Journal of Alzheimer's Disease - Volume 32, issue 2

Authors: Yu, Peng | Dean, Robert A. | Hall, Stephen D. | Qi, Yuan | Sethuraman, Gopalan | Willis, Brian A. | Siemers, Eric R. | Martenyi, Ferenc | Tauscher, Johannes T. | Schwarz, Adam J. | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The goal of this study was to identify the optimal combination of magnetic resonance imaging (MRI), [18 F]-fluorodeoxyglucose positron emission tomography (FDG-PET), and cerebrospinal fluid (CSF) biomarkers to predict conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) dementia within two years, for enriching clinical trial populations. Data from 63 subjects in the Alzheimer's Disease Neuroimaging Initiative aMCI cohort who had MRI and FDG-PET imaging along with CSF data at baseline and at least two years clinical follow-up were used. A Bayesian classification method was used to determine which combination of 31 variables (MRI, FDG-PET, CSF measurements, apolipoprotein …E (ApoE) genotype, and cognitive scores) provided the most accurate prediction of aMCI to AD conversion. The cost and time trade-offs for the use of these biomarkers as inclusion criteria in clinical trials were evaluated. Using the combination of all biomarkers, ApoE genotype, and cognitive scores, we achieved an accuracy of 81% in predicting aMCI to AD conversion. With only ApoE genotype and cognitive scores, the prediction accuracy decreased to 62%. By comparing individual modalities, we found that MRI measures had the best predictive power (accuracy = 78%), followed by ApoE, FDG-PET, CSF, and the Alzheimer's disease assessment scale-cognitive subscale. The combination of biomarkers from different modalities, measuring complementary aspects of AD pathology, provided the most accurate prediction of aMCI to AD conversion within two years. This was predominantly driven by MRI measures, which emerged as the single most powerful modality. Overall, the combination of MRI, ApoE, and cognitive scores provided the best trade-off between cost and time compared with other biomarker combinations for patient recruitment in clinical trial. Show more

Keywords: Alzheimer's disease, apolipoprotein E, biomarker, cerebrospinal fluid, conversion, FDG-PET, magnetic resonance imaging, mild cognitive impairment, prodromal, progression

DOI: 10.3233/JAD-2012-120832

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 373-385, 2012

Authors: Bai, Feng | Shi, Yongmei | Yuan, Yonggui | Yue, Chunxian | Zhuang, Liying | Xu, Xiaohui | Liu, Xiaoyan | Zhang, Zhijun

Article Type: Research Article

Abstract: The glycogen synthase kinase-3β (GSK-3β) gene has been implicated in Alzheimer's disease (AD). Polymorphisms in this gene are plausible modulators of brain function. However, little is known about the potential role of the GSK-3β rs334558 polymorphism, which has been associated with amnestic mild cognitive impairment (aMCI), which is itself associated with a high risk of AD. In this study, 43 aMCI patients and 30 healthy controls underwent resting-state functional magnetic resonance imaging, and their GSK-3β rs334558 genotypes were evaluated to determine the effect of the risk variant on regional brain activity and functional networks in these subjects. Then, gene-brain-behavior relationships …were examined. Compared with the controls, aMCI subjects with the higher risk T allele had more deficits in regional activation of the right superior frontal gyrus (rSFG), while a higher functional connectivity of the rSFG was observed in TT/CT carriers. Further correlative analyses revealed that the increase in rSFG connectivity was robustly positively correlated with non-memory performance in aMCI GSK-3β rs334558 TT/CT carriers. Our findings are the first to show that a clinically significant proportion of resting-state brain function variation in aMCI patients may be explained by genetic variation at the GSK-3βrs334558 locus in ways that are distinguishable from controls. Show more

Keywords: Brain function, functional magnetic resonance imaging, genetic imaging, glycogen synthase kinase, mild cognitive impairment, resting state

DOI: 10.3233/JAD-2012-120631

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 387-396, 2012

Authors: Bialopiotrowicz, Emilia | Szybinska, Aleksandra | Kuzniewska, Bozena | Buizza, Laura | Uberti, Daniela | Kuznicki, Jacek | Wojda, Urszula

Article Type: Research Article

Abstract: Cell cycle (CC) reentry in neurons precedes the formation of amyloid-β (Aβ) plaques in Alzheimer's disease (AD). CC alterations were also detected in lymphocytes from sporadic AD patients. In the present study, we investigated the influence of nine presenilin 1 (PS1) mutations (P117R, M139V, L153V, H163R, S170F, F177L, I213F, L226F, E318G) on CC and Aβ production in immortalized B-lymphocytes from familial AD (FAD) patients and in stably transfected human embryonic kidney cells. In both cell types, only the P117R mutation increased levels of key G1/S phase regulatory proteins, p53, and its effector p21, causing G1 phase prolongation with simultaneous S …phase shortening, and lowering basal apoptosis. The CC changes were rescued by inhibition of p53, but not of γ-secretase. Moreover, the investigated PS1 mutants showed differences in the increased levels of secreted Aβ40 and Aβ42 and in Aβ42 /Aβ40 ratios, but these differences did not correlate with CC patterns. Altogether, we found that both CC regulation and Aβ production differentiate PS1 mutations, and that CC PS1 activity is mediated by p53/p21 signaling but not by γ-secretase activity. The identified CC dysregulation linked with increased p53 and p21 protein levels distinguishes the highly pathogenic PS1 P117R mutation and may contribute to the specific severity of the clinical progression of FAD associated with the mutation in the PS1 117 site. These findings suggest that impairment in lymphocyte CC might play a pathogenic function in AD and are relevant to the development of new diagnostic approaches and personalized therapeutic strategies. Show more

Keywords: Amyloid-β, cell cycle, familial Alzheimer's disease, human lymphocytes, presenilin 1, p21, p53

DOI: 10.3233/JAD-2012-121129

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 397-415, 2012

Authors: Flores, Betsi | von Bernhardi, Rommy

Article Type: Research Article

Abstract: Chronic neuroinflammation has been proposed as a driving force for Alzheimer's disease (AD), which is characterized by amyloid-β (Aβ) deposition, neurofibrillary tangles, neuronal loss, and activation of glial cells. Persistent activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) pathway has been reported, which induces an increased expression of inflammatory mediators. Transforming growth factor β1 (TGFβ1) is an inflammation modulator whose levels are increased in AD. However, its canonical signaling pathway, Smad, appears to be impaired. Our previous findings indicate that TGFβ1 plays a key role in the pathogenesis of neuroinflammation, but the molecular mechanisms underlying its …effects are not completely elucidated. Here, we studied the potential role of MKP-1, a phosphatase that exerts negative regulation on MAPK signaling, in the modulatory actions of TGFβ1. Using rat primary glial cultures, we found that pretreatment with TGFβ1 for 48 h reduced the production of inflammatory mediators induced by Aβ42 , a result that was associated with prevention of MAPK p38 activation, attenuation of NF-κB p65 nuclear translocation, and an increase in MKP-1 levels. Moreover, suppression of MKP-1 expression by siRNA and inhibition of Smad3 reversed the modulation of inflammatory response exerted by TGFβ1. These results indicate that TGFβ1 induces the expression of MKP-1 in glial cells through the Smad pathway and inhibits MAPK and NF-κB signaling, thus revealing a novel mechanism for the neuroprotective actions of TGFβ1. Further research would be important in order to characterize the role of this mechanism in the pathogenesis of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, glial cells, inflammation, MKP-1 phosphatase, TGFβ1

DOI: 10.3233/JAD-2012-120721

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 417-429, 2012

Authors: Mukaetova-Ladinska, Elizabeta B. | Abdel-All, Zeinab | Andrade, Joana | McNally, Richard J.Q. | James, Peter W. | Kalaria, Raj N. | O'Brien, John T.

Article Type: Research Article

Abstract: We report a 16.5% increase in platelet immunoglobulin (Ig) content in subjects with Alzheimer's disease (AD) in relation to cognitively intact individuals (p = 0.021), whereas the plasma Ig levels were unaltered (p = 0.428). The upregulation of platelet Ig was not explained by age, duration of dementia, or degree of cognitive impairment. However, AD subjects treated with cholinesterase inhibitors (n = 21) had lower levels of platelet Ig (p = 0.009) than AD subjects not treated with anti-dementia drugs (n = 4) and similar to those of control subjects (n = 24; p = 0.069). The anti-dementia treatment did …not influence the plasma Ig levels (p = 0.177). These preliminary findings require further confirmation in studies on larger number of AD subjects with various stages of cognitive impairment, and who would be assessed prior to initiation of and during cholinesterase inhibitor treatment. Show more

Keywords: Alzheimer's disease, anti-dementia treatment, cholinesterase inhibitors, immunoglobulin, plasma, platelets

DOI: 10.3233/JAD-2012-120481

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 431-436, 2012

Authors: Hashimoto, Gakuji | Sakurai, Mikako | Teich, Andrew F. | Saeed, Faisal | Aziz, Fahad | Arancio, Ottavio

Article Type: Research Article

Abstract: Serotonin 4 (5-HT4 ) receptor signaling does not only have the physiological function of improving cognition, but might also be helpful in the therapy of Alzheimer's disease (AD) through regulation of the production of soluble amyloid-β protein precursor alpha (sAβPPα). To analyze the relationship between 5-HT4 receptor signaling and sAβPPα production, we stably transfected H4 cells with AβPP and 5-HT4 receptor (H4/AβPP/5-HT4 cells). We found that 24-h incubation with the 5-HT4 receptor agonist RS-67333 upregulates matrix metalloproteinase-9 (MMP-9). Furthermore, MMP-9 overexpression enhanced sAβPPα levels, whereas knockdown with MMP-9 siRNA decreased sAβPPα levels. When RS-67333 was injected …for 10 days in Tg2576 mice, a model of amyloid-β peptide (Aβ) deposition, there was an increase in hippocampal levels of sAβPPα, C-terminal fragment α, and MMP-9, as well as a decrease in hippocampal senile plaque number and levels of the 40 amino acid peptide, Aβ40 . Taken all together, these experiments demonstrate that 5-HT4 receptor stimulation induces expression of MMP-9 which cleaves AβPP through α-secretase-like activity, leading to an increase of sAβPPα levels and a reduction of Aβ load. Show more

Keywords: α-secretase, amyloid-β protein precursor, matrix metalloproteinase 9, serotonin 4 receptor

DOI: 10.3233/JAD-2012-111235

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 437-445, 2012

Authors: Farr, Susan A. | Price, Tulin O. | Banks, William A. | Ercal, Nuran | Morley, John E.

Article Type: Research Article

Abstract: Oxidative damage is associated with neurodegenerative disorders such as Alzheimer's disease (AD). The antioxidant alpha-lipoic acid has been found to improve memory in mouse models of AD. Here, we administered alpha-lipoic acid daily to SAMP8 mice starting at 11 months of age and continuing until death. We found that treatment with alpha-lipoic acid decreased survival from 34 weeks in those receiving vehicle to 20 weeks. A subset of 18 month old mice given alpha-lipoic acid for two weeks and then tested in an object-place recognition paradigm had improved memory. A second subset of 18 month old mice given alpha-lipoic acid …for two weeks and tested in the Barnes maze had improved learning. After testing, the mice were sacrificed and indices of oxidative damage were measured in the brain tissue. The mice that received alpha-lipoic acid had significantly increased glutathione and decreased glutathione peroxidase and malondialdehyde indicating reversal of oxidative stress. These results indicate that alpha-lipoic acid improves memory and reverses indices of oxidative stress in extremely old SAMP8 mice, but decreases lifespan. These findings are similar to studies using other types of antioxidants. Show more

Keywords: Alpha-lipoic acid, antioxidants, learning and memory, lifespan, SAMP8 mice

DOI: 10.3233/JAD-2012-120130

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 447-455, 2012

Authors: Tales, Andrea | Leonards, Ute | Bompas, Aline | Snowden, Robert J. | Philips, Michelle | Porter, Gillian | Haworth, Judy | Wilcock, Gordon | Bayer, Antony

Article Type: Research Article

Abstract: We used an exogenous target detection cueing paradigm to examine whether intra-individual reaction time variability (IIV) or phasic alerting varied significantly between patients with amnestic mild cognitive impairment (aMCI) (n = 45) and healthy older adult controls (n = 31) or between those with aMCI who, within a 2.5 year follow-up period, developed dementia (n = 13) and those who did not (n = 26). Neither IIV, nor simple reaction time, differentiated aMCI from healthy aging, indicating that raised IIV and overall response slowing are not general characteristics of aMCI. However, within the aMCI group, IIV did differentiate between those …who converted to dementia and those who remained with a diagnosis of aMCI (non-converters), being significantly more variable in those who later developed dementia. Furthermore, there was no difference in IIV between non-converters and healthy controls. High IIV appears related to an increased probability that an individual with aMCI will become demented within 2.5 years, rather than to amnestic dysfunction per se. In contrast, phasic alerting performance significantly differentiated aMCI from healthy aging, but failed to discriminate those with aMCI who developed dementia from those who did not. In addition, those patients with aMCI who did not develop dementia still showed a significantly poorer phasic alerting effect compared to healthy aging. The phasic alerting abnormality in aMCI compared to healthy aging does not appear specifically related to the performance of those patients for whom aMCI represents the prodromal stages of dementia. Show more

Keywords: Aging, dementia, mild cognitive impairment, reaction time, visual attention

DOI: 10.3233/JAD-2012-120505

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 457-466, 2012

Authors: Royall, Donald R. | Palmer, Raymond F. | Vidoni, Eric D. | Honea, Robyn A. | Burns, Jeffrey M.

Article Type: Research Article

Abstract: We have employed structural equation models to explicitly distinguish dementia-relevant variance in cognitive task performance (i.e., δ) from the variance that is unrelated to a dementing process (i.e., g'). Together g' and d comprise Spearman's “g”. Although d represents only a minor fraction of the total variance in cognitive task performance, it is more strongly associated with dementia severity than is g'. In this analysis, we replicate δ in a new dataspace, the University of Kansas Brain Aging Project, and associate it specifically with regional grey matter atrophy by voxel-based morphometry of magnetic resonance imaging data. The latent variable d …localizes to elements of the default mode network and related structures in the R hemisphere. Show more

Keywords: Aging, cognition, dementia, g, functional status

DOI: 10.3233/JAD-2012-120424

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 467-478, 2012

Authors: Raychaudhuri, Mithu | Roy, Kasturi | Das, Samir | Mukhopadhyay, Debashis

Article Type: Research Article

Abstract: Based on the observations that Grb2 overexpression altered the trafficking route of amyloid-β protein precursor (AβPP) by inhibiting its release via exosomal vesicles, and subsequently increased its endogenous level, in the present study we aimed to elucidate the mechanism of traffic impairment and the role of different Grb2 domains in this process. We found that the N-SH3 domain of Grb2 was involved in the protein vesicular localization. The C-SH3 domain could also form very small puncta, but were not characteristic Grb2 containing vesicles. Vesicles containing the N-SH3-SH2 domain had a mixed population of early and late endosomes but C-SH3-SH2 domain …containing vesicles were of early endosomal type. The N-SH3 domain therefore seems to be involved in the maturation of early endosomes to late endosomes. Almost all the features shown by overexpression of full-length type Grb2, for example, entrapment of endogenous AβPP in vesicles, affecting the turnover of AβPP in terms of decrease in exosomal release and increase in endogenous concentration of the protein, could be reproduced by the N-SH3-SH2 domain and, to a very limited extent, by the C-SH3-SH2 domain. The middle SH2 domain alone did not show any involvement in AβPP trafficking. By mutational analysis of both N and C terminal SH3 domains, attempts were made to elucidate the molecular basis of this functional anomaly. Show more

Keywords: AβPP, AICD, Grb2, SH3 domain

DOI: 10.3233/JAD-2012-120388

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 479-493, 2012

Authors: Moreira, Eduardo Luiz Gasnhar | de Oliveira, Jade | Nunes, Jean Costa | Santos, Danúbia Bonfanti | Nunes, Fernanda Costa | Vieira, Daniella Serafim Couto | Ribeiro-do-Valle, Rosa Maria | Pamplona, Fabrício Alano | de Bem, Andreza Fabro | Farina, Marcelo | Walz, Roger | Prediger, Rui Daniel

Article Type: Research Article

Abstract: There is increasing evidence that hypercholesterolemia during midlife may represent a predictor of subsequent mild cognitive impairments and dementia decades later. However, the exact mechanism underlying this phenomenon remains unknown since plasmatic cholesterol is not able to cross the blood-brain barrier. In the present study, we evaluated the hypothesis that cognitive impairments triggered by hypercholesterolemia during aging may be related to brain oxidative stress and altered brain acetylcholinesterase (AChE) activity. We also performed a neuropathological investigation in order to analyze whether the cognitive impairments may be associated with stroke-related features. To address these questions we used three- and fourteen-month-old low-density …lipoprotein receptor-deficient mice (LDLr−/− ). The current findings provide new evidence that aged LDLr−/− mice, exposed to over three-fold cholesterol levels from early life, show working, spatial reference, and procedural memory impairments, without alterations in motor function. Antioxidant imbalance and oxidative damage were evidenced by a marked increase in lipid peroxidation (thiobarbituric acid reactive substances levels) and glutathione metabolism (increase in glutathione levels, glutathione reductase, and glutathione peroxidase activities) together with a significant increase in the AChE activity in the prefrontal cortex of aged hypercholesterolemic LDLr−/− mice. Notably, hypercholesterolemia was not related to brain infarcts and neurodegeneration in mice, independent of their age. These observations provide new evidence that hypercholesterolemia during aging triggers cognitive impairments on different types of learning and memory, accompanied by antioxidant imbalance, oxidative damage, and alterations of cholinergic signaling in brain areas associated with learning and memory processes, particularly in the prefrontal cortex. Show more

Keywords: Acetylcholinesterase activity, aging, cognitive deficits, LDL receptor knockout mice (LDLr−/−), oxidative stress

DOI: 10.3233/JAD-2012-120541

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 495-511, 2012

Article Type: Other

DOI: 10.3233/JAD-2012-120542

Citation: Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 513-515, 2012