bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of writing in patients with the semantic variant of Primary Progressive Aphasia
Authors: Machado Thais Helena , Pereira Rafaela Souza , Campanha Aline Carvalho , de Araujo Caroline Martins , Carthery‐Goulart Maria Teresa , de Paula França Resende Elisa , de Souza Leonardo Cruz , Caramelli Paulo 
Published: January 2025

AbstractBackgroundLanguage impairment manifestations in patients with the semantic variant of primary progressive aphasia (S‐PPA) include surface dysgraphia. Word and pseudoword dictation helps characterize errors in these patients’ writing to better conduct their therapeutic strategies. Few studies have addressed written language in patients with dementia, and even fewer have done so in PPA. The objective was to analyze, classify, and quantify the types of writing errors in adults with S‐PPA using word and pseudoword dictation.MethodsThis cross‐sectional study was conducted in a Cognitive and Behavioral Neurology Outpatient Clinic. Its project was approved by the Research Ethics Committee. The research analyzed 19 patients with S‐PPA and 30 healthy individuals using a word and pseudoword dictation protocol. The two groups were matched for age, sex, and education level. The inclusion criteria for the control group were subjects whose Mini‐Mental State Examination score was appropriate to their age and education level, without any neurological and/or psychiatric diseases, and not taking medications that interfere with cognition. For the patients’ group, they were only required to be medically diagnosed with S‐PPA. Descriptive statistical analysis was performed, showing data frequency.ResultsThe S‐PPA group performed worse than controls on the word and pseudoword writing task. Both groups performed worse in irregular words and grapheme substitution.ConclusionPatients with S‐PPA performed worse in word and pseudoword writing than controls, most often in grapheme substitution and irregular words, which can be explained by the frequent occurrence of surface dysgraphia present in S‐PPA, which hinders their access to the lexical route.
Differential Effects of Anticholinergic Medications in Patient hiPSC‐Derived Neurons
Authors: Schwarze‐Taufiq Tiara A. , Pranoto Inez , Hui Katherine , Ogg Jordan , Zhu Ruowei , Crane Paul K. , Gray Shelly L , Young Jessica E. 
Published: January 2025

AbstractBackgroundAnticholinergic (AC) use remains common in older adults despite evidence of safety risks, including dementia risk. Evidence from population studies suggests that dementia risk may vary by AC class. This variation might be explained by confounding by indication. In vitro models, using human neural cells where cells are directly experimentally exposed to a drug and phenotypic outcomes are measured, may address this issue. We identified classes of AC medications with and without an association with dementia based on population studies. We treated human induced pluripotent stem cell‐derived neurons (hiPSC‐Ns) with each AC medication and performed cellular assays to examine the effects on AD phenotypes.MethodWe have generated hiPSC lines from participants in the Adult Changes in Thought Study (ACT), a longitudinal study in Seattle, WA. We differentiated hiPSC‐Ns from ACT cell lines using protocols in our laboratory. We treated neurons with different classes of AC medications: antidepressants (amitriptyline, doxepin, paroxetine), antihistamines (diphenhydramine, chlorpheniramine), bladder antimuscarinics (oxybutynin, tolterodine), and antispasmodics (atropine). As a control, we treated cells with the classic cholinergic compound carbachol. Cells were treated with two drug doses (10 uM, 50 uM) at two time points (24 hours, 48 hours). We used molecular assays to test AD‐associated cellular outcomes (neurotoxicity, synaptic gene expression and Amyloid beta [Aβ]).ResultWe document differential effects of medications on cytotoxicity, secreted Aβ levels, and synaptic gene expression. Several drugs demonstrated dose‐dependent (doxepin, oxybutynin, paroxetine, amitriptyline) and/or time dependent (oxybutynin, paroxetine) neurotoxicity. We also observed differential effects on Aβ secretion. Oxybutynin, a bladder antimuscarinic, consistently induced an increase in the Aβ42/40 ratio, largely driven by increased secreted Aβ42. Further, all antidepressants and bladder antimuscarinics tested increased the secreted Aβ42/40 ratio at 50 uM. These findings are consistent across lines of different genetic backgrounds.ConclusionStem cell‐derived neuronal models provide a useful strategy to complement pharmacoepidemiological studies to help distinguish molecular pathways versus confounding by indication of drugs associated with dementia risk. Preliminary results suggest that different AC medications have differential effects on AD‐associated cellular outcomes that are consistent across hiPSC‐Ns derived from individuals with various genetic backgrounds, indicating a molecular effect of the drug.
Characterization bacterial metabolites and peripheral immune cell populations in stable and progressive Alzheimer’s disease
Authors: Loew Ethan B , Tracy Matthew , Jo Cynthia , McCormick Beth , Haran John P 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia which results in debilitating memory loss as the disease advances. However, among older adults with AD, some may experience rapid cognitive decline while others may maintain a stable cognitive status for years. In addition to the amyloid plaques, tau tangles, and neuronal inflammation characteristic of AD, there is strong evidence of dysregulation in the peripheral immune system, including decreased naïve T cells and increased memory T cells among older adults with AD. It is currently unknown what underlies dysfunction in the peripheral immune system or whether changes in peripheral immune cells are associated with cognitive decline.MethodWe have performed unbiased metabolomics and characterized stool metabolites present in 35 AD versus 35 propensity matched healthy controls. In our ongoing work, we are longitudinally characterizing resting peripheral immune cell populations by flow cytometry and gut microbiome composition by metagenomic sequencing.ResultWe have identified an increase in the metabolites methionine sulfone (1.46 fold, p<0.05), homocysteine (1.67 fold, p<0.05), and cysteine (1.33 fold, p<0.05) in the stool of older adults with AD compared to controls. Among the population of AD patients experiencing cognitive decline, determined by increasing ADAS‐Cog score >6 points over one year (n = 7 declining vs n = 8 stable cognition), we have identified increases in the bacterial genes responsible for methionine production at the point of cognitive decline compared to previous timepoints and between patients with decline versus stable cognition. In accordance with the role of methionine in promoting immune cell proliferation and differentiation, we have compared the composition of peripheral immune cells among adults with declining versus stable cognition and identified a decrease in CD4+/CD62L+ naïve T cells (percent of CD4+ lymphocytes, stable 0.3055 vs declining 0.0955, p = 0.0042) and increased effector memory CD4+ T cells (percent of CD4+ lymphocytes, stable = 0.2375 vs declining = 0.4164, p = 0.0225).ConclusionThis longitudinal clinical study identifies changes in stool metabolites and resting peripheral T cell populations in AD patients and among AD patients with cognitive decline. We propose that gut bacterial produced methionine acts to promote peripheral immune differentiation and dysfunction, leading to cognitive decline in AD.
Automated Neurofibrillary tangle detections in digital histopathology sections of the brain
Authors: Arezoumandan Sanaz , Teunissen‐Bermeo Eric , Capp Noah , Zablah Jamila , Ohm Daniel T , Phillips Jeffrey S , McMillan Corey T , Lee Eddie B , Wolk David A , Yushkevich Paul A. , Irwin David J 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the most common neurodegenerative disease, and it is characterized by aggregation of misfolded proteins in the brain. Intraneuronal accumulation of tau pathology form neurofibrillary tangles (NFT) in AD. The assessment of the severity of intraneuronal inclusions holds significance in studying the clinicopathological associations in neurodegenerative diseases. Using machine learning methods, we have developed an automated tool to detect NFTs in immunohistochemically stained sections.MethodWe trained a weakly supervised machine learning algorithm called WildCat to classify inclusions in AT8‐stained 6µm sections of the hippocampus and locate areas with high probability of NFTs in the tissue. Next, we utilized the WildCat activation outputs and improved the NFT detections by thresholding and applying morphological filters. Finally, in order to validate our methods, we generated a validation dataset using QuPath software by manually annotating NFTs (N = 600) in 175 × 175µm regions of interest (N = 103). We then tested the correlation between manual and automated measurements to validate our method (Fig. 1).ResultThe WildCat classification model showed outstanding performance by accurately distinguishing NFTs from non‐tangle inclusions, achieving high accuracy (97.31%), recall (99.37%), and precision (99.3%). In addition, we tested the correlation between final output of our model with manual measurements of tangles in our validation dataset, where we found strong correlations in tangle counts and tangle percent area‐occupied between the two methods (R = 0.84‐0.88, p<0.001) (Fig. 1).ConclusionAutomated tools can reliably generate measurements of NFT density in AD tissue sections. Moreover, this method can be applied to other types of pathologies and may offer a helpful tool for the study of other neurodegenerative diseases.
Preliminary Insights from a Multi‐Ancestry TWAS in Alzheimer’s Disease in African and European Populations
Authors: Sun Xinyu , Mews Makaela , Wheeler Nicholas R. , Benchek Penelope , Reitz Christiane , Naj Adam C. , Below Jennifer Elizabeth , Kunkle Brian W. , Griswold Anthony J. , Bush William S. 
Published: January 2025

AbstractBackgroundRecent advances in Alzheimer’s Disease (AD) research have emphasized the importance of recruiting from diverse populations. Notably, African‐descent individuals have an almost doubled risk of developing AD compared to European‐descent individuals. Transcriptome‐wide association studies (TWAS) have advanced the analysis of non‐coding variants by integrating gene expression with GWAS data. The newly developed Multi‐ancEstry TRanscriptOme‐wide analysis (METRO) method leverages gene expression data from multiple ancestries, enhancing TWAS power. Addressing this knowledge gap, our study utilized METRO, incorporating both African and European expression and genotype data from the Multi‐Ancestry Genomics, Epigenomics, and Transcriptomics of Alzheimer’s (MAGENTA), to identify AD‐associated genes in each population.MethodQuality control (QC) on genotype data included filtering SNPs with MAF>0.05 and removing samples with outlier global principal components (PCs). Post‐QC, 199 African and 236 European samples from MAGENTA, with both whole‐blood expression and genotype data, were retained. cis‐eQTL analysis was performed for each protein‐coding gene within a 500kb region, adjusting for age, sex, PCs, and PEER factors. We obtained African American AD GWAS statistics from Kunkle et al. 2021 (n = 8,006) and European AD GWAS statistics from Douglas et al. 2021, excluding 23andMe and UKBB samples (n = 398,058). High‐coverage 1kGP WGS data served as the linkage disequilibrium (LD) reference panel for GWAS statistics. METRO analysis utilized both ancestries’ summary‐level eQTL and GWAS statistics.ResultWe identified 276 statistically significant genes using European‐descent individuals after Bonferroni correction. In contrast, no significant genes were found using African‐descent individuals, except within the APOE locus. Excluding APOE locus genes, gene‐set enrichment analysis using DisGeNET revealed enrichment in AD and related dementia pathways among the top 10 pathways. Among the 246 significant genes, excluding APOE locus, identified in individuals of European‐descent, 131 exhibited the same gene‐trait association direction in individuals of African‐descent.ConclusionThe multi‐ancestry TWAS identified 276 genes potentially associated with AD, particularly in pathways related to the disease. These findings may enhance our understanding of AD genetic risk. The limited sample size in African‐descent AD GWAS may explain the lack of significant gene identification beyond the APOE locus. Future studies with more diverse populations are essential for discovering novel AD‐related genes in underrepresented groups.
Cross‐species protein interactome network‐based analysis of GWAS and human brain quantitative trait loci (x‐QTL) data identifies risk genes and drug targets for Alzheimer’s disease
Authors: Xu Jielin , Zhou Yadi , Hou Yuan , Pieper Andrew A. , Cheng Feixiong , Leverenz James B 
Published: January 2025

AbstractBackgroundThe emerging tools of protein‐protein interactome network offer a platform to explore not only the molecular complexity of human diseases, but also to identify risk genes and drug targets. Integration of the genome, transcriptome, proteome, and the interactome networks are essential for such identification, including Alzheimer’s disease (AD), Parkinson disease (PD), and Amyotrophic lateral sclerosis (ALS)MethodIn this study, we performed multi‐modal analyses of cross‐species protein interactome networks and human brain functional genomics data to identify risk genes and drug targets for neurodegenerative diseases. We presented a multi‐view topology‐based deep learning framework to identify disease‐associated genes for cross‐species interactome (TAG‐X). We re‐constructed comprehensive protein‐protein interactome networks for human, Drosophila melanogaster (fruit fly), Caenorhabditis elegans (worm), and Saccharomyces cerevisiae(yeast), by assembling high quality binary protein‐protein interactions (PPI). The fundamental premise of TAG‐X is that AD risk genes exhibit distinct functional characteristics compared to non‐risk genes and, therefore, can be distinguished by their aggregated human brain‐specific functional genomic features from various quantitative trait loci (x‐QTL), including expression QTL (eQTL), protein QTL (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL).ResultAfter integration genome‐wide association studies (GWAS) and x‐QTL data into the interactome networks via TAG‐X, we found that unique integration of fly, worm and yeast interactome networks boosted performance in risk gene prediction compared with the human protein‐protein interactome across AD (e.g., fly: NDUFAF6, CHRNA2; worm and yeast: TOMM40), PD (e.g., fly: SCARB2; worm: AGAP1; yeast: SLC2A13, BCKDK) and ALS (e.g., fly: SOD1; worm: SARM1; yeast: VCP, PRDX6). We found that human brain‐specific PPI network presented the strongest potential for AD risk gene discovery (e.g., AD: ACE, BIN1, INPP5D,MS4A4A, SYK; PD: SNCA, LRRK2, DGKQ; ALS: SCFD1, G2E3). Furthermore, interactome network‐predicted genes are significantly enriched in known drug targets and are significantly enriched in disease‐related pathobiological processes.ConclusionIn summary, we presented a cross‐species protein interactome network methodology that utilizes functional genomic and GWAS findings to identify disease risk genes and drug targets for AD and other neurodegenerative diseases if broadly applied. Functional observations of candidate targets and genes are warranted in the future.
Differentially expressed genes and biological processes shared by alternative and mouse models of Alzheimer’s disease
Authors: Pereira Flávia Suelen De Oliveira , Carello‐Collar Giovanna , Ryssina Vitória Vitalina Margarita , Ávila Daiana Silva , de Bastiani Marco Antônio , Zimmer Eduardo R. 
Published: January 2025

AbstractBackgroundReplacement, Reduction, and Refinement (3R) guidelines propose the use of alternative models to study human diseases. These models have high homology and are less onerous compared to rodents, which dominate Alzheimer’s disease (AD) research. However, it is still necessary to investigate whether evolutionary components are conserved among AD models cross‐species. Thus, we aimed to determine similar and different core molecular programs and biological processes in alternative and mouse models of AD.MethodsWe searched the Gene Expression Omnibus (GEO) repository for available RNa‐sequencing studies of alternative (Caenorhabditis elegans, Drosophila melanogaster, and Danio rerio) and mouse (Mus musculus) models of amyloidosis. The following datasets were selected for alternative (GSE198684, GSE109489, GSE158233) and mouse (GSE186710 and GSE144746) models of AD. According to the species, we selected the brain (hippocampus), head, or whole body as samples. Data was downloaded using the GEOquery package and the differentially expressed genes were defined as having FDR‐ adjusted p‐value < 0.05. Using the R Studio and Cytoscape software, we grouped DEGs into clusters of gene ontology for biological processes (GOBPs) according to their function.ResultsA greater number of DEGs were shared between D. rerio and mouse models of amyloidosis when compared to other species (Figure 1). By comparing alternative models, C. elegans has more DEG‐intersections with D. melanogaster than with D. rerio (Figure 1). Regarding biological processes, more overlap of GOBPs was found between D. melanogaster and M. musculus (Figure 2). C. elegans, despite having present DEGs in common with D. rerio and M. musculus, did not share GOBP terms with these vertebrates, but only with D. melanogaster (Figure 2). The shared biological processes conserved among the species were classically associated with AD pathology, such as protein misfolding response, immune and inflammatory systems, neurotransmission, and metabolic processes (Figure 3).ConclusionsThe findings suggest that alternative models share transcriptomic similarities with mouse models of amyloidosis. Thus, these models may serve to accelerate the understanding of amyloid‐related pathophysiological processes and the development of innovative therapeutics in AD.
Pupil dilation during visual search is sensitive to plasma pTau181 levels in cognitively healthy older adults
Authors: Festa Elena K , Heindel William C , Marangi Camille A. , Zou Jingjing , Galasko Douglas R. , Salmon David P. , Jacobs Diane M. 
Published: January 2025

AbstractBackgroundPathological changes of Alzheimer’s disease (AD) occur in the locus coeruleus (LC) years before clinical symptoms. This may affect LC activity that can be indexed by changes in pupil dilation. AD also disrupts connections between related but functionally distinct cortical areas leading to visual feature binding deficits. Thus, feature binding in individuals with preclinical AD may require additional cognitive effort that engages LC activity. Pupil dilation during conjunctive visual search may therefore be a particularly sensitive marker of preclinical AD.MethodSixty‐three cognitively unimpaired older adults from the UCSD Alzheimer’s Disease Research Center (51% men; overall mean age = 78.4 years, education = 17.5 years, and MoCA score = 25.9), performed a conjunctive visual search task while their pupil diameter was continuously recorded. There were 108 trials in which the participant searched for a target stimulus (a black dot moving up‐and‐down) among distractor stimuli that shared target features (white dots moving up‐and‐down and black dots moving left‐and‐right). Search displays contained 1, 3, or 5 stimuli with a target present on half of the trials. Reaction time and accuracy in detecting presence of a target were recorded. Plasma levels of the AD biomarker pTau181 were determined by the National Centralized Repository for Alzheimer’s Disease using Quanterix (v2). Plasma pTau181>4.09 pg/mL was considered AD positive.ResultAD positive (n = 19) and AD negative (n = 44) groups did not differ on age, education, sex, or MoCA scores. Despite similar behavioral performance in visual search, the groups displayed striking differences in pupillary responses across conditions. Both groups showed more pupil dilation with increasing display size, consistent with the application of cognitive effort. However, only the AD‐positive group showed significantly greater pupil dilation in the target‐present than target‐absent condition. This selective pupil modulation in the AD‐positive group may reflect greater demands associated with maintaining the search template in working memory or with performing template‐matching processes to guide attention.ConclusionResults suggest early functional changes in the LC noradrenergic system are detectable in biomarker‐positive cognitively healthy older adults. Pupillary responsivity under task‐induced conjunction search conditions may serve as a particularly sensitive marker of preclinical AD.
Digital Cognitive Screening Outcomes in Older Women at the Annual Well Woman Visit
Authors: Rizer Sandra , Joyce Jillian L. , Dargie Samantha A. , Chapman Silvia , Libon David J. , Mora Laura , Tom Sarah E. , Marder Karen , Rosser Mary , Cosentino Stephanie 
Published: January 2025

AbstractBackgroundMild cognitive impairment, a precursor to Alzheimer’s disease and related disorders (ADRD), is widely underdiagnosed. Routine screenings are key for identifying older adults with emerging neurodegenerative disease. As women have increased risk of ADRD and often use their gynecologist as their primary care physician, the annual well woman visit offers a critical opportunity to screen older women for ADRD. This study aimed to examine objective cognitive outcomes using a novel digital screening tool easily deployed in clinical settings.MethodWomen 50 and older were invited to participate in the current study at the time of their annual visit to the Columbia University Integrated Women’s Health Center. Participants completed a brief tablet‐based cognitive screener, the Core Cognitive Evaluation (CCE), developed by Linus Health. The CCE includes an immediate and delayed three‐word recall (3 points) and clock drawing (2 points) for a maximum of 5 points (Normal>3, Borderline 2‐3, Impaired<2), based on both core and error/process variables. A continuous 100‐point clock score is also produced with eight indices.ResultOf 130 eligible participants, 71(55%) agreed to participate in the study (see Table 1 for demographics). Continuous clock scores ranged from 16 to 100 (Mean(SD) = 73.15(21.2)). As described in Table 2, 62% participants scored in the Normal range, 37% in the Borderline range and 1% in the Impaired range. After a delay, 76% of participants recalled all or more of the words initially recalled. Lower scores were observed in clock drawing than delayed word recall, with spatial reasoning being the lowest the clock index score on average. See Figure 1 for clock indices.ConclusionThe majority of women obtained Normal CCE scores while 38% performed in the Borderline or Impaired range. By capturing subtle information about the process used to complete cognitive tasks, tablet‐based testing offers a sensitive means of detecting cognitive changes. Future work is needed to evaluate screener outcomes in relation to comprehensive neuropsychological testing and cognitive change over time. A limitation of this study is the sociodemographic homogeneity of the participants. Future work aims to expand into gynecology settings with more diverse patient populations.