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Thanks to recent advances and discoveries. We will discuss the relationship between the vascular system and the neurodegeneration, specifically Lewy body disorders. Our guest is the first author of the review. She is Sephira Ryman from the Department of Neurology University of New Mexico Albuquerque in the US and also from the Mind Research Network.
The title of the article is Abnormal Cerebrovascular Activity, Perfusion and Glymphatic Clearance in Lewy Body Diseases. So Sephira, welcome to the MDS Podcast.
[00:00:51] Prof. Sephira Ryman: Thank you for having me. I'm so excited to be here.
[00:00:54] Dr. Michele Matarazzo: Well I would like to start from the background of the issue here as a movement disorder [00:01:00] neurologist, I have to confess that vascular neurologist and movement disorders specialist, we don't share much in our regular routine in the hospital. How did you end up focusing on the connection between neurovascular health and Lewy body diseases?
[00:01:14] Prof. Sephira Ryman: So I, I really appreciate this question. So I am a clinical neuropsychologist. And I see patients essentially across all disciplines from neurology, psychiatry, internal medicine. And it's always interesting how each of the different specialties really conceptualizes disease mechanisms even within neurological specialties.
So in my practice, vascular risk factors are always big red flags. We know there's certainly big predictors of adverse cognitive outcomes. So and in terms of movement disorders, we're obviously taught that we want to rule out vascular Parkinsonism differentiate idiopathic PD, but I was never really satisfied by some of the mechanisms [00:02:00] which we are taught with, regards to Parkinson's disease and the vascular influences on cognitive outcomes. It's quite a murky topic if, if you really dive in and there's so many disparate frameworks about how to even approach that topic. I worked at a the Pacific Udall Center, which is a large Parkinson's center focused on cognition, as well as the Stanford Alzheimer's Disease Research Center, which is obviously, the intersection of memory disorders and and movement disorders.
So I think I've been fortunate as a neuropsychologist to kind of be at the intersection of all these different fields and kind of gathering the different perspectives in a way throughout my training and I was really fortunate to come back to New Mexico where I've now, work within the movement disorders here with Dr. Pirio Richardson, who's been wonderful support. I've been working with Andrew Mayer, who's sort of disambiguating the role of neurovascular [00:03:00] influences on traumatic brain injury outcomes. And then finally Gary Rosenberg, who's a vascular neurologist, and he's kind of done some foundational work in the mechanisms of cerebrovascular small vessel disease. And so this has all kind of come together in a, RO3 project that we're doing now, evaluating the cerebrovascular contributions to cognitive impairment in Lewy body diseases.
My early conceptualizations of this are actually somewhat different than what ended up in this review paper. Based on what we know about cerebrovascular disease, my early thoughts where it was maybe this co occurring disease process.
So,
similar to Alzheimer's disease, you get some individuals who have co occurring cerebrovascular disease, and that certainly predicts worse cognitive outcomes. But as we collected the data and started to look at this new cerebrovascular reactivity paradigm, Which is, essentially putting [00:04:00] individuals in the MRI scanner, exposing them to carbon dioxide, and that elicits this robust cerebrovascular response. And what we found was quite interesting in that Parkinson's patients showed a pretty significantly delayed response, as well as generally reduced response relative to the healthy controls in our study, this really was against this conceptualization of co occurring disease as we saw really robust across all of the Parkinson's patients. but it kind of was one of those findings that essentially opens up more questions than it answered, because, you it suggests it's more central to the disease.
[00:04:45] Dr. Michele Matarazzo: Yeah. Well, that's very interesting. You were touching a lot of different aspects that are extremely interesting and they're fundamental to what's the neuropathology and what's the basis of your Lewy diseases. You were talking about copathology. You were talking about how [00:05:00] the vascular health influences some of the aspects of the body diseases, such as the cognition, but also how the vascular problems are inherent to the lower body diseases themselves. And I think, well, as you were saying, there are a lot of unanswered questions and that you try to answer somehow in this review.
And actually there are three aspects that are the focus here on, of your review, which are the cerebrovascular activity, perfusion, and the glymphatic clearance. And they're all related to something that you call the neurovascular unit or the neurovascular complex. Those are some concepts that might be very clear to you, but that are not in the daily vocabulary of movement disorder experts.
Can you explain what these terms mean and their significance in the context of Lewy body diseases?
[00:05:50] Prof. Sephira Ryman: Yeah, absolutely. So I'm sure your listeners are aware that many different disciplines have been interested in this neurovascular unit, which, broadly [00:06:00] speaking, is really essentially the interaction between the neurons, glial cells, and the cerebrovascular system. So the term Neurovascular coupling is most commonly used to understanding that interaction, which you know, initially was maybe conceptualized as as one directional relationship, but it's increasingly appreciated sort of this, there's this bidirectional relationship between the neurons and glial cells and the cerebrovascular system. And you can break down the different components of these systems based on their roles, there's the, the role of providing adequate perfusion to the brain and then there's also the blood brain barrier, which allows for the passage of blood. Selective substances in and out of the brain as well as some waste clearance. And then the third component is the the glymphatic system, which is sort of this relatively new system that we're really trying to kind of [00:07:00] understand at a fundamental level. But we know it's very active during sleep and is involved in the clearance of, waste products in the brain. and I think one, one thing that we highlight in the review paper, which from my perspective is particularly important to movement disorders, is that early conceptualization of neurovascular unit really focused kind of that interaction, but a more recent sort of expansion of the concept has now termed it the neurovascular complex.
And what that distinction is making is that, there's so many upstream influences on neurovascular coupling that we've somewhat neglected to incorporate and kind of with regard to the Findings that I mentioned earlier, we were seeing that Parkinson's patients just have this global delay in their cerebrovascular response. That kind of highlights to me that maybe there is some upstream influences because it seems so broadly in the [00:08:00] brain. It's not necessarily specific to any one region. And I think it really highlights, the complex role between autonomic system and providing sufficient blood flow, as well as, the role of cardiovascular risk factors.
So we highlight this as a really important area of future research to, to sort of begin to understand the cerebrovascular activity.
[00:08:21] Dr. Michele Matarazzo: Yeah. I really liked the figures of the paper because you can really see the upstream and the downstream effect of what is the neurovascular complex and how it interacts with a lot of different things in the brain. And it's very much complex and there are a lot of loops that are very difficult to dissect.
And I think, There will be a lot of research that will help us understand how this impacts these diseases in the future. Now going back to one of these aspects as you mentioned in the paper, there is evidence that the cerebrovascular blood flow impacts some steps of the neurodegenerative cascade in Parkinson's disease.
How [00:09:00] this happen?. What I mean is, what factors are involved and what are the consequences in the brain, such as alpha synuclein aggregation or neuronal loss, which are some of the things you mentioned in the paper. Yeah, so one of the
[00:09:15] Prof. Sephira Ryman: things I was trying to answer is, you know, so if this is something that we, if we see altered cerebrovascular activity in the review paper, we also highlight that there's, pretty consistent findings that there's reduced perfusion in regions that are central to Parkinson's. I wanted to explore, this is very much a sort of a hypothesis generation activity at this stage. But you know, what are the potential mechanisms if these are potentially early disease processes, how could those influence established disease processes such as Alpha synuclein aggregation and neuronal loss.
So one of the things is the most obvious mechanism, if you're [00:10:00] getting reduced perfusion, you might have hypoxia insufficient glucose. There's several basic studies that have linked hypoxia and insufficient glucose to the initiation of alpha synuclein aggregation. Most of the studies haven't connected the hypoxia to altered cerebrovascular activity, which is something we, we sort of highlight in the article. But there's a lot of Potential different pathways that can influence each other certainly there's an increase in reactive oxygen species that can potentially damage the mitochondria, you can see increased inflammatory responses. And then the other component of our model is sort of this episodic hypoperfusion that we, we think is a key mechanism, but then the, there's this sort of failure of the metabolic clearance system, which is the glymphatic system we've sort of mentioned.
But it's definitely a topic that's [00:11:00] interesting and across neurodegenerative conditions where, if we're emphasizing that the misfolding and aggregation of different proteins are causing these diseases. It would be particularly exciting if we can understand how the failure of this clearance system might be influencing those disease processes and, and potentially highlighting an avenue for intervention.
[00:11:24] Dr. Michele Matarazzo: Indeed. And actually, when you think about the intervention and how, you know this like the cerebral blood flow, for example, impact or even relate to Parkinson's disease. One of the problem is that we need to measure it accurately. And the cerebrovascular reactivity, which is one of the outcome measure or biomarkers that you looked into, but what biomarkers in general do we have?
If you can talk a little bit more about that specific measure or what else can we do to measure in vivo the health of our neurovascular system.
[00:11:54] Prof. Sephira Ryman: Yeah, so the there's sort of a lot of work in the vascular [00:12:00] cognitive impairment fields that are sort of further along in terms of developing these MRI biomarkers and a lot of that work focuses on flare imaging, quantifying the white matter hyperintensities, some diffusion tensor imaging techniques. And I think a challenge. With regard to movement disorders is we're sort of in that complicated, potentially co occurring cerebral small vessel disease that we might capture with flare imaging but now based on our work, we're kind of shifting to Think that maybe some of these are actually more central to the disease process.
So our review paper focused on perfusion, which is, quantifying cerebral blood flow, which is usually based on arterial spin, labeling, imaging and then the cerebral vascular reactivity paradigm, which I mentioned before, which that's a really nice paradigm for Capturing how robust is the cerebral vascular response by [00:13:00] using carbon dioxide.
We, we're basically challenging the system so we can see how robust that responses for each individual. So in a way, I kind of think of it like a stress test for your, your cerebral vascular system. You're challenging it, and then you can kind of quantify different aspects of the response. And then the glyphatic system, I would say we don't have many great measures at this point. There's the, a diffusion tensor imaging metric that looks along the perivascular spaces to quantify diffusion along that space. There's some studies that quantify the sinuses some are looking at flow. Some are just overall looking at volume and things.
So many indirect approaches are sort of underway. And 1 of the things that I'm actually particularly interested in is that there's actually a lot of work highlighting that exposure to carbon dioxide. Or a change in cerebrospinal fluid [00:14:00] flow to a much greater degree than other components such as cardiac pulsatility, or just general respiration. So we know in terms of studying the glymphatic system that cardiac signal and respiration both kind of have this sort of pulsatile influence on CSF flow.
So it's actually in a way activating the lymphatic system for lack of a better word, but our cerebrovascular reactivity paradigm actually is driving CSF flow as well. We're working on a manuscript now illustrating that, that those are actually closely coupled. So in terms of the biomarkers, I would say that we kind of have a lot of work to do almost differentiating the mechanisms and what, the interaction of potential cerebrovascular small vessel disease versus what might be central to Parkinson's before we can really try and get a biomarker to, be able to quantify that system and sort of differentiate patients from controls
[00:14:59] Dr. Michele Matarazzo: [00:15:00] yeah, I think it, as you were mentioning all of these things, I think it sounds that we are at very early stages of this to understand what, what will be the best biomarkers to look into this different aspects. We probably will end up with different biomarkers to look at different aspects of our neurovascular health and how it influences this neurodegeneration and specifically Lewy body diseases.
And also While you were talking, one other big problem is is going to be the classical problem of association versus causation because, there may be a lot of things that will be associated with PD or with Lewy body dementia, but to understand what is causing what, it's going to be very much complicated unless we end up with a very good biomarker and we can apply it longitudinally and even probably a prodromal stage in Lewy body diseases. And actually, you have discussed quite a lot. [00:16:00] of the glymphatic system already, like it's a normal thing. But when I was studying medicine, it didn't exist. So let's just get a little bit back into that. And let's explain a little bit to our audience, what is it and what is its role physiologically in the healthy brain and what evidence do we have that it has anything to do at all with with PD and and Lewy body diseases.
[00:16:26] Prof. Sephira Ryman: Absolutely. Yep. You can tell I get excited talking about the glymphatic system.
So I'm sure all your listeners know that it's, it's established that, the kind of foundational models or CSF flows from the choroid plexus through the ventricular system and subarachnoid spaces, ultimately is absorbed into the arachnoid granulation.
So the glymphatic system is almost like an extension of that system in a way. We're sort of learning that some of the CSF flows into the perivascular spaces surrounding the blood [00:17:00] vessels. And the theory is that it's kind of pushed into the interstitial space and that there's some sort of, They call it bulk flow or flow between the different perivascular spaces and that flow is, what's helping clean metabolic waste products. And then that's taken up and transferred into the meningeal lymphatic vessels for cleanup. So, historically we didn't, we basically just thought that the brain didn't really have a lymphatic system or the equivalent of what the. peripheral system has. So the glymphatic system now we're realizing is there's sort of some parallels there. And a lot of the foundational work has focused on sleep. So we know that the system is particularly active in sleep. The aquaporin 4 channels are just These channels that open up during our non REM sleep phases, and they actually facilitate significantly more interstitial [00:18:00] fluid into the system. And then a key thing that was sort of relevant to the cerebrovascular system is that we're now appreciating that the cerebrovascular system is also kind of the the pulsatility of the cerebral vascular system or changes in the blood flow might actually be one mechanism by which the kind of fluid flow travels through the interstitial space. So I think it's definitely a system that there's still several unknowns. There's so many components that are somewhat even speculative. And even the question of if the bulk flow travels from the perivascular spaces into the perivenous spaces is controversial.
Some argue that there's maybe just local exchange within the the periarteal spaces. Hopefully that's a A decent primer, but I'm sure there's going to be we're going to be learning a lot about this system in the [00:19:00] years to come.
[00:19:01] Dr. Michele Matarazzo: but recently, there's It's almost a hype with the glymphatic system these days. So they're talking a lot about the possibility of the glymphatic system being responsible to clean the brain from all this protein that are accumulating. And well obviously there is a lot of discussion about.
What are actually tau or alpha synuclein and so on doing in the brain, but there is some evidence that when the glymphatic system is not working properly these proteins accumulate more in the brain. Is that right?
[00:19:34] Prof. Sephira Ryman: Yeah, so that's the theory and the interest in understanding the system is that, if you have altered lymphatic clearance, so you're getting accumulations of things potentially in Parkinson's. Alpha synuclein, and that system's failing to clear it. And I think a really exciting future area is, is certainly that we know that, sleep disturbances are so common in Parkinson's disease. Obviously, there's REM [00:20:00] sleep behavior disorder, but there's a lot of other components that even, insomnia in midlife. So, there's a lot of evidence that the sort of sleep disturbances are one component that's driving the failure of this lymphatic system. And from our review paper, we're also emphasizing that The altered cerebrovascular function is also failing to drive this system, so you sort of get a significant reduction in the clearance and then the end result is potentially the increase in alpha synuclein and potential aggregation, and things like that.
[00:20:38] Dr. Michele Matarazzo: Okay. Now we are running out of time, but I don't want to close the interview without asking you about another crucial aspect you discuss in the paper, which is the blood brain barrier permeability. How does this fit into the overall story of the Lewy body diseases and its pathology?
[00:20:56] Prof. Sephira Ryman: So, in our framework I think the [00:21:00] changes in the blood brain barrier, which some of the literature would highlight that it's actually, the blood brain barrier changes might not be the earliest thing to happen. It's sort of a maybe an after the disease mechanisms have kind of progressed to a point where there's high levels of inflammation. And that's what might be damaging the blood brain barrier. So certainly this is all, all very theoretical at this point, but we posit that it's, it's more of a later component of the mechanistic framework.
[00:21:30] Dr. Michele Matarazzo: Now I just want you to tell me if you have something more in mind for future research in the field, or could you highlight some of the most promising direction that might lead to early intervention or even treatments for Lewy body diseases?
[00:21:44] Prof. Sephira Ryman: So I think this work kind of highlights a lot of future directions. What we're most interested is exploring this interaction between cerebral vascular activity as a driver of glymphatic clearance. I think it's really important to understand that [00:22:00] interaction of the autonomic dysfunction, more traditional cardiovascular risk influence, and sleep system dysfunction. Particularly early in the disease, I think, it'd be most impactful if we can identify if any of these changes can be used to detect early disease changes. And, we identify those individuals early. much earlier than, more significant neurodegeneration has occurred.
So, that's sort of the future directions that we're moving towards.
[00:22:30] Dr. Michele Matarazzo: Well, thank you for so much for being with us today. We have had Sephira Ryman from the Department of Neurology, University of New Mexico, Albuquerque in the US and also from the Mind Research Network. And we have discussed the article abnormal cerebrovascular activity, perfusion and glymphatic clearance in Lewy body diseases.
Thank you, Sephira. And thank you all for listening.
[00:22:52] Prof. Sephira Ryman: Thank you so much for having me. It's been a pleasure.
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