bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microglia from individuals with mild cognitive impairment (MCI) and AD show differences in transcriptional burst kinetics
Authors: Jin Bowen , Pericak‐Vance Margaret A. , Martin Eden R. , Farrer Lindsay A. , Haines Jonathan L. , Bush William S. 
Published: December 2023

AbstractBackgroundMicroglia are the innate immune cells in the central nervous system that responds to brain injury and pathogens. The loss of homeostatic microglia is associated with neurodegenerative diseases. Multiple studies of AD mouse models have identified AD‐associated microglia subtypes, e.g., disease associated microglia (DAM). However, studies of human microglia have not reported similar microglia subtypes. Therefore, how human microglia change in the presence of amyloid‐ protein deposition and phosphorylated Tau remains an open question.MethodWe have developed an approach that estimates transcriptional kinetics from scRNA‐seq data. This approach models how “bursty” and variable a gene expression is. We hypothesize that transcriptional bursts of key genes are different within AD cases compared to MCI individuals. We used the ROSMAP scRNAseq microglia dataset of 8 AD cases and 4 MCI cases and applied our approach to estimate the transcriptional kinetics for each subject. We then compared the difference in transcriptional kinetics of genes that are estimated both in AD and MCI.ResultFirst, we found that 96% of microglia cells in AD and MCI shows a similar co‐occurrence pattern of expressed genes and, therefore, likely reflect the same cell type. Within the assumed homogeneous microglia cells, we identified two genes, C1QC and ACTB, showing significant differences in their transcriptional kinetics between AD and MCI cases. Both C1QC and ACTB show larger burst sizes in MCI than in AD cases (p‐value for C1QC:0.0038; p‐value for ACTB: 0.00918). Consequently, C1QC and ACTB show a higher expression level variability among microglia cells in MCI cases than AD.ConclusionOur result suggests C1QC and ACTB may be associated with AD risk via changes in variability of gene expression rather than total gene expression levels. The increased variability in transcription of C1QC and ACTB in MCI individuals relative to AD cases might indicate more mobile and active physiological states of microglia. These results may point to functional changes in these genes with AD progression and are prime targets for further experimental validation.
Multimodal and multiregional atlas of Alzheimer’s disease changes
Authors: Gabitto Mariano I , Travaglini Kyle J , Ariza Jeanelle , Close Jennie , Ding Yi , Long Brian , Rachleff Victoria M , Chakrabarty Rushil , Crane Paul K , Ferrer Rebecca , Gatto Nicole M , Goldy Jeff , Grabowski Thomas J , Guilford Nathan , Guzman Junitta , Hawrylycz Michael J , Hodge Rebecca D , Jayadev Suman , Kaplan Eitan S , Keene C Dirk , Larson Eric B , Latimer Caitlin S , Levi Boaz P , Mahoney Joseph T , Melief Erica J , Miller Jeremy A , Mukherjee Shubhabrata , Pham Thanh , Smith Kimberly , Torkelson Amy , Chakka Anish Bhaswanth , Lein Ed S 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia. The progression of AD throughout the brain follows a stereotypical pattern that can be described by the quantification of histopathological changes in several brain regions. As part of The Seattle Alzheimer’s Disease Cell Atlas (SEA‐AD, https://sea-ad.org), we previously quantified pathological proteins in the middle temporal gyrus (MTG) and used them to describe disease progression, vulnerable cell types, and the MTG molecular changes related to diseaseMethodIn this work, we expanded our results and undertook a comparative approach. We measured a battery of neuropathological proteins (staining NeuN, AT8, IBA1, GFAP, 6e10, pTDP43, and a‐Syn immunoreactivity, and analyzing them with machine learning) in the middle temporal gyrus, the middle frontal gyrus, and medial entorhinal cortex in 84 donors. In addition, we undertook a multimodal single‐cell analysis of such regions, profiling cells using single‐cell RNA‐seq, ATAC‐seq, Multiome, and spatial transcriptomic.Borrowing from our hierarchically resolved cell types in MTG, based on the BRAIN initiative cell type reference, we used machine learning algorithms to create multimodal cell type maps across regions. We used Bayesian statistics to identify differentially accessible regulatory elements, link them to the affected genes and the regulatory transcriptional machinery binding in such elements.ResultWe identified regional vulnerable neuronal populations and a core set of transcriptionally similar cell types susceptible to disease across the cortex. We created a cortex‐wide disease progression map combining neuropathological data from our three profiled regions with latent Bayesian statistical algorithms. In each area, we developed an AD pseudo‐progression timescale that describes the burden of disease in the area and, next, combined all areas to create a cortex‐wide holistic pseudo‐progression. We used the mapped cell types and our developed scale to synchronize changes occurring in each patient, describing abundances, gene expression, and chromatin accessibility modifications.ConclusionThe progression scale developed in this study serves as a reference to align changes across brain regions and, in the future, to reconcile differences across cohorts.
Epigenome‐Wide‐Association‐Scan Reveals Epigenetic Profile Changes Using Neurofilament Light as a Neurodegeneration Proxy Biomarker in Mexican Americans
Authors: Housini Mohammad , Zhou Zhengyang , Reid Danielle M , Daniel Ann Abraham , Silzer Talisa , O'Bryant Sid E. , Phillips Nicole , Barber Robert , Pathak Gita 
Published: December 2023

AbstractBackgroundRecent literature shows Alzheimer’s Disease (AD) has both genetic and epigenetic components resulting in disease manifestation. Furthering our prior work on AD epigenetics in the Health and Aging Brain Study – Health Disparities (HABS‐HD) participants, we seek to identify differential CpG methylation profiles of Neurofilament Light (NfL) as a proxy for neurodegeneration in Mexican‐American participants with Normal Cognition (NC) or Mild Cognitive Impairment (MCI).MethodUsing data from the Epigenome Wide Association Scan (EWAS) that our group already published for 90 Mexican Americans in HABS‐HD (formerly Healthy Aging in Latino Elders Study [HABLE]), we conducted preliminary analysis in 32 individuals (NC = 21, MCI = 11) to assess the role of epigenetic markers in neurodegeneration among Mexican Americans. We performed the EWAS using the AT(N) biomarker, Neurofilament Light (NfL), as the outcome in our pilot group of 32 Mexican Americans. We first tested if the NfL data was normalized using the Shapiro Test, then tested NfL differences between NC and MCI with a Wilcox Test. We further tested CpG sites with NfL using a disease‐stratified and unstratified model with linear regression modelling and adjusted for covariates, such as age, gender, and education.ResultResults of our analysis for the association between CpG methylation profiles and NfL showed 14 down‐regulated CpG sites and 1 up‐regulated CpG site with significant P values after multiple testing. These significant CpG sites residing in LRP4 (Chr11p11.2), ABCB9 (Chr12q24.31), and KIAA (Chr13q14.13) are implicated in the CpG methylation profile changes. These genes have been implicated in AD pathogenesis by other molecular studies. When we stratified NfL count by disease subtype, we did not find any significance in this dataset. We are expanding our ongoing work to identify methylation profiles of NfL in a larger cohort.ConclusionOur pilot findings are critical in understanding epigenetic profiles of biomarkers for neurodegeneration. Results suggest that epigenetics play a major role in the pathophysiology of AD development and manifestation, and that this effect may be different by ethnicity. Future studies will include a larger sample size, longitudinal analyses, and additional ethnic groups to help bridge the health disparities gap in the literature.
Pervasive biases in GWAS using family history of Alzheimer’s disease as proxy phenotypes
Authors: Sun Zhongxuan , Wu Yuchang , Fletcher Jason M , Lu Qiongshi 
Published: December 2023

AbstractBackgroundUsing family health history as proxy phenotype has become a common approach in genome‐wide association studies (GWAS) of Alzheimer’s disease (AD). This approach leverages large samples in population biobanks where most mid‐aged participants do not have any AD diagnosis. However, methodological issues in GWAS‐by‐proxy (GWAX) and quality of its association results have not been carefully investigated.MethodWe performed GWAX on parental AD history in UK Biobank (N = 48,031 proxy cases and 315,286 controls). We then applied GWAS‐by‐subtraction to obtain the non‐AD component underlying AD GWAX. We computed genetic correlations of AD case‐control GWAS, AD GWAX, and the non‐AD component underlying GWAX with a suite of complex traits. We also explored the impact of various quality control procedures and additional covariates in AD GWAX analysis.ResultAD GWAS and GWAX showed drastically different genetic correlations with several other complex traits especially cognitive abilities (Figure 1). AD GWAX had a surprising genetic correlation with higher education (rg = 0.167, p = 1.7e‐11) as opposed to the negative AD‐education correlation observed for GWAS (rg = ‐0.133, p = 2.4e‐5). The positive genetic correlation between AD and cognition is explained by the non‐AD component in AD GWAX (rg = 0.260 with education, p = 5.2e‐11). The non‐AD component in GWAX also showed correlations with lower risks of health outcomes such as coronary artery disease (rg = ‐0.136, p = 2.8e‐3) and diabetes (rg = ‐0.206, p = 2.8e‐3), indicating substantial survival bias in samples reporting parental AD history. Adjusting for parental age in GWAX substantially reduced but did not fully remove the genetic correlation of AD and higher education (rg = 0.013, p = 0.67), hinting at additional unaccounted factors in the current GWAX practice. We also provide evidence that genetic correlation between family health history awareness and education (rg = 0.285, p = 1.4e‐10) leads to these biases in GWAX associations.ConclusionGWAX based on parental health history introduces substantial and systematic biases in AD genetic associations due to the non‐representativeness of the biobank health history survey. Naively combining GWAX with regular case‐control GWAS will lead to misleading results both at the single variant level and in genome‐wide analyses such as genetic correlation estimation and polygenic risk score applications.
Older people with mild cognitive impairment exhibit lower semantic noise after six months of frequent social conversations
Authors: Chen Liu , Dodge Hiroko H , Asgari Meysam 
Published: December 2023

AbstractBackgroundSemantic noise (SN) is a linguistic measurement that quantifies how well the conversation focuses on topics they are discussing. We hypothesized that by engaging in high frequent conversation which aimed to enhance cognitive reserve, the SN observed in older people’s conversations with mild cognitive impairment (MCI) would resemble those with normal cognition (NC).MethodWe analyzed transcriptions from a behavioral intervention randomized controlled trial, I‐CONECT (NCT02871921), which involved semi‐structured conversations between facilitators and participants. In the project, the experimental group engaged in 30‐minute semi‐structured conversations (four times per week for 6 months) via video‐chats. Every video‐chat is oriented to a predefined topic which was provided in a standardized order (e.g., dancing is the 1st conversation topic in the 2nd week). Out of 186 subjects randomized into the trial, 64 participants were randomized into the experimental group. Among them, 52 participants (26 MCI and 26 normal based on NACC D1) with sufficient recording quality during the 2nd week of the intervention (baseline) and during the last week (i.e., 24th) before the month 6 (M6) post‐intervention assessments (post‐trial assessments at M6) were used in this analysis. We utilized an automatic speech recognition (ASR) system to transcribe these recordings and measured each transcription’s SN. We analyzed the statistical difference of MSN (mean SN) between participants with MCI and those with NC at baseline (2nd week) and M6 (24th week).ResultsUsing two‐tailed t‐test, we found that at the baseline, MSN in MCI group was significantly higher than NC group (MCI: 2.09(0.34), NC: 1.87(0.35), p‐value: 0.024). After six months of social interaction, MCI and NC group were not significantly different (MCI: 1.81(0.47), NC: 1.95(0.47), p‐value: 0.280). Moreover, in MCI group, baseline’s MSN was significantly higher than M6’ (p‐value: 0.017), while, in NC group, there was no significant difference between baseline and M6 (p‐value: 0.465).ConclusionsWe showed that, through six months of social interaction, MCI group’s MSN reduces from significantly higher than NC group at the baseline to not significantly different from NC group at M6. This indicates that the high dosage of interactive conversations reduces MSN in the MCI group.
Resilience in aging: characterizing social and emotional pandemic stress with age in a multi‐ethnic sample of middle‐aged and older adults
Authors: Schuck Lauren A , Arentoft Alyssa , Cham Heining , Oleas Denise S. , Breen Elizabeth Anne , Slaughter Alexander W. , Camuy Alicia M , Talavera Sandra , Mindt Monica Rivera 
Published: December 2023

AbstractBackgroundCOVID‐19 pandemic stress differentially affects older adults and persons from minoritized, underrepresented populations (URPs; e.g., Black, Latinx), yet potential protective factors are not well understood. This study aimed to evaluate whether pandemic‐related social and emotional stressors negatively affect functional capacity, mental health, and cognitive outcomes in an ethnoculturally diverse sample of middle‐aged and older adults.MethodCross‐sectional data were obtained from adults (55± years) participating in SALUD, an ongoing study examining risk and resilience factors for dementia in diverse populations. Participants completed a well‐validated, comprehensive battery of questionnaires and cognitive assessments. Aggregate scores of social and emotional pandemic stressors (e.g., more anxiety, loneliness) from Item 3 of the Pandemic Stress Index (PSI‐3) were examined in association with demographics, Patients Assessment of Own Functioning Inventory (PAOFI; self‐reported functional status measure), and Patient Health Questionnaire‐2 (PHQ‐2; self‐report depressive symptomatology measure). Demographically‐adjusted norms were used to compute Global Neurocognition (NC) and eight domain‐specific NC average T‐scores (e.g., learning, memory). Spearman’s correlations, Kruskal‐Wallis, Mann‐Whitney U‐tests were used for non‐normal variables.ResultThe sample included 110 adults (37.3% Non‐Latinx Black [NLB], 33.6% Latinx, and 29.1%, non‐Latinx White [NLW]; 63% female; M
age = 65.27 [SD = 7.11]; M
ed = 13.89 [SD = 3.07]). Age was negatively correlated with the PSI‐3 (rs = ‐.25, p<.01), but education (rs= ‐.05, p = .59) and gender (U<.01, p = .99) were not. PSI‐3 differed across ethnocultural groups (H = 8.00, p = .02), such that Latinx participants had the highest PSI‐3 scores. However, this relationship became non‐significant after accounting for age (p = .11). PAOFI impairment scores (rs = .37, p = .01) and PHQ‐2 scores (rs = .29, p = .01) were positively related to the PSI‐3, but Global NC and domain‐specific NC average T‐scores were not significant (rs = ‐.08 ‐ .10, ps> .05).ConclusionIn this ethnoculturally diverse sample, findings suggest older adults may be more resilient to pandemic‐related stress. Older age was associated with lower social and emotional pandemic stress, while greater functional impairment and depression were moderately associated with higher pandemic‐related stress. As pandemic‐related increases in psychosocial stressors (e.g., worry and depression) continue to affect middle‐aged and older adults, longitudinal research should investigate the risk and resilience factors that may buffer against developing these negative outcomes.
Grumpy old men: agitation, aggression, and impulsivity in older adults and risk of incident dementia
Authors: Ghahremani Maryam , Ismail Zahinoor 
Published: December 2023

AbstractBackgroundImpulse dyscontrol, i.e., excessive motor activity and/or physical and verbal aggression is common in dementia. However, impulse dyscontrol can also emerge in advance of dementia, but is often normalized due to age, or framed as a psychiatric condition. Thus, the association between these symptoms and incident dementia is unclear. Mild behavioral impairment (MBI) leverages risk associated with later‐life emergent and persistent neuropsychiatric symptoms (NPS) to identify a high‐risk group for incident dementia. Impulse dyscontrol is one of five MBI domains. Here, in dementia‐free participants, we assessed risk of progression to dementia in MBI‐impulse dyscontrol and conventionally‐measured impulse dyscontrol symptoms (Conv‐ID).MethodDementia‐free National Alzheimer Coordinating Centre participants were included. Neuropsychiatric Inventory Questionnaire irritability, agitation, and aberrant motor behavior items were used to identify impulse dyscontrol. MBI‐impulse dyscontrol was operationalized by symptom presence at more than two‐thirds of pre‐dementia study visits (symptom persistence criterion) in those with no history of psychiatric disorders (symptom emergence criterion). Conv‐ID required symptoms only at baseline without consideration of past psychiatric history. Kaplan‐Meier survival curves and Cox proportional hazards models, adjusted for age, sex, education, race, and APOE‐e4 status, were generated to compare survival probability and dementia incidence rates of MBI‐impulse dyscontrol and Conv‐ID to No‐NPS.ResultsThe sample comprised 1,884 MBI‐impulse dyscontrol (age = 74.5±9.7; 40.9% female), 3,676 Conv‐ID (age = 71.0±9.4; 47.0% female), and 6,362 No‐NPS participants (age = 71.0±10.3; 64.7% female) (Table 1). MBI‐impulse dyscontrol had lower dementia‐free survival (p<0.0001) and 2.23‐fold greater dementia incidence compared to No‐NPS (CI:1.99‐2.50, p<0.001, Figure 1(A)); Conv‐ID had lower dementia‐free survival (p<0.0001) and 1.39‐fold greater dementia incidence compared to No‐NPS (CI:1.25‐1.54, p<0.001, Figure 1(B)).ConclusionCompared with a conventional approach to assess agitated and impulsive behaviors, MBI‐impulse dyscontrol was associated with greater dementia incidence. Applying the MBI criteria of later‐life emergence and persistence of symptoms provides a more specific approach to identify those at risk for incident dementia, who might otherwise be dismissed due to normalization of these behaviors in older persons or labelled with a psychiatric condition. This approach may allow for earlier implementation of preventative measures, pharmacological and non‐pharmacological, improving outcomes and quality of life for patients and their caregivers.
Investigating the role of GPNMB in modulating LPS mediated inflammation in progranulin‐deficient macrophages
Authors: Gillett Drew A , Neighbarger Noelle , Huarte Oihane Uriarte , Tansey Malu Gámez 
Published: December 2023

AbstractBackgroundProgranulin (PGRN) is a glycosylated holoprotein that is critical to endo‐lysosomal health and regulating inflammatory responses over the lifespan. Insufficient PGRN due to nonsense mutations in the GRN gene has been linked to increased risk of developing Frontotemporal Dementia (FTD) and Neuronal Ceroid Lipofuscinosis (NCL‐11). The precise mechanism(s) behind the onset and progression of disease is unclear, and no disease‐modifying treatment exists. Previous work has identified increased glycoprotein non‐metastatic B (GPNMB) in both the cortex and plastma of Grn−/− mice relative to Grn+/+ mice, and our lab has recently identified different GPNMB expression in PGRN‐deficient immune cell populations, but it remains unclear how this increase in GPNMB modifies the inflammatory response(s) with PGRN deficits. This work seeks to investigate GPNMB expression over the course of the immune response in PGRN‐deficient cells, and the extent to which GPNMB modulates inflammation.MethodTo investigate the role(s) of GPNMB in PGRN‐deficient myeloid cells, we isolated peritoneal macrophages (pMacs) from Grn+/+,and Grn−/− mice and quantified GPNMB protein before and after lipopolysaccharide (LPS) stimulation with western blot. We also determined the extent to which exposure to the GPNMB extracellular domain (ECD) modifies LPS‐elicited markers of inflammation in both Grn+/+and Grn−/‐ pMacs via qPCR. Finally, we determined how markers of inflammation were altered in pMacs from Grn−/−Gpmnb−/‐ relative to Grn+/+and Grn−/‐ with and without LPS stimulation.ResultWe determined that the additional loss of GPNMB in Grn−/−Gpmnb−/− pMacs altered the expression of inflammatory markers after LPS challenge relative to both Grn−/−and Grn+/+ pMacs. We also discovered that GPNMB is dynamically regulated during and after LPS challenge in both Grn+/+ and Grn−/− pMacs. Finally, we determined that the addition of GPNMB ECD before and during LPS treatment ameliorated the altered expression of inflammatory markers during LPS challenge.ConclusionThe increase of GPNMB expression in Grn−/‐ myeloid cells is a significant modulator of inflammatory responses and may be a potential target in the development of therapeutics.
Assessing amyloid plaque burden in aging marmosets and genetically engineered PSEN1 mutation carriers using 11C‐PiB PET
Authors: Schaeffer David J , Dubberley Lauren R , Schaeffer Lauren K Hayryren , Park Jung Eun , Homanics Gregg E , Strick Peter L , Carter Gregory W , Rizzo Stacey J Sukoff , Silva Afonso C 
Published: December 2023

AbstractBackgroundThere is an urgent need to develop novel animal models to investigate the underlying cellular and molecular root causes of the pathogenesis and progression of AD. Our group has worked to establish the common marmoset as the first primate‐specific model of AD to reveal the earliest cellular and molecular events of AD processes and allow charting of AD progression from its inception. For this, we established a colony of outbred marmosets and used genetic engineering techniques to generate marmosets carrying the PSEN1‐C410Y and PSEN1‐A426P mutations that cause early‐onset, familial AD. The present study aims to use PET imaging to access and track the progression of Ab plaque burden non‐invasively and longitudinally in our marmoset models of AD.MethodMarmosets anesthetized with isoflurane delivered via a facemask were placed in a preclinical PET/CT scanner customized with marmoset‐specific beds. Respiratory rate, heart rate, arterial O2 saturation, and rectal temperature were monitored and maintained at normal physiological values. Our PET imaging protocol follows the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The amyloid‐binding 11C‐Pittsburgh Compound B (11C‐PiB) was delivered intravenously in doses varying from 18.5 – 185 MBq (0.5 – 5 mCi). A 90‐min dynamic acquisition was performed immediately following the radiotracer injection, followed by a 3D CT scan acquired at 200 µm isotropic resolution. After the PET/CT neuroimaging scan, the marmosets were recovered from anesthesia and returned to their home cages.ResultWe observed positive 11C‐PiB binding and retention in the brains of aging outbred marmosets and in marmosets harboring PSEN1 mutations. Significant 11C‐PiB retention was observed in the cortex and white matter tracts. The areas with the highest 11C‐PiB retention were the lateral frontal cortex, anterior cingulate cortex, and temporal lobe regions.ConclusionThis study demonstrates using 11C‐PiB to track Ab plaque burden in the brains of aging marmosets and marmosets harboring PSEN1 mutations. As observed in human patients of AD, the amount of 11C‐PiB bound (measured in SUV and SUVR units) varied from animal to animal, and we are currently performing group analysis to investigate the dependence of 11C‐PiB retention on age and sex.This research was funded by NIH/NIA grants R24AG073190 and U19AG074866.