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Prof. Irena Rektorová: Thank you very much, Michele. It's really a pleasure to be here.
Dr. Michele Matarazzo: Okay, so let's start with the broader context here. You focus on MCILB. Yet another acronym we have to learn, the mild cognitive impairment with Lewy Bodies. Can you explain to our listeners what that is and how it is different from, let's say, Parkinson's disease MCI [00:01:00] or dementia with Lewy bodies or other types of mild cognitive impairment?
Prof. Irena Rektorová: Yes, mild cognitive impairment with Lewy bodies is actually a prodromal, case of dementia with Lewy bodies, which can also start with affective disorder or with delirium. So MCI is one of the starts as MCI in Parkinson's disease. It typically affects attention and executive functions, but also visual processing and visual spatial functions and visual memory.
The core features include, hallucinations, Parkinsonism, REM sleep behavioral disorder, meaning that the muscles are not relaxed during REM sleep. And the people shout and enact their dreams. They move as well. And then there is fluctuating cognition and only two of these core features may be present to diagnose probable mild cognitive impairment with Lewy bodies. Nowadays we may also have indicative [00:02:00] biomarkers like dopaminergic SPECT or PET, and also MIBG synography.
So these are the indicative biomarkers, but they are done at nuclear medicine. They are invasive, they're very expensive and not broadly available. It is actually now an aim to use MRI to identify these subjects with MCI with sleepy bodies. You also asked about how different it is from Parkinson's disease with mild cognitive impairment.
I would say it's not much different, but in Parkinson's disease usually. There is first Parkinsonism and then mild cognitive impairment and dementia later on follows. However, in MCI with lewy bodies, it is rather first mild cognitive impairment, and Parkinsonism doesn't have to be present from many years.
And there are other features that I have already mentioned that combined with MCI. So this is the main difference. Also according to [00:03:00] Borghammer and others, there is this hypothesis that actually synucleinopathy, which is both MCI with Lewy bodies and Parkinson's disease, of course in case of dementia with Lewy bodies, it starts in the gut and spreads to the brain.
In case of Parkinson's disease. It is hypothesized that it starts asymmetrically in the brain and then spreads to the body. We actually did an MRI study to first differentiate or try to differentiate mild cognitive impairment with Lewy bodies from healthy controls using a specific neuro melanin sensitive sequence of MRI.
Dr. Michele Matarazzo: Sorry if I interrupt you just before we get into that now clarify what MCILB is let's move to the definition or the importance of locus coeruleus here. Now, the locus coeruleus is not very often at the center of the discussion when we talk about Parkinson's or dementia with lewy bodies.
What led you and your team to focus on the [00:04:00] locus coeruleus and why specifically in patient with MCI due to Lewy body pathology?
Prof. Irena Rektorová: There are actually many reasons because we know, I already mentioned the spread gut first and brain first. In case of gut first it is actually, pons and first dorsal nucleus of vagus then pons, and then mesencephalon to be affected in case of dementia with Lewy bodies as compared to Parkinson's disease where it's starts in the brain and then spreads via the brainstem to the to the gut, for example.
According to this hypothesis, pons would be affected before mesencephalon and substantia nigra. And it is true that based on meta-analysis and also on biopsies or necropsies actually it is really the mesencephalon that is affected before substantia nigra and substantia nigra is affected only in 66% of [00:05:00] cases of MCI with Lewy bodies. Since locus coeruleus is located in the pons we decided to study this nucleus. And second it is actually the major noradrenergic structure and we know that the noradrenaline is very important for cognitive impairment because, it is the main noradrenergic structure and the networks involve adrenal cortex and hippocampal formation for memory functions. Also, amygdala for emotional memory and stress response, for example. Then also dorsal prefrontal cortex and prefrontal cortex that is engaged in attention, working memory and executive functions.
And then control of arousal is also the function of locus coeruleus and last but not least locus coeruleus is also important for sleep and for REM sleep behavioral disorder, which is the feature which usually is present in MCI with Lewy bodies and [00:06:00] dementia with Lewy bodies, so that's why we focused on this structure.
Dr. Michele Matarazzo: Yeah. Okay. So many function for such as small nucleus. Right. And you used neuro melanin sensitive MRI to evaluate this structure, as you mentioned before. So for our listeners who may not be familiar with this technique, could you briefly explain what neuro melanin sensitive MRI is and how it works or what it tells us in the context of neurodegeneration?
Prof. Irena Rektorová: Yes it is actually T1 fast spin echo sequence. So it's very easy to acquire and it could be very widely available. We know that dopaminergic neurons in substantia nigra and noradrenergic neurons in locus coeruleus contain pigment neuro melanin. And neuro melanin is associated with both dopamine and noradrenaline meta bodies. And the source of neuro melanin contrast in this neuro melanin sensitive MRI is actually neuro melanin bind to [00:07:00] iron. And iron is paramagnetic. That's why in patients with Parkinson's disease as well as in patients with dementia with Lewy bodies or MCI, with Lewy bodies, in our case the signal in both locus coeruleus and then later on in substantia nigra is decreased as compared to healthy controls.
Dr. Michele Matarazzo: Okay. So let's get to the study itself. So you included 38 patients with MCILB and 59 healthy controls. Both underwent a series of evaluation as well as the brain MRI. Could you walk us through the design of your study?
Prof. Irena Rektorová: Yes. Actually as you mentioned these numbers of subjects underwent detailed cognitive examination, first of all, to really identify those with MCI, with Lewy bodies and also to have a look whether the neuro melanin sensitive sequence this locus coeruleus contrast ratio would differ between MCI with Lewy bodies and healthy controls.[00:08:00]
Our hypothesis was that it would indeed differ. It would be decreased signal. Then our hypothesis was that it would be mostly decreased in the caudal part because in this study we actually separated the locus coeruleus into caudal medium and rostral part to see which part is first involved in MCI with Lewy bodies, and then based on the projections of locus coeruleus we were also interested in examining how this signal in locus coeruleus is related to impairment of cognitive functions.
And we particularly thought that it would be memory, visual memory functions or executive functions that would be related to the signal decrease in the locus coeruleus.
Dr. Michele Matarazzo: Before we get to the results and we're getting there, but I was interesting to know how technically challenging is to look at such tiny portion of a nucleus that is already quite small. Was [00:09:00] it easy or you, do you feel confident that, you could really differentiate the three parts that you were mentioning?
The caudal, the rostral caudal, and the middle part of the nucleus.
Prof. Irena Rektorová: Yeah this was based on necropsy studies and we used three different slice. Very close slic e to each other. And the first one was caudal and middle and rostral. So it was as easy as that. And we used the mask where we actually visually and manually looked into the presence of the signal of the locus coeruleus on this neuro melanin insensitive MRI.
Dr. Michele Matarazzo: Okay. Now let's move to your findings. What were the key differences that you observed between MCILB patients and healthy controls?
Prof. Irena Rektorová: As predicted we could find that there was difference in between those two groups. We were a little bit surprised that it was much more on the right side. Also the difference in between left and right sides was higher in MCI with Lewy bodies as compared to age matched [00:10:00] healthy controls.
And we could indeed see that the major difference was in the caudal part. So when we separated the three parts of the locus, it was only the caudal part where patients differed from healthy controls and we could also find that. The signal in the whole right-sided locus coeruleus correlated with visual memory in MCI with Lewy bodies, which was not the case in healthy controls.
And exploratory analysis also showed that the caudal part of the locus coeruleus with the severity of symptoms of REM sleep behavioral disorder.
Dr. Michele Matarazzo: Great. And, You know, in these diseases Alzheimer's disease co pathology is very frequent. And it might represent a possible confounder for the brain pathology and for the selective vulnerability of specific brain areas such as the locus coeruleus. Now, you included in analysis the [00:11:00] plasma p-tau181, which is an Alzheimer's disease, a biomarker.
How did it affect the association that you found?
Prof. Irena Rektorová: Yes we did that. This is a biomarker of Aβ accumulation, and we know that co pathology in up to one third of all patients with already MCI, with Lewy bodies. So I thought it was an important thing to do also because the memory was the major finding, right? It did not affect the correlation.
So the correlation remained significant even after controlling for the effects of plasma p-tau181.
Dr. Michele Matarazzo: So you were confirming that, the correlation that you were seeing are not related to a Alzheimer's co pathology, because also in Alzheimer's you have locus coeruleus involvement, right?
Prof. Irena Rektorová: Yes, exactly. It might have played some role, but definitely not the major role and the major role was that of synucleinopathy, interestingly enough, in Alzheimer's disease, this nucleus is also very early to be affected, but it's rather the rostral [00:12:00] part of it. That's another proof that it's of course different from what's happening in MCI with Lewy bodies and DLB.
Dr. Michele Matarazzo: And one other thing that you mentioned in the paper is the changes of locus coeruleus are related not just to cognitive problems, but also to other non-motor symptoms such as depression or sleep disorders. What were the findings in that sense?
Prof. Irena Rektorová: That were exploratory findings. So we put them in supplementary material. That was not really the major finding, but we could find that the right locus coeruleus especially the middle part correlated with GDS depression, geriatric scale evaluating depressive symptoms of our MCI with Lewy bodies.
Dr. Michele Matarazzo: Fantastic. Now of course when, we're looking at the paper and the data and the figures although you found quite significant differences. There was some overlap between healthy controls and patients. Now, you are mentioning that. This is a very useful and possibly [00:13:00] easily available technique. I'm talking about the neuro melanin sensitive MRI. Now do you see this as a potential biomarker for early diagnosis or prognosis or DLB? Or in other words, do you think that apart from correlating with specific manifestation, this can be used on a patient level? Or do you think that there's too much overlap to be used at a patient level and it can be used maybe just as a research biomarker?
What's your take on this?
Prof. Irena Rektorová: Actually, interestingly enough the signal of locus coeruleus has been tested visually quite recently by radiologists in a larger amount of dementia with lewy bodies. So this were not early stages of dementia with Lewy bodies, but already demented patients and just by visual assessment in individual subjects the radiologist could disentangle DLB from healthy controls with more than 82% sensitivity and specificity without any other tool.
So I think yes. And we know that now [00:14:00] that neuro melanin sensitive sequence is used particularly for substantia nigra and they're automated approaches that have been used and there the sensitivity and specificity may be very high to differentiate early Parkinson's disease from dementia from healthy controls.
So I think that automated assessment of locus coeruleus might be the way forward in early stages of dementia with Lewy bodies.
Dr. Michele Matarazzo: Great. And also thinking about the translational application of this do you need specific, for example, you can you do this on a 1.5 Tesla MRI do you think? Do you need a 3T MRI or is it different or it's more or less the same?
Prof. Irena Rektorová: Yeah, it's actually I'm not aware of many studies that would use 1.5 Tesla MRI for locus coeruleus? For substantia nigra, yes. But for locus coeruleus honestly, I'm not aware of any so, it's usually either three Tesla or even [00:15:00] seven Tesla. Seven Tesla has been used at the beginning showing the decrease of the signal in this very small structure, as you say.
But it's very well, possible to assess it with three Tesla MRI, which is now widely available. I would say so, but I'm not sure about 1.5. I think probably not. Not as well.
Dr. Michele Matarazzo: Okay. Thank you. What are the next steps for your research from that point of view? Are you planning to do longitudinal studies? Because, also looking whether this change with time, I guess that would be very interesting to know and very useful.
Prof. Irena Rektorová: Yes, We now have actually a cohort of around 160 subjects with MCI, with Lewy bodies that we follow longitudinally. So we've already started assessing neuro melanin sensitive sequence from the locus coeruleus, substantia nigra, and also other sequences as well, like diffusion imaging. And, other probably very good sequences for that, like free water imaging or quantitative [00:16:00] susceptibility mapping.
So these are the sequences we've been using and we've been doing that. Yes. And also, we are very much interested in compensatory mechanisms and locus coeruleus, is again, a very interested structure in this regard. So we will use this now assessing our longitudinal data.
Dr. Michele Matarazzo: Great. Is there anything else that you want to share with our listeners?
Prof. Irena Rektorová: Hopefully the results of the longitudinal cohort as soon as we have them.
Dr. Michele Matarazzo: Okay we'll look forward to it. Okay. Irena, thank you so much for sharing your work and your insights with us. And it's been a pleasure to have you.
Prof. Irena Rektorová: Thank you very much, Michele. Thank you for inviting me.
Dr. Michele Matarazzo: We've been discussing the article Early Changes in the Locus Coeruleus in Mild Cognitive Impairment with Lewy Bodies, published in the Movement Disorders Journal with its lead author, Professor Irena Rektorová. Thank to all our listeners for tuning in and if you enjoyed the episode, don't forget to download the article and subscribe to the MDS podcast to stay informed about the [00:17:00] latest research in movement disorders.
Bye.