bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between Cortical Thickness and Mild Behavioral Impairment in a Southeast Asian Population ‐ Biomarkers and Cognition Study, Singapore BIOCIS
Authors: Leow Yi Jin , Vipin Ashwati , Tanoto Pricilia , Azam Mohammed Adnan , Sandhu Gurveen Kaur , Lee Faith Phemie Hui En , Ghildiyal Smriti , Liew Shan Yao , Tan Isabelle Yu Zhen , Kandiah Nagaendran 
Published: January 2025

AbstractBackgroundMild Behavioral Impairment (MBI) is the onset of sustained neuropsychiatric symptoms that are considered as a possible precursor to neurodegenerative conditions, especially dementia. The concept of MBI recognizes that behavioral changes may be an early sign of brain changes due to neurodegeneration. Very recent research has shown behavioral changes in MBI might be linked to changes in brain structure, including cortical thickness. Cortical thickness is associated with various neurodegenerative diseases, including Alzheimer’s disease and other forms of dementia. We examined the association between cortical thickness and neuropsychiatric symptoms(NPS) in a multi‐ethnic Southeast Asian population.Method657 participants were recruited from the community living in Singapore. 399 were cognitively unimpaired (CU), 253 with mild cognitive impairment (MCI), and overall, the mean age = 59.86 years, mean education = 14.52 years with 40.2% males.Participants completed the Mild Behavioural Impairment‐Checklist (MBI‐C), a self‐reported questionnaire. Mild Behavioural Impairment(MBI) classification was based on established clinical cut‐offs of 8.5.Participants underwent magnetic resonance imaging (MRI) scan on a 3T Siemens Prisma Fit (Siemens, Erlangen, Germany). Structural MRI was acquired using T1‐weighted MPRAGE sequence. Structural images were preprocessed using FreeSurfer (https://surfer.nmr.mgh.harvard.edu/, software version 7.2). For each participant’s T1 images, automated segmentation and cortical parcellation was carried out using the FreeSurfer “recon‐all” processing stream, which included motion correction, removal of nonbrain tissue, automated Talairach transformation, intensity correction, volumetric segmentation, and cortical surface reconstruction and parcellation.ResultIn the left hemisphere, the cortical thickness of the cuneus, entorhinal, parstriangularis, precuneus, rostral anterior cingulate, was significantly associated with the likelihood of being classified as MBI. The right – entorhinal, inferior parietal, pars orbitalis, supramarginal and frontal pole cortical thickness was significantly associated with the likelihood of being classified as MBI.ConclusionThe results highlight the importance of MBI as potential early indicators of cognitive impairment and suggest that these impairments are associated with changes in cortical thickness and increased risk of cognitive decline. The complex interplay between behavioral and cognitive symptoms in aging and neurodegenerative diseases needs to be defined.
Deciphering a Single‐cell atlas and loss‐of‐function analysis revealing ABCA7’s transcriptome insights in Alzheimer’s disease
Authors: De Deyn Lara , Duchateau Lena , Watzeels Tijs , Vicente Cristina , Van Dongen Jasper , Bijnens Baukje , De Pooter Tim , De Rijk Peter , Strazisar Mojca , Vandenberghe Wim , Thal Dietmar Rudolf , Mancuso Renzo , Rademakers Rosa , Küçükali Fahri , Sleegers Kristel 
Published: January 2025

AbstractBackgroundABCA7, an important risk gene for AD, encodes a transporter implicated in lipid transport and phagocytosis, and its disruptions have been linked to AD pathogenesis. However, the impact of these mutations on AD risk is complex due to their interaction with a multifaceted transcriptional architecture and cell type‐specificexpression patterns. This study aims to analyze the intricate patterns of ABCA7 expression across diverse cell types, considering various ABCA7 genotypes in relation to AD patients and non‐carrier controls, while also exploring the effects of ABCA7 mutations on transcriptome‐wide gene expression.MethodTo address this complexity, we performed droplet‐based single‐nuclei RNA sequencing on BA10 brain samples (ABCA7 mutation carriers [n = 9], non‐carrier AD patients [n = 6], and non‐carrier control [n = 8]) using 10x Chromium library preparation followed by sequencing on a NovaSeq6000 platform. Cell type annotation was performed using scSorter. Differential gene expression was analyzed using limma‐voom, and pathway analyses were performed using fgsea in R across cell types and studied groups.ResultWe obtained over 400,000 nuclei across 23 samples. Excitatory neurons had the highest proportion of cells expressing ABCA7. However, the highest average expression of ABCA7 was noted in microglia. We detected numerous differentially expressed genes between carrier and non‐carrier AD patients (pval_FDR_adj < 0.05 & abs(logFC) >1). Pathway analysis revealed a notable decrease in the expression of translation‐related genes in microglia, including those associated with nonsense‐mediated mRNA decay, in individuals carrying the mutation.ConclusionIn conclusion, our study unveils distinctive patterns of ABCA7 expression and enriched pathways across major brain cell types, suggesting different roles of ABCA7 in different cell types.
Pathologically confirmed advanced stage of limbic predominant age related TDP‐43 encephalopathy (LATE): A case report
Authors: Jung Young Hee H , Lee Jin Hwan H , Park Sung‐Hye 
Published: January 2025

AbstractBackgroundWe herein introduce a case that was pathologically confirmed as an advanced stage of LATE.Method(case presentation) An 81‐year‐old woman visited a memory clinic complaining of memory impairment in the past few years. She had no psychiatric history and a history of significant hyperlipidemia and hypertension. On MMSE she scored 20 with CDR of 1 (SOB 6). T In the first‐year post‐onset, brain MRI indicated diffuse brain atrophy with hippocampal atrophy MTA‐Gr2). At the fifth year, the patient was unable to perform all ADL and frequently exhibited severe BPSD. Contrary to the worsening of clinical symptoms, brain CT revealed only slight increase in hippocampal atrophy (MTA‐Gr3), with no significant difference from the MRI findings 5 years ago. The patient died at the age of 88.ResultThe brain autopsy revealed global brain atrophy with 923g in brain weight. Final pathological diagnosis was Alzheimer’s disease (AD), limbic‐predominant age‐related TDP43 encephalopathy (LATE), and cerebrovascular disease. In detail, under the NIA‐AA ADNP grading, the level is intermediate, with scores of A3, B3, and C2 adding up to 8. The Thal phase is rated 3 out of a possible 5. The Braak stage, which indicates the progression of Alzheimer’s tau pathology, is at stages V to VI out of VI. The CERAD score was 2 out of 3. No evidence of cerebral amyloid angiopathy (CAA) was found (score of 0). The stage of LATE was 6 by Joseph staging system, thus, TDP43‐positive intraneuronal inclusions and neurites were found in the amygdala, entorhinal and temporal lobes, hippocampal cornu ammonis and dentate, basal ganglia, and tectum of the midbrain and olivary nucleus of the medulla oblongata. However, there was no hippocampal sclerosis.ConclusionIn this report, the subject was initially diagnosed with Alzheimer’s dementia while alive; however, a post‐mortem autopsy revealed the primary condition to be an advanced stage of LATE, specifically at Joseph stage 6, coexisting with Alzheimer’s disease and cerebrovascular pathology. This case underscores the importance of understanding the pathological characteristics of TDP‐43 protein abnormalities and their related clinical manifestations.
A novel analysis approach to Mirror Tracing Task performance to detect fine‐grained age‐related differences
Authors: Garrido Pablo F. , Bråthen Anne Cecilie Sjøli , Falch Emilie Sogn , Kransberg Jonas , Sørensen Øystein , Walhovd Kristine B 
Published: January 2025

AbstractBackgroundThe Mirror Tracing Task (MTT) is a widely known test of motor learning. Participants are required to trace a star looking at their hand as a reflection in a mirror. In this work we introduce a new way of analysis beyond its simplicity.MethodThree versions of the MTT were employed in this project: paper‐based, online version, and an app version developed in the group, with over 3000 drawn stars and 170 participants. A generalization and standardization of the data is proposed to analyze all the possible stars and regular shapes. The proposed analysis method determines the distance between the drawn path and the mean star (the residuals), and the number of pixels drawn in a certain area (the density). These variables are measured for each unit of angle around the center of the star, providing us richer information about an MTT performance (Figure 1).ResultResiduals and density were summarized as single values representing the overall MTT performance. The sum of the density for all the angles and the sum of the absolute value of the residuals are used, respectively. They both correlate with the number of times a person draws outside the border, becoming a good alternative to it providing, at the same time, more complex information. Together with task time, these three variables show a clear positive association with age (all p‐values<0.001, see Figure 2). Through the study of the residuals and density as a function of the angle, areas of greatest difficulty for the participants can be identified. Moreover, a more refined analysis indicates that the results obtained in certain areas show a dependence on age (Figure 3).ConclusionThe proposed analysis provides an innovative approach to a simple task like the MTT. With this method, areas of special difficulty appear with age. These measures could be applied to the study of cognitive decline in aging or dementia, allowing us to look at the evolution of the performance with age and through the different trials.
Structural and functional analysis of TREM2 interactions with amyloid beta reveal molecular mechanisms that drive phagocytosis of oligomeric amyloid beta
Authors: Greven Jessica A , Alexander‐Brett Jennifer M , Brett Thomas J 
Published: January 2025

AbstractBackgroundThe development of new innovative treatments to prevent and ameliorate Alzheimer’s disease (AD) requires knowledge of molecular mechanisms that are critical to neuronal health. The receptor TREM2 is part of a signaling complex that modulates inflammatory responses, phagocytosis and cell survival in microglia– resident immune cells in the brain that play a critical role in clearing misfolded aggregates such as amyloid beta (Aβ). In recent years, TREM2 has emerged as a promising drug target for AD. Understanding the molecular mechanisms underlying TREM2 signaling in microglia will facilitate the development of specific, safe and efficacious therapies for AD that target TREM2. With this in mind, we set out to determine the structural mechanism for TREM2 phagocytosis of oligomeric Ab (oAb). We utilized comprehensive structural, biophysical, and functional analysis to achieve this goal.MethodWe used comprehensive biolayer interferometry (BLI) analysis to investigate TREM2 interactions with oAb42 WT and familial variants. We used X‐ray crystallography to determine the structure of TREM2 in complex with an Ab peptide. We used BLI with structure‐guided TREM2 variants to validate the Ab binding site on TREM2. Finally, we used Ab phagocytosis assays in HMC3 microglia cells for functional investigations.ResultWe found that N‐terminal variants in Ab did not bind TREM2. Using this information, we co‐crystallized a short peptide (Ab 1‐8) in complex with TREM2 and determined the structure. We found that it bound at CDR1 hear the hydrophobic site. This was validated by BLI, and mutations to the TREM2 hydrophobic site ablated binding to oAb42. Finally, we found that the interactions between the N‐terminal region of Ab and TREM2 were critical to drive phagocytosis in HMC3 cells.ConclusionOur results indicate that TREM2 uses the hydrophobic site (consisting of the CDR1, CDR2, and CDR3 loops) to engage the N‐terminal region of the Ab42 peptide to drive phagocytosis of oAb42. They also suggest that therapeutics that either directly bind or allosterically alter the hydrophobic site on TREM2 should modulate TREM2 signaling as potential AD treatments.
An AD‐associated variant in TTC3 alters the actin cytoskeleton organization and synaptic function in iPSC‐derived forebrain neurons
Authors: Cukier Holly N. , Duarte Carolina L. , Coombs Lauren , Lambert Caleb Avery , Van Booven Derek , DeRosa Brooke A. , Pericak‐Vance Margaret A , Griswold Anthony J. , Dykxhoorn Derek M. 
Published: January 2025

AbstractBackgroundWe identified the missense variant Ser1038Cys (rs377155188) in the tetratricopeptide repeat domain 3 (TTC3) gene that segregate in a non‐Hispanic white late onset Alzheimer disease (LOAD) family. This variant is predicted to be deleterious and extremely rare (MAF<0.01%). Expression of TTC3 is decreased in the brains of LOAD patients and negatively correlated with AD neuropathology.MethodsCRISPR/Cas9 genome editing was used to introduce the TTC3 Ser1038Cys variant into a control iPSC line. induced pluripotent stem cells (iPSCs) were developed that were homozygous for the TTC3 variant and validated for pluripotency. To understand the mechanism(s) by which this TTC3 variant may contribute to LOAD risk, this isogenic pair of edited and unedited iPSCs was differentiated into forebrain neurons and assessed for the cellular, molecular, and transcriptional consequences of this variant, including neuronal morphology, synaptic functionality, and vesicular trafficking.ResultsNeuronal progenitor cells (NPCs) derived from the isogenic iPSC lines showed that TTC3 variant‐bearing cells had elevated migration rates compared to their wild type counterparts as assessed by wound healing assays. Forebrain neurons bearing the Ser1038Cys variant showed elongated neurites and higher numbers of branchpoints compared to the wild type neurons phenocopying the effect of TTC3 loss of function analysis (siRNA‐mediated silencing of TTC3 in mouse neurons). This phenotype could be reversed using small molecule modulators of actin polymerization. Immunoblot analysis showed alterations in the expression of pre‐ and post‐synaptic markers in the TTC3 Ser1038Cys neurons compared to control neurons. RNA‐seq analysis of day 70 neurons identified 978 differentially expressed protein‐coding genes (FDR<0.05), including known AD genes (BACE1, A2M, INPP5F, UNC5C) and genes in AD GWAS loci (ADAMTS1, MAF, NCK2). Pathway analysis identified differential expression in PI3K‐Akt signaling pathway, as well as genes involved in axon guidance, the GABAergic synapse, and the Wnt signaling pathways.ConclusionsThe results of these studies suggest that the TTC3 p.Ser1038Cys variant causes a loss of function leading to alterations in neurite outgrowth, branching, and synapse formation, phenotypes consistent with alterations in actin stability. These studies in iPSC‐derived neurons implicate alterations in actin as potential mechanisms by which TTC3 may contribute to LOAD risk.
Sustained clinically meaningful response in patients with agitation associated with dementia due to Alzheimer’s disease treated with brexpiprazole: post hoc analysis
Authors: Brubaker Malaak , Wang David , Chumki Sanjeda R , Such Pedro , Zhang Zhen , Palma Anton M 
Published: January 2025

AbstractBackgroundA reduction in the frequency of agitation behaviors is a clinically meaningful outcome among patients with agitation associated with dementia due to Alzheimer’s disease. This post hoc analysis aimed to determine the percentage of patients treated with brexpiprazole who achieved sustained clinically meaningful response (CMR), over 12 and 24 weeks.MethodData for brexpiprazole 2 or 3 mg/day were obtained from two trials of patients with agitation associated with dementia due to Alzheimer’s disease: a 12‐week, randomized, double‐blind, placebo‐controlled trial (ClinicalTrials.gov identifier: NCT03548584) and a 12‐week, active‐treatment extension trial (NCT03594123). According to previous anchor‐ and distribution‐based analyses, a 20‐point reduction from baseline in Cohen‐Mansfield Agitation Inventory Total score represents a meaningful within‐patient change in this population. Hazard ratios (HRs) for non‐response and Kaplan–Meier curves for the cumulative proportions achieving CMR (a 20‐point score reduction) and sustained clinically meaningful response (SCMR; a 20‐point score reduction that was maintained to trial end) were calculated over (A) 12 weeks (data from the randomized trial for brexpiprazole versus placebo) and (B) 24 weeks (data from the randomized + extension trials for ‘prior brexpiprazole’ [i.e., received brexpiprazole in both trials] versus ‘prior placebo’ [i.e., received placebo in the randomized trial and brexpiprazole in the extension trial]).ResultOver 12 weeks, the percentages of patients achieving CMR were 61.8% for brexpiprazole (n = 225) versus 44.8% for placebo (n = 116); HR = 0.64; p = 0.006. Corresponding percentages of patients achieving SCMR were 49.3% for brexpiprazole versus 32.8% for placebo; HR = 0.58; p = 0.004. Over 24 weeks, the percentages of patients achieving CMR were 81.8% for prior brexpiprazole (n = 159) versus 72.6% for prior placebo (n = 95); HR = 0.63; p = 0.011. Corresponding percentages of patients achieving SCMR were 75.5% for prior brexpiprazole versus 68.4% for prior placebo; HR = 0.59; p = 0.010 (Figure).ConclusionAmong patients with agitation associated with dementia due to Alzheimer’s disease, a high percentage of patients on brexpiprazole 2 or 3 mg/day achieved sustained clinically meaningful response.
Efficacy of brexpiprazole on agitation in patients with dementia due to Alzheimer’s disease exhibiting behaviors most bothersome to caregivers: post hoc pooled analysis of two randomized controlled trials
Authors: Brubaker Malaak , Wang David , Chumki Sanjeda R , Such Pedro , Zhang Zhen , Palma Anton M 
Published: January 2025

AbstractBackgroundAgitation associated with dementia due to Alzheimer’s disease encompasses a wide range of behaviors, including excessive motor activity, verbal aggression, and physical aggression. In a survey of unpaid caregivers living with an individual with Alzheimer’s disease, the “most bothersome” agitation behaviors (which may influence the decision to transfer the patient to long‐term care) were: cursing or verbal aggression, spitting, repetitive sentences or questions, hitting, constant unwarranted requests for attention or help, trying to get to a different place, inappropriate dress or disrobing, pacing/aimless wandering, grabbing onto people, and throwing things. This post hoc analysis aimed to determine the efficacy of brexpiprazole on agitation in patients frequently exhibiting these bothersome behaviors.MethodData were included from two 12‐week, randomized, double‐blind, placebo‐controlled, parallel‐arm trials of fixed‐dose brexpiprazole in patients with agitation associated with dementia due to Alzheimer’s disease (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Efficacy was assessed using the Cohen‐Mansfield Agitation Inventory (CMAI), which comprises 29 agitation items scored from 1 (never occurs) to 7 (occurs a few times an hour). Least squares mean changes in CMAI Total score from baseline to Week 12 were determined in ten subsamples, each comprising patients for whom a specific “most bothersome” behavior occurred at least once per week (CMAI item score ≥3) at baseline. Data for brexpiprazole 2 or 3 mg/day (FDA‐approved dose) and for placebo were pooled.ResultThe pooled sample comprised 610 patients (brexpiprazole, n = 363; placebo, n = 247). At baseline, the ten “most bothersome” agitation behaviors occurred at least weekly in subsamples ranging from 134 patients (spitting) to 513 patients (pacing/aimless wandering). At Week 12, in the ten subsamples, between‐group least squares mean differences in CMAI Total score change favored brexpiprazole (all p<0.05 versus placebo) (Figure). In 8/10 subsamples, greater improvement for brexpiprazole versus placebo was observed from (at least) Week 8 onwards.ConclusionAgitation behaviors that are most bothersome to caregivers of patients with dementia due to Alzheimer’s disease (including excessive motor activity, verbal aggression, and physical aggression) were generally well represented in the brexpiprazole trials. In patients frequently exhibiting these bothersome behaviors, fixed‐dose brexpiprazole 2 or 3 mg/day was associated with larger improvements than placebo.
Metacognition as a tool to differentiate cognitively unimpaired from impaired subjects: judgments of learning in prospective memory task
Authors: Mendes Augusto J. , Ribaldi Federica , Chicherio Christian , Bastien Mathilde , Cappa Stefano F , Kliegel Matthias , Frisoni Giovanni B. 
Published: January 2025

AbstractBackgroundMetacognition may give useful insight in early stages of Alzheimer’s disease (AD) continuum. Recent studies suggest differences in the ability of judging their own cognitive performance along clinical stages. For instance, subjects with mild cognitive impairment (MCI) overestimate, whereas people with subjective cognitive decline (SCD) tend to underestimate their cognitive performance. One cognitive function compromised in prodromal AD is prospective memory (PM), which refers to the ability to remember something that has to be done. However, the metacognitive abilities in PM tasks are still not clear when comparing individuals with varying degrees of cognitive impairment.MethodOur study included 94 subjects from the Geneva Memory Center which are cognitively unimpaired (CU; n = 53), SCD (n = 26), and MCI (n = 15). All subjects performed a PM task with judgements of learning (JOL) to evaluate their metacognition. For that, participants were instructed to memorize a list of pairs of words and to press a specific key if the first word of the pair appeared in a posterior lexical decision task. A one‐way ANOVA tested the differences in PM performance and corresponding JOLs among the three clinical groups. Lastly, the association of PM metacognition with subjective complaints and anxiety levels was tested using Pearson correlations.ResultThe PM ability was significantly different among clinical groups (F = 10.5, p<0.001). Post‐hoc analysis revealed that MCI showed significantly lower PM in comparison with CU (p<0.001) and SCD (p = 0.003). Moreover, the JOL of PM also differed among the three groups (F = 4.5, p = 0.02), namely the MCI group showed lower JOLs in comparison with CU (p = 0.04). Likewise, correlations suggested a significant association between PM‐JOLs and subjective complaints (self‐other; R = 0.33, p = 0.006), whereas the association with anxiety was not statistically significant (p>0.05).ConclusionOur study suggested differences in the PM and its JOL between MCI and CU/SCD. However, our study was not able to differentiate between the CU and SCD groups at the PM and the corresponding JOL, even though their difference was significantly correlated with subjective functioning.