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The Role of Tau and Neuroinflammation in Progressive Supranuclear Palsy and Alzheimer’S Disease

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The Role of Tau and Neuroinflammation in Progressive Supranuclear Palsy and Alzheimer’S Disease The role of tau and neuroinflammation in Progressive Supranuclear Palsy and Alzheimer’s Disease Patricia Vázquez Rodríguez Lucy Cavendish University of Cambridge A thesis submitted for the degree of Doctor of Philosophy October 2019 1 2 A mi familia, y en especial a mis ángeles de la guarda, Fabio y Abu Socorro. 3 4 “I have already lost touch with a couple of people I used to be” Joan Didion 5 6 Declaration I hereby declare that except where specific reference is made to the work of others, the contents of this dissertation are original and have not been submitted in whole or in part for any other degree, diploma or qualification at the University of Cambridge or any other universities. This thesis is the result of my own work except where specifically indicated in the text, and have been carried out at the University of Cambridge between January 2015 and November 2018 under the supervision of Professor James Rowe. Due to the collaborative nature of multimodal imaging neuroscience, the work presented here uses the first-person plural (“we”). Below is an overview of contributions to each chapter. Chapter 2 summarises the relevant parts of the protocol of the NIMROD study. This is a collaboration led by Professors James B. Rowe and John O’Brien, with research assistant support from Dr Richard Bevan-Jones, and Robert Arnold. I undertook the majority of PSP investigation, and contributed to investigation of other groups. This chapter has been published at BMJ Open (Bevan-Jones et al., 2017). Chapter 3 includes neuropsychological data obtained under the NIMROD research study collected partly by me (mainly PSP cases) with normative and Alzheimer case data by Mr Robert Arnold and Dr Richard Bevan-Jones. The analysis, interpretation and writing represent my own work. Chapter 4 and chapter 5 draw on data from a large NIMROD study team collaboration, with multiple researchers affiliated with the Wolfson Brain Imaging Centre (WBIC) at Cambridge University, and the departments of PET-CT and Pathology at Addenbrooke’s hospital. The recruitment of patients was by me (PSP cases) and Robert Arnold. PET data pre-processing was carried out by Dr Tim Fryer and Dr Young Hong. Analysis and interpretation was the result of joint work by Dr Luca Passamonti and myself. 7 Dr Kieren Allison (Cambridge Brain Bank) provided the specific brain tissue needed for these chapters. Dr David Wilkinson and myself performed the phosphor screen autoradiographies using both PET tracers, [18F]AV1451 and [11C](R)- PK11195. I have also assisted Dr Wilkinson during the immunohistochemistry work for chapter 4, while Oliver Green and Robert Fincham conducted this task for chapter 5. Dr Luca Passamonti contributed to the published manuscript, focusing on PET results. I developed the pathological sections. This work was published with co-first authors, as Passamonti, Vázquez Rodríguez et al., Brain 2017 and Passamonti, Vázquez Rodríguez et al., Neurology 2018. The research questions for each of the studies in this thesis were developed by myself in consultation with my supervisor, Professor James Rowe. The length of this thesis does not exceed the 60,000-word limit set by the Degree Committee for the faculties of Clinical Medicine and Clinical Veterinary Medicine. 8 Acknowledgments I would like to thank my supervisor Professor James Rowe, who has been more than my academic supervisor. I believe that I managed to complete (even to start) this PhD mainly because he is leading this group. I will never forget his support from the start to the end, but in particular since I re-joined his group in January 2015. I perfectly remember that day. I came upstairs and after asking me how I was getting on, he told me that I could do this. He also warned me that it was not going to be easy, but he trusted me and he was going to be there for me. Indeed he was. At this point I am supposed to say as well that I am grateful to him for welcoming me in his group, giving me the opportunity to design and set up some exciting projects in Cambridge and in collaboration with other groups. However, what I am really most grateful for is for helping me through one of the toughness moments of my life. I would like to thank Dr Richard Bevan-Jones. I would be literally lost without him. He is always calm, and his constant encouragement and positivity made me believe that at the end of the tunnel there was light even if sometimes I could not see it. Thank you very much, Rich. I honestly cannot remember how many times I have cried with you. Another very important person for me is Dr Luca Passamonti. I find it impossible to describe how much I have learnt from him. His time, ideas and help throughout my PhD have been invaluable. He became a mentor and a friend for life. A huge thank you goes to the NIMROD team, and especially to Professor John O’Brien, Robert Arnold, Dr Ajenthan Surendranathan, Dr Su Li, and Dr Elijah Foo. I would also like to acknowledge the Cambridge Brain Bank members, Dr Kieren Allison, Dr Robert Fincham, and Oliver Green for their help proving me with the brain tissue and running part of the immunohistochemistry experiments. Also thanks to Dr David Williamson for teaching me the magical world of phosphor screen autoradiography, and our amusing conversations during our ‘coffee’ break. 9 Massive thanks to the Wolfson Brain Imaging Centre (WBIC) and PET-CT teams for helping me with the scanning sessions: Victoria Lupson, Karen Welsh, Dr Marius Mada, Dr Jonathan Coles, Gloria Stocks-Gee, Victoria Warnes, and Suzanne Boniface. I would like to thank the WBIC Radiopharmaceutical Unit for producing the radiotracers for my in vivo and post mortem studies: Dr Istvan Boros, Dr Robert Smith, and Dr Roberto Canales Candela. Last but not least thanks to Dr Young Hong and Dr Tim Fryer for preprocessing all the PET data, and for a couple of Starbucks coffees. I would like to thank the Progressive Supranuclear Palsy Association (in particular, Kate Arkell), NIHR Cambridge BRC, Wellcome Trust, and James S. McDonnell Foundation for funding part of my PhD. I would also like to mention AVID, as they provided the AV1451 base compound for free. Also to my college, Lucy Cavendish, for their support and generous travel grant funding. This PhD would not have been possible without the participation of all those patients and controls who volunteered to take part in my studies. Thank you to the Progressive Supranuclear Palsy patients for their time and for sharing a part of their lives with me, you have made my PhD a memorable experience. Thank you to all my colleagues and friends at the Herchel Smith Building for Brain and Mind Sciences: Alicia Wilcox (she taught me to behave like a turtle rather than a cheetah), Sarah Ayerst, Kate Dawson, Merete Bergmann, Dr Claire Lansdall, Dr Alexander Murley, Julie Wiggins, Dr Sanne Kaalud, Dr Tom Cope, Lucy Bowns, Caroline Timberlake, Simon Jones, Maura Malpetti, Katrine Sværke, Matthew Rouse, Bea Kiddle, Dr Rong Ye, Dr Hollie Phillips, Professor Karalyn Patterson, Sandra Zurborg, Dr Ian Coyle-Gilchrist, Robin Borchert, Win Li, and the remaining members of the Rowe Lab. More thanks to Dr Hannah Jongsma, Dr Richard Bethlehem, Bianca Oltean, Holly Bennet, Roxanne Hook, Dr Claire O’Callaghan, Dr George Savulich, and Dr Thomas Piercy. Thank you all for supporting me during my PhD and making the HSB a fun place to work and form strong friendships. I would like to give a special thank you to all the friends I have made in Cambridge who shared with me my excitement and concerns during my studies, 10 and further: Pawel, Shannon, Anna and Benji, Rosanna, Sian, Ricardo and Eric, Maria, Laetitia, Lucy, Romina, and Ruwani. My incredible rowing club has also been extremely important in this particular PhD rollercoaster. Their love, care and good vibes have been critical for my mental health. A million thanks to my best friends: Patricia, Cristina, Angela, Magda, Teresa, Beatriz, Megan and Laura for allowing me to disconnect from the PhD during our travels around the world, you kept me going. I love you very much, girls. Dr Emma Woodberry. I will never forget your support since I approached you when you had a visit in NCCU many years ago. She has literally changed my professional life. Dr Woodberry opened many doors for me and encouraged to be fearless, hardworking and not settling for the mediocre. During my time with her, I discovered that on top of being a fantastic clinical psychologist, she is one of the most caring people I know. Thank you very much, Emma. I am going to miss seeing you through the window. Finally, thank you to my amazing family, especially to my caring parents. You picked me up every time I was down, stressed, discouraged or I did not believe in myself. Thank you to my mum for her strength and for being a great role model. Thank you to my dad for using his particular reverse psychology and having unforgettable conversations around Europe. Thank you to my sister who empathises and guides me every day. Thank you to my little brother who often makes me feel like I am his little sister due to his wise advice. Thank you to the rest of my family: Cayetano, Mari, Catavo, Aurora, Carmen, Carmeli, Maria Antonia, Maria, Eduardo, Javier, Carlos and Javi for your love and support throughout my studies. A special thanks to the two men of my life. To Gunther, my partner, who provided constant support and kept me going throughout the ups and downs since we met.
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