Frontotemporal dementia and its subtypes: a genome-wide association study

SummaryBackground Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with {FTD} and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with {FTD} and 4308 controls), we did separate association analyses for each {FTD} subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and {FTD} overlapping with motor neuron disease FTD-MND), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, \{HLA\} locus (immune system), for rs9268877 (p=1·05 × 10−8; odds ratio=1·204 95% \{CI\} 1·11–1·30), rs9268856 (p=5·51 × 10−9; 0·809 0·76–0·86) and rs1980493 (p value=1·57 × 10−8, 0·775 0·69–0·86) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural \{FTD\} subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10−7; 0·814 0·71–0·92). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

Funder: QingLan Research Project of Jiangsu for Outstanding Young TeachersFunder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical UniversityFunder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical UniversityAbstract: We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

Un sistema para hallar oportunidades de mejora en la enseñanza basado en la percepción de los alumnos An analytical system to determine opportunities for teaching improvement based on student perceptions

Introducción: El objetivo de este trabajo es evaluar un sistema para hallar oportunidades de mejora en la enseñanza partiendo de una encuesta de satisfacción de los alumnos. Materiales y Métodos: Se administró una encuesta a alumnos de 15 materias durante 2003, dividida en 3 secciones: datos generales, cuantitativa (escala de Likert pentanivel) y cualitativa. Las preguntas se agruparon en 5 dominios: satisfacción general (SG), actividad docente (AD), contenidos (Co), evaluación (Ev) y estructura y confort (EC). Se realizó análisis factorial y determinación de la confiabilidad mediante coeficiente a de Cronbach. Las respuestas se evaluaron por materia y dominio, comparando niveles y significación de las diferencias con la prueba U de Mann-Whitney Resultados: Se obtuvieron 179 encuestas de 190 alumnos ( 94%). El coeficiente a de Cronbach fue 0,90. EC no correlacionó con los otros dominios. Las respuestas se ubicaron: 27.6 % en nivel 3, 12.8 % en los niveles inferiores y 57.7 % en los superiores, indicando determinación. En los niveles superiores SG obtuvo 62%, AD 64%, Co 60%, Ev 49% y EC 50%, las teóricas 80%, los prácticos 51%, la posibilidad de participar 61%, los contenidos 81% y los conocimientos de los docentes 58%. El 83% recomendaría cursar en esta unidad (pregunta control). La pregunta referida a los objetivos obtuvo la mayor indeterminación. Conclusiones: La encuesta demostró ser un instrumento de medición fiable. La comparación entre materias mediante análisis estadístico de las diferencias de percepción de los alumnos permitió determinar las oportunidades individuales de mejora para cada materia.<br>Rationale: The aim of the study was to evaluate a system to determine opportunities for teaching improvement, from a survey of student perceptions, and the level of student satisfaction regarding the quality of medical education. Methods: A survey divided into three main areas - general data, quantitative and qualitative sections - was carried out across a sample of students from 15 courses throughout 2003. For the quantitative section, a five-level scale was used. Questions were grouped in domains: general satisfaction (GS), teaching activity (TA), contents (Co), evaluation (Ev) and structure and comfort (SC). Factor analysis and reliability were calculated using Spearman and simple correlation matrix and Cronbach´s alpha-coefficient, respectively. Answers were evaluated individually, by domain and course, comparing levels and significance of the differences with the Mann-Whitney U test. Results: 179 surveys were obtained from 190 students. The Cronbach´s alpha-coefficient was 0.90. The answers indicated determination in choices, since only 28% of the surveyed students chose the indetermination level, while 13% chose the two lower levels, and 59% chose the higher ones. In the higher levels GS yielded 62%, TA 64%, Co 60%, Ev 49% and SC 50%, and bedside training 51%. Among surveyed students, 83% would recommend taking courses in the hospital in question (control question). The question referring to teaching objectives showed the highest level of indetermination. Conclusions: This student satisfaction survey proved to be a reliable tool for the evaluation of education. The analytical system comparing courses through different statistical tools mainly used in quality programs made it possible to identify specific improvement opportunities for each course

Un sistema para hallar oportunidades de mejora en la enseñanza basado en la percepción de los alumnos

Introducción: El objetivo de este trabajo es evaluar un sistema para hallar oportunidades de mejora en la enseñanza partiendo de una encuesta de satisfacción de los alumnos. Materiales y Métodos: Se administró una encuesta a alumnos de 15 materias durante 2003, dividida en 3 secciones: datos generales, cuantitativa (escala de Likert pentanivel) y cualitativa. Las preguntas se agruparon en 5 dominios: satisfacción general (SG), actividad docente (AD), contenidos (Co), evaluación (Ev) y estructura y confort (EC). Se realizó análisis factorial y determinación de la confiabilidad mediante coeficiente a de Cronbach. Las respuestas se evaluaron por materia y dominio, comparando niveles y significación de las diferencias con la prueba U de Mann-Whitney Resultados: Se obtuvieron 179 encuestas de 190 alumnos ( 94%). El coeficiente a de Cronbach fue 0,90. EC no correlacionó con los otros dominios. Las respuestas se ubicaron: 27.6 % en nivel 3, 12.8 % en los niveles inferiores y 57.7 % en los superiores, indicando determinación. En los niveles superiores SG obtuvo 62%, AD 64%, Co 60%, Ev 49% y EC 50%, las teóricas 80%, los prácticos 51%, la posibilidad de participar 61%, los contenidos 81% y los conocimientos de los docentes 58%. El 83% recomendaría cursar en esta unidad (pregunta control). La pregunta referida a los objetivos obtuvo la mayor indeterminación. Conclusiones: La encuesta demostró ser un instrumento de medición fiable. La comparación entre materias mediante análisis estadístico de las diferencias de percepción de los alumnos permitió determinar las oportunidades individuales de mejora para cada materia

Metabolic aspects and complications of hyperuricemia

The results of epidemiological observations have led to a revaluation of uric acid role in different metabolic, cardiovascular and renal illnesses. The role of hyperuricemia as an independent cardiovascular risk factor is difficult to evaluate even in multivariate models analysis, since there are inconclusive and weak results in most studies. This difficulty is observed due to the strong association of uric acid with other classic cardiovascular risk factors which do not allow its distinction as an independently risk factor. For many years it was considered a biologically inert substance, but later, it was found that it has many biological properties which could be beneficial or harmful for human beings. Nowadays there is a controversial discussion about its role, whether it is protective for having anti-oxidant properties or harmful due to its pro-oxidants in the atherosclerotic plaque and in adipose tissue which could determine that it is not only a risk marker, but also a causal factor for metabolic illnesses as diabetes mellitus, metabolic syndrome, cardiovascular and/or renal illnesses. In this consensus we have updated these concepts trying to clarify the mentioned role, so that in the future, regulations could be introduced, which are not established so far, in order to decide whether hyperuricemia must be treated, in which cases, which cut-off levels must be used and which should be the therapeutic objectives in each circumstance

Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes

BACKGROUND: This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. METHODS: In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level. RESULTS: The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons). CONCLUSIONS: The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.)