Volume 84, Number 4, IN PRESS

Review
Angie K. Torres, Claudia Jara, Han S. Park-Kang, Catalina M. Polanco, Diego Tapia, Fabián Alarcón, Adely de la Peña, Jesus Llanquinao, Gabriela Vargas-Mardones, Javiera A. Indo, Nibaldo C. Inestrosa, Cheril Tapia-Rojas (Handling Associate Editor: Paula Moreira)
Synaptic Mitochondria: An Early Target of Amyloid-β and Tau in Alzheimer’s Disease
Abstract: Alzheimer's disease (AD) is characterized by cognitive impairment and the presence of neurofibrillary tangles and senile plaques in the brain. Neurofibrillary tangles are composed of hyperphosphorylated tau, while senile plaques are formed by amyloid-β (Aβ) peptide. The amyloid hypothesis proposes that Aβ accumulation is primarily responsible for the neurotoxicity in AD. Multiple Aβ-mediated toxicity mechanisms have been proposed including mitochondrial dysfunction. However, it is unclear if it precedes Aβ accumulation or if is a consequence of it. Aβ promotes mitochondrial failure. However, AβPP could be cleaved in the mitochondria producing Aβ peptide. Mitochondrial-produced Aβ could interact with newly formed ones or with Aβ that enter the mitochondria, which may induce its oligomerization and contribute to further mitochondrial alterations, resulting in a vicious cycle. Another explanation for AD is the tau hypothesis, in which modified tau trigger toxic effects in neurons. Tau induces mitochondrial dysfunction by indirect and apparently by direct mechanisms. In neurons mitochondria are classified as non-synaptic or synaptic according to their localization, where synaptic mitochondrial function is fundamental supporting neurotransmission and hippocampal memory formation. Here, we focus on synaptic mitochondria as a primary target for Aβ toxicity and/or formation, generating toxicity at the synapse and contributing to synaptic and memory impairment in AD. We also hypothesize that phospho-tau accumulates in mitochondria and triggers dysfunction. Finally, we discuss that synaptic mitochondrial dysfunction occur in aging and correlates with age-related memory loss. Therefore, synaptic mitochondrial dysfunction could be a predisposing factor for AD or an early marker of its onset.

Review
Bruna Schultz, Jéssica Taday, Leonardo Menezes, Anderson Cigerce, Marina C. Leite, Carlos-Alberto Gonçalves
Calpain-Mediated Alterations in Astrocytes Before and During Amyloid Chaos in Alzheimer’s Disease
Abstract: One of the changes found in the brain in Alzheimer’s disease (AD) is increased calpain, derived from calcium dysregulation, oxidative stress, and/or neuroinflammation, which are all assumed to be basic pillars in neurodegenerative diseases. The role of calpain in synaptic plasticity, neuronal death, and AD has been discussed in some reviews. However, astrocytic calpain changes sometimes appear to be secondary and consequent to neuronal damage in AD. Herein, we explore the possibility of calpain-mediated astroglial reactivity in AD, both preceding and during the amyloid phase. We discuss the types of brain calpains but focus the review on calpains 1 and 2 and some important targets in astrocytes. We address the signaling involved in controlling calpain expression, mainly involving p38/mitogen-activated protein kinase and calcineurin, as well as how calpain regulates the expression of proteins involved in astroglial reactivity through calcineurin and cyclin-dependent kinase 5. Throughout the text, we have tried to provide evidence of the connection between the alterations caused by calpain and the metabolic changes associated with AD. In addition, we discuss the possibility that calpain mediates amyloid-β clearance in astrocytes, as opposed to amyloid-β accumulation in neurons.

Short Communication
Neal R. Swerdlow, Juliana E. Kotz, Yash B. Joshi, Jo Talledo, Joyce Sprock, Juan L. Molina, Branko Huisa, Steven F. Huege, Jairo Alberto Romero, Michael J. Walsh, Lisa Delano-Wood, Gregory A. Light (Handling Associate Editor: Joseph Quinn)
Using Biomarkers to Predict Memantine Effects in Alzheimer’s Disease: A Proposal and Proof-Of-Concept Demonstration
Abstract: Memantine’s benefits in Alzheimer’s disease (AD) are modest and heterogeneous. We tested the feasibility of using sensitivity to acute memantine challenge to predict an individual’s clinical response. Eight participants completed a double-blind challenge study of memantine (placebo versus 20 mg) effects on autonomic, subjective, cognitive, and neurophysiological measures, followed by a 24-week unblinded active-dose therapeutic trial (10 mg bid). Study participation was well tolerated. Subgroups based on memantine sensitivity on specific laboratory measures differed in their clinical response to memantine, some by large effect sizes. It appears feasible to use biomarkers to predict clinical sensitivity to memantine.

Short Communication
Agathe Vrillon, Vincent Deramecourt, Florence Pasquier, Éloi Magnin, David Wallon, Pierre Lozeron, Élodie Bouaziz-Amar, Claire Paquet
Association of Amyotrophic Lateral Sclerosis and Alzheimer’s Disease: New Entity or Coincidence? A Case Series
Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia have a strong clinical, genetic, and pathological connection but association of ALS with Alzheimer’s disease (AD) is seldom reported. We report a series of 5 cases of AD associated with ALS. Our patients presented with cognitive deterioration with episodic memory impairment meeting criteria for AD. ALS occurred subsequently in all cases and its phenotype was not homogenous. Amyloid process was confirmed in four cases with cerebrospinal fluid biomarkers. One case underwent postmortem exam, demonstrating hallmarks lesions of both diseases. This series highlights that ALS-AD phenotype could be a specific underexplored entity.

Short Communication
Qiang Zhang, Jordan L. Schultz, Georgina M. Aldridge, Jacob E. Simmering, Youngcho Kim, Amy C. Ogilvie, Nandakumar S. Narayanan
COVID-19 Case Fatality and Alzheimer’s Disease
Abstract: Previous studies have identified dementia as a risk factor for death from coronavirus disease 2019 (COVID-19). However, it is unclear whether Alzheimer’s disease (AD) is an independent risk factor for COVID-19 case fatality rate. In a retrospective cohort study, we identified 387,841 COVID-19 patients through TriNetX. After adjusting for demographics and comorbidities, we found that AD patients had higher odds of dying from COVID-19 compared to patients without AD (Odds Ratio: 1.20, 95% confidence interval: 1.09-1.32, p<0.001). Interestingly, we did not observe increased mortality from COVID-19 among patients with vascular dementia. These data are relevant to the evolving COVID-19 pandemic.

Commentary
Nicholas Clute-Reinig, Suman Jayadev, Kristoffer Rhoads, Anne-Laure Le Ny
Alzheimer’s Disease Diagnostics Must Be Globally Accessible
Abstract: Dementia and Alzheimer’s disease (AD) are global health crises, with most affected individuals living in low- or middle-income countries. While research into diagnostics and therapeutics remains focused exclusively on high-income populations, recent technological breakthroughs suggest that low-cost AD diagnostics may soon be possible. However, as this disease shifts onto those with the least financial and structural ability to shoulder its burden, it is incumbent on high-income countries to develop accessible AD healthcare. We argue that there is a scientific and ethical mandate to develop low-cost diagnostics that will not only benefit patients in low-and middle-income countries but the AD field as a whole.

Commentary
Poul F. Høilund-Carlsen, Abass Alavi
Aducanumab (Marketed as Aduhelm) Approval Is Likely Based on Misinterpretation of PET Imaging Data
Abstract: According to the FDA, aducanumab (Aduhelm), the recently approved anti-Alzheimer drug, reduces the level of cerebral amyloid plaques—a hallmark finding in patients with Alzheimer’s disease—and this will result in a reduction in clinical decline. The authors of this article are not convinced that amyloid deposits are a hallmark of Alzheimer’s disease and are of the opinion that the apparent reduction in amyloid accumulation following aducanumab treatment is likely instead a result of continued and advanced cerebral cell death and, thus, not a sign of improvement but of an even more advanced disease.

Cendrine Foucard, Juliette Palisson, Catherine Belin, Chloé Bereaux, Julien Dumurgier, Claire Paquet, Bertrand Degos, Elodie Bouaziz-Amar, Didier Maillet, Marion Houot, Béatrice Garcin (Handling Associate Editor: Leonardo Cruz de Souza)
The Diagnostic Value of a Short Memory Test: The TNI-93
Abstract: Background: The TNI-93 is a quick memory test designed for all patients regardless of their education level. A significant proportion of patients with Alzheimer’s disease (AD) are illiterate or poorly educated, and only a few memory tests are adapted for these patients. Objective: In this study we aimed at assessing the diagnostic value of the TNI-93 for diagnosis of patients with biologically confirmed amyloid status. Methods: We included all patients who had an analysis of AD cerebrospinal fluid biomarkers, a neuropsychological assessment including a TNI-93 and an anatomical brain imaging at Avicenne Hospital between January 2009 and November 2019. We compared the TNI-93 scores in patients with amyloid abnormalities (A+) and patients without amyloid abnormalities (A-) according to the AT(N) diagnostic criteria. Results: 108 patients were included (mean age: 66.9±8.5 years old, mean education level: 8.9±5.2 years). Patients from the A+ group (N=80) were significantly more impaired than patients from the A- group (N=28) on immediate recall (A+: 5.9±2.8; A-: 7.4±2.6; p=0.001), free recall (A+: 3.5±2.7; A-: 5.9±2.8; p<0.001), total recall (A+: 5.7±3.5; A-: 7.8±2.8; p<0.001), and on number of intrusions during the recall phase (A+: 1±1.8; A-: 0.1±0.3; p=0.002). ROC curves revealed that the best scores to discriminate A+ from A- patients were immediate recall (Area under curve (AUC): 0.70), number of encoding trials (AUC: 0.73), free recall (AUC: 0.74), and total recall (AUC: 0.74). Conclusion: The TNI-93’s immediate, free, and total recalls are valuable tools for the diagnosis of AD.

Saifudeen Ismael*, Golnoush Mirzahosseini*, Heba A. Ahmed, Arum Yoo, Modar Kassan, Kafait U. Malik, Tauheed Ishrat *These authors contributed equally to this work.
Renin-Angiotensin System Alterations in the Human Alzheimer's Disease Brain
Abstract: Background: Understanding Alzheimer's disease (AD) in terms of its various pathophysiological pathways is essential to unravel the complex nature of the disease process and identify potential therapeutic targets. The renin-angiotensin system (RAS) has been implicated in several brain diseases, including traumatic brain injury, ischemic stroke, and AD. Objective: This study was designed to evaluate the protein expression levels of RAS components in postmortem cortical and hippocampal brain samples obtained from AD versus non-AD individuals. Methods: We analyzed RAS components in the cortex and hippocampus of postmortem human brain samples by western blotting and immunohistochemical techniques in comparison with age-matched non-demented controls. Results: The expression of AT1R increased in the hippocampus, whereas AT2R expression remained almost unchanged in the cortical and hippocampal regions of AD compared to non-AD brains. The Mas receptor was downregulated in the hippocampus. We also detected slight reductions in ACE-1 protein levels in both the cortex and hippocampus of AD brains, with minor elevations in ACE-2 in the cortex. We did not find remarkable differences in the protein levels of angiotensinogen and Ang II in either the cortex or hippocampus of AD brains, whereas we observed a considerable increase in the expression of brain-derived neurotrophic factor in the hippocampus. Conclusion: The current findings support the significant contribution of RAS components in AD pathogenesis, further suggesting that strategies focusing on the AT1R and AT2R pathways may lead to novel therapies for the management of AD.

Anna E. Bruus, Gunhild Waldemar, Asmus Vogel
Impairment of Episodic-Specific Autobiographical Memory in Individuals with Subjective Cognitive Decline and in Patients with Prodromal or Mild Alzheimer’s Disease
Abstract: Background: Autobiographical memory (AM) is a personal form of memory that becomes impaired in the early, clinical stages of Alzheimer’s disease (AD). In the “preclinical” phase of AD, neuropathological hallmarks are present (especially in a brain network underpinning AM), but performance on standardized neuropsychological tests is normal. Even so, some patients have subjective cognitive decline (SCD). Objective: The aim was to 1) investigate AM performance on two tests with different approaches in SCD, and in prodromal and mild AD, and 2) examine the association between the AM tests. Methods: We included 17 SCD patients with heightened risk of AD, 17 amnestic mild cognitive impairment (aMCI) patients, 17 patients with mild dementia due to AD, and 30 healthy controls. Patients were diagnosed according to international criteria, and all participants had MMSE scores ≥24. AM was assessed using the Columbia Autobiographical Memory Interview-Short Form (CAMI-SF) and the Three Events Test. These tests measure the production of contextual details. Results: Significant group effects were found for the Three Events Test and the CAMI-SF. All patient groups produced significantly fewer contextual details than the controls on the Three Events Test. On CAMI-SF, the aMCI and mild AD groups were able to answer fewer questions or gave significantly less detailed answers than the other groups. The SCD patients performed below the controls on CAMI-SF, but the difference was not significant. Conclusion: AM may be impaired in very early AD, even in the phases where standardized episodic memory tests show no decline.

Mehdi Shojaie, Solale Tabarestani, Mercedes Cabrerizo, Steven T. DeKosky, David E. Vaillancourt, David Loewenstein, Ranjan Duara, Malek Adjouadi
PET Imaging of Tau Pathology and Amyloid-β, and MRI for Alzheimer’s Disease Feature Fusion and Multimodal Classification
Abstract: Background: Machine learning is a promising tool for biomarker-based diagnosis of Alzheimer’s disease (AD). Performing multimodal feature selection and studying the interaction between biological and clinical AD can help to improve the performance of the diagnosis models. Objective: This study aims to formulate a feature ranking metric based on the mutual information index to assess the relevance and redundancy of regional biomarkers and improve the AD classification accuracy. Methods: From the Alzheimer’s Disease Neuroimaging Initiative (ADNI), 722 participants with three modalities, including florbetapir-PET, flortaucipir-PET, and MRI, were studied. The multivariate mutual information metric was utilized to capture the redundancy and complementarity of the predictors and develop a feature ranking approach. This was followed by evaluating the capability of single-modal and multimodal biomarkers in predicting the cognitive stage. Results: Although amyloid-β deposition is an earlier event in the disease trajectory, tau PET with feature selection yielded a higher early-stage classification F1-score (65.4%) compared to amyloid-β PET (63.3%) and MRI (63.2%). The SVC multimodal scenario with feature selection improved the F1-score to 70.0% and 71.8% for the early and late-stage, respectively. When age and risk factors were included, the scores improved by 2 to 4%. The Amyloid-Tau-Neurodegeneration [AT(N)] framework helped to interpret the classification results for different biomarker categories. Conclusion: The results underscore the utility of a novel feature selection approach to reduce the dimensionality of multimodal datasets and enhance model performance. The AT(N) biomarker framework can help to explore the misclassified cases by revealing the relationship between neuropathological biomarkers and cognition.

Chiara C. Brück, Frank J. Wolters, M. Arfan Ikram, Inge M.C.M. de Kok
Heterogeneity in Reports of Dementia Disease Duration and Severity: A Review of the Literature
Abstract: Background: The burden of dementia is changing due to population aging and changes in incidence and risk factor profiles. Reliable projections of future disease burden require accurate estimates of disease duration across different stages of dementia severity. Objective: To provide an overview of current evidence on severity stage and disease duration in patients with dementia. Methods: We reviewed the literature on duration of mild cognitive impairment (MCI), dementia, and various dementia severity stages. Data on study setting, country, sample size, severity stages, dementia type, and definition of disease duration was collected. Weighted averages and Q-statistics were calculated within severity stages and duration definitions. Results: Of 732 screened articles, 15 reported the duration of one or more severity stages and only half of those reported severity stage onset to conversion to the following stage. In those studies, MCI, very mild dementia, and mild dementia stages lasted 3-4 years and moderate and severe dementia stages lasted 1-2 years. Information on the disease duration was reported in 93 (13%) of screened articles and varied from 1 to 17 years. Reporting of dementia severity stage and disease duration in the literature was highly heterogeneous, which was accounted for only in part by dementia type, study setting, or continent of data collection. Conclusion: The duration of dementia disease stages shortens with advancing stage. However, reliable modelling of future dementia burden and informing of intervention strategies will require more consistently reported duration estimates from studies that follow individuals longitudinally throughout their entire disease course.

Andreja Speh, Rui Wang, Bengt Winblad, Milica G. Kramberger, Lars Bäckman, Chengxuan Qiu, Erika J. Laukka
The Relationship Between Cardiovascular Health and Rate of Cognitive Decline in Young-Old and Old-Old Adults: A Population-Based Study
Abstract: Background: Modifiable vascular risk factors have been associated with late-life cognitive impairment. The Life Simple 7 (LS7) score comprises seven cardiovascular health metrics: smoking, diet, physical activity, body mass index, plasma glucose, total serum cholesterol, and blood pressure. Objective: To investigate the association between individual and composite LS7 metrics and rate of cognitive decline, and potential differences in these associations between young-old and old-old individuals. Methods: This cohort study included 1,950 participants aged ≥60 years (M = 70.7 years) from the Swedish National Study on Aging and Care-Kungsholmen (SNAC-K), who underwent repeated neuropsychological testing (episodic and semantic memory, verbal fluency, processing speed, global cognition) across 12 years. The LS7 score was assessed at baseline and categorized as poor, intermediate, or optimal. Level and change in cognitive performance as a function LS7 categories were estimated using linear mixed-effects models. Results: Having an optimal LS7 total score was associated with better performance (expressed in standard deviation units) at baseline for perceptual speed (β = 0.21, 95% CI 0.12-0.29), verbal fluency (β = 0.08, 0.00-0.16), and global cognition (β = 0.06, 0.00-0.12) compared to the poor group. Age-stratified analyses revealed associations for cognitive level and change only in the young-old (< 78 years) group. For the specific metrics, diverging patterns were observed for young-old and old-old individuals. Conclusion: Meeting the LS7 criteria for ideal cardiovascular health in younger old age is associated with slower rate of cognitive decline. However, the LS7 criteria may have a different meaning for cognitive function in very old adults.

Meghan K. Mattos, Carol A. Manning, Mark Quigg, Eric M. Davis, Laura Barnes, Ann Sollinger, Michelle Eckstein, Lee M. Ritterband Handling Associate Editor: Tania Alves)
Feasibility and Preliminary Efficacy of an Internet-Delivered Intervention for Insomnia in Individuals with Mild Cognitive Impairment
Abstract: Background: Approximately 50% of older adults with cognitive impairment suffer from insomnia. When untreated, pre-existing cognitive problems may be exacerbated and potentially contribute to further cognitive decline. One promising approach to maintain cognitive health is to improve sleep quantity and quality. Objective: To determine feasibility, acceptability, and preliminary efficacy of Sleep Health Using the Internet for Older Adult Sufferers of Insomnia and Sleeplessness (SHUTi OASIS), an Internet-delivered cognitive behavioral therapy for insomnia (CBT-I) program in older adults with mild cognitive impairment (MCI). Methods: Older adults with MCI and insomnia were recruited from hospital-based memory and sleep disorders clinics and enrolled in a single-arm pilot study. Participants completed the six cores of SHUTi OASIS, over nine weeks with two-week baseline and post-assessments using self-reported sleep diaries. Feasibility and acceptability were informed by usage statistics and qualitative interviews; preliminary efficacy was informed by patient-generated sleep data. Results: Twelve participants enrolled and, on average, were 75.8 years of age. Ten participants completed the study and logged in most days. Most participants reported a positive overall experience, and interviews revealed successful and independent program management and completion. There were significant changes on all baseline to post-assessment sleep measures, including clinically meaningful improvements on the Insomnia Severity Index (13.5 to 8.3, p < 0.01), sleep efficiency, wake after sleep onset, and sleep onset latency (ps < 0.02). There was no statistically significant change in cognitive measures (p > 0.05). Conclusion: This study supports that older adults with cognitive impairment can independently complete CBT-I via the Internet and achieve clinical sleep improvements.

Fanglei Han, Jia Zhao, Guoqing Zhao
Prolonged Volatile Anesthetic Exposure Exacerbates Cognitive Impairment and Neuropathology in the 5xFAD Mouse Model of Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease which shows a set of symptoms involving cognitive changes and psychological changes. Given that AD is the most common form of dementia in aging population and the increasing demand for anesthesia/surgery with aging, there has been significant interest in the exact impact of volatile anesthetics on cognitive function and pathological alterations in AD population. Objective: This study aimed to investigate behavioral changes and neuropathology in the 5xFAD mouse model of Alzheimer’s disease with short-term exposure or long-term exposure to desflurane, sevoflurane, or isoflurane. Methods: In this study, we exposed 5xFAD mouse model of AD to isoflurane, sevoflurane, or desflurane in two different time periods (30 min and 6 h), and the memory related behaviors as well as the pathological changes in 5xFAD mice were evaluated 7 days after the anesthetic exposure. Results: We found that short-term exposure to volatile anesthetics did not affect hippocampus dependent memory and the amyloid-β (Aβ) deposition in the brain. However, long-term exposure to sevoflurane or isoflurane significantly increased the Aβ deposition in CA1 and CA3 regions of hippocampus, as well as the glial cell activation in amygdala. Besides, the PSD-95 expression was decreased in 5xFAD mice with exposure to sevoflurane or isoflurane and the caspase-3 activation was enhanced in isoflurane, sevoflurane, and desflurane groups. Conclusion: Our results demonstrate the time-dependent effects of common volatile anesthetics and implicate that desflurane has the potential benefits to prolonged anesthetic exposure in AD patients.

James E. Galvin, Stephanie Chrisphonte, Lun-Ching Chang
Medical and Social Determinants of Brain Health and Dementia in a Multicultural Community Cohort of Older Adults
Abstract: Background: Socioeconomic status (SES), race, ethnicity, and medical comorbidities may contribute to Alzheimer’s disease and related disorders (ADRD) health disparities. Objective: Analyze effects of social and medical determinants on cognition in 374 multicultural older adults participating in a community-based dementia screening program. Methods: We used the Montreal Cognitive Assessment (MoCA) and AD8 as measures of cognition, and a 3-way race/ethnicity variable (White, African American, Hispanic) and SES (Hollingshead index) as predictors. Potential contributors to health disparities included: age, sex, education, total medical comorbidities, health self-ratings, and depression. We applied K-means cluster analyses to study medical and social dimension effects on cognitive outcomes. Results: African Americans and Hispanics had lower SES status and cognitive performance compared with similarly aged Whites. We defined three clusters based on age and SES. Cluster #1 and #3 differed by SES but not age, while cluster #2 was younger with midlevel. Cluster #1 experienced the worse health outcomes while cluster #3 had the best health outcomes. Within each cluster, White participants had higher SES and better health outcomes, African Americans had the worst physical performance, and Hispanics had the most depressive symptoms. In cross-cluster comparisons, higher SES led to better health outcomes for all participants. Conclusion: SES may contribute to disparities in access to healthcare services, while race and ethnicity may contribute to disparities in the quality and extent of services received. Our study highlights the need to critically address potential interactions between race, ethnicity, and SES which may better explain disparities in ADRD health outcomes.

Vania Karami, Giulio Nittari, Enea Traini, Francesco Amenta
An Optimized Decision Tree with Genetic Algorithm Rule-Based Approach to Reveal the Brain’s Changes During Alzheimer’s Disease Dementia
Abstract: Background: It is desirable to achieve acceptable accuracy for computer aided diagnosis system (CADS) to disclose the dementia-related consequences on the brain. Therefore, assessing and measuring these impacts is fundamental in the diagnosis of dementia. Objective: This study introduces a new CADS for deep learning of magnetic resonance image (MRI) data to identify changes in the brain during Alzheimer’s disease (AD) dementia. Methods: The proposed algorithm employed a decision tree with genetic algorithm rule-based optimization to classify input data which were extracted from MRI. This pipeline is applied to the healthy and AD subjects of the Open Access Series of Imaging Studies (OASIS). Results: Final evaluation of the CADS and its comparison with other systems supported the potential of the proposed model as a novel tool for investigating the progression of AD and its great ability as an innovative computerized help to facilitate the decision-making procedure for the diagnosis of AD. Conclusion: The one-second time response, together with the identified high accurate performance, suggests that this system could be useful in future cognitive and computational neuroscience studies.

Cristina Udina, Emmeline Ayers, Marco Inzitari, Joe Verghese (Handling Associate Editor: Marco Canevelli)
Walking While Talking and Prefrontal Oxygenation in Motoric Cognitive Risk Syndrome: Clinical and Pathophysiological Aspects
Abstract: Background: Motoric cognitive risk syndrome (MCR) combines slow gait and cognitive complaints and has been proposed as a predementia syndrome. The nature of dual-task performance in MCR has not been established. Objective: To assess differences in dual-task performance between participants with and without MCR and to study the prefrontal cortex (PFC)-based brain activity during dual-task using functional near-infrared spectroscopy. Methods: Cohort study of community-dwelling non-demented older adults included in the “Central Control of Mobility in Aging” study. Comprehensive assessment included global cognition and executive function tests along with clinical variables. Dual-task paradigm consisted in walking while reciting alternate letters of the alphabet (WWT) on an electronic walkway. We compared dual-task performance between MCR (n=60) and No MCR (n=478) participants and assessed the relationship of dual-task performance with cognitive function. In a subsample, we compared PFC oxygenation during WWT between MCR (n=32) and No MCR (n=293). Results: In our sample of 538 high-functioning older adults (76.6±6.5 years), with 11.2% prevalence of MCR, dual-task cost was not significantly different, compared to No MCR participants. Among MCR participants, no significant relationship was found between WWT velocity and cognitive function, whereas No MCR participants with better cognitive function showed faster WWT velocities. PFC oxygenation during WWT was higher in MCR compared to No MCR (1.02 ± 1.25 versus 0.66 ± 0.83, p=0.03). Conclusion: MCR participants showed no significant differences in the dual-task cost while exhibiting higher PFC oxygenation during dual-task walking. The dual-task performance (WWT velocity) in MCR participants was not related to cognition.

Nhi Hin, Morgan Newman, Stephen Pederson, Michael Lardelli
Iron Responsive Element-Mediated Responses to Iron Dyshomeostasis in Alzheimer’s Disease
Abstract: Background: Iron trafficking and accumulation is associated with Alzheimer’s disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterized, making it difficult to explore these in existing datasets. Objective: To identify sets of genes predicted to contain iron responsive elements (IREs) and use these to explore possible iron dyshomeostasis-associated gene expression responses in AD. Methods: Comprehensive sets of genes containing predicted IRE or IRE-like motifs in their 3’ or 5’ untranslated regions (UTRs) were identified in human, mouse, and zebrafish reference transcriptomes. Further analyses focusing on these genes were applied to a range of cultured cell, human, mouse, and zebrafish gene expression datasets. Results: IRE gene sets are sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, changes in IRE transcript abundance are among the earliest observable changes in zebrafish familial AD (fAD)-like brains, preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some IREs in the 3’ untranslated regions of transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead display decreased stability, indicating that this is not a generalizable paradigm. Conclusion: Our results reveal IRE gene expression changes as early markers of the pathogenic process in fAD and are consistent with iron dyshomeostasis as an important driver of this disease. Our work demonstrates how differences in the stability of IRE-containing transcripts can be used to explore and compare iron dyshomeostasis-associated gene expression responses across different species, tissues, and conditions.

Julia Schneider, Jennifer Miller, Winfried Teschauer, Andreas Kruse, Birgit Teichmann (Handling Associate Editor: Jochen René Thyrian)
Evaluation and Effectiveness of a Two-Day Dementia Training Program for Hospital Staff Working in an Emergency Department
Abstract: Background: Entering the hospital via an emergency department (ED) is a pivotal moment in the life of people with dementia (PwD) and often starts an avoidable downward spiral. Therefore, it is required to further educate ED staff to raise awareness of the needs of PwD. Although there are many studies about existing dementia training programs for the hospital setting, empirical evidence for the ED setting and cross-level training evaluations are lacking. Objective: The study aims to evaluate a two-day dementia training course for ED staff on the outcome levels of learning, individual performance, and organizational performance. Furthermore, the study examines whether the training fulfilled participants’ expectations. Methods: Mixed methods were used to assess data from head nurses, nursing, and administrative staff working in EDs. We conducted semi-structured interviews three weeks before (N = 18) and eight months after (N = 9) the training. Questionnaire data were assessed before the training, three months, and six months after the training (N = 44). A qualitative content analysis was conducted to analyze qualitative data; quantitative data was described descriptively. Results: The intervention seems to be effective on both learning and individual performance levels. However, we did not observe any changes in the organizational performance. The training program met attendees’ expectations only partly. The working environment of EDs needs to be taken more into account. Conclusion: Hospital staffs’ expectations of a dementia training program depend on the work area in which they operate. Results support the implementation of intervention bundles to enable sustainable cross-level changes.

Hui Jin Ryu, Yeonsil Moon, Minyoung Kim, Hee-Jin Kim, James E. Galvin, Seol-Heui Han (Handling Associate Editor: Sang Won Seo)
Validation of the Korean Quick Dementia Rating System (K-QDRS)
Abstract: Background: The Quick Dementia Rating System (QDRS) is a brief and rapid dementia staging tool that does not require a trained rater. Objective: The purpose of this study is to demonstrate the validity, reliability, and diagnostic usefulness of the Korean version of the QDRS (K-QDRS). Methods: We collected a total of 411 subject-informant dyads including cognitively unimpaired (CU, n=22), mild cognitive impairment (MCI, n=198), and dementia (n=191). The Clinical Dementia Rating (CDR) scale, Korean version of the Mini-Mental State Examination (K-MMSE), Korean version of instrumental activity of daily living (K-IADL), Short Form of the Geriatric Depression Scale, Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI), and detailed neuropsychological tests were administered as gold standards of dementia staging, cognition, function, mood, and behavior. Results: Internal consistency of the K-QDRS was excellent with Cronbach's alpha of 0.933. Concurrent validity was also satisfactory, with the K-QDRS correlating highly with the CDR Sum of Boxes (Pearson's r = 0.791), K-MMSE (Pearson's r = -0.518), K-IADL (Pearson's r = 0.727), and CGA-NPI (Pearson's r = 0.700). The K-QDRS was highly correlated with the global CDR, K-IADL, and CGA-NPI. We suggested two types of comparisons (for initial diagnosis and for follow-up evaluation). The cutoff scores for follow-up were 1.0 for MCI, 3.5 for very mild dementia, 6.5 for mild dementia, and 11.0 for moderate dementia. Conclusion: The K-QDRS is a valid and reliable dementia rating questionnaire and can be used, briefly and rapidly, in various settings like clinical practices, longitudinal cohort studies, and community primary care.

Jinghuan Gan*, Shuai Liu*, Xiao-Dan Wang, Wenzheng Hu, Yang Lv, Jianping Niu, Xinling Meng, Yongjie Chen, Zhihong Shi, Yong Ji *These authors contributed equally to this work.
The Association Between Hyperhidrosis and Dementia: A Community-Based Research
Abstract: Background: Dementia and hyperhidrosis (HH) are common in the elderly while there is little research to investigate the association between them. Objective: To clarify a possible association between HH and dementia in population of adults ≥65 years old in China. Methods: A cross-sectional survey for elderly adults ≥65 years old was conducted from April to December 2019. A total of 5,958 participants were analyzed after two phases investigation. Goodness-of-fit tests (Pearson and deviance) were used to estimate the dispersion parameter and examine the adequacy of the models. Logistic and linear regression analyses were used to evaluate the association between HH and dementia. Results: The overall prevalence of all-cause dementia was 10.17%, that of dementia with Lewy bodies (DLB) was 1.41%, and HH was 14.97%. Prevalence rates of HH were higher in participants with dementia and DLB. There was a significant positive relationship between HH duration and MMSE score (r = 0.207, p < 0.001, Durbin-Watson test = 1.806). Participants with HH were 1.275 (95% CI: 1.015–1.601, p = 0.037) times to have dementia, and 3.616 (95% CI: 2.267–5.767, p < 0.001) times to suffer from DLB than those without HH. Pearson and deviance chi square tests did not indicate overdispersion (p > 0.05 in the logistic regression models). Conclusion: HH was common in the Chinese population ≥65 years old. It can increase the risk of dementia, particularly in DLB, in the elderly. It is important to improve the awareness of HH among dermatologists and neurologists.

Minna Rusanen, Tuomas Selander, Virve Kärkkäinen, Anne Koivisto (Handling Associate Editor: Silke Kuske)
The Positive Effects of Pet Ownership on Alzheimer’s Disease
Abstract: Background: Human-animal interactions are known to have many beneficial psychosocial and psychophysiological effects on persons with and without medical health conditions. There are no previous prospective studies with long follow-up times on the effects of domestic pets on the persons with Alzheimer’s disease (AD) living at home. Objective: To investigate the effects of pets on the activities of daily living (ADL), disease progression, and neuropsychiatric symptoms (NPS) during a five-year follow-up on the persons with AD. Methods: Altogether 223 home-dwelling persons (mean age 75.2 years) with very mild (CDR 0.5) or mild (CDR 1) AD at baseline were included for this study. ADCS-ADL, NPI, MMSE, and CDR-SOB were measured at baseline, annually for three years and after five years. Results: Totally 40 (17.9%) participants had a pet. At the baseline, pet owners and non-pet owners had no significant differences in age, gender, or the ADCS-ADL, NPS, and CDR-SOB scores, while MMSE was lower in pet owners than non-pet owners (20.2 versus 21.7; p=0.009). Over the follow-up, pet owners had significantly better mean ADCS-ADL (57.5 versus 54.0; p=0.031), NPI (9.3 versus 13.0; p=0.038), and CDR-SOB scores (5.7 versus 6.6; p=0.004) compared to non-pet owners. The differences in the MMSE scores between the groups detected at baseline attenuated over time. Conclusion: Significant positive effects of the pets on ADL functions, NPS, and disease progression were detected over the whole follow-up suggesting that having a pet may support daily activity and slow the disease progression in AD.

Jolanta Upīte*, Thomas Brüning*, Luisa Möhle, Mirjam Brackhan, Pablo Bascuñana, Baiba Jansone, Jens Pahnke (Handling Associate Editor: Ragnhild Østerhus) *These authors contributed equally to this work.
A New Tool for the Analysis of the Effect of Intracerebrally Injected Anti-Amyloid-β Compounds
Abstract: Background: A wide range of techniques has been developed over the past decades to characterize amyloid-β (Aβ) pathology in mice. Until now, no method has been established to quantify spatial changes in Aβ plaque deposition due to targeted delivery of substances using ALZET® pumps. Objective: Development of a methodology to quantify the local distribution of Aβ plaques after intracerebral infusion of compounds. Methods: We have developed a toolbox to quantify Aβ plaques in relation to intracerebral injection channels using Zeiss AxioVision® and Microsoft Excel® software. For the proof of concept, intracerebral stereotactic surgery was performed in 50-day-old APP-transgenic mice injected with PBS. At the age of 100 days, brains were collected for immunhistological analysis. Results: The toolbox can be used to analyze and evaluate Aβ plaques (number, size, and coverage) in specific brain areas based on their location relative to the point of the injection or the injection channel. The tool provides classification of Aβ plaques in pre-defined distance groups using two different approaches. Conclusion: This new analytic toolbox facilitates the analysis of long-term continuous intracerebral experimental compound infusions using ALZET® pumps. This method generates reliable data for Aβ deposition characterization in relation to the distribution of experimental compounds.

Andrew J. Petkus, Diana Younan, Xinhui Wang, Daniel P. Beavers, Mark A. Espeland, Margaret Gatz, Tara Gruenewald, Joel D. Kaufman, Helena C. Chui, Joshua Millstein, Stephen R. Rapp, JoAnn E. Manson, Susan M. Resnick, Gregory A. Wellenius, Eric A. Whitsel, Keith Widaman, Jiu-Chiuan Chen (Handling Associate Editor: Andrea Zammit)
Associations Between Air Pollution Exposure and Empirically Derived Profiles of Cognitive Performance in Older Women
Abstract: Background: Elucidating associations between exposures to ambient air pollutants and profiles of cognitive performance may provide insight into neurotoxic effects on the aging brain. Objective: We examined associations between empirically derived profiles of cognitive performance and residential concentrations of particulate matter of aerodynamic diameter < 2.5 (PM2.5) and nitrogen dioxide (NO2) in older women. Method: Women (N=2,142) from the Women’s Health Initiative Study of Cognitive Aging completed a neuropsychological assessment measuring attention, visuospatial, language, and episodic memory abilities. Average yearly concentrations of PM2.5 and NO2 were estimated at the participant’s addresses for the 3 years prior to the assessment. Latent profile structural equation models identified subgroups of women exhibiting similar profiles across tests. Multinomial regressions examined associations between exposures and latent profile classification, controlling for covariates. Result: Five latent profiles were identified: low performance across multiple domains (poor multi-domain; n=282;13%), relatively poor verbal episodic memory (poor memory; n=216; 10%), average performance across all domains (average multi-domain; n=974; 45%), superior memory (n=381; 18%), and superior attention (n=332; 15%). Using women with average cognitive ability as the referent, higher PM2.5 (per interquartile range [IQR]=3.64 μg/m3) was associated with greater odds of being classified in the poor memory (OR=1.29; 95% Confidence Interval [CI]=1.10-1.52) or superior attention (OR=1.30; 95%CI=1.10-1.53) profiles. NO¬2 (per IQR=9.86 ppb) was associated with higher odds of being classified in the poor memory (OR=1.38; 95%CI=1.17-1.63) and lower odds of being classified with superior memory (OR=0.81; 95%CI=0.67-0.97). Conclusion: Exposure to PM2.5 and NO2 are associated with patterns of cognitive performance characterized by worse verbal episodic memory relative to performance in other domains.

Hee-Jeong Jeong, Young-Min Lee, Je-Min Park, Byung-Dae Lee, Eunsoo Moon, Hwagyu Suh, Hak-Jin Kim, Kyoungjune Pak, Kyung-Un Choi, Young-In Chung
Reduced Thickness of the Anterior Cingulate Cortex as a Predictor of Amnestic-Mild Cognitive Impairment Conversion to Alzheimer’s Disease with Psychosis
Abstract: Background: A long-term follow-up study in patients with amnestic mild cognitive impairment (aMCI) is needed to elucidate the association between regional brain volume and psychopathological mechanisms of Alzheimer’s disease with psychosis (AD+P). Objective: The purpose of this study was to investigate the effect of the thickness of the angular cingulate cortex (ACC) on the risk of AD+P conversion in patients with aMCI. Methods: This was a hospital-based prospective longitudinal study including 174 patients with aMCI. The main outcome measure was time-to-progression from aMCI to AD+P. Subregions of the ACC (rostral ACC, rACC; caudal ACC, cACC) and hippocampus (HC) were measured as regions of interest with magnetic resonance imaging and the Freesurfer analysis at baseline. Survival analysis with time to incident AD+P as an event variable was calculated with Cox proportional hazards models using the subregions of the ACC and HC as a continuous variable. Results: Cox proportional hazard analyses showed that the risk of AD+P was associated with sub-regional ACC thickness but not HC volume: reduced cortical thickness of the left cACC (HR [95% CI], 0.224 [0.087–0.575], p = 0.002), right cACC (HR [95% CI], 0.318 [0.132–0.768], p = 0.011). This association of the cACC with the risk of AD also remained significant when adjusted for HC volume. Conclusion: We found that reduced cortical thickness of the cACC is a predictor of aMCI conversion to AD+P, independent of HC, suggesting that the ACC plays a vital role in the underlying pathogenesis of AD+P.

Keita Sakurai, Tamaki Iwase, Daita Kaneda, Yuto Uchida, Shohei Inui, Satoru Morimoto, Yasuyuki Kimura, Takashi Kato, Takashi Nihashi, Kengo Ito, Yoshio Hashizume (Handling Associate Editor: Nils Richter)
Sloping Shoulders Sign: A Practical Radiological Sign for the Differentiation of Alzheimer’s Disease and Argyrophilic Grain Disease
Abstract: Background: Although hippocampal atrophy is a well-known imaging biomarker of Alzheimer’s disease (AD), this finding is not useful to differentiate AD from argyrophilic grain disease (AGD) which is a common AD mimicker presenting with similar amnestic symptoms and medial temporal atrophy. Instead, we propose use of the “sloping shoulders sign”, defined as a distinct configuration of the bilateral hippocampal heads showing lateral and downward slopes on axial magnetic resonance imaging (MRI). Objective: We investigated the diagnostic utility of the “sloping shoulders sign” as a simple radiological discriminator of AD from AGD. Methods: Using axial and coronal three-dimensional MRI, our newly proposed “sloping shoulders sign”, other quantitative indices including the axial hippocampal head angle (AHHA), and well-known medial temporal atrophy (MTA) score were evaluated in pathologically-proven advanced-stage 24 AD and 11 AGD patients. Results: Detection rate of the “sloping shoulders sign” was significantly higher in all AD groups (83%; 20/24) and AD with Braak neurofibrillary tangle V/VI stage subgroup (88%; 15/17) than in AGD patients (18% - 2/11; p < 0.001 and p < 0.001, respectively). In contrast to the MTA score, this sign as well as AHHA demonstrated higher diagnostic performance and reproducibility, especially to differentiate all AD patients from AGD ones (accuracies of 71.4%, 82.9% and 82.9%; Cohen’s kappa of 0.70 and 0.81, and intraclass correlation coefficient of 0.96, respectively). Conclusion: The “sloping shoulders sign” is useful to differentiate advanced-stage AD from AGD. Its simplicity and reproducibility based on visual inspection using axial MRI make it suitable for routine clinical practice.

James E. Galvin, Michael J. Kleiman, Stephanie Chrisphonte, Iris Cohen, Shanell Disla, Conor B. Galvin, Keri K. Greenfield, Claudia Moore, Susan Rawn, Mary Lou Riccio, Amie Rosenfeld, Judith Simon, Marcia Walker, Magdalena I. Tolea
The Resilience Index: A Quantifiable Measure of Brain Health and Risk of Cognitive Impairment and Dementia
Abstract: Background: There is increasing interest in lifestyle modification and integrative medicine approaches to treat and/or prevent mild cognitive impairment (MCI) and Alzheimer’s disease and related dementias (ADRD). Objective: To address the need for a quantifiable measure of brain health, we created the Resilience Index (RI). Methods: This cross-sectional study analyzed 241 participants undergoing a comprehensive evaluation including the Clinical Dementia Rating and neuropsychological testing. Six lifestyle factors including physical activity, cognitive activity, social engagements, dietary patterns, mindfulness, and cognitive reserve were combined to derive the RI (possible range of scores: 1-378). Psychometric properties were determined. Results: The participants (39 controls, 75 MCI, 127 ADRD) had a mean age of 74.6 ± 9.5 years and a mean education of 15.8 ± 2.6 years. The mean RI score was 138.2 ± 35.6. The RI provided estimates of resilience across participant characteristics, cognitive staging, and ADRD etiologies. The RI showed moderate-to-strong correlations with clinical and cognitive measures and very good discrimination (AUC: 0.836; 95%CI: 0.774-0.897) between individuals with and without cognitive impairment (diagnostic odds ratio=8.9). Individuals with high RI scores (>143) had better cognitive, functional, and behavioral ratings than individuals with low RI scores. Within group analyses supported that controls, MCI, and mild ADRD cases with high RI had better cognitive, functional, and global outcomes than those with low RI. Conclusion: The RI is a brief, easy to administer, score and interpret assessment of brain health that incorporates six modifiable protective factors. Results from the RI could provide clinicians and researchers with a guide to develop personalized prevention plans to support brain health.

Avik Roy, Madhuchhanda Kundu, Sudipta Chakrabarti, Dhruv R. Patel, Kalipada Pahan
Oleamide, a Sleep-Inducing Supplement, Upregulates Doublecortin in Hippocampal Progenitor Cells via PPARα
Abstract: Background: Doublecortin (DCX), a microtubule associated protein, has emerged as a central biomarker of hippocampal neurogenesis. However, molecular mechanisms by which DCX is regulated are poorly understood. Objective: Since sleep is involved with the acquisition of memory and oleamide or 9-Octadecenamide (OCT) is a sleep-inducing supplement in human, we examined whether OCT could upregulate DCX in hippocampal progenitor cells (HPCs). Methods: We employed real-time PCR, western blot, immunostaining, chromatin immunoprecipitation, lentiviral transduction in HPCs, and the calcium influx assay. Results: OCT directly upregulated the transcription of Dcx in HPCs via activation of peroxisome proliferator-activated receptor α (PPARα), a lipid-lowering transcription factor. We observed that, HPCs of Ppara-null mice displayed significant impairment in DCX expression and neuronal differentiation as compared to that of wild-type mice. Interestingly, treatment with OCT stimulated the differentiation process of HPCs in wild-type, but not Ppara-null mice. Reconstruction of PPARα in mouse Ppara-null HPCs restored the expression of DCX, which was further stimulated with OCT treatment. In contrast, a dominant-negative mutant of PPARα significantly attenuated the stimulatory effect of OCT on DCX expression and suppressed neuronal differentiation of human neural progenitor cells. Furthermore, RNA microarray, STRING, chromatin immunoprecipitation, site-directed mutagenesis, and promoter reporter assay have identified DCX as a new target of PPARα. Conclusion: These results indicate that OCT, a sleep supplement, directly controls the expression of DCX and suggest that OCT may be repurposed for stimulating the hippocampal neurogenesis.

Erin E. Sundermann, Lisa L. Barnes, Mark W. Bondi, David A. Bennett, David P. Salmon, Pauline M. Maki
Improving Detection of Amnestic Mild Cognitive Impairment with Sex-Specific Cognitive Norms
Abstract: Background: Despite a female advantage in verbal memory, normative data for verbal memory tests used to diagnose Alzheimer’s disease (AD) dementia and amnestic mild cognitive impairment (aMCI) often are not sex-adjusted. Objective: To determine whether sex-adjusted norms improve aMCI diagnostic accuracy when accuracy was evaluated by progression to AD dementia over time. Methods: Non-sex-specific and sex-specific verbal memory test norms were incorporated into Jak/Bondi aMCI criteria and applied to older (age 65-90) non-demented women (N=1,036) and men (N=355) from the Rush Memory and Aging Project. Using sex-specific aMCI diagnosis as the “true” condition versus non-sex-specific aMCI diagnosis as the “predicted” condition, we identified True Positives, False Positives, True Negatives, and False Negatives and compared AD dementia risk over 10 years among groups. Results: Rates of aMCI were higher in men versus women (χ2=15.39, p<0.001) when determined based on typical diagnostic criteria, but this difference reversed when using sex-specific diagnostic criteria (χ2=8.38, p=0.004). We identified 8% of women as False Negatives and 12% of men as False Positives. Risk of incident AD dementia in False Positive men was significantly lower than in True Positive men (HR=0.26, 95%CI=0.12-0.58, p=0.001). Risk of incident AD dementia in False Negative women was substantially higher than in True Negative women (HR=3.11, 95%CI=2.09-4.63, p<0.001). Conclusion: Results suggest that previous reports of higher aMCI rates in men versus women may be an artifact of non-sex-adjusted norms/cut-scores. Incorporation of sex-specific norms/cut-scores for verbal memory impairment into aMCI diagnostic criteria may improve diagnostic accuracy and avoid diagnostic errors in approximately 20%.

Min Chu*, Li Liu*, Jingjuan Wang, Lin Liu, Yu Kong, Donglai Jing, Kexin Xie, Yue Cui, Bo Cui, Jing Zhang, Hong Ye, Junjie Li, Lin Wang, Pedro Rosa-Neto, Serge Gauthier, Liyong Wu *These authors contributed equally to this work.
Investigating the Roles of Anterior Cingulate in Behavior-Variant Frontotemporal Dementia: A PET/MRI Study
Abstract: Background: The anterior cingulate cortex (ACC) seems to play an important role in behavioral deficits and executive dysfunctions in patients with behavior-variant frontotemporal dementia (bvFTD), while its specific and independent contribution requires clarification. Objective: To identify whether ACC abnormalities in gray matter (GM) volume and standardized uptake value ratio (SUVR) images are associated with disease severity of bvFTD, by analyzing hybrid T1 and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET). Methods: We enrolled 21 bvFTD patients and 21 healthy controls in the study. Each subject underwent a hybrid PET/MRI study and a standardized neuropsychologic assessment battery. GM volume and SUVR are voxel-wise calculated and compared. Then we estimate the mean value inside ACC for further partial Pearson’s correlation to explore the association between GM volume/SUVR of the ACC and severity of behavioral deficit as well as executive dysfunction. Results: ACC was shown to be involved in both atrophy and hypometabolism patterns. The partial Pearson’s correlation analysis showed that the SUVR of the ACC was strongly correlated with frontal behavior inventory total score (left r = −0.85, right r = −0.85, p < 0.0001), disinhibition subscale score (left r = −0.72, p = 0.002; right = −0.75, p < 0.0001), and apathy subscale score (left = −0.87, right = −0.85, p < 0.0001). Conclusion: These findings demonstrated decreased ACC activity contributes to behavioral disturbances of both apathetic and disinhibition syndromes of bvFTD, which can be sensitively detected using 18F-FDG PET.

Christiana Bjorkli, Claire Louet, Trude Helen Flo, Mary Hemler, Axel Sandvig, Ioanna Sandvig
In Vivo Microdialysis in Mice Captures Changes in Alzheimer’s Disease Cerebrospinal Fluid Biomarkers Consistent with Developing Pathology
Abstract: Background: Preclinical models of Alzheimer’s disease (AD) can provide valuable insights into the onset and progression of the disease, such as changes in concentrations of amyloid-β (Aβ) and tau in cerebrospinal fluid (CSF). However, such models are currently underutilized due to limited advancement in techniques that allow for longitudinal CSF monitoring. Objective: An elegant way to understand the biochemical environment in the diseased brain is intracerebral microdialysis, a method that has until now been limited to short-term observations, or snapshots, of the brain microenvironment. Here we draw upon patient-based findings to characterize CSF biomarkers in a commonly used preclinical mouse model for AD. Methods: Our modified push-pull microdialysis method was first validated ex vivo with human CSF samples, and then in vivo in an AD mouse model, permitting assessment of dynamic changes of CSF Aβ and tau and allowing for better translational understanding of CSF biomarkers. Results: We demonstrate that CSF biomarker changes in preclinical models capture what is observed in the brain; with a decrease in CSF Aβ observed when plaques are deposited, and an increase in CSF tau once tau pathology is present in the brain parenchyma. We found that a high molecular weight cut-off membrane allowed for simultaneous sampling of Aβ and tau, comparable to CSF collection by lumbar puncture in patients. Conclusion: Our approach can further advance AD and other neurodegenerative research by following evolving neuropathology along the disease cascade via consecutive sampling from the same animal and can additionally be used to administer pharmaceutical compounds and assess their efficacy (Bjorkli, unpublished data).

Jen-Hau Chen, Hua-San Shih, Jennifer Tu, Jeng-Min Chiou, Shu-Hui Chang, Wei-Li Hsu, Liang-Chuan Lai, Ta-Fu Chen, Yen-Ching Chen (Handling Associate Editor: Emmeline Ayers)
A Longitudinal Study on the Association of Interrelated Factors Among Frailty Dimensions, Cognitive Domains, Cognitive Frailty, and All-Cause Mortality
Abstract: Background: Cognitive frailty integrating impaired cognitive domains and frailty dimensions has not been explored. Objective: This study aimed to explore 1) associations among frailty dimensions and cognitive domains over time and 2) the extended definitions of cognitive frailty for predicting all-cause mortality. Methods: This four-year cohort study recruited 521 older adults at baseline (2011-2013). We utilized 1) generalized linear mixed models exploring associations of frailty dimensions (physical dimension: modified from Fried et al.; psychosocial dimension: integrating self-rated health, mood, and social relationship and support; global frailty: combining physical and psychosocial frailty) with cognition (global and domain-specific) over time and 2) time-dependent Cox proportional hazard models assessing associations between extended definitions of cognitive frailty (cognitive domains-frailty dimensions) and all-cause mortality. Results: At baseline, the prevalence was 3.0% for physical frailty and 37.6% for psychosocial frailty. Greater physical frailty was associated with poor global cognition (adjusted odds ratio=1.43-3.29, β: -1.07), logical memory (β: -0.14 to -0.10), and executive function (β: -0.51 to -0.12). Greater psychosocial frailty was associated with poor global cognition (β: -0.44) and attention (β: -0.15 to -0.13). Three newly proposed definitions of cognitive frailty, “mild cognitive impairment (MCI)-psychosocial frailty,” “MCI-global frailty,” and “impaired verbal fluency-global frailty,” outperformed traditional cognitive frailty for predicting all-cause mortality (adjusted hazard ratio=3.49, 6.83, 3.29 versus 4.87; AIC= 224.3, 221.8, 226.1 versus 228.1). Conclusion: Notably, extended definitions of cognitive frailty proposed by this study better predict all-cause mortality in older adults than the traditional definition of cognitive frailty, highlighting the importance of psychosocial frailty to reduce mortality in older adults.

Hannah Gardener, Bonnie Levin, Janet DeRosa, Tatjana Rundek, Clinton B. Wright, Mitchell S.V. Elkind, Ralph L. Sacco
Social Connectivity Is Related to Mild Cognitive Impairment and Dementia
Abstract: Background: Evidence supports a relationship between loneliness, social isolation, and dementia, but less is known about whether social connections confer protection against cognitive decline in disadvantaged neighborhoods. Objective: This longitudinal population-based study examines the relationship between social connectivity and cognitive impairment in a multi-ethnic cohort with low socioeconomic status and high vascular disease risk. Methods: Northern Manhattan Study participants self-reported frequency of social visits, phone calls, satisfaction with social visits, number of friends, and loneliness at baseline, and were followed prospectively with a series of neuropsychological assessments. Social connectivity was examined in relation to incident mild cognitive impairment (MCI)/dementia using logistic regression adjusting for demographics and vascular risk factors. Results: Among 952 participants (mean age at first neuropsychological assessment=69±8 years, 62% women, 17% Black, 13% white, 68% Hispanic), 24% developed MCI/dementia. Participants who had phone contact with friends/family 2+ times/week (91%) had a lower odds of MCI/dementia (OR=0.52, 95% CI=0.31-0.89), with no association for frequency of in-person visits. Compared to those who were neither socially isolated (≥3 friends) nor lonely (reference, 73%), those who were socially isolated and lonely (3%) had an increased odds of MCI/dementia (OR=2.89, 95% CI=1.19-7.02), but differences were not observed for those who were socially isolated but not lonely (10%, OR=1.05, 95% CI=0.60-1.84), nor those who were lonely but not isolated (11%, OR=1.58, 95% CI=0.97-2.59). Conclusion: This study raises the possibility that social connections confer some protection for cognitive health in the face of adversity and supports potential opportunities for community social interventions for improving cognition in disadvantaged populations.

Susan Tomczak Matthiesen, Sophie Rosenkjær, Moa Pontén, Karin B. Jensen, Hanne Gottrup, Lene Vase
Does Certainty of Genuine Treatment Increase the Drug Response in Alzheimer’s Disease Patients: A Meta-Analysis and Critical Discussion
Abstract: Background: Non-specific treatment effects, such as expectations, contribute to the effectiveness of pharmacological treatments across diseases. However, the contribution of expectancy, i.e., certainty of receiving treatment, in patients with Alzheimer’s disease (AD) is unknown. Objective: The aim is to investigate whether certainty of receiving a genuine treatment influences the response to active treatment in AD patients. Methods: The efficacy of active treatments in open-label trials, where patients are certain of receiving treatment (100% certainty), was compared to the same active treatments in randomized controlled trials (RCT), where patients are uncertain of receiving treatment or placebo (50% certainty). Results: In the seven open-label trials, there was no significant difference between post- and pre-treatment scores (difference in means = 0.14, 95% CI [-0.51; 0.81], p = 0.66). In the eight RCT trials, there was a significant difference between post- and pre-treatment (difference in means = -0.91, 95% CI [-1.43; -0.41], p < 0.001). There was a statistically significant difference between open-label and RCT trials (difference = 1.06, 95% CI [0.23; 1.90], p = 0.001). Conclusion: Patients with AD did not benefit from certainty of receiving genuine treatment. This could be due to the nature/progression of the disease, but it could also be related to an order effect in the practice of running AD trials, where RCTs are conducted prior to open label. These findings have implications for the understanding of non-specific treatment effects in AD patients as well as for the design of clinical trials that test pharmacological treatments in AD.