Lewy Body Dementias and the Immune System with David Gate, PhD

Erin Spain, MS [00:00:10] This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, MS, host of the show. Lewy body dementia is among the top three causes of dementia worldwide, affecting more than one million Americans. And existing therapies have been unable to slow the progression of this disease, which some scientists say may affect quality of life more so than Alzheimer's or Huntington's disease. Now, new Northwestern Medicine research has established the detrimental role the immune system plays in Lewy body dementias, such as Parkinson's disease dementia and dementia with Lewy bodies, potentially offering new prospects for additional treatments that target the immune system. Here to discuss these findings is Dr. David Gate, PhD, assistant professor in the Department of Neurology at Northwestern and lead author of this groundbreaking study just published in Science. Welcome to the show, Dr. Gate.
 
David Gate, PhD [00:01:06] Thank you very much for having me, Erin.
 
Erin Spain, MS [00:01:08] Your lab just opened at Northwestern in the fall of 2021. Now, this has been a dream of yours to have your own lab. Tell me about some of your current research goals and what's happening in the lab.
 
David Gate, PhD [00:01:19] Our lab is focused on the intersection of the immune system and neurodegenerative disease. I came to Northwestern because of the size of their neurodegeneration patient groups here. So we're focused specifically on human diseases and working with human samples and to identify potential disease targets and therapeutic modalities for these devastating disorders. So we're very much focused on genomics — that is the changes that occur to our genome in neurodegenerative disease. A lot of these changes to the genome are acquired with age or acquired through interactions with our environment. So we're interested in teasing those out and seeing how the immune system responds to these changes and could perhaps be used to treat these disorders.
 
Erin Spain, MS [00:02:04] So you've been studying Alzheimer's disease quite a bit, but your latest research explores the role of the immune system and Lewy body dementia. Before we get into that research, just tell me a little bit about Lewy body dementia. We don't hear of that as often as Alzheimer's. Give me some background about this disease.
 
David Gate, PhD [00:02:21] Absolutely. Lewy body dementia is an umbrella term that encompasses two disorders: Parkinson's disease dementia, which I'm sure your listeners are more familiar with, and another disease called dementia with Lewy bodies. These disorders are becoming more well known in the public eye. Robin Williams famously passed away with dementia with Lewy bodies. An NBA coach by the name of Jerry Sloan, who coached the Utah Jazz for decades and also played in the NBA, he died of dementia with Lewy bodies as well. Essentially, these disorders are very similar to neurodegenerative diseases such as Alzheimer's disease, where toxic proteins accumulate in the brain. In Alzheimer's disease, you have the accumulation of amyloid beta, whereas in Lewy body dementias, you have the accumulation of a separate toxic protein known as alpha synuclein. And this alpha synuclein accumulates to form what are called Lewy bodies, and these Lewy bodies are thought to be very harmful for brain biology. Essentially, these toxic Lewy bodies build up in regions of the brain that control cognition, and they control your thought processes. So it's a pretty devastating disorder that limits your ability to think. And in the case of Parkinson's disease dementia can affect your ability to move. The communication between your brain and your muscles is compromised.
 
Erin Spain, MS [00:03:46] In terms of diagnosis, how is it diagnosed and how does it differ? How do people know it's this versus Alzheimer's?
 
David Gate, PhD [00:03:53] Very difficult to tease out clinically, although our ability to do so is improving. Most of these disorders, for instance, in the case of Robin Williams, physicians didn't know, as far as I know, didn't know that he had dementia with Lewy bodies until an autopsy was done on his brain. Of course, his family observed behavioral changes. He became very depressed later in his life, and this can be tied to the pathology that was occurring in his brain.
 
Erin Spain, MS [00:04:18] Scientists do believe that the quality of life is worse with Lewy body dementias than Alzheimer's or Huntington's. Why is that?
 
David Gate, PhD [00:04:25] Yeah, I think that's a debatable question. I think these diseases are all pretty devastating. Alzheimer's disease is a little bit more well known, and I think that families are more quick to respond to changes in the person's memory. You know, grandma is getting old and she's forgetting things. This makes sense, especially with the growing baby boomer population, which are reaching this age where these neurodegenerative diseases really come about. The difference with Lewy body dementias is where the pathology occurs tends to affect people in a different way than Alzheimer's. As I mentioned, these pathologies are in different brain regions and in dementia with Lewy bodies, it can affect your logical reasoning and your ability to think clearly and can make you depressed, which it's not so obvious to family members when their elderly family members start to experience these symptoms.
 
Erin Spain, MS [00:05:19] Tell me a little bit about you and your path to studying this disease. What got you interested in it?
 
David Gate, PhD [00:05:25] So my training is in neuroimmunology, combining neuroscience and immunology. And when I started my PhD, this was really a budding field, particularly in the Alzheimer's disease world. I was trained by a neuroimmunologist who studied Alzheimer's disease and then for my postdoctoral training, after receiving my PhD, I worked in a lab that was also very focused on neuroimmunology and Alzheimer's in particular. And I was very fortunate to have at my disposal access to thousands of patient samples, including patients with Alzheimer's disease and Lewy body dementias. And so I was highly interested in doing human research. I think that a lot of the research in Alzheimer's disease has been done in mouse models, and it's informed us of a lot of really good biology for the disease. But in a lot of ways, it's also kind of misled us. And a lot of the therapies that have been developed based on mouse models have failed in clinical trials. So I wanted to do human-focused research. I think it was this sort of serendipitous time where the techniques and the samples were there for me to analyze, and I was very fortunate that it led to some really, I think, impactful and significant findings.
 
Erin Spain, MS [00:06:46] What drew you to Northwestern? Tell me about why you decided to come here.
 
David Gate, PhD [00:06:51] I love the city of Chicago. I've been a lifelong Cubs fan. I think that was sort of in the back of my mind biasing me towards Northwestern. But more than anything, I was really drawn by the patient clinics here and the strength of the departments here that are focused on Parkinson's disease and Alzheimer's and ALS. I have an interest in all of these diseases. I am a neuroimmunologist. I'm not a Alzheimer's or Parkinson's disease researcher. So the large patient clinics were a big factor. The promise to be able to access these samples was another huge factor for me. I have the tools to be able to make key findings in these samples, and I think the university saw that the impact of human focused research and I think our interests aligned there.
 
Erin Spain, MS [00:07:43] So let's talk about this recent study in the journal Science. You looked at the role T cells play in this type of dementia. Share with me a little more about the study and the main findings.
 
David Gate, PhD [00:07:55] So this study, we started by performing what's known as genomic sequencing of cells of the cerebrospinal fluid. The cerebrospinal fluid is a liquid that flows in and around your brain. It's popularly known to provide a cushion to the brain in the case of injury, so your brain is constantly floating in the cerebrospinal fluid, also called CSF. But what's less known about the CSF is that it has an immune system and it has a very specialized immune system. My initial studies of the CSF were focused on Alzheimer's disease, where we found a very interesting T cell phenotype there, and we simply transitioned to studying Lewy body dementias because we had developed techniques to be able to analyze the cerebrospinal fluid immune system. So we started there and we found very similar findings to what we found in Alzheimer's disease, where the T cells seemed to reflect changes in the brain. And we were able to tie these changes on the genomic level to changes on the protein level. So we found a mechanism by which we believe these cells enter the Lewy body dementia brain. We found a receptor on the surface of these T cells. You can think of this receptor as a sort of antenna that allows the cells to home to the brain. And we identified the signal that the brain secretes to attract this T cell receptor or the antenna into the brain. And we believe that this pathway, it's an immune pathway, we believe this pathway can be modulated to suppress or inhibit the inflammatory aspect of this disease.
 
Erin Spain, MS [00:09:31] So, you know, there are existing therapies out there, but they're unable to slow the progression of Lewy body dementias. But this research offers a ray of hope. What existing therapies are there already and what might be on the horizon based on this developing research?
 
David Gate, PhD [00:09:45] So what we believe we've uncovered is an autoimmune aspect of this disease where the immune system mounts a detrimental response to the brain. And we believe that this inflammatory immune response can be targeted to mitigate the autoimmune aspect of the disease and potentially could even be used to detect changes in the immune system early in the disease course that could potentially diagnose the disorder much earlier than the clinical manifestations allow.
 
Erin Spain, MS [00:10:16] Could this research also be extended to the other neurodegenerative diseases that we talked about, Alzheimer's, or maybe even MS, for example?
 
David Gate, PhD [00:10:24] What we're finding is that these diseases happen to have different immune pathways that are altered. For instance, in Alzheimer's, we found a completely different type of T cell that was dysregulated compared to Lewy body dementias. So we think that these immune system changes are perhaps unique to these neurodegenerative diseases. Of course, this makes sense because they affect different regions of the brain, which may be responding to the pathology in different ways and calling in the immune system in a different manner. So we believe that while the immune system can be used potentially to modulate the disorders, it's sort of a case by case basis where we need to identify that immune pathway and then ideally develop therapeutics that target those specific pathways that are disease specific.
 
Erin Spain, MS [00:11:12] Lewy body dementias, as we mentioned, have been largely under-researched in the recent past, and your lab is helping to change that. Why has it been the case that Lewy body dementias haven't really been on the map in terms of a public health priority?
 
David Gate, PhD [00:11:27] I think it's been a very difficult disease to study. Dementias have historically all kind of been lumped into the same category, and we're finding now that there are very distinguishable characteristics of these diseases. I sort of touched on this earlier where you have region specific changes in the brain that really underscore these disorders. I think the techniques that we have at our disposal now are much more impactful than what we've been able to do in the past. Instead of looking simply at a patient's brain after they die, we can now look at, for instance, the cerebrospinal fluid, and we can perform genomic sequencing on individual cells, which is an extremely powerful technique that we utilize in our research. This technique essentially allows you to look at all of the genes of an individual cell, and you can look at thousands of cells from a patient's cerebrospinal fluid, so it's highly informative for analyzing the immune system of a living patient.
 
Erin Spain, MS [00:12:30] So in this study, you use samples from both living people and folks who have passed away from this dementia. Tell me about these samples that you used and how in the future you'll be able to use samples to perhaps diagnose this illness earlier.
 
David Gate, PhD [00:12:46] We're fortunate to be able to isolate cerebrospinal fluid from living patients who generously donated part of their body to science essentially. We're very fortunate to the families who donated their deceased relatives' brains to this study as well. Without these donations, we simply wouldn't be able to do our research and we highly value human research. We believe that this is more translatable to human conditions and is more likely to lead to formidable therapeutics. Going forward, we're interested in expanding these studies to try to find whether the immune pathway that we've found disregulated in Lewy body dementia could be targeted therapeutically. Using the cerebrospinal fluid, we want to try to determine whether we can detect changes in patients as they progress from healthy aging towards neurodegenerative diseases. And if we can retrospectively predict whether a patient will progress towards neurodegenerative disease by looking at their cerebrospinal fluid immune profile.
 
Erin Spain, MS [00:13:53] Have you been able to meet some of these patients and see sort of the setup that we have with these clinics, where people are coming in on a regular basis and taking part in studies?
 
David Gate, PhD [00:14:01] I have not, but I've been fortunate to work with the talented clinicians here and to formulate protocols to make best use of patient samples. I think this is a key thing. Patients want to know that if you're taking their cerebrospinal fluid, if you're analyzing their blood, or if if they're consenting to donate their brain to science, I think it's really important that they know these are valuable resources to us and that we're going to actually use them in the best way we possibly can to make findings that impact the future patients. I think that's a very selfless thing to donate a part of your body to science. And I really have a lot of admiration and respect for these patients who do this. It's really a brave thing to do. And you know, a lot of these diseases, they impact families. You know, a patient may have had a relative in the past who had very similar symptoms to them. And, you know, grandma died much earlier than anyone would have expected, and they're seeing this trend in their family, and they don't want the same impact on the future generations of their families.
 
Erin Spain, MS [00:15:09] Do you think there is a genetic piece to this?
 
David Gate, PhD [00:15:12] There certainly are genetic risk factors for pretty much every neurodegenerative disease. And interestingly, many of these genetic risk factors are directly tied to the immune system, which is a bit shocking. The majority of patients who have neurodegenerative diseases, it's not a direct familial connection, but there are genetic risk factors. I like to call them immuno-genetic risk factors that impact your propensity to develop these diseases.
 
Erin Spain, MS [00:15:47] What are those?
 
David Gate, PhD [00:15:48] A lot of them are involved in T cell responses. A lot of them are involved in the immune system of the brain. So your brain has an endogenous immune system comprised of what are known as innate immune cells or microglial cells. These immune cells go into the brain when you're developing as an embryo. It's pretty fascinating. And so you have these immune cells in your brain throughout your life, and a lot of the genes that are risk factors for neurodegenerative diseases are directly tied to these microglial cells. These cells are responsible for responding to viruses and for responding to pathogens in the brain. And even these toxic proteins that I mentioned, including amyloid beta and alpha synuclein. And so we believe these genes alter the immune response to these toxic proteins. Or perhaps there's some evidence to suggest that viral infections are involved in these neurodegenerative diseases. And the microglial cells that I've been mentioning, these cells are thought to interact with T cells. And in fact, in my research, we showed that there are T cells that are directly interacting with both microglia and Lewy bodies at the same time. We show images of this phenomenon. And so we think that these microglial cells interacting with T cells are part of the disease.
 
Erin Spain, MS [00:17:15] What was the reaction to this paper published in Science from the community? What did you hear?
 
David Gate, PhD [00:17:20] Well, I think the reaction has been very positive. I think it's a rigorous study. It involves over 300 patients. We looked at these patient samples in every possible way we could. I think what we found is a very unique and distinguishable aspect of the disease where we identified this immune pathway we think is involved in the disease, but could be specific to a particular group of patients with Lewy body dementias. I think there's still a lot to be learned about the distinguishing features of these disorders. For instance, my research shows a very particular response to alpha synuclein peptides, I mentioned. These are the proteins that comprise the Lewy bodies. We show that these toxic proteins can elicit a very specific immune response, and we believe this response is toxic. Other labs in also rigorous studies have identified T cells that respond in a different way to alpha synuclein peptides, and I don't think either of us are wrong. I think that there's just a diverse response to these toxic proteins, and this is likely mediated by immunogenetics.
 
Erin Spain, MS [00:18:40] Now that we are in this era of human genomics, it's so much easier to gather these samples and sequence them and see what you have. Do you think that the timeline is going to move up here as far as therapeutics?
 
David Gate, PhD [00:18:51] Absolutely. I think that's sort of the prerogative now is to make use of these tools that we now have. I would call this the era of big data where you can now generate reams of data to the point where we can't even store this data on a computer. We have to use powerful servers that store tons of data and to crunch this data down, to extract out these key findings from these large volumes of data and to synthesize this into a comprehensive message that the masses can understand and that drug companies can utilize to develop therapeutics.
 
Erin Spain, MS [00:19:31] What's next on the horizon for you? You recently received an NIH Pathway to Independence Award and an Early Career Award from 10X Genomics. Tell me about those and what other research projects you're now going to be able to embark upon.
 
David Gate, PhD [00:19:45] These awards have been very humbling for me to receive early in my independent research career. They set me up very well. You know, I was given funding by Northwestern University to start my lab. The NIH award was federal money, which is provided by taxpayers, so thank you all, all the viewers out there who pay their taxes. We wouldn't be able to do this research without the support from Northwestern and from the NIH, and this award from 10X Genomics has really set me up well to utilize the state of the art technology in the field of genomics.
 
[00:20:22] So going forward, we're interested in utilizing these genomics technologies, not just to analyze cells, but we can now apply very similar techniques to tissue samples. So historically, we've been really limited by what we can assess in a tissue sample and now we can take these tissues — many of these tissues have been preserved in pathology departments for decades. We can take these samples and cut slices of these brains and put them onto slides and then sequence the genes from those tissues. And so we're interested in applying our same genomics analyses to these brain tissues and to see if the changes that we see in the immune system reflect changes in the brain. And this is, I think, a really exciting time to be involved in neuroimmunology because it seems like every week we're making a new finding in this field that is still, I think, in its infancy. There are very talented people in this field that study these neurodegenerative disorders in particular. I think going forward, we're going to see some really major advances in therapeutic development therapies that target the immune system specifically. You know, I'm optimistic. I think these disorders are devastating, and pretty much every family in the United States is affected by a neurodegenerative disorder in some manner. There's six million patients with Alzheimer's disease alone. Parkinson's disease, also millions of patients. But I am an optimist. I think that there is a lot of talent, a lot of brilliant people working in this area, and I think that we're going to see some real strong advances in therapeutic development in the next decade.
 
Erin Spain, MS [00:22:16] Thank you so much, Dr. David Gate, for sharing this information with us. We hope to have you on again when new studies come out and we'll be following your research and your story here.
 
David Gate, PhD [00:22:26] It was my pleasure. Thank you so much for the discussion.
 
Erin Spain, MS [00:22:37] Thanks for listening. And be sure to subscribe to this show on Apple Podcasts or wherever you listen to podcasts and rate and reviews. Also for medical professionals, this episode of Breakthroughs is available for CME Credit. Go to our website, feinberg.northwestern.edu, and search CME.