Journal of Alzheimer's Disease - Volume 84, issue 2

Authors: Bagheri, Nasser | Mavoa, Suzanne | Tabatabaei-Jafari, Hossein | Knibbs, Luke D. | Coffee, Neil T. | Salvador-Carulla, Luis | Anstey, Kaarin J.

Article Type: Research Article

Abstract: Background: Dementia is a major global health challenge and the impact of built and social environments’ characteristics on dementia risk have not yet been fully evaluated. Objective: To investigate associations between built and social environmental characteristics and diagnosed dementia cases and estimated dementia risk. Methods: We recruited 25,511 patients aged 65 and older from family physicians’ practices. We calculated a dementia risk score based on risk and protective factors for patients not diagnosed with dementia. Our exposure variables were estimated for each statistical area level 1: social fragmentation, nitrogen dioxide, public open spaces, walkability, socio-economic status, …and the length of main roads. We performed a multilevel mixed effect linear regression analysis to allow for the hierarchical nature of the data. Results: We found that a one standard deviation (1-SD) increase in NO2 and walkability score was associated with 10% higher odds of any versus no dementia (95% CI: 1%, 21% for NO2 and 0%, 22% for walkability score). For estimated future risk of dementia, a 1-SD increase in social fragmentation and NO2 was associated with a 1% increase in dementia risk (95% CI: 0, 1%). 1-SD increases in public open space and socioeconomic status were associated with 3% (95% CI: 0.95, 0.98) and 1% decreases (95% CI: 0.98, 0.99) in dementia risk, respectively. There was spatial heterogeneity in the pattern of diagnosed dementia and the estimated future risk of dementia. Conclusion: Associations of neighborhood NO2 level, walkability, public open space, and social fragmentation with diagnosed dementia cases and estimated future risk of dementia were statistically significant, indicating the potential to reduce the risk through changes in built and social environments. Show more

Keywords: Dementia, green spaces, social fragmentation, spatial analysis, walkability

DOI: 10.3233/JAD-210208

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 621-632, 2021

Authors: Kang, Sung Hoon | Cho, Hanna | Shin, Jiho | Kim, Hang-Rai | Noh, Young | Kim, Eun-Joo | Lyoo, Chul Hyoung | Jang, Hyemin | Kim, Hee Jin | Koh, Seong-Beom | Na, Duk L. | Suh, Mee Kyung | Seo, Sang Won

Article Type: Research Article

Abstract: Background: Primary progressive aphasia (PPA) is associated with amyloid-β (Aβ) pathology. However, clinical feature of PPA based on Aβ positivity remains unclear. Objective: We aimed to assess the prevalence of Aβ positivity in patients with PPA and compare the clinical characteristics of patients with Aβ-positive (A+) and Aβ-negative (A–) PPA. Further, we applied Aβ and tau classification system (AT system) in patients with PPA for whom additional information of in vivo tau biomarker was available. Methods: We recruited 110 patients with PPA (41 semantic [svPPA], 27 non-fluent [nfvPPA], 32 logopenic [lvPPA], and 10 unclassified [ucPPA]) …who underwent Aβ-PET imaging at multi centers. The extent of language impairment and cortical atrophy were compared between the A+ and A–PPA subgroups using general linear models. Results: The prevalence of Aβ positivity was highest in patients with lvPPA (81.3%), followed by ucPPA (60.0%), nfvPPA (18.5%), and svPPA (9.8%). The A+ PPA subgroup manifested cortical atrophy mainly in the left superior temporal/inferior parietal regions and had lower repetition scores compared to the A–PPA subgroup. Further, we observed that more than 90% (13/14) of the patients with A+ PPA had tau deposition. Conclusion: Our findings will help clinicians understand the patterns of language impairment and cortical atrophy in patients with PPA based on Aβ deposition. Considering that most of the A+ PPA patents are tau positive, understanding the influence of Alzheimer’s disease biomarkers on PPA might provide an opportunity for these patients to participate in clinical trials aimed for treating atypical Alzheimer’s disease. Show more

Keywords: Amyloid-β, biomarker, language, primary progressive aphasia, tau

DOI: 10.3233/JAD-210392

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 633-645, 2021

Authors: Culibrk, Robert A. | Arabiyat, Ahmad S. | DeKalb, Carisa A. | Hahn, Mariah S.

Article Type: Research Article

Abstract: Background: A significant subset of patients with Alzheimer’s disease (AD) exhibit low bone mineral density and are therefore more fracture-prone, relative to their similarly aged neurotypical counterparts. In addition to chronic immune hyperactivity, behavioral dysregulation of effector peripheral sympathetic neurons—which densely innervate bone and potently modulate bone remodeling—is implicated in this pathological bone reformation. Objective: Thus, there exists a pressing need for a robust in vitro model which allows interrogation of the paracrine interactions between the putative mediators of AD-related osteopenia: sympathetic neurons (SNs) and mesenchymal stem cells (MSCs). Methods: Toward this end, activated SN-like …PC12 cells and bone marrow derived MSCs were cultured in poly(ethylene glycol) diacrylate (PEGDA) hydrogels in the presence or absence of the AD-relevant inflammatory cytokine tumor necrosis factor alpha (TNF-α) under mono- and co-culture conditions. Results: PC12s and MSCs exposed separately to TNF-α displayed increased expression of pro-inflammatory mediators and decreased osteopontin (OPN), respectively. These data indicate that TNF-α was capable of inducing a dysregulated state in both cell types consistent with AD. Co-culture of TNF-α-activated PC12s and MSCs further exacerbated pathological behaviors in both cell types. Specifically, PC12s displayed increased secretion of interleukin 6 relative to TNF-α stimulated monoculture controls. Similarly, MSCs demonstrated a further reduction in osteogenic capacity relative to TNF-α stimulated monoculture controls, as illustrated by a significant decrease in OPN and collagen type I alpha I chain. Conclusion: Taken together, these data may indicate that dysregulated sympathetic activity may contribute to AD-related bone loss. Show more

Keywords: Alzheimer’s disease, inflammation, mesenchymal stem cells, osteopenia

DOI: 10.3233/JAD-215007

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 647-658, 2021

Authors: Wei, Qiang | Cao, Shanshan | Ji, Yang | Zhang, Jun | Chen, Chen | Wang, Xiaojing | Tian, Yanghua | Qiu, Bensheng | Wang, Kai

Article Type: Research Article

Abstract: Background: The white matter hyperintensities (WMHs) are considered as one of the core neuroimaging findings of cerebral small vessel disease and independently associated with cognitive deficit. The parietal lobe is a heterogeneous area containing many subregions and play an important role in the processes of neurocognition. Objective: To explore the relationship between parietal subregions alterations and cognitive impairments in WHMs. Methods: Resting-state functional connectivity (rs-FC) analyses of parietal subregions were performed in 104 right-handed WMHs patients divided into mild (n  = 39), moderate (n  = 37), and severe WMHs (n  = 28) groups according to the Fazekas scale and …36 healthy controls. Parietal subregions were defined using tractographic Human Brainnetome Atlas and included five subregions for superior parietal lobe, six subregions for inferior parietal lobe (IPL), and three subregions for precuneus. All participants underwent a neuropsychological test battery to evaluate emotional and general cognitive functions. Results: Differences existed between the rs-FC strength of IPL_R_6_2 with the left anterior cingulate gyrus, IPL_R_6_3 with the right dorsolateral superior frontal gyrus, and the IPL_R_6_5 with the left anterior cingulate gyrus. The connectivity strength between IPL_R_6_3 and the left anterior cingulate gyrus were correlated with AVLT-immediate and AVLT-recognition test in WMHs. Conclusion: We explored the roles of parietal subregions in WMHs using rs-FC. The functional connectivity of parietal subregions with the cortex regions showed significant differences between the patients with WMHs and healthy controls which may be associated with cognitive deficits in WMHs. Show more

DOI: 10.3233/JAD-210315

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 659-669, 2021

Authors: Lazarova, Maria | Tancheva, Lyubka | Alexandrova, Albena | Tsvetanova, Elina | Georgieva, Almira | Stefanova, Miroslava | Tsekova, Daniela | Vezenkov, Lyubomir | Kalfin, Reni | Uzunova, Diamara | Petkova-Kirova, Polina

Article Type: Research Article

Abstract: Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive functions decline, is a leading cause for dementia and currently ranked as the sixth foremost cause of death. As of present, treatment of AD is symptomatic without convincing therapeutic benefits and new, effective, therapeutic agents are pursued. Due to massive loss of cholinergic neurons and decreased acetylcholine levels, cholinesterase inhibitors like galantamine, remain the backbone of pharmacological treatment of the disease. In the present study, using behavioral and biochemical methods, four newly synthesized galantamine derivatives, Gal 34, Gal 43, Gal 44, and Gal 46, were evaluated for …a beneficial effect in a scopolamine model of dementia in mice. They were designed to have all the advantages of galantamine and additionally to inhibit β-secretase and exert favorable effects on plasma lipids. Behavioral tests included step-through inhibitory avoidance, T-maze, and the hole-board test, whereas biochemical evaluations involved assessment of acetylcholinesterase activity, brain monoamines levels, lipid peroxidation, catalase, glutathione peroxidase, and superoxide dismutase activities along with measurement of total glutathione. Results show that Gal 43, Gal 44, and, in particular, Gal 46 are especially effective in improving both short- and long-term memory and in the case of Gal 46 having a significant effect on exploratory activity as well. Although Gal 34 did not show behavioral effects as convincing as those of the other three galantamine derivatives, it demonstrated persuasive antioxidant and restorative capacities, making all four galantamine derivatives promising AD treatment agents and prompting further research, especially that in many of our studies they performed better than galantamine. Show more

Keywords: Alzheimer’s disease, cholinesterase inhibitors, dementia, galantamine, scopolamine

DOI: 10.3233/JAD-215165

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 671-690, 2021

Authors: Lazris, David | Perkins, Molly M. | Bay, Allison A. | Hackney, Madeleine E.

Article Type: Research Article

Abstract: Background: 10%to 20%of Americans aged 65 and older have mild cognitive impairment (MCI) with 10%progressing to Alzheimer’s disease (AD) each year. Underserved groups, including African Americans (AAs), are among the most vulnerable to MCI and AD. Although evidence continues to amass, the benefits of exercise and movement for AD is still understudied in AD. Objective: Understanding the attitudes, perceptions, and beliefs about motor-cognitive integration and examining the physical activity of a sample of predominantly Black women community members with self-reported memory problems will allow improved recruitment and refinement of multimodal interventions designed to improve motor-cognitive and cognitive function. …Methods: We conducted focus groups with older adults who reported subjective memory complaints (n  = 15; Black: n  = 12, White: n  = 3, mean age 71.7±5.8). Results: Findings from thematic analysis showed most participants knew of benefits of exercise. However, most participants reported not getting adequate exercise due to factors such as pain, increased responsibilities, and fear of injury. Despite barriers, participants expressed enthusiasm for multimodal interventions designed to target body and brain health and provided several suggestions to improve or enhance the proposed interventions. Conclusion: Results provide useful insights regarding improving participation among historically under-represented groups in clinical movement-based research. Participants’ discussion focused primarily on the way motor-cognitive integration prevents falls, maintains memory, and provides a social benefit. The reported perceived benefits and limitations of exercise, as this population understands it, can help researchers and physicians better engage the community for lifestyle changes that will support greater motor-cognitive health. Show more

Keywords: Alzheimer’s disease, cognitive impairment, exercise, motor cognition, older adults, patient engagement, patient’s perspective

DOI: 10.3233/JAD-210617

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 691-703, 2021

Authors: Read, Sanna | Hu, Bo | Wittenberg, Raphael | Brimblecombe, Nicola | Robinson, Louise | Banerjee, Sube

Article Type: Research Article

Abstract: Background: Understanding the changes of unmet need in dementia may enable effective targeting of help and allow people to stay in their homes longer. Objective: We investigated changes in unmet need and functioning over a 4-year period and the role of socio-demographic factors in these changes among people with dementia. Methods: 234 community-dwelling people with dementia at baseline were studied in three consecutive waves (four years) of the English Longitudinal Study of Ageing (ELSA). Unmet needs (self/informant-reported limitations for which no help was received) and functional limitations (self/informant-reported difficulties in activities/instrumental activities of daily living and …mobility) were modelled with latent growth curves. Sex, age, partnership, and socioeconomic status at baseline were used as predictors. Admission to a care home was an additional outcome. Results: Unmet needs increased over time, especially among those who initially had more functional limitations. Unmet needs contributed to faster decline in functional capability, except among those with many limitations initially. The major driver of increased unmet needs was not having a partner (direct effect). Age, sex, and wealth contributed indirectly via the initial level of functional limitations and/or unmet need. Those with several functional limitations but few unmet needs were most likely to move to a care home. Conclusion: Unmet need increases over time in those with dementia with mitigating effects of having a partner and initial levels of functioning. Meeting needs at early stages of dementia, especially for those living alone and when functional limitations are low may help slow functional decline. Show more

Keywords: Dementia, functional status, longitudinal survey, needs, social inequalities

DOI: 10.3233/JAD-210724

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 705-716, 2021

Authors: Katz, Joseph | Gao, Hanzhi

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease with unclear etiology. Recent studies have demonstrated a potential role for gut microbiome. There is, however, a significant dearth in epidemiological correlation between gut bacteria and AD. Objective: To investigate the association between Escherichia coli (E. coli ) infection and AD. Methods: Counts of patients with ICD 10 diagnoses of AD, E. coli , urinary tract infection, and comorbidities were retrieved from the electronic health records at the University of Florida Health Center. Results: The relative risk for AD with a previous event of E. …coli was 5.17 (95%CI 4.0786 to 6.5446, p  < 0.0001). In the unadjusted association, patients with E. coli infection had odds ratio (OR) of 20.83 to have AD (95%CI, 17.7–24.34; p  < 0.0001); after adjusting for gender (OR = 12.71; 95%CI, 10.82–14.83; p  < 0.0001), race (OR = 13.97; 95%CI, 11.84–16.36; p  < 0.0001), age group (OR = 11.51; 95%CI, 9.73–13.54; p  < 0.0001), diabetes (OR = 9.23; 95%CI, 7.79–10.87; p  < 0.0001), stroke (OR = 5.31; 95%CI, 4.47–6.28; p  < 0.0001), and hypertension (OR = 4.55; 95%CI, 3.86–5.32; p  < 0.0001). Conclusion: These results should be taken cautiously. This retrospective cross-sectional study cannot infer causality and had used aggregate data that did not allow simultaneous adjustments of covariates. Future studies are warranted to investigate the link between gut bacteria and AD. Show more

Keywords: Alzheimer’s disease, association, E. coli, infection

DOI: 10.3233/JAD-215004

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 717-721, 2021

Authors: Galvin, James E. | Kleiman, Michael J. | Walker, Marcia

Article Type: Research Article

Abstract: Background: Screening for Alzheimer’s disease and related disorders (ADRD) and mild cognitive impairment (MCI) could increase case identification, enhance clinical trial enrollment, and enable early intervention. MCI and ADRD screening would be most beneficial if detection measures reflect neurodegenerative changes. Optical coherence tomography (OCT) could be a marker of neurodegeneration (part of the amyloid-tau-neurodegeneration (ATN) framework). Objective: To determine whether OCT measurements can be used as a screening measure to detect individuals with MCI and ADRD. Methods: A retrospective cross-sectional study was performed on 136 participants with comprehensive clinical, cognitive, functional, and behavioral evaluations including OCT …with a subset (n  = 76) completing volumetric MRI. Pearson correlation coefficients tested strength of association between OCT and outcome measures. Receiver operator characteristic curves assessed the ability of OCT, patient-reported outcomes, and cognitive performance measures to discriminate between individuals with and without cognitive impairment. Results: After controlling for age, of the 6 OCT measurements collected, granular cell layer-inner plexiform layer (GCL + IPL) thickness best correlated with memory, global cognitive performance, Clinical Dementia Rating, and hippocampal atrophy. GCL + IPL thickness provided good discrimination in cognitive status with a cut-off score of 75μm. Combining GCL + IPL thickness as a proxy marker for hippocampal atrophy with a brief patient-reported outcome and performance measure correctly classified 87%of MCI and ADRD participants. Conclusion: Multimodal approaches may improve recognition of MCI and ADRD. OCT has the potential to be a practical, non-invasive biomarker for ADRD providing a screening platform to quickly identify at-risk individuals for further clinical evaluation or research enrollment. Show more

Keywords: Alzheimer’s disease, dementia, granular cell layer, internal plexiform layer, mild cognitive impairment, optical coherence tomography

DOI: 10.3233/JAD-210328

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 723-736, 2021

Authors: Capuano, Ana W. | Wilson, Robert S. | Leurgans, Sue E. | Sampaio, Carolina | Farfel, Jose M. | Barnes, Lisa L. | Bennett, David A.

Article Type: Research Article

Abstract: Background: Literacy is more consistently reported than education as protective against dementia in developing regions. Objective: To study the association of verbal literacy, numeracy, and music literacy with dementia in older Black and White Brazilians with a broad spectrum of education. Methods: We studied 1,818 Black, Mixed-race, and White deceased Brazilians 65 years or older at death (mean = 79.64). Data were retrospectively obtained within 36 hours after death in a face-to-face interview with an informant, usually a family member. Dementia was classified using the Clinical Dementia Rating (CDR) scale. Three forms of literacy were ascertained: verbal literacy …(10 questions: reading and writing), numeracy (3 questions: multiplication, percentages, and use of a calculator), and music literacy (1 question: reading music). Black (11%) and Mixed-race (23%) older adults were combined in analyses. Models adjusted for age and sex. Results: Dementia was identified in 531 people. Participants had 0 to 25 years of education (median = 4). More literacy was associated with lower odds of dementia (all p ≤0.039). Participants that read music had about half the odds of having dementia. Participants in the highest quartile of numeracy and verbal literacy had respectively 27%and 15%lower odds of having dementia compared to the lowest quartile. Literacy was lower in Blacks (p  < 0.001, except music p  = 0.894) but the effect of literacy on dementia was similar (interaction p  > 0.237). In secondary analyses, playing instruments without reading music was not associated with dementia (p  = 0.887). Conclusion: In a large sample of Brazilians, verbal literacy, numeracy, and music literacy were associated with lower odds of dementia. The effect was similar across races. Show more

Keywords: African American, Brazil, education, latinos, race

DOI: 10.3233/JAD-210601

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 737-744, 2021