Chapter 1: What is the main topic discussed in this episode?
Great. Thanks, Eric, for inviting me. I'm super excited.
Yeah. So let's get right into the topic. The connection between sleep and neurodegenerative disease, particularly Alzheimer's, what's your overall perspective about how they come together?
Well, I think there's two broad areas, at least that I'm aware of, in which sleep and neurodegeneration overlap. One is with Alzheimer's disease and how sleep or circadian disruption may have a two-way direction with early Alzheimer's disease pathology, where we know, obviously, once people get Alzheimer's dementia, they have a very high prevalence of sleep problems.
Chapter 2: What is the connection between sleep and neurodegenerative diseases?
But we now know that even in the preclinical stage, meaning prior to any cognitive symptoms, people may have sleep disturbances that are detectable through a variety of means. Also, there's some evidence to suggest that having sleep disruption may promote or speed up um, the, uh, the buildup of Alzheimer's disease-related proteins like amyloid plaques and tau tangles.
So, you know, in the past, say, 15, 20 years or so, there's been a lot of data, uh, you know, starting with mice in the Holtzman lab here at WashU that have really looked at the, uh, interaction between sleep and, um, Alzheimer's disease proteins. Um,
And I think as time has passed and as the biomarker field in Alzheimer's disease has advanced, we're getting more and more of these data in humans as well. So that's one large area that's, I think, of concern to many of us.
The other area in which sleep and neurodegeneration overlap a lot is in synucleinopathies, and this is a group of disorders that includes Parkinson's, dementia with Lewy bodies, multiple system atrophy.
We know that there's a specific sleep disorder called REM sleep behavior disorder that people who have that sleep disorder are at heightened risk of being diagnosed with one of those synucleinopathies within 5, 10 years. So we know that sleep can be a signal and sometimes a very specific signal as to neurodegenerative disease processes that may be ongoing in the brain well before symptoms occur.
All right. Well, so you made the link between the two most important neurodegenerative diseases, Alzheimer's and Parkinson's. But regarding the mechanism, is this really related to the primacy of deep sleep, the slow wave portion of sleep, or is it really other phases as well?
So I'm a sleep doctor by training. So I think that non-REM sleep and REM sleep are both important. They're like my children, right? They are important. But when it comes to at least amyloid and tau, we think that it is the slow-wave sleep, which is kind of the deep part of non-REM sleep, that's important.
One experiment that we did in my lab to really drill down into which specific part of sleep is linked to amyloid
is we did a study where people came in and spent two nights, at least a month apart, and we set up a closed-loop system where, you know, after they fell asleep, we were reading their brain waves, and there was an automated system where once they started getting into deep, slow-wave sleep, they would get a little beep through headphones.
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Chapter 3: How does deep sleep impact Alzheimer's and tau proteins?
So do they have a sleep disorder? Do they have some other reason to be having the sleep problems in the first place? So it may not necessarily be the drug. It could be whatever is going on that is causing them to want or need the sleep drug in the first place. I don't think necessarily the NBBRase, you know, the class of drugs that zolpidem is in, I don't think that they're necessarily bad.
You know, I prescribe it in a small number of patients if it's appropriate. But really, for any sleep drug, we want people to be taking it on a temporary basis as short as possible. I think that... permanent, you know, never-ending daily use of a drug to improve sleep, I don't think that's healthy.
Okay, so next, the medical community isn't yet really aware, even though it's been available for some time now, on the erection group of drugs, which are supposedly ideally suited if you're going to prescribe a medicine to help sleep. Can you talk about those?
Sure. So DORAS, which stands for dual orexin receptor antagonist, they came on the market a few years ago. There's now three of them, suvorexin, lemborexin, and daridorexin. And these all work by blocking the action of orexin. Orexin is also called hypocretin. When hypocretin is low, that's what causes narcolepsy. So orexin is a wake-promoting pathway.
So it's a new class of sleep drug in that all the prior ones, basically, they increase sleep. pathways, whereas this was the first one to tamp down a wake-promoting pathway. So it's a new class of drug in the past few years. You know, it does have objectively measured improvements in total sleep time and sleep efficiency compared to placebo. And, you know, they've been available.
I think the uptake has been kind of slow because they are expensive. And, you know, in the U.S., we are very limited by what insurance covers. And it is unfortunate that, you know, while drugs are on patent, the drugs can be out of reach even for people with good insurance.
You know, they've been on the market and, you know, I think it really kind of depends on the person, whether they respond better or compared to, you know, any of the other sleep drugs or other insomnia treatment methods. But I have noticed that, you know, it tends to help people kind of say, I can't turn my mind off, you know, if that's the issue, you know. But, you know, it's not 100%.
And like all drugs, you know, they have different side effects. But they did have good clinical trials. And I'm curious to see what the long-term data look like as there's more widespread usage. You know, so far, I think the safety data look pretty good. But, you know, zolpidem and the other NBBRAs also looked pretty good when they came out. It took some time for that data to accumulate.
So I am curious to see, you know, what happens in the next 5-10 years as we get more experience with these drugs.
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Chapter 4: What role do sleep regularity and duration play in health outcomes?
So, you know, that's what I recommend for, say, you know, my patients. We have two psychologists at our sleep center who do CBTI. You know, that's primarily what they do for their practice. So that's my top choice. Wow. that's not always affordable or feasible for people. In which case, you know, there's a variety of different apps. And nowadays there's like AI-assisted apps or programs.
It can't hurt to try. You know, I think there's decent data on some of these app-based ones compared to CBTI. But, you know, I'm like, well, you should still do the real CBTI if you can. Otherwise, I think it's always reasonable to try an electronic version.
Okay, so no comments about particular electronic digital ones. There's not one that you think has helped people particularly?
Not necessarily, and I've had different patients use different ones, so I don't think there's any one that like jumps out to, you know, in my memory as being particularly more effective. And sometimes, you know, it's just like with a therapist. I think sometimes there's just like a better fit between the person and the app or, you know. And it can take multiple tries.
So this is what I tell patients a lot is don't give up after the first try, right? You can always try again. Take a break and try again.
They vary. I mean, some are just like for reducing your level of anxiety, calm, talk space, and others are really trying to get at this issue in more depth and specificity. What about naps? What's your sense of?
What do I think about naps? So naps are great if you are a good napper. So we say keep your naps before 3 p.m. so that it doesn't interfere with sleeping at night. And then you want to avoid getting sleep inertia. That's that groggy sensation where your brain is still like a little bit in molasses when you wake up. And that tends to get worse the longer you've been asleep.
So you really want to try to end your nap by 30 minutes. So I tell people set an alarm so that you don't get into real deep sleep and get sleep inertia. I would say in general, people are either good nappers or bad nappers. And by good nappers, I mean they fall asleep and they wake up. easily. So I am a bad napper, so I don't take naps because I can't fall asleep.
And then if I do, I feel real groggy, right? So most people kind of know if they're good nappers or bad nappers. So people who are good nappers, if they're able to keep those naps brief before 3 p.m. and it's not interfering with their nighttime sleep, it's great. It's good. It'll help boost their cognitive function. You know, they've done studies looking at
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