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I have with me Dr. Tommaso Schirinzi from the neurology unit at the Tor Vergata University of Rome, and we are going to discuss his recently published paper, Immunometabolic Signature Antiopathy Markers in Blood Cells of Progressive Supranuclear Palsy. This was published recently in Movement Disorders. Hello, Tommaso, and thank you very much for joining us today.
[00:00:54] Dr. Tommaso Schirinzi: Hi Eduardo, Thank you for your kind invitation to the podcast.
[00:00:58] Dr. Eduardo de Pablo-Fernandez: Just before we dived into [00:01:00] your paper, I would like to discuss a bit of the role of neuroinflammation and neurodegeneration. So we have different types of diseases and there is growing evidence that there is an interaction between neuroinflammation and neurodegeneration. We have diseases like multiple sclerosis where the primary pathophysiological mechanism is immune, but then the progressive part of the disease shares some similarities with neurodegeneration than other conditions such as anti-IgLON5 where there is a both inflammatory and neurodegenerative component. And then we have neurodegenerative disorders where there is growing evidence that neuroinflammation and inflammatory mechanisms play a pathophysiological role.
And we can include among this progressive supranuclear palsy, PSP. Can you tell us a bit more about the role of neuroinflammation in neurodegeneration in general, but in particular in progressive supranuclear palsy?
[00:01:54] Dr. Tommaso Schirinzi: Yes, we already know that inflammation, neuro inflammation, the immune [00:02:00] activation in the central nervous system or at a systemic level is now considered the major players in the pathogenesis and progression of neurodegenerative disease. Most of evidence, indeed, derives from common disorders like Alzheimer's and Parkinson's and basically consists in pathology studies showing brain infiltrates of immune cells around the neurodegeneration points.
Or in studies obtained from, living patients, in which we can find the specific immune changes that can occur even earlier than the disease onset. Or, in patients with overt disease, we can measure increased markers into the fluids or the tissues, like the gut, for example. PSP is a more rare disorder compared to PD or Alzheimer's. So we do [00:03:00] not have this body of evidence. However, the literature is growing in last years. So we have reports regarding the increase, for example, of inflammatory Cytokines into the CSF of PSP patients. So we have reports showing that the new trophics into the blood are increased in PSP patients. and also we have a very nice, PET studies showing that the neuro inflammation and tau pathology, co -localize in the brain of PSP patients and, may predict the clinical severity of disease.
So we have the basis to suppose that inflammation, immune activity are critical for the development for the progression of PSP.
[00:03:47] Dr. Eduardo de Pablo-Fernandez: and your study contributes to this this hypothesis with a series of elegant experiments. Your results demonstrate that there is a role of neuroinflammation. Your study focuses on blood on the peripheral blood [00:04:00] mononuclear cells and as I said we can probably discuss the step by a step, all the series of experiments that form part of your study.
To start with, you do the cell count to demonstrate an immune systemic response in a relatively large sample of PSP patients who were clinically diagnosed. Can you tell us a bit about the methods in this study and the results that you found?
[00:04:23] Dr. Tommaso Schirinzi: Yes, as you see, this study is composed by different parts and integrates different methodologies just to outline biological features of the peripheral immune cells in PSP. So this part regarding the blood cell count is just a case control analysis between relatively large PSP population, about 50 -60 PSP patients and 50 age and sex -matched healthy controls.
And we, collected the blood cell count and we [00:05:00] calculated the neutrophil to lymphocyte ratio. That is an index, a very easy and cheap index of immune activation. And we found that in PSP patients the blood, the white cell number was higher than controls and also the neutrophils number, was higher than controls and the neutrophil to lymphocyte was higher than controls.
And, these suggest indeed a sort of, systemic, inflammation occurring in PSP patients. That is in line with the some, results obtained by other authors in previous works.
[00:05:39] Dr. Eduardo de Pablo-Fernandez: And then you take this to a next level where in a subset of patients you isolate this mononucleate cells from peripheral blood and you run a series of experiments to try to describe the immuno metabolic signature of these cells. And you look at the mitochondrial bioenergetics and then regulatory pathways [00:06:00] of inflammation and cellular stress.
Can you tell us a bit about this second part of your study?
[00:06:06] Dr. Tommaso Schirinzi: So this part was restricted to a subgroup, as you said. We collected because basically because of experimental issues, it's not so easy working on fresh blood cells. We collected about 15 PSP patients and 15 controls and, we could assess the, bioenergy performance of, the leukocytes by, seahorse based, mito stress test that is an assay which allows for measuring, for quantifying, the consumption of the oxygen, under different experimental conditions.
And so we found that the leukocytes, the PBMC of PSP patients, had an increased consumption of oxygen compared to controls. And that is consistent with a sort of hyper metabolic state And, if we consider that [00:07:00] there is inflammation because of blood cell count data, we can suppose that this hypermetabolic state is related to the increased energy demand to sustain the inflammation. To complete this kind of evaluation of bioenergetic metabolic evaluation we also went to assess the Nrf2 pathway.
NRF2 is a transcription factor which regulates several cellular pathways, including those related to the inflammatory response in leukocytes. And, now here we use the western blot basic technique, just to measure the expression the protein quantity of the Nrf2, and it's downstream target product that is H1 one, that is promoted by the Nrf2. And we found that in the PBMC, these proteins and NRF2 and H1 were increased compared to controls that is [00:08:00] consistent with an activation of the pathway. NRF2 pathway is activated in the leukocytes of PSP patients and probably mediated the metabolic reprogramming of the leukocytes and the increased energetic production occurring in the leukocytes.
[00:08:19] Dr. Eduardo de Pablo-Fernandez: So we have an increased cell count with an immune systemic response demanding more energy. And there is evidence of over activation or over expression of the regulatory pathways. And then the last part of your study assess that the presence of tau and phosphorylated tau in these blood cells.
Can you again tell us a bit about the methods and the results that you found?
[00:08:42] Dr. Tommaso Schirinzi: Yes the methods are almost the same, just a western blot assay of the proteins. We went to measure two Tau species the total Tau and the phospho tau. And we found that in the leukocytes both the proteins, the tau proteins were increased, but the [00:09:00] significance was only for the phospho tau.
So indeed the leukocytes accumulates. pathological tau species, in PSP. Another point, is that the levels, of the phospho tau are inversely related to the PSP rating scale of the patients. So we found that the higher phospho tau in the leukocytes, the lower PSP rating scale score. And this is quite intriguing because, seem to suggest that the phagocytic capability of the leukocytes may have a role to some extent in the clinical and pathological features of the disease.
[00:09:38] Dr. Eduardo de Pablo-Fernandez: That leads to my next question. So you used a peripheral biomarker blot, which is has a lot of advantages about the practicalities and easy to obtain a biomarker, but how do you think this results of a systemic inflammatory response translate into the neuroinflammatory mechanisms that happen in the central nervous system in [00:10:00] PSP?
[00:10:01] Dr. Tommaso Schirinzi: You mentioned the clinical correlation with the findings of phosphorylated tau in their peripheral blood cells. How do you think this translates or reflects what's happening in the central nervous system?
Our findings are derived by leukocytes, no? So we are dealing with the immune system. So, first, we should refer our results to immune system issues, but, since the leukocytes accumulate the pathological tau species, probably we can imagine to use the PBMC. it is a model for PSP, indeed, the leukocyte the PBMC have the signature of the disease, the pathological tau, and also have some molecular, impairment, molecular changes.
[00:10:48] Dr. Tommaso Schirinzi: We can, suppose that the events occurring in the peripheral blood cells may to some extent reflects the events occurring at central level. So [00:11:00] maybe one possibility as is the use of PBMC as a model for PSP. The other point is regarding the tauopathy markers. We have, peripheral source, the blood cells, which have tauopathy markers. And so we may, immediately, assess and measure these pathology biomarker in a peripheral fluid and this could give boost in the development of biomarkers, in PSP. And finally, we have findings that may open, the landscape of potential targets, therapeutic targets in PSP. The immunometabolism landscape offers a series of targets into a therapeutic perspective.
[00:11:46] Dr. Eduardo de Pablo-Fernandez: These results are very promising in terms of opening a new avenue for biomarkers but also like potential therapeutic targets. Again, I would like to discuss a bit now, how would you take this forward or [00:12:00] what would be the next steps to advance in the field of neuroinflammation, particularly using a peripheral biomarkers in progressive supranuclear palsy?
What would be the next research studies needed?
[00:12:12] Dr. Tommaso Schirinzi: Yes. So it's not easy doing research in PSP, field, because the disease is very complex from a clinical and pathological points. And also we do not have, reliable models, preclinical models for PSP, in my opinion, we should implement the translational research. So in the next future we should go to work more on biological samples on different matrices. For example, we can use the peripheral blood cells, the CSF, the skin, the olfactory neurons, and use these samples to explore different biological pathways and so identify novel targets for biomarker purposes or therapeutic development.
[00:12:56] Dr. Eduardo de Pablo-Fernandez: You mentioned that doing research in the field of PSP [00:13:00] is challenging for technical reasons, but also the practicalities, as you said, PSP is a relatively rare condition, very heterogeneous clinical presentation, and I think probably there should be more international collaboration in this field.
My final question is as well do you think that in neuroinflammation in PSP is one of the main drivers of neurodegeneration? What do you feel? You mentioned the macrophagocytic ability of the peripheral blood cells. Do you think there is an initial protective mechanism that then when it's sustained over time it contributes to the cell damage?
What are your thoughts on this?
[00:13:37] Dr. Tommaso Schirinzi: It's a good question. It's also my question. But, now we do not have elements to to say, what's come first, no? But for sure we we can see that two main biological events. The inflammation, the immune activation and the neurodegeneration are, related, no? Are in association and [00:14:00] probably, these two biological pathways go in parallel and, may have reciprocal interaction.
For example, they can trigger or counteract each other and depending, for example, on the basis of the genetic background of patients or the comorbidities, they collectively lead the individual course of the disease.
[00:14:24] Dr. Eduardo de Pablo-Fernandez: Thank you very much Tommaso for joining us today and sharing the results of your research. I think the results are very interesting and I would encourage the listeners to read the full paper published in Movement Disorders. Bye bye for now.
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