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Find video protocols related to scientific articles indexed in Pubmed.
Frontotemporal dementia and its subtypes: a genome-wide association study.
Raffaele Ferrari, Dena G Hernandez, Michael A Nalls, Jonathan D Rohrer, Adaikalavan Ramasamy, John B J Kwok, Carol Dobson-Stone, William S Brooks, Peter R Schofield, Glenda M Halliday, John R Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Eric Haan, Isabel Hernández, Agustin Ruíz, Mercè Boada, Barbara Borroni, Alessandro Padovani, Carlos Cruchaga, Nigel J Cairns, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Gianluigi Forloni, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Elio Scarpini, Jordi Clarimón, Alberto Lleó, Rafael Blesa, Maria Landqvist Waldö, Karin Nilsson, Christer Nilsson, Ian R A Mackenzie, Ging-Yuek R Hsiung, David M A Mann, Jordan Grafman, Christopher M Morris, Johannes Attems, Timothy D Griffiths, Ian G McKeith, Alan J Thomas, P Pietrini, Edward D Huey, Eric M Wassermann, Atik Baborie, Evelyn Jaros, Michael C Tierney, Pau Pastor, Cristina Razquin, Sara Ortega-Cubero, Elena Alonso, Robert Perneczky, Janine Diehl-Schmid, Panagiotis Alexopoulos, Alexander Kurz, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Ekaterina Rogaeva, Peter St George-Hyslop, Giacomina Rossi, Fabrizio Tagliavini, Giorgio Giaccone, James B Rowe, Johannes C M Schlachetzki, James Uphill, John Collinge, Simon Mead, Adrian Danek, Vivianna M Van Deerlin, Murray Grossman, John Q Trojanowski, Julie van der Zee, William Deschamps, Tim Van Langenhove, Marc Cruts, Christine Van Broeckhoven, Stefano F Cappa, Isabelle Le Ber, Didier Hannequin, Véronique Golfier, Martine Vercelletto, Alexis Brice, Benedetta Nacmias, Sandro Sorbi, Silvia Bagnoli, Irene Piaceri, Jørgen E Nielsen, Lena E Hjermind, Matthias Riemenschneider, Manuel Mayhaus, Bernd Ibach, Gilles Gasparoni, Sabrina Pichler, Wei Gu, Martin N Rossor, Nick C Fox, Jason D Warren, Maria Grazia Spillantini, Huw R Morris, Patrizia Rizzu, Peter Heutink, Julie S Snowden, Sara Rollinson, Anna Richardson, Alexander Gerhard, Amalia C Bruni, Raffaele Maletta, Francesca Frangipane, Chiara Cupidi, Livia Bernardi, Maria Anfossi, Maura Gallo, Maria Elena Conidi, Nicoletta Smirne, Rosa Rademakers, Matt Baker, Dennis W Dickson, Neill R Graff-Radford, Ronald C Petersen, David Knopman, Keith A Josephs, Bradley F Boeve, Joseph E Parisi, William W Seeley, Bruce L Miller, Anna M Karydas, Howard Rosen, John C van Swieten, Elise G P Dopper, Harro Seelaar, Yolande A L Pijnenburg, Philip Scheltens, Giancarlo Logroscino, Rosa Capozzo, Valeria Novelli, Annibale A Puca, Massimo Franceschi, Alfredo Postiglione, Graziella Milan, Paolo Sorrentino, Mark Kristiansen, Huei-Hsin Chiang, Caroline Graff, Florence Pasquier, Adeline Rollin, Vincent Deramecourt, Florence Lebert, Dimitrios Kapogiannis, Luigi Ferrucci, Stuart Pickering-Brown, Andrew B Singleton, John Hardy, Parastoo Momeni.
Lancet Neurol
PUBLISHED: 06-20-2014
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Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
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Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.
Valentina Escott-Price, Celine Bellenguez, Li-San Wang, Seung-Hoan Choi, Denise Harold, Lesley Jones, Peter Holmans, Amy Gerrish, Alexey Vedernikov, Alexander Richards, Anita L Destefano, Jean-Charles Lambert, Carla A Ibrahim-Verbaas, Adam C Naj, Rebecca Sims, Gyungah Jun, Joshua C Bis, Gary W Beecham, Benjamin Grenier-Boley, Giancarlo Russo, Tricia A Thornton-Wells, Nicola Denning, Albert V Smith, Vincent Chouraki, Charlene Thomas, M Arfan Ikram, Diana Zelenika, Badri N Vardarajan, Yoichiro Kamatani, Chiao-Feng Lin, Helena Schmidt, Brian Kunkle, Melanie L Dunstan, Maria Vronskaya, , Andrew D Johnson, Agustin Ruíz, Marie-Therese Bihoreau, Christiane Reitz, Florence Pasquier, Paul Hollingworth, Olivier Hanon, Annette L Fitzpatrick, Joseph D Buxbaum, Dominique Campion, Paul K Crane, Clinton Baldwin, Tim Becker, Vilmundur Gudnason, Carlos Cruchaga, David Craig, Najaf Amin, Claudine Berr, Oscar L Lopez, Philip L De Jager, Vincent Deramecourt, Janet A Johnston, Denis Evans, Simon Lovestone, Luc Letenneur, Isabel Hernández, David C Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M Goate, Nathalie Fiévet, Matthew J Huentelman, Michael Gill, Kristelle Brown, M Ilyas Kamboh, Lina Keller, Pascale Barberger-Gateau, Bernadette McGuinness, Eric B Larson, Amanda J Myers, Carole Dufouil, Stephen Todd, David Wallon, Seth Love, Ekaterina Rogaeva, John Gallacher, Peter St George-Hyslop, Jordi Clarimón, Alberto Lleó, Anthony Bayer, Debby W Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, Petra Proitsi, John Collinge, Sandro Sorbi, Florentino Sanchez Garcia, Nick C Fox, John Hardy, Maria Candida Deniz Naranjo, Paolo Bosco, Robert Clarke, Carol Brayne, Daniela Galimberti, Elio Scarpini, Ubaldo Bonuccelli, Michelangelo Mancuso, Gabriele Siciliano, Susanne Moebus, Patrizia Mecocci, Maria Del Zompo, Wolfgang Maier, Harald Hampel, Alberto Pilotto, Ana Frank-García, Francesco Panza, Vincenzo Solfrizzi, Paolo Caffarra, Benedetta Nacmias, William Perry, Manuel Mayhaus, Lars Lannfelt, Hakon Hakonarson, Sabrina Pichler, Minerva M Carrasquillo, Martin Ingelsson, Duane Beekly, Victoria Alvarez, Fanggeng Zou, Otto Valladares, Steven G Younkin, Eliecer Coto, Kara L Hamilton-Nelson, Wei Gu, Cristina Razquin, Pau Pastor, Ignacio Mateo, Michael J Owen, Kelley M Faber, Palmi V Jonsson, Onofre Combarros, Michael C O'Donovan, Laura B Cantwell, Hilkka Soininen, Deborah Blacker, Simon Mead, Thomas H Mosley, David A Bennett, Tamara B Harris, Laura Fratiglioni, Clive Holmes, Renée F A G de Bruijn, Peter Passmore, Thomas J Montine, Karolien Bettens, Jerome I Rotter, Alexis Brice, Kevin Morgan, Tatiana M Foroud, Walter A Kukull, Didier Hannequin, John F Powell, Michael A Nalls, Karen Ritchie, Kathryn L Lunetta, John S K Kauwe, Eric Boerwinkle, Matthias Riemenschneider, Mercè Boada, Mikko Hiltunen, Eden R Martin, Reinhold Schmidt, Dan Rujescu, Jean-Francois Dartigues, Richard Mayeux, Christophe Tzourio, Albert Hofman, Markus M Nöthen, Caroline Graff, Bruce M Psaty, Jonathan L Haines, Mark Lathrop, Margaret A Pericak-Vance, Lenore J Launer, Christine Van Broeckhoven, Lindsay A Farrer, Cornelia M van Duijn, Alfredo Ramírez, Sudha Seshadri, Gerard D Schellenberg, Philippe Amouyel, Julie Williams.
PLoS ONE
PUBLISHED: 01-01-2014
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Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
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Unfolded protein response signaling by transcription factor XBP-1 regulates ADAM10 and is affected in Alzheimers disease.
FASEB J.
PUBLISHED: 10-28-2013
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In Alzheimers disease (AD), disturbed homeostasis of the proteases competing for amyloid precursor protein processing has been reported: a disintegrin and metalloproteinase 10 (ADAM10), the physiological ?-secretase, is decreased in favor of the amyloid-?-generating enzyme BACE-1. To identify transcription factors that modulate the expression of either protease, we performed a screening approach: 48 transcription factors significantly interfered with ADAM10/BACE-1-promoter activity. One selective inducer of ADAM10 gene expression is the X-box binding protein-1 (XBP-1). This protein regulates the unfolded protein-response pathway. We demonstrate that particularly the spliced XBP-1 variant dose dependently regulates ADAM10 expression, which can be synergistically enhanced by 100 nM insulin. Analysis of 2 different transgenic mouse models (APP/PS1 and 5xFAD) revealed that at early time points in pathology XBP-1 metabolism is induced. This is accompanied by a 2-fold augmented ADAM10 amount as compared with nontransgenic littermates (P=0.011). Along with aging of the mice, the system is counterregulated, and XBP-1 together with ADAM10 expression level decreased to ?50% as compared with control animals. Analyses of expression levels in human AD brains showed that ADAM10 mRNA correlated with active XBP-1 (r=0.3120), but expression did not reach levels of healthy age-matched controls, suggesting deregulation of XBP-1 signaling. Our results demonstrate that XBP-1 is a driver of ADAM10 gene expression and that disturbance of this pathway might contribute to development or progression of AD.-Reinhardt, S., Schuck, F., Grösgen, S., Riemenschneider, M., Hartmann, T., Postina, R., Grimm, M., Endres, K. Unfolded protein response signaling by transcription factor XBP-1 regulates ADAM10 and is affected in Alzheimers disease.
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Adult monozygotic twins discordant for intra-uterine growth have indistinguishable genome-wide DNA methylation profiles.
Genome Biol.
PUBLISHED: 03-25-2013
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Low birth weight is associated with an increased adult metabolic disease risk. It is widely discussed that poor intra-uterine conditions could induce long-lasting epigenetic modifications, leading to systemic changes in regulation of metabolic genes. To address this, we acquire genome-wide DNA methylation profiles from saliva DNA in a unique cohort of 17 monozygotic monochorionic female twins very discordant for birth weight. We examine if adverse prenatal growth conditions experienced by the smaller co-twins lead to long-lasting DNA methylation changes.
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The "DGPPN-Cohort": A national collaboration initiative by the German Association for Psychiatry and Psychotherapy (DGPPN) for establishing a large-scale cohort of psychiatric patients.
Heike Anderson-Schmidt, Lothar Adler, Chadiga Aly, Ion-George Anghelescu, Michael Bauer, Jessica Baumgärtner, Joachim Becker, Roswitha Bianco, Thomas Becker, Cosima Bitter, Dominikus Bönsch, Karoline Buckow, Monika Budde, Martin Bührig, Jürgen Deckert, Sara Y Demiroglu, Detlef Dietrich, Michael Dümpelmann, Uta Engelhardt, Andreas J Fallgatter, Daniel Feldhaus, Christian Figge, Here Folkerts, Michael Franz, Katrin Gade, Wolfgang Gaebel, Hans-Jörgen Grabe, Oliver Gruber, Verena Gullatz, Linda Gusky, Urs Heilbronner, Krister Helbing, Ulrich Hegerl, Andreas Heinz, Tilman Hensch, Christoph Hiemke, Markus Jäger, Anke Jahn-Brodmann, Georg Juckel, Franz Kandulski, Wolfgang P Kaschka, Tilo Kircher, Manfred Köller, Carsten Konrad, Johannes Kornhuber, Marina Krause, Axel Krug, Mahsa Lee, Markus Leweke, Klaus Lieb, Mechthild Mammes, Andreas Meyer-Lindenberg, Moritz Mühlbacher, Matthias J Müller, Vanessa Nieratschker, Barbara Nierste, Jacqueline Ohle, Andrea Pfennig, Marlenna Pieper, Matthias Quade, Daniela Reich-Erkelenz, Andreas Reif, Markus Reitt, Bernd Reininghaus, Eva Z Reininghaus, Matthias Riemenschneider, Otto Rienhoff, Patrik Roser, Dan Rujescu, Rebecca Schennach, Harald Scherk, Max Schmauss, Frank Schneider, Alexandra Schosser, Björn H Schott, Sybille G Schwab, Jens Schwanke, Daniela Skrowny, Carsten Spitzer, Sebastian Stierl, Judith Stöckel, Susanne Stübner, Andreas Thiel, Hans-Peter Volz, Martin von Hagen, Henrik Walter, Stephanie H Witt, Thomas Wobrock, Jürgen Zielasek, Jörg Zimmermann, Antje Zitzelsberger, Wolfgang Maier, Peter G Falkai, Marcella Rietschel, Thomas G Schulze.
Eur Arch Psychiatry Clin Neurosci
PUBLISHED: 03-01-2013
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The German Association for Psychiatry and Psychotherapy (DGPPN) has committed itself to establish a prospective national cohort of patients with major psychiatric disorders, the so-called DGPPN-Cohort. This project will enable the scientific exploitation of high-quality data and biomaterial from psychiatric patients for research. It will be set up using harmonised data sets and procedures for sample generation and guided by transparent rules for data access and data sharing regarding the central research database. While the main focus lies on biological research, it will be open to all kinds of scientific investigations, including epidemiological, clinical or health-service research.
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Haplotype structure, adaptive history and associations with exploratory behaviour of the DRD4 gene region in four great tit (Parus major) populations.
Mol. Ecol.
PUBLISHED: 02-01-2013
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The assessment of genetic architecture and selection history in genes for behavioural traits is fundamental to our understanding of how these traits evolve. The dopamine receptor D4 (DRD4) gene is a prime candidate for explaining genetic variation in novelty seeking behaviour, a commonly assayed personality trait in animals. Previously, we showed that a single nucleotide polymorphism in exon 3 of this gene is associated with exploratory behaviour in at least one of four Western European great tit (Parus major) populations. These heterogeneous association results were explained by potential variable linkage disequilibrium (LD) patterns between this marker and the causal variant or by other genetic or environmental differences among the populations. Different adaptive histories are further hypothesized to have contributed to these population differences. Here, we genotyped 98 polymorphisms of the complete DRD4 gene including the flanking regions for 595 individuals of the four populations. We show that the LD structure, specifically around the original exon 3 SNP is conserved across the four populations and does not explain the heterogeneous association results. Study-wide significant associations with exploratory behaviour were detected in more than one haplotype block around exon 2, 3 and 4 in two of the four tested populations with different allele effect models. This indicates genetic heterogeneity in the association between multiple DRD4 polymorphisms and exploratory behaviour across populations. The association signals were in or close to regions with signatures of positive selection. We therefore hypothesize that variation in exploratory and other dopamine-related behaviour evolves locally by occasional adaptive shifts in the frequency of underlying genetic variants.
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Pharmacogenomics in Alzheimers disease: a genome-wide association study of response to cholinesterase inhibitors.
Neurobiol. Aging
PUBLISHED: 01-29-2013
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We conducted a genome-wide association study in a cohort of 176 Italian Alzheimers disease (AD) patients with extreme phenotype of response to cholinesterase inhibitors. Patients were classified into responders in case of positive, stable, or ?1 worsening of mini-mental state examination score and into nonresponders if >3 points worsening during a median follow-up of 0.85 years of treatment. Forty-eight single-nucleotide polymorphisms were selected for replication in 198 additional AD-treated patients. By using the dichotomous response trait and a quantitative trait approach (change of mini-mental state examination), a nominal replication and evidence of association when combining data were achieved for 2 single-nucleotide polymorphisms associated with response to treatment: rs6720975A (pcombined = 2.9 × 10(-5), beta regression coefficient: 1.61) and rs17798800A (pcombined = 6.8 × 10(-6), odds ratio = 0.38, 95% confidence interval = 0.25-0.58). Rs6720975 maps in the intronic region of PRKCE, a protein kinase involved in several cellular functions, whereas rs17798800 is intergenic and, according to expression quantitative trait locus (eQTL) analysis, it acts as a cis-regulator of NBEA, an A kinase-anchoring protein playing a substantial role in the maturation of the nervous system. Despite its limitations, this project paves the way for the application of personalized medicine in AD patients and for collaborative efforts in this field.
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MRI plaque imaging detects carotid plaques with a high risk for future cerebrovascular events in asymptomatic patients.
PLoS ONE
PUBLISHED: 01-01-2013
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The aim of this study was to investigate prospectively whether MRI plaque imaging can identify patients with asymptomatic carotid artery stenosis who have an increased risk for future cerebral events. MRI plaque imaging allows categorization of carotid stenosis into different lesion types (I-VIII). Within these lesion types, lesion types IV-V and VI are regarded as rupture-prone plaques, whereas the other lesion types represent stable ones.
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Impact of the COMT Val(108/158)Met polymorphism on the mu-opioid receptor system in the human brain: mu-opioid receptor, met-enkephalin and beta-endorphin expression.
Neurosci. Lett.
PUBLISHED: 08-13-2011
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The Val(108/158)Met polymorphism of the catechol-O-methyltransferase gene (COMT) is known to interact with the function of various neuroreceptor systems in the brain. We have recently shown by post-mortem receptor autoradiography that the number of mu-opioid (MOP) receptor binding sites depends on the number of COMT Met(108/158) alleles in distinct human brain regions. We now investigated COMT Val(108/158)Met related levels of the MOP receptor protein and its endogenous ligands met-enkephalin and beta-endorphin in the human frontal cortex, thalamus and basal ganglia. Semiquantitative immunostaining and in situ hybridization were applied in a cohort of 17 human brain tissues from healthy donors. MOP receptor protein levels paralleled previous ligand binding results with a significantly higher MOP receptor expression in the mediodorsal nucleus of the thalamus of COMT Met(108/158) allele carriers. Also met-enkephalin peptide levels correlated with the genotype in this structure, with the lowest expression in COMT Met(108/158) homozygous individuals. Beta-endorphin was not detectable in the cortex, basal ganglia or thalamus, and therefore is unlikely to contribute to changes of the MOP receptor system. These results confirm the impact of the COMT Val(108/158)Met polymorphism on the MOP receptor system and may support the hypothesis of an enkephalin related turnover of MOP receptors at least in some brain structures.
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From brain to food: analysis of phosphatidylcholins, lyso-phosphatidylcholins and phosphatidylcholin-plasmalogens derivates in Alzheimers disease human post mortem brains and mice model via mass spectrometry.
J Chromatogr A
PUBLISHED: 04-11-2011
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Alzheimers disease (AD) is a devastating neurodegenerative disorder characterized by extracellular senile plaques mainly consisting of A?, a 40-42 amino acid long peptide, and intracellular neurofibrillary tangles, accompanied by an excessive loss of synapses. Recently evidence accumulated that nutrition, especially polyunsaturated fatty acids, influences AD pathogenesis. Especially mid-life food habits with the consumption of specific fatty acids (FA) appear to influence the disease risk. The timely separation between food intake and disease makes a direct correlation with detailed analysis of eating habits combined with accurate food analysis nearly unattainable. A possible solution to circumvent these difficulties is to investigate the FA composition in human post mortem brain. In this study we focused on the main phospholipids phosphatidylcholin (PC), phosphatidylcholin-plasmalogen (PC-PL) and lyso-phosphatidylcholin (lyso-PC) in AD brains compared to control brains. Frontal cortices, temporal cortices and cerebellum of 30 AD (mean 78 years) and 14 control aged matched brains (mean 77.4 years) as well as APP transgenic mice compared to control mice were analyzed using an AB Sciex 4000 Qtrap mass spectrometer utilizing a FIA MS/MS method. PC, PC-PL and lyso-PC metabolites were analyzed in respect to saturation level and FA composition. As expected, the majority of the lipid species showed no significant differences, but interestingly a few species revealed a highly significant reduction in AD brains. These FAs are potential candidates for further food analysis in respect to AD pathology. Additionally, we show that the method applied with multiple reaction monitoring (MRM) used for this study is suitable for semi quantitative analysis of small amounts (10 ?l) of brain tissue.
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Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimers disease.
Paul Hollingworth, Denise Harold, Rebecca Sims, Amy Gerrish, Jean-Charles Lambert, Minerva M Carrasquillo, Richard Abraham, Marian L Hamshere, Jaspreet Singh Pahwa, Valentina Moskvina, Kimberley Dowzell, Nicola Jones, Alexandra Stretton, Charlene Thomas, Alex Richards, Dobril Ivanov, Caroline Widdowson, Jade Chapman, Simon Lovestone, John Powell, Petroula Proitsi, Michelle K Lupton, Carol Brayne, David C Rubinsztein, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Kristelle S Brown, Peter A Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Clive Holmes, David Mann, A David Smith, Helen Beaumont, Donald Warden, Gordon Wilcock, Seth Love, Patrick G Kehoe, Nigel M Hooper, Emma R L C Vardy, John Hardy, Simon Mead, Nick C Fox, Martin Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Eckart Rüther, Britta Schürmann, Reiner Heun, Heike Kölsch, Hendrik van den Bussche, Isabella Heuser, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Harald Hampel, John Gallacher, Michael Hüll, Dan Rujescu, Ina Giegling, Alison M Goate, John S K Kauwe, Carlos Cruchaga, Petra Nowotny, John C Morris, Kevin Mayo, Kristel Sleegers, Karolien Bettens, Sebastiaan Engelborghs, Peter P De Deyn, Christine Van Broeckhoven, Gill Livingston, Nicholas J Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panagiotis Deloukas, Ammar Al-Chalabi, Christopher E Shaw, Magda Tsolaki, Andrew B Singleton, Rita Guerreiro, Thomas W Mühleisen, Markus M Nöthen, Susanne Moebus, Karl-Heinz Jöckel, Norman Klopp, H-Erich Wichmann, V Shane Pankratz, Sigrid B Sando, Jan O Aasly, Maria Barcikowska, Zbigniew K Wszolek, Dennis W Dickson, Neill R Graff-Radford, Ronald C Petersen, , Cornelia M van Duijn, Monique M B Breteler, M Arfan Ikram, Anita L Destefano, Annette L Fitzpatrick, Oscar Lopez, Lenore J Launer, Sudha Seshadri, Claudine Berr, Dominique Campion, Jacques Epelbaum, Jean-Francois Dartigues, Christophe Tzourio, Annick Alpérovitch, Mark Lathrop, Thomas M Feulner, Patricia Friedrich, Caterina Riehle, Michael Krawczak, Stefan Schreiber, Manuel Mayhaus, S Nicolhaus, Stefan Wagenpfeil, Stacy Steinberg, Hreinn Stefansson, Kari Stefansson, Jón Snaedal, Sigurbjorn Bjornsson, Palmi V Jonsson, Vincent Chouraki, Benjamin Genier-Boley, Mikko Hiltunen, Hilkka Soininen, Onofre Combarros, Diana Zelenika, Marc Delepine, María J Bullido, Florence Pasquier, Ignacio Mateo, Ana Frank-García, Elisa Porcellini, Olivier Hanon, Eliecer Coto, Victoria Alvarez, Paolo Bosco, Gabriele Siciliano, Michelangelo Mancuso, Francesco Panza, Vincenzo Solfrizzi, Benedetta Nacmias, Sandro Sorbi, Paola Bossù, Paola Piccardi, Beatrice Arosio, Giorgio Annoni, Davide Seripa, Alberto Pilotto, Elio Scarpini, Daniela Galimberti, Alexis Brice, Didier Hannequin, Federico Licastro, Lesley Jones, Peter A Holmans, Thorlakur Jonsson, Matthias Riemenschneider, Kevin Morgan, Steven G Younkin, Michael J Owen, Michael O'Donovan, Philippe Amouyel, Julie Williams.
Nat. Genet.
PUBLISHED: 03-10-2011
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We sought to identify new susceptibility loci for Alzheimers disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimers Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ? 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimers disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).
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New Alzheimer amyloid beta responsive genes identified in human neuroblastoma cells by hierarchical clustering.
PLoS ONE
PUBLISHED: 07-11-2009
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Alzheimers disease (AD) is characterized by neuronal degeneration and cell loss. Abeta(42), in contrast to Abeta(40), is thought to be the pathogenic form triggering the pathological cascade in AD. In order to unravel overall gene regulation we monitored the transcriptomic responses to increased or decreased Abeta(40) and Abeta(42) levels, generated and derived from its precursor C99 (C-terminal fragment of APP comprising 99 amino acids) in human neuroblastoma cells. We identified fourteen differentially expressed transcripts by hierarchical clustering and discussed their involvement in AD. These fourteen transcripts were grouped into two main clusters each showing distinct differential expression patterns depending on Abeta(40) and Abeta(42) levels. Among these transcripts we discovered an unexpected inverse and strong differential expression of neurogenin 2 (NEUROG2) and KIAA0125 in all examined cell clones. C99-overexpression had a similar effect on NEUROG2 and KIAA0125 expression as a decreased Abeta(42)/Abeta(40) ratio. Importantly however, an increased Abeta(42)/Abeta(40) ratio, which is typical of AD, had an inverse expression pattern of NEUROG2 and KIAA0125: An increased Abeta(42)/Abeta(40) ratio up-regulated NEUROG2, but down-regulated KIAA0125, whereas the opposite regulation pattern was observed for a decreased Abeta(42)/Abeta(40) ratio. We discuss the possibilities that the so far uncharacterized KIAA0125 might be a counter player of NEUROG2 and that KIAA0125 could be involved in neurogenesis, due to the involvement of NEUROG2 in developmental neural processes.
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No association of common VCP variants with sporadic frontotemporal dementia.
Neurobiol. Aging
PUBLISHED: 02-20-2009
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Mutations in the gene for valosin containing protein (VCP) cause autosomal dominant inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD). To investigate the role of this novel gene in sporadic forms of frontotemporal dementia (FTD), we genotyped 27 single nucleotide polymorphisms covering the entire VCP genomic region in 198 patients with sporadic FTD and 184 matched controls from Germany. No significant association could be demonstrated. There is no evidence, that common variants in VCP confer a strong risk to the development of sporadic FTD.
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No association of TDP-43 with sporadic frontotemporal dementia.
Neurobiol. Aging
PUBLISHED: 02-20-2009
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A hyperphosphorylated, ubiquitinated form of TDP-43, known as pathologic TDP-43, was shown to be a central component of ubiquitin-positive, tau-negative and alpha-synuclein-negative inclusions in frontotemporal lobar degeneration (FTLD-U) and amytrophic lateral sclerosis (ALS). To investigate the role of the TDP-43 gene in sporadic forms of frontotemporal dementia (FTD), we genotyped 10 single nucleotide polymorphisms covering the entire TDP-43 genomic region, including the MASP2 gene in 173 patients with sporadic FTD (including 7 patients that were diagnosed with FTD and ALS) and 184 matched controls from Germany. Although we could observe a weak trend towards a potential disease association in a few FTD/ALS patients, no significant association with sporadic FTD could be demonstrated. There is no evidence, that common variants in TDP-43 confer a strong risk to the development of sporadic FTD.
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Brain metabolic correlates of cerebrospinal fluid beta-amyloid 42 and tau in Alzheimers disease.
Dement Geriatr Cogn Disord
PUBLISHED: 02-04-2009
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The cerebrospinal fluid (CSF) proteins beta-amyloid 42 (Abeta42) and Tau are believed to indirectly reflect some core pathological features of Alzheimers disease (AD). Their topographic origin and their association with synaptic dysfunction are still not well understood.
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Beta amyloid in Alzheimers disease: increased deposition in brain is reflected in reduced concentration in cerebrospinal fluid.
Biol. Psychiatry
PUBLISHED: 01-08-2009
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A decreased concentration of beta amyloid (1-42) (Abeta42) has consistently been found in the cerebrospinal fluid (CSF) of patients with Alzheimers disease (AD) and is considered a diagnostic biomarker. However, it is not clear to which extent CSF Abeta42 levels are reflective of cerebral pathology in AD. The aim of the study was to determine the association between cerebral amyloid plaque load, as measured by means of the positron emission tomography (PET) tracer carbon-11-labeled Pittsburgh Compound B ([11C]PiB) and CSF Abeta42 in AD.
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Plasmalogens inhibit APP processing by directly affecting ?-secretase activity in Alzheimers disease.
ScientificWorldJournal
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Lipids play an important role as risk or protective factors in Alzheimers disease (AD). Previously it has been shown that plasmalogens, the major brain phospholipids, are altered in AD. However, it remained unclear whether plasmalogens themselves are able to modulate amyloid precursor protein (APP) processing or if the reduced plasmalogen level is a consequence of AD. Here we identify the plasmalogens which are altered in human AD postmortem brains and investigate their impact on APP processing resulting in A? production. All tested plasmalogen species showed a reduction in ?-secretase activity whereas ?- and ?-secretase activity mainly remained unchanged. Plasmalogens directly affected ?-secretase activity, protein and RNA level of the secretases were unaffected, pointing towards a direct influence of plasmalogens on ?-secretase activity. Plasmalogens were also able to decrease ?-secretase activity in human postmortem AD brains emphasizing the impact of plasmalogens in AD. In summary our findings show that decreased plasmalogen levels are not only a consequence of AD but that plasmalogens also decrease APP processing by directly affecting ?-secretase activity, resulting in a vicious cycle: A? reduces plasmalogen levels and reduced plasmalogen levels directly increase ?-secretase activity leading to an even stronger production of A? peptides.
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