The first genome-wide association study in the Argentinian and Chilean populations identifies shared genetics with Europeans in Alzheimer's disease.

INTRODUCTION: Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities. METHODS: We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta-analysis and tested their genetic risk score (GRS) performance in this admixed population. RESULTS: We detected apolipoprotein E ε4 as the single genome-wide significant signal (odds ratio  = 2.93 [2.37-3.63], P = 2.6 × 10-23 ). The meta-analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD-GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose. DISCUSSION: We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations. HIGHLIGHTS: This is the first genome-wide association study on Alzheimer's disease (AD) in a population sample from Argentina and Chile. Trans-ethnic meta-analysis reveals four new loci involving lysosomal function in AD. This is the first independent replication for TREM2L, IGH-gene-cluster, and ADAM17 loci. A genetic risk score (GRS) developed in Europeans performed well in this population. The higher the Native American ancestry the lower the GRS values.

Analysis of modular gene co-expression networks reveals molecular pathways underlying Alzheimer's disease and progressive supranuclear palsy.

A comprehensive understanding of the pathological mechanisms involved at different stages of neurodegenerative diseases is key for the advance of preventive and disease-modifying treatments. Gene expression alterations in the diseased brain is a potential source of information about biological processes affected by pathology. In this work, we performed a systematic comparison of gene expression alterations in the brains of human patients diagnosed with Alzheimer's disease (AD) or Progressive Supranuclear Palsy (PSP) and animal models of amyloidopathy and tauopathy. Using a systems biology approach to uncover biological processes associated with gene expression alterations, we could pinpoint processes more strongly associated with tauopathy/PSP and amyloidopathy/AD. We show that gene expression alterations related to immune-inflammatory responses preponderate in younger, whereas those associated to synaptic transmission are mainly observed in older AD patients. In PSP, however, changes associated with immune-inflammatory responses and synaptic transmission overlap. These two different patterns observed in AD and PSP brains are fairly recapitulated in animal models of amyloidopathy and tauopathy, respectively. Moreover, in AD, but not PSP or animal models, gene expression alterations related to RNA splicing are highly prevalent, whereas those associated with myelination are enriched both in AD and PSP, but not in animal models. Finally, we identify 12 AD and 4 PSP genetic risk factors in cell-type specific co-expression modules, thus contributing to unveil the possible role of these genes to pathogenesis. Altogether, this work contributes to unravel the potential biological processes affected by amyloid versus tau pathology and how they could contribute to the pathogenesis of AD and PSP.

Differential transcript usage unravels gene expression alterations in Alzheimer's disease human brains.

Alzheimer's disease (AD) is the leading cause of dementia in aging individuals. Yet, the pathophysiological processes involved in AD onset and progression are still poorly understood. Among numerous strategies, a comprehensive overview of gene expression alterations in the diseased brain could contribute for a better understanding of the AD pathology. In this work, we probed the differential expression of genes in different brain regions of healthy and AD adult subjects using data from three large transcriptomic studies: Mayo Clinic, Mount Sinai Brain Bank (MSBB), and ROSMAP. Using a combination of differential expression of gene and isoform switch analyses, we provide a detailed landscape of gene expression alterations in the temporal and frontal lobes, harboring brain areas affected at early and late stages of the AD pathology, respectively. Next, we took advantage of an indirect approach to assign the complex gene expression changes revealed in bulk RNAseq to individual cell types/subtypes of the adult brain. This strategy allowed us to identify previously overlooked gene expression changes in the brain of AD patients. Among these alterations, we show isoform switches in the AD causal gene amyloid-beta precursor protein (APP) and the risk gene bridging integrator 1 (BIN1), which could have important functional consequences in neuronal cells. Altogether, our work proposes a novel integrative strategy to analyze RNAseq data in AD and other neurodegenerative diseases based on both gene/transcript expression and regional/cell-type specificities.

Is patient-prosthesis mismatch a perioperative predictor of long-term mortality after aortic valve replacement?

OBJECTIVES: To determine the perioperative predictors of long-term mortality after aortic valve replacement (AVR). The authors hypothesized that perioperative variables are more important predictors of mortality than patient-prosthesis mismatch (PPM). DESIGN: A retrospective study of prospectively collected data. SETTING: A tertiary care university hospital. PARTICIPANTS: One-hundred-ninety-nine adult patients who underwent AVR. INTERVENTIONS: After Research and Ethics Committee approval, the authors studied consecutive adult patients that underwent AVR in 1999 from the time of procedure to 5 years later. Demographic data, hemodynamic profile obtained after the induction of anesthesia, and perioperative data were analyzed. Primary endpoint was 5-year survival. MEASUREMENTS AND MAIN RESULTS: Actuarial survival rate was 95.98%, 91.46%, and 81.91% at 30 days, 1 year, and 5 years, respectively. On univariate analysis, patients who died were significantly older (p<0.0001), had pulmonary hypertension (PHT), longer cardiopulmonary bypass (CPB) (p = 0.0001) and cross-clamping duration (p = 0.003), more frequent return to CPB (p = 0.036), or the use of an intra-aortic balloon pump to wean from CPB (p = 0.015). PPM was not related to 5-year mortality (p = 0.0649). Using Cox survival analysis, the only independent risk factors related to 5-year mortality after AVR were PHT using the mean arterial pressure-to-mean pulmonary artery pressure ratio (HR: 1.39, 95% CI 1.01-1.92, p = 0.0413) and the presence of complex separation from CPB (HR: 2.66, 95% CI 1.08-6.50, p = 0.0324). CONCLUSIONS: In patients undergoing AVR, 5-year survival was mostly related to the severity of PHT and intraoperative factors, mainly complexity of weaning from CPB.

As principais evoluções dos comportamentos alimentares: o caso da França / Main evolutions in human food practices: French example

Durante a segunda metade do século XX, o desenvolvimento econômico e as evoluções dos modos de vida ocasionaram modificações importantes nos comportamentos alimentares. Tais evoluções foram particularmente analisadas para o caso da França. Confrontadas a um contexto de abundância, as populações adotaram uma conduta alimentar mais energética. Tal conduta resume-se, sobretudo, em um alto consumo de produtos de origem animal. Porém, entre grupos de indivíduos ricos e após um período de saturação, a atração pelo consumo desmedido tal produto, tornou-se menos intensiva. Novas preocupações orientadas à saúde e às formas de mantê-la em bom estado foram despertadas. O aumento do número de mulheres salariadas e o desenvolvimento das atividades de lazer alteraram a gestão do tempo empregado à alimentação. Na busca pelo ganho de tempo, os consumidores passaram a procurar por alimentos prontos para serem consumidos e a realizarem suas refeições fora do domicílio. As culturas alimentares não evoluem tão rapidamente como as transformações ocorridas em todo o sistema de oferta alimentar, com isso afirma-se que a industrialização, a internacionalização e as inovações de toda a cadeia agroalimentar geram ansiedades no consumidor. Todas essas transformações e tendências, que são observadas em países ricos, podem ser percebidas quando os comportamentos alimentares de populações ricas de países em desenvolvimento são analisados.