Distinct contribution of white matter damage to the clinical syndrome of Alzheimer's disease by Jean-Philippe Coutu B.Eng. Engineering Physics, Ecole Polytechnique de Montreal (2010) Submitted to the Division of Health Sciences and Technology in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY IN MEDICAL ENGINEERING MEDICAL PHYSICS at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY February 2016 @ 2016 Massachusetts Institute of Technology. All rights reserved. Signature redacted A uthor ..................... .... .... Division of HealtN Sciences and Technology -..- Noveiber 25, 2015 Certified by................ Signature redacted David H. Salat, PhD Associate Professor in Radiology, Harvard Medical School Theds Supervisor Accepted by Signature redacted... Emery N. Brown, MD, PhD Director, Harvard-M T Program in Health Sciences and Technology Professor of Computational Neuroscience and Health Sciences and Technology MASSACHUSETT INSTITUTE OF TECHNOLOGY MAR 14 2016 LIBRARIES 2 Distinct contribution of white matter damage to the clinical syndrome of Alzheimer's disease by Jean-Philippe Coutu Submitted to the Division of Health Sciences and Technology on November 25, 2015, in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY IN MEDICAL ENGINEERING MEDICAL PHYSICS Abstract Alzheimer's disease is a neurodegenerative disorder affecting over 5.1 million individ- uals in the United States today. The dementia exhibited with the disease is currently thought to be primarily due to amyloid plaques and neurofibrillary tangles. However, several other changes occur, including severe white matter damage that is yet to be fully understood. Such white matter damage includes white matter lesions (WML), which are more common in individuals with Alzheimer's disease than in non-demented individuals. WML are of presumed vascular origin because they show features of small-vessel disease and are more prevalent in individuals with vascular risk. It is currently unclear whether WML are linked to the neurodegenerative pathologies of Alzheimer's disease or are an independent factor that influences clinical course. In this work, we used sensitive diffusion MRI measures to determine that the tis- sue properties of WML slightly differed microstructurally between individuals with Alzheimer's disease and non-demented controls, and were strongly related to ventric- ular enlargement. In order to further understand the role of WML, we factored the volume of WML with four other neuroimaging markers affected in Alzheimer's disease and discovered two statistically distinct factors presumed to be due to differing under- lying disease processes. One process strongly related to volume and tissue properties of WML, ventricular enlargement, age and cerebral perfusion, while the other process related to imaging markers associated with neurodegeneration. A decrease over time in the first process, interpreted as the age- and vascular-related factor, led to similar cognitive decline as the neurodegenerative factor independently, demonstrating the potential added therapeutic benefit of targeting this disease process that is distinct from the classical neurodegenerative component of the disease. Thesis Supervisor: David H. Salat, PhD Title: Associate Professor in Radiology, Harvard Medical School 3 4 Acknowledgements Personal acknowledgements I want to thank first and foremost my thesis supervisor, David Salat, for his mentoring throughout the last five years. It has been a privilege, an honor and a great pleasure for me to learn from him. He has always been very supportive of my ideas and has given me plenty of room to explore new projects. Thank you for feeding my curiosity and being the greatest contributor to my scientific growth. I also want to thank my thesis chair, Bruce Rosen, for his mentoring through his regular student meetings and my thesis committee meetings, and for making the Martinos center a very open and collaborative environment from which I have learned greatly. I also want to thank my other two committee members for their mentoring and help through my PhD, Doug Greve in particular for his precious technical insight and David Boas in particular for looking at my work from a different angle. I also want to thank several other mentors I have had, beginning with Jean Chen, who welcomed me into David's research group and helped me get started on several interesting projects. I also want to thank Diana Rosas for her clinical insight and the many opportunities she has offered me throughout and beyond my PhD. I also want to thank Bruce Fischl and members of his wonderful FreeSurfer group with whom I have interacted with throughout my PhD and who have provided both great technical insight and friendship. I also want to thank Steve Greenberg and Edip Gurol for offering their clinical perspective to my work and for teaching me about small-vessel disease. Next, I want to thank individuals I have interacted with on a regular basis and who have contributed to my graduate work in many different ways, in particular Alison Goldblatt, Emily Lindemer, Paul Wilkens, Tyler Triggs, as well as all other members of the lab who were instrumental to the completion of my graduate work and other research projects: Emma Boyd, Jeanne Tong, Casey Callaghan, Kim Stephens, Keith Malarick, Suzanne Imbriglio, Matt Linehan, Robert McKinnis, Lisa Glukhovsky, Ali Amin-Mansour and Steven Swinford. I also want to thank my collaborators from South Korea: Seon Young Ryu, Seung Hwan Lee and Chang-Woo Ryu; as well as some of my colleagues at the Martinos center and MIT who I have enjoyed working with and from whom I have learned a lot: Juliette Selb, Phoebe Chan, Jon Polimeni, Jayashree Kalpathy-Cramer, Elfar Adalsteinsson, Maria Mody, Trey Hedden and Randy Gollub. In particular, I want to express my gratitute to members of our regular journal club: Melissa Amick, Jean Augustinack, Andre van der Kouwe, Vincent Corbo and Meghan Robinson. It was great learning with you! I would also like to thank those who have made my journey to MIT possible, in particular Caroline Boudoux and Frederic Lesage, as well as Thomas Gervais, who have inspired me to 5 apply to MIT and have supported me and my application in various ways. I also want to thank the HST office and faculty for being extremely welcoming in the early days of my PhD and throughout, in particular Julie Greenberg, Laurie Ward, Richard Cohen, Joseph Stein, Lora Maurer, Brett Bouma and Traci Anderson. I also want to thank everyone who welcomed me at my first home in the United States, the Sidney-Pacific Graduate Residence, in particular Roger and Dottie Mark, Amy Bilton, Chelsea Curran and Anand Oza, and the many friends I have made there: Ece Gulsen, George Lan, George Tucker, Holly Johnsen, George Chen, Sumit Dutta, Ramesh Sridharan and many others. I also want to acknowledge many friends I met in the HST program and at the Martinos Center: Audrey Fan, Christin Sander, Jeffrey Stout, Pavitra Krishnaswamy, Stephanie Yaung, Kevin Chen, Dan Chonde, as well as my first roommate on this side of the border, Justin Lo, and many others. I also want to make a special mention of Louis Gagnon, a fellow French Canadian who has been very supportive of my early days in the HST program and at the Martinos center, and who has been a precious friend. I also want to acknowledge other French Canadian friends I met during my time in Boston and Cambridge: Rosalie Belanger-Rioux, Vincent Corbo, Chenjie Xia, Vincent Laverdiere, Roxane Lavoie, Vincent Beliveau, Sam Osseiran and Antoine Ramier. I also want to thank my undergraduate friends for their support and the fun times we spent together before and during my PhD: Dany Chagnon, Alexandre Robitaille, Amelie St-Georges- Robillard, Benoit Bourrassa-Moreau, and Laurent Potvin-Trottier and Kathy Beaudette who also came to study in Boston and Cambridge and have made my journey in this foreign land feel a little bit more like home. I also want to thank my relaxation crew, who has provided me with many timely breaks to maintain my sanity throughout my journey, especially towards the end: Dany Chagnon, Patrick Lavoie, Pascale Brunet and Claude Mercure-Dansereau. Finally, I want to acknowledge and thank members of my family: my father Yves Coutu, my mother, Liliane Samson, and my two wonderful sisters, Marie-Pier Coutu and Val6rie Coutu. You have made me who I am and I am extremely grateful that I was able to come this far thanks to you and your support. I also want to acknowledge my cat, Pepsi, for his love and purring support. Last, but not least, I want to give an enormous thank you to my fiancee, Sunny Vanderboll, who I met during my time here and who has made this journey much greater than anything I could have dreamed of. Thank you so much for your support and your love; I am looking forward to more adventures with you in the future! Funding and data sources My thesis research was funded by the National Institutes of Health grants R01NR010827, NS042861, NS058793 and was carried out at the Athinoula A. Martinos Center for Biomedical Imaging within the Massachusetts General Hospital (MGH), using resources provided by the Center for Functional Neuroimaging Technologies, P41RR14075, a P41 Regional Resource supported by the Biomedical Technology Program of the National Center for Research Resources (NCRR), National Institutes of Health. This work also involved the use of 6 instrumentation supported by the NCRR Shared Instrumentation Grant Program and/or High- End Instrumentation Grant Program; specifically, grant numbers S1ORRO21110, S10RR023401, S10RR019307, S10RR019254 and S10RR023043. I am also grateful for having been funded by the Medical Engineering Medical Physics Fellowship of the MIT/Harvard Division of Health Sciences and Technology (HST), the Advanced Multimodal Neuroimaging Training Program (2T90DA022759; P.I. Bruce Rosen) of the MGH/HST Athinoula A. Martinos Center for Biomedical Imaging, the Natural Sciences and Engineering Research Council of Canada, the Fonds de Recherche du Quebec - Nature et les Technologies, the Fonds de Recherche du Quebec - Sante, and the HST IDEA2 Program supported by the Peter C.