Methotrexate and relative risk of dementia amongst patients with rheumatoid arthritis:A multi-national multi-database case-control study

Background: Inflammatory processes have been shown to play a role in dementia. To understand this role, we selected two anti-inflammatory drugs (methotrexate and sulfasalazine) to study their association with dementia risk. Methods: A retrospective matched case-control study of patients over 50 with rheumatoid arthritis (486 dementia cases and 641 controls) who were identified from ele

Analysis of effects of benzodiazepine ligands in an animal model of anxiety.

In the present study, behavioural effects of benzodiazepine receptors ligand were investigated in a model of social conflict in mice. In this ethologically-based model animals show a wide repertoire of acts and postures reflecting various degrees of offensive and defensive-escape tendency. The study was focused to the analysis of behavioral dose-response curves in full and partial benzodiazepine receptor ligands administered alone or in combination with an antagonist and to the investigation of behavioural changes produced by withdrawal from diazepam or alprazolam and their experimental therapy with zolpidem or Ro 19-8022.Available from STL, Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi

Alzheimer's Disease Assessment Scale-Cognitive subscale variants in mild cognitive impairment and mild Alzheimer's disease: change over time and the effect of enrichment strategies

Background Development of new treatments for Alzheimer’s disease (AD) has broadened into early interventions in individuals with modest cognitive impairment and a slow decline. The 11-item version of the Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-Cog) was originally developed to measure cognition in patients with mild to moderate AD. Attempts to improve its properties for early AD by removing items prone to ceiling and/or by adding cognitive measures known to be impaired early have yielded a number of ADAS-Cog variants. Using Alzheimer’s Disease Neuroimaging Initiative data, we compared the performance of the 3-, 5-, 11- and 13-item ADAS-Cog variants in subjects with early AD. Given the interest in enrichment strategies, we also examined this aspect with a focus on cerebrospinal fluid (CSF) markers. Methods Subjects with mild cognitive impairment (MCI) and mild AD with available ADAS-Cog 13 and CSF data were analysed. The decline over time was defined by change from baseline. Direct cross-comparison of the ADAS-Cog variants was performed using the signal-to-noise ratio (SNR), with higher values reflecting increased sensitivity to detect change over time. Results The decline over time on any of the ADAS-Cog variants was minimal in subjects with MCI. Approximately half of subjects with MCI fulfilled enrichment criteria for positive AD pathology. The impact of enrichment was detectable but subtle in MCI. The annual decline in mild AD was more pronounced but still modest. More than 90 % of subjects with mild AD had positive AD pathology. SNRs were low in MCI but greater in mild AD. The numerically largest SNRs were seen for the ADAS-Cog 5 in MCI and for both the 5- and 13-item ADAS-Cog variants in mild AD, although associated confidence intervals were large. Conclusions The possible value of ADAS-Cog expansion or reduction is less than compelling, particularly in MCI. In mild AD, adding items known to be impaired at early stages seems to provide more benefit than removing items on which subjects score close to ceiling

Evaluation of the Efficacy of BI 425809 Pharmacotherapy in Patients with Schizophrenia Receiving Computerized Cognitive Training: Methodology for a Double-blind, Randomized, Parallel-group Trial

BACKGROUND AND OBJECTIVE: Cognitive impairments associated with schizophrenia (CIAS) predict poor functional outcomes, but there are currently no approved pharmacological treatments for patients with CIAS. Additional cognitive stimulation may be required for pro-cognitive medications to improve efficacy, and computerized cognitive training (CCT) can be used to increase cognitive activity. A trial evaluating the effects of the novel glycine transporter inhibitor BI 425809 compared with placebo, on a background of regularly self-administered CCT in clinically stable patients with schizophrenia has commenced and its methodology is described here. This Phase II, multinational, randomized, double-blind, placebo-controlled, parallel-group trial will randomize 200 clinically stable outpatients, aged 18-50 years with established schizophrenia and no other major psychiatric disorder, 1:1 to BI 425809 or placebo once daily for 12 weeks. Following screening, which included a 2-week CCT run-in period, patients sufficiently compliant with CCT (target: ≥ 2 h of CCT per week during CCT run-in) will be randomized. During the 12-week treatment period, all patients should complete a total of approximately 30 h of CCT. The primary endpoint is change from baseline in neurocognitive function as measured by the neurocognitive composite score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB), after 12 weeks of treatment. Secondary endpoints include change from baseline in overall MCCB score, Schizophrenia Cognition Rating Scale, Positive and Negative Syndrome Scale, and safety (adverse events [AEs]) and serious AEs. Primary and secondary endpoints will be analyzed using the Restricted Maximum Likelihood-based mixed model for repeated measures. Novel endpoints include the Balloon Effort Task to evaluate patients' motivation and the Virtual Reality Functional Capacity Assessment Tool to assess skills for daily functioning. This is one of the largest and longest trials to date to combine pharmacological therapy with CCT in patients with schizophrenia and will determine the benefit of combining BI 425809 pharmacotherapy with cognitive stimulation through self-administered CCT. This trial will further evaluate whether improvements in neurocognition translate into improved everyday functioning, whether self-administered CCT can be effectively implemented in a large multinational trial, and the role of motivation in neurocognitive and functional improvements. Registered on Clinicaltrials.gov on March 1, 2019 (NCT03859973)

Wide spectrum modulation by KP-544 in models relevant for neuronal survival

Reduced neurotrophic signalling has been proposed as a part of the pathophysiology behind neuronal death and dysfunction. The small molecule KP-544 was developed with the intention to enhance nerve growth factor signalling. To characterize the actions of KP-544 pharmacologically, we used four diverse models with relevance for neuronal function and survival. We found that 300-1000 nM KP-544 enhanced the neurite outgrowth in PC12 cells in response to a suboptimal concentration of nerve growth factor. KP-544 also protected the cerebellar granule cells from excitotoxicity apoptosis induced by the mitochondrial toxin methyl-phenyl-pyridinium, and modulated inflammation by inhibiting interleukin-6 production in primary astrocytes. Chronic treatment of rats with KP-544 prevented the hyper-responsiveness to amphetamine of animals treated with methylazoxymethanol acetate, a recently described neurodevelopmental model of schizophrenia.publishe

Alzheimer's Disease Assessment Scale-Cognitive subscale variants in mild cognitive impairment and mild Alzheimer's disease: change over time and the effect of enrichment strategies.

BackgroundDevelopment of new treatments for Alzheimer's disease (AD) has broadened into early interventions in individuals with modest cognitive impairment and a slow decline. The 11-item version of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) was originally developed to measure cognition in patients with mild to moderate AD. Attempts to improve its properties for early AD by removing items prone to ceiling and/or by adding cognitive measures known to be impaired early have yielded a number of ADAS-Cog variants. Using Alzheimer's Disease Neuroimaging Initiative data, we compared the performance of the 3-, 5-, 11- and 13-item ADAS-Cog variants in subjects with early AD. Given the interest in enrichment strategies, we also examined this aspect with a focus on cerebrospinal fluid (CSF) markers.MethodsSubjects with mild cognitive impairment (MCI) and mild AD with available ADAS-Cog 13 and CSF data were analysed. The decline over time was defined by change from baseline. Direct cross-comparison of the ADAS-Cog variants was performed using the signal-to-noise ratio (SNR), with higher values reflecting increased sensitivity to detect change over time.ResultsThe decline over time on any of the ADAS-Cog variants was minimal in subjects with MCI. Approximately half of subjects with MCI fulfilled enrichment criteria for positive AD pathology. The impact of enrichment was detectable but subtle in MCI. The annual decline in mild AD was more pronounced but still modest. More than 90 % of subjects with mild AD had positive AD pathology. SNRs were low in MCI but greater in mild AD. The numerically largest SNRs were seen for the ADAS-Cog 5 in MCI and for both the 5- and 13-item ADAS-Cog variants in mild AD, although associated confidence intervals were large.ConclusionsThe possible value of ADAS-Cog expansion or reduction is less than compelling, particularly in MCI. In mild AD, adding items known to be impaired at early stages seems to provide more benefit than removing items on which subjects score close to ceiling

Additional file 3: of Alzheimer’s Disease Assessment Scale–Cognitive subscale variants in mild cognitive impairment and mild Alzheimer’s disease: change over time and the effect of enrichment strategies

MMSE score up to 24 months for subjects with MCI and mild AD. Supplementary table providing details of MMSE score up to 24 months for subjects with MCI and mild AD. (DOCX 14 kb