bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unmet Needs in the Diagnosis and Management of Early AD in Community‐Based Settings in the United States
Authors: Juday Timothy R , Holub Ashley A , Betts Keith A. , Mattke Soeren , Kitchen Sophie A , Liu Hongjiao , Malik Amyn , Batrla Richard , Frech Feride H , Khachaturian Ara S 
Published: January 2025

AbstractBackgroundDisparities in the quality and timeliness of care for Alzheimer’s disease (AD) are well documented. This study assessed the impact of demographic characteristics on the diagnosis and management of early AD patients in community‐based settings.MethodThis cross‐sectional study abstracted medical chart data for patients aged 50‐89 years who had newly diagnosed early AD (mild cognitive impairment [MCI] or mild AD) within the past 2 years and a clinic visit within the past 12 months. Data collected included use of neurocognitive assessments, imaging/biomarker tests, laboratory tests, referrals, and treatments. Descriptive statistics were stratified by patient age at diagnosis, sex, race, and residence.ResultA total of 1284 early AD patients (817 MCI/467 mild AD) had a mean age at diagnosis of 70 years, 43% were female, 31% were non‐white, and 17% were rural. The number of visits from initial complaint to diagnosis was lower (2.6 vs 3.0, p<0.001), and time to referral consult was faster (20.9% vs 54.4% waited ≥4 months, p<0.001) for patients ≥65 relative to <65 years. Biomarker/imaging tests were also more common (78.2% vs 72.4%, p<0.05), and beta‐amyloid medications were less frequently prescribed (3.0% vs 15.6%, p<0.001). Practices were similar for female and male patients. Non‐white patients had a longer time to diagnosis (5.5 vs 4.6 months, p<0.01) and were less likely to receive any neurocognitive assessments (80.1% vs 85.5%, p<0.05) than white patients. APOE‐e4 testing was more often used in non‐white patients (20.9% vs 17.5%, p<0.01). Urban/suburban patients were more likely to receive the ADAS‐Cog (19.2% vs 11.6%, p<0.01), while rural patients were more likely to receive the MoCA (28.2% vs 18.9%, p<0.01). Rural patients were less likely to be prescribed beta‐amyloid medications (2.3% vs. 6.5%) and more likely to wait at least 4 months for a prescription (80.0% vs.45.6%).ConclusionInitiatives that shorten the time to diagnosis and to referral consults in patients aged <65, and that promote the use of neurocognitive assessments in non‐white patients may help close the gap. As early detection and treatment are critical to optimize patient outcomes, more effort needs to be focused on reducing care disparities.
Unveiling the Multifaceted Neuroprotection of Dihydroxytrimethoxyflavone: Memory Enhancement Beyond Cholinergic Boost
Authors: Singh Varinder , Singh Manjinder , Shri Richa 
Published: January 2025

AbstractBackgroundSeveral studies have shown the influential role of nutraceuticals on cognition and mental functions. Dihydroxytrimethoxyflavone, a natural flavone found in herbal drugs, is documented to be neuroprotective in different model systems. Nevertheless, possible memory improvement effects of dihydroxytrimethoxyflavone via nuclear factor‐E2‐related factor 2 (Nrf2) (a crucial regulator of antioxidative system) has not been systematically evaluated. Thus, the present study was aimed to investigate the memory improvement effects of dihydroxytrimethoxyflavone in mouse model of lead induced memory impairment and to reveal the possible molecular mechanism involving Nrf2, oxidative stress, cholinergic signalling and beta amyloid.MethodMemory impairment in mice was induced by administering lead acetate for 28 days. Dihydroxytrimethoxyflavone (5‐10 mg/kg, p.o.) was administered daily to animals 60 min prior to lead acetate for 28 days. Memory functions (Morris Water Maze), brain acetylcholinesterase (AChE) activity, oxidative stress, beta amyloid and histopathological studies (H&E and congo red staining for beta amyloid) were determined to measure memory improvement effects of dihydroxytrimethoxyflavone.ResultDihydroxytrimethoxyflavone showed improvement in memory of animals. It reduced acetylcholinesterase activity and beta amyloid levels. Further, dihydroxytrimethoxyflavone could significantly increase antioxidant enzymes, Nrf2 expression and its nuclear translocation as well as its downstream antioxidant protein expression, NAD(P)H/quinone oxidoreductase 1 and heme oxygenase‐1.ConclusionDihydroxytrimethoxyflavone improved memory in animals via activating Nrf2‐mediated antioxidant pathway, increasing antioxidant defence and inhibiting and amyloid protein burden. Thus, dihydroxytrimethoxyflavone may have beneficial effects in lowering the onset of dementia.
The Role of Blood‐Based Proteomic Biomarkers in Sleep Spindle‐Slow Oscillation Coupling and Incident Dementia
Authors: Chen Zachary Xin , Zhang Can , Mondal Prasenjit , Benitez Bruno A. , Sun Haoqi 
Published: January 2025

AbstractBackgroundSleep is impaired in dementia. Therefore, sleep has been proposed as an intervention target for incident dementia. The microstructures of sleep electroencephalography (EEG), such as spindle, slow oscillation (SO), and their coupling, have neuronal bases and functions in learning and memory. Higher spindle‐SO coupling is linked to lower risk of incident dementia in epidemiological studies. Here, we aim to use proteomics to explore the molecular basis of this link.MethodThis retrospective study used the Framingham Heart Study (FHS) Offspring and OMNI 1 Cohorts, accessible through BioLINCC. The inclusion criteria are (1) plasma proteomics available, where the blood was drawn at FHS‐Exam5 and profiled using SOMAscan (1373 proteins); (2) sleep EEGs from the Sleep Heart Health Study on National Sleep Research Resources obtained at FHS‐Exam6. The exclusion criteria are (1) missing covariates: age, sex, education, APOE ε4 allele, body mass index, and smoking; (2) pre‐existing dementia before sleep recording. Spindle‐SO coupling was defined as the fraction of spindles within SO at N2 or N3 stages of sleep, detected using Luna. Incident dementia was based on FHS consensus. We performed a proteome‐wide association study (PWAS) for spindle‐SO coupling using Spearman’s correlation. We also performed PWAS for incident dementia using Fine‐Gray survival analysis with death as competing risk. We then found the common proteins between the two PWASes. Since the proteins were from the blood, we filtered them by assessing their blood‐brain expression correlations using Genotype‐Tissue Expression.ResultThe PWAS for incident dementia had n=1048 (52% female) with maximum 47‐year follow‐up, revealing 35 proteins reaching Bonferroni‐corrected significance. In contrast, the PWAS for spindle‐SO coupling had n=146 (57% female), with no Bonferroni‐corrected significance. There were 28 proteins common to both PWASes before Bonferroni correction. Among them, intercellular adhesion molecule 2 (ICAM2), C‐reactive protein, and myoglobin demonstrated significant blood‐brain correlations, with ICAM2 exhibiting brain‐wide expression (Figure 1). One standard deviation increase in ICAM2 is associated with hazard ratio of 0.48 (95% confidence interval 0.23‐0.99, p=0.048) for incident dementia. ICAM2 and spindle‐SO coupling have Spearman’s correlation at 0.24 (0.08‐0.39, p=0.0036).ConclusionICAM2 may serve as the proteomic basis for the association between spindle‐SO coupling and incident dementia.
Loneliness, dementia status and their association with all‐cause mortality among older US adults
Authors: Georgescu Michael F , Beydoun May A , Ashe Jason , Vieytes Christian A Maino , Beydoun Hind A , Evans Michele K , Zonderman Alan B 
Published: January 2025

AbstractBackgroundLoneliness, dementia, and mortality are interconnected. Thus, understanding the pathways, along with their potential interaction provides a relevant area of research to be developed.MethodThe study tested bi‐directional relationships between dementia, loneliness and mortality, while examining both interactions and mediating effects in a large sample of older US adults participating in the nationally representative Health and Retirement Study. Out of ≤6,468 older participants selected in 2010, with mean baseline age of 78.3 y and a follow‐up time up to end of 2020, 3,298 died with a rate of 64 per 1,000 P‐Y. Cox proportional hazards models were used, stratifying by sex, race and interaction between loneliness scores (continuous or tertiles) and dementia status or Loge(odds) were examined. Four‐way decomposition models were also carried out to test bi‐directional mediation and interaction between dementia odds and loneliness in relation to mortality risk.ResultProbable dementia was consistently linked to over two‐folds increased mortality risk. The presence of dementia and Loge(odds) were equally strongly related with mortality risk across tertiles of loneliness score. The study also found that the loneliness z‐score was linked to an elevated risk of mortality regardless of age, sex, or race or ethnicity, and that its total effect (TE) on mortality was partially mediated by Loge odds of dementia (z‐scored), with up to 40% of TE being a pure indirect effect. In contrast, a very small proportion (<5%) of the TE of dementia odds (Loge transformed, z‐scored) on mortality risk was explained by the loneliness z‐score.Conclusiontransformed, z‐scored) on mortality risk was explained by the loneliness z‐score. Conclusions. In sum, dementia was positively associated with mortality risk, in similar fashion across loneliness score tertiles, while loneliness was associated with mortality risk in the overall sample. The total effect of loneliness on mortality risk was partially mediated by dementia probability, particularly when models were only adjusted for age, sex, and race/ethnicity.
Development and analytical validation of AB40, AB42, A‐Syn, CD33, P‐Tau 181, Tau, and TREM2 in human serum, plasma, or CSF
Authors: Surls Jacqueline , Ibanez Robyn Vega , Brown Lindsey , Kemp Josh 
Published: January 2025

AbstractBackgroundMeasurement of blood‐based biomarkers for Alzheimer disease is simpler and more accessible when compared to CSF. We report the development and validation of seven Simoa® immunoassays for the detection of AB40, AB42, A‐Syn, CD33, P‐Tau 181, Tau, and TREM2 in human serum, plasma, or CSF.MethodUsing the Quanterix® Simoa® technology (SR‐X) platform, AB40, AB42, A‐Syn, CD33, P‐Tau 181, Tau, and TREM2 were developed and analytically validated in human serum, plasma, or CSF per CLSI standards.ResultWe have developed and analytically validated Simoa® immunoassays to detect AB40, AB42, A‐Syn, CD33, P‐Tau 181, Tau, and TREM2 in human serum, plasma, or CSF. The assays met acceptance criteria for sensitivity, precision, stability, interference, and parallelism. The calibration curves in serum/plasma were linear from 16‐2000 pg/mL for AB40, 18‐40,000 pg/mL for AB42, 0.13‐80 ng/mL for A‐Syn, 0.012‐60 ng/mL for CD33, 0.60‐3000 pg/mL for P‐Tau 181, 0.12‐600 pg/mL for Tau, and 0.30‐38 ng/mL for TREM2. For CSF, the linear ranges were from 626‐80,000 pg/mL for AB40, 72‐160,000 pg/mL for AB42, 0.013‐8.0 ng/mL for A‐Syn, 0.012‐60 ng/mL for CD33, 30‐150,000 pg/mL for P‐Tau 181, 0.30‐1500 pg/mL for Tau, and 0.60‐76 ng/mL for TREM2. The three quality controls met inter assay precision with %CV ≤16% for levels 1 and 2, and ≤20% for level 3 across all analytes. No interference was observed with bilirubin, hemoglobin, or triglyceride. The sensitivity of the assays in human serum/plasma was demonstrated by the LLOQ values of 28 pg/mL, 47 pg/mL, 0.20 ng/mL, 0.11 ng/mL, 2.8 pg/mL, 0.22 pg/mL, and 0.59 ng/mL for AB40, AB42, A‐Syn, CD33, P‐Tau 181, Tau, and TREM2, respectively. For human CSF, the LLOQ values of 1139 pg/mL, 187 pg/mL, 0.020 ng/mL, 0.11 ng/mL, 142 pg/mL, 0.56 pg/mL, and 1.2 ng/mL for AB40, AB42, A‐Syn, CD33, P‐Tau 181, Tau, and TREM2 in human CSF, respectively. The stability of the analytes was established under various conditions, such as freeze‐thaw cycles, short‐term and long‐term storage.ConclusionThese assays demonstrated acceptable performance for clinical implementation as research use only and may be useful for blood‐based biomarker studies in clinical trials.
Elevating brain GLP‐1 and GIP levels as a treatment strategy for neurodegenerative disorders
Authors: Greig Nigel H , Wang Yun , Hoffer Barry J , Sambamurti Kumar , Lahiri Debomoy K. , Tones Michael A , Zaleska Margaret M , Mattison Julie A 
Published: January 2025

AbstractBackgroundEpidemiological studies report an elevated risk of neurodegenerative disorders, particularly Parkinson’s disease (PD), in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed incretin mimetics or dipeptidyl peptidase 4 inhibitors (DPP‐4Is). Incretin mimetic repurposing appears promising in human PD and Alzheimer’s disease (AD) clinical trials. DPP‐4Is are yet to be evaluated in PD or AD human studies.MethodsIncretin mimetics have been evaluated in multiple cellular/animal PD models, including in 6‐hdroxydopamine (6‐OHDA) rats, and have demonstrated efficacy. The clinically approved DPP‐4Is, sitagliptin (Januvia) and PF‐00734200 (gosogliptin/Saterex) were hence evaluated in the classic 6‐OHDA unilateral medial forebrain bundle rat PD model to evaluate their repurposing potential when administered as human equivalent oral doses. Equivalent doses then were administered to naive nonhuman primates (NHPs) to evaluate whether biomarkers of efficacy in rat could be reproduced in NHPs as a further translational step towards human studies. Pharmacokinetics, DPP‐4 inhibition, GLP‐1/GIP and dopamine levels, together with dopaminergic and neuroinflammatory markers, and GLP‐1/GIP receptor levels were quantified.ResultsSitagliptin/PF‐00734,200 pre‐ or post‐treatment mitigated 6‐OHDA‐induced dopaminergic neurodegeneration, dopamine level loss and neuroinflammation, and augmented neurogenesis in lesioned substantia nigra pars compacta and in striatum, and reduced classical methamphetamine‐induced rotation in rats. This efficacy associated with 70‐80% plasma and 20‐30% brain DPP‐4 inhibition, and with elevated plasma and brain GLP‐1/GIP levels. Alike plasma/CSF DPP‐4 inhibition and elevated GLP‐1/GIP levels were determined in NHPs administered rat equivalent (human translational) sitagliptin doses. In relation to the drug targets, brain GLP‐1/GIP receptor protein levels were age‐dependently maintained in rodents, preserved in rats challenged with 6‐OHDA, and in humans with PD. Combined GLP‐1+GIP receptor activation in neuronal cultures resulted in neurotrophic/neuroprotective actions superior to single agonists alone – particularly when combined with a DPP‐4IConclusionsThese studies support further evaluation of repurposing clinically approved drugs that elevate plasma/brain/CSF GLP‐1/GIP as a treatment strategy for neurodegenerative disorders. Incretin mimetics are already in clinical evaluation in PD and AD. Similarly, the repurposing of gliptins warrants evaluation both alone and in combination with an effective incretin mimetic.
The role of social support and social contact in cognitive aging: A study of sex/gender and sexuality in the Health and Retirement Study
Authors: Hanes Douglas William , Stinchcombe Arne , Clouston Sean A.P. 
Published: January 2025

AbstractBackgroundSexual‐minority (e.g., lesbian, gay, bisexual [SM]) people may be at an increased risk of Alzheimer’s disease or a related dementia (ADRD) from stress related to experiences of minoritization. Strong levels of social contact and social support decreases dementia risk; these effects may differ by sex/gender and sexuality. The purpose of this presentation is to elucidate the relationship between cognitive function, social support, and social networks with a focus on sexuality and sex/gender.MethodData analyzed were from waves 8‐14 (2006‐2018) of the Health and Retirement Study, a longitudinal survey of U.S. residents aged ≥51 years (N = 18,183). Participants who reported their sexual orientation as lesbian, gay, or bisexual, or those in same‐sex relationships for at least one wave were classified as SMs. A gender/sexuality variable was created with four levels: SM‐women (n = 101), heterosexual women (n = 9,942), SM‐men (n = 106), and heterosexual men (n = 8,034). Social contact and support were reported for network size, frequency of contact, and quality of interactions across four relationships: spouses, children, family, and friends. Cognitive function was measured on a 27‐point scale. The primary analysis consisted of a series of multiple linear regression models, treating cognition as the outcome, and adjusting for age, wealth, education, and race.ResultDescriptive analysis showed that SM‐men and SM‐women tended to be younger and join the study later than heterosexual men and women, and at baseline, heterosexual men had lower cognitive scores compared to the other three groups (F = 82.44, p<0.001). Moderation analysis showed the relationship between positive spousal support and cognition was inconsistent across gender/sexuality groups (χ2 = 11.58, p = 0.009); SM‐women did not benefit from positive spousal support as much as other gender/sexuality groups. Greater frequency of social contact was associated with higher cognitive function, except among SM‐women where greater social contact was associated with lower cognitive function (χ2 = 9.65, p = 0.023). Support from other social groups did not have differential effects across gender/sexuality groups.ConclusionFindings highlighted variable and gendered effects of social support and social contact on cognitive functioning in aging SM people. Examining differential effects for SM/gender groups is essential to inclusive ADRD research.
Reproducibility Challenges in Brain PET Data Analysis
Authors: Naseri Maryam , Carmichael Owen T. , Pillai Sreekrishna R. 
Published: January 2025

AbstractBackgroundWhile a great deal of recent effort has focused on addressing a perceived reproducibility crisis within brain structural magnetic resonance imaging (MRI) and functional MRI research communities, less attention has been paid to reproducibility of brain positron emission tomography (PET) research.MethodsWe examined the current landscape of factors that contribute to reproducible neuroimaging data analysis, comparing brain MRI to brain PET. The factors included scientific standards, analytic plan pre‐registration, data and code sharing, containerized workflows, and standardized processing pipelines. To demonstrate the positive impact that further developing such reproducibility factors would have on brain PET research, we conducted one case study in which the brain PET processing pipeline developed for one flagship study (Alzheimer's Disease Neuroimaging Initiative, ADNI) for brain 18F‐florbetapir and 18F‐fluorodeoxyglucose (FDG) analysis was reproduced in our laboratory.ResultsCompared to fMRI, PET research encounters substantial challenges in adopting essential reproducibility practices. While 85% of fMRI studies adhere to the standardized reporting practices, PET is in the early stages of establishing reporting practices, lacking a standardized checklist. Pre‐registration is prevalent for fMRI (57.6%) but notably absent in PET, with no pre‐registered PET studies found on platforms such as the Center for Open Science. The number of shared datasets is higher for fMRI compared to PET, with 92 fMRI datasets and only 9 PET datasets on repositories like OpenNeuro. Moreover, there are very few data repositories for newer PET radiotracers. Containerized software availability also favor fMRI, with platforms like (Brain Imaging Data Structure, BIDS) apps hosting 66% dedicated fMRI tools, while no PET‐specific software is available. Standardized processing pipelines follow the same trend, with fMRI boasting optimized workflows for specific protocols, while PET has few dedicated pipelines and lacks validation studies for existing options. Furthermore, while our case study demonstrated excellent correlation results for both the 18F‐FDG and 18F‐florbetapir methods (Figure 2), the replication of the ADNI PET pipeline posed substantial challenges and implementation delays. These obstacles and delays in execution were due to incomplete documentation and ambiguities in application details.ConclusionPET neuroimaging lags behind its MRI‐related counterparts in achieving robust reproducibility.
History of adverse pregnancy outcomes and cognitive decline among older adults: the Adult Changes in Thought study
Authors: Tom Sarah E. , Harrington Laura B , Chau Kristi , Wartko Paige D , Muiruri Roxanne , Krakauer Chloe , McEvoy Linda K. , LaCroix Andrea Z. , Miller Eliza C. 
Published: January 2025

AbstractBackgroundWhether history of adverse pregnancy outcomes (APOs) contributes to cognitive decline in later life is not understood because few cohorts have information on pregnancy history and later‐life cognition. We hypothesized that history of any APO would be related to lower global cognition and faster cognitive decline among older adults, compared to no APO history.MethodThe Adult Changes in Thought (ACT) Study is a prospective cohort study embedded in an integrated health care system of adults aged 65 and older without dementia at enrollment. Among ACT participants enrolled between 1994 and 2020 (n = 5,763, 58% women), women eligible for our study were born in 1940 or later, had evidence of ≥1 child or pregnancy, and had maternal or pregnancy information in their medical record (n = 444). APOs of interest were preterm birth, hypertensive disorders of pregnancy (including gestational hypertension and preeclampsia), low birth weight, small for gestational age, and stillbirth. Cognition at ACT enrollment and every two years thereafter was assessed by the Cognitive Abilities Screening Instrument, a 40‐item instrument of global cognition, further processed using item‐response theory (CASI‐IRT); points are standard deviation units of CASI‐IRT in the study population. We fit linear models using generalized estimating equations to assess associations between history of any APO with (1) cognition score and (2) cognitive decline.ResultAmong eligible participants, 13% had a history of any APO. Among people of the same age, birth cohort, education, and marital status, CASI‐IRT scores were expected to be 0.23 point lower (95% CI: ‐0.54, 0.07) among people with a history of APOs than those without; this difference did not reach statistical significance. Expected 4‐year rates of cognitive change among people with a history of APOs [‐0.01; 95% CI ‐0.25, 0.23] was not found to differ significantly from those without [0.02; 95% CI ‐0.05, 0.09].ConclusionThere is some inconclusive evidence that history of any APO may be associated with lower cognition level in older adulthood. We failed to find any convincing evidence of the association between history of APOs and the rate of cognitive decline.