Ep. 220: Role of Biomarkers in Translational Neurology for Monitoring Therapeutic Efficacy

00:00:00: Welcome to EA Uncast, your weekly source for education research and updates from the European Academy

00:00:19: of Neurology.

00:00:36: with two experts of the field, Henrik Teterberg and Chemma Salvador.

00:00:42: Henrik is professor of neurochemistry in different universities in many countries including Sweden United States UK and Hong Kong.

00:00:53: she's a worldwide well-known researcher with special focus for fluid biomarkers for neurological disorders especially neurodegenerative disorders.

00:01:04: Gemma Salvador is research group leader at the Barcelona Beta Research Center and associate researcher up in the Biofinder Group, Sweden.

00:01:15: Her expertise ranges from fluid to imaging biomarkers for neurodegenerative diseases especially for preclinical Alzheimer's disease.

00:01:24: Welcome everybody

00:01:26: Thank you.

00:01:29: So we will talk about most exciting Milestones that happened in the last twenty-twenty five years, let's start now to have a concrete clinical applications.

00:01:40: Since we've seen many milestones and advances in this field I would like you maybe give us short overview of what happens with the state of art.

00:01:51: where are currently in the application of fluid biomarkers in neurology especially in neurodegenerative diseases?

00:02:00: Yes, maybe I can start with some.

00:02:03: since i started this field in two thousand and one.

00:02:06: And at that time there was not much hope for blood biomarkers.

00:02:12: to be completely honest because...I think most biofluid researchers focusing on neurological diseases were worried about the blood brain barrier.

00:02:23: This of course we now know is not a barrier but something much more dynamic.

00:02:28: At that time, when we regarded the blood brain barrier as a big problem in terms of getting brain-derived molecules out reliably into the bloodstream and we had immunoassays to detect proteins related to Alzheimer's disease brain changes.

00:02:44: That worked on CSF but then tried those assays in blood with got no signal or very strange results.

00:02:51: so for while I was thinking okay let us focus on Sardospinal fluid Let's teach the world how to do safe and simple CSF sampling, but after ten years approximately new technological developments happened.

00:03:05: One important step was compartmentalization of detection reaction in standard enzyme-linked immunosorbent assays.

00:03:15: that suddenly made it possible for counter molecules in biofluid And when we started to collaborate with researchers who invented that technology, We could actually take our regular ELISA's.

00:03:28: that worked in CSF put the antibody combinations onto this digital ELISA and then relatively quickly.

00:03:36: But it got much more sensitive as is.

00:03:40: The analytical sensitivity improvement was for some biomarkers five hundred fold.

00:03:47: so it opened up a whole new a whole new class of biomarkers and we could suddenly start to measure neurofilament light, tau- and phosphorylated tau forms in blood.

00:04:00: And with the best assays we started seeing correlations with these established CSEF biomarker's.

00:04:05: that was an important step.

00:04:07: That is also where Gemma has started doing lots research on all this data.

00:04:12: I don't know if you would like to fill it here.

00:04:17: I started a little bit later than you, around ten years ago when i remember that at that time still blood biomarkers were not the thing and even thought as impossible.

00:04:29: As you are mentioning.

00:04:31: but in the last five seven years... ...I think that the explosion of biomarker and how accurate they have changed a lot changed the field enormously and we started with the first Aveda biomarkers which were not super good, but then with NFL Pitao-one eight one as you are mentioning.

00:04:56: And then we start it with Pitaot two seventeen that now I think Most useful biomarkers for Alzheimer's disease, and this started a new world in which we now can accurately measure amyloid or Alzheimer's-disease related pathology with development of new biomarker that are starting.

00:05:24: I could also add if I may Lorenzo... The technological developments have been super important.

00:05:31: But then we also have all the wonderful cohorts that our clinical colleagues have built over the years.

00:05:39: And these cohorts, I think this thing is different from twenty years ago... At that time we relied on clinical diagnosed Alzheimer's disease and were often examining people in their dementia phase.

00:05:51: Then we had controls who were sort of clinically not demented basically but no clue whether they started to accumulate Alzheimer or other neurodegenerative brain changes.

00:06:04: But now in the modern cohorts, study participants are so deeply phenotyped.

00:06:11: So there is often CSF data when we compare with blood but it's also an amyrobit tau-pit advanced MRI imaging very advanced neuropsychological testing genetics and all this has made sort of easier to evaluate biomarker candidates against better reference tests.

00:06:33: And now I mean the last meeting in London, The Old Summer Association International Conference was.

00:06:39: there are so many great new data.

00:06:42: it's the field has really also i think thanks to advancements in therapeutics that feel as really really gained speed.

00:06:51: if you feel its almost hard keep up.

00:06:54: yeah I fully agree, and if i can just add a minimal thing to what you said Henrik.

00:07:02: On top of that now we see these big collaboration studies which are also giving the robustness that we need for clinical implementation right?

00:07:12: So few years ago you were seeing important studies published in fifty patients hundred patient or a few hundreds Now studies with thousands of people, including cohorts from around the world.

00:07:30: Including subjects that are a little bit more diverse even if we're still not in good track yet but... ...more diverse than before making it so that there's more robust results and they can give us better and secure results for applying to real-world data.

00:07:53: Exactly!

00:07:54: I think all agreed.

00:07:55: One of the major advancement is that we found out that these biomarkers not only work in research contexts but they are really, really a clinical applicability and usefulness in real-world context.

00:08:10: We all agree it's an exciting time for working on this topic And now that we're starting also to have therapeutic consequences maybe we can summarize also which biomarkers are mostly used in trial settings and can be now translated into clinical activities for selecting patients or disease modifying therapies, especially for Alzheimer's disease.

00:08:46: And especially this is something that I have to look at the next years where biomarker adequate for following patients during treatment.

00:09:00: Yeah, I think that this is really a very important topic.

00:09:05: as you say Lorenzo I think at the moment Plasma Pitout to Seventeen that i was mentioning before, so the phosphorylated tau at Epitope to Seventeen is the one.

00:09:15: this is more useful both in diagnostics but also clinical trials for selecting participants.

00:09:24: So we have different trials already going on which they had been used either as a pre-screening or screening with nothing else than plasma.

00:09:36: So this is telling us that it's really very important, but its accurate enough.

00:09:42: However, this biomarker although it relates both to amyloid beta and tau tangles It's more tightly related to amylode.

00:09:51: so it's good To select those participants who have amyload in their brain But not as good at selecting or classifying whether someone has elevated tau tangles in their brain or not.

00:10:08: And this is important because although most of the more advanced trials that we are seeing now related to amyloid, We have seen previous trials where participants who behave better and have a better response for these treatments are those with very low levels of tau in their brains although without this vending, it's very useful and I'm sure that will be continuing use.

00:10:42: We may need another biomarker than now.

00:10:46: we're using Taupet but of course as being a difficult marker to be generalized across the world... ...we'll need blood tests for that!

00:10:57: At the moment We are starting with MTBR.

00:11:01: It seems that this is a promising biomarker, but still I think it needs to be validated in more cohorts and diverse populations.

00:11:12: And

00:11:13: aside from these, maybe you can jump on here... ...I also need some biomarkers for other copathologies because we know they're also affecting cognition and how the patients may respond to their treatments?

00:11:33: I agree completely with this, Gemma.

00:11:36: And now it's...I almost have a feeling that the phosphotide markers are so good we should of course continue to polish them a bit learn more about potential confounders in heterogeneous clinical settings but i think you can be very happy.

00:11:55: phosphorylated tau, especially p-tau two one seven and perhaps actually brain drive p-tau two on seven although it's a little bit unclear how essential that component of the assay eventually would be.

00:12:08: And EMTBR tau biomarkers detect tangle pathology.

00:12:12: I think thats super good!

00:12:15: One thing we are struggling with now is at least i thought that phosphotide I mean, we know that the anti-analroid antibodies decrease... ...the concentration of plasma in people getting treatment.

00:12:32: My hope was this would predict who responded well or not and i have tried to nudge a lot.. ..of people looking into these data are mixed.

00:12:44: so for awhile hoping it will decrease... Eighteen month outcome or something like that because that would have made sense to me from my understanding on how this biomarker Works, but what is clear?

00:13:02: Is that the anti animal treatment reduces plasma for statue one seven by Thirty percent.

00:13:09: some antibodies That are coming now might and against amyloid might reduce it by fifty percent even And that's good.

00:13:17: They're better than greater reduction in bed writing.

00:13:22: This reduction happens over the first six, nine, twelve months and then it doesn't decrease more.

00:13:27: So there is no complete normalization.

00:13:29: And why that is the case?

00:13:31: Is unclear.

00:13:32: but I think it relates to what you said at Gemma That this biomarker reflects amyloid But also some amyload triggered tau pato fysiologio And perhaps that amylord trigger tau patofysiology has gone amyroid independent basically.

00:13:50: So it would be very exciting to see what happens if you start treatment with other positive people.

00:13:55: That don't have that high for stop tube on seven, but they don't increase further or something like this.

00:14:02: But that's therapeutic monitoring which we are also going talk about is a bit more difficult through the biofluid based biomarkers.

00:14:10: so I think at the moment we clinically will have to rely on following their patients clinically carefully and then perhaps use some imaging measure off to declare removal of amyloid.

00:14:24: And then we have the other pathologies that you talked about, I mean it's so clear nowadays that an old summer brain especially in a slightly older person often contains some ophthalmocrine and sometimes also or often even TDP-VIII.

00:14:37: Of course everything could happen on the background of salivarovascular changes.

00:14:43: Figuring out now who is the optimal person for anti-amyloid treatment?

00:14:48: Or what would need treatment.

00:14:51: Who was the amelot-posted?

00:14:52: people would also benefit from some treatment against other neuropathological changes, that is where research front line is at a moment and there we have seen great advances I think with alpha synuclein in cerebrospinal fluid by acid amplification as it actually works quite well to qualitatively tell who has or doesn't have Alpha Synucleon aggregation.

00:15:18: That I'll say That type of assay or that assay category has also been employed in skin biopsies, which I also had this instinctive and dangerous reaction to not believe.

00:15:31: But it really looks like could be working.

00:15:36: but why is happens into the skin also?

00:15:37: I'm not sure... but exciting!

00:15:40: So yeah..that kind of qualitative alpha-sneaking positive negative readout can help us develop new biomarkers for alpha-synukin in blood, I think.

00:15:51: Because then one could in the cohorts classify it as other participants who have given CSF or a skin biopsy into amlopost even negative and that we couldn't see what in the proteome differs.

00:16:02: perhaps there could be a bland signature to reflect this in reliable manner And there are some promising results.

00:16:08: TDP is very important.

00:16:11: Other pathological change does need biomarkers.

00:16:15: That has turned out quite difficult.

00:16:17: So perhaps that's a whole topic in itself.

00:16:21: And cerebrovascular disease, of course there we have advanced MRI imaging but it would be nice with a blood biomarker pulse file That could reflect long tau alpha-synutin TDP for three degree off cerebro vascular changes potential.

00:16:36: also some downstream synactic markers where this samurso very organized results on For example MPTX are in blood.

00:16:47: Since we have two expert researchers, I would like also to ask a bit of provocative questions because amyloid and tau biomarkers are the biomarker that we know best.

00:16:58: And our roots answer this question but... The provocative question is do you still need research on amylloids or tau biomarks?

00:17:08: We saw the unmet needs in implementation of these biomarkes so they feel in which we still tell knowledge.

00:17:16: And I think we can also agree, as you said that maybe for multiple monitoring patients.

00:17:22: We need a panel of different and multiple biomarkers reflecting not only Alzheimer's pathology but the consequences of Alzheimer's Pathology Neuronal Damage Astrophobia Injuries in Objective Function As you've said pathology so may be.

00:17:40: were going to get direction on building this multi-panels also for clinical application?

00:17:50: From my end, I think that we still are far away from characterizing AD patients.

00:17:57: We're missing a lot of pieces in the puzzle and have been talking about some of them.

00:18:07: The parts that Henry just mentioned, the copathologies are important.

00:18:12: We know that but there even other aspects we haven't talked about like microglial reactivity astroglyaldreactivity and these kind of things.

00:18:20: on how this might affect the progression of the disease?

00:18:25: We still don't know.

00:18:26: so...we have to research it.

00:18:30: I think For amyloid, maybe we have a good biomarker with the beta-otosilentine.

00:18:36: But yeah We still don't know who is gonna progress to accumulate tau or Who's going to develop symptoms?

00:18:45: We have a lot of people with Amyloids in their brains that never developed symptoms.

00:18:51: So there isn't still a lot Of unknowns That if we had better biomarkers Or specific biomarkings for these questions would be better are diagnosing, treating and monitoring the response to treatments.

00:19:10: I agree completely.

00:19:11: there are so many things that also...I mean i think we should be super proud and happy with Amurodental biomarkers And having this plasma-phosphate as an acid.

00:19:25: Many of the clinical chemistry companies now they're producing a clinical grade.

00:19:32: many laboratories now have implemented in clinical practice.

00:19:34: And it's really thinking about how you... I mean, with the knowledge that we should initiate anti-annular treatment of people who are optimal candidates for a little bit of cardiovascular disease and not too advanced diseases as early as possible then this to me is wonderful tool That i feel should be implemented in primary care together A basic evaluation of cognitive dysfunction so that people could rapidly, People who might be candidates.

00:20:07: Could rapidly be identified and referred for further evaluation at a specialty clinic to potentially start with anti-ambulance treatment.

00:20:16: And in this new scenario time is sort of brain here also much like the stroke and people have talked about The importance of time.

00:20:24: Of course their timescale is different but I really think Now, it's not time to lean back regarding people with suspected Alzheimer's disease if there are symptoms that look a bit progressive.

00:20:37: So here I think the marker will work.

00:20:41: but now when we're doing it in clinical practice We are looking at thousands and thousands of patients And sometimes... Not often But some times we get strange results.

00:20:52: There is so many things to discover In those cases And we have to be humble when we interpret clinical samples in individual patients, and make sure that the clinician understands this is one part of their evaluation.

00:21:07: That should be integrated with other evaluation pieces... ...and not put too much emphasis on the phosphotide-to-one-seven test itself but make sure to diagnose the patient using a complete clinical skill set many people have developed when they see patients with suspected cognitive disease.

00:21:28: And I am a bit afraid of one thing, and that is that... So, post-torture one seven is really good biomarker!

00:21:37: That will make it possible for clinicians to identify amyloid in people with cognitive diseases.

00:21:44: There IS a risk—I actually think there's a real risk.

00:21:46: One has to be super careful here —that one gets biased towards diagnosing Alzheimer's disease in a patient with cognitive dysfunction and a post-depositive test.

00:21:59: In those cases, it would be so important to still make sure one is best connect the biomarker abnormality with the clinical picture that we don't label people with Alzheimer's when their cognitive dysfunction might have been related to alcohol misuse or sleep.

00:22:19: When you are on this early phase of cognition stressed for other reasons.

00:22:23: So a complete evaluation is needed and fostered to one's own as part of it, And then we have the current inability To easily measure the other pathologies which we will have to work on.

00:22:35: so I think you should continue to work On their existing biomarkers.

00:22:38: in Polish them.

00:22:38: learn about confounder strange cases.

00:22:42: For example We just had one case with that foster two-one seven concentration of eighteen pico gram per millilitre Which is like almost twenty-fold as high as you see in other people and this is of course something wrong.

00:22:55: But we can dilute the concentration, it's probably a real concentration In other fields.

00:23:01: in clinical chemistry.

00:23:02: We haven't learned about macro troponins for example.

00:23:06: It might have antibodies against troponin that changes to half life giving you higher concentrations.

00:23:12: Perhaps there are macro phosphatide two one seven teams also And I mean yeah.

00:23:17: so we should continue to be very alert in this field and continue to examine the existing biomarkers, but it's slightly more urgent also get new biomarker for other pathologies.

00:23:32: I just wanted say that i fully agree with Henrik.

00:23:36: It is as important try to develop new biomarks the people that see the patients and they really understand what they mean.

00:23:50: And I completely agree, we don't have to disregard... What is most important?

00:23:57: The symptoms or clinical evaluation of biomarkers should be a help not on the basis of diagnosis.

00:24:07: Lorenzo could i mention one other thing because there's one thing.

00:24:14: It's also, it might become clinically relevant very soon.

00:24:19: And that is how we best detect pre-clinical amyloid pathology if there are clinical trials on the treatment of people with amylloid according to biomarkers and no clinical symptoms?

00:24:37: There one thing has been very clear.

00:24:38: I think Screening in other settings will know this immediately, but when you do a screening using a test of the population which is then generally not enriched for risk or disease.

00:24:54: The lower prevalence of Alzheimer's pathophysiological changes would make that same test less predictive.

00:25:02: so positive predictive value off a positive test result becomes lower in a low prevalence setting than the high-prevalence setting.

00:25:13: And this sort of low prevalence problem, we have to solve that!

00:25:17: I think you can still work with foster two one seven but might had use as screen test.

00:25:23: put the cut also.

00:25:23: it supersets very sensitive with these cases and then apply more specific tests into positive population.

00:25:32: Then will start talk about is different way people if they would screening test that tells people they might have Alzheimer's.

00:25:42: That could cause harm, but if we had a screen test indicates the person can get to know okay there was positive result now and do this additional testing before we conclude on anything.

00:25:54: it would be very valuable.

00:25:55: It could be combination of FOSTA-II and GFAP for example which is very simplistic thinking.

00:26:01: It also could combine with FOSDA-II with digital cognitive assessment.

00:26:08: It could be something completely different also.

00:26:10: The important thing is that the screening test and the confirmatory tests should look at disease from different aspects, so it can't be two phosphotide tests for example because a person who is false positive one seven is much more likely to be false positive or another also but there are some exciting new biomarkers with that measure circular RNAs That could be released from neurons affected by meloid, perhaps a combination of foster to one seven with circular armies or something innovative like that I think could become really useful.

00:26:48: At the moment we could still do this by doing foster two and seven not making any strong claims on that in a screening setting but posted people who can't do a csf.

00:27:05: It would work from a sort of diagnostic pathway, theoretically but it could be challenging for the healthcare systems.

00:27:15: So that's another area where we need to work harder and do more research.

00:27:23: I'm really happy to see that Björn shared great excitement at the top and look forward to seeing what comes next in the next years.

00:27:34: We are running out of time, so I think we can start to conclude this episode.

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