Hippocampal subfield volumetry: differential pattern of atrophy in different forms of genetic frontotemporal dementia

BACKGROUND: Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder, with a strong genetic component. Previous research has shown that medial temporal lobe atrophy is a common feature of FTD. However, no study has so far investigated the differential vulnerability of the hippocampal subfields in FTD. OBJECTIVES: We aimed to investigate hippocampal subfield volumes in genetic FTD. METHODS: We in6/2/2018vestigated hippocampal subfield volumes in a cohort of 75 patients with genetic FTD (age: mean (standard deviation) 59.3 (7.7) years; disease duration: 5.1(3.4) years; 29 with MAPT, 28 with C9orf72, and 18 with GRN mutations) compared with 97 age-matched controls (age: 62.1 (11.1) years). We performed a segmentation of their volumetric T1-weighted MRI scans to extract hippocampal subfields volumes. Left and right volumes were summed and corrected for total intracranial volumes. RESULTS: All three groups had smaller hippocampi than controls. The MAPT group had the most atrophic hippocampi, with the subfields showing the largest difference from controls being CA1-4 (24–27%, p < 0.0005). For C9orf72, the CA4, CA1, and dentate gyrus regions (8–11%, p < 0.0005), and for GRN the presubiculum and subiculum (10–14%, p < 0.0005) showed the largest differences from controls. CONCLUSIONS: The hippocampus was affected in all mutation types but a different pattern of subfield involvement was found in the three genetic groups, consistent with differential cortical-subcortical network vulnerability

The XMM-Newton Extended Survey of the Taurus Molecular Cloud (XEST)

(abridged:) The XMM-Newton Extended Survey of the Taurus Molecular Cloud (XEST) surveys the most populated ~5 square degrees of the Taurus star formation region, using the XMM-Newton X-ray observatory to study the thermal structure, variability, and long-term evolution of hot plasma, to investigate the magnetic dynamo, and to search for new potential members of the association. Many targets are also studied in the optical, and high-resolution X-ray grating spectroscopy has been obtained for selected bright sources. The X-ray spectra have been coherently analyzed with two different thermal models (2-component thermal model, and a continuous emission measure distribution model). We present overall correlations with fundamental stellar parameters that were derived from the previous literature. A few detections from Chandra observations have been added. The present overview paper introduces the project and provides the basic results from the X-ray analysis of all sources detected in the XEST survey.Comprehensive tables summarize the stellar properties of all targets surveyed. The survey goes deeper than previous X-ray surveys of Taurus by about an order of magnitude and for the first time systematically accesses very faint and strongly absorbed TMC objects. We find a detection rate of 85% and 98% for classical and weak-line T Tau stars (CTTS resp. WTTS), and identify about half of the surveyed protostars and brown dwarfs. Overall, 136 out of 169 surveyed stellar systems are detected. We describe an X-ray luminosity vs. mass correlation, discuss the distribution of X-ray-to-bolometric luminosity ratios, and show evidence for lower X-ray luminosities in CTTS compared to WTTS. Detailed analysis (e.g., variability, rotation-activity relations, influence of accretion on X-rays) will be discussed in a series of accompanying papers.Comment: 75 pg, 77 figs. Accepted by A&A, to appear in a special section/issue dedicated to the XMM-Newton Extended Survey of the Taurus Molecular Cloud (XEST). V2: ASCII Table 14 added. Version with higher resolution figures at http://www.issibern.ch/teams/Taurus/papers.html or http://www.astro.phys.ethz.ch/papers/guedel/guedel_p_nf.htm

The stellar association around Gamma Velorum and its relationship with Vela OB2

We present the results of a photometric BVI survey of 0.9 square degrees around the Wolf-Rayet binary gamma^2 Vel and its early-type companion gamma^1 Vel. Several hundred PMS stars are identified and the youth of a subset of these is confirmed by the presence of lithium, H-alpha emission and X-ray activity. We show that the PMS stars are kinematically coherent and spatially concentrated around gamma Vel. The PMS stars have similar proper motions to gamma Vel, to main-sequence stars around gammaVel and to early-type stars of the wider Vela OB2 association of which gamma^2 Vel is the brightest member. The ratio of main-sequence stars to low-mass (0.1-0.6 Msun) PMS stars is consistent with a Kroupa mass function. Main-sequence fitting to stars around gamma Vel gives a distance modulus of 7.76+/-0.07 mag, consistent with a similarly-determined distance for Vela OB2 and with interferometric distances to gamma^2 Vel. High-mass stellar models indicate an age of 3-4 Myr for gamma^2 Vel, but the low-mass PMS stars have ages of ~10 Myr according to low-mass evolutionary models and 5-10 Myr by empirically placing them in an age sequence with other clusters based on colour-magnitude diagrams and lithium depletion. We conclude that the low-mass PMS stars form a genuine association with gamma Vel and that this is a subcluster within the larger Vela OB2 association. We speculate that gamma^2 Vel formed after the low-mass stars, expelling gas, terminating star formation and unbinding the association. The velocity dispersion of the PMS stars is too low for this star forming event to have produced all the stars in Vela OB2. Instead, star formation must have started at several sites within a molecular cloud, either sequentially or, simultaneously after some triggering event [abridged].Comment: Accepted for publication in MNRA

X-Ray Spectroscopy of Stars

(abridged) Non-degenerate stars of essentially all spectral classes are soft X-ray sources. Low-mass stars on the cooler part of the main sequence and their pre-main sequence predecessors define the dominant stellar population in the galaxy by number. Their X-ray spectra are reminiscent, in the broadest sense, of X-ray spectra from the solar corona. X-ray emission from cool stars is indeed ascribed to magnetically trapped hot gas analogous to the solar coronal plasma. Coronal structure, its thermal stratification and geometric extent can be interpreted based on various spectral diagnostics. New features have been identified in pre-main sequence stars; some of these may be related to accretion shocks on the stellar surface, fluorescence on circumstellar disks due to X-ray irradiation, or shock heating in stellar outflows. Massive, hot stars clearly dominate the interaction with the galactic interstellar medium: they are the main sources of ionizing radiation, mechanical energy and chemical enrichment in galaxies. High-energy emission permits to probe some of the most important processes at work in these stars, and put constraints on their most peculiar feature: the stellar wind. Here, we review recent advances in our understanding of cool and hot stars through the study of X-ray spectra, in particular high-resolution spectra now available from XMM-Newton and Chandra. We address issues related to coronal structure, flares, the composition of coronal plasma, X-ray production in accretion streams and outflows, X-rays from single OB-type stars, massive binaries, magnetic hot objects and evolved WR stars.Comment: accepted for Astron. Astrophys. Rev., 98 journal pages, 30 figures (partly multiple); some corrections made after proof stag

Advanced carcinoma of the hypopharynx: functional results after circumferential pharyngolaryngectomy with flap reconstruction

Surgical treatment of advanced cancers of the hypopharynx inevitably impairs swallowing, respiration and phonation. The purpose of this study was to analyze the functional results after circumferential pharyngolaryngectomy (CPL) and flap reconstruction, in order to offer decisional guidelines for the choice of the most effective reconstructive method. We performed a retrospective analysis on the medical records of patients submitted to reconstructive surgery after CPL from July 1991 to November 2011. 75% of the 94 patients underwent reconstruction with a free flap (group A), while 25% underwent reconstruction with a pedicled flap (group B); 80% of patients in group A and none in group B were discharged with a free diet; 14% of patients in group A and 26% in group B were unable to resume oral feeding and were discharged with NG-tube or PEG. None of the patients acquired a satisfactory oesophageal voice; 17% of patients in group A and 7% in group B underwent voice restoration with tracheo-oesophageal voice-prosthesis. In conclusion, free flaps should be considered the first choice for reconstruction of the hypopharynx after CPL because of the better functional results obtained. Pedicled flaps represent a valid alternative in patients with contraindications to microvascular surgery

A comprehensive analysis of methods for assessing polygenic burden on Alzheimer’s disease pathology and risk beyond APOE

Genome-wide association studies have identified dozens of loci that alter the risk to develop Alzheimer’s disease. However, with the exception of the APOE-ε4 allele, most variants bear only little individual effect and have, therefore, limited diagnostic and prognostic value. Polygenic risk scores aim to collate the disease risk distributed across the genome in a single score. Recent works have demonstrated that polygenic risk scores designed for Alzheimer’s disease are predictive of clinical diagnosis, pathology confirmed diagnosis and changes in imaging biomarkers. Methodological innovations in polygenic risk modelling include the polygenic hazard score, which derives effect estimates for individual single nucleotide polymorphisms from survival analysis, and methods that account for linkage disequilibrium between genomic loci. In this work, using data from the Alzheimer’s disease neuroimaging initiative, we compared different approaches to quantify polygenic disease burden for Alzheimer’s disease and their association (beyond the APOE locus) with a broad range of Alzheimer’s disease-related traits: cross-sectional CSF biomarker levels, cross-sectional cortical amyloid burden, clinical diagnosis, clinical progression, longitudinal loss of grey matter and longitudinal decline in cognitive function. We found that polygenic scores were associated beyond APOE with clinical diagnosis, CSF-tau levels and, to a minor degree, with progressive atrophy. However, for many other tested traits such as clinical disease progression, CSF amyloid, cognitive decline and cortical amyloid load, the additional effects of polygenic burden beyond APOE were of minor nature. Overall, polygenic risk scores and the polygenic hazard score performed equally and given the ease with which polygenic risk scores can be derived; they constitute the more practical choice in comparison with polygenic hazard scores. Furthermore, our results demonstrate that incomplete adjustment for the APOE locus, i.e. only adjusting for APOE-ε4 carrier status, can lead to overestimated effects of polygenic scores due to APOE-ε4 homozygous participants. Lastly, on many of the tested traits, the major driving factor remained the APOE locus, with the exception of quantitative CSF-tau and p-tau measures

Exercise plus caloric restriction lowers soluble RAGE in adults with chronic kidney disease

Introduction: The incidence of chronic kidney disease (CKD) has increased in recent years. CKD is associated with obesity, type 2 diabetes, and cardiovascular disease, although the mechanism remains unclear. Elevated soluble form of the receptor for advanced glycation end products (RAGE) is related to proinflammatory signaling pathways that may promote diabetic nephropathy and vascular dysfunction. Because lifestyle modification reduces systematic inflammation in adults with obesity and hyperglycaemia, the hypothesis that exercise plus caloric restriction would lower soluble RAGE in adults with CKD was tested in this study. Methods: Eight adults (n = 6 females; age: 56.3 ± 2.8 y; BMI: 43.7 ± 2.2 kg/m2; 2-h OGTT glucose: 215 ± 9.8 mg/dL; eGFR: 49.6 ± 3.3 mL/min/1.73 m2) were enrolled in a 12-week pilot lifestyle intervention (supervised aerobic exercise [5 d/wk, up to 60 min/d at approximately 65%-85% HRmax] plus low-fat dietary counseling). Body composition (DXA), aerobic fitness (VO2max), insulin sensitivity (120 min 75 g OGTT; Matsuda Index), plasma levels of soluble RAGE and fetuin-A were measured before and after the intervention. Results: Exercise reduced body weight, fasting glucose, and fetuin-A as well as increased VO2max, glucose tolerance, and insulin sensitivity (all P \u3c .05). Lifestyle intervention decreased plasma soluble RAGE (pre: 1018.1 ± 163 vs post: 810.6 ± 119.6 ng/mL; P =.02), and the decrease was associated with a lower 2-hour blood glucose (r = 0.76, P =.03) and with increased insulin sensitivity (r = −0.90, P \u3c .01). Conclusions: Exercise and caloric restriction are effective at lowering soluble RAGE in relation to glucose regulation in patients with CKD

De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures.

Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability