bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective Study of Endogenous Estrogen History and Cognitive Decline in the Nurses' Health Study
Authors: Juramt Namuunaa , Kang Jae H. , Wang Dong D. , Vyas Chirag M. , Peng Cheng , Curhan Sharon , Warner Erica T. , Zeleznik Oana A. , Rosner Bernard A. , Wang Molin , Stampfer Meir J. , Okereke Olivia I. , Eliassen A Heather 
Published: January 2025

AbstractBackgroundEndogenous estrogen history across the life course may be associated with better cognitive maintenance. Few large longitudinal studies have evaluated this prospectively, and results have been inconsistent. We assessed the association of reproductive span, an indicator of endogenous estrogen history, with cognitive change in older women.MethodWe followed 13,419 Nurses’ Health Study participants who were free of stroke, were ≥70 years old as of 1995‐2001, reported natural menopause or bilateral oophorectomy and had information on ages at menarche and menopause. Reproductive span was defined as age at menopause minus age at menarche. Four telephone‐based cognitive assessments were administered (at 1.5‐2 year intervals). The primary outcome was the global composite score, averaging z‐scores of 6 tests measuring general cognition (the Telephone Interview of Cognitive Status, TICS), verbal memory, category fluency, and attention. Linear mixed‐effects models, adjusted for age, education, depression, menopausal hormone therapy (MHT) within 10 years of menopause, surgical menopause, and other lifestyle and health variables, were used to estimate the differences in annual rate of change over time by quintiles (Qs) of reproductive span. We examined interactions with menopause type, MHT duration and apolipoprotein E (APOE) e4 allele (among 5,434 women).ResultThe mean baseline age was 74.3 years, the mean follow‐up was 6.6 years, and the mean reproductive span was 36.4 years (range = 7‐46 years). Longer reproductive span was significantly associated with more favorable cognitive change: compared with women with the shortest reproductive span (Q1: ≤33 years), women with the longest reproductive span (Q5: ≥41 years) demonstrated better maintenance in global cognition (difference in annual rate of changeQ5vs.Q1 = 0.007; 95% CI: 0.00001, 0.01; p‐trend = 0.02); this difference was equivalent to that observed in women 1.4 years apart in age. We observed similar trends with TICS and verbal memory (p‐trends≤0.04), but not category fluency (longer reproductive span was associated with better baseline performance, p≤0.01; but not differences in rates of decline) and attention (no associations found). We observed no interactions with surgical menopause, MHT, or APOE e4.ConclusionLonger reproductive span, an indicator of greater endogenous estrogen history, was significantly associated with more favorable cognitive maintenance in older women.
Suboptimal seizure control is associated with increased risk of MCI among Adult Patients with Epilepsy
Authors: Shen Jia Yi , Soh Chirin , Chew Wee Jin , Siew Rachel , Saffari Seyed Ehsan , Koh Pei Xuan , Tan Yee Leng , D/O Srinivasan Sheila , Tan Nigel Choon Kiat , Loh Ngai Kun , Tan Louis CS , Ng Kok Pin 
Published: January 2025

AbstractBackgroundEpilepsy is associated with increased risk for dementia, which adversely impacts the quality of life for patients and their families. Mild cognitive impairment (MCI) is the prodromal stage of dementia offering an important window for intervention. However, the epilepsy related risk factors for MCI are not well understood. The ongoing Mild Cognitive Impairment among Adult Patients with Epilepsy (MCAPE) study is a longitudinal study evaluating the prevalence and risk factors for MCI amongst adult patients with epilepsy (PWE). This abstract summarizes the interim findings.MethodAdult PWE were recruited from outpatient clinics at a tertiary centre, the National Neuroscience Institute, Singapore. Patients with previous stroke, known dementia, or intellectual disability were excluded. Participants underwent a self‐administered questionnaire on their lifestyle risk factors and epilepsy‐specific factors, followed by cognitive testing with the Mini Mental State Assessment (MMSE) and Montreal Cognitive Assessment (MOCA). A MOCA cut‐off of <27 was used to diagnose MCI. Logistic regressions evaluated the associations of clinical risk factors with presence of MCI, corrected for age and education as confounders.ResultForty‐six participants were recruited and completed cognitive testing. Twenty‐three participants (50.0%) had subjective cognitive complaints. Cognitive assessment revealed that 16 participants (34.8%) had MCI. Among epilepsy factors, multivariate logistic regression found that a seizure frequency of once a month or more was strongly associated with increased risk of MCI (OR 109, p = 0.004). Epilepsy subtype, duration and use of multiple anti‐seizure medications were not significantly associated with MCI.ConclusionThis pilot cross‐sectional study showed that MCI is a significant problem among PWE, and that suboptimal seizure control was associated with increased risk of MCI. Prospective studies are need to determine effective interventions to mitigate MCI among PWE.
Utility of two computerized assessments for predicting clinical progression in individuals with early Alzheimer’s Disease
Authors: Schoemaker Dorothee , Atkins Alexandra , Abraham Chelsea , Welch Matthew , Plassman Brenda L , Sickel Nancy , Madsen Corrine , Klein Hans , DiGregorio Danielle T , Welsh‐Bohmer Kathleen A. , Keefe Richard SE 
Published: January 2025

AbstractBackgroundInterventional trials in Alzheimer’s Disease (AD) are increasingly targeting early disease stages. To optimize the likelihood of successful outcomes for these trials, there is an important need for tools capable of identifying individuals prone to exhibit clinical progression throughout the course of the trial. The Expanded Brief Assessment of Cognition (Expanded‐BAC) and the Virtual Reality Functional Capacity Assessment Tool – Short List (VRFCAT‐SLx) are two computerized tests assessing cognitive and functional abilities, respectively. They offer automated instructions and scoring, which significantly improves standardization and reduces administration errors. Importantly, they minimize reliance on caregiver availability, which can be a significant barrier to trial participation. The goal of this project was to evaluate the value of the Expanded‐BAC and VRFCAT‐SLx in predicting clinical progression in individuals with early AD.MethodA total of 51 participants with clinical diagnoses of MCI or early AD (NIA‐AA clinical criteria) completed both a baseline and follow‐up visit including the CDR, Expanded‐BAC, and VRFCAT‐SLx. The mean follow‐up interval was of 9.5 months (SD = 4.7 months). Clinical progression was operationalized as a change of 0.5 or more on the CDR Sum of Boxes score (CDR SoB) over the follow‐up interval. Baseline performance on the Expanded‐BAC and the VRFCAT‐SLx was contrasted between clinical progressors and non‐progressors using ANCOVAs adjusting for follow‐up duration. Linear regression models were computed to assess the predictive value of baseline performance on the Expanded‐BAC and the VRFCAT‐SLx on CDR SoB changes over time, also adjusting for follow‐up duration.ResultAt follow‐up, there were 18 clinical progressors and 33 non‐progressors. The Expanded‐BAC composite score and the VRFCAT‐SLx total adjusted time at baseline significantly differed between progressors and non‐progressors, with progressors showing poorer performance on both measures (Figure 1). In linear regression models, performance at baseline on the Expanded‐BAC (r2 = 0.24, p<0.01) and the VRFCAT‐SLx (r2 = 0.16, p<0.05) significantly predicted changes in CDR SoB over the follow‐up interval.ConclusionThese preliminary results suggest that performance on the Expanded‐BAC and the VRFCAT‐SLx can predict clinical progression in individuals with early AD. These two computerized tests might thus be useful tools to identify individuals likely to exhibit clinical progression in the course of a trial.
Longitudinal differences in language in middle‐aged and older people with normal cognition, subjective cognitive impairment, and mild cognitive impairment. Results of the Compostela Aging Study
Authors: Facal David , Campos‐Magdaleno Maria , Pérez‐Blanco Lucía , Felpete Alba , Nieto‐Vieites Ana , Mallo Sabela Carme , Arora Sonali , Fernández‐Feijoo Fátima 
Published: January 2025

AbstractBackgroundLanguage performance has been considered a potential screening tool in the continuum from healthy cognitive aging to cognitive impairment and dementia. Language impairment and most notably impairment in semantic verbal fluency has been shown to increase with the progress in this continuum (Liampas et al., 2023).MethodThe study sample was drawn from the participants of the Compostela Aging Study who completed baseline and two follow‐up assessment, each of them about 18 months after the previous cognitive and neuropsychological evaluation (Pereiro et al., 2021). Sample included 22 persons with uni‐domain mild cognitive impairment (MCI), 20 with multi‐domain MCI, 46 with subjective cognitive decline and 73 cognitively unimpaired participants. Language performance was assessed via Boston naming test, semantic, phonemic and ideational fluency. GLM repeated measures were implemented comparing performance in the three assessments for each of the language measures as a dependent variable, and the diagnostic group as a factor. Age and years of formal education were included as covariates.ResultA significant interaction between time of assessment and group was only found for the Boston naming test (F = 1.75, p<0.05, η2 = 0,03, B‐1 = 0,53). Age, but not education, was a significant covariate for all the language measures.ConclusionEven though language measures could be relevant to detect early changes in cognitive status, these measures has scarcely been studied in recent literature. According to these preliminary analyses of the longitudinal results of our study, the Boston naming test could be a linguistic marker of cognitive changes in late adulthood.References:Lampas, I., Folia, V., Morfakidou, R., Siokas, V., Yannakoulia, M., Sakka, P., Scarmeas, N., Hadjigeorgiou, G., Dardiotis, E., Kosmidis, M.H. (2023). Language differences among individuals with normal cognition, amnestic and non‐amnestic MCI, and Alzheimer’s disease. Archives of Clinical Neuropsychology 38, 525. https://doi.org/10.1093/arclin/acac080Pereiro, A.X., Valladares‐Rodríguez, S., Felpete, A. Lojo‐Seoane, C., Campos‐Magdaleno, M., Mallo, S.C., Facal, D., Anido‐Rifón, L., Belleville, S., Juncos‐Rabadán, O. (2021). Relevance of complaint severity in predicting the progression of subjective cognitive decline and mild cognitive impairment: A machine learning approach. Journal of Alzheimers Disease 82, 3, 1229‐1242. https://doi.org/10.3233/JAD‐210334.
Cholinergic white matter pathways in Alzheimer’s disease, dementia with Lewy bodies, and other neurodegenerative diseases: a post‐mortem MRI study
Authors: López‐González Francisco J. , Nemy Milan , Rabano Alberto , Grothe Michel J. , Sanchez‐Juan Pascual , Ferreira Daniel 
Published: January 2025

AbstractBackgroundIn‐vivo magnetic resonance imaging (MRI) has recently shown that patients with clinically diagnosed Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) exhibit degeneration of the cholinergic nucleus basalis of Meynert and its white matter (WM) projections through the cingulum and external capsule pathways1. Here, we propose an imaging‐pathologic validation study aimed at investigating cholinergic WM pathways using post‐mortem MRI of autopsy‐confirmed AD, Lewy body dementia (LBD), and other neurodegenerative diseases (OTH).MethodWe included 53 brain donors (34 AD, 10 LBD, and 9 OTH, mainly including frontotemporal lobe degeneration and vascular disease, Table 1). All donors underwent post‐mortem MRI in situ within 5 hours after death and were later subjected to neuropathological examination performed according to published consensus criteria. Post‐mortem MRI examination included 3D T1 structural imaging and diffusion‐weighted imaging acquired using a 3T scanner. Previously established masks of cholinergic WM pathways (i.e., cingulum and external capsule pathways) were transformed from standard MNI space to each individual’s b0 image in native space using the nonlinear SyN registration algorithm. Native space mean diffusivity (MD) maps were estimated for each donor using the FMRIB Diffusion Toolbox from FSL. Microstructural properties of each participant’s cholinergic WM pathway were then estimated by averaging the MD values within the back‐transformed masks in native space. Differences in age‐adjusted MD values between diagnostic groups were analysed using the Mann‐Whitney U‐test.ResultAD donors were older than LBD donors (p = 0.007), and both groups were older than the OTH group. After adjusting for age, AD showed significantly higher MD values in cholinergic WM pathways when compared with OTH (Cohen’s d = 1.45, p<0.001) and LBD (Cohen’s d = 0.91, p<0.01) (Figure 1). Elevated MD values in LBD compared to OTH did not reach statistical significance in this small sample (Cohen’s d = 0.85, p = 0.11).ConclusionWe expanded previous in‐vivo MRI findings to post‐mortem MRI and confirmed the degeneration of cholinergic WM pathways in AD. Additionally, we highlighted the difference between AD and LBD donors, with a more severe cholinergic pathway degeneration in AD donors.References:1. Schumacher J, et al. Cholinergic WM pathways in dementia with Lewy bodies and AD. Brain. 2022 Jun 3;145(5):1773‐1784.
Neuroinflammation and synapse loss determines the cognitive fate in Alzheimer Disease
Authors: Kumar Sunny , Diez Ibai , Amaral Ana Claudia , Aguero Cinthya , Klein Charles Zachary , Scapellato Margaret , Sinha Riddhimaa , Gomez‐Isla Teresa 
Published: January 2025

AbstractBackgroundSome individuals can tolerate the presence of Alzheimer disease neuropathologic changes (ADNC) (e.g., plaques and tangles) without developing dementia. A better understanding of the mechanisms underlying this brain resilience to ADNC may inform the development of novel disease biomarkers and therapies. We investigated the differences in brain changes and gene expression profiles associated with opposite cognitive outcomes (dementia vs. no dementia) in the presence of ADNC.MethodsWe studied postmortem brain samples from 103 participants in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). They all had undergone longitudinal antemortem cognitive assessments. At autopsy, 51 fulfilled neuropathologic criteria for high likelihood of AD (25 demented and 26 cognitively normal ‘resilient’), and 52 fulfilled criteria for low likelihood of AD (26 demented ‘frail’ and 26 cognitively normal ‘controls’). Cases were matched for age, gender, level of education, and co‐pathologies (vascular lesions, Lewy bodies, and TDP‐43 aggregates). Detailed quantitative neuropathological and biochemical assessments and bulk RNA‐seq‐based transcriptomic analyses were conducted in superior temporal and dorsolateral prefrontal cortices.ResultsDemented AD had a similar number of tau tangles compared to resilient but a significantly higher tau neuropil thread burden and soluble hyperphosphorylated tau oligomer levels in synapse‐enriched fractions. The burden of CD68+ microglia was significantly higher in demented AD and frail but not in resilient compared with control brains. Demented AD and frail had a higher loss of synapses than resilient compared with control brains. These differential brain changes paralleled a significant reduction in resilient compared to demented AD in the expression of genes associated with apoptotic, neuroinflammation/response to cytokines, and protein phosphorylation processes. Levels of soluble hyperphosphorylated tau oligomers in synapses and CD68+ microglia burden emerged as the strongest correlates with synaptic densities and antemortem measures of cognition.ConclusionsThese findings suggest that enhanced tau pathology in neurites and synapses may instigate glial inflammatory responses and synapse elimination, determining the cognitive fate of individuals who harbor ADNC.
Domain Specific Age at Onset of Decline in Down Syndrome
Authors: Kennedy James Tyler , Handen Benjamin L , Head Elizabeth , Mapstone Mark , Christian Bradley T. , Ances Beau 
Published: January 2025

AbstractBackgroundIndividuals with Down syndrome (DS) typically develop Alzheimer’s disease (AD) at an early age. Estimates of the age of decline vary, but typically place it in the early‐mid 50s. As AD onset can be difficult to identify in intellectually impaired cohorts, understanding the expected timing of decline may help individuals and caregivers prepare. It is unclear how timing in changes in different domains relates to the onset of AD dementia.MethodData was obtained for individuals with DS (188 total, 53% male), ages 25 to 61, from the Alzheimer’s Biomarker Consortium–Down Syndrome and used in cross‐sectional analyses based on the baseline session. Decline was determined by performance on direct measures of cognition with participants and interviews of caregivers. Diagnosis of AD related decline was arrived at by group consensus. Domain‐specific decline was dichotomized as a stable vs decline binary for Adaptive, Behavioral/Emotional, Cognitive, Interpersonal, Memory, and Psychomotor changes. Consensus and domain‐specific data (Consensus n = 175, 18 declining, Domain n = 186‐187, 21‐60 declining) was available. The association between age and decline was analyzed in logistic generalized additive models (GAM), controlling for sex. Ages where individuals were equally likely to be stable or declining were extracted from GAM models. The relationship between domains/consensus was also examined using tetrachoric correlations. Results were considered significant at a p < .05 following multiple comparison correction.ResultAge was significantly associated with decline for all measures except the Behavioral/Emotional domain. AD related decline began at age 54, domain‐specific estimates varied: earliest in Memory (49.7) and Cognitive (49.8) and latest in Behavioral/Emotional (64.7). The relationship between age and decline probability was linear except for AD consensus where slope slows at age 44 and the Cognitive measure where slope increases at age 37. Age at decline did not differ between sexes. Correlations ranged from 0.96 (Memory with Consensus) to 0.47 (Consensus with Behavioral/Emotional).ConclusionAD decline occurs at the age of 54 and is preceded by a change in cognition and memory ∼4 years earlier. Sex does not affect decline onset. Change in memory and cognition are closely related while behavioral/emotional changes are not strongly associated with AD‐related decline or other domains.
Uncovering the role of cerebrovascular phenotypes in AD through deep multi‐omic molecular profiling of human brains
Authors: D'Oliveira Albanus Ricardo , Aladyeva Ekaterina , Bertucci Taylor , Brase Logan ,   Dominantly Inherited Alzheimer Network (DIAN), Benitez Bruno A. , Sutherland Greg T , Karch Celeste M. , Temple Sally , Harari Oscar 
Published: January 2025

AbstractBackgroundThe cerebrovasculature is an essential component of brain homeostasis. Cerebrovascular disorders are associated with an increased risk for neurodegenerative diseases, including Alzheimer’s disease (AD). However, the mechanisms by which cerebrovascular dysfunction contributes to neurodegeneration are poorly understood.MethodWe optimized nuclei isolation from human brains to increase the representation of cerebrovascular cells (CVC) and performed single‐nucleus transcriptomic profiles (snRNA‐seq) of parietal cortex from healthy and AD donors from the Australian Brain Bank Network (ABBN; n = 72 brains), which are richly annotated for cerebrovascular phenotypes, including cerebral amyloid angiopathy (CAA). In parallel, we generated spatially resolved transcriptomic profiles for a subset of these samples. We integrated our new data with seven public snRNA‐seq datasets to create a comprehensive cerebrovascular atlas. Simultaneously, we reprocessed public snATAC‐seq data from cases and controls to identify regulatory elements in CVC likely mediating AD gene risk.ResultOur cerebrovascular atlas encompassed ∼133K CVC across five major cell types (endothelial, smooth muscle, pericytes, fibroblasts, ependymal). This high resolution allowed the identification of perturbed CVC transcriptional programs between cases and controls, including pronounced disruptions in cellular homeostasis via heat shock proteins and smooth‐muscle‐specific downregulation of ANKRD36 in early‐onset AD patients. Rare variants in ANKRD36 were recently implicated in AD in a whole‐exome sequencing study. We also identified transcriptional signatures associated with CAA in vascular and glial cells. We validated these results using spatial transcriptomics and data from the Seattle AD cohort. Lastly, we prioritized eight independent AD risk loci, including APP and APOE, where at least one fine‐mapped risk variant (95% credible set) overlapped a regulatory element active in vascular cells. At the APH1B locus, we identified a vascular enhancer likely regulating TPM1 and USP3. All loci putatively acting through vascular cells were shared with at least one other cell type (e.g., CASS4 with microglia), supporting reports of shared genetic risk between AD and cerebrovascular disease but suggesting the shared risk is mediated in a cell type‐specific manner (Figure 1).ConclusionOur work provides novel insights into the role of cerebrovascular dysfunction in AD and identifies genes and regulatory elements mediating AD genetic risk through CVC.
Reduction of neurogranin protein correlates with increases of inflammasome proteins in post mortem cases of intermediate Alzheimer’s disease
Authors: Vontell Regina T , Barreda Ayled , Blennow Kaj , Zetterberg Henrik , Vaccari Juan Pablo de Rivero , Bramlett Helen M , Dietrich W Dalton , Keane Robert W , Davis David A. , Rundek Tatjana , Sun Xiaoyan 
Published: January 2025

AbstractBackgroundNeurogranin (Ng) is considered a biomarker for synaptic dysfunction in Alzheimer’s disease (AD). In contrast, the inflammasome complex has been shown to exacerbate AD pathology.MethodWe investigated the protein expression, morphological differences of Ng and correlated Ng to hyperphosphorylated tau in the postmortem brains of 17 AD cases and 17 age and sex‐matched controls. In addition, we correlated the Ng expression with two different epitopes of apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC).ResultWe show a reduction of Ng immunopositive neurons and morphological differences in AD compared to controls. Ng immunostaining was negatively correlated with neurofibrillary tangles, humanized anti‐ASC (IC100) positive neurons and anti‐ ASC positive microglia, in AD.ConclusionThe finding of a negative correlation between Ng and ASC speck protein expression in postmortem brains of AD suggests that the activation of inflammasome/ASC speck pathway may play an important role in synaptic degeneration in AD.