bluuebunny/crossref_metadata_2025_split huggingface dataset:
Language and Cognitive Control in Aging Urban and Rural Cohorts in India
Authors: Menon Meenakshi , Malo Palash K , Lingegodwa Abhishek Mensegere , Stezin Albert , Hameed Shafeeq K Shahul , Narayanasamy Rajitha , Vishwanath Vindhya , R Meghana , M Divya N , Partha Ajith , M Amitha C , HS Dev Kumar , Arvind Prathima , Agrawal Deepashri , HS Sunitha , Velavarajan Goutham , Mondal Banashree , Sundarakumar Jonas S. , Issac Thomas Gregor 
Published: January 2025

AbstractBackgroundCognitive control deficits can be early indicators of cognitive decline in individuals. Studies have found a bilingual advantage in cognitive control, however, there is little research on the Indian population, particularly those residing in rural areas. We aimed to investigate how cognitive control is influenced by the number of languages known to individuals among the aging population in both urban and rural settings in South India.MethodThe study comprises cross‐sectional data from healthy individuals aged 45 years and above, with 1058 participants from the urban Tata Longitudinal Study on Ageing (CBR‐TLSA) cohort and 4820 participants from the rural Srinivaspura Ageing, Neuro Senescence, and Cognition (CBR‐SANSCOG) study cohort. Both study protocols are harmonized. Cognitive control was assessed using the Stroop, visuospatial span, categorical fluency, and letter fluency tests. Mann‐Whitney U test was used to compare monolingual and multilingual participants’ performance in cognitive control tasks separately. The differences in monolingualism and multilingualism on cognitive control were adjusted with age, gender, years of education, cohort, and Hamilton Depression Rating Scale (Ham‐D) scores using the General Linear Model.ResultUrban participants performed better than their rural counterparts in all four cognitive control tasks (Table 1). Within the urban cohort, multilingual participants’ performed better than the monolingual participants in the categorical fluency task, whereas, in the rural cohort, multilingual participants performed better in all four tasks. Monolingual and multilingual participants in the urban cohort performed better than their respective counterparts in the rural cohort in the cognitive control tasks. After adjusting for the covariates, we found a significant difference between monolingual and multilingual participants on the categorical fluency task, with multilingual participants performing better than monolinguals (Table 2).ConclusionOur results indicated a multilingual advantage in cognitive control in aging Indians.
Assessing the impact of physical activity on cognitive function among urban elderly population: a cross‐sectional analysis
Authors: HS Deva Kumar , Selva Monisha , Lingegodwa Abhishek Mensegere , Stezin Albert , Partha Ajith , Mallikarjun Divya N , M Amitha C , Narayanasamy Rajitha , Menon Meenakshi , R Meghana , Vishwanath Vindhya , Velavarajan Goutham , Malo Palash K , Arvind Prathima , Hameed Shafeeq K Shahul , HS Sunitha , Mondal Banashree , Agrawal Deepashri , Sundarakumar Jonas S. , Issac Thomas Gregor 
Published: January 2025

AbstractBackgroundEvidence from multiple converging sources has demonstrated the clear benefits of physical activity in promoting mental health and improving cognitive function. However, more than 54% of Indians do not engage in the recommended amount of physical activity. The present study aims to explore the association of physical activity with cognitive abilities among the elderly aging population in an urban Indian setting.MethodsThe study utilized baseline data of 1250 till Dec 2023 from the ongoing Tata Longitudinal Study of Ageing cohort study. We categorized subjects into physically active (PA) and sedentary groups (SG)based on the time they spend doing different types of physical activity in a typical week using the Global Physical Activity Questionnaire (GPAQ). Cognitive assessments were performed using Addenbrooke’s Cognitive Examination III (ACE‐III). Multiple linear regression was performed where cog variables were loaded as dependent variables, physical activity was a predictor, and covariates used were education, gender, socioeconomic status, and clinical dementia rating scores.ResultThe mean age SD) of the study sample was 62.6 (9.6) years. Among 1250 participants, 804 (64.3%) were physically active and 446 (35.7%) belonged to the sedentary group. The physically active group had significantly higher median years of education (14.9 vs 14.6; p = <0.001), more proportion of males (56.3% vs 43.5%, p < 0.001), upper socioeconomic class (62.8% vs 34.2%) and lesser people with mild cognitive impairment (6.1% vs 14.2, p <0.001) as shown in Table 1. Multiple linear regression analysis shows that after controlling for confounding variables, the physically active group performed better in ACE total (β = ‐1.330, p = 0.002), ACE memory (β = ‐0.627, p < 0.001), ACE fluency (β = ‐0.257, p = 0.043) and ACE language (β = ‐0.263, p = 0.012) when compared to the sedentary group as shown in Table 2. ACE attention and ACE visuospatial scores were not statistically significant between both groups.ConclusionOur findings indicate that physically active participants had better global cognition and better performance in memory, executive functioning, and perceptual‐motor function. Promotion of physical activity should hence be implemented for enhancing cognitive abilities in elderly individuals.
Similar brain proteomic signatures in Alzheimer’s disease and epilepsy
Authors: Leitner Dominique , Pires Geoffrey , Kavanagh Tomas , Kanshin Evgeny , Askenazi Manor , Ueberheide Beatrix , Devinsky Orrin , Drummond Eleanor , Wisniewski Thomas 
Published: January 2025

AbstractBackgroundPrevalence of epilepsy is increased among Alzheimer’s Disease (AD) patients and cognitive impairment is common among people with epilepsy, with seizures occurring in 10‐22% of AD patients, subclinical epileptiform abnormalities in 22‐54% of AD patients, and cognitive deficits in up to 80% of epilepsy patients. These shared pathophysiological changes remain poorly defined.MethodsWe aimed to identify protein differences associated with epilepsy and AD using published proteomics datasets, including our previous analysis in epilepsy hippocampus and from our searchable database of 38 AD proteomics studies (NeuroPro). Additionally, laser capture microdissection was performed in dual diagnosed (AD+epilepsy) cases, epilepsy, AD, and control cases in hippocampal CA1‐3 (n = 7/group), followed by label‐free quantitative mass spectrometry to identify protein differences.ResultsWe observed a significant overlap in protein differences in epilepsy and AD: 89% (689/777) of proteins altered in the hippocampus of epilepsy patients were significantly altered in advanced AD. Of the proteins altered in both epilepsy and AD, 340 were altered in the same direction, while 216 proteins were altered in the opposite direction. Synapse and mitochondrial proteins were markedly decreased in epilepsy and AD, suggesting common disease mechanisms. In contrast, ribosome proteins were increased in epilepsy but decreased in AD. Notably, many of the proteins altered in epilepsy interact with tau or are regulated by tau. This suggests tau likely mediates common protein changes in epilepsy and AD. Immunohistochemistry for amyloid‐beta and multiple phosphorylated tau species (pTau396/404, pTau217, pTau231) showed a trend for increased intraneuronal pTau217 and pTau231 but no phosphorylated tau aggregates or amyloid plaques in epilepsy hippocampal sections. To better understand mechanisms of epilepsy in AD, we performed localized proteomics in the hippocampal CA1‐3 of dual diagnosed cases. We observed protein changes compared to controls (275 proteins), with fewer differences than either AD (67) or epilepsy (87) alone cases. Altered proteins in Dual vs. AD included those associated with mTOR signalling related pathways, regulation of eIF4 and p70S6K (p = 1.62 × 10‐4) and mTOR signalling (p = 2.19 × 10‐2).ConclusionOur results provide insights into common mechanisms in epilepsy and AD and highlight the potential role of tau and mTOR signalling in both disease groups.
The Role of diet x gene interaction in LOAD2.Plcg2M28L mice
Authors: Rangel‐Barajas Claudia , Oblak Adrian L , Ingraham Cynthia M , Lloyd Christopher D , Territo Paul R , Rizzo Stacey J Sukoff , Carter Gregory W , Sasner Michael , Howell Gareth R , Lamb Bruce T. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) and other neurodegenerative diseases are typified by a robust microglial‐mediated immune response. Genetic studies have demonstrated that variants in microglial genes are linked to risk for AD. Genome‐wide association studies (GWAS) originally identified Phospholipase C gamma 2 (PLCγ2) as a novel risk gene of Alzheimer’s disease (AD). Since then, accumulating evidence from in vitro, in vivo, and human‐based studies have corroborated and extended this association, promoting Plcg2 as one of the most important risk genes of both early‐onset and late‐onset AD, harboring both common and rare risk variants with relatively large effect on AD risk.MethodTo investigate the impact of Plcg2 gene expression on microglia biology and disease pathology, we have generated Plcg2M28L mice on an APOE4.Trem2R47H.hAb (LOAD2) background. Cohorts of mice were established at IU and aged to 18 months on a high fat diet (HFD). Animals began the HFD at 2 months of age and were longitudinally followed to 18 months of age. At 4, 12 and 18 months, mice received an MRI and blood draws for biomarker analysis. A second cohort of animals was analyzed cross sectionally at 4, 12, 18 and 24 months of age. PET studies were completed in a third cohort. Post‐mortem studies at both sites included blood chemistry, immunohistochemistry, and molecular studies. Studies of transcriptomics and proteomics were also completed on brain tissue.ResultUtilizing our multi‐analyte approach, we are able to correlate changes in the mice and human LOAD. Overall, at 18 months there is an increase in microgliosis in male mice that is age dependent. On a high fat diet, microgliosis is observed in both male and female within the cortex, but in the subiculum, IBA1 increased only in females.ConclusionOur findings provide evidence that Plcg2 plays an important role in LOAD and the addition of Plcg2M28L to a sensitized LOAD model (LOAD2) more closely align phenotypes in the mouse to outcomes observed in human AD.
Lipid Droplet Dynamics are Modulated by Age and APOE Genotype
Authors: Stephens Isaiah O , Satish Diksha , Friday Cassi , Smith Katy , Devanney Nicholas A , Cornea Ana Maria L/K , Gordon Scott , Johnson Lance A 
Published: January 2025

AbstractBackgroundAging microglia accumulate lipid droplets (LDs), secrete pro‐inflammatory cytokines, and are defective in phagocytosis. The E4 allele of Apolipoprotein E (APOE) is the strongest genetic risk factor for late‐onset Alzheimer’s disease (LOAD) and is associated with increased neuroinflammation and LD accumulation. Here, we aimed to determine if the effects of aging and the E4 allele are synergistic in causing the accumulation of LDs seen in LOAD. Specifically, we hypothesize that APOE genotype modulates the LD proteome and lipidome at baseline and with inflammation. Additionally, we show the effects of APOE genotype and age on LD accumulation in monocyte‐derived human macrophages treated with sex‐matched exogenous serum.MethodPrimary microglia were isolated from mice expressing human ApoE3 and ApoE4. Microglia were exposed to oleic acid (OA), LPS, OA+LPS, dead N2A cells, or dead N2As+LPS to stimulate an inflammatory response, then lipid droplet content was analyzed. To examine the impact of inflammation on LDs in vivo, ApoE3 and ApoE4 mice were injected with saline or LPS and liver tissue collected at 24h. Density gradient centrifugation was used for isolation of LD‐enriched fractions and these were analyzed using mass spectrometry proteomics. To determine the impact of age on circulating factors that may affect LD dynamics, human Peripheral Blood Mononuclear Cells (PBMCs) were treated with serum from different aged donors and the impact on LDs was analyzed.ResultPrimary microglia from ApoE4 mice accumulated significantly more LDs at baseline, with OA, LPS, and N2As as a percentage of E3 control. Proteomics revealed that LD fractions from E4 mice are enriched for proteins involved in innate immunity, while E3 LDs are enriched for lipid b‐oxidation proteins. Lipidomics showed an increase in phosphatidylcholine distribution in the LD membrane of E4‐control and LPS‐treated droplets. Finally, a significant positive correlation between the age of serum samples used to treat human macrophages and LD accumulation in the PBMCs was observed.ConclusionIn agreement with prior studies, E4 microglia accumulate more LDs compared to E3 microglia under all conditions tested. The proteomic profile of E4 LDs support the hypothesis that E4 expression increases inflammation under basal and stimulated conditions, causing a more robust response.
Investigating the additive effects of Alzheimer’s disease biomarker staging and subjective cognitive decline in the prediction of clinical progression
Authors: Stark Melina , Wagner Michael , Kuhn Elizabeth , Bürger Katharina , Düzel Emrah , Hellmann‐Regen Julian , Heneka Michael T. , Laske Christoph , Perneczky Robert , Peters Oliver , Priller Josef , Schmid Matthias , Schneider Anja , Spottke Annika , Teipel Stefan , Wiltfang Jens , Jessen Frank , Kleineidam Luca 
Published: January 2025

AbstractBackgroundThe identification of cognitively unimpaired individuals at risk of short‐term cognitive decline is a critical task for Alzheimer´s disease (AD) research. Cognitively normal individuals with amyloid and/or tau pathology have a high risk for short‐term cognitive decline. However, not all of these individuals show clinical progression. Individuals in clinical stage 2 of AD, characterized e.g. by subjective cognitive decline (SCD), are thought to be temporally closer to clinical progression to mild cognitive impairment (MCI), but this hypothesis has not been rigorously investigated yet.MethodWe included 195 memory clinic SCD patients and 83 cognitively normal participants without SCD (CN) with baseline CSF and longitudinal cognitive data from the observational DELCODE study. Participants were categorized into three AD biomarker stages (A‐T‐, A+T‐, A+T+) based on their baseline CSF Aβ42/40 and p‐tau181 status. The groups were compared in their longitudinal preclinical Alzheimer´s cognitive composite (PACC5) trajectories and average time until progression to MCI. Group differences in the time until progression to MCI, over eight years of follow‐up, were estimated with restricted mean survival time models. All analyses were adjusted for demographic covariates.ResultCompared to the A‐T‐ group (62 CN, 123 SCD), A+T‐ (16 CN, 49 SCD) and A+T+ (5 CN, 23 SCD) participants showed significantly accelerated PACC5 decline and a faster progression to MCI (A+T‐: 2.7 [‐5.7‐11.2] and A+T+: 22.4 [8.1‐36.8] months earlier than A‐T‐;). SCD patients had a significantly faster PACC5 decline and progression to MCI (15.5 [9.8‐21.1] months) than CN participants. The effects of SCD and the biomarker stages on both outcome measures remained significant when the predictors were entered in the same models. In exploratory analyses, SCD patients tended to show a faster progression to MCI than CN participants within the same biomarker group (A+T‐: 19.0 [6.3‐31.7] and A+T+: 14.0 [‐20.8‐48.8] months earlier than CN in same biomarker group).ConclusionSCD provides incremental information for the identification of individuals at high risk of imminent cognitive decline beyond a biomarker‐based classification of AD pathology. In cognitively unimpaired individuals, the clinical stage should be taken into account additionally to AD biomarkers for an improved prediction of the time until clinical progression.
Molecular and functional analysis using Presenilin‐1 G206A mutation iPSC lines to understand age‐of‐onset variability in autosomal dominant Alzheimer disease
Authors: Celis Katrina 
Published: January 2025

AbstractBackgroundPathogenic variants in Presenilin‐1 (PSEN1) cause autosomal dominant forms of early‐onset Alzheimer disease (AD). Despite the high penetrance, substantial interindividual variability in age‐of‐onset (AOO) is observed among different PSEN1 mutations. Attempting to understand the molecular mechanisms leading to variability in AOO in PSEN1 mutations, we focused on three mutations located at codon 206 (G206A, G206S and G206D) of this gene. The G206A variant is associated with a wide range AOO, 30‐90 years, while G206S and G206D have a less variable AOO reported in only a few cases (30‐35 years). Molecular and functional analysis from induced pluripotent stem cells (iPSC) carrying these mutations may help us identify the transcriptomic changes and cellular pathways associated with AAO variability.MethodWe identified 46 carriers of the G206A mutation using whole genome sequencing from 182 families recruited as part of the Puerto Rican Alzheimer Disease Initiative (PRADI). We collected peripheral blood mononuclear cells (PBMCs) for iPSC generation from 19 of those 46 PRADI G206A carriers. We selected six G206A carriers, three with AOO <60 and three with AOO >65 years. CRISPR/Cas9 genome editing technologies were used to introduce the G206S, G206D and G206WT (wild type) variants from a G206A iPSC line. All eight lines (six G206A, one G206S and one G206D) will go under neuronal differentiation and spheroid generation protocol for transcriptomic, proteomic and AD‐related functional analysis.ResultWe have successfully reprogrammed six iPSC lines carrying the G206A mutation. CRISPR genome editing has been performed for the G206D and G206S variants. and confirmed by Sanger sequence. Next steps include neuronal differentiation and spheroids generation from iPSC lines, followed by bulk RNA sequencing from neurons, single cell RNA sequencing from spheroids and AD functional analysis including assays for Aβ40, Aβ42, APP, Tau, and NOTCH.ConclusionOur iPSC lines will be instrumental to identify potential molecular determinants of AOO in PSEN1 mutation carriers. Transcriptomic and functional data is in process and will be presented at the conference. These data will be informative for the identification of molecular changes associated with PSEN1 mutations in neurons and other cell types that will further increase our understanding of PSEN1 role in AD pathogenesis.
Feasibility of Using Smartphone‐Based Cognitive Testing Among People Living with Alzheimer’s Disease and Related Dementias
Authors: Moore Raeanne C , Kuehn Kevin , Khullar Diviya , Jantz Carissa , Song Jessie M , Padmanabham Prasanna , Mausbach Brent , Martin Jennifer L , Song Yeonsu 
Published: January 2025

AbstractBackgroundUnsupervised high‐frequency cognitive‐ecological momentary assessment (EMA) on smartphones is increasingly used to assess preclinical risk for Alzheimer’s disease and related dementias (ADRD). While these tests are reliable and valid for individuals with preclinical ADRD, it is unclear whether administering cognitive EMAs to people living with ADRD is feasible and valid. Our study explored the feasibility and validity on cognitive EMA tests in people living with moderate to severe ADRD.MethodA total of 31 with ADRD received cognitive EMA web links through their care partners' smartphone three times/day for seven days at baseline as part of an ongoing clinical trial of a dyadic sleep intervention. Of which, 23 completed any of three cognitive EMA tests using the NeuroUX platform (Quick Tap 1 [QT1], Quick Tap 2 [QT2], Matching Pair [MP]). We examined baseline adherence to cognitive EMA prompts, performance distributions, and within‐day variability of cognitive performance. We also compared this data to a normative sample.ResultOn average, participants completed 60% of cognitive EMAs (SD = 27%). This was lower than a normative sample of cognitively normal adults aged 20‐79 (N = 394; mean adherence = 88%, SD = 21%). Participants tapped the response correctly 78.68% (SD = 0.25%) of the time on QT1, a measure of psychomotor speed, and took an average of 936.83 milliseconds (SD = 294.86) to respond correctly (see Table 1 for comparison to normative data). On a measure of response inhibition (QT2), participants responded correctly on 33.07% of the items (SD = 0.19%), with mean correct response times of 602.19 milliseconds (SD = 238.18). Finally, participants scored a mean of 108.08 (SD = 65.60) on MP, a measure of processing speed. Performance on QT2 and MP (% of correct response) did not differ throughout the day; however, participants response times to QT2 was significantly slower in the morning than in the afternoon or evening (morning M = 643.81; afternoon M = 587.14; evening M = 578.19; F(df = 1) = 7.24, p < 0.01).ConclusionCurrent findings extend research on people with preclinical ADRD, demonstrating that reliable and valid cognitive EMA data can be obtained from this group and employed in research.
Production and characterization of human tau protein with site‐specific phosphorylation utilizing E. coli with an expanded genetic code
Authors: Ammermann Erik J , Cho Yongku P 
Published: January 2025

AbstractBackgroundWith insight into the elevated levels of phosphorylation of diseased tau, it is believed that specific modifications occur in a time‐dependent manner that contribute to tau’s role in Alzheimer’s disease pathogenesis and progression. Present methods to obtain phospho‐tau (p‐tau) from post‐mortem tissue or recombinantly are insufficient to answer the foremost questions in the field, and there is currently no way to study each disease‐relevant modification reproducibly or in isolation. To this point, learning about tau phosphorylation at the resolution of a single modification has been a major obstacle in clarifying whether certain sites are causative of disease or just a by‐product of other harmful mechanisms. Furthermore, a standardized p‐tau reagent with known, consistent modifications is urgently needed to develop diagnostic and phospho‐specific tools.MethodUsing a phosphoserine orthogonal translation system, we describe a method to produce full‐length human tau in engineered E. coli with genetically defined phosphoserine (pSer) sites. This p‐tau can be readily purified with traditional chromatography techniques and subsequently used for in vitro assays to assess differences in tau biochemistry due to individual PTMs for the first time. To date, we have produced 12 different p‐tau variants with a single disease‐relevant pSer site ranging from pSer199 to pSer422.ResultIn experiments to measure tau aggregation in vitro (thioflavin‐T and HEK cell biosensor), our preliminary results indicate that the disease‐associated pSer396 modification of 2N4R tau may have increased aggregation and seeding capabilities relative to other tested pSer tau. Strikingly, in the thioflavin‐T experiment, spontaneous aggregation of pSer396 was observed in which no heparin was added to the reaction mixture. Also, using Western blot, we clearly demonstrate a simple but powerful method to assess the specificity of phospho‐specific antibodies.ConclusionThe ability to readily produce recombinant human tau with known PTMs will be a critical tool in helping researchers develop, validate, and assess the specificity of p‐tau detection platforms and antibody‐based technologies. With the idea of developmentally significant PTM sites in mind, we have preliminary results suggesting that even single tau PTMs can dramatically alter tau biochemistry and lead to disease‐like molecular behaviors.