bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancing Accessibility: Readability Analysis of Alzheimer’s Disease Information on Reputable Health Websites
Authors: Punukollu Manvi , Venkatesan Archana 
Published: January 2025

AbstractBackgroundAlzheimer’s disease poses significant global health challenges, particularly as people increasingly turn to online platforms for health information in the digital era. Given the intricate nature of Alzheimer’s, it is imperative to evaluate the readability of online content. This study aims to assess the readability of information related to Alzheimer’s disease on reputable health websites.MethodWe carefully selected websites based on authority and prevalence through Google, the most popular search engine. Utilizing the neutral term “Alzheimer’s” ensured a broader sample of websites. We identified common domains within the top ten search results and meticulously sorted and saved them. Texts were then extracted and cleaned using Microsoft Office Excel. To evaluate readability, we employed various readability formulas using Python. The Flesch Reading Ease Score (FRES), Flesch–Kincaid grade level (FKGL), Simple Measure of Gobbledygook (SMOG), Gunning Fog (GFOG), Coleman–Liau score (CL), automated readability index (ARI), and Linsear Write (LW) were utilized.ResultWhen comparing our readability results to the sixth‐grade level recommended by the American Medical Association and the National Institute of Health, we observed that the scores exceeded the recommended level. Findings from widely used internet resources revealed variations in readability scores across different websites. Notably, publicly accessible data related to Alzheimer’s disease tends to be presented at a higher reading level than recommended for general comprehension, carrying critical implications for patient education and health literacy within the Alzheimer’s context.ConclusionAssessing the readability of online health information for Alzheimer’s disease is crucial to ensure accessibility and comprehension for diverse audiences. This study provides valuable insights into the readability landscape of reputable health websites, uncovering a potential gap between the complexity of information and the general public’s reading ability in the context of Alzheimer’s disease. Recognizing and addressing this gap is essential for enhancing patient education and empowerment, ultimately contributing to improved health outcomes in the realm of Alzheimer’s.
Brain effects of 5:2 intermittent fasting and the healthy living diet in a randomized controlled trial
Authors: Manolopoulos Apostolos , Mullins Roger J , Delgado‐Peraza Francheska , Mustapic Maja , Nogueras‐Ortiz Carlos , Yao Pamela J. , Cookson Mark R , Egan Josephine M. , Frangou Sophia , Mattson Mark P. , Kapogiannis Dimitrios 
Published: January 2025

AbstractBackgroundInsulin Resistance (IR) is implicated in brain aging and Alzheimer’s disease (AD) pathogenesis. Dietary changes may promote brain health in older adults with metabolic abnormalities. An extensive animal literature suggests pro‐cognitive and beneficial systemic and brain effects of intermittent fasting (IF) that may mitigate AD risk. We conducted a randomized clinical trial comparing brain effects and the potential for AD biomarker modulation of IF and a continuous diet.MethodForty overweight, cognitively intact individuals > 55 years old with peripheral IR were randomized (1:1) to 5:2 IF (2 days 480 Kcal/day; 5 non‐restricted days) or Healthy Living (HL) diet by USDA recommendations for 8 weeks.ResultBoth IF and HL improved biomarkers of brain IR in neuron‐derived extracellular vesicles (NDEVs), decreased regional BrainAGE (brain‐age‐gap estimate on structural MRI) in the anterior cingulate and ventromedial prefrontal cortex, reduced glucose concentration on brain magnetic resonance spectroscopy (MRS) indicating optimized metabolism, and improved executive function and memory. Moreover, both diets decreased weight, BMI, and waist circumference suggesting high compliance, and HOMA2‐IR indicating IR alleviation. They also increased blood beta‐hydroxybutyrate and acetoacetate suggesting increased ketogenesis. Although effects of IF and HL were statistically comparable, greater numerical improvements were observed with IF for several measures of brain health, cognition, and peripheral metabolism. However, cerebrospinal fluid (CSF) and NDEVs showed no changes in AD biomarkers (Aβ42, total Tau, p181‐Tau, GFAP). In exploratory analysis, effects were moderated by polymorphisms in ApoE ε4 genotype, with cognitive benefits and decreased MRS glucose solely in ε4 non‐carriers; ε4 carriers showed no cognitive benefits, no decreases in MRS glucose, but increased CSF Aβ42/Aβ40 ratio, NfL and GFAP.ConclusionBeneficial effects of HL and, especially, IF on NDEV‐derived brain IR, BrainAGE, brain glucose concentration, executive function and memory indicate that healthy diets may improve brain health even over short periods of time, albeit with no evidence for AD cascade modulation. Genetic factors, such as ApoE ε4 polymorphisms, may influence the brain’s response to diets. Future clinical trials encompassing IF and other dietary interventions and stratified by ApoE ε4 carrier status may provide avenues for slowing the pace of brain aging.
Real‐world analysis of the clinical care pathway of patients living with Alzheimer’s disease in the United States according to stage of cognitive impairment at diagnosis
Authors: Fazio‐Eynullayeva Elnara , Cotton Sarah , Jones Eddie , Kirkman Sophie , Mystkowski Paul , Mattke Soeren , Lv Lei 
Published: January 2025

AbstractBackgroundWe analyzed the clinical care pathway of patients from symptom development to diagnosis at varying stages of Alzheimer’s disease (AD) to understand the path and barriers to diagnosis.MethodsData were from the US Adelphi Real World Dementia Disease Specific Programme™ (cross‐sectional survey of physicians and their patients with retrospective data collection) between December 2022 and September 2023. Physicians (primary care physicians [PCPs] and specialists) reported patient characteristics and disease severity, and patients reported their disease experience. Patients were aged ≥50 years with probable AD based on physician diagnosis and cognitive impairment severity assessed by Mini‐Mental State Examination (MMSE) scores: 26‒29, mild cognitive impairment (MCI) due to AD; 21‒25, mild AD dementia; 11‒20, moderate AD dementia; 0‒10, severe AD dementia.ResultsOverall, 191 physicians (83 PCPs, 108 specialists) reported data for 870 patients. Mean (SD) age was 74.7 (8.4) years and 48.3% of patients were female. At initial diagnosis, 22% of patients had MMSE scores consistent with MCI due to AD, 49% mild AD dementia, 26% moderate AD dementia and 2% severe AD dementia.Irrespective of AD severity, short‐term memory loss prompted first physician evaluation for 83% of patients. Most patients (53.1%) delayed evaluation because they perceived memory issues to be a normal part of aging.Median (IQR) time between symptom onset and first evaluation was 17.3 (4.4;43.4) weeks, and time from first evaluation to diagnosis was 3.0 (0.0;13.1) weeks. Around half of patients (47.0%) were referred to a secondary physician before diagnosis, with median (IQR) time from first evaluation to referral of 8.7 (2.3;19.9) weeks. For referred patients, median (IQR) time from first evaluation to diagnosis was 9.9 (3.1;26.2) weeks.In 75.3% of cases, patients first visited a PCP (range: 71.4‐76.8%, across severity subgroups). Specialists made 57.9% of initial diagnoses versus 41.8% by PCPs; 61.9% versus 38.1%, respectively, for MCI due to AD and 57.1% versus 42.9%, respectively, for severe AD dementia.ConclusionWhile specialists and PCPs both diagnosed AD across all stages, specialists were more likely to diagnose patients in the MCI stage. Delays in AD diagnosis are common and new strategies to address these are warranted.
Hypothalamic substructural integrity is associated with age, sex and cognitive function across lifespan: A comparative analysis of two large population‐based cohort studies
Authors: Xu Peng , Estrada Santiago , Etteldorf Rika , Liu Dan , Shahid Mohammad , Frueh Deborah , Reuter Martin , Breteler Monique M.B. , Aziz N. Ahmad 
Published: January 2025

AbstractBackgroundThe hypothalamus is the body’s principal homeostatic center and plays a crucial role in the modulation of cognition. However, detailed assessments of age and sex effects on hypothalamic substructural integrity and its cognitive correlates across lifespan are still lacking. Therefore, we aimed to investigate the hypothalamic structural integrity in relation to age, sex and cognitive performance across lifespan in the general population.MethodWe used cross‐sectional data from the Rhineland Study (RS) (N = 5816, 55.2 ± 13.6 years, 58% women) and the UK Biobank Study (UKB) (N = 45076, 64.2 ± 7.7 years, 53% women), two large‐scale population‐based cohort studies. Volumes of hypothalamic structures were derived from 3T structural magnetic resonance images through application of a recently developed automatic parcellation procedure (FastSurfer‐HypVINN). The standardized cognitive domain scores were derived from extensive neuropsychological test batteries. We employed multivariable linear regressions to assess the age and sex effects on volumes of hypothalamic structures, and the relation between these volumes and cognitive function.ResultMean volumes of the total hypothalamus were 1188.4 mm3 (SD 113.6) in RS and 1101.9 mm3 (SD 119.9) in UKB. With increasing age, the volumes of total, anterior and posterior hypothalamus and mammillary bodies decreased (betas between ‐1.22 to ‐0.09 mm3/year in RS and between ‐3.84 to ‐0.49 mm3/year in UKB), and of medial hypothalamus and tuberal region increased (betas between 0.38 to 0.74 mm3/year in RS and between 0.21 to 0.68 mm3/year in UKB). Volumes of all hypothalamic structures were larger in men compared to women. Larger posterior hypothalamus volumes were associated with better global cognition (b ± standard error (SE): 0.033 ± 0.014 [RS] and 0.028 ± 0.006 [UKB], both p<0.001) and total memory (0.033 ± 0.018 [RS] and 0.015 ± 0.008 [UKB], both p,0.001), while larger anterior hypothalamus volumes were related to better executive function (0.028 ± 0.019 [RS] and 0.026 ± 0.011 [UKB], both p<0.004).ConclusionWe found strong age and sex effects on hypothalamic structures, as well as robust associations between these structures and domain‐specific cognitive functions. Overall, these findings thus implicate specific hypothalamic substructures as both markers of age‐associated cognitive decline and potential targets for future interventions.
Tau Positivity for Flortaucipir using a Commercial Tau Quantification Software: Comparison to Visual Interpretation
Authors: Fahmi Rachid 
Published: January 2025

AbstractBackground18F‐flortaucipir allows in‐vivo visualization of tau tangles in Alzheimer’s disease (AD) with a standardized definition of tau‐PET positivity. However, semi‐quantification is often used in research and in therapeutic trials and plays an important role in the AT(N) framework. This work aims to determine quantitative positivity thresholds and compare semi‐quantification to visual interpretation.MethodN=189 flortaucipir scans from A05 (NCT02016560) study were included (15 young‐controls (YC), 48 elderly cognitively unimpaired (eCU), 85 MCIs, and 41 with AD) (Table 1), wherein the scans were visually interpreted as either T+/T‐. Using a PET‐only tau quantification software, volume‐weighted SUVRs were calculated on Braak I‐II, Braak III‐IV, Braak V‐VI, and temporal‐meta region (TMR) (Figure 3). Three methods to calculate T+ cut‐points were used: (T1) Youden‐index (MCI/AD vs. Aβ‐ eCU), (T2) mean+2SDs of Aβ‐ eCU, and (T3) mean+2SDs of YC SUVRs. Using calculated cut‐points, a subject is hierarchically assigned to a Braak stage if they are T+ at that stage and at all previous stages, otherwise, the subject is Braak‐staging discordant.ResultPatients characteristics and visual A+/T+ proportions are summarized in Table 1. T1‐derived thresholds are: 1.26 (Braak I‐II), 1.18 (Braak III‐IV), 1.17 (Braak V‐VI), and 1.29 (TMR) (Table 2). TMR‐based T+ threshold using T2 was 1.30. Overall, the concordance of visual read with TMR‐based quantification was 92%, 93%, and 88.4%, and only 8/189 (4.2%), 6/189 (3.2%), and 0% subjects were Braak staging discordant, using thresholding methods T1, T2, and T3, respectively (Figure 2b). Braak staging was associated with cognitive decline (MMSE and ADAS‐Cog‐11), and with increase in A+/T+ proportions. All Braak V‐VI subjects had a T+ visual read. These subjects were also all Aβ+ MCI/ADs. However, 80% (8/10) of Braak III‐IV, 26.9% (7/26) of Braak I‐II, and 86% (44/51) of TMR+ subjects, using T1‐derived thresholds, had a T+ read, whereas 95.7% (44/46) of TMR+ subjects who were also Aβ+ had a T+ read.ConclusionUsing the temporal‐meta region, visual read and SUVR were highly concordant. Visual T+ aligns more with amyloid positivity. Hierarchical Braak staging was associated with cognitive performance and amyloid load and its concordance with visual interpretation was moderate‐to‐high for the limbic and neocortical stages.
Lower Risk of Alzheimer’s Disease and Related Dementias associated with Angiotensin Receptor II Blockers (ARBs) treatment for individuals with Hypertension in High‐volume Claims Data
Authors: Lundin Sori Kim , Hu Xinyue , Feng Jingna , Lundin Karl Kristian , Li Lu , Chen Yong , Schulz Paul E , Tao Cui 
Published: January 2025

AbstractBackgroundFindings regarding the protective effect of Angiotensin II receptor blockers (ARBs) against Alzheimer’s disease and related dementias (ADRD) and cognitive decline have been inconclusive.MethodA total of 6,390,826 hypertensive individuals were included in this study from Optum’s de‐identified Clinformatics® Data Mart. We identified antihypertensive medication (AHM) drug classes and subclassified ARBs by blood‐brain barrier (BBB) permeability. We compared baseline characteristics and used the Kaplan‐Meier (KM) survival curve and adjusted Cox proportional hazards (PH) model for survival analyses.ResultAHM non‐users (N = 1,184,809) had a lower incidence of all comorbidities and consumption of metformin and statins compared to ARBs users (N = 1,839,176) and non‐ARBs AHM users (N = 3,366,841) (all P<0.0001). The KM curve showed that ARB users had lower cumulative hazard than other AHM users or AHM non‐users (P<0.0001). In Cox PH analysis, ARB users showed a 20% lower adjusted hazard of developing ADRD compared to angiotensin‐converting enzyme inhibitor (ACEI) users and a 29% and 18% reduced risk when compared to non‐ARB/ACEI AHM users and AHM non‐users (all P<0.0001). Consumption of BBB‐crossing ARBs was linked to a lower risk of ADRD development than non‐BBB‐crossing ARBs, undetermined ARBs, and non‐consumption of AHMs by 11%, 25%, and 31% (all P<0.0001).ConclusionThis study suggests that ARBs are superior to ACEIs, non‐ARB/ACEI AHMs, or non‐use of AHMs in reducing the risk of ADRD among hypertensive patients. Also, BBB‐permeability in ARBs was associated with lower ADRD risk. There is no cure for AD, ADRD, or vascular dementia; hence, these findings are significant in preventing those disorders in an inexpensive, convenient, and safe way.
Advance Care Planning Among Diverse U.S. Older Adults with Varied Cognition Levels
Authors: Rahemi Zahra , Adams Swann Arp 
Published: January 2025

AbstractBackgroundOlder adults from minority groups often experience elevated rates of chronic diseases and cognitive impairment, coupled with lower rates of engagement in advance care planning (ACP) and comfort care as they approach end of life. The complexities of ACP and end‐of‐life care become particularly pronounced in older adults with cognitive impairment. As cognitive and decisional capacity changes, healthcare decisions are commonly delegated to family members or proxies. This can present challenges, especially when life expectations are uncertain and discussions regarding ACP have not taken place. This study explores the disparities in ACP among diverse U.S. older adults with varying levels of cognitive function.MethodSecondary data analyses were performed utilizing the 2014 Health and Retirement Study. The outcome variables assessed were the possession of a living will, durable power of attorney for healthcare (DPOAH), and both a living will and DPOAH. Logistic regression models were applied to each outcome variable (living will, DPOAH, and both) with stratification based on cognition (dementia/impaired cognition versus normal cognition). Prediction variables encompassed race, ethnicity, rurality, marital status, gender, education, age, and social support.ResultAmong the 17,698 respondents, 77.8% exhibited normal cognition, while 22.2% received a diagnosis of dementia or impaired cognition. Black and Hispanic participants, as well as younger individuals with lower levels of education, demonstrated a reduced likelihood of having a living will or both DPOAH and a living will. In the normal cognition group, race and ethnicity emerged as significant predictors of DPOAH, but this association was not observed in the dementia group. Additionally, rurality significantly predicted the presence of a living will and both DPOAH/living will for the normal cognition group, while such an association was not evident in the dementia/impaired cognition group.ConclusionOur study revealed that individuals facing cognitive impairments exhibited lower rates of engagement in ACP. Notably, among the variables examined, race, ethnicity, rural residence, education, and age emerged as significant predictors of ACP in a national sample of older adults in the U.S. These findings underscore the importance of incorporating these sociodemographic factors into the design of interventional studies aimed at enhancing ACP and mitigating disparities.
Analyzing Response Rates and Respondent Demographics in Online Surveys Assessing Public Perception of Alzheimer’s Disease‐Modifying Therapies
Authors: Nakashima Saki , Sato Kenichiro , Niimi Yoshiki , Toda Tatsushi , Iwatsubo Takeshi 
Published: January 2025

AbstractBackgroundWith the recent approval of lecanemab, a disease‐modifying therapy (DMT) for Alzheimer’s Disease (AD), there is an urgent need to address healthcare system challenges to ensure the safe, effective, and sustainable delivery of approved DMT drugs.Understanding public perceptions of these challenges through online surveys might be helpful. Achieving sufficient responses that reflect the characteristics of the respondents is crucial for a successful online survey, however, details about the respondent characteristics for this kind of survey are largely uncertain.MethodWe analyzed data from an anonymous online survey conducted using Google Forms from November 28 to December 16, 2023 to participants of a Japanese trial‐ready cohort (J‐TRC) web study, a web‐based online registry aiming to enroll individuals with preclinical AD to facilitate AD prevention trials.ResultAmong approximately 10,400 J‐TRC web study participants to whom we sent invitation e‐mails, we received 1,761 responses (16.9% response rate) within two weeks of the response acceptance period. The demographic split of survey respondents was 47% male and 52% female, primarily between the ages of 50‐70. Male respondents were more predominant in older age groups (Chi‐squared p<0.001). Regarding the days of the week when invitation e‐mails were sent (Tuesday to Saturday), Tuesday had the highest response rate, followed by Saturday, Wednesday, Thursday, and Friday. Female respondents were more predominant on Wednesday, Friday, and Saturday. Respondents from Tuesday to Friday were more likely to be retirees, whereas those on Saturday were not. The effect of retirement on increasing response rates was more pronounced in males than in females.ConclusionOur analysis evaluated the response rate and respondent characteristics for an online survey concerning public perceptions of DMTs for AD. The current results could be useful for future efforts to improve response rates of online surveys targeting health‐conscious individuals aged 50‐80 with an interest in dementia treatment, by optimizing the timing and methods of sending survey invitations.
Frontal Memory‐related Brainwaves Differentially Correlate with AD and Astrocyte Plasma Biomarkers
Authors: Jiang Yang , Wu Xian , Katsumata Yuriko , Clark Maria F , Foley Kate E. , Wang Baoxi , Sudduth Tiffany L. , Wilcock Donna M. , Jicha Gregory A , Norris Christopher M. 
Published: January 2025

AbstractBackgroundWe currently lack in the dementia field accurate, noninvasive, quick, and affordable screening tools for brain dysfunctions associated with early subtle risk of mild cognitive impairment (MCI). Our Kentucky aging cohort demonstrates that asymptomatic older individuals with MCI‐like frontal memory‐related brainwave patterns convert to MCI within a short 5‐year period, as opposed to individuals with NC‐like patterns (1) that remain normal 10 years later (2). Astrocyte reactivity influences amyloid‐β effects on tau pathology in preclinical Alzheimer’s disease (3). Leveraging blood‐based AD and astrocyte biomarkers and the cognitive electroencephalogram (EEG) signatures (4), we test the hypothesis that predictive frontal memory‐related EEG changes correlate with preclinical and early AD plasma biomarkers.Method34 (19 women) older volunteers with or without MCI, average age 79 (SD 8.53) years old, from a longitudinal cohort followed by University of Kentucky ADRC participated. Each participant’s EEG was recorded (64‐ or 14‐channels) during a working memory (modified delayed match‐to‐sample) task. Principal component analysis (PCA) was performed on 64‐channel EEG data to create PC scores (PC1 & PC2). For multiple linear regression of EEG PC scores on multiple neurodegenerative plasma biomarkers including Aβ42/40, pTau181, total Tau, and GFAP (Astrocyte reactivity), we adjusted age, sex, education, and gap years between collection dates.ResultThe 61% of variance in frontal signals can be explained by PC1 in normal cognition (NC) and MCI individuals, and PC2 counts for 35% of variance (Figure 1). The decreased brainwaves (MCI‐like) seen in left frontal sites significantly correlate with increased pTau181, GFAP, and PC2 (Figure 2). Curiously, right frontal EEG relations with pTau181, GFAP showed the opposite trend. Bilateral frontal signals showed negative correlations with Aβ42/40 and positive correlations with total Tau.ConclusionOur results indicate that GFAP & pTau181 trend in similar asymmetry ways with frontal cognitive brainwaves, but Aβ42/40 & total Tau correlate to a different component of frontal EEG. That is, distinct cognitive brainwaves correlate with astrocyte reactivity differentially that influence pathologies of beta‐amyloid accumulations and Tau development. Cognitive pathophysiological signatures and AD–Astrocyte plasma biomarkers have great potential for predicting subtle cognitive decline and specific dementia risk in healthy normal individuals.