Journal of Alzheimer's Disease - Volume 54, issue 1

Authors: Calvo-Rodríguez, María | García-Durillo, Mónica | Villalobos, Carlos | Núñez, Lucía

Article Type: Research Article

Abstract: The most important risk factor for Alzheimer’s disease (AD) is aging. Neurotoxicity in AD has been linked to dyshomeostasis of intracellular Ca2+ induced by small aggregates of the amyloid-β peptide 1-42 (Aβ42 oligomers). However, how aging influences susceptibility to neurotoxicity induced by Aβ42 oligomers is unknown. In this study, we used long-term cultures of rat hippocampal neurons, a model of neuronal in vitro aging, to investigate the contribution of aging to Ca2+ dishomeostasis and neuron cell death induced by Aβ42 oligomers. In addition, we tested whether non-steroidal anti-inflammatory drugs (NSAIDs) and R-flurbiprofen prevent apoptosis …acting on subcellular Ca2+ in aged neurons. We found that Aβ42 oligomers have no effect on young hippocampal neurons cultured for 2 days in vitro (2 DIV). However, they promoted apoptosis modestly in mature neurons (8 DIV) and these effects increased dramatically after 13 DIV, when neurons display many hallmarks of in vivo aging. Consistently, cytosolic and mitochondrial Ca2+ responses induced by Aβ42 oligomers increased dramatically with culture age. At low concentrations, NSAIDs and the enantiomer R-flurbiprofen lacking anti-inflammatory activity prevent Ca2+ overload and neuron cell death induced by Aβ42 oligomers in aged neurons. However, at high concentrations R-flurbiprofen induces apoptosis. Thus, Aβ42 oligomers promote Ca2+ overload and neuron cell death only in aged rat hippocampal neurons. These effects are prevented by low concentrations of NSAIDs and R-flurbiprofen acting on mitochondrial Ca2+ overload. Show more

Keywords: Aβ42 oligomers, aging, Alzheimer’s disease, calcium, hippocampal neurons, mitochondria, non-steroidal anti-inflammatory drugs, NSAIDs, R-flurbiprofen

DOI: 10.3233/JAD-151189

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 207-221, 2016

Authors: Malpas, Charles B. | Vivash, Lucy | Genc, Sila | Saling, Michael M. | Desmond, Patricia | Steward, Christopher | Hicks, Rodney J. | Callahan, Jason | Brodtmann, Amy | Collins, Steven | Macfarlane, Stephen | Corcoran, Niall M. | Hovens, Christopher M. | Velakoulis, Dennis | O’Brien, Terence J.

Article Type: Research Article

Abstract: Background: There is increasing interest in targeting hyperphosphorylated tau (h-tau) as a disease modifying approach for Alzheimer’s disease (AD). Sodium selenate directly stimulates the activity of PP2A, the main enzyme responsible for h-tau dephosphorylation in the brain. Objective: This study assessed the safety and tolerability of 24-week treatment with VEL015 (sodium selenate) in AD. Investigating the effects of VEL015 on cognitive, CSF, and neuroimaging biomarkers of AD were secondary, exploratory objectives. Data were used to identify biomarkers showing most promise for use in subsequent efficacy trials. Methods: A 24-week, multicenter, Phase IIa, double-blinded randomized controlled …trial. Forty patients aged ≥55 y with mild-moderate AD (MMSE 14–26) were randomized to supranutritional (VEL015 10 mg tds [n  = 20]) and control (VEL015 320μg tds [n  = 10] or placebo [n  = 10]) groups. Patients were regularly monitored for safety, adverse events (AEs), and protocol compliance. Exploratory biomarkers included cognitive tests, neuroimaging (diffusion MR), and CSF (p-tau, t-tau, and Aβ1-42 ). Results: Thirty-six (90%; [supranutritional n  = 18, control/placebo n  = 18]) patients completed the trial. There were no differences in the incidence of specific AEs between groups. Only one secondary biomarker, diffusion MR measures, showed group differences, with less deterioration in the supranutritional group (p  < 0.05). Conclusion: Treatment with VEL015 at doses up to 30 mg per day for 24 weeks was safe and well-tolerated in patients with AD. Diffusion MR measures appear to be the most sensitive biomarkers to assess disease progression over 24 weeks. Show more

Keywords: Alzheimer’s disease, clinical trial, dementia, sodium selenate

DOI: 10.3233/JAD-160544

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 223-232, 2016

Authors: Ettcheto, Miren | Petrov, Dmitry | Pedrós, Ignacio | Alva, Norma | Carbonell, Teresa | Beas-Zarate, Carlos | Pallas, Merce | Auladell, Carme | Folch, Jaume | Camins, Antoni

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is currently an incurable aging-related neurodegenerative disorder. Recent studies give support to the hypotheses that AD should be considered as a metabolic disease. The present study aimed to explore the relationship between hippocampal neuropathological amyloid-β (Aβ) plaque formation and obesity at an early presymptomatic disease stage (3 months of age). For this purpose, we used APPswe/PS1dE9 (APP/PS1) transgenic mice, fed with a high-fat diet (HFD) in order to investigate the potential molecular mechanisms involved in both disorders. The results showed that the hippocampus from APP/PS1 mice fed with a HFD had an early significant decrease in Aβ …signaling pathway specifically in the insulin degrading enzyme protein levels, an enzyme involved in (Aβ) metabolism, and α -secretase. These changes were accompanied by a significant increase in the occurrence of plaques in the hippocampus of these mice. Furthermore, APP/PS1 mice showed a significant hippocampal decrease in PGC-1α levels, a cofactor involved in mitochondrial biogenesis. However, HFD does not provoke changes in neither insulin receptors gene expression nor enzymes involved in the signaling pathway. Moreover, there are no changes in any enzymes (kinases) involved in tau phosphorylation, such as CDK5, and neither in brain oxidative stress production. These results suggest that early changes in brains of APP/PS1 mice fed with a HFD are mediated by an increase in Aβ1 ‒ 42 , which induces a decrease in PKA levels and alterations in the p-CREB/ NMDA2B /PGC1-α pathway, favoring early AD neuropathology in mice. Show more

Keywords: Alzheimer’s disease, APPSwe/PS1dE9, hippocampus, insulin receptor, mitochondria, tau

DOI: 10.3233/JAD-160150

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 233-251, 2016

Authors: Middelstädt, Jennifer | Folkerts, Ann-Kristin | Blawath, Sabrina | Kalbe, Elke

Article Type: Research Article

Abstract: Background: Increasing evidence demonstrates the efficacy of cognitive stimulation (CS) in individuals with dementia. However, conducting studies in nursing homes engenders specific challenges that have limited the data gathered on this topic so far. Objective: The aim of this randomized controlled trial was to investigate the effects of CS on cognition, quality of life (QoL), behavioral symptoms, and activities of daily life in persons with dementia living in nursing homes. We further aimed to identify predictors of the intervention’s benefits. Methods: Seventy-one persons with mild to moderate dementia were randomly allocated to the experimental group …(EG; n  = 36) that visited a CS program twice weekly for eight weeks or to the control group (CG; n  = 35) that was receiving usual care. Neuropsychological tests were conducted before and after the intervention period and at six-week follow-up. Results: There were no significant interaction effects Time×Group for the outcome measures. However, regression analysis revealed that a low cognitive baseline level predicted cognitive improvements. Furthermore, a low baseline level of QoL predicted a QoL benefit. For both findings, depression was a significant moderator, meaning that persons with fewer depressive symptoms had a higher probability of showing improvements. Conclusion: This study provides data on profiles of patients who are most likely to profit from CS intervention in nursing-home settings and demonstrates that treatment of depression is of the utmost relevance for a positive outcome of CS. Living conditions will have to be considered more thoroughly in future research. Show more

Keywords: Cognitive stimulation, dementia, depression, intervention, nursing homes, quality of life

DOI: 10.3233/JAD-160181

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 253-268, 2016

Authors: Honda, Kazuhiro

Article Type: Research Article

Abstract: Background: An impairment of amyloid-β (Aβ) clearance has been suggested in Alzheimer’s disease. Perivascular drainage along cerebrovascular vessels is considered an important amyloid clearance pathway. Objective: This study examined the effect of reduced arterial pulsation that could cause an impairment in cerebral amyloid drainage on the prevalence of cortical microbleeds (CMBs), a surrogate marker for cerebral amyloid angiopathy (CAA). Methods: Patients who lost depiction of either side of the carotid artery or the middle cerebral artery on magnetic resonance angiography were studied. Those who showed acute cerebral infarction or a previous cortical cerebral infarction were …excluded. The number of CMBs was counted on the occluded and non-occluded sides of the brain in each subject. The number of subjects who showed more CMBs on the occluded side of the brain was compared with the number of subjects who showed more CMBs on the non-occluded side of the brain. Results: Twenty-eight patients were studied. The extent of lacunar infarction and white matter lesions was not different, irrespective of the occluded vessels or the distribution of CMBs. The prevalence of CMBs was not different between the occluded and non-occluded sides of the brain. Conclusion: In this cross-sectional study, reduction of arterial pulsation was not associated with a higher prevalence of CAA. Therefore, reduced arterial pulsation alone may not be enough to promote CAA. Show more

Keywords: Alzheimer’s disease, carotid occlusion, cerebral amyloid angiopathy, cortical microbleeds, perivascular drainage

DOI: 10.3233/JAD-160499

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 269-274, 2016

Authors: Wang, Hao | Wang, Ying | Hong, Xiaoyu | Li, Shuiming | Wang, Yong

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease with well-characterized pathological features. Yet the underlying mechanisms have not been resolved and an effective therapeutic approach is lacking. Cerebral hypoxia is considered a risk factor of AD. Objective: We tested whether oxygen supplementation can relieve AD symptoms and how it affects the expression levels of proteins in the lens. Methods: Triple transgenic AD model (3xTg-AD) mice were divided into oxygen treated (OT) and control (Ctrl) groups. Their cognitive performances were tested in a Morris water maze (MWM) paradigm. Then, their eye lens tissues were subjected to …quantitative proteomics analysis by the iTRAQ (isobaric tags for relative and absolute quantification) method. The up- and downregulated proteins were classified according to a Gene Ontology (GO) database in PANTHER. Behavioral and proteomic data were compared between the groups. Results: Mice in the OT group had better learning and memorizing performance compared with the Ctrl group in MWM test. Lenses from the OT group had 205 differentially regulated proteins, relative to lenses from the Ctrl group, including proteins that are involved in the clearance of amyloid β-protein. Conclusion: The results of this study indicate that oxygen treatment can improve cognitive function in AD model mice and alters protein expression in a manner consistent with improved redox regulation. Show more

Keywords: Alzheimer’s disease, iTRAQ, mass spectrometry, oxygen, proteomics, water maze

DOI: 10.3233/JAD-160263

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 275-286, 2016

Authors: van Steenoven, Inger | Aarsland, Dag | Weintraub, Daniel | Londos, Elisabet | Blanc, Frédéric | van der Flier, Wiesje M. | Teunissen, Charlotte E. | Mollenhauer, Brit | Fladby, Tormod | Kramberger, Milica G. | Bonanni, Laura | Lemstra, Afina W. | on behalf of the European DLB consortium

Article Type: Research Article

Abstract: Background: Concomitant Alzheimer’s disease (AD) pathology is observed in Lewy body diseases (LBD), but the clinical impact is unknown. Only a few biomarker studies in LBD exist and have included small cohorts from single centers. Objective: We aimed to evaluate the prevalence of abnormal cerebrospinal fluid (CSF) AD biomarkers across the spectrum of LBD in a large multicenter cohort and to assess whether an AD biomarker profile was associated with demographic and clinical differences in dementia with Lewy bodies (DLB). Methods: We included 375 DLB patients, 164 Parkinson’s disease (PD) patients without dementia, and 55 …PD patients with dementia (PDD) from 10 centers. CSF amyloid-beta42 (Aβ42 ), total tau (t-tau), and phosphorylated tau (p-tau) values were dichotomized as abnormal or normal according to locally available cut-off values. A CSF AD profile was defined as abnormal Aβ42 combined with abnormal t-tau and/or p-tau. Results: A substantial proportion of DLB patients had abnormal values for CSF Aβ42 , t-tau, and p-tau, while abnormal values were uncommon in PD without dementia. Patients with PDD had values in between. A CSF AD profile was observed in 25% of DLB patients, compared with only 9% of PDD and 3% of PD without dementia. Within DLB, patients with a CSF AD profile were older, more often female, performed worse on the Mini-Mental State Examination, and had shorter disease duration compared with patients with normal CSF. Conclusion: A CSF AD profile is more common in DLB compared with PDD and PD, and is associated with more severe cognitive impairment in DLB. Show more

Keywords: Amyloid beta-protein (1-42), biomarkers, cerebrospinal fluid, dementia with Lewy bodies, Lewy body disease, tau protein

DOI: 10.3233/JAD-160322

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 287-295, 2016

Authors: Yu, Lixia | Chen, Yuan | Wang, Weiguang | Xiao, Zhonghai | Hong, Yan

Article Type: Research Article

Abstract: Hypobaric hypoxia (HH) leads to reduced oxygen delivery to brain. It could trigger cognitive dysfunction and increase the risk of dementia including Alzheimer’s disease (AD). The present study was undertaken in order to examine whether B vitamins (B6, B12, folate, and choline) could exert protective effects on hypoxia-induced memory deficit and AD related molecular events in mice. Adult male Kunming mice were assigned to five groups: normoxic control, hypoxic model (HH), hypoxia+vitamin B6/B12/folate (HB), hypoxia+choline (HC), hypoxia+vitamin B6/B12/folate+choline (HBC). Mice in the hypoxia, HB, HC, and HBC groups were exposed to hypobaric hypoxia for 8 h/day for 28 days in a …decompression chamber mimicking 5500 meters of high altitude. Spatial and passive memories were assessed by radial arm and step-through passive test, respectively. Levels of tau and glycogen synthase kinase (GSK)-3β phosphorylation were detected by western blot. Homocysteine (Hcy) concentrations were determined using enzymatic cycling assay. Mice in the HH group exhibited significant spatial working and passive memory impairment, increased tau phosphorylation at Thr181, Ser262, Ser202/Thr205, and Ser396 in the cortex and hippocampus, and elevated Hcy levels compared with controls. Concomitantly, the levels of Ser9-phosphorylated GSK-3β were significantly decreased in brain after hypoxic treatment. Supplementations of vitamin B6/B12/folate+choline could significantly ameliorate the hypoxia-induced memory deficits, observably decreased Hcy concentrations in serum, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites through upregulating inhibitory Ser9-phosphorylated GSK-3β. Our finding give further insight into combined neuroprotective effects of vitamin B6, B12, folate, and choline on brain against hypoxia. Show more

Keywords: Homocysteine, hypoxia, memory improvement, tau phosphorylation, vitamin B

DOI: 10.3233/JAD-160329

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 297-306, 2016

Authors: Martire, Sara | Fuso, Andrea | Mosca, Luciana | Forte, Elena | Correani, Virginia | Fontana, Mario | Scarpa, Sigfrido | Maras, Bruno | d’Erme, Maria

Article Type: Research Article

Abstract: Amyloid-beta peptide accumulation in the brain is one of the main hallmarks of Alzheimer’s disease. The amyloid aggregation process is associated with the generation of free radical species responsible for mitochondrial impairment and DNA damage that in turn activates poly(ADP-ribose)polymerase 1 (PARP-1). PARP-1 catalyzes the poly(ADP-ribosylation), a post-translational modification of proteins, cleaving the substrate NAD+ and transferring the ADP-ribose moieties to the enzyme itself or to an acceptor protein to form branched polymers of ADP-ribose. In this paper, we demonstrate that a mitochondrial dysfunction occurs in Alzheimer’s transgenic mice TgCRND8, in SH-SY5Y treated with amyloid-beta and in 7PA2 cells. …Moreover, PARP-1 activation contributes to the functional energetic decline affecting cytochrome oxidase IV protein levels, oxygen consumption rates, and membrane potential, resulting in cellular bioenergetic deficit. We also observed, for the first time, an increase of pyruvate kinase 2 expression, suggesting a modulation of the glycolytic pathway by PARP-1. PARP-1 inhibitors are able to restore both mitochondrial impairment and pyruvate kinase 2 expression. The overall data here presented indicate a pivotal role for this enzyme in the bioenergetic network of neuronal cells and open new perspectives for investigating molecular mechanisms underlying energy charge decline in Alzheimer’s disease. In this scenario, PARP-1 inhibitors might represent a novel therapeutic intervention to rescue cellular energetic metabolism. Show more

Keywords: Alzheimer’s disease, bioenergetic metabolism, mitochondria, PARP-1, PKM2

DOI: 10.3233/JAD-151040

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 307-324, 2016

Authors: Roalf, David R. | Quarmley, Megan | Mechanic-Hamilton, Dawn | Wolk, David A. | Arnold, Steven E. | Moberg, Paul J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The transition from mild cognitive impairment (MCI) to Alzheimer’s disease is characterized by a decline in cognitive performance in many domains. Cognitive performance profiles in MCI are heterogeneous, however, and additional insights into markers of incipient dementia are needed. Typically, studies focus on average or mean performance, but ignore consistency of performance across domains. WIV (within-individual variability) provides an index of this consistency and is a potential marker of cognitive decline. Objective: To use neurocognitive data from the Alzheimer’s Disease Neuroimaging Initiative cohort to measure neurocognitive variability. Methods: The utility of WIV was measured, …in addition to global neurocognitive performance (GNP), for identifying AD and MCI. In addition, the association between changes in neurocognitive variability and diagnostic transition over 12 months was measured. Results: As expected, variability was higher in AD and MCI as compared to healthy controls; GNP was lower in both groups as compared to healthy subjects. Global neurocognitive performance alone best distinguished those with dementia from healthy older adults. Yet, for individuals with MCI, including variability along with GNP improved diagnostic classification. Variability was higher at baseline in individuals transitioning from MCI to AD over a 12-month period. Conclusion: We conclude that variability offers complementary information about neurocognitive performance in dementia, particularly in individuals with MCI, and may provide beneficial information about disease transition. Show more

Keywords: ADNI, Alzheimer’s disease, intra-individual variability, mild cognitive impairment, neurocognitive function

DOI: 10.3233/JAD-160259

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 325-335, 2016