bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of Neighborhood Walkability with Cognitive Impairment Depend on Geographic Context
Authors: Rosso Andrea L , Shaaban C. Elizabeth , Cheng Greta , Buchanich Jeanine M , Butters Meryl A , Cohen Annie , Dubowitz Tamara , Faulkner Melanie Y , Gogniat Marissa A. , Lopez Oscar L. , Saeed Anum , Reis Steven E. , Troxel Wendy M , Weinstein Andrea M. 
Published: January 2025

AbstractBackgroundNeighborhood walkability may affect cognitive impairment through promotion of physical activity. However, most studies are conducted in urban, predominantly White samples. We assessed how walkability is related to presence of cognitive impairment and whether the relation differs by neighborhood population density (differences in likelihood of promoting physical activity) and/or racial composition (differences in quality of neighborhood resources). We hypothesized that lower walkability is related to greater likelihood of having cognitive impairment and that this association is stronger in areas with higher population density (i.e., more urban) and with a lower percentage of Black residents.MethodsWe used cross‐sectional data from 4 harmonized studies of cognition and dementia across Southwestern Pennsylvania (n = 1625, Table). Walkability was defined by quartiles of the Environmental Protection Agency walkability index at the participant’s residential census tract. Cognitive impairment was defined as clinically adjudicated mild cognitive impairment or dementia (3 studies) or a Clinical Dementia Rating of ≥0.5 (1 study). US census data were used for population density (> or ≤ 2500 people/square mile) and racial composition (0%‐10%, >10%‐50%, or >50% Black residents) of each census tract. Logistic regression models with robust standard errors to account for clustering at the census tract modelled the association of walkability and cognitive impairment with adjustment for participant age, sex, years of education, marital status, race, and tract area deprivation index. Multiplicative terms were included in the models to test interactions of walkability with either population density or racial composition. Models were stratified when interaction p‐values <0.1.ResultsIn adjusted analyses, walkability was not related to cognitive impairment in the full sample (OR = 0.89 (95% CI: 0.61‐1.28 for highest vs lowest quartile). Walkability interacted with population density (p interaction = 0.09 for highest vs lowest quartile), such that low walkability was associated with greater likelihood of cognitive impairment, but only in areas with high population density (OR = 1.85 (95% CI: 1.08‐3.17 for highest vs lowest quartile; Figure). There was no interaction with racial composition.ConclusionsNeighborhood walkability may be an important population‐level modifiable risk factor for cognitive impairment but accounting for geographic context such as urbanicity is important for considering implications and interventions.
Anticholinergic burden and cognitive decline: findings from the ELSA‐Brasil cohort study
Authors: dos Santos Adriana Nancy Medeiros , Gonçalves Natalia G , Goulart Alessandra C. , Viana Maria Carmen , Lotufo Paulo A , Bensenor Isabela M , Suemoto Claudia Kimie 
Published: January 2025

AbstractBackgroundUsing multiple drugs with anticholinergic properties is common and might lead to cumulative anticholinergic toxicity and increased risk of cognitive decline. The cumulative adverse effects of anticholinergic medications that a person takes are called the “anticholinergic burden”. We hypothesized that a high anticholinergic burden may be a risk factor for cognitive decline. We aimed to investigate the longitudinal association between Anticholinergic Cognitive Burden (ACB) and cognitive decline in the ELSA‐Brasil study during eight years of follow‐up.MethodParticipants were evaluated in three study waves (2008‐2010, 2012‐2014, and 2017‐2019). The ACB was calculated based on the medications in use. Cognitive performance was evaluated using a standardized battery of tests (immediate recall, late recall, recognition, semantic and phonemic verbal fluency, and the trail‐making tests). A global composite z‐score was derived from these tests. The association of ACB with cognitive performance over time was evaluated using linear mixed‐effects models, adjusted for sociodemographic and clinical variables.ResultA total of 15,105 participants were recruited and 2,040 were excluded, leaving 13,065 participants whose data were analyzed. Participants had a mean age of 51.7±9.0 years old, 55% were women, and 53% were white. During the follow‐up time, the ACB burden was associated with a decline in global cognition (β = ‐0.001, 95% CI = ‐0.013, ‐0.002, p = 0.004), memory performance (β = ‐0.002, 95% CI = ‐0.002, 0.000, p = 0.044) and executive function (β = ‐0.002, 95% CI = ‐0.004, 0.000, p = 0.014).ConclusionDuring eight years of follow‐up, the ACB burden was associated with cognitive decline, particularly in the memory and executive function domains.
Similarity of regional brain blood flow and glucose utilization imaging biomarkers in older adults
Authors: Lepping Rebecca J , Taylor Jasmine M , Honea Robyn A , Hess Benjamin J , Vidoni Eric D , Brooks William M , Burns Jeffrey M , Swerdlow Russell H 
Published: January 2025

AbstractBackgroundCerebral blood flow (CBF) and glucose utilization have both proven sensitive biomarkers of brain function in Alzheimer’s disease. However, while blood flow supplies glucose to cells to meet local demand, and therefore, are inter‐related, the two aspects are physiologically distinct. Our goal was to conduct a region‐to‐region correlation of magnetic resonance imaging (MRI) and 18F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) biomarkers of cerebral blood flow and glucose utilization to determine whether these physiologically distinct biomarkers yield functionally distinct information.Method108 older adults who were cognitively unimpaired (n=71), or had mild cognitive impairment (n=17) or dementia due to Alzheimer’s disease (n=18), and who were enrolled in the KUMC Alzheimer’s Center Cohort completed both MRI T1‐weighted structural and pseudocontinuous arterial spin labelling (PCASL) and FDG‐PET scanning. Participant‐unique brain regions were created by segmentation of the T1‐weighted images with FreeSurfer, combined into large regions of interest for anterior/posterior cingulate, frontal, temporal, and parietal cortices. Preprocessing in SPM12 and AFNI were conducted for the PCASL and FDG‐PET data separately, and regional CBF and glucose utilization (specific uptake value ratio [SUVR]) were extracted. Correlation analysis was conducted in SPSS 29.ResultCBF and FDG‐PET SUVR were significantly positively correlated in the ACC‐PCC (r=.22, p=.02), Temporal (r=.26, p<.01), and Parietal (r=.37, p<.001) cortices, but not in the Frontal cortex (r=.13, p=.19). The correlations were modest, with the largest at .37 in Parietal cortex.ConclusionOur results indicate an expected, yet somewhat modest correlation in the majority compared regions. Additionally, the correlation was not identical across the brain, and non‐significant in frontal regions. This analysis revealed that CBF and FDG‐PET are complementary measures that provide non‐overlapping information. We conclude that these two biomarkers yield unique information and may have unique value in elucidating the relationship between blood flow and neuronal function, potentially more so for frontal rather than parietal regions.
Retinal imaging in polarized light of two different protein deposit types found in the retina in different neurodegeneration diseases (NDDs)
Authors: Campbell Melanie CW , Gallop Hannah , Mason Erik L , Emptage Laura , Redekop Rachel , Kitor Monika , Hsiung Ging‐Yuek Robin , MacKenzie Ian R , Hirsch‐Reinshagen Veronica 
Published: January 2025

AbstractBackgroundAmyloid and alpha synuclein proteins are brain biomarkers of different neurodegenerative diseases, many years before symptoms. We have shown that imaging dye‐free with polarized light makes retinal amyloid deposits visible as a biomarker, in the brain, of amyloid and Alzheimer's disease (AD) severity. Here, we extend to presumed retinal alpha synuclein deposits in those with brain pathology consistent with alpha synuclein. We have previously shown, using machine learning, that polarized light interactions of pure amyloid beta deposits and pure alpha synuclein deposits, grown on glass, differ.MethodsEyes and brains were donated by 10 individuals with brain pathology consistent with amyloid and moderate to high likelihood of AD, and from two individuals with pathology in which brain alpha synuclein is expected ‐ one with dementia with Lewy bodies (DLB) and one with multiple system atrophy (MSA). Retinas were fixed and flat‐mounted, then imaged in differing polarized light states. 274, 47 and 12 deposits were imaged in retinas of those with AD, DLB and MSA respectively. Interactions with polarized light were calculated for each protein deposit imaged.ResultsPresumed amyloid beta and alpha synuclein deposits were visible in polarized light in retinas with brain pathologies consistent with AD, or DLB and MSA respectively (Figure 1). After correction for repeated measures, the means of many polarized light interactions were significantly different for the two presumed deposit types (Table 1). The distributions of the strengths of polarized light interactions and deposit areas (Figure 2) overlapped across deposit types. However, a combination of polarized light interactions separated the presumed retinal deposits of amyloid from those of alpha synuclein in two machine learning algorithms: random forest with an accuracy of >85% and a convolutional neural network (CNN) with an accuracy of > 90%. Linear retardance, which helped to separate the two types of retinal deposits in CNN was previously used to separate deposits of the two pure proteins.ConclusionsMultiple interactions with polarized light differ between deposits of different retinal proteins. Dye‐free polarized light imaging of the retina shows promise in differentiating these deposits as biomarkers of different neurodegenerative diseases in the brain.
TDP‐43 association with Subiculum and CA1 Hippocampal Subfield Atrophy in Primary Age‐Related Tauopathy
Authors: Youssef Hossam , Gatto Rodolfo G. , Pham Nha Trang Thu , Petersen Ronald C. , Machulda Mary M. , Reichard Ross R. , Dickson Dennis W. , Jack Clifford R. , Whitwell Jennifer L. , Josephs Keith A. 
Published: January 2025

AbstractBackgroundThe TAR DNA‐binding protein of 43 kDa (TDP‐43) is linked to hippocampal volume loss and faster rates of hippocampal atrophy in Alzheimer's disease and primary age‐related tauopathy (PART). Hence, TDP‐43 is becoming an important player in age‐related neurodegeneration. To advance our understanding of TDP‐43 effect on hippocampus, we conducted an imaging‐pathological study to determine which specific hippocampal subfields are affected by TDP‐43 in cases of PART.MethodOne‐hundred fifteen autopsied cases from Mayo Clinic Alzheimer Disease Center, Study of Aging and Neurodegenerative Research Group were analyzed. All had completed antemortem brain MRIs, underwent neuropathological examination per NIA and Alzheimer’s Association (NIA‐AA) criteria and had additional assessment for TDP‐43 deposition. Only cases meeting criteria for PART (Thal phases 0‐2 and Braak NFT stages I‐IV) were included. Hippocampal subfield segmentation was performed using FreeSurfer‐7. Brain volumes were normalized to total intracranial volume (TIV) when comparing TDP‐43 groups. Statistical analyses including logistic regression analyses were utilized to explore associations between TDP‐43 status and hippocampal subfield volumes.ResultForty‐nine of the 115 cases (43%) with PART were female. Thirty‐seven (32%) cases were TDP‐positive. Mean age at last MRI was 84 years. There were no differences in pathological characteristics between both groups except for presence of hippocampal sclerosis which was more frequent in the TDP(+) group (P <0.001). Whole hippocampal volume was significantly smaller in the TDP(+) group (176 ±31 vs. 188 ±27, p=0.049). After stratification of hippocampus into head, body, and tail, TDP‐positive cases had smaller volumes of hippocampal body (p=0.031) and tail (p=0.021) but did not reach significance for hippocampal head (p=0.129). When regions were subdivided into hippocampal subfields, TDP(+) cases showed smaller volumes of molecular layer of the hippocampal body (p=0.046), CA1 body (p=0.031), subiculum body (p=0.023), and presubiculum body (p=0.046) compared to TDP(‐) cases. Logistic regression analysis adjusting for TIV confirmed these associations.ConclusionThis study underscores the association between TDP‐43 and the hippocampus and provides further evidence that TDP‐43 targets multiple regions and subfields of the hippocampus in patients with PART. Intriguingly, regions targeted are those where TDP‐43 deposition is microscopically observed, suggesting a direct “hit” by TDP‐43 deposition.
Network‐based Plasma Proteomics Reveals Molecular Overlap Between Physical Activity and Dementia Risk
Authors: Saloner Rowan , Paolillo Emily W. , Cadwallader Claire J. , VandeBunte Anna M. , Chen Coty , Wyss‐Coray Tony , Kramer Joel H. , Casaletto Kaitlin B. 
Published: January 2025

AbstractBackgroundPhysical activity (PA) is associated with lower dementia risk; however, underlying molecular pathways are poorly understood. We leveraged large‐scale plasma proteomics to identify biological signatures of objectively‐monitored PA in cognitively unimpaired (CU) older adults and cross‐validated signatures in independent exercise intervention and Alzheimer’s disease (AD) cohorts.MethodDiscovery cohort included 65 CU adults (meanage = 76.6; 60% female; 34% PET Ab+) from the UCSF Memory and Aging Center with plasma assayed on SomaScan v4.1 (7,288 proteins). 30‐days of observational FitbitTM monitoring quantified PA (average daily steps). Generalized linear models (GLMs) examined individual protein correlates of PA, adjusting for age and sex. Weighted gene network analysis assembled proteins into unbiased modules of protein co‐expression, which were annotated for gene ontology and cell‐type enrichment. Modules were tested for overrepresentation of PA‐related proteins using Fisher’s exact tests with false discovery rate (FDR) correction. To validate PA pathways, modules were cross‐referenced with published plasma exercise intervention data (Robbins et al., 2023) of proteins that changed following a 20‐week endurance training intervention. To establish clinical relevance, PA‐related proteins from discovery analyses were compared between CU (N=189) and AD patients (N=55) from an independent cohort with plasma SomaScan (Stanford ADRC).ResultDiscovery: PA related to 568 proteins in GLMs. Of 32 protein modules identified from network analyses, six showed overrepresentation of PA‐related proteins. Module 12 (M12) positively associated with PA and harbored the largest proportion of PA‐related proteins. M12 was enriched for extracellular matrix (ECM) and nervous system development pathways with endothelial, neuronal, and oligodendrocyte cell type markers. Validation: M12 was significantly enriched for ECM‐related proteins that increased in the exercise intervention. Four proteins from M12 were significantly decreased in AD plasma compared to CU after FDR correction, including highly‐connected ‘hub’ proteins anthrax toxin receptor cell adhesion molecules 1 and 2 (ANTXR1, ANTXR2) and matrix remodeling associated 8 (MXRA8).ConclusionLarge‐scale analysis of the plasma proteome highlights ECM and neurodevelopmental pathways that increase with PA and decrease in AD. Cross‐validation with independent cohorts identified a biological link between PA and dementia risk. PA‐related ‘hub’ proteins, such as ANTXR1, ANTXR2, and MXRA8, may represent key molecular targets for dementia prevention.
Subclinical Vascular Disorders in Relation to Cognitive Decline and Impairment: The Multi‐Ethnic Study of Atherosclerosis
Authors: Tanley Jordan E. , Jaeger Byron C , Chen Haiying , Rudolph Marc D. , Sachs Bonnie C. , Li Clara , Rascovsky Katya , Luchsinger Jose A. , Hayden Kathleen M. , Ding Jingzhong , Liu Yongmei , Bertoni Alain G. , Heckbert Susan R. , Post Wendy , Szklo Moyses , Lockhart Samuel N. , Hughes Timothy M. 
Published: January 2025

AbstractBackgroundVascular disorders are proposed as modifiable risk factors for dementia; yet, physiologic mechanisms connecting vascular disorders to cognitive impairment remain unknown. We examined subclinical cardiovascular measures to determine which predict global cognitive decline and domain specific cognitive impairment and point to potential pathways linking subclinical vascular disease and dementia.MethodsMESA includes a diverse cohort of 6,814 participants free from clinical cardiovascular disease with follow‐up over 6 clinical examinations and annual follow‐up calls. At baseline in 2000‐2002, 24 subclinical vascular measures were collected (e.g., blood pressure, carotid distensibility, artery elasticity index, heart rate, coronary calcification, carotid intima media thickness) that prior work generalized into four uncorrelated factor composites representing: atherosclerosis, arteriosclerosis, blood pressure, and cardiac function (Table 1). During Exam 5, participants began cognitive testing with the Cognitive Abilities Screening Instrument (CASI), which was repeated 10 years later (2010‐2012 to 2019‐2021) and modeled using linear mixed effects models. At Exam 6 (2019‐2021), the Uniform Data Set v3 battery was administered. Scores were normed, grouped into domains (e.g., Memory, Processing Speed, Executive Function) and modeled using generalized linear models. Cognitive impairment was adjudicated as mild cognitive impairment (MCI) or probable dementia and modeled using logistic regression. Results are reported as beta estimates or odds ratios and 95% confidence intervals (95%CI) including adjustment for baseline CAIDE dementia risk score (Figure 1), race/ethnicity, and language.ResultsBaseline arteriosclerosis and atherosclerosis were independently associated with greater cognitive decline 10 years later (Figure 1a), lower domain specific cognitive performance (Figure 1b) and higher odds of cognitive impairment 20 years later (Table 2) after multi‐variable adjustment. One standard deviation increase in baseline arteriosclerosis was associated with modestly increased odds of MCI and almost two fold increased odds of probable dementia. Baseline cardiac function and blood pressure were not significantly associated with cognitive decline or impairment beyond CAIDE. Cognitive decline results were generally consistent across racial and ethnic groups (Figure 1c, p‐interaction>0.10).ConclusionsThese findings suggest that arteriosclerosis and atherosclerosis are more consistently associated with cognitive impairment and global cognitive decline than cardiac function and blood pressure in a diverse population with 20 years of follow‐up.
Do patients with early‐stage cognitive impairment have an increased risk to have a reduction in walking speed? A cross‐sectional study
Authors: Lopes Pedro de Castro , Leopoldino Amanda Aparecida Oliveira , Machado João Carlos Barbosa , Barbosa Maira Tonidandel , Garcia Luana Rodrigues , Aguiar Bianca Pessoa , de Souza Júlia Caroline Barbosa , Ferreira João Pedro Neres Antunes 
Published: January 2025

AbstractBackgroundGait speed is an important measure in the evaluation of elderly patients. The gait speed reduction is associated with high‐impact outcomes such as: loss of functionality, frailty and increased mortality. Several clinical conditions lead to a reduction in gait speed. In patients with advanced dementia, it could be associated with disability. However, the relationship between cognition and motor function is not well known, especially in the early stages of dementia and further studies are needed. It is also important to understand whether patients with mild cognitive impairment have increased risk of a worse gait speed.MethodThis is a cross‐sectional study in which 87 community‐dwelling elderly people were included and evaluated in relation to the presence of cognitive impairment and gait speed. Patients with severe cognitive impairment, assessed by a score less than 6 in the CS‐10 (Point Cognitive Screening) were excluded. Individuals with a score between 6 and 7 on the CS‐10 were considered to have mild or moderate cognitive impairment and participants with a score greater than 7 on this test were considered to have no cognitive impairment. In order to evaluate gait speed, individuals were stimulated to walk for 4 meters, and those with a walking speed lower than 0.82 m/s were considered to have it reduced. With the aim of estimate the association between the characteristics, Pearson’s chi‐square test was used. If the p‐value was lower than the significance level of 0.05, it is possible to conclude the association between the lower walking speed and a worse score in CS‐10.ResultStatistical analysis showed an association between the reduction in gait speed and CS‐10 score (p‐value 0.041). Patients who had lower score on the cognitive assessment are likely to have a lower gait speed. The mean CS‐10 score for patients with gait impairment is 7.91, while for patients without gait impairment is 8.95 points. The Kruskal‐Wallis test indicates that there is a significant difference in the results (p‐value 0.016).ConclusionIndividuals with mild cognitive impairment have an increased risk of developing reduced gait speed.
Older Adults’ Views about Blood Biomarker Testing for Alzheimer’s Disease: Update from the U.S. National Poll on Healthy Aging
Authors: Cox Chelsea G , Roberts J. Scott 
Published: January 2025

AbstractBackgroundBlood‐based biomarker testing (BBT) for Alzheimer’s disease (AD) to detect amyloid‐beta and tau is becoming part of dementia care, with likely future clinical use in asymptomatic populations. Little is known about older adults’ awareness of BBT or their perceptions of its potential benefits, risks, and limitations.MethodWe analyzed data from the March 2023 fielding of the University of Michigan National Poll on Healthy Aging, a nationally representative web and telephone survey of community‐dwelling older U.S. adults. Poll respondents ages 65‐80 were provided a brief definition of BBT for AD and asked about their 1) awareness of BBT, 2) perceptions of its risks and benefits, and 3) anticipated responses if they tested positive. Multivariable logistic regression analyses examined self‐reported sociodemographic (i.e., age, sex, race and ethnicity, education, income, employment, martial status) and clinical characteristics (i.e., physical health, mental health, subjective memory, family history of dementia) associated with BBT awareness and anticipated negative responses to a positive AD blood biomarker result.ResultOf 1,298 U.S. adults surveyed, 19% said they were at least somewhat familiar with BBT for AD. Older adults with more education and better mental health had higher odds of BBT awareness (p<0.05). Overall, older adults were more likely to endorse possible benefits versus risks of testing. For example, 76% said BBT could be useful to inform medical care or advance planning, while 32% endorsed concern about the privacy of their results. More than half of older adults were somewhat or very likely to say that a positive BBT result would prompt potential negative reactions, including beliefs that they would develop AD (72%), have significant distress (61%), or be viewed differently by others (54%). Being female, non‐Hispanic White (compared to Hispanic), and having a family history of dementia were associated with higher odds of anticipating negative outcomes of BBT (p<0.05).ConclusionMost older U.S. adults are not aware of BBT for AD but view it as potentially beneficial for informing clinical care. Many older adults anticipate potential social and psychological challenges of receiving a positive BBT result, with these test perceptions differing significantly by gender and race/ethnicity.