Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Lennon, Matthew J. | Rigney, Grant | Raymont, Vanessa | Sachdev, Perminder

Article Type: Research Article

Abstract: Effective, disease modifying therapies for Alzheimer’s disease (AD) remain a quandary, following a panoply of expensive failures in human clinical trials. Given the stagnation in therapeutics, alternative approaches are needed. Recent successes of genetic therapies in other neurodegenerative diseases may highlight the way forward. This scoping review explores suggested targets of genetic therapy in AD, with a focus on vector-based approaches in pre-clinical and clinical trials. Putative targets of genetic therapies tested in pre-clinical trials include amyloid pathway intermediates and enzymes modulation, tau protein downregulation, APOE4 downregulation and APOE2 upregulation, neurotrophin expression (nerve growth factor (NGF) and brain-derived …neurotrophic factor), and inflammatory cytokine alteration, among several other approaches. There have been three completed human clinical trials for genetic therapy in AD patients, all of which upregulated NGF in AD patients, showing some mixed evidence of benefit. Several impediments remain to be surpassed before genetic therapies can be successfully applied to AD, including the challenge of delivering monogenic genetic therapies for complex polygenic disorders, risks in the dominant delivery method (intracranial injection), stability of genetic therapies in vivo , poor translatability of pre-clinical AD models, and the expense of genetic therapy production. Genetic therapies represent an exciting opportunity within the world of AD therapeutics, but clinical applications likely remain a long term, rather than short term, possibility. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, gene, genetic therapy, review, tau, therapy

DOI: 10.3233/JAD-215145

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Nan, Haitian | Kim, Yeon-Jeong | Tsuchiya, Mai | Fukao, Toko | Hara, Noriko | Hagihara, Atsushi | Nishioka, Kenya | Hattori, Nobutaka | Hara, Norikazu | Ikeuchi, Takeshi | Ohtsuka, Toshihisa | Takiyama, Yoshihisa

Article Type: Short Communication

Abstract: Familial dementia is a rare inherited disease involving progressive impairment of memory, thinking, and behavior. We report a novel heterozygous pathogenic variant (c.199G > A, p.Val67Ile) in the CIAO1 gene that appears to be co-segregated with Alzheimer’s disease in a Japanese family. Biochemical analysis of CIAO1 protein revealed that the variant increases the interaction of CIAO1 with immature amyloid-β protein precursor (AβPP), but not mature or soluble AβPP, indicating plausible CIAO1 involvement in AβPP processing. Our study indicates that a heterozygous variant in the CIAO1 gene may be closely related to autosomal dominant familial dementia.

Keywords: Alzheimer’s disease, amyloid-β protein precursor processing, CIAO1, CIAO1 protein, cognitive decline, dementia, familial, neurogenetics

DOI: 10.3233/JAD-210706

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Lazarova, Maria | Tancheva, Lyubka | Alexandrova, Albena | Tzvetanova, 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. Pre-press, no. Pre-press, pp. 1-20, 2021

Authors: Wang, Qixin | Dong, Xiaofang | Zhang, Ran | Zhao, Changqi

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a central neurodegenerative disease generally among the elderly; it accounts for approximately 50–75%of total cases of dementia patients and poses a serious threat to physical and mental health. Currently available treatments for AD mainly relieves its symptoms, and effective therapy is urgently needed. Deposition of amyloid-β protein in the brain is an early and invariant neuropathological feature of AD. Currently the main efforts in developing anti-AD drugs focus on anti-amyloidogenic therapeutics that prevent amyloid-β production or aggregation and decrease the occurrence of neurotoxic events. The results of an increasing number of studies suggest that natural extracts …and phytochemicals have a positive impact on brain aging. Flavonoids belong to the broad group of polyphenols and recent data indicate a favorable effect of flavonoids on brain aging. In this review, we collect relevant discoveries from 1999 to 2021, discuss 75 flavonoids that effectively influence AD pathogenesis, and summarize their functional mechanisms in detail. The data we have reviewed show that, these flavonoids belong to various subclasses, including flavone, flavanone, biflavone, etc. Our results provide a reference for further study of the effects of flavonoids on AD and the progress of anti-AD therapy. Show more

Keywords: Alzheimer’s disease, amyloid-β protein, flavonoids, phytochemicals, structure-activity relationship

DOI: 10.3233/JAD-210735

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-29, 2021

Authors: Block, Michelle L. | Kodavanti, Urmila P.

Article Type: Research Article

Abstract: The mechanisms underlying how urban air pollution exposure conveys Alzheimer’s disease risk and affects plaque pathology is largely unknown. Because particulate matter, the particle component of urban air pollution, varies across location, pollution source, and time, a single model representative of all ambient particulate matter is unfeasible for research investigating the role of ar pollution in central nervous system diseases. More specifically, the investigation of several models of particulate matter with enrichment of source-specific components are essential to employ, in order to more fully understand what characteristics of particulate matter affects Alzheimer’s disease, including standardized diesel exhaust particles.

Keywords: Air pollution, Alzheimer’s disease, diesel exhaust particles, particulate matter models

DOI: 10.3233/JAD-215201

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-2, 2021

Authors: Chen, Huiyi | Chen, Feng | Zhang, Miaoping | Chen, Yanting | Cui, Lili | Liang, Chunmei

Article Type: Research Article

Abstract: Autophagy is a basic physiological process maintaining cell renewal, the degradation of dysfunctional organelles, and the clearance of abnormal proteins and has recently been identified as a main mechanism underlying the onset and progression of Alzheimer’s disease (AD). The APOE ɛ4 genotype is the strongest genetic determinant of AD pathogenesis and initiates autophagic flux at different times. This review synthesizes the current knowledge about the potential pathogenic effects of ApoE4 on autophagy and describes its associations with the biological hallmarks of autophagy and AD from a novel perspective. Via a remarkable variety of widely accepted signaling pathway markers, such …as mTOR, TFEB, SIRT1, LC3, p62, LAMP1, LAMP2, CTSD, Rabs, and V-ATPase, ApoE isoforms differentially modulate autophagy initiation; membrane expansion, recruitment, and enclosure; autophagosome and lysosome fusion; and lysosomal degradation. Although the precise pathogenic mechanism varies for different genes and proteins, the dysregulation of autophagic flux is a key mechanism on which multiple pathogenic processes converge. Show more

Keywords: Alzheimer’s disease, apolipoproteins E, autophagy, neurodegenerative diseases

DOI: 10.3233/JAD-210602

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 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. Pre-press, no. Pre-press, pp. 1-14, 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. Pre-press, no. Pre-press, pp. 1-5, 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. Pre-press, no. Pre-press, pp. 1-8, 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. Pre-press, no. Pre-press, pp. 1-12, 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. Pre-press, no. Pre-press, pp. 1-11, 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. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Dutzi, Ilona | Schwenk, Michael | Kirchner, Marietta | Jooss, Eva | Bauer, Jürgen M. | Hauer, Klaus

Article Type: Research Article

Abstract: Background: Cognitive impairment (CI) has been reported to negatively impact rehabilitation outcomes. Knowledge about differences in rehabilitation received in dependence of CI as a potential mediating factor is limited. Objective: To analyze whether CI affects amount and frequency of rehabilitation received and if associations between CI and rehabilitation outcome are mediated by the provided amount of therapy. Methods: Observational cohort study in ward-based geriatric rehabilitation consecutively including 373 patients (mean age 82.0±6.69 years, mean MMSE 23.66±5.31). Outcome measures were amount, frequency, and type of multi-professional therapy sessions and rehabilitation outcome assessed with the Barthel Index (BI). …Cognitive status was measured with the Mini-Mental-State Examination (MMSE) classifying three patient subgroups according to cognitive status were considered. Results: Patients with more severe CI received least total therapy hours (TTH) (MMSE <  17, 13.67±6.58 versus MMSE 17–26, 16.12±7.19 and MMSE >  26, 17.79±8.88 h, p  = 0.014) and were less often included in occupational therapy (MMSE <  17, 48.9%versus MMSE 17–26, 65.5%and MMSE >  26, 71.4%, p  = 0.019) and group-based physiotherapy (MMSE <  17, 73.3%versus MMSE 17–26, 88.5%and MMSE >  26, 81.2%, p  = 0.027). Regression models showed that CI negatively impacted TTH (β= 0.24, p  = 0.003) and rehabilitation outcome (β= 0.41, p  = 0.008). In the mediation model, TTH accounted for 23.18%(p  <  0.001) of the relationship between CI and rehabilitation outcome. Conclusion: Cognitive impairment negatively impacted rehabilitation received. The lower TTH partly mediated the negative association between CI and rehabilitation outcome. Future research should identify specific barriers to therapy provision and optimal length, intensity, and dosage of rehabilitation programs to optimize rehabilitation outcomes in CI. Show more

Keywords: Cognitive impairment, functional outcome, rehabilitation, therapy provision

DOI: 10.3233/JAD-210620

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

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 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. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Lan, Yu-Tung | Blacker, Deborah | Yuan, Changzheng | Chibnik, Lori B. | Hofman, Albert | Ma, Yuan

Article Type: Research Article

Abstract: Background: The evidence regarding dementia and late-life weight change is inconsistent, and data on body weight fluctuation and dementia are limited. Objective: To test the hypothesis that weight loss and substantial weight fluctuation predict cognitive decline independent of body weight and traditional risk factors of dementia. Methods: This study utilized longitudinal data from the National Alzheimer’s Coordinating Center for 10,639 stroke- and dementia-free older adults (60.9%female, mean age 71.6 years, median follow-up 5.5 years). Trends in weight change and weight fluctuation were estimated for each individual by regressing repeated body weight measurements on time. Cognitive decline …was examined as diagnostic progression from normal to mild cognitive impairment (MCI) or dementia and from MCI to dementia. Results: Compared to participants with stable weight, those with weight loss had increased odds of diagnostic progression (adjusted OR = 1.35, 95%CI [1.21, 1.51 ]). Also, large weight fluctuation was associated with increased odds of diagnostic progression (OR comparing the extreme quartiles = 1.20, 95%CI [1.04, 1.39 ]) after adjusting for traditional risk factors for dementia and body weight change. The magnitude of the association appeared larger among those older than 80 and those with 3 or more cardiometabolic risk factors at baseline (both p for interaction <  0.05). Conclusion: Weight loss and substantial weight fluctuation during late-life were associated with increased odds of cognitive decline independent of body weight and traditional risk factors of dementia. Our results suggested the linkage between late-life body weight instability and cognitive decline especially among those with greater age or higher cardiometabolic risk. Show more

Keywords: Alzheimer’s disease, body weight, dementia, epidemiology

DOI: 10.3233/JAD-210625

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Mulak, Agata

Article Type: Research Article

Abstract: Recently, the concept of the brain-gut-microbiota (BGM) axis disturbances in the pathogenesis of Alzheimer’s disease (AD) has been receiving growing attention. At the same time, accumulating data revealing complex interplay between bile acids (BAs), gut microbiota, and host metabolism have shed new light on a potential impact of BAs on the BGM axis. The crosstalk between BAs and gut microbiota is based on reciprocal interactions since microbiota determines BA metabolism, while BAs affects gut microbiota composition. Secondary BAs as microbe-derived neuroactive molecules may affect each of three main routes through which interactions within the BGM axis occur including neural, immune, …and neuroendocrine pathways. BAs participate in the regulation of multiple gut-derived molecule release since their receptors are expressed on various cells. The presence of BAs and their receptors in the brain implies a direct effect of BAs on the regulation of neurological functions. Experimental and clinical data confirm that disturbances in BA signaling are present in the course of AD. Disturbed ratio of primary to secondary BAs as well as alterations in BA concertation in serum and brain samples have been reported. Aging-related shift in the gut microbiota composition associated with its decreased diversity and stability observed in AD patients may significantly affect BA metabolism and signaling. Given recent evidence on BA neuroprotective and anti-inflammatory effects, new therapeutic targets have been explored including gut microbiota modulation by probiotics and dietary interventions, ursodeoxycholic acid supplementation, and use of BA receptor agonists. Show more

Keywords: Alzheimer’s disease, bile acids, brain-gut-microbiota axis

DOI: 10.3233/JAD-210608

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Golzari-Sorkheh, Mahdieh | Brown, Carla | Weaver, Donald F. | Reed, Mark

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common form of dementia. Although AD is one of the most socioeconomically devastating diseases confronting humanity, no “curative” disease modifying drug has been identified. Recent decades have witnessed repeated failures of drug trials and have called into question the utility of the amyloid hypothesis approach to AD therapeutics design. Accordingly, new neurochemical processes are being evaluated and explored as sources of alternative druggable targets. Among these newly identified targets, neuroinflammation is emerging as a front-runner, and within the realm of neuroinflammation, the inflammasome, particularly the NLRP3 complex, is garnering focussed attention. This review summarizes …current data and approaches to understanding the role of the NLRP3 inflammasome in neuroinflammation and AD, and systematically identifies and evaluates multiple targets within the NLRP3 inflammasome cascade as putative drug targets. Show more

Keywords: Alzheimer’s disease, dementia, inflammasome, innate immune, NLRP3

DOI: 10.3233/JAD-210660

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 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 fears 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. Pre-press, no. Pre-press, pp. 1-13, 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. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Kitani-Morii, Fukiko | Friedland, Robert P. | Yoshida, Hideki | Mizuno, Toshiki

Article Type: Research Article

Abstract: Accumulating evidence show that the gut microbiota is deeply involved not only in host nutrient metabolism but also in immune function, endocrine regulation, and chronic disease. In neurodegenerative conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis, the gut-brain axis, the bidirectional interaction between the brain and the gut, provides new route of pathological spread and potential therapeutic targets. Although studies of gut microbiota have been conducted mainly in mice, mammalian gut microbiota is highly diverse, complex, and sensitive to environmental changes. Drosophila melanogaster, a fruit fly, has many advantages as a laboratory animal: short …life cycle, numerous and genetically homogenous offspring, less ethical concerns, availability of many genetic models, and low maintenance costs. Drosophila has a simpler gut microbiota than mammals and can be made to remain sterile or to have standardized gut microbiota by simple established methods. Research on the microbiota of Drosophila has revealed new molecules that regulate the brain-gut axis, and it has been shown that dysbiosis of the fly microbiota worsens lifespan, motor function, and neurodegeneration in AD and PD models. The results shown in fly studies represents a fundamental part of the immune and proteomic process involving gut-microbiota interactions that are highly conserved. Even though the fly’s gut microbiota are not simple mimics of humans, flies are a valuable system to learn the molecular mechanisms of how the gut microbiota affect host health and behavior. Show more

Keywords: Alzheimer’s disease, cross-seeding, Drosophila melanogaster, gut-brain axis, gut microbiota, inflammation, neurodegeneration, Parkinson’s disease

DOI: 10.3233/JAD-215031

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Seo, Seung-Jun | Chang, Won-Seok | Jeon, Jae-Geun | Choi, Younshick | Kim, EunHo | Kim, Jong-Ki

Article Type: Research Article

Abstract: Background: The coexistence of magnetite within protein aggregates in the brain is a typical pathologic feature of Alzheimer’s disease (AD), and the formation of amyloid-β (Aβ) plaques induces critical impairment of cognitive function. Objective: This study aimed to investigate the therapeutic effect of proton stimulation (PS) targeting plaque magnetite in the transgenic AD mouse brain. Methods: A proton transmission beam was applied to the whole mouse brain at a single entrance dose of 2 or 4 Gy to test the effect of disruption of magnetite-containing Aβ plaques by electron emission from magnetite. The reduction in Aβ plaque …burden and the cognitive function of the PS-treated mouse group were assayed by histochemical analysis and memory tests, respectively. Aβ-magnetite and Aβ fibrils were treated with PS to investigate the breakdown of the amyloid protein matrix. Results: Single PS induced a 48–87%reduction in both the amyloid plaque burden and ferrous-containing magnetite level in the early-onset AD mouse brain while saving normal tissue. The overall Aβ plaque burden (68–82%) and (94–97%) hippocampal magnetite levels were reduced in late onset AD mice that showed improvements in cognitive function after PS compared with untreated AD mice (p  <  0.001). Analysis of amyloid fibrils after exposure to a single 2 or 4 Gy proton transmission beam demonstrated that the protein matrix was broken down only in magnetite-associated Aβ fibrils. Conclusion: Single PS targeting plaque magnetite effectively decreases the amyloid plaque burden and the ferrous-containing magnetite level, and this effect is useful for memory recovery. Show more

Keywords: Adult neurogenesis, Alzheimer’s disease, amyloid plaque magnetite, iron toxicity, memory recovery, proton-stimulated magnetite, proton transmission beam

DOI: 10.3233/JAD-210739

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Brugulat-Serrat, Anna | Cañas, Alba | Canals, Lidia | Marne, Paula | Gramunt, Nina | Milà-Alomà, Marta | Suárez-Calvet, Marc | Arenaza-Urquijo, Eider M. | Grau-Rivera, Oriol | González-de-Echávarri, José María | Minguillon, Carolina | Fauria, Karine | Kollmorgen, Gwendlyn | Suridjan, Ivonne | Zetterberg, Henrik | Blennow, Kaj | Gispert, Juan Domingo | Molinuevo, José Luis | Sánchez-Benavides, Gonzalo | for the ALFA study

Article Type: Research Article

Abstract: Background: Cognitive performance of a given individual should be interpreted in the context of reference standards obtained in cognitively healthy populations. Recent evidence has shown that removing asymptomatic individuals with biomarker evidence of Alzheimer’s disease (AD) pathology from normative samples increases the sensitivity of norms to detect memory impairments. These kind of norms may be useful for defining subtle cognitive decline, the transitional cognitive decline between normal cognition and mild cognitive impairment. Objective: The present study aims to provide norms for the Free and Cued Selective Reminding Test (FCSRT) and the Logical Memory subtest of the Wechsler Memory …Scale-IV in a sample of individuals aged 50–70 years with normal levels of amyloid (A) and tau (T) cerebrospinal fluid (CSF) biomarkers. Methods: The sample was composed of 248 individuals from the ALFA+ study with negative amyloid-β and tau CSF biomarker levels. Regression-based norms were developed, including adjustments for age, education, and sex when applicable. Results: We found that education was associated with the performance in all the variables of both tests while age had a marginal effect only in the delayed free recall of the FCSRT. Sex was also related to the performance in the FCSRT, with women outperforming men. Equations to calculate z-scores and normative percentile tables were created. As compared with previously published norms the reference data presented were more sensitive but less specific, as expected. Conclusion: The use of the norms provided in this work, in combination with the already published conventional norms, may contribute to detecting subtle memory impairment. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cognition, memory, norms, sex

DOI: 10.3233/JAD-210640

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Tarawneh, Hadeel Y. | Mulders, Wilhelmina H.A.M. | Sohrabi, Hamid R. | Martins, Ralph N. | Jayakody, Dona M.P.

Article Type: Research Article

Abstract: Background: Objectively measuring auditory functions has been proposed as an avenue in differentiating normal age-related cognitive dysfunction from Alzheimer’s disease (AD) and its prodromal states. Previous research has suggested auditory event-related potentials (AERPs) to be non-invasive, cost-effective, and efficient biomarkers for the diagnosis of AD. Objective: The objective of this paper is to review the published literature on AERPs measures in older adults diagnosed with AD and those at higher risk of developing AD, i.e., mild cognitive impairment (MCI) and subjective cognitive decline. Methods: The search was performed on six major electronic databases (Ovid MEDLINE, OVID …EMBASE, PsycINFO, PubMed, Scopus, and CINAHL Plus). Articles identified prior to 7 May 2019 were considered for this review. A random effects meta-analysis and analysis of between study heterogeneity was conducted using the Comprehensive Meta-Analysis software. Results: The search identified 1,076 articles; 74 articles met the full inclusion criteria and were included in the systematic review, and 47 articles were included into the analyses. Pooled analysis suggests that AD participants can be differentiated from controls due to significant delays in ABR, N100, P200, N200, and P300 latencies. P300 amplitude was significantly smaller in AD participants compared to controls. P300 latencies differed significantly between MCI participants and controls based on the pooled analysis. Conclusion: The findings of this review indicate that some AERPs may be valuable biomarkers of AD. In conjunction with currently available clinical and neuropsychological assessments, AERPs can aid in screening and diagnosis of prodromal AD. Show more

Keywords: Alzheimer’s disease, cognitive function, event-related potentials, meta-analysis, mild cognitive impairment

DOI: 10.3233/JAD-210556

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-30, 2021

Authors: Cianflone, Alessandra | Coppola, Luigi | Mirabelli, Peppino | Salvatore, Marco

Article Type: Research Article

Abstract: Background: An amyloid-β (Aβ) positron emission tomography (Aβ-PET) scan of the human brain could lead to an early diagnosis of Alzheimer’s disease (AD) and estimate disease progression. However, Aβ-PET imaging is expensive, invasive, and rarely applicable to cognitively normal subjects at risk for dementia. The identification of blood biomarkers predictive of Aβ brain deposition could help the identification of subjects at risk for dementia and could be helpful for the prognosis of AD progression. Objective: This study aimed to analyze the prognostic accuracy of blood biomarkers in predicting Aβ-PET status along with progression toward AD. Methods: …In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched bibliographic databases from 2010 to 2020. The quality of the included studies was assessed by the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Results: A total of 8 studies were retrieved. The prognostic accuracy of Aβ-PET status was calculated by obtaining ROCs for the following biomarkers: free, total, and bound Aβ 42 and Aβ 40 ; Aβ 42/40 ratio; neurofilaments (NFL); total tau (T-tau); and phosphorylated-Tau181 (P-tau181). Higher and lower plasma baseline levels of P-tau181 and the Aβ 42/40 ratio, respectively, showed consistently good prognostication of Aβ-PET brain accumulation. Only P-tau181 was shown to predict AD progression. Conclusion: In conclusion, the Aβ 42/40 ratio and plasma P-tau181 were shown to predict Aβ-PET status. Plasma P-tau181 could also be a preclinical biomarker for AD progression. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, mild cognitive impairment, preclinical Alzheimer’s disease, positron emission tomography, prognostic accuracy, sensitivity, specificity

DOI: 10.3233/JAD-210496

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Mohr, Wiebke | Rädke, Anika | Afi, Adel | Edvardsson, David | Mühlichen, Franka | Platen, Moritz | Roes, Martina | Michalowsky, Bernhard | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Person-centered care (PCC) is an important concept in many countries’ national guidelines and dementia plans. Key intervention categories, i.e., a taxonomy of person-centered (PC)-interventions, to provide person-centered dementia care, are difficult to identify from literature. Objective: This systematic review aimed to identify and categorize published PC-interventions into key intervention categories to guide the provision of person-centered dementia care. Methods: Conduct of this systematic review followed Cochrane guidelines. A search of the dimensions ‘Dementia’, ‘Person-Centered Care’, and ‘Intervention’ combined was performed in PubMed, EMBASE, and Web of Science. Study selection was based on 2-stage screening against …eligibility criteria, limited to controlled study designs. Information about interventions and outcomes was extracted into an “Effects Table”. The identified PC-interventions were categorized in intervention categories to provide person-centered dementia care. Results: Searches identified 1,806 records. 19 studies were included. These covered a range of psychosocial interventions, oftentimes multi-component interventions, which followed heterogeneous approaches. Studies were conducted in long-term care/hospital settings. Nine key intervention categories were identified: social contact, physical activities, cognitive training, sensory enhancement, daily living assistance, life history oriented emotional support, training and support for professional caregivers, environmental adjustments, and care organization. Conclusion: Our findings provide a current overview of published PC-interventions in dementia, which followed heterogeneous approaches under the PCC-concept. The heterogeneity made it challenging to identify a well-defined concept of PCC and common key intervention categories. An effectiveness-evaluation of “PC”-including “relationship-centered”-interventions may be valuable, to assess whether an explicit focus on relationships around PCC-interventions yields an added benefit. PROSPERO-ID: CRD42021225084. Show more

Keywords: Alzheimer’s disease, dementia, patient-centered care, patient-focused care, patient preferences, person-centered care, person-centered dementia care, person-centered interventions, psychosocial intervention

DOI: 10.3233/JAD-210647

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-24, 2021

Authors: Ferreira-Brito, Filipa | Ribeiro, Filipa | Aguiar de Sousa, Diana | Costa, João | Caneiras, Cátia | Carriço, Luís | Verdelhoa,

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) and dementia are associated with increased age. MCI is a clinical entity described as a transitional state between normal cognition and dementia. Video games (VGs) can potentially promote cognition and functional capacity since multiple cognitive domains are recruited during gameplay. However, there is still a lack of consensus regarding the efficacy of VGs as therapeutic tools, particularly in neurodegenerative diseases. Objective: We aimed to analyze the impact of VGs on cognition and functional capacity outcomes in MCI/dementia patients. Methods: We conducted a systematic review and meta-analysis study (PROSPERO [CRD42021229445]). PubMed, Web …of Science, Epistemonikos, CENTRAL, and EBSCO electronic databases were searched for RCT (2000-2021) that analyzed the impact of VGs on cognitive and functional capacity outcomes in MCI/dementia patients. Results: Nine studies were included (n  = 409 participants), and Risk of Bias (RoB2) and quality of evidence (GRADE) were assessed. Data regarding attention, memory/learning, visual working memory, executive functions, general cognition, functional capacity, quality of life were identified, and pooled analyses were conducted. An effect favoring VGs interventions was observed on Mini-Mental State Examination (MMSE) score (MD  = 1.64, 95%CI 0.60 to 2.69). Conclusion: Although promising, the effects observed should be interpreted with caution since serious methodological shortcomings were identified in the studies included. Nonetheless, the effect observed is higher than the minimum clinically important difference (1.4 points) established to MMSE. Future studies on the current topic urge. Recommendations for the design and conduction of cognitive RCT studies are presented. Show more

Keywords: Cognition, dementia, independent living, mhealth, mild cognitive impairment, telerehabilitation, video games

DOI: 10.3233/JAD-210545

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Rutten, Jeanine J.S. | van Kooten, Janine | van Loon, Anouk M. | van Buul, Laura W. | Joling, Karlijn J. | Smalbrugge, Martin | Hertogh, Cees M.P.M.

Article Type: Research Article

Abstract: Background: The COVID-19 pandemic has led to high mortality rates in nursing homes (NHs) in Europe. For adequate risk management and good prognostications, it is essential to identify mortality risk factors. Objective: This study aimed to determine whether previously identified risk factors for 30-day mortality in Dutch NH residents with COVID-19 are unique to COVID-19. Methods: In this cohort study, we included 1,294 NH residents with COVID-19 (cases) and 17,999 NH residents without COVID-19 (controls, from the pre-COVID-19 period). We used descriptive statistics and Cox proportional hazard models to compare mortality rates in residents with and …without COVID-19, categorized by risk factors. Results: Cases had a more than 18 times higher hazard of death within 30 days compared to controls (HR 18, 95%CI: 16–20). For residents with COVID-19, being male, having dementia, and having Parkinson’s disease (PD) were all associated with a higher 30-day mortality (HR 1.8 versus 1.3 versus 1.7). Being male was also associated with a higher mortality (HR 1.7) in the control group, whereas having dementia and PD were not. COVID-19 symptomatology was very similar for residents with and without dementia or PD, except for delirium and malaise which was more frequent in residents with dementia. Conclusion: Dementia and PD were significant additional risk factors for mortality in Dutch NH residents with COVID-19, whereas male gender was not unique to residents with COVID-19. The frailty of PD and dementia in NH residents with COVID-19 are relevant to consider in prognostication, communication, and care planning with residents and their families. Show more

Keywords: Coronavirus, dementia, long-term care facilities, Parkinson’s disease, SARS-CoV-2

DOI: 10.3233/JAD-210319

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Kootar, Scherazad | Huque, Md Hamidul | Arthur, Richard | Mortby, Moyra | Anstey, Kaarin J.

Article Type: Research Article

Abstract: Background: Findings on the associations between anxiety and cognitive decline are mixed and often confounded. Objective: We studied whether anxiety symptoms were associated with the risk of cognitive decline after adequate adjustment of confounding factors. Methods: Our study consists of 2,551 community-dwelling older adults recruited between the ages of 60–64 years and followed up for 12 years in the PATH Through Life cohort study. Anxiety symptoms were measured using the Goldberg Anxiety Scale (GAS; range 0–9). General cognitive function, episodic memory, working memory, verbal intelligence, processing speed, and psychomotor speed were measured. Multilevel analyses were carried …out to investigate the association between anxiety symptoms and cognitive decline over 12 years, taking into account confounding variables. Results: We did not find a significant association between baseline anxiety symptoms and cognitive decline over 12 years. Although some associations between anxiety symptoms with psychomotor speed (β= –0.04, 99%CI: –0.08, 0.00) and processing speed (β= –0.27, 99%CI: –0.48, –0.07) were found, these were attenuated after adjusting for depression. We also did not find an association between cumulative anxiety and decline in cognitive performance. Conclusion: In this sample of cognitively healthy men and women aged 60 years and above, anxiety symptoms were not associated with the risk of cognitive decline. Long follow-up study time, appropriate selection of confounding factors, and estimating the effect of cumulative anxiety are important to establish the association between anxiety and cognitive symptoms. Show more

Keywords: Anxiety, anxiolytics, cognitive decline, depression, longitudinal study

DOI: 10.3233/JAD-210282

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Yamada, Yasunori | Shinkawa, Kaoru | Kobayashi, Masatomo | Caggiano, Vittorio | Nemoto, Miyuki | Nemoto, Kiyotaka | Arai, Tetsuaki

Article Type: Research Article

Abstract: Background: Gait, speech, and drawing behaviors have been shown to be sensitive to the diagnosis of Alzheimer’s disease (AD) and mild cognitive impairment (MCI). However, previous studies focused on only analyzing individual behavioral modalities, although these studies suggested that each of these modalities may capture different profiles of cognitive impairments associated with AD. Objective: We aimed to investigate if combining behavioral data of gait, speech, and drawing can improve classification performance compared with the use of individual modality and if each of these behavioral data can be associated with different cognitive and clinical measures for the diagnosis of …AD and MCI. Methods: Behavioral data of gait, speech, and drawing were acquired from 118 AD, MCI, and cognitively normal (CN) participants. Results: Combining all three behavioral modalities achieved 93.0%accuracy for classifying AD, MCI, and CN, and only 81.9%when using the best individual behavioral modality. Each of these behavioral modalities was statistically significantly associated with different cognitive and clinical measures for diagnosing AD and MCI. Conclusion: Our findings indicate that these behaviors provide different and complementary information about cognitive impairments such that classification of AD and MCI is superior to using either in isolation. Show more

Keywords: Drawing, gait analysis, handwriting, machine learning, speech, voice, walking

DOI: 10.3233/JAD-210684

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Wang, Quan | Su, Ning | Huang, Jin | Liang, Xinyu | Yuan, Jing | Yao, Ming | Zhou, Li-Xin | Jin, Zheng-Yu | Zhang, Shu-Yang | Cui, Li-Ying | Gong, Gaolang | Tian, Feng | Zhu, Yi-Cheng | Ni, Jun

Article Type: Research Article

Abstract: Background: Few studies have investigated the association between cognition and brain volume associated with cerebral small vessel disease (CSVD). Objective: We investigated the association between cognition and brain volume and neuroimaging markers of CSVD in a community-dwelling population. Methods: Participants (n  = 993, age≥35 years) from the community-based Shunyi Study were included to investigate the association between neuroimaging markers and cognition cross-sectionally. Magnetic resonance imaging markers included brain volume measurements of the total cerebrum, white matter, gray matter, and CSVD imaging markers. Cognitive performance was assessed using neuropsychological tests of the Mini-Mental State Examination (MMSE), Montreal Cognitive …Assessment (MoCA), Fuld Object Memory, digit span, Trail Making Test (TMT)-A, and TMT-B. Results: For brain volume measurement, subcortical white matter fraction was positively associated with MMSE score (β= 0.034, p  = 0.0062) and MoCA score (β= 0.034, p  = 0.0174), and negatively associated with TMT-A and TMT-B completion time (β= –2.319, p  = 0.0002; β= –2.827, p  = 0.0073, respectively). For evaluation of CSVD imaging markers, the presence of lacunes was positively associated with TMT-B completion time (β= 17.241, p  = 0.0028). Conclusion: In community-dwelling populations, reduced white matter volumes, as a consequence of aging and vascular damage, are associated with worse global cognition and executive function. Our findings provide potential insights into the correlation between cognition and CSVD-associated subcortical white matter injury. Show more

Keywords: Brain volume, cerebral small vessel disease, cognition, gray matter, magnetic resonance imaging, white matter

DOI: 10.3233/JAD-210367

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Wei,, Shan | Shang, Suhang | Dang, Liangjun | Gao, Fan | Gao, Yao | Gao, Ling | Chen, Chen | Huo, Kang | Wang, Jingyi | Wang, Jin | Qu, Qiumin

Article Type: Research Article

Abstract: Background: Studies have found that blood lipids are associated with plasma amyloid-β (Aβ) levels, but the underlying mechanism is still unclear. Two Aβ transporters, soluble form of low-density lipoprotein receptor related protein-1 (sLRP1) and soluble receptor of advanced glycation end products (sRAGE), are crucial in peripheral Aβ transport. Objective: The aim was to investigate the effects of lipids on the relationships between plasma Aβ and transporter levels. Methods: This study included 1,436 adults aged 40 to 88 years old. Blood Aβ, sLRP1, sRAGE, and lipid levels were measured. Univariate and multivariate analyses were used to analyze …the relationships between lipids and plasma Aβ, sLRP1, and sRAGE. Results: After adjusting for all possible covariates, high-density lipoprotein (HDL-c) was positively associated with plasma Aβ 42 and sRAGE (β= 6.158, p  = 0.049; β= 121.156, p  <  0.001, respectively), while triglyceride (TG) was negatively associated with plasma Aβ 40 , Aβ 42 , and sRAGE (β= –48.389, p  = 0.017; β= –11.142, p  = 0.020; β= –147.937, p  = 0.003, respectively). Additionally, positive correlations were found between plasma Aβ and sRAGE in the normal TG (Aβ 40 : β= 0.034, p  = 0.005; Aβ 42 : β= 0.010, p  = 0.001) and HDL-c groups (Aβ 40 : β= 0.023, p  = 0.033; Aβ 42 : β= 0.008, p  = 0.002) but not in the high TG and low HDL-c groups. Conclusion: Abnormal levels of TG and HDL-c are associated with decreased Aβ and sRAGE levels. Positive correlations between plasma Aβ and sRAGE were only found in the normal TG and HDL-c groups but not in the high TG and low HDL-c groups. These results indicated that dyslipidemia contributing to plasma Aβ levels might also be involved in peripheral Aβ clearance. Show more

Keywords: Alzheimer’s disease, amyloid-β, high density lipoprotein, soluble low-density lipoprotein receptor-related protein-1, soluble receptor of advanced glycation end products, triglyceride

DOI: 10.3233/JAD-210405

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Sogorb-Esteve, Aitana | Colas, Romain A. | Dalli, Jesmond | Rohrer, Jonathan D.

Article Type: Research Article

Abstract: Background: The pathophysiology of frontotemporal dementia (FTD) is poorly understood but recent studies implicate neuroinflammation as an important factor. However, little is known so far about the role of the resolution pathway, the response to inflammation that allows tissue to return to a homeostatic state. Objective: We aimed to measure the concentrations of lipid mediators including specialized proresolving mediators (SPMs) and proinflammatory eicosanoids in the cerebrospinal fluid (CSF) of people with FTD. Methods: 15 people with genetic FTD (5 with C9orf72 expansions, 5 with GRN mutations, and 5 with MAPT mutations) were recruited …to the study along with 15 age- and sex-matched healthy controls. Targeted liquid chromatography-tandem mass spectrometry techniques were used to measure the CSF concentrations of lipid mediators in the docosahexaenoic acid (DHA), n-3 docosapentaenoic acid, eicosapentaenoic acid, and arachidonic acid (AA) metabolomes. Results: Only the C9orf72 expansion carriers had higher concentrations of SPMs (DHA-derived maresins and DHA-derived resolvins) compared with controls. In contrast, GRN and MAPT mutation carriers had normal concentrations of SPMs but significantly higher concentrations of the proinflammatory AA-derived leukotrienes and AA-derived thromboxane compared with controls. Additionally, the C9orf72 expansion carriers also had significantly higher concentrations of AA-derived leukotrienes. Conclusion: This initial pilot study of lipid mediators provides a window into a novel biological pathway not previously investigated in FTD, showing differential patterns of alterations between those with C9orf72 expansions (where SPMs are higher) and GRN and MAPT mutations (where only proinflammatory eicosanoids are higher). Show more

Keywords: C9orf72, frontotemporal dementia, lipid mediators, neuroinflammation, progranulin, tau.

DOI: 10.3233/JAD-210559

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Doshi, Kinjal | Henderson, Stacey Lee | Fan, Qianqian | Wong, Kian Foong | Lim, Julian

Article Type: Research Article

Abstract: Background: Current pharmacological and behavioral treatment options for mild cognitive impairment (MCI) are limited, motivating a search for alternative therapies that might slow the progression of cognitive decline. Objective: We investigated the effectiveness of a cognition-focused mindfulness-based intervention. Methods: An open-label, three arm randomized controlled trial was conducted at a public tertiary medical center. Older persons (ages 45–75; N = 76) diagnosed with MCI were recruited and randomized into either Mindfulness-based training (MBT), cognitive rehabilitation therapy (CRT), or treatment as usual (TAU). Participants in the intervention arms received 8 weekly 2-h sessions delivered in a group setting and …engaged in home practice. Primary outcomes measures included changes in index scores for attention, immediate memory, and delayed memory as measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Depression was a secondary outcome. Results: Using intent-to-treat analysis, we found that participants receiving MBT showed significant improvements in global cognition (d = 0.26; [95%CI 0.03–0.56]) and delayed memory (d = 0.36; [95%CI 0.17–0.57]), with significantly greater improvements in delayed memory than CRT (ηp 2  = 0.10). However, there was no benefit of MBT over TAU. No change in depression was observed in the MBT group. Reductions in depression were associated with improvements in cognitive functioning in the MBT group only. Conclusion: Our results suggest that a cognition-focused MBT did not improve cognitive functioning in MCI patients substantially more than spontaneous reversion rates, possibly as mood symptoms were not significantly alleviated in this group. Show more

Keywords: Cognition, depression, memory, mild cognitive impairment, mindfulness, neuropsychology

DOI: 10.3233/JAD-215035

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Allen, Herbert B.

Article Type: Research Article

Abstract: Utilizing the pathology and microbiology found in tissue from patients with documented Alzheimer’s disease (AD), the pathogenesis of this fateful disorder has been made clear. Borrelia burgdorferi and Treponema denticola spirochetes enter the brain, mostly via neuronal pathways and the entorhinal circulation. These organisms easily pass through the blood-brain barrier and have an affinity for neural tissue. Once in the brain, the spirochetes make intra- and extracellular biofilms, and it is the biofilms that create the pathology. Specifically, it is the intracellular biofilms that are ultimately responsible for neurofibrillary tangles and dendritic disintegration. The extracellular biofilms are responsible …for the inflammation that initially is generated by the first responder, Toll-like receptor 2. The hypothesis that arises from this work is two-pronged: one is related to prevention; the other to treatment. Regarding prevention, it is very likely possible that AD could be prevented by periodic administration of penicillin (PCN), which would kill the spirochetes before they made biofilms; this would prevent the disease and would not allow any of the above deleterious changes generated by the biofilms to occur. As regards treatment, it may be possible to slow or prevent further decline in early AD by administration of PCN together with a biofilm disperser. The disperser would disrupt the biofilm coating and enable the PCN to kill the spirochetes. This protocol could be administered in a trial with the control arm utilizing the current treatment. The progress of the treatment could be evaluated by one of the current blood tests that is semi-quantitative. The specific protocols are listed. Show more

Keywords: Amyloid-β, biofilm disperser, biofilms, hyperphosphorylated tau, penicillin, spirochetes, Toll-like receptor 2

DOI: 10.3233/JAD-210429

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Kuipers, Sanne | Biessels, Geert Jan | Greving, Jacoba P. | Amier, Raquel P. | de Bresser, Jeroen | Bron, Esther E. | van der Flier, Wiesje M. | van der Geest, Rob J. | Hooghiemstra, Astrid M. | van Oostenbrugge, Robert J. | van Osch, Matthias J.P. | Kappelle, L. Jaap | Exalto, Lieza G. | Heart-Brain Connection Consortium

Article Type: Research Article

Abstract: Background: Emerging evidence shows sex differences in manifestations of vascular brain injury in memory clinic patients. We hypothesize that this is explained by sex differences in cardiovascular function. Objective: To assess the relation between sex and manifestations of vascular brain injury in patients with cognitive complaints, in interaction with cardiovascular function. Methods: 160 outpatient clinic patients (68.8±8.5 years, 38% female) with cognitive complaints and vascular brain injury from the Heart-Brain Connection study underwent a standardized work-up, including heart-brain MRI. We calculated sex differences in vascular brain injury (lacunar infarcts, non-lacunar infarcts, white matter hyperintensities [WMHs], and …microbleeds) and cardiovascular function (arterial stiffness, cardiac index, left ventricular [LV] mass index, LV mass-to-volume ratio and cerebral blood flow). In separate regression models, we analyzed the interaction effect between sex and cardiovascular function markers on manifestations of vascular brain injury with interaction terms (sex*cardiovascular function marker). Results: Males had more infarcts, whereas females tended to have larger WMH-volumes. Males had higher LV mass indexes and LV mass-to-volume ratios and lower CBF values compared to females. Yet, we found no interaction effect between sex and individual cardiovascular function markers in relation to the different manifestations of vascular brain injury (p -values interaction terms > 0.05). Conclusion: Manifestations of vascular brain injury in patients with cognitive complaints differed by sex. There was no interaction between sex and cardiovascular function, warranting further studies to explain the observed sex differences in injury patterns. Show more

Keywords: Cardiovascular function, cerebrovascular disorders, cognitive dysfunction, female, male, sex, vascular brain injury

DOI: 10.3233/JAD-210360

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Sato, Tomohiko | Hanyu, Haruo | Koyama, Yumi | Horita, Haruka | Aoki, Toshinori | Hirao, Kentaro | Kanetaka, Hidekazu | Shimizu, Soichiro

Article Type: Research Article

Abstract: Background: In Alzheimer’s disease (AD) patients, the severity of cognitive impairment is thought to correlate with the degree of brain imaging abnormalities. However, some patients show only mild cognitive deficit, despite severe brain atrophy on magnetic resonance imaging (MRI) or marked hypoperfusion in the cerebral cortices on single-photon emission computed tomography (SPECT). This suggests that cognitive reserve (CR) can compensate for the clinical manifestations of AD in patients with extensive brain pathology. Objective: We aimed to determine whether this discrepancy between cognitive and imaging findings is associated with CR. Methods: Factors associated with the discrepancy between …the degree of cognitive impairment and MRI (medial temporal lobe atrophy) and SPECT (posterior cerebral hypoperfusion) findings were analyzed in 135 patients with probable AD. Factors as proxies for CR included education, occupation, leisure activity, comorbidities, frailty, and other demographics. The discrepancy index (DI) was calculated as the difference between the degree of imaging abnormalities and the degree of cognitive dysfunction. Results: Multiple regression analysis showed that leisure activity and education were significantly associated with the discrepancy between cognitive and imaging findings. When the level of CR was determined based on leisure activity and education, the high-CR group showed a significantly larger DI than the moderate- and low-CR groups. Conclusion: The discrepancy between cognitive and imaging findings in patients with AD is associated with CR, measured using a combination of two indicators, i.e., leisure activity and education. Therefore, lifestyle interventions may delay the appearance of clinical symptoms resulting from underlying AD pathology, by increasing CR. Show more

Keywords: Alzheimer’s disease, brain imaging, cognition, cognitive reserve, education, leisure activity

DOI: 10.3233/JAD-210728

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Abdulkadir, Teslim S. | Dawud, Fatima A. | Isa, Ahmed Sherif | Ayo, Joseph O.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease associated with deficiency in motor coordination, cognitive impairment, and excessive reactive oxygen species production in the brain. Objective: The study evaluated effects of taurine and camel milk (CM) on neurobehavior, amyloid-beta peptide 1–42 (Aβ ) expression, acetylcholinesterase, and superoxide dismutase activities in aluminum chloride (AlCl3 ) model of Alzheimer’s disease in rats. Methods: Thirty-five female Wistar rats were divided into seven groups (n  = 5): Normal saline (0.2 mL/kg body weight); AlCl3 (100 mg/kg) (AD); CM (33 mL/kg); Taurine (50 mg/kg); AlCl3 (100 mg/kg) + CM (33 mL/kg); AlCl3 (100 mg/kg) + Taurine …(50 mg/kg); and AlCl3 (100 mg/kg) + CM (33 mL/kg) + Taurine (50 mg/kg). The administration lasted for eight weeks via oral gavage. After the eighth week, neurobehavior assessments were performed. Rats were sacrificed, and brain and blood samples collected for analysis. Results: There was a significant (p  <  0.0001) increase in the duration of motor endurance in AD + CM rats, compared to AD rats. Duration of forced swimming time was lowest (p  <  0.0001) in AlCl3 + Taurine rats, compared to that of AD rats. Concentration of Aβ peptide decreased (p  <  0.05) in AD rats, treated with CM and/or combination. In taurine-treated rats, superoxide dismutase activity was significantly (p  <  0.05) higher than in AD rats. Treatment with taurine + CM increased (p  <  0.05) acetylcholinesterase activity compared to controls. Conclusion: Taurine and CM enhanced cognition and sensorimotor activity by decreasing Aβ peptide concentration and increasing superoxide dismutase and acetylcholinesterase activities in AD rats. Show more

Keywords: Aluminum chloride, amyloid-beta peptide, camel milk, neurobehavior, oxidative stress, taurine

DOI: 10.3233/JAD-210130

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Kolinko, Yaroslav | Marsalova, Lucie | Pena, Stephanie Proskauer | Kralickova, Milena | Mouton, Peter R.

Article Type: Research Article

Abstract: Background: Microcirculatory factors play an important role in amyloid-β (Aβ)-related neuropathology in Alzheimer’s disease (AD). Transgenic (Tg) rat models of mutant Aβ deposition can enhance our understanding of this microvascular pathology. Objective: Here we report stereology-based quantification and comparisons (between- and within-group) of microvessel length and number and associated parameters in hippocampal subregions in Tg model of AD in Fischer 344 rats and non-Tg littermates. Methods: Systematic-random samples of tissue sections were processed and laminin immunostained to visualize microvessels through the entire hippocampus in Tg and non-Tg rats. A computer-assisted stereology system was used to quantify …microvessel parameters including total number, total length, and associated densities in dentate gyrus (DG) and cornu ammonis (CA) subregions. Results: Thin hair-like capillaries are common near Aβ plaques in hippocampal subregions of Tg rats. There are a 53% significant increase in average length per capillary across entire hippocampus (p ≤0.04) in Tg compared to non-Tg rats; 49% reduction in capillary length in DG (p ≤0.02); and, higher microvessel density in principal cell layers (p ≤0.03). Furthermore, within-group comparisons confirm Tg but not non-Tg rats have significant increase in number density (p ≤0.01) and potential diffusion distance (p ≤0.04) of microvessels in principal cell layers of hippocampal subregions. Conclusion: We show the Tg deposition of human Aβ mutations in rats disrupts the wild-type microanatomy of hippocampal microvessels. Stereology-based microvascular parameters could promote the development of novel strategies for protection and the therapeutic management of AD. Show more

Keywords: Alzheimer’s disease, capillary, hippocampus, microvessels, stereology, TgF344-AD rat

DOI: 10.3233/JAD-210738

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Colato, Elisa | Chiotis, Konstantinos | Ferreira, Daniel | Mazrina, Mariam S. | Lemoine, Laetitia | Mohanty, Rosaleena | Westman, Eric | Nordberg, Agneta | Rodriguez-Vieitez, Elena | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: In Alzheimer’s disease (AD), the abnormal aggregation of hyperphosphorylated tau leads to synaptic dysfunction and neurodegeneration. Recently developed tau PET imaging tracers are candidate biomarkers for diagnosis and staging of AD. Objective: We aimed to investigate the discriminative ability of 18 F-THK5317 and 18 F-flortaucipir tracers and brain atrophy at different stages of AD, and their respective associations with cognition. Methods: Two cohorts, each including 29 participants (healthy controls [HC], prodromal AD, and AD dementia patients), underwent 18 F-THK5317 or 18 F-flortaucipir PET, T1-weighted MRI, and neuropsychological assessment. For each subject, we quantified regional 18 …F-THK5317 and 18 F-flortaucipir uptake within six bilateral and two composite regions of interest. We assessed global brain atrophy for each individual by quantifying the brain volume index, a measure of brain volume-to-cerebrospinal fluid ratio. We then quantified the discriminative ability of regional 18 F-THK5317, 18 F-flortaucipir, and brain volume index between diagnostic groups, and their associations with cognition in patients. Results: Both 18 F-THK5317 and 18 F-flortaucipir outperformed global brain atrophy in discriminating between HC and both prodromal AD and AD dementia groups. 18 F-THK5317 provided the highest discriminative ability between HC and prodromal AD groups. 18 F-flortaucipir performed best at discriminating between prodromal and dementia stages of AD. Across all patients, both tau tracers were predictive of RAVL learning, but only 18 F-flortaucipir predicted MMSE. Conclusion: Our results warrant further in vivo head-to-head and antemortem-postmortem evaluations. These validation studies are needed to select tracers with high clinical validity as biomarkers for early diagnosis, prognosis, and disease staging, which will facilitate their incorporation in clinical practice and therapeutic trials. Show more

Keywords: Alzheimer’s disease, atrophy, cognitive dysfunction, dementia, positron emission tomography, tau protein

DOI: 10.3233/JAD-210614

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Sriwichaiin, Sirawit | Chattipakorn, Nipon | Chattipakorn, Siriporn C.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) has become a major health problem among the elderly population. Some evidence suggests that metabolic disturbance possibly plays a role in the pathophysiology of AD. Currently, the study of metabolomics has been used to explore changes in multiple metabolites in several diseases, including AD. Thus, the metabolomics research in AD might provide some information regarding metabolic dysregulations, and their possible associated pathophysiology. This review summarizes the information discovered regarding the metabolites in the brain and the blood from the metabolomics research of AD from both animal and clinical studies. Additionally, the correlation between the changes in metabolites …and outcomes, such as pathological findings in the brain and cognitive impairment are discussed. We also deliberate on the findings of cohort studies, demonstrating the alterations in metabolites before changes of cognitive function. All of these findings can be used to inform the potential identity of specific metabolites as possible biomarkers for AD. Show more

Keywords: Aging, Alzheimer’s disease, dementia, metabolomics

DOI: 10.3233/JAD-210737

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-28, 2021

Authors: Xia, Lei | Pang, Yayan | Li, Junjie | Wu, Bin | Du, Yehong | Chen, Yuxin | Luo, Man | Wang, Yan | Dong, Zhifang

Article Type: Research Article

Abstract: Background: Tauopathies are a group of neurodegenerative disorders, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration with tau pathology. Hyperphosphorylation modification promotes tau protein misfolding and aggregation into neurofibrillary tangles, leading to impairments of synaptic plasticity and learning and memory. However, very limited therapeutic strategies are available. Objective: In the present study, we wanted to investigate the potential effects of Dihydroartemisinin (DHA) on tauopathies. Methods: We constructed adeno-associated virus carrying hTau cDNA (AAVhTau ) to establish a mouse model of tauopathy through intrahippocampal microinjection. Using a combination of behavioral test, electrophysiological recording, and western blotting assay, …we examined the neuroprotective effects of DHA on learning and memory deficits in mice with tauopathy. Results: DHA improved learning and memory and increased hippocampal CA1 long-term potentiation (LTP) in mice overexpressed human tau (hTau) in the hippocampus. More importantly, further study revealed that DHA could induce protein O-GlcNAcylation modification and reduce protein phosphorylation. O-GlcNAc transferase inhibitor alloxan could suppress DHA-induced protein O-GlcNAcylation, and subsequently prevent therapeutic effect of DHA on the deficits of learning and memory as well as synaptic plasticity in hTau mice. Conclusion: These results indicate that DHA may exert neuroprotective role in tauopathy through a crosstalk between O-GlcNAcylation and phosphorylation, suggesting a potential therapeutic for learning and memory deficits associated with tau pathology. Show more

Keywords: Dihydroartemisinin, learning and memory, long-term potentiation, O-GlcNAcylation, phosphorylation, tau

DOI: 10.3233/JAD-210643

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: DeFeis, Brittany | Ying, Gelan | Kurasz, Andrea M. | De Wit, Liselotte | Amofa Sr., Priscilla | Chandler, Melanie | Locke, Dona | Shandera-Ochsner, Anne | Phatak, Vaishali | Smith, Glenn

Article Type: Research Article

Abstract: Background: In Alzheimer’s disease and related disorders (ADRD) research, common outcome measures include cognitive and functional impairment, as well as persons with mild cognitive impairment (pwMCI) and care partner self-reported mood and quality of life. Studies commonly analyze these measures separately, which potentially leads to issues of multiple comparisons and/or multicollinearity among measures while ignoring the latent constructs they may be measuring. Objective: This study sought to examine the latent factor structure of a battery of 12-13 measures of domains mentioned above, used in a multicomponent behavioral intervention (The HABIT® program) for pwMCI and their partners. …Methods: Exploratory factor analysis (EFA) involved 214 pwMCI-partner pairs. Subsequent Confirmatory factor analyses (CFA) used 730 pairs in both pre- and post-intervention conditions. Results: EFA generated a three-factor model. Factors could be characterized as partner adjustment (29.9%), pwMCI adjustment (18.1%), and pwMCI impairment (12.8%). The subsequent CFA confirmed our findings, and the goodness-of-fit for this model was adequate in both the pre- (CFI = 0.937; RMSEA = 0.057, p  = 0.089) and post-intervention (CFI = 0.942; RMSEA = 0.051, p  = 0.430) groups. Conclusion: Results demonstrated a stable factor structure across cohorts and intervention conditions suggesting that three broad factors may provide a straightforward and meaningful model to assess intervention outcome, at least during the MCI phase of ADRD. Show more

Keywords: Behavioral intervention, caregiver burden, factor analysis, functional status, mild cognitive impairment

DOI: 10.3233/JAD-210582

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Werber, Tom | Bata, Zsofia | Vaszine, Eniko Szabo | Berente, Dalida Borbala | Kamondi, Anita | Horvath, Andras Attila

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the leading cause of cognitive impairment in the elderly. Recent evidence suggests that preventive interventional trials could significantly reduce the risk for development of dementia. Periodontitis is the most common dental disease characterized by chronic inflammation and loss of alveolar bone and perialveolar attachment of teeth. Growing number of studies propose a potential link between periodontitis and neurodegeneration. In the first part of the paper, we overview case-control studies analyzing the prevalence of periodontitis among AD patients and healthy controls. Second, we survey observational libraries and cross-sectional studies investigating the risk of cognitive decline in patients …with periodontitis. Next, we describe the current view on the mechanism of periodontitis linked neural damage, highlighting bacterial invasion of neural tissue from dental plaques, and periodontitis induced systemic inflammation resulting in a neuroinflammatory process. Later, we summarize reports connecting the four most common periodontal pathogens to AD pathology. Finally, we provide a practical guide for further prevalence and interventional studies on the management of cognitively high-risk patients with and without periodontitis. In this section, we highlight strategies for risk control, patient information, dental evaluation, reporting protocol and dental procedures in the clinical management of patients with a risk for periodontitis and with diagnosed periodontitis. In conclusion, our review summarizes the current view on the association between AD and periodontitis and provides a research and intervention strategy for harmonized interventional trials and for further case-control or cross-sectional studies. Show more

Keywords: Alzheimer’s disease, dental health, intervention, neurodegeneration, neuroinflammation, periodontitis, prevention

DOI: 10.3233/JAD-210491

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2021

Authors: Wong, Fennie Choy Chin | Saffari, Seyed Ehsan | Yatawara, Chathuri | Ng, Kok Pin | Kandiah, Nagaendran | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The associations between small vessel disease (SVD) and cerebrospinal amyloid-β1-42 (Aβ1-42 ) pathology have not been well-elucidated. Objective: Baseline (BL) white matter hyperintensities (WMH) were examined for associations with month-24 (M24) and longitudinal Aβ1-42 change in cognitively normal (CN) subjects. The interaction of WMH and Aβ1-42 on memory and executive function were also examined. Methods: This study included 72 subjects from the Alzheimer’s Disease Neuroimaging Initiative. Multivariable linear regression models evaluated associations between baseline WMH/intracranial volume ratio, M24 and change in Aβ1-42 over two years. Linear mixed effects models evaluated interactions between …BL WMH/ICV and Aβ1-42 on memory and executive function. Results: Mean age of the subjects (Nmales  = 36) = 73.80 years, SD  = 6.73; mean education years = 17.1, SD  = 2.4. BL WMH was significantly associated with M24 Aβ1-42 (p  = 0.008) and two-year change in Aβ1-42 (p  = 0.006). Interaction between higher WMH and lower Aβ1-42 at baseline was significantly associated with worse memory at baseline and M24 (p  = 0.003). Conclusion: BL WMH was associated with M24 and longitudinal Aβ1-42 change in CN. The interaction between higher WMH and lower Aβ1-42 was associated with poorer memory. Since SVD is associated with longitudinal Aβ1-42 pathology, and the interaction of both factors is linked to poorer cognitive outcomes, the mitigation of SVD may be correlated with reduced amyloid pathology and milder cognitive deterioration in Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, cognition, memory, white matter hyperintensities

DOI: 10.3233/JAD-210333

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Cox, Kay L. | Clare, Linda | Cyarto, Elizabeth V. | Ellis, Kathryn A. | Etherton-Beer, Christopher | Southam, Jenny | Ames, David | Flicker, Leon | Almeida, Osvaldo P. | LoGiudice, Dina | Liew, Danny | Vlaskovsky, Philip | Lautenschlager, Nicola T.

Article Type: Research Article

Abstract: Background: Increasing physical activity (PA) in those who have memory concerns requires innovative approaches. Objective: To compare in this randomized controlled trial (RCT) the effects on PA, adherence, and fitness of two approaches to deliver a 6-month home-based PA program in older, inactive individuals at risk of cognitive decline. Methods: Individuals (n  = 52) aged 60–85 years, inactive with mild cognitive impairment or subjective cognitive decline were recruited from the community and memory clinics. Randomization was to 6 months of 150 min/week moderate intensity PA with either: goal-setting with mentor support; or education and peer contact. A subset …of participants (n  = 36) continued for a further 6 months. PA, moderate and vigorous PA, and secondary outcomes, fitness, goal performance/satisfaction and self-efficacy were assessed at baseline, 6 and 12 months. Modelling of primary and secondary outcomes was conducted with linear mixed models. Results: Participants were mean age (±sd) 70.1 (6.4) years. Six-month retention was 88.5%(n  = 46). No significant between-group differences were observed for PA or fitness. Post-hoc combined group data showed a significant, moderate-large effect size increase in PA with time. PA increased by a mean 1,662 (943, 2383) steps/day (95%CI) and 1,320 (603, 2037) steps/day at 6 and 12 months (p  <  0.001). Median (quartiles Q1-Q3) 6 and 6–12 month combined group adherence was 88.9 (74.4–95.7)%and 84.6 (73.9–95.4)%respectively. Conclusion: In this target group, no differences were detected between groups both intervention strategies were highly effective in increasing PA and fitness. Show more

Keywords: Aged, cognitive dysfunction, exercise, goals, mentors, physical fitness, sedentary behavior, volunteers

DOI: 10.3233/JAD-210479

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2021

Authors: Morris, Kevin | Nami, Mohammad | Bolanos, Joe F. | Lobo, Maria A. | Sadri-Naini, Melody | Fiallos, John | Sanchez, Gilberto E. | Bustos, Teshia | Chintam, Nikita | Amaya, Marco | Strand, Susanne E. | Mayuku-Dore, Alero | Sakibova, Indira | Biso, Grace Maria Nicole | DeFilippis, Alejandro | Bravo, Daniela | Tarhan, Nevzat | Claussen, Carsten | Mercado, Alejandro | Braun, Serge | Yuge, Louis | Okabe, Shigeo | Taghizadeh-Hesary, Farhad | Kotliar, Konstantin | Sadowsky, Christina | Chandra, P. Sarat | Tripathi, Manjari | Katsaros, Vasileios | Mehling, Brian | Noroozian, Maryam | Abbasioun, Kazem | Amirjamshidi, Abbas | Hossein-Zadeh, Gholam-Ali | Naraghi, Faridedin | Barzegar, Mojtaba | Asadi-Pooya, Ali A. | Sahab-Negah, Sajad | Sadeghian, Saeid | Fahnestock, Margaret | Dilbaz, Nesrin | Hussain, Namath | Mari, Zoltan | Thatcher, Robert W. | Sipple, Daniel | Sidhu, Kuldip | Chopra, Deepak | Costa, Francesco | Spena, Giannantonio | Berger, Ted | Zelinsky, Deborah | Wheeler, Christopher J. | Ashford, J. Wesson | Schulte, Reinhard | Nezami, M. A. | Kloor, Harry | Filler, Aaron | Eliashiv, Dawn S. | Sinha, Dipen | DeSalles, Antonio A.F. | Sadanand, Venkatraman | Suchkov, Sergey | Green, Ken | Metin, Barish | Hariri, Robert | Cormier, Jason | Yamamoto, Vicky | Kateb, Babak

Article Type: Research Article

Abstract: Neurological disorders significantly impact the world’s economy due to their often chronic and life-threatening nature afflicting individuals which, in turn, creates a global disease burden. The Group of Twenty (G20) member nations, which represent the largest economies globally, should come together to formulate a plan on how to overcome this burden. The Neuroscience-20 (N20) initiative of the Society for Brain Mapping and Therapeutics (SBMT) is at the vanguard of this global collaboration to comprehensively raise awareness about brain, spine, and mental disorders worldwide. This paper aims to provide a comprehensive review of the various brain initiatives worldwide and highlight the …need for cooperation and recommend ways to bring down costs associated with the discovery and treatment of neurological disorders. Our systematic search revealed that the cost of neurological and psychiatric disorders to the world economy by 2030 is roughly $16T. The cost to the economy of the United States is $1.5T annually and growing given the impact of COVID-19. We also discovered there is a shortfall of effective collaboration between nations and a lack of resources in developing countries. Current statistical analyses on the cost of neurological disorders to the world economy strongly suggest that there is a great need for investment in neurotechnology and innovation or fast-tracking therapeutics and diagnostics to curb these costs. During the current COVID-19 pandemic, SBMT, through this paper, intends to showcase the importance of worldwide collaborations to reduce the population’s economic and health burden, specifically regarding neurological/brain, spine, and mental disorders. Show more

DOI: 10.3233/JAD-215190

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-39, 2021

Authors: Cotton, Quinton D. | Kind, Amy J.H. | Kim, Alice J. | Block, Laura M. | Thyrian, Jochen René | Monsees, Jessica | Shah, Manish N. | Gilmore-Bykovskyi, Andrea

Article Type: Research Article

Abstract: Background: Family caregivers of people living with dementia benefit from supportive service use to address care needs associated with caregiving. Yet, research consistently demonstrates low rates of service use. Existing research has focused on barriers and facilitators to service use, with few studies examining the influence of caregivers’ environmental context which often patterns social advantage and health services accessibility. Objective: To describe the perspectives caregivers residing in socially disadvantaged areas have in regards to utilizing supportive services. Methods: Ten informal caregivers residing in socially disadvantaged areas participated in in-depth interviews that were analyzed using thematic analysis. …Results: Across all interviews, caregivers spontaneously described common precedents of service use (crisis or accumulation of unmet needs) and a distinct sequence of stages (seeking, initiating, and utilizing) surrounding service engagement. Major themes characterizing caregivers’ experiences throughout service engagement highlight the varied influence of personal, familial, health, and social system-related factors. Findings demonstrate that caregivers may have different service needs as dementia progresses and that gerontological social work practice can facilitate service use. Conclusion: While preliminary, these findings provide important insights into new domains that can be further examined in future research and intervention efforts to improve supportive service use in socially disadvantaged and underserved communities. Show more

Keywords: Caregiving, dementia, health disparities, social support

DOI: 10.3233/JAD-210609

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: van de Veen, Dennis | Bakker, Christian | Peetoom, Kirsten | Pijnenburg, Yolande | Papma, Janne M. | The PRECODE Study Group | de Vugt, Marjolein | Koopmans, Raymond

Article Type: Research Article

Abstract: Background: There has been growing interest in young people living with dementia. Future research requires consensus on the terminology and operational definition of this group. Objective: The purpose of this integrative review was to explore and include all operational definitions used to define dementia at a young age. Methods: On August 14, 2020, the PubMed, Embase, Cinahl, and PsycInfo databases were searched for empirical and theoretical literature using Google. Various terms to describe and define ‘dementia’ and ‘at a young age’ were used to collect literature concerning terminology; age-related aspects, including cut-off ages and criteria; and …etiologies of dementia at a young age. Results: The search yielded 6,891 empirical and 4,660 theoretical publications, resulting in the inclusion of 89 publications, including 36 publications containing an explicit discussion and 53 publications as confirmation. ‘Young-onset dementia’ was the most commonly used term of seven identified terms, in the last two decades. The age of 65 years at symptom onset was used most frequently when considering a total of six upper age limits and four criteria to define a cut-off age. Eight lower age limits and an option for subdivision based on age were included. We identified 251 different etiologies and 27 categories of etiologies. Conclusion: Despite relative consensus on the term young-onset dementia and an age at symptom onset being used as a cut-off criterion, much is still unclear concerning possible etiologies of dementia at a young age. In the current study, controversies were detected for discussion in an international consensus study. Show more

Keywords: Definition, operationalization, young-onset dementia

DOI: 10.3233/JAD-210458

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-26, 2021

Authors: Zhang, Xiao-Qin | Xu, Le | Yang, Si-Yu | Hu, Lin-Bo | Dong, Fei-Yuan | Sun, Bing-Gui | Shen, Hao-Wei

Article Type: Research Article

Abstract: Background: Abnormal morphology and function of neurons in the prefrontal cortex (PFC) are associated with cognitive deficits in rodent models of Alzheimer’s disease (AD), particularly in cortical layer-5 pyramidal neurons that integrate inputs from different sources and project outputs to cortical or subcortical structures. Pyramidal neurons in layer-5 of the PFC can be classified as two subtypes depending on the inducibility of prominent hyperpolarization-activated cation currents (h-current). However, the differences in the neurophysiological alterations between these two subtypes in rodent models of AD remain poorly understood. Objective: To investigate the neurophysiological alterations between two subtypes of pyramidal neurons …in hAPP-J20 mice, a transgenic model for early onset AD. Methods: The synaptic transmission and intrinsic excitability of pyramidal neurons were investigated using whole-cell patch recordings. The morphological complexity of pyramidal neurons was detected by biocytin labelling and subsequent Sholl analysis. Results: We found reduced synaptic transmission and intrinsic excitability of the prominent h-current (PH) cells but not the non-PH cells in hAPP-J20 mice. Furthermore, the function of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels which mediated h-current was disrupted in the PH cells of hAPP-J20 mice. Sholl analysis revealed that PH cells had less dendritic intersections in hAPP-J20 mice comparing to control mice, implying that a lower morphological complexity might contribute to the reduced neuronal activity. Conclusion: These results suggest that the PH cells in the medial PFC may be more vulnerable to degeneration in hAPP-J20 mice and play a sustainable role in frontal dysfunction in AD. Show more

Keywords: Alzheimer’s disease, excitatory circuit, prefrontal cortex, pyramidal neurons

DOI: 10.3233/JAD-210585

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Pytel, Vanesa | Cabrera-Martín, María Nieves | Delgado-Álvarez, Alfonso | Ayala, José Luis | Balugo, Paloma | Delgado-Alonso, Cristina | Yus, Miguel | Carreras, María Teresa | Carreras, José Luis | Matías-Guiu, Jorge | Matías-Guiu, Jordi A

Article Type: Research Article

Abstract: Background: Primary progressive aphasia (PPA) is a neurodegenerative syndrome for which no effective treatment is available. Objective: We aimed to assess the effect of repetitive transcranial magnetic stimulation (rTMS), using personalized targeting. Methods: We conducted a randomized, double-blind, pilot study of patients with PPA receiving rTMS, with a subgroup of patients receiving active- versus control-site rTMS in a cross-over design. Target for active TMS varied among the cases and was determined during a pre-treatment phase from a list of potential regions. The primary outcome was changes in spontaneous speech (word count). Secondary outcomes included changes in …other language tasks, global cognition, global impression of change, neuropsychiatric symptoms, and brain metabolism using FDG-PET. Results: Twenty patients with PPA were enrolled (14 with nonfluent and 6 with semantic variant PPA). For statistical analyses, data for the two variants were combined. Compared to the control group (n  = 7), the group receiving active-site rTMS (n  = 20) showed improvements in spontaneous speech, other language tasks, patient and caregiver global impression of change, apathy, and depression. This group also showed improvement or stabilization of results obtained in the baseline examination. Increased metabolism was observed in several brain regions after the therapy, particularly in the left frontal and parieto-temporal lobes and in the precuneus and posterior cingulate bilaterally. Conclusion: We found an improvement in language, patient and caregiver perception of change, apathy, and depression using high frequency rTMS. The increase of regional brain metabolism suggests enhancement of synaptic activity with the treatment. Trial registration : NCT03580954 (https://clinicaltrials.gov/ct2/show/NCT03580954 ) Show more

Keywords: Apraxia of speech, brain stimulation, frontotemporal dementia, neuromodulation, primary progressive aphasia, transcranial magnetic stimulation

DOI: 10.3233/JAD-210566

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: He, Fangmei | Zhang, Yuchen | Wu, Xiaofeng | Li, Youjun | Zhao, Jie | Fang, Peng | Fan, Liming | Li, Chenxi | Liu, Tian | Wang, Jue | and Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Amnestic mild cognitive impairment (aMCI) is the transitional stage between normal aging and Alzheimer’s disease (AD). Some aMCI patients will progress into AD eventually, whereas others will not. If the trajectory of aMCI can be predicted, it would enable early diagnosis and early therapy of AD. Objective: To explore the development trajectory of aMCI patients, we used diffusion tensor imaging to analyze the white matter microstructure changes of patients with different trajectories of aMCI. Methods: We included three groups of subjects:1) aMCI patients who convert to AD (MCI-P); 2) aMCI patients who remain in MCI …status (MCI-S); 3) normal controls (NC). We analyzed the fractional anisotropy and mean diffusion rate of brain regions, and we adopted logistic binomial regression model to predicate the development trajectory of aMCI. Results: The fraction anisotropy value is significantly reduced, the mean diffusivity value is significantly increased in the two aMCI patient groups, and the MCI-P patients presented greater changes. Significant changes are mainly located in the cingulum, fornix, hippocampus, and uncinate fasciculus. These changed brain regions significantly correlated with the patient’s Mini-Mental State Examination scores. Conclusion: The study predicted the disease trajectory of different types of aMCI patients based on the characteristic values of the above-mentioned brain regions. The prediction accuracy rate can reach 90.2%, and the microstructure characteristics of the right cingulate band and the right hippocampus may have potential clinical application value to predict the disease trajectory. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, diffusion tensor imaging, cognition, early microstructure changes

DOI: 10.3233/JAD-210495

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Haddad, Mohamed | Perrotte, Morgane | Ben Khedher, Mohamed Raâfet | Madec, Elise | Lepage, Aurelie | Fülöp, Tamás | Ramassamy, Charles

Article Type: Research Article

Abstract: Background: Growing evidence supports that receptor for advanced glycation end products (RAGE) and glyoxalase-1 (GLO-1) are implicated in the pathophysiology of Alzheimer’s disease (AD). Extracellular vesicles (EVs) are nanovesicles secreted by almost all cell types, contribute to cellular communication, and are implicated in AD pathology. Recently, EVs are considered as promising tools to identify reliable biomarkers in AD. Objective: The aim of our study was to determine the levels of RAGE and GLO-1 in circulating EVs from mild cognitive impairment (MCI) and AD patients and to analyze their correlation with the clinical Mini-Mental State Examination and Montreal Cognitive …Assessment scores. We have studied the possibility that neuronal cells could release and transfer GLO-1 through EVs. Methods: RAGE and GLO-1 levels were measured in circulating EVs, respectively, by Luminex assay and western blot. Released-EVs from SK-N-SH neuronal cells were isolated and GLO-1 levels were determined by western bot. Results: Our data showed higher levels of RAGE in EVs from late AD patients while GLO-1 levels in EVs from early AD were lower as compared to control and MCI patients. Interestingly, levels of RAGE and GLO-1 in EVs were correlated with the cognitive scores regardless of age. For the first time, we demonstrated that GLO-1 was released from neuronal cells through EVs. Conclusion: Although more samples will be needed, our preliminary results support the use of peripheral EVs cargo as new tools for the discovery of peripheral AD biomarkers. Show more

Keywords: Alzheimer’s disease, extracellular vesicles, glyoxalase-1, mild cognitive impairment, receptor for advanced glycation end products

DOI: 10.3233/JAD-210441

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Macpherson, Helen | McNaughton, Sarah A. | Lamb, Karen E. | Milte, Catherine M.

Article Type: Research Article

Abstract: Background: Higher quality diets may be related to lower dementia rates. Midlife is emerging as a critical life stage for a number of dementia risk factors. Objective: This study examines whether diet quality is related to brain structure during midlife, and if this differs by sex. Methods: This study used data from 19184 UK Biobank participants aged 40–65 years. Diet quality was assessed using three dietary indices including the Mediterranean Diet Score (MDS), Healthy Diet Score (HDS), and Recommended Food Score (RFS). MRI brain measures included total, grey, white and hippocampal volume. Linear regression examined associations …between diet quality and brain volume, controlling for potential confounders. Results: Better quality diet across all indices was significantly related to larger grey matter volume: MDS β= 429.7 (95%CI: 65.2, 794.2); HDS β= 700.1 (348.0, 1052.1); and RFS β= 317.1 (106.8, 527.3). Higher diet scores were associated with greater total volume: HDS β= 879.32 (286.13, 1472.50); RFS β= 563.37 (209.10, 917.65); and white matter volume: RFS β= 246.31 (20.56, 472.05), with the exception of Mediterranean diet adherence. Healthy eating guidelines and dietary variety associations with total and grey matter volume were more prominent in men. Conclusion: Findings suggest that diet quality is associated with brain structure during midlife, potentially decades prior to the onset of dementia. Show more

Keywords: Alzheimer’s disease, brain volume, dementia, healthy diet, Mediterranean diet

DOI: 10.3233/JAD-210705

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Caldieraro, Marco Antonio | Laufer-Silva, Tatiana | Cassano, Paolo

Article Type: Research Article

Abstract: Background: Major depressive disorder (MDD) is prevalent and has significant impact on individuals and society. Cognitive symptoms are frequent in MDD and insufficiently treated by antidepressant medications. Transcranial photobiomodulation (t-PBM) is a novel device therapy which shows promise as an antidepressant and pro-cognitive treatment. To date, despite the encouraging results, the optimal stimulation parameters of t-PBM to treat MDD are not established, and clinical studies are very heterogeneous in terms of these parameters. While the literature provides guidance on the appropriate fluence to achieve therapeutic results, little is known on the other parameters. Objective: To evaluate the relationship …between different parameters and the antidepressant effect of t-PBM. Methods: We reviewed clinical studies on MDD and on depressive symptoms comorbid with other diseases. We calculated the standardized effect size of the change in symptoms severity before and after t-PBM and we performed a descriptive analysis of the reviewed papers. Results: The greatest effect sizes for the antidepressant effect were found in studies using pulse-wave t-PBM with high peak irradiance (but low average irradiance) over large skin surface. One well-designed and sufficiently powered, double-blind, sham-controlled trial indicated that t-PBM with low irradiance over a small skin surface is ineffective to treat depression. Conclusion: The use of t-PBM for Alzheimer’s disease and for dementia is still at its inception; these dosimetry lessons from the use of t-PBM for depression might serve as guidance. Show more

Keywords: Alzheimer’s disease, cognition disorders, depression, low-level light therapy, photobiomodulation

DOI: 10.3233/JAD-210586

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Yu, Wenlei | Lu, Linjie | Ji, Xintong | Qian, Qiwei | Lin, Xiaohan | Wang, Huanhuan

Article Type: Research Article

Abstract: Chronic periodontitis caused by Porphyromonas gingivalis (P. gingivalis ) infection generally lasts for a lifetime. The long-term existence and development of P. gingivalis infection gradually aggravate the accumulation of inflammatory signals and toxic substances in the body. Recent evidence has revealed that P. gingivalis infection may be relevant to some central nervous system (CNS) diseases. The current work collects information and tries to explore the possible relationship between P. gingivalis infection and CNS diseases, including the interaction or pathways between peripheral infection and CNS injury, and the underlying neurotoxic mechanisms.

Keywords: Epigenetic regulation, nervous system damage (CNS), neuroinflammation, Porphyromonasgingivalis

DOI: 10.3233/JAD-215143

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Katzourou, Ioanna | Leonenko, Ganna | Ivanov, Dobril | Meggy, Alun | Marshall, Rachel | Sims, Rebecca | Williams, Julie | Holmans, Peter | Escott-Price, Valentina | the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The rate of cognitive decline in Alzheimer’s disease (AD) has been found to vary widely between individuals, with numerous factors driving this heterogeneity. Objective: This study aimed to compute a measure of cognitive decline in patients with AD based on clinical information and to utilize this measure to explore the genetic architecture of cognitive decline in AD. Methods: An in-house cohort of 616 individuals, hereby termed the Cardiff Genetic Resource for AD, as well as a subset of 577 individuals from the publicly available ADNI dataset, that have been assessed at multiple timepoints, were used …in this study. Measures of cognitive decline were computed using various mixed effect linear models of Mini-Mental State Examination (MMSE). After an optimal model was selected, a metric of cognitive decline for each individual was estimated as the random slope derived from this model. This metric was subsequently used for testing the association of cognitive decline with apolipoprotein E (APOE ) genotype. Results: No association was found between the number of APOE ɛ 2 or ɛ 4 alleles and the rate of cognitive decline in either of the datasets examined. Conclusion: Further exploration is required to uncover possible genetic variants that affect the rate of decline in patients with AD. Show more

Keywords: Alzheimer’s disease, APOE , cognitive decline, dementia, genetics

DOI: 10.3233/JAD-210685

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Farace, Paolo | Tamburin, Stefano

Article Type: Article Commentary

Abstract: Amyloid-β deposition is one of the neuropathological hallmarks of Alzheimer’s disease (AD), but pharmacological strategies toward its reduction are poorly effective. Preclinical studies indicate that low-dose radiation therapy (LD-RT) may reduce brain amyloid-β. Animal models and proof-of-concept preliminary data in humans have shown that magnetic resonance guided focused ultrasound (MRgFUS) can reversibly open the blood-brain-barrier and facilitate the delivery of targeted therapeutics to the hippocampus, to reduce amyloid-β and promote neurogenesis in AD. Ongoing clinical trials on AD are exploring whole-brain LD-RT, which may damage radio-sensitive structures, i.e., hippocampus and white matter, thus contributing to reduced neurogenesis and radiation-induced …cognitive decline. However, selective irradiation of cortical amyloid-β plaques through advanced LD-RT techniques might spare the hippocampus and white matter. We propose combined use of advanced LD-RT and targeted drug delivery through MRgFUS for future clinical trials to reduce amyloid-β deposition in AD since its preclinical stages. Show more

Keywords: Alzheimer’s disease, amyloid-β , blood-brain barrier, clinical trial, drug delivery, health technology, hippocampus, magnetic resonance guided focused ultrasound, radiation therapy, therapy

DOI: 10.3233/JAD-215041

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2021

Authors: Isernia, Sara | Cabinio, Monia | Tella, Sonia Di | Pazzi, Stefania | Vannetti, Federica | Gerli, Filippo | Mosca, Irene Eleonora | Lombardi, Gemma | Macchi, Claudio | Sorbi, Sandro | Baglio, Francesca

Article Type: Research Article

Abstract: Background: The Smart Aging Serious Game (SASG) is an ecologically-based digital platform used in mild neurocognitive disorders. Considering the higher risk of developing dementia for mild cognitive impairment (MCI) and vascular cognitive impairment (VCI), their digital phenotyping is crucial. A new understanding of MCI and VCI aided by digital phenotyping with SASG will challenge current differential diagnosis and open the perspective of tailoring more personalized interventions. Objective: To confirm the validity of SASG in detecting MCI from healthy controls (HC) and to evaluate its diagnostic validity in differentiating between VCI and HC. Methods: 161 subjects (74 …HC: 37 males, 75.47±2.66 mean age; 60 MCI: 26 males, 74.20±5.02; 27 VCI: 13 males, 74.22±3.43) underwent a SASG session and a neuropsychological assessment (Montreal Cognitive Assessment (MoCA), Free and Cued Selective Reminding Test, Trail Making Test). A multi-modal statistical approach was used: receiver operating characteristic (ROC) curves comparison, random forest (RF), and logistic regression (LR) analysis. Results: SASG well captures the specific cognitive profiles of MCI and VCI, in line with the standard neuropsychological measures. ROC analyses revealed high diagnostic sensitivity and specificity of SASG and MoCA (AUCs  >  0.800) in detecting VCI versus HC and MCI versus HC conditions. A classification accuracy acceptable-to-excellent was found for MCI and VCI (HC versus VCI; RF: 90%, LR: 91%. HC versus MCI; RF: 75%; LR: 87%). Conclusion: SASG allows the early assessment of cognitive impairment through ecological tasks and potentially in a self-administered way. These features make this platform suitable for being considered a useful digital phenotyping tool, allowing a non-invasive and valid neuropsychological evaluation, with evident implications for future digital-health trails and rehabilitation. Show more

Keywords: Dementia, digital medicine, mild cognitive impairment, mild neurocognitive disorder, neuropsychological assessment, serious games, telemonitoring, vascular cognitive impairment, virtual reality

DOI: 10.3233/JAD-210347

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Pievani, Michela | Mega, Anna | Quattrini, Giulia | Guidali, Giacomo | Ferrari, Clarissa | Cattaneo, Annamaria | D’Aprile, Ilari | Mascaro, Lorella | Gasparotti, Roberto | Corbo, Daniele | Brignani, Debora | Bortoletto, Marta

Article Type: Research Article

Abstract: Background: Default mode network (DMN) dysfunction is well established in Alzheimer’s disease (AD) and documented in both preclinical stages and at-risk subjects, thus representing a potential disease target. Multi-sessions of repetitive transcranial magnetic stimulation (rTMS) seem capable of modulating DMN dynamics and memory in healthy individuals and AD patients; however, the potential of this approach in at-risk subjects has yet to be tested. Objective: This study will test the effect of rTMS on the DMN in healthy older individuals carrying the strongest genetic risk factor for AD, the Apolipoprotein E (APOE ) ɛ4 allele. Methods: We …will recruit 64 older participants without cognitive deficits, 32 APOE ɛ4 allele carriers and 32 non-carriers as a reference group. Participants will undergo four rTMS sessions of active (high frequency) or sham DMN stimulation. Multimodal imaging exam (including structural, resting-state, and task functional MRI, and diffusion tensor imaging), TMS with concurrent electroencephalography (TMS-EEG), and cognitive assessment will be performed at baseline and after the stimulation sessions. Results: We will assess changes in DMN connectivity with resting-state functional MRI and TMS-EEG, as well as changes in memory performance in APOE ɛ4 carriers. We will also investigate the mechanisms underlying DMN modulation through the assessment of correlations with measures of neuronal activity, excitability, and structural connectivity with multimodal imaging. Conclusion: The results of this study will inform on the physiological and cognitive outcomes of DMN stimulation in subjects at risk for AD and on the possible mechanisms. These results may outline the design of future non-pharmacological preventive interventions for AD. Show more

Keywords: Alzheimer’s disease, at-risk healthy subjects, APOE ɛ4 allele, default mode network, functional connectivity, repetitive transcranial magnetic stimulation

DOI: 10.3233/JAD-210659

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: González-Ortega, Guillermo | Llamas-Velasco, Sara | Arteche-López, Ana | Quesada-Espinosa, Juan Francisco | Puertas-Martín, Verónica | Gómez-Grande, Adolfo | López-Álvarez, Jorge | Saiz Díaz, Rosa Ana | Lezana-Rosales, José Miguel | Villarejo-Galende, Alberto | González de la Aleja, Jesús

Article Type: Short Communication

Abstract: The haploinsufficiency of the methyl-binding domain protein 5 (MBD5 ) gene has been identified as the determinant cause of the neuropsychiatric disorders grouped under the name MBD5 -neurodevelopment disorders (MAND). MAND includes patients with intellectual disability, behavioral problems, and seizures with a static clinical course. However, a few reports have suggested regression. We describe a non-intellectually disabled female, with previous epilepsy and personality disorder, who developed early-onset dementia. The extensive etiologic study revealed a heterozygous nonsense de novo pathogenic variant in the MBD5 gene. This finding could support including the MBD5 gene in the study of patients …with atypical early-onset dementia. Show more

Keywords: Early-onset dementia, gene, human phenotype ontology, MBD5-neurodevelopment disorders, methyl-binding domain protein 5 (MBD5), personality disorder, seizures

DOI: 10.3233/JAD-210648

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2021

Authors: Liu, Zihuan | Maiti, Tapabrata | Bender, Andrew R. | and for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The transition from mild cognitive impairment (MCI) to dementia is of great interest to clinical research on Alzheimer’s disease and related dementias. This phenomenon also serves as a valuable data source for quantitative methodological researchers developing new approaches for classification. However, the growth of machine learning (ML) approaches for classification may falsely lead many clinical researchers to underestimate the value of logistic regression (LR), which often demonstrates classification accuracy equivalent or superior to other ML methods. Further, when faced with many potential features that could be used for classifying the transition, clinical researchers are often unaware of the relative …value of different approaches for variable selection. Objective: The present study sought to compare different methods for statistical classification and for automated and theoretically guided feature selection techniques in the context of predicting conversion from MCI to dementia. Methods: We used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to evaluate different influences of automated feature preselection on LR and support vector machine (SVM) classification methods, in classifying conversion from MCI to dementia. Results: The present findings demonstrate how similar performance can be achieved using user-guided, clinically informed pre-selection versus algorithmic feature selection techniques. Conclusion: These results show that although SVM and other ML techniques are capable of relatively accurate classification, similar or higher accuracy can often be achieved by LR, mitigating SVM’s necessity or value for many clinical researchers. Show more

Keywords: Alzheimer’s disease, classification, machine learning, mild cognitive impairment, support vector machine, variable selection

DOI: 10.3233/JAD-201398

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Handy, Alex | Lord, Jodie | Green, Rebecca | Xu, Jin | Aarsland, Dag | Velayudhan, Latha | Hye, Abdul | Dobson, Richard | Proitsi, Petroula | on behalf of the Alzheimer’s Disease Neuroimaging initiative | AddNeuroMed, and the GERAD1 Consortium

Article Type: Research Article

Abstract: Background: Blood plasma proteins have been associated with Alzheimer’s disease (AD), but understanding which proteins are on the causal pathway remains challenging. Objective: Investigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian randomization (MR). Methods: Following a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritized proteins with and without the apolipoprotein E region (APOE+/–PRS) and tested for association with AD status across three cohorts (n  = 6,244). An AD PRS was also tested for association with protein levels …in one cohort (n  = 410). Proteins showing association with AD were taken forward for MR. Results: For APOE ɛ3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p  <  0.00017). No protein APOE- PRS or AD PRS (APOE+/–) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p  = 0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p  = 0.025, protein APOE- PRS p  = 0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the five proteins demonstrated a causal association (p  <  0.05) in either direction. Conclusion: Apolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, accessible risk factor. While evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power. Show more

Keywords: Alzheimer’s disease, apolipoprotein B-100, apolipoprotein E, blood proteins, C-reactive protein, insulin-like growth factor binding protein 2, mendelian randomization analysis, polygenic trait, vitamin D-binding protein

DOI: 10.3233/JAD-210462

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Zhang, Zhizhong | Wang, Mengmeng | Yuan, Shuai | Cai, Huan | Zhu, Shuang-Gen | Liu, Xinfeng

Article Type: Research Article

Abstract: Background: Observational studies have reported that coffee consumption was associated with Alzheimer’s disease (AD) and stroke risk. However, the results are inconclusive. Objective: We aimed to evaluate whether genetically predicted coffee consumption is associated with AD and stroke using Mendelian randomization (MR) design. Methods: Summary-level data for AD (n  = 54,162), ischemic stroke (n  = 440,328), and intracerebral hemorrhage (ICH, n  = 3,026) was adopted from publicly available databases. Summary-level data for coffee consumption were obtained from two genome-wide association studies, comprising up to 375,833 subjects. Results: Genetically predicted coffee consumption (cups/day) was associated with an increased …risk of AD (OR = 1.26, 95%CI = 1.05–1.51). Moreover, genetically predicted 50%increase of coffee consumption was associated with an increased risk of ICH (OR: 2.27, 95%CI: 1.08–4.78) but a decreased risk of small vessel stroke (OR: 0.71, 95%CI: 0.51–0.996). Estimate for AD and ICH in FinnGen consortium is directionally consistent. Combined analysis of different databases further confirmed that genetically predicted coffee consumption was associated with an increased risk of AD and ICH. In the multivariable MR analysis, genetically predicted coffee consumption retained a stable effect with AD and ICH when adjusting for smoking (p  <  0.05), while the association with AD attenuated when adjusting for alcohol use. Conclusion: Our results indicate that genetically predicted coffee consumption may be associated with an increased risk of AD and ICH. The underlying biological mechanisms warrant further study. Show more

Keywords: Alzheimer’s disease, coffee, mendelian randomization, stroke

DOI: 10.3233/JAD-210678

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Hamblin, Michael R. | Salehpour, Farzad

Article Type: Introduction

DOI: 10.3233/JAD-210743

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2021

Authors: Bommarito, Giulia | Van De Ville, Dimitri | Frisoni, Giovanni B. | Garibotto, Valentina | Ribaldi, Federica | Stampacchia, Sara | Assal, Frédéric | Allali, Gilles | Griffa, Alessandra

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) pathology impacts the response to treatment in patients with idiopathic normal pressure hydrocephalus (iNPH), possibly through changes in resting-state functional connectivity (rs-FC). Objective: To explore the relationship between cerebrospinal fluid biomarkers of AD and the default mode network (DMN)/hippocampal rs-FC, in iNPH patients based on their outcome after cerebrospinal fluid tap test (CSFTT), and in patients with AD. Methods: Twenty-six iNPH patients (mean age: 79.9±5.9 years; 12 females) underwent MRI and clinical assessment before and after CSFTT and were classified as responders (Resp) or not (NResp), based on the improvement at the …timed up and go test and walking speed. Eleven AD patients (mean age: 70.91±5.2 years; 5 females), matched to iNPH for cognitive status, were also included. DMN and hippocampal rs-FC was related to amyloid-β42 and phosphorylated tau (pTau) levels. Results: Lower amyloid-β42 levels were associated with reduced inter- and intra-network rs-FC in NResp, and the interaction between amyloid-β42 and rs-FC was a predictor of outcome after CSFTT in iNPH. The rs-FC between DMN and salience networks positively correlated to amyloid-β42 levels in both NResp and AD patients. The increase in inter-network rs-FC after CSFTT was associated with higher pTau and lower amyloid-β42 levels in NResp, and to lower pTau levels in Resp. Conclusion: Amyloid-β42 and pTau impact on rs-FC and its changes after CSFTT in iNPH patients. The interaction between AD biomarkers and rs-FC might explain the responder status in iNPH. Show more

Keywords: Alzheimer’s disease, amyloid, CSF tap test, default mode network, functional connectivity, hippocampus, normal pressure hydrocephalus, tau

DOI: 10.3233/JAD-210534

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Ma, Heather | Kiekhofer, Rachel E. | Hooper, Sarah M. | Dulaney, Sarah | Possin, Katherine L. | Chiong, Winston

Article Type: Research Article

Abstract: Background: Advance care planning has been shown to improve end of life decision-making for people with dementia. However, the impact of goals of care conversations between people with dementia and their caregivers has not been characterized. Objective: In this study, we evaluate the association between goals of care conversations and advance care planning outcomes. Methods: Retrospective advance care planning measures were collected via a questionnaire administered to 166 caregivers after the death of the person with dementia for whom they provided care. Results: At time of death, the majority of decedents with dementia had …advance directives, health care agents, and previous goals of care conversations with their caregiver. Goals of care conversations were significantly associated with the perceived usefulness of advance directives, the perceived adherence to advance directives, and decedent dying at their desired place of death, but not with disagreements around end-of-life care. Conclusion: Our findings suggest that goals of care conversations are an important component of advance care planning. These findings support the development of interventions that facilitate such conversations between people with dementia and their caregivers. Show more

Keywords: Advance care planning, Alzheimer’s disease, dementia, patient preference, terminal care

DOI: 10.3233/JAD-210720

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Zhang, Jing–Jing | Li, Lin | Liu, Dan | Hu, Fei-Fei | Cheng, Gui-Rong | Xu, Lang | Yan, Ping-Ting | Tian, Yuan | Hu, Heng | Yu, Ya-Fu | Gan, Xu-Guang | An, Li-Na | Zhang, Bo | Qian, Jin | Fu, Li-Yan | Cheng, Xi | Lian, Peng-Fei | Zou, Ming-Jun | Chen, Chong | Wu, Qing-Ning | Zeng, Yan

Article Type: Research Article

Abstract: Background: Some studies have demonstrated an association between low and high body mass index (BMI) and an increased risk of dementia. However, only a few of these studies were performed in rural areas. Objective: This cross–sectional study investigated the associations between BMI and cognitive impairment among community–dwelling older adults from rural and urban areas. Methods: 8,221 older persons enrolled in the Hubei Memory & Ageing Cohort Study (HMACS) were recruited. Sociodemographic and lifestyle data, comorbidities, physical measurements, and clinical diagnoses of cognitive impairment were analyzed. Logistic regression was performed to assess the associations of BMI categories …with cognitive impairment. A series of sensitivity analyses were conducted to test whether reverse causality could influence our results. Results: Being underweight in the rural–dwelling participants increased the risk of cognitive impairment. Being overweight was a protective factor in rural–dwelling participants aged 65–69 years and 75–79 years, whereas being underweight was significantly associated with cognitive impairment (OR, 1.37; 95% CI: 1.03–1.83; p  < 0.05). Sensitivity analyses support that underweight had an additive effect on the odds of cognitive impairment and was related to risk of dementia. Interaction test revealed that the differences between urban/rural in the relationship between BMI and cognitive impairment are statistically significant. Conclusion: Associations between BMI and cognitive impairment differ among urban/rural groups. Older people with low BMI living in rural China are at a higher risk for dementia than those living in urban areas. Show more

Keywords: Body mass index, cognitive impairment, community–dwelling older adults, cross–sectional study, rural–urban disparity

DOI: 10.3233/JAD-210295

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Pisu, Maria | Martin, Roy C. | Shan, Liang | Pilonieta, Giovanna | Kennedy, Richard E. | Oates, Gabriela | Kim, Young-Il | Geldmacher, David S.

Article Type: Research Article

Abstract: Background: Use of specialists and recommended drugs has beneficial effects for older adults living with Alzheimer’s disease and related dementia (ADRD). Gaps in care may exist for minorities, e.g., Blacks, and especially in the United States (U.S.) Deep South (DS), a poor U.S. region with rising ADRD cases and minority overrepresentation. Currently, we have little understanding of ADRD care utilization in diverse populations in this region and elsewhere in the U.S. (non-DS), and the factors that adversely impact it. Objective: To examine utilization of specialists and ADRD drugs (outcomes) in racial/ethnic groups of older adults with ADRD and …the personal or context-level factors affecting these outcomes in DS and non-DS. Methods: We obtained outcomes and personal-level covariates from claims for 127,512 Medicare beneficiaries with ADRD in 2013–2015, and combined county-level data in exploratory factor analysis to define context-level covariates. Adjusted analyses tested significant association of outcomes with Black/White race and other factors in DS and non-DS. Results: Across racial/ethnic groups, 33%–43% in DS and 43%–50% in non-DS used specialists; 47%–55% in DS and 41%–48% in non-DS used ADRD drugs. In adjusted analyses, differences between Blacks and Whites were not significant. Vascular dementia, comorbidities, poverty, and context-level factor “Availability of Medical Resources” were associated with specialist use; Alzheimer’s disease and senile dementia, comorbidities, and specialist use were associated with drug use. In non-DS only, other individual, context-level covariates were associated with the outcomes. Conclusion: We did not observe significant gaps in ADRD care in DS and non-DS; however, research should further examine determinants of low specialist and drug use in these regions. Show more

Keywords: Access to care, affordability, disparities, drug use, equity, physician availability, socioeconomic context, socioeconomic status, specialist use

DOI: 10.3233/JAD-210240

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Utsumi, Kumiko | Fukatsu, Ryo | Hara, Yuko | Takamaru, Yuji | Yasumura, Shuichi

Article Type: Research Article

Abstract: Background: Many cases of dementia with Lewy bodies (DLB) present with various psychotic features, including hallucinations, depression, catatonia, and delusions before the onset of cognitive impairment. However, the characteristic features of these psychotic symptoms in prodromal DLB have not been sufficiently described. Objective: To clarify and describe the psychotic features of prodromal DLB before overt cognitive impairment. Methods: The authors analyzed the characteristic psychotic features of prodromal DLB in 21 subjects who developed severe psychotic symptoms without dementia and were diagnosed as DLB after the longitudinal observation period. They were then confirmed to have DLB through …indicative and supportive biomarkers of scintigraphy. Results: The psychotic features included a wide variety of symptoms, but convergent to three principal categories: catatonia, delusions-hallucinations, and depression and/or mania. Catatonia was observed in nine cases, five were delusional-hallucinatory, and seven were manic and/or depressive. Seven of the 21 cases exhibited delirium during longitudinal observation. A psychotic state repeatedly appeared without any trigger in 20 of the 21 patients. All subjects developed cognitive impairment at 9.1±4.6 (mean±SD) years after the initial appearance of psychotic symptoms, and subsequently diagnosed with DLB at 71.3±6.1 (mean±SD) years. Conclusion: Elderly patients with psychotic symptoms, such as catatonia, delusion-hallucination, manic and/or depressive features, and delirium without dementia, could indicate symptomatic psychosis or a prodromal stage of any neurocognitive disorder such as DLB. Therefore, further extensive workout (e.g., radioisotope neuroimaging) is required to avoid misdiagnosis. Show more

Keywords: Catatonia, delirium, delusional-hallucinatory feature, dementia with Lewy bodies, manic and/or depressive feature, prodromal

DOI: 10.3233/JAD-210416

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Canevelli, Marco | Di Pucchio, Alessandra | Marzolini, Fabrizio | Mayer, Flavia | Massari, Marco | Salvi, Emanuela | Palazzesi, Ilaria | Lacorte, Eleonora | Bacigalupo, Ilaria | Di Fiandra, Teresa | Vanacore, Nicola

Article Type: Research Article

Abstract: Background: Italy has one of the oldest populations in the World and more than one million dementia cases can be estimated at the national level. Objective: The objectives of this national survey include: 1) to report the administrative features and the professional competencies of Centers for Cognitive Disorders and Dementias (CCDDs); 2) to document possible discrepancies by geographic macro-area; and 3) to identify the features of CCDDs that are associated with a better quality in the provision of care. Methods: A survey of Italian CCDDs was conducted between February 2014 and December 2015. A list of …CCDDs was obtained through direct interactions with designed delegates from each Italian region. A questionnaire was defined on five sections concerning: 1) location of the CCDD; 2) access to the CCDD; 3) organization of the CCDD; 4) services and treatments provided; and 5) quantitative data on the activities of the CCDD. Results: Overall, 577 out of the 597 eligible CCDDs returned the completed survey questionnaire (response rate: 96.6%): 260 (45.1%) from Northern Italy, 103 (17.8%) from Central Italy, and 214 (37.1%) from Southern-Islands Italy. More than a third of CCDDs were open only once or twice weekly. A median of 450 (IQR: 200–800) patients regularly attended these services. Most patients (70%) were affected by dementia or mild cognitive impairment (19%). Conclusion: We have provided a snapshot of the organization and activities of CCDDs in Italy and documented existing inequalities in the provision of care. Show more

Keywords: Cognitive disorders, dementia, healthcare services, memory clinics, public health, services, survey

DOI: 10.3233/JAD-210634

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Briceño, Emily M. | Gross, Alden L. | Giordani, Bruno J. | Manly, Jennifer J. | Gottesman, Rebecca F. | Elkind, Mitchell S.V. | Sidney, Stephen | Hingtgen, Stephanie | Sacco, Ralph L. | Wright, Clinton B. | Fitzpatrick, Annette | Fohner, Alison E. | Mosley, Thomas H. | Yaffe, Kristine | Levine, Deborah A.

Article Type: Research Article

Abstract: Background: Meta-analyses of individuals’ cognitive data are increasing to investigate the biomedical, lifestyle, and sociocultural factors that influence cognitive decline and dementia risk. Pre-statistical harmonization of cognitive instruments is a critical methodological step for accurate cognitive data harmonization, yet specific approaches for this process are unclear. Objective: To describe pre-statistical harmonization of cognitive instruments for an individual-level meta-analysis in the blood pressure and cognition (BP COG) study. Methods: We identified cognitive instruments from six cohorts (the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Coronary Artery Risk Development in Young Adults study, Framingham Offspring Study, Multi-Ethnic …Study of Atherosclerosis, and Northern Manhattan Study) and conducted an extensive review of each item’s administration and scoring procedures, and score distributions. Results: We included 153 cognitive instrument items from 34 instruments across the six cohorts. Of these items, 42%were common across ≥2 cohorts. 86%of common items showed differences across cohorts. We found administration, scoring, and coding differences for seemingly equivalent items. These differences corresponded to variability across cohorts in score distributions and ranges. We performed data augmentation to adjust for differences. Conclusion: Cross-cohort administration, scoring, and procedural differences for cognitive instruments are frequent and need to be assessed to address potential impact on meta-analyses and cognitive data interpretation. Detecting and accounting for these differences is critical for accurate attributions of cognitive health across cohort studies. Show more

Keywords: Cognition, dementia, epidemiology, methods

DOI: 10.3233/JAD-210459

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Vemuri, Prashanthi | Davey, Cynthia | Johansen, Kirsten L. | Zuk, Samantha M. | Reid, Robert I. | Thostenson, Kaely B. | Reddy, Ashritha L. | Jack Jr., Clifford R. | Knopman, David S. | Murray, Anne M.

Article Type: Research Article

Abstract: Background: Chronic kidney disease (CKD), a growing public health issue in the elderly, is associated with increased risk of cognitive impairment. Objective: To investigate the mechanisms through which CKD impacts brain health using longitudinal imaging. Methods: We identified 97 participants (74 CKD and 23 non-CKD) from the BRINK (BRain IN Kidney Disease), a longitudinal study of CKD with two MRI scans (baseline and 3-year follow-up). We measured the associations between baseline and change in kidney disease biomarkers of estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR), considered a measure of microvascular inflammation, …and imaging outcomes of cortical thickness and ventricular volume from structural MRI, white matter hyperintensities (WMH) volume from FLAIR images, and fractional anisotropy of the corpus callosum (FACC). Results: There were white matter-specific changes as observed by increased WMH volume and decreased FACC in CKD participants, as well as ventricular volume increase in both CKD and non-CKD groups reflective of aging-related changes. Decline in eGFR was associated with decrease in the FACC, suggesting that subtle early white matter changes due to kidney disease can be captured using DTI. An increase in UACR was associated with increase in ventricular volume. Conclusion: Our results support the role of eGFR as a measure of kidney microvascular disease which is associated with concurrent white matter damage in CKD. Future work is needed to investigate the possible link between endothelial microvascular inflammation (as measured by an increased UACR) and ventricular volume increase. Show more

Keywords: Brain health, chronic kidney disease, diffusion tensor imaging, white matter damage, white matter hyperintensities

DOI: 10.3233/JAD-210604

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Cummings, Jeffrey | Schwartz, Gregory G. | Nicholls, Stephen J. | Khan, Aziz | Halliday, Chris | Toth, Peter P. | Sweeney, Michael | Johansson, Jan O. | Wong, Norman C.W. | Kulikowski, Ewelina | Kalantar-Zadeh, Kamyar | Lebioda, Kenneth | Ginsberg, Henry N. | Winblad, Bengt | Zetterberg, Henrik | Ray, Kausik K.

Article Type: Research Article

Abstract: Background: Epigenetic changes may contribute importantly to cognitive decline in late life including Alzheimer’s disease (AD) and vascular dementia (VaD). Bromodomain and extra-terminal (BET) proteins are epigenetic “readers” that may distort normal gene expression and contribute to chronic disorders. Objective: To assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized trial of patients at high risk for major cardiovascular events (MACE). Methods: The Montreal Cognitive Assessment (MoCA) was performed on all patients 70 years or older at the time of randomization. …464 participants were randomized to apabetalone or placebo in the cognition sub-study. In a prespecified analysis, participants were assigned to one of three groups: MoCA score≥26 (normal performance), MoCA score 25–22 (mild cognitive impairment), and MoCA score≤21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group. Results: Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of≤21 (p  = 0.02). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% versus 7.9%). Conclusion: In this randomized controlled study, apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders. Show more

Keywords: Alzheimer’s disease, apabetalone, BET inhibitor, clinical trial, epigenetics, montreal cognitive assessment

DOI: 10.3233/JAD-210570

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Platen, Moritz | Fleßa, Steffen | Rädke, Anika | Wucherer, Diana | Thyrian, Jochen René | Mohr, Wiebke | Scharf, Annelie | Mühlichen, Franka | Hoffmann, Wolfgang | Michalowsky, Bernhard

Article Type: Research Article

Abstract: Background: Low-value care (LvC) is defined as care unlikely to provide a benefit to the patient regarding the patient’s preferences, potential harms, costs, or available alternatives. Avoiding LvC and promoting recommended evidence-based treatments, referred to as high-value care (HvC), could improve patient-reported outcomes for people living with dementia (PwD). Objective: This study aims to determine the prevalence of LvC and HvC in dementia and the associations of LvC and HvC with patients’ quality of life and hospitalization. Methods: The analysis was based on data of the DelpHi trial and included 516 PwD. Dementia-specific guidelines, the “Choosing …Wisely” campaign and the PRISCUS list were used to indicate LvC and HvC treatments, resulting in 347 LvC and HvC related recommendations. Of these, 77 recommendations (51 for LvC, 26 for HvC) were measured within the DelpHi-trial and finally used for this analysis. The association of LvC and HvC treatments with PwD health-related quality of life (HRQoL) and hospitalization was assessed using multiple regression models. Results: LvC was highly prevalent in PwD (31%). PwD receiving LvC had a significantly lower quality of life (b  = –0.07; 95% CI –0.14 – –0.01) and were significantly more likely to be hospitalized (OR = 2.06; 95% CI 1.26–3.39). Different HvC treatments were associated with both positive and negative changes in HRQoL. Conclusion: LvC could cause adverse outcomes and should be identified as early as possible and tried to be replaced. Future research should examine innovative models of care or treatment pathways supporting the identification and replacement of LvC in dementia. Show more

Keywords: Alzheimer’s disease, health-related quality of life, hospitalization, low-value care, patient-centered outcomes

DOI: 10.3233/JAD-210439

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Syverstad Skaaraas, Gry H.E. | Melbye, Christoffer | Puchades, Maja A. | Yi Leung, Doreen Siu | Jacobsen, Øyvind | Rao, Shreyas B. | Ottersen, Ole Petter | Leergaard, Trygve B. | Torp, Reidun

Article Type: Research Article

Abstract: Background: Vascular pathology is a common feature in patients with advanced Alzheimer’s disease, with cerebral amyloid angiopathy (CAA) and microvascular changes commonly observed at autopsies and in genetic mouse models. However, despite a plethora of studies addressing the possible impact of CAA on brain vasculature, results have remained contradictory, showing reduced, unchanged, or even increased capillary densities in human and rodent brains overexpressing amyloid-β in Alzheimer’s disease and Down’s syndrome. Objective: We asked if CAA is associated with changes in angiogenetic factors or receptors and if so, whether this would translate into morphological alterations in pericyte coverage and …vessel density. Methods: We utilized the transgenic mice carrying the Arctic (E693G) and Swedish (KM670/6701NL) amyloid precursor protein which develop severe CAA in addition to parenchymal plaques. Results: The main finding of the present study was that CAA in Tg-ArcSwe mice is associated with upregulated angiopoietin and downregulated hypoxia-inducible factor. In the same mice, we combined immunohistochemistry and electron microscopy to quantify the extent of CAA and investigate to which degree vessels associated with amyloid plaques were pathologically affected. We found that despite a severe amount of CAA and alterations in several angiogenetic factors in Tg-ArcSwe mice, this was not translated into significant morphological alterations like changes in pericyte coverage or vessel density. Conclusion: Our data suggest that CAA does not impact vascular density but might affect capillary turnover by causing changes in the expression levels of angiogenetic factors. Show more

Keywords: Alzheimer’s disease, amyloid-β , angiogenesis, cerebral amyloid angiopathy, HIF1a, mouse model, pericytes, VEGF

DOI: 10.3233/JAD-210571

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Lim, Yen Ying | Ayton, Darshini | Perin, Stephanie | Lavale, Alexandra | Yassi, Nawaf | Buckley, Rachel | Barton, Christopher | Bruns Jr, Loren | Morello, Renata | Pirotta, Stephanie | Rosenich, Emily | Rajaratnam, Shantha M.W. | Sinnott, Richard | Brodtmann, Amy | Bush, Ashley I. | Maruff , Paul | Churilov, Leonid | Barker, Anna | Pase, Matthew P. | on behalf of the BetterBrains Research Group

Article Type: Research Article

Abstract: Background: Several modifiable risk factors for dementia have been identified, although the extent to which their modification leads to improved cognitive outcomes remains unclear. Objective: The primary aim is to test the hypothesis that a behavior modification intervention program targeting personalized risk factors prevents cognitive decline in community-dwelling, middle-aged adults with a family history of dementia. Methods: This is a prospective, risk factor management, blinded endpoint, randomized, controlled trial, where 1510 cognitively normal, community-dwelling adults aged 40–70 years old will be recruited. Participants will be screened for risk factors related to vascular health (including physical inactivity), …mental health, sleep, and cognitive/social engagement. The intervention is an online person-centered risk factor management program: BetterBrains. Participants randomized to intervention will receive telehealth-based person-centered goal setting, motivational interviewing, and follow-up support, health care provider communication and community linkage for management of known modifiable risk factors of dementia. Psychoeducational health information will be provided to both control and intervention groups. Results: The primary outcome is favorable cognitive performance at 24-months post-baseline, defined as the absence of decline on one or more of the following cognitive tests: (a) Cogstate Detection, (b) Cogstate One Card Learning, (c) Cogstate One Back, and (d) Cognitive Function Instrument total score. Conclusion: We will test the hypothesis that the BetterBrains intervention program can prevent cognitive decline. By leveraging existing community services and using a risk factor management pathway that tailors the intervention to each participant, we maximize likelihood for engagement, long-term adherence, and for preserving cognitive function in at-risk individuals. Show more

Keywords: Alzheimer’s disease, clinical trial, cognitive decline, dementia, lifestyle intervention, non-pharmacological, randomized control trial

DOI: 10.3233/JAD-210589

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2021

Authors: Wang, Cuiling | Katz, Mindy J. | Chang, Katherine H. | Qin, Jiyue | Lipton, Richard B. | Zwerling, Jessica L. | Sliwinski, Martin J. | Derby, Carol A. | Rabin, Laura

Article Type: Research Article

Abstract: Background: The Uniform Data Set, Version 3 Neuropsychological Battery (UDSNB3.0), from the database of the University of Washington’s National Alzheimer’s Coordinating Center (NACC), is widely used to characterize cognitive performance in clinical and research settings; however, norms for underrepresented community-based samples are scarce. Objective: We compared UDSNB 3.0 test scores between the Einstein Aging Study (EAS), composed of racially/ethnically diverse, community-dwelling older adults aged≥70 and the NACC, and report normative data from the EAS. Methods: Analyses included 225 cognitively normal EAS participants and comparable data from 5,031 NACC database participants. Linear regression models …compared performance between the samples, adjusting for demographics (sex, age, education, race/ethnicity), depressive symptoms, and whether English was the first language. Linear regression models to examine demographic factors including age, sex, education and race/ethnicity as predictors for the neuropsychological tests were applied in EAS and NACC separately and were used to create a demographically adjusted z-score calculator. Results: Cognitive performance across all domains was worse in the EAS than in the NACC, adjusting for age, sex, education, race/ethnicity, and depression, and the differences remained in visuo-construction, visuospatial memory, confrontation naming, visual attention/processing speed, and executive functioning after further adjusting for whether English was the first language. In both samples, non-Hispanic Whites outperformed non-Hispanic Blacks and more education was associated with better cognitive performance. Conclusion: Differences observed in demographic, clinical, and cognitive characteristics between the community-based EAS sample and the nationwide NACC sample suggest that separate normative data that more accurately reflect non-clinic, community-based populations should be established. Show more

Keywords: Aging, cognitive test norms, community sample, mild cognitive impairment, neuropsychology, racial/ethnic diversity

DOI: 10.3233/JAD-210538

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Tofiq, Avin | Zetterberg, Henrik | Blennow, Kaj | Basun, Hans | Cederholm, Tommy | Eriksdotter, Maria | Faxén-Irving, Gerd | Hjorth, Erik | Jernerén, Fredrik | Schultzberg, Marianne | Wahlund, Lars-Olof | Palmblad, Jan | Freund-Levi, Yvonne

Article Type: Research Article

Abstract: Background: Studies have suggested a connection between a decrease in the levels of polyunsaturated fatty acids (PUFAs) and Alzheimer’s disease (AD). We aimed to assess the effect of supplementation with omega-3 fatty acids (n-3 FAs) on biomarkers analyzed in the cerebrospinal fluid (CSF) of patients diagnosed with AD. Objective: To investigate the effects of daily supplementation with 2.3 g of PUFAs in AD patients on the biomarkers in CSF described below. We also explored the possible correlation between these biomarkers and the performance in the cognitive test Mini-Mental State Examination (MMSE). Methods: Thirty-three patients diagnosed with …AD were randomized to either treatment with a daily intake of 2.3 g of n-3 FAs (n  =  18) or placebo (n  =  15). CSF samples were collected at baseline and after six months of treatment, and the following biomarkers were analyzed: Aβ 38, Aβ 40, Aβ 42, t-tau, p-tau, neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), soluble IL-1 receptor type II (sIL-1RII), and IL-6. Results: There were no significant differences between the groups concerning the level of the different biomarkers in the CSF at baseline. Within the treatment group, there was a small but significant increase in both YKL-40 (p = 0.04) and NfL (p = 0.03), while the other CSF biomarkers remained stable. Conclusion: Supplementation with n-3 FAs had a statistically significant effect on NfL and YKL-40, resulting in an increase of both biomarkers, indicating a possible increase of inflammatory response and axonal damage. This increase in biomarkers did not correlate with MMSE score. Show more

Keywords: Chitinase-3-like protein 1, dementia, inflammation, mini-mental state examination, neurodegeneration, neurofilament light, YKL-40

DOI: 10.3233/JAD-210007

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Qureshi, Zaina P. | Thiel, Ellen | Nelson, James | Khandker, Rezaul

Article Type: Research Article

Abstract: Background: Insomnia is associated with worsened clinical outcomes among Alzheimer’s disease dementia (AD) patients, increased caregiver burden, and healthcare utilization. Objective: This study aimed to characterize the incremental healthcare burden of insomnia in AD using real-world data. Methods: A retrospective observational study was conducted on AD patients selected from the IBM® MarketScan Commercial and Medicare Supplemental Databases. AD patients with claims-based evidence of insomnia were direct matched to a non-insomnia cohort based on demographic factors. Healthcare utilization and associated costs were assessed for a 12-month follow-up period. Results: A total of 3,500 insomnia AD …patients and 9,884 non-insomnia AD patients were analyzed. The insomnia cohort had a higher comorbidity burden at baseline (mean score on Charlson Comorbidity Index 2.5 versus 2.2, p  <  0.001) and higher proportions of patients with baseline diagnoses for other conditions including depression: 40%, insomnia cohort versus 25%, non-insomnia (p  <  0.001). AD patients with insomnia were more likely to have a claim for inpatient hospitalizations (39.8%versus 32.3%), emergency room services (56.4%versus 48.0%), and skilled-nursing services (42.6%versus 31.9%) (all p  <  0.05). Mean total annual healthcare costs during the 12-month follow-up period were significantly higher among AD patients with insomnia as compared to those without. (Mean costs: $37,356 versus $27,990, p  <  0.001). Conclusion: AD patients with comorbid insomnia are more likely to use higher-cost healthcare services such as inpatient hospitalization, and skilled nursing, and have higher total healthcare costs. This real-world analysis provides evidence that AD disease management should consider proper treatment of comorbid insomnia due to the incremental burden and cost implications. Show more

Keywords: Alzheimer’s disease, dementia, facilities and services utilization, health care economics, sleep initiation and maintenance disorders

DOI: 10.3233/JAD-210713

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Atkins, Kelly J. | Scott, David | Silbert, Brendan | Pike, Kerryn E. | Evered, Lis

Article Type: Research Article

Abstract: Background: Perioperative neurocognitive disorders (PND), including postoperative delirium (POD), are common in older adults and, for many, precipitate functional decline and/or dementia. Objective: In this protocol, we describe a novel multidisciplinary, multicomponent perioperative intervention that seeks to prevent or reduce POD and associated cognitive decline. Methods: We will conduct a prospective, single-blind, pragmatic, randomized-controlled trial to compare our tailored multi-disciplinary perioperative pathway against current standard of care practices. We will recruit a total of 692 elective surgical patients aged 65 years or more and randomize them in a 1:1 design. Our perioperative intervention …targets delirium risk reduction strategies by emphasizing the importance of early mobilization, nutrition, hydration, cognitive orientation, sensory aids, and avoiding polypharmacy. To promote healthy behavior change, we will provide a tailored psychoeducation program both pre- and postoperatively, focusing on cardiovascular and psychosocial risks for cognitive and functional decline. Results: Our primary outcome is the incidence of any PND (encapsulating POD and mild or major postoperative neurocognitive disorder) at three months postoperative. Secondary outcomes include any incidence of POD or neurocognitive disorder at 12 months. A specialized delirium screening instrument, the Confusion Assessment Method (3D-CAM), and a neuropsychological test battery, will inform our primary and secondary outcomes. Conclusion: Delirium is a common and debilitating postoperative complication that contributes to the cognitive and functional decline of older adults. By adopting a multicomponent, multidisciplinary approach to perioperative delirium prevention, we seek to reduce the burden of delirium and subsequent dementia in older adults. Show more

Keywords: Anesthesia and analgesia, cognition, delirium, dementia, healthy aging, perioperative medicine, prehabilitation, preventive medicine, rehabilitation

DOI: 10.3233/JAD-210438

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Sierra-Fonseca, Jorge A. | Rodriguez, Minerva | Themann, Anapaula | Lira, Omar | Flores-Ramirez, Francisco J. | Vargas-Medrano, Javier | Gadad, Bharathi S. | Iñiguez, Sergio D.

Article Type: Research Article

Abstract: Background: Fluoxetine (FLX) represents the antidepressant of choice for the management of pediatric mood-related illnesses. Accumulating preclinical evidence suggests that ontogenic FLX exposure leads to deregulated affect-related phenotypes in adulthood. Mood-related symptomatology constitutes a risk-factor for various neurological disorders, including Alzheimer’s disease (AD), making it possible for juvenile FLX history to exacerbate the development of neurodegenerative diseases. Objective: Because AD is characterized by the pathological accumulation of hyperphosphorylated tau, which can result from impaired function of protein degradation pathways, such as autophagy and the ubiquitin-proteasome system (UPS), we evaluated the long-term effects of adolescent FLX exposure …on these pathways, using mice as a model system. Methods: We subjected C57BL/6 adolescent male mice to FLX (20 mg/kg/day) from postnatal day (PD) 35 to PD49. Twenty-one days after the last FLX injection (i.e., adulthood; PD70), mice were euthanized and, using immunoblotting analysis, we evaluated protein markers of autophagy (Beclin-1, LC3-II, p62) and the UPS (K48-pUb), as well as AD-associated forms of phosphorylated tau, within the hippocampus and prefrontal cortex. Results: Juvenile FLX pre-exposure mediated long-term changes in the expression of protein markers (increased LC3-II and decreased p62) that is consistent with autophagy activation, particularly in the prefrontal cortex. Furthermore, FLX history induced persistent accumulation of AD-associated variants of tau in both the hippocampus and prefrontal cortex Conclusion: Adolescent FLX treatment may have enduring effects in the neuronal protein degradation machinery, which could adversely influence clearance of abnormal proteins, potentially predisposing individuals to developing AD in later life. Show more

Keywords: Abnormal protein accumulation, Alzheimer’s disease, antidepressant, drug safety, juvenile, LC3-II, long-term effects, p62, proteostasis, SSRI

DOI: 10.3233/JAD-210475

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Hill, Nikki L. | Bhargava, Sakshi | Bratlee-Whitaker, Emily | Turner, Jennifer R. | Brown, Monique J. | Mogle, Jacqueline

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) may be an early indicator of cognitive impairment, but depressive symptoms can confound this relationship. Associations may be influenced by differences between individuals (i.e., between-persons) or how each individual changes in their experiences over time (i.e., within-persons). Objective: We examined depressive symptoms as a mediator of the between- and within-person associations of SCD and objective memory in older adults. Methods: Coordinated analyses were conducted across four datasets drawn from large longitudinal studies. Samples (range: n  = 1,889 to n  = 15,841) included participants 65 years of age or older with no dementia at …baseline. We used multilevel structural equation modeling to examine the mediation of SCD and objective memory through depressive symptoms, as well as direct relationships among SCD, objective memory, and depressive symptoms. Results: Older adults who were more likely to report SCD had lower objective memory on average (between-person associations), and depressive symptoms partially mediated this relationship in three of four datasets. However, changes in depressive symptoms did not mediate the relationship between reports of SCD and declines in objective memory in three of four datasets (within-person associations). Conclusion: Individual differences in depressive symptoms, and not changes in an individual’s depressive symptoms over time, partially explain the link between SCD and objective memory. Older adults with SCD and depressive symptoms may be at greater risk for poor cognitive outcomes. Future research should explore how perceived changes in memory affect other aspects of psychological well-being, and how these relationships influence cognitive decline and Alzheimer’s disease risk. Show more

Keywords: Aging, cognition, depression, memory

DOI: 10.3233/JAD-210230

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Tok, Sean | Ahnaou, Abdallah | Drinkenburg, Wilhelmus

Article Type: Research Article

Abstract: Network hyperexcitability (NH) has recently been suggested as a potential neurophysiological biomarker of Alzheimer’s disease (AD), as new, more accurate biomarkers of AD are sought. NH has generated interest as a potential biomarker of certain stages in the disease trajectory and even as a disease mechanism by which network dysfunction could be modulated. NH has been demonstrated in several animal models of AD pathology and multiple lines of evidence point to the existence of NH in patients with AD, strongly supporting the physiological and clinical relevance of this indication. Several hypotheses have been put forward to explain the prevalence of …NH in animal models through neurophysiological, biochemical, and imaging techniques. However, some of these hypotheses have been built on animal models with limitations and caveats that may have derived NH through other mechanisms or mechanisms without translational validity to sporadic AD patients, potentially leading to an erroneous conclusion of the underlying cause of NH occurring in patients with AD. In this review, we discuss the substantiation for NH in animal models of AD pathology and in human patients, as well as some of the hypotheses considering recently developed animal models that challenge existing hypotheses and mechanisms of NH. In addition, we provide a preclinical perspective on how the development of animal models incorporating AD-specific NH could provide physiologically relevant translational experimental data that may potentially aid the discovery and development of novel therapies for AD. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, epilepsy, hippocampus, hyperexcitability, laboratory animal models, tau proteins, translational research

DOI: 10.3233/JAD-210397

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-28, 2021

Authors: Ge, Feifei | Zhu, Donglin | Tian, Minjie | Shi, Jingping

Article Type: Research Article

Abstract: The thyroid gland is crucial for the regulation of metabolism, growth, and development of various tissues, organs, systems, including the central nervous system. Recent studies have implicated the role of thyroid dysfunction in the etiology of Alzheimer’s disease (AD), while AD leads to a significant increase in the prevalence of thyroid dysfunction. In this review, we have analyzed the role of thyroid function in the pathophysiology of AD as well as its biomarkers. The present review aims to provide encouraging targets for early screening of AD risk factors and intervention strategies.

Keywords: Alzheimer’s disease, biomarkers, cognitive impairment, thyroid

DOI: 10.3233/JAD-210339

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Brenowitz, Willa D. | Zeki Al Hazzouri, Adina | Vittinghoff, Eric | Golden, Sherita H. | Fitzpatrick, Annette L. | Yaffe, Kristine

Article Type: Research Article

Abstract: Background: Depressive symptoms may increase risk for dementia, but findings are controversial because late-life depression may be a prodromal dementia symptom. Life course data on depression and dementia risk may clarify this association; however, data is limited. Objective: To impute adult depressive symptoms trajectories across adult life stages and estimate the association with cognitive impairment and decline. Methods: Using a pooled study of 4 prospective cohorts (ages 20–89), we imputed adult life course depressive symptoms trajectories based on Center for Epidemiologic Studies Depression Scale-10 (CESD-10) and calculated time-weighted averages for early adulthood (ages 20–49), mid-life (ages …50–69), and late-life (ages 70–89) for 6,122 older participants. Adjusted pooled logistic and mixed-effects models estimated associations of imputed depressive symptoms with two cognitive outcomes: cognitive impairment defined by established criteria and a composite cognitive score. Results: In separate models, elevated depressive symptoms in each life stage were associated with cognitive outcomes: early adulthood OR for cognitive impairment = 1.59 (95%CI: 1.35,1.87); mid-life OR = 1.94 (95%CI:1.16, 3.26); and late-life OR = 1.77 (95%CI:1.42, 2.21). When adjusted for depressive symptoms in the other life-stages, elevated depressive symptoms in early adulthood (OR = 1.73; 95%CI: 1.42,2.11) and late-life (OR = 1.43; 95%CI: 1.08,1.89) remained associated with cognitive impairment and were also associated with faster rates of cognitive decline (p  <  0.05). Conclusion: Imputing depressive symptom trajectories from pooled cohorts may help expand data across the life course. Our findings suggest early adulthood depressive symptoms may be a risk factor for cognitive impairment independent of mid- or late-life depressive symptoms. Show more

Keywords: Cognitive impairment, dementia, depression, imputation, life course

DOI: 10.3233/JAD-210588

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Matsuoka, Teruyuki | Ueno, Daisuke | Ismail, Zahinoor | Rubinstein, Ellen | Uchida, Hiroyuki | Mimura, Masaru | Narumoto, Jin

Article Type: Research Article

Abstract: Background: Mild behavioral impairment (MBI) is associated with accelerated cognitive decline and greater risk of dementia. However, the neural correlates of MBI have not been completely elucidated. Objective: The study aimed to investigate the correlation between cognitively normal participants and participants with amnestic mild cognitive impairment (aMCI) using resting-state functional magnetic resonance imaging. Methods: The study included 30 cognitively normal participants and 13 participants with aMCI (20 men and 23 women; mean age, 76.9 years). The MBI was assessed using the MBI checklist (MBI-C). Region of interest (ROI)-to-ROI analysis was performed to examine the correlation between …MBI-C scores and functional connectivity (FC) of the default mode network, salience network, and frontoparietal control network (FPCN). Age, Mini-Mental State Examination score, sex, and education were used as covariates. A p- value of 0.05, with false discovery rate correction, was considered significant. Results: A negative correlation was observed between the MBI-C total score and FC of the left posterior parietal cortex with the right middle frontal gyrus. A similar result was obtained for the MBI-C affective dysregulation domain score. Conclusion: FPCN dysfunction was detected as a neural correlate of MBI, especially in the affective dysregulation domain. This dysfunction may be associated with cognitive impairment in MBI and conversion of MBI to dementia; however, further longitudinal data are needed to examine this relationship. Show more

Keywords: Default mode network, fronto-parietal control network, functional magnetic resonance imaging, mild behavioral impairment, salience network

DOI: 10.3233/JAD-210628

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Sakurai, Keita | Kaneda, Daita | Uchida, Yuto | Inui, Shohei | Bundo, Masahiko | Akagi, Akio | Nihashi, Takashi | Kimura, Yasuyuki | Kato, Takashi | Ito, Kengo | Ohashi, Wataru | Hashizume, Yoshio

Article Type: Research Article

Abstract: Background: The differentiation of idiopathic normal pressure hydrocephalus (iNPH) from neurodegenerative diseases such as Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) is often challenging because of their non-specific symptoms. Therefore, various neuroradiological markers other than ventriculomegaly have been proposed. Despite the utility of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) for the appropriate selection of shunt surgery candidates, the specificity and neuropathology of this finding have not been sufficiently evaluated. Objective: Investigation of the clinicopathological features and comparison of the neuroradiological findings between DESH with postmortem neuropathological diagnoses (pDESH) and clinically-diagnosed iNPH (ciNPH) patients are the main purposes …of this study. Method: In addition to the retrospective evaluation of clinicopathological information, quantitative, semiquantitative, and qualitative magnetic resonance imaging (MRI) indices were compared between pathologically-investigated 10 patients with pDESH and 10 patients with ciNPH Results: Excluding one patient with multiple cerebral infarctions, the postmortem neuropathological diagnoses of the pathologically-investigated patients were mainly neurodegenerative diseases (five AD, one DLB with AD pathologies, one DLB, one argyrophilic grain disease, and one Huntington’s disease). In addition to the common neuroradiological features Conclusion: Hippocampal atrophy and deformation with temporal horn enlargement seem to be characteristic neuroradiological findings of long-standing severely demented patients with DESH and neurodegenerative diseases, mainly advanced-stage AD. Show more

Keywords: Disproportionately enlarged subarachnoid-space hydrocephalus, hippocampal atrophy, hippocampal deformation, idiopathic normal pressure hydrocephalus, magnetic resonance imaging, temporal horn enlargement

DOI: 10.3233/JAD-210535

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Jiang, Ziying | Han, Xiaolei | Wang, Yongxiang | Hou, Tingting | Cong, Lin | Tang, Shi | Han, Xiaodong | Ngandu, Tiia | Kivipelto, Miia | Winblad, Bengt | Launer, Lenore J. | Du, Yifeng | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Evidence has emerged that anemia is associated with dementia, but data on the relationships of red blood cell distribution width (RDW) with dementia and cognitive function in older adults are sparse. Objective: We sought to investigate the associations of RDW with dementia and global cognitive performance among rural-dwelling Chinese older adults and further to examine their associations by anemia status. Methods: This population-based cross-sectional study included 5,115 participants (age≥65 years, 57.0%women) in the baseline examination (March-September 2018) of the Multimodal Interventions to Delay Dementia and Disability in rural China (MIND-CHINA). We collected data through face-to-face …interviews, clinical examinations, and laboratory tests. Global cognitive function was evaluated using the Mini-Mental State Examination (MMSE). We defined dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) following the respective international criteria. Data were analyzed using multinomial logistic and general linear regression models. Results: Of all participants, 300 were diagnosed with dementia, including 195 with AD and 95 VaD. The multiple-adjusted odds ratio of dementia associated with quartiles of RDW were 1.45 (95%CI: 0.87–2.44), 1.00 (reference), 1.77 (1.07–2.93), and 2.28 (1.40–3.72). Similar J-shaped patterns existed for the association of RDW with odds ratio of AD and VaD. Anemia was not significantly associated with dementia. The J-shaped associations of RDW with dementia and subtypes were statistically evident only among participants without anemia. There was an inverted J-shaped relationship between RDW quartiles and β-coefficients of MMSE score. Conclusion: There is a J-shaped association between RDW level and likelihood of dementias among rural-dwelling Chinese older adults, especially among people without anemia. Show more

Keywords: Alzheimer’s disease, anemia dementia, elderly, population-based study, red cell distribution width

DOI: 10.3233/JAD-210517

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Cioffi, Federica | Ibrahim Adam, Rayan Hassan | Bansal, Ruchi | Broersen, Kerensa

Article Type: Research Article

Abstract: Oxidative stress is associated with the progression of Alzheimer’s disease (AD). Reactive oxygen species can modify lipids, DNA, RNA, and proteins in the brain. The products of their peroxidation and oxidation are readily detectable at incipient stages of disease. Based on these oxidation products, various biomarker-based strategies have been developed to identify oxidative stress levels in AD. Known oxidative stress-related biomarkers include lipid peroxidation products F2-isoprostanes, as well as malondialdehyde and 4-hydroxynonenal which both conjugate to specific amino acids to modify proteins, and DNA or RNA oxidation products 8-hydroxy-2’-deoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8-OHG), respectively. The inducible enzyme heme oxygenase type …1 (HO-1) is found to be upregulated in response to oxidative stress-related events in the AD brain. While these global biomarkers for oxidative stress are associated with early-stage AD, they generally poorly differentiate from other neurodegenerative disorders that also coincide with oxidative stress. Redox proteomics approaches provided specificity of oxidative stress-associated biomarkers to AD pathology by the identification of oxidatively damaged pathology-specific proteins. In this review, we discuss the potential combined diagnostic value of these reported biomarkers in the context of AD and discuss eight oxidative stress-related mRNA biomarkers in AD that we newly identified using a transcriptomics approach. We review these genes in the context of their reported involvement in oxidative stress regulation and specificity for AD. Further research is warranted to establish the protein levels and their functionalities as well as the molecular mechanisms by which these potential biomarkers are involved in regulation of oxidative stress levels and their potential for determination of oxidative stress and disease status of AD patients. Show more

Keywords: Alzheimer’s disease, biomarkers, genes, mild cognitive impairment, oxidative stress, transcriptomics

DOI: 10.3233/JAD-210497

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-25, 2021

Authors: El Haj, Mohamad | Allain, Philippe | Annweiler, Cédric | Boutoleau-Bretonnière, Claire | Chapelet, Guillaume | Gallouj, Karim | Kapogiannis, Dimitrios | Roche, Jean | Boudoukha, Abdel Halim

Article Type: Research Article

Abstract: Background: In a previous study, we assessed burnout in geriatric healthcare workers during the first lockdown that lasted from March to May 2020 in France, in response to the COVID-19 crisis. Objective: We carried out a follow-up study to assess burnout in the same population during the second lockdown that was implemented at the end of October 2020. Methods: We used an online survey to assess burnout in terms of exhaustion and disengagement in a sample of 58 geriatric healthcare workers. Results: We found higher levels of exhaustion, disengagement, and burnout among geriatric healthcare …workers during the second than during the first lockdown. We also found high levels of exhaustion but moderate disengagement and burnout during the second lockdown. Conclusion: The increased exhaustion, disengagement, and burnout during the second lockdown can be attributed to the increased workload in geriatric facilities throughout this crisis and during the second lockdown due to shortage in staff and increased number of shifts and allocated duties. The high levels of exhaustion reported among geriatric healthcare workers during the second lockdown can reflect their physical fatigue, as well as their feelings of being emotionally overextended and exhausted by their workload. Show more

Keywords: Burnout, COVID-19, disengagement, exhaustion, healthcare professionals

DOI: 10.3233/JAD-210615

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Wimo, Anders | Belger, Mark | Bon, Jaka | Jessen, Frank | Dumas, Annette | Kramberger, Milica G. | Jamilis, Laura | Johansson, Gunilla | Rodrigo Salas, Adrián | Rodríguez Gómez, Octavio | Sannemann, Lena | Stoekenbroek, Malou | Gurruchaga Telleria, Miren | Valero, Sergi | Vermunt, Lisa | Waterink, Lisa | Winblad, Bengt | Visser, Peter Jelle | Zwan, Marissa | Boada, Mercè | Collaborators and members of the MOPEAD consortium

Collaborators: Escher, Claus | Müller, Theresa | Bogdanovic, Nenad | Andersen, Pia | Spulber, Gabriela | Sundström, Maria | Westman, Eric | Ferreira, Daniel | Jelic, Vesna | Haglund, Anders | Stomrud, Erik | Nelvig, Anders | Saha, Samir | Petek, Davorina | Serné, Erik

Article Type: Research Article

Abstract: Background: For care planning and support, under-detection and late diagnosis of Alzheimer’s disease (AD) is a great challenge. Models of Patient-Engagement for Alzheimer’s Disease (MOPEAD) is an EU-funded project aiming at testing different strategies to improve this situation. Objective: To make a cost-consequence analysis of MOPEAD. Methods: Four screening strategies were tested in five countries (Germany, the Netherlands, Slovenia, Spain, and Sweden): 1) a web-approach; 2) Open-House initiative; 3) in primary care; and 4) by diabetes specialists. Persons-at-risk of AD in all strategies were offered referral to a hospital-based specialist. The primary health-economic outcome was the …cost per true-positive case (TP) of AD from the screened population. Results: Of 2,847 screened persons, 1,121 screened positive (39%), 402 were evaluated at memory clinics (14%), and 236 got an AD diagnosis (8%). The cost per TP of those screened was 3,115€ with the web-approach, 2,722€ with the Open-House, 1,530€ in primary care, and 1,190€ by diabetes specialists. Sensitivity analyses that more likely reflect the real-world situation confirmed the results. The number-needed-to-screen was 30 with the web-approach, 8 with the Open-House and primary care, and 6 with the diabetes specialists. There were country differences in terms of screening rates, referrals to memory clinics, staff-types involved, and costs per TP. Conclusion: In primary care and by the diabetes specialist, the costs per TP/screened population were lowest, but the capacity of such settings to identify cases with AD-risk must be discussed. Hence new diagnostic strategies such as web-solutions and Open-House initiatives may be valuable after modifications. Show more

Keywords: Alzheimer’s disease, cost-consequence analysis, cost analysis, costs, dementia, diagnosis, diagnostic work-up, screening

DOI: 10.3233/JAD-210303

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Wang, Hualong | Xu, Ying | Ren, Rujing | Yao, Feng | Chen, Mei | Sheng, Zhihua | Guo, Xin | Li, Yan | Chen, Shengdi | Wang, Gang

Article Type: Research Article

Abstract: Background: Previous studies revealed that abnormal blood pressure (BP) plays an important role in the pathogenesis of Alzheimer’s disease (AD). However, little is known about the ambulatory BP characteristics of AD in the mild or severe stage. Objective: We explored the ambulatory BP characteristics of AD in the mild or severe stage. Methods: In the present study, 106 AD patients (42.5%male, average age 81.6 years) were enrolled from three centers in China. Clinal BP measurements at the supine and standing positions, neurological evaluations, and the 24 h ambulatory BP monitoring were performed. Statistical methods included the two-sample …t -test, chi-square test, Spearman correlation analysis, and multivariate linear regression. Results: In the 106 AD patients, 49.2%, 36.8%, and 70%of patients had 24 h, daytime, and nighttime systolic hypertension, respectively, while 19.8%, 29.2%, and 5.7%had 24 h, daytime, and nighttime diastolic hypotension. The prevalence of the reduced and reverse dipping pattern was 34.0%and 48.1%for systolic BP and 32.1%and 45.3%for diastolic BP, respectively. The daytime diastolic BP was significantly correlated with cognitive performance. After adjustment for age, sex, and body mass index, only daytime diastolic BP was associated with remarkable cognitive deterioration (p ≤0.008). Further, AD patients in the severe stage had significantly lower levels of the 24 h, daytime, and nighttime diastolic BP, compared with those in the mild stage. Conclusion: In general, AD patients were featured with high nighttime systolic BP, low daytime diastolic BP, and abnormal circadian BP rhythm of reduced and reverse dipping. The diastolic BP, especially daytime diastolic BP, was adversely correlated with the cognitive deterioration in AD. Show more

Keywords: Alzheimer’s disease, ambulatory blood pressure, blood pressure variability, dipping

DOI: 10.3233/JAD-210679

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Sorrentino, Federica | Arighi, Andrea | Serpente, Maria | Arosio, Beatrice | Arcaro, Marina | Visconte, Caterina | Rotondo, Emanuela | Vimercati, Roberto | Ferri, Evelyn | Fumagalli, Giorgio G. | Pietroboni, Anna M. | Carandini, Tiziana | Scarpini, Elio | Fenoglio, Chiara | Galimberti, Daniela

Article Type: Research Article

Abstract: Background: Variants in Niemann-Pick Type C genes (NPC1 and NPC2 ) have been suggested to play a role as risk or disease modifying factors for Alzheimer’s disease (AD). Objective: The aim of this study was to analyze NPC1 and NPC2 variability in demented patients with evidence of brain amyloid-β 1–42 (Aβ) deposition and to correlate genetic data with clinical phenotypes. Methods: A targeted Next Generation Sequencing panel was customized to screen NPC1 , NPC2 , and main genes related to neurodegenerative dementias in a cohort of 136 demented patients with cerebrospinal fluid (CSF) …low Aβ levels or positive PET with Aβ tracer and 200 non-demented geriatric subjects. Results: Seven patients were carriers of NPC variants in heterozygosis. Four of them displayed pathogenic variants previously found in NPC patients and one AD patient had a novel variant. The latter was absent in 200 non-demented elderly subjects. Five of seven patients (70%) exhibited psychiatric symptoms at onset or later as compared with 43%in non-carriers (p  >  0.05). Conclusion: The frequency of NPC1 and NPC2 heterozygous variants in patients with CSF evidence of Aβ deposition is higher than in the general population. Show more

Keywords: Amyloid, cerebrospinal fluid, NPC1, NPC2, Niemann-Pick Type C, psychiatric onset, variability

DOI: 10.3233/JAD-210453

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Lazarova, Maria I. | Tsekova, Daniela S. | Tancheva, Lyubka P. | Kirilov, Kiril T. | Uzunova, Diamara N. | Vezenkov, Lyubomir T. | Tsvetanova, Elina R. | Alexandrova, Albena V. | Georgieva, Almira P. | Gavrilova, Petja T. | Dragomanova, Stela T. | Papazova, Maria G. | Handzhiyski, Yordan S. | Kalfin, Reni E.

Article Type: Research Article

Abstract: Background: Inhibitors of acetylcholinesterase (AChE) are used to treat many disorders, among which are neurodegenerative upsets, like Alzheimer’s disease (AD). One of the limited licensed AChE inhibitors (AChEIs) used as drugs is the natural compound galantamine (Gal). Objective: As Gal is a toxic compound, here we expose data about its four derivatives in hybrid peptide-norgalantamine molecules, which have shown 100 times lower toxicity. Methods: Four newly synthesized galantamine derivatives have been involved in docking analysis made by Molegro Virtual Docker. Biological assessments were performed on ICR male mice. The change in short and long-term memory performance …was evaluated by passive avoidance test. AChE activity and levels of main oxidative stress parameters: lipid peroxidation, total glutathione (GSH), enzyme activities of catalase (CAT), superoxide dismutase, and glutathione peroxidase were measured in brain homogenates. Results: Our experimental data revealed that the new hybrid molecules did not impair memory performance in healthy mice. Two of the compounds demonstrated better than Gal AChE inhibitory activity in the brain. None of them changed the level of lipid peroxidation products, one of the compounds increased GSH levels, and all of them increased CAT enzyme activity. Conclusion: The new galantamine-peptide hybrids demonstrated a potential for inhibition of AChE and antioxidant activity and deserve further attention. Show more

Keywords: Acetylcholine esterase, galantamine derivatives, inhibition, peptide

DOI: 10.3233/JAD-210577

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Yang, Hyun Ju | Lee, Subin | Koh, Myeong Ju | Lee, Ho Kyu | Kim, Bong Soo | Kim, Ki Woong | Park, Joon Hyuk

Article Type: Research Article

Abstract: Background: Frailty, one of serious global health problems in the elderly, is a growing concern in patients with Alzheimer’s disease (AD) because of its high prevalence in AD and its impact on the prognosis. Objective: To investigate the quantitative association between white matter hyperintensities (WMH) and frailty in AD. Methods: A total of 144 outpatients were included. All subjects were evaluated by using Korean version of the CERAD assessment battery and diagnosed very mild to moderate AD. WMH volume was calculated using automated segmentation analysis from the 3D MRI image and further partitioned according to the …distance from the ventricular surface. Using the Korean Frailty Index, prefrailty was defined by the scores of 3 and 4 and frailty by the score of 5 and higher. Results: In total, 23.6%were frailty, 32.6%were pre-frailty, and 43.8%were classified as a robust group. The frailty group had higher WMH volume compared to the robust group (p  = 0.02), and these trends remained significant after linear regression analyses. According to the subclassification of WMH, using the robust group as a reference, total WMH (OR = 6.297, p  = 0.013, 95%CI = 1.463–27.114), juxtaventricular WMH (OR = 12.955, p  = 0.014, 95%CI = 1.687–99.509), and periventricular WMH (OR = 3.382, p  = 0.025, 95%CI = 1.163–9.8531) volumes were associated with frailty, but deep WMH volume was not. Conclusions: A quarter of patients with very mild to moderate AD is suffering from frailty. Our study provides the evidence of a cross-sectional relationship between WMH and frailty, and there is a difference in the association between the subclassification of WMH volume and frailty. Show more

Keywords: Alzheimer’s disease, frailty, gait, magnetic resonance imaging, white matter hyperintensities

DOI: 10.3233/JAD-210494

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Zangrossi, Andrea | Montemurro, Sonia | Altoè, Gianmarco | Mondini, Sara

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) patients show heterogeneous cognitive profiles which suggest the existence of cognitive subgroups. A deeper comprehension of this heterogeneity could contribute to move toward a precision medicine perspective. Objective: In this study, we aimed 1) to investigate AD cognitive heterogeneity as a product of the combination of within- (factors) and between-patients (sub-phenotypes) components, and 2) to promote its assessment in clinical practice by defining a small set of critical tests for this purpose. Methods: We performed factor mixture analysis (FMA) on neurocognitive assessment results of N = 230 patients with a clinical diagnosis of AD. …This technique allowed to investigate the structure of cognitive heterogeneity in this sample and to characterize the core features of cognitive sub-phenotypes. Subsequently, we performed a tests selection based on logistic regression to highlight the best tests to detect AD patients in our sample. Finally, the accuracy of the same tests in the discrimination of sub-phenotypes was evaluated. Results: FMA revealed a structure characterized by five latent factors and four groups, which were identifiable by means of a few cognitive tests and were mainly characterized by memory deficits with visuospatial difficulties (“Visuospatial AD”), typical AD cognitive pattern (“Typical AD”), less impaired memory (“Mild AD”), and language/praxis deficits with relatively spared memory (“Nonamnestic AD”). Conclusion: The structure of cognitive heterogeneity in our sample of AD patients, as studied by FMA, could be summarized by four sub-phenotypes with distinct cognitive characteristics easily identifiable in clinical practice. Clinical implications under the precision medicine framework are discussed. Show more

Keywords: Alzheimer’s disease, factor mixture analysis, heterogeneity, precision medicine

DOI: 10.3233/JAD-210719

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Mommaerts, Kathleen | Willemse, Eline A.J. | Marchese, Monica | Larue, Catherine | van der Flier, Wiesje M. | Betsou, Fay | Teunissen, Charlotte E.

Article Type: Research Article

Abstract: Background: An N-terminal octapeptide cleavage of the cystatin C protein was discovered by mass spectrometry when cerebrospinal fluid (CSF) was stored at –20°C for 3 months, which did not occur when CSF was stored at –80°C. Objective: The aim was to develop an immunoassay as quality assessment tool to detect this –20°C cleavage of cystatin C in CSF and support Alzheimer’s disease research. Methods: A specific monoclonal antibody and a double indirect sandwich ELISA were developed: one assay quantifies the octapeptide uncleaved protein specifically and the other quantifies the total cystatin C present in the biological …fluid (both cleaved and uncleaved forms). The ratio of these concentrations was calculated to assess the extent of cleavage of cystatin C. The novel ELISA was validated and applied in a short-term (up to 4 weeks) and mid-term (up to one year) stability study of CSF stored at 4°C, –20°C, –80°C, and liquid nitrogen. Impact of freeze-thaw cycles, adsorption, and protease inhibitors were tested. Results: The ratio of truncated protein was modified following –20°C storage and seemed to reach a plateau after 6 months. The ratio was impacted neither by freeze-thaw cycles nor adsorption. The –20°C specific cleavage was found to be protease related. Conclusion: Using this novel double indirect sandwich ELISA, absolute levels of the total and uncleaved cystatin C and the ratio of truncated cystatin C can be measured. This assay is an easily applicable tool which can be used to confirm that CSF biospecimen are fit-for-purpose for Alzheimer’s disease research. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cystatin C, double indirect ELISA, protein stability

DOI: 10.3233/JAD-210741

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Esteban de Antonio, Ester | Pérez-Cordón, Alba | Gil, Silvia | Orellana, Adelina | Cano, Amanda | Alegret, Montserrat | Espinosa, Ana | Alarcón-Martín, Emilio | Valero, Sergi | Martínez, Joan | de Rojas, Itziar | Sotolongo-Grau, Óscar | Martín, Elvira | Vivas, Assumpta | Gomez-Chiari, Marta | Tejero, Miguel Ángel | Bernuz, Mireia | Tárraga, Lluis | Ruiz, Agustín | Marquié, Marta | Boada, Mercè | on behalf of the BIOFACE study group

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) diagnosis is based on cerebrospinal fluid (CSF) or neuroimaging biomarkers. Currently, non-invasive and inexpensive blood-based biomarkers are being investigated, such as neuronal-derived plasma exosomes (NPEs). Neuroinflammation and early vascular changes have been described in AD pathogenesis and can be traced in plasma and NPEs. However, they have not been studied in early onset MCI (EOMCI). Objective: To describe the rationale, design, and baseline characteristics of the participants from the BIOFACE cohort, a two-year observational study on EOMCI conducted at Fundació ACE. The study goal is to characterize the …different phenotypes from a clinical, neuropsychological, and biomarker point of view and to investigate the CSF and plasma proteomics as well as the role of NPEs as early biomarkers of AD. Methods: Participants underwent extended neurological and neuropsychological batteries, multimodal biomarkers including brain MRI, blood, saliva, CSF, anthropometric, and neuro-ophthalmological examinations. Results: Ninety-seven patients with EOMCI were recruited. 59.8%were women. Mean age at symptom onset was 57 years; mean MMSE was 28. First degree and presenile family history of dementia was present in 60.8%and 15.5%, respectively. Depressive and anxiety disorders along with vascular risk factors were the most frequent comorbidities. 29%of participants were APOE ɛ4 carriers, and 67%showed a CSF normal ATN profile. Conclusion: BIOFACE is a two-year study of clinical, cognition, and biomarkers that will shed light on the physiopathology and the potential utility of plasma and NPEs as non-invasive early diagnostic and prognostic biomarkers in people younger than 65 years. Show more

Keywords: Alzheimer’s disease, biomarkers, dementia, early onset Alzheimer’s disease, exosomes, mild cognitive impairment, presenile, proteomics

DOI: 10.3233/JAD-210254

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Felisberti, Fatima M.

Article Type: Research Article

Abstract: Background: Hedonic (or aesthetic) preferences to repeated sensory stimulation can remain stable over time (Island of Stability Effect, ISE) or vary with prior exposures (Mere Exposure Effect, MEE). Objective: Here we compared the liking ratings of seniors with cognitive impairments (mostly mild-to-moderate dementia, DPs) and neurotypical senior controls (CNs) to audio and visual stimuli and examined whether those ratings conformed to the ISE or the MEE predictions. Method: Participants (n  = 212) rated sets of stimuli repeated three times at weekly intervals: images of Picasso’s paintings, PANTONE color cards, and avant-garde music clips. Results: The …aggregated liking ratings of DPs and CNs were stable over time, in line with the ISE model. However, latent growth modeling indicated that those stable responses might have masked differences at the individual level, since seniors in both cohorts exhibited clusters of different responses over the time evaluated, supporting the predictions of the MEE. Notably, there was a dampening of hedonic experiences in DPs comparatively to CNs. Conclusion: The presence of hedonic responses (and individual variations) in DPs is relevant not only to their wellbeing and therapy interventions involving audio and visual stimulation, but also to the design of spaces that offset the downturn in hedonic experiences affecting seniors with cognitive impairments. Show more

Keywords: Aesthetics, cognitive impairments, color, dementia, island of stability effect, mere exposure effect, music, paintings

DOI: 10.3233/JAD-210520

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Schenning, Katie J. | Holden, Sarah | Davis, Brett A. | Mulford, Amelia | Nevonen, Kimberly A. | Quinn, Joseph F. | Raber, Jacob | Carbone, Lucia | Alkayed, Nabil J.

Article Type: Research Article

Abstract: Background: Geriatric surgical patients are at higher risk of developing postoperative neurocognitive disorders (NCD) than younger patients. The specific mechanisms underlying postoperative NCD remain unknown, but they have been linked to genetic risk factors, such as the presence of APOE4 , compared to APOE3 , and epigenetic modifications caused by exposure to anesthesia and surgery. Objective: To test the hypothesis that compared to E3 mice, E4 mice exhibit a more pronounced postoperative cognitive impairment associated with differential DNA methylation in brain regions linked to learning and memory. Methods: 16-month-old humanized apolipoprotein-E targeted replacement mice bearing E3 …or E4 were subjected to surgery (laparotomy) under general isoflurane anesthesia or sham. Postoperative behavioral testing and genome-wide DNA methylation were performed. Results: Exposure to surgery and anesthesia impaired cognition in aged E3, but not E4 mice, likely due to the already lower cognitive performance of E4 prior to surgery. Cognitive impairment in E3 mice was associated with hypermethylation of specific genes, including genes in the Ephrin pathway implicated in synaptic plasticity and learning in adults and has been linked to Alzheimer’s disease. Other genes, such as the Scratch Family Transcriptional Repressor 2, were altered after surgery and anesthesia in both the E3 and E4 mice. Conclusion: Our findings suggest that the neurocognitive and behavioral effects of surgery and anesthesia depend on baseline neurocognitive status and are associated with APOE isoform-dependent epigenetic modifications of specific genes and pathways involved in memory and learning. Show more

Keywords: Alzheimer’s disease, anesthesia, apolipoprotein E4, behavior, DNA methylation, ephrins, epigenomics, hippocampus, postoperative cognitive complications, surgery

DOI: 10.3233/JAD-210499

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2021