Benjamin Lam
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The Alzheimer’s Spectrum: Diagnostic Challenges and Nosology in a Clinically Heterogeneous Disease by Benjamin Lam A thesis submitted in conformity with the requirements for the degree of Master of Science Institute of Medical Science University of Toronto © Copyright by Benjamin Lam (2017) The Alzheimer’s Spectrum: Diagnostic Challenges and Nosology in a Clinically Heterogeneous Disease Benjamin Lam Master of Science Institute of Medical Science University of Toronto 2017 Abstract Hypothesis: Alzheimer’s disease (AD) is not a unitary condition but a phenotype spectrum. Rationale: Mounting evidence suggests AD is more complex than previously thought. A new AD conceptualization accounting for this biologic and clinical complexity is needed. Aim: To review existing evidence for, provide a specific example of, and investigate the nosological impact of AD heterogeneity. Methods: Three studies were done using (1) literature review, (2) imaging analysis case series, and (3) systematic chart review. Results: AD is heterogeneous and sub-syndromes exist. Extreme heterogeneity results in syndrome mimicry with blending of imaging markers. Wide variation in diagnostic classification occurs even with standardized application of consensus criteria. Conclusions: AD is not a single disease but a spectrum of sub-syndromes (core phenotype and atypical sub-syndromes). The AD conceptual framework must evolve to acknowledge, define, and anticipate this complexity, harnessing it to improve diagnostic precision and facilitate treatment discovery. ii Acknowledgements I am greatly indebted to the many individuals and organizations that have supported me throughout this endeavour and made this collaborative work possible. First are my friends and colleagues at the L.C. Campbell Cognitive Neurology Research Unit, which has been my second family for the past eight years. They and our predecessors gathered the data and conducted much of the preliminary analysis that generated the data for the Sunnybrook Dementia Study upon which this thesis is based. In particular I would like to thank my co-fellows, including Drs. Alexandra Kim, Kie Honjo, Yannick Nadeau, and Laura Middleton, who were ever ready sounding boards for ideas, no matter how eccentric. As a clinician, I would be lost without the guidance of the L.C. Campbell imaging team, including Dr. Joel Ramirez, Christopher Scott, Gregory Szilagyi, Melissa Holmes, and Alicia McNeeley, who helped me better understand the finer details of image acquisition and processing, and gain a better appreciation and respect for the imaging data that makes up much of this dissertation. Second are my clinical colleagues in the Division of Neurology, who have been role- models, shaping my growth both as an aspiring researcher and physician. They have provided constant encouragement, and made possible that often seemingly impossible task of balancing the tasks of a doctor and being a graduate student. They taught me that each enables and strengthens, rather than occurs at the expense of the other, and that dedicating, as always, is the key ingredient. I am in particular indebted to Dr. Mario Masellis, who has been an unfailing mentor and friend, who provided immeasurable guidance throughout my thesis preparation. iii Third are the patients, study participants, and their care partners who made all this research possible. They are possessed of great, and often seemingly supernal resilience and humanity, and they have reminded me how important it was that we never stop seeking better answers, better understanding, and better treatments for this scourge of our day. Their strength in the face of Alzheimer’s also put in perspective the travails of academic toil. Compared to what they did as a matter of course, what were a few sleepless nights spent studying and researching? Fourth are the donors and funding agencies, without whose generosity none of this would be possible. I would like to sincerely thank the Slaight Family Foundation, the L.C. Campbell Foundation, the Canadian Partnership for Stroke Recovery, the Brill Chair in Neurology, the CIHR Training Program in Neurodegenerative Lipidomics, Roy and Joan Hinsta, and Nancy and Sigmund Levy. Fifth are the journal editors and reviewers of the papers comprising this thesis. Not only did they take the time to hold a harsh but fair light to these manuscripts, but had the faith to trust and support our findings. Sixth are my parents Jane and Kin Lam, who never stopped believing in what often seemed like an interminable and insurmountable challenge. Their love has been unfailing, and their support has been unwavering. Although never researchers themselves, they imparted in me that love of learning – that filo sophia – which is so fundamental to the scientific endeavour. I am, always, in their debt for all things. iv Last and most certainly not least, is my supervisor and mentor, Dr. Sandra E. Black, and the members of my Program Advisory Committee, Drs. Morris Freedman and Donald T. Stuss, whose ceaseless mentorship and truly inexhaustible patience are beyond what words can describe. If I am now an acceptable researcher, it is because of their herculean efforts and friendship. The trust and confidence they have shown in me, have at times been nothing less than a leap of faith. If I can follow in their footsteps, and join them in the great working of knowledge that is clinical research, I can think of no higher honour. I dedicate this thesis to my parents, Dr. Sandra E. Black, Dr. Morris Freedman, and Dr. Donald T. Stuss. v Contributions Please refer to the contributions section within each chapter for a detailing of specific contributions by co-authors. In all cases, the funding agencies had no involvement in the design, analysis , or conduct of the research. vi The Alzheimer’s spectrum: Diagnostic challenges and nosology in a clinically heterogeneous disease Contents Abstract ............................................................................................................................................ii Acknowledgements ......................................................................................................................... iii Contributions .................................................................................................................................. vi List of Tables: .................................................................................................................................. xi List of Figures: ................................................................................................................................ xii List of Abbreviations ..................................................................................................................... xiii Foreword ........................................................................................................................................ xv 1. Introduction & Literature Review ............................................................................................... 1 1.1. Origins of the AD Paradigm and the Classical View of Alzheimer’s and Dementia ............. 2 1.2. Core Features of Prototypic AD............................................................................................ 4 1.2.1. Age of Onset .................................................................................................................. 4 1.2.2. Course ............................................................................................................................ 4 1.2.3. Cognition ........................................................................................................................ 5 1.2.4. Behaviour ....................................................................................................................... 6 1.2.5. Function ......................................................................................................................... 7 1.2.6. Imaging .......................................................................................................................... 7 1.2.7. Co-morbidities ............................................................................................................... 8 1.2.8. Pathology and Biology ................................................................................................... 9 1.2.9. Summary: Prototypic AD ............................................................................................. 10 1.3. A Cautionary Case: The Story of Auguste Deter ................................................................ 11 1.4. The AD Syndrome Paradigm Evolves ................................................................................. 14 1.4.1. Evolution of Age of Onset ............................................................................................ 15 1.4.2. Evolution of Course ..................................................................................................... 16 1.4.3. Evolution of Cognition ................................................................................................. 16 vii 1.4.4. Evolution of Behaviour ................................................................................................ 16 1.4.5. Evolution of Function .................................................................................................. 18 1.4.6. Evolution of Imaging .................................................................................................... 19 1.4.7. Evolution