bluuebunny/crossref_metadata_2025_split huggingface dataset:
International comparison of gender differences in Informant reports of cognitive decline in older adults
Authors: Cantu Phillip A 
Published: January 2025

AbstractBackgroundThe goal of this study is to examine how gender of research participants affects informants assessments of cognitive functioning in older adults. Informant assessments are important tools when clinicians diagnose cognitive decline and dementia and have been used to characterize highly impaired adults in population studies. Contextual and social factors for men and women in different countries may make informants more or less likely to report changes in functioning and cognitive declines at different levels of cognitive impairment.Methodhis study examines gender differences in informant reports of cognitive function in different national contexts using data derived from the Harmonized Cognitive Assessment Protocol (HCAP) of the Health and Retirement Study (HRS)(n = 2,966) and the Mexican Cognitive Aging Study (MexCOG)(n = 1,750). Participants in the HCAP in each nation undergo a direct assessment of cognitive function as well as an informant assessment of cognitive functioning. The HCAP and MexCog contain 19 comparable informant questions and we control for age, gender, education, directly assessed cognition using the Mini Mental Status Examination (MMSE), informant type (spouse, child, or other) and coresidence status.ResultBoth nations have gender differences in informant reports of memory impairments, but now always in the same direction. Informants were more likely to report conversation impairments for women in Mexico. There are fewer gender differences in orientation questions for each nation, may be related to high level of impairment. There were more gender differences in reports of functional limitation in the U.S. than in Mexico. Additionally we found that the gender differences were specific to each nation.ConclusionInformants were MORE likely to report symptoms of cognitive decline in the U.S. than in the Mexico. Informants were more likely to report memory issues (forgets were things are kept, forgets where they put things), and difficulty with chores for women in both countries. Gender differences were not the same in each nation. Relative to Mexico, informants in the U.S. were less likely to report memory problems and talking about the past for women and more likely to report forgetting when last saw informant and difficulty handling money.
Novel small molecule agonist improves behavior deficits and synaptic plasticity in a model of Alzheimer’s disease
Authors: Amin Raj , Steinke Ian , Wibowo Fajar , Yoo Sieun , Suppiramaniam Vishnu , Singh Meenakshi , Arnold Robert Rusty 
Published: January 2025

AbstractBackgroundThe increased incidence of Alzheimer’s disease (AD) rate represent an unmet medical need and thus critical for the development of novel molecular therapeutics. Recent work focusing on patients with apoE4 alleles has highlighted the association of brain cholesterol dysregulation with elevated pathological burden and neurodegeneration. These studies have highlighted the importance of the nuclear receptor Liver X receptor (LXR) for developing AD therapies. Unfortunately many current LXR agonists have failed at the clinical levels due to hepatotoxicity and neutropenia in humans. Our newest LXR agonist, AU403, was developed in silico as a novel Liver X Receptor‐β (LXRβ) with partial PPARδ/α activity. Thus our design serves as a dual LXRβ/ PPARα agonist. This strategy seeks to avoid the unwanted side effects of traditional LXRα agonists. Lastly our studies in 3xTgAD mice have observed an increase in gene and protein expression of ABCB1, the lipid efflux protein.MethodOur library of compounds and lead compound AU403 was designed computationally using Schrodinger software and molecular dynamics to model enzymatic activity using crystal structures of LXR beta and alpha. Further AU403, drug design was optimized by modeling ADME properties using both QikProp and GastroPlus to enhance distribution to the CNS. 11 month aged 3xTgAD mice were given orally 10mg/Kg/day for 1 month. Animal behavior for working declarative memory was observed, using Y‐maze and Novel object recognition studies Electrophysiological studies (LTP) and analysis of pathological markers (Amyloid beta and pTau) were measured.ResultOur in silico design led to the development of our lead compound, AU403, which avoids Trp443 and Leu439, which are deep in the LXRα‐AF2 ligand binding pocket. Furthermore, we observed significant improvement in working declarative memory and long‐term potentiation in 12‐month‐old 3xTgAD mice treated with our lead compound AU403. Mechanistically, we observed enhanced microglia interaction with dendritic spine density and reduced amyloid‐beta plaque levels as well as reduced pay levels.ConclusionWe have observed that AU403 can serve as a highly novel potential therapeutic agent for AD.
Heart rate variability during routine cognitive testing: preliminary analyses of time and frequency domain metrics
Authors: Bateman James R. , Schaich Christopher L. , Shaltout Hossam A , Alphin Kathryn H , Lockhart Samuel N. , Hughes Timothy M. , Lindquist Kristen A , Craft Suzanne 
Published: January 2025

AbstractBackgroundEarly autonomic function changes in Alzheimer’s disease (AD) may represent a biomarker for early affective changes in prodromal disease. We report preliminary differences in metrics of heart rate variability (HRV) before and during routine cognitive testing.MethodWe enrolled 50 participants from the Wake Forest Alzheimer’s Disease Research Center to wear continuous ECG devices during their visit to assess time and frequency domain based metrics of HRV over 5 minutes at rest and during cognitive testing. We used linear mixed effects models adjusted for age, sex, race, education, and APOE genotype to estimate the effect of condition (rest vs. cognitive testing) on HRV by cognitive status.ResultThe sample (n=50) included 39 (78%) individuals adjudicated as having normal cognition (NC), 11 (22%) had MCI, 72% women, 12% Black, 86% White, and 2% Asian. The average age was 73±7 years old, and average education was 15.5±2.6 years. There were no significant differences in time‐ or frequency‐based metrics of HRV between rest and cognitive testing in the total sample (Figure 1). MCI tended towards lower root mean square of successive differences (RMSSD; p=0.11) and higher low‐frequency/high‐frequency (LF/HF) ratio (p=0.062) at rest. RMSSD (p=0.05) but not LF/HF (p=0.99) remained lower during cognitive testing (Table 1, Figure 2).ConclusionPreliminary findings from our ongoing study using gold‐standard continuous ECG‐tracing during routine cognitive testing suggest no differences in HRV during the rest and cognitive testing conditions among the total sample, but may preliminarily suggest a shift to higher sympathetic and lower parasympathetic tone in participants with MCI.
Association of brain MRI signatures with Alzheimer Disease CSF biomarkers
Authors: Cheng You , Gopinath Karthik , Billot Benjamin , Iglesias Juan Eugenio , Touroutoglou Alexandra , Kivisäkk Pia , Wu Chao‐Yi , Dodge Hiroko H , Hyman Bradley T. T , Arnold Steven E , Das Sudeshna 
Published: January 2025

AbstractBackgroundThe relationship between CSF measures of Alzheimer disease (AD) pathologies and their neurodegenerative signatures is not fully understood. This study seeks to employ machine learning approaches on clinical MRI data to identify patterns associated with amyloid and tau, aiming to guide diagnosis and therapeutic interventions.MethodWe selected brain volumes that differed significantly between AD pathology and control groups. Then we utilized logistic LASSO regression to identify and compare neurodegenerative signatures associated with amyloid and tau burdens using selected brain volumes. Our methods were applied to a dataset that included clinical MRI scans from patients who also had cerebrospinal fluid (CSF) biomarkers assessed within a year of the MRI scan (Figure 1). Model performance was measured using the cross‐validation area under the receiver operating characteristic curve (AUROC), as well as the accuracy, sensitivity, and specificity in a 25% held‐out test set.ResultFor amyloid status, among 30 amyloid‐positive, tau‐negative (A+T‐) patients and 24 cognitively unimpaired A‐T‐ controls, we identified 25 significant features associated with amyloid status, including subcortical areas (e.g., amygdala, thalamus, hippocampus), cortical areas (e.g., inferior temporal cortex, inferior parietal cortex, precuneus), ventricles (lateral ventricle, inferior lateral ventricle, and the 3rd ventricle), cerebellum (cerebellum white matter and cerebellum cortex), and brain stem (Figure 2A). Our model with these features yielded an AUROC of 0.792 (95% CI: [0.783, 0.801]), and a sensitivity of 0.857 at specificity of 1 (Figure 2B). In the assessment of tau status, where the amyloid‐negative, tau‐positive group (A‐T+) included 14 patients and the control group comprised 24. The volumes showed significant difference associated with tau status, including subcortical areas (amygdala, ventral diencephalon, hippocampus), the 4th ventricle, and cerebellum white matter (Figure 3A). The model achieved an AUROC of 0.858 (95% C.I. [0.85, 0.866]), with a sensitivity of 1 at specificity of 1 (Figure 3B and C).ConclusionThe study underscores the potential of using widely available clinical MRI images to measure AD and associated pathologies in the brain, which hold significant promise for guiding treatment interventions.
Methodology of INDICATE: Investigating Neuromarkers for Decline & Impairment of Cognition After Thrombectomy for ELVO
Authors: Harp Jordan P. , Fraser Justin F , McLouth Christopher J , Frank Jacqueline A , Isaacs Jennifer , Dahlke Elise , Pennypacker Keith R 
Published: January 2025

AbstractBackgroundVascular cognitive impairment and dementia (VCID) is present in 25‐30% of stroke patients, and a need exists to develop predictive biomarkers to identify patients that will incur chronic cognitive impairment. The National Plan to Address Alzheimer’s Disease and the NHLBI‐NINDS VCID Workshop called for increased research on VCID prediction, especially in underserved populations. Our stroke patient population is comprised of 70% from Appalachian areas, part of US Stroke Belt, so we are uniquely situated to perform this study. We present the design, rationale, and early implementation considerations of the INDICATE study (Investigating Neuromarkers for Decline & Impairment of Cognition After Thrombectomy for ELVO), an expansion of our novel blood and clot registry (Blood And Clot Thrombectomy Registry and Collaboration; BACTRAC).MethodThe study is prospectively enrolling 225 patients, collecting systemic arterial blood at the time of thrombectomy and venous blood thereafter to analyze protein expression. Blood collections start at time of thrombectomy followed by from 3 months to 2 years post‐thrombectomy. At these time points, measures of cognition, functional status, and social determinants of health (SDoH) are also surveyed. The plasma will be analyzed for biomarkers for Alzheimer disease and related disorders (ADRD), and inflammatory proteomic biomarkers. Advanced statistical modeling will be utilized to identify biomarkers that predict functional and cognitive impairment after stroke.ResultOur group has previously identified inflammatory proteins expressed at time of thrombectomy that were predictive of functional and cognitive impairment. The study aims to validate these predictors in a broader sample with more rigorous procedures. These predictors will enable clinicians to target patients that would benefit from intensive rehabilitation.ConclusionCapitalizing on an already existing translational model for studying stroke, we were able to design a large scale study to evaluate the relationship between ischemic stroke and cognitive outcome in human patients. The addition of ADRD biomarkers, additional time points, and more sensitive cognitive measures will strengthen our predictive model for function and cognition after stroke. We will discuss preliminary experiences with recruitment, retention, and implementation, as well as future directions.
BDNF Val66Met polymorphism moderates the neuroprotective effects of physical activity in older adults
Authors: Cadwallader Claire J. , Fischer David Luke , VandeBunte Anna M. , Chen Coty , Diaz Valentina E. , Lee Shannon Y. , Chan Brandon , Lago Argentina Lario , Rojas Julio C. , Kramer Joel H. , Paolillo Emily W. , Saloner Rowan , Casaletto Kaitlin B. 
Published: January 2025

AbstractBackgroundPhysical activity (PA) is associated with increased release of brain derived neurotrophic factor (BDNF), a mechanism that may underlie protective effects of PA on cognitive and brain aging. The Met allele of the BDNF Val66Met single‐nucleotide polymorphism reduces activity‐dependent BDNF release and is associated with increased phosphorylated tau (p‐tau181) in dementia populations. We sought to determine whether BDNF Val66Met influences the effects of PA on plasma p‐tau181 and cognition in older adults without dementia.Method123 older adults from the UCSF Memory and Aging Center completed blood draw assayed for p‐tau181 (Quanterix Simoa), BDNF Val66Met (rs6265) genotyping (Sequenom), 30‐days of FitbitTM actigraphy monitoring, and comprehensive neuropsychological evaluation (Mage = 73.93; SDage = 8.88, 59% female, 42% Met‐allele carriers). Habitual PA levels were operationalized via average daily step count. Composite z‐scores were calculated for cognitive domains of memory and executive functioning. Linear regression was used to determine the moderating effect of BDNF genotype on the relationship between PA and plasma p‐tau181. Moderated mediation analyses subsequently examined the consequences of this moderation effect on cognitive outcomes.ResultAverage PA, plasma p‐tau181, and cognitive z‐scores did not differ between Met‐allele carriers and Val/Val participants. BDNF genotype moderated the relationship between PA and plasma p‐tau181 (b = 0.18, p = 0.036), whereby higher PA was associated with lower plasma p‐tau181 concentrations in Val/Val participants only (Figure 1). In moderated mediation analyses examining cognitive outcomes, plasma p‐tau181 concentration mediated the relationship between PA and executive function for Val/Val participants only (index of mod‐med = ‐0.037, p = 0.031; Figure 2). Models examining memory did not reach statistical significance.ConclusionFindings converge with prior studies highlighting BDNF release as a potential mechanism underlying the neuroprotective effects of physical activity, including lower AD pathological burden and better cognition. These results further elucidate sources of individual variation observed in the effects of PA on the brain in older adults. Future work should further examine the molecular pathways bridging the effects of the BDNF Val66Met polymorphism on PA‐related benefits for brain aging to guide personalized neurotrophic treatments in older adults.
Decreased levels of CSF CXCL8 in clinical and biological profiles of Alzheimer's disease: results of a cohort of Brazilian older adults
Authors: Burgos Ivonne Carolina Bolaños , Barreto Júlia de Almeida , Ribeiro Caio Mendes , Aquino Pedro Henrique Oliveira , Real Ana Paula Bernardes , de Souza Aline Siqueira , Ribeiro Aloisio Joaquim Freitas , Montenegro Lourdes Coral Contreras , Engelmann Gabriela Tomé Oliveira , Hansen Erika de Oliveira , Dias Natália Silva , Carvalho Andréa Teixeira , de Miranda Debora Marques , Romano‐Silva Marco Aurélio , de Marco Luiz Armando Cunha , Viana Bernardo M , Bicalho Maria Aparecida Camargos 
Published: January 2025

AbstractBackgroundInflammation plays a key role in Alzheimer's disease (AD) progression. Interleukin 8 (CXCL8) has emerged as an important cytokine involved in neuroinflammation. It is known as an inflammatory factor that induces a chemotactic response to sites of injury, involving the infiltration of neutrophils. In AD, interactions between CXCL8, Aβ42, and Tau suggest that CXCL8 amplifies inflammatory reactivity induced by Aβ42 and increases Tau phosphorylation and subsequent NFT formation. Our main objective was to determine the CXCL8 profile and its relationship with AD biomarkers in clinical and biological groups in a cohort of Brazilian older adults.Methodseventy‐four older adults were recruited and grouped based on different cognitive profile: Alzheimer’s dementia (n=33), Mild Cognitive Impairment (MCI) (n= 22) and normal cognition (NC) (n=19). CSF samples were collected by lumbar puncture and levels of Aβ42, p‐Tau, t‐Tau and, CXCL8 were assessed by the Luminex xMAP technique. Subsequently, based on biological criteria, the participants were classified in accordance with the AT(N) system into two groups AD continuum and non‐AD. Spearman correlation test and comparison between groups using the Mann‐Whitney U‐test and Kruskal‐Wallis's test were performed. Significant associations between CSF levels of Aβ42, p‐Tau, and p‐Tau/Aβ42 and CXCL8 were further explored in multiple linear regression analyses adjusted for age, sex, education, and APOE allele ε4 carrier status.ResultA significant correlation was found between CSF IL‐8 levels and the pTau/Aβ42 ratio (r=‐.456; p=.009) only in individuals with AD. We observed decreased CSF CXCL8 levels in the AD continuum compared to the non‐AD group [U=450.0; p=.022]. Considering clinical groups, we also observed decreased CXCL8 levels in AD group compared to the MCI group [X2 (2): 8.2; p=.016]. A significant positive association adjusted by sex, age, formal education and allele Ɛ4 was found between CXCL8 and Aβ42 (ß=.316; p=.016) and a negative association with pTau/Aß42 ratio (ß=. ‐257; p=.036).Conclusiona decrease in CXCL8 levels was observed in the AD‐related groups and there was an increase in the MCI group, suggesting that IL‐8 may be more active in the prodromal stage of the disease and then its activity decreases as the disease progresses.
Days, rather than hours of care, mediate the effect of older adults’ cognitive performance on the burden of informal caregivers
Authors: de Carvalho Pelegrini Lucas Nogueira , Palma Leticia Fernanda , Rebecchi Laís , Pulgatti Karen Letícia , Victoriano Pedro Henrique Moreira , de Sousa Danilo Barroso , Grigoli Marina Mantellatto , Popolin Cecilia Patricia , da Silva Vanessa Alexandre , de Oliveira Sabrina Dorta , Manzine Patricia Regina , Cominetti Marcia Regina 
Published: January 2025

AbstractBackgroundInformal care of older adults impacts the lives of millions worldwide. Critically, low‐ and middle‐income countries have the highest proportion of dementia costs related to informal care. Research suggests that older adults’ cognitive decline is associated with burden among caregivers, which corroborates the worsening in caregivers’ quality of life and mental health. Understanding factors related to this relationship may contribute to creating strategies to reduce the caregiver’s burden. This study analyzes whether hours and days dedicated to care mediate the relationship between older adults’ cognitive performance and caregiver burden.MethodParticipants were informal caregivers (n = 92) of healthy older adults (n = 74) and persons living with Alzheimer’s Disease (PLwAD, n = 18) from a middle‐income country (Brazil). The assessment comprised the following instruments: a sociodemographic questionnaire, Zarit burden scale, Memory Complaint Scale‐caregiver’s version (MCS), Pfeffer Functional Activities Questionnaire (FAQ), and IQCODE. ACE‐R was used to assess older adults’ cognitive performance.ResultCaregivers were mostly female (72.8%), daughters (42.4%), or wives (43.5%), who were dedicated to caring, on average, 7.6 (±9.1) hours per day and 5 (±2) days per week. PLwAD caregivers had higher scores on the Zarit Scale (t = ‐5.35; p<0.001), MCS (t = ‐11.54; p<0.001), FAQ (t = ‐14.31; p<0.001), IQCODE (t = ‐6.36; p<0.00). They also provided more hours of care (t = ‐3.97; p<0.001; 95%CI [‐15.89 to ‐4.93]), for more days per week (t = ‐2.30; p = 0.028; 95%CI [‐2.65 to ‐0.16]). Mediation analysis indicated that cognitive performance had a total effect of ‐0.374 (p<0.001; 95%CI [‐0.52 to ‐0.23]) on caregivers’ burden. When controlling for days of care, the direct effect of cognitive performance on the burden was ‐0.3251 (p<0.001; 95%CI [‐47 to ‐0.18]), and there was an indirect effect of ‐0.0698 (95%BCaCI [‐0.14 to ‐0.01]) through the mediation of days of care. Considering hours of care per day, the indirect effect of cognitive performance on the burden was not significant (95%BCaCI [‐0.21 to 0.005]), which suggests it does not mediate this relationship.ConclusionOur findings suggest that days dedicated to care mediate the effect of older adults’ cognitive performance on caregivers' burden. These findings underscore the importance of considering the temporal aspects of caregiving in developing strategies to alleviate caregiver burden.
Metabolic PET brain networks predict clinical conversion prior to amyloid positivity in cognitively unimpaired individuals
Authors: Limberger Christian , Martins Gabriel Colissi , Carello‐Collar Giovanna , Schlickmann Thomas Hugentobler , Peixoto Guilherme G. Schu , de Bastiani Marco Antônio , Machado Luiza Santos , Povala Guilherme , Pascoal Tharick A. , Rosa‐Neto Pedro , de Souza Débora Guerini , Zimmer Eduardo R. 
Published: January 2025

AbstractBackgroundThe default‐mode network (DMN) consists of brain regions with higher resting activity levels. Amyloid‐β (Aβ) deposition in Alzheimer’s disease (AD) occurs predominantly throughout the DMN, suggesting that activity within the network may facilitate disease processes. Indeed, increased neural activity is positively associated with Aβ production. In this context, variations in DMN activity and associated metabolic networks may be linked to the risk of developing AD. However, how patterns of metabolic disruption relate to the progression of AD pathology remains unknown. Here, we investigated whether the metabolic brain networks (MBNs) architecture predicts clinical conversion in cognitively unimpaired (CU) individuals.MethodWe selected CU individuals negative to amyloid and tau (A‐T‐) from the ADNI cohort with [18F]FDG‐PET imaging data at baseline. These patients were divided in stable (non‐converters, n = 18) and clinical progressors (converters, n = 22). Individuals were age‐ and APOEε4‐matched (Table 1). The mean [18F]FDG standard uptake value ratio (SUVR, pons as reference) of brain regions of interest (ROIs) was extracted based on the DKT atlas. MBNs were assembled with a multiple sampling bootstrap scheme and corrected for group imbalance with the Adaptive Synthetic Sampling Approach for Imbalance (ADASYN) and for multiple comparisons using FDR (p < 0.05).Result[18F]FDG regional SUVRs presented no differences between groups (Figure 1). However, converters had a prominent brain PET metabolic hyperconnectivity compared to non‐converters, with a 1.5 fold‐change in connection density (p < 0.001, Figure 2A). Notably, this hyperactivation was not limited to the ROIs comprising the DMN; MBNs constructed with all brain regions reveal that the brains of converters typically display metabolic hyperactivity before the onset of CI (Figure 2B).ConclusionOur findings suggest the existence of early metabolic alterations at the network level in amyloid negative converters. This corroborates the notion that early soluble forms of amyloid, considered synaptoxins, may trigger brain metabolic hyperconnectivity. MBNs hold promise as biomarkers for detecting individuals at risk of clinical progression, even before amyloid positivity status.