Journal of Alzheimer's Disease - Volume 33, issue 4

Authors: Hughes, Timothy M. | Rosano, Caterina | Evans, Rhobert W. | Kuller, Lewis H.

Article Type: Review Article

Abstract: Cholesterol metabolism is implicated in the etiology of Alzheimer's disease (AD) and amyloid production in the brain. While brain cholesterol cannot be measured directly in vivo, the oxysterol, 24S-hydroxycholesterol (24-OHC), is the predominant metabolite of brain cholesterol and can be measured in the blood. The aim of this review is to evaluate plasma 24-OHC as a potential biomarker of AD risk and discuss factors related to its levels in the brain and blood. This systematic review examines studies published between 1950 and June 2012 that examined the relationship between plasma 24-OHC, cognition, brain structure, and dementia using the following key …words (“24S-hydroxycholesterol” or “24-hydroxycholesterol”) and (“Brain” or “Cognitive”). We found a total of 28 studies of plasma 24-OHC and neurodegenerative disease, including a subset of 12 that used dementia as a clinical endpoint. These studies vary in the direction of the observed associations. Results suggest plasma 24-OHC may be higher in the early stages of cognitive impairment and lower in more advanced stages of AD when compared to cognitively normal controls. Measures of 24-OHC in the blood may be an important potential marker for cholesterol metabolism in the brain and risk of AD. Further studies of plasma 24-OHC and dementia must account for the stage of disease, establish the temporal trends in oxysterol concentrations, and employ neuroimaging modalities to assess the structural and metabolic changes occurring in the brain prior to the onset of cognitive impairment. Show more

Keywords: Alzheimer's disease, brain, dementia, 24-hydroxycholesterol, 24S-hydroxycholesterol, oxysterols

DOI: 10.3233/JAD-2012-121585

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 891-911, 2013

Authors: Hanford, Nicholas | Figueiro, Mariana

Article Type: Review Article

Abstract: Sleep disturbances are common in persons with Alzheimer's disease or related dementia (ADRD), resulting in a negative impact on the daytime function of the affected person and on the wellbeing of caregivers. The sleep/wake pattern is directly driven by the timing signals generated by a circadian pacemaker, which may or may not be perfectly functioning in those with ADRD. A 24-hour light/dark pattern incident on the retina is the most efficacious stimulus for entraining the circadian system to the solar day. In fact, a carefully orchestrated light/dark pattern has been shown in several controlled studies of older populations, with and …without ADRD, to be a powerful non-pharmacological tool to improve sleep efficiency and consolidation. Discussed here are research results from studies looking at the effectiveness of light therapy in improving sleep, depression, and agitation in older adults with ADRD. A 24-hour lighting scheme to increase circadian entrainment, improve visibility, and reduce the risk of falls in those with ADRD is proposed, and future research needs are discussed. Show more

Keywords: Alzheimer's disease, circadian rhythm, lighting design, light therapy, sleep, wayfinding

DOI: 10.3233/JAD-2012-121645

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 913-922, 2013

Authors: O'Dowd, Seán T. | Ardah, Mustafa T. | Johansson, Per | Lomakin, Aleksey | Benedek, George B. | Roberts, Kinley A. | Cummins, Gemma | El Agnaf, Omar M. | Svensson, Johan | Zetterberg, Henrik | Lynch, Timothy | Walsh, Dominic M.

Article Type: Short Communication

Abstract: Elevated cerebrospinal fluid concentrations of tau discriminate Alzheimer's disease from other neurodegenerative conditions. The reasons for this are unclear. While commercial assay kits are widely used to determine total-tau concentrations, little is known about their ability to detect different aggregation states of tau. We demonstrate that the leading commercial enzyme-linked immunosorbent assay reliably detects aggregated and monomeric tau and evinces good recovery of both species when added into cerebrospinal fluid. Hence, the disparity between total-tau levels encountered in Alzheimer's disease and other neurodegenerative conditions is not due to differential recognition of tau assembly forms or the extent of degeneration.

Keywords: Alzheimer's disease, cerebrospinal fluid, ELISA, tau

DOI: 10.3233/JAD-2012-121393

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 923-928, 2013

Authors: Choo, IL Han | Ni, Ruiqing | Schöll, Michael | Wall, Anders | Almkvist, Ove | Nordberg, Agneta

Article Type: Research Article

Abstract: The biomarker-based new diagnostic criteria have been proposed for Alzheimer's disease (AD) spectrum. However, any biomarker alone has not been known to have satisfactory AD predictability. We explored the best combination model with baseline demography, neuropsychology, 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET), cerebrospinal fluid (CSF) biomarkers, and apolipoprotein E (APOE) genotype evaluation to predict progression to AD in mild cognitive impairment (MCI) patients. A longitudinal clinical follow-up (mean, 44 months; range, 1.6–161.7 months) of MCI patients was done. Among 83 MCI patients, 26 progressed to AD (MCI-AD) and 51 did not deteriorate (MCI-Stable). We applied that univariate and multivariate logistic …regression analyses, and multistep model selection for AD predictors including biomarkers. In univariate logistic analysis, we selected age, Rey Auditory Verbal Retention Test, parietal glucose metabolic rate, CSF total tau, and presence or not of at least one APOE ε4 allele as predictors. Through multivariate stepwise logistic analysis and model selection, we found the combination of parietal glucose metabolic rate and total tau representing the best model for AD prediction. In conclusion, our findings highlight that the combination of regional glucose metabolic assessment by PET and CSF biomarkers evaluation can significantly improve AD predictive diagnostic accuracy of each respective method. Show more

Keywords: Biomarkers, combination, mild cognitive impairment, predictor

DOI: 10.3233/JAD-2012-121489

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 929-939, 2013

Authors: Inestrosa, Nibaldo C. | Carvajal, Francisco J. | Zolezzi, Juan M. | Tapia-Rojas, Cheril | Serrano, Felipe | Karmelic, Daniel | Toledo, Enrique M. | Toro, Andrés | Toro, Jessica | Santos, Manuel J.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, accumulation of the amyloid-β peptide (Aβ), increase of oxidative stress, and synaptic alterations. The scavenging of reactive oxygen species through their matrix enzyme catalase is one of the most recognized functions of peroxisomes. The induction of peroxisome proliferation is attained through different mechanisms by a set of structurally diverse molecules called peroxisome proliferators. In the present work, a double transgenic mouse model of AD that co-expresses a mutant human amyloid-β protein precursor (AβPPswe) and presenilin 1 without exon 9 (PS1dE9) was utilized in order to …assess the effect of peroxisomal proliferation on Aβ neurotoxicity in vivo. Mice were tested for spatial memory and their brains analyzed by cytochemical, electrophysiological, and biochemical methods. We report here that peroxisomal proliferation significantly reduces (i) memory impairment, found in this model of AD; (ii) Aβ burden and plaque-associated acetylcholinesterase activity; (iii) neuroinflammation, measured by the extent of astrogliosis and microgliosis; and (iv) the decrease in postsynaptic proteins, while promoting synaptic plasticity in the form of long-term potentiation. We concluded that peroxisomal proliferation reduces various AD neuropathological markers and peroxisome proliferators may be considered as potential therapeutic agents against the disease. Show more

Keywords: Amyloid β-peptide, peroxisomal proliferation, spatial memory, synaptic plasticity, transgenic mice

DOI: 10.3233/JAD-2012-120397

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 941-959, 2013

Authors: Cho, Eun Bin | Seo, Sang Won | Kim, HoJeong | Lee, Jong-Min | Yoon, Uicheul | Im, Kiho | Kim, Geon Ha | Noh, Young | Cho, Hanna | Yoon, Cindy W. | Kim, Hee Jin | Na, Duk L.

Article Type: Research Article

Abstract: There are some studies identifying the association between kidney dysfunction and cognitive impairment through various mechanisms including small vessel disease. However, results concerning the relationship between kidney dysfunction and cortical atrophy have been inconsistent. Thus, we aimed to evaluate the relationship among kidney dysfunction, small vessel disease, and cortical thinning in probable Alzheimer's disease (AD) dementia patients. Patients consisted of 162 subjects with probable AD dementia who underwent high-resolution T1-weighted volumetric magnetic resonance imaging (MRI) scans using the same scanner. The estimated glomerular filtration rate (GFR) was calculated and divided into the quartiles of patients for comparison. Volume of white …matter hyperintensities (WMH) was automatically measured. Two neurologists counted the number of lacunes. Cortical thickness was measured using a surface-based method. GFR was not associated with WMH and the number of lacunes. However, the lowest quartile group of GFR (GFR 1) had cortical thinning in each lobe, compared to the highest quartile group of GFR (GFR 4). The topography of cortical thinning in the GFR 1 group was distributed predominantly in temporoparietal regions, compared to GFR 4. After further adjustment of small vessel disease MRI markers, the association between GFR and the cortical thinning remained. Our findings suggested that kidney dysfunction, represented by GFR, was related to temporoparietal thinning independent of small vessel disease in probable AD dementia patients. Show more

Keywords: Alzheimer's disease, cortical thinning, glomerular filtration rate, kidney function

DOI: 10.3233/JAD-2012-121180

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 961-968, 2013

Authors: Rossi, Giacomina | Conconi, Donatella | Panzeri, Elena | Redaelli, Serena | Piccoli, Elena | Paoletta, Laura | Dalprà, Leda | Tagliavini, Fabrizio

Article Type: Research Article

Abstract: In addition to the main function of promoting polymerization and stabilization of microtubules, other roles are being attributed to tau, now considered a multifunctional protein. In particular, previous studies suggest that tau is involved in chromosome stability and genome protection. We performed cytogenetic analysis, including molecular karyotyping, on lymphocytes and fibroblasts from patients affected by frontotemporal lobar degeneration carrying different mutations in the microtubule-associated protein tau gene, to investigate the effects of these mutations on genome stability. Furthermore, we analyzed the response of mutated lymphoblastoid cell lines to genotoxic agents to evaluate the participation of tau to DNA repair systems. …We found a significantly higher level of chromosome aberrations in mutated than in control cells. Mutated lymphocytes showed higher percentages of stable lesions, clonal and total aneuploidy (medians: 2 versus 0, p ≪ 0.01; 1.5 versus 0, p ≪ 0.01; 16.5 versus 0, p ≪ 0.01, respectively). Fibroblasts of patients showed higher percentages of stable lesions, structural aberrations and total aneuploidy (medians: 0 versus 0, p = 0.03; 5.8 versus 0, p = 0.02; 26.5 versus 12.6, p ≪ 0.01, respectively). In addition, the in depth analysis of DNA copy number variations showed a higher tendency to non-allelic homologous recombination in mutated cells. Finally, while our analysis did not support an involvement of tau in DNA repair systems, it revealed its role in stabilization of chromatin. In summary, our findings indicate a role of tau in genome and chromosome stability that can be ascribed to its function as a microtubule-associated protein as well as a protein protecting chromatin integrity through interaction with DNA. Show more

Keywords: Chromosome aberrations, DNA copy number variations, genome instability, MAPT, mutation, tau protein, tauopathies

DOI: 10.3233/JAD-2012-121633

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 969-982, 2013

Authors: Herculano, Bruno | Tamura, Minami | Ohba, Ayaka | Shimatani, Mayu | Kutsuna, Natsumaro | Hisatsune, Tatsuhiro

Article Type: Research Article

Abstract: Our goal in this study was to determine whether or not feeding young (4 months old) Alzheimer's disease model transgenic mice with a high fat diet (HFD), consisting of 32% fat, is capable of causing cognitive decline and whether treatment with β-alanyl-L-histidine (carnosine) is capable of reducing these effects. Carnosine is an endogenous antioxidant and antiglycating agent that is abundantly present in the brain and muscle tissues of vertebrates. After 8 weeks of feeding with HFD, we observed a significant decline in the contextual memory in transgenic mice fed with HFD as compared to transgenic mice fed with a normal …diet as well as to normal diet-wild type mice. Treatment with carnosine at a dose of 5 mg/day for 6 weeks was effective in preventing cognitive decline, as the transgenic group fed with HFD and treated with carnosine displayed a level of cognition comparable to controls. No differences in senile plaque load were observed between all groups. However, we observed an increase in the expression of RAGE in blood vessels as well as increased microglial activation in the hippocampus of animals fed with HFD, effects that were reversed when treated with carnosine. Given these results, there is a possibility that inflammation and cerebrovascular abnormalities might be the cause of cognitive decline in this model. Show more

Keywords: Alzheimer's disease, carnosine, high fat diet, oxidative stress

DOI: 10.3233/JAD-2012-121324

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 983-997, 2013

Authors: Kehoe, Patrick Gavin | Davies, Neil Martin | Martin, Richard Michael | Ben-Shlomo, Yoav

Article Type: Research Article

Abstract: We investigated whether angiotensin II receptor blockers and angiotensin converting enzyme inhibitors were associated with risk of mortality or inpatient hospitalization for patients with dementia compared to other antihypertensive medications. We extracted a clinical cohort of 6,290 patients with dementia from the United Kingdom General Practice Research Database, prescribed antihypertensive medication at diagnosis of dementia with around 10 years follow-up. Using survival analysis we estimated associations of exposure to antihypertensive medication with subsequent hospitalization and mortality risk, stratified by dementia type (Alzheimer's disease, vascular and other dementias). Angiotensin converting enzyme inhibitors (but not angiotensin II receptor blockers) were associated with …an increased risk of mortality in patients with Alzheimer's disease (adjusted hazard ratio: 1.19; 95% CI 1.07, 1.33, p = 0.002), but no convincing evidence of increased hospitalization. Angiotensin II receptor blockers were inversely associated with hospitalization for any form of dementia, but after adjustment for covariates, these associations became consistent with chance. Further evidence is required to either support or refute the observation that exposure to angiotensin converting enzyme inhibitors in patients with dementia is associated with increased mortality. Show more

Keywords: Alzheimer's disease, amyloid, angiotensin, dementia, hospitalization, mortality, vascular dementia

DOI: 10.3233/JAD-2012-121090

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 999-1008, 2013

Authors: Goñi, Joaquín | Cervantes, Sebastián | Arrondo, Gonzalo | Lamet, Isabel | Pastor, Pau | Pastor, María A.

Article Type: Research Article

Abstract: The aim of our study was to elucidate whether specific patterns of gray matter loss were associated with apolipoprotein E ε4 (APOE ε4) and microtubule-associated protein tau (MAPT)-H1) genetic variants in subjects with mild cognitive impairment (MCI) at a baseline visit. Gray matter voxel-based morphometry analysis of T1 magnetic resonance imaging scans were performed in 65 amnestic-MCI subjects. MCI APOE ε4 carriers compared with non-carriers showed increased brain atrophy in right hippocampus and rostral amygdala, superior and middle temporal gyrus, and right parietal operculum, including inferior frontal gyrus, inferior parietal, and supramarginal gyrus. MAPT-H1/H1 MCI carriers showed an increased bilateral …atrophy in superior frontal gyri (including frontal eye fields and left prefrontal cortex) and precentral gyrus but also unilateral left atrophy in the inferior temporal gyrus and calcarine gyrus. In addition, MCI subjects carrying both APOE ε4 and MAPT-H1/H1 variants showed gray matter loss in the supplementary motor area and right pre- and postcentral gyri. The effect of APOE ε4 on gray matter loss in right hippocampus suggests that, at least in some AD sub-types, the neuronal vulnerability could be increased in the right hemisphere. The pattern of frontal gray matter loss observed among MCI MAPT H1/H1 carriers has also been found in other tauopathies, suggesting that MCI may share etiological factors with other tauopathies. Frontal and parietal cortex vulnerability was found when adding MAPT H1/H1 and APOE ε4 effects, suggesting a synergistic effect of these variants. These results could be due to changes in APOE ε4 and MAPT expression. Show more

Keywords: APOE, genetic risk, genetics, magnetic resonance imaging, MAPT, mild cognitive impairment, single nucleotide polymorphism, tau, voxel based morphometry, Alzheimer disease

DOI: 10.3233/JAD-2012-121174

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1009-1019, 2013

Authors: Pannee, Josef | Portelius, Erik | Oppermann, Madalina | Atkins, Alan | Hornshaw, Martin | Zegers, Ingrid | Höjrup, Peter | Minthon, Lennart | Hansson, Oskar | Zetterberg, Henrik | Blennow, Kaj | Gobom, Johan

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) are increasingly used in research centers, clinical trials, and clinical settings. However, their broad-scale use is hampered by lack of standardization across analytical platforms and by interference from binding of amyloid-β (Aβ) to matrix proteins as well as self-aggregation. Here, we report on a matrix effect-resistant method for the measurement of the AD-associated 42 amino acid species of Aβ (Aβ42 ), together with Aβ40 and Aβ38 in human CSF based on mass spectrometric quantification using selected reaction monitoring (SRM). Samples were prepared by solid-phase extraction and quantification was performed using …stable-isotope labeled Aβ peptides as internal standards. The diagnostic performance of the method was evaluated on two independent clinical materials with research volunteers who were cognitively normal and AD patients with mild to moderate dementia. Analytical characteristics of the method include a lower limit of quantification of 62.5 pg/mL for Aβ42 and coefficients of variations below 10%. In a pilot study on AD patients and controls, we verified disease-association with decreased levels of Aβ42 similar to that obtained by ELISA and even better separation was obtained using the Aβ42 /Aβ40 ratio. The developed assay is sensitive and is not influenced by matrix effects, enabling absolute quantification of Aβ42 , Aβ40 , and Aβ38 in CSF, while it retains the ability to distinguish AD patients from controls. We suggest this SRM-based method for Aβ peptide quantification in human CSF valuable for clinical research and trials. Show more

Keywords: Alzheimer's disease, amyloid-β, cerebrospinal fluid, mass spectrometry, selected reaction monitoring

DOI: 10.3233/JAD-2012-121471

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1021-1032, 2013

Authors: Bastin, Christine | Willems, Sylvie | Genon, Sarah | Salmon, Eric

Article Type: Research Article

Abstract: Recognition memory can rely on recollection (recall of the details from the encoding episode) and familiarity (feeling that some information is old without any recollection). In Alzheimer's disease (AD), where there is a clear deficit of recollection, the evidence regarding familiarity is mixed, with some studies showing preserved familiarity and others reporting impairment. The current study examined whether recognition memory performance can be improved in AD when the use of familiarity is facilitated by the salience of processing fluency due to an earlier encounter with the information. Fifteen AD patients and 16 healthy controls performed a verbal recognition memory task …where the salience of fluency was manipulated by means of letters overlap. Studied and unstudied words were constituted of either two separate sets of letters (no-overlap condition, high fluency salience) or the same set of letters (overlap condition, low fluency salience). The results showed that, although performance was globally poorer in AD patients than in the controls, both groups performed significantly better in the no-overlap condition than in the overlap condition. This suggests that AD patients benefited as much as the controls from the salience of fluency. Show more

Keywords: Alzheimer's disease, episodic memory, familiarity, recognition

DOI: 10.3233/JAD-2012-121678

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1033-1039, 2013

Authors: Peters, Owen M. | Connor-Robson, Natalie | Sokolov, Vladimir B. | Aksinenko, Alexey Yu. | Kukharsky, Michail S. | Bachurin, Sergey O. | Ninkina, Natalia | Buchman, Vladimir L.

Article Type: Research Article

Abstract: Dimebon belongs to a fast-growing group of “old” drugs that were suggested to be effective for therapy of pathological conditions different from their original targets. Following initial reports of successful Phase II clinical trials for mild-to-moderate Alzheimer's and Huntington's diseases, effects of Dimebon on various neurodegenerative conditions were investigated both in follow-up clinical trials and in various model systems. Although results of Phase III clinical trials carried out so far were disappointing, there is growing body of evidence that this drug can affect neuronal physiology in a way that would be beneficial at particular stages of development of certain types …of neurodegeneration. To reveal what molecular and cellular pathological processes might be affected by Dimebon, we tested the ability of this drug to ameliorate pathology in model systems recapitulating particular pathogenic mechanisms involved in the development and progression of neurodegenerative diseases. Here we assessed the ability of Dimebon to modify several prominent features of tauopathies using transgenic tauP301S mice as a model. Chronic treatment with Dimebon was found to partially protect against the progressive decline in motor function and accumulation of tau-positive dystrophic neurons characteristic of tauP301S mice. Similar results were obtained with two further γ-carbolines structurally similar to Dimebon. Our data suggest that Dimebon and Dimebon-like compounds might be considered as drugs possessing disease-modifying activity for diseases with prominent tau pathology. Show more

Keywords: Alzheimer's disease, dimebolin, latrepirdine, tauopathy, therapeutics, transgenic mice

DOI: 10.3233/JAD-2012-121732

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1041-1049, 2013

Authors: Cankurtaran, Mustafa | Yesil, Yusuf | Kuyumcu, Mehmet Emin | Oztürk, Zeynel Abidin | Yavuz, Burcu Balam | Halil, Meltem | Ulger, Zekeriya | Cankurtaran, Eylem Sahin | Arıoğul, Servet

Article Type: Research Article

Abstract: Increasing evidence supports the theory that oxidative stress plays an important role in the pathogenesis of Alzheimer's disease (AD). Homocysteine (Hcy), uric acid (UA), bilirubin, and albumin are simple laboratory parameters that are related to oxidative stress. In this study we compared serum Hcy and antioxidant levels in patients with AD and normal cognitive function. In this cross-sectional study, 143 AD patients and 1,553 patients with normal cognitive function aged 65 years and over were enrolled. Mean values of UA and albumin levels of AD patients were significantly lower than normal cognitive function subjects (p: 0.003 versus p < 0.001, …respectively). Mean value of Hcy levels of AD patients was significantly higher than normal cognitive function subjects (p = 0.031). Multivariate regression analysis revealed that Mini-nutritional assessment short form (OR: 0.905, 95% CI: 0.850–0.965, p = 0.002), hypertension (OR: 1.573, 95% CI: 1.148–2.155, p = 0.005), UA (OR: 0.879, 95% CI: 0.788–0.981, p = 0.021), Hcy (OR: 1.040, 95% CI: 1.022–1.059, p < 0.001), and albumin (OR: 0.505, 95% CI: 0.339–0.753, p < 0.001) were independent variables predicting the occurrence of AD. Our study supports the hypothesis that a decrease in antioxidants and an increase in oxidative damage are linked to AD. Show more

Keywords: Alzheimer's disease, antioxidant, elderly, homocysteine, oxidative stress, uric acid

DOI: 10.3233/JAD-2012-121630

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1051-1058, 2013

Authors: Gupta, Veer B. | Monica, Florence S. | Berrocal, Ruben | Rao, K. Subba | Rao, K.S. Jagannatha

Article Type: Research Article

Abstract: Amyloid-β peptide is presumably a key etiological factor involved in the pathogenesis of Alzheimer's disease (AD), and several hypotheses exist on the possible ways Aβ contributes to the progression of the disease. There are reports on the nuclear localization of Aβ and very limited evidence on its DNA binding property. The present study provided the mechanism of Aβ enantiomers binding to DNA and showed that Aβ40 L induces ψ-DNA, while Aβ40 D causes only altered B-DNA. Further, we evidenced the DNA nicking property of Aβ enantiomers and endonuclease mimicking behavior. The role of Aβ in modulating DNA stability was reported …by altered melting temperature and ethidium bromide binding studies. The data provides new evidence on stereospecific dependent Aβ-DNA interaction and we discuss its biological relevance to neurodegeneration. Our results imply that Aβ-DNA interaction needs to be considered as a significant cause of the toxicity in the pathogenesis of AD. Show more

Keywords: Alzheimer's, Amyloid beta, conformation, DNA nicking, enantiomers

DOI: 10.3233/JAD-121249

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1059-1071, 2013

Authors: Schwab, Claudia | Yu, Sheng | Wong, Winnie | McGeer, Edith G. | McGeer, Patrick L.

Article Type: Research Article

Abstract: The GABAergic system is the main inhibitory neurotransmitter system in the vertebrate brain. Although it is well established that the GABAergic system is affected in neuropsychiatric disorders, in Alzheimer's disease (AD) it has been considered to be relatively spared. In this study we describe the immunohistochemical localization of the main enzymes of the GABAergic system; glutamate decarboxylase 65 (GAD65), GAD67, and GABA transferase (GABAT) in human brain. In neocortex, hippocampus, basal ganglia, and cerebellum, GAD65 and GAD67 immunoreactivity were found in neuropil granules, possibly axonal boutons or terminals, and in a subset of small to midsized neurons. GAD65 preferentially stained …neuropil granules, while GAD67 preferentially stained neuronal cell bodies. GABAT intensely labeled many types of neurons and glia cells. While GAD65 and GAD67 stained the cytoplasm of cells homogeneously, GABAT labeling appeared irregular and granular. GAD65 immunoreactivity of neurons and neuropil was severely reduced in AD middle temporal gyrus, hippocampus, and putamen as determined by fluorescence and light microscopic immunohistochemistry. Western blotting revealed a similar reduction of GAD65, but not GAD67, protein levels in the middle temporal gyrus of AD. Our results suggest that the GABAergic system is more severely affected in AD than previously reported. This deficit may contribute to AD pathogenesis by loss of GABAergic inhibitory activity. Show more

Keywords: ABAT, Alzheimer's disease, GABAergic system, GABAT, GAD65, GAD67, human, immunohistochemistry, western blot

DOI: 10.3233/JAD-2012-121330

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1073-1088, 2013

Authors: Arnold, Steven E. | Vega, Irving E. | Karlawish, Jason H. | Wolk, David A. | Nunez, Jessica | Negron, Mirna | Xie, Sharon X. | Wang, Li-San | Dubroff, Jacob G. | McCarty-Wood, Elisabeth | Trojanowski, John Q. | Van Deerlin, Vivianna

Article Type: Research Article

Abstract: The frequency and clinical and pathological characteristics associated with the Gly206Ala presenilin 1 (PSEN1) mutation in Puerto Rican and non-Puerto Rican Hispanics were evaluated at the University of Pennsylvania's Alzheimer's Disease Center. DNAs from all cohort subjects were genotyped for the Gly206Ala PSEN1 mutation. Carriers and non-carriers with neurodegenerative disease dementias were compared for demographic, clinical, psychometric, and biomarker variables. Nineteen (12.6%) of 151 unrelated subjects with dementia were discovered to carry the PSEN1 Gly206Ala mutation. Microsatellite marker genotyping determined a common ancestral haplotype for all carriers. Carriers were all of Puerto Rican heritage with significantly younger age of onset, …but otherwise were clinically and neuropsychologically comparable to those of non-carriers with AD. Three subjects had extensive topographic and biochemical biomarker assessments that were also typical of non-carriers with AD. Neuropathological examination in one subject revealed severe, widespread plaque and tangle pathology without other meaningful disease lesions. The PSEN1 Gly206Ala mutation is notably frequent in unrelated Puerto Rican immigrants with dementia in Philadelphia. Considered together with the increased prevalence and mortality of AD reported in Puerto Rico, these high rates may reflect hereditary risk concentrated in the island which warrants further study. Show more

Keywords: Age of onset, dementia, haplotype, presenilin

DOI: 10.3233/JAD-2012-121570

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1089-1095, 2013

Authors: Farkas, Melinda | Keskitalo, Salla | Smith, Desiree E.C. | Bain, Nadja | Semmler, Alexander | Ineichen, Benjamin | Smulders, Yvo | Blom, Henk | Kulic, Luka | Linnebank, Michael

Article Type: Research Article

Abstract: Hyperhomocysteinemia is associated with Alzheimer's disease (AD). The causality of this association is controversial. In this study we tested the effect of a hyperhomocysteinemia-inducing diet in the ArcAβ transgenic AD mouse model. At 14 months of age, the hyperhomocysteinemia-inducing diet yielded higher plasma homocysteine levels in ArcAβ mice compared with wild-type mice. Levels of plasma 5-methyltetrahydrofolate (5-MTHF) in 14-month-old mice on hyperhomocysteinemia-inducing diet were lower in the transgenic than in the wild-type mice. The folate derivate 5-MTHF serves as cofactor in homocysteine metabolism. Oxidative stress, which occurs in the course of disease in the ArcAβ mice, consumes 5-MTHF. Thus, the …transgenic mice may plausibly be more vulnerable to 5-MTHF-depleting effects of hyperhomocysteinemia and more vulnerable to hyperhomocysteinemia-inducing diet. This argues that AD pathology predisposes to hyperhomocysteinemia, i.e., as a facultative consequence of AD. However, we also observed that dietary-induced folate reduction and homocysteine increase was associated with an increase of plasma (young animals) and brain (older animals) amyloid-β concentrations. This suggests that the hyperhomocysteinemia-inducing diet worsened pathology in the transgenic mice. In conclusion, this data may argue that folate reduction and hyperhomocysteinemia may contribute to neurodegeneration and may also be triggered by neurodegenerative processes, i.e., represent both a cause and a consequence of neurodegeneration. Such a vicious cycle may be breakable by dietary or supplementation strategies increasing the availability of 5-MTHF. Show more

Keywords: Alzheimer's disease, diet, folic acid, homocysteine, hyperhomocysteinemia, mice, transgenic, vitamin B6, vitamin B12

DOI: 10.3233/JAD-2012-121378

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1097-1104, 2013

Authors: Conde-Sala, Josep L. | Reñé-Ramírez, Ramón | Turró-Garriga, Oriol | Gascón-Bayarri, Jordi | Juncadella-Puig, Montserrat | Moreno-Cordón, Laura | Viñas-Diez, Vanesa | Garre-Olmo, Josep

Article Type: Research Article

Abstract: This study aimed to determine the factors that predict anosognosia in patients with Alzheimer's disease (AD) and to examine the effect of anosognosia on patient and caregiver perceptions of the patient's quality of life (QoL-p), using a cross-sectional design with 164 patients and their caregivers. Instruments of measurement included Anosognosia Questionnaire-Dementia, Geriatric Depression Scale, Quality of Life in AD (QoL-AD), Disability Assessment for Dementia, Neuropsychiatric Inventory, and the Global Deterioration Scale (GDS). A binary logistic regression analysis was performed to identify the factors that predict anosognosia, while a linear regression analysis was conducted to determine the factors associated with QoL-AD. …The degree of anosognosia increased in line with GDS stage (F (2,161) = 41.3, p < 0.001). In the binary regression analysis, the variables that predicted anosognosia were more neuropsychiatric symptoms (OR = 1.11, 95% CI: 1.06–1.17, p < 0.001), deficits in ADL (OR = 0.88, 95% CI: 0.83–0.94, p < 0.001), less depression (OR = 0.66, 95% CI: 0.54–0.82, p < 0.001), and older age (OR = 1.08, 95% CI: 1.00–1.15, p = 0.027). With regards to QoL-p, the multiple linear regression analysis for patients (r2 = 0.486) showed that less depression (β = −0.52, p < 0.001) and greater anosognosia (β = 0.40, p < 0.001) explained 33% and 10% of the variance in QoL-AD, respectively. Greater anosognosia was associated with better perceived QoL-p, especially in advanced GDS stages. Anosognosia was associated with greater caregiver burden and a greater discrepancy between patient and caregiver ratings of QoL-p. Show more

Keywords: Alzheimer's disease, anosognosia, awareness, caregivers, depression, neuropsychiatry, patients, quality of life

DOI: 10.3233/JAD-2012-121360

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1105-1116, 2013

Authors: Sinadinos, Christopher | Quraishe, Shmma | Sealey, Megan | Samson, P. Benjamin | Mudher, Amrit | Wyttenbach, Andreas

Article Type: Research Article

Abstract: Reduction of tau phosphorylation and aggregation by manipulation of heat shock protein (HSP) molecular chaperones has received much attention in attempts to further understand and treat tauopathies such as Alzheimer's disease. We examined whether endogenous HSPs are induced in Drosophila larvae expressing human tau (3R-tau) in motor neurons, and screened several chemical compounds that target the HSP system using medium-throughput behavioral analysis to assay their effects on tau-induced neuronal dysfunction in vivo. Tau-expressing larvae did not show a significant endogenous HSP induction response, whereas robust induction of hsp70 was detectable in a similar larval model of polyglutamine disease. Although pan-neuronal …tau expression augmented the induction of hsp70 following heat shock, several candidate HSP inducing compounds induced hsp70 protein in mammalian cells in vitro but did not detectably induce hsp70 mRNA or protein in tau expressing larvae. The hsp90 inhibitors 17-AAG and radicicol nevertheless caused a dose-dependent reduction in total human tau levels in transgenic larvae without specifically altering tau hyperphosphorylated at S396/S404. These and several other HSP modulating compounds also failed to rescue the tau-induced larval locomotion deficit in this model. Tau pathology in tau-expressing larvae, therefore, induces weak de novo HSP expression relative to other neurodegenerative disease models, and unlike these disease models, pharmacological manipulation of the hsp90 pathway does not lead to further induction of the heat shock response. Forthcoming studies investigating the effects of HSP induction on tau-mediated dysfunction/toxicity in such models will require more robust, non-pharmacological (perhaps genetic) means of manipulating the hsp90 pathway. Show more

Keywords: Alzheimer's disease, Drosophila, heat shock protein, hyperphosphorylated tau locomotion, motor neurons, tauopathy, tau

DOI: 10.3233/JAD-2012-121534

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1117-1133, 2013

Authors: Lu, Jianghua | E, Lezi | Roy, Nairita | Hutfles, Lewis | Selfridge, Eva | Funk, Eric | Burns, Jeffrey M. | Swerdlow, Russell H.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) patients have reduced brain acetylcholine and reversing this deficit yields clinical benefits. In this study we explored how increased cholinergic tone impacts cell bioenergetics, which are also perturbed in AD. We treated SH-SY5Y neuroblastoma cells with carbachol, a cholinergic agonist, and tested for bioenergetic flux and bioenergetic infrastructure changes. Carbachol rapidly increased both oxidative phosphorylation and glycolysis fluxes. ATP levels rose slightly, as did cell energy demand, and AMPK phosphorylation occurred. At least some of these effects depended on muscarinic receptor activation, ER calcium release, and ER calcium re-uptake. Our data show that increasing cholinergic signaling enhances …cell bioenergetics, and reveal mechanisms that mediate this effect. Phenomena we observed could potentially explain why cholinesterase inhibitor therapy increases AD brain glucose utilization and N-acetyl aspartate levels. The question of whether cholinesterase inhibitors have a disease modifying effect in AD has long been debated; our data suggest a theoretical mechanism through which such an effect could potentially arise. Show more

Keywords: Acetylcholine, Alzheimer's disease, bioenergetics, carbachol, glycolysis, mitochondria

DOI: 10.3233/JAD-2012-121822

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1135-1146, 2013

Authors: Wang, Jun | Wright, Harold M. | Vempati, Prashant | Li, Henry | Wangsa, Julie | Dzhuan, Anastasiya | Habbu, Karishma | Knable, Lindsay A. | Ho, Lap | Pasinetti, Giulio M.

Article Type: Research Article

Abstract: Nebivolol is a selective β1 adrenergic receptor antagonist with nitric oxide-mediated vasodilatory properties utilized in the treatment of hypertension. Previously, nebivolol was shown to modulate amyloid-β protein precursor processing in vitro. In this study, we investigated the in vivo effects of nebivolol on the modulation of amyloid neuropathology in the Tg2576 mouse model of Alzheimer's disease (AD). We found that nebivolol is brain bioavailable and can be readily detected in the brain following three weeks of treatment at a dose of 1 mg/kg/day. Moreover, this treatment regime resulted in a significant reduction of amyloid-β neuropathology in the brain, and this …reduction was inversely correlated with plasma levels of amyloid-β. Chronic nebivolol treatment of Tg2576 mice with established amyloid neuropathology and cognitive impairments significantly reduced brain amyloid content but failed to improve cognitive function. Our study demonstrates that nebivolol is highly tolerable and safe and can significantly reduce amyloid neuropathology in the brain, which could be one of the most important parameters for primary prevention of AD. Our studies support the continued investigation of nebivolol for the treatment of AD at very early stages of the disease. Show more

Keywords: Adrenergic receptor blocker, Alzheimer's disease, brain bioavailability, inflammatory response, plaque

DOI: 10.3233/JAD-2012-120904

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1147-1156, 2013

Authors: Serra, Laura | Giulietti, Giovanni | Cercignani, Mara | Spanò, Barbara | Torso, Mario | Castelli, Diana | Perri, Roberta | Fadda, Lucia | Marra, Camillo | Caltagirone, Carlo | Bozzali, Marco

Article Type: Research Article

Abstract: This study investigates whether different patterns of grey matter (GM) loss may account for the different neuropsychological profiles observed in patients with amnestic (a-) and non-amnestic (na-) mild cognitive impairment (MCI), and may predict patients' clinical evolution. Fifty-five consecutive individuals complaining of cognitive dysfunction (referred to specialist dementia clinics) were screened and included in the study if they met the diagnostic criteria for MCI on a neurodegenerative basis. After an extensive neuropsychological assessment, patients were classified as suffering from a-MCI or na-MCI. Twenty-eight healthy individuals were also recruited and served as controls. All participants underwent magnetic resonance imaging at 3T, …including conventional images and volumetric scans. Volumetric data were processed using voxel-based morphometry to assess between-group differences in regional GM volumes and correlations with neuropsychological performances. When compared to controls, a-MCI patients showed prominent GM volume reductions in the medial temporal lobes, while those with na-MCI showed reduced GM volumes in the orbito-frontal cortex and basal ganglia. In a-MCI patients, significant associations were found between verbal long-term memory performance and GM volumes in the hippocampus. Conversely, in na-MCI patients, associations were found between scores at tests exploring executive functions and GM volumes in the orbito-frontal cortex. At one-year follow-up, conversions were recorded exclusively toward Alzheimer's disease (AD) in the a-MCI group, and toward non-AD dementia in the na-MCI group. This study confirms that MCI is a heterogeneous clinical identity including different neurodegenerative entities; specific patterns of regional GM loss appear to account for specific neuropsychological features and are likely to predict patients' clinical evolution. Show more

Keywords: Alzheimer's disease, amnestic mild cognitive impairment, magnetic resonance imaging, non-amnestic mild cognitive impairment, voxel-based morphometry

DOI: 10.3233/JAD-2012-121663

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1157-1165, 2013

Authors: Lim, Yen Ying | Ellis, Kathryn A. | Harrington, Karra | Pietrzak, Robert H. | Gale, Joanne | Ames, David | Bush, Ashley I. | Darby, David | Martins, Ralph N. | Masters, Colin L. | Rowe, Christopher C. | Savage, Greg | Szoeke, Cassandra | Villemagne, Victor L. | Maruff, Paul | For the AIBL Research Group

Article Type: Research Article

Abstract: We aimed to characterize the nature and magnitude of cognitive decline in a group of adults with amnestic mild cognitive impairment (aMCI) with high and low levels of amyloid-β (Aβ) in relation to healthy older adults with low Aβ levels. Healthy older adults and adults with aMCI enrolled in the Australian Imaging, Biomarker, and Lifestyle study, completed the CogState brief battery at baseline and 18 months, and underwent positron emission tomography neuroimaging for Aβ at baseline. In this study, we included adults with MCI who had been classified as having high and low levels of Aβ and healthy older adults …who had been classified as having low levels of Aβ. Linear model analyses adjusted for baseline cognitive function indicated that relative to healthy older adults with low Aβ, adults with aMCI and high Aβ showed greater decline in working memory and in verbal and visual episodic memory at 18 months. Adults with aMCI and low Aβ also showed greater decline in working memory; however they did not evidence any decline in episodic memory at 18 months. The results of our study suggests that relative to healthy older adults and adults with aMCI with low Aβ, adults with aMCI and high levels of Aβ showed faster rates of decline on measures of episodic memory over 18 months, and this was approximately twice that observed previously for healthy older adults with high Aβ levels. Show more

Keywords: Alzheimer's disease, amyloid-β, cognitive change, cognitive neuropsychology, mild cognitive impairment

DOI: 10.3233/JAD-121771

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1167-1176, 2013

Authors: Alvarez-López, María Jesús | Castro-Freire, Marco | Cosín-Tomás, Marta | Sanchez-Roige, Sandra | Lalanza, Jaume F. | del Valle, Jaume | Párrizas, Marcelina | Camins, Antonio | Pallás, Merce | Escorihuela, Rosa María | Kaliman, Perla

Article Type: Research Article

Abstract: The senescence-accelerated SAMP8 mouse is considered a useful non-transgenic model for studying aspects of progressive cognitive decline and Alzheimer's disease (AD). Using SAMR1 mice as controls, here we explored the effects of 6 months of voluntary wheel running in 10-month-old female SAMP8 mice. Exercise in SAMP8 mice improved phenotypic features associated with premature aging (i.e., skin color and body tremor) and enhanced vascularization and BDNF gene expression in the hippocampus compared with controls. With the aim of identifying genes involved in brain aging responsive to long-term exercise, we performed whole genome microarray studies in hippocampus from sedentary SAMP8 (P8sed), SAMR1 …(R1sed), and exercised SAMP8 (P8run) mice. The genes differentially expressed in P8sed versus R1sed were considered as putative aging markers (i) and those differentially expressed in P8run versus P8sed were considered as genes modulated by exercise (ii). Genes differentially expressed in both comparisons (i and ii) were considered as putative aging genes responsive to physical exercise. We identified 34 genes which met both criteria. Gene ontology analysis revealed that they are mainly involved in functions related to extracellular matrix maintenance. Selected genes were validated by real-time quantitative PCR assays, i.e., collagen type 1 alpha 1 (col1a1), collagen type 1 alpha 2 (col1a2), fibromodulin (fmod), prostaglandin D(2) synthase (ptgds), and aldehyde dehydrogenase (Aldh1a2). As a whole, our study suggests that exercise training during adulthood may prevent or delay gene expression alterations and processes associated with hippocampal aging in at-risk subjects. Show more

Keywords: Aging, Alzheimer's disease, brain, exercise, gene, long-term, mice, microarrays, SAMP8, voluntary

DOI: 10.3233/JAD-121264

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1177-1190, 2013

Authors: Ashford, J. Wesson | Bayley, Peter J.

Article Type: Article Commentary

DOI: 10.3233/JAD-2012-121124

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1191-1193, 2013

Article Type: Other

DOI: 10.3233/JAD-121265

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1195-1196, 2013

Article Type: Other

DOI: 10.3233/JAD-33428

Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 1197-1208, 2013