Ep. 205: Neurofilaments as Biomarkers in ALS and frontotemporal dementia: From Bench to Bedside

00:00:00: Welcome to EANcast, your weekly source for education research and updates from the European Academy of Neurology.

00:00:14: Hello!

00:00:14: And welcome to Eancast's Weekly Neurology.

00:00:18: My name is Raffaele Dupilso.

00:00:20: I'm Associate Professor of Neurology and Clinical Neurophysiologist at University Federico II of Naples specializing in Metrophic Laterosclerosis and Neurostimulation.

00:00:31: This mass topic is ALS and frontotemporal dementia.

00:00:35: In today's episode, we will talk about neurofilaments as a biomarker in ALS and FTD.

00:00:41: My guests are Andrea Malaspina and Francesco Di Lorenzo.

00:00:46: Andrea Malaspina is a clinician scientist specializing in neurodegenerative disorders at the clinic academic lead of the Queen Square Modern Neural Disease Center Institute of Neurology UCL-UK with focus on translational research.

00:01:04: Francesco Di Lorenzo is a neurologist at the RRCCS Foundation of Santa Lucia, whose research focuses on frontotemporal dimension related neurodegenerative disorders.

00:01:17: His works combine advanced neurophysiological technique with biomarker research to better understand disease mechanisms and progression.

00:01:25: Andrea Francesco thank you both for joining us today.

00:01:30: So, to set the stage for our discussion let's begin with a fundamental question.

00:01:35: Andrea many neurologists have heard about neurofilaments but not everyone is familiar with the biological meaning.

00:01:44: what exactly are neurofilments and why they become such an important biomarker?

00:01:50: Well thank you Raphael.

00:01:51: this I think is a fundamental questions.

00:01:55: Neurofilaments essentially proteins that make up the structure and also participate in the function of neurons, particularly abundant in axons.

00:02:11: We think they are predominantly expressed large myelinated axons but this observation obviously always limited by what we see experimentally.

00:02:27: they have a role in maintaining the structure and dimension of the axon.

00:02:35: They've been implicated, potentially other functional type of roles as support.

00:02:43: but fundamentally that's what we are.

00:02:46: there are different isoforms.

00:02:48: they essentially part of intermediate filament family.

00:02:55: We know only general consideration about the specific expression, either peripheral or central and some isophore may have more central expressions like alpha-internexine.

00:03:10: Some other like periphery which has another isophobe.

00:03:13: it's supposed to be more within the neuromuscular system but all this can obviously re-evaluate as we learn more.

00:03:22: okay thank you Francesco, would you add anything from the perspective of cognitive and behavioral neuro-degenerative disorders?

00:03:31: First of all thank you for the invitation to participate in this topic that I think is becoming really relevant.

00:03:38: And we need to set some important points.

00:03:41: as Professor Marspina just said NFL is an important component structure and function of the central nervous system and of the peripheral nervous system.

00:03:56: And, of course differently from ALS which is a disease that might affect primary secondary upper lower motor neural usually in front to temporal dementia we have mainly involvement of neurofilaments belonging but to the central nerve systems as they are part structure of the axons cell, you know their biological role.

00:04:22: It's really important in shaping the efficacy of the synaptic machinery especially for example with a function of the dendritic spines or the glutamatergic and dopaminergic neurotransmission?

00:04:35: And we know that also.

00:04:37: we studied also in FTD patients how these neurotransmitter patterns can be altered in FTd patient and neurofilament involvement might.

00:04:49: Okay, perfect.

00:04:50: So now let's move from biology to clinical interpretation.

00:04:54: Andrea when we receive a laboratory report showing elevated neurofilament levels what are we actually measuring?

00:05:03: Another fundamental question in value or concentration is not I think interpretable in absolute terms.

00:05:14: probably this isn't entirely true because very high level of neurofilaments would I think invariably associated with something happening at a neurological level.

00:05:24: But essentially, when neurofilaments were initially measured in an accessible biofluids which is blood and... We have contributed to this quite significantly developing the first essay for plasma neurofilament Guy.

00:05:46: here is Jan Skule in Basel, he did a fantastic job on this.

00:05:52: So following these initial I would say development the question has been how we could gather more information about neurodegenerative disorders their initiation and development stage.

00:06:07: there was clear understanding that neurofilaments were essentially largely as specific so not disease-specific.

00:06:16: And the other important aspect is normativity.

00:06:19: So what is a normal range of neurofilaments in relation to age, in relation pathology and healthy state?

00:06:28: When we see level of neuro-filaments as result?

00:06:31: obviously you have put it into the context of our diagnostic question.

00:06:36: so each condition has its own essentially underlying baggage presumption, if you want of assumptions.

00:06:49: So in a myotrophilateral sclerosis they are I think relatively helpful and differentiating mimics although it is clearly not resting only on neurofilaments as your clinical acumen is ruling out other potential confounders by doing investigations.

00:07:08: but essentially yes It's one of the information we use together with other clinical or paraclinical data to to characterize a condition and probably help towards diagnosis, certainly in the monitoring of the conditions.

00:07:24: Okay thank you.

00:07:26: Francesco what about this equation in FTD?

00:07:30: Well from biological point-of-view so as we say that NFL are part components of the CITO skeleton when we found in biologically fluid elevated levels of NFL we're facing an axonal damage.

00:07:46: We could say axonal damage mainly due to neurodegeneration.

00:07:51: So we are facing a neurodegenerative disease when we're having these higher levels of NFL and that's also the issue one, but will talk about this later poorness of specificity in terms of disease specificities, because there are many neurodegenerative diseases.

00:08:10: Essentially something that has been found quite relevant amount of this is activity.

00:08:20: So I can say that maybe NFL reflects the intensity of the neuron action, degeneration usually explain as a marker off rate of damage rather than simply the presence of disease.

00:08:32: because we don't know it's not important.

00:08:34: It's not a diagnostic criteria.

00:08:36: Because for sample two patient may both have FTD but one has got higher NFL levels.

00:08:42: That means probably saving a more active neurodegenerative process, and of course an effect does not tell us nothing about the driving protein or in proteinopathy.

00:08:53: The underlying proteanopathy which is out to the p-forty three or another pathology but can give us valuable information about the extent of the neuronal injury.

00:09:02: Okay thank you.

00:09:04: And now we know that neurofilament can be measured both in CSF and blood.

00:09:10: Why is blood testing become such a major adverse for clinician Andrea, especially in ALS?

00:09:18: So you're asking

00:09:20: about CSF versus Blood.

00:09:24: And why it's important that the blood measurement is important.

00:09:29: so I think It goes without saying that as a blood is more accessible biofluid and although lumbar puncturing may be sometimes requested and considered for ALS, perhaps not for the diagnosis but dissecting that condition from other potential mimics.

00:09:53: So access in blood is always an easier thing.

00:10:00: now The main problem with developing essays on low abundance protein In blood.

00:10:06: there's been a lack of parallelism.

00:10:10: so essentially Blood is a very, plasma are complex matrix measuring low abundance proteins in blood suffers from the interference of many other proteins.

00:10:23: And so you don't have this neat and linear signal and concentration when your diluting your sample in your calibration curve as you had for your standard.

00:10:35: So it was difficult to develop the SA for NFL.

00:10:38: for these reasons It is now available and equally informative as CSF for blood, it's a major development of our ability to understand the disease and monitor.

00:10:54: Okay thanks.

00:10:55: And Francesco do you think that blood based biomarker are changing in way cognitive disorder or the way they did memory clinics?

00:11:05: Yes definitely memory clinics because we know that the main diseases is Alzheimer's disease, in which now there is already shifting a revolution in therapeutics driven also the diagnostic so plasma biomarker.

00:11:22: and actually we need still international consensus and guidance to properly face this issue.

00:11:28: But of course it's also very important for the neurofilament.

00:11:33: firstly because you know its non-invasive as Professor Maspina just said much more easier biological characterization of the cognitive disorder, so we hope that they're still coming.

00:11:48: We do it for research but also other neurodegenerative or cognitive disorders like for example PSBLBD could come because this will really help researchers and also patients and their caregivers to better understand.

00:12:03: And of course NFL has been one of the first examples of this transformation.

00:12:08: first to make this kind of study.

00:12:11: In FTD is really important, we know that neurofilament are... We found it in the blood with one-to-forty ratio for the CSF and there's a strict correlation between blood and CSF.

00:12:27: so means that we can repeat multiple times.

00:12:32: also follow up follow up, not just in clinical trials as you will see.

00:12:36: that maybe is the main use of NFL.

00:12:39: It would be the main user but especially for FTD in genetic forms because pre-synchromatic patient subjects curing mutation already might have.

00:12:53: usually they had some high levels of NFL related to healthy population hence the neurodegeneration process flares, we see this increase of NFL levels.

00:13:10: so it's much easier to monitor disease progression with blood sampling for conversion.

00:13:20: To see when they will probably be able to converse a much more pathogenetic pathological activity.

00:13:28: Of course, specifically also because we know that they are really important.

00:13:32: They correlate very well with the progression of cognitive deficit like mini-mental CDR and also with other survival rates.

00:13:41: so it's really really important to have a much more easier way to see these NFL levels.

00:13:49: Yeah I think you raised an important question about presentomatic patients but where will talk later on?

00:13:57: Yeah, let's now move to the diagnostic value of neurofilaments.

00:14:02: So Andrea how useful are neurofilament in distinguishing ALS from other comos mimics such as neuropathy or myopathy?

00:14:14: I think your discrimination under the curve is reasonably good but essentially I think you discriminate very well when you've done already a bit of thinking neurologically, say your ALS, your motoneural disease patient with features that strongly point towards MND is clinically different from your neuropathy and add areas sometimes initial overlap as we know.

00:14:45: We call them mimics like for example cases of IBM or occlusion body myositis be slightly more difficult to distinguish, but neurofilament should actually give us a bit of insight and these situations.

00:14:59: So diagnostically when the disease is established or manifest at their role it's probably minimal.

00:15:08: But as Francesco was mentioning It becomes very important When you want to establish an early diagnosis in pre-syntomatic individual mutation carriers.

00:15:21: so the rise of neurofilaments indicates that you are essentially going through a prodromal stage of the disease.

00:15:31: So I think probably early diagnosis is what I would use neurofilaments for an individual at risk developing their disease.

00:15:39: Okay,

00:15:40: perfect.

00:15:41: so now let's start to the FTD perspective in FTD challenges often different because psychiatric disorders frequently enter differential diagnoses.

00:15:52: How useful is neurofilament in distinguishing behavioural variant, the FTD from primary psychiatric disorders?

00:16:02: This is the most clinically relevant application of neurofilaments in FTD.

00:16:08: That's because the behavioural variants which are one of the symptomatic parts or clinical picture of FTD Usually starts with psychotic symptoms, so resembling closely in major depression, bipolar disorder, obsessive-comparsive disorder or schizophrenic symptoms.

00:16:29: and usually we know for experience that this patient been seen already by other psychiatrists at first, the majority I refer to as bi psychiatrist after the prescription of an MRI when we see they're ready.

00:16:42: The atrophy and so in this case will know that the atrophy is uh...that we see with neuroimaging tell us that were already facing a new generation And In This Case the NFL strong.

00:16:55: the NFL levels, so the measurement of NFL level strongly support presence and underlying neurodegenerative process.

00:17:02: So I can tell you that these are so far it's very important And i think this message should be also given to the psychiatrist because they're especially for patient who exhibit onset or symptoms at a later age after fifty years old which usually is uncommon for a pure psychiatric disease, because we use it as clinician researcher quite commonly.

00:17:27: Maybe you know from another point of view if I ever see slight atrophy at the MRI or I see hypometabolism FDG i can be quite confident that we are facing and neurological disorder not a psychiatric one.

00:17:43: Of course.

00:17:43: in NFL We saw there is some studies very well conducted improved the diagnostic from this point of view.

00:17:54: And another interesting thing, sorry that I want to add is however NFL has been elevated also in other subcategories of FTD like non-fluent variant and semantic variants but not in the logopanic variant of PPA of the primary progressive aphasia.

00:18:12: a reason to explain this, because we know that the logopanic variant of the PPA is caused by amyloid pathology.

00:18:19: So there's another driving pathological process that it's affecting people with the logopenic band.

00:18:28: so in these cases and even... And then when all that however in Alzheimer disease we have some maximum damage but at least different extent.

00:18:36: also the NFL levels usually are not so elevated or raised as this is, so also in people who have belonged to primary progression of aphasia we can never increase the neurofilament but not in logopenic variant because it's amyloid pathology.

00:18:54: Okay really interesting!

00:18:56: So now let's move on another field about prognosis in ALS.

00:19:00: I would say that one of the most exciting aspects of neurofilment is their prognostic value.

00:19:07: how well do neurofilaments reflect?

00:19:09: Andreas, predict this is progression survival in ALS.

00:19:13: And I would say also that NFL changed the way we discuss prognosis with patients and family.

00:19:20: what do you think about it Andrea?

00:19:23: Yeah!

00:19:24: I mean i tend to not use neurofilament levels as routinely a prognostic indicator.

00:19:34: We have to consider the fact.

00:19:36: there are some cases.

00:19:38: We describe here neurofilament negative.

00:19:40: patients as an individual have a condition, neurodegenerative conditions.

00:19:45: I'm talking about mostly ALS whose neurofilm and levels remain quite low?

00:19:51: And this is one of the most interesting thing to understand because there are a range of variability in these neurofilaments within the phenotypic variant that diseases quite broad In general assessment of neurofilament levels in your statistical work, then they have a very good effect on prognostication.

00:20:17: So... They do.

00:20:19: but there are also other tools like for example the ENCALS risk core.

00:20:22: you can put different variables into this kind.

00:20:26: regression analysis gives us a disease trajectory.

00:20:30: I personally don't use it in a systematic way.

00:20:35: I tend to be clinically oriented, see the trajectory of the disease which is essentially your LSFRS slope from when you know the patient.

00:20:45: And if you ask... You can provide information based on all these pieces of knowledge essentially.

00:20:52: Okay thanks.

00:20:53: Francesco.

00:20:54: what about FTD and neurofilaments that help us to identify patients with a more aggressive disease course?

00:21:03: useful r-serial measurements over time.

00:21:07: Yes, this is one of the most consistent findings across FTD studies that higher NFL levels are associated with cancer disease progression.

00:21:15: and they can tell you also in my clinical practice really these morning I saw a patient which has an aggressive form of FTD particularly aggressive for more so from a clinical point of view.

00:21:28: he started so and he's got very high levels of neurofilament level both blood and CSF, and it is really going very fast.

00:21:42: So I can tell also in the clinical point-of view this is really relevant.

00:21:47: you know what makes NFR particularly valuable?

00:21:49: Is that really captures very well the intensity at an individual level!

00:21:53: This was or something this morning.

00:21:55: experience with these patients doesn't give us many information only about the diagnosis, but all about the aggressivity of this disease.

00:22:04: And it's important for patients.

00:22:05: care planning also for the patient and their caregiver from a point-of view is also important for clinical trial stratification.

00:22:16: there I really see that huge value off the NFL especially because coming back to your second part of question The serial measurements are very promising.

00:22:27: also given the high reliability of blood with CSF, repeated assessment really may allow us to monitor dynamics of pathology over time.

00:22:38: Also because there are some studies that show often the NFL levels in some FTP codes remain relatively stable after initially increasing so maybe reflecting a kind of sustained neurodegenerative process or maybe compensation for this neurodegeneration.

00:22:57: from a scientific point of view, this can be also really interesting.

00:23:00: From the trial perspective, serum misurements are particularly attractive because they may help us understand whether specific treatment is actually slowing neuronal damage.

00:23:12: so that's a field in which it's moving very rapidly than an effect application.

00:23:17: Okay Andrea just what about you said in ALS about longitudinal studies?

00:23:26: This has been done extensively by myself and also by Mike Panatar in the UK.

00:23:33: We have used this longitudinal cohorts, essentially biological samples collected at each visit time point over time And then we have essentially tracked changing concentration of neurofilaments.

00:23:51: So what do you see?

00:23:54: I think neurofilament-heavy and light chain, bear in mind that data on neurofilment heavy chains are mostly from CSF because the SA in plasma is not well established.

00:24:08: Indicate following disease onset at a level of neurofilaments remain fairly stable which itself has been challenged by different studies as shown for example a decrease over time and other that shows the show an increase particularly in fast-progressing patients.

00:24:30: But, I think this observation gives us more room for wondering what is determining the concentration of neurofilaments whether it's simply at the demise or the axon or motor cells?

00:24:46: Or there something else that affect the catabolism or interfere with your immune assay when you are essentially testing them.

00:24:57: So, the longitudinal profile neurofilaments is an important observation but it's something about which we know very little and... And we tend to come to a quick conclusion where sometimes the matter may be more complex than what appears.

00:25:19: Okay, thanks.

00:25:21: So now let's look even earlier in the disease process.

00:25:25: Andrea studies suggest that neurofilaments increase before symptom onset and genetic ALS.

00:25:31: how close are we to using them in preventive trials?

00:25:35: We have closed so far...we're testing their use already.

00:25:41: one disease contests which is the sodium gene mutation carriers taking part in the atlas clinical trial, which is essentially the early use of Toffersen upon disease onset.

00:25:57: In this subgroup or patients whether this something applicable to other areas risk developing ALS This unfortunately still an open question but we don't have much else happening.

00:26:15: The clinical trials based mostly on ASO in C-NINO, seventy two patients have so far not delivered any convincing results and therefore it would be difficult to think about prevention.

00:26:29: In that context we have published a couple of papers in twenty five.

00:26:37: there've been a few papers for publication last year About panel or biomarker prediction of ALS onset, and this is based on testing markers from large immune assays or buying the sort of ligand type of assays like Somerscan.

00:27:03: And targeting perhaps a general population in large natural history studies.

00:27:11: but we are far in what is sporadic ALS, therefore prevention and then use on neurofilaments in prevention it's still a bit limited.

00:27:24: Okay

00:27:24: thanks really interesting.

00:27:27: so Francesco you have already talked about genetic form of FTD and NFL.

00:27:33: What opportunities does this open for future disease modifying therapies?

00:27:40: Really the Genetic FTD course has changed way.

00:27:43: we think about biomarkers because we identify patients, the new generation in subjects years before they met the neuropsychrateria.

00:27:53: The major opportunity.

00:27:54: as you say there is a possibility to identify individuals who are entering early stage of disease and these early stages of diseases it's time frame which maybe therapy can have highest success rate because we're allowing them preventive on very interventional trials.

00:28:16: so In the future, I think that NFL might serve both as a marker of disease conversion and also an outcome measure to assess whether treatment is successfully reducing the neuronal injury.

00:28:32: So now we are approaching to end our discussion.

00:28:35: so if a general neurologist listening this podcast remembers only one message about neurofilaments What should that message be, Andrea?

00:28:48: The message in my view should of essentially very promising development using a tool to change the way we conceive for example clinical trials and also more we know about it.

00:29:06: More we collect information essentially approach our patients prognostication earlier on, there are a few pitfalls but essentially it can be integrated in our clinical practice.

00:29:20: I think the most interesting thing about neurofilaments to me is about how we use them to make clinical trial more targeted and cost effective not really focused on the pharmacodynamic effect of neurofilaments.

00:29:44: So we know that it is very likely, the neurofilament decrease as there is a treatment response probably preceding clinical efficacy.

00:29:56: But this is something still to be established and that there might be a lot of caveats.

00:30:00: We don't know, we don't the timings.

00:30:03: what I'm also referring to you as a priori stratification or patients allows you increase the signal from clinical trial.

00:30:10: There are some examples.

00:30:12: they have been published And The use up of stratification leading into a clinical trial like for example using anchors risk score Is good news for clinical trial.

00:30:26: Francesco, your TECOM message.

00:30:29: If I had to summarize neurofilaments in one sentence... ...I would say that NFR is currently the most practical and clinical use for biomarkers of Neuronaxonal damage in cognitive neurology.

00:30:41: It helps us in dinos but much more essential in pronosticate And increasing the monitor.

00:30:49: disease activity doesn't replace clinical imaging or this specific biomarker assessment, but it's a really powerful biological measure of neurodegeneration.

00:31:04: And maybe the most clinical value is in distinguished behavioural variant of frontotemporal dementia from psychiatric disease output for future stratification.

00:31:21: Thank you again, Andrea and Francesco for this insightful discussion.

00:31:25: Today we have explored how neurofilaments evolve from research tools into biomarker with genuine clinical relevance across DLS and FTD spectrums.

00:31:35: We discussed a how neuro filaments reflect ongoing neroaxonal injury And how advanced in the ultrasensitivity essay has enabled realable blood-based measurements making this biomarker increasingly accessible in everyday clinical practice.

00:31:53: We heard how neofilaments can support diagnostic confidence, provide valuable prognostic information regarding disease progression and survival ,and are becoming increasingly important clinical trials as marker of biological treatment effects.

00:32:08: At the same time important challenges remain including standardization across laboratories interpretation of longitudinal change integration with other emerging biomarkers.

00:32:19: The key message from today's discussion is that nonfinanents are no longer simply research biomarker, in ALS they already helping clinicians better understand disease severity and prognosis.

00:32:31: In FTD They're emerging as valuable tools to support diagnosis and monitor disease progression.

00:32:37: Looking ahead, the future will likely involve multimodal biomarker panas combined with neurofilament with marker of protein pathology, neuroinflammation, neuroimaging and neurophysiology.

00:32:47: And digital biomarkers to provide a more comprehensive picture of disease biology.

00:32:53: On behalf for everyone listening I would like sincerely thank Professor Andrea Malaspina, Professor Francesco Di Lorezzo For sharing their expertise inside.

00:33:02: Thank you for joining us today.

00:33:04: Goodbye!

00:33:05: Thank you

00:33:07: very much.

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