bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translational profiling identifies sex‐specific metabolic and epigenetic reprogramming of microglia in cerebral amyloidosis models with an antibiotic‐altered gut microbiome
Authors: Shaik Shabana M 
Published: January 2025

AbstractBackgroundHost commensal gut microbes are shown to be crucial for microglial maturation, and functions that involve innate immune responses to maintain brain homeostasis. Sex has a crucial role in the incidence of neurological diseases with females showing higher progression of AD compared with males. Transcriptomics has been a powerful tool for the characterization of microglial phenotypes however, there is a large gap in relating to their functional protein abundances. Here, we generated ‘APPPS1‐21‐CD11br’ a translating ribosome affinity purification (TRAP) mice model and assessed the influence of gut microbiome on microglial protein networks during their phenotypic transition in a sex‐specific manner.MethodsAPPPS1‐21 mice were crossed with WT‐CD11br mice wherein a CD11b‐promoter drives expression of ribosomal protein L10a (RpL10) that is fused to FLAG/EGFP at the amino‐terminus to generate APPPS1‐21‐CD11br transgenic mice. Six groups of mice that included WT‐CD11br, antibiotic (ABX) or vehicle‐treated APPPS1‐21‐CD11br male and female were sacrificed at 7‐weeks of age (n = 15/group) and used for immunoprecipitation of microglial polysomes from cortical homogenates using anti‐FLAG antibody. Liquid chromatography coupled to tandem‐mass‐spectrometry (LC‐MSMS) and label‐free quantification was used to identify newly synthesized peptides extracted from polysomes.ResultsProteomic analysis reveal that Aβ‐induced microglial activation resulted in increased FcgR‐mediated‐phagocytosis and actin organization in male and female AD mice respectively. ABX‐treatment resulted in substantial remodeling of epigenetic landscape, leading to a metabolic shift that accommodates the increased bioenergetic and biosynthetic demands associated with microglial polarization in a sex‐specific manner. While microglia in ABX‐treated male mice exhibited a metabolic shift towards ketogenesis to promote neuroprotective phenotype mediating lysosomal Aβ clearance, microglia in ABX‐treated female mice exhibited persistent mitochondrial dysfunction and impaired clearance associated with inflammatory phenotypes. Targeted metabolomics show sex‐specific changes in immunomodulatory gut metabolites mediated by ABX‐treatment.ConclusionsOur studies provide first snapshot of dynamic translational state of microglia in cerebral Aβ‐amyloidosis models with an altered gut‐microbiome. Gut metabolites can support microglial metabolic plasticity to modulate immune responses and amyloid clearance in a sex‐specific manner. Reprogramming of microglial metabolism could be a promising strategy for restoring their physiological functions in a manner that might halt the progression of AD.
Recurrent Prenatal‐Postpartum Stress Mediates Acute Cognitive Dysfunction and Alzheimer’s Disease‐Relevant Pathology in Primiparous Rats
Authors: Edem Edem E ,   Stress and Neuroimmunology Group
Published: January 2025

AbstractBackgroundStress during pregnancy and postpartum periods has been associated with short‐term cognitive deficits with potential long‐term Alzheimer’s disease (AD) risk. However, the biological mechanisms mediating these effects remain poorly understood. This study investigated the impacts of recurrent heat and simulated refugee camp stress across pregnancy and the postpartum period on cognition, affective behaviour, and AD neuropathological changes in primiparous rats.MethodsControl dams underwent normal housing while stress dams were exposed to daily prenatal heat (38°C) from gestational day 12‐20 alternating with overnight food/water deprivation and overcrowded conditions to model refugee crises. This recurrent stress continued weekly from postnatal days 23‐37 (postweaning of the first litters). Learning and memory were assessed using the Y‐maze and V‐maze novel object recognition (NOR) tests. Anxiety‐ and depressive‐like behaviours were determined using the elevated plus maze (EPM) and sucrose splash tests, respectively. Following behavioural analyses, hippocampal and frontal cortical levels of pathogenic AD biomarkers amyloid‐beta 42 (Aβ42) and phosphorylated tau (p‐tau) were measured along with neuroinflammation and synaptic integrity markers.ResultRecurrent prenatal‐postpartum stress induced acute cognitive impairment including impaired recognition memory and spatial learning and memory, increased anxiety‐like behaviour, and mediated AD‐relevant pathological changes including elevated hippocampal and cortical amyloid‐beta aggregation, tau hyperphosphorylation, neuroinflammation, and synaptic alterations compared to the unstressed control group.ConclusionRecurrent prenatal‐postpartum stress elicits both immediate neurobehavioral dysfunction and pathological changes potentially increasing AD susceptibility in primiparous rats. These findings may inform interventions to mitigate recurrent perinatal stress impacts on maternal cognitive function and resilience against neurodegeneration.
Identification of underlying AD pathology in cognitively unimpaired individuals with subjective cognitive decline by the means of automated speech and language processing
Authors: Sánchez‐Benavides Gonzalo , Doerr Felix , Rădoi Andreea , Grau‐Rivera Oriol , Minguillon Carolina , Rodríguez Carlota Medina , Fauria Karine , Tröger Johannes , Linz Nicklas , Gispert Juan Domingo , König Alexandra 
Published: January 2025

AbstractBackgroundChanges in speech and language functions have shown to be early symptoms of AD pathology. Recent developments in automatic speech and language processing have opened avenues for objective assessments of these changes. The primary objective of this study is to explore whether speech and language markers extracted from cognitive testing conducted during an automated phone call differ according to underlying AD pathology as measured in cerebrospinal fluid (CSF) in preclinical or early stage individuals.MethodWithin the PROSPECT‐AD project, speech and gold‐standard clinical and biomarker data were obtained from the Beta‐AARC cohort in Barcelona, Spain. The sample consisted of N = 41 cognitively unimpaired Spanish and Catalan speakers with Subjective Cognitive Decline. Speech features were extracted from phone recordings of the Rey Auditory Verbal Learning Task (RAVLT) and the Semantic Verbal Fluency Task (SVF). The Speech‐Biomarker for Cognition (SB‐C) was computed based on 43 temporal and semantic features. Based on established cutoffs, the sample was divided into amyloid beta 42 positive and negative and pTau positive and negative groups. Kruskal‐Wallis tests were used to compare the positive and negative groups with regards to their overall cognition score and the SB‐C subscores memory, executive function and processing speed for each of the CSF biomarkers respectively.ResultsThe results of the group comparisons with regards to the amyloid beta 42 and pTau groups can be found in Table 1 and Table 2 respectively. Corresponding boxplots are presented in Figure 1. In summary, the amyloid beta negative group scored significantly higher on the SB‐C than the amyloid beta positive group. In particular, the difference had a strong effect size for the processing speed subscore and a medium effect size for the executive function subscore. No significant difference was found with regards to the memory subscore. For the pTau groups, the difference in overall cognition score showed a trend towards significance.ConclusionThis approach could establish a non‐invasive and accessible means of identifying potential indicators of AD, contributing to early detection and timely intervention strategies.
Cognitive Reserve in Individuals with Frontotemporal Dementia: A Systematic Review
Authors: Grebe Lauren A , Vonk Jet MJ , Galletta Elizabeth , Goral Mira 
Published: January 2025

AbstractBackgroundIn comparison to robust evidence for cognitive reserve (CR) in individuals with Alzheimer’s‐related dementia, the literature on CR in frontotemporal dementia (FTD) is still emerging. A clear consensus on the relationship among CR, brain status, and clinical performance has not been reached. The aims of this systematic review were to: 1) document the FTD disorders represented in this literature and their diagnosis descriptions, 2) classify the sociobehavioral proxies of CR used, 3) identify the tools used to measure disease severity, clinical performance, and brain status, and 4) examine the relationship between CR and brain status in individuals with FTD.MethodSystematic review of the literature was conducted using a comprehensive range of relevant search terms in Medline, PsychINFO, PubMed, and Web of Science. Eligibility criteria were for studies to: include at least one proxy of CR and one brain status measure for individuals with FTD, be published in a peer‐reviewed journal, and be published in English. The Newcastle‐Ottawa Quality Assessment Scale was used to assess the quality of the included studies and risk of bias based on three domains: participant selection, comparability of included groups, and quality of outcome measures.ResultA total of 220 titles and abstracts were screened, with 13 studies meeting inclusion criteria. Together, these studies report 1,423 participants diagnosed with FTD. Across studies, three proxies of CR were incorporated as either continuous or categorical variables: education, occupation, and leisure. Seven tools were used to measure disease severity and three neuroimaging tools were used to measure brain status. All included studies reported significant associations between a CR proxy and a brain measure. However, only partial support was demonstrated for the CR theory in individuals with FTD when education, occupation, and leisure involvement were analyzed in relation to disease severity.ConclusionThe variable results among studies could be related to the different tools used to measure CR, the numerous brain status measures incoporated, and the different ways researchers determine disease severity. Recommendations for future studies include incorporating longitudinal designs, using in‐depth neuropsychological testing, improving measurement of disease duration, and transparant reporting of statistical output.
Genetic analyses of the plasma proteome and metabolome from the same cohort pinpoint AD risk associated molecular phenotypes
Authors: Yang Chengran , Gorijala Priyanka , Timsina Jigyasha , Wang Lihua , Wang Ciyang , Liu Menghan , Holtzman David M. , Morris John C. , Sung Yun Ju , Cruchaga Carlos 
Published: January 2025

AbstractBackgroundThe recent European‐ancestry based genome‐wide association study (GWAS) of Alzheimer disease (AD) by Bellenguez2022 has identified 75 significant genetic loci, but only a few have been functionally mapped to effector gene level. Besides the large‐scale RNA expression, protein and metabolite levels are key molecular traits bridging the genetic variants to AD risk, and thus we decided to integrate them into the genetic analysis to pinpoint key proteins and metabolites underlying AD etiology. Few studies have generated more than one layer of post‐transcriptional phenotypes, limiting the scale of biological translation of disease modifying treatments.MethodsWe first performed the plasma proteomic (6,907 proteins by SomaScan) and metabolomic (1,483 metabolites by Metabolon) GWAS from the same participants of European (N = 2,300) ancestry. Using these significant variant‐trait associations, we next performed multiple post‐GWAS analyses (functional summary‐based imputation (FUSION) and genetic colocalization) to identify the AD associated proteins and metabolites. To annotate these findings with brain aging clocks predicated from the plasma proteomics data, we performed association tests between the aging gaps with the molecular phenotypes.ResultsWe identified hundreds to thousands of QTLs (quantitative trait loci). In the proteomic GWAS, we found 2,400 proteins with 2,848 study‐wide significant pQTLs. In the metabolomic GWAS, we reported 403 metabolites with 490 study‐wide significant mQTLs. In total, 86% and 98% of these associations have supported by the previous larger‐scale plasma‐based studies in proteome and metabolome, respectively. Under the FUSION framework, we found 95 proteins were study‐wide significant associated with AD risk, including, proteins TREM2, APOE, and NfL. After removing the bias of linkage disequilibrium by colocalization, we obtained a list of 53 proteins, of which 42 were not reported. On the other hand, 35 nominal significant metabolites, such as androsterone sulfate, were associated with AD in the FUSION analysis. Of these findings, eight metabolites were also highly colocalized with AD. There were 14 proteins and three metabolites significantly associated with the brain aging gaps, which included TREM2, but not APOE.ConclusionsOur study serves the first duo‐omics post‐transcriptional genetic study for studying AD risk effectors and can facilitate developing novel disease modifying treatments.
Subcortical correlates of sleep across Alzheimer’s Disease and cognitively healthy adults: an in vivo study
Authors: Falgàs Martínez Neus , Val‐Guardiola Andrea , Mayà Gerard , Peña Marta , Fernandez‐Villullas Guadalupe , Bosch‐Capdevila Beatriz , Lladó Albert , Muñoz‐Moreno Emma , Iranzo Álex , Grinberg Lea T. , Sanchez‐Valle Raquel 
Published: January 2025

AbstractBackgroundNeuromodulatory subcortical systems (NSS) are affected from the early stages of Alzheimer’s Disease (AD) by the accumulation of tau pathology. Increased tau burden within the subcortical nucleus that are in control of sleep and wake regulation may contribute to the breakdown of sleep‐wake patterns in AD. A recent postmortem study showed that subcortical wake‐promoting neurons were related to sleep phenotypes in AD and PSP, being that greater neuronal count in locus coeruleus (LC), tuberomammillary nucleus (TMN), and lateral hypothalamic area (LHA) associated with a decreased sleep drive (Oh et al., 2022). However, evidence studying this relationship in vivo is still lacking. The current study examines the association between sleep metrics and wake/sleep‐promoting nuclei using polysomnography and MRI.MethodsForty‐three subjects with AD biomarker‐based diagnosis and 15 cognitively healthy individuals with normal pTau plasma levels were recruited at the Hospital Clínic de Barcelona. All participants completed the Epworth Sleepiness Scale (ESS) and Pittsburg Sleep Quality Index (PSQI). All participants underwent overnight polysomnography and a 3T MRI scan, including T1 and fast spin‐echo sequences. We measured volumes of wake‐promoting nuclei: LC, posterior hypothalamus (including TMN and LHA), dorsal raphe and basal forebrain, and sleep‐promoting nucleus: anterior hypothalamus (including preoptic area and paraventricular nucleus) (Billot et al., 2020; Rolls et al., 2020; Greve et al., 2020). Correlation analysis between sleep metrics and subcortical volumes were performed.ResultsPreliminary results from 25 AD participants and 2 healthy controls showed that wake‐promoting nuclei volumes were predominantly associated with measures indicating decreased sleep drive (Figure 1): Greater LC volumes associated with increased awakenings (p<0.01), arousals (p<0.05), number of sleep stage changes (p<0.05) and NREM arousal index (p<0.05). Regarding the sleep‐promoting nucleus, greater volumes of the anterior hypothalamus were associated with decreased sleep latency (p<0.05). No significant correlations were found with sleep questionnaires. Further analyses increasing the sample size will be performed.ConclusionsThe current preliminary study suggests that the subcortical system is a primary mechanism associated with sleep disturbances in the early stages of neurodegenerative diseases, reinforcing previous neuropathological findings.
Autologous macrophages stimulated by epoxides of polyunsaturated fatty acids and protected by inhibitors of soluble epoxide hydrolase or cGAS/STING pathway repair amyloid‐β pathology in the Alzheimer’s disease (AD) brain
Authors: Fiala Milan , Whitelegge Julian , Hammock Bruce D. , Kesari Santosh 
Published: January 2025

AbstractBackgroundBrain accumulation of amyloid‐ß1‐42 (Aß) in plaques and neurons is the cause of AD neuropathology that is opposed by autologous monocyte/macrophages (MMs) in health but this defense fails in AD.MethodRNAseq, immunochemistry of the brain, immunofluorescence, and confocal microscopy of macrophages.ResultIn the AD brain, MMs shuttle Aß from parenchyma to vessels, which develop vasculitis, causing amyloid‐related imaging abnormalities (ARIAs). AD patients’ MMs are inflammatory and lack enzymes in energy, and chaperones for unfolded protein response (UPR) and Aß degradation. Epoxides of polyunsaturated fatty acids (EpFAs), in combination with the inhibitors of soluble epoxide hydrolase (sEH) TPPU or EC5026 or the cGAS/STING pathway, regulate in macrophages in a homeostatic fashion Aβ‐degrading enzymes, inflammatory cytokines, and unfolded protein response (UPR) transcripts, and recover a pro‐resolution macrophage phenotype. The repaired macrophages display increased phagocytosis of FITC‐ Aß at 2 hours and increased degradation of Aβ at 24 hours. Others showed in a mouse model that restoration of cellular bioenergetics through inhibition of the prostaglandin E2 (PGE2) receptor 4 (EP4R) signaling restored cognition.ConclusionInhibiting macrophage inflammation by the sEH receptor inhibitors TPPU and EC5026 or the STING inhibitor H‐151 in AD macrophages could restore cognition in AD patients.
Single‐nucleus multi‐ome profiling of epigenomic modifications and transcriptome characterization of heterogeneity in early and late‐stage Alzheimer’s disease
Authors: Shi Zechuan , Das Sudeshna , Morabito Samuel , Emerson Nora , Rahimzadeh Negin , Kwang Nellie , Head Elizabeth , Swarup Vivek 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD), characterized by tau lesions and amyloid plaques, has traditionally been investigated within the cortical domain. Recent neuroimaging studies have implicated micro‐ and macrostructural abnormalities in cortical layers during the progression of AD. While examinations from diverse brain regions have contributed to comprehending the regional severity, these approaches have constrained the ability to delineate cortical alterations in AD. Our study employed a single‐cell resolution approach to characterize transcriptomic and epigenomic alternations in the human brain affected by the disease.MethodWe conducted a comprehensive analysis utilizing snRNA‐Seq and single‐nucleus epigenomic profiling on samples obtained from more than 2 million cells over 100 individuals with early and late‐stage AD cases, along with controls. Four samples were procured from each participant, derived from the human pre‐frontal cortex (PFC) and temporal cortex (TCX). Our analysis utilized multi‐ome profiling, which simultaneously profiles gene expression and epigenomic changes. Data processing utilized Scanpy and Signac for gene expression and histone processing. Cicero identified cis‐regulatory elements (cCREs), overlaid with GWAS variants, creating a genome‐wide map. Transcription factor (TF) footprinting was done for cell types and disease‐associated subclusters.ResultUMAP and Leiden clustering on batch‐corrected data identified discrete cell‐type clusters from snRNA‐Seq and additional multi‐ome profiling. Enhancer‐promoter links were identified, constructing disease‐enriched, region‐specific, and shared TF regulatory networks in AD. Pseudotime trajectory analysis revealed changes from early to late‐stage AD.ConclusionThe single nucleus multi‐ome data produced in this study represents a valuable asset for the AD research community. Compared to bulk ATAC‐seq, our single‐nucleus epigenomic data provides precise insights into active and repressive activities. The study illuminates crucial TFs and their roles in AD, offering insights into cell‐specific and region‐specific mechanisms in AD pathology. Experimental validation underscores the functional relevance of the targeted TF in AD, highlighting its potential medical significance.
Prevalence of people living with dementia with cyclic temporal pattern of behavioral and psychological symptoms of dementia in a tertiary memory clinic: A descriptive diary‐based study
Authors: Rak‐Areekul Tara , Likijaroen Yuttachai , Hiransuthikul Akarin , Booncharoen Kittithatch , Sarutikriangkri Yuthachai 
Published: January 2025

AbstractBackgroundBehavioral and psychological symptoms of dementia (BPSD) profoundly impact individuals with dementia and their caregivers. Despite existing pharmacological interventions, symptom control remains challenging, often prompting polypharmacy with potential risks. Notably, in clinical practice, caregivers frequently report recurring patterns in patients' BPSD but lack empirical studies supporting these observations. The primary objective of our research is to explore the prevalence of predictable, cyclic BPSD patterns to enhance symptom control and minimize risks associated with excessive medication use.MethodImplementing a diary‐based approach, we recruited 24 dementia patients attending a memory clinic. Participants documented patients’ BPSD occurrences using hourly recordings across a 28‐day period. We categorized and quantified BPSD subcategories based on the Neuropsychiatric Inventory Questionnaire (NPI‐Q) framework. Cyclic patterns were defined by the recurrence of BPSD in at least 3 episodes, showing consistent intervals within a permissible range exceeding 50% of all episodes. This range allowed a deviation of up to 50% from the median interval.ResultStrikingly, 83% (n = 20) of participants exhibited cyclic BPSD patterns. Among the various BPSD subcategories, anxiety, apathy, nighttime behavioral disturbances, and appetite/eating abnormalities emerged as the most prominent features within these predictable fluctuations. Median intervals varied among subcategories, with irritability exhibiting the longest duration (3.5 days) and anxiety, delusion, and nighttime disturbances displaying the shortest (1.0 day), supporting the biopsychosocial model of BPSD pathogenesis.ConclusionCyclic BPSD patterns are surprisingly common, suggesting potential for personalized medication schedules based on predicted symptom peaks. Further research with larger populations is needed to validate these findings and develop tailored interventions for improved dementia care.