Journal of Alzheimer's Disease - Volume 81, issue 2

Authors: Harb, Amro A. | Chen, RuiJun | Chase, Herbert S. | Natarajan, Karthik | Noble, James M.

Article Type: Research Article

Abstract: Background: Patients with dementia are vulnerable during the coronavirus disease 2019 (COVID-19) pandemic, yet few studies describe their hospital course and outcomes. Objective: To describe and compare the hospital course for COVID-19 patients with dementia to an aging cohort without dementia in a large New York City academic medical center. Methods: This was a single-center retrospective cohort study describing all consecutive patients age 65 or older with confirmed COVID-19 who presented to the emergency department or were hospitalized at New York-Presbyterian/Columbia University Irving Medical Center between March 6 and April 7, 2020. Results: A …total of 531 patients were evaluated, including 116 (21.8%) with previously diagnosed dementia, and 415 without dementia. Patients with dementia had higher mortality (50.0%versus 35.4%, p  = 0.006); despite similar comorbidities and complications, multivariate analysis indicated the association was dependent on age, sex, comorbidities, and code status. Patients with dementia more often presented with delirium (36.2%versus 11.6%, p  < 0.001) but less often presented with multiple other COVID-19 symptoms, and these findings remained after adjusting for age and sex. Conclusion: Hospitalized COVID-19 patients with dementia had higher mortality, but dementia was not an independent risk factor for death. These patients were approximately 3 times more likely to present with delirium but less often manifested or communicated other common COVID-19 symptoms. For this high-risk population in a worsening pandemic, understanding the unique manifestations and course in dementia and aging populations may help guide earlier diagnosis and optimize medical management. Show more

Keywords: Advance directives, COVID-19, delirium, dementia, geriatrics, neurology

DOI: 10.3233/JAD-210050

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 679-690, 2021

Authors: Schmidt, Sergio L. | Boechat, Yolanda Eliza Moreira | Schmidt, Guilherme J. | Nicaretta, Denise | van Duinkerken, Eelco | Schmidt, Juliana J.

Article Type: Research Article

Abstract: Background: The Clinical Dementia Rating (CDR) scale is commonly used to stage cognitive impairment, despite having educational limitations. In elderly with low education, a previous study has shown that intraindividual variability of reaction time (CV) and commission errors (CE), measured using a culture-free Go/No-Go task, can reliably distinguish early Alzheimer’s disease (AD) from mild cognitive impairment (MCI) and healthy controls. Objective: We aimed to extend the clinical utility of this culture-free Go/No-Go task in a sample with high educational disparity. Methods: One hundred and ten participants with a wide range of years of formal education (0–14 …years) were randomly selected from a geriatric unit and divided based on their CDR scores into cognitively unimpaired (CDR = 0), MCI (CDR = 0.5), and early AD (CDR = 1). All underwent a 90-s reaction-time test that measured the variables previously found to predict CDR in low educated elderly. Here we added years of formal education (educational level) to the model. Multivariate analyses compared differences in group means using educational level as confounding factor. A confirmatory discriminant analyses was performed, to assess if CDR scores could be predicted by the two Go/No-Go variables in a sample with high educational disparity. Results: Over all three groups, differences in both CE and CV reached statistical significance (p  < 0.05). The discriminant analysis demonstrated that CV and CE discriminated cognitively impaired from cognitively normal elderly. These results remained similar when discriminating MCI from cognitively unimpaired elderly. Conclusion: The Go/No-Go task reliably discriminates elderly with MCI from elderly without cognitive impairment independent of educational disparity. Show more

Keywords: Attention, cognitive dysfunction, dementia, neuropsychology, reaction time

DOI: 10.3233/JAD-210151

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 691-697, 2021

Authors: Zhang, Yun | Natale, Ginny | Clouston, Sean

Article Type: Research Article

Abstract: Background: Larger, more active social networks are estimated to be associated with lower risks of cognitive decline. However, roles of various social relationships in a broad social network in protecting against cognitive decline remain to be elucidated. Objective: We aimed to investigate how social roles within a social network and number of social network members are associated with cognitive decline. Methods: Six waves of National Health and Aging Trends Study (2011-2016, NHATS) were utilized to examine the development of mild cognitive impairment (MCI) and probable dementia determined using validated criteria. Multivariable-adjusted multi-state survival models were used …to model incidences and transitions, jointly with misclassification errors. Results: A total of 6,078 eligible NHATS participants were included (average age: 77.49±7.79 years; female: 58.42%; non-Hispanic white: 68.99%). Multivariable-adjusted analyses revealed that having more social network members was associated with lower hazards of conversion from MCI to probable dementia (adjusted Hazard Ratio; aHR = 0.82; 95%confidence intervals; 95%CI = [0.67–0.99]), meanwhile having at least one college-educated family member within a social network was associated with lower incidence of probable dementia (aHR = 0.37 [0.26–0.51]). Having at least one friend within a social network was associated with a lower hazard of incidence of probable dementia (aHR = 0.48 [0.33–0.71]), but a higher risk of mortality in the MCI group (aHR = 2.58 [1.47–4.51]). Conclusion: Having more social network members, having at least one friend, and having at least one college-educated family member within a social network, were associated with lower risks of incidence of dementia or conversion from MCI to dementia. Show more

Keywords: Cognition, dementia, multistate modeling, social networking

DOI: 10.3233/JAD-201196

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 699-710, 2021

Authors: Beydoun, May A. | Hossain, Sharmin | MacIver, Peter H. | Srinivasan, Dhivya | Beydoun, Hind A. | Maldonado, Ana I. | Katzel, Leslie I. | Davatzikos, Christos | Gullapalli, Rao P. | Seliger, Stephen L. | Erus, Guray | Evans, Michele K. | Zonderman, Alan B. | Waldstein, Shari R.

Article Type: Research Article

Abstract: Background: Anemia and red cell distribution width (RDW) have been linked to poor cognitive performance, pending studies of underlying mechanisms. Objective: We examined cross-sectional relationships of initial RDW status (v1 ), RDW change (δ ), and anemia with brain structural magnetic resonance imaging (sMRI) markers, including global and cortical brain and hippocampal and white matter lesion (WML) volumes, 5–6 years later. Methods: Data were used from three prospective visits within the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study with complete v1 (2004–2009) and v2 (2009–2013) exposures and ancillary sMRI …data at vscan (2011–2015, n  = 213, mean v1 to vscan time: 5.7 years). Multivariable-adjusted linear regression models were conducted, overall, by sex, by race, and within non-anemics, correcting for multiple testing with q-values. Results: In minimally adjusted models (socio-demographics and follow-up time), anemiav1 and RDWv1 were consistently associated with smaller bilateral hippocampal volumes overall, and among females (q  < 0.05), without significant sex differences. RDWv1 was related to smaller select regional cortical brain gray and white matter volumes in hematological measure-adjusted models; anemiav1 was associated with larger WML volumes only among whites. Conclusion: In summary, baseline anemia and RDW were consistently associated with smaller bilateral hippocampal volumes, particularly among females, while anemia was linked to larger WML volume among Whites. In hematological measure-adjusted models, baseline RDW was linked to smaller regional gray and white matter volumes. Pending studies with sMRI repeats, randomized controlled trials are needed, demonstrating associations of anemia and elevated RDW with reduced brain volumes and cognitive dysfunction. Show more

Keywords: Aging, anemia, brain volumes, hippocampus, red cell distribution width, white matter lesion

DOI: 10.3233/JAD-201386

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 711-727, 2021

Authors: Martínez-Florez, Juan F. | Osorio, Juan D. | Cediel, Judith C. | Rivas, Juan C. | Granados-Sánchez, Ana M. | López-Peláez, Jéssica | Jaramillo, Tania | Cardona, Juan F.

Article Type: Research Article

Abstract: Background: Amnestic mild cognitive impairment (aMCI) is the most common preclinical stage of Alzheimer’s disease (AD). A strategy to reduce the impact of AD is the early aMCI diagnosis and clinical intervention. Neuroimaging, neurobiological, and genetic markers have proved to be sensitive and specific for the early diagnosis of AD. However, the high cost of these procedures is prohibitive in low-income and middle-income countries (LIMCs). The neuropsychological assessments currently aim to identify cognitive markers that could contribute to the early diagnosis of dementia. Objective: Compare machine learning (ML) architectures classifying and predicting aMCI and asset the contribution of …cognitive measures including binding function in distinction and prediction of aMCI. Methods: We conducted a two-year follow-up assessment of a sample of 154 subjects with a comprehensive multidomain neuropsychological battery. Statistical analysis was proposed using complete ML architectures to compare subjects’ performance to classify and predict aMCI. Additionally, permutation importance and Shapley additive explanations (SHAP) routines were implemented for feature importance selection. Results: AdaBoost, gradient boosting, and XGBoost had the highest performance with over 80%success classifying aMCI, and decision tree and random forest had the highest performance with over 70%success predictive routines. Feature importance points, the auditory verbal learning test, short-term memory binding tasks, and verbal and category fluency tasks were used as variables with the first grade of importance to distinguish healthy cognition and aMCI. Conclusion: Although neuropsychological measures do not replace biomarkers’ utility, it is a relatively sensitive and specific diagnostic tool for aMCI. Further studies with ML must identify cognitive performance that differentiates conversion from average MCI to the pathological MCI observed in AD. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, cognitive markers, healthy aging, machine learning

DOI: 10.3233/JAD-201447

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 729-742, 2021

Authors: Zheng, Yi-Ming | Zhao, Yang-Yang | Zhang, Ting | Hou, Xiao-He | Bi, Yan-Lin | Ma, Ya-Hui | Xu, Wei | Shen, Xue-Ning | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Heart failure has been considered as a potential modifiable risk factor for cognitive impairment and dementia. Left ventricular ejection fraction (LVEF), an indicator of cardiac dysfunction, has also been associated with cognitive aging. However, the effect of LVEF on Alzheimer’s disease (AD) pathology is still less known. Objective: We aimed to investigate the associations of LVEF with cerebrospinal fluid (CSF) biomarkers for AD in cognitively normal elders. Methods: A total of 423 cognitively normal individuals without heart failure were included from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study. Participants were divided …into low LVEF group (50%≤LVEF < 60%) and high LVEF group (LVEF≥60%). The associations of LVEF with CSF AD biomarkers including CSF amyloid-β 42 (Aβ42 ), total-tau (t-tau), and phosphorylated tau (p-tau) were analyzed using multivariate linear regression models. Results: Participants with low LVEF had higher levels of CSF t-tau (β= –0.009, p  = 0.006) and t-tau/Aβ42 ratios (β= –0.108, p  = 0.026). Subgroup analyses showed that the associations only existed in female and middle-aged groups (< 65 years old). Besides, participants with low LVEF had higher levels of CSF p-tau (β= –0.002, p  = 0.043) in middle-aged group. Conclusion: In conclusion, our findings revealed the associations between LVEF and AD pathology, which may provide new insights into AD prevention through maintaining cardiac function. Show more

Keywords: Alzheimer’s disease, biomarker, cerebrospinal fluid, left ventricular ejection fraction

DOI: 10.3233/JAD-201222

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 743-750, 2021

Authors: Williams, Victoria J. | Carlsson, Cynthia M. | Fischer, Anne | Johnson, Sterling C. | Lange, Kate | Partridge, Eileen | Roan, Carol | Asthana, Sanjay | Herd, Pamela

Article Type: Research Article

Abstract: Background: There is growing consensus that non-genetic determinants of dementia can be linked to various risk- and resiliency-enhancing factors accumulating throughout the lifespan, including socioeconomic conditions, early life experiences, educational attainment, lifestyle behaviors, and physical/mental health. Yet, the causal impact of these diverse factors on dementia risk remain poorly understood due to few longitudinal studies prospectively characterizing these influences across the lifespan. Objective: The Initial Lifespan’s Impact on Alzheimer’s Disease and Related Dementia (ILIAD) study aims to characterize dementia prevalence in the Wisconsin Longitudinal Study (WLS), a 60-year longitudinal study documenting life course trajectories of educational, family, occupational, …psychological, cognitive, and health measures. Methods: Participants are surveyed using the modified Telephone Interview for Cognitive Status (TICS-m) to identify dementia risk. Those scoring below cutoff undergo home-based neuropsychological, physical/neurological, and functional assessments. Dementia diagnosis is determined by consensus panel and merged with existing WLS data for combined analysis. Results: Preliminary findings demonstrate the initial success of the ILIAD protocol in detecting dementia prevalence in the WLS. Increasing age, hearing issues, lower IQ, male sex, APOE4 positivity, and a steeper annualized rate of memory decline assessed in the prior two study waves, all increased likelihood of falling below the TICS-m cutoff for dementia risk. TICS-m scores significantly correlated with standard neuropsychological performance and functional outcomes. Conclusion: We provide an overview of the WLS study, describe existing key lifespan variables relevant to studies of dementia and cognitive aging, detail the current WLS-ILIAD study protocol, and provide a first glimpse of preliminary study findings. Show more

Keywords: Alzheimer’s disease, dementia, epidemiologic determinants, health risk behaviors, prevalence

DOI: 10.3233/JAD-201422

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 751-768, 2021

Authors: Gómez-López, Vıctor Manuel | Viramontes-Pintos, Amparo | Ontiveros-Torres, Miguel Ángel | Garcés-Ramírez, Linda | de la Cruz, Fidel | Villanueva-Fierro, Ignacio | Bravo-Muñoz, Marely | Harrington, Charles R. | Martínez-Robles, Sandra | Yescas, Petra | Guadarrama-Ortíz, Parménides | Hernandes-Alejandro, Mario | Montiel-Sosa, Francisco | Pacheco-Herrero, Mar | Luna-Muñoz, José

Article Type: Research Article

Abstract: Background: Transmissible spongiform encephalopathies (TSEs) are rare neurodegenerative disorders that affect animals and humans. Bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeld-Jakob Disease (CJD) in humans belong to this group. The causative agent of TSEs is called “prion”, which corresponds to a pathological form (PrPSc ) of a normal cellular protein (PrPC ) expressed in nerve cells. PrPSc is resistant to degradation and can induce abnormal folding of PrPC , and TSEs are characterized by extensive spongiosis and gliosis and the presence of PrPSc amyloid plaques. CJD presents initially with clinical symptoms similar to Alzheimer’s disease (AD). In …AD, tau aggregates and amyloid-β protein plaques are associated with memory loss and cognitive impairment in patients. Objective: In this work, we study the role of tau and its relationship with PrPSc plaques in CJD. Methods: Multiple immunostainings with specific antibodies were carried out and analyzed by confocal microscopy. Results: We found increased expression of the glial fibrillary acidic protein (GFAP) and matrix metalloproteinase (MMP-9), and an exacerbated apoptosis in the granular layer in cases with prion disease. In these cases, tau protein phosphorylated at Thr-231 was overexpressed in the axons and dendrites of Purkinje cells and the extensions of parallel fibers in the cerebellum. Conclusion: We conclude that phosphorylation of tau may be a response to a toxic and inflammatory environment generated by the pathological form of prion. Show more

Keywords: Cerebellum, neuronal death, prion encephalopathy, prion protein, tau protein

DOI: 10.3233/JAD-201308

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 769-785, 2021

Authors: Kanatome, Ayana | Ano, Yasuhisa | Shinagawa, Kazushi | Ide, Yumiko | Shibata, Midori | Umeda, Satoshi

Article Type: Research Article

Abstract: Background: Epidemiological studies have shown that dairy product consumption is beneficial for cognitive function in elderly individuals. β-lactolin is a Gly–Thr–Trp–Tyr lacto-tetrapeptide rich in fermented dairy products that improves memory retrieval, attention, and executive function in older adults with subjective cognitive decline and prevents the pathology of Alzheimer’s disease in rodents. There has been no study on the effects of β-lactolin on neural activity in humans. Objective: We investigated the effects of β-lactolin on neural activity and cognitive function in healthy adults. Methods: In this randomized, double-blind, placebo-controlled study, 30 participants (45–64 years old) consumed β-lactolin …or placebo for 6 weeks. Neural activity during auditory and language tasks was measured through 64-channel electroencephalography. Moreover, verbal fluency tests were performed at baseline and after 6 weeks. Results: The β-lactolin group had a significantly higher P300 amplitude at the Cp2 site (a part of the parietal lobe near the center of brain, p  = 0.011), and C4 site (the area between the frontal and parietal lobe, p  = 0.02) during the auditory tasks after 6 weeks than the placebo group. Thus, β-lactolin supplementation promoted neural activity in the parietal area, which increases concentration and attention during auditory cognitive tasks. Compared with the placebo group, the β-lactolin group also showed significant changes in the scores of verbal fluency test after 6 weeks (p  = 0.033). Conclusion: Our findings provide insight into the mechanisms underlying the effects of β-lactolin on attention in healthy adults. Show more

Keywords: attention, clinical trial, cognitive function, EEG, β-lactoglobulin, β-lactolin, β-lactopeptide, memory, P300, whey

DOI: 10.3233/JAD-201413

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 787-796, 2021

Authors: Eeza, Muhamed N.H. | Singer, Rico | Höfling, Corinna | Matysik, Jörg | de Groot, Huub J.M. | Roβner, Steffen | Alia, A.

Article Type: Research Article

Abstract: Background: Circadian rhythm disturbance is commonly observed in Alzheimer’s disease (AD). In mammals, these rhythms are orchestrated by the superchiasmatic nucleus (SCN). Our previous study in the Tg2576 AD mouse model suggests that inflammatory responses, most likely manifested by low GABA production, may be one of the underlying perpetrators for the changes in circadian rhythmicity and sleep disturbance in AD. However, the mechanistic connections between SCN dysfunction, GABA modulation, and inflammation in AD is not fully understood. Objective: To reveal influences of amyloid pathology in Tg2576 mouse brain on metabolism in SCN and to identify key metabolic sensors …that couple SCN dysfunction with GABA modulation and inflammation. Methods: High resolution magic angle spinning (HR-MAS) NMR in conjunction with multivariate analysis was applied for metabolic profiling in SCN of control and Tg2576 female mice. Immunohistochemical analysis was used to detect neurons, astrocytes, expression of GABA transporter 1 (GAT1) and Bmal1. Results: Metabolic profiling revealed significant metabolic deficits in SCN of Tg2576 mice. Reductions in glucose, glutamate, GABA, and glutamine provide hints toward an impaired GABAergic glucose oxidation and neurotransmitter cycling in SCN of AD mice. In addition, decreased redox co-factor NADPH and glutathione support a redox disbalance. Immunohistochemical examinations showed low expression of the core clock protein, Bmal1, especially in activated astrocytes. Moreover, decreased expression of GAT1 in astrocytes indicates low GABA recycling in this cell type. Conclusion: Our results suggest that redox disbalance and compromised GABA signaling are important denominators and connectors between neuroinflammation and clock dysfunction in AD. Show more

Keywords: Alzheimer’s disease, GABA dysfunction, 1H high-resolution magic angle spinning NMR, metabolic deficit, suprachiasmatic nucleus, Tg2576 mouse model

DOI: 10.3233/JAD-201575

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 797-808, 2021