Alzheimer Disease: He Y

Liu Y, Wang K, Yu C, He Y, Zhou Y, Liang M, Wang L, Jiang T. · National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China. · Neuropsychologia. · Pubmed #18346763 No free full text.

Abstract: Resting-state functional magnetic resonance imaging (fMRI), a promising technique for measuring brain activities during rest, has attracted much attention in the past few years. In this paper, we review recent progress on the study of Alzheimer's disease (AD) based on resting-state fMRI. First, we briefly introduce some AD-related studies from other groups. Then we describe our AD-related work in detail from three aspects: (1) alterations in regional homogeneity (ReHo) of the fMRI signal in the resting state, (2) altered patterns of functional connectivity from regions of interest and whole brain analyses, and (3) discriminative analyses based on classification features from resting-state fMRI data for differentiating AD patients from healthy elders. Finally, we summarize the main results and some prospects for future work.

Feldman HH, Ferris S, Winblad B, Sfikas N, Mancione L, He Y, Tekin S, Burns A, Cummings J, del Ser T, Inzitari D, Orgogozo JM, Sauer H, Scheltens P, Scarpini E, Herrmann N, Farlow M, Potkin S, Charles HC, Fox NC, Lane R. · Division of Neurology, University of British Columbia Hospital, Vancouver, Canada. · Lancet Neurol. · Pubmed #17509485 No free full text.

Abstract: OBJECTIVE: To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimer's disease (AD) and the rate of cognitive decline. METHODS: The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0.5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00000174. FINDINGS: Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17.3% of patients on rivastigmine and 21.4% on placebo progressed to AD (hazard ratio 0.85 [95% CI 0.64-1.12]; p=0.225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (-0.10 [95% CI -0.63 to 0.44], p=0.726). Serious adverse events were reported by 141 (27.9%) rivastigmine-treated patients and 155 (30.5%) patients on placebo; adverse events of all types were reported by 483 (95.6%) rivastigmine-treated patients and 472 (92.7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group. INTERPRETATION: There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns.

Lane RM, He Y. · Novartis Neuroscience, Novartis Pharmaceuticals Corporation, 59 Route 10, East Hanover, NJ 07936-1080, USA. · Med Hypotheses. · Pubmed #19359103 No free full text.

Abstract: Non-enzymatic functions of butyrylcholinesterase (BuChE) include prevention of the aggregation of amyloid-beta peptide (A beta) in a concentration-dependent manner. This is mediated by the C-terminus of the protein, distal from the enzymatic site. The BuChE-K variant polymorphism lowers expression of BuChE protein and/or alters C-terminal activity. In combination with factors that increase production or reduce elimination of A beta, and/or increase susceptibility to A beta toxicity - such as the apolipoprotein E (APOE) epsilon 4 allele and/or hyperhomocysteinemia - BuChE-K may accelerate cholinergic synaptic and neuronal damage and cognitive decline. A beta-mediated damage to ascending cholinergic pathways may be further accentuated by Lewy body and/or cerebrovascular disease. As the disease advances and functioning cholinergic synapses disappear, both the rapid cognitive decline and response to cholinesterase inhibitor therapy in individuals with these factors may diminish. Non-enzymatic functions of the BuChE protein, APOE epsilon 4 status and hyperhomocysteinemia influence the progression of pathology, symptom expression, and response to cholinesterase inhibition in a stage-specific manner in neurodegenerative disorders associated with Alzheimer, Lewy body and vascular pathology.

Ballard C, Sauter M, Scheltens P, He Y, Barkhof F, van Straaten EC, van der Flier WM, Hsu C, Wu S, Lane R. · Wolfson Centre for Age-Related Diseases, King's College, London, UK. · Curr Med Res Opin. · Pubmed #18674411 No free full text.

Abstract: OBJECTIVE: The aim was to evaluate the efficacy, safety and tolerability of rivastigmine capsules in patients diagnosed with probable vascular dementia (VaD). METHODS: VantagE (Vascular Dementia trial studying Exelon) was a 24-week, multicentre, double-blind study. VaD patients aged 50-85 years were randomized to rivastigmine capsules (3-12 mg/day) or placebo. Efficacy assessments included global and cognitive performances, activities of daily living and neuropsychiatric symptoms. Adverse events were recorded. Additional exploratory analyses determined whether heterogeneity in pathologies and symptoms extended to differential treatment effects. TRIAL REGISTRATION: NCT00099216. RESULTS: 710 patients were randomized. Rivastigmine demonstrated superiority over placebo on three measures of cognitive performance (Vascular Dementia Assessment Scale, Alzheimer's Disease Assessment Scale cognitive subscale, Mini-Mental State Examination; all p< or = 0.05, intent-to-treat population [ITT]), but not other outcomes. Predominant adverse events were nausea and vomiting. Exploratory analyses indicated that older patients (> or =75 years old), assumed more likely to also have Alzheimer's disease (AD) pathology, demonstrated significant cognitive responses to rivastigmine and a safety profile similar to that seen in AD patients. Younger patients, assumed less likely to have concomitant AD pathology, showed no efficacy response and were associated with slight elevations of blood pressure, cerebrovascular accidents and mortality. Rivastigmine-placebo differences in patients with, versus those without, medial temporal atrophy (also suggestive of concomitant AD) showed a numerical difference similar to that seen between the older versus younger patients, but did not attain statistical significance. CONCLUSION: Consistent with trials evaluating other cholinesterase inhibitors, rivastigmine did not provide consistent efficacy in probable VaD. The efficacy apparent on cognitive outcomes was derived from effects in older patients likely to have concomitant Alzheimer pathology. This is supportive of an existing argument that the putative cholinergic deficit in VaD reflects the presence of concomitant Alzheimer pathology.

He Y, Chen Z, Evans A. · McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4. · J Neurosci. · Pubmed #18448652 links to  free full text

Abstract: Recent research on Alzheimer's disease (AD) has shown that cognitive and memory decline in this disease is accompanied by disrupted changes in the coordination of large-scale brain functional networks. However, alterations in coordinated patterns of structural brain networks in AD are still poorly understood. Here, we used cortical thickness measurement from magnetic resonance imaging to investigate large-scale structural brain networks in 92 AD patients and 97 normal controls. Brain networks were constructed by thresholding cortical thickness correlation matrices of 54 regions and analyzed using graph theoretical approaches. Compared with controls, AD patients showed decreased cortical thickness intercorrelations between the bilateral parietal regions and increased intercorrelations in several selective regions involving the lateral temporal and parietal cortex as well as the cingulate and medial frontal cortex regions. Specially, AD patients showed abnormal small-world architecture in the structural cortical networks (increased clustering and shortest paths linking individual regions), implying a less optimal topological organization in AD. Moreover, AD patients were associated with reduced nodal centrality predominantly in the temporal and parietal heteromodal association cortex regions and increased nodal centrality in the occipital cortex regions. Finally, the brain networks of AD were about equally as robust to random failures as those of controls, but more vulnerable against targeted attacks, presumably because of the effects of pathological topological organization. Our findings suggest that the coordinated patterns of cortical morphology are widely altered in AD patients, thus providing structural evidence for disrupted integrity in large-scale brain networks that underlie cognition. This work has implications for our understanding of how functional deficits in patients are associated with their underlying structural (morphological) basis.

Lane R, Feldman HH, Meyer J, He Y, Ferris SH, Nordberg A, Darreh-Shori T, Soininen H, Pirttilä T, Farlow MR, Sfikas N, Ballard C, Greig NH. · Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936-1080, USA. · Pharmacogenet Genomics. · Pubmed #18334913 No free full text.

Abstract: OBJECTIVE: To evaluate the synergistic effects of the apolipoprotein E (APOE) epsilon4 and butyrylcholinesterase K-variant (BCHE-K) alleles on progression to Alzheimer's disease (AD) in individuals with mild cognitive impairment (MCI). METHODS: This was a post-hoc exploratory analysis from a 3-4-year, randomized, placebo-controlled study of rivastigmine in participants with MCI (InDDEx study). Participants who consented to genetic testing were included in the current analyses. The incidence of progression to AD, cognitive decline and changes in MRI brain volumes were investigated in participants from the placebo arm of the InDDEx study. RESULTS: Of the 1018 participants in the overall study, 464 were successfully genotyped for both APOE and butyrylcholinesterase. Of these, 68 (14.7%) carried > or =1 APOE epsilon4 and > or =1 BCHE-K allele. The presence of APOE epsilon4 was associated with a significantly higher incidence of progression to AD whereas the presence of BCHE-K had no independent effect on progression. A synergistic effect of the combined presence of APOE epsilon4 and BCHE-K on the time to clinical diagnosis of AD and on MRI brain volumes was seen. Progression to AD and hippocampal volumetric loss was greatest in participants who carried both APOE epsilon4 and BCHE-K alleles and lowest in BCHE-K carriers without the APOE epsilon4 allele. CONCLUSION: In MCI, the risk of cognitive decline, hippocampal volumetric loss and progression to AD seems to be the greatest in individuals who carry at least one copy of both the BCHE-K and APOE epsilon4 alleles.

Salins P, He Y, Olson K, Glazner G, Kashour T, Amara F. · Department of Biochemistry and Medical Genetics, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, MB R3E 0W3 Canada. · Neurosci Lett. · Pubmed #18063474 No free full text.

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder, due to excess amyloid-beta peptide (Abeta). TGF-beta1 and beta-catenin signaling pathways have been separately implicated in modulating Abeta-neurotoxicity. However, the underlying mechanisms remain unclear. Here, we report that TGF-beta1 and nuclear Smad7 and beta-catenin levels were markedly upregulated in cortical brain regions of the TgCRND8 mice, a mouse model of familial Alzheimer's disease. Coimmunoprecipitation of cortical brain tissue lysates revealed an interaction between Smad7 and beta-catenin. This interaction which was significantly enhanced in the TgCRND8 mice was also associated with an increase in TCF/LEF DNA-shift binding activity. TCF/LEF reporter gene activity was significantly increased in mouse primary cortical neuronal cultures (MCN) from the TgCRND8 mice, compared to controls. Interestingly, exposure of MCN to Abeta(1-42) led to an increase in TGF-beta1 and nuclear levels of both beta-catenin and Smad7. Furthermore, addition of TGF-beta1 to the MCN caused an increase in apoptosis and Smad7 levels. When Smad7 or beta-catenin levels were reduced by siRNA, TGF-beta1-induced apoptosis was suppressed, indicating that both Smad7 and beta-catenin are required for TGF-beta1-induced neurotoxicity. Since Abeta(1-42)-induced TGF-beta1, we suggest that TGF-beta1 may amplify Abeta(1-42)-mediated neurodegeneration in AD via Smad7 and beta-catenin interaction and nuclear localization.

He Y, Wang L, Zang Y, Tian L, Zhang X, Li K, Jiang T. · National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing 100080, PR China. · Neuroimage. · Pubmed #17254803 No free full text.

Abstract: Recent functional imaging studies have indicated that the pathophysiology of Alzheimer's disease (AD) can be associated with the changes in spontaneous low-frequency (<0.08 Hz) blood oxygenation level-dependent fluctuations (LFBF) measured during a resting state. The purpose of this study was to examine regional LFBF coherence patterns in early AD and the impact of regional brain atrophy on the functional results. Both structural MRI and resting-state functional MRI scans were collected from 14 AD subjects and 14 age-matched normal controls. We found significant regional coherence decreases in the posterior cingulate cortex/precuneus (PCC/PCu) in the AD patients when compared with the normal controls. Moreover, the decrease in the PCC/PCu coherence was correlated with the disease progression measured by the Mini-Mental State Exam scores. The changes in LFBF in the PCC/PCu may be related to the resting hypometabolism in this region commonly detected in previous positron emission tomography studies of early AD. When the regional PCC/PCu atrophy was controlled, these results still remained significant but with a decrease in the statistical power, suggesting that the LFBF results are at least partly explained by the regional atrophy. In addition, we also found increased LFBF coherence in the bilateral cuneus, right lingual gyrus and left fusiform gyrus in the AD patients. These regions are consistent with previous findings of AD-related increased activation during cognitive tasks explained in terms of a compensatory-recruitment hypothesis. Finally, our study indicated that regional brain atrophy could be an important consideration in functional imaging studies of neurodegenerative diseases.

Blesa R, Bullock R, He Y, Bergman H, Gambina G, Meyer J, Rapatz G, Nagel J, Lane R. · Hospital Sta Creu i Sant Pau, Barcelona, Spain. · Pharmacogenet Genomics. · Pubmed #17047484 No free full text.

Abstract: A randomized double-blind trial evaluated the efficacy and tolerability of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and donepezil, an AChE-selective inhibitor, in patients with Alzheimer's disease over a 2-year period. A retrospective analysis showed differential responses to cholinesterase inhibitors (ChE-Is) in patients younger than 75 years. This analysis investigated the effect of BuChE genotype on response to ChE-I therapy in these patients. In a retrospective analysis, patients younger than 75 who had consented to pharmacogenetic analysis were divided into groups according to BuChE genotype. Efficacy measures were the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), Global Deterioration Scale (GDS), Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL). Changes on efficacy parameters were calculated for rivastigmine-treated and donepezil-treated patients in both groups. Of 114 (34.1%) patients younger than 75 who were successfully assessed for BuChE genotype, 76 (66.7%) were homozygous for wild-type BuChE, and 38 (33.3%) carried at least one BuChE K-variant allele. Wild-type BuChE carriers showed significantly greater responses to rivastigmine than to donepezil on the SIB, ADCS-ADL, GDS and NPI. No significant between-treatment differences in efficacy were observed in BuChE K-variant carriers, although adverse events were more frequent in rivastigmine-treated patients. In this retrospective analysis, Alzheimer's disease patients younger than 75 with wild-type BuChE exhibited differential efficacy to rivastigmine, while BuChE K-variant carriers experienced similar long-term treatment effects with both agents. These differences may reflect rivastigmine's ability to inhibit BuChE and AChE.

Bullock R, Bergman H, Touchon J, Gambina G, He Y, Nagel J, Lane R. · Kingshill Research Centre, Swindon, UK. · Curr Med Res Opin. · Pubmed #16574032 No free full text.

Abstract: BACKGROUND: Younger Alzheimer's disease (AD) patients appear to differ genetically and neuropathologically from older AD patients, and may experience a more aggressive disease course compared with older patients. A randomised trial investigated the efficacy and tolerability of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and donepezil, an AChE-selective inhibitor, in patients with AD over a 2-year period. This retrospective analysis investigated whether younger and older patients showed differential tolerability and efficacy responses to cholinesterase inhibitor treatment. METHODS: For the current analysis, patients were divided according to age at baseline: those aged < 75 years and those aged >or= 75 years. Efficacy measures were the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), Global Deterioration Scale (GDS), Mini-Mental State Examination (MMSE) and the AD Cooperative Study Activities of Daily Living scale (ADCS-ADL). Changes in efficacy parameters and adverse event frequencies were calculated for rivastigmine and donepezil-treated patients in both age groups. Exploratory analyses were also conducted on SIB, ADCS-ADL and NPI in patients who consented to pharmacogenetic testing at baseline. Genotyping of the apolipoprotein E (APOE) epsilon4 allele and the BuChE K-variant was conducted using the TaqMan assay. Main efficacy analyses were based on an intent-to-treat last observation carried forward (ITT-LOCF) population. RESULTS: Of the 994 patients who received the study drug, 362 (36.4%) were younger than 75 years and 632 (63.6%) were aged 75 years or over. Rivastigmine provided significant benefits in younger patients compared with donepezil on the NPI-10, NPI-12, NPI-D, GDS and ADCS-ADL (all p < 0.05, ITT-LOCF). With the exception of the NPI-D in favour of donepezil (p < 0.05, ITT-LOCF), no significant treatment differences were observed in older patients. Younger patients with two wild-type BuChE alleles had a significantly greater response to rivastigmine than donepezil on the ADCS-ADL (p < 0.01, ITT-LOCF) and SIB (p < 0.05, ITT-LOCF). The most common adverse events were nausea and vomiting and these were more frequent in rivastigmine-treated patients. CONCLUSION: In this sub group analysis, patients younger than 75 years of age showed greater treatment responses to rivastigmine than donepezil. Analysis of response by BuChE genotype suggests that this differential effect may be due to the inhibition of BuChE, in addition to AChE, by rivastigmine.

Wang L, Zang Y, He Y, Liang M, Zhang X, Tian L, Wu T, Jiang T, Li K. · Department of Radiology, Xuanwu Hospital of Capital University of Medical Sciences, Beijing 100053, PR China. · Neuroimage. · Pubmed #16473024 No free full text.

Abstract: A selective distribution of Alzheimer's disease (AD) pathological lesions in specific cortical layers isolates the hippocampus from the rest of the brain. However, functional connectivity between the hippocampus and other brain regions remains unclear in AD. Here, we employ a resting state functional MRI (fMRI) to examine changes in hippocampal connectivity comparing 13 patients with mild AD versus 13 healthy age-matched controls. Hippocampal connectivity was investigated by examination of the correlation between low frequency fMRI signal fluctuations in the hippocampus and those in all other brain regions. We found that functional connectivity between the right hippocampus and a set of regions was disrupted in AD; these regions are: medial prefrontal cortex (MPFC), ventral anterior cingulate cortex (vACC), right inferotemporal cortex, right cuneus extending into precuneus, left cuneus, right superior and middle temporal gyrus and posterior cingulate cortex (PCC). We also found increased functional connectivity between the left hippocampus and the right lateral prefrontal cortex in AD. In addition, rightward asymmetry of hippocampal connectivity observed in elderly controls was diminished in AD patients. The disrupted hippocampal connectivity to the MPFC, vACC and PCC provides further support for decreased activity in "default mode network" previously shown in AD. The decreased connectivity between the hippocampus and the visual cortices might indicate reduced integrity of hippocampus-related cortical networks in AD. Moreover, these findings suggest that resting-state fMRI might be an appropriate approach for studying pathophysiological changes in early AD.

Feng X, Zhao P, He Y, Zuo Z. · Department of Anesthesiology, University of Virginia, Charlottesville, VA 22908, USA. · Gene. · Pubmed #16426772 No free full text.

Abstract: Alzheimer's disease (AD) is the most common cause of dementia in humans. A pathological hallmark in the brain of an AD patient is extracellular amyloid plaques formed by accumulated beta-amyloid protein (Abeta), a metabolic product of amyloid precursor protein (APP). Studies have revealed a strong genetic linkage in the early-onset familial form (<60 years old) of AD. For example, some mutant APPs are transmitted dominantly and are segregated with inheritance of early onset AD. These mutants facilitate Abeta production. The "Swedish" mutations (APP(SW)) and the "London" mutation (APP(LON)) are examples of these mutants. Selective silencing of these mutant alleles holds therapeutic promise for AD. Here we show that the expression of the mutant APPs was selectively inhibited by RNA interference. The best selectivity was obtained when the mismatches were centrally placed in the antisense strand of small interfering RNAs. Introducing an additional mismatch in the antisense strand may improve the selectivity. The addition of a G at 5' end of the antisense strand may enhance the efficacy of gene silencing by RNA interference. Our results illustrate the guiding principles for selection of targeted sequences to achieve allele-specific silencing. The sequences that are effective to silence APP(SW) and APP(LON) as identified in this study may be useful in both in vivo and in vitro studies to investigate the pathophysiological role of APP(SW) and APP(LON) in AD development.

He Y, Sun SH, Chen RW, Guo YJ, He XW, Huang L, Chen ZH, Shi K, Zhu WJ. · Department of Medical Genetics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, PR China. · Alzheimer Dis Assoc Disord. · Pubmed #16327342 No free full text.

Abstract: Alzheimer disease (AD) is a neurodegenerative disorder characterized by neuropathological hallmarks including deposits of the beta-amyloid peptide (AssP). Studies have shown that immunization with Abeta42 peptide reduces both the spatial memory impairments and Alzheimer disease-like neuropathologic changes in Alzheimer disease transgenic mice, but can cause side effect of a cell-mediated autoimmune meningoencephalitis. Recently, some studies showed that DNA vaccination could be used to generate an antibody response to Abeta without the adverse cell-mediated immune effect. In the current study, we generate four DNA vaccine plasmids (pV-GE1, pV-GE2, pV-GE3, and pV-GE4) against Alzheimer disease by separately fusing Abeta epitope sequences (coding for EFGH, DAEFGH, EFGH+EFGH, and EFGH+DAEFGH) with IgG heavy chain coding region of mouse. Meanwhile, the full-length gene Abeta encoding plasmid (pV-Abeta), empty vector (pVAX) and synthetic AssP were also included as control. The sera of BALB/c mice immunized via intramuscular with plasmids and peptide were tested by indirect ELISA for auto-AssP immunoreactivity. The results showed that all the DNA vaccine plasmids induced AssP-specific antibodies; moreover pV-GE2 and pV-Abeta constructs elicited higher antibody titers than other constructs (P < 0.05). To further enhance the immune response, GM-CSF encoding plasmid (pGM-CSF) and purified BCG-DNA were used as molecular adjuvants. BCG-DNA could enhance humoral and cellular immune responses simultaneously and did not alter the phenotype of the immune responses, whereas pGM-CSF showed no obvious effect on immune response. These results suggest that this immunization strategy of using Abeta epitope encoding plasmid plus BCG-DNA adjuvant may serve as the basis for developing anti-Alzheimer disease vaccines.

He Y, Zhou H, Tang H, Luo Y. · Laboratory of Protein Chemistry, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing, China. · J Biol Chem. · Pubmed #16269408 links to  free full text

Abstract: Endostatin is an endogenous inhibitor of tumor angiogenesis and tumor growth. It has two pairs of disulfide bonds in a unique nested pattern, which play a key role in its native conformation, stability, and activity. Here, we constructed a disulfide-deficient variant of endostatin, endo-all-Ala, to examine the effects of the two disulfide bonds on fibrillogenesis of endostatin under nondenaturing conditions. Based on thioflavin T fluorescence, atomic force microscopy, far-UV circular dichroism, and Fourier transform infrared spectroscopy, we found that endo-all-Ala, which has a higher alpha-helical content compared with wild type, is prone to forming fibrils in a pH-dependent manner. Subsequently, more hydrophobic patches with a lower stability of endo-all-Ala were observed when compared with wild type, which possibly contributes to the propensity of amyloid formation of endo-all-Ala. To our surprise, the significant increase of the alpha-helical content in endostatin induced by trifluoroethanol can also facilitate fibril formation. In addition, the cytotoxicity of fibrillar aggregates of endo-all-Ala, which were generated at different stages of the fibril formation process, was evaluated by cell viability assay. The results indicate that the cytotoxicity is not due to the fibrils but rather due to the granular aggregates of endo-all-Ala. Moreover, endostatin was interestingly found to be reduced by glutathione at physiological concentrations. Our present work not only elucidates the correlation between the existence of disulfide bonds and the fibril formation of endostatin but also may provide some insights into the structural and functional basis of endostatin in Alzheimer disease brains.

Bullock R, Touchon J, Bergman H, Gambina G, He Y, Rapatz G, Nagel J, Lane R. · Kingshill Research Centre, Victoria Hospital, Swindon, UK. · Curr Med Res Opin. · Pubmed #16083542 No free full text.

Abstract: OBJECTIVES: Randomised controlled trials that directly compare cholinesterase inhibitors for the treatment of Alzheimer's disease have been characterised by significant methodological limitations. As a consequence, they have failed to establish whether there are differences between agents in this class. To help address this question, a double-blind, randomised, controlled, multicentre trial was designed to evaluate the efficacy and tolerability of cholinesterase inhibitor treatment in patients with moderate to moderately-severe Alzheimer's disease over a 2-year period. METHODS: Patients were randomly assigned to rivastigmine 3-12 mg/day or donepezil 5-10 mg/day. Efficacy measures comprised assessments of cognition, activities of daily living, global functioning and behavioural symptoms. Safety and tolerability assessments included adverse events and measurement of vital signs. RESULTS: In total, 994 patients received cholinesterase inhibitor treatment (rivastigmine, n = 495; donepezil, n = 499), and 57.9% of patients completed the study. The most frequent reason for premature discontinuation in both treatment groups was adverse events, primarily gastrointestinal. Adverse events were more frequent in the rivastigmine group during the titration phase, but similar in the maintenance phase. Serious adverse events were reported by 31.7% of rivastigmine- and 32.5% of donepezil-treated patients, respectively. Rivastigmine and donepezil had similar effects on measures of cognition and behaviour, but rivastigmine showed a statistically significant advantage on measures of activities of daily living and global functioning in the ITT-LOCF population. However, this was not maintained in the non-ITT-LOCF populations. In secondary subgroup analyses, AD patients who had genotypes that encoded for full expression of the butyrylcholinesterase enzyme (BuChE wt/wt; n = 226/340), who were < 75 years of age (n = 362/994) or who had symptoms suggestive of concomitant Lewy body disease (n = 49/994) showed significantly greater benefits from rivastigmine treatment. CONCLUSIONS: Cholinesterase inhibitor treatment may offer continued therapeutic benefit for up to 2 years in patients with moderate AD. Although both drugs performed similarly on cognition and behaviour, rivastigmine may provide greater benefit in activities of daily living and global functioning.

Chang Q, He Y, Ni B, Feng K, Jiang Y, Jiang B. · Institute of Geriatrics, Chinese PLA General Hospital, Beijing 100853, China. · Zhonghua Liu Xing Bing Xue Za Zhi. · Pubmed #15631750 No free full text.

Abstract: OBJECTIVE: To investigate the risk of Alzheimer's disease (AD) associated with life style, early exposure to magnetic fields, family history of dementia and other risk factors. METHODS: We conducted a case-control study among the inpatients of Chinese PLA General Hospital in 2000 - 2003. Sixty-two AD cases and 124 controls were selected and matched for age. Univariate and multivariate analyses were conducted using logistic regression model. RESULTS: All subjects were males aged 66 to 102. In univariate analysis, lack of social activities, more physical exercises, early exposure to magnetic fields, suffering from negative life events and family history of dementia were statistically different between two groups (P < 0.05). Multivariate analysis showed that after adjusting for potential confounders, suffering from negative life events, family histories of dementia increased the risk of AD with odds ratio (OR) and 95% confidence interval (CI) 3.27 (1.53 - 6.97) and 5.78 (1.39 - 24.10). Early exposure to magnetic fields seemed a possible risk factor for AD, with OR (95% CI) 2.49 (0.96 - 6.45). The amount of social activities, cigarette smoking and history of cancers were negatively correlated with AD and their ORs (95% CI) were 0.81 (0.72 - 0.92), 0.46 (0.21 - 1.00) and 0.31 (0.12 - 0.82) respectively. CONCLUSION: The study demonstrated that suffering from negative life events and family history of dementia were risk factors for AD, and the early exposure to magnetic fields might also play a role.

Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC. · Department of Neurology, Indiana University School of Medicine, Clinical Building, Room 299, 541 Clinical Drive, Indianapolis, IN 46202-5111, USA. · Neurology. · Pubmed #15557508 No free full text.

Abstract: OBJECTIVE: The authors aimed to use baseline data of an ongoing large, prospective study in subjects with mild cognitive impairment (MCI) to investigate the impact of APOE genotype on the symptom profile of the condition. METHODS: Cognitive assessments included the AD Assessment Scale cognitive subscale (ADAS-cog), the Mini-Mental State Examination (MMSE), and a cognitive battery for assessment of memory, attention, and executive function. Behavioral assessments included the Neuropsychiatric Inventory and Beck Depression Inventory. Activities of daily living were assessed by the AD Cooperative Study Activities of Daily Living (ADCS-ADL) scale. Hippocampal volumes were measured with MRI. RESULTS: A total of 494 of 1,018 study subjects provided APOE data. Approximately 40% of the subjects were APOE epsilon4 carriers. APOE epsilon4 carriers had lower MMSE (p = 0.01) and higher ADAS-cog (p < 0.0001) scores than noncarriers, indicating worse cognitive impairment. APOE epsilon4 carriers also had greater deficits on New York University delayed paragraph recall and Buschke free and cued selective reminding tests, and on the ADCS-ADL scale (p < 0.001). They also had smaller hippocampal volumes (p = 0.002). Behavioral scores were similar across the subgroups. CONCLUSION: MCI subjects carrying the APOE epsilon4 allele showed distinct cognitive and imaging profiles, which appeared to resemble those of early Alzheimer patients. APOE epsilon4 genotype was associated with greater impairments in memory and functional activities as well as hippocampal atrophy.

Farlow M, Lane R, Kudaravalli S, He Y. · Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA. · Pharmacogenomics J. · Pubmed #15289797 No free full text.

Abstract: This retrospective analysis of two double-blind, placebo-controlled studies in patients with mild to moderately severe AD investigated the efficacy of rivastigmine 6-12 mg/day on cognitive outcomes in patients with or without the apolipoprotein (APOE) epsilon4 allele. APOE data were collected from patients who consented to pharmacogenetic testing. Treatment differences within each subgroup were compared, using the Observed Case (OC) population. The APOE epsilon4 and non-APOE epsilon4 subgroups comprised 246 and 121 patients, respectively. Overall, APOE epsilon4 noncarriers showed greater decline than carriers (P<0.05). However, at 26 weeks, placebo-treated APOE epsilon4 patients declined 3.04 points below baseline on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), and rivastigmine-treated patients improved by 1.67 points. Non-APOE epsilon4 placebo-treated patients declined by 4.59 points and rivastigmine-treated patients declined by 0.48 points. Thus, non-APOE epsilon4 carriers showed a less favorable course under either placebo or rivastigmine, but both genotype-defined subgroups showed quantitatively similar responses to therapy (both P<0.05 vs placebo).