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Continuum Audio features conversations with the guest editors and authors of Continuum: Lifelong Learning in Neurology, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. AAN members can earn CME for listening to interviews for review articles and completing the evaluation on the AAN’s Online Learning Center.

4 DAYS AGO

Genetics and Neuropathology of Neurodegenerative Dementias With Dr. Sonja Scholz

Recent progress in neurogenetics and molecular pathology has improved our understanding of the complex pathogenetic changes associated with neurodegenerative dementias. In this episode, Katie Grouse, MD, FAAN, speaks with Sonja W. Scholz, MD, PhD, FAAN, an author of the article “Genetics and Neuropathology of Neurodegenerative Dementias,” in the Continuum® December 2024 Dementia issue. Dr. Grouse is a Continuum® Audio interviewer and a clinical assistant professor at the University of California San Francisco in San Francisco, California. Dr. Scholz is a senior investigator at the National Institutes of Health in Bethesda, Maryland and an adjunct professor of neurology at Johns Hopkins University in Baltimore, Maryland. Additional Resources Read the article: Genetics and Neuropathology of Neurodegenerative Dementias Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN 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, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Grouse: This is Dr Katie Grouse. Today I'm interviewing Dr Sonia Scholz about her article on genetics and neuropathy of neurodegenerative dementias, which appears in the December 2024 Continuum issue on dementia. Welcome to the podcast, and please introduce yourself to our audience. Dr Scholz: Thank you so much for inviting me. My name is Sonia Scholz. I'm a neurologist working at the National Institutes of Health. My main focus of research and clinical work are neurodegenerative diseases, and I have a particular interest in using modern genomic tools to understand these diseases and potentially leverage it for new translational applications. Dr Grouse: Sonia, we're really excited to have you today and thanks for joining us. Dr Scholz: I'm pleased to be here. Dr Grouse: I'd like to start by asking what you think is the most important message or takeaway point from your article? Dr Scholz: So, this is an article that really captures a very broad and exciting field. So, one thing I wanted to really highlight is that there's a lot of heterogeneity, clinical, pathological, molecular heterogeneity in age-related neurodegenerative dementia syndromes. Our article was really aimed at providing a bird's eye view of the pertinent pathological characteristics, but also important genetic advances and insights and how we can leverage that, particularly in the new physician medicine era, hopefully come up with better treatments and better ways to counsel our patients. Dr Grouse: What do you think is the most challenging aspect of understanding the genetics and neuropathologic basis of neurodegenerative dementias? Dr. Scholz: That's a good question. There’re many big and challenging questions, but I think one of the things we struggle the most with is really the heterogeneity. I see patients with one and the same Mendelian form of dementia. One patient is in their forties another patient is in their eighties, and the clinical manifestations can be very different from one patient to another. There's a lot of heterogeneity, also, on the pathological level. Not every patient has exactly the same distribution. And so, we're starting to slowly define what the underlying causes are, but it's still quite baffling and quite challenging to put them together and understand them. Dr Grouse: Do you feel that the genome-wide association studies has helped our understanding of these diseases, specifically the heterogeneity? And if so how? Dr Scholz: That's a great question, but you're talking to a geneticist here. And I definitely would say genome-wide association studies have helped us a lot in identifying what the underlying disease pathways are and what the relationships between neurodegenerative disease entities are. It really also gave us a better understanding of apparently sporadic diseases where genetic factors are still playing a role. And we can leverage that type of knowledge increasingly to highlight high-risk groups, but also, we can increasingly use it to stratify patients for clinical trials, for example. And that's really exciting and there's still a lot of knowledge that we have to garner very quickly, especially in the non-Alzheimer dementia space. Dr Grouse: You've mentioned, of course, the heterogeneity and these syndromes. And in your article, you go into a lot of the issue of the significant crossover between the genetic links and the neuropathological findings for the various types of neurodegenerative dementias. Do you think that this crossover has been more of a help or a hindrance in better understanding these diseases? Dr Scholz: Yeah, it can be a little bit, you know, challenging to wrap one 's mind around it. But by and large, I think it’s actually good news because it highlights that there is a shared biology between many of the neurodegenerative disease entities. And by figuring out which the pathways are that are very often involved, we can prioritize certain targets for therapy development. But we can also be smarter about how we developed treatments. We could repurpose a drug that has been developed for Alzheimer's disease very easily for Lewy body dementia because we increasingly understand the overlap. And we can also leverage new clinical trials design, like basket trials. This is something that has been really transformative in the oncology sphere and now, increasingly, neurodegeneration. We're trying to apply that kind of thinking as well to our patient populations. Dr Grouse: What do you think our listeners will find to be most surprising when they read the article? Dr Scholz: We often present these diseases in our textbooks as these black-and-white entities, but the reality is that there's a lot of overlap. And we also see that co-pathologies are actually the norm and not the exception, and a lot of the molecular risk factors are shared. It's not really surprising. And I think that overlap and crosstalk between the various diseases is something that's a little bit strange to think about, but it actually makes increasingly sense now that we see the genetic risk profiles coming up. Dr Grouse: In reading your article, I was really struck by how many, or how much the prior studies have been lacking in inclusion of different ethno-racial backgrounds in the patients who've been studied. How can this be improved going forward? Dr Scholz: Yeah, thank you. That's a really important and crucial question, and I think it really takes the collective effort of everybody in the healthcare research community to improve upon that. We need to talk to our patients about genetic testing, about brain donation programs, about referrals to clinical trials, and don't feel shy about reaching out to our colleagues and academic centers, even if you don't have the resources in a smaller institution. We also not only need to engage with the communities, we also need to build up a healthcare research community that has representatives from these various communities. So, it's really a collective effort that we build up and are proactive about building a more equitable healthcare system and research system that works for all of us and that really is going to provide us with the precision medicines that work for everybody. Dr Grouse: What do you think is the biggest debate or controversy related to the genetics and neuropathology of neurodegenerative dementias? Dr Scholz: Yeah, there are loads of interesting debates, but I think in my field, in particular in the genetics is what to do with risk variance. What is it that I actually communicate to the patient? Obviously, I can learn a lot on the bench and I think I can use a lot of the genetic risk factors for molecular modeling, etc. But to which extent should I share that information? Because genetic information is something that we cannot alter and many of the risk factors are actually mild, that they may never result in disease. And so, communicating risk with patients is something that's very challenging and we used to just steer away from it. But now the discussion is starting to shift a little bit. You know, nowadays we are starting to offer, for example, testing for the APOE4 allele in individuals who are considering antiamyloid therapies. And this really, this is precision medicine in his earliest days because it allows us to stratify patients into those that are high-risk versus low-risk and those that need more frequent follow-up or may be advised not to pursue this treatment. And we're probably going to see more of those discussions and the ethics around it. And it's even harder in an aged population where you know, you may never manifest any of the symptoms despite carrying a lot of these risk deals. Dr Grouse: You mentioned, you know, that testing, APOE4 testing for certain populations when deciding to do the antiamyloid immunotherapies. Apart from that, which I think is a really good example of where genetic testing makes sense, what other scenarios do you think it makes sense at this point in time to recommend genetic testing for symptomatic patients who are concerned about

19 min
JAN 1

Fluid Biomarkers in Dementia Diagnosis With Dr. Joseph Quinn

Blood-based biomarkers for dementia diagnosis are emerging and rapidly evolving. These fluid biomarkers should be used when the results will impact management decisions, including patient and family counseling, symptomatic therapies, and disease-modifying therapies. In this episode, Allison Weathers, MD, FAAN, speaks with Joseph F. Quinn, MD, FAAN, an author of the article “Fluid Biomarkers in Dementia Diagnosis,” in the Continuum® December 2024 Dementia issue. Dr. Weathers is a Continuum® Audio interviewer and associate chief medical information officer at the Cleveland Clinic in Cleveland, Ohio. Dr. Quinn is a professor in the Department of Neurology at Oregon Health & Science University in Portland, Oregon. Additional Resources Read the article: Fluid Biomarkers in Dementia Diagnosis Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Transcript Full interview 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, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Weathers: This is Dr Allison Weathers. Today, I'm interviewing Dr Joseph Quinn, author along with Dr Nora Gray, of Fluid Biomarkers in Dementia Diagnosis from the December 2024 Continuum issue on dementia. Welcome to the podcast and please introduce yourself to our audience. Dr Quinn: Sure. I'm Joe Quinn. I'm a neurologist at the medical school in Oregon, Oregon Health Science University, and I work in neurodegenerative disease, Alzheimer's disease, and Parkinson's disease. Dr Weathers: Certainly some really weighty topics. But again, as I said, today we want to focus on a really fascinating one, the concept of fluid biomarkers in dementia diagnosis. And we'll perhaps get into monitoring of treatment as well. So, this search for reliable biomarkers in the diagnosis of dementia, certainly not a new topic, but you and your co-author Dr Nora Gray did a really fantastic job in the article right from the get-go, laying out the urgency around this now that there are FDA of treatments that depend on pathologic diagnosis. And it feels like they're more and more announced by the day. Even as I was preparing for this interview a few days ago, the FDA approval for donanemab was announced, with the news making every major media outlet. Well, there are several really critical points made by you both in the article. What do you feel is the most important clinical message of your article? What do you want our listeners to walk away with as their one key takeaway? Dr Quinn: I think we still have the best evidence for CSF biomarkers, cerebrospinal fluid biomarkers, really making a diagnosis with some confidence. PET scans are available for visualizing amyloid and Tau now, but they're so expensive and they're not covered. So, the spinal tap information is what most of us around here really rely on when we want to be sure about what's going on. The blood tests are very promising, very exciting, but as you probably know, there's a lot of different opinions about this out there. Some people are sure that it's a done deal and that we now have a blood test for Alzheimer's disease. After I sent the article off, I opened up my issue of Neurology and there was an editorial saying these blood tests will never work. So, there's different ends of the spectrum on this and we tried to strike a balance with that. So they're very promising. I think before the article is due for revision, things are going to be different. But right now, spinal fluid is probably where we have the most confidence. Dr Weathers: I think that's a really solid takeaway to start our discussion with. And then, I think you both did really strike that very delicate balance in what is right now an area where, as I said, you know, things still are changing by the day. I know for our listeners who do subscribe, and I hope that most of them do, Table 9.1, clinically useful CSF biomarkers for the differential diagnosis of dementia, is one that I personally think I will frequently return to. You and Doctor Gray did just a wonderful job organizing these very complex concepts into an easy read and really powerful tool, especially for use at the bedside. Along the lines of knowing which biomarker to use, how frequently routine care are you ordering these tests on your patients? And do you anticipate this changing the media future? Is this another one of those things that by next week, we'll have a different kind of answer in how we use these tests? Dr Quinn: Yeah, as you said in your preliminary comments, the whole picture has been changed by the approval of these antibody therapies for Alzheimer's disease, lecanumab and just last week, donanemab. Prior to the approval of those two medications, I didn't use spinal fluid tests routinely, but I relied on them when I really needed to make a diagnosis with certainty of something really important hung in the balance. If we were trying to rule out some other treatable, more treatable problem. You know, for example, if it was a question of whether somebody primarily had a psychiatric problem or a neurodegenerative disease, this is something that would really allow me to objectify things. And- but that was a minority of people that I would see for dementia evaluation. You know, now that the two therapies are approved, I'm not actively engaged in administering those therapies very frequently but I can see already that the, the patients that I am discussing this with that spinal fluid is where we're probably going to rely for making a diagnosis of the amyloid burden in the in the living patient until PET scans are approved. If amyloid PET scans are- not approved, but covered by insurance, then those will probably replace the spinal fluid. So those tests in that table, A beta 42, tau, p-tau, one of them that's relatively new is this test for aggregated alpha-synuclein. Those I order with some frequency when I'm in those circumstances. Dr Weathers: That's really helpful for our listeners to hear from an expert such as yourself and to think about as they encounter similar patients. Whenever discussing complex topics such as this one, I'm always curious about, what is the most common misconception or pitfall regarding the use of biomarkers for the diagnosis of Alzheimer's and other dementia that you encounter? Dr Quinn: With respect to the blood biomarkers, you know, we were saying a moment ago that there's a lot of evidence available, but the jury is still out to some degree as to how reliable they are. And I think an important message with respect to those blood biomarkers is that they really are confounded by comorbidities. Remember, we're dealing with an elderly population, so comorbidities like hypertension and renal insufficiency and those kinds of things are relatively common and they can really throw off the blood biomarkers in a more dramatic way than cerebrospinal fluid biomarkers. The other fact, and I can't remember how well we cited this in the article, was that the blood biomarkers don't perform as well in underrepresented minorities. And you know, all of us are appropriately paying more attention to that problem in our practice of medicine. And for these blood biomarkers, that's a real issue. And whether the inferior performance in underrepresented groups is due to more comorbidity or just due to genetic differences is unclear at this time. So those are really important cautions. We mentioned the renal insufficiency and, I think, some of the other comorbidities, but it's a reason to really be careful with the blood biomarkers. Dr Weathers: I think a really important point, especially again, kind of going back to what we were talking about at the beginning of our discussion, there's so much excitement around them. There's so much potential. People think we finally have that kind of silver bullet of diagnosis. So, I think really something to keep in mind. What about in the use of their- in monitoring the efficacy of treatments? Dr Quinn: So that's I think a little earlier in its history in terms of what biomarkers would be useful for monitoring. But the donanemab trial really relied on blood biomarkers as outcome measures and really showed some interesting phenomena. One of them was that plasma neurofilament light, which is all the rage now and all over neurology, people are measuring plasma neurofilament light. It's a nonspecific marker of neuronal damage that makes it out into the serum. So, you can measure it in serum and detect CNS damage in the serum. And intuitively, you would think that would be a good measure of efficacy, but in terms of detecting a treatment effect with donanemab, it didn't perform very well. Conversely, GFAP, which is a marker of astrocyte activation, which I would not have predicted was going to be a sensitive marker for treatment efficacy, performed well in at least the donanemab trial. So, I think it's early in the history of using these markers as outcome measures in clinical trials. And I think we're going to continue to learn as each therapy comes along and as these things come to pass. Dr Weathers: Don't make any assumptions yet? Woul

16 min
12/25/2024

LATE, Hippocampal Sclerosis, and Primary Age-related Tauopathy With Dr. Vijay Ramanan

Although Alzheimer disease (AD) is the most common neurodegenerative cause of dementia, other etiologies can mimic the typical amnestic-predominant syndrome and medial temporal brain involvement. Neurologists should recognize potential mimics of AD for clinical decision-making and patient counseling. In this episode, Kait Nevel, MD, speaks with Vijay K. Ramanan, MD, PhD, an author of the article “LATE, Hippocampal Sclerosis, and Primary Age-related Tauopathy,” in the Continuum December 2024 Dementia issue. Dr. Nevel is a Continuum® Audio interviewer and a neurologist and neuro-oncologist at Indiana University School of Medicine in Indianapolis, Indiana. Dr. Ramanan is a consultant and assistant professor of neurology in the Division of Behavioral Neurology at Mayo Clinic College of Medicine and Science in Rochester, Minnesota. Additional Resources Read the article: LATE, Hippocampal Sclerosis, and Primary Age-related Tauopathy Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: IUneurodocmom Guest: @vijaykramanan Full episode transcript available here Dr Jones: This is Dr Lyle 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, which features conversations with Continuum 's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Nevel: This is Dr Kait Nevel. Today I'm interviewing Dr Vijay Ramanan about his article he wrote with Dr Jonathan Graff-Radford on LATE hippocampal sclerosis and primary age-related tauopathy, which appears in the December 2024 Continuum issue on dementia. Welcome to the podcast. Vijay, can you please introduce yourself to the audience? Dr Ramanan: Thanks so much, Kait. I'm delighted to be here. So, I am a cognitive neurologist and neuroscientist at the Mayo Clinic in Rochester, Minnesota. I have roles in practice, education and research, but amongst those I see patients with cognitive disorders in the clinic. I help direct our Alzheimer's disease treatment clinic and also do research, including clinical trial involvement and some observational research on genetics and biomarkers related to Alzheimer's and similar disorders. Dr Nevel: Great, thanks for that. So, I'd like to start off by talking about why is LATE hippocampal sclerosis, why is this important for the neurologist practicing in clinic to know about these things? Dr Ramanan: That's a great question. So, if we take a step back, we know that degenerative diseases of the brain are really, really common, and they get more and more common as we get older. I think all neurologists, and in fact most clinicians and large swaths of the general public, are well aware of Alzheimer's disease, which is the most common degenerative cause of cognitive impairment in the population. But there are non-Alzheimer’s degenerative diseases which can produce cognitive difficulties as well. And it's important to be aware of those disorders, of their specific presentations and their implications, in part because it's always a healthy thing when we can be as precise and confident about diagnosis and expectation with our patients as possible. I'll look to the analogy of a patient presenting with a myelopathy. As neurologists, we would all find it critical to clarify, is that myelopathy the result of a compressive spondylotic change? The result of an inflammatory disorder, of a neoplastic disorder, of an infectious disorder? It's critical to guide the patient and choose appropriate management options based on the cause of their syndrome. It would potentially harm the patient if you treated an infectious myelopathy with steroids or other immune-suppressant drugs. So, a similar principle holds in cognitive neurology. I accept with humility that we can never be 100% crystal clear certain about things in medicine, just because when you think you got it all figured out there's a curveball. But I want to get as close to that 100% as possible. And recognizing that disorders like LATE or PART can mimic the symptoms, sometimes even the imaging features of Alzheimer's disease. I think it's critical to have heightened awareness of those disorders, how they look, to be able to apply appropriate counseling and management options to patients. I think this becomes particularly critical as we move into an era of disease-specific, and sometimes disease-modifying, therapies, where applying a choice of a treatment option could have significant consequences to a patient if the thing you're treating isn't the thing that the drug is trying to accomplish. So, having awareness and spreading awareness about some of these non-AD causes of cognitive difficulty, I think, is a big mission in the field. Dr Nevel: Yeah, that makes total sense. And kind of leaning into this, you know, trying to differentiate between these different causes of late-life amnestic cognitive impairment. You know, I'll point out to the listeners today to please read your article, but in addition to reading your article, I'd like to note that there's a really nice table in your article, Table 6-1, where you kind of go through the different causes of amnestic cognitive impairment and the different features that better fit with diagnosis X, Y, or Z, because I think it's a really nice table to reference and really easy to look at and reference back to. But on that note, what is your typical approach when you're seeing a patient in clinic, have a new referral for an older patient presenting with a predominantly progressive amnestic-type features? Dr Ramanan: Excellent question. And this is one that I think has relevance not just in a subspecialty memory clinic, but to all the clinicians who help to diagnose and manage cognitive disorders, including in primary care and general neurology and others. One principle that I think it's helpful to keep in our minds is that in cognitive neurology, no one data point takes precedence over all the others. We have a variety of information that we can gather from history, from exam, from imaging, from fluid biomarkers. And really the fun, the challenge, the reward is in piercing together that information. It's almost like being a lawyer and compiling the evidence, having possibilities on your list and raising and lowering those possibilities to get as close to the truth as you can. So, for patients with a cognitive syndrome, I think the first plank is in defining that syndrome. As you mentioned, if I'm seeing someone with a progressive amnestic-predominant syndrome, I first want to make sure, are we talking about the same thing, the patient, the care partner, and I? Can often be helpful to ask them for some examples of what they see, because sometimes what patients may report as memory troubles may in fact reflect cognitive difficult in other parts of our mental functioning. For example, executive functioning or naming of objects. And so helpful to clarify that in the history to get a sense of the intensity and the pace of change over time, and then to pair that with a good general neurologic exam and some type of standardized assessment of their cognitive functioning. At the Mayo Clinic, where partial to the short test of mental status. There are other ways to accomplish that, such as with an MMSE or a MoCA. If I understand that the syndrome is a progressive amnestic disorder, Alzheimer's disease is the most common cause of that presentation in older adults, it deserves to be on my differential diagnosis. But there might be some other features in the story that could raise or lower those mimics on my list. So, in patients who are, say, older than the age of seventy five, disorders like LATE or PART start to rise higher on the likelihood for me, in particular if I know that their clinical course has been more slow brewing, gradually evolving. And again, most degenerative disorders we expect to evolve not over days or weeks, but over many months to many years. But in comparison with Alzheimer's disease, patients with LATE or with PART would be expected to have a little more slow change where maybe year over year they or their care partners really aren't noticing big declines. Their daily function is relatively spare. There might not be as much involvement into other non-memory cognitive domains. So, these are some of the pieces of the story that can help to perhaps isolate those other non-AD disorders on the list as being more likely and then integrating, as a next level, diagnostic testing, which helps you to rule in and rule out or support those different causes. So, for example, with LATE there can be often out of proportion to the clinical picture, out of proportion to what you see on the rest of their imaging or other profiles, very predominant hippocampal and medial temporal volume loss. And so that can be a clue in the right setting that you may not be dealing with Alzheimer's disease or pure Alzheimer's disease, but that this other entity is there. So, in the big picture, I would say being systematic, recognizing that multiple data points being put together helps you get to that confident cause or etiology of the syndrome. And in particular, taking a step back and thinking about big picture factors like age and course to help you order those elements of the differential, whether AD or ot

25 min
12/18/2024

Vascular Cognitive Impairment With Dr. Lisa C. Silbert

Vascular cognitive impairment is a common and often underrecognized contributor to cognitive impairment in older individuals, with heterogeneous etiologies requiring individualized treatment strategies. In this episode, Katie Grouse, MD, FAAN speaks with Lisa C. Silbert, MD, MCR, FAAN, an author of the article “Vascular Cognitive Impairment,” in the Continuum December 2024 Dementia issue. Dr. Grouse is a Continuum® Audio interviewer and a clinical assistant professor at the University of California San Francisco in San Francisco, California. Dr. Silbert is 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 Read the article: Vascular Cognitive Impairment Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Full 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, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Grouse: This is Dr Katie Grouse. Today I'm interviewing Dr Lisa Silbert about her article on vascular cognitive impairment, which is part of the December 2024 Continuum issue on dementia. Welcome to the podcast and please introduce yourself to our audience. Dr Silbert: Hi Katie. Thanks for having me here today. Like you mentioned, my name is Lisa Silbert. I am a behavioral neurologist at Oregon Health and Science University and my research focus is in the area of vascular contributions to cognitive impairment and dementia. Dr Grouse: It's such a pleasure to have you and I really enjoyed reading your article. Just incredibly relevant, I think, to most practicing general neurologists, and really to any subspecialty. I'd like to start by asking, what do you think is the main takeaway point of your article for our listeners? Dr Silbert: Yeah. I think, you know, the field of vascular cognitive impairment has changed and evolved over the last several decades. And I would say the main take-home message is that vascular cognitive impairment or vascular dementia is no longer a diagnosis that is only considered in someone who's had acute decline following a clinical stroke. That we have to expand our awareness of vascular contributions to cognitive impairment and consider other forms of the disease that can cause a more subacute or slowly progressive form of cognitive impairment. And there are many, many forms of vascular cognitive impairment that present in a more slowly progressive manner. The other thing I would say as a major take-home message is that we know that cerebrovascular disease is a very common copathology with other forms of dementia and that it lowers one 's threshold for manifesting cognitive impairment in the context of multiple pathologies. And so, in this way, vascular cognitive impairment should be considered as a contributing and potentially modifiable factor in any dementia. Dr Grouse: I found that last point just really, really fascinating. And also, you know, the reminder that a combination of pathologies are more common than any one. To your initial point, I'm actually curious, could you kind of outline for us how you approach diagnosing vascular cognitive impairment? Dr Silbert: Yeah. So with everything in neurology, a lot of it comes down to the initial history taking. And so part of the work up always includes a very detailed history of the presentation of cognitive impairment. Any time there is an acute change in cognition, vascular contribution should be considered, particularly if it's in the context of a clinical stroke or some kind of event that might have lowered cerebral blood flow to the brain. And then having said that, I already mentioned there are many forms of vascular cognitive impairment that can mimic neurodegenerative disease in terms of its course. So being more slowly progressive. And so because of that neuroimaging, and in particular MRI, has become an extremely valuable tool in the workup of anyone who presents with cognitive impairment in order to evaluate contributions from cerebral vascular disease. And so, MRI is a really helpful tool when it comes to teasing out what may be contributing to a patient's clinical syndrome, as well as their other comorbid medical issues, including stroke risk factors and other kind of medical conditions that might contribute to reduce cerebral blood flow. Dr Grouse: I'd love to talk a little bit more about that. You know, as is often the case with neurologic disease associated with vascular pathology, the importance of prevention, you know, focusing on prevention of vascular diseases is so important. What are some things that we can make sure to focus on with our patients and, you know, particularly anything new to be aware of in counseling them? Dr Silbert: Yeah, I'm really glad you asked me that question because like I mentioned, you know, cerebral vascular disease is so common, it lowers one's threshold for cognitive impairment in the face of other age-related brain pathologies. And so, it's really important for all of us to focus on preserving our cognitive health, even starting in midlife. And so, there are a number of areas that I counsel my patients on when it comes to preserving cerebral health and maximizing cerebrovascular health. And so, these stem from the American Heart Association's Life's Essential 8 because we know that preserving cardiovascular health is likely going to also preserve cerebral vascular health. And so, some of the things that I'm very commonly discussing with my patients are controlling stroke risk factors such as blood pressure, blood sugars and cholesterol, maintaining a healthy weight, and then also working towards a lifestyle that includes a healthy diet, no smoking, regular exercise. And then new within the last couple years is also the recommendation that people get adequate sleep, which is something that hasn't been focused on previously. Dr Grouse: I was really interested in reading your article to learn about enlarged perivascular spaces and the role as a mediating factor in the interaction between through a vascular dysfunction and development and progression of neurodegenerative pathology. Can you elaborate on this further? Dr Silbert: So, this is an area that's still largely unknown in the field, and it's an area where there's a lot of emerging work being done. The short answer is, we really don't know with great certainty how it directly connects with accumulating Alzheimer's pathology. But there is some evidence to suggest that the perivascular space is involved in the clearance of toxic solutes from the brain, including Alzheimer's disease pathology. And so there's a lot of work looking at how potentially cerebrovascular risk factors might affect the clearance of those toxic solutes through the perivascular space, including pulse pressure changes that might occur with accumulating cerebrovascular disease and other potential contributors. But one thing I can say with more certainty is that the, you know, location of perivascular spaces is thought to help distinguish those who might have cognitive symptoms due to cerebrovascular disease versus due to cerebral amyloid angiopathy. Or I guess I should say location is helpful in terms of recognizing vascular contributions to cognitive impairment that's due to arteriolosclerosis versus that due to cerebral amyloid angiopathy. In so much that… when we see a lot of perivascular spaces in the basal ganglia in the subcortical structures, that is thought to be more associated with arteriolosclerosis and hypertension type related vascular cognitive impairment. Whereas when we see multiple perivascular spaces within the centrum semiovale, that tends to be more associated with cerebral amyloid angiopathy. Dr Grouse: That's so interesting. And on the topic ofcerebral amyloid angiopathy, you did go into this a good deal. And you know, I think I encourage everybody to revisit the article to remind themselves about, you know, the findings that can increase the suspicion of tribal amyloid angiopathy. However, you also talked about transient focal neurologic episodes, which I think is just a great reminder that, you know, these can occur in this setting and definitely not to miss. Tell us more about what to look for with these types of episodes. Dr Silbert: Transit focal neurologic episodes can be very difficult to tease apart from a transient ischemic attack. And these transient focal neurologic episodes due to CAA can present in a number of different ways. And I think the important take home message for that is that in people who have neuroimaging evidence of CAA to inform them that they are at increased risk for having these focal neurologic episodes and that if they do present to a hospital or an emergency department with any kind of neurologic event, that those treating them are aware that they have evidence of CAA on their neuroim

20 min
12/11/2024

Lewy Body Dementia With Dr. James E. Galvin

Lewy body dementia is a common cause of cognitive impairment in older adults but is often subject to significant delays in diagnosis and treatment, increasing the burden on patients and family caregivers. Understanding key features of the disease and use of biomarkers will improve recognition. In this episode, Allison Weathers, MD, FAAN, speaks with James E. Galvin, MD, MPH, author of the article “Lewy Body Dementia,” in the Continuum December 2024 Dementia issue. Dr. Weathers is a Continuum® Audio interviewer associate chief medical information officer at the Cleveland Clinic in Cleveland, Ohio. Dr. Galvin is a professor of neurology at the University of Miami Miller School of Medicine in Miami, Florida. Additional Resources Read the article: Lewy Body Dementia Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN 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, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Weathers: This is Dr Allison Weathers. Today I'm interviewing Dr James Galvin, author of Lewy body dementias from the December 2024 Continuum issue on dementia. Welcome to the podcast, Dr Galvin. Please introduce yourself to our audience. Dr Galvin: Thank you, Allison. My name is Jim Galvin. I'm a neurologist, a professor of neurology at the University of Miami Miller School of Medicine. Dr Weathers: We're so happy to have you with me today. Thanks, Jim, for your time. And as you highlight right from the start in your really outstanding and comprehensive overview of this really complex topic, even though Lewy body dementia is the second most common cause of neurodegenerative dementia, it often goes unrecognized in clinical practice, resulting in really potentially lengthy diagnostic delays. So, this is a really important article for a neurologist and an important topic for our listeners. So, I'm thrilled we're having this conversation today. While I traditionally start by asking the authors what they feel is the most important clinical message of their article, I would love to actually start a step earlier in this conversation with you. Can you start us off by explaining what's actually meant when we say Lewy body dementia? Dr Galvin: Great. So, you know, I think this is a, this is an interesting concept. So, we're really talking about two diseases that have a shared common pathology. So, Parkinson's sees dementia and dementia with Lewy bodies. So, their shared pathology is a Lewy body and that's why they're often grouped together as the Lewy body dementias. And then there's arguments back and forth as to whether these are distinct diseases or sort of two ends of the same candle burning in different directions. So, Parkinson's dementia is a lot like what it sounds like. So, if someone has Parkinson's disease, then at some point later they develop a dementia. And so back in the 1800’s when Parkinson's disease was like first described as an entity, we basically felt that cognition wasn't affected. But we now know that's not true. And so most patients with Parkinson's do have some cognitive symptoms and a large proportion of them will eventually develop dementia. Perhaps up to 80% of Parkinson's patients will develop a dementia. The flip side is the dementia with Lewy body picture. And these are people who present primarily with a cognitive behavioral syndrome that may or may not have parkinsonism. So, they will sometimes have bradykinesia. They rarely have a rest tremor. And so, these are the people that are very much in the delayed diagnosis group. The Parkinson's dementia is more whether the clinician is checking their cognition as part of their annual visit. The flip side is that the people with DLB are often misdiagnosed early on, but together, this is Lewy body dementia, which is the most common disease that many people have never heard of. Dr Weathers: That's a great tagline, I think, for the whole article and for this concept. So now that that we're all on the same page about what's meant when we use that the term, what would you want our listeners to walk away with as their one key takeaway from our conversation today? Dr Galvin: Well, I think the article makes several key points, but I think if I put those all together into a single key point, it would really be that the Lewy body dementias are underrecognized, they're underdiagnosed, yet it is very possible to make the diagnosis using the standardized clinical criteria. They're very, very, very specific. They lack a little bit in sensitivity. So, because other diseases sometimes can look like this, but they're really quite specific. So, if you're confident clinically that the person has Lewy body dementia, you're probably going to be right. And in today's world, we have tests available to help confirm our diagnosis. The world is changing. We can make these diagnosed with much more confidence and we have confirmatory diagnosis laboratory tests that can help us. Dr Weathers: I want to talk more about the diagnosis in one minute, but first, how common actually are dementia with Lewy bodies and Parkinson's disease dementia? Dr Galvin: That's a great question. I think one of the challenges, of course, we really don't know how many people have any disease because it's going to largely rely on how well people code the diseases in the medical record. So, if you look at the most common cause of dementia in the United States, it's really dementia not otherwise specified, right? But we believe it to be the second most common cause of dementia. The Lewy Body Dementia Association, about a decade ago, started to try to develop some estimates. So, we have an estimate about how many people roughly have Parkinson's disease and that about 80% of those individuals would go on to develop dementia. And we know from the dementia population that about 40% of those individuals coming to autopsy have Lewy bodies. So, when you start to put that all together, you can get a reasonable estimate of how many people likely have the disease. And then that can be expanded on an annual basis, just like the Alzheimer's Association uses, by extrapolating those estimates onto the census data. So, we estimate right now there are about 1.4 to 1.6 million Americans who are living with Lewy body dementia. That's less than the 6.8 million people who have Alzheimer's disease, but more than a lot of other common diseases. So, if you think about, again, I said before, it's the most common disease no one's ever heard of. You know, there are about a million people who have multiple sclerosis. There are about eight hundred thousand people who have a stroke. There are about seven hundred thousand people who have a brain tumor. There are two hundred and fifty thousand people who have muscular dystrophy. There are twelve thousand people who have ALS. But I think if you stopped clinicians or people in the street and say have you ever heard of ALS or muscular dystrophy, they would say yes. If you ask them if they've heard of Lewy body dementia, they would say no. Dr Weathers: That's an excellent point. And I know over the years I think there's been some increased awareness. I think sadly with some of the celebrities that have been impacted, I think that did a lot to raise awareness. But I think you're right that it's still so less commonly recognized by the lay public, by non-neurologists, than so many other diseases that you mentioned. And I think that leads back well into my next question into something that we've already mentioned just a few times already in our short conversation, this unfortunate and very common delay in the diagnosis. Why? And you mentioned earlier that there are these, you know, clinical criteria, these now ancillary tests. So, what makes the diagnosis so challenging? What aspects in particular do you think that neurologists find to be the most challenging in diagnosing patients? What trips us up? Dr Galvin: So, there's an old analogy, right, that, you know, if you'll be three blind men to an elephant and each of them are touching a different part of the elephant, they'll each think it's something different. So because Lewy body dementia has so many different diverse kind of symptoms, it would really depend on who's seeing the patient first. So, if a person presents predominantly with a memory cognitive disorder and they go see someone who specializes in memory disorders, they're highly likely to be called Alzheimer's disease. If they present predominantly with the movement problem, they're going to see a movement disorder person and be called Parkinson's disease. If they present with a behavioral disorder, they're going to go see a psychiatrist. Then they'll get diagnoses like, you know, geriatric schizophrenia or bipolar disease or major depressive disorder. If they present with the constitutional symptoms, which are very common and drive patients absolutely batty. So chronic constipation, REM sleep disorder, runny nose, you know, heat intolerance, urinary frequency, obstipation, and you know, they're going to be called all sorts of things. So, if you start thinking

24 min
12/04/2024

Diagnosing Alzheimer Disease With Dr. Gregory S. Day

A pragmatic and organized approach is needed to recognize patients with symptomatic Alzheimer Disease in clinical practice, stage the level of impairment, confirm the clinical diagnosis, and apply this information to advance therapeutic decision making. In this episode, Aaron Berkowitz, MD, PhD, FAAN, speaks with Gregory S. Day, MD, MSc, MSCI, FAAN, author of the article “Diagnosing Alzheimer Disease,” in the Continuum December 2024 Dementia issue. Dr. Berkowitz is a Continuum® Audio interviewer associate chief medical information officer at the Cleveland Clinic in Cleveland, Ohio. Dr. Day is an associate professor in the Department of Neurology at Mayo Clinic Florida in Jacksonville, Florida. Additional Resources Read the article: Diagnosing Alzheimer Disease Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @AaronLBerkowitz Guest: @GDay_Neuro Full episode transcript available here Dr Jones: This is Doctor 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, which features conversations with Continuum's guest editors and authors, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Berkowitz: This is Dr Aaron Berkowitz, and today I have the pleasure of interviewing Dr Gregory Day about his article on Alzheimer disease, which appears in the December 2024 Continuum issue on dementia. Welcome to the podcast, Dr Day. Would you mind introducing yourself to our audience? Dr Day: Thanks very much, Aaron. I'm Gregg Day. I'm a behavioral neurologist at Mayo Clinic in Jacksonville, Florida, which means that my primary clinical focus is in the assessment of patients presenting typically with memory concerns and dementia in particular. Dr Berkowitz: Fantastic. Well, as we were talking about before the interview, I've heard your voice many times over the Neurology podcast and Continuum podcast. I've always learned a lot from you in this rapidly changing field over the past couple of years, and very excited to have the opportunity to talk to you today and pick your brain a little bit on this very common issue of evaluating patients presenting with memory loss who may have concerns that they have dementia and specifically Alzheimer disease. So, in your article, you provide a comprehensive and practical approach to a patient presenting for evaluation for possible dementia and the question of whether they have Alzheimer disease. The article is really packed with clinical pearls, practical advice. I encourage all of our listeners to read it. In our interview today, I'd like to talk through a theoretical clinical encounter and evaluation so that I and our listeners can learn from your approach to a patient like this. Let's say we have a theoretical patient in their seventies who comes in for evaluation of memory loss and they and/or their family are concerned that this could be Alzheimer disease. How do you approach the history in a patient like that? Dr Day: It's a great way to approach this problem. And if you're reading the article, know that I wrote it really with this question in mind. What would I be doing, what do we typically do, when we're seeing patients coming with new complaints that concern the patient and typically also concern those that know the best? So be that a family member, close friend, adult child. And in your scenario here, this seventy year old individual, we're going to use all the information that we have on hand. First off, really key, if we can, we want to start that visit with someone else in the room. I often say when talking to individuals who come alone that there's a little bit of irony in somebody coming to a memory assessment alone to tell me all the things they forgot. Some patients get the joke, others not so much, but bringing someone with them really enhances the quality of the interview. Very important for us to get reliable information and a collateral source is going to provide that in most scenarios. The other thing that I'm going to start with, I'm going to make sure that I have appropriate time to address this question. We've all had that experience. We're wrapping up a clinical interview, maybe one that's already ran a little bit late and there's that one more thing that's mentioned on the way out the door: I'm really concerned about my memory or I'm concerned about mom 's memory. That's not the opportunity to begin a memory assessment. That's the opportunity to schedule a dedicated visit. So, assuming that we've got someone else in the room with us, we've got our patient of interest, I'm going to approach the history really at the beginning. Seems like an easy thing to say, but so often patients in the room and their caregivers, they've been waiting for this appointment for weeks or months. They want to get it out all out on the table. They're worried we're going to rush them through and not take time to piece it together. And so, they're going to tell you what's going on right now. But the secret to a memory assessment, and particularly getting and arriving at an accurate diagnosis that reflects on and thinks about cause of memory problems, is actually knowing how symptoms began. And so, the usual opening statement for me is going to be: Tell me why you're here, and tell me about the first time or the first symptoms that indicated there was an ongoing problem. And so, going back to the beginning can be very helpful. This article is focused on Alzheimer disease and our clinical approach to the diagnosis of Alzheimer disease. And so, what I'm going to expect in a patient who has a typical presentation of Alzheimer disease is that there may be some disagreement between the patient and the spouse or other partners sitting in the room with me about when symptoms began. If you've got two partners sitting in the room, maybe an adult child and a spouse, there may be disagreement between them. What that tells me is at the onset, those first symptoms, they're hard to pin down. Symptoms typically emerge gradually in patients with symptomatic Alzheimer disease. They may be missed early on, or attributed or contributed to other things going on in the patient's time of life, phase of life. It's okay to let them sort of duke it out a little bit to determine, but really what I'm figuring out here is, are we talking about something that's happened across weeks, months or more likely years? And then I'm going to want to listen to, how did symptoms evolve? What's been the change over time? With Alzheimer disease and most neurodegenerative diseases, we expect gradual onset and gradual progression, things becoming more apparent. And at some point, everyone in the room is going to agree that, well, as of this state, there clearly was a problem. And then we can get into talking about specific symptoms and really begin to pick that apart the way that we traditionally do in any standard neurological assessment. Dr Berkowitz: Fantastic. And so, what are some of the things you're listening for in that history that would clue you in to thinking this patient may indeed be someone who could have Alzheimer's disease and going to require a workup for that diagnosis? Dr Day: It's pretty common when I have new trainees that come to clinic, they just head into the exam room and they sort of try to approach it the way that we would any patient in the emergency department or any other clinical scenario. The challenge with that is that, you know, we're taught to let the patient speak and we're going to let the patient speak - open-ended questions are great - but there's only so many questions you need to sort out if someone has a memory problem. And memory is really only one part, one component, of a thorough cognitive evaluation. And so, I'm going to help by asking specific questions about memory. I'm going to make sure that there is memory challenges there. And whenever possible, I'm going to solicit some examples to back that up, add credibility and sort of structure to the deficits. I'm also going to choose examples that help me to understand how does this concern, or this complaint, how does that actually affect the patient in their day-to-day life? Is it simply something that they're aware of but yet hasn't manifested in a way that their partner knows about? Is it to a level where their partner’s actually had to take over their responsibility? It's causing some difficulties, disability even, associated with that. That's going to be important for me as I try to understand that. So, I'll ask questions when it comes to memory, not just, you know, do you forget things, but do you manage your own medications? You remember to take those in the morning? Do you need reminders from your partner? What about appointments; health appointments, social appointments? Are you managing that on your own? Sometimes we need a little bit of imagination here. Partnerships, and particularly those who have been together for a long time, it's natural that different people are going to assume different responsibilities. And so, might have to say, Imagine that you went away for the weekend. Would you worry about your partner remembering to take their medications over that time frame? That can help to really solidify how much of an impact are these challenges having

28 min
11/27/2024

December 2024 Dementia Issue With Dr. Lisa Silbert

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 Social Media 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

21 min
11/20/2024

Neuromodulation for Neuropathic Pain Syndromes With Dr. Prasad Shirvalkar

For certain diagnoses and patients who meet clinical criteria, neuromodulation can provide profound, long-lasting relief that significantly improves quality of life. In this episode, Aaron Berkowitz, MD, PhD, FAAN speaks with Prasad Shirvalkar, MD, PhD, author of the article “Neuromodulation for Neuropathic Pain Syndromes,” in the Continuum® October 2024 Pain Management in Neurology issue. Dr. Berkowitz is a Continuum® Audio interviewer and a professor of neurology at the University of California San Francisco in the Department of Neurology and a neurohospitalist, general neurologist, and clinician educator at the San Francisco VA Medical Center at the San Francisco General Hospital in San Francisco, California. Dr. Shirvalkar is an associate professor in the Departments of Anesthesia and Perioperative Care, Neurological Surgery, and Neurology at Weill Institute for Neurosciences at the University of California, San Francisco in San Francisco, California. Additional Resources Read the article: Neuromodulation for Neuropathic Pain Syndromes Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @AaronLBerkowitz Guest: @PrasadShirvalka 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, which features conversations with Continuum's guest editors and authors, who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Berkowitz: This is Dr Aaron Berkowitz, and today I'm interviewing Dr Prasad Shirvalkar about his article on neuromodulation for painful neuropathic diseases, which appears in the October 2024 Continuum issue on pain management in neurology. Welcome to the podcast, and if you wouldn't mind, please introducing yourself to our listeners. Dr Shirvalkar: Thanks, Aaron. Yes, of course. So, my name is Prasad Shirvalkar. I'm an associate professor in anesthesiology, neurology and neurological surgery at UCSF. I am one of those rare neurologists that's actually a pain physician. Dr Berkowitz: Fantastic. And we're excited to have you here and talk to you more about being a neurologist in in the field of pain. So, you wrote a fascinating article here about current and emerging neuromodulation devices and techniques being used to treat chronic pain. And in our interview today, I'm hoping to learn and for our listeners to learn about these devices and techniques and how to determine which patients may benefit from them. But before we get into some of the clinical aspects here, can you first just give our listeners an overview of the basic principles of how neuromodulation of various regions of the nervous system is thought to reduce pain? Dr Shirvalkar: Yeah, I would love to try. But I will promise you that I will not succeed because I think to a large extent, we don't understand how neuromodulation works to treat pain, to describe or to define neuromodulation. Neuromodulation is often described as using electrical stimuli or a chemical stimuli to alter nervous system activity to really influence local activity, but also kind of distant network activity that might be producing pain. On one level, we don't fully understand how pain arises, specifically how chronic pain arises in the nervous system. It's a huge focus of study from the NIH Heal Initiative and many labs around the world. But acute pain, which is kind of when you stub your toe or you burn your finger, is thought to be quite different from the changes over time and the kind of plasticity that produces emotional, cognitive and sensory dimensions. Really what I think is its own disease, chronic pain, of which there are multiple syndromes when we use neuromodulation, either peripheral nerve stimulation or electrical spinal cord stimulation. One common or predominant theory actually comes from a paper in science from 1967 and people still use it, foundational theory and it's called the gate control theory. Two authors, Melzack and Wall, postulated that at the spinal level, there are, there's a local inhibitory circuit or, you know, there's a local circuit where if you provide input to either peripheral nerves or either spinal cord ascending fibers that to kind of summarize it, there's only so much bandwidth, you know, that nerves can carry. And so that if you literally pass through artificial signals electrically, that you will help gate out or block natural pathological but natural pain signals that might be arising from the periphery or spinal cord. So, you know, one idea is that you are kind of interfering with activity that's arising for chemical neuromodulation. The most common is something known as intrathecal drug infusion drug delivery ITTD for that we quite literally put a catheter in the spinal fluid, you know, at the level of the dorsal horn neurons that we think are responsible for perpetuating or creating the pain. Where's the pain generator? And you really, you can infuse local anesthetic, you can infuse opioids. And what's nice is you avoid a lot of systemic side effects and toxicity because it goes right to the spinal cord, you know, by infusing in the fluid. So there's a couple of modalities, but I will say just, like maybe all of our living experience, pain is in the brain. And so, we don't really understand, I would say, what neuromodulation is doing to the higher spinal or brain levels. Dr Berkowitz: Fascinating topic. And yeah, very interesting to hear both what our current understanding is that some of our current understanding is based on data that's 60 years old and that we're actually probably learning about pain by using these modulation techniques, even though we don't really understand how they might be working. So interesting feedback loop there as well as in as in the as in this land. So, your article very nicely organizes the neuromodulation techniques from peripheral to central. So, encourage our listeners to check out your article. And first before we get into some of the clinical applications, just to give the listeners the lay of the land, can you sort of lay out the devices and techniques available for treating pain at each level of the neuroaxis? We'll get into some of the indications in patient selection in a moment, but just sort of to lay out the landscape. What's available that you and your colleagues can use or implant at different levels when we're thinking of referring patients too? Dr Shirvalkar: Absolutely. So, starting from the least invasive or you know, over the counter patients can purchase themselves a TENS machine. Many folks listening to this have probably tried a TENS machine in the past. And the idea is that you put a couple of pads, at least two. So you have like a dipole or you have a positive and a negative lead and you basically inject some current. So, the pads are attached to a battery and you can put these pads over muscle. If you have areas where myofascial pain or sore muscles, you can put them, frankly, over nerves as well and stimulate nerves that are deeper. Most TENS machines kind of use electrical pulses that occur at different rates. You change the rates, you can change the amplitude and patient can kind of have control for what works best. Then getting slightly more invasive, we can often stimulate electrically peripheral nerves. To do this we implant through a needle, a small wire that consists of anywhere from one electrical contact to four or even eight electrical contact. What I think is particularly cool, like TENS, which is transcutaneous electrical nerve stimulation that goes through the skin. Peripheral nerve stimulation aims to stimulate nerves, but you don't have to be right up against the nerve. So, yeah. We typically do this under an ultrasound and you can visualize a nerve like the sciatic nerve, peroneal nerve, or you know, even if someone has an ulnar or a neuropathy, you know, that's the compression. There's a role obviously for surgery and release, but if they have predominantly pain, it's not related to a mechanical problem per se, you could prevent a wire from a peripheral nerve stimulator as far as one centimeter from a nerve and it'll actually stimulate that that modulated and then, you know, kind of progressing even more deeply. The spinal cord stimulation, SCS, it's probably the most ubiquitous or popular form of neuromodulation for pain. People use it for all kinds of diseases. But what it roughly involves is a trial period, which is a placement of either two cylindrical wires, not directly over the spinal cord, but actually in the epidural space, right? So, it's kind of like when you get an epidural injection or doing labor and delivery, when women get epidural catheters, placing spinal cord stimulator leads in that same potential space outside the dura, and you're stimulating through the dura to actually target the ascending dorsal column fibers. And so, you do a trial period or a test drive where the patients get these wires put in. They're coming out of the skin, they're connected to a battery, and they walk around at home for about a week, take careful notes, check in with them, and they keep a diary or a log about how much it helps. Separately. I will say it's hard to distinguish this, the placebo effect often, but you know, sometime

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Welcome to the New Continuum Audio

Continuum Audio features conversations with the guest editors and authors of Continuum: Lifelong Learning in Neurology, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. AAN members can earn CME for listening to interviews for review articles and completing the evaluation on the AAN’s Online Learning Center. Read the articles: ContinuumJournal.com Subscribe to Continuum: shop.lww.com/Continuum More about the American Academy of Neurology: aan.com

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Genetics and Neuropathology of Neurodegenerative Dementias With Dr. Sonja Scholz

Fluid Biomarkers in Dementia Diagnosis With Dr. Joseph Quinn

LATE, Hippocampal Sclerosis, and Primary Age-related Tauopathy With Dr. Vijay Ramanan

Vascular Cognitive Impairment With Dr. Lisa C. Silbert

Lewy Body Dementia With Dr. James E. Galvin

Diagnosing Alzheimer Disease With Dr. Gregory S. Day

December 2024 Dementia Issue With Dr. Lisa Silbert

Neuromodulation for Neuropathic Pain Syndromes With Dr. Prasad Shirvalkar

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Genetics and Neuropathology of Neurodegenerative Dementias With Dr. Sonja Scholz

Fluid Biomarkers in Dementia Diagnosis With Dr. Joseph Quinn

LATE, Hippocampal Sclerosis, and Primary Age-related Tauopathy With Dr. Vijay Ramanan

Vascular Cognitive Impairment With Dr. Lisa C. Silbert

Lewy Body Dementia With Dr. James E. Galvin

Diagnosing Alzheimer Disease With Dr. Gregory S. Day

December 2024 Dementia Issue With Dr. Lisa Silbert

Neuromodulation for Neuropathic Pain Syndromes With Dr. Prasad Shirvalkar

Trailer

Welcome to the New Continuum Audio

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Much better way

Not as informative

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