Genetic and Epidemiological Factors in Cognitive Impairment and Dementia

Alzheimer's disease (AD) is a multifactorial and progressive form of dementia with a senile onset that affects specific areas of the brain. Recent genome wide association (GWA) studies reported that the allele 4 of apolipoprotein E (APOE) and single nucleotide polymorphisms (SNPs) in other genes that regulate inflammatory pathways, such as the gene coding for clusterin (CLU), are associated with AD. The hypothesis is that all of these genes may be involved in different mechanisms mediated by herpes viruses and we argued that the concomitant presence of SNPs in these genes in the same individual may represent a genetic signature predisposing to AD. \ud The present study is focused on SNPs in CLU, interferon (IFN)-λ3/IL-28B, Med23 and the transcription factor IRF7, which are genes involved in antiviral responses and their association with AD and cognitive deterioration. Moreover, the effects of IL-28B, Med23 and IRF7 genotypes upon the presence of epstein-barr virus (EBV) and human herpes virus 6 (HHV-6) in the peripheral blood of AD and controls (CTR) have been also investigated. The activation of the innate immune system has a key role as a promoting factor for AD and in AD patients activated microglia release cytokines that induce neuro-inflammation. In this thesis gene variants and different expression of genes involved in the innate immune response in case-control population studies and in a mouse model of AD were investigated. Results from these experiments suggest that individuals with a particular genetic makeup in defensive mechanisms of the innate immunity may be at risk of defective immune responses. Impaired immunity against persistent viruses such as those of herpes family, might result in chronic and inappropriate activation of microglia, abnormal Aβ production and increased amyloid deposition. Cycles of virus latency and infections may therefore contribute to neurodegeneration associated with AD in genetically predisposed elderly

Withdrawal Syndrome Following Discontinuation of 28 Antidepressants: Pharmacovigilance Analysis of 31,688 Reports from the WHO Spontaneous Reporting Database

Introduction: Evidence is lacking on withdrawal syndrome related to individual antidepressants and relevant risk factors for severe reactions. Objective: To ascertain whether antidepressants are associated with an increased reporting of withdrawal syndrome as compared with other medications, and to investigate risk factors for severe reactions. Methods: This is a case/non-case pharmacovigilance study, based on the VigiBase®, the WHO global database of individual case safety reports of suspected adverse drug reactions. We performed a disproportionality analysis of reports of antidepressant-related withdrawal syndrome (calculating reporting odds ratio [ROR] and Bayesian information component [IC]). We compared antidepressants to all other drugs, to buprenorphine (positive control), and to each other within each class of antidepressants (selective serotonin reuptake inhibitors [SSRIs], tricyclics and other antidepressants). Antidepressants with significant disproportionate reporting were ranked in terms of clinical priority. Serious versus non-serious reactions were compared. Results: There were 31,688 reports of antidepressant-related withdrawal syndrome were found. A disproportionate reporting was detected for 23 antidepressants. The estimated ROR for antidepressants altogether, compared to all other drugs, was 14.26 (95% CI 14.08-14.45), 17.01 for other antidepressants (95% CI 16.73-17.29), 13.65 for SSRIs (95% CI 13.41-13.90) and 2.8 for tricyclics (95% CI 2.59-3.02). Based on clinical priority ranking, the strongest disproportionate reporting was found for paroxetine, duloxetine, venlafaxine and desvenlafaxine, being comparable to buprenorphine. Withdrawal syndrome was reported as severe more often in males, adolescents, persons in polypharmacy, and with a longer antidepressant treatment duration (p < 0.05). Conclusions: Antidepressants are associated with an increased reporting of withdrawal syndrome compared with other drug classes. When prescribing and discontinuing antidepressants, clinicians should be aware of the potentially different proclivity of withdrawal syndrome across individual antidepressants, and the liability to experience more severe withdrawal symptoms in relation to specific patient characteristics

New insight into antiphospholipid syndrome: antibodies to \u3b22glycoprotein I-domain 5 fail to induce thrombi in rats

Clinical studies have reported different diagnostic/predictive values of antibodies to domain 1 or 4/5 of \u3b22glycoproteinI in terms of risk of thrombosis and pregnancy complications in patients with antiphospholipid syndrome. To obtain direct evidence for the pathogenic role of anti-domain 1 or anti-domain 4/5 antibodies, we analysed the in vivo pro-coagulant effect of two groups of 5 serum IgG each reacting selectively with domain 1 or domain 5 in LPS-treated rats. Antibody-induced thrombus formation in mesenteric vessels was followed by intravital microscopy and vascular deposition of \u3b22glycoproteinI, human IgG and C3 was analyzed by immunofluorescence. Five serum IgG with undetectable anti-\u3b22glycoproteinI antibodies served as controls. All the anti-domain 1 positive IgG exhibited potent pro-coagulant activity while the anti-domain 5 positive and the negative control IgG failed to promote blood clot and vessels occlusion. A stronger granular deposit of IgG/C3 was found on the mesenteric endothelium of rats treated with anti-domain 1 antibodies, as opposed to a mild linear IgG staining and absence of C3 observed in rats receiving anti-domain 5 antibodies. Purified anti-domain 5 IgG, unlike anti-domain 1 IgG, did not recognize cardiolipin-bound \u3b22glycoprotein I while able to interact with fluid-phase \u3b22glycoproteinI. These findings may explain the failure of anti-domain 5 antibodies to exhibit in vivo thrombogenic effect and the interaction of these antibodies with circulating \u3b22glycoproteinI suggest their potential competitive role with the pro-coagulant activity of anti-domain 1 antibodies. These data aim at better defining really at risk patients for more appropriate treatments to avoid recurrences and disability

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

The 21st century epidemic: Infections as inductors of neuro-degeneration associated with Alzheimer's Disease

Alzheimer's disease (AD) is a complex disease resulting in neurodegeneration and cognitive impairment. Investigations on environmental factors implicated in AD are scarce and the etiology of the disease remains up to now obscure. The disease's pathogenesis may be multi-factorial and different etiological factors may converge during aging and induce an activation of brain microglia and macrophages. This microglia priming will result in chronic neuro-inflammation under chronic antigen activation. Infective agents may prime and drive iper-activation of microglia and be partially responsible of the induction of brain inflammation and decline of cognitive performances. Age-associated immune dis-functions induced by chronic sub-clinical infections appear to substantially contribute to the appearance of neuro-inflammation in the elderly. Individual predisposition to less efficient immune responses is another relevant factor contributing to impaired regulation of inflammatory responses and accelerated cognitive decline. Life-long virus infection may play a pivotal role in activating peripheral and central inflammatory responses and in turn contributing to increased cognitive impairment in preclinical and clinical AD

Variants in antiviral genes are risk factors for cognitive decline and dementia

A gene association study of factors regulating antiviral response such as interferon (IFN)-\u3bb3, also known as IL-28B, mediator complex (Med) 23, and interferon regulatory factor (IRF) 7 with cognitive deterioration and Alzheimer's disease (AD) was performed. Differences in the TT genotype distribution of IL-28B single nucleotide polymorphism (SNP) between AD patients and controls were found. The GG genotype of Med23 gene appeared to influence the progression of the disease, being more frequent in the APOE \u3b54 negative elderly that developed AD during the five year follow-up. Leukocyte positivity for Epstein Barr virus (EBV) and human herpes virus (HHV)-6 DNA was analyzed. Med23 GG genotype correlated with the positivity to HHV-6 DNA. EBV and HHV-6 plasma IgG levels were also investigated and EBV IgG levels were increased in AD with the IRF7 GG genotype. A differential genetic background in genes regulating anti-virus responses was associated with an increased risk of cognitive decline and AD. EBV and HHV-6 appeared to be risk factors for AD in genetically susceptible elderly

Antipsychotic-Related DRESS Syndrome: Analysis of Individual Case Safety Reports of the WHO Pharmacovigilance Database.

INTRODUCTION Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is gaining attention in pharmacovigilance, but its association with antipsychotics, other than clozapine, is still unclear. METHODS We conducted a case/non-case study with disproportionality analysis based on the World Health Organization (WHO) global spontaneous reporting database, VigiBase®. We analyzed individual case safety reports of DRESS syndrome related to antipsychotics compared to (1) all other medications in VigiBase®, (2) carbamazepine (a known positive control), and (3) within classes (typical/atypical) of antipsychotics. We calculated reporting odds ratio (ROR) and Bayesian information component (IC), with 95% confidence intervals (CIs). Disproportionate reporting was prioritized based on clinical importance, according to predefined criteria. Additionally, we compared characteristics of patients reporting with serious/non-serious reactions. RESULTS A total of 1534 reports describing DRESS syndrome for 19 antipsychotics were identified. The ROR for antipsychotics as a class as compared to all other medications was 1.0 (95% CI 0.9-1.1). We found disproportionate reporting for clozapine (ROR 2.3, 95% CI 2.1-2.5; IC 1.2, 95% CI 1.1-1.3), cyamemazine (ROR 2.3, 95% CI 1.5-3.5; IC 1.2, 95% CI 0.5-1.7), and chlorpromazine (ROR 1.5, 95% CI 1.1-2.1; IC 0.6, 95% CI 0.1-1.0). We found 35.7% of cases with co-reported anticonvulsants, and 25% with multiple concurrent antipsychotics in serious compared to 8.6% in non-serious cases (p = 0.03). Fatal cases were 164 (10.7%). CONCLUSIONS Apart from the expected association with clozapine, chlorpromazine and cyamemazine (sharing an aromatic heteropolycyclic molecular structure) emerged with a higher-than-expected reporting of DRESS. Better knowledge of the antipsychotic-related DRESS syndrome should increase clinicians' awareness leading to safer prescribing of antipsychotics

Peripheral leukocyte expression of the potential biomarker proteins Bdnf, Sirt1, and Psen1 is not regulated by promoter methylation in Alzheimer's disease patients

The identification of Alzheimer's disease (AD) biomarkers is crucial to support drug discovery. Within putative biomarkers, peripheral Bdnf levels correlate with cognitive decline and AD, although conflicting findings are reported. Sirtuin 1 (Sirt1) serum levels are lower in AD patients and Presenilin 1 (Psen1) is expressed by blood cells. DNA methylation is altered in AD patients, suggesting that epigenetic mechanisms play a role in AD pathophysiology. The objective of this study was to investigate promoter methylation levels of potential biomarkers in AD cases and controls. Peripheral blood DNA methylation levels were analysed by methylation-specific primer real-time PCR. Bdnf promoter methylation levels did not differ between AD patients and controls. Similarly, Sirt1 promoter revealed minimal levels of methylation which did not display significant differences between groups. No significant difference was revealed between AD patients and controls also in Psen1 methylation, showing a large variability of values among subjects. Although peripheral Bdnf expression is associated with differential promoter methylation in psychiatric and neurological disorders, our results suggest that different mechanisms take place in AD. The finding that the control of Sirt1 protein levels in blood is not exerted through the repression of mRNA expression by promoter hypermethylation is in agreement with previous data. In contrast, other studies reported that Psen1 methylation may be increased or decreased in AD patients, suggesting that additional studies are required. In conclusion, this study shows that peripheral levels of the potential AD biomarker proteins Bdnf, Sirt1, and Psen1 are not regulated by different promoter methylation

The challenges of lupus anticoagulants

The term "lupus anticoagulant" (LA) refers to a heterogeneous group of immunoglobulins behaving as acquired in vitro inhibitors of coagulation. These antibodies, namely anti-\u3b22GPI and anti-prothrombin antibodies, induce the in vitro elongation of clotting time interfering with phospholipid-dependent coagulation cofactors. Positive LA is associated with thrombosis and pregnancy complications, providing one of the three laboratory criteria for the classification of the anti-phospholipid syndrome. LA is the strongest predictor of clinical events, especially when associated with other anti-phospholipid antibodies. Much more controversial is the risk conveyed by isolated and weak LA. LA detection is technically laborious, envisaging screening, mixing and confirming tests. Hopefully critical issues in LA detection, such as the interference of anticoagulants, will be overcome, in the next future