bluuebunny/crossref_metadata_2025_split huggingface dataset:
A 5‐hydroxymethylation‐based clock derived from cell‐free DNA in blood reveals accelerated epigenetic aging in patients with Alzheimer’s disease
Authors: Zhang Zhou , Beadell Alana , Cui Xiao‐long , Capuano Ana W. , Bennett David A. A , He Chuan , Arvanitakis Zoe , Zhang Wei 
Published: December 2023

AbstractBackgroundEnvironmental exposure and lifestyle factors can induce epigenetic aging acceleration that has been implicated in various complex diseases. Enabling technologies compatible with convenient biospecimens, e.g., 2‐3 mL of blood, will facilitate clinical application. Targeting 5‐hydroxymethylcytosines (5hmC), a stable and under‐investigated regulator in the human genome, may improve our understanding of epigenetic aging and its implications in Alzheimer’s disease (AD).MethodUsing our previously published genome‐wide 5hmC profiles derived from cell‐free DNA (cfDNA) in blood (∼1,200 healthy individuals [HEA], 48.2±10.9 yrs, 59.3% males, 2:1 randomization for training and testing) using the 5hmC‐Seal technique and next‐generation sequencing, a 5hmC‐based clock was constructed to characterize epigenetic ages (5hmC‐age). Epigenetic‐chronological age correlation, median error, and mean aging acceleration were evaluated. An independent set of cfDNA samples collected from 20 subjects (86.2±4.3 yrs, 60.0% males) with pathologically confirmed AD and 17 matched controls on chronological age, sex, and education (86.8±3.8 yrs, 58.8% males) without AD (non‐AD), from the Rush Memory and Aging Project, were employed to calibrate and examine epigenetic aging in AD.ResultChronological ages were found to be associated with the 5hmC modification levels of a significant proportion of genes in HEA, particularly those genes involved in immune response, inflammation, metabolism, and environmental exposure. An epigenetic clock comprised of ∼300 genes was then constructed. In HEA samples, we observed Pearson correlations of 0.88 and 0.65, median errors of 3.7 and 4.9 years, and mean aging accelerations of 0.03 and 0.57 years between chronological age and 5hmC‐age in training and testing samples, respectively, indicating that 5hmC‐age was a robust estimation of chronological age. In the independent small sample of AD and non‐AD subjects, a general acceleration of 5hmC‐ages relative to chronological ages was observed, with a calibrated mean aging acceleration of 2.55 years in persons with AD relative to non‐AD subjects.ConclusionThe 5hmC‐Seal appears to provide a convenient tool to evaluate epigenetic aging in blood that may facilitate preventive and precision medicine. Specifically, accelerated epigenetic aging was found in AD, suggesting that epigenetic age assessed in blood may be a novel biomarker for this neurodegenerative disease. This study was supported partially by the NIH (RF1AG074549, R01AG17917).
Regional variation in diagnostic intensity of dementia among older U.S. adults: a cross‐sectional study
Authors: Bynum Julie 
Published: December 2023

AbstractBackgroundAlzheimer’s disease and related dementias (ADRD) are known to be underdiagnosed; but little is understood about how the likelihood of obtaining a diagnosis varies across place or demographic subgroups. Using observed diagnosed cases from national billing data, we report variation by region, age, and race/ethnicity in newly diagnosed dementia cases taking into account underlying population risk.MethodAmong a 20% random sample of fee‐for‐service Medicare beneficiaries, we identified those who received a new ADRD diagnosis in 2019 using billing data. The rate of new ADRD diagnosis was estimated overall and by Hospital Referral Region (HRR) and stratified by age category (65‐74, 75‐84, ≥85) and by race/ethnicity. A measure of ADRD diagnosis intensity across HRRs was calculated as the observed‐to‐expected ratio (O:E ratio) of new cases; expected new ADRD cases for each HRR were estimated using Poisson regression adjusted for regional measures of education, population health (diabetes, obesity, and smoking), and diagnostic intensity for chronic illness. Among older Americans, the probability of receiving an ADRD diagnosis was estimated according to regional ADRD diagnosis intensity.Result3.0% (143,029 of 4,842,034) of older adults received a new ADRD diagnosis in 2019 and ranged from 1.7‐5.4% across HRRs (Figure 1). The unadjusted mean ADRD diagnosis rate was 2.9 per 100 and differed by age (age ≥ 85 = 8.8/100, 75‐84 = 3.4/100, and 65‐74 = 1.0/100, p<.001) and race (White = 2.9/100, Black 3.4/100, and Hispanic 2.8/100, p<.001). Variability across HRRs was largest among the youngest age category, Black, and Latino groups. In adjusted analyses, all the regional characteristics explained 33% of the variation in new ADRD diagnosis (pseudo‐R2 = 0.33). Adjusted for regional characteristics, the ADRD diagnosis intensity (i.e., O:E ratio) varied from 0.7 to 1.4 across HRRs overall (Figure 2) and was most variable among the youngest age category (65‐74), Black, and Latino groups. These groups also had the greatest difference in the likelihood of diagnosis if residing in low versus high ADRD diagnosis intensity (Figure 3).ConclusionThe likelihood of receiving an ADRD diagnosis varies across the U.S., particularly among those 65‐74 years of age, and Black, and Latino groups.
Temporal lobe function during memory encoding in older individuals prior to the onset of cognitive impairment
Authors: Beason‐Held Lori L , Shafer Andrea T , Calcagno Nicole , Kitner‐Triolo Melissa , Resnick Susan M. 
Published: December 2023

AbstractBackgroundPrevious studies have shown that resting state brain function begins to change in the years leading up to the development of cognitive impairment. This study examines temporal lobe function during memory encoding approximately 2.5 years before the onset of cognitive impairment in Baltimore Longitudinal Study of Aging (BLSA) participants.MethodsBLSA participants with subsequent memory impairment (Subsequently Impaired (SI), n = 22, mean age = 83.6, time to impairment = 2.5 ± 1.1 SD years post‐scan) and age, sex, and education matched cognitively normal participants (Cognitively Normal (CN), n = 64, mean age = 84.9) performed a face‐scene encoding task during fMRI scanning. Group differences in task performance and brain activation patterns were examined during encoding trials they later remembered, and trials they later forgot during the recognition phase of the task.ResultsThe SI group performed more poorly than the CN group during the recognition phase of the task. Both CN and SI activated the occipitotemporal visual pathway during memory encoding. Yet relative to CN participants, the SI group showed decreased activation of the hippocampus, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus during encoding of face‐scene pairs. This decreased activation was seen during both encoding of pairs they later remembered and pairs they forgot during recognition.ConclusionsBoth memory dysfunction and decreased temporal lobe activity during encoding begin before the onset of clinically evident cognitive impairment. In the SI group, the decreased temporal lobe activation was seen regardless of whether they later remembered or forgot the face‐scene pairs during the recognition task. This suggests that those who go on to develop impairment have an overall weaker functional response in temporal lobe regions during memory encoding. Further examination of the functional connectivity of these regions may help to determine if differences in brain network characteristics are related to subsequently remembered or forgotten visual stimuli during encoding.This work was supported by the Intramural Research Program of the NIH, National Institute on Aging.
Geographic variation of prevalence of Alzheimer’s Disease and related dementias in the Central Appalachian region of the United States
Authors: Wing Jeffrey , Rajczyk Jenna , Burke James 
Published: December 2023

AbstractBackgroundAreas within the Appalachian region may have a greater burden of under diagnosed Alzheimer’s disease and related dementias (ADRD). As rural areas have lower reported ADRD prevalence compared to urban areas in spite of lower educational attainment (which should lead to higher ADRD prevalence) this argues that the true burden of ADRD is likely underestimated in areas without adequate detection resources. There is need to understand if ADRD prevalence is truly lower in rural areas, or if this is a disease detection difference. The objective of this proposal is to assess the burden of ADRD in Central Appalachia.MethodsCenters for Medicare and Medicaid Services Public Use Files from 2015‐2018 were used to estimate county‐level ADRD prevalence among all fee‐for‐service beneficiaries in Central Appalachia (Kentucky, North Carolina, Ohio, Tennessee, Virginia, and West Virginia). Negative binomial regression was used to estimate prevalence overall, by Appalachian Regional Commission’s Appalachian/non‐Appalachian designation, and by rural/urban (Rural‐Urban Continuum Codes) classification. Models were then adjusted for county‐level demographics including age, gender, Medicaid eligibility, and comorbidities (atrial fibrillation, chronic kidney disease, depression, diabetes, heart failure, hyperlipidemia, hypertension, ischemic heart disease, schizophrenia/other psychotic disorders, and stroke).ResultsThe prevalence of ADRD did not vary over the time period but was higher for Appalachian counties both overall (12.0% vs. 11.6%; p = 0.001; Figure 1) and among both urban (p<0.001) and rural counties (p = 0.024; Figure 2). Urban Appalachian counties had 2‐4% higher prevalence compared to urban non‐Appalachian counties with this difference reaching statistical significance in 2017 and 2018. While a similar trend was observed in rural counties (Appalachian counties having 1‐3% higher prevalence), these yearly ratios did not reach statistical significance. After adjustment, the associations attenuated in urban counties, but over the entire study period, rural Appalachian counties had 2.2% higher prevalence than rural non‐Appalachian counties (Figure 3).ConclusionThere is a consistent difference between Appalachian and non‐Appalachian counties, demonstrated overall and by rural status, with Appalachian counties having ADRD prevalence in the range of 1.0‐4.5% higher than non‐Appalachian counties. However, while county‐level demographics and comorbidities explained the difference in urban counties, the elevated prevalence in rural‐Appalachian counties persisted.
Design, Molecular Docking, Synthesis and Evaluation of Xanthoxylin Hybrids as Dual Inhibitors of IL‐6 and Acetylcholinesterase for Alzheimer’s Disease
Authors: Kaur Sukhvir , Bansal Yogita 
Published: December 2023

AbstractBackgroundIL‐6 and AChE play a pivotal role in progression of AD, it is hypothesised that simultaneous inhibition of IL‐6 and AChE may prove as an effective strategy for treatment of AD. Therefore, the present study is undertaken to design novel molecules capable of acting as dual inhibitors of IL‐6 and AChE. Literature review reveals that xanthoxylin and a disubstituted amines or a carbamoyl amines are pharmacophores for IL‐6 and AChE inhibition, respectively.MethodXanthoxylin is coupled with various disubstituted amines or carbamoyl amines through alkyl linkers of different lengths (1‐4 carbon atoms) to design two series of 80 compounds. All designed compounds were docked into AChE to identify the best fit compounds for synthesis and evaluation of AChE inhibitory activity. The compounds showing >45% inhibition of EeAChE are selected for evaluation of IL‐6 and butyrylcholinesterase (BuChE) inhibitory activities. The compound found to be most potent against AChE, BuChE and IL‐6 inhibition was finally evaluated in vivo using STZ‐induced amnesia model in mice at three doses (0.2, 0.4 and 0.8 mg/kg).ResultCompound K13g is found to be the most potent inhibitor of EeAChE, BuChE and IL‐6. It is further evaluated in vivo, wherein it shows dose‐dependent effects. It is observed to be less active at lower doses, but completely reversed the STZ‐induced memory deficit at 0.8 mg/kg.ConclusionThe findings suggest that a compound having a xanthoxylin moiety connected to a piperazine ring through a three‐carbon atom chain may provide a useful template for the development of new chemical entities effective against AD.
Increased medial temporal lobe functional connectivity is critical in Alzheimer’s disease: evidences from longitudinal analyses across the whole cognitive continuum
Authors: Chauveau Léa , Landeau Brigitte , Dautricourt Sophie , Delarue Marion , Hébert Oriane , la Sayette Vincent De , Chetelat Gael , de Flores Robin 
Published: December 2023

AbstractBackgroundThe medial temporal lobe is extensively connected to the whole brain through two functional networks: the anterior‐temporal (AT) and posterior‐medial (PM) systems. While both increased and decreased functional connectivity (FC) have been reported in Alzheimer’s disease (AD), the specific changes in each network and their clinical relevance throughout AD stages remain to be elucidated. To fill this gap, we aimed to provide a comprehensive overview of AT‐ and PM‐FC changes, and links with AD imaging‐biomarkers, clinical severity and dementia onset, using longitudinal data covering the whole cognitive continuum.MethodLongitudinal data were acquired in 209 cognitively unimpaired (CU) adults aged 19‐85 (n = 56 Aβ‐ over 60), 26 Aβ+ patients with mild cognitive impairment (MCI) (n = 18 AD‐converters), and 26 Aβ+ AD‐demented patients, all followed up to 4 years. All underwent resting‐state (rs)‐fMRI, T1‐w MRI, Florbetapir‐ and FDG‐PET. Connectivity maps were generated from seed‐to‐voxels analyses applied to rs‐fMRI using individual ROIs (AT = perirhinal cortex, PM = parahippocampal cortex). The networks were defined by comparing baseline CU Aβ‐ AT to PM maps (and vice‐versa) using paired permutation t‐tests with FWE correction. Mean FC was then extracted from these masks for each participant. Generalized additive and linear mixed models were run to assess AT‐ and PM‐FC changes across the whole cognitive continuum, and their relationships with i)‐amyloid uptake, ii)‐glucose metabolism, iii)‐hippocampal volume and iv)‐cognitive deficit within participants>60yo, and v)‐AD‐conversion time in MCI patients.ResultResults showed that AT‐FC linearly increased from younger to Aβ+ AD‐demented adults while PM‐FC decreased along the healthy lifespan and then remained stable across the AD continuum (Aβ+ individuals). Higher AT‐FC was associated with i)‐higher amyloid uptake, ii)‐lower glucose metabolism, iii)‐smaller hippocampal volume, iv)‐lower MMSE/Mattis scores and v)‐faster AD‐dementia onset. No such relationships were found with PM‐FC.ConclusionBy encompassing the whole cognitive continuum and assessing longitudinal changes, we highlighted that AT‐ and PM‐FC alterations differ in aging and AD. While reduced PM connectivity seems restricted to age‐related processes (corroborated by no correlation with AD‐signature changes), increased AT connectivity seems to result from specific AD‐related mechanisms. Importantly, we evidenced that AT hyper‐connectivity appears critical in AD and might predict clinical and pathological outcomes.
Volume of the posterior and not anterior hippocampus predicts spatial memory performance in Alzheimer´s Disease
Authors: Kara Esra , Toelke Sophia , Onur Oezguer A. 
Published: December 2023

AbstractBackgroundHippocampal volume atrophy is one of the most acknowledged supportive biomarkers for Alzheimer´s disease (AD). However, how hippocampal volumes along the anterior‐posterior axis mediate memory in aging and dementia is still subject of ongoing research. This study aimed to investigate the difference in volume of the hippocampus and its anterior and posterior subregions in a healthy young and senior control group as well as in mild cognitive impairment (MCI) due to AD and its ability to predict performance in spatial memory tasks.MethodThirteen healthy young controls (24.9 ± 2.8 years), fourteen healthy senior controls (66.6 ± 8.2 years) as well as fifteen MCI patients (71.1 ± 6.0 years) with biomarkers typical for AD were included in this study. Subject‐specific manual tracing of hippocampi according to the EADC‐ADNI Harmonized Protocol for Hippocampal Segmentation (HarP) was performed on high‐resolution T1‐weighted MRI. Following the segmentation into anterior and posterior hippocampal parts, volumetry of anterior, posterior and total hippocampus was computed. Every subject performed a combined spatial memory and object recognition paradigm. Brain‐behavior correlations were conducted in order to explore prediction of spatial memory performance.ResultVolume measures of the hippocampi significantly differentiated healthy from pathological aging. Larger volume of posterior hippocampus in MCI patients correlated with higher performance scores in the spatial memory task (mean percentage of successfully retrieved object locations) whereas total and anterior hippocampal volume did not predict performance in the spatial memory task.ConclusionThese results support a functional hippocampal anterior‐posterior differentiation in memory processes and further stress the importance of integrating the dissociation of the hippocampus along its long‐axis concerning functional connectivity in memory processes and dementia.
Deletion of miR‐155 in microglia enhances their response to neurodegeneration and mitigates cognitive impairment in a mouse model of Alzheimer’s disease
Authors: Yin Zhuoran , Herron Shawn , Silveira Sebastian , Kleemann Kilian , Gauthier Christian , Mallah Dania , Cheng Caterina , Margeta Milica , Pitts Kristen , Barry Jen‐Li , Subramanian Ayshwarya , Shorey Hannah , Brandao Wesley N , Durao Ana , Delpech Jean Christophe , Madore Charlotte , Jedrychowski Mark P , Ajay Amrendra K. , Gopal Murugaiyan , Hersh Samuel Walter , Ikezu Seiko , Ikezu Tsuneya , Butovsky Oleg 
Published: December 2023

AbstractBackgroundMicroglia, the resident brain immune cells, play a critical role in brain homeostasis and disease progression. In neurodegenerative conditions, microglia acquire the neurodegenerative phenotype (MGnD), whose function is poorly understood. MicroRNA‐155 (miR‐155), enriched in immune cells, critically regulates MGnD. However, its role in Alzheimer’s disease (AD) pathogenesis remains unclear.MethodsWe used RNAseq and immunohistochemistry (n = 6‐8 per sex per group) to investigate the gene expression profile and AD pathology. We further utilized single‐cell RNAseq (n = 5 per group) to identify microglial clusters. Whole‐tissue proteomics (n = 4) was applied to detect the protein changes in brain milieu. Moreover, we used spontaneous alternation and forced alternation tests to evaluate the cognition (n = 33‐36).ResultWe report that microglial deletion of miR‐155 induces a pre‐MGnD activation state via interferon‐g (IFNg) signaling and blocking IFNg signaling attenuates MGnD induction and microglial phagocytosis. Single‐cell RNAseq analysis of microglia from AD mouse model identifies Stat1 and Clec2d as pre‐MGnD markers. This phenotypic transition enhances amyloid plaque compaction, reduces dystrophic neurites, attenuates plaque‐associated synaptic degradation, and improves cognition.ConclusionOur study demonstrates a novel miR‐155‐mediated regulatory mechanism of MGnD and the beneficial role of IFNg‐responsive pre‐MGnD in restricting neurodegenerative pathology and preserving cognitive function in an AD mouse model, highlighting miR‐155 and IFNg as potential therapeutic targets for AD.
Associations of orthostatic hypotension and frailty with dementia and mortality in older adults: a cohort study
Authors: Xia Xin , Tazzeo Clare , Jönsson Linus , Qiu Chengxuan , Rizzuto Debora , Laukka Erika J , Okoye Chukwuma , Grande Giulia , Fratiglioni Laura , Vetrano Davide Liborio 
Published: December 2023

AbstractBackgroundOrthostatic hypotension (OH) has been considered a frailty marker and is associated with a higher risk of dementia and mortality. We sought to assess whether OH is associated with dementia and mortality in older adults while taking onto account frailty.MethodWe conducted a population‐based cohort study of 2703 dementia‐free individuals (mean age: 73.7; 63.3% females) from the Swedish National Study on Aging and Care in Kungsholmen, regularly followed from 2001‐2004 to 2016‐2019. OH was defined as systolic/diastolic blood pressure drops ≥20/10 mmHg one minute after standing up from a supine position. Fried’s frailty phenotype was used to assess frailty/pre‐frailty. Dementia was diagnosed following the DSM‐IV criteria. Individuals were cross‐classified into four groups based on their OH and frailty status and followed until dementia diagnosis, death, or dropout, whichever came first. Flexible parametric survival models with follow‐up time as the time scale were applied to estimate the associations of OH and frailty with dementia and mortality, adjusting for age, sex, education, vascular risk factors, and comorbidities. We also tested the interaction between OH and frailty on dementia or mortality risk on the multiplicative and additive scales.ResultDuring the follow‐up period, 418 (15.5%) individuals developed dementia, and 933 (34.5%) died without dementia. Compared with OH‐free and robust people, robust people with OH (adjusted HR = 1.90; 95% CI = 1.27‐2.86) had a higher risk of developing dementia. Pre‐frail/frail people without OH (HR = 1.67; 95% CI = 1.22‐2.28) and pre‐frail/frail people with OH (HR = 2.36; 95% CI = 1.62‐3.42) also had a higher dementia risk. Robust people with OH did not have a higher mortality hazard (HR = 1.11; 95% CI = 0.83‐1.48), but pre‐frail/frail people without OH (HR = 1.25; 95% CI = 1.04‐1.51) and pre‐frail/frail people with OH (HR = 1.55; 95% CI = 1.23‐1.94) had a higher mortality hazard than robust and OH‐free people. There was no evident interaction between OH and frailty on dementia or mortality risk on either the multiplicative or additive scale.ConclusionOlder adults with OH, whether robust or frail, may have a higher dementia risk than those without OH. Robust older adults with OH do not seem to have a higher mortality rate than robust older adults without OH.