bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma Exchange reduces amyloid plaques and microglial activation in APP/PS1 mice at the advanced stage of pathology
Authors: Koerich Suelyn , Ramirez Santiago , Astudillo Natalia , Soto Claudio 
Published: January 2025

AbstractBackgroundAmyloid plaques predominantly consist of extracellular aggregates of amyloid‐β (Aβ) peptide and represent a hallmark pathological feature of Alzheimer’s disease (AD). Evidence suggests that peripheral Aβ plays a crucial role in AD pathogenesis. Additionally, studies have indicated that Plasma Exchange (PE) with albumin replacement can slow the decline or stabilize AD symptoms. However, the factors that influence the mechanisms behind this are largely unknown. In this context, we have previously demonstrated the potential benefit of PE in reducing Aβ plaques in APP/PS1 mice at the early stage of AD pathology. Here, we tested the effectiveness of using PE monthly to decrease Aβ accumulation and alter brain inflammation in APP/PS1 mice at the advanced stage of pathology.Methods300µL of blood was obtained monthly from APP/PS1 mice from the jugular vein. Subsequently, the blood was centrifuged to remove the plasma, and the same volume was replaced with 5% albumin in saline and reinfused into the jugular vein (Figure 1). The procedure was performed four times between 11 and 14 months, and animals were humanely euthanized at 15 months. For histological analysis, brains were dissected after transcardiac brain perfusion. The right hemisphere was fixed for histology, and 10µm sections were stained with thioflavin‐S (Thio‐S) to analyze burden, number of plaques, and plaques size or incubated with anti‐Aβ antibody 4G8 plus Iba‐1 to analyze Aβ burden and microglia area. All images were analyzed using NIH Image J software.ResultsThe data demonstrate that PE with a 5% mouse albumin solution effectively reduced thioflavin‐S‐positive amyloid burden and plaque size in the cortex and Aβ burden in the cortex and hippocampus. Additionally, the Iba‐1+ area in the hippocampus was significantly lower in PE‐treated animals than in controls.ConclusionsThese results suggest that PE reduced amyloid plaques applied at advanced stages of the disease and supports PE’s potential efficacy as an alternative non‐pharmacological intervention for attenuating the progression of AD pathology.
Emory Wisconsin Card Sorting Test and Trail Making Test B as Measures of Executive Dysfunction
Authors: Lincoln Gabrielle A , Pal Subhamoy , Reader Jonathan M , Rose Savannah G , Maher Amanda Cook , Giordani Bruno 
Published: January 2025

AbstractBackgroundWisconsin Card Sorting Test (WCST) and Trail Making Test‐Part B (Trails B) are commonly used neuropsychological measures of executive functioning. Previously, Trails B was found to be more sensitive than the WCST in predicting executive dysfunction. The Emory WCST (eWCST) was adapted to remove cards with multiple sort options and duplicate cards, creating a more direct measure of executive function. This study aimed to assess whether the eWCST was a better predictor of executive dysfunction compared to Trails B.MethodData from 864 participants enrolled in the longitudinal University of Michigan Memory and Aging Project within the Michigan Alzheimer’s Disease Center were analyzed (34.3% Male, 34.7% Black/African American). Participants completed baseline neuropsychological testing and other Unified Data Set activities and received a consensus diagnosis: Cognitively Normal, amnestic Mild Cognitive Impairment (aMCI), non‐amnestic MCI (naMCI), or dementia due to suspected Alzheimer’s disease (AD). eWCST total errors and Trails B completion time were standardized and converted to T‐scores. Mean test scores within each diagnostic group were compared via Welch 2 sample t‐tests. Analysis of variance (ANOVAs) were used to compare group differences in eWCST and Trails B performance. Multinomial logistic regression was used to predict cognitive diagnosis using eWCST and Trails B performance.ResultWithin the three impaired groups (aMCI, naMCI, AD), mean T‐scores were lower (e.g., less impaired) for eWCST compared to Trails B (p’s<0.01). There was no between‐test difference for the cognitively normal group. All four groups showed significant differences for Trails B scores while eWCST differences were seen between all groups except between aMCI and naMCI. Logistic regression results found Trails B performance distinguished AD from both MCI groups (aMCI OR = 0.97, p<0.001; naMCI OR = 0.98, p<0.01), whereas eWCST errors trended toward differentiating AD from aMCI (p = 0.06) but not naMCI.ConclusionFindings suggest Trails B completion time better differentiates AD from both amnestic and non‐amnestic MCI compared to the eWCST, similar to previous findings (Hammers et al., 2015). Determining the best predictors of cognitive diagnosis enables the selection of a concise testing battery to minimize participant burden and maximizing diagnostic utility, given the limited time and resources available at research centers.
Exploring cortical perivascular space as a biomarker in neurodegenerative diseases through optimized CSF‐only MRI at 7T
Authors: Demir Zeynep , Saib Gael , Talagala Lalith , Taylor Paul , Kwan Justin Y , Koretsky Alan 
Published: January 2025

AbstractBackgroundDetecting changes in perivascular spaces (PVS) holds promise as a biomarker for neurodegenerative diseases. These spaces exhibit increased protein accumulation and dilatation in neurodegenerative diseases even preceding symptomatic stages. Advanced MRI techniques at high fields offer unparalleled clarity in visualizing these subtle structures. Notably, patients with Alzheimer’s disease (AD) show increased number of dilated PVS compared to healthy individuals in 7T MRI. While previous studies have primarily focused on white matter PVS due to their large size and visibility, cortical PVS remain relatively unexplored despite their potential diagnostic significance in diseases such as AD and motor neuron disease (MND). Recently, we optimized heavily T2‐weighted Turbo Spin Echo (TSE) at 7T, exclusively highlighting cerebrospinal fluid (CSF) signals, thus enabling the visualization of cortical PVS for the first time in healthy individuals. Leveraging this ability to detect cortical PVS, we aim to investigate cortical PVS in neurodegenerative diseases.MethodSeven MND and 5 AD/ADRD patients enrolled in an NIH IRB approved protocol (NCT03225144), and 20 healthy controls were scanned using Seimens Terra 7T MRI with our optimized T2‐weighted TSE sequence (TR = 2430 ms, TE = 500 ms, ETL = 108, TA = 10 min) achieving an isotropic resolution of 0.5 mm (125 nl voxels).ResultThe optimized sequence achieved a CSF‐to‐tissue signal ratio of approximately 30:1. After thresholding above noise, it was possible to detect CSF volumes of 10 nanoliters per voxel. In controls, cortical perivascular spaces were detected with unique morphology and have a density of 1‐2% of grey matter with the highest density in insular region. In one control, the CSF images revealed extensive PVS‐like structures in a previously suspected cyst formation at the juxtacortical area (Figure 1). Furthermore, patients with MND exhibited multiple distinct cortical PVS, most pronounced in the motor cortex (Figure 2).ConclusionOur findings underscore the utility of CSF‐only MRI in uncovering intricate structural details of cortical PVS, which can be explored in neurodegenerative diseases. This non‐invasive imaging modality holds promise as a sensitive biomarker for neurodegenerative diseases, with ongoing efforts aimed at quantifying disease‐specific cortical PVS and elucidating clinical implications of changes on cortical PVS.
The integration of epigenomic and transcriptomic sequencing data reveals cell‐specific Bexarotene‐induced transcriptional activity in APP/PS1 mouse brain
Authors: Lu Yi , Saibro‐Girardi Carolina , Fitz Nicholas F , Lefterov Iliya , Koldamova Radosveta 
Published: January 2025

AbstractBackgroundTreatment with the RXR‐specific agonist Bexarotene exerts neuroprotective effects in Alzheimer’s disease (AD) mouse models by improving cognition and increasing Aβ clearance. At the transcriptional level, ligand‐activated RXR receptors regulate gene networks linked to neural development, neuroinflammation, and metabolism. This study aimed to reveal the association between changes in chromatin architecture and transcriptional activity in the brain of Bexarotene‐treated APP/PS1 mice.MethodsAPP/PS1D9 mice were treated orally with bexarotene or vehicle (corn oil, DMSO 1%). Mouse brains were dissociated and used for cDNA library generation on a 10x Genomics platform for single‐cell resolution. Seurat pipeline was performed to resolve cell populations and for differential expression analysis, followed by GO analysis to reveal cell population‐specific transcriptional response to Bexarotene. Changes in chromatin architecture were evaluated by single‐cell ATAC‐seq. scATAC‐seq data were processed and integrated with scRNA‐seq using the ArchR pipeline.ResultsWe present a single‐cell‐resolution map of transcriptomic and epigenomic changes in Bexarotene‐treated mice. We profiled transcriptional and epigenomic landscapes of 37,640 cells (scRNA‐seq) and 61,353 individual nuclei (snATAC‐seq) from 8 samples (4 Bexa and 4 vehicle controls). To predict candidate upstream regulators that may be shaping the chromatin accessibility landscape of brain cells following ligand activation of RXR and contributing to cell type identity and cell fate specification, we used chromVar. We discovered 67 high‐confidence candidate regulators that show strong correlations between TF enrichment and ATAC‐inferred expression and between ATAC‐inferred expression and RNA‐measured expression. Next, we used the integrated single cell RNA‐seq and ATAC‐seq data to identify cell type‐ and disease‐specific cis‐regulatory elements (CREs) and their target genes by correlating gene expression with chromatin accessibility across all nuclei in the dataset. We then asked if the differential gene expression we observed could be mediated by candidate CREs. The majority of the DEGs identified between Bexa and control nuclei had a linked peak in the same cell type where the gene was differentially expressed. An example is Apoe gene located in the Apoe/Apoc locus that was significantly upregulated by Bexa in microglia but not in astrocytes.ConclusionsResults revealed that Bexarotene affected chromatin accessibility in microglia in correlation with Apoe expression.
Amyloid hypothesis: 20 years of failure in Alzheimer’s research
Authors: Tran Lloyd , Tran Zung Vu 
Published: January 2025

AbstractBackgroundWe reviewed the data of past failures to determine how aducanumab and lecanemab might differ from the rest of this class of drugs. Specifically, whether the differences between treatment and placebo are different.MethodWe systematically analyzed the data in publications where treatments were an anti‐Aβ monoclonal antibody drug, and data were available from published clinical trials. Only anti‐Aβ monoclonal antibody drugs that have completed at least a phase 2 trial were included. This class of drugs included, aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, ponezumab, semorinemab, and solanezumab. We focused on two outcome measures that were most frequently reported ‐ CDR‐SB and ADAS‐Cog. Nearly all trials reported the post‐treatment difference between drug and placebo, i.e., the difference between scores of the treatment relative to the placebo at the end of the trial. On a scale where a higher score is “worse,” a negative (‐) difference “favors” treatment (lower score – higher score = ‐ value). We use bootstrapping methodology, a machine‐learning statistical procedure that resamples from a single dataset (with replacement) to create multiple samples. This resampling distribution allows for the calculation of means, median, standard errors, confidence intervals (CI), and other statistics. The means and 95%CI of these published differences were estimated by performing 10,000 resamples.ResultAll the clinical trials analyzed were randomized, placebo controlled. Sample sizes varied for the phase 3 trials, from 253 to 1072 per arm (median = 519 participants); trial lengths were from 76 to 105 weeks (median = 78 weeks). The estimated bootstrap mean and 95%CI for differences between placebo and drug, for CDR‐SB and for ADAS‐Cog were: CDR‐SB; mean (95%CI) = ‐0.08 (‐0.31 to +0.22), range of differences = ‐0.70 to 1.30; ADAS‐Cog; mean (95%CI) = ‐0.53 (‐1.03 to +0.22), range of differences = ‐1.60 to +4.74.ConclusionThe cumulative mean changes for CDR‐SB were ‐0.08; for ADAS‐Cog it was ‐0.53, with both 95%CI including zero. The score range for CDR‐SB is 0 to 18; the range for ADAS‐Cog is 0 to 70/90. These mean differences across the many trials conducted cannot be considered to be either clinically or statistically significant.
A Novel Ultrasensitive Single‐Molecule Counting Technology for Quantitation of Neurological Biomarkers in Blood
Authors: Tobias Renee , Wagner Peter , Sandlund Johanna , Aoyagi Katsumi , Moriyama Kazushige , Zaugg Frank , Dave Gipshu , Inaoka Daigo , Kimura Hayato , Kobayashi Ko , Brachet Valerie 
Published: January 2025

AbstractBackgroundThere is a need for sensitive, robust, and scalable analytical methods for accurate, early detection of disease using less invasive sampling methods. Small volumes and low marker concentrations present challenges to achieving sufficient sensitivity and accuracy with traditional immunoassay methods ‐ particularly when measuring markers for Alzheimer’s (AD) and other neurological diseases in blood, where levels are typically much lower than in CSF.Here we introduce a novel optofluidic single‐molecule counting platform for ultrasensitive detection of low‐abundance biomarkers in plasma samples. Analytical validation data is presented for three Alzheimer’s Disease plasma biomarker assays developed on a fully automated benchtop analyzer with integrated ultrasensitive (US) detector.MethodFluorescence‐based immunoassays for pTau181, Aβ1‐40, and Aβ1‐42 were developed using high performance monoclonal antibodies and reagents (Fujirebio Inc, Japan). Capture antibodies were immobilized on magnetic particles, and detection antibodies conjugated to a proprietary fluorescent reporter construct. Multiple incubation and wash steps were followed by dissociation of immune complexes and separation of reporter‐Ab from magnetic particles. Released reporter‐Ab molecules were injected into the US detector device for single molecule counting.ResultWe performed analytical performance evaluation of each of the three assays, assessing sensitivity (LOD/LLOQ), linearity, parallelism, precision, and repeatability with clinical samples. Assay LLOQs of endogenous analyte spiked in plasma matrix were estimated at 0.2 pg/mL, 0.5 pg/mL, 0.5 pg/mL respectively for pTau181, Aβ1‐40, and Aβ1‐42 markers. Comparison to Lumipulse G1200 Plasma Tests for pTau181, Aβ1‐40, and Aβ1‐42 (Fujirebio Diagnostics, Inc.) yielded correlation coefficients of >0.998 through a working range of >4 logs.ConclusionWe have developed a new single‐molecule counting platform able to detect biomarkers at sub‐pg/ml levels, with the potential to provide sensitive and accurate diagnostic testing of low abundance neurological markers in blood with improved performance and reproducibility over currently available methods. Such technologies can create new clinical value through higher detection sensitivity and accuracy in areas of need such as Alzheimer’s and other neurological diseases, to support clinical research and translation to clinical practice.
Na+‐Ca2+ exchanger isoform‐3 in Aβ1‐42‐induced Alzheimer’s disease pathology
Authors: Afewerky Henok Kessete 
Published: January 2025

AbstractBackgroundThe relevance of a plasma membrane Na+‐Ca2+ exchanger isoform‐3 protein, NCX3, is widely evidenced in neuronal physiology. However, the mechanisms leading to NCX3 expression deficits in Alzheimer’s disease (AD) pathology and its value as a target in AD pharmacological medicine remain incomplete.MethodsInhibition and rescue experiments were performed in cultured primary neurons of 5×FAD mice model of AD using pathological Aβ1‐42 isolated from a conditioned medium of BHK cells, a cell line which does not constitutively express NCX3, stably transfected with a plasmid expressing human wild type Aβ1‐42.ResultsPathological forms of Aβ1‐42 interfere with NCX3 expression level and neuronal viability. Pronounced expression levels of NCX3 and state of endurance were observed in the control group compared with those treated with pathological Aβ1‐42.ConclusionNCX3 merits in‐depth study consideration as a predictive biomarker and in developing a potential novel pharmaceutical intervention method for AD.Keywords: Alzheimer’s disease, Aβ1‐42, Na+‐Ca2+ exchanger isoform‐3
Regional Deep Atrophy: Using Temporal Information to Automatically Identify Regions Associated with Alzheimer’s Disease Progression from Longitudinal MRI
Authors: Dong Mengjin , Xie Long , Wisse Laura , de Flores Robin , Das Sandhitsu R. , Wolk David A , Yushkevich Paul A. 
Published: January 2025

AbstractBackgroundAssessment of longitudinal hippocampal atrophy is a well‐studied biomarker for Alzheimer’s disease (AD). However, most state‐of‐the‐art measurements calculate changes directly from MRI images using image registration/segmentation, which may misreport head motion or MRI artifacts as neurodegeneration. We present a deep learning method Regional Deep Atrophy (RDA) that (1) estimates atrophy sensitive to progression by quantifying time‐associated changes in images, especially in preclinical AD stage (as in DeepAtrophy (Dong et al., 2021)), and (2) identifies regions where longitudinal changes significantly influence temporal inference.MethodRDA was trained on longitudinal T1‐weighted MRI from 155 ADNI participants and evaluated on 326 participants (Figure 1(c)). During training, two image pairs from the same participant are fed into two instances of the RDA network in arbitrary temporal order. Within each RDA network, a U‐Net is applied to one image pair of arbitrary order to predict attention regions informative of shrinkage/expansion. Attention regions are used to mask a deformation field computed by ALOHA (Das et al., 2012), and derive a total volume change measurement for attention areas. The attention regions are optimized by the Scan Temporal Order (STO) loss for one scan pair to evaluate if volume changes align with input image order, and the Relative Interscan Interval (RISI) metric to determine if larger volume changes correspond to longer interscan intervals for the whole RDA model (Figure 1). Only one longitudinal image pair is required for testing, directly generating the total volume change as atrophy measurement.ResultRDA achieves the similar ability to detect differences in atrophy between stages on the AD continuum as DeepAtrophy, especially in preclinical AD (Figure 2), while having additional explainability in the form of heatmaps that summarize expansion/shrinkage regions in the brain that contribute to the RDA change measurement (Figure 3). These heatmaps, derived in a fully data‐driven manner, largely recapitulate the areas of atrophy and expansion in the MTL reported by prior studies.ConclusionRDA has similar prediction accuracy as DeepAtrophy, but its additional interpretability makes it more acceptable for use in clinical settings, and may lead to more sensitive biomarkers for disease monitoring and progression understanding in preclinical AD.
The Berkeley PET Imaging Pipeline: Harmonization of Alzheimer’s disease PET biomarkers across studies
Authors: Harrison Theresa M. , Landau Susan M. , Baker Suzanne L. , Boswell Martin , Jagust William J. 
Published: January 2025

AbstractBackgroundCollection of neuroimaging data is resource‐intensive. Multi‐site studies have emerged as an effective way to amass large collections of PET scans, but data collected across many sites and scanners require specialized processing approaches. The Berkeley PET Imaging Pipeline (BPIP) and tools for numerical data post‐processing allow us to 1) process multi‐site and multi‐study PET scans using harmonized, largely automated tools and 2) disseminate numerical quantitative data.MethodPET data are harmonized by first using standard, tracer‐specific PET protocols and applying spatial smoothing to achieve a uniform resolution across scanners and sites. Using BPIP we complete MRI‐dependent or MRI‐free processing of PET scans which includes 1) definition of ROIs (MRI‐dependent: FreeSurfer Desikan‐Killiany in native space; MRI‐free: normalized probability Desikan‐Killiany in template space), 2) intensity normalization using a primary reference region, and 3) calculation of standardized uptake value ratios (SUVRs) across atlas ROIs, composite ROIs (e.g., temporal metaROI for tau tracers) and alternative reference regions (e.g., for longitudinal analyses). Tau‐PET scans are also partial volume corrected. BPIP runs on the XNAT platform on a dedicated server. For the MRI‐dependent pipeline, visual quality control (QC) is performed on automatically generated QC images that allow us to assess co‐registration and ROI delineation. We use a suite of software tools to curate and format the standardized numerical data. For studies that allow it, we release numerical quantitative PET data to the research community. For research conducted in our lab, we create datasets that combine neuroimaging data with other variables (e.g., demographic, genetic, cognitive).ResultUsing our current approach, we have processed over 20,000 PET scans across 8 Ab and tau tracers and corresponding T1 MRIs from more than a dozen studies. We have made data from more than 10,000 Ab and tau‐PET scans available in publicly shared ADNI, SCAN and POINTER Imaging datasets. For studies where we are not able to share numerical data publicly, we share data with individual investigators when formal approval is granted by the original study.ConclusionBPIP and associated software for data post‐processing are a powerful engine supporting the analysis and dissemination of Alzheimer’s disease PET biomarker data.