New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Dying peacefully in residents with dementia in long-term care facilities: a good quality indicator?

Background: Little is known about whether people with dementia die peacefully. This may be influenced by the (palliative) care provided. If so, dying peacefully may serve as a quality indicator for palliative care in dementia. Aims: (1) To describe the proportion of residents with dementia in long-term care facilities that dies peacefully. (2) To explore whether the available quality indicator “the percentage of relatives who indicate that the patient died peacefully” captures quality differences between different care facilities and hence is a discriminative and useful indicator. Methods: We used written questionnaires about quality of dying completed by families and physicians in the Dutch End of Life in Dementia study, performed in 34 long-term care facilities in the Netherlands between January 2007 and July 2010. The percentage of residents dying peacefully was calculated for each facility and Generalized Estimating Equation models were used to explore associations between long-term care facility characteristics and the proportion of peaceful deaths. Results: Relatives of 233 residents with dementia indicated that the resident died peacefully in 56% of cases. This percentage ranged from 33-85% across facilities. This range points to the discriminative power of this quality indicator, enabling a comparison of care provided by long-term care facilities to residents with dementia. Residents were more likely to have died peacefully in facilities with a moderate (versus no) “perceived influence of religious affiliation on end-of-life decision making”, and when “family finds staffing sufficient”. Conclusion: According to their relatives, about half of Dutch people with dementia die peacefully. This proportion varies between care facilities. Differences in scores appeared to be related to characteristics of the long-term care facilities, which suggests that the percentage of residents with dementia dying peacefully is an indicator of the quality of care in this setting

The Aging Imageomics Study: rationale, design and baseline characteristics of the study population

Biomarkers of aging are urgently needed to identify individuals at high risk of developing age-associated disease or disability. Growing evidence from population-based studies points to whole-body magnetic resonance imaging's (MRI) enormous potential for quantifying subclinical disease burden and for assessing changes that occur with aging in all organ systems. The Aging Imageomics Study aims to identify biomarkers of human aging by analyzing imaging, biopsychosocial, cardiovascular, metabolomic, lipidomic, and microbiome variables. This study recruited 1030 participants aged >= 50 years (mean 67, range 50-96 years) that underwent structural and functional MRI to evaluate the brain, large blood vessels, heart, abdominal organs, fat, spine, musculoskeletal system and ultrasonography to assess carotid intima-media thickness and plaques. Patients were notified of incidental findings detected by a certified radiologist when necessary. Extensive data were also collected on anthropometrics, demographics, health history, neuropsychology, employment, income, family status, exposure to air pollution and cardiovascular status. In addition, several types of samples were gathered to allow for microbiome, metabolomic and lipidomic profiling. Using big data techniques to analyze all the data points from biological phenotyping together with health records and lifestyle measures, we aim to cultivate a deeper understanding about various biological factors (and combinations thereof) that underlie healthy and unhealthy aging.Cardiovascular Aspects of Radiolog

Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

In cancer, recurrent somatic single-nucleotide variants—which are rare in most paediatric cancers—are confined largely to protein-coding genes1–3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5′ splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5′ cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer

Searches for neutrino counterparts of gravitational waves from the LIGO/Virgo third observing run with KM3NeT

International audienceThe KM3NeT neutrino telescope is currently being deployed at two different sites in the Mediterranean Sea. First searches for astrophysical neutrinos have been performed using data taken with the partial detector configuration already in operation. The paper presents the results of two independent searches for neutrinos from compact binary mergers detected during the third observing run of the LIGO and Virgo gravitational wave interferometers. The first search looks for a global increase in the detector counting rates that could be associated with inverse beta decay events generated by MeV-scale electron anti-neutrinos. The second one focuses on upgoing track-like events mainly induced by muon (anti-)neutrinos in the GeV--TeV energy range. Both searches yield no significant excess for the sources in the gravitational wave catalogs. For each source, upper limits on the neutrino flux and on the total energy emitted in neutrinos in the respective energy ranges have been set. Stacking analyses of binary black hole mergers and neutron star-black hole mergers have also been performed to constrain the characteristic neutrino emission from these categories

Search for Neutrino Emission from GRB 221009A using the KM3NeT ARCA and ORCA detectors

International audienceGamma-ray bursts are promising candidate sources of high-energy astrophysical neutrinos. The recent GRB 221009A event, identified as the brightest gamma-ray burst ever detected, provides a unique opportunity to investigate hadronic emissions involving neutrinos. The KM3NeT undersea neutrino detectors participated in the worldwide follow-up effort triggered by the event, searching for neutrino events. In this letter, we summarize subsequent searches, in a wide energy range from MeV up to a few PeVs. No neutrino events are found in any of the searches performed. Upper limits on the neutrino emission associated with GRB 221009A are computed