bluuebunny/crossref_metadata_2025_split huggingface dataset:
Examining the diagnostic utility of the mnemonic discrimination task for classification of cognition and amyloid‐β burden
Authors: Kim Soyun , Chappel‐Farley Miranda G. , Keator David B. , Janecek John , Mikhail Abanoub , Hollearn Martina K , McMillan Liv , Yassa Michael A. 
Published: December 2022

AbstractBackgroundDeveloping non‐invasive diagnostics that can effectively predict amyloid‐β (Aβ) burden is crucial, as this technology could help to identify individuals with increased risk for AD and provide a window for potential treatment or intervention. Mnemonic discrimination tasks (MDTs) are designed to assess the ability to discriminate highly similar episodic memory representations (e.g., objects or spatial locations). The relationship between the MDT performance and Aβ burden, however, has not yet been directly tested. In this study, we investigated whether MDT performance can successfully classify cognitive status or Aβ load in older adults.MethodA sample of 85 older adults (60‐91 yrs old) with normal cognition and 9 older adults with a clinical diagnosis of Mild Cognitive Impairment (MCI) (62 ‐89 yrs old) underwent either cerebrospinal fluid (CSF) lumbar punctures or 18F‐florbetapir‐PET imaging. Cognitively normal individuals were stratified into Aβ+ and Aβ‐ subgroups based on quantitative thresholds for Aβ positivity (SUVR >1.11, CSF Ab1‐42/1‐40 < 0.062). Participants performed the object and spatial versions of the MDT. We used a random forest classification algorithm, including MDT performance metrics and demographic factors (age, gender, education) as features to classify cognitive status (normal vs. MCI) and Aβ status (positive vs. negative). We evaluated the area under the receiver operating characteristic curve (AUC) using the classifiers in a leave‐one‐out cross validation design.ResultFor classification of cognitive status, the best model performance was achieved by including all the features of object and spatial MDT metrics and demographics (AUC = 0.80). For classification of Aβ status in cognitively normal participants, the best model performance was also achieved by including all the features of object and spatial MDT metrics and demographics (AUC = 0.65).ConclusionOur findings suggest that MDT performance measures may have clinical utility as a diagnostic tool to predict cognitive status and in vivo Aβ burden in preclinical older adults.
Functional hyperconnectivity is associated with higher levels of sPDGFRβ, a marker of blood brain barrier breakdown, in older adults
Authors: Contreras Joey A , Fujisaki Kimiko , Ortega Nancy E , Barisano Giuseppe , Sagare Abhay P , Zlokovic Berislav V , Toga Arthur W. , Pa Judy 
Published: December 2022

AbstractBackgroundApolipoprotein E4 (APOE4) has toxic effects on the cerebrovascular system, neuronal function, and functional connectivity of brain networks (e.g., default‐mode, frontal‐attention, and salience networks). The thalamus, a vital structure that acts as a relay station between many networks, has become of interest in AD research with studies showing atrophy among those with early AD and diminished cortical‐thalamic connections among those with vascular impairment. Additionally, CSF soluble platelet‐derived growth factor receptor‐β (sPDGFRβ), a marker of blood‐brain barrier breakdown, has been associated with AD risk, especially in APOE4 carriers. The present study investigated the relationship between CSF sPDGFRβ and functional connectivity in APOE4 carriers and non‐carriers.MethodOne hundred sixty‐six older adults from the Los Angeles area were selected from a larger cohort (96 females, mean age+SD=67.4+10.7, 68 APOE4 carriers) based on availability of rsfMRI data. Image data was processed using CONN‐toolbox v19c. Grey matter was parcellated using Harvard/Oxford brain atlas, excluding cerebellum. ROI‐to‐ROI analyses were conducted selecting the thalamus as seed region averaging mean connectivity between the left and right structure of other parcellated brain regions. Linear regression models evaluated significant associations between blood oxygen level‐dependent (BOLD) and network connectivity among seed‐target regions and CSF sPDGFRβvalues, while covarying for age and sex. Comparison of averaged functional connectivity values between seed and all target regions among APOE4 carriers and non‐carriers was also examined.ResultHigher functional connectivity between the thalamus and resting state network hub regions were associated with higher CSF sPDGFRβ (Fig 1A, 1C). Cortical regions within the networks included posterior cingulate gyrus, anterior cingulate gyrus, and frontal eye field. Averaged functional connectivity between these areas was significantly higher in APOE4 carriers compared to non‐carriers (Fig 1B).ConclusionThe thalamus is a key subcortical structure for relaying signals across the brain for memory, attention and sleep/wakefulness cycles, and more recently with relevance to AD. These findings suggest a link between early BBB breakdown and elevated functional connectivity in brain regions known to have high synaptic activity and early pathology among non‐demented older adults at risk for AD.
Multi‐tissue profiling of RNA and DNA‐methylation signatures of progressive tau neuropathology in tau transgenic mice
Authors: Kulkarni Ameya S , Ideozu Justin , Vasanthakumar Aparna , Ammar Areej , Murphy Erin , Asque Elizabeth , Plaas Christian , Klein Corinna , Ried Janina S , Barghorn Stefan , Gasparini Laura 
Published: December 2022

AbstractBackgroundIntracellular abnormal aggregation of hyperphosphorylated tau protein is a neuropathological hallmark associated with Alzheimer’s Disease (AD). The insoluble tau aggregates called neurofibrillary tangles lead to microtubule dysfunction and neurodegeneration with AD progression. The TG4510 transgenic mice overexpressing the P301L mutant human tau protein exhibit region‐specific tau inclusions, brain atrophy, and behavioral deficits, thereby serving as a widely used animal model of tauopathy in AD. This study aims to characterize the tissue‐specific transcriptomic and epigenomic signatures of progressive tau pathology in TG4510 mice as well as investigate the correlation of brain and blood expression and epigenomic changes.MethodUsing UMI‐based bulk RNA‐Sequencing and Reduced‐representation Bisulfite Sequencing (RRBS), we profiled the gene expression and DNA‐methylation changes respectively, in the cortex, hippocampus, cerebellum and pre‐sacrifice and terminal whole blood between three age groups (2‐3 months, 6‐7 months, 8‐9 months old; N=20/tissue/group) of male and female TG4510 mice.ResultThe cortex and hippocampus show the largest transcriptional differences between mice, recapitulating phenotype differences with loss of neurotransmission and increased inflammation in these tissues. Systems‐level co‐expression analysis reveals common gene modules in immune system, behaviour and cognition and ECM/synaptic pathways between cortex/hippocampus and blood. Furthermore, the genes correlated between brain regions and blood in these mice were prioritized as potential biomarkers of tau pathology, which can be further validated in preclinical animal models and ultimately human studies.ConclusionThis study serves as one of the first evidence of multiomic molecular underpinnings in a tauopathy mouse model providing potential novel targets and biomarkers of progressive tau pathology in AD.DisclosuresAll authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.
Dementia Research Engagement on Social Media: A Content Analysis
Authors: Hrincu Viorica , An Zijian , Joseph Kenneth A , Jiang Yu Fei , Shi Elaine , Robillard Julie M. 
Published: December 2022

AbstractBackgroundSocial media is a powerful tool for engaging diverse audiences in dementia research, especially healthy individuals who may not be actively seeking dementia research education or opportunities. However, there is little data summarizing current social media practices, content exchange, and ethical considerations in the context of dementia research. To inform ethical dementia research engagement on social media, we characterized current practices by analyzing public Facebook and Twitter posts.MethodWe searched for and downloaded from Facebook (2‐yr period) and Twitter (1‐yr period) all posts containing dementia research‐related keywords. We retrieved n = 7,990 Facebook posts after filtering for inclusion and exclusion criteria. The Facebook data aided the development of a machine learning model to search Twitter for dementia research‐related posts (n = 600,000). After filtering, we retrieved n = 10,000 top retweeted posts. We performed content analysis on a random sample (10%) of the Facebook and Twitter posts. Codebook development followed a qualitative manual coding strategy. Coding ceased when no new codes emerged from the data.ResultThe top 5 Facebook user spaces were Public groups (18%), Nonprofit organizations (18%), Medical & health (9%), Communities (8%), and Medical companies (7%). On Twitter, users with academic/research affiliations were the largest group. Sharing knowledge was the primary form of content exchange on Facebook (19%) and Twitter (21%); there were fewer research opportunities (<9%). Most posts contained linked or embedded media in the form of science news articles. Twitter likes (>100,000) were overall higher than Facebook reactions (>45,000). Although dementia ‘prevention/risk’ and ‘treatment’ were major topics for Facebook and Twitter, posts about ‘diagnostics’ had the most Facebook reactions (29%). Justice was a prominent ethics topic regarding inequalities related to race, ethnicity, culture, gender, and intersecting modes of marginalization in dementia research.ConclusionThe results demonstrate the importance of social media as an engagement tool of current topics in dementia research and reveal areas of potential for increased engagement. More data is needed on the social media guidelines followed by dementia researchers, especially regarding their effectiveness and contextual application. The next project phase will use these data to inform the development of a consensus on best practices in this area.
Association of residential road proximity with cognitive decline and dementia: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Parker‐Allotey Naa Adoley , Bennett Erin E , Lynch Katie M , Xu Xiaohui , Whitsel Eric A , Smith Richard L , Stewart James D , Ying Qi , Park Eun Sug , Wei Jingkai , Power Melinda C 
Published: December 2022

AbstractBackgroundIncreasing evidence links higher midlife air pollution exposures to increased risk of cognitive impairment, and there is growing interest in the role of noise in cognitive aging. Although associations of incident dementia with risk factors are often strongest when values of risk factors in midlife are considered, few studies have considered such associations with mid‐life exposures to traffic‐related air pollution or road noise. Thus, our objective was to determine if midlife residential proximity to major roads, a proxy for traffic‐related air pollution exposure and road noise, is associated with increased risk of incident dementia in the Atherosclerosis Risk in Communities (ARIC) study.MethodARIC participants were enrolled from 4 US sites in 1987‐1989 at ages 45 to 65. We considered data from 12,135 participants who participated in ARIC Visit 2 (1990‐1992, study baseline). We calculated midlife residential Euclidean distance to a major (A1, A2, or A3) road based on geocoded residential addresses at Visit 2. We ascertained dementia status through 2019 via in‐person study visits with neurocognitive assessment, telephone cognitive interview, informant interview, and access to hospitalization and death records. We estimated the association between residential road proximity in midlife and incident dementia using adjusted Weibull models.ResultAt study baseline, the mean age of participants was 57 years, 22% were black, 56% were female, 48% lived within 200m of a major road, and 36% lived within 200 to 500m of a major road. 20% developed dementia during follow‐up. While residing closer to major roads in midlife was associated with increased risk of incident dementia in unadjusted models, this association did not persist in adjusted analyses.ConclusionResidence near a major road in midlife, which may lead to higher exposure to traffic‐related air pollution and noise, does not appear to increase risk of dementia.
Sex‐specific Biomarkers in Alzheimer's Disease Progression: Framingham Heart Study
Authors: Liu Chunyu , Li Yi , Ang Ting Fang Alvin , Liu Yulin , Devine Sherral A. , Au Rhoda , Doraiswamy P. Murali 
Published: December 2022

AbstractBackgroundResearch shows that women have a higher risk of developing Alzheimer’s disease (AD) than men. This study seeks to identify sex‐specific risk profiles linked to the development of AD.MethodWe analyzed multiple blood biomarkers for risk of development of AD as well as with cognitive decline in the community‐based longitudinal Framingham Heart Study Offspring Cohort. A total of 2962 participants (mean age 60 year, 55% women) without any type of dementia were followed up to a median of 12 years with cognitive testing, blood sampling and dementia assessments. This study analyzed participants 60 years and older. Proportional hazards models were performed to investigate associations between biomarkers and the time to incident AD. Linear models were used to quantify the associations between biomarkers and annualized, domain‐specific cognitive decline. Covariates included age, sex, education, and baseline cognitive measurement.ResultDuring the follow‐up, 7.3% (119/1631) women and 4.7% (63/1331) men developed AD; 8.6% (141/1631) women and 7.1% (94/1331) men developed all‐cause dementia. We found that women were 41% more likely than men to be diagnosed with AD (P = 0.029) while found no gender differences in the time to develop all‐cause dementia (P = 0.16). We found that lower plasma amyloid‐beta42 level was significantly predictive for the future risk of AD in women (P = 0.0018) and not in men (P = 0.069), while the hazards ratio were not significantly different between men and women (Pdiff = 0.92). Further, lower plasma amyloid‐beta42 was significantly associated with annualized memory decline in women (P = 0.00023) but not in men (P = 0.55) (Pdiff = 0.026 between men and women for regression estimates). Several vascular risk factors, such as fasting glucose levels, were predictive of AD/dementia in both men and women.ConclusionOur study may offer new insights into how blood tests can be better personalized for predicting future AD risk in women versus men.
Association of ambient air pollutants and cognitive impairment in a community‐dwelling elderly population: A four‐year cohort study
Authors: Kuo Emily , Chen Jen‐Hau , Yu Hwa‐Lung , Chiou Jeng‐Min , Chen Ta‐Fu , Chen Yen‐Ching 
Published: December 2022

AbstractBackgroundLong‐term ambient air pollution has known to affect cognitive function. However, limited studies investigated the relationship between co‐exposure to ambient air pollutants and cognitive functions in non‐demented older adults. Therefore, this study aimed to explore this association in a community‐based prospective cohort study.MethodThis four‐year prospective cohort study is part of the ongoing Taiwan Initiative Geriatric Epidemiological Research (TIGER, 2011‐present) and included 286 non‐demented older adults between 2015‐2019. Ambient air pollution data were collected from 29 monitoring stations from Taiwan Environmental Protection Administration (TEPA) between 1994 and 2019. Global and domain‐specific (memory, attention, executive function, and language) cognitive functions were assessed using the Taiwanese version of Montreal Cognitive Assessment (MoCA‐T) and a battery of neuropsychological tests. The generalized linear mixed models were used to evaluate the association of co‐exposure to air pollutants with cognitive function adjusting for important covariates. Furthermore, we conducted stratified analyses by olfaction, known as an early marker of dementia.ResultExcept for PM2.5, the annual average exposure of the other five pollutants was below the TEPA standards. A 25‐year high‐level exposure of NO2 (≥ 27.7 ppb) was associated with good performance executive function (β = 0.25) over four years. For joint effect, high‐level (the highest tertile) PM2.5 with low to medium concentration level of NO2, CO, or SO2 were significantly associated with the poor performance of memory (β = ‐0.39 to ‐0.35). Similarly, high‐level PM2.5 with low to medium concentration level of NO2, PM10 with O3 were significantly associated with poor executive function (β = ‐0.28 to ‐0.19). In participants with normal olfaction, high co‐exposure level to PM2.5 and PM10, with CO, SO2, O3, and NO2 was significantly associated with poor memory and executive function (β = ‐0.55 to ‐0.30). No significant associations were found in participants with abnormal olfaction.ConclusionLong‐term low to medium‐level co‐exposure to NO2, CO, or SO2 and high‐level PM2.5 was associated with poor memory; co‐exposure to O3 with PM10 and co‐exposure to NO2 with PM2.5 was associated with poor executive function. A revision on exposure standards shall be considered to protect older adults at the preclinical phase of dementia.
CSF Proteome Changes Depend on APOE Genotype in Prodromal AD
Authors: Vromen Eleonora M. , Wesenhagen Kirsten E. J. , van der Kant Rik , Gobom Johan , Scheltens Philip , Teunissen Charlotte E. , Dobricic Valerija , Bertram Lars , Zetterberg Henrik , Visser Pieter Jelle , Tijms Betty M. 
Published: December 2022

AbstractBackground
APOE Ɛ4, the major genetic risk factor for sporadic Alzheimer’s disease (AD), has a dose‐dependent effect on the risk of development of AD. It remains unclear how APOE Ɛ4 dose affects different pathophysiological processes in AD, and therefore we studied APOE genotype effects on the CSF proteome of prodromal AD individuals.MethodCSF proteomics was performed using TMT‐MS in 77 prodromal AD individuals (mean age 70±7 years, 42 (55%) female, n=25 Ɛ3Ɛ3, n=38 Ɛ3Ɛ4, n=14 Ɛ4Ɛ4) and 41 cognitively normal individuals used as a reference group (mean age 64±7 years, 21 (51%) female, biomarker A‐T‐, all Ɛ3Ɛ3) from the EMIF cohort. APOE Ɛ2‐carriers were excluded due to the low number. In total, 2535 proteins were detected, of which we selected 1143 observed in at least 70% of the individuals. APOE genotype effects on CSF protein concentrations were tested with linear regressions adjusting for age and sex in comparison to our reference group.ResultIn total, 134 (12%) proteins showed APOE genotype dependent differences in prodromal AD individuals compared with the reference group (P < 0.05, Fig. 1). Of these, 6 proteins, including SMOC1 and YWHAB, showed differences in all prodromal AD individuals, reflecting general disease processes. Comparing each genotype to the reference group, 23 proteins differed in Ɛ3Ɛ3 prodromal AD, of which 21 showed higher concentrations, without enrichment for any specific biological pathways; 54 proteins differed in Ɛ3Ɛ4 prodromal AD, of which 51 proteins, enriched for glucose metabolism, showed higher concentrations; and 110 proteins differed in Ɛ4Ɛ4 prodromal AD, of which 98 proteins, enriched for glucose metabolism, (oxidative stress‐induced) apoptosis and interleukin‐12 signaling, showed higher concentrations and 12 proteins, enriched for complement activation, showed lower concentrations. Comparing APOE Ɛ4 dose within prodromal AD, 21 proteins showed differences between Ɛ3Ɛ4 and Ɛ4Ɛ4, of which 7 proteins, enriched for complement activation, showed downregulation in Ɛ4Ɛ4.ConclusionThe CSF proteome of prodromal AD individuals showed APOE genotype dependent alterations, which were associated with distinct biological processes, including glucose metabolism, apoptosis and complement activation. Most of these alterations were Ɛ4 dose‐dependent. These differences should be considered in selection of future therapy targets.
Examining the effects of sex and age on tau PET binding in the absence of beta‐amyloid pathology
Authors: Gordon Brian A. , Flores Shaney , Dincer Aylin , Keefe Sarah J. , McKay Nicole S. , Hobbs Diana A. , Wisch Julie K. , Hornbeck Russ C. , Franklin Erin E. , Jack Clifford R. , Koeppe Robert A. , Xiong Chengjie , van Dyck Christopher H , McDade Eric , Klein Gregory , Pariente Jeremie , Bateman Randall J. , Morris John C. , Ances Beau M , Benzinger Tammie L.S. , Perrin Richard J. 
Published: December 2022

AbstractBackgroundTau PET imaging is an established tool for studying Alzheimer Disease but its sensitivity to primary age‐related tauopathy (PART) as well as sex effects in individuals without abnormal levels of amyloid are unknown.MethodsCross‐sectional data were collected from 2014 to 2019 in 144 cognitively normal younger, middle‐aged, and older adults free from amyloid pathology as quantified using PET. Regional values of tau PET binding were measured using flortaucipir. Statistical models examined the main effects of increasing age, sex, race, and sub‐threshold levels of amyloid. Secondary analyses also examined the relationship between tau PET binding and iron as measured using T2* weighted imaging and calcification as measured using CT.ResultsThere were significant positive associations between tau binding and age in 19 regions, with the largest effects seen in the inferior temporal cortex (t=4.59), caudate (t=9.58), and putamen (t=12.57). Iron as measured using T2* imaging mediated only a modest (11.9%) amount of the association between age and tau binding. Elevated tracer uptake in females was present in 23 regions in frontal, lateral parietal, and temporal regions including, most prominently the rostral middle frontal gyrus (t=7.48), superior temporal gyrus (t=5.12) and the inferior temporal gyrus (t=4.22). There were no significant effects of race or sub‐threshold levels of amyloid.ConclusionsTau PET is sensitive to primary effects of age in regions consistent with the neuropathological definition of PART although strong age effects in regions of off‐target binding were also present. There was a robust effect of sex, suggesting prior observations of elevated binding in women is not solely a potentiation of Alzheimer pathology but instead represents an ubiquitous phenomenon. Understand how both sex and age impact tracer binding is critical to understanding the utility of PET tracers as well as interpreting tracer values in the context of disease.