Running during pregnancy mitigates Alzheimer-linke neurovascular dysfunction in mouse offspring

Körperliche Aktivität verbessert sowohl die Funktion des Gehirns von Gesunden als auch von Personen, die an der Alzheimer-Krankheit erkrankt sind. Bisher gab es jedoch nur wenige Untersuchungen, die sich mit dem Effekt von mütterlicher Aktivität auf die Gehirnfunktion der Nachkommen beschäftigt haben und wenn beschränkten sich diese auf gesunde Individuen. Vorarbeiten konnten zeigen, dass mütterliches Laufen während der Schwangerschaft die Amyloidpathologie der Nachkommen im Alzheimer-Mausmodell signifikant verringert. In dieser Arbeit wurde darauf aufbauend der Einfluss pränataler physischer Aktivität auf die neurovaskuläre Dysfunktion im Tiermodell der Alzheimer-Erkrankung untersucht, als mögliche Erklärung dieses Effekts. Hierbei wurde die mütterliche Stimulation durch freiwilliges Laufen im Laufrad während der Schwangerschaft im Gegensatz zur Standardhaltung gewährleistet. Nach 5-monatiger Standardhaltung der Transgenen und Wildtyp-Mäuse wurden die Gehirne der Nachkommen untersucht. Dabei zeigt sich eine Verbesserung der neurovaskulären Funktion der transgenen Tiere durch veränderte Expression der Amyloid-β-Transporter und eine gesteigerte Angiogenese. Der Amyloid-β-Efflux Transporter Multidrug Resistance Protein 1 (MDR1) ist nach mütterlichem Laufen hochreguliert, während der Aβ-Influx Transporter Receptor for advanced glycation enproducts (RAGE) herabreguliert ist. Low-density lipoprotein receptor-related preotein 1 (LRP1), ein weiterer Amyloid-β-Efflux Transporter, zeigt sich unverändert. Jedoch konnte die transkriptionelle Herabregulation eines LRP1-Inhibitors festgestellt werden. Daraus lässt sich schlussfolgern, dass der positive Effekt mütterlichen Laufens auf die Amyloidpathologie der Nachkommen durch eine Veränderung der neurovaskulären Funktion mitverursacht ist. Einen möglichen Übertragungsweg stellen epigenetische Veränderungen der Nachkommen dar. Die Übertragbarkeit dieser Ergebnisse auf den Menschen unterliegt der eingeschränkten Vergleichbarkeit vom Tiermodell der Alzheimer-Krankheit und der humanen Alzheimer-Erkrankung. Dennoch können diese experimentellen Daten zeigen, dass körperliches Training nicht nur auf das Individuum selbst sondern auch auf die nachfolgende Generation positive Effekte ausüben und damit der Entstehung einer neurodegenerativen Erkankung präventiv entgegenwirken kann.Physical activity protects brain function in healthy individuals and those with Alzheimer’s disease (AD). Evidence for beneficial effects of parental exercise on the health status of their progeny is sparse and limited to nondiseased individuals. Previous research show that maternal running interferes with offspring’s AD-like pathology. This work sought to decipher the underlying mechanisms in TgCRND8 mice. Maternal stimulation was provided by voluntary wheel running vs. standard housing during pregnancy. Following 5 month of standard housing of transgenic and wild-type offspring, their brains were examined for neurovascular dysfunction. Running during pregnancy improved the neurovascular function by orchestrating different Amyloid-Beta transporters and increasing angiogenesis. One possible explanation are epigenetic changes of the progeny

Effects of acetyl-DL-leucine on cerebellar ataxia (ALCAT trial): study protocol for a multicenter, multinational, randomized, double-blind, placebo-controlled, crossover phase III trial

BACKGROUND: Cerebellar ataxia (CA) is a frequent and often disabling condition that impairs motor functioning and impacts on quality of life (QoL). No medication has yet been proven effective for the symptomatic or even causative treatment of hereditary or non-hereditary, non-acquired CA. So far, the only treatment recommendation is physiotherapy. Therefore, new therapeutic options are needed. Based on three observational studies, the primary objective of the acetyl-DL-leucine on ataxia (ALCAT) trial is to examine the efficacy and tolerability of a symptomatic therapy with acetyl-DL-leucine compared to placebo on motor function measured by the Scale for the Assessment and Rating of Ataxia (SARA) in patients with CA. METHODS/DESIGN: An investigator-initiated, multicenter, European, randomized, double-blind, placebo-controlled, 2-treatment 2-period crossover phase III trial will be carried out. In total, 108 adult patients who meet the clinical criteria of CA of different etiologies (hereditary or non-hereditary, non-acquired) presenting with a SARA total score of at least 3 points will be randomly assigned in a 1:1 ratio to one of two different treatment sequences, either acetyl-DL-leucine (up to 5 g per day) followed by placebo or vice versa. Each sequence consists of two 6-week treatment periods, separated by a 4-week wash-out period. A follow-up examination is scheduled 4 weeks after the end of treatment. The primary efficacy outcome is the absolute change in the SARA total score. Secondary objectives are to demonstrate that acetyl-DL-leucine is effective in improving (1) motor function measured by the Spinocerebellar Ataxia Functional Index (SCAFI) and SARA subscore items and (2) QoL (EuroQoL 5 dimensions and 5 level version, EQ-5D-5 L), depression (Beck Depression Inventory, BDI-II) and fatigue (Fatigue Severity Score, FSS). Furthermore, the incidence of adverse events will be investigated. DISCUSSION: The results of this trial will inform whether symptomatic treatment with the modified amino-acid acetyl-DL-leucine is a worthy candidate for a new drug therapy to relieve ataxia symptoms and to improve patient care. If superiority of the experimental drug to placebo can be established it will also be re-purposing of an agent that has been previously used for the symptomatic treatment of dizziness. TRIAL REGISTRATION: The trial was prospectively registered at www.clinicaltrialsregister.eu (EudraCT no. 2015-000460-34) and at https://www.germanctr.de (DRKS-ID: DRKS00009733 )

Cytokines (IL1β, IL6, TNFα) and serum cortisol levels may not constitute reliable biomarkers to identify individuals with post-acute sequelae of COVID-19

Background: Post-acute sequelae of COVID-19 (PASC) comprise a broad spectrum of symptoms such as fatigue, general weakness, compromised attention and sleep or anxiety disorders. PASC represents a medical and socio-economic challenge. Objectives: Our study evaluated cytokines (IL-1β, IL-6 and TNFα) and cortisol levels in a cohort of typical patients with PASC, suffering concentration problems, fatigue and difficulties finding words. Design: This was a prospective cohort study. Four groups were analysed and compared: those who had never contracted SARS-CoV-2 ( n  = 13), infected but had no PASC ( n  = 34), infected with former PASC that resolved ( n  = 40) and patients with ongoing PASC after infection ( n  = 91). Methods: Cytokine and cortisol serum levels were determined in patients’ blood samples. Results: Cytokine levels of IL-1β, IL-6, TNFα and cortisol levels did not differ between groups analysed. Conclusion: This may indicate a non-organic/psychosomatic genesis of PASC; further studies are needed to elucidate the underlying causes of PACS, and non-organic causes should not be overlooked