bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alzheimer disease clinical progression by intellectual disability levels in Down syndrome
Authors: Vaqué‐Alcázar Lídia , Videla Laura , Carmona María , Benejam Bessy , Barroeta Isabel , Hoyo Laura Del , Hernandez Aida Sanjuan , Rodríguez‐Baz Íñigo , Arriola‐Infante José Enrique , Arranz Javier , Maure‐Blesa Lucía , Morcillo‐Nieto Alejandra O. , Bejanin Alexandre , Lleo Alberto , Bartrés‐Faz David , Fortea Juan , Fernandez Susana 
Published: January 2025

AbstractBackgroundThe extended life expectancy in individuals with Down Syndrome (DS) has led to the emergence of age‐related diseases, with Alzheimer’s disease (AD) being particularly noteworthy due to its nearly full penetrance. The level of intellectual disability (ID), regarded as a proxy for cognitive reserve (CR), explains heterogeneity in cognitive and functional abilities. Despite this, there is a notable lack of exploration into the characterization of resilience factors and their potential influence on the progression along the AD continuum in this population. The main goal was to study whether premorbid ID levels (i.e., Mild, Moderate, Severe) could influence the AD clinical onset (prodromal [pDS] or dementia [dDS] diagnosis) and cognitive trajectories among asymptomatic DS (aDS).MethodWe analyzed longitudinal data (> 6 months follow‐up) from a single‐center cohort study involving DS adults (aged >18 years) recruited at the Alzheimer‐Down Unit from the Catalan Down Syndrome Foundation and Hospital of Sant Pau. Clinical progression was evaluated using Kaplan‐Meier curves, ANOVA was conducted to test differences in the age of onset across ID groups, and cognitive trajectories (assessed with Cambridge Cognitive Examination for Older Adults with Down Syndrome [CAMCOG‐DS]) were analyzed using linear mixed‐effects models to explore age‐related effects by ID.ResultA total of 778 adults with DS (mean [SD] age, 43.32 [11.07] years; 361 women [46.4%]; aDS = 527, pDS = 86, dDS = 165) were included. Kaplan‐Meier curves showed that aDS with ID‐Severe progressed faster (p = .0016; Figure 1A), whereas no differences were found in the prodromal stage (p = 0.270; Figure 1B). While no significant differences were identified regarding the age of onset for pDS (Figure 1C), the ID‐Severe slightly showed a later age of dDS diagnosis than ID‐Mild (p = .044; Figure 1D). CAMCOG‐DS scores were higher for ID‐Mild than those with ID‐Moderate (mean [SE] difference, −19.24 [1.68]); p<.001). Nevertheless, there were no group differences among trajectories (Figure 2A), neither when estimated by different age ranges (Figure 2B).ConclusionDespite the lack of evidence, there is an increasing interest in understanding how CR proxies contribute to cognitive resilience in DS. Further analyses including AD‐related biomarkers are essential to uncover the neurobiological mechanisms involved, which could significantly contribute to targeted primary prevention strategies.
Total Healthcare Costs across the Alzheimer’s Disease Continuum in the United States (US)
Authors: Monfared Amir Abbas Tahami , Hummel Noemi , Naslazi Emi , Khachatryan Artak , Zhang Raymond , Gao Ran , Zhang Quanwu 
Published: January 2025

AbstractBackgroundThis study describes the total healthcare costs integrating direct, indirect, and intangible or emotional cost components across the severity stages of Alzheimer’s disease (AD) in US.MethodUtilizing Health and Retirement Study (HRS) data (1994‐2018), a bi‐annual US national survey of older adults, we assessed out‐of‐pocket and indirect costs, including unpaid caregiving services, missed workdays, and early retirement. HRS, analyzed with sampling weights, provided a representative US national sample. Mild cognitive impairment (MCI) and AD severity were ascertained using the modified telephone interview of cognitive status (TICS‐M). Besides data from HRS, 100 pairs of patients and their caregivers were referred by physicians and surveyed for quality of life (QoL). Patient and caregiver responses to QoL were converted to utility values. The MCI‐ or AD‐specific health utility value was subtracted from the age‐standardized health utility value from the general US population to derive the estimate of utility reduction due to AD. Intangible costs were calculated using the willingness to pay threshold of $150,000 for one quality‐adjusted life year gained. Direct costs were derived from current literature, comprising patient and caregiver healthcare costs, patient social care costs and nursing home costs. Costs were adjusted to the 2023 US price index.ResultHRS patient sample (N = 18,786) with MCI (n = 17,885) and AD (n = 901) were aged 67.8±10.7 and 80.9±9.3 years, 55.7% and 63.3% female, and 28.3% and 0.9% employed, respectively. A total of 100 patient‐caregiver pairs with MCI (n = 27) and AD (n = 73) were surveyed, with 21% and 47% of patients > 75 years, 59% and 48% female, and 7.4% and 4.1% employed, respectively. Figure 1 shows mean annual costs per patient across AD severity levels, with direct costs from literature, indirect costs estimated from HRS and intangible costs estimated from the patient‐caregiver survey. Total annual healthcare costs increased from $69,380 for MCI to $150,488 for severe AD.ConclusionThis study provides a comprehensive view of escalating healthcare costs with worsening AD severity, emphasizing the need for targeted interventions to address the multifaceted economic impact on patients, caregivers, and society.
Remote associations between beta‐amyloid and tau are mediated by between‐network connectivity
Authors: Hojjati Seyed Hani , Butler Tracy A , de Leon Mony J. , Gupta Ajay H , Nayak Siddharth , Luchsinger Jose A. , Chiang Gloria , Razlighi Qolamreza R 
Published: January 2025

AbstractBackgroundThe accumulation of tau tangles and beta‐amyloid (Aβ) are hallmarks of Alzheimer's disease (AD). Despite the hypothesis that Aβ may trigger tau spread across remote brain regions, the specific pathological processes remain unclear.MethodsOur study utilized 18F‐Florbetaben Aβ positron emission tomography (PET), 18F‐MK6240 tau PET, and resting‐state functional magnetic resonance imaging (rs‐fMRI). We included 361 healthy control (HC) subjects from the Northern Manhattan Study of Metabolism and Mind (NOMEM) [mean age 64.96 ± 3.17 years, 230 females]. Among them, 46 subjects underwent follow‐up scans at 2 to 3 year intervals. Additionally, 120 HC subjects from the Brain Health Imaging Institute (BHII) studies were included (mean age 68.71 ± 6.16 years, 54 females). Cross‐sectional elderly subjects were categorized into four groups based on normal (n) and abnormal (a) levels of Aβ and tau, as compared to young normative subjects (age < 40): nAβ/nTau, aAβ/nTau, nAβ/aTau, and aAβ/aTau. Assortativity, a graph theory metric, was computed on the average functional connectivity maps for each group. We also compared the connectivity between the limbic network and other functional networks among these groups of subjects. Finally, using longitudinal subjects, we explored the role of between‐network connectivity of the limbic network in mediating the association between cortical Aβ in six functional networks and annual tau elevation in the limbic network.ResultsFigure 1 illustrates that among the four groups in both datasets, aAβ/nTau subjects displayed the highest assortativity values (0.767 for NOMEM and 0.627 for BHII). In both datasets, aAβ/nTau showed significant increases (t‐value > 4.49, p‐value < 0.0001) in between‐network connectivity of the limbic network (Figure 2) compared with the other three groups. 14 Aβ‐positive subjects achieved highly significant results (p‐value < 0.013) for indirect relationships in all six functional networks (Figure 3).ConclusionOur study highlights the early accumulation of Aβ and its role in increasing between‐network connectivity. We also demonstrated that between‐network connectivity mediates the remote relationships between Aβ and tau pathologies in the preclinical stages of AD.
Holistic dementia care continuum from the point of diagnosis to the end of life: Progress and challenges in translating national dementia policies into daily practice in Japan
Authors: Nakanishi Miharu , Ogawa Asao , Nishida Atsushi 
Published: January 2025

AbstractBackgroundThe WHO’s Global Dementia Action Plan comprises seven action areas, including dementia diagnosis, treatment, care, and support. Palliative care is called for as a core component of the care continuum from the diagnosis to the end of life. Japan has pursued a holistic care approach in dementia policies. However, from our review, we found that palliative care components are not fully represented. We aim to present how Japanese policies have been translated into practice and highlight challenges that remain to be addressed.MethodWe performed empirical research derived from real‐world data to examine the potential gaps between policies and daily practice in Japan. We focused on four topics: advance care planning, neuropsychiatric symptoms, physical restraint in acute care, and end‐of‐life care.ResultEngagement of advance care planning was typically triggered by a clinical dementia diagnosis, and the doctor providing the diagnosis was not often involved in the conversation with the patient. We developed a psychosocial intervention program (DEMBASE®) to reduce neuropsychiatric symptoms in collaboration with a Swedish BPSD‐registry team, for which effectiveness was verified. Physical restraint of inpatients was prevalent even in units with a dementia care benefit. The onset of the COVID‐19 pandemic triggered the shift to hospital deaths, which were uniquely observed in deaths from dementia.ConclusionJapanese dementia policies promote “aging in place,” which is now a mainstream strategy globally. However, dementia care remains suboptimal. Baseline palliative care should be integrated into dementia diagnoses, treatment, care, and support.
Advancing Early Detection of Alzheimer’s Disease in the Primary Care Setting in the United States
Authors: Mielke Michelle M. , Kurzman H. Ricky , Hu Yan Helen , Cho Min , Liss Jonathan , Burns Jeffrey M , Obisesan Thomas O , Hornbecker Michael , Pallay Arnold , Smith Steven R. , Honig Lawrence S. , Parker Monica W , Bell Joanne , Hampel Harald 
Published: January 2025

AbstractBackgroundRecent advances in diagnostics have made it possible to identify early signs of the pathophysiological changes underlying Alzheimer’s Disease (AD) via blood tests. However, the use of blood‐based biomarkers (BBBMs) for the early detection of AD may be limited in primary care settings despite its potential for wide access and early detection of AD (PMID: 37295421). Therefore, there is a need to understand the barriers and facilitators of BBBM testing for AD in primary care.MethodWe employed a combination of qualitative research, advisory board, and quantitative survey to engage with clinical/scientific advisors and community‐based physicians in primary care. In‐depth interviews with primary care physicians (PCPs) (n = 23) were conducted to understand the current awareness and clinical practice of AD identification in the primary care setting, followed by an advisory board to establish hypotheses about the barriers and opportunities of BBBM testing in the primary care setting. We subsequently conducted a quantitative survey with US PCPs (n = 600) to understand their attitudes and beliefs on screening and diagnosing AD in their practice, including opinions and willingness to use BBBM as part of the evaluation of individuals with mild cognitive impairment (MCI) or mild dementia.ResultsPreliminary findings revealed that the majority of PCPs believe that MCI/mild AD is underdiagnosed and BBBM will likely facilitate better and faster diagnosis. Identified obstacles encompass inadequate financial coverage for BBBM testing, limited awareness among PCPs regarding the tests’ availability and value, limited awareness about monoclonal antibody (mAb) treatment for early‐stage AD, and lack of understanding of where and how to incorporate BBBM testing into primary care. Suggested solutions included education to equip PCPs with necessary knowledge on BBBM testing, clear guidelines on incorporating BBBMs simultaneously with clinical and cognitive assessments, and adequate financial coverage for both BBBMs and mAb treatments. Final survey results will be presented at the AAIC.ConclusionThe findings suggest that PCPs recognize the substantial value of BBBMs in detecting early AD, and that there is an urgent need for a concerted effort to improve awareness and address the barriers to adopting BBBMs in primary care.
Low Food Security is Related with More Memory Complaints in a Clinic‐Based Sample of Latino Adults
Authors: Saenz Joseph , Tanner Laura 
Published: January 2025

AbstractBackgroundLow food security has been linked with both diminished objective cognitive outcomes and lower subjective assessments of cognition in studies across the globe. Subjective memory complaints may be an important indicator of memory problems experienced in one’s daily life. However, few studies have explored links between low food security and subjective memory in Latinos, despite the higher prevalence of food insecurity in the Latino population. The aim of this study is to investigate potential links between low food security and subjective memory complaints in a sample of Latinos.MethodWe used the Sangre Por Salud (SPS) data, a sample of Latino adults from a federally qualified community health center in Phoenix, Arizona who enrolled between 2013 and 2018. Individuals age 45+ (n = 1,041) are included in our analytic sample. Food security was assessed using the Household Food Security scale and memory complaints were measured using the Frequency of Forgetting scale. Potential links between low food security and subjective memory complaints were tested using linear regression controlling for demographic factors (age, gender, education, nativity), self‐rated health, and perceived social support.ResultPreliminary results indicated that 75% of the sample were highly/marginally food secure, 18% had low food security, and 7% had very low food security. Food security was more common in the US born and among those with higher social support. In multivariate analyses, compared to the highly/marginally food secure, low food security related with 0.26 standard deviations higher memory complaint (p<0.01) whereas very low food security related with 0.28 standard deviations higher memory complaint (p<0.05).ConclusionFindings suggest an association between experiences of low food security and higher subjective memory complaints in Latinos. Subjective memory complaints are related with future cognitive impairment and dementia. Future studies should evaluate the potential cognitive benefits of interventions targeting food insecurity.
Identification of Chemical Tool Compounds to Investigate the Role of Lyn Kinase in TREM2‐Mediated Microglia Activation and Phagocytosis
Authors: Weerawarna Pathum M , Robo Michael T , Chu Shaoyou , Mason Emily R , Davis Chris , Angus Steven P , Richardson Timothy I. 
Published: January 2025

AbstractBackgroundLyn kinase, a member of the Src family of tyrosine kinases, predominantly phosphorylates ITIM and ITAM motifs linked to immune receptors and adaptor proteins, and is emerging as a target for Alzheimer’s disease (AD). The role of Lyn in TREM2‐mediated microglial activation and phagocytosis, a critical pathway for clearing Aβ plaques, remains unclear and potent, selective, and brain penetrant Lyn inhibitors are unavailable. In this study, we report the characterization of Lyn kinase inhibitors from the literature as well as the establishment of an advanced virtual screening platform at the IUSM‐Purdue‐TREAT‐AD center to identify new type II Lyn inhibitors suitable as molecular probes.MethodWe first performed a thorough literature survey and found 14 reported Lyn kinase inhibitors. We then validated their Lyn inhibitor activities and Lyn selectivities using the HotSpot kinase assay. We tested these compounds for microglia activation in a high‐content imaging assay using HMC3 (human) and BV2 (mouse) microglia‐like cell lines. We also performed kinome profiling in these cells to evaluate cellular target engagement and selectivity. Finally, we screened a million‐compounds using a computational pipeline that combined molecular docking, shape‐based screening, and MD simulations to identify novel and potent type II Lyn kinase inhibitors.ResultOur findings revealed that Type I inhibitors, particularly Saracatinib and Bosutinib, potently inhibit Lyn within the picomolar (pM) range. On the other hand, Type II inhibitors, such as Masitinib and Imatinib, displayed pronounced >20‐fold selectivity for Lyn over Hck with low nM Lyn inhibitor activities. Saracatinib and Bosutinib significantly induced phagocytosis in HMC3 cells, whereas Type II inhibitors demonstrated moderate activity in both HMC3 and BV2 cells. Our virtual screening platform identified a new type II Lyn inhibitor with picomolar activity and good Lyn/Hck selectivity.ConclusionWe have successfully evaluated previously reported inhibitors and introduced a novel type II Lyn kinase inhibitor with picomolar (pM) activities suitable for use as chemical probes to investigate the role of Lyn in TREM2‐mediated microglial activation.
LATE‐LIFE EDUCATION IMPROVES ADULT EXECUTIVE FUNCTION: THE PROAME TRIAL
Authors: Friedlaender Clarisse Vasconcelos , de Faria Rocha João Victor , dos Santos Tomaz Kelle Luisa , Ruppert Emma Patrice , Lourandes Aida , Zacarias Ana Paula , de Castro Magalhães Assenção Joanna , Rincon Luciana Paula , Ribeiro Norton Gray Ferreira , Rosen Howard J. , Grinberg Lea T. , Maciel Francisca Izabel Pereira , Caramelli Paulo , de Paula França Resende Elisa 
Published: January 2025

AbstractBackgroundEducation is a recognized modifiable dementia risk factor. To boost cognitive reserve and reduce dementia risk in Brazil’s vulnerable populations, we conceived a literacy program (PROAME trial) targeting low‐educated adults, aiming to explore how executive function and individual differences influence program effectiveness.MethodWe screened 130 adults, with 108 meeting enrollment criteria. They were allocated in control (CG, n = 51) and intervention (IG, n = 57) groups, according to residence area. Subjects underwent a comprehensive neuropsychological assessment at baseline and after six months, covering global cognition, executive function, memory, and language.ResultWe excluded 28 participants for incomplete post‐intervention assessments. 77 completed all procedures, with 62 (CG = 26; IG = 36) finishing all executive function tasks. Mean age = 59.16 years (±9.22), mean education = 2.21 years (±2.20), with 62.3% mixed‐race, 29.5% Black, and 75.8% female. Mini‐Mental State Examination mean score = 22.08 (±2.74). We created an executive function composite score (EFCS) including phonemic verbal fluency, reverse digit span, and rapid naming. Comparing EFCS pre‐ and post‐ intervention using a linear regression, participants (in both groups) with higher baseline EFCS showed less post‐intervention improvement (ANCOVA; F = 6.233; p<0.001). IG displayed significant EFCS enhancement compared to CG (p = 0.003). Considering possible adult illiteracy causes, participants who reported learning difficulties exhibited the lowest EFCS at baseline, compared to rural residence, lack of family support, and childhood labor groups.ConclusionThe literacy program positively impacted executive function. IG exhibited significant EFCS improvement after six months, demonstrating late formal education acquisition as an effective cognition‐enhancing strategy. Notably, those with lower initial executive function levels experienced greater improvements, suggesting enhanced benefits for those initially lacking executive skills. However, the learning difficulties group derived lesser benefits from the intervention, highlighting the importance of considering individual differences. Childhood learning difficulties may hint at undiagnosed developmental disorders, influencing cognitive reserve development early on. Recognizing the pivotal role of executive function in enhancing cognitive reserve, promoting this domain through literacy‐focused interventions can be a valuable tool in preventing cognitive decline and dementia.
LatAm‐FINGERS: Navigating Diversity in the Engagement of a Subcontinental Trial for Dementia Prevention
Authors: Calandri Ismael Luis , Crivelli Lucia , Caramelli Paulo , Lopera Francisco , Nitrini Ricardo , Sosa Ana Luisa , Vellila Lina Marcela , Salinas‐Contreras Rosa Maria , Suemoto Claudia Kimie , Yassuda Monica Sanches , Sevlever Gustavo , Acosta Daisy M , Charamelo Ana , Cusicanqui María Isabel , Custodio Nilton , Delgado Carolina , Duque Lissette , Velazquez Ivonne Z. Jimenez , Leon‐Salas Jorge M , Snyder Heather M , Carrillo Maria C. , Kivipelto Miia , Allegri Ricardo ,   LatAm‐FINGERS Consortium
Published: January 2025

AbstractBackgroundLatAm‐FINGERS is the first non‐pharmacological multicenter randomized clinical trial aimed at preventing cognitive impairment in Latin America. It encompasses twelve countries that collectively represent 45% of the territory in the Americas. Its objective is to reach populations that, despite sharing commonalities such as language, are culturally and economically diverse. Above all, these populations have different perspectives on goals related to healthy aging, access to healthcare, and participation in clinical trials. The challenge is twofold: on one hand, achieving commitment across all centers to ensure recruitment and adherence; on the other hand, utilizing these strategies to instill awareness in society about the scourge of dementia and the possibility of its prevention.MethodsOur aim is to describe the recruitment strategies and their effectiveness in the design and implementation of the initial phases of the trial. The most relevant strategies included: a) decentralized design, where the 12 site principal investigators collaborated across all phases of the trial design rather than merely implementing it. They were asked to present solutions and barriers based on the idiosyncrasies of their target population and share them with the rest. b) assess cultural beliefs about clinical trials, c) disseminate information about dementia prevention strategies, d) collaborate with community partners in outreach and recruitment.ResultsThe most utilized strategies included 1) assess population with cognitive complaints or concern for prevention (for centers with clinical setting) and 2) community dissemination for universities and research centers. A total of 1,877 candidates were evaluated, of which 1,232 were included. Pre‐screening strategies were implemented to reduce staff burden at most centers.ConclusionsOur results demonstrate that, despite the diversity present in Latin America, it is possible to conduct a unified trial with successful recruitment. Carefully designed strategies that respect local culture, coupled with knowledge of local stakeholders, hold the key to success. Moreover, it highlights that a clinical trial, in addition to being a tool to test treatment effectiveness, can serve as a catalyst for awareness campaigns.