11 research outputs found

    CD33 auf humanen Mikroglia und seine Rolle bei der Entstehung von Morbus Alzheimer

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    Mikroglia repräsentieren das Immunsystem im ZNS und nehmen somit eine zentrale Rolle auch bei neurodegenerativen Erkrankungen ein. In der vorliegenden Arbeit wurde die Expression des CD33-Rezeptor auf humanen Mikroglia untersucht, um die mögliche Rolle der Mikroglia in der Pathogenese des Morbus Alzheimer genauer aufzuklären. Zusammenfassend konnte in der vorliegenden Arbeit der Nachweis einer Transkription des cd33-Gens mittels PCR und einer CD33-Rezeptor-Expression auf iPSdM-Mikroglialinien mittels Immunozytochemie und Durchflusszytometrie erbracht werden. Durch Sialidase-Behandlung ließ sich das Detektionsniveau von CD33 in der Durchflusszytometrie deutlich erhöhen, da maskierende Sialinsäuren welche auf der Zelloberfläche cis- und trans-Bindungen mit CD33 eingehen um ein konstitutives inhibitorisches Signal aufrecht zu erhalten, durch Sialidasen abgespalten werden. In menschlichem Gehirngewebe konnten die in den iPSdM gewonnenen Daten bezüglich Transkription und Expression verifiziert werden. Bei der immuno-histochemischen Analyse menschlicher Gehirnschnitte von Kontroll- und Alzheimer-Patienten zeigte sich eine gesteigerte Expressionsrate von CD33 auf den Mikroglia der Alzheimer-Patienten, welche auf eine höhere Expressionsrate von Protein pro Zelle verursacht wurde. Die Anzahl der Mikroglia in den untersuchten Gehirnschnitten zeigte eine gering erhöhte Zellzahl bei den Alzheimer-Patienten. Diese Daten sind gut mit kürzlich publizierten Arbeiten vereinbar, welche sich demselben Thema widmeten

    Interactive cohort exploration for spinocerebellar ataxias using synthetic cohort data for visualization

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    Motivation: Visualization of data is a crucial step to understanding and deriving hypotheses from clinical data. However, for clinicians, visualization often comes with great effort due to the lack of technical knowledge about data handling and visualization. The application offers an easy-to-use solution with an intuitive design that enables various kinds of plotting functions. The aim was to provide an intuitive solution with a low entrance barrier for clinical users. Little to no onboarding is required before creating plots, while the complexity of questions can grow up to specific corner cases. To allow for an easy start and testing with SCAview, we incorporated a synthetic cohort dataset based on real data of rare neurological movement disorders: the most common autosomal-dominantly inherited spinocerebellar ataxias (SCAs) type 1, 2, 3, and 6 (SCA1, 2, 3 and 6). Methods: We created a Django-based backend application that serves the data to a React-based frontend that uses Plotly for plotting. A synthetic cohort was created to deploy a version of SCAview without violating any data protection guidelines. Here, we added normal distributed noise to the data and therefore prevent re-identification while keeping distributions and general correlations. Results: This work presents SCAview, an user-friendly, interactive web-based service that enables data visualization in a clickable interface allowing intuitive graphical handling that aims to enable data visualization in a clickable interface. The service is deployed and can be tested with a synthetic cohort created based on a large, longitudinal dataset from observational studies in the most common SCAs

    The Diagnostic Value of Cerebrospinal Fluid Lactate for Detection of Sepsis in Community-Acquired Bacterial Meningitis

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    Community-acquired bacterial meningitis conveys significant morbidity and mortality due to intracranial and systemic complications, and sepsis is a major contributor to the latter. While cerebrospinal fluid (CSF) analysis is essential in the diagnosis of bacterial meningitis, its predictive utility for detection of sepsis is unknown. We investigated the diagnostic performance of CSF parameters for sepsis defined by the Sepsis-3 criteria in a retrospective cohort of patients with community-acquired bacterial meningitis. Among 103 patients, 69.5% developed sepsis. CSF lactate was associated with sepsis with an odds ratio of 1.11 (p = 0.022), while CSF cell counts, glucose and protein levels were not (all p > 0.4). Employing the optimal cutoff of 8.2 mmol/L, elevated CSF lactate resulted in a sensitivity of 81.5% and specificity of 61.5% for sepsis. In exploratory analyses, CSF lactate was also associated with in-hospital mortality with an odds ratio of 1.21 (p = 0.011). Elevated CSF lactate might contribute to early diagnosis of sepsis as well as prognostication in patients with community-acquired bacterial meningitis

    Patient-reported, health economic and psychosocial outcomes in patients with Friedreich ataxia (PROFA): protocol of an observational study using momentary data assessments via mobile health app

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    Introduction Friedreich ataxia (FA) is the most common hereditary ataxia in Europe, characterised by progressively worsening movement and speech impairments with a typical onset before the age of 25 years. The symptoms affect the patients’ health-related quality of life (HRQoL) and psychosocial health. FA leads to an increasing need for care, associated with an economic burden. Little is known about the impact of FA on daily lives and HRQoL. To fill that gap, we will assess patient-reported, psychosocial and economic outcomes using momentary data assessment via a mobile health application (app).Methods and analysis The PROFA Study is a prospective observational study. Patients with FA (n=200) will be recruited at six European study centres (Germany, France and Austria). We will interview patients at baseline in the study centre and subsequently assess the patients’ health at home via mobile health app. Patients will self-report ataxia severity, HRQoL, speech and hearing disabilities, coping strategies and well-being, health services usage, adverse health events and productivity losses due to informal care on a daily to monthly basis on the app for 6 months. Our study aims to (1) validate measurements of HRQoL and psychosocial health, (2) assess the usability of the mobile health app, and (3) use descriptive and multivariate statistics to analyse patient-reported and economic outcomes and the interaction effects between these outcomes. Insights into the app’s usability could be used for future studies using momentary data assessments to measure outcomes of patients with FA.Ethics and dissemination Ethical approval has been obtained from the Ethics Committee of the University Medicine of Greifswald, (BB096/22a, 26 October 2022) and from all local ethics committees of the participating study sites. Findings of the study will be published in peer-reviewed journals, presented at relevant international/national congresses and disseminated to German and French Patient Advocacy Organizations.Trial registration number ClinicalTrials.gov Registry (NCT05943002); Pre-results

    Evolution of Clinical Outcome Measures and Biomarkers in Sporadic Adult-Onset Degenerative Ataxia

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    BackgroundSporadic adult-onset ataxias without known genetic or acquired cause are subdivided into multiple system atrophy of cerebellar type (MSA-C) and sporadic adult-onset ataxia of unknown etiology (SAOA). ObjectivesTo study the differential evolution of both conditions including plasma neurofilament light chain (NfL) levels and magnetic resonance imaging (MRI) markers. MethodsSPORTAX is a prospective registry of sporadic ataxia patients with an onset >40 years. Scale for the Assessment and Rating of Ataxia was the primary outcome measure. In subgroups, blood samples were taken and MRIs performed. Plasma NfL was measured via a single molecule assay. Regional brain volumes were automatically measured. To assess signal changes, we defined the pons and middle cerebellar peduncle abnormality score (PMAS). Using mixed-effects models, we analyzed changes on a time scale starting with ataxia onset. ResultsOf 404 patients without genetic diagnosis, 130 met criteria of probable MSA-C at baseline and 26 during follow-up suggesting clinical conversion to MSA-C. The remaining 248 were classified as SAOA. At baseline, NfL, cerebellar white matter (CWM) and pons volume, and PMAS separated MSA-C from SAOA. NfL decreased in MSA-C and did not change in SAOA. CWM and pons volume decreased faster, whereas PMAS increased faster in MSA-C. In MSA-C, pons volume had highest sensitivity to change, and PMAS was a predictor of faster progression. Fulfillment of possible MSA criteria, NfL and PMAS were risk factors, CWM and pons volume protective factors for conversion to MSA-C. ConclusionsThis study provides detailed information on differential evolution and prognostic relevance of biomarkers in MSA-C and SAOA. (c) 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

    Autosomal Recessive Cerebellar Ataxias in Europe: Frequency, Onset, and Severity in 677 Patients

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    Progress in next-generation sequencing has led to an explosion of novel genes and phenotypes of autosomal recessive cerebellar ataxias (ARCAs) in the last decade, with >170 recessive conditions manifesting with ataxia identified.1 With large-scale natural history and mechanistic treatment trials on the horizon for many ARCAs, up-to-date knowledge is required not only on relative frequencies but also on real-world age and disease severity distributions as key information for trial design planning and recruitment. In this multicenter study, we provide data on the relative frequency of ARCAs in Europe, delineate the spectrum of age at disease onset, and present real-world data on disease severity distributions of patients with ARCA that help to inform future trial planning

    Blood transcriptome sequencing identifies biomarkers able to track disease stages in spinocerebellar ataxia type 3

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    Transcriptional dysregulation has been described in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), an autosomal dominant ataxia caused by a polyglutamine expansion in the ataxin-3 protein. As ataxin-3 is ubiquitously expressed, transcriptional alterations in blood may reflect early changes that start before clinical onset and might serve as peripheral biomarkers in clinical and research settings. Our goal was to describe enriched pathways and report dysregulated genes, which can track disease onset, severity or progression in carriers of the ATXN3 mutation (pre-ataxic subjects and patients). Global dysregulation patterns were identified by RNA sequencing of blood samples from 40 carriers of ATXN3 mutation and 20 controls and further compared with transcriptomic data from post-mortem cerebellum samples of MJD patients and controls. Ten genes - ABCA1, CEP72, PTGDS, SAFB2, SFSWAP, CCDC88C, SH2B1, LTBP4, MEG3 and TSPOAP1 - whose expression in blood was altered in the pre-ataxic stage and simultaneously, correlated with ataxia severity in the overt disease stage, were analysed by quantitative real-time PCR in blood samples from an independent set of 170 SCA3/MJD subjects and 57 controls. Pathway enrichment analysis indicated the Gαi signalling and the oestrogen receptor signalling to be similarly affected in blood and cerebellum. SAFB2, SFSWAP and LTBP4 were consistently dysregulated in pre-ataxic subjects compared to controls, displaying a combined discriminatory ability of 79%. In patients, ataxia severity was associated with higher levels of MEG3 and TSPOAP1. We propose expression levels of SAFB2, SFSWAP and LTBP4 as well as MEG3 and TSPOAP1 as stratification markers of SCA3/MJD progression, deserving further validation in longitudinal studies and in independent cohorts.</p
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