CORTICOBASAL SYNDROME: CLINICAL, NEUROPSYCHOLOGICAL, IMAGING, GENETIC AND PATHOLOGICAL FEATURES by Mario Masellis A thesis submitted in conformity with the requirements for the degree of Doctorate of Philosophy in the Graduate Department of Institute of Medical Sciences, University of Toronto © Copyright by Mario Masellis (2012) Library and Archives Bibliothèque et Canada Archives Canada Published Heritage Direction du Branch Patrimoine de l'édition 395 Wellington Street 395, rue Wellington Ottawa ON K1A 0N4 Ottawa ON K1A 0N4 Canada Canada Your file Votre référence ISBN: 978-0-494-97827-6 Our file Notre référence ISBN: 978-0-494-97827-6 NOTICE: AVIS: The author has granted a non- L'auteur a accordé une licence non exclusive exclusive license allowing Library and permettant à la Bibliothèque et Archives Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par télécommunication ou par l'Internet, prêter, telecommunication or on the Internet, distribuer et vendre des thèses partout dans le loan, distrbute and sell theses monde, à des fins commerciales ou autres, sur worldwide, for commercial or non- support microforme, papier, électronique et/ou commercial purposes, in microform, autres formats. paper, electronic and/or any other formats. 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Corticobasal Syndrome: Clinical, Neuropsychological, Imaging, Genetic and Pathological Features Doctorate of Philosophy 2012 Mario Masellis Graduate Department of Institute of Medical Sciences, University of Toronto ABSTRACT Corticobasal Syndrome (CBS) is a rare movement and cognitive disorder. There is significant heterogeneity observed in it clinical presentation, neuroimaging, pathology and genetics. Understanding this heterogeneity is a priority and may help to shed light on underlying pathogenic mechanisms. We first demonstrated that truncating mutations in the progranulin gene (PGRN) can cause familial CBS associated with frontotemporal lobar degeneration (FTLD)- ubiquitin pathology. This study identified a mutation in PGRN (Intervening Sequence 7+1 guanine > adenine [IVS7+1G>A]) that segregated with CBS in a family. The mutation was predicted to result in a shortened messenger RNA (mRNA) sequence and the absence of the mutant PGRN allele was confirmed in the reverse transcriptase-polymerase chain reaction (RT- PCR) product, which supported the model of haploinsufficiency for PGRN-linked disease. In a second familial study, clinical, radiological, genetic, and pathological studies were performed to contrast clinical features of the affected members. Sequencing PGRN revealed a novel, heterozygous cytosine-adenine dinucleotide deletion in exon 11 (g.2988_2989delCA, P439_R440fsX6). The proband`s clinical diagnosis was frontotemporal dementia and parkinsonism (FTDP). The proband‟s brother with the same mutation presented initially as a progressive non-fluent aphasia (PNFA), and later evolved into a CBS. Pathological analysis ii revealed Frontotemporal Lobar Degeneration-Ubiquitin (FTLD-U)/ TAR DNA-binding protein 43 (TDP43) positive pathology. The next studies shift away from pathogenic mechanisms to focus on brain-behavioural correlations and phenotypic heterogeneity in a prospective sample of 31 CBS cases. We provide the first direct correlative analysis between the severity of ideomotor apraxia, a common sign in CBS, and cerebral SPECT perfusion imaging. Reductions in perfusion within the left inferior parietal lobule (t=5.7, p=0.03, Family-Wise Error [FWE] corrected), including the left angular gyrus (t=5.7, p=0.02, FWE corrected), were associated with more severe ideomotor apraxia. We stratified the sample into CBS presenting with early motor features (CBS-M; n=9) or early dementia (CBS-D; n=22), which identified that CBS-M were more likely to have cortical sensory loss than CBS-D (p=0.005). In contrast, the presence of aphasia was found to be more common and severe in CBS-D compared to CBS-M (p=0.02). CBS-M patients had significantly reduced perfusion in the right supplementary and premotor areas compared to CBS-D (p<0.05). iii ACKNOWLEDGEMENTS I would like to first and foremost thank my supervisor, Dr. Sandra Black, for her support and mentorship over the many years that I have known her. I first met Dr. Black (a.k.a. Sandy) back in 2001 when I began my residency program in psychiatry. I attended many of her cognitive neurology clinics as an intern and it was this initial exposure to the field of neurology and neurodegenerative disease that made me decide to transfer into the neurology residency program. The commitment and passion that she displayed towards treating patients and their families afflicted with these devastating diseases was truly an inspiration for me. She taught me that every patient has something unique to offer not only in terms of developing my clinical skills, but also importantly in terms of asking novel questions about the diseases and their heterogeneous presentations that could be assessed using the scientific method and valuable data gathered from clinical and neuroimaging studies. In 2004, I had an opportunity to do my fourth year project course in her lab, which further stimulated me to pursue a career in research and enroll in the Ph.D. program following completion of my residency. Needless to say, my experiences in her lab have been outstanding. As a result of this training, I have learned a new research method, applied neuroimaging, which I now can add to my repertoire of techniques to use in my clinical and genetic studies. Sandy‟s enthusiasm for research is incredible and her passion to understand and to investigate novel therapies to treat these devastating disorders has also stimulated me to pursue a career as a clinician-scientist. I would also like to thank Sandy for her support of my research ideas, which have led to several peer-reviewed funding projects during and beyond my training. Thank you Sandy for your ongoing support and I look forward to collaborating with you on many interesting projects to come! iv I would also like to thank Dr. James Kennedy (a.k.a. Jim) for his mentorship over many years and also for his contribution to and participation on my program advisory committee. Jim stimulated my initial interest in scientific research in the mid-1990s when I completed a M.Sc. in his laboratory. My thesis was on pharmacogenetics and I am pleased to say that I continue this very interesting line of research using the combination of my genetic, clinical and neuroimaging training. I would also like to thank Dr. Robert Chen for his commitment and contributions that he has made as a member of my program advisory committee. I appreciate the efforts of Dr. Antonio Strafella for reading my thesis under tight time lines and also for being present at my final program advisory committee meeting to participate as an additional examiner. I would like to thank my friends and colleagues: Dr. Brad MacIntosh, Dr. Kie Honjo, Dr. Galit Kleiner-Fisman, Dr. Ekaterina Rogaeva, Dr. Anthony E. Lang, Dr. Eric Roy, Isabelle Guimont, Philip Francis, and Gregory Szilagyi. Their technical and thought-stimulating advice and suggestions have helped to bring me to this point today. I would also like to thank Kayla Sherborn for her impeccable organizational skills in helping to assemble components of this thesis. I would like to thank my in-laws for their support over the last few years and also for their assistance in making home life more manageable. I would like to thank my parents for providing me with the opportunities to pursue higher level education and for providing the right environment for me to succeed. I greatly appreciate their continued support and inspiration and I v am indebted to them for their patience especially over the last few years during the preparation of this thesis. Last but not least, I would like to thank my beautiful wife, Paola Masellis, for her incredible patience and support that she has provided since the first day that I met her and over the course of the last few years during the completion of this thesis. We have been through a lot together, especially in recent years, and I am indebted to her kindness, love, and caring attitude. With the completion of this thesis, I look forward to many good times ahead and many more years of positive and happy life experiences together with her. Thanks for all that you do! vi TABLE OF CONTENTS TITLE PAGE i ABSTRACT ii ACKNOWLEDGEMENTS iv TABLE OF CONTENTS vii LIST OF TABLES xi LIST OF FIGURES xiii ABBREVIATIONS xvii CONTRIBUTIONS xxv 1.0: GENERAL INTRODUCTION 1 1.1 Corticobasal Degeneration: Historical