Journal of Alzheimer's Disease - Volume 43, issue 1

Authors: Olsson, Erika | Karlström, Brita | Kilander, Lena | Byberg, Liisa | Cederholm, Tommy | Sjögren, Per

Article Type: Research Article

Abstract: Background: Adherence to dietary patterns has been associated with cognitive decline and dementia, but studies are inconsistent. Objective: Dietary patterns, i.e., WHO recommendations (Healthy Diet Indicator), a Mediterranean-like diet (modified Mediterranean Diet Score, mMDS), and a low carbohydrate high protein diet (LCHP), were related to incident cognitive dysfunction, as indicated by Alzheimer's disease (AD), all-type dementia, and all-type cognitive impairment, in a cohort of 1,138 elderly Swedish men. Methods: Dietary patterns were derived from 7-day records. Risk relations were calculated by Cox and logistic regression analyses, adjusted for potential confounders. Sensitivity analysis was performed in a …subpopulation (n = 564) with energy intake according to the Goldberg cut-off. Results: During a mean follow-up of 12 years, 84, 143, and 198 men developed AD, all-type dementia, and all-type cognitive impairment, respectively. There was no association between Healthy Diet Indicator and any of the outcomes. Hazard ratios associated with 1 standard deviation (SD) increment in the LCHP score were 1.16 (95% confidence interval [CI]: 0.95, 1.43) for AD and 1.16 (95% CI: 0.99, 1.37) for all-type dementia. mMDS was not associated with dementia diagnosis. Odds ratio (OR)/1 SD increase for mMDS and all-type cognitive impairment was 0.82 (95% CI: 0.65, 1.05). In the subpopulation OR for mMDS and all-type cognitive impairment was 0.32 (95% CI: 0.11, 0.89). Conclusion: We found no strong associations with development of cognitive dysfunction for any of the dietary patterns investigated. However, there was a potentially beneficial association for a Mediterranean-like diet on the development of cognitive dysfunction in the subpopulation. Show more

Keywords: Alzheimer's disease, cognition disorders, cohort study, dementia, diet, dietary carbohydrates, dietary proteins, Mediterranean diet

DOI: 10.3233/JAD-140867

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 109-119, 2015

Authors: Gifford, Katherine A. | Liu, Dandan | Carmona, Hugo | Lu, Zengqi | Romano, Raymond | Tripodis, Yorghos | Martin, Brett | Kowall, Neil | Jefferson, Angela L.

Article Type: Research Article

Abstract: Background: The relation between the source of cognitive complaint and objective cognitive performance is not well understood. Objective: Examine self and informant cognitive complaint as predictors of objective cognitive and functional trajectory in non-demented elders. Methods: Participants from the National Alzheimer's Coordinating Center had a baseline diagnosis of normal cognition (NC; n = 6133, 72 ± 8 years, 68% female) or mild cognitive impairment (MCI; n = 3010, 74 ± 8 years, 55% female). Four independent groups defined cognitive complaint: no complaint, self-only complaint, informant-only complaint, or mutual complaint (both self and informant complaint). Linear mixed …model regression analyses related complaint status (referent was no complaint) to cognitive and functional trajectories, adjusting for age, sex, race, education, and follow-up period. Results: Among NC participants, mutual complaint related to faster decline in global cognition (p < 0.0001), language (all p-values <0.0001), processing speed (p = 0.0002), and executive functioning (p = 0.0006). Informant-only complaint related to faster decline in global cognition (p = 0.0001) and processing speed (p = 0.0001). Self-only complaint related to greater decline in immediate (p < 0.0001) and delayed (p = 0.0005) episodic memory. In MCI, mutual complaint related to faster decline in global cognition (p < 0.0001), verbal episodic memory (all p-values <0.0001), language (all p-values <0.0001), and processing speed (all p-values <0.0006). Informant-only or self-only complaint associations with cognitive trajectory did not survive correction factor for multiple comparisons. Conclusion: Cognitive complaint appears to have clinical significance, as it is related to declines in objective cognitive performance over time. Mutual complaint was associated with the worst cognitive trajectory in both NC and MCI elders, highlighting the importance of incorporating an informant into evaluation of elders whenever feasible. Show more

Keywords: Mild cognitive impairment, cognitive complaint, dementia, cognition, Alzheimer's disease

DOI: 10.3233/JAD-131925

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 121-132, 2015

Authors: Chen, Teng | Hou, Ruihua | Li, Chao | Wu, Chengyuan | Xu, Shujun

Article Type: Research Article

Abstract: Endothelial dysfunction and disruption of the blood-brain barrier have been found to be associated with Parkinson's disease (PD). However, the mechanisms underlying these effects have yet to be elucidated. It has also been found that activated protein C (APC) displays neuroprotective properties. Presently, the effects of APC on PD remain unknown. Using a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) neurotoxin rodent model of PD, we found that administration of MPTP can reduce expression of endothelial protein C receptor (EPCR), an N-glycosylated type I membrane protein that has the ability to enhance protein C activation. However, the use of MPTP does not …alter levels of thrombomodulin. These findings were verified in an in vitro study showing that 1-methyl-4-phenylpyridinium (MPP+) treatment leads to suppression of EPCR along with reduction of protein C activation in human primary endothelial cells. Importantly, our results display that activation of the transcriptional factor SP1 is involved in the inhibitory effects of MPTP/MPP+ on EPCR expression. We found that using 300 nM of the SP1 inhibitor MIT can abolish the effects of MPP+ on EPCR expression. Consistently, SP1 silencing using small RNA interference was able to prevent the inhibitory effects of MPTP/MPP+ on the reduction of EPCR expression and impairment of protein C activation. Importantly, our results indicate that overexpression of SP1 inhibits EPCR promoter activity. Our study suggests that EPCR-APC may be a potential therapeutic target for endothelial dysfunction in PD. Show more

Keywords: Endothelial protein C receptor, MPTP/MPP+, Parkinson's disease, protein C, SP1

DOI: 10.3233/JAD-140126

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 133-142, 2015

Authors: Ye, Byoung Seok | Chin, Juhee | Kim, Seong Yoon | Lee, Jung-Sun | Kim, Eun-Joo | Lee, Yunhwan | Hong, Chang Hyung | Choi, Seong Hye | Park, Kyung Won | Ku, Bon D. | Moon, So Young | Kim, SangYun | Han, Seol-Hee | Lee, Jae-Hong | Cheong, Hae-Kwan | Park, Sun Ah | Jeong, Jee Hyang | Na, Duk L. | Seo, Sang Won

Article Type: Research Article

Abstract: We evaluate the longitudinal outcomes of amnestic mild cognitive impairment (aMCI) according to the modality of memory impairment involved. We recruited 788 aMCI patients and followed them up. aMCI patients were categorized into three groups according to the modality of memory impairment: Visual-aMCI, only visual memory impaired; Verbal-aMCI, only verbal memory impaired; and Both-aMCI, both visual and verbal memory impaired. Each aMCI group was further categorized according to the presence or absence of recognition failure. Risk of progression to dementia was compared with pooled logistic regression analyses while controlling for age, gender, education, and interval from baseline. Of the sample, …219 (27.8%) aMCI patients progressed to dementia. Compared to the Visual-aMCI group, Verbal-aMCI (OR = 1.98, 95% CI = 1.19–3.28, p = 0.009) and Both-aMCI (OR = 3.05, 95% CI = 1.97–4.71, p < 0.001) groups exhibited higher risks of progression to dementia. Memory recognition failure was associated with increased risk of progression to dementia only in the Visual-aMCI group, but not in the Verbal-aMCI and Both-aMCI groups. The Visual-aMCI without recognition failure group were subcategorized into aMCI with depression, small vessel disease, or accelerated aging, and these subgroups showed a variety of progression rates. Our findings underlined the importance of heterogeneous longitudinal outcomes of aMCI, especially Visual-aMCI, for designing and interpreting future treatment trials in aMCI. Show more

Keywords: Alzheimer's disease, amnesia, mild cognitive impairment, neuropsychology

DOI: 10.3233/JAD-140318

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 143-152, 2015

Authors: Wang, Xiu-Lian | Zeng, Ji | Yang, Yang | Xiong, Yan | Zhang, Zhi-Hua | Qiu, Mei | Yan, Xiong | Sun, Xu-Ying | Tuo, Qing-Zhang | Liu, Rong | Wang, Jian-Zhi

Article Type: Research Article

Abstract: Abnormal hyperphosphorylation of microtubule-associated protein tau is involved in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease (AD). Helicobacter pylori (H. pylori) infection has been reported to be related with a high risk of AD, but the direct laboratory evidence is lacking. Here we explored the effect of H. pylori infection on tau phosphorylation. The results showed that H. pylori filtrate induced significant tau hyperphosphorylation at several AD-related tau phosphorylation sites, such as Thr205, Thr231, and Ser404, both in mouse neuroblastoma N2a cells and rat brains with activation of glycogen synthase kinase-3β (GSK-3β). Application of GSK-3 inhibitors efficiently attenuated …the H. pylori-induced tau hyperphosphorylation. Our data provide evidence supporting the role of H. pylori infection in AD-like tau pathology, suggesting that H. pylori eradication may be beneficial in the prevention of tauopathy. Show more

Keywords: Alzheimer's disease, glycogen synthase kinase-3β, Helicobacter pylori, tau hyperphosphorylation

DOI: 10.3233/JAD-140198

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 153-165, 2015

Authors: Villars, Hélène | Dupuy, Charlotte | Perrin, Amélie | Vellas, Bruno | Nourhashemi, Fati

Article Type: Research Article

Abstract: Background: Therapeutic patient education is expanding in the field of Alzheimer's disease (AD). Objective: To evaluate the impact of a therapeutic educational program, on AD-affected patients and their caregivers, living in the community, on the patient's quality of life. Methods: Non experimental before and after study. Patient/caregiver dyads were recruited in the geriatric department of the Toulouse University Hospital. The intervention consisted of an educational program, designed for both patients and caregivers. It included two individual sessions (at baseline (M0) and two months later (M2)) and four group sessions for caregivers only, one per week between …M0 and M2. The primary outcome was the patient's quality of life at two months, hetero-evaluated by the caregiver. We compared the QoL-AD score between M0 and M2 with a paired Student's test. The secondary outcomes were patient’s autonomy (activities of daily living) and caregiver's burden (Zarit Burden interview). Results: 29 patient/caregiver dyads were recruited. The QoL-AD score was 24.6 ± 5.1 at M0 versus 27.2 ± 6.0 at M2 (p = 0.038). This difference is statistically significant. There was no difference in the secondary outcomes. Conclusion: This study revealed a significant positive impact of a therapeutic educational program on patients' quality of life. Our results led us to design a randomized controlled trial called the THERAD study (THERapeutic education in Alzheimer's disease). It started in January 2013, and the results will be available in 2015. If the efficacy of this approach is proven, it will be important to implement educational programs in the care plan of these patients. Show more

Keywords: Alzheimer's disease, therapeutic education, caregiver, quality of life

DOI: 10.3233/JAD-141179

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 167-176, 2015

Authors: Perez de Lara, María J. | Pintor, Jesús

Article Type: Research Article

Abstract: The aim of this study was to assess the changes of extracellular ATP levels during the progress of Alzheimer's disease by using a murine model of the disease. Retinal nucleotide release was measured from flattened whole-mounts stimulated with 59 mM KCl or non-stimulated maintained in Ringer solution. Mice exhibited an increase in retinal ATP release as long as the pathology progressed up to 14 months. This value decreased to normal values by 18 months of age. Changes occurred also when comparing to non-pathological mice. The increase in the presence of ATP levels may contribute, together with other factors, to the …changes in the functionality of the retina and the concomitant death of retinal cells. Show more

Keywords: Alzheimer's disease, ATP, B6C3F1 mice, B6C3-Tg (AβPPswe, PSEN1dE9) mice

DOI: 10.3233/JAD-141005

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 177-181, 2015

Authors: Lewczuk, Piotr | Lelental, Natalia | Spitzer, Philipp | Maler, Juan Manuel | Kornhuber, Johannes

Article Type: Research Article

Abstract: Background: The increasing role of cerebrospinal fluid (CSF) biomarkers in the early diagnosis of Alzheimer's disease (AD) is reflected in recently published diagnostic and/or research criteria. A growing body of evidence suggests better diagnostic performance of the amyloid-β (Aβ)42/40 CSF concentration ratio compared to the Aβ42 concentration alone. Objective: (a) to analytically validate two novel ELISAs capable to measure Aβ1-40 and Aβ1-42 in the CSF, and (b) to compare the diagnostic accuracies of Aβ1-42 and Aβ42/40 ratio. Methods: In this study, (a) the novel Aβ1-40 and Aβ1-42 ELISAs …(IBL International GmbH, Hamburg, Germany) have been analytically validated, and (b) a clinical study has been performed comparing the diagnostic performance of the CSF Aβ42/40 concentration ratio and the CSF Aβ42 concentration. Results: In the analytical part of the study, only marginal cross-reactivity (Aβ1-42 versus Aβ1-40 ) was observed; recoveries were in the range of 85–100% for the samples diluted 1 : 20–1 : 640 (Aβ1-40 ), and 92–104% for the samples diluted 1 : 20–1 : 320 (Aβ1-42 ). For Aβ1-40 , the intra-assay imprecision was 2.1%, the inter-assay imprecision was 4.4%, and the inter-lot imprecision was 5.4 %. For Aβ1-42 , the numbers were 3.1%, 6.2%, and 6.9%, respectively. The goodness of the fit of the average standard curves was >0.99 for both assays, and the imprecision of the optical densities in ten repetitions of the standard curves was ≤5% for all standards. In the clinical part, at the cut off value 691 pg/mL, Aβ1-42 showed sensitivity and specificity of 69.3% and 88.9%, respectively, whereas at the cut off value 0.06, the Aβ42/40 ratio showed significantly improved performance with sensitivity and specificity of 93.3% and 100%, respectively. The area under the ROC curve for Aβ42/40 (0.974) was highly significantly larger compared to Aβ1-42 concentration ROC curve (0.827, p < 0.0001). Conclusions: (a) the novel Aβ1-40 and Aβ1-42 ELISA assays characterize with very good analytical performance; (b) we reconfirm that the CSF Aβ42/40 concentration ratio shows significantly better diagnostic performance compared to the CSF Aβ1-42 concentration alone. Show more

Keywords: Alzheimer's disease, Aβ42/40 ratio, amyloid-β, biomarkers, cerebrospinal fluid, validation

DOI: 10.3233/JAD-140771

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 183-191, 2015

Authors: Montero-Odasso, Manuel | Muir-Hunter, Susan W. | Oteng-Amoako, Afua | Gopaul, Karen | Islam, Anam | Borrie, Michael | Wells, Jennie | Speechley, Mark

Article Type: Research Article

Abstract: Background: Gait deficits are prevalent in people with dementia and increase their fall risk and future disability. Few treatments exist for gait impairment in Alzheimer's disease (AD) but preliminary studies have shown that cognitive enhancers may improve gait in this population. Objective: To determine the efficacy of donepezil, a cognitive enhancer that improves cholinergic activity, on gait in older adults newly diagnosed with AD. Methods: Phase II clinical trial in 43 seniors with mild AD who received donepezil. Participants had not previously received treatment with cognitive enhancers. Primary outcome variables were gait velocity (GV) and stride …time variability (STV) under single and dual-task conditions measured using an electronic walkway. Secondary outcomes included attention and executive function. Results: After four months of treatment, participants with mild AD improved their GV from 108.4 ± 18.6 to 113.3 ± 19.5 cm/s, p = 0.010; dual-task GV from 80.6 ± 23.0 to 85.3 ± 22.3 cm/s, p = 0.028. Changes in STV were in the expected direction although not statistically significant. Participants also showed improvements in Trail Making Tests A (p = 0.030), B (p = 0.001), and B-A (p = 0.042). Conclusion: Donepezil improved gait in participants with mild AD. The enhancement of dual-task gait suggests the positive changes achieved in executive function as a possible causal mechanism. This study yielded a clinically significant estimate of effect size; as well, the findings are relevant to the feasibility and ethics considerations for the design of a Phase III clinical trial. Show more

Keywords: Aged, Alzheimer's disease, cholinesterase inhibitors, clinical trials, donepezil, executive function, falls, gait

DOI: 10.3233/JAD-140759

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 193-199, 2015

Authors: Andrade de Oliveira, Ailton | Carthery-Goulart, Maria Teresa | Oliveira Júnior, Pedro Paulo de Magalhães | Carrettiero, Daniel Carneiro | Sato, João Ricardo | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Neuroimaging techniques combined with computational neuroanatomy have been playing a role in the investigation of healthy aging and Alzheimer's disease (AD). The definition of normative rules for brain features is a crucial step to establish typical and atypical aging trajectories. Objective: To introduce an unsupervised pattern recognition method; to define multivariate normative rules of neuroanatomical measures; and to propose a brain abnormality index. Methods: This study was based on a machine learning approach (one class classification or novelty detection) to neuroanatomical measures (brain regions, volume, and cortical thickness) extracted from the Alzheimer's Disease Neuroimaging Initiative …(ADNI)'s database. We applied a ν-One-Class Support Vector Machine (ν-OC-SVM) trained with data from healthy subjects to build an abnormality index, which was compared with subjects diagnosed with mild cognitive impairment and AD. Results: The method was able to classify AD subjects as outliers with an accuracy of 84.3% at a false alarm rate of 32.5%. The proposed brain abnormality index was found to be significantly associated with group diagnosis, clinical data, biomarkers, and future conversion to AD. Conclusion: These results suggest that one-class classification may be a promising approach to help in the detection of disease conditions. Our findings support a framework considering the continuum of brain abnormalities from healthy aging to AD, which is correlated with cognitive impairment and biomarkers measurements. Show more

Keywords: Dementia, neurodegeneration, neuroimaging, normative, outliers, pattern recognition, support vector machines

DOI: 10.3233/JAD-140189

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 201-212, 2015