bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing the Utility of a Knowledge Based Algorithm for Classifying Alzheimer disease and Mild Cognitive Impairment in the Recruitment and Retention for Alzheimer’s Disease Diversity Cohorts in the ADSP (READD‐ADSP) Project
Authors: Zaman Andrew F. , Mena Pedro R. , McInerney Katalina F , Celis Katrina , Adams Larry D. , Duke Tina , Sanchez Jose Javier , Chavez Jenny , Cespedes Jennifer , Starks Takiyah D. , Laux Renee A. , Hamilton‐Nelson Kara L. , Rajabli Farid , Byrd Goldie S. , Reitz Christiane , Tosto Giuseppe , Ogrocki Paula K. , Caban‐Holt Allison M , Haines Jonathan L. , Vance Jeffery M. , Pericak‐Vance Margaret A , Cuccaro Michael L. 
Published: January 2025

AbstractBackgroundOver 13,000 individuals from both domestic and African sites will be collected for the READD‐ADSP study. Adjudicating this number of individuals is challenging, so we evaluated knowledge‐based decision tree algorithms to predict clinical diagnoses using nationally representative norms and standard cut‐offs. Additional models were constructed using culturally adjusted cut‐offs, domain average cut‐offs, and exclusion of the Trail Making Test (TMT) which performed poorly. Our aim was to evaluate the accuracy of these decision tree models in the READD‐ADSP dataset.MethodClinically adjudicated diagnoses by at least two neuropsychologists and/or neurologists were available for 150 individuals from the READD‐ADSP sample (44%‐Unaffected, 36%‐MCI, 9.3%‐AD, 2.7%‐Dementia not AD, 8%‐Cognitively Impaired– Vascular; 19% Hispanic, 81% African‐American, 76%‐Female, Age: 73.0 years, Education: 13.7 years). Eight models were used to classify our sample into the diagnostic categories above and varied in test cut‐offs (standard vs. culturally adjusted), use of domain average cut‐offs (no average vs. average), and use of TMT (inclusion vs. exclusion). Model accuracy was assessed using the F1 score (which balances precision and sensitivity). F1 scores >0.9 are considered excellent, >0.8 are good, and those between 0.6‐0.8 are acceptable.ResultThe two models that used culturally adjusted cut‐offs and domain average cut‐offs performed best (with TMT, F1 = 0.81; without TMT, F1 = 0.78). All other models had F1 scores ranging from 0.63‐0.73. While the two best models were similarly accurate based on F1 scores, the difference in the frequency of diagnoses between them was notable. In the model that excluded TMT, 38% of the sample were classified as Unaffected vs. 30% in the model that included TMT; (41% and 47% were classified MCI, respectively).ConclusionOur findings show that culturally sensitive adjusted cut‐offs and inclusion of domain average cut‐offs improved the accuracy of decision tree model classifications. These findings suggest that implementation of decision tree model approaches in the READD‐ADSP dataset can accurately and efficiently classify individuals. Finally, we plan improve overall accuracy by using a hybrid method where models classify individuals who are clearly Unaffected or AD while more complex cases will be assigned to human adjudication.
The auditory phenotype of behavioural variant and right temporal variant frontotemporal dementia
Authors: Johnson Jeremy , Levett Benjamin Aaron , Requena‐Komuro Mai‐Carmen , Benhamou Elia , Jiang Jessica , Bamiou Doris‐Eva , Hardy Chris JD , Warren Jason D 
Published: January 2025

AbstractBackgroundPatients with behavioural variant frontotemporal dementia (bvFTD) and right temporal variant frontotemporal dementia (rtvFTD) commonly exhibit abnormal hedonic and other behavioural responses to sounds, however hearing dysfunction in this disorder is poorly characterised. Here we addressed this issue using the Queen Square Tests of Auditory Cognition (QSTAC) – a neuropsychological battery for the systematic assessment of central auditory functions (including pitch pattern perception, environmental sound recognition, sound localisation and emotion processing) in cognitively impaired people.MethodThe QSTAC was administered to 12 patients with bvFTD, 7 patients with rtvFTD and 24 patients with comparator dementia syndromes (primary progressive aphasia and typical Alzheimer’s disease) and 15 healthy age‐matched individuals. Participants also underwent pure tone audiometry to assess peripheral hearing function and a comprehensive general neuropsychological assessment.ResultAfter accounting for nonverbal executive and peripheral hearing performance, patients with bvFTD and rtvFTD showed deficits of environmental sound and auditory emotion recognition and sound localisation, compared both with healthy controls and patients with Alzheimer’s disease. Patients with bvFTD showed a deficit in dichotic listening compared with the rtvFTD group.ConclusionbvFTD and rtvFTD have distinct phenotype of auditory cognitive dysfunction which likely contributes to the hearing alterations that many patients with this diagnosis experience in daily life. Our findings call attention to an under‐recognised issue in frontotemporal dementia that warrants further clinical interpretation and the development of management strategies tailored to real‐world acoustic environments.
Vascular risk factors, subjective cognitive decline, and mild behavioral impairment: A CAN‐PROTECT study
Authors: Guan Dylan X. , Aundhakar Aditya , Farias Sarah Tomaszewski , Smith Eric E. , Ismail Zahinoor 
Published: January 2025

AbstractBackgroundSubjective cognitive decline (SCD) and mild behavioral impairment (MBI) identify older persons that are more likely to be at preclinical stages of Alzheimer’s disease (AD) than those without SCD and MBI. However, vascular co‐pathologies may also contribute to new onset and persistent cognitive and behavioral symptoms. We investigated vascular risk factor associations with SCD and MBI in older persons without mild cognitive impairment or dementia.MethodData for 1285 participants from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behaviour, Function, and Caregiving in Aging (CAN‐PROTECT) study were analyzed [Figure 1]. Vascular risk factors were body mass index (normal, overweight, obese), hypertension, high cholesterol, diabetes, and smoking (never, past, active). Outcomes were measured using the Everyday Cognition (ECog‐II) scale and MBI Checklist (MBI‐C). SCD was operationalized based on a score of ≥2 (i.e., consistently a little or much worse) on any ECog‐II item. MBI+ status was defined by MBI‐C total scores ≥8. Propensity scores were used to balance age, sex, years of education, marital status, and ethnocultural origin across exposure groups using inverse probability of treatment weighting. Weighted negative binomial and logistic regressions were used to model vascular risk factor (exposure) associations with ECog‐II and MBI‐C total scores, and SCD and MBI+ statuses, respectively.ResultParticipant characteristics are summarized in Table 1. As shown in Table 2, all vascular risk factors assessed in the study were associated with higher ECog‐II total score, with the exception of past (i.e., not active), smoking behavior. Diabetes and active smoking showed the largest magnitudes of effect in relation to ECog‐II total scores. Active smoking and obesity showed the largest magnitudes of effect in relation to MBI‐C total scores. When assessing outcomes as categorical variables (i.e., SCD+ and MBI+), the same associations were found.ConclusionVascular risk factors were associated with poorer everyday cognition, more severe MBI symptoms, and greater odds for classification as SCD+ and MBI+ in a sample of older persons without objective cognitive impairment. These findings suggest potential vascular contributions to cognitive and behavioral markers traditionally linked to AD.
ROCK inhibitors alter brain proteomic profiles and tau phosphorylation in iPSC‐derived human neurons and mouse model of Alzheimer’s disease
Authors: Collu Roberto , Giunti Elisa , Yin Zheng , Daley Sarah , Chen Mei , Li Qinqing , Morin Peter J , Killick Richard , Wong Stephen T.C. , Xia Weiming 
Published: January 2025

AbstractBackgroundWe aim to investigate efficacies of Ras homolog (Rho)‐associated kinases (ROCK) inhibitors on Alzheimer’s disease (AD) pathological proteins in human induced pluripotent stem cell (iPSC)‐differentiated human neurons and the P301S tau transgenic mouse model (PS19).MethodQuantitative liquid chromatography‐mass spectrometry (LC‐MS/MS) and targeted ELISA were implemented to investigate the effect of treatment with fasudil or its derivatives on the human neurons and brains from PS19 mice. We explored the efficacy of these ROCK inhibitors in reducing tau phosphorylation, and the brain proteomic profiles after their administration in mice.ResultWe found a significant negative correlation between the brain levels of phosphorylated tau (pTau) and both fasudil and its metabolite hydroxyfasudil. Human neuronal culture exposed to selective ROCK inhibitors exhibited similar efficacies. Proteomic profiling of mice brains exposed to fasudil revealed the activation of the mitochondrial tricarboxylic acid (TCA) cycle and blood‐brain barrier (BBB) gap junction metabolic pathways.ConclusionOur results provide evidence to support the development of ROCK inhibitors as AD therapeutics.
The dynamics of auditory working memory impairment in logopenic variant primary progressive aphasia and typical Alzheimer’s disease
Authors: Levett Benjamin Aaron , Novoa Catalina , Core Lucy , Jiang Jessica , Warren Jason D , Hardy Chris JD 
Published: January 2025

AbstractBackgroundImpaired auditory verbal working memory is a diagnostic hallmark and integral driver of the clinical phenotype in logopenic variant primary progressive aphasia (lvPPA). However, the physiology of the working memory buffer in this syndrome is poorly characterised. Here we addressed the temporal dynamics of auditory verbal working memory in patients with lvPPA and typical Alzheimer’s disease (tAD).MethodIn a cohort of 8 patients with lvPPA, 17 patients with tAD and 18 healthy age‐matched controls, we assessed how temporal manipulations of a standard auditory verbal working memory tasks (forward digit span and phrasal repetition) affected performance. We varied tempo of delivery and inter‐trial gap and performed a detailed analysis of error types. Participants also underwent pure tone audiometry to assess peripheral hearing function and a comprehensive general neuropsychological assessment.ResultCompared with healthy controls, patients with lvPPA and tAD showed increased sensitivity to temporal manipulation of auditory verbal working memory tasks and error profiles suggesting a dynamic physiological lesion of the working memory buffer. These effects were particularly marked in the lvPPA group.ConclusionOur findings open a novel physiological window on working memory dynamics in Alzheimer’s disease syndromes. Further work is warranted to assess how this dynamic deficit impacts communication in patients’ daily lives, how it can best inform management interventions and its potential as a novel, rapid read‐out of neural function in the era of disease‐modifying therapies.
Serial‐position effect in participants cognitively unimpaired with Subjective Cognitive Complaints (SCCs) and with Mild Cognitive Impairment (MCI) that revert, remain stable or worsen: Evidence from the Compostela Aging study (CompAS)
Authors: Rozas Arturo X. Pereiro , Campos‐Magdaleno Maria , Lojo‐Seoane Cristina , Pérez‐Blanco Lucía , Mallo Sabela Carme , Arora Sonali , Fernández‐Feijoo Fátima , Facal David 
Published: January 2025

AbstractBackgroundHigher recency effect in episodic memory (EM) has been found for MCI and dementia (Martin et al., 2013; Campos et al., 2016). Additional research should be conducted on the pre‐symptomatic stages and on their ability to predict progression to cognitive decline. Our aim is to analyze the differences in the serial‐position effect in cognitively unimpaired and MCI participants that revert, remain stable or worsen.MethodA sample of 162 participants from the CompAS were classified in five groups considering change or stability from its baseline diagnoses to the 2nd follow‐up (48‐76 months after baseline) as follows: Stable‐SCC (SCC who remain stable; N = 97), Worsen‐SCC (SCC who worsening to MCI/dementia; N = 32), Stable‐MCI (MCI who remain stable; N = 13), Worsen‐MCI (MCI who worsening to dementia; N = 8), and Reverters (participants who revert from MCI; N = 12). The Spanish version of the CVLT were administered and corrected regional scores were computed (see Campos et al., 2016). A mixed model was carried out to test group differences considering the intrasubject factors Regions (Primacy, Middle, Recency) and Measurements (baseline, 1st follow‐up, 2nd follow‐up).ResultsSignificant effects was found for the interaction between Group*Region*Measurement also achieved significance (F(16,628) = 1.87; p<.021; ηp
2
= .045, observed power = .957). Differences between Measurements were not found in any Region for Reverters and Stable‐SCC. In both, Stable‐MCI and Worsen‐SCC groups differences showed better performance in 1st than in 2nd follow‐up in Middle and poor retrieval in Baseline than in 2nd follow‐up in Recency regions. Worsen‐MCI showed better retrieval in Baseline than in 2nd follow‐up for the Middle region but poor retrieval in Baseline than in 1st and 2nd follow‐up for the Recency region (see Figure 1). Group differences were found mainly in Middle and Recency regions (see Table 1) and in the 1st and particularly 2nd follow‐up showing poor retrieval particularly for the Worsen‐MCI.ConclusionsRecency effect becomes prominent compensatory mechanism as cognitive decline progress. Retrieval in Middle region decrease only MCI participants. Poor retrieval in Middle region scores could be useful to improve identification of SCC at risk.
The Impact of Spatial Navigation Task Types: Moderator Analysis in Meta‐Analysis on Mild Cognitive Impairment
Authors: Kossowska‐Kuhn Dorota , Gouveia Gillian , Charness Neil 
Published: January 2025

AbstractBackgroundDementia exerts a significant global impact on societies and individuals. Spatial disorientation emerges as one of the initial symptoms of Alzheimer’s Disease (AD) (Coughlan et al., 2018). In our Meta‐analysis on spatial navigation in Mild Cognitive Impairment (MCI) we obtained the standardized mean difference (Hedge’s g) between this population and cognitively healthy older adults at the level of g = .88, which corresponds to the large effect size.MethodThe potential moderators such as year of study publication, country of study, age of participants in each population, gender, education, forms of test administration (i.e., real‐world, virtual reality), type of measure (time, accuracy), type of task (i.e., A Maze, Environment Navigation, Money Road Map Test) were coded for moderator analysis.ResultModerator analysis for 125 effect sizes across 47 studies, involving 2916 participants (1415 with MCI, 1501 cognitively healthy older adults) revealed that both age and the type of task were statistically significant (p < .05).ConclusionFurther discussion on the definition of spatial navigation skills is essential to reach a consensus regarding the tasks used for assessments. Given the potential role of spatial navigation as an early marker of dementia, the significance of understanding this complex skill is paramount.
Loss of presenilin 2 function increases susceptibility to kainate‐induced status epilepticus and attenuates associated increases in hippocampal kainate‐type glutamate receptor expression
Authors: Robinson‐Cooper Larissa , Davidson Stephanie , Koutoubi Rami , Barker‐Haliski Melissa 
Published: January 2025

AbstractBackgroundPresenilin 2 (PSEN2) is one of three deterministic risk genes that increases the risk of early‐onset Alzheimer’s Disease. People with PSEN2 variants have increased risk of unprovoked seizures versus age‐matched unaffected individuals yet few studies have interrogated the contributions of PSEN2 on seizure susceptibility. Critically, PSEN proteolytic capacity may be a novel regulator of hippocampal kainate‐type glutamate receptors (KARs), with PSEN deletion reducing KAR availability and synaptic transmission in vitro (Barthet et al 2022). Kainic acid (KA) is a naturally occurring agonist for KARs that evokes sustained, severe seizures and status epilepticus (SE). We thus hypothesized PSEN2‐KO mice would demonstrate reduced KA‐SE latency, increased SE severity, worsened outcomes 7‐days later, and have altered hippocampal KAR expression versus similarly treated WT mice.MethodUsing a repeated low‐dose systemic KA administration model to evoke SE, we quantified the latency to SE and extent of SE‐induced neuropathology in 3–4‐month‐old male and female PSEN2‐KO versus WT mice (n = 10‐16 mice/group/sex). GluK5, a KAR subunit, expression was colocalized in astrocytes and neurons by immunohistochemistry 7 days after KA‐SE or sham to define the impacts of PSEN2 deletion and SE on hippocampal KAR expression.ResultRegardless of sex, PSEN2‐KO mice were more susceptible to KA‐SE than WT mice. Male PSEN2‐KO mice progressed to SE faster than WTs (78.6±25.3 versus 98.2±16.0 min; t = 2.43, p = 0.027); female PSEN2‐KO mice were also more susceptible to KA‐SE relative to WTs (85.3±32.2 versus 112.2±15.4 min; t = 2.45, p = 0.022). Basal GluK5 expression did not differ between sexes or genotypes. However, in male mice 7‐days post‐KA‐SE insult GluK5 expression was significantly increased over basal levels in WT mice (p = 0.0028), but PSEN2‐KO mice GluK5 levels were unchanged from basal expression (p = 0.9819). Regardless of genotype, female mice GluK5 levels were unchanged from basal expression at 7‐days post‐KA‐SE insult, revealing sex differences in post‐SE outcomes.ConclusionLoss of normal PSEN2 function increases susceptibility to KA‐induced seizures and SE, which cannot be explained by basal GluK5 expression differences. However, increased GluK5 expression in male WT relative to PSEN2‐KO mice 7‐days post KA‐SE, further substantiates a role of PSEN2 in KAR availability. Sex differences in GluK5 and GFAP were also apparent post‐SE.
Validation of Various Pan‐ApoE and Isoform‐Specific ApoE Antibodies
Authors: Siano Dahlia , Golden Lesley R , MacLean Steven M , Hernandez Gabriela , Johnson Lance A 
Published: January 2025

AbstractBackgroundApolipoprotein E (ApoE) exists in three protein isoforms: E2, E3, and E4, which differ by only one or two amino acids. These slight differences profoundly effect protein structure and function, allowing each isoform to differentially impact Alzheimer’s Disease (AD) risk. Relative to the most common E3 isoform, E4 dramatically increases risk, while E2 confers a substantial decrease in risk. The close similarity between protein isoforms makes it difficult to develop isoform‐specific antibodies that are reliable and selective. Here, we aim to validate and optimize a number of common, commercially available ApoE antibodies to determine isoform specificity.MethodControl samples included plasma and brain collected from APOE knockout (KO), homozygous E2, E3 and E4 humanized APOE (hAPOE) mice, and human plasma from all 6 possible APOE genotypes. Western blotting was used on plasma and brain homogenates to determine isoform specificity of E2, E3, or E4 antibodies. Commercial antibodies tested included pan‐ApoE antibodies from Cell Signaling Technologies (CST) and Abcam, ApoE4 antibodies from Novus and CST, ApoE2 antibodies from CST, and ApoE3 antibodies from Abcam and Novus. Additionally, pan‐ApoE antibodies were kindly gifted to us by collaborators (Drs. Lammich and Haass, LMU) and tested. Antibodies were also tested for use in immunohistochemistry (IHC) using hAPOE and APOE KO mouse brain sections (30 uM).ResultDespite the ApoE3 antibodies being marketed as isoform‐specific, they did not show efficacy in either application. Commercial pan‐ApoE antibodies were outperformed by the LMU antibodies, but still showed efficacy. When used for western blotting, the CST ApoE4 and ApoE2 antibodies showed clear isoform specificity in hAPOE mouse and human samples. While none of the isoform‐specific antibodies passed controls for IHC purposes, multiple pan‐ApoE antibodies were variably effective for staining of brain tissue.ConclusionThese data identify several isoform‐specific ApoE antibodies that are reliable and selective across multiple sample types and applications; albeit some display higher affinity for one application over another. Overall, we hope these results will provide AD researchers with important resources that are crucial for visualizing and quantifying ApoE isoform distribution in heterozygote individuals and across a number of AD models, systems, and studies.
TabCAT Brain Health Assessment: Preliminary validation in a multicultural Israeli population
Authors: Haddad Rafi , Tsoy Elena , Tanne David , Ayoub Rawan , Shihada Essam , Natalya Yarovinsky , Erlhoff Sabrina J , Fisher Tali , Aharon‐Peretz Judith , Ben‐Hayun Rachel , Valcour Victor , Possin Katherine L 
Published: January 2025

AbstractBackgroundThe Israeli population, primarily comprised of Israeli Jews (74%) and Arabs (21%), is one of the most diverse aging societies around the world. The need for brief, accurate, and culturally appropriate cognitive measures in Israel is high, as they can facilitate early detection of cognitive disorders across clinical settings. We examined the discrimination accuracy and concurrent validity of the brief Tablet‐based Cognitive Assessment Tool (TabCAT) Brain Health Assessment (BHA) battery in a multicultural Israeli sample.MethodsParticipants were 79 Hebrew and Arabic speaking older adults (age: 67±6; 58% female; education: 15±4). Clinically normal participants (n = 63) were community‐dwelling individuals with no self‐ or informant‐reported cognitive symptoms or functional decline. Cognitively impaired participants (n = 16) with diagnoses of mild cognitive impairment (n = 15) or dementia (n = 1) were recruited from a large neurology center. Diagnoses were based on the published clinical criteria, and all patients underwent comprehensive neurological and neuropsychological evaluations independent of study procedures. All participants completed the TabCAT‐BHA and the Montreal Cognitive Assessment (MoCA) in their primary language. Logistic regressions with ROC curves were used to examine discrimination accuracy, controlling for age, sex, education, and testing language. Concurrent validity was evaluated against the MoCA indices for the same domains.ResultsThe TabCAT‐BHA battery showed excellent discrimination accuracy (AUC = .99, sensitivity = .81, and specificity = .95) outperforming the MoCA (AUC = .94, sensitivity = .63, specificity = 0.97). Moderate associations were observed between TabCAT Favorites (associative memory) and MoCA Memory Index (r = .49, P < .001), and between TabCAT Match (executive functions) and MoCA Executive Index (r = .64, P < .001). Weaker associations were found between TabCAT Line Orientation (visuospatial skills) and MoCA Visuospatial Index (r = ‐.27, P = .02).ConclusionsOur preliminary findings support the validity of the 10‐minute TabCAT‐BHA battery in culturally diverse Israeli older adults. The battery exhibited excellent performance in detecting cognitive impairment in our sample outperforming a widely used brief cognitive assessment tool, the MoCA. Future studies, including development of Israel‐specific normative data and replication of these results in larger samples, are ongoing.