Prodromal autonomic dysfunction in Lewy body diseases

 Today, I am delighted to be joined by three outstanding experts, David Goldstein from the NIH, whose work has been fundamental in defining the role of autonomic failure and catecholamine deficiency in synucleinopathies, including seminal studies on pure autonomic failure as a prodromal condition.

David, thank you for joining [00:01:00] us.

 Abhimanyu Mahajan whose recent work has focused on autonomic dysfunction as an early biomarker in neurodegenerative diseases, including his recent study exploring autonomic features in prodromal synucleinopathies. Abhi, thank you for being with us today.

Dr. Abhimanyu Mahajan: Thank you Michele, and thanks for having me.

Dr. Michele Matarazzo: And Alison Yarnall, professor of geriatric medicine recognized for her work on cognitive and non-motor features of Lewy body diseases, including longitudinal studies on prodromal dementia with Lewy bodies and early non-motor phenotyping. Thank you, Alison, for being with me today.

Dr. Alison Yarnall: Thanks for the invitation.

Dr. Michele Matarazzo: So, David, let me start with you. Your work has really shaped how we think about autonomic dysfunction as an early manifestation of synucleinopathies. What clinical or biomarker evidence supports the presence of autonomic dysfunction in the prodromal phase of Lewy body diseases?

Dr. David Goldstein: I think the strongest evidence is from cardiac sympathetic neuroimaging. [00:02:00] Not necessarily with I-123 MIBG which is what's used worldwide. And we can get into that later a little bit, if needed. But by fluorodopamine, [18F]fluorodopamine PET scanning, which I developed at the NIH a long time ago, and have used for more than 30 years.

The initial report was in 1997 in the New England Journal of Medicine and in that report we described for the first time a distinction between the Lewy body diseases, pure autonomic failure in Parkinson's disease. And the non Lewy body synucleinopathy, Shy-Drager syndrome, which came to be called multiple system atrophy.

Over the course of the last three decades we confirmed postmortem by looking at norepinephrine in the heart. And there's just no question that there's a profound cardiac noradrenergic [00:03:00] deficiency in the Lewy body diseases. And by and large none in multiple system atrophy.

So this biomarker not only distinguished the conditions, but also was validated by postmortem neurochemistry. Of course, then the question comes up, when does this happen? And that took a long time, but now it's pretty clear that at least in, what's called the body first form of central synucleinopathies, which again, we can get into later.

But at least in the body first form, there's no doubt that the the cardiac sympathetic lesion precedes the onset of either Parkinsonism or cognitive dysfunction as in dementia with Lewy bodies. The fluorodopamine cardiac results were also confirmed by cardiac catheterization showing that there's a drastic decrease in the rate of entry of norepinephrine into the venous range of the heart in the Lewy body diseases and not in multiple [00:04:00] system atrophy.

So I think the autonomic lesion is cardioselective in Lewy body diseases. And finally there's the matter of what about synucleinopathy elsewhere, and I'm sure we'll be talking about skin biopsies and synuclein seeding activity and the gut and vagal afferent traffic and so forth and how these are related remains a mystery.

And I think that is crucial. When you have skin biopsies that show alpha-synuclein deposition and sympathetic nerves, and you have synucleinopathy picked up on some sort of assay done in the gut, and you do this cardiac sympathetic imaging. How are they related? And to a large extent, nobody knows.

Dr. Michele Matarazzo: Yes. You really set the stage here with a lot of information already about a lot of different manifestation and a lot of different ways of measuring this. And Abhi, maybe let me bring you in [00:05:00] here. Are there any specific autonomic domains like for example cardiovascular dysfunction versus gastrointestinal, or maybe urinary symptoms, that are more frequently abnormal in prodromal cohorts?

Dr. Abhimanyu Mahajan: First of all, I could just listen to Dr. Goldstein talk about this for a few hours, and that would be the best time ever spent. My experience of course we don't have access to the incredible resources developed by him at the NIH and a large part of what of what I've been trying to do is to look at clinical cohorts and look at scale based measurements to see how they can inform the care of our patients.

The data set that we used was the PPMI, the Parkinson's Progressions Markers Initiative, which as we know is quite a rich source of data on patients, on subjects with with prodromal Parkinson's disease. Of course, there have been other data sets in the past as well, other cohorts in the past.

I think I should start by saying that one of the best papers on this early on was in 2013 by Professor Ron Postuma, where he described autonomic features, autonomic [00:06:00] symptoms, and clinical measurements by the bedside, such as orthostatic hypotension in a group of about 9 patients, and a good control group.

And he noted that there was at least one symptom per autonomic subdomain. So if you're talking about cardiovascular, gastrointestinal, genital, urinary, sexual, so on and so forth, he described at least one symptom per subdomain in a large proportion of these patients with prodromal Parkinson's disease and in the PPMI as well. It gets tricky because how much do you want to peel the onion, right?

So if you want it to be highly sensitive and you want to consider one question, so the scale that used was SCOPA-AUT, which is a validated scale by the MDS, and it has been used for a number of years. And each subsection, each autonomic subsection has multiple questions. If you take even a positive answer on one of those questions in each subdomain, then it is amazing how many of these [00:07:00] patients who are supposedly prodromal in their disease and prodromal being defined by the onset of motor features, of course. Almost all of them will have at least one question that they answer yes to.

As Dr. Goldstein said the greatest impact, at least with the outcome that we were investigating which is incident mild cognitive impairment, cardiovascular autonomic symptom burden was the one that was, we found to be most influential with a pretty high hazards ratio of 5.21. But yeah, there were others as well.

Dr. Michele Matarazzo: So you think that cardiovascular biomarkers are currently the most robust or do you think we are underestimating other domains like gastrointestinal or let's say pseudo motor dysfunction, there is something that we almost don't talk about.

Dr. Abhimanyu Mahajan: I think there's some merit to that. I think cardiovascular autonomic dysfunction has had robust biomarkers developed without doubt. And I think the more we know, the more we know how less we know. So, I wouldn't be surprised if better biomarkers are developed in other subdomains and we find them.

It [00:08:00] is also known, the study that I'm thinking about is a PD risk study from the NIH, but there've been other cohorts as well. Even if you stop talking about prodromal Parkinson's disease and we look at the recent paper that was published out of UCL London on pure autonomic failure. All of these cohorts tell a similar story.

So if you focus on cardiovascular autonomic burden, yes, you will find an association with cognition. You will find an association with pheno conversion, even survival, but constipation, genital, urinary catheter use, et cetera, has been associated with pheno conversion to MSA, for example, instead of PD DLB, right?

I think if we look more, we'll find stronger correlations with not just develop pheno conversion, but pheno conversion to a specific disease type.

Dr. Michele Matarazzo: And Alison, I'd like you bring your perspective here especially considering your work on prodromal dementia with Lewy bodies and cognitive first phenotypes. How do autonomic symptoms compare in sensitivity and [00:09:00] specificity to other prodromal markers, such as, REM sleep behavior disorder, cognitive fluctuation on neuropsychiatric symptoms?

Dr. Alison Yarnall: I wonder if I can just go back first and reflect a bit of what Abhi was just been discussing and talk about our experience in prodromal dementia with Lewy bodies. So looking at mild cognitive impairment with Lewy bodies, where we have deeply phenotype cohorts here in Newcastle that we followed up over a number of years and compared that to mild cognitive impairment with Alzheimer's and with controls.

Certainly from our experience, we did find that autonomic symptoms were commonly reported, and that was more common compared to normal aging, but in fact, it wasn't more common compared to those with MCI with Alzheimer's type pathology. And again, as Abhi says we're selling the same story.

We found that gastric and secretory psychomotor symptoms were commonly reported, but those cardiovascular type symptoms were reported as more severe.

So to go to what you've asked me specifically about was how do we compare insensitive and [00:10:00] specificity? The many of these symptoms have high sensitivities, so they're commonly present. So we see them in more than half of prodromal DLB cases, especially constipation or orthostatic hypotension, but it has much lower specificity compared to other core markers that we see. So the presence of REM sleep behavior disorder or abnormal dopamine transporter imaging.

And again, I'd very much go back to the study that Abhi talked about, which really set the scene in Parkinson's anyway, looking at IBD and following up that cohort over a number of years, which has really stood us in the stead. I think there's also been some more recent work from a group in Bologna that was published in neurology just last year.

And they looked at what the hazard ratios were for conversion, pheno converting. And again, the same sort of symptoms came out. So neurogenic orthostatic hypotension, blunted regal responses, significant risk factors for predicting pheno conversion.

Dr. Michele Matarazzo: And now talking about the [00:11:00] different symptoms in some of your work, including studies looking at early non-motor feature and progression patterns, autonomic dysfunction appears alongside cognitive neuropsychiatric symptoms rather than in isolation. Now, do you think the autonomic dysfunction is currently underweighted in the existing frameworks?

First of all, compared to dementia first where we are considering non-motor dominant trajectories. Do you think we don't think so much about autonomic dysfunction? Also if you want to comment, Alison about frameworks like the MDS research criteria from prodromal Parkinson's disease.

And so they already include the autonomic dysfunction. But do you think this criteria fully captured the spectrum we now see and we are knowing more and more, especially when considering the different types and the different phenotypes of Lewy body diseases.

Dr. Alison Yarnall: Yeah, I think an evolving landscape and I think that we're just recognizing it more and more. And I think if we delve deeper, we're going to see this and we do see this commonly. I think [00:12:00] on the flip side, a lot of these symptoms are also commonly reported in older adults and common as we get older.

And therefore there is this overlap between aging as well and between Lewy body disease.

Dr. Michele Matarazzo: Okay, now let's move into diagnostics. David, I'll come back to you. Of course, everybody feel free to jump in. So which emerging methods for evaluating autonomic function hold the most promise for detecting prodromal disease?

Dr. David Goldstein: I think it's important to distinguish clinical from objective laboratory biomarkers. This is crucial. So when it comes to orthostatic hypotension, for instance, which I think is underrepresented. It's because neurologists don't think about it unless the patient has a symptom.

It's very unusual to have orthostatic vital signs measured routinely in a neurology clinic. So of course, you're gonna underestimate the frequency of orthostatic [00:13:00] hypotension if you depend on symptoms. I'm a big fan of biomarkers and there are physiological, there are neurochemical, there are neuroimaging, there's micro neuroimaging biomarkers, and they all overlap in kind of a Venn diagram.

When it comes to physiological, I think especially about indices of diver reflex, sympathetic neural function. When it comes to neurochemical, I think about CSF levels of catecholamines and their metabolites. I'm not sure there's really too much to talk about when it comes to plasma levels, let's just say, of catecholamines and their metabolites in these conditions, except for pure autonomic failure. When it comes to neuroimaging, we already talked about the PET scanning thing and in the real world you've got your MIBG SPECT scanning, that sort of thing, looking at the heart. And when it comes to micro neuroimaging, then you've got your skin biopsies. In addition to the [00:14:00] neurochemistry about catecholamines, of course there's the synuclein seeding thing, which at least in our study was predictive in a longitudinal perspective study.

So that's also valuable. So as I see it, there's there are different domains of biomarkers, and I'm hoping that in the future there'll be a switch from purely clinical observations because I think so insensitive and nonspecific. And instead there'll be more emphasis on these different domains of biomarkers.

Dr. Michele Matarazzo: Okay, so before going to Abhi, I know you want to add something, but let me just go a little bit further talking about biomarkers. So do you think we should routinely use more of these biomarkers in clinical practice and if you had to say one or two that will become, or will have a lot of impact in the future of our clinical practice let's say in 5-10 years, what would you pick?

Dr. David Goldstein: I would take a kind of an algorithmic [00:15:00] approach. You start with things that are quick, cheap, safe, but adequately sensitive. And I think from that point of view you've got your heart rate variability analysis especially in the frequency domain.

I think that's what we found to be predictive. But there's a trade off because there's just a lot of false positives and false negatives and that sort of thing. After that, I would think I would move to the something related to synuclein.

And I think you guys know what I'm talking about. And after that, I think I would go to PET scanning, fluorodopa PET scanning of the brain. And if it can be done fluorodopa PET scanning of the heart. So we go from cheap, simple, fast, safe to who does that?

Dr. Michele Matarazzo: Yeah. Okay. So I like the idea of an algorithm. That's a very good idea. What do you think about Abhi, and what did you want to add on the biomarker discussion.

Dr. Abhimanyu Mahajan: So just something tangential to what Dr. Goldstein said, the way I think about this, I [00:16:00] think having very specific biomarkers which are very sophisticated is extremely important for us to understand the pathophysiology. Not just pathophysiology, physiology of how all of this works.

At the same time, I think there's quite a bit of merit in my opinion to not underestimate the benefit of the bedside and what we can do at the bedside. I completely agree that even orthostatic blood pressures, for example, this study happened at the University of Cincinnati a few years ago now. And we looked at patients who had bedside objective measurements of orthostatic hypotension.

And then we asked 'em about symptoms of orthostatic hypotension. And about 30% of people had no idea that their blood pressures were orthostatic. Importantly, even if they did not have an idea, even if they were asymptomatic, the risk of worse ADLs and falls were still high, right? So just because the patient doesn't recognize it does not mean that it's not impactful. At the same time, at least in my clinic, I try as much as possible have a very low threshold to get orthostatic blood pressures.[00:17:00] 

Despite the relative low sensitivity of symptoms, I still think it's very important to capture them at the bedside. A lot of our information that we have about the impact of orthostatic symptom burden and its impact on other domains in Parkinson's in studies and in cohorts followed in clinic is based on such scales, such as SCOPA and others. And not just prodromal, I think through the disease course you're talking about cognitively unimpaired Parkinson's, established Parkinson's, and even advanced DLB patients as well.

So it follows throughout the disease course and not just in prodromal Parkinson's and has potentially a therapeutic impact. One last thing I'd like to add, I think the ability to do these scales and these assessments at the bedside affords us the ability to capture information from large sample sizes which helps us to account for some of the disease heterogeneity that we see.

No matter how much we try to make these cohorts as specific as possible, there's still a fair amount [00:18:00] of heterogeneity. And so having bedside assessments helps us increase that sample size. And also it makes it more generalizable for clinical trials and what we know about the clinic.

So I do think both of these approaches to assessing autonomic dysfunction have to work in parallel. They're complimentary, of course.

Dr. Michele Matarazzo: Now let me ask the three of you, what do you think about very high and costly research biomarkers and then down to bedside to do something more easily available. But let's go one step further and let's talk about continuous monitoring. Something that we can get directly from the patient remotely. What do you think the place of this kind of devices for the future of, not just diagnosis but also understanding what happens to these patients, whether they're not with us in the hospital or in the research clinic, Alison.

Dr. Alison Yarnall: Yeah I'm a huge fan of this and I think it's the way the world is going. Here in the UK we have a 10 year plan for our NHS, one of which of the three pillars is [00:19:00] moving from hospital to community, sickness to prevention, to care at home. And I think that this is the way that we're going for any of these measures that we're talking about, as well as a multitude of other me measures, sleep, fatigue, mobility, gait, cognition even. Measuring this in someone's own environment over a seven day period means we don't have the snapshot that won't capture the inherent fluctuations that are part of Parkinson's disease and dementia Lewy bodies. And I very much think that this is where we're going and where we're moving towards.

And it would potentially reduce burden on clinician time. If we have real time patient outcomes as well, we might be able to make changes remotely prevent people having to come up to clinic. It allows for inclusion as well. So older, frailer patients, people in a rural location it would allow them to have a similar care to those living near huge university centers [00:20:00] both in a clinical and a research setting.

And I very much think that this is the way we're going, and probably not looking at one thing, so not a univar approach but taking together the algorithm that David discussed. So probably a plethora of measures, orthostatic blood pressure, heart rate variability, et cetera. And perhaps a score and being able to differentiate those who progress more quickly, more slowly, and those who require intervention. I think this is the way forward.

Dr. Michele Matarazzo: Great. So the next question was actually about using these kind of tools for risk stratification and maybe whether autonomous dysfunction could help us identify individuals at higher risk of conversion within cohorts that are already at risk of Parkinson's disease or also dementia with Lewy bodies.

Do you want to add something else on this? Maybe David.

Dr. David Goldstein: I'll refer to the PD risk study 'cause it's one of the few longitudinal perspective studies of people who have multiple risk factors to see what the predictive value is of [00:21:00] adding in different types of biomarkers. I think that's a key aspect of the PD risk study that made it almost unique.

The prediction, just based on risk factors, family history, dreaming enacting behavior, olfactory dysfunction, orthostatic intolerance, that sort of stuff. Those are very strong. Especially in combination. Substantially increase predictive, prognostic kind of outcomes in terms of pheno conversion in the future. But when you add in the biomarkers, then in essence, it's not really a matter of risk anymore. You have the disease. It's a matter of time. And I think that was the main take home lesson from the PD risk study. Those biomarkers will change a relative risk of, I don't know, fivefold to a hundred percent, it's just basically that's it. I think the future is in adding in especially cardiac [00:22:00] biomarkers to the risk factors that we've already talked about. I wanted to mention again, just pursuing the idea of doing remote or online monitoring.

I agree, that's really powerful. Very powerful. And I would add in, measures of continuous blood pressure or frequently measure blood pressure, ambulatory blood pressure monitoring, that sort of thing. Because a lot of patients don't have orthostatic symptoms, but they do have postprandial hypotension that you can pick up.

I think it's really important to find out in the patients when their orthostatic hypotension is worse during the day. Because often it's worse in the morning, and if it's worse in the morning, then you're not gonna treat the person with a vasoconstrictor around the clock.

Having that monitoring which can be assessed remotely, I think that's the future.

Dr. Michele Matarazzo: Okay, so I see we have three big fans of biomarkers here which is nice. And I also think the last message on how actionable this information is for actual [00:23:00] patients like you were mentioning David for blood pressure. That's something that we should really keep in mind.

Now after talking about this, I want to talk a little bit about the pathophysiology. Now, maybe Abhi, if you can comment on this, what can autonomic dysfunction in the prodromal phase of disease teach us about the underlying pathophysiology of Lewy body diseases?

Of course you can talk about whatever you prefer. But we've been already mentioning this body first, brain first kind of discussion. What do you think about this?

Dr. Abhimanyu Mahajan: As long as I have the license to wildly speculate, I can speculate based on what we know. But just one quick comment to what Dr. Yarnall said earlier. I couldn't help feel just 2% envy when she mentioned that the NHS has a 10 year plan of incorporating these because I can tell you we currently have a research program on using ambulatory blood pressure monitors at our center. And recently two of our patients basically lost the blood pressure monitors and that was $6,000. And I'm [00:24:00] still hoping that comes out of our research budget. So we are trying to do that for specifically all the reasons that I mentioned. But it has to come out of a grant and not from from government funding.

Having vented about that, going to your question. I think there are a number of reasonable evidence, if not in prodromal disease, then definitely in early PD and early DLB about what could be the underlying pathophysiology.

A number of these are first of all, speaking about cardiovascular autonomics dysfunction and cognition. The lowest hanging fruit I think for me to mention is cerebral autoregulation and impairment of that. I know Dr. Rymans published on this recently in the Movement Disorders journal, but there was a really nice systematic review and meta-analysis where they showed that there was a direct correlation, actually, they showed causation because it was dose responsive as well, between peripheral blood pressure fluctuations and cerebral blood flow in those with neurogenic orthostatic hypotension. So essentially, if you have blood pressure [00:25:00] fluctuations, you can have cerebral blood flow fluctuations, which would explain some of these cognitive symptoms that we see.

A case series we published recently in MDCP, we saw that in four patients there was a drop in blood pressure within an hour before patient caregiver reported cognitive fluctuation. So that's one part of it. Of course locus coeruleus has been a very hot topic for a fairly long time, and it's gaining in prominence I think recently.

Through release of noradrenaline you can have an effect not only on the autonomic features, but also on attention. By the way, this may not be specific to Lewy body disorders, but definitely in Lewy body disorders the cholinergic system, which again, I know Dr. Yarnall has published on loss of cholinergic drive. The question of alpha synuclein deposition, whether centrally or peripherally, is always in the mix, and I'm not convinced that association has completely been investigated. And I think definitely needs to. And then of course sympathetic denervation, right? Which Dr. [00:26:00] Goldstein covered early on.

So this is not an exhaustive list. It is possible that some of these, or all of these are involved in the pathophysiology. It is highly likely that the combination of which of these is involved differs by disease type and patient type. So I think all of this needs to be understood if we need to actually talk about patient treatment that works for that individual patient.

Dr. Michele Matarazzo: Okay. Well, Alison and David, you've been cited by Abhi during his answer. So if you wanna add something on this.

Dr. David Goldstein: Well, there are two fundamental questions that have never really been answered when it comes to pathophysiology. The first is what causes the catecholamine deficiency? The putamen dopamine deficiency is drastic, like 98%. No other neurotransmitter, there are other transmitters, of course, that are involved, but nothing like 98%. What causes that?

Are a variety of reactions that take place in dopamine terminals. Which of 'em are screwed up? The result [00:27:00] in that extent of deficiency. The second question is, what links the catecholamine deficiency with Lewy bodies, or in more modern terms with alpha synucleinopathy?

Why is that? That was described by Tretiakoff more than more than a century ago. This link between Lewy bodies, which he came up with as a designation and the nigral depigmentation, which now would be dopamine deficiency, the neurochemical problem.

What is the basis for that length? Those are the two questions. I have an answer. But now it's all this is a matter of concept. It's not a matter of clear data. If there were clear data, I'd be getting prizes all over the place. This is just an idea.

The idea is that what causes the catecholamine deficiency is mainly an inability to store catecholamines in vesicles, [00:28:00] vesicular storage defect. This occurs, I think, early on before there's denervation. I call it sick, but not dead phenomenon.

And what links this deficiency with alpha synuclein?

That I think is from products of the metabolism of catecholamines called aldehydes, catechol aldehydes. The aldehyde of dopamine is called DOPAL. When it spontaneously oxidizes it very potently oligomerizes forms of the protein and aggregates alpha synuclein. I think that's the link.

Lewy body diseases are not synucleinopathies, exactly. They are diseases where alpha synuclein meets up with the catecholamine metabolites, such as DOPAL. And there's a lot of preclinical evidence and so forth. DOPAL is built up in the putamen postmortem compared to dopamine in Parkinson disease.

But to [00:29:00] really convince a skeptic, you would have to do a study where you interfere with that link and then show that when you do that, you don't develop the disease. And that hasn't happened.

Dr. Michele Matarazzo: Also, the question is, why did that happen in the first place?

Dr. David Goldstein: DOPAL is being made all the time. Dopamine is being made all the time. So it's considered to be an auto toxin. It's not an environmental exposome kind of thing. It's not a genetic thing. This is part of life. It happens all the time.

In some people, if you can't detoxify that aldehyde, because let's just say you have an aldehyde dehydrogenase problem that you're born with, or you're exposed to a pesticide that is gonna inhibit aldehyde dehydrogenase activity. That is what translates an ongoing sort of challenge to homeostasis into a disease process.

This is all theoretical, but that's what I think about the pathophysiology.

Dr. Michele Matarazzo: [00:30:00] Great. Alison, before we talk about the therapeutic implication, do you wanna add something on pathophysiology or 

Dr. Alison Yarnall: Yeah, I just enjoyed these discussions and hearing all about it.

I think it all just points to the fact that Parkinson's, Lewy body diseases, DLB, they're all have a great deal of heterogeneity and it's perhaps these relative deficiency in the different neurotransmitters that contribute to that.

And I think going on to the next question it points to the therapeutic implications of this. So perhaps in the future, in this ideal rosy world where we have these biomarkers, patient came into the clinic, you were able to tell whether they were deficient in various neurotransmitters, what autonomic symptoms they had that might define their treatments and their treatments options. Additionally, I think what autonomic pro features can tell us about prodomal diseases. Also can give us an idea about risk and risk stratification. And that can lend support to who you put forward into a clinical trial.

And [00:31:00] potentially the ultimate clinical trial will be something that prevents someone pheno converting from prodromal disease into manifest DLB, PD. Potentially by determining these clinical and biomarker features of autonomic disease, it might help us decide who goes into which clinical trial.

Dr. Michele Matarazzo: Okay, so using autonomic dysfunction markers to enrich clinical trials and, help us going towards this famous and very, very much used concept right now of precision medicine, finding the right treatment for the right patient. 

Dr. Alison Yarnall: Correct. Yeah.

Dr. Abhimanyu Mahajan: May I add one point to that?

Dr. Michele Matarazzo: Of course, Abhi.

Dr. Abhimanyu Mahajan: Yeah, I think enriching clinical trials absolutely is the right way to go, but I would also say that now that we know that early autonomic dysfunction is associated with a faster time to pheno conversion, is associated with greater morbidity, lesser survival, perhaps greater cognitive risk. Even if we are not [00:32:00] using autonomic burden as an outcome, we are not using autonomic burden to enrich clinical trials. I think it's extremely important to stratify the sample in clinical trials because what we think of as normative data in terms of, the speed of progression and things like that. Is very different for those with autonomic dysfunction.

And it's a dose response relationship. So for example, in pure autonomic failure the 10 year observational cohort that was published out of UCL earlier this year, 281 patients. So it's not a small cohort. The degree of severity of orthostatic hypotension was one of the risk factors towards mortality, towards survival, and speed of progression.

So it is important that these factors be taken into account to understand what is quote unquote normal or normative data in your average patient who's been recruited into any of these studies. I think that's an important point to understand.

Otherwise, understanding of disease modification, for example, we are often comparing graphs and looking at time [00:33:00] to fill in the blank, right? And if that varies because of presence of autonomic burden, then I think that needs to be taken into account.

Dr. Michele Matarazzo: So using the knowledge we have about the predictive values of these markers and put them in the analysis of the results of clinical trials. I think that would be something very interesting. Thank you very much. We've had a very interesting and amazing conversation, so I really want to thank you.

Before we finish, I'd like to ask you one last question, the same question for the three of you. And again, I'll start with David. What do you think or what do you see as the top research priority in this field over the next 5-10 years?

Dr. David Goldstein: Identifying preclinical biomarkers.

The concept is that even if having prodromal disease there's very extensive damage already. If you develop a cognitive dysfunction, if you develop non-diagnostic Parkinsonism, that sort of thing. I think that the hope for the [00:34:00] future is identifying the disease process before the person has symptoms at all. And then the goal is not to prolong the period of symptomatic disease. It's just the opposite. The goal is to delay the onset of symptomatic disease. Everybody's gonna die.

But if you can prolong health span for a given lifespan that would be the societal goal. 

Dr. Michele Matarazzo: Perfect. Thank you. Now, Alison, what is your top research priority in the field over the next five to 10 years?

Dr. Alison Yarnall: I think management of these difficult to treat autonomic symptoms is important. There's a relative dear in the current evidence base at the present time, and it's often significant impairments to quality of life. So that would be my top research priority.

Dr. Michele Matarazzo: Great, Abhi.

Dr. Abhimanyu Mahajan: I think for me, over the next five to 10 years, if the appropriate capture of autonomic burden for every patient with a synucleinopathy who comes to the clinic, whether [00:35:00] it is a prodromal patient, early PD, late DLB, as long as you can appropriately capture it and treat those symptoms, not just for the effect of those symptoms but also, and this is a pie in the sky picture to prevent associated symptoms in the future. I think that would be the first priority for me. Specifically, I think cognitive impairment, we don't have enough things in our arsenal to attack cognitive impairment.

And I think autonomic burden, cardiovascular autonomic burden, is one of those things. It's right there in front of us. We need to do a better job in demonstrating an intervention that actually leads to an improvement in cognition. Outside of what we can surmise from correlative studies, that for me is the biggest one.

Dr. Michele Matarazzo: This has been truly a fascinating discussion, so I'd like now to thank the three of you. Thank you, David. Thank you, Abhi. Thank you, Alison, for joining me today.

Dr. Alison Yarnall: Thanks for having me.

Dr. David Goldstein: It's a pleasure.

Dr. Michele Matarazzo: And I also want to thank you of course, Sephira Ryman and the MDS Scientific Issues Committee [00:36:00] for helping shape this episode. As a reminder, the discussion will also be published as a blog post on the MDS website, curated and edited by Sephira.

And if you enjoyed this episode, don't forget also to subscribe to the MDS podcast. And thank you all for listening.