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2019 Spring/Summer Highlights of Hope

RESEARCH A SURPRISING

RESEARCH A SURPRISING DISCOVERY How the appendix is transforming our understanding of Parkinson’s When it comes to Parkinson’s disease, the appendix is usually not the first thing that comes to mind — but perhaps it should be, according to Van Andel Research Institute’s Dr. Viviane Labrie. In October, Labrie and her colleagues published revolutionary new findings that peg the appendix as a starting point for Parkinson’s, a discovery that provides a path forward for devising powerful new ways to predict and possibly prevent the disease. The findings were hailed as a major — and surprising — breakthrough by scientists around the world. “We’re in the midst of a watershed moment in Parkinson’s research,” Labrie said. “Right now, there are no ways to prevent, slow or stop Parkinson’s, or even to objectively diagnose it prior to the onset of motor symptoms. We are extremely hopeful that our work will help change that.” The findings come at a time when experts are warning of a looming Parkinson’s epidemic, largely the result of an aging global population. Between 1990 and 2015, the prevalence of Parkinson’s doubled to an estimated 7 million people worldwide. By 2040, the number is expected to double again. These statistics are sobbering, but thanks to a dedicated Parkinson’s research and patient community, we now know more about Parkinson’s than any other time in human history, and we are closer than ever before to making a lasting impact on how we diagnose and treat this devastating disease. The team’s research shows that removing the appendix — a surgery called an appendectomy — significantly reduces the risk of developing Parkinson’s disease by eliminating a major reservoir for abnormal proteins linked to its onset. Called alpha-synuclein, these proteins travel from cell to cell, clumping together and clogging up the cellular machinery required for normal, healthy function. Their results also indicate that people who have had their appendix removed early in their lives are 19 percent less likely to develop Parkinson’s. In people who live in rural areas, that number is even higher, with appendectomies reducing the risk of developing the disease by 25 percent. Parkinson’s often is more prevalent in rural populations, which studies suggest may be related to pesticide exposure. The findings also show that appendectomy may slow the disease’s progress, pushing back diagnosis by an average of 3.6 years. Because diagnosing Parkinson’s is closely tied to onset of movement-related symptoms, this means people have more time before these symptoms become pronounced enough to be noticed. That is an important caveat, however. Removal of the appendix — and the Parkinson’s-associated alpha-synuclein proteins contained within it — must occur before the disease process begins to impact risk. This window of time can vary from person to person, with evidence suggesting the disease process starts as early as 20 years before diagnosis. Removal of the appendix also doesn’t appear to prevent or delay Parkinson’s in people whose disease has a purely genetic cause — a group that comprises less than 10 percent of those with Parkinson’s disease. “Right now, there are no ways to prevent, slow or stop Parkinson’s — or even to objectively diagnose it prior to the onset of motor symptoms. We are extremely hopeful that our findings will help change that.” - DR. VIVIANE LABRIE Labrie and her colleagues stress that people shouldn’t opt for an appendectomy as a way to mitigate risk for two major reasons. First, despite its undeserved reputation as useless, the appendix actually acts as an important storehouse for bacteria that play a role in the immune system. Second, appendectomy only demonstrated benefit decades before the onset of Parkinson’s and would not be protective in people who have already developed the disease. It’s also worth noting that all surgeries carry risk and that, while an appendectomy reduced the chances of developing Parkinson’s, it did not eliminate the disease. Instead, Labrie said, this discovery could lead to new ways to more effectively reduce the levels of alpha-synuclein proteins before they cause trouble. “There are many new medications designed to break up these problematic protein clumps undergoing rigorous testing in clinical trials,” she said. “If successful, we could have a new way to interfere with disease progression, an urgent unmet need and something current treatments can’t do.” 4 | VAN ANDEL INSTITUTE HIGHLIGHTS OF HOPE

DR. VIVIANE LABRIE In an unexpected turn, Labrie and her team also found alphasynuclein pathology in the appendixes of healthy people of all ages, as well as people with Parkinson’s, raising new questions about the mechanisms that cause the disease and propel its progression. Prior to this study, alpha-synuclein pathology was thought to only be present in people with Parkinson’s. “We found alpha-synuclein pathology in people of all ages, and with and without the disease, which suggests that it is not unique to Parkinson’s,” Labrie said. “Parkinson’s is relatively rare — less than 1 percent of the population — so there has to be some other mechanism or confluence of events at play that allows the appendix to affect Parkinson’s risk. That’s what we plan to look at next — which factor or factors tip the scale in favor of Parkinson’s?” Data for the study was gleaned from an in-depth characterization and visualization of alpha-synuclein forms in the appendix, which bore a remarkable resemblance to those found in the Parkinson’s disease brain, as well as analyses of two large health-record databases. The first dataset was garnered from the Swedish National Patient Registry, a one-of-a-kind database that contains de-identified medical diagnoses and surgical histories for the Swedish population beginning in 1964, and Statistics Sweden, a Swedish governmental agency responsible for official national statistics. The VARI team collaborated with researchers at Lund University, Sweden, to comb through records for 1,698,000 people followed up to 52 years, a total of nearly 92 million person-years. The second dataset was from the Parkinson’s Progression Marker Initiative (PPMI), which includes details about patient diagnosis, age of onset, demographics and genetic information. “The expansion of Parkinson’s disease research into areas outside of the brain and affecting the GI tract and immune system has really opened the door for understanding this illness,” Labrie said. “We know more about disease initiation than ever before and are committed to leveraging our findings to improve patients’ lives.” In addition to Labrie, authors include Dr. Bryan A. Killinger, Zachary Madaj, Dr. Lena Brundin, Dr. Patrik Brundin, Alec J. Haas and Yamini Vepa of Van Andel Research Institute; Dr. Jacek W. Sikora and Dr. Paul M. Thomas of Northwestern University; Dr. Nolwen Rey of Paris-Saclay Institute of Neuroscience; Dr. Daniel Lindqvist of Lund University; and Dr. Honglei Chen of Michigan State University. VAN ANDEL INSTITUTE HIGHLIGHTS OF HOPE | 5

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