bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bulk brain tissue cell type deconvolution with bias correction for single‐nuclei RNA‐seq
Authors: O'Neill Nicholas K , Hu Junming , Stein Thor D. , Zhang Xiaoling , Farrer Lindsay A. 
Published: December 2022

AbstractBackgroundQuantifying cell type percentages from bulk brain RNA‐sequencing enables researchers to better understand the components underlying disease pathogenesis. Despite being designed for single‐cell RNA‐sequencing (scRNA‐seq) data, MuSiC deconvolution algorithm can use single‐nuclei RNA‐sequencing (snRNA‐seq) data generated from brain tissue to estimate cell type proportions in bulk brain RNA‐sequencing data but does not fully compensate for sequencing differences between bulk and snRNA‐seq data. We modified MuSiC's gene weighing scheme to compensate for this sequencing bias.MethodsMuSiC calculates gene weight each iteration using the residual from the previous iteration, gene variation among subjects, and other factors. We calculated the RNA capture rate difference between genes in single‐nuclei and bulk sequencing data and reduced MuSiC’s weight for genes with strong differences. We compared the accuracy of deconvoluted data from MuSiC and our modified algorithm (mMuSiC) by simulating bulk data with seven brain cell types and calculating the concordance correlation coefficient (CCC) between true and estimated cell type percentages. The accuracy of the original and modified deconvolution algorithms was also assessed using human brain dorsolateral prefrontal cortex (DLPFC) bulk RNA‐seq data sets from ROSMAP with subject‐matched immunohistochemistry (IHC) measurements for 69 samples and bulk RNA‐seq from the Framingham Heart Study/Boston University Alzheimer Disease Research Center with subject‐matched microglial (IBA1+) cell density measurements for 163 samples from the same brain region.ResultsmMuSiC improves the concordance correlation coefficients (CCC) between estimated and true cell fractions in our four simulations for each cell type with a p‐value of 0.014. This improvement is especially pronounced for both inhibitory and excitatory neurons, with an average CCC of 0.45 for mMuSiC and 0.22 for MuSiC. In human brain DLPFC bulk RNA‐seq data, our method also improves the CCC between cell fraction estimates and IHC measurements for each cell type tested in ROSMAP, with mMuSiC averaging 0.14 and MuSiC averaging 0.10. The correlation between microglia cell fraction estimates and IBA1+ cell density measurements is also improved in mMuSiC (R=0.33, p=1.5e‐5) over MuSiC (R=0.12, p=0.11).ConclusionmMuSiC improves cell fraction estimates of bulk brain RNAseq datain studies using snRNA‐seq. This is particularly useful for brain research where snRNA‐seq is unavailable.
Identification of transcriptional signatures of cognitive resilience using single nucleus RNA sequencing
Authors: Hadad Niran , Telpoukhovskaia Maria , Zhang Jigang , Samuels Michael , Robson Paul , Philip Vivek M. , Kaczorowski Catherine C. 
Published: December 2022

AbstractBackgroundIt is estimated that a third of the elderly population is not diagnosed with Alzheimer’s disease (AD) due to the absence of cognitive impairment despite carrying risk variants of AD or presenting AD pathology post‐mortem. This suggests that at‐risk individuals may carry protective mechanisms that promote resilience to cognitive impairment, however the underlying molecular processes that promote resilience remain unknown.MethodTo determine transcriptional changes associated with resilience, we profiled the hippocampal transcriptome at the single cell level in 7 resilient and 7 susceptible strains from the AD‐BXD mouse reference panel1, a genetically diverse mouse model of AD that better mimics human AD. Here, we used contextual fear memory paradigm to assess short‐term memory function in AD‐BXDs carrying the 5XFAD mutation. Resilience was defined based on age‐related change in cognitive function relative to that of the entire AD‐BXD population, where strains showing no or lower than average decline were considered resilient.ResultUsing single nucleus RNA‐sequencing, we profiled ∼220 K nuclei from the hippocampal formation and identified 32 cell clusters representing the major cell types in the hippocampus including glutamatergic neurons, GABAergic neurons, astrocytes, oligodendrocytes and microglia. With the exception of GABAergic neurons, transcriptional changes associated with the 5XFAD mutation were greater in susceptible AD‐BXDs. Gene expression changes associated with cognitive resilience were primarily observed in excitatory neurons, specifically in the CA1 and dentate gyrus and were enriched for ribosomal genes and nuclear encoded mitochondrial genes. In attempt to infer potential ligands that regulate resilience‐associated transcriptional changes we used a ligand‐target interaction analysis and predicted potential ligands regulating resilience programs in excitatory neurons.ConclusionOur findings demonstrate that the rate of cognitive decline is concomitant with increased transcriptional changes associated with the 5XFAD mutation across cell types in the hippocampus. We show that molecular programs associated with resilience in excitatory neurons are enriched in protein metabolism, cellular respiration and translation, possibly indicating a response to energy demand and maintenance of cellular homeostasis.Neuner SM, Heuer SE, Huentelman MJ, O'Connell KMS, Kaczorowski CC. Harnessing Genetic Complexity to Enhance Translatability of Alzheimer's Disease Mouse Models: A Path toward Precision Medicine. Neuron. 2019.
Selection Factors Influencing Participation in National Alzheimer’s Coordinating Center (NACC) Studies Compared to the Nationally Representative Health and Retirement Study (HRS)
Authors: Evangelista Nicole D. , Renteria Miguel Arce , Mobley Taylor M , Fox‐Fuller Joshua T. , Minto Lex , Avila Justina F , Deters Kacie D , Medina Luis D , Bettcher Bri M 
Published: December 2022

AbstractBackgroundRacial/ethnic disparities in ADRD are well documented such that prevalence of ADRD and known risk factors (e.g., cardiovascular disease, educational attainment) disproportionately impact Black and Latinx populations compared to their White counterparts. To generalize findings on the mechanisms and disease course and mitigate racial/ethnic disparities in ADRD, it is critical that diverse populations are well represented in studies of ADRD. We examined selection factors across racial/ethnic groups included in National Alzheimer’s Coordinating Center data (NACC) compared to the general U.S. population using data from the Health and Retirement Study (HRS).MethodAnalyses included baseline NACC data from 33,998 participants (Mage = 74.1yrs±8.0; Medu = 15.5±6.9; 56.7% women) and the 2010 wave of HRS weighted up to the 2010 US population aged 60+ years (weighted n = 48,726,070; Mage = 71.3yrs; Medu = 12.9yrs; 54.3% women). We assessed covariate balance between NACC and the 2010 US population aged 60+ by calculating standardized mean differences across harmonized sociodemographic factors, self‐reported health characteristics, depressive symptoms, and subjective memory concerns stratified by race/ethnicity. Standardized mean differences greater than +/‐ 0.25 were considered strong selection factors into NACC.ResultAcross all racial/ethnic groups, NACC participants were more likely to be older, have higher educational attainment, and report subjective memory concerns and hearing difficulties compared to the 2010 US population aged 60+ years (Figure). Standardized mean differences for age, educational attainment, and memory concerns were larger among non‐Latinx Whites compared to differences among non‐Latinx Black and Latinx participants. There was greater representation of non‐Latinx Black women in NACC, and non‐Latinx Black and Latinx NACC participants were less likely to endorse depressive symptoms. Additionally, results suggested non‐Latinx White participants were less likely to report diabetes and hypertension compared to their 2010 aged 60+ US population counterparts.ConclusionResults suggest that NACC participants are not representative of the U.S. population in key demographic and health factors and self‐reported memory concerns. These selection factors differed across racial/ethnic groups and are suggestive of selection bias. Future studies should leverage statistical tools that aimed at generalizing findings to general populations. Studies should also consider mitigating these sources of bias through inclusive recruitment efforts across Alzheimer’s Disease Centers to improve generalizability.
Word Generation from Letter and Semantic Categories Across the Alzheimer’s Disease Spectrum
Authors: Menendez Natalia R. , Smirnov Denis S. , Thomas Kelsey R. , Bondi Mark W. , Gollan Tamar H. , Jacobs Diane M. , Galasko Douglas R. , Salmon David P. 
Published: December 2022

AbstractBackgroundIndividuals with mild dementia or mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) often have verbal fluency deficits with greater impairment in generating exemplars from a semantic category (e.g., “animals”) than words that begin with a particular letter (e.g., ‘F’). This may reflect early development of pathology in cortical regions mediating semantic knowledge/organization required to efficiently generate words from a conceptually‐related set of exemplars. We sought to determine if this word generation deficit and discrepancy between category and letter fluency emerges in the preclinical stage of AD.Participants and MethodsSemantic and letter fluency tasks were completed by 394 participants. Correct words generated in one minute from each category was summed across animals, fruits, and vegetables (AFV), and across letters ‘F’, ‘A’, and ‘S’ (FAS). CSF was obtained within one year of the fluency tasks and levels of Aβ40, Aβ42, phosphorylated tau (p‐tau), and total tau were measured. Participants were classified as cognitively normal (CN) with negative AD biomarker (CN‐Neg; n = 179), CN with positive AD biomarker (tau/Aβ42 ratio>.609) (CN‐Pos; n = 59), MCI (all biomarker positive; n = 46), and AD dementia (all biomarker positive; n = 110).ResultsA Group X Task repeated measures ANOVA (adjusting for age and education) showed participants generated more correct words for AFV than FAS (F(1,380) = 20.44; p.001), there was a general stepwise decline in words generated across the AD spectrum (AD<MCI<CN‐Pos = CN‐Neg) (F(3,380) = 144.13; p.001), and this decline was greater on AFV than FAS (interaction F(3,380) = 18.59; p.001). CN‐Pos and CN‐Neg did not differ in correct words generated on either task, but AFV (r = ‐.304; p = .018) and FAS (r = ‐.290; p = .025) scores were negatively correlated with levels of p‐tau in amyloid positive (Aβ42/40 ratio<.056), but not amyloid negative, CN individuals.ConclusionsAlthough word generation was not impaired in the CN‐Pos group, a negative relationship with CSF p‐tau in the context of amyloid positivity suggests that changes in verbal fluency may be emerging in preclinical AD. A similar relationship with p‐tau for letter and semantic fluency implies that mechanisms common to both tasks (e.g., initiation of effortful retrieval) are affected earlier than mechanisms with greater specificity to the semantic fluency task (e.g., semantic knowledge/organization).
Neuropathological validation of plasma GFAP
Authors: Benedet Andréa Lessa , Smirnov Denis S. , Ashton Nicholas J. , Hiniker Annie OF , Simrén Joel , Rodriguez Juan Lantero , Zimmer Eduardo R , Zetterberg Henrik , Blennow Kaj , Galasko Douglas R. 
Published: December 2022

AbstractBackgroundGlial fibrillary acidic protein (GFAP) is an astrocytic marker that has been recently associated with fluid and imaging biomarkers of amyloid and tau pathologies in the Alzheimer’s disease (AD) spectrum. Plasma GFAP has also shown to be a strong indicator of early brain amyloidosis in preclinical AD. However, it remains to be confirmed how plasma GFAP associates with neuropathological hallmarks of AD and which pathological entities are being reflected by this plasmatic marker.MethodPlasma GFAP concentrations were measured using a commercial Simoa assay on participants of the UCSD Shiley‐Marcos Alzheimer’s Disease Research Center (ADRC), consisting of 271 participants with brain autopsy data. Amyloid and tau pathologies were assessed following the CERAD, Braak and NIA‐Reagan criteria, as well as with tangle and plaque counts (147 participants). Cerebral amyloid angiopathy (CAA) was graded as recommended by NACC Neuropathology Working Group. Non‐AD pathologies were also assessed: Lewy body disease, hippocampal sclerosis, TDP‐43 and vascular pathology. The distribution of GFAP concentration was compared across groups using ANCOVA models adjusting for age and sex, followed by post‐hoc Tukey’s HSD test. The association between GFAP and the pathological indexes was tested using linear models and adjusted by covariates.ResultConcentrations of plasma GFAP were higher in females as compared to males (P=0.008) and no age effect was observed. GFAP also increased with severity of AD pathological stages (P<0.001), with increased neuritic (P<0.001) and diffuse plaque density or counts (P=0.001), as well as with Braak stages and tangle counts (P<0.05). We found no association between tangle counts and GFAP when accounting for the effect of plaque counts. The presence of co‐pathologies did not affect average GFAP levels. We found no association between GFAP and CAA.ConclusionPlasma GFAP showed again here to highly reflect amyloid deposition. Results indicate, however, that this association is due to the accumulation of extra‐cellular amyloid in the form of plaques rather than its deposition in blood vessels. Abnormal accumulation of non‐AD proteins did not show any marked effect on GFAP levels. More detailed analysis, including longitudinal retrospective data, is ongoing.
Cx3cr1 deficiency aggravates Aβ driven neurodegeneration and cognitive decline in a mouse model of Alzheimer's disease.
Authors: Puntambekar Shweta S , Moutinho Miguel , Lin Peter Bor‐Chian , Jadhav Vaishnavi , Tumbleson‐Brink Danika , Balaji Ananya , Benito Martin A , Xu Guixiang , Oblak Adrian L , Reeves Cristian A Lasagna , Landreth Gary E , Lamb Bruce T 
Published: December 2022

AbstractBackgroundDespite its identification as a key checkpoint regulator of microglial activation in Alzheimer’s disease, the overarching role of CX3CR1 signaling in modulating mechanisms of Aβ driven neurodegeneration, including accumulation of hyperphosphorylated tau in is not well understood.MethodUsing 4 ‐ and 6‐month old 5xFAD;Cx3cr1+/+ and 5xFAD;Cx3cr1‐/‐ mice, we use immunohistochemistry, western blotting, transcriptomic analysis and quantitative real time PCR to investigate accumulation of soluble and insoluble Aβ species, plaque associated microglial activation, synaptic dysregulation and neurodegeneration with disease progression. Flow cytometry based, Aβ uptake assays are used for in‐vivo characterization of the effects of CX3CR1‐signaling on microglial phagocytosis and degradation of methoxy‐X04+ fibrillar Aβ. Lastly, we use Y‐maze testing to analyze the effects of Cx3cr1 deficiency on working memory in 5xFAD mice.ResultWe show that disease progression in 5xFAD;Cx3cr1‐/‐ mice is characterized by increased deposition of filamentous plaques that display defective microglial plaque engagement, along with impaired microglial Aβ phagocytosis and lysosomal acidification in‐vivo. Interestingly, Cx3cr1 deficiency resulted in heighted accumulation of neurotoxic, oligomeric Aβ, which correlated with severe neuritic dystrophy, preferential loss of post‐synaptic densities, exacerbated tau pathology, neuronal loss and cognitive impairment. Transcriptomic analyses using cortical RNA coupled with real time PCR validation using FACS‐purified microglial cells revealed dysregulated TGFβ responses, inflammatory signaling and oxidative stress responses in 5xFAD;Cx3cr1‐/‐ mice.ConclusionIn contrast to increased Aβ uptake by Cx3cr1‐/‐ microglia during early disease, Cx3cr1 deficiency impairs microglial uptake and degradation of fibrillar Aβ, thereby triggering an accumulation of neurotoxic soluble and insoluble Aβ species with disease progression. Our results indicate that Aβ‐driven microglial dysfunction in Cx3cr1‐/‐ mice aggravates tau hyperphosphorylation, neurodegeneration, synaptic dysregulation and impairs working memory. This study underscores the importance of investigating the time‐dependent role of CX3CR1‐driven microglial responses in AD.
Evaluation of ethnoracial differences in self‐ and study partner‐reported subjective cognitive decline in the A4 Study screen data
Authors: Robinson Talia L , Klinger Hannah , Buckley Rachel F. , Deters Kacie D , Quiroz Yakeel T. , Rentz Dorene M. , Sperling Reisa A. , Amariglio Rebecca E. 
Published: December 2022

AbstractBackgroundSubjective cognitive decline (SCD) may represent an early clinical manifestation of Alzheimer’s disease (AD) pathology. There is evidence of an association between amyloid deposition and SCD. Given disparities in risk of AD and cognitive impairment across ethnoracial groups, there is need to evaluate SCD, cognition, and markers of AD across diverse samples, as well as study partners as reporters of SCD.MethodParticipants included 267 non‐Hispanic Black, 5241 non‐Hispanic White, 225 Hispanic White, and 228 Asian individuals who presented for screening for the Anti‐Amyloid in Asymptomatic Alzheimer’s Disease (A4) study (N = 5961). Participants completed the Preclinical Alzheimer Cognitive Composite (PACC) and self‐ and study partner‐report of SCD (Cognitive Function Instrument/CFI). A subsample of participants underwent amyloid PET (N = 4416). In a series of within‐group linear regressions, we evaluated the relationships between 1) self‐reported SCD and cognitive performance 2) study partner‐ and self‐reported SCD, and 3) participant amyloid status and SCD.ResultAsian participants self‐reported the highest SCD and non‐Hispanic White participants reported the lowest. Controlling for age, education, and gender, PACC performance was significantly associated with self‐reported SCD in non‐Hispanic White (R2 = 0.039, b = ‐0.141, p < .0001), non‐Hispanic Black (R2 = 0.055, b = ‐0.158, p < .01), and Asian samples (R2 = 0.093, b = ‐0.318, p < .0001), with better PACC performance associated with lower CFI. PACC was not significantly associated with CFI in the Hispanic sample (R2 = .003, b = ‐0.097, p = .0636). Self‐ and study partner report of SCD were significantly correlated in all groups. Amyloid burden was associated with greater self‐reported SCD in non‐Hispanic White (R2 = 0.018, b = 0.452, p < .001) and Asian samples (R2 = 0.046, b = 1.58, p < .01), but not in the non‐Hispanic Black (R2 = 0.020, b = ‐.501, p = .277) and Hispanic participants (R2 = 0.016, b = 0.638, p = .169).ConclusionSCD appears similarly related to cognitive performance across most groups, and there is alignment between self‐ and study‐partner report of SCD across groups. There is evidence of variability in the association between AD biomarkers and SCD across racial groups, albeit in a smaller subsample with PET imaging. Future work should evaluate sociocultural factors that may contribute to differences in the value of SCD in individuals at risk for symptomatic AD.
Aβ1‐42 oligomers induce pericyte dysfunction via p75 Neurotrophin Receptor
Authors: Bobinger Hanna V. , Bauman Allison J. , Randall Ryleigh B. , Saiyasit Napatsorn , Nelson Amy R. 
Published: December 2022

AbstractBackgroundAmyloid beta (Aβ) aggregates and tau tangles are hallmark pathologies of Alzheimer’s disease (AD). There is growing evidence that vascular dysfunction may contribute to the pathophysiology of AD. Pericyte injury and/or deterioration leading to blood‐brain barrier (BBB) breakdown occur in normal aging and are associated with cognitive impairment in AD patients. Furthermore, there is reduced cerebral blood flow in AD. Because vascular resistance occurs in capillaries, we hypothesize that Aβ1‐42 causes aberrant pericyte contraction and cell death via p75 neurotrophin receptor (p75NTR).Methodp75NTR levels were quantified via Western blotting in mouse vascular brain pericytes treated with either artificial cerebrospinal fluid (aCSF) as a control or 72 nM Aβ1‐42 oligomers for either 20 minutes or 24 hours. Furthermore, LIVE/DEAD assays were performed to quantify pericyte deterioration after exposure to 72 nM Aβ1‐42 for various time points. In mouse models, changes in red blood cell (RBC) flow due to pericyte contraction around capillaries were measured using intravital microscopy in the somatosensory cortex of anesthetized C57 mice and applying either topical aCSF or 72 nM Aβ1‐42.ResultAfter 20 minutes of aCSF or Aβ1‐42 treatment, there is a statistically significant increase in p75NTR levels (n = 3, p = 0.016, two‐tailed t‐test), while there is a statistically significant decrease by 43% in p75NTR levels after 24 hours (n = 6, p = 0.0028, two‐tailed t‐test). After 48 hours of aCSF or Aβ1‐42 treatment, 75.6% of the control pericytes were viable, whereas only 65.3% of the Aβ1‐42 treated pericytes were viable. Preliminary in vivo studies revealed that 72 nM Aβ1‐42 treatment stalled RBC flow.ConclusionPericytes were confirmed to express p75NTR. Aβ1‐42 treatment upregulates p75NTR expression after 20 minutes while downregulating its expression after 24 hours. This suggests that acute increases in p75NTR levels may mediate increased pericyte contraction and play a role in reduced cerebral blood flow during the progression of AD. Because the details of this mechanism are unknown, future in vivo studies will involve pericyte‐specific p75NTR knock‐out mice.