C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts
Por:
Costa B., Manzoni C., Bernal-Quiros M., Kia D.A., Aguilar M., Alvarez I., Alvarez V., Andreassen O.A., Anfossi M., Bagnoli S., Benussi L., Bernardi L., Binetti G., Blackburn D.J., Boada M., Borroni B., Bowns L., Bråthen G., Bruni A.C., Chiang H.-H., Clarimon J., Colville S., Conidi M.E., Cope T.E., Cruchaga C., Cupidi C., Di Battista M.E., Diehl-Schmid J., Diez-Fairen M., Dols-Icardo O., Durante E., Flisar D., Frangipane F., Galimberti D., Gallo M., Gallucci M., Ghidoni R., Graff C., Grafman J.H., Grossman M., Hardy J., Hernández I., Holloway G.J.T., Huey E.D., Illán-Gala I., Karydas A., Khoshnood B., Kramberger M.G., Kristiansen M., Lewis P.A., Lleó A., Madhan G.K., Maletta R., Maver A., Menendez-Gonzalez M., Milan G., Miller B.L., Mol M.O., Momeni P., Moreno-Grau S., Morris C.M., Nacmias B., Nilsson C., Novelli V., Öijerstedt L., Padovani A., Pal S., Panchbhaya Y., Pastor P., Peterlin B., Piaceri I., Pickering-Brown S., Pijnenburg Y.A.L., Puca A.A., Rainero I., Rendina A., Richardson A.M.T., Rogaeva E., Rogelj B., Rollinson S., Rossi G., Roßmeier C., Rowe J.B., Rubino E., Ruiz A., Sanchez-Valle R., Sando S.B., Santillo A.F., Saxon J., Scarpini E., Serpente M., Smirne N., Sorbi S., Suh E., Tagliavini F., Thompson J.C., Trojanowski J.Q., van Deerlin V.M., van der Zee J., van Broeckhoven C., van Rooij J.G.J., van Swieten J.C., Veronesi A., Vitale E., Waldö M.L., Woodward C., Yokoyama J.S., Escott-Price V., Polke J.M., Ferrari R.
Publicada:
1 ene 2020
Resumen:
Objective We sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases. Methods We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions. Results We found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10-5; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10-2; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy. Conclusions Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes. © 2020 Lippincott Williams and Wilkins. All rights reserved.
Filiaciones:
Costa B.:
University College London, Institute of Neurology, United Kingdom
Manzoni C.:
School of Pharmacy, University College London, United Kingdom
Bernal-Quiros M.:
Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, London, United Kingdom
Kia D.A.:
University College London, Institute of Neurology, United Kingdom
Aguilar M.:
Aptima Clinic, Terrassa, Barcelona, Spain
Alvarez I.:
Memory Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Barcelona, Spain
Alvarez V.:
Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain
Andreassen O.A.:
NORMENT, Institute of Clinical Medicine, University of Oslo, Norway
Anfossi M.:
Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy
Bagnoli S.:
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Italy
Benussi L.:
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Bernardi L.:
Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy
Binetti G.:
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Blackburn D.J.:
Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience, University of Sheffield, United Kingdom
Boada M.:
Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya (UIC), Barcelona, Spain
Borroni B.:
Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Italy
Bowns L.:
Department of Clinical Neurosciences, Cambridge University, United Kingdom
Bråthen G.:
Department of Neurology, University Hospital of Trondheim, Norway
Bruni A.C.:
Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy
Chiang H.-H.:
Karolinska Institutet, Dept NVS, Division of Neurogeriatrics, Bioclinicum, Solna, Sweden
Clarimon J.:
Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Colville S.:
Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, United Kingdom
Conidi M.E.:
Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy
Cope T.E.:
Department of Clinical Neurosciences, Cambridge University, United Kingdom
Cruchaga C.:
NeuroGenomics and Informatics, Washington University, Department of Psychiatry, St. Louis, MO, United States
Cupidi C.:
Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy
Di Battista M.E.:
Cognitive Impairment Center, Local Health Authority n.2 Marca Trevigiana, Treviso, Italy
Diehl-Schmid J.:
Technical University of Munich, School of Medicine, Department of Psychiatry and Psychotherapy, Germany
Diez-Fairen M.:
Memory Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Barcelona, Spain
Dols-Icardo O.:
Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Durante E.:
Immunohematology and Transfusional Medicine Service, Local Health Authority n.2 Marca Trevigiana, Treviso, Italy
Flisar D.:
Department of Neurology, University Medical Center, Ljubljana, Slovenia
Frangipane F.:
Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy
Galimberti D.:
University of Milan, Dino Ferrari Center, Italy
Gallo M.:
Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy
Gallucci M.:
Cognitive Neuroscience Lab, Think and Speak Lab, Shirley Ryan AbilityLab, Chicago, IL, United States
Ghidoni R.:
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Graff C.:
Karolinska Institutet, Dept NVS, Division of Neurogeriatrics, Bioclinicum, Solna, Sweden
Grafman J.H.:
Cognitive Neuroscience Lab, Think and Speak Lab, Shirley Ryan AbilityLab, Chicago, IL, United States
Grossman M.:
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Hardy J.:
UCL, Dementia Research Institute, Wing 1.2 Cruciform Building, London, United Kingdom
Hernández I.:
Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya (UIC), Barcelona, Spain
Holloway G.J.T.:
Royal Edinburgh Hospital, Edinburgh, United Kingdom
Huey E.D.:
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, United States
Illán-Gala I.:
Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Karydas A.:
Department of Neurology, Memory and Aging Center, University of California, San Francisco, United States
Khoshnood B.:
Karolinska Institutet, Dept NVS, Division of Neurogeriatrics, Bioclinicum, Solna, Sweden
Kramberger M.G.:
Department of Neurology, University Medical Center, Ljubljana, Slovenia
Kristiansen M.:
UCL Genomics, UCL, Great Ormond Street Institute of Child Health, London, United Kingdom
Lewis P.A.:
Royal Veterinary College, Department of Comparative Biomedical Sciences, London, United Kingdom
Lleó A.:
Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Madhan G.K.:
UCL Genomics, UCL, Great Ormond Street Institute of Child Health, London, United Kingdom
Maletta R.:
Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy
Maver A.:
Clinical Institute of Medical Genetics, University Medical Center, Ljubljana, Slovenia
Menendez-Gonzalez M.:
Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain
Milan G.:
Geriatric Center Frullone, ASL Napoli 1 Centro, Napoli, Italy
Miller B.L.:
Department of Neurology, Memory and Aging Center, University of California, San Francisco, United States
Mol M.O.:
Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands
Momeni P.:
Rona Holdings, Silicon Valley, CA, United States
Moreno-Grau S.:
Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya (UIC), Barcelona, Spain
Morris C.M.:
Newcastle Brain Tissue Resource, Institute of Neuroscience, Newcastle University, Edwardson Building, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom
Nacmias B.:
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Italy
Nilsson C.:
Department of Neurology, Skåne University Hospital, Malmö, Sweden
Novelli V.:
Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Öijerstedt L.:
Karolinska Institutet, Dept NVS, Division of Neurogeriatrics, Bioclinicum, Solna, Sweden
Padovani A.:
Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Italy
Pal S.:
Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, United Kingdom
Panchbhaya Y.:
UCL Genomics, UCL, Great Ormond Street Institute of Child Health, London, United Kingdom
Pastor P.:
Memory Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Barcelona, Spain
Peterlin B.:
Clinical Institute of Medical Genetics, University Medical Center, Ljubljana, Slovenia
Piaceri I.:
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Italy
Pickering-Brown S.:
Division of Neuroscience and Experimental Psychology, University of Manchester, United Kingdom
Pijnenburg Y.A.L.:
Amsterdam University Medical Center, VU University Medical Center, Netherlands
Puca A.A.:
Cardiovascular Research Unit, IRCCS Multimedica, Milan, Italy
Rainero I.:
Neurology I, Department of Neuroscience, University of Torino, Italy
Rendina A.:
NeurOMICS Laboratory, Institute of Biochemistry and Cell Biology (IBBC), CNR Napoli, Italy
Richardson A.M.T.:
Manchester Centre for Clinical Neurosciences, Salford Royal NHS Trust, Manchester, United Kingdom
Rogaeva E.:
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Canada
Rogelj B.:
Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia
Rollinson S.:
Division of Neuroscience and Experimental Psychology, University of Manchester, United Kingdom
Rossi G.:
Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Roßmeier C.:
Technical University of Munich, School of Medicine, Department of Psychiatry and Psychotherapy, Germany
Rowe J.B.:
Department of Clinical Neurosciences, Cambridge University, United Kingdom
Rubino E.:
Neurology I, Department of Neuroscience, University of Torino, Italy
Ruiz A.:
Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya (UIC), Barcelona, Spain
Sanchez-Valle R.:
Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic of Barcelona, Spain
Sando S.B.:
Department of Neurology, University Hospital of Trondheim, Norway
Santillo A.F.:
Clinical Memory Research Unit, Lund University, Sweden
Saxon J.:
Manchester Centre for Clinical Neurosciences, Salford Royal NHS Trust, United Kingdom
Scarpini E.:
University of Milan, Dino Ferrari Center, Italy
Serpente M.:
University of Milan, Dino Ferrari Center, Italy
Smirne N.:
Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy
Sorbi S.:
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Italy
Suh E.:
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Tagliavini F.:
Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Thompson J.C.:
Manchester Centre for Clinical Neurosciences, Salford Royal NHS Trust, Manchester, United Kingdom
Trojanowski J.Q.:
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
van Deerlin V.M.:
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
van der Zee J.:
Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium
van Broeckhoven C.:
Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium
van Rooij J.G.J.:
Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands
van Swieten J.C.:
Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands
Veronesi A.:
Cognitive Impairment Center, Local Health Authority n.2 Marca Trevigiana, Treviso, Italy
Vitale E.:
NeurOMICS Laboratory, Institute of Biochemistry and Cell Biology (IBBC), CNR Napoli, Italy
Waldö M.L.:
Division of Clinical Sciences Helsingborg, Department of Clinical Sciences Lund, Lund University, Sweden
Woodward C.:
Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, London, United Kingdom
Yokoyama J.S.:
Department of Neurology, Memory and Aging Center, University of California, San Francisco, United States
Escott-Price V.:
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, United Kingdom
Dementia Research Institute, Cardiff University, United Kingdom
Polke J.M.:
Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, London, United Kingdom
Ferrari R.:
University College London, Institute of Neurology, United Kingdom
Department of Neurodegenerative Disease, University College London, Institute of Neurology, United Kingdom
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