thereby inhibit their toxicity. We tested this hypothesis using Abeta fragments with the general formula Abeta(x-42) (x = 28-39). A cell viability screen identified Abeta(31-42) as the most potent inhibitor. In addition, the shortest peptide, Abeta(39-42), also had high activity. Both Abeta(31-42) and Abeta(39-42) inhibited Abeta-induced cell death and rescued disruption of synaptic activity by Abeta42 oligomers at micromolar concentrations. Biophysical characterization indicated that the action of these peptides likely involved stabilization of Abeta42 in nontoxic oligomers. Computer simulations suggested a mechanism by which the fragments coassembled with Abeta42 to form heterooligomers. Thus, Abeta(31-42) and Abeta(39-42) are leads for obtaining mechanism-based drugs for treatment of AD using a systematic structure-activity approach.

Doody RS, Corey-Bloom J, Zhang R, Li H, Ieni J, Schindler R. · Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, Texas 77030, USA. · Drugs Aging. · Pubmed #18257603 No free full text.

Abstract: BACKGROUND: Donepezil is licensed for the treatment of mild-to-moderate Alzheimer's disease (AD) at doses of 5-10 mg/day and has recently been approved in the US for severe AD. Multiple studies have suggested that donepezil 10 mg/day provides additional cognitive and functional benefits over the 5 mg/day dose. Higher doses of donepezil, if safe and well tolerated, might provide further benefits for patients with AD. OBJECTIVE: To evaluate the safety and tolerability of donepezil at doses of 15 and 20 mg/day. METHOD: A 24-week, randomized, double-blind, placebo-controlled, pilot study conducted at two investigational sites in the US. Enrolled patients (male and female; aged 50-86 years) had a diagnosis of probable AD at the mild-to-moderate stage (Mini-Mental State Examination [MMSE] score 10-26). All patients had been treated with donepezil 10 mg/day for 12-30 months prior to enrolment. Patients (n = 31) were randomized 1 : 1 to receive either a standard dose of donepezil (donepezil 10 mg/day plus placebo 5 mg/day for weeks 1-12; donepezil 10 mg/day plus placebo 10 mg/day for weeks 13-24) or a higher dose of donepezil (donepezil 15 mg/day for weeks 1-12; donepezil 20 mg/day for weeks 13-24). Primary outcome measures were tolerability (as determined by monitoring of discontinuations, dose modifications and adverse events) and safety (as determined by adverse event monitoring, physical examinations, clinical laboratory tests and ECGs). Psychometric measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-cog], MMSE and Clinician's Interview-Based Impression of Change with caregiver information [CIBIC+]) and pharmacokinetic/pharmacodynamic parameters were secondary outcomes. RESULTS: No patients withdrew from the study and there were no serious adverse events or deaths. By week 24, 15 of 16 patients in the higher-dose group tolerated the maximum 20 mg/day dose; one patient had a permanent dose reduction to donepezil 15 mg/day. In the standard-dose group, 14 of 15 patients tolerated donepezil 10 mg/day plus placebo 10 mg/day by the end of the study; one patient had a permanent dose reduction to donepezil 10 mg/day plus placebo 5 mg/day. Temporary dose reductions occurred in two patients (one from each group). Adverse events reported were as expected for donepezil and were all mild to moderate in intensity. Adverse events considered to be possibly or probably related to treatment were reported for three patients in the standard-dose group and six patients in the higher-dose group. One patient in the higher-dose group had weight loss reported as possibly or probably treatment related. Mean changes on ECGs were not clinically significant in either group, and the incidence of bradycardia was comparable. No treatment difference on any of the psychometric measures was observed between the groups. Pharmacokinetic analyses showed that an increased donepezil dose was associated with an increase in donepezil plasma concentrations from baseline. CONCLUSION: In this small pilot study of patients with mild-to-moderate AD already stabilized on donepezil 10 mg/day, doses of 15 and 20 mg/day of donepezil appeared safe and well tolerated. These results justify initiation of larger clinical trials designed to investigate the efficacy and safety of doses of donepezil higher than 10 mg/day in patients with AD.

Li H, Wetten S, Li L, St Jean PL, Upmanyu R, Surh L, Hosford D, Barnes MR, Briley JD, Borrie M, Coletta N, Delisle R, Dhalla D, Ehm MG, Feldman HH, Fornazzari L, Gauthier S, Goodgame N, Guzman D, Hammond S, Hollingworth P, Hsiung GY, Johnson J, Kelly DD, Keren R, Kertesz A, King KS, Lovestone S, Loy-English I, Matthews PM, Owen MJ, Plumpton M, Pryse-Phillips W, Prinjha RK, Richardson JC, Saunders A, Slater AJ, St George-Hyslop PH, Stinnett SW, Swartz JE, Taylor RL, Wherrett J, Williams J, Yarnall DP, Gibson RA, Irizarry MC, Middleton LT, Roses AD. · GlaxoSmithKline, Research Triangle Park, North Carolina, USA. · Arch Neurol. · Pubmed #17998437 links to  free full text

Abstract: OBJECTIVE: To identify single-nucleotide polymorphisms (SNPs) associated with risk and age at onset of Alzheimer disease (AD) in a genomewide association study of 469 438 SNPs. DESIGN: Case-control study with replication. SETTING: Memory referral clinics in Canada and the United Kingdom. PARTICIPANTS: The hypothesis-generating data set consisted of 753 individuals with AD by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria recruited from 9 memory referral clinics in Canada and 736 ethnically matched control subjects; control subjects were recruited from nonbiological relatives, friends, or spouses of the patients and did not exhibit cognitive impairment by history or cognitive testing. The follow-up data set consisted of 418 AD cases and 249 nondemented control cases from the United Kingdom Medical Research Council Genetic Resource for Late-Onset AD recruited from clinics at Cardiff University, Cardiff, Wales, and King's College London, London, England. MAIN OUTCOME MEASURES: Odds ratios and 95% confidence intervals for association of SNPs with AD by logistic regression adjusted for age, sex, education, study site, and French Canadian ancestry (for the Canadian data set). Hazard ratios and 95% confidence intervals from Cox proportional hazards regression for age at onset with similar covariate adjustments. RESULTS: Unadjusted, SNP RS4420638 within APOC1 was strongly associated with AD due entirely to linkage disequilibrium with APOE. In the multivariable adjusted analyses, 3 SNPs within the top 120 by P value in the logistic analysis and 1 in the Cox analysis of the Canadian data set provided additional evidence for association at P< .05 within the United Kingdom Medical Research Council data set: RS7019241 (GOLPH2), RS10868366 (GOLPH2), RS9886784 (chromosome 9), and RS10519262 (intergenic between ATP8B4 and SLC27A2). CONCLUSIONS: Our genomewide association analysis again identified the APOE linkage disequilibrium region as the strongest genetic risk factor for AD. This could be a consequence of the coevolution of more than 1 susceptibility allele, such as APOC1, in this region. We also provide new evidence for additional candidate genetic risk factors for AD that can be tested in further studies.

Black SE, Doody R, Li H, McRae T, Jambor KM, Xu Y, Sun Y, Perdomo CA, Richardson S. · Division of Neurology, Department of Medicine and Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada. · Neurology. · Pubmed #17664405 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy and safety of donepezil for severe Alzheimer disease (AD). METHODS: Patients with severe AD (Mini-Mental State Examination [MMSE] scores 1 to 12 and Functional Assessment Staging [FAST] scores > or =6) were enrolled in this multinational, double-blind, placebo-controlled trial at 98 sites. Patients were randomized to donepezil 10 mg daily or placebo for 24 weeks. Primary endpoints were the Severe Impairment Battery (SIB) and Clinician's Interview-Based Impression of Change-Plus caregiver input (CIBIC-Plus). Secondary endpoints included the MMSE, the Alzheimer Disease Cooperative Study-Activities of Daily Living-severe version (ADCS-ADL-sev), the Neuropsychiatric Inventory (NPI), the Caregiver Burden Questionnaire (CBQ), and the Resource Utilization for Severe Alzheimer Disease Patients (RUSP). Efficacy analyses were performed in the intent-to-treat (ITT) population using last post-baseline observation carried forward (LOCF). Safety assessments were performed for patients receiving > or =1 dose of donepezil or placebo. RESULTS: Patients were randomized to donepezil (n = 176) or placebo (n = 167). Donepezil was superior to placebo on SIB score change from baseline to endpoint (least squares mean difference 5.32; p = 0.0001). CIBIC-Plus and MMSE scores favored donepezil at endpoint (p = 0.0473 and p = 0.0267). Donepezil was not significantly different from placebo on the ADCS-ADL-sev, NPI, CBQ, or RUSP. Adverse events reported were consistent with the known cholinergic effects of donepezil and with the safety profile in patients with mild to moderate AD. CONCLUSION: Patients with severe AD demonstrated greater efficacy compared to placebo on measures of cognition and global function.

Zhang ZX, Zahner GE, Román GC, Liu XH, Wu CB, Hong Z, Hong X, Tang MN, Zhou B, Qu QM, Zhang XJ, Li H. · Department of Clinical Epidemiology, Peking Union Medical College Hospital, Beijing, PR China. · Neuroepidemiology. · Pubmed #17035714 links to  free full text

Abstract: OBJECTIVE: To characterize sociodemographic variations in the prevalence of AD and VaD in China. METHODS: Data were collected in a 1997-1998, cross-sectional, door-to-door prevalence survey of 34,807 community residents ages > or =55 years in Beijing, Shanghai, Chengdu and Xian. Initial diagnoses of AD and VaD were assessed by clinicians using standardized protocols, according to the NINCDS-ADRDA and NINDS-AIREN criteria; diagnoses were confirmed after 6 months by repeating neuropsychological evaluations. Prevalence odds ratios were estimated in logistic models adjusting for survey design, age, and other sociodemographic factors. RESULTS: We identified 732 prevalent cases of AD and 295 cases of VaD. Adjusting for all sociodemographic factors concurrently, prevalence odds of AD and VaD were higher in northern versus southern China. Age trends for AD appeared different in western and eastern China. AD also showed an age-adjusted elevation among women and, in the fully adjusted model, a gender education interaction indicating a female preponderance in the highest education group. North-south variation for VaD was age-dependent. In the fully adjusted model, for AD, widowed had significantly higher prevalence odds; for VaD, widowed persons and minorities had significantly lower prevalence odds; professionals had statistically significant and borderline lower prevalence odds for both VaD and AD; sales-service occupations had significantly lower odds for AD only. CONCLUSION: We observed variations in prevalence for AD and VaD in different regions and demographic groups in China that persisted after controlling for potential confounding factors. Sociodemographic factors are probable surrogates for conditions such as lifestyle, environment, comorbidities, and life expectancy.

Becaria A, Lahiri DK, Bondy SC, Chen D, Hamadeh A, Li H, Taylor R, Campbell A. · Department of Community and Environmental Medicine, Center for Occupational and Environmental Health Sciences, University of California, Irvine, Irvine, CA 92697-1825, USA. · J Neuroimmunol. · Pubmed #16697052 No free full text.

Abstract: Inflammatory and oxidative events are up-regulated in the brain of AD patients. It has been reported that in animal models of AD, exposure to aluminum (Al) or copper (Cu) enhanced oxidative events and accumulation of amyloid beta (Abeta) peptides. The present study was designed to evaluate the effect of a 3-month exposure of mice to copper sulfate (8 microM), aluminum lactate (10 or 100 microM), or a combination of the salts. Results suggest that although Al or Cu may independently initiate inflammatory or oxidative events, they may function cooperatively to increase APP levels.

Wang H, Zhang Q, Cai B, Li H, Sze KH, Huang ZX, Wu HM, Sun H. · Department of Chemistry and Open Laboratory of Chemical Biology, The University of Hong Kong, Pokfulam Road, Hong Kong, PR China. · FEBS Lett. · Pubmed #16413543 No free full text.

Abstract: Alzheimer's disease is characterized by progressive loss of neurons accompanied by the formation of intraneural neurofibrillary tangles and extracellular amyloid plaques. Human neuronal growth inhibitory factor, classified as metallothionein-3 (MT-3), was found to be related to the neurotrophic activity promoting cortical neuron survival and dendrite outgrowth in the cell culture studies. We have determined the solution structure of the alpha-domain of human MT-3 (residues 32-68) by multinuclear and multidimensional NMR spectroscopy in combination with the molecular dynamic simulated annealing approach. The human MT-3 shows two metal-thiolate clusters, one in the N-terminus (beta-domain) and one in the C-terminus (alpha-domain). The overall fold of the alpha-domain is similar to that of mouse MT-3. However, human MT-3 has a longer loop in the acidic hexapeptide insertion than that of mouse MT-3. Surprisingly, the backbone dynamics of the protein revealed that the beta-domain exhibits similar internal motion to the alpha-domain, although the N-terminal residues are more flexible. Our results may provide useful information for understanding the structure-function relationship of human MT-3.

Kulic L, Kurosinski P, Chen F, Tracy J, Mohajeri MH, Li H, Nitsch RM, Götz J. · Division of Psychiatry Research, University of Zürich, August Forel Str. 1, 8008 Zürich, Switzerland. · Neurobiol Dis. · Pubmed #16289870 No free full text.

Abstract: Amyloid beta-peptide (Abeta) containing plaques and neurofibrillary tangles (NFT) are the two major histopathological hallmarks of Alzheimer's disease (AD). According to the amyloid cascade hypothesis, deposition of Abeta is an initial and essential step in the pathogenesis of AD, and formation of NFT has been proposed to be caused by increased Abeta levels. Several previous studies revealed that Abeta plaque formation can be reduced or even prevented by active immunization with Abeta preparations or by administration of Abeta-specific antibodies. To assess the role of fibrillar preparations of Abeta42 in NFT formation, we previously performed intracerebral (i.c.) injections of Abeta42 into brains of NFT-forming P301L tau transgenic mice which caused significant increases in NFT numbers. To determine whether these increases in NFT can be blocked or reduced by active immunization, P301L tau mice were immunized with intraperitoneal injections of preaggregated Abeta42. Abeta42-specific titers were monitored and the mice injected i.c. with Abeta42. We found that i.c. injection of Abeta42 caused significant increases in NFT formation. However, this induction was not affected by active immunization despite high serum anti-Abeta42 titer levels and binding of anti-Abeta42 antibodies to the injected Abeta42 aggregates. We conclude that active immunization is not sufficient to prevent the effect of Abeta42 on tau aggregation in our model system. Further studies are required to determine whether modifications of our protocol could affect the Abeta42-mediated induction of NFT formation.

Zhang ZX, Zahner GE, Román GC, Liu J, Hong Z, Qu QM, Liu XH, Zhang XJ, Zhou B, Wu CB, Tang MN, Hong X, Li H. · Department of Clinical Epidemiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China. · Arch Neurol. · Pubmed #15767510 links to  free full text

Abstract: BACKGROUND: Prevalences of Alzheimer disease (AD) and vascular dementia (VaD) in China reportedly differ from those in Western countries. OBJECTIVE: To estimate prevalence of AD and VaD in 4 regions of China. DESIGN: Cross-sectional, population-based prevalence survey with a stratified, multistage cluster sampling design. SETTING: Rural (n = 99) and urbanized (n = 71) communities of Beijing, Xian, Shanghai, and Chengdu. PARTICIPANTS: A sample of 34 807 community residents (94% of those eligible) 55 years or older. MAIN OUTCOME MEASURES: Participants were screened with the Chinese Mini-Mental State Examination. Those who screened positive (n = 3950) underwent a standardized diagnostic workup. Screening sensitivity was assessed in a 3.3% random sample (n = 1008 of the 30 857 who passed the screening). Diagnoses of AD and VaD were made according to National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer Disease and Related Disorders Association and National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria, respectively. Final diagnoses were made after a 6-month confirmation interval. RESULTS: We identified 732 AD cases and 295 VaD cases. Prevalence in persons 65 years or older was 3.5% (95% confidence interval, 3.0%-3.9%) for AD and 1.1% (95% confidence interval, 0.9%-1.1%) for VaD. After post hoc correction for negative screening errors, prevalence increased to 4.8% for AD and remained at 1.1% for VaD. CONCLUSION: Prevalence of dementia subtypes in China is comparable with that in Western countries.

Li H, Wood CL, Getchell TV, Getchell ML, Stromberg AJ. · Department of Statistics, 815 Patterson Office Tower, University of Kentucky, Lexington, Kentucky 40506-0027, USA. · BMC Bioinformatics. · Pubmed #15626348 links to  free full text

Abstract: BACKGROUND: Two or more factor mixed factorial experiments are becoming increasingly common in microarray data analysis. In this case study, the two factors are presence (Patients with Alzheimer's disease) or absence (Control) of the disease, and brain regions including olfactory bulb (OB) or cerebellum (CER). In the design considered in this manuscript, OB and CER are repeated measurements from the same subject and, hence, are correlated. It is critical to identify sources of variability in the analysis of oligonucleotide array experiments with repeated measures and correlations among data points have to be considered. In addition, multiple testing problems are more complicated in experiments with multi-level treatments or treatment combinations. RESULTS: In this study we adopted a linear mixed model to analyze oligonucleotide array experiments with repeated measures. We first construct a generalized F test to select differentially expressed genes. The Benjamini and Hochberg (BH) procedure of controlling false discovery rate (FDR) at 5% was applied to the P values of the generalized F test. For those genes with significant generalized F test, we then categorize them based on whether the interaction terms were significant or not at the alpha-level (alphanew = 0.0033) determined by the FDR procedure. Since simple effects may be examined for the genes with significant interaction effect, we adopt the protected Fisher's least significant difference test (LSD) procedure at the level of alphanew to control the family-wise error rate (FWER) for each gene examined. CONCLUSIONS: A linear mixed model is appropriate for analysis of oligonucleotide array experiments with repeated measures. We constructed a generalized F test to select differentially expressed genes, and then applied a specific sequence of tests to identify factorial effects. This sequence of tests applied was designed to control for gene based FWER.

Wang H, Yu X, Li S, Chen Y, Li H, He J. · Department of Geriatric Psychiatry, Peking University Institute of Mental Health, Beijing, China. · Alzheimer Dis Assoc Disord. · Pubmed #15592136 No free full text.

Abstract: This study was designed to examine the utility of the ADAS-Cog, Chinese version (ADAS-Cog-C) for staging of dementia in Alzheimer disease (AD). A total of 305 patients with AD (199 mild AD and 106 moderate AD) meeting the NINCDS-ADRDA criteria of probable AD were recruited. The ADAS-Cog-C was administered to all AD subjects. The total score of ADAS-Cog-C and each item score differed significantly between mild and moderate AD groups, with moderate AD group scoring higher. Statistical analysis showed insignificant influence of age or educational level on the ADAS-Cog-C total score. The item score of orientation and constructional praxis and the ADAS-Cog total score could classify mild and moderate AD efficiently, with a sensitivity of 78% to 82% and a specificity of 70% to 73%. The results of this study indicate that the ADAS-Cog-C can discriminate mild AD from moderate AD efficiently and be useful for staging of AD. It is recommended that the ADAS-Cog-C be introduced for monitoring the cognitive efficacy in AD drug treatment among Chinese AD patients.

Echeverria V, Ducatenzeiler A, Alhonen L, Janne J, Grant SM, Wandosell F, Muro A, Baralle F, Li H, Duff K, Szyf M, Cuello AC. · Department of Pharmacology & Therapeutics, McGill University, Montreal, Canada. · J Alzheimers Dis. · Pubmed #15201476 No free full text.

Abstract: In this communication we report the characterization of several transgenic rat lines expressing human AbetaPP carrying the Swedish and Indiana mutations (coded UKUR28), the human presenilin 1 transgene with the 'Finn' mutation (coded UKUR19) and double transgenic rats expressing both transgenes (coded UKUR25). In these Tg rats, the AbetaPP and PS1 transgene expression was largely restricted to the hippocampus and neocortex. The PS1 transgenic rats did not produce visible changes in Abeta immunoreactivity. The AbetaPP transgenic rats (both the single Tg UKUR28, and double Tg UKUR25) generated a phenotype of intra-neuronalbeta accumulation without plaque formation and with no increased immunoreactivity for AbetaPP amino and carboxyl-terminal epitopes. This phenotype was apparent as early as 6 months of age in the transgenic rat lines carrying the human AbetaPP transgene. No senile plaques of aggregated Abeta were observed in any of the transgenic lines generated, up to 24 months of age. The hAbetaPP single homozygous Tg line (UKUR28) showed an increase in ERK2, without changes in glycogen synthase kinase 3 (GSK3) activity. A preliminary protein analysis of the hippocampus of the double transgenic rat (UKUR25) by mass spectrometry showed differences in the protein profile between this transgenic line and controls.

Mohajeri MH, Kuehnle K, Li H, Poirier R, Tracy J, Nitsch RM. · Division of Psychiatry Research, University of Zurich, August Forel Str. 1, 8008 Zurich, Switzerland. · FEBS Lett. · Pubmed #15043995 No free full text.

Abstract: Abnormally high concentrations of beta-amyloid peptide (Abeta) and amyloid plaque formation in Alzheimer's disease (AD) may be caused either by increased generation or by decreased degradation of Abeta. Therefore, activation of mechanisms that lower brain Abeta levels is considered valuable for AD therapy. Neuronal upregulation of neprilysin (NEP) in young transgenic mice expressing the AD-causing amyloid precursor protein mutations (SwAPP) led to reduction of brain Abeta levels and delayed Abeta plaque deposition. In contrast, a comparable increase of brain NEP levels in aged SwAPP mice with pre-existing plaque pathology did not result in a significant reduction of plaque pathology. Therefore, we suggest that the potential of NEP for AD therapy is age-dependent and most effective early in the course of AD pathophysiology.

Shi J, Zhang S, Tang M, Liu X, Li T, Han H, Wang Y, Guo Y, Zhao J, Li H, Ma C. · Key Laboratory of Biotherapy of Human Diseases, Department of Medical Genetics, West China Hospital and Division of Human Morbid Genomics, Ministry of Education, Sichuan University, Chengdu, 610041, China. · Brain Res Mol Brain Res. · Pubmed #14741412 No free full text.

Abstract: 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.

Duan LL, Zhang ZX, Huang JB, Hong X, Wen HB, Wang QH, Li H. · Department of Epidemiology, Chinese Academy of Meedical Sciences and Peking Union Medical College, Beijing 100005, China. · Zhonghua Liu Xing Bing Xue Za Zhi. · Pubmed #12816717 No free full text.

Abstract: OBJECTIVE: To formulate the classification criteria of disability weight for Alzheimer's disease (AD) and Parkinson's disease (PD) in China and to evaluate the disability weight of AD and PD in population over 60 years old in Beijing. METHODS: Based on the criteria of Global Burden of Disease (GBD), a seven-grade disability classification was used to develop a new disability classification criteria for AD and PD in terms of Delphi method in China. Using the data from epidemiological survey for AD and PD in Beijing in 1997 and new criteria, mean disability weights of AD and PD in population over 60 years old in Beijing were obtained. RESULTS: The mean disability weights of Alzheimer's disease was 0.40 in population over 60 years old who received treatment in Beijing and 0.52 in those without treatment while the mean disability weights of Parkinson's disease were 0.30 in the patient receiving treatment and 0.23 in those without treatment. CONCLUSION: Difference between the result of this study and the data of GBD study in the mean disability weight for AD and PD was noticed.

Yao J, Li H, Zhang Z. · Department of Epidemiology, Institute of Basic Medical Sciences, CAMS & PUMC, Beijing 100005, China. · Zhonghua Liu Xing Bing Xue Za Zhi. · Pubmed #12015112 No free full text.

Abstract: OBJECTIVE: To explore the relationship between Alzheimer's disease and its family history of the patients. METHODS: Stratified analyses and logistic regression analysis were used to examine the association between Alzheimer's disease and its family history exposure in 127 cases and 254 matched controls from a population-based case-control study. RESULTS: The risk of Alzheimer's disease was significantly higher in those who had at least one first-degree relative with dementia or major psychosis as compared to those who had no dementia or major relatives with psychosis (OR = 6.25; 8.33). Adjusted for age and level of education, family history of dementia was still associated with Alzheimer's disease positively (OR = 2.07). CONCLUSION: This study provides evidence that familial aggregation of Alzheimer's disease might exist among people living Beijing.

Hong X, Zhang X, Li H. · Department of Neurology, Peiking Union Medical College Hospital, Beijing 100730, China. · Zhonghua Liu Xing Bing Xue Za Zhi. · Pubmed #11769698 No free full text.

Abstract: OBJECTIVE: To investigate the risk of Alzheimer's disease (AD) associated with endogenous estrogen. METHODS: A population based, m: n matched case-control study was conducted, including 115 female AD patients identified from sample population aged 55 years or older as cases and 1,041 non-cognitive impairment individuals from same population matched for age and sex as controls. RESULTS: Age at natural menopause had significant effect on AD using multivariate analysis. The odds ratio (OR) for AD was 0.672 for individuals whose age at natural menopause were between 47 to 50 years old, compared with individuals whose age at menopause were less than 47 years old. The OR was 0.452 for individuals whose age at menopause were more than 50 years old comparing with individuals whose age at menopause were less than 47 years old (P = 0.0207). The OR for AD increased parallel to the increase of age at menarche (adjusted OR = 1.160 for each increased year, P = 0.0342). CONCLUSION: The decrease of endogenous level in postmenopausal women might serve an etiological factor for AD.