"Sleep, Memory, and Dementia" Ina Djonlagic (03/09/2022)

March 15, 2022

ID7541

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00:00Alright, I think we are.
00:04Being recorded, folks are joining.
00:09As in good spirits of prior to
00:12zoom conferences, I see people
00:14having lunch, which is wonderful.
00:18That's great.
00:21Let's see, I am on my phone, Eric,
00:23so I can't tell how many people have joined.
00:25We're up to 40.
00:27Looks like alright, perfect, great,
00:31and so good afternoon everyone.
00:34My name is Andres in truck and I
00:37just wanted to welcome everyone back
00:39to another edition of the joint
00:44Northeastern I should call it sleep
00:47conferences now that includes several
00:51different academic programs and we're
00:54really excited to have you back.
00:56And joining us today and we have
00:59a very special speaker with us
01:01today that Eric will introduce.
01:03And just to remind you that
01:06during conference,
01:06please keep your mikes muted and post your
01:11questions into the chat and we will have.
01:16Our panel answer questions and Eric
01:19will guide that at the end of the talk.
01:23If you wanted to receive CME
01:25for today's activity, you can.
01:27You just have to be registered with the
01:29LC ME and the code to put into the CME.
01:38App is going to be posted in the
01:41chat as well by Debbie Lovejoy,
01:43and so thank you all again for joining us.
01:45I'm going to hand it over
01:47to Eric to introduce him.
01:50Wonderful good afternoon.
01:51Everyone had the pleasure of introducing,
01:53you know dialogic today who.
01:57It did her medical training at
01:59Georg August University in Germany
02:01and something I did not realize
02:03is that she actually did pediatric
02:05training first at Carl Gustav Carus
02:08University in Dresden before coming
02:10to the US and pursuing neurology
02:12training being both a resident chief
02:14resident at Dartmouth Hitchcock and
02:16then undergoing Sleep Medicine,
02:18clinical training at Brigham and Women's.
02:21And since then,
02:22she's maintained an active clinical practice,
02:25first at Brigham and Women's Hospital,
02:27and more recently at Beth
02:28Israel Deaconess Medical Center,
02:30where she's risen to the to be assistant
02:33professor in neurology at Harvard
02:35Medical School and has had active
02:38involvement Precepting Fleet Fellows,
02:40which is greatly appreciated
02:42for both fellowships.
02:43She's also had leadership roles,
02:45including being a medical director
02:47during her time at the clinic
02:49at the at at Brigham Women.
02:51And she is a ad hoc reviewer for many
02:55different journals and has also had a
02:59series of funded research projects early on.
03:03Having a relationship with
03:06Roberts trickled in his lab and.
03:10And having many projects in
03:11the areas of sleep learning,
03:13memory consolidation,
03:14EG analysis and cognitive decline,
03:17including its relationships with
03:19Parkinson's disease and Alzheimer's
03:21and that's generated over 20
03:22publications and makes her very
03:24well qualified to speak on the topic
03:27that she's joining us for today for.
03:29So thank you very much for taking the time.
03:32Thanks, Eric. Thanks for having me.
03:35So I'm going to dive right in second.
03:40OK. So I. I like to start with a
03:46little bit of a historic background.
03:49There was a book that actually put together
03:54many famous people and how much they
03:58presumably step because there is still
04:01this notion that if you're a genius,
04:03whether you're a writer, painter,
04:06composer, you can live on very little
04:09sleep and that really disproved that.
04:12So it shows that most famous.
04:15And productive and prolific people
04:17in the past have actually slept more
04:19than we thought they did or got a good
04:22eight hours of sleep or even more.
04:27This one. So the first publication
04:34on sleep and Memory was actually
04:38from Jenkins and Dallenbach in 1924.
04:41There was a person that had previously looked
04:46at nonsense syllables and they had taken it.
04:50They were taking it a little bit further.
04:53What is interesting is.
04:56That this was done 100 years ago,
04:58and at that time it was enough to use
05:01just two students in each group, and so
05:04they had them learn nonsense syllables.
05:07And they had two students who were sleeping,
05:13and who students who stayed awake
05:15over this interval of eight hours.
05:18And as you can see in the graph here,
05:23the students who slept,
05:25they were able to retain these syllables
05:28a lot better than those who stayed awake.
05:32And uhm. Then not much happened, Uhm?
05:38Not meant that there wasn't
05:40much research for many decades,
05:42and I think that.
05:46There were a couple of obstacles that
05:49prevented people from really believing
05:52that sleep was meaningful in in cognition,
05:56and one reason is listed on the left.
06:00If you look at how many hours of
06:03sleep different species require,
06:05you can see humans down here at #3.
06:09Only below are the cow in the wars
06:11here and many other animals are above,
06:13and so there's no clear correlation between.
06:16Among animals or mammals,
06:18how much sleep they are getting
06:20and their cognitive ability.
06:23Similarly.
06:26This is a publication from Jerry
06:28Siegel assigns publication,
06:30who showed the amount of REM sleep and
06:34relation to humans and on the left side you
06:37can see animals that have a lot of REM sleep,
06:41which includes the platypus not considered
06:44the smartest animal on the right,
06:46you see a dolphins having
06:49very little REM sleep,
06:51and so there was this notion that
06:53it doesn't really make sense.
06:55There's no correlation about.
06:56You know if if REM sleep or
06:58sleep was that important,
06:59it would really correlate with you
07:01know humans should have the most
07:03and so that really took a break
07:05on a lot of research and I think
07:08eventually we started to understand
07:10a lot more about the way memories
07:14function and I'm just going.
07:16I should have said that at the beginning,
07:18I'm assuming that we're all that
07:20the audience has very different
07:22backgrounds in terms of neurology
07:25and condition and memories.
07:26So I'm I'm.
07:29Trying to be very very basic and and
07:32trying to give an overview so that
07:36hopefully everybody can understand.
07:402nd So this is. Altered a little bit,
07:46but this is from a publication from 1968
07:50and that's still more or less how we
07:53look at other different memory systems.
07:55So you start at the left.
07:58You have a sensory input and that can be,
08:00for example learning a
08:03skill or reading something,
08:05and if you're not paying attention,
08:07that information is immediately lost.
08:10If you pay attention,
08:12and if it's important to you,
08:13it gets initially.
08:15Put into short term memory storage and
08:18again if it's not rehearsed or it it gets.
08:23Also it's in a label state.
08:25It has to be encoded and consolidated
08:28to then move into the long term
08:32memory storage which.
08:35Can also be lost overtime,
08:36but it's much more stable
08:38and much more permanent.
08:44When we look at the different types
08:47of memories that we can study,
08:49we typically divide the long term memory in
08:53non declarative and declarative memories.
08:57So non declarative memories are the memories
09:00of procedural memories riding a bike,
09:02motor skills and motional memories.
09:05Declarative memories are subdivided into
09:07episodic and semantic memories, so those
09:10are the memories for facts and events.
09:13So what did I have for dinner last night?
09:16What is the capital of Paris?
09:18Those are all declarative memories,
09:21so we subgroup them. And.
09:25When we think about what is happening across
09:31with sleep dependent memory consolidation,
09:35we. Have initially he is an
09:38example of the memory game on.
09:41Yeah, I think you call it concentration
09:44so the person is encoding and learning
09:47where the cards are and during
09:50that time the memory is temporarily
09:52stored in the hippocampus and then
09:55there is a consolidation process
09:58during which the memory is changed.
10:01There is, you know,
10:04synaptic downscaling there.
10:06Is the memory is moved into more
10:09the cortex in different areas and
10:12it becomes a more permanent trace
10:15and then there is the retrieval
10:17process which is our ability to
10:20have access to the stored memory.
10:25And we think that the
10:27consolidation process can take
10:29place during wakefulness.
10:31But sleep is especially
10:33important for this process.
10:37And so a lot of the stuff these that I'm
10:40going to start talking about are using.
10:45Two time points to test people.
10:47That's very important.
10:48We usually have a session either in
10:50the evening and then in the morning
10:51or in the morning and the evening.
10:53But the the key is really to have
10:57two sessions where one is usually
10:59learning and the other one is.
11:01Recall to see what happens
11:03in in between those times.
11:07So I'm gonna talk 1st about
11:10non declarative memory.
11:12So again learning
11:14instrument tying your shoes.
11:16For that type of learning,
11:19one test that has become very
11:22established is the motor Skill,
11:25learning task or finger tapping tasks.
11:28With this test,
11:30people have to type a sequence,
11:33usually 5 digit number with
11:35their left non dominant hand.
11:37The sequence is displayed on the
11:39computer at all times you do the typing.
11:41In 32nd trials you rest and
11:44you do this 12 times.
11:46So you have 12 trials.
11:49And. Up 20 years ago.
11:55Matt Walker, Bob Stickgold published
11:57this paper in Neuron where they
12:00proof that this type of memory really
12:03improves with a night of sleep.
12:05So on the left. A person trained
12:09first on the finger tapping test.
12:11In the morning they come back 12
12:14hours later in the evening and you
12:17can see here a little bit improvement,
12:19but not significant.
12:20Then they go to sleep and in the morning
12:23they show the significant improvement.
12:26There could have been a question
12:28about the sequence of things,
12:29so they also had a group that trained
12:33in the evening and then you see the
12:36significant improvement in the morning
12:38and then they do the test again that
12:41after 12 hours and not much changes.
12:44So it's really sleep that
12:46provides the benefit.
12:48They also found a correlation between
12:50overnight improvement and stage two sleep,
12:52and now we know in follow-up studies
12:55that it's actually the spindles.
12:56Trying to take the stage to sleep
12:59that are particularly important
13:01in in improving this memory.
13:04So, uhm.
13:05What I did then is I wanted to see
13:11if N2 seat is that important.
13:12What happens when we look at patients
13:17with obstructive sleep apnea?
13:19And so we trained healthy controls
13:23and OSA people on the MSD on the
13:28motorcycle test in the evening and
13:30then tested them again in the morning.
13:32And you can see very nicely here that
13:35the OSA patients really improved by
13:39half of what the healthy controls improved.
13:42And then we looked further into.
13:47Correlations these were actually
13:49fairly young participants,
13:51so they were on average in their 40s.
13:54They had fairly mild sleep apnea
13:57and what we found was a correlation
13:59between the apnea hypoxemia index,
14:01the oxygen, and the arousal,
14:04and if you put everything in a model,
14:07it's really the arousal,
14:08so the the sleep fragmentation that
14:11seems to be the most detrimental to
14:14this type of memory consolidation.
14:16Because our participants were very young,
14:19the next question was what happens if
14:22we look at older people or at aging,
14:25does this?
14:27Have any impact also on on memory,
14:30consolidation and.
14:35We took a group with a wide age range and.
14:41The top you see patients who don't have
14:44OSA in blue at the bottom are patients
14:48with I'm sorry participants with
14:50healthy participants at the bottom are
14:53patients with OSA and what we showed
14:56is that if you don't have OSA and you
14:59can get old and still preserve your
15:03ability to consolidate moder memories,
15:06if you have our say first of all
15:10you perform at. Much lower level,
15:13you have far less overnight improvement,
15:16but on top of that.
15:18As you get older, your skills also decline.
15:23So sleep apnea offers a much
15:25stronger age effect on on this type
15:29of memory consolidation.
15:35The next question if was.
15:39If non REM sleep is really that important
15:42for this type of memory consolidation,
15:46what happens if we look at patients
15:49with who only have OSA during REM sleep?
15:52Because REM sleep doesn't seem to
15:55be important and so here we took
16:00participants with healthy controls
16:02that have displayed in blue.
16:05We had REM only OSA patients, so these are.
16:09Participants who had normal hi
16:11during non REM sleep so it was below
16:145 and then we had a group that had
16:17OSA during then REM sleep and non
16:20REM sleep and on the left.
16:22This is a different display
16:23of the motorcycle test.
16:25You can see the individual training
16:27sessions here at this place so
16:29there are 12 training sessions
16:31in the evening participants.
16:32There's a little bit of a difference
16:35but it's actually not significant
16:37so more or less they perform.
16:39When they learn the tests in
16:41the same way and then the next
16:43morning when they get retested,
16:45you can see very nicely that
16:47the people who have non REM,
16:49R.E.M., OSA don't show any.
16:52Don't show much improvement versus
16:55the REM OSA patients and the
16:59controls that perform absolutely
17:02identical so fragmented REM sleep
17:04doesn't seem to affect this type
17:07of RAM memory consolidation.
17:10There was another so you can
17:13using REM related apnea is a very
17:16elegant way to fragment REM sleep.
17:18You can also use pharmacotherapy
17:22and young born from Germany.
17:26Has published a paper a few years
17:29ago where they gave participants
17:31REM suppressing medication so they
17:34gave them an SSRI and SNRI that
17:38those fluvoxamine and reboxetine
17:41and at the top you can see how
17:45the participant had far less REM
17:48sleep with these medication.
17:49And interestingly when they had
17:52them perform the same test.
17:54The motor skill learning tests
17:56and also in mirror drawing test.
17:58Which is another procedural test,
18:00and they found that participant
18:03actually performed better than those
18:05that didn't receive the medication.
18:07And even though this was published
18:09in Nature Neuroscience,
18:10they don't provide a lot of explanation.
18:15All they say is, well,
18:17REM sleep can't be important
18:19then for this type of memory.
18:21But this really also emphasizes that
18:25the different sleep stages are truly.
18:28Important for different types of memories.
18:34I'd like to move to a emotional memories now,
18:38which, UM, as as we all know,
18:41hold it dear spot in all our memories on the
18:44left I usually show because I'm from Germany,
18:46the fall of the the wall,
18:48which is about 33 years ago and I have
18:52to say that at that time things looked a
18:55lot more bright than they do now, but.
18:59For to test emotional memory.
19:03We use something called an
19:05emotional tradeoff test,
19:07which was developed by Elizabeth Kensinger,
19:09who's now at Boston College.
19:13And in this task you have objects
19:17and backgrounds you have on the left.
19:19You have an example of neutral backgrounds.
19:25And a neutral object.
19:26And here is a neutral background and emotion.
19:30Negative emotional background object
19:33and the task pass the neutral objects
19:38with with the neutral backgrounds with
19:41either neutral objects or emotional
19:44objects and initially participants
19:46just have to take a look at these
19:49pictures and and try and study them
19:52and then when they get retested.
19:54They only see the object or the background
19:57in isolation and they are asked,
20:00but they are also at the recall test.
20:03They're being shown similar items
20:06and completely new items,
20:08and they are asked if specifically is
20:11this the same that you saw before?
20:14Is it similar or is it a new item and?
20:19Jessica Payne,
20:21who worked in bucked Stickels group,
20:24looked at this task with healthy
20:27college students.
20:28And we can first look on the right
20:31side on the neutral scenes.
20:33People were tested repeatedly
20:36and over the course of time.
20:39The combination of neutral objects
20:41and neutral backgrounds doesn't
20:44really change that much,
20:45so there's no big disk discrepancy
20:49when you look on the left,
20:51the first thing you can notice is that the
20:55negative scenes are remembered a lot better,
20:58and what happens though.
21:01When people sleep,
21:03is that they appear to remember
21:05after a night of sleep,
21:07they appear to remember the negative objects
21:10lot better at the cost of the objects,
21:13so they really filter out that
21:16negative memory at the expense of
21:20the of the object or the background.
21:23And so,
21:25that's that's what we call
21:27the emotional tradeoff,
21:28which is facilitated by by sleep,
21:31and I'm sorry.
21:37So we felt that it was important to look
21:40also at OSA patients because there's
21:43a lot of depression, anxiety and.
21:48Psychopathology in these patients.
21:51And we used the Group of healthy
21:54controls and patients with OSA.
21:58And we gave them the emotional tradeoff
22:01test and the question was, are they
22:04showing the same emotional trade off?
22:06And how are they remembering
22:08these these objects?
22:10And what we found was that across
22:13the board OSA patients remember less.
22:16They remember less objects,
22:18they remember less.
22:20Background, it doesn't matter.
22:23Neutral objects,
22:24emotional objects,
22:25the the memory is just not as
22:28good as in healthy participants.
22:30What they still preserved was the ability to.
22:35Half the emotional trade off,
22:37so that doesn't seem to be affected
22:39and that just shows that even though
22:43these people have less REM sleep,
22:46which is often correlates with poorer
22:49memory consolidation on this task,
22:51they still preserve this ability.
22:57So next I want to move to the effect
23:01of treatment on memory recovery.
23:04So there is. There's short term
23:09CPAP effect and the reason I wanted
23:12to look at that is because a lot
23:15of patients say the first night of
23:18CPAP is can be very life altering,
23:22can have a big impact and I wanted
23:25to see if it would also resolve
23:28some of these memory deficits.
23:31And so here we had three groups,
23:35one group that was a healthy
23:39control Group One group with.
23:41Sleep apnea, OSA and one group
23:43that received the first night of
23:45C Pap in their life so they work.
23:47Pap. Naive.
23:48They were just diagnosed with OSA and
23:51you can see that the see PAP group
23:53and Control group have very similar.
23:56Hi, they were not significantly different.
24:01Also, sleep stages didn't
24:03show significant differences,
24:05so overall they sleep looked very
24:08similar as opposed to the OSA group,
24:10which as expected had a hi hi, lower nedeia.
24:16And here you can see how
24:19these groups performed during
24:21evening training on the left.
24:24In blue you have the group before
24:28they get CPAP, so they actually
24:30performed a little bit worse,
24:32but it wasn't significant.
24:33Here's the group, the OSA Group,
24:36which remains without treatment.
24:38And then you have controls.
24:41The next morning,
24:42the controls outperform
24:44everybody and then the.
24:49At morning retest the see PAP group that
24:53supposedly slept better is actually down
24:56here and the OSA group is in the middle.
24:59We then also just to see if it has to do
25:03with. Sometimes recall has to do with.
25:07Sleep inertia, sleepiness, or attention.
25:11We often have them learn a new
25:13sequence to see how they perform in
25:15general in the morning, and here's
25:17how they all learn and look sequence,
25:19so that's very similar. So.
25:24Overall this no improvement after a
25:28first night of using CPAP despite
25:33changes in sleep architecture.
25:35What did change was the we also
25:39have them do the PDT.
25:41The second motor vigilance test.
25:44This is the change in reaction time from
25:47the evening session to the morning session.
25:49So the see PAP group here in blue.
25:51They were much faster in the morning,
25:53so much more attention vigilance always.
25:56A group was slower and control
25:59so more or less the same. Uhm?
26:03What was striking, though,
26:05was also that the group that received
26:09CPAP felt subjectively much more
26:12rested compared to the OSA group.
26:14So in summary, they feel more rested,
26:18they have better attention,
26:20but the sleep dependent memory consolidation
26:22really hasn't changed that quickly.
26:25And.
26:27As a follow up.
26:33I wanted to see what happens when
26:36participants of inpatients you
26:38cpap for longer periods of time.
26:40Is there recovery possible?
26:43So for this I actually used.
26:45I have to introduce a new test so
26:47I'm not using the MST anymore.
26:49I moved on to the declarative memory test.
26:53Which is a word pair task in which
26:58participants have to learn 40 related
27:00word pairs that are presented on
27:03a computer so they look at them.
27:05Then they have a recall test where
27:09they see the first word and they
27:11have to put in the second one and
27:13that list is presented repeatedly in
27:15a different order until they recall
27:18at least 24 word pairs correctly,
27:20and that's called the 60% criterion.
27:22The reason we do that is so that
27:26everybody achieves the same level.
27:29Uh-huh learns this the the test to the
27:33same level and then in the morning we
27:35give them a piece of paper with the
27:38first word and they have to put in
27:40the second word and that determines
27:43their recall across the night of sleep.
27:48So for this experiment,
27:52we enrolled our essay patients
27:56and healthy controls initially
27:59and part one was just to get a
28:02sense of how different are they
28:06consolidating this declarative memory.
28:08So that was part one of the overnight visit.
28:11Uhm? Then the also patients
28:17were randomized into a C PAP
28:19group and an oak PAP group.
28:24The see PAP Group received a device
28:28and auto titrating device both groups
28:31watched a presentation on healthy
28:34lifestyle changes and exercise.
28:37We had long debated whether we
28:40should use spam pub or sham CPAP.
28:43Or you know something else.
28:45But we decided that a lot of people
28:49change their behavior when they get
28:51a diagnosis of OSA and that's why we
28:53why we focus on lifestyle changes and.
28:58Patients were asked to use the see
29:00PAP for three months and during that
29:02time we checked their compliance.
29:04We worked with them.
29:06We also checked on their diet and
29:09exercise and both groups and then
29:11they came back after three months
29:13and they again went were tested with
29:15a new version of the declarative
29:17test of the learned new set of word
29:20pairs in the evening and then in
29:22the morning they have the recall
29:24test and we just published this.
29:28In the Blue journal.
29:31It showed that overall there
29:35was a nice recovery of the sleep
29:38dependent declarative memory
29:40deficits after three months of CPAP.
29:43So I'll walk you through these through
29:46these bars so and blue you see the
29:50baseline performance and you have the
29:53group here to the left that did not receive.
29:56That has OSA, but did not receive C PAP.
30:00You have the pop group.
30:01That's that baseline,
30:03and this is after three months of
30:07using C PAP and then on the right in
30:10you have the healthy control group
30:12and what is really uplifting to see is
30:16that the C Pap group really reached the
30:20same level as the healthy controls.
30:25I will say though,
30:26that because it was a small study,
30:28they received a lot of attention and
30:30they had really excellent compliance.
30:33So they were all between 5:00 and
30:34six hours of using their CPAP.
30:40And, uh. When we looked closer,
30:44what is determining the improvement
30:47it was actually the end 3 sleep the
30:50amount of N3 sleep that they were in,
30:54so that has been shown before
30:55but that was at the baseline.
30:58Comparing controls and OSA
31:00patients and then we were able to
31:04show that in the C PAP group the
31:07amount of ends we increase really
31:10determined also how much they were.
31:13Better able to remember the word pairs.
31:21And so I just want to stop for
31:24a moment and talk about the.
31:27The street light effect which is,
31:30I think part of the problem,
31:33why some of the larger studies that
31:37have looked at the effect of skypad
31:39like the Apple study for example,
31:41have had trouble seeing an effect.
31:45So the streetlight effect is where
31:48a person is under a street lamp
31:51and is looking for the wallet,
31:53and the policeman comes and says,
31:55is this where you lost your wallet?
31:57And the person says no,
31:58I lost a bullet in the park,
31:59but this is where the light is,
32:01and so we tend to gravitate to
32:04things that are familiar to us.
32:06And so initially,
32:07what a lot of studies were using were
32:11the traditional cognitive testing.
32:16That or neuro psych testing,
32:19which is really only studying
32:21participants at one time point.
32:25And also is using things like number back
32:30or which are relying more on attention?
32:34UM, so they are really if I
32:36hope you can see my cursor,
32:38they really just looking more
32:40into the short term memory.
32:42Of these participants,
32:43rather than the long term consolidation,
32:47which is where,
32:48wherever,
32:49whatever test on cognitive tests
32:52I used always say patients were
32:55impaired and showed impairment,
32:56and the reason if you only test them once
32:59I bring in this example from the REM group,
33:02when we trained people in the evening,
33:05we really didn't see a huge
33:07difference in their performance,
33:09so they were able to encode
33:11this new task just.
33:12Time,
33:13but in the you really mainly see
33:15the difference in in in performance
33:17when you have them come back and
33:19you test them a second time.
33:21That's really when you see the difference.
33:26So what a potential mechanisms very briefly?
33:32In animal studies this is from.
33:37Doctor Wilson at MIT.
33:38This is an older study now,
33:40but I think it's still very beautifully
33:43done when animals learn maze at the
33:48top here you can see firing in the
33:51temple area as they learn the maze
33:54to navigate the maze and when these
33:57animals go to sleep over striking
33:59is that you see the same firing
34:02patterns in the hippocampal area
34:04and that was a proof that there is.
34:07Reactivation of things that we learned
34:09during the day at night when we sleep.
34:12Now this is a lot harder to do in humans.
34:15But a study that came very close is again
34:18from Young Bones Group in in Germany,
34:20where they actually used smell to
34:24prove that memory gets reactivated.
34:26So I briefly want to go over this
34:29because it's really a beautiful study.
34:31So in here again is the the memory
34:35of concentration game is used and
34:38there are different experimental
34:40conditions that you can see here.
34:43So the first group.
34:44When they learn this memory test,
34:47they are exposed to a rose order.
34:51Then the order is.
34:54Again,
34:55they exposed to the same order at
34:57the beginning of the night when we
34:58presumably have more slow wave sleep,
35:00which is needed for this type of
35:03memory consolidation and retrieval.
35:04They have no order.
35:05There's another group that doesn't
35:08receive order in the learning condition,
35:10but at night when they sleep
35:13during slow wave sleep again order
35:15and the big when they train,
35:18and then later during the night when
35:21they have more REM sleep and then.
35:23They receive an order when they learn it,
35:25and then right before they go to bed
35:28because there might be also a time
35:30when we saw when before we go to bed
35:33that we people think maybe there's
35:36some consolidation taking place
35:38and then no odor during retrieval.
35:41And the main finding is here.
35:44On the left is that the people that
35:47receive order when they learn this
35:49task and during the early time of
35:52sleep when they have slow wave sleep.
35:54When we presumably consolidate
35:56this type of memory,
35:57they are performed a lot better
36:00than all the other groups as.
36:05It's only indirect,
36:06but it's probably as good as it gets
36:09in terms of showing that there is some
36:12reactivation taking place when we sleep.
36:17So now towards the last part I.
36:22Not one to cover the link
36:25between sleep and dementia,
36:26which has become a lot more popular.
36:33And. Uh. It's really one of the.
36:40In most interesting and I think
36:43also showing studies was done from
36:47Spirae where they looked at the
36:50association between self reported
36:52sleep and amyloid deposition,
36:55and this is fairly small.
36:57But on the left you have people
37:00who sleep more than 7 hours.
37:02Then you have people who sleep
37:04between 6:00 and seven hours,
37:06and then people who sleep less than
37:08six hours and more red means more
37:11amyloid and you can see very nicely
37:14is that people who sleep less tend
37:16to have more amyloid. And this is.
37:19But this is self reported sleep.
37:22So that was one
37:25really hot data proof that there is a
37:29direct correlation between the amount
37:31of sleep and and amyloid deposition.
37:34Then a little bit later,
37:36most of you might be familiar with her data.
37:40Need a God showed very nicely
37:44that when we go to sleep,
37:47there is a change in how.
37:52Come in the interstitial fluids and
37:57they showed in in animals that amyloid
38:00increase with the time of awake,
38:02and then decrease during sleep and
38:04that sleep really promotes the
38:07removal of amyloid from the brain,
38:10and the idea is that or the possibility
38:14is that maybe neurodegenerative disorders
38:16are the result of a MIS management
38:20of toxic molecules which accumulate.
38:22In the brain. This is still,
38:25you know, I have a hypothesis.
38:27I think some people think that
38:29this is the way it is.
38:30I think that.
38:33The challenge is that this shows
38:36things more amyloid leakage,
38:38and it's hard to say whether this
38:41truly means that we're those.
38:45Animals, and now we also have
38:48experiments with MRI by Laura Lewis.
38:52In humans, whether it really means that
38:56it leads to a long term accumulation of
39:00amyloid and truly a higher risk of dementia.
39:03So I think all of this is is very important
39:06and very interesting, but it's still.
39:09I think the link from this to long
39:13term accumulation of amyloid and the
39:16development of dementia is still,
39:18you know, it's a it's a hypothesis.
39:23The other important study is
39:26looking at this is from at walkers.
39:28Lab is showing that amilo
39:33amyloid accumulation.
39:35Is directly affecting memory consolidation,
39:41so here they had elderly people
39:43and they looked they localized
39:46amyloid which is very unusual in the
39:50temporal area and they showed that.
39:54This correlated with declarative
39:57memory consolidation.
39:58So when you had more amyloid,
39:59you didn't consolidate memories as well.
40:03They also went further and not only looked
40:06at sleep stages and slow wave in itself,
40:09but also at how slow wave
40:13sleep and spindles interact.
40:16As we look deeper into microstates of
40:19of sleep and beyond just sleep stages,
40:23we found that.
40:25In healthy people there is this nice.
40:28Synchrony between slow
40:29wave sleep and spindles,
40:31and if they are perfectly aligned,
40:32that seems to offer the best
40:36benefit for affective memory
40:38consolidation as people get older,
40:41that relationship shifts a little bit,
40:44just buy regular aging,
40:46and then presumably,
40:48if you have a neurocognitive
40:51disorder such as dementia,
40:53there's even further shift.
40:57So those are different
40:59mechanisms that seem to affect.
41:01Sleep and memory consolidation.
41:10So earlier studies that I've showed
41:14have mainly focused on amyloid
41:16because that was available to us and.
41:21A lot of people believe more that
41:24amyloid is really the most important.
41:27A protein that was the driver.
41:29I think there's a big shift that we
41:32now think that Tao and Larry tangles
41:36have received a lot more attention.
41:40What I want to make clear that
41:43everybody understands is that when
41:45we talk about clinical dementia,
41:47that's the time point that is fairly
41:49at the end of this trajectory.
41:52The process itself often starts
41:56decades before the clinical symptoms,
42:00and so there is a gradual increase
42:02in amyloid, but also Tau.
42:04We now think that Tau might actually be
42:07driving a lot more of of the changes.
42:10Tao is also much easier to localize,
42:14and there are different Brooks stages,
42:16and it has different dynamics, that's why.
42:22Uhm? Myself and Jasmine are at chat.
42:25Well, we have a grant together
42:29looking at Tao up in PET scans,
42:34which is something that became
42:35available over the last few years.
42:38And we were interested in looking at
42:42early Tau changes in older patients,
42:46and to correlate that with their
42:49sleep to see if there's any.
42:52If there's anything there.
42:54And So what we found is this is a
42:58fairly fresh data, unpublished.
43:02This is from participants of the
43:04habit aging brain study which is
43:07a longitudinal study looking at
43:09healthy aging and its control.
43:12People have regular repeated
43:15scans and cognitive testing,
43:17and we added a home sleep studies for PSG's.
43:20And what we've found is that
43:23in areas that are early on,
43:26affected in dementia,
43:27which is the enter rhinal
43:29and inferior temporal Tau,
43:31there is a correlation between increased
43:34Tau and the amount of slow wave sleep.
43:39And this.
43:42Is also 8. Remains even
43:45when you control for age,
43:47so that's very solid.
43:50It doesn't depend on the amyloid burden,
43:54so this is completely independent
43:57of how much amyloid a person has,
44:02so it's not an additional effect.
44:04So Tau seems to have its own
44:08mechanism on and effect on
44:11slow wave slow wave modulation.
44:19And finally, I also want to point out
44:22that we saw that less REM sleep was also
44:26associated with Greater Talbert and one
44:29of the points that I would like to make
44:32is that people often hyperfocus on slow
44:34wave sleep and and and delta waves,
44:36and if we can only restore delta waves,
44:39people will be cognitively intact.
44:42I don't think it's that simple.
44:43I think there's many studies that have now
44:46shown not just our results, but others.
44:49That REM sleep also seems to play an
44:52important role and seems to decrease in
44:55the setting of cognitive impairment.
45:01So in the end, it's really becoming
45:06a mix of factors that weight into.
45:12Sleep and cognition.
45:14And if we stop with sleep fragmentation from
45:18our say we saw that it changes cognition.
45:23Doesn't change, doesn't make a
45:25person more susceptible to dementia.
45:27That's very difficult to say.
45:30There are some studies that suggest that,
45:33but I think there are also a lot
45:36of people with severe OSA who
45:38not everybody becomes demented,
45:40so they're obviously other factors
45:43that play a role.
45:45The accumulation of amyloid and Tau in
45:48itself can cause further sleep fragmentation,
45:51and so it becomes suspicious cycle.
45:551. Last aspect that I want to talk
45:59about is as the AP Epsilon E4,
46:01which is a risk factor for as
46:03many of you know, for dementia.
46:05So if you have one allele,
46:07you have a higher risk if you have two
46:08alleles, you have even higher risk.
46:11Many studies have shown that if you have.
46:15If you're at a point you've
46:17carrier and for carrier,
46:18and you have OSA,
46:19you have much higher risk for
46:21having cognitive problems or have
46:24more pronounced cognitive problems.
46:26Well, this is also unpublished data,
46:29although I showed it at the last week
46:32meeting is that we look at young,
46:35healthy participants.
46:39They were tested with Wechsler
46:41tests so they were they had no
46:44subjective and objective cognitive.
46:46Problems we had a group of April E4
46:50carriers and a group of non carriers.
46:54We have them all to do the declarative
46:57memory test and the input for carriers
47:02also showed far less overnight memory
47:05consolidation compared to the healthy,
47:07healthy non carious.
47:09And the April 4 carriers actually
47:13show at the same level as the OSA
47:17patients and this just speaks again,
47:20unfortunately to the fact that.
47:24Cognitive decline people
47:26usually use the analogy of the
47:28iceberg starts very early on.
47:30It's very subtle, but that might
47:32actually be the very vulnerable
47:34time when we might be able to.
47:39Provide treatment for these
47:41people because a lot of times.
47:46Once clinical symptoms starts and
47:49we have seen it in the clinic,
47:52you cannot reverse dementia.
47:53You can improve some of the symptoms.
47:55Some of the attention if you have
47:58somebody with dementia who also has OSA.
48:01I might put temporarily be
48:03a little bit more alert,
48:06but you really can't reverse
48:08the the the trip trajectory,
48:10so it's probably a matter of timing and and
48:14the kind of treatment that we can provide,
48:17but there's definitely a strong correlation
48:20between sleep and and cognition and dementia,
48:23hopefully with better biomarkers.
48:25We can determine who is at higher risk
48:29and and then treatment to be determined.
48:32So ending with Christoph Niemann,
48:36who's a did, a list of goodnight and
48:40a list of drawings for The New Yorker.
48:44But goodnight and good luck getting a
48:47good night's sleep is actually a lot
48:49more complicated than what we think.
48:51Thank you.
48:59Doctor John logic.
49:00Thank you very much for reviewing
49:03that fascinating presentation.
49:06If folks can submit questions
49:08into the chat, we can help plan.
49:12Moderate this Aahe and
49:15Stuart men just posted one.
49:18Do patients with longstanding by
49:20history untreated OSA have higher
49:23beta amyloid levels in their brain?
49:27That's a question we don't I?
49:28I mean I would love.
49:31Uhm, that's that's $1,000,000 question.
49:33I think that there's no way to trace back
49:37when OSA started and and how severe it was.
49:41It's sort of a gradual process.
49:43I think there are.
49:46On on maybe some prospective studies
49:48that are starting to look at it,
49:50but I think for now we don't have an answer.
49:53I'm not necessarily sure that
49:57it's just a matter of time.
49:59I think there are other factors that it's,
50:02I think the person's ability to deal with
50:05OSA and itself that also plays a big role.
50:08The ability to generate slow
50:10wave sleep despite having OSA,
50:12you see that in some participants.
50:16We also,
50:17you know we have people in our group of hot.
50:20The habit aging brain study who in
50:23the 80s and 90s now and and they get
50:25their first sleep study in their life.
50:27They have no symptoms.
50:28They have no sleepiness.
50:29They are fine and I think it's and they
50:33probably had it for for a really long time.
50:35So I think it's I'm not sure if
50:38it's a it's a time effect as much
50:40as it's the cognitive reserve or
50:42the ability the way the brain
50:44deals with sleep deprivation.
50:46Skip fragmentation.
50:50Wonderful and a couple more popping up here.
50:52Doctor Gary is asked,
50:53do you think the lack of improvement
50:55in memory after one night of C PAP
50:58use was related to the potential sleep
51:00disruption from the first night of PAP use?
51:04Could it? That I could see Pap actually
51:07worse than some elements of sleep
51:09because patients were not yet
51:11customed to sleeping with the mask.
51:13But if it did, it wasn't.
51:15We didn't measure it,
51:17they didn't have a high arousal index.
51:19It is possible that there was some
51:21things that we didn't measure,
51:23but I think at least from the.
51:28Looking at, I actually did look
51:31at sleep spindles to come and
51:35they didn't seem to recover,
51:37so it could be that there my my
51:42more thinking that there are deep
51:45structural changes that don't recover
51:48overnight rather than that there was
51:51the CPAP or the treatment imposing.
51:56Fragmentation or or some some.
52:00Affecting the quality of sleep.
52:05Doctor Yagi asks do you think
52:07sleep effects are potentially
52:08limited to Alzheimer's dementia?
52:10Or could it be playing a role in
52:11other forms of dementia like Blue
52:13Lewy body or vascular dementia?
52:17I think it has the potential to play a
52:19role in in other dimensions as well.
52:22I mean, we know that many dimensions does
52:24also have from run behavior disorders.
52:26To sleep is definitely affected. And.
52:32The question is how much of it it how?
52:36Is it? Is it parallel other because
52:39sleep and memory use the same
52:42networks and so could it be part of
52:45the same decline of a network that?
52:48Changes sleep and memory in parallel or
52:50is are they interfering with each other?
52:53So that's I think the big question
52:55that is not really answered.
52:57We're hoping that with this study
52:59that we're doing right now where
53:01we actually follow participant
53:03longitudinally with their sleep,
53:05so they have consecutive sleep
53:07studies and imaging that we can see.
53:09Maybe what is driving what,
53:11but I think it's difficult to
53:13tell at this time.
53:16And Stuart man asks, can you further
53:19discuss the relationship of slow wave
53:21sleep and spindle interact actions?
53:25Yeah, so they are.
53:27Basically it's it's mostly slow
53:30oscillation that come from the cortex
53:32that occur in the same. You know,
53:35in a certain timeliness with spindles.
53:39So there is that's this is called.
53:43Oscillation spindle coupling and they seem
53:46to if you have good memory consolidation,
53:51you usually have good coupling.
53:54It's it's a, I think a a mirror of how
53:58well your brain is consolidating these.
54:02It's functioning.
54:03And as people get older just by aging,
54:08this coupling changes and and so
54:11it becomes less connected and
54:14we think that it it falls apart.
54:17This is 1 aspect of what might
54:21interfere with. Sleep and memory.
54:24Like I said,
54:25I think if we just focus on on
54:27too much on slow it's sleep.
54:29We actually lose track.
54:30That REM sleep is also very important
54:34and often gets overlooked unfortunately.
54:41And then I will ask if N3 sleep
54:44is critical for recovery.
54:46Although as you mentioned,
54:47not the whole story.
54:48Given that it naturally diminishes with age,
54:50do you think there's a potential
54:52that the recovery and learning that
54:53you can generate with CPAP therapy
54:56diminishes inherently with age?
54:58Your ability to recover diminishes with age.
55:02Yeah, do you hypothesize that
55:05that's the that's the case?
55:09It depends, I guess on how much
55:11you are recoverable, right?
55:12I mean, I think that's probably
55:15also very depends on how much
55:17your brain is able to recover,
55:20but there's definitely a
55:21correlation, so if you.
55:25Recover so we even saw that in
55:27our little group. If they are,
55:30they were definitely some participants
55:32who didn't recover as much and with
55:34with with CPAP and so those are the
55:37ones that showed the least memory
55:39improvement and the ones that had
55:42more recovery had more improvement.
55:45I think in general the ability to
55:49recover might be lower as you get older,
55:52and the question whether it
55:53makes a difference or not.
55:55I'm not sure, I don't know.
55:57It's a good question mark.
56:04Well, I think we have gone through
56:06all the questions in the chat,
56:08so unless there's any other burning
56:11questions, I think we all greatly
56:14appreciate a fantastic talk on dry.
56:17Not sure if you have anything else to add.
56:19This was great. Thank you so much.
56:21I mean I I think that my my only
56:23question was you know the largest
56:25randomized smoke with trial of
56:27new outcomes and sleep apnea.
56:29Apples showed no impact on.
56:32Neuro cognition, including memory,
56:34verbal and learning, and so.
56:36I was just wondering if maybe you
56:38could speak a little bit to the
56:40reasons why you think that might
56:42be the case and how we might.
56:44Re address that question with
56:45a better trial at some point.
56:48Yeah, that's I just want that's
56:50what I've met with the this.
56:53This streetlight effect I think
56:55the problem is the is twofold.
56:57One is the there's several trials,
56:59but I think in the apples where
57:02participants only wore it for
57:04three or four hours per night.
57:06So it might be the amount of time
57:09that people you know the compliance.
57:11We had a small group as you saw 15.
57:1516 in each group and we had a
57:18research assistant who was available.
57:20We had somebody who was a trained
57:23respiratory therapist in the past
57:26who gave them really, we had mass.
57:28I mean, we offered them the service that
57:30you could normally not offer in real life.
57:33So that was one part,
57:34but I think the more important one is
57:36the type of memory test that you use.
57:39So if you use the traditional
57:42neurocognitive tests,
57:43that neuropsychologists are using.
57:45If you do one one time testing,
57:48which is what Apple used,
57:50you're not gonna see a lot of effect.
57:53UM, this one time testing if
57:55we do that with with Allah,
57:57you know,
57:57usually when patients are tested
57:59or participants are tested in the
58:01evening and they learn a test,
58:03you don't see a big difference
58:05during that training sessions,
58:07which is similar to when you give
58:10them the number of backwards or.
58:13You know any of the other traditional?
58:18Neurocognitive tests,
58:18but it's only when you test them a
58:22second time over over a night of sleep
58:25that you really see and. And really,
58:27I mean I stopped at one point because,
58:29you know I had a grand and I did
58:32emotional procedural. You know,
58:34we did various types of memories and also
58:37patients were impaired on all of them.
58:39Whatever we tested.
58:40So at some point you're just going to say,
58:43OK, I don't need to do this anymore.
58:45This, you know, it doesn't make.
58:47Yeah I should more testing.
58:48I think that. So using the proper test,
58:53now that it's still a question,
58:55are they also reflective?
58:57If you perform poorly on these tests?
58:59Does that mean that that also
59:02shows a risk for dementia?
59:05Or you know how does this you
59:07know there's still a missing link?
59:09I think with.
59:11But I think in in the immediate
59:14improvement and and looking at,
59:16I think people need to use different tests.
59:22Alright, well thank you so much,
59:24I appreciate it and we
59:26will see you next month.
59:28Thank you everybody, that's good.
59:30Thanks for having me bye bye.