bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparing Psychometric Characteristics of a Computerized Cognitive Test (BrainCheck‐Assess) against the Montreal Cognitive Assessment (MoCA)
Authors: Huynh Duong , Ghomi Reza Hosseini , Huang Bin , Patterson Mary 
Published: January 2025

AbstractBackgroundPrevious validation studies demonstrated that BrainCheck Assess (BC‐Assess), a computerized cognitive test battery, can reliably and sensitively distinguish individuals with different levels of cognitive impairment (i.e., normal cognition (NC), mild cognitive impairment (MCI), and dementia). Compared with other traditional paper‐based cognitive screening instruments commonly used in clinical practice, the MoCA is generally accepted to be among the most comprehensive and robust screening tools, with high sensitivity/specificity in distinguishing MCI from NC and dementia. In this study, we examined: (1) the linear relationship between BC‐Assess and MoCA and their equivalent cut‐off scores, and (2) the extent to which they agree on their impressions of an individual’s cognitive status.MethodA subset of participants (N = 55; age range 54‐94, mean/SD = 80/9.5) from two previous studies who took both the MoCA and BC‐Assess were included in this analysis. Linear regression was used to calculate equivalent cut‐off scores for BC‐Assess based on those originally recommended for the MoCA to differentiate MCI from NC (cut‐off = 26), and dementia from MCI (cut‐off = 19). Impression agreement between the two instruments were measured through overall agreement (OA), positive percent agreement (PPA), and negative percent agreement (NPA).ResultA high Pearson correlation coefficient of 0.77 (CI = 0.63 ‐ 0.86) was observed between the two scores. According to this relationship, MoCA cutoffs of 26 and 19 correspond to BC‐Assess scores of 89.6 and 68.5, respectively. These scores are highly consistent with the currently recommended BC‐Assess cutoffs (i.e. 85 and 70). The two instruments also show a high degree of agreement in their impressions based on their recommended cut‐offs: (i) OA = 70.9%, PPA = 70.4%, NPA = 71.4% for differentiating dementia from MCI/NC; (ii) OA = 83.6%, PPA = 84.1%, NPA = 81.8% for differentiating dementia/MCI from NC.ConclusionThis study provides further validation of BC‐Assess in a sample of older adults by showing its high correlation and agreement in impression with the widely used MoCA.
Gender Differences in the Association Between Subjective and Objective Cognitive Decline in a Diverse Cohort: LifeAfter90 Study
Authors: Chen Nancy X , Corrada María M. M. , Gilsanz Paola , Farias Sarah Tomaszewski , George Kristen M. , Posis Alexander Ivan B. , Meunier Claire C. , Lor Yi , Whitmer Rachel A. 
Published: January 2025

AbstractBackgroundFew studies have investigated the relationship between subjective cognitive concerns and objective cognitive decline in the oldest‐old or examined gender differences. We evaluated this association and stratification by gender in a diverse cohort of adults ages 90+.MethodsLifeAfter90 is an ongoing cohort of adults ages 90+. Verbal episodic memory (VEM) and executive function (EF) were assessed every 6‐months since 2018 using the Spanish and English Neuropsychological Assessment Scales. We operationalized subjective cognition two ways: 1) Dichotomously as yes/no via self‐report of subjective memory concerns (SMC)‐ “are you concerned that you have a memory or other thinking problem?”; 2) Continuously as degree of self‐rated changes in cognition using the 16‐item Everyday Cognition Scale (ECog). Linear mixed models with random intercepts and slopes estimated associations of SMC or ECog with VEM and EF at baseline and longitudinally, pooled and stratified by gender (female/male). Models adjusted for baseline age, gender (in pooled models), race/ethnicity, education, interview mode (in‐person or phone), and practice effects. Sensitivity models further stratified by SMC.ResultsParticipants’ (N = 499) mean baseline age 93±2.4 years, mean follow‐up time 2.7±1.1 years, 62% women, 64% racial/ethnic minorities, 41% endorsed SMC, and mean ECog score 1.45±0.5. Overall, SMC and ECog were associated with worse baseline VEM (βSMC = ‐0.44,95%CI ‐0.61,‐0.27; βECog = ‐0.40,95%CI ‐0.58,‐0.22) and worse baseline EF (βSMC = ‐0.23,95%CI ‐0.39,‐0.07; βECog = ‐0.43,95%CI ‐0.59,‐0.27) (Table 2). ECog was associated with greater decline in EF (β = ‐0.05, 95%CI ‐0.10,0.00; Table 2). There were no gender differences in associations between SMC (p = 0.44) or ECog (p = 0.33) and VEM, nor ECog and EF (p = 0.76). The association between SMC and EF differed across genders (p = 0.01). In gender‐stratified models, both genders with SMC had worse baseline VEM and worse baseline EF, though not significantly for women (βmen = ‐0.54,95%CI ‐0.79,‐0.29; βwomen = ‐0.07,95%CI ‐0.27,0.13) (Table 2). Both genders with greater ECog had worse baseline VEM (βmen = ‐0.56,95%CI ‐0.87,‐0.26; βwomen = ‐0.33,95%CI ‐0.56,‐0.10) and worse baseline EF (βmen = ‐0.43,95%CI ‐0.70,‐0.14; βwomen = ‐0.41,95%CI ‐0.61,‐0.22) (Table 2). After stratification by SMC, among those with SMC, ECog was associated with worse baseline EF (β = ‐0.47,95%CI ‐0.68,‐0.26; Table 2).ConclusionIn this diverse cohort of 90+, the association between subjective memory concerns and worse baseline EF was more pronounced in men than in women.
LUHMES Cells: In Vitro Model for Studying Tauopathy in Alzheimer’s Disease
Authors: Moffett Madeline , Parmar Mayur S 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a common neurodegenerative disorder that results in the accumulation of amyloid‐beta, neurofibrillary tangles, and progressive cognitive decline. Despite extensive research into the pathophysiology of AD and potential treatments, a definitive cure remains elusive. Appropriate in vitro cell models are crucial for understanding pathophysiology and drug screening for AD. Cell lines like HEK293, HeLa, SH‐SY5Y, and PC have been used to study AD pathology. However, these models lack neuronal cell characteristics and do not express endogenous tau, a microtubule‐associated protein implicated in AD pathophysiology. The Lund Human Mesencephalic (LUHMES) cell line is a promising in vitro neuronal cell model that expresses endogenous tau protein, allowing a deeper exploration of tau pathophysiology and the assessment of biotherapeutics.MethodThe data was collected through the PubMed database. Review articles were selected based on the following keywords: “in vitro tauopathy,” “LUHMES and neurodegenerative disease,” “LUHMES and tauopathy,” “LUHMES and Alzheimer’s disease,” and “neuron cell line.” Articles utilized for the purpose of this study were primary research articles published in academic journals between 2014 and 2023.ResultThe LUHMES cell line is used to model known tauopathies, like AD and progressive supranuclear palsy (PSP), yet few studies have harnessed their potential. One study revealed that PP242, a dual inhibitor of mTORC1 and mTORC2, could reverse fenazaquin‐induced tau aggregation in LUHMES cells. Another study discovered that activating PERK, an endoplasmic reticulum stress sensor, reduced tau phosphorylation and aggregation in LUHMES cells. As human‐origin cells with neuronal properties, LUHMES cells provide an essential model for studying tau pathology in AD. The insights gathered from these LUHMES‐based studies highlight the utility and relevance of these cells in propelling our understanding of tauopathy forward.ConclusionThe LUHMES are an important neuronal cell line that can be utilized for in vitro experiments to study tauopathy and evaluate biotherapeutics for their ability to modulate tau pathology. These cells have endogenous tau expression, a key characteristic differentiating this line from more commonly used cell lines, such as HEK293 and SH‐SY5Y. Significant progress toward evaluating effective treatments can be made by using the LUHMES cell line to study AD‐related tauopathy pathology.
Diverse genomic alterations in single neurons after chronic brain trauma
Authors: Miller Michael B , Ma Chanthia , Dong Guanlan , Naik Samuel , McDonough Gannon , Mao Shulin , McKee Ann C. , Huang August Yue , Lee Eunjung Alice , Walsh Christopher A 
Published: January 2025

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head impact (RHI) although little is known about its molecular pathogenesis. Previous studies of single neurons showed that private somatic mutations increase both during normal aging and in neurodegenerative disorders, and show diverse mutational patterns.MethodWe applied two orthogonal single‐nucleus whole‐genome sequencing (snWGS) methods to neurons isolated from the prefrontal cortex of 15 individuals with CTE, and 4 individuals with RHI but no CTE diagnosis, and compared mutational rates and spectra with neurons from neurotypical controls and Alzheimer’s disease (AD).ResultWe found a modest but significant elevation of somatic double‐stranded single‐nucleotide variants (SNVs) that resembles a pattern previously reported in AD. In addition, we found a strikingly large burden of small insertions and deletions (indels) and used duplex sequencing to show that these indels are mainly single‐stranded, and again found a similar phenomenon in neurons from AD brain.ConclusionOur results suggest that neurons in CTE brain are exposed to stereotyped mutational processes, and that these processes are shared between AD and CTE suggesting potentially shared pathogenic mechanisms. Furthermore, the absence of similar changes in RHI neurons without CTE suggests that the development of CTE entails a mechanism beyond that caused by RHI alone.
Differential effects of Apoe Christchurch (R136S) mutation on amyloid plaque and tau pathology in transgenic mouse models
Authors: Tran Kristine M , Kawauchi Shimako , Kwang Nellie , Mar Cassandra , Chao Donna , Da Cunha Celia , Tenner Andrea J , LaFerla Frank M , MacGregor Grant R , Green Kim N. 
Published: January 2025

AbstractBackgroundA case study on a PSEN1 (E280A) carrier with APOECh (R136S) mutation revealed changes in APOE protein function led to a protective effect on AD outcomes. Notably, there is an intriguing disparity between the two hallmark pathologies: a reduction in tauopathy but no change in plaque burden. Given that the APOE protein is predominantly produced by astrocytes and activated microglia, and the APOE gene is among the disease‐associated microglia (DAM) genes, it is conceivable that the variance in pathological outcomes may be rooted in the glial response. Therefore, studying the APOEch mutation will provide a unique opportunity to investigate the role of APOE in tau and Aβ plaque development, with a particular emphasis on the proposed link: neuroinflammation.MethodWe used CRIPSR‐Cas9 to introduce ApoeCh into the mouse genome. Mice were then bred and crossed to homozygosity with the 5xFAD and PS19 transgenic mouse models to study the effect of the variant on amyloid plaque and tauopathy, respectively. Brain slices were immunolabeled for microglia and reactive astrocytes, and single‐cell spatial transcriptomics/proteomics was investigated using multiplexed error‐robust fluorescence in situ (MERFISH) technology. Plasma neurofilament light chain (NfL) along with Ab and tau protein levels were measured via MSD technology.ResultIn the 5xFAD mouse model, analysis of confocal images reveals reduction in plaque load in the 5xFAD mice at 12 months of age that is reflected in the global decrease in microglia and astrocyte number with ApoeCh. However, there is an increase in DAM response to plaque observed through elevated CD11c+ staining along with upregulation of DAM genes and protein levels via spatial transcriptomics and proteomics. In the PS19 mice, although there is an increase in phospho‐tau level, there is a stark reduction in microgliosis to tauopathy. Plasma neurofilament light chain levels reveal that ApoeCh reduces plasma NfL level in response to plaques but not tau.ConclusionApoeCh mutation has differential effects on glial responses to plaque and tau. ApoeCh decreases plaque load and plasma NfL but increases inflammatory response to plaques. Whereas in a tau model, ApoeCh increases phosphorylated tau level but decreases microgliosis and inflammatory response to tau pathology.
ASSESSING DYNAMIC AFFECT RECOGNITION FOR DISTINGUISHING FRONTOTEMPORAL DEMENTIA SUBTYPES
Authors: Ulugut Hulya 
Published: January 2025

AbstractBackgroundRecent international work suggests that more precise subtyping within frontotemporal dementia (FTD) syndromes leads to better prediction of pathology, supporting individualized disease‐specific treatments. Recent studies emphasize that identification of one such subtype, semantic behavioral variant FTD (sbvFTD), relies in part on measuring emotion recognition abilities.MethodIn order to evaluate the effectiveness of current tools, we compared the brief video‐based Dynamic Affect Recognition Test (DART) against the TASIT Emotion Evaluation (EET) and Comprehensive Affect Testing System Affect Matching tests. 105 individuals in the very early stages (CDR≤1) of FTD (61 behavioral variant FTD [bvFTD], 25 semantic variant primary progressive aphasia [svPPA], 19 sbvFTD), and 71 healthy older participants underwent emotion testing and structural MRI.ResultTests using dynamic (video) stimuli outperformed static face stimuli for distinguishing sbvFTD from bvFTD, but the DART outperformed the EET distinguishing sbvFTD from svPPA (Figure 1). Structural VBM analysis of DART performance showed predominant contribution of right‐sided structures involved in semantics and attention (e.g. temporal pole, insula), though in sbvFTD, who had worse DART scores than all other syndromes (p<0.05), DART performance also corresponded with temporo‐orbitofrontal structures mediating hedonic evaluation.ConclusionOur findings indicate that emotion reading tests using dynamic stimuli are best for differentiating among FTD syndromes. Also, unique profiles of emotion reading deficits emerging from different syndromes correspond to distinct patterns of damage to emotion, semantics, attention, and reward‐related brain networks. Emotion identification deficits are a core feature of FTD, therefore careful selection of tests that reflect the key underlying neural circuits will result in more accurate phenotyping.
Identifying the regulatory cascade governing amyloid precursor protein macropinocytosis and subsequent production of amyloid‐beta
Authors: Krupa Jordan M , Naqvi Abdul Moiz , Tsang Adrianna R , Seah Claudia , Pasternak Stephen H 
Published: January 2025

AbstractBackgroundPreviously, we identified macropinocytosis as a novel mechanism for direct and rapid trafficking of cell surface APP to lysosomes, bypassing early and late endosomes. This process depends on the activity of Arf6 and several Rho‐GTPases, and inhibition of macropinocytosis reduces amyloid‐beta (Aβ) production. Macropinocytosis is relatively unstudied in neurons and neuronal cells. Based on data from neuronal and non‐neuronal cell types, we hypothesized that the crosslinking of APP at the cell surface recruits Fe65, which acts as a scaffold for the recruitment and activation of Arf6. Arf6 then recruits the Rho‐GTPases Rac1, Cdc42 and RhoA, resulting in APP internalization by macropinocytosis and its cleavage to Aβ within the lysosome.MethodsNeuro2a (N2a) neuronal cells or human IPSC‐derived primary cortical neurons were transduced with fluorescent‐tagged Fe65, Arf6, Rac1, Cdc42 or RhoA. Membrane PI(4,5)P2 was used to mark membrane ruffling using fluorescent‐tagged PLCδ‐PH. Live neuronal cells or neurons were incubated with anti‐APP antibodies on ice to crosslink cell surface APP. Cells were incubated at 37°C and imaged at specific time points using confocal microscopy and live cell imaging.ResultCrosslinking APP resulted in rapid recruitment of Fe65 and Arf6 to APP and membrane ruffles within 30 sec, which rapidly decreased by 2 min. The Rho‐GTPases Rac1, Cdc42 and RhoA demonstrated sustained colocalization with APP and ruffles from 30 sec through to 2 min. This decreased at 5 and 10 min as APP was internalized. The inhibition of Arf6 using NAV2729 prevented the recruitment of itself, Rac1, Cdc42, and RhoA at 30 sec. However, inhibition of Rac1 by EHT 1864 had no significant effect on the recruitment of Rac1 to crosslinked APP.ConclusionThese results demonstrate the sequential recruitment of regulatory proteins which regulate macropinocytosis of APP in response to its crosslinking. Fe65 and Arf6 are rapidly recruited to APP, followed by sustained recruitment of Rac1, RhoA and Cdc42. These regulatory proteins could be targeted to modulate APP‐lysosomal trafficking and reduce Aβ production.
Influence of ageing, cognitive factors, and task modality on social cognitive performance in nondemented older adults
Authors: Chander Russell J , Grainger Sarah A , Mather Karen A , Cleary Rhiagh , Kochan Nicole A. , Henry Julie D , Sachdev Perminder S. 
Published: January 2025

AbstractBackgroundSocial cognition is crucial to optimal social functioning outcomes in older adults, with implications for overall health and wellbeing. Moreover, poor social cognition is a diagnostic criterion for neurocognitive disorders (NCDs). Prior work has studied the social cognitive subdomains (theory of mind (ToM), affective empathy, emotion recognition, and social behaviour) and found mild cognitive impairment and dementia to be associated with poorer performance in specific tasks and informant‐reported changes respectively. These patterns in NCDs need to be distinguished from normal age‐related changes, and more information is needed to ascertain what factors predict social cognitive decline in healthy ageing.Method132 non‐demented participants [mean MMSE 29.23 (SD 0.99)] aged 60 to 100 underwent comprehensive social cognitive assessments that varied based on modality of information (Figure 1), alongside neurocognitive assessments and affective questionnaires. Participants were divided based on decades to study age‐related changes. Linear regression models identified significant predictors of social cognition performance amongst demographic, neuropsychological assessment scores, affective scores, and social networks.ResultAge was associated with poorer performance in ToM tasks, specifically the Reading the Mind in the Eyes Test (RMET), Multifaceted Empathy Test (MET) Cognitive subscale, and The Awareness of Social Inference Test (TASIT) part 3, and emotion recognition tasks, specifically the FACES task and TASIT 1, for expressions of anger, disgust, and sadness (Table 1). In regression models (Table 2), age was a significant predictor of RMET and FACES performance. In MET cognitive and both TASITs, neuropsychological tasks, mainly executive function, were predictive. Poorer executive function predicted performance for identifying unspoken emotions (“Feel” subscore) in TASIT 3. MET Emotional and the self‐rated Interpersonal Reactivity Index (IRI) Empathic Concern subscale was associated with less anxiety and more positive emotions at assessment.ConclusionIn ToM and emotion recognition, unimodal task performance was associated with age and some cognitive factors, and multimodal task performance was largely associated with executive function. Performance in affective empathy tasks was linked to affective measures. Poor performance in multimodal tasks likely reflects executive dysfunction in consolidating multiple streams of social information, while some declining performance in unimodal tasks may be normative to ageing.
FunGen‐xQTL atlas: a multi‐omic atlas of quantitative trait loci in human brain and cerebrospinal fluid for target identification and prioritization in Alzheimer’s disease
Authors: Leung Yuk Yee 
Published: January 2025

AbstractBackgroundTo gain a deeper understanding of underlying molecular mechanisms in genomic regions associated with Alzheimer’s disease (AD), the National Institute on Aging (NIA) launched the Alzheimer’s Disease Sequencing Project (ADSP) Functional Genomics Consortium (FunGen‐AD) in 2021.MethodThe first effort of this collaboration, coordinated by the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), aggregated functional genomics (FG) data from 5 cohorts, including ∼3,000 samples of European (EA) and African ancestries (AA). We used this data to map Quantitative Trait Loci (xQTL) on AD‐specific human tissues and cells, providing insights into how non‐coding genetic variants contribute to AD risk. We developed reproducible computational pipelines to uniformly process the data, generating xQTL from >30 datasets profiled from human brain, cerebrospinal fluid, myeloid cells, and whole blood. The genetic data was processed exactly as the ADSP WGS datasets (GRCh38, same variant/gene annotations). For each QTL dataset, performed quality control and imputed missing data, inferred hidden confounders, and conducted genome‐wide association testing for cis‐ and trans‐acting QTLs. We also performed statistical fine‐mapping to identify potential causal variants. The consolidated summary statistics contain effect alleles normalized to the GRCh38.ResultOverall, this resource yielded >10 million cis‐ and trans‐QTL on DNA methylation, histone acetylation, RNA expression, RNA splicing, proteins, and metabolites. To support the identification of potential causal variants for molecular traits and AD, we have created a multi‐ancestry linkage disequilibrium reference panel using ADSP WGS data from >16,000 individuals of self‐reported EA and >5,000 individuals of self‐reported AA.Beyond this unique FunGen‐xQTL atlas, other FG datasets generated by other non‐ADSP members are needed for AD genetics analyses. We developed the Harmonization and Integration Pipeline for Functional Genomics (hipFG) to harmonize all FunGen‐xQTL data together with other public resources such as GTEx, eQTL catalog, and metaBrain. Using controlled vocabularies, hipFG produces a standardized metadata describing all outputs. This pipeline is used to expand FILER (FunctIonaL gEnomics Repository), a framework for querying large‐scale genomics knowledge with a scalable genomic search and querying interface.ConclusionThe FunGen‐xQTL resource will be made publicly available through Sage Bionetworks and NIAGADS.