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International Parkinson and Movement Disorder Society
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Concomitant pathologies and their clinical impact in multiple system atrophy

April 15, 2024
Dr. Eduardo Fernandez discusses with Dr. Hiroaki Sekiya the surprising findings of his study evaluating the presence of concomitant pathologies and how they impact the disease progression in a large cohort of patients with MSA from the Mayo Clinic brain bank. Read the article

[00:00:00] Eduardo Fernandez: Hello everyone, and welcome to a new episode of the MDS Podcast, the official podcast of the International Parkinson and Movement Disorder Society. My name is Eduardo Fernandez from the UCL Queen Square Brain Bank in London, and we are going to discuss today the importance of copathologies in multiple system atrophy.

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One of the challenges that we face as clinicians in an ageing population is the presence of multiple comorbidities and polypharmacy, but also the pathologist face a different problem and we will probably soon in clinical practice face the same challenge of the presence of multiple copathologies. And when we analyze brain tissue.

We are going to discuss the paper recently published in Movement Disorders, Frequency of Comorbid Pathologists and Their Clinical Impact in Multiple System Atrophy. I have [00:01:00] the pleasure to have with me, Dr. Hiroaki Sekiya from the department of neuroscience and Mayo clinic in Florida. Thank you very much for joining us today.

[00:01:09] Dr. Hiroaki Sekiya: Thank you for inviting me. Nice to meet you.

[00:01:12] Eduardo Fernandez: So comorbid pathologists there are different terms. Comorbid, concomitant, co pathologists. What do they mean by that? And how do we know which are comorbid and not the main pathology? And why is it important to do research on them? 

[00:01:27] Dr. Hiroaki Sekiya: So in our study, in our study context, so we focus on multiple system atrophy, MSA. So the pathological hallmark of multiple system atrophy is an abnormal aggregates of alpha synuclein. So other pathological conditions like Alzheimer's disease, neuropathologic change, or even Lewy pathology are considered comorbid pathologies in this text, in context. Yes.

[00:01:53] Eduardo Fernandez: And why do you think it's important to assess them? So, it's something that we commonly find in neurodegenerative disorders. As [00:02:00] I said, it's something that's probably challenged in a different way as clinicians. So why is it important to evaluate comorbid pathologies in neurodegenerative disorders in general?

[00:02:10] Dr. Hiroaki Sekiya: Yeah, in general, yeah, mixed pathology is very common because aging is one of the most important factors for developing neurodegenerative disorders. And as we get older, we might get more pathologies in our brains. So it is kind of common stuff to have more than one pathologies in our brain. But when we think about a treatment. So especially in the age of the protein focused therapies, we have to find a good target for the treatment. So we considered comorbid pathologies. Especially the frequency of the comorbid pathologies are important to think about a suitable target of the therapeutic target.

[00:02:52] Eduardo Fernandez: So let's focus now on your study. So you assessed as you said the copathologies in a large cohort of patients with multiple system [00:03:00] atrophy. 160 patients, which is an impressive figure. Tell us a bit about the methods of the study, where these patients recruited from and what neuropathological assessment did you perform in your study?

[00:03:13] Dr. Hiroaki Sekiya: Thank you. So we aim to understand the frequency of comorbid pathologies in autopsy confirmed MSA in our brain bank, the Mayo Clinic Brain Bank. So we recruit many brains from all over the United States. So the brains are sent to us and we examine brains. Standardized method and we, in this study, we examined the comorbid pathologies, pathological conditions, including Alzheimer disease, neuropathologic change, ADNC, and Lewy-related pathology and atrophic brain disease or AGT and age-related T astrogliopathy, or ARTAG.

And TDP 43 pathology and cerebral amyloid angiopathy CAA and cerebral small vessel disease. [00:04:00] So we examined seven pathological conditions besides MSA, yes.

[00:04:05] Eduardo Fernandez: So it's a very detailed and systematic assessment of the main and neurodegenerative diseases and what was your results with regards to the prevalence of copathologies in this cohort? How frequent were they?

[00:04:18] Dr. Hiroaki Sekiya: So among 160 MSA cases, 8 percent had ADNC and 5 percent had radiated pathology, 8 percent had AGT and 9 percent had ARTAG, 7 percent had TDP 43 pathology. 18 percent had CAA and 8 percent had small vessel disease. So regarding the number of copathologies, 62 percent had no significant copathologies and 21 percent had one copathology and 13 percent had two and 3 percent had three and 1 percent had four and 1 percent had five.

So, the majority of MSA patients in this study had no significant comorbid pathologies. [00:05:00] And even when we include one or two, minor, pathologies, more than 80 percent had fewer comorbid pathologies. So that was kind of surprising for us because in as we've talked, the mixed pathology is very common in many neurodegenerative disorders.

So MSA, we found a bit surprising that majority of patients didn't have it.

[00:05:23] Eduardo Fernandez: It is a bit surprising, particularly when comparing your results with other neurodegenerative disorders. And we will discuss a bit more about that now, but so in summary, the majority of patients with MSA present a pure MSA, let's call it this way without any additional pathologies. And as you mentioned before there was some suggestions that some of the copathologies, the addition of copathologies may be related to age.

Is that correct? 


[00:05:48] Dr. Hiroaki Sekiya: Yeah, that's why our next step was, we divided cases into four groups based on the age at onset, because age should be a very important factor to increase the number of comorbid [00:06:00] pathologies. So we compare the frequency of comorbid pathologies among those groups and found out, of course, the number of comorbid pathologies increased in older age groups, but the median number was even in the oldest.

Age group, it was one, so it was very, relatively few concerning the age. So, at the same time, we consider the age at death, not only age at onset, should affect more on comorbid pathologies. So we did the same analysis based on the groups using the age at death, and the results were similar to those in groups based on the age at onset.

[00:06:36] Eduardo Fernandez: Excellent. Let's focus now on the second part of the study, which would try to evaluate the, clinical impact of this comorbidities on the disease course of patients with multiple system atrophy. So you look at four different variables. One was disease duration. The other one was the association of comorbidities of the clinical subtype of MSA where there is cerebellar or Parkinsonian [00:07:00] and the presence of cognitive dysfunction and also the Rate of misdiagnosis, which may be a sort of a marker of sort of atypical presentation of MSA. What were your main findings of the study?

[00:07:12] Dr. Hiroaki Sekiya: Yeah, we did analysis among those kind of variables and comorbid pathologies did not affect on disease duration. So we assumed that the duration might affect, but actually there was no correlation. So even with a larger number of comorbid pathologies, they didn't shorten the disease course.

And clinical subtypes, there was no correlation between comorbid pathologies. And regarding the diagnosis accuracy, there was a kind of tendency that the patients with comorbid pathologies were less likely diagnosed as MSA. So the patients were compared to patients without comorbid pathologies.

So, it can be reasonable because if they have more comorbid pathologies, they might [00:08:00] affect or they might add some more clinical features that they had learned the incorrect diagnosis, perhaps. And at the last, we did another comparison between the cases with and without cognitive dysfunction because in this study, 30 percent of patients had cognitive dysfunction.

And the number of comorbid pathologies did not differ between patients with and without cognitive dysfunction. And among the comorbid pathologies, only ADNC was more frequent in patients with cognitive dysfunction. Which is very reasonable, but still when we consider maybe. examined the frequency of ADNC, only 15 percent of the patients with cognitive dysfunction had ADNC.

So the majority of the patients, even with cognitive dysfunction, did not have ADNC. So, which was also surprising because, almost all features were driven by the single factor, that is [00:09:00] pathological alpha synuclein in our study.

[00:09:02] Eduardo Fernandez: As you said, again, that the second part of the results were surprising again, that even when, so the copathologies are present in a minority of patients, but even when they are present, they have very little impact on the presentation of the disease. And they are surprising probably because we are comparing this with other previous studies or other diseases where the presence of copathologies are much more common and where they have a demonstrated influence on cognitive or motor symptoms.

For example, let's say Parkinson's disease where the influence of Alzheimer's disease neuropathological changes is well established in the development of cognitive dysfunction and progression to the dementia. So how would you interpret these results in the context of all the neurodegenerative disorders?

Is this something that you expected? Is this surprising? And how would you put this in the context of neurodegenerative diseases.

[00:09:52] Dr. Hiroaki Sekiya: Yeah, actually, this is very difficult to understand why there are so few comorbid [00:10:00] pathologies in MSA, because our study is kind of observational study, so we didn't understand the reason why this kind of phenomenon happened. But our study suggests that alpha synuclein in MSA is a very important factor to develop the whole clinical features, clinical manifestations.

So yeah, our interpretation is that MSA is relatively driven by single factor, that is synuclein. And that's why MSA can be considered unique among neurodegenerative disorders.

[00:10:36] Eduardo Fernandez: So it is striking how different Parkinson's disease and MSA, despite both being diseases associated to synuclein deposition how they behave completely different even from a neuropathological point of view and also the presence of copathologies. 

Thank you very much. I don't know if you have anything else to add to the discussion or anything that you wanted to discuss that we haven't touched [00:11:00] upon.

[00:11:00] Dr. Hiroaki Sekiya: Thank you very much. So, we think MSA appears to be driven by a single factor. That can be a synuclein oligomers, the area grade alpha synuclein, perhaps, or at least as a alpha synuclein itself. So it is reasonable to target alpha synuclein for therapeutic target and for MSA. So this is a very important research from our study, I think.

Thank you very much.

[00:11:24] Eduardo Fernandez: It is indeed. Yeah. Sorry. I forgot like the clinical implications of the presence of copathologies as we discussed at the beginning. This can have a relevant role in other pathologies, but it seems that they have very little impact in patients with multiple system atrophy.

Thank you very much for your time today, Hiroaki. Thank you very much to the listeners and I hope you enjoyed the episode. Bye bye for now. [00:12:00] 

Special thank you to:

Dr. Hiroaki Sekiya
The department of neuroscience and Mayo clinic
Jacksonville, Florida, USA

Eduardo de Pablo-Fernández, MD, PhD 

Department of Movement and Clinical Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom

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