Journal of Alzheimer's Disease - Volume 22, issue 4

Authors: Garre-Olmo, Josep | López-Pousa, Secundino | Vilalta-Franch, Joan | de Gracia Blanco, Manuel | Vilarrasa, Antoni Bulbena

Article Type: Research Article

Abstract: Behavioral and psychological symptoms of dementia (BPSD) are characterized by fluctuations in their frequency and severity as well as by differences in the concurrent presentation of different symptoms. The goal of the current study was to identify groups of patients with Alzheimer's disease (AD) that had similar trajectories in the expression of BPSD. Over a 24-month period, an observational study was conducted using a population of ambulatory patients with AD of mild or moderate severity. The Neuropsychiatric Inventory (NPI) was administered every 6 months to the patient's caregiver. To classify patients according to changes in the frequency and severity of …BPSD, growth mixture models were fitted to the applied to the grouping of NPI subscales in the following three categories: psychotic syndrome (hallucinations and delusions), affective syndrome (depression, anxiety, irritability, and agitation), and behavioral syndrome (disinhibition, euphoria, apathy, and aberrant motor behavior). The sample population consisted of 491 patients (70.9% women) that had an average age of 75.2 years (SD = 6.6). Different trajectory patterns were identified based on differences in changes over the time in the frequency (stable, increasing, decreasing, or fluctuating in course) and severity (low, moderate, or elevated severity) for psychotic syndrome, emotional syndrome, and behavior syndrome. Patients with AD display a high degree of variability in the evolutionary course of BPSD. It is possible to identify groups of patients with similar evolutionary trajectories in terms of changes in the frequency and severity of BPSD. Show more

Keywords: Alzheimer's disease, latent growth mixture, longitudinal study, mood disorders, neurobehavioral manifestations, psychotic disorders, statistical model

DOI: 10.3233/JAD-2010-101215

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1169-1180, 2010

Authors: Martínez-García, Ana | Sastre, Isabel | Recuero, María | Aldudo, Jesús | Vilella, Elisabet | Mateo, Ignacio | Sánchez-Juan, Pascual | Vargas, Teo | Carro, Eva | Bermejo-Pareja, Félix | Rodríguez-Rodríguez, Eloy | Combarros, Onofre | Rosich-Estrago, Marcel | Frank, Ana | Valdivieso, Fernando | Bullido, María J.

Article Type: Research Article

Abstract: Oxidative stress, which plays a critical role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), is intimately linked to aging, the best established risk factor for AD. Studies in neuronal cells subjected to oxidative stress, mimicking such stress in AD brains, are therefore of great interest. PLA2G3 is the most overexpressed gene in a human neuronal model of oxidative stress induced by the free radical-generating xanthine/xanthine oxidase (X-XOD) system, which provokes apoptotic cell death. In this work, we describe that PLA2G3 gene silencing produced a marked inhibition of X-XOD induced cell death, and that PLA2G3 polymorphisms are …associated with AD in a Spanish case-control sample. The capacity to respond to oxidative stress may therefore modulate the risk of AD, and PLA2G3 is a potential target to regulate neuronal damage induced by free radicals. Show more

Keywords: Alzheimer's disease, cell injury, genetic association, neurodegeneration, oxidative stress, PLA2G3

DOI: 10.3233/JAD-2010-101348

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1181-1187, 2010

Authors: Liu, Yan-Ying | Bian, Jin-Song

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is pathologically characterized by the accumulation of senile plaques, containing activated microglia and amyloid-β peptides (Aβ). We found that aggregated Aβ1–40 peptide (25 μM, 24 h) significantly decreased viability of BV-2 microglial cells. This was concentration-dependently attenuated by NaHS (a hydrogen sulfide (H2 S) donor, 25–500 μM). NaHS also significantly attenuated Aβ-induced LDH release and the up-regulation of protein expression of growth arrest DNA damage (GADD 153). These data suggest that H2 S may attenuate Aβ-induced cell toxicity and cell cycle re-entry. Pretreatment with NaHS also suppressed the release of nitric oxide and the upregulation of …inducible nitric oxide synthase. These effects were attenuated by exogenous application of NaHS or stimulation of endogenous generation of H2 S with S-adenosyl-L-methionine, a cystathionine β synthase activator. NaHS also decreased the releases of TNF-α and suppressed the up-regulation of protein expression of cyclooxygenase 2, which were mimicked by blockade of p38 and JNK-MAPK. In addition, Aβ induced loss of mitochondrial member potential (ΔΨm) and activation of p38-, JNK-, and ERK-MAPKs. Application of NaHS attenuated these effects but failed to affect the activation of ERK. In conclusion, we demonstrated for the first time that H2 S may protect cell against Aβ-induced cell injury by inhibition of inflammation, promotion of cell growth and preservation of mitochondrial function in a p38- and JNK-MAPK dependent manner. Our results suggest that H2 S may have potential therapeutic value for treatment of AD. Show more

Keywords: Alzheimer's disease, amyloid, hydrogen sulfide, microglia, neuroprotection

DOI: 10.3233/JAD-2010-101002

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1189-1200, 2010

Authors: Winblad, Bengt | Giacobini, Ezio | Frölich, Lutz | Friedhoff, Lawrence T. | Bruinsma, Gosse | Becker, Robert E. | Greig, Nigel H.

Article Type: Research Article

Abstract: To gather preliminary evidence in Alzheimer's disease (AD) for the efficacy of phenserine, a non-competitive acetylcholinesterase inhibitor that has independent modulatory effects on amyloid-β generation, a 12-week comparison of patients receiving phenserine (10 and 15 mg BID) or placebo was conducted under double-blind conditions. Patients who completed 12 weeks of the double-blind before others were continued in the double-blind to determine longer-term treatment effects. At 12 weeks, mean ADAS-cog (AD assessment scale-cognitive) changes from baseline were −2.5 and −1.9 for high-dose phenserine (n = 83) and placebo (n = 81) groups, respectively, a non-statistically significant improvement for the high-dose phenserine …group relative to placebo. CIBIC+ (clinician's interview based impression of change + caregiver's input) values for the high-dose and placebo groups were similar at 12 weeks. For patients who received more than 12 weeks of therapy, the ADAS-cog changes were −3.18 and −0.66 for the high-dose phenserine (n = 52) and placebo (n = 63) groups, respectively, a difference achieving statistical significance (p = 0.0286). After 12 weeks, CIBIC+ values were 3.59 and 3.95 for the high-dose (n = 54) and placebo (n = 66) groups respectively (p = 0.0568). These results from this short-term study are consistent with phenserine potentially benefiting mild to moderate Alzheimer's disease symptomatically but do not address possible amyloid metabolic mediated effects on disease processes in AD. Show more

Keywords: Acetylcholinesterase, Alzheimer's disease, Alzheimer clinical trial, amyloid-β peptide, amyloid-β protein precursor, cholinesterase inhibitor, phenserine

DOI: 10.3233/JAD-2010-101311

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1201-1208, 2010

Authors: Milagre, Inês | Nunes, Maria João | Moutinho, Miguel | Rivera, Isabel | Fuso, Andrea | Scarpa, Sigfrido | Gama, Maria João | Rodrigues, Elsa

Article Type: Research Article

Abstract: The major mechanism of brain cholesterol elimination is the conversion of cholesterol into 24S-hydroxycholesterol by CYP46A1, a neuron-specific cytochrome P450. Since increasing evidence suggests that upregulation of CYP46A1 may be relevant for the treatment of Alzheimer's disease, we aim to identify the molecular mechanisms involved in CYP46A1 transcription. Our previous studies demonstrated the role of Sp transcription factors in basal expression and histone deacetylase (HDAC) inhibitor-dependent derepression of CYP46A1. Here, we show that the demethylating agent 5'-Aza-2'-deoxycytidine (DAC) is a CYP46A1 inducer and that pre-treatment with DAC causes a marked synergistic activation of CYP46A1 transcription by trichostatin A. Surprisingly, bisulfite …sequencing analysis revealed that the CYP46A1 core promoter is completely unmethylated in both human brain and non-neuronal human tissues where CYP46A1 is not expressed. Therefore, we have investigated Sp expression levels by western blot and real-time PCR, and their binding patterns to the CYP46A1 promoter, by electrophoretic mobility shift assay and chromatin immunoprecipitation assays, after DAC treatment. Our results showed that DAC decreases not only Sp1 and Sp3 protein levels, but also the binding activity of Sp3 to the +1 region of the CYP46A1 locus. Concomitantly, HDAC1 and HDAC2 were also significantly dissociated from the promoter. In conclusion, DAC induces CYP46A1 gene expression, in a DNA methylation-independent mechanism, decreasing Sp3/HDAC binding to the proximal promoter. Furthermore, by affecting the expression of the Sp3 transcription factor in neuronal cells, DAC might affect not only brain cholesterol metabolism, but also the expression of many other neuronal genes. Show more

Keywords: 5'-Aza-2'-deoxycytidine, brain cholesterol homeostasis, CYP46A1, 24S-hydroxycholesterol, epigenetics, Sp transcription factors, Trichostatin A

DOI: 10.3233/JAD-2010-100651

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1209-1221, 2010

Authors: Sundelöf, Johan | Sundström, Johan | Hansson, Oskar | Eriksdotter-Jönhagen, Maria | Giedraitis, Vilmantas | Larsson, Anders | Degerman-Gunnarsson, Malin | Ingelsson, Martin | Minthon, Lennart | Blennow, Kaj | Kilander, Lena | Basun, Hans | Lannfelt, Lars

Article Type: Research Article

Abstract: Cathepsin B is suggested to be involved in amyloid-β (Aβ) processing and Alzheimer's disease (AD). Studies of cathepsin B levels in plasma and cerebrospinal fluid (CSF) have not been previously performed. We examined cathepsin B levels in plasma and CSF samples in persons with AD, mild cognitive impairment (MCI), and healthy controls in order to test the hypothesis that cathepsin B levels can discriminate persons with AD or MCI from healthy controls. Cathepsin B, Cystatin C, Aβ1–40 and Aβ1–42 , total tau, phosphorylated tau, and albumin levels in plasma and CSF were analyzed by ELISA (Cathepsin B) turbidimetry (cystatin …C), xMAP Luminex technology (Aβ1–40 and Aβ1–42 and tau), and Cobas C501 analyzer (albumin) in persons with AD (n = 101), MCI (n = 84), and healthy control subjects (n = 28). Plasma cathepsin B levels were higher in persons with AD compared to healthy controls, both in unadjusted models and in multivariable models adjusting for age, gender, APOE genotype, cystatin C, and albumin levels: Odds ratio (OR) for AD per 1 SD of plasma cathepsin B; 2.04, 95% confidence interval (CI); 1.01–4.14, p = 0.05. There was no difference between diagnostic groups in cathepsin B levels in CSF: OR for AD per 1 SD of CSF cathepsin B; 0.93, 95% CI; 0.37–2.30, p = 0.87. Plasma cathepsin B levels were higher in persons with AD compared to healthy controls whereas there was no difference between diagnostic groups in cathepsin B levels in CSF. Further investigation of cathepsin B as a predictor of AD is warranted. Show more

Keywords: Alzheimer's disease, biomarkers, case control study, cathepsin B, cystatin C, epidemiology, risk factor

DOI: 10.3233/JAD-2010-101023

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1223-1230, 2010

Authors: Tierney, Mary C. | Moineddin, Rahim | McDowell, Ian

Article Type: Research Article

Abstract: While neuropsychological tests have been identified for the early prediction of Alzheimer's disease, this has not been established for prediction of all-cause dementia. This would be helpful for clinicians concerned about the risk of progression to dementia in patients who may present with a variety of medical and neurological conditions. We wanted to determine whether neuropsychological tests could accurately predict incident dementia within 10 and five years of diagnosis in a community-based sample. The Canadian Study of Health and Aging was conducted in three waves over a 10-year period (1991–2002). We studied 1472 non-demented participants who completed neuropsychological testing in …1991 and received a diagnostic assessment for dementia in 2001 (n = 284). We also studied 1231 non-demented participants who completed neuropsychological testing in 1996 and received a diagnostic assessment in 2001 (n = 634). Diagnosticians were blinded to performance on the predictive tests. Age, education, and sex were included as covariates in all regression analysis. Ten-year prediction: 2 tests, Rey Auditory Verbal Learning Test (RAVLT) short delayed verbal recall and Wechsler Adult Intelligence Test Revised (WAIS-R) Digit Symbol, were significant predictors of dementia (sensitivity = 78%, specificity = 72%, positive likelihood ratio = 2.81). Five-year prediction: 4 tests, Wechsler Memory Scale Information, RAVLT short delayed verbal recall, animal fluency, and WAIS-R Digit Symbol, significantly predicted incident dementia (sensitivity = 75%, specificity = 74%, positive likelihood ratio = 2.90). Regression models were supported with bootstrapping estimates. Neuropsychological tests can accurately predict progression to all-cause dementia within 10 years of diagnosis in a large community-based sample of non-demented participants. Show more

Keywords: Alzheimer's disease, dementia, neuropsychological tests, prognosis, risk prediction

DOI: 10.3233/JAD-2010-100516

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1231-1240, 2010

Authors: Tzimopoulou, Sofia | Cunningham, Vincent J. | Nichols, Thomas E. | Searle, Graham | Bird, Nick P. | Mistry, Prafull | Dixon, Ian J. | Hallett, William A. | Whitcher, Brandon | Brown, Andrew P. | Zvartau-Hind, Marina | Lotay, Narinder | Lai, Robert Y. K. | Castiglia, Mary | Jeter, Barbara | Matthews, Julian C. | Chen, Kewei | Bandy, Dan | Reiman, Eric M. | Gold, Michael | Rabiner, Eugenii A. | Matthews, Paul M.

Article Type: Research Article

Abstract: Here we report the first multi-center clinical trial in Alzheimer's disease (AD) using fluorodeoxyglucose positron emission tomography ([18 F]FDG-PET) measures of brain glucose metabolism as the primary outcome. We contrasted effects of 12 months treatment with the PPARγ agonist Rosiglitazone XR versus placebo in 80 mild to moderate AD patients. Secondary objectives included testing for reduction in the progression of brain atrophy and improvement in cognition. Active treatment was associated with a sustained but not statistically significant trend from the first month for higher mean values in Ki index and CMRglu index , novel quantitative indices related to the …combined forward rate constant for [18 F]FDG uptake and to the rate of cerebral glucose utilization, respectively. However, neither these nor another analytical approach recently validated using data from the Alzheimer's Disease Neuroimaging Initiative indicated that active treatment decreased the progression of decline in brain glucose metabolism. Rates of brain atrophy were similar between active and placebo groups and measures of cognition also did not suggest clear group differences. Our study demonstrates the feasibility of using [18 F]FDG-PET as part of a multi-center therapeutics trial. It suggests that Rosiglitazone is associated with an early increase in whole brain glucose metabolism, but not with any biological or clinical evidence for slowing progression over a 1 year follow up in the symptomatic stages of AD. Show more

Keywords: 18F-FDG, Alzheimer's disease, analysis, dementia, PPARγ, rosiglitazone

DOI: 10.3233/JAD-2010-100939

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1241-1256, 2010

Authors: Borro, Marina | Cavallaro, Rosaria A. | Gentile, Giovanna | Nicolia, Vincenzina | Fuso, Andrea | Simmaco, Maurizio | Scarpa, Sigfrido

Article Type: Research Article

Abstract: Late Onset Alzheimer's Disease (LOAD) can be associated to high homocysteine level and alteration of one-carbon metabolism. We previously demonstrated in the TgCRND8 mice strain, over-expressing human amyloid-β protein precursor, that B vitamin deficiency causes alteration of one-carbon metabolism, together with unbalance of S-adenosylmethionine/S-adenosylhomocysteine levels, and is associated with AD like hallmarks as increased amyloid-β plaque deposition, hyperhomocysteinemia, and oxidative stress. The same model of nutritional deficit was used here to study the variation of the brain protein expression profile associated to B vitamin deficiency. A group of proteins mainly involved in neuronal plasticity and mitochondrial functions was identified as …modulated by one-carbon metabolism. These findings are consistent with increasing data about the pivotal role of mitochondrial abnormalities in AD patho-physiology. The identified proteins might represent new potential biomarkers of LOAD to be further investigated. Show more

Keywords: Alzheimer's disease, homocysteine, proteomics, S-adenosylmethionine

DOI: 10.3233/JAD-2010-101107

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1257-1268, 2010

Authors: Didic, Mira | Ranjeva, Jean-Philippe | Barbeau, Emmanuel | Confort-Gouny, Sylviane | Le Fur, Yann | Felician, Olivier | Mancini, Julien | Poncet, Michel | Ceccaldi, Mathieu | Cozzone, Patrick

Article Type: Research Article

Abstract: In the early stages of Alzheimer's disease (AD), neurofibrillary tangles develop in the mesial temporal lobe (MTL), first in the anterior subhippocampal (perirhinal/entorhinal) cortex and then in the hippocampal formation. This region plays a key role in visual recognition memory (VRM). VRM has been reported to be impaired in patients with amnestic mild cognitive impairment (aMCI). The aim of the present study was to determine if an impairment of VRM is associated with metabolic changes in the MTL using magnetic resonance spectroscopic imaging and if evaluating VRM can contribute to the early diagnosis of AD. 28 patients with aMCI and …28 controls underwent a full neuropsychological assessment including an evaluation of VRM using the DMS48. NAA/mIno ratios, reduced in patients with AD and associated with the severity of pathological changes, were determined in the MTL. aMCI-patients were further divided into two subgroups according to their VRM performance. aMCI-patients showed decreased NAA/mIno levels in the right hippocampus compared with controls. aMCI-patients with impaired VRM showed decreased NAA/mIno ratios in the MTL bilaterally, including a region that sampled the left anterior subhippocampal cortex, compared to controls. No changes were found in aMCI patients with normal VRM. Performance on the DMS48 correlated with NAA/mIno levels in the anterior MTL. Clinical 6-year follow-up data (available for 78.6% of the aMCI-patients) indicates that impaired performance on the DMS48 could predict conversion to AD with a sensitivity and specificity of 81.8%. These findings provide further evidence that impaired VRM, as a hallmark of MTL dysfunction, may contribute to the early diagnosis of AD. Show more

Keywords: Alzheimer's disease, entorhinal cortex, magnetic resonance spectroscopy, mesial temporal lobe, mild cognitive impairment, MRSI, perirhinal cortex, visual recognition memory, DMS48

DOI: 10.3233/JAD-2010-101257

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1269-1279, 2010