Volume 94, Number 1, IN PRESS

Roxane Dilcher, Charles B. Malpas, Terence J. O’Brien, Lucy Vivash (Handling Associate Editor: Sandra Baez)
Social Cognition in Behavioral Variant Frontotemporal Dementia and Pathological Subtypes: A Narrative Review
Abstract: Behavioral variant frontotemporal dementia (bvFTD) belongs to the spectrum of frontotemporal lobar degeneration (FTLD) and is characterized by frontal dysfunction with executive deficits and prominent socio-emotional impairments. Social cognition, such as emotion processing, theory of mind, and empathy may significantly impact daily behavior in bvFTD. Abnormal protein accumulation of tau or TDP-43 are the main causes of neurodegeneration and neurocognitive decline. However, differential diagnosis is difficult due to the heterogeneous pathology in bvFTD and the high clinicopathological overlap with other FTLD syndromes, especially in late disease stages. Despite recent advances, social cognition in bvFTD has not yet received sufficient attention, nor has its association with underlying pathology. This narrative review evaluates social behavior and social cognition in bvFTD, by relating these symptoms to neural correlates and underlying molecular pathology or genetic subtypes. Negative and positive behavioral symptoms, such as apathy and disinhibition, share similar brain atrophy and reflect social cognition. More complex social cognitive impairments are probably caused by the interference of executive impairments due to increasing neurodegeneration. Evidence suggests that underlying TDP-43 is associated to neuropsychiatric and early social cognitive dysfunction, while patients with underlying tau pathology are marked by strong cognitive dysfunction with increasing social impairments in later stages. Despite many current research gaps and controversies, finding distinct social cognitive markers in association to underlying pathology in bvFTD is essential for validating biomarkers, for clinical trials of novel therapies, and for clinical practice.

Herbert Y.H. Hui, An Ran Ran, Jia Jia Dai, Carol Y. Cheung (Handling Associate Editor: Defu Yang)
Deep Reinforcement Learning-Based Retinal Imaging in Alzheimer’s Disease: Potential and Perspectives
Abstract: Alzheimer’s disease (AD) remains a global health challenge in the 21st century due to its increasing prevalence as the major cause of dementia. State-of-the-art artificial intelligence (AI)-based tests could potentially improve population-based strategies to detect and manage AD. Current retinal imaging demonstrates immense potential as a non-invasive screening measure for AD, by studying qualitative and quantitative changes in the neuronal and vascular structures of the retina that are often associated with degenerative changes in the brain. On the other hand, the tremendous success of AI, especially deep learning, in recent years has encouraged its incorporation with retinal imaging for predicting systemic diseases. Further development in deep reinforcement learning (DRL), defined as a subfield of machine learning that combines deep learning and reinforcement learning, also prompts the question of how it can work hand in hand with retinal imaging as a viable tool for automated prediction of AD. This review aims to discuss potential applications of DRL in using retinal imaging to study AD, and their synergistic application to unlock other possibilities, such as AD detection and prediction of AD progression. Challenges and future directions, such as the use of inverse DRL in defining reward function, lack of standardization in retinal imaging, and data availability, will also be addressed to bridge gaps for its transition into clinical use.

Marcus J. Andersson1, Jonathan Stone
Best Medicine for Dementia: The Life-Long Defense of the Brain
Abstract: This review deals with an unwelcome reality about several forms of dementia, including Alzheimer’s disease—that these dementias are caused, in part or whole, by the aging of the vasculature. Since the vasculature ages in us all, dementia is our fate, sealed by the realities of the circulation; it is not a disease with a cure pending. Empirically, cognitive impairment before our 7th decade is uncommon and considered early, while a diagnosis in our 11th decade is late but common in that cohort (>40%). Projections from earlier ages suggest that the prevalence of dementia in people surviving into their 12th decade exceeds 80%. We address the question why so few of many interventions known to delay dementia are recognized as therapy; and we try to resolve this few-and-many paradox, identifying opportunities for better treatment, especially pre-diagnosis. The idea of dementia as a fate is resisted, we argue, because it negates the hope of a cure. But the price of that hope is lost opportunity. An approach more in line with the evidence, and more likely to limit suffering, is to understand the damage that accumulates with age in the cerebral vasculature and therefore in the brain, and which eventually gives rise to cognitive symptoms in late life, too often leading to dementia. We argue that hope should be redirected to delaying that damage and with it the onset of cognitive loss; and, for each individual, it should be redirected to a life-long defense of their brain.

Systematic Review
Hong-Li Chen*, Cheng Li*, Jing Wang, Yang Fei, Min Min, Yue Zhao, En-Fang Shan, Yue-Heng Yin, Chong-Yuan Liu, Xian-Wen Li *These authors contributed equally to this work.
Non-Pharmacological Interventions for Feeding and Eating Disorders in Persons with Dementia: Systematic Review and Evidence Summary
Abstract: Background: Feeding and eating disorders related to cognitive and psycho-behavioral symptoms are strongly associated with health status in persons with dementia (PWD). Non-pharmacological interventions have been the priority selection to address this significant issue. However, the direct targets of non-pharmacological interventions are unclear and there is no consistent evidence of recommendations on the intervention of different dementia stages and the settings of intervention practice. Objective: To provide caregivers with a set of self-help non-pharmacological interventions for feeding and eating disorders in PWD. Methods: Based on the process of evidence summary, a systematic literature search was performed on dementia websites and seven databases. Two researchers screened the studies independently and appraise the quality. The evidence was graded by Joanna Briggs Institute Grades of Recommendation. Results: Twenty-eight articles were included. Twenty-three non-pharmacological intervention recommendations were categorized into six themes containing oral nutritional supplementation, assistance with eating and drinking, person-centered mealtime care, environmental modification, education or training, and multi-component intervention. These interventions corresponded to three direct targets including improving engagement, making up for loss ability, and increasing food intake directly. They were applied to different stages of dementia and most interventions were targeted at PWD in long-term care institutions. Conclusion: This article summarized the direct targets and the specific implementation of recommendations at different stages of dementia to provide caregivers with self-help non-pharmacological interventions. The practice of recommendations was more applicable to institutionalized PWD. When applied to PWD at home, caregivers need to identify the specific feeding and eating conditions at different stages and adopted the interventions in conjunction with the wishes of the PWD and professional advice.

Short Communication
Julia Zinman, Arunima Kapoor, Kevin Si, Sajeevan Sujanthan, Alisia Southwell, Megan L. Cayley, Michelle N. Sicard, Karen Lien, Brian J. Murray, Krista Lanctôt, Nathan Herrmann, Dar Dowlatshahi, Demetrios J. Sahlas, Gustavo Saposnik, Jennifer L. Mandzia, Leanne K. Casaubon, Ayman Hassan, Yael Perez, Richard H. Swartz
Men Are at Higher Risk of Screening Positive for Vascular Cognitive Impairment Compared to Women after Stroke and Transient Ischemic Attack
Abstract: While women have greater incidence of dementia, men have higher prevalence of vascular risk factors. This study examined sex differences in risk of screening positive for cognitive impairment after stroke. Ischemic stroke/TIA patients (N = 5969) participated in this prospective, multi-centered study, which screened for cognitive impairment using a validated brief screen. Men showed a higher risk of screening positive for cognitive impairment after adjusting for age, education, stroke severity, and vascular risk factors, suggesting that other factors may be contributing to increased risk among men (OR= 1.34, CI 95% [1.16, 1.55], p<0.001). The effect of sex on cognitive impairment after stroke warrants further attention.

Short Communication
Andrea González, Camila Calfio, Valentina Lüttges, Antonia González-Madrid, Cristian Guzmán
The Multifactorial Etiopathogenesis of Alzheimer’s Disease: Neuroinflammation as the Major Contributor
Abstract: Alzheimer’s disease (AD) is the most common form of dementia in the elderly. AD is a multifactorial disease, affected by several factors including amyloid-β42 oligomers, self-assembled tau, microbiota molecules, etc. However, inflammatory components are critical to trigger AD. Neuroinflammatory pathology links glial activation by “damage signals” with tau hyperphosphorylation, as explained by the Neuroimmunomodulation Theory, discovered by the ICC laboratory. This theory elucidates the onset and progression of several degenerative diseases and concept of “multitarget” therapy. These studies led to the rationale to identify inflammatory targets for the action of bioactive molecules or drugs against AD.

Ileana De Anda-Duran, Vijaya B. Kolachalama, Owen T. Carmichael, Phillip H. Hwang, Camilo Fernandez, Rhoda Au, Lydia A. Bazzano, David J. Libon
Midlife Neuropsychological Profiles and Associated Vascular Risk: The Bogalusa Heart Study
Abstract: Background: Individuals with Alzheimer’s disease (AD) often present with coexisting vascular pathology that is expressed to different degrees and can lead to clinical heterogeneity. Objective: To examine the utility of unsupervised statistical clustering approaches in identifying neuropsychological (NP) test performance subtypes that closely correlate with carotid intima-media thickness (cIMT) in midlife. Methods: A hierarchical agglomerative and k-means clustering analysis based on NP scores (standardized for age, sex, and race) was conducted among 1,203 participants (age 48 ± 5.3 years) from the Bogalusa Heart Study. Regression models assessed the association between cIMT ≥50th percentile and NP profiles, and global cognitive score (GCS) tertiles for sensitivity analysis. Results: Three NP profiles were identified: Mixed-low performance [16%, n=192], scores ≥1 SD below the mean on immediate, delayed free recall, recognition verbal memory, and information processing; Average [59%, n= 704]; and Optimal [26%, n=307] NP performance. Participants with greater cIMT were more likely to have a Mixed-low profile [OR=3.10, 95% CI (2.13, 4.53), p<0.001] compared to Optimal. After adjusting for education and cardiovascular (CV) risks, results remained. The association with GCS tertiles was more attenuated [lowest (34%, n=407) versus highest (33%, n=403) tertile: adjusted OR=1.66, 95% CI (1.07, 2.60), p=0.024] Conclusion: As early as midlife, individuals with higher subclinical atherosclerosis were more likely to be in the Mixed-low profile, underscoring the potential malignancy of CV risk as related to NP test performance, suggesting that classification approaches may aid in identifying those at risk for AD/vascular dementia spectrum illness.

Jieyi Liu*, Yirong Xie*, Yao Lu*, Zhiqiang Zhao, Zhixiong Zhuang, Linqing Yang, Haiyan Huang, Hongya Li, Zhiyi Mao, Shurong Pi, Fubin Chen, Yun He *These authors contributed equally to this work.
APP/PS1 Gene-Environmental Cadmium Interaction Aggravates the Progression of Alzheimer’s Disease in Mice via the Blood-Brain Barrier, Amyloid-β, and Inflammation
Abstract: Background: There is limited information about gene-environment interaction on the occurrence and the progression of Alzheimer’s disease. Objective: To explore the effect of environmental low-dose cadmium (Cd) exposure on the progress of Alzheimer’s disease and the underlining mechanism. Methods: We administered 1 mg/L, 10 mg/L cadmium chloride (treated groups), and water (control group) to C57BL/6J and APP/PS1 mice through drinking water, from one week before mating, until the offspring were sacrificed at 6 months of age. The behaviors, Cd level, blood-brain barrier (BBB) leakage, Aβ1-42 deposition, and inflammation expression were evaluated in these mice. Results: Mice of both genotypes had similar blood Cd levels after exposure to the same dose of Cd. The toxic effects of Cd on the two genotypes differed little in terms of neuronal histomorphology and BBB permeability. Cd caused a series of pathological morphological changes in the mouse brains and more fluorescent dye leakage at higher doses. Furthermore, the APP/PS1 mice had more severe damage than the C57BL/6J mice, based on the following five criteria. They are increasing anxiety-like behavior and chaos movement, spatial reference memory damage, Aβ plaque deposition in mouse brains, increasing microglia expression in the brain, and IL-6 higher expression in the cortex and in the serum. Conclusion: Low-dose Cd exposure for 6 months increases Aβ plaque deposition and BBB permeability, exacerbates inflammatory responses, and activates microglia, in APP/PS1 mice. APP/PS1 gene-environmental Cd interaction aggravates the progression of Alzheimer’s disease in mice.

Yu Fu*, Xiaolong Li*, Ting Wang*, Shuhua Yan, Xisheng Zhang, Geng Hu, Jin Zhou, Yan Wang, ChangShu Liu, Sai Wang, Yang Cong, Liangkai Chen, Tingting Li, Shuang Rong *These authors contributed equally to this work.
The Prevalence and Agreement of Sarcopenic Obesity Using Different Definitions and Its Association with Mild Cognitive Impairment
Abstract: Background: The consistent definition of sarcopenic obesity (SO) is limited, its association with mild cognitive impairment (MCI) has not been clarified. Objective: This study aimed to evaluate the prevalence and agreement of SO using different definitions and the association between SO and MCI. Methods: SO was diagnosed by the co-existence of sarcopenia defined by the Asia Working Group for Sarcopenia (AWGS) and obesity by body mass index (BMI), visceral fat area (VFA), waist circumference (WC), or body fat percentage (BF%). Cohen’s kappa was used to assess the agreement between the different definitions. The association between SO and MCI was assessed using multivariable logistic regression. Results: Among 2,451 participants, the prevalence of SO ranged from 1.7% to 8.0% under different definitions. SO defined by AWGS and BMI (AWGS+BMI) showed fair agreements with the other three criteria (κ ranged from 0.334 to 0.359). The other criteria showed good agreements with each other. The κ statistics were 0.882 for AWGS+VFA and AWGS+BF%, 0.852 for AWGS+VFA and AWGS+WC, and 0.804 for AWGS+BF% and AWGS+WC, respectively. When using different diagnoses of SO, compared with the health group, the adjusted ORs of MCI for SO were 1.96 (95% CI: 1.29-2.99, SO: AWGS+WC), 1.75 (95% CI: 1.14-2.68, SO: AWGS+VFA), 1.37 (95% CI: 1.03-1.82, SO: AWGS+BF%), and 1.45 (95% CI: 0.67-3.12, SO: AWGS+BMI), respectively. Conclusion: Using different obesity indicators combined with AWGS to diagnose SO, BMI had lower prevalence and agreement compared with other three indicators. SO was associated with MCI under different methods (WC, VFA, or BF%).

Manon Querry, Frédéric Blanc, Olivier Bousiges, Nathalie Philippi, Benjamin Cretin, Catherine Demuynck, Candice Muller, Anne Botzung (Handling Associate Editor: Carla Abdelnour)
Memory Outcome in Prodromal and Mild Dementia with Lewy Bodies and Alzheimer’s Disease: A Longitudinal Study
Abstract: Background: Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) are likely to induce memory impairments from the prodromal stage but, to our knowledge, no longitudinal study of these patients’ memory profile has been conducted to date. Objective: The aim of our study was to describe the characteristics and the evolution of the long-term memory profile of patients with prodromal and mild DLB and AD. Methods: We collected verbal (RL/RI-16) and visual (DMS48) memory scores from 91 DLB patients, 28 AD patients, 15 patients with both conditions (DLB/AD), and 18 healthy control subjects at their inclusion visit and at 12, 24, and 48 months. Results: On the RL/RI-16, DLB patients performed better than AD patients in terms of total recall (p<0.001), delayed total recall (p<0.001), recognition (p=0.031), and loss of information over time (p=0.023). On the DMS48, differences between these two groups were not significant (p>0.05). Longitudinally, the memory performance of DLB patients was stable over 48 months, unlike that of AD patients. Conclusion: Four indicators were relevant to distinguish between DLB and AD patients in terms of memory performance: DLB patients benefitted greatly from semantic cueing, their recognition and consolidation abilities were well-preserved, and both their verbal and visual memory performance remained remarkably stable over four years. However, no performance differences between DLB and AD patients were found regarding visual memory, either qualitatively (memory profile) or quantitatively (severity of impairment), indicating the lesser relevance of this test in distinguishing between these two diseases.

Nida Buawangpong, Kanokporn Pinyopornpanish, Phichayut Phinyo, Wichuda Jiraporncharoen, Chaisiri Angkurawaranon, Atiwat Soontornpun
Effect of Comorbidities on Ten-Year Survival in Patients with Dementia
Abstract: Background: There is a verified association between comorbidity and survival in patients with dementia. Objective: To describe the ten-year survival probability of patients with dementia and to identify the impact of comorbidity. Methods: The prognostic retrospective cohort study was conducted using data from adults with dementia who had visited the outpatient departments at Maharaj Nakorn Chiang Mai hospital between 2006 and 2012. Dementia was verified in accordance with standard practice guidelines. Secondary data detailing about patient age, gender, date of dementia diagnosis and death, types of dementia, and comorbidities at the time of dementia diagnosis was obtained from electronic medical records. The association between comorbidity, patients’ underlying disease at dementia diagnosis, and overall survival were analyzed using a multivariable Cox proportional hazard model adjusted for age, gender, types of dementia, and other comorbidities. Results: Of the 702 patients, 56.9% were female. Alzheimer's disease (39.6%) was the most prevalent type of dementia. Median overall survival was 6.0 years (95% CI 5.5-6.7). The comorbidities associated with a high risk of mortality included liver disease (aHR 2.70, 95% CI 1.46- 5.00), atrial fibrillation (aHR 2.15, 95% CI 1.29-3.58), myocardial infarction (aHR 1.55, 95% CI 1.07-2.26), and type 2 diabetes mellitus (aHR 1.40, 95% CI 1.13-1.74). Conclusion: Overall survival rate of patients with dementia in Thailand was comparable to previous studies. Several comorbidities were associated with a ten-year survival. The prognosis of patients with dementia may be improved by appropriate care of comorbidities.

Hiroaki Mori, Yuta Yoshino, Jun-ichi Iga, Shinichiro Ochi, Yu Funahashi, Kiyohiro Yamazaki, Hiroshi Kumon, Yuki Ozaki, Shu-ichi Ueno
Aberrant Expression of GABA-Related Genes in the Hippocampus of 3xTg-AD Model Mice from the Early to End Stages of Alzheimer’s Disease
Abstract: Background: We explored the gene expression levels in the brain of 3xTg-AD model mice to elucidate the molecular pathological changes from the early to end stages of Alzheimer’s disease (AD). Objective: We re-analyzed our previously published microarray data obtained from the hippocampus of 3xTg-AD model mice at 12 and 52 weeks of age. Methods: Functional annotation and network analyses of the up- and downregulated differentially expressed genes (DEGs) in mice aged 12 to 52 weeks were performed. Validation tests for gamma-aminobutyric acid (GABA)-related genes were also performed by quantitative polymerase chain reaction (qPCR). Results: In total, 644 DEGs were upregulated and 624 DEGs were downregulated in the hippocampus of both the 12- and 52-week-old 3xTg-AD mice. In the functional analysis of the upregulated DEGs, 330 gene ontology biological process terms, including immune response, were found, and they interacted with each other in the network analysis. In the functional analysis of the downregulated DEGs, 90 biological process terms, including several terms related to membrane potential and synapse function, were found, and they also interacted with each other in the network analysis. In the qPCR validation test, significant downregulation was seen for Gabrg3 at the ages of 12 (p = 0.02) and 36 (p = 0.005) weeks, Gabbr1 at the age of 52 weeks (p = 0.001), and Gabrr2 at the age of 36 weeks (p = 0.02). Conclusion: Changes in immune response and GABAergic neurotransmission may occur in the brain of 3xTg mice from the early to end stages of AD.

Rebecca M. Bollinger, Matthew Gabel, Dean W. Coble, Szu-Wei Chen, Audrey A. Keleman, Jeff Doralus, Erin Chin, Jennifer H. Lingler, Joshua D. Grill, Susan L. Stark, Dorothy F. Edwards (Handling Associate Editor: Russell Swerdlow)
Retention of Study Partners in Longitudinal Studies of Alzheimer Disease
Abstract: Background: Study partners are required for all participants at Alzheimer Disease Research Centers (ADRCs). Study partners’ attitudes and beliefs may contribute to missed visits and negatively impact retention of participants in longitudinal AD studies. Objective: Study partners (N=212) of participants (Clinical Dementia Rating [CDR]≤1) at four ADRCs were randomly surveyed to examine their facilitators and barriers to continued participation in AD studies. Methods: Reasons for participation were analyzed with factor analysis and regression analysis. Effects of complaints and goal fulfillment on attendance were estimated with fractional logistic models. Open-ended responses were characterized with a Latent Dirichlet Allocation topic model. Results: Study partners participated for personal benefit and altruism. They emphasized personal benefits more when their participants had a CDR>0 than when they had a CDR=0. This difference declined with participant age. The majority of study partners rated their ADRC participation as positive and meeting their goals. Although half reported at least one complaint, very few regretted participating. Those who reported that ADRC participation fulfilled their goals or had fewer complaints were more likely to have perfect attendance. Study partners requested more feedback about test results and better management of study visits. Conclusion: Study partners are motivated by both personal and altruistic goals. The salience of each goal depends on their trust in researchers and the participant’s cognitive status and age. Retention may improve with perceived goal fulfillment and fewer complaints. Potential areas for improving retention are providing more information about the participant’s test results and better management of study visits.

Guerry M. Peavy
Can’t Have One Without the Other: Study Partner Retention in Alzheimer's Disease Research
Abstract Alzheimer’s disease (AD) clinical research depends on engaging and enrolling appropriate research participants to address specific scientific questions. Investigators, however, are beginning to recognize the importance of participant study partners who contribute to AD research in multiple ways, including their contributions to the diagnostic process through observations of participant cognition and daily functioning. These contributions justify increased efforts to understand factors that impede or facilitate their willingness to remain in this role in longitudinal studies and clinical trials. Study partners, including those from diverse, underrepresented communities, are stakeholders significantly invested in AD research that benefits all living with the disease.

Woo Hyun Paik*, Dong Kee Jang*, Soyoung Cho, Jin Ho Choi, Min Kyu Kim, In Rae Cho, Ji Kon Ryu, Yong-Tae Kim, Kyung-Do Han, Sang Hyub Lee *These authors equally contributed to this work.
Acute Pancreatitis and the Risk of Dementia in Diabetes: A Nationwide Cohort Study Using Korean Healthcare Claims Database
Abstract: Background: Diabetes is a major risk factor for the development of dementia, which has been proven to be associated with systemic inflammation. Acute pancreatitis, also a local and systemic inflammatory disease, is the most common gastrointestinal disease requiring acute hospitalization. Objective: The effect of acute pancreatitis on dementia was investigated in type 2 diabetic patients. Methods: Data was collected from the Korean National Health Insurance Service. The study sample included type 2 diabetes patients who received general health examination from 2009 to 2012. Cox proportional hazard regression analysis was used to evaluate the association between acute pancreatitis and dementia with adjustment of confounders. Stratified subgroup analysis by age, sex, smoking, alcohol consumption, hypertension, dyslipidemia, and body mass index was conducted. Results: Among the 2,328,671 participants in total, 4,463 patients had a history of acute pancreatitis before the health examination. During a median follow-up of 8.1 (IQR, 6.7–9.0) years, 194,023 participants (8.3%) developed all-cause dementia. Previous history of acute pancreatitis was a significant risk factor for dementia after adjustment of confounding variables (HR 1.39 [95% CI 1.26–1.53]). In the subgroup analysis, patient characteristics such as age under 65 years, male, current smoker, and alcohol consumption were significant risk factors for dementia in patients with a history of acute pancreatitis. Conclusion: The history of acute pancreatitis was associated with the development of dementia in patients with diabetes. Because the risk of dementia increases with alcohol consumption and smoking in diabetic patients with history of acute pancreatitis, abstinence from alcohol and smoking should be recommended.

Christopher Gonzalez, Kayden J. Mimmack, Rebecca E. Amariglio, J. Alex Becker, Jasmeer P. Chhatwal, Colleen D. Fitzpatrick, Jennifer R. Gatchel, Keith A. Johnson, Zoe S. Katz, Madeline K. Kuppe, Joseph J. Locascio, Onyinye J. Udeogu, Kathryn V. Papp, Pranitha Premnath, Michael J. Properzi, Dorene M. Rentz, Aaron P. Schultz, Reisa A. Sperling, Patrizia Vannini, Sharon Wang, Gad A. Marshall
Associations of the Harvard Automated Phone Task and Alzheimer’s Disease Pathology in Cognitively Normal Older Adults: Preliminary Findings
Abstract: Background: Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer’s disease (AD) is critical. Objective: The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults. Methods: Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid. Results: Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone. Conclusion: Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.

Zhiping Mi*, Eric E. Abrahamson*, Angela Y. Ryu, Michael Malek-Ahmadi, Julia K. Kofler, Kenneth N. Fish, Robert A. Sweet, Victor L. Villemagne, Julie A. Schneider, Elliott J. Mufson, Milos D. Ikonomovic *These authors contributed equally to this work.
Vesicular Glutamate Transporter Changes in the Cortical Default Mode Network During the Clinical and Pathological Progression of Alzheimer’s Disease
Abstract: Background: Altered glutamatergic neurotransmission may contribute to impaired default mode network (DMN) function in Alzheimer’s disease (AD). Among the DMN hub regions, frontal cortex (FC) was suggested to undergo a glutamatergic plasticity response in prodromal AD, while the status of glutamatergic synapses in the precuneus (PreC) during clinical-neuropathological AD progression is not known. Objective: To quantify vesicular glutamate transporter VGluT1- and VGluT2-containing synaptic terminals in PreC and FC across clinical stages of AD. Methods: Unbiased sampling and quantitative confocal immunofluorescence of cortical VGluT1- and VGluT2-immunoreactive profiles and spinophilin-labeled dendritic spines were performed in cases with no cognitive impairment (NCI), mild cognitive impairment (MCI), mild-moderate AD (mAD), or moderate-severe AD (sAD). Results: In both regions, loss of VGluT1-positive profile density was seen in sAD compared to NCI, MCI, and mAD. VGluT1-positive profile intensity in PreC did not differ across groups, while in FC it was greater in MCI, mAD, and sAD compared to NCI. VGluT2 measures were stable in PreC while FC had greater VGluT2-positive profile density in MCI compared to sAD, but not NCI or mAD. Spinophilin measures in PreC were lower in mAD and sAD compared to NCI, while in FC they were stable across groups. Lower VGluT1 and spinophilin measures in PreC, but not FC, correlated with greater neuropathology. Conclusion: Frank loss of VGluT1 in advanced AD relative to NCI occurs in both DMN regions. In FC, an upregulation of VGluT1 protein content in remaining glutamatergic terminals may contribute to this region’s plasticity response in AD.

Lihui Tu, Zhijiang Wang, Xiaozhen Lv, Teng Xie, Zili Fan, Ming Zhang, Huali Wang, Xin Yu
Characteristics of Odor Identification and Hedonics and Their Association with Piriform Cortex-Based Resting-State Functional Connectivity in Amnestic Mild Cognitive Impairment
Abstract: Background: Olfactory identification dysfunction (OID) might be an early sign of amnestic mild cognitive impairment (aMCI). However, odor hedonics, the ability to perceive odor pleasantness, is neglected. Also, the neural substrate of OID remains unclear. Objective: To explore the characteristics of odor identification and hedonics in aMCI and examine the potential neural correlates of OID by analyzing olfactory functional connectivity (FC) patterns in MCI. Methods: Forty-five controls and 83 aMCI patients were examined. The Chinese smell identification test was used to assess olfaction. Global cognition, memory, and social cognition were assessed. Resting-state functional networks associated with olfactory cortex seeds were compared between the cognitively normal (CN) and aMCI groups, as well as between aMCI subgroups by the degree of OID. Results: Compared to controls, aMCI patients had a significant deficit in olfactory identification, mainly reflected in the identification of pleasant and neutral odors. aMCI patients also rated pleasant and neutral odors much lower than controls. A positive correlation between olfaction and social cognition was found in aMCI. The seed-based FC analysis found that aMCI patients had higher FC between the right orbitofrontal cortex and right frontal lobe/middle frontal gyrus than controls. Subgroup analysis showed that, compared to aMCI without OID, aMCI with severe OID had abnormal FC in the bilateral piriform region. Conclusion: Our results suggest that OID in aMCI primarily refers to the identification of pleasant and neutral odors. The FC alterations in bilateral orbitofrontal cortex and piriform cortices might contribute to the impairment in odor identification.

Jonas Alexander Jarholm, Atle Bjørnerud, Turi Olene Dalaker, Mehdi Sadat Akhavi, Bjørn Eivind Kirsebom, Lene Pålhaugen, Kaja Nordengen, Gøril Rolfseng Grøntvedt, Arne Nakling, Lisa F. Kalheim, Ina S. Almdahl, Sandra Tecelão, Tormod Fladby, Per Selnes
Medial Temporal Lobe Atrophy in Predementia Alzheimer’s Disease: A Longitudinal Multi-Site Study Comparing Staging and A/T/N in a Clinical Research Cohort
Abstract: Background: Atrophy of the medial temporal lobe (MTL) is a biological characteristic of Alzheimer’s disease (AD) and can be measured by segmentation of magnetic resonance images (MRI). Objective: To assess the clinical utility of automated volumetry in a cognitively well-defined and biomarker-classified multi-center longitudinal predementia cohort. Methods: We used Automatic Segmentation of Hippocampal Subfields (ASHS) to determine MTL morphometry from MRI. We harmonized scanner effects using the recently developed longitudinal ComBat. Subjects were classified according to the A/T/N system, and as normal controls (NC), subjective cognitive decline (SCD), or mild cognitive impairment (MCI). Positive or negative values of A, T, and N were determined by cerebrospinal fluid measurements of the Aβ42/40 ratio, phosphorylated and total tau. From 406 included subjects, longitudinal data was available for 206 subjects by stage, and 212 subjects by A/T/N. Results: Compared to A-/T-/N- at baseline, the entorhinal cortex, anterior and posterior hippocampus were smaller in A+/T+orN+. Compared to NC A- at baseline, these subregions were also smaller in MCI A+. Longitudinally, SCD A+ and MCI A+, and A+/T-/N- and A+/T+orN+, had significantly greater atrophy compared to controls in both anterior and posterior hippocampus. In the entorhinal and parahippocampal cortices, longitudinal atrophy was observed only in MCI A+ compared to NC A-, and in A+/T-/N- and A+/T+orN+ compared to A-/T-/N-. Conclusion: We found MTL neurodegeneration largely consistent with existing models, suggesting that harmonized MRI volumetry may be used under conditions that are common in clinical multi-center cohorts.

Neha Sinha, Bernadette A. Fausto, Bryce Mander, Mark A. Gluck
High-Quality Sleep Mitigates ABCA7-Related Generalization Deficits in Healthy Older African Americans
Abstract: Background: Both sleep deficiencies and Alzheimer’s disease (AD) disproportionately affect older African Americans. Genetic susceptibility to AD further compounds risk for cognitive decline in this population. Aside from APOE ε4, ABCA7 rs115550680 is the strongest genetic locus associated with late-onset AD in African Americans. While sleep and ABCA7 rs115550680 independently influence late-life cognitive outcomes, we know too little about the interplay between these two factors on cognitive function. Objective: We investigated the interaction between sleep and ABCA7 rs115550680 on hippocampal-dependent cognitive function in older African Americans. Methods: One-hundred fourteen cognitively healthy older African Americans were genotyped for ABCA7 risk (n = 57 carriers of risk “G” allele; n =57 non-carriers), responded to lifestyle questionnaires, and completed a cognitive battery. Sleep was assessed via a self-reported rating of sleep quality (poor, average, good). Covariates included age and years of education. Results: Using ANCOVA, we found that carriers of the risk genotype who reported poor or average sleep quality demonstrated significantly poorer generalization of prior learning—a cognitive marker of AD—compared to their non-risk counterparts. Conversely, there was no genotype-related difference in generalization performance in individuals who reported good sleep quality. Conclusion: These results indicate that sleep quality may be neuroprotective against genetic risk for AD. Future studies employing more rigorous methodology should investigate the mechanistic role of sleep neurophysiology in the pathogenesis and progression of AD associated with ABCA7. There is also need for the continued development of non-invasive sleep interventions tailored to racial groups with specific AD genetic risk profiles.

Mingxia Liu*, Mo Li*, Jing He, Yi He, Jian Yang, Zuoli Sun (Handling Associate Editor: Jianping Jia) *These authors contributed equally to this work.
Chiral Amino Acid Profiling in Serum Reveals Potential Biomarkers for Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is a complex neurodegenerative disease, and increasing evidence has linked dysregulation of amino acids to AD pathogenesis. However, the existing studies often ignore the chirality of amino acids, and some results are inconsistent and controversial. The changes of amino acid profiles in AD from the perspective of enantiomers remain elusive. Objective: The purpose of this study is to investigate whether the levels of amino acids, especially D-amino acids, are deregulated in the peripheral serum of AD patients, with the ultimate goal of discovering novel biomarkers for AD. Methods: The chiral amino acid profiles were determined by HPLC-MS/MS with a pre-column derivatization method. Experimental data obtained from 37 AD patients and 34 healthy controls (HC) were statistically analyzed. Results: Among the 35 amino acids detected, D-proline, D/total-proline ratio, D-aspartate, and D/total-aspartate ratio were decreased, while D-phenylalanine was elevated in AD compared to HC. Significant age-dependent increases in D-proline, D/total-proline ratio, and D-phenylalanine were observed in HC, but not in AD. Receiver operator characteristic analyses of the combination of D-proline, D-aspartate, D-phenylalanine, and age for discriminating AD from HC provided satisfactory area under the curve (0.87), specificity (97.0%), and sensitivity (83.8%). Furthermore, the D-aspartate level was significantly decreased with the progression of AD, as assessed by the Clinical Dementia Rating Scale and Mini-Mental State Examination. Conclusion: The panels of D-proline, D-phenylalanine, and D-aspartate in peripheral serum may serve as novel biomarker candidates for AD. The latter parameter is further associated with the severity of AD.

Haimei Yang*, Xia Gao*, Yan Lian, Tingting Wu, Zongming Yang, Qianrong Wu (Handling Associate Editor: Mariagnese Barbera) *These authors contributed equally to this work.
Associations of Leisure Activities and Sleep Duration with Cognitive Function: A Nationwide Prospective Cohort Study of Chinese Old Adults
Abstract: Background: Leisure activities and sleep duration are correlated and have been linked to cognitive function, but most studies have examined only one of these factors. Objective: To investigate the independent and joint associations of leisure activities and sleep duration with cognitive function among older adults. Methods: We included 7,796 participants aged ≥65 years from the Chinese Longitudinal Healthy Longevity Survey during 2008-2018 (waves 5-8). Self-reported leisure activities and sleep duration were assessed at baseline, and cognitive function was measured repeatedly using the Chinese version of the Mini-Mental State Examination (MMSE) at baseline and during follow-up. We used linear mixed models to estimate regression coefficients (β) and 95% confidence intervals (CI). Results: The median follow-up duration was 5.77 years. After adjusting for each other and potential confounders, both lower leisure activity score (each 1-point decrease β=-0.33, 95% CI: -0.36 to -0.30) and longer sleep duration (each 1-hour increase β=-0.17, 95% CI: -0.22 to -0.11) were independently associated with lower MMSE score. Furthermore, we observed an additive interaction between leisure activities and sleep duration (pinteraction <0.001). A combination of low leisure activity score and long sleep duration was strongly associated with decreased MMSE score (β=-2.51, 95% CI: -2.85 to -2.16) compared with the group with combined high leisure activity score and normal sleep duration. Conclusion: Both leisure activities and sleep duration were independently associated with cognitive function. Moreover, the combination of leisure inactivity and prolonged sleep duration predicted worse cognitive function (a preclinical hallmark of Alzheimer's disease) in an additive manner.

Geri Meduri, Kevin Guillemeau, Corentin Daguinot, Omar Dounane, Melanie Genet, Luigi Ferrara, Beatrice Chambraud, Etienne Emile Baulieu, Julien Giustiniani
Concomitant Neuronal Tau Deposition and FKBP52 Decrease Is an Early Feature of Different Human and Experimental Tauopathies
Abstract: Background: Pathological tau proteins constitute neurofibrillary tangles that accumulate in tauopathies including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and familial frontotemporal lobar degeneration (FTLD-Tau). We previously showed that the FKBP52 immunophilin interacts functionally with tau and strongly decreases in AD brain neurons in correlation with tau deposition. We also reported that FKBP52 co-localizes with autophagy-lysosomal markers and an early pathological tau isoform in AD neurons, suggesting its involvement in autophagic tau clearance. Objective: Our objective was to evaluate if differences in neuronal FKBP52 expression levels and subcellular localization might be detected in AD, PSP, familial FTLD-Tau, and in the hTau-P301S mouse model compared to controls. Methods: Cell by cell immunohistofluorescence analyses and quantification of FKBP52 were performed on postmortem brain samples of some human tauopathies and on hTau-P301S mice spinal cords. Results: We describe a similar FKBP52 decrease and its localization with early pathological tau forms in the neuronal autophagy-lysosomal pathway in various tauopathies and hTau-P301S mice. We find that FKBP52 decreases early during the pathologic process as it occurs in rare neurons with tau deposits in the marginally affected frontal cortex region of AD Braak IV brains and in the spinal cord of symptomless 1-month-old hTau-P301S mice. Conclusion: As FKBP52 plays a significant role in cellular signaling and conceivably in tau clearance, our data support the idea that the prevention of FKBP52 decrease or the restoration of its normal expression at early pathologic stages might represent a new potential therapeutic approach in tauopathies including AD, familial FTLD-Tau, and PSP.

Jing Di*, Ruth S. Nelson*, Gregory A. Jicha, Daniela C. Moga, Justin M. Barber, Matthew D. Cykowski, David W. Fardo, Erin L. Abner, Peter T. Nelson *These authors contributed equally to this work.
Urinary Incontinence in a Community-Based Autopsy Cohort Is Associated with Limbic Predominant Age-Related TDP-43 Encephalopathy Neuropathologic Changes
Abstract: Background: Dementia and urinary incontinence (UI) are etiologically complex clinical syndromes. Dementia and UI often occur in the same individuals, but underlying factors connecting them are incompletely understood. Objective: Query data from a community-based autopsy series to assess pathologies that underlie UI. Methods: Included research subjects came to autopsy from the University of Kentucky Alzheimer’s Disease Research Center longitudinal cohort. A total of 368 research volunteers met inclusion criteria for this cross-sectional study. The average age at death was 85.3 years and the average number of annual clinic visits was 5.2 visits. Statistical models were run to evaluate which pathologies were associated with UI. Data included pathologies scored according to conventional stage-based systems, and these studies were complemented by quantitative digital neuropathology. Results: Dementia was diagnosed at the final clinical visit in 208 (56.7% of the sample) and UI was documented in 156 (42.7%). UI was associated with depression and dementia (both p<0.001). More women than men had a history of UI (p<0.04), and women with UI had had more biological children than those without UI (p<0.005). Participants with limbic predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) were more likely to have UI than those without LATE-NC (p<0.001). The presence of LATE-NC (Stage >1) was associated with UI with or without severe Alzheimer’s disease neuropathologic changes and/or Lewy body pathology. Conclusion: In this community-based autopsy cohort, multiple factors were associated with UI, but the neuropathologic change most robustly associated with UI was LATE-NC.

Tim Martin, Katherine Kero, Rok Požar, Bruno Giordani, Voyko Kavcic
Mild Cognitive Impairment in African Americans Is Associated with Differences in EEG Theta/Beta Ratio
Abstract: Background: Identification of older individuals with increased risk for cognitive decline can contribute not only to personal benefits (e.g., early treatment, evaluation of treatment), but could also benefit clinical trials (e.g., patient selection). We propose that baseline resting-state electroencephalography (rsEEG) could provide markers for early identification of cognitive decline. Objective: To determine whether rsEEG theta/beta ratio (TBR) differed between mild cognitively impaired (MCI) and healthy older adults. Methods: We analyzed rsEEG from a sample of 99 (ages 60-90) consensus-diagnosed, community-dwelling older African Americans (58 cognitively typical and 41 MCI). Eyes closed rsEEGs were acquired before and after participants engaged in a visual motion direction discrimination task. rsEEG TBR was calculated for four midline locations and assessed for differences as a function of MCI status. Hemispheric asymmetry of TBR was also analyzed at equidistant lateral electrode sites. Results: Results showed that MCI participants had a higher TBR than controls (p=0.04), and that TBR significantly differed across vertex location (p<0.001) with the highest TBR at parietal site. MCI and cognitively normal controls also differed in hemispheric asymmetries, such that MCI show higher TBR at frontal sites, with TBR greater over right frontal electrodes in the MCI group (p=0.003) and no asymmetries found in the cognitively normal group. Lastly, we found a significant task aftereffect (post-task compared to pre-task measures) at posterior locations with higher TBR at posterior locations (Oz p=0.002, Pz p=0.057). Conclusion: TBR and TBR asymmetries differ between MCI and cognitively normal older adults and may reflect neurodegenerative processes underlying MCI symptoms.

Saeed Karima, Vajiheh Aghamollaii, Somayeh Mahmoodi Baram, Laurent Balenci, Krista L. Lanctôt, Alex Kiss, Abbas Tafakhori, Meisam Mahdavi, Shima Rajaei, Somayeh Shateri, Amir Yarhoseini, Farzad Mokhtari ,Akbar Fotouhi, Ali Riazi
Boswellic Acids Improve Clinical Cognitive Scores and Reduce Systemic Inflammation in Patients with Mild to Moderate Alzheimer’s Disease
Abstract: Background: Recent therapeutic approaches for Alzheimer’s disease (AD) have had limited success. Considering the association of neuroinflammation with AD symptoms as demonstrated in multiple studies, assessment of the clinical efficacy of molecules that reduce systemic or brain inflammation is warranted. Objective: This clinical trial assessed whether boswellic acids can improve cognitive and neuropsychiatric symptoms while reducing inflammation in AD patients. Methods: A double-blind, placebo-controlled, study was conducted on 85 AD patients randomized to boswellic acids (K-Vie™ as the main ingredient in Memowell™) or placebo for 6 months. Clinical Dementia Rating–Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) scores were compared to baseline and between groups and constituted the co-primary clinical efficacy endpoints. Secondary outcomes included neuropsychiatric assessment (Neuropsychiatric Inventory-Questionnaire, NPI-Q) and assessment of AD and inflammation biomarkers. Results: Patients on K-Vie™ showed a 3.1- and 1.6-unit improvement in MMSE and CDR-SOB scores, respectively, when compared to patients on placebo. NPI-Q analysis revealed significant improvement in the K-Vie™ but not in the placebo group. Only mild gastrointestinal side effects were reported in a few patients. Patients on K-Vie™ showed improvement in plasma AD biomarkers and reduction of key inflammatory cytokines including IL-6 and TNF. Conclusion: Our results support the positive cognitive effects of boswellic acids by reducing the systemic inflammation.

Caleigh A. Findley, Samuel A. McFadden, MaKayla F. Cox, Lindsey N. Sime, Mackenzie R. Peck, Kathleen Quinn, Andrzej Bartke, Kevin N. Hascup, Erin R. Hascup
Prodromal Glutamatergic Modulation with Riluzole Impacts Glucose Homeostasis and Spatial Cognition in Alzheimer’s Disease Mice
Abstract: Background: Prior research supports a strong link between Alzheimer’s disease (AD) and metabolic dysfunction that involves a multi-directional interaction between glucose, glutamatergic homeostasis, and amyloid pathology. Elevated soluble amyloid-β (Aβ) is an early biomarker for AD-associated cognitive decline that contributes to concurrent glutamatergic and metabolic dyshomeostasis in humans and male transgenic AD mice. Yet, it remains unclear how primary time-sensitive targeting of hippocampal glutamatergic activity may impact glucose regulation in an amyloidogenic mouse model. Previous studies have illustrated increased glucose uptake and metabolism using a neuroprotective glutamate modulator (riluzole), supporting the link between glucose and glutamatergic homeostasis. Objective: We hypothesized that targeting early glutamatergic hyperexcitation through riluzole treatment could aid in attenuating co-occurring metabolic and amyloidogenic pathologies with the intent of ameliorating cognitive decline. Methods: We conducted an early intervention study in male and female transgenic (AβPP/PS1) and knock-in (APPNL-F/NL-F) AD mice to assess the on- and off-treatment effects of prodromal glutamatergic modulation (2-6 months of age) on glucose homeostasis and spatial cognition through riluzole treatment. Results: Results indicated a sex- and genotype-specific effect on glucose homeostasis and spatial cognition with riluzole intervention that evolved with disease progression and time since treatment. Conclusion: These findings support the interconnected nature of glucose and glutamatergic homeostasis with amyloid pathology and petition for further investigation into the targeting of this relationship to improve cognitive performance.

Dan Li, Yue-yi Yu, Nan Hu, Min Zhang, Fang-ling Sun, Li Liu, Li-mei Fan, Shi-shuang Ruan, Fen Wang, Pedro Rosa-Neto (Handling Associate Editor: Jin-Tai Yu)
Composite Indices of the Color-Picture Version of Boston Naming Test Have Better Discriminatory Power: Reliability and Validity in a Chinese Sample with Diverse Neurodegenerative Diseases
Abstract: Background: The Boston Naming Test (BNT) is the most widely used measure to assess anomia. However, it has been criticized for failing to differentiate the underlying cognitive process of anomia. Objective: We validated the color-picture version of BNT (CP-BNT) in a sample with diverse neurodegenerative dementia diseases (NDDs). We also verified the differential ability of the composite indices of CP-BNT across NDDs groups. Methods: The present study included Alzheimer’s disease (n=132), semantic variant primary progressive aphasia (svPPA, n=53), non-svPPA (n=33), posterior cortical atrophy (PCA, n=35), and normal controls (n=110). We evaluated psychometric properties of CP-BNT for the spontaneous naming (SN), the percentage of correct responses on semantic cuing and word recognition cuing (%SC, %WR). Receiver operating characteristic analysis was used to examine the discriminatory power of SN alone and the composite indices (SN, %SC, and %WR). Results: The CP-BNT had sufficient internal consistency, good convergent, divergent validity, and criterion validity. Different indices of CP-BNT demonstrated distinct cognitive underpinnings. Category fluency was the strongest predictor of SN (β=0.46, p<0.001). Auditory comprehension tests highly associated with %WR (Sentence comprehension: β=0.22, p=0.001; Word comprehension: β=0.20, p=0.001), whereas a lower visuospatial score predicted %SC (β= -0.2, p=0.001). Composite indices had better predictability than the SN alone when differentiating between NDDs, especially for PCA versus non-svPPA (area under the curve increased from 63.9% to 81.2%). Conclusion: The CP-BNT is a highly linguistically relevant test with sufficient reliability and validity. Composite indices could provide more differential information beyond SN and should be used in clinical practice.