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

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