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While you would think an issue will be worse only in the off stage, There's some evidence suggesting that dopaminergic replacement might reduce some aspects of cognitive function. Joining us today are Dr. Joseph Seemiller and Dr. Kelly Mills from the Department of Neurology, Johns Hopkins. They are co authors of the paper, Impact of Acute Dopamine Replacement on Cognitive Function in Parkinson's Disease, published in May issue of Movement Disorders Clinical [00:01:00] Practice.
Welcome Dr. Seemiller and Dr. Mills.
[00:01:03] Dr. Kelly Mills: Thanks for having us.
[00:01:04] Dr. Hugo Morales: A pleasure. Now to kick things off. Okay For instance, what were the gaps in knowledge that prompted you to study this association?
[00:01:23] Dr. Joesph Seemiller: So there's a variety of tests that can be used and they could be administered in different fashions. So there is variable literature some with acute dopaminergic replacement even involving, for example, the tests that we did in this study, the Stroop and the Symbol Digit modalities test, which are the two cognitive tests we used in the study.
Variably, they might use a written variation or they might look at different subscores, for example, of the stroke. So that can change from process to process. I think overall, these studies tend to have a low sample size and our ability to comment robustly on these changes might be a little limited.
[00:01:59] Dr. Hugo Morales: [00:02:00] Understand. Now using these two different tests I wonder if you can specify for the audience what are the differences between the Symbol digit modality test and the Stroop test?
[00:02:10] Dr. Joesph Seemiller: So in short the Stroop test involves 3 different components that are measured in clinic. Both of these tests read on verbally. So the Stroop test, 1, they name as many colors as they can in 45 seconds, then they name as many words as they can in 45 seconds, then they name as many mismatched color words in 45 seconds. There is the added effect, the added difficulty of the mismatched color words is what's known as interference. So, there are really kind of four ways we can look at the Stroop test in that way. The Symbol Digit Modality Test, they have 90 seconds to pair specific numbers with geometric figures.
So quite, quite different in that way.
[00:02:50] Dr. Hugo Morales: Now let's move into the details of your study and specifically the characteristics of the cohort and your population. And sort of what is [00:03:00] the experimental design in terms of how the patients were evaluated in two different states, in the off and on state.
[00:03:09] Dr. Joesph Seemiller: Yeah, in this study, 200 people with idiopathic Parkinson's disease were recruited. They came in for the morning for the study off of medication. So they had to withdraw overnight for 12 hours plus not so dissimilar to what we do for DBS testing, right? Then they had a battery of psychiatric and cognitive tests. Then they took their regular symptomatic medication dosing for the morning. And when reporting a medication on state, then they repeated the battery tests. So the two tests that are relevant to this study would be the Stroop and the Symbol digit modalities test, both done off. And then when they had the kick in of their regular morning medication.
[00:03:49] Dr. Hugo Morales: And roughly how long did it take for patients to complete both tests, in an on and off state?
[00:03:55] Dr. Joesph Seemiller: Yeah So this battery was part of a larger battery actually [00:04:00] designed by our colleague Greg Pontone who was with us at Johns Hopkins at the time and is now at the University of Florida. But he was
[00:04:08] Dr. Kelly Mills: very interested in looking at non motor symptoms and their association with dopamine replacement in Parkinson's disease. So these two cognitive tests were given. In addition to numerous other non motor assessments, both subjective and objective. Assessing anxiety, depression and other non motor symptoms that can occur in Parkinson's disease, and these are reported elsewhere. So the battery was a little over an hour for each. But the cognitive evaluations were sure to be done when there was a patient reported best on time.
[00:04:44] Dr. Hugo Morales: Thank you. And so, what are the key findings of the study, and I wonder how these results, changed the way we see acute dopaminergic treatment in Parkinson's.
[00:04:55] Dr. Joesph Seemiller: To go back to briefly how the subcomponents of these things and look at [00:05:00] how each of them improved or worsened the Stroop's components. So the color and the word naming. How many they can name in 45 seconds, right? Not mismatched, just straight naming. Those got better with levodopa.
They're thought to relate more to processing speed and working memory. And that was a consistent finding with other literature that often processing speed and working memory improved with levodopa. The other part of this group's a little bit more confusing, right? It's harder to name the mismatched color words, right?
And the added difficulty there is the interference, and that's about to represent a more executive function. It involves some level of decision making and maybe suppressing your tendency to just say the word or the color, right? And this we found did not change with levodopa. And I, I found mixed literature on this.
It wasn't clear which way that would go, but there's also a lot of different ways you can calculate this. So it's a little, it's a little bit murky to comment on how interference in the script changes or is in other literature.
The symbol digit modality test [00:06:00] which they're matching numbers with geometric figures is thought to represent traditionally a lot of processing speed.
There's some recent literature, especially in the multiple sclerosis literature, suggesting that there's other executive aspects or paired associate learning or lexical access that's involved in this test. So it's maybe more complicated than thought. We found that this got, got worse with levodopa which we thought suggests maybe some other of these higher order functions might deteriorate on levodopa.
This was maybe in opposition to some other studies, but they might have used, for example, a written or a different way of assessing it. Some people use computerized assessments, which involves more of a motor component right where we use an oral, which kind of negates as much of that as possible.
[00:06:46] Dr. Hugo Morales: So I find these results fascinating, but at the same time puzzling and I wonder is there any theoretical explanation behind the reduced performance in the Symbol digit modality test in the one hand and the [00:07:00] other hand, the Stroop test improvement on the on stage. I asked myself, is there any biological plausibility?
Is there any pathways? That differ between these two tests?
[00:07:12] Dr. Joesph Seemiller: Yeah, it's a great question. It's important to bring up the dopamine overdose hypothesis. As it regards executive function, especially, right? So we would think that, first off, these tests are a little bit messy, right? And they might involve multiple different cognitive facilities. And insofar as maybe executive function measures contribute to the symbol digit modality test, maybe this would explain why it got worse.
The dopamine overdose hypothesis would be in Parkinson's disease, there's a degeneration of dopaminergic neurons, but it's done in a gradient. So the dorsal striatum might be affected most initially, which might innervate motor circuitry, and that would cause the tremor rigidity slowness, and then eventually it'll affect more ventral striatum.
This would be in the loop that innervates the prefrontal cortex, which is important for executive [00:08:00] function. And then when we take oral dopamine, it might help more the dorsal strata loop and suppress the motor symptoms. But It will also, perhaps, overload that ventral loop, which doesn't need as much and then might cause some level of overdosing of this striatal frontal circuit and the prefrontal cortex circuitry and worsen the executive measures.
[00:08:21] Dr. Hugo Morales: Yeah But we know that as time goes by, there's a progressive, process and in that regard, I don't know if you find any correlation between that the decrement or abnormalities in the symbol digits modalities test and the duration of the disease in your patients or even other variables.
[00:08:50] Dr. Joesph Seemiller: So. We found that a lot of these measures in general worsen with progressive years of disease. So, as the disease becomes more advanced. In terms [00:09:00] of years of disease, the performance on these measures gets lower. We also looked at the levodopa equivalent daily dose that these people receive, and we found that the test decline with more duration of disease and with higher levodopa equivalent dosing and when we put both of those into our regression model, it's more driven by the years of disease. So this matches our expectations of slower processing speed and more executive problems with more advanced disease in general.
[00:09:33] Dr. Hugo Morales: Now that wraps up today's episode of the MDS podcast. A big thank you to Dr. Joseph Seemiller and Dr. Kelly Mills for sharing their valuable insights. Stay tuned for our next episode where we'll continue exploring the latest advancement in movement disorders. Until then, stay curious and keep learning.
Thanks again. [00:10:00]