bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood‐brain barrier permeability and risk of conversion to dementia in patients with mild cognitive impairment
Authors: Puig‐Pijoan Albert , Fernández‐Lebrero Aida , Garcia‐Escobar Greta , Navalpotro‐Gómez Irene , Manero‐Borr Rosa Maria , Contador José , Suárez‐Pérez Antoni , Puente‐Periz Víctor , Grau‐Rivera Oriol , Suarez‐Calvet Marc , Jimenez‐Balado Joan , Roquer Jaume , Ois Angel ,   CardioStressCI Consortium. ERA‐CVD Transnational Call
Published: December 2023

AbstractBackgroundCardiovascular risk factors (CVRF) have been associated with an increased risk of cognitive decline and dementia. Increase of blood‐brain barrier permeability (BBBp) measured by CSF/serum albumin ratio (Qalb) have been associated with CVRF. The aim of this study was to analyze the possible role of Qalb as a predictor of conversion to dementia in patients with mild cognitive impairment (MCI).MethodA total of 144 individuals with MCI were recruited from the BIODEGMAR cohort at Hospital del Mar (Barcelona) from 2017 to 2021. Study protocol included neuropsychological assessment, blood sampling, lumbar puncture and brain MRI. Follow‐up visits were performed yearly (12 +‐2 months) until January 2023. The endpoint of the study was a diagnosis of dementia (Global Deterioration Scale –GDS‐ > 3 and/or Clinical Dementia Rating ‐CDR‐ score > 0.5). BBBp was measured by CSF/serum albumin ratio (Qalb). Azheimer’s Disease (AD) was biologically‐defined according to CSF Aβ42/p‐tau ratio (AD+/‐). A composite vascular score (CVS) was calculated by assigning one point for the presence of each of the following CVRF (hypertension, hyperlipidemia and diabetes mellitus) plus another point if Fazekas scale higher than 1 or presence of brain infarcts on MRI. We performed a multivariate Cox regression analysis including the following variables: age, sex, AD and CVS.ResultSixty‐two cases (39.2%) developed dementia in a median follow‐up of 25.89 +/‐ 13.98 months. Univariate analysis showed that Qalb (p < 0.01), AD+ (p < 0.01) and CVS (p = 0.016) were associated with dementia. The regression model results showed an independent relationship between conversion to dementia and Qalb, HR = 1.333 (95% CI 1.185‐1.499) and AD+, HR = 4.118 (2.202‐7.699).ConclusionAn increase in BBBp was independently associated with a higher risk of conversion to dementia in MCI patients. This result points to a potential role of Qalb as a useful biomarker of clinical prognosis of MCI patients.
Walking energetics and white matter hyperintensities: findings from the Baltimore Longitudinal Study of Aging (BLSA)
Authors: Dougherty Ryan J. , An Yang , Tian Qu , Wanigatunga Amal A , Simonsick Eleanor M , Ferrucci Luigi , Resnick Susan M. , Schrack Jennifer A 
Published: December 2023

AbstractBackgroundWhite matter hyperintensities (WMH) increase with advancing age and may contribute to the development of Alzheimer’s Disease. Energy utilization, as defined by walking efficiency, worsens with advancing age and is a prognostic marker of physical and cognitive function in older adults. While both WMH and energy utilization have been associated with cognition and Alzheimer’s‐related pathology, the links between WMH and walking energy utilization are unexplored. The purpose of this study was to examine the cross‐sectional association between walking energy utilization and WMH in cognitively normal middle‐to‐late aged men and women.MethodThe study included 708 BLSA participants who completed standardized slow‐ and peak‐pace walking assessments with indirect calorimetry (VO2 ml/kg/min) and underwent brain magnetic resonance imaging. Energy utilization was defined as the ratio of slow‐to‐peak walking energy capacity (the cost‐ratio), which describes the percentage of peak walking capacity required for the standardized slow walking task; a higher percentage indicates worse energy utilization. T2‐weighted scans and FLAIR images based on a validated support vector machine classifier approach were used to quantify total WMH volumes, which were log‐transformed to normalize the distribution. Sample characteristics were summarized using means and standard deviations. Linear regression was used to examine the association between WMH and the cost‐ratio adjusted for total white matter volume, age, sex, race, lean mass, fat mass, education, height, and comorbid conditions.ResultIn this sample of cognitively normal adults (56% women, mean age 66.7±15.3 years) the average cost‐ratio was 71.6±12.2% (range 34.3‐98.7) and mean log10(WHH) was 3.01±0.80 (range 0.08‐4.68). After covariate adjustment, a higher cost‐ratio was associated with greater total WMH (B = 0.008; SE = 0.002; p<.001; Table 1). Aside from age and total white matter volume, which track closely with WMH, the cost‐ratio was most strongly associated with WMH in our model (Table 1).ConclusionIn a large sample of community‐dwelling middle‐to‐late aged adults, walking energy utilization was associated with WMH volumes, suggesting that a combination of higher energy cost of walking and lower peak walking energy capacity is associated with adverse brain health in mid‐to‐late life. Longitudinal research is needed to elucidate the directionality and temporality of the observed association.
Apathy, empathy and depression in Alzheimer’s disease and frontotemporal dementia: Examining the constructs and white matter correlates
Authors: Quang Halle , Mencevski Filip , Piguet Olivier , Husain Masud , Landin‐Romero Ramon , Kumfor Fiona 
Published: December 2023

AbstractBackgroundApathy and reduced empathy are commonly observed in Alzheimer’s disease (AD) and the core features of behavioural‐variant frontotemporal dementia (bvFTD). Depression is also prevalent in these syndromes. Recent work has proposed a multidimensional framework of apathy which includes three aspects of apathy: executive apathy (reduction of planning and organisation), emotional apathy (emotional indifference and decreased social engagement) and initiation apathy (reduced behaviour execution). These aspects can manifest as symptoms resembling empathy loss and/or depression. The extent to which these symptoms represent similar/divergent clinical dimensions, and their underpinning neural networks, remains unclear. This study investigated the interrelations between apathy, empathy loss and depression, and its white matter correlates, in AD and bvFTD.MethodThirty‐four AD and 51 bvFTD patients participated in the study. Items of the Dimensional Apathy Scale, Interpersonal Reactivity Index and Depression Anxiety Stress‐Depression Subscale were examined using Principal Component Analysis (PCA). White matter integrity and its associations with clinical components were measured via changes in fibre density and cross‐section using fixel‐based analysis.ResultThree components were identified through the PCA (Fig 1). Component 1 consisted of items assessing emotional apathy and empathy, while Component 2 included executive apathy items. Finally, all depression items loaded into Component 3. Regarding white matter correlates, Component 2 were strongly related to reduced white matter bundle density and cross‐section in fibres connecting the bilateral frontal lobe and subcortical structures (Fig 2), whereas Components 1 and 3 were associated with distributed white matter reductions.ConclusionThis study demonstrates that while emotional apathy and empathy loss share the underlying construct, executive apathy and depression are rather independent. White matter changes have strong implications for executive apathy, but not for emotional apathy, empathy and depression. Improved conceptualisation of these symptoms will be important for the development of personalised symptom‐specific therapies.
Using Spontaneous Speech Recognition as a Biomarker to Distinguish Dementia Patients
Authors: Nyongesa Cynthia , Pa Judy 
Published: December 2023

AbstractBackgroundDigital biomarkers such as individual speech recordings, are a cost‐effective tool for assessing cognitive status using linguistic and acoustic content. The purpose of this study is to investigate whether Natural Language Processing (NLP) methods and audio feature extraction can distinguish spontaneous speech outputs in dementia patients from a healthy population.Method240 audio samples and transcripts of clinician‐participant dialogues involving the Cookie‐Theft visual description were acquired from the DementiaBank Pitt corpus (Dementia group (DG) n = 169; healthy controls (CG) n = 71). Lexical variety, syntactic complexity, salience of information, disfluency patterns, and sentiment analysis were evaluated. Sound synthesis and an acoustic R analysis package were used to filter and examine acoustic properties of recorded audio such as silence and speech segmentation, pitch tracking, and frequency modulation of vibrato or jitter. DG and CG were compared using non‐parametric Kruskal‐Wallis tests, Dunn’s multiple comparison, and Mann‐Whitney U‐test in the statistical analysis. In comparison to CG, we hypothesized that DG would differ in levels of lexical diversity, grammatical complexity, and overall salience.ResultOverall, text analysis showed no variations in disfluencies between groups, but there were significant differences in lexical diversity, syntactic complexity and reference rate to reality (p<0.0001). Additionally, there were no appreciable differences in the frequency of salient information between the two groups, however the frequency of non‐salient information and disfluencies was considerably higher in the DG (p<0.05). Analysis of acoustic features revealed that DG had longer average speech duration and speech segment durations compared to CG (p<0.001).. On the other hand, the rate of change of acoustic characteristics including pitch, mean entropy, and harmonics‐to‐noise ratios did not significantly differ between DG and CG.ConclusionIn conclusion, this paradigm reveals that, in comparison to healthy controls, dementia patients exhibited increased lexical diversity yet lower linguistic complexity, and a shift towards characterizing non‐salient objects in given stimuli, as well as longer segments of speech. Further examination of the rhythmic and acoustic characteristics of speech may provide a comprehensive framework towards defining speech as a potential digital biomarker for dementia risk, and provide applications to regions experiencing increasing socioeconomic disparities.
Improvements in Heart Rate Variability among Dementia Family Caregivers Receiving a Home‐Visit Based Intervention: Preliminary Results from a Randomized Controlled Trial
Authors: Lee Jung‐Ah , Zhang Jiuchen , Sabino‐Laughlin Eilleen , Ju Eunae , Rahmani Amir , Qu Annie 
Published: December 2023

AbstractBackgroundEmotional stress of family caregivers of persons with dementia (PWD) is often a topic of concern, as many experience negative health outcomes resulting from their years‐long caregiving role. A home‐visit based educational intervention focused on improving caregiving skills and managing stress was delivered to ethnically diverse dementia family caregivers in California in their preferred language. Previously, survey data were used to evaluate caregivers’ stress and well‐being. However, there might be limitations in using survey instruments to measure stress among diverse caregivers with limited English proficiency. Data collected via wearable technology (e.g., smartrings) can objectively measure stress in the form of Heart Rate Variability (HRV). We examined the intervention’s effect on stress levels measured by HRV among diverse dementia family caregivers using wearable technology.MethodsThe study design was a randomized controlled trial. Family caregivers of community dwelling PWD identifying as either Korean, Vietnamese, Hispanic/Latino, or Non‐Hispanic White were recruited through community outreach. Participants were randomly assigned with a 2:1 ratio to either the intervention group (IG) receiving language‐specific home‐visit based education or the attention control group (AG) receiving only care resource information. All participants wore smartrings monitoring HRV for 3 months. We used linear mixed models to assess the differences in HRV between the two groups using random intercept and slope for intervention, controlling for the covariates (age, gender, relationship, cohabitation, ethnicity, education).ResultsHRV data was collected from 59 caregivers (69% IG and 31% AG). Demographics included: 20 Korean (33.9%), 17 Vietnamese (28.8%), 10 Hispanic (17%), 12 Non‐Hispanic White (20.3%); 32 spouses (54%), 27 off‐spring (46%); 45 females (76%), ages 34 to 87 years (mean = 65.3, SD = 13.6). The linear mixed models showed a significant improvement in stress (higher HRV indicating better stress management) among IG caregivers compared to the AG caregivers over time (Beta coefficient = .079, P‐value = .032).ConclusionsMeasuring stress using smartrings was feasible and effective to track stress levels among diverse caregivers. Preliminary analyses suggest the home‐visit based intervention may have a positive effect on stress in ethnically diverse family caregivers of PWD compared to those only provided with care resource information.
Cytochrome P450 2C9 polymorphism in Puerto Rican Alzheimer’s patients and its role in the pharmacokinetics of THC and Melatonin (IGC‐AD1), an investigational drug
Authors: Rao Jagadeesh S , Gutierrez Evelyn , Grimaldi Claudia , De Jesus William Julio , Shahnawaz Saadia S , Mukunda Ram 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a complex and chronic neurodegenerative illness. The AD patients were on many medications to manage their symptoms. Cytochrome P450 2C9 (CYP2C9) is the main enzyme involved in the metabolism of many drugs, including tetrahydrocannabinol (THC), which converts THC into the active metabolite 11‐hydroxy‐delta‐9‐THC metabolite. Individuals who lack CYP2C9 activity will have an increased risk of side effects from the drugs. CYP2C9 phenotypes are graded into groups, including poor (PM), intermediate (IM), normal (NM), and ultra‐rapid (UM) metabolizing phenotypes. IGC‐AD1 has major active ingredients that contain THC and melatonin.MethodIn our FDA‐regulated Phase‐1 trial, we evaluated a pilot study on the CYP2C9 polymorphism and pharmacokinetics of THC in AD patients (n = 12) from the Puerto Rican (PR) population as a safety measure. Using the Mass ARRAY Analyzer 4 instrument (Invitae Inc., MAA4, Agena, San Diego, CA), we determined the following CYP2C9 alleles: *2,*3,*4,*5,*6,*8,*11,*13,*15. We also investigate how polymorphism affects THC PK in IGC‐AD1 patients.ResultIn a Phase I clinical trial, we found that 62% of participants (n = 8) are carriers of at least one polymorphism. One participant has a rare heterozygous CYP2C9*1/*11 polymorphism. The participants with intermediate metabolizers (*1/*3 and *1/*2 allele) showed an increased half‐life of THC and an increased cMAX of OH‐THC compared to normal metabolizers (*1/*1). Participants who were intermediate metabolizers with *1/*2 variance had a lower AUC for THC levels. Altered CYP2C9 will affect the PK of THC and its metabolites.ConclusionFuture studies should include a larger sample size of AD patients from PR and other regions, that will be allowing access to CYP2C9 genetic polymorphism in AD and understand the drug‐related adverse reactions associated with CYP2C9 genetic polymorphism. Polymorphism plays an important role in drug metabolism and should be considered as a part of dosing.
An Interplay between Health Equity and Disparity in Cognitive Decline
Authors: Wang Chen‐Pin , Gonzales Mitzi M. , Satizabal Claudia L. , Seshadri Sudha , Hazuda Helen 
Published: December 2023

AbstractBackgroundCognitive decline may be an early indicator of Alzheimer diseases and related dementia (ADRD). To identify the intervention targets that ameliorate disparities in ADRD, it is critical to employ disparity measures that account for health equity. We aimed to investigate disparity estimates in cognitive decline built on three health equity measures.MethodThe study sample (n = 451) was derived from the bi‐ethnic community‐dwelling San Antonio Longitudinal Study of Aging (SALSA). The latent variable mixture model classified cognitive function trajectory strata based on four repeated measures of the Mini Mental Status Examination (MMSE) over 8.5±1.3 years of follow‐up. Three risk adjustments were employed to optimize equity in social determinants of health (SDoH: income, education, social interactions) between Hispanics and non‐Hispanics. 1) Average constrained regression adjustment minimized the impact of SDoH for Hispanics. 2) Covariance constrained adjustment derived estimates with a near independence between the residuals with ethnicity. 3) Net compensation penalized regression imposed a penalty for excess lower MMSE among Hispanics. Inverse propensity score weighting (IPSW) estimates of disparity further adjusted away confounding due to covariates (demographics, disease burdens) between ethnic groups.ResultTable 1 contrasted baseline characteristics of the study sample between Hispanics and non‐Hispanics. Two MMSE trajectory strata were identified: cognitive decline stratum (38%) with mean MMSE decreased from 23.9 to 21.2; and stable cognitive function stratum (62%) with mean MMSE around 28 throughout. Average constrained and covariance constrained risk adjustments attained optimal SDoH equity across three fairness metrics: predictive ratios, fair covariance, and net compensation (Table 2). Ethnic disparity in cognitive decline (Table 3) was strong conditioned on SDoH equity alone (log(aOR) = 4.27, p<0.001). Balancing covariates alone via IPSW without equity in SDoH also fell short for parity (aOR = 1.16, p<0.001). Parity in cognitive decline could be achievable under both SDoH equity and balanced covariates between ethnic groups (aOR = 0.85, p = 0.21).ConclusionOur study suggested that integrating equity metrices in ADRD disparity research could guide the paths to improve equity and reduce disparity. The field would be better served by identifying the causal drivers of disparities through the advancement in equity metrices and mediation analyses that delineate intricate interactions between SDoH and ADRD risk factors.
Plasma p‐tau forms as potential diagnostic biomarkers for Alzheimer’s disease
Authors: Kulczynska‐Przybik Agnieszka , Zetterberg Henrik , Blennow Kaj , Dulewicz Maciej , Ashton Nicholas J. , Karikari Thomas K , Mroczko Jan , Borawska Renata , Slowik Agnieszka , Mroczko Barbara 
Published: December 2023

AbstractBackgroundAccumulation of tau aggregates is a pathological hallmark of Alzheimer’s disease (AD) that is closely related to the emergence of neurodegeneration and manifestation of clinical symptoms. Currently, CSF and plasma biomarkers of tau pathology, which would improve the diagnostic process in everyday clinical practice and facilitate the classification of patients for clinical trials, are the focus of research. Biomarkers of tau pathology correlate with post‐mortem AD pathology. Furthermore, they allow for differentiation of AD from other types of dementia, and prediction of future progression from normal cognition and mild cognitive impairment to AD. The availability of The clinical utility of novel assays for the detection of several isoforms of tau pathophysiology in the blood, which are currently available, requires verification. Therefore, the aim of the present study was evaluation of tau proteins in the blood of AD patients and non‐demented controls, and assessment of their diagnostic utility.MethodPlasma concentrations of pTau181 and pTau231 were assessed using a Single molecule array (Simoa). CSF biomarkers, including Aβ‐42, Aβ‐42/Aβ‐40, tau and pTau181 were evaluated in 20 AD patients and 18 elderly subjects without cognitive deficits by ELISA technique.ResultStatistically significantly higher blood levels of pTau181 and pTau231 were observed in AD patients in comparison to cognitively normal individuals. Increased concentration of pTau231 correlated with age and MMSE. Furthermore, the associations between the levels of plasma pTau231 and plasma pTau181, CSF Tau and pTau181, as well as Aβ‐42 were observed in the whole study group.ConclusionThe results indicate that plasma P‐tau181 and P‐tau231 may be diagnostic biomarkers that can help to predict cognitive decline and that they hold promise for use in routine clinical practice.
Determinants of Cognitive Trajectories in Lower Educated Older Adults: Evidence from Brazil.
Authors: Ribeiro Fabiana , Duarte Yeda Aparecida de Oliveira , Leist Anja K. 
Published: December 2023

AbstractBackgroundPatterns of cognitive change and modifiable factors for declining versus stable cognitive trajectories have rarely been described in a lower‐educated older population. Our goal was to identify heterogeneous long‐term trajectories of cognitive functioning and explore possible factors associated with cognitive decline beyond education, among older Brazilian adults.MethodWe used data on n = 1,042 adults aged ≥ 60 from the Health, Welfare and Aging (SABE) without cognitive impairment at baseline over four waves (2000‐2015) in São Paulo, Brazil. We applied group‐based trajectory modelling to identify cognitive trajectories. Cognition was measured using the abbreviated version of the Mini‐Mental State Examination (MMSE).ResultWe identified three cognitive groups: stable (n = 754), mild declining (n = 183), and strongly declining (n = 105). The probability of being in the strongly declining group membership was 10.7%. According to the MMSE classification, the mild declining group reached the average threshold for cognitive impairment on the last follow‐up, while the strongly declining group was on the second follow‐up. Furthermore, respondents in the stable trajectory were more likely to report more than primary education, to be white and married, to earn more than four times the minimum wage/month, to live in urban areas during childhood, and to practice vigorous physical activity at least three times a week. On the other hand, those in the strongly declining trajectory were more likely to identify as black or mixed, to self‐report subjective emptiness, and to have lower BMI, diabetes, and stroke. Moreover, both mild and strongly declining participants presented higher average age and lower MMSE scores at baseline compared to the stable trajectory. The multinomial logistic regression analysis revealed that respondents who self‐reported being mixed, had higher age, had primary education, had a stroke, and smoked at baseline were more likely to be in the strongly declining group.ConclusionOur findings suggest that besides education, interventions to reduce cognitive decline might include health and social policies addressing inequalities and modifiable risk factor burdens to improve later‐life cognitive functioning of at‐risk individuals. Sample attrition suggests estimates of the magnitude of the risk factors for cognitive decline to be conservative.