27 research outputs found
PRM140 Health-Related Quality of Life (HRQoL) in Patients Treated by Novel Oral Anticoagulants (NOACs): Reduced Version of the Sawicki Questionnaire
Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers
Altres ajuts: European Alzheimer DNA BioBank, EADB; EU Joint Programme, Neurodegenerative Disease Research (JPND); Neurodegeneration research program of Amsterdam Neuroscience; Stichting Alzheimer Nederland; Stichting VUmc fonds; Stichting Dioraphte; JPco-fuND FP-829-029 (ZonMW projectnumber 733051061); Dutch Federation of University Medical Centers; Dutch Government (from 2007-2011); JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A); German Research Foundation (DFG RA 1971/6-1, RA1971/7-1, RA 1971/8-1); Grifols SA; FundaciĂłn bancaria 'La Caixa'; FundaciĂł ACE; CIBERNED; Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa'); NIH (P30AG066444, P01AG003991); Alzheimer Research Foundation (SAO-FRA), The Research Foundation Flanders (FWO), and the University of Antwerp Research Fund. FK is supported by a BOF DOCPRO fellowship of the University of Antwerp Research Fund; Siemens Healthineers; Valdecilla Biobank (PT17/0015/0019); Academy of Finland (338182); German Center for Neurodegenerative Diseases (DZNE); German Federal Ministry of Education and Research (BMBF 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434, 01GI0711); ZonMW (#73305095007); Health~Holland, Topsector Life Sciences & Health (PPP-allowance #LSHM20106); Hersenstichting; Edwin Bouw Fonds; Gieskes-Strijbisfonds; NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012); Swedish Alzheimer Foundation (AF-939988, AF-930582, AF-646061, AF-741361); Dementia Foundation (2020-04-13, 2021-04-17); Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALF 716681); Swedish Research Council (11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2019-01096); Swedish Research Council for Health, Working Life and Welfare (2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 2005-0762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 2013-2496); Swedish Brain Power, HjĂ€rnfonden, Sweden (FO2016-0214, FO2018-0214, FO2019-0163); Alzheimer's Association Zenith Award (ZEN-01-3151); Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159); Alzheimer's Association (IIRG-03-6168, IIRG-09-131338); Bank of Sweden Tercentenary Foundation; Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-81392, ALFGBG-771071); Swedish Alzheimer Foundation (AF-842471, AF-737641, AF-939825); Swedish Research Council (2019-02075); Swedish Research Council (2016-01590); BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (024.004.012); Swedish Research Council (2018-02532); Swedish State Support for Clinical Research (ALFGBG-720931); Alzheimer Drug Discovery Foundation (ADDF), USA (201809-2016862); UK Dementia Research Institute at UCL; Swedish Research Council (#2017-00915); Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615); Swedish Alzheimer Foundation (#AF-742881); HjĂ€rnfonden, Sweden (#FO2017-0243); Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986); National Institute of Health (NIH), USA, (#1R01AG068398-01); Alzheimer's Association 2021 Zenith Award (ZEN-21-848495); National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG064614); Chuck Zuckerberg Initiative (CZI).Amyloid-beta 42 (AÎČ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for AÎČ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple AÎČ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume
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 Δ4 allele
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 Δ4 allele
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Dietary αâLinolenic Acid, Marine Ïâ3 Fatty Acids, and Mortality in a Population With High Fish Consumption: Findings From the PREvenciĂłn con DIeta MEDiterrĂĄnea (PREDIMED) Study
Background: Epidemiological evidence suggests a cardioprotective role of αâlinolenic acid (ALA), a plantâderived Ïâ3 fatty acid. It is unclear whether ALA is beneficial in a background of high marine Ïâ3 fatty acids (longâchain nâ3 polyunsaturated fatty acids) intake. In persons at high cardiovascular risk from Spain, a country in which fish consumption is customarily high, we investigated whether meeting the International Society for the Study of Fatty Acids and Lipids recommendation for dietary ALA (0.7% of total energy) at baseline was related to allâcause and cardiovascular disease mortality. We also examined the effect of meeting the society's recommendation for longâchain nâ3 polyunsaturated fatty acids (â„500 mg/day). Methods and Results: We longitudinally evaluated 7202 participants in the PREvenciĂłn con DIeta MEDiterrĂĄnea (PREDIMED) trial. Multivariableâadjusted Cox regression models were fitted to estimate hazard ratios. ALA intake correlated to walnut consumption (r=0.94). During a 5.9ây followâup, 431 deaths occurred (104 cardiovascular disease, 55 coronary heart disease, 32 sudden cardiac death, 25 stroke). The hazard ratios for meeting ALA recommendation (n=1615, 22.4%) were 0.72 (95% CI 0.56â0.92) for allâcause mortality and 0.95 (95% CI 0.58â1.57) for fatal cardiovascular disease. The hazard ratios for meeting the recommendation for longâchain nâ3 polyunsaturated fatty acids (n=5452, 75.7%) were 0.84 (95% CI 0.67â1.05) for allâcause mortality, 0.61 (95% CI 0.39â0.96) for fatal cardiovascular disease, 0.54 (95% CI 0.29â0.99) for fatal coronary heart disease, and 0.49 (95% CI 0.22â1.01) for sudden cardiac death. The highest reduction in allâcause mortality occurred in participants meeting both recommendations (hazard ratio 0.63 [95% CI 0.45â0.87]). Conclusions: In participants without prior cardiovascular disease and high fish consumption, dietary ALA, supplied mainly by walnuts and olive oil, relates inversely to allâcause mortality, whereas protection from cardiac mortality is limited to fishâderived longâchain nâ3 polyunsaturated fatty acids. Clinical Trial Registration URL: http://www.Controlled-trials.com/. Unique identifier: ISRCTN35739639
Multiancestry analysis of the HLA locus in Alzheimerâs and Parkinsonâs diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes
Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinsonâs disease (PD) and Alzheimerâs disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased AÎČ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues
Electronic structure of IPR and non-IPR endohedral metallofullerenes: Connecting orbital and topological rules
10.1016/j.crci.2011.09.004The electronic structure of endohedral metallofullerenes is rationalized by connecting the apparently independent orbital and topological rules that explain the stability of this family of fullerenes. The separation of the 12 pentagons of the fullerene, which is maximized in order to minimize the Coulomb repulsion, is found to be correlated with the orbital energies of the cage that accepts the electron transfer from the internal cluster. An explanation for the absence of non-IPR cages in large-size EMFs is also provided
Unexpected Isomerism in cis-2 Bis(pyrrolidino)[60]Fullerene Diastereomers
10.1002/anie.201306957A one-step regio- and diastereoselective synthesis of three new bis(pyrrolidine)[60]fullerenes, one cis-1 and two unprecedented cis-2 diastereoisomers, is reported (see scheme). The compounds are easily purified using simple chromatographic techniques, and were fully characterized by spectroscopic techniques and X-ray crystallography. A mechanism for the isomeric conversion observed is proposed
The relevance of the association between inflammation and atrial fibrillation.
10.1111/eci.1204