bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations between default‐mode functional connectivity and distress, cardiovascular and metabolic risks and cognition in middle aged and older adults
Authors: Rashid Barnaly , Glasser Matthew F. , Nichols Thomas , Van Essen David , Juttukonda Meher R , Schwab Nadine A , Yacoub Essa , Lovely Allison , Terpstra Melissa , Harms Michael P , Bookheimer Susan Y. , Ances Beau M , Salat David H , Arnold Steven E. 
Published: December 2022

AbstractBackground“Stress” and cardiovascular and metabolic (CVM) conditions are frequently related and affect brain function and increase risk for neurocognitive disorders in aging. The mechanisms by which these occur are unclear. This study investigates how indices of psychological distress and CVM relate to functional connectivity (FC) of the default‐mode network (DMN) and cognition in generally healthy middle‐aged and older adults.MethodStructural, Resting‐state fMRI, and fieldmap scans were collected in a large sample of 930 healthy volunteers aged 36 to 90+ years old (mean ± SD: 61.6 ± 16 years; female= 55.6%) from the Human Connectome Project in Aging (HCP‐A) study. Data were preprocessed using the currently recommended HCP pipelines, including precise spatial preprocessing, multi‐modal cross‐subject alignment, and selective temporal denoising. FC values were computed using full correlation with FSLNets amongst the neocortical brain areas of the HCP’s multi‐modal parcellation and standard FreeSurfer subcortical structures and converted to z‐scores with the Fisher transform. A psychological distress index (PDI) was composed from standard measures of external and social stressors, personality and mental health factors. A CVM index (CVMI) was composed from common physiological and laboratory measures (e.g., blood pressure, lipids, C‐reactive protein), and cognitive functioning was summarized with a multi‐domain cognition composite index (CCI) with standard measures of general cognition, memory, processing speed, and executive functioning. Using linear regression models controlling for age, associations between DMN FC and PDI, CVMI and CCI were evaluated.ResultFigure 1 highlights the associations (uncorrected, p<0.05) between DMN FC and (a) PDI, (b) CVMI and (c) CCI. The overlapping associations in Figure 1(d) suggest that there might be a shared mechanism through which PDI and CVMI impact DMN FC and cognition. Although associations based on PDI were relatively weak, it is possible that effects may be linked to specific elements or subgroups, and this will be explored in future work.ConclusionOur findings indicate that psychological distress and CVM health affect the integrity of DMN connectivity, and that these effects show regional overlaps with the associations between DMN connectivity and cognition.
Tau burden is associated with cross‐sectional and longitudinal neurodegeneration in the medial temporal lobe in cognitively normal individuals
Authors: Xie Long , Wisse Laura EM , Das Sandhitsu R. , Lyu Xueying , de Flores Robin , Yushkevich Paul A. , Wolk David A. 
Published: December 2022

AbstractBackgroundNeurofibrillary tangle pathology is thought to drive neurodegeneration in beta‐amyloid positive (A+) cognitively normal (CN) individuals, i.e., preclinical Alzheimer’s disease (AD).However, in beta‐amyloid negative (A‐) CN, the contribution of tau pathology [primary age‐related tauopathy (PART)] to neurodegeneration remains uncertain. We investigate the correlation between tau burden measured by PET in the medial temporal lobe (MTL) and MRI‐derived cross‐sectional and longitudinal structural atrophy in these cohorts.Methods420 CN (A‐/A+: 294/101, Table 1) individuals from ADNI with AV1451 PET and T1‐weighted MRI acquired within one year were included. Bilateral anterior/posterior hippocampal volume and thickness of entorhinal cortex (ERC), Brodmann areas 35/36 (BA35/BA36) and parahipocampal cortex (PHC) were obtained from baseline MRI scans. Bilateral MTL tau burden was computed as AV1451 uptake across ERC and BA35. Beta‐amyloid status was determined with PET by standard cut‐offs (Florbetapir: 1.11; Florbetaben: 1.08). In a subset of participants with prospective longitudinal MRI scans (up to 4.5 years), annualized volume change rate of each MTL subregion was estimated. Intracranial volume and MRI follow‐up time were additional covariates for cross‐sectional and longitudinal analysis respectively. We performed the analysis separately for each hemisphere in the whole CN cohort and its A+ and A‐ subgroups.ResultsTau burden was significantly associated with cross‐sectional left BA35/36 thickness in the whole cohort and bilateral volume in both A+ CN and the whole cohort (Table 2, Figure 1), but not in in A‐ CN. Stronger correlations between MTL tau burden and longitudinal atrophy, despite smaller sample size, was observed in almost all the MTL subregions regardless of amyloid status (Table 3, Figure 1). In general, effects from the left hemisphere were stronger than those from the right hemisphere. All significant correlations were maintained when corrected for beta‐amyloid PET SUVR.ConclusionsThe results demonstrated that elevated tau predicts subsequent neurodegeneration in early Braak regions in CN subjects regardless of amyloid status. This indicates that PART may be an important driver of neurodegeneration already during normal ageing in cognitively normal individuals.
First results of the AMYPAD Prognostic and Natural History Study: amyloid‐PET Centiloid predicts cognitive functioning in a pre‐dementia population
Authors: García David Vállez , Collij Lyduine E. , Mastenbroek Sophie E , Alves Isadora Lopes , Gispert Juan Domingo , Ritchie Craig W. , Boada Mercè , Marquié Marta , Grau‐Rivera Oriol , Fauria Karine , Scheltens Philip , Vandenberghe Rik , Hanseeuw Bernard J , Schöll Michael , Frisoni Giovanni B , Boecker Henning , Jessen Frank , Wolz Robin , Grootoonk Sylke , Stephens Andrew W , Buckley Chris J , Ford Lisa , Visser Pieter Jelle , Farrar Gill , Barkhof Frederik ,   AMYPAD consortium
Published: December 2022

AbstractBackgroundThe AMYPAD Prognostic and Natural History Study aims to evaluate the value of (semi‐) quantitative amyloid PET imaging for predicting progression within an Alzheimer’s disease risk probability spectrum. The project is actively recruiting non‐demented participants from 17 sites across Europe, with a particular interest in those with emerging amyloid pathology.MethodsAs of 17th January 2022, a total of 1,460 participants had been included. Of those, clinical data of 1,015 were processed, with 688 (68%) having at least a quantified amyloid PET at baseline, with [18F]flutemetamol or [18F]florbetaben. The primary metric used to assess amyloid burden was the Centiloid (CL), measured from the ratio of the GAAIN cortical target and whole cerebellum. Scans were categorized as negative (CL≤12), gray‐zone (12<CL≤50), or positive (CL>50). The distribution of these groups was assessed using a Gaussian mixture model. Independent linear mixed‐effect models were used to explore the predictive value of CL, and its interaction with time, for several cognitive outcomes: mini‐mental state examination (MMSE), memory (immediate recall, IR), attention (digit‐span forward, DSF), language, visuospatial, and executive functions. In addition, years from baseline, parent cohort, age, sex, education, APOE‐ε4, and the Clinical Dementia Rating (CDR) score were used as independent variables.ResultsDemographics are shown in Table 1. At baseline, 88% of the subjects were classified as cognitively unimpaired (CDR=0). A majority of 384 (56%) was categorized as negative (1±7CL), 210 (30%) as grey‐zone (14±11CL), and 94 (14%) as positive (58±31CL) [Figure 1]. Baseline CL (‐0.007 [‐0.010; ‐0.004]) and its interaction with time (‐0.002 [‐0.003; ‐0.001]) were predictive of IR. Baseline CL, but not its interaction with time, predicted MMSE (‐0.007, 95%CI [‐0.010; ‐0.003]) and DSF (‐0.003 [‐0.005; ‐0.001]) [Figure 2]. No significant relationships were observed for executive, language, or visuospatial function.ConclusionsHigher baseline CL were associated with lower global cognitive function and attention scores. Whereas, higher CL were associated with a steeper memory decline over time. Current results suggest that cerebral amyloid accumulation is predictive of future overall cognitive function, attention, and memory decline. Further analysis is assured, including more participants, longitudinal PET outcomes, and other biomarkers of the disease.
Tau antibody 77G7 targeting microtubule binding domain suppresses oligomeric tau to seed tau aggregation
Authors: Liu Fei , Li Longfei , Miao Jin , Chu Dandan , Jin Nana , Tung Yunn Chyn , Dai Chunling , Hu Wen , Gong Cheng‐Xin , Iqbal Khalid 
Published: December 2022

AbstractBackgroundNeurofibrillary tangle (NFT) of hyperphosphorylated tau is a hallmark of Alzheimer’s disease (AD) and related tauopathies. Tau lesion starts in the trans‐entorhinal cortex, from where it spreads to limbic regions, followed by neocortical areas. The regional distribution of NFTs associates with the progression of AD. Accumulating evidence suggests that proteopathic tau can seed tau aggregation in a prion‐like fashion in vitro and in vivo. Inhibition of the seeding activity of proteopathic tau could provide a potential therapeutic opportunity to block the propagation of tau pathology. In the present study, we investigated the role of 77G7, a monoclonal tau antibody to the microtubule‐binding repeats, in the seeding activity of proteopathic tau.MethodAffinity of 77G7 to various tau strains, including oligomeric tau (AD O‐tau), sarkosyl insoluble tau (SI‐tau), and heat stable normal tau (HS‐tau) isolated from frozen autopsied AD brains by sedimentation, was analyzed by immuno‐dot‐blots. Seeding activity of AD O‐tau was accessed by the level of aggregated tau in vitro and in cultured cells and by overlay capture assay. Tau pathology in human tau transgenic mice was induced by hippocampal injection of AD O‐tau. 77G7 was mixed with AD O‐tau or was intravenously administrated weekly for 6 weeks started one week prior to AD O‐tau injection. Tau phosphorylation and tau pathology were analyzed by immunohistochemical staining and Western blots 8‐10 weeks after AD O‐tau injection.ResultWe found that 77G7 had a higher affinity toward aggregated tau strains than un‐aggregated tau derived from AD brain. 77G7 inhibited the internalization of tau aggregates by cells, blocked AD O‐tau to capture normal tau and to seed tau aggregation in vitro and in cultured cells. AD O‐tau induced tau pathology in hippocampus of 3xTg‐AD mice was reduced by mixing 77G7 with AD O‐tau. Intravenous administration of 77G7 ameliorated site‐specific hyperphosphorylation of tau induced by AD O‐tau in the hippocampi of Tg/hTau mice.ConclusionThese findings indicate that 77G7 can effectively suppress the seeding activity of AD O‐tau and thus, could be developed as a potential immunotherapeutic drug to inhibit the propagation of tau pathology in AD and related tauopathies.
Diagnostic value of serum versus plasma phospho‐tau for Alzheimer’s disease
Authors: Kac Przemyslaw Radoslaw , González‐Ortiz Fernándo , Simrén Joel , Vanmechelen Eugeen , Zetterberg Henrik , Blennow Kaj , Ashton Nicholas J. , Karikari Thomas K 
Published: December 2022

AbstractBackgroundBlood phosphorylated tau (p‐tau) forms are promising Alzheimer’s disease (AD) biomarkers, but validation in matrices other than ethylenediaminetetraacetic acid (EDTA) plasma is limited. Firstly, we assessed the diagnostic potential of p‐tau231 and p‐tau181 in paired plasma and serum. Secondly, we compared serum and cerebrospinal fluid (CSF) samples from biomarker‐positive AD and biomarker‐negative control participants.MethodWe studied three independent cohorts (n=120 total): cohorts 1 and 2 included individuals with paired plasma and serum, while cohort‐3 included paired serum and CSF. Blood‐based p‐tau231 and p‐tau181 were measured using in‐house or commercial Single molecule array (Simoa) methods.ResultSerum and plasma p‐tau231 and p‐tau181 were two‐fold increased in biomarker‐positive AD versus biomarker‐negative controls (P≤0.0008). Serum p‐tau231 distinguished between diagnostic groups with area under the curve (AUC) of 82.2%‐88.2% compared with 90.2% for plasma. Similarly, p‐tau181 showed AUC of 89.6%‐89.8% in serum versus 85.4% in plasma. P‐tau231 and p‐tau181 correlated slightly better in serum (rho=0.92‐0.93) than in plasma (rho=0.88). Within‐individual p‐tau231 concentrations were twice higher in plasma versus serum, but p‐tau181 levels were not statistically different despite a trend of higher concentrations in plasma. Bland‐Altman plots revealed that the relative difference between serum/plasma was larger in the lower range. P‐tau levels in paired plasma and serum correlated strongly with each other (rho=0.75‐0.93) as well as with CSF Aβ42 (rho= ‐0.56 – ‐0.59), p‐tau and total‐tau (rho=0.53–0.73).ConclusionComparable diagnostic performances and strong correlations between serum versus plasma pairs suggest that p‐tau analyses can be expanded to research cohorts and hospital systems that prefer serum to other blood matrices. However, absolute biomarker concentrations may not be interchangeable, indicating that plasma and serum samples should be used independently. These results should be validated in independent cohorts.
Depressive Symptoms Associated with an Earlier Age at Onset Differ as a Function of Race‐Ethnicity: An Exploratory Analysis
Authors: Zaman Andrew , Mena Pedro Ramon , Adams Larry D. , Contreras Maricarmen , Lacroix Faina C , Tejada Sergio , Starks Takiyah D. , Feliciano‐Astacio Briseida E. , Silva Concepcion , Caban‐Holt Allison M , Byrd Goldie S. , Martinez Izri , Ayodele Temitope , Baez Penelope , Blackshire Gabrielle , Kennedy Sara , Reitz Christiane , Haines Jonathan L. , Vance Jeffery M. , Vance Margaret A. , Cuccaro Michael L. 
Published: December 2022

AbstractBackgroundDepression (DEP) is a known risk factor for . However, DEP symptoms vary by race‐ethnicity (e.g. greater somatization among African Americans). The relationship between DEP and AD progression in underrepresented groups is not well‐understood. We hypothesize that certain DEP symptoms will be associated with earlier AAO, and that this relationship is moderated by race‐ethnicityMethodSelf‐declared Non‐Hispanic White (NWH), African American (AA), and Hispanic (HI) participants with AD and CDR data were identified from a larger genetic study. Our dataset consisted of 549 persons with a self‐completed GDS (mean CDR = 0.6; 15% NWH, 43% AA, 42% HI), 334 persons with informant completed CSDD (CDR = 1.7; 41% NWH, 20% AA, 39% HI), and 266 persons with self‐reported DEP and anxiety in a medical history exam (CDR = 0.7; 26% NWH, 23% AA, 51% HI). All measures were completed after the onset of AD. Univariate linear regressions examined the relationship between AAO and DEP (total scores and individual items), and race‐ethnicity x DEP interactions after controlling for sex, race‐ethnicity, disease duration, and APOE‐e4.ResultSelf‐reported (p = 0.04), informant‐reported anxiety (CSDD) (p = 0.02), and self‐reports of feeling empty (GDS) (p = 0.02) were associated with an earlier AAO across all groups. Informant‐reports of poor self‐esteem (CSDD) was associated with an earlier AAO overall (p < 0.01), but an interaction showed that this was not significant in HI (p = 0.). Unique items associated with an earlier AAO in NHW included higher GDS total scores (p = 0.01), feeling bored (GDS) (p < 0.01), and perceived problems with memory (GDS) (p < 0.01). In AA self‐reported DEP was associated with an earlier AAO (p = 0.02). No items were uniquely associated with AAO in HI.ConclusionSelf‐ and informant‐reported anxiety and self‐reported feelings of emptiness were associated with an earlier AAO in all groups. However, several DEP symptoms associated with earlier AAO differed as a function of race‐ethnicity. We believe our findings suggest that the occurrence of DEP may be culturally or ancestrally influenced, which in turn has a differential impact on AAO in underrepresented groups.
Sphingosine 1‐phosphate receptor signaling is dysregulated in a mouse model of Alzheimer's disease
Authors: Jung Younghun , Lopez‐Benitez Jonathan G , Tognoni Christina M , Carreras Isabel , Dedeoglu Alpaslan 
Published: December 2022

AbstractBackgroundSphingosine 1‐phosphate (S1P) through the activation of five G‐protein‐coupled S1P receptors 1‐5 (S1PR1‐5) plays crucial roles in cellular events. Aberrant sphingolipid metabolism has been identified in the brains of Alzheimer’s disease (AD) patients which implies the significance of S1P/S1PR signaling system. Activation of S1PRs with Fingolimod, an analog of S1P that binds to 4 of the 5 S1PRs, provides neuroprotection in animal models of AD i.e., reduces of Aβ neurotoxicity, inhibits the activation of microglia and astrocytes, and increases the production of brain derived neurotrophic factor (BDNF). The pathways by which dysfunctional S1P/S1PR signaling may promote the development of AD pathology remain unknown. Here we examine the changes occurring in the S1P/S1PR signaling system in 5xFAD mice.MethodThe gene and protein expression of S1P receptors and S1PR1 signaling pathways were examined in the cortex of male wild‐type mice (WT, n=5) and 5xFAD mice (n=5) at 3, 8, and 14 months of age using quantitative real‐time polymerase chain reaction (real‐time PCR) and Western blots. Statistical analyses of the data were performed using one‐ or two‐way ANOVAs with Sidak's multiple‐comparisons test.ResultS1PR1 gene expression is the most abundant S1PRs in the cortex of both WT and 5xFAD mice. The protein level of S1PR1 is significantly increased in 5xFAD mice compared to WT mice at 3, 8, and 14 months of age. The level of SphK2 that is involved in the activation of S1P as a signaling molecule is also increased in 5xFAD mice at the ages studied. Together with increased level of the truncated form of TrkB, the specific receptor of BDNF, we detected increased levels of the phosphorylated forms of Akt and mTor in 5xFAD mice.ConclusionOur previous findings on the neuroprotective effects of Fingolimod in 5xFAD mice directly support the new findings that increased expression of S1PR1 is associated with the development of AD‐like pathology in 5xFAD mice. Our results presage that S1PR1 regulates the activation of downstream signaling pathways Akt and mTor known to contribute to AD‐related pathogenesis and behavior. Together, these studies suggest that S1PR modulators may potentially have therapeutic benefits in AD.
Social epigenetics of racial disparities in aging
Authors: Yannatos Isabel , Xie Sharon X , Brown Rebecca , McMillan Corey T 
Published: December 2022

AbstractBackgroundRacial disparities in many aging‐related health outcomes are persistent and pervasive among older Americans. There are well‐documented inequities in the social determinants of health for older adults, including the social and physical environment, due to structural and environmental racism, but there is little understanding of the biological intermediates by which social determinants affect disparate health outcomes. Biological aging measured by DNA methylation (DNAm) is robustly associated with worse age‐related outcomes and higher social adversity. We hypothesize that individual social determinants, the social environment, and air pollution exposures interact to contribute to racial disparities in DNAm aging according to GrimAge and Dunedin Pace of Aging methylation (DPoAm).MethodWe performed retrospective cross‐sectional analyses among 3250 non‐Hispanic participants (80.3% white, 19.7% Black) in the Health and Retirement Study whose 2016 epigenetic age is linked to survey responses and geographic data. DNAm aging is defined as the residual after regressing epigenetic age on chronological age. Measures of the neighborhood social environment include the Social Deprivation Index and perceived social stress. Air pollution exposures include particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone. Individual‐level determinants include socioeconomic status, healthcare access, health status, and health behaviors. We implemented multivariable linear regression models to identify significant associations, interactions, and mediators in the relationship between each DNAm aging measure and the social and environmental determinants.ResultWe found on average Black individuals have significantly accelerated DNAm aging compared to white individuals (599% and 498%) according to GrimAge and DPoAm, respectively. Individual‐level factors evaluated account for approximately 43% of the disparity in GrimAge and 34% in DPoAm. Further results suggest that associations between neighborhood social environment and DNAm aging are significant and mediated by individual‐level factors. PM2.5 may be associated with DPoAm acceleration in certain sub‐populations. NO2 and ozone are not significantly associated with DNAm aging. We are investigating individual‐level factors that mediate social environmental exposures and increase vulnerability to PM2.5.ConclusionDNAm aging may play a role in social determinants “getting under the skin” and contributing to age‐related health disparities between Black and white Americans. Work is ongoing to determine the environmental and individual factors that contribute to these disparities.
Association of Cognition with Alcohol Consumption in Cognitively Unimpaired Older Adults: Results from the A4 study
Authors: Nallapu Bhargav Teja , Petersen Kellen K. , Lipton Richard B. , Grober Ellen , Ezzati Ali 
Published: December 2022

AbstractBackgroundExcessive alcohol intake and no alcohol intake are associated with an increased risk of dementia relative to low to moderate alcohol consumption. We aimed to investigate the cross‐sectional association between different levels of alcohol consumption and cognition in the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4 Study). We examined whether this association would differ between sexes or based on individuals’ β‐amyloid (Aβ) status (Aβ+ vs Aβ‐; Aβ+: PET Composite SUVR > 1.15, Aβ‐: Others).MethodA total of 4387 cognitively unimpaired older adults who had both objective and subjective cognitive assessments and amyloid Positron Emission Tomography (PET) imaging. Participants were classified into 4 categories based on their average daily alcohol use: none, one, two, and three or more drinks/day. Multivariable linear regression was used to test the main effects as well as interactions with sex and Aβ levels.ResultParticipants were on average 71.28 (SD = 4.67) years old and 59% female. In the whole population, individuals who reported no alcohol consumption had lower scores on the Preclinical Alzheimer Cognitive Composite (PACC) compared to those who reported consuming one (β[SE] = 0.19[0.08], p = 0.017) or two (β[SE] = 0.22[0.11], p = 0.05) drinks/day (Table 1, Figure 1). In sex‐stratified analysis, the association between alcohol consumption and cognition was more prominent in females. Female participants who consumed two drinks/day had better performance on PACC (β[SE] = 0.32[0.16], p = 0.043) and Cognitive Function Index (CFI; β[SE] = ‐0.27[0.12], p = 0.026) compared to those who reported no alcohol consumption (Figure 2). In an Aβ status‐stratified sample, the association between alcohol consumption and cognition was present only in the Aβ‐ subgroup. Among Aβ‐ individuals, those who consumed one drink/day had better performance on PACC (β[SE] = 0.28[0.09], p = 0.003) and CFI (β[SE] = ‐0.18[0.07], p = 0.009) compared to those who reported no alcohol consumption (Figure 3). The interaction between Aβ status and alcohol consumption on cognition was not significant.ConclusionLow or moderate consumption of alcohol is associated with better cognitive performance in cognitively unimpaired individuals. The association is more prominent in Aβ‐ individuals, which might indicate that the pathophysiologic mechanism underlying the effect of alcohol on cognition is independent of AD‐pathology. The interaction with Aβ status requires further investigation with larger samples consuming 3 or more drinks/day.