Journey With Parkinson’s: (Part 2) A Different Side of Life

“Yesterday is but today’s memory, and tomorrow is today’s dream.” Khalil Gibran

“Time is free, but it’s priceless. You can’t own it, but you can use it. You can’t keep it, but you can spend it. Once you’ve lost it you can never get it back.” Harvey Mackay

Introduction: I am a scientist, trained as a protein chemist with expertise in food biochemistry. Following my Ph.D., I became a biological chemist where I have been on the faculty at The University of North Carolina at Chapel Hill School of Medicine since the late 1980s. My laboratory studied the process of how blood clots and there were typically ~10 people working in the lab group [usually students (undergraduate, graduate and medical), postdoctoral fellows, technicians, and visiting scholars]. I am also an educator and have spent more than 30 years teaching medical students on topics like hematology and immunology and undergraduates about blood diseases. Lastly, I have Parkinson’s disease. My remaining life’s mission is to help anyone better understand this disorder, help everyone improve their quality of life, and commit to being a translator of science and medicine where clarity is needed. This is why the blog exists.

“This time, like all times, is a very good one, if we but know what to do with it.” Ralph Waldo Emerson

COVID-19 Pandemic and Trying to Explain the Gap in Time: We have all been living surrounded by the hovering shadow of the new coronavirus named SARS-Cov-2 (aka, COVID-19). Likely, life has been complicated and challenging. My blog posting absence has neither been due to lack of focus nor due to my Parkinson’s; I needed extra time writing and publishing papers. I am amazed at all the people who can work and continue their blog at the same time. The first part of this blog series was entitled “Another Side of Life”, and it focused on writing this blog and it described my teaching, and other writing activities. Part 2 is here and entitled “A Different Side of Life”, and it describes my research and publishing papers.

“The strongest of all warriors are these two — Time and Patience.” Leo Tolstoy

Manuscripts, Publications, and Review Articles- A banner of excellence in any field of academics is the quality and yes, the quantity, of your publications [an untold story yet for the readers of the blog is my ‘phased-retirement’ plan, which will be the subject of a future blog post]. This year, something took over my mind because I thought it was essential to get some papers published in peer-reviewed journals. Having these papers published re-established me to some extent, and it refocused me in my new field of Parkinson’s scholarship. These papers brought me full-circle from receiving my diagnosis, accepting my disorder, and being able to live fully in the presence of Parkinson’s.

For much of this year, I have been organizing, writing, submitting, and publishing manuscripts (research and reviews) on different aspects of both Parkinson’s disease and educational processes for work. Even after 34 years of a career in academic medicine, I can still mentor students (undergraduate, graduate, and medical) by helping them get training in writing and publishing articles. The focus of this current blog post will highlight our recent published work from 2020.

Reuland, Carolyn J., and Frank C. Church. “Synergy between plasminogen activator inhibitor-1, α-synuclein, and neuroinflammation in Parkinson’s disease.” Medical Hypotheses 138 (2020): 109602. Open access and free download: https://www.sciencedirect.com/science/article/pii/S0306987719313751

The first Parkinson’s paper from my laboratory by the last undergraduate student in my lab group, CJ Reuland. This was CJ’s senior thesis, and she is now a 2nd year medical student at Johns Hopkins University. It is truly exciting for me to share and describe this work, as it represents our first peer-reviewed science paper dealing with Parkinson’s.

We started by studying a protein very well known to the lab group, plasminogen activator inhibitor-1 (PAI-1). PAI-1 is a potent protease inhibitor that regulates tissue plasminogen activator and urokinase, two very important proteases with several diverse physiological/pathological roles. We have published many papers on PAI-1, here is a link to a review article (https://www.sciencedirect.com/science/article/pii/S0049384809005647) . Typically, when something like inflammation happens, PAI-1 levels increase and potential badness follows. The hypothesis we began testing was would an increase in neuroinflammation lead to an increase in PAI-1 levels, which would result in accumulation of α-synuclein (α-syn) would then contribute to dopamineric neuronal cell death and to the development of Parkinson’s.

This is what we studied. In Parkinson’s, (a) neuroinflammation results both in increased PAI-1 levels and decreased plasmin cleavage of α-syn, to promote α-syn aggregation. (2) This activates microglia and astrocytes, which leads to further neuroinflammation and increased PAI-1 production. (3) The increased level of PAI-1 is sustained by an amplification loop between α-syn aggregation and neuroinflammation. Therefore, we hypothesize the existence of a self-sustaining pathologic loop in Parkinson’s between PAI-1, α-syn, and neuroinflammation.

We began this study using a mouse model of Parkinson’s utilizing immunohistochemistry (a technique where you add antibodies to recognize antigens in tissues slices). At this stage in my career/lab group, we ultimately decided to pursue this work more as a literary hypothesis and not as a laboratory study. We searched the literature for plasminogen activation inhibitor-1 (PAI-1) linked to alpha-synuclein expression and neuroinflammation in Parkinson’s. The drawing below describes the paper; however, for the details on the putative role for PAI-1 in Parkinson’s, please read the paper.

Hribar, Casey A., Peter H. Cobbold, and Frank C. Church. “Potential Role of Vitamin D in the Elderly to Resist COVID-19 and to Slow Progression of Parkinson’s Disease.” Brain Sciences 10.5 (2020): 284. Open access and free download: https://www.mdpi.com/2076-3425/10/5/284

My friend Peter Cobbold and I had been exchanging thoughts about CAM therapy for treating Parkinson’s, with some great dialogue about vitamin D. After thinking more on the topic, I recruited Casey, currently a 3rd-year medical student at UNC-CH, and we collectively wrote the above-cited paper. Maybe it was the novelty of combining Parkinson’s with COVID-19, perhaps it was the importance of the pandemic and advancing any treatment strategy, and perhaps we just crafted a well-written and well-defended paper. Whatever the reason(s), this paper has been viewed by thousands of people. The article has even been written about and compared to other COVID-19 and vitamin D papers; see this review: https://covid.us.org/2020/06/10/vitamin-d-versus-covid-19-part-three-expert-opinion/ (notable because we only recommend taking the usual normal daily supplement amount of vitamin D3).

We researched in our paper if vitamin D deficiency in older adults, especially those with Parkinson’s, contributes to an increased susceptibility to COVID-19. Additionally, we studied if vitamin D supplementation could offer some protection from COVID-19 while helping to slow the progression of Parkinson’s and improve quality of life. Bottom-line, we made some recommendations based on the literature, and if you are an older adult and you have Parkinson’s, you are potentially in a high-risk group for COVID-19; thus, taking a small amount of vitamin D3 on a daily basis could offer both protection from COVID-19 but also (over time) slow progression of the disease (see the drawing below).

Hall, Mary-Frances E., and Frank C. Church. “Integrative Medicine and Health Therapy for Parkinson Disease.” Topics in Geriatric Rehabilitation 36.3 (2020): 176-186. Open access and free download: https://bit.ly/3kIDY2K

The journal (Topics in Geriatric Rehabilitation) had organized a summer issue dedicated to Parkinson’s. An important aspect of the blog relates to complementary and alternative medicine (CAM) in Parkinson’s. We thought the Editors of the Journal would appreciate an integrative medicine and health strategy for Parkinson’s. To help me out with the writing and the background research, I was most fortunate to have Mary-Frances as a co-author. Ms. Hall is currently a 2nd-year medical student at UNC-CH, and she had a background in neuroscience.

There were several goals of this paper, including (a) description of integrative medicine and health therapy, (b) application of CAM with a review of the literature supporting their potential use for treating Parkinson’s, and (c) a case study that utilizes such an integrative medicine plan to treat Parkinson’s. The CAM substances were considered based on each substance having one or more than one characteristics based on the following algorithm: Does the compound counteract one of the proposed causes of Parkinson’s ? Does the compound augment one of the biological mechanisms that could contribute to slowing progression of Parkinson’s? Does the substance contribute to overall brain health? Does the compound penetrate the blood-brain barrier? Is there any published information on the substance in animal model systems or in human clinical trials? Are the compounds easy to take orally and relatively inexpensive? Furthermore, we consider the role of various types of exercise in their impact to improve the quality of life in Parkinson’s. We also discuss the importance of frequent stretching. Finally, the role of mindfulness is described to help reduce stress and calm the mind, which are contributing factors to making symptoms harder to control in Parkinson’s.

The integrative medicine strategy includes the use of (i) conventional and (ii) non-conventional drugs and substances to combat the motor and non-motor symptoms of Parkinson’s, and (iii) lifestyle changes that have been shown to either improve quality of life or slow disease progression, including exercise, stretching, and mind body approach of mindfulness. The drawing below highlights some of the key aspects of this paper.

Hall, Mary-Frances E., and Frank C. Church. “Exercise for Older Adults Improves the Quality of Life in Parkinson’s Disease and Potentially Enhances the Immune Response to COVID-19.” Brain Sciences 10.9 (2020): 612. Open access and free download: https://www.mdpi.com/2076-3425/10/9/612

Mary-Frances returned for the summer with fellowship funding to study the role of exercise in Parkinson’s; however, the COVID-19 pandemic and rules established by the School of Medicine to insure everyone’s safety changed our plans. In its place, we applied for the 4th IRB (Internal Review Board) the group has needed to complete our studies in the past 2 years. Just knowing that it takes on average 50 days to write, submit, revise, review, review again and (hopefully) finally get approval for most IRB application, and she had only ~8-9 weeks of summer to work. The IRB material may hopefully one day yield some interesting data and result in another publication. In the interim, we spent much of the summer related to the article cited above. Like Mary-Frances’s first article (mentioned above), exercise is a huge component to the blog, and a very important aspect to my life and so very important for your overall health, in the absence or presence of Parkinson’s. And we added a twist, including the role of exercise in helping resist infection by COVID-19.

Much like the vitamin D and Parkinson’s and COVID-19 paper mentioned earlier, we had an idea that this merging of the role of exercise to modulate the immune system could alter one’s susceptibility to COVID-19 infection, and when combined with the growing importance of exercise in Parkinson’s we thought this would be a relevant and timely review. The obstacle was balancing the writing on these topics: Exercise, Immune System, Parkinson’s, COVID-19, Exercise and Modulation of the Immune System, Exercise to Protect from Parkinson’s, and the ability of Exercise to Protect from COVID-19. In many respects, though the big-pictures were similar goals between our two COVID-19 and Parkinson’s papers, this was a much harder paper to compose due to it’s breadth and huge amount of published research on exercise with Parkinson’s and exercise with the immune system and upper respiratory viral infections.

There are three take home messages from our review. (1) Exercise and physical activity improve the health of older adults. (2) There are many benefits to exercising in the presence of Parkinson’s and include positive impact on the immune system, reducing neuroinflammation that would promote a neuroprotective effect. The benefit of more high intensity exercise could possibly promote neuroplasticity. (3) The immune response is strengthened from moderate-intensity exercise. We concluded the paper as follows: “Older adults, with or without PD, are more susceptible to SARS-CoV-2 viral infection, and moderate exercise may help to improve the immune response to COVID-19 infection. Moderate-intensity exercise may also help boost the immune system response to the COVID-19 vaccination when it becomes available.” The schematic below demonstrates potential role of exercise to help Parkinson’s and COVID-19 infection.

McGreevy, Kristen M., and Frank C. Church. “Active Learning: Subtypes, Intra-Exam Comparison, and Student Survey in an Undergraduate Biology Course.” Education Sciences 10.7 (2020): 185. Open access and free download: https://www.mdpi.com/2227-7102/10/7/185

Switching gears from Parkinson’s to Education scholarship now this is a paper published with Kristen McGreevy, who is now a graduate student in biostatistics at UCLA. In my undergraduate class I’ve always had a major component in the day education part in active learning. What is active learning? Active learning is a teaching method that engages students with subject material to enhance the learning experience compared to traditional lecturing styles. Kristen and I defined active learning as follows: (i) an interactive teaching method that calls upon students to discover the subject material through student-based activities. (ii) Active learning requires the expression of ideas and opinions in small groups that ultimately blend into an entire class discussion; thus, it ignites students’ innate curiosity. (iii) Active learning activities strengthen team-based skills of collaboration, conversation, cooperation, and collegiality. (iv) Active learning engages all types of students with each other and the instructor, promoting the disintegration of racial, socioeconomic, and intelligence boundaries. our paper involves a six-year study which encompasses 10 semester of the biology blood disease class looking at active learning versus didactic lecturing learning.

There were four goals to this study: (1) we describe and introduce active learning subtypes; (2) we explore the efficacy of active learning subtypes; (3) we compare student comprehension between course material taught with active learning or lecturing within a course; and (4) we determine student satisfaction with active learning using a survey. Our results indicate active learning subtypes may be useful for differentiating student comprehension, provide additional evidence that active learning is more beneficial to student comprehension, and show that student perceptions of active learning are positively changing.

I am proud of this paper because of the time and effort it took us to get it published. It was an effort to introduce a new concept of education, with the difficulty being we are basic scientists and not truly educators by training. The drawing below illustrates and describes our active learning subtypes based on Bloom’s taxonomy of learning.

Top Panel- Active learning subtypes with their associated learning taxonomy. The types of classroom experience(s) that best represent each of the subtypes and descriptive terms for each active learning subtype are given. Middlee and Bottom Panels- The five active learning subtypes compared to the six components of Bloom’s Revised Taxonomy of Learning..

The Next Few Manuscripts: I will give you the next two papers submitted for publication but no details of the two manuscripts being written. Why? Two reasons. I am slightly superstitious and one never knows when and where a paper will eventually get published. (1) “PRIME Immunology: Self-directed Introduction to Medical School Immunology” Tomasi, Alessandra G., Thomas Belhorn, and Frank C. Church (Submitted for publication). (2) “Hands-on: The Science and Application of Vaccines” Seth M. Alexander, Johanna H. Foster, Gene W. Hobbs, Carol P. Kozel, Thomas Belhorn, and Frank C. Church (submitted for publication).

A Final Thank You to my Talented First Authors: Writing articles is an interesting process. It is a coordination of choosing the appropriate topics, getting minds to focus together, merging writing styles, work philosophy, determination and perseverance, and a commitment to excellence. It can be a joyful process; when successful, the manuscript always turns out far superior to what you could have written yourself. I owe a huge thank you to my first authors of these five manuscripts: CJ Reuland, Casey Hribrar, Mary-Frances Hall, and Kristen McGreevy. I learned so much this year in how to write a paper, and I owe you each a tremendous amount of gratitude. These publications exist because of our successful collaboration to write together. Thank you!

Time is clearly not our natural dimension. Thus it is that we are never really at home in time. Alternately, we find ourselves wishing to hasten the passage of time or to hold back the dawn. We can do neither, of course, but whereas the fish is at home in water, we are clearly not at home in time–because we belong to eternity.” Neal A. Maxwell

Supplemental Information- A Visit Down Memory Lane and Some of my Publications (clicking on each paper will give you a larger and more readable text):

Cover image by Frank Winkler from Pixabay

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