Georgia State University ScholarWorks @ Georgia State University Neuroscience Institute Dissertations Neuroscience Institute 8-7-2018 Prodromal Variability in Huntington's Disease Progression and Resistance Jennifer Ciarochi Follow this and additional works at: https://scholarworks.gsu.edu/neurosci_diss Recommended Citation Ciarochi, Jennifer, "Prodromal Variability in Huntington's Disease Progression and Resistance." Dissertation, Georgia State University, 2018. https://scholarworks.gsu.edu/neurosci_diss/39 This Dissertation is brought to you for free and open access by the Neuroscience Institute at ScholarWorks @ Georgia State University. It has been accepted for inclusion in Neuroscience Institute Dissertations by an authorized administrator of ScholarWorks @ Georgia State University. For more information, please contact [email protected]. PRODROMAL VARIABILITY IN HUNTINGTON’S DISEASE PROGRESSION AND RESISTANCE by JENNIFER CIAROCHI Under the Direction of Jessica Turner, Ph.D. ABSTRACT Huntington’s disease (HD) is a neurodegenerative movement disorder caused by abnormal cytosine-adenine-guanine (CAG) expansion on the HTT gene. As both a proteinopathy and the most common PolyQ disease, HD shares key features with several disorders that disproportionately affect the growing elderly population in the United States, including delayed- onset, selective neuronal death, and protein misfolding. Across these conditions, there are few treatments and no known cures; however, their shared features suggest common underlying mechanisms, and delayed-onset hints at possible prevention or reversal. CAG-expansion-number and age are related to diagnosis and can be used to estimate age-of-onset for prodromal (pre- diagnosis) individuals, who possess the causal mutation but have not manifested diagnosis- associated motor symptoms. Over a decade before diagnosis, prodromal individuals differ from controls in brain structure and connectivity, cognition, and motor functioning. Although age and CAG-number account for most observed variability in HD-onset, persons with identical CAG- numbers often develop symptoms at different ages, indicating that additional genetic and environmental factors also mediate decline. Little is known about detrimental and protective genetic factors in HD. Studying prodromal progression can inform interventions by highlighting early prevention targets. This research leverages advanced multivariate techniques applied to legacy PREDICT- HD data to characterize brain structure, cognition, and motor functioning across prodromal HD and investigate genetic factors accounting for variability in these domains. Regarding brain structure, these experiments provide evidence for: regional co-occurrence in prodromal decline, early fronto-striatal degradation, dorso-ventral reduction gradients, and delayed atrophy in certain movement-related and subcortical regions. The genetic findings suggest a protective role of NTRK2 and identify NCOR1 and ADORA2B variants with early, CAG-independent detrimental effects on gray matter. Previously identified onset-delaying variants are also confirmed as CAG-independent modulators of brain structure and clinical functioning. Clinical findings highlight motor functioning as the best indicator of brain-structural integrity until the late prodrome and demonstrate that distinct regions coincide with cognitive compared to motor functioning; furthermore, regions that most align with clinical functioning vary at different prodromal stages. INDEX WORDS: Huntington’s disease, Genetic modifiers, Multivariate methods, Prodromal symptoms, Disease progression, Brain-derived neurotrophic factor, Tropomyosin receptor kinase B, Supplementary motor, Independent component analysis PRODROMAL VARIABILITY IN HUNTINGTON’S DISEASE PROGRESSION AND RESISTANCE by JENNIFER CIAROCHI A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the College of Arts and Sciences Georgia State University 2018 Copyright by Jennifer Ashley Ciarochi 2018 PRODROMAL VARIABILITY IN HUNTINGTON’S DISEASE PROGRESSION AND RESISTANCE by JENNIFER CIAROCHI Committee Chair: Jessica Turner Committee: Jingyu Liu Daniel Cox Mukesh Dhamala Electronic Version Approved: Office of Graduate Studies College of Arts and Sciences Georgia State University August 2018 iv DEDICATION To the 1,449 people who generously participated in the PREDICT-HD study, in many cases over several years and with no obvious direct benefit to themselves. Their committed involvement has and will continue to enable great advancements in our understanding of Huntington’s Disease, providing hope for a cure for future generations. v ACKNOWLEDGEMENTS Several entities contributed to the success of this project; notably, my committee members (Drs. Jessica Turner, Jingyu Liu, Daniel Cox, and Mukesh Dhamala) have been exceedingly patient with my procrastination, spotty scheduling capabilities, and verbose writing style (as evidenced by this absurdly long dissertation), and I am grateful for their guidance over the years. Dr. Turner has been a wonderful advisor, donating her time whenever it is needed (despite her obscenely busy schedule) and readily demonstrating patience and level-headedness in a field that is often anything but. She is more organized than I could ever hope to be, and none of this would have been possible without her. Dr. Liu has patiently worked with me over the years, on a weekly basis, to nurture my understanding of imaging, genetics, and ICA-based techniques and has several times greatly assisted in interpreting the results of these experiments. Dr. Cox has been steadfastly supportive of my often overly-ambitious research agenda, and has enabled me to take this research a step further by addressing my questions in the context of a wet-lab environment; despite my inexperience, I have learned so much from him about studying disease in Drosophila. Dr. Dhamala has supported my professional development in the classroom, on my qualifying exam committee, and again during my dissertation proposal and defense, and has never once complained. Again, I cannot thank my committee enough for their time and support. This work would also not be possible without my co-authors and the PREDICT-HD researchers and contributors from across the globe who diligently worked to amass such a comprehensive dataset from a rare clinical population. Of particular note are Jane S. Paulsen, the PREDICT-HD principal investigator who generously shared her expertise and data at all levels of this project; Hans Johnson, who provided guidance and R code that I would not have had a vi snowball’s chance in hell of generating myself on this timeline; and Vince Calhoun, who first made ICA approachable and may respond to e-mails faster than any other human on the planet. I would also like to thank my parents (both biological and otherwise), not only for my literal existence but for nurturing my interests, never saying no when I asked for a book, and always encouraging me to be my best rather than the best, even when that meant I never did my homework. My brother Nick also deserves mentioning; he has always been there to remind me that I am, indeed, not the best. Aside from those who encouraged me to succeed, I owe my gratitude to those who helped me relax; these include the writers of several trashy Netflix shows that will not be named here (and the people who dubbed them in Spanish), NPR’s written news for providing a slightly less depressing alternative to their radio news (and for overusing the word “imbroglio” when discussing Russia), the man who must have donated hours of his time pronouncing words for Dictionary.com (I’m looking at you, “imbroglio”), that one old man who seems to narrate every free audio book (from Aesop’s Fables to Plato’s Republic), GrubHub delivery drivers, Beyoncé (obviously), pizza (obviously), and the White House (for providing a steady stream of drama during lulls in available Netflix material). Last, but certainly not least, I would like to thank my significant other (Aaron) for his unwavering support and at least six months of groceries, as well as his geriatric dog (Dakota), who is smacking me as I write this. vii TABLE OF CONTENTS ACKNOWLEDGEMENTS ............................................................................................ V LIST OF TABLES ....................................................................................................... XVI LIST OF FIGURES .................................................................................................. XVIII LIST OF ABBREVIATIONS ....................................................................................... XX 1 INTRODUCTION ...................................................................................................... 1 1.1 Background .......................................................................................................... 1 1.2 Prodromal Brain Structure and Clinical Functioning..................................... 3 1.3 Genetic Modifiers of Prodromal Symptoms ..................................................... 5 1.4 Purpose of the Study ........................................................................................... 7 1.4.1 Experiment 1 ................................................................................................... 7 1.4.2 Experiment 2 ................................................................................................... 8 1.4.3 Experiment 3 ..................................................................................................