Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Pepperberg, David R.

Article Type: Research Article

Abstract: Cerebral hypoperfusion-induced hypoxia, a condition that impairs oxygen utilization and thus ATP production by mitochondrial oxidative phosphorylation (oxphos), is thought to contribute to neural degeneration in Alzheimer’s disease. However, hypoxia upregulates the generation of amyloid-β (Aβ), a group of peptides known to impair/inhibit the electron transport chain (ETC) of reactions that support oxphos in the inner mitochondrial membrane (IMM). This is a hypothesis paper that reconciles the hypoxia-induced upregulation of Aβ with Aβ’s ETC-inhibiting action and, specifically, posits an oxphos-enhancing effect of this inhibition under conditions of newly developing or otherwise mild hypoxia. This effect is typically transient; that is, …under conditions of prolonged or severe hypoxia, the oxphos-enhancing activity is overwhelmed by Aβ’s well-known toxic actions on mitochondria and other cellular components. The hypothesis is motivated by evidence that the IMM transmembrane potential Ψ m , an important determinant of ETC activity, exhibits heterogeneity, i.e., a range of values, among a given local population of mitochondria. It specifically proposes that during oxygen limitation, Aβ selectively inactivates ETC complexes in mitochondria that exhibit relatively low absolute values of Ψ m , thereby suppressing oxygen binding and consumption by complex IV of the ETC in these mitochondria. This effect of Aβ on low-Ψ m mitochondria is hypothesized to spare hypoxia-limited oxygen for oxphos-enabling utilization by the ETC of the remaining active, higher-Ψ m local mitochondria, and thereby to increase overall ATP generated collectively by the local mitochondrial population, i.e., to ameliorate hypoxia-induced oxphos reduction. The protective action of Aβ hypothesized here may slow the early development of hypoxia-associated cellular deterioration/loss in Alzheimer’s disease and perhaps other neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, amyloid-β, hypoxia, mitochondrial transmembrane potential, neurodegeneration, oxidative phosphorylation

DOI: 10.3233/JAD-190476

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Nitzan, Keren | Benhamron, Sandrine | Valitsky, Michael | Kesner, Eyal | Lichtenstein, Michal | Ben-Zvi, Ayal | Ella, Ezra | Segalstein, Yehudit | Saada, Ann | Lorberboum-Galski, Haya | Rosenmann, Hanna

Article Type: Research Article

Abstract: Pathogenesis of neurodegenerative diseases involves dysfunction of mitochondria, one of the most important cell organelles in the brain, with its most prominent roles in producing energy and regulating cellular metabolism. Here we investigated the effect of transferring active intact mitochondria as a potential therapy for Alzheimer’s disease (AD), in order to correct as many mitochondrial functions as possible, rather than a mono-drug related therapy. For this purpose, AD-mice (amyloid-β intracerebroventricularly injected) were treated intravenously (IV) with fresh human isolated mitochondria. One to two weeks later, a significantly better cognitive performance was noticed in the mitochondria treated AD-mice relative to vehicle …treated AD-mice, approaching the performance of non-AD mice. We also detected a significant decrease in neuronal loss and reduced gliosis in the hippocampus of treated mice relative to untreated AD-mice. An amelioration of the mitochondrial dysfunction in brain was noticed by the increase of citrate-synthase and cytochrome c oxidase activities relative to untreated AD-mice, reaching activity levels of non-AD-mice. Increased mitochondrial activity was also detected in the liver of mitochondria treated mice. No treatment-related toxicity was noted. Thus, IV mitochondrial transfer may possibly offer a novel therapeutic approach for AD. Show more

Keywords: Alzheimer’s disease, amyloid-ICV model, cognition, mitochondria, mitochondrial-transfer

DOI: 10.3233/JAD-190853

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2019

Authors: Castellani, Rudy J. | Smith, Margaret | Bailey, Kristi | Perry, George | deJong, Joyce L.

Article Type: Research Article

Abstract: Traumatic brain injury (TBI) is widely assumed to be causal in neurodegenerative disease, based on epidemiological surveys demonstrating an increased risk of Alzheimer disease (AD) following TBI, and on recent theories surrounding repetitive head movement. We tested this assumption by evaluating 30 consecutive forensic examinations in which neuropathology consultation was sought, and in which a history of remote TBI was uncovered during the course of the investigation. In this series, there was a high frequency of psychiatric co-morbidities (100%), remote contusion (90%), and seizures (63%). Extent of proteinopathy showed no differences with age-matched controls. A subset of the cases showed …focal geographic tauopathy that correlated with older age at autopsy, but had no correlation with clinical signs, and was minimal in comparison with the encephalomalacia secondary to trauma. The results suggest that cerebral contusion and post-traumatic epilepsy may be over-represented in civilian TBI, while structural brain damage from trauma is the predominant cause of morbidity following TBI. We found no evidence that TBI initiates a progressive proteinopathy. Show more

Keywords: Amyloid-β, contusion, epilepsy, neurodegenerative disease, phosphorylated tau, traumatic brain injury

DOI: 10.3233/JAD-190782

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Elshatoury, Heba | Avots, Egils | Anbarjafari, Gholamreza | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: In this research work, machine learning techniques are used to classify magnetic resonance imaging brain scans of people with Alzheimer’s disease. This work deals with binary classification between Alzheimer’s disease and cognitively normal. Supervised learning algorithms were used to train classifiers in which the accuracies are being compared. The database used is from The Alzheimer’s Disease Neuroimaging Initiative (ADNI). Histogram is used for all slices of all images. Based on the highest performance, specific slices were selected for further examination. Majority voting and weighted voting is applied in which the accuracy is calculated and the best result is 69.5% for …majority voting. Show more

Keywords: Alzheimer’s disease, computer vision, feature extraction, individual grey matter, machine learning, magnetic resonance imaging

DOI: 10.3233/JAD-190704

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Seblova, Dominika | Brayne, Carol | Machů, Vendula | Kuklová, Marie | Kopecek, Miloslav | Cermakova, Pavla

Article Type: Research Article

Abstract: Background: Studies from North America and Western Europe suggest stable or declining trends in impaired cognition across birth cohorts. Objective: We aimed to examine changes in the age-specific prevalence of cognitive impairment in the Czech Republic. Methods: The study used two samples from the population-based Czech Survey on Health, Ageing and Retirement in Europe. Age-specific prevalence of cognitive impairment (defined based on scores in verbal fluency, immediate recall, delayed recall, and temporal orientation) was compared between participants in wave 2 (2006/2007; n  = 1,107) and wave 6 (2015; n  = 3,104). Logistic regression was used to estimate the …association between the wave and cognitive impairment, step-wise adjusting for sociodemographic and clinical characteristics. Multiple sensitivity analyses, focusing on alternative operationalizations of relative cognitive impairment, impact of missing cognitive data, and survival bias, were carried out. Results: The most conservative estimate suggested that the age-specific prevalence of cognitive impairment declined by one fifth, from 11% in 2006/2007 to 9% in 2015. Decline was observed in all sensitivity analyses. The change was associated with differences in physical inactivity, management of high blood cholesterol, and increases in length education. Conclusion: Older adults in the Czech Republic, a country situated in the Central and Eastern European region, have achieved positive developments in cognitive aging. Longer education, better management of cardiovascular factors, and reduced physical inactivity seem to be of key importance. Show more

Keywords: Cognitive impairment, Czech Republic, epidemiology, prevalence, trends

DOI: 10.3233/JAD-190688

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Turriziani, Patrizia | Smirni, Daniela | Mangano, Giuseppa Renata | Zappalà, Giuseppe | Giustiniani, Andreina | Cipolotti, Lisa | Oliveri, Massimiliano

Article Type: Research Article

Abstract: Background: The lack of effective pharmacological or behavioral interventions for memory impairments associated with Alzheimer’s disease (AD) emphasizes the need for the investigation of approaches based on neuromodulation. Objective: This study examined the effects of inhibitory repetitive transcranial magnetic stimulation (rTMS) of prefrontal cortex on recognition memory in AD patients. Methods: In a first experiment, 24 mild AD patients received sham and real 1Hz rTMS over the left and right dorsolateral prefrontal cortex (DLPFC), in different sessions, between encoding and retrieval phases of a non-verbal recognition memory task. In a second experiment, another group of 14 …AD patients underwent sham controlled repeated sessions of 1Hz rTMS of the right DLPFC across a two week treatment. Non-verbal recognition memory task was performed at baseline, at the end of the two weeks period and at a follow up of 1 month. Results: Right real rTMS significantly improved memory performance compared to right sham rTMS (p  = 0.001). Left real rTMS left the memory performance unchanged as compared with left sham rTMS (p  = 0.46). The two sham conditions did not differ between each other (p  = 0.24). In the second experiment, AD patients treated with real rTMS showed an improvement of memory performance at the end of the two weeks treatment (p  = 0.0009), that persisted at 1-month follow-up (p  = 0.002). Conclusion: These findings provide evidence that inhibitory rTMS over the right DLPFC can improve recognition memory function in AD patients. They also suggest the importance of a new approach of non-invasive brain stimulation as a promising treatment in AD. Show more

Keywords: Alzheimer’s disease, prefrontal cortex, recognition memory, repetitive transcranial magnetic stimulation

DOI: 10.3233/JAD-190888

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: D’Cunha, Nathan M. | McKune, Andrew J. | Isbel, Stephen | Kellett, Jane | Georgousopoulou, Ekavi N. | Naumovski, Nenad

Article Type: Research Article

Abstract: The use of existing public spaces by people living with dementia, such as museums and art galleries, are becoming popular due to their ability to facilitate programs which promote social engagement and inclusion. However, few studies have investigated physiological outcomes of art gallery-based programs. Using a quasi-experimental design, the present study aimed to investigate the levels of salivary biomarkers of cortisol and interleukin-6, quality of life (QoL), depressive symptoms, cognition, and wellbeing, after attending the National Gallery of Australia (NGA) Art and Dementia program. Twenty-eight people living with dementia, each supported by a carer or family member, were recruited for …a six-week program and were followed up at twelve weeks. In total, 25 participants (17 female; mean age 84.6±7.27 years) completed the study, and 22 provided viable saliva samples. The waking to evening salivary cortisol ratio was higher post-intervention (p  = 0.033), and returned to baseline levels at follow-up (p  = 1.00), indicating a more dynamic salivary cortisol rhythm in response to the six-week program. Interleukin-6 levels remained unchanged (p  = 0.664). No improvements in QoL (DEMQOL-Carer) were observed between baseline and post-intervention (p  = 0.076). However, self-reported depressive symptoms decreased post-intervention compared with baseline (p  = 0.015), and memory (immediate recall) (p  = 0.009) and verbal fluency (p  = 0.027) improved between the same timepoints. The NGA Art and Dementia program appears to have quantifiable benefits, including improved hypothalamic-pituitary-adrenal axis function, justifying a need for longer controlled trial inclusive of physiological outcomes. Show more

Keywords: Alzheimer’s disease, art, cognitive function, cortisol, dementia, psychophysiology, quality of life

DOI: 10.3233/JAD-190784

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Orgeta, Vasiliki | Tuijt, Remco | Leung, Phuong | Verdaguer, Elisabet Sole | Gould, Rebecca L. | Jones, Rebecca | Livingston, Gill

Article Type: Research Article

Abstract: Engaging in meaningful and enjoyable activities is an important contributor to well-being and maintaining good quality of life. There is a paucity of randomized controlled trials of interventions supporting people with mild dementia to engage in meaningful and purposeful activity. The aim of this study was to assess whether Behavioral Activation (BA) is an acceptable psychological intervention for people with mild dementia and whether a large-scale trial is feasible. Participants were randomly assigned to BA (n  = 42) or treatment as usual (TAU) (n  = 21). BA aimed at increasing engagement in enjoyable and meaningful activity, and preventing low mood. Follow-up was …at 3 and 6 months. Assessors were blind to treatment allocation (trial registration number: ISRCTN75503960). Retention rate was above 80% at both assessment time points. Treatment acceptability and credibility were high. Depressive symptoms remained unchanged in both groups. There was evidence of improvement associated with BA for every day function (–3.92, 95% Confidence Interval (CI) –6.87 to –0.97), and engagement in meaningful and enjoyable activity (5.08, 95% CI 0.99 to 9.16) post-treatment (3 months) in comparison to TAU. Both carer-rated patient health-related quality of life (0.16, 95% CI 0.04 to 0.28) and physical health (11.31, 95% CI 2.03 to 20.59) showed evidence of improvement at 3 months. Improvements in meaningful and enjoyable activity were maintained at 6 months. BA for people with mild dementia is feasible and acceptable and may be associated with clinically significant changes in function and quality of life. A full scale randomized controlled trial of clinical effectiveness is now needed. Show more

Keywords: Acceptability, activity scheduling, behavioral activation, behavioral therapy, dementia, feasibility, low mood, pleasant events, randomized controlled trial

DOI: 10.3233/JAD-190696

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: van Husen, Lea S. | Schedin-Weiss, Sophia | Trung, Minh Nguyen | Kazmi, Manija | Winblad, Bengt | Sakmar, Thomas P. | Elsässer, Simon J. | Tjernberg, Lars O.

Article Type: Research Article

Abstract: The amyloid-β protein precursor (AβPP) is critical in the pathophysiology of Alzheimer’s disease (AD), since two-step proteolytic processing of AβPP generates the neurotoxic amyloid-β peptide (Aβ). We developed a dual fluorescence labeling system to study the exact subcellular location of γ -secretase cleavage of AβPP. The C-terminal tail of AβPP was fluorescently labeled using a SNAP-tag, while the Aβ region of AβPP was fluorescently tagged with a dye at a genetically-encoded noncanonical amino acid (ncAA). The ncAA was introduced at specific positions in AβPP using a genetic code expansion strategy and afterwards, the reactive side-chain of the ncAA was coupled …to the dye using a bioorthogonal labeling chemistry. In proof-of-concept experiments, HEK293T cells were transfected with plasmids containing engineered AβPP harboring an amber mutation and an amber codon suppression system with an evolved tRNA synthetase/tRNA pair and grown in the presence of a lysine-derived ncAA. Processing of the AβPP variants was validated with ELISA and immunoblotting, and seven AβPP mutants that showed similar cleavage pattern as wild-type AβPP were identified. The AβPP mutant was fluorescently labeled with 6-methyl-tetrazine-BDP-FL and TMR-Star at the ncAA and SNAP-tag, respectively. Using this approach, AβPP was fluorescently labeled at two sites in living cells with minimal background to allow monitoring of Aβ and C-terminal cleavage products simultaneously. The method described provides a powerful tool to label Aβ with minimal perturbations of its processing, thus enabling studies of the trafficking of the cleavage products of AβPP. Show more

Keywords: Alzheimer’s disease, amber codon, amyloid-β precursor protein, cell biology, click chemistry, confocal microscopy, γ-secretase

DOI: 10.3233/JAD-190898

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Aulston, Brent | Liu, Qing | Mante, Michael | Florio, Jazmin | Rissman, Robert A. | Yuan, Shauna H.

Article Type: Research Article

Abstract: Extracellular vesicles (EVs) are a heterogeneous group of secreted particles consisting of microvesicles, which are released by budding of the cellular membrane, and exosomes, which are secreted through exocytosis from multivesicular bodies. EV cargo consists of a wide range of proteins and nucleic acids that can be transferred between cells. Importantly, EVs may be pathogenically involved in neurodegenerative diseases such as Alzheimer’s disease (AD). While EVs derived from AD neurons have been found to be neurotoxic in vitro , little is known about the pathological consequences of AD EVs in vivo . Furthermore, although all known familial AD (fAD) mutations …involve either amyloid-β protein precursor (AβPP) or the machinery that processes AβPP, hyperphosphorylation of the microtubule associated protein tau appears to play a critical role in fAD-associated neurodegeneration, and previous reports suggest EVs may propagate tau pathology in the AD brain. Therefore, we hypothesized that fAD EVs may have a mechanistic involvement in the development of fAD-associated tau pathology. To test this, we isolated EVs from iPSC-derived neuronal cultures generated from an fAD patient harboring a A246E mutation to presenilin-1 and stereotactically injected these EVs into the hippocampi of wild-type C57BL/6 mice. Five weeks after injection, mice were euthanized and pathology evaluated. Mice injected with fAD EVs displayed increased tau phosphorylation at multiple sites relative to PBS and non-disease control EV injected groups. Moreover, fAD EV injected hippocampi contained significantly more tau inclusions in the CA1 hippocampal neuronal field than controls. In total, these findings identify EVs as a potential mediator of fAD-associated tau dysregulation and warrant future studies to investigate the therapeutic potential of EV-targeted treatments for fAD. Show more

Keywords: Alzheimer’s disease, C57BL/6, extracellular vesicles induced pluripotent stem cells, tau, tauopathy

DOI: 10.3233/JAD-190656

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019