bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aggregation Trumps Phosphorylation in Tau‐mediated Toxicity
Authors: Cooper Amber , Richardson Brad , Zhang Yongrui , Moreno Miguel Ramírez , Batchelor Ben , Price Ray , Skoulakis Efthimios M. C. , Allan Douglas , Mudher Amritpal 
Published: January 2025

AbstractBackgroundDisease‐modifying therapies for tauopathies like Alzheimer’s disease have targeted Tau hyperphosphorylation and aggregation, as both pathological changes are implicated in Tau‐mediated toxicity. However, the interplay between Tau hyperphosphorylation and aggregation, and their relative contribution towards overall Tau toxicity is not entirely understood.MethodLeveraging the genetic tractability of Drosophila, we generated novel transgenic lines designed to manipulate Tau phosphorylation and aggregation to address these questions and unpick the relationship between these pathological changes. Tau accumulation and neurodegenerative phenotypes were visualised and quantified using Confocal and super resolution (Structured Illumination Microscopy, SIM) microscopy. Changes in total and phosphorylated Tau in Drosophila brain homogenates were also quantified by western blot analysis.ResultWe report profound neurodegeneration following expression of phospho‐mimicking human Tau, indicative that phosphorylation is a key driver of Tau toxicity in tauopathies. However, when Tau is rendered unable to aggregate, through deletion of a known aggregation motif, Tau toxicity was completely abolished even in the presence of phospho‐mimicking mutations. To phenocopy the neuroprotective effects of genetically suppressing aggregation, a peptide inhibitor that targets the same aggregation‐promoting motif, was also efficacious in significantly reducing Tau phenotypes throughout the lifespan of Tau expressing flies.ConclusionOur data demonstrates that Tau phosphorylation mediates neurodegeneration through a mechanism gated via Tau aggregation such that if hyperphosphorylated Tau cannot aggregate, it is no longer toxic. These results should inform the next generation of Tau therapeutics as suppression of Tau aggregation may have profound disease‐modifying potential without the need to clear pathogenic phosphorylated species. Funded by Alzheimer’s Society of Canada and Mike & Valeria Rosenbloom Foundation Research Award: Award Number: AWD‐019542 ALZSOCCA 2020o.
Link Prediction of Cortical Atrophy in Alzheimer’s Disease using Morphometric Correlation Networks
Authors: Luo Tiffany , Wang Chencai , Ellingson Benjamin M. , Cankurtaran Ceylan Z. 
Published: January 2025

AbstractBackgroundPredictive biomarkers characterizing disease progression are called for in the context of emerging treatments for Alzheimer’s disease. We implemented a link prediction model on morphometric correlation networks(MCN) generated from structural MRI.MethodHigh‐resolution T1MPRAGE images were retrospectively collected at two timepoints (interval 2.6 ± 1.2 years) for each of the 32 AD patients (AD)(mean age 74.6 ± 6.8, 14F/18M) and age‐matched cognitively normal controls (CN)(n = 32, mean age 75.0 ± 6.3, 16F/16M) from Alzheimer’s Disease Neuroimaging Initiative database. Images were processed using Freesurfer(version7.2) cortical reconstruction pipeline followed by cortical volume quantification. Whole‐brain surface‐based analyses (set at p < 0.05 and FDR < 0.05) were performed to identify regions showing significant differences between CN and AD, and significant atrophy between two timepoints across AD followed by computation of interregional correlations of cortical volume changes. Topological robustness of the MCNs for both timepoints were quantified to assess the network robustness of AD in response to the removal of predominant nodes. The MCN was used to build a link prediction model. Graph embedding was implemented to learn and extract features of each node in the MCN, and the light gradient boosting machine algorithm was applied to classify the cortical changes as atrophy. The AUC(area under the receiver operating characteristic curve) was used to evaluate the model’s performance.ResultAD showed widespread cortical volume reduction. When examining the longitudinal cortical atrophy, the left superior temporal gyrus (STGl,p = 0.0108), precuneus (p = 0.0262), inferior(IPLl, p = 0.0019) and superior parietal lobule (SPLl,p = 0.0007), lingual gyrus(LGl,p = 0.0004); the right lateral occipital cortex (LOCr,p = 0.0168) and hippocampus(HCP r,p<0.0001); and bilateral supramarginal gyri(SMGl,p = 0.0227; r,p = 0.0181) showed significant volume loss (Fig. 1) and were identified as predominant nodes in the MCN that led the co‐atrophy as AD progressed (Fig. 2). With AD progression, robustness was weaker and removal of predominant nodes significantly reduced network resilience. The link prediction model predicted the cortical atrophy pattern in AD with AUC of 0.97 (Fig. 3).ConclusionWe successfully implemented a model to predict progression of cortical atrophy and identified atrophy‐leading brain regions in AD. Future clinical translation of our approach can serve as an imaging biomarker.
Development of Alzheimer’s disease immunotherapies using conformationally constrained β‐strands and β‐hairpins from Aβ and tau
Authors: Kreutzer Adam , Zhu Jason , Plancarte Jovanna , Ruttenberg Sarah , Nowick James 
Published: January 2025

AbstractBackgroundPeptide antigens that mimic disease‐related conformations of Aβ and tau were designed and created, and antibodies against these peptide antigens were generated and characterized.MethodThe peptide antigens were designed to mimic β‐strands formed by Aβ and tau in the cryo‐EM structures of the Alzheimer’s disease brain‐derived fibrils. Peptide antigens were also designed to mimic β‐hairpins of Aβ and oligomers formed by the β‐hairpins. These β‐strand and β‐hairpin antigens were then used to generate antibodies in rodents. Ex vivo immunohistochemical and biochemical studies in Alzheimer’s disease brain‐tissue and cell‐based studies were performed to characterize the antibodies.ResultThe antibodies raised against the Aβ‐derived peptide antigens recognized Aβ plaques in Alzheimer’s disease brain tissue and in 5xFAD mouse brains and protected iPSC‐derived human neurons from Aβ toxicity. Biochemical characterization of these Aβ‐derived antibodies showed that the antibodies exhibit some selectivity for aggregated forms of Aβ. The antibodies raised against the tau‐derived peptide antigens recognized tau neurofibrillary tangles in Alzheimer’s disease brain tissue and inhibited tau seeding in a cell‐based tau biosensor assay.ConclusionAntibodies generated against conformationally constrained β‐strand and β‐hairpin antigens designed to mimic disease‐related conformations of Aβ and tau exhibit characteristics beneficial for immunotherapy, such as recognition of Aβ and tau pathology, and protection against Aβ cytotoxicity and inhibition of tau seeding.
Chemical chaperones mitigate chronic short sleep induced cognitive impairment
Authors: Sengupta Kamalini , Scherbakova Katya , Mason Sydney , Naidoo Nirinjini 
Published: January 2025

AbstractBackgroundEpidemiological studies indicate that chronic short sleep and/or disrupted sleep are all associated with metabolic dysfunction, cardiovascular risk, cognitive impairments, and increased risk for Alzheimer’s disease. We have shown that acute sleep deprivation disrupts proteostasis, leading to the activation of an adaptive endoplasmic reticulum (ER) stress response known as the unfolded protein response (UPR). However, prolonged ER stress triggers the integrated stress response, which has been implicated in memory impairments. In this study, we investigated the effects of chronic short sleep (CSS) exposure in young adult wild‐type (WT) mice on learning and proteostasis in the presence and absence of chaperone therapy.Method2‐month‐old male and female C57BL/6 mice underwent 4 weeks of CSS for 8hrs/day; 3 days/week by exposure to an enriched environment with or without 4‐phenyl butyrate (PBA) treatment. Control mice were left undisturbed, (n = 10/group/condition). Following CSS and recovery for 2 weeks mice were tested for hippocampal dependent learning. Brains were harvested for histology and biochemical analyses.ResultSpatial object recognition testing revealed no differences between any of the groups 2 weeks post CSS. However, SOR at 5 weeks post CSS revealed that the vehicle treated male CSS mice performed worse than the rested vehicle treated mice (p<0.02) and the PBA treated CSS mice performed better than the saline treated CSS mice (p<0.04). Similar results were observed in the female mice but at 7 weeks post CSS. Preliminary histological analyses for integrated stress markers indicate that PBA reduces PERK activation and signaling in the hippocampi of CSS mice. Analyses of other markers are in progress.ConclusionOur data suggest that relieving proteostatic stress with chemical chaperones mitigates the effects of CSS on learning and memory.
Diet, APOE‐e4, and cognition in middle‐aged women at increased risk of Alzheimer’s disease
Authors: Wessinger Chadsley M , Park Kyoung Shin , DuBois Samantha L , Kibildis Samuel , Som‐Pimpong Hadassah , Vance Jarod C , Armstrong Brittany D , Wideman Laurie , Etnier Jennifer L 
Published: January 2025

AbstractBackgroundImproving modifiable risk factors, like diet quality, can protect against Alzheimer’s disease (AD). The association between diet and cognition in midlife as a function of APOE‐e4 genotype, a strong risk factor for AD, remains unknown. Therefore, this study examined the relationship between dietary intake and executive function (EF) in middle‐aged sedentary women with a family history of AD (FH+), and if the association was moderated by APOE‐e4 carrier status.MethodBaseline data from an ongoing clinical trial (NIH‐R01AG058919) were analyzed. Participants (n = 102, age = 56.9±5.8 yrs) were cognitively normal, middle‐aged women with (FH+). APOE genotype was determined from passive drool saliva samples (carriers, n = 41, non‐carriers, n = 61). Dietary data were collected using the Diet History Questionnaire III (DHQ‐III) and Healthy Eating Index (HEI), a measure of diet quality, was computed based on adherence to the Dietary Guidelines for Americans. Core EF was assessed via NIH Toolbox Flankers Test and Spatial Working Memory test (SWM). Linear regression moderation analyses were conducted using PROCESS v4.2 in SPSS including Flankers and SWM as the outcome, HEI as the predictor, APOE‐e4 carrier status as the moderator, and age, BMI, and education as covariates.ResultHEI did not predict Flankers performance after controlling for covariates (p = 0.14). However, the interaction between HEI and APOE‐e4 status trended towards significance (p = 0.05). After controlling for covariates, better HEI scores predicted better SWM performance (p<0.001). The interaction between HEI and APOE‐e4 carrier status was also statistically significant (p<0.05), suggesting APOE‐e4 carrier status moderated the relationship between HEI and SWM performance. For both the Flankers and SWM, better HEI predicted better EF in non‐carriers (p<0.05 and p<0.01, respectively) but not in carriers.ConclusionWhile better HEI predicted better EF in non‐ APOE‐e4 carriers, carriers did not experience this effect, suggesting that improving diet quality may not offset the negative effects of APOE‐e4 on cognition in middle‐aged women at increased risk of AD. Future research should explore if the effects of prescriptive dietary interventions on cognition vary by APOE genotype. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Chimeric antigen receptor T cell targeting colony‐stimulating factor 1 receptors alleviates amyloid‐β and tau pathologies in Alzheimer’s disease‐pathologic male mice
Authors: Xu Jun , Wang Yanli , Yu Feng , Wang Xiaohong , Jiang Jiwei , Jiang Tianlin 
Published: January 2025

AbstractBackgroundMicroglia play a critical role in the pathogenesis and development of Alzheimer’s disease (AD). Selective small‐molecule colony‐stimulating factor 1 receptors (CSF1R) inhibitor, designed to deplete microglia, could be used to meliorate AD. This study aimed to investigate the effects and mechanisms of chimeric antigen receptor T (CAR‐T) cells targeting CSF1R in 6‐month‐old APP/PS1 male mice.MethodThe Morris water maze test, Y‐maze test, tail suspension test, swimming test, nesting score assay, and three‐chamber social interaction assay were performed to assess cognitive function. Western blotting, immunofluorescence staining, enzyme‐linked immunosorbent assay, and Bio‐Plex Pro Mouse Cytokine 23‐plex assays were conducted to explore AD‐core pathologies, neuroinflammation, microglial activation and polarization, and pyroptosis.ResultiCSF1R.CAR‐T cells ameliorated cognitive deficits and reduced β‐amyloid load, tau hyperphosphorylation, and synapse‐related proteins, as well as microglial activation and polarization in 6‐month‐old APP/PS1 male mice. Furthermore, iCSF1R.CAR‐T cells significantly inhibited pyroptosis and attenuated neuroinflammation in these mice.ConclusionThe results suggest that iCSF1R.CAR‐T cells improve cognitive decline and neuroinflammation, possibly by suppressing caspase‐1/GSDMD‐mediated pyroptosis. Consequently, iCSF1R.CAR‐T cells could be a potential therapeutic approach for AD and other neurological disorders characterized by microglial dysfunction.
Investigation of structural connectivity in the whole brain and frontoparietal network in groups at risk of Alzheimer’s disease dementia
Authors: Tahara‐Eckl Lenore T , Morgan Catherine A , Roberts Reece P , Dell'Acqua Flavio , Kirk Ian J , Melzer Tracy R , Dalrymple‐Alford John C , Anderson Tim J , Cutfield Nicholas J , Tippett Lynette J 
Published: January 2025

AbstractBackgroundBrain connectivity patterns, measured with Magnetic Resonance Imaging (MRI), have been recently studied as a potential biomarker for Alzheimer’s disease dementia (AD). A ‘disconnected brain’ has been associated with greater cognitive impairment in pathological aging (Bennett & Madden, 2014), but it is unclear how this occurs in groups at risk of AD.MethodParticipants (n = 227; aged 55+ years) from the Dementia Prevention Research Clinic, New Zealand, were classified as control (C; n = 35), subjective cognitive decline (SCD; n = 60), single‐domain amnestic mild cognitive impairment (aMCI; n = 54), multiple‐domain MCI (mMCI; n = 52), and AD (n = 26). Longitudinal changes (over two years) were investigated in a subset (total n = 119). Using diffusion MRI, we measured the white matter connections between brain regions with fiber bundle capacity (FBC), a proxy of white matter connection strength (Smith et al., 2022).ResultCross‐sectionally, a significant linear trend of lower FBC was found across groups (C > SCD > aMCI > mMCI > AD; p < .05), mostly affecting interhemispheric connections (see Figure 1). Over time, FBC significantly decreased in only one connection between the left precentral and left parahippocampal region, but several intrahemispheric connections FBC connections increased over time (see Figure 2). A significant interaction (F(4, 114) = 10.60, p < .001, η2
= 0.27) showed that the AD group had significantly decreased structural connectivity than all other groups over time (see Figure 3).ConclusionWe explored different threshold/processing strategies to ensure robust results. The preliminary results show the following: widespread disruption in structural connectivity was found cross‐sectionally in groups at higher risk of AD. Lower interhemispheric structural connectivity across groups may reflect degenerated commissural white matter tracts (e.g., corpus callosum) found in MCI and AD. The unexpected increasing intrahemispheric structural connectivity over time may suggest some structural reorganization, possibly in response to disrupted interhemispheric connections, or inflammation of the tracts. Alternatively, a general degeneration of commissural tracts may also explain an apparent increase of associative connectivity.Bennett & Madden (2014). Neuroscience. https://doi.org/10.1016/j.neuroscience.2013.11.026Smith et al. (2022). Aperture Neuro. https://doi.org/10.52294/apertureneuro.2022.2.neod9565
Intercept‐AD: Development and qualification of a highly sensitive immunoassay to detect total sabirnetug (ACU193) in human CSF
Authors: Zhang Hao , Monsheimer Sarah , Gillies Jennifer , Johnson Derrick , McOwen Nathan , Cline Erika N , Rafizadeh Mahsan , Dean Robert A , Moore Jerome A , Jerecic Jasna 
Published: January 2025

AbstractBackgroundSabirnetug (ACU193) is a humanized monoclonal antibody targeting soluble amyloid beta (Aβ) oligomers, which are early contributors to the pathogenesis of Alzheimer’s Disease (AD). An ultrasensitive assay was developed to measure sabirnetug pharmacokinetics (PK) in CSF of individuals with early AD in the Phase 1 study INTERCEPT‐AD (NCT04931459).MethodThe immunoassay was developed on the Meso Scale Diagnostics (MSD) S‐PLEX with improved sensitivity through TURBO‐TAG® technology. Twenty‐four anti‐sabirnetug antibody pairs were screened. Assay selectivity, target interference, dilutional linearity, and stability were evaluated. Assay accuracy and precision were tested, and the lower limit of quantitation (LLOQ) was determined. Target interference was tested by spiking various concentrations of Aβ oligomers and monomers into the sabirnetug calibrators prepared in CSF. Total drug (sabirnetug bound and unbound to AβOs) concentrations were measured in individual study participant CSF samples.ResultTwo anti‐idiotypic antibodies against sabirnetug were selected for capture and detection based on sensitivity and background of blank matrix. Final minimal required dilution (MRD) was 1:4. Optimized concentrations for capture and detection antibodies were 0.0625 µg/mL and 0.2 µg/mL. Assay stability was 12 hours room temperature and 5 freeze/thaw cycles. No interference with recovery of standard curve was observed with Aβ oligomers or monomers. Dilutional linearity data showed accurate dilution up to 1:65,536. Five selectivity CSF samples were spiked with sabirnetug at high, medium, and low doses. Recovery of selectivity samples at all doses met acceptance criteria. Nine of 10 independent accuracy and precision runs met acceptance criteria. LLOQ (6 pg/mL) and upper limit of quantitation (6000 pg/mL) were established through 9 reproducibility runs. All pre‐dose CSF sabirnetug concentrations were <LLOQ. All post‐dose concentrations were measurable in a dose‐dependent manner.ConclusionAn ultra‐sensitive CSF total sabirnetug immunoassay was successfully developed on the MSD S‐PLEX platform. Assay qualification demonstrated sensitivity, accuracy and precision, selectivity, specificity, dilutional linearity, and stability of the method. Analysis of CSF samples collected during INTERCEPT‐AD showed the method is applicable for quantification of total drug exposure of sabirnetug in clinical trials.
Study Protocol: Quantitative evaluation of The Agitation in Alzheimer’s Screener for Caregivers AASC™, a novel tool for improving recognition of agitation in Alzheimer’s dementia
Authors: Clevenger Carolyn K , Brubaker Malaak , Jackson William C , Stroud Jared , Peschin Sue , Fehnel Sheri , Brown T. Michelle , Bratlee‐Whitaker Emily , Bucior Iwona , Patel Mehul , Grossberg George T 
Published: January 2025

AbstractBackgroundAgitation, manifesting as aggressive and non‐aggressive behaviors, is one of the most common neuropsychiatric symptoms in Alzheimer’s dementia, presenting in approximately half of all patients. Despite the high prevalence, recognition of agitation in Alzheimer’s dementia (AAD) remains a challenge that impacts timely diagnosis and treatment. The International Psychogeriatric Association (IPA) established a new standard definition of agitation in cognitive disorders, which provides guidance for advancing recognition and improving patient care. The Agitation in Alzheimer’s Screener for Caregivers (AASC™), an easy‐to‐use and pragmatic tool, was developed based on IPA criteria to support caregivers and healthcare professionals (HCPs) in recognizing AAD, thereby facilitating caregiver‐HCP discussions and supporting timely treatment planning.MethodThe AASC™ was developed and qualitatively evaluated through a rigorous, iterative process involving clinical experts, patients, and caregivers. For quantitative validation, this prospective, multisite, single‐visit observational study will calculate predictive metrics for the identification of agitation by comparing responses on the AASC™, completed by caregivers, to HCPs judgement based on implementation of the IPA criteria (Figure 1). Community‐dwelling patients must have a recorded diagnosis of Alzheimer’s dementia; caregivers must be aged 18‐85 years, provide patient care ≥10 hours/week, and attend the office visit. Data will be collected and analyzed in 2 parts: an interim analysis (n = 50 dyads) will determine the rate of agreement (yes/no), and a final analysis (n = 150 dyads) will determine sensitivity and specificity of the AASC™. Caregiver‐reported items include caregiver and patient demographics and AASC™ responses. HCPs will complete assessments for the presence of IPA‐defined agitation and the severity of Alzheimer’s dementia.ResultResults will include: descriptive statistics, the percentage agreement and Cohen’s kappa coefficient characterizing the interrater reliability between the caregiver‐completed AASC™ and IPA‐based HCP decision (part 1), sensitivity, specificity, positive and negative predictive values of the AASC™ against the HCP decision, goodness of fit metrics (e.g., concordance), and receiver operating characteristic curves (part 2).ConclusionThe AASC™ was developed following a rigorous process established to support its medical credibility and implementation in clinical practice. Results from this study will quantitatively validate the AASC™, leveraging caregiver observations to aid in facilitating earlier identification and treatment of AAD.
Research Trends on Social Isolation: A Bibliometric Analysis
Authors: YANG HYUN , Shin Jiwon , Yun Sohyeon , Kim Inhye , An Hyunseo , Park Hae Yean 
Published: January 2025

AbstractBackgroundResearch on social isolation has been ongoing, recognizing it as a significant social problem due to the disruption or absence of meaningful relationships providing essential resources for life maintenance. This study aims to analyze the social isolation research trend using quantitative bibliographic methods.MethodThis study collected literature containing 'social isolation' in the title using the Web of Science database and analyzed the number of publications anually and research fields. VOS viewer generated a visualization map based on document relationships, along with academic journals, countries/regions, institutes, and keyword analyses. Additionally, CiteSpace analyzed research keyword trends on social isolation.ResultFrom 1980 to March 4, 2024, 2,874 documents were surveyed, with a rapid increase in publications from the 2010s. Neuroscience dominates, with PLOS One leading in publications. The United States leads in research activity, but influential studies from British institutes have a higher total link strength. Keyword analysis highlights ‘Loneliness’, ‘Health’, ‘Depression’, and ‘Mortality’. The top three keyword clusters were classified through the analysis of keywords by time, and each was described as ‘harmfulness of social isolation and loneliness’, ‘social isolation and mental health’ and ‘deepening of social isolation and influencing factors’.ConclusionThis study identifies research trends in social isolation, providing a basis for future research revival and development