Alzheimer’s disease related transcriptional sex differences in myeloid cells

Sex differences have been identified in many diseases associated with dysregulated immune responses, including Alzheimer’s disease (AD), for which approximately two-thirds of patients are women. An accumulating body of research indicates that microglia may play a causal role in the pathogenesis of this disease. We hypothesised that sex differences in the transcriptome of human myeloid cells may contribute to the sex difference observed in AD prevalence. To explore this, we assessed bulk and single-nuclear RNA sequencing data sets generated from four human derived myeloid cell populations: post-mortem microglial nuclei, peripheral monocytes, monocyte-derived macrophages (MDMs) and induced pluripotent stem cell derived microglial-like cells (MGLs). We found that expression of AD risk genes, gene signatures associated with the inflammatory response in AD, and genes related to proinflammatory immune responses were enriched in microglial nuclei isolated from aged female donors without ante-mortem neurological disease, relative to those from males. In addition, these inflammation-associated gene sets were found to be enriched in peripheral monocytes isolated from postmenopausal women and in MDMs obtained from premenopausal individuals relative to age-matched males. Expression of these gene sets did not differ in MDMs derived from women whose blood was sampled across the menstrual cycle or in MGLs cultured with 17β-oestradiol. This suggests that the observed gene set enrichments in myeloid cells from women were not being driven by acute hormonal influences. Together, these data support the hypothesis that the increased prevalence of AD in women may be partly explained by a myeloid cell phenotype biased towards expression of biological processes relevant to AD

Stress Management in Women with Hashimoto’s thyroiditis: A Randomized Controlled Trial

Aim: Stress has been implicated in the pathogenesis of Hashimoto's thyroiditis (HT), nevertheless evidence is scarce regarding the effect of stress management on individuals suffering from HT. The purpose of this study was to evaluate the impact of an 8-week stress management intervention on the anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG) antibodies as well as thyroid-stimulating hormone (TSH) levels of women with HT. Secondary endpoints included the effect on the patients’ lifestyle, body mass index (BMI), depression, anxiety and stress. Methods: This was a two-arm parallel group (stress management intervention vs. standard care groups) randomized controlled study. Adult women with Hashimoto's thyroiditis, completed questionnaires on stress, anxiety, depression and lifestyle, at the beginning of the programme and 8 weeks later. Laboratory thyroid function tests (anti-TPO, anti-TG antibodies and TSH) were also measured at baseline and at the end of the study. Results: A total of 60 women with HT, aged 25-76 years, participated in the study (30 patients in each group). After eight weeks, patients in the intervention group demonstrated statistically significant beneficial decrements in the rate change of anti-TG titers and the levels of stress, depression and anxiety as well as better lifestyle scores, compared to the control group.   

A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer's disease

Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer's disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased β-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD.</p

Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases

Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state.Published versionThe authors thank the UK MS Society for financial support (grant number: C008-16.1). DRO was funded by an MRC Clinician Scientist Award (MR/N008219/1). P.M.M. acknowledges generous support from Edmond J Safra Foundation and Lily Safra, the NIHR Senior Investigator programme and the UK Dementia Research Institute which receives its funding from DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK. P.M.M. and D.R.O. thank the Imperial College Healthcare Trust-NIHR Biomedical Research Centre for infrastructure support and the Medical Research Council for support of TSPO studies (MR/N016343/1). E.A. was supported by the ALS Stichting (grant “The Dutch ALS Tissue Bank”). P.M. and B.B.T. are funded by the Swiss National Science Foundation (projects 320030_184713 and 310030_212322, respectively). S.T. was supported by an “Early Postdoc.Mobility” scholarship (P2GEP3_191446) from the Swiss National Science Foundation, a “Clinical Medicine Plus” scholarship from the Prof Dr. Max Cloëtta Foundation (Zurich, Switzerland), from the Jean et Madeleine Vachoux Foundation (Geneva, Switzerland) and from the University Hospitals of Geneva. This work was funded by NIH grants U01AG061356 (De Jager/Bennett), RF1AG057473 (De Jager/Bennett), and U01AG046152 (De Jager/Bennett) as part of the AMP-AD consortium, as well as NIH grants R01AG066831 (Menon) and U01AG072572 (De Jager/St George-Hyslop)

A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease

Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer’s disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased β-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD

Addictions [Addictions]

This year, the actuality for addictions in this edition addresses four points. The disease model of addiction is criticized by the cognitive neurosciences which need to consider the agentivity of the persons. Regarding the societal actuality, clinical pharmacology review of cannabidiol presents an update on legal cannabis. The suicidality of excessive gamblers may be prevented specifically. Addiction and first psychotic episodes need an integrated care

Comparing efficacy and safety in catheter ablation strategies for atrial fibrillation: protocol of a network meta-analysis of randomised controlled trials

INTRODUCTION: Atrial fibrillation (AF) is the most common sustained arrhythmia. Catheter ablation (CA) of AF is an increasingly offered therapeutic approach, primary to relieve AF-related symptoms. Despite the development of new ablation approaches, there is no consensus regarding the most efficient ablation strategy. The objective of this network meta-analysis (NMA) is to compare the efficacy and safety of all different CA approaches for the treatment of patients with paroxysmal (PAF) and non-PAF (non-PAF). METHODS AND ANALYSIS: We will perform a systematic search to identify randomised controlled trials of different CA approaches for the treatment of PAF and non-PAF, through the final search date of 1 March 2020. Information sources will include major bibliographic databases (MEDLINE, Web of Science and CENTRAL) and clinical trial registries. Our primary outcomes will be the efficacy (recurrence-free survival) and safety of different CA approaches for the treatment of AF. Secondary outcomes will be all-cause mortality and procedural time. An NMA will be performed to determine the relative effects of different catheter ablation approaches (such as pulmonary vein isolation alone or in combination with ablation lines, ablation of complex fractionated atrial electrograms, etc). In PAF, a separate analysis will be performed including different energy sources (such as radiofrequency, cryogenic and laser energy). Risk of bias assessment and sensitivity analyses will be conducted to assess the robustness of the findings to potential bias. ETHICS AND DISSEMINATION: No ethical approval will be needed because data are collected from previous studies. The results will be presented through peer-review journals and conference presentation. PROSPERO REGISTRATION NUMBER: CRD42020169494. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ