bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accumulation of Novel Amyloidosis‐associated proteins in the Progression of Alzheimer’s disease
Authors: Tsering Wangchen , Lolo Kiara , Phillips Jennifer L , Golde Todd , Prokop Stefan 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is one of the leading causes of death among seniors in the United States and costs the nation over $300 billion each year. Neuropathologically, AD is characterized by neuronal loss, Aβ deposits in the form of plaques, and intracellular aggregates of tau protein in the form of neurofibrillary tangles (NFT). The amyloid cascade hypothesis, one of the leading hypotheses of AD pathogenesis, suggests that Aβ aggregates are directly neurotoxic, triggering downstream neurodegeneration. However, direct evidence supporting the neurotoxicity of Aβ aggregates in vivo is lacking. For example, not all Aβ deposits elicit neurotoxicity. Diffuse plaques are typically negative for Congo‐Red and have very loose shapes and sizes, while neuritic plaques have congophilic cores and are surrounded by swollen neurites. If Aβ is directly neurotoxic, why does Aβ in diffuse plaques not elicit harmful responses while neuritic plaques are associated with neurodegenerative changes? Recent proteomic and transcriptomic studies suggest that there are many biologically active proteins that co‐accumulate with amyloid plaques, which are termed amyloidosis‐associated proteins (AAP). Most of AAP are signaling molecules, and some, such as APOE and Clusterin, are previously shown to be involved in AD pathophysiology. We evaluated the spatiotemporal distribution of diffuse plaques and neuritic plaques, and spatiotemporal accumulation of AAP in postmortem human AD brains of different AD neuropathological changes.MethodWe used immunohistochemistry (IHC) and IF on post‐mortem brain tissue specimens to assess the disease stage and brain region specific distribution of NP and amyloidosis associated proteins in cases with low, intermediate and high AD neuropathological changes. In addition, we also use spatial biology to analyze protein level differences in different Aß plaque types.ResultWe identified brain region and disease stage specific differences in the distribution and ratio of NP and other Aß‐deposits and correlated these findings with local microglia activation and co‐depositing proteins.ConclusionCharacterization and quantification of neuritic plaque and co‐depositing proteins in different brain regions and AD stages will guide effective therapeutic treatment for Alzheimer’s disease.
Assessing the Effect of Combined Humanization of Apolipoprotein E, Amyloid and Tau on Cognition and Alzheimer’s Disease Pathology
Authors: Arrar Aya , Longmuir Madison , Onuska Kate M. , Muratori Beatriz G , Lung Bryan , Schmidt Scheila , Salahinejad Arash , Cerutti Suzete M , Saksida Lisa M , Bussey Timothy J , Andrews Tallulah S , Schmitz Taylor W. , Prado Vania F , Prado Marco A.M 
Published: January 2025

AbstractBackgroundApolipoprotein E (ApoE) exhibits isoform‐specific interactions with Alzheimer’s disease (AD)‐related pathology. In comparison with the more common ApoE3 isoform, ApoE4 promotes amyloid‐β (Aβ) deposition, enhances tau‐mediated neurodegeneration and inflammation. However, the lack of appropriate preclinical models has limited the ability to evaluate the potential synergistic effect of Aβ, tau and ApoE on cognition and disease progression. To overcome this, we developed new mouse models harbouring humanized variants of the ApoE genotypes (ApoE3 or ApoE4), hApp (AppNL or AppNL‐F) and hMAPT (tau) and evaluated whether the interaction among these AD‐related factors influence cognition, brain structure, and pathological load.MethodAn array of biochemical and imaging techniques including single‐nuclei (sn)RNA sequencing, magnetic resonance imaging (MRI), immunofluorescence microscopy, and Western blots were performed. Attentional demand was assessed, using the cross‐species Continuous Performance Task, an automated touchscreen test.ResultPreliminary results indicate that AppNL‐F (ApoE3 or ApoE4), but not AppNL (ApoE3 or ApoE4) mice presented plaque pathology and insoluble Aβ. Moreover, increased levels of insoluble Aβ, plaque burden, plaque size and neuroinflammation were observed in the cortex of AppNL‐F ApoE4 mice in comparison to AppNL‐F ApoE3 at 9 and 12 months of age. At 16 months of age AppNL‐F ApoE3 and ApoE4 mice showed similar levels of insoluble Aβ. In vivo 9.4T MRI analyses indicated reduced grey matter volume in fronto‐cortical regions of AppNL‐F ApoE4 mice when compared to controls. snRNA sequencing also indicated a reduction of excitatory neurons in the cortex and upregulation of gliosis related genes and astrocytic populations at 9 months in AppNL‐F ApoE4 mice. Attentional deficits were observed on the CPT as early as 6 months of age in AppNL‐F ApoE4 mice that were maintained at 9 and 12 months of age.ConclusionResults from this project provide new insights into how amyloid, ApoE, and tau conspire to trigger and accelerate disease progression. We show that amyloid interacts with both ApoE3 and ApoE4 to drive degeneration, but in that the rate of this progression is faster in the ApoE4 background. Our findings also demonstrate that cognitive deficits are detectable much earlier than expected, in putative pre‐plaque stages of disease.
Diagnostic Utility of the Social Behavior Observer Checklist in Neurodegenerative Disease Assessment: insights from a biomarker‐enriched cohort in Spain
Authors: Selma‐Gonzalez Judit , Sánchez‐Saudinós María Belén , Sala Isabel , Rubio‐Guerra Sara , Castro Jesús Garcia , Zhu Nuole , Arranz Javier , Rodríguez‐Baz Íñigo , Arriola‐Infante José Enrique , Maure‐Blesa Lucía , Fortea Juan , Alcolea Daniel , Santos‐Santos Miguel A , Carmona‐Iragui Maria , Lleo Alberto , Illán‐Gala Ignacio 
Published: January 2025

AbstractBackgroundPatients with neurodegenerative diseases can display early behavioral changes during the clinical assessment that can be captured with the Social Behavior Observer Checklist (SBOC). Nevertheless, the incremental diagnostic utility of this structured observational instrument, when used in conjunction with conventional neuropsychological assessments, has not been ascertained across diverse cultural contexts. We aimed to determine the diagnostic value of the SBOC in large biomarker supported cohort of patients with different neurodegenerative diseases.MethodParticipants from the SPIN cohort underwent extensive diagnostic protocols, including neuropsychological evaluation and cerebrospinal fluid biomarker analysis. Diagnostic categories were assigned based on consensus criteria. We derived cognitive composites (memory, language, executive function, and visuospatial function) by averaging scaled scores measuring parallel neuropsychological constructs. A total SBOC score and three subscale scores (disorganized, reactive, and insensitive subscales) were calculated. We explored the correlation between SBOC scores and cognitive domains. We studied the diagnostic accuracy of SBOC measures by calculating the Area Under the Receiver Operating Curve (AUROC). We compared the AUROC of SBOC‐derived scores and cognitive composites with the DeLong’s test.ResultThe cohort included 572 participants: 126 cognitively healthy controls (HC), 166 with Frontotemporal Lobar Degeneration Syndromes (FTLD‐S), and 280 with Alzheimer’s disease (AD). FTLD‐S encompassed 95 with behavioral variant frontotemporal dementia (bvFTD), 26 non‐fluent/agrammatic, 8 semantic variant primary progressive aphasias, and 37 progressive supranuclear palsy‐corticobasal degeneration spectrum disorders. SBOC scores exhibited modest correlations with executive functions. FTLD‐S patients had higher SBOC scores than HC and AD, with bvFTD patients showing the greatest elevations. The diagnostic accuracy of the SBOC was high for distinguishing FTLD‐S from HC (AUROC = 0.91 for total and 0.94 for disorganized scores) and bvFTD from HC (AUROC = 0.90 for total and 0.92 for disorganized scores), matching the accuracy of cognitive composites. However, SBOC scores did not differentiate between FTLD‐S and AD (AUROC = 0.61) or between FTLD‐S subtypes.ConclusionThe SBOC is a useful scale that can complement the information obtained from formal neuropsychological testing and help identifying prototypical behaviors associated with different neurodegenerative diseases.
Extending Molecular Subtyping in Alzheimer’s using Machine Learning Techniques and Alternative Splicing Data
Authors: Palmer Lewis Edward 
Published: January 2025

AbstractBackgroundRecent studies suggest the existence of distinct molecular subtypes within the AD patient cohort, characterized by distinct gene expression patterns in AD‐relevant genes and pathways. Understanding these putative subtypes may prove pivotal to the greater understanding of AD pathology and developing targeted therapeutic interventions. This study aims to extend existing research by employing omics data modalities beyond gene expression, gathered from the ROSMAP and MSBB Alzheimer’s studies.MethodAlternative splicing (AS) events were extracted from patient‐level RNAseq data. Dimensionality‐reduction and clustering techniques from machine learning were employed to detect the presence of robust clusters within the AD patient cohort. Bootstrapping of said techniques on random samples of patients and data was used to measure the robustness of the observed clustering.ResultsInitial results indicate the presence of three robust clusters within the AD patient cohort, using AS data alone. This result echoes that of existing research that uses gene expression data from the same patient cohorts. This paves the way for further analysis of the AS events that separate the clusters, and their significance to previously described genes or pathways implicated in AD pathology.ConclusionThis work demonstrates the potential of AS in further describing putative molecular subtypes of AD and aims to highlight AS events in specific areas of interest that distinguish such subtypes from each other, further developing the emerging picture of the diverse molecular underpinnings of AD and hopefully contributing to more precise and effective medical interventions. Refining of the machine learning portion of the work to achieve the clearest delineation possible between clusters will facilitate a clearer understanding of the molecular signatures that characterise each patient cluster.
Perceived cognitive effectiveness and performance‐based cognitive dysfunction in heart failure
Authors: Martin Catherine M , Pressler Susan J , Jung Miyeon 
Published: January 2025

AbstractBackgroundCognitive dysfunction occurs in approximately 40% of individuals diagnosed with heart failure (HF). This study aims to describe perceived cognitive effectiveness among patients with HF and examine associations with performance‐based measures of cognitive dysfunction.MethodBaseline data were used from a 2‐group randomized controlled trial testing a cognitive intervention to improve attention among 73 patients with HF. Data were collected by telephone interviews due to COVID‐19 pandemic from July 2020 to May 2021. Perceived cognitive effectiveness was measured by the Attentional Function Index (AFI). AFI has 13 items assessing self‐reported effectiveness of performing cognitive activities in domains of attention, working memory, and executive function on a visual analogue scale (possible range: 0 – 100 by averaging the 13‐item scores, higher = better). Performance‐based cognitive dysfunction was measured by Oral Trail Making A and B for attention and executive function, respectively (higher response time in seconds = worse). Pearson’s correlation coefficients were used to examine associations between AFI and Oral Trail Making A and B. The significance level was set at p < .05.ResultOf 73 patients HF, 56% were women, and the average age was 66 years. On average, perceived cognitive effectiveness was moderate (AFI = 68.4 ± 15.03, range = 23 ‐ 98). Only 35.6% of patients reported high perceived cognitive effectiveness (AFI total score ≥ 75). Mean Oral Trail Making A score was 9.4 seconds (SD = 4.0); Oral Trail Making B score was 38.2 seconds (SD = 17.9). Better perceived cognitive effectiveness was significantly correlated with better attention (Oral Trail Making A, r = ‐0.38, p < .001) as well as better executive function (Oral Trail Making B, r = ‐0.27, p = .021).ConclusionMost participants with HF perceived themselves to be moderately effective in performing cognitive activities. Given the statistically significant but small to moderate correlations between subjective and objective measures of cognitive dysfunction, administering both types of measures may aid in early detection of persons at risk for developing cognitive impairment.
Shared and Distinct Epigenetic Profiles in Primary Age‐Related Tauopathy and Alzheimer’s Disease: Insights into Tangle Formation and Spread
Authors: Wadhwani Anil R , Goldberg David , Wolk David A , Lee Eddie B , Farrell Kurt W. , Crary John F. , Bennett David A. , De Jager Philip L. , Schneider Julie A. , Zhou Wanding , McMillan Corey T , Group Part Working 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is characterized by neocortical dissemination of neurofibrillary tangles (NFTs) while primary age‐related tauopathy (PART) has NFTs largely confined to the hippocampus and adjacent structures. Thus, PART and AD represent two extremes of a spectrum of NFT spread. We investigated epigenetic mechanisms of interindividual variation in NFT spread.MethodWe evaluated DNA methylation (DNAm) in frontal cortex by Infinium EPIC BeadChip array in the multi‐center PART Working Group cohort (PWG, N = 398), controlling for age, sex, and batch effects. Using SeSAMe and a false discovery rate of p<0.05, we identified differentially methylated positions (DMPs) associated with PART pathology quantitated from immunohistochemically‐stained sections. To assess amyloid effects, we compared this set with DMPs associated with neuritic amyloid plaque using the CERAD score. We identified novel DMPs not previously implicated in AD. We validated our findings in the Religious Orders Study and Memory and Aging Project cohort (ROSMAP, N = 707). We then related DMPs to differential expression of linked genes and performed enrichment analyses using KnowYourCG.ResultWe identified DMPs associated with NFTs [PWG: 8 novel / 8 total; ROSMAP: 31 novel / 68 total]. In the PWG cohort, of the 550 total [539 novel] DMPs that associated with CERAD score, there was no overlap with NFT‐associated DMPs. In the ROSMAP cohort, 57 total [3 novel] DMPs are associated with both NFTs and diagnosis of PART vs. AD and are linked to genes related to T‐cells and axonal transport. In contrast, the 11 total [10 novel] DMPs associated with NFTs alone are linked to genes related to synaptic signaling, heparin sulfate proteoglycan biosynthesis, and microtubule architecture.ConclusionDNA methylation distinguishes PART and AD brain. We identify tau‐specific DMPs that account for variance in NFT burden among aging individuals, both in the absence and presence of amyloid plaques in PART and AD, respectively. In PART, tau‐DMPs are fully orthogonal to the set of amyloid‐DMPs. In contrast, in AD, the tau‐DMPs have both amyloid‐associated and amyloid‐independent subsets with separate gene enrichment profiles. Therefore, distinct epigenetic events may drive pathology within the limbic system compared to those that drive tau spread to neocortex.
Exploring the factors impacting episodic memory decline in a longitudinal urban cohort
Authors: R Meghana , Lingegodwa Abhishek Mensegere , Narayanasamy Rajitha , Vishwanath Vindhya , Menon Meenakshi , Mallikarjun Divya N , M Amitha C , Partha Ajith , Stezin Albert , HS Dev Kumar , Arvind Prathima , HS Sunitha , Velavarajan Goutham , Agrawal Deepashri , Sundarakumar Jonas S. , Issac Thomas Gregor 
Published: January 2025

AbstractBackgroundIn the early stages of typical Alzheimer’s disease, there is a well‐documented pattern of memory deficits, especially episodic memory, substantiated with evidence of medial temporal lobe atrophy, specifically of the hippocampus in line with the memory deficits. Studies have shown that several other demographic, biological, and lifestyle factors influence memory and there is a need for identifying early risk factors and for the development of clinical intervention programs to delay or prevent cognitive decline. Therefore, the objective of this study is to explore the impact of various factors on episodic memory decline in an urban cohort.MethodA longitudinal analysis within the TATA Longitudinal Study of Aging (TLSA) examined episodic memory in a Bangalore urban cohort (n = 212). The analysis utilized data from baseline and a 2‐year follow‐up, employing the logical memory test for episodic memory assessment. Various demographic, clinical characteristics, and lifestyle factors were analyzed with episodic memory. Chi‐square and binominal logistic regression were used to analyze the data.ResultIn a study sample of 212,51.4% women and 48.6% were men. The mean age of the study sample was 67.71 and the mean years of education was 14.9. There was a statistically significant association between alcohol consumption and episodic memory delayed recall score after two years [OR = 3.31 (1.19, 9.21)], indicating that people who consumed alcohol were 3.31 times more likely to experience a decline in episodic memory performance. Additionally, a significant association was identified between hypertension and delayed recall score [OR = 2.76 (1.34‐5.66)], implying that individuals with hypertension were 2.76 times more likely to exhibit episodic memory decline over the two years. Age, gender, education, smoking, diabetes, depression and anxiety were not significant with episodic memory.ConclusionThere was an association between alcohol consumption, hypertension, and episodic memory decline, indicating that individuals who engage in alcohol consumption or have hypertension are more prone to experiencing a decline in episodic memory over two years. This research study underscores the importance of Clinical programs promoting healthier lifestyles, particularly around alcohol consumption and blood pressure management, which could significantly mitigate memory‐related problems in aging populations.
Patterns of iron‐rich gliosis in FTLD‐TDP versus FTLD‐Tau
Authors: Emrani Sheina , Arezoumandan Sanaz , Cousins Katheryn A Q , Capp Noah , Lee Eddie B , Wolk David A , Yushkevich Paul A. , McMillan Corey T , Tisdall M. Dylan , Irwin David J 
Published: January 2025

AbstractBackgroundWe recently found region‐specific patterns of iron‐rich gliosis in frontotemporal lobar degeneration (FTLD) groups with tau (FTLD‐Tau; PSP) and TDP‐43 (FTLD‐TDP) pathology using iron‐sensitive MRI of whole‐hemispheres. These patterns largely corresponded to regions of early pathology reported in previous traditional histopathologic staging schemes of protein inclusions for FTLD‐Tau and FTLD‐TDP. Ferritin light chain (FLC) reactivity highlights activated glia but has not been studied extensively in FTLD. We hypothesize neuroinflammation marked by FLC‐reactive glia may relate to protein aggregation and contribute to partially distinct regional patterns of Tau vs TDP‐43 propagation in FTLD.MethodsWe used digital histopathology to measure FLC % area occupied (%AO) in a pilot cohort of 48 FLTD‐Tau and 83 FTLD‐TDP patients in three frontal cortical regions implicated early in FTLD‐Tau (i.e., motor cortex [MOT]) and FTLD‐TDP (orbitofrontal cortex [OFC]) staging and an intermediate region for both staging schemes (medial frontal cortex [MFC]). We used linear mixed effect (LME) models to test the effect of region*group on FLC %AO while adjusting for age, sex, disease duration, and hemisphere sampled; individual was included as random‐intercept. Similarly, within‐group LME models tested for the association of %AO of Tau/TDP inclusions on FLC %AO. Between‐ and within‐group t‐tests were used to further examine FLC %AO levels.ResultsIn the total cohort, we found lower FLC%AO in MFC (Beta = ‐.008, SE = .002, p = <.001) and OFC (Beta = ‐.008 SE = .002, p = <.001) than MOT of FTLD‐Tau compared to FTLD‐TDP (Figure 1). T‐tests showed OFC FLC%AO was higher in FTLD‐TDP than FTLD‐Tau (p = <.001; Figure 1) and MOT FLC%AO was higher than OFC FLC%AO in FTLD‐Tau (p = 0.01). Separate LME models for Tau and TDP %AO was positively associated with FLC%AO across regions (Tau; Beta = 0.1 SE = .06, p = .03; TDP; Beta = 0.5 SE = .2, p = .02).ConclusionIn our preliminary sampling, iron‐rich gliosis is associated with protein aggregation in partially‐dissociated regional patterns in FLTD‐Tau vs FTLD‐TDP, recapitulating previous histopathological staging schemes. Future work will more comprehensively model the association of iron‐rich gliosis and protein aggregation across the brain.
Task‐related brain activation moderates age‐related structural decline in cognitive flexibility: A longitudinal study
Authors: Hasanzadeh Fatemeh , Stern Yaakov , Habeck Christian G , Gazes Elaine 
Published: January 2025

AbstractBackgroundAging is accompanied by declines in brain structure and executive functions like cognitive flexibility ‐ the ability to switch between tasks. However, there are substantial individual differences in degree of impairment, as some elders maintain high functioning despite accumulation of brain damage. This variability suggests higher cognitive reserve (CR) which enables older adults to cope more effectively with structural brain changes. We examined whether greater task‐related brain activation can mitigate effects of structural decline on flexibility over time, operating as a neural CR mechanism.Methods82 older and 21 young adults completed MRI scans and a set‐shifting paradigm with switch and nonswitch conditions at baseline; 75 older and 17 younger returned after 5 years. Switch cost, measured as the reaction time difference between switch and nonswitch conditions, indicating flexibility. We integrated cortical volume, cortical thickness, white matter hyperintensity burden, fractional anisotropy and mean diffusivity into a multivariate structural index using an autoencoder technique. We applied ordinal trend analysis to baseline fMRI data to identify patterns displaying increases in activation from nonswitch to switch conditions. The difference in pattern expression scores between conditions indicated differential task‐related activation (dOrT). We tested if baseline dOrT moderates the impact of structural changes on 5‐year switch cost changes using a linear mixed effect model.ResultsThe results indicated a positive main effect of brain structural index (β = 0.129, p<0.05) and a negative interaction term of brain index and dOrT (β = ‐0.282, p<0.05) on switch cost in older adults. The significant interaction demonstrates that with higher dOrT, brain structural index related less strongly to rising costs. This moderation effect implies enhanced engagement of specified OrT patterns during demanding conditions buffers effects of age‐related structural deterioration on declining cognitive flexibility.ConclusionsOlder adults utilizing task‐related functional brain networks to meet increasing demands showed attenuation of effects of structural decline on reducing cognitive flexibility over time. Results suggest differential activation of identified functional networks, serving as a neural implementation of CR, elucidating neuroprotective factors that preserve executive functions into advanced age.