Investigating the Effect of Mild Cognitive Impairment on Brain Activity during completion of the Clock-Drawing Test by Natasha Arti Talwar A thesis submitted in conformity with the requirements for the degree of Master of Science Institute of Medical Science University of Toronto © Copyright by Natasha Arti Talwar 2019 Investigating the Effect of Mild Cognitive Impairment on Brain Activity during completion of the Clock-Drawing Test Natasha Arti Talwar Master of Science Institute of Medical Science University of Toronto 2019 Abstract There is a lack of quick cognitive assessments for general practitioners to use to screen for MCI, resulting in missed diagnoses. The CDT is essential in assessment of dementia, therefore has potential as a screening tool for MCI. Studies have identified MCI-related behavioural impairment on the CDT, however there is less knowledge regarding the effect of MCI on CDT- related brain activity. This study combined fMRI and an fMRI-compatible tablet to measure brain activity during a naturalistic version of the CDT in an MCI and control cohort. Although patients with MCI performed worse on the CDT, the test did not have adequate sensitivity and specificity to MCI. Patients with MCI exhibited less extensive CDT-related activity in the frontal and parietal lobes relative to controls. Both areas have important cognitive functions for CDT completion, suggesting that reduced activity in these regions may cause the behavioural impairment observed in patients with MCI. ii Acknowledgments First, I would like to thank my supervisor, Dr. Tom Schweizer for his support and guidance throughout my experience in his lab. He has provided me with valuable advice and knowledge, which has helped me grow to become a better aspiring scientist. I am truly grateful for the amazing opportunity to be his graduate student. I would also like to extend my gratitude to the other members of my PAC for their help and encouragement. Thank you to Dr. Corinne Fischer for taking time out of her busy schedule as a clinician to provide valuable feedback as a committee member, as well for her instrumental role in patient recruitment. Thank you to Dr. Simon Graham for offering his expertise and advise throughout multiple new versions of analyses and paper drafts. I would also like to thank both Dr. Graham and Fred Tam as well as the lab at Sunnybrook Research Institute for their construction of the fMRI-compatible tablet, which played a vital role in my thesis project. Thank you to the entire Schweizer Lab, both past and present, for their constant support and endless laughs, which have made this experience truly unforgettable. I would like to give a special thanks to Dr. Nathan Churchill teaching me how to use PRONTO/OPPNI and about the intricacies of fMRI analysis. He was always patient and willing to answer my questions, making him both a great teacher and mentor. A huge thank you to Megan Hird who was essential in development of the project and continued to give me guidance and advice even after leaving to attend medical school. Thank you to Iryna Pshonyak for being more than just a co-worker, but a friend. Completion of my thesis would not have been possible without her help with the project and destress sessions chatting about TV shows, food or life in general. My gratitude to everyone else who has helped with running scans, in particular Tahira Tasneem and Breanna Jessop. I would also like to thank Anthony Sheen and Cindy Hamid, the research technologists at SMH for their help, patience and fun conversations while running the MRI. Finally, and most importantly, I would like to thank my family and friends who have given me endless love and support. Thank you for your patience when I am stressed out and emotional. Thank you for believing in me and giving me the strength to continue to pursue my passions. I would not have made it this far without you. In particular, thank you to my sisters and my parents. Since the day we were born, my parents have given us every opportunity possible to help us achieve our dreams. I share this degree and every other accomplishment with them. iii Contributions Dr. Tom Schweizer (1) provided the funding for the current study, (2) supervised the development of the study protocol, participant recruitment, participant testing, data analysis and interpretation, (3) provided detailed feedback and revisions of the thesis throughout the writing process, (4) provided guidance on my academic progress. Dr. Corinne Fischer referred all of the patients with MCI included in the current investigation from the Memory Disorders Clinic at SMH, helped with development of the protocol, and provided detailed revisions of the thesis. Dr. Simon Graham helped develop the fMRI- compatible tablet, assisted with development of the study protocol and provided detailed revisions of the thesis. Megan Hird was essential in the development and initiation of this project. She was thoroughly involved in applying for funding, creating the tablet tasks and early stages of recruitment and participant testing. She trained me on the study protocol and how to extract and analyze the data. Dr. Nathan Churchill taught me how to use the PRONTO/OPPNI software, which I used to analyze the fMRI data. He helped develop an analysis plan, supervised my analysis, addressed any issues I encountered, assisted with interpretations of the results and provided detailed revisions of the thesis. Iryna Pshonyak was involved in participant testing throughout the duration of the current study. Co-op students in the lab, including Tahira Tasneem, Breanna Jessop, Eden Shaul and Maryam Yossofzai, also helped with participant recruitment, participant testing and double scoring of the CDT. This work was supported by an Alzheimer’s Association Research Grant from the Alzheimer’s Association awarded to Dr. Tom Schweizer. iv Table of Contents Abstract ........................................................................................................................................... ii Acknowledgments.......................................................................................................................... iii Contributions.................................................................................................................................. iv Table of Contents .............................................................................................................................v List of Tables ................................................................................................................................. ix List of Figures ..................................................................................................................................x List of Appendices ......................................................................................................................... xi List of Abbreviations .................................................................................................................... xii Chapter 1 Introduction ..............................................................................................................1 1.1 Overview ..............................................................................................................................1 1.2 Background ..........................................................................................................................3 1.2.1 Age-Related Effects on Cognition ...........................................................................3 1.2.2 Alzheimer’s Disease (AD) .......................................................................................3 1.2.3 Mild Cognitive Impairment (MCI) ..........................................................................4 1.2.4 Importance of Detecting MCI ..................................................................................7 1.2.5 Limitations of Testing for MCI................................................................................8 1.2.6 Current Cognitive Assessments for MCI .................................................................9 1.3 The Clock-Drawing Test (CDT) ........................................................................................12 1.3.1 History and Use of the CDT ..................................................................................12 1.3.2 Administration of the CDT ....................................................................................13 1.3.3 Scoring Systems and Common Errors on the CDT ...............................................13 1.3.4 CDT and Dementia ................................................................................................14 1.3.5 CDT in the context of MCI ....................................................................................15 1.4 Neuroimaging of AD and MCI ..........................................................................................17 1.4.1 fMRI and Blood Oxygen Level Dependent (BOLD) Signal .................................19 v 1.4.2 Strengths and Limitations of fMRI Compared to Other Neuroimaging Modalities ..............................................................................................................20 1.4.3 Studying Neural Correlates of Cognitive Tasks ....................................................22 1.4.4 Neuroimaging of the CDT .....................................................................................24 1.5 Knowledge Gaps ................................................................................................................27