| 1. |
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| 2. |
- van Rheenen, W, et al.
(författare)
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Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
- 2021
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 53:12, s. 1636-
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
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| 3. |
- Shulevski, A., et al.
(författare)
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The peculiar radio galaxy 4C 35.06 : a case for recurrent AGN activity?
- 2015
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 579, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Using observations obtained with the LOw Fequency ARray (LOFAR), the Westerbork Synthesis Radio Telescope (WSRT) and archival Very Large Array (VLA) data, we have traced the radio emission to large scales in the complex source 4C 35.06 located in the core of the galaxy cluster Abell 407. At higher spatial resolution (~ 4″), the source was known to have two inner radio lobes spanning 31 kpc and a diffuse, low-brightness extension running parallel to them, offset by about 11 kpc (in projection). At 62 MHz, we detect the radio emission of this structure extending out to 210 kpc. At 1.4 GHz and intermediate spatial resolution (~ 30″), the structure appears to have a helical morphology. We have derived the characteristics of the radio spectral index across the source. We show that the source morphology is most likely the result of at least two episodes of AGN activity separated by a dormant period of around 35 Myr. The outermost regions of radio emission have a steep spectral index (α< − 1), indicative of old plasma. We connect the spectral index properties of the resolved source structure with the integrated fluxdensity spectral index of 4C 35.06 and suggest an explanation for its unusual integrated flux density spectral shape (a moderately steep power law with no discernible spectral break), possibly providing a proxy for future studies of more distant radio sources through inferring their detailed spectral index properties and activity history from their integrated spectral indices. The AGN is hosted by one of the galaxies located in the cluster core of Abell 407. We propose that it is intermittently active as it moves in the dense environment in the cluster core. In this scenario, the AGN turned on sometime in the past, and has produced the helical pattern of emission, possibly a sign of jet precession/merger during that episode of activity. Using LOFAR, we can trace the relic plasma from that episode of activity out to greater distances from the core than ever before. Using the the WSRT, we detect H I in absorption against the center of the radio source. The absorption profile is relatively broad (FWHM of 288 kms-1), similar to what is found in other clusters. The derived column density is NHI ~ 4 × 1020 cm-2 for a Tspin = 100 K. This detection supports the connection – already suggested for other restarted radio sources – between the presence of cold gas and restarting activity. The cold gas appears to be dominated by a blue-shifted component although the broad H I profile could also include gas with different kinematics. Understanding the duty cycle of the radio emission as well as the triggering mechanism for starting (or restarting) the radio-loud activity can provide important constraints to quantify the impact of AGN feedback on galaxy evolution. The study of these mechanisms at low frequencies using morphological and spectral information promises to bring new important insights in this field.
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| 4. |
- Penston, M. V., et al.
(författare)
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The extended narrow line region of NGC 4151. I. Emission line ratios and their implications
- 1990
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Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 236:1, s. 53-6262
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Tidskriftsartikel (refereegranskat)abstract
- The paper presents the first results from long-slit spectra of the Seyfert galaxy NGC 4151 which give average diagnostic ratios of weak lines in the extended narrow line region (ENLR) of that galaxy and the first direct density measurement in an ENLR. These data confirm that the ENLR is kinematically undisturbed gas in the disc of the galaxy which is illuminated by an ionizing continuum stronger by a factor of 13 than a power law interpolated between observed ultraviolet and X-ray fluxes. Explanations of this apparent excess include a hot thermal continuum, time variations and an anisotropic radiation field. The authors give reasons for favouring anisotropy which might be caused by shadowing by a thick accretion disc or by relativistic beaming. Shadowing by a molecular torus is unlikely, given the absence of an infrared signal from the reradiated flux absorbed by any torus. Anisotropy would have important implications for the bolometric luminosity and nature of active galactic nuclei
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| 5. |
- Rottgering, H., et al.
(författare)
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The "Sausage" and "Toothbrush" clusters of galaxies and the prospects of LOFAR observations of clusters of galaxies
- 2013
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Ingår i: Astronomische Nachrichten. - : Wiley. - 0004-6337 .- 1521-3994. ; 334:4-5, s. 333-337
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Tidskriftsartikel (refereegranskat)abstract
- LOFAR, the Low Frequency Radio Array, is a new pan-European radio telescope that is almost fully operational. One of its main drivers is to make deep images of the low frequency radio sky. To be able to do this a number of challenges need to be addressed. These include the high data rates, removal of radio frequency interference, calibration of the beams and correcting for the corrupting influence of the ionosphere. One of the key science goals is to study merger shocks, particle acceleration mechanisms and the structure of magnetic fields in nearby and distant merging clusters. Recent studies with the GMRT and WSRT radio telescopes of the "Sausage" and the "Toothbrush" clusters have given a very good demonstration of the power of radio observations to study merging clusters. Recently we discovered that both clusters contain relic and halo sources, large diffuse regions of radio emission not associated with individual galaxies. The 2 Mpc northern relic in the Sausage cluster displays highly aligned magnetic fields and and exhibits a strong spectral index gradient that is a consequence of cooling of the synchrotron emitting particles in the post-shock region. We have argued that these observations provide strong evidence that shocks in merging clusters are capable of accelerating particles. For the Toothbrush cluster we observe a puzzling linear relic that extends over 2 Mpc. The proposed scenario is that a triple-merger can lead to such a structure. With LOFAR's sensitivity it will not only be possible to trace much weaker shocks, but also to study those shocks due to merging clusters up to redshifts of at least one. (C) 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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| 6. |
- Rottgering, H., et al.
(författare)
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LOFAR and APERTIF Surveys of the Radio Sky: Probing Shocks and Magnetic Fields in Galaxy Clusters
- 2011
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Ingår i: Journal of Astrophysics and Astronomy. - : Springer Science and Business Media LLC. - 0250-6335 .- 0973-7758. ; 32:4, s. 557-566
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Tidskriftsartikel (refereegranskat)abstract
- At very low frequencies, the new pan-European radio telescope LOFAR is opening the last unexplored window of the electromagnetic spectrum for astrophysical studies. The revolutionary APERTIF-phased arrays that are about to be installed on the Westerbork radio telescope (WSRT) will dramatically increase the survey speed for the WSRT. Combined surveys with these two facilities will deeply chart the northern sky over almost two decades in radio frequency from similar to 15 up to 1400 MHz. Here we briefly describe some of the capabilities of these new facilities and what radio surveys are planned to study fun-damental issues related to the formation and evolution of galaxies and clusters of galaxies. In the second part we briefly review some recent observational results directly showing that diffuse radio emission in clusters traces shocks due to cluster mergers. As these diffuse radio sources are relatively bright at low frequencies, LOFAR should be able to detect thousands of such sources up to the epoch of cluster formation. This will allow addressing many question about the origin and evolution of shocks and magnetic fields in clusters. At the end we briefly review some of the first and very preliminary LOFAR results on clusters.
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| 7. |
- Chetelat, G., et al.
(författare)
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Amyloid-PET and 18-F-FDG-PET in the diagnostic investigation of Alzheimer's disease and other dementias
- 2020
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Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 19:11, s. 951-962
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Forskningsöversikt (refereegranskat)abstract
- Various biomarkers are available to support the diagnosis of neurodegenerative diseases in clinical and research settings. Among the molecular imaging biomarkers, amyloid-PET, which assesses brain amyloid deposition, and F-18-fluorodeoxyglucose (F-18-FDG) PET, which assesses glucose metabolism, provide valuable and complementary information. However, uncertainty remains regarding the optimal timepoint, combination, and an order in which these PET biomarkers should be used in diagnostic evaluations because conclusive evidence is missing. Following an expert panel discussion, we reached an agreement on the specific use of the individual biomarkers, based on available evidence and clinical expertise. We propose a diagnostic algorithm with optimal timepoints for these PET biomarkers, also taking into account evidence from other biomarkers, for early and differential diagnosis of neurodegenerative diseases that can lead to dementia. We propose three main diagnostic pathways with distinct biomarker sequences, in which amyloid-PET and F-18-FDG-PET are placed at different positions in the order of diagnostic evaluations, depending on clinical presentation. We hope that this algorithm can support diagnostic decision making in specialist clinical settings with access to these biomarkers and might stimulate further research towards optimal diagnostic strategies.
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| 8. |
- Bailey, D. L., et al.
(författare)
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Combined PET/MRI : Global Warming-Summary Report of the 6th International Workshop on PET/MRI, March 27-29, 2017, Tubingen, Germany
- 2018
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Ingår i: Molecular Imaging and Biology. - : SPRINGER. - 1536-1632 .- 1860-2002. ; 20:1, s. 4-20
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Forskningsöversikt (refereegranskat)abstract
- The 6th annual meeting to address key issues in positron emission tomography (PET)/magnetic resonance imaging (MRI) was held again in Tubingen, Germany, from March 27 to 29, 2017. Over three days of invited plenary lectures, round table discussions and dialogue board deliberations, participants critically assessed the current state of PET/MRI, both clinically and as a research tool, and attempted to chart future directions. The meeting addressed the use of PET/MRI and workflows in oncology, neurosciences, infection, inflammation and chronic pain syndromes, as well as deeper discussions about how best to characterise the tumour microenvironment, optimise the complementary information available from PET and MRI, and how advanced data mining and bioinformatics, as well as information from liquid biomarkers (circulating tumour cells and nucleic acids) and pathology, can be integrated to give a more complete characterisation of disease phenotype. Some issues that have dominated previous meetings, such as the accuracy of MR-based attenuation correction (AC) of the PET scan, were finally put to rest as having been adequately addressed for the majority of clinical situations. Likewise, the ability to standardise PET systems for use in multicentre trials was confirmed, thus removing a perceived barrier to larger clinical imaging trials. The meeting openly questioned whether PET/MRI should, in all cases, be used as a whole-body imaging modality or whether in many circumstances it would best be employed to give an in-depth study of previously identified disease in a single organ or region. The meeting concluded that there is still much work to be done in the integration of data from different fields and in developing a common language for all stakeholders involved. In addition, the participants advocated joint training and education for individuals who engage in routine PET/MRI. It was agreed that PET/MRI can enhance our understanding of normal and disrupted biology, and we are in a position to describe the in vivo nature of disease processes, metabolism, evolution of cancer and the monitoring of response to pharmacological interventions and therapies. As such, PET/MRI is a key to advancing medicine and patient care.
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| 9. |
- Jansen, Willemijn J, et al.
(författare)
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Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
- 2022
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
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Tidskriftsartikel (refereegranskat)abstract
- One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
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