medRxiv : the preprint server for health sciences最新文献

{"title":"Opioids Diminish the Placebo Antidepressant Response: A Post Hoc Analysis of a Randomized Controlled Ketamine Trial.","authors":"Theresa R Lii, Josephine R Flohr, Robin L Okada, Lisa J Cianfichi, Laura M Hack, Alan F Schatzberg, Boris D Heifets","doi":"10.1101/2024.09.24.24314243","DOIUrl":"10.1101/2024.09.24.24314243","url":null,"abstract":"<p><strong>Background: </strong>The endogenous opioid system is thought to play a role in the placebo antidepressant response. A recent trial comparing the rapid antidepressant effects of ketamine versus placebo in surgical patients, some of whom were on chronic opioid therapy, revealed a substantial placebo effect. This finding provided an opportunity to test the hypothesis that opioid agonist exposure interacts with placebo antidepressant responses.</p><p><strong>Methods: </strong>This post hoc analysis utilized data from a previously reported randomized, anesthesia-blinded, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery. Mixed-effects models were used to determine whether baseline opioid use influenced antidepressant responses to the trial interventions, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) over 1 to 14 days post-treatment.</p><p><strong>Results: </strong>In the placebo arm, baseline opioid use was associated with a 10-point increase (95% CI: 0.81-19.4) in MADRS scores across all post-treatment time points, indicating worse depression in this subgroup. In an alternative model using percent change in MADRS scores, the difference between opioid users and non-users was 38.4% (95% CI: 8.59-68.2), with opioid users experiencing less improvement. For ketamine-treated participants, baseline opioid use did not significantly impact MADRS scores or the percent change in MADRS scores. Pain intensity was not a significant predictor of MADRS outcomes, and the correlation between post-treatment MADRS scores and pain intensity was negligible (R=0.12).</p><p><strong>Limitations: </strong>This analysis was unregistered and conducted on a small sample; the findings need to be confirmed by prospective controlled studies.</p><p><strong>Conclusions: </strong>Opioid use at baseline attenuated the placebo antidepressant response independently of pain in depressed patients who received the study treatment under general anesthesia for routine surgery. The antidepressant response was preserved in opioid users who received intravenous ketamine.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11469457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Raising awareness of potential biases in medical machine learning: Experience from a Datathon.","authors":"Harry Hochheiser, Jesse Klug, Thomas Mathie, Tom J Pollard, Jesse D Raffa, Stephanie L Ballard, Evamarie A Conrad, Smitha Edakalavan, Allan Joseph, Nader Alnomasy, Sarah Nutman, Veronika Hill, Sumit Kapoor, Eddie Pérez Claudio, Olga V Kravchenko, Ruoting Li, Mehdi Nourelahi, Jenny Diaz, W Michael Taylor, Sydney R Rooney, Maeve Woeltje, Leo Anthony Celi, Christopher M Horvat","doi":"10.1101/2024.10.21.24315543","DOIUrl":"https://doi.org/10.1101/2024.10.21.24315543","url":null,"abstract":"<p><strong>Objective: </strong>To challenge clinicians and informaticians to learn about potential sources of bias in medical machine learning models through investigation of data and predictions from an open-source severity of illness score.</p><p><strong>Methods: </strong>Over a two-day period (total elapsed time approximately 28 hours), we conducted a datathon that challenged interdisciplinary teams to investigate potential sources of bias in the Global Open Source Severity of Illness Score. Teams were invited to develop hypotheses, to use tools of their choosing to identify potential sources of bias, and to provide a final report.</p><p><strong>Results: </strong>Five teams participated, three of which included both informaticians and clinicians. Most (4/5) used Python for analyses, the remaining team used R. Common analysis themes included relationship of the GOSSIS-1 prediction score with demographics and care related variables; relationships between demographics and outcomes; calibration and factors related to the context of care; and the impact of missingness. Representativeness of the population, differences in calibration and model performance among groups, and differences in performance across hospital settings were identified as possible sources of bias.</p><p><strong>Discussion: </strong>Datathons are a promising approach for challenging developers and users to explore questions relating to unrecognized biases in medical machine learning algorithms.</p><p><strong>Author summary: </strong>Disadvantaged groups are at risk of being adversely impacted by biased medical machine learning models. To avoid these undesirable outcomes, developers and users must understand the challenges involved in identifying potential biases. We conducted a datathon aimed at challenging a diverse group of participants to explore an open-source patient severity model for potential biases. Five groups of clinicians and informaticians used tools of their choosing to evaluate possible sources of biases, applying a range of analytic techniques and exploring multiple features. By engaging diverse participants with hands-on data experience with meaningful data, datathons have the potential to raise awareness of potential biases and promote best practices in developing fair and equitable medical machine learning models.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced Cortical Excitability is Associated with Cognitive Symptoms in Concussed Adolescent Football Players.","authors":"Kevin C Yu, Alex I Wiesman, Elizabeth Davenport, Laura A Flashman, Jillian Urban, Srikantan S Nagarajan, Kiran Solingpuram Sai, Joel Stitzel, Joseph A Maldjian, Christopher T Whitlow","doi":"10.1101/2024.09.23.24314232","DOIUrl":"10.1101/2024.09.23.24314232","url":null,"abstract":"<p><strong>Background: </strong>American tackle football is associated with high rates of concussion, leading to neurophysiological disturbances and debilitating clinical symptoms. Previous investigations of the neurophysiological effects of concussion have largely ignored aperiodic neurophysiological activity, which is a marker of cortical excitability.</p><p><strong>Purpose: </strong>We examined whether concussion during a season of high school football is related to changes in aperiodic and periodic neurophysiological activity and whether any such changes are associated with clinical outcomes.</p><p><strong>Materials and methods: </strong>Pre- and post-season resting-state magnetoencephalography (MEG) data were collected from 91 high school football players over as many as four seasons of play, for a total of 278 data collections. During these seasons of football play, a cohort of 10 individuals were diagnosed with concussion. MEG data were source-imaged, frequency-transformed and parameterized, and linear mixed models were used to examine effects of concussion on pre-to-post-season changes in neurophysiological activity. Scores on the Post-Concussive Symptom Inventory were correlated with pre-to-post-season neurophysiological changes to determine their clinical relevance.</p><p><strong>Results: </strong>Concussion was associated with increased aperiodic exponents in superior frontal cortices, indicating a relative reduction in cortical excitability. This slowing of aperiodic neurophysiology mediated concussion effects on raw delta and gamma power and was associated with worse cognitive concerns across participants. Pre-to-post-season changes in aperiodic-corrected alpha and theta rhythmic activity were also decreased in posterior cortices in concussed players.</p><p><strong>Conclusion: </strong>These findings indicate that concussion alters both the excitability and rhythmic signaling of the cortex, with differing spatial topographies and implications for clinical symptoms.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11469467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of Postoperative Delirium in Older Adults from Preoperative Cognition and Occipital Alpha Power from Resting-State Electroencephalogram.","authors":"Matthew Herbert Ning, Andrei Rodionov, Jessica M Ross, Recep A Ozdimir, Maja Burch, Shu Jing Lian, David Alsop, Michele Cavallari, Bradford C Dickerson, Tamara G Fong, Richard Jones, Towia A Libermann, Edward R Marcantonio, Emiliano Santarnecchi, Eva M Schmitt, Alexandra Touroutoglou, Thomas G Travison, Leah Acker, Melody Reese, Haoqi Sun, Michael Brandon Westover, Miles Berger, Alvaro Pascual-Leone, Sharon K Inouye, Mouhsin M Shafi","doi":"10.1101/2024.08.15.24312053","DOIUrl":"10.1101/2024.08.15.24312053","url":null,"abstract":"<p><strong>Background: </strong>Postoperative delirium is the most common complication following surgery among older adults, and has been consistently associated with increased mortality and morbidity, cognitive decline, and loss of independence, as well as markedly increased health-care costs. Electroencephalography (EEG) spectral slowing has frequently been observed during episodes of delirium, whereas intraoperative frontal alpha power is associated with postoperative delirium. We sought to identify preoperative predictors that could identify individuals at high risk for postoperative delirium, which could guide clinical decision-making and enable targeted interventions to potentially decrease delirium incidence and postoperative delirium-related complications.</p><p><strong>Methods: </strong>In this prospective observational study, we used machine learning to evaluate whether baseline (preoperative) cognitive function and resting-state EEG could be used to identify patients at risk for postoperative delirium. Preoperative resting-state EEGs and the Montreal Cognitive Assessment were collected from 85 patients (age = 73 +- 6.4 years, 12 cases of delirium) undergoing elective surgery. The model with the highest f1-score was subsequently validated in an independent, prospective cohort of 51 older adults (age = 68 +- 5.2 years, 6 cases of delirium) undergoing elective surgery.</p><p><strong>Results: </strong>Occipital alpha powers have higher f1-score than frontal alpha powers and EEG spectral slowing in the training cohort. Occipital alpha powers were able to predict postoperative delirium with AUC, specificity and accuracy all >90%, and sensitivity >80%, in the validation cohort. Notably, models incorporating transformed alpha powers and cognitive scores outperformed models incorporating occipital alpha powers alone or cognitive scores alone.</p><p><strong>Conclusions: </strong>While requiring prospective validation in larger cohorts, these results suggest that strong prediction of postoperative delirium may be feasible in clinical settings using simple and widely available clinical tools. Additionally, our results suggested that the thalamocortical circuit exhibits different EEG patterns under different stressors, with occipital alpha powers potentially reflecting baseline vulnerabilities.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11343253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Basic helix-loop-helix transcription factor <i>BHLHE22</i> monoallelic and biallelic variants cause a neurodevelopmental disorder with agenesis of the corpus callosum, intellectual disability, tone and movement abnormalities.","authors":"Carolyn Le, Emanuela Argilli, Elizabeth George, Tuğba Kalaycı, Zehra Oya Uyguner, Birsen Karaman, Tanju Demirören, Delphine Heron, Isabelle Sabatier, Lance H Rodan, Katta Mohan Girisha, Periyasamy Radhakrishnan, Carol Saunders, Bonnie Sullivan, Emily Fleming, Javeria Raza Alvi, Tipu Sultan, Henry Houlden, Stephanie Efthymiou, Maria J Guillen Sacoto, Melanie Goodman, Lucie Pierron, Jean-Madeleine De Sainte-Agathe, Alexandra Durr, Elliott H Sherr","doi":"10.1101/2024.10.11.24312856","DOIUrl":"https://doi.org/10.1101/2024.10.11.24312856","url":null,"abstract":"<p><p><i>BHLHE22</i> encodes a Class II basic helix-loop-helix transcription factor (bHLH). It is expressed exclusively in the retina and central nervous system (CNS), and functions as an important regulator of retinogenesis and neuronal differentiation. Mice lacking bhlhe22 show nearly complete loss of three brain comminsure, including the corpus callosum. Here we report eleven individuals from nine unrelated families with <i>BHLHE22</i> variants, with a neurodevelopmental disorder presenting with absent or limited speech, severely impaired motor abilities, intellectual disability (ID), involuntary movements, autistic traits with stereotypies, abnormal muscle tone. The majority of individuals have partial or complete agenesis of the corpus callosum (ACC). Additional symptoms comprised epilepsy, variable dysmorphic features, and eye anomalies. One additional individual had spastic paraplegia without delayed development and ACC, expanding the phenotype to milder and later onset forms. Four individuals carry <i>de novo</i> missense variants within the highly conserved helix-loop-helix domain while seven individuals from five unrelated families carry a recurrent homozygous frameshift variant, p.(Gly74Alafs*18). Our findings implicate <i>BHLHE22</i> variants in causing a previously unidentified autosomal dominant and recessive neurodevelopmental disorder associated with ACC, severe motor, language, and cognitive delays, abnormal tone, and involuntary movements. To our knowledge, this is the first report of Class II bHLH variants in humans shown to significantly disrupt brain development, cognition, and movement.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An atlas of genetic effects on the monocyte methylome across European and African populations.","authors":"Wanheng Zhang, Xiao Zhang, Chuan Qiu, Zichen Zhang, Kuan-Jui Su, Zhe Luo, Minghui Liu, Bingxin Zhao, Lang Wu, Qing Tian, Hui Shen, Chong Wu, Hong-Wen Deng","doi":"10.1101/2024.08.12.24311885","DOIUrl":"10.1101/2024.08.12.24311885","url":null,"abstract":"<p><p>Elucidating the genetic architecture of DNA methylation is crucial for decoding complex disease etiology. However, current epigenomic studies are often limited by incomplete methylation coverage and heterogeneous tissue samples. Here, we present the first comprehensive, multi-ancestry human methylome atlas of purified human monocytes, generated through integrated whole-genome bisulfite sequencing and whole-genome sequencing from 298 European Americans (EA) and 160 African Americans (AA). By analyzing over 25 million methylation sites, we identified 1,383,250 and 1,721,167 methylation quantitative trait loci (meQTLs) in <i>cis-</i> regions for EA and AA populations, respectively, revealing both shared (880,108 sites) and population-specific regulatory patterns. Furthermore, we developed population-specific DNAm imputation models, enabling methylome-wide association studies (MWAS) for 1,976,046 and 2,657,581 methylation sites in EA and AA, respectively. These models were validated through multi-ancestry analysis of 41 complex traits from the Million Veteran Program. The identified meQTLs, MWAS models, and data resources are freely available at www.gcbhub.org and https://osf.io/gct57/ .</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11361221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142116729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Telemedicine in Eye Care During the COVID-19 Pandemic: A Review of Patient & Physician Perspectives.","authors":"Christina Perjuhi Halajyan, Jonathan Thomas, Benjamin Xu, Jeffrey Gluckstein, Xuejuan Jiang","doi":"10.1101/2024.10.25.24316160","DOIUrl":"https://doi.org/10.1101/2024.10.25.24316160","url":null,"abstract":"<p><strong>Purpose: </strong>There has been an increase in the adoption of telemedicine during the COVID-19 pandemic. This review used systematic search and review criteria to assess the literature on patient and physician perspectives toward telemedicine for vision care during the pandemic.</p><p><strong>Methods: </strong>We conducted a comprehensive search on PubMed, Embase, and Scopus using relevant MeSH terms to identify peer-reviewed studies examining telemedicine use in eye care during the pandemic. The search strategy encompassed three key concepts: COVID-19 or pandemic, telehealth or telemedicine, and eye care. Further screening of references and similar articles was conducted to identify additional relevant studies.</p><p><strong>Results: </strong>We identified 24 relevant studies published between 2020 and 2022. Of these, 15 focused on patients' perspectives, while 12 explored physicians' perspectives. Predominantly cross-sectional in design, these studies were mainly conducted during the initial wave of the pandemic (March 2020 to June 2020), primarily in urban locations and hospital settings. Patients were satisfied with telemedicine and considered it equally effective to in-person visits. Patients believed telemedicine was convenient, improved eye care access, and a beneficial triage tool. Physicians acknowledged telemedicine's convenience for follow-up assessment and its ability to expand the capacity for emergency cases. However, both patients and physicians voiced concerns about the absence of ancillary examination and technological challenges.</p><p><strong>Conclusion: </strong>Our review highlights the positive impact of telemedicine in eye care during the pandemic. Nonetheless, most studies were limited in sample size. They did not delve into potential disparities based on race/ethnicity, socioeconomic status, and geographic location, factors that could influence patient attitudes toward telemedicine. Further research is warranted to validate the findings from our selected studies and explore factors that influence the implementation of telemedicine, particularly across various eye care subspecialties.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"5hmC-profiles in Puerto Rican Hispanic/Latino men with aggressive prostate cancer.","authors":"Manishkumar S Patel, Mousa Almubarak, Jaime Matta, Carmen Ortiz-Sanchez, Jarline Encarnacion, Gilberto Ruiz-Deya, Julie Dutil, Jasreman Dhillon, Kosj Yamoah, Anders Berglund, Hyun Park, Deepak Kilari, Yoganand Balagurunathan, Liang Wang, Jong Y Park","doi":"10.1101/2024.10.26.24315621","DOIUrl":"https://doi.org/10.1101/2024.10.26.24315621","url":null,"abstract":"<p><p>Puerto Rican (PR) Hispanic/Latino (H/L) men are an understudied population that has the highest prostate cancer (PCa) specific mortality among other Hispanic populations. Little information is known about the higher mortality in PR H/L men. It is thought that epigenetic changes in key genes may play a critical role in aggressive tumors. We aimed to identify key 5-hydroxymethylcytosine (5hmC) changes in PR H/L men with aggressive PCa. We performed sequencing analysis using the 5hmC-enriched DNA from 22 prostate tumors and 24 adjacent normal FFPE samples. We identified 808 differentially methylated genes (DMGs) in tumors compared to adjacent normal tissues (FDR<0.05, log2FC>|0.4|). Pathway analysis of DMGs demonstrated that DNA repair pathway was most upregulated in tumors. Since 5hmC abundance positively correlates with gene expression levels, we further investigated 808 DMGs in TCGA PCa gene expression data. Further, we identified 59 DMGs (80.1%, FDR<0.05, ΔGE (gene expression) >|1|) with significant gene expression changes in the same direction. Additionally, we identified 111 aggressiveness-related DMGs, of which, two hypomethylated genes ( <i>CCDC122</i> , <i>NUDT15</i> ) and four hypermethylated genes ( <i>PVT1</i> , <i>RPL30</i> , <i>TRMT12</i> , <i>UBR5</i> ) were found to be altered at transcriptomic level in a concordant manner in PR H/L PCa patients (N=86). The aberrant 5hmC (N=55) and GE (N=497) changes in these six genes were also associated with progression-free survival in the mixed PCa population. In conclusion, our study identified 59 DMGs showing concordant epigenetic and transcriptomic changes in tumor tissues and 111 DMGs showing association with aggressive PCa among PR H/L men.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel alpha-synuclein G14R missense variant is associated with atypical neuropathological features.","authors":"Christof Brücke, Mohammed Al-Azzani, Nagendran Ramalingam, Maria Ramón, Rita L Sousa, Fiamma Buratti, Michael Zech, Kevin Sicking, Leslie Amaral, Ellen Gelpi, Aswathy Chandran, Aishwarya Agarwal, Susana R Chaves, Claudio O Fernández, Ulf Dettmer, Janin Lautenschläger, Markus Zweckstetter, Ruben Fernandez Busnadiego, Alexander Zimprich, Tiago Fleming Outeiro","doi":"10.1101/2024.09.23.24313864","DOIUrl":"10.1101/2024.09.23.24313864","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) affects millions of people worldwide, but only 5-10% of patients suffer from a monogenic form of the disease with Mendelian inheritance. <i>SNCA,</i> the gene encoding for the protein alpha-synuclein (aSyn), was the first to be associated with familial forms of PD and, since then, several missense variants and multiplications of the <i>SNCA</i> gene have been established as rare causes of autosomal dominant forms of PD.</p><p><strong>Aim and methods: </strong>A patient carrying aSyn missense mutation and his family members were studied. We present the clinical features, genetic testing - whole exome sequencing (WES), and neuropathological findings. The functional consequences of this aSyn variant were extensively investigated using biochemical, biophysical, and cellular assays.</p><p><strong>Results: </strong>The patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous <i>SNCA</i> variant (cDNA 40G>A; protein G14R). Neuropathological examination showed extensive atypical aSyn pathology with frontotemporal lobar degeneration (FTLD) and nigral degeneration pattern with abundant ring-like neuronal inclusions, and few oligodendroglial inclusions. Sanger sequencing confirmed the <i>SNCA</i> variant in the healthy, elderly parent of the patient patient suggesting incomplete penetrance. NMR studies suggest that the G14R mutation induces a local structural alteration in aSyn, and lower thioflavin T binding in in vitro fibrillization assays. Interestingly, the G14R aSyn fibers display different fibrillar morphologies as revealed by cryo-electron microscopy. Cellular studies of the G14R variant revealed increased inclusion formation, enhanced membrane association, and impaired dynamic reversibility of serine-129 phosphorylation.</p><p><strong>Summary: </strong>The atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the <i>SNCA</i> variant with a distinct clinical and pathological phenotype, which is further supported by the properties of the mutant aSyn, compatible with the strain hypothesis of proteinopathies.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11469355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Persistence of training-induced visual improvements after occipital stroke.","authors":"Hanna E Willis, Berkeley Farenthold, Rebecca S Millington-Truby, Rebecca Willis, Lucy Starling, Matthew Cavanaugh, Marco Tamietto, Krystel Huxlin, Holly Bridge","doi":"10.1101/2024.10.24.24316036","DOIUrl":"https://doi.org/10.1101/2024.10.24.24316036","url":null,"abstract":"<p><p>Damage to the primary visual cortex causes homonymous visual impairments that appear to benefit from visual discrimination training. However, whether improvements persist without continued training remains to be determined and was the focus of the present study. After a baseline assessment visit, 20 participants trained twice daily in their blind-field for a minimum of six months (median=155 sessions), using a motion discrimination and integration task. At the end of training, a return study visit was used to assess recovery. Three months later, 14 of the participants returned for a third study visit to assess persistence of recovery. At each study visit, motion discrimination and integration thresholds, Humphrey visual fields, and structural MRI scans were collected. Immediately after training, all but four participants showed improvements in the trained discrimination task, and shrinkage of the perimetrically-defined visual defect. While these gains were sustained in seven out of eleven participants who improved with training, four participants lost their improvement in motion discrimination thresholds at the follow-up visit. Persistence of recovery was not related to age, time since lesion, number of training sessions performed, proportion of V1 damaged, deficit size, or optic tract degeneration measured from structural MRI scans. The present findings underscore the potential of extended visual training to induce long-term improvements in stroke-induced vision loss. However, they also highlight the need for further investigations to better understand the mechanisms driving recovery, its persistence post-training, and especially heterogeneity among participants.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}