Alzheimer Disease: Chen K

Li W, Mak M, Jiang H, Wang Q, Pang Y, Chen K, Han Y. · Department of Applied Biology & Chemical Technology, Institute of Modern Chinese Medicine, the Hong Kong Polytechnic University, Hong Kong SAR, China. · Neurotherapeutics. · Pubmed #19110209 No free full text.

Abstract: Alzheimer's disease (AD) is a progressive and degenerative brain disorder that has emerged as one of the major public health problems in adults. Unfortunately, its molecular pathology and therapeutic strategies remain elusive. Because there are multiple factors closely indicated in the pathogenesis of AD, multiple drug therapy will be required to address the varied pathological aspects of this disease. Existing pharmacological approaches with one-molecule-one-target are limited in their ability to modify the pathology of AD. Novel therapeutics strategies comprise multifunctional compounds specifically designed to target concurrently on different sites at multifactorial etiopathogenesis of AD, thereby providing greater therapeutic efficacy. Over the past decade, our group has developed several series of dimeric acetylcholinesterase (AChE) inhibitors derived from tacrine and huperzine A, a unique anti-Alzheimer's drug originally discovered from a traditional Chinese medicinal plant. Bis(7)-Cognitin, one of our novel dimers, through inhibition of AChE, N-methyl-D-aspartate receptor, nitric oxide synthase, and amyloid precursor protein/beta-amyloid cascade concurrently, possesses remarkable neuroprotective activities. More importantly, the synergism between these targets might serve as one of the most effective therapeutic strategies to arrest/modify pathological process of AD in addition to improving the cognitive functions for AD.

Bortolato M, Chen K, Shih JC. · Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA. · Adv Drug Deliv Rev. · Pubmed #18652859 No free full text.

Abstract: Monoamine oxidases (MAOs) A and B are mitochondrial bound isoenzymes which catalyze the oxidative deamination of dietary amines and monoamine neurotransmitters, such as serotonin, norepinephrine, dopamine, beta-phenylethylamine and other trace amines. The rapid degradation of these molecules ensures the proper functioning of synaptic neurotransmission and is critically important for the regulation of emotional behaviors and other brain functions. The byproducts of MAO-mediated reactions include several chemical species with neurotoxic potential, such as hydrogen peroxide, ammonia and aldehydes. As a consequence, it is widely speculated that prolonged excessive activity of these enzymes may be conducive to mitochondrial damages and neurodegenerative disturbances. In keeping with these premises, the development of MAO inhibitors has led to important breakthroughs in the therapy of several neuropsychiatric disorders, ranging from mood disorders to Parkinson's disease. Furthermore, the characterization of MAO knockout (KO) mice has revealed that the inactivation of this enzyme produces a number of functional and behavioral alterations, some of which may be harnessed for therapeutic aims. In this article, we discuss the intriguing hypothesis that the attenuation of the oxidative stress induced by the inactivation of either MAO isoform may contribute to both antidepressant and antiparkinsonian actions of MAO inhibitors. This possibility further highlights MAO inactivation as a rich source of novel avenues in the treatment of mental disorders.

Chen K, Huang J, Gong W, Zhang L, Yu P, Wang JM. · School of Agriculture and Biology, Shanghai Jiaotong University, Shanghai 201101, China. · Cell Mol Immunol. · Pubmed #16893496 links to  free full text

Abstract: CD40 and its cognate ligand (CD40L) are a pair of regulators of pro-inflammatory and immune responses. In the central nervous system (CNS), CD40 is expressed on a variety of cells, including vascular endothelial cells, smooth muscle cells, astrocytes and microglia (the brain macrophages, being the most sensitive cell type to respond to CD40 ligand). Interaction between CD40 on microglia and CD40L presented by infiltrating T lymphocytes and other resident CNS cells triggers a series of intracellular signaling events that promote the production of a wide array of cytokines, chemokines and neurotoxins. Thus, both molecules serve as amplifiers of pro-inflammatory and immune responses in the CNS and constitute important molecular targets for therapeutic intervention of diseases.

Chen K, Reiman EM, Alexander GE, Bandy D, Renaut R, Crum WR, Fox NC, Rossor MN. · Positron Emission Tomography Center, Banner Good Samaritan Regional Medical Center, 1111 E. McDowell Road, Phoenix, AZ 85006, USA. · Neuroimage. · Pubmed #15110003 No free full text.

Abstract: This article introduces an automated method for the computation of changes in brain volume from sequential magnetic resonance images (MRIs) using an iterative principal component analysis (IPCA) and demonstrates its ability to characterize whole-brain atrophy rates in patients with Alzheimer's disease (AD). The IPCA considers the voxel intensity pairs from coregistered MRIs and identifies those pairs a sufficiently large distance away from the iteratively determined PCA major axis. Analyses of simulated and real MRI data support the underlying assumption of a linear relationship in paired voxel intensities, identify an outlier distance threshold that optimizes the trade-off between sensitivity and specificity in the detection of small volume changes while accounting for global intensity changes, and demonstrate an ability to detect changes as small as 0.04% of brain volume without confounding effects of between-scan shifts in voxel intensity. In eight patients with probable AD and eight age-matched normal control subjects, the IPCA was comparable to the established but partly manual digital subtraction (DS) method in characterizing annual rates of whole-brain atrophy: resulting rates were correlated (Spearman rank correlation = 0.94, P < 0.0005) and comparable in distinguishing probable AD from normal aging (IPCA-detected atrophy rates: 2.17 +/- 0.52% per year in the patients vs. 0.41 +/- 0.22% per year in the controls [Wilcoxon-Mann-Whitney test P = 7.8 x 10(-4)]; DS-detected atrophy rates: 3.51 +/- 1.31% per year in the patients vs. 0.48 +/- 0.29% per year in the controls [P = 7.8 x 10(-4)]). The IPCA could be used in tracking the progression of AD, evaluating the disease-modifying effects of putative treatments, and investigating the course of other normal and pathological changes in brain morphology.

Du J, Sun B, Chen K, Fan L, Wang Z. · Protein Science Key Laboratory of the Ministry of Education, Department of Biological Sciences and Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, PR China. · Biochem Biophys Res Commun. · Pubmed #19422805 No free full text.

Abstract: Recent evidences show that peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in the modulation of the amyloid-beta (Abeta) cascade causing Alzheimer's disease (AD) and treatment with PPARgamma agonists protects against AD pathology. However, the function of PPARgamma steady-state activity in Abeta cascade and AD pathology remains unclear. In this study, an antagonist of PPARgamma, GW9662, was injected into the fourth ventricle of APP/PS1 transgenic mice to inhibit PPARgamma activity in cerebellum. The results show that inhibition of PPARgamma significantly induced Abeta levels in cerebellum and caused cerebellar motor dysfunction in APP/PS1 transgenic mice. Moreover, GW9662 treatment markedly decreased the cerebellar levels of insulin-degrading enzyme (IDE), which is responsible for the cellular degradation of Abeta. Since cerebellum is spared from significant Abeta accumulation and neurotoxicity in AD patients and animal models, these findings suggest a crucial role of PPARgamma steady-state activity in protection of cerebellum against AD pathology.

Langbaum JB, Chen K, Lee W, Reschke C, Bandy D, Fleisher AS, Alexander GE, Foster NL, Weiner MW, Koeppe RA, Jagust WJ, Reiman EM, Anonymous00091. · Banner Alzheimer's Institute and Banner Good Samaritan PET Center, Phoenix, AZ, USA. · Neuroimage. · Pubmed #19349228 No free full text.

Abstract: In mostly small single-center studies, Alzheimer's disease (AD) is associated with characteristic and progressive reductions in fluorodeoxyglucose positron emission tomography (PET) measurements of the regional cerebral metabolic rate for glucose (CMRgl). The AD Neuroimaging Initiative (ADNI) is acquiring FDG PET, volumetric magnetic resonance imaging, and other biomarker measurements in a large longitudinal multi-center study of initially mildly affected probable AD (pAD) patients, amnestic mild cognitive impairment (aMCI) patients, who are at increased AD risk, and cognitively normal controls (NC), and we are responsible for analyzing the PET images using statistical parametric mapping (SPM). Here we compare baseline CMRgl measurements from 74 pAD patients and 142 aMCI patients to those from 82 NC, we correlate CMRgl with categorical and continuous measures of clinical disease severity, and we compare apolipoprotein E (APOE) varepsilon4 carriers to non-carriers in each of these subject groups. In comparison with NC, the pAD and aMCI groups each had significantly lower CMRgl bilaterally in posterior cingulate, precuneus, parietotemporal and frontal cortex. Similar reductions were observed when categories of disease severity or lower Mini-Mental State Exam (MMSE) scores were correlated with lower CMRgl. However, when analyses were restricted to the pAD patients, lower MMSE scores were significantly correlated with lower left frontal and temporal CMRgl. These findings from a large, multi-site study support previous single-site findings, supports the characteristic pattern of baseline CMRgl reductions in AD and aMCI patients, as well as preferential anterior CMRgl reductions after the onset of AD dementia.

Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, Ayutyanont N, Keppler J, Reeder SA, Langbaum JB, Alexander GE, Klunk WE, Mathis CA, Price JC, Aizenstein HJ, DeKosky ST, Caselli RJ. · Banner Alzheimer's Institute and the Positron Emission Tomography Center, Good Samaritan Regional Medical Center, Phoenix, AZ 85006, USA. · Proc Natl Acad Sci U S A. · Pubmed #19346482 links to  free full text

Abstract: Fibrillar amyloid-beta (Abeta) is found in the brains of many cognitively normal older people. Whether or not this reflects a predisposition to Alzheimer's disease (AD) is unknown. We used Pittsburgh Compound B (PiB) PET to characterize the relationship between fibrillar Abeta burden and this predisposition in cognitively normal older people at 3 mean levels of genetic risk for AD. Dynamic PiB PET scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest (ROIs) were used to characterize and compare cerebral-to-cerebellar PIB distribution volume ratios, reflecting fibrillar Abeta burden, in 28 cognitively normal persons (mean age, 64 years) with a reported family history of AD and 2 copies, 1 copy, and no copies of the apolipoprotein E (APOE) epsilon4 allele. The 8 epsilon4 homozygotes, 8 heterozygotes, and 12 noncarriers did not differ significantly in terms of age, sex, or cognitive scores. Fibrillar Abeta was significantly associated with APOE epsilon4 carrier status and epsilon4 gene dose in AD-affected mean cortical, frontal, temporal, posterior cingulate-precuneus, parietal, and basal ganglia ROIs, and was highest in an additional homozygote who had recently developed mild cognitive impairment. These findings suggest that fibrillar Abeta burden in cognitively normal older people is associated with APOE epsilon4 gene dose, the major genetic risk factor for AD. Additional studies are needed to track fibrillar Abeta accumulation in persons with different kinds and levels of AD risk; to determine the extent to which fibrillar Abeta, alone or in combination with other biomarkers and risk factors, predicts rates of cognitive decline and conversion to clinical AD; and to establish the role of fibrillar Abeta imaging in primary prevention trials.

Hou DR, Wang Y, Zhou L, Chen K, Tian Y, Song Z, Bao J, Yang QD. · Department of Neurology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China. · Chin Med J (Engl). · Pubmed #19080340 links to  free full text

Abstract: BACKGROUND: Alzheimer disease (AD) is a neurodegenerative disease related to aging. At present, its pathological mechanisms remain unclear. Family members of the renin-angiotensin system (RAS) play a role in neuronal plasticity, as well as formation of learning and memory. In this study, we explore the effects of altered angiotensin-converting enzyme (ACE), and investigate the possible mechanisms of perindopril, an ACE inhibitor, on brain structure and function in a rat model of AD, as well as the role that ACE plays in AD. METHODS: Sixty Sprague-Dawley rats were selected and randomly divided into 3 groups: control, AD, and perindopril. Each group consisted of 20 rats, with 10 rats for determining pathology, and the remaining 10 rats for quantifying ACE activity. The rat AD model was established by stereotactically injecting amyloid beta protein (A-beta) 1-42 into the right hippocampus. Learning and memory functions were tested using the Y-type electric maze. The number and morphology of abnormal neurons were determined by haematoxylin and eosin staining. Amyloid deposition was measured by Congo red staining. Finally, ACE activity was estimated by spectrophotometry. RESULTS: Compared with the control group, the number of times needed to escape electrical stimuli increased (23.70 +/- 3.13, P < 0.001), the number of normal neurons in the CA1 region was reduced (density of 96.5 +/- 32.6/mm, P < 0.001), amyloid deposition was obvious, and ACE activity increased ((34.4 +/- 6.6) nmol x g(-1) x min(-1), P < 0.001) in the AD group. In the perindopril group, the number of times needed to escape electrical stimuli decreased (18.50 +/- 3.66, P < 0.001), the number of abnormal neurons increased (density of CA1 neurons was 180.8 +/- 28.5/mm, P < 0.001), amyloid deposition was reduced, and ACE activity was down-regulated ((26.2 +/- 6.2) nmol x g(-1) x min(-1), P < 0.001). CONCLUSIONS: ACE activity increased in the brains of AD rats. Perindopril improved learning and memory in AD rats, which correlated with decreased ACE activity and delayed AD pathogenesis.

Caselli RJ, Chen K, Lee W, Alexander GE, Reiman EM. · Department of Neurology, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA. · Arch Neurol. · Pubmed #18779428 No free full text.

Abstract: BACKGROUND: Before symptomatic memory loss, healthy apolipoprotein E epsilon4 (APOE epsilon4) (OMIM 104310) carriers demonstrate accelerated longitudinal decline on memory tests, suggesting the existence of a transitional state between normal aging and mild cognitive impairment (MCI), which we have called amnestic pre-MCI. OBJECTIVE: To support our neuropsychological construct of pre-MCI by characterizing and comparing the relationship between measurements of baseline regional hypometabolism and subsequent rates of memory decline in a group of individuals with neuropsychologically defined asymptomatic memory decline (pre-MCI group) and in nondecliners after controlling for APOE epsilon4 gene dose. DESIGN: Longitudinal study. SETTING: Academic medical center. PARTICIPANTS: Of 139 healthy individuals in the Arizona APOE Cohort aged 50 to 69 years who underwent longitudinal neuropsychological testing and fludeoxyglucose F 18-positron emission tomography (FDG-PET) since 1994, 10 met our criteria for amnestic pre-MCI, and 15 showed no decline. MAIN OUTCOME MEASURES: Correlations between lower regional cerebral metabolic rates for glucose (CMRgl) and rates of verbal memory test decline that occurred at a mean of 41 months after baseline FDG-PET using an automated brain mapping algorithm (SPM5). RESULTS: The pre-MCI and nondecliner groups did not differ in mean (SD) age (56.8 [4.8] years), education (16.5 [2.3] years), sex (19 women [76%]), or APOE epsilon4 carrier status (12 epsilon4 carriers [48%)]. After controlling for APOE epsilon4 gene dose, the pre-MCI group had significant correlations between lower baseline CMRgl in the posterior cingulate, bilateral parietal, and left prefrontal regions (known to be preferentially affected by Alzheimer disease) and subsequent verbal memory decline. Nondecliners had significant correlations bilaterally in the posterior and midcingulate cortices. Correlations in the left parietal, left temporal, and bilateral frontal regions were significantly greater in the pre-MCI group than those in the nondecliner group. CONCLUSION: Individuals with amnestic pre-MCI showed significantly greater correlations between cerebral hypometabolism and subsequent long-term memory decline than nondecliners in Alzheimer disease-affected brain regions.

Reiman EM, Chen K, Caselli RJ, Alexander GE, Bandy D, Adamson JL, Lee W, Cannon A, Stephan EA, Stephan DA, Papassotiropoulos A. · Banner Alzheimer's Institute and Banner Good Samaritan PET Center, Phoenix, AZ 85006, USA. · Neuroimage. · Pubmed #18280754 links to  free full text

Abstract: We recently implicated a cluster of nine single nucleotide polymorphisms from seven cholesterol-related genes in the risk of Alzheimer's disease (AD) in a European cohort, and we proposed calculating an aggregate cholesterol-related genetic score (CREGS) to characterize a person's risk. In a separate study, we found that apolipoprotein E (APOE) epsilon4 gene dose, an established AD risk factor, was correlated with fluorodeoxyglucose (FDG) positron emission tomography (PET) measurements of hypometabolism in AD-affected brain regions in a cognitively normal American cohort, and we proposed using PET as a presymptomatic endophenotype to help assess putative modifiers of AD risk. Thus, the objective in the present study is to determine whether CREGS is related to PET measurements of hypometabolism in AD-affected brain regions. DNA and PET data from 141 cognitively normal late middle-aged APOE epsilon4 homozygotes, heterozygotes and noncarriers were analyzed to evaluate the relationship between CREGS and regional PET measurements. Cholesterol-related genetic risk scores were associated with hypometabolism in AD-affected brain regions, even when controlling for the effects of APOE epsilon4 gene dose. The results support the role of cholesterol-related genes in the predisposition to AD and support the value of neuroimaging in the presymptomatic assessment of putative modifiers of AD risk.

Stonnington CM, Tan G, Klöppel S, Chu C, Draganski B, Jack CR, Chen K, Ashburner J, Frackowiak RS. · Wellcome Trust Centre for Neuroimaging, Institute of Neurology, UCL, London, UK. · Neuroimage. · Pubmed #18032068 links to  free full text

Abstract: Large, multi-site studies utilizing MRI-derived measures from multiple scanners present an opportunity to advance research by pooling data. On the other hand, it remains unclear whether or not the potential confound introduced by different scanners and upgrades will devalue the integrity of any results. Although there are studies of scanner differences for the purpose of calibration and quality control, the current literature is devoid of studies that describe the analysis of multi-scanner data with regard to the interaction of scanner(s) with effects of interest. We investigated a data-set of 136 subjects, 62 patients with mild to moderate Alzheimer's disease and 74 cognitively normal elderly controls, with MRI scans from one center that were acquired over 10 years with 6 different scanners and multiple upgrades over time. We used a whole-brain voxel-wise analysis to evaluate the effect of scanner, effect of disease, and the interaction of scanner and disease for the 6 different scanners. The effect of disease in patients showed the expected significant reduction of grey matter in the medial temporal lobe. Scanner differences were substantially less than the group differences and only significant in the thalamus. There was no significant interaction of scanner with disease group. We describe the rationale for concluding that our results were not confounded by scanner differences. Similar analyses in other multi-scanner data-sets could be used to justify the pooling of data when needed, such as in studies of rare disorders or in multi-center designs.

Chen K, Reiman EM, Alexander GE, Caselli RJ, Gerkin R, Bandy D, Domb A, Osborne D, Fox N, Crum WR, Saunders AM, Hardy J. · Banner Alzheimer Institute, Banner Good Samaritan PET Center, 1111 E. McDowell Rd., Phoenix, AZ 85006, USA. · Am J Psychiatry. · Pubmed #17541051 links to  free full text

Abstract: OBJECTIVE: The purpose of this study was to characterize the relationship between whole brain atrophy rates and three levels of genetic risk for Alzheimer's disease in cognitively normal persons. The authors previously found accelerated whole brain atrophy rates in patients with probable Alzheimer's disease by computing changes in brain volume from sequential magnetic resonance images (MRIs). METHODS: The authors assessed 36 late-middle-aged persons from three genetic groups: those with two, one, and no copies of the apolipoprotein E (APOE) epsilon4 allele, a common Alzheimer's disease susceptibility gene. The participants had clinical ratings, neuropsychological tests, and volumetric T1-weighted MRIs during a baseline visit and again approximately 2 years later. Two different image-analysis techniques, brain boundary shift integration and iterative principal component analysis, were used to compute whole brain atrophy rates. RESULTS: While there were no baseline, follow-up, or between-visit differences in the clinical ratings or neuropsychological test scores among the three subject groups, whole brain atrophy rates were significantly greater in the epsilon4 homozygote group than in noncarriers and were significantly correlated with epsilon4 gene dose (i.e., the number of epsilon4 alleles in a person's APOE genotype). CONCLUSION: Since APOE epsilon4 gene dose is associated with an increased risk of Alzheimer's disease and a younger median age at dementia onset, this study suggests an association between the risk of Alzheimer's disease and accelerated brain atrophy rates before the onset of cognitive impairment.

Zuo Z, Gang C, Zou H, Mok PC, Zhu W, Chen K, Jiang H. · Drug Discovery and Design Centre, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China. · Comput Biol Chem. · Pubmed #17500040 No free full text.

Abstract: Beta-secretase is a potential target for inhibitory drugs against Alzheimer's disease as it cleaves amyloid precursor protein (APP) to form insoluble amyloid plaques and vascular deposits in the brain. Beta-secretase is matured from its precursor protein, called beta-secretase zymogen, which, different from most of other zymogens, is also partially active in cleaving APP. Hence, it is important to study on the mechanism of the zymogen's activation process. This study was to model the 3-D structure of the zymogen, followed by intensive molecular dynamics (MD) simulations to identify the most probable 3-D model and to study the dynamic structural behavior of the zymogen for understanding the effects of pro-segment on the function of the enzyme. The results revealed that the dropping in catalytic activity of the beta-secretase zymogen could be attributed to the occupation of the entrance of the catalytic site of the zymogen by its pro-segment. On the other hand, the partial catalytic activity of the zymogen could be explained by high fluctuation of the pro-segment in comparison with that of other zymogens, resulting in the occasionally exposure of the catalytic site for access its substrate APP. Indeed, steered MD (SMD) simulation revealed a weak pulling force at quasi-equilibrium state for the pro-segment of the zymogen leaving from the entrance, indicating that this swinging process could take place spontaneously. Furthermore, MM-PBSA calculation revealed a small change of free energy of 10.56 kal/mol between the initial and final states of the process of pro-segment swung outside the binding pocket of beta-secretase zymogen. These results not only account for the partial catalytic activity of beta-secretase zymogen, but also provide useful clues for discovering new potent ligands, as new type of drug leads for curing Alzheimer's disease, to prevent the pro-segment of the zymogen from leaving its catalytic site.

Chen K, Kazachkov M, Yu PH. · Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. · J Neural Transm. · Pubmed #17401529 No free full text.

Abstract: Formaldehyde and methylglyoxal are generated via deamination from methylamine and aminoacetone respectively catalyzed by semicarbazide-sensitive amine oxidase (SSAO). Malondialdehyde (MDA) and 4-hydroxynonenal (HNE) are end products of lipid peroxidation due to oxidative stress. These aldehydes are capable of inducing protein cross-linkage. Elevated levels of aldehydes were found in Alzheimer's disease (AD). These reactive metabolites may potentially play important roles in beta-amyloid (Abeta) aggregation related to the pathology of AD. In the present study thioflavin-T (ThT) fluorometry, an immuno-dot-blot assay and atomic force microscopy (AFM) were employed to reveal the effect of aldehydes on Abeta aggregation in vitro. The target on Abeta for interaction with formaldehyde was identified. The results support the involvement of endogenous aldehydes in amyloid deposition related to AD.

Chen K, Maley J, Yu PH. · Neuropsychiatry Research Unit, Department of Psychiatry, Saskatchewan Structural Sciences Centre, University of Saskatchewan, Saskatoon, Canada. · J Neurochem. · Pubmed #17074066 No free full text.

Abstract: Aldehydes are capable of inducing protein cross-linkage. An increase in aldehydes has been found in Alzheimer's disease. Formaldehyde and methylglyoxal are produced via deamination of, respectively, methylamine and aminoacetone catalyzed by semicarbazide-sensitive amine oxidase (SSAO, EC 1.4.3.6. The enzyme is located on the outer surface of the vasculature, where amyloidosis is often initiated. A high SSAO level has been identified as a risk factor for vascular disorders. Serum SSAO activity has been found to be increased in Alzheimer's patients. Malondialdehyde and 4-hydroxynonenal are derived from lipid peroxidation under oxidative stress, which is also associated with Alzheimer's disease. Aldehydes may potentially play roles in beta-amyloid aggregation related to the pathology of Alzheimer's disease. In the present study, thioflavin-T fluorometry, dynamic light scattering, circular dichroism spectroscopy and atomic force microscopy were employed to reveal the effect of endogenous aldehydes on beta-amyloid at different stages, i.e. beta-sheet formation, oligomerization and fibrillogenesis. Formaldehyde, methylglyoxal and malondialdehyde and, to a lesser extent, 4-hydroxynonenal are not only capable of enhancing the rate of formation of beta-amyloid beta-sheets, oligomers and protofibrils but also of increasing the size of the aggregates. The possible relevance to Alzheimer's disease of the effects of these aldehydes on beta-amyloid deposition is discussed.

Caselli RJ, Chen K, Bandy D, Smilovici O, Boeve BF, Osborne D, Alexander GE, Parish JM, Krahn LE, Reiman EM. · Department of Neurology, Mayo Clinic, Scottsdale, Arizona 85259, USA. · Sleep. · Pubmed #16895260 No free full text.

Abstract: STUDY OBJECTIVES: To test the hypothesis that healthy adults reporting dream-enactment behavior (DEB+) have reduced cerebral metabolic rate for glucose (CMRgl) in regions preferentially affected in patients with dementia with Lewy bodies (DLB). DESIGN: Automated brain-mapping algorithms were used to compare regional fluorodeoxyglucose (FDG) positron emission tomography (PET) measurements from previously evaluated DEB cases and controls. SETTING: Tertiary-care academic medical centers. PARTICIPANTS: Seventeen cognitively normal patients with DEB+ and 17 control subjects (DEB-) who were individually matched for age (59 +/- 11 years), education level (16 +/- 4 years), sex (67% women), body mass index (26 +/- 4.8 kg/m2), first-degree relative with dementia (85%), and proportion of apolipoprotein E (APOE) e4 carriers (13 e4 carriers, 4 noncarriers). INTERVENTIONS: FDG-PET. MEASUREMENTS AND RESULTS: DEB was associated with significantly lower CMRgl in several brain regions known to be preferentially affected in both DLB and Alzheimer disease (parietal, temporal, and posterior cingulate cortexes) and in several other regions, including the anterior cingulate cortex (p < .001, uncorrected for multiple comparisons). The DEB-associated CMRgl reductions were significantly greater in the APOE e4 noncarriers than in the carriers. CONCLUSIONS: These preliminary findings suggest that cognitively normal persons with DEB have reduced CMRgl in brain regions known to be metabolically affected by DLB, supporting further study of DEB as a possible risk factor for the development of DLB.

Chen K, Iribarren P, Hu J, Chen J, Gong W, Cho EH, Lockett S, Dunlop NM, Wang JM. · Laboratory of Molecular Immunoregulation, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702, USA. · J Biol Chem. · Pubmed #16339765 links to  free full text

Abstract: The human G-protein-coupled formyl peptide receptor-like 1 (FPRL1) and its mouse homologue mFPR2 mediate the chemotactic activity of a variety of polypeptides associated with inflammation and bacterial infection, including the 42-amino acid form of amyloid beta peptide (Abeta42), a pathogenic factor in Alzheimer disease. Because mFPR2 was inducible in mouse microglial cells by proinflammatory stimulants, such as bacterial lipopolysaccharide, a ligand for the Toll-like receptor 4 (TLR4), we investigated the role of TLR2 in the regulation of mFPR2. We found that a TLR2 agonist, peptidoglycan (PGN) derived from Gram-positive bacterium Staphylococcus aureus, induced considerable mFpr2 mRNA expression in a mouse microglial cell line and primary microglial cells. This was associated with a markedly increased chemotaxis of the cells in response to mFPR2 agonist peptides. In addition, activation of TLR2 markedly enhanced mFPR2-mediated uptake of Abeta42 by microglia. Studies of the mechanistic basis showed that PGN activates MAPK and IkappaBalpha, and the effect of PGN on induction of mFPR2 was dependent on signaling pathways via ERK1/2 and p38 MAPKs. The use of TLR2 on microglial cells by PGN was supported by the fact that N9 cells transfected with short interfering RNA targeting mouse TLR2 failed to show increased expression of functional mFPR2 after stimulation with PGN. Our results demonstrated a potentially important role for TLR2 in microglial cells of promoting cell responses to chemoattractants produced in lesions of inflammatory and neurodegenerative diseases in the brain.

Johnson SC, Schmitz TW, Moritz CH, Meyerand ME, Rowley HA, Alexander AL, Hansen KW, Gleason CE, Carlsson CM, Ries ML, Asthana S, Chen K, Reiman EM, Alexander GE. · Geriatric Research Education and Clinical Center, Wm. S. Middleton VA Hospital, 2500 Overlook Terrace (11G), GRECC, Madison, WI 53705, USA. · Neurobiol Aging. · Pubmed #16226349 links to  free full text

Abstract: This study examined the functionality of the medial temporal lobe (MTL) and posterior cingulate (PC) in mild cognitive impairment amnestic type (MCI), a syndrome that puts patients at greater risk for developing Alzheimer disease (AD). Functional MRI (fMRI) was used to identify regions normally active during encoding of novel items and recognition of previously learned items in a reference group of 77 healthy young and middle-aged adults. The pattern of activation in this group guided further comparisons between 14 MCI subjects and 14 age-matched controls. The MCI patients exhibited less activity in the PC during recognition of previously learned items, and in the right hippocampus during encoding of novel items, despite comparable task performance to the controls. Reduced fMRI signal change in the MTL supports prior studies implicating the hippocampus for encoding new information. Reduced signal change in the PC converges with recent research on its role in recognition in normal adults as well as metabolic decline in people with genetic or cognitive risk for AD. Our results suggest that a change in function in the PC may account, in part, for memory recollection failure in AD.

Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, Hardy J. · Positron Emission Tomography Center, Banner Good Samaritan Medical Center, Phoenix, AZ 85006, USA. · Proc Natl Acad Sci U S A. · Pubmed #15932949 links to  free full text

Abstract: Patients with Alzheimer's disease (AD) have abnormally low positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgl) in regions of the precuneus and the posterior cingulate, parietotemporal, and frontal cortex. Apolipoprotein E (APOE) epsilon4 gene dose (i.e., the number of epsilon4 alleles in a person's APOE genotype) is associated with a higher risk of AD and a younger age at dementia onset. We previously found that cognitively normal late-middle-aged APOE epsilon4 carriers have abnormally low CMRgl in the same brain regions as patients with probable Alzheimer's dementia. In a PET study of 160 cognitively normal subjects 47-68 years of age, including 36 epsilon4 homozygotes, 46 heterozygotes, and 78 epsilon4 noncarriers who were individually matched for their gender, age, and educational level, we now find that epsilon4 gene dose is correlated with lower CMRgl in each of these brain regions. This study raises the possibility of using PET as a quantitative presymptomatic endophenotype to help evaluate the individual and aggregate effects of putative genetic and nongenetic modifiers of AD risk.

Zeng L, Chen K, Muller M, Zhou MM. · Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, New York, NY 10029, USA. · J Mol Neurosci. · Pubmed #15314254 No free full text.

Abstract: Ionotropic glutamate receptors (GluRs) function as an excitatory transmitter system in the human brain, particularly in learning and memory. Development of small molecules that are capable of selectively potentiating the ion channel activity of AMPA-subtype GluRs holds promise for potential new treatment of neurodegenerative diseases such as Alzheimer's. In working towards this goal, we obtained main-chain nuclear magnetic resonance (NMR) assignments of the extracellular ligand-binding domain of GluR2 that enables us to investigate receptor-ligand interactions in physiological conditions at atomic detail. With NMR structure-based methods, chemical compounds that can selectively modulate the ion chancel activity of GluR2 alone or synergistically with glutamate or kainate were identified. Our NMR structural analysis of GluR2 S1S2 further reveals that the regions of the receptor dimer interface exhibit distinct conformational dynamics, which we hypothesize to be linked to receptor functions in interactions with an agonist or antagonist. This coupling of ligand binding to receptor dimerization, gating, and desensitization may serve as an in vitro biophysical parameter to evaluate potential biological effects of the chemical ligands being developed here.

Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, Hardy J. · Positron Emission Tomography Center, Banner Good Samaritan Medical Center, Phoenix, AZ 85006, USA. · Proc Natl Acad Sci U S A. · Pubmed #14688411 links to  free full text

Abstract: Fluorodeoxyglucose positron emission tomography (PET) studies have found that patients with Alzheimer's dementia (AD) have abnormally low rates of cerebral glucose metabolism in posterior cingulate, parietal, temporal, and prefrontal cortex. We previously found that cognitively normal, late-middle-aged carriers of the apolipoprotein E epsilon4 allele, a common susceptibility gene for late-onset Alzheimer's dementia, have abnormally low rates of glucose metabolism in the same brain regions as patients with probable AD. We now consider whether epsilon4 carriers have these regional brain abnormalities as relatively young adults. Apolipoprotein E genotypes were established in normal volunteers 20-39 years of age. Clinical ratings, neuropsychological tests, magnetic resonance imaging, and PET were performed in 12 epsilon4 heterozygotes, all with the epsilon3/epsilon4 genotype, and 15 noncarriers of the epsilon4 allele, 12 of whom were individually matched for sex, age, and educational level. An automated algorithm was used to generate an aggregate surface-projection map that compared regional PET measurements in the two groups. The young adult epsilon4 carriers and noncarriers did not differ significantly in their sex, age, educational level, clinical ratings, or neuropsychological test scores. Like previously studied patients with probable AD and late-middle-aged epsilon4 carriers, the young epsilon4 carriers had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex. Carriers of a common Alzheimer's susceptibility gene have functional brain abnormalities in young adulthood, several decades before the possible onset of dementia.

Alexander GE, Chen K, Pietrini P, Rapoport SI, Reiman EM. · Arizona Alzheimer's Research Center and Department of Psychiatry, Arizona State University, Tempe, 85287-1104, USA. · Am J Psychiatry. · Pubmed #11986126 links to  free full text

Abstract: OBJECTIVE: It is well established that regional cerebral metabolic rates for glucose assessed by [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in patients with Alzheimer's disease in the mental resting state (eyes and ears covered) provide a sensitive, in vivo metabolic index of Alzheimer's disease dementia. Few studies, however, have evaluated longitudinal declines in regional cerebral glucose metabolism in patients with dementia caused by Alzheimer's disease. In addition, the available studies have not used recently developed brain mapping algorithms to characterize the progression of Alzheimer's disease throughout the brain, and none considered the statistical power of regional cerebral glucose metabolism in testing the ability of treatments to attenuate the progression of dementia. METHOD: The authors used FDG PET and a brain mapping algorithm to investigate cross-sectional reductions in regional cerebral glucose metabolism, longitudinal decline in regional cerebral glucose metabolism after a 1-year follow-up, and the power of this method to evaluate treatments for Alzheimer's disease in patients with mild to moderate dementia. PET scans were initially acquired in 14 patients with Alzheimer's disease and 34 healthy comparison subjects of similar age and sex. Repeat scans were obtained in the patients 1 year later. Power analyses for voxels showing maximal decline over the 1-year period in regional cerebral glucose metabolism (mg/100 g per minute) were computed to estimate the sample sizes needed to detect a significant treatment response in a 1-year, double-blind, placebo-controlled treatment study. RESULTS: The patients with Alzheimer's disease had significantly lower glucose metabolism than healthy comparison subjects in parietal, temporal, occipital, frontal, and posterior cingulate cortices. One year later, the patients with Alzheimer's disease had significant declines in glucose metabolism in parietal, temporal, frontal, and posterior cingulate cortices. Using maximal glucose metabolism reductions in the left frontal cortex, we estimated that as few as 36 patients per group would be needed to detect a 33% treatment response with one-tailed significance of p</=0.005 and 80% power in a 1-year, double-blind, placebo-controlled treatment study. CONCLUSIONS: These findings indicate that brain metabolism as assessed by FDG PET during mental rest is a sensitive marker of disease progression in Alzheimer's disease over a 1-year period. These findings also support the feasibility of using FDG PET as an outcome measure to test the ability of treatments to attenuate the progression of Alzheimer's disease.

Valla J, Chen K, Berndt JD, Gonzalez-Lima F, Cherry SR, Games D, Reiman EM. · Alzheimer's Disease Research Laboratory, Harrington Arthritis Research Center, USA. · Neuroimage. · Pubmed #11969312 No free full text.

Abstract: Fluorodeoxyglucosepositron emission tomography (PET) studies find that persons with Alzheimer's disease have preferential reductions in posterior cingulate activity. Using fluorodeoxyglucose autoradiography, we found that transgenic mice overexpressing a mutant form of the human amyloid precursor protein have preferentially reduced activity in the same region, providing a potential brain imaging indicator of Alzheimer's disease in these animals. In this study, we considered the feasibility of using in vivo imaging techniques, such as PET, to detect this reduction despite their limitations in spatial resolution. Autoradiographic measurements of posterior cingulate activity were remeasured in the previously studied PDAPP transgenic and littermate control mice after the images were filtered to lower spatial resolutions. We continued to detect significantly lower cingulate activity in the transgenic mice when the images were blurred to 0.50 mm, failed to detect significantly abnormal activity when the images were blurred to 0.75 mm, and, indeed, found significantly higher activity when the images were blurred to 1.0 mm. Reversal in direction of the abnormality appears attributable to a previously observed truncation in the corpus callosum in PDAPP mice. With the possible exception of future in vivo imaging techniques that have a spatial resolution greater than or equal to 0.50 mm and high sensitivity, noninvasive functional brain imaging techniques like PET may not be suitable for detecting declines in regional activity in PDAPP mice. It remains possible that these imaging techniques will prove useful in transgenic mouse lines that do not exhibit the same morphological abnormalities in neighboring white matter regions.

Reiman EM, Caselli RJ, Chen K, Alexander GE, Bandy D, Frost J. · Department of Psychiatry, University of Arizona, Tucson, AZ 85724, USA. · Proc Natl Acad Sci U S A. · Pubmed #11248079 links to  free full text

Abstract: Cross-sectional positron emission tomography (PET) studies find that cognitively normal carriers of the apolipoprotein E (APOE) epsilon4 allele, a common Alzheimer's susceptibility gene, have abnormally low measurements of the cerebral metabolic rate for glucose (CMRgl) in the same regions as patients with Alzheimer's dementia. In this article, we characterize longitudinal CMRgl declines in cognitively normal epsilon4 heterozygotes, estimate the power of PET to test the efficacy of treatments to attenuate these declines in 2 years, and consider how this paradigm could be used to efficiently test the potential of candidate therapies for the prevention of Alzheimer's disease. We studied 10 cognitively normal epsilon4 heterozygotes and 15 epsilon4 noncarriers 50-63 years of age with a reported family history of Alzheimer's dementia before and after an interval of approximately 2 years. The epsilon4 heterozygotes had significant CMRgl declines in the vicinity of temporal, posterior cingulate, and prefrontal cortex, basal forebrain, parahippocampal gyrus, and thalamus, and these declines were significantly greater than those in the epsilon4 noncarriers. In testing candidate primary prevention therapies, we estimate that between 50 and 115 cognitively normal epsilon4 heterozygotes are needed per active and placebo treatment group to detect a 25% attenuation in these CMRgl declines with 80% power and P = 0.005 in 2 years. Assuming these CMRgl declines are related to the predisposition to Alzheimer's dementia, this study provides a paradigm for testing the potential of treatments to prevent the disorder without having to study thousands of research subjects or wait many years to determine whether or when treated individuals develop symptoms.

Wen Z, Xie J, Guan Z, Sun D, Yao W, Chen K, Yan ZY, Mu Q. · Department of Medical Physics, Beijing Medical University, PR China. · Clin Hemorheol Microcirc. · Pubmed #11081463 No free full text.

Abstract: To evaluate the change of hemorheological indexes for patients with Alzheimer's disease (AD) at the early stages and to discuss effects of these changes on AD, high shear value of whole blood viscosity (etabh), reduced high shear value of whole blood viscosity (retabh), low shear value of whole blood viscosity (etabl), reduced low shear, value of whole blood viscosity (retabl), KT value of whole blood viscosity, hematocrit (HCT) and blood plasma viscosity (etaP) were measured in 31 patients with probable AD at the early stages and 33 age-matched healthy subjects. There were significant differences of all hemorheological indexes between AD group and control group except HCT. Step discriminant analysis revealed 81.25% of overall group-classified accuracy in a hemorheological discriminant function consisting of etabl, retabl, retabh and HCT. Significant difference of hemorheological indexes existed between AD and age-matched healthy control subjects. The results showed that measurement of hemorheological indexes could be used as one of reference standards of diagnosis in AD.