The Palo Alto Young Onset Parkinson’s Disease support group’s January 2020 meeting featured the medical director from the Parkinson’s Institute and Clinical Center, Dr. Kristin Andruska. She discussed what we currently understand about the gut-brain connection and genetic testing for PD. We at Stanford Parkinson’s Community Outreach attended the meeting and are sharing our notes.  

Attendees from the Parkinson’s Institute in Mountain View, CA included Kristin Andruska, MD, PhD, Medical Director and Brian Coulter, CEO.

For additional informational resources on constipation and other GI issues common in PD—including downloadable guides, links to online resources, and webinars and podcasts—see this page on the Stanford Parkinson’s Community Outreach website.

If you live/work in the Palo Alto area and were diagnosed with Parkinson’s Disease by age 50, let Robin Riddle with Stanford know if you’d like to be added to the meeting reminder email list.  Please contact Robin Riddle at (650) 724-6090 or rriddle@stanford.edu.

Now… on to our notes from the webinar.

– Lauren

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The Parkinson’s Institute discussed the gut-brain connection and current clinical research

Palo Alto Young Onset Parkinson’s Disease Support Group Meeting

January 14, 2020

Notes by Lauren Stroshane, Stanford Parkinson’s Community Outreach

The medical director of the Parkinson’s Institute and Clinical Center (PICC) is Dr. Kristin Andruska. She spoke about the current state of research into the gut-brain connection in PD, ending with a question-and-answer session on genetic testing. 

Does PD begin in the gut rather than the brain?

As long ago as 1817, Dr. James Parkinson made note of the fact that his patients with PD experienced changes in their gastrointestinal function as well as their motor symptoms. Constipation and delayed transit times are well-established as common issues in PD. In 2003, a German neurology researcher named Heiko Braak published a new theory about a possible cause of PD, called the Braak Hypothesis.

There is a protein called alpha-synuclein (a-synuclein for short) that is found in large quantities in the brain, as well as other tissues in the body such as muscle and gut. Its primary function is not well understood, but it seems to have an effect on the regulation of dopamine. Sometimes a-synuclein mis-folds, forming clumps of misshapen protein which aggregate around brain cells (neurons), causing cell death and forming what we call “Lewy bodies,” which are found in the brains of those with PD and also Alzheimer’s disease (AD). Mysteriously, not all people who have Lewy bodies in their brains will have PD or AD; some do not have neurologic symptoms at all.

To learn more about a-synuclein, visit here.

The Braak Hypothesis proposed that PD might be caused by the introduction of an unknown pathogen, such as a bacterium or virus, triggering the formation of Lewy bodies to begin in the gut [1]. He theorized that these Lewy bodies cause changes in the intestinal microbiome, causing the gut to be leaky and allowing autoimmune cells to enter. Braak suggested that the vagus nerve, a large nerve that connects multiple systems in the body including the gut and the brain, offers a means for the Lewy bodies to travel in stages from the gut to the brain, proliferating in a predictable way into the brain stem and then spreading to other areas of the brain.

Although Braak did not know at the time of his hypothesis that the misfolded proteins making up Lewy bodies would be identified as a-synuclein, there is some evidence to support his theory. Long before we see significant loss of dopamine-producing neurons in the substantia nigra (the part of the brain where PD pathology occurs), there is already a-synuclein proliferating in the brain. Dr. Andruska explained that biopsies from the gastrointestinal (GI) tracts taken for other reasons, such as cancer screening, shows a-synuclein aggregating before an eventual diagnosis of PD. Additionally, clumped a-synuclein in the gut seems to correlate with GI symptoms, even before a PD diagnosis.

How to test this theory? Disrupt the pathway connecting the gut to the brain, via a procedure called a vagotomy – permanently severing the vagus nerve. This surgery had been used in the past to relieve the pain of chronic peptic ulcer disease (PUD), which is now generally treated with oral medication. Still, there was a significant cohort of people who had undergone vagotomy to treat their PUD in the 1970s-1990s. Follow-up studies of some of these individuals showed that vagotomy seemed to be protective against developing PD, though there remained some risk. It is possible that those who underwent a vagotomy and still developed PD may have undergone the procedure after misfolded a-synuclein had already started to spread into the brain. Some individuals also had partial rather than total vagotomies.

Dr. Andruska summarized a 2016 study from the journal Cell that used mice to evaluate the connection between the gut microbiome and PD [2].  Mice that were raised in a sterile environment did not tend to develop PD, even when they were genetically bred to do so. “Wild-type” mice that were not bred to develop PD but received gut bacteria (microbiota) from human patients with PD had a higher rate of developing the disease than mice implanted with gut bacteria from healthy human controls. See the Sources list at the end of the article for a link to the full text.

Ultimately, it is clear there is some kind of connection between our gut microbiome and Parkinson’s disease. However, there is still a lot we don’t understand; a lot of the literature on this topic is quite recent and ongoing. You can’t currently get a vagotomy to prevent PD, for instance. We cannot yet define what are “good” and “bad” gut bacteria, or which ones we need to worry about; scientists are working on genotyping these bacteria but there is not yet consensus in the literature. The gut microbiome tends to be highly variable among people and families.

Should patients take probiotics and/or consume fermented foods that contain live cultures? Most neurologists feel that it likely couldn’t hurt, and might help, to consume them. Dr. Andruska explained that the research on probiotics is still very mixed and there aren’t clear guidelines. However, anecdotally, some people find they are helpful. Keep in mind that any significant changes to the metabolism – whether from changes in diet or consumption of probiotics – can sometimes change the body’s absorption of oral medications for good or ill, so your PD medications might need to be adjusted if this is the case.

Q&A about genetic testing and PD

Q: To what degree is PD inherited genetically? Should my kids get genetic testing if I have PD?

A: Most people with PD have what is called “sporadic” or “idiopathic” PD, which means it arises spontaneously for unknown reasons, versus those who have a strong genetic risk for it. About one percent of people over the age of 70 will get PD; the risks increase with age. However, up to 20 percent of people with PD have their disease due to known genetic mutations (there may be other genetic mutations that lead to or contribute to the development of PD, but which scientists have not yet identified). The most well-known of these are mutations in the genes GBA (which makes the enzyme glucocerebrosidase) and LRRK2 (leucine-rich repeat kinase 2, which may lead to accumulation of a-synuclein). There are other mutations that, on their own or in combination with other genetic mutations, can lead to PD as well.

Q: Why do some people decide to get genetic testing for PD?

A: It’s important to know that, currently, your treatment for PD will not change based on the results of genetic testing. There are several reasons why some people decide to get tested:

• It can confirm a diagnosis, if a person wants certainty.
• It can identify mutations which might have implications for family members who could be at risk for PD.  
• Some clinical trials specifically recruit PD patients with confirmed genetic mutations, so genetic testing can open up more options for those interested in participating in research.

Q: How do I go about getting genetic testing for PD? Who do I see and what do I ask for?

A: The place to start is with your neurologist, to speak with them about your interest in genetic testing. Home kits offered by companies such as 23andMe are quite limited and not the most reliable source of testing, as they don’t look at all the relevant genes.

There is a difference between genotyping and genetic sequencing. Genotyping looks at specific points on a gene to see if common mutations are present at that point. Sequencing is when every letter of the gene is evaluated, and is much more comprehensive; it can also be more expensive. Sometimes individual genes are tested, or sometimes there is a panel of genes that are ordered. Your neurologist or movement disorder specialist can discuss your goals and what you are hoping to get out of the testing to help decide what is most appropriate for you. They may refer you to speak with a genetic counselor to help you assess your goals and understand the potential implications of either a positive or negative test, for you and for your family.

Most insurance does not cover genetic testing, and individuals typically have to pay out of pocket for testing which can cost hundreds or even thousands of dollars, though a Kaiser patient who attended the meeting mentioned that she had a very straightforward experience and didn’t have to pay anything out of pocket when she underwent genetic testing for PD.

The PICC offers genetic testing through a proprietary 68 gene sequencing panel. Patients do not have to already be patients at the PICC and can request an appointment just to discuss genetic testing. The proprietary panel has a retail cost of $5000 but this is reduced for PICC patients down to a maximum of $575 out of pocket. If results are positive, a genetic counseling appointment is offered to discuss what the results mean for the patient and their family members.

Sources:

1.     Exploring Braak’s hypothesis of Parkinson’s disease. Front Neurol. 2017 Feb 13; 8: 37. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304413/

2.     Sampson TR, Debelius JW, Thron T, Wittung-Stafshede P, Knight R, Mazmanian SK. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell. 2016 Dec 1; 167 (6): 1469-1480. Retrieved from https://www.cell.com/fulltext/S0092-8674%2816%2931590-2#secsectitle0080