5/2019 – NACNR – Obstructive Sleep Apnea in Men and Women: Brain Changes Linked with Symptoms

5/2019 – NACNR – Obstructive Sleep Apnea in Men and Women: Brain Changes Linked with Symptoms


[music playing]>>Paul Macey: Thank you very
much for inviting me. It’s a pleasure to be here. And, I’ll be giving just
a few little anecdotes that, hopefully, will relate either directly
to the precision medicine or, maybe, in parallel
to precision medicine. And, I’m going to start
with my perspective because people always find
this interesting. So, this is the world
with New Zealand at the center. [laughter] And, you see, we’re a long way
from anywhere. So, I studied engineering, and while I was
studying engineering, I was looking
at — speaking with someone, looking at babies. And, I spent half my time
in the engineering school and the other half of the time
sitting in the — this is the pediatric
outpatient ward. You know, an American
and the Christchurch Hospital. And, some of the time
in the nurse’s — this is the old nurse’s hostel. And, there are two
kind of formative anecdotes I want to talk about here. My colleague — I was looking
at breathing from babies — my colleague, Craig Tuffnell,
and good friend, was sitting — who would sit beside me —
was looking at temperature, and he turned a baby into
a model, three compartments. So, there’s head, trunk,
and blood. And he wanted to just show —
model what happens with a baby. Its temperature during sleep. And on the left, we have
what happens in a real baby. Let’s see, temperature drops,
and we have oscillations. And this is what
his model showed, which was kind of similar. So, in other words,
turning a baby into three boxes, we can actually replicate some
of what we see in a real baby. Now, at the same time,
in the room next door to me, I was sitting with these
community pediatric nurses, or community nurses — there’s not quite an equivalent
in the States, but these would go out,
and they were doing a study on helping pregnant
mothers reduce smoking. They would go sit in
with these mothers-to-be and just work
with them individually, and find their goals, and just help them
cut down their smoking. So, these two experiences
are sort of — have, on reflection,
helped inform my outlook. So, I came to the States to look
at Obstructive Sleep Apnea. And this was on adults
who have done several other studies
in children. And, so, I’ll be looking
at Obstructive Sleep Apnea from now on in the talk.
And, Obstructive Sleep Apnea — its proximal cause
is essentially that you have
this upper airway muscle, and, for some reason,
it loses tone. So when people go to breathe in, airway muscle gets sucked
against the back of the throat and it causes a blockage. So that is obstructive
sleep apnea. And, there’s a few symptoms that are classically
associated with this. So, snoring, especially
gasping or choking. Snoring has been
a classical symptom along with daytime sleepiness. Also, in terms
of what’s considered a normal symptom: fatigue. And this is more along
moving into a sense of, like, depressive symptoms. Morning headache. And, these latter
are more common in women with sleep apnea.
Why do we care? Well, one reason is we have
an increased risk for all-cause mortality. So, this is a study
out of Australia. Again, I’m from New Zealand. So, this was, yeah,
a six-fold risk of mortality over a 14-year period.
And people diagnose. So, these are the people
that are actually, presumably, treated.
And, probably the — what’s going on is that
the stress of the sleep apnea is leading
to other difficulties. And so, if we look at —
what are the actual problems? Well, we have many
co-morbidities, physical and psychological,
beyond just the sleepiness. And our treatment of choice,
CPAP, doesn’t really resolve
these co-morbidities. It can help. Furthermore, the first thing
someone will say to you if they’re diagnosed
with sleep apnea is, “Well, I don’t want to use CPAP.
Who wants to wear a mask for the rest of their lives
while they sleep?” And, so, there’s low compliance
and it’s disliked. And, even people
who want to use it still struggle
with it sometimes. A lot of people we see,
this is probably biased because of the people that come
through our study, but — [music playing] I feel like I should
start dancing. [laughter] — it is that they’re frustrated
that they’re using CPAP, but it’s not — they still
have trouble thinking, they still have trouble
with depression, they have trouble
not feeling well. And this, turns out, is more
probably more common in females with sleep apnea than males. Females are also less likely
to be diagnosed. This is changing somewhat, but it has traditionally
been seen as a male disease. And I love this.
This, from the ’90s, this one paper
talked about females having abnormal symptoms, as if the correct symptoms
to have were male symptoms — [laughter] — and the females were causing
an inconvenience by having abnormal symptoms. [laughter] So, and while they are — it is less common in females — it does seem that,
for the same level of disease, women are more affected
by sleep apnea. So, let’s look at what we know.
Research. This is just the fun way
of looking at the amount of research articles
per month in PubMed. So, you can see it’s up to 2,
300 a month at the moment. So, thank you, NIH. And, a fun way of looking at
what are people researching. So, let’s do this
with a word cloud. So, we take
all of those publications that have an abstract. Let’s look at what words
are in there. So, these are the most frequent
words in those abstracts to give us a sense
of what’s been studied. There’s obviously treatment,
CPAP, years, disease, breathing, surgery
used to be very common, treatment,
pressure, respiratory. What I don’t see in here is what I hear people
complain to me about. People who are struggling
in their job. They have a professional job.
They can’t think. They can’t remember.
They’re feeling, not just sleepy,
but just not able to carry on. So, it’s more in the realm of
something we would call stress. If we measure out anxiety
symptoms or depressive symptoms, anxiety symptoms
come out highest. But I’m not sure that you would say
it’s an anxiety disorder per se. So, a lot of the research, then, is not getting at
what people complain about. And, so then we go, “Well,
where are our knowledge gaps?” Well, I would say, you know,
what is the source? What’s going on? Why do we have so many symptoms
beyond just the sleepiness? Are there alternatives to CPAP? Are there effective alternatives
to CPAP? This word, effective,
is interesting. We’ll get back to that. And why do symptoms
remain with CPAP? So, you know, this study. Although the title
is very absolute, “No Cardiovascular Benefits
for CPAP in OSA” — it’s probably an unfair title,
actually, based on the study — but this is what the point is: that, even if CPAP does help,
it doesn’t fix. It doesn’t resolve. So, I’ve been looking at
what the brain might have to do
with all of this. And, so, we can come up again.
Engineer. Let’s have a simple model.
Sleep apnea, brain injury, brain doesn’t work so well
or is altered. And then we have some symptoms.
Simplistically speaking, this is consistent
with what we might see. Remember, we said the treatment,
the CPAP, doesn’t seem to fix everything. So, okay.
How does that fit here? Well, presumably, CPAP will
effectively stop sleep apnea. Basically, what it does
is it stops the blockages in the airway
and the air keeps flowing. It’s like a reverse
vacuum cleaner if you’re not familiar with it. And, so,
this would stop further injury, but if there’s existing injury,
it wouldn’t treat it. So, perhaps what’s going on
is even though you stop more damage,
existing damage remains. That’s possible. This was sort of supported
by animal models from mice 20 years ago that showed that, with two days
of intermittent hypoxia, which is one of the
characteristics of sleep apnea, you get cell death, which is
represented in this slide. And, so, the first study I did, which is actually still
my most cited study, was looking at a patient — a small group of people
with sleep apnea use MRI scans. And using the traditional way
of presenting changes that we have neuroimaging,
we have a background, in this case,
of sort of gray image. It’s fuzzy because it’s
an average of 40 images that represents areas. And then,
in these colored blobs — we actually call them blobs — that represents statistically
meaningful differences. And, in this case, where it was
a smaller hippocampi or smaller gray matter.
And then we’ve got — the hippocampus is one area
that keeps coming up. So, more recently —
we can zoom in — we have much higher
quality images. So, this is the hippocampus
in yellow. And, we have this image here, which is looking
just at the hippocampus. And, so, this gray shape that’s
there, and we often rotate because it’s easier to see
a 3-D shape with rotation. So that represents
an average hippocampus. We each have these and have one
on each side. And the colors represent areas where there’s a change
in the volume. So, the red orange is actually
a swelling in this case. Maybe some information. And the blue
is sort of a shrinkage, perhaps reflective of damage.
And, just — what’s interesting is we’re talking about
this precision medicine that, and this should’ve, to get these
sensitive measures of change. As you can see,
we had 66 sleep apnea subjects, which is fairly difficult
for a neuroimaging study, but close to 1,000 controls. And this is where we use a large
population study of MRI scans. And then we could take
our 66 subjects and compare it with those. And we had some of our
own controls as well. But I think this is a little —
and many, whatever, small precision
or low precision. We don’t have a million,
but, having many, many measures that we can bring in
with our study does two things: it makes our study
more sensitive, and it means that another group
can take those same measures and compare their patients
against them. So, I think it’s just
a little aside to — a sort of a shout out for,
I think, you know, all of us. If it’s done right,
has got Verily. Now, just to
complete the look — recently, I wrote an editorial,
so this is my two cents’ worth. And it’s called,
“Damage to the Hippocampus in Obstructive Sleep Apnea:
A Link No Longer Missing.” So, there was a group
in Scandinavia and has worked
with an Australian team to look at post-mortem
slides of people who were known
to have sleep apnea. And they found that, indeed,
in the hippocampus, there was damage. So, this is a region
in the non-sleep apnea, post-mortem slide showing that it’s a thicker CA1 area
compared to the sleep apnea. And this was looked at
at a population level. So, we went from animal,
to human imaging, to precisely looking
at the hippocampus, to seeing that yes,
in post-mortem studies, there really is
a difference as well. And, just kind of
briefly touch on: well, how does this relate
to symptoms? And, so, one sentiment,
this first one I really was interested
in was depressive symptoms. Roughly half of the people
with sleep apnea in studies report having high
levels of depressive symptoms. Again, this is not necessarily
a depressive disorder. I actually think
this is an underestimate compared to actual
clinical populations. When we try and study people, and we try to exclude
people on antidepressants, that cuts about
half of these people, I would say probably close
to the two thirds. And, why do we care? Again, when you add depression
to sleep apnea, things get worse.
So, commercial drivers are at higher risk of accidents
if they have OSA. So, there’s a three-fold risk
just from having OSA. But if you have that
with depression, you can go to over
six-fold risk of crash. And, so, this is a study we did
several years ago that looked at —
well, okay. So, we have high levels
of depressive symptoms in some people with sleep apnea,
but not others. So, let’s see if there’s
anything in the brain that also changes with that. And this slide is from a paper
that showed that the people
with more depressive symptoms did indeed have markers of,
in this case, damage, compared to people
with sleep apnea with low levels
of depressive symptoms. So, in other words, those
with symptoms also had markers of some kind of change
in the brain. And we’ve looked at anxiety
as well, and also some physical symptoms
like diabetes and hypertension, which I won’t show the results.
We have those findings as well. So, then,
what about sex differences? And, we have sex differences
in symptoms and presentation. So, at first, we weren’t focused
on this, but several years ago, I was walking past a poster
at a neuroscience conference that showed an animal
in vitro study. And, it was —
this is the paper that came out. It’s called, “Sex Differences
in Susceptibility to Oxidative Injury
from Intermittent Hypoxia.” So, in other words, they took
slices, brain slices — I’m not sure if it was
a mouse or a rat — and they exposed those slices
to intermittent hypoxia. Those from the male brain
showed more damage than those
from the female brains. So, I thought,
“Well, that’s interesting.” And we did the same study
using imaging in humans. And we found that indeed
there were differences, and this is an area
that the NINR has supported me for several years now
to really look at what we see in the brain
separately in males and females. And part of a nice
piece along this — I’m going to go back to —
this is our hippocampus. This is, essentially,
the same representation as that. Both hippocampuses
have just got a slightly more stringent
statistical threshold. So, again, we’re looking
at roughly 1,000 people versus 66 people
with sleep apnea. We see a few areas;
again, they’re smaller because of
a high statistical threshold. And we included sex
as a covariate because we knew it was important
and that’s what we saw. But what happens if we look
at men and women separately? So, rather than having
one big model where we can put
everyone together, we have a statistical
control for sex. Why don’t we look at males
and females separately? So, we did, and we get
something quite different. So, if we look
at males separately, using the same population,
the same statistical threshold. So, again, we got roughly half
the number of people here compared to there. So, if anything,
it should be less sensitive. We get this, and I’ll explain
this in a moment. If we look at females,
we get this one on the right. So, the first thing
that should be obvious is that there are
a lot more colored areas here and here than on the left. So, if we had stopped at this
finding, we would have said, “This is the effect
of sleep apnea on the brain.” But, when we take it
one step further and just go, “Well, no.
I don’t want to combine. I want to look separately.” So, roughly the group
of 500 males, roughly the group
of 500 females. And we go, “What’s
the effect of sleep apnea?” This is what we get.
And, so, we see both. There’s a whole lot more
that shows up, and also, we see differences. And I’ve highlighted one here
with a star. So, this is the tail of
the posterior hippocampus. And this is an area
that’s tied in with depression. Females with sleep apnea
tend to report higher levels of depressive symptoms, you know, so there’s
some association here. So, obviously,
there’s the immediate finding. Maybe we’re doing — there’s
some biological independing of the differences in symptoms. But, also, it has the message
that combining male and female, and perhaps other combinations, can hide
what’s actually going on. So, let’s look at possible
mechanisms. I’m going to focus on one
that’s kind of recent. Working with a group
of people at UCLA — my colleagues, collaborators
for many years — we have techniques
where we can look at levels of chemicals
in the brain. So, NAA, which is related
to neuronal function, glutamate. We can get these maps
across all different areas. And, so, a preliminary study
we did was to look at GABA
and glutamate. So, these are the most common
neurotransmitters in the brain. And we will start on the left,
in the GABA. So, what we have here. We have a structure
called the insula, which is the key
to many of the symptoms. And we’ve got the left side
and the right side. And then the gray bars
are the sleep apnea, and the white bars
are the healthy controls. And what we see is the gray
is lower than the white. The gray is lower
than the white. If we go to glutamate, the most common neurotransmitter
in the brain, we see the gray
is higher than the white. The gray is higher
than the white. Now, you know,
how do we interpret this? Well, since GABA
is considered inhibitory, we can think of it as like
the braking, slowing chemical. Since glutamate
is considered excitatory, we can think of it as the,
kind of, accelerating chemical. And then we,
using the simplistic metaphor, then we would say,
“The sleep apnea patients have less brake
and more accelerator.” Is this related to the very
high sympathetic tone, high levels of anxiety,
or any other measures of stress? Well, my students just finished,
last week, presented a study
looking at perceived stress and, of course, sleep apnea
that’s also high. And, also, we know
that high levels of glutamate can lead to excited toxicity.
Now, of course, I want to know: is this different
in men and women? And that’s what the NHLBI
has just funded me to look at, so I’m at the beginning
of an R01 for that project. And I wish I knew
the answers now. So, this is the pilot data
for that grant. I’m going to touch on a couple
of interventions. First is CPAP. So, this is another
two cents that I had. And there’s
a couple of groups. One in Australia,
and one in Italy. There were published studies
showing that if you treat people
with sleep apnea, it does seem to reverse some
of the changes in the brain. So, this is promising.
There are some caveats to that. We have some preliminary data
that suggests that as well. And going to symptoms,
and this is, again, pilot data from another grant
that we’re trying to get funded. We have this cross-sectional
study looking at cognitive performance using a very simple,
10-minute test. And we have the healthy,
untreated sleep apnea, sleep apnea on CPAP. With this measure,
with this group of people, we’ve found that
the treated sleep apnea and healthy were similar levels;
the untreated were lower. This is consistent
with what people report as trouble thinking,
trouble making decisions, especially if they’re
in a profession that requires a lot
of intellectual power. We’ve got the males and females
separated out there. Then, we look at depressive
symptoms in the same group. We see it’s low
in the healthy group, and it’s high
in the untreated group. And then we see this difference
between the men and the women
in the treated group, where we have even higher
in the females, high levels of depressive
symptoms compared to the males. So, again, this is —
does this hold? We don’t know. So, the Office of Research
on Women’s Health, along with the NINR,
who have supported a kind of 56 to sort of start
looking at this and link it to what’s
going on in the brain. So, the final piece, which is
looking at another intervention. This is Inspiratory Muscle
Training. So, if you remember,
people don’t like CPAP and it doesn’t always work. And if we go back to just
looking at things very simply, like I said. If we take the “turn the baby
into a box” approach, what’s happening
with sleep apnea is this tongue muscle,
if you like, is losing tone. So, what if we just tone it up?
How do we tone up muscles? We go to the gym.
We do weights. So, how do we do this
with this muscle? It’s not easy to do.
The first study related to this is was looking
at playing a didgeridoo. So, if you —
what happens is people Google, they find they have sleep apnea,
or they worry they have it. So, before they even go in
for a sleep study they go, “What could the treatment be?” They Google “treatment,”
they see CPAP, they go, “I don’t want that.
What else is there?” So, they’ll say,
“The didgeridoo.” So, when we see people they go,
“What about the didgeridoo?” And there’s a very small study
that showed that, indeed, playing the didgeridoo
seemed to help. And maybe this is, you know, training those up
airway muscles. I think the original — I have a couple of digeridoos
in my office and they look way
more cool like this. And it’s tricky to play. This is the one
they used for the study, which is much more boring. And, so,
I had that on background. They’re a nice sort of group
in Tucson did this pilot study
where they did something called, “Inspiratory Muscle Training.” And they found
that modulated blood pressure and plasma catecholamines. And because I’ve been
more focused on cardiovascular than respiratory,
I immediately thought, “Hang on. You’re doing
a respiratory training, but you’re getting a change
in blood pressure and plasma catecholamines?
Like, what’s going on?” So, I immediately rushed out,
bought one of the devices. We spoke with the PI
about how they did this study. And, so, inspiratory muscle
training — this is one way of doing it. And it’s traditionally been used
in the exercise world when it comes to, like,
exercise training, performance. And, so, if you Google you
get people who look like this who are very cool and don’t look
like someone with sleep apnea. And we inert started with
the protocol that they use. And we ended up adapting it
a lot based on talking with the patients
but, in essence,
it’s like a set of 30 reps, if you’ve been to the gym,
except it’s breathing. So, you’re breathing hard
30 times, and then that’s it. That’s it for the day. And typical studies
have been six weeks. We, again, we did six weeks and then we found
we needed to extend it based on, kind of, talking with
the people who were doing it. So, this is another preliminary
one where we’re really trying to get more. And so, this, you know, we did
sleep studies before and after. It’s hard to say
if there’s any change. A lot of these people started
with only mild sleep apnea. We measured blood pressure
using these home devices, so we had a lot of measures.
So, we had dozens of measures. Maybe systolic went down. When we look over
a longer period of time it seems to go down,
but maybe it didn’t. Sleepiness started very low,
so it went down. But what does that mean?
But here’s what’s interesting. People loved it.
People really clicked with this. Now, again,
there are no studies, so who’s to say that it’s not
that they loved being with us in the study? But people reported
feeling better. Like, there’s this — and they talked about
their breathing feeling better. And this gets back to the very
last question you had. I think, is that, well, let’s say
we find these measures, and we find that, you know,
you fit in this profile. And where does what you want
come in as a patient? And these people —
the fact that there was so much positiveness
that we didn’t capture. We did a sort of
many-qualitative study with some of our colleagues,
but it’s — there’s something going on
where people were, like, more than happy to use it,
and they just felt good. There’s something about
their breathing felt good. Was it the actual
muscle training? I don’t know. Also do
a little bit of mindfulness where it can affect
one of the training grants was from my student who did
mindfulness and hypertension. How much is actually, you know, perhaps through training
their breathing, they’re getting the experience
of mindfulness? Since a lot of mindfulness
or meditation is based on breathing awareness. I don’t know. But I thought
it was very intriguing. And, so, where next? So, I think
this idea of balancing, like, looking at:
what do we choose, having all of us initiative,
like, what do we measure? Let’s think about the models. The models, at least,
give us somewhere, narrowing down what’s important.>>Ann Cashion: Dr. Macey,
you have about two more minutes.>>Paul Macey: Right.
Then I’ll finish up. So then –>>Ann Cashion: [laughs]
Maybe 90 seconds.>>Paul Macey: Very good. And I know you said that people
should finish on time. [laughter] So, and then this idea of, like,
personalizing interventions based on what people want.
So, this is the people to thank. I think these slides will be
available, so there are many. And here we go. [laughter] [applause]>>Ann Cashion: That was just
such a fascinating talk. I’m afraid we’re probably
going to have a lot –>>Paul Macey: Yeah.>>Ann Cashion: —
of questions. So, I would like to give time
for just one or two, if there are some. If there is something.
Shirley, did you?>>Shirley Moore: So, I’m one
of the people who got one of
the supplement grants on looking at Alzheimer’s
disease and related things, and we’re using imaging, brain imaging as well
as blood markers to look at. And I had never thought to ask
if they had sleep apnea as one of my other indices
that I do, because, as I look
at your thing, you know, is the — are the brain changes
due to the sleep apnea, or are they other-induced that
were creating Alzheimer’s-like, you know, dementia? But it seems that,
when we do these studies now, we might want to add that
question to more of our studies, because it looks like
it could be, you know, as we ask other
possible confounding variables.>>Paul Macey: It was first
in 2017, I started hearing one in several
talks about sleep apnea as a precursor to MCI
and Alzheimer’s. I think this is
a great example where, just by adding
that one question, it can open the door
to looking at that question — to looking at that.

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