"Sleep and Alzheimer’s Disease: A Bi-Directional Relationship" Brendan Lucey (10.14.2020)

October 18, 2020

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00:46So with that I'm going to turn it
00:49over to Brian Minor who is going
00:51to be introducing today's speaker.
00:53OK, good afternoon everyone.
00:55When you first join the conference,
00:57you might have noticed,
00:58but I'll just draw attention to it.
01:01Our next joint Yale Harvard Sleep
01:03Medicine Seminar will be on Wednesday,
01:05December 9th,
01:06same time 2:00 o'clock and the speaker
01:09for that talk will be Janet Mollington,
01:11who's a professor in neurology
01:13at Harvard Medical School,
01:15and she's going to be talking about
01:17the cost of insufficient sleep.
01:20So today it is my pleasure to
01:23introduce doctor Brendan Lucey,
01:24who has become a close colleague of
01:27mine in the field of sleep and aging.
01:30Doctor Lucy completed his
01:32undergraduate work at the University
01:34of Vermont in Burlington,
01:35where he graduated summa cum Lau Dai
01:38before going on to Johns Hopkins,
01:41where he got his medical degree.
01:44This was followed by postgraduate training,
01:47first as a resident in neurology at the
01:50Barnes Jewish hospital in Saint Louis.
01:53He did a fellowship in clinical
01:55neurophysiology at Brigham
01:56and Women's Hospital,
01:58and he's also completed a Masters of
02:01Science and clinical investigation.
02:04After his postgraduate training,
02:05he spent four years as chief of neurology
02:08on Nellis Air Force Base in Nevada,
02:11and he rose to the rank of major
02:13in the United States Air Force.
02:16And then he came back to Washington
02:19University in Saint Louis,
02:20where he is now a tenured associate
02:23professor of neurology and the director
02:25of their Sleep Medicine Section.
02:27With respect to his research,
02:30he's been well funded by the NIH,
02:33especially the National Institute on aging,
02:35as well as some non governmental
02:38organizations for his work which
02:40is really focused on looking
02:41at sleep as a potential novel
02:44modulator of Alzheimer's pathology.
02:46He's received two very prestigious
02:48awards from the N IAD Gemstar Ward,
02:51which is focused on some specialists
02:54who are transitioning to aging
02:57research as well as the pool be sin.
03:00Urging leaders career Development Award.
03:02This is a K Award given by the
03:04NIH that really looks to identify
03:07and develop emerging leaders in
03:09the field of aging research.
03:11He has looked at sleep quality and
03:14amyloid beta kinetics and whether these
03:16can be modulated by pharmacological
03:19behavioral manipulation of sleep.
03:20He has looked at sleep and circadian
03:23biology and the fact of these on
03:26Alzheimer's disease and related
03:27disorders and he's also looked at
03:30whether we can manipulate sleep
03:32to prevent Alzheimer's disease.
03:33And on a personal note,
03:36I just want to acknowledge my relationship
03:38with doctor Lucy and what would a
03:40friend and colleague he has been to me.
03:43We've known each other
03:44for a couple years now.
03:46We started ouf cheering a paper
03:47session together at the sleep meeting,
03:49and since that time he is really been
03:52very generous in terms of reaching
03:54out to me to help me with my own
03:57research and the field of sleeping.
03:59Aging is a pretty small field,
04:01so it's it's nice to have a friend and.
04:04I really appreciate all the help that
04:06he's given me and I think it's really
04:09exciting to have him here today to
04:11talk about a topic that we haven't
04:13heard so much about in this session.
04:15And so he is going to be speaking today
04:18about the bidirectional relationship
04:19between sleep and Alzheimer's disease so.
04:22Doctor Lucy,
04:23thank you for coming and I will
04:25turn it over to you.
04:29Thank you very much, doctor minor.
04:31I'm honored to have the invitation
04:34to speak to you today about
04:38sleep and Alzheimer's disease.
04:40And the work that that I've been involved
04:43in and many others at Washington
04:47University and other institutions.
04:49These are my excuse me.
04:51My disclosures I've put asterisk
04:54with my active research
04:55support primarily from the NIH,
04:57as well as other research
05:00support that has funded some of
05:03the work that I'll be showing.
05:05I like to disclose that I consult
05:07for Merck and additional disclosure
05:09that's not directly relevant
05:11for my financial interests,
05:14but is that doctors,
05:15Randall Bateman,
05:16and David Holtzman as well
05:19as Washington University?
05:20Have a licensed intellectual
05:22property to a company called
05:24C2 N Diagnostics that they also
05:26a financial investment in.
05:28I do not unfortunately have a
05:30financial investment in C2 N Diagnostics.
05:36So the objectives today for our
05:38discussion is going to go over a brief
05:42Alzheimer's disease primmer kind of to
05:44get everybody on the same page about
05:47about a D when I present to anadi
05:50audience I always give asleep primmer.
05:53Then we'll go over the evidence for
05:56a bidirectional relationship between
05:58sleep and Alzheimer's disease,
06:00and then discuss.
06:01Discuss several potential mechanisms
06:03that may mediate that relationship,
06:05including a beta reduction and clearance,
06:08Cal Phosphorylation and the erection system.
06:12So Alzheimer's disease is progressive,
06:15neurodegenerative disease.
06:16It's characterized by the deposition
06:19of extracellular amyloid beta plaques.
06:22The deposition of amyloid plaque
06:25is concentration dependent,
06:26so the greater the concentration
06:29of amyloid beta in the brain,
06:33such as insoluble in the cerebral
06:36spinal fluid, the more likely you
06:40will have plaque formation.
06:42And different forms of amyloid beta are
06:46more likely to form analyte path plaques.
06:50For instance,
06:51amyloid beta 42 is most likely
06:55to aggregate as plaque inform,
06:58inform amyloid deposition.
07:00There's also neurofibrillary
07:02tangles of hyper phosphorylated Tau
07:05aggregates that form inside neurons.
07:07An results in neuronal death.
07:11Loss of synaptic,
07:13synaptic loss of neurons and synaptic
07:16to function lead to brain atrophy such
07:19as as seen in the figure on the left.
07:24Formation is also involved in
07:26eventually memory problems,
07:28other cognitive deficits and dementia.
07:38This slide shows some of the neuroimaging
07:41that can look at the changes in the brain
07:45that we see with Alzheimer's disease.
07:47In the left column are images
07:50taking from individuals with
07:51Alzheimer's disease and on the right,
07:54or individuals who are clinically normal.
07:56The first set of scans,
07:58A&BRFDG pet scans.
07:59Looking at metabolism,
08:01you can see that there's lower
08:03metabolism in the 80 brain.
08:06Looking at the MRI changes,
08:08there's significant atrophy that
08:10occlude occurs in those with Alzheimer's
08:13disease and Pittsburgh Compound B.
08:15Amyloid pet scans show significantly
08:17increased amyloid deposition and those
08:19with Alzheimer's disease compared
08:21to those who are clinically normal.
08:26In recent years we've also.
08:29There's also been a development of Tau pet,
08:33which allows for us to look at Tau Pathology
08:37in vivo and this figure from Keith
08:41Johnson's group that was published in 2016,
08:45and the annals of neurology shows that as
08:49the mini mental state exam score declines,
08:53there's increasing tab pathology.
08:55In the medial temporal regions that
08:58then spreads out through the temporal
09:01lobes and the remainder of the Cortex.
09:05And using neuroimaging and also
09:07measuring employed beta and Tau
09:09in cerebral spinal fluid,
09:11we've been able to, as a field,
09:15determine when we see changes in these
09:18different biomarkers across 80 pathogenesis.
09:20So this figure shows a typical what's
09:24sometimes called Jacks curves for
09:26Clifford Jack from the male clinic
09:29who have been the lead author.
09:32A number of papers describing
09:34this biomarker model.
09:36On the X axis we have the clinical
09:39disease stage of Alzheimer's disease
09:42from cognitively normal to mild
09:44cognitive impairment between the
09:47dashed lines and then dementia,
09:49and you can see that very early
09:52on amyloid deposition begins.
09:54This can be 15 to 20 years before
09:58cognitive and cognitive symptom.
10:00Begin and by the time cognitive
10:03symptoms start employed,
10:04deposition is nearly at its peak.
10:08Towel lags behind that.
10:12About 5 to 7 years before clinical
10:15symptoms followed by changes in brain
10:19structure such as hippocampal atrophy,
10:22changes in memory and followed by
10:25clinical deterioration when the
10:27individual progressed toward full dementia.
10:33A major goal of the field for
10:35processing last 20 years has been
10:38to define these biomarker changes
10:40to both define who who is likely
10:43to get Alzheimer's disease, too.
10:46222 correctly. Attempted categorized
10:51individuals into the right.
10:54Disease processes there are other
10:57causes of dementia than Alzheimer's
10:59disease and potentially to guide
11:01intervention trials and to push the
11:04intervention period as early as possible,
11:07and some of that is coming to fruition
11:10with trials that are beginning
11:12during the clinically normal period.
11:15In some specialized groups.
11:20So I'd like to to to move on to
11:22some of the evidence that connects
11:25sleep and Alzheimer's disease.
11:27We've known for decades that individuals
11:30with dementia have disturbed sleep.
11:32But what's been increasingly recognized
11:35over proxy in the last 15 years is that
11:39changes in sleep may serve as a marker
11:42for risk of future cognitive impairment
11:45or risk of future Alzheimer's disease.
11:48Or a marker for the underlying pathology.
11:52So in a study in 2011 from Ricardo
11:55Osorio from NYU individuals who reported
11:57insomnia had a faster progression from
12:00normal cognition to dementia and in
12:03multiple other studies list some of them,
12:06many of them listed at the bottom of
12:09the slide have associated numerously
12:12parameters with either 80 pathology or
12:15risk or risk of cognitive impairment
12:17in the future.
12:19And so basically parameters include
12:21total sleep time, sleep efficiency,
12:24non ram, slide activity and sleep
12:26disorders like sleep apnea.
12:34Considering total sleep time
12:36and risk of impaired cognition,
12:39many studies have shown that both
12:41short and long sleep duration
12:43are associated with increased
12:45risk of cognitive impairment.
12:48So at the in this top bullet point,
12:51short sleep duration of less
12:54than equal to five hours in.
12:58Cohort of 18 / 1800 community dwelling
13:02older women had increased risk of
13:05cognitive impairment after two years.
13:09Another study of over 3000
13:11dwelling older men,
13:12those reporting greater than 9
13:15hours of sleep Cross Sectionally
13:17had increased cognitive impairment
13:19and there's many other studies
13:22that I could I could go over.
13:24Some show also showing short sleep
13:27duration being associated with cognitive
13:29problems or long sleep duration,
13:32or both,
13:32such as this figure on the right that that
13:37came out recently in JAMA Network Open.
13:40Journal this was a pooled study of two
13:44cohorts of over 20,000 individuals,
13:46and they found that the self reported
13:50sleep duration that was very low is
13:54probably less than five hours of
13:56sleep per night or on the higher end,
14:00say 7 1/2 hours of sleep per night.
14:03That was self reported.
14:05There was declines in cognitive
14:08performance on a cognitive composite of.
14:11Several tests.
14:12And so this suggests that potentially short,
14:15and I think it's very good evidence
14:18that short and long sleep duration
14:21could be a marker for cognitive
14:25impairment and also a predictor of it.
14:28I think that the I think the the
14:30reason why short sleep duration could
14:33be a risk factor is fairly evident.
14:36They're just not getting enough restorative
14:39sleep for longer sleep duration.
14:41I suspect that the quality
14:43of the sleep is poor,
14:45either due to an unrecognized sleep
14:47problem or other or other other issue.
14:53Obstructive sleep apnea has been associated
14:55with increased risk of dementia.
14:57This is work from Christine Ya Phase
15:00Group at UCSF that's published in
15:03JAMA nine years ago and this study of
15:06300 older women who are cognitively
15:09normal and followed for four years,
15:12oxygens de saturation index greater than
15:15equal to 15 was associated with 1.7.
15:18Your odds of getting cottonmouth,
15:21cotton impairment or dementia
15:23compared to those with less than
15:2615 de saturation events per hour,
15:29and this is after adjusting
15:32for multiple covariates.
15:34And if spending greater than 7% of
15:38the night in apnea hypocapnia had
15:41an odds ratio of two for having risk
15:46of cognitive impairment or dementia,
15:49again also adjusting for multiple
15:52potential confounders.
15:57Studies have also looked at cognitively
16:00normal individuals and whether or not
16:03their sleep is disturbed when they have
16:06evidence of Alzheimer's disease pathology.
16:08The figure on the left is from Adam Spira in
16:12the Baltimore longitudinal study of aging,
16:15or where Conley Normal,
16:17older adults who reported less than
16:20or equal to six hours of sleep per
16:23night had greater amyloid deposition
16:26on pet scans compared to those.
16:29Or reporting sleeping 6 to 7 hours
16:32or greater than 7 hours per night.
16:35From my institution.
16:37UL Joo measured sleep efficiency using
16:39actigraphy and cognitively normal older
16:42adults who also had cerebral spinal
16:44fluid for amyloid beta concentrations,
16:47so she was able to establish whether
16:50they were cognitively everything,
16:52whether they are employed
16:54negative or positive,
16:55based on the employee.
16:57Beta 42 concentrations.
16:59The concentration of amyloid beta
17:01decreases when your amyloid positive
17:04so less than or equal to 500 picograms
17:07fermil was consistent with being amyloid
17:10positive and a larger percentage of.
17:15Individuals who are kind of normal amyloid
17:19positive or more likely to have lower
17:22sleep efficiency compared to those who are
17:25cognitively normal but amyloid negative.
17:28So evidence that from these two studies that
17:32changes in sleep can reflect underlying
17:36changes in amyloid beta pathology.
17:39Looking at non ram slow wave activity.
17:43This is also been a marker of great
17:46interest to our group and other groups.
17:49Figure on the left is from Matthew Walker's
17:53group at UC Berkeley and they studied 26.
17:56Can't be normal.
17:57Older adults and using pet scans looked
18:00at the medial prefrontal cortex and
18:02the Android Burden there and show that
18:05is amyloid increased in this region.
18:08There is a decrease in non REM
18:12slave activity.
18:13Here in Washington University we
18:15looked at a mix of Conley Normalan,
18:19mildly impaired older adults.
18:21There is total of 38.
18:23About 80% were cognitively normal,
18:26and we found that non REM sleep
18:29activity at both 1 to 4.5 Hertz and
18:32and also it was the most significant
18:36effect that wanted to herds,
18:39was was inversely associated with.
18:43Tau deposition on pet scans,
18:45where as the sort of activity decreased,
18:49there was an increase in the
18:52Tau deposition and this is after
18:55adjusting for multiple covariates.
18:58These figures show regional analysis
18:59where we use the same model,
19:01but instead of using the global composite,
19:04included each region separately and
19:05these are the regions that remain
19:07significant even after adjusting
19:09for multiple comparisons,
19:10so they were they were highly significant
19:13in terms of the relationship with
19:15with an on ramp slow of activity.
19:22So the two questions that really
19:25underlie my work are based on the
19:27idea that sleep dysfunction is
19:29associated with the risk of cognitive
19:32impairment and Alzheimer's disease,
19:34and there's a long lead time for
19:37Alzheimer disease pathogenesis.
19:38So we chicken in the egg question about this.
19:42About this bidirectional relationship.
19:43What is what is what is coming first?
19:47Or is it for? Is it possible?
19:49Is what I think that you could have.
19:53Sleep disturbances that are being
19:55caused by Alzheimer's disease pathology
19:57but also Alzheimer's disease with
19:58sleep disturbances can be promoting.
20:00Same resumes pathology.
20:04And in the remainder of the talk,
20:06I want to go through a few mechanisms
20:09that may explain this relationship.
20:18Actually, I before I get to the mechanisms
20:20I didn't want to make one point about
20:23the complexity of trying to sort out.
20:28What what, what,
20:29what changes are occurring and when in
20:32terms of sleep and 80 the pathogenesis,
20:35the factors that affect 80 risk and sleep.
20:40Are many so age, sex, physical activity,
20:43depression, vascular disease,
20:45health disparities could affect both
20:47sleep quality as well as the risk
20:51of developing Alzheimer's disease.
20:53And some of these factors may
20:56affect each each other.
20:58For instance,
20:59decreased physical activity with age,
21:01increased medical comorbidities
21:03such as vascular disease with age,
21:06and it's not understood how
21:08these factors may interact.
21:11Modify or mediate each other
21:13and it just illustrate that that
21:15point I'd like to highlight this
21:17paper from Carla Styles for go.
21:19So and Tom Gill at Yale that
21:21when I was putting together
21:23my career development award,
21:25really,
21:26really brought together a lot of
21:28things that I was reading and thinking
21:31about and was a nice framework
21:33for me and I think illustrates
21:35the effect of just age alone.
21:38On trying to get at the bottom of.
21:41Of the relationship between
21:43sleep and Alzheimer's disease.
21:44Now we know that there are
21:47multiple factors that a sleep,
21:49sleep, sleep,
21:50sleep factors that change
21:52during normal aging,
21:53such as decreased slow wave activity.
21:56And there can be sex differences
21:58for some of these factors.
22:01There's precipitating factors that
22:02occur with usual aging like increased
22:05incidence of primary sleep disorders,
22:07change in health status.
22:09There can be psychosocial factors
22:11like social isolation and bereavement.
22:14And these can interact together
22:16to affect sleep that could
22:18potentially lead to adverse outcomes,
22:20and these adverse outcomes in and
22:23of themselves could potentially
22:24feedback and impair asleep.
22:26And so I think that just underlies
22:29the complex.
22:30The complexity of the task to really
22:33establish the relationship between
22:34sleep in Alzheimer's disease,
22:36especially with the eye toward
22:38using it using a sleep intervention
22:41to prevent or delay AD.
22:47OK, now onto the mechanism.
22:49So first I want to talk about is
22:52amyloid beta production and clearance.
22:57We know that amyloid beta fluctuates
23:00with the sleep Wake Cycle.
23:02This has been shown in mice and
23:05the figure on the on the left,
23:07where the interstitial fluid
23:10concentration of amyloid beta.
23:12Oscillates with the minutes awake
23:14per hour when those are lower,
23:17their concentration is lower.
23:20And it's also been seen in humans.
23:23This is a study that was
23:25conducted by Randall Bateman at
23:28watching Washington University,
23:29where lumbar catheters or placed in CSF
23:33was sampled every hour for 36 hours.
23:37A beta 42 and a beta 40 were shown
23:40to oscillate over this 36 hour period
23:43and to be associated with with sleep,
23:47and so the triangles are the total
23:49sleep time in minutes per hour.
23:52You'll notice that there is a delay of
23:55approximately 5 hours between changes
23:58in a beta and changes and sleep,
24:01and this is due to the transit time
24:04from the brain to the lumbar catheter.
24:07In the lower back.
24:12One mechanism that that
24:15that has been proposed to.
24:18Mediate the changes in concentration
24:21with changes in sleep.
24:23Wake activity is neuronal activity.
24:26So neural activity decreases during sleep.
24:29In this study they had monitored sleep.
24:32You can see slow waves that were
24:36recorded and they correlated with.
24:40Metabolic activity on a pet scan
24:43showed that as the slave activity
24:46increased that there was a
24:48decrease in metabolic activity in
24:51the regions that they looked at.
24:54More.
24:57Controlled experiments in animal models
25:00have shown that stimulating pathway
25:04electrical stimulation has increased
25:08amyloid beta concentrations in the
25:12interstitial fluid and blocking.
25:15Oral activity has decreased them and
25:18other proteins that are released
25:20with neural activity such as Tau
25:23and Alpha Synuclein,
25:24have shown the same effect in mice,
25:28where stimulation increases,
25:29the concentration of both.
25:34On the foot on the opposite side
25:37of production we have clearance
25:39and there's a clearance mechanism
25:42that's been proposed to to control
25:45the oscillation of amyloid beta.
25:47This is the glymphatic system where
25:50convective bulk flow of fluid from the
25:54arterial system to the venous system
25:57removes solid waste products from the brain.
26:01First described in.
26:04If it's Association with sleep in this
26:07landmark paper from making it regards
26:10lab at the University of Rochester,
26:13where dye injected on the cortical surface.
26:16In this case, the green died during sleep,
26:20penetrates into the prank comma
26:22much more deeply than that.
26:24The red dye injected during during
26:27wakefulness and the proposed mechanism is
26:30that when we're when individual is younger,
26:33this flow is.
26:34Very efficient at removing waste
26:37products such as amyloid beta,
26:39but becomes disrupted with age
26:41leading to those we didn't.
26:44Emily beta accumulating in
26:45the brain forming pathology,
26:47further disrupting it and acting as
26:50a especially a feedback mechanism.
26:54I think that's you know,
26:56since since a beta of fluctuates,
26:59a sleep wake activity,
27:00it immediately raises the question
27:02of if you can manipulate sleep,
27:04can you manipulate amyloid beta and
27:07studies in mice have shown that
27:10sleep deprivation does increase.
27:12Soluble amyloid beta concentrations
27:15in this very elegant study from Ulju.
27:20Slow wave sleep was selectively
27:22disrupted using tones while participants
27:25were sleeping and they had a lumbar
27:27puncture in the morning following the
27:29intervention and also did it twice
27:32with a sham procedure where slowed
27:34sleep was not being disrupted and
27:37what she had shown was that great of
27:40the disruption in slow wave sleep.
27:42The greater the increase in slave
27:44activity between the two interventions
27:46and was really elegant about this method,
27:49is it isolated.
27:52Non REM slow wave sleep and did not
27:55actually result in differences in
27:57the total sleep time between the
28:00participants and there was no difference
28:02in a beta for any changes in total
28:04sleep time and I thought it was very
28:08elegant and well executed study.
28:10My lab has been very interested in.
28:15Translating the findings from mice to humans,
28:18and to do this,
28:19we we brought in 30 to 60 year old
28:23cognitively normal participants in place.
28:26Lumbar catheters at 7:00 in the morning
28:29and sampled cerebral spinal fluid
28:32every two hours for 36 hours and had
28:35them under different sleep conditions.
28:38In this study there was eight participants,
28:41but they all came back and
28:44repeated the study so.
28:46Four of the participants
28:47did all three of the arms.
28:48They did the control group, which is in blue.
28:51They did sleep.
28:52The sleep deprived group in red
28:55and the green drug group where they
28:57received sodium oxybate and the goal
29:00of sodium oxybate was to increase
29:02slow wave sleep and hopefully
29:05decrease the concentration of amyloid
29:07beta and cerebral spinal fluid.
29:09The other four participants
29:10repeated the study twice,
29:12so there's twenty time courses
29:15that went into this data.
29:18Because the participants were all kept
29:20awake for the first 12 hours of the study,
29:23we normalized all of the time points
29:26to the average of that first 12 hours.
29:28That's why the curves line up,
29:30and then at 9:00 PM at the
29:33vertical dashed line,
29:34the control participants were
29:35allowed to sleep as they were able.
29:37The drug group got their first
29:39dose of sodium oxybate and a second
29:42dose at 1:00 in the morning,
29:44and then the sleep deprived
29:46group was permitted to.
29:47They just stay with that.
29:49They just stayed awake.
29:51They were behaviorally kept
29:52awake without any stimulants.
29:54The shaded area is the overnight period,
29:56accounting for the transit time
29:58from the brain and captures this.
30:00Period for all the participants
30:03and we found that a beta 3840
30:06and 42 is was increased about 30%
30:09compared to the control group.
30:13As far as these isoforms,
30:15we've talked about a beta 42.
30:17This is the one most likely to
30:20aggregate into plaque in the brain.
30:22Abeta 40 is the most abundant
30:25form of amyloid beta.
30:27Followed by a beta 38.
30:33We've looked at in these samples at
30:36other proteins that are released with
30:38synaptic activity that some one of
30:40which you've looked at Alpha Synuclein,
30:42which in the sweet ride
30:45participants also increases.
30:46Significantly, and this is unpublished
30:49data that was done in collaboration
30:52with Paul Worley's lab at Johns
30:55Hopkins Neural Pentraxin two,
30:57which also is increased.
31:03Finally, in this experiment we
31:05infused all the participants
31:07with carbon 13 labeled leucine.
31:10This is for stable isotope
31:12labeling kinetics to measure
31:13production and clearance rates.
31:15They were infused at 9:00 PM and you
31:17can see the delay before you start
31:20to see any labeled Amyloid Beta and
31:23the labeling curve at the rise in
31:25the percent labeled Peak and then
31:28it starts to starts to drop and.
31:32Based on the kinetic modeling,
31:34the changes in concentration that we we
31:36found were due primarily to production.
31:39That seemed to be the really the
31:42necessary and critical factor that was
31:44driving the changes in concentration,
31:46and the reason sort of just
31:49the simple reason too.
31:52That when you look at the curves to
31:54tell it there's there's not a difference
31:56in clearance is that the curves are
31:59superimposable in terms of the upslope,
32:01their peak time and the down the down slope.
32:04The fact that there's a little bit
32:07of it's a little bit lower here for
32:10the for the in the control group.
32:13Is not a significant part of the
32:16modeling help explain that I just
32:18want to show this sensitivity
32:20analysis that was done as part of
32:22the paper we published this result.
32:24Here we change the production rate plus or
32:27minus 99% and you can only see the black.
32:31The black set of baseline line because
32:33there's no difference in the labeling curve.
32:36But as you change the fractional
32:39turnover rate to plus or minus 5 to 20%.
32:42You begin to see that the curve
32:45separate or the faster turnover
32:46and green has a steeper upslope,
32:49earlier peak time and then drops
32:51faster with the opposite being
32:53true for the slower turnover.
32:55And in a real world example of these changes,
33:00is looking at different individuals
33:03with different amyloids status.
33:06So this is a study of 101 older older
33:11adults who had the labeling infused.
33:16And our zero and then were sampled for
33:1936 hours and the amyloid negative group.
33:22Medic changes of a beta 3840
33:24and 42 are all overlapping.
33:27You don't see any differences, but an animal.
33:30A positive individuals.
33:32Data 42,
33:33which is more likely to aggregate into
33:36plaque as a steeper rise and earlier peak,
33:39and then it drops faster on the
33:42tail and the reason why you see
33:45this faster turnover is that the
33:47A Beta 42 is being retained in
33:50the brain as insoluble plaque.
33:53And essentially functionally from
33:55the point of view of the catheter,
33:58which is in the lower back essentially
34:01being cleared from the from the.
34:04Fluid.
34:07I think that the stabilized and
34:10labeling the stabilized labeling
34:12kinetics is a very powerful method to
34:15look at protein kinetics in vivo and
34:18a number of proteins have been looked
34:21at for neurodegenerative diseases,
34:23and I just if there's more if
34:25you'd like more information to
34:27review this very complicated topic,
34:30there is this review article
34:33that came out last year.
34:36I just want to point out as well
34:39that not all proteins that we've
34:41looked at are affected by sleep.
34:44When we looked at proteins that are
34:46not released with synaptic activity,
34:48we don't see any changes with
34:50sleep deprivation,
34:51so neurofilament light chain,
34:52which is a marker for Alzheimer's disease,
34:55is not increased sleep duration and
34:58the same is true with for GF AP.
35:02And what happens if you sleep deprived?
35:04If you're sleep deprived for
35:06a long period of time,
35:08chronic sleep deprivation that's been
35:10tested in mice and sleep deprivation.
35:1321 days resulted in increased amyloid
35:17deposition in multiple regions
35:20compared to compared to controls.
35:23Suggesting that this could this could be
35:27a mechanism whereby sleep sleep disturbance,
35:30increasing wakefulness during sleep increases
35:33the concentration which overtime promotes.
35:36The deposition of amyloid plaque.
35:40A second mechanism I'd like to
35:42go over is Tau phosphorylation.
35:45I didn't mention Tau previously,
35:47but we have looked at Tao,
35:49which is also released with neural activity,
35:52and we see that it is increased 30
35:56to 40% compared to control for a
35:59number of different forms of Tao.
36:01This is 381,
36:02eighty one or two 181,
36:05Syrian 202 or 202, and three.
36:07I mean 217 or T 217.
36:10This is the same.
36:12Data from using the samples from the
36:16study have already been discussing with
36:18the same normalization and it looks very
36:22similar to the to the amyloid beta data,
36:25so that sleep duration is increasing
36:28Tau soluble forms of Tau and human
36:31cerebral spinal fluid and prolonged sleep
36:34duration and mice can promote Tau pathology.
36:37This paper,
36:38published last year and science
36:40involved seeds of Tau injected.
36:42The Locusts Arulius and those animals
36:45that were chronically sleep deprived
36:47had increased Tau pathology on
36:48the same side that the seeds were
36:51injected compared to the controls.
36:57One very interesting and
36:59unexpected finding was that when
37:01we looked at phosphorylated Tau,
37:04we saw differences depending on
37:06the site that was phosphorylated.
37:09So looking at phosphorylated T 181 very
37:12similar to the unphosphorylated form but P.
37:16202 was I think it's pretty clear
37:19the sleep duration is much lower
37:22and it's the same as the control.
37:26It's slightly above the drug group,
37:29whereas phosphorylate 217
37:30was actually increased.
37:32Instead of being 30 to 40% increase its
37:3565 to 80% increased above controls.
37:40And another way to look at this is the ratio,
37:43which gives a measure of
37:45the phosphorylation rate,
37:46and here during the sleep period and it
37:49actually across the whole time course,
37:52the all of the intervention
37:54groups are overlapping,
37:55whereas there's a decline in the
37:57phosphorus phosphorylation ratio
37:59for 202 where the secret group is
38:01actually lower than the control group.
38:03And in here we can see the 202.
38:06Seventeen is phosphorylated
38:08at a greater rate.
38:09In the in the secret group
38:13compared to control.
38:15I think the phosphorylated T 217 is
38:19very interesting form of touted to be
38:22increased 'cause it's recently been
38:25shown to be a marker for the early AD.
38:29This is a paper that was published
38:31in nature medicine earlier this
38:34year from the Domeli inherited
38:37Alzheimer Disease Network.
38:38Looking at individual mutations
38:40that Predispose Domani inherited
38:42for AD and phosphorylated T 217.
38:45Increases earlier even than 181 and
38:48appears to be a marker for amyloid plaque.
38:52There's also been extremely promising
38:54data came out over the summer,
38:57showing that in the blood phosphorylated
39:00T 217 as a marker for amyloid plaque.
39:05And so I think the implications of
39:08the relation of our finding with sleep
39:10deprivation increasing this form of of
39:13tower not not yet fully understood,
39:16but certainly suggests that we're
39:18increasing the risk at the very
39:20earliest stages of Alzheimer's disease.
39:23I don't have an explanation for
39:25how sleep is potentially affecting
39:27Tau phosphorylation,
39:28but I'm going to give my best thoughts on it.
39:32Tell phosphorylation is complex.
39:33I showed this slide nearly to state that
39:37to show that this shows that the town,
39:39the Tau protein,
39:41and the different regions that
39:43are have been known to be.
39:45I've been found to be phosphorylated
39:47and the enzymes involved and you
39:49can see that there are numerous
39:51enzymes and numerous.
39:55Sites that are phosphorylated and
39:58a potential mechanism that makes.
40:00Lane this is that.
40:03Work in Mysore last two years that is shown
40:06that changes in sleep wake activity effect,
40:09protein phosphorylation. In the brain.
40:12So in this 2018 nature paper,
40:15mice were sleep deprived for one to six
40:18days and over that time the amount of
40:21phosphoproteome increased at every every
40:24time point that they that they measured,
40:27and one of the one of the proteins that
40:30they had found was was affected was Mark 2,
40:34which is a kinase that has been shown
40:38to have one of many that has a role.
40:42Intel phosphorylation.
40:46And then a paper last year published
40:49in science showed that that
40:52phosphorylation of proteins at synapses
40:55cycles with the sleep wake activity.
40:59And here in a they found 2200
41:02proteins that that fossil peptides
41:05that cycled across the day
41:08and during sleep deprivation.
41:11That number drops.
41:12So there was only two point 3%.
41:16Of the proteins that they measured.
41:20We were cycling during the
41:22sleep deprivation period.
41:27And there are previous examples of
41:31behavioral or environmental intervention
41:33changing Tau phosphorylation.
41:36Is 2001 JJVC paper three days of starvation?
41:41Increase the activity of
41:44protein phosphatase 2A,
41:46which is another enzyme involved in town.
41:51Phosphorylation and another study.
41:54Prolonged starvation in mice also increased.
41:59Fast forward T 217.
42:03Over that time,
42:04and this is one of the models that
42:07was proposed to explain how starvation
42:10could lead to Tao hyper phosphorylation.
42:13As you can see,
42:15it's quite it's quite complicated
42:17with phosphorylation potentially
42:18changing the activity of different
42:21kinases and phosphatases with
42:23the end result of altering Tau
42:26phosphorylation and leading to Tau.
42:28Hyperphosphorylation,
42:29and I think something potentially
42:31similar could be going on with.
42:34Sleep on the on phosphopeptides,
42:36but I think a lot more work is
42:39really needed in this area.
42:43Last time we talked about
42:46the erection system,
42:48so inducing sleep with dual orexin
42:51receptor antagonists decreases the soluble
42:54concentration of amyloid beta in mice.
42:57This is Elmer Accent and given across
43:01these light dark periods and keeps the
43:05amount of interstitial fluid a beta.
43:08The concentration very very steady
43:11and prolonged administration.
43:13Of Alma Rex and decreased amyloid
43:16plaque in multiple brain regions,
43:18including Intercel Cortex,
43:20the pyriform cortex.
43:23And an APP, PS1 transgenic mice
43:26that develop amyloid deposition.
43:28As you can see in this,
43:31this micrograph in a knocking out the
43:34rexon gene leads to decreased amyloid
43:37deposition and these are age matched animals,
43:41strongly suggesting a role for for
43:44the rexon system in developing mcloyd
43:47pathology there is some evidence in
43:50humans that directs and efficiency can.
43:54Can can alter amyloid deposition
43:56is a study from the University of
43:59Montpellier looking at narcolepsy type
44:02one subjects who had amyloid pet scan?
44:06And then age and sex matched controls
44:09from the Admin Cohort and Mattie Cohort.
44:12And they found that there was decreased
44:15amyloid pathology on these pet scans
44:18compared to their their matched controls.
44:20So some suggestive evidence that the
44:24direction deficiency may lead to.
44:27Altered amyloid pathology.
44:30And so putting this bidirectional
44:33relationship altogether,
44:34you know we have processes
44:37that can decrease sleep time.
44:39It could be from aging, sleep disorders,
44:43or multiple other factors that
44:46are known to impact sleep,
44:48social, environmental, mental,
44:50physical activity, medical comorbidities,
44:52and this increased wakefulness at
44:55night impacts the production and
44:58release of amyloid beta and Tau.
45:01The clearance of amyloid beta and Tau
45:03and the end result is you have higher
45:07concentrations of those proteins.
45:08Phosphorylation of Tau appears
45:10to be affected as well,
45:12and that promotes the formation
45:14of Alzheimer disease pathology,
45:16neurodegeneration,
45:16which then feeds back through synaptic.
45:18Internal dysfunction to disrupt sleep.
45:23And in numerous these factors such as aging,
45:27erexin and these other factors here,
45:30such as social and environmental,
45:32also can have effects on.
45:36No degeneration, and I think
45:40that this provides multiple.
45:46Areas for us to investigate potential
45:48changes that we may see in sleep
45:51wake activity during different
45:53stages of Alzheimer disease,
45:55as well as the potential for
45:57interventions to try to change the
46:00trajectory of Alzheimer's disease.
46:02To show that there is some
46:05evidence that you can.
46:08Do a sleep intervention and change
46:11the directory of some of these
46:14proteins we've been discussing.
46:16I'd just like to highlight this work
46:19again from UL joo published in 2019.
46:22Annals of neurology,
46:23where individuals with obstructive
46:25sleep apnea at a baseline study
46:28had a lumbar puncture and measured
46:30cerebral spinal fluid for amyloid beta.
46:32This is 40 and 42,
46:34as well as Tau and total protein,
46:37and then they were treated with C Pap.
46:41And then they return for another
46:44sleep study on C Pap told by another
46:47lumbar puncture the next morning,
46:49and what she found what doctors you
46:52found was that the greater the change
46:55in the nature of the drop in the hi,
46:59more of the decrease.
47:00In Emma Lloyd beta 42 and Tao,
47:03suggesting that this is just over.
47:06I believe it was.
47:09Relatively short period of time
47:11of three months, but it's.
47:15Extrapolating forward,
47:16it certainly provides evidence that if
47:19we were to do this on an ongoing basis,
47:22we might decrease the formation of amyloid
47:25plaques or the spreading of tab mythology.
47:29And I I think I, I think that as we get
47:32more evidence that we can affect the.
47:35These these critical proteins,
47:36these proteins that are critical
47:38for Alzheimer's disease.
47:39We really need to know when to target.
47:44A sleep intervention.
47:45So should we do it?
47:47You know, after before amyloid
47:49plaque is begin to form or or after,
47:52but before there's significant cow
47:55pathology and I think that that's the
47:58timing of when an intervention will occur is.
48:02To be really critical here,
48:04as well as what is the intervention
48:06which I think as I've been alluding to,
48:09could be incredibly complicated
48:11depending on the underlying sleep,
48:12disorder and other characteristics
48:14of the participants.
48:15But the ultimate goal is to
48:17administer a sleep intervention
48:19that would move them from high risk,
48:21potentially down to the lower risk.
48:25For developing cognitive symptoms from AD.
48:30So just to conclude,
48:32we discussed some of the evidence
48:35for the bidirectional relationship
48:38between sleep and Alzheimer's disease.
48:41Sleep may be a potential marker of a D,
48:44but I think additional work needs
48:47to be done to define exactly
48:49what sleep parameter might.
48:52Be most efficient in terms of
48:54being something that we could
48:57follow relatively easily,
48:59either to assess clinical risk.
49:04Or or to follow in a drug trial and
49:08understanding how other factors such
49:10as age or sex physical activity
49:13affect the use of that marker.
49:15I think using sleep as an intervention
49:18to prevent or delay Alzheimer's.
49:20These are really need to narrow
49:21down more and what the mechanism
49:23is exactly that's working.
49:25Is it changes in amyloid beta
49:27production and clearance or the
49:29release of proteins like Tao or the
49:32phosphorylation of Tau or all of them,
49:34and you know is there a special
49:36role for the erection system here.
49:40And I've already talked briefly about the,
49:43you know what intervention might
49:45be appropriate depending on what
49:47the sleep problem is,
49:49it could drastically change
49:50what would be selected.
49:52I think that longitudinal intervention,
49:54interventional,
49:55and implementation studies are really
49:57critically needed in order to to address the.
50:00These these questions.
50:04I'd like to thank you all for
50:06your attention like to thank
50:08the participants for their time.
50:10As you can imagine,
50:12the catheter studies that I lead
50:14are very intensive and I appreciate
50:17their willingness to undertake
50:19them and I'd like to thank everyone
50:21listed here and in the picture,
50:23which is the Alzheimer's disease research
50:26community here at Washington University.
50:28Thank you.
50:36Alright, thank you doctor Lucy,
50:37that was quite a tour through pretty
50:40much all of a nice primer on everything
50:42you need to know about sleep and its
50:46connection with Alzheimer's disease.
50:48So we do have a question and at
50:50this point I do want to welcome
50:53people to unmute themselves and ask
50:56a question or to put a question in
50:58the chat and so we'll start with
51:01the first question in the chat,
51:03which is will the need of seeing
51:06the full scope of sleep disruption.
51:08Forced the usage of full
51:11polysomnographers fee versus just
51:13screening for OSA with home sleep.
51:15Apnea testing
51:21so I think that.
51:24I think that it would depend on what.
51:28What what you're looking to to measure.
51:30So the home sleep apnea test.
51:33If you were, if you were looking to target.
51:39Sleep apnea and to treat that
51:41and try to prevent or delay
51:44Alzheimer's disease than a home.
51:46Sleep apnea test may be appropriate.
51:49I think that otherwise it's
51:51likely not going to provide any.
51:56Helpful information I do think
51:58home monitoring in general though
52:01could play an important role.
52:03So the study that I showed
52:05where we looked at non ram
52:08slow of activity at our center.
52:11We use a device that's worn on the
52:14forehead called the sleep profiler.
52:17It records a single EG from the forehead
52:21and we do that for multiple nights.
52:25And and that allows that.
52:27We've shown how that relates
52:29to Poly Sonography,
52:30and I think that you know that sort of
52:34monitoring or actigraphy monitoring
52:36would be feasable to be done at home.
52:39Another possibility that's that's in
52:42the paper that we published in 2019,
52:45is that if we could,
52:47we could look at different
52:49different sleep measures.
52:53Collected by different different
52:54methods and show how they relate
52:57in the same the same models.
52:59We might be able to to identify a
53:01similar question or set of questions or
53:04similar monitoring that we could do as
53:07an example in those 38 subjects where
53:09you found that non ram slow of activity.
53:13When it decreases,
53:15we have increased choupette signal.
53:17We also we also found that the Minutes
53:20reported napping was was positively
53:22associated with Tau pet signals,
53:25so that the longer they
53:27reported napping during the day,
53:29the greater the evidence of Tauopathy
53:32on pet that was in the same participants
53:35using the dissolver cord on the same nights.
53:39And I mean, 38 participants.
53:41I wouldn't.
53:42I wouldn't put a lot of a lot of
53:46my cards on that, but it certainly.
53:49Suggest that if you could do more
53:52studies or more participants at with
53:55other groups and really validate that
53:58that question gives you similar information,
54:01you could potentially imagine
54:03using something like that to screen
54:06for evidence of towel risk,
54:08risk of tap ethnology.
54:13So as a follow up comment, the comment is.
54:16It would be nice of the sleep if the
54:19sleep fields could come to agreement on
54:22the automated identification of slow slow
54:25wave activity versus Delta versus M3.
54:31And I, you know,
54:33I think related to that point.
54:35You know, sleep disturbance
54:38sleep complaints come in in
54:41so many different flavors.
54:44And so I'm sort of wondering is is it?
54:48Should we really just be focusing on?
54:51Slow wave activity?
54:53Or is it? Is that premature?
54:58I I don't I I don't think I would
55:01focus exclusively on slave activity.
55:04I there are a number of like I had discussed.
55:09There's there are multiple sleep
55:11parameters that have been found to be
55:15associated or associated with risk
55:18of cognitive impairment or risk of or
55:21evident risk of having a D pathology.
55:25And I think it.
55:28I think what I think about using
55:30sleep as a marker is that the rise
55:33of these blood based markers,
55:35which is really just come in
55:37the last couple of years.
55:38I think changes a little bit the
55:40way that I've been thinking about
55:42using sleep changes across AD.
55:44The original thought when we when I
55:46started on this work eight years ago
55:48is that it would be a noninvasive
55:50measure that could be used in the
55:53clinic to assess for risk along
55:55with other factors.
55:56I really don't think it will
55:58ever replace and.
55:59Amyloid pet scan or a Tau pet scan
56:02or CSF measures for amyloid and Tau,
56:06but something that could be a non
56:08invasively screened and potentially
56:10followed in an intervention trial.
56:12With the rise of these blood markers
56:15which are seem to be very robust in
56:19terms of identifying people with 80
56:21pathology and are going to be more
56:24less expensive and probably better
56:26tolerated by participants in patients,
56:29I think that defining how sleep
56:31changes across 80 pathogenesis.
56:33Could be critically important,
56:35maybe not as a marker,
56:36but for defining when you would
56:39want to intervene.
56:40That what that intervention with
56:43that intervention would be.
56:46I think to to use it as a screening method.
56:49I think we need to do PSG's.
56:52That could be a real challenge given
56:55just the numbers of individuals that
56:57we're talking about as we as we go
57:00forward from what the models project,
57:02the many millions that will be
57:04at risk of Alzheimer's disease.
57:06But if we can, you know.
57:10Use some of these.
57:13EG based and another sleep parameters
57:16to validate more easily deployable
57:19methods that I think would be very
57:23powerful as a screening tool.
57:27So another question is what is
57:29your thought about why sodium
57:30oxybate did not decrease amyloid
57:32or Tau in your experiments or in
57:34the experiments you mentioned?
57:36That's a great question.
57:39I think there's two potential explanations.
57:45One is that we did have a wide
57:48wide variability in the effect
57:50of sodium oxybate on sleep,
57:53meaning that although we had
57:56statistically significant differences
57:57and all the sleep measures we
58:00looked at such as total sleep time,
58:02sleep efficiency, other other things for.
58:07Sleep deprivation group
58:08compared to control and drug.
58:10We did not have statistically
58:12significant differences between
58:14the control and drug group,
58:16so it may be that we didn't
58:19have an adequate effect on.
58:22On sleep,
58:23in order to change the concentrations,
58:26the other is that you know the slow
58:29waves that are pharmacologically
58:31induced by sodium oxybate may be
58:34different than physiologic slow waves,
58:37in which case methods such as closed
58:41loop acoustic stimulation to increase
58:43low waves may be a better approach to.
58:47To increase flow waves and
58:49decrease the concentrations of.
58:52Amyloid and Tau.
58:55Alright, well we are at the top of the hour.
58:58Want to thank our speaker again for
59:01this this great tour and then Lauren
59:03I think you had an announcement
59:05for everybody before they peel off.
59:07Yeah thanks everybody.
59:08Just wanted to let you know that we do
59:11not have a talk next week because it's the
59:14American College of Physicians Conference.
59:16But we will resume on October 28 with
59:18the talk by Frank sheer at Harvard.
59:21Who's going to be speaking about
59:23night work and disease in the
59:25role of circadian misalignment?
59:26So look forward to seeing you all then
59:29thanks so much. Thank you alright.
59:32Thanks again, Brendan.
59:33Thank you friend, thank you.
59:38I you know it is worth noting,
59:40I think at peak we were we had
59:43about 85 participants so.
59:45Oh, that's great.
59:46I think.
59:46Yeah, I think it was hard to
59:48tell. I would see the pings coming
59:50would cost like the screen would
59:52be like so and so's entered the
59:54waiting room. So yeah. Yeah yeah.
59:56So there was. There was a lot
59:58of activity, so good that's great.
01:00:00Alright, well thank you so
01:00:02much for the invitation and
01:00:04for the thank you for coming
01:00:06virtually and I'll be in touch.
01:00:13Some reason I muted myself somehow,
01:00:16but I also want to say that the
01:00:18paper was just accepted today.
01:00:20Oh good, the one you sent me.
01:00:23OK, yeah, so I'm sure by the time so.
01:00:26So if you were going to use anything
01:00:29in an application, you'll be able to
01:00:32decide as impressed. Yeah, OK, good,
01:00:34alright? Alright, Thanks again. Take
01:00:37care bye bye.