bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Impact of Social Frailty, Physical Frailty and Intrinsic Capacity Profiles on 2‐year Cognition in Healthy Older Persons: A Cluster Analysis
Authors: Lim Wee‐Shiong , Tan Cai‐Ning , Yeo Audrey , Pek Kalene , Chia Jia Qian , Lim Jun Pei , Chew Justin 
Published: January 2025

AbstractBackgroundIntrinsic capacity (IC) and frailty are inter‐related yet distinct constructs which encapsulate functional capacities of older adults. There is uncertainty how IC is related to and interacts with the social (SF) and physical (PF) dimensions of frailty to influence cognition. We aim to examine IC, PF and SF profiles and compare the association between identified subtypes with change in cognition at 2 yearsMethodsWe studied 230 healthy community‐dwelling older adults (age:67.2±7.4 years) from the GeriLABS‐2 cohort study. We assessed: 1) IC, using modified Integrated Care for Older Adults (ICOPE); 2) PF, using Fried Frailty Phenotype; 3) SF, via 8‐item Social Frailty Scale. To identify subtypes, we performed two‐step cluster analysis with age, PF, SF, IC and CFAB. Cluster associations with change in cognition [Chinese Mini Mental State Examination (CMMSE, range:0‐28) and Chinese Frontal Assessment Battery (CFAB, range:0‐18)] at 2 years were examined using hierarchical linear regression sequentially adjusted for age, gender and education (step 1); PF, SF or IC (step 2); and PF, SF and IC (step 3).ResultsThree distinct clusters were identified – C1: PF/High IC (N = 54, 24%); C2: SF/Low IC (N = 69, 30%); and C3: Robust (Physical/Social) /High IC (N = 106, 46%). There were more men in C1, whilst C2 was older with fewer years of education and scored lowest in CMMSE [C1 to C3, mean (SD): 26.20(1.58) vs 25.32(1.86) vs 26.60(1.53), p<0.001] and CFAB [17.20(0.86) vs 14.59(2.28) vs 17.26(1.04), p<0.001]. At 2 years, C1 experienced greatest improvement in CMMSE [0.69(1.60) vs 0.11(1.81) vs 0.03(1.70), p = 0.088) vis‐à‐vis C2 for CFAB [0.06(1.22) vs 1.21(2.07) vs ‐0.19(1.64), p<0.001). The association of CMMSE improvement in C1 became non‐significant when adjusted for PF (β = 0.63, P = 0.261), SF (β = 0.60, P = 0.058), or IC (β = 0.57, P = 0.072), but remained significant for CFAB improvement in C2 even in step 3 (β = 1.423, P = 0.004).ConclusionAmongst healthy community‐dwelling older adults, SF and IC are complementary to physical frailty measures for better profiling of at‐risk individuals with lower executive function beyond general cognition. Further research is required to explicate the differential longitudinal improvement between clusters in general cognition and executive function and the factors underpinning the improvement.
Folate deficiency aggravates SARS‐CoV‐2‐induced endothelial barrier disruption in Mthfr heterozygous knockout mice
Authors: Umar Meenakshi , Ismael Saifudeen , Volic Milla , Hall Gregory W , Bix Gregory J 
Published: January 2025

AbstractBackgroundIncreasing evidence suggests that SARS‐CoV‐2 infection may lead to early onset and aggravation of pre‐existing vascular dementia and Alzheimer’s disease. Methylene tetrahydrofolate reductase (Mthfr) is a critical enzyme in folate metabolism, also required for optimal brain function. Mthfr deficient mice display cognitive impairments and neurovascular deficits and polymorphisms in MTHFR increases dementia risk. Intriguingly, a globally prevalent polymorphism in MTHFR (C677T) is linked with the COVID‐19 incidence and mortality. Many studies have reported association of MTHFR polymorphisms with COVID‐19 severity suggesting it as a genetic risk factor of COVID‐19, however, there is a need of mechanistic evaluation of the underlying mechanism. In this study, we investigated the role of folate deficiency due to MTHFR polymorphism on SARS‐CoV‐2 mediated neuroinflammation and blood‐brain barrier disruption.MethodC57 wild‐type (WT) and Mthfr heterozygous knockout (Mthfr±) mice were inoculated intranasally with mock or 1 × 104 PFU of the mouse adapted (MA10) strain of SARS‐CoV‐2 that is capable of infecting WT mice. After 3 days post‐infection, lung and brain were collected for pathological evaluation. Additionally, mouse brain microvascular endothelial cells (bEnd.3) cultured in folate‐sufficient and folate‐deficient medium were treated with SARS‐CoV‐2 spike proteins for 24h.ResultMthfr± mice showed slightly higher disease associated weight loss (10.5%) compared to WT mice (8.5%). In addition, lung viral load estimation indicated an elevated trend in Mthfr± infected mice (6.3±0.5 × 107 copies/100ng RNA) compared to WT (5.8±0.9 × 107 copies/100ng RNA). Blood‐brain barrier integrity, as measured by ZO‐1 mRNA level, was significantly reduced by MA10 infection in Mthfr± mice compared to WT and Mthfr± mice. Immunostaining further confirmed significant reduction in ZO‐1 expression in brain cortical regions of MA10 infected Mthfr± mice compared to WT infected mice. In addition, Mthfr+/ mice displayed less activated microglia in comparison to WT mice. Our preliminary in vitro study showed that folate deficiency decreased Claudin‐5 and Occludin mRNA expression in bEnd.3 cells. Additionally, exposure to SARS‐CoV‐2 spike proteins showed a further decrease in Claudin‐5 expression in folate‐deficient bEnd.3 cells.ConclusionSARS‐Cov‐2 infection may aggravate blood‐barrier disruption in the context of Mthfr disruption potentially increasing susceptibility to COVID‐19 morbidity and worsened post‐COVID neurocognitive effects.
Single vascular insult aggravates amyloid accumulation with age triggering glial activation in AD mice
Authors: Diwakar Latha , Gupta Mayank , Talukdar Ankita , Hussain Rehab 
Published: January 2025

AbstractBackgroundVascular pathology is often seen in cases of mixed dementia affecting elderly population including Alzheimer’s disease (AD). AD is generally characterized by the presence of amyloid‐β (Aβ) plaques and tau deposits. However, many factors influence the onset and progression of AD pathology. In the present study, we are looking for brain vascular pathology like blood brain barrier (BBB) breach by vascular insult and associated microglial activation in small vessels increase risk of developing pathology over age. It is often hypothesized that in presence of increased Aβ, vascular insults could synergistically trigger neuroinflammation leading to cognitive impairment accelerating neurodegeneration.MethodLearning and memory deficits were performed in slow progressing APPswe mice injected with 2µg/2μl of ET‐1(endothelin‐1) bilaterally into lateral ventricles after 30 days of ET‐1 injection. BBB structural changes were assessed by immunohistochemistry for markers of endothelial cells and pericytes. Aβ plaque load and vascular deposition of Aβ were tested to understand the effect of vascular insult on AD pathology in double transgenic J20 mice. Further, microglial activation was estimated using specific markers.ResultBBB breaching was increased after vasoconstriction following ET‐1 injection after 30 days with increasing age causing memory deficits in AD mice. The extent of structural changes in BBB increased with age indicating the susceptibility with mutation. Aβ plaque load and glial activation was increased in J20 mice after ET‐1 injection.ConclusionAPP mutation increases susceptibility to ET‐1 induced single vascular insult bringing about BBB leakage, memory deficits, increased Aβ aggregation and glial activation with increasing age given enough time of 30 days to rescue. However, there was rescue in case of wild type mice.
Butyrate and Lauric acid effect on Astrocytes and Neurons in Alzheimer’s disease
Authors: Senarath R.M. Uththara Sachinthanie , Oikari Lotta E , Bharadwaj Prashant , Jayasena Vijay , Martins Ralph N , Fernando Warnakulasuriya Mary Ann Dipika Binosha 
Published: January 2025

AbstractBackgroundRecently, there has been substantial interest in investigating the role of short‐chain fatty acids (SCFAs) and, medium chain fatty acids (MCFA) in the neuroinflammation associated with Alzheimer’s disease (AD). Specifically, butyrate (SCFA) and lauric acid (MCFA) have demonstrated potential in alleviating neuroinflammation and reducing toxicity associated with amyloid proteins. Additionally, they have been found to enhance mitochondrial function and reduce neuronal hyperactivity. However, the mechanisms by which butyrate and lauric acid either suppress or activate astrocytes and neurons, as well as how they influence Aβ‐mediated activation of astrocytes and neurons, remain unclear. This study aims to address this knowledge gap by investigating the independent and synergistic effects of butyrate and lauric acid on AD pathogenesis—a research endeavour not undertaken previously.MethodButyrate and lauric acid were administered independently and synergistically to cultures of astrocytes, neurons derived from induced pluripotent stem cells (iPSCs) obtained from healthy human control subjects. Inflammatory responses of astrocytes and neurons were measured under synthetic amyloid beta stimulating conditions similar to AD. Legend Plex Human Inflammatory Panel was used to quantify the response of inflammatory cytokines (Interleukin IL‐1β, IL‐6, IL‐8, IL‐18, IL‐33, etc.) to inflammatory stimuli. The statistical analysis was carried out using the GraphPad Prism version 10.1.2. One‐way ANOVA was used to analyse the data.ResultButyrate and lauric acid, independently and synergistically demonstrate a positive association with pro‐inflammatory cytokines. There were negative association with anti‐inflammatory cytokines in neuron, astrocytes and spontaneous co‐cultures of astrocytes and neurons.ConclusionThe findings indicate that both butyrate and lauric acid inhibit inflammation in Alzheimer’s‐induced astrocytes and neurons. Ongoing investigations aim to evaluate their effects on various cytokines and determine the responsible genes through qPCR analysis.
Preserved transcriptional networks in immune signaling pathways associated with chronic disease identified in Alzheimer’s disease and Parkinson’s disease, cross‐tissue analysis
Authors: Strickland Samantha L , Tsai Wei , Chen Xuan , Cherukuri Yesesri , Allen Mariet , Quicksall Zachary , Wang Xue , Kantarci Kejal , Carrasquillo Minerva M. , Nho Kwangsik , Saykin Andrew J. , Petersen Ronald C. , Reddy Joseph S. , Ertekin‐Taner Nilüfer 
Published: January 2025

AbstractBackgroundSystemic inflammation plays a pivotal role in many chronic diseases including Alzheimer’s disease (AD). Assessing the composition of immune pathways in neurodegenerative diseases can contribute to precision medicine. Using publicly available transcriptomic data, we sought to elucidate transcriptional networks pertinent to inflammatory pathways across brain regions and peripheral blood in AD/mild cognitive impairment (MCI) and peripheral blood in Parkinson’s disease (PD).MethodFor the AD/MCI vs. control dataset, we analyzed bulk‐RNAseq collected from 6 brain regions of donors from ROSMAP, Mayo Clinic, and Mount Sinai School of Medicine (MSSM) brain banks available from the AMP‐AD consortium. Ante‐mortem, blood RNAseq expression data was retrieved from the AMP‐AD Emory Vascular cohort and Mayo Clinic Study of Aging (MCSA). We also collected blood‐derived microarray expression data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). For the PD vs Control dataset, blood‐derived bulk‐RNAseq from the PDBP and PPMI cohorts were available through the AMP‐PD consortium. Following quality control, normalization, and residual generation to account for biological and technical variables, co‐expression network modules and their enriched pathways were identified using WGCNA within each dataset. Module/trait correlation tests for aging and diagnosis (cases [AD/MCI or PD] vs control) phenotypes were evaluated. Gene Ontology enrichment analyses were executed to identify enriched pathways and brain or blood cell types within the modules. Modules were tested for preservation across cohorts.ResultWe identified conserved immune signatures across brain regions and cohorts. Modules involved in immune response were preserved across all cohorts. Blood consensus modules involved in immune response were preserved in the brain and vice versa. Some immune modules were associated with AD/MCI, PD, and/or aging. Brain immune modules are significantly associated with aging and/or AD. Significant correlations (q<0.05) with PD diagnosis were present. In the MCSA and Emory vascular cohorts, there were no significant (q<0.05) associations between modules and diagnosis, while in ADNI there were nominal (p<0.05) associations.ConclusionPreserved transcriptional immune networks were identified across blood and brain and across two neurodegenerative diseases. Expanding gene co‐expression network analyses to other diseases and integrating additional omics measures and phenotypes can further strengthen these findings to unravel the immune signatures across complex diseases.
Genetically predicted levels of sex hormones are associated with cerebrovascular disease pathology in the Alzheimer’s disease brain
Authors: Libby Julia B. , Beecham Gary , Montine Thomas J. , Toga Arthur W. , Cuccaro Michael L. , Keene C Dirk , Larson Eric B , Crane Paul K. , Mukherjee Shubhabrata , Panizzon Matthew S. , Biber Sarah A , Kukull Walter A. , Bennett David A. , Schneider Julie A. , Barnes Lisa L. , De Jager Philip L. , Menon Vilas , Hohman Timothy J. , Dumitrescu Logan C. 
Published: January 2025

AbstractBackgroundCerebrovascular pathology frequently co‐occurs with Alzheimer’s disease (AD) pathology and the combinations of these forms of pathology may underly AD dementia. Sex hormones influence many aspects of cerebrovascular systems and may contribute to cerebrovascular pathology, but many studies of aging and AD do not measure hormones. Therefore, in this study, we explored whether a polygenic score predicting sex hormone levels relates to cerebrovascular pathology in the AD brain.MethodSex‐specific Polygenic Risk Scores (PRS) of the sex hormones testosterone (Nmales: 146,339; Nfemales: 142,778) and estradiol (Nmales: 147,690; Nfemales: 163,985) were built using a linkage‐disequilibrium (LD) clumping method from published sex‐stratified GWAS from UK Biobank, using individuals with an age range of 40‐69 years old. Each PRS was scaled before analysis. Genetic data and harmonized cerebrovascular pathology data were leveraged from non‐Hispanic White autopsy participants from three independent studies of aging and AD: Adult Changes in Thought (ACT), the National Alzheimer’s Coordinating Center (NACC), and the Religious Orders Study/Rush Memory and Aging Project (ROSMAP) (Nmales: 4,269; Nfemales: 4,609). Characteristics of the participants are described in Table 1. Sex‐specific logistic regression models were used to evaluate whether each PRS relate to cerebrovascular disease (CVD) outcomes, including presence or absence of macroscopic infarcts, microinfarcts, atherosclerosis, or arteriolosclerosis. Covariates included age at death, last clinical diagnosis before death, and education.ResultHigher genetically predicted levels of testosterone in males were associated with the presence of macroscopic infarcts (Table 2; b = 0.11, p = 0.03). Interestingly, higher genetically predicted levels of estradiol in males were associated with the presence of arteriolosclerosis (Table 2; b = 0.13, p = 0.02). No significant associations were observed for the other CVD outcomes in men and none in women. Significant results did not survive corrections for multiple comparisons.ConclusionThe results show that a PRS of sex hormones can be used to explore the effect of sex hormone levels on cerebrovascular pathology as it pertains to AD. The results also support the need for more studies investigating the role of sex hormones on sex‐specific phenotypes of cerebrovascular pathology in the presence of AD. Future work is needed to better understand the mechanisms behind the observed associations.
Targeted proteomic analysis of 3R and 4R tau in marmoset and human brain tissue
Authors: Shapley Sarah M , Huhe Hasi , Duong Duc M , Wu Fang , Carter Gregory W , Silva Afonso C , Rizzo Stacey J Sukoff , Seyfried Nicholas T 
Published: January 2025

AbstractBackgroundThe microtubule‐associated Tau gene (MAPT) undergoes alternative splicing to produce isoforms with varying combinations of microtubule‐binding region (MTBR) repeats (3R, 4R). The MTBR is the predominant region that forms paired helical filaments and neurofibrillary tangles fibrils in disease. Alzheimer’s disease (AD) is a mixed Tauopathy containing both 3R and 4R isoforms. Previously, marmosets have been shown to spontaneously develop the key pathological hallmarks of AD during advanced age, positioning them as a model system to overcome the rodent‐to‐human translational gap for AD. Yet, Tau isoform expression has been understudied in marmosets with conflicting reports of isoform expression. Recently, our lab found 3R and 4R Tau to be expressed in adult marmoset brains. Additionally, AD pathology related phospho‐epitopes of soluble (pT181, pT217, pT231) and insoluble (pS396/404 and pS202/205) Tau were conserved. The present study sought to comprehensively characterize Tau isoforms in marmosets and corroborate antibody‐based results with a targeted proteomics assay.MethodMarmoset (n = 7), human AD (n = 4), human non‐demented control (n = 4), and mouse (n = 1) brain lysates were analyzed via targeted mass spectrometry. The detection of the 3R Tau isoform unique peptide, KVQIVY, was obtained through the use of the LysargiNase enzyme that cleaves N‐terminal to K/R residues. Recombinant 3R and 4R Tau (rTau) proteins were used to generate peptide spectral libraries and served as technical controls.ResultTau peptides were identified via retention time and co‐elution. The marmoset product ions mirrored the human peaks and highly corresponded to the 3R and 4R peptide library spectra, providing mass spectrometry evidence of both isoform expressions in marmoset brains. 3R Tau was enriched in the fetal marmoset. In conjunction, the 4R rTau isoform and mouse samples did not match the 3R recombinant library spectrum.ConclusionOverall, we found marmosets to be a promising translational model of AD that overcomes the limitations of mice concerning the expression of both 3R and 4R Tau isoforms. These data extend our previous findings from western blots in a cohort of unrelated marmosets. Additionally, proteotyping of other Tauopathies may lend insight for novel biomarkers and personalized therapeutics.
Examining additive risk for cerebrovascular dysfunction in a novel late‐onset Alzheimer’s disease model
Authors: Reagan Alaina M , Kotredes Kevin P , O'Rourke Rita , Herrick Sarah , Cossette Travis L , Sasner Michael , Howell Gareth R 
Published: January 2025

AbstractBackgroundMechanisms driving cerebrovascular decline during Alzheimer’s disease and related dementias (ADRD) are poorly understood. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme in the folate/methionine pathway. Variants in MTHFR, notably 677C>T, are associated with ADRD. ∼30% of individuals carry at least one copy of MTHFR677C>T, causing a 50% decrease in MTHFR enzyme efficiency. Reduced efficiency can lead to elevated homocysteine in blood, resulting in vascular inflammation and increased risk for cerebrovascular damage. To examine vascular risk in a late‐onset Alzheimer’s disease (LOAD) model, MODEL‐AD created a mouse carrying known ADRD risk factors with the Mthfr677C>T variant. While plasma‐based protein biomarkers hold promise for identifying ADRD pathology, additional markers are necessary. Studies support eye exams as a synergistic strategy due to overlapping mechanisms of damage in retina and brain, so retinal phenotyping has been incorporated in our study.MethodsThe LOAD2.Mthfr677C>T model was created by the IU/JAX/PITT MODEL‐AD Center by incorporating the Mthfr677C>T allele with the LOAD2 alleles (hAbeta/APOE4/Trem2*R47H). Cerebrovascular health is assessed in 4, 12, 18 and 24 month‐old mice by immunofluorescence to examine barrier integrity in cells that make up the cerebrovascular unit: endothelium, smooth muscle, pericytes, basement membrane, tight junctions, and extracellular deposition of blood products. Differential expression of vascular related genes/proteins is being examined by RNA‐sequencing and proteomics. In vivo retinal imaging, including optical coherence tomography and fluorescence angiography, and ex vivo retinal IF was performed to assess and compare neuronal and vascular health in the retina to the brain.ResultsAll mice have been aged, and in vivo assays completed. Compared to LOAD2 controls, LOAD2.Mthfr677C>T mice do not show significant changes in frailty, activity, or cognition. At 24 mos, transcriptomic and proteomic data suggest LOAD2 and LOAD2.Mthfr677C>T show some expression changes similar to those seen in human AD. By immunofluorescence, like LOAD2, Mthfr677C>T mice do not develop ThioS‐positive amyloid plaques, but assessment of vascular‐specific changes is in progress. Plasma and retinal biomarker analysis is also in progress.ConclusionsMODEL‐AD continues to create strains that develop endophenotypes of LOAD for preclinical testing. Ultimately, this work will aid in the identification of novel therapeutic approaches that reduce cerebrovascular pathology in ADRDs.
Effects of Chronic Binge Alcohol Consumption on Alzheimer’s Disease Neuropathogenesis in 3xTg‐AD mice
Authors: Sloan Lucy J. , Chilton Paula M. , Rao Aakarsha V. , Zhang JingWen , Myers Scott A. , Reddy Sreelatha , Lee Jiyeon , Rodriguez Walter , Gobejishvili Leila , Chariker Julia , Rouchka Eric , Ghare Smita S. , McClain Craig J. , Barve Shirish 
Published: January 2025

AbstractBackgroundChronic, excessive alcohol consumption causes neurodegeneration and is associated with an increased risk for Alzheimer’s disease (AD) and other dementias. Moreover, there has been a consistent rise in alcohol consumption in older adults in the past few decades. However, there is minimal research showing how alcohol consumption affects AD neuropathogenesis and biological mechanisms remain unclear. We hypothesize that mid‐life chronic binge alcohol consumption accelerates AD neuropathology in the hippocampus, among the first brain regions affected by AD, through dysregulation of processes associated with AD pathogenesis.MethodsFemale triple transgenic (3xTg; n = 15) mice and non‐transgenic (NonTg) control mice (B6.129; n = 13) were given EtOH binges twice/week (4g/kg) by oral gavage for 3.5 months (from 6‐9.5 months) while untreated controls (3xTg n = 6 and NonTg n = 4) received sham gavages. Memory was evaluated with the novel object recognition test (NORT). RNA was extracted from the mid‐brain region of one hemisphere for RNA‐Sequencing (Illumina NextSeq2000; STAR/HTSeq/DESeq2 pipeline) and qPCR, while protein lysates from the opposite hemisphere’s midbrain region was used for Western blot (WB) analyses. Plasma neurofilament light chain (NfL) was measured with a MesoScale Discovery kit.ResultsOne week after the final EtOH gavage, hippocampal‐dependent memory was significantly impaired in EtOH binged 3xTg mice, while NonTg mice were unaffected. Similarly, EtOH binge slightly increased plasma NfL in 3xTg mice, indicating persistent EtOH‐induced neurodegeneration, while nonTg mice showed a significant decrease. RNA‐seq from the mid‐brain region containing the hippocampus revealed that chronic EtOH binge significantly affected 8477 genes (4473 up‐ and 4004 down‐regulated) in 3xTg mice, while only 4 genes were significantly affected (2 up‐ and 2 down‐regulated) in nonTg mice. Enrichment analyses showed EtOH altered several processes associated with neurodegeneration in 3xTg mice including regulation of synaptic plasticity and autophagy.ConclusionsResults indicate that 3xTg mice are more sensitive to EtOH‐mediated effects on neurodegeneration and memory impairment than nonTg controls. There was also significant EtOH‐induced dysregulation of AD‐related processes in the mid‐brain of 3xTg mice, a region affected early by AD neuropathology. Together, these data show that chronic mid‐life EtOH binging accelerates early AD neuropathology in 3xTg mice.