bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered HDL Cholesterol Efflux Capacity and LCAT Activity is APOE‐Specific in Alzheimer Disease and Mild Cognitive Impairment Patients
Authors: Hong Brian V. , Agus Joanne , Zheng Jack Jingyuan , Lebrilla Carlito B. , Jin Lee‐Way , Maezawa Izumi , Harvey Danielle J. , Zivkovic Angela M. 
Published: December 2022

AbstractBackgroundHigh‐density lipoproteins (HDL) in circulation perform a crucial role in maintaining cholesterol homeostasis by removing cholesterol from peripheral tissues for excretion. High HDL has been linked with a lower risk of developing Alzheimer’s Disease (AD). However, the concentration of HDL only partially accounts for the variation in the ability of HDL to perform their primary function to efflux cholesterol. Apolipoprotein E (APOE) is the strongest genetic risk factor for AD, and its role in regulating cholesterol is implicated in AD. However, the complex relationship between APOE genotype and the function of peripheral HDL in AD patients remains largely unknown.MethodWe isolated HDL from plasma of 194 age‐ and sex‐matched, ApoE genotyped participants (non‐demented controls, n = 83; mild cognitive impairment, n = 40; AD dementia, n = 71) using two‐step flotation ultracentrifugation, followed by size exclusion chromatography. HDL cholesterol efflux capacity (CEC) and lecithin‐cholesterol acyltransferase (LCAT) activity were measured. We further explored the relationships between HDL functional capacity and cognitive, functional, and imaging scores.ResultRegardless of diagnosis, ApoE3/E4 carriers had significantly lower CEC index (p = 0.003) and LCAT activity (p < 0.001) vs. ApoE3/E3 carriers. When participants were stratified by APOE genotype and diagnosis, ApoE3/E3 MCI patients had significantly lower CEC index than controls (p = 0.042). In contrast, the CEC index of ApoE3/E4 AD patients was paradoxically increased compared to controls (p = 0.016). ApoE3/E3 MCI and AD patients had lower LCAT activity than controls (p = 0.012 and p = 0.004, respectively), but there were no differences in LCAT activity in ApoE3/E4 participants by diagnosis group. LCAT activity was positively correlated with verbal memory score (p = 0.033) and negatively correlated with clinical dementia rating (p = 0.025).ConclusionTo our knowledge, our study revealed for the first time an APOE genotype‐dependent alteration in peripheral HDL functional capacity among AD and MCI patients compared with non‐demented controls and an association between HDL LCAT activity and cognitive and functional scores.
Evolution of awareness for cognitive decline across several cognitive domains in stable vs clinically progressing participants.
Authors: Gagliardi Geoffroy Pierre , Vannini Patrizia , Mimmack Kayden J. 
Published: December 2022

AbstractBackgroundAwareness of memory impairment has been shown to vary across the AD spectrum with an initial heightened awareness at the preclinical stage, and a subsequent loss of awareness with AD progression (Hanseeuw et al.,2020). Whether there are potential differences in the evolution of awareness for cognitive domains other than memory is unknown. In this study, we investigated the evolution of awareness in visuospatial, language, planning, divided attention and organization in cognitively older adults that later progressed versus those who remained stable.MethodsOur study included 621 cognitively normal (CN) ADNI participants (Tab1). Individuals were considered Stable or Progressors (n = 147) on the basis on the Clinical Dementia Rating scale global score (stable: scores at first and last observation both 0, progression:last score≥0.5). Cognitive complaints were recorded using the Everyday Cognition (ECog) questionnaire, using both participant’s and informant’s average complaints in each of the six subscales: divided attention, language, memory, organization, planning and visuo‐spatial. Generalized linear mixed‐effect models were run to predict complaints within each subscale, using time, the source of complaint (informant vs participant), and their interaction as independent variables, adjusting for age, gender and education. Jonhson‐Neyman Points (JNP) were computed for significant interactions, and simple slopes analyses were performed.ResultsStable participants displayed a similar evolution of both informant and participant complaints (Fig1, left panels). Among progressors, all models showed significant interactions with participants expressing greater, and subsequent lower complaints than informants (Fig1, right panels). JNP analyses revealed that, while on some subscales this transition occurred only after/close to progression (i.e., divided attention, language, memory and organization), it could be observed years before progression in others (i.e., planning and visuo‐spatial).ConclusionsProgressive participants expressed greater, and then lower complaints as compared to their informant, demonstrating a transition from heightened to reduced awareness over time. Our results attest that, while most studies are focusing on memory awareness, other domains might also show early changes in awareness. This advocates for including the informant’s appraisal in the examination process, as well as to expand the focus to other cognitive abilities.
Linking histology to post‐mortem 7T MRI measures of neurodegeneration
Authors: Sadaghiani Shokufeh , Ravikumar Sadhana , Ittyerah Ranjit , Lim Sydney A , Chung Eunice , Bedard Madigan L , Xie Long , Das Sandhitsu R. , Schuck Theresa , Grossman Murray , Lee Eddie B , Tisdall Dylan M , Prabhakaran Karthik , Detre John A. , Mizsei Gabor , Trojanowski John Q , Irwin David J. , Wisse Laura EM , Wolk David A. , Yushkevich Paul A. 
Published: December 2022

AbstractBackgroundNeurodegenerative disorders are associated with different pathologies that often co‐occur and have differential contribution to the pattern of cognitive impairment. The majority of these pathologies cannot be detected or measured by in‐vivo methods; therefore, recognition of the topographic patterns of them and association with MRI findings may provide probabilistic non‐invasive biomarkers. We investigated the association of cortical and medial temporal lobe subregional thickness measured from postmortem MRI and semi‐quantitative pathologic measures in order to provide a methodological approach for linking pathological and radiological measures.Method22 brain hemispheres from donors with Alzheimer’s disease (AD) spectrum diagnosis were included. T2‐weighted images were obtained on 7 Tesla scanner (0.28 mm isotropic) and patches of cortex around 16 anatomical locations were segmented using semi‐automated active contour segmentation in ITK‐SNAP. Immunohistochemistry evaluation was performed using previously validated antibodies to detect amyloid‐β, phosphorylated tau, phosphorylated TDP‐43 deposits and pathological conformation of α‐synuclein on contralateral hemispheres. Neuronal loss was visually assessed. Thickness measures at each location were associated with pathology measures at corresponding or closest to corresponding anatomical location. Multivariate linear models were used for statistical analyses.ResultThe mean age of donors at death was 80.2±10.7 years (range 63‐99) and 8 (36%) were female. The median Braak stage was 5 (range: 2‐6). Linear models including regional Tau and TDP43 scores and age showed significant relationships between increased regional tau score and reduced thickness in anterior temporal pole, entorhinal, angular and superior parietal cortices. (Table 1, Figure 1) Linear models including Braak stages, TDP43 scores and age showed significant correlation between Braak stage and thickness in anterior temporal pole and entorhinal cortices and BA35 region of medial temporal lobe.ConclusionThe aim of the current study is to validate methods for development of 3D pathology maps which can be directly linked to local neurodegeneration measures. As the primary result of such an effort, the present study demonstrates an association of semi‐quantitative measures of AD pathology and with local tissue loss in several common AD regions despite limited range of pathology in these cases. These promising results provide support for future studies directly linking pathology with post‐mortem measures of structure.
Sex differences implications in hippocampal volumetry during midlife
Authors: Caillaud Marie , Foret Janelle T , Gallagher Isabelle , Haley Andreana 
Published: December 2022

AbstractBackgroundSex differences in adult brain morphology are frequently reported. Hippocampal and medio‐temporal (MTL) cortices in women and men are frequently implicated in Alzheimer’s Disease (AD) pathology, and women are disproportionally more affected by AD than men. Modifications in these regions’ volumetry are described during aging and in pathology, but their specificities during midlife regarding sex are still debated. Also, the multifaceted interactions between sex and dementia risk factors in these brain areas are not fully established. The aim of this study is to precisely identify the differences between women and men in the volumetry of hippocampal and MTL subregions, as well as the moderation effects of risk factors for dementia such as hypertension (diastolic blood pressure), hypercholesterolemia, obesity (body mass index), physical inactivity, and inflammation (C‐Reactive Protein), on sex.MethodData from 210 cognitively healthy participants were analyzed (106 women; 104 men; age 40‐65). Automatic segmentation was performed to determine the volume of the bilateral anterior and posterior hippocampus, and of entorhinal, perirhinal (BA35 and BA36), and parahippocampal cortices (ASHS‐PMC‐T1 atlas). The total intracranial volume was obtained to calculate adjusted‐volumes for every participant. An analysis of covariance (ANCOVA) was performed to compare women and men subregions’ volumes, corrected for age. Linear regressions were performed to analyze the interactions between sex and dementia risk factors on the volumetry of these regions.ResultWomen and men were significantly different in the volume of the left (p < .001) and right (p < .001) hippocampus, on the right BA35 (p = .008), and on the left (p < .001) and right (p < .001) parahippocampal cortices. No significant interaction was highlighted between sex and risk factor variables.ConclusionBeyond basic demography, sex is essential to consider in research, as women and men appear to be inherently different in their brain morphometry, even from midlife. Volumetric differences in AD‐linked brain regions, regardless of potential dementia risk factors, may be an innocuous sex‐specific feature at the preclinical phase. In this regard, women’s vulnerability to AD may not occur until later in aging, potentially linked to hormonal decline.
Tau levels are higher in objective subtle cognitive decline, but not subjective memory complaint
Authors: Thomas Kelsey R. , Weigand Alexandra J. , Edwards Lauren C. , Edmonds Emily C. , Bangen Katherine J. , Ortiz Gema , Walker Kayla S. , Bondi Mark W. 
Published: December 2022

AbstractBackgroundThe 2018 NIA‐AA Alzheimer’s disease (AD) Research Framework states that subtle cognitive decline in cognitively unimpaired individuals can be measured by subjective report or evidence of objective decline on neuropsychological measures. Both subjective memory complaint (SMC) and objective subtle cognitive decline (Obj‐SCD) have been shown to be associated with future cognitive decline and AD biomarkers. We examined whether there are tau PET differences in a) SMC‐ vs. SMC+ participants, b) Obj‐SCD‐ vs. Obj‐SCD+ participants, and c) participants with overlapping/discrepant SMC and Obj‐SCD classifications.MethodParticipants without MCI or dementia from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 236) were classified at baseline as positive or negative for SMC (SMC‐ n = 77; SMC+ n = 159) based on the first 12 items of the Cognitive Change Index and/or classified as positive or negative for Obj‐SCD (Obj‐SCD‐ n = 173; Obj‐SCD+ n = 63) based on previously defined neuropsychological criteria. Analyses of covariance, adjusting for age, sex, APOE ε4 status, and pulse pressure, examined group differences in tau PET (AV‐1451) using a composite SUVR for regions consistent with Braak stage III/IV. Chi‐squared tests examined tau positivity rates across groups.ResultObj‐SCD+ participants had higher tau levels (p = .035, ηp
2 = .019) and higher rates of tau positivity (15.8% Obj‐SCD‐ vs. 30.2% Obj‐SCD+) than Obj‐SCD‐ participants. Neither tau levels (p = .381, ηp2 = .003) nor tau positivity rates (18.2% SMC‐ and 20.1% SMC+) differed for SMC groups. There was little agreement between SMC and Obj‐SCD (42%; κ = 0.01, p = .811). Participants with only Obj‐SCD had the highest tau PET levels and differed from participants with only SMC (p = .022). Tau levels in SMC+/Obj‐SCD+ participants did not differ from those with only Obj‐SCD (p = .216). Tau positivity rates across SMC‐/Obj‐SCD‐, SMC+/Obj‐SCD‐, SMC‐/Obj‐SCD+, and SMC+/Obj‐SCD+ groups were 10.5%, 18.1%, 40.0%, and 25.6%, respectively.ConclusionParticipants with Obj‐SCD had greater tau burden than those without Obj‐SCD, but SMC was not associated with higher tau levels. The combination of SMC and Obj‐SCD did not have higher tau levels than Obj‐SCD alone. Findings add to the evidence that the Obj‐SCD classification is associated with AD biomarkers and faster cognitive decline in ADNI participants, but further work is needed to validate this approach in more representative/diverse cohorts.
Independent and interactive effects of APOEε4 and β‐amyloid on cortical thickness in Alzheimer’s disease
Authors: Tennant Victoria R , Rajagopalan Priya , Thomopoulos Sophia I , Thompson Paul M 
Published: December 2022

AbstractBackgroundThe apolipoprotein (APOE) ε4 allele is a major risk factor for Alzheimer’s disease (AD) and potentiates β‐amyloid (Aβ) accumulation. Both APOEε4 and Aβ individually contribute to neurodegeneration in the aging brain. Here, we investigate the independent and interactive effects of APOEε4 and global Aβ load on cortical thickness and disease severity across the AD continuum.MethodWe used FreeSurfer v7.1.1 to derive brain morphometry measures from regions‐of‐interest (ROIs) in 796 subjects (N=475 controls (CN), N=77 participants with mild cognitive impairment (MCI), N=244 with dementia; Table 1) to analyze associations between cortical thickness, APOEε4, and Aβ using available T1‐weighted MRI scans from ADNI phases 2 and 3. Multiple linear regression models were run, covarying for age and sex, to examine the effects of APOEε4 status, global Aβ, and their interaction on morphometric measures from ROIs known to be vulnerable to Aβ deposition in aging and disease (Figure 1‐ adapted from La Joie et al.).ResultIn the MCI and dementia groups, higher global Aβ was associated with lower cortical thickness in middle temporal, fusiform, and parietal regions (p<0.05), but was not associated with cortical thickness in controls. In the dementia group, there was a significant effect of Aβ (p<0.001) and an APOEε4 by Aβ interaction (p=0.01) in the inferior parietal gyrus (Figure 2). The interaction effect requires replication due to the multiple hypothesis testing.ConclusionUnlike in healthy aging, as disease severity increases, the interactive effect of Aβ and APOEε4 status significantly affects cortical thickness in regions associated with Aβ deposition. This suggests that APOEε4 differentially affects cortical thinning during different stages of disease severity.
Learning Streamline Embeddings with Variational Autoencoder for Intersubject Bundle Comparison in Alzheimer’s Disease
Authors: Feng Yixue , Chandio Bramsh Q , Chattopadhyay Tamoghna , Thomopoulos Sophia I , Owens‐Walton Conor , Garyfallidis Eleftherios , Jahanshad Neda , Thompson Paul M 
Published: December 2022

AbstractBackgroundTractograms generated from diffusion MRI (dMRI) can be used to evaluate white matter abnormalities in Alzheimer's Disease patients (AD). However, the large quantity of streamlines causes problems for downstream analysis. Here we use a variational autoencoder (VAE) with a 1D convolutional layer (ConvVAE) to embed streamlines in a 2D latent space. The generative nature of ConvVAE allows us to apply Euclidean distances directly to embeddings and perform intersubject fiber bundle comparisons.MethodMulti‐shell dMRI from 141 subjects ‐ 87 cognitively normal controls (CN), 44 with mild cognitive impairment (MCI), 10 with dementia (AD) ‐ from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were preprocessed using the ADNI3 dMRI protocol. 30 white matter tracts were extracted from whole brain tractograms per subject using DIPY's RecoBundles. A control subject with 51,654 streamlines was used to train the ConvVAE with Evidence lower bound (ELBO) loss. We evaluated results by visualizing 2D embeddings and reconstructed streamlines. K‐nearest neighbor (KNN) clustering with Euclidean distance (k=5) was performed on the control subject in a bundle labeling task, to evaluate the alignment between embeddings and generated bundle labels.Result2D embeddings for the control subject used for training and a randomly selected MCI and AD subject are shown in Fig. 1, colored by bundles (top) and hemisphere (bottom). Embeddings for each bundle are aligned between subjects, reflecting the shape, size and orientation of the bundle in the streamline space. Embeddings, streamlines and reconstruction for 4 left hemisphere bundles are plotted in Fig. 2. Linearly interpolated points sampled from the latent space translate into smooth transitions in the streamline space, so Euclidean distance can be used in downstream tasks. The fitted KNN model was evaluated on all other subjects where the weighted accuracy for each group was 80.56% (CN), 78.59% (MCI) and 75.76% (AD).ConclusionConvVAE generates 2D embeddings that preserve bundles' spatial and shape information. It learns a smooth latent space from streamlines, which allows for meaningful decodings from sampled points and can be directly applied to new data. Distance‐based algorithms can be used in downstream tasks, such as bundle labeling and intersubject comparisons.
Inhibition of cPLA2 ameliorates memory deficits and reduces neuroinflammation in ApoE4‐TR mice
Authors: Wang Shaowei , Ebright Brandon , Sun Yi , Li Boyang , Asante Isaac , Louie Stan G , Yassine Hussein N. 
Published: December 2022

AbstractBackgroundThe activation of calcium‐dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling by promoting the conversion of arachidonic acid (AA) into eicosanoids, while catabolizing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We previously found higher cPLA2 activation correlated with increased pro‐inflammatory lipid metabolites in APOE4 brains. However, it is not known whether the inhibition cPLA2 will decrease neuroinflammation ApoE4‐mice.MethodFirst, ApoE4 targeted replacement mice (ApoE4‐TR, n = 3, male, 4 months old) were treated daily with vehicle or the specific cPLA2 inhibitor ASB14780 (10 mg/kg, intraperitoneal) for three days. The brains were collected and analyzed using LC‐MS based lipidomics. Second, ApoE2‐TR (n = 14, 8M/6F), ApoE3‐TR (n = 12, 5M/7F) and ApoE4‐TR (n = 17, 8M/9F) mice were fed a low‐DHA diet starting at 6 months old. ApoE4 mice were treated daily for three weeks with vehicle (n = 8, 4M/4F) or 10mg/kg/day ASB14780 IP (n = 9, 5M/4F) starting at 14 months old. Behavioral tests were subsequently conducted on the mice, after which the brains were collected for lipidomic and biochemical analyses.ResultIP ASB14780 was detected in brain tissue corresponding with decreases in pro‐inflammatory metabolites of AA after only 3 days treatment in ApoE4‐TR mice. In addition, long term ASB14780 treatment decreased brain cPLA2 phosphorylation levels and significantly increased brain EPA and DHA levels (p<0.01 for both) but did not change brain AA levels in ApoE4‐TR mice. Compared to ApoE3‐TR mice, untreated ApoE4‐TR mice had higher levels of inflammatory eicosanoids (e.g., prostaglandin E2, PGE2) resulting from AA metabolism. However, ASB14780 treatment decreased inflammatory metabolites in ApoE4‐TR mice. Additionally, ASB14780‐treatment was able to reduce microglia activation in ApoE4‐TR mice (p = 0.04 for hippocampus and p<0.01 for cortex). For behavioral experiments, ApoE4‐TR mice had significantly lower discrimination index compared to ApoE3‐TR mice at 15 months using the novel object recognition test (p = 0.029). Treatment with ASB14780 ameliorated the recognition deficits of ApoE4‐TR mice but the effects did not reach statistical significance (p = 0.15).ConclusionOur findings reveal inhibition of cPLA2 with ASB14780 could ameliorate eicosanoid‐driven neuroinflammation in ApoE4 mice, restoring synaptic dysfunction, and preventing behavioral deficits. cPLA2 represents a potential drug target to mitigate increased neuroinflammation with APOE4 and AD.
Neighborhood Deprivation and Mortality Risk among Medicare Beneficiaries with Alzheimer’s Disease and Related Dementia
Authors: Paley Joshua , Hernandez Inmaculada , Brown Joshua , Wu Yonghui , Bian Jiang , Anton Stephen , Guo Jingchuan 
Published: December 2022

AbstractBackgroundAlzheimer’s Disease (AD) and Related Dementias (ADRD) is a class of progressive fatal degenerative diseases that presents multiple causations and outcomes related to its biological, medical, and social determinants of health (SDoH). Studies have extensively explored biological and medical factors, however, SDoH, which is known to contribute to structural inequities in health outcomes, is understudied. We aimed to study the association between neighborhood deprivation (an important SDoH measurement of socioeconomic disadvantage), and the risk of mortality among older adults diagnosed with AD/ADRD.MethodUsing a 5% random sample of national Medicare claims data, we identified individuals newly diagnosed with ADRD in 2006‐2013. The outcome of interest was all‐cause mortality. The exposure of interest was area deprivation index (ADI), a validated neighborhood deprivation measure that incorporates factors of poverty, education, housing, and employment. ADI was spatiotemporally linked to the study cohort using 9‐digit ZIP codes and index scores were classified into 6 categories: quartiles plus the 10th and 90th percentile. We applied generalized estimation equations to model an odds ratio (OR) of mortality across the ADI categories while adjusting for demographic and clinical factors. Subgroup analyses were modeled within urban and rural areas, respectively.ResultsWe included 74,462 patients with ADRD diagnosis, with a mean age of 82 (SD: 8.2) years; 72.3% were women and 65.8% (n = 31218) died over a median follow‐up of 3.5 years. A dose‐gradient association between the ADI and all‐cause mortality was observed in the ADRD population, with the risk of mortality gradually increasing with greater deprivation (Table). The dose‐gradient association between ADI and mortality remained after stratifying by urban and rural areas. ADRD patients in rural areas had a higher mortality risk than those in urban areas (Table).ConclusionOur findings suggest neighborhood deprivation is an important risk factor of mortality among older adults with ADRD while accounting for individuals’ demographic and clinical characteristics. The current results underscore the need for the design and implementation of intervention and policy programs to address structural disparities in outcomes of ADRD patients.