Volume 81, Number 2, IN PRESS

Nancy L. Olson, Benedict C. Albensi
Dementia-Friendly “Design”: Impact on COVID-19 Death Rates in Long-Term Care Facilities Around the World
Abstract: Persons with dementia (PWD) make up a large portion of the long-term care (LTC) population the world over. Before a global pandemic swept the world, governments and healthcare providers struggled with how to best care for this unique population. One of the greatest challenges is a PWD’s tendency to “walk with purpose” and exhibit unsafe wayfinding and elopement, which places them at risk of falls and injury. Past solutions included increased use of restraints and pharmacological interventions, but these have fallen out of favor over the years and are not optimal. These challenges put enormous strain on staff and caregivers, who are often poorly trained in dementia care, underpaid, overworked, and overstressed. PWD are impacted by these stresses, and unmet needs in LTC places an even greater stress on them and increases their risks of morbidity and mortality. The physical design of their environments contributes to the problem. Old, institutionalized buildings have poor lighting, poor ventilation, long dead-end hallways, poor visual cues, lack of home-like décor, shared bedrooms and bathrooms, and are often dense and overcrowded. These design elements contribute to the four ‘A’s’ of dementia: apathy, anxiety, agitation, and aggression, and they also contributed to the rapid spread of COVID-19 in these facilities the world over. In this review, we present current “dementia friendly” design models in the home, community, and LTC, and argue how they could have saved lives during the pandemic and reduced the stresses on both the dementia resident and the caregiver/staff.

Review
Makoto Hashimoto, Gilbert Ho, Shuei Sugama, Takato Takenouchi, Masaaki Waragai, Hiromu Sugino, Satoshi Inoue, Eliezer Masliah
Possible Role of Activin in the Adiponectin Paradox-Induced Progress of Alzheimer’s Disease
Abstract: Accumulating evidence suggests that the adiponectin (APN) paradox might be involved in promoting aging-associated chronic diseases such as Alzheimer’s disease (AD). In human brain, APN regulation of the evolvability of amyloidogenic proteins (APs), including amyloid-β (Aβ) and tau, in developmental/reproductive stages, might be paradoxically manifest as APN stimulation of AD through antagonistic pleiotropy in aging. The unique mechanisms underlying APN activity remain unclear, a better understanding of which might provide clues for AD therapy. In this paper, we discuss the possible relevance of activin, a member of transforming growth factor β (TGFβ) superfamily of peptides, to antagonistic pleiotropy effects of APN. Notably, activin, a multiple regulator of cell proliferation and differentiation, as well as an endocrine modulator in reproduction and an organizer in early development, might promote aging-associated disorders, such as inflammation and cancer. Indeed, serum activin, but not serum TGFβ increases during aging. Also, activin/TGFβ signal through type II and type I receptors, both of which are transmembrane serine/threonine kinases, and the serine/threonine phosphorylation of APs, including Aβ42 serine 8 and αS serine 129, may confer pathological significance in neurodegenerative diseases. Moreover, activin expression is induced by APN in monocytes and hepatocytes, suggesting that activin might be situated downstream of the APN paradox. Finally, a meta-analysis of genome-wide association studies demonstrated that two SNPs relevant to the activin/TGFβ receptor signaling pathways conferred risk for major aging-associated disease. Collectively, activin might be involved in the APN paradox of AD and could be a significant therapeutic target.

Review
Maria Tsamou, Francesca Pistollato, Erwin L. Roggen
A Tau-Driven Adverse Outcome Pathway Blueprint Toward Memory Loss in Sporadic (Late-Onset) Alzheimer’s Disease with Plausible Molecular Initiating Event Plug-Ins for Environmental Neurotoxicants
Abstract: The worldwide prevalence of sporadic (late-onset) Alzheimer’s disease (sAD) is dramatically increasing. Aging and genetics are important risk factors, but systemic and environmental factors contribute to this risk in a still poorly understood way. Within the frame of BioMed21, the Adverse Outcome Pathway (AOP) concept for toxicology was recommended as a tool for enhancing human disease research and accelerating translation of data into human applications. Its potential to capture biological knowledge and to increase mechanistic understanding about human diseases has been substantiated since. In pursuit of the tau-cascade hypothesis, a tau-driven AOP blueprint toward the adverse outcome of memory loss is proposed. Sequences of key events and plausible key event relationships, triggered by the bidirectional relationship between brain cholesterol and glucose dysmetabolism, and contributing to memory loss are captured. To portray how environmental factors may contribute to sAD progression, information on chemicals and drugs, that experimentally or epidemiologically associate with the risk of AD and mechanistically link to sAD progression, are mapped on this AOP. The evidence suggests that chemicals may accelerate disease progression by plugging into sAD relevant processes. The proposed AOP is a simplified framework of key events and plausible key event relationships representing one specific aspect of sAD pathology, and an attempt to portray chemical interference. Other sAD-related AOPs (e.g., Aβ-driven AOP) and a better understanding of the impact of aging and genetic polymorphism are needed to further expand our mechanistic understanding of early AD pathology and the potential impact of environmental and systemic risk factors.

Short Communication
Jagan A. Pillai, James Bena, Lynn M. Bekris, Nancy Foldvary-Schaefer, Catherine Heinzinger, Sujata Rao, Stephen M. Rao, James B. Leverenz, Reena Mehra
Unique Sleep and Circadian Rhythm Dysfunction Neuroinflammatory and Immune Profiles in Alzheimer’s Disease with Mild Cognitive Impairment
Abstract: Sleep dysfunction has been identified in the pathophysiology of Alzheimer’s disease (AD); however, the role and mechanism of circadian rhythm dysfunction is less well understood. In a well-characterized cohort of patients with AD at the mild cognitive impairment stage (MCI-AD), we identify that circadian rhythm irregularities were accompanied by altered humoral immune responses detected in both the cerebrospinal fluid and plasma as well as alterations of cerebrospinal fluid biomarkers of neurodegeneration. On the other hand, sleep disruption was more so associated with abnormalities in circulating markers of immunity and inflammation and decrements in cognition.

Short Communication
Francois Bernier, Kazuya Ohno, Noriko Katsumata, Takashi Shimizu, Jinzhong Xiao
Association of Plasma Hemoglobin A1c with Improvement of Cognitive Functions by Probiotic Bifidobacterium breve Supplementation in Healthy Adults with Mild Cognitive Impairment
Abstract:
We demonstrated the benefit of the probiotic strain, Bifidobacterium breve MCC1274 (synonym B. breve A1), at improving cognition in our previous double-blind, placebo-controlled clinical study. Analysis of the association of blood parameters changes with the improvement of cognitive function revealed an inverse correlation of HbA1c with total RBANS score amelioration after the study only in the probiotic group (ρ=-0. 4218, p=0.0067). A stratified analysis based on baseline HbA1c with a median value showed a more remarkable benefit by the probiotic supplementation in the higher median subgroup. These data support the mechanism of anti-inflammation in improving cognition by the probiotic strain.

Short Communication
Xin Liu*, Ke-Liang Chen*, Yi Wang, Yu-Yuan Huang, Shi-Dong Chen, Qiang Dong, Mei Cui, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
A Novel ITM2B Mutation Associated with Familial Chinese Dementia
Abstract: Mutations in ITM2B have been found to be associated with familial Danish dementia (FDD) and familial British dementia (FBD). Here, we describe a patient with dementia caused by a novel ITM2B p.*267Leuext*11 mutation. The patient presented with dementia, ataxia, deafness, and paraplegia. Amyloid PET and Tau PET showed abnormal deposition of amyloid and tau protein in brain. Summarized from previous 26 FBD and FDD cases, the clinical phenotype of ITM2B; p.*267Leuext*11 mutation in ITM2B is different from the features of FBD and FDD. Our findings increased genetic knowledge of familial dementia and extend the ethnic distribution of ITM2B mutations.

Quan Feng Liu, Suganya Kanmani, Jinhyuk Lee, Geun-Woo Kim, Songhee Jeon, Byung-Soo Koo
Neoline Improves Memory Impairment and Reduces Amyloid-β Level and Tau Phosphorylation Through AMPK Activation in the Mouse Alzheimer’s Disease Model
Abstract Background: Alzheimer’s disease (AD) is the most general, chronic, and progressive neurodegenerative senile disorder characterized clinically by progressive cognitive deterioration and memory impairment. Neoline is effective against neuropathic pain models, but the effects of neoline against AD-like phenotypes have not been investigated. Objective: We offer the investigation of the effects of neoline in AD. Methods: In this study, a Tg-APPswe/PS1dE9 AD mouse model was treated orally with neoline at a concentration of 0.5 mg/kg or 0.1 mg/kg starting at 7.5 months and administered for three months, and its anti-AD effects were evaluated. Results: Neoline improved memory and cognition impairments and reduced the number of amyloid-beta plaque and the amount of amyloid-β in the brain of AD mice. Furthermore, neoline reduced the anxiety behavior in the AD mouse model. The chronic administration of neoline also induced AMPK phosphorylation and decreased tau, amyloid-β, and BACE1 expression in the hippocampus. These findings indicate that chronic administration of neoline has therapeutic effects via AMPK activation, and BACE1 downregulation resulted in a decrease in the amyloid-β levels in the brain of Tg-APPswe/PS1dE9 AD mice. Conclusion: Our results suggest that neoline is a therapeutic agent for the cure of neurodegenerative diseases like AD.

Hongyan Qiu*, Ruoqi Zhao*, Guoqiang Fei*, Xiaoli Pan, Shaoming Sang, Yangqi Xu, Boru Jin, Lirong Jin, Xiaoqin Cheng, Chunjiu Zhong *These authors contributed equally to this work.
Dynamic Change of Intracellular Metabolism of Microglia Evaluated by Transcriptomics in an Alzheimer’s Mouse Model
Abstract: Background: Microglia play diverse roles in Alzheimer’s disease (AD). Intracellular metabolism has been indicated an important factor in modulating the function of microglia. However, it is not clear whether the intracellular metabolism of microglia changes dynamically in different stages of AD. Objective: To determine whether microglia intracellular metabolism changes dynamically in different stages of AD. Methods: Microglia were extracted from APPSwe/PS1dE9 (APP/PS1) mice and wild-type littermates at 2, 4, and 8 months old by fluorescence-activated cell sorting and used for RNA-sequencing analysis and quantitative PCR. Morphologies of amyloid plaques and microglia were detected by immunofluorescence staining. Results: Compared with control littermates, the microglia of APP/PS1 mice exhibited significant transcriptional changes at 2-month-old before microglia morphological alterations and the plaque formation. The changes continued drastically following age with defined morphological shift of microglia and amyloid plaque enhancement in brains. Further analysis of those genotype and age dependent transcriptomic changes revealed that differentially expressed genes enriched in pathways related to energy metabolism. Compared with wild-type mice, there were changes of some vital genes related to glucose metabolism and lipid metabolism pathways in APP/PS1 mice at different ages. Glucose metabolism may play a major role in early activation of microglia, and lipid metabolism may be more important in later activation period. Conclusion: Our results showed that microglia actively participate in the pathological progress of AD. The intracellular metabolism of microglia changed significantly in different stages of AD, even preceding amyloid-β deposition.

Xuewei Wang, Hai Bui, Prashanthi Vemuri, Jonathan Graff-Radford, Clifford R. Jack Jr, Ronald C. Petersen, Michelle M. Mielke
Lipidomic Network of Mild Cognitive Impairment from the Mayo Clinic Study of Aging
Abstract: Background: Lipid alterations contribute to Alzheimer’s disease (AD) pathogenesis. Lipidomics studies could help systematically characterize such alterations and identify potential biomarkers. Objective: To identify lipids associated with mild cognitive impairment and amyloid-β deposition, and to examine lipid correlation patterns within phenotype groups. Methods: Eighty plasma lipids were measured using mass spectrometry for 1,255 non-demented participants enrolled in the Mayo Clinic Study of Aging. Individual lipids associated with mild cognitive impairment (MCI) were first identified. Correlation network analysis was then performed to identify lipid species with stable correlations across conditions. Finally, differential correlation network analysis was used to determine lipids with altered correlations between phenotype groups, specifically cognitively unimpaired versus MCI, and with elevated brain amyloid versus without. Results: Seven lipids were associated with MCI after adjustment for age, sex, and APOE4. Lipid correlation network analysis revealed that lipids from a few species correlated well with each other, demonstrated by subnetworks of these lipids. 177 lipid pairs differently correlated between cognitively unimpaired and MCI patients, whereas 337 pairs of lipids exhibited altered correlation between patients with and without elevated brain amyloid. In particular, 51 lipid pairs showed correlation alterations by both cognitive status and brain amyloid. Interestingly, the lipids central to the network of these 51 lipid pairs were not significantly associated with either MCI or amyloid, suggesting network-based approaches could provide biological insights complementary to traditional association analyses. Conclusion: Our attempt to characterize the alterations of lipids at network-level provides additional insights beyond individual lipids, as shown by differential correlations in our study.

Danelly Rodríguez, Emmeline Ayers, Erica F. Weiss, Joe Verghese
Cross-Cultural Comparisons of Subjective Cognitive Complaints in a Diverse Primary Care Population
Abstract: Background: Very few studies have explored the utility of subjective cognitive complaints (SCCs) in primary care settings. Objective: We aim to investigate associations between SCCs (item-level), objective cognitive function (across domains and global), and mood in a diverse primary care population, including subjects with mild cognitive impairment. Methods: We studied 199 (75.9% females; 57.8% Hispanics; 42.2% African Americans) older adults (mean age 72.5 years) with memory concerns at a primary care clinic. A five-item SCC questionnaire, and objective cognitive assessments, including the Montreal Cognitive Assessment (MoCA) and the Geriatric Depression Scale, were administered. Results: Logistic regression analyses showed associations between SCC score and depressive symptoms. A memory-specific (“memory worsening”) SCC predicted scores on the MoCA (p = 0.005) in Hispanics. Conclusion: SCCs are strongly linked to depressive symptoms in African Americans and Hispanics in a primary care setting; a specific type of SCC is related to global cognitive function in Hispanics.

Sid O’Bryant, Fan Zhang, Melissa Petersen, Leigh Johnson, James Hall, Robert A. Rissman
A Precision Medicine Approach to Treating Alzheimer’s Disease Using Rosiglitazone Therapy: A Biomarker Analysis of the REFLECT Trials
Abstract: Background: The REFLECT Trials were conducted to examine the treatment of mild-to-moderate Alzheimer’s disease utilizing a peroxisome proliferator-activated receptor gamma agonist. Objective: To generate a predictive biomarker indicative of positive treatment response using samples from the previously conducted REFLECT trials. Methods: Data were analyzed on 360 participants spanning multiple negative REFLECT trials, which included treatment with rosiglitazone and rosiglitazone XR. Support vector machine analyses were conducted to generate a predictive biomarker profile. Results: A pre-defined 6-protein predictive biomarker (IL6, IL10, CRP, TNFα, FABP-3, and PPY) correctly classified treatment response with 100% accuracy across study arms for REFLECT Phase II trial (AVA100193) and multiple Phase III trials (AVA105640, AV102672, and AVA102670). When the data was combined across all rosiglitazone trial arms, a global RSG-predictive biomarker with the same 6-protein predictive biomarker was able to accurately classify 98% of treatment responders. Conclusion: A predictive biomarker comprising of metabolic and inflammatory markers was highly accurate in identifying those patients most likely to experience positive treatment response across the REFLECT trials. This study provides additional proof-of-concept that a predictive biomarker can be utilized to help with screening and predicting treatment response, which holds tremendous benefit for clinical trials.

Valeria Manera, Guenda Galperti, Erika Rovini, Radia Zeghari, Gianmaria Mancioppi, Laura Fiorini, Auriane Gros, Aurélie Mouton, Philippe Robert, Filippo Cavallo
Grasping Social Apathy: The Role of Reach-To-Grasp Action Kinematics for the Assessment of Social Apathy in Mild Neurocognitive Disorders
Abstract: Background: Social apathy, a reduction in initiative in proposing or engaging in social activities or interactions, is common in mild neurocognitive disorders (MND). Current apathy assessment relies on self-reports or clinical scales, but growing attention is devoted to defining more objective, measurable and non-invasive apathy proxies. Objective: In the present study we investigated the interest of recording action kinematics in a social reach-to-grasp task for the assessment of social apathy. Methods: Thirty participants took part in the study: 11 healthy controls (HC; 6 females, mean age= 68.3 ± 10.5 years) and 19 subjects with MND (13 females, mean age= 75.7 ± 6.3 years). Based on the Diagnostic Criteria for Apathy, MND subjects were classified as socially apathetic (A-MND, N=9) versus non-apathetic (NA-MND, N=10). SensRing, a ring-shaped wearable sensor, was placed on their index finger, and subjects were asked to reach and grasp a can to place it into a cup (individual condition) and pass it to a partner (social condition). Results: In the reach-to-grasp phase of the action, HC and NA-MND showed different acceleration and velocity profiles in the social versus individual condition. No differences were found for A-MND. Conclusion: Previous studies showed the interest of recording patients’ level of weekly motor activity for apathy assessment. Here we showed that a 10-min reach-to-grasp task may provide information to differentiate socially apathetic and non-apathetic subjects with MND, thus providing a tool easily usable in the clinical practice. Future studies with a bigger sample are needed to better characterize these findings.

Yunzhe Zhou, Yan Wang, Meina Quan, Huiying Zhao, Jianping Jia
Gut Microbiota Changes and Their Correlation with Cognitive and Neuropsychiatric Symptoms in Alzheimer’s Disease
Abstract: Background: Gut microbiota can influence human brain function and behavior. Recent studies showed that gut microbiota might play an important role in the pathogenesis of Alzheimer’s disease (AD). Objective: To investigate the composition of gut microbiota in AD patients and their association with cognitive function and neuropsychiatric symptoms (NPS). Methods: The fecal samples from 60 AD patients (30 with NPS and 30 without NPS) and 32 healthy control subjects (HC) were collected and analyzed by 16S ribosomal RNA sequencing. The functional variations of gut microbiota were predicted using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States. The correlation between different bacterial taxa and cognitive (Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR)), and NPS measures were analyzed. Results: The fecal microbial composition of AD patients was quite distinct from HC. Bifidobacterium, Sphingomonas, Lactobacillus, and Blautia were enriched, while Odoribacter, Anaerobacterium, and Papillibacter were reduced. AD patients with NPS showed decreased Chitinophagaceae, Taibaiella, and Anaerobacterium compared with those without NPS. Functional pathways were different between AD and HC, and between AD patients with and without NPS. Correlation analysis showed that Sphingomonas correlated negatively with MMSE; Anaerobacterium and Papillibacter correlated positively with MMSE and negatively with CDR. Cytophagia, Rhodospirillaceae, and Cellvibrio correlated positively with NPS, while Chitinophagaceae, Taibaiella, and Anaerobacterium correlated negatively with NPS. Conclusion: AD patients have gut microbiota alterations related to cognition, and differential taxa between AD patients with and without NPS associated differently with NPS domains, which helps further understand the pathogenesis of AD and explore potential therapeutic targets.

William W. Aitken, Joanna Lombard, Kefeng Wang, Matthew Toro, Margaret Byrne, Maria I. Nardi, Jack Kardys, Abraham Parrish, Chuanhui Dong, José Szapocznik, Tatjana Rundek, Scott C. Brown
Relationship of Neighborhood Greenness to Alzheimer’s Disease and Non-Alzheimer’s Dementia Among 249,405 U.S. Medicare Beneficiaries
Abstract: Background: Neighborhood greenness (vegetative presence) has been linked to multiple health outcomes, but its relationship to Alzheimer’s disease (AD) and non-Alzheimer’s (non-AD) dementia has been less studied. Objective: This study examines the relationship of greenness to both AD and non-AD dementia in a population-based sample of Medicare beneficiaries. Methods: Participants were 249,405 US Medicare beneficiaries aged >65 living in Miami-Dade County, FL, from 2010 to 2011. Multi-level analyses examined the relationship of greenness, assessed by mean Census block level Normalized Difference Vegetation Index (NDVI), to odds of each of AD, Alzheimer’s disease and related dementias (ADRD), and non-AD dementia, respectively. Covariates included age, gender, race/ethnicity, number of comorbid health conditions, and neighborhood income. Results: Higher greenness was associated with reduced risk of AD, ADRD, and non-AD dementia, respectively, adjusting for individual and neighborhood sociodemographics. Compared to the lowest greenness tertile, the highest greenness tertile was associated with reduced odds of AD by 20% (odds ratio, 0.80; 95% CI, 0.75-0.85), ADRD by 18% (odds ratio, 0.82; 95% CI, 0.77-0.86), and non-AD dementia by 11% (odds ratio, 0.89; 95% CI, 0.82-0.96). After further adjusting for number of comorbidities, compared to the lowest greenness tertile, the highest greenness tertile was associated with reduced odds of AD (OR, 0.94; 95% CI, 0.88-1.00) and ADRD (OR, 0.93; 95% CI, 0.88-0.99), but not non-AD dementia (OR, 1.01; 95% CI, 0.93-1.08). Conclusion: High neighborhood greenness may be associated with lower odds of AD and ADRD. Environmental improvements, such as increasing neighborhood vegetation, may be a strategy to reduce risk for AD and possibly other dementias.

Lílian Viana dos Santos Azevedo, Ismael Luis Calandri, Andrea Slachevsky, Héctor Gastón Graviotto, Maria Carolina Santos Vieira, Caíssa Bezerra de Andrade, Adriana Peredo Rossetti, Alana Barroso Generoso, Karoline Carvalho Carmona, Ludmilla Aparecida Cardoso Pinto, Marcos Sorbara, Alejandra Pinto, Tania Guajardo, Loreto Olavarria, Daniela Thumala, Lucía Crivelli, Ludmila Vivas, Ricardo Francisco Allegri, Maira Tonidandel Barbosa, Cecilia M. Serrano, Claudia Miranda-Castillo, Paulo Caramelli
Impact of Social Isolation on People with Dementia and Their Family Caregivers
Abstract: Background: People with dementia and their family caregivers may face a great burden through social isolation due to the COVID-19 pandemic, which can be manifested as various behavioral and clinical symptoms. Objective: To investigate the impacts of social isolation due to the COVID-19 pandemic on individuals with dementia and their family caregivers. Methods: Two semi-structured questionnaires were applied via telephone to family caregivers of people diagnosed with dementia in three cities in Argentina, Brazil, and Chile, in order to assess clinical and behavioral changes in people with dementia and in their caregivers. Results: In general, 321 interviews were conducted. A significant decline in memory function has been reported among 53.0% of people with dementia. In addition, 31.2% of individuals with dementia felt sadder and 37.4% had increased anxiety symptoms. These symptoms of anxiety were greater in individuals with mild to moderate dementia, while symptoms of agitation were greater in individuals with severe dementia. Moreover, compulsive-obsessive behavior, hallucinations, increased forgetfulness, altered appetite, and increased difficulty in activities of daily living were reported more frequently among individuals with moderate to severe dementia. Caregivers reported feeling more tired and overwhelmed during this period and these symptoms were also influenced by the severity of dementia. Conclusion: Social isolation during the COVID-19 pandemic triggered a series of negative behavioral repercussions, both for people with dementia and for their family caregivers in these three South American countries.

Camillo Marra, Chiara Piccininni, Giovanna Masone Iacobucci, Alessia Caprara, Guido Gainotti, Emanuele Maria Costantini, Antonio Callea, Annalena Venneri, Davide Quaranta
Semantic Memory as an Early Cognitive Marker of Alzheimer’s Disease: Role of Category and Phonological Verbal Fluency Tasks
Abstract: Background: The assessment of semantic memory may be a useful marker to identify individuals with mild cognitive impairment (MCI) who will progress to Alzheimer’s disease (AD) in the early stages of the disease. Objective: The aim of this five-year follow-up longitudinal study is to assess whether semantic assessment could predict progression in MCI. Methods: A population of MCI (N=251); mild (N=178) and moderate AD (N=114); and a sample of healthy participants (HP; N=262) was investigated. The five-year follow-up of the MCI group was completed by 178 patients. Semantic and episodic memory measures were used, including a measure of the discrepancy between categorical and phonological verbal fluency, the semantic–phonological delta (SPD). The main outcome was the progression of MCI due to AD to dementia. Results: A general linear model showed a significant effect of diagnosis on SPD (Wilks’ Lambda=0.591; p<0.001). The estimated marginal means were -0.91 (SE=0.185) in HP, -1.83 (SE=0.187) in MCI, -1.16 (SE=0.218) in mild AD, and -1.02 (SE=0.275) in moderate AD. Post-hoc comparisons showed a significant difference between MCI and HP (p<0.001). The follow-up was completed by 178 MCI individuals. SPD in MCI patients who progress to dementia was significantly lower than in MCI that will not progress (p=0.003). Together with the Mini-Mental State Examination, the SPD was the only measure with a significant predicting effect at the five-years follow-up (p=0.016). Conclusion: The SPD indicate the impairment of semantic memory in individuals with underlying AD at the MCI early stage, reflecting the early involvement of perirhinal and entorhinal cortices in the earliest stages of AD neuropathological process.

Gustaf Boström, Eva Freyhult, Johan Virhammar, Daniel Alcolea, Hayrettin Tumani, Markus Otto, Rose-Marie Brundin, Lena Kilander, Malin Löwenmark, Vilmantas Giedraitis, Alberto Lleó, Christine A.F. von Arnim, Kim Kultima*, Martin Ingelsson* *These authors contributed equally to this work.
Different Inflammatory Signatures in Alzheimer’s Disease and Frontotemporal Dementia Cerebrospinal Fluid
Abstract: Background: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases. Objective: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD. Methods: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing. Results: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC]=1.32, 95% confidence interval [CI] 1.14–1.53, q=0.018; MCI/AD: FC=1.53, 95% CI 1.20–1.94, q=0.045; and FTD: FC=1.42, 95% CI 1.10–1.83, q=0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q<0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q<0.05). Conclusion: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.

Jennifer Li, Andres M. Bur, Mark R. Villwock, Suraj Shankar, Gracie Palmer, Kevin J. Sykes, Jennifer A. Villwock
Olfactory Phenotypes Differentiate Cognitively Unimpaired Seniors from Alzheimer’s Disease and Mild Cognitive Impairment: A Combined Machine Learning and Traditional Statistical Approach
Abstract: Background: Olfactory dysfunction (OD) is an early symptom of Alzheimer’s disease (AD). However, olfactory testing is not commonly performed to test OD in the setting of AD. Objective: This work investigates objective OD as a non-invasive biomarker for accurately classifying subjects as cognitively unimpaired (CU), mild cognitive impairment (MCI), and AD. Methods: Patients with MCI (n=24) and AD (n=24), and CU (n=33) controls completed two objective tests of olfaction (Affordable, Rapid, Olfactory Measurement Array – AROMA; Sniffin’ Sticks Screening 12 Test – SST12). Demographic and subjective sinonasal and olfaction symptom information was also obtained. Analyses utilized traditional statistics and machine learning to determine olfactory variables, and combinations of variables, of importance for differentiating normal and disease states. Results: Inability to correctly identify a scent after detection was a hallmark of MCI/AD. AROMA was superior to SST12 for differentiating MCI from AD. Performance on the clove scent was significantly different between all three groups. AROMA regression modeling yielded six scents with AUC of the ROC of 0.890 (p<0.001). Random forest model machine learning algorithms considering AROMA olfactory data successfully predicted MCI versus AD disease state. Considering only AROMA data, machine learning algorithms were 87.5% accurate (95% CI 0.4735, 0.9968). Sensitivity and specificity were 100% and 75%, respectively with ROC of 0.875. When considering AROMA and subject demographic and subjective data, the AUC of the ROC increased to 0.9375. Conclusion: OD differentiates CUs from those with MCI and AD and can accurately predict MCI versus AD. Leveraging OD data may meaningfully guide management and research decisions.

Helena M. Blumen, Emily Schwartz, Gilles Allali, Olivier Beauchet, Michele Callisaya, Takehiko Doi, Hiroyuki Shimada, Velandai Srikanth, Joe Verghese
Cortical Volume, Thickness, and Surface Area in the Motoric Cognitive Risk Syndrome
Abstract: Background: The motoric cognitive risk (MCR) syndrome is a pre-clinical stage of dementia characterized by slow gait and cognitive complaint. Yet, the brain substrates of MCR are not well established. Objective: To examine cortical thickness, volume, and surface area associated with MCR in the MCR-Neuroimaging Consortium, which harmonizes image processing/analysis of multiple cohorts. Methods: Two-hundred MRIs (M age 72.62 years; 47.74% female; 33.17% MCR) from four different cohorts (50 each) were first processed with FreeSurfer 6.0, and then analyzed using multivariate and univariate general linear models with 1,000 bootstrapped samples (n-1; with resampling). All models adjusted for age, sex, education, white matter lesions, total intracranial volume, and study site. Results: Overall, cortical thickness was lower in individuals with MCR than in those without MCR. There was a trend in the same direction for cortical volume (p = 0.051). Regional cortical thickness was also lower among individuals with MCR than individuals without MCR in prefrontal, insular, temporal, and parietal regions. Conclusion: Cortical atrophy in MCR is pervasive, and include regions previously associated with human locomotion, but also social, cognitive, affective, and motor functions. Cortical atrophy in MCR is easier to detect in cortical thickness than volume and surface area because thickness is more affected by healthy and pathological aging.

Nathalie Bodd Halaas, Henrik Zetterberg, Ane-Victoria Idland, Anne-Brita Knapskog, Leiv Otto Watne, Kaj Blennow
Cerebrospinal Fluid Concentration of Neurogranin in Hip Fracture Patients with Delirium
Abstract: Background: Delirium is associated with an increased risk of incident dementia and accelerated progression of existing cognitive symptoms. Reciprocally, dementia increases the risk of delirium. Cerebrospinal fluid (CSF) concentration of the dendritic protein neurogranin has been shown to increase in early Alzheimer’s disease (AD), likely reflecting synaptic dysfunction and/or degeneration. Objective: To elucidate the involvement of synaptic dysfunction in delirium pathophysiology, we tested the association between CSF neurogranin concentration and delirium in hip fracture patients with different AD-biomarker profiles, while comparing them to cognitively unimpaired older adults (CUA) and AD patients. Methods: The cohort included hip fracture patients with (n=70) and without delirium (n=58), CUA undergoing elective surgery (n=127), and AD patients (n=46). CSF was collected preoperatively and diagnostically in surgery and AD patients respectively. CSF neurogranin concentrations were analyzed in all samples with an in-house ELISA. Delirium was assessed pre-and postoperatively in hip fracture patients by trained investigators using the Confusion Assessment Method. Hip fracture patients were further stratified based on pre-fracture dementia status, delirium subtype, and AD fluid biomarkers. Results: No association was found between delirium and CSF neurogranin concentration (main analysis: delirium versus no delirium, p=0.68). Hip fracture patients had lower CSF neurogranin concentration than AD patients (p=0.001) and CUA (p=0.035) in age-adjusted sensitivity analyses. Conclusion: The findings suggest that delirium is not associated with increased CSF neurogranin concentration in hip fracture patients, possibly due to advanced neurodegenerative disease and age and/or because synaptic degeneration is not an important pathophysiological process in delirium.

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

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

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

May A. Beydoun, Sharmin Hossain, Peter H. MacIver, Dhivya Srinivasan, Hind A. Beydoun, Ana I. Maldonado, Leslie I. Katzel, Christos Davatzikos, Rao P. Gullapalli, Stephen L. Seliger, Guray Erus, Michele K. Evans, Alan B. Zonderman, Shari R. Waldstein
Red Cell Distribution Width, Anemia, and Brain Volumetric Outcomes Among Middle-Aged Adults
Abstract: Background: Anemia and red cell distribution width (RDW) have been linked to poor cognitive performance, pending studies of underlying mechanisms. Objective: We examined cross-sectional relationships of initial RDW status (v1), RDW change (δ), and anemia with brain structural magnetic resonance imaging (sMRI) markers, including global and cortical brain and hippocampal and white matter lesion (WML) volumes, 5-6 years later. Methods: Data were used from three prospective visits within the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study with complete v1 (2004-2009) and v2 (2009-2013) exposures and ancillary sMRI data at vscan (2011-2015, n=213, mean v1 to vscan time: 5.7 years). Multivariable-adjusted linear regression models were conducted, overall, by sex, by race, and within non-anemics, correcting for multiple testing with q-values. Results: In minimally adjusted models (socio-demographics and follow-up time), anemiav1 and RDWv1 were consistently associated with smaller bilateral hippocampal volumes overall, and among females (q<0.05), without significant sex differences. RDWv1 was related to smaller select regional cortical brain gray and white matter volumes in hematological measure-adjusted models; anemiav1 was associated with larger WML volumes only among Whites. Conclusion: In summary, baseline anemia and RDW were consistently associated with smaller bilateral hippocampal volumes, particularly among females, while anemia was linked to larger WML volume among Whites. In hematological measure-adjusted models, baseline RDW was linked to smaller regional gray and white matter volumes. Pending studies with sMRI repeats, randomized controlled trials are needed, demonstrating associations of anemia and elevated RDW with reduced brain volumes and cognitive dysfunction.

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

Yi-Ming Zheng*, Yang-Yang Zhao*, Ting Zhang*, Xiao-He Hou*, Yan-Lin Bi*, Ya-Hui Ma, Wei Xu, Xue-Ning Shen, Qiang Dong, Lan Tan, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Left Ventricular Ejection Fraction and Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease Pathology in Cognitively Normal Older Adults: The CABLE Study
Abstract: Background: Heart failure has been considered as a potential modifiable risk factor for cognitive impairment and dementia. Left ventricular ejection fraction (LVEF), an indicator of cardiac dysfunction, has also been associated with cognitive aging. However, the effect of LVEF on Alzheimer’s disease (AD) pathology is still less known. Objective: We aimed to investigate the associations of LVEF with cerebrospinal fluid (CSF) biomarkers for AD in cognitively normal elders. Methods: A total of 423 cognitively normal individuals without heart failure were included from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study. Participants were divided into low LVEF group (50%≤LVEF<60%) and high LVEF group (LVEF≥60%). The associations of LVEF with CSF AD biomarkers including CSF amyloid-β 42 (Aβ42), total-tau (t-tau), and phosphorylated tau (p-tau) were analyzed using multivariate linear regression models. Results: Participants with low LVEF had higher levels of CSF t-tau (β = -0.009, p = 0.006) and t-tau/Aβ42 ratios (β = -0.108, p = 0.026). Subgroup analyses showed that the associations only existed in female and middle-aged groups (<65 years old). Besides, participants with low LVEF had higher levels of CSF p-tau (β = -0.002, p = 0.043) in middle-aged group. Conclusion: In conclusion, our findings revealed the associations between LVEF and AD pathology, which may provide new insights into AD prevention through maintaining cardiac function.

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

Víctor Manuel Gómez-López, Amparo Viramontes-Pintos, Miguel Ángel Ontiveros-Torres, Linda Garcés-Ramírez, Fidel de la Cruz, Ignacio Villanueva-Fierro, Marely Bravo-Muñoz, Charles R. Harrington, Sandra Martínez-Robles, Petra Yescas, Parménides Guadarrama-Ortíz, Mario Hernándes-Alejandro, Francisco Montiel-Sosa, Mar Pacheco-Herrero, José Luna-Muñoz
Tau Protein Phosphorylated at Threonine-231 Is Expressed Abundantly in the Cerebellum in Prion Encephalopathies
Abstract: Background: Transmissible spongiform encephalopathies (TSEs) are rare neurodegenerative disorders that affect animals and humans. Bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeld-Jakob Disease (CJD) in humans belong to this group. The causative agent of TSEs is called “prion”, which corresponds to a pathological form (PrPSc) of a normal cellular protein (PrPC) expressed in nerve cells. PrPSc is resistant to degradation and can induce abnormal folding of PrPC, and TSEs are characterized by extensive spongiosis and gliosis and the presence of PrPSc amyloid plaques. CJD presents initially with clinical symptoms similar to Alzheimer's disease (AD). In AD, tau aggregates and amyloid-β protein plaques are associated with memory loss and cognitive impairment in patients. Objective: In this work, we study the role of tau and its relationship with PrPSc plaques in CJD. Methods: Multiple immunostainings with specific antibodies were carried out and analyzed by confocal microscopy. Results: We found increased expression of the glial fibrillary acidic protein (GFAP) and matrix metalloproteinase (MMP-9), and an exacerbated apoptosis in the granular layer in cases with prion disease. In these cases, tau protein phosphorylated at Thr-231 was overexpressed in the axons and dendrites of Purkinje cells and the extensions of parallel fibers of the cerebellum. Conclusion: We conclude that phosphorylation of tau may be a response to the toxic and inflammatory environment generated by the pathological form of prion.

Ayana Kanatome*, Yasuhisa Ano*, Kazushi Shinagawa, Yumiko Ide, Midori Shibata, Satoshi Umeda *These authors contributed equally to this study
β-Lactolin Enhances Neural Activity, Indicated by Event-Related P300 Amplitude, in Healthy Adults: A Randomized Controlled Trial
Abstract: Background: Epidemiological studies have shown that dairy product consumption is beneficial for cognitive function in elderly individuals. β-lactolin is a lacto-tetrapeptide Gly–Thr–Trp–Tyr rich in fermented dairy products that improves memory retrieval, attention, and executive function in older adults with subjective cognitive decline and prevents the pathology of Alzheimer’s disease in rodents. There has been no study on the effects of β-lactolin on neural activity in humans. Objective: We investigated the effects of β-lactolin on neural activity and cognitive function in healthy adults. Methods: In this randomized, double-blind, placebo-controlled study, 30 participants (45–64 years old) consumed β-lactolin or placebo for 6 weeks. Neural activity during auditory and language tasks was measured through 64-channel electroencephalography. Moreover, verbal fluency tests were performed at baseline and after 6 weeks. Results: The β-lactolin group had a significantly higher P300 amplitude at the Cp2 site (a part of the parietal lobe near the center of brain, p = 0.008), and C4 site (the area between the frontal and parietal lobe, p = 0.021) during the auditory tasks after 6 weeks than the placebo group. Thus, β-lactolin supplementation promoted neural activity in the parietal area, which increases attention during auditory cognitive tasks. Compared with the placebo group, the β-lactolin group also showed significant changes in the scores of verbal fluency test after 6 weeks (p = 0.03). Conclusion: Our findings provide insight into the mechanisms underlying the effects of β-lactolin on attention in healthy adults.

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

Lisa Damron, Irene Litvan, Ece Bayram, Sarah Berk, Bernadette Siddiqi, Holly Shill
Hispanic Perspectives on Parkinson’s Disease Care and Research Participation
Abstract: Background: Hispanics are under-represented in Parkinson’s disease (PD) research despite the importance of diversity for results to apply to a wide range of patients. Objective: To investigate the perspective of Hispanic persons with Parkinson disease (PWP) regarding awareness, interest, and barriers to participation in research. Methods: We developed and administered a survey and qualitative interview in English and Spanish. For the survey, 62 Hispanic and 38 non-Hispanic PWP linked to a tertiary center were recruited in Arizona. For interviews, 20 Hispanic PWP, 20 caregivers, and six physicians providing service to Hispanic PWP in the community were recruited in California. Survey responses of Hispanic and non-Hispanic PWP were compared. Major survey themes were identified by applying grounded theory and open coding. Results: The survey found roughly half (Q1 54%, Q2 55%) of Hispanic PWP linked to a tertiary center knew about research; there was unawareness among community Hispanic PWP. Most preferred having physician recommendations for research participation and were willing to participate. Hispanics preferred teams who speak their native language and include family. Research engagement, PD knowledge, role of family, living with PD, PD care, pre-diagnosis/diagnosis emerged as themes from the interview. Conclusion: Barriers exist for participation of Hispanic PWP in research, primarily lack of awareness of PD research opportunities. Educating physicians of the need to encourage research participation of Hispanic PWP can address this. Physicians need to be aware of ongoing research and should not assume PWP disinterest. Including family members and providing research opportunities in their native language can increase research recruitment.

Seung Wan Suh, You Joung Kim, Kyung Phil Kwak, Kiwon Kim, Moon-Doo Kim, Byung-Soo Kim, Bong Jo Kim, Shin Gyeom Kim, Jeong Lan Kim, Tae Hui Kim, Seok Woo Moon, Kyung Won Park, Jong-Il Park, Joon Hyuk Park, Jae Nam Bae, Jiyeong Seo, Su Jeong Seong, Sang Joon Son, Il-Seon Shin, Seung-Ho Ryu, Kang Joon Lee, Nam-Jin Lee, Dong Young Lee, Dong Woo Lee, Seok Bum Lee, Chang Uk Lee, Sung Man Chang, Hyun-Ghang Jeong, Maeng Je Cho, Seong-Jin Cho, Jin Hyeong Jhoo, Young Min Choe, Ji Won Han, Ki Woong Kim
A 9-Year Comparison of Dementia Prevalence in Korea: Results of NaSDEK 2008 and 2017
Abstract: Background: In many high-income Western countries, the prevalence of dementia had been reduced over the past decades. Objective: We investigated whether the prevalence of all-cause dementia, Alzheimer's disease, vascular dementia, and mild cognitive impairment (MCI) had changed in Korea from 2008 to 2017. Methods: Nationwide Survey on Dementia Epidemiology of Korea (NaSDEK) in 2008 and 2017 was conducted on representative elderly populations that were randomly sampled across South Korea. Both surveys employed a two-stage design (screening and diagnostic phases) and diagnosed dementia and MCI according to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders and the consensus criteria from the International Working Group, respectively. The numbers of participants aged 65 years or older in the screening and diagnostic phases were 6,141 and 1,673 in the NaSDEK 2008 and 2,972 and 474 in the NaSDEK 2017, respectively. Results: The age- and sex-standardized prevalence of all-cause dementia and Alzheimer’s disease showed nonsignificant decrease (12.3% to 9.8%, odds ratio [OR] = 0.89, 95% confidence interval [CI] = 0.54–1.48 for all-cause dementia; 7.6% to 6.8%, OR [95% CI] = 0.91 [0.58–1.42] for Alzheimer’s disease). Vascular dementia decreased in the young-old population aged less than 75 years (2.7% to 0.001%, OR [95% CI] = 0.04 [0.01–0.15]) and in women (1.9% to 0.5%, OR [95% CI] = 0.27 [0.10–0.72]) while MCI remained stable (25.3% to 26.2%, OR [95% CI] = 1.08 [0.67–1.73]). Conclusion: We found that the prevalence of dementia in Korea showed a nonsignificant decrease between 2008 and 2017.

Morag E. Taylor, Annika Toots, Stephen R. Lord, Narelle Payne, Jacqueline C.T. Close (Handling Associate Editor: Manuel Montero-Odasso)
Cognitive Domain Associations with Balance Performance in Community-Dwelling Older People with Cognitive Impairment
Abstract: Background: In older people with cognitive impairment (CI), executive function (EF) has been associated with motor performance including balance and gait. The literature examining and supporting a relationship between balance performance and other cognitive domains is limited. Objective: To investigate the relationship between global cognition and cognitive domain function and balance performance in older people with CI. Methods: The iFOCIS randomized controlled trial recruited 309 community-dwelling older people with CI. Baseline assessments completed before randomization were used for analyses including the Addenbrooke’s Cognitive Examination-III (ACE-III; global cognition) and its individual cognitive domains (attention; memory; verbal fluency; language; visuospatial ability) and the Frontal Assessment Battery (FAB), a measure of EF. A composite balance score was derived from postural sway and leaning balance tests. Results: In linear regression analyses adjusted for covariates, global cognition and each cognitive domain were significantly associated with balance performance. EF (verbal fluency; β=-0.254, p<0.001, adjusted R2=0.387) and visuospatial ability (β=-0.258, p<0.001, adjusted R2=0.391) had the strongest associations with balance performance. In a comprehensively adjusted multivariable model including all of the ACE-III cognitive domains, visuospatial ability and EF (verbal fluency) were independently and significantly associated with balance performance. Conclusion: Poorer global cognition and cognitive domain function were associated with poorer balance performance in this sample of people with CI. Visuospatial ability and EF were independently associated with balance, highlighting potential shared neural networks and the role higher-level cognitive processes and spatial perception/processing play in postural control.

Carola Roßmeier*, Julia Hartmann*, Lina Riedl, Bianca Dorn, Julia Fischer, Florentine Hartmann, Silvia Egert-Schwender, Victoria Kehl, Helga Schneider-Schelte, Ralf J. Jox, Andreas Dinkel, Janine Diehl-Schmid *These authors contributed equally to this work.
How Do Persons with Young and Late Onset Dementia Die?
Abstract: Background: End of life symptoms and symptom management as well as the quality of dying (QoD) of persons with advanced dementia (PWAD) have not yet been systematically studied in Germany. Objective: 1) To investigate symptoms, treatment and care at the end of life, advance care planning, and circumstances of death of recently deceased PWAD; 2) To determine whether there are differences between young and late onset dementia (YOD and LOD). Methods: The study was performed in the context of the project EPYLOGE (IssuEs in Palliative care for persons in advanced and terminal stages of Young-onset and Late-Onset dementia in Germany). Closest relatives of recently deceased patients with advanced YOD (N=46) and LOD (N= 54) living at home or in long term care were interviewed. Results: Circumstances of death, symptoms, and treatment appeared to be similar between YOD and LOD, except that persons with LOD had significantly more somatic comorbidities and were admitted to hospital in the last three months of life more often than persons with LOD. At end of life, 60% of PWAD appeared to be “at peace”. Difficulty swallowing, gurgling, shortness of breath, and discomfort were observed most frequently. Large interindividual differences in suffering and QoD were present. Determinants of QoD were not identified. Conclusion: Our findings suggest that low QoD was caused by inadequate recognition and/or insufficient treatment of burdensome physical and emotional symptoms. PWADs’ needs should be assessed regularly, and strategies focusing on treatment and implementing support for both the patient and caregiver must be established.