bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial Dissection of the Distinct Cellular Reponses to Normal Aging and Alzheimer’s Disease
Authors: Gong Yun , Haeri Mohammad , Zhang Xiao , Li Yisu , Liu Anqi , Wu Di , Zhang Qilei , Yan Xiaoxin , Jazwinski S. Michal , Jiang Lindong , Chen YiPing , Swerdlow Russell H , Shen Hui , Deng Hong‐Wen 
Published: January 2025

AbstractBackgroundAging significantly elevates the risk for Alzheimer’s disease (AD), contributing to the accumulation of AD pathologies, such as amyloid‐β (Aβ), inflammation, and oxidative stress. The human prefrontal cortex (PFC) is highly vulnerable to the impacts of both aging and AD. Unveiling and understanding the molecular alterations in PFC associated with normal aging (NA) and AD is essential for elucidating the mechanisms of AD progression and developing novel therapeutics for this devastating disease.MethodIn this study, for the first time, we employed a cutting‐edge spatial transcriptome platform, SpaTial Enhanced Resolution Omics‐sequencing (Stereo‐seq), to generate the first comprehensive, subcellular resolution spatial transcriptome atlas of the PFC from six AD cases at various neuropathological stages and six age, sex, and ethnicity matched controls.ResultOur analyses revealed distinct transcriptional alterations across six neocortex layers, highlighted the AD‐associated disruptions in laminar architecture, and identified changes in layer‐to‐layer interactions as AD progresses. Further, throughout the progression from NA to various stages of AD, we discovered specific genes that were significantly upregulated in neurons experiencing high stress and in nearby non‐neuronal cells, compared to cells distant from the source of stress. Notably, the cell‐cell interactions between the neurons under the high stress and adjacent glial cells that promote Aβ clearance and neuroprotection were diminished in AD in response to stressors compared to NA. Through cell‐type specific gene co‐expression analysis, we identified three modules in excitatory and inhibitory neurons associated with neuronal protection, protein dephosphorylation, and negative regulation of Aβ plaque formation. These modules negatively correlated with AD progression, indicating a reduced capacity for toxic substance clearance in AD subject samples. Moreover, we have discovered a novel transcription factor, ZNF460, that regulates all three modules, establishing it as a potential new therapeutic target for AD.ConclusionOverall, utilizing the latest spatial transcriptome platform, our study developed the first transcriptome‐wide atlas with subcellular resolution for assessing the molecular alterations in the human PFC due to AD. This atlas sheds light on the potential mechanisms underlying the progression from NA to AD.
End‐to‐End 3D CycleGAN Model for Amyloid PET Harmonization
Authors: DONG XUANZHAO , Wang Yalin , Shah Jay , Ghisays Valentina , Luo Ji , Chen Yinghua , Lee Wendy , Li Baoxin , Chen Kewei , Reiman Eric M. , Wu Teresa , Su Yi 
Published: January 2025

AbstractBackgroundAmyloid PET (Positron Emission Tomography) is crucial in detecting amyloid burden within the brain. However, the diversity of amyloid tracers and the scarcity of paired data significantly challenge the collaboration between cross‐center studies. In this research, we introduce a novel patch‐based 3D end‐to‐end image transformation model. This model works as a harmonization strategy, transferring the amyloid PET images from one tracer type to another.Method51 florbetapir (FBP) and 604 PiB images from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) were processed using established pipelines to extract regional standard uptake value ratios (SUVRs), mean cortical SUVRs (mcSUVRs), and SUVR images. 3D Cycle‐Consistent Generative Adversarial Networks (CycleGAN) was used to learn the end‐to‐end 3D image transformation using adversarial training strategies in conjunction with Resnet generators and multilayer discriminators within different tracer domains. Data augmentation techniques were applied to process the FBP images to balance the training samples and patch‐based learning was used throughout the experiment. The trained CycleGAN model was then applied to an independent dataset with 46 paired images from www.gaain.org/centiloid‐project for performance evaluation. Correlation analyses were conducted voxel‐wise and on mcSUVR, comparing the FBP/synthetic PiB to the true PiB data. The Structural Similarity Index Measure (SSIM) and Peak Signal‐to‐Noise Ratio (PSNR) were also evaluated between the synthetic and real PiB SUVR images.ResultThe synthetic PiB SUVR images were visually more similar to real PiB SUVR images than FBP. Voxel‐wise correlation improved from 0.942 between FBP and real PiB to 0.958 between the virtual and real PiB SUVR image (p < 0.0001). The agreement of mcSUVR improved from r = 0.909 to r = 0.954 (p<0.001) in the independent test dataset. The SSIM and PSNR between synthetic and real PiB are 0.762 and 25.370 in the independent dataset.ConclusionWe proposed a novel end‐to‐end image transformation model for 3D PET image synthesis. The model finds the nonlinear mapping between different tracers and eliminates the requirement for paired training images. The result was confirmed using an independent dataset to demonstrate its effectiveness.
Long‐term mortality in the SPRINT cohort
Authors: Jaeger Byron C , Gaussoin Sarah A. , Williamson Jeff D. , Pajewski Nicholas M. , Reboussin David M. 
Published: January 2025

AbstractBackgroundThe Systolic Blood Pressure Intervention Trial (SPRINT) showed intensive blood pressure (BP) control, defined by systolic BP goal of < 120 mm Hg, reduced cardiovascular morbidity and mortality. However, a secondary analysis that incorporated approximately 4‐years of observational follow‐up found that mean BP levels increased after the trial and the benefit of intensive BP control on cardiovascular and all‐cause mortality attenuated. We re‐examined these findings using an updated version of the observational data that includes approximately 8‐years of follow‐up.MethodsSPRINT included patients 50 years and older with hypertension and increased cardiovascular risk but without diabetes or history of stroke. The SPRINT intervention ended on August 20, 2015, and trial close‐out visits occurred through July 2016. Extended observational follow‐up for mortality was obtained via the US National Death Index from 2016 through 2023.ResultsAmong 9361 randomized participants, the mean (standard deviation) age was 67.9 (9.4) years, and 3332 (35.6%) were women. Over a maximum follow‐up of 13 years, 2597 all‐cause and 907 CVD mortality events occurred (Figure). During the trial, intensive treatment was beneficial for both cardiovascular mortality (hazard ratio [HR], 0.66; 95% CI, 0.49‐0.89) and all‐cause mortality (HR, 0.83; 95% CI, 0.68‐1.00). During the 8‐year observational period, the benefit of intensive BP control attenuated for both outcomes (CVD mortality HR: 1.02; 95% CI, 0.84‐1.24; all‐cause mortality HR: 1.08; 95% CI, 0.94‐1.23). Overall (i.e., combining trial and observational periods), intensive BP control was beneficial for CVD mortality (HR, 0.84; 95% CI, 0.74‐0.96) but not all‐cause mortality (HR, 0.96; 95% CI, 0.89‐1.04).ConclusionsIntensive BP control reduced CVD mortality risk during the trial and overall, but its benefits were less evident during the observational period. Given increasing BP levels during the observational period, maintaining BP control may be essential for sustaining long‐term benefit.Figure: Cumulative incidence of cardiovascular and non‐cardiovascular mortality by treatment group
How Low Should We Go to Prevent Brain Aging Associated with Exposure to Ambient Fine Particles?
Authors: Wang Xinhui , Chen Jiu‐Chiuan , Salminen Lauren , Petkus Andrew J , Millstein Joshua , Espeland Mark A. , Braskie Meredith N , Thompson Paul M. , Gatz Margaret , Resnick Susan M. , Kaufman Joel D. , Rapp Stephen R. , Tooze Janet A , Shumaker Sally A. , Younan Diana 
Published: January 2025

AbstractBackgroundLate‐life exposure to PM2.5 is a risk factor for Alzheimer’s disease (AD) and related dementias. Accelerated brain aging associated with PM2.5 exposure likely takes place at preclinical stage. In Feb.2024, US EPA lowered the annual standard for fine particulate matter (PM2.5) from 12‐ to 9‐µg/m3. Whether the new exposure standard is sufficient to protect the aging brain is unclear.MethodThis current study examined whether PM2.5‐associated brain aging is present at lower‐level exposures. We used longitudinal data from older women (n = 421; aged 77.3±3.5) enrolled in the Women’s Health Initiative Memory Study MRI‐1 (2005‐6) and MRI‐2 (2009‐10), living at locations with PM2.5 below 12‐µg/m3 (including 130 complying with EPA’s new standard) and without MCI, dementia or stroke prior to MRI‐1. PM2.5 exposures at residential locations were estimated as 3‐year annual averages prior to MRI‐1, based on validated regionalized universal kriging models. AD pattern similarity (AD‐PS) scores, developed by supervised machine learning and validated with ADNI data, were used to assess AD‐related neurodegeneration. Bilateral gray matter volumes of the hippocampus, amygdala, parahippocampal gyrus (PHG), and entorhinal cortex were summed to define the regional volume of medial temporal lobe (MTL). We used linear regressions to estimate exposure effects on 5‐year changes in the AD‐PS scores and atrophies of MTL and its subregions, adjusting for intracranial volume, sociodemographic, lifestyle, and clinical characteristics.ResultDuring 5 years of follow‐up, on average AD‐PS scores increased by 0.16±0.15, while MTL volume shrank by 0.42±1.02 cm3. Among older women with PM2.5 <12‐µg/m3, each 1‐µg/m3 increment was associated with increased AD‐PS scores (βAD‐PS = 0.013, 95%CI = [0.003, 0.021], p<0.01) and additional MTL shrinkage (βMTL = ‐0.079, 95%CI = [‐0.138, ‐0.019], p = 0.01; primarily affecting PHG), equivalent to 3.0%‐3.6% higher dementia risks. PM2.5 exposure < 9‐µg/m3 remained significantly associated with progressive PHG atrophy (βPHG = ‐0.087, 95%CI = [‐0.169, ‐0.005], p = 0.04), but the associations with increased AD‐PS score or progressive MTL atrophy had less precise effect estimates. Further restricting the analyses to older women who remained cognitively normal at MRI‐2 did not materially change the results.ConclusionOur study supports EPA’s new decision to lower PM2.5 standard, but could not rule out the possibility of neurotoxic effects on aging brain with PM2.5 <9‐µg/m3.
Discovery of dementia type specific biomarkers with untargeted CSF proteomics
Authors: Stokkel Marijke E. , Vermunt Lisa , Knol Jaco , Piersma Sander , Pham Thang V. , Gagestein Berend , de Haas Richard R. de Goeij , Lemstra Afina Willemina , Pijnenburg Yolande A.L. , Visser Pieter Jelle , Tijms Betty M. , Teunissen Charlotte , Jimenez Connie R. 
Published: January 2025

AbstractBackgroundDifferent pathologies can cause dementia, including Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia. Understanding the biological mechanisms underlying these diseases is important in order to develop therapies. Here we performed cerebrospinal fluid (CSF) proteomics in AD, DLB and FTD in order to study proteomic changes and identify novel potential biomarkers.MethodIndividuals from the discovery (n = 80) and validation (n = 77) cohort were selected from the Amsterdam Dementia Cohort based on clinical diagnosis and availability of a CSF sample. Single shot nano‐LC‐MS/MS was performed using a data independent acquisition (DIA) method in a QExactive HF (Qe) mass spectrometer. Additionally, the validation cohort was remeasured on a newly acquired EVosep‐TimsTOF‐HT (Bruker) allowing for deeper proteomic profiling. For each cohort, protein intensities were log2 transformed, and scaled according to the mean and standard deviation of the SCD group. Next, all groups were compared to each other on the levels for each protein with linear regression models, including age and sex as covariates. We performed Gene Ontology enrichment analysis for the differentially expressed proteins in the TimsTOF dataset.ResultIn total we identified 3501 unique proteins, 803 in the discovery cohort, 1296 in the Qe measurements of the validation cohort, and 2873 in the recent TimsTOF remeasurements of the validation cohort (Figure 1A). We identified 37, 30, and 34 differentially expressed proteins in AD, DLB and FTD, of which 11, 3 and 8 replicated in the Qe measurements cohort (Figure 1B‐D). Proteins that replicated between cohorts included ALDOA, SMOC1, CHI3L1 and PKM for AD, NPTX2 and VGF for DLB and SERPINA3 and CHI3L1 for FTD. Investigation of the most statistically enriched biological terms shows processes related to synaptic signaling to be downregulated in AD, DLB and FTD. Similar to literature (Bader et al., 2020), metabolic processes were found to be upregulated in AD. In contrast, upregulation of adaptive immune responses in DLB and complement activation and fibrinolysis in FTD have not been previously observed (del Campo et al., 2023; van der Ende et al., 2019)ConclusionImprovements in mass spectrometers enable deeper proteome profiling, essential for uncovering novel processes underlying disease.
Improved Precision and Sensitivity: Refinement of a Homebrew Simoa Assay for Detecting pTau181 in Plasma and Serum
Authors: Vanbrabant Jeroen , Bayoumy Sherif , Antwi‐Berko Daniel , van der Flier Wiesje M. , Verberk Inge M.W. , Teunissen Charlotte , Stoops Erik 
Published: January 2025

AbstractBackgroundPlasma tau phosphorylated at Threonine181 (pTau181) has been extensively studied as an accessible biomarker of amyloid pathology and is compared in various studies with other pTau epitopes. ADx has developed a Quanterix Homebrew Simoa assay using a highly pTau181 specific capture mAb (ADx252) and an N‐terminal tau detector ADx204 demonstrating high clinical performance (Janelidze et al., 2023; Ashton et al., 2022; Bayoumy et al., 2021). Nevertheless, measuring pTau181 in samples from young adults or serum that have lower levels remains challenging due to limited sensitivity and precision in the low calibrator range. This work describes an updated Homebrew assay for detection of pTau181 in human plasma and serum with increased precision and sensitivity compared to the previously published ADx pTau181 Simoa assay.MethodThe ADx pTau181 assay was updated using re‐engineered formats of ADx252 (RD‐070) and ADx204 (RD‐073). Antibody conjugation to beads was optimized by C‐terminal incorporation of a tag to enhance antibody conjugation efficiency and robustness. The assay was further optimized using alternative diluents resulting in a linear curve over the full calibrator range. The clinical performance of the assay format was compared to the previous pTau181 assay version using plasma from 50 AD patients (defined by CSF biomarker profile) and 50 cognitively healthy donors from the Dutch Brain Research Registry (Hersenonderzoek.nl). Paired plasma and serum from a prospective collection of healthy donors (n = 50) were also analyzed using the optimized pTau181 assay.ResultThe optimized assay showed a higher AUC of 0.96 (95% CI 0.92‐0.99) compared to 0.88 (95% CI 0.82 – 0.95) for the previous version (ΔAUC = 0.08, DeLong’s p = 0.047). Furthermore, our optimized assay was able to measure serum pTau 181, exhibiting a strong correlation of the analyte between plasma and serum and with pTau217 levels. Additionally, precision and sensitivity were improved (no vs. 18 plasma samples with CV%>20 on duplicate measurements; mean plasma sample S/N increased from 4.3 to 9.8).ConclusionOur study illustrates the successful development of an optimized Homebrew pTau181 assay, with enhanced analytical and clinical performance achieved by an improved sensitivity and precision at measuring pTau 181 in plasma and serum samples.
APOE genotype, polygenic risk for Alzheimer’s disease, and plasma cytokines in participants of the multisite SuperAging Research Initiative
Authors: Huentelman Matt , Piras Ignazio , Naymik Marcus , Stark Bobbi , Bonfitto Anna , Taguinod Francis , Schafer Rhiana , Martersteck Adam , Maher Amanda Cook , Geula Changiz , Rogalski Emily J ,   The SuperAging Research Initiative
Published: January 2025

AbstractBackgroundThe SuperAging Research Initiative (SRI) seeks to identify factors that promote cognitive healthspan. SuperAgers are defined as individuals aged 80 and older with episodic memory performance that is at least average for people who are two to three decades younger. A goal of the SRI is to identify the genomic contributors to SuperAging and herein we describe the interim results of DNA‐ and plasma protein‐based analyses.MethodBiospecimens were collected in concert with in‐person cognitive assessments. Genomic DNA (n = 125 SuperAgers) was isolated from PAXGene DNA tubes using a Promega Maxwell instrument. Genome‐wide SNP genotypes were generated using the GSA BeadChip (Illumina) and imputation was performed via TOPMed. Polygenic risk scores (PRS) for Alzheimer’s disease (AD) were generated using the summary statistics from the AD GWAS reported by Lambert et al. Plasma samples (n = 59 SuperAgers and 52 Controls) were analyzed using a Luminex panel that included 24 cytokine and inflammatory markers.ResultAPOE allele and genotype frequencies were found to be similar to neuropathologically‐assessed control samples from the “TGen II” AD GWAS cohort (e4 allele frequency; SuperAgers = 9.8%. Controls = 10.8%). AD PRS distributions in the SuperAger samples were also similar to the TGen II Controls; however, three SuperAgers were noted to have AD PRS values that were significantly high risk. Two cytokines demonstrated association with SuperAging, IL‐7 (increased in SuperAgers; p = 0.003) and Interferon‐gamma (increased in SuperAgers; p = 0.04). However, after multiple hypothesis correction, neither remained significant.ConclusionThese results suggest that SuperAgers are not at lower risk for AD based on their APOE genotypes and AD polygenic risk scores. However, this does not account for all SuperAger participants as 15% are e4 allele carriers and 3% demonstrate AD PRS scores that are significantly elevated. Lastly, immune system profiling suggests that IL‐7 and Interferon‐gamma may be elevated in SuperAger plasma, suggesting that immune system function may be associated with SuperAging. This interim analysis of the SRI cohort supports the concept that the propensity to be a SuperAger is likely heterogenic. SuperAgers with high genetic risk for dementia may represent unique opportunities to search for resilience factors.
Perception of change in sexual activity and sexual satisfaction in Alzheimer’s Disease: views of people with dementia and their spouse‐carers
Authors: Nogueira Marcela Moreira Lima , Lacerda Isabel , Baptista Maria Alice , Belfort Tatiana , Dourado Marcia C. N. 
Published: January 2025

AbstractBackgroundThe progression of dementia may be followed by decreased sexual activity for People with Alzheimer’s Disease (PwAD) and their spouse‐carers. We designed this study to investigate the perception of change in sexual activity and sexual satisfaction among couples whose spouses were diagnosed with Alzheimer’s Disease (AD).MethodUsing a cross‐sectional design, we compared 74 dyads of people with Alzheimer´s disease (PwAD) and their spouse‐carers, and 21 elderly dyads control. We assessed sexual satisfaction with Questionnaire on Sexual Experience and Satisfaction (QSES), cognition using a Mini‐Mental State Examination (MMSE), disease severity using a Clinical Dementia Rating scale (CDR), awareness of disease with Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia (ASPIDD), functionality with Pfeffer Functional Activities Questionnaire (FAQ), depressive symptoms with Cornell Scale for Depression in Dementia (CSDD), quality of life using a Quality of Life in Alzheimer’s Disease Scale (QoL‐AD), and burden using a Zarit Burden Interview (ZBI). Univariate and multivariate regression analyses were conducted to identify the factors that influenced couples’ sexual satisfaction.ResultWe found a significant difference between the perception and no perception of change in sexual activity of PwAD (p < 0.001), spouse‐carers (p < 0.01), and controls (p < 0.05). Moderate to severe sexual dissatisfaction was observed in 36.5% of PwAD, 65% of spouse‐carers, and 31% of controls. PwAD sexual satisfaction was related to cognitive impairment (p < 0.05). Spouse‐caregivers sexual satisfaction was related to gender (p < 0.05) and the presence of sexual activity (p < 0.001).ConclusionThe perception of change and consequent interruption of sexual activity, with higher sexual dissatisfaction, were higher in PwAD and their spouse‐carers, in comparison with control group. We also found that spouse‐carers experienced lower levels of sexual satisfaction than PwAD and healthy elderly couples. Moreover, PwAD sexual satisfaction was related to the level of cognitive impairment and spouse‐carers’ sexual satisfaction was related to gender and the presence of sexual activity.
MRI‐visible perivascular space volume: An in vivo marker of post‐mortem vascular pathology
Authors: Silbert Lisa C , Lahna David , Schwartz Daniel , Roese Natalie E , Hurworth Justin , Wall Rachel C , Krajbich Victoria , Woltjer Randall 
Published: January 2025

AbstractBackgroundMR‐visible perivascular space (PVS) burden is associated with clinical and MRI features of cerebrovascular disease. Its utility as an in vivo biomarker of post‐mortem pathology is uncertain.MethodEighteen older adults (age at death 98.0, sd 5.5; 83% female) with autopsy consent were followed longitudinally in the Oregon Alzheimer’s Disease Research Center with MRI and cognitive assessments until death. In vivo MR‐visible white matter (WM) PVS volumes were derived using an automated segmentation algorithm based on T1 intensity thresholding and morphological constraints. Basal ganglia (BG) PVS were hand‐traced on a single axial T1 slice with highest number of PVS. WM and BG PVS volumes were summed and normalized to brain volume to create a PVS score. General linear models (GLM) examined relationships between whole brain PVS score and: 1) cognition, and 2) post‐mortem vascular pathologies. Models were adjusted for age, sex, and time between MRI and death when applicable.ResultIn vivo MRI PVS score was associated with greater post‐mortem deep microvascular lesions (p = 0.002), arteriolosclerosis (p = 0.004), and atherosclerosis (p = 0.002). In separate models, PVS score was associated with worse performance on Trails B (p = 0.006) and MMSE (p = 0.02), but not memory (p = 0.6).ConclusionGreater whole brain in vivo PVS burden is associated with worse cognitive performance in domains commonly associated with cerebrovascular disease and multiple post‐mortem cerebrovascular pathologies. Findings support the use of in vivo PVS as a candidate “V” marker in A/T/N classifications of older individuals