Victor Montal1,2, Eduard Vilaplana1,2, Jordi Pegueroles1,2, Alexandre Bejanin1,2, Daniel Alcolea1,2, María Carmona-Iragui1,2,3, Jordi Clarimón1,2, Johannes Levin4,5,6, Carlos Cruchaga7,8,9,10, Neill R Graff-Radford11, James M Noble12, Jae-Hong Lee13, Ricardo Allegri14, Celeste M Karch15, Christoph Laske16,17, Peter R Schofield18,19, Stephen Salloway20, Beau Ances7,8,10,21, Tammie Benzinger10,21, Eric McDale7,10, Randall Bateman7,8,10, Rafael Blesa1,2, Raquel Sánchez-Valle22, Alberto Lleó1,2, Juan Fortea1,2,3. 1. Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. 2. Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain. 3. Barcelona Down Medical Center, Fundació Catalana de Síndrome de Down, Barcelona, Spain. 4. Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany. 5. German Center for Neurodegenerative Diseases, Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 6. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 7. Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA. 8. The Hope Center for Neurological Disorders, St. Louis, Missouri, USA. 9. NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, Missouri, USA. 10. Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA. 11. Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA. 12. Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, New York, USA. 13. Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. 14. Department of Cognitive Neurology, Institute for Neurological Research Fleni, Buenos Aires, Argentina. 15. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA. 16. German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. 17. Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany. 18. Neuroscience Research Australia, Sydney, Australia. 19. School of Medical Sciences, University of New South Wales, Sydney, Australia. 20. Neurology and the Memory and Aging Program, Butler Hospital, Providence, Rhode Island, USA. 21. Department of Radiology, Washington University in St. Louis, St. Louis, Missouri, USA. 22. Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic, Fundació Clínic per a la Recerca Biomèdica, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
Abstract
INTRODUCTION: A biphasic model for brain structural changes in preclinical Alzheimer's disease (AD) could reconcile some conflicting and paradoxical findings in observational studies and anti-amyloid clinical trials. METHODS: In this study we tested this model fitting linear versus quadratic trajectories and computed the timing of the inflection points vertexwise of cortical thickness and cortical diffusivity-a novel marker of cortical microstructure-changes in 389 participants from the Dominantly Inherited Alzheimer Network. RESULTS: In early preclinical AD, between 20 and 15 years before estimated symptom onset, we found increases in cortical thickness and decreases in cortical diffusivity followed by cortical thinning and cortical diffusivity increases in later preclinical and symptomatic stages. The inflection points 16 to 19 years before estimated symptom onset are in agreement with the start of tau biomarker alterations. DISCUSSION: These findings confirm a biphasic trajectory for brain structural changes and have direct implications when interpreting magnetic resonance imaging measures in preventive AD clinical trials.
INTRODUCTION: A biphasic model for brain structural changes in preclinical Alzheimer's disease (AD) could reconcile some conflicting and paradoxical findings in observational studies and anti-amyloid clinical trials. METHODS: In this study we tested this model fitting linear versus quadratic trajectories and computed the timing of the inflection points vertexwise of cortical thickness and cortical diffusivity-a novel marker of cortical microstructure-changes in 389 participants from the Dominantly Inherited Alzheimer Network. RESULTS: In early preclinical AD, between 20 and 15 years before estimated symptom onset, we found increases in cortical thickness and decreases in cortical diffusivity followed by cortical thinning and cortical diffusivity increases in later preclinical and symptomatic stages. The inflection points 16 to 19 years before estimated symptom onset are in agreement with the start of tau biomarker alterations. DISCUSSION: These findings confirm a biphasic trajectory for brain structural changes and have direct implications when interpreting magnetic resonance imaging measures in preventive AD clinical trials.
Authors: Gaël Chételat; Victor L Villemagne; Kerryn E Pike; Jean-Claude Baron; Pierrick Bourgeat; Gareth Jones; Noel G Faux; Kathryn A Ellis; Olivier Salvado; Cassandra Szoeke; Ralph N Martins; David Ames; Colin L Masters; Christopher C Rowe Journal: Brain Date: 2010-08-25 Impact factor: 13.501
Authors: Rahul S Desikan; Linda K McEvoy; Wesley K Thompson; Dominic Holland; J Cooper Roddey; Kaj Blennow; Paul S Aisen; James B Brewer; Bradley T Hyman; Anders M Dale Journal: Ann Neurol Date: 2011-10-14 Impact factor: 10.422
Authors: Juan Fortea; Eduard Vilaplana; Daniel Alcolea; María Carmona-Iragui; María-Belén Sánchez-Saudinos; Isabel Sala; Sofía Antón-Aguirre; Sofía González; Santiago Medrano; Jordi Pegueroles; Estrella Morenas; Jordi Clarimón; Rafael Blesa; Alberto Lleó Journal: Ann Neurol Date: 2014-06-13 Impact factor: 10.422
Authors: Eric McDade; Guoqiao Wang; Brian A Gordon; Jason Hassenstab; Tammie L S Benzinger; Virginia Buckles; Anne M Fagan; David M Holtzman; Nigel J Cairns; Alison M Goate; Daniel S Marcus; John C Morris; Katrina Paumier; Chengjie Xiong; Ricardo Allegri; Sarah B Berman; William Klunk; James Noble; John Ringman; Bernardino Ghetti; Martin Farlow; Reisa A Sperling; Jasmeer Chhatwal; Stephen Salloway; Neill R Graff-Radford; Peter R Schofield; Colin Masters; Martin N Rossor; Nick C Fox; Johannes Levin; Mathias Jucker; Randall J Bateman Journal: Neurology Date: 2018-09-14 Impact factor: 9.910
Authors: Roser Sala-Llonch; Albert Lladó; Juan Fortea; Beatriz Bosch; Anna Antonell; Mircea Balasa; Nuria Bargalló; David Bartrés-Faz; José Luis Molinuevo; Raquel Sánchez-Valle Journal: Neurobiol Aging Date: 2014-12-24 Impact factor: 4.673
Authors: Anne M Fagan; Chengjie Xiong; Mateusz S Jasielec; Randall J Bateman; Alison M Goate; Tammie L S Benzinger; Bernardino Ghetti; Ralph N Martins; Colin L Masters; Richard Mayeux; John M Ringman; Martin N Rossor; Stephen Salloway; Peter R Schofield; Reisa A Sperling; Daniel Marcus; Nigel J Cairns; Virginia D Buckles; Jack H Ladenson; John C Morris; David M Holtzman Journal: Sci Transl Med Date: 2014-03-05 Impact factor: 17.956
Authors: Sterling C Johnson; Bradley T Christian; Ozioma C Okonkwo; Jennifer M Oh; Sandra Harding; Guofan Xu; Ansel T Hillmer; Dustin W Wooten; Dhanabalan Murali; Todd E Barnhart; Lance T Hall; Annie M Racine; William E Klunk; Chester A Mathis; Barbara B Bendlin; Catherine L Gallagher; Cynthia M Carlsson; Howard A Rowley; Bruce P Hermann; N Maritza Dowling; Sanjay Asthana; Mark A Sager Journal: Neurobiol Aging Date: 2013-10-23 Impact factor: 4.673
Authors: Nicholas M Vogt; Jack F Hunt; Nagesh Adluru; Douglas C Dean; Sterling C Johnson; Sanjay Asthana; John-Paul J Yu; Andrew L Alexander; Barbara B Bendlin Journal: Cereb Cortex Date: 2020-05-14 Impact factor: 5.357
Authors: Jorge J Llibre-Guerra; Yan Li; Suzanne E Schindler; Brian A Gordon; Anne M Fagan; John C Morris; Tammie L S Benzinger; Jason Hassenstab; Guoqiao Wang; Ricardo Allegri; Sarah B Berman; Jasmeer Chhatwal; Martin R Farlow; David M Holtzman; Mathias Jucker; Johannes Levin; James M Noble; Stephen Salloway; Peter Schofield; Celeste Karch; Nick C Fox; Chengjie Xiong; Randall J Bateman; Eric McDade Journal: JAMA Netw Open Date: 2019-12-02
Authors: Maria Florencia Iulita; Diana Garzón Chavez; Maria Klitgaard Christensen; Natalia Valle Tamayo; Oleguer Plana-Ripoll; Sonja A Rasmussen; Marta Roqué Figuls; Daniel Alcolea; Laura Videla; Isabel Barroeta; Bessy Benejam; Miren Altuna; Concepción Padilla; Jordi Pegueroles; Susana Fernandez; Olivia Belbin; María Carmona-Iragui; Rafael Blesa; Alberto Lleó; Alexandre Bejanin; Juan Fortea Journal: JAMA Netw Open Date: 2022-05-02
Authors: Joshua T Fox-Fuller; Heirangi Torrico-Teave; Federico d'Oleire Uquillas; Kewei Chen; Yi Su; Yinghua Chen; Michael Brickhouse; Justin S Sanchez; Cinthya Aguero; Heidi I L Jacobs; Olivia Hampton; Edmarie Guzmán-Vélez; Clara Vila-Castelar; Daniel C Aguirre-Acevedo; Ana Baena; Arabiye Artola; Jairo Martinez; Celina F Pluim; Sergio Alvarez; Martin Ochoa-Escudero; Eric M Reiman; Reisa A Sperling; Francisco Lopera; Keith A Johnson; Bradford C Dickerson; Yakeel T Quiroz Journal: Alzheimers Dement (Amst) Date: 2021-09-14
Authors: Ignacio Illán-Gala; Victor Montal; Sergi Borrego-Écija; Maria Luisa Mandelli; Neus Falgàs; Ariane E Welch; Jordi Pegueroles; Miguel Santos-Santos; Alexandre Bejanin; Daniel Alcolea; Oriol Dols-Icardo; Olivia Belbin; Mª Belén Sánchez-Saudinós; Nuria Bargalló; Sofía González-Ortiz; Albert Lladó; Rafael Blesa; Bradford C Dickerson; Howard J Rosen; Bruce L Miller; Alberto Lleó; Maria Luisa Gorno-Tempini; Raquel Sánchez-Valle; Juan Fortea Journal: Alzheimers Res Ther Date: 2022-02-09 Impact factor: 6.982
Authors: Concepcion Padilla; Victor Montal; Madeleine J Walpert; Young T Hong; Tim D Fryer; Jonathan P Coles; Franklin I Aigbirhio; Sigan L Hartley; Ann D Cohen; Dana L Tudorascu; Bradley T Christian; Benjamin L Handen; William E Klunk; Anthony J Holland; Shahid H Zaman Journal: Alzheimers Dement (Amst) Date: 2022-04-01
Authors: Elena Rodriguez-Vieitez; Victor Montal; Jorge Sepulcre; Cristina Lois; Bernard Hanseeuw; Eduard Vilaplana; Aaron P Schultz; Michael J Properzi; Matthew R Scott; Rebecca Amariglio; Kathryn V Papp; Gad A Marshall; Juan Fortea; Keith A Johnson; Reisa A Sperling; Patrizia Vannini Journal: Mol Psychiatry Date: 2021-09-29 Impact factor: 15.992
Authors: David Reyes-Leiva; Oriol Dols-Icardo; Sonia Sirisi; Elena Cortés-Vicente; Janina Turon-Sans; Noemi de Luna; Rafael Blesa; Olivia Belbin; Victor Montal; Daniel Alcolea; Juan Fortea; Alberto Lleó; Ricard Rojas-García; Ignacio Illán-Gala Journal: Front Neurol Date: 2022-01-18 Impact factor: 4.003