Volume 84, Number 2, IN PRESS

Review
Agata Mulak
Bile Acids as Key Modulators of the Brain-Gut-Microbiota Axis in Alzheimer’s Disease
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.

Review
Fukiko Kitani-Morii, Robert P. Friedland, Hideki Yoshida, Toshiki Mizuno
Drosophila as a Model for Microbiota Studies of Neurodegeneration
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.

Review
Matthew J. Lennon, Grant Rigney, Vanessa Raymont, Perminder Sachdev
Genetic Therapies for Alzheimer’s Disease: A Scoping Review
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.

Review
Qixin Wang, Xiaofang Dong, Ran Zhang, Changqi Zhao
Flavonoids with Potential Anti-Amyloidogenic Effects as Therapeutic Drugs for Treating Alzheimer’s Disease
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.

Review
Huiyi Chen, Feng Chen, Miaoping Zhang, Yanting Chen, Lili Cui, Chunmei Liang
A Review of APOE Genotype-Dependent Autophagic Flux Regulation in Alzheimer's Disease
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 ε4 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.

Review
Jiayi Song, Xuehan Yang, Ming Zhang, Chunyan Wang, Li Chen
Glutamate Metabolism in Mitochondria Is Closely Related to Alzheimer’s Disease
Abstract: Glutamate is the main excitatory neurotransmitter in the brain, and its excitatory neurotoxicity is closely related to the occurrence and development of Alzheimer’s disease. However, increasing evidence shows that in the process of Alzheimer’s disease, glutamate is not only limited to its excitotoxicity as a neurotransmitter but also related to the disorder of its metabolic balance. The balance of glutamate metabolism in the brain is an important determinant of central nervous system health, and the maintenance of this balance is closely related to glutamate uptake, glutamate circulation, intracellular mitochondrial transport, and mitochondrial metabolism. In this paper, we intend to elaborate the key role of mitochondrial glutamate metabolism in the pathogenesis of Alzheimer’s disease and review glutamate metabolism in mitochondria as a potential target in the treatment of Alzheimer's disease.

Review
Mahdieh Golzari-Sorkheh, Carla Brown, Donald F. Weaver, Mark Reed
The NLRP3 Inflammasome in the Pathogenesis and Treatment of Alzheimer’s Disease
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.

Short Communication
Haitian Nan*, Yeon-Jeong Kim*, Mai Tsuchiya, Toko Fukao, Noriko Hara, Atsushi Hagihara, Kenya Nishioka, Nobutaka Hattori, Norikazu Hara, Takeshi Ikeuchi, Toshihisa Ohtsuka, Yoshihisa Takiyama *These authors contributed equally to this work.
A Novel Heterozygous Missense Variant in the CIAO1 Gene in a Family with Alzheimer’s Disease: The Val67Ile Variant Promotes the Interaction of CIAO1 and Amyloid-β Protein Precursor
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.

Commentary
Michelle L. Block, Urmila P. Kodavanti
The Use of Standardized Diesel Exhaust Particles in Alzheimer’s Disease Research
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.

Andrew C. Robinson, Yvonne S. Davidson, Federico Roncaroli, James Minshull, Phillip Tinkler, Margaret Cairns, Michael A. Horan, Antony Payton*, David M.A. Mann* (Handling Associate Editor: Gabriella Marcon) *These authors contributed equally to this work.
Telephone Interview for Cognitive Status Scores Associate with Cognitive Impairment and Alzheimer’s Disease Pathology at Death
Abstract:Background: Early diagnosis of Alzheimer’s disease (AD) provides an opportunity for early intervention. Cognitive testing has proven to be a reliable way to identify individuals who may be at risk of AD. The Telephone Assessment for Cognitive Screening (TICS) is proficient in screening for cognitive impairment. However, its ability to identify those at risk of developing AD pathology is unknown. Objective: We aim to investigate associations between TICS scores, collected over a period of 13 years, and the cognitive status of participants at death. We also examine relationships between TICS scores and neuropathological indices of AD (CERAD score, Thal phase, and Braak stage). Methods: Between 2004 and 2017, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent cognitive assessment using TICS. Scores from four time points were available for analysis. Cognitive impairment and AD pathology at death was evaluated in 101 participants. Results: TICS scores at time points 2, 3, and 4 were significantly lower in those cognitively impaired at death compared to those considered cognitively normal. There were significant negative correlations between TICS scores and CERAD score and Braak stage at time points 2 and 4. No correlations between Thal phase and TICS were found. Conclusion: Findings indicate that TICS could be used not only to screen for cognitive impairment, but also to identify individuals at risk of developing AD pathology, many years before any overt symptoms occur. Once identified, ‘at risk’ individuals could be targeted for early interventions which could attenuate the progression of the disease.

Nasser Bagheri, Suzanne Mavoa, Hossein Tabatabaei-Jafari, Luke D. Knibbs, Neil T. Coffee, Luis Salvador-Carulla, Kaarin J. Anstey (Handling Associate Editor: Lilian Calderón-Garcidueñas)
The Impact of Built and Social Environmental Characteristics on Diagnosed and Estimated Future Risk of Dementia
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.

Sung Hoon Kang*, Hanna Cho*, Jiho Shin, Hang-Rai Kim, Young Noh, Eun-Joo Kim, Chul Hyoung Lyoo, Hyemin Jang, Hee Jin Kim, Seong-Beom Koh, Duk L. Na, Mee Kyung Suh**, Sang Won Seo** *,**These authors contributed equally to this work.
Clinical Characteristic in Primary Progressive Aphasia in Relation to Alzheimer’s Disease Biomarkers
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.

Robert A. Culibrk, Ahmad S. Arabiyat, Carisa A. DeKalb, Mariah S. Hahn
Modeling Sympathetic Hyperactivity in Alzheimer’s Related Bone Loss
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.

Qiang Wei*, Shanshan Cao*, Yang Ji*, Jun Zhang, Chen Chen, Xiaojing Wang, Yanghua Tian, Bensheng Qiu, Kai Wang *These authors contributed equally to this work.
Altered Functional Connectivity Patterns of Parietal Subregions Contribute to Cognitive Dysfunction in Patients with White Matter Hyperintensities
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.

Maria Lazarova, Lyubka Tancheva, Аlbena Аlexandrova, Еlina Tzvetanova, Almira Georgieva, Miroslava Stefanova, Daniela Tsekova, Lyubomir Vezenkov, Reni Kalfin, Diamara Uzunova, Polina Petkova-Kirova
Effects of New Galantamine Derivatives in a Scopolamine Model of Dementia in Mice
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.

David Lazris, Molly M. Perkins, Allison A. Bay, Madeleine E. Hackney
Qualitative Evaluation Informs Understanding of Motor Cognition and Therapies in Older Adults with Mild Cognitive Impairment
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.

Sanna Read, Bo Hu, Raphael Wittenberg, Nicola Brimblecombe, Louise Robinson, Sube Banerjee
A Longitudinal Study of Functional Unmet Need Among People with Dementia
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.

Joseph Katz, Hanzhi Gao
The Alzheimer–E. coli Axis: What Can We Learn from an Electronic Health Record Platform
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.

James E. Galvin, Michael J. Kleiman, Marcia Walker
Using Optical Coherence Tomography to Screen for Cognitive Impairment and Dementia
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 75 µm. 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.

Ana W. Capuano, Robert S. Wilson, Sue E. Leurgans, Carolina Sampaio, Jose M. Farfel, Lisa L. Barnes, David A. Bennett
Relation of Literacy and Music Literacy to Dementia in older Black and White Brazilians
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.

Ilona Dutzi, Michael Schwenk, Marietta Kirchner, Eva Jooss, Jürgen M. Bauer, Klaus Hauer (Handling Associate Editor: Manuel Montero-Odasso)
Influence of Cognitive Impairment on Rehabilitation Received and Its Mediating Effect on Functional Recovery
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.

Giovanni Palermo, Elisabetta Belli, Luca Tommasini, Riccardo Morganti, Daniela Frosini, Valentina Nicoletti, Gloria Tognoni, Gabriele Siciliano, Ubaldo Bonuccelli, Filippo Baldacci, Roberto Ceravolo (Handling Associate Editor: Annachiara Cagnin)
Dissecting the Interplay Between Time of Dementia and Cognitive Profiles in Lewy Body Dementias
Abstract: Background: Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) are differentiated by the time of onset of cognitive and motor symptoms (‘1-year rule’). We explored the neuropsychological continuum of DLB and PDD subjects with different timing of dementia onset. Objective: To compare the neuropsychological profile of DLB and PDD patients with different timing of dementia onset. Methods: Neuropsychological findings at the diagnosis of dementia of 66 PDD and 42 DLB patients were retrospectively compared. Patients with PDD were divided into three tertile subgroups according to the time interval between the onset of parkinsonism and dementia (N=24, 2-4 years; N=17, 5-7 years; N=25 ≥8 years, respectively). Results: DLB patients performed worse on the Stroop and semantic fluency tests than PDD, even in comparison to PD with early dementia onset. No significant differences among PDD subgroups were reported. Conclusion: Executive and semantic language tests could differentiate DLB and PD patients with earlier development of dementia relative to parkinsonism.

Alaa Heggy, Aisha Masoumi, Maryam Al-Yafei, Fatima Al-Bader, Tamara Al-Abdi, Zumin Shi
Habitual Tea and Coffee Consumption and Mean Reaction Time Among Qatari Adults
Abstract: Background: Tea and coffee consumption is associated with cognitive function in some studies. Objective: We aimed to identify tea and coffee drinking patterns and their association with mean reaction time among Qatari adults. Method: The study included 1,000 adults aged 20 years and above attending the Qatar Biobank Study (QBB). Habitual tea and coffee consumption during the previous year was assessed by questionnaire. Tea and coffee drinking patterns were identified using factor analysis. In a computer-based self-administered touch screens test, mean reaction time (MRT) was used as an indicator of cognitive function. Results: The mean age of the participants was 35.8 (SD 10.3) years. Herbal tea and regular coffee consumption was inversely associated with MRT. In the multivariable model, compared with non-consumers, the regression coefficients for MRT were -34.34 (-65.36, -3.33) and -37.85 (-71.03, -4.67) for daily consumers of herbal tea and regular coffee, respectively. Of the two tea and coffee drinking patterns identified, pattern 1 (high consumption of tea, Arabic coffee, and herbal tea) was not associated with MRT but pattern 2 (high loadings of instant coffee, regular coffee, and Karak) was inversely associated with MRT in the unadjusted model. There was a significant interaction between pattern 2 and low-density lipoprotein (LDL) in relation to MRT. Pattern 2 was inversely associated with MRT among those with a low LDL. Conclusion: There was an inverse association between regular coffee and herbal tea consumption with mean reaction time. There was an interaction between Western coffee pattern and LDL.

Yu-Tung Lan, Deborah Blacker, Changzheng Yuan, Lori B. Chibnik, Albert Hofman, Yuan Ma
Longitudinal Body Weight Change, Visit-To-Visit Body Weight Fluctuation, and Cognitive Decline Among Older Adults
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.

Kosuke Matsuzono, Masayuki Suzuki, Kumiko Miura, Tadashi Ozawa, Takafumi Mashiko, Reiji Koide, Ryota Tanaka, Shigeru Fujimoto
Internal Jugular Vein Velocity and Spontaneous Echo Contrast Correlate with Alzheimer’s Disease and Cognitive Function
Abstract: Background: Many issues persist in the today’s Alzheimer’s disease (AD) screening and the breakthrough method is desired. Objective: We aim to validate the association between venous reflux and AD, and to develop a new method for AD screening. Methods: We examined spontaneous echo contrast, area, diameter, retrograde velocity, and anterograde velocity of the bilateral cervical internal jugular vein (IJV) using carotid ultrasonography. Results: A total of 112 patients participated in this study, with 26 diagnosed as AD. The proportion of both or either IJV spontaneous echo contrast (+) occupied 25 of total 26 AD patients, which showed 96.2% of sensitivity and 98.5% negative predictive value. The IJV velocities also showed significant correlation with AD diagnosis, although the IJV area or diameter did not. Conclusion: Our results indicate that the validation of the spontaneous echo contrast or velocities of the IJV are convenient AD diagnosis screening methods and that the venous reflux disturbance correlates with AD development.

Anne Fink, Gabriele Doblhammer, Gültekin Tamgüney (Handling Associate Editor: Suzanne Tyas)
Recurring Gastrointestinal Infections Increase the Risk of Dementia
Abstract: Background: Gastrointestinal infections cause significant health problems, including those affecting the immune, musculoskeletal, and nervous system, and are one of the leading causes for death worldwide. Recent findings suggest that microbiota of the gastrointestinal tract contribute to dementia. Objective: In this nested case-control study we investigated the role of common gastrointestinal infections on the subsequent risk of dementia. Methods: We used a longitudinal sample of 202,806 individuals from health claims data of the largest German health insurer and applied a nested case-control design with 23,354 initial dementia cases between 2006 and 2014 and 23,354 matched controls. We used conditional logistic regression to compute odds ratios (ORs) for dementia and corresponding 95% confidence intervals (CIs), adjusting for potential confounders. Results: The risk of dementia was increased in patients with recurring incidences of quarters with diagnosed gastrointestinal infections when compared to the unexposed population (one quarter: OR = 1.49, 95% CI = 1.40–1.58; two quarters: OR = 1.70, 95% CI = 1.51–1.91; three or more quarters: OR = 1.64, 95% CI = 1.40–1.93), adjusted for potential confounders. Conclusion: Our findings suggest that recurring gastrointestinal infections are associated with an increased risk of subsequent dementia.

Haruhisa Fukuda, Rei Ono, Megumi Maeda, Fumiko Murata (Handling Associate Editor: Bernhard Michalowsky)
Medical Care and Long-Term Care Expenditures Attributable to Alzheimer’s Disease Onset: Results from the LIFE Study
Abstract: Background: Alzheimer's disease (AD) can increase both medical care and long-term care (LTC) costs, but the latter are frequently neglected in estimates of AD’s economic burden. Objective: To elucidate the economic burden of new AD cases in Japan by estimating patient-level medical care and LTC expenditures over 3 years using a longitudinal database. Methods: The study was performed using monthly claims data from residents of 6 municipalities in Japan. We identified patients with new AD diagnoses between April 2015 and March 2016 with 3 years of follow-up data. Medical care and LTC expenditures were estimated from 1 year before onset until 3 years after onset. To quantify the additional AD-attributable expenditures, AD patients were matched with non-AD controls using propensity scores, and their differences in expenditures were calculated. Results: After propensity score matching, the AD group and non-AD group each comprised 1748 individuals for analysis (AD group: mean age ± standard deviation, 81.9 ± 7.6 years; women, 66.0%). The total additional expenditures peaked at $1398 in the first month, followed by $1192 and $1031 in the second and third months, respectively. The additional LTC expenditures increased substantially 3 months after AD onset ($227), and gradually increased thereafter. These additional LTC expenditures eventually exceeded the additional medical care expenditures in the second year after AD onset. Conclusion: Although total AD-attributable expenditures peaked just after disease onset, the impact of LTC on these expenditures rose over time. Failure to include LTC expenditures would severely underestimate the economic burden of AD.

Corinne E. Fischer, Nathan Churchill, Melissa Leggieri, Veronica Vuong, Michael Tau, Luis R. Fornazzari, Michael H. Thaut, Tom A. Schweizer (Handling Associate Editor: Sandra Garrido)
Long-Known Music Exposure Effects on Brain Imaging and Cognition in Early-Stage Cognitive Decline: A Pilot Study
Abstract: Background: Repeated exposure to long-known music has been shown to have a beneficial effect on cognitive performance in patients with AD. However, the brain mechanisms underlying improvement in cognitive performance are not yet clear. Objective: In this pilot study we propose to examine the effect of repeated long-known music exposure on imaging indices and corresponding changes in cognitive function in patients with early-stage cognitive decline. Methods: Participants with early-stage cognitive decline were assigned to three weeks of daily long-known music listening, lasting one hour in duration. A cognitive battery was administered, and brain activity was measured before and after intervention. Paired-measures tests evaluated the longitudinal changes in brain structure, function, and cognition associated with the intervention. Results: Fourteen participants completed the music-based intervention, including 6 musicians and 8 non-musicians. Post-baseline there was a reduction in brain activity in key nodes of a music-related network, including the bilateral basal ganglia and right inferior frontal gyrus, and declines in fronto-temporal functional connectivity and radial diffusivity of dorsal white matter. Musician status also significantly modified longitudinal changes in functional and structural brain measures. There was also a significant improvement in the memory subdomain of the Montreal Cognitive Assessment. Conclusion: These preliminary results suggest that neuroplastic mechanisms may mediate improvements in cognitive functioning associated with exposure to long-known music listening and that these mechanisms may be different in musicians compared to non-musicians.

Jing Hao, Yuchen Qiao, Tingting Li, Jianwei Yang, Yang Song, Longfei Jia, Jianping Jia
Investigating Changes in the Serum Inflammatory Factors in Alzheimer's Disease and Their Correlation with Cognitive Function
Abstract: Background: Serum levels of inflammatory factors, such as C3, C4, C-reactive protein (CRP), immunoglobulin (Ig) G, IgA, and IgM, in patients with Alzheimer’s disease (AD) and their correlation with cognitive function remain unexplored. Objective: To investigate the expression of serum inflammatory factors in patients with AD and its correlation with cognitive function. Methods: Serum levels of C3, C4, CRP, IgG, IgA, and IgM in 200 patients with AD (mild, moderate, and severe) and those in 174 normal controls were assessed. Spearman’s rank correlation analysis was used to explore the relationships among biomarker levels, cognitive function, and activities of daily living (ADL). Results: Among these inflammatory factors, C3 and CRP levels were significantly lower, and IgG and IgA levels were significantly higher in the AD group than in the control group (p<0.05). There were no significant differences in C4 and IgM levels between the two groups (p>0.05). In all participants, CRP level was positively correlated with the Mini-Mental State Examination and Montreal Cognitive Assessment scores (p<0.05). In the AD group, IgA level was negatively associated with ADL scores (p<0.05). No significant correlation was detected between the other factors and different cognitive scores (p>0.05). Conclusion: Inflammatory factors C3, CRP, IgG, and IgA have the potential to serve as biomarkers for AD. Furthermore, serum IgA was not only correlated with AD but also with ADL. These results support the hypothesis that inflammation is involved in the occurrence and development of AD.

Kate J. Russin, K. Sreekumaran Nair, Thomas J. Montine, Laura D. Baker, Suzanne Craft
Diet Effects on Cerebrospinal Fluid Amino Acids Levels in Adults with Normal Cognition and Mild Cognitive Impairment
Abstract: Background: Exploration of cerebrospinal fluid (CSF) amino acids and the impact of dietary intake on central levels may provide a comprehensive understanding of the metabolic component of Alzheimer’s disease. Objective: The objective of this exploratory study was to investigate the effects of two diets with varied nutrient compositions on change in CSF amino acids levels in adults with mild cognitive impairment (MCI) and normal cognition (NC). Secondary objectives were to assess the correlations between the change in CSF amino acids and change in Alzheimer’s disease biomarkers. Methods: In a randomized, parallel, controlled feeding trial, adults (NC, n=20; MCI, n=29) consumed a high saturated fat (SFA)/glycemic index (GI) diet [HIGH] or a low SFA/GI diet [LOW] for 4 weeks. Lumbar punctures were performed at baseline and 4 weeks. Results: CSF valine increased and arginine decreased after the HIGH compared to the LOW diet in MCI (ps=0.03 and 0.04). This pattern was more prominent in MCI versus NC (diet by diagnosis interaction ps =0.05 and 0.09), as was an increase in isoleucine after the HIGH diet (p=0.05). Changes in CSF amino acids were correlated with changes in Alzheimer’s disease CSF biomarkers Aβ42, total tau, and p-Tau 181, with distinct patterns in the relationships by diet intervention and cognitive status. Conclusion: Dietary intake affects CSF amino acid levels and the response to diet is differentially affected by cognitive status.

Emilie Wawrziczny, Pascal Antoine, Karyn Doba
Modeling the Distress of Adult-Child Caregivers of People with Dementia: The Mediating Role of Self-Efficacy
Abstract: Background: The increased tasks and responsibilities involved in supporting a parent with dementia (PWD) can induce distress in adult-child caregivers. Previous studies have shown that distress can be influenced by PWD and caregiver determinants, but few studies have considered the associations between these variables. Objective: This study tested a complex model of adult-child caregiver distress in which PWD and caregiver determinants and their associations are considered. Methods: 159 adult-child caregivers participated in this online study. PWD and caregiver determinants were assessed using questionnaires and their associations were investigated using the partial least squares path method. Results: The model showed a significant partial mediation through self-efficacy (confidence in one’s ability to organize and manage caregiving situations) between poor self-rated health and distress. Self-efficacy was a significant mediator of the relationship between informal social support and distress, and between preparedness and distress. The direct path between parental overprotection and distress was significant. The association between care and distress was significantly stronger for adult-child caregivers not living with their PWD. Conclusion: The model revealed the important mediating role of self-efficacy. Clinical interventions should improve the preparedness of adult-child caregivers and the quality of social support. The positive perception of their self-rated health may thus be promoted.

Songyang Dai*, Fanlin Zhou*, Jieyun Sun, Yu Li *These authors contributed equally to this work.
NPD1 Enhances Autophagy and Reduces Hyperphosphorylated Tau and Amyloid-β42 by Inhibiting GSK3β Activation in N2a/APP695swe Cells
Abstract: Background: The most prevalent kind of dementia, Alzheimer’s disease (AD), is a neurodegenerative disease. Previous research has shown that glycogen synthase kinase-3β (GSK-3β) is involved in the etiology and progression of AD, including amyloid-β (Aβ), phosphorylated tau, and mitochondrial dysfunction. NPD1 has been shown to serve a neuroprotective function in AD, although the mechanism is unclear. Objective: The effects of NPD1 on Aβ expression levels, tau protein phosphorylation, apoptosis ratio, autophagy activity, and GSK-3β activity in N2a/APP695swe cells (AD cell model) were studied, as well as the mechanism behind such effects. Methods: N2a/APP695swe cells were treated with NPD1, SB216763, or wortmannin as an AD cell model. The associated proteins of hyperphosphorylated tau and autophagy, as well as the activation of GSK3β, were detected using western blot and RT-PCR. Flow cytometry was utilized to analyze apoptosis and ELISA was employed to observe Aβ42. Images of autophagy in cells are captured using transmission electron microscopy. Results: In N2a/APP695swe cells, NPD1 decreased Aβ42 and hyperphosphorylated tau while suppressing cell death. NPD1 also promoted autophagy while suppressing GSK-3β activation in N2a/APP695swe cells. The outcome of inhibiting GSK-3β is comparable to that of NPD1 therapy. However, after activating GSK-3β, the opposite experimental results were achieved. Conclusion: NPD1 might minimize cell apoptosis, downregulate Aβ expression, control tau hyperphosphorylation, and enhance autophagy activity in AD cell models to promote neuronal survival. NPD1’s neuroprotective effects may be mediated via decreasing GSK-3β.

Munira Sultana, Karen Campbell, Morgan Jennings, Manuel Montero-Odasso, J.B. Orange, Jill Knowlton, Armin St. George, Dianne Bryant (Handling Associate Editor: Sylvie Belleville)
Virtual Reality Experience Intervention May Reduce Responsive Behaviors in Nursing Home Residents with Dementia: A Case Series
Abstract: Background: People with advanced dementia often exhibit responsive behaviors such as apathy, depression, agitation, aggression, and psychosis. Non-pharmacological approaches (e.g., listening to music, watching television, doing arts and crafts) are now considered as a first-line strategy to manage responsive behaviors in clinical practice due to the potential risks associated with the antipsychotic medications. To date, no evaluations of immersive non-head mounted virtual reality (VR) experience as a non-pharmacologic approach for people with advanced dementia living in nursing homes have been reported. Objective: To evaluate the feasibility (acceptance and safety) of VR experience. Methods: A single site case series (nonrandomized and unblinded) with a convenience sample (N=24; age=85.8 ±8.6 years; Cognitive Performance Scale score=3.4 ± 0.6) measuring depression and agitation before and after the intervention. The intervention was a 30-min long research coordinator–facilitated VR experience for two weeks (10 sessions). Results: The intervention was feasible (attrition rate=0%; adverse events=0). A reduction in depression and in agitation was observed after the intervention. However, we suggest extreme caution in interpreting this result considering the study design and small sample size. Conclusion: This study provides the basis for conducting a randomized controlled trial to evaluate the effect of VR experience on responsive behaviors in nursing homes. Since our intervention uses a smart remote-controlled projector without a headset, infectious exposure can be avoided following the COVID-19 pandemic-induced physical distancing policy in care homes.

Xiaomin Yin*, Zheng Zhou*, Yanyan Qiu*, Xing Fan, Chenhao Zhao, Junze Bao, Chenxu Liu, Fei Liu, Wei Qian (Handling Associate Editor: Xiaochuan Wang) *These authors contributed equally to this work.
SIRT1 Regulates Tau Expression and Tau Synaptic Pathology
Abstract: Background: Amyloid plaques and neurofibrillary tangles are two pathological hallmarks of Alzheimer’s disease (AD). However, synaptic deficits occur much earlier and correlate stronger with cognitive decline than amyloid plaques and neurofibrillary tangles. Mislocalization of tau is an early hallmark of neurodegeneration and precedes aggregations. Sirtuin type 1 (SIRT1) is a deacetylase which acts on proteins including transcriptional factors and associates closely with AD. Objective: The present study investigated the association between SIRT1 and tau expression in cells and in mice brains. Methods: Western blot was performed to detected tau, SIRT1, C/EBPα, and GAPDH protein levels. Immunological fluorescence assay was used to assess tau localization in primary cortical neuronal cells. Golgi staining was performed to evaluated dendritic spine morphology in mice brains. Results: In the present study, we found that SIRT1 negatively regulates expression of tau at the transcriptional level through transcriptional factor C/EBPα. Inhibition of the activity of SIRT1 limits the distribution of tau to the neurites. In the meantime, the alteration of dendritic spine morphology is also observed in the brains of SIRT1+/- mice. Conclusion: SIRT1 may be a potential drug target for early intervention in AD.

Yasuhiro Aso, Noriyuki Kimura, Etsuro Matsubara
Novel Serum Biomarkers of Neurovascular Unit Associated with Cortical Amyloid Deposition
Abstract: Background: Whether blood biomarkers of neurovascular unit are associated with cortical amyloid deposition on positron emission tomography (PET) imaging remains unclear. Objective: To investigate the association between novel serum biomarkers of neurovascular unit, such as protein tyrosine phosphatase receptor type B (PTPRB), gap junction protein alpha-5 (GJA5), adenosine triphosphate-sensitive inward rectifier potassium channel-8 (KCNJ8), and von Willebrand factor (vWF), and cortical amyloid deposition. Methods: Between 2012 and 2018, 68 elderly individuals with amnestic mild cognitive impairment (32 men and 36 women; mean age 75.2 years) were enrolled. All participants underwent 11C-Pittsburgh compound-B (PiB)-PET, 18F-fluorodeoxyglucose-PET, and measurement of serum PTPRB, GJA5, KCNJ8, and vWF levels using commercially available human enzyme-linked immunosorbent assay kits. Based on the mean cortical standardized uptake value ratio, the participants were divided into two groups: PiB-negative group and PiB-positive groups. Serum levels of PTPRB, GJA5, KCNJ8, and vWF were compared between the two groups. Multiple linear regression analysis was performed to investigate the relationship between serum PTPRB, GJA5, KCNJ8, and vWF levels and cortical amyloid deposition. Results: PTPRB and GJA5 levels were significantly lower and KCNJ8 and vWF levels were significantly higher in the PiB-positive group than in the PiB-negative group. PTPRB and GJA5 levels inversely correlated with mean PiB uptake, whereas KCNJ8 and vWF levels positively correlated with mean PiB uptake. Conclusion: Serum levels of PTPRB, GJA5, KCNJ8, and vWF correlate with cortical amyloid deposition. These novel blood biomarkers of NVU are useful for identifying elderly individuals at risk of developing Alzheimer’s disease.