Aims The aim of this 13 week, randomized, parallel-group study was to evaluate the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of low-dose intermittent oral methotrexate (LDMTX) in patients with psoriasis. Methods Twenty-four psoriatic patients (15 male and 9 female, aged 31-73 years) were given weekly doses of MTX doses of either 7.5 mg or 15 mg with each dose divided into three aliquots given at 12 h intervals. The pharmacokinetics of MTX were evaluated at weeks 1 and 13. Skin impairment was assessed using the PASIscoring system (The Psoriasis Area and Severity Index) at baseline and at weeks 5, 9 and 13 of therapy. Haematological and biochemistry tests were also performed at these times. Results The comparison of the areas under the plasma concentration-time curve (AUC MTX ) after the first and third weekly doses showed that the extent of MTX accumulation in plasma was only about 12%. Two-way ANOVA (factors: subject and the week of therapy) on the log-transformed AUC MTX showed no effect of the week of therapy (P>0.8). Moreover, the intraindividual variability in the AUC MTX was at least 4-fold less than the interindividual variability (F-test; P<0.01). The steady-state total plasma clearance of MTX ranged from 5.0 to 18.2 l h x1 and was proportional to the renal clearance (r 2 =0.45, P<0.001) which accounted for 65t20% of the former. The renal clearance of 7-OHMTX was approximately 4-8% of that of the parent compound. PK/PD analysis revealed a highly significant inverse relationship between PASI (expressed as a percent of the initial value) and a steady-state AUC MTX (r s =x0.65, P<0.001). Seventeen subjects (8 from the 7.5 mg group and 9 from the 15 mg group MTX, P=0.67) achieved a greater than 50% decrease in the initial PASI score and were classified as responders. Thirteen of 14 subjects with AUC(24,36 h)i700 nmol l x1 h responded to pharmacotherapy. Conversely, only 4 out of 10 subjects with AUC(24,36 h)<700 nmol l x1 h were responders (P<0.01, Fisher's exact test).Conclusions A strong correlation was observed between the pharmacokinetics (AUC MTX at the steady state) and antipsoriatic effect (PASI-score) of LDMTX. The considerable interindividual variability and low intraindividual variability in MTX pharmacokinetics support a role for therapeutic monitoring and dose individualization at the start of pharmacotherapy. The results of this study suggest that a steady state AUC MTX values of 700 nmol l x1 h and higher are associated with a significantly better success rate of antipsoriatic therapy than lower values.

Alzheimer's disease (AD) is characterized by high heterogeneity in disease manifestation, progression and risk factors. High phenotypic variability is currently regarded as one of the largest hurdles in early diagnosis and in the design of clinical trials; there is therefore great interest in identifying factors driving variability that can be used for patient stratification. In addition to genetic and lifestyle factors, the individual's sex and gender are emerging as crucial drivers of phenotypic variability. Evidence exists on sex and gender differences in the rate of cognitive deterioration and brain atrophy, and in the effect of risk factors as well as in the patterns of diagnostic biomarkers. Such evidence might be of high relevance and requires attention in clinical practice and clinical trials. However, sex and gender differences are currently seldom appreciated; importantly, consideration of sex and gender differences is not currently a focus in the design and analysis of clinical trials for AD. The objective of this position paper is (i) to provide an overview of known sex and gender differences that might have implications for clinical practice, (ii) to identify the most important knowledge gaps in the field (with a special regard to clinical trials) and (iii) to provide conclusions for future studies. This scientific statement is endorsed by the European Academy of Neurology.

The relationship between MTX pharmacokinetics (AUC or erythrocytic MTX) and pharmacodynamics (PASI score) may exist. It is likely that the efficacy of psoriasis therapy with MTX could be improved by adjusting the dose according to plasma concentrations obtained after the first MTX administration.

IMPORTANCE Women represent two-thirds of patients with Alzheimer disease (AD), and sex differences might affect results of randomized clinical trials (RCTs). However, little information exists on differences in sex as reported in RCTs for AD.OBJECTIVE To assess the ratio of females to males and the reporting of sex-stratified data in large pharmaceutical RCTs for AD.DATA SOURCES A search for pharmaceutical RCTs for AD was conducted on September 4, 2019, using ClinicalTrials.gov with the key word Alzheimer disease, and articles related to those trials were

Digital biomarkers are defined as objective, quantifiable physiological and behavioral data that are collected and measured by means of digital devices. Their use has revolutionized clinical research by enabling high-frequency, longitudinal, and sensitive measurements. In the field of neurodegenerative diseases, an example of a digital biomarker-based technology is instrumental activities of daily living (iADL) digital medical application, a predictive biomarker of conversion from mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) to dementia due to AD in individuals aged 55 + . Digital biomarkers show promise to transform clinical practice. Nevertheless, their use may be affected by variables such as demographics, genetics, and phenotype. Among these factors, sex is particularly important in Alzheimer’s, where men and women present with different symptoms and progression patterns that impact diagnosis. In this study, we explore sex differences in Altoida’s digital medical application in a sample of 568 subjects consisting of a clinical dataset (MCI and dementia due to AD) and a healthy population. We found that a biological sex-classifier, built on digital biomarker features captured using Altoida’s application, achieved a 75% ROC-AUC (receiver operating characteristic — area under curve) performance in predicting biological sex in healthy individuals, indicating significant differences in neurocognitive performance signatures between males and females. The performance dropped when we applied this classifier to more advanced stages on the AD continuum, including MCI and dementia, suggesting that sex differences might be disease-stage dependent. Our results indicate that neurocognitive performance signatures built on data from digital biomarker features are different between men and women. These results stress the need to integrate traditional approaches to dementia research with digital biomarker technologies and personalized medicine perspectives to achieve more precise predictive diagnostics, targeted prevention, and customized treatment of cognitive decline.

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Background: Identifying modifiable risk factors for cognitive decline can reduce burden of dementia. Objective: We examined whether homocysteine was associated with memory performance, mediated by entorhinal volume, hippocampal volume, total gray matter volume, or white matter lesions, and moderated by APOE ɛ4 allele, B vitamins, creatinine, total cholesterol, or triglycerides. Methods: All 204 members of the Czech Brain Aging Study with subjective cognitive decline (SCD; n = 60) or amnestic mild cognitive impairment (aMCI; n = 144) who had valid data were included. Linear regression was used, followed by conditional process modeling to examine mediation and moderation. Results: Controlling for age, sex, and education, higher homocysteine was related to poorer memory performance overall (b = –0.03, SE = 0.01, p = 0.017) and in participants with SCD (b = –0.06, SE = 0.03, p = 0.029), but less so in aMCI (b = –0.03, SE = 0.02, p = 0.074); though sensitivity analyses revealed a significant association when sample was reduced to aMCI patients with more complete cognitive data (who were also better functioning; b = –0.04, SE = 0.02, p = 0.022). Results were unchanged in fully adjusted models. Neither mediation by markers of brain integrity nor moderation by APOE ɛ4, B vitamins, creatinine, and cardiovascular factors were significant. Memory sub-analyses revealed that results for SCD were likely driven by non-verbal memory. The homocysteine-memory relationship was significant when hippocampal volume was below the median (b = –0.04, SE = 0.02, p = 0.046), but not at/above the median (p = 0.247). Conclusion: Higher homocysteine levels may adversely influence memory performance, particularly in those without cognitive impairment. Results appear to be independent of brain health, suggesting that homocysteine may represent a good target for intervention.

BackgroundDementia syndrome is one of the most devastating conditions in older adults. As treatments to stop neurodegeneration become available, accurate and timely diagnosis will increase in importance. One issue is that cognitive performance sometimes does not match the corresponding level of neuropathology, affecting diagnostic accuracy. Cognitive reserve (CR), which can preserve cognitive function despite underlying neuropathology, explains at least some variability in cognitive performance. We examined the influence of CR proxies (education and occupational position) on the relationship between hippocampal or total gray matter volume and cognition.MethodsWe used data from the Czech Brain Aging Study. Participants were clinically confirmed to be without dementia (n = 457, including subjective cognitive decline and amnestic mild cognitive impairment) or with dementia syndrome (n = 113).ResultsFor participants without dementia, higher education magnified the associations between (a) hippocampal volume and executive control (b = 0.09, p = 0.033), (b) total gray matter volume and language (b = 0.12, p &lt; 0.001), and (c) total gray matter volume and memory (b = 0.08, p = 0.018). Similarly, higher occupational position magnified the association between total gray matter volume and (a) attention/working memory (b = 0.09, p = 0.009), (b) language (b = 0.13, p = 0.002), and (c) memory (b = 0.10, p = 0.013). For participants with dementia, the associations between hippocampal (b = –0.26, p = 0.024) and total gray matter (b = –0.28, p = 0.024) volume and visuospatial skills decreased in magnitude with higher education.ConclusionWe found that the association between brain volume and cognitive performance varies based on CR, with greater CR related to a stronger link between brain volume and cognition before, and a weaker link after, dementia diagnosis.