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

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

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

Development of SARA(home), a new video-based tool for the assessment of ataxia at home

BACKGROUND: Clinical scales such as the Scale for the Assessment and Rating of Ataxia (SARA) cannot be used to study ataxia at home or to assess daily fluctuations. The objective of the current study was to develop a video-based instrument, SARA(home), for measuring ataxia severity easily and independently at home. METHODS: Based on feasibility of self-application, we selected 5 SARA items (gait, stance, speech, nose-finger test, fast alternating hand movements) for SARA(home) (range, 0-28). We compared SARA(home) items with total SARA scores in 526 patients with spinocerebellar ataxia types 1, 2, 3, and 6 from the EUROSCA natural history study. To prospectively validate the SARA(home), we directly compared the self-applied SARA(home) and the conventional SARA in 50 ataxia patients. To demonstrate feasibility of independent home recordings in a pilot study, 12 ataxia patients were instructed to obtain a video each morning and evening over a period of 14 days. All videos were rated offline by a trained rater. RESULTS: SARA(home) extracted from the EUROSCA baseline data was highly correlated with conventional SARA (r = 0.9854, P < 0.0001). In the prospective validation study, the SARA(home) was highly correlated with the conventional SARA (r = 0.9254, P < 0.0001). Five of 12 participants of the pilot study obtained a complete set of 28 evaluable videos. Seven participants obtained 13-27 videos. The intraindividual differences between the lowest and highest SARA(home) scores ranged from 1 to 5.5. CONCLUSION: The SARA(home) and the conventional SARA are highly correlated. Application at home is feasible. There was a considerable degree of intraindividual variability of the SARA(home) scores

Consensus Recommendations for Clinical Outcome Assessments and Registry Development in Ataxias: Ataxia Global Initiative (AGI) Working Group Expert Guidance

To accelerate and facilitate clinical trials, the Ataxia Global Initiative (AGI) was established as a worldwide research platform for trial readiness in ataxias. One of AGI’s major goals is the harmonization and standardization of outcome assessments. Clinical outcome assessments (COAs) that describe or reflect how a patient feels or functions are indispensable for clinical trials, but similarly important for observational studies and in routine patient care. The AGI working group on COAs has defined a set of data including a graded catalog of COAs that are recommended as a standard for future assessment and sharing of clinical data and joint clinical studies. Two datasets were defined: a mandatory dataset (minimal dataset) that can ideally be obtained during a routine clinical consultation and a more demanding extended dataset that is useful for research purposes. In the future, the currently most widely used clinician-reported outcome measure (ClinRO) in ataxia, the scale for the assessment and rating of ataxia (SARA), should be developed into a generally accepted instrument that can be used in upcoming clinical trials. Furthermore, there is an urgent need (i) to obtain more data on ataxia-specific, patient-reported outcome measures (PROs), (ii) to demonstrate and optimize sensitivity to change of many COAs, and (iii) to establish methods and evidence of anchoring change in COAs in patient meaningfulness, e.g., by determining patient-derived minimally meaningful thresholds of change

SCAview: an Intuitive Visual Approach to the Integrative Analysis of Clinical Data in Spinocerebellar Ataxias

With SCAview, we present a prompt and comprehensive tool that enables scientists to browse large datasets of the most common spinocerebellar ataxias intuitively and without technical effort. Basic concept is a visualization of data, with a graphical handling and filtering to select and define subgroups and their comparison. Several plot types to visualize all data points resulting from the selected attributes are provided. The underlying synthetic cohort is based on clinical data from five different European and US longitudinal multicenter cohorts in spinocerebellar ataxia type 1, 2, 3, and 6 (SCA1, 2, 3, and 6) comprising > 1400 patients with overall > 5500 visits. First, we developed a common data model to integrate the clinical, demographic, and characterizing data of each source cohort. Second, the available datasets from each cohort were mapped onto the data model. Third, we created a synthetic cohort based on the cleaned dataset. With SCAview, we demonstrate the feasibility of mapping cohort data from different sources onto a common data model. The resulting browser-based visualization tool with a thoroughly graphical handling of the data offers researchers the unique possibility to visualize relationships and distributions of clinical data, to define subgroups and to further investigate them without any technical effort. Access to SCAview can be requested via the Ataxia Global Initiative and is free of charge

Sexual dysfunction in cervical dystonia and blepharospasm

M Marek,1 M Grobe-Einsler,1 JR Bedarf,1 B Wabbels,2 S Paus1 1Department of Neurology, University of Bonn, Bonn, Germany; 2Department of Ophthalmology, University of Bonn, Bonn, Germany Background: Sexual dysfunction is a frequent, yet underrated, symptom of neurological disease. While knowledge of non-motor comorbidity in focal dystonia is growing rapidly, there is no information on the prevalence of sexual dysfunction in cervical dystonia (CD) or blepharospasm (BL). Methods: In this controlled study, we examined sexual dysfunction in 65 patients with CD and 54 patients with BL by the Arizona Sexual Experience Scale, a validated self-rating scale. Results: Sexual dysfunction was significantly higher in CD patients (45%) than in controls (24%), and frequent in BL (39%). Interestingly, variables of dystonia such as disease duration or severity did not influence sexuality; yet, 23% of CD patients ascribed worsening of their sexual life to dystonia. Symptoms of depression were identified as the most important predictors for sexual dysfunction, followed by age, and personal status (single). Conclusion: Our observations establish sexual dysfunction as a frequent non-motor symptom in CD and BL that is perceived as a burden. It should be considered when investigating patients with adult-onset focal dystonia. Keywords: dystonia, cervical dystonia, blepharospasm, sexual dysfunction, depression&nbsp

SARAspeech—Feasibility of automated assessment of ataxic speech disturbance

Abstract Ataxias are a group of movement disorders that are characterized by progressive loss of balance, impaired coordination and speech disturbance, which together lead to markedly reduced quality of life. Speech disturbance is clinically diagnosed, but methods for objective assessment of severity are lacking. Using 71 sets of speech recordings from ataxia patients, we developed an automated classification system. With a tolerance of ±1 point, this classification system correctly predicted experts’ ratings of speech disturbance according to item 4 of the Scale for Assessment and rating of ataxia (SARA) in 80% of cases. We thereby demonstrate feasibility of computer-assisted voice analysis for automated assessment of severity of speech disturbance

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

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