bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSF sTREM2 has opposite association with brain structural damage rate at early and late stage of Alzheimer’s disease
Authors: Leng Fangda , Zhan Zhenying , Edison Paul , Sun Yunchuang , Liu Fang , Sun Yongan , wang Zhaoxia 
Published: June 2023

AbstractBackgroundThe role of neuroinflammation in the pathogenesis of Alzheimer’s disease (AD) is still controversial. Recent studies proposed that microglial response may have a stage‐dependent effect on disease progression. Considering the CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) has emerged as a promising marker of microglial activation, we aimed to further test this hypothesis by studying the association between baseline sTREM2 with dynamic brain structural changes in different stage of AD.Method22 amyloid‐positive (A+) and tau‐positive (T+) AD patients and 24 A+T+ MCI patients were identified from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The patients had baseline measurements of CSF A‐beta, P‐Tau, sTREM2, baseline and follow‐up T1‐weighted and diffusion tensor imaging (DTI) scans, and were followed up for at least one year. Voxel‐based morphometry (VBM) analysis was performed to assess grey matter volumetric change, while fractional anisotropy (FA) and mean diffusivity (MD) were derived from DTI scans to evaluate white matter microstructural integrity. Linear mixed effect models were then applied to model the longitudinal change of grey and white matter integrity, and to analyze the influence of baseline sTREM2 on the rate of brain structural changes.ResultIn A+T+ AD patients, baseline CSF sTREM2 was associated with faster FA decline and MD increase in association fibers including corpus callosum, inferior longitudinal fasciculus, cingulum, inferior fronto‐occipital fasciculus, and superior longitudinal fasciculus. In A+T+ MCI patients, baseline CSF sTREM2 was associated slower grey matter volumetric loss in regions including Alzheimer’s signature cortices such as angular gyrus and precuneus, while mixed findings were found regarding white matter integrity, with a protective effect with regard to MD but a potential negative effect against FA values in association fibers.ConclusionThe current study suggests that microglial activation at early AD stage might have a protective effect against neurodegeneration, while at late stage, it might facilitate neurodegenerative process. These observations support the hypotheses that microglial response is an active factor in the process of Alzheimer’s pathogenesis, and that it has stage‐dependent effects on disease progression. Future efforts on modulating microglial activation could be promising, given a carefully selected time window for intervention.
Impact of episodes of lucidity on people living with dementia and their caregivers: A qualitative study
Authors: Gilmore‐Bykovskyi Andrea L , Block Laura M , Benson Clark , Fehland Jess , Botsch Meghan , Mueller Kimberly D 
Published: June 2023

AbstractBackgroundEpisodes of lucidity (EL) are generally characterized by a spontaneous and unexpected return of abilities previously believed to be lost in individuals with Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD). Among the myriad implications of lucidity are the impact these episodes have on the person living with ADRD and their family caregivers. Family caregivers provide the majority of support for persons with AD/ADRD and frequently experience complex grief associated with identity and relationship changes over the course of the disease. Consequentially, a transient return of abilities and connection in the person with AD/ADRD may have a substantial impact on their conceptualization of consciousness in the care recipient living with AD/ADRD, approach to care, and emotional wellbeing. It is also not understood how persons living with AD/ADRD may respond to EL.MethodsThis study utilized a descriptive qualitative method employing semi‐structured interviews with family caregivers (N = 22) of persons living with AD/ADRD. Interviews elicited information about participant’s experiences with EL, interpretation of these events, and appraisal of the impact of the event on themselves and the person experiencing it. Interview data were analyzed using a modified, two‐phase thematic analysis approach.ResultsEL were commonly conceptualized by caregivers as illustrative of the ongoing presence of self and consciousness in the person living with AD/ADRD that they posit is at other times concealed due to cognitive impairment. Caregivers overwhelmingly reported that these episodes were valued moments that offered meaningful connection to their loved ones, also at times facilitating acts of saying goodbye or making hard decisions. Caregivers perceived EL as having variable impact on the person living with AD/ADRD. In some situations, EL were perceived as providing the person living with AD/ADRD greater capacity to engage. Sometimes, EL were described as being accompanied by insight regarding deficits and perceived as upsetting to the person living with AD/ADRD.ConclusionWe found that EL can have both positive and negative impacts on caregivers and people living with AD/ADRD. Future research is needed to address ethical considerations surrounding EL and to support caregivers in how to anticipate and respond to these events.
UPS of the CNS: Longitudinal profiling of mitochondrial DNA in neuronal‐enriched packages from plasma of individuals with cognitive decline
Authors: Hall Courtney , Barber Robert , Phillips Nicole 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is a complex neurodegenerative disorder that disproportionately burdens Mexican Americans (MAs) due to a combination of population‐specific environmental exposures and genetic risk factors. In addition to AD, MAs have a higher prevalence of metabolic comorbidities such as type 2 diabetes (T2D) that have been implicated in accelerated age‐related cognitive impairment. Tissue‐specific mitochondrial dysfunction and oxidative stress are early and prominent features of both AD and T2D that propagate systemic inflammation as these diseases progress. Despite the shared pathophysiology, we do not fully understand the underlying molecular mechanisms linking cognitive decline and metabolic stress, especially in understudied minority populations. Mitochondrial dysfunction may serve as the biological basis of the AD health disparity in MAs who experience earlier onset of symptoms and have an overrepresentation of T2D compared to non‐Hispanic whites (NHWs). This project aims to study T2D‐related risk for cognitive impairment by assessing the packages that neurons secrete to communicate with cells in the periphery. These neuronal‐enriched exosomes (NEEs) can cross the blood‐brain barrier and are thus capable of mediating systemic inflammation in response to CNS‐sourced stress through their mitochondrial DNA (mtDNA) cargo. We hypothesize that plasma NEE mtDNA load will reflect cognitive status and T2D comorbidity over time.MethodsExosomes of neuronal origin were enriched via CD171‐based immunocapture in longitudinal plasma samples (two timepoints, 5 years apart) from 348 Texas Alzheimer’s Research and Care Consortium (TARCC) participants stratified by race/ethnicity (MA/NHW), cognitive status (AD/MCI/NC), and T2D comorbidity (+/‐). The success of NEE isolation was assessed using nanoparticle tracking analysis (NTA) and immunoblotting against CD171 and CD81 (canonical exosome surface marker). Following extraction of total DNA from NEEs, absolute mtDNA load and deletion ratio were estimated using a real‐time qPCR assay targeting sites within the minor (D‐loop) and major (ND4) arcs.ResultsHerein, we demonstrate the ability to isolate NEEs from plasma and quantify their mtDNA cargo. Resultant values were analyzed for longitudinal differences and correlation with disease status based on various neuropsychological measures.ConclusionAs the first effort to assess mtDNA in NEEs, this project provides novel insight into how T2D confers risk for AD across different populations over time.
Impact of APOE on amyloid progression in Alzheimer disease
Authors: Chen Gengsheng , Cruchaga Carlos , Su Yi , Joseph‐Mathurin Nelly , Massoumzadeh Parinaz , Liu Jingxia , Gordon Brian A. , McKay Nicole S. , Hobbs Diana A. , Morris John C , Benzinger Tammie L.S. 
Published: June 2023

AbstractBackgroundIt is well recognized that β‐amyloid (Aβ) pathology plays an important role in Alzheimer Disease (AD) pathophysiology. The amount of Aβ in the brain varies substantially within both preclinical and symptomatic AD populations. Part of this inter‐individual variability in amyloid pathology may be explained by the genotype variation of Apolipoprotein E (APOE), with the allele e4 found to be the most significant genetic risk factor for late‐onset AD. However, the impact of APOE genotype on the rate of amyloid accumulation is less clear and requires further investigation. In this study, we focus on longitudinal approaches to investigate how APOE genotype influences the trajectories of the Aβ pathology.MethodFor this project, we used longitudinal data of participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Washington University Knight Alzheimer Disease Research Center (Knight ADRC). We included 247 participants with available APOE genotype data, and longitudinal measure of Aβ burden via florbetapir (AV45) PET data, see table 1. Imaging PET data from ADNI and ADRC were harmonized using a centiloid conversion. The rate of Aβ accumulation was estimated as the slope of the random coefficient model using all available time points of longitudinal imaging data for each participant, controlling for age, sex, education and cohort. Generalized linear model was used to test the association between APOE genotype and the rate of change in amyloid.ResultThe rate of change in amyloid burden was not significantly different among all APOE genotype groups (Figure 1A; F = 1.64, p = 0.15). When looking specifically at the effect of allele count for APOE‐e4, we observed the rate of change in amyloid burden increased with e4 allele (Figure 1B; F = 4.18, P = 0.02). Pairwise comparison showed significant differences in rate of amyloid accumulation between e4e4 and e2e3 APOE genotype groups (p = 0.04), and between e4e4 and e3e3 APOE genotype groups (p = 0.04), see table 2. There was no significant difference in rate of amyloid accumulation between other genotype groups.ConclusionAPOE e4 increases AD risk by accelerating the amyloid deposition. Future direction will include a larger sample size to investigate the effect of e2 and e3 on amyloid progression in AD.
Unique combinations of shape morphometric features improves discriminability of ftld phenotypes
Authors: Stocks Jane K , Popuri Karteek , Beg Mirza Faisal , Cobigo Yann , Rosen Howard J. , Wang Lei 
Published: June 2023

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) is associated with diverse clinical phenotypes underlain by multiple disease pathologies and genetic mutations. As such, traditional structural MRI analyses lack sensitivity and specificity for discriminating FTLD syndromes. Here, we use data‐driven methods to extract a concise set of MRI‐derived shape morphometric features and examine the discriminatory capability of their unique combinations in four FTLD clinical phenotypes.Method190 patients with sporadic or familial FTLD spectrum disorders (i.e., behavioral variant (bvFTD, n = 107), non‐fluent variant primary progressive aphasia (nfvPPA, n = 27), semantic variant primary progressive aphasia (svPPA, n = 12) and progressive supranuclear palsy (PSP, n = 44)) and 27 controls without pathogenic mutations from the ALLFTD cohort were evaluated. MRI data were preprocessed with FreeSurfer software and four cortical measures were extracted and indexed to a normalized surface atlas: cortical thickness (CT), surface area (SA), surface curvature (SC) and jacobian white matter surface metric distortion (JW). For all phenotypes, each shape feature was contrasted with controls using linear models adjusted for age and gender. Principal component analysis (PCA) was then applied to each individual structural measure and the discriminatory power based on individual and combined measures was assessed using logistic regression and 10‐fold cross‐validation.ResultFigure 1 displays FDR‐corrected T‐scores of differences from controls in each morphometric feature in bvFTD. Results reveal complementary patterns of CT, SA, SC and JW for each phenotype, with greatest differences observed in CT across groups. In Figure 2, we display the features derived from the PCA, weighted by eigenvector coefficients, in bvFTD. In Figures 3‐6, receiver operating characteristic curves for individual and combined measures alongside areas under the curve (AUCs) are shown for each phenotype. In bvFTD, nfvPPA and PSP, the superior model included CT and SC at AUCs of 88.3, 87, and 78.6, respectively. For svPPA, the superior model included CT, SC and JW at an AUC of 85.6.ConclusionIntegrating additional MRI‐derived surface morphometric features improved classification performance in all FTLD phenotypes. The principal component analysis‐based approach indicated distinct brain regions contribute to discrimination for each shape feature, suggesting they may reflect unique aspects of neurodegeneration across groups.
Classification of amyloid positivity in PET imaging using end‐to‐end deep learning: a multi‐cohort, multi‐tracer analysis
Authors: Fan Shuyang , Ha Sung Min , Chakrabarty Satrajit , Lee John , Flores Shaney , LaMontagne Pamela , Gordon Brian A. , Raji Cyrus A. , Benzinger Tammie L.S. , Morris John C , Ances Beau M. , Marcus Daniel S. , Sotiras Aristeidis 
Published: June 2023

AbstractBackgroundPositron emission tomography (PET) imaging with amyloid‐specific tracers is the gold standard for assessing amyloid positivity in vivo. However, visual interpretation of PET images is limited by availability of clinicians and interobserver variability. Classification of amyloid status typically requires calculation of standardized uptake value ratios (SUVRs), correspondence with neuroanatomy from magnetic resonance imaging, and additional complex, computationally intensive preprocessing steps requiring specialized software. We developed a deep learning model that can automatically classify unprocessed PET images as amyloid positive or negative.MethodFlorbetapir (AV45), florbetaben (FBB), and Pittsburgh compound B (PiB) images from the Alzheimer’s Disease Neuroimaging Association (ADNI), AV45 and PiB images from the Open Access Series of Imaging Studies 3 (OASIS3), and FBB, flutametamol (FMT), and flutafuranol (NAV4694) images from the Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL) were used (Table 1). Each image was resized to isotropic 2 mm voxels, and voxel intensities between the 5th and 95th percentile were normalized to zero mean and unit variance. We trained and internally validated a convolutional neural network (CNN) on AV45 images from ADNI before testing it on images from an independent cohort and/or acquired with a different tracer.ResultThe model achieved an AUC of 0.98 [0.97, 1.0] on test AV45 images from ADNI and generalized well to AV45 images from OASIS3, achieving an AUC of 0.95 [0.92, 0.97] (Table 2). Critically, the model’s performance remained robust even when evaluating imaging from different tracers, including FBB, FMT, PiB, and NAV4694, scoring an AUC of at least 0.97 on each and demonstrating its ability to learn a tracer‐agnostic pattern of abnormality. Similar conclusions can be drawn from other performance metrics.ConclusionWe developed a deep learning model that can classify amyloid PET scans with a high degree of accuracy. We demonstrated that the model generalizes well to unseen images acquired from an independent cohort, under a different protocol, and/or with tracers unseen during training. Our model may usefully provide concise metrics for amyloid research as well as support clinical assessment of amyloid‐specific PET when expertise or computational resources are limited.
Towards the development of a chemical probe targeting the disruption of SYK tandem SH2 domain and FCεR1γ interactions for Alzheimer’s disease
Authors: Potjewyd Frances M. , Katis Vittorio , Du Yuhong , Bradshaw William , Sikdar Arunima , Nwogbo Felix , Leisner Tina , Wang Dongxue , Hardy Brian P. , Kireev Dmitri B. , Pearce Kenneth H. , Fu Haian , Frye Stephen V. , Axtman Alison D. 
Published: June 2023

AbstractBackgroundSpleen tyrosine kinase (SYK) and FCεR1γ were identified as targets for Alzheimer’s disease (AD) via multi‐omics human data by AMP‐AD teams. These proteins were selected for further target validation and medicinal chemistry efforts by members of the Target Enablement to Accelerate Therapy Development for Alzheimer’s Disease (TREAT‐AD) program. SYK has a reported role in AD (PMID: 31324720), and SYK activation can occur upon binding to the phospho‐ITAM region of the FCεR1γ receptor via the tandem SH2 domains (tSH2) of SYK (PMID: 29440271). Therefore, disruption of this interaction is proposed to slow AD related pathology. Through the generation of target enabling packages (TEPs) we aim to provide experimental validation of these targets for AD and develop a high‐quality chemical probe that targets this interaction.MethodFirstly, tSH2 domains of SYK were purified, followed by crystallography of these tSH2 in the presence of phospho‐ITAM‐containing peptides. A TR‐FRET‐based assay was developed using the SYK tSH2 domain and phospho‐ITAM peptide of FCεR1γ. This assay was miniaturized for ultra‐high‐throughput screening (uHTS) of a screening library of compounds. In parallel, a DNA encoded library (DEL) screen was executed to identify compounds that bind the SYK tSH2 domain. The hits generated using these hit finding campaigns were validated in dose‐response and via orthogonal biophysical methods. Medicinal chemistry campaigns to expand upon these hits are underway.ResultWe have crystallography data of the SYK tSH2 domains bound to phospho‐ITAM peptides and have established a TR‐FRET based assay to identify inhibitors of the interaction between FCεR1γ and SYK. Hit compounds have been identified through uHTS and DEL screening methods. Further validation of these hits in orthogonal assays are underway, alongside medicinal chemistry efforts to identify more potent analogues.ConclusionThrough the generation of a SYK/FCεR1γ TEP, we have provided the tools to allow for experimental validation of these target for AD and have begun to generate inhibitors of this interaction.
Medial temporal lobe (MTL) – default‐mode network (DMN) functional connectivity disruption in the early stages of the progression of Alzheimer’s disease in a multimodal ADNI3 MP‐RAGE and EPI‐BOLD Advanced cohort
Authors: Grajski Kamil A 
Published: June 2023

AbstractBackgroundA cross‐sectional same‐session multi‐modal analysis of T1 structural MRI and resting‐state functional connectivity (rsfMRI) was performed to assess potential biomarkers of the progression from cognitively normal (CN) to significant memory concern (SMC) and early and late mild cognitive impairment (EMCI, LMCI).MethodsAn ADNI‐3 EPI‐BOLD Advanced protocol sub‐population (N = 49) with baseline diagnosis CN (N = 14), SMC (N = 15), EMCI (N = 11) and LMCI (N = 9), matched for age (p = 0.37), education (p = 0.65), gender (p = 0.29), and morphometric (FreeSurfer 7) and fMRI (AFNI) measurements, was processed with a hybrid a priori data‐driven method for identifying anchor‐target ROI pairs in rsfMRI [1]. Anchor‐target ROI pairwise correlations were False Detection Rate (FDR) corrected in a parallel group‐level one‐way four‐factor (CN, SMC, EMCI, LMCI) ANOVA and post hoc pairwise t tests were performed for significant tests only.Results
MRI. FreeSurfer subcortical segmentation, but not cortical thickness, yielded significant tests in a parallel group‐level one‐way four‐factor ANOVA test (q = 0.05, p* = 2.8×10−3) for left hippocampus. rsfMRI. A 3‐mm grid of ROI (r = 6mm) seeds in left MTL yielded 1,012 ROI “anchors”. 3D (Fisher Z‐transformed) correlation maps were computed for each subject for each anchor ROI and input to a group‐level one‐way four‐factor 3D ANOVA. Cluster analysis (Nvox = 20; p = 0.02; P = 3.45) of the 3D F statistic maps yielded 3,954 target ROIs. An r = 6mm ROI was placed at the center of mass of each target cluster. ROI anchor‐target pair correlations were input to a group‐level one‐way four‐factor ANOVA FDR corrected (q = 0.005; p* = 0.0067, estimated by permutation, N = 1000) which identified 1,454 significant tests (ROI pairs). Post hoc pairwise t tests only on the significant ANOVA tests were FDR‐corrected (q = 0.005) and yielded 34 significant SMC‐CN tests (p* = 1.1×10−4); 329 EMCI‐CN tests (p* = 1.1×10−3); and 78 LMCI‐CN tests (p* = 2.6×10−4). For each pairwise contrast, the significant target ROI masks were summed which resulted in 20‐50 clusters which were bilaterally distributed in MTL and DMN‐associated regions. An independent analysis of right hemisphere yielded similar results.ConclusionsA hybrid a priori data‐driven approach applied to anchor ROIs in MTL and multiple subcortical regions identified target ROIs that were predominantly, but not uniformly associated with DMN.[1] Grajski, K. A., Bressler, S., and ADNI. (2019). Neuroimage Clin. 2019;23:101860.
Evaluation of a comprehensive multicomponent support program for people with dementia and their carers: Study protocol for pilot trial
Authors: D'Cunha Nathan M , Isbel Stephen , Bail Kasia , Gibson Diane 
Published: June 2023

AbstractBackgroundA growing body of evidence demonstrates the importance of comprehensive multicomponent, person‐centred interventions, including education and support for people living with dementia and their carers following a diagnosis of dementia. However, in Australia, people with dementia and carers frequently face challenges accessing appropriate information, care and support services to support living in the community with different stages of dementia.MethodThe Sustainable Personalised Interventions for Cognition, Care, and Engagement (SPICE) program consists of evidence‐based therapeutic activities for people with dementia and carers. The project aims to recruit 24 dyads (24 people with dementia and 24 carers; four groups of six) to participate in a twelve‐week, twice per week support program using a randomised waiting‐list study design. The SPICE program intervention is delivered by allied health professionals and includes physical activity, cognitive stimulation therapy, and nutrition assessment for the person with dementia. Carers will receive support aimed to promote capacity building and self‐care, including practical strategies to manage behavioural changes. The dyad will also receive the Care of People with Dementia in their Environments (COPE) program which focuses on problem solving and goal setting in the home.ResultThe primary outcome for the intervention is quality of life of the person with dementia using the health‐related quality of life (DEMQOL) questionnaire. Secondary outcomes will assess cognition (Addenbrookes Cognitive Examination (ACE‐III)), neuropsychiatric symptoms (NPI), health and functional ability (WHODAS 2.0), physical function assessments, carer quality of life (C‐DEMQOL), and program satisfaction of the dyad. Categorical data will be summarised using frequency statistics and visualisation. Continuous and other numerical data will be visually explored and summarised using sample descriptive statistics, selected as appropriate based on apparent distributions.ConclusionThe SPICE program has the potential to promote quality of life of people with dementia and potentially delay cognitive decline while also providing a toolkit for carers to reduce carer burden. If successful, the outcomes of the study have the potential to improve post‐diagnostic care and clinical practice for people with dementia and their carers in Australia and inform services worldwide.