medRxiv (Cold Spring Harbor Laboratory)最新文献

{"title":"Mapping the common barriers to optimal COPD care in high and middle-income countries: qualitative perspectives from clinicians","authors":"Orjola Shahaj, Anne Meiwald, Krishnan Puri Sudhir, Rupert Gara-Adams, Peter Wark, Alexis Cazaux, Abelardo Elizondo Rios, Sergey Avdeev, Elisabeth Jane Adams","doi":"10.1101/2023.11.13.23298474","DOIUrl":"https://doi.org/10.1101/2023.11.13.23298474","url":null,"abstract":"Background: Although predominantly preventable and treatable, chronic obstructive pulmonary disease (COPD) is a leading cause of death globally. Guidelines for managing the condition are widely available, yet COPD care remains suboptimal in many settings, including high and middle-income countries (HICs and MICs). Several approaches are used to diagnose and manage COPD, resulting in substantial variation in its care pathways. This study aimed to explore how barriers to optimal COPD care vary across HICs and MICs by identifying common and unique barriers to COPD care in six countries to inform global policy initiatives for better care while addressing specific challenges. Methods: Based on international and national guidelines, we mapped COPD care pathways for Australia, Spain, Taiwan, Argentina, Mexico, and Russia. Country-specific pathways were populated with published epidemiological, health economic, and clinical data identified through a pragmatic literature review. Semi-structured interviews with 17 respiratory care clinicians further informed and validated the pathways, data inputs, and key issues arising in each country. Thematic content analysis was used to analyse common and unique barriers across countries. Results: Six themes were common in most HICs and MICs: Challenges in COPD diagnosis\" , \"Strengthening the role of primary care\" , \"Fragmented healthcare systems and coordination challenges\" , \"Inadequate management of COPD exacerbations\" ; \"Limited access to specialised care\" and, \"Impact of underfinanced and overloaded healthcare systems\" . One theme, \"Insurance coverage and reimbursement challenges\" , was more relevant for MICs. HICs and MICs differ in patient and healthcare provider awareness, primary care involvement, spirometry access, and specialised care availability. Both face issues with healthcare fragmentation, guideline adherence, and COPD exacerbation management. MICs also grapple with resource limitations and healthcare infrastructure challenges. Conclusion: Many challenges to COPD care are the same in both HICs and MICs, underscoring the pervasive nature of these issues. While country-specific issues require customised solutions, there are untapped possibilities for implementing global respiratory strategies that motivate countries to manage COPD effectively. In addition to healthcare system-level initiatives, there is a crucial need for political prioritisation of COPD to secure the essential resources it requires.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"72 4","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136347735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lymphocyte profiles after a first demyelinating event suggestive of multiple sclerosis reveal early monocyte and B cell alterations","authors":"Cesar Alvarez-Gonzalez, Annika Wiedemann, Maria Schroeder-Castagno, Sussana Asseyer, Claudia Chien, Joseph Kuchling, Judith Bellmann-Strobl, Klemens Ruprecht, Carmen Infante- Duarte, Thomas Doerner, Friedemann Paul","doi":"10.1101/2023.11.13.23298459","DOIUrl":"https://doi.org/10.1101/2023.11.13.23298459","url":null,"abstract":"Introduction Often, isolated clinical event suggestive of CNS demyelination confers a risk of conversion to multiple sclerosis. In this study, we investigate lymphocyte profiles after a first clinical event suggestive of multiple sclerosis (MS), which could contribute to the current understanding of early inflammatory responses in this demyelinating disease. Methods Twenty treatment-naive clinically isolated syndrome (CIS) patients and fifteen healthy participants were included in our assessment of lymphocyte profiles and B cell subsets using multicolour flow cytometry. Analysis was made at 3-6 months (Baseline), 12, and 24 months after a first clinical event. We also performed a sub-analysis of patients that received glatiramer acetate (GLAT) after their baseline visit up to 24 months after the first clinical event. Results Our analysis revealed monocyte and B cell differences between groups. Percentages of CD19+CD20+ B cells were lower in CIS patients compared to healthy individuals at baseline. Additionally, monocyte distribution among groups was different. A subgroup analysis of patients treated with GLAT (n= 10) showed an increased percentage of naive (p<0.05) and memory pre-switched (p<0.01) B cells up to 24 months after their baseline visit compared to the untreated group (n= 10). Conclusion Our results showed early monocyte and B cell subsets alterations in pwCIS. Further research is needed to elucidate the role of B cells and monocyte disturbances during inflammatory processes after a first clinically-MS suggestive event.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"83 7","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136347849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correlation between umbilical cord torsion and Doppler parameters of umbilical artery: a single-center retrospective case-control study","authors":"Yuan Li, Dirong Zhang, Yu Shi","doi":"10.1101/2023.11.12.23298437","DOIUrl":"https://doi.org/10.1101/2023.11.12.23298437","url":null,"abstract":"Objective:To explore the correlation between umbilical cord torsion and the changes of umbilical artery Doppler parameters, to provide valuable information for prenatal ultrasound screening of umbilical cord torsion, and to explore the possible mechanism of umbilical artery Doppler parameters changes during umbilical cord torsion. Method:The subjects were 962 pregnant women who were discharged from our hospital from January 2015 to November 2021 and were eligible for inclusion (415 in the case group and 547 in the control group). The measurement data of umbilical artery Doppler parameters (PSV, S/D, RI, PI) were collected from 21 to 40 weeks of gestation, and the differences among the above parameters were statistically analyzed. Results:The peak systolic velocity (PSV) of umbilical artery is positively correlated with gestational age, while the Doppler resistance parameters (S/D, RI, PI) of umbilical artery are negatively correlated with gestational age. The mean values of umbilical artery Doppler parameters (PSV, S/D, RI, PI) in the case group were significantly lower than those in the control group of the same pregnancy age (P < 0.05). Conclusion: The decrease of Doppler parameters of umbilical artery in late pregnancy is significantly related to umbilical cord torsion, which may be a clue for prenatal ultrasound screening of umbilical cord torsion. The Doppler parameters of umbilical artery during umbilical cord torsion are consistent with the basic principle of Doppler parameters change after vascular stenosis in other parts of the human body. It is necessary to conduct multicenter prospective study in the future.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"8 3","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136348239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial proteo-transcriptomic profiling reveals the molecular landscape of borderline ovarian tumors and their invasive progression","authors":"Lisa Schweizer, Rahul Krishnan, Aasa Shimizu, Andreas Metousis, Hilary Kenny, Rachelle Mendoza, Thierry M. Nordmann, Sarah Rauch, Lucy Kelliher, Janna Heide, Florian A. Rosenberger, Agnes Bilecz, Sanaa N. Borrego, Maximilian T. Strauss, Marvin Thielert, Edwin Rodriguez, Johannes B. Mueller-Reif, Mengjie Chen, S. Diane Yamada, Andreas Mund, Ricardo Lastra, Matthias Mann, Ernst Lengyel","doi":"10.1101/2023.11.13.23298409","DOIUrl":"https://doi.org/10.1101/2023.11.13.23298409","url":null,"abstract":"Serous borderline tumors (SBT) are epithelial neoplastic lesions of the ovaries that commonly have a good prognosis. In 10-15% of cases, however, SBT will recur as low-grade serous cancer (LGSC), which is deeply invasive and responds poorly to current standard chemotherapy 1,2,3 . While genetic alterations suggest a common origin, the transition from SBT to LGSC remains poorly understood 4 . Here, we integrate spatial proteomics5 with spatial transcriptomics to elucidate the evolution from SBT to LGSC and its corresponding metastasis at the molecular level in both the stroma and the tumor. We show that the transition of SBT to LGSC occurs in the epithelial compartment through an intermediary stage with micropapillary features (SBT-MP), which involves a gradual increase in MAPK signaling. A distinct subset of proteins and transcripts was associated with the transition to invasive tumor growth, including the neuronal splicing factor NOVA2, which was limited to expression in LGSC and its corresponding metastasis. An integrative pathway analysis exposed aberrant molecular signaling of tumor cells supported by alterations in angiogenesis and inflammation in the tumor microenvironment. Integration of spatial transcriptomics and proteomics followed by knockdown of the most altered genes or pharmaceutical inhibition of the most relevant targets confirmed their functional significance in regulating key features of invasiveness. Combining cell-type resolved spatial proteomics and transcriptomics allowed us to elucidate the sequence of tumorigenesis from SBT to LGSC. The approach presented here is a blueprint to systematically elucidate mechanisms of tumorigenesis and find novel treatment strategies.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"67 6","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136348260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>UBTF</i>Tandem Duplications in Pediatric MDS and AML: Implications for Clinical Screening and Diagnosis","authors":"Juan M. Barajas, Masayuki Umeda, Lisett Contreras, Mahsa Khanlari, Tamara Westover, Michael P. Walsh, Emily Xiong, Chenchen Yang, Brittney Otero, Marc Arribas-Layton, Sherif Abdelhamed, Guangchun Song, Xiaotu Ma, Melvin E. Thomas, Jing Ma, Jeffery M. Klco","doi":"10.1101/2023.11.13.23298320","DOIUrl":"https://doi.org/10.1101/2023.11.13.23298320","url":null,"abstract":"Recent genomic studies in adult and pediatric acute myeloid leukemia (AML) demonstrated recurrent in-frame tandem duplications (TD) in exon 13 of upstream binding transcription factor ( UBTF ). These alterations, which account for ~4.3% of AMLs in childhood and up to 3% in adult AMLs under 60, are subtype-defining and associated with poor outcomes. Here, we provide a comprehensive investigation into the clinicopathological features of UBTF-TD myeloid neoplasms in childhood, including 89 unique pediatric AML and 6 myelodysplastic syndrome (MDS) cases harboring a tandem duplication in exon 13 of UBTF . We demonstrate that UBTF-TD myeloid tumors are associated with dysplastic features, low bone marrow blast infiltration, and low white blood cell count. Furthermore, using bulk and single-cell analyses, we confirm that UBTF-TD is an early and clonal event associated with a distinct transcriptional profile, whereas the acquisition of FLT3 or WT1 mutations is associated with more stem cell-like programs. Lastly, we report rare duplications within exon 9 of UBTF that phenocopy exon 13 duplications, expanding the spectrum of UBTF alterations in pediatric myeloid tumors. Collectively, we comprehensively characterize pediatric AML and MDS with UBTF-TD and highlight key clinical and pathologic features that distinguish this new entity from other molecular subtypes of AML.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"11 2","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136348372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence, treatment, and factors associated with cryptococcal meningitis post introduction of integrase inhibitors antiretroviral based regimens among people living with HIV in Tanzania","authors":"Makyao Minja, Tusaligwe Mbilinyi, Bryceson Mkinga, Erick G. Philipo, Joyce Owenya, Manase Kilonzi","doi":"10.1101/2023.11.13.23298478","DOIUrl":"https://doi.org/10.1101/2023.11.13.23298478","url":null,"abstract":"Objective: This study aimed to assess the prevalence of CM, treatment practice, and the associated factor’s post-introduction of Tenofovir Lamivudine and Dolutegravir (TLD) regimen among PLHIV in Tanzania. Methods: This was an analytical cross-sectional study, and the data was collected retrospectively in three public regional referral hospitals (RRHs) in Dar es Salaam, Tanzania. A total of 405 files of the PLHIV admitted in the medical wards on the TLD regimen from January 2019 to December 2022 were reviewed. The collected information includes patient demographic characteristics, Cryptococcal status, CD4 level at the time of CM diagnosis, status of using ART, CM treatment approach, and outcome. Data was analyzed using SPSS software version 23. Results: Out of 405, the majority 267(65.9%) were female, 224(55.3%) were aged between 36 - 55 years, and 293(72.3%) married. ART defaulters were found to be 37(9.1%). The prevalence of CM was found to be 48(11.9%), out of which 42(87.5%) received fluconazole alone. ART defaulter and marital status significantly (p-value < 0.05) were associated with those who tested CM positive. Conclusion: The study found the prevalence of CM among PLHIV to be significantly high and the majority were treated with fluconazole alone. ART defaulters and marital status were significantly associated with one being CM positive. Responsible authorities and stakeholders should enforce guideline adherence and PLHIV should be encouraged on medication adherence.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"68 2","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136348407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotype-microbiome-metabolome associations in early childhood, and their link to BMI and childhood obesity","authors":"Andrea Aparicio, Zheng Sun, Diane R Gold, Augusto A. Litonjua, Scott T. Weiss, Kathleen Lee-Sarwar, Yang-Yu Liu","doi":"10.1101/2023.11.13.23298467","DOIUrl":"https://doi.org/10.1101/2023.11.13.23298467","url":null,"abstract":"The influence of genotype on defining the human gut microbiome has been extensively studied, but definite conclusions have not yet been found. To fill this knowledge gap, we leverage data from children enrolled in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) from 6 months to 8 years old. We focus on a pool of 12 genes previously found to be associated with the gut microbiome in independent studies, establishing a Bonferroni corrected significance level of p-value < 2.29x10^(-6). We identified significant associations between SNPs in the FHIT gene (known to be associated with obesity and type 2 diabetes) and obesity-related microbiome features, and the children's BMI through their childhood. Based on these associations, we defined a set of SNPs of interest and a set of taxa of interest. Taking a multi-omics approach, we integrated plasma metabolome data into our analysis and found simultaneous associations among children's BMI, the SNPs of interest, and the taxa of interest, involving amino acids, lipids, nucleotides, and xenobiotics. Using our association results, we constructed a quadripartite graph where each disjoint node set represents SNPs in the FHIT gene, microbial taxa, plasma metabolites, or BMI measurements. Network analysis led to the discovery of patterns that identify several genetic variants, microbial taxa and metabolites as new potential markers for obesity, type 2 diabetes, or insulin resistance risk.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"70 10","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136348697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Connectome reorganization associated with temporal lobe pathology and its surgical resection","authors":"Sara Lariviere, Bo-yong Park, Jessica Royer, Jordan DeKraker, Alexander Ngo, Ella Sahlas, Judy Chen, Raul Rodriguez-Cruces, Yifei Weng, Birgit Frauscher, Zhengge Wang, Bratislav Misic, Golia Shafiei, Andrea Bernasconi, Neda Bernasconi, Michael D Fox, Zhiqiang Zhang, Boris Bernhardt","doi":"10.1101/2023.11.13.23298482","DOIUrl":"https://doi.org/10.1101/2023.11.13.23298482","url":null,"abstract":"Network neuroscience offers a unique framework to understand the organizational principles of the human brain. Despite recent progress, our understanding of how the brain is modulated by focal lesions remains incomplete. Resection of the temporal lobe is the most effective treatment to control seizures in pharmaco-resistant temporal lobe epilepsy (TLE), making this syndrome a powerful model to study lesional effects on network organization in young and middle-aged adults. Here, we assessed the downstream consequences of a focal lesion and its surgical resection on the brain's structural connectome, and explored how this reorganization relates to clinical variables at the individual patient level. We included adults with pharmaco-resistant TLE (n = 37) who underwent anterior temporal lobectomy between two imaging time points, as well as age- and sex-matched healthy controls who underwent comparable imaging (n = 31). Core to our analysis was the projection of high-dimensional structural connectome data - derived from diffusion MRI tractography from each subject - into lower-dimensional gradients. We then compared connectome gradients in patients relative to controls before surgery, tracked surgically-induced connectome reconfiguration from pre- to postoperative time points, and examined associations to patient-specific clinical and imaging phenotypes. Before surgery, TLE presented with marked connectome changes in bilateral temporo-parietal regions, reflecting an increased segregation of the ipsilateral anterior temporal lobe from the rest of the brain. Surgery-induced connectome reorganization was localized to this temporo-parietal subnetwork, but primarily involved postoperative integration of contralateral regions with the rest of the brain. Using a partial least-squares analysis, we uncovered a latent clinical-imaging signature underlying this pre- to postoperative connectome reorganization, showing that patients who displayed postoperative integration in bilateral fronto-occipital cortices also had greater preoperative ipsilateral hippocampal atrophy, lower seizure frequency, and secondarily generalized seizures. Our results bridge the effects of focal brain lesions and their surgical resections with large-scale network reorganization and inter-individual clinical variability, thus offering new avenues to examine the fundamental malleability of the human brain.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"20 5","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136351757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ancestry diversity in the genetic determinants of the human plasma proteome and associated new drug targets","authors":"Saredo Said, Alfred Pozarickij, Kuang Lin, Sam Morris, Christiana Kartsonaki, Neil Wright, Hannah Fry, Yiping Chen, Huaidong Du, Derrick Bennett, Daniel Avery, Dan Valle Schmidt, Liming Li, Jun Lv, Canqing Yu, Dianjianyi Sun, Pei Pei, Junshi Chen, Michael Hill, Richard Peto, Rory Collins, Robert Clarke, Iona Millwood, Zhengming Chen, Robin Walters","doi":"10.1101/2023.11.13.23298365","DOIUrl":"https://doi.org/10.1101/2023.11.13.23298365","url":null,"abstract":"The proteome is fundamental to human biology and disease but little is known about ancestral diversity of its genetic determinants. In GWAS of plasma levels of 1,451 proteins in 3,974 Chinese adults, we identified pQTLs for 1,082 proteins, including 743 with at least one cis-pQTL. Fine-mapping defined credible sets for 3,336 independent pQTLs, of which 31% did not overlap with corresponding analyses in European adults. We assessed 777 sentinel cis-pQTLs in phenome-wide MR analyses using GWAS Catalog and identified Bonferroni-significant associations for 22 protein-disease pairs. Among 10 protein-disease pairs identified from East Asian-specific GWAS, four had evidence of colocalisation. Evaluation of current drug development confirmed indications for one protein target, identified potential repurposing for seven, and discovered nine potential novel targets, including GP2 for Type-2-diabetes. The findings demonstrate the importance of extending genome-wide plasma proteomic analyses to non-European ancestry populations to identify potential novel drug targets for major diseases.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"64 24","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136282299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Olanzapine, Risperidone and Clozapine prescribing is associated with increased risk for Alzheimers Disease reflecting antipsychotic-specific effects on microglial phagocytosis","authors":"Mrityunjoy Mondal, Shiden Solomon, Jiangwei Sun, Nirmal Sampathkumar, Ivo Carre, Marie-Caroline Cotel, Puja Mehta, Lawrence Rajendran, Anthony C Vernon, Fang Fang, Jacqueline Mitchell","doi":"10.1101/2023.11.10.23298358","DOIUrl":"https://doi.org/10.1101/2023.11.10.23298358","url":null,"abstract":"Epidemiological data provides evidence for a positive correlation between schizophrenia diagnosis and an increased risk to develop dementia. Whether and how use of antipsychotic medication may contribute to this association is however unknown. We therefore conducted a pharmaco-epidemiological study based on Swedish Patient and Prescribed Drug Registers to investigate the effect of three antipsychotics, Olanzapine, Risperidone, and Clozapine, on dementia risk. Our data suggest that prescription of all three antipsychotics is significantly associated with increased risk of Alzheimers disease (AD) and other dementias including vascular dementia. To provide a nexus of causality to this association, we explored the impact of these drugs on microglia and neurons using cells derived from human induced pluripotent stem cells (hiPSCs). Acute exposure to Olanzapine and Risperidone did not significantly alter amyloid-Abeta (Abeta) production in hiPSC-derived cortical neurons, but suppressed hiPSC-derived microglial-mediated Abeta clearance, leading to Abeta accumulation. Neither Olanzapine nor Risperidone had any significant effect on hiPSC-derived microglial synaptosome phagocytosis. Conversely, Clozapine significantly reduced Abeta production in neurons, and increased microglial uptake of Abeta but also synaptosomes, consistent with higher lysosomal levels in Clozapine-exposed hiPSC-derived microglia. These data provide the first evidence that antipsychotics prescribed to individuals with schizophrenia are associated with increased risk for dementia and suggest potential cellular bases for this effect via the modulation of microglia uptake of Abeta and synapses in a drug specific manner.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"48 20","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136282547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}