bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergism across neurodegenerative diseases using biological definitions
Authors: Poston Kathleen L. 
Published: January 2025

AbstractThe ability to define neurodegenerative diseases of aging based of biology rather than clinically defined syndromic presentations follows from biomarker development and reflects underlying pathology in living people. The NIA‐AA Research Framework (Jack et al 2018 Alzheimers Dement) proposed the biological definition for Alzheimer’s disease (AD) and sought to provide a common language to identify and stage research participants, who were not cognitively impaired but had abnormal AD biomarkers; it has been revised. The biological classification of Huntington’s disease (Tabrizi et al 2022 Lancet Neurology) included a biological research definition with an integrated staging system, centered on biological, clinical, and functional assessments. Simuni et al (2024 Lancet Neurology) proposed the Neuronal Synuclein Disease (NDS) biological definition, also with integrated staging system, encompassing anyone with biomarker evidence of predominantly neuronal alpha‐synuclein pathology, including people with Parkinson’s disease, dementia with Lewy bodies, or related clinical phenotypes, based on the seed amplification assay biomarker. A key paradigm shift central across these neurodegenerative diseases is diagnosis is not based on the clinical manifestations, but rather disease occurs and can be diagnosed regardless of specific, or in some cases without any, clinical signs or symptoms. It’s recognized these disease processes begin before the onset of symptoms, possibly decades before. Thus, these biological definitions translate this long‐touted recognition into actional research frameworks. There are numerous implications for such a paradigm shift. For one, this allows people to enroll in clinical studies and in clinical trials before the manifestation of classic clinical syndromes, and is likely the only way to test potential therapies for indications that prevent clinical symptoms in people with underlying disease. Further, by separating the syndrome from biology, these definitions recognize that syndromic presentations are not always specific for the underlying pathology, addressing the ongoing challenge of clinical heterogeneity in trials. Another implication of these biological definitions is the co‐occurrence of multiple pathologies, a long under‐recognized entity, can be prospectively studied in living people across the entire clinical spectrum from asymptomatic to severe functional impairment. As these biological definitions iterate upon newly obtainable and validated biomarker data from observational cohorts a more complete molecular characterization of neurodegeneration in aging, independent of syndromic classification, can begin to emerge.
A novel culprit in glucose hypometabolism in Alzheimer’s disease
Authors: Penalva Ylauna , Hernandez Marina Ruelas , Cinkornpumin Jessica , Kaartinen Mari , Pastor William , Munter Lisa 
Published: January 2025

AbstractBackgroundAlzheimer’s disease is characterized by early decreases in cerebral glucose metabolism which are linked to reduced glucose transporter 1 (GLUT1) expression at the blood‐brain barrier (BBB). Another key disease hallmark is the abundance of Aβ peptides as plaques in the brain which arise from the processing of the amyloid precursor protein (APP). Autosomal dominant inherited mutations causatively link APP itself to AD, rendering it imperative to fully understand APP’s physiological functions to define the underlying biology of AD. Previous studies in APP knockout (KO) mice implicate APP in metabolic processes such as mitochondrial function and insulin action. However, GLUT1 regulation as well as glucose metabolism at the BBB has yet to be investigated.MethodWe use APP KO mouse embryonic fibroblasts (MEFs), mouse primary cerebral endothelial cells, and vessels enriched from mouse brains to study GLUT1 physiology. RNAseq data was collected in MEFs to determine transcriptional changes underlying studied phenotypes.ResultSeahorse analysis of APP KO MEFs revealed a 50% decrease in glycolytic activity and 75% decrease in mitochondrial respiration as compared to control. Glucose uptake was also significantly decreased in the absence of APP. These metabolic defects were underlined by a 2‐fold decrease in GLUT1 total expression and a 5‐fold decrease in GLUT1 cell surface levels. The investigation of signaling pathways responsible for GLUT1 upregulation showed that PI3K/Akt/mTORC pathway was downregulated in APP KO MEFs as compared to control. Primary cerebral endothelial cells and vessels recapitulated the decrease in GLUT1 expression as well as decreased activation of the PI3K/Akt/mTORC pathway, suggesting a completely novel role for APP in cerebral glucose metabolism. Analysis of RNAseq data collected in MEFs for pathways regulating glucose metabolism revealed widespread changes in extracellular matrix gene expression.ConclusionOur findings posit APP as a major regulator of GLUT1 expression and glucose metabolism. This new perspective on APP is crucial for AD therapy as novel approaches could be developed to target decreased cerebral glucose metabolism.
Detecting Major Depressive Disorder from EEG Signals as a Biomarker for Alzheimer’s Disease
Authors: Orimaye Sylvester O , Smith Jeremy , Colado Guy , Tong Sunvy , Jager Tomas 
Published: January 2025

AbstractBackgroundMajor Depressive Disorder (MDD) is a complex and multifaceted condition. Traditional screening methods may not capture the full spectrum of symptoms, causing delayed diagnoses or misdiagnoses. Further, MDD is highly prevalent among patients with mild cognitive impairment (MCI), which may then progress to Alzheimer’s disease (AD). Research suggests that MDD among patients with MCI substantially accelerates cognitive decline many years before the onset of AD. We show that a machine learning model can aid MDD diagnoses as a potential biomarker of AD.MethodSince MDD is associated with changes in prefrontal brain activity, we used electroencephalogram (EEG) signals from this brain region to train a two‐class multi‐layer perceptron (MLP) neural network model that discriminates between MDD patients and healthy controls. The MLP parameters include the lbfgs solver, three hidden layers, 1000 max iterations, alpha of 1e‐6, a relu function, tolerance level of 1e‐3, and a learning rate of 0.1. We used the Multi‐Modal Open Dataset for Mental Disorder Analysis (MODMA) data, which contains three EEG channels, including Fp1, Fp2, and Fpz locations. We extracted predictive features from each channel by transforming the raw EEG signals to train our model. Our features included the EEG signal’s maximum, mean, standard deviation, skewness, kurtosis, and mean absolute Fast Fourier Transform extended with multiple imputed data on the original 50 patients. This led to 1550 observations at 775 per MDD or control. Training and testing data was split using a ratio of 0.70 to 0.30, and experiments were performed using the Scikit‐learn Python library.ResultThe experimental results indicate that the selected three‐channel EEG features can distinguish between MDD and healthy control subjects. The classification accuracy score was 76.8%, and the area under the curve (AUC) score was 85.3% (CI: 83.4% to 87.2%).ConclusionWe have demonstrated the effectiveness of using EEG signals to detect MDD in patients. The potential applications of our findings are the ability to aid in early medical diagnosis and serve as probable biomarkers of MCI and AD. Additional research is warranted to investigate more predictive features from the EEG signals.
Advanced glycation end products (AGEs) involvements in the development of frank Alzheimer’s disease (FAD)
Authors: Oghenekevbe Vincent , Olughor O 
Published: January 2025

AbstractBackgroundAGEs is one of the Maillard’s reaction products (MRPs) found in over‐processed common diets, causing food‐nutrients abnormal modifications. Some MRPs are potentially toxic or carcinogenic. MRPs present in stages: initial, intermediate and final. The aim of this presentation is to state roles played by AGEs in the development of AD as recent findings.MethodThrough threaded literature reviewResult1) MRPs and disease causing associations were first recognized by Swedish scientists in 2002 and involvement of AGEs in development of AD in 2010; 2) MRPs include: N'fructoselysine (furosine), 5‐ Hydroxymethyl furfural (HMF), acrylamide, heterocyclic amines and melanoidins; 3) some neurotransmitters are modified amino acids, known as monoamines; 4) some other neurotransmitters are unmodified amino acids; 5) certain short chain amino acids (peptides) function as neuromodulators, by being able to alter a neuron’s response to a neurotransmitter, or block its release; 6) a neurotransmitter’s effect depends upon its concentration, the types and numbers of receptors and ion channels on the receiving cells' membranes; 7) neurotransmitters affect each other’s levels, the same neurotransmitter can even have opposite effects on different types of cells; 8) AD is due to depleted Acetylcholine (Ach) neurotransmitter in the brain, causing imbalance. Ach coordinates functions in the brain by enhancing nerve transmission in a horizontal direction and also inhibiting transmission in a vertical direction; 9) Ach can both inhibit and stimulate because it can bind two types of receptors: on basket cells (to decrease levels of GABA production and stimulate horizontal nerve transmission) and on bipolar cells (to increase GABA production and strengthen the inhibition of vertical transmission).ConclusionHow AGEs disrupts some of these functions to contribute to the development of AD (typified by ‘forgetfulness and difficult‐thinking’) will be discussed.
A/T(N) Status Biomarkers Associate with Polymorphisms in Purinergic Signaling Genes
Authors: Costa Luciana Rocha , de Bastiani Marco Antônio , Machado Luiza Santos , Borelli Wyllians Vendramini , Benedet Andrea , Zimmer Eduardo R. , Souza Diogo O. , de Souza Débora Guerini 
Published: January 2025

AbstractBackgroundPurinergic signaling is vital in various cellular processes like neuroinflammation, synaptic transmission, Aβ clearance, and tau phosphorylation regulation. This study aims to examine if SNPs in purinergic signaling genes are associated to A/T(N) status biomarkers in Alzheimer’s Disease through Genome Wide Association Studies.MethodThe SNPRelate package was used to analyze SNPs in genes related to purinergic signaling and A/T(N) markers. We included 152 cognitively unimpaired and 359 cognitively impaired individuals from the ADNI cohort. Generalized linear models were applied to investigate associations between independent variables (SNPs, APOE4 status, sex, age, education, and diagnosis), and A/T(N) markers, specifically tau status (CSF/Plasma ptau181), amyloid status (CSF Aβ and AV45‐PET ratio of cortical grey matter/whole cerebellum), and neurodegeneration status (average FDG‐PET metaROI). We also conducted a voxel‐wise linear regression testing the association between [18F]FDG metabolism and SNP carriership, corrected by sex and age. The analysis was corrected for multiple comparisons using the cluster‐wise random field theory method (significant t>3.11, p<0.001, df = 495).ResultWe identified 13 SNPs in the intronic region of purinergic signaling genes that had a significant association with A/T(N) status biomarkers (Table 1). CSF Aβ levels were associated with polymorphisms in the adenosine deaminase 1 (ADA1) and 2 (ADA2) genes. AV45‐PET binding was associated with SNPs in ADA2, ADORA1, and P2×1 genes. CSF ptau181 levels were associated with polymorphisms in the ADORA1, NTPDase‐2/CD39L1, and pannexin 1 gene. Increased FDG uptake was associated with a polymorphism in the ADORA2B gene. Finally, a polymorphism in the ADORA1 gene presented a positive association with [18F]FDG metabolism in the parietal lobe white matter (tmax = 3.97, p<0.0001) (Figure 1).ConclusionMultiple SNPs within genes related to purinergic signaling have been identified to be linked with A/T(N) status markers. These results underscore the significance of purinergic signaling in cellular processes relevant to brain homeostasis, suggesting potential implications for Alzheimer’s disease (AD). Consequently, these findings highlight promising cellular mechanisms underlying the development of dementia.
Assessing the Impact of Gepirone on Major Depressive Disorder ‐ A systematic review and meta analysis
Authors: Khalifa Mostafa A. , Salaheldin Abdelmoneim Osama , Elsead Jana Ahmed , Aboud Fatama Azzam , Korim Basmala Mohamed , Abdalsttar Shehab Sherif , Mahmoud Abdalla Ahmed 
Published: January 2025

AbstractBackgroundMajor depression has been affecting more than 280 million of the general population, and this number continue to rise. Thus, impairing daily life activities. Research on Major depression has been since the 19th century for the sake of elevating symptoms with less side effects. The aim of our study is to assess the impact of a potential game changer in treatment of Major depression, GeprioneMethodwe have conducted a comprehensive search, including key databases such as Cochrane, PubMed, SCOPUS, and ScienceDirect, to ensure thorough coverage of all relevant literature, using appropriate key mesh terms. Search date ranged from 1987 to 2024. Randomized controlled studies published between that studied Patients with Major Depressive Disorder (MDD) diagnosed based on standardized criteria such as DSM‐5 with Geprione only as administration while comparing it to a placebo reflected as reduction in depressive symptoms for outcome were included. Exclusion criteria included populations with induced major depression such as substance abuse and breast‐feeding women, studies assessing other drugs from azapirones family than Geprione, with comparison to any drug other than placebo, and randomized controlled studies with incomplete outcome data. This systematic review was registered with PROSPERO [CRD42024510595] and followed PRISMA guidelines. Risk of bias was assessed using Cochrane library tool RoB 2 (revised tool for Risk of Bias in randomized trials). Data syntheses will be performed through Rev‐Man programResultSeven Randomized controlled trails (n = 7) were included from 203 identified titles, after excluding duplicates (n = 13) and not fulfilling the inclusion and eligibility criteria (n = 183). A pilot study was conducted on 4 of these papers, revealing that all studies demonstrated that Gepirone is a potential treatment for major depression disorder and Our systematic review is currently in progress and is expected to be completed by the end of 2024ConclusionThe study views Gepirone as a potential treatment for major depression disorder with regard to fewer side effects and higher efficacy compared to standard treatment e.g., atypical antidepressants and tricyclic antidepressants. We encourage further research across variable populations for more robust evidence.
Associations between CYP4F2 missense variant rs3093105 A>C and Alzheimer’s disease phenotypes
Authors: Noor Shiropa , Mori‐Fegan Daniel K , Wong Yuen Yan , Wu Che‐Yuan , Roman Richard J. , Taha Ameer Y. , Swardfager Walter ,   Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

AbstractBackground20‐hydroxyeicosatetranoic acid (20‐HETE) is a potent vasoconstrictor synthesized by the CYP4F2 enzyme. The CYP4F2 missense variant rs3093105 A>C (W12G) has been implicated in hypertension and stroke, risk factors for Alzheimer’s disease (AD), and with decreased 20‐HETE activity. To explore the potential role of the CYP4F2/20‐HETE pathway and AD, this study investigated associations between the rs3093105 variant and AD phenotypes.MethodParticipants from the Alzheimer’s Disease Neuroimaging Initiative with amyloid‐beta 42 positive PET status and a diagnosis of AD or mild cognitive impairment were selected. Linear regressions explored the relationship between rs3093105 C‐allele carrier status (AC/CC vs AA) and cognition, assessed as executive function and memory composites and Rey Auditory Verbal Learning Test (RAVLT) scores; and brain volumetric measures at baseline, obtained using FreeSurfer on MRI T1‐weighted images. Longitudinal associations (up to 48 months) were explored via interactions between carrier status and time in mixed effects models. Covariates included baseline age, sex, APOE e4 status, years of education, intracranial volume, and Mini Mental State Exam score.ResultThe rs3093105 variant was present at a minor allele frequency of 19.2% in 315 individuals (mean age 73.3 ± 7.57, 43.2% women). At baseline, C‐allele carriers had higher executive function composite scores (B = 0.315, SE = 0.119, p = 0.009, n = 315) and RAVLT immediate (sum of trials 1‐5) scores (B = 2.46, SE = 1.24, p = 0.048, n = 315), and larger whole brain volume (B = 14.19, SE = 6.84, p = 0.039, n = 310). Over time, carriers had higher memory composite scores (B = 0.116, SE = 0.052, p = 0.027, n = 183) and RAVLT learning (trial 5 minus trial 1) scores (B = 0.484, SE = 0.207, p = 0.021, n = 179), and retention in hippocampal volume (B = 4.19, SE = 1.71, p = 0.016, n = 127).ConclusionAltogether, rs3093105 C‐allele carriers show better performance on memory tests and retention of hippocampal volume. These findings suggest a potential role of the CYP4F2/20‐HETE pathway in AD progression and warrants replication studies in other cohorts.
Characterization of GPR3 function in astrocytes in a preclinical AD mouse model
Authors: Osorio Carlos Alberto Ayhllon , Espinosa Diego Rolando Hernandez , Huang Yunhong , Guimarães Thais Rafael , Thathiah Amantha 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD) is neuropathologically characterized by the accumulation of Amyloid‐β (Aβ) plaques, neurofibrillary tangles, and neuroinflammation. GPR3 is a G protein‐coupled receptor (GPCR) that has been implicated in Aβ pathogenesis via β‐arrestin 2 (βarr2)‐mediated intracellular signaling. Genetic deletion of Gpr3 reduces the Aβ plaque burden and cognitive decline in AD transgenic mice. However, Gpr3 deficiency is also associated with adverse effects, e.g., increased anxiety‐ and depression‐like behavior. Recently, our lab demonstrated that selective inhibition of GPR3‐mediated βarr2 signaling maintains the beneficial physiological functions of GPR3‐mediated G protein‐signaling while reducing the Aβ plaque burden in the AppNL‐G‐F
AD knockin (KI) mouse model. We also determined that GPR3 is more abundantly expressed in astrocytes relative to neurons and microglia. Nevertheless, GPR3 function in astrocytes has not been investigated to date.MethodsWe performed bulk RNAseq analysis of cortical brain samples from AppNL‐G‐F; hemagglutinin‐tagged (HA)‐GPR3 (AD KI) and AppNL‐G‐F; G protein‐biased HA‐GPR3 (Biased AD KI) mice at 6‐months of age. We are currently utilizing flow cytometry to analyze Biased AD KI relative to AD KI brains at 6‐, 12‐, and 18‐months of age (early‐, mid‐, and late‐stage pathology). We are labeling Aβ plaques in vivo with a fluorescent Congo‐red derivative, methoxy‐X04 (MX04). Three hours after MX04 administration, the mice are euthanized. One brain hemisphere is dissociated and analyzed by flow cytometry for ACSA2+/MX04+ astrocytes, GFAP+/MX04+activated astrocytes, and markers of proliferation (Ki67).ResultsWe determined that astrocytes exhibit increased hypertrophy and expression of Gfap in Biased AD KI mice. In accordance with these findings, we observe differential expression of several cytokines (e.g., Il‐1β, Il‐5, and Chil3/5), chemokines (e.g., Ccl6, Ccl9, and Cxcl9), and growth factors (e.g., Fgf3, Pdgfd, and Vegfd) in Biased AD KI mice, suggesting that GPR3 is involved in the crosstalk between astrocyte, microglia, and neurons. Preliminary FACS analysis also indicates differential expression of markers of astrocyte activation in astrocytes isolated from our Biased AD KI mice.ConclusionThese studies provide strong evidence for the astrocytic function of GPR3 in AD, which has therapeutic potential to reduce neuroinflammation and AD pathology and counteract neurodegeneration.
Qualitative use of the RE‐AIM/PRISM framework for adaptation of a primary care educational program on the care of persons with behavioral and psychological symptoms of dementia
Authors: LeCaire Tamara J. , Schroeder Molly , Paniagua Uriel , Stone Jonathan A , Albrecht Tammi , Houston Stephanie , Schrager Sarina , Carlsson Cynthia M. , Walaszek Art 
Published: January 2025

AbstractBackgroundPrimary care clinicians report limited self‐efficacy for managing complex behavioral and psychological symptoms in persons with dementia (BPSD). Complementary approaches, the academic detailing model and the DICE ApproachTM, improved self‐efficacy for memory clinic clinicians and their teams to identify and manage BPSD. Methods guided by the RE‐AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) / PRISM (Practical, Robust, Implementation and Sustainability Model) framework are shared for pre‐implementation adaptation of this program for generalist primary care.MethodsA stakeholder‐engaged qualitative study with both current and future program stakeholders was used to identify a) gaps in BPSD management, and b) multi‐level barriers and facilitators to the academic detailing model. Framework guided semi‐structured interview topics included contextual factors impacting program reach, reasons for adoption and program effectiveness, and barriers and facilitators for implementation. The team completed 14 interviews; 7 with clinicians practicing in primary care integrated memory clinics with prior academic detailing participation (Champions) and among 7 clinician colleagues with no or minimal program experience (Novices). Inductive and deductive qualitative thematic analysis approaches were used, the latter organized by RE‐AIM domains and multi‐level context.ResultsA sample of themes and adaptations for shaping program access and fit (Reach) are shared. 1) Applied learning supports knowledge and self‐efficacy for BPSD care. Case‐based, experiential learning fits for both experienced and inexperienced clinicians. Champions acknowledge experiential learning builds confidence (facilitator), while Novices note having limited direct care experience (barrier). Adaptations for Novices will include more extensive introduction to identifying and managing BPSD and emphasize building confidence. 2) Improve access to education and materials. Champions noted the challenge to “keep tools at your fingertips” could be overcome with reference materials or templates while Novices highlighted needing access to more structured resources in light of numerous guidelines to follow in primary care. In response, user‐friendly BPSD management resource guides to support clinical decisions have been developed.ConclusionsWe provide a novel qualitative application RE‐AIM/PRISM with both current and future stakeholders to inform adaptations pre‐implementation. This approach will aid identifying contextual barriers and facilitators to reach, adoption, implementation, and effectiveness of academic detailing for delivery to generalist primary care teams.