Amyloid-precursor-protein-lowering small molecules for disease modifying therapy of Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia in the elderly with progressive cognitive decline and memory loss. According to the amyloid-hypothesis, AD is caused by generation and subsequent cerebral deposition of β-amyloid (Aβ). Aβ is generated through sequential cleavage of the transmembrane Amyloid-Precursor-Protein (APP) by two endoproteinases termed beta- and gamma-secretase. Increased APP-expression caused by APP gene dosage effects is a risk factor for the development of AD. Here we carried out a large scale screen for novel compounds aimed at decreasing APP-expression. For this we developed a screening system employing a cell culture model of AD. A total of 10,000 substances selected for their ability of drug-likeness and chemical diversity were tested for their potential to decrease APP-expression resulting in reduced Aβ-levels. Positive compounds were further evaluated for their effect at lower concentrations, absence of cytotoxicity and specificity. The six most promising compounds were characterized and structure function relationships were established. The novel compounds presented here provide valuable information for the development of causal therapies for AD

The MoxFo initiative-Mechanisms of action: Biomarkers in multiple sclerosis exercise studies

background: as exercise exerts neurobiological and immunomodulatory effects, it might also act as a disease-modifying intervention in MS. however, a clear mechanistic link between exercise and disease-modifying effects in MS has yet to be established.objective: establish recommendations for future mechanistic exercise studies in MS.Methods: In regular meetings, members of the mechanisms of action group within the MoXFo (Moving eXercise research Forward in MS) initiative evaluated gaps of knowledge and discussed unmet needs in mechanistic MS research.results: we concluded that biomarkers assessed in translational studies in humans and animals are essential to decipher the underlying mechanisms of exercise in MS. consequently, we defined clear definitions of different types of biomarkers examined in MS exercise studies and operationalized their use to align with the research question and optimal testing time points. Furthermore, we provide key considerations to improve the rigor of translational studies and defined minimal reporting criteria for animal studies.conclusion: the resulting recommendations are intended to improve the quality of future mechanistic exercise studies in MS and consequently lead to a better understanding of therapeutic approaches

Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis—a randomized controlled trial

Background Only few aerobic exercise intervention trials specifically targeting cognitive functioning have been performed in multiple sclerosis. Objective and Methods This randomized controlled trial with 34 patients in the intervention group (IG) (mean: 38.2 years (±9.6)) and 34 patients in the control group (CG) (mean: 39.6 years (±9.7)) aimed to determine the effects of aerobic exercise on cognition in relapsing-remitting multiple sclerosis (RRMS). The primary outcome was verbal learning assessed by the verbal learning and memory test (VLMT). Patients were randomized to an IG or a waitlist CG. Patients in the IG exercised according to an individually tailored training schedule (with two to three sessions per week for 12 weeks). The primary analysis was carried out using the intention-to-treat (ITT) sample with ANCOVA adjusting for baseline scores. Results A total of 77 patients with RRMS were screened and 68 participants randomized (CG n = 34; IG n = 34). The sample comprised 68% females, had a mean age of 39 years, a mean disease duration of 6.3 years, and a mean expanded disability status scale of 1.8. No significant effects were detected in the ITT analysis for the primary endpoint VLMT or any other cognitive measures. Moreover, no significant treatment effects were observed for quality of life, fatigue, or depressive symptoms. Conclusion This study failed to demonstrate beneficial effects of aerobic exercise on cognition in RRMS. The trial was prospectively registered at clinicaltrials.gov (NCT02005237)

Cognitive-motor interference in multiple sclerosis and healthy controls: results from single, dual, and triple task posturography

Aim: This article is based on our previous research, which was presented as a poster at the ECTRIMS Congress 2018 and published as a conference abstract (https://www.professionalabstracts.com/ectrims2018/iplanner/#/presentation/1698). Cognitive-motor interference (CMI) has been observed in both healthy controls (HC) and persons with multiple sclerosis (pwMS), but limited and contradictory data is making it difficult to assess the impact of motor and cognitive functioning levels on CMI. The aim of this study was to investigate CMI in pwMS and HC by means of a dual task postural paradigm, to compare them between groups and to analyse the influence of motor and cognitive functioning levels assessed with complementary instruments on observed CMI. Methods: The dual task posturography paradigm serves to quantify the impact of a cognitive (i.e., performing serial subtractions), a motor challenge (closing eyes), or both challenges combined (triple task) on body sway during standing in an upright position feet closed. The data analysed were acquired in one interventional and four observational studies and selected based on predefined criteria and by systematic quality control. A total of 113 pwMS and 42 HC were selected for analysis. Results: Comparable changes in motor and cognitive performance due to cognitive or combined cognitive-motor challenges were observed in both HC and pwMS. Combining both tasks did not result in further changes in motor performance but resulted in a decrease in cognitive performance. This reduction in cognitive performance with an additional motor challenge correlated with lower levels of cognitive and motor functioning in pwMS. Unexpectedly, an increase in body sway due to a cognitive or combined cognitive-motor challenges was primarily observed in pwMS and HC with better cognitive and motor functioning. Conclusions: The results suggest that dual-task effects are not disease-specific but rather reflect individually different adaptation strategies depending on the specific motor and cognitive functioning levels

The MoxFo initiative—Mechanisms of action: Biomarkers in multiple sclerosis exercise studies

Background: As exercise exerts neurobiological and immunomodulatory effects, it might also act as a disease-modifying intervention in MS. However, a clear mechanistic link between exercise and diseasemodifying effects in MS has yet to be established. Objective: Establish recommendations for future mechanistic exercise studies in MS. Methods: In regular meetings, members of the mechanisms of action group within the MoXFo (Moving eXercise research Forward in MS) initiative evaluated gaps of knowledge and discussed unmet needs in mechanistic MS research. Results: We concluded that biomarkers assessed in translational studies in humans and animals are essential to decipher the underlying mechanisms of exercise in MS. Consequently, we defined clear definitions of different types of biomarkers examined in MS exercise studies and operationalized their use to align with the research question and optimal testing time points. Furthermore, we provide key considerations to improve the rigor of translational studies and defined minimal reporting criteria for animal studies. Conclusion: The resulting recommendations are intended to improve the quality of future mechanistic exercise studies in MS and consequently lead to a better understanding of therapeutic approaches.Advanced Clinician-Scientist Fellowship from the BMBF (iSTAR, 01EO2106)Hertie Network of Excellence in Clinical Neuroscience of the Gemeinnützige Hertie- StiftungUniversity Medical Center Hamburg-Eppendorf, Deutsche Forschungsgemeinschaft (SFB1328, SPP1738, KFO296, FOR2289, FOR2879, FOR5068, and FR1720/11-2)Gemeinnützige Hertie-Stiftung, Deutsche Multiple Sklerose Gesellschaft (DMSG; V6.2)Bundesministerium für Bildung und Forschung (Target validation, 16GW0308K

Validation of Computer-Adaptive Contrast Sensitivity as a Tool to Assess Visual Impairment in Multiple Sclerosis Patients

International audienceBackground: Impairment of visual function is one of the major symptoms of people with multiple sclerosis (pwMS). A multitude of disease effects including inflammation and neurodegeneration lead to structural impairment in the visual system. However, the gold standard of disability quantification, the expanded disability status scale (EDSS), relies on visual assessment charts. A more comprehensive assessment of visual function is the full contrast sensitivity function (CSF), but most tools are time consuming and not feasible in clinical routine. The quantitative CSF (qCSF) test is a computerized test to assess the full CSF. We have already shown a better correlation with visual quality of life (QoL) than for classical high and low contrast charts in multiple sclerosis (MS).Objective: To study the precision, test duration, and repeatability of the qCSF in pwMS. In order to evaluate the discrimination ability, we compared the data of pwMS to healthy controls.Methods: We recruited two independent cohorts of MS patients. Within the precision cohort (n = 54), we analyzed the benefit of running 50 instead of 25 qCSF trials. The repeatability cohort (n = 44) was assessed by high contrast vision charts and qCSF assessments twice and we computed repeatability metrics. For the discrimination ability we used the data from all pwMS without any previous optic neuritis and compared the area under the log CSF (AULCSF) to an age-matched healthy control data set.Results: We identified 25 trials of the qCSF algorithm as a sufficient amount for a precise estimate of the CSF. The median test duration for one eye was 185 s (range 129–373 s). The AULCSF had better test–retest repeatability (Mean Average Precision, MAP) than visual acuity measured by standard high contrast visual acuity charts or CSF acuity measured with the qCSF (0.18 vs. 0.11 and 0.17, respectively). Even better repeatability (MAP = 0.19) was demonstrated by a CSF-derived feature that was inspired by low-contrast acuity charts, i.e., the highest spatial frequency at 25% contrast. When compared to healthy controls, the MS patients showed reduced CSF (average AULCSF 1.21 vs. 1.42, p < 0.01).Conclusion: High precision, usability, repeatability, and discrimination support the qCSF as a tool to assess contrast vision in pwMS

The MoxFo initiative—Mechanisms of action: Biomarkers in multiple sclerosis exercise studies

International audienceBackground: As exercise exerts neurobiological and immunomodulatory effects, it might also act as a disease-modifying intervention in MS. However, a clear mechanistic link between exercise and disease-modifying effects in MS has yet to be established. Objective: Establish recommendations for future mechanistic exercise studies in MS. Methods: In regular meetings, members of the mechanisms of action group within the MoXFo (Moving eXercise research Forward in MS) initiative evaluated gaps of knowledge and discussed unmet needs in mechanistic MS research. Results: We concluded that biomarkers assessed in translational studies in humans and animals are essential to decipher the underlying mechanisms of exercise in MS. Consequently, we defined clear definitions of different types of biomarkers examined in MS exercise studies and operationalized their use to align with the research question and optimal testing time points. Furthermore, we provide key considerations to improve the rigor of translational studies and defined minimal reporting criteria for animal studies. Conclusion: The resulting recommendations are intended to improve the quality of future mechanistic exercise studies in MS and consequently lead to a better understanding of therapeutic approaches

Amyloid-precursor-protein-lowering small molecules for disease modifying therapy of Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia in the elderly with progressive cognitive decline and memory loss. According to the amyloid-hypothesis, AD is caused by generation and subsequent cerebral deposition of β-amyloid (Aβ). Aβ is generated through sequential cleavage of the transmembrane Amyloid-Precursor-Protein (APP) by two endoproteinases termed beta- and gamma-secretase. Increased APP-expression caused by APP gene dosage effects is a risk factor for the development of AD. Here we carried out a large scale screen for novel compounds aimed at decreasing APP-expression. For this we developed a screening system employing a cell culture model of AD. A total of 10,000 substances selected for their ability of drug-likeness and chemical diversity were tested for their potential to decrease APP-expression resulting in reduced Aβ-levels. Positive compounds were further evaluated for their effect at lower concentrations, absence of cytotoxicity and specificity. The six most promising compounds were characterized and structure function relationships were established. The novel compounds presented here provide valuable information for the development of causal therapies for AD

Amyloid-Precursor-Protein-Lowering Small Molecules for Disease Modifying Therapy of Alzheimer's Disease

<div><p>Alzheimer's disease (AD) is the most common form of dementia in the elderly with progressive cognitive decline and memory loss. According to the amyloid-hypothesis, AD is caused by generation and subsequent cerebral deposition of β-amyloid (Aβ). Aβ is generated through sequential cleavage of the transmembrane Amyloid-Precursor-Protein (APP) by two endoproteinases termed beta- and gamma-secretase. Increased APP-expression caused by APP gene dosage effects is a risk factor for the development of AD. Here we carried out a large scale screen for novel compounds aimed at decreasing APP-expression. For this we developed a screening system employing a cell culture model of AD. A total of 10,000 substances selected for their ability of drug-likeness and chemical diversity were tested for their potential to decrease APP-expression resulting in reduced Aβ-levels. Positive compounds were further evaluated for their effect at lower concentrations, absence of cytotoxicity and specificity. The six most promising compounds were characterized and structure function relationships were established. The novel compounds presented here provide valuable information for the development of causal therapies for AD.</p></div