Diagnosing Alzheimer’s Disease

[Music] so happy to see you all again my name is Serge Allah not that we met last week I'm happy to see you back to learn a little bit more about the neurodegenerative diseases I think we had a pretty good first session where we were able to provide you with an overview of the neurodegenerative diseases distinguished between the different diseases of the brain and the clinical syndromes they caused give you a big picture view of how we think about neurodegenerative diseases I think we had a pretty good discussion also to kick things off today we're gonna start to narrow things down a little bit I've invited my colleague dr. George nasaan he is the director of our clinical services in the UCSF memory and Ageing Center a dear colleague of mine and he's gonna give you a more detailed view overview of a specific disease Alzheimer's disease which you learned last time we met is the most common neurodegenerative disease worldwide he's gonna delve into the pathology and then the clinical syndromes this is these causes and after his lecture we're gonna have an interactive question-and-answer session with with him as well as to invited guests from the memory and Ageing Center dr. Leah Greenberg who leads our neuropathology department or neuropathology core and dr. Lajoie renato joy who is a neuroscientist researcher that is really spending his time thinking about all of the tests that we can order to diagnose Alzheimer's disease in life specifically the PET scans okay so without further ado I introduce my colleague dr. Nelson take care all right thank you everybody I'm really excited to be here I think this is the first time that I talked a group of people that aren't medical students or physicians so I hope I do a good job so we're gonna talk today about Alzheimer's disease and I'm going to start with a story so on November 25th in 1901 so that's more than 100 years ago Carl who was a German office clerk brought his wife August II who was 51 years old at the time to a mental institution and Frankfurt Germany he was having difficult time taking care of her at home and said that she had started having memory difficulties a few years prior he also described that she was having paranoid delusions feelings of jealousy thinking that he is sleeping with other women she was convinced that there was there were people out there trying to kill her and she also had difficulty speaking and verbalizing her thoughts and her ideas she was described as having some auditory hallucinations hearing things that that when nobody was speaking and also unpredictable behavior and that night the physician on call who examined her was named a Louis Alzheimer he was 27 years old and this is this is a picture of August II it was taken about a year after or maybe a drawing actually I'm not sure but it was it was documented to be a year after she was admitted and interestingly not necessarily with that picture but some of the notes from dr. Alzheimer the night that he admitted her said that she sat on the bed with a helpless expression and it's just interested that this was the picture captured of her these are some of the notes from Alzheimer's of his conversation with this patient he asked her what is your name and she answered August II last name August II what is your husband's name August I think your husband my husband and then she looks as if she didn't understand the question so these are all from his notes are you married to Augusta mrs. D yes yes Augusta D which was her her name how long have you been here she seems to be trying to remember three weeks what is this and I show her a pencil and she answers a pen what did I show you I don't know I don't know it's difficult is it that so anxious so anxious so this were some of the notes that there was more but this was some some extracts of the notes of that first dialogue that that Alzheimer's had with with August II and then he she passed away in on April 8th of 1906 so about five years after she was admitted to the institution and analyst Alzheimer asked for her brain and described some of the findings that he found under the microscope in her in the brain cells and he described what we now know which we're going to talk about later as neurofibrillary tangles and amyloid plaques which have become the pathologic hallmark of this disease and the actual term Alzheimer's disease wasn't coined until 1910 so a few years after by by another psychiatrist and the handbook of psychiatry and these are the drawings from from Alzheimer's and I will show you later sort of what actually these look like under a microscope in reality so we're gonna cover a few things today we're gonna talk about how does Alzheimer's disease present itself when it affects people and how what are the different symptoms that they can manifest you know how do they how do they present to us in clinic and and we will see that there are different ways in which all some disease can manifest itself these are four of the most common ways so it could be a memory syndrome and I'll talk about that in a little bit visual syndrome a language syndrome or a frontal lobe syndrome and we'll talk about that and then we will dive a little bit into neuropathology just to discuss these findings that that a Louis Alzheimer's described we will talk about some of the genetic factors of the disease and then we will finish by some of the modern biomarkers or sort of techniques to test for this disease in our current day and age so supposing that you know this is one person and the span of their life from say 30 when they're 30 years old and they're healthy and nothing's going on to when there are 90 and maybe they have Alzheimer's disease you know it seems that there is there's a gradual progression of Alzheimer's disease where it starts affecting the brain way before we actually can detect any sign and we call this the asymptomatic sort of phase of Alzheimer's disease and then they may start showing up in people's thinking memory behavior etc but that could be mild enough and we'll discuss what that means you know and we call them what kind of impairment or they could be more progressed and cause people to be dependent on others for their well-being and their day-to-day life and then we call that dementia so mild cognitive impairment or MCI is described really a clinical state where a person has cognitive or behavioral decline of any cause really but it's specifically here Alzheimer's disease that does not significantly interfere with independent living so these are people who maybe they forget but they can continue to take care of themselves you remember to take their medications they can shop and cook and pay bills and take care of their hygiene etc and as opposed to this the term dementia describes a clinical state where we do have cognitive or behavioral decline again of any cause but this time it does significant interfere with a person's independence in completing their day to day function and so they become progressively more reliant on family loved ones hired caregivers in order to provide different levels of care that they need so really it's important to understand that not every person who has dementia or MCI necessarily has Alzheimer disease so both these terms and CI and dementia are just clinical terms and a lot of things can cause them and also not every person with math kind of impairment necessarily will progress to have dementia so we have all of the possibilities you know that person can be clinically asymptomatic they can have mild cognitive impairment or they can have the amount one may progress to the other but not necessarily all right so we're gonna we're gonna start diving a little bit more into Alzheimer's disease and how it manifests itself so I'll talk in a little bit about the pathology of Alzheimer disease that you see on the left side but let us focus first on the clinical syndromes which which means the the the way that the disease manifests itself in humans so these are like I said earlier the four most common syndromes and the first one which we're gonna start talking about the memory syndrome is probably the one that is considered the most typical or classical Alzheimer's disease manifestation and when when people in the community say Alzheimer disease usually this is what they think of they think of memory loss and I would like to start this is a poem that I love by Emily they can send this is even before a Louis Alzheimer sort of described this finding it's in the 1800's but it's really interesting to me how she describes what could be what could what we could feel when we have memory problem so I'm just gonna read it real quick I thought went up my mind today that I have had before but did not finish some way back I could not fix the year nor where it went nor why it came the second time to me nor definitely what it was have I the art to say but somewhere in my soul I know I've met the thing before it just reminded me it was all and came my way no more so let me start talking about memory syndrome so people who have this typical or classical what we call a monastic manifestation of Alzheimer's disease their first sign usually is a sign of short-term memory loss meaning that they start forgetting things that happened recently not long ago last week three weeks ago this morning and as the disease progressed that time delay might become shorter and shorter where they might forget a conversation that just happened an hour ago or something that someone said 10 minutes ago typically the memories for things that occurred long time ago remain preserved sometimes - even a later stage of the disease however we we do know that that the the pass can start marching backwards in the sense that people start recalling more vividly things progressively from earlier an earlier period of their times in fact some patients when they progress they might start recalling very vivid memories from when they were at school or children etc so the way that that it manifests itself is that people may forget events that they want to they may forget conversations they may repeat stories tell you something that they have already just told you or that they told you three days ago they can misplace their belongings because they forget where they put something down and they go to look for it over time other symptoms might arise that are not necessary related to memory so they might start having difficulty navigating and getting lost and this is a combination of not recalling where things are and they're in their internal map but also having some visual problems and we'll talk a little bit about visual spacial difficulties in Alzheimer's disease and a little bit it can also progress to include language difficulties forgetting words that they used to be able to say it may affect behavior some people may become anxious other people might become more detached and late in the disease you know other cognitive domain might be affected as well such as executive functions problem-solving etc so when the classical or typical Alzheimer disease occurs we believe that that the the memory is happening because the the disease is affecting a very particular part of the brain called the hippocampus which on this cartoon you can see it right here and this is an MRI of a patient that doesn't have the disease you can see the hippocampus is nice and plum you know it's it's it's that gray rounded area and it fills it's quite big and bulky and I'll and I'll show you in a little bit what it looks like in disease but was I really like the word hippocampus is a little bit interesting how its named so it's named after a seahorse so this is if you take this out it looks like that because it looks so much like a seahorse you know hippocampus a seahorse and Greek and and and patients who have Alzheimer's disease they poke AMPAS might really lose a lot of volume because brain cells are dying as time goes by and so instead of having that sort of really nice and plump hippocampus you might have a space and the place where it's supposed to be and you may not see a hippocampus any longer so this is this was in summary sort of the presentation of somebody with primarily memory problem now people those I'm disease may also present with primary difficulties with visual processing not necessarily affecting their memory and this is a syndrome that is currently known as posterior cortical atrophy and some people refer to it at the posterior variant of Alzheimer's disease so in in these people usually the disease presents earlier for reasons we don't understand so there are younger maybe in their early 60s or late 50s the first sign and symptom of this is impairment in visual processing they start having difficulty locating things in space they may open a fridge to look for the milk and you know there's a lot of things in the fridge and they're not able to visually process you know where where the carton of milk is located in the fridge they may have difficulty with sizes of things so go to fetch I don't know a big glass or mug and they fetch a smaller one or placement of how to put you know the table placement they also have difficulty navigating their own space so a room like this would be very difficult to navigate for somebody with this type of Alzheimer's disease because if to be able to like go through where is the door and on which side I have to go and how do I like not bump into people it's it's very very difficult they may also have difficulty recognizing faces or objects and so these patients may earlier in the course of the disease have difficulty recognizing family members or famous people on television over time the disease may progress to then include memory problems and then it and later on start to look the same like the Alzheimer's like the amnestic form of Alzheimer's disease so but most of the time in the first two or three years it's primarily a visual problem for these patients these patients are the least likely to not have I'm sorry to have to not have insight of their disease which means out of all the people other arm disease they are the ones that recognize the most that there is a problem going on and that they are unable to manage their space and and some people believe that because of that but also maybe other factors related to where the illness is attacking you know they may be very depressed or very anxious this is a picture that we often show our patients in order to determine how well they are processing visual cues and stimuli so we ask them to describe to us what's going on in the picture and as you can see there's a lot going on in this picture right there is water running you know the mom has her back turned to her kids who are maybe stealing you know cookies from a cookie jar and and this would be the way that you would want somebody to describe that picture but people with this type of Alzheimer's disease may actually not be able to do that because they may not be able to tend to all of the visual stimuli going on at the same time they may be able to describe one thing I've had patients just describe what's outside the window and not talk at all about what is happening inside the kitchen so so the this is this is one way in which we can test this at the bedside and in people with this type of Alzheimer disease it affects a very different part of the brain which is the posterior part of the brain so let me orient you a little bit this is an MRI of a person with this type of Alzheimer's disease and this is the the front of the head and this is the back imagining them imagining that they are laying down on on the scanner on the table and you are looking through their feet not through the top of the head but through their feet so this is the right side this is the left side this is the front and this is the back and and we are starting at the very top of the brain the very top of the head and you see here if you just compare the front to the back you see that there's a lot of black spaces in the back that don't exist in the front the front is mostly comprised of brain that is nice and full and plump and gray and the back is a lot of deep spaces that are black like the one that I'm showing here or here or here this is a part of the brain that's called the parietal lobe and it is responsible for a lot of our visual processing but also some other things like math and calculation it plays a role in language and it plays some other roles and sensory how we feel things etc and and you notice how much volume lost there is in the back part of the brain whereas the remaining brain looks more or less ok this is the hippocampus here it's a different cut than the one I showed you earlier but it is relatively slightly more plump than what we expect for somebody with other arm disease and so the main problem is here in the posterior part all right so so far - two different ways it presents and two different parts of the brain that are being affected the language syndrome what is referred to as Luca panic variant of Alzheimer's disease is a third way in which awesome disease can present itself it also tends to occur mostly in younger people and the first sign is a language difficulty and specifically people have a really hard time coming up with words and spontaneous speech they would be talking and then all of a sudden they blank on a word they may try to talk around it like if they were to say a hanger they might say you know the thing that that it goes and the closet and then you put your your clothes on it and they just they blank on the word and they say all of these things around the word the the exact process that is being impaired in these patients is that they have a really hard time with anything that comprises the sounds of language and to explain that to you a little bit let me invite you to think a little bit about language with me language is a very abstract concept right the who decided that if I say the the sound door you know that means something to us you know it's it's the door that we open to enter a place and if I say the sound that's not there's nothing you know it doesn't mean anything but that's still a sound you know we it's a very abstract concept we we have learned since we were young that these particular sounds are associated with a particular meaning or concept and and there is a part in our brain that is responsible at all times to sift through all the sounds that you get from your environment and allow you to differentiate between ambient sound and language sounds and then once you are able to process all of that you then attach the meaning to each of the sounds and that's how language even starts to be processed in the brain and there are other parts that sort of take over for you to you know add the richness and texture of what it is that you are being told how you're gonna respond to it etcetera so these are other things that we're not gonna cover today but that initial process of understanding the sounds of language is what's being affected in these patients and so that's why they start blanking on words because they can't hear them they cannot hear what they sound like and also they start having difficulty listening to people talk especially if they are being told something that's really long because it's theirs it's way more sounds right so if I were to tell you get out this these are two two sounds two syllables it's way easier to process than if I say make sure to get ready we are going now for dinner we're gonna be late that starts at 8:00 p.m. this is a lot of sounds that the brain now has to process so for people who have this variant of Alzheimer's disease they will have a really hard time with these long sentences as opposed to shorter sentences as the disease progresses they may have more and more difficulty with language so that their communication might be really impaired some patients do do become sort of close to mute or unable to really provide any meaningful conversation early on it might also affect calculation faculty because we're gonna see this is in the part of the brain that's close to where we process sounds of language and then they may start developing more visual problems similar to the first to the group that I showed you right before this one these patients probably also have a lot of memory problems that might be hard to detect because if you cannot speak we may not have an opportunity to know that you forgot something because it may not come up in a conversation and let me show you just a video of a patient that has this end and this is a test that we give to this patient in order to see how they're processing the sounds of language the test is really simple we ask them to repeat a sentence and repeating a sentence does not require you to really understand it or that it requires you to do is to be able to process the sounds of that sentence and reproduce these sounds and so people may not be able to understand what they're saying but they may still be able to repeat it however people with this very awesome disease have a really hard time so let me just play this real quick can you repeat this phrase today was a warm and sunny day [Music] today was a warm and sunny day can you repeat that again yes it was I said its day was Jason was summer and neither tend to look your face it's tricky isn't it let's start with something easier how about today is Monday buddy today is Monday how about the flowers were in the park ours were in the blood in the air all right so you notice how he's really struggling with these sounds even when those sentences were relatively sort of simple and what's interesting and if you notice there were some errors in the words that he he made they sounded like what you're saying but they were not the right words you know he's that summer as opposed to sunny day and this is an error that often these patients make because as they are searching for the sounds other sounds you know are being grasped in the brain and they're going there so this is to show you where in the brain that says so again I'm gonna reorient you like we did the first time this is the top of the front of the of the head or actually you can see here the top of it these are the top of the eyes so that's the face here that's the back this is your left side this is your right side and I'm gonna bring your attention to this part of the brain where you see that there is a lot of spaces like this big space here some of these spaces here as compared to that side of the brain so this is the right this is the left this is part of the parietal lobe which I showed you earlier but it's a little bit lower and it is where we are processing some of these sounds of language and this is the reason why these patients struggle alrighty so the last point we're going to talk about today but not the least is the the executive syndrome or the frontal syndrome and so this is a variant that that also occurs at earlier age and it affects the front part of the brain which we haven't talked about yet so the front part of the brain is responsible for a lot of really important day-to-day things you know it is it I think of it as the CEO of our brain you know it is little guys sitting there making decisions you know allowing us to to know what we want to do today plan our day execute that plan motivate us in order to sort of go go ahead with our plan it motivated all of you to come here today and listen to this lecture and helps us organize at cetera so when it is affected by Alzheimer's disease then people start losing this capacity and they might start having difficulty with problem-solving maybe they were always good at mechanics and they stopped knowing how to do that you know maybe they had they tended to their garden and knew how to organize it and stop doing that a lot of people it can come up show up at work because remember these are people that could be younger and their fifties and so often times they are still working and they may start making errors or judgment problems at work because the front part of the brain is yes we have a question so the question is whether this is referred to as frontal problem and not necessarily it can depending on how it presents itself so from temporal dementia is another syndrome that describes it has a particular criteria about what patients present with and I think it's gonna be talked about in the next lecture after this one but this may be called from temporal dementia as a syndrome if the primary presentation is that of a behavioral change but then the the cause of it would still be Alzheimer's disease yeah and and so that's a great question to segue into the next thought which is because the front part of the brain in addition to being sort of the decision-maker and the executive processor you know it is also the part of the brain that is helping us select the best behavior and any particular social setting that we are in if you think about social situations you could be in a very in a very professional situation or in a family situation or you could be out with friends having drinks and if the same scenario or the same conversation happen in each one of these three situations you might respond differently because you're in a different space maybe you're having fun at night with your friends but you know with your boss you have to like take things seriously so so the the front of the brain as well as allowing us to process all the time what's coming at us from from the environment and be able to select what is what is the best way to behave right now given the setting that I am and so patients may start having difficulty with knowing what to do from a social perspective and a lot of them become either inappropriate in social setting or disinhibited etc and again over time this this condition progresses to involve also other cognitive domains like memory language and visual as we saw previously alrighty so I'm going to move next to talk a little bit about the neuro pathology of Alzheimer's disease or what is happening inside the brain ok so we talked about how it manifests itself and now we're gonna try and take a dive into the pathology so the hallmark as we as we saw in that first story I told you about Alzheimer as is the presence of 2 main findings one called amyloid plaques and the other called neurofibrillary tangles that are made of a protein called tau and let's take a deep dive into the brain to sort of understand better what that means so on our brain cells we all have this molecule called the amyloid precursor protein and and the amino precursor protein we're not quite sure what these do but we know that when it is snipped in ways to cause what we call beta amyloid which is the smaller sort of yellow portion that you see on the screen here these bottom units can aggregate together and form what we call a better amyloid plaque and the better amyloid plaque can come in two forms either what we call diffuse plaques like what you see on here all of these spots or what we call a neritic plaque and and both both of these are outside a brain cell because it's being this is the brain cell it's being clipped and outside of it we are having all of these aggregate together and i'm and i'm i'm i really want to thank dr. leigh Graham who's going to be joining us later today as a moderator you know she provides us with a lot of these nice pictures and images in order to talk about pathology and she knows way more than I do about this so if I make an Irish I'm sure that she'll be able to clarify that afterwards so this is the amyloid protein part of Alzheimer's disease and then there's another part awesome disease which is related to another protein called tau and tau is a protein that is usually part of the architecture of a cell so any any cell in our body and and specifically our brain cell sort of are made of a skeleton and that skeleton that sort of holds the cell together is made of proteins that are called tau and they sort of like come together in order to make these these tubules like here to like make the skeleton of the cell however at times when some things go wrong inside the cell which you are not quite sure what that something is the proteins that the tau proteins may become hyper phosphorylated meaning they have too much phosphorus attached to them and they are unable to form these really nice tubules and then instead they aggregate together and and form this unwanted sort of part of the cell and I will show you here on this scan so this is a neurofibrillary tangles here or here you can see it in black and these are actually inside a brain cell because they are the the tau protein is supposed to be inside to form the skeleton and then when it's unable to do that it a grenade inside the cell and causes contributes to causing brain cells to to die as time goes by so Alzheimer's disease is the term that we use to describe the specific narrative disease of the brain that is associated with progressive accumulation of these amyloid plaques and the tau tangles that over time they lead to irreversible degeneration of neurons meaning that neurons die as time goes by all right there are different ways in which we can stage Alzheimer's disease from a pathology perspective and let me actually start with the beta amyloid staging so we had talked about these two different types of amyloid the diffuse deposits and the neurotic plaques and then there are two different ways in which pathologists look at a brain and decide as to how much of amyloid plaque there is or what is the distribution of it and so down here you see different ways of sort of staging by distribution of the diffuse and energetic plaques inside the brain and so you know phases one to five and form us about where in the brain these amyloid plaques are being found this is another scheme by which we can sort of quantify and it's and it's by looking just at the neurotic plaques and see how dense they are on anyone microscope slide so you can see for example here there is nothing but also I think I'm cheating this is just a blank square this is not actually from from a patient but then this is when they are sparse so you see a few of them but they're not too many this is moderate where you see a little bit more and this is frequent where we see a lot more than a slide and so these are two ways in which we quantify the amyloid presence and the in the brain yes correct this is all on autopsy and occasionally very very rarely patients get a biopsy of their brain because people aren't quite sure what's going on and they think you know this might be a good diagnostic way and we sometimes find it on biopsy but most most of this are as on autopsy correct and regarding that the tau staging the Tau seems to have a much more predictable way in which it spreads in the brain and it seems to always start close to the hippocampus in this region called trans and toroidal region you don't need to remember that some of some of us don't even remember that at times and then and then it starts spreading from there to the hippocampus and then involves more of the hippocampus or and of that part of the brain called the temporal lobe and then as it spreads more to the cortex and involve different cortices it becomes more and more widespread in the brain and so every one of these has a stage which was first described by by by Brock and Brock and so we call this a Brock staging of the tau presence and the brain and and the the more the Brock staging in the brain sort of the more diffuse the tau tangles are and usually this correlates with severity of the symptoms so the more symptom or tau you have the more symptoms you have but the accumulation of the amyloid does not always necessarily correlate with the severity of the symptoms yes the question was as this moves from one stage to the other is there anything that we are that is being done for for patients that have this unfortunately we have not yet scientifically found how we can stop this disease from spreading and we do not currently have medications that have been shown to halt it in its place there are several experimental medications some of which have been are being have been tested for the past decade to try and clear the amyloid plaques from the brain and and so far we have gotten non favorable results and some patients we were able to demonstrate that the amyloid plaque has been removed but that wasn't paralleled by an improvement in disease or a stopping of the progression and there may be other factor that we still don't understand or know about this and there are other current medications also that are trying to clear the tau angle from the cells and see if we can sort of stop that from continuing to form but this is also still under experimentation and we're not quite sure where we're gonna go so but we're hoping that as we learn more and more about the biology of this and how it spreads from cell to cell and how it forms in the first place that we will be able to have more targeted medications to try and hold this process or even reverse it if we can yeah all right so so we talked about the pathology we talked about the manifestation and let me talk a little bit about the genetics of Alzheimer's disease before we dive in into ways in which we can detect it in our current day and age so Alzheimer's disease is actually rarely caused by a single gene variant this is what we call a pie chart so it's kind of like a pie and we're you know slicing it and what you see in orange here is all the cases of people with Alzheimer's disease that we call sporadic meaning that they presented to us with no family history of Alzheimer's disease whatsoever and this is the majority 75% of people and then in purple you see the the part of the slice of patients with Alzheimer's disease that presented to us with with familial Alzheimer's disease but this is also defined as also M disease and people who have two or three relative with Alzheimer's disease but they don't necessarily have a dominant gene meaning a gene that if you were to have it you have the disease no question these are a very very small portion of the pie in green here you could barely see it they are less than 1% and here you can see better the number so 75% of patients with sporadic no family sure of all same disease 24 percent of patients with familiar having two or more relatives with Alzheimer's disease and less than 1% of patients have an autosomal dominant genetically transmitted Alzheimer's disease and out of these less than 1% the majority have a gene called prison alone one sixty five percent the second group have a gene called a PP it stands for amyloid precursor protein and and the rare group have a have a gene called prison alone too and I'll talk in detail about about some of these genes soap reasonable one occurs on chromosome number fourteen so all of us have 23 pairs of chromosomes and every cell of our body and these chromosomes really contain in them the entire code of who we are you know internally on the outside everything you know it is it is the genetics that dictates everything about us and every different cell in our body expressed sometimes different parts of these 23 chromosomes so you can imagine a skin cell is very different than a cell in the heart then a cell in the brain and so these three cells have the same 23 chromosomes with all the codes however they are expressing different parts of them to become these different cells in the body so priests another one is on chromosome 14 when patients have it they can present with arzamas disease at a fairly young age usually the onset is between the age of 25 and 60 with the average age is for around the age of 14 the symptoms can be quite different than what we just talked about so it's not just memory problems but people can have Parkinson like movement problems ataxia which means in coordination and their movement they can have behavioural changes and of course it's caused the the the mutation causes build-up of amyloid beta in our brain cells and this is what causes the disease and there are a few founder variants meaning that these are the places in the world where we have found families that have this gene and so you see that it's really in very specific parts of the world that this gene is present the prisoner to remember is extremely rare so the majority of cases are presented on one or AP P this is extremely rare and it is present on chromosome 1 and again the onset is young between 40 to 75 years of age with the mean of 50 and it mostly occurs and people with German Italian and Spanish descent and again leads to build-up of amyloid protein and the amyloid precursor protein which is the second most common gene is on chromosome 21 and you know for those of you who know this down people with Down syndrome who have trisomy 21 this is that chromosome you know have three copies of that chromosome instead of the regular two that that all of us have and and somewhere because of the three copies they are at a very highly increased risk of developing Alzheimer's disease in fact people trust me 21 the majority of them if not all of them if they live long enough you know they will develop Alzheimer's disease and again this is caused by build-up of amyloid beta as well yes sorry I can't see you go ahead so the question was what is being done about the the families that have this in terms of trying to understand better that's this disease and there are studies that are looking at understanding better the biology of course but also you know trying to look at treatment in this population because what is unique about this population is that we know they're going to get Alzheimer's disease if they have the gene so even when they are young and have no symptoms and have no buildup in their brain we already know that this is gonna lead to that so this this is a great group of people in whom we can if we find a good drug that can stop or even prevent azam disease from happening in the first place this is a good group of people in home to test this and and I am aware of a couple studies that are looking at that I don't think that there is any results yet there are translatable to our community but hopefully we will have more information as time goes by of course and before we move on from this I would like to talk a little bit about April lipoprotein II or April II which some of you might have heard of and a lot of people now in the day and age of 23andme they are getting their genetic testing done sort of on their own with various private companies and they are getting results of whether or not they are quote unquote at risk for things like Alzheimer's disease so a lack of protein E as is a gene that has three major different forms and you have two copies of it because we all have like I said a pair of chromosomes and so you can either have you can have two of any of these three forms the e2 e3 and e4 and e2 is considered to be protective against Alzheimer's disease III is considered to be neutral it doesn't necessarily do anything and if four is considered to confer risk on patients who have it to develop all some disease none of these is positive so so you do not you do not need a poor effort to have Alzheimer's disease and also having a point for does not mean that you will develop Alzheimer's disease so this is not a cause it just increases the likelihood or the risk that you may develop it given maybe other factor having efore may mean that you develop a stem disease earlier in life than people who don't have the apoe4 but like I said it's not necessary or sufficient for the disease and we actually medically speaking do not recommend for people to get their a pony for gene testing and know what their status is because we may not have any recommendations to give you one way or another so this is just showing what the majority of people have and as you can see most everybody in the world has at III III so ii III 61% of people about 25 percent have at least one April F or or two and then the rest they have like e 2 or e 2 e 3 and this is just to show you the risk of Alzheimer's disease this is the risk if we don't look at genotyping whatsoever so it's about 10 to 11 percent and men and 14 to 70% in room and this is lifetime risk so at all ages having e 2 as you can see can be protective so the the rest becomes less 4 to 5% or 6 to 8% and women having e 3 is kind of neutral so it doesn't really change the percentage that's much but when you start having efore that's when the percentages increase both in men and women so in general 1 1 cot 1.e4 copy is associated with an 18 to 35 percent lifetime risk of Alzheimer's disease and to e4 copies are associated with 31 to 40 percent of lifetime risk of Alzheimer's disease and and before I move on from this I just want to thank our genetic counselor Jamie Fong you know who does a lot of great work with this and she actually provided me with most of the information on these slides I just want to say thank you to her alrighty so we talked about how it presents we talked about what it looks like in the brain we talked about some genetic factors that can affect that let's finish by talking about well how can we detect or be more confident about Alzheimer's disease when when you know when we are still alive and we're not doing an autopsy so in our day and age we have biomarkers of Alzheimer's disease which are kind of like a proof of evidence of how I like to think about it having a biomarker that is quote-unquote positive increases the certainty that whatever syndrome you're seeing so the memory problem or the visual problem or the language problem is indeed being caused by Alzheimer's disease and biomarkers fall into well three categories there are biomarkers for amyloid deposition where we can detect whether there is amyloid pathology and these come in two forms you want to talk about one is measuring the amyloid protein levels in the fluid that is around the brain and our spine if you can imagine at all times our brain our spine are actually floating inside a cavity and our brain that is filled with a fluid and this fluid is called cerebrospinal fluid because we're not very creative and and that cavity extends from from the skull all the way down to the spine and people here who have gotten or have seen people got an epidural no this is what a spinal tap is and I'll show you in a little bit some images about that but this is where we get that fluid from and we can test it for amyloid markers and I'll show you a little bit what what the findings might be or another technique for amyloid is doing a PET scan which I'll describe in a little bit and and checking whether there are amyloid plaques or amyloid depositions in the brain the second biomarker which is sort of really state-of-the-art and is still under investigation but it's really promising is a PET scan for that for tau protein and it's a PET scan that can allow us to visualize or to see a biomarker of tau depositions in the brains of people of Alzheimer's disease and then the third type of biomarker is really biomarker of neuronal injury meaning that it may not necessarily be specific to Alzheimer's disease in the sense that it's not showing us the amyloid plaques evidence for that or the tau tangles but it is telling us that brain cells are dying and and we can see this again in cerebrospinal fluid or what we call CSF and I'll show you in a little bit or on an MRI like what I show you earlier a scan of the brain or in a PET scan that is being done with just sugar to see how the brain is eating and utilizing sugar and we'll talk about all of these things all right so let's start with the cerebrospinal fluid of truth as what I call it so this is how a lumbar puncture is done so we go with a needle in the lower back of a person after of course we've cleaned it really well and we view them anesthetic so that they don't feel the pain and we go in the space that is so this is the the the your vertebral bones and then they are there to protect that cavity that is filled with that fluid and that the spine is n-now where we go and the needle the spine has already sort of ended but there are nerves sort of going down so we're not at risk to injure this the spinal cord that is extending from the brain but we just want to get to that cavity in order to get the fluid and that fluid is in continuum with the fluid around the brain so it's really the same it's one pool and and the fluid is all the time sort of go passing through this entire pool so it contains information that are also important to the brain and once we get this fluid we send it to the lab and it comes back with a report where they show us the levels of the amyloid protein and the in that fluid and the tau protein in the fluid now this may not make a lot of sense but bear with me if amyloid protein is low and the CSF fluid this is the marker for Alzheimer's disease and we don't quite understand this biology really well you know but sort of the way that I try to think about it to sort of make sense of it is that if the if the amyloid is forming the plaque then not enough of it is circulating in the fluid for us to detect it so so so keep that in mind you know the if the amyloid level is low then this is a biomarker of Alzheimer's disease and if the tau level is high this is a biomarker of neuronal loss so it's not a biomarker of tau that position necessarily it doesn't necessarily tell you that there is tel tangles in the brain but it tells you that brain cells are dying and as they're dying they are exploding and and putting all that tau protein in the fluid and this is what we are picking up okay and what's what's really nice about doing a spinal tap or a lumbar puncture is that we can also measure for other things that that sometimes may be causing memory problems and aren't Alzheimer's disease like inflammations and the brain infections of the brain tumors lymphomas things like that you know so getting a sample of the fluid allow us to test for other things that aren't Alzheimer's disease and that's that's always you know nice and it complements the workup now let's talk a little bit about the PET scan and I want to really thank r''l as well who you're gonna meet in a little bit he's gonna be part of our panel as well because he gave me all of these slides and you know it's way more eloquent than I am but I'm gonna try to do a good job explaining this so a PET scan stands for positron emission tomography and so it's it's a it's a complicated process that we're gonna try to simplify basically we have a certain material whatever it is that we want that we tagged with a substance that's radioactive so something that's radioactive is sort of all the time sort of emitting a positron which are you know just little like nuclear molecules and then we inject the blood with that substance and then that substance goes through the blood and reaches our brain because it's in the blood you know and our brain is receiving blood all the time from the heart and then depending on what we tagged it will it will go to places in the brain so for example if we put a piece that fits on to the amyloid plaque and then we tag that piece with something radioactive the piece will go to the amyloid plaque and then we'll emit the positron and then that complicated machine will detect the positron and say aha you know I see that you know this this molecule that you tagged is hanging out in the brain whereas if there's nothing in the brain it's gonna pass through the blood go to the brain find nothing to latch on to then be cleared and then we take an image and nothing's gonna happen we're not gonna get any positron does that make sense great so it really depends on what you what you injected with so we call we call the thing we injected with a tracer because it's really like going and trying to latch on to the thing that sort of like looks like it so you could have an amyloid tracer or at our tracer or we see in a little bit you know we could just have sugar that is being traced and tagged with with a radioactive material all right so when we use an amyloid tracer here's what happens so it goes to the brain if there is amyloid it will latch on to the amyloid and they were able to detect that on the top part here you see a PET scan and emulate PET scan of a patient that doesn't have Alzheimer's disease and and if you if you look at the colors anything that sort of like dark or blue means that nothing what was taken up so there's a really low uptake of the tracer okay and then the more you sort of go and the colors of like yellow orange and red then there's really high uptake so this is a patient that does not have Alzheimer's disease notice that there's a little bit of uptick here and what we call the white matter of the brain the white matter of the brain is usually on the inside not on the surface and the best way to think about it is it's all the wires that is connecting different brain cells to each other as opposed to the surface of the brain while most of the brains live and then down here you see the scan of a person who has Alzheimer's disease and you can notice the huge difference between the two where now there's a lot of uptake and you don't see any differentiation anymore between the white matter that's on the inside and the gray matter that's on the outside and so the entire scan sort of is is what we call hot you know it's there's really really high signal and this is because that tracer went and latched onto all the amyloid plaques and is giving out all these signals and and this is just to show you the correlation of the amyloid pet-scan with actual autopsy results so this has been done on 179 patients who died three years after they got a PET scan and then we did autopsy on their brains and and notice how the PET scan starts exactly as signal as early as remember earlier I showed you this different phases so for the Tull phase as early as sort of phase 3 maybe even with 2 we start seeing a signal but really 3 4 5 and then for the Surat score when it's moderate and frequent at the PET scan is really detecting it so it's it's really faithful and correlates really well with autopsy so it's a very specific way to detect amyloid plaques in the brain now the tau pet is a similar concept where instead of the tracer latching onto the amyloid plaque it's gonna latch on to the the tau protein and and this is still not as well refined as the amyloid PET scan and it's still being under investigation because we are finding other molecules in the brain that what we're calling the tau tracer is latching onto so the top tracer doesn't seem to be right now you know as specific to the tau protein but it's latching on to other things however in Alzheimer's disease it is actually incredibly specific and that's primarily because there's a really high signal of tau in the parts of the brain that are affected by Alzheimer's disease that I showed you earlier the hippocampus the seahorse the parietal lobe the temporal lobe etc so it's still being refined but I hope it's a very promising technique and what's really nice about it that how does correlate with symptoms as we talked about earlier so I think it's gonna provide a really great insight once it is very well refined about sort of where we are in the disease stages all right and finally this is a PET scan that is when people just say PET scan usually that's what they mean and a lot of people might be familiar with PET scan from like the cancer world or other other medical fields and so this is a PET scan that we call fdg-pet scan it's basically a molecules of sugars that are tagged radioactively and what we are looking for is how different cells in the body and in this situation brain cells are eating up the sugar and so healthy cells should be eating the sugar really well because they're taking blood and there are sort of feeding of the blood and so we are supposed to see high signal as you see here in a clinically normal person you know you see high signal all throughout and it's it's hot all around because we kind of want it that way you know we want it we want the sugar to be sort of utilized in the entire brain and then for somebody who has Alzheimer disease that may have lost brain cells in these areas so that's sort of the temporal lobe here parietal lobe there you see that you start losing that nice signal here it it's not being there is no uptake as much as in the other parts of the brain and that's because the cells are not functioning well enough to sort of take take up the sugar so that's another way in which we can detect no injury but this is not specific to either amyloid protein or the tau protein all right so to summarize so here are the the few things to hopefully remember from all of this if you don't remember anything else the the neuropathology hallmark of Alzheimer's disease is accumulation of amyloid and tau protein inside the brain Alzheimer's disease can lead to significantly different clinical syndromes and patient can go through distinct stages from silent disease or asymptomatic tumar cognitive impairment to dementia not all patient with mouth cognitive impairment or dementia unnecessarily have Alzheimer's disease less than one percent of the cases really are genetically dominant and then there are modern biomarkers that can improve the accuracy of our diagnosis but currently the autopsy remains the gold standard of sort of confirming the disease so thank you so much everyone I acknowledge all these people who helped me put the stock together thank you all right thank you very much so now we're gonna open up the space for some questions and today we have two guests we have dr. Leah grin grin burg who as I said before is co-leads our neuropathology core so she would be the person to ask questions around neuropathology we also have her know Renauld la joie is that correct - Wow good I think I didn't say it correctly last time who's a neuroscientist in our Marine Center and his is focused on doing research on the biomarkers especially that fed by America so he would be the right question - bright person to ask all the questions around pets and then clinical questions who our colleague dr. Hassan so the last time I started with questions in the front row and went back row by row maybe today we can start with a back row and go to the front and to kick off the questions maybe I have two questions to get the engines going maybe the first one would be for or not so maybe you can help us understand the difference between the sensitivity and the specificity of tests and how that pertains to PET scans and you know within the context of AD and and then what are the limitations basically of these PET scans and thank you for the question and thank you for inviting me I'm very happy to be speaking in front of you today and addressing some questions you saw nice images and I'm trying to talk a little bit about what can be complicated about using these images so you mentioned sensitivity and specificity these are two terms that we use a lot in the biomedical field there are like basically complementary measures to kind of measure good a test can be to detect disease and an ideal test would always detect the disease when its present and oh it would always tell you oh there's no disease when the disease is not there but we know that no test and medicine is like this so the sensitivity is very important since it's a sensitive test is a test that's going to actually tell you when the disease is there it's gonna wonder when the patient has a disease the test is going to be positive it's gonna be uh-oh there is something going on with this patient so you want a test to be very positive very sensitive but also you want your tests to be very specific because the specificity is about being able to rule out the disease when there's no disease so you also don't want a test that's going to be positive and every one you want it to only be positive when there's a disease and so this is like the trade off of any biomarker in medicine and that's really a struggle for us to find tests are both sensitive and specific and so I think George showed a nice data on amyloid pet and comparing amyloid results to autopsy data which is our gold standard and what I can tell you is that amyloid pet I'm lode imaging is a pretty sensitive measure and it's also very specific meaning that when we have the signal on images almost all the time it means there's amyloid in the brain but amyloid pet is a great measure of amyloid plaques and I think George made a very good point in explaining that alzhiemer's disease is not just unload its amyloid and tau so actually we're having issues of a lot of people who can be cognitively normal and actually have unloaded in their brain we've known that from pathology studies we can see that now with imaging but amyloid is not a lommers disease so the test itself amyloid pet is not very specific to Alzheimer's disease it's specific to unload and I hope this distinction is very clear good great and I have a question for dr. Greenberg also to get get us thinking about other questions that may come up we've presented so far you know purposefully a way of thinking of these diseases in a structured sort of simple way but as you and we know there's far more complexities to this right so you that are seeing the brains sometimes stumble on a patient has reached autopsy for example there has been characterized clinically as having one of the variants of Alzheimer's disease but when you look inside of the brain you may find that there isn't real evidence of Alzheimer's disease so I want you to talk a little bit about this dissociation that sometimes happens where a clinical syndrome looks to be you know pointing towards Alzheimer's disease but we find that different pathology and that's because that's something that my colleague next week is going to expand a little bit more about and what does that mean to you and how much the history matter in your evaluation is a neuropathologist okay so I will start saying good evening to everybody and thank you for coming here it's really a pleasure to be talking to you and this is a very relevant question we pathologists we have this joke that we are always right but we are always late and most of our research revolves around of not only learning what is the process going on in the brain when someone develops dementia but what we can do to be better in predicting what is causing the men showing leaving patients so we will be able to treat and because of this kind of studies we also cause a lot of confusion because the more we learn we change the naming the nomenclature so if you've been here three years ago probably you are hearing something slightly different this time because we are evolving very quickly and one of the things that it's very clear when we do this kind of studies in which we have the opportunity to contrast what we see in the brain with the clinical history is that we have a lot of patients that will come to our clinics and they will say they fit the bill for oxeye more disease they start having memory problems and they evolve in the way we see we associate with Alzheimer disease but actually when we look at the brain they have something different so what are these things that can cause something that's very similar to octamer disease the first one of them and I think it's very important because it's very prevalent and we don't talk a lot about it is what we call vascular dementia so in the same way that when our vessels are not good and we have heart problems we also have brain problems and these brain problems they look a lot like ox Amer disease in most of the people they will have a combination of plaques and tangles and these vascular changes in the brain and the more we put these things together the worse it is so everything we can do to prevent vessel problems blood vessel problems it will help the brain so this is the first thing and the second thing that's becoming more evident from us and we have been learning there's a lot in the news about this athletes especially football players they have what they call this repetitive brain injury and these leads many years later to a disease that we call chronic traumatic encephalopathy have ever heard about a very complicated name and we have been learning that people that had brain trauma not as severe as these football players maybe you know because they had they were in car accidents in the time we did the new safety bell or you know they were even in amateur sports that they would have some kicks in their head it might predispose to dementia later on in a way that looks very much like Alzheimer disease clinically so it opens show us a lot of opportunities because both of the conditions I told you about they are preventable in a way so we feel that only by preventing these two diseases we can lower the incidence of dementia by a lot thank you so much for these insightful responses and also one of the sessions that we have in the future is gonna touch on prevention as well so I thought maybe we can start with that last row and go in order some questions in the last row yes sir great question the question is what is it about these regions of the brain that makes them have a predisposition for Alzheimer's pathology who wants to take that question it's an area of research I can take that question this is a I think one of the most important questions that we are trying to solve nowadays we call this phenomenon selective vulnerability and the question is why some neurons in the brain they are more vulnerable to a disease and other they are resistant to the disease and truth is that we don't know very well so what are we doing to find out so the first step is really to map to understand what's going on to identify which are the neurons they are more vulnerable and which are the neurons they are less vulnerable and this seems relatively simple but it's not and the reason for this is because one of the only ways we can do it is by doing post-mortem studies because imaging although it's getting better and better each day it doesn't have the resolution yet to see single cells and most of the brains that come you know to our hands to research they are donated by research participants that we enroll in a memory clinic so they already are very sick by the time the brain gets to us so it's very difficult to really understand early stages of the disease but we do have some of these brains and then with these brains we map which cells go first and in the past we used to do biochemical studies immunised or chemical studies to understand what they have but now we have much better tools for instance one thing we are using nowadays it's called single nucleus RNA sequencing so we can nowadays put barcodes in each one of the cells we are studying and then do netic studies or any other cambio chemical studies and understand what is coming from each one of these cells so by doing this we we are comparing what are the difference from this vulnerable cells to these know vulnerable cells because the idea is to create treatments that can create a shield in the vulnerable cells so they won't be successful to the disease great I will just add briefly and I learned something every time I listen to Leia talks thank you I would just add briefly that you know there is progressively more evidence which is still at the infancy stage like I think there is more work to do to demonstrate that but people are starting to see that sometimes when patients develop the syndromes that aren't the memory syndromes like say the language syndrome there is a portion of these people that have all their life had some sort of a language problem maybe they had this lecture when they were younger maybe not and that doesn't mean that people with dyslexia will develop us on this but but it seems like they are represented in that population and a much higher frequency than what you would expect just by chance same for people who have the visual syndrome there has been some it's mild evidence that sort of remains to be proven that they may have had some like eye injury or some eyesight problem or something that sort of led to that region of the brain being weaker or more vulnerable and so when the disease does hit for whatever reason that we don't understand it is hitting these parts of the brain first as opposed to the hippocampus which is what we think of as maybe the default part that should be hit by Alzheimer's disease yes see just one less word about this I didn't think about it until you start to talk about differences between people and some factors that can make some people more vulnerable I think George mentioned this gene that is a risk factor for Alzheimer's disease April especially the apoe4 form of the gene and we know that it's not just a random risk factor for the disease it's a risk factor specifically or more strongly for the amnestic form of the disease and when you look at patients with the the language variant or the visuospatial variant actually they don't have that gene so much so we think that the gene a way for it really makes your brain more vulnerable to Alamos disease but especially this like hippocampus system and this amnestic form of the disease so I think there's a there's a mix of genetic factors in the process I think we have a question in the back lady in the back yes great question the question is if at the very last stage of dementia do all syndromes develop and maybe dr. Nathan can address how the disease changes as dementia advances yeah this is a very important question and I think a really difficult one to answer for many reasons and I'll say why but you know a long time ago when I was a medical student and learning about this I think people thought that yeah as dementia progresses all the Manchus will eventually look the same because they're gonna affect you know the entire part of the brain but I don't know necessarily that we see this and and Leia can talk more about sort of the pathology but I think what happens is that the parts of the brain that are the most affected become if affected enough that you might not be able to see anymore if the other areas are still active or not then let me give you an example which I think we mentioned briefly for the language if somebody is having a language problem and that gets advanced enough that they are mute or unable to communicate we're never gonna know whether this disease progress to affect memory or not because there is no way that we're gonna be able to ask them to remember something because they can't communicate same if somebody can't see things can you know leave the room can do something it it might be difficult to think well gee are they're doing this because they cannot find their way or is this a behavior problem so I think the symptoms start clouding each other as the disease progress and and I do think that as we become more specific about diagnosing these we need to be careful to provide the correct matched support for patients having in mind what is the predominant symptoms that they have taking that in my turn I guess do you want talk about pathology also so thank you for our question even at early stages of the disease it's not that the whole brain is affected we still have many areas of the brain they are preserved in the case of Alzheimer disease it's a very long disease because the areas of the brain they are important for our survival get the fact that very late in the disease but then even at this point we don't see these areas affected and just to make a contrast this is the complete opposed to the Lou Gehrig disease amyotrophic lateral sclerosis because in this disease the areas that we need to survive for reading and motor control they are affected very early so unfortunately the person will pass because of this even with all the cognition still doing very well so depends on the area and even at late stages it won't take the whole brain so let me just add to this and and sort of summarize the concept which i think is an important concept we have to keep in mind throughout the series that these diseases like I explained the in the first lecture are focal in onset meaning that this certain like dr. Greenwood just explained certain areas that are affected earlier and therefore we if we see patients early we can pick up on the signs and symptoms that take us to that region of the brain and then make us think of what is the pathology that may be getting there but as the patients advance in their disease these substrates these protein OPA these they will travel to different regions of the brain or expand and therefore the clinical syndrome will change and therefore a person that begins with a just animistic presentation over time will have language problems will have visual problems and if they live long enough with this disease then as you just heard there that disease is gonna start affecting those vital centers of the brain that control things like walking swallowing breathing unfortunately this is this is when things get complicated there's a next row so yes sir so vascular dementia is a different cause of them I think what we were hearing about earlier is that what I was trying to introduce is the concept that oftentimes especially the older the patient is it's not always very clean meaning that it's not like you only have Alzheimer's disease in your brain Alzheimer's disease as we advanced in age tends to be accompanied by vascular changes as well so we would say this person had both Alzheimer's disease and vascular disease causing that person's dementia does that make sense I would say there's a fair statement for for especially for patients over what age you would say ruff I think maybe the right statement based on evidence we have right now is that they are so prevalent both of them they often they happen together there are some questions if they will feed each other you know synergistically I don't think we have super strong evidence to say yes or no but certainly they are very prevalent they work together so we know that and this is proposed Martin studies that's very possible for someone to pass away with a lot of amyloid and tau in the brain without having any symptoms however it's not possible to see the same situation if the person on the top of it has also these micro vascular changes in the brain so if the brain structure is not doing well to start with because there is lack of oxygen and no it's the same situation for the heart so the brain has more difficulties to you know overcome this accumulation of proteins there so and again this is preventable in a way maybe over here move forward yes so this will we'll discuss more in in a subsequent session but I can say that diabetes is recognized as one is the one of the risk factors of cognitive impairment late in life there's many it's an association and we have some hypotheses as to why one would be that diabetes leads to vascular changes in the brain just like it does in the heart in other parts of the body yes sir and then we'll move this way that's a great question so the question is how do we think I was here was amount of fluid and why does it contain proteins in the first place that we are measuring so it's a fluid that like any fluid in our body is composed of different types of molecule and things you know like for example if you take a sample of your blood in your blood you can measure various different things you know sodium level potassium level enzymes etc and so the cerebral spinal fluid is another type of fluid you know it's not blood but it does contain a lot of information about the cells that are in the brain and the spine and it can contain first of all cells like cells that are there to protect the brain so if there's an infection sometimes the number of cells will be really high in the fluid because they're all becoming to the rescue of the brain it can contain blood if you're bleeding somewhere it will it will sort of appear and the surface mount of fluid and it can contain different types of proteins that if you're not measuring them you won't know that they're there but if you measure them that you can know the level of them and so one of them is amyloid and so normally all of us if we were to take a sample of everybody here from their silver spinal fluid we will have an amyloid protein level and it's usually pretty high and like the 800 is sort of the number you know and then if if that level the more that level decreases the more likelihood that we have Alzheimer's disease going on but you know or I guess I should correct and say amyloidosis going on meaning that there's like an some sort of amyloid protein process happening in the brain does that help frame that a little bit were employed in the system and in the circles fluid anymore so this is how we understand it is amyloid starts to get solid in a way and it deposits in this blocks so there is less amyloid to voted a spinal fluid if tau is the opposite tau is inside the cell and starts killing the cells so when the cell is killed this tau is released so you have an increase of tau in the spinal fluid okay one question here and then we'll move to the next row any further there Alzheimer is a human disease what we have in primates in some of them we can have accumulation of amyloid with not necessarily a cognitive decline I had the opportunity once to examine a collection of very old chimpanzees they were almost over 40 years of age which is very odd for chimpanzees and they only have tau in very specific structures of the brain stem which is this part of the brain that's in our neck so they don't accumulate it they don't accumulate also in rodents even they are annoyed itself so when we produce animal models to study Alzheimer disease we have to in artificial way add these proteins there because they don't occur naturally but finally dogs they accumulate amyloid and it caused them to get blind when they get older and some dots they also can get agitated because they are not seeing very well and they get anxious and they can bite so this happens to dogs a lot is it is it due to amyloid a community in cortical emulator it's a true amyloid accumulated specially in the areas that control vision right and actually newman's we know that has this tendency to accumulate in vessels in the visual area too so it's a vulnerable area for ambulating dogs and humans here we'll go down this way I don't think so not that we have a very solid scientific evidence for however that being said there is more and more studies being done on the retina and changes that happen in the retina that might reflect changes that are happening in the brain in many ways the eyes are just a part of the brain so it's an extension the direct extension of the brain and so there's there's a lot of theories that you know changes that are occurring in the brain could be displayed or could affect the eyes and there are there's there are other neurodegenerative disease and which I think we are starting to have more evidence so I don't know if you guys will talk about Lewy body disease and another session yes yeah but Lewy body disease is another type of neurodegenerative disease that causes brain cells to die as well and can look like Alzheimer's disease at times and there's progressively some evidence that there are changes in the retina that are very similar to the changes that we see in the brain and Lewy body disease and so I think that this is this is something that hopefully we will learn more about as time goes by and more scientists look at that all right I think I've been alerted that we have time for one more question maybe going down the road to be democratic so the question is what's the association between hearing loss and the brain and why are we treating hearing loss in the first place if that doesn't treat the brain I think having hearing loss may predispose some parts of the brain to be vulnerable to disease because they're not being stimulated by sound when you don't receive enough sound to process it inside the brain and so in the same way that becoming blind might be dispose the visual parts of the brain to to degenerate because they're not working not hearing you know might be disposed the hearing part of the brain to also to generate but that being said if you do have a few cells that are still working to try and understand language or what's happening in the environment it would be great to help them by making sure that they are receiving clear sound and clear speech so I think the hearing aid is is important in a therapeutic way and I do spend a lot of time and clinic you know trying to convince my patients why this is important and I think it's exactly for that that even even if it's not necessarily treating the disease itself whatever remaining brain cells you have that are really doing as much as they can to support your cognitive function it would be great to not make them work even harder to like hear but but allow allow them to receive the sound as clear as possible does that answer your question understand I mean brain cells or not the only half of them right now working on fearing the other have to go to something else what do you think Leona doubt neurogenesis or neuroplasticity is something that's still very controversial we don't know exactly how it happens and if it happens but what we know is that the neurons have the capacity to try to work harder at least for a certain time to overcome the disease at least in early stages of the disease so what we see biologically in exam or disease for instance is when a region of the brain gets affected instead of going down internal function it goes up at least for some times and then you know it cannot cope with this anymore so in a way it's a kind of plasticity not more neurons but certainly a higher functioning of these neurons but I think we have still a lot to learn about it and again one of the issues in studying this has to do with this difficulties in getting to research individuals that don't have dementia but they want to participate in this kind of risk and with that hint that we need volunteers so it's great to have you [Applause] [Music] you

Channel: University of California Television (UCTV)

Views: 33,388

Rating: 4.8382025 out of 5

Keywords: Alzheimer's, dementia, Neuropathology, AD

Id: C7NQahSxDkk

Length: 87min 27sec (5247 seconds)

Published: Sat Jul 27 2019