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Translating blood biomarkers into the clinic for neurodegenerative diseases with Henrik Zetterberg
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Translating blood biomarkers into the clinic for neurodegenerative diseases with Henrik Zetterberg
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T00H07M07S
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Upload Date:
2023-02-03T01:15:47.3256576Z
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Language: EN.
Segment:1 Translating blood biomarkers into the clinic for neurodegenerative diseases with Henrik Zetterberg.
[MUSIC PLAYING]
Segment:2 Please could you introduce yourself and tell us about your current research focuses?.
HENRIK ZETTERBERG: My name is Henrik Zetterberg. I am a professor of neurochemistry here at UCL, and I've been working with Wolfson since 2012. My research focus is fluid biomarkers for neurodegenerative diseases, in general, but with some focus on Alzheimer's disease.
Segment:3 Can you tell us about some of the most promising new areas of research in the search for blood biomarkers for the pre-clinical phase of Alzheimer’s disease?.
HENRIK ZETTERBERG: There have been a lot of research the last few years on this, so we have developed fluid biomarkers for cerebrospinal fluid. But that, it requires a lumbar puncture.
HENRIK ZETTERBERG: It's a little bit hard to do, at least in population-based settings and in people who are asymptomatic. So we have been working quite hard on developing very sensitive assays that make it possible to measure the interesting proteins in blood samples. And the most promising one was developed here and evaluated here, and that is neurofilament light, which is a biomarker, often, neuronal loss, neuronal degeneration.
HENRIK ZETTERBERG: And the second most promising, I think, is actually beta-amyloid, which is the protein that forms clumps in the brain of Alzheimer's disease patients. And there-- the results are a little bit less promising, but there is a signal in blood, and I think it will be possible to make sense out of that signal in a population-based setting in preclinical Alzheimer's disease, especially if we take it into account together with neurofilament light and, perhaps, some of the tau markers we are working with in blood.
Segment:4 One of the biggest challenges surrounding blood-based biomarkers for neurodegenerative disease is the lack of replication and reproducibility. What could be done to overcome these obstacles?.
HENRIK ZETTERBERG: So I think a lot of the-- a lot of the problems with lack of replicability is that we have been measuring proteins and other biomarkers at concentrations just where the variation of the assays is the highest, and that makes the data uncertain. And the typical thing, then, is that some research groups report finding a significant association. It's just on the limit of significance or with very large numbers.
HENRIK ZETTERBERG: And then people try to replicate with these assays that do perform just at the limit of what they're-- they can do, and then you get these types of studies where you can't replicate the findings really. But if you develop assays that are very sensitive and specific and really measure the analyte in a predictable manner, the way you want it to be measured in the sample, then I am sure we will see-- we will start to see replication after replication, and we'll be, sort of, move this field towards a couple of solid, lab-based biomarkers for neurodegeneration.
HENRIK ZETTERBERG: And neurofilament light is such a marker. It has been replicated during the last two, three years in many, many studies, and plasma AB is getting there. Plasma tau is getting there also. So it then-- to me, it then-- five years ago, I was not that hopeful that this would work, but I think this is going to work. And then for example, if a general practitioner comes to you-- has a patient with complaints about, perhaps, subtle memory problems, I feel like it's a very reachable goal now that the GP could send off a blood sample for analysis and then get advice on whether to send the patient for further evaluation.
Segment:5 In relation to serum neurofilament light, how might the challenge of specificity be addressed?.
HENRIK ZETTERBERG: I think that it's not a challenge. I see it as an advantage, so-- but this is a common criticism against neurofilament light as a biomarker. It is not disease-specific. But I think that's great because then this could be a screening test. So that it will never tell if a patient has a certain neurodegenerative disease, but it will tell if there is neurodegeneration-- or neuronal injury, actually.
HENRIK ZETTERBERG: It doesn't have to be neurodegeneration. So it could be a minor stroke, it could be cerebrovascular disease, it could be neuroinflammatory diseases that injures-- that injures axons. So I see this as a big advantage, because then one could have it as a screening test and continue with more specific tests and, of course, the clinical evaluation and the medical history and neuroimaging, and all those things we do.
HENRIK ZETTERBERG: But it could be a first pass. And then it could also be-- which I think is an exciting use-- to use it as sort of a general biomarker for treatment efficacy. So if we have-- irrespective of disease and therapeutic intervention, if there is neurodegeneration as a component of that disease and the drug is aimed at reducing neurodegeneration, neurofilament light should normalize, or at least drop a little bit and become more age normal.
HENRIK ZETTERBERG: So when-- so I wouldn't want to address the issue with the disease and specificity. I think it's a good thing.
Segment:6 What further steps are required for the clinical translation of blood-based biomarkers?.
HENRIK ZETTERBERG: More validation. That is always the case in clinical translation. It may sound a bit boring, actually, to do all that work, but it's extremely important, and a lot of things are happening as we speak. So, for example, for neurofilament light, we have formed a consortium in collaboration with the International Federation of Clinical Chemistry and Laboratory Medicine, where we will develop a reference material for neurofilament light, then abso-- biosamples with known absolute concentrations of neurofilament light that can be used as calibrators for other commercially available assays.
HENRIK ZETTERBERG: And by having common calibrators like this, we can achieve the standardization of the measurement, if we also have a good reference method to measure neurofilament light. So validation, analytical validation, and standardization, with reference materials and methods, that will be very important. And then also, more studies across the globe in cohorts with different forms of neurodegenerative diseases and in different stages, so that we know-- learn when the biomarker becomes abnormal, if it plateaus at an abnormal level, if it goes down or up with disease progression, and things like that.
HENRIK ZETTERBERG: And ultimately, we need to know what happens in response to successful treatment, which we are lacking today for Alzheimer's, for ALS, and for frontotemporal dementia, but we have started to see breakthroughs in that field too. For example, spinal muscular atrophy, which is a pediatric neurodegenerative disease. There is an antisense-based therapy that really saves the lives of these kids.
HENRIK ZETTERBERG: And-- it might sound a bit strange, and you will hear, at the time, a lab physician-- but the biomarker normalizes. The clinicians do not need the biomarker because they see that the kids are much better, get much better. But to me, it was, of course, that's wonderful, but it was also cool to see the biomarker change. So I hope we will see this in Alzheimer's, frontotemporal dementia, Huntington's, ALS, Creutzfeldt's, and things like that.
HENRIK ZETTERBERG: [MUSIC PLAYING]
