Advances in Supranuclear Palsy Research | Congress 2022

[00:00:49] Dr. Yaroslau Compta: Hello, and thank you to the MDs and yourself for inviting me to take part of this podcast.

[00:00:55] Dr. Eduardo de Pablo Fernandez: So it is exciting times for progressive supranuclear palsy research, and a lot of clinical research and other studies have taken place in the last few years. Would you like to summarize your highlights from those studies for us?

[00:01:10] Dr. Yaroslau Compta: Yeah, absolutely. I think that after several decades, since its original description, and I wouldn't want to forget to say a few words on the recent passing of John Steel a coauthor of the seminal description of the condition in the sixties and heavily involved in research of PSP and for the disease and an example to follow for all of us.

So, since the description and due to PSP being a rare condition, research was really challenging and difficult. But as you were saying, there's been a lot of developments. And I think we can discuss some developments from neuropathology, genetics, biomarkers, clinical aspects and the results of recent clinical trials.

[00:01:49] Dr. Eduardo de Pablo Fernandez: Let's just start with the neuropathology. And recently published diagnostic criteria. Can you tell us what's new?

[00:01:57] Dr. Yaroslau Compta: Yeah, yeah. I think that sometimes we think, okay, neuropathology, PSP is a tauopathy, we already know what everything that that needs to be known. But I think that there have been a couple of interesting papers.

One, the new neuropathological diagnostic criteria, but also the neuropathological PSP stages. So similar to Braak synuclein stages for Parkinson's or the Braak tau stages for Alzheimer's. Now we have the PSP stages, the neuropathological stages.

And in contrast to the synuclein and tau stages, it is very clear that this is a very complex condition, because there are different topographical patterns for the astrocytic and the and, and the nueronal components of the tauopathy. But in spite of these hurdle, the authors, through complex metrics analysis, were able to define six stages.

And to cut a long story short, because these are quite complicated, you can see that from the early stages, which is stage one, you get the involvement of the globus pallidus and the striatum and the thalamic nucleus. And then from stage two, you get very mild and initial involvement of the frontal cortex, but also of the ceberal white matter and thalmatic nucleus and then from stage four to the sixth stage, you get involvement of the occipital cortex.

So what the author saw in these papers is also interesting and something that has been said before, that seemingly the the glial component of the taupathy precedes the neuronal one. So this is also something that probably might have implications in the future.

And then, we have the new neuropathological diagnostic criteria for PSP. And these are also interesting. And this new neuropathological PSP diagnostic criteria require the presence of Neurofibrillary tangles, AP tangles in at least two of the following areas: the globus pallidus, subthalamic nucleus and the substantial niagra. Plus tufted astrocytes in either the perirolandic cortex or the, the putamen. So I think both these stages and these neuropathological criteria are interesting, because they get it clear that PSP is mostly a sub cortical condition with variable involvement of cortical areas, which are mostly the frontal and the varietal areas, and to lesser extent the occipital area.

And I am fond of this, because we have this classification of PSP under the front temporal degeneration umbrella. And you cannot see the temporal lobe in either the stages or the criteria. So maybe it's time for us to rethink enabling PSP as a frontal temporal condition. And maybe as we are increasingly doing, just saying that this is a neural and glial for a tauopathy with prominent subcortical and some cortical involvement.

[00:04:43] Dr. Eduardo de Pablo Fernandez: As you said, is a very complex condition from a neuropathological point of view, and also from a clinical point of view. And then probably similar challenges were faced at the time where the MDS clinical diagnostic criteria were developed. And you were part of the group developing this diagnostic criteria. This challenging, or this diagnostic conundrum, makes the development of biomarkers to help with the diagnosis even more crucial.

Would you like to highlight a few aspects of the advances biomarkers?

Absolutely.

[00:05:15] Dr. Yaroslau Compta: Yes. In one of the plenary sessions Dr. Nicely covered this complex topic. It is true that the clinical diagnosis, in spite of the relatively recent MDS clinical diagnosis criteria for PSP are difficult, and this criteria are complex because we have four domains, and three letters of diagnostic certainty, and all the new phenotypes that have been added to the original phenotype of PSP. And yes, biomarkers are most needed. So in the plenary session several different possibilities or avenues for biomarker development were covered.

And I think that we could summarize it as imaging and fluid biomarkers, mostly. And in terms of imaging, obviously we have MRI, which is a very readily and widely available tool that we have in all hospitals. But certain techniques or sequences may not be that easily applicable. But we have MRI tools like mid brain measures and the MRPI that have been published over and over to have high accuracy for PSP. But again, the consistency and the variability between measures sometimes is an important issue.

Then we have other tools which are also relatively widely available, as FDG PET. So metabolism and studies using PET imaging. And again, there have been, over several years, different studies that have highlighted the potential of this tool to differentiate between types of dimensions on the one hand and between types of Parkinsonisms on the other. But again, the figures are variable and sometimes there is a concern on the lack of consistency.

And there is now an important promise or at least interest and attention focused on PET imaging of tau lesions, so tau traces for PET. And over the last years, we have had a number of traces like FAD1451, PHK53501 and PI2620. And there is a promise that maybe these traces can allow for differentiating between tauopathies. So maybe more critical binding in Alzheimer's, and more subcortical binding in PSP. And then within PSP, so maybe rich and subcortical phenotype like Parkinsonian and variant of PSP, more subcortical bind. And then more uptake in frontal cortical areas, in speech language and frontal behavioral variants of PSP.

So this is, again, something that more work is needed, and one of the future directions that needs to be covered in multicentric studies. And is one of the areas of interest of the MDS PSP endorsed Study group, seeing if this PET imaging of tau may allow for an area diagnosis of PSP, for instance, in suggestive cases, which have the lower clinical diagnostic certainty.

[00:08:05] Dr. Eduardo de Pablo Fernandez: So you mentioned about the MDS endorsed PSP Study Group that you are a member, and also talking about the future development of diagnostic tools. What's in the future pipeline for PSP research and also for PSP treatment?

[00:08:19] Dr. Yaroslau Compta: Yeah, definitely. Obviously always improving our knowledge of disease because we all know nowadays that PSP tauopathy. But again, putting all the money on a single horse may be risky and probably tauopathy is not the only thing going wrong in PSP. So strategies on other pathogenic pathways involved in PSP are important.

And here, I would like to mention a genetic study led by Ed Jabari, which was published last year. And with using a genome white association approach, the authors found that a genetic variant associated with increased expression of LRRK2, which is a one known monogenic cause of Parkinson's disease was associated with short survival in PSP.

So we have known since description of LRRK2 that LRRK2 can be associated with tauopathy as well, but this is further strengthening this link, and this might have a clinical implications. Nowadays, we are testing in Parkinson's disease LRRK2 inhibitors should this approaches shown to be useful in Parkinson's disease. Perhaps we could try to apply them in PSP or in certain PSP cases carrying these genetic variant.

And then other lines that the MDS PSP group is pursuing, is trying to get biomarkers, not only for the diagnosis of PSP, but for an earlier diagnosis. So these suggestive PSP cases that you are not certain, whether they will turn out to have actually PSP in the end or not, having a tool, be it imaging or fluid biomarker that gives you a higher likelihood or certainty that the person actually has PSP. This would be very important.

And then in terms of treatment, we have been lucky, recent years in spite of PSP being rare condition. We have had a number of clinical trials. Unfortunately, in recent years, the trials with antibodies and against tau has been negative. And there is also an ongoing debate on how to interpret these negative results. But I think that more clinical trials certainly still targeting tau in spite of these negative results must be conducted with immune approach or maybe with other approaches, like antisense oligonucleotides.

But then also obviously being open minded and think about other possibilities for treating PSP, maybe the LRRK2 pathway could be one, and there are others like gene methylation and, and other approaches.

[00:10:43] Dr. Eduardo de Pablo Fernandez: As you said, I think that the neuropathological and then clinical complexity of the condition probably secondary to a complex interaction of different pathophysiological avenues. And definitely, I think probably all of them should be explored.

Exciting times ahead for PSP research. And I hope that we can have great news in the next MDS Congress. Thank you very very much for your time, yaroslau, and I hope you enjoyed the interview.

[00:11:09] Dr. Yaroslau Compta: It's been a great pleasure. Thank you very much.