Emerging Therapies and Biomarkers in Neurological Disorders

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Lisa C. Silbert, MD, MCR, FAAN, who served as a guest editor of the Continuum® December 2024 Dementia issue. They provide a preview of the issue, which publishes on December 2, 2024.

Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota.

Dr. Silbert is co-director at Oregon Alzheimer's Disease Research Center, a Gibbs Family Endowed professor of neurology, a professor of neurology at Oregon Health & Science University, a staff neurologist, director of Cognitive Care Clinic, and director of the Geriatric Neurology Fellowship Program at Portland Veterans Affairs Health Care System in Portland, Oregon.

Additional Resources

Continuum website: ContinuumJournal.com

Subscribe to Continuum: shop.lww.com/Continuum

More about the American Academy of Neurology: aan.com

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facebook.com/continuumcme

@ContinuumAAN

Host: @LyellJ

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology, clinical review and CME journal from the American Academy of Neurology.

Thank you for joining us on Continuum Audio, a companion podcast to the journal.

Continuum Audio features conversations with the guest editors and authors of Continuum who are the leading experts in their fields. Subscribers to the Continuum Journal have access to exclusive audio content not featured on the podcast. If you're not already a subscriber, we encourage you to become one. For more information, please visit the link in the show notes.

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today I'm interviewing Dr Lisa Silbert, who recently served as Continuum's co-guest editor for our latest issue on dementia alongside Dr Lianna Apostolova. Dr Silbert is a professor in the Department of Neurology at Oregon Health and Science University of the School of Medicine in Portland, Oregon, where she's also the director of the Neuroimaging Core and now the co-director of the Alzheimer's Disease Research Center. She also serves as director of the dementia clinic at the VA Portland Healthcare System. Which, Dr Silbert, sounds like a lot of work? Anyway, welcome. I really appreciate you taking the time to join us today and co-guest editing this issue. Why don't you introduce yourself a little bit to our listeners?

Dr Silbert: Well, thank you so much for interviewing with me today and for inviting me to be the guest, co-guest editor of this issue. It's a really exciting time for dementia care and dementia research. As you already said, my name is Lisa Silbert. I'm in Oregon Health and Science University in Portland, Oregon. I've been involved in caring for dementia patients and their families for over twenty years now and been involved in a lot of really exciting research during that time. But I would say now is probably the most dynamic time in dementia research and care that I've seen. So, it's really, really exciting to be here.

Dr Jones: It really is an interesting time. So, I look back in our last issue of Continuum focusing on dementia came out in 2022, which doesn't sound like that long ago, but a lot has changed, right? With the anti-amyloid monoclonals for Alzheimer's disease, new biomarkers and so on. And as the guest editor, you have this unique view, Dr Silbert, of the issue and the whole topic of dementia. As you were reading these really outstanding articles, what was the biggest "aha" moment for you or the biggest change in practice that you saw that's come up over the last couple of years?

Dr Silbert: I think, you know, in reading through the different manuscripts or chapters in this issue, it really struck home the advances that have been made throughout all the different areas of dementia. Not just- so, we hear a lot about Alzheimer's biomarkers and Alzheimer's treatments on the horizon, which is really exciting, but this is happening across other dementias as well. There's biomarkers on the horizon for a Lewy body disease and potentially for some of the frontaotemporal dementias. And so that to me really struck home as this is really, across the board, a change in the entire field that we're looking at.

Dr Jones: That is exciting. And I'd like to come back to some of those biomarker developments because I think that's an area where we've really been lacking in neurology as a specific way to diagnose those disorders. I think a topic which you just alluded to that a lot of our listeners and readers are thinking about are those antiamyloid monoclonal therapies for Alzheimer's disease. So, addicanumab, lecanumab and most recently the approval of donanemab. For these drugs specifically, how are you using them in your practice and how should our listeners be thinking about these drugs?

Dr Silbert: These are, you know, relatively new, really exciting new and emerging therapies for Alzheimer's disease. They are shown to remove amyloid from the brain. Patients who have clinical manifestations of Alzheimer's disease, and that is those in the stages of mild cognitive impairment or mild dementia. We are using lecanemab at Oregon Health and Science University through our therapeutics and clinical units. It's a really exciting time and it's a time where we have to be, also, cautious about who undergoes these therapies. So being really informed about the use, who's appropriate to undergo these therapies, what kind of safety tests need to be undergone, how do you assess risk in individual patients so that you can counsel them. So, all of these factors need to be weighed in when you're making a decision about whether or not to treat a patient with a monoclonal antibody therapy. And specifically, we do neuroimaging to assess whether there are already the presence of microhemorrhages in the brain. We do genetic testing to look for APOE 4 genotypes that can increase the risk of Aria, which is amyloid-related imaging abnormalities. And all of these factors go into how we counsel patients and discuss whether or not to pursue treatment with monoclonal antibodies.

Dr Jones: So certainly a complex patient selection process and drug administration and monitoring of therapy for those patients. And that- it brings to mind for me how we already have too few neurologists in the US. And now for a really prevalent disorder, Alzheimer's disease, we're making it a lot more complicated to deliver these new disease-modifying therapies. What do you think or what do you see as the role of the neurologists in caring for patients with dementia? And do these developments change that role?

Dr Silbert: For now, I think these developments make it even more important in a way that neurologists are involved in making a very specific clinical diagnosis of which dementia is playing a factor in the patient 's clinical presentation. I think one thing to note is with these emerging biomarkers, a lot of them can be positive before there are clinical symptoms and multiple etiologies are also very prevalent. And so just having one positive biomarker, it doesn't necessarily tell you what's going on with an individual patient. You need to take the whole picture into consideration. So, I think a really detailed evaluation by the neurologist, especially with these emerging therapies that have potential risks, is extremely important right now. Just getting a test is really not sufficient. You really have to take the entire clinical picture into account and know the ins and outs of the risks involved in these disease-modifying therapies.

Dr Jones: Which brings us back to something you mentioned earlier, right? Which is good news. We have on the horizon new potential biomarkers for other neurodegenerative causes of dementia. I can foresee and maybe I'm, you know, being an alarmist here, Dr Silbert, but if we have sensitive biomarkers for other neurodegenerative conditions, we know patients often have copathologies. Is that going to help clarify things? Is it going to confuse us? How is that going to work?

Dr Silbert: Well, I think ultimately, it's going to help clarify things. Because there are multiple pathologies that are common in age related cognitive impairment, any kind of additional specific input that we can get with different biomarkers is going to be helpful in putting the pieces together to come up with what's happening clinically with each individual patient. Ultimately, I think these biomarkers, they're not- any one biomarker isn't going to be a solution to diagnosis, but putting them together to help improve early and accurate diagnosis is really the goal here. Having a very early diagnosis, having a very accurate diagnosis will improve our ability to give prognosis and also improve effective treatment strategies moving forward. I think that these biomarkers have the promise in facilitating that for us.

Dr Jones: And progress is always a good thing. We just have to learn how to adapt and use the evidence appropriately. There have been and I think most of our listeners will be familiar with some of the controversies related to these, these new disease-modifying drugs for Alzheimer's disease. Do you want to walk us through a couple of those, and what are your thoughts about those controversies?

Dr Silbert: Yeah, these new therapies, they're very exciting for everyone in the field, but they, like you mentioned, they're not without their controversies. I think one controversy or one potential downside to these therapies is access to them. Like you already mentioned there, there's really not enough neurologists out there. There's not enough behavioral neurologists out there. There's limitations to infusion centers, sites and prescribers. Access to these therapies is is significantly limited. They are requiring infusions quite frequently. So, if you're not living near specialty care, you're not really able to feasibly undergo these kinds of treatments. Another controversy is the fact that the treatment effects are considered by some to be fairly modest when looking at the clinical data and in association with that, there are risks involved. Like I already mentioned, there's the amyloid-related imaging abnormalities, which sounds kind of like a benign thing, but they really consist of microhemorrhages that can lead to bigger hemorrhages and edema in the brain. These risks are relatively small - they are seeing more commonly in those who have a specific genotype, an APOE E 4 genotype - but they're risks nonetheless.

And so, there's controversy about the risk-benefit ratio and access to care with these new therapies.

Dr Jones: It's very exciting, but we should be cautious, right? I recall a few years ago as a program director, a neurology residency program director, interest in different areas of neurology would often follow developments in those areas, right? Lots of interest in autoimmune neurology when those developments would proceed in neuro oncology, etc. And I wonder if the therapeutic advances in in behavioral neurology and neurodegenerative cognitive disorders, I wonder if that's going to stimulate interest among our trainees to pursue behavioral neurology? Do you have a view on that or have you seen much change in interest in in this field?

Dr Silbert: You know, we are seeing a lot more interest in our trainees. The residents are very interested in these new therapies and how to apply them. And I'm really excited about that.

I'm hopeful that this will stimulate interest in the field. And we need those specialists, we need those sub specialists to undergo fellowship training in behavioral neurology and geriatric neurology so that we have more access to the subspecialty care and delivering these new therapies. So, I agree with you, I'm hopeful about it and I am seeing new interest in our trainees about these new therapies.

Dr Jones: We can hope so. And all the other fellowship directors will be anxious if neurology residents start leaving to go into behavioral neurology. But there's certainly demand. And I know that under the best of circumstances, dementia is so common. It's something that we have to care for in partnership with primary care and community resources. And these disease-modifying therapies capture a lot of attention, but it's really a small part of the continuum of care of these patients. And Dr Silbert as an expert, you know, if we put that disease-modifying therapy to the side for a second and just said, well, what are the biggest gaps in the care for patients with dementia? What do you see as those biggest gaps and, and what can we do to fix them at not just a neurology level, but at a societal level?

Dr Silbert: That's a big question. And you know, what I see almost every day are gaps in the support mechanisms for families who are caring for patients with dementia. These caregivers are under a lot of stress and oftentimes they just don't have the resources to take care of somebody who at some point will often need twenty-four hour care and supervision. Caregivers are older, usually of older age themselves and have their medical issues as well. And then we're just not doing a good job as a nation in in supporting patients and their families with like supportive care and respite care that's really needed. So, you know, I'm not just seeing and treating patients with dementia, but I'm seeing and I'm really trying to support and care for those who are taking care of patients with dementia. To me, that's the biggest gap in our system.

Dr Jones: Yeah. And as I look through this issue of Continuum, we touched on not only the conventional topics in dementia and behavioral neurology. I'm really happy in hindsight that we have invited some discussion of the psychiatric symptoms in dementia, which I think are really important and often underrecognized and maybe undermanaged or mismanaged, and really also focusing on the caregiver burden and support services. We do have an article dedicated to that as well, and I think that'll be useful to our readers and listeners when we when we publish those podcasts. We we've heard this year especially a lot of public conversation about cognitive impairment and dementia. I sometimes wonder if that public attention is helpful and constructive for the population of patients with dementia. Sometimes I wonder if that conversation is counterproductive. What's your take on that?

Dr Silbert: You know, I think it's- it can be a mixed bag, but ultimately, it's in the conversation. We're talking about it. And I think that's only a good thing. There's more public awareness of it.

There is more interest in therapies. So, I think at the end of the day, talking about it, making it more prevalent in the ether, it stimulates the conversation and discussion. And even if there's controversies about it, we're talking about it. And I think that's kind of the first step in acknowledging that we need more support, we need more therapies.

Dr Jones: Yeah, I agree. And I think often patients with neurologic disorders and their caregivers and families often appreciate being seen.

Dr Silbert: Yeah, no, absolutely true. So, I'd say in regards to the monoclonal antibody treatments, you know, despite the controversies with these new treatments, I think there's a real promise and a real hope and a real excitement across a lot of behavioral neurologists, including myself, that this is just the beginning. That even if these first line, first generation therapies maybe have downsides, that there'll be second generation and third generation variations on these kinds of treatments that are going to be more accessible, have less side effects and hopefully be more clinically effective. And, and down the line, the other real hope for the field is that these maybe second generation therapies will actually delay the onset or prevent clinical manifestation of the disease. And that's the real goal here.

Dr Jones: And that's a great segue to the to the next thing I wanted to ask you about and you, you may have already answered the question. We talked about how we have and will have new biomarkers which will help us with diagnosis. We have hopefully the first phase in increasingly effective disease modifying therapies for Alzheimer, maybe prevent Alzheimer's disease. Wouldn't that be great? Are there any other things on the horizon that you see maybe for other neurodegenerative disorders from a therapeutic perspective? What do you, what do you think the next big thing will be in that area?

Dr Silbert: Well, that's a great question. I think, you know, there's a lot of exciting research in Lewy body dementia and targeting alpha synuclein pathologies. We really need biomarkers.

So, we're ways off from therapeutics, but I think there's a lot of exciting progress in that area.

Dr Jones: So, like many areas of neurology, there are rewarding and challenging aspects to the care of these patients. What do you- what's the most rewarding aspect of your practice, Dr Silbert?

Dr Silbert: You know, a lot of… I hear from trainees over the years that, you know, they can't imagine or it's difficult for them to think about caring for patients who have a neurodegenerative disease that has no cure. But I feel like that's a lot of what neurologists do. We don't necessarily cure all diseases, but we treat the patient throughout their disease process. And to me that is extremely satisfying. You know, I enjoy listening to patients' stories and hearing about what they have been through over the years. And I really feel, like, appreciated for the care that I provide in giving not just an accurate diagnosis, which a lot of people come in lacking, but talking about future planning and, really, treatment throughout the course of the disease. And I was in clinic yesterday and talking to one of my patients' caregivers, and we were talking about a particularly difficult behavioral manifestation that her husband was going through. And we were talking through how to manage it. And she said to me, you know, Dr Silbert, I really feel like I have a partner in going through this disease. And you know, that's kind of what it's all about for me. So, to me, it's extremely rewarding field. It's also a very exciting field, especially right now with all these new biomarkers and treatments. So, I just think there isn't a better area of neurology to be involved in right now.

Dr Jones: What a great place to land and end the interview. And I hope our listeners and our readers really do enjoy this issue. It's really a fantastic, not just an update, but a survey of a very dynamic aspect of the field of neurology. And Dr Silbert, I want to thank you for joining us and thank you for such a thorough and fascinating discussion on caring for patients with dementia.

Dr Silbert: It was my pleasure. Thank you.

Dr Jones: Again, we've been speaking with Dr Lisa Silbert, co-guest editor, alongside Dr Leanna Apostolova for Continuum 's most recent issue on dementia. Please check it out, and thank you to our listeners for joining us today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. Thank you for listening to Continuum Audio.