Navigating Neurodegenerative Therapies

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

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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.