Alzheimer Disease: Zhu Y

Wang G, Zhu Y, Kong DH, Chen SD. · No affiliation provided · Sheng Li Ke Xue Jin Zhan. · Pubmed #15469099 No free full text.

This publication has no abstract.

Scharre DW, Shiovitz T, Zhu Y, Amatniek J. · Division of Cognitive Neurology, Department of Neurology, Ohio State University, Columbus, OH, USA. · Alzheimers Dement. · Pubmed #18631948 No free full text.

Abstract: BACKGROUND: Our purpose was to assess the safety and tolerability of extended-release galantamine (GAL-ER), using a 1-week dose titration in Alzheimer's patients. METHODS: An open-label, 12-week, multicenter study was performed (n = 82). Results were compared with findings from a placebo-controlled trial using a 4-week titration of GAL-ER and immediate-release galantamine. The primary analysis compared incidences of adverse events (AEs). RESULTS: Although not statistically significant, more patients in the 1-week titration study experienced an AE. More patients with a 1-week titration had at least one prespecified gastrointestinal (GI) AE. These findings correlated with a higher baseline incidence of GI disturbances. Four patients experienced serious AEs; no deaths occurred. Mean Mini-Mental State Examination scores improved by 1.8 and 1.9 points at weeks 4 and 12, respectively. CONCLUSIONS: A 1-week titration of GAL-ER was generally safe and well tolerated, with a potential risk of more GI side effects. A 1-week titration may permit dosing flexibility and promote increased adherence to medication regimens.

Lyketsos CG, Reichman WE, Kershaw P, Zhu Y. · Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Osler 320, 600 North Wolfe Street, Baltimore, MD 21287, USA. · Am J Geriatr Psychiatry. · Pubmed #15353385 No free full text.

Abstract: OBJECTIVE: The authors evaluated the long-term safety, efficacy, and tolerability of galantamine 24 mg/day in the treatment of Alzheimer disease by means of a 12-month, open-label extension of an earlier 5-month, double-blind, placebo-controlled trial with a 6-week withdrawal phase. METHODS: Patients completing two double-blind, placebo-controlled trials (N=699) were escalated to a 24-mg dose (12 mg bid) of galantamine during a period of 2 weeks and treated for 12 months beyond the initial 6.5-month, double-blind period (total treatment duration: 18.5 months). The primary efficacy measure was the change from baseline in the Alzheimer's Disease Assessment Scale (ADAS-Cog/11) score at 18.5 months; secondary endpoints included total scores on the Alzheimer's Disease Cooperative Study of Activities of Daily Living and the Neuropsychiatric Inventory. Standard safety evaluations, including adverse-event monitoring, were performed. RESULTS: Patients taking galantamine continuously throughout the double-blind and open-label studies (N=288) showed sustained cognitive benefits on ADAS-Cog/11 scores at 18.5 months. Patients were maintained close to baseline cognitive ability for 12 months, and safety was as expected and documented in other large studies of galantamine. Analysis of the subgroup of patients (N=113) who completed the entire 18.5 months of galantamine treatment showed that cognitive function was maintained up to 14 months. CONCLUSIONS: Results of this open-label extension support the findings from previous galantamine studies and demonstrate the safety and tolerability of galantamine for up to 18.5 months.

Galasko D, Kershaw PR, Schneider L, Zhu Y, Tariot PN. · Department of Neurosciences, University of California at San Diego, San Diego, California, USA. · J Am Geriatr Soc. · Pubmed #15209643 No free full text.

Abstract: OBJECTIVES: To examine the effect of galantamine on activities of daily living (ADLs) with respect to baseline dementia severity, correlation with cognitive and global function, specific ADLs affected, and maintenance of ADL independence. DESIGN: Secondary analysis of a 5-month randomized, placebo-controlled trial. SETTING: Multiple U.S. clinical centers. PARTICIPANTS: Six hundred fifty-nine patients with mild to moderate Alzheimer's disease (AD) who completed 5 months of treatment. INTERVENTION: Galantamine at a maintenance dose of 16 or 24 mg/d. MEASUREMENTS: The AD Cooperative Study ADL Inventory (ADCS/ADL). RESULTS: Galantamine resulted in more improvement in ADCS/ADL scores than placebo regardless of baseline dementia severity, with the greatest differences occurring in patients with more severe disease. Changes in ADCS/ADL scores correlated significantly with change scores on the cognitive subscale of the AD Assessment Scale (r=-0.24). Galantamine treatment resulted in maintenance or improvement of basic and instrumental ADLs, and change from baseline to Month 5 in scores for each individual ADL item favored galantamine over placebo in three of six basic ADLs and six of 17 instrumental ADLs. CONCLUSION: Galantamine has a favorable effect on ADL performance in patients with AD, detectable after 5 months of treatment, regardless of dementia severity. The ADCS/ADL appears to better measure distinct abilities that may be relevant not only in clinical trials but also in individual patients than do cognitive assessments.

Wilcock G, Howe I, Coles H, Lilienfeld S, Truyen L, Zhu Y, Bullock R, Kershaw P, Anonymous00494. · Department of Care of the Elderly, University of Bristol, Frenchay Hospital, Bristol, UK. · Drugs Aging. · Pubmed #12875613 No free full text.

Abstract: OBJECTIVE: To compare the long-term efficacy and safety of galantamine 24 mg/day and donepezil 10 mg/day in patients with Alzheimer's disease. PATIENTS AND STUDY DESIGN: This was a rater-blinded, randomised, parallel-group multicentre study (18 outpatient clinics) in the UK. 182 patients (69 male, 113 female) with Alzheimer's disease were randomised to galantamine (n = 94) or donepezil (n = 88) for 52 weeks. MAIN OUTCOME MEASURES: The effects of galantamine and donepezil on function using the Bristol Activities of Daily Living Scale (BrADL); cognition using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog/11); behaviour using the Neuropsychiatric Inventory (NPI); caregiver burden using the Screen for Caregiver Burden; and safety were assessed. RESULTS: BrADL total scores showed no significant difference between treatment groups in mean change from baseline to week 52. In the total population, in terms of cognition, galantamine patients' scores on the MMSE at week 52 did not differ significantly from baseline (-0.52 +/- 0.39, p < 0.5 vs baseline), whereas donepezil patients' scores deteriorated significantly from baseline (-1.58 +/- 0.42, p < 0.0005 vs baseline). The between-group difference in MMSE change, which showed a trend for superiority of galantamine, did not reach statistical significance (p < or = 0.1). In the ADAS-cog/11 analysis, between-group differences for the total population were not significant, whereas galantamine-treated patients with MMSE scores of 12-18 demonstrated an increase (worsening) in the ADAS-cog/11 score of 1.61 +/- 0.80 versus baseline, compared with an increase of 4.08 +/- 0.84 for patients treated with donepezil, with a significant between-group difference in favour of galantamine (p < or = 0.05). More caregivers of patients receiving galantamine reported reductions in burden compared with donepezil. Changes from baseline in NPI were similar for both treatments.Both treatments were well tolerated; most adverse events were transient and of mild-to-moderate intensity, and were consistent with the findings of previous clinical trials. CONCLUSIONS: Significant advantages were found in the treatment response to galantamine (versus donepezil) on cognition as measured by response rates on the MMSE and ADAS-cog/11.

Zhu Y, Bickford PC, Sanberg P, Giunta B, Tan J. · Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, Florida 33613, USA. · Rejuvenation Res. · Pubmed #18789000 No free full text.

Abstract: Alzheimer's Disease (AD) is the most common age-related dementia, with a current prevalence in excess of five million individuals in the United States. The aggregation of amyloid-beta (A beta) into fibrillar amyloid plaques is a key pathological event in the development of the disease. Microglial proinflammatory activation is widely known to cause neuronal and synaptic damage that correlates with cognitive impairment in AD. However, current pharmacological attempts at reducing neuroinflammation mediated via microglial activation have been largely negative in terms of slowing AD progression. Previously, we have shown that microglia express proinflammatory cytokines and a reduced capacity to phagocytose A beta in the context of CD40, A beta peptides and/or lipopolysaccharide (LPS) stimulation, a phenomenon that can be opposed by attenuation of p44/42 mitogen-activated protein kinase (MAPK) signaling. Other groups have found that blueberry (BB) extract both inhibits phosphorylation of this MAPK module and also improves cognitive deficits in AD model mice. Given these considerations and the lack of reduced A beta quantities in behaviorally improved BB-fed mice, we wished to determine whether BB supplementation would alter the microglial proinflammatory activation state in response to A beta. We found that BB significantly enhances microglial clearance of A beta, inhibits aggregation of A beta(1-42), and suppresses microglial activation, all via suppression of the p44/42 MAPK module. Thus, these data may explain the previously observed behavioral recovery in PSAPP mice and suggest a means by which dietary supplementation could mitigate an undesirable microglial response toward fibrillar A beta.

Geng JS, Zhou AL, Shi HY, Hu YE, Mao JH, Zhu Y. · Medical School of Nantong University, Nantong 226001, China. · Zhongguo Zhong Yao Za Zhi. · Pubmed #18652361 No free full text.

Abstract: OBJECTIVE: To observe the effects of Naoyikang (NYK) on expression of choline acetyltransferase (ChAT) in brain of rats with Alzheimer' s disease (AD). METHOD: Bilateral infusions of Ibotenic acid (IBO) into nucleus basalis of Meynert (NBM) using hamilton syringe and stereotaxic apparatus were adopted to establish the rat model of AD. After intragastrically administrated with different solution for 28 days, immunohistochemistry and Western-blot were adopted to study the expression of ChAT in frontal cortex of AD rats. RESULT: NYK could improve the morphology and increase the number of ChAT immunoreactive neurons, and significantly promote ChAT protein expression. CONCLUSION: NYK may be able to increase the synthesis of acetylcholine (ACh) through elevating the expression of ChAT protein, thus improving the level of brain ACh so as to protect central cholinergic neurons.

Zhu Y, Tong XY, Zhao Y, Chen H, Jiang FC. · School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. · Yao Xue Xue Bao. · Pubmed #18630262 No free full text.

Abstract: Based on ninety three acetylcholinesterase inhibitors (AChEIs) which have the same mechanism of action but are different in structural characteristics, the pharmacophore model for acetylcholinesterase inhibitor was constructed by the CATALYST system. The optimal pharmacophore model with three hydrophobic units, a ring aromatic unit and a hydrogen-bond acceptor unit were confirmed (Weight = 3.29, RMS = 0.53, total cost-null cost = 62.75, Correl = 0.93, Config = 19.05). This pharmacophore model will act on the double active site of acetylcholinesterase and is able to predict the activity of known acetylcholinesterase inhibitors that are used for clinical treatment of Alzheimer's disease (AD), and can be further used to identify structurally diverse compounds that have higher activity treating with Alzheimer's disease (AD) by virtual screening.

Nikolic WV, Hou H, Town T, Zhu Y, Giunta B, Sanberg CD, Zeng J, Luo D, Ehrhart J, Mori T, Sanberg PR, Tan J. · Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Medicine, University of South Florida, Tampa, FL 33613, USA. · Stem Cells Dev. · Pubmed #18366296 links to  free full text

Abstract: Modulation of immune/inflammatory responses by diverse strategies including amyloid-beta (Abeta) immunization, nonsteroidal anti-inflammatory drugs, and manipulation of microglial activation states has been shown to reduce Alzheimer's disease (AD)-like pathology and cognitive deficits in AD transgenic mouse models. Human umbilical cord blood cells (HUCBCs) have unique immunomodulatory potential. We wished to test whether these cells might alter AD-like pathology after infusion into the PSAPP mouse model of AD. Here, we report a marked reduction in Abeta levels/beta-amyloid plaques and associated astrocytosis following multiple low-dose infusions of HUCBCs. HUCBC infusions also reduced cerebral vascular Abeta deposits in the Tg2576 AD mouse model. Interestingly, these effects were associated with suppression of the CD40-CD40L interaction, as evidenced by decreased circulating and brain soluble CD40L (sCD40L), elevated systemic immunoglobulin M (IgM) levels, attenuated CD40L-induced inflammatory responses, and reduced surface expression of CD40 on microglia. Importantly, deficiency in CD40 abolishes the effect of HUCBCs on elevated plasma Abeta levels. Moreover, microglia isolated from HUCBC-infused PSAPP mice demonstrated increased phagocytosis of Abeta. Furthermore, sera from HUCBC-infused PSAPP mice significantly increased microglial phagocytosis of the Abeta1-42 peptide while inhibiting interferon-gammainduced microglial CD40 expression. Increased microglial phagocytic activity in this scenario was inhibited by addition of recombinant CD40L protein. These data suggest that HUCBC infusion mitigates AD-like pathology by disrupting CD40L activity.

Galvin JE, Cornblatt B, Newhouse P, Ancoli-Israel S, Wesnes K, Williamson D, Zhu Y, Sorra K, Amatniek J. · Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA. · Alzheimer Dis Assoc Disord. · Pubmed #18317244 No free full text.

Abstract: Deficits in attention are present early in the course of Alzheimer disease (AD). Acetylcholine receptors are appealing molecular targets for intervention as cholinergic pathways are involved in the neurobiology of attention. For this reason, measures of attention were included in 2 independent, multicenter, randomized, parallel, controlled trials in subjects with AD comparing the effects of galantamine, an acetylcholinesterase inhibitor and postulated nicotinic receptor modulator, and donepezil, an acetylcholinesterase inhibitor. The attention battery of the Cognitive Drug Research computerized assessment system was used in both trials. Small magnitude, positive signals were observed for simple and choice reaction times for both compounds. Attention task performance tended to improve early for galantamine-treated subjects. A consistent temporal pattern of improvement was not observed in donepezil-treated subjects. Quantitative findings appeared more pronounced in subjects with moderate AD. Galantamine's proposed action as a nicotinic receptor modulator may bear on these findings. Improved attention may have positive effects on cognitive and functional outcomes for AD patients, although this hypothesis requires further study and validation.

Erkinjuntti T, Gauthier S, Bullock R, Kurz A, Hammond G, Schwalen S, Zhu Y, Brashear R. · Memory Research Unit, Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland. · J Psychopharmacol. · Pubmed #18308781 No free full text.

Abstract: Alzheimer's disease combined with cerebrovascular disease (AD with CVD) is associated with progressive decline, with CVD impacting AD onset and severity of progression. Subjects with confirmed diagnosis of AD with CVD were treated with galantamine during a six-month, randomized, placebo-controlled trial (N = 285). Responder analyses were performed for cognitive, behavioural and functional outcome measures. Galantamine treatment resulted in significantly greater cognitive and functional improvements compared with placebo at six months, and a significantly higher percentage of treatment responders. The proportion of responders demonstrating improved or maintained cognition on the 11-item AD assessment scale-cognitive subscale (ADAS-cog/11) was 60.5% for galantamine versus 46.0% for placebo (P = 0.013). The proportion of patients responding by at least four-points on the ADAS-cog/11 was significantly greater for the galantamine group compared with placebo (33.6% versus 17.2%; P = 0.003). Seventy-five percent of galantamine-treated subjects improved or remained stable as assessed by CIBIC-plus compared with 53.6% on placebo (P = 0.0006). Significantly higher responder rates were observed with galantamine for behaviour (64.9% versus 56.6%; P = 0.024), and numerically favourable responder rates were seen with galantamine for activities of daily living. Treatment-emergent adverse events were generally related with the gastrointestinal system (nausea 20% versus 10%; vomiting 12% versus 5%; galantamine and placebo groups, respectively). Three deaths occurred during double-blind treatment: 2 of 188 subjects receiving galantamine, and 1 of 97 subjects receiving placebo. These findings are consistent with a broad range of cognitive, functional and behavioural benefits with galantamine across the spectrum of AD and AD with CVD.

Chen X, Huang T, Zhang J, Song J, Chen L, Zhu Y. · Department of Neurology, Fujian Institute of Geriatrics, the Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, China. · Brain Res. · Pubmed #18289510 No free full text.

Abstract: Increasing evidence have shown that beta-amyloid (Abeta) induced hyperphosphorylation of tau, which eventually resulted in the disruption of microtubule (MT) integrity. Cyclin-dependent kinase 5 (CDK5) and its activator p35 are required for neurite outgrowth. The cleavage of p35 to p25, mediated by calpain and calcium, caused CDK5 dislocation and subsequently p25/CDK5-induced tau hyperphosphorylation, which disrupted the cytoskeleton and resulted in neuronal death. In the present study we investigated the effects of ginsenoside Rb1 on fibrillar Abeta(25-35)-induced tau hyperphosphorylation in primary cultured cortical neurons and also the potential involvement of Ca(2+)-calpain-CDK5 signal pathway. The present study suggests that Ca(2+), calpain, and p25 in CDK5 pathway may play important roles in Abeta(25-35)-induced tau hyperphosphorylation.

Zhu Y, Xu J, Kwong WH, Wai SM, Lam WP, Yew DT. · Department of Histology and Embryology School of Preclinical Medicine, Sun Yat-sen University, Guangzhou, China. · Int J Neurosci. · Pubmed #17729152 No free full text.

Abstract: The brains of three Alzheimer patients aged 93, 94, and 104 years old were analyzed. Although cell death was apparent in different cortices, the prefrontal cortex and the Broca's appeared to be hit hardest. The different CA areas of the hippocampal formation all displayed equivalent degrees of cell death but the entorhinal areas showed the most severe degree of cell degeneration. Both apoptosis and necrosis were observed in the different cerebral regions of these very old patients, as expected.

Katz I, de Deyn PP, Mintzer J, Greenspan A, Zhu Y, Brodaty H. · Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA, and Department of Neurology, Memory Clinic, Middelheim Hospital, ZNA, Wilrijk-Antwerp, Belgium. · Int J Geriatr Psychiatry. · Pubmed #17471598 No free full text.

Abstract: BACKGROUND: Dementia typically includes behavioral and psychological symptoms of dementia (BPSD) as well as cognitive decline. Psychosis of Alzheimer's disease (AD) is a specific component of AD, characterized by delusions, misidentifications, and hallucinations. METHODS: This study is a meta-analysis of patients with psychosis of AD from four large placebo-controlled clinical trials of risperidone in dementia. Three trials included patients diagnosed with heterogeneous symptoms of BPSD (those with psychosis of AD were included in this analysis), while one trial included only those diagnosed with psychosis of AD. Efficacy was measured using the Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD) Psychosis subscale and Clinical Global Impression (CGI). RESULTS: Primary analyses in the psychosis of AD population demonstrated that risperidone significantly improved scores on the BEHAVE-AD Psychosis subscale and CGI scale compared with placebo. Secondary analyses demonstrated that patients with more severe symptoms showed a more pronounced response to treatment with risperidone compared with placebo than those patients with less severe symptoms. Extrapyramidal symptoms and somnolence were more frequent with risperidone than placebo (p=0.04). Cerebrovascular adverse events and all-cause mortality were observed more frequently, although not statistically significantly, with risperidone versus placebo. CONCLUSIONS: This meta-analysis of psychosis of AD showed improvement in psychotic symptoms and general clinical improvement in patients with psychosis of AD treated with risperidone compared with placebo. The benefits of treatment were most significant in patients with severe symptoms. The safety profile of risperidone in this psychosis of AD population was similar to the more general BPSD population.

Dunbar F, Zhu Y, Brashear HR. · Janssen-Ortho Inc., Toronto, Ontario, Canada. · Clin Ther. · Pubmed #16750451 No free full text.

Abstract: BACKGROUND: A once-daily extended-release galantamine(GAL-ER) formulation has been designed to improve tolerability compared with twice-daily immediate-release galantamine (GAL-IR). OBJECTIVE: The aim of this study was to conduct a post hoc analysis of the clinical presentation of nausea and vomiting with GAL-ER compared with GAL-IR in subjects with mild to moderate Alzheimer's disease (AD). METHODS: This is the report of a post hoc analysis of a large, randomized, double-blind, placebo-controlled, multicenter trial of GAL-ER with GAL-IR as the active control in subjects with mild to moderate AD. Galantamine dose was titrated every 4 weeks by increments of 8 mg/d to a daily dose of 16 or 24 mg, based on tolerability. Daily rates of nausea and vomiting were compared for the GAL-ER and GAL-IR groups. AUCs of the daily percentage of subjects reporting nausea/vomiting during dose titration were calculated. Antiemetic use for nausea/vomiting was compared between GAL-ER and GAL-IR groups. RESULTS: Demographic characteristics were similar between the GAL-ER, GAL-IR, and placebo groups. Nausea was reported by 16.9% (54/319) of GAL-ER, 13.8% (45/326) of GAL-IR, and 5.0% (16/320) of placebo patients; vomiting was reported for 6.6% (21/319) of GAL-ER, 8.6% (28/326) of GAL-IR, and 2.2% (7/320) of placebo patients. The mean (SD) daily rate of nausea in the total population was 3.1 (13.43%) in the GAL-ER group and 5.2% (22.07%) in the GAL-IR group (P = NS); the mean (SD) daily rate of vomiting for the total population was 0.6% (4.14%) in the GAL-ER group and 1.6% (14.50%) in the GAL-IR group (P = NS). The mean (SD) daily rate of nausea or vomiting in the total population was 1.2 (8.46) and 0.4 (5.44) in the placebo group, respectively. For subjects reporting nausea, the mean (SD, SE) percentage of days with nausea was lower with GAL-ER than with GAL-IR (18.4% [28.22%, 5.31%] vs 38.0% [48.23%, 6.04%]; P = 0.014). AUC of the daily percentage of subjects reporting nausea/vomiting during dose titration was significantly higher in the GAL-IR group compared with the placebo group (320.9 vs 102.9; P = 0.01); there was no statistical difference between the GAL-ER group and placebo (171.1 vs 102.9; P = NS). Antiemetic use by subjects reporting nausea or vomiting was significantly lower in the GAL-ER group than the GAL-IR group (33.3% vs 53.4%; P = 0.028). CONCLUSIONS: In these subjects with AD, the daily percentage of subjects reporting nausea and vomiting, and the percentage of days with vomiting among subjects reporting vomiting, did not significantly differ between the GAL-ER and GAL-IR groups. However, GAL-ER was associated with a significantly lower percentage of days with nausea than GAL-IR among subjects reporting nausea. AUC of the daily percentage of subjects with nausea or vomiting during dose titration did not differ significantly between the GAL-ER and placebo groups but was significantly higher in the GAL-IR group than placebo. Subjects with nausea or vomiting who received GAL-ER reported significantly less antiemetic use than those treated with GAL-IR. These results suggest the need for additional studies to explore the potential differences in the tolerability of these formulations.

Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang J, LeBlanc A, Smith D, Rigby M, Shearman MS, Clarke EE, Zheng H, Van Der Ploeg LH, Ruffolo SC, Thornberry NA, Xanthoudakis S, Zamboni RJ, Roy S, Nicholson DW. · Department of Pharmacology, Biochemistry, and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Merck Research Laboratories, Kirkland, Quebec, Canada. · Cell. · Pubmed #10319819 No free full text.

Abstract: The amyloid-beta precursor protein (APP) is directly and efficiently cleaved by caspases during apoptosis, resulting in elevated amyloid-beta (A beta) peptide formation. The predominant site of caspase-mediated proteolysis is within the cytoplasmic tail of APP, and cleavage at this site occurs in hippocampal neurons in vivo following acute excitotoxic or ischemic brain injury. Caspase-3 is the predominant caspase involved in APP cleavage, consistent with its marked elevation in dying neurons of Alzheimer's disease brains and colocalization of its APP cleavage product with A beta in senile plaques. Caspases thus appear to play a dual role in proteolytic processing of APP and the resulting propensity for A beta peptide formation, as well as in the ultimate apoptotic death of neurons in Alzheimer's disease.