Chief Concern Series: Assessing Cognitive Changes

We walk through a practical approach to evaluating cognitive change with Dr. Seth Gale, from fast domain-based questions and high-yield screening to when, and how, to utilized imaging and biomarkers meaningfully. We also cover reversible factors, older medications used in dementia management, lifestyle changes that can benefit, and how new Alzheimer’s treatments shift urgency in making a definitive diagnosis.

Understanding Hypophosphatemia: Recognition, Diagnosis, and Treatment
Endocrine experts distinguish Hypophosphatemia from osteoporosis & osteomalacia

Listen on: Apple Podcasts   Spotify

Chapters

• 0:00 Meet The Hosts And Today’s Focus
• 1:06 Why Early Cognitive Evaluation Matters
• 2:10 Common Referrals And Chief Complaints
• 3:31 Parsing Domains: Memory, Attention, Executive
• 6:35 Visual Spatial Clues And Orientation
• 7:27 Patient Versus Informant Reports
• 9:59 [Ad] Understanding Hypophosphatemia: Recognition, Diagnosis, and Treatment
• 10:24 (Cont.) Patient Versus Informant Reports
• 11:12 Multifactorial Causes And Reversibility
• 12:48 Core Neurodegenerative Patterns
• 15:19 Frontotemporal Signs In Behavior And Language
• 18:04 Mood, Meds, Sleep, And Substances
• 22:52 Exam Pearls And MRI Value
• 25:47 Quick Cognitive Tests With High Yield
• 29:11 Biomarkers: CSF, PET, And Blood
• 33:44 Using Legacy Drugs Wisely
• 36:26 Lifestyle Levers And Risk Reduction
• 39:42 Resources, Registries, And Closing

Transcript

Michael Kentris: 0:04

Hello, everybody, and welcome back to the neurotransmitters. Uh, we're very glad to have you with us again today as we continue our chief concerns. We are your co-hosts for this. I'm Dr. Michael Kentris, and I am joined again today by the inevitable Dr. Galena Geifman. Galena, how are you today?

SPEAKER_02: 0:23

Hi, Michael. Thanks so much for having me back. I am loving this series and so excited to co-host yet another one with you. And I'm especially excited this morning to welcome a friend and mentor and colleague, uh, Dr. Seth Gale, to talk with us about the topic of cognitive change. Dr. Gale is co-director of the Brain Health Program at the Mass General Brigham and one of the leaders in our division of cognitive and behavioral neurology. And he spends a lot of his time working with patients with various cognitive changes as well as leading our Alzheimer's treatment program and several clinical trials and uh some other fun things on the side that maybe we'll get to as well. Welcome, Seth.

SPEAKER_01: 1:06

Thank you so much for having me. It's a pleasure to be here. I look forward to uh taking your lead, Galina, on uh on getting some information out there to everybody.

SPEAKER_02: 1:16

Well, I'm really excited for today's uh session in particular because I remember that over the course of my own training as a resident, what we did for patients with cognitive change has changed. Right. So I think in the past we were kind of like, okay, yeah, it's okay if you have a memory complaint. We have time to figure this out. And with the ability to potentially make treatment available to patients, I think all of us have that kind of, you know, higher level of, you know, sense of a threshold to make a diagnosis, to make a gain understanding of what's going on. So let's just start really taking a step back and think about, you know, you being in the cognitive clinic, what are the most common referrals that you get? And how do patients get to you if they're being seen by someone else who thinks they should be seen by someone who's a cognitive specialist?

SPEAKER_01: 2:09

That's a great question. It really varies, right? So in our setup, most of the referrals are internal from our health system. So it's often from primary care. There will, there will also be uh general neurologists and psychiatrists who will refer on to cognitive and behavioral neurology. I mean, it is like like everything in our medical world, it's subs, it's a real subspecialized. And so, you know, there's a variety, but um, but that's usually the referral pattern. And I'd say it's it's there's a couple of um particular patient and family reports that are the most common. So one is this uh word finding difficulty or like tip of the tongue, you know, phenomena, where um, you know, I I know what I want to say, it's on the tip of my tongue, and I just can't, you know, I can't get, I can't la label it. I can't get the the name out or the or the object out. So yeah, so people describe that as word finding difficulty. And sometimes when you start a cognitive focused history, you'll hear something like memory complaints or or word finding, but you have to kind of dig into it a bit. So sometimes memory actually means word-finding difficulty. Sometimes word-finding difficulty means short-term memory. So, so anyway, this is where you start to think about the brain in different cognitive domains, which we can talk a little bit more about. But your history can be a bit kind of like domain-focused where you have in mind that you're gonna try to get at executive function. But the way you would ask it is not saying, do you have executive function problems, but are you having difficulty with thinking through or executing the sequence of uh uh the sequences in a task or problem solving things like that. So you take the lead on the chief complaint and you start to dissect it, which I think is a general rubric for how we try to operate in the clinic, I'd say.

Michael Kentris: 4:09

Yeah, that makes sense. And I think one of the most frustrating situations, and I'm sure that our primary care colleagues run into this even more, is that a lot of that takes a lot of time. So if you had to, let's say, prioritize what pieces of that problem to dissect, let's say, in, you know, God forbid, 15-minute visit, what uh what kind of things would be the the biggest red flags that I need to definitely have this on my like you know, have like something a little bit more than just maybe, you know, quote unquote uh senile problems uh to use an archaic term.

SPEAKER_01: 4:44

Yeah, yeah. So I mean, I think if you think about, let's say, we'll give it like four different domains of cognition. So let's say attention is one. So as an interviewer, if you have in mind, you know, focus and attention, you can ask, are you having difficulty, you know, keeping focus or sustaining your focus? So then in your mind, you're kind of working through this, these domains. And that would be one kind of domain in a cognitive clinic. I mentioned memory. So you can ask questions like, again, you're thinking of the memory domain, you can ask questions like, you know, are you having difficulty retaining information from conversations in the short term? So people might describe this as short-term memory problems. So I might ask something like, I'll give an example quickly in this interview. In this interview format, I'm describing where you might say, you're talking with your spouse tomorrow at, you know, you decide that there's something you're gonna do tomorrow at one o'clock, you're gonna go have lunch, you know, with the Jones family. So those that's all pieces of new information. So you can ask in a patient or family, you give them that scenario. So in your conversation with a loved one, are you holding on to information that that you get that's new in the short term? That would be a way to ask about short-term memory difficulties. If we go on to executive function, like I was mentioning before, you might ask questions like around the house using appliances or doing small repairs or something. You know, are you noticing some difficulty with doing the kinds of things you did six months ago or a year ago? So the key is that you're focused. You have you have limited time, you have three or four domains executive function, memory, attention. Let's say that's probably good. If you get something about this visual spatial or spatial kind of orientation from difficulties from this conversation, you might ask about that. Um, that's another of the kind of key brain domains. But that might be something like um, you know, do you notice that it's hard to differentiate like the background from the foreground in the room that you go into? Or when you find yourself sitting in the car, either at as a passenger or driver, and thinking about where you're going, do you have difficulty um knowing how you're gonna do it? So basically what we call like topographical orientation. So I'm gonna take a left on Main Street and go by the grocery store, et cetera. So that that that's a way to kind of key into that kind of domain.

Michael Kentris: 7:26

Oh, that's excellent. It's something you kind of mentioned that I always find I'm just curious your opinion. How often, like when someone's like coming in with that chief complaint of the tip of the tongue word finding or the you know the short-term memory kind of issue, whether that is themselves versus is it a concern of let's say their spouse or one of their adult children? Does one of those elevate your suspicion higher than the other?

SPEAKER_01: 7:51

That's a great question. I I would say no. I'd say you have to weigh these these the informant, the collateral, and the person equally. I the the the script I have in mind is when I try to open up the interview and make it easy for people to kind of talk about these things, which is not always easy when you're in the room with a family member or or or friend or someone. I try to say, I'm not hanging my hat on any one piece of information here or any report. I'm just collecting information as an observer to try to get it out. And the reason why you kind of have to weigh those things equally in my mind is that there's, as people know, there's some degree of unawareness or inosygnosia that's that's particularly common. Um, even, or you can see the tip of it in even early neurodegenerative dementia that you might be screening for. You kind of have to, there's that, and and there's also the fact that, you know, people, some people are more naturally self-reflective and in tune with their own mental functioning and cognitive functioning, and some people are not. It's like emotional literacy too, or emotional self-labeling and stuff, where you know, psychiatrists have to kind of manage this, I think, as well. I listen to everyone, I see if there's congruence between the two. I think you can get a sense pretty quickly if there's a really concerned loved one who says, Look, I've noticed two or three years of progressive short-term memory difficulty. And then I might then ask the patient gently, have you noticed some changes in your thinking or memory? And if the person says, you know, I not really, I'm fine, then you already kind of see incongruence between what the family member is saying. By the way, in a in a setting like that, what you can then say is something like, well, you know, as we all get older, you know, this is this is, you know, for better or for worse, you're not going to want to hear this, but we all are a little bit sharp less sharp than we used to be when we're younger. Have you noticed changes with normal, what we might describe as normal aging when you think about yourself compared to your friends? And then you can get people to open up a bit and acknowledge that maybe they've had some changes along those lines. So you kind of have to, you have to be open about it in a way.

SPEAKER_02: 10:17

Yeah, I actually wanted to follow up on that. I had the same question about who to ask the intro, the history to. But the other thing that I've actually seen some patients in my practice say is almost kind of like kind of excusing the symptoms. Like I, for example, saying, Oh, I've never been a guy, like someone who could know my way around a city anyway. Like, you know, I was always lost even without the GPS, let alone now. I'm so kind of saying, like, I would have never been, you know, high high, high performing in that domain. Versus the other sense, I also have patients who, for example, I have an artist who is just like, no one else would know, but I am not the same, you know, and so kind of in their own domain, being having been a high performer in the past, noticing a decrement. So I'm curious how you account, whether you take that into account, kind of low, high performing self-report or by prior career experience, and just how do we account for that? And do we account for that in that initial history?

SPEAKER_01: 11:13

Yeah, yeah, that's a great point. And there's a lot of different kinds of variability there where you have this self-agnol, you know, kind of self-awareness, but you would never observe it, et cetera, like you described. So the framework that I often use for that is what's helpful for me in learning about this history, this is what I would say to patients and families, is think comparing yourself to yourself. So, like when we think about you now compared to say, and I always say this is a hard question, but say compared to six months or a year ago, do you, and or you can ask this to the loved one as well, does you do you see this person as different in how they are functioning? So this gets out of the kind of targeted questions, especially related to daily functioning, where you might say, like, are you driving now? Are you doing personal finances now? If you it and if you if you start like that and you start to go through instrumental activities of daily living to try to kind of tease it out, you get quickly in the weeds of, like you said, Galina, you know, I've never done finances, I've never used a microwave, I've never done it, never done this, and then you're kind of a little bit lost in the specifics. Whereas if you open it up from the beginning and sort of say, when you think about your husband or your wife or your mother, and if I were to videotape their life a year ago and videotape a day in their life now, what changes in daily functioning and mental activity, mental acuity, or you know, I don't wouldn't use those terms always, do you see our differences? And that puts a that that allows us to be like patient-centered actually and really get at what you know changes for that person. You made me also think about this is this is hard to do, you know, tease this apart. And this is where you start to combine obtaining clinical data and then integrating it into the history that you're getting. If I have a mixed view about what the have at there actually, what changes have actually happened cognitively with this person because the history is incongruent between the loved one and the person. And again, I think this can happen pretty quickly. I I don't think this is that, you know, doesn't have to be, to Michael's point, doesn't have to be that in-depth of a, you know, one-hour interview kind of thing. It can be within 10, 15 minutes. This is when you start to integrate the kind of data that you get on um, you know, basic cognitive screening tests, which we can get into. And sometimes the things start to declare themselves and the truth comes out a little bit if you see, if you see someone that's really impaired on a cognitive screener, whether or not they have awareness into the impairment or not. Does that make sense? You're sort of like starting to dig into like the out of the subjective quote unquote, and a little bit into the objective data gathering situation.

Michael Kentris: 14:02

Aaron Ross Powell No, that's a great point and I think a great approach. I would be remiss as we as we go forward here, things that things that act like dementia but are not dementia or cognitive decline that I think uh we all see quite a lot of in that assessment process. Again, to borrow another archaic phrase, the sometimes think of them almost as like the worried well. How do you sort out these things when you're kind of going through, like, as you said, the more subjective side of things? Are there any specific symptoms or habits that would point you more towards maybe uh a you know, again, I know it's not the current vogue, uh a pseudo-dementia, if you will.

SPEAKER_01: 14:41

Yeah, yeah. So I mean, one big principle comes to mind when I hear this, which is that it is more common to have multiple factors, medical, psychological, etc., to be the cause of cognitive impairment than it is to try to whittle down a differential diagnosis to get at, you know, one disease. So it's not that you're not thinking that way as a provider, right? You are, you know, you're you're wondering when you see even the chief complaint, you start to try to figure out is this a progressive problem that is declining over time? So therefore, I'm in the neurodegenerative kind of framework of thinking about the disease, or is this something that, you know, there was a particular triggered event, like an ICU stay or something in which the cognition, you know, kind of started to be apparent. But when you're thinking about that and you start to ask about psychiatric history and current psychiatric symptoms and current medications that someone is taking, these are the other causes for cognitive impairment, right, in this age group. I'm just what I'm um trying to to um to get at here is that it is okay to not be sure whether someone's, you know, pre-cognitive impairment depression is still playing a role in their current cognitive performance, for example. Right. I mean, you are trying to, we do have the goal to try to make, say, a neurological diagnosis, and that's fine, but I just want to sensitize to the idea that it's often multifactorial. And so, like a great example of that is you know, you have a patient who comes in, you know, they're in their 70s, they have say one year or one to two years of cognitive concerns, the pace is not clear exactly, it's not clearly progressive, but you wonder about it, and people, let's say the spouse is a little bit more concerned and observes more than the patient sees. And then you get a screening lab test, battery of tests like thyroid, like TSH and B12 folic acid, say vitamin D or something, and the TSH is off. So a kind of Occam's razor thought there is like, well, this must be the thyroid that's the problem because you know there's there's really high TSH, et cetera. And I'm just guarding against closing off at that point and saying, you know, well, then this cognitive impairment of this older person is clearly hypothyroidism, right? That's all. Because it is really common to have multiple things. You know, that person might also be taking anticholinergic or, you know, medication as well. But but the, I mean, the traditional divide between this dementia and pseudodementia is this idea of like, and this is not, you know, as accurate as the words would imply, but there's kind of reversible and irreversible dementia or dementia and pseudodementia. And it it is worth, and people probably know and remember that in this like formally kind of reversible category are things like metabolic disturbances like thyroid and vitamin B12 deficiency, you know, polypharmacy, severe depression, you know, things along those lines. But but anyway, so it is worth it, but just keeping your mind open is important as well. One thing I'll add there is that it's helpful, I think, hopefully, for all providers to hear that if you have in mind in the neurodegenerative space that you're seeing someone, you're assessing them for the first time. If you think about the three or four major neurodegenerative diseases, and it's worth talking about. So, say, you know, Alzheimer's disease, Lewy body dementia, and say frontotemporal dementia. So I'm not, I'm not putting vascular dementia in that category because let's say for argument's sake, it's not neurodegenerative, even though you can have degenerative changes, but let's assume that it's a little bit more static for the argument that I'm making. It's really helpful to know the basic symptoms and syndromes that you see with those like three diseases. That will go a long way. Alzheimer's disease, even though it has different presentations, cognitive type of presentations, the most common is like a slowly progressive memory-predominant decline for people in older age. For example, just that basic idea will help you because if you start to take a history and it's just not clear, it's progressive, and it just doesn't seem to be memory predominant, it decreases your diagnostic confidence or certainty that you should really like evaluate that further. I'm just thinking of the kind of way that you would approach a patient in which they just have they're older and they have cognitive complaints. And it's like, where where do you really start with it, right? Similarly, let's take something like Louis Body. If you have the basic symptoms um in mind and the basic cognitive profile, you know, so I'll tell you, you know, so it's someone that has dream enactment and or nocturnal vocalizations that could have started a while ago. It's important to ask about that. You know, sometimes it's 10, 15 years before. There's interesting data on that and and predicting someone developing one of the alpha synuclean diseases like Louis Body, you know, and you start you hear that or you ask about sleep and you get that history, you're then starting to think about things like, you know, mild Parkinsonism with an early patient. So you might have some rigidity and things like that. Then you might ask, you know, do you see things that other people don't? Don't see, or do you have some changes with your vision or or visual misperceptions? You know, you can say something doesn't look like it should be, then you're sort of building a little bit of a pattern to do a focus interview. My point to zoom out is just that you're not you don't have to go in blindly if you have the couple of symptoms for the major three or four conditions that you're gonna see commonly, and that can help you kind of whittle things down. I think I think I diverged into a couple of different topics there, but that's that's my long answer to the question about like kind of what what do you do when you start this interview? And you're just not sure. It's pace, it's pattern, and it's kind of what are the other factors that could be reversible that are playing that are part of the picture. Those are all important.

SPEAKER_02: 21:05

Seth, I I really like that summary and that framework. Can you wrap up with the third one for us for those listening? So for frontotemporal, what would the hallmark signs be?

SPEAKER_01: 21:17

So the typical kind of syndrome we would say. So what you see in the patient, the behavior, is um there's a couple different variants. There's the behavioral variant of frontotemporal dementia or couple phenotypes, I should say, in which someone um often has changes of uh social cognition. So like their decorum, you know, seems, you know, off. There's off there can be um behavioral disinhibition. So their their filter is a little bit less filtered. They um they might be, and this can you can see the tip of the iceberg of this, they might be just a little bit inappropriate, a little bit um socially inappropriate, for example. Um, you know, you can also see changes of dietary patterns. It can be the classic description for this as a sweet tooth. So you can ask about whether have have there been changes, you know, I the example I usually ask is something like this person never liked um uh you know Chinese food until last week, and now they have to have it all the time, you know, in in the last couple of weeks. So it's not just this classic sweet tooth example, but it's adoption of a kind of restricted behavior that's out of the ordinary and appropriate. Those are kind of obvious things that you can see with the beginnings of frontotemporal dementia. And then the other common, just for simplicity's sake, of that condition is in the language domain. And those people might be familiar with hearing like the primary progressive aphasias or the language predominance. And there, there you can get at, you can ask questions like has there been a change in language output or speech output for this person? Do you notice word substitutions? Do you notice output problems where it's kind of it sounds like a broke is aphasia sometimes, you know? So the way that you'd ask a patient, a family is is the speech halting, and it feels like it's hard for them to get out the sounds and and the words. Again, those are the typical examples of the of the primary progressive aphagias and the behavioral variant front. But you you kind of sometimes see the tip of the iceberg for that when you're doing initial assessments. So again, if you have in mind back to my previous point, hey, I'm gonna, this is a person where I'm getting a flavor that it's not cognition alone, right? Meaning it's not executive function or attention or memory, but actually I'm getting a flavor of some behavior or some language. I'm gonna dig into that. I'm not gonna let a passing observation of it seems like dad is a his filter's a little bit off. I'm gonna dig into that a little bit and ask, give me the examples, what situation, um, and then I might ask about restricted behaviors and things like that. So you just let the, you know, what the report is guide you and dig in a little bit more to it. I think I did justice to that final disease, hopefully, Galena.

SPEAKER_02: 24:16

Yeah, you did. That's so helpful to hear your approach. What I've loved about these series is that we have this kind of pattern, you know, the first higher level point is like, you know, don't, you know, trust but verify the history. Like the words that patients may use may differ. And then the second is that you have this almost um, I heard someone say something called like the accordion of the neurological history or the exam where you can kind of open it up and close it in. And, you know, you're not really going in with those guided questions or leading questions, but if you hear and pick up on something in your mind, you're categorizing it and and then pursuing it further. So that's really helpful. I also appreciated, Seth, your description of some of the, you know, quote unquote, whether it's the right term or not, reversible or irreversible factors. And I tried to think about that as well. And I'm jumping a little to management, but in my mind, I often ask about the things I potentially could have an impact on. So I'll ask about sleep or substance use, for example, when I'm doing my history and then kind of circle back. So can you talk to us about uh those two elements? And is there anything else that you're asking about when you kind of think about those reversible elements?

SPEAKER_01: 25:25

So I think that mood is a is one important place to start there. So, you know, concurrent with complaints of cognitive decline over time is often changes of mood. And I tell people that that is normal. I mean, whether or not you have reversible or irreversible quote unquote cognitive difficulties, that, you know, it it itself can be the cause or the trigger of being down or anxious or, you know, frustrated about the cognitive complaints. So I I I'll I'll dig into that in interview and try to get that out a little bit more. You know, I mean, I will I will ask about basic questions, getting pleasure out of activities, the kinds of things that you would ask to screen for major depression, I think you can ask in this population as well. Um, you know, are you getting joy out of some of the activities that you do? Um, um, do you feel down some of the time, a lot of the time? You know, as opposed to are you down, are you depressed? You know, you can kind of give them an out and an easy way to start to talk about it. So I think get digging into mood, and I'll put into mood also, you know, so mood we think about depression and mood changes, but you know, like things like anxiety, so using terms like, you know, more nervous than you used to be, is you know, is it different in do you feel more anxious during this time in which you or your loved one has also noticed cognitive difficulties as a way to kind of dig into that more? Looking at medications and med reconciliation is really important for cognitive um uh side effects of medications. I mentioned anticholinergic medications before. I mean, there's a couple of kind of you know key culprits that are pretty anticholinergic medications. I'll I'll throw oxybutanin under the bus because for neurologists listening or primary care other providers, you know, this is like I have seen, you know, examples of sort of like this medication causing like significant cognitive difficulties. So I'll do like a general medication review, of course. But also I think another thing in this realm of questioning is when did this all start, so to speak, right? You know, it's not uncommon for there to be an unmasking if of of a dementia process, of a neurogenic process, in something that we want to uh in an event that we want to attribute as the cause, or family members were often will often say, you know, it all started at this time. But it's not that the ICU stay or you know the urinary tract infection is now the cause of what seems to be an emerging Alzheimer's disease. It's just that the brain has only so much reserve. And when you sort of like, you know, have a metabolic derangement like UTI or or someone has a concussion like of or basic head impact without a lot of post-concussive sequelia, but you just, you know, you find out that, you know, dad hasn't been the same since like the the car door came and you know, trunk came and slammed on his head, it's easy to attribute and say, oh, well, then it must be because his cognitive difficulties are because the cognitive. And I've had many, many cases where if you ask about the history prior to the event in which the family is attributing as the beginning, you get some subtle changes. So the term, the questions I will often ask in that situation is let's go back to before the ICU state, even if it was subtle, did you notice that things were a little bit different with short-term memory and word finding or with and you know, you you may get a positive or negative there, but all that to say is that like everything in medicine, you're looking at what you see now and what what happened before, and then you're trying to figure out what this is gonna be in the future, if that makes sense to people. So it's really important to kind of pinpoint the beginning part of that. Sleep is also important for a number of reasons. A common question I'll get in the clinic these days because there's a lot of headlines and public discussion about, you know, chronic poor sleep and increased risk of dementia, which is true in that we know from epi studies and population-based studies that, you know, the risk is for chronic suboptimal poor sleep that there's higher risk. But practically speaking, with an N equals one patient sitting in front of you, you know, it's it's difficult to sort of say, you know, this person is chronic, you know, to say to a patient or family, well, you've had chronic sleep for 20 years, and this is the reason why you have like early Alzheimer's disease, right? This is a really challenging thing to navigate when you're trying to figure out what's going on with someone. So, practically speaking, related to sleep, I think if you ask about current sleep, you get a brief history of sleep in their adult life, briefly, and then recently, you can start to gear things towards treatment, first understanding what it is and then thinking about it. One thing with sleep that comes to mind is that neurodegenerative diseases like the ones we've talked about have sleep fragmentation and sleep difficulty as part of the process, as part of the syndrome that you see with the pathophysiology. You can someone, again, to the point about the worsening of prior problems, someone can have intermittent, you know, insomnia or poor sleep, and then it kind of all unravels and gets worse when Alzheimer's disease starts, for example. So, you know, you can also have new onset sleep difficulty and memory difficulty, let's say, as the first presentations of something like Alzheimer's disease. Um, so it's it's a mixed bag, but those those are the main things that that I think about. You mentioned, I think, Alina's substance abuse too, or substance use. This is a really common, at least in my cognitive clinic, which is it's often, so say it's you know, frequent alcohol use, or I've seen a lot of cannabis use, for example, in this older population for different reasons. I would say that most of the time I'm I'm thinking about when I hear history of current alcohol abuse or alcohol intake, as well as cannabis, I'm thinking more of what contribution is this causing to the person's cognitive difficulties, especially if I'm concerned about like an early neurodegenerative dementia, rather than attributing the cognitive difficulties to the cannabis use or alcohol use. Right. So people may know or should you know could probably remember that there is a kind of dementia with severe chronic alcohol use that is called alcohol dementia or alcohol-related cognitive impairment, in which you have confabulation and some of these dramatic cases that the providers may remember from learning about in medical school. But it's it's really exceedingly uncommon, at least in my practice, to have to just attribute, you know, you really like kind of chronic alcohol use to what we would call alcoholic dementia. And there really isn't like any biological marker for that. Of course, there's MRI findings that you can find and attribute. So, practically speaking, we do know, and the pendulum has swung in the direction people may know, sort of like advising against against less and less alcohol intake than it would than it than we did a couple of years ago, even. Practically speaking, reducing substance use for things like cannabis and alcohol that can really impact cognition is a great way to start to tease apart contributions to their cognitive complaints. I usually tell someone who has current alcohol intake to start during this evaluation process to start by trying to cut alcohol in half, for example, you know, to sort of see what's going on. Yeah, so it's messy, you know, like everything we do. But this attribution issue of having in your mind and kind of figuring out what is at play here and having a little bit of a rubric to dig into those different factors will help you assess, you know, what is what is the contribution here. We I I well, go ahead, Michael.

Michael Kentris: 33:43

Oh, so you know, I know a lot of what we've been talking about is kind of, you know, a lot of the examination of these kinds of people is talking and asking questions. Are there anything is there anything in the physical exam itself that you would say is not necessarily typical as part of someone's usual screening neurologic assessment?

SPEAKER_01: 34:03

Aaron Powell That's a great question. I think that, for example, what comes to mind is we didn't mention vascular cognitive impairment or vascular dementia. So this is maybe the second most common reason for older age, you know, dementia, cognitive impairment. And one thing that I do in the clinic neurologic exam-wise is on motor exam, for example, I'll look for some laterality in weakness or you know, findings that would suggest, you know, some kind of motor dysfunction. Because if I haven't, and you know, if I combine that with a patient who has a history of systemic vascular disease like hypertension or hyperclusterolemia and things like that, I'm building a little bit of a picture of, well, you know, maybe they have subcortical ischemic vascular disease, maybe they have some lacuna infarcts, maybe they haven't been imaged before. So that's one thing. So laterality on motor exam. For patients who, after say, you know, a cognitive screening test, like a Montreal cognitive assessment that's clearly abnormal, you know, or something along those lines, people that have some uh psychotic breakdown on motor exam, I mean, on eye movement exam can be a part of the picture. Uh, again, as you said, you know, it's not pathonomonic for dementias, but you often see some psychotic breakdown in in patients who are further along in impairment with dementia. Gosh, I mean, I think our best tools in the cognitive clinic, I actually think about it in three ways. I think there's three helpful pieces of information. Hopefully, this is helpful for PCPs to kind of think about too, which is the symptoms, which is like the syndromes, the pace, the specific domains we talked about, the behavior, the the affect, just basically the symptoms, imaging, so neuroimaging of the brain. So MRI is typically you know better if possible to get than CT of scan, and then cognitive and functional performance, so cognitive testing, memory testing. And that can be in a in a primary care office, that can be a screening test, like the Montreal cognitive assessment, the Adambrook cognitive assessment assessment is a good one. The ACE, it's a little bit more comprehensive than the MMSC, than the Mini Mental Status Exam. I encourage people to check it out. The ACE is just one that comes to mind. There's the Addenbrook Cognitive Examination Revised, or R. I think that's in the public domain. You can find that. So I think about those three pieces of streams of data that help you narrow what can be a really wide differential diagnosis. So that begs a number of questions, like, you know, I see someone, the pace is slowly progressive, memory decline. I'm not sure, but I'm concerned about a neurodegenerative disease, could be Alzheimer's. I do a MOCA test, the mocha is, you know, 22, 23 out of 30. You know, do I get brain imaging for that for a patient like this? And I think that increasingly I'd say that the answer to that should should be yes, right? In in at the primary care level. And I know we were chatting a little bit before about how hard it is, you know, in having a short amount of time, in seeing a patient like this in a primary care office or in a general neurology clinic or or geriatrician's office or anywhere, what do I do? Like what do I actually obtain for this patient? I think if you think about these three streams of information and you've done a little bit in each, which has helped to include a you know brain MRI scan, which just to talk about briefly, you can see on MRI scan if there's significant changes in the white matter. So, you know, people might be familiar with like white matter disease, microvascular disease in the brain, what you can call subcortical ischemic vascular disease. You can see strategic strokes where someone had, you know, a silent stroke in the cortex that is part of a frontal dysfunction. Let's say it's a you know a frontal stroke or something along those lines, et cetera. And you can also see, and this is the more tricky and nuanced part, but it's helpful to get as you're saying maybe waiting for someone to get to a neurologist's office, you can see a pattern of volume loss or atrophy that in the right setting is suggestive of neurodegeneration. So, what I mean by that is if you have a one-time scan of someone in their 60s or 7 or I, and you see a little bit of, say, volume loss in the hippocampus or the medial temporal lobe, which is a common place that you start to see atrophy as diseases go on, by itself, you can't say that, you know, oh, this is supportive, or I should say that this is, you know, clearly a neurodegenerative disease like Alzheimer's. But in the right context, you can say that combined with the history, it's like it's like everything that we do in medicine, right? Putting all the pieces together, combined with history, combined with symptoms, uh, which is history, combined with neurocognitive testing and MRI scan, you can kind of start to build the picture. So I don't know what hopefully that that uh starts to get at this this this question.

Michael Kentris: 39:26

So I did want to add in one thing, or I should say ask. So I know you mentioned several cognitive assessment tools. The one that I probably see the most that has been done in PCP's office when they get referred to me as the minicog. I know obviously it is probably the most brief out of all of these. Does it have value as far as like, as a let's say as a screening tool?

SPEAKER_01: 39:50

I think it does. I think it does. And again, I think it's easy to learn and easy to administer, and the other tests take longer. And I do think that an abnormal mini cog combined with a good 10 minute history that teases apart kind of the stuff that we talked about, and maybe a can something concerning on MRI is a really good value add for going towards a diagnosis. I do think so. You know. On the other side of things, which is that if you, let's say, are in primary care and you see someone back where you're building these tests, you have a little, you have some evaluation done, and you've already done a test like the MOCA and it's borderline. One really helpful cognitive test to throw in is that you can do really easily and learn easily, which can kind of help your differential diagnosis towards something like Alzheimer's, for example, is ver a verbal fluency test. So you can ask someone to do two things. You give them a letter of the alphabet, like F or S, and you take your watch or phone out and you time them for one minute and you have them generate as many words as you can that you say, tell me as many words as you can that start with that letter. It's called phonemic verbal fluency. And you just write down, you count how many letters, how many words that they generated. And then you do the same thing with a category. So you say you give them either animals or vegetables or something like that. And you say, I'm going to give you a minute. I want you to list as many as you can. A really helpful clinical pearl with the results of that test is if they have worse category fluency. So they name less category items than items that are based that are generated from one letter or the phonemic fluency. And especially say if it's a significant gap between those two. So say it's 17 S words, but five or six category words in vegetables, combined with an abnormal Mocha test or even an abnormal mini cog, and a history suggesting progressive cognitive difficulties, in particular something that's memory focused, which is the most common, then that's really helpful for Alzheimer's, for like kind of having a diagnostic confidence that Alzheimer's disease is higher. So that's a verbal fluency test. Another test that just comes to mind that I really like is there, there's there's a couple different to think of, but one that's easy to do is the trail making test, part B and part A, that people might be familiar with. Takes a little more time to explain, but essentially you're having them track on a sheet of paper, and you can find the stimuli online if you search for trail making tests part A and B. You can use each of them respectively to get a sense of processing speed and working memory in one case, and the other is more of kind of the tri the part B is more of kind of executive function and like what we call set shifting. So you would do a test like that if you noticed, and I think the big picture here is if you see the divisions of the mocha are divided into things like memory and abstraction and attention. If you if you see real impairments in one of those and you want to tease it apart a little bit more, in particular for say attention or processing speed or thinking, these are tests that you can do pretty easily to kind of corroborate that or challenge that.

Michael Kentris: 43:24

We talked a little bit about MRI brain as as you know part of our diagnostic imaging, but there's been a lot more emphasis in recent years on like different biomarker testing, you know, both via like lumbar puncture, spinal fluid testing, as well as like these, you know, pet tracer scans. And I think just in the last few weeks there was clearance for a serum marker for Alzheimer's. So what's your perspective on these? Should we because I I am in my gut, I am sure that we're all going to be seeing a lot more referrals for patients who are going to be having some of these positive tests. And the symptoms may or may not correspond, right? As far as that you know, imaging clinical divide there. What role do they have in your practice? And what role do you think they should have in a primary care practice?

SPEAKER_01: 44:11

Those are great questions. And they're active area of clinical research, of course, and everything. They're they're really here and used and present, and they're they're everywhere in our in our clinic. Um so just starting with like the two gold standards for assessing Alzheimer's disease pathology that we've been using in the clinic and the Cogner Clinic, actually, as people probably know for you know 10 plus years, starting with that one first, is spinal fluid testing. So spinal fluid testing with a pattern of a beta amyloid and tau protein in the fluid in a particular pattern is really helpful. This is really like a confirmatory biomarker. So when would you use a test like this? So there are actually appropriate use criteria published for spinal fluid testing for amyloid for Alzheimer's disease. But in brief, if there are cases where the history and the age and the domains affected, so say not memory, not clearly someone in their, say, late 60s to late 70s, and I guess those are the kind of main things. And you want a confirmatory biomarker, like a test like spinal fluid Alzheimer's biomarkers, that is going to be like a tiebreaker or sort of like a helpful decision maker to confirm the disease, then that's the setting that you would use a test like that. And whereas in a typical, say, I'm going to say a typical case where you have slow progressive memory decline with abnormal cognitive testing, and let's say even an MRI that has like a pattern of some tissue loss in the temporal lobe and prior lobes, I just described, by the way, like a typical Alzheimer's disease patient, you really don't need to do an amyloid confirmatory biomarker either by spinal fluid or by or by PET scan. Now, having said that, since the two new drugs for Alzheimer's disease have been out in the last year and a half, plus, which it which are monoclonal antibodies, anti-amyloid antibodies, lacanimab and denanomab, the whole paradigm of doing biomarkers has shifted. And I know, Galina, you mentioned at the top of this hour that, gosh, there's a kind of urgency now in neurology clinics when you see a patient who could have specifically early Alzheimer's disease to get the necessary testing and diagnostic confidence that they have Alzheimer's to get them to treatment. This is a total kind of paradigm shift in our use of these biomarkers. And in the last year and a half as well, we started to use amyloid PET. So that's tracer for beta amyloid in a PET scan in the clinic, more commonly, overwhelmingly more commonly, because it's less invasive than doing spinal fluid testing, and it gives equivalent information actually to what you can get in spinal fluid. We've been doing those to evaluate patients with to confirm early Alzheimer's disease. Now, just almost ready for prime time, but I don't think at the recording of this podcast we're fully ready to use blood biomarkers yet, even despite the FDA green light for the lumi pulse test that Michael was getting at. The story with blood-based biomarkers is that amyloid in the brain is just challenging broadly because people with normal, so to say, with normal aging or people that get in their 70s and 80s can have a level of amyloid in the brain in which they would have a positive amyloid PET scan, but at a low level. Those folks, you know, and there's debate about this given the current consensus criteria, but those folks who don't have any symptoms, let's say, but have a positive biomarker test, um don't are not eligible for treatment with one of the two new medications. So they've been described as having preclinical or asymptomatic Alzheimer's disease. Okay, and this is a a really interesting topic for maybe like a whole nother podcast to do, but those patients um are by the 2024 criteria of Alzheimer's disease, by the Alzheimer's Association criteria, are technically have stage one of Alzheimer's disease. So stage one is biomarker positive, no symptoms. Now back so there's there's things to unpack there for sure. But thinking about blood testing, blood blood marker testing of these fragments that are shed in the brain, phospho phosphorylated tau and beta amyloid 42, for example, or beta amyloid proteins, that kind of testing is good to corroborate these days in the gold standard amyloid PET scan or spinal fluid testing. So I don't think we're ready, even in the specialty office in my clinic, to use those alone to confirm a diagnosis of the disease. We're almost there, but we need a little bit more real-world evidence given just the huge variability of what you see in patients and how to interpret the levels of those testing. So that's a long answer to a very short question, but um I I think it's gonna be some time before the blood test can be used in primary care as a screening test. Um, although we may get there. And even still, I think the current gold standard in the right situations is to do an amyloid pet or spinal fluid amyloid test to try to sum it up a bit.

Michael Kentris: 49:57

No, that was an excellent answer to a uh definitely controversial topic in a lot of quarters. So thank you very much. Um I know even in my my own practice where you are, I have to refer folks for the amyloid pets, and if they do want to get any of the anti-amyloid therapies, just because we're not set up for it uh locally, so I always have to refer them to one of our local academic centers. But um, you know, kind of moving back to the to the primary care or even the general neurology side of things, you know, what right there's all these medications that have been around for ages. What role do they have? You know, thinking of things like like dinepazil or romantine or you know, some of the other uh medications kind of in a similar vein, do they have a large role to play and what kind of expectation should we have for their performance in practice?

SPEAKER_01: 50:45

That that's a great question. I think they do have a role. And even though the studies that led to their approval and why they've been used for or studies led to approval were, you know, had modest benefits over six months or a year, et cetera, there are responders to these medications. There are people who have a clear observable boost in cognition. You know, maybe it's 30% or 40% of patients just anecdotally, like is the number I have in mind in my clinic where for short periods of time, six months or a year, families and patients observe some boost in these medications. They are, I think, really important to consider still and to use. So there's different reasons for that. You know, one is that the majority of patients that we all will see in clinic, not majority, but let's say like close to a majority, maybe past the point of being eligible for getting the new anti-amyloid therapies. And so we have to be aware that I think everyone deserves a trial of pharmacologic intervention for Alzheimer's disease. You know, this is my view, and I think the view of a lot of like cognitive subspecialists. Um and and so, and that's because you people can respond, and they do respond. And so I think we should keep these in mind. A common thing that I see is that someone I think it's important to note that most care of cognitive repairment and dementia patients, just numbers-wise statistically, is done in internal medicine and in primary care. If we think about the distribution of care in this country, and so many PCPs and family practice folks and geriatricians are are actually using donepazil and rivastigmine and galantamine and have experience with it and have used them. One common thing that I see is um, you know, say a patient with a presumed Alzheimer's diagnosis is being treated with donepazil, which is Aercep, for example, and it's on for some period of time, maybe a year or two, and then the conclusion is it doesn't work. You know, it's not working. And so it it forces us to examine like what is the goal, what was the goal of that medication, which gets at your expectations question, Michael. You know, what do we expect in these medications? So I think the general experience is that some people can observe that there's improvement, some people smaller amount can't tolerate them. They do the cholinesterase inhibitors like do have some GI side effects. We have to be aware of that. But I think knowing that that there's modest expectations and that as long as there's no kind of contraindications in the patient's other medications for taking those meds, it does make sense to keep them on board as long as it's reasonable for longer than six months or a year or a year and a half. I mean, I typically will keep them on board until there's a good argument to get rid of them. Now, part of that is because there are some studies and anecdotal experiences that when you get rid of medications like Aerosept and Mementine, you sometimes do see worse cognitive performance and at least definitely a rocky period. And again, if there isn't a compelling reason to stop them, like polypharmacy, and sometimes there is compelling reasons to stop the medications. I typically keep them on board because I do think they're boosting the brain. I mean, they're they're providing acetylcholine in the case of acetylcholine estrase inhibitors, and they're having some benefit on excitotoxicity with mementine in the brain. I do I'm I'm of the camp where they should be maintained for the foreseeable future for most patients, so for these types of patients. Maybe I'm an outlier there, but I I I think it's important to get that voice out there. There is a bit of a nihilism with them. I appreciate that, but you know, those medications were never studied or presumed to be curative medications, of course, or even reversal medications. And so if we can give people a boost for diseases like this, I think we should do that in any way.

SPEAKER_02: 55:04

That makes a lot of sense, Seth. And I like that you mentioned that often that is being trialed at that, you know, primary care stage, like if if it can be offered, especially while someone's waiting, or just to give it a go. And I'm wondering if you could just touch on in the last minute on anything else that you think our primary care providers can counsel on. As you mentioned, they're kind of seeing the burden of these patients and probably also doing the burden of the education around lifestyle changes and prevention. And that's really their, you know, that that's their expertise, our primary care physicians. So what are your kind of, you know, Seth Gill stamped um lifestyle changes that they should be counseling patients about?

SPEAKER_01: 55:42

That is a great question, a great way to end. So I think what what I would add it to this, to the kind of population, patient population we're talking about, is there is this idea of subjective cognitive complaints. Okay. So these are people in which they often have a family history of of dementia, not always, but they could. They have some subjective complaints of memory and thinking difficulties, and they come and they they they are concerned, of course, like anyone would be about developing dementia. So for those patients who we who we put in this like kind of subjective cognitive complaints category, because if you do general cognitive screening for them, like a mocha test or even detailed neuropsychic evaluation, they're often normal. They have they have normal, you know, normal results. They're a great population to advise on brain healthy behaviors. Now, everyone who is 30 and above should be doing brain healthy behaviors. And I often will say that to patients that, you know, here's the kinds of things to do. And so those include, you know, aerobic exercise. So that's like really recommendation one, two, and three is the way I think about it, based on based on what we have from all the Epie and population-based studies. And again, practically speaking, to help patients, it's baby steps here. You know, you have people who are a little bit active, but not very active, but their heart rate hasn't gone up a lot. You don't want to tell them that they have to do 150 minutes a week of light to moderate aerobic exercises, which is what the World Health Organization advises, because they're not, they're not gonna do it. They even with a good relationship with you, they're they're gonna they're gonna come back in six months. So, so this is like any human behavior change, right? You know, you lay out the counseling that, hey, it's really important to exercise, and here's why. We have good evidence of reduced risk of dementia, et cetera. And then you say, you know, let's walk a quarter mile around the high school track near your house, you know, every day for the next five weeks. Or not every day, three times a week for the next five weeks. You know what I mean. So you're inching, it's incrementalism, right? You're inching people forward on behavior change. There's that. There's healthy eating and diet is important in these studies for reducing cognitive decline and dementia. Typically the Mediterranean style diet and the variation of that people might have heard of called the mind diet, which is a variation that's M-I-N-D, like brain mind, mind. It's a variation of the dietary approach to stop hypertension or the DASH diet and the Mediterranean diet are important. And again, this is a marathon here. So, you know, people, you know, have developed their diet habits, they're in their 60s, 70s, but you can give them a food pyramid of the Mediterranean diet. Most people have seen it. You know, doctors like to talk about diet and exercise, right? This is not rocket science, but it's really important. You can really budge the risk of, so to emphasize that point, these things I'm mentioning are are really important. Of course, they're good for the heart, they're good for the brain as well. And I guess the third bucket in this is this kind of keeping the brain active bucket, this social and mental stimulation category. And a common question there is, you know, well, you know, I talk with my nephews and family members on the phone a couple of times a week, but I don't play card games or, you know, or watch history channel programs. You know, that's fine, right? Because there's no, there's no, you know, prospective study that has shown that crocheting, you know, is better than doing cognitive tests on the computer. And I think this is a really important point, right? That the way that we know what I'm saying to be true from the large population studies is that you ask people over time, tell me about the mental and cognitive activities that you've participated in this month. And you do that for years and years in these long-term aging studies. And it's a lot of different things that people can do that are that seem to be part of the recipe for reducing dementia risk. It's it doesn't have to be a particular thing. And back to my behavior change point if someone is inclined towards picking up or going to sit at the piano that they haven't played for years, but they used to play piano, when they're inclined to just do that for five or ten minutes a day, it's much more likely they're going to sustain that for the next couple of years than if you, you know, give them something like that. I think that's a really important point with lifestyle. But those are kind of Of the three buckets. And I'd also tell people finally that there's some great resources on this and on brain health to check out. You know, I'll just plug the Massachusetts Alzheimer's Disease Research Center or M A D R C. You can Google it. You can find it. There's some great handouts on that page for patients and families that are called the roadmap series. Of course, that's what I go to in my mind because it's regional here, but that's something to check out.

SPEAKER_02: 1:00:45

I absolutely love that those buckets, the reminder of how important this is. I'm also a bit of an annoying stickler. I make everyone get hearing tests and check their eyes out. And I say, if you can't hear, you're definitely not going to remember what was told to you by your family.

unknown: 1:00:59

Yeah.

SPEAKER_02: 1:01:00

But I feel like I've uh reversed a few dementias.

SPEAKER_01: 1:01:03

I I feel proud of those successes. You should be. Those are in the modifiable risk categories. And there is like absolutely, absolutely. You're doing the right thing.

SPEAKER_02: 1:01:14

Well, Seth, this has been so wonderful. I always learn something new when I talk with you. And it's just incredible to see you and your colleagues and in the cognitive um neurosciences just really like take on this new wave of opportunity and enthusiasm that we all have for potentially having treatments for some of our neurodegenerative conditions. So thanks again for joining us and sharing your wisdom.

SPEAKER_01: 1:01:36

Yeah. It's been a pleasure. Thanks for the conversation. It's been great.

Michael Kentris: 1:01:40

I learned a lot too. Thank you, Dr. Seth Gale. Anything else that you want to plug other than the resources you've given us so far? Any projects that you would want people to check out or other resources?

SPEAKER_01: 1:01:52

One thing that comes to mind is for people, for your patients that are interested, there is something called the Brain Health Registry to check out in this last category. That's something to check out. This is like an online study for anyone age 18 and above to be involved with. You can register and it's sort of like we'll feed you some cognitive questions every couple of months. And it's a kind of a way to for people especially that want to be part of a registry and parted research, it's an easy online way to do things. Um but otherwise, um I I can't think of anything else, and I I appreciate the conversation.

Michael Kentris: 1:02:27

Likewise, thank you so much. So uh thank you everyone again for listening to us. This was, I thought, a very edifying conversation. As always, you know, if you liked what you heard today, share it with your friends, share it with people who work in medicine, and you know, leave us a rating review. Well, only if it's five stars, though. Uh, you can find us on X at neuro underscore podcast, and you can always find our past work at our website, theneurotransmitters.com. Thank you, Dr. Gale and Dr. Geifman, as always. Take care.