Biomedical knowledge graph learning for drug repurposing by extending guilt-by-association to multiple layers

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 15, 2023

Abstract Computational drug repurposing aims to identify new indications for existing drugs by utilizing high-throughput data, often in the form of biomedical knowledge graphs. However, learning on graphs can be challenging due dominance genes and a small number disease entities, resulting less effective representations. To overcome this challenge, we propose “semantic multi-layer guilt-by-association" approach that leverages principle guilt-by-association - “similar share similar functions", at drug-gene-disease level. Using approach, our model DREAMwalk: Drug Repurposing through Exploring Associations using Multi-layer random walk uses semantic information-guided generate disease-populated node sequences, allowing mapping both diseases unified embedding space. Compared state-of-the-art link prediction models, improves drug-disease association accuracy up 16.8%. Moreover, exploration space reveals well-aligned harmony between biological contexts. We demonstrate effectiveness case studies breast carcinoma Alzheimer’s disease, highlighting potential perspective

Language: Английский

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Proteomic analysis of Alzheimer’s disease cerebrospinal fluid reveals alterations associated with APOE ε4 and atomoxetine treatment

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(753)

Published: June 26, 2024

Alzheimer’s disease (AD) is currently defined by the aggregation of amyloid-β (Aβ) and tau proteins in brain. Although biofluid biomarkers are available to measure Aβ pathology, few markers complex pathophysiology that associated with these two cardinal neuropathologies. Here, we characterized proteomic landscape cerebrospinal fluid (CSF) changes pathology 300 individuals using different technologies—tandem mass tag spectrometry SomaScan. Integration both data types allowed for generation a robust protein coexpression network consisting 34 modules derived from 5242 measurements, including disease-relevant autophagy, ubiquitination, endocytosis, glycolysis. Three strongly apolipoprotein E ε4 ( APOE ε4) AD risk genotype mapped oxidant detoxification, mitogen-associated kinase signaling, neddylation, mitochondrial biology overlapped previously described lipoprotein module serum. Alterations all three blood were dementia more than 20 years before diagnosis. Analysis CSF samples an phase 2 clinical trial atomoxetine (ATX) demonstrated abnormal elevations glycolysis module—the most correlated cognitive function—were reduced ATX treatment. Clustering based on their profiles revealed heterogeneity pathological not fully reflected tau.

Language: Английский

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Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 19(5), P. 2182 - 2196

Published: Jan. 15, 2023

Abstract The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau‐associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction cortical lesions. Accumulating evidence supports role behavioral neuropsychiatric manifestations featured AD. Experimental studies even suggest that AD‐associated drives brain neuroinflammatory status contributes to progression, including exacerbation Given important pathophysiologic etiologic roles involve AD stages, there is an urgent need expand our understanding mechanisms underlying vulnerability more precisely detail clinical progression changes Here, Professional Interest Area International Society Advance Research Treatment highlights knowledge gaps about within provides recommendations priorities specific research, biomarker development, modeling, intervention. Highlights Neuromodulatory degenerate pathological stages. pathophysiology exacerbated by degeneration. symptoms dementia. Biomarkers integrity would be value‐creating dementia care. present strategic prospects disease‐modifying therapies.

Language: Английский

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Noradrenergic and cholinergic systems take centre stage in neuropsychiatric diseases of ageing

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 149, P. 105167 - 105167

Published: April 11, 2023

Noradrenergic and cholinergic systems are among the most vulnerable brain in neuropsychiatric diseases of ageing, including Alzheimer's disease, Parkinson's Lewy body dementia, progressive supranuclear palsy. As these fail, they contribute directly to many characteristic cognitive psychiatric symptoms. However, their contribution symptoms is not sufficiently understood, pharmacological interventions targeting noradrenergic have met with mixed success. Part challenge complex neurobiology systems, operating across multiple timescales, non-linear changes adult lifespan disease course. We address challenges a detailed review outlining roles cognition behaviour, how influence disease. By bridging levels analysis, we highlight opportunities for improving drug therapies pursuing personalised medicine strategies.

Language: Английский

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Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer's disease

Neurobiology of Aging, Journal Year: 2023, Volume and Issue: 125, P. 98 - 108

Published: Feb. 1, 2023

Language: Английский

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Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer’s disease: systematic review and meta-analysis

Journal of Neurology Neurosurgery & Psychiatry, Journal Year: 2022, Volume and Issue: 93(10), P. 1080 - 1090

Published: July 5, 2022

Background Dysfunction of the locus coeruleus-noradrenergic system occurs early in Alzheimer’s disease, contributing to cognitive and neuropsychiatric symptoms some patients. This offers a potential therapeutic target, although noradrenergic treatments are not currently used clinical practice. Objective To assess efficacy drugs with principally action improving disease. Methods The MEDLINE, Embase ClinicalTrials.gov databases were searched from 1980 December 2021. We generated pooled estimates using random effects meta-analyses. Results included 19 randomised controlled trials (1811 patients), which six judged as ‘good’ quality, seven ‘fair’ ‘poor’. Meta-analysis 10 these studies (1300 patients) showed significant small positive effect on global cognition, measured Mini-Mental State Examination or Disease Assessment Scale—Cognitive Subscale (standardised mean difference (SMD): 0.14, 95% CI: 0.03 0.25, p=0.01; I 2 =0%). No was seen measures attention (SMD: 0.01, −0.17 0.19, p=0.91; =0). apathy meta-analysis eight (425 detected large 0.45, 0.16 0.73, p=0.002; =58%). still present following removal outliers account for heterogeneity across studies. Discussion Repurposing established is most likely offer effective treatment disease general cognition apathy. However, several factors should be considered before designing future trials. These include targeting appropriate patient subgroups understanding dose individual their interactions other minimise risks maximise effects. PROSPERO registeration number CRD42021277500.

Language: Английский

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Declining locus coeruleus–dopaminergic and noradrenergic modulation of long-term memory in aging and Alzheimer’s disease

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 153, P. 105358 - 105358

Published: Aug. 17, 2023

Language: Английский

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Searching Reproducible Brain Features using NeuroMark: Templates for Different Age Populations and Imaging Modalities

NeuroImage, Journal Year: 2024, Volume and Issue: 292, P. 120617 - 120617

Published: April 1, 2024

A primary challenge to the data-driven analysis is balance between poor generalizability of population-based research and characterizing more subject-, study- population-specific variability. We previously introduced a fully automated spatially constrained independent component (ICA) framework called NeuroMark its functional MRI (fMRI) template. has been successfully applied in numerous studies, identifying brain markers reproducible across datasets disorders. The first template was constructed based on young adult cohorts. recently expanded this initiative by creating standardized normative multi-spatial-scale using over 100,000 subjects, aiming improve comparability studies involving diverse While unified lifespan desirable, comprehensive investigation similarities differences components from different age populations might help systematically transform our understanding human revealing most well-replicated variable network features throughout lifespan. In work, we two significant expansions templates generating replicable fMRI for infants, adolescents, aging cohorts, second incorporating structural (sMRI) diffusion (dMRI) modalities. Specifically, built spatiotemporal 6,000 resting-state scans four datasets. This attempt create robust ICA covering dynamic development For sMRI dMRI data, used large publicly available including than 30,000 build reliable templates. employed spatial similarity identify investigate degree which unique similar patterns are reflective populations. Our results suggest remarkably high resulting adapted components, even extreme differences. With new templates, allows us perform age-specific adaptations capture adaptable each modality, therefore facilitating biomarker identification sum, present work demonstrates suggests potential boost accuracy mental health advance cross-modal alterations.

Language: Английский

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A Review of Recent Advances in the Management of Alzheimer’s Disease

Cureus, Journal Year: 2024, Volume and Issue: unknown

Published: April 16, 2024

Alzheimer's disease (AD) is the most common neurodegenerative condition and a form of dementia encountered in medical practice. Despite many proposed attempted treatments, this remains major puzzle public health systems worldwide. The initial part article provides an overview illustration primary mechanisms responsible for neuronal damage AD. Subsequently, it offers critical evaluation noteworthy studies on pharmacological therapy AD outlines recent advancements novel approaches to managing condition. Main properties, categorization, Food Drug Administration (FDA) status, action, benefits, side effects classical recently treatments are described. conventional agents revised comprise cholinesterase inhibitors, monoclonal antibodies, other therapies, such as memantine, valproic acid, rosiglitazone. innovative reviewed antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, semorinemab. Nutritional supplements alpha-tocopherol (vitamin E) caprylidene also revised. Tau amyloid-targeting include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), oxidized MT, tramiprosate, which inhibits beta-amyloid (Aβ) monomer aggregation into toxic oligomers. Antidiabetic anti-neuroinflammation drugs treatment discussed. antidiabetic NE3107, anti-inflammatory insulin sensitizer, diabetes mainstream drug metformin. anti-neuroinflammatory therapies use sodium oligomannate (GV-971), infusions with intravenous immunoglobulin aiming decrease plasma levels constituents Aβ plaques, masitinib, tyrosine kinase inhibitor that impacts mast microglia cells. Additional being currently tested phase-2 clinical trials, atomoxetine (selective norepinephrine reuptake inhibitor), losartan (angiotensin 2 receptor agonist), genistein (anti-inflammatory isoflavone neuroprotective agent), trans-resveratrol (polyphenol antioxidant plant estrogen), benfotiamine (synthetic thiamine precursor), were reviewed. Lastly, targeting Alzheimer's-associated symptoms, brexpiprazole (serotonin dopamine activity modulator) suvorexant (orexin antagonist), respectively, used agitation insomnia patients, As experimental investigations research progress, there possibility combination newly medications traditional ones may emerge promising option future.

Language: Английский

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EKGDR: An End-to-End Knowledge Graph-Based Method for Computational Drug Repurposing

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(6), P. 1868 - 1881

Published: March 14, 2024

The lengthy and expensive process of developing new drugs from scratch, coupled with a high failure rate, has prompted the emergence drug repurposing/repositioning as more efficient cost-effective approach. This approach involves identifying therapeutic applications for existing approved drugs, leveraging extensive drug-related data already gathered. However, diversity heterogeneity data, along limited availability known drug-disease interactions, pose significant challenges to computational design. To address these challenges, this study introduces EKGDR, an end-to-end knowledge graph-based repurposing. EKGDR utilizes power graph, comprehensive repository information that encompasses interactions various categorization information, well structural molecular descriptors drugs. employs graph neural networks, cutting-edge representation learning technique, embed (nodes relations) in manner. By doing so, can effectively learn underlying causes (intents) behind recursively aggregate combine relational messages between nodes different multihop neighborhood paths (relational paths). generates representations disease nodes, enabling predict interaction probability each pair obtained results demonstrate outperforms previous models all three evaluation metrics: area under receiver operating characteristic curve (AUROC = 0.9475), precision-recall (AUPRC 0.9490), recall at top-200 recommendations (Recall@200 0.8315). further validate EKGDR's effectiveness, we evaluated top-20 candidate suggested Alzheimer's Parkinson's diseases.

Language: Английский

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