Journal of Alzheimer's Disease - Volume 72, issue 2

Authors: Nie, Ran | Wu, Zhou | Ni, Junjun | Zeng, Fan | Yu, Weixian | Zhang, Yufeng | Kadowaki, Tomoko | Kashiwazaki, Haruhiko | Teeling, Jessica L. | Zhou, Yanmin

Article Type: Research Article

Abstract: Abnormal accumulation of amyloid-β (Aβ) in the brain is the most significant pathological hallmark of Alzheimer’s disease (AD). We have found that chronic systemic exposure to lipopolysaccharide of Porphyromonas gingivalis (P. gingivalis ) induces the accumulation of Aβ in the brain of middle-aged mice. On the other hand, recent research has shown that circulating Aβ is transferred into the brain; however, the involvement of chronic systemic P. gingivalis infection in the peripheral Aβ metabolism is unknown. We hypothesized that chronic P. gingivalis infection expands Aβ pools in peripheral inflammatory tissues and thereby contributes to the accumulation of …Aβ in the brain of patients with periodontitis. We showed that the increased expression of IL-1β, AβPP770 , CatB, Aβ1-42 , and Aβ3-42 was mainly co-localized with macrophages in the liver of P. gingivalis infected mice. Blocking CatB and NF-κ B significantly inhibited the P. gingivalis- induced expression of IL-1β, AβPP770 , Aβ1-42 , and Aβ3-42 in RAW264.7 cells. Aβ3-42 , but not Aβ1-42 , induced the significant death of macrophages, and the reduction of phagocytic abilities induced by Aβ3-42 tended to be higher than that induced by Aβ1-42 . Additionally, the expression of AβPP770 , CatB, Aβ1-42 , and Aβ3-42 was determined in the macrophages of gingival tissues from periodontitis patients. These findings indicate that chronic systemic P. gingivalis infection induces the Aβ accumulation in inflammatory monocytes/macrophages via the activation of CatB/NF-κ B signaling, thus suggesting monocytes/macrophages serve as a circulating pool of Aβ in patients with periodontitis. Taken together, CatB may be a novel therapeutic target for preventing the periodontitis-related AD initiation and pathological progression. Show more

Keywords: Alzheimer’s disease, Cathepsin B, interleukin 1β, monocytes/macrophages, nuclear factor-kappa B, peripheral amyloid-β, Porphyromonas gingivalis infection, systemic inflammation

DOI: 10.3233/JAD-190298

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 479-494, 2019

Authors: Vonk, Jet M.J. | Arce Rentería, Miguel | Medina, Valerie M. | Pericak-Vance, Margaret A. | Byrd, Goldie S. | Haines, Jonathan | Brickman, Adam M. | Manly, Jennifer J.

Article Type: Research Article

Abstract: Background: The APOE ɛ 4 allele is a well-known risk factor for Alzheimer’s disease (AD). Previous research argues that higher education helps to preserve cognition in older adults with AD pathology because of its key role in cognitive reserve and resilience. Objective: To test if higher educational level buffers the effect of APOE ɛ 4 on cognition among older non-Hispanic Blacks. Methods: Participants were 849 non-demented older non-Hispanic Blacks (38.3% APOE ɛ 4 +), who underwent a comprehensive neuropsychological evaluation. Multiple linear regression models tested the relationship between APOE ɛ …4 status and twelve cognitive measures with education (up to high school and beyond high school) as a moderator. Results: Education buffered the effects of the APOE ɛ 4 allele, such that there was no impact of APOE ɛ 4 status on word-list memory retention and working memory among participants with more than a high school degree. This pattern was not observed for ten other cognitive measures of verbal and visual episodic memory, semantic memory, executive function, and processing speed—although a similar trend was observed for switching ability in executive functioning. The buffering effect of education was stronger among women than men. Conclusion: Our findings suggest that genetic effects on late-life cognition may be modified by environmental factors such as educational attainment. These results are consistent with the framework of cognitive reserve such that engaging in cognitively enriching activities and acquiring skills and knowledge with more years of education may increase the capacity to maintain cognitive function despite high genetic risk for impairment. Show more

Keywords: African American, Alzheimer’s disease, APOE, cognitive reserve, educational attainment, episodic memory, genetic risk, neuropsychological evaluation

DOI: 10.3233/JAD-190415

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 495-506, 2019

Authors: Goldstein, Felicia C. | Loring, David W. | Thomas, Tiffany | Saleh, Sabria | Hajjar, Ihab

Article Type: Research Article

Abstract: Background: The utility of recognition memory for identifying persons with biomarker evidence of Alzheimer’s disease (AD) is unclear since prior studies of mild cognitive impairment (MCI) relied only on clinical diagnosis and did not include simultaneous measures of central amyloidosis and tauopathy. Objective: We evaluated whether recognition memory and associated indices, including discriminability and response bias from signal detection theory, differentiate persons with amnestic MCI (aMCI) due to prodromal AD from non-prodromal AD. Method: Sixty older adults with aMCI were classified as prodromal AD (n  = 28) or non-prodromal AD (n  = 32) based upon cerebrospinal fluid levels …of amyloid-β and tau. Memory was assessed using the Hopkins Verbal Learning Test-Revised which includes free recall and recognition. Results: ANCOVAs adjusting for age indicated comparable (all p  > 0.05) performances between prodromal and non-prodromal MCI groups respectively on traditional HVLT-R recognition measures of hits (mean±SD: 9.5±3.0 versus 10.9±1.7), false alarms (1.8±1.8 versus 1.5±1.5), and hits minus false alarms (7.7±3.0 versus 9.2±2.6). In contrast, discriminability (d’), which reflects how easily targets and distractors are distinguished, was significantly (p  = 0.009) poorer in the prodromal versus non-prodromal groups (3.1±1.9 versus 4.8±2.0, effect size = 0.87). In addition, only d’ significantly predicted group membership (OR = 0.66, CI = 0.48–0.92, p  = 0.04). Response bias, the tendency to report that a target did or did not appear, was comparable between groups (0.08±1.1 versus –0.04±1.3). Conclusion: Recognition discriminability is significantly poorer in aMCI with biomarker evidence of prodromal AD. In contrast to traditional recognition indices, discriminability from signal detection theory may be superior in identifying aMCI due to AD versus non-AD etiologies. Show more

Keywords: Alzheimer’s disease, amyloid-β , amyloidosis, biomarkers, mild cognitive impairment, prodromal Alzheimer’s disease, recognition memory, signal detection, tau

DOI: 10.3233/JAD-190468

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 507-514, 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. 72, no. 2, pp. 515-524, 2019

Authors: Kehoe, Patrick G. | Al Mulhim, Noura | Zetterberg, Henrik | Blennow, Kaj | Miners, James S.

Article Type: Research Article

Abstract: Observations in autopsied brain tissue indicate that overactivation of the classical renin-angiotensin system (cRAS) and underactivity within regulatory RAS pathways (rRAS) are associated with pathology in Alzheimer’s disease (AD). The primary aim of this study was to investigate whether cerebrospinal fluid (CSF) markers of RAS are altered in AD in relation to established CSF markers of disease pathology (lower Aβ42 and elevated tau) and CSF markers of capillary dysfunction. We studied 40 controls and 40 AD cases grouped according to a biomarker profile (i.e., AD cases t-tau>400 pg/mL, pTau >60 pg/mL, and Aβ42 <550 pg/mL). Angiotensin-II converting enyme-1 …(ACE1) and ACE2 enzyme activity was measured using fluorogenic peptide substrates; sPDGFRβ and albumin level by sandwich ELISA; and angiotensin-I (Ang-I), Ang-II, and Ang-(1-7) by direct ELISA. CSF Aβ42 , total, and phosphorylated tau levels were previously measured by INNOTEST sandwich ELISA. CSF ACE1 activity was significantly elevated in AD (p  = 0.008) and positively correlated with ACE2 in AD (r  = 0.420, p  = 0.007). CSF ACE1 weakly correlated with t-tau (r  = 0.294, p  = 0.066) and p-tau (r  = 0.329, p  = 0.038) but not with Aβ42 in the controls but not in AD. ACE1 correlated positively with sPDGFRβ (r  = 0.426, p  = 0.007), a marker of pericyte injury, and ACE2 correlated positively with albumin (r  = 0.422, p  = 0.008), a marker of blood-brain barrier integrity. CSF Ang-I, Ang-II, and Ang-(1-7) levels were unchanged in AD. This cross-sectional CSF study indicates RAS dysfunction in relation to capillary damage in AD. Show more

Keywords: Alzheimer’s disease, angiotensin-II, angiotensin-(1-7), angiotensin-II converting enyme-1 (ACE1), angiotensin-II converting enyme-2 (ACE2), cerebrospinal fluid, renin-angiotensin system

DOI: 10.3233/JAD-190721

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 525-535, 2019

Authors: van Husen, Lea S. | Schedin-Weiss, Sophia | Trung, Minh Nguyen | Kazmi, Manija A. | 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. 72, no. 2, pp. 537-548, 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. 72, no. 2, pp. 549-562, 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. 72, no. 2, pp. 563-574, 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. 72, no. 2, pp. 575-585, 2019

Authors: Nitzan, Keren | Benhamron, Sandrine | Valitsky, Michael | Kesner, Eyal E. | 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. 72, no. 2, pp. 587-604, 2019