Journal of Alzheimer's Disease - Volume 59, issue 2

Authors: Nagai, Michiaki | Dote, Keigo | Kato, Masaya | Sasaki, Shota | Oda, Noboru | Kagawa, Eisuke | Nakano, Yoshinori | Yamane, Aya | Higashihara, Tasuku | Miyauchi, Shunsuke | Tsuchiya, Akane

Article Type: Review Article

Abstract: While hypertension has been shown to be a risk factor for vascular dementia, several studies have also demonstrated that hypertension also increases the risk of Alzheimer’s disease (AD). Although the relationship between visit-to-visit blood pressure variability (VVV) and cognitive impairment, including AD, have been provided, the mechanisms remain poorly understood. This review paper focuses on the relationship of VVV with AD and summarizes the pathophysiology underlying that relationship, which appears to be mediated by arterial stiffness.

Keywords: Alzheimer’s disease, amyloid beta, cognitive impairment, hypertension, visit-to-visit blood pressure variability

DOI: 10.3233/JAD-161172

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 515-526, 2017

Authors: Xie, Fang | Peng, Fangyu

Article Type: Review Article

Abstract: Aging is a risk factor for Alzheimer’s disease (AD). There are changes of brain metabolism and biometal fluxes due to brain aging, which may play a role in pathogenesis of AD. Positron emission tomography (PET) is a versatile tool for tracking alteration of metabolism and biometal fluxes due to brain aging and AD. Age-dependent changes in cerebral glucose metabolism can be tracked with PET using 2-deoxy-2-[18 F]-fluoro-D-glucose (18 F-FDG), a radiolabeled glucose analogue, as a radiotracer. Based on different patterns of altered cerebral glucose metabolism, 18 F-FDG PET was clinically used for differential diagnosis of AD and Frontotemporal dementia (FTD). …There are continued efforts to develop additional radiopharmaceuticals or radiotracers for assessment of age-dependent changes of various metabolic pathways and biometal fluxes due to brain aging and AD with PET. Elucidation of age-dependent changes of brain metabolism and altered biometal fluxes is not only significant for a better mechanistic understanding of brain aging and the pathophysiology of AD, but also significant for identification of new targets for the prevention, early diagnosis, and treatment of AD. Show more

Keywords: Alzheimer’s disease, metabolism, glucose metabolism, lipid metabolism, amino acid transport, protein synthesis, biometal, copper, iron, zinc, manganese, positron emission tomography, radiopharmaceuticals

DOI: 10.3233/JAD-170280

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 527-536, 2017

Authors: Mandal, Pravat K. | Shukla, Deepika | Govind, Varan | Boulard, Yves | Ersland, Lars

Article Type: Research Article

Abstract: Glutathione (GSH) is a major antioxidant in humans that is involved in the detoxification of reactive radicals and peroxides. The molecular structural conformations of GSH depend on the surrounding micro-environment, and it has been experimentally evaluated using NMR and Raman spectroscopic techniques as well as by molecular dynamics simulation studies. The converging report indicates that GSH exists mainly in two major conformations, i.e., “extended” and “folded”. The NMR-derived information on the GSH conformers is essential to obtain optimal acquisition parameters in in vivo MRS experiments targeted for GSH detection. To further investigate the implications of GSH conformers in in …vivo MRS studies and their relative proportions in healthy and pathological conditions, a multi-center clinical research study is necessary with a common protocol for GSH detection and quantification. Show more

Keywords: Antioxidant, brain, conformation, glutathione, magnetic resonance spectroscopy, molecular dynamics, nuclear magnetic resonance

DOI: 10.3233/JAD-170350

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 537-541, 2017

Authors: Trumbore, Conrad N.

Article Type: Research Article

Abstract: Liquid sheared amyloid-β (Aβ) initiates amyloid cascade reactions, producing unstable, potentially toxic oligomers. There is a need for new analytical tools with which to study these oligomers. A very small bore capillary flow system is proposed as a tool for studying the effects of liquid shear in amyloid research. This simple system consists of injecting a short cylindrical liquid sample plug containing dissolved amyloid into a liquid mobile phase flowing through an empty, very small internal diameter capillary tube. For liquid samples containing a single protein sample, under conditions in which there is laminar flow and limited sample protein molecular …diffusion, chromatograms monitoring the optical protein absorbance of capillary effluent contain either one or two peaks, depending on the mobile phase flow rate. By controlling the sample diffusion times through changes in flow rate and/or capillary diameter, this tool can be used to generate aliquot samples with precise, reproducible amounts of shear for exploring the effects of variable shear on amyloid systems. The tool can be used for producing in-capillary stopped flow spectra of shear-stressed Aβ monomers as well as for kinetic studies of Aβ dimer- and oligomer-forming reactions between shear stressed Aβ monomers. Many other experiments are suggested using this experimental tool for studying the effects of shear on different Aβ and other amyloid systems, including testing for potentially serious amyloid sampling errors in spinal tap quantitative analysis. The technique has potential as both a laboratory research and a clinical tool. Show more

Keywords: Aggregation, amyloid-β, amyloid cascade, amyloid dimer, amyloid oligomers, capillary analysis, limited diffusion, protein misfolding, spinal tap

DOI: 10.3233/JAD-170259

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 543-557, 2017

Authors: Stoccoro, Andrea | Siciliano, Gabriele | Migliore, Lucia | Coppedè, Fabio

Article Type: Short Communication

Abstract: Mitochondrial impairment is a feature of neurodegeneration and many investigators have suggested that epigenetic modifications of the mitochondrial DNA (mtDNA) might be involved in late-onset Alzheimer’s disease (LOAD), but evidence in humans is limited. We assessed the methylation levels of the mtDNA D-loop region in blood DNA from 133 LOAD patients and 130 controls, observing a significant 25% reduction of DNA methylation levels in the first group (2.3 versus 3.1%). Overall, the present data indicate that there is a decreased methylation of the D-loop region in LOAD peripheral blood DNA, suggesting that mtDNA epimutations deserve further investigations in AD pathogenesis.

Keywords: Alzheimer’s disease, D-loop region, DNA methylation, epigenetics, mitochondrial DNA, mtDNA

DOI: 10.3233/JAD-170139

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 559-564, 2017

Authors: Padala, Kalpana P. | Padala, Prasad R. | Lensing, Shelly Y. | Dennis, Richard A. | Bopp, Melinda M. | Roberson, Paula K. | Sullivan, Dennis H.

Article Type: Research Article

Abstract: Background/Objective: Balance problems are common in older adults with Alzheimer’s disease (AD). The objective was to study the effects of a Wii-Fit interactive video-game-led physical exercise program to a walking program on measures of balance in older adults with mild AD. Methods: A prospective randomized controlled parallel-group trial (Wii-Fit versus walking) was conducted in thirty community-dwelling older adults (73±6.2 years) with mild AD. Home-based exercises were performed under caregiver supervision for 8 weeks. Primary (Berg Balance Scale, BBS) and secondary outcomes (fear of falls and quality of life) were measured at baseline, 8 weeks (end of intervention), and …16 weeks (8-weeks post-intervention). Results: At 8 weeks, there was a significantly greater improvement (average inter-group difference [95% CI]) in the Wii-Fit group compared to the walking group in BBS (4.8 [3.3–6.2], p  < 0.001), after adjusting for baseline. This improvement was sustained at 16 weeks (3.5 [2.0–5.0], p  < 0.001). Analyses of the secondary outcome measures indicated that there was a significantly greater improvement in the Wii-Fit group compared to walking group in Activity-specific Balance Confidence scale (6.5 [3.6–9.4], p  < 0.001) and Falls Efficacy Scale (–4.8 [–7.6 to –2.0], p  = 0.002) at 8 weeks. However, this effect was not sustained at 16 weeks. Quality of life improved in both groups at 8 weeks; however, there were no inter-group differences (p  = 0.445). Conclusion: Home-based, caregiver-supervised Wii-Fit exercises improve balance and may reduce fear of falling in community-dwelling older adults with mild AD. Show more

Keywords: Alzheimer’s disease, balance, fear of falling, older adults

DOI: 10.3233/JAD-170120

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 565-574, 2017

Authors: Adegoke, Oludotun O. | Qiao, Fangfang | Liu, Yanying | Longley, Kirsty | Feng, Shelley | Wang, Hongmin

Article Type: Research Article

Abstract: Ubiquilin-1 (Ubqln1) is a ubiquitin-like protein that has been implicated in Alzheimer’s disease (AD). However, whether Ubqln1 modulates learning and memory and alters AD-like behavior and/or pathology has not been determined in animal models. To understand the function of Ubqln1 in vivo , we previously generated Ubqln1 transgenic (TG) mice that overexpress mouse Ubqln1. With the model, we here characterized the TG mouse cognitive behaviors and found that Ubqln1 TG mice showed better spatial learning and memory capabilities than their wild-type littermates in both radial arm water maze and Y-maze tests. Additionally, we crossed the Ubqln1 TG mice with the …AβPPswe/PSEN1dE9 double transgenic AD mouse to generate the AD/Ubqln1 triple TG (AD/TG) mice. Our results suggest that at 12 months of age following the onset of AD, AD/TG mice showed better spatial learning and memory than AD mice. AD/TG mice also exhibited better motor function than AD mice at the same age. Furthermore, compared to AD mice, AD/TG mice showed significant reduction in amyloid-β 40 (Aβ40 ) and Aβ42 levels in the cerebral cortex and in the hippocampus at the post-onset stage. The number of Aβ plaques was significantly decreased in the cerebral cortex of AD/TG mice at this post-onset stage. Moreover, mature AβPP level in AD/TG hippocampus was lower than that in AD hippocampus. These data not only provide a direct link between overexpression of Ubqln1 and altered learning and memory, but also raise the possibility that Ubqln1 is a potential therapeutic target for treating AD and possibly other neurodegenerative disorders. Show more

Keywords: Alzheimer’s disease, amyloid-β, learning and memory, plaques, ubiquilin-1

DOI: 10.3233/JAD-170173

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 575-590, 2017

Authors: Zhang, Zhong-Hao | Wu, Qiu-Yan | Chen, Chen | Zheng, Rui | Chen, Yao | Liu, Qiong | Ni, Jia-Zuan | Song, Guo-Li

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a complex and progressive neurological disorder, and amyloid-β (Aβ) has been recognized as the major cause of AD. Inhibiting Aβ production and/or enhancing the clearance of Aβ to reduce its levels are still the effective therapeutic strategies pursued in anti-AD research. In previous studies, we have reported that selenomethionine (Se-Met), a major form of selenium in animals and humans with significant antioxidant capacity, can reduce both amyloid-β (Aβ) deposition and tau hyperphosphorylation in a triple transgenic mouse model of AD. In this study, a Se-Met treatment significantly decreased the Aβ levels in Neuron-2a/AβPPswe (N2asw) cells, and …the anti-amyloid effect of Se-Met was attributed to its ability to inhibit Aβ generation by suppressing the activity of BACE1. Furthermore, both the LC3-II/LC3-I ratio and the number of LC3-positive puncta were significantly decreased in Se-Met-treated cells, suggesting that Se-Met also promoted Aβ clearance by modulating the autophagy pathway. Subsequently, Se-Met inhibited the initiation of autophagy through the AKT-mTOR-p70S6K signaling pathway and enhanced autophagic turnover by promoting autophagosome-lysosome fusion and autophagic clearance. Our results further highlight the potential therapeutic effects of Se-Met on AD. Show more

Keywords: Alzheimer’s disease, amyloid-β pathology, autophagy, clearance, selenomethionine

DOI: 10.3233/JAD-170216

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 591-602, 2017

Authors: Iaccarino, Leonardo | Chiotis, Konstantinos | Alongi, Pierpaolo | Almkvist, Ove | Wall, Anders | Cerami, Chiara | Bettinardi, Valentino | Gianolli, Luigi | Nordberg, Agneta | Perani, Daniela

Article Type: Research Article

Abstract: Assessments of brain glucose metabolism (18 F-FDG-PET) and cerebral amyloid burden (11 C-PiB-PET) in mild cognitive impairment (MCI) have shown highly variable performances when adopted to predict progression to dementia due to Alzheimer’s disease (ADD). This study investigates, in a clinical setting, the separate and combined values of 18 F-FDG-PET and 11 C-PiB-PET in ADD conversion prediction with optimized data analysis procedures. Respectively, we investigate the accuracy of an optimized SPM analysis for 18 F-FDG-PET and of standardized uptake value ratio semiquantification for 11 C-PiB-PET in predicting ADD conversion in 30 MCI subjects (age 63.57±7.78 years). Fourteen subjects converted to …ADD during the follow-up (median 26.5 months, inter-quartile range 30 months). Receiver operating characteristic analyses showed an area under the curve (AUC) of 0.89 and of 0.81 for, respectively, 18 F-FDG-PET and 11 C-PiB-PET. 18 F-FDG-PET, compared to 11 C-PiB-PET, showed higher specificity (1.00 versus 0.62, respectively), but lower sensitivity (0.79 versus 1.00). Combining the biomarkers improved classification accuracy (AUC = 0.96). During the follow-up time, all the MCI subjects positive for both PET biomarkers converted to ADD, whereas all the subjects negative for both remained stable. The difference in survival distributions was confirmed by a log-rank test (p  = 0.002). These results indicate a very high accuracy in predicting MCI to ADD conversion of both 18 F-FDG-PET and 11 C-PiB-PET imaging, the former showing optimal performance based on the SPM optimized parametric assessment. Measures of brain glucose metabolism and amyloid load represent extremely powerful diagnostic and prognostic biomarkers with complementary roles in prodromal dementia phase, particularly when tailored to individual cases in clinical settings. Show more

Keywords: Alzheimer’s disease, 11C-PiB-PET, conversion prediction, dementia, early diagnosis, 18F-FDG-PET, mild cognitive impairment, prognosis

DOI: 10.3233/JAD-170158

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 603-614, 2017

Authors: Bellanti, Francesco | Iannelli, Giuseppina | Blonda, Maria | Tamborra, Rosanna | Villani, Rosanna | Romano, Adele | Calcagnini, Silvio | Mazzoccoli, Gianluigi | Vinciguerra, Manlio | Gaetani, Silvana | Giudetti, Anna Maria | Vendemiale, Gianluigi | Cassano, Tommaso | Serviddio, Gaetano

Article Type: Research Article

Abstract: A disruption to circadian rhythmicity and the sleep/wake cycle constitutes a major feature of Alzheimer’s disease (AD). The maintenance of circadian rhythmicity is regulated by endogenous clock genes and a number of external Zeitgebers, including light. This study investigated the light induced changes in the expression of clock genes in a triple transgenic model of AD (3×Tg-AD) and their wild type littermates (Non-Tg). Changes in gene expression were evaluated in four brain areas¾suprachiasmatic nucleus (SCN), hippocampus, frontal cortex and brainstem¾of 6- and 18-month-old Non-Tg and 3×Tg-AD mice after 12 h exposure to light or darkness. Light exposure exerted significant effects on …clock gene expression in the SCN, the site of the major circadian pacemaker. These patterns of expression were disrupted in 3×Tg-AD and in 18-month-old compared with 6-month-old Non-Tg mice. In other brain areas, age rather than genotype affected gene expression; the effect of genotype was observed on hippocampal Sirt1 expression, while it modified the expression of genes regulating the negative feedback loop as well as Ror α, Csnk1 ɛ and Sirt1 in the brainstem. In conclusion, during the early development of AD, there is a disruption to the normal expression of genes regulating circadian function after exposure to light, particularly in the SCN but also in extra-hypothalamic brain areas supporting circadian regulation, suggesting a severe impairment of functioning of the clock gene pathway. Even though this study did not demonstrate a direct association between these alterations in clock gene expression among brain areas with the cognitive impairments and chrono-disruption that characterize the early onset of AD, our novel results encourage further investigation aimed at testing this hypothesis. Show more

Keywords: Aging, Alzheimer’s disease, clock genes, light exposure, suprachiasmatic nucleus

DOI: 10.3233/JAD-160942

Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 615-631, 2017