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211 results on '"Gómez-Tortosa, Estrella"'

1. A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

Author

Swift, Imogen J., Rademakers, Rosa, Finch, NiCole, Baker, Matt, Ghidoni, Roberta, Benussi, Luisa, Binetti, Giuliano, Rossi, Giacomina, Synofzik, Matthis, Wilke, Carlo, Mengel, David, Graff, Caroline, Takada, Leonel T., Sánchez-Valle, Raquel, Antonell, Anna, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Schreiber, Stefanie, Vielhaber, Stefan, Arndt, Philipp, Santana, Isabel, Almeida, Maria Rosario, Moreno, Fermín, Barandiaran, Myriam, Gabilondo, Alazne, Stubert, Johannes, Gómez-Tortosa, Estrella, Agüero, Pablo, Sainz, M. José, Gohda, Tomohito, Murakoshi, Maki, Kamei, Nozomu, Kittel-Schneider, Sarah, Reif, Andreas, Weigl, Johannes, Jian, Jinlong, Liu, Chuanju, Serrero, Ginette, Greither, Thomas, Theil, Gerit, Lohmann, Ebba, Gazzina, Stefano, Bagnoli, Silvia, Coppola, Giovanni, Bruni, Amalia, Quante, Mirja, Kiess, Wieland, Hiemisch, Andreas, Jurkutat, Anne, Block, Matthew S., Carlson, Aaron M., Bråthen, Geir, Sando, Sigrid Botne, Grøntvedt, Gøril Rolfseng, Lauridsen, Camilla, Heslegrave, Amanda, Heller, Carolin, Abel, Emily, Gómez-Núñez, Alba, Puey, Roger, Arighi, Andrea, Rotondo, Enmanuela, Jiskoot, Lize C., Meeter, Lieke H. H., Durães, João, Lima, Marisa, Tábuas-Pereira, Miguel, Lemos, João, Boeve, Bradley, Petersen, Ronald C., Dickson, Dennis W., Graff-Radford, Neill R., LeBer, Isabelle, Sellami, Leila, Lamari, Foudil, Clot, Fabienne, Borroni, Barbara, Cantoni, Valentina, Rivolta, Jasmine, Lleó, Alberto, Fortea, Juan, Alcolea, Daniel, Illán-Gala, Ignacio, Andres-Cerezo, Lucie, Van Damme, Philip, Clarimon, Jordi, Steinacker, Petra, Feneberg, Emily, Otto, Markus, van der Ende, Emma L., van Swieten, John C., Seelaar, Harro, Zetterberg, Henrik, Sogorb-Esteve, Aitana, and Rohrer, Jonathan D.

Published
2024
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2. Plasma Biomarkers in the Distinction of Alzheimer's Disease and Frontotemporal Dementia.

Author

Gómez-Tortosa, Estrella, Agüero-Rabes, Pablo, Ruiz-González, Alicia, Wagner-Reguero, Sonia, Téllez, Raquel, Mahillo, Ignacio, Ruiz-Calvo, Andrea, Sainz, María José, Nystrom, Anna Lena, del Ser, Teodoro, and Sánchez-Juan, Pascual

Subjects
*ALZHEIMER'S disease, *FRONTOTEMPORAL dementia, *ALZHEIMER'S patients, *DEMENTIA patients, *CEREBROSPINAL fluid
Abstract

Plasma biomarkers are promising tools for the screening and diagnosis of dementia in clinical settings. We analyzed plasma levels of Alzheimer's core biomarkers, neurofilament light chain (NfL) and glial fibrillary acid protein (GFAP), through single-molecule Array in 108 patients with Alzheimer's (AD, cerebrospinal fluid with an amyloid+ tau+ neurodegeneration+ profile), 73 patients with frontotemporal dementia (FTD, 24 with genetic diagnosis), and 54 controls. The best area under the curve (AUC) was used to assess the discriminative power. Patients with AD had lower Aß42/40 ratios and NfL levels, along with higher levels of p-tau181 and GFAP, compared with FTD patients. Single biomarkers discriminated well between dementia patients and controls: the Aß42/40 ratio (AUC:0.86) or GFAP (AUC:0.83) was found for AD, and the NfL (AUC:0.84) was found for FTD patients. However, a combination of two (NfL with p-tau181, or the GFAP/NfL ratio, AUCs ~0.87) or three biomarkers (NfL, P-tau181, and Aß42/40 ratio, AUC: 0.90) was required to distinguish between AD and FTD. Biomarker profiles were similar across different FTD phenotypes, except for carriers of PGRN mutations, who had higher levels of NfL than C9orf72 expansion carriers. In our series, NfL alone provided the best distinction between FTD and controls, while a combination of two or three biomarkers was required to obtain good discrimination between AD and FTD. [ABSTRACT FROM AUTHOR]

Published
2025
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3. Prevalence of Cerebral Amyloid Pathology in Persons Without Dementia: A Meta-analysis

Author

Jansen, Willemijn J, Ossenkoppele, Rik, Knol, Dirk L, Tijms, Betty M, Scheltens, Philip, Verhey, Frans RJ, Visser, Pieter Jelle, Aalten, Pauline, Aarsland, Dag, Alcolea, Daniel, Alexander, Myriam, Almdahl, Ina S, Arnold, Steven E, Baldeiras, Inês, Barthel, Henryk, van Berckel, Bart NM, Bibeau, Kristen, Blennow, Kaj, Brooks, David J, van Buchem, Mark A, Camus, Vincent, Cavedo, Enrica, Chen, Kewei, Chetelat, Gael, Cohen, Ann D, Drzezga, Alexander, Engelborghs, Sebastiaan, Fagan, Anne M, Fladby, Tormod, Fleisher, Adam S, van der Flier, Wiesje M, Ford, Lisa, Förster, Stefan, Fortea, Juan, Foskett, Nadia, Frederiksen, Kristian S, Freund-Levi, Yvonne, Frisoni, Giovanni B, Froelich, Lutz, Gabryelewicz, Tomasz, Gill, Kiran Dip, Gkatzima, Olymbia, Gómez-Tortosa, Estrella, Gordon, Mark Forrest, Grimmer, Timo, Hampel, Harald, Hausner, Lucrezia, Hellwig, Sabine, Herukka, Sanna-Kaisa, Hildebrandt, Helmut, Ishihara, Lianna, Ivanoiu, Adrian, Jagust, William J, Johannsen, Peter, Kandimalla, Ramesh, Kapaki, Elisabeth, Klimkowicz-Mrowiec, Aleksandra, Klunk, William E, Köhler, Sebastian, Koglin, Norman, Kornhuber, Johannes, Kramberger, Milica G, Van Laere, Koen, Landau, Susan M, Lee, Dong Young, de Leon, Mony, Lisetti, Viviana, Lleó, Alberto, Madsen, Karine, Maier, Wolfgang, Marcusson, Jan, Mattsson, Niklas, de Mendonça, Alexandre, Meulenbroek, Olga, Meyer, Philipp T, Mintun, Mark A, Mok, Vincent, Molinuevo, José Luis, Møllergård, Hanne M, Morris, John C, Mroczko, Barbara, Van der Mussele, Stefan, Na, Duk L, Newberg, Andrew, Nordberg, Agneta, Nordlund, Arto, Novak, Gerald P, Paraskevas, George P, Parnetti, Lucilla, Perera, Gayan, Peters, Oliver, Popp, Julius, Prabhakar, Sudesh, Rabinovici, Gil D, Ramakers, Inez HGB, Rami, Lorena, de Oliveira, Catarina Resende, Rinne, Juha O, Rodrigue, Karen M, and Rodríguez-Rodríguez, Eloy

Subjects
Health Services and Systems, Health Sciences, Alzheimer's Disease, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Vascular Cognitive Impairment/Dementia, Neurosciences, Dementia, Cerebrovascular, Acquired Cognitive Impairment, Brain Disorders, Prevention, Alzheimer's Disease Related Dementias (ADRD), Neurodegenerative, Aging, 2.1 Biological and endogenous factors, 4.2 Evaluation of markers and technologies, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Adult, Age Factors, Aged, Aged, 80 and over, Amyloid beta-Peptides, Apolipoprotein E4, Biomarkers, Brain, Cerebrospinal Fluid, Cognitive Dysfunction, Female, Genotype, Humans, Male, Middle Aged, Positron-Emission Tomography, Prevalence, Risk Factors, Amyloid Biomarker Study Group, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

ImportanceCerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.ObjectiveTo use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI).Data sourcesRelevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators.Study selectionStudies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity.Data extraction and synthesisIndividual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies.Main outcomes and measuresPrevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations.ResultsThe prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality.Conclusions and relevanceAmong persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

Published
2015

4. CSF ADAM10 levels in AD patients in relationship to ADAM10 gene variants

Author

Agüero, Pablo, primary, Cremades‐Jimeno, Lucía, additional, García‐Ayllón, María‐Salud, additional, Gea‐González, Adriana, additional, Sainz, María José, additional, Téllez, Raquel, additional, Cárdaba, Blanca, additional, Sáez‐Valero, Javier, additional, Pérez‐Pérez, Julián, additional, and Gómez‐Tortosa, Estrella, additional

Published
2023
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5. Posterior cortical atrophy in clinical practice

Author

Maure‐Blesa, Lucía, primary, Agüero, Pablo, additional, Sainz, María José, additional, Téllez, Raquel, additional, Lorda‐Sánchez, Isabel, additional, Ávila‐Fernández, Almudena, additional, Gallego‐Merlo, Jesús, additional, Pérez‐Pérez, Julián, additional, and Gómez‐Tortosa, Estrella, additional

Published
2023
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7. Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer’s disease

Author

De Roeck, Arne, Van den Bossche, Tobi, van der Zee, Julie, Verheijen, Jan, De Coster, Wouter, Van Dongen, Jasper, Dillen, Lubina, Baradaran-Heravi, Yalda, Heeman, Bavo, Sanchez-Valle, Raquel, Lladó, Albert, Nacmias, Benedetta, Sorbi, Sandro, Gelpi, Ellen, Grau-Rivera, Oriol, Gómez-Tortosa, Estrella, Pastor, Pau, Ortega-Cubero, Sara, Pastor, Maria A., Graff, Caroline, Thonberg, Håkan, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, de Mendonça, Alexandre, Martins, Madalena, Borroni, Barbara, Padovani, Alessandro, Almeida, Maria Rosário, Santana, Isabel, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Clarimon, Jordi, Lleó, Alberto, Fortea, Juan, Tsolaki, Magda, Koutroumani, Maria, Matěj, Radoslav, Rohan, Zdenek, De Deyn, Peter, Engelborghs, Sebastiaan, Cras, Patrick, Van Broeckhoven, Christine, Sleegers, Kristel, Bessi, Valentina, Bagnoli, Silvia, do Couto, Frederico Simões, Verdelho, Ana, Fratiglioni, Laura, Padovani, Alessandro, Rohan, Zdenek, Razquin, Cristina, Lorenzo, Elena, Iglesias, Elena, Seijo-Martínez, Manuel, Rene, Ramon, Gascon, Jordi, Campdelacreu, Jaume, Blesa, Rafael, and On behalf of the European Early-Onset Dementia (EU EOD) consortium

Published
2017
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8. ADAM10 Gene Variants in AD Patients and Their Relationship to CSF Protein Levels

Author

Agüero-Rabes, Pablo, primary, Pérez-Pérez, Julián, additional, Cremades-Jimeno, Lucía, additional, García-Ayllón, María-Salud, additional, Gea-González, Adriana, additional, Sainz, María José, additional, Mahillo-Fernández, Ignacio, additional, Téllez, Raquel, additional, Cárdaba, Blanca, additional, Sáez-Valero, Javier, additional, and Gómez-Tortosa, Estrella, additional

Published
2023
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13. Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia

Author

Philtjens, Stéphanie, Van Mossevelde, Sara, van der Zee, Julie, Wauters, Eline, Dillen, Lubina, Vandenbulcke, Mathieu, Vandenberghe, Rik, Ivanoiu, Adrian, Sieben, Anne, Willems, Christiana, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Borroni, Barbara, Padovani, Alessandro, Pastor, Pau, Diez-Fairen, Monica, Aguilar, Miquel, de Mendonça, Alexandre, Miltenberger-Miltényi, Gabriel, Hernández, Isabel, Boada, Merce, Ruiz, Agustín, Nacmias, Benedetta, Sorbi, Sandro, Almeida, Maria Rosário, Santana, Isabel, Clarimón, Jordi, Lleó, Alberto, Frisoni, Giovanni B., Sanchez-Valle, Raquel, Lladó, Albert, Gómez-Tortosa, Estrella, Gelpi, Ellen, Van den Broeck, Marleen, Peeters, Karin, Cras, Patrick, De Deyn, Peter P., Engelborghs, Sebastiaan, Cruts, Marc, and Van Broeckhoven, Christine

Published
2018
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15. TRIM25 mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early‐onset autosomal dominant dementia with amyloid load and parkinsonism.

Author

Gómez‐Tortosa, Estrella, Baradaran‐Heravi, Yalda, Dillen, Lubina, Choudhury, Nila Roy, Agüero Rabes, Pablo, Pérez‐Pérez, Julián, Kocoglu, Cemile, Sainz, M. José, Ruiz González, Alicia, Téllez, Raquel, Cremades‐Jimeno, Lucía, Cárdaba, Blanca, Van Broeckhoven, Christine, Michlewski, Gracjan, and van der Zee, Julie

Abstract

INTRODUCTION: Patients with familial early‐onset dementia (EOD) pose a unique opportunity for gene identification studies. METHODS: We present the phenotype and whole‐exome sequencing (WES) study of an autosomal dominant EOD family. Candidate genes were examined in a set of dementia cases and controls (n = 3712). Western blotting was conducted of the wild‐type and mutant protein of the final candidate. RESULTS: Age at disease onset was 60 years (range 56 to 63). The phenotype comprised mixed amnestic and behavioral features, and parkinsonism. Cerebrospinal fluid and plasma biomarkers, and a positron emission tomography amyloid study suggested Alzheimer's disease. WES and the segregation pattern pointed to a nonsense mutation in the TRIM25 gene (p.C168*), coding for an E3 ubiquitin ligase, which was absent in the cohorts studied. Protein studies supported a loss‐of‐function mechanism. DISCUSSION: This study supports a new physiopathological mechanism for brain amyloidosis. Furthermore, it extends the role of E3 ubiquitin ligases dysfunction in the development of neurodegenerative diseases. Highlights: A TRIM25 nonsense mutation (p.C168*) is associated with autosomal dominant early‐onset dementia and parkinsonism with biomarkers suggestive of Alzheimer's disease.TRIM25 protein studies support that the mutation exerts its effect through loss of function.TRIM25, an E3 ubiquitin ligase, is known for its role in the innate immune response but this is the first report of association with neurodegeneration.The role of TRIM25 dysfunction in development of amyloidosis and neurodegeneration merits a new line of research. [ABSTRACT FROM AUTHOR]

Published
2023
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17. Common SNP-Based Haplotype Analysis of the 4p16.3 Huntington Disease Gene Region

Author

Lee, Jong-Min, Gillis, Tammy, Mysore, Jayalakshmi Srinidhi, Ramos, Eliana Marisa, Myers, Richard H., Hayden, Michael R., Morrison, Patrick J., Nance, Martha, Ross, Christopher A., Margolis, Russell L., Squitieri, Ferdinando, Griguoli, Annamaria, Di Donato, Stefano, Gomez-Tortosa, Estrella, Ayuso, Carmen, Suchowersky, Oksana, Trent, Ronald J., McCusker, Elizabeth, Novelletto, Andrea, Frontali, Marina, Jones, Randi, Ashizawa, Tetsuo, Frank, Samuel, Saint-Hilaire, Marie-Helene, Hersch, Steven M., Rosas, Herminia D., Lucente, Diane, Harrison, Madaline B., Zanko, Andrea, Abramson, Ruth K., Marder, Karen, Sequeiros, Jorge, MacDonald, Marcy E., and Gusella, James F.

Published
2012
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18. Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort

Author

Goeman, Johan, Nuytten, Dirk, Vandenbulcke, Mathieu, Santens, Patrick, De Bleecker, Jan, Sieben, Anne, Dermaut, Bart, Versijpt, Jan, Michotte, Alex, Deryck, Olivier, Bergmans, Bruno, Willems, Christiana, Ivanoiu, Adrian, Salmon, Eric, Alexopoulos, Panagiotis, Sorbi, Sandro, Bessi, Valentina, Bagnoli, Silvia, Santana, Isabel, Simões do Couto, Frederico, Martins, Madalena, Thonberg, Håkan, Fratiglioni, Laura, Padovani, Alessandro, Rohan, Zdenek, Razquin, Cristina, Lorenzo, Elena, Iglesias, Elena, Seijo-Martínez, Manuel, Rene, Ramon, Gascon, Jordi, Campdelacreu, Jaume, Koutroumani, Maria, Lleó, Alberto, Fortea, Juan, Blesa, Rafael, Verheijen, Jan, van der Zee, Julie, Gijselinck, Ilse, Van den Bossche, Tobi, Dillen, Lubina, Heeman, Bavo, Gómez-Tortosa, Estrella, Lladó, Albert, Sanchez-Valle, Raquel, Graff, Caroline, Pastor, Pau, Pastor, Maria A., Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Clarimon, Jordi, de Mendonça, Alexandre, Gelpi, Ellen, Tsolaki, Magda, Diehl-Schmid, Janine, Nacmias, Benedetta, Almeida, Maria Rosário, Borroni, Barbara, Matej, Radoslav, Ruiz, Agustín, Engelborghs, Sebastiaan, Vandenberghe, Rik, De Deyn, Peter P., Cruts, Marc, Van Broeckhoven, Christine, and Sleegers, Kristel

Published
2018
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19. Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum

Author

Jansen, Willemijn J., Janssen, Olin, Tijms, Betty M., Vos, Stephanie J.B., Ossenkoppele, Rik, Visser, Pieter Jelle, Aarsland, Dag, Alcolea, Daniel, Altomare, Daniele, Von Arnim, Christine, Baiardi, Simone, Baldeiras, Ines, Barthel, Henryk, Bateman, Randall J., Van Berckel, Bart, Binette, Alexa Pichet, Blennow, Kaj, Boada, Merce, Boecker, Henning, Bottlaender, Michel, Den Braber, Anouk, Brooks, David J., Van Buchem, Mark A., Camus, Vincent, Carill, Jose Manuel, Cerman, Jiri, Chen, Kewei, Chételat, Gaël, Chipi, Elena, Cohen, Ann D., Daniels, Alisha, Delarue, Marion, Didic, Mira, Drzezga, Alexander, Dubois, Bruno, Eckerström, Marie, Ekblad, Laura L., Engelborghs, Sebastiaan, Epelbaum, Stéphane, Fagan, Anne M., Fan, Yong, Fladby, Tormod, Fleisher, Adam S., Van Der Flier, Wiesje M., Förster, Stefan, Fortea, Juan, Frederiksen, Kristian Steen, Freund-Levi, Yvonne, Frings, Lars, Frisoni, Giovanni B., Fröhlich, Lutz, Gabryelewicz, Tomasz, Gertz, Hermann Josef, Gill, Kiran Dip, Gkatzima, Olymbia, Gómez-Tortosa, Estrella, Grimmer, Timo, Guedj, Eric, Habeck, Christian G., Hampel, Harald, Handels, Ron, Hansson, Oskar, Hausner, Lucrezia, Hellwig, Sabine, Heneka, Michael T., Herukka, Sanna Kaisa, Hildebrandt, Helmut, Hodges, John, Hort, Jakub, Huang, Chin Chang, Iriondo, Ane Juaristi, Itoh, Yoshiaki, Ivanoiu, Adrian, Jagust, William J., Jessen, Frank, Johannsen, Peter, Johnson, Keith A., Kandimalla, Ramesh, Kapaki, Elisabeth N., Kern, Silke, Kilander, Lena, Klimkowicz-Mrowiec, Aleksandra, Klunk, William E., Koglin, Norman, Kornhuber, Johannes, Kramberger, Milica G., Kuo, Hung Chou, Van Laere, Koen, Landau, Susan M., Landeau, Brigitte, Lee, Dong Young, De Leon, Mony, Leyton, Cristian E., Lin, Kun Ju, Lleó, Alberto, Löwenmark, Malin, Madsen, Karine, Maier, Wolfgang, Marcusson, Jan, Marquié, Marta, Martinez-Lage, Pablo, Maserejian, Nancy, Mattsson, Niklas, De Mendonça, Alexandre, Meyer, Philipp T., Miller, Bruce L., Minatani, Shinobu, Mintun, Mark A., Mok, Vincent C.T., Molinuevo, Jose Luis, Morbelli, Silvia Daniela, Morris, John C., Mroczko, Barbara, Na, Duk L., Newberg, Andrew, Nobili, Flavio, Nordberg, Agneta, Olde Rikkert, Marcel G.M., De Oliveira, Catarina Resende, Olivieri, Pauline, Orellana, Adela, Paraskevas, George, Parchi, Piero, Pardini, Matteo, Parnetti, Lucilla, Peters, Oliver, Poirier, Judes, Popp, Julius, Prabhakar, Sudesh, Rabinovici, Gil D., Ramakers, Inez H., Rami, Lorena, Reiman, Eric M., Rinne, Juha O., Rodrigue, Karen M., Rodríguez-Rodriguez, Eloy, Roe, Catherine M., Rosa-Neto, Pedro, Rosen, Howard J., Rot, Uros, Rowe, Christopher C., Rüther, Eckart, Ruiz, Agustín, Sabri, Osama, Sakhardande, Jayant, Sánchez-Juan, Pascual, Sando, Sigrid Botne, Santana, Isabel, Sarazin, Marie, Scheltens, Philip, Schröder, Johannes, Selnes, Per, Seo, Sang Won, Silva, Dina, Skoog, Ingmar, Snyder, Peter J., Soininen, Hilkka, Sollberger, Marc, Sperling, Reisa A., Spiru, Luisa, Stern, Yaakov, Stomrud, Erik, Takeda, Akitoshi, Teichmann, Marc, Teunissen, Charlotte E., Thompson, Louisa I., Tomassen, Jori, Tsolaki, Magda, Vandenberghe, Rik, Verbeek, Marcel M., Verhey, Frans R.J., Villemagne, Victor, Villeneuve, Sylvia, Vogelgsang, Jonathan, Waldemar, Gunhild, Wallin, Anders, Wallin, Åsa K., Wiltfang, Jens, Wolk, David A., Yen, Tzu Chen, Zboch, Marzena, Zetterberg, Henrik, Jansen, Willemijn J., Janssen, Olin, Tijms, Betty M., Vos, Stephanie J.B., Ossenkoppele, Rik, Visser, Pieter Jelle, Aarsland, Dag, Alcolea, Daniel, Altomare, Daniele, Von Arnim, Christine, Baiardi, Simone, Baldeiras, Ines, Barthel, Henryk, Bateman, Randall J., Van Berckel, Bart, Binette, Alexa Pichet, Blennow, Kaj, Boada, Merce, Boecker, Henning, Bottlaender, Michel, Den Braber, Anouk, Brooks, David J., Van Buchem, Mark A., Camus, Vincent, Carill, Jose Manuel, Cerman, Jiri, Chen, Kewei, Chételat, Gaël, Chipi, Elena, Cohen, Ann D., Daniels, Alisha, Delarue, Marion, Didic, Mira, Drzezga, Alexander, Dubois, Bruno, Eckerström, Marie, Ekblad, Laura L., Engelborghs, Sebastiaan, Epelbaum, Stéphane, Fagan, Anne M., Fan, Yong, Fladby, Tormod, Fleisher, Adam S., Van Der Flier, Wiesje M., Förster, Stefan, Fortea, Juan, Frederiksen, Kristian Steen, Freund-Levi, Yvonne, Frings, Lars, Frisoni, Giovanni B., Fröhlich, Lutz, Gabryelewicz, Tomasz, Gertz, Hermann Josef, Gill, Kiran Dip, Gkatzima, Olymbia, Gómez-Tortosa, Estrella, Grimmer, Timo, Guedj, Eric, Habeck, Christian G., Hampel, Harald, Handels, Ron, Hansson, Oskar, Hausner, Lucrezia, Hellwig, Sabine, Heneka, Michael T., Herukka, Sanna Kaisa, Hildebrandt, Helmut, Hodges, John, Hort, Jakub, Huang, Chin Chang, Iriondo, Ane Juaristi, Itoh, Yoshiaki, Ivanoiu, Adrian, Jagust, William J., Jessen, Frank, Johannsen, Peter, Johnson, Keith A., Kandimalla, Ramesh, Kapaki, Elisabeth N., Kern, Silke, Kilander, Lena, Klimkowicz-Mrowiec, Aleksandra, Klunk, William E., Koglin, Norman, Kornhuber, Johannes, Kramberger, Milica G., Kuo, Hung Chou, Van Laere, Koen, Landau, Susan M., Landeau, Brigitte, Lee, Dong Young, De Leon, Mony, Leyton, Cristian E., Lin, Kun Ju, Lleó, Alberto, Löwenmark, Malin, Madsen, Karine, Maier, Wolfgang, Marcusson, Jan, Marquié, Marta, Martinez-Lage, Pablo, Maserejian, Nancy, Mattsson, Niklas, De Mendonça, Alexandre, Meyer, Philipp T., Miller, Bruce L., Minatani, Shinobu, Mintun, Mark A., Mok, Vincent C.T., Molinuevo, Jose Luis, Morbelli, Silvia Daniela, Morris, John C., Mroczko, Barbara, Na, Duk L., Newberg, Andrew, Nobili, Flavio, Nordberg, Agneta, Olde Rikkert, Marcel G.M., De Oliveira, Catarina Resende, Olivieri, Pauline, Orellana, Adela, Paraskevas, George, Parchi, Piero, Pardini, Matteo, Parnetti, Lucilla, Peters, Oliver, Poirier, Judes, Popp, Julius, Prabhakar, Sudesh, Rabinovici, Gil D., Ramakers, Inez H., Rami, Lorena, Reiman, Eric M., Rinne, Juha O., Rodrigue, Karen M., Rodríguez-Rodriguez, Eloy, Roe, Catherine M., Rosa-Neto, Pedro, Rosen, Howard J., Rot, Uros, Rowe, Christopher C., Rüther, Eckart, Ruiz, Agustín, Sabri, Osama, Sakhardande, Jayant, Sánchez-Juan, Pascual, Sando, Sigrid Botne, Santana, Isabel, Sarazin, Marie, Scheltens, Philip, Schröder, Johannes, Selnes, Per, Seo, Sang Won, Silva, Dina, Skoog, Ingmar, Snyder, Peter J., Soininen, Hilkka, Sollberger, Marc, Sperling, Reisa A., Spiru, Luisa, Stern, Yaakov, Stomrud, Erik, Takeda, Akitoshi, Teichmann, Marc, Teunissen, Charlotte E., Thompson, Louisa I., Tomassen, Jori, Tsolaki, Magda, Vandenberghe, Rik, Verbeek, Marcel M., Verhey, Frans R.J., Villemagne, Victor, Villeneuve, Sylvia, Vogelgsang, Jonathan, Waldemar, Gunhild, Wallin, Anders, Wallin, Åsa K., Wiltfang, Jens, Wolk, David A., Yen, Tzu Chen, Zboch, Marzena, and Zetterberg, Henrik

Abstract

Importance: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design. Objective: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates. Design, Setting, and Participants: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria. Exposures: Alzheimer disease biomarkers detected on PET or in CSF. Main Outcomes and Measures: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations. Results: Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%])

Published
2022

20. Heterozygous and Homozygous Variants in SORL1 Gene in Alzheimer’s Disease Patients: Clinical, Neuroimaging and Neuropathological Findings

Author

Alvarez-Mora, Maria Isabel, primary, Blanco-Palmero, Victor Antonio, additional, Quesada-Espinosa, Juan Francisco, additional, Arteche-Lopez, Ana Rosa, additional, Llamas-Velasco, Sara, additional, Palma Milla, Carmen, additional, Lezana Rosales, Jose Miguel, additional, Gomez-Manjon, Irene, additional, Hernandez-Lain, Aurelio, additional, Jimenez Almonacid, Justino, additional, Gil-Fournier, Belén, additional, Ramiro-León, Soraya, additional, González-Sánchez, Marta, additional, Herrero-San Martín, Alejandro Octavio, additional, Pérez-Martínez, David Andrés, additional, Gómez-Tortosa, Estrella, additional, Carro, Eva, additional, Bartolomé, Fernando, additional, Gomez-Rodriguez, Maria Jose, additional, Sanchez-Calvin, María Teresa, additional, Villarejo-Galende, Alberto, additional, and Moreno-Garcia, Marta, additional

Published
2022
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21. Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum

Author

Jansen, Willemijn J, Janssen, Olin, von Arnim, Christine, Marquié, Marta, Martinez-Lage, Pablo, Maserejian, Nancy, Mattsson, Niklas, de Mendonça, Alexandre, Meyer, Philipp T, Miller, Bruce L, Minatani, Shinobu, Mintun, Mark A, Mok, Vincent C T, Baiardi, Simone, Molinuevo, Jose Luis, Morbelli, Silvia Daniela, Morris, John C, Mroczko, Barbara, Na, Duk L, Newberg, Andrew, Nobili, Flavio, Nordberg, Agneta, Olde Rikkert, Marcel G M, de Oliveira, Catarina Resende, Baldeiras, Ines, Olivieri, Pauline, Orellana, Adela, Paraskevas, George, Parchi, Piero, Pardini, Matteo, Parnetti, Lucilla, Peters, Oliver, Poirier, Judes, Popp, Julius, Prabhakar, Sudesh, Barthel, Henryk, Rabinovici, Gil D, Ramakers, Inez H, Rami, Lorena, Reiman, Eric M, Rinne, Juha O, Rodrigue, Karen M, Rodríguez-Rodriguez, Eloy, Roe, Catherine M, Rosa-Neto, Pedro, Rosen, Howard J, Bateman, Randall J, Rot, Uros, Rowe, Christopher C, Rüther, Eckart, Ruiz, Agustín, Sabri, Osama, Sakhardande, Jayant, Sánchez-Juan, Pascual, Sando, Sigrid Botne, Santana, Isabel, Sarazin, Marie, Van Berckel, Bart, Scheltens, Philip, Schröder, Johannes, Selnes, Per, Seo, Sang Won, Silva, Dina, Skoog, Ingmar, Snyder, Peter J, Soininen, Hilkka, Sollberger, Marc, Sperling, Reisa A, Binette, Alexa Pichet, Spiru, Luisa, Stern, Yaakov, Stomrud, Erik, Takeda, Akitoshi, Teichmann, Marc, Teunissen, Charlotte E, Thompson, Louisa I, Tomassen, Jori, Tsolaki, Magda, Vandenberghe, Rik, Blennow, Kaj, Verbeek, Marcel M, Verhey, Frans R J, Villemagne, Victor, Villeneuve, Sylvia, Vogelgsang, Jonathan, Waldemar, Gunhild, Wallin, Anders, Wallin, Åsa K, Wiltfang, Jens, Wolk, David A, Boada, Merce, Yen, Tzu-Chen, Zboch, Marzena, Zetterberg, Henrik, Boecker, Henning, Tijms, Betty M, Bottlaender, Michel, den Braber, Anouk, Brooks, David J, Van Buchem, Mark A, Camus, Vincent, Carill, Jose Manuel, Cerman, Jiri, Chen, Kewei, Chételat, Gaël, Chipi, Elena, Vos, Stephanie J B, Cohen, Ann D, Daniels, Alisha, Delarue, Marion, Didic, Mira, Drzezga, Alexander, Dubois, Bruno, Eckerström, Marie, Ekblad, Laura L, Engelborghs, Sebastiaan, Epelbaum, Stéphane, Ossenkoppele, Rik, Fagan, Anne M, Fan, Yong, Fladby, Tormod, Fleisher, Adam S, Van der Flier, Wiesje M, Förster, Stefan, Fortea, Juan, Frederiksen, Kristian Steen, Freund-Levi, Yvonne, Frings, Lars, Visser, Pieter Jelle, Frisoni, Giovanni B, Fröhlich, Lutz, Gabryelewicz, Tomasz, Gertz, Hermann-Josef, Gill, Kiran Dip, Gkatzima, Olymbia, Gómez-Tortosa, Estrella, Grimmer, Timo, Guedj, Eric, Habeck, Christian G, Group, Amyloid Biomarker Study, Hampel, Harald, Handels, Ron, Hansson, Oskar, Hausner, Lucrezia, Hellwig, Sabine, Heneka, Michael, Herukka, Sanna-Kaisa, Hildebrandt, Helmut, Hodges, John, Hort, Jakub, Aarsland, Dag, Huang, Chin-Chang, Iriondo, Ane Juaristi, Itoh, Yoshiaki, Ivanoiu, Adrian, Jagust, William J, Jessen, Frank, Johannsen, Peter, Johnson, Keith A, Kandimalla, Ramesh, Kapaki, Elisabeth N, Alcolea, Daniel, Kern, Silke, Kilander, Lena, Klimkowicz-Mrowiec, Aleksandra, Klunk, William E, Koglin, Norman, Kornhuber, Johannes, Kramberger, Milica G, Kuo, Hung-Chou, Van Laere, Koen, Landau, Susan M, Altomare, Daniele, Landeau, Brigitte, Lee, Dong Young, de Leon, Mony, Leyton, Cristian E, Lin, Kun-Ju, Lleó, Alberto, Löwenmark, Malin, Madsen, Karine, Maier, Wolfgang, Marcusson, Jan, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Neurodegeneration, Radiology and nuclear medicine, Laboratory Medicine, Amsterdam Neuroscience - Neuroinfection & -inflammation, APH - Personalized Medicine, APH - Methodology, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, and Psychiatrie & Neuropsychologie

Subjects
Male, MILD COGNITIVE IMPAIRMENT, epidemiology [Cognitive Dysfunction], positron emission tomography, Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1], epidemiology [Alzheimer Disease], Neuroscience(all), diagnostic imaging [Cognitive Dysfunction], Amyloidogenic Proteins, tau Proteins, cerebrospinal fluid [Amyloid beta-Peptides], DIAGNOSIS, cerebrospinal fluid, Apolipoproteins E, Alzheimer Disease, Prevalence, Humans, Amyloid, Alzheimer, PET, Cognitive Dysfunction, ddc:610, cerebrospinal fluid [Peptide Fragments], Aged, Amyloid beta-Peptides, neurology, DEMENTIA, Correction, ASSOCIATION, Amyloidosis, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], health care planning, clinical trial design, Peptide Fragments, cerebrospinal fluid [Alzheimer Disease], PET, DRIFT, Cross-Sectional Studies, cerebrospinal fluid [Biomarkers], cerebrospinal fluid [tau Proteins], Radiology Nuclear Medicine and imaging, Positron-Emission Tomography, genetics [Apolipoproteins E], Female, Neurology (clinical), diagnostic imaging [Alzheimer Disease], cerebral amyloid aggregation, Biomarkers
Abstract

Importance: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.Objective: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.Design, Setting, and Participants: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Exposures: Alzheimer disease biomarkers detected on PET or in CSF.Main Outcomes and Measures: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Results: Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P = .18).Conclusions and Relevance: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

Published
2022
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23. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

Author

Barbier, Mathieu, Camuzat, Agnès, Hachimi, Khalid El, Guegan, Justine, Rinaldi, Daisy, Lattante, Serena, Houot, Marion, Sánchez-Valle, Raquel, Sabatelli, Mario, Antonell, Anna, Molina-Porcel, Laura, Clot, Fabienne, Couratier, Philippe, van der Ende, Emma, van der Zee, Julie, Manzoni, Claudia, Camu, William, Cazeneuve, Cécile, Sellal, François, Didic, Mira, Golfier, Véronique, Pasquier, Florence, Duyckaerts, Charles, Rossi, Giacomina, Bruni, Amalia C, Alvarez, Victoria, Gómez-Tortosa, Estrella, de Mendonça, Alexandre, Graff, Caroline, Masellis, Mario, Nacmias, Benedetta, Oumoussa, Badreddine Mohand, Jornea, Ludmila, Forlani, Sylvie, Van Deerlin, Viviana, Rohrer, Jonathan D, Gelpi, Ellen, Rademakers, Rosa, Van Swieten, John, Le Guern, Eric, Van Broeckhoven, Christine, Ferrari, Raffaele, Génin, Emmanuelle, Brice, Alexis, Ber, Le, Isabelle Alexis Brice, Sophie, Auriacombe, Serge, Belliard, Anne, Bertrand, Anne, Bissery, Fre ́ de, ́ ric Blanc, Marie-Paule, Boncoeur, Ste, ́ phanie Bombois, Claire Boutoleau-Bretonnie` re, Agne`, s Camuzat, Mathieu, Ceccaldi, Marie, Chupin, Philippe, Couratier, Olivier, Colliot, Vincent, Deramecourt, Mira, Didic, Bruno, Dubois, Charles, Duyckaerts, Fre ́ de, ́ rique Etcharry-Bouyx, Aure, ́ lie Guignebert-Funkiewiez, Maı ̈te, ́ Formaglio, ́ ronique Golfier, Ve, Marie-Odile, Habert, Didier, Hannequin, Lucette, Lacomblez, Julien, Lagarde, ́ raldine Lautrette, Ge, Isabelle Le Ber, Benjamin Le Toullec, Richard, Levy, Marie-Anne, Mackowiak, Bernard-Franc ̧ois Michel, Florence, Pasquier, Thibaud, Lebouvier, Carole Roue, ́ -Jagot, Christel Thauvin- Robinet, Catherine, Thomas-Anterion, Je ́ re, ́ mie Pariente, Franc ̧ois Salachas, Sabrina, Sayah, Franc ̧ois Sellal, Assi-Herve, ́ Oya, Daisy, Rinaldi, Adeline, Rollin-Sillaire, Martine, Vercelletto, David, Wallon, Armelle, Rametti-Lacroux, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavan, Ramasamy, Kwok, John B. J., Carol Dobson- Stone, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Isabel Herna, ́ ndez, Agustı ́n Ruiz, Merce`, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Diego, Albani, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, ́ n, Jordi Clarimo, Alberto Lleo, ́, Rafael, Blesa, Maria Landqvist Waldo, ̈, Karin, Nilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietro, Pietrini, Edward, Uey, Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, Rowe, James B., Schlachetzki, Johannes C. M., James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Van Deerlin, Vivianna M., Murray, Grossman, Trojanowski, John Q., Julie van der Zee, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle, Leber, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Maria Grazia Spillantini, Morris, Huw R., Patrizia, Rizzu, Peter, Heutink, Snowden, Julie S., Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., David, Knopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, van Swieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Adeline, Rollin, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni., Neurology, Amsterdam Neuroscience - Neurodegeneration, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Dupuytren [CHU Limoges], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Center for Molecular Neurology (VIB-UAntwerp), University of Antwerp (UA), University College of London [London] (UCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Yves le Foll, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Hospital Central de Asturias, Institute of Health Research of Principado de Asturias (ISPA), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Karolinska University Hospital [Stockholm], Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione Don Carlo Gnocchi, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), The French clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS, The International Frontotemporal Dementia Genomics Consortium, The European Early Onset Dementia (EU -EOD) Consortium, Brainbank Neuro-CEB Neuropathology Network, and Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS

Subjects
Adult, Male, TDP-43, C9orf72, SLITRK2, amyotrophic lateral sclerosis, frontotemporal dementia, Nerve Tissue Proteins, Settore MED/03 - GENETICA MEDICA, Polymorphism, Single Nucleotide, Cohort Studies, Genes, X-Linked, 80 and over, Medicine, Dementia, Humans, Allele, Age of Onset, Polymorphism, Aged, Aged, 80 and over, biology, C9orf72 Protein, business.industry, Membrane Proteins, MESH: Frontotemporal Lobar Degeneration / epidemiology, Frontotemporal Lobar, Degeneration / genetics, Genes, X-Linked / genetics, Genome-Wide Association Study / methods, Frontotemporal lobar degeneration, Single Nucleotide, Middle Aged, X-Linked, medicine.disease, Amyotrophic lateral sclerosis, Minor allele frequency, Genes, Immunology, Synaptophysin, biology.protein, Female, MESH: Adult, C9orf72 Protein / genetics, Frontotemporal Lobar Degeneration / diagnosis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, Neurology (clinical), MESH: Humans, Membrane Proteins / genetics, Nerve Tissue Proteins / genetics, Polymorphism, Single Nucleotide / genetics, Age of onset, Frontotemporal Lobar Degeneration, business, Frontotemporal dementia, Genome-Wide Association Study
Abstract

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

Published
2021
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25. Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16

Author

Djoussé, Luc, Knowlton, Beth, Hayden, Michael R., Almqvist, Elisabeth W., Brinkman, Ryan R., Ross, Christopher A., Margolis, Russel L., Rosenblatt, Adam, Durr, Alexandra, Dode, Catherine, Morrison, Patrick J., Novelletto, Andrea, Frontali, Marina, Trent, Ronald J. A., McCusker, Elizabeth, Gómez-Tortosa, Estrella, Mayo Cabrero, David, Jones, Randi, Zanko, Andrea, Nance, Martha, Abramson, Ruth K., Suchowersky, Oksana, Paulsen, Jane S., Harrison, Madaline B., Yang, Qiong, Cupples, L. Adrienne, Mysore, Jayalakshmi, Gusella, James F., MacDonald, Marcy E., and Myers, Richard H.

Published
2004
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26. Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia

Author

Dols-Icardo, Oriol, García-Redondo, Alberto, Rojas-García, Ricard, Sánchez-Valle, Raquel, Noguera, Aina, Gómez-Tortosa, Estrella, Pastor, Pau, Hernandez, Isabel, Esteban-Pérez, Jesus, Suárez-Calvet, Marc, Antón-Aguirre, Sofía, Amer, Guillermo, Ortega-Cubero, Sara, Blesa, Rafael, Fortea, Juan, Alcolea, Daniel, Capdevila, Aura, Antonell, Anna, Lladó, Albert, Muñoz-Blanco, José Luis, Mora, Jesus S., Galán-Dávila, Lucia, De Rivera, Francisco Javier Rodriguez, Lleó, Alberto, and Clarimón, Jordi

Published
2014
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29. Nonsense mutation in ADAM10 (p.tyr167*) associated with familial Alzheimer's disease: a clinical correlate of alfa-secretase haploinsufficiency

Author

Agüero, Pablo, Sainz, María José, García-Ayllón, María-Salud, Sáez-Valero, Javier, Téllez, Raquel, Guerrero-López, Rosa, Pérez-Pérez, Julián, Jiménez-Escrig, Adriano, and Gómez-Tortosa, Estrella

Abstract

Trabajo presentado al 6th Congress of the European Academy of Neurology, celebrado de forma virtual del 23 al 26 de mayo de 2020., [Background and aims]: The disintegrin metalloproteinase 10 (ADAM 10) us the main α-secretase acting in the non-amyloidogenic processing of the amyloid precursor protein. Some ADAM10 gene variants have been associated with higher susceptibility to develop late-onset disease, though a clear clinical-genetic correlate has not been reported yet. We present a family in whom development of AD was associated with a nonsense ADAM10 prodomain mutation (p.Tyr167*) causing haploinsufficiency, [Methods]: Clinical-genetic and CSF biomarker study of a family with AD., [Results]: The p.Tyr167* mutation was absent from public databases and segregated with the disease. Age at onset for 3 affected siblings ranged from 58 to 68 years, and their clinical phenotypes have been noteworthy for the slow disease evolution. CSF Ab42, total tau, and phosphorylated tau biomarkers were consistent with AD. Haploinsufficiency was demonstrated by: a) ADAM10 isoforms in CSF decreased around 50%, and b) 70% reduction of CSF sAPPα peptide, both compared to controls. Sporadic AD cases had a similar decrease in CSF ADAM10 levels to that of mutants, though their sAPPα levels resembled those of controls., [Conclusion]: This family provides the first example of a deleterious coding variant in ADAM10 associated with familial AD, and further implicates the amyloidogenic process in the development of the disease. Similarities between clinical and biomarker findings suggest that this family could represent a genetic model of sporadic late-onset AD due to an age-related down-regulation of α-secretase.

Published
2020

31. Dementia with Lewy bodies

Author

McLean, Pamela J., primary, Gómez-Tortosa, Estrella, additional, Irizarry, Michael C., additional, and Hyman, Bradley T., additional

Published
2002
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34. Dementia with Lewy Bodies

Author

Gómez-Tortosa, Estrella, Ingraham, Aubrey O., Irizarry, Michael C., and Hyman, Bradley T.

Published
1998

36. Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study

Author

Gillis Tammy, Mysore Jayalakshmi, Djoussé Luc, Xu Gang, Prakash Ranjana, Wheeler Vanessa C, Lazzarini Alice, Ashizawa Tetsuo, Jones Randi, Paulsen Jane S, Frontali Marina, Novelletto Andrea, McCusker Elizabeth, Trent Ronald JA, Klimek Mary, Suchowersky Oksana, García Carmen, Gómez-Tortosa Estrella, Frati Luigi, Squitieri Ferdinando, Rosenblatt Adam, Margolis Russell L, Ross Christopher A, Nance Martha, Morrison Patrick J, Durr Alexandra, Warby Simon C, Hayden Michael R, Li Jian-Liang, Hakky Michael, Cupples L Adrienne, Saint-Hilaire Marie H, Cha Jang-Ho J, Hersch Steven M, Penney John B, Harrison Madaline B, Perlman Susan L, Zanko Andrea, Abramson Ruth K, Lechich Anthony J, Duckett Ayana, Marder Karen, Conneally P Michael, Gusella James F, MacDonald Marcy E, and Myers Richard H

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Age at onset of Huntington's disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the HD gene; however, several studies have indicated that other genetic factors also contribute to the variability in HD age at onset. To identify modifier genes, we recently reported a whole-genome scan in a sample of 629 affected sibling pairs from 295 pedigrees, in which six genomic regions provided suggestive evidence for quantitative trait loci (QTL), modifying age at onset in HD. Methods In order to test the replication of this finding, eighteen microsatellite markers, three from each of the six genomic regions, were genotyped in 102 newly recruited sibling pairs from 69 pedigrees, and data were analyzed, using a multipoint linkage variance component method, in the follow-up sample and the combined sample of 352 pedigrees with 753 sibling pairs. Results Suggestive evidence for linkage at 6q23-24 in the follow-up sample (LOD = 1.87, p = 0.002) increased to genome-wide significance for linkage in the combined sample (LOD = 4.05, p = 0.00001), while suggestive evidence for linkage was observed at 18q22, in both the follow-up sample (LOD = 0.79, p = 0.03) and the combined sample (LOD = 1.78, p = 0.002). Epistatic analysis indicated that there is no interaction between 6q23-24 and other loci. Conclusion In this replication study, linkage for modifier of age at onset in HD was confirmed at 6q23-24. Evidence for linkage was also found at 18q22. The demonstration of statistically significant linkage to a potential modifier locus opens the path to location cloning of a gene capable of altering HD pathogenesis, which could provide a validated target for therapeutic development in the human patient.

Published
2006
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37. Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort

Author

Verheijen, Jan, primary, van der Zee, Julie, additional, Gijselinck, Ilse, additional, Van den Bossche, Tobi, additional, Dillen, Lubina, additional, Heeman, Bavo, additional, Gómez-Tortosa, Estrella, additional, Lladó, Albert, additional, Sanchez-Valle, Raquel, additional, Graff, Caroline, additional, Pastor, Pau, additional, Pastor, Maria A., additional, Benussi, Luisa, additional, Ghidoni, Roberta, additional, Binetti, Giuliano, additional, Clarimon, Jordi, additional, de Mendonça, Alexandre, additional, Gelpi, Ellen, additional, Tsolaki, Magda, additional, Diehl-Schmid, Janine, additional, Nacmias, Benedetta, additional, Almeida, Maria Rosário, additional, Borroni, Barbara, additional, Matej, Radoslav, additional, Ruiz, Agustín, additional, Engelborghs, Sebastiaan, additional, Vandenberghe, Rik, additional, De Deyn, Peter P., additional, Cruts, Marc, additional, Van Broeckhoven, Christine, additional, Sleegers, Kristel, additional, Goeman, Johan, additional, Nuytten, Dirk, additional, Vandenbulcke, Mathieu, additional, Santens, Patrick, additional, De Bleecker, Jan, additional, Sieben, Anne, additional, Dermaut, Bart, additional, Versijpt, Jan, additional, Michotte, Alex, additional, Deryck, Olivier, additional, Bergmans, Bruno, additional, Willems, Christiana, additional, Ivanoiu, Adrian, additional, Salmon, Eric, additional, Alexopoulos, Panagiotis, additional, Sorbi, Sandro, additional, Bessi, Valentina, additional, Bagnoli, Silvia, additional, Santana, Isabel, additional, Simões do Couto, Frederico, additional, Martins, Madalena, additional, Thonberg, Håkan, additional, Fratiglioni, Laura, additional, Padovani, Alessandro, additional, Rohan, Zdenek, additional, Razquin, Cristina, additional, Lorenzo, Elena, additional, Iglesias, Elena, additional, Seijo-Martínez, Manuel, additional, Rene, Ramon, additional, Gascon, Jordi, additional, Campdelacreu, Jaume, additional, Koutroumani, Maria, additional, Lleó, Alberto, additional, Fortea, Juan, additional, and Blesa, Rafael, additional

Published
2018
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38. SORL1 Variants in Familial Alzheimer’s Disease

Author

Gómez-Tortosa, Estrella, primary, Ruggiero, María, additional, Sainz, Ma José, additional, Villarejo-Galende, Alberto, additional, Prieto-Jurczynska, Cristina, additional, Venegas Pérez, Begoña, additional, Ordás, Carlos, additional, Agüero, Pablo, additional, Guerrero-López, Rosa, additional, and Pérez-Pérez, Julián, additional

Published
2018
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39. TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Author

van der Zee, Julie, Gijselinck, Ilse, Van Mossevelde, Sara, Perrone, Federica, Dillen, Lubina, Heeman, Bavo, Bäumer, Veerle, Engelborghs, Sebastiaan, De Bleecker, Jan, Baets, Jonathan, Gelpi, Ellen, Rojas García, Ricardo, Clarimon, Jordi, Lleó Bisa, Alberto, Diehl‐Schmid, Janine, Alexopoulos, Panagiotis, Perneczky, Robert, Synofzik, Matthis, Just, Jennifer, Schöls, Ludger, Graff, Caroline, Thonberg, Håkan, Borroni, Barbara, Padovani, Alessandro, Jordanova, Albena, Sarafov, Stayko, Tournev, Ivailo, de Mendonça, Alexandre, Miltenberger‐Miltényi, Gabriel, Simões do Couto, Frederico, Ramirez, Alfredo, Jessen, Frank, Heneka, Michael T., Gómez‐Tortosa, Estrella, Danek, Adrian, Cras, Patrick, Vandenberghe, Rik, De Jonghe, Peter, De Deyn, Peter P., Sleegers, Kristel, Cruts, Marc, Van Broeckhoven, Christine, Goeman, Johan, Nuytten, Dirk, Smets, Katrien, Robberecht, Wim, Damme, Philip Van, Bleecker, Jan De, Santens, Patrick, Dermaut, Bart, Versijpt, Jan, Michotte, Alex, Ivanoiu, Adrian, Deryck, Olivier, Bergmans, Bruno, Delbeck, Jean, Bruyland, Marc, Willems, Christiana, Salmon, Eric, Pastor, Pau, Ortega‐Cubero, Sara, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Hernández, Isabel, Boada Rovira, Mercè, Ruiz Laza, Agustín, Sorbi, Sandro, Nacmias, Benedetta, Bagnoli, Silvia, Sánchez Valle, Raquel, Lladó, Albert, Santana, Isabel, Rosário Almeida, Maria, Frisoni, Giovanni B, Maetzler, Walter, Matej, Radoslav, Fraidakis, Matthew J., Kovacs, Gabor G., Fabrizi, Gian Maria, Testi, Silvia, van der Zee, Julie, Gijselinck, Ilse, Van Mossevelde, Sara, Perrone, Federica, Dillen, Lubina, Heeman, Bavo, Bäumer, Veerle, Engelborghs, Sebastiaan, De Bleecker, Jan, Baets, Jonathan, Gelpi, Ellen, Rojas García, Ricardo, Clarimon, Jordi, Lleó Bisa, Alberto, Diehl‐Schmid, Janine, Alexopoulos, Panagiotis, Perneczky, Robert, Synofzik, Matthis, Just, Jennifer, Schöls, Ludger, Graff, Caroline, Thonberg, Håkan, Borroni, Barbara, Padovani, Alessandro, Jordanova, Albena, Sarafov, Stayko, Tournev, Ivailo, de Mendonça, Alexandre, Miltenberger‐Miltényi, Gabriel, Simões do Couto, Frederico, Ramirez, Alfredo, Jessen, Frank, Heneka, Michael T., Gómez‐Tortosa, Estrella, Danek, Adrian, Cras, Patrick, Vandenberghe, Rik, De Jonghe, Peter, De Deyn, Peter P., Sleegers, Kristel, Cruts, Marc, Van Broeckhoven, Christine, Goeman, Johan, Nuytten, Dirk, Smets, Katrien, Robberecht, Wim, Damme, Philip Van, Bleecker, Jan De, Santens, Patrick, Dermaut, Bart, Versijpt, Jan, Michotte, Alex, Ivanoiu, Adrian, Deryck, Olivier, Bergmans, Bruno, Delbeck, Jean, Bruyland, Marc, Willems, Christiana, Salmon, Eric, Pastor, Pau, Ortega‐Cubero, Sara, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Hernández, Isabel, Boada Rovira, Mercè, Ruiz Laza, Agustín, Sorbi, Sandro, Nacmias, Benedetta, Bagnoli, Silvia, Sánchez Valle, Raquel, Lladó, Albert, Santana, Isabel, Rosário Almeida, Maria, Frisoni, Giovanni B, Maetzler, Walter, Matej, Radoslav, Fraidakis, Matthew J., Kovacs, Gabor G., Fabrizi, Gian Maria, and Testi, Silvia

Abstract

We investigated the mutation spectrum of the TANK‐Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early‐Onset Dementia Consortium. We assessed pathogenicity of predicted protein‐truncating mutations by measuring loss of RNA expression. Functional effect of in‐frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB‐induced luciferase reporter assay and measuring phosphorylated TBK1. The protein‐truncating mutations led to the loss of transcript through nonsense‐mediated mRNA decay. For the in‐frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high‐risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD‐ALS.

Published
2017

40. TBK1Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Author

UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, van der Zee, Julie, Gijselinck, Ilse, Van Mossevelde, Sara, Perrone, Federica, Dillen, Lubina, Heeman, Bavo, Bâumer, Veerle, Engelborghs, Sebastiaan, De Bleecker, Jan, Baets, Jonathan, Gelpi, Ellen, Rojas-García, Ricardo, Clarimón, Jordi, Lleó, Alberto, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Perneczky, Robert, Synofzik, Matthis, Just, Jennifer, Schöls, Ludger, Graff, Caroline, Thonberg, Hakan, Borroni, Barbara, Padovani, Alessandro, Jordanova, Albena, Sarafov, Stayko, Tournev, Ivailo, de Mendonça, Alexandre, Miltenberger-Miltényi, Gabriel, Simões do Couto, Frederico, Ramirez, Alfredo, Jessen, Frank, Heneka, Michael T., Gómez-Tortosa, Estrella, Danek, Adrian, Cras, Patrick, Vandenberghe, Rik, De Jonghe, Peter, De Deyn, Peter P., Sleegers, Kristel, Cruts, Marc, Van Broeckhoven, Christine, Goeman, Johan, Nuytten, Dirk, Smets, Katrien, Robberecht, Wim, Damme, Philip Van, Bleecker, Jan De, Santens, Patrick, Dermaut, Bart, Versijpt, Jan, Michotte, Alex, Ivanoiu, Adrian, Deryck, Olivier, Bergmans, Bruno, Delbeck, Jean, Bruyland, Marc, Willems, Christiana, Salmon, Eric, Pastor, Pau, Ortega-Cubero, Sara, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Hernàndez, Isabel, Boada, Mercè, Ruiz, Agustín, Sorbi, Sandro, Nacmias, Benedetta, Bagnoli, Silvia, Sanchez-Valle, Raquel, Llado, Albert, Santana, Isabel, Rosàrio Almeida, Maria, Frisoni, Giovanni B, Maetzler, Walter, Matej, Radoslav, Fraidakis, Matthew J., Kovacs, Gabor G., Fabrizi, Gian Maria, Testi, Silvia, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, van der Zee, Julie, Gijselinck, Ilse, Van Mossevelde, Sara, Perrone, Federica, Dillen, Lubina, Heeman, Bavo, Bâumer, Veerle, Engelborghs, Sebastiaan, De Bleecker, Jan, Baets, Jonathan, Gelpi, Ellen, Rojas-García, Ricardo, Clarimón, Jordi, Lleó, Alberto, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Perneczky, Robert, Synofzik, Matthis, Just, Jennifer, Schöls, Ludger, Graff, Caroline, Thonberg, Hakan, Borroni, Barbara, Padovani, Alessandro, Jordanova, Albena, Sarafov, Stayko, Tournev, Ivailo, de Mendonça, Alexandre, Miltenberger-Miltényi, Gabriel, Simões do Couto, Frederico, Ramirez, Alfredo, Jessen, Frank, Heneka, Michael T., Gómez-Tortosa, Estrella, Danek, Adrian, Cras, Patrick, Vandenberghe, Rik, De Jonghe, Peter, De Deyn, Peter P., Sleegers, Kristel, Cruts, Marc, Van Broeckhoven, Christine, Goeman, Johan, Nuytten, Dirk, Smets, Katrien, Robberecht, Wim, Damme, Philip Van, Bleecker, Jan De, Santens, Patrick, Dermaut, Bart, Versijpt, Jan, Michotte, Alex, Ivanoiu, Adrian, Deryck, Olivier, Bergmans, Bruno, Delbeck, Jean, Bruyland, Marc, Willems, Christiana, Salmon, Eric, Pastor, Pau, Ortega-Cubero, Sara, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Hernàndez, Isabel, Boada, Mercè, Ruiz, Agustín, Sorbi, Sandro, Nacmias, Benedetta, Bagnoli, Silvia, Sanchez-Valle, Raquel, Llado, Albert, Santana, Isabel, Rosàrio Almeida, Maria, Frisoni, Giovanni B, Maetzler, Walter, Matej, Radoslav, Fraidakis, Matthew J., Kovacs, Gabor G., Fabrizi, Gian Maria, and Testi, Silvia

Abstract

We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS.

Published
2017

41. Prevalence of cerebral amyloid pathology in persons without dementia

Author

Jansen, Willemijn J., Ossenkoppele, Rik, Knol, Dirk L., Tijms, Betty M., Scheltens, Philip, Verhey, Frans R. J., Visser, Pieter Jelle, Aalten, Pauline, Aarsland, Dag, Alcolea, Daniel, Alexander, Myriam, Roe, Catherine M., Rot, Uros, Rowe, Christopher C., Rüther, Eckart, Sabri, Osama, Sanchez-Juan, Páscual, Santana, Isabel, Sarazin, Marie, Schröder, Johannes, Schütte, Christin, Almdahl, Ina S., Seo, Sang W., Soetewey, Femke, Soininen, Hilkka, Spiru, Luiza, Struyfs, Hanne, Teunissen, Charlotte E., Tsolaki, Magda, Vandenberghe, Rik, Verbeek, Marcel M., Villemagne, Victor L., Arnold, Steven E., Vos, Stephanie J. B., van Waalwijk van Doorn, Linda J. C., Waldemar, Gunhild, Wallin, Anders, Wallin, Åsa K., Wiltfang, Jens, Wolk, David A., Zboch, Marzena, Zetterberg, Henrik, Baldeiras, Inês, Barthel, Henryk, van Berckel, Bart N. M., Bibeau, Kristen, Blennow, Kaj, Brooks, David J., van Buchem, Mark A., Camus, Vincent, Cavedo, Enrica, Chen, Kewei, Chetelat, Gael, Cohen, Ann D., Drzezga, Alexander, Engelborghs, Sebastiaan, Fagan, Anne M., Fladby, Tormod, Fleisher, Adam S., van der Flier, Wiesje M., Ford, Lisa, Förster, Stefan, Fortea, Juan, Foskett, Nadia, Frederiksen, Kristian S., Freund-Levi, Yvonne, Frisoni, Giovanni B., Froelich, Lutz, Gabryelewicz, Tomasz, Gill, Kiran Dip, Gkatzima, Olymbia, Gómez-Tortosa, Estrella, Gordon, Mark Forrest, Grimmer, Timo, Hampel, Harald, Hausner, Lucrezia, Hellwig, Sabine, Herukka, Sanna-Kaisa, Hildebrandt, Helmut, Ishihara, Lianna, Ivanoiu, Adrian, Jagust, William J., Johannsen, Peter, Kandimalla, Ramesh, Kapaki, Elisabeth, Klimkowicz-Mrowiec, Aleksandra, Klunk, William E., Köhler, Sebastian, Koglin, Norman, Kornhuber, Johannes, Kramberger, Milica G., Van Laere, Koen, Landau, Susan M., Lee, Dong Young, de Leon, Mony, Lisetti, Viviana, Lleó, Alberto, Madsen, Karine, Maier, Wolfgang, Marcusson, Jan, Mattsson, Niklas, De Mendonça, Alexandre, Meulenbroek, Olga, Meyer, Philipp T., Mintun, Mark A., Mok, Vincent, Molinuevo, José Luis, Møllergård, Hanne M., Morris, John C., Mroczko, Barbara, Van der Mussele, Stefan, Na, Duk L., Newberg, Andrew, Nordberg, Agneta, Nordlund, Arto, Novak, Gerald P., Paraskevas, George P., Parnetti, Lucilla, Perera, Gayan, Peters, Oliver, Popp, Julius, Prabhakar, Sudesh, Rabinovici, Gil D., Ramakers, Inez H. G. B., Rami, Lorena, Resende de Oliveira, Catarina, Rinne, Juha O., Rodrigue, Karen M., Rodríguez-Rodríguez, Eloy, and Repositório da Universidade de Lisboa

Abstract

Copyright © 2015 American Medical Association. All rights reserved., Importance: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. Objective: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). Data sources: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. Study selection: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. Data extraction and synthesis: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. Main outcomes and measures: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. Results: The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. Conclusions and relevance: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia., The research leading to these results has received support from 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. BIOMARKAPD is an EU Joint Programme–Neurodegenerative Disease Research (JPND) project. The project is supported through national funding organizations under the aegis of JPND (http://www.jpnd.eu). In the Netherlands, this is ZonMw. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission as part of the 6th framework programme (contract No. 37670). This research was performed within the framework of the Center for Translational Molecular Medicine (CTTM) (http://www.ctmm.nl), project LeARN (grant 02N-101). The AIBL study was funded in part by the study partners (Australian Commonwealth Scientific Industrial and Research Organization [CSIRO], Edith Cowan University [ECU], Mental Health Research Institute [MHRI], Alzheimer’s Australia [AA], National Ageing Research Institute [NARI], Austin Health, CogState, Hollywood Private Hospital, Sir Charles Gardner Hospital). The study also received support from the National Health and Medical Research Council (NHMRC) and the Dementia Collaborative Research Centres program (DCRC2), as well as ongoing funding from the Science and Industry Endowment Fund (SIEF). Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health grant U01 AG024904) and the US Department of Defense ADNI (W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; BioClinica; Biogen Idec; Bristol-Myers Squibb Company; Eisai; Elan Pharmaceuticals; Eli Lilly; F. Hoffmann-La Roche and its affiliated company Genentech; GE Healthcare; Innogenetics; IXICO; Janssen Alzheimer Immunotherapy Research & Development; Johnson & Johnson Pharmaceutical Research & Development; Medpace; Merck; Meso Scale Diagnostics; NeuroRx Research; Novartis Pharmaceuticals; Pfizer; Piramal Imaging; Servier; Synarc; and Takeda Pharmaceutical. 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 (http://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 Southern California. The Dementia Competence Network (DCN) has been supported by a grant from the German Federal Ministry of Education and Research (BMBF): Kompetenznetz Demenzen (01GI0420). Additional funding related to the randomized clinical trials came from Janssen-Cilag and Merz Pharmaceuticals. The latter funds were exclusively used for personnel, pharmaceuticals, blistering and shipment of medication, and monitoring and as capitation fees for recruiting centers. Funding source for the Chandigarh study is the Indian Council of Medical Research (ICMR), India. Funding for the St Louis contribution was provided by the National Institute on Aging (P50 AG005681, P01 AG003991, and P01 AG026276); Fred Simmons and Olga Mohan, and the Charles and Joanne Knight Alzheimer’s Research Initiative of the Washington University Knight Alzheimer’s Disease Research Center. The Tours study received financial support of the French Ministry of Health grant PHRC-N 2008 1004 and the EC-FP6-project DiMI, LSHB-CT-2005-512146. The Caen study was funded by Agence Nationale de la Recherche, Programme Hospitalier de Recherche Clinique, Région Basse Normandie, and Institut National de la Santé et de la Recherche Médicale (Inserm). The research leading to the Munich contribution to the Mattsson multicenter study has received funding from the program “Investissements d’avenir” (ANR-10-IAIHU-06). The study from Pittsburgh was supported by National Institutes of Health grants (P50 AG005133, R37 AG025516, P01 AG025204). The New York contributions to the Mattsson multicenter study were in part supported by P30 AG008051, R01 AG13616, R01 AG022374, and R01 AG12101. Data from Brescia in this article were collected by Translational Outpatient Memory Clinic (TOMC) working group at IRCCS Fatebenefratelli in Brescia, Italy. Contributors to the TOMC are G. Amicucci, S. Archetti, L. Benussi, G. Binetti, L. Bocchio-Chiavetto, C. Bonvicini, E. Canu, F. Caobelli, E. Cavedo, E. Chittò, M. Cotelli, M. Gennarelli, S. Galluzzi, C. Geroldi, R. Ghidoni, R. Giubbini, U. P. Guerra, G. Kuffenschin, G. Lussignoli, D. Moretti, B. Paghera, M. Parapini, C. Porteri, M. Romano, S. Rosini, I. Villa, R. Zanardini, and O. Zanetti. The JPND Project is supported in Italy by the Italian Ministry of Health. The assembling of the TU Munich data set was supported in part by the German research foundation (Deutsche Forschungsgemeinschaft) (HE 4560/1-2, DR 445/3-1 and DR 445/4-1 to A.D.), and by a KKF grant for clinical research of the Technische Universität München (to A.D. and T.G.). The Florbetaben phase 2 study from which data were derived for this multicenter evaluation was sponsored by Bayer Healthcare/Piramal Imaging (Berlin, Germany). This work was supported by the University of Antwerp Research Fund; the Alzheimer Research Foundation (SAO-FRA); the Research Foundation Flanders (FWO); the Agency for Innovation by Science and Technology (IWT); the Belgian Science Policy Office Interuniversity Attraction Poles (IAP) program; and the Flemish Government–initiated Methusalem excellence grant.

Published
2015

42. TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Author

van der Zee, Julie, primary, Gijselinck, Ilse, additional, Van Mossevelde, Sara, additional, Perrone, Federica, additional, Dillen, Lubina, additional, Heeman, Bavo, additional, Bäumer, Veerle, additional, Engelborghs, Sebastiaan, additional, De Bleecker, Jan, additional, Baets, Jonathan, additional, Gelpi, Ellen, additional, Rojas-García, Ricardo, additional, Clarimón, Jordi, additional, Lleó, Alberto, additional, Diehl-Schmid, Janine, additional, Alexopoulos, Panagiotis, additional, Perneczky, Robert, additional, Synofzik, Matthis, additional, Just, Jennifer, additional, Schöls, Ludger, additional, Graff, Caroline, additional, Thonberg, Håkan, additional, Borroni, Barbara, additional, Padovani, Alessandro, additional, Jordanova, Albena, additional, Sarafov, Stayko, additional, Tournev, Ivailo, additional, de Mendonça, Alexandre, additional, Miltenberger-Miltényi, Gabriel, additional, Simões do Couto, Frederico, additional, Ramirez, Alfredo, additional, Jessen, Frank, additional, Heneka, Michael T., additional, Gómez-Tortosa, Estrella, additional, Danek, Adrian, additional, Cras, Patrick, additional, Vandenberghe, Rik, additional, De Jonghe, Peter, additional, De Deyn, Peter P., additional, Sleegers, Kristel, additional, Cruts, Marc, additional, Van Broeckhoven, Christine, additional, Goeman, Johan, additional, Nuytten, Dirk, additional, Smets, Katrien, additional, Robberecht, Wim, additional, Damme, Philip Van, additional, Bleecker, Jan De, additional, Santens, Patrick, additional, Dermaut, Bart, additional, Versijpt, Jan, additional, Michotte, Alex, additional, Ivanoiu, Adrian, additional, Deryck, Olivier, additional, Bergmans, Bruno, additional, Delbeck, Jean, additional, Bruyland, Marc, additional, Willems, Christiana, additional, Salmon, Eric, additional, Pastor, Pau, additional, Ortega-Cubero, Sara, additional, Benussi, Luisa, additional, Ghidoni, Roberta, additional, Binetti, Giuliano, additional, Hernández, Isabel, additional, Boada, Mercè, additional, Ruiz, Agustín, additional, Sorbi, Sandro, additional, Nacmias, Benedetta, additional, Bagnoli, Silvia, additional, Sanchez-Valle, Raquel, additional, Llado, Albert, additional, Santana, Isabel, additional, Rosário Almeida, Maria, additional, Frisoni, Giovanni B, additional, Maetzler, Walter, additional, Matej, Radoslav, additional, Fraidakis, Matthew J., additional, Kovacs, Gabor G., additional, Fabrizi, Gian Maria, additional, and Testi, Silvia, additional

Published
2017
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43. Novel Mutation (Gly212Val) in the PS2 Gene Associated with Early-Onset Familial Alzheimer’s Disease

Author

Marín-Muñoz, Juan, primary, Noguera-Perea, Ma Fuensanta, additional, Gómez-Tortosa, Estrella, additional, López-Motos, David, additional, Antequera-Torres, Martirio, additional, Martínez-Herrada, Begoña, additional, Manzanares-Sánchez, Salvadora, additional, Vivancos-Moreau, Laura, additional, Legaz-García, Agustina, additional, Rábano-Gutiérrez del Arroyo, Alberto, additional, and Antúnez-Almagro, Carmen, additional

Published
2016
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44. Diversity of Cognitive Phenotypes Associated with C9ORF72 Hexanucleotide Expansion

Author

Gómez-Tortosa, Estrella, primary, Prieto-Jurczynska, Cristina, additional, Serrano, Soledad, additional, Franco-Macías, Emilio, additional, Olivié, Laura, additional, Gallego, Jesús, additional, Guerrero-López, Rosa, additional, Trujillo-Tiebas, María José, additional, Ayuso, Carmen, additional, García Ruiz, Pedro, additional, Pérez-Pérez, Julián, additional, and Sainz, María José, additional

Published
2016
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45. TAA repeat variation in the GRIK2 gene does not influence age at onset in Huntington’s disease

Author

Lee, Ji-Hyun, Lee, Jong-Min, Ramos, Eliana Marisa, Gillis, Tammy, Mysore, Jayalakshmi S., Kishikawa, Shotaro, Hadzi, Tiffany, Hendricks, Audrey E., Hayden, Michael R., Morrison, Patrick J., Nance, Martha, Ross, Christopher A., Margolis, Russell L., Squitieri, Ferdinando, Gellera, Cinzia, Gomez-Tortosa, Estrella, Ayuso, Carmen, Suchowersky, Oksana, Trent, Ronald J., McCusker, Elizabeth, Novelletto, Andrea, Frontali, Marina, Jones, Randi, Ashizawa, Tetsuo, Frank, Samuel, Saint-Hilaire, Marie-Helene, Hersch, Steven M., Rosas, Herminia D., Lucente, Diane, Harrison, Madaline B., Zanko, Andrea, Abramson, Ruth K., Marder, Karen, Sequeiros, Jorge, Bernhard Landwehrmeyer, G., Shoulson, Ira, Myers, Richard H., MacDonald, Marcy E., and Gusella, James F.

Published
2012
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46. Prevalence of cerebral amyloid pathology in persons without dementia:a meta-analysis

Author

Jansen, Willemijn J, Ossenkoppele, Rik, Knol, Dirk L, Tijms, Betty M, Scheltens, Philip, Verhey, Frans R J, Visser, Pieter Jelle, Aalten, Pauline, Aarsland, Dag, Alcolea, Daniel, Alexander, Myriam, Almdahl, Ina S, Arnold, Steven E, Baldeiras, Inês, Barthel, Henryk, van Berckel, Bart N M, Bibeau, Kristen, Blennow, Kaj, Brooks, David J, van Buchem, Mark A, Camus, Vincent, Cavedo, Enrica, Chen, Kewei, Chetelat, Gael, Cohen, Ann D, Drzezga, Alexander, Engelborghs, Sebastiaan, Fagan, Anne M, Fladby, Tormod, Fleisher, Adam S, van der Flier, Wiesje M, Ford, Lisa, Förster, Stefan, Fortea, Juan, Foskett, Nadia, Frederiksen, Kristian S, Freund-Levi, Yvonne, Frisoni, Giovanni B, Froelich, Lutz, Gabryelewicz, Tomasz, Gill, Kiran Dip, Gkatzima, Olymbia, Gómez-Tortosa, Estrella, Gordon, Mark Forrest, Grimmer, Timo, Hampel, Harald, Hausner, Lucrezia, Hellwig, Sabine, Johannsen, Peter, Waldemar, Gunhild, Jansen, Willemijn J, Ossenkoppele, Rik, Knol, Dirk L, Tijms, Betty M, Scheltens, Philip, Verhey, Frans R J, Visser, Pieter Jelle, Aalten, Pauline, Aarsland, Dag, Alcolea, Daniel, Alexander, Myriam, Almdahl, Ina S, Arnold, Steven E, Baldeiras, Inês, Barthel, Henryk, van Berckel, Bart N M, Bibeau, Kristen, Blennow, Kaj, Brooks, David J, van Buchem, Mark A, Camus, Vincent, Cavedo, Enrica, Chen, Kewei, Chetelat, Gael, Cohen, Ann D, Drzezga, Alexander, Engelborghs, Sebastiaan, Fagan, Anne M, Fladby, Tormod, Fleisher, Adam S, van der Flier, Wiesje M, Ford, Lisa, Förster, Stefan, Fortea, Juan, Foskett, Nadia, Frederiksen, Kristian S, Freund-Levi, Yvonne, Frisoni, Giovanni B, Froelich, Lutz, Gabryelewicz, Tomasz, Gill, Kiran Dip, Gkatzima, Olymbia, Gómez-Tortosa, Estrella, Gordon, Mark Forrest, Grimmer, Timo, Hampel, Harald, Hausner, Lucrezia, Hellwig, Sabine, Johannsen, Peter, and Waldemar, Gunhild

Published
2015

47. Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer's disease.

Author

Roeck, Arne, Bossche, Tobi, Zee, Julie, Verheijen, Jan, Coster, Wouter, Dongen, Jasper, Dillen, Lubina, Baradaran-Heravi, Yalda, Heeman, Bavo, Sanchez-Valle, Raquel, Lladó, Albert, Nacmias, Benedetta, Sorbi, Sandro, Gelpi, Ellen, Grau-Rivera, Oriol, Gómez-Tortosa, Estrella, Pastor, Pau, Ortega-Cubero, Sara, Pastor, Maria, and Graff, Caroline

Subjects
GENETICS of Alzheimer's disease, STOP codons, GENETIC mutation
Abstract

Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene ( ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment ( p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD. [ABSTRACT FROM AUTHOR]

Published
2017
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48. Reelin expression and glycosylation patterns are altered in Alzheimer's disease

Author

Fundación la Caixa, Pfizer, Fundació La Marató de TV3, Ministerio de Ciencia y Tecnología (España), Botella-López, Arancha, Burgaya, Ferran, Gavín, Rosalina, García-Ayllón, María-Salud, Gómez-Tortosa, Estrella, Peña-Casanova, Jordi, Ureña, Jesús Mariano, Río, José Antonio del, Blesa, Rafael, Soriano, Eduardo, Sáez-Valero, Javier, Fundación la Caixa, Pfizer, Fundació La Marató de TV3, Ministerio de Ciencia y Tecnología (España), Botella-López, Arancha, Burgaya, Ferran, Gavín, Rosalina, García-Ayllón, María-Salud, Gómez-Tortosa, Estrella, Peña-Casanova, Jordi, Ureña, Jesús Mariano, Río, José Antonio del, Blesa, Rafael, Soriano, Eduardo, and Sáez-Valero, Javier

Abstract

Reelin is a glycoprotein that is essential for the correct cytoarchitectonic organization of the developing CNS. Its function in the adult brain is less understood, although it has been proposed that Reelin is involved in signaling pathways linked to neurodegeneration. Here we analyzed Reelin expression in brains and cerebrospinal fluid (CSF) from Alzheimer’s disease (AD) patients and nondemented controls. We found a 40% increase in the Reelin protein levels in the cortex of AD patients compared with controls. Similar increases were detected at the Reelin mRNA transcriptional level. This expression correlates with parallel increases in CSF but not in plasma samples. Next, we examined whether CSF Reelin levels were also altered in neurological diseases, including frontotemporal dementia, progressive supranuclear palsy, and Parkinson’s disease. The Reelin 180-kDa band increased in all of the neurodegenerative disorders analyzed. Moreover, the 180-kDa Reelin levels correlated positively with Tau protein in CSF. Finally, we studied the pattern of Reelin glycosylation by using several lectins and the anti-HNK-1 antibody. Glycosylation differed in plasma and CSF. Furthermore, the pattern of Reelin lectin binding differed between the CSF of controls and in AD. Our results show that Reelin is up-regulated in the brain and CSF in several neurodegenerative diseases and that CSF and plasma Reelin have distinct cellular origins, thereby supporting that Reelin is involved in the pathogenesis of a number of neurodegenerative diseases.

Published
2006

50. A genome scan for modifiers of age at onset in Huntington disease : The HD MAPS study.

Author

Li, Jian-Liang, Hayden, Michael R, Almqvist, Elisabeth W, Brinkman, Ryan R, Durr, Alexandra, Dodé, Catherine, Morrison, Patrick J, Suchowersky, Oksana, Ross, Christopher A, Margolis, Russell L, Rosenblatt, Adam, Gómez-Tortosa, Estrella, Cabrero, David Mayo, Novelletto, Andrea, Frontali, Marina, Nance, Martha, Trent, Ronald J A, McCusker, Elizabeth, Jones, Randi, Paulsen, Jane S, Harrison, Madeline, Zanko, Andrea, Abramson, Ruth K, Russ, Ana L, Knowlton, Beth, Djoussé, Luc, Mysore, Jayalakshmi S, Tariot, Suzanne, Gusella, Michael F, Wheeler, Vanessa C, Atwood, Larry D, Cupples, L Adrienne, Saint-Hilaire, Marie, Cha, Jang-Ho J, Hersch, Steven M, Koroshetz, Walter J, Gusella, James F, MacDonald, Marcy E, Myers, Richard H, Li, Jian-Liang, Hayden, Michael R, Almqvist, Elisabeth W, Brinkman, Ryan R, Durr, Alexandra, Dodé, Catherine, Morrison, Patrick J, Suchowersky, Oksana, Ross, Christopher A, Margolis, Russell L, Rosenblatt, Adam, Gómez-Tortosa, Estrella, Cabrero, David Mayo, Novelletto, Andrea, Frontali, Marina, Nance, Martha, Trent, Ronald J A, McCusker, Elizabeth, Jones, Randi, Paulsen, Jane S, Harrison, Madeline, Zanko, Andrea, Abramson, Ruth K, Russ, Ana L, Knowlton, Beth, Djoussé, Luc, Mysore, Jayalakshmi S, Tariot, Suzanne, Gusella, Michael F, Wheeler, Vanessa C, Atwood, Larry D, Cupples, L Adrienne, Saint-Hilaire, Marie, Cha, Jang-Ho J, Hersch, Steven M, Koroshetz, Walter J, Gusella, James F, MacDonald, Marcy E, and Myers, Richard H

Abstract

Huntington disease (HD) is caused by the expansion of a CAG repeat within the coding region of a novel gene on 4p16.3. Although the variation in age at onset is partly explained by the size of the expanded repeat, the unexplained variation in age at onset is strongly heritable (h2=0.56), which suggests that other genes modify the age at onset of HD. To identify these modifier loci, we performed a 10-cM density genomewide scan in 629 affected sibling pairs (295 pedigrees and 695 individuals), using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were HD affected, estimates of allele sharing identical by descent at and around the HD locus were adjusted by a positionally weighted method to correct for the increased allele sharing at 4p. Suggestive evidence for linkage was found at 4p16 (LOD=1.93), 6p21-23 (LOD=2.29), and 6q24-26 (LOD=2.28), which may be useful for investigation of genes that modify age at onset of HD.

Published
2003
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