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Dementia is a broad term which covers many conditions, including Alzheimer's disease, vascular dementia, frontotemporal dementia, and others. In this episode, Marwan Sabbagh, MD provides insights around diagnostic criteria for the most common dementias, as well as their differential features.

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Differential Diagnosis in Dementia

Podcast Transcript

Intro: Neuro Pathways, a Cleveland Clinic podcast, exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD: Diagnosing dementia and its many types can be challenging for physicians. It is estimated that 5% of individuals over the age of 65 have severe dementia, and 10 to 15% are at least mildly impaired. As the size of the elderly population expands, the number of individuals with dementia will inevitably increase. Early and accurate diagnosis is the major objective in dementia evaluation. In today's episode of neuro Pathways, we'll discuss differential diagnosis in dementia. I'm your host, Glen Stevens, Neurologist, Neuro-oncologist in Cleveland Clinic's Neurological Institute. I am very pleased to have Dr. Sabbagh join me for today's conversation. Dr. Sabbagh is a Neurologist in Cleveland Clinic and the Lou Ruvo Center for Brain Health in Las Vegas. Marwan, welcome to Neuro Pathways.

Marwan Sabbagh, MD: Thank you for including me.

Glen Stevens, DO, PhD: So I have to admit, I'm a baby boomer, which scares me about today's topic. But we're all getting older, and as we get older, we all start to forget some things. Many older people have a slight loss of memory that doesn't affect their daily lives, but memory loss that gets worse may be a sign of dementia. Can you set the stage for us and discuss common etiologies and differential diagnosis of dementia?

Marwan Sabbagh, MD: Yeah, so dementia is a category, Dr. Stevens, and to be clear on this, dementia by its definition is cognitive impairment rising to the severity of having functional impairment. So the technical definition is one or more domains of impairment associated, with a functional impairment. It is a categorical description, but it's not an ideological diagnosis. So we have to break it into then the etiological diagnosis, and the etiological diagnosis might be Alzheimer's dementia, Lewy body dementia, et cetera. But your earlier comments are important, because we're talking about the fact that before they get to dementia, they might go to a transitional stage called mild cognitive impairment, and often the tip of the tongue early symptom might not be full dementia, that happens much later, we hope, but might be the beginning of a mild cognitive impairment state. But all I'm saying to you is that by the time we're in dementia, we're quite severe.

Glen Stevens, DO, PhD: And some common etiologies and differential when you see these patients?

Marwan Sabbagh, MD: So I've worked now in the dementia stage, of course, the most common type dementia. To be clear on this, this is a very prevalent thing. So all neurologists say that their specialty is the most common, we always joke about that among neurologists, but we're talking about the most common disease among neurologists, which is dementia. Eight million people in the United States have dementia, 5.5 million people have Alzheimer's dementia. Another five million probably have mild cognitive impairment. Dementia as a category, it subsumes Alzheimer's dementia, Lewy body dementia, Parkinson's dementia, frontotemporal dementia, vascular dementia, and then there are the reversible causes like hypothyroidism, normal pressure hydrocephalus, and the like. So there is a broad differential diagnosis, and the presenting features is what kind of differentiates them.

Glen Stevens, DO, PhD: So I know you're a specialist, so you would end up seeing patients being screened before they come to you. Do you still see patients, I'm just curious, that are diagnosed with thyroid related problems by the time they get to you, or is that screened out?

Marwan Sabbagh, MD: I would say that most of the time it's screened out. Amazingly enough, I still see a TSH that shocks you because it's so high, maybe once a year. But I think the fundamental issue for me, much like you would see with other conditions like depression, is that people say that's the cause. So let's say I have a patient with a TSH of 20, and I'm going to say, "Aha, their impairment is related to their hypothyroidism," and guess what? I will normalize it, I'll give them the levothyroxine, get their TSH under two, and what happens? It turns out they probably have hypothyroidism and Alzheimer's dementia, not the exclusive cause. I have to tell you, true hyperthyroidism causing dementia, I have not seen in probably a decade. So yeah, by the time they get to me, they've been screened out for those things.

Glen Stevens, DO, PhD: So historically, how have we managed patients who are diagnosed with dementia?

Marwan Sabbagh, MD: So the first thing we would tell you is it depends on the dementia. Like you, today, I'm in clinic, and my first patient I saw today either has PSP dementia or Lewy body dementia, and I'm trying to decide which one that person has. But the way we manage it would depend on what the cause is. So the clinical presentation is very relevant. A patient with a strong neuropsychiatric presentation, meaning hallucinations, fluctuations, Parkinsonism, you got to think Lewy body dementia. How I manage Lewy body dementia is completely different than how I manage Alzheimer's dementia.

The reason I'm bringing that up is Alzheimer's dementia is the most common. Alzheimer's as a disease has three phenotypes or three clinical presentations. One is the classic amnestic disorder, two is the language presentation called logopenic primary and progressive aphasia, and three is the visual spatial impairment that's called posterior cortical atrophy, or PCA. So how we manage it depends on the etiological, but let's assume for a moment, almost all Alzheimer's is amnestic. So how I would manage that is quite different from how I would manage a Lewy body patient. Of course, you try cholinesterase inhibitors, you might try memantine, and then you would address target symptoms like anxiety, the sleeplessness, agitation, psychosis, et cetera.

Glen Stevens, DO, PhD: I remember back to the old days, the earliest drug that I remember that came out, I think was Cognex.

Marwan Sabbagh, MD: Oh my gosh, you're aging yourself, Dr. Stevens.

Glen Stevens, DO, PhD: Yes.

Marwan Sabbagh, MD: That's tacrine, that's 1994.

Glen Stevens, DO, PhD: Yeah, and the thing that I remembered about it was that of course, if you look around the nursing homes, it's all elderly women. Us men don't seem to make it that long.

Marwan Sabbagh, MD: That's correct.

Glen Stevens, DO, PhD: And there are small elderly women, and the drug had to be taken four times a day, was my recollection.

Marwan Sabbagh, MD: That's correct. That's correct.

Glen Stevens, DO, PhD: And it caused some GI related problems.

Marwan Sabbagh, MD: Huge.

Glen Stevens, DO, PhD: And you would have weight loss in very small, old women, and they couldn't tolerate it. So thankfully, you've moved to newer generation medications and much more tolerable.

Marwan Sabbagh, MD: But weight loss is a common problem with the meds, and weight loss is a common problem in that population.

Glen Stevens, DO, PhD: So from a provider's standpoint, can you elaborate on the different types of dementias that you had discussed? So number one, vascular dementia?

Marwan Sabbagh, MD: So vascular dementia, I think is very commonly called when it is not necessarily. So everybody, if you do an MRI, has a little bit of periventricular ischemic white matter change. A lot of doctors say, "Well, there's a lot of white matter. It must be vascular." It has to be a lot of white matter. So if there are strokes in key areas, if there is more than 50 CCs of white matter rarefaction, then I'm more likely to call vascular dementia. But if they have a little white matter and their exam is normal, and they have a progressive amnestic history without any focality and no vascular risk factors, I'm not calling vascular. People with vascular dementia actually have known stroke. In fact, the term now is called VCI, vascular cognitive impairment. We don't use the word VAD anymore, it's VCI.

Glen Stevens, DO, PhD: See, I learn all the time. It's good.

Marwan Sabbagh, MD: Cool.

Glen Stevens, DO, PhD: What about Lewy body dementia? You hit on that a little bit.

Marwan Sabbagh, MD: Yeah. Lewy body dementia is much more common than most people think. It's the second most common dementia after Alzheimer's. A million people in the United States have it. It has a very distinctive clinical phenotype of fluctuation, meaning good days, bad days. They have Parkinsonism, mostly gait and a little tremor, but not a lot of tremor. The chronicity means that they have their cognitive and motor declines coming on roughly around the same time. Within a year of each other, they have hallucinations, big time visual hallucinations/ So to this audience, if I see a patient with well-described visual hallucinations, I'm looking after Lewy body first, and Alzheimer's second, because well-described visual hallucinations is one of the telltale signs.

And then the last thing is they act out dreams. So in our world, of course, if you have a patient who has a sleep study and is showing REM behavioral disturbance, they have called a synucleinopathy, either they're going to get Lewy body or they're going to get Parkinson's, that's a bad thing, so we would check for that. So those are the things that we would say... You need to know though, it's a tricky disease to manage because patients are very sensitive to medications. The classic description is neuroleptic sensitivity, but they tend to be sensitive to everything. So you have to be super-duper careful when you're managing these patients.

Glen Stevens, DO, PhD: So then moving to frontal temporal dementia.

Marwan Sabbagh, MD: So I see a lot of patients with suspected frontal temporal dementia. The first thing you need to know is these are young people. My definition of a young person, Dr. Stevens, is under the age of 65, or even under the age of 60. So the young person would be something to think about. Second is there's two presentations, there's a behavioral variant, and a language barrier. The language variant means they're aphasic. Remember, aphasia can be acquired or degenerative. Acquired meaning stroke and head injury, degenerative means primary progressive aphasia, and that is one of the subtypes of frontal temporal dementia. But the classic one that everybody knows about, the Pick's disease, that's the one that is behavioral variant. So they have impulsivity, socially inappropriate behavior, they're out of control. These patients are very, very difficult to manage, and medicines don't work very well.

Glen Stevens, DO, PhD: And then lastly, Alzheimer's?

Marwan Sabbagh, MD: Yeah, Alzheimer's is of course, the big daddy of them all, constituting two thirds of all dementia. And if you actually look at it, if you actually went back and looked at autopsy, if you look at all the autopsy, seriously, up to 75% of everybody with dementia have plaques and tangles in their brain. Most of them are overlaps with synuclein deposits for the brain, vascular changes, et cetera. But Alzheimer's of course, in its classic iteration, is a progressive amnestic disorder, has functional impairment that comes along with it, and then in the moderate stage, you start to see the emergence of neuropsychiatric features, the agitation, the wandering, the restlessness, the paranoia, et cetera. So it has a very distinctive phenotype.

Glen Stevens, DO, PhD: Mm-hmm (affirmative). And if you look at individuals that are in care settings with dementias, and obviously Alzheimer's is the greatest percentage, but on a percentage of it, who's most likely to end up there. What type of a dementia?

Marwan Sabbagh, MD: I would say by far and away, the most common in a long-term care or memory care is Alzheimer's dementia. I would say more than 80% of your population will be there. The driver of people in the long-term care or memory care is the emergence of what I call the big three, falls, and comments and behavior. And number one is drivers behavior, so agitation, aggression, paranoia, wandering, restlessness, et cetera. The happy demented stay home, but the agitated dementia are the ones that get put in memory care.

So the reason I say this to you is that the people in memory care are the ones that are having big time neuropsychiatric behavioral symptoms, and those are the ones that mostly end up being Alzheimer's. Lewy body has a shorter life expectancy, so the life expectancy of an Alzheimer's patient could be up to 10 years, but a Lewy body, the latest data is like five and a half years or something like that. Of course, the frontal temporal dementia will get into long-term care early, but they're young and healthy and they'll stay in long-term care for decades, literally decades. So we unfortunately, don't have a lot of them.

Glen Stevens, DO, PhD: And within the differential diagnosis group, how about a comment on normal pressure hydrocephalus?

Marwan Sabbagh, MD: Yeah. So normal pressure hydrocephalus has the classic triad of the gait, magnetic gait, like their feet are stuck to the ground, incontinence and dementia. It's important to understand that the response to shunting and lumbar puncture is best driven by the response to the gait, not the cognitive. So in other words, if you're going to shunt somebody because you have the suspected triad, if they're not getting better on the gait side after the lumbar puncture, then they're not going to get better from the shunt. So the driver for decision on shunting should be the gait, not the cognition. The thing that gets least better is cognition. So the rule of thumb, as I say, 75% improvement in gait, 50% incontinence, and 25% in cognition.

Glen Stevens, DO, PhD: Yeah, I think that's a really good point, and again, when I go back to my days as a younger neurologist, we used to say the 30/30, that we would take off 30 CCs and wait 30 minutes and have them do 30 steps-

Marwan Sabbagh, MD: That's correct.

Glen Stevens, DO, PhD: ... and see how they did, and if they really didn't improve there, then we would say, "It's probably not NPH." It sounds like that probably still holds fairly true.

Marwan Sabbagh, MD: Yes, but now we have gait labs, we'll do a measuring of their gait, trajectory, stride length, weight bearing, all that stuff, and it's much more accurate. I can now predict who's going to get a good response with great accuracy nowadays.

Glen Stevens, DO, PhD: Yeah, that's great. I know that the NPH group at the main campus here has that whole program that they do.

Marwan Sabbagh, MD: Yep.

Glen Stevens, DO, PhD: So as a leading expert in Alzheimer's disease and dementia, can you tell us about the latest research and how it might change how we diagnose and treat patients with dementia?

Marwan Sabbagh, MD: Yeah, so there's a lot to say there. The good news for us is that I think a lot of people like myself believe we're in a transformative moment in the field. The first part of that is we're going from a diagnosis of exclusion, meaning B12, TSH, MRI, to a diagnosis of inclusion. Just a month or two ago, the first blood test, plasma amyloid test, called the Precivity test, was approved to measure the ratio of amyloid a-beta 42 to 40, and that is now available. Of course, I would use it for the negative predictive value, meaning if the value is normal, then you don't have target pathology, if the value is abnormal, then you have the possibility, and then I would go to a tiered approach, CSF testing or PET.

So what I'm saying too, is that the diagnostic accuracy is going from 70%. That's where it's lived for decades, as a diagnostic guide to 70%, to a diagnostic accuracy well north of 90%. if this audience gets nothing else out of this podcast, I want this audience to understand that we do not look at Alzheimer's that you can only diagnose with an autopsy now. CSF testing is a remarkably precise, amyloid PET, remarkably precise, and now plasma amyloid a-beta 42 to 40 is remarkably precise. So the tests have come along, and our ability to diagnose.

The second major thing, Dr. Stevens, is that we're months away from the approval of a first potential disease modifying therapy, which would be a monoclonal antibody. As you know, biologics are big in your world, but biologics are finally starting to come to Alzheimer's. So they're not new to medicine, they're just new to Alzheimer's. And we have four biologics, monoclonal antibodies, that are making their way, one has already filed with the FDA, three of which are moving their way along. We could be coming standard practice. So the amyloid test that I was talking about, we're going to use it like a PSA, right? So eventually, you'll get a blood test, if it's abnormal, you get more tests, and if you don't have it, if it's normal, you don't get more tests, and then we'll be screening patients to make them eligible for DMT. So it's a really exciting time and a transformative moment.

Glen Stevens, DO, PhD: We've made great strides in identification and treatment of dementias. Before we sound off, do you have any closing takeaways for the members of our audience, who may face the challenges of diagnosing and treating patients with dementias?

Marwan Sabbagh, MD: What I would say is that again, a transformative time, the diagnostic accuracy has gone up. We at the Cleveland Clinic are doing a lot of things to kind of advance the field and advance practice of medicine and neurology. So if you don't know, seek us out and see if we can help.

Glen Stevens, DO, PhD: Well, Marwan, thank you very much for joining us today. I really appreciate your time and insights.

Marwan Sabbagh, MD: Pleasure. Thank you.

Outro: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, ClevelandClinic.org/neuropodcast or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our consult QD website. That's consultqd.clevelandclinic.org/neuro or follow us on Twitter @CleClinicMD, all one word and thank you for listening.

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Neuro Pathways

A Cleveland Clinic podcast for medical professionals exploring the latest research discoveries and clinical advances in the fields of neurology and neurosurgery. Learn how the landscape for treating conditions of the brain, spine and nervous system is changing from experts in Cleveland Clinic's Neurological Institute.

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