Journal of Alzheimer's Disease - Volume 26, issue 4

Authors: Zhang, Yanlei | Kivipelto, Miia | Solomon, Alina | Wimo, Anders

Article Type: Research Article

Abstract: Risk scores based on modifiable factors have recently been developed for dementia. This study aims to estimate the cost-effectiveness of a potential preventive intervention program meant to lower the score related to increased dementia risk. Analyses were based on a Markov model adapted to Swedish circumstances. Risk score categories and risk probabilities were derived from the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) study in Finland. Figures of costs, utilities, and mortality were obtained from literature or databases. One-way sensitivity analysis and probabilistic sensitivity analysis were carried out to investigate the robustness of the model and to identify …which model inputs had most impact on the results. In the base case, the usual care had a cost of 621,000 SEK and utilities of 11.8438 quality-adjusted life year (QALYs). The intervention had a cost of 599, 026 SEK and utilities of 11.8950 QALYs. The cost was 21,974 SEK lower in the intervention with 0.0511 QALYs gained over a 20 years horizon, indicating absolute dominance. The support for cost-effectiveness was insensitive to changes in the value of QALY for demented, mortality, and risk of dementia. If the intervention program was assumed to run every year, the incremental cost-effectiveness ratio did not show absolute dominance but was still under the willingness-to-pay level. The probabilistic sensitivity analysis indicated cost effectiveness in 67% of the samplings given a willingness-to-pay level of 600,000 SEK/year. This is a promising outlook for future research on preventive interventions in dementia, emphasizing the need of conducting multi-domain randomized trials. Show more

Keywords: Cost and cost analysis, dementia, economics, risk, risk reduction behavior

DOI: 10.3233/JAD-2011-110065

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 735-744, 2011

Authors: Yang, Eric | Farnum, Michael | Lobanov, Victor | Schultz, Tim | Raghavan, Nandini | Samtani, Mahesh N. | Novak, Gerald | Narayan, Vaibhav | DiBernardo, Allitia | and the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Hypothetical models of AD progression typically relate clinical stages of AD to sequential changes in CSF biomarkers, imaging, and cognition. However, quantifying the continuous trajectories proposed by these models over time is difficult because of the difficulty in relating the dynamics of different biomarkers during a clinical trial that is significantly shorter than the duration of the disease. We seek to show that through proper synchronization, it is possible to de-convolve these trends and quantify the periods of time associated with different pathophysiological changes associated with Alzheimer's disease (AD). We developed a model that replicated the observed progression of ADAS-Cog …13 scores and used this as a more precise estimate of disease-duration and thus pathologic stage. We then synchronized cerebrospinal fluid (CSF) and imaging biomarkers according to our new disease timeline. By de-convolving disease progression via ADAS-Cog 13, we were able to confirm the predictions of previous hypothetical models of disease progression as well as establish concrete timelines for different pathobiological events. Specifically, our work supports a sequential pattern of biomarker changes in AD in which reduction in CSF Aβ42 and brain atrophy precede the increases in CSF tau and phospho-tau. Show more

Keywords: clinical trials, disease timeline, progression modeling, synchronization

DOI: 10.3233/JAD-2011-110551

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 745-753, 2011

Authors: Chen, Kevin H. | Reese, Edmund A. | Kim, Hyung-Wook | Rapoport, Stanley I. | Rao, Jagadeesh S.

Article Type: Retraction

Abstract: This article has been retracted. IOS Press has retracted the publication from its online content due to incorrect data and figures.

DOI: 10.3233/JAD-2011-110002

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 755-766, 2011

Authors: Akhter, Hasina | Katre, Ashwini | Li, Ling | Liu, Xuebo | Liu, Rui-Ming

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-β peptide (Aβ) in the brain, one of the pathological features of AD, is considered to be a central disease-causing and disease-promoting event in AD. In this study, we showed that feeding male AβPP/PS1 transgenic mice, a well established mouse model of AD, with a diet containing phenolic antioxidant tert-butylhydroquinone (TBHQ) dramatically reduced brain Aβ load with no significant effect on the amounts of alpha- and beta-C-terminal fragments or full-length AβPP. Further studies showed that TBHQ diet inhibited the expression of plasminogen …activator inhibitor-1 (PAI-1), a protease inhibitor which plays a critical role in brain Aβ accumulation in AD, accompanied by increases in the activities of tissue type and urokinase type plasminogen activators (tPA and uPA) as well as plasmin. Moreover, we showed that TBHQ diet increased the expression of low density lipoprotein related protein-1, a multi ligand endocytotic receptor involved in transporting Aβ out of the brain, and plasma Aβ40 and Aβ42 levels. We also showed that TBHQ diet increased the concentration of glutathione, an important antioxidant, and suppressed the expression of NADPH oxidase 2 as well as lipid peroxidation. Collectively, our data suggest that TBHQ may have therapeutic potential for AD by increasing brain antioxidant capacity/reducing oxidative stress level and by stimulating Aβ degradation/clearance pathways. Show more

Keywords: Alzheimer's disease, amyloid-β degradation, amyloid-β efflux, antioxidant

DOI: 10.3233/JAD-2011-110512

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 767-778, 2011

Authors: Lim, Nastasia K.-H. | Villemagne, Victor L. | Soon, Cynthia P.W. | Laughton, Katrina M. | Rowe, Christopher C. | McLean, Catriona A. | Masters, Colin L. | Evin, Genevieve | Li, Qiao-Xin

Article Type: Research Article

Abstract: Pathological changes in the Alzheimer's disease (AD) brain include amyoid-β (Aβ) plaques, and neurofibrillary tangles, as well as neuronal death and synaptic loss. Matrix metalloproteinases MMP-2 and MMP-9 are known to degrade Aβ, and their expressions are increased in the AD brain, in particular in the astrocytes surrounding amyloid plaque. To investigate a possible association between plasma metalloproteinases and AD, we quantified MMP-2 and MMP-9 activities in the plasma of healthy controls (HC, n = 56), cases with mild cognitive impairment (MCI, n = 45), and AD (n = 50). All cases had previously been imaged with Pittsburgh compound B …(PiB) and had a Mini-Mental Status Examination (MMSE) assessment. MMP-2 and MMP-9 activity was determined using gelatine-zymography. There was a significant 1.5-fold decrease in MMP-2 activity in the AD group compared to HC (p < 0.001) and a 1.4-fold decrease compared to MCI (p < 0.01). There was no difference in MMP-9 levels between the three groups. A positive correlation was identified between MMP-2 plasma activity and MMSE score (r = 0.16, p < 0.05), but there was no association with PiB. This is the first report of a change in MMP-2 activity in AD plasma and these findings may provide some insight into AD pathogenesis. Show more

Keywords: Alzheimer's disease, matrix metalloproteinase-2, matrix metalloproteinase-9, mild cognitive impairment, Pittsburgh compound B, plasma biomarker

DOI: 10.3233/JAD-2011-101974

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 779-786, 2011

Authors: Serpente, Maria | Fenoglio, Chiara | Villa, Chiara | Cortini, Francesca | Cantoni, Claudia | Ridolfi, Elisa | Clerici, Francesca | Marcone, Alessandra | Benussi, Luisa | Ghidoni, Roberta | Boneschi, Filippo Martinelli | Gallone, Salvatore | Cappa, Stefano | Binetti, Giuliano | Franceschi, Massimo | Rainero, Innocenzo | Giordana, Maria Teresa | Mariani, Claudio | Bresolin, Nereo | Scarpini, Elio | Galimberti, Daniela

Article Type: Research Article

Abstract: The oxidized LDL receptor 1 gene (OLR1) rs1050283 single nucleotide polymorphism (SNP) has been previously shown to be associated with Alzheimer's disease (AD). An association analysis of OLR1 was carried out in a population of 443 patients with AD as compared with 393 age-matched controls. In addition, an expression analysis of OLR1 and its regulatory hsa-miR369-3p was performed in peripheral mononuclear blood cells (PBMC) from 20 patients and 15 controls. Logistic regression analysis, adjusted for gender and apolipoprotein E (ApoE) status, showed a statistically significant association of OLR1 rs1050283 under the assumption of a dominant model (CC and CT individuals …versus TT: p = 0.014, OR: 1.50, 95%CI: 1.08–2.08) and a genotypic model (TC versus TT: p = 0.002, OR: 1.61, 95%CI: 1.14–2.26). No significant differences in OLR1 expression was observed between patients and controls (p > 0.05). However, stratifying patients according to the rs1050283 status, significantly decreased relative PBMC expression levels of OLR1 were observed in carriers of CC+CT genotypes as compared with TT carriers (0.13 ± 0.013 versus 0.46 ± 0.028, p = 0.022), whereas no differences in relative expression levels of the hsa-miR369-3p were observed (p > 0.05). The effect observed was not due to the presence of the ApoE ε4 allele. The OLR1 rs1050283 SNP likely acts as a risk factor for sporadic AD. The presence of at least one C allele is associated with a decreased expression of OLR1 mRNA in the absence of hsa-miR369-3p de-regulation, suggesting that the presence of the polymorphic allele influences the binding of hsa-miR369-3p to its 3'UTR consensus sequence. Nevertheless, the limited power of the study requires further investigations with a larger sample size. Show more

Keywords: Alzheimer's disease, hsa-miR369-3p, oxidized LDL receptor 1, OLR1, peripheral mononuclear blood cells, single nucleotide polymorphism

DOI: 10.3233/JAD-2011-110074

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 787-793, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-110075

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 795-796, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-26417

Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 797-808, 2011