On Friday, July 22, 2022 Charles Seaks successfully defended his dissertation and earned his doctoral degree. Congratulations, Dr. Seaks!
An investigation of HHV6's impact on the cognitive progression and microglial changes in an Alzheimer's disease cohort
Abstract
The role of herpesviruses and, more specifically, HHV6 in the development of Alzheimer’s disease (AD) and associated cognitive decline is still being investigated. High ubiquity and prevalence in the population have led to a high degree of skepticism about HHV6 as a potential contributor to cognitive decline and dementias. However, recent evidence related to another herpesvirus, herpes simplex virus 1, suggests that reactivation, not carriage, of the virus may be the key factor to explain the dissonance between the virus’ ubiquity and contributions to dementias. With that in mind, we set out to assess cases from the Sanders-Brown Center on Aging for evidence of HHV6 reactivation, both current and past, and how it relates to the rate of cognitive decline of these patients in eight cognitive domains. HHV6 reactivation was assessed by 1) patient self-report surveys, 2) anti-HHV6 serology, and 3) viral gene amplification via droplet digital PCR (ddCPR) in post-mortem temporal lobe and cerebellum tissue. We extracted RNA from these regions of postmortem tissue and performed the NanoString Human Inflammatory Panel to assess gene expression changes concomitant with HHV6 carriage and reactivation. Based on these results, we more closely examined changes to microglial activation and functional capacity based on the presence of HHV6. Finally, we investigated the role T-cells played in the development of these changes and subsequent pathology. Ultimately, we observed some predictive power from the patient reported survey in terms of cognitive decline. Serological evidence of reactivation showed no statistically significant relationship in any of the cognitive domains. ddPCR revealed no significant correlations related to HHV6 carriage. NanoString gene expression assays showed an upregulation of several neuroinflammatory genes, as well as microglial markers and T-cell signaling cytokines in cases with HHV6. We observed few differences in microglial activation, morphology, or phagocytosis as a function of HHV6. We did observe evidence of HHV6 within some amyloid beta plaques examined, and several T-cells surrounding plaques throughout diseased tissue with confirmed HHV6. These results contribute to the ongoing debate surrounding the role of HHV6 in the development of Alzheimer’s disease while providing evidence that suggests that reactivation may not be a key factor connecting HHV6 to Alzheimer’s disease.
Acknowledgements
Dissertations are, incorrectly, considered the culmination of an individual’s efforts during their doctoral training. They are the result of countless meetings, trainings, conversations, presentations, critiques, challenges, triumphs, defeats, and discussions that necessarily involve the role of others beyond the trainee. The work herein could not have been achieved or even approximated without the myriad of individuals supporting me. To save time, I will state once here: I could not have made it to this point without the help of each and every person mentioned here. First and foremost, to Donna: your patience, support, mentorship, and guidance have been at the core of everything I have achieved during the past 5 years. From the day I walked into your office with this crazy half-baked idea, you have supported me to pursue what I was interested in, even when it fell outside your expertise. I thank you (and preemptively apologize) for years’ worth of questions you are going to get about this work on my behalf. I cannot fathom the pain in the rear I have been to train, but I will never not be grateful for all you have done for me. Thank you for pushing me and driving me to get things done, even when I was scuffling and struggling. I appreciate all of your efforts to help me network, connect and figure out what I want to do when I grow up. I truly do not believe I would have made it to the end of this journey if I had had anyone else as my mentor, and I am eternally grateful for that. To Tiffany, thank you for everything you do every day, every week, every month for each of us in this lab. I think every trainee before and after me would agree that it really isn’t possible to get close to thanking you sufficiently for all you do for us. It would be easy for you to put your head down and focus on the immense amount you have to do and ignore us. But you don’t. You make time for us when we have questions or desperately need to come up with a plan. Thank you for taking so much of the extra bureaucratic nonsense off our plates and letting us focus on our research and work. Thank you for your understanding and patience with me. I know I have not made your life easy by any means, but I appreciate all you have done for me. Thank you for everything you have taught me and helped me with. To Erica, I really have no idea what these past 5 years would have been like if you hadn’t come back from Canada, but I am beyond grateful that you did. Thank you so much for your guidance over the years. Thank you so much for being available to vent to and feeling comfortable enough to vent to me. Thank you for game nights and lab activities that made us all closer. Thank you for reading my half-baked attempts at writing and helping make them presentable. I know each trainee takes a portion of your time, but we all are incredibly grateful for your advice and guidance. You are an excellent scientist and an even better mentor and teacher. Thank you for serving as an example for all of us. To Zach, if it wasn’t for the presence of each other, who knows how quickly we could have finished our degrees. That said, I wouldn’t want it any other way. I will never forget our St. Patrick’s Day 2AM discussions of everything wrong with our projects and how we can totally fix them. I would say I’ll never forget the various rabbit holes we found ourselves in, but there were a lot of them, so the details are getting fuzzy already. Thank you for being a constant help whenever I needed it, particularly statistically. Thank you for being a sounding board for my various ideas and interpretations of different studies. Thank you for being as consistently skeptical of every scientific finding we’ve come across. I look forward to seeing everything you are going to achieve. To Courtney, if it wasn’t for your presence, I don’t know if Zach and I would have qualified yet. I can’t begin to thank you enough for your help and support through the past 5 years. We have been through so much together; I can’t begin to describe it here. I hope one day you find it in your heart to forgive hot tea and buy a dresser that Dobby can’t easily hide in. Thank you for informing me when I was being an idiot and needed to reassess whatever it was I was trying to do. Thank you for being there at conferences to help my socially-awkward-self network. Thank you for continually driving me to be better. You have always had a clear vision of what you wanted and what you had to do to get there. These are things I have clearly struggled with and you have pushed me to figure aspects of myself out in order to get to that point. So thank you for everything you have done for and continue to do for me. To Alex, had I not met Taylor Valentino in my IBS class, I would have thought a person as effortlessly positive and supportive as you did not exist. I truly cannot fathom having the capacity for genuine compassion and support at any given moment that you do. And I really don’t think I could have kept going some days without that support in my corner. I know the circumstances leading you to our lab were painful and difficult, but, selfishly, I am glad that you ended up here. Thank you for always being there when I’ve had a terrible day or need to vent about something. Thank you for keeping me on task when I have needed it. Thank you for being here and being yourself. Kate, in the short time you’ve been here, you’ve been so helpful in listening to ideas, running code, and encouraging me to do more than I think I am capable of. You are an infectiously good person and science as a whole needs people like you. Thank you for letting me help in any small ways that I have. Thank you for keeping the sense of camaraderie and community alive in the lab as others have left and faces have changed. Thank you for coming to our lab and making us all better for it. Katelynn, thank you for finally taking the title of the youngest full-time person in the lab from me. I’ve been needing an excuse to talk about how old I am and now I have one. Helping you learn techniques, think about your project, and different opportunities and things to pursue has led to the first and only time I’ve considered mentoring as part of my career moving forward. You are going to be an exceptional graduate student and I am proud that I have been able to contribute in my own small way. Thank you for immediately being a seamless fit in the lab and adapting to our own unique brands of idiocy. You are going to be here during years of considerable change, I’m sure, and I look forward to seeing all you are going to accomplish and achieve. Colleen, I can’t thank you enough for being there for Beth and me through some of the more difficult times over the past few years. Thank you for always being available to listen. Thank you for everything. You are going to be an amazing professor down in Alabama and I could not be prouder to call you my friend. Lyndsay, I haven’t met a person as driven and hardworking as you in a long time. You have always been someone I strive to get even close to in terms of all that you have achieved. Thank you for welcoming me like family to Kentucky from our first semester here on. Thank you for putting up with Beth’s weird habit of yelling at you for no reason. I will miss tailgates, Keeneland, Christmas parties, trivia, and everything else we’ve done together. Josh, thank you for subsidizing my housing for the past 4 years. Honestly though, if someone had told me during our interview that in a matter of months that the guy with the corduroy jacket with elbow patches was going to be my best friend and I was going to be in his wedding, I probably would have called them crazy. But that’s what happened, and I couldn’t be happier because of it. Thank you for being there to let me avoid whatever recent disaster was plaguing me. Thank you for never saying no anytime I have asked for a favor in or outside of work. Thank you for letting me be a part of your family. Asher and Piper are beyond lucky to have you as a dad. I hope I can continue to corrupt and see them grow up. Emily, thank you for telling me when I’m being an idiot. Thank you for trusting me with your kids and letting me be a part of your family. Thank you for being there through the tough times as well as the good. You all are family. Zach (Williamson), thank you for looking out for me when I sure as hell wasn’t looking out for myself. You have welcomed me from day one of my summer rotations and you’ve been there ever since. Thank you for the game nights that have kept me sane. Thank you for including me on the social committee that was such a source of fun and community for so many of us. Thank you for staying on to make this place and the IBS program a better place for everyone involved. Mom, Dad, and Christina: It’s been a wild 5 years for all of us. I love all of you and wish the best for each of you. I know it’s been difficult to understand what or why I was doing certain things during these last five years. And I know it’s even harder to support me regardless of whether or not you fully get it yourselves. So, I thank you for supporting me and my decisions through the hard times and the slightly less hard times. Beth: I can’t really describe how important you are to me. Thank you for punching me during my interview and being stubborn enough to get it through my thick skull that you might be interested. Thank you for telling me when I’m being ridiculous or more neurotic than normal. Thank you for keeping me on task when I need it. Thank you for putting up with all we’ve been through and continue to go through. Thank you for the little family that we have built together. I can’t wait for what the future holds for us. I love you so much and will always be grateful for all you have done and continue to do for me. I am sure there are others I have forgotten here but thank you everyone who has helped me on this journey in any capacity. The past 5 years have been a wild ride and I am looking forward to what the future holds for myself and all of us. So, one last time: thank you