bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of gantenerumab amyloid removal therapy on established Alzheimer Disease fluid biomarkers
Authors: Ibanez Laura , Li Yan , McDade Eric , Llibre‐Guerra Jorge J. , Clifford David B. , Mills Susan , Santacruz Anna , Wang Guoqiao , Supnet‐Bell Charlene , Benzinger Tammie L.S. , Gordon Brian A. , Klein Gregory , Baudler Monika , Doody Rachelle S. , Kerchner Geoffrey A. , Bittner Tobias , Atri Alireza , Bateman Randall J. 
Published: January 2025

AbstractBackgroundAnti‐amyloid monoclonal antibody therapies have successfully removed amyloid plaque as measured using imaging techniques. However, the characteristic fluid biomarker trajectories following plaque removal remains understudied, particularly during the preclinical phases of disease. We investigated biomarker trajectories in the context of the gantenerumab open label extension (OLE) of the Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN‐TU) secondary prevention trial (DIAN‐TU‐001) in Autosomal Dominant Alzheimer’s disease (ADAD) mutation carriers.MethodCerebrospinal fluid (CSF) amyloid beta 1‐42/40 (ABeta 42/40) ratio, total tau, phosphorylated Tau 217 (pTau217) and microtubule‐binding region of tau containing residue 243 (MTBR‐Tau243) were measured using Immuno‐Precipitation followed by Mass Spectrometry (IP‐MS) in all participants. Linear mixed‐effects models assessed temporal changes in biomarker levels. Correlations between biomarker measurements, clinical data, and imaging parameters were evaluated, considering estimated age at onset (EYO), and dosage.ResultDuring both the DIAN‐TU‐001 double‐blind and OLE phases, we observed a significant increase in the CSF ABeta 42/40 ratio, notably among presymptomatic individuals. This change approached the levels considered to be healthy (11.58%), even in participants beyond their EYO. In addition, CSF pTau 217 levels declined in the participants treated with gantenerumab compared to the placebo group during the double blind and OLE phases in both asymptomatic and symptomatic groups. Higher doses were associated with faster rates of change for both biomarkers. A significant decrease in total tau was observed across treatment groups (gantenerumab and placebo) during the OLE phase. No changes were observed for MTBR243.ConclusionTreatment with amyloid‐removing therapy induced changes in biomarker measurements consistent with a healthier state. Improvement in biomarker levels in individuals receiving treatment prior to their EYO supports the potential of early amyloid‐removal therapy to mitigate the risk of progression. Importantly, the rate of biomarker change was directly proportional to dosage, suggesting potential dose‐dependent benefits. Additional trials are warranted to elucidate the progression of both biomarkers and clinical symptoms after effective brain amyloid removal.
Extracellular CIRP induces neurotoxic A1 astrocytes via TREM‐1 in Alzheimer’s disease
Authors: Sharma Archna , Aylar Dilara , Lee Yongchan , Brenner Max , Marambaud Philippe , Wang Ping 
Published: January 2025

AbstractBackgroundWhile A1 astrocytes are reported in Alzheimer’s disease (AD), the underlying molecular mechanisms are complex and remain elusive. Proinflammatory extracellular cold‐inducible RNA‐binding protein (eCIRP) is released by microglia in response to AD‐associated neuronal amyloid‐β. eCIRP activates the triggering receptor expressed on myeloid cells‐1 (TREM‐1). Thus, we hypothesized that increased levels of eCIRP in AD due to inflammatory stress induce A1 via astrocytic TREM‐1.MethodELISA was performed in the AD patients’ cerebrospinal fluid (CSF; in‐house Alzheimer’s Disease Center repository) or plasma (Precision Biospecimen Solutions, Bethesda, MD) or hTau.P301S mice (Dr. Michel Goedert, Cambridge, UK) plasma. C8‐D1a cells (ATCC) or magnetically purified primary astrocytes, from C57BL/6 mice ± small anti‐CIRP peptide M3 or from TREM1‐KO mice, were stimulated with eCIRP. C57BL/6 mice were injected intracerebroventricular (icv) with eCIRP. Expression of mRNA was quantified by qPCR, protein by immunoblotting and released levels by ELISA or R&D proteome profiler. Student’s t‐test was used for two‐group analysis, one‐way analysis of variance (ANOVA)‐SNK test for multigroup analysis, and Spearman’s‐Rho analysis for correlations, with significance if p < 0.05.ResultLevels of eCIRP were elevated in the CSF and plasma of AD patients, in hTau.P301S mice, and plasma eCIRP strongly correlated with astrocyte activation marker glial fibrillary acidic protein (GFAP) in AD patients (Fig. 1). eCIRP strongly induced A1 astrocyte‐specific genes and astrocyte release of proinflammatory and neurotoxic factors in C8‐D1a cells, primary astrocytes and icv eCIRP‐injected mice brains. In particular, eCIRP increased Complement 3, an A1 astrocytic marker involved in neuroinflammation‐associated neurodegeneration. Primary astrocytes from TREM‐1 knockout mice were resistant to eCIRP induction of A1 astrocytes. Moreover, astrocytes exposed to eCIRP had higher TREM‐1 total and surface protein levels, increased Syk phosphorylation, and upregulated NFκB mRNA. Importantly, M3 effectively inhibited eCIRP’s induction of A1 astrocytes and their release of proinflammatory and neurotoxic mediators.ConclusionCollectively, our data provides a strong correlation of eCIRP with astrocyte reactivity in AD patients, identifies a novel molecular mechanism by which eCIRP induces A1 astrocytes via TREM‐1 and M3 peptide attenuation of eCIRP‐induced A1 astrocytes. These findings point to a novel therapeutic opportunity targeting neurotoxic A1 astrocytes in AD.
New proteomic signatures in Alzheimer Disease identification and Mild Cognitive Impairment Classification
Authors: Hu Manyue , Robinson Oliver J , Lill Christina C , Matton Anna , Puerta Raquel , Ruiz Agustin , Middleton Lefkos T 
Published: January 2025

AbstractBackgroundEmerging technologies and novel biomarker tools are transforming the field of Alzheimer’s disease, allowing for a more in‐depth exploration of biological mechanisms underpinning the disease aetio‐pathogenesis. In this context, there is growing recognition of the potential of plasma proteomics for AD risk assessment and disease characterization. On the other hand, differences between proteomics platforms introduce uncertainties regarding cross‐platform applicability.MethodElastic net analysis was applied to 190 analytes measured by the Luminex xMAP platform in plasma from 566 participants [58 cognitively normal (CN), 396 with mild cognitive impairment (MCI) and 58 with dementia due to AD], from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Validation was conducted on 1303 participants (113 CN, 795 MCI, 395 AD) from the Spanish ACE study, which was analysed by the SOMAscan 7k proteomic platform. MCI participants were classified into MCI stable or decliners according to their follow‐up diagnosis (ADNI: 158 vs. 217, Ace: 449 vs. 346). Signatures derived from our elastic net analysis and other methods applied in prior ADNI proteomic signature studies were compared, with our approach aimed at reducing dimensionality of signatures of AD vs. CN or MCI subgroup classification.ResultWe identified a signature including 11 plasma analytes and sex, age, and APOEε4 gene status, for distinguishing AD from CN, with 94% accuracy on ADNI (sensitivity 88%, specificity 94%) and 95% on Ace (specificity 96%, sensitivity 93%). Another 19‐analyte signature with the above confounders was used for classifying MCI stable and decliners, with a 77% accuracy on ADNI (sensitivity 85%, specificity 40%) and 51% on Ace (sensitivity 68%, specificity 36%). These two signatures share one common analyte, Vitronectin, a protein found to appear in degenerative diseases related abnormal deposits, such as amyloid.ConclusionCompared with prior proteomic signature studies, all based on ADNI, our findings attained higher specificity and sensitivity, while utilizing a smaller panel for AD classification. They also confirm the reliability and consistency of a group of plasma proteomic biomarkers across two different platforms.
Oxford Cognitive Screen Brazilian Version: Assessment of Vascular Cognitive Impairment
Authors: Ramos Claudia Cristina Ferreira , Ogusuku Caroline Suemi , Brucki Sonia Maria Dozzi , Nitrini Ricardo 
Published: January 2025

AbstractBackgroundCognitive impairment is very common in stroke patients and is rarely diagnosed. Cognitive deficits involving language functions, praxis, visuospatial, visuoconstructive skills and memory are prominent. The available cognitive assessment tests do not address some specific characteristics of stroke patients and have important limitations in relation to the most compromised cognitive domains.MethodObservational and descriptive study, with cognitively normal individuals and patients with a history of Cerebral Vascular Accident (CVA) from the Unified Health System of São Caetano do Sul and São Paulo in Brazil from September 2021 to July 2023.Result108 participants were included in this evaluation, 50 (46.3%) from the stroke group and 58 (53.7%) from the healthy group. The average age was 67 years for the stroke group and 69 years for the healthy group. Our total average number of years of study was 9 years. When comparing the OCS‐Br scores between the groups, we found that there was a significant difference between the groups in writing tasks, executive functions (attention, change of strategy) and memory (Table 1). The comparison of scores on the OCS‐Br by classification of cognition was carried out with a group stratified between Cognitively Healthy and Cognitive Impairment With and Without Dementia, with a statistically significant result between the groups in orientation (p<0.013), visual field (p< 0.045), free evocation (p<0.002), recognition (p<0.010) and circles in seconds (p<0.008).ConclusionWith our results, the need for adequate monitoring and rehabilitation of post‐stroke patients becomes more evident. The advantages of the OCS‐Br are: focus on specific cognitive aspects of stroke, such as visual inattention and visual field testing; assessment in patients with aphasia and visual impairment and prognostic value to predict long‐term functioning
Alzheimer’s Biomarkers in the Community: Learnings and Best Practices from the SiteRx Neurology Network
Authors: Gautieri Daniel , Stalder Michael 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease community care is rapidly evolving as investigative therapies receive approvals and many more investigative molecules continue to show promising late phase data. While interventional approaches have been shown to have real clinical application, implementation of new diagnostics such as blood‐based biomarkers for beta‐amyloid confirmation has lagged in the community setting. This narrative explores Alzheimer’s biomarkers within the SiteRx Alzheimer’s Real‐World Data network, the challenges stakeholders (physicians, patients, and biomarker infrastructure) are facing, and best practices for adoption of continually emerging interventions and diagnostics.MethodsSiteRx analyzes data related to the uptake of biomarkers (e.g., CSF, PET Amyloid, blood‐based) within SiteRx’s Alzheimer’s Real‐World Data network, along with HCP and practice‐level qualitative insights to identify bottlenecks in initial and sustained adoption of biomarkers in the community‐setting. This mix of primary and secondary data highlights disparities across the community ranging from provider readiness (e.g., awareness or buy‐in) to implementation readiness (e.g., connectedness with diagnostics infrastructure).ResultWhile uptake of biomarker use is fragmented in the community‐setting, there is increasing utilization of diagnostics and a growing cohort of biomarker‐positive patients within the SiteRx Alzheimer’s Real‐World Data network. The primary lagging indicator of adoption is Leqembi uptake, with physicians prescribing the mAb administering 5‐10x more diagnostics than. non‐prescribers. Anecdotally, the challenge for low‐to‐no adoption physicians is primarily driven by a lack of clear direction on how to navigate the diagnostics infrastructure. On the other end, high prescribers face mounting difficulty coordinating continued diagnostic requirements for patients on Leqembi due to required support staff, limited availability of PET amyloid appointments, and other factors.ConclusionsThe uptake of Alzheimer’s diagnostics has been slow overall, but continues to increase, especially in certain geographies and practices. As more diagnostic methods emerge, providers are becoming more well‐equipped to understand the disease and develop enhanced care plans for those living with Alzheimer’s disease. In turn, SiteRx’s Alzheimer’s Real‐World Data network is enriched with biomarker‐positive patients, growing the potential pool of interested and suitable patients for breakthrough therapies, promising investigational therapies, and further utilization of disease‐characterizing diagnostics.
Facebook Interaction as a Potential Marker of Cognitive Decline
Authors: Qansuwa Esraa M , Mohamed Abdelhamid , Elbekery Aliaa , El‐Kafrawy Passent , Eldawlatly Seif , Salama Mohamed 
Published: January 2025

AbstractBackgroundThe growth of social media and the continuous improvement of machine‐learning algorithms suggest that social media‐based screening methods for mental diseases will become increasingly feasible with high accuracy in the next few years. Additionally, Artificial Intelligence, particularly predictive machine learning (ML) Models, has been established as one of the more powerful approaches to building reliable models that might be useful as an early predictor for Mental disorders. Specifically, one of the current challenges in brain disorders is identifying patients with Mild Cognitive Impairment (MCI) that might be converted to Alzheimer’s (AD) or other types of dementia. Cognitive decline in older adults is associated with decreased social interaction and behavioral changes features.MethodUsing vast quantities of historical Facebook data from participants aged 50 and above who conducted the MoCA test as a Cognitive Assessment Tool, checking the changes in their written language mistakes and a range psychological features derived from Natural Language Processing (NLP) algorithms, LIWC 2022 dataset, and emotion dataset, using supervised Classification ML tools, such as support Vector Machine Model (SVM) and XGB Model to predict MCI using among (n = 225) participants. We consider formulating Language mistakes and social interactions. Then, we will perform a longitudinal and cross‐sectional examination of the data to examine the changes in a range of features extracted from Facebook subjects’ data over time.ResultSVM and XGB classification machine learning models show significant promising predictive results, differentiating between patients and normal subjects. SVM Recall is 66%. XGB Recall is 67.5%. Therefore, using our suggested pipeline, which shows promising primary results in building a predictive model, can detect MCI in the early stages.ConclusionFacebook data could allow us to investigate the relationship between objective daily activity patterns and objective psychological digital markers of cognitive decline. This would be a promising project that provides an ML model for Facebook activity features among subjects that can be correlated to cognitive changes. Additionally, it matches common diagnostic practices with knowledge acquired from Facebook. We seek to scale this project up globally and build decision support for a diagnostic framework for practitioners that can be used independently.
Lecanemab induces phenotypic change in glial and microglial cells in Alzheimer’s disease models: vitro and vivo evidences
Authors: Callizot Noelle , Henriques Alexandre , Esther Steidl , Rouviere Laura , Waly Bilal El , Wojcinski Alexandre , Poindron Philippe 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is characterized by the extracellular accumulation of senile plaques composed of beta‐amyloid (Aβ) and the intracellular deposition of neurofibrillary tangles composed of hyperphosphorylated tau (Tp). Aβ induces a chronic neuroinflammation that contributes to the neurite network disorganization and finally neuronal death.Lecanemab, a humanized monoclonal antibody (Ab) that recognizes protofibrils/oligomers and prevents Aβ deposition, is the first US approved Ab for AD. Its mode of action especially on inflammatory cells is still vague. We investigated Lecanemab’s effects in vitro in microglial cells and astrocytes phenotype after Aβ stress and in an aged mouse brains exposed to Aβ1‐42 (model of AD) and treated with LecanemabMethodPrimary rat cortical neurons, co‐cultured with microglia and astroglial cells were used. After 11 days of culture, cells were injured with Aβ up to 72h. Lecanemab was applied one hour before Aβ injury. After fixation, microglia and astroglia phenotype were analyzed. For both cell types, pro and anti‐inflammatory markers were assessed. Aged mice were stereotaxically infused with Aβ oligomeric fraction in CA1 hippocampal area. Animals were chronically treated with Lecanemab up to 4 weeks after the lesion. Histological analysis on brains was performed, inflammation markers were investigated.ResultApplication of Aβ induced a proliferation of astrocytes and microglial cells. In addition, a significant increase in M1 microglia was observed (TREM2/OX‐41 and Iba1) 72h after Aβ application followed with an increase of phagocytosis phenotype. A strong reduction of CD206 (M2 markers) was also detected. For astrocytes, a moderate astrogliosis was observed. Interestingly, Lecanemab treatment was able to increase number of S100A (+) cells (A2 population), associated with a moderate increase of GFAP area. In AD aged mice, cognition performances were improved and were associated with a significant reduction of brain amyloidic load in treated animals. Hippocampal section showed an increase of microglial activation (M1 and M2), and large astrogliosis.ConclusionLecanemab was able to decrease Aβ1‐42‐induced toxicity and modulated the Aβ1‐42‐induced neuroinflammatory response. These important and intriguing changes were observed both in vitro and in vivo. This study attempted to decipher the complex and unclear mode of action of Lecanemab.
Sex Differences in Tau Biomarkers and Brain Functional Connectivity in Alzheimer’s Disease
Authors: Yang Jack Lei , Williamson Jordan , Yang Yuan 
Published: January 2025

AbstractBackgroundAs of 2024, an estimated 6.9 million individuals reside in the United States with Alzheimer’s Disease (AD). Previous studies suggest that AD disproportionately affects females, who exhibit a higher incidence rate, poorer performance on various neuropsychological tasks, and more significant total brain atrophy. Recent investigations reveal differences in hippocampal functional connectivity based on sex, potentially contributing to the observed sex‐related disparities in AD. Moreover, individuals carrying higher levels of the tau protein show reduced hippocampal functional connectivity.MethodUsing Resting State fMRI and T2 MRI data from participants with AD (n = 20, female = 9) and cognitively normal individuals (n = 20, female = 9) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we employed the Functional Connectivity Toolbox (CONN) for analysis.ResultOur findings revealed differences in hippocampal functional connectivity between individuals with higher and lower levels of plasma NT1‐tau levels in each group. Additionally, sex differences in hippocampal functional connectivity were observed among AD participants with higher tau protein levels.ConclusionThese results enhance our understanding of the complex interplay between sex, tau levels, and hippocampal function in AD. Such insights into biomarkers may inform the development of sex‐specific interventions aimed at enhancing AD treatment efficacy.
Novel fluid biomarker detects TDP‐43 loss of function in individuals at elevated risk of Alzheimer’s disease
Authors: Irwin Katherine E , Sinha Irika , Wilson Rachael E , Carlsson Cynthia M. , Zetterberg Henrik , Johnson Sterling C. , Ling Jonathan P , Wong Philip C 
Published: January 2025

AbstractBackgroundTDP‐43 nuclear clearance and cytoplasmic aggregation occur in an estimated 30‐60% of cases of Alzheimer’s disease (AD), but this pathology can currently only be established at autopsy. Nuclear clearance of TDP‐43 leads to inclusion of cryptic exons in pre‐mRNA, some of which are spliced in‐frame and translated into proteins carrying novel cryptic exon‐encoded epitopes. We developed a Meso Scale Discovery (MSD) ELISA against the TDP‐43‐associated cryptic neoepitope within the HDGFL2 protein and found significantly elevated levels of this cryptic neoepitope in biofluids of presymptomatic ALS‐FTD (Irwin et al., Nature Medicine, 2024), indicating that cryptic HDGFL2 could serve as a biomarker for loss of TDP‐43 function. Here, we used our MSD assay to analyze TDP‐43 dysfunction in individuals at increased risk of AD due to family history.MethodA total of 266 CSF samples from 107 individuals (average age = 66.6 years, 40.8% phosphorylated‐tau181/Aβ42 ratio positive) in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) were analyzed for cryptic HDGFL2 by MSD.ResultSixty‐eight samples (25.6%) showed elevated levels of cryptic HDGFL2. These cryptic HDGFL2‐positive samples had a significantly higher proportion of phosphorylated‐tau/Aβ42‐positive cases (64.1%, p = 0.001). Twenty‐nine of the 107 individuals (27.1%) analyzed were positive for cryptic HDGFL2 at least once longitudinally. In 10 of the 29 (34.5%) individuals, cryptic HDGFL2 levels increased across each longitudinal sample collection, while they decreased longitudinally in 13 (44.8%). In six (20.7%), cryptic HDGFL2 levels displayed a peak during the longitudinal sampling. Twenty‐three of the 29 individuals had associated cognitive data. Eight individuals (34.8%) were from the group with increasing cryptic HDGFL2 levels, 11 (47.8%) from the group with decreasing levels, and four (17.4%) from the group displaying a peak. Each of these individuals was cognitively normal, besides one person in the decreasing group with Mild Cognitive Impairment (MCI). In this individual, cryptic HDGFL2 levels were already elevated prior to MCI diagnosis.ConclusionThe proportion of individuals with elevated cryptic HDGFL2 levels corresponds with the expected percentage of AD cases with co‐pathology of TDP‐43. Our findings of TDP‐43 dysfunction in many cognitively normal individuals suggest that TDP‐43 loss of function is an early event in disease that can precede symptom development.