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Melanie Cole (Host): Recent work in Parkinson’s Disease has uncovered important links between activation of the immune system and the progression of Parkinson’s Disease. My guest to tell us about this today, is Dr. David Standaert. He’s the John N. Whitaker Professor and Chair of Neurology at UAB Medicine. Dr. Standaert, let’s start with a little bit of an explanation about why it’s important to understand inflammation and the immune system as it relates to Parkinson’s Disease.

David Standaert, MD, PhD (Guest): Well the role of the immune system in Parkinson’s Disease is really a hot new topic in research. Parkinson’s is a very common disorder. There are over a million people in the United States who are affected by Parkinson’s Disease and although we have treatments that can address the symptoms; there really is no treatment that can slow or alter the course of the disease. And the discovery of the role of the immune system is really opening new doors to thinking about ways of treating or perhaps even preventing Parkinson’s Disease.

Host: Then tell us about some of the latest research on this relationship and how it relates to the start or the progression of Parkinson’s.

Dr. Standaert: It’s actually been known for a long time that the brain shows inflammation in Parkinson’s Disease. This was discovered more than 20 years ago. But it was always assumed that this was a reaction to the disease process. In Parkinson’s there are neurons dying off in the brain, particularly neurons that make a dopamine. And the thinking was that the reason there was inflammation is there were dead cells and the immune system was sort of coming in to clean up the debris. What’s really changed in the last five or seven years is we’ve turned this on its head and started to ask maybe the immune system is actually causing damage. Maybe the immune system is part of the driver that makes Parkinson’s Disease get worse from year to year.

Host: Is it now considered an autoimmune disorder?

Dr. Standaert: I wouldn’t go so far as to say it’s an autoimmune disorder. There are upstream triggers for Parkinson’s Disease. We know some things about the cause of Parkinson’s. There is a genetic element to the disease, in fact, more than 50 different genes have been discovered, each of which contribute a small degree of risk. And there are certain proteins that are known to be involved such as the protein alpha-synuclein. Build up of this protein alpha-synuclein seems to be a core feature of Parkinson’s. It’s found in the Lewy body which is the feature that pathologists look for in the brain to diagnose Parkinson’s. So, there are some upstream drivers. But what we think is going on and I think many in the field have come to recognize is that these upstream causes eventually lead the immune system to engage. Build up of synuclein leads to abnormal forms of synuclein, then that gets recognized by the immune system which starts its attack and really drives the progression of the disease.

Host: So, then let’s talk about your research and the focus on neuroinflammatory mechanisms and the gap that you’ve seen in the research portfolio in centers across the country.

Dr. Standaert: Right, so, this work has really evolved in our laboratory and other laboratories around the world in the last five to seven years. A lot of the early work was done in animal model systems. So, in mouse models you can replicate many of these features. You can produce a mouse model of Parkinson’s Disease by overexpressing alpha-synuclein. This can be done through a variety of genetic techniques or you can actually just directly inject abnormal forms of synuclein into the brain and they seem to trigger off this process of aggregation and propagation. So, these kinds of models have been used to study the role of the immune system.

When you do this in an animal model, you do get a very vigorous immune response and we and others have shown that you can knock out very specific pieces of this, shut down the immune response and prevent the damage to the dopaminergic system in animal models. I think just in the last couple of years; this has started to move into human phase research. So, there has been some very important work done. Some of it out of New York and other places looking at the state of the immune system in patients with Parkinson’s Disease, showing that there’s specific abnormalities of T-cells and monocytes in the blood early in Parkinson’s Disease. And we’ve recently launched a large-scale project with the support of the NIH, funded through what’s called a Udall Center. These are large federal research centers around Parkinson’s Disease and ours is dedicated to really exploring the role of the immune system in patients with Parkinson’s at the earliest stags of the disease.

Host: Dr. Standaert, what type of providers would be needed to collaborate on this type of extensive research?

Dr. Standaert: Well, one of the things about studying Parkinson’s is we see a lot of patients with Parkinson’s here at UAB. We see over 7000 patient visits in the Parkinson’s clinic every year. But one of the things about studying this disease is we are really interested in the very early phases of this condition. We are really interested in reaching and being able to study patients who are at the very earliest stages and those are often ones who are not seen necessarily in our clinic. Many patients with Parkinson’s first present to their primary care provider, maybe a community neurologist and it’s sometimes difficult to get those patients referred in quickly enough that we can actually engage them in research. They tend to be referred much later in the course of the disease, where it’s harder to ask questions about the cause of the disease later in the game.

Host: Doctor, one of the things I found interesting during my research for this segment was the role of inflammation in Parkinson’s Disease as its pretty wide reaching, has led to another very hot topic in the field of this type of research which is specifically the gut of patients with Parkinson’s Disease. Speak about that a little bit.

Dr. Standaert: Right. So, the question becomes what are the drivers? If there is an immune response here in Parkinson’s; where does it begin and what really drives it? And as you mentioned, the gut – the mind-gut connection is now becoming a very important area of research and one of the causes of this may be the fact that some of these antigens, things like alpha-synuclein are found not just in the brain; they are actually found in the nervous system, in the neurons that are in the wall of the gut and in neurons in the peripheral part of the body as well.

And so, the question is whether there could be a bacterial component here. Could there be abnormal bacteria flora that trigger abnormal synuclein and thereby sort of ignite the immune process? What’s the evidence for this? Well, one of the pieces of evidence for this is that constipation is very common in Parkinson’s Disease and in fact, if you ask what is the best predictor that somebody in their 20s and 30s will later develop Parkinson’s; it’s actually constipation. There’s a large study done in Hawaii, the Honolulu Heart Study which looked at this and in men who had constipation, meaning less than one bowel movement a day, 30 years later they have a 12-fold increase risk of Parkinson’s Disease. This is really remarkable but shows that some of the Parkinson’s pathology probably begins outside of the brain. It begins in the bowel, it begins in the gut and it may in fact, be driven by some of the microflora that are present in our GI tract.

Host: Wow. That’s absolutely fascinating. And so, where do you see some of this research going? What do you see are some other uses for all of this information that you are getting, Dr. Standaert, that might be applied to other disease courses or additional work for Parkinson’s?

Dr. Standaert: Well, one of the things we are doing is we are trying to tackle directly this question of what is the state of inflammation in early Parkinson’s Disease. So, our Udall Center here is enrolling patients. We are using advanced imaging techniques like positron emission tomography to look directly at brain inflammation and studying more peripheral markers of inflammation. The idea to understand the state of immune activation early in the disease and could that serve as a target? Could that serve as a readout for an effective therapy of the disorder? If we can shut down the brain inflammation would that provide us a clue in terms of how to move forward with therapy of Parkinson’s. This idea probably can be extended to other degenerative diseases. There’s good evidence for inflammation in Alzheimer’s Disease. There’s a strong component of inflammation in diseases like Lou Gehrig’s Disease or ALS. So, many of these other neurodegenerative diseases may in fact, have an immune component and understanding the immune activation in Parkinson’s may allow us to bring these kinds of therapies forward to other chronic degenerative diseases of the brain as well.

Host: And as you wrap up to give other providers pretty much your best information on the research going on between the role of the immune system and Parkinson’s Disease; tell us a little bit about the NIH funded center and how this could possibly help to slow or stop the advance of Parkinson’s Disease.

Dr. Standaert: Yeah, our new NIH funded center which is called the Alabama Udall Center is really dedicated to this question. As I mentioned, it is going to be enrolling a cohort of patients with Parkinson’s and really studying them very carefully at the early stage of the disease. We also have projects in animal models that are looking at potential therapies. One of them is interfering with the action of a gene called LRRK2 or LRRK2 that’s linked to Parkinson’s. Another is a signaling pathway that’s known to be inflammation for which actually there are drugs already in development for other diseases that we might be able to repurpose for Parkinson’s Disease if we understood more about the signaling pathways. So, the NIH funded center is to really bring these ideas together and to bring the translational investigators and the clinicians together around this question of what are the targets? What are the opportunities for changing the function of the immune system in a way that might slow Parkinson’s Disease?

Host: What an interesting topic. Dr. Standaert, thank you so much for coming on explaining your research and the Udall Center to us and sharing your expertise for other providers. Thank you again. A community physician can refer a patient to UAB Medicine by calling the MIST line at 1-800-UAB-MIST. That’s 1-800-822-6478. You’re listening to UAB Med Cast. For more information on resources available at UAB Medicine you can go to www.uabmedicine.org/physician, that’s www.uabmedicine.org/physician. This is Melanie Cole. Thanks so much for listening.