bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship of daily, institutional and structural racism with cognition in ethnically/racially diverse middle‐age Americans
Authors: Seblova Dominika , Avila Justina F , Kraal A.Zarina , Starks Tiara M. , Adkins‐Jackson Paris AJ , Brickman Adam M. , Manly Jennifer J 
Published: December 2022

AbstractBackgroundRacism is a social determinant of health that operates at multiple levels ‐ interpersonal, institutional, structural ‐ producing stress and limiting access to resources that have dire biopsychosocial effects for historically marginalized communities. Research on older adults suggests interpersonal and structural racism, separately, are associated with worse cognition and may be an underlying reason for racial/ethnic disparities in cognitive aging. An evidence gap remains on how multilevel racism influences cognition throughout the life‐course.MethodWe assessed 942 middle‐aged community‐dwelling adults (mean age = 55, SD = 11; 64% women; 19% non‐Latinx White; 23% non‐Latinx Black; 55% Latinx). Daily interpersonal racism was ascertained by the Everyday Discrimination (ED) scale, institutional racism by the Major Discrimination (MD) Scale, and structural racism in early life was measured by residential segregation of the census block group in which parents of our respondents lived. Our outcomes were derived from a neuropsychological evaluation with the Digit Span assessing attention and working memory, and delayed recall from the Selective Reminding Test capturing episodic memory. Two fluency measures (animal and letter) were also studied. The relationship between multilevel racism indicators and cognition was estimated using age‐adjusted linear regression models. Additional models were stratified by racialized/ethnic group and added education as a covariate.ResultExposure to multilevel racism varied across racialized/ethnic group. Non‐Latinx Black respondents scored highest on interpersonal racism, second highest on institutional racism, and were more likely to grow up in segregated residential areas with higher proportion of other Black residents. Exposure to interpersonal (Figure A) and institutional racism (Figure B) was associated with lower memory scores and these associations were driven by non‐Latinx Black respondents. Structural racism was associated with lower episodic memory in the full sample.ConclusionOur findings indicate that multilevel racism related to cognition and due to higher exposure among marginalized groups may be a substantial driver of racial/ethnic disparities in cognitive health. In future, additive and multiplicative effects of our exposures will be examined.
Prevalence and clinical associations of atrophy subtypes using clinical routine image analysis software in MCI patients from a memory clinic population
Authors: Schwarz Adam J. , Cavedo Enrica , Gordon Elizabeth , Samper‐González Jorge , dos Santos Clarisse Longo ,   the MEMENTO Study Group
Published: December 2022

AbstractBackgroundThree patterns of brain atrophy have been consistently identified in cases of Alzheimer’s dementia [1]: a limbic‐predominant (LP) phenotype, with atrophy of the hippocampus but relatively spared neocortex; a hippocampal sparing (HS) phenotype, with atrophy in the cortex (especially lateral temporal and parietal lobes) but sparing of the hippocampus; and a typical/diffuse (TD) phenotype that presents with atrophy in both. A recent study extended this concept to a less severely affected memory clinic population (the MEMENTO Study). Here, we assessed atrophy subtypes in that same population using an approach based on the output of QyScore® an FDA‐approved and CE‐marked image analysis software.Method1642 MCI participants from the MEMENTO cohort (Age 71±9, MMSE 27.8±2.0, CDR‐SB 0.6±0.7) had 3DT1 MRI scans analyzed with QyScore®. 678 (41%) had amyloid status from CSF or PET, of which 193 (28%) were amyloid‐positive (A+). Neurodegeneration‐positive (N+) atrophy subtypes were defined on individual scans using z‐scores from parietal cortex and hippocampus volumes referenced to 1290 cognitively normal individuals. LP and HS were defined by atrophy (z<‐1.64) of parietal lobe or hippocampus only, and TD by atrophy in both structures (otherwise N‐).ResultThe proportion of single‐domain amnestic (aMCIsd), multi‐domain amnestic (aMCImd), single‐domain non‐amnestic (naMCIsd) and multi‐domain non‐amnestic (naMCImd) individuals was 10%, 50%, 21% and 18% respectively. N+ subtypes were more prevalent in amnestic (aMCIsd 18%, aMCImd 17%) than non‐amnestic (naMCIsd 8%, naMCImd 10%) presentations. N+ subtypes were more common in A+ participants, especially the amnestic presentations (aMCIsd 42%, aMCImd 29%). Overall, the HS subtype was the most common (8% of all cases, 16% of A+ cases), followed by LP (4%/6%) and TD (2%/3%). The LP subtype was more prevalent in amnestic presentations.ConclusionThe relatively low prevalence of the TD subtype in this cohort is consistent with [2]. The overall prevalence of N+ subtypes in MEMENTO by this method is intermediate between those previously reported using a similar method for ADNI CN A+ and aMCI A+ cohorts [3].[1] Ferriera et al. (2020) Neurology 94:436 [2] Planche et al. (2021) Alz & Dem 17(4):651 [3] Charil et al. (2018) AAIC
Interplay of the human exposome, metabolome and gut microbiome in dementia and major depression
Authors: van Duijn Cornelia M , Amin Najaf , Liu Jun , Bonnechere Bruno , MahmoudianDehkordi Siamak , Arnold Matthias , Batra Richa , Chiou Yu‐Jie , Fernandes Marco , Ikram M. Arfan , Kraaij Robert , Krumsiek Jan , Newby Danielle , Nho Kwangsik , Radjabzadeh Djawad , Saykin Andrew J. , Shi Liu , Sproviero William , Winchester Laura M , Yang Yang , Nevado‐Holgado Alejo J , Kastenmüller Gabi , Kaddurah‐Daouk Rima 
Published: December 2022

AbstractBackgroundThe pathogenesis of dementia and depression is complex involving the interplay of genetic and environmental risk factors including diet, life‐style and the gut microbiome. Dementia and depression co‐occur and metabolomics studies may shed light on the interplay of the various risk factors.MethodsWe have studied the metabolome of 118,466 individuals including 8462 cases with a history of major depression (MDD) and 1,364 patients who developed dementia during follow‐up from the UK Biobank (UKB). The human metabolome was profiled using the Nightingale platform.ResultFor both disorders, we find direct evidence that metabolites involved in the tricarboxylic acid (TCA) cycle are altered in patients, albeit that different metabolites emerge as the most significant drivers in the two disorders. Both dementia and MDD dementia patients show a marked change in the HDL/VLDL axis in blood, with similar changes in particular small and extra large HDL subfractions seen in patients with MDD and those who develop depression in the future. The two patients groups further show similar changes in fat metabolism as measured by omega 3, omega 6 and PUFA levels. When comparing metabolic profiles over environmental risk factors for MDD and dementia, we find that MDD clusters with dementia risk factors physical activity, history of previous smoking and social isolation. Integrating the metabolic profiles of major depression and the gut microbiome we find that the gut microbiome may be a key mediator in the relationship between various metabolites involved in the HDL subfractions associated to both MDD and dementia.ConclusionOur study shows that energy and fat metabolism is disturbed in patients with MDD as well as patients who develop dementia in the future and that the interplay between the genome, exposome, gut microbiome, human metabolome may play role in the co‐occurrence of major depression and dementia.
A Novel Protective locus significantly reduces the ApoEε4 risk for Alzheimer’s Disease in individuals of African Ancestry.
Authors: Vasquez Marina Lipkin , Rajabli Farid , Beecham Gary W. , Hendrie Hugh C , Baiyewu Olusegun , Ogunniyi Adesola , Gao Sujuan , Kushch Nicholas A. , Hamilton‐Nelson Kara L. , Young Juan J , Dykxhoorn Derek M. , Nuytemans Karen , Kunkle Brian W. , Wang Liyong , Jin Fulai , Liu Xiaoxiao , Feliciano‐Astacio Briseida E. , Dalgard Clifton L. , Griswold Anthony J. , Byrd Goldie S. , Reitz Christiane , Haines Jonathan L. , Pericak‐Vance Margaret A. , Vance Jeffery M. ,   Alzheimer’s Disease Sequencing Project,   Alzheimer’s Disease Genetic Consortium
Published: December 2022

AbstractBackgroundAfrican ancestry populations have a lower risk for developing Alzheimer disease (AD) from ApoEε4 compared to other populations. Understanding this mechanism of protection could lead new therapeutic insights for AD. Our goal is to identify areas of the genome that interact with ApoEε4 in African ancestry that result in the lowered risk for developing AD in this population.MethodsWe performed association analyses using a logistic regression model with ApoEε4 allele as an interaction term and adjusted for genome‐wide ancestry, age, and sex. Discovery analysis included imputed SNP data from 1,850 African American (AA) individuals with AD and 4,331 AA controls. We performed replication analysis on whole‐genome sequenced (WGS) data from 1) 63 Ibadan (Nigerian) AD individuals and 648 Ibadan controls; 2) WGS 273 Puerto Rican (PR) AD individuals and 275 PR controls; and 3) SNPs imputed from 8,463 non‐Hispanic White (NHW) AD individuals and 11,365 NHW controls.ResultsWe identified a significant interaction with the ApoE ε4 allele and the SNP rs10423769_A allele, that reduces the odds ratio for AD risk from 7.2 for ApoEε4/ε4 without the A allele to 2.1 for allele ApoEε4/ε4 carriers with at least one A allele. rs10423769 (frequency = 0.11 in AA, NHW= 0.003) is located approximately 2 megabases distal to ApoE, in a large cluster of pregnancy specific beta‐1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. rs10423769 is reported to be a splicing QTL (sQTL) for TMEM145, whose highest brain expression is in the cerebellum. This interaction analysis was identified in the discovery AA dataset (β=‐0.54, SE=0.12,p‐value=7.50x10‐6), and this finding was replicated in both the Ibadan (β = ‐1.32,SE = 0.52,p‐value = 1.15x10‐2) and PR (β=‐1.27,SE=0.64,p‐value=4.91x10‐2) datasets while it trended but was not significant in the NHW dataset.ConclusionThis study identified a new African‐ancestry specific locus that reduces the risk effect of ApoEε4 for developing AD by approximately 75%. The genes lying near this protective locus suggest potential new protective mechanisms for AD development.
Short Telomeres Associate with Hyperphosphorylated Tau Burden in Primary Age‐Related Tauopathy
Authors: McMillan Corey T , Adhikari Bandita , Farrell Kurt W. , Wolk David A. , Lee Eddie B ,   PART Working Group, Crary John F. , Johnson F Brad 
Published: December 2022

AbstractBackgroundPrimary age‐related tauopathy (PART) is characterized by neuropathological hyperphosphorylated tau burden (p‐tau) in the absence of significant amyloid pathology. Aging is a major risk factor for p‐tau that is generally defined chronologically in years since birth. Telomeres shorten with age and various sources of DNA damage and thus telomere lengths (TL) provide an alternative measure of biological age. Additionally, DNA methylation (DNAm) changes over time and may contribute to changes in TL. Together, we hypothesize that shorter mean TL will be associated with increased risk of p‐tau burden and that this process may be mediated by DNAm.MethodWe extracted DNA from frontal cortex of 113 individuals (Age=87.3+9.3; 37% Female) that met neuropathological criteria for definite PART. We measured mean TL using qPCR to determine the copy number of telomere repeat DNA in comparison to a single copy gene. The assays were performed in a blinded fashion, and each sample was measured using two different amounts of input DNA to ensure linearity. We also measured bisulfite‐converted DNA methylation using the Illumina MethylationEPIC BeadChip Kit for ∼850K CpGs. P‐tau burden was measured in medial temporal cortex (entorhinal cortex and hippocampus proper) using an Aperio Digital Pathology Slide Scanner. Linear regression related TL to p‐tau burden, adjusting for age. We used eWAS to relate methylation to TL. Lastly, non‐parametric bootstrapping using the mediation package in R was used to evaluate whether TL association with p‐tau burden may be mediated by DNAm.ResultShorter TL was significantly associated with increased p‐tau burden (B=‐0.28; p=‐.003), including adjustment for age (B=0.003; p=0.003). eWAS identified six CpG sites significantly associated with TL (all q<0.05). Causal mediation analyses identified that two of these CpGs partially mediate the association between TL length and p‐tau burden: 32.5% proportion mediated by cg08701686 (UNC5D) and 48.6% proportion mediated by cg24533059 (near IFNGR1 and OLIG3).ConclusionShorter TL is associated with increased p‐tau pathological burden in PART and may be mediated in part by DNAm at particular loci. These findings support the concept that biological aging, as measured with TL and DNAm, may contribute to tauopathy beyond chronological age effects.
Choice of Inversion Time for Arterial Spin Labeling MRI in the U.S. POINTER Lifestyle Intervention Trial
Authors: Jung Youngkyoo , Hong Sarah Y. , Kim Donghoon , Vemuri Prashanthi , Borowski Bret J. , Jack Clifford R. , Koeppe Robert A. , Lockhart Samuel N. , Harrison Theresa M. , Gordineer Leslie , Woolard Nancy , Espeland Mark A. , Harvey Danielle J. , Lovato Laura , Toga Arthur W. , Masdeu Joseph C. , Oh Hwamee , Gitelman Darren R. , Aggarwal Neelum T. , Carrillo Maria C. , Snyder Heather M. , Whitmer Rachel A. , Baker Laura D. , DeCarli Charles S. , Landau Susan M. 
Published: December 2022

AbstractBackgroundThe U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2‐year randomized controlled trial to evaluate the effect of lifestyle interventions in older adults (60‐79 years). The POINTER Imaging ancillary study is collecting Arterial Spin Labeling (ASL) MRI data to map cerebral blood flow (CBF) and evaluate the effect of interventions in the perfusion imaging biomarker. The optimization of timing parameters is essential for robust and efficient acquisition of ASL MRI.MethodA subset (n=83; F/M=51/32; age=69.0±5.5) of POINTER Imaging participants at two imaging sites underwent two ASL MRI scans during the same baseline session. Two 3D Pulsed ASL were obtained with TI1 of 790ms and TI2 values of 2000ms or 2750ms, which provide the delay times (between labeling and imaging) of 1210ms or 1960ms. ASL images were quantified into a physiological unit of CBF, ml/100g/min, using a single compartment kinetic model. CBF maps from two scans were normalized into a standard space and a voxel‐wise paired t‐test was performed after site variations were harmonized and covariates (age and sex) were adjusted. The age and sex effects in the difference of CBF values between two scans were also examined using linear regression. To control false positives, clusters smaller than 41ml were removed based on a simulation with α=0.05.ResultThe CBF values in ASL MRI rely on the timing of image acquisition: only a fraction of label bolus arrives in the tissue with a short delay while images suffer from low signal due to the magnetization decay with a long delay. Figure 1 shows the regions that require a long delay time (red) or a short delay (blue). The difference in CBF is proportional to arterial transit time (ATT) and the analysis shows females have shorter ATT mainly in the peri‐Sylvian region (Figure 2). No cluster survived correction in the analysis of the aging effect.ConclusionThe acquisition of two CBF maps not only offers optimization of acquisition timing but provides an additional perfusion parameter, arterial transit time, which may be a potential biomarker of cerebrovascular pathophysiology.
Learning differentially increases the synaptic levels of AMPA receptor subunits (GluA1‐GluA4) in the rodent hippocampus: a single‐synapse approach
Authors: Prieto G. Aleph , Rodriguez‐Ortiz Carlos J. , Kitazawa Masashi , Cotman Carl W. 
Published: December 2022

AbstractBackgroundDecades of experimental work support the idea that synapses are the anatomical substrate for experience‐dependent plasticity in the brain. Changes in the synaptic strength underlie learning and memory via the accumulation of glutamate AMPA receptors (AMPAR) at the surface of excitatory synapses. AMPAR are tetrameric receptors constituted by multiple combination of four subunits: GluA1 GluA2, GluA3, and GluA4. However, the relative contribution of each AMPAR subunit on learning and memory is relatively unexplored.MethodHere, we introduce Fluorescence Analysis of Single‐Synapse Potentiation induced by Learning (FASS‐PiL), a flow cytometry‐based method to quantify surface levels of all four GluA‐AMPAR subunits, in parallel, in isolated synaptosomes after a learning episode in rodents. We evaluated surface levels of all four AMPAR subunits in synaptosomes of mice trained in a learning protocol commonly used for studying episodic memory in the hippocampus (e.g., Object Location Memory (OLM) and Object Recognition Memory (ORM) tasks). Briefly, after exploring novel objects in a novel environment for 10 min, mice were returned to their home cage for 60 min. After hippocampus dissection, synaptosome isolation, and immunostaining, samples were analyzed via flow cytometry.ResultWe first demonstrated that FASS‐PiL is a simple and sensitive method to track all four GluAs at the synaptosome surface (each GluA subunit was paired with the presynaptic marker Neurexin‐1beta to focus on synaptosome particles containing both pre‐ and postsynaptic compartments). Notably, by profiling hundreds of events, our data showed that the OLM training increases the number of hippocampal synaptosomes expressing high levels of GluA1 and GluA2, but not GluA3 and GluA4 (vs control animals).ConclusionOur results indicate that plasticity‐related mechanisms underlying learning are AMPA‐subunit‐specific in hippocampal synapses. Our approach could provide the basis for protocols to study behavioral‐relevant mechanisms of plasticity directly at the synapse, with single‐event resolution.
Distinguishing between amyloid‐beta‐directed antibodies: Ability of PMN310 to target toxic oligomers despite competing species
Authors: Gibbs Ebrima , Coutts Juliane , Roman Andrei , Zhao Beibei , Kaplan Johanne , Cashman Neil R 
Published: December 2022

AbstractBackgroundA large body of evidence indicates that the most pathogenic species of Abeta in Alzheimer’s disease (AD) consist of soluble toxic oligomers as opposed to insoluble fibrils and monomers. The ability of a therapeutic antibody to target toxic Abeta oligomers without being diverted by binding to competing non‐toxic species is expected to result in greater efficacy. This is supported by clinical results to date showing poor efficacy of non‐selective antibodies but improved success with partially selective antibodies that bind oligomers and plaque. As a next generation antibody, PMN310 is a therapeutic candidate designed to more selectively target toxic oligomers. Avoiding interaction with plaque and vascular deposits has the additional advantage of potentially decreasing the incidence of amyloid‐related imaging abnormalities (ARIA). In this study, PMN310 was compared to other Abeta antibodies for selectivity and ability to maintain interaction with toxic oligomers in the presence of competing monomers.MethodsThe binding of multiple Abeta‐directed antibodies (PMN310 and biosimilars donanemab, aducanumab, lecanemab, crenezumab, solanezumab) to synthetic oligomers, with and without pre‐exposure to competing monomers, was evaluated by surface plasmon resonance (SPR). Binding of the antibodies to a toxic oligomer‐enriched low molecular fraction of brain extract from AD patients was similarly evaluated by SPR, with and without monomer competition. Binding to insoluble Abeta deposits was examined by immunohistochemistry (IHC) of AD brain sections.ResultsPMN310 showed little or no interaction with monomers and was among the least impacted by excess monomer competition in binding to synthetic oligomers or naturally occurring toxic oligomers in AD brain extract. This characteristic was shared by other Abeta antibodies that have shown positive clinical outcomes. Non‐selective antibodies that failed in the clinic were strongly inhibited by monomer competition. In contrast to other Abeta antibodies, PMN310 additionally avoided interaction with plaque and vascular deposits as determined by IHC.ConclusionsPMN310 distinguishes itself from other Abeta antibodies by its enhanced selectivity for toxic oligomers (negligible binding to monomers and plaque) along with its ability to withstand competition by abundant monomers. Additionally, the avoidance of interaction with plaque and vascular deposits by PMN310 could potentially reduce the risk of ARIA.
Event timelines for atrophy‐defined subtypes of Alzheimer’s disease
Authors: Aksman Leon M. 
Published: December 2022

AbstractBackgroundA variety of studies have consistently identified three distinct atrophy subtypes in AD1. However, little is known about the timeline of progression for each subtype. Here, for the first time, we identify these timelines using data‐driven disease progression models.MethodWe used a cross‐sectional subtyping model to identify known atrophy subtypes followed by longitudinal disease progression models to identify subtype‐specific event timelines. We first applied the mixture version of Subtype and Stage Inference (SuStaIn2,3) algorithm to 1133 subjects’ CSF‐based amyloid (ABETA), total and phosphorylated tau (TAU and PTAU), MRI‐based hippocampal and cortical volume and cognition (ADAS13 and MMSE). For each biomarker, we built mixture models using cognitively normal, CSF amyloid negative subjects to define normality and diagnosed AD subjects to define abnormality. We used each subject’s last available MRI visit and built a four‐subtype model. We identified the ‘typical’, ‘cortical’ and ‘subcortical’ subtypes and a fourth subtype with non‐AD related progression, which we excluded from further analysis. We also excluded those at stage zero (controls). This left 828 subjects: 540 typical, 177 cortical and 67 subcortical. We then applied the Temporal Event Based Model (TEBM3) to each subtype separately, using all available longitudinal data for each subject. We used the mixture model version of the TEBM with the same eight biomarkers and the same mixture modeling approach. We bootstrapped each subtype’s TEBM model 30 times to estimate confidence intervals for each event.ResultThe TEBM models strongly agreed with the ordering of events in the SuStaIn model (Figures 1 and 2). The typical subtype’s event timeline has onset of cognitive impairment occurring roughly 15‐20 years after tau abnormality (Figure 2). In the cortical subtype, cognitive impairment occurs several years earlier (roughly 5‐12 years), whereas in the subcortical subtype abnormal MMSE and ADAS13 are the earliest events, with decreased hippocampal volume following.ConclusionThere are clear differences in both the timing and uncertainty of events across subtypes.References1. Ferreira, et al., 2019, Neurology.2. Young, et al., 2018, Nature Communications.3. Aksman, Wijeratne, et al., 2021, SoftwareX.4. Wijeratne and Alexander, 2021, IPMI.