bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blarcamesine in Early Alzheimer Disease Phase 2b/3 Randomized Clinical Trial
Authors: Sabbagh Marwan N. , Chezem William R. , Jin Kun , Missling Christopher U ,   Anavex Life Sciences Research Group
Published: January 2025

AbstractBackgroundThere are no approved oral disease‐modifying treatments for Alzheimer disease (AD). This study was intended to assess efficacy and safety of blarcamesine (ANAVEX®2‐73), an orally available small‐molecule activator of the sigma‐1 receptor (SIGMAR1) designed to exert neuroprotection through restoration of cellular homeostasis including autophagy enhancement.MethodANAVEX®2‐73‐AD‐004 is a multicenter (52 medical research centers/hospitals in 5 countries), randomized, double‐blind, placebo‐controlled, 48‐week phase 2b/3 trial that enrolled 508 participants with early AD (mild cognitive impairment/mild dementia) from July 2018 to June 2021 (last patient visit in June 2022). Participants were randomized to receive blarcamesine (n = 338) or placebo (n = 170) oral capsules once daily for 48 weeks.The co‐primary cognitive and functional outcomes were the change in ADAS‐Cog13 and ADCS‐ADL scores from baseline to 48 weeks. Additional clinical outcomes include the secondary outcome CDR‐SB and the exploratory outcome CGI‐I. All clinical endpoints were analyzed using a mixed model for repeated measures (MMRM).ResultThe blarcamesine group demonstrated improvement compared to the placebo group in all clinical endpoints at 48 weeks: when comparing least‐squares mean (LSM) change in ADAS‐Cog13 score (difference, −1.783 [95% CI, −3.314 to −0.251]; P = 0.0226), LSM change in ADCS‐ADL score (difference, 1.019 [95% CI, −0.66 to 2.70]; P = 0.234), LSM change in CDR‐SB score (difference, −0.456 [95% CI, −0.831 to −0.080]; P = 0.0175), and LSM change in CGI‐I score (difference, −0.285 [95% CI, −0.474 to −0.095]; P = 0.0033). Participants with ≥1 serious treatment‐emergent adverse events (TEAEs) occurred in 56 participants (16.7%) in the blarcamesine group and 17 (10.1%) in the placebo group. Common treatment‐emergent adverse events included dizziness, which was mostly mild to moderate in severity.ConclusionIn this phase 2b/3 randomized clinical trial, we found that among participants with early AD, blarcamesine significantly slowed clinical progression on prespecified primary outcome global and cognitive measures at 48 weeks in the ITT population. These results suggest that blarcamesine may be an effective, safe, and novel scalable oral treatment for early AD.
APOE‐ε4 associations with smartphone‐based cognitive markers
Authors: Rosická Anna M , Fittipaldi Sol , Gallagher Eoghan , Hanlon Anna K , Ibáñez Agustín , Bridgeman Katie , Muniz‐Terrera Graciela , Ritchie Karen , Ritchie Craig W , O'Brien John T , Koychev Ivan , Lawlor Brian , Naci Lorina , Gillan Claire M 
Published: January 2025

AbstractBackgroundSmartphone‐based assessments are a promising tool for early detection of cognitive decline in midlife. Previous research has shown such cognitive markers can be sensitive to a range of potentially modifiable dementia risk factors even in healthy adults. However, their sensitivity to genetic risk factors like APOE‐ε4 is likely to differ by cognitive domain, with evidence of strong negative effects on wayfinding tasks but mixed for other domains. We investigated the associations between a set of previously validated smartphone‐based cognitive markers and APOE‐ε4.MethodN = 87 cognitively unimpaired, APOE‐genotyped participants (aged 44‐67, 57.5% female) of the PREVENT study completed a self‐administered module in the smartphone application Neureka, including gamified cognitive tasks and memory self‐evaluation (completion rates: 81%–99%). Controlling for age, gender, education, and parental history of dementia, we compared APOE‐ε4 carriers (n = 35) with non‐carriers in their performance on five cognitive measures: model‐based planning, visual working memory, processing speed (∼Trails A), cognitive flexibility (∼Trails B), and subjective memory problems. We conducted receiver operating characteristic (ROC) analysis to assess if APOE‐ε4 status can be predicted from norm‐adjusted cognitive scores, i.e., the difference between observed cognitive performance and what we would predict for given demographics based on an additional benchmark sample (N = 3,376, aged 18‐84, 65% female).ResultIn univariate analyses, APOE‐ε4 carriers did not significantly differ from non‐carriers in their demographic characteristics or cognitive scores except for visual working memory, which was better in carriers (t(63.226) = 2.245; p = .028). After controlling for covariates, APOE‐ε4 status was not significantly linked to, which was better in APOE‐ε4 carriers (β[bootstrapped 95% CI] = ‐0.29[‐0.53,‐0.06]; t = ‐2.30; p = .025). In ROC‐analysis, norm‐adjusted visual working memory scores modestly differentiated between carriers and non‐carriers (AUC(SE) = .648(0.067); bootstrapped 95% CIs = 0.515–0.774).ConclusionThe non‐significant associations between APOE‐ε4 and most cognitive markers suggest limited sensitivity to genetic risk. Interestingly, APOE‐ε4 carriers outperformed non‐carriers in visual working memory, which could be due to antagonistic pleiotropy effects, but needs to be replicated in larger samples. The current study shows limited evidence for the clinical utility of our cognitive markers as indicators of genetic risk in middle‐aged cognitively unimpaired adults.
Identifying common disease trajectories of Alzheimer’s disease with electronic health records
Authors: Fu Mingzhou , Chang Timothy S ,   UCLA Precision Health Data Discovery Repository Working Group
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD), a leading cause of dementia, poses a growing global public health challenge. While recent studies have identified AD risk factors, they often focus on specific comorbidities, neglecting the complex interrelations and temporal dynamics. Our study addresses this by analyzing AD progression through longitudinal trajectories, utilizing clinical diagnoses over time. Using machine learning and network analysis, we created a computational framework to identify common AD progression patterns.MethodWe analyzed patient diagnoses from UCLA Health’s Electronic Health Records, coded with the International Classification of Diseases, version 10 (ICD‐10). Using the Fine and Gray model to detect significant temporal risk factors between diagnoses, we examined associations between diagnosis pairs and refined the patients' diagnostic trajectories, eliminating irrelevant disease transitions and delineating all possible trajectory combinations. These refined trajectories were compared using Dynamic Time Warping and grouped into clusters with hierarchical clustering. We investigated common AD trajectories through network analysis and compared patient demographics, AD manifestations, and genetic profiles across clusters. The Greedy Equivalence Search algorithm helped infer causal relationships within these trajectories.ResultOur analysis included 6,969 eligible AD patients, narrowing down to 1,486 patients with 3,372 unique AD progression trajectories after refinement. We identified four trajectory clusters: 1) a mental disorder cluster centered around major depressive disorder (MDD) (e.g., anxiety disorder → MDD) (N_patient = 525); 2) a cerebrovascular disease cluster (e.g. hypertensive crisis → other cerebrovascular diseases) (N_patient = 348); 3) a neurodegenerative disease cluster characterized (e.g., Parkinson’s disease → other degenerative disease of nervous system) (N_patient = 742); and 4) an outlier cluster predominantly involving external causes like infectious diseases (N_patient = 7). Significant differences were observed in race‐ethnicity, age at AD onset, disease duration, and the polygenic risk score (PRS) for AD across clusters. For example, patients in the cerebrovascular disease cluster exhibited higher mean AD PRS compared to other clusters (p = 0.05). Causal analysis indicated that 56.1% (47 out of 91) of the identified trajectory connections were causal.ConclusionWe uncovered AD diagnosis trajectories, incorporating temporal aspects and causal relationships. These insights could improve understanding of AD development, aid in subtype classification, and enhance risk assessment, which could significantly benefit patient care and medical research.
User Perceptions of a Robot‐based Music Intervention System for Dementia Care
Authors: Morris Tyler , Walker Sydney P. , Holder Laython V. , Vaughan Eric , Petrovsky Darina , Swaminathan Sai , Zhao Xiaopeng 
Published: January 2025

AbstractBackgroundTo address the rapid increase in the number of persons with Alzheimer’s disease or related dementia (PwADRD), we seek to combine the benefits of music intervention with the adaptability of social robotics. Our system, the Music intervention Using Socially Engaging robotics (MUSE) system, seeks to provide a structured music intervention session to a group of PwADRD using the social robot Pepper. As seen in Figure 1, the Pepper robot leads the PwADRD through a 3‐step music intervention session. To assess the user perception of the MUSE system, we conducted two workshops with PwADRD.MethodWe gathered groups of PwADRD with mild to moderate Alzheimer’s/dementia at assisted living facilities in the Knoxville, Tennessee area. Within these groups, the PwADRD participated in a MUSE session guided by the social robot. Afterward, they filled out a brief survey (5‐point Likert Scale questions) and participated in a semi‐structured interview.ResultFrom the workshops conducted, we had a total of 15 participants. Regarding Pepper robot, the average survey score for all questions was 3.58/5 with a standard deviation of 1.12. These questions covered various design aspects of the robot’s design. Furthermore, the survey showed positive results for the MUSE app. Covering the activities of the MUSE session, participants gave an average score of 3.86/5 with a standard deviation of 0.89. Additionally, in the interview, participants proclaimed their admiration for the system. However, most participants did note that it was difficult to hear the robot at times and that the tablet interface was difficult to see.ConclusionThe workshops showed that the MUSE system was positively received by the target community. As the research team observed participants engaging with the system, we found that most PwADRD enjoyed the musical activities and the robot that presented them. However, we also found ways to improve the MUSE system. Moving forward, we seek to address these issues and hopefully improve the user acceptance of the MUSE. Nonetheless, the workshops prove that the MUSE system can and will be positively received by the PwADRD community and therefore is a viable way to provide a meaningful intervention to PwADRD.
Perspectives from Underrepresented Patients and Families Following Biomarker‐Informed ADRD Diagnoses: Insights from the PARADE Study
Authors: Knox Melissa L , Witbracht Megan G. , Grill Joshua D , Lingler Jennifer H 
Published: January 2025

AbstractBackgroundAs the landscape of ADRD diagnoses evolves to include biomarker testing, there is a pressing need to understand the unique experiences, challenges, and support needs of families undergoing evaluations of cognitive decline, particularly in a manner that prioritizes cultural considerations from voices historically underrepresented in ADRD research. The current study aims to understand the AD biomarker disclosure journey of persons from underrepresented groups with the goal of informing culturally responsive approaches to the care of patients and their families navigating the complexities of ADRD diagnoses.MethodVirtual focus groups are being conducted over a secure video conferencing platform, with a trained facilitator guiding the discussion. Participants represent a purposively selected subsample of those enrolled in Patient And family member Reactions to biomarker‐informed ADRD DiagnosEs (PARADE NIH RF1AG080591), a current add‐on to the New IDEAS study, a CMS coverage with evidence development study of amyloid PET with an explicit objective to represent diverse patients by enrolling >50% who identify as Black, African American, or Hispanic. Employing a semi‐structured interview approach, the focus group guide consists of 5 lead questions and follow‐up probes, aiming to explore participants' experiences in receiving amyloid PET results and to characterize their post‐disclosure information and support needs. Verbatim transcripts of focus group recordings will be analyzed using thematic analyses.ResultPreliminary findings from initial focus groups with Black, African American and Hispanic participants and families will provide perspectives on decision‐making, expectations, and post‐disclosure experiences. This study is anticipated to yield novel insights into patient and family preferences for receiving high stakes ADRD diagnostic information and to identify potential gaps in current support mechanisms.ConclusionThe results from this focus group investigation will contribute to a more comprehensive understanding of the information and support needs of culturally diverse families post‐ADRD diagnosis. Ultimately, this study seeks to inform culturally responsive care practices and will be disseminated to AD Research Centers and dementia experts, fostering the enhancement of best practices for biomarker disclosure and dementia‐related education.
Investigating the Relevance of Genetic Variation at Post‐Translational Modification Sites in the Polygenic Risk Model for Alzheimer’s disease‐associated Phenotypes
Authors: Paço Samantha LG , Pereira Felipe Luiz , Andrews Shea J , Grinberg Lea T. , Naslavsky Michel Satya 
Published: January 2025

AbstractBackgroundThe outcomes of extensive Genome‐Wide Association Study (GWAS) data in Polygenic Risk Score (PRS) studies exhibit varying odds ratios (ORs), ranging from 1.13 (Bellenguez) to 1.34 (Kunkle). These diverse outcomes stem from inherent limitations within the tool, including SNP selection criteria, rare variant exclusion, the absence of biological information integration, and considerations for diverse populations.Overcoming PRS limitations and enhancing efficiency requires strategic integration of genetic loci annotations with post‐translational modifications (PTMs), impacting AD‐related processes and genes (NFT, PSEN1, PSEN2, APP).Furthermore, the inclusion of diverse populations, specifically working with admixed populations like the Brazilian dataset, is essential for a nuanced understanding of these factors. This approach is critical for a comprehensive application of PRS in advancing our understanding of Alzheimer’s disease.Consequently, The main goal is to evaluate PTM impact on Alzheimer’s disease phenotypes using Polygenic Risk Score models in Brazilian and European populations.MethodThe initial outcomes of the project involve the establishment of the PTMflex Annotator. This annotator seamlessly integrates the PTMnet and PhosphoSitePlus datasets with functional protein information from the NCBI platform. Serving as a unified tool, it facilitates efficient access and exploration of PTM sites and types. Users can input parameters such as genomic position, Ref seq transcript, or protein ID for precise inquiry.The whole‐genome sequence datasets from the European Population (ADNI) and the Brazilian Population (ABraOM) will be integrated into the PTMflex Annotator for PTM extraction and verification. Subsequent tasks include logistic regression to determine PTM weights for each variant and calculating the total PTMs feature of each sample. The project concludes with a comprehensive PRS enrichment analysis, assessing the combined impact of PTMs and the PRS model through PLINK software, utilizing PGS003957 ‐ Kunkle (12,002 Variants) and PGS003953 ‐ Bellenguez (1,937 Variants) as base dataset.ResultThe ongoing phases of the project include applying target data into the PTMflex Annotator.ConclusionAnticipating discernible differences in the influence of PTMs within the prediction model across the two populations, the comprehensive whole‐genome sequence dataset is expected to identify rare variants linked to PTMs that could impact the Alzheimer’s disease phenotype.
Simian varicella virus infection in rhesus macaques is associated with amyloid deposition in multiple organs and arteries and production of an amyloidogenic state
Authors: Mahalingam Ravi , Bubak Andrew N. , Bustillos Amalia , Feia Brittany , Das Arpita , de Haro Eileen , Doyle‐Meyers Lara , Looper Jayme , Niemeyer Christy S. , Restrepo Diego , Nagel Maria A. , Traina‐Dorge Vicki 
Published: January 2025

AbstractBackgroundVaricella zoster virus (VZV) is latent in ganglionic neurons in >90% of the world population and reactivates to produce herpes zoster in older adults. Zoster increases dementia risk, of which Alzheimer’s disease (AD) is the most common. However, a critical barrier in studying the mechanisms by which VZV contributes to dementia is that VZV is an exclusively human virus. Simian varicella virus (SVV) is the non‐human primate homolog of VZV that produces the same clinical spectrum of disease from varicella to latency to zoster. Thus, we used the SVV infection model in vivo to examine how infection may recapitulate AD pathology, specifically the induction of amyloidogenic peptides and amyloid deposition, thereby accelerating disease progression.MethodRhesus macaques were infected with SVV such that they developed varicella, established virus latency, then developed zoster following immune suppression; serum, tissues, and arteries were harvested across timepoints. Blood was examined for the presence of SVV DNA by PCR from pre‐inoculation to zoster. Serum was analyzed by ELISAs and Thio‐T assays (following an amylin spike) for the presence of amyloidogenic peptides and an amyloid‐promoting environment, respectively. Various tissues and arteries in the periphery and central nervous system were examined by immunohistochemistry for SVV antigen and amyloid.ResultsAt the height of SVV viremia, increased amylin was seen and an amyloidogenic environment was induced in serum compared to pre‐inoculation and viremia resolution. SVV antigen co‐localized with amyloid in the periphery (pancreas, GI tract, temporal artery, olfactory epithelium and bulb) and amyloid was found in central nervous system (cerebral arteries).ConclusionVaricella infection may accelerate AD progression, in part through increasing the amyloid burden. In particular, the presence of amyloid in cerebral arteries in infected monkeys further support the role of varicella infection in the cerebrovascular disease (including cerebral amyloid angiopathy) seen in AD brains.
Effects of Different Intensity Exergame Balance Training on Balance and Cognition in Patients with MCI
Authors: Saeed Aruba , Amjad Imran 
Published: January 2025

AbstractIntegrating balance and cognitive training of varied intensities through exergame balance training may offer a distinct approach to enhancing balance and cognitive abilities in patients with mild cognitive impairment. The objective is to determine the relationship and effects of exergame balance training of different intensities on balance and cognition in patients with mild cognitive impairment (MCI). In this four‐arm parallel design Randomized Clinical Trial, ninety‐seven participants with mild cognitive impairments MoCA (18‐24), between the ages of 50 and 75 years, participated in novel exergame balance training. They were randomly assigned to one of four exergame balance training groups (mild, moderate, high, and control). All participants received twenty‐four sessions including forty minutes/sessions three times/week. The MoCA and BDNF were used to assess cognition, time up and go test (TUG), TUG dual task for functional mobility, Gait speed normal and fast for dynamic stability at baseline, after the 4th and 8th week. The correlation between cognition and balance was determined by spearman’s correlation. The mixed model analysis of covariance while fixing the baseline values as a covariate was used to determine interaction effects between interventions and time. Post hoc analysis was performed to investigate the findings between different complexity levels and the control group, and repeated measure ANOVA to determine within group differences.There was a strong relationship between MoCA and TUG, TUG dual task with (rs = 0.41), (rs = 0.43) respectively and moderate relationship between MoCA and slow and Fast gait speed (rs = 0.15), (rs = 0.24) respectively of high intensity group. A significant interaction effect of group and time was observed for MoCA, TUG (1,3) = 19.34, <0.001, η2 = 0.217, TUG dual task (1,3) = 21.24, <0.001, η2 = 0.233, gait speed fast tests (1,3) = 11.889, 0.001, η2 = 0.151. Post‐hoc analysis at different intensities demonstrated a significant difference between mild, moderate and high complexity groups with the control group for MoCA, TUG, TUG dual task, Gait speed normal and fast (p<0.01).The results indicate that exergame balance training of mild, moderate and high complexity influence the balance and cognition abilities differently with the improvement in the high intensity to a greater extent.
(In)Equity in Alzheimer’s Clinical Trials: A Long Road Ahead?
Authors: de Souza Ana Cláudia , Borelli Wyllians Vendramini , Rosa‐Neto Pedro 
Published: January 2025

AbstractBackgroundDementia is a complex condition that affects individuals in various ways around the world, with a particularly high prevalence and incidence in low‐ to middle‐income countries. However, the majority of clinical trials on immunomodulators in Alzheimer’s disease have predominantly been conducted in specific geographic regions and populations. Our objective is to assess the diversity and inclusiveness of the participant samples in terminated phase 2 or 3 clinical trials for anti‐amyloid therapies.MethodWe performed a systematic review for completed and terminated phase 2 or 3 clinical trials for Alzheimer’s disease in ClinicalTrials.gov with results published. We also searched for MEDLINE using “((anti‐amyloid) AND (alzheimer disease[MeSH Terms])) AND (therapy[MeSH Terms] OR (drug) OR (trial))”. We selected only trials using anti‐amyloid therapies regardless of the disease stage (Figure 1. Flowchart). We included all studies that provided sociodemographic characteristics of the sample studied. Variables collected were gender, race, countries where the trial was conducted, and mean years of education.ResultA total of 16055 individuals over 12 trials were evaluated in this work (ENGAGE, EMERGE, GRADUATE I and II, CLARITY‐AD, A4, EXPEDITION3, ELN115727, CREAD and CREAD 2, TRAILBLAZER‐ALZ 1 and 2). Gender was similarly distributed among studies (8911 females, 55.5%). Participants included were mostly white individuals (13664, 85.1%), with a minority of asian individuals (1259, 7.8%), and black individuals (202, 1.2%). Ethnic origins were demonstrated in 8 studies and only 774 (4.8%) individuals self‐reported as being hispanic. Studies were conducted in 164 countries taken altogether, but included only 25 (15.2%) low‐ and middle‐income countries.ConclusionClinical trials using anti‐amyloid drugs have failed to represent the majority of individuals living with AD‐related cognitive impairment on a global scale. It ultimately increases the disparities presented in the diagnosis and treatment of individuals with dementia. Ideally, anti‐amyloid trials should incorporate the epidemiology of individuals with dementia worldwide. These observations underscore the urgent need for coordinated efforts involving scientists, societies, local governments, and industry to prioritize equity as a central goal in science.