111 results on '"Hernández, Isabel"'
Search Results
2. Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers
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Jansen, Iris E., van der Lee, Sven J., Gomez-Fonseca, Duber, de Rojas, Itziar, Dalmasso, Maria Carolina, Grenier-Boley, Benjamin, Zettergren, Anna, Mishra, Aniket, Ali, Muhammad, Andrade, Victor, Bellenguez, Céline, Kleineidam, Luca, Küçükali, Fahri, Sung, Yun Ju, Tesí, Niccolo, Vromen, Ellen M., Wightman, Douglas P., Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Amouyel, Philippe, Athanasiu, Lavinia, Bahrami, Shahram, Bailly, Henri, Belbin, Olivia, Bergh, Sverre, Bertram, Lars, Biessels, Geert Jan, Blennow, Kaj, Blesa, Rafael, Boada, Mercè, Boland, Anne, Buerger, Katharina, Carracedo, Ángel, Cervera-Carles, Laura, Chene, Geneviève, Claassen, Jurgen A. H. R., Debette, Stephanie, Deleuze, Jean-Francois, de Deyn, Peter Paul, Diehl-Schmid, Janine, Djurovic, Srdjan, Dols-Icardo, Oriol, Dufouil, Carole, Duron, Emmanuelle, Düzel, Emrah, Fladby, Tormod, Fortea, Juan, Frölich, Lutz, García-González, Pablo, Garcia-Martinez, Maria, Giegling, Ina, Goldhardt, Oliver, Gobom, Johan, Grimmer, Timo, Haapasalo, Annakaisa, Hampel, Harald, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Helisalmi, Seppo, Heneka, Michael T., Hernández, Isabel, Herukka, Sanna-Kaisa, Holstege, Henne, Jarholm, Jonas, Kern, Silke, Knapskog, Anne-Brita, Koivisto, Anne M., Kornhuber, Johannes, Kuulasmaa, Teemu, Lage, Carmen, Laske, Christoph, Leinonen, Ville, Lewczuk, Piotr, Lleó, Alberto, de Munain, Adolfo López, Lopez-Garcia, Sara, Maier, Wolfgang, Marquié, Marta, Mol, Merel O., Montrreal, Laura, Moreno, Fermin, Moreno-Grau, Sonia, Nicolas, Gael, Nöthen, Markus M., Orellana, Adelina, Pålhaugen, Lene, Papma, Janne M., Pasquier, Florence, Perneczky, Robert, Peters, Oliver, Pijnenburg, Yolande A. L., Popp, Julius, Posthuma, Danielle, Pozueta, Ana, Priller, Josef, Puerta, Raquel, Quintela, Inés, Ramakers, Inez, Rodriguez-Rodriguez, Eloy, Rujescu, Dan, Saltvedt, Ingvild, Sanchez-Juan, Pascual, Scheltens, Philip, Scherbaum, Norbert, Schmid, Matthias, Schneider, Anja, Selbæk, Geir, Selnes, Per, Shadrin, Alexey, Skoog, Ingmar, Soininen, Hilkka, Tárraga, Lluís, Teipel, Stefan, Tijms, Betty, Tsolaki, Magda, Van Broeckhoven, Christine, Van Dongen, Jasper, van Swieten, John C., Vandenberghe, Rik, Vidal, Jean-Sébastien, Visser, Pieter J., Vogelgsang, Jonathan, Waern, Margda, Wagner, Michael, Wiltfang, Jens, Wittens, Mandy M. J., Zetterberg, Henrik, Zulaica, Miren, van Duijn, Cornelia M., Bjerke, Maria, Engelborghs, Sebastiaan, Jessen, Frank, Teunissen, Charlotte E., Pastor, Pau, Hiltunen, Mikko, Ingelsson, Martin, Andreassen, Ole A., Clarimón, Jordi, Sleegers, Kristel, Ruiz, Agustín, Ramirez, Alfredo, Cruchaga, Carlos, Lambert, Jean-Charles, and van der Flier, Wiesje
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- 2022
- Full Text
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3. Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.
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van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, and Clarimón, Jordi
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DESGESCO ,EADB ,IFGC ,IPDGC ,RiMod-FTD ,Netherlands Brain Bank ,GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group ,Acquired Cognitive Impairment ,Brain Disorders ,Neurodegenerative ,Alzheimer's Disease ,Dementia ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurosciences ,Aging ,Parkinson's Disease ,Genetics ,2.1 Biological and endogenous factors ,Neurological ,Neurology & Neurosurgery ,Clinical Sciences - Abstract
The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.
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- 2020
4. Automatized FACEmemory® scoring is related to Alzheimer’s disease phenotype and biomarkers in early-onset mild cognitive impairment: the BIOFACE cohort
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Alegret, Montserrat, Sotolongo-Grau, Oscar, de Antonio, Ester Esteban, Pérez-Cordón, Alba, Orellana, Adelina, Espinosa, Ana, Gil, Silvia, Jiménez, Daniel, Ortega, Gemma, Sanabria, Angela, Roberto, Natalia, Hernández, Isabel, Rosende-Roca, Maitee, Tartari, Juan Pablo, Alarcon-Martin, Emilio, de Rojas, Itziar, Montrreal, Laura, Morató, Xavier, Cano, Amanda, Rentz, Dorene M., Tárraga, Lluís, Ruiz, Agustín, Valero, Sergi, Marquié, Marta, and Boada, Mercè
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- 2022
- Full Text
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5. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.
- Author
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van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, and Clarimón, Jordi
- Subjects
DESGESCO (Dementia Genetics Spanish Consortium) ,EADB ,EADB ,IFGC (International FTD-Genomics Consortium) ,IPDGC ,IPDGC ,RiMod-FTD ,Netherlands Brain Bank ,GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group ,Alzheimer’s disease ,Amyotrophic lateral sclerosis ,Dementia with Lewy bodies ,Frontotemporal dementia ,Longevity ,Multiple sclerosis ,Neurodegenerative disease ,PLCG2 ,Parkinson’s disease ,Phospholipase C Gamma 2 ,Progressive supranuclear palsy ,Alzheimer's disease ,Parkinson's disease ,Alzheimer's Disease ,frontotemporal dementia ,dementia with Lewy-bodies ,progressive suprauclear palsy ,Parkinson's Disease ,amyotrophic lateral sclerosis ,multiple sclerosis ,neurodegenerative disease ,longevity ,Clinical Sciences ,Neurosciences ,Neurology & Neurosurgery - Abstract
The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.
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- 2019
6. The role of sex and gender in the selection of Alzheimer patients for clinical trial pre-screening
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Rosende-Roca, Maitee, Abdelnour, Carla, Esteban, Ester, Tartari, Juan Pablo, Alarcon, Emilio, Martínez-Atienza, Juliana, González-Pérez, Antonio, Sáez, María E., Lafuente, Asunción, Buendía, Mar, Pancho, Ana, Aguilera, Nuria, Ibarria, Marta, Diego, Susana, Jofresa, Sara, Hernández, Isabel, López, Rogelio, Gurruchaga, Miren Jone, Tárraga, Lluís, Valero, Sergi, Ruiz, Agustín, Marquié, Marta, and Boada, Mercè
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- 2021
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7. Association of lysophosphatidic acids with cerebrospinal fluid biomarkers and progression to Alzheimer’s disease
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Ahmad, Shahzad, Orellana, Adelina, Kohler, Isabelle, Frölich, Lutz, de Rojas, Itziar, Gil, Silvia, Boada, Mercè, Hernández, Isabel, Hausner, Lucrezia, Bakker, Margot H. M., Cabrera-Socorro, Alfredo, Amin, Najaf, Ramírez, Alfredo, Ruiz, Agustín, Hankemeier, Thomas, and Van Duijn, Cornelia M.
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- 2020
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8. A computerized version of the Short Form of the Face-Name Associative Memory Exam (FACEmemory®) for the early detection of Alzheimer’s disease
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Alegret, Montserrat, Muñoz, Nathalia, Roberto, Natalia, Rentz, Dorene M., Valero, Sergi, Gil, Silvia, Marquié, Marta, Hernández, Isabel, Riveros, Catalina, Sanabria, Angela, Perez-Cordon, Alba, Espinosa, Ana, Ortega, Gemma, Mauleón, Ana, Abdelnour, Carla, Rosende-Roca, Maitee, Papp, Kathryn V., Orellana, Adela, Benaque, Alba, Tarraga, Lluís, Ruiz, Agustín, and Boada, Mercè
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- 2020
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9. Author Correction: Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
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de Rojas, Itziar, Moreno-Grau, Sonia, Tesi, Niccolo, Grenier-Boley, Benjamin, Andrade, Victor, Jansen, Iris E., Pedersen, Nancy L., Stringa, Najada, Zettergren, Anna, Hernández, Isabel, Antúnez, Carmen, Antonell, Anna, Tankard, Rick M., Bis, Joshua C., Sims, Rebecca, Bellenguez, Céline, Quintela, Inés, González-Perez, Antonio, Calero, Miguel, Macías, Juan, Blesa, Rafael, Cervera-Carles, Laura, Menéndez-González, Manuel, Royo, Jose Luís, Moreno, Fermin, Huerto Vilas, Raquel, Baquero, Miquel, Diez-Fairen, Mónica, Lage, Carmen, García-González, Pablo, Valero, Sergi, Ullgren, Abbe, Naj, Adam C., Lemstra, Afina W., Benussi, Alberto, Rábano, Alberto, Padovani, Alessandro, Squassina, Alessio, de Mendonça, Alexandre, Arias Pastor, Alfonso, Kok, Almar A. L., Meggy, Alun, Pastor, Ana Belén, Espinosa, Ana, Corma-Gómez, Anaïs, Sanabria, Ángela, DeStefano, Anita L., Schneider, Anja, Haapasalo, Annakaisa, Kinhult Ståhlbom, Anne, Tybjærg-Hansen, Anne, Hartmann, Annette M., Spottke, Annika, Corbatón-Anchuelo, Arturo, Rongve, Arvid, Borroni, Barbara, Arosio, Beatrice, Nacmias, Benedetta, Nordestgaard, Børge G., Kunkle, Brian W., Charbonnier, Camille, Masullo, Carlo, Martínez Rodríguez, Carmen, Muñoz-Fernandez, Carmen, Dufouil, Carole, Graff, Caroline, Ferreira, Catarina B., Chillotti, Caterina, Reynolds, Chandra A., Fenoglio, Chiara, Van Broeckhoven, Christine, Clark, Christopher, Pisanu, Claudia, Satizabal, Claudia L., Holmes, Clive, Buiza-Rueda, Dolores, Aarsland, Dag, Rujescu, Dan, Alcolea, Daniel, Galimberti, Daniela, Wallon, David, Seripa, Davide, Grünblatt, Edna, Dardiotis, Efthimios, Düzel, Emrah, Scarpini, Elio, Conti, Elisa, Rubino, Elisa, Gelpi, Ellen, Rodriguez-Rodriguez, Eloy, Duron, Emmanuelle, Boerwinkle, Eric, Ferri, Evelyn, Tagliavini, Fabrizio, Küçükali, Fahri, Pasquier, Florence, Sanchez-Garcia, Florentino, Mangialasche, Francesca, Jessen, Frank, Nicolas, Gaël, Selbæk, Geir, Ortega, Gemma, Chêne, Geneviève, Hadjigeorgiou, Georgios, Rossi, Giacomina, Spalletta, Gianfranco, Giaccone, Giorgio, Grande, Giulia, Binetti, Giuliano, Papenberg, Goran, Hampel, Harald, Bailly, Henri, Zetterberg, Henrik, Soininen, Hilkka, Karlsson, Ida K., Alvarez, Ignacio, Appollonio, Ildebrando, Giegling, Ina, Skoog, Ingmar, Saltvedt, Ingvild, Rainero, Innocenzo, Rosas Allende, Irene, Hort, Jakub, Diehl-Schmid, Janine, Van Dongen, Jasper, Vidal, Jean-Sebastien, Lehtisalo, Jenni, Wiltfang, Jens, Thomassen, Jesper Qvist, Kornhuber, Johannes, Haines, Jonathan L., Vogelgsang, Jonathan, Pineda, Juan A., Fortea, Juan, Popp, Julius, Deckert, Jürgen, Buerger, Katharina, Morgan, Kevin, Fließbach, Klaus, Sleegers, Kristel, Molina-Porcel, Laura, Kilander, Lena, Weinhold, Leonie, Farrer, Lindsay A., Wang, Li-San, Kleineidam, Luca, Farotti, Lucia, Parnetti, Lucilla, Tremolizzo, Lucio, Hausner, Lucrezia, Benussi, Luisa, Froelich, Lutz, Ikram, M. Arfan, Deniz-Naranjo, M. Candida, Tsolaki, Magda, Rosende-Roca, Maitée, Löwenmark, Malin, Hulsman, Marc, Spallazzi, Marco, Pericak-Vance, Margaret A., Esiri, Margaret, Bernal Sánchez-Arjona, María, Dalmasso, Maria Carolina, Martínez-Larrad, María Teresa, Arcaro, Marina, Nöthen, Markus M., Fernández-Fuertes, Marta, Dichgans, Martin, Ingelsson, Martin, Herrmann, Martin J., Scherer, Martin, Vyhnalek, Martin, Kosmidis, Mary H., Yannakoulia, Mary, Schmid, Matthias, Ewers, Michael, Heneka, Michael T., Wagner, Michael, Scamosci, Michela, Kivipelto, Miia, Hiltunen, Mikko, Zulaica, Miren, Alegret, Montserrat, Fornage, Myriam, Roberto, Natalia, van Schoor, Natasja M., Seidu, Nazib M., Banaj, Nerisa, Armstrong, Nicola J., Scarmeas, Nikolaos, Scherbaum, Norbert, Goldhardt, Oliver, Hanon, Oliver, Peters, Oliver, Skrobot, Olivia Anna, Quenez, Olivier, Lerch, Ondrej, Bossù, Paola, Caffarra, Paolo, Dionigi Rossi, Paolo, Sakka, Paraskevi, Mecocci, Patrizia, Hoffmann, Per, Holmans, Peter A., Fischer, Peter, Riederer, Peter, Yang, Qiong, Marshall, Rachel, Kalaria, Rajesh N., Mayeux, Richard, Vandenberghe, Rik, Cecchetti, Roberta, Ghidoni, Roberta, Frikke-Schmidt, Ruth, Sorbi, Sandro, Hägg, Sara, Engelborghs, Sebastiaan, Helisalmi, Seppo, Botne Sando, Sigrid, Kern, Silke, Archetti, Silvana, Boschi, Silvia, Fostinelli, Silvia, Gil, Silvia, Mendoza, Silvia, Mead, Simon, Ciccone, Simona, Djurovic, Srdjan, Heilmann-Heimbach, Stefanie, Riedel-Heller, Steffi, Kuulasmaa, Teemu, del Ser, Teodoro, Lebouvier, Thibaud, Polak, Thomas, Ngandu, Tiia, Grimmer, Timo, Bessi, Valentina, Escott-Price, Valentina, Giedraitis, Vilmantas, Deramecourt, Vincent, Maier, Wolfgang, Jian, Xueqiu, Pijnenburg, Yolande A. L., Smith, A. David, Saenz, Aldo, Bizzarro, Alessandra, Lauria, Alessandra, Vacca, Alessandro, Solomon, Alina, Anastasiou, Anna, Richardson, Anna, Boland, Anne, Koivisto, Anne, Daniele, Antonio, Greco, Antonio, Marianthi, Arnaoutoglou, McGuinness, Bernadette, Fin, Bertrand, Ferrari, Camilla, Custodero, Carlo, Ferrarese, Carlo, Ingino, Carlos, Mangone, Carlos, Reyes Toso, Carlos, Martínez, Carmen, Cuesta, Carolina, Muchnik, Carolina, Joachim, Catharine, Ortiz, Cecilia, Besse, Céline, Johansson, Charlotte, Zoia, Chiara Paola, Laske, Christoph, Anastasiou, Costas, Palacio, Dana Lis, Politis, Daniel G., Janowitz, Daniel, Craig, David, Mann, David M., Neary, David, Jürgen, Deckert, Daian, Delphine, Belezhanska, Diyana, Kohler, Eduardo, Castaño, Eduardo M., Koutsouraki, Effrosyni, Chipi, Elena, De Roeck, Ellen, Costantini, Emanuele, Vardy, Emma R. L. C., Piras, Fabrizio, Roveta, Fausto, Piras, Federica, Prestia, Federico Ariel, Assogna, Francesca, Salani, Francesca, Sala, Gessica, Lacidogna, Giordano, Novack, Gisela, Wilcock, Gordon, Thonberg, Håkan, Kölsch, Heike, Weber, Heike, Boecker, Henning, Etchepareborda, Ignacio, Piaceri, Irene, Tuomilehto, Jaakko, Lindström, Jaana, Laczo, Jan, Johnston, Janet, Deleuze, Jean-François, Harris, Jenny, Schott, Jonathan M., Priller, Josef, Bacha, Juan Ignacio, Snowden, Julie, Lisso, Julieta, Mihova, Kalina Yonkova, Traykov, Latchezar, Morelli, Laura, Brusco, Luis Ignacio, Rainer, Malik, Takalo, Mari, Bjerke, Maria, Del Zompo, Maria, Serpente, Maria, Sanchez Abalos, Mariana, Rios, Mario, Peltonen, Markku, Herrman, Martin J., Kohler, Matias, Rojo, Matias, Jones, Matthew, Orsini, Michela, Medel, Nancy, Olivar, Natividad, Fox, Nick C., Salvadori, Nicola, Hooper, Nigel M., Galeano, Pablo, Solis, Patricia, Bastiani, Patrizia, Passmore, Peter, Heun, Reinhard, Antikainen, Riitta, Olaso, Robert, Perneczky, Robert, Germani, Sandra, López-García, Sara, Love, Seth, Mehrabian, Shima, Bagnoli, Silvia, Kochen, Silvia, Andreoni, Simona, Teipel, Stefan, Todd, Stephen, Pickering-Brown, Stuart, Natunen, Teemu, Tegos, Thomas, Laatikainen, Tiina, Strandberg, Timo, Polvikoski, Tuomo M., Matoska, Vaclav, Ciullo, Valentina, Cores, Valeria, Solfrizzi, Vincenzo, Lisetti, Viviana, Sevillano, Zulma, Abdelnour, C., Aguilera, N., Alarcon, E., Alegret, M., Benaque, A., Boada, M., Buendia, M., Cañabate, P., Carracedo, A., de Rojas, I., Diego, S., Espinosa, A., Gailhajenet, A., García-González, P., Gil, S., Guitart, M., González-Pérez, A., Hernández, I., Ibarria, M., Lafuente, A., Macias, J., Maroñas, O., Martín, E., Martínez, M.T., Marquié, M., Mauleón, A., Montrreal, L., Moreno-Grau, S., Moreno, M., Orellana, A., Ortega, G., Pancho, A., Pelejá, E., Pérez-Cordon, A., Pineda, J.A., Preckler, S., Quintela, I., Real, L.M., Rosende-Roca, M., Ruiz, A., Sáez, M.E., Sanabria, A., Serrano-Rios, M., Sotolongo-Grau, O., Tárraga, L., Valero, S., Vargas, L., Adarmes-Gómez, A.D., Alarcón-Martín, E., Alonso, M.D., Álvarez, I., Álvarez, V., Amer-Ferrer, G., Antequera, M., Antúnez, C., Baquero, M., Bernal, M., Blesa, R., Bullido, M.J., Burguera, J.A., Calero, M., Carrillo, F., Carrión-Claro, M., Casajeros, M.J., Clarimón, J., Cruz-Gamero, J.M., de Pancorbo, M.M., del Ser, T., Diez-Fairen, M., Escuela, R., Garrote-Espina, L., Fortea, J., Franco-Macías, E., Frank-García, A., Garcia Madrona, S., Gómez-Garre, P., Hevilla, S., Jesús, S., Labrador Espinosa, M.A., Lage, C., Legaz, A., Lleó, A., Lopez de Munain, A., López-García, S., Macias-García, D., Manzanares, S., Marín, M., Marín-Muñoz, J., Marín, T., Martín Montes, A., Martínez, B., Martínez, C., Martínez, V., Martínez-Lage Álvarez, P., Medina, M., Mendioroz Iriarte, M., Menéndez-González, M., Mir, P., Molinuevo, J.L., Pastor, P., Pérez Tur, J., Periñán-Tocino, T., Pineda-Sanchez, R., Piñol-Ripoll, G., Rábano, A., Real de Asúa, D., Rodrigo, S., Rodríguez-Rodríguez, E., Royo, J.L., Sanchez del Valle Díaz, R., Sánchez-Juan, P., Sastre, I., Vicente, M.P., Vigo-Ortega, R., Vivancos, L., Macleod, C., McCracken, C., Brayne, Carol, Bresner, Catherine, Grozeva, Detelina, Bellou, Eftychia, Sommerville, Ewen W., Matthews, F., Leonenko, Ganna, Menzies, Georgina, Windle, Gill, Harwood, Janet, Phillips, Judith, Bennett, K., Luckuck, Lauren, Clare, Linda, Woods, Robert, Saad, Salha, Burholt, Vanessa, Kehoe, Patrick Gavin, Garcia-Ribas, Guillermo, Sánchez-Juan, Pascual, Pastor, Pau, Pérez-Tur, Jordi, Piñol-Ripoll, Gerard, Lopez de Munain, Adolfo, García-Alberca, Jose María, Bullido, María J., Álvarez, Victoria, Lleó, Alberto, Real, Luis M., Mir, Pablo, Medina, Miguel, Scheltens, Philip, Holstege, Henne, Marquié, Marta, Sáez, María Eugenia, Carracedo, Ángel, Amouyel, Philippe, Schellenberg, Gerard D., Williams, Julie, Seshadri, Sudha, van Duijn, Cornelia M., Mather, Karen A., Sánchez-Valle, Raquel, Serrano-Ríos, Manuel, Orellana, Adelina, Tárraga, Lluís, Blennow, Kaj, Huisman, Martijn, Andreassen, Ole A., Posthuma, Danielle, Clarimón, Jordi, Boada, Mercè, van der Flier, Wiesje M., Ramirez, Alfredo, Lambert, Jean-Charles, van der Lee, Sven J., Ruiz, Agustín, Smith, A David, Saenz, Aldo, Bizzarro, Alessandra, Lauria, Alessandra, Vacca, Alessandro, Solomon, Alina, Anastasiou, Anna, Richardson, Anna, Boland, Anne, Koivisto, Anne, Daniele, Antonio, Greco, Antonio, Marianthi, Arnaoutoglou, McGuinness, Bernadette, Fin, Bertrand, Ferrari, Camilla, Custodero, Carlo, Ferrarese, Carlo, Ingino, Carlos, Mangone, Carlos, Reyes Toso, Carlos, Martínez, Carmen, Cuesta, Carolina, Muchnik, Carolina, Joachim, Catharine, Ortiz, Cecilia, Besse, Céline, Johansson, Charlotte, Zoia, Chiara Paola, Laske, Christoph, Anastasiou, Costas, Palacio, Dana Lis, Politis, Daniel G, Janowitz, Daniel, Craig, David, Mann, David M, Neary, David, Jürgen, Deckert, Daian, Delphine, Belezhanska, Diyana, Kohler, Eduardo, Castaño, Eduardo M, Koutsouraki, Effrosyni, Chipi, Elena, De Roeck, Ellen, Costantini, Emanuele, Vardy, Emma R L C, Piras, Fabrizio, Roveta, Fausto, Piras, Federica, Prestia, Federico Ariel, Assogna, Francesca, Salani, Francesca, Sala, Gessica, Lacidogna, Giordano, Novack, Gisela, Wilcock, Gordon, Thonberg, Håkan, Kölsch, Heike, Weber, Heike, Boecker, Henning, Etchepareborda, Ignacio, Piaceri, Irene, Tuomilehto, Jaakko, Lindström, Jaana, Laczo, Jan, Johnston, Janet, Deleuze, Jean-François, Harris, Jenny, Schott, Jonathan M, Priller, Josef, Bacha, Juan Ignacio, Snowden, Julie, Lisso, Julieta, Mihova, Kalina Yonkova, Traykov, Latchezar, Morelli, Laura, Brusco, Luis Ignacio, Rainer, Malik, Takalo, Mari, Bjerke, Maria, Del Zompo, Maria, Serpente, Maria, Sanchez Abalos, Mariana, Rios, Mario, Peltonen, Markku, Herrman, Martin J, Kohler, Matias, Rojo, Matias, Jones, Matthew, Orsini, Michela, Medel, Nancy, Olivar, Natividad, Fox, Nick C, Salvadori, Nicola, Hooper, Nigel M, Galeano, Pablo, Solis, Patricia, Bastiani, Patrizia, Passmore, Peter, Heun, Reinhard, Antikainen, Riitta, Olaso, Robert, Perneczky, Robert, Germani, Sandra, López-García, Sara, Love, Seth, Mehrabian, Shima, Bagnoli, Silvia, Kochen, Silvia, Andreoni, Simona, Teipel, Stefan, Todd, Stephen, Pickering-Brown, Stuart, Natunen, Teemu, Tegos, Thomas, Laatikainen, Tiina, Strandberg, Timo, Polvikoski, Tuomo M, Matoska, Vaclav, Ciullo, Valentina, Cores, Valeria, Solfrizzi, Vincenzo, Lisetti, Viviana, Sevillano, Zulma, Abdelnour, C., Aguilera, N., Alarcon, E., Alegret, M., Benaque, A., Boada, M., Buendia, M., Cañabate, P., Carracedo, A., Corbatón-Anchuelo, A., de Rojas, I., Diego, S., Espinosa, A., Gailhajenet, A., García-González, P., Gil, S., Guitart, M., González-Pérez, A., Hernández, I., Ibarria, M., Lafuente, A., Macias, J., Maroñas, O., Martín, E., Martínez, M. T., Marquié, M., Mauleón, A., Montrreal, L., Moreno-Grau, S., Moreno, M., Orellana, A., Ortega, G., Pancho, A., Pelejá, E., Pérez-Cordon, A., Pineda, J. A., Preckler, S., Quintela, I., Real, L. M., Rosende-Roca, M., Ruiz, A., Sáez, M. E., Sanabria, A., Serrano-Rios, M., Sotolongo-Grau, O., Tárraga, L., Valero, S., Vargas, L., Adarmes-Gómez, A. D., Alarcón-Martín, E., Alonso, M. D., Álvarez, I., Álvarez, V., Amer-Ferrer, G., Antequera, M., Antúnez, C., Baquero, M., Bernal, M., Blesa, R., Buiza-Rueda, D., Bullido, M. J., Burguera, J. A., Calero, M., Carrillo, F., Carrión-Claro, M., Casajeros, M. J., Clarimón, J., Cruz-Gamero, J. M., de Pancorbo, M. M., Del Ser, T., Diez-Fairen, M., Escuela, R., Garrote-Espina, L., Fortea, J., Franco-Macías, E., Frank-García, A., García-Alberca, J. M., Garcia Madrona, S., Garcia-Ribas, G., Gómez-Garre, P., Hevilla, S., Jesús, S., Labrador Espinosa, M. A., Lage, C., Legaz, A., Lleó, A., Lopez de Munain, A., López-García, S., Macias-García, D., Manzanares, S., Marín, M., Marín-Muñoz, J., Marín, T., Martín Montes, A., Martínez, B., Martínez, C., Martínez, V., Martínez-Lage Álvarez, P., Medina, M., Mendioroz Iriarte, M., Menéndez-González, M., Mir, P., Molinuevo, J. L., Pastor, P., Pérez Tur, J., Periñán-Tocino, T., Pineda-Sanchez, R., Piñol-Ripoll, G., Rábano, A., Real de Asúa, D., Rodrigo, S., Rodríguez-Rodríguez, E., Royo, J. L., Sanchez Del Valle Díaz, R., Sánchez-Juan, P., Sastre, I., Vicente, M. P., Vigo-Ortega, R., Vivancos, L., Macleod, C., McCracken, C., Brayne, Carol, Bresner, Catherine, Grozeva, Detelina, Bellou, Eftychia, Sommerville, Ewen W, Matthews, F., Leonenko, Ganna, Menzies, Georgina, Windle, Gill, Harwood, Janet, Phillips, Judith, Bennett, K., Luckuck, Lauren, Clare, Linda, Woods, Robert, Saad, Salha, Burholt, Vanessa, Rongve, Arvid, Brussels Heritage Lab, Clinical sciences, Neuroprotection & Neuromodulation, and Neurology
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polygenic risk scores ,Multidisciplinary ,Common variants ,Neuroscience(all) ,neurology ,Medizin ,General Physics and Astronomy ,ddc:500 ,General Chemistry ,Alzheimer's disease ,General Biochemistry, Genetics and Molecular Biology ,RISK STRATIFICATION - Abstract
The original version of this Article omitted from the author list the 212th author Patrizia Mecocci, who is from the Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy. Consequently, the “Sample Contribution” section of Author Contributions was updated to add “P.M” between “P.D.” and “R.C.”. Additionally, the original version of this Article contained the incorrect affiliation for author Patrick Gavin Kehoe, which incorrectly read “German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany”. The correct version replaces this affiliation with “Bristol Medical School (THS), University of Bristol, Southmead Hospital, Bristol, UK”. This has been corrected in both the PDF and HTML versions of the Article. CA extern
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- 2023
10. Altered microRNAs related to synaptic function as potential plasma biomarkers for Alzheimer’s disease
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Siedlecki-Wullich, Dolores, Català-Solsona, Judit, Fábregas, Cristina, Hernández, Isabel, Clarimon, Jordi, Lleó, Alberto, Boada, Merce, Saura, Carlos A., Rodríguez-Álvarez, José, and Miñano-Molina, Alfredo J.
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- 2019
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11. Macular vessel density in the superficial plexus is not associated to cerebrospinal fluid core biomarkers for Alzheimer's disease in individuals with mild cognitive impairment: The NORFACE cohort.
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Marquié, Marta, García-Sánchez, Ainhoa, Alarcón-Martín, Emilio, Martínez, Joan, Castilla-Martí, Miguel, Castilla-Martí, Luis, Orellana, Adelina, Montrreal, Laura, de Rojas, Itziar, García-González, Pablo, Puerta, Raquel, Olivé, Clàudia, Cano, Amanda, Hernández, Isabel, Rosende-Roca, Maitée, Vargas, Liliana, Tartri, Juan Pablo, Antonio, Ester Esteban-De, Bojaryn, Urszula, and Ricciardi, Mario
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MILD cognitive impairment ,ALZHEIMER'S disease ,CEREBROSPINAL fluid ,OPTICAL coherence tomography ,CHRONIC obstructive pulmonary disease - Abstract
Background: Optical coherence tomography angiography (OCT-A) is a novel method in the dementia field that allows the detection of retinal vascular changes. The comparison of OCT-A measures with established Alzheimer's disease (AD)-related biomarkers is essential to validate the former as a marker of cerebrovascular impairment in the AD continuum. We aimed to investigate the association of macular vessel density (VD) in the superficial plexus quantified by OCT-A with the AT(N) classification based on cerebrospinal fluid (CSF) Ab1-42, p181-tau and t-tau measurements in individuals with mild cognitive impairment (MCI). Materials and methods: Clinical, demographic, ophthalmological, OCT-A and CSF core biomarkers for AD data from the Neuro-ophthalmology Research at Fundació ACE (NORFACE) project were analyzed. Differences in macular VD in four quadrants (superior, nasal, inferior, and temporal) among three AT(N) groups [Normal, Alzheimer and Suspected non-Alzheimer pathology (SNAP)] were assessed in a multivariate regression model, adjusted for age, APOE +4 status, hypertension, diabetes mellitus, dyslipidemia, heart disease, chronic obstructive pulmonary disease and smoking habit, using the Normal AT(N) group as the reference category. Results: The study cohort comprised 144 MCI participants: 66 Normal AT(N), 45 Alzheimer AT(N) and 33 SNAP AT(N). Regression analysis showed no significant association of the AT(N) groups with any of the regional macular VD measures (all, p > 0.16). The interaction between sex and AT(N) groups had no effect on differentiating VD. Lastly, CSF Aβ1-42, p181-tau and t-tau measures were not correlated to VD (all r < 0.13; p > 0.13). Discussion: Our study showed that macular VD measures were not associated with the AT(N) classification based on CSF biomarkers in patients with MCI, and did not differ between AD and other underlying causes of cognitive decline in our cohort. [ABSTRACT FROM AUTHOR]
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- 2023
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12. Correlations between the NMR Lipoprotein Profile, APOE Genotype, and Cholesterol Efflux Capacity of Fasting Plasma from Cognitively Healthy Elderly Adults.
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de Rojas, Itziar, del Barrio, Laura, Hernández, Isabel, Montrreal, Laura, García-González, Pablo, Marquié, Marta, Valero, Sergi, Cano, Amanda, Orellana, Adelina, Boada, Mercè, Mañes, Santos, and Ruiz, Agustín
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APOLIPOPROTEIN E ,OMEGA-3 fatty acids ,CHOLESTEROL ,GENOTYPES ,ALZHEIMER'S disease ,BLOOD lipoproteins - Abstract
Cholesterol efflux capacity (CEC) is of interest given its potential relationship with several important clinical conditions including Alzheimer's disease. The inactivation of the APOE locus in mouse models supports the idea that it is involved in determining the CEC. With that in mind, we examine the impact of the plasma metabolome profile and the APOE genotype on the CEC in cognitively healthy elderly subjects. The study subjects were 144 unrelated healthy individuals. The plasma CEC was determined by exposing cultured mouse macrophages treated with BODIPY-cholesterol to human plasma. The metabolome profile was determined using NMR techniques. Multiple regression was performed to identify the most important predictors of CEC, as well as the NMR features most strongly associated with the APOE genotype. Plasma 3-hydroxybutyrate was the variable most strongly correlated with the CEC (r = 0.365; p = 7.3 × 10
−6 ). Male sex was associated with a stronger CEC (r = −0.326, p = 6.8 × 10−5 ). Most of the NMR particles associated with the CEC did not correlate with the APOE genotype. The NMR metabolomics results confirmed the APOE genotype to have a huge effect on the concentration of plasma lipoprotein particles as well as those of other molecules including omega-3 fatty acids. In conclusion, the CEC of human plasma was associated with ketone body concentration, sex, and (to a lesser extent) the other features of the plasma lipoprotein profile. The APOE genotype exerted only a weak effect on the CEC via the modulation of the lipoprotein profile. The APOE locus was associated with omega-3 fatty acid levels independent of the plasma cholesterol level. [ABSTRACT FROM AUTHOR]- Published
- 2023
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13. The Synergic Effect of AT(N) Profiles and Depression on the Risk of Conversion to Dementia in Patients with Mild Cognitive Impairment.
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Marquié, Marta, García-Gutiérrez, Fernando, Orellana, Adelina, Montrreal, Laura, de Rojas, Itziar, García-González, Pablo, Puerta, Raquel, Olivé, Clàudia, Cano, Amanda, Hernández, Isabel, Rosende-Roca, Maitée, Vargas, Liliana, Tartari, Juan Pablo, Esteban-De Antonio, Ester, Bojaryn, Urszula, Ricciardi, Mario, Ariton, Diana M., Pytel, Vanesa, Alegret, Montserrat, and Ortega, Gemma
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MILD cognitive impairment ,DISEASE risk factors ,DEMENTIA patients ,ALZHEIMER'S disease ,MENTAL depression ,CEREBROSPINAL fluid - Abstract
Few studies have addressed the impact of the association between Alzheimer's disease (AD) biomarkers and NPSs in the conversion to dementia in patients with mild cognitive impairment (MCI), and no studies have been conducted on the interaction effect of these two risk factors. AT(N) profiles were created using AD-core biomarkers quantified in cerebrospinal fluid (CSF) (normal, brain amyloidosis, suspected non-Alzheimer pathology (SNAP) and prodromal AD). NPSs were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). A total of 500 individuals with MCI were followed-up yearly in a memory unit. Cox regression analysis was used to determine risk of conversion, considering additive and multiplicative interactions between AT(N) profile and NPSs on the conversion to dementia. A total of 224 participants (44.8%) converted to dementia during the 2-year follow-up study. Pathologic AT(N) groups (brain amyloidosis, prodromal AD and SNAP) and the presence of depression and apathy were associated with a higher risk of conversion to dementia. The additive combination of the AT(N) profile with depression exacerbates the risk of conversion to dementia. A synergic effect of prodromal AD profile with depressive symptoms is evidenced, identifying the most exposed individuals to conversion among MCI patients. [ABSTRACT FROM AUTHOR]
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- 2023
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14. Differences in macular vessel density in the superficial plexus across cognitive impairment: the NORFACE cohort.
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Marquié, Marta, Valero, Sergi, Martínez, Joan, Alarcón-Martín, Emilio, García-Sánchez, Ainhoa, de Rojas, Itziar, Castilla-Martí, Miguel, Castilla-Martí, Luis, Hernández, Isabel, Rosende-Roca, Maitée, Vargas, Liliana, Tartari, Juan Pablo, Esteban-De Antonio, Ester, Bojaryn, Urszula, Pytel, Vanesa, Narvaiza, Leire, Alegret, Montserrat, Ortega, Gemma, Espinosa, Ana, and Sanabria, Ángela
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COGNITION disorders ,ALZHEIMER'S disease ,MILD cognitive impairment ,OPTICAL coherence tomography ,MINI-Mental State Examination - Abstract
Optical coherence tomography angiography (OCT-A) allows the detection of retinal vessel density (VD) loss, which is a reflection of brain vascular pathology. We aimed to investigate differences in macular VD in the superficial plexus in a large cohort of individuals cognitively unimpaired (CU), with mild cognitive impairment due to Alzheimer´s disease (MCI-AD), MCI due to cerebrovascular pathology (MCI-Va), probable Alzheimer´s disease dementia (ADD) and Vascular Dementia (VaD). Clinical, demographical, ophthalmological and OCT-A data from the Neuro-ophthalmology Research at Fundació ACE (NORFACE) project were analyzed. Differences of macular VD in four quadrants (superior, nasal, inferior and temporal) among the five diagnostic groups were assessed in a multivariate regression model, adjusted by age, sex, education, hypertension, diabetes mellitus, heart disease and stroke. The study cohort comprised 672 participants: 128 CU, 120 MCI-AD, 111 MCI-Va, 257 ADD and 56 VaD. Regression analysis showed a significantly higher VD in the temporal quadrant in MCI-AD compared to CU participants (49.05 ± 4.91 vs 47.27 ± 4.17, p = 0.02, d = 0.40), and a significantly lower VD in the inferior quadrant in MCI-Va compared to CU participants (48.70 ± 6.57 vs 51.27 ± 6.39, p = 0.02, d = 0.40). Individuals with heart disease presented significantly lower VD in the inferior quadrant than those without (p = 0.01). The interaction of sex and diagnosis had no effect in differentiating VD. Mini-Mental State Examination (MMSE) scores were not correlated to VD (all r < 0.16; p > 0.07). In conclusion, our study showed that the MCI-AD and MCI-Va groups had significant differences in macular VD in opposite directions in the temporal and inferior quadrants, respectively, compared to CU participants, suggesting that macular VD might be able to differentiate two pathogenic pathways (AD- and cerebrovascular-related) in early stages of cognitive decline. [ABSTRACT FROM AUTHOR]
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- 2022
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15. Long runs of homozygosity are associated with Alzheimer’s disease
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Moreno-Grau, Sonia, Fernández, María Victoria, de Rojas, Itziar, García-González, Pablo, Hernández, Isabel, Farias, Fabiana, Pineda Vergara, Juan Antonio, Macías Sánchez, Juan, Mir Rivera, Pablo, Periñán Tocino, María Teresa, and Universidad de Sevilla. Departamento de Medicina
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Alzheimer’s disease - Abstract
Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer’s disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a finescale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [βAVROH (CI 95%) = 0.070 (0.037–0.104); P = 3.91 × 10−5; βFROH (CI95%) = 0.043 (0.009–0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10−16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10−4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in wholeexome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability. Consejería de Salud de la Junta de Andalucía PI-0001/2017
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- 2021
16. Establishing In-House Cutoffs of CSF Alzheimer's Disease Biomarkers for the AT(N) Stratification of the Alzheimer Center Barcelona Cohort.
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Orellana, Adelina, García-González, Pablo, Valero, Sergi, Montrreal, Laura, de Rojas, Itziar, Hernández, Isabel, Rosende-Roca, Maitee, Vargas, Liliana, Tartari, Juan Pablo, Esteban-De Antonio, Ester, Bojaryn, Urszula, Narvaiza, Leire, Alarcón-Martín, Emilio, Alegret, Montserrat, Alcolea, Daniel, Lleó, Alberto, Tárraga, Lluís, Pytel, Vanesa, Cano, Amanda, and Marquié, Marta
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ALZHEIMER'S disease ,CEREBROSPINAL fluid examination ,BLAND-Altman plot ,CEREBROSPINAL fluid ,POSITRON emission tomography ,MILD cognitive impairment ,ENZYME-linked immunosorbent assay ,CHEMILUMINESCENCE immunoassay - Abstract
Background: Clinical diagnosis of Alzheimer's disease (AD) increasingly incorporates CSF biomarkers. However, due to the intrinsic variability of the immunodetection techniques used to measure these biomarkers, establishing in-house cutoffs defining the positivity/negativity of CSF biomarkers is recommended. However, the cutoffs currently published are usually reported by using cross-sectional datasets, not providing evidence about its intrinsic prognostic value when applied to real-world memory clinic cases. Methods: We quantified CSF Aβ1-42, Aβ1-40, t-Tau, and p181Tau with standard INNOTEST
® ELISA and Lumipulse G® chemiluminescence enzyme immunoassay (CLEIA) performed on the automated Lumipulse G600II. Determination of cutoffs included patients clinically diagnosed with probable Alzheimer's disease (AD, n = 37) and subjective cognitive decline subjects (SCD, n = 45), cognitively stable for 3 years and with no evidence of brain amyloidosis in 18F-Florbetaben-labeled positron emission tomography (FBB-PET). To compare both methods, a subset of samples for Aβ1-42 (n = 519), t-Tau (n = 399), p181Tau (n = 77), and Aβ1-40 (n = 44) was analyzed. Kappa agreement of single biomarkers and Aβ1-42/Aβ1-40 was evaluated in an independent group of mild cognitive impairment (MCI) and dementia patients (n = 68). Next, established cutoffs were applied to a large real-world cohort of MCI subjects with follow-up data available (n = 647). Results: Cutoff values of Aβ1-42 and t-Tau were higher for CLEIA than for ELISA and similar for p181Tau. Spearman coefficients ranged between 0.81 for Aβ1-40 and 0.96 for p181TAU. Passing–Bablok analysis showed a systematic and proportional difference for all biomarkers but only systematic for Aβ1-40. Bland–Altman analysis showed an average difference between methods in favor of CLEIA. Kappa agreement for single biomarkers was good but lower for the Aβ1-42/Aβ1-40 ratio. Using the calculated cutoffs, we were able to stratify MCI subjects into four AT(N) categories. Kaplan–Meier analyses of AT(N) categories demonstrated gradual and differential dementia conversion rates (p = 9.815−27 ). Multivariate Cox proportional hazard models corroborated these findings, demonstrating that the proposed AT(N) classifier has prognostic value. AT(N) categories are only modestly influenced by other known factors associated with disease progression. Conclusions: We established CLEIA and ELISA internal cutoffs to discriminate AD patients from amyloid-negative SCD individuals. The results obtained by both methods are not interchangeable but show good agreement. CLEIA is a good and faster alternative to manual ELISA for providing AT(N) classification of our patients. AT(N) categories have an impact on disease progression. AT(N) classifiers increase the certainty of the MCI prognosis, which can be instrumental in managing real-world MCI subjects. [ABSTRACT FROM AUTHOR]- Published
- 2022
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17. PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment
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KLEINEIDAM, Luca, Chouraki, Vincent, Próchnicki, Tomasz, van der Lee, Sven, Madrid‑Márquez, Laura, Wagner-Thelen, Holger, Karaca, Ilker, WEINHOLD, Leonie, Wolfsgruber, Steffen, Boland, Anne, Martino Adami, Pamela, Lewczuk, Piotr, POPP, Julius, Brosseron, Frederic, Jansen, Iris, HULSMAN, Marc, Kornhuber, Johannes, Peters, Oliver, Berr, Claudine, Heun, Reinhard, Frölich, Lutz, Tzourio, Christophe, Dartigues, Jean-François, Hüll, Michael, Espinosa, Ana, Hernández, Isabel, de Rojas, Itziar, ORELLANA, Adelina, VALERO, Sergi, STRINGA, Najada, Van Schoor, Natasja, Huisman, Martijn, Scheltens, Philip, For The Alzheimer'S Disease Neuroimaging Initiative, (ADNI), Rüther, Eckart, Deleuze, Jean-François, Wiltfang, Jens, Tarraga, Lluis, Schmid, Matthias, Scherer, Martin, Riedel-Heller, Steffi, Heneka, Michael, Amouyel, Philippe, Jessen, Frank, Boada, Merce, Maier, Wolfgang, Schneider, Anja, González‑Pérez, Antonio, van der Flier, Wiesje, Wagner, Michael, Lambert, Jean-Charles, Holstege, Henne, Saez, Mª Eugenia, Latz, Eicke, Ruiz, Agustin, Ramirez, Alfredo, University Hospital Bonn, Universität zu Köln, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Epidémiologie et de Santé Publique [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Amsterdam UMC, Vrije Universiteit Amsterdam [Amsterdam] (VU), Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] (CAEBi), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Universitätsklinikum Erlangen [Erlangen], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), University of Bialystok, Lausanne University Hospital, University hospital of Zurich [Zurich], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Universität Heidelberg [Heidelberg], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Albert-Ludwigs-Universität Freiburg, Universitat Internacional de Catalunya [Barcelona] (UIC), Instituto de Salud Carlos III [Madrid] (ISC), University Medical Center Göttingen (UMG), Universidade de Aveiro, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Universität Leipzig [Leipzig], University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Open Access funding provided by Projekt DEAL. This publication was funded in part by the German Federal Ministry of Education and Research (BMBF) (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434, grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B). Analyses were also funded by the German Federal Ministry of Education and Research (BMBF 01EA1410A) within the project 'Diet-Body-Brain: from epidemiology to evidence-based communication'. Part of the work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Part of the analysis was funded by the German Research Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case–control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Data collection and sharing for this project were funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, Araclon Biotech, BioClinica, Inc., Biogen, Bristol-Myers Squibb Company, CereSpir, Inc., Cogstate, Eisai Inc., ElanPharmaceuticals, Inc., Eli Lilly and Company, EuroImmun, F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc., Fujirebio, GE Healthcare, IXICO Ltd., Janssen Alzheimer Immunotherapy Research and Development, LLC., Johnson and Johnson Pharmaceutical Research and Development LLC., Lumosity, Lundbeck, Merck and Co., Inc., Meso Scale Diagnostics, LLC., NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corporation, Pfizer Inc., Piramal Imaging, Servier, Takeda Pharmaceutical Company, and transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California. The Three-City Study genotyping and analysis was funded by the GENMED Labex, the Joint Programming Initiative on Neurodegenerative Diseases Research (JPND, PERADES project), the Institute Pasteur de Lille, the University of Lille, and the Nord-Pas de Calais Regional Council. This work also benefited from the Lille Métropole Communauté Urbaine Council, the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to Alzheimer’s disease). In addition, the Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. Additional funding for the 3C Study was also obtained from the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM 'Cohortes et collections de données biologiques' programme. Lille Génopôle received an unconditional grant from Eisai. Fundacio ACE cohort receives support from the Innovative Medicines Initiative 2 Joint Undertaking which receives support from the European Union’s Horizon 2020 research and innovation programme (ADAPTED Grant No. 115975). A. Ruiz’s research is also supported by Instituto de Salud Carlos III (ISCIII) grants PI13/02434, PI16/01861, and PI19/01301. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de Hacer Europa'), by Fundación bancaria 'La Caixa' and Grifols SA (GR@ACE project). For the Longitudinal Aging Study Amsterdam (LASA) supports was largely obtained from a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The data collection in 2012–2013 was financially supported by the Netherlands Organization for Scientific Research (NWO) in the framework of the project 'New Cohorts of young old in the twenty-first century' (File Number 480-10-014). Genotyping using Axiom-NL array was financially supported by EMGO+ Research Institute. PL was supported by the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. JW is supported by an Ilídio Pinho professorship and iBiMED (UID/BIM/04501/2013), at the University of Aveiro, Portugal. JP was supported by a grant from the Swiss National Science Foundation (320030L_141179)., Universität zu Köln = University of Cologne, Amsterdam UMC - Amsterdam University Medical Center, Universität Heidelberg [Heidelberg] = Heidelberg University, Universität Leipzig, Alzheimer's Disease Neuroimaging Initiative (ADNI), Kleineidam, L., Karaca, I., Heneka, M.T., Maier, W., Schneider, A., Wagner, M., Chouraki, V., Amouyel, P., Lambert, J.C., Próchnicki, T., Latz, E., van der Lee, S.J., Jansen, I.E., Hulsman, M., Scheltens, P., van der Flier, W.M., Holstege, H., Madrid-Márquez, L., González-Pérez, A., Sáez, M.E., Wagner-Thelen, H., Martino Adami, P.V., Jessen, F., Ramirez, A., Weinhold, L., Schmid, M., Wolfsgruber, S., Brosseron, F., Boland, A., Deleuze, J.F., Lewczuk, P., Kornhuber, J., Popp, J., Peters, O., Berr, C., Heun, R., Frölich, L., Tzourio, C., Dartigues, J.F., Hüll, M., Espinosa, A., Hernández, I., de Rojas, I., Orellana, A., Valero, S., Ruiz, A., Tarraga, L., Boada, M., Stringa, N., van Schoor, N.M., Huisman, M., Rüther, E., Wiltfang, J., Scherer, M., Riedel-Heller, S., Neurology, Human genetics, Epidemiology and Data Science, APH - Aging & Later Life, APH - Societal Participation & Health, Amsterdam Neuroscience - Complex Trait Genetics, APH - Personalized Medicine, APH - Methodology, Sociology, and The Social Context of Aging (SoCA)
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Apolipoprotein E ,Male ,pathology [Cognitive Dysfunction] ,Cognitive decline ,genetics [Alzheimer Disease] ,Disease ,SEPIA ,pathology [Alzheimer Disease] ,0302 clinical medicine ,Cognition ,genetics [Amyloid beta-Peptides] ,Medicine ,Aged, 80 and over ,0303 health sciences ,education.field_of_study ,Microglia ,physiology [Cognition] ,Middle Aged ,medicine.anatomical_structure ,Disease Progression ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,analysis [Biomarkers] ,Alzheimer’s disease ,Amyloid ,Phospholipase C gamma 2 ,Population ,tau Proteins ,Pathology and Forensic Medicine ,PLCG2 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,SDG 3 - Good Health and Well-being ,Alzheimer Disease ,Humans ,Cognitive Dysfunction ,ddc:610 ,education ,Mild cognitive impairment ,HEALTHY ,030304 developmental biology ,Aged ,metabolism [Phospholipase C gamma] ,Original Paper ,Amyloid beta-Peptides ,TREM2 ,business.industry ,Phospholipase C gamma ,genetics [Cognitive Dysfunction] ,metabolism [tau Proteins] ,cerebrospinal fluid [tau Proteins] ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Immunology ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Biomarkers - Abstract
A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aβ1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.
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- 2020
18. Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity
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van der Lee, Sven J, Conway, Olivia J, Zettergren, Anna, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W, Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, van der Flier, Wiesje M, Holstege, Henne, Mead, S., Synofzik, M., Andlauer, Till F M, van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Diez-Fairen, Monica, Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Simon-Sanchez, Javier, Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldö, M., Lleó, Alberto, Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G-Y R, Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., McKeith, I. G., Zetterberg, Henrik, Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Nygaard, Marianne, Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Blauwendraat, Cornelis, Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., Savage, Jeanne E, van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Mengel-From, Jonas, Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Jansen, Iris, Moreno-Grau, Sonia, Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Wagner, Michael, Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Fortea, Juan, Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G. P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Keogh, Michael J, Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H-H, Graff, C., Pasquier, F., Rollin, A., Blennow, Kaj, Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Coppola, G., Skoog, Ingmar, Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., DeCarli, C., Friese, Manuel A, Geschwind, D. H., Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, Carrasquillo, Minerva M, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Kleineidam, Luca, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart N M, Alcolea, Daniel, Wiendl, Heinz, van den Akker, Erik, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO, EADB, IFGC, IPDGC, RiMod-FTD, Bank, Netherlands Brain, Boeve, Bradley F, Hernández, Isabel, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel J T, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, van Eijk, Kristel R, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Stringa, Najada, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande A L, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Chen, Jason A, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild I A, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT, and Clarimón, Jordi
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0301 basic medicine ,Dementia with Lewy bodies ,Disease ,Bioinformatics ,Neurodegenerative disease ,0302 clinical medicine ,Missense mutation ,media_common ,2. Zero hunger ,Longevity ,Brain ,Parkinson Disease ,Phospholipase C Gamma 2 ,Biobank ,3. Good health ,ddc ,Frontotemporal Dementia ,Microglia ,Alzheimer's disease ,Alzheimer’s disease ,Amyotrophic lateral sclerosis ,Frontotemporal dementia ,Multiple sclerosis ,PLCG2 ,Parkinson’s disease ,Progressive supranuclear palsy ,Lewy Body Disease ,Risk ,Multiple Sclerosis ,media_common.quotation_subject ,education ,Neuroimaging ,Genomics ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,SDG 3 - Good Health and Well-being ,Alzheimer Disease ,medicine ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,Alleles ,Phospholipase C gamma ,business.industry ,Amyotrophic Lateral Sclerosis ,Correction ,medicine.disease ,030104 developmental biology ,Mutation ,Dementia ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target. The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.
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- 2019
19. Cognitive Composites Domain Scores Related to Neuroimaging Biomarkers within Probable-Amnestic Mild Cognitive Impairment-Storage Subtype
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Espinosa, Ana, Alegret, Montserrat, Pesini, Pedro, Valero Ventura, Sergi, Lafuente, Asunción, Buendía, Mar, San José, Itziar, Ibarria, Marta, Tejero, Miguel Ángel, Giménez Ruiz, Joan, Ruiz, Susana, Hernández, Isabel, Pujadas, Francesc, Martínez Lage, Pablo, Munuera, Josep, Arbizu, Javier, Tárraga, Lluís, Hendrix, Suzanne B., Ruiz, Agustín, Becker, James T., Landau, Susan M., Sotolongo Grau, Oscar, Sarasa, Manuel, Boada, Mercè, and Universitat Autònoma de Barcelona
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0301 basic medicine ,cognition ,Male ,positron emission tomography ,hippocampus ,Neuropsychological Tests ,Hippocampus ,memory ,Cognition ,0302 clinical medicine ,Hippocampus (mythology) ,magnetic resonance imaging ,Neuropsychological assessment ,Composite material ,Aged, 80 and over ,Aniline Compounds ,medicine.diagnostic_test ,General Neuroscience ,amyloid ,Brain ,General Medicine ,Organ Size ,Alzheimer's disease ,3. Good health ,Psychiatry and Mental health ,Clinical Psychology ,Female ,Psychology ,Alzheimer’s disease ,Research Article ,Amyloid ,Positron emission tomography ,Prodromal Symptoms ,Neuroimaging ,03 medical and health sciences ,amnestic mild cognitive impairment ,Magnetic resonance imaging ,Memory ,Alzheimer Disease ,Fluorodeoxyglucose F18 ,mental disorders ,medicine ,Dementia ,Humans ,Cognitive Dysfunction ,Survival analysis ,Aged ,medicine.disease ,Survival Analysis ,Thiazoles ,030104 developmental biology ,Positron-Emission Tomography ,Mental Recall ,Amnestic mild cognitive impairment ,Geriatrics and Gerontology ,Radiopharmaceuticals ,030217 neurology & neurosurgery - Abstract
The probable-amnestic (Pr-a) mild cognitive impairment (MCI)-storage subtype is a phenotype with 8.5 times more risk of conversion to dementia, mainly Alzheimer's disease (AD), than the possible non-amnestic (Pss-na) MCI. The aim of this study was to find the optimized cognitive composites (CCs) domain scores most related to neuroimaging biomarkers within Pr-aMCI-storage subtype patients. The Fundació ACE (ACE) study with 20 Pr-aMCI-storage subtype subjects (MCI) were analyzed. All subjects underwent a neuropsychological assessment, a structural MRI, FDG-PET, and PIB-PET. The adjusted hippocampal volume (aHV) on MRI, the standard uptake value ratio (SUVR) on FDG-PET and PIB-PET SUVR measures were analyzed. The construction of the CCs domain scores, and the aHV on MRI and FDG-PET SUVR measures, were replicated in the parental AB255 study database (n = 133 MCI). Partial correlations adjusted by age, gender, and education were calculated with the associated p -value among every CC domain score and the neuroimaging biomarkers. The results were replicated in the "MCI due to AD" with memory storage impairments from ADNI. Delayed Recall CC domain score was significantly correlated with PIB-PET SUVR (β= -0.61, p = 0.003) in the ACE study and also with aHV on MRI (β= 0.27, p = 0.01) and FDG-PET SUVR (β= 0.27, p = 0.01) in the AB255 study. After a median survival time of 20.6 months, 85% from the ACE MCI converted to AD. The replication of our results in the ADNI dataset also confirmed our findings. Delayed Recall is the CC domain score best correlated with neuroimaging biomarkers associated with prodromal AD diagnosis.
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- 2017
20. From Face-to-Face to Home-to-Home: Validity of a Teleneuropsychological Battery.
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Alegret, Montserrat, Espinosa, Ana, Ortega, Gemma, Pérez-Cordón, Alba, Sanabria, Ángela, Hernández, Isabel, Marquié, Marta, Rosende-Roca, Maitée, Mauleón, Ana, Abdelnour, Carla, Vargas, Liliana, de Antonio, Ester Esteban, López-Cuevas, Rogelio, Tartari, Juan Pablo, Alarcón-Martín, Emilio, Tárraga, Lluís, Ruiz, Agustín, Boada, Mercè, and Valero, Sergi
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CONFIRMATORY factor analysis ,EXPLORATORY factor analysis ,MILD cognitive impairment ,FACTOR structure ,NEUROPSYCHOLOGICAL tests ,CLINICAL neuropsychology ,PERCEIVED Stress Scale ,MEMORY ,MEDICAL consultation ,POCKET computers ,ATTENTION ,TELEMEDICINE - Abstract
Background: Over the last decade, teleneuropsychology has increased substantially. There is a need for valid neuropsychological batteries to be administered home-to-home. Since 2006, the neuropsychological battery of Fundació ACE (NBACE) has been administered face-to-face in our clinical settings. Recently, we adapted the NBACE for teleneuropsychology use to be administered home-to-home (NBACEtn).Objective: The aims of the present study are: 1) to determine the home-to-home NBACE equivalence compared to its original face-to-face version; and 2) to examine home-to-home NBACE discriminant capacity by differentiating among cognitively healthy, mild cognitive impairment, or mild dementia subjects and comparing it with the face-to-face version.Methods: Data from 338 individuals assessed home-to-home (NBACEtn) were contrasted with 7,990 participants assessed with its face-to-face version (NBACE). Exploratory and confirmatory factorial structure, and invariance analysis of the two versions of the battery were performed.Results: Exploratory and confirmatory factor analysis supported the four-factor model (attention, memory, executive, and visuospatial/constructional functions). Configural, metric, and scalar measurement invariance was found between home-to-home and face-to-face NBACE versions. Significant differences in most of the neuropsychological variables assessed were observed between the three clinical groups in both versions of administration. No differences were found between the technological devices used by participants (computer or tablet and mobile devices).Conclusion: For the first time, invariance analysis findings were addressed by determining a teleneuropsychological battery's equivalence in comparison with its face-to-face version. This study amplifies the neuropsychological assessment's applicability using a home-to-home format, maintaining the original measure's structure, interpretability, and discriminant capacity. [ABSTRACT FROM AUTHOR]- Published
- 2021
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21. Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.
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de Rojas, Itziar, Moreno-Grau, Sonia, Tesi, Niccolo, Grenier-Boley, Benjamin, Andrade, Victor, Jansen, Iris E., Pedersen, Nancy L., Stringa, Najada, Zettergren, Anna, Hernández, Isabel, Montrreal, Laura, Antúnez, Carmen, Antonell, Anna, Tankard, Rick M., Bis, Joshua C., Sims, Rebecca, Bellenguez, Céline, Quintela, Inés, González-Perez, Antonio, and Calero, Miguel
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ALZHEIMER'S disease ,ALZHEIMER'S patients - Abstract
Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease. Known genetic loci account for only a fraction of the genetic contribution to Alzheimer's disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer's disease polygenic risk score. [ABSTRACT FROM AUTHOR]
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- 2021
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22. Neuropsychiatric profiles and conversion to dementia in mild cognitive impairment, a latent class analysis.
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Roberto, Natalia, Portella, Maria J., Marquié, Marta, Alegret, Montserrat, Hernández, Isabel, Mauleón, Ana, Rosende-Roca, Maitee, Abdelnour, Carla, de Antonio, Ester Esteban, Gil, Silvia, Tartari, Juan P., Vargas, Liliana, Espinosa, Ana, Ortega, Gemma, Pérez-Cordón, Alba, Sanabria, Ángela, Orellana, Adelina, de Rojas, Itziar, Moreno-Grau, Sonia, and Montrreal, Laura
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NEUROPSYCHIATRY ,ALZHEIMER'S disease ,DEMENTIA ,MENTAL depression ,PARKINSON'S disease - Abstract
Neuropsychiatric symptoms (NPS) have been recently addressed as risk factors of conversion to Alzheimer's disease (AD) and other dementia types in patients diagnosed with Mild Cognitive Impairment (MCI). Our aim was to determine profiles based on the prominent NPS in MCI patients and to explore the predictive value of these profiles on conversion to specific types of dementia. A total of 2137 MCI patients monitored in a memory clinic were included in the study. Four NPS profiles emerged (classes), which were defined by preeminent symptoms: Irritability, Apathy, Anxiety/Depression and Asymptomatic. Irritability and Apathy were predictors of conversion to dementia (HR = 1.43 and 1.56, respectively). Anxiety/depression class showed no risk effect of conversion when compared to Asymptomatic class. Irritability class appeared as the most discriminant neuropsychiatric condition to identify non-AD converters (i.e., frontotemporal dementia, vascular dementia, Parkinson's disease and dementia with Lewy Bodies). The findings revealed that consistent subgroups of MCI patients could be identified among comorbid basal NPS. The preeminent NPS showed to behave differentially on conversion to dementia, beyond AD. Therefore, NPS should be used as early diagnosis facilitators, and should also guide clinicians to detect patients with different illness trajectories in the progression of MCI. [ABSTRACT FROM AUTHOR]
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- 2021
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23. Longitudinal Neuroimaging Analysis in Mild-Moderate Alzheimer's Disease Patients Treated with Plasma Exchange with 5% Human Albumin
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Cuberas-Borrós, Gemma, Roca Bielsa, María Isabel, Boada, Mercè, Tárraga, Lluís, Hernández, Isabel, Buendia, Mar, Rubio, Lourdes, Torres, Gustavo, Bittini, Ángel, Guzmán-de-Villoria, Juan A., Pujadas, Francesc, Torres, Mireia, Núñez, Laura, Castell Conesa, Joan, Páez, Antonio, and Universitat Autònoma de Barcelona
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0301 basic medicine ,Male ,medicine.medical_specialty ,Pathology ,Time Factors ,Perfusion scanning ,Neuroimaging ,Serum Albumin, Human ,Statistical parametric mapping ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Internal medicine ,medicine ,Humans ,Longitudinal Studies ,Cerebral perfusion pressure ,Aged ,Aged, 80 and over ,Tomography, Emission-Computed, Single-Photon ,medicine.diagnostic_test ,Plasma Exchange ,business.industry ,single-photon emission computed tomography ,General Neuroscience ,Albumin ,Magnetic resonance imaging ,General Medicine ,Alzheimer's disease ,Middle Aged ,Magnetic Resonance Imaging ,Psychiatry and Mental health ,Clinical Psychology ,030104 developmental biology ,Treatment Outcome ,Brain size ,Cardiology ,Female ,Geriatrics and Gerontology ,business ,Perfusion ,Alzheimer’s disease ,030217 neurology & neurosurgery ,Brodmann area ,Research Article - Abstract
Altres ajuts: This study was funded by Grifols. [...] James T. Becker (Department of Psychiatry, Neurology and Psychology. University of Pittsburgh, Pittsburgh PA, USA) read and commented on an earlier draft of the manuscript. Jordi Bozzo PhD, CMPP (Grifols) is acknowledged for medical writing and editorial assistance in the preparation of the manuscript. Recently, modifications of Aβ levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer's disease (AD) treated with plasma exchange (PE) with albumin replacement. To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial. Patients received between 3 and 18 PE with albumin (Albutein ® 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam ®) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline. 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls. Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion.
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- 2018
24. Dementia Care in Times of COVID-19: Experience at Fundació ACE in Barcelona, Spain.
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Benaque, Alba, Gurruchaga, Miren Jone, Abdelnour, Carla, Hernández, Isabel, Cañabate, Pilar, Alegret, Montserrat, Rodríguez, Isabel, Rosende-Roca, Maitee, Tartari, Juan Pablo, Esteban, Ester, López, Rogelio, Gil, Silvia, Vargas, Liliana, Mauleón, Ana, Espinosa, Ana, Ortega, Gemma, Sanabria, Angela, Pérez, Alba, Alarcón, Emilio, and González-Pérez, Antonio
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COVID-19 ,COVID-19 pandemic ,MILD cognitive impairment ,PATIENT safety ,DEMENTIA ,CORONAVIRUS disease treatment ,TREATMENT of dementia ,VIRAL pneumonia ,RESEARCH ,RESEARCH methodology ,PATIENT-centered care ,EVALUATION research ,MEDICAL cooperation ,HOLISTIC medicine ,COMPARATIVE studies ,EPIDEMICS ,TELEMEDICINE ,LONGITUDINAL method - Abstract
Background: Fundació ACE is a non-profit organization providing care based on a holistic model to persons with cognitive disorders and their families for 25 years in Barcelona, Spain. Delivering care to this vulnerable population amidst the COVID-19 pandemic has represented a major challenge to our institution.Objective: To share our experience in adapting our model of care to the new situation to ensure continuity of care.Methods: We detail the sequence of events and the actions taken within Fundació ACE to swiftly adapt our face-to-face model of care to one based on telemedicine consultations. We characterize individuals under follow-up by the Memory Unit from 2017 to 2019 and compare the number of weekly visits in 2020 performed before and after the lockdown was imposed.Results: The total number of individuals being actively followed by Fundació ACE Memory Unit grew from 6,928 in 2017 to 8,147 in 2019. Among those newly diagnosed in 2019, most patients had mild cognitive impairment or mild dementia (42% and 25%, respectively). Weekly visits dropped by 60% following the suspension of face-to-face activity. However, by April 24 we were able to perform 78% of the visits we averaged in the weeks before confinement began.Discussion: We have shown that Fundació ACE model of care has been able to successfully adapt to a health and social critical situation as COVID-19 pandemic. Overall, we were able to guarantee the continuity of care while preserving the safety of patients, families, and professionals. We also seized the opportunity to improve our model of care. [ABSTRACT FROM AUTHOR]- Published
- 2020
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25. Evaluation of macular thickness and volume tested by optical coherence tomography as biomarkers for Alzheimer's disease in a memory clinic.
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Sánchez, Domingo, Castilla-Marti, Miguel, Marquié, Marta, Valero, Sergi, Moreno-Grau, Sonia, Rodríguez-Gómez, Octavio, Piferrer, Albert, Martínez, Gabriel, Martínez, Joan, Rojas, Itziar De, Hernández, Isabel, Abdelnour, Carla, Rosende-Roca, Maitée, Vargas, Liliana, Mauleón, Ana, Gil, Silvia, Alegret, Montserrat, Ortega, Gemma, Espinosa, Ana, and Pérez-Cordón, Alba
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BIOMARKERS ,OPTICAL coherence tomography ,ALZHEIMER'S disease ,RETINAL ganglion cells ,IMAGE quality analysis - Abstract
Building on previous studies that report thinning of the macula in Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients, the use of optical coherence tomography (OCT) has been proposed as a potential biomarker for AD. However, other studies contradict these results. A total of 930 participants (414 cognitively healthy people, 192 with probable amnestic MCI, and 324 probable AD patients) from a memory clinic were consecutively included in this study and underwent a spectral domain OCT scan (Maestro, Topcon) to assess total macular volume and thickness. Macular width measurements were also taken in several subregions (central, inner, and outer rings) and in layers such as the retinal nerve fiber (RNFL) and ganglion cell (CGL). The study employed a design of high ecological validity, with adjustment by age, education, sex, and OCT image quality. AD, MCI, and control groups did not significantly vary with regard to volume and retinal thickness in different layers. When these groups were compared, multivariate-adjusted analysis disclosed no significant differences in total (p = 0.564), CGL (p = 0.267), RNFL (p = 0.574), and macular thickness and volume (p = 0.380). The only macular regions showing significant differences were the superior (p = 0.040) and nasal (p = 0.040) sectors of the inner macular ring. However, adjustment for multiple comparisons nullified this significance. These results are not supporting existing claims for the usefulness of macular thickness as a biomarker of cognitive impairment in a memory unit. OCT biomarkers for AD should be subject to further longitudinal testing. [ABSTRACT FROM AUTHOR]
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- 2020
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26. The MAPT H1 Haplotype Is a Risk Factor for Alzheimer's Disease in APOE ε4 Non-carriers.
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Sánchez-Juan, Pascual, Moreno, Sonia, de Rojas, Itziar, Hernández, Isabel, Valero, Sergi, Alegret, Montse, Montrreal, Laura, García González, Pablo, Lage, Carmen, López-García, Sara, Rodrííguez-Rodríguez, Eloy, Orellana, Adelina, Tárraga, Lluís, Boada, Mercè, and Ruiz, Agustín
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ALZHEIMER'S disease ,APOLIPOPROTEIN E4 ,MICROTUBULE-associated proteins ,TAU proteins - Abstract
An ancestral inversion of 900 kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene, defines two haplotype clades in Caucasians (H1 and H2). The H1 haplotype has been linked inconsistently with AD. In a previous study, we showed that an SNP tagging this haplotype (rs1800547) was associated with AD risk in a large population from the Dementia Genetics Spanish Consortium (DEGESCO) including 4435 cases and 6147 controls. The association was mainly driven by individuals that were non-carriers of the APOE ε4 allele. Our aim was to replicate our previous findings in an independent sample of 4124 AD cases and 3290 controls from Spain (GR@ACE project) and to analyze the effect of the H1 sub-haplotype structure on the risk of AD. The H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0025). Stratification analysis showed that this association was mainly driven by the APOE ε4 non-carriers (OR = 1.15; p = 0.0022). Pooled analysis of both Spanish datasets (n = 17,996) showed that the highest AD risk related to the MAPT H1/H2 haplotype was in those individuals that were the oldest [third tertile (>77 years)] and did not carry APOE ε4 allele (p = 0.001). We did not find a significant association between H1 sub-haplotypes and AD. H1c was nominally associated but lost statistical significance after adjusting by population sub-structure. Our results are consistent with the hypothesis that genetic variants linked to the MAPT H1/H2 are tracking a genuine risk allele for AD. The fact that this association is stronger in APOE ε4 non-carriers partially explains previous controversial results and might be related to a slower alternative causal pathway less dependent on brain amyloid load. [ABSTRACT FROM AUTHOR]
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- 2019
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27. Genome‐wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project.
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Moreno‐Grau, Sonia, de Rojas, Itziar, Hernández, Isabel, Quintela, Inés, Montrreal, Laura, Alegret, Montserrat, Hernández‐Olasagarre, Begoña, Madrid, Laura, González‐Perez, Antonio, Maroñas, Olalla, Rosende‐Roca, Maitée, Mauleón, Ana, Vargas, Liliana, Lafuente, Asunción, Abdelnour, Carla, Rodríguez‐Gómez, Octavio, Gil, Silvia, Santos‐Santos, Miguel Ángel, Espinosa, Ana, and Ortega, Gemma
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Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome‐wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta‐analyzed with additional genome‐wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta‐analysis strategy revealed the ANKRD31‐rs4704171 and NDUFAF6‐rs10098778 and confirmed SCIMP‐rs7225151 and CD33‐rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta‐analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series. Highlights: We detected three gene categories operating differently in AD subgroups of patients.Vasculature regulation may be an essential part of the causative mechanism in pure AD.Two novel signals reached genome‐wide significance in ANKRD31 and NDUFAF6loci.We confirmed SCIMP‐rs7225151 and CD33‐rs3865444 to be genome‐wide significant.Genetic discoveries are strongly impacted by the presence of subgroups of AD. [ABSTRACT FROM AUTHOR]
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- 2019
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28. MAPT H1 haplotype is associated with late-onset Alzheimer's disease risk in APOE ε 4 noncarriers: Results from the dementia genetics Spanish consortium
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Pastor, Pau, Moreno, Fermín, Antonell, Anna, Elcoroaristizabal, Xabier, Lleó, Alberto, Blesa, Rafael, Fortea, Juan, Belbin, Olivia, Alcolea, Daniel, Carmona-Iragui, María, Sánchez-Saudinós, M Belén, Sala, Isabel, Anton-Aguirre, Sofía, Coto, Eliecer, Morenas, Estrella, Ribosa, Roser, Colom-Cadena, Martí, Cervera, Laura, Muñoz, Laia, Dols-Icardo, Oriol, Clarimón, Jordi, Ortega-Cubero, Sara, Hernandez, Isabel, Tárraga, Lluís, Boada, Mercè, Kulisevsky, Jaime, Vázquez-Higuera, José Luis, Infante, Jon, Rábano, Alberto, Fernández-Blázquez, Miguel Ángel, Valentí, Meritxell, Indakoetxea, Begoña, Barandiarán, Myriam, Gorostidi, Ana, Frank-García, Ana, Sastre, Isabel, Lorenzo, Elena, Ruiz, Agustín, Pastor, María A, Lennarz, Martina, Maier, Wolfgang, Rámirez, Alfredo, Serrano-Ríos, Manuel, Lee, Suzee E, Sánchez-Juan, Pascual, Consortium, Dementia Genetic Spanish, Combarros, Onofre, Lorenzo-Betancor, Oswaldo, Pastor, Maria A, Hernández, Isabel, Lafuente, Asunción, Rosende-Roca, Maitée, Mauleón, Ana, Vargas, Liliana, Rodríguez, Octavio, Calero, Miguel, Abdelnour, Carla, Alegret, Montserrat, Espinosa, Ana, Ortega, Gemma, Sanabria, Ángela, Ibarria, Marta, Diego, Susana, Canyabate, Pilar, Moreno, Mariola, Buendía, Mar, López de Munain, Adolfo, Pancho, Ana, Palacio, María Eugenia, Ruiz, Susana, Tantinya, Natalia, Tarragona, Marina, Morera, América, Guitart, Marina, Sotolongo Grau, Oscar, Martín, Elvira, Fernández, Victòria, Bullido, Maria J, Sánchez-Valle, Raquel, Molinuevo, José Luis, Lladó, Albert, Rami, Lorena, Alvarez, Victoria, de Pancorbo, Marian M, Pozueta, Ana, González Suarez, Andrea, Carro, Eva, Rodriguez-Rodriguez, Eloy, Mateo, Ignacio, Berciano, José, Bullido, María J, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Universidad Pública de Navarra, Universidad del País Vasco, Universidad Autónoma de Madrid, Fundació ACE. Institut Català de Neurociències Aplicades, University of Bonn, University of California, Universitat de Barcelona, Universitat Autònoma de Barcelona, and Universitat Oberta de Catalunya (UOC)
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Gerontology ,Male ,associació genètica ,genetic association ,Apolipoprotein E4 ,A152T ,enfermedad de Alzheimer ,genetics [Alzheimer Disease] ,frontotemporal dementia ,MAPT ,Alzheimer, Enfermedad de ,genetics [Genetic Predisposition to Disease] ,genetics [Frontotemporal Dementia] ,genetics [Apolipoprotein E4] ,Aged, 80 and over ,General Neuroscience ,General Medicine ,demencia frontotemporal ,Middle Aged ,Alzheimer's disease ,Psychiatry and Mental health ,Clinical Psychology ,demència frontotemporal ,genetics [Polymorphism, Single Nucleotide] ,Christian ministry ,Female ,Alzheimer’s disease ,Frontotemporal dementia ,Late onset ,MAPT protein, human ,tau Proteins ,Polymorphism, Single Nucleotide ,asociación genética ,Alzheimer Disease ,malaltia d'Alzheimer ,mental disorders ,medicine ,Dementia ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,Genetic association ,Aged ,business.industry ,Haplotype ,medicine.disease ,nervous system diseases ,H1H2 ,genetics [tau Proteins] ,Alzheimer, Malaltia d' ,Logistic Models ,Haplotypes ,Spain ,Disease risk ,Geriatrics and Gerontology ,business - Abstract
The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR)=2.03; p=0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR=1.12; p=0.0005). Stratification analysis showed that this association was mainly driven by APOE ε4 noncarriers (OR=1.14; p=0.0025). MAPT H1 was also associated with risk for PD (OR=1.30; p=0.0003) and PSP (OR=3.18; p=8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ε4 AD., Spanish Ministry of Science and Innovation SAF 2006-10126 (2006–2009) and SAF2010-22329-C02-01 (2011–2013) to P.P and by the UTE project FIMA to P.P. Grants from the Ministry of Science (SAF2010-15558) and CIBERNED. Agust´ın Ruiz is supported by grant PI13/02434 (Acción Estratégica en Salud. Instituto de Salud Carlos III. Ministerio de Economía y Competitividad, Spain). Grant: Consolider (CSD2010-00045).
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- 2015
29. Exploring Genetic Associations of Alzheimer's Disease Loci With Mild Cognitive Impairment Neurocognitive Endophenotypes.
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Espinosa, Ana, Hernández-Olasagarre, Begoña, Moreno-Grau, Sonia, Kleineidam, Luca, Heilmann-Heimbach, Stefanie, Hernández, Isabel, Wolfsgruber, Steffen, Wagner, Holger, Rosende-Roca, Maitée, Mauleón, Ana, Vargas, Liliana, Lafuente, Asunción, Rodríguez-Gómez, Octavio, Abdelnour, Carla, Gil, Silvia, Marquié, Marta, Santos-Santos, Miguel A., Sanabria, Ángela, Ortega, Gemma, and Monté-Rubio, Gemma
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- 2018
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30. ATP5H/KCTD2 locus is associated with Alzheimer's disease risk
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Boada, Mercè, Antúnez, Carmen, Ramírez Lorca, Repo, DeStefano, Anita L., González Pérez, A., Gayán, Javier, López Arrieta, Jesús, Ikram, M. Arfan, Hernández, Isabel, Marín, J., Galán, José Jorge, Bis, Joshua C., Mauleón, Ana, Rosende-Roca, Maitée, Moreno Rey, Concha, Gudnason, Vilmundur, Morón, Francisco Jesús, Velasco, Juan, Carrasco, José Miguel, Alegret, Montserrat, Espinosa, Ana, Vinyes, Georgina, Lafuente, Asunción, Vargas, Liliana, Fitzpatrick, Annette L., Launer, Lenore Joy, Sáez, María Eugenia, Vázquez, Enrique, Becker, James T., López, Oscar L., Serrano Ríos, Manuel, Tárraga, Lluís, van Duijn, Cornelia M., Real, Luis M., Seshadri, Sudha, Ruiz, Agustín, Universitat Autònoma de Barcelona, Radiology & Nuclear Medicine, and Epidemiology
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Male ,Genotyping Techniques ,SNP ,Locus (genetics) ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,molecular epidemiology ,Cohort Studies ,Cellular and Molecular Neuroscience ,Alzheimer Disease ,medicine ,genomics ,Humans ,GWAS ,Computer Simulation ,Genetic Predisposition to Disease ,Molecular Biology ,Genotyping ,Genetic association ,Genetics ,Aged, 80 and over ,Odds ratio ,Genomics ,Middle Aged ,Alzheimer's disease ,medicine.disease ,3. Good health ,Psychiatry and Mental health ,Genetic Loci ,Molecular epidemiology ,Female ,Original Article ,Mitochondrial ADP, ATP Translocases ,Genome-Wide Association Study - Abstract
To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P
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- 2014
31. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease
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Escott-Price, Valentina, Bellenguez, Céline, DeStefano, Anita L, Galimberti, Daniela, Scarpini, Elio, Bonuccelli, Ubaldo, Mancuso, Michelangelo, Siciliano, Gabriele, Moebus, Susanne, Mecocci, Patrizia, Zompo, Maria Del, Maier, Wolfgang, Hampel, Harald, Lambert, Jean-Charles, Pilotto, Alberto, Frank-García, Ana, Panza, Francesco, Solfrizzi, Vincenzo, Caffarra, Paolo, Nacmias, Benedetta, Perry, William, Mayhaus, Manuel, Lannfelt, Lars, Hakonarson, Hakon, Ibrahim-Verbaas, Carla A, Pichler, Sabrina, Carrasquillo, Minerva M, Ingelsson, Martin, Beekly, Duane, Alvarez, Victoria, Zou, Fanggeng, Valladares, Otto, Younkin, Steven G, Coto, Eliecer, Hamilton-Nelson, Kara L, Naj, Adam C, Gu, Wei, Razquin, Cristina, Pastor, Pau, Mateo, Ignacio, Owen, Michael J, Faber, Kelley M, Jonsson, Palmi V, Combarros, Onofre, O'Donovan, Michael C, Cantwell, Laura B, Sims, Rebecca, Soininen, Hilkka, Blacker, Deborah, Mead, Simon, Mosley, Thomas H, Bennett, David A, Harris, Tamara B, Fratiglioni, Laura, Holmes, Clive, de Bruijn, Renee F A G, Passmore, Peter, Jun, Gyungah, Montine, Thomas J, Bettens, Karolien, Rotter, Jerome I, Brice, Alexis, Morgan, Kevin, Foroud, Tatiana M, Kukull, Walter A, Hannequin, Didier, Powell, John F, Nalls, Michael A, Bis, Joshua C, Ritchie, Karen, Lunetta, Kathryn L, Kauwe, John S K, Boerwinkle, Eric, Riemenschneider, Matthias, Boada, Mercè, Hiltunen, Mikko, Martin, Eden R, Schmidt, Reinhold, Rujescu, Dan, Beecham, Gary W, Dartigues, Jean-François, Mayeux, Richard, Tzourio, Christophe, Hofman, Albert, Nöthen, Markus M, Graff, Caroline, Psaty, Bruce M, Haines, Jonathan L, Lathrop, Mark, Pericak-Vance, Margaret A, Grenier-Boley, Benjamin, Launer, Lenore J, Van Broeckhoven, Christine, Farrer, Lindsay A, van Duijn, Cornelia M, Ramirez, Alfredo, Seshadri, Sudha, Schellenberg, Gerard D, Amouyel, Philippe, Williams, Julie, Study, Cardiovascular Health, Russo, Giancarlo, Olson, Jean, Kronmal, Richard, Arnold, Alice M, Robbins, John, Carlson, Michelle, Burke, Gregory, Kuller, Lewis H, Tracy, Russell, Gottdiener, John, Prineas, Ronald, Wang, Li-San, Thornton-Wells, Tricia A, Becker, James T, Enright, Paul, Klein, Ronald, O'Leary, Daniel H, Denning, Nicola, Smith, Albert V, Chouraki, Vincent, Thomas, Charlene, Ikram, M Arfan, Zelenika, Diana, Vardarajan, Badri N, Kamatani, Yoichiro, Lin, Chiao-Feng, Choi, Seung-Hoan, Schmidt, Helena, Kunkle, Brian, Dunstan, Melanie L, Vronskaya, Maria, Consortium, United Kingdom Brain Expression, Johnson, Andrew D, Ruiz, Agustin, Bihoreau, Marie-Thérèse, Reitz, Christiane, Pasquier, Florence, Harold, Denise, Hollingworth, Paul, Hanon, Olivier, Fitzpatrick, Annette L, Buxbaum, Joseph D, Campion, Dominique, Crane, Paul K, Baldwin, Clinton, Becker, Tim, Gudnason, Vilmundur, Cruchaga, Carlos, Jones, Lesley, Craig, David, Amin, Najaf, Berr, Claudine, Lopez, Oscar L, De Jager, Philip L, Deramecourt, Vincent, Johnston, Janet A, Evans, Denis, Lovestone, Simon, Letenneur, Luc, Holmans, Peter, Hernández, Isabel, Rubinsztein, David C, Eiriksdottir, Gudny, Sleegers, Kristel, Goate, Alison M, Fiévet, Nathalie, Huentelman, Matthew J, Gill, Michael, Brown, Kristelle, Kamboh, M Ilyas, Gerrish, Amy, Keller, Lina, Barberger-Gateau, Pascale, McGuinness, Bernadette, Larson, Eric B, Myers, Amanda J, Dufouil, Carole, Todd, Stephen, Wallon, David, Love, Seth, Rogaeva, Ekaterina, Vedernikov, Alexey, Gallacher, John, George-Hyslop, Peter St, Clarimon, Jordi, Lleo, Alberto, Bayer, Anthony, Tsuang, Debby W, Yu, Lei, Tsolaki, Magda, Bossù, Paola, Spalletta, Gianfranco, Richards, Alexander, Proitsi, Petra, Collinge, John, Sorbi, Sandro, Garcia, Florentino Sanchez, Fox, Nick C, Hardy, John, Naranjo, Maria Candida Deniz, Bosco, Paolo, Clarke, Robert, Brayne, Carol, Neurology, Radiology & Nuclear Medicine, Epidemiology, UAM. Departamento de Medicina, Universidad de Cantabria, and United Kingdom Brain Expression
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Genetics and Molecular Biology (all) ,Alzheimer Disease ,Carrier Proteins ,Case-Control Studies ,Genome-Wide Association Study ,Heat-Shock Proteins ,Humans ,Polymorphism, Single Nucleotide ,Receptors, Antigen, B-Cell ,Agricultural and Biological Sciences (all) ,Biochemistry, Genetics and Molecular Biology (all) ,Medicine (all) ,genotype ,Medizin ,lcsh:Medicine ,genetics [Alzheimer Disease] ,Genome-wide association study ,Genomics--Data processing ,Disease ,genetics [Carrier Proteins] ,Biochemistry ,Alzheimer's disease ,0302 clinical medicine ,genetics [Heat-Shock Proteins] ,genetics [Receptors, Antigen, B-Cell] ,Disease susceptibility--Genetic aspects ,Receptors ,Pathology ,Medicine and Health Sciences ,lcsh:Science ,Genetics ,0303 health sciences ,Multidisciplinary ,pathogenesis ,Genomics ,Single Nucleotide ,Neurology ,Antigen ,Physical Sciences ,protein degradation ,Alzheimer disease ,Engineering sciences. Technology ,Statistics (Mathematics) ,Research Article ,medicine.medical_specialty ,Medicina ,Geriatrik ,Late onset ,Biostatistics ,Biology ,Medical sciences ,03 medical and health sciences ,Molecular genetics ,Mental Health and Psychiatry ,Genome-Wide Association Studies ,medicine ,chromosome 8 ,Dementia ,ddc:610 ,Polymorphism ,QH426 ,Genetic Association Studies ,030304 developmental biology ,TP53INP1 protein, human ,lcsh:R ,Case-control study ,B-Cell ,Biology and Life Sciences ,Computational Biology ,Human Genetics ,Genome Analysis ,medicine.disease ,R1 ,Human genetics ,immune system ,Geriatrics ,FOS: Biological sciences ,Alzheimer's disease--Genetic aspects ,RC0321 ,lcsh:Q ,Mathematics ,030217 neurology & neurosurgery - Abstract
Background: 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. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease, The i-Select chips was funded by the French National Foundation on Alzheimer's disease and related disorders. The French National Fondation on Alzheimer's disease and related disorders supported several I-GAP meetings and communications. Data management involved the Centre National de Génotypage,and was supported by the Institut Pasteur de Lille, Inserm, FRC (fondation pour la recherche sur le cerveau) and Rotary. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) and by the LABEX GENMED grant (Medical Genomics). The French National Foundation on Alzheimer's disease and related disorders and the Alzheimer's Association (Chicago, Illinois) grant supported IGAP in-person meetings, communication and the Alzheimer's Association (Chicago, Illinois) grant provided some funds to each consortium for analyses. EADI The authors thank Dr. Anne Boland (CNG) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille and the Centre National de Génotypage. The Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Agence Nationale de la Recherche, ANR supported the COGINUT and COVADIS projects. Fondation de France and the joint French Ministry of Research/INSERM «Cohortes et collections de données biologiques» programme. Lille Génopôle received an unconditional grant from Eisai. The Three-city biological bank was developed and maintained by the laboratory for genomic analysis LAG-BRC - Institut Pasteur de Lille. Belgium sample collection: The patients were clinically and pathological characterized by the neurologists Sebastiaan Engelborghs, Rik Vandenberghe and Peter P. De Deyn, and in part genetically by Caroline Van Cauwenberghe, Karolien Bettens and Kristel Sleegers. Research at the Antwerp site is funded in part by the Belgian Science Policy Office Interuniversity Attraction Poles program, the Foundation Alzheimer Research (SAO-FRA), the Flemish Government initiated Methusalem Excellence Program, the Research Foundation Flanders (FWO) and the University of Antwerp Research Fund, Belgium. Karolien Bettens is a postdoctoral fellow of the FWO. The Antwerp site authors thank the personnel of the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge and the Departments of Neurology and Memory Clinics at the Hospital Network Antwerp and the University Hospitals Leuven. Finish sample collection: Financial support for this project was provided by the Health Research Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, and the Nordic Centre of Excellence in Neurodegeneration. Italian sample collections: the Bologna site (FL) obtained funds from the Italian Ministry of research and University as well as Carimonte Foundation. The Florence site was supported by grant RF-2010-2319722, grant from the the Cassa di Risparmio di Pistoia e Pescia (Grant 2012) and the Cassa di Risparmio di Firenze (Grant 2012). The Milan site was supported by a grant from the «fondazione Monzino». The authors thank the expert contribution of Mr. Carmelo Romano. The Roma site received financial support from Italian Ministry of Health, Grant RF07-08 and RC08-09-10-11-12. The Pisa site is grateful to Dr. Annalisa LoGerfo for her technical assistance in the DNA purification studies. Spanish sample collection: the Madrid site (MB) was supported by grants of the Ministerio de Educación y Ciencia and the Ministerio de Sanidad y Consumo (Instituto de Salud Carlos III), and an institutional grant of the Fundación Ramón Areces to the CBMSO. The authors thank I. Sastre and Dr. A. Martínez-García for the preparation and control of the DNA collection, and Drs. P. Gil and P. Coria for their cooperation in the cases/controls recruitment. The authors are grateful to the Asociación de Familiares de Alzheimer de Madrid (AFAL) for continuous encouragement and help. Swedish sample collection: Financially supported in part by the Swedish Brain Power network, the Marianne and Marcus Wallenberg Foundation, the Swedish Research Council (521-2010-3134), the King Gustaf V and Queen Victoria's Foundation of Freemasons, the Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and the Karolinska Institutet, the Swedish Brain Foundation and the Swedish Alzheimer Foundation. CHARGE AGES: The AGES-Reykjavik Study is funded by National Institutes of Health (NIH) contract N01-AG-12100 (National Institute on Aging (NIA) with contributions from the National Eye Institute, National Institute on Deafness and Other Communication Disorders and National Heart, Lung, and Blood Institute (NHLBI)), the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). ASPS/PRODEM: The Austrian Stroke Prevention Study and The Prospective Dementia Register of the Austrian Alzheimer Society was supported by The Austrian Science Fond (FWF) grant number P20545-P05 (H. Schmidt) and P13180; The Austrian Alzheimer Society; The Medical University of Graz. Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and HHSN268200960009C; and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629, AG15928, AG20098, AG027058 and AG033193 (Seshadri) from the NIA. A full list of CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Framingham Heart Study (FHS): This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with A_ymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This study as also supported by grants from the National Institute on Aging: AG08122 and AG033193 (Seshadri). Drs. Seshadri and DeStefano were also supported by additional grants from the National Institute on Aging: (R01 AG16495; AG031287, AG033040), the National Institute of Neurological Disorders and Stroke (R01 NS17950), and the National Heart, Lung and Blood Institute (U01 HL096917, HL093029 and K24HL038444, RC2-HL102419 and UC2 HL103010. Fundació ACE would like to thank patients and controls who participated in this project. This work has been funded by the Fundación Alzheimur (Murcia), the Ministerio de Educación y Ciencia (PCT-010000-2007-18), (DEX-580000-2008-4), (Gobierno de España), Corporación Tecnológica de Andalucía (08/211) and Agencia IDEA (841318) (Consejería de Innovación, Junta de Andalucía). The authors thank to Ms. Trinitat Port-Carbó and her family for their generous support of Fundació ACE research programs. The Rotterdam Study: The Rotterdam Study was funded by Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission;and the Municipality of Rotterdam; by grants from the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), Internationale Stichting Alzheimer Onderzoek, Hersenstichting Nederland, the Netherlands Genomics Initiative–Netherlands Organization for Scientific Research (Center for Medical Systems Biology and the Netherlands Consortium for Healthy Aging), the Seventh Framework Program (FP7/2007-2013), the ENGAGE project (grant agreement HEALTH-F4-2007-201413), MRACE-grant from the Erasmus Medical Center, the Netherlands Organization for Health Research and Development (ZonMW Veni-grant no. 916.13.054). ARIC: The Atherosclerosis Risk in Communities Study (ARIC) is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01- HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022 and grants R01-HL087641, RC2-HL102419 (Boerwinkle, CHARGE-S), UC2 HL103010, U01-HL096917 (Mosley) and R01-HL093029; NHGRI contract U01- HG004402; and NIH contract HHSN268200625226C and NIA: R01 AG033193 (Seshadri). Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. GERAD Cardiff University was supported by the Wellcome Trust, Medical Research Council (MRC), Alzheimer's Research United Kingdom (ARUK) and the Welsh Government. ARUK supported sample collections at the Kings College London, the South West Dementia Bank, Universities of Cambridge, Nottingham, Manchester and Belfast. The Belfast group acknowledges support from the Alzheimer's Society, Ulster Garden Villages, N. Ireland R & D Office and the Royal College of Physicians/Dunhill Medical Trust. The MRC and Mercer's Institute for Research on Ageing supported the Trinity College group. DCR is a Wellcome Trust Principal Research fellow. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer's and Care of the Elderly. The Charles Wolfson Charitable Trust supported the OPTIMA group. Washington University was funded by NIH grants, Barnes Jewish Foundation and the Charles and Joanne Knight Alzheimer's Research Initiative. Patient recruitment for the MRC Prion Unit/UCL Department of Neurodegenerative Disease collection was supported by the UCLH/UCL Biomedical Centre and their work was supported by the NIHR Queen Square Dementia BRU. LASER-AD was funded by Lundbeck SA. The Bonn group would like to thank Dr. Heike Koelsch for her scientific support. The Bonn group was funded by the German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant number 01GI0102, 01GI0711, 01GI0420. The AgeCoDe study group was supported by the German Federal Ministry for Education and Research grants 01 GI 0710, 01 GI 0712, 01 GI 0713, 01 GI 0714, 01 GI 0715, 01 GI 0716, 01 GI 0717. The Homburg group was funded by the German Federal Ministry of Education and Research (BMBF): German National Genome Research Network (NGFN); Alzheimer's disease Integrated Genome Research Network; AD-IG: 01GS0465. Genotyping of the Bonn case-control sample was funded by the German centre for Neurodegenerative Diseases (DZNE), Germany. The GERAD Consortium also used samples ascertained by the NIMH AD Genetics Initiative. Harald Hampel was supported by a grant of the Katharina-Hardt-Foundation, Bad Homburg vor der Höhe, Germany. The KORA F4 studies were financed by Helmholtz Zentrum München; German Research Center for Environmental Health; BMBF; German National Genome Research Network and the Munich Center of Health Sciences. The Heinz Nixdorf Recall cohort was funded by the Heinz Nixdorf Foundation (Dr. Jur. G.Schmidt, Chairman) and BMBF. Coriell Cell Repositories is supported by NINDS and the Intramural Research Program of the National Institute on Aging. The authors acknowledge use of genotype data from the 1958 Birth Cohort collection, funded by the MRC and the Wellcome Trust which was genotyped by the Wellcome Trust Case Control Consortium and the Type-1 Diabetes Genetics Consortium, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development and Juvenile Diabetes Research Foundation International. The Nottingham Group (KM) are supported by the Big Lottery. MRC CFAS is part of the consortium and data will be included in future analyses. ADGC The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, R01 AG041797; MIRAGE R01 AG025259; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG06781, UO1 HG004610; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, and UL1 RR029893; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653, AG041718; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG034504 to AJM, The Banner Alzheimer's Foundation, The Johnnie B. Byrd Sr. Alzheimer's Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE), Alzheimer's Research Trust (ART), BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. Marcelle Morrison-Bogorad, PhD., Tony Phelps, PhD and Walter Kukull PhD are thanked for helping to co-ordinate this collection. ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, Glaxo-SmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. Data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514. The authors thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-o_cio ADGC members. Support was also from the Alzheimer's Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the United States Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. Peter St George-Hyslop is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health
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- 2014
32. Exploring APOE genotype effects on Alzheimer's disease risk and amyloid β burden in individuals with subjective cognitive decline: The FundacioACE Healthy Brain Initiative (FACEHBI) study baseline results.
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Moreno–Grau, Sonia, Rodríguez‐Gómez, Octavio, Sanabria, Ángela, Pérez‐Cordón, Alba, Sánchez‐Ruiz, Domingo, Abdelnour, Carla, Valero, Sergi, Hernández, Isabel, Rosende‐Roca, Maitée, Mauleón, Ana, Vargas, Liliana, Lafuente, Asunción, Gil, Silvia, Santos‐Santos, Miguel Ángel, Alegret, Montserrat, Espinosa, Ana, Ortega, Gemma, Guitart, Marina, Gailhajanet, Anna, and de Rojas, Itziar
- Abstract
Introduction: Subjective cognitive decline (SCD) has been proposed as a potential preclinical stage of Alzheimer's disease (AD). Nevertheless, the genetic and biomarker profiles of SCD individuals remain mostly unexplored. Methods: We evaluated apolipoprotein E (APOE) ε4's effect in the risk of presenting SCD, using the Fundacio ACE Healthy Brain Initiative (FACEHBI) SCD cohort and Spanish controls, and performed a meta‐analysis addressing the same question. We assessed the relationship between APOE dosage and brain amyloid burden in the FACEHBI SCD and Alzheimer's Disease Neuroimaging Initiative cohorts. Results: Analysis of the FACEHBI cohort and the meta‐analysis demonstrated SCD individuals presented higher allelic frequencies of APOE ε4 with respect to controls. APOE dosage explained 9% (FACEHBI cohort) and 11% (FACEHBI and Alzheimer's Disease Neuroimaging Initiative cohorts) of the variance of cerebral amyloid levels. Discussion: The FACEHBI sample presents APOE ε4 enrichment, suggesting that a pool of AD patients is nested in our sample. Cerebral amyloid levels are partially explained by the APOE allele dosage, suggesting that other genetic or epigenetic factors are involved in this AD endophenotype. Highlights: The FACEHBI sample presents APOE ε4 enrichment, suggesting it contains a pool of AD patients.APOE ε4 is a risk factor of being diagnosed with SCD.APOE ε4 only explains ≈10% of brain amyloid burden variability in SCD.The relationship between APOE and brain amyloid burden across clinical diagnoses highlights the importance of adjusting for clinical status when conducting GWAS of cerebral Aβ levels. [ABSTRACT FROM AUTHOR]
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- 2018
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33. Retinal Microperimetry: A New Tool for Identifying Patients With Type 2 Diabetes at Risk for Developing Alzheimer Disease.
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Ciudin, Andreea, Simó-Servat, Olga, Hernández, Cristina, Arcos, Gabriel, Diego, Susana, Sanabria, Ángela, Sotolongo, Óscar, Hernández, Isabel, Boada, Mercè, and Simó, Rafael
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TYPE 2 diabetes ,COGNITION disorders ,DEMENTIA risk factors ,MAGNETIC resonance imaging ,POSITRON emission tomography ,NEURODEGENERATION ,TYPE 2 diabetes complications ,ALZHEIMER'S disease ,DEOXY sugars ,LONGITUDINAL method ,PERIMETRY ,RADIOPHARMACEUTICALS ,CASE-control method - Abstract
Type 2 diabetes is associated with a high risk of cognitive impairment and dementia. Therefore, strategies are needed to identify patients who are at risk for dementia. Given that the retina is a brain-derived tissue, it may provide a noninvasive way to examine brain pathology. The aims of this study were to evaluate whether retinal sensitivity 1) correlates with the specific parameters of brain imaging related to cognitive impairment and 2) discriminates patients with diabetes with mild cognitive impairment (MCI) from those with normal cognition and those with Alzheimer disease (AD). For this purpose, a prospective, nested case-control study was performed and included 35 patients with type 2 diabetes without cognitive impairment, 35 with MCI, and 35 with AD. Retinal sensitivity was assessed by Macular Integrity Assessment microperimetry, and a neuropsychological evaluation was performed. Brain neurodegeneration was assessed by MRI and fludeoxyglucose-18 positron emission tomography (18FDG-PET). A significant correlation was found between retinal sensitivity and the MRI and 18FDG-PET parameters related to brain neurodegeneration. Retinal sensitivity was related to cognitive status (normocognitive > MCI > AD; P < 0.0001). Our results suggest that retinal sensitivity assessed by microperimetry is related to brain neurodegeneration and could be a useful biomarker for identifying patients with type 2 diabetes who are at risk for developing AD. [ABSTRACT FROM AUTHOR]
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- 2017
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34. Social Representation of Dementia: An Analysis of 5,792 Consecutive Cases Evaluated in a Memory Clinic.
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Cañabate, Pilar, Martínez, Gabriel, Rosende-Roca, Maitée, Moreno, Mariola, Preckler, Silvia, Valero, Sergi, Sotolongo, Oscar, Hernández, Isabel, Alegret, Montserrat, Ortega, Gemma, Espinosa, Ana, Mauleón, Ana, Vargas, Liliana, Rodríguez, Octavio, Abdelnour, Carla, Sánchez, Domingo, Martín, Elvira, Ruiz, Agustín, Tárraga, Lluís, and Boada, Mercè
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DEMENTIA ,MILD cognitive impairment ,COGNITION disorders ,MEDICAL care ,PUBLIC health - Abstract
Background: Different interpretations of cognitive impairment and dementia due to differences in health structures, such as cultural differences could affect the diagnosis and treatment of the condition. it is reasonable to expect that the social and family impact of the disease and coping strategies will differ among societies.Objective: The general aim of this study is to understand the social representations of dementia, its associated practices, and the effects they imply.Methods: People diagnosed with clinical dementia and their families were assessed from 2005 to 2015 in the memory clinic of the Fundació ACE, Institut Català de Neurociències Aplicades in Barcelona, Spain.Results: 9,898 people were examined and 5,792 were diagnosed with dementia. For those with a caregiver (71%), the decision-making fell on the person with dementia in 16.2% of the cases; and for those without a caregiver, in 26.4% of the cases the family did not perceive the deficits as a disease, which led to multiple risk situations (74.6%).Conclusions: The recognition of dementia as part of aging is common among families. Consequently, risk situations may arise and diagnosis and access to treatment may be delayed. The incorporation of a social appraisal to the diagnostic process is a necessity to evaluate these situations. [ABSTRACT FROM AUTHOR]- Published
- 2017
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35. Impact of Recruitment Methods in Subjective Cognitive Decline.
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Abdelnour, Carla, Rodríguez-Gómez, Octavio, Alegre, Montserrat, Valero, Sergi, Moreno-Grau, Sonia, Ángela, Sanabria, Hernández, Isabel, Rosende-Roca, Maitee, Vargas, Liliana, Mauleón, Ana, Sánchez, Domingo, Espinosa, Ana, Ortega, Gemma, Pérez-Cordón, Alba, Diego, Susana, Gailhajanet, Anna, Guitart, Marina, Sotolongo-Grau, Óscar, Ruiz, Agustín, and Tárraga, Lluiz
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MILD cognitive impairment ,ALZHEIMER'S disease ,DEMENTIA ,LOGISTIC regression analysis ,NEUROPSYCHOLOGY ,APOLIPOPROTEINS ,COMPARATIVE studies ,DISEASE susceptibility ,NEUROPSYCHOLOGICAL tests ,RESEARCH methodology ,MEDICAL cooperation ,RESEARCH ,SEX distribution ,EVALUATION research ,EDUCATIONAL attainment ,PATIENT selection ,SELF diagnosis - Abstract
Background: Recruitment methods can determine sample characteristics in mild cognitive impairment and Alzheimer's disease dementia, but little is known about its influence in subjective cognitive decline (SCD).Objective: To determine the influence of two types of recruitment methods in the characteristics of individuals with SCD.Methods: We select and compare clinical and neuropsychological features, and frequency of APOE ɛ4 allele of 326 subjects with SCD from two cohorts: Open House Initiative (OHI) versus Memory Unit (MU). A logistic regression analysis (LRA), using gender and years of education as covariates, was used to examine the neuropsychological variables.Results: The OHI sample were mostly women (75.9% versus 64.5%, p < 0.05), with higher educational level (12.15 [3.71] versus 10.70 [3.80] years, p = 0.001), and more family history of dementia (138 [62.7%] versus 44 [41.5%], p < 0.001) than the MU sample. Also, the OHI sample showed better overall neuropsychological performance than the MU sample, and after a LRA, this trend continued in automatic response inhibition capacity, abstract reasoning, and recognition memory. We did not find differences in age, depression history, and/or APOE ɛ4 allele frequency.Conclusion: SCD subjects showed different demographic and neuropsychological characteristics depending on the recruitment method, which should be taken into account in the design of research studies with this target population. [ABSTRACT FROM AUTHOR]- Published
- 2017
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36. Alzheimer's disease risk variants modulate endophenotypes in mild cognitive impairment.
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Louwersheimer, Eva, Wolfsgruber, Steffen, Espinosa, Ana, Lacour, André, Heilmann-Heimbach, Stefanie, Alegret, Montserrat, Hernández, Isabel, Rosende-Roca, Maitée, Tárraga, Lluís, Boada, Mercè, Kornhuber, Johannes, Peters, Oliver, Frölich, Lutz, Hüll, Michael, Rüther, Eckart, Wiltfang, Jens, Scherer, Martin, Riedel-Heller, Steffi, Jessen, Frank, and Nöthen, Markus M.
- Abstract
Introduction We evaluated the effect of Alzheimer's disease (AD) susceptibility loci on endophenotypes closely related with AD pathology in patients with mild cognitive impairment (MCI). Methods We selected 1730 MCI patients from four independent data sets. Weighted polygenic risk scores (PGS) were constructed of 18 non-apolipoprotein E ( APOE ) AD risk variants. In addition, we determined APOE genotype. AD endophenotypes were cognitive decline over time and cerebrospinal fluid (CSF) biomarkers (aβ, tau, ptau). Results PGS was modestly associated with cognitive decline over time, as measured by mini-mental state examination (MMSE) (β ± SE:−0.24 ± 0.10; P = .012), and with CSF levels of tau and ptau (tau: 1.38 ± 0.36, P = 1.21 × 10 −4 ; ptau: 1.40 ± 0.36, P = 1.02 × 10 −4 ). Discussion In MCI, we observed a joint effect of AD susceptibility loci on nonamyloid endophenotypes, suggesting a link of these genetic loci with neuronal degeneration in general rather than with Alzheimer-related amyloid deposition. [ABSTRACT FROM AUTHOR]
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- 2016
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37. Beneficial Effects of an Integrated Psychostimulation Program in Patients with Alzheimer's Disease.
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Ibarria, Marta, Alegret, Montserrat, Valero, Sergi, Morera, Amèrica, Guitart, Marina, Cañabate, Pilar, Moreno, Mariola, Lara, Susana, Diego, Susana, Hernández, Joan, Tantinyá, Natàlia, Vera, Maribel, Hernández, Isabel, Becker, James T., Ruíz, Agustín, Boada, Mercè, and Tárraga, Lluís
- Subjects
ALZHEIMER'S disease ,AGE factors in cognition ,DEMENTIA patients ,HYDROPEROXIDES ,BLOOD circulation ,ALZHEIMER'S disease diagnosis ,ALZHEIMER'S disease treatment ,CHOLINESTERASE inhibitors ,ACTIVITIES of daily living ,COGNITION ,COMBINED modality therapy ,COMPARATIVE studies ,NEUROPSYCHOLOGICAL tests ,RESEARCH methodology ,MEDICAL cooperation ,PSYCHOTHERAPY ,QUESTIONNAIRES ,RESEARCH ,RESEARCH funding ,EVALUATION research ,TREATMENT effectiveness ,SEVERITY of illness index ,DISEASE progression ,PSYCHOLOGY ,THERAPEUTICS - Abstract
Background: The existing pharmacological treatments for Alzheimer's disease (AD) can only slow the progression of symptoms or delay admission to long-term care facilities. The beneficial effects of non-drug treatments are poorly studied.Objective: To describe the effects of an Integrated Psychostimulation Program (IPP) in patients with mild-moderate AD treated with acetylcholinesterase inhibitors; and to identify factors related to greater benefit of the IPP.Methods: 206 patients (mean age = 75.9 years; MMSE = 19.6) were evaluated before starting the IPP and 3, 6, 9, and 12 months later. Measures included: Mini-Mental State Examination (MMSE), Cognitive Subscale of Alzheimer's Disease Assessment Scale (ADAS-Cog), Rapid Disability Rating Scale (RDRS-2), and Neuropsychiatric Inventory Questionnaire (NPI-Q).Results: Patients remained cognitively stable (MMSE/ADAS-Cog) for more than 6 months and significantly worsened at 9-month and 12-month follow-ups, without clinically significant functional changes (RDRS-2) or psychiatric symptoms(NPI-Q). The mean annual change on MMSE and ADAS-Cog were 2.06 and 3.56 points, respectively, lower than the annual decline demonstrated previously in similar patients (2.4 and 4.5, respectively). 42.7% of patients maintained or improved global cognitive scores between baseline and 12-month follow-up. The patients who maintained cognitive functions were older than those who did not (77.5 versus 74.7 years).Conclusions: The IPP may be an effective treatment to maintain cognition, functionality, and psychiatric symptoms in AD patients pharmacologically treated, and older age seems to increase beneficial effects of IPP. [ABSTRACT FROM AUTHOR]- Published
- 2016
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38. Concordance between Subjective and Objective Memory Impairment in Volunteer Subjects.
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Alegret, Montserrat, Rodríguez, Octavio, Espinosa, Ana, Ortega, Gemma, Sanabria, Angela, Valero, Sergi, Hernández, Isabel, Rosende-Roca, Maitée, Vargas, Liliana, Abdelnour, Carla, Mauleón, Ana, Gailhajanet, Anna, Martín, Elvira, Tárraga, Lluís, Rentz, Dorene M., Amariglio, Rebecca E., Ruíz, Agustín, and Boada, Mercè
- Subjects
MEMORY disorders ,COGNITIVE testing ,ASSOCIATIVE memory (Psychology) ,ALZHEIMER'S disease ,MILD cognitive impairment ,FOLLOW-up studies (Medicine) - Abstract
Background: Subjective memory impairment (SMI) refers to subjective awareness of initial memory decline undetectable with existing standardized cognitive tests. The Face Name Associative Memory Exam (FNAME) was created to detect memory deficits in individuals with preclinical Alzheimer's disease (AD). We reported normative data of a Spanish version of FNAME (S-FNAME) in cognitively normal (CN) Spanish-speaking subjects >49.Objective: To determine whether higher SMI [a modification of Memory Failures Everyday (MFE-30)] was related to worse memory performance (S-FNAME) or associated with greater affective symptoms in subjects >49; and whether MFE-30 and FNAME were able to discriminate between CN and mild cognitive impairment (MCI) subjects.Methods: 317 subjects (CN = 196, MCI = 121) were included in the analysis because they attended the annual "Open House Initiative" at Memory Clinic Fundació ACE, were >49 years, literate, received S-FNAME, MFE-30, and Hospital Anxiety and Depression Scale, had Mini-Mental State Examination scores ≥27, and returned to complete a comprehensive diagnostic assessment.Results: MFE-30 scores were associated with affective symptoms but not with S-FNAME performance. S-FNAME scores were related to performance on memory variables of NBACE (neuropsychological battery used in Fundació ACE). Although the MCI group showed significantly higher MFE-30 and worse S-FNAME scores than the CN group, their discriminability values were similar (Sensitivity: 49.6 versus 52.9; Specificity: 85.1 versus 83.6, respectively).Conclusions: SMI was more related to depressive symptoms than to S-FNAME memory performance; and S-FNAME scores were related to other episodic memory test performances, but neither to affective symptoms nor to SMI. MFE-30 and S-FNAME are not optimal for discriminating between CN and MCI groups. Longitudinal follow-up will determine if lower S-FNAME and higher SMI are related to increased risk of AD. [ABSTRACT FROM AUTHOR]- Published
- 2015
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39. Validation of the Spanish Version of the Face Name Associative Memory Exam (S-FNAME) in Cognitively Normal Older Individuals.
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Alegret, Montserrat, Valero, Sergi, Ortega, Gemma, Espinosa, Ana, Sanabria, Angela, Hernández, Isabel, Rodríguez, Octavio, Rosende-Roca, Maitee, Mauleón, Ana, Vargas, Liliana, Martín, Elvira, Ruíz, Agustín, Tárraga, Lluís, Amariglio, Rebecca E., Rentz, Dorene M., and Boada, Mercè
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ASSOCIATIVE memory (Psychology) ,FACE perception ,PSYCHOMETRICS ,ALZHEIMER'S disease ,MEDICAL sciences ,EPISODIC memory - Abstract
The Face Name Associative Memory Exam (FNAME) is a paired associative memory test that has demonstrated sensitivity to amyloid burden in cognitively normal individuals, a biomarker of preclinical Alzheimer's disease. Normative data adjusted for age were reported in American healthy individuals older than 57. We aimed to report the psychometric characteristics of a Spanish version of FNAME (S-FNAME) when administered to Spanish-speaking people. We sought to investigate convergent validity of S-FNAME with another memory measure and to identify which demographic characteristics might be associated with performance on S-FNAME. We administered the S-FNAME to 110 literate, cognitively normal, Spanish individuals older than 49 years from the Memory Clinic Fundació ACE. Construct validity of S-FNAME showed 2 components: face-name and face-occupation. A significant correlation between S-FNAME and Word List from the WMS-III supported convergent validity. The S-FNAME was also associated with age and gender. Thus, we provide normative data for age and gender. [ABSTRACT FROM AUTHOR]
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- 2015
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40. Cognitive, Genetic, and Brain Perfusion Factors Associated with Four Year Incidence of Alzheimer's Disease from Mild Cognitive Impairment.
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Alegret, Montserrat, Cuberas-Borrós, Gemma, Espinosa, Ana, Valero, Sergi, Hernández, Isabel, Ruíz, Agustín, Becker, James T., Rosende-Roca, Maitée, Mauleón, Ana, Sotolongo, Oscar, Castell-Conesa, Joan, Roca, Isabel, Tárraga, Lluís, and Boada, Mercè
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MILD cognitive impairment ,ALZHEIMER'S disease research ,NEUROPSYCHOLOGICAL tests ,BRAIN imaging ,BRAIN research - Abstract
Background: There is a range of factors that predict the development of Alzheimer's disease (AD) dementia among patients with amnestic mild cognitive impairment (MCI). Objectives: To identify the neuropsychological, genetic, and functional brain imaging data that best predict conversion to AD dementia in patients with amnestic MCI. Methods: From an initial group of 42 amnestic MCI patients assessed with neurological, neuropsychological, and brain SPECT, 39 (25 converters, 14 non-converters) were followed for 4 years, and 36 had APOE ε4 genotyping. Baseline neuropsychological data and brain SPECT data were used to predict which of the MCI patients would develop dementia by the end of the 4 years of observation. Results: The MCI patients who had converted to AD dementia had poorer performance on long-term visual memory and Semantic Fluency tests. The MCI subjects who developed dementia were more likely to carry at least one copy of the APOE ε4 allele (Hazard Risk = 4.22). There was lower brain perfusion in converters than non-converters, mainly in postcentral gyrus. An additional analysis of the SPECT data found differences between the MCI subjects and controls in the posterior cingulate gyrus and the basal forebrain. When the brain imaging and neuropsychological test data were combined in the same Cox regression model, only the neuropsychological test data were significantly associated with time to dementia. Conclusion: Although the presence of reduced brain perfusion in postcentral gyrus and basal forebrain indicated an at-risk condition, it was the extent of memory impairment that was linked to the speed of decline from MCI to AD. [ABSTRACT FROM AUTHOR]
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- 2014
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41. Design of a comprehensive Alzheimer’s disease clinic and research center in Spain to meet critical patient and family needs.
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Boada, Mercè, Tárraga, Lluís, Hernández, Isabel, Valero, Sergi, Alegret, Montserrat, Ruiz, Agustín, Lopez, Oscar L., and Becker, James T.
- Abstract
Abstract: Objectives: Alzheimer's disease (AD) affects people worldwide, and the prevalence is increasing as the population ages. There is an international effort to understand the biology of AD to develop primary and secondary prevention strategies, and to develop effective therapeutic interventions for individuals who are already symptomatic. One of the critically important pieces of all national plans to address AD is the call for the development of service models to deliver quality, effective care based on the best evidence available. Methods: We describe one type of care model developed by the Fundacio ACE, Institut Catala de Neurociencies Aplicades (Fundacio ACE, Barcelona, Spain) that integrates diagnosis, therapy, follow-up care, daycare, and a day hospital, and does so in the context of an active clinical research and educational program. Results: There were 13,048 individuals newly evaluated and diagnosed in Fundacio ACE between 1996 and 2011. Of these, 6132 had AD (47.0%), 3871 had mild cognitive impairment (MCI) (29.7%), and 1958 had no cognitive impairment (15.0%). Follow-up information is available on 4735 (47.3%) AD and MCI patients, and these data indicate that MCI develops into dementia at a rate of 222.6/1000 person-years. Apolipoprotein E (APOE) genotyping was available in 22.4% of the patients. The ε4 allele occurred in 45.7% of the AD patients, in 37.8% of the MCI subjects, and in 31.6% of those without cognitive impairment. Conclusions: Fundació ACE can serve as a model system that can be adapted to other settings within their specific cultural, governmental, and legal constraints. [Copyright &y& Elsevier]
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- 2014
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42. A Two-Year Follow-Up of Cognitive Deficits and Brain Perfusion in Mild Cognitive Impairment and Mild Alzheimer's Disease.
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Alegret, Montserrat, Cuberas-Borrós, Gemma, Vinyes-Junqué, Georgina, Espinosa, Ana, Valero, Sergi, Hernández, Isabel, Roca, Isabel, Ruíz, Agustín, Rosende-Roca, Maitée, Mauleón, Ana, Becker, James T., Castell-Conesa, Joan, Tárraga, Lluís, and Boada, Mercè
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ALZHEIMER'S disease ,MILD cognitive impairment ,SINGLE photon emission computerized tomography centers ,LONGITUDINAL method ,PATIENTS - Abstract
The 15-Objects Test (15-OT) provides useful gradation of visuoperceptual impairment from normal aging through Alzheimer's disease (AD) and correlates with temporo-parietal perfusion. The objectives of this study were to analyze progression of 15-OT performance in mild cognitive impairment (MCI) and AD, and its correlates with cognition and single photon emission computerized tomography (SPECT), as well as to examine neuropsychological and SPECT differences between the MCI patients who developed AD and those who did not. From the initial 126 participants (42/group), 38 AD, 39 MCI, and 38 elderly controls (EC) were reassessed (SPECT: 35 AD, 33 MCI, 35 EC) after two years. The progression of cognitive and SPECT scores during this period was compared between groups, and baseline data between converters and non-converters. The 15-OT was the only measure of progression that differed between the three groups; worsening scores on 15-OT were associated with worsening in verbal and visual retention, and decreased perfusion on left postsubicular area. In the MCI patients, cerebral perfusion fell over the two years in medial-posterior cingulate and fronto-temporo-parietal regions; AD showed extensive changes involving almost all cerebral regions. No SPECT changes were detected in controls. At baseline, the MCI patients who developed AD differed from non-converters in verbal recognition memory, but not in SPECT perfusion. In conclusion, SPECT and 15-OT appear to provide a potential measure to differentiate between normal aging, MCI, and AD. Worsening on 15-OT was related to decreased perfusion in postsubicular area; but further longitudinal studies are needed to determine the contribution of 15-OT as a predictor of AD from MCI. [ABSTRACT FROM AUTHOR]
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- 2012
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43. The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease.
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Antúnez, Carmen, Boada, Mercè, González-Pérez, Antonio, Gayán, Javier, Ramírez-Lorca, Reposo, Marín, Juan, Hernández, Isabel, Moreno-Rey, Concha, Morón, Francisco Jesús, López-Arrieta, Jesús, Mauleón, Ana, Rosende-Roca, Maitée, Noguera-Perea, Fuensanta, Legaz-García, Agustina, Vivancos-Moreau, Laura, Velasco, Juan, Carrasco, José Miguel, Alegret, Montserrat, Antequera-Torres, Martirio, and Manzanares, Salvadora
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ALZHEIMER'S disease ,PRESENILE dementia ,CLEAN rooms ,META-analysis ,GENES - Abstract
Background: In order to identify novel loci associated with Alzheimer's disease (AD), we conducted a genomewide association study (GWAS) in the Spanish population. Methods: We genotyped 1,128 individuals using the Affymetrix Nsp I 250K chip. A sample of 327 sporadic AD patients and 801 controls with unknown cognitive status from the Spanish general population were included in our initial study. To increase the power of the study, we combined our results with those of four other public GWAS datasets by applying identical quality control filters and the same imputation methods, which were then analyzed with a global meta-GWAS. A replication sample with 2,200 sporadic AD patients and 2,301 controls was genotyped to confirm our GWAS findings. Results: Meta-analysis of our data and independent replication datasets allowed us to confirm a novel genomewide significant association of AD with the membrane-spanning 4-domains subfamily A (MS4A) gene cluster (rs1562990, P = 4.40E-11, odds ratio = 0.88, 95% confidence interval 0.85 to 0.91, n = 10,181 cases and 14,341 controls). Conclusions: Our results underscore the importance of international efforts combining GWAS datasets to isolate genetic loci for complex diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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44. The MTHFD1L Gene rs11754661 Marker is Not Associated with Alzheimer's Disease in a Sample of the Spanish Population.
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Ramírez-Lorca, Reposo, Boada, Mercé, Antúnez, Carmen, López-Arrieta, Jesús, Moreno-Rey, Concha, Hernández, Isabel, Marín, Juan, Gayán, Javier, González-Pérez, Antonio, Alegret, Montserrat, Tárraga, Lluis, Real, Luis M., and Ruiz, Agustín
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VITAMIN B complex ,FOLIC acid ,HOMOCYSTEINE ,POPULATION genetics ,DISEASE susceptibility ,ALZHEIMER'S disease ,GENES - Abstract
The MTHFD1L gene SNP variant rs11754661 was found to increase the risk of Alzheimer's disease in a recent Whole Genome Association Study [1]. We have carried out an independent study of this genetic variant in 2467 individuals from Spain. We found no evidence of association between the MTHFD1L marker and susceptibility to Alzheimer's disease in our sample. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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45. Brain Perfusion Correlates of Visuoperceptual Deficits in Mild Cognitive Impairment and Mild Alzheimer's Disease.
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Alegret, Montserrat, Vinyes-Junqué, Georgina, Boada, Mercè, Martínez-Lage, Pablo, Cuberas, Gemma, Espinosa, Ana, Roca, Isabel, Hernández, Isabel, Valero, Sergi, Rosende-Roca, Maitée, Mauleón, Ana, Becker, James T., and Tárraga, Lluís
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ALZHEIMER'S disease research ,VISUAL perception ,COGNITION disorders ,PERFUSION ,DIAGNOSIS ,ANALYSIS of variance - Abstract
Visuoperceptual processing is impaired early in the clinical course of Alzheimer's disease (AD). The 15-Objects Test (15-OT) detects such subtle performance deficits in mild cognitive impairment (MCI) and mild AD. Reduced brain perfusion in the temporal, parietal, and prefrontal regions have been found in early AD and MCI patients. The objectives of this study were to confirm the role of the 15-OT in the diagnosis of MCI and AD and to investigate the brain perfusion correlates of visuoperceptual dysfunction (15-OT) in subjects with MCI, AD, and normal aging. Forty-two AD, 42 MCI, and 42 healthy elderly control subjects underwent a brain Single Photon Emission Tomography (SPECT) and separately completed the 15-OT. An analysis of variance compared 15-OT scores between groups. SPM5 was used to analyse the SPECT data. 15-OT performace was impaired in the MCI and AD patients. In terms of the SPECT scans, AD patients showed reduced perfusion in temporal-parietal regions, while the MCI subjects had decreased perfusion in the middle and posterior cingulate. When MCI and AD groups were compared, a significant brain perfusion reduction was found in temporo-parietal regions. In the whole sample, 15-OT performance was significantly correlated with the clinical dementia rating scores, and with the perfusion in the bilateral posterior cingulate and the right temporal pole, with no significant correlation in each separate group. Our findings suggest that the 15-OT performance provides a useful gradation of impairment from normal aging to AD, and it seems to be related to perfusion in the bilateral posterior cingulate and the right temporal pole. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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46. CALHM1 P86L Polymorphism is Associated with Late-Onset Alzheimer's Disease in a Recessive Model.
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Boada, Mercè, Antúnez, Carmen, López-Arrieta, Jesús, Galán, José Jorge, Morón, Francisco J., Hernández, Isabel, Marín, Juan, Martínez-Lage, Pablo, Alegret, Montserrat, Carrasco, Jose M., Moreno, Concha, Real, Luis M., González-Perez, Antonio, Tárraga, Lluís, and Ruiz, Agustín
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GENETIC polymorphisms ,ALZHEIMER'S disease research ,PRESENILE dementia ,DEMENTIA research ,SENILE dementia - Abstract
CALHM1 gene coding non-synonymous SNP P86L (rs2986017) was reported to increase the risk of Alzheimer's disease (AD) in a recent study. We have investigated this genetic variant in 2470 individuals from Spain to conduct an independent replication study of the proposed SNP marker. By applying a recessive model, we observed weak evidence of an association between P86L mutation and late-onset AD (LOAD) susceptibility in our case-control study (OR =1.38 C.I. = [1.01–1.89]). Meta-analysis of available studies also supports a recessive model for CALHM1 P86L variant and provides evidence of between study heterogeneity. Importantly, we found that adjusted mean age at AD onset in P86L homozygous LOAD patients was significantly earlier that in the rest of patients (77.01 ± 6.1 for P86L homozygous carriers versus 79.0 ± 6.0 for the rest of patients, p=0.002). We concluded that the CALMH1 gene may contribute to AD risk in our study population. The observed genetic model (recessive) and the estimated magnitude of the effect both imply that virtually all studies performed to date were markedly underpowered to detect this effect and underscore the importance of follow up, replication, and meta-analyses of promising genetic signals. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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47. GOLPH2 Gene Markers are Not Associated with Alzheimer's Disease in a Sample of the Spanish Population.
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Antúnez, Carmen, Boada, Mercé, López-Arrieta, Jesús, Ramirez-Lorca, Reposo, Hernández, Isabel, Marín, Juan, Martínez-Lage, Pablo, González-Pérez, Antonio, Galan, José Jorge, Gayán, Javier, Real, Luis M., and Ruiz, Agustín
- Subjects
GENETIC markers ,ALZHEIMER'S disease risk factors ,GENOMES ,DISEASE susceptibility - Abstract
GOLPH2 gene SNP variants Rs10868366 and Rs7019241 were reported to decrease the risk of Alzheimer's disease in a recent Whole Genome Association Study. We have investigated these genetic variants in 2470 individuals from Spain to conduct an independent replication study of the proposed SNP markers. We found no evidence of association between GOLPH2 markers and susceptibility to Alzheimer's disease in our series. We concluded that GOLPH2 gene does not contribute to risk of disease in this study sample. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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48. Detection of visuoperceptual deficits in preclinical and mild Alzheimer's disease.
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Alegret, Montse, Boada-Rovira, Mercè, Vinyes-Junqué, Georgina, Valero, Sergi, Espinosa, Ana, Hernández, Isabel, Modinos, Gemma, Rosende-Roca, Maitee, Mauleón, Ana, Becker, JamesT., and Tárraga, Lluís
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NEUROPSYCHOLOGICAL tests ,VISUAL agnosia ,MEMORY ,PATIENTS ,ALZHEIMER'S disease ,REGRESSION analysis ,MULTIVARIATE analysis - Abstract
Exhaustive neuropsychological assessment of mild cognitive impairment (MCI) subjects frequently identifies cognitive deficits other than memory. However, visuoperception has rarely been investigated in MCI. The 15-Objects Test (15-OT), a visual discrimination task based on the Poppelreuter Test, consists of 15 overlapping objects. Poppelreuter-type tests are frequently used to detect visual agnosia. However, more complex tests, such as the 15-OT, are required to detect visuoperceptual signs in those patients who perform correctly on simple tests. The aim of the present study was to investigate visuoperceptual deficits in MCI patients and to assess the usefulness of the 15-OT to discriminate Alzheimer's disease (AD) and MCI patients from controls. The 15-OT, and a neuropsychological battery included in the diagnostic assessment, was administered to 44 healthy controls, 44 MCI patients, and 44 mild AD patients. Performance on the 15-OT was significantly different between groups. MCI scored between AD and controls. When MCI and AD patients had relatively normal performance on simple tests (Poppelreuter), increased significant abnormalities were found by a more difficult visuoperceptual test (15-OT). Regression analyses showed that the 15-OT was a significant predictor of group membership, but the Poppelreuter Test did not significantly contribute to the models. Visuoperceptual processing is impaired early in the clinical course of AD. The 15-OT allows detection of visuoperceptual deficits in the preclinical and mild AD stages, when classical tests are still unable to detect subtle deficits. So, its inclusion in neuropsychological batteries that are nowadays used in the clinical practice would allow increasing their diagnostic potential. [ABSTRACT FROM AUTHOR]
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- 2009
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49. Ubiquitin-negative mini-pick-like bodies in the dentate gyrus in p301l tauopathy.
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Ferrer, Isidro, Hernández, Isabel, Puig, Berta, Rey, María Jesús, Ezquerra, Mario, Tolosa, Eduardo, and Boada, Merce
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UBIQUITIN , *DENTATE gyrus , *DEMENTIA , *ALZHEIMER'S disease , *IMMUNOGLOBULINS - Abstract
Neuropathological and biochemical findings are reported in a patient who had suffered from frontotemporal dementia associated with a P310L mutation in the tau gene and included in the H1 haplotype. tau accumulation, as revealed with phospho-specific anti-tau antibodies Thr181, Ser199, Ser202, Ser214, Ser262, Ser396, Ser422 and AT8 (Ser202 and Thr205), was found in neurons with pre-tangles, and astrocytes and oligodendrocytes through the brain. The most characteristic feature was tau immunoreactivity decorating the perinuclear region and small cytoplasmic aggregates designed as mini-Pick-like bodies, mainly in the dentate gyrus. Inclusions were not stained with anti-ubiquitin antibodies and did not recruit tubulins. Tau accumulation in individual cells was associated with increased expression of kinases linked with tau phosphorylation, mainly active (phosphorylated) stress kinases SAPK/JNK and p38 (SAPK/JNK-P and p38-P). Phosphorylated GSK-3β at Ser9 (GSK-3β-P), that inactivates the kinase, was particularly abundant in mini-Pick-like bodies, thus suggesting alternative roles of GSK-3 probably involved in cell survival. Western blots of sarkosyl-insoluble fractions revealed a double band pattern of phospho-tau of 68/66 kDa and 64 kDa in the hippocampus and white matter in the P310L mutation. Sarkosyl-insoluble fractions of the hippocampus were enriched in p38-P and GSK-3β-P in Alzheimer's disease (AD) cases, processed in parallel for comparative purposes, but not in the P310L mutation. In addition, no bands of high molecular weight were found in P310L in contrast with AD in these fractions. These findings indicate that the major sites of tau phosphorylation, and the expression of kinases involved in tau phosphorylation are active in P310L mutation as in AD and other tauopathies. Yet the P310L mutation has particular phospho-tau inclusions that are not tag with ubiquitin and appear to be rather soluble when compared with AD. [ABSTRACT FROM AUTHOR]
- Published
- 2003
50. PLD3 in non-familial Alzheimer's disease.
- Author
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Heilmann, Stefanie, Drichel, Dmitriy, Clarimon, Jordi, Fernández, Victoria, Lacour, André, Wagner, Holger, Thelen, Mathias, Hernández, Isabel, Fortea, Juan, Alegret, Montserrat, Blesa, Rafael, Mauleón, Ana, Roca, Maitée Rosende, Kornhuber, Johannes, Peters, Oliver, Heun, Reinhard, Frölich, Lutz, Hüll, Michael, Heneka, Michael T., and Rüther, Eckart
- Subjects
PHOSPHOLIPASE D ,ALZHEIMER'S disease ,FAMILIAL diseases - Abstract
A letter to the editor is presented in response to an article by C. Cruchaga et al. in a 2014 issue of "Nature," which provided evidence supporting the role of rare variants in the phospholipase D3 (PLD3) gene in both familial and non-familial late-onset Alzheimer's disease.
- Published
- 2015
- Full Text
- View/download PDF
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