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Hi, Edwin. Thank you so much for joining us on the MDS Podcast, and of course, congratulations on the award you're receiving.
[00:00:59] Dr. Edwin Jabbari: Thank [00:01:00] you very much. And thank you for the invite. It's a real pleasure to take part in this.
[00:01:04] Prof. Tiago Outeiro: It's great talking to you. Before we get into the topic of your research, which I very much want to hear about, I would like to talk a bit about your background. So, you have a PhD, and you are finishing your neurology residence. So, how is it to combine your clinical activities with your research interests?
[00:01:22] Dr. Edwin Jabbari: Yeah. So, and this is a, a well trodden path for many clinical academics in terms of combining clinical and academic work. I personally did my my PhD halfway through my medical training. So before I started my specialty neurology training which meant that I, got to spend a good chunk of time.
So four years conducting my PhD at UCL under the supervision of, professor Hugh Morris where we worked on PSP in terms of the genetics mainly of that condition. But really, the challenge comes afterwards as a postdoctoral researcher, [00:02:00] combining that with residency training, how to remain relevant in your field and managing your time is a challenge.
But I guess if it's something you're very passionate about, it's something that you eventually find ways to overcome those tricky stumbling blocks.
[00:02:13] Prof. Tiago Outeiro: And during your PhD, so it's good that you could focus on that, but unfortunately that's not the situation in many other countries. People have to combine these two activities, so this is very challenging, right?
[00:02:25] Dr. Edwin Jabbari: Yes. Yeah. Completely. People have a wide range of experiences from this when I speak to others. And yeah, it's never easy for sure.
[00:02:33] Prof. Tiago Outeiro: Yeah. Well, and now regarding your research, so the topic of your abstract, and we'll get into that, but it's focused on the use of seed amplification assays for aiding diagnostic of these neurodegenerative diseases. So generally, do you think these assays are now robust enough to really do what they're supposed to do, which is to help us in diagnosing these diseases?
[00:02:56] Dr. Edwin Jabbari: So I guess there's a few layers to [00:03:00] answering that question. So first of all, do I think that the assays are robust at detecting Lewy body pathology? Yes, I think they are. And I think that's been shown in many different alpha synuclein assays, both commercial and research based and generally the concordance in results when you look across different alpha synuclein assays it is quite high.
So yes, I think the assays are robust at detecting Lewy body pathology. In terms of whether I think these assays are ready to be applied to clinical practice at accurately diagnosing parkinson's disease. I think that there are certain, as with any test, there are certain limitations that we have to consider.
The impact of copathologies, the impact of incidental Lewy body pathology are both really important factors that will impact on our interpretation of results. And I think that there are a couple of potential solutions [00:04:00] to these problems that have partly been born out of the research that I've done. Where we could overcome these potential issues.
So in summary, I think that these assays are great. I think they're going to be a very powerful tool. I don't think we're quite there yet in terms of applying it to clinical practice. But I definitely foresee that being used in the near future for sure.
[00:04:21] Prof. Tiago Outeiro: Yeah, so you mentioned some of the limitations and of course there are some. One argument that I've heard is that "oh, these assays are not good because they report on aggregation and we don't even know if aggregation is relevant in the disease progress." So what do you think about this and how can we look at this and still consider that they might be valuable tools.
[00:04:45] Dr. Edwin Jabbari: Well, you raise a really important question. What is the relevance of this aggregation? And is it impacting on the clinical profile of a patient is impacting on the rate of disease progression, which [00:05:00] brings up another question of whether these assays may have prognostic benefits as well as diagnostic and actually through our own work, we've begun to look at this and other groups have also reported that some of the kinetic measures value in, either predicting or tracking clinical disease progression, which I guess adds a layer of evidence that actually aggregation is important. It is relevant to the progression of these conditions. So yes, I think it is very important.
[00:05:29] Prof. Tiago Outeiro: Yeah. And also the way I look at this is also that, even if we cannot say for sure whether aggregation is relevant or not, that's also beyond the point of the assay, because the assay is trying to measure something that we can associate with disease. And so as long as that's the case, then I think it's, fine because we are not looking for a mechanism.
We're looking for a readout. And so in that sense, I think this is looking like a promising tool, like you said, I mean, there's limitations. So now let's really talk about your abstract. What was the reason for your award? So [00:06:00] can you briefly describe to us what is the work that you will be presenting at the Congress?
[00:06:04] Dr. Edwin Jabbari: Yeah, sure. So I guess a good place to start is the the background to the work and what the aim of the project was. So as we all know, 1 of the main differential diagnoses for patients with suspected Parkinson's disease are the atypical Parkinsonian syndromes, and 1 of the most common atypical Parkinsonian syndromes is is PSP, progressive supranuclear palsy, and pathologically PSP and Parkinson's disease are two very distinct conditions, with Parkinson's disease being characterized by neuronal Lewy body disease and PSP being a four repeat tauopathy, but we know from clinical practice that actually clinically, It's a very different story.
There's a great deal of clinical overlap between the two conditions, especially in the early stages of symptomatic disease. So there is an [00:07:00] unmet need to have an objective diagnostic biomarker that can tease apart these two conditions. And, that is something that is lacking and the consequence of it lacking is that there are rates of misdiagnosis and also delays in diagnosis.
So we know from various cohort studies of patients with clinically diagnosed Parkinson's that if you follow these patients up, they fulfilled clinical diagnostic criteria for Parkinson's, but you follow them up over time and around 10% of them will have a revision in their diagnosis. And that in turn then leads to delays in diagnosis, which is a big issue for the atypical Parkinsonian syndrome.
So again, through our own work, we've found that diagnostic latency in PSP can be up to three and a half, four years, which in a rapidly progressive disease like PSP, we can and should be doing better than this. So I guess the aim of the project really was, twofold. First on the, back of the, [00:08:00] great deal of interest in the alpha synuclein seed amplification assay.
We wanted to see what the performance of this assay was in our own CSF samples from UCL. So both clinically diagnosed Parkinson's disease samples and also clinically diagnosed PSP samples to see what the positivity rates were in those samples. And then the second aim was the development and an application of a four repeat tau seed amplification assay to see whether the combined application of both synuclein and a tau assay can enhance diagnostic accuracy for patients presenting with a Parkinsonian syndrome.
So that's the background. In terms of the samples that we had through collaboration with professor Tom Fulton from UCL, we had access to CSF samples from Parkinson's disease patients. These were patients that are enrolled in the ongoing exenatide PD three trial. So this is a trial of a GLP one agonist [00:09:00] exenatide as a central disease modifying therapy.
And through collaboration with Professor Hugh Morris, we had access to CSF samples from clinically diagnosed PSP patients and healthy controls, age matched healthy controls. Through the Prospect UK study. This is a UK wide longitudinal study of atypical Parkinsonian syndromes. And the project itself was funded by the UK PSP association which enabled me to travel to the NIH Rocky Mountain laboratories.
So this is a team led by Dr. Byron Caughey and colleagues in particular Dr. Christina Orru` and Dr. Efrosini Artikis, who I worked with on this project. And the first port of call was to apply the alpha synuclein assay to our CSF samples from those three different groups. And what we found was through the application of that assay, in PSP samples, we found that eight out of 52, so around 15% [00:10:00] of the PSP samples were alpha synuclein positive.
And then unsurprisingly in the Parkinson's cohorts, we found that 63 out of 66 of the PD samples were alpha synuclein positive. So around 95% of them, which is in line with other studies that have looked at the positivity rates in PD cohorts. And just to complete the picture that the nine healthy controls that we tested, they were all alpha synuclein negative.
So then we went one step further and in contrast to previous studies that have looked at this and taken a binary classification approach by saying whether a sample is positive or negative, We wanted to drill down into the kinetics to see if there were distinct patterns that would emerge from this.
And we found that pretty much most of the positive PSP samples for alpha synuclein had very low and slow kinetics. So what I mean by low and slow kinetics is the low part is that the [00:11:00] maximum thioflavin T fluorescent signal was much lower compared to unequivocally positive samples. And then the slow aspect is that the lag time, the time to threshold was much longer.
And if you took a plot of the bottom quartile of all of the positive samples for the max THT and the lag time, you found that there was this subgroup of samples that fell into that low and slow category. And these were most of the PSP samples, but interestingly, also a subset of the Parkinson's samples fell into that low and slow category.
Now, the interpretation of this is quite wide ranging. So in the PSP samples, what does it mean to be alpha synuclein positive with these low and slow kinetics? We suspect that this actually relates to Lewy body copathology, and actually our positivity rate of 15 percent pretty much mirrors what you find at post [00:12:00] mortem in PSP.
So we know that around 10 to 20 percent of PSP cases that come to post mortem have low Braak stage Lewy body pathology that's restricted to the brainstem. And in fact, some of our clinically diagnosed PSP cases had come to post mortem, which confirmed they definitely did have PSP, but also the alpha synuclein positive cases did have Lewy body copathology at post mortem.
So we think that's a pretty robust finding. Now, in contrast in the clinically diagnosed Parkinson's disease cases that were either alpha synuclein negative or alpha synuclein positive, but with low and slow kinetics, what does that mean? I think that there are a range of possibilities here.
So first of all, I think that the chance of misdiagnosis here is higher, and this is misdiagnosis for either non neurodegenerative causes of Parkinsonian signs like essential tremor or dystonic tremor but also the possibility [00:13:00] of misdiagnosis for one of the atypical Parkinsonian syndromes, i. e. MSA or PSP. Or even, Actually potentially one of the monogenic forms of Parkinson's disease, in particular LRRK2 PD where we know from the PPMI study, the large scale PPMI study that up to a third of LRRK2 PD patients are alpha synuclein positive. So a range of possibilities here. And really the way to look into these various hypotheses are longitudinal follow up of patients up to post mortem the application of genetics to genetically characterized cases, and also to test a 4 repeat Tau assay alongside the alpha synuclein assay. So that then prompted the final part of the project, which was the development of this 4 repeat Tau SAA.
So what we did here was Dr. Caughey's lab at the Rocky Mountain Laboratories have been working on this for quite a few years. And my [00:14:00] involvement really was in the optimizing of the assay to enhance its performance when applied to brain tissue, but also to get it working when applied to anti mortem CSF, which is obviously the aim of the game.
That's what, that's what we want to achieve here. But the starting point was brain tissue. So first of all, PSP being a four repeat telepathy, we wanted to make sure that when we applied this assay to other tauopathies, that we wouldn't be getting signal that we don't want to see. So we applied it to brain tissue from Alzheimer's patients being a mixed three and four repeat telepathy and also Pick's disease being a pure three repeat telepathy.
And in both those experiments, we found a completely flatline, no signal at all. Then we applied it to six PSP brain tissue samples from Queens Square Brain Bank. And we found that in all six samples, we had very clear signal, clear positives in all four replicates of those [00:15:00] experiments.
And then finally we applied it to six healthy control so neurologically normal controls that have donated their brains to Queen Square Brain Bank. And in those we found that five of the samples were completely negative flat lines. And in one of the samples we found that actually the four repeat tau assay was was positive.
And this concerned is initially we wondered whether this was a problem with the performance of the assay. But actually we went back and asked our neuropathologist to look at that brain in more detail. And lo and behold, what she found was incidental four repeat tau pathology, which again brings up this potential stumbling block that we need to be mindful of, of incidental pathology.
But for all intents and purposes, it appears that this four repeat tau seed amplification assay is working. It's picking up even low level incidental pathology and next steps are optimizing it for the use in anti mortem CSF.
[00:15:57] Prof. Tiago Outeiro: Well, this sounds very, very [00:16:00] interesting. And to have now the ability to look at these two types of pathology. To help improve the diagnosis. I mean, this is fantastic. I'll be really looking forward to seeing the data and talking to you at the Congress. So what are the next steps for your work?
Do you have anything planned that you want to do right away to follow up on this?
[00:16:19] Dr. Edwin Jabbari: Yeah, so there's two bits of ongoing work. The first one I've already outlined, which is, getting the assay working for anti mortem CSF. That will be a very important next step. So that work is ongoing and we're hoping to be able to report on our data in the coming weeks and next couple of months.
The other area that I'm, there's ongoing work in that I'm very interested in, as we touched on earlier, was whether these assays can be used for prognostic purposes as well. So one thing we've looked at in the Parkinson's disease samples is whether the baseline kinetic measures, so the maximum THT signal. The lag time and the AUC, whether these measures [00:17:00] can correlate with clinical disease severity. And we've done this by correlating those measures with the MDS UPDRS Part 3 scores and also the MoCA scores as a marker of cognitive severity. And actually what we've found is that the kinetic measures do correlate very nicely with the MoCA scores.
And what we suspect is that that represents how the kinetic measures are reflective of seeding capacity. So the higher your kinetic measures, the higher the seeding capacity, and therefore the more likely you are to see cortical spread of Lewy body pathology, which then leads to cognitive impairment and lower MoCA scores.
So again, the ongoing work in this respect is looking at this longitudinally. So, can the baseline measures predict a longitudinal decline in motor scores and cognitive scores? And that's something that we, again, we hope to report in the coming weeks.
[00:17:54] Prof. Tiago Outeiro: That sounds very interesting. Well, so maybe now just to end, I would like to ask you for [00:18:00] a final word to other junior colleagues that are trying to do what you've been doing, combining your clinical practice with research. Can you give them a word of encouragement so that they don't give up and they continue these two important activities together.
[00:18:17] Dr. Edwin Jabbari: Yeah, absolutely. I'd love to. I think I really love what I do. And yes, it's definitely difficult combining clinical work and academic work. But my advice to more junior colleagues would be stick with it. Find something you're really passionate about. And I feel the other thing is, which I think is really important is to have a good clinical grounding.
So see loads of patients, get familiar with the natural history of the conditions that you're researching, because by doing that, the research questions will come up just naturally from studying these patients in great detail. That is the basis of all of the research that we do coming up with questions that ultimately by answering them, we can help patients. [00:19:00] So that would be one bit of advice. And then the last bit of advice, I guess, would be to have good people around you. So mentors, clinical mentors, academic mentors both senior and junior. I found that to be particularly beneficial to me. So, yeah, I think that's a really important aspect of navigating the challenges of a clinical academic career.
[00:19:19] Prof. Tiago Outeiro: Wonderful. Edwin, it was really a great pleasure talking to you, learning about your exciting work. So thank you so much for taking the time and talking to us for the MDS podcast.
[00:19:29] Dr. Edwin Jabbari: Thank you for having me.
[00:19:30] Prof. Tiago Outeiro: We have just interviewed Dr. Jabbari on his junior award at the MDS Congress in Philadelphia. So thank you all for listening and join us in our upcoming podcasts. [00:20:00]