In early March 2020, The Cure Parkinson’s Trust presented a webinar about the role of inflammation in Parkinson’s disease (PD), featuring a panel of speakers including neurologists, a clinical researcher, and a dietitian who has PD.  Their discussion included an overview of neuro-inflammation, or inflammation in the central nervous system; other inflammatory diseases such as arthritis and inflammatory bowel disease (IBD); and current theories and research on the connections between immune function, inflammation, and PD. We at Stanford Parkinson’s Community Outreach listened to the webinar and are sharing our notes.  

The speakers on the panel included:

• Dr. Patrik Brundin, Editor-in-Chief of the Journal of Parkinson’s disease
• Dr. Roger Barker, a clinical neurologist with the University of Cambridge, UK
• Dr. Ashley Harms, a pre-clinical researcher with the University of Alabama who studies inflammation in animal models of PD
• Richelle Flanagan, a dietician from Ireland who has Parkinson’s disease

This webinar was recorded and can be viewed on YouTube.

If you have questions about the webinar, you can contact Cure Parkinson’s at helen@cureparkinsons.org.uk

In the question-and-answer session, there was a question about the gut-brain connection.  For more information about the gut-brain connection, check out this Stanford Parkinson’s Community blog post from January 2020.

Now… on to our notes from the webinar.

– Lauren

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Inflammation and PD – Webinar notes

Presented by The Cure Parkinson’s Trust, Parkinson’s Movement, and the Journal of Parkinson’s Disease

Webinar on March 3, 2020

Summary by Lauren Stroshane, Stanford Parkinson’s Community Outreach

The presentation started with the questions, “What is inflammation, and is there any difference in inflammatory responses in people with Parkinson’s disease (PD) compared to other people?”

Your immune system mounts three main responses: clearing bacteria and viruses; removing dead and dying cells within tissues, whether in your brain, liver, or other areas; and sometimes, excessive activation of the immune system, when your immune system is hyper-vigilant and attacks cells and proteins in your body that it shouldn’t attack. In PD, researchers think this third function may be active.

The central nervous system (CNS) refers to your brain and spinal cord. Neuro-inflammation in the central nervous system occurs when all of these immune responses are taking place simultaneously and working together.

Your immune system is comprised of the innate system, involving microglia and macrophage cells, that is responsible for removing dead and dying cells in the body, and also the adaptive system, involving T or B cell types, that combat “foreign invaders” in a tailored response.

What may set PD apart from other illnesses is that the particular proteins involved in PD may be mis-recognized by the immune system. We know that neuro-inflammation is occurring in the central nervous systems of people with PD.

A scientific paper in the 1980s noted that microglia – a type of innate immune cell – residing in the brains of people with PD were assumed to be responding to cell death from the disease. Now we know that microglia are important communicators between the different types of immune cells in the peripheral immune system with the central (brain) immune system. Their presence may not be bad, in and of itself.

Immune function and PD

In PD, the immune system may be activated when it shouldn’t be and have trouble shutting down. Our immune function changes drastically as we age, and PD is an age-related disorder, so there may also be alterations in how our body reacts to these proteins over time.  

Other diseases such as arthritis and inflammatory bowel disease are caused by the immune system attacking the body. Historically, treatments for these illnesses affected the immune system very broadly and indiscriminately, but now many therapies are becoming more targeted and selective depending on what is needed, for instance with antibody therapy.

We also do not know whether there are immune differences – and therefore different treatment needs – according to different types of PD. Some people have inherited forms of PD due to mutations from the genes LRRK2 or GBA; others have sporadic PD without a known cause; and there may be other forms that we have not yet identified.

There seems to be a link between inflammatory bowel disease and PD; those with inflammatory bowel disease have a higher risk of developing PD. There appear to be some genetic links or overlaps between the two, and some parallels in the gradual progression, such as prodromal periods of many years before symptoms appear.

The role of alpha-synuclein

The protein alpha-synuclein is an integral part of the Lewy bodies that build up in the brain in PD. It has a role in how nerve cells communicate, and scientists theorize it may have a role in immune function normally, helping to trap foreign invaders.

Researchers are trying to determine what this role may be; alpha-synuclein seems to activate some immune cells, but we do not yet understand how this works or what it activates them to do. It may be that alpha-synuclein is driving the inflammation, and if we can slow down or decrease the inflammation, we may be able to slow progression of the disease overall.

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Question & Answer Session

Q: What kind of drugs might we use to treat PD if it is an inflammatory illness? Might we be able to use other drugs that have already been developed for other immune diseases, or do we need to find an inflammatory target and develop new drugs to address that target?

If inflammation is actually a primary driver or a contributor to the illness, then it is very tractable because we may be able to use some existing drugs. But we do not yet know exactly where in the CNS the inflammation is located – primarily in the brain, or in the spinal cord? Or is it more of a systemic issue – throughout the whole body? These questions are unresolved so far, but they matter because different drugs access different areas; not all drugs are able to cross into the brain, for instance.

Q: What do we think is the influence of extra-cellular vesicles that either come from the brain or the blood in the context of inflammation?

A: For background, we learned about 10-15 years ago that cells which secrete tiny vesicles (also called exosomes) that contain tiny messenger molecules. The idea is that we could measure the molecules within the vesicles, they could theoretically be collected and tested to try to extrapolate what is happening in the brain. 

It is hard to know where these vesicles originate and what type of cells they came from. We do not yet know if these are a useful biomarker for assessing PD and degree of inflammation. Therapeutically, in multiple sclerosis, researchers have looked at the potential for using stem cells to secrete anti-inflammatory effects, but these are different types of cells. If we can find a way to track where the vesicles started and determine which came from the brain, then this has potential in the future.

Q: Regarding diet, is there any evidence that there might be diets that reduce inflammation and slow the progression of PD, or that might reduce the risk of developing PD?

A: This is a big question! There is so much variety in PD that you can’t really offer a one-size-fits-all diet for all PD patients. A Mediterranean diet is consistently recommended for those with PD; many of the foods included in that diet have anti-inflammatory effects. The microbiome refers to the small “universe” of bacteria that normally live in our gut. Small intestine bacterial overgrowth may occur in many people with PD, meaning an imbalance in the populations of these bacteria. But there is so much we don’t know about the microbiome and PD; we do not yet have evidence for any further recommendations.

Q: What do you think about the concerns about dairy and PD?

A: Most dieticians are on the fence about this; the evidence is equivocal whether dairy is actually harmful in PD. There are confounders in the current data; for instance, there are great differences between diary in different countries, with non-organic American dairy potentially containing lots of other growth factors, antibiotics, and other chemicals as compared to dairy produced in Ireland that is generally quite organic. Dairy can still be very beneficial for many reasons, including bone health and keeping up a healthy weight, which many who have PD struggle with. Richelle does not recommend giving up diary completely.

Q: Is PD an autoimmune disease?

A: We discuss and debate this all the time. People are cautious about labeling it an autoimmune disease; this may be premature. There is definitely inflammation going on. Maybe it is an auto-inflammatory disease? Research is lacking on what is activating in the immune system, and PD is a very heterogeneous disease, so it is hard to say at this point.

Q: How do we know that the neuro-inflammation that we see in PD is damaging versus protective?

A: This is a great question! It is hard to reconcile what we see in animal models (such as mice) versus human patients. We may not know the answer definitively until someday when we are able to test immunomodulating therapies in humans. We also have to keep in mind the potential for unintended side effects of changing our immune function.

Q: What is the contribution of aging microglia in this whole process?

A: There is very little research done in PD for identifying senescent (aging) cells. We know that microglia are long-lived; they can replace themselves as they age and die. “Inflam-aging” is the idea that these cells may become less responsive and vigilant over time. Likely aging has a big impact on all these processes; it is hard to study in the lab.

Q: How do the gut and brain communicate with each other?

A: You absorb things through the gut and into your bloodstream, so that is one way. Not everything crosses over the “blood-brain barrier” from the bloodstream, however. The other way is neurological. The gut has an enormous nervous system, a huge number of nerve cells. The big nerve that does that is the vagus nerve, a huge nerve which connects the gut and many other critical organs to the brain. The vagus nerve has been a huge area of interest into the gut-brain connection in PD.

Q: How many people would you need to test the theory that those with inflammatory bowel disease are more prone to also developing PD?

A: This is a very complex research question that would require a great deal of time. Likely epidemiological studies looking at retrospective patient records would be the best

The medications for inflammatory bowel disease (IBD) that might be helpful – anti-TNF antibodies – are very expensive and can cause substantial side effects, also. There can also be a lot of confounding factors in

Another challenge is the lack of a biomarker for us to detect patients at risk for PD. Eventually if we identify a biomarker that allows us to track patients over time, this will help to make these connections in real time rather than after the fact.

Q: What would you recommend patients do in their daily lives to reduce inflammation?

A: From a diet point of view, the Mediterranean diet is a safe bet. You can consider intermittent fasting only if cleared by your doctor and not losing weight. A very high proportion of those with PD have constipation; be proactive about your bowel health and make sure you are having regular bowel movements.

Regular exercise is one of the only things that is showing a serious impact on PD symptoms, though we do not know if it is addressing inflammation directly.