Sleep & the Pathophysiology of Alzheimer's Disease

great [Music] hello everyone um and welcome to oscar fisher uh lecture series this has been a a great series and i'm sorry we're not all in the same auditorium together um but uh the the show must go on and uh so we've uh adapted to this virtual platform you may remember that um in the uh spring our last uh was last spring we had uh bruce miller and tony weiss corey we've taken a bit of a break um adapted to uh pandemic uh times um and our um uh thrilled to to have uh david holtzman uh join us today this is a um this uh lecture series is a um uh it's a great thing um it brings together a number of different schools across the university um and whether it's in engineering cns and um and liberal arts and others and it gets us all talking and thinking together about this important uh condition um oscar fisher disease um we're fortunate to have the support of jim trachard who's provide support and really his vision allowed us to kick this off and his demand that we find the the the treatment for uh for these conditions um and uh david's gonna talk shortly about a sleep and and alzheimer's a really interesting connection after after that adam spira and bryce mander will lead a discussion um and there's a qa button or ask a question button on the bottom of your screen and if you all have a question please use that and we'll get to those questions at the end so um we're really fortunate to have david holtzman joining us hopefully at some point in reality but today just virtually from washington university so i know uh david well um he and i were junior faculty together in fact he was junior faculty when i was still a resident at the university of california san francisco um and uh you know he was one of those cool faculty members doing really great things even as a junior faculty and i remember him talking i think he seemed to enjoy his time at ucsf but i remember talking to him about his love for st louis and he's always given us updates on how the sports teams were doing there so no surprise uh when when he moved back um and you know as young people i remember going to the ana that american neurological association meeting uh with david and you know i didn't know any of these old guys all these you know all the great things that they'd done but i knew david and we i had a great conversation a great meeting and learned a ton just from chatting with him so uh definitely um very influential in my thinking early on about the importance of moving neuroscience forward and he's just done amazing things since then so he did move back to st louis at washu he quickly became the chair and has been the ship for the last 18 years he's won all almost all the major awards and has really moved the field of of alzheimer's forward dramatically a lot of great work in terms of biomarkers for for alzheimer's disease a clarified understanding of e4's role how it works how it's related to alzheimer's disease and i mean just a multitude of other really fascinating discoveries amazing to me that he can be the chair and do all this great science it's really um uh for me uh inspirational and i don't i don't know that that is possible in a dean's role um it it uh but one can only aspire i'm thrilled to to uh have you here today david and i'm going to get out of your way and really excited to uh to hear your presentation well great thanks so much please it's wonderful to uh visit austin even if virtually uh and i really look forward to visiting in person it's one of the few great places uh uh that i've not visited so i look forward in the future to coming there in person um this is a real treat for me an honor that that i've been invited to give the uh oscar fix fisher lecture um uh there's many of my old friends uh clay and others that we'll hear from later today that it's been great to talk to today but also i had a real chance to meet a number of of people that i didn't know so well during my visit today so actually if we could put up the first slide um what i'd like to discuss today is a relationship between sleep and alzheimer's disease that we really stumbled across through just making some observations in the course of studying the metabolism of some of the proteins involved in alzheimer's disease and i think one of the main lessons from what i'll tell you about today is to keep your eyes and ears open as a scientist because sometimes you'll find things that lead you in another direction and don't be afraid to jump into something that you don't know so much about often uh often unbiased observations lead you to some of the most interesting findings okay so i will uh start uh show my disclosures um and what i'd like to do today is very briefly give some background about alzheimer's disease to make sure everybody's on roughly the same page and then discuss some of the work that we were doing at the time trying to better understand the relationship between neuronal activity neuronal metabolism and how that led us to studying sleep and then i'll talk more on the second and third parts of my talk about sleep and some of the proteins involved in alzheimer's disease so dementia is a decline in memory and other cognitive abilities that is sufficient to impair social and occupational functioning and one of the reasons that were society is so interested in this is that the prevalence of dementia is only about two to three percent at age 70 but after the age of 85 it's as common as about 50 of individuals and of course there's many different diseases that can cause or contribute to dementia in the united states it's estimated that about 70 75 percent of people that develop dementia that alzheimer's disease is contributing to and it's probably one of the most costly diseases if not the most costly disease right now because it costs so much to take care of patients with this problem as well as of course the time that family members and friends need away from work to to help individuals with these problems so the typical clinical features of this disease is usually a very gradual onset in progression usually first of difficulty with or recent memory or episodic memory but in almost all cases there is other cognitive dysfunction that occurs concomitantly such as difficulty with executive function manifests difficulty with problem solving usually some attentional problems and then as the disease progresses there's there's difficulty with language praxis visual spatial dysfunction behavioral dysfunction is frequent with early on apathy and often depression and then as the disease progresses there's a variety of other changes such as disruption sleep circadian rhythm as well so there's two major types of alzheimer's disease there's a very rare form so-called autosomal dominant alzheimer's disease which is only less than one percent of cases but has been very informative about the pathophysiology of the disease and then there's the late onset form which is onset usually after the age of 60 and this is most of the people that we actually see clinically now one of the interesting things is of course other than the strong risk factor for the disease being age is that alzheimer's disease the late onset form is one of the most strongly genetic diseases in humans so if you think about the other common diseases in man's diabetes heart disease cancer alzheimer's disease is is as are as strong uh genetic factors leading diseases any of those diseases so the major underlying pathology under the microscope that you see with this disease is like a lot of other degenerative diseases it's a disorder where particular proteins aggregate and accumulate in the brain one of them is the amyloid beta peptide shown here in red normally it's produced by the amyloid precursor protein which is at high levels in all neurons and it's released the norm the app protein probably plays a normal role in synaptic function and it's not entirely clear whether the a beta peptide from which which is derived from app has a normal role but unfortunately it tends to aggregate in the into this in the central nervous system in the brain and when it does this it forms these things called amyloid plaques in the extracellular space of the brain the other major protein that aggregates in alzheimer's disease is tau and that is a microtubule associated protein expressed at high levels in neurons and when it aggregate when tau aggregates it aggregates in the cytoplasm of neurons both in the cell body and then in dendrites of course there's also wherever these pathologies occur you wouldn't have cognitive problems if there wasn't loss of synapses and neurons which which occurs in regions especially where tau accumulates and then the other major feature of the disease is this very strong innate immune response where microglia and astrocytes become very reactive and while it used to be felt that these changes were secondary it's really clear that these changes are very much involved in the actual progression of the disease so one of the most important things to know about both alzheimer's disease as well as several of the other neurodegenerative diseases is that these diseases don't start when symptoms begin so if you look at somebody who happened to develop very mild uh cognitive changes so-called mild cognitive impairment or very mild dementia if the underlying brain changes that cause that cognitive impairment are related to alzheimer's disease and you look at the pathology and the extent of it at that time point very mild disease clinical disease the amount of amyloid beta accumulation in the brain is already close to its maximal extent in the neocortex the amount of neurofibrillary tangle pathology that's accumulating is already on its way up as the disease progression begins a clinical disease progression and there's also a very strong inflammatory response that's occurring both linked with the amyloidosis as well as the neurofibrillary tangle changes so this is one of the key things if you want to understand about what's leading to these pathologies you really need to understand what's going on before they start to like what's actually causing them to occur in the first place and this is a complicated slide but but one of the highly uh discussed theories over time about this disease is called the amyloid cascade hypothesis and basically it stated that as the amyloid beta peptide converts from a monomeric form to an aggregated form that that somehow leads to disease and while it is i think entirely it's very there's very strong evidence that the accumulation of the amyloid beta peptide is a necessary component of alzheimer's disease it's certainly not sufficient and there's a lot of other things that need to happen for some a person to go on to develop this disease beyond simply having amyloid beta deposition in the brain there's it's clear that somehow the a beta peptide drives tau pathology to get further along in the brain and there's a very strong element of inf inflammatory related damage that's occurring which involve a number of cellular changes which i won't get into in detail here but one of the things that i began to our lab began to focus on about 20 years or so ago is if the a beta peptide and its aggregation is central to ultimately leading to a number of events that leads to disease if we could understand what alters the level of this monomeric peptide we know that the level of that peptide will ultimately determine whether it will aggregate in the brain so we began to we actually developed a method to measure the levels of this peptide in real time in the brain of living animals and in humans and it was a variant of a micro dialysis method that john cerrito then a graduate student developed in my lab and it was at this time that there was a paper that came out published by roberto malinow's lab that showed that in cell culture then one of the things that regulates the the release of the a beta peptide from neurons is synaptic activity so we wondered whether that was true in vivo and using this in vivo micro dialysis technique we began to explore that and one of the things all we found is that the amyloid precursor protein is enriched at synapses in the brain and when synaptic vesicles fuse with the plasma membrane they get re-endocytosed rapidly and when that happens the amyloid precursor protein also goes more rapid endocytosis and cell biologically when this happens there's enzymes that cleave the amyloid precursor protein here shown in blue called beta and gamma secretase and they are active in endosomes and then once these enzymes are active it produces the a beta peptide in green and these vesicles then refuse with the plasma membrane releasing more a beta so basically through a series of papers we found that synaptic activity is directly linked with increasing levels of release of this amyloid beta peptide and this this kind of event occurs both pre and postsynaptically so it was around this time that we began to ex perform a number of other experiments to ask what uh when an animal for example is behaving normally and you follow what regulates the level of this peptide how does this peptide get regulated so i just mentioned that we we can find the synaptic activity regulates the level of the peptide and in the process of doing experiments one of my graduate students at that time started doing experiments to look at are there other things beyond simply synaptic activity that impact on this that regulate the level of the peptide and this is where we stumbled across this relationship between the sleep wake cycle and the a beta peptide so what jan kong then a phd student found is that when she monitored in this case mice and just did microdialysis so that we could measure in real time the levels of different proteins in the brain including the a beta peptide what we found is that it was higher in the dark and lower in the light and this would just go on and on for several days that we did this monitoring and rodents mice in particular are nocturnal and they're awake more during the dark and sleep more during the light and we can see a correlation between the minutes number of minutes awake and the levels of this peptide so once we saw that we we did other experiments to validate this result and these experiments were done by another graduate student adam bureau who again found if you monitor in the cortex or hippocampus of a mouse you can see that the level of the abated peptide is lower in the light when animals sleep more and it's higher in the dark when they're awake more what was also very interesting is that the levels of the peptide correlated strongly with them with the metabolite lactate and many other studies have shown that the levels of lactate are directly linked with the amount of synaptic activity that's occurring either in the brain or also just in cell culture when astrocytes and neurons are present what's also interesting is that if you monitor the levels of lactate in the brain of a living animal and you monitor it just every second when an animal goes from waking to sleeping the levels of lactate change suddenly by 35 percent up when it's awake downwind is asleep just demonstrating the the biological uh neuroscience of sleep is that there must be a very large change in neuronal energy metabolism and or synaptic activity that occur in brain regions when you go from waking to sleeping so one of the things that we wanted to know is are these kind of changes we see in this particular disease-related protein a beta also occurring in humans and my colleague randy bateman had developed a nice method to measure the a beta peptide in the cerebrospinal fluid of humans by putting in lumbar catheters this is kind of like an intravenous line that was put into the lumbar space and then people could uh have would have this in place for up to 36 to 48 hours and they would behave normally watch television eat etc and when he measured the a beta peptide during the sleep wake cycle of these humans you could see that it also changed in the csf by about 20 to 25 percent uh uh from light to from when people are awake to being asleep so when we first made these findings we wanted to understand are these changes due to changes in sleep wake or are they on other changes that are perhaps related to circadian changes that also regulates the sleep wake cycle so one of the first experiments we did is we measured the level of the a beta peptide again by micro dialysis and we administered the weight promoting peptide erection into the into the ventricle of these mice and normally what would happen is that the a beta peptide would continue to go down during the light phase but when we administer erection the animals stay awake more and the peptide stays higher we then did the converse experiment and asked okay if we give it an erection receptor antagonist which inhibits the erection erection actions in the brain this when a beta is supposed to be going higher during the dark phase it stayed lower and the animals slept more which is a known effect of this kind of a drug so these acute changes in the a beta peptide that we're seeing just over hours appears to be regulated in some way by being awake or asleep so then one of the things we wanted to know is okay well if you chronically caused animals to be more awake or more asleep would this affect not just the monomeric a beta peptide which is normally not apparently causing a problem in the brain but the aggregated form of this peptide or amyloid beta deposition that we see in the in the disease state so in these animals miranda lim then a chief resident in neurology was also a very good physician scientist came into my lab and she did these sleep deprivation experiments and mice that develop amyloid deposition and she started to sleep deprive the animals just before amyloid deposition developed and we did this for about a six week period when we do this we find in all the brain regions where amyloid develops there was about a two to three fold increase in amyloid deposition when we chronically sleep deprived these animals she then did the converse experiment and gave these amyloid depositing mice alma rexat an erection receptor antagonist once a day that caused them to sleep more and it also over a four to six week period decreased the onset of amyloid deposition quite dramatically suggesting again that chronically sleep deprivation increase this pathology and decreasing an increasing sleep decrease this pathology so we i would have spec and i still speculate at this point that one of the reasons that we're probably seeing this effect of sleep deprivation is due to altered release of the a beta peptide altering the levels of the peptide in the brain which cause it to be more or less likely over time to aggregate and build up now a few years after we made these observations the lab of macon needer guard began to publish papers looking at an effect of a system that they called the glymphatic system in the brain where there is fluid flow in the interstitial fluid of the brain which she shows by a variety of methods that tends to go from the arterials to the interstitial fluid along the venules and then ultimately into the csf and one of the ways that she tried to demonstrate this fluid flow which might promote clearance of different metabolites and proteins was to look to see whether the a beta peptide was affected by the clearance system that was induced by what she called the glymphatic system so she took the amyloid beta peptide that was radioactively labeled and injected into the brain and measured its removal and you can see in the animals that are awake the clearance in orange is slower than the animals that were either sleeping or anesthetized and based on this she argued that perhaps one of the things that sleep promotes is the clearance of proteins like this from the brain now whether or not the effects that i just showed you are due to effects of sleep wake cycle altering the release or production of the of proteins like a beta or it's due to clearance as make and neither guard might suggest or both we still don't completely know although i would say that in regard to this lymphatic system we don't yet really know we don't have evidence from dr nedergaard lab or other labs that endogenous proteins that are made in the brain are actually undergoing this pathway and i think this is something that needs to be further worked on so given that sleep disruption and sleep promotion acutely affects this peptide we wanted to also know does this occur in humans so these uh in studies that were led by brendan lucy who was trained in part in my lab but also with randy bateman brendan began to do studies in humans where he also used this technique where he put in lumbar catheters into into people and in this case they were 18 to 60 years old they volunteered for these studies and all of the subjects had two over a three to six month period they actually had two lumbar catheters placed one where they had a polysomnogram and these underwent a normal night of sleep and the day they were awake or they um were sleep deprived overnight and they had the same procedure done the other things that all these individual volunteers had done was metabolic labeling with c13 labeled leucine so an amino acid that was labeled so we could actually measure how fast proteins were being produced or cleared if you focus the uh on these results that brendan obtained by sampling the csf from the lumbar catheter every two hours if you look at uh what brendan did is he measured the levels of the a beta peptide species a beta 38 40 and 42 by mass spectrometry and you can see in the red line are individuals that were sleep deprived and the blue and green lines are people that were not sleep deprived and you can see in humans just as we found in animals that when you sleep deprive a human being that their a beta peptide monomeric a beta peptide goes up by about 40 to 50 percent just in with overnight sleep deprivation the other thing though that brendan did by doing these metabolic labeling he could look at the percent of a beta that was labeled or unlabeled and what he found is that these curves look identical and if the clearance if the make and neater guard theory was correct and the clearance of a beta was altered these this red curve would divert to the left and it does not however if the synthesis and release of the peptide were altered the curves would overlap so at least in humans this argues that the reason that sleep deprivation causes this increase in a beta is due to an alteration in release or production not a change in clearance one of the other things people have been interested in are things that affect lifestyle like sleep which may for example affect a beta production do they interact with other things that affect levels of a beta and accumulation like apoe4 which affects clearance not production there's some studies in humans that might suggest there's an interaction between apoe genotype which is a risk factor big risk factor for alzheimer's disease and sleep um and we've in some unpublished data that we're just working on now chiang wang a talented postdoc in my lab has begun to investigate this uh issue and uh one of the experiments that he's recently done is to take a mice app and ps1 mice these are mice that are genetically engineered to get amyloid deposition and we cross them to mice that express human apoe4 or apoe3 and when we sleep and when he sleep deprives these mice you can see if on these right panels for example in hippocampus if you sleep deprives them off and on for two months the animals that are sleep deprived that are apoe4 positive develop twice as much amyloid accumulation in multiple brain regions but what's interesting is the apoe3 expressing animals did not have the same effect this is something i think is really interesting and we're now beginning to explore the mechanisms that might underlie this change so one of the things that's been come interesting to several groups is is is this progressive accumulation of a protein like amyloid beta in the brain not uh is it actually associated with causing abnormalities in the sleep wake cycle and so one of the ways we approached this in mice was to look at amyloid depositing mice and we monitored the amount of wake and sleep they had a different time points in their life so if you focus on this middle panel during the light phase animals these mice should sleep more than they're awake which they do at three months of age when there's very little to no amyloid pathology but then as they develop more amyloid pathology they they are awake more which is very abnormal it's inc their wakefulness is increased by about 50 percent so we didn't know if this was due to a over expression of the transgenes and these mice are truly due to amyloid accumulation so to address this we did active vaccination of these animals when they're young with the a beta peptide this results in strong development of amyloid antibodies that prov that have been shown previously to clear amyloid from the brain so in these vaccinated mice you can see as has been reported before we can virtually block all the amyloid accumulation in the brain but we know this does not affect the amyloid precursor protein from which the a beta is derived in the pbs vaccinated mice they see plant we see plenty of amyloid accumulation and then if we look at the sleep wake cycle in these animals the pbs vaccinated mice have a marked abnormality and wakefulness during the light phase they're awake half the time and they should be sleeping a lot more than that during this period however in the vaccinated mice they had a completely normal sleep wake cycle from mice so that implies that that it's specifically the accumulation of a beta in this model that is leading to these abnormalities in sleep wake so is there any evidence for this in humans and some of this work comes from our discussions today adam spira as well as bryce mander who both showed doing using different technologies that if you look at amyloid beta deposition that occurs in people while they're still cognitively normal the so-called pre-clinical phase of alzheimer's disease that either by looking at self-reported sleep in atom study or looking at non-rem slow waves in the frontal lobe in relation to memory consolidation that there are already abnormalities that you can see in the brain that are linked with this a beta accumulation in human brain so i'll move on to looking at the relationship between sleep and tau and one of the reasons we began to look at this is because of what i showed you earlier namely that we know that the accumulation of the amyloid beta peptide occurs many years before symptoms arise and as this accumulates there's really no major change in cognition in people however what correlates quite strongly with changes in memory language or wherever this peptide uh accumulates is the accumula is the buildup of tau in neurofibrillary tangles and neuropill threads in the brain so we wanted to understand whether the sleep wake cycle might be related to the build-up of tau in the brain and one again further evidence for the reason we wanted to study tao is shown from this recent paper from gilroy binovich's lab at ucsf where they looked at baseline in individuals who had amyloid deposition in blue as shown by amyloid imaging or they had tau accumulation as measured by tau pet scan and what happened is if you look at the amount of tau accumulation and then follow the people over over years it's tau accumulation in the in the early cognitive abnormalities that you see in alzheimer's disease that strongly correlates with brain atrophy and further cognitive damage but that the relationship is not present with a beta just further emphasizing why we wanted to study tau so like in studies we did with a beta we also wanted to see if synaptic activity itself was related to the release of tau from cells even though it's a cytoplasmic protein it is released by cells and if you look in this lower panel c and these experiments carried out by a talented postdoc kira yamada she found that by simple depolarization of neurons in the brain with high potassium we can see by microdialysis that tao has increased more than two-fold over several hours in the brain of mice karen's karen duff's lab at columbia then looked at chronic stimulation resulting in increased neuronal activity and a mouse model that develops tau accumulation and if you focus on this middle panel she can see that there's an increase in tau tangles in the brain after a month of chronically increased neuronal activity compared to the unstimulated side of the brain arguing that perhaps these acute and chronic changes may be linked to each other so we began to study this in relation to sleep and if you focus on this panel a in these studies carried out by jarrah holth then a postdoc in my lab she was measuring in black circles the levels of tau in the extracellular space of the hippocampus of wild-type mice you can see that the levels are pretty flat during the light phase when animals are sleeping more and as as they become more awake during the dark phase tau goes up by about two fold if you then do the same experiment when you sleep deprive these mice the tile protein in the extracellular space increases by more than two-fold compared to baseline if we then do the same experiment here labeled in blue where we sleep deprive the animals but tetrodotoxin which blocks neuronal activity is infused in the hippocampus that completely blocks the increase in tau suggesting that wakefulness promotes the release of tao and that that is due to the effect of wakefulness on synaptic activity we again look to see if this kind of phenomenon was present in humans and in these samples that brendan lucy had collected earlier from his lumbar catheter studies we can see in red in these sleep deprived individuals where we measure tau in the csf of humans in the overnight sleep deprivation there's more than a 50 percent increase in csf tau induced by acute sleep deprivation this is interestingly also found with another disease related protein alpha synuclein where you can also see about a 25 to 30 percent increase with sleep deprivation so one of the things we began to wonder as well is everything affected by sleep deprivation or is it only some proteins so one of the things that we know about some of these disease associated proteins is that they're highly they're they're not in synaptic vesicles but they're highly localized to the synapse so when we look at other proteins in human csf that are in the cell body of neurons but are not enriched at the synapse like neurofilament like chain shown on the top we can see here that sleep deprivation had no effect on this protein it also had no effect on the on the astrocyte protein gfap which is present in cell bodies so again to look at whether these kind of changes affect not just monomeric or non-disease associated tau but the aggregated form of tau we used a model where we injected aggregated tau into the brain of an animal that's susceptible developed how seeds are aggregates and you can see in these top figures after we injected these aggregates of tau into the brain of these mice that results in local seeding of the of the endogenous tau is sown in brown and in some of these mice after we injected these seeds a few days later we chronically sleep deprived them for four weeks or not and while there was no effect of sleep deprivation on the local seeding of tile pathology what we found is that in synaptically connected regions of the brain such as the entero such as the anterinal cortex and in this case shown here on the right the locus cyrillius there was over a twofold increase in tile spreading that occurred with sleep deprivation arguing that these acute changes might ultimately lead to more chronically to tolerant pathology spreading in the brain then finally we also have looked to see whether these changes that we see in these disease associated proteins are they due to changes that we induce with sleep deprivation that are truly linked with sleep wake or are they other changes that can occur when you when you behaviorally uh sleep deprived animals like due to stress to try to address this we developed a technique we learned a technique from uh nigel peterson and patrick fuller and cliff saper at beth israel at harvard where they had developed a chemogenetic technology to stimulate a weight promoting area in the brain called the super mammalary nucleus and if you put one of these dreads related channels in this region of the brain and then you turn on these channels with a otherwise innocuous molecule called cno if we administer this compound and turn on these neurons you can see that we can cause the animals here shown in red to be a hundred percent awake for several hours in a row which is very very abnormal for a mouse and yet then the animal returns to a normal uh sleep wake cycle and when we do this we find the animals are behaviorally fine during this and there's no increase in any stress hormones that we induce by causing this change however when we measure proteins like the a beta peptide as i showed you earlier it's increased by about 40 percent due to this increase in wakefulness the specific increase in wakefulness and we also find very similar change in red here in tao when we acutely sleep deprive the animals i'm sorry we acutely simulate wakefulness with with this neuronal approach to affecting the sleep wake cycle okay so then finally i told you earlier that the a beta peptide accumulation is linked to abnormalities in the sleep wake cycle what about tau and in this a study that brendan lucy has recently published what we found is that we studied over 100 individuals with biomarkers of alzheimer's disease either in their csf or by amyloid and tau imaging when we studied about 80 percent of the subjects we studied were clinically normal that had either had this pathology or they did not and a few of them were mild i had mild cognitive impairment what we found is that there was a significant relationship when correcting for a variety of other factors between the accumulation of tau in the brain and non-rem slow wave sleep implying that somehow the accumulation of tau was significantly linked with an electrical change in in slow wave sleep that we can detect with this methodology this was not associated with a clinical change in the individuals who had this and as bryce mander had shown in his previous paper um we also tried to see if there was a linkage between amyloid in the brain and these changes and there was there was a linkage with the number of patients we had it was a little more subtle but the linkage appeared to be stronger with the accumulation of tau protein so in summary some of the data that we've accumulated over the last number of years suggests that fragmented sleep wake can lead to excessive a beta release that over time might accelerate amyloid deposition which in and of itself could further injure sleep wake centers or or cortical regions that affect sleep and that this same process might be also relevant with other proteins that aggregate like tau that further exacerbate this problem so in summary i think sleep weight changes in endogenous neuronal activity metabolism appears to regulate levels of these peptides in the extracellular space of the brain and this may ultimately determine the likelihood of whether these proteins begin to aggregate and i think our data suggests that stimulation of a wake center in the brain suggests these effects are by influencing sleep wake and not necessarily by other linked mechanisms such as stress so a beta and tau aggregation may lead to sleep disruption and i think this might occur during the stage of pre-clinical alzheimer's disease when the disease is developing when people are still cognitively normal and there's a series of questions which i think we'll go through in the discussion so i won't go through them here and i wanted to thank many people that were involved in these studies that i tried to thank along the way so i will stop there and maybe we could start the discussion at this point thank you david for a really excellent talk uh covering both the general principles of of the pathophysiology as well as your interesting work on sleep and alzheimer's disease progression and the relationship between the two so we have with us two discussants who are experts in this area and they will discuss some talking points that we that were on the last slide of david's david's presentation the first person is bryce mander who is an assistant professor in psychiatry and human behavior in the school of medicine of uc irvine his research is concerned with characterizing the role of sleep in cognitive function and overall brain health across the lifespan in both healthy populations and populations at risk for neurodegenerative disease and the second discussant is adam spira who's a professor and vice chair for research and faculty in the department of mental health at johns hopkins bloomberg school of public health his research is focused on disturbed sleep as a risk factor for poor health outcomes in older adults including cognitive decline alzheimer's disease biomarkers and functional decline and the pathophysiology and its links with both sleep and i mean the psychopathology and its links with both sleep and cognition in elderly populations so bryce and adam thanks very much for joining us today um i i have here a series of questions that david has raised for us to discuss and the first one i would like to to throw at adam if you will and that is do you know of other genetic factors um including apoe which david began to discuss but others as well that influenced the effect of sleep on alzheimer's disease pathogenesis and if so what is known about this right so i think the most that is known is first of all it's an honor to be here and uh you know in the oscar fischer series and uh dave your work has been so inspirational that uh it's really great to be joining you for this event but i think what is known most we know the most about the role of apoe and particularly apoe4 as it interacts with sleep disturbance uh to affect cognitive outcomes and um to a certain degree a d pathology less is known i would say about other a.d risk genes to be sure although there was a paper recently published in annals of neurology by ue lang and colleagues who work with christine yaffi at ucsf that looked at polygenic risk uh for alzheimer's disease in the uk biobank in about 400 000 plus people and showed that uh and i'm trusting my memory here that uh it was only after age 55 or so that there was an association between risk for a.d and self-reported sleep duration so you didn't see an association between uh you know how much of a genetic burden that would increase your risk for alzheimer's disease you didn't see a link between that and self-reported sleep duration until people got to an age where they might begin to develop some pathology that would be uh a.d pathology that's the interpretation at least that the authors had roughly speaking but we do see interactions uh with um there was an andrew lim paper that dave showed previously showing that the effect of e4 on uh cognitive decline i believe it was and maybe neurofibrillary tangles was um attenuated if you had better more consolidated sleep but i don't know that we know much about other sort of in uh you know sleep genetic interactions it's probably too early yes bryce i'd love to hear from other people about in particular about how that is making uh how that happens that's that's the question even if you just think about e4 what's going on to facilitate that interaction does anybody want to take up that follow-up question i can throw out some possibilities um i mean i think i first of all it's also for me it's an honor and thank you dave and thank you um um bob for inviting us on it's it's really fun to be able to talk about this kind of stuff and see such an excellent presentation um i think right now we're still in a discovery phase in this field uh there's a lot of candidates uh one really promising one that uh dr holtzman brought up earlier which i think needs a lot more exploration is really this interaction with the inflammatory system and whether neuroinflammation can be sort of a way in which sleep or sleep disturbance can kind of impact and influence that uh you know we we know that apoe is involved with some of the inflammatory pathways um and we don't really understand how sleep interacts with that but there there is some you know there are certain people as investigating that right now i think if you ask this question in a year or two we'll know a lot more about those interactions there's also a lot of other candidate genetic mechanisms that we could be interested in such as what are mutations in trem2 doing to sleep we really don't know anything about that you know and that's going to be a promising angle but we do know that sleep disturbance is directly and intimately tied to neural inflammation and if that's going to be a mechanism for a beta's impacting tao if you couple that with sleep you're going to have a massive effect on the production of the pathology and that's you know i think one possible candidate for sure alongside just production and release associated with these pathologies now i completely agree with you guys i think the exploration of the innate immune response is obviously very important in alzheimer's disease from all the genetics and other biology that's been done recently but if there is an interaction with sleep that's something that would be really important to understand yeah outside alzheimer's disease that that link is there right right age-related inflammation is tied to sleep and so it's an obvious candidate right so so that kind of begs the question which i would think some people in the audience are probably thinking can you manipulate the sleep wake cycle as a treatment and you know you you talked about elmer excellent uh erection receptor antagonists is that being postulated as a potential early therapy for people with mild cognitive impairment for example or anything like that yeah so um the first erection risks after antagonist that was approved for use in promoting sleep was a drug called balsamra that merck developed and they've already that merck group has already published a paper that you if you give patients who have alzheimer's disease that that drug at least it does appear to help their sleep now whether whether that would affect their cognition over time is something that i know they and many other people are interested in exploring um we're particularly interested here and understanding if you if you did promote the kind of sleep that those drugs promote and you did it more in a prevention mode would it actually affect the pathology like i was showing you earlier in animals so i think that's something we've we're very interested in we've actually started in collaboration with one of my colleagues here a study to to assess that in humans great can i add a follow-up point to that i just i just want to emphasize um uh dave's point on this because there's a lot of sleep aids out there and some of them actually might have negative influences or impacts on cognition and they can profoundly affect the way the brain expresses sleep but one of the interesting things about these doras these erection antagonists is that they affect the propensity to sleep not they don't hijack the sleep machinery itself and so one promising thing about this approach is that you might be actually inducing naturalistic sleep rather than kind of something that's in between sedation and sleep right right like benzodiazepines things like that yeah it's a very good point um let me ask one more uh question that came directly out of the talk and you touched a little bit on this but i'm i'm particularly interested david and others on a comment are there other pathways intracellular pathways by which sleep disruption leads to accumulation of misfolded proteins for example we talked a little bit about inflammation if you could say a little bit more about how that might work but also things like autophagy mitophagy you alluded to mitochondrial dysfunction well cert certainly the process of autophagy and ubiquitin proteosome system would be are very important in degrading proteins like tau for example in the cell especially aggregated forms of tau so to my knowledge i don't know if anyone yet has explored the effects of sleep in the brain on autophagy but i think it would be a great candidate to look into because we know that autophagy in different cell types including microglia is an important way to regulate the inflammatory response and and how those cells really act in when there is pathology in the brain so it's pretty unexplored to my knowledge but something that should be looked at for sure well uh time is marching on now and so what i want to do is take have you guys take a a stab at some questions from the audience and i would just remind folks banner has come up periodically that you can ask your questions um submit your questions through the ask a question button on your screen at the top right and there's the banner again and so the first question um was from sophie sanchez which is are there sex differences in the effects of sleep deprivation on a beta dynamics um i don't know the answer uh we've not explored that so it's a good ques it is a good question because as as people probably are aware um females are uh at a higher risk to get alzheimer's disease than than males and so um important but we haven't looked at directly i don't know adam or bryce do you have anything in your human data to to talk about sex differences that you know anything about not uh when it comes to these biomarkers no not yet but i think the hope is that we can develop large enough uh cohorts with these biomarkers such that we can test associations that might require greater statistical power you know i wonder just how much uh you know perimenopausal sleep disturbance for example might uh push up the uh proportion of uh women who develop a.d versus men i think that's an open question we just don't know yeah there's not enough known about sex emphasis at all and i don't think it has to be even limited to alzheimer's disease for example there are sex different form of neurogenic disease and where it goes the opposite way and we don't know what role sleep plays in that the only thing we know is that sleep deservance is pretty much present any neurological or degenerative disorder you can think of um the features of it are also really different based on disorder so it might be that men and women for biological or societal or behavioral reasons might be put at different risk for different kinds of conditions um but yeah just like just like adam and dave were saying we just really don't know the answer to that yet um but it's something that's actually being explored and i think that even in sleep itself there are sleep disturbances that show up across the life span and become more common as you get older and you see that differently by sex as well and sleep expression differs by sex as well and we really need to get a handle on that even something like sleep apnea which increases risk for alzheimer's disease the way it's expressed in men and women can be very different where you might have hypothetic and ethnic events that are occurring in rem sleep more in women than in men and that tends to be more directly tied to cognitive dysfunction so you know they might this might be an example of how it could uh women are also more likely to get insomnia which seems to have a more selective increase in risk for alzheimer's disease than apnea itself so there's a lot of possibilities i think we're just we just don't know yet great um the second question from the audience was from christopher file following a night of sleep deprivation is there a return to normal abated dynamics following a few nights of normal sleep yeah uh well the issue in humans the way we do this we can only leave these lumbar catheters in for about 36 hours we don't want to do it longer than that because of potential complications so we don't know although we because we've brought people back a few months later and re-study them their dynamics are certainly normal when we study them later so i suspect it because in mice it is i suspect only human data looks that way so i'd be shocked if it doesn't return completely to normal by the next day that's hopeful that's a good thing uh the third the third question from the audience uh was from dr james trichard and he asked how does acetylcholine relate to the sleep wake cycle one you guys want to shoot try that or eye control yeah i can i can give my two cents about this uh so acetylcholine is a critical chemical in the brain for regulating the expression of rem sleep and there's actually a whole other arm of research looking at the effects of degeneration of this network on sleep expression in mci and alzheimer's disease and one of the things you see is that so rem sleep looks a lot like the brain state of wakefulness typically and when that states that when cholinergic system starts to degenerate um it looks like what you see is a loss of that eg desynchrony in rem sleep so rem sleep no longer looks like rem sleep really or it looks less like rem sleep and it looks like that's tied to the generation of cholinergic system so whether or not that's related to cognitive deficits i think is unknown whether or not that shows up before mild cognitive impairment is unknown uh what the pathology associated with is unknown though it's probably tau driven degeneration of cholinergic system this changing rem sleep expression we know rem sleep is also important for cognitive function so there's probably a relationship there but it's understudied that's good good answer do you guys adam do you have a comment to add to that no that was uh comprehensive thank you thanks bryce that was great and i did not plant that question um the the fourth question uh and i would encourage the audience to ask any more questions if you wish but the fourth question for discussion is from dr steve roach what are the effects of mid sleep disorders like sleep apnea on the incidence or onset of alzheimer's disease and you talked a little bit about this price but maybe you want to talk a bit more yeah sure and i'm sure adam and dave also have a lot to say about this um from the evidence that we have is that having a sleep disorder um likes sleep apnea or insomnia it's pretty i think clear from the evidence out there that that increases risk for alzheimer's disease um there's some discussion about the idea of whether or not if you get apnea when you're at midlife versus if you get it later in life there may be a differential effect such that it's less risky when you get in your 70s and 80s than it is if you get in your 40s especially if you get in your 40s and you don't treat it though we need a lot more evidence to see what treatment does to aid risk but there certainly is a lot of evidence that sleep apnea generally increases your risk for alzheimer's disease and i think a lot of what people are expecting is if you have a chronic sleep disturbance that lasts for decades that most likely is not going to be good for your risk some something else that uh comes up for me when i when i think about midlife is what we've seen uh we know that sleep disorder breathing sleep apnea is a risk factor for hypertension and stroke uh and we know that midlife hypertension is bad news with respect to subsequent ad pathology particularly amyloid deposition for example and i think that considering the vascular contributions that might result from sleep disorder breathing in concert with the consequences of sleep loss and hypoxemia it just seems like uh a stew that if you don't take care of that uh toot sweet you can you know it's gonna have significant implications for your brain health yeah speaking on that just one final quick point is i think really supporting adam's point um there's new evidence coming out of um ricardo rosario's group at nyu um that is basically showing that the cognitive decline and dementia effects of obstructive sleep apnea are really strongly there if you have hypertension but not as obvious if you don't well that's interesting so we have a fifth question and this is from our very own bill schwartz who uh last but not least our short naps at the wrong circadian phase of course because bill is focused on circadian rhythms are they an effective prophylaxis for all of this a beta accumulation yeah well i don't think everybody knows of course the answer that although it would be certainly good if that's true but i don't think we really i don't think any experiments to my knowledge have been done to try to address that i don't know unless you guys are aware of something that well you know it's very interesting that there is a literature on of course napping and dementia risk and it's really it's mixed and i think it's because people as they get older in particular nap for you know a range of reasons and one napper is not the same as another napper and one nap is not the same as another nap there was a timing question that came in there which of course is important that is a whole the whole circadian question is you know something that's lurking in the background and really we could have a whole other uh one of these on that probably but i don't think we know at all yeah it's an open question uh we have some unpublished data from a collaborative mind that suggests that and this is a really strange finding but if you're a man and you don't have sleep disorders and you're fairly old if you have slept for you know 30 years earlier you to a nap during the day you actually had a lower risk um but it probably it but as long as it was less than an hour right so if the nap wasn't too long if you didn't have other significant medical comorbidities you know really like if you nap because you're trying to catch up on sleep loss that's probably really different than if you nap because you have a medical comorbidity that disrupts the restorative quality of your sleep and i think that's why there's mixed literature there might also be sex effects like we were finding uh so it's really an open question and i think the timing matters now you said it at the wrong circadian time but i kind of take issue with that because there is a time of day when you're supposed to nap you know you have that post lunch dip you know the skating timing if you get a nap there that's probably better than if you take a nap at 5 or 6 p.m right before you go to bed [Music] right right from weekend experience i can attest to that well i want to thank you all so much for uh for doing this event putting this event on for the discussants and of course for dr holtzman for for uh virtually coming all the way from st louis into our into our room our houses and offices here i think this is a wonderful example of science that went from bench to bedside and has the potential to impact the lives of many many people i think it'll all make us rethink the concept of sleep hygiene that being the uh the brave warrior who stays up all night to get that paper done or or do whatever that they can brag about in the morning is probably not a good thing for your health and you probably ought to do sleep hygiene just like you do dental hygiene regularly and do it carefully and do it well um and for those of us who don't sleep well and who have a problem with insomnia you know it's worth actually getting screened going to somebody who's a sleep specialist a good one and in particular treatable things like sleep apnea as as you you guys have mentioned so uh this and the other oscar fischer lectures that we've had and are planning in the future really reflect our current interest here at ut austin and building expertise in neurodegenerative disease and that's through the departments of neuroscience which i now chair and neurology chaired by david pedophar which we could build on the basic science streams in neuroscience and particularly in the center for learning and memory and also in the clinical expertise that exists now in the maldi clinic for the neurosciences and so we hope that we can grow our own program here much like you have david at st louis which is a fantastic place to do this kind of research i want to also thank the audience for joining us and i would invite all of you who are doing research to submit your research for a chance to win the oscar fisher prize there will be information about that when we end this session and the the submission deadline is mid-november so you can learn more by visiting the website which will be placed on the screen at the end of this session i'd like to thank all of you again doctors holtzman speer and amanda and those of you in the audience for submitting your questions and for everybody for joining us today so thank you very very much thank you thank you you're welcome you

Channel: Dell Medical School

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Id: zCmngDk9VDU

Length: 63min 50sec (3830 seconds)

Published: Tue May 18 2021