bluuebunny/crossref_metadata_2025_split huggingface dataset:
Omega 3 fatty acid alleviates sleep deprivation‐induced oxidative stress, inflammation, and cognitive impairment in the hippocampus of Male Wistar rats
Authors: Ochai Joy , Umana Uduak Emmanuel , Musa Sunday Abraham , Oladele Samuel B 
Published: January 2025

AbstractBackgroundSleep deprivation leads to an increase in oxidative stress and activation of inflammatory response and both could increase the production and accumulation of toxic beta‐amyloid in the hippocampus which is considered one of the molecular drivers of Alzheimer’s pathogenesis and progression. Despite these findings, obtaining sleep is still challenging in our modern society that values work around the clock. Omega‐3 fatty acids represents an active biological agent with vital antioxidant and anti‐inflammatory activities that could protect memory in the face of insufficient sleep. This study evaluated the anti‐oxidative, anti‐inflammatory, and neurocognitive effect of omega‐3 fatty acids on memory impairment caused by sleep deprivation in male Wistar rats.MethodThirty male Wistar rats were randomly divided into five groups of six rats each. Group I received 2ml/kg distilled water, Group II, III IV and V were sleep deprived for 18 hours daily for a 21 days duration using the modified multiple platform method. Additionally, group III, IV and V received 100mg/kg, 200mg/kg and 400mg/kg of omega‐3 fatty acids respectively via oral route. Neurobehavioral assay for spatial learning and memory using the Morris water maze (MWM) test was carried out. The animals were euthanised and the brain tissues excised, fixed, and processed for β‐amyloid study using Congo red stain. Tissue homogenate was used for assessment of malondialdehyde (MDA), superoxide dismutase (SOD), interleukin‐6 (IL‐6) and tumor necrosis factor‐alpha (TNF‐α) levels.ResultThe result revealed a marked increase in the time‐spent in locating the escape platform in the MWM test, and an increased in β‐amyloid burden in the sleep deprived only group. Biochemical assessment also showed significant increase in MDA, IL‐6 and TNF‐ α and decrease in SOD level within this group. However, significant improvement in memory retention ability, decreased β‐amyloid accumulation, MDA, IL‐6, TNF‐ α and increase in SOD level were observed in the omega‐3 fatty acid treated groups. The observed changes were dose dependent.ConclusionOmega‐3 fatty acids protects the hippocampus against memory impairment caused by sleep deprivation.
Cell type‐specific signatures of resilience to cognitive decline in the presence of brain pathologies
Authors: Luquez Tain , Sreenivas Dhwani , Bennett David A. , De Jager Philip L. , Menon Vilas 
Published: January 2025

AbstractBackgroundTo identify discrete and continuous cell type signatures in brain tissue from donors with minimal cognitive decline despite harboring substantial proteinopathies associated with Alzheimer’s Disease and Alzheimer’s Disease‐related dementias.MethodThree large‐scale single‐nucleus RNA‐seq studies on Alzheimer’s Disease post‐mortem human tissue were re‐annotated and integrated to identify cell type composition associations with cognitive resilience to various neuropathologies. Cell type signatures were defined in two ways: using an integrated clustering approach and using a continuous factor‐based analysis. Cognitive resilience was also defined in two ways: using a categorical grouping of donors as well as a continuous definition based on the slope of decline across each of five cognitive domains.ResultWe report two microglial cell types associated with resilience to Alzheimer’s and alpha‐synuclein proteinopathies. Individuals cognitively resilient to substantial cortical alpha‐synuclein aggregates have higher levels of a microglial subset enriched for redox genes and overexpressing APOE, TYROBP and SPP1. By contrast, cognitively resilient individuals with high amyloid burden show lower proportions of a microglial subset marked by TMEM163+. On the neuronal side, a subset of glutamatergic layer 2/3 neurons was higher in individuals resilient to visuospatial decline despite harboring alpha‐synucleinopathy. A different L2/3 excitatory neuron cluster is depleted in the same individuals, thus highlighting preferential loss or preservation of neuronal subclasses in individuals with cognitive resilience. Finally, we find lower levels of committed oligodendrocyte precursor cells and FTH1+/CRYAB1+ oligodendrocytes in individuals with amyloid and alpha‐synuclein aggregates with better preserved visuospatial, semantic memory and global cognition.ConclusionUsing a combination of categorical and continuous definitions of resilience, together with existing single‐nucleus RNA‐sequencing data on cortical tissue from >600 human donors, we uncovered cell‐type compositional changes in microglia, neurons and oligodendrocytes that are associated with global and domain‐specific cognitive resilience to amyloid, tau and alpha‐synuclein proteinopathies.
Localized Proteomics of Amyloid Plaque Tissue in Down Syndrome and Alzheimer’s Disease
Authors: Ariza Mitchell Marta , Leitner Dominique , Suazo Jianina , Pedrosa Ana Giusti , Kanshin Evgeny , Ueberheide Beatrix , Fortea Juan , Lleo Alberto , Wisniewski Thomas 
Published: January 2025

AbstractBackgroundDown syndrome (DS) is strongly associated with Alzheimer’s disease (AD), attributable to APP overexpression, displaying common features with early‐onset AD (EOAD) and late‐onset AD (LOAD) like Amyloid‐β (Aβ) and tau pathology. Here, we evaluated the Aβ plaques proteome of DS, EOAD and LOAD.MethodWe used unbiased localized proteomics to analyze amyloid plaques and the adjacent plaque‐devoid tissue (‘AD non‐plaque’) from post‐mortem paraffin‐embedded tissues in three subtypes of AD (n = 20/group): DS (59.8 ±4.99 y/o), EOAD (63 ±4.07 y/o), and LOAD (82.1 ±6.37 y/o). Functional associations were analyzed using Gene Ontology (GO) enrichment and protein interaction networks.ResultWe identified 132, 192 and 128 differentially abundant proteins in DS, EOAD and LOAD Aβ plaques (FDR<5%, fold‐change<1.5). Common plaque‐associated proteins constituted 14% across all groups, with 15% only in DS, 32% in EOAD, and 17% in LOAD. Significant correlations (p<0.0001) existed between DS and EOAD (R2 = 0.77) and DS and LOAD (R2 = 0.73), compared to EOAD and LOAD (R2 = 0.67). Top BP GO terms (p<0.0001) were lysosomal transport, regulation of the immune system process and lysosome organization for DS, EOAD and LOAD, respectively. Protein networks revealed a characteristic signature across all AD subtypes involving APP metabolism, immune response, and lysosomal pathways. We identified 263, 269, and 301 differentially abundant proteins in DS, EOAD and LOAD non‐plaques. Common differentially abundant proteins constituted 12% across AD subtypes, with 24% only in DS, 14% in EOAD and 26% in LOAD. DS correlated significantly (p<0.0001) with EOAD (R2 = 0.59) and with LOAD (R2 = 0.33), compared to EOAD and LOAD (R2 = 0.79). The top BP GO term for all three subtypes was chromatin remodeling (p = 0.0013, p = 5.79 × 10‐9, and p = 1.69 × 10‐10, respectively). Additional GO terms for DS included extracellular matrix and integrin‐mediated signaling (p = 0.0068), while EOAD and LOAD were associated with protein‐DNA complexes and regulation of gene expression (p<0.0001).ConclusionWe identified proteome differences in Aβ plaques across AD subtypes. Correlation and functional analyses revealed that DS and LOAD plaque‐associated proteins primarily participate in lysosomal pathways, while EOAD proteins are linked to immune response. In contrast, EOAD and LOAD non‐plaque proteins correlated better compared to DS, with functional differences reflected in the top GO terms.
Exploring the pathophysiological consequences of TDP‐43 mislocalization in retinal cells
Authors: Sørensen Maja Højvang , Xu Yan , Lee Virginia M.‐Y. , Porta Sílvia 
Published: January 2025

AbstractBackgroundGlaucoma is characterized by progressive optic nerve degeneration that results in irreversible blindness, and it can be considered a neurodegenerative disorder of both the eye and the brain. Increasing evidence suggest that glaucoma shares some common neurodegenerative pathways with Frontotemporal Lobar Degeneration (FTLD), Amyotrophic Lateral Sclerosis (ALS), and Alzheimer’s Disease (AD) among others. Interestingly, a recent study revealed the presence of abnormal TAR DNA‐binding protein 43 (TDP‐43) inclusions and aggregates in retinal ganglion cells and other retinal cell types in FTLD‐TDP patients; however, the significance of this pathology and its impact on retinal function and optical nerve integrity is unknown. In these patients, optic nerve degeneration has been linked to the spread of aggregated TDP‐43 beyond the brain. Thus, this study aims to explore the role TDP‐43 mislocalization and aggregation contributes to glaucoma.MethodThe expression of the mutant cytoplasmic human TDP‐43 transgene (hTDP‐43NLSm) in a doxycycline‐regulatable TDP‐43 transgenic mouse line (rNLS8), was induced for 2, 4 and 6 weeks (i.e., Off‐Dox), thus causing a time‐dependent cytoplasmic translocation of TDP‐43 in neurons. rNLS8 mice were euthanized, perfused, and intact eyeballs collected for histological examination. The expression of hTDP‐43 and its phosphorylated form (p409/410) together with cleaved caspase‐3 and p62 was examined by immunohistochemistry in 5 µm paraffin ‐embedded retinal sections.ResultrNLS8 mice kept Off‐Dox expressed hTDP‐43NLSm in all neuronal layers in the retina, in all the time‐points analyzed. Interestingly, in rNLS8 mice at 6 weeks Off‐Dox, revealed mild phosphorylation of TDP‐43 together with an increase of cleaved caspase‐3 and p62 protein immunoreactivity.ConclusionThus far, this data indicates the activation of apoptotic and autophagy signaling pathways concomitant to the presence of mislocated and phosphorylated TDP‐43. Altogether, this indicates that the rNLS8 transgenic mouse line serves as a good model to evaluate the pathophysiological consequences of TDP‐43 mislocalization in retina cells and its role in optic nerve degeneration.
Co‐methylation network analysis of Psychosis in Alzheimer’s disease
Authors: Kouhsar Morteza P , Weymouth Luke , Smith Adam , Imm Jennifer , Bredemeyer Claudia , Wedatilake Yehani , Torkamani Ali , Bergh Sverre , Selbaek Geir , Mill Jonathan , Ballard Clive G , Sweet Robert , Kofler Julia , Creese Byron , Pishva Ehsan , Lunnon Katie 
Published: January 2025

AbstractBackgroundPsychosis (broadly delusions and hallucinations) has a cumulative disease prevalence of around 40% in Alzheimer’s disease (AD). The epigenomic, genomic, and neuropathological data provide powerful evidence that AD+P has a distinct neurobiological profile. Here, we used the weighted gene co‐expression network analysis (WGCNA) method to investigate DNA methylation associated with AD+P in the dorsolateral prefrontal cortex of 153 post‐mortem brain samples.MethodOur primary analysis focused on applying WGCNA to the PITT‐ADRC cohort, followed by subsequent replication of its findings in the BDR cohort. The genotype data from PITT‐ADRC and the WGCNA results were further utilized to identify the most significant methylation Quantitative Trait Loci (mQTLs) associated with psychosis. Subsequently, we explored RNA sequencing data from PITT‐ADRC to identify genes affected by the replicated findings uncovered in our primary analysis.ResultWe identified five AD+P‐related modules in the PITT‐ADRC cohort, with one of them being replicated in the BDR cohort. This replicated AD+P‐related module exhibits a high enrichment in the T cell receptor signalling pathway. According to the colocalization analysis results, this module shares significant SNPs in some regions that are also significantly associated with Schizophrenia and Educational Attainment.ConclusionUnderstanding molecular differences between AD and Psychosis at the genetic and epigenetic levels could guide us in discovering appropriate treatments for AD+P cases. To this end, we initiated a comprehensive, large sample‐sized network analysis study based on genetic and epigenetic data.
TA‐RNN: an Attention‐based Time‐aware Recurrent Neural Network Architecture to Predict Progression of Alzheimer’s Disease
Authors: Olaimat Mohammad Al , Bozdag Serdar , Saeed Fahad ,   Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD) is a widespread neurodegenerative disease with Mild Cognitive Impairment (MCI) acting as an interim phase between normal cognitive state and AD. The irreversible nature of AD and the difficulty in early prediction present significant challenges for patients, caregivers, and the healthcare sector. Deep learning (DL) methods such as Recurrent Neural Networks (RNN) have been utilized to analyze Electronic Health Records (EHR) to model disease progression and predict diagnosis. However, these models do not address some inherent irregularities in EHR data such as irregular time intervals between clinical visits. Furthermore, most DL models are not interpretable. To address these issues, we developed a novel DL architecture called Time‐Aware RNN (TA‐RNN) to predict MCI to AD conversion at the next clinical visit.MethodTA‐RNN comprises of a time embedding layer, attention‐based RNN, and prediction layer based on multi‐layer perceptron (MLP) (Figure 1). For interpretability, a dual‐level attention mechanism within the RNN identifies significant visits and features impacting predictions. TA‐RNN addresses irregular time intervals by incorporating time embedding into longitudinal cognitive and neuroimaging data based on attention weights to create a patient embedding. The MLP, trained on demographic data and the patient embedding predicts AD conversion. TA‐RNN was evaluated on Alzheimer’s Disease Neuroimaging Initiative (ADNI) and National Alzheimer’s Coordinating Center (NACC) datasets based on F2 score and sensitivity.ResultMultiple TA‐RNN models were trained with two, three, five, or six visits to predict the diagnosis at the next visit. In one setup, the models were trained and tested on ADNI. In another setup, the models were trained on the entire ADNI dataset and evaluated on the entire NACC dataset. The results indicated superior performance of TA‐RNN compared to state‐of‐the‐art (SOTA) and baseline approaches for both setups (Figure 2A and 2B). Based on attention weights, we also highlighted significant visits (Figure 3A) and features (Figure 3B) and observed that CDRSB and FAQ features and the most recent visit had highest influence in predictions.ConclusionWe propose TA‐RNN, an interpretable model to predict MCI to AD conversion while handling irregular time intervals. TA‐RNN outperformed SOTA and baseline methods in multiple experiments.
The Ego‐Allo Switching Task for Assessing Visuospatial Memory in Brazilian Old Adults
Authors: Cetraro Victoria Sciascia , Silva Ana Beatriz , Cunha Ana Luiza Nunes , Souza Carolina Pinto , Tumas Vitor , Foss Maria Paula 
Published: January 2025

AbstractBackgroundSpatial orientation involves egocentric and allocentric strategies that switch in the brain. Disturbances in switching may indicate Neurocognitive Disorders, which contribute to early detection of Alzheimer’s Disease. The “Ego‐Allo‐Switching Task” (EAST) needs to be adapted for cross‐cultural use in Brazil.Method61 participants were divided into Cognitively Healthy Seniors (CHS; n = 21), mild Neurocognitive Disorder (mND; n = 20), and Major Neurocognitive Disorder (MND; n = 20). The EAST was applied to all participants, and CHS individuals were retested within 1‐2 weeks. In this study, we modified the original EAST to better suit Brazilian older adults, considering their unfamiliarity with specific geometric shapes. Thus, we developed an adapted version focused on shape recognition rather than free recall. Before the test, two examiners evaluated all participants using the Clinical Dementia Rating (CDR) to ensure they fit into one of the three groups. The test‐retest reliability was analyzed by intraclass correlation coefficient. Additionally, demographics (age and education) were compared between groups using the Kruskal‐Wallis test, followed by Dunn’s post hoc test and a multivariate linear regression analysis was conducted. All data were analyzed with SPSS 17.0.ResultThe global results of the EAST demonstrated high consistency in the test‐retest comparison (ICCs = 0.84). Initial discrepancies in age and education among CHS, mND, and MND groups (p < 0.001) were corrected using multivariate linear regression. The analysis highlighted distinct EAST performances between groups, as follows: ego‐ego (CHS > mND > MND); alo‐alo (CHS > (mND and MND)); ego‐alo (CHS > (mND e MND)); alo‐ego ((CHS e mND) > MND); EAST total score (CHS > mMD > MND) (Table 1 and 2).ConclusionEAST detects changes in spatial orientation skills related to neurodegenerative diseases over time and has temporal reliability. Future research should expand its psychometric properties to Brazilian seniors. This study fills the gap in neuropsychological measures for detecting task‐switching ability.
Current advances in remote and unsupervised digital cognitive assessment in preclinical Alzheimer’s disease
Authors: Polk Sarah E. , Öhman Fredrik , Hassenstab Jason J. , König Alexandra , Papp Kathryn V. , Schöll Michael , Berron David 
Published: January 2025

AbstractBackgroundTraditional pen‐and‐paper neuropsychological assessments fail to capture subtle cognitive changes in the early stages of Alzheimer’s disease (AD). Remote and unsupervised digital assessments available on smartphones, tablets, and personal computers may offer a solution to this by increasing the amount and types of data available to researchers and clinicians, while simultaneously improving ecological validity and alleviating patient burden. As these remote and unsupervised digital cognitive assessment tools become more widely available, it is important that they are validated in a systematic way. In this review, we evaluate the validity of available remote tools, focusing on active assessment tools with which the patient interacts with (i.e., cognitive tests, active speech) that have been used to investigate subtle cognitive differences in preclinical AD, defined as clinically unimpaired individuals with biomarkers indicating increased risk of dementia due to AD.MethodsWe performed a systematic literature review on PubMed, Web of Science, and PsycInfo using terms such as “digital,” “remote,” “unsupervised,” “cognition,” “aging,” and “Alzheimer’s,” which resulted in a total of 1,453 unique peer‐reviewed articles and pre‐prints. After filtering for tools that were remotely self‐administered in humans, and excluding papers detailing findings in populations with other diseases than AD (e.g., multiple sclerosis, Parkinson’s disease) or papers reporting findings of intervention studies, 14 papers reporting the use or planned use of 14 tools to detect AD pathology in preclinical AD were selected (as of Jan. 2024).ResultsWe evaluate each tool with regards to its use‐case and usability, as well as various types of validity, and suggest a framework with which future tools may also be evaluated. Additionally, we discuss current directions in the field of remote and unsupervised digital cognitive assessment in early AD.ConclusionWith this review, we hope to show that the systematic and validated use of such tools will increase our understanding of subtle changes in cognition due to AD pathology, as well as make screening for clinical trials and treatment more accessible.
Using polygenic risk scores and APOE e4 to evaluate the risk for Alzheimer’s disease in European ancestry populations
Authors: Lai Dongbing , Zhang Michael , Foroud Tatiana M. 
Published: January 2025

AbstractBackgroundAPOE e4 has been used to evaluate the risk for Alzheimer’s diseases (AD) but there exist other AD risk genes, and their effects can be collectively measured by polygenic risk scores (PRS). In this study, we sought to use both PRS (APOE excluded) and APOE e4 to evaluate the AD risk.MethodThe discovery dataset was meta‐analysis of three large‐scale European ancestry AD GWAS (Kunkle et al, 2019, the UK Biobank, and the FinnGen consortium). SNPs within 500Kb from transcript starting and ending sites of APOE were excluded. PRS‐CS was used to calculate PRS. Target datasets were European ancestry samples from NIA Alzheimer’s disease centers (ADC, 2,413 cases and 3,423 controls) and All of Us research program (AOU, 1,177 cases and 60,607 controls). Participants having age at onset (cases) or age at the last interview (controls) <60 were excluded. The prevalence of AD were higher in ADC (41.35%) and lower in AOU (1.91%) than those in general populations; therefore, we combined ADC and AOU samples to approximate the PRS distribution in general populations. Then we dichotomized PRS as high (highest 10%) and other (the remaining 90%) based on the PRS distribution of combined sample. Cox proportional hazard model was used to test the effects of dichotomized PRS and e4 genotypes (0, 1, and 2 copies of e4 alleles) by adjusting for sex. Additionally, we performed sex stratified analyses in ADC only as numbers of high PRS and e4/e4 carriers in AOU in either sex were <5.ResultResults are summarized in Table 1. We used those having other PRS and no e4 as the reference group. In both ADC and AOU, high PRS or e4 were significantly associated with the AD risk (PRS hazard ratios (HRs): 1.31‐1.74, P‐values≤0.01; e4 HRs: 1.39‐8.68, P‐values≤2.80E‐06) but having both substantially increased the AD risk (HRs: 2.07‐14.26, P‐values≤6.80E‐05). In ADC, both high PRS and e4 had larger effects in females than in males.ConclusionThe effects of PRS were modest and cannot be used alone to evaluate the AD risk; however, PRS can potentially be used with APOE e4 to evaluate the AD risk.