| 1. |
- Davies, G., et al.
(författare)
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Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function
- 2018
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
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| 2. |
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| 3. |
- Davies, G., et al.
(författare)
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Genetic contributions to variation in general cognitive function : a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)
- 2015
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 20:2, s. 183-192
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Tidskriftsartikel (refereegranskat)abstract
- General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health-and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N = 53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P = 3.93 x 10(-9), MIR2113; rs17522122, P = 2.55 x 10(-8), AKAP6; rs10119, P = 5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P = 1x10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N = 6617) and the Health and Retirement Study (N = 5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e. = 5%) and 28% (s.e. = 7%), respectively. Using polygenic prediction analysis, similar to 1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N = 5487; P = 1.5 x 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.
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| 4. |
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| 5. |
- Aalbers, J., et al.
(författare)
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A next-generation liquid xenon observatory for dark matter and neutrino physics
- 2023
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Ingår i: Journal of Physics G: Nuclear and Particle Physics. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 50:1
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Forskningsöversikt (refereegranskat)abstract
- The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for weakly interacting massive particles, while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector.
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| 6. |
- Chauhan, G., et al.
(författare)
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Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting
- 2019
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 92:5
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.MethodsWe performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.ResultsThe mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 x 10(-8); and LINC00539/ZDHHC20, p = 5.82 x 10(-9). Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p([BI]) = 9.38 x 10(-25); p([SSBI]) = 5.23 x 10(-14) for hypertension), smoking (p([BI]) = 4.4 x 10(-10); p([SSBI]) = 1.2 x 10(-4)), diabetes (p([BI]) = 1.7 x 10(-8); p([SSBI]) = 2.8 x 10(-3)), previous cardiovascular disease (p([BI]) = 1.0 x 10(-18); p([SSBI]) = 2.3 x 10(-7)), stroke (p([BI]) = 3.9 x 10(-69); p([SSBI]) = 3.2 x 10(-24)), and MRI-defined white matter hyperintensity burden (p([BI]) = 1.43 x 10(-157); p([SSBI]) = 3.16 x 10(-106)), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p 0.0022), without indication of directional pleiotropy.ConclusionIn this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.
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| 7. |
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| 8. |
- Satizabal, Claudia L., et al.
(författare)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Tidskriftsartikel (refereegranskat)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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| 9. |
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| 10. |
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| 11. |
- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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| 12. |
- Province, M. A., et al.
(författare)
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CYP2D6 Genotype and Adjuvant Tamoxifen : Meta-Analysis of Heterogeneous Study Populations
- 2014
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Ingår i: Clinical Pharmacology and Therapeutics. - New York, USA : Nature Publishing Group. - 0009-9236 .- 1532-6535. ; 95:2, s. 216-227
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Tidskriftsartikel (refereegranskat)abstract
- The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1), CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.
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| 13. |
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| 14. |
- Boen, Rune, et al.
(författare)
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Beyond the global brain differences : intraindividual variability differences in 1q21.1 distal and 15q11.2 bp1-bp2 deletion carriers
- 2024
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Ingår i: Biological Psychiatry. - 0006-3223 .- 1873-2402. ; 95:2, s. 147-160
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Tidskriftsartikel (refereegranskat)abstract
- Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure.Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference.Results: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness.Conclusions: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.
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| 15. |
- Warr, N., et al.
(författare)
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The Miniball spectrometer
- 2013
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Ingår i: European Physical Journal A. Hadrons and Nuclei. - : Springer Science and Business Media LLC. - 1434-6001. ; 49:3
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Tidskriftsartikel (refereegranskat)abstract
- The Miniball germanium detector array has been operational at the REX (Radioactive ion beam EXperiment) post accelerator at the Isotope Separator On-Line facility ISOLDE at CERN since 2001. During the last decade, a series of successful Coulomb excitation and transfer reaction studies have been performed with this array, utilizing the unique and high-quality radioactive ion beams which are available at ISOLDE. In this article, an overview is given of the technical details of the full Miniball setup, including a description of the.-ray and particle detectors, beam monitoring devices and methods to deal with beam contamination. The specific timing properties of the REX-ISOLDE facility are highlighted to indicate the sensitivity that can be achieved with the full Miniball setup. The article is finalized with a summary of some physics highlights at REX-ISOLDE and the utilization of the Miniball germanium detectors at other facilities.
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| 16. |
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| 17. |
- Hurst, A. M., et al.
(författare)
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Measurement of the sign of the spectroscopic quadrupole moment for the 2(1)(+) state in Se-70: No evidence for oblate shape
- 2007
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Ingår i: Physical Review Letters. - 1079-7114. ; 98:7
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Tidskriftsartikel (refereegranskat)abstract
- Using a method whereby molecular and atomic ions are independently selected, an isobarically pure beam of Se-70 ions was postaccelerated to an energy of 206 MeV using REX-ISOLDE. Coulomb-excitation yields for states in the beam and target nuclei were deduced by recording deexcitation gamma rays in the highly segmented MINIBALL gamma-ray spectrometer in coincidence with scattered particles in a silicon detector. At these energies, the Coulomb-excitation yield for the first 2(+) state is expected to be strongly sensitive to the sign of the spectroscopic quadrupole moment through the nuclear reorientation effect. Experimental evidence is presented here for a prolate shape for the first 2(+) state in Se-70, reopening the question over whether there are, as reported earlier, deformed oblate shapes near to the ground state in the light selenium isotopes.
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| 18. |
- Habs, D., et al.
(författare)
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The REX-ISOLDE project
- 2000
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Ingår i: Hyperfine Interactions. - 0304-3843 .- 1572-9540. ; 129:1-4, s. 43-66
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Tidskriftsartikel (refereegranskat)abstract
- The Radioactive Beam Experiment REX-ISOLDE [1-3] is a pilot experiment at ISOLDE (CERN) testing the new concept of post acceleration of radioactive ion beams by using charge breeding of the ions in a high charge state ion source and the efficient acceleration of the highly charged ions in a short LINAC using modern ion accelerator structures. In order to prepare the ions for the experiments singly charged radioactive ions from the on-line mass separator ISOLDE will be cooled and bunched in a Penning trap, charge bred in an electron beam ion source (EBIS) and finally accelerated in the LINAC. The LINAC consists of a radiofrequency quadrupole (RFQ) accelerator, which accelerates the ions up to 0.3 MeV/u, an interdigital H-type (IH) structure with a final energy between 1.1 and 1.2 MeV/u and three seven gap resonators, which allow the variation of the final energy. With an energy of the radioactive beams between 0.8 MeV/u and 2.2 MeV/u a wide range of experiments in the field of nuclear spectroscopy, astrophysics and solid state physics will be addressed by REX-ISOLDE.
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| 19. |
- Niedermaier, O., et al.
(författare)
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"Safe" Coulomb excitation of Mg-30
- 2005
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Ingår i: Physical Review Letters. - 1079-7114 .- 0031-9007. ; 94:17, s. 172501 (artno)-
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Tidskriftsartikel (refereegranskat)abstract
- We report on the first radioactive beam experiment performed at the recently commissioned REX-ISOLDE facility at CERN in conjunction with the highly efficient γ spectrometer MINIBALL. Using Mg-30 ions accelerated to an energy of 2.25 MeV/u together with a thin Ni-nat target, Coulomb excitation of the first excited 2(+) states of the projectile and target nuclei well below the Coulomb barrier was observed. From the measured relative deexcitation γ-ray yields the B(E2;0(gs)(+)&RARR; 2(1)(+)) value of Mg-30 was determined to be 241(31)e(2) fm(4). Our result is lower than values obtained at projectile fragmentation facilities using the intermediate-energy Coulomb excitation method, and confirms the theoretical conjecture that the neutron-rich magnesium isotope Mg-30 resides outside the "island of inversion."
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| 20. |
- Niedermaier, O., et al.
(författare)
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The neutron-rich Mg isotopes: first results from MINIBALL at REX-ISOLDE
- 2005
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Ingår i: Nuclear Physics A. - : Elsevier BV. - 0375-9474. ; 752, s. 273-273
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Tidskriftsartikel (refereegranskat)abstract
- We report on the first radioactive beam experiment performed at the recently commissioned REX-ISOLDE facility at CERN in conjunction with the highly efficient γ spectrometer MINIBALL. Using Mg-30 ions accelerated to an energy of 2.25 MeV/u together with a thin Ni-nat target, Coulomb excitation of the first excited 2(+) states of the projectile and target nuclei well below the Coulomb barrier was observed. From the measured relative deexcitation γ-ray yields the B(E2;0(gs)(+)&RARR; 2(1)(+)) value of Mg-30 was determined to be 241(31)e(2) fm(4). Our result is lower than values obtained at projectile fragmentation facilities using the intermediate-energy Coulomb excitation method, and confirms the theoretical conjecture that the neutron-rich magnesium isotope Mg-30 resides outside the "island of inversion."
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| 21. |
- Scheit, H., et al.
(författare)
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Coulomb excitation of neutron-rich beams at REX-ISOLDE
- 2005
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Ingår i: European Physical Journal A. - : Springer Science and Business Media LLC. - 1434-601X .- 1434-6001. ; 25:Suppl. 1, s. 397-402
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Konferensbidrag (refereegranskat)abstract
- After the successful commissioning of the radioactive beam experiment at ISOLDE (REX-ISOLDE) - an accelerator for exotic nuclei produced by ISOLDE - in 2002 and the promotion to a CERN user facility in 2003, first physics experiments using these beams were performed. Initial experiments focused on the region of deformation in the vicinity of the neutron-rich Na and Mg isotopes. Preliminary results on the neutron-rich Na and Mg isotopes show the high potential and physics opportunities offered by the exotic isotope accelerator REX in conjunction with the modern Germanium gamma spectrometer MINIBALL.
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| 22. |
- Stefanescu, I., et al.
(författare)
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Coulomb Excitation of 68,70Cu: First Use of Postaccelerated Isomeric Beams
- 2007
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Ingår i: Physical Review Letters. ; 98
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Tidskriftsartikel (refereegranskat)abstract
- We report on the first low-energy Coulomb excitation measurements with radioactive Ipi=6- beams of odd-odd nuclei 68,70Cu. The beams were produced at ISOLDE, CERN and were post-accelerated by REX-ISOLDE to 2.83 MeV/nucleon. gamma rays were detected with the MINIBALL spectrometer. The 6- beam was used to study the multiplet of states (3-, 4-, 5-, 6-) arising from the pi2p3/2nu1g9/2 configuration. The 4- state of the multiplet was populated via Coulomb excitation and the B(E2;6--->4-) value was determined in both nuclei. The results obtained illustrate the fragile stability of the Z=28 shell and N=40 subshell closures. A comparison with large-scale shell-model calculations using the 56Ni core shows the importance of the proton excitations across the Z=28 shell gap to the understanding of the nuclear structure in the neutron-rich nuclei with N[approximate]40.
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| 23. |
- Cederkäll, Joakim, et al.
(författare)
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Sub-Barrier Coulomb Excitation of ^110Sn and Its Implications for the ^100Sn Shell Closure
- 2007
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Ingår i: Physical Review Letters. - 1079-7114. ; 98:17, s. 172501-
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Tidskriftsartikel (refereegranskat)abstract
- The first excited 2+ state of the unstable isotope 110Sn has been studied in safe Coulomb excitation at 2.82 MeV/u using the MINIBALL array at the REX-ISOLDE post accelerator at CERN. This is the first measurement of the reduced transition probability of this state using this method for a neutron deficient Sn isotope. The strength of the approach lies in the excellent peak-to-background ratio that is achieved. The extracted reduced transition probability, B(E2:0+-->2+)=0.220±0.022e2b2, strengthens the observation of the evolution of the B(E2) values of neutron deficient Sn isotopes that was observed recently in intermediate-energy Coulomb excitation of 108Sn. It implies that the trend of these reduced transition probabilities in the even-even Sn isotopes is not symmetric with respect to the midshell mass number A=116 as 100Sn is approached.
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| 24. |
- de Walle, J. V., et al.
(författare)
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Coulomb excitation of the N=50 nucleus Zn-80
- 2008
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Ingår i: AIP Conference Proceedings. - 1551-7616 .- 0094-243X. ; 1012, s. 291-295 453
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Konferensbidrag (refereegranskat)abstract
- Neutron rich Zinc isotopes, including the N=50 nucleus Zn-80, were produced and post-accelerated at the Radioactive Ion Beam (RIB) facility REX-ISOLDE (CERN). Low-energy Coulomb excitation was induced on these isotopes after post-acceleration, yielding B(E2) strengths to the first excited 2(+) states. For the first time, an excited state in Zn-80 was observed and the 2(1)(+) state in Zn-78 was established. The measured B(E2,2(1)(+) -> 0(1)(+)) values are compared to two sets of large scale shell model calculations. Both calculations reproduce the observed B(E2) systematics for the full Zinc isotopic chain. The results for N=50 isotones indicate a good N=50 shell closure and a strong Z=28 proton core polarization. The new results serve as benchmarks to establish theoretical models, predicting the nuclear properties of the doubly magic nucleus Ni-78.
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| 25. |
- Ekström, Andreas, et al.
(författare)
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0(gs)+ -->2(1)+ transition strengths in 106Sn and 108Sn.
- 2008
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Ingår i: Physical Review Letters. - 1079-7114. ; 101:1
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Tidskriftsartikel (refereegranskat)abstract
- The reduced transition probabilities, B(E2; 0(gs)+ -->2(1)+), have been measured in the radioactive isotopes (108,106)Sn using subbarrier Coulomb excitation at the REX-ISOLDE facility at CERN. Deexcitation gamma rays were detected by the highly segmented MINIBALL Ge-detector array. The results, B(E2;0(gs)+ -->2(1)+)=0.222(19)e2b2 for 108Sn and B(E2; 0(gs)+-->2(1)+)=0.195(39)e2b2 for 106Sn were determined relative to a stable 58Ni target. The resulting B(E2) values are approximately 30% larger than shell-model predictions and deviate from the generalized seniority model. This experimental result may point towards a weakening of the N=Z=50 shell closure.
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| 26. |
- Ekström, Andreas, et al.
(författare)
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Sub-barrier Coulomb excitation of Sn-106,Sn-108,Sn-110
- 2008
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Ingår i: Frontiers in Nuclear structure, Astrophysics and Reactions - Finustar 2, AIP Conference Proceedings. - : AIP. - 0094-243X .- 1551-7616. ; 1012, s. 296-299
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Konferensbidrag (refereegranskat)abstract
- The reduced transition probabilities between the first excited 2(+) state and the 0(+) ground state, B(E2; 0(+) -> 2(+)), have been measured in Sn-106,Sn-108,Sn-110 using sub-barrier Coulomb excitation in inverse kinematics at REX-ISOLDE. The results are, B(E2;0(+) -> 2(+)) = 0.220(22),0.226(17), and 0.228(32) e(2)b(2), for Sn-110, Sn-108, and Sn-106, respectively. The results for Sn-106,Sn-108 are preliminary. De-excitation gamma-rays were detected by the MINIBALL Ge-array. The B(E2) reveals detailed information about the nuclear wave function. A shell model prediction based on an effective CD-Bonn interaction in the nu(0g(7/2),2s, 1d, 0h(11/2)) model space using e(eff)(nu) =1.0 e follows the experimental values for the neutron rich Sn isotopes, but fails to reproduce the results presented here.
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| 27. |
- Jia, TY, et al.
(författare)
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Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group
- 2021
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 26:8, s. 3884-3895
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Tidskriftsartikel (refereegranskat)abstract
- DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)—three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.
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| 28. |
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| 29. |
- Kröll, Th, et al.
(författare)
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Quadrupole Collectivity of neutron-rich nuclei around 132Sn
- 2008
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Ingår i: Frontiers in Nuclear Structure, Astrophysics, and Reactions, FINUSTAR 2007. - : AIP. - 9780735405325 ; 1012, s. 296-299
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Konferensbidrag (refereegranskat)abstract
- We report on the "safe" Coulomb excitation of neutron-rich Cd, Xe, and Ba isotopes in the vicinity of the doubly-magic nucleus 132Sn. The radioactive nuclei have been produced by ISOLDE at CERN and postaccelerated by the REX-ISOLDE facility. The γ-decay of excited states has been detected by the MINIBALL array. The presented preliminary results for the B(E2) values are consistent with expectations from phenomenological systematics and will be compared with theoretical calculations.
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| 30. |
- Sønderby, Ida E., et al.
(författare)
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1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans
- 2021
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Ingår i: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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| 31. |
- van der Meer, Dennis, et al.
(författare)
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Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition
- 2020
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 77:4, s. 420-430
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
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| 32. |
- Walle, J. Van de, et al.
(författare)
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Coulomb Excitation of Neutron-Rich Zn Isotopes: First Observation of the 2[sub 1][sup +] State in [sup 80]Zn
- 2007
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Ingår i: Physical Review Letters. ; 99:14, s. 142501-
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Tidskriftsartikel (refereegranskat)abstract
- Neutron-rich, radioactive Zn isotopes were investigated at the Radioactive Ion Beam facility REX-ISOLDE (CERN) using low-energy Coulomb excitation. The energy of the 21+ state in 78Zn could be firmly established and for the first time the 2+-->01+ transition in 80Zn was observed at 1492(1) keV. B(E2,21+-->01+) values were extracted for 74,76,78,80Zn and compared to large scale shell model calculations. With only two protons outside the Z=28 proton core, 80Zn is the lightest N=50 isotone for which spectroscopic information has been obtained to date. Two sets of advanced shell model calculations reproduce the observed B(E2) systematics. The results for N=50 isotones indicate a good N=50 shell closure and a strong Z=28 proton core polarization. The new results serve as benchmarks to establish theoretical models, predicting the nuclear properties of the doubly magic nucleus 78Ni.
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| 33. |
- Jeppesen, H. B., et al.
(författare)
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Investigation of the Li-9+H-2 -> Li-8+t reaction at REX-ISOLDE
- 2006
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Ingår i: Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693. ; 635, s. 17-17
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Tidskriftsartikel (refereegranskat)abstract
- The one-neutron transfer reaction Li-9 + H-2 -> Li-8 + t has been investigated in an inverse kinematics experiment by bombarding a deuterated polypropylene target with a 2.36 MeV/u Li-9 beam from the post-accelerator REX-ISOLDE at CERN. Excitation energies in Li-8 as well as angular distributions of the tritons were obtained and spectroscopic factors deduced. (c) 2006 Elsevier B.V. All rights reserved.
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| 34. |
- Jeppesen, H. B., et al.
(författare)
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Low energy reactions with radioactive ions at REX-ISOLDE - the Li-9+H-2 case
- 2005
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Ingår i: Nuclear Physics A. - : Elsevier BV. - 0375-9474. ; 748, s. 374-374
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Tidskriftsartikel (refereegranskat)abstract
- At the newly constructed postaccelerator REX-ISOLDE (Radioactive beam Experiment at ISOLDE) we have investigated reactions induced by a Li-9 beam incident on a deuterium target at an energy of 2.36 MeV/u. Most reaction channels were recorded. From one-neutron transfer the differential cross-section for the low lying Li-10 spectrum is found. The results from the other channels demonstrate the great applicability and many possibilities that REX-ISOLDE opens up.
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| 35. |
- Kester, O., et al.
(författare)
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Accelerated radioactive beams from REX-ISOLDE
- 2003
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Ingår i: Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms. - 0168-583X. ; 204, s. 20-20
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Konferensbidrag (refereegranskat)abstract
- In 2001 the linear accelerator of the Radioactive beam EXperiment (REX-ISOLDE) delivered for the first time accelerated radioactive ion beams, at a beam energy of 2 MeV/u. REX-ISOLDE uses the method of charge-state breeding, in order to enhance the charge state of the ions before injection into the LINAC. Radioactive singly-charged ions from the on-line mass separator ISOLDE are first accumulated in a Penning trap, then charge bred to an A/q
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| 36. |
- Sonderby, Ida E., et al.
(författare)
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Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia
- 2020
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:3, s. 584-602
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Tidskriftsartikel (refereegranskat)abstract
- Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
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| 37. |
- Van de Walle, J., et al.
(författare)
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Coulomb excitation of neutron-rich Zn isotopes: First observation of the 2(1)(+) state in Zn-80
- 2007
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Ingår i: Physical Review Letters. - 1079-7114. ; 99:14
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Tidskriftsartikel (refereegranskat)abstract
- Neutron-rich, radioactive Zn isotopes were investigated at the Radioactive Ion Beam facility REX-ISOLDE (CERN) using low-energy Coulomb excitation. The energy of the 2(1)(+) state in Zn-78 could be firmly established and for the first time the 2(+)-> 0(1)(+) transition in Zn-80 was observed at 1492(1) keV. B(E2,2(1)(+)-> 0(1)(+)) values were extracted for Zn-74,Zn-76,Zn-78,Zn-80 and compared to large scale shell model calculations. With only two protons outside the Z=28 proton core, Zn-80 is the lightest N=50 isotone for which spectroscopic information has been obtained to date. Two sets of advanced shell model calculations reproduce the observed B(E2) systematics. The results for N=50 isotones indicate a good N=50 shell closure and a strong Z=28 proton core polarization. The new results serve as benchmarks to establish theoretical models, predicting the nuclear properties of the doubly magic nucleus Ni-78.
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| 38. |
- Ashraf, A., et al.
(författare)
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Plasma transferrin and hemopexin are associated with altered A beta uptake and cognitive decline in Alzheimer's disease pathology
- 2020
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Heme and iron homeostasis is perturbed in Alzheimer's disease (AD); therefore, the aim of the study was to examine the levels and association of heme with iron-binding plasma proteins in cognitively normal (CN), mild cognitive impairment (MCI), and AD individuals from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohorts. Methods Non-targeted proteomic analysis by high-resolution mass spectrometry was performed to quantify relative protein abundances in plasma samples from 144 CN individuals from the AIBL and 94 CN from KARVIAH cohorts and 21 MCI and 25 AD from AIBL cohort. ANCOVA models were utilized to assess the differences in plasma proteins implicated in heme/iron metabolism, while multiple regression modeling (and partial correlation) was performed to examine the association between heme and iron proteins, structural neuroimaging, and cognitive measures. Results Of the plasma proteins implicated in iron and heme metabolism, hemoglobin subunit beta (p = 0.001) was significantly increased in AD compared to CN individuals. Multiple regression modeling adjusted for age, sex, APOE epsilon 4 genotype, and disease status in the AIBL cohort revealed lower levels of transferrin but higher levels of hemopexin associated with augmented brain amyloid deposition. Meanwhile, transferrin was positively associated with hippocampal volume and MMSE performance, and hemopexin was negatively associated with CDR scores. Partial correlation analysis revealed lack of significant associations between heme/iron proteins in the CN individuals progressing to cognitive impairment. Conclusions In conclusion, heme and iron dyshomeostasis appears to be a feature of AD. The causal relationship between heme/iron metabolism and AD warrants further investigation.
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| 39. |
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| 40. |
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| 41. |
- Revelas, M., et al.
(författare)
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High polygenic risk score for exceptional longevity is associated with a healthy metabolic profile
- 2023
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Ingår i: Geroscience. - : Springer Science and Business Media LLC. - 2509-2715 .- 2509-2723. ; 45:1, s. 399-413
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Tidskriftsartikel (refereegranskat)abstract
- Healthy metabolic measures in humans are associated with longevity. Dysregulation leads to metabolic syndrome (MetS) and negative health outcomes. Recent exceptional longevity (EL) genome wide association studies have facilitated estimation of an individual's polygenic risk score (PRS) for EL. We tested the hypothesis that individuals with high ELPRS have a low prevalence of MetS. Participants were from five cohorts of middle-aged to older adults. The primary analyses were performed in the UK Biobank (UKBB) (n = 407,800, 40-69 years). Replication analyses were undertaken using three Australian studies: Hunter Community Study (n = 2122, 55-85 years), Older Australian Twins Study (n = 539, 65-90 years) and Sydney Memory and Ageing Study (n = 925, 70-90 years), as well as the Swedish Gothenburg H70 Birth Cohort Studies (n = 2273, 70-93 years). MetS was defined using established criteria. Regressions and meta-analyses were performed with the ELPRS and MetS and its components. Generally, MetS prevalence (22-30%) was higher in the older cohorts. In the UKBB, high EL polygenic risk was associated with lower MetS prevalence (OR = 0.94, p = 1.84 x 10(-42)) and its components (p < 2.30 x 10(-8)). Meta-analyses of the replication cohorts showed nominal associations with MetS (p = 0.028) and 3 MetS components (p < 0.05). This work suggests individuals with a high polygenic risk for EL have a healthy metabolic profile promoting longevity.
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| 42. |
- Su, Ji-Hu, et al.
(författare)
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The electronic structures of the S(2) states of the oxygen evolving complexes of photosystem II in plants and cyanobacteria in the presence and absence of methanol
- 2011
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Ingår i: Biochimica et Biophysica Acta. - Amsterdam : Elsevier. - 0006-3002 .- 1878-2434 .- 0005-2728 .- 1879-2650. ; 1807:7, s. 829-840
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Tidskriftsartikel (refereegranskat)abstract
- The electronic properties of the Mn(4)O(x)Ca cluster in the S(2) state of the oxygen evolving complex (OEC) were studied using X- and Q-band EPR and Q-band (55)Mn-ENDOR using photosystem II preparations isolated from the thermophilic cyanobacterium T. elongatus and higher plants (spinach). The data presented here show that there is very little difference between the two species. Specifically it is shown that: (i) only small changes are seen in the fitted isotropic hyperfine values, suggesting that there is no significant difference in the overall spin distribution (electronic coupling scheme) between the two species; (ii) the inferred fine-structure tensor of the only Mn(III) ion in the cluster is of the same magnitude and geometry for both species types, suggesting that the Mn(III) ion has the same coordination sphere in both sample preparations; and (iii) the data from both species are consistent with only one structural model available in the literature, namely the Siegbahn structure [Siegbahn, P. E. M. Accounts Chem. Res.2009, 42, 1871-1880, Pantazis, D. A. et al., Phys. Chem. Chem. Phys.2009, 11, 6788-6798]. These measurements were made in the presence of methanol because it confers favorable magnetic relaxation properties to the cluster that facilitate pulse-EPR techniques. In the absence of methanol the separation of the ground state and the first excited state of the spin system is smaller. For cyanobacteria this effect is minor but in plant PS II it leads to a break-down of the S(T)=½ spin model of the S(2) state. This suggests that the methanol-OEC interaction is species dependent. It is proposed that the effect of small organic solvents on the electronic structure of the cluster is to change the coupling between the outer Mn (Mn(A)) and the other three Mn ions that form the trimeric part of the cluster (Mn(B), Mn(C), Mn(D)), by perturbing the linking bis-μ-oxo bridge. The flexibility of this bridging unit is discussed with regard to the mechanism of O-O bond formation.
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| 43. |
- Agelidis, Alex, et al.
(författare)
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Disruption of innate defense responses by endoglycosidase HPSE promotes cell survival
- 2021
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Ingår i: JCI Insight. - : American Society For Clinical Investigation. - 2379-3708. ; 6:7
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Tidskriftsartikel (refereegranskat)abstract
- The drive to withstand environmental stresses and defend against invasion is a universal trait extant in all forms of life. While numerous canonical signaling cascades have been characterized in detail, it remains unclear how these pathways interface to generate coordinated responses to diverse stimuli. To dissect these connections, we followed heparanase (HPSE), a protein best known for its endoglycosidic activity at the extracellular matrix but recently recognized to drive various forms of late-stage disease through unknown mechanisms. Using herpes simplex virus-1 (HSV-1) infection as a model cellular perturbation, we demonstrate that HPSE acts beyond its established enzymatic role to restrict multiple forms of cell-intrinsic defense and facilitate host cell reprogramming by the invading pathogen. We reveal that cells devoid of HPSE are innately resistant to infection and counteract viral takeover through multiple amplified defense mechanisms. With a unique grasp of the fundamental processes of transcriptional regulation and cell death, HPSE represents a potent cellular intersection with broad therapeutic potential.
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| 44. |
- Ames, William, et al.
(författare)
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Theoretical Evaluation of Structural Models of the S(2) State in the Oxygen Evolving Complex of Photosystem II : Protonation States and Magnetic Interactions
- 2011
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 133:49, s. 19743-19757
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Tidskriftsartikel (refereegranskat)abstract
- Protonation states of water ligands and oxo bridges are intimately involved in tuning the electronic structures and oxidation potentials of the oxygen evolving complex (OEC) in Photosystem II, steering the mechanistic pathway, which involves at least five redox state intermediates S(n) (n = 0-4) resulting in the oxidation of water to molecular oxygen. Although protons are practically invisible in protein crystallography, their effects on the electronic structure and magnetic properties of metal active sites can be probed using spectroscopy. With the twin purpose of aiding the interpretation of the complex electron paramagnetic resonance (EPR) spectroscopic data of the OEC and of improving the view of the cluster at the atomic level, a complete set of protonation configurations for the S(2) state of the OEC were investigated, and their distinctive effects on magnetic properties of the cluster were evaluated. The most recent X-ray structure of Photosystem II at 1.9 Å resolution was used and refined to obtain the optimum structure for the Mn(4)O(5)Ca core within the protein pocket. Employing this model, a set of 26 structures was constructed that tested various protonation scenarios of the water ligands and oxo bridges. Our results suggest that one of the two water molecules that are proposed to coordinate the outer Mn ion (Mn(A)) of the cluster is deprotonated in the S(2) state, as this leads to optimal experimental agreement, reproducing the correct ground state spin multiplicity (S = 1/2), spin expectation values, and EXAFS-derived metal-metal distances. Deprotonation of Ca(2+)-bound water molecules is strongly disfavored in the S(2) state, but dissociation of one of the two water ligands appears to be facile. The computed isotropic hyperfine couplings presented here allow distinctions between models to be made and call into question the assumption that the largest coupling is always attributable to Mn(III). The present results impose limits for the total charge and the proton configuration of the OEC in the S(2) state, with implications for the cascade of events in the Kok cycle and for the water splitting mechanism.
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| 45. |
- Ashton, Nicholas J., et al.
(författare)
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A plasma protein classifier for predicting amyloid burden for preclinical Alzheimer's disease.
- 2019
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Ingår i: Science advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- A blood-based assessment of preclinical disease would have huge potential in the enrichment of participants for Alzheimer's disease (AD) therapeutic trials. In this study, cognitively unimpaired individuals from the AIBL and KARVIAH cohorts were defined as Aβ negative or Aβ positive by positron emission tomography. Nontargeted proteomic analysis that incorporated peptide fractionation and high-resolution mass spectrometry quantified relative protein abundances in plasma samples from all participants. A protein classifier model was trained to predict Aβ-positive participants using feature selection and machine learning in AIBL and independently assessed in KARVIAH. A 12-feature model for predicting Aβ-positive participants was established and demonstrated high accuracy (testing area under the receiver operator characteristic curve = 0.891, sensitivity = 0.78, and specificity = 0.77). This extensive plasma proteomic study has unbiasedly highlighted putative and novel candidates for AD pathology that should be further validated with automated methodologies.
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| 46. |
- Dhiman, K., et al.
(författare)
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Cerebrospinal Fluid Neurofilament Light Predicts Risk of Dementia Onset in Cognitively Healthy Individuals and Rate of Cognitive Decline in Mild Cognitive Impairment: A Prospective Longitudinal Study
- 2022
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Biomarkers that are indicative of early biochemical aberrations are needed to predict the risk of dementia onset and progression in Alzheimer's disease (AD). We assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) chain for screening preclinical AD, predicting dementia onset among cognitively healthy (CH) individuals, and the rate of cognitive decline amongst individuals with mild cognitive impairment (MCI). Methods: Neurofilament light levels were measured in CSF samples of participants (CH, n = 154 and MCI, n = 32) from the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL). Cases of preclinical AD were identified using biomarker-guided classification (CH, amyloid-beta [A beta]+, phosphorylated-tau [P-tau]+ and total-tau [T-tau]+/-; A+T+/N +/-). The prediction of dementia onset (questionable dementia) among CH participants was assessed as the risk of conversion from Clinical Dementia Rating [CDR = 0] to CDR >= 0.5 over 6 years. Mixed linear models were used to assess the utility of baseline CSF NfL levels for predicting the rate of cognitive decline among participants with MCI over 4.5 years. Results: Neurofilament light levels were significantly higher in preclinical AD participants (CH, A+T+/N +/-) as compared to A-T-N- (p < 0.001). Baseline levels of CSF NfL were higher in CH participants who converted to CDR >= 0.5 over 6 years (p = 0.045) and the risk of conversion to CDR >= 0.5 was predicted (hazard ratio [HR] 1.60, CI 1.03-2.48, p = 0.038). CH participants with CSF NfL > cut-off were at a higher risk of developing dementia (HR 4.77, CI 1.31-17.29, p = 0.018). Participants with MCI and with higher baseline levels of CSF NfL (>median) had a higher rate of decline in cognition over 4.5 years. Conclusion: An assessment of CSF NfL levels can help to predict dementia onset among CH vulnerable individuals and cognitive decline among those with MCI.
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| 47. |
- Evered, Lisbeth, et al.
(författare)
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Cerebrospinal Fluid Biomarker for Alzheimer Disease Predicts Postoperative Cognitive Dysfunction.
- 2016
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Ingår i: Anesthesiology. - 1528-1175. ; 124:2, s. 353-361
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Tidskriftsartikel (refereegranskat)abstract
- Postoperative cognitive dysfunction (POCD) affects 16 to 21% of the elderly 3 months after anesthesia and surgery and is associated with adverse outcomes. The exact cause of POCD remains unknown. The authors hypothesized that elderly individuals with Alzheimer disease (AD) neuropathology, identified by cerebrospinal fluid (CSF) analysis, would have increased the risk for POCD.
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| 48. |
- Ferreira, D, et al.
(författare)
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A 'Disease Severity Index' to identify individuals with Subjective Memory Decline who will progress to mild cognitive impairment or dementia
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7, s. 44368-
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Tidskriftsartikel (refereegranskat)abstract
- Subjective memory decline (SMD) is a heterogeneous condition. While SMD might be the earliest sign of Alzheimer’s disease (AD), it also occurs in aging and various neurological, medical, and psychiatric conditions. Identifying those with higher risk to develop dementia is thus a major challenge. We tested a novel disease severity index generated by multivariate data analysis with numerous structural MRI measures as input. The index was used to identify SMD individuals with high risk of progression to mild cognitive impairment (MCI) or AD. A total of 69 healthy controls, 86 SMD, 45 MCI, and 38 AD patients were included. Subjects were followed up for 7.5 years. Clinical, cognitive, PET amyloid imaging and APOE ε4 data were used as outcome variables. The results showed that SMD evidenced cognitive performance intermediate between healthy controls and MCI. The disease severity index identified eleven (13%) SMD individuals with an AD-like pattern of brain atrophy. These individuals showed lower cognitive performance, increased CDR-SOB, higher amyloid burden and worse clinical progression (6.2 times higher likelihood to develop MCI, dementia or die than healthy controls). The current disease severity index may have relevance for clinical practice, as well as for selecting appropriate individuals for clinical trials.
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| 49. |
- Kaput, J, et al.
(författare)
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The case for strategic international alliances to harness nutritional genomics for public and personal health
- 2005
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Ingår i: The British journal of nutrition. - : Cambridge University Press (CUP). - 0007-1145 .- 1475-2662. ; 94:5, s. 623-632
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Tidskriftsartikel (refereegranskat)abstract
- Nutrigenomics is the study of how constituents of the diet interact with genes, and their products, to alter phenotype and, conversely, how genes and their products metabolise these constituents into nutrients, antinutrients, and bioactive compounds. Results from molecular and genetic epidemiological studies indicate that dietary unbalance can alter gene–nutrient interactions in ways that increase the risk of developing chronic disease. The interplay of human genetic variation and environmental factors will make identifying causative genes and nutrients a formidable, but not intractable, challenge. We provide specific recommendations for how to best meet this challenge and discuss the need for new methodologies and the use of comprehensive analyses of nutrient–genotype interactions involving large and diverse populations. The objective of the present paper is to stimulate discourse and collaboration among nutrigenomic researchers and stakeholders, a process that will lead to an increase in global health and wellness by reducing health disparities in developed and developing countries.
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| 50. |
- Navarro, Montserrat Perez, et al.
(författare)
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Ammonia binding to the oxygen-evolving complex of photosystem II identifies the solvent-exchangeable oxygen bridge (µ-oxo) of the manganese tetramer
- 2013
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 110:39, s. 15561-15566
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Tidskriftsartikel (refereegranskat)abstract
- The assignment of the two substrate water sites of the tetramanganese penta-oxygen calcium (Mn4O5Ca) cluster of photosystem II is essential for the elucidation of the mechanism of biological O-O bond formation and the subsequent design of bio-inspired water-splitting catalysts. We recently demonstrated using pulsed EPR spectroscopy that one of the five oxygen bridges (mu-oxo) exchanges unusually rapidly with bulk water and is thus a likely candidate for one of the substrates. Ammonia, a water analog, was previously shown to bind to the Mn4O5Ca cluster, potentially displacing a water/substrate ligand [Britt RD, et al. (1989) J Am Chem Soc 111(10):3522-3532]. Here we show by a combination of EPR and time-resolved membrane inlet mass spectrometry that the binding of ammonia perturbs the exchangeable mu-oxo bridge without drastically altering the binding/exchange kinetics of the two substrates. In combination with broken-symmetry density functional theory, our results show that (i) the exchangable mu-oxo bridge is O5 {using the labeling of the current crystal structure [Umena Y, et al. (2011) Nature 473(7345):55-60]}; (ii) ammonia displaces a water ligand to the outer manganese (Mn-A4-W1); and (iii) as W1 is trans to O5, ammonia binding elongates the Mn-A4-O5 bond, leading to the perturbation of the mu-oxo bridge resonance and to a small change in the water exchange rates. These experimental results support O-O bond formation between O5 and possibly an oxyl radical as proposed by Siegbahn and exclude W1 as the second substrate water.
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