Journal of Alzheimer's Disease - Volume 24, issue 4

Authors: Carrasquillo, Minerva M. | Belbin, Olivia | Hunter, Talisha A. | Ma, Li | Bisceglio, Gina D. | Zou, Fanggeng | Crook, Julia E. | Pankratz, V. Shane | Sando, Sigrid B. | Aasly, Jan O. | Barcikowska, Maria | Wszolek, Zbigniew K. | Dickson, Dennis W. | Graff-Radford, Neill R. | Petersen, Ronald C. | Morgan, Kevin | for the Alzheimer's Research Trust Consortium (ART) | Younkin, Steven G.

Article Type: Research Article

Abstract: The most recent late-onset Alzheimer's disease (LOAD) genome-wide association study revealed genome-wide significant association of two new loci: rs744373 near BIN1 (p = 1.6 × 10−11 ) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (p = 6.5 × 10−9 ). We have genotyped these variants in a large (3,287 LOAD, 4,396 controls), independent dataset comprising eleven case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and also tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE ε4 status. Meta-analysis results showed no evidence of series heterogeneity and logistic regression analysis successfully …replicated the association of BIN1 (rs744373) with LOAD with an odds ratio (OR = 1.17, p = 1.1 × 10−4 ) comparable to that previously reported (OR = 1.15). The variant near EXOC3L2 (rs597668) showed only suggestive association with LOAD (p = 0.09) after correcting for the presence of the APOE ε4 allele. Addition of our follow-up data to the results previously reported increased the strength of evidence for association with BIN1 (11,825 LOAD, 32,570 controls, rs744373 Fisher combined p = 3.8 × 10−20 ). We also tested for epistatic interaction between these variants and APOE ε4 as well as with the previously replicated LOAD GWAS genes (CLU: rs11136000, CR1: rs3818361, and PICALM: rs3851179). No significant interactions between these genes were detected. In summary, we provide additional evidence for the variant near BIN1 (rs744373) as a LOAD risk modifier, but our results indicate that the effect of EXOC3L2 independent of APOE ε4 should be studied further. Show more

Keywords: Alzheimer's disease, case-control studies, heterogeneity, late onset, meta-analysis

DOI: 10.3233/JAD-2011-101932

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 751-758, 2011

Authors: Arai, Masaya | Saito, Mitsunari | Takatsu, Hirokatsu | Fukui, Koji | Urano, Shiro

Article Type: Research Article

Abstract: To define whether hyperoxia induces the dysfunction of membrane fusion between synaptic vesicles with pre-synaptic plasma membranes in the nerve terminals, and whether vitamin E prevents this abnormal event, we investigated the influence of hyperoxia on the fusion ability of isolated synaptic vesicles and the inside-out type pre-synaptic plasma membrane vesicles from rat brain using the fluorescence tracing method. The membrane fusion ability of both membranes from rats subjected to hyperoxia was markedly decreased compared with the membranes from a normal rat. Rats subjected to hyperoxia in the form of oxidative stress showed significant increases in the levels of thiobarbituric …acid reactive substances (TBARS), conjugated dienes, and protein carbonyl moieties in both synaptic vesicles and pre-synaptic plasma membranes. When rats were supplemented with vitamin E, these abnormalities were inhibited even when rats were subjected to hyperoxia. Show more

Keywords: Neurotransmission, oxidative brain damage, oxidative stress, synaptic membrane fusion, vitamin E

DOI: 10.3233/JAD-2011-101785

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 759-766, 2011

Authors: Hensley, Kenneth | Barnes, Lisa L. | Christov, Alexandar | Tangney, Christy | Honer, William G. | Schneider, Julie A. | Bennett, David A. | Morris, Martha Clare

Article Type: Research Article

Abstract: Ventricular cerebrospinal fluid (vCSF) obtained at autopsy from 230 participants in the Religious Orders Study was analyzed for alpha tocopherol (αT, vitamin E) and gamma tocopherol (γT) in relation to brain tissue neuropathological diagnoses (NIA-Reagan criteria); neuritic plaque density and neurofibrillary tangle state (Braak stage); and cognitive function proximate to death. Neither vCSF αT nor γT was related to the pathological diagnosis of Alzheimer's disease, but vCSF αT concentration was inversely related to neuritic plaque density (β = −0.21, SE = 0.105, p = 0.04) in regression models adjusted for age, gender, education, and APOE-4. Ventricular CSF αT concentration was …positively associated with perceptual speed (β = 0.27, SE = 0.116, p = 0.02) whereas the γT/αT ratio was negatively associated with episodic memory (β = −0.037, SE = 0.017, p = 0.04). Only vCSF αT, but not γT, was correlated with postmortem interval (PMI). Adjustment for PMI had no effect on significance of associations between αT and perceptual speed or γT/αT and episodic memory, but after this adjustment the αT concentration was no longer significantly associated with neuritic plaques. These data suggest that vCSF αT, but not γT, is weakly associated with less Alzheimer's disease neuropathology, specifically neuritic plaques, and correlates with better performance on tests of perceptual speed. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, Religious Orders Study, tocopherol, vitamin E

DOI: 10.3233/JAD-2011-101995

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 767-774, 2011

Authors: Yang, Wenlu | Lui, Ronald L.M. | Gao, Jia-Hong | Chan, Tony F. | Yau, Shing-Tung | Sperling, Reisa A. | Huang, Xudong

Article Type: Research Article

Abstract: There is an unmet medical need to identify neuroimaging biomarkers that allow us to accurately diagnose and monitor Alzheimer's disease (AD) at its very early stages and to assess the response to AD-modifying therapies. To a certain extent, volumetric and functional magnetic resonance imaging (fMRI) studies can detect changes in structure, cerebral blood flow, and blood oxygenation that distinguish AD and mild cognitive impairment (MCI) subjects from healthy control (HC) subjects. However, it has been challenging to use fully automated MRI analytic methods to identify potential AD neuroimaging biomarkers. We have thus proposed a method based on independent component analysis …(ICA) for studying potential AD-related MR image features that can be coupled with the use of support vector machine (SVM) for classifying scans into categories of AD, MCI, and HC subjects. The MRI data were selected from the Open Access Series of Imaging Studies (OASIS) and the Alzheimer's Disease Neuroimaging Initiative databases. The experimental results showed that the ICA method coupled with SVM classifier can differentiate AD and MCI patients from HC subjects, although further methodological improvement in the analytic method and inclusion of additional variables may be required for optimal classification. Show more

Keywords: Alzheimer's disease, independent component analysis, magnetic resonance imaging, mild cognitive impairment, neuroimaging biomarker, support vector machine

DOI: 10.3233/JAD-2011-101371

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 775-783, 2011

Authors: Tiribuzi, Roberto | Orlacchio, Antonio | Crispoltoni, Lucia | Maiotti, Mariangela | Zampolini, Mauro | De Angeliz, Massimiliano | Mecocci, Patrizia | Cecchetti, Roberta | Bernardi, Giorgio | Datti, Alessandro | Martino, Sabata | Orlacchio, Aldo

Article Type: Research Article

Abstract: Multiple epidemiological studies have shown that individuals affected by type-2 diabetes mellitus (T2DM) carry a 2-to-5-fold higher risk of developing Alzheimer's disease (AD) when compared to non-diabetic subjects. Thus, biochemical parameters that can be easily and routinely assessed for high-confidence evaluation of diabetic conditions leading to AD (AD-T2DM) are regarded as efficient tools aimed at early diagnosis and, in turn, timely AD treatment. In this regard, the activity of lysosomal glycohydrolases may of use, in light of the implication of these enzymes in early events that underlie AD pathology and an overt correlation, in diabetes, between altered metabolic homeostasis, abnormal …glycohydrolase secretion in body fluids, and occurrence of diabetic complications. Based on marked up-regulation previously shown in a peripheral, cell-based model of AD, we selected β-Galactosidase, β-Hexosaminidase, and α-Mannosidase to discriminate T2DM from AD-T2DM subjects. A screen of 109, 114, and 116 patients with T2DM, AD and AD-T2DM, respectively, was performed by testing enzyme activities in both blood plasma and peripheral blood mononuclear cells. Compared to age-matched, healthy controls (n = 122), β-Galactosidase and β-Hexosaminidase activities markedly diverged across the three groups, whereas virtually unchanged values were observed for α-Mannosidase. In particular, plasma β-Galactosidase and β-Hexosaminidase levels were higher in patients with AD-T2DM compared to those with T2DM, suggesting different mechanisms leading to enzyme secretion. Statistical analyses based on ROC curves showed that both β-Galactosidase and β-Hexosaminidase activities, either intracellular or plasma-secreted, may be used to discriminate AD patients from controls and AD-T2DM from T2DM patients. Show more

Keywords: Alzheimer's disease, diagnostic correlation, lysosomal glycohydrolases, type 2 diabetes

DOI: 10.3233/JAD-2011-100525

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 785-797, 2011

Authors: Balducci, Claudia | Mehdawy, Bisan | Mare, Lydia | Giuliani, Alessandro | Lorenzini, Luca | Sivilia, Sandra | Giardino, Luciana | Calzà, Laura | Lanzillotta, Annamaria | Sarnico, Ilenia | Pizzi, Marina | Usiello, Alessandro | Viscomi, Arturo R. | Ottonello, Simone | Villetti, Gino | Imbimbo, Bruno P. | Nisticò, Giuseppe | Forloni, Gianluigi | Nisticò, Robert

Article Type: Research Article

Abstract: Abnormal amyloid-β (Aβ) production and deposition is believed to represent one of the main causes of Alzheimer's disease (AD). γ-Secretase is the enzymatic complex responsible for Aβ generation from its precursor protein. Inhibition or modulation of γ-secretase represents an attractive therapeutic approach. CHF5074 is a new γ-secretase modulator that has been shown to inhibit brain plaque deposition and to attenuate memory deficit in adult AD transgenic mice after chronic treatment. To date, it is not known whether the positive behavioral effects of this compound also occur in young transgenic mice without plaque deposition. Here, we evaluated the effects of acute …and subchronic treatment with CHF5074 on contextual and recognition memory and on hippocampal synaptic plasticity in plaque-free Tg2576 mice. We found that at 5 months of age, contextual memory impairment was significantly attenuated after acute subcutaneous administration of 30 mg/kg CHF5074. At 6 months of age, recognition memory impairment was fully reversed after a 4-week oral treatment in the diet (≈60 mg/kg/day). These cognitive effects were associated with a reversal of long-term potentiation (LTP) impairment in the hippocampus. A significant reduction in brain intraneuronal AβPP/Aβ levels and hyperphosphorylated tau, but no change in soluble or oligomeric Aβ levels was detected in Tg2576 mice showing functional recovery following CHF5074 treatment. We conclude that the beneficial effects of CHF5074 treatment in young transgenic mice occurred at a stage that precedes plaque formation and were associated with a reduction in intraneuronal AβPP/Aβ and hyperphosphorylated tau. Show more

Keywords: Alzheimer's disease, amyloid-β, fear conditioning, γ-secretase modulators, long-term potentiation, non-steroidal anti-inflammatory drugs, recognition memory

DOI: 10.3233/JAD-2011-101839

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 799-816, 2011

Authors: Echeverria, Valentina | Zeitlin, Ross | Burgess, Sarah | Patel, Sagar | Barman, Arghya | Thakur, Garima | Mamcarz, Magorzota | Wang, Li | Sattelle, David B. | Kirschner, Daniel A. | Mori, Takashi | Leblanc, Roger M. | Prabhakar, Rajeev | Arendash, Gary W.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) affects millions of people world-wide and new effective and safe therapies are needed. Cotinine, the main metabolite of nicotine, has a long half-life and does not have cardiovascular or addictive side effects in humans. We studied the effect of cotinine on amyloid-β (Aβ) aggregation as well as addressed its impact on working and reference memories. Cotinine reduced Aβ deposition, improved working and reference memories, and inhibited Aβ oligomerization in the brains of transgenic (Tg) 6799 AD mice. In vitro studies confirmed the inhibitory effect of cotinine on Aβ1-42 aggregation. Cotinine stimulated Akt signaling, including the inhibition …of glycogen synthase kinase 3β (GSK3β), which promotes neuronal survival and the synaptic plasticity processes underlying learning and memory in the hippocampus and cortex of wild type and Tg6799 AD mice. Simulation of the cotinine–Aβ1-42 complex using molecular dynamics showed that cotinine may interact with key histidine residues of Aβ1-42 , altering its structure and inhibiting its aggregation. The good safety profile in humans and its beneficial effects suggest that cotinine may be an excellent therapeutic candidate for the treatment of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, cotinine, neurodegeneration, oligomerization

DOI: 10.3233/JAD-2011-102136

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 817-835, 2011

Article Type: Correction

Abstract: Erratum to [Journal of Alzheimer's Disease 22(1), 2010, 135-150], DOI 10.3233/JAD-2010-100639.

DOI: 10.3233/JAD-2011-111438

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 837-837, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-102137

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 839-841, 2011