bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linking Cognitive Function Index Item‐Level Responses to Tau Pathology in Amyloid Positive Cognitively Unimpaired individuals: Findings from The A4 Study
Authors: Demirsoy Idris , Petersen Kellen K. , Nallapu Bhargav Teja , Ghanbarian Elham , Lipton Richard B. , Rabin Laura , Ezzati Ali 
Published: January 2025

AbstractBackgroundThe Cognitive Function Index (CFI) is a validated test used to assess changes in self‐perceived cognitive and functional status as reported by an individual and their study partner. Previous studies have demonstrated an inverse correlation between higher amyloid‐beta (Aβ) burden and CFI, with certain CFI items exhibiting stronger associations than others. However, there is limited understanding of the association between declines in cognition and function, as assessed by CFI, and Tau levels measured by PET.MethodsParticipants were 339 cognitively unimpaired, Aβ positive, individuals enrolled in the Anti‐Amyloid Asymptomatic Alzheimer’s (A4) Study who underwent tau‐PET imaging. Participants were classified as tau‐PET positive (T+) or negative (T‐) based on tau levels in the medial temporal lobe (TMTL+/TMTL‐). Participants and their study partners assessed subjective changes in cognition and function over the past year using a 15‐item CFI questionnaire. For each CFI item, the relationship between Tau and CFI reports (Yes/Maybe vs No) was investigated using logistic regression models.ResultsParticipants were on average 72.38(SD = 4.87) years old, 58.1% were female, and 23.6% was TMTL+. Table 1 summarizes the sample characteristics. Higher TMTL was significantly associated with participant report of decline on six items, seeing a doctor about memory concerns (OR = 1.746, p = 0.002) and getting lost while travelling to another city (OR = 1.557, p = 0.003) showing the highest odds ratios. By contrast, Higher TMTL was associated with study partner report of decline on only one item: needing help from others to remember appointments/occasions (OR = 1.592, p = 0.002).ConclusionUnique CFI items were associated differentially with higher TMTL for participants and their study partners. The value of the CFI questionnaire with participant as the source of information may be higher than responses provided by informant in terms of the association with Tau‐PET positivity. This is consistent with the idea that self‐awareness of cognitive decline might precede the observations made by others.
Identification of USP16 cryo‐EM protein structure and development of a small molecule inhibitor to restore compromised neural stem cell regeneration in a mouse Alzheimer’s model
Authors: Ho William Hai Dang , Djomehri Sabra I. , Alford Vincent M. , Chen Elizabeth Y. , Reinitz Felicia , Gottlieb Sydney , Igboabuchi Francie I. , Chung Grace Yuna , Fernandez Daniel , Montabana Elizabeth , Singal Bharti , Qi Zhen , Kuo Angera H. , Qian Dalong , Clarke Michael F. 
Published: January 2025

AbstractBackgroundHallmark pathologies of Alzheimer’s Disease (AD) include the accumulation of both extracellular amyloid and intracellular tau proteins. While a significant body of knowledge exists surrounding the role of the protein aggregates in the context of AD, research supporting these as targets for therapeutic development have yielded inconsistent findings. One significant barrier is the inability to restore cognitive function despite the successful clearance of these proteins. In our recently published paper, we discuss a novel target for AD, USP16, which has been shown to promote ubiquitination of histones allowing for transcription of CDKN2A, a cell cycle regulator. We demonstrated that knockdown of USP16 improved neurosphere initiating capacity in mouse neural stem cells. Moreover, reduction of USP16 expression via heterozygosity resulted in improved cognition in 12‐month‐old mice. From these findings, our lab aims to identify the full‐length protein structure of USP16 using cryogenic electron microscopy (cryo‐EM) and develop a small molecule drug to inhibit its activity for end‐use as a viable AD therapeutic option.MethodsTruncated regions corresponding to the active and zinc‐finger (ZnF) domains of USP16 were expressed in both HEK293T and SF9 cells. Whole cell lysates were purified using affinity chromatography and identity was verified using Western blot. The purified protein products were submitted for cryo‐EM to determine their respective structures. Focusing on the ZnF domain, we utilized both a previously published proton NMR‐derived structure as well as AlphaFold‐predicted USP16 protein structure to serve as model scaffolding onto which we could perform in silico small molecule drug screening. Libraries were obtained from Schrodinger, MilliporeSigma, Emanine, MolPort, Thermo Fisher, MedChemExpress, Life Chemicals, ChemDiv, and Mcule.ResultsChromatogram from affinity chromatography and Western blot imaging together indicate successful isolation of truncated USP16 domains expressed in HEK293T and SF9 cells. Preliminary findings from cryo‐EM on the WT SF9 construct recapitulates the major domains predicted by AlphaFold. Over 9.5 million small molecule hit interactions against the ZnF domain have been identified.ConclusionCryo‐EM was successful in generating a course model of USP16. In silico protein modeling and drug screening was able to identify potential ligands against the ZnF domain of USP16.
Multi‐Ethnic Analysis of Expression Quantitative Trait Loci (eQTL) in Alzheimer’s Disease: A Focus on Health Disparity Populations
Authors: Wheeler Nicholas R. , Mews Makaela , Gu Tianjie , Gomez Lissette , Whitehead Patrice L. , Hamilton‐Nelson Kara L. , Sanchez Jose Javier , Adams Larry D. , Mena Pedro R. , Starks Takiyah D. , Silva Concepcion , Illanes‐Manrique Maryenela , Cuccaro Michael L. , Vance Jeffery M. , Cornejo‐Olivas Mario , Byrd Goldie S. , Feliciano‐Astacio Briseida E. , Haines Jonathan L. , Beecham Gary , Pericak‐Vance Margaret A. , Griswold Anthony J. , Bush William S. 
Published: January 2025

AbstractBackgroundDespite its high heritability, the genetic mechanisms influencing Alzheimer’s Disease (AD), particularly in health disparity populations like African Americans (AA) and Hispanics (HI), are not fully understood. The lack of ancestral diversity in genetic datasets, notably in eQTL studies that associate genetic variation with gene expression, exacerbates these disparities. Our study seeks to address this gap by comparing the AD interactions of racially and ethnically diverse expression Quantitative Trait Loci (eQTL) effects to investigate the genetic influence on AD in underrepresented populations.MethodWe investigated the impact of AD status on multi‐ethnic eQTLs across 3 diverse ancestral cohorts: AA, HI, and Non‐Hispanic White (NHW). Genotype and gene expression data were collected from samples of each genetic ancestry (AA = 224, HI = 293, NHW = 235), all with known AD status, with a focus on generating whole blood RNAseq data. We modified the TensorQTL pipeline to incorporate an interaction term for AD status to identify eQTL effects potentially induced by disease. We examined the top eQTL association per gene to assess the impact of AD status across the three ancestral cohorts.ResultOur preliminary analysis reveals striking variations in the impact of AD status on gene expression across AA, HI, and NHW cohorts. Several genes in each ancestry show statistically significant (pv<10e‐8) interaction effects (G X AD) (AA = 11, HI = 5, NHW = 9), indicating that genetic variation within those genes influences gene expression in an AD‐status dependent manner. A number of genes displayed interesting interaction patterns, where the most significant eQTL‐AD interaction was identical in two of the three ancestries studied, suggesting a potential ancestrally‐shared connection to AD risk (AA+HI = 4, AA+NHW = 3, HI+NHW = 5, AA+HI+NHW = 0), though notably there were no genes with induced eQTLs across all three ancestries.ConclusionOur study highlights the impact the AD disease process has on genetic variants that alter whole‐blood gene expression. We also highlight differences by population, prompting the development of ethnically diverse gene expression panels that pave the way for more accurate genetic studies in health disparity populations. Our findings also underscore the potential for discovering novel genetic mechanisms influencing AD risk, which could lead to more effective and inclusive therapeutic strategies.
Relationship between cortical diffusivity and neuropathological substrates in Alzheimer’s disease
Authors: Debatisse Justine , Leng Fangda , Edison Paul 
Published: January 2025

AbstractBackgroundPathological alterations in Alzheimer’s disease (AD) begin several years before the onset of symptoms. Grey matter mean diffusivity (MD) may be used as a measure of early grey matter damage in AD as it reflects the breakdown of microstructural barriers, which precede volumetric changes and affect cognitive function. In this study, we investigated the changes in MD early on in the disease trajectory, and relate them to the amyloid and tau deposition.MethodWe analysed multimodal PET, DTI and MRI data of 90 participants, stratified into amyloid‐β negative and positive, cognitively normal (CN), mild cognitive impaired (MCI) and AD patients.ResultWe found that MD was significantly increased in Aβ‐positive MCI and AD compared with CN in frontal, parietal, temporal cortex, hippocampus, and medial temporal lobe. We also found that cortical MD is significantly correlated with cortical thickness only in patients without amyloid deposition and is not significant in Aβ‐positive patients.ConclusionOur results suggest that cortical MD is an early marker of neuronal damage as it is observed simultaneously as Aβ deposition and as it is correlated with cortical thickness when there is no Aβ deposition. This suggests that cortical MD provides information about early microstructural changes before macrostructural changes.
Sex Differences in Cerebrovascular Reactivity to Hypercapnia in Older Adults
Authors: Engstrom Allison C , Kapoor Arunima , Dutt Shubir , Alitin John Paul M , Gaubert Aimée , Lohman Trevor , Sible Isabel , Marshall Anisa J , Shenasa Fatemah , Shao Xingfeng , Wang Danny JJ , Nation Daniel A. 
Published: January 2025

AbstractBackgroundCerebrovascular reactivity (CVR) is a marker of cerebrovascular function defined by blood flow changes in response to vasoactive stimuli, which may represent a valuable indicator of risk for vascular brain injury and cognitive decline. Understanding of sex specific CVR patterns is limited, yet likely important for understanding vascular risk. Previous research on sex differences in CVR is mixed, and has predominantly focused on younger adults and utilized Transcranial Doppler ultrasound approaches that focus on large intracranial artery flow. We sought to determine sex differences in CVR responses in older adults using MRI approaches focused on microvascular vasodilatory responses.MethodIndependently living older adults, (N = 127, mean age = 69.9 years; SD = 7.27; age range 55‐90 years, 34.6% male, mean education = 16.7 years; SD = 2.2) free of dementia, clinical stroke, and major neurological or psychiatric disorder, were recruited from the community and underwent brain MRI and clinical interview. Pseudo‐continuous arterial spin‐labeling MRI and capnography was used to quantify whole brain cerebral perfusion during CVR to hypercapnia induced by visually guided, 15sec breath‐hold exercises. Sex differences in whole brain CVR to hypercapnia were studied.ResultAn independent samples t‐test revealed women (M = 6.52, SD = 5.40) to have significantly higher CVR to hypercapnia than men (M = 4.24, SD = 4.20), t(125) = 2.63, p = 0.01, which remained significant in an ANCOVA model after correcting for age F(125) = 4.407, p = 0.038.ConclusionOlder men exhibited lower cerebral vasodilatory responses to hypercapnia relative to women, independent of the effects of aging. These results are consistent with prior findings suggesting that women have higher cerebral blood flow relative to age‐matched men. Findings could suggest older women are at increased risk of vascular brain injury and resulting cognitive decline, and inform future studies of CVR as a marker of risk in this population.
Validation of a questionnaire to measure the attitude of the Peruvian population regarding brain donation for the purpose of investigation
Authors: Bulgarelli Lucia , Benavidez‐Carbajal Ernesto , Canevaro‐Sesarego Fiorella , Rodriguez‐Lopez Ethel , Cruzalegui‐Bazán Claudia , Mejia‐Rojas Claudia , Campos Marzhio , Cruz Eddy De La , Mejia‐Rojas Koni 
Published: January 2025

AbstractBackgroundResearch into human brain tissue is important for medical scientific advancement. Brain Banks worldwide allow the receipt of brains for such purposes through voluntary donation. Attitude towards organ donation can be influenced by cultural, ethical and social factors. The lack of a validated questionnaire to evaluate it in the Peruvian population highlights the need for this study in the context of the creation of the First Brain Bank in Peru.MethodAn observational, descriptive cross‐sectional study was carried out.The questionnaire was applied to 52 Peruvians over 18 years of age, selected by convenience in different areas of Peru, who agreed to participate voluntarily.The questionnaire developed took as reference the “Health Street” questionnaire, created by the University of Florida. Then adapted taking into consideration the Peruvian context, according to the comments of experts on the subject. It resulted in 43 items with responses via Likert scale, 1 dichotomous, 10 polytomous and 3 open.The questionnaire was applied to the participants through an in‐person and/or virtual interview. Likewise, after signing the informed consent, in some cases the administration was guided by the researcher, and in others it was self‐administered.Finally, the internal consistency of the instrument was evaluated using Cronbach’s Alpha coefficient.ResultThe questionnaire was applied to 52 Peruvians with different socioeconomic and clinical conditions (tab.1 and tab.2), recollected from different parts of the country and whose average age was 38.61 years.The Cronbach’s alpha coefficient calculation was 0.97.ConclusionThe evaluation of the questionnaire by the experts was adequate: there were 5 experts, as recommended in the literature.This questionnaire demonstrated good reliability in relation to the questions (Cronbach’s alpha was 0.97) so there is a good acceptability of the instrument.
Beyond urate lowering: neuroprotective potential of Allopurinol
Authors: Balendra Vyshnavy 
Published: January 2025

AbstractBackgroundOxidative stress is formed by a perturbation of redox homeostasis and linked to the development of Alzheimer’s disease (AD) [1]. This imbalance results in an abundance of free radicals that exceeds the antioxidant capacity. Xanthine oxidase (XO) is an enzyme responsible for producing uric acid through the metabolism of purine nucleotides, specifically hypoxanthine and xanthine to uric acid [2]. XO has shown to be upregulated in inflammatory conditions such as AD promoting the generation of free radicals. Thus, allopurinol, an anti‐gout medication, which works to inhibit XO, has a neuroprotective effect and therapeutic potential in delaying neurodegeneration.MethodA literature search was conducted across scientific, international databases for English, peer‐reviewed articles and reviews published in the last decade using the following terms: allopurinol, xanthine oxidase and Alzheimer’s disease. Focus was placed on animal‐ or human‐based studies. Case reports were excluded.ResultIn‐ vitro studies revealed that elevated XO was associated with increased glial cell proliferation and reduced neuronal survival [3]. Other experimental studies showed XO overexpression in transgenic mice enhanced oxidative stress with increased secretion of pro‐inflammatory cytokines [4]. Allopurinol, an XO inhibitor, has shown to delay neurodegeneration in animal models with AD. Biochemical results in rodents showed decreased oxidative stress (myeloperoxidase levels), mild degenerative impairments in multipolar and bipolar neurons, and decreased apoptotic changes in glial cells after allopurinol treatment [5]. Inhibition of inflammatory molecules reduced vascular damages to the brain and GFAP immunoreactivity in the hippocampus [6]. The drug attenuated microglia infiltration, reduced astrocytes reactivation and prevented axonal loss and demyelination in mouse models [7,8]. Clinically, in population‐based, case‐control studies, allopurinol was associated with a 13‐34% lower risk of AD, lowered cognitive decline, and decreased behavioral symptoms [9,10].ConclusionEvidence ‐ based studies reveal allopurinol, a xanthine oxidase inhibitor, to have a neuroprotective potential against Alzheimer’s disease. Based on the current perspective, further research needs to be conducted in a clinical setting.
AD genes and microglia phenotypes: does microglia phenotypic heterogeneity matter?
Authors: Olah Marta 
Published: January 2025

AbstractThe view of microglial role in the pathogenesis of Alzheimer’s disease (AD) has been shaped by two major breakthroughs in the past decade: the discovery that many of the AD susceptibility genes are preferentially expressed in microglia, and the finding that microglia exist in a variety of previously not described functional phenotypes in the aged human central nervous system. As much as these discoveries brought paradigm shifts to the field, they also revealed major gaps in our understanding of the functional consequences of both the expression of AD susceptibility genes and microglia phenotypic heterogeneity. While there is progress being made in understanding the role of individual AD susceptibility genes in microglia function and what role the different microglia phenotypes might play in disease pathogenesis in AD, the connection between these two determining factors has not been established yet. In order to explore the relationship between the expression of AD susceptibility genes and the different microglia phenotypes that have been described in the aged and AD human brain, we explored the protein expression levels of AD relevant markers in a microglia subset specific way. Our findings highlight the importance of considering the phenotypic heterogeneity of microglia in the course of functional genomic studies and for any future disease modifying therapies targeting AD susceptibility genes in microglia.
Microglial and neuronal subpopulations associated with cognitive resilience to amyloid deposition in genetically diverse mice
Authors: Uyar Asli , Heuer Sarah E , Skelly Daniel A , Carter Gregory W , Bloss Erik B , Howell Gareth R 
Published: January 2025

AbstractBackgroundData from human and model organism studies suggest that genetic background influences susceptibility and resilience to Alzheimer’s Disease (AD) neuropathology. We previously showed that, wild‐derived PWK/PhJ (PWK) mice carrying the APP/PS1 transgene (PWK.APP/PS1) exhibit cognitive and synaptic resilience compared to traditionally‐studied B6.APP/PS1 inbred mice in presence of amyloid beta (Aβ) plaque deposition. PWK.APP/PS1 mice also contain different proportions of transcriptionally‐defined microglia compared to B6.APP/PS1. The precise molecular mechanisms underlying these differences between strains remain unknown. In this study, we aim to identify and characterize cell populations in the hippocampi of genetically distinct B6 and PWK mouse strains, and investigate cell‐type specific gene expression patterns associated with cognitive resilience in presence of amyloid deposition.MethodWe generated cohorts of B6.APP/PS1 and PWK.APP/PS1 transgenic female mice and wild‐type (WT) littermates as controls (n = 4 per strain/genotype group). At 8 months of age mice were euthanized, hippocampi collected, and single nuclear RNA sequencing (snRNAseq) was performed using 10x Genomics Chromium platform. Seurat R package (version 5.0.1) was used for major data analysis.ResultWe identified subpopulations of microglial cells characterized by varying expression patterns of a set of genes including Hk2, Itgam and Dock8. Neuronal subtypes were clustered by top marker genes Plk5 and Adarb2. Oligodendrocytes, oligodendrocyte progenitor cells, and endothelial cells were marked by expression of Mog, Neu4 and Abcc9, respectively. Differential expression and pathway enrichment analysis revealed strain‐specific immune and cell signaling pathways altered in distinct cell populations in response to amyloid pathogenesis. Cross‐species mapping of these transcriptomic signatures with human hippocampal gene modules identified AD‐relevant molecular mechanisms observed in mouse models of AD at the cell‐type level.ConclusionThis study suggests that cell‐type specific transcriptomic response to amyloid is modulated by genetic background and our findings re‐iterate the importance of incorporating genetic diversity to model phenotypic and molecular heterogeneity in AD. Since the nuclei enriched in this dataset are enriched for neurons, future interrogations will provide evidence for specific neuronal populations and molecular mechanisms that differentiate cognitively resilient PWK from susceptible B6 mice, providing insights into mechanisms that can be leveraged to promote AD resilience.
Evaluating ambroxol as an agent to boost lysosomal function and reduce beta amyloid in 3xTg mice
Authors: Tsang Adrianna R , Wang Lynn , Gajavelli Sairam , Pasternak Stephen H 
Published: January 2025

AbstractBackgroundAmbroxol is an expectorant under study as a treatment for synucleinopathies, such as Parkinson’s disease. It is a pharmacological chaperone of the lysosomal enzyme β‐glucocerebrosidase (GCase), increasing this enzyme and subsequently reducing accumulation of alpha‐synuclein. Although the mechanism of enhanced clearance is not fully understood, ambroxol stimulates lysosomal function through activation of transcription factor EB (TFEB), which drives hundreds of lysosomal genes. This project aims to investigate the usefulness of ambroxol as a disease‐modifying treatment for Alzheimer’s disease (AD). We hypothesize that ambroxol will enhance expression of lysosomal proteins and increase clearance of beta‐amyloid (Aβ) in the 3xTg mouse model of AD.MethodsWild‐type (B6;129) or 3xTg mice (APP/PS1/MAPT) mice were used. A ‘prevention’ group was treated at 6 months of age for 2 months, during initial Aβ deposition. A second ‘treatment group’ was fed ambroxol from 8 to 10 months of age, after Aβ deposits had developed. Mice received either 1) normal mouse chow, 2) low dose (1200 mg/kg) chow, or 3) or high dose (2400 mg/kg) chow. Brains were collected for immunohistochemistry, western blotting and ELISAs.ResultsBy immunostaining, mean expression of ambroxol treated animals demonstrated increased GCase and LAMP1 staining, as predicted. This was accompanied by a significant dose dependant reduction of Aβ in aged 3xTg mice.ConclusionsOur findings demonstrate that ambroxol is able to reduce intracellular accumulation of Aβ by upregulating lysosomal activity, and therefore may be a promising treatment for AD.