Continuum Audio

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? Would that be a good way to sum that up?  Dr Quinn: I think that's, yes. I think that's very fair that that we have to be careful about these things.  Dr Weathers: OK. So, in summary, I think, does it sound like it's fair to say that the pitfall might be to say it's too early to make any assumptions or any conclusions quite yet? Dr Quinn: That's right. And, and I think, you know, we're going to need to monitor these therapies. I think all of us in neurology have become very accustomed to how you do that in multiple sclerosis, right? We've got MRI scans to be used to monitor therapy, maybe NFL is going to be an appropriate assay there as well. But, you know, there we've all had the experience of a chronic disease and seeing how well your therapy is doing, changing therapy if it fails. So, we’re absolutely going to need those things in in Alzheimer's disease and other neurodegenerative diseases, but it's a little early for us to be sure exactly what the right measures are to make those important decisions. Dr Weathers: And a lot more work to be done for sure. As I mentioned, this is a topic of such great interest and I know, you know, certainly most of our listeners are neurologists or people in our world, medical students and trainees. I know I have one regular nonneurologist listener, my father. He really gets a kick out of listening to my interviews. Even though he is a retired sales manager from IBM and most of the time the topics of discussion are pretty different from his usual favorite podcasts. But this one he will be particularly interested in and I'm sure I will get a list of questions about, particularly because my grandfather unfortunately had Alzheimer's disease. So, I'm sure one of his questions will be about the use of these biomarkers in asymptomatic patients. How do you counsel family members of patients when they inquire about the use of biomarkers for that youth case? What is their utility in presymptomatic testing? Dr Quinn: We know from studies like the Alzheimer's disease neuroimaging initiative and other biomarker studies that some of these markers will be sensitive to pathology. Even in asymptomatic people, that pathology appears long before people develop symptoms. Despite that, I don't recommend that asymptomatic people get any of the testing right now because we do not have evidence that early intervention at the completely asymptomatic stage is valuable. And those clinical trials are underway. There are trials underway right now for people who don't even meet the memory deficit required to have a diagnosis of mild cognitive impairment, people who are entirely cognitively intact, but who on one biomarker study or another have evidence of pathology burden. And the interventions are being started early. And in a few years, we'll know the answer to that. Right now, for somebody to find out that they have pathology without any ability to act on it, I think is not valuable. So, I discourage people from pursuing that.  Dr Weathers: And that is really important guidance. Thank you. I know you have, as you mentioned, a beginning in a really diverse neurologic background with expertise, as you said, not only in dementia, but also in Parkinson's disease. And you didn't even mention this, but I know expertise in stroke as well, but your research has been primarily in Alzheimer's. What drew you to dementia and to this specific the aspect of it? How did you become an expert in biomarkers?  Dr Quinn: Well, I'll start with the dementia part. So, you know, I was always just interested intuitively in trying to understand how, you know, the brain mediates the mind. So as an undergraduate, I got started working in a lab that was working on the cholinergic system in the brain, which was still being sorted out at that time. It is important in Alzheimer's disease, but it was really where the focus was. And that's what got me interested in Alzheimer's disease, which incidentally is what got Alzheimer interested in Alzheimer's disease. You know, he was very interested in trying to find the biological footprints of all these different neurological and psychiatric diseases. And he usually came up empty-handed until he came across the patient with Alzheimer's disease where there were actual footprints in the brain that he thought was pointing towards what was going on. And we're still wondering about that a hundred years later, I guess that's how I got interested in dementia and Alzheimer's disease. I think I have always spent part of my time as a clinician. I think that's what got me interested in biomarkers, that this problem has always been there that, you know, we've got quite, you know, research criteria for making diagnosis and all that sort of thing. But we've really needed some biological evidence to help us firm this up even before the availability of the therapies. And that's what got me interested in- I'm making another point. I thought that computer research biomarkers are going to help point me towards the causes of the disease, and unfortunately that part hasn't entirely panned out. We've got some research in that area on micro-RNA biomarkers that maybe will bear some fruit down the road, but that's been a tougher, tougher nut to crack. Dr Weathers: But it's so incredibly important work. Well, this has been wonderful. I really enjoyed our conversation, and I always like to end on a hopeful note. What developments in the biomarker space are coming on the horizon are you most excited about? Dr Quinn: I'm hoping that these biomarkers that allow us to evaluate disease efficacy, blood biomarkers that don't require extraspinal taps and that sort of thing. I hope that all comes to pass. And I do think that there is a lot of research underway looking at biomarkers in a novel way that I think could help point us to new targets for therapy, things that you and I haven't even thought of yet. Those are the two things. I guess you asked me for one, I gave you two.  Dr Weathers: Oh I think very fair. I agree. Both of those would certainly be wonderful and, and I'm excited as well. Well, thank you, Dr Quinn, for taking the time to speak with me this evening.  Dr Quinn: A pleasure. Thank you for having me. Thank you for inviting me to do the piece. It was really a great experience.   Dr Weathers: Again, today I've been interviewing Dr Joseph Quinn, who's written with Doctor Nora Gray on fluid biomarkers and dementia diagnosis. This article appears in the December 2024 Continuum issue on Dementia. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining 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. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.

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 otherwise. Dr Nevel: Great, thanks. In your article, you talk about different imaging modalities that can be used, as you mentioned, you know, just another piece of the puzzle, if you will, to try and put together what may be going on with the patient, and recognizing that some of these imaging techniques are imaging is special imaging, not available in a lot of places.  You know, and maybe other diagnostic type tests that could be helpful in differentiating between these different disorders may not be available, you know, for the general neurologist practicing in the community. So, what do you suggest to the general neurologist maybe practicing somewhere where they don't have access to some of these ancillary tests that could assist with a diagnosis?  Dr Ramanan: Critical question. And here I think there's not likely to be one single answer. As with most things, awareness and recognition is a good place to start. So, some of those clues that I mentioned earlier about the clinical course, about the age, the- we're talking about clinical setting there. So, comfort with and understanding that the clinical setting can help you to be more confident about, for example, LATE or PART being present in contrast to AD. That's important information. It deserves to be part of the discussion. It doesn't necessarily need other tests to have value on its own. A second piece is that tests help, in some cases, to rule in and rule out causes for cognitive difficulty. As part of a standard cognitive evaluation, we would all be interested in getting some blood tests to look for thyroid dysfunction or vitamin deficiencies. Some type of structural head imaging to rule out big strokes, tumors, bleeds. Head CT can accomplish some of that perspective. It's ideal if a brain MRI can be obtained, but again, keeping in mind, what's the primary goal of that assessment? It's to assess structure. Occasionally you can get even deeper clues into a syndrome from the MRI. For example, that very profound hippocampal or medial temporal atrophy. So, increasing awareness amongst clinicians throughout our communities to be able to recognize that change and put it in the context of what they see in other brain regions that can be affected by Alzheimer's or related disorders. For example, the parietal regions can be helpful. And recall that MRI can also be helpful in assessing for chronic cerebrovascular disease changes. This is another mimic that shows up in that table that you mentioned. And so multiple purposes can be satisfied by single tests. Now, you're absolutely right that there are additional test modalities that, perhaps in a subspecialty clinic at an academic medical center, we're very used to relying on and finding great value on; for example, glucose PET scans or sometimes fluid biomarkers from the blood or from the spinal fluid. And these are not always as widely available throughout our communities. Part of the challenge for all of us as a field is therefore to take the expertise that we have gathered in more subspecialty settings and tertiary care settings and translate and disseminate that out into our communities where we need to take care of patients. That's part of the challenge. The other challenge is in continued tool and technological development. There's a lot of optimism in our field that the availability of blood-based biomarkers relevant for Alzheimer's disease may play a part in helping to address some of the disparities in resource and access to care. You can imagine that doing a blood test to give you some high-quality information, there are going to be less barriers to doing that in many settings compared to thinking about a lumbar puncture or a PET scan, both in terms of cost to the patient as well as infrastructure to the clinicians and the care team. So I'm optimistic about a lot of those changes. In the meantime, I think there are, through both clinical evaluation and some basic testing including structural head imaging, there are clues that can help navigate these possibilities. Dr Nevel: So, let's say you have your patient in clinic, you've done your evaluation, maybe gotten some ancillary testing, and you highly suspect either LATE or PART. How do you counsel those patients and their families? How do you manage those patients moving forward who you really suspect don't have, you know, some sort of co-pathology? Dr Ramanan: So, it's- I think it's helpful to remember when patients are coming to see us, either they or the people around them have noticed an issue. And very likely it's an issue that's been brewing for a little while. I think it can be very valuable, very helpful for patients to have answers. What's the cause for the issue? Once you have answers, even if sometimes those answers are not the most welcome things or the things that you'd be looking forward to, answers give you an opportunity to grab hold of what's going on, to define a game plan. So, understanding there is a degenerative disease there, it sheds light on why that individual had had memory symptoms over the years. And it gives them a general expectation that over time on an individualized basis, but generally expecting gradually over many months to many years, there may be some worsening in some of those symptoms helps them to plan and helps them to make the adaptations that are a-ok and great to make to just help you to do the things you want to do. As much as I can, I try to put the focus here closer to how we would view things like high blood pressure or high cholesterol. Those are also chronic issues that tend to be more common as we get older, tend to get more troublesome as we get older. The goal is, know what you're dealing with and take the combination of lifestyle modifications, adaptations in your day-to-day and maybe medications to keep them as mild and as slow-changing as possible. With something like LATE, we don't have specific medication therapies to help support cognitive functioning at this time. There's a lot of hope that with additional research we will have those therapies. But even so, I think it's an important moment to emphasize some of those good healthy lifestyle habits. Staying mentally, socially and physically active, getting a good night's sleep, eating a healthy, balanced diet, keeping good control of vascular risk factors, all of that is critical to keeping the brain healthy, keeping the degenerative disease as mild and slow-brewing as possible. And understanding what some of the symptoms to expect could be. So, with LATE the syndrome tends to be very memory-predominant. There may be some trouble with maybe naming of objects or perhaps recall of emotionally salient historical knowledge, world events, but you're not expecting, at least over the short to medium term, huge intervening on other cognitive functioning. And so that can be helpful for patients to understand. So, the hope is once you know what what you're dealing with, you understand that the disease can look different from person to person. Having a general map of what to expect and what you can do to keep it in check, I think, is the goal. Dr Nevel: I agree with you 100% that it really can be helpful even if we can't, quote unquote, fix it, that for people, family, the patient have a name for what they have and kind of have some sort of idea of what to expect in the future. And they may come in thinking that they have Alzheimer's or something like that. And then, so, to get that information that this is going to be a little different, we expect this to go a little bit differently then it would if you had a diagnosis of Alzheimer's, I can see how that would be really helpful for people.  Dr Ramanan: I completely agree. And here's another challenge for us in the field when most patients have heard about Alzheimer's disease and many have perhaps even heard of dementia with Lewy bodies or frontotemporal dementia, but may not have heard of things like LATE. And they're not always easy to go online or find books that talk about these things. Having a name for it and being able to pair that with patient-friendly information is really critical. I see our appointments where we're sharing those diagnosis and making initial game plans as an initial foray into that process.  Dr Nevel: Yeah, absolutely. What is the greatest inequity or disparity that you see in taking care of patients with progressive amnestic cognitive impairment? Dr Ramanan: Yeah, great question. I think two big things come to mind. The first, you hinted at very well earlier that there are disparities in access to care, access to diagnostic testing, access to specialists and expertise throughout our communities. If we want diagnostics and therapeutics to be broadly applicable, they do need to be broadly available. And that's a big challenge for us as a field to work to address those disparities. There's not going to be one single cause or contributor to those iniquities, but as a field, I'm heartened to see thought and investment into trying to better address those. Another big weakness, and this is not just limited to cognitive neurology, it's a challenge throughout neurology, is that too many of our research studies are lacking in diversity. And that impacts our biological and pathophysiological understanding of these disorders. It also impacts our counseling and management. Again, if we want a new drug treatment to be broadly applicable throughout all of the patients that we take care of, we need to have data which guides how we apply those treatments. And so again, I'm heartened. This is a big challenge. It's a long standing challenge. It will take deep and long standing committed efforts to reverse. But I'm heartened that there are efforts in the field to broaden clinical trial enrollment, broaden observational research enrollment, and again, broaden access to tools and expertise. As a neurologist, I got into this field because I want to help people, use my expertise and my training to help people. These are steps that we can take to make sure that that help is broadly applicable throughout everybody in our communities. Dr Nevel: Yeah, absolutely. So, kind of segueing from you mentioning research and how we can better include patients in research. What do you think the next breakthrough is going to be? What do you think the next big thing is going to be in these disorders? What do we still need to learn? Dr Ramanan: There's a lot. I think for LATE and PART, the development of specific biomarkers would be top of the agenda. Now, biomarkers are by their nature imperfect. Even with Alzheimer's disease, where in comparison, we know quite a lot. We have a variety of imaging and fluid biomarkers that we can use to support or rule out a diagnosis. There are nuances in how you interpret those biomarkers. Patients can have signs of amyloid plaques in their brain and have completely normal cognition. They may be at risk for developing cognitive trouble due to Alzheimer's disease in the future, but it's one piece of the puzzle. Patients can have the changes of Alzheimer's disease amyloid plaques and tau tangles in the brain. We can confirm that through biomarkers. But at the end of the day, their cognitive syndrome might be driven by something else. Maybe it's Lewy body disease, maybe it's LATE, maybe it's a combination of factors. So, integrating and interpreting those biomarkers is challenging. But I do think, again, from the standpoint of giving patients answers with a diagnosis, having those biomarkers is really critical to just kind of closing the loop. It will also be critical to have those biomarkers as we're assessing for treatment response. So, for example, patients who may have coexistent Alzheimer's disease and LATE, I don't think we know the answer fully as to how likely they are to benefit from, say, newer antiamyloid monoclonal antibodies for Alzheimer's disease in the setting of that second pathology. So, wouldn't it be great if, similar to an oncologic setting where you engage in a treatment and then you're tracking two or three or four plasma measures and you're tracking tumor size with imaging, if we had this multimodal ability to track neurodegenerative pathology through biomarkers? I think that'll be a critical next step. And so, filling out that for non-Alzheimer’s diseases, including LATE and PART, I think is item number one on the agenda. Dr Nevel: Wonderful, thank you so much. I really appreciate you taking the time to chat with me today about your article. I really enjoyed our conversation, certainly learned a lot. Dr Ramanan: Thank you so much, Kait. Love talking with you. And again, it was an honor to write this article. I hope it's helpful to many out in the field who take care of patients with cognitive issues.  Dr Nevel: Yeah, I think it will be. So again, today I'm interviewing Dr Vijay Ramanan about his article that he wrote with Dr Jonathan Graff-Radford on LATE hippocampal sclerosis and primary age-related tauopathy, which appears in the most recent issue of Continuum on dementia. Be sure to check out Continuum audio episodes from this and other issues. And thank you, Vijay, 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. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.

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 neuroimaging because the treatment of course is quite different. So, it's someone presenting with ATIA who has transient neurologic symptoms might be considered urgently to get a thrombolytic or, you know, TPA, whereas someone who has known cerebral amyloid angiopathy or suspected CAA, they likely already have microbleeds on their neuroimaging and in those cases thrombolytics and TPA would be contraindicated and not helpful in terms of the etiology of their neurologic symptoms. Dr Grouse: That's a really good point to make. And I think also in your article you mentioned the use of aspirin if you're suspecting ATIA versus a, you know, a transient amyloid related focal neurologic episode. You know, one you would treat with aspirin and the other one you wouldn't.  Dr Silbert: That's right.  Dr Grouse: Another sort of interesting topic you delved into was cerebral microinfarct and how this can also contribute to vascular impairment. Could you elaborate a little more on that? Dr Silbert: Yeah. So cerebral microinfarcts are kind of the hidden cause of or a hidden cause of vascular cognitive impairment. And it's extremely challenging because by definition they are not visible on routine clinical neuroimaging. It's something that we are more aware of based on pathological studies and neuroimaging studies that have been done at ultra-high field strength like 7T MRI. And so, we are just learning more about how prevalent they are in certain conditions and how we can only look at these after death when we're looking at brain tissue and then go back and realize that these play a significant role in cognitive decline when someone is alive. It's important to understand that we're probably only appreciating kind of the tip of the iceberg when we're evaluating a patient and looking at their neuroimaging. That what we're actually seeing on MRI are only the things that are actually quite relatively big and obvious. And that a lot of these neuroimaging features of vascular cognitive impairment are actually associated with pathologic features that we're missing such as microinfarcts. But the hope is that by treating all individuals, particularly those who already have signs of vascular cognitive impairment, by modulating their stroke risk factors and focusing on maintaining brain health, that those will, interventions will also reduce the incidence of microinfarcts. Dr Grouse: What do you think is the greatest inequity or disparity you see in treating patients with vascular cognitive impairment? Dr Silbert: I think the greatest disparity is- really starts way before I treat a patient. That relates to really focusing on healthy lifestyle factors early in life and being able to, you know, afford fruits and vegetables, and having the advantages of being able to exercise regularly, and just being aware that all of these things are extremely important before older age. So, these are things that, you know, I think more education and awareness and greater access to healthcare will definitely improve access to. Even preventative healthcare is a disparity and not available across all of the population and geographic locations. So, I think of the- all the dementias, vascular cognitive impairment probably has the greatest association with health and social disparities in terms of primary prevention and access to care.  Dr Grouse: All really important things to consider. I have to say when, you know, reading your article, dare I say I came away with a little bit of hope thinking, you know, even with, you know, how little we still, you know, or how much we still need to do to really learn how to fight Alzheimer's and, you know, prevent it and, and, you know, help with its progression. The idea that in so many cases, even just doing what we can to prevent the vascular or cognitive impairment can really help any type of dementia. That was really a strong message for me. Do you mind elaborating on that a little more?  Dr Silbert: No, not at all. I agree. I really am hopeful about the prevention and treatment of dementias and through the treatment and prevention of cerebrovascular disease. I think that is a true reality, just like, you know, as we were discussing before, the treatment and prevention of cerebrovascular disease really should be a part of the treatment of any type of cognitive impairment and recommendations for prevention of cognitive impairment. This is the, you know, one thing we know is largely modifiable and preventable in most cases. I think the, really the key thing is just education and making sure that people understand that these are things that really need to be, they need to be engaged in in midlife and that it's much harder to reverse these- the damages once you have them in later life. Having said that, I do think that there's greater awareness of maintaining healthy lifestyle and maintaining awareness of stroke risk factors. And I think we're already starting to see a reduction in dementia worldwide in several large population-based studies, and probably that is due to more attention to the modifying stroke risk factors. So, I agree with you, it's very encouraging.  Dr Grouse: Is there anything exciting on the horizon that you can tell us about that we should all be keeping our eyes out for? Dr Silbert: Yeah. So, you know, I'm really interested in this connection between vascular cognitive impairment and Alzheimer's disease. And it's a real area of exciting new research. And so I think we're going to have more answers as to how, whether and how, cerebrovascular disease is directly linked to accumulating neurodegenerative disease or neurodegenerative pathologies. The other area that's, I think, really exciting, that's moving forward, is the in the area of blood-based biomarkers for vascular cognitive impairment. As these emerge, we'll be able to really identify those at greatest risk for vascular cognitive impairment, but also identify novel mechanisms that lead to VCI that can be targeted for therapeutic intervention. Dr Grouse: Well, I'm really excited to see what's coming down the pipeline and what more we'll learn in this area. So, thank you so much for everything you've done to contribute to this field. Dr Silbert: Yeah.  Dr Grouse: I wanted to ask a little bit more about you. What drew you to this work?  Dr Silbert: Well, actually, so my very first published manuscript in medical school was a case report and review on MELAS, which is mitochondrial encephalopathy with lactic acidosis and strokelike syndrome. And so, I was really fortunate to have Dr Jose Biller, who is a renowned expert in stroke and cerebrovascular disorders, as my mentor for that paper. And so, that got me really interested in neuroimaging findings of cerebral vascular disease. And so when I was a fellow at Oregon Health and Science University, I was then really fortunate to  be able to work with Jeffrey Kaye's oldest old population. And in working with that population, I really became interested in their neuroimaging findings of these white matter lesions and just realizing how prevalent they were in that population, you know, it just led me to start investigating their clinical significance and etiology, which kind of led me along this path. Dr Grouse: You know, Lisa, thank you so much. I really learned a lot from your article, and I think our listeners will definitely find that it was very helpful for their practice. Thank you so much for joining us. Dr Silbert: Thank you so much, Katie. It's been really fun.  Dr Grouse: Again, today I've been interviewing Dr Lisa Silbert, whose article on vascular cognitive impairment appears in the most recent issue of Continuum on dementia. Be sure to check out Continuum audio episodes from this and other issues. And thank you to our listeners for joining 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. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.

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 about this, who do you show up with first is going to guide how fast you can get a diagnosis. So, we interviewed at point over a thousand caregivers and what we found was there was about an eighteen month delay after seeing five to six doctors for the majority of patients, of which Lewy body dementia was misdiagnosed about 75% of the time for the initial diagnosis.  Dr Weathers: Wow, what a sobering statistic. And you spoke about the criteria and some of the ancillary tests. What can really help, do you think, kind of mitigate or prevent this misdiagnosis? What is your approach in your own patients?  Dr Galvin: Well, I think like every good clinician, not starting off with a preconceived notion of what the person has and trying to collect all the valuable information. So, one of the things I highlighted in the article was, while there are diagnostic criteria and people can follow diagnostic criteria, the truth is at your fingertips. You don't always sit and think about whether someone meets diagnostic criteria. So, in the first table in the article, we tried to really then put all the different common symptoms into buckets, right? Because people present like that. They say, well, I have this and I have this and I have this and I have this. Well, then you can start to think about, well, they have a cognitive symptom that's predominantly executive attention or visual perceptual in nature. And gee, they have constipation and heat intolerance and they say they can't smell quite as well as they once did, right, and they're having some disturbance in their sleep with excessive daytime sleepiness. Now you can start to say, well, even though that didn't fit the core and suggestive criteria, the fact is that spectrum of symptoms makes it much easier to begin to make a diagnosis. And so, it's investigative work. A lot of neurology is still investigative work. The old days, they used to say, we knew everything but could do nothing, but now we know everything and can do something about it. And so, I think it's really important that we try to apply this information in clinically useful ways. That was part of the gist of putting this Continuum article together was to try to present it not just as listing the diagnostic criteria, because you can get that anywhere, but how do you actually apply it in clinical practice? Dr Weathers: That's a great point. And that table that you referenced was really fantastic. And I know I say this a lot, but they're true. So, you know, many of the tables, the reference to Continuum, one I will certainly kind of come back to again, again, as an excellent point of care tool. So, I know in, in preparing for today and reading more about, about you and your areas of research that one of your particular areas of focus and expertise is in healthcare disparities, especially in the early detection of neurodegenerative dementias. What is the greatest inequity or disparity that you see in the diagnosis and treatment of patients with Lewy body dementia?  Dr Galvin: So, there's a couple things that are that are really interesting. So first, unlike Alzheimer's disease, which tends to be a little bit more female predominant, the Lewy body dementias are male predominant. It's about 1.6 men for everyone woman. So, it's going to be a different presentation. It's going to be largely men and their caregivers are largely going to be their spouses. So, you're going to see sort of a different person looking, you know, staring on the other side of the table to you. It's going to be largely a male. And the other thing that's really interesting is that almost all of the series, case series, case reports, clinical papers are in predominantly white populations. So, this lends to some interesting things. So, you know, is the disease less common in African Americans and other minority populations or are we just really bad at ascertaining the disease? You know, many of the case reports in Alzheimer's disease include African Americans. In fact, we know that African Americans may be at a twofold increased risk of developing Alzheimer's disease compared to nonHispanic whites, probably due to vascular risk factors. But in case series of Lewy body dementia, almost all the patients are non-Hispanic white. There also seems to be a higher risk in Asian populations, and in fact, some of the very earliest case reports were from Japan. Is this a case ascertainment problem or is this really a disparity in how the disease presents? And I think those are really important questions that still need to be asked. I know as researchers, we struggle to try to develop cohorts that could help us understand that. I would say in my twenty five years of seeing these patients, I would say the large percentage of them, and I've seen a lot of them, have been no-Hispanic white.  Dr Weathers: So, so definitely more research needed in this very important area. So, moving on to somewhat of a personal question, I always, this is such an honor. I always talk about that I get to have this time to sit down with the authors of these outstanding articles and learn not only more about their subjects, but about them as people. I had shared during my last interview that my paternal grandmother had Alzheimer's disease, and unfortunately also my maternal grandmother actually did as well. In preparing for this, I had listened to one of your previous interviews and learned that you also have a personal connection that led you to this subspecialty with several family members impacted. How has this connection inspired your research and your interactions with your patients?  Dr Galvin: Yeah, I mean, so my personal connection was that my maternal grandfather had Lewy body dementia. So, I grew up in a two family home in New Jersey. My grandparents lived on the second floor. We lived on the first floor. I wass very close to my grandparents. I'm still close to my grandmother, who's a hundred and three years old. But when I was a high junior in high school, my grandfather was driving me home from a swimming practice. I was thinner, fitter and more athletic at that point in my life, and he made the world 's slowest left hand turn and we were broadsided. So luckily no one was hurt. But I remember because I was sixteen at the time and just learning how to drive us, Grandpa, what happened? And he's like, oh, the car didn't react. Or, you know, he was blaming the car. And I didn't think much of it because, you know, I was sixteen years old. Sometime after that he was at work, and he was a greaser. So, he would climb through the machines at Colgate Palmolive and keep them all moving. And so, he was at work and he fell off a ladder and then broke his ribs. And in the emergency room, when my grandmother went to pick him up, the ER doctor turned to her and said, how long has your husband had Parkinson’s disease? And she's like, what are you talking about? And then that was the first time that all of us had noticed his rest tremor. And the reason he turned the wheel so slow is because he was Bradykinetic. And so then over the next few years, he progressed in his motor symptoms. And then as I got into college, he developed the cognitive symptoms. And so, by the time I had finished medical school that was doing my residency, he was no longer oriented to time. So that even though I had finished medical school, I was in my neurology residency, I was married and with children, I was still in college at that time for him. So, he would always ask me, you know, have I heard anything from getting to medical school and the like. So, I got to watch this person who I grew up with go through all of the different stages of disease. And then eventually he developed lots of hallucinations. And although he was relatively immobile, he experienced a hallucination and jumped out of his chair, fell down, and broke his hip. And so, he underwent a hip replacement, being rather severely demented, and then passed away in the rehab hospital. As I was living this with my grandparents, the one thing that my grandfather, while he could still communicate, and that my grandmother continued to say to me, you know, up until fairly recently was, you know, what are you going to do about this? You know, we're counting on you to make a difference. And so, a lot of my research is really focused on how I can make a difference for people. One, to make sure they get diagnosed properly. Two that we would have something to offer the patient and the family. And three, we can provide hope that we are actually going to come away with effective treatments to make a difference in their lives. Dr Weathers: Well, that is really inspiring. And I think you have really done that in your work. I always like to end these conversations on a hopeful note. So, what are the developments that are on the horizon in terms of diagnosis and treatment of Lewy body dementia that you are most excited about?  Dr Galvin: Well, I think there are three things that are of great interest right now. I mean, there's lots of things, but I think three things of great interest are, one, on the diagnostic side is that we now have assays that allow us to assess synuclein in body fluids and body tissues. So, we can measure synuclein seeding assays in the spinal fluid and we can visualize Lewy bodies through skin biopsies. And that's a tremendous advance because we were really, really limited otherwise to using indirect evidence, and the only indirect evidence we had was abnormalities on DAT scanning. So, we're looking at dopamine deficiencies. But as I mentioned earlier, that's very abnormal in Parkinson's disease. But in dementia with Lewy bodies, it's a little more subtle. So, the extent of dopamine degeneration in- particularly in early DLB is limited. So, you have to look very carefully. If we're not doing quantitative DAT scan imaging, then you may miss those subtle changes. So, I think that being able to directly visualize either synuclein seeding or synuclein aggregation has really changed the game. Plasma assays, blood-based biomarkers are probably a little farther away because they're- the red blood cells have a lot of synuclein and so it interferes with the ability to get a good sensitive assay. But I do think in the next couple of years we will see PET ligands that also bind  synnuclein. So, I think diagnostically we're going to be able to provide better, earlier, and more precise diagnoses. From a treatment perspective, traditionally we've just borrowed medicines from other fields to treat symptoms, but there are a number of disease-modifying trials that are ongoing. I was fortunate to be the academic PI on two very large NIH grants where we test tested disease modifying medicines. Both of those studies are fully recruited and we should get a readout toward the end of 2024 or the beginning of 2025. So very, very excited about that. I also am fortunate to be MPI an NIH grant where we're just going to be testing the first inhuman synuclein vaccine. So very, very excited about the potential to offer disease-modifying medicines and to fulfill the promise that I made to my grandma and grandpa twenty years ago. And I think the third thing is that right now there's a little bit of like an emerging controversy about developing some integrated staging paradigms between the movement disorder world and the cognitive world. And so, while those paradigms are currently published, you know, not everybody agrees with them. But I think whether I like that staging paradigm now or not, the fact that we're coming together and trying to develop some unified staging paradigms, I think, is going to make a big difference in increasing the ability for clinicians to make early diagnoses that are more precise so that we can either get people into clinical trials or into clinical treatment protocols at the earliest possible time. And that's going to make all the difference in the world for the patients and their families.  Dr Weathers: I think that was a fantastic answer. Really, all really exciting things that I think are all, I normally, I say on the horizon. I'm thinking, you know, pretty far ahead. And I think the really wonderful thing is that all of these are either here now or very, very close to being here. So, definitely a very positive way to end this discussion. Well, Jim, thank you so much for taking the time to speak with me today. Dr Galvin: Thank you. This was wonderful. I hope the listeners found this enjoyable and interesting and read the Continuum issue. I think it's going to be the latest and greatest on what we know about the dementias.  Dr Weathers: Again, thank you again, Dr Galvin, for joining me on Continuum Audio. Again, today I've been reviewing Dr James Galvin, his article on the Lewy body dementias, dementia with Lewy bodies, and Parkinson's disease dementia appears in the December 2024 Continuum issue on dementia. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining 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. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.