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

Authors: Kumar, Dhiraj | Kumar, Pravir

Article Type: Research Article

Abstract: Intracellular accumulation of aggregated amyloid-β, misfolded and non-functional proteinopathy, is the hallmark feature in Alzheimer’s disease (AD). There are several mechanisms to clear the amyloid burden in a cell, including transcytosis across the blood-brain barrier, immune mediated, lysosomal pathway associated autophagy, enzymatic degradation by insulin degrading enzyme/neprilysin, and the proteasomal pathway. Among them, the ubiquitin proteasome system (UPS) is playing a critical role to prevent the intracellular amyloid-β deposition and to clear off the cellular burden in association with ubiquitin E3 ligase enzymes in AD. For ubiquitination, lysine moiety in a protein acts like a docking site for the attachment …of ubiquitin molecule and different lysine residues act differently in this reaction. Therefore, it is pertinent to understand and link the role of various lysine residues along with their effector molecules, for instance, E3 ligases PARK2 and STUB1 in the ubiquitination cascade. Herein, we 1) modeled the structure of AβPP and determined its topologies and studied the impact of lysine residues in AβPP stability, 2) reported K351 as the most promising target for AβPP ubiquitination, 3) investigated the plausible role of lysine residues in non-covalent interactions mediated ubiquitin positioning in the ubiquitination, 4) detected conserved amino acids that is crucial for AβPP ubiquitination, and 5) identified the key ubiquitination enzymes and their interaction network playing major role in the ubiquitination of AβPP. Show more

Keywords: Amyloid-β, amyloid-β protein precursor, lysine, neurodegeneration, therapeutics, ubiquitination

DOI: 10.3233/JAD-181219

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1125-1150, 2019

Authors: Somers, Charisse | Lewczuk, Piotr | Sieben, Anne | Van Broeckhoven, Christine | De Deyn, Peter Paul | Kornhuber, Johannes | Martin, Jean-Jacques | Bjerke, Maria | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Background: Despite decades of research on the optimization of the diagnosis of Alzheimer’s disease (AD), its biomarker-based diagnosis is being hampered by the lack of comparability of raw biomarker data. In order to overcome this limitation, the Erlangen Score (ES), among other approaches, was set up as a diagnostic-relevant interpretation algorithm. Objective: To validate the ES algorithm in a cohort of neuropathologically confirmed cases with AD (n  = 106) and non-AD dementia (n  = 57). Methods: Cerebrospinal fluid (CSF) biomarker concentrations of Aβ1-42 , T-tau, and P-tau181 were measured with commercially available single analyte ELISA kits. Based …on these biomarkers, ES was calculated as previously reported. Results: This algorithm proved to categorize AD in different degrees of likelihood, ranging from neurochemically “normal”, “improbably having AD”, “possibly having AD”, to “probably having AD”, with a diagnostic accuracy of 74% using the neuropathology as a reference. Conclusion: The ability of the ES to overcome the high variability of raw CSF biomarker data may provide a useful diagnostic tool for comparing neurochemical diagnoses between different labs or methods used. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, dementia, harmonization, standardization, tau

DOI: 10.3233/JAD-180563

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1151-1159, 2019

Authors: Yang, Hyun-Sik | Chhatwal, Jasmeer P. | Xu, Jishu | White, Charles C. | Hanseeuw, Bernard | Rabin, Jennifer S. | Papp, Kathryn V. | Buckley, Rachel F. | Schultz, Aaron P. | Properzi, Michael J. | Gatchel, Jennifer R. | Amariglio, Rebecca E. | Donovan, Nancy J. | Mormino, Elizabeth C. | Hedden, Trey | Marshall, Gad A. | Rentz, Dorene M. | Johnson, Keith A. | De Jager, Philip L. | Sperling, Reisa A.

Article Type: Research Article

Abstract: Background: The UNC5C rs3846455G allele has been linked to poor cognitive resilience against age-related neuropathologies, but this association remains to be replicated, and the allele’s effect on hippocampal neurodegeneration needs to be examined. Objective: To further validate the association between rs3846455G and faster cognitive decline, especially among cognitively normal older adults, and to assess whether rs3846455G predicts accelerated hippocampal volume loss in older adults. Methods: We assessed participants in the Harvard Aging Brain Study (HABS), a longitudinal cohort study of older adults who were clinically normal at baseline. To avoid bias from …population admixture, analyses were limited to participants of European descent with longitudinal neuroimaging data (n  = 174). Linear mixed effect models were used to examine the effect of rs3846455G on longitudinal change of the Preclinical Alzheimer Cognitive Composite (PACC) and MRI-measured bilateral hippocampal volume, adjusting for baseline amyloid-β (Aβ) measured by the cortical Pittsburgh Compound B PET distributed volume ratio. We also tested whether hippocampal atrophy mediates the association between rs3846455G and greater PACC decline through a mediation analysis. Results: rs3846455G was associated with greater PACC decline (β= –0.087/year, 95% CI –0.169 to –0.005, p  = 0.039) after controlling for baseline Aβ. Further, rs3846455G predicted accelerated hippocampal atrophy after controlling for baseline Aβ (β= –57.3 mm3 /year, 95% CI –102.8 to –11.9, p  = 0.014). The association between rs3846455G and greater PACC decline was partially mediated by accelerated hippocampal atrophy (mediated effect (relative scale) = –0.014, 95% CI –0.032 to –6.0×10–4 , p  = 0.039). Conclusion: UNC5C rs3846455G predicts greater cognitive decline and accelerated hippocampal atrophy in clinically normal older adults. Show more

Keywords: Alzheimer’s disease, amyloid plaques, cognitive reserve, genetics, hippocampus, neuroimaging

DOI: 10.3233/JAD-180788

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1161-1170, 2019

Authors: Zhou, Sheng-Lan | Tan, Chen-Chen | Hou, Xiao-He | Cao, Xi-Peng | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: TREM2 (triggering receptor expressed on myeloid cells 2) gene variants were reported to increase the risk of Alzheimer’s disease (AD) and even other neurodegenerative diseases (frontotemporal dementia (FTD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS)), but so far, no definite conclusion has been drawn. The aim of our systematic review and meta-analysis was to investigate the role of TREM2 variants in neurodegenerative diseases. A total of 39 papers (including 26 case-control studies and 13 case reports) were retrieved from PubMed, MEDLINE, EMBASE, and the Cochrane library in this study. A fixed effect model was used to pool …results in the analysis. Three variants in TREM2 (rs75932628 (R47H), rs2234255 (H157Y), and rs143332484 (R62H)) were significantly associated with AD risk, but the similar associations between rs104894002 (Q33X), rs2234253 (T96K), rs142232675 (D87N), rs2234256 (L211P), and AD were not proven. Rs75932628 also increased risk of PD in North Americans and FTD, but not PD in Europeans or ALS. In the systematic review, 12 biallelic TREM2 mutations (e.g., rs104894002, rs201258663 (T66M), and rs386834144, etc.) have been described to cause Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL) in 14 families. And homozygous mutations also have been reported to cause FTD without typical bone phenotypes in 7 families. This study demonstrates that multiple variants in TREM2 have association with the onset of AD, FTD, and PD in North Americans and also play a key role in the phenotypes of the rare familial genetic disorder. Show more

Keywords: Meta-analysis, neurodegenerative diseases, PLOSL, TREM2 , variant

DOI: 10.3233/JAD-181038

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1171-1184, 2019

Authors: Klimova, Blanka | Kuca, Kamil | Valis, Martin | Hort, Jakub

Article Type: Research Article

Abstract:  Currently, there is an increase in the number of older people worldwide. Unfortunately, this demographic trend causes a rise in aging diseases, one of which is dementia. Recent research studies have indicated that mild cognitive impairment (MCI) may serve as a predictor of dementia in many patients. At present, there is no pharmacological treatment against MCI. Therefore, there is constant search for novel alternative non-pharmacological approaches to improve MCI. One of the effective complementary emerging approaches seems to be Traditional Chinese Medicine (TCM), which is nowadays becoming quite popular in the treatment of different disorders. The purpose of this study …is to explore the efficacy of TCM as an effective complementary non-pharmacological tool for the improvement and treatment of MCI in older adults. The methods used for this review study included a literature search in the world’s databases: Web of Science, Scopus, PubMed, and Springer. Afterwards, methods of comparison and evaluation of the findings from the selected studies were applied. The results of this review study indicate that TCM might be a beneficial complementary non-pharmacological approach to the improvement and treatment of MCI in older individuals. Nevertheless, more rigorously designed quality randomized clinical trials should be conducted in order to conclusively prove efficacy of TCM on the improvement of MCI among older population groups. In addition, there is an urgent call for a functional collaboration between western and eastern medicinal approaches, which could contribute to the enhancement of the overall quality of life of these aging population groups. Show more

Keywords: Benefits, collaboration, intervention, limitations, mild cognitive impairment, older people, Traditional Chinese Medicine

DOI: 10.3233/JAD-181281

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1185-1192, 2019

Authors: Hascup, Kevin N. | Britz, Jesse | Findley, Caleigh A. | Tischkau, Shelley | Hascup, Erin R.

Article Type: Research Article

Abstract: Chronically elevated basal glutamate levels are hypothesized to attenuate detection of physiological signals thereby inhibiting memory formation and retrieval, while inducing excitotoxicity-mediated neurodegeneration observed in Alzheimer’s disease (AD). However, current medication targeting the glutamatergic system, such as memantine, shows limited efficacy and is unable to decelerate disease progression, possibly because it modulates postsynaptic N-methyl-D-aspartate receptors rather than glutamate release or clearance. To determine if decreasing presynaptic glutamate release leads to long-term procognitive effects, we treated AβPP/PS1 mice with LY379268 (3.0 mg/kg; i.p.), a metabotropic glutamate receptor (mGluR)2/3 agonist from 2–6 months of age when elevated glutamate levels are first observed …but cognition is unaffected. C57BL/6J genetic background control mice and another cohort of AβPP/PS1 mice received normal saline (i.p.) as vehicle controls. After 6 months off treatment, mice receiving LY379268 did not show long-term improvement as assessed by the Morris water maze (MWM) spatial learning and memory paradigm. Following MWM, mice were isoflurane anesthetized and a glutamate selective microelectrode was used to measure in vivo basal and stimulus-evoked glutamate release and clearance independently from the dentate, CA3, and CA1 hippocampal subregions. Immunohistochemistry was used to measure hippocampal astrogliosis and plaque pathology. Similar to previous studies, we observed elevated basal glutamate, stimulus evoked glutamate release, and astrogliosis in AβPP/PS1 vehicle mice versus C57BL/6J mice. Treatment with LY379268 did not attenuate these responses nor diminish plaque pathology. The current study builds upon previous research demonstrating hyperglutamatergic hippocampal signaling in AβPP/PS1 mice; however, long-term therapeutic efficacy of LY379268 in AβPP/PS1 was not observed. Show more

Keywords: Alzheimer’s disease, amyloid-β , cognition, early intervention, glial fibrillary acidic protein, metabotropic glutamate receptor

DOI: 10.3233/JAD-181231

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1193-1209, 2019

Authors: Lim, Yen Ying | Yassi, Nawaf | Bransby, Lisa | Properzi, Michael | Buckley, Rachel

Article Type: Research Article

Abstract: Background: Characterizing the earliest demonstrable cognitive decline in middle-aged adults at risk of Alzheimer’s disease (AD) will allow for the better understanding of the early disease trajectory, and the provision of therapies prior to clinical symptom onset. We developed an online platform— healthybrainproject.org.au (Healthy Brain Project; HBP)— to recruit, assess, and monitor at-risk middle-aged adults. Objective: Describe the HBP methodology and report baseline characteristics and adherence indices of participants. Methods: Between February 2017 and August 2018, 4,000 community-based middle-aged Australian adults with a first or second-degree family history of dementia enrolled at our website (healthybrainproject.org.au). Participants …were directed to complete five modules: “Basics”, “Health History”, “How You Feel”, “How You Live”, and “How You Think”. Of these, 1,816 participants have received a saliva sampling kit for genetic analysis. Results: Participants had a mean (SD) age of 55.5 (6.8) years, 11.8 (3.4) years of education, and annual personal income of AUD$68,830 ($35,044). Participants took 26.4 (49.7) days after enrolment to complete questionnaires and cognitive tests. Most participants were from Victoria (63%), followed by New South Wales (14%). Most participants (74%) were female and 76% identified as Caucasian. Approximately 36% of participants completed all modules (n  = 1,450), and 56% (n  = 2,221) completed 4 out of 5 modules. Most saliva kits (89%) had been returned. Conclusion: The HBP joins a handful of online registries worldwide that assess and monitor a large cohort of individuals at risk of AD. Our study extends on these efforts by focusing on midlife, where the earliest signs of cognitive and pathological changes will manifest. Show more

Keywords: Alzheimer’s disease, neuropsychological test, neuropsychology, neuroscience, online systems, psychological test

DOI: 10.3233/JAD-181139

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1211-1228, 2019

Authors: Zhutovsky, Paul | Vijverberg, Everard G.B. | Bruin, Willem B. | Thomas, Rajat M. | Wattjes, Mike P. | Pijnenburg, Yolande A.L. | van Wingen, Guido A. | Dols, Annemiek

Article Type: Research Article

Abstract: Background: Patients with behavioral variant of frontotemporal dementia (bvFTD) initially may only show behavioral and/or cognitive symptoms that overlap with other neurological and psychiatric disorders. The diagnostic accuracy is dependent on progressive symptoms worsening and frontotemporal abnormalities on neuroimaging findings. Predictive biomarkers could facilitate the early detection of bvFTD. Objective: To determine the prognostic accuracy of clinical and structural MRI data using a support vector machine (SVM) classification to predict the 2-year clinical follow-up diagnosis in a group of patients presenting late-onset behavioral changes. Methods: Data from 73 patients were included and divided into probable /definite …bvFTD (n  = 18), neurological (n  = 28), and psychiatric (n  = 27) groups based on 2-year follow-up diagnosis. Grey-matter volumes were extracted from baseline structural MRI scans. SVM classifiers were used to perform three binary classifications: bvFTD versus neurological and psychiatric, bvFTD versus neurological, and bvFTD versus psychiatric group(s), and one multi-class classification. Classification performance was determined for clinical and neuroimaging data separately and their combination using 5-fold cross-validation. Results: Accuracy of the binary classification tasks ranged from 72–82% (p  < 0.001) with adequate sensitivity (67–79%), specificity (77–88%), and area-under-the-receiver-operator-curve (0.80–0.9). Multi-class accuracy ranged between 55–59% (p  < 0.001). The combination of clinical and voxel-wise whole brain data showed the best performance overall. Conclusion: These results show the potential for automated early confirmation of diagnosis for bvFTD using machine learning analysis of clinical and neuroimaging data in a diverse and clinically relevant sample of patients. Show more

Keywords: behavioral variant frontotemporal dementia, classification, magnetic resonance imaging, prognosis, support vector machine

DOI: 10.3233/JAD-181004

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1229-1241, 2019

Authors: Boscher, Emmanuelle | Husson, Thomas | Quenez, Olivier | Laquerrière, Annie | Marguet, Florent | Cassinari, Kevin | Wallon, David | Martinaud, Olivier | Charbonnier, Camille | Nicolas, Gaël | Deleuze, Jean-François | Boland, Anne | Lathrop, Mark | Frébourg, Thierry | FREX Consortium | Campion, Dominique | Hébert, Sébastien S. | Rovelet-Lecrux, Anne

Article Type: Research Article

Abstract: Early-onset Alzheimer’s disease (EOAD) accounts for 5-10% of all AD cases, with a heritability ranging between 92% to 100%. With the exception of rare mutations in APP , PSEN1, and PSEN2 genes causing autosomal dominant EOAD, little is known about the genetic factors underlying most of the EOAD cases. In this study, we hypothesized that copy number variations (CNVs) in microRNA (miR) genes could contribute to risk for EOAD. miRs are short non-coding RNAs previously implicated in the regulation of AD-related genes and phenotypes. Using whole exome sequencing, we screened a series of 546 EOAD patients negative for …autosomal dominant EOAD mutations and 597 controls. We identified 86 CNVs in miR genes of which 31 were exclusive to EOAD cases, including a duplication of the MIR138-2 locus. In functional studies in human cultured cells, we could demonstrate that miR-138 overexpression leads to higher Aβ production as well as tau phosphorylation, both implicated in AD pathophysiology. These changes were mediated in part by GSK-3β and FERMT2, a potential risk factor for AD. Additional disease-related genes were also prone to miR-138 regulation including APP and BACE1 . This study suggests that increased gene dosage of MIR138-2 could contribute to risk for EOAD by regulating different biological pathways implicated in amyloid and tau metabolism. Additional studies are now required to better understand the role of miR-CNVs in EOAD. Show more

Keywords: Copy number variants, early-onset Alzheimer’s disease, microRNA, miR-138

DOI: 10.3233/JAD-180940

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1243-1255, 2019

Authors: Wang, Desheng

Article Type: Research Article

Abstract:  Previous studies have shown tumor necrosis factor-alpha (TNF-α ) may impact neurodegeneration in Alzheimer’s disease (AD) by regulating amyloid-β and tau pathogenesis. However, it is unclear whether TNF-α has a role in a cholesterol-fed rabbit model of AD or TNF-α affects the electrophysiological properties of rabbit hippocampus. This study was designed to investigate whether long-term feeding of cholesterol diet known to induce AD pathology regulates TNF-α expression in the hippocampus and whether TNF-α would modulate electrophysiological properties of rabbit hippocampal CA1 neurons. TNF-α ELISA showed dietary cholesterol increased hippocampal TNF-α expression in a dose-dependent …manner. Whole-cell recordings revealed TNF-α altered the membrane properties of rabbit hippocampal CA1 neurons, which was characterized by a decrease in after-hyperpolarization amplitudes; Field potential recordings showed TNF-α inhibited long-term potentiation but did not influence presynaptic function. Interestingly, TNF-α did not significantly affect the after-hyperpolarization amplitudes of hippocampal CA1 neurons from cholesterol fed rabbits compared to normal chow fed rabbits. In conclusion, dietary cholesterol generated an in vivo model of chronic TNF-α elevation and TNF-α may underlie the learning and memory changes previously seen in the rabbit model of AD by acting as a bridge between dietary cholesterol and brain function and directly modulating the electrophysiological properties of hippocampal CA1 neurons. Show more

Keywords: Cholesterol, hippocampus, membrane properties, synaptic plasticity, tumor necrosis factor-alpha

DOI: 10.3233/JAD-190043

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1257-1271, 2019

Authors: Boomsma, Jooske M.F. | Exalto, Lieza G. | Barkhof, Frederik | van den Berg, Esther | de Bresser, Jeroen | Heinen, Rutger | Leeuwis, Anna E. | Prins, Niels D. | Scheltens, Philip | Weinstein, Henry C. | van der Flier, Wiesje M. | Biessels, Geert Jan | behalf of the TRACE-VCI study group

Article Type: Research Article

Abstract: Background: Memory clinic patients frequently present with different forms of vascular brain injury due to different etiologies, often co-occurring with Alzheimer’s disease (AD) pathology. Objective: We studied how cognition was affected by different forms of vascular brain injury, possibly in interplay with AD pathology. Methods: We included 860 memory clinic patients with vascular brain injury on magnetic resonance imaging (MRI), receiving a standardized evaluation including cerebrospinal fluid (CSF) biomarker analyses (n  = 541). The cognitive profile of patients with different forms of vascular brain injury on MRI (moderate/severe white matter hyperintensities (WMH) (n  = 398), microbleeds (n  = 368), …lacunar (n  = 188) and non-lacunar (n  = 96) infarct(s), macrobleeds (n  = 16)) was assessed by: 1) comparison of all these different forms of vascular brain injury with a reference group (patients with only mild WMH (n  = 205) without other forms of vascular brain injury), using linear regression analyses also stratified for CSF biomarker AD profile and 2) multivariate linear regression analysis. Results: The cognitive profile was remarkably similar across groups. Compared to the reference group effect sizes on all domains were <0.2 with narrow 95% confidence intervals, except for non-lacunar infarcts on information processing speed (age, sex, and education adjusted mean difference from reference group (β: – 0.26, p  = 0.05). Results were similar in the presence (n  = 300) or absence (n  = 241) of biomarker co-occurring AD pathology. In multivariate linear regression analysis, higher WMH burden was related to a slightly worse performance on attention and executive functioning (β: – 0.08, p  = 0.02) and working memory (β: – 0.08, p  = 0.04). Conclusion: Although different forms of vascular brain injury have different etiologies and different patterns of cerebral damage, they show a largely similar cognitive profile in memory clinic patients regardless of co-occurring AD pathology. Show more

Keywords: Cerebral small vessel diseases, cerebrovascular disorders, cognitive disorders, neuropsychological test

DOI: 10.3233/JAD-180696

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1273-1286, 2019

Authors: Andrés-Benito, Pol | Gelpi, Ellen | Povedano, Mónica | Ausín, Karina | Fernández-Irigoyen, Joaquín | Santamaría, Enrique | Ferrer, Isidro

Article Type: Research Article

Abstract: Background: Frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) may appear as sporadic (sFTLD-TDP) or linked to mutations in various genes including expansions of the non-coding region of C9ORF72 (c9FTLD). Objective: Analysis of differential mRNA and protein expression in the frontal cortex in c9FLTD and evaluation with previous observations in frontal cortex in sFTLD-TDP and amyotrophic lateral sclerosis with TDP-43 inclusions. Methods: Microarray hybridization and mass spectrometry-based quantitative proteomics followed by RT-qPCR, gel electrophoresis, and western blotting in frontal cortex area 8 in 19 c9FTLD cases and 14 age- and gender-matched controls. Results: …Microarray hybridization distinguish altered gene transcription related to DNA recombination, RNA splicing regulation, RNA polymerase transcription, myelin synthesis, calcium regulation, and ubiquitin-proteasome system in c9FTLD; proteomics performed in the same tissue samples pinpoints abnormal protein expression involving apoptosis, inflammation, metabolism of amino acids, metabolism of carbohydrates, metabolism of membrane lipid derivatives, microtubule dynamics, morphology of mitochondria, neuritogenesis, neurotransmission, phagocytosis, receptor-mediated endocytosis, synthesis of reactive oxygen species, and calcium signaling in c9FTLD. Conclusion: Transcriptomics and proteomics, as well as bioinformatics processing of derived data, reveal similarly altered pathways in the frontal cortex in c9FTLD, but different RNAs and proteins are identified by these methods. Combined non-targeted ‘-omics’ is a valuable approach to deciphering altered molecular pathways in FTLD provided that observations are approached with caution when assessing human postmortem brain samples. Show more

Keywords: C9ORF72, frontotemporal lobar degeneration, FTLD-TDP, gene expression, proteomics

DOI: 10.3233/JAD-181123

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1287-1307, 2019

Article Type: Correction

DOI: 10.3233/JAD-199001

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1309-1309, 2019