bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integration of multiple single cell microglial datasets reveals radial differentiation into long‐lived substates associated with Alzheimer’s pathology
Authors: Baumgartner Andrew , Robinson Max , Huang Sui , Hadlock Jennifer , Funk Cory C 
Published: December 2023

AbstractBackgroundUnsupervised classification of brain cell types can be readily achieved through analysis of gene expression patterns in multidimensional space. However, the small transcriptional differences between microglia subtypes require more principled, robust, and reproducible approaches to expose and distinguish biological differences from noise.MethodHere we leverage Fokker‐Planck diffusion maps [1,2] to examine the dynamics of microglia subtypes by finding a low dimensional representation of the underlying stochastic dynamical system responsible for generating these transcriptional states. Clustering directly on this projection allows us to reduce noise, assign time scales to these substates, and generate a hierarchy of microglial cell states. Once these subtypes have been defined, we apply pseudobulk differential expression analysis to identify marker genes, and use those genes to build a boosted tree model to classify cells states. We then apply Shapley additive explanations (SHAP) to identify which genes are most important for distinguishing between cell states.ResultWe observe a radial transition pattern emanating, with a subtype that appears homeostatic, inactivated, and poised for transition. This is consistent with the observation that microglia dynamics are sensitive to their microenvironment. Deconvolution of an independent bulk microglia dataset (n = 130) showed depletion in subtypes linked to protein misfolding and myelin phagocytosis, as well as enrichment in immunoreactive microglia in Alzheimer’s patients. SHAP reveals DUSP1, CD83, PLCG2, OLR1,CCL2, and JUN among the most important genes for differentiating into these AD‐associated clusters.ConclusionOur approach enables us to reproducibly identify microglial subtypes across sets of single cell‐resolution high dimensional molecular profile data, identifying likely drivers of subtype differentiation. With several of our driver genes already associated with Alzheimer’s via GWAS and other analyses, our results will enable us to elucidate the role of these genes in determining microglial subtypes.References:[2] Nadler, B., Lafon, S., Coifman, R. R., & Kevrekidis, I. G. (2006). Diffusion maps, spectral clustering and reaction coordinates of dynamical systems. Applied and Computational Harmonic Analysis, 21(1), 113‐127.[2] Coifman, R. R., Kevrekidis, I. G., Lafon, S., Maggioni, M., & Nadler, B. (2008). Diffusion maps, reduction coordinates, and low dimensional representation of stochastic systems. Multiscale Modeling & Simulation, 7(2), 842‐864.
The development of an explainable machine learning system for predicting brain atrophies from electronic health records
Authors: Ghosheh Mohammad , Ghosheh Ghadeer , Ghosheh Jamal 
Published: December 2023

AbstractBackgroundThe number of elderly living with dementia is projected to dramatically increase, especially in low‐income and middle‐income countries (LMICs). While obtaining brain scans to detect atrophies and significant radiology findings related to dementia might be costly, the use of electronic health record (EHR) for elderly patients could facilitate identifying patients at a high risk based on routinely collected data. This works, evaluates the use of an interpretable machine learning‐based system that predicts brain atrophies and small vessel disease based on EHR data.MethodWe develop a machine learning predictive system to predict atrophies or small vessel disease from retrospective anonymized EHR data recorded for patients above the age of 50 years from a multispecialty outpatient medical center from Ramallah, Palestine. The patient labelling involved using natural language processing to identify cases in unstructured radiology reports for structural brain Magnetic Resonance Imaging (MRI). For input features, we extracted and preprocessed 30 features for the most commonly collected clinical features such as demographics and laboratory results. The dataset was split into training and test sets, where data preprocessing and augmentation, and hyperparameter tuning were applied before training multiple models including Xgboost, Support Vector Machines, Random Forest, and Logistic Regression. To better understand the relative impact each feature had on the model’s prediction, shapely feature importance analysis was conducted for the top performing model.ResultThe top preforming model was Random Forest, with a performance of Area Under the Precision‐Recall Curve (AUPRC) of 0.989, and 0.842 for Area Under Receiving Operating Curve (AUROC). The feature importance analysis revealed that age, sex, Vitamin D, Vitamin B12 and red blood cell distribution width were the features with highest impact on the model’s predictionConclusionPredicting atrophies from EHRs for elderly visiting outpatient clinics could assist in case‐finding for dementia patients and ultimately help identify patients that would benefit from an MRI. In future works, we aim to further investigate building low‐cost diagnostic tools based on a smaller feature set, which could be valuable for facilities from LMICs.
APOE‐targeted epigenome therapy for late onset Alzheimer’s disease
Authors: Kantor Boris , Rittiner Joseph , Odonovan Bernadette , Chiba‐Falek Ornit 
Published: December 2023

AbstractBackgroundCarrying the APOEe4 variant significantly increases lifetime risk for LOAD. The accumulating evidence suggest that alteration of the expression of APOEe4 and APOE may hold promise as a potential therapeutics target for LOAD. In this study we developed an epigenome therapy platform to reduce APOE and APOEe4 specifically by targeted modification of the epigenome landscape within APOE locus.MethodOur approach is based on CRISPR/dCas9‐editing strategy. The novel system based on the novel bipartite repressor platform, recently developed in the laboratory. We designed targeting of APOEe4 in the allele‐discriminatory fashion, as such the editing is allele specific and precise. Furthermore, we developed a similar approach to target the regulatory elements within APOE promoter. We evaluated our platform in vitro using human hiPSC‐derived neurons and organoids, as well as in vivo by stereotactic injection of the developed system into the hippocampus of the ApoE‐humanized mice, harboring human ApoE loci replaced the mouse ortholog.ResultUsing the system, we demonstrated an efficient and precise editing of APOeE4 and APOE expressions in the hiPSC‐derived neurons and the human isogenic APOEe4 organoids. We showed that the system can robustly reduce the levels of APOE‐mRNA and the protein in both models. Importantly, the allele‐discrimination approach has resulted in no detectable editing of the e3 allele in the isogeneic hiPSC‐derived neurons, and organoids homozygous for the e3 allele. Moving onto in vivo studies, the promoter‐targeted approach using adeno‐associated‐ dCas9‐KRAB‐MeCP2 vector injected into the hippocampus of APOEe4 and APOEe3 mice, showed 50‐70% decrease in the mRNA and the protein levels. Similar effect was observed using lentivirus‐ CRISPR/Cas system targeted ApoEe4 in allele‐specific manner. Collectively, our results provided in vitro and in vivo proof‐of‐concept for the utility and efficacy of the APOE‐targeted epigenome therapy.ConclusionOur epigenome therapy strategy for fine‐tuning of APOE expression based on dCas9 technology is translational toward the development of a therapeutics approach to prevent and/or delay LOAD onset. Furthermore, the technology offers the opportunity to refine the platform for the development of gene‐specific and even allele‐ and cell‐type‐ specific therapies, and by that enables the advancement of strategies for precision medicine in LOAD.
Evaluation of the neurocognitive and neuroprotective potentials of selected Nigerian medicinal plants in experimental models of dementia
Authors: Atunwa Soliu A. 
Published: December 2023

AbstractBackgroundRecent studies have implicated oxidative stress, chronic neuroinflammation, functional cholinergic deficits, and glutamatergic pathway disruptions in the pathophysiology of dementia. However, certain medicinal plants are being used in the management of dementias by the inhabitants of Ibarapa Area of South‐Western Nigeria, hence this study.MethodEthno‐pharmacological survey of medicinal plants used in the management of dementias in Ibarapa Area of Oyo State, South‐Western Nigeria was conducted using semi‐structured questionnaires and open‐ended interviews. Phytochemical, antioxidant, anti‐inflammatory, anti‐nociceptive, and cholinesterase‐inhibiting screenings were conducted on selected medicinal plants (SMPs) using standard assays. Preliminary cytotoxicity screening of promising crude extracts were determined using brine shrimp lethality assay (BSLA). LD50, acute and sub‐chronic administrations of the SMPs into groups of mice were determined using Organization of Economic Cooperation and Development (OECD) 423 guideline. Haematological, biochemical, and histopathological examinations following single and repeated doses of crude extracts of SMPs into groups of mice were determined using standard assays. Behavioural studies using relevant mouse models were conducted. Mechanistic studies using cell lines are being carried out on the promising SMPs. Data are expressed as mean ± standard error of mean (SEM) and analyzed using one‐way analysis of variance (ANOVA) followed by post‐hoc test (Student‐Newman‐Keuls test).ResultThe ethnomedicinal survey revealed about 105 medicinal plants belonging to more than 50 families being used as memory enhancers in the management of dementias by the inhabitants of Ibarapa Area of Oyo State in south‐Western Nigeria. Phoenix dactylifera, Combretum mucranthum, Parquitena nigrescens, Crinum jagus, Blighia sapida, Entandrophragma utile, Ficus exasperate showed significant antioxidant, anti‐inflammatory, and anti‐cholinergic activities. Results of BSLA revealed LC50 values of 100 ‐ 1000 ppm for the screened plants. The oral LD50 values of crude methanol extracts of SMPs are 2000 ‐ 5000 mg/kg. Findings from haematological, biochemical, histological and behavioural assays following both single and repeated administrations of the tested SMPs in mice showed that they are safe and possess promising neurobehavioural potentials that warranted further exploration.ConclusionThe SMPs are safe, highly rich in beneficial phytochemicals, exhibited significant antioxidant, anti‐inflammatory, anti‐cholinesterase, nootropic and neuroprotective potentials thereby suggesting the rationale for their ethnomedicinal use in the management of NNDs.
Efficient use of open label extension data to support additional evidence of efficacy and disease modification hypotheses
Authors: Hennessey Sean , Dickson Samuel P. , Mallinckrodt Craig , Nicodemus‐Johnson Jessie , Knowlton Newman , Wassom Mitchell , Hendrix Suzanne B. 
Published: December 2023

AbstractBackgroundMany clinical trials have open label extension (OLE) phases in which all patients from the randomized controlled study go onto active treatment for some period of time. These OLEs provide the opportunity for placebo patients to have access to active treatment. Trial sponsors also want to get meaningful information from the OLE data.MethodWe evaluate the types of hypotheses that can be tested with OLE data in degenerative diseases and propose analyses aligned with these hypotheses. Challenges with OLE data are also enumerated and discussed. For these analyses, and for simplicity of examples, we are assuming that the randomized phase and the OLE phase are each 1 year in duration.Result6 key hypotheses can be addressed with OLE data. 1. Treatment effects differ during the randomized phase and the OLE, 2. Treatment groups differ at the end of the OLE, 3. The slope for placebo patients in the randomized phase differs from their slope during the OLE, 4. The slope over the entire duration of the randomized phase and the OLE phase differs between groups, 5. The slope of decline during the first 12 months of treatment combined across the original active patients and the placebo patients during the OLE phase differs from the placebo slope of decline during the original 12 month randomized phase. 6. The slope of the original placebo group differs from the original active group during the OLE phase. If a significant treatment effect is seen during the randomized phase, then hypotheses 2 and 6 can demonstrate disease modification in a pseudo staggered start analysis if they demonstrate that the treatment groups also differ at the end of the OLE phase, and are not converging during the OLE. Challenges with OLE analyses include high dropout rates, differential dropout between groups, ceiling and floor effects resulting in differing slopes (nonlinearity) during the randomized and OLE phases.ConclusionOLE phases can add to the weight of evidence for efficacy in clinical trials and can identify disease modifying effects as long as issues such as dropout and non‐linearity are accounted for.
Direct Reprogramming of the Marmoset Dermal Fibroblasts into Neural Stem Cells and Neurons
Authors: Park Jung Eun , Guimaraes Thais Rafael , Hachem Stephanie , Thathiah Amantha , Silva Afonso C 
Published: December 2023

AbstractBackgroundThe neuropathological hallmarks of Alzheimer’s Disease (AD) are characterized by the accumulation of beta‐amyloid (Ab) plaques and neurofibrillary tangles (NFTs) of a hyperphosphorylated form of the microtubule‐associated protein tau (MAPT) in the brain. However, Ab and tau accumulate in the brain decades before the clinical symptoms emerge and the biological basis for the relationship between abnormal aggregation of AD‐related proteins and neuronal deterioration remains unknown. Cell models play an imperative role in understanding the pathogenesis of the disorder. For this, the present studies aimed to establish a marmoset induced neurons directly converted from fibroblasts (induced neurons; iNs) as well as induced neural stem cells (iNSCs) that are further differentiated into neurons to quantify the spontaneous presence of AD‐related pathology in marmoset cell cultures in vitro.MethodMarmoset fibroblasts were cultured from skin biopsies and reprogrammed into iNSCs by transfection with episomal reprogramming vectors carrying the Oct4, Sox2, Nanog, Lin28, Klf4, and L‐Myc and culture in the presence of small molecule inhibitors CHIR99021 and SB431542. The iNSCs were subsequently differentiated into neurons. Direct neuronal conversion from the marmoset fibroblast was performed by co‐overexpression of Ngn2 and Ascl1 under the control of the doxycycline‐inducible tetOn promoter and supplementation of medium containing doxycycline in combination with a defined cocktail of small molecule‐based pathway modulators.ResultHighly proliferative marmoset iNSCs were established and expressed neural stem cell markers, including Sox2 and Pax6 when detected by immunofluorescence. iNSCs were differentiated into neurons and stained the neuron‐specific markers such as Tuj1, Map2, and NeuN. The Ngn2 and Ascl1 overexpressed marmoset fibroblasts underwent a morphological change into a neuron‐like structure within a few hours of neuronal induction and the resultant iNs were expressed the pan‐neuronal markers in the neurite‐like projection and cell bodies.ConclusionThe directly reprogrammed iNSC and iNs have been shown to have neuronal characteristics and offer a cellular model system to quantify the natural incidence of AD‐related pathology in marmosets. The marmoset cellular system of AD will provide mechanistic insight into the etiology of the disease and may serve as a beneficial tool for drug discovery to treat the disorder.
Streamlining and standardizing logistical, administrative, and regulatory workflows for sharing data from AD trials
Authors: Brown Christopher T. ,   Banner Alzheimer’s Institute
Published: December 2023

AbstractFailure to share data successfully and quickly results in the waste of scientific resources as experiments are erroneously repeated or future resources are misallocated. Successful data sharing maximizes prior public and private investment of time, personal and cost in AD trials. To date, training resources regarding general regulatory requirements for managing data are widely available, however trainings addressing common logistical and administrative decision‐making and providing administrative strategies in the context of data sharing by AD trial teams and sponsoring partners are rare or too rigid to be broadly applicable. A widely available and well‐known training and education resource will provide a coherent systematic approach for multi‐stakeholder research projects that intend to share data publicly. Such projects are at increased risk of delay or mismanagement and a cohesive effort to generate flexible, streamlined modules offering repeatable solutions for multi‐stakeholder AD research data sharing would benefit the research team as well as the requesting investigators. AD research staff should rapidly develop familiarity and a common understanding of the practices and policies of data sharing so that this aspect of research similarly streamlined to other research practices such as informed consent, data privacy, etc. Attendees will participate in a discussion establish a priori principles for charting a course for establishing broad competence in data sharing by combining principles of scientific rigor with a synthesis of best practices for logistical, scientific, and regulatory workflows.
Phosphorylation differentially regulates tau isoforms
Authors: Naseri Nima N 
Published: December 2023

AbstractBackgroundSix major tau isoforms are alternatively spliced in an age‐dependent manner: 3R tau (3‐repeat domain) is expressed in development, while both 3R and 4R (4‐repeat domain) tau isoforms are expressed in adult brain. While FTDP‐17‐causing point mutations in tau show isoform‐dependent effects on aggregation and microtubule stabilization, there are not tau mutations linked to Alzheimer’s disease. Meanwhile, effects of phosphorylation on different tau isoforms remain largely unexplored.MethodWe use a combination of recombinant proteins, mouse aging studies and iPSC‐derived neurons to test for isoform‐dependent effects of tau phosphorylation on its function and dysfunction.ResultPhosphorylation at certain sites selectively diminishes microtubule polymerization activity by the fetal tau isoform while a comparable adult isoform was largely unaffected. Conversely, phosphorylation at these same sites accelerated in vitro aggregation of an adult isoform compared to the fetal isoform.ConclusionPhosphorylation to tau has isoform‐dependent effects on its function and dysfunction, thus emphasizing the importance of distinguishing pathological and regulatory phospho‐tau species in future therapeutic efforts.
Cognitive performance and normative data between Hispanic and non‐Hispanic cohorts: Results from the South Texas Alzheimer’s Disease Research Center (ADRC)
Authors: Patel Aishwarya N. , LaRoche Ashley , Young Vanessa M. , Alliey‐Rodriguez Ney , Sullivan A. Campbell , Satizabal Claudia L. , Savoia Sarah E. , Katragadda Haritha V. , Saklad Amy R. , Shipp Eric L. , Gilliam Frank , Mavarez Rosa P. , Patel Neela K. , Tanner Jeremy A. , Parker Alicia S. , Salardini Arash , de Erausquin Gabriel A. , Maestre Gladys E. , Seshadri Sudha , Gonzales Mitzi M. 
Published: December 2023

AbstractBackgroundThe prevalence of Alzheimer’s disease and related dementias (ADRD) in the United States was estimated as 6.5 million people in 2022, with a five‐fold increase for the Hispanic/Latinx population expected by 2060. The South Texas Alzheimer’s Disease Center (STAC) was designated as a new ADRC in 2021 by the National Institute on Aging (NIA) with a specific aim to serve the growing needs of the local underrepresented Hispanic population. As cultural and linguistic factors can impact performance on cognitive tests, the goal of the study was to compare UDS‐3 cognitive test raw scores and normative data in Hispanic and non‐Hispanic adults without cognitive impairment residing in South Texas.MethodParticipants from the STAC cohort completed the Uniform Data Set (UDS), V.3.0, which includes demographics and neuropsychological battery. All batteries were administered in the participants’ preferred language, English. Normative data was calculated using Weintraub et al. (2018)’s age, sex, and education adjusted regression models for UDSNB 3.0. Mean differences between baseline visit raw scores and normative data were compared using independent sample t‐tests among Hispanic and non‐Hispanic participants.ResultThirty‐four Hispanic (mean age = 70.4, 67.6% female) and thirty‐eight non‐Hispanic (mean age = 71.9, 57.9% female) participants were included. Hispanic participants had fewer years of education relative to non‐Hispanic participants [M(SD)] = [14.7(2.5)] to [16.5(2.5)], respectively; (t(70.1) = 3.0, p = 0.004); although, the groups did not differ in age or sex distribution (p>0.05). Hispanic and non‐Hispanic participants generally performed equivalently on the neuropsychological battery. However, Hispanics had lower mean raw scores on the Montreal Cognitive Assessment (MoCA) (t(70.8) = 3.6, p<0.001) and the Multilingual Naming Test (MINT) (t(71) = 4.0, p<0.001) relative to non‐Hispanic participants, which persisted when normative data was applied (MoCA: t(71) = 2.3, p = 0.024, MINT: t(71) = 2.8, p = 0.006).ConclusionOverall, Hispanic and non‐Hispanic participants performed similarly on the UDS‐3 neuropsychological battery. However, Hispanics had lower mean raw and normative scores on the MINT, as well as the MoCA which also includes language measures. Our findings highlight the importance of future research validating the sensitivity and specificity of normative data used in underrepresented populations, especially those at higher risk for ADRD.