Kirsi M Kinnunen1, David M Cash2, Teresa Poole3, Chris Frost3, Tammie L S Benzinger4, R Laila Ahsan1, Kelvin K Leung1, M Jorge Cardoso5, Marc Modat5, Ian B Malone1, John C Morris6, Randall J Bateman6, Daniel S Marcus4, Alison Goate7, Stephen P Salloway8, Stephen Correia8, Reisa A Sperling9, Jasmeer P Chhatwal9, Richard P Mayeux10, Adam M Brickman10, Ralph N Martins11, Martin R Farlow12, Bernardino Ghetti13, Andrew J Saykin14, Clifford R Jack15, Peter R Schofield16, Eric McDade6, Michael W Weiner17, John M Ringman18, Paul M Thompson19, Colin L Masters20, Christopher C Rowe21, Martin N Rossor1, Sebastien Ourselin5, Nick C Fox1. 1. Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK. 2. Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK; Department of Medical Physics and Bioengineering, Translational Imaging Group, Centre for Medical Image Computing, University College London, London, UK. Electronic address: d.cash@ucl.ac.uk. 3. Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK; Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK. 4. Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA. 5. Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK; Department of Medical Physics and Bioengineering, Translational Imaging Group, Centre for Medical Image Computing, University College London, London, UK. 6. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. 7. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 8. Department of Neurology, Butler Hospital, Warren Alpert Medical School, Brown University, Providence, RI, USA. 9. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. 10. Department of Neurology, Columbia University Medical Center, New York, NY, USA. 11. Centre of Excellence for Alzheimer's Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia. 12. Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA. 13. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. 14. Department of Radiology and Imaging Sciences, Centre for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, USA. 15. Department of Radiology, Mayo Clinic, Rochester, MN, USA. 16. Neuroscience Research Australia, Randwick, NSW, Australia; School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia. 17. Department of Radiology, School of Medicine, University of California, San Francisco, San Francisco, CA, USA. 18. Department of Neurology, Keck USC School of Medicine, Los Angeles, CA, USA. 19. Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA. 20. The Florey Institute, University of Melbourne, Parkville, VIC, Australia. 21. Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, VIC, Australia; Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, Australia.
Abstract
INTRODUCTION: Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. METHODS: Serial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. RESULTS: Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. DISCUSSION: Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression.
INTRODUCTION: Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. METHODS: Serial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. RESULTS:Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. DISCUSSION: Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression.
Authors: Clifford R Jack; Matt A Bernstein; Bret J Borowski; Jeffrey L Gunter; Nick C Fox; Paul M Thompson; Norbert Schuff; Gunnar Krueger; Ronald J Killiany; Charles S Decarli; Anders M Dale; Owen W Carmichael; Duygu Tosun; Michael W Weiner Journal: Alzheimers Dement Date: 2010-05 Impact factor: 21.566
Authors: Wai-Ying Wendy Yau; Dana L Tudorascu; Eric M McDade; Snezana Ikonomovic; Jeffrey A James; Davneet Minhas; Wenzhu Mowrey; Lei K Sheu; Beth E Snitz; Lisa Weissfeld; Peter J Gianaros; Howard J Aizenstein; Julie C Price; Chester A Mathis; Oscar L Lopez; William E Klunk Journal: Lancet Neurol Date: 2015-06-29 Impact factor: 44.182
Authors: Davis C Ryman; Natalia Acosta-Baena; Paul S Aisen; Thomas Bird; Adrian Danek; Nick C Fox; Alison Goate; Peter Frommelt; Bernardino Ghetti; Jessica B S Langbaum; Francisco Lopera; Ralph Martins; Colin L Masters; Richard P Mayeux; Eric McDade; Sonia Moreno; Eric M Reiman; John M Ringman; Steve Salloway; Peter R Schofield; Reisa Sperling; Pierre N Tariot; Chengjie Xiong; John C Morris; Randall J Bateman Journal: Neurology Date: 2014-06-13 Impact factor: 9.910
Authors: Yakeel T Quiroz; Chantal E Stern; Eric M Reiman; Michael Brickhouse; Adriana Ruiz; Reisa A Sperling; Francisco Lopera; Bradford C Dickerson Journal: J Neurol Neurosurg Psychiatry Date: 2012-11-07 Impact factor: 10.154
Authors: John C Morris; Paul S Aisen; Randall J Bateman; Tammie L S Benzinger; Nigel J Cairns; Anne M Fagan; Bernardino Ghetti; Alison M Goate; David M Holtzman; William E Klunk; Eric McDade; Daniel S Marcus; Ralph N Martins; Colin L Masters; Richard Mayeux; Angela Oliver; Kimberly Quaid; John M Ringman; Martin N Rossor; Stephen Salloway; Peter R Schofield; Natalie J Selsor; Reisa A Sperling; Michael W Weiner; Chengjie Xiong; Krista L Moulder; Virginia D Buckles Journal: Clin Investig (Lond) Date: 2012-10-01
Authors: Anders M Fjell; Kristine B Walhovd; Lars T Westlye; Ylva Østby; Christian K Tamnes; Terry L Jernigan; Anthony Gamst; Anders M Dale Journal: Neuroimage Date: 2010-01-25 Impact factor: 6.556
Authors: Kelvin K Leung; Matthew J Clarkson; Jonathan W Bartlett; Shona Clegg; Clifford R Jack; Michael W Weiner; Nick C Fox; Sébastien Ourselin Journal: Neuroimage Date: 2009-12-23 Impact factor: 6.556
Authors: Brian A Gordon; Tyler M Blazey; Jon Christensen; Aylin Dincer; Shaney Flores; Sarah Keefe; Charles Chen; Yi Su; Eric M McDade; Guoqiao Wang; Yan Li; Jason Hassenstab; Andrew Aschenbrenner; Russ Hornbeck; Clifford R Jack; Beau M Ances; Sarah B Berman; Jared R Brosch; Douglas Galasko; Serge Gauthier; James J Lah; Mario Masellis; Christopher H van Dyck; Mark A Mintun; Gregory Klein; Smiljana Ristic; Nigel J Cairns; Daniel S Marcus; Chengjie Xiong; David M Holtzman; Marcus E Raichle; John C Morris; Randall J Bateman; Tammie L S Benzinger Journal: Brain Date: 2019-04-01 Impact factor: 13.501
Authors: Oliver Preische; Stephanie A Schultz; Anja Apel; Jens Kuhle; Stephan A Kaeser; Christian Barro; Susanne Gräber; Elke Kuder-Buletta; Christian LaFougere; Christoph Laske; Jonathan Vöglein; Johannes Levin; Colin L Masters; Ralph Martins; Peter R Schofield; Martin N Rossor; Neill R Graff-Radford; Stephen Salloway; Bernardino Ghetti; John M Ringman; James M Noble; Jasmeer Chhatwal; Alison M Goate; Tammie L S Benzinger; John C Morris; Randall J Bateman; Guoqiao Wang; Anne M Fagan; Eric M McDade; Brian A Gordon; Mathias Jucker Journal: Nat Med Date: 2019-01-21 Impact factor: 53.440
Authors: Robert X Smith; Jeremy F Strain; Aaron Tanenbaum; Anne M Fagan; Jason Hassenstab; Eric McDade; Suzanne E Schindler; Brian A Gordon; Chengjie Xiong; Jasmeer Chhatwal; Clifford Jack; Celeste Karch; Sarah Berman; Jared R Brosch; James J Lah; Adam M Brickman; David M Cash; Nick C Fox; Neill R Graff-Radford; Johannes Levin; James Noble; David M Holtzman; Colin L Masters; Martin R Farlow; Christoph Laske; Peter R Schofield; Daniel S Marcus; John C Morris; Tammie L S Benzinger; Randall J Bateman; Beau M Ances Journal: Brain Connect Date: 2021-03-31
Authors: Victor Montal; Eduard Vilaplana; Jordi Pegueroles; Alexandre Bejanin; Daniel Alcolea; María Carmona-Iragui; Jordi Clarimón; Johannes Levin; Carlos Cruchaga; Neill R Graff-Radford; James M Noble; Jae-Hong Lee; Ricardo Allegri; Celeste M Karch; Christoph Laske; Peter R Schofield; Stephen Salloway; Beau Ances; Tammie Benzinger; Eric McDale; Randall Bateman; Rafael Blesa; Raquel Sánchez-Valle; Alberto Lleó; Juan Fortea Journal: Alzheimers Dement Date: 2020-11-16 Impact factor: 21.566
Authors: Ophir Keret; Adam M Staffaroni; John M Ringman; Yann Cobigo; Sheng-Yang M Goh; Amy Wolf; Isabel Elaine Allen; Stephen Salloway; Jasmeer Chhatwal; Adam M Brickman; Dolly Reyes-Dumeyer; Randal J Bateman; Tammie L S Benzinger; John C Morris; Beau M Ances; Nelly Joseph-Mathurin; Richard J Perrin; Brian A Gordon; Johannes Levin; Jonathan Vöglein; Mathias Jucker; Christian la Fougère; Ralph N Martins; Hamid R Sohrabi; Kevin Taddei; Victor L Villemagne; Peter R Schofield; William S Brooks; Michael Fulham; Colin L Masters; Bernardino Ghetti; Andrew J Saykin; Clifford R Jack; Neill R Graff-Radford; Michael Weiner; David M Cash; Ricardo F Allegri; Patricio Chrem; Su Yi; Bruce L Miller; Gil D Rabinovici; Howard J Rosen Journal: Alzheimers Dement (Amst) Date: 2021-07-05
Authors: Kamen A Tsvetanov; Stefano Gazzina; P Simon Jones; John van Swieten; Barbara Borroni; Raquel Sanchez-Valle; Fermin Moreno; Robert Laforce; Caroline Graff; Matthis Synofzik; Daniela Galimberti; Mario Masellis; Maria Carmela Tartaglia; Elizabeth Finger; Rik Vandenberghe; Alexandre de Mendonça; Fabrizio Tagliavini; Isabel Santana; Simon Ducharme; Chris Butler; Alexander Gerhard; Adrian Danek; Johannes Levin; Markus Otto; Giovanni Frisoni; Roberta Ghidoni; Sandro Sorbi; Jonathan D Rohrer; James B Rowe Journal: Alzheimers Dement Date: 2020-11-20 Impact factor: 16.655
Authors: Brian A Gordon; Tyler M Blazey; Yi Su; Amrita Hari-Raj; Aylin Dincer; Shaney Flores; Jon Christensen; Eric McDade; Guoqiao Wang; Chengjie Xiong; Nigel J Cairns; Jason Hassenstab; Daniel S Marcus; Anne M Fagan; Clifford R Jack; Russ C Hornbeck; Katrina L Paumier; Beau M Ances; Sarah B Berman; Adam M Brickman; David M Cash; Jasmeer P Chhatwal; Stephen Correia; Stefan Förster; Nick C Fox; Neill R Graff-Radford; Christian la Fougère; Johannes Levin; Colin L Masters; Martin N Rossor; Stephen Salloway; Andrew J Saykin; Peter R Schofield; Paul M Thompson; Michael M Weiner; David M Holtzman; Marcus E Raichle; John C Morris; Randall J Bateman; Tammie L S Benzinger Journal: Lancet Neurol Date: 2018-02-01 Impact factor: 44.182