Congratulations Zach Winder, PhD

On April 22, 2022, Zach Winder sucessfully defended his dissertation and earned his doctoral degree.  

Evaluating the Relationship Between Plasma Biomarkers and Dementia using Hierarchical Clustering Analysis and Linear Modeling

Doctoral Committee

Donna Wilcock, PhD, Mentor
Gregory Jicha, MD
Ken Campbell, PhD
Ryan Temel, PhD
Erin Abner, PhD
Brian Golden, PhD, Outside Examiner

Abstract 

Dementia is a disorder characterized by a significant decline from baseline in one or more cognitive domains that interferes with independence. Prevalence of dementia worldwide is estimated at 50 million people, with that number expected to triple by 2030, coming with a cost of roughly $2 trillion. Clinically, dementia is diagnosed using cognitive evaluations, with varying domains affected and to different degrees depending on the underlying pathology and stage of disease. Alzheimer’s disease (AD) and vascular contributions to cognitive impairment and dementia (VCID) are the two leading causes of dementia, and both have pathologies which can be visualized using MRI. Additionally, protein quantification from cerebral spinal fluid (CSF) can be both diagnostic and prognostic for AD. However, the high costs of MRIs and the invasiveness of CSF draws limit their utility as screening tools for dementia. Therefore, we must look toward a more cost effective and less invasive screening tool, which leads us to plasma-based biomarkers. In this dissertation, I will discuss three experiments which examine the association between plasma-based biomarkers and dementia using hierarchical clustering analyses (HCA) and linear modeling.

In the first experiment, we compared two models of HCA to create plasma profiles of participants with mild cognitive impairment due to VCID. Both models identified a profile consisting of elevated VEGF-A, MMP1, MMP9, and IL-8, which suggests patients with this profile have an increased angiogenic and inflammatory state potentially coinciding with pathological progression. In the second experiment, we evaluated the association between plasma biomarkers and various dementia neuropathologies in an autopsy cohort of participants. In this study, we found that PlGF was positively associated with amyloid angiopathy, while IL-6 was inversely associated with more severe chronic vascular grade. Additionally, we found that VEGF-A was positively associated with Ab plaque score, while Ab 42/40 was inversely associated with more severe AD pathology. These results demonstrate that increased angiogenesis is positively associated with worsening AD neuropathology and should be further studied in a larger longitudinal cohort. Lastly, we evaluated the relationship between plasma biomarkers and cognitive impairment in a longitudinal cohort of participants and found that 6-years post-baseline GFAP and NfL were associated with a decline in verbal memory and verbal fluency, respectively. Interestingly, the anti-inflammatory cytokine, IL-10, was found to be positively associated with both verbal memory and verbal fluency at both 3- and 6-years post-baseline. These results suggest that higher levels of neurodegenerative biomarkers at baseline may be predictive of long-term cognitive decline, while higher levels of anti-inflammatory cytokines at baseline may prove beneficial in preventing middle- and long-term cognitive decline.

Overall, we have shown how angiogenic and inflammatory plasma biomarkers have the potential to be used as prognostic indicators of both pathology and cognitive impairment. Moving forward, these markers will need to be validated in larger more generalizable cohorts through multi-center trials. The goal for these markers will be to use them in the clinic to facilitate the diagnosis of dementia and help physicians make more informed predictions about the progression of the disease.

ACKNOWLEDGEMENTS

            First and foremost, I would like to thank all my teachers and mentors from kindergarten to graduate school, who have helped nurture my passion for learning. I simply do not know where I would be without each one of you. I would also like to thank several people who were instrumental in my graduate school success.

            Donna, beginning with our first conversation on my interview day for the MD/PhD program, you made me feel right at home. Every chat and meeting we’ve had since then has always lifted my spirits no matter the situation and kept me motivated to keep pursuing my goals. Thank you for introducing me to the study of biomarkers and providing me with incredible opportunities to meet with and present my research to other leaders in the field. I am incredibly lucky to have learned from you not only laboratory techniques but also how to work in a larger science team to conduct clinical trials. The experiences I have had under your training are without compare and I am forever thankful for your guidance in helping me down my path to becoming a physician-scientist.

            Tiffany, thank you for helping me stay organized and for running all the plasma assays I used in my analyses. Without your help, I would have never been able to complete any of my experiments. Finding someone like you to work with for the rest of my career will be next to impossible and I sincerely appreciate all the help you have given me throughout my time in the lab.

            Erica, I’m unbelievably happy you decided to come back to Lexington. I can safely say that all of us graduate students look up to you immensely. Your willingness to help us through any problem (which we know there were many) whether big or small makes you a great mentor to us and we all thank you for it. Thank you for sharing my love of bourbon and trying mellow corn with Charles and I (even though it didn’t live up to the hype), and for organizing lab game night despite me still never winning with Pete. You have been an instrumental part in making this graduate experience enjoyable and I cannot thank you enough for that.

            Courtney, Charles, and Alex, thank you all for being the best graduate student family I could ask for. Thanks for indulging all my inquiries, scientific and not, and for being there to bounce ideas off. There are far too many memories to list here but I am happy that we got to share them all together and I’m thankful that I was able to make such great friends during graduate school. I could not have asked for a better group of people to hang out with, and I hope that every graduate student finds a family like the one we have.

            To the rest of the Wilcock Lab, thank you for putting up with all my shenanigans and for continuing to provide a great working environment necessary to foster our scientific contributions.

            To the MD/PhD program, you have all been invaluable in the support you provide to me through our monthly meetings and annual retreat. Being able to learn from the experiences of others who are going down the same path has been extremely helpful for my success.

            Chelsey, thank you for being so supportive of me and my chosen career. Since I’ve met you, you’ve always been understanding of what I have to do to achieve my goals and you’ve not only encouraged me to continue to pursue them but also helped me stay organized and focus and pushed me to be the best person that I can possibly be. I love you more than you know, and I can’t wait to see what our future has in store.

            Sami, Syd, Mom, and Dad, I love you all so much. Words cannot explain how much you all mean to me. You always saw the potential that I had and never stopped believing in what I could accomplish. You are my rocks and are always there to support me through tough times and celebrate with me in my successes. Everything that I achieve, I attribute to all of you.