bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain health index as a predictor of possible vascular cognitive impairment (pVCI) in the Mexican Health and Aging Study (MHAS) 2012‐2015
Authors: Aguilar‐Navarro Sara Gloria , Moctezuma‐Gallegos Rogelio , Yeverino Sara , Arango Silvia Mejia , Funes José Alberto Avila , Mimenza Alberto 
Published: December 2022

AbstractBackgroundVascular dementia is the second most common cause of dementia. Brain health is defined as the capacity to function adaptively in the environment, and its partially determined by cardiovascular risk factors, which are a potential target for the prevention of all cause dementia. We developed a brain health index (BHI) to establish association with possible vascular cognitive impairment.MethodMHAS is a longitudinal cohort study of Mexican adults ≥50 years. The cardiovascular risk factors (CVRF) considered for the index were: diabetes, hypertension, myocardial infarction, depression, obesity, physical inactivity and smoking. pVCI was defined if scores in two or more cognitive domains in the Cross‐Cultural Cognitive Examination were ≥1.5 standard deviations below the mean on reference norms for self‐respondents or for proxy respondents a score ≥3.4 on the Informant Questionnaire on Cognitive Decline in the Elderly, with limitations in ≥1 instrumental activities of daily living and a history of stroke. A cognitive unimpaired and dementia without stroke groups were included. We compared the groups with ANOVA; a multinomial regression model was developed to predict the association of the BHI with the groups and a Cox regression model to determineResult12,427 individuals were included, 513 were identify as dementia without stroke and 75 as pVCI. For pVCI, 57.3% were female, with mean age of 75.28 (SD 9.31) years and education of 3.25 (SD 4.75) years. The mean BHI for the cohort was 2.21 (SD 1.27), for dementia without stroke 2.79 (SD 1.17), and with pVCI 3.28 (SD 1.23). The OR for pVCI was 1.904 (CI 1.4‐2.6, p <0.001) and the HR with a 3 year follow‐up was 1.75 (CI 1.4‐2.17, p <0.001).ConclusionThe BHI predicted the development of pVCI up to 74.5% in the 3 year follow‐up after adjusting for covariables. This index could potentially be used to identify pVCI in adults with potentially modifiable CVRF. Further studies should be carried out in other populations and with longer follow‐ups.
A fundamental study on the relationship between cognitive function and psychological load while driving in older adult drivers
Authors: Suzuki Mio 
Published: December 2022

AbstractBackgroundAlthough many media outlets have sounded the alarm about dangerous driving by elderly drivers, serious accidents do not occur on a daily basis, and the dangerous events of daily driving have not been clarified. However, serious accidents do not occur on a daily basis, and the risk events of daily driving have not been clarified. Also, the relationship between cognitive function and drivers' cognitive function has not been clarified. In addition, cognitive function fluctuates from day to day, and it is difficult to obtain an accurate picture of cognitive function from a one‐time test. However, in Japan, the system currently determines whether a driver’s license is revoked or not depending on the results of the test, and it is difficult to say that we can properly diagnose the driving of elderly drivers.MethodIn this study, we observed the heart rate during driving and examined the changes in psychological load that occur during driving. I observed 80 subjects' driving data.ResultAs a result, it was found that the heart rate of drivers with cognitive decline increased when they were approached by a trivial voice or an unexpected obstacle, followed by a rapid decrease in the heart rate and a state of excessive relaxation.In addition, when they were in the state of excessive relaxation, they slowed down their obstacle avoidance behavior and forgot to activate the blinker.ConclusionTherefore, it is necessary to find a way to equalize the tension during driving in order to support the safe driving of elderly drivers.
Spatiotemporal transcriptomic characterization of an amyloid mouse model of Alzheimer’s disease
Authors: Miyoshi Emily , Morabito Samuel , Henningfield Caden M , Michael Neethu , Shabestari Sepideh Kiani , Das Sudeshna , Shahin Saba , AD MODEL , Green Kim N , Swarup Vivek 
Published: December 2022

AbstractBackgroundTranscriptomic studies of Alzheimer's disease (AD) have identified both tissue‐level and cell‐type specific gene expression changes. However, with both "bulk"‐tissue and single‐cell approaches, we lose pertinent spatial information, such as cell‐to‐cell proximity or proximity to pathological features. Recently several techniques have emerged, aiming to profile gene expression while preserving the spatial architecture, and we have leveraged one of these techniques—spatial transcriptomics—to interrogate AD gene expression changes in the 5XFAD, an amyloid mouse model, in a spatial and temporal manner.MethodsWe generated spatial transcriptomic (10x Genomics Visium) data from 5XFAD and wildtype mice at the ages of 4, 6, 8, and 12 months (n = 80 total samples, sex‐balanced). Prior to generating libraries, we stained our tissue sections with Amylo‐glo and the conformation‐specific antibody OC to analyze gene expression changes in spatial relativity to amyloid pathology.ResultsWe profiled 18,000‐20,000 total genes per sample with 1,800‐2,700 genes per spatial spot and identified brain region‐specific transcriptionally distinct clusters. We also examined the spatial distribution of AD risk genes, identified by GWAS, throughout the disease progression. Further, we identified gene expression changes spatially related to amyloid pathology localization.ConclusionsWe have characterized the 5XFAD transcriptome, identifying spatiotemporal AD gene expression changes and providing further insight into the role of amyloid pathology in the modulation of gene expression in AD.
Alzheimer’s Disease Related Neurodegeneration Partially Mediates Associations Between Air Pollution and Medial Temporal Lobe Atrophy in Older Women
Authors: Petkus Andrew J. , Wang Xinhui , Salminen Lauren , Millstein Joshua , Beavers Daniel P. , Espeland Mark A. , Resnick Susan M. , Gatz Margaret , Braskie Meredith N , Thompson Paul M , Kaufman Joel D. , Younan Diana , Chen Jiu‐Chiuan 
Published: December 2022

AbstractBackgroundAmbient air pollutants are toxic to the vascular systems, and recent studies have shown the late‐life exposures may result in neurodegeneration and increased risks for AD. It is unclear if cerebrovascular damage and AD‐related neurodegeneration contribute to the atrophies of medial temporal lobe. Here we assessed whether AD related neurodegeneration and cerebrovascular disease mediated adverse effects of air pollution exposure on MTL atrophy.MethodParticipants included 624 community‐dwelling older women without dementia (mean age 77.4 +/‐ 3.4 years) who underwent two structural brain MRI scans (MRI‐1: 2005‐6; MRI‐2: 2010‐11) as part of the Women’s Health Initiative Memory Study. Regionalized universal kriging was used to estimate annual concentrations of PM2.5 (fine particulate matter) and NO2 at residential locations aggregated to 3‐year averages prior to MRI‐1. The outcome was 5‐year standardized change in the MTL volumes. Mediators included spatial pattern of neurodegeneration of AD (AD pattern similarity scores [ADPS], validated ADNI data) and a proxy of global cerebrovascular damage (small‐vessel ischemic disease [SVID]). Whether the associations between exposures on MTL atrophy were mediated by the initial level or concurrent change in ADPS or global SVID were examined by the structural equation models with latent‐difference scores. All effect paths were adjusted for sociodemographic, lifestyle, clinical characteristics, and intracranial volume.ResultLiving in locations with higher PM2.5 (per interquartile range [IQR] = 3.21µg/m3) and NO2 (per IQR = 6.72ppb) were both associated with greater atrophy of the MTL (βPM2.5 = ‐.27, 95% confidence interval [CI] = [‐.38,‐.16]; βNO2 = ‐.12,95%CI = [‐.22,‐.02]). PM2.5 was associated with increased ADPS (βPM2.5 = .02, 95%CI = [.01,.05]) over time, which partially mediated associations with MTL atrophy (26%, 95% CI = [10%,49%; Figure 1 Panel A). NO2 was positively associated with ADPS at MRI‐1 (βNO2 = .02, 95%CI = [.01,.04]), which partially mediated the association with MTL atrophy (14%, 95% CI = [1%,94%]; Figure 1 Panel B). Global SVID at MRI‐1 or change in SVID did not significantly mediate observed associations between exposures and MTL atrophy (Figure 1 Panels C and D).ConclusionOur study supports the mediating role of AD neurodegeneration contributing to MTL atrophy associated with late‐life exposures to air pollutants. Findings support the hypothesis that multiple neuropathological processes of brain aging are affected by air pollution neurotoxicity.
The association of gabapentin use and change of cognitive and functional status in older adults with normal cognition
Authors: Oh GYeon , Moga Daniela C , Fardo David W. , Abner Erin L 
Published: December 2022

AbstractBackgroundAlthough gabapentin has been increasingly prescribed to older adults, the relationship between gabapentin and cognition/functional status is not well studied. Therefore, we aimed to examine the association of gabapentin use and cognitive/functional change in older adults.MethodsA retrospective cohort study was conducted using National Alzheimer’s Coordinating Center Uniform Data Set (2005‐March 2021). Gabapentin new users with normal cognition at the visit of gabapentin initiation (i.e., index visit) were included. New‐users were matched on year of first enrollment and time of gabapentin initiation since enrollment to randomly select nonusers with replacement. The decline of cognitive/functional status, including Clinical Dementia Rating global score (CDRGLOB), Clinical Dementia Rating sum of boxes (CDRSUM), Mini‐Mental State Examination (MMSE), sum of Functional Activities Questionnaire (FAQ), and mean of FAQ, was assessed from index to index+1 and index+2 visits. The criteria of cognitive/functional status decline were any increase of CDRGLOB, 1 point increase of CDRSUM, 1 point decrease of MMSE, 3 point increase of sum of FAQ, and 0.3 point increase of mean of FAQ. To mitigate confounding and selection bias, stabilized inverse probability of treatment weights and stabilized inverse probability of censoring weights were used. Generalized estimating equations with an exchangeable working correlation structure were used to account for within‐participant correlations and obtain robust standard errors.ResultsWe included 496 new‐users (mean age [SD]: 78.0 [7.1]; male 35.9%) and 4,464 nonusers (77.4 [7.1]; 35.1%) with normal cognition at index. Among the participants who had information of seizure history (57.1% of new‐users and 58.0% of nonusers), 2.2% and 1.6% of new‐users and nonusers, respectively, reported having seizure history, indicating that gabapentin is widely prescribed off‐label in older adults. Gabapentin use was significantly associated with cognitive/functional status decline with outcomes, including CDRGLOB at index+1 visit (odds ratio [95% confidence interval]: 1.57 [1.08, 2.31]); CDRSUM at index+1 visit (1.89 [1.16, 3.06]) and at index+2 visit (1.66 [1.05, 2.63]); and mean of FAQ at index+2 visit (2.23 [1.22, 4.07]) (Figure 1).ConclusionsGabapentin use was significantly associated with decline in cognitive and functional status among older adults with initially normal cognition. Further studies are needed to examine the association.
Impact of Study Partner Replacement in Mild Cognitive Impairment Clinical Trials
Authors: Dolmadjian Lucy A , Ryan Mary M , Grill Joshua , Gillen Daniel L. 
Published: December 2022

AbstractBackgroundIn Alzheimer’s disease (AD) clinical trials, including trials enrolling patients with Mild Cognitive Impairment (MCI), participants must enroll with a study partner (SP). SPs ensure compliance and provide study data, including assessments of the participant’s cognition and function. Thus, consistency in SP reporting is essential to trial integrity. We quantified the impact of SP replacement on bias and variance of SP‐reported AD Cooperative Study Activities of Daily Living (ADCS‐ADL‐MCI) scores in a large Phase 3 MCI trial.MethodWe analyzed data from the ADCS Donepezil/Vitamin E MCI Trial. We used logistic regression to estimate the association between SP type (spouse or non‐spouse) and the odds of experiencing an SP change. We used generalized estimating equations (GEE) to longitudinally model the differences in ADL scores recorded at consecutive visits as a function of whether an SP change occurred. All models adjusted for confounding factors, including SP type, participant age, time (in months) since baseline visit, gender, and ADL score at previous visit.ResultAmong the 768 participants, 41 (5%) experienced at least one SP change (Table 1). We estimated that the odds of experiencing an SP change were 60% lower for spousal SP dyads when compared to non‐spousal SP dyads (OR = 0.40; 95% CI: [0.18, 0.88]). Compared to those with consistent SP, participants who experienced SP replacement had, on average, a consecutive visit absolute score difference that was 1.76 points larger in magnitude (95% CI: [0.24, 3.29]; Figure 1). ADL scores were neither systematically larger nor smaller, on average, when a participant experienced a SP change (‐0.60; 95% CI: [‐2.61, 1.41]; Figure 2). The difference in the variance for end‐of‐study change from baseline ADL was higher for those who experienced an SP change compared to those who did not (110.35 vs 86.78; p‐value = 0.25).ConclusionOur results suggests that while SP replacement may not result in systematic bias on functional outcomes, it does increase variability. Efforts to reduce replacement or otherwise account for variability may be necessary.
Comprehensive CSF Tau Profiling Identifies Soluble Tau Pathophysiological Stages in Dominantly Inherited Alzheimer Network (DIAN): Implications for the DIAN‐TU Tau Next Generation Platform
Authors: Horie Kanta , Barthélemy Nicolas R. , Li Yan , Sato Chihiro , Gordon Brian A. , Benzinger Tammie L.S. , Sachdev Pallavi , McDade Eric , Bateman Randall J. 
Published: December 2022

AbstractBackgroundBrain tau aggregation is a pathological hallmark of Alzheimer’s disease (AD) and the tau microtubule binding region (MTBR) is the core of AD tau tangles. Recently, we identified the enrichment of some specific MTBR species in sporadic AD brain tangles. Corresponding soluble MTBR species in the CSF increased together with clinical progression and tau pathology measured by tau‐PET. Because extracellular MTBR‐tau was discovered in human AD, MTBR‐tau has become a high priority target for antibodies binding this region. In this study, we sought to determine when these MTBR‐tau changes occurred and the relationship to clinical, cognitive and biomarker changes in the DIAN.MethodWe designed a mass spectrometry‐based method to quantify more than a dozen tau species in CSF. To profile MTBR‐tau, we conducted the immunoprecipitation using the anti‐MTBR antibody, E2814 which is bi‐epitopic to R2 and R4 regions and a tau drug in clinical trial. We analyzed CSF from 227 mutation carriers (MCs) (152 asymptomatic, 77 symptomatic) and 141 non‐carriers enrolled in the DIAN‐observational cohort.ResultCSF MTBR‐tau specifically increased in MCs and changed at different times over the disease course. The change of MTBR‐tau299 (residue 299‐317) in R2‐3 occurred at an estimated years to symptom onset (EYO) of −22, close to the first detection of change in p‐tau217 occupancy (EYO −21). The increase of MTBR‐tau354 (residue 354‐369) in R4 saturated in late clinical stages, potentially due to the deposition into brain tangles. Notably, the ratio of MTBR‐tau299/354 which expected to recapitulate tau pathophysiology highly correlated with p‐tau217 occupancy, an early amyloid marker, in especially asymptomatic MCs (r = 0.82). This indicates MTBR‐tau and p‐tau217 could be useful as biomarkers to assess anti‐MTBR therapies in tau‐PET negative populations.ConclusionWe identified a soluble measure of tau tangles, CSF MTBR species, with changes many years before symptom onset and continuing through symptomatic stages, suggesting early pre‐symptomatic prevention trials can be implemented with anti‐MTBR‐tau antibodies, such as E2814. These results have been utilized to design the tau next generation platform in the DIAN Trials Unit (DIAN‐TU) E2814 drug arm to target soluble MTBR‐tau in independent cohorts of asymptomatic and symptomatic mutation carriers.
Characterization of behavioral changes, MRI brain volumetry and brain metabolic profile of 5xFAD mouse model of Alzheimer’s disease
Authors: Heikkinen Taneli , Karhunen Petri , Stenius Taina‐Kaisa , Kosunen Henni , Lehtimäki Kimmo , Shatillo Artem , Oksman Juho , Dudek Mateusz , Miszczuk Diana 
Published: December 2022

AbstractBackground5xFAD mice (B6SJL‐Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax)) express five AD linked mutations in human APP (K670N/M671L, I716V and V717I) and PSEN1 (M146L and L286V) transgenes. APP and PSEN1 mutations cause human like AD pathology by overproducing Aβ42, leading to plaque accumulation in the brain. The objective of this study was to characterize the behavioral changes, brain volumetry and metabolic profile, beta amyloid accumulation and other biomarkers in 5xFAD mice.Method14 female and 15 male transgenic mice and 11 female and 10 male wild‐type mice were used for the study. The mice were subjected to behavioral tests including open field (OF), elevated plus maze (EPM), Y‐maze tests (YM), nest building (NB) and radial arm water maze (RAWM). Brain volumes and hippocampal metabolic profile were measured using MRI and MRS. In addition, the FDG PET and functional ultrasound (fUS) imaging were performed. In vivo measurements were performed at 4‐10 months and brain samples were collected at 6 and 11 months for analysis of beta amyloid levels.ResultRAWM and NB showed a significant deficit in 5xFAD mice. OF, YM and EPM did not reveal significant phenotype. FDG uptake was significantly reduced in 5xFAD, and hippocampal metabolic profile was altered at 6 months.ConclusionThese data suggest that the 5xFAD mice exhibit cognitive and metabolic changes resembling those observed in AD. These deficits were evident starting from 6 months of age. The 5xFAD mice offers a tool to investigate potential treatment effects in a model of beta amyloid over expression.
Differential expression of Mical2 and its activator (Sema3a) in Alzheimer’s disease mouse model
Authors: P A Haseena , Kommaddi Reddy Peera , Ravindranath Vijayalakshmi 
Published: December 2022

AbstractBackgroundMicals are actin regulatory enzymes which can enhance depolymerization of actin filaments (F‐Actin). Activated Micals catalyze the selective oxidation of methionine residues, Met44 and Met47 within the D‐loop of F‐actin. The oxidation of methionine residues disrupts the interaction between G‐actin monomers, thus facilitating F‐actin depolymerization. Dendritic spines are enriched with filamentous actin (F‐actin) where it regulates the formation, elimination and structural plasticity of spines. Early stage of AD is associated with loss of dendritic spines and F‐actin from synapses, leading to memory deficits. However, the potential mechanism involved in the loss of F‐actin remains largely unknown. Therefore, we aimed to elucidate the role of Micals and semaphorins in actin depolymerization at the synapse of AD mouse model.MethodsTotal RNA was isolated from the cortex, hippocampus and entorhinal cortex of adolescent, young, and middle aged wildtype and APP/PS1 mice as well as from the synaptosomes of respective age groups. The cDNA is synthesized and qRT‐PCR is performed using SYBR green reagents with specific primers to Micals and Semaphorins. Data was analyzed using two tailed non parametric test with a p value of <0.05 signifies the result.ResultsThe mRNA expression levels of Micals and Semaphorins in entorhinal cortex, hippocampus, and cortex of wildtype and APP/PS1 as well as in the synaptosomes of age matched animals were measured by qRT‐PCR. We found that Semaphorin3a showed differential mRNA expression levels in entorhinal cortex of adolescence and young adults of APP/PS1 mice in comparison to wildtype littermate controls. Further, we detected that the synapse specific mRNA levels of Mical 2 and Semaphorin3a are significantly decreased in adolescent APP/PS1 mice in comparison to WT mice. However, we did not detect any significant alteration in the mRNA expression levels of Mical1, Mical3 and Semaphorin3f in APP/PS1 mice at different age groups in comparison to WT littermate controls.ConclusionAltered expression levels of actin regulatory proteins like Micals and Semaphorins at the dendritic spines could play critical roles in Aβ mediated F‐actin depolymerization in Alzheimer's disease pathology.
Evaluating Digital Twins for Alzheimer’s Disease using Data from a Completed Phase 2 Clinical Trial
Authors: Walsh Jonathan R. , Roumpanis Spyros , Bertolini Daniele , Delmar Paul 
Published: December 2022

AbstractBackgroundComplex Alzheimer’s Disease (AD) clinical trials that require a large number of subjects leads to long trial timelines and significant costs. Our novel methods can accelerate randomized clinical trials (RCT) by reducing the required number of subjects using a combination of deep learning‐based predictive models and statistical methods while meeting regulatory requirements. Our method leverages historical control clinical data in a way that allows for faster trials without sacrificing the reliability of traditional RCT analyses. A Phase 2 study on crenezumab (the ABBY study, NCT01343966) in mild‐to‐moderate AD was used to retrospectively assess the validity of this approach for AD clinical trials and the potential impact on future studies.MethodA probabilistic deep learning model of AD progression was used to predict longitudinal outcomes using baseline data for 184 subjects from the placebo arm of the ABBY study. These clinical predictions are called Digital Twins, and are comprehensive outputs across several outcomes, including the 12‐component Alzheimer’s Disease Assessment Scale ‐ Cognitive Subscale (ADAS‐Cog12), the Clinical Dementia Rating Sum‐of‐Boxes (CDR‐SB), labs, and vitals. After Digital Twins were created blind to subject outcomes, they were compared to observed outcomes across visits and statistical metrics were computed to evaluate the utility of predictions in accelerating this Phase 2 clinical trial. The Pearson correlation coefficient defines the extent to which Digital Twins can provide a reduction in subjects in a clinical trial.ResultUsing the 18‐month outcomes for the change in ADAS‐Cog12 and CDR‐SB scores from baseline, the Digital Twin predictions had a correlation of 0.46 (ADAS‐Cog12) and 0.37 (CDR‐SB) with the observed values from subjects that took placebo. These values suggest that in similarly designed studies, this approach can yield 21% (ADAS‐Cog12) or 14% (CDR‐SB) smaller studies when maintaining randomization, or 35% (ADAS‐Cog12) and 24% (CDR‐SB) smaller control arms when maintaining treatment arm size.ConclusionWhen used with appropriate statistical analysis methods, Digital Twins offer the ability to accelerate RCTs by requiring fewer subjects to achieve a desired power. Because these methods follow regulatory guidance, they can be applied in large pivotal studies to reduce trial timelines, costs, and potentially bring effective therapies to market faster.