Journal of Alzheimer's Disease - Volume 68, issue 3

Authors: Orr, Adam L. | Kim, Chaeyoung | Jimenez-Morales, David | Newton, Billy W. | Johnson, Jeffrey R. | Krogan, Nevan J. | Swaney, Danielle L. | Mahley, Robert W.

Article Type: Research Article

Abstract: Apolipoprotein (apo) E4, the major genetic risk factor for Alzheimer’s disease (AD), alters mitochondrial function and metabolism early in AD pathogenesis. When injured or stressed, neurons increase apoE synthesis. Because of its structural difference from apoE3, apoE4 undergoes neuron-specific proteolysis, generating fragments that enter the cytosol, interact with mitochondria, and cause neurotoxicity. However, apoE4’s effect on mitochondrial respiration and metabolism is not understood in detail. Here we used biochemical assays and proteomic profiling to more completely characterize the effects of apoE4 on mitochondrial function and cellular metabolism in Neuro-2a neuronal cells stably expressing apoE4 or apoE3. Under basal conditions, apoE4 …impaired respiration and increased glycolysis, but when challenged or stressed, apoE4-expressing neurons had 50% less reserve capacity to generate ATP to meet energy requirements than apoE3-expressing neurons. ApoE4 expression also decreased the NAD+ /NADH ratio and increased the levels of reactive oxygen species and mitochondrial calcium. Global proteomic profiling revealed widespread changes in mitochondrial processes in apoE4 cells, including reduced levels of numerous respiratory complex subunits and major disruptions to all detected subunits in complex V (ATP synthase). Also altered in apoE4 cells were levels of proteins related to mitochondrial endoplasmic reticulum–associated membranes, mitochondrial fusion/fission, mitochondrial protein translocation, proteases, and mitochondrial ribosomal proteins. ApoE4-induced bioenergetic deficits led to extensive metabolic rewiring, but despite numerous cellular adaptations, apoE4-expressing neurons remained vulnerable to metabolic stress. Our results provide insights into potential molecular targets of therapies to correct apoE4-associated mitochondrial dysfunction and altered cellular metabolism. Show more

Keywords: Alzheimer’s disease, apoE4, mitochondrial respiration, neurodegeneration, neuronal metabolism, protein expression

DOI: 10.3233/JAD-181184

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 991-1011, 2019

Authors: Yan, Tianyi | Wang, Yonghao | Weng, Zizheng | Du, Wenying | Liu, Tiantian | Chen, Duanduan | Li, Xuesong | Wu, Jinglong | Han, Ying

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is one of the most common progressive and irreversible neurodegenerative diseases. The study of the pathological mechanism of AD and early-stage diagnosis is essential and important. Subjective cognitive decline (SCD), the first at-risk stage of AD occurring prior to amnestic mild cognitive impairment (aMCI), is of great research value and has gained our interest. To investigate the entire pathological development of AD pathology efficiently, we proposed a machine learning classification method based on a multimodal support vector machine (SVM) to investigate the structural and functional connectivity patterns of the three stages of AD (SCD, aMCI, and AD). …Our experiments achieved an accuracy of 98.58% in the AD group, 97.76% in the aMCI group, and 80.24% in the SCD group. Moreover, in our experiments, we identified the most discriminating brain regions, which were mainly located in the default mode network and subcortical structures (SCS). Notably, with the development of AD pathology, SCS regions have become increasingly important, and structural connectivity has shown more discriminative power than functional connectivity. The current study may shed new light on the pathological mechanism of AD and suggests that whole-brain connectivity may provide potential effective biomarkers for the early-stage diagnosis of AD. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, machine learning, multimodal MRI, resting-state fMRI

DOI: 10.3233/JAD-181049

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1013-1027, 2019

Authors: Cholerton, Brenna | Weiner, Michael W. | Nosheny, Rachel L. | Poston, Kathleen L. | Mackin, R. Scott | Tian, Lu | Ashford, J. Wesson | Montine, Thomas J.

Article Type: Research Article

Abstract: The study of cognition in Parkinson’s disease (PD) traditionally requires exhaustive recruitment strategies. The current study examines data collected by the Brain Health Registry (BHR) to determine whether ongoing efforts to improve the recruitment base for therapeutic trials in Alzheimer’s disease may be similarly effective for PD research, and whether online cognitive measurements can discriminate between participants who do and do not report a PD diagnosis. Participants enrolled in the BHR (age ≥50) with self-reported PD data and online cognitive testing available were included (n  = 11,813). Associations between baseline cognitive variables and diagnostic group were analyzed using logistic regression. Linear …mixed effects models were used to analyze longitudinal data. A total of 634 participants reported PD diagnosis at baseline with no self-reported cognitive impairment and completed cognitive testing. Measures of visual learning and memory, processing speed, attention, and working memory discriminated between self-reported PD and non-PD participants after correcting for multiple comparisons (p values < 0.006). Scores on all cognitive tests improved over time in PD and controls with the exception of processing speed, which remained stable in participants with PD while improving in those without. We demonstrate that a novel online approach to recruitment and longitudinal follow-up of study participants is effective for those with self-reported PD, and that significant differences exist between those with and without a reported diagnosis of PD on computerized cognitive measures. These results have important implications for recruitment of participants with PD into targeted therapeutic trials or large-scale genetic and cognitive studies. Show more

Keywords: Aging, cognition, neuropsychology, Parkinson’s disease, patient selection, registries

DOI: 10.3233/JAD-181009

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1029-1038, 2019

Authors: Campos, Jennifer L. | Höbler, Fiona | Bitton, Etty | Labreche, Tammy | McGilton, Katherine S. | Wittich, Walter

Article Type: Research Article

Abstract: Vision impairments are prevalent, but underdiagnosed in individuals with dementia living in long-term care (LTC). Effective screening tools could identify remediable vision problems. This scoping review was conducted to identify vision screening tests used with individuals with dementia and assesses their suitability for administration by nurses in LTC. A literature search using the Arksey and O’Malley (2005) method included research articles, conference proceedings, and dissertations. Data were included from participants over 65 years of age with a diagnosis of probable dementia. A panel of vision experts evaluated the suitability of the candidate vision tests. The search yielded 179 publications that …met the inclusion criteria. Of 134 vision tests that were identified, 19 were deemed suitable for screening by nurses in LTC. Tests screened for acuity (12), visual field (1), anatomy (2), color vision (2), and general visual abilities (2). Tests were excluded because of complexity of interpretation (90), need for specialized training (83), use in research only (57), need for specialized equipment (54), not assessing visual function (44), long test duration (21), uncommonness (13), and needing an act reserved for specialists (7). Psychometric properties were not often reported for tests. Few of the tests identified had been validated for use with individuals with dementia. Based on our review, few tests were deemed suitable for use by nurses to assess this population in LTC. Identifying appropriate tools to screen vision in individuals with dementia is a necessary first step to interventions that could potentially improve functioning and quality of life. Show more

Keywords: Aging, cognition, decline, low vision, nursing, sensory

DOI: 10.3233/JAD-181129

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1039-1049, 2019

Authors: Zhu, Lingyan | Gong, Li | Yang, Tianlun | Xiao, Xiangwei

Article Type: Research Article

Abstract:  Aged people have a high chance to develop two prevalent diseases, diabetes and Alzheimer’s disease (AD), which are characterized with hyperglycemia and neurodegeneration, respectively. Interestingly, recent evidence suggest that diabetes is a predisposing factor for AD. Nevertheless, the mechanisms underlying the association of diabetes with AD remain poorly defined. Here, we studied the effects of diabetes on AD in mice. The APP-PS1 mouse, an AD-prone strain, was administrated with streptozotocin (STZ) to destroy 75% beta cell mass to induce sustained hyperglycemia. We found that STZ-treated APP-PS1 mice exhibited poorer performance in the social recognition test, Morris water maze, and plus-maze …discriminative avoidance task, compared to saline-treated normoglycemic APP-PS1 mice, likely resulting from increases in brain deposition of amyloid-β peptide aggregates (Aβ). Since formation of Aβ is known to be induced by protein hyperphosphorylation mediated by calpain (CAPN)-induced cleavage of p35 into p25, we examined levels of these proteins in mouse brain. We detected not only increased p35-to-p25 conversion, but also enhanced CAPN1 activity via increased protein but not mRNA levels. The internal CAPN1 inhibitor, calpastatin (CAST), was downregulated in STZ-treated APP-PS1 mouse brain, as a basis for the increase in CAPN1. In vitro , a human neuronal cell line, HCN-2, increased CAPN1 activity and downregulated CAST levels when incubated for 8 days in high glucose level, resulting in increased cell apoptosis. Together, these data suggest that chronic hyperglycemia may promote AD development through downregulating CAST. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide aggregates, calpain 1, calpastatin, diabetes

DOI: 10.3233/JAD-190004

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1051-1059, 2019

Authors: Manca, Chloé | Hopes, Lucie | Kearney-Schwartz, Anna | Roch, Véronique | Karcher, Gilles | Baumann, Cédric | Marie, Pierre-Yves | Malaplate-Armand, Catherine | Jonveaux, Thérèse Rivasseau | Verger, Antoine

Article Type: Research Article

Abstract: Background/Objective: The aim of this study was to assess, in routine, the rates with which an amyloid deposition was documented by 18 F-florbetaben PET in patients with suspected Alzheimer’s disease (AD) but with isolated increases in cerebrospinal fluid (CSF) tau-protein concentrations, and the subsequent impact of these PET results on medical management. Methods: This prospective study included 34 patients with mild neurocognitive disorders (MND) and suspected AD (73±9 years, 16 women) and with abnormal CSF concentrations in total-tau (T-tau) and/or phosphorylated-tau (P-tau) proteins but normal Aβ42 concentration and Aβ42 /Aβ40 ratio. These patients were referred to …8 F-florbetaben PET from which the PET-related changes in the confidence for AD diagnosis (low, intermediate, or high) and treatments were reported. Results: The PET examinations were positive for amyloid deposition (brain amyloid plaque load, BAPL score >1) in none of the 9 patients with an increase in only T-tau proteins and in 8 among the 25 (32%) with an increase in P-tau proteins (one BAPL score of 2 and seven BAPL scores of 3). Knowledge of the PET results was associated with subsequent changes in diagnostic confidence in 44% of patients (15/34) and in the intention-to-treat with a cholinesterase inhibitor drug in 18% (6/34). Conclusion: In patients with suspected AD and isolated increase in CSF tau protein concentrations, an amyloid deposition is documented by 18 F-florbetaben PET in as much as one third of cases when the concentration of P-tau is abnormal, and PET results are associated with significant further changes in medical management. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, positron emission tomography

DOI: 10.3233/JAD-181146

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1061-1069, 2019

Authors: Aiello Bowles, Erin J. | Crane, Paul K. | Walker, Rod L. | Chubak, Jessica | LaCroix, Andrea Z. | Anderson, Melissa L. | Rosenberg, Dori | Keene, C. Dirk | Larson, Eric B.

Article Type: Research Article

Abstract: Background: Past research has focused on risk factors for developing dementia, with increasing recognition of “resilient” people who live to old age with intact cognitive function despite pathological features of Alzheimer’s disease (AD). Objective: To evaluate demographic factors, mid-life characteristics, and non-AD neuropathology findings that may be associated with cognitive resilience to AD pathology. Methods: We analyzed data from 276 autopsy cases with intermediate or high levels of AD pathology from the Adult Changes in Thought study. We defined cognitive resilience as having Cognitive Abilities Screening Instrument scores ≥86 within two years of death and no …clinical dementia diagnosis; non-resilient people had dementia diagnoses from AD or other causes before death. We compared mid-life characteristics, demographics, and additional neuropathology findings between resilient and non-resilient people. We used multivariable logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for being resilient compared to not being resilient adjusting for demographic and neuropathology factors. Results: We classified 68 (25%) people as resilient and 208 (75%) as not resilient. A greater proportion of resilient people had a college degree (50%) compared with non-resilient (32%, p  = 0.01). The odds of being resilient were significantly increased among people with a college education (OR = 2.01, 95% CI = 1.01–3.99) and significantly reduced among people with additional non-AD neuropathology findings such as hippocampal sclerosis (OR = 0.28, 95% CI = 0.09–0.89) and microinfarcts (OR = 0.34, 95% CI = 0.15–0.78). Conclusion: Increased education and absence of non-AD pathology may be independently associated with cognitive resilience, highlighting the importance of evaluating co-morbid factors in future research on mechanisms of cognitive resilience. Show more

Keywords: Aging, Alzheimer’s disease, cognition, dementia, education, neuropathology

DOI: 10.3233/JAD-180942

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1071-1083, 2019

Authors: Goodman, Michelle S. | Zomorrodi, Reza | Kumar, Sanjeev | Barr, Mera S. | Daskalakis, Zafiris J. | Blumberger, Daniel M. | Fischer, Corinne E. | Flint, Alastair | Mah, Linda | Herrmann, Nathan | Pollock, Bruce G. | Bowie, Christopher R. | Mulsant, Benoit H. | Rajji, Tarek K. | The PACt-MD Study Group

Collaborators: Mulsant, B.H. | Rajji, T.K. | Herrmann, N. | Pollock, B.G. | Lourenco, L. | Blumberger, D.M. | Bowie, C.R. | Butters, M. | Fischer, C.E. | Flint, A. | Gallagher, D. | Golas, A. | Graff, A. | Kennedy, J.L. | Kumar, S. | Mah, L. | Ovaysikia, S. | Rapoport, M. | Thorpe, K. | Verhoeff, N.P.L.G. | Voineskos, A.N.

Article Type: Research Article

Abstract: While several studies have found that neural oscillations play a key role in the functioning of working memory, the nature of aberrant oscillatory activity underlying working memory impairments in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) remains largely unexplored. These individuals often display structural alterations in brain regions and pathways involved in working memory processes and therefore may also display altered oscillatory activity during memory activation. Electroencephalographic (EEG) activity was recorded during the N-back working memory task in three groups: AD (n  = 29), MCI (n  = 100), and healthy controls (HCs; n  = 40). Theta (4–7 Hz) and alpha (7.5–12 Hz) modulation was …measured in response to the stimulus presentation during correct and incorrect responses. This modulation represents the change in EEG activity associated with the stimulus onset and was measured as a ratio of post stimulus power to pre stimulus power. We also assessed the relationship between change in oscillatory power and working memory performance. Compared to HCs, the AD group demonstrated the lowest working memory accuracy and a smaller theta ratio for correct responses on the 2-back condition; the MCI group demonstrated a smaller theta ratio for correct responses on the 3-back condition. Finally, we observed that the theta ratio, but not the alpha ratio, was a significant predictor of working memory performance in the three groups for all conditions. Taken together, these behavioral and electrophysiological results suggest that in addition to impairments in working memory performance, modulation of theta, but not alpha power, may be impaired in MCI and AD. Show more

Keywords: Alpha power, Alzheimer’s disease, electroencephalography, mild cognitive impairment, theta power, working memory

DOI: 10.3233/JAD-181195

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1085-1094, 2019

Authors: Cao, Long-Long | Guan, Pei-Pei | Liang, Yun-Yue | Huang, Xue-Shi | Wang, Pu

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is reported to be associated with the accumulation of calcium ions (Ca2+ ), which is responsible for the phosphorylation of tau. Although a series of evidence have demonstrated this phenomenon, the inherent mechanisms remain unknown. Using tauP301S and cyclooxygenase-2 (COX-2) transgenic mice and neuroblastoma (n)2a cells as in vivo and in vitro experimental models, we found that Ca2+ stimulates the phosphorylation of tau by activating COX-2 in a prostaglandin (PG) E2 -dependent EP receptor-activating manner. Specifically, Ca2+ incubation stimulated COX-2 and PGE2 synthase activity, microsomal PGE synthase 1 and the synthesis …of PGE2 by activating the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in n2a cells. Elevated levels of PGE2 were responsible for phosphorylating tau in an EP-1, -2, and -3 but not EP4-dependent glycogen synthase kinase 3-activating manner. These observations were corroborated by results that showed tau was phosphorylated when it colocalized with activated COX-2 in tauP301S and COX-2 transgenic mice or n2a cells. To further validate these observations, treatment of mice with the COX-2 inhibitor rofecoxib decreased the phosphorylation of tau via EP1-3 but not EP4. Collectively, our observations fill the gaps between Ca2+ and the phosphorylation of tau in a COX-2-dependent mechanism, which potentially provides therapeutic targets for combating AD. Show more

Keywords: Alzheimer’s disease, cyclooxygenase-2, EP receptors, prostaglandin E2 , tau

DOI: 10.3233/JAD-181066

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1095-1111, 2019

Authors: Calderón-Garcidueñas, Lilian | Mukherjee, Partha S. | Kulesza, Randy J. | Torres-Jardón, Ricardo | Hernández-Luna, Jacqueline | Ávila-Cervantes, Rodrigo | Macías-Escobedo, Edgar | González-González, Oscar | González-Maciel, Angélica | García-Hernández, Kevin | Hernández-Castillo, Ariatna | Research Universidad del Valle de México UVM Group | Villarreal-Ríos, Rodolfo

Collaborators: Vacaseydel-Aceves, Nora B. | Luévano-Castro, Samuel C. | Romero-Sánchez, Ely | Ramírez-Sánchez, Silvia | Moya-Morales, Ramón | Ramírez-Covarrubias, Nadia A. | Camacho-Montoya, Cindy N. | Parra-Mendoza, Sandra P. | Rivera-Ramírez, Jessica | Fierro-Fimbres, Noelia G. | Souza-Araiza, Ana T. | López-Torres, Dania S. | Navarro-Valencia, Imelda G. | García-Bojórquez, Carlos A. | García-Rojas, Edgar | Ramirez-Chacón, Gabriela del Carmen | Escobar-Nataren, Eugenia | Chang-Lozano, Enrique | Arías-García, Nallely A. | Alvarado-Hernández, Diana L. | Vargas-Cisneros, María Eugenia | Mendoza-Luna, Fernanda | Cortés-Zúñiga, Cristian G. | Rodríguez-Castillo, Isaías | Torres-Solorio, Karen | Brito-Aguilar, Rafael | Jiménez-Hernández, Luis E. | Molina-Olvera, Gabriela | Nogueda-Orozco, María José | Sánchez-Villalvazo, Vania A. | Rosas-Jacinto, Zaira | Tiburcio-Bonilla, Rubén A. | Godinez-Cerón, Isabel | González-Gutiérrez, Leopoldo E. | Gómez-Maqueo-Chew, A | Mendoza-Cerezo, Susana | Domínguez-Lonngi, Lorena | Lazcano-Zamora, Ana P. | Joaquín-Ascencio, Guadalupe | Rascón-Castelo, Edgar A. | Alvarado-Hernández, Diana L. | Galindo Marmolejo, María J. | Segoviano-Ramírez, Juan Carlos | Palacios-Delgado, Jorge R. | Coronado-Cerda, Erika | Suárez-Villanueva, Alexis S. | Padilla-Rivera, Violeta C. | Alvarado-Ruiz, Liliana | Villanueva-Duque, José A.

Article Type: Research Article

Abstract: Exposures to fine particulate matter PM2.5 and ozone O3 are associated with Alzheimer’s disease (AD) risk. Mexico City residents have lifetime exposures to PM2.5 and O3 above annual USEPA standards and their brains contain high redox, combustion, and friction-derived magnetite nanoparticles. AD pathological changes with subcortical pre-tangle stages in infancy and cortical tau pre-tangles, NFT Stages I-II, and amyloid phases 1-2 are identified by the 2nd decade. Given their AD continuum, a reliable identification of cognitive impairment is of utmost importance. The Montreal Cognitive Assessment (MoCA) was administered to 517 urbanites, age 21.60±5.88 years, with 13.69±1.28 …formal education years, in Mexican PM2.5 polluted cities. MoCA score was 23.92±2.82, and 24.7% and 30.3% scored ≤24 and ≤22, respectively (MCI≤24, AD≤22). Cognitive deficits progressively targeted Visuospatial, Executive, Language, and Memory domains, body mass index (BMI) impacting total scores negatively (p  = 0.0008), aging driving down Executive, Visuospatial, and Language index scores (p  < 0.0001, 0.0037, and 0.0045), and males performing better in Executive tasks. Average age for AD MoCA scores was 22.38±7.7 years. Residency in polluted cities is associated with progression of multi-domain cognitive impairment affecting 55% of Mexican seemingly healthy youth. Normal BMI ought to be a neuroprotection goal. MoCA provides guidance for further mandatory neuropsychological testing in young populations. Identifying and lowering key neurotoxicants impacting neural risk trajectories in the developing brain and monitoring cognitive performance would greatly facilitate multidisciplinary early diagnosis and prevention of AD in high risk young populations. Cognitive deficits hinder development of those representing the force moving the country in future years. Show more

Keywords: Alzheimer’s disease, air pollution, attention, body mass index, cognition, combustion and friction-derived nanoparticles, dementia, females, food, gender, Mexico City, mild cognitive impairment, Montreal Cognitive Assessment, obesity, overweight, PM2.5 , tauopathies, young adults.

DOI: 10.3233/JAD-181208

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1113-1123, 2019