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Transcript for October 2015

>> All right, so we're recording. So I'm very happy to introduce our guest presenter for tonight's [inaudible] from the department of psychology. Also, I'm going to talk about cognitive changes and the effects of daily functioning and other [inaudible] for dementia. And Paul and I are people that know each other for around ten years now. We came to SCSU at the same time, and we've talked a number of times about this program. I've served on our masters committee for college students. They've really gotten to know his [inaudible] value the work that he does. So I'm very happy to have you join us and talk a little bit about what you do to really kind of introduce our students to the area of cognitive disability. So welcome.

 

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>> Great. Well, thank you very much. So thank you all for taking the time to come to listen to the presentation today. And please, if you have questions during the talk, feel free asking formal in this discussion as possible. So I'm going to talk about the cognitive changes we see in people who have Alzheimer's disease. And to give you guys an idea of what Alzheimer's is, I'm going to take a step back in the life span progression of the disease and talk about a stage we call mild cognitive impairment, also called mild neurocognitive disorder in the new DSM5, but we won't get into the DSM5 criteria. And it also talks about how this relates to daily functioning. So do these cognitive changes received in individuals affect the way they function in daily life? So it give you a few statistics here on Alzheimer's disease. So it's most common cause of dementia for people over the age of 65. So dementias not an umbrella term. Under dementia there's also other types of cognitive disorders. There's HIV related dementia, there's [inaudible], vascular. Alzheimer's disease is just one example of that. In the common media they often equate Alzheimer's to dementia so they're really not exactly the same thing. And there's 5.2 million people diagnosed with AD in the United States. 5 million of these people are over the age of 65.

 

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This is typical weight onset Alzheimer's disease, so slower progression develops later in life. There are about 200,000 cases are under the age of 65. And some of these cases involve fully onset Alzheimer's which is much more genetically based and can begin in the 50's. We'll focus mostly on the late onset dementia in this case. So one in eight individuals over the age of 65 carries a diagnosis of Alzheimer's disease which is a pretty significant number and it's estimated that the numbers going to rise from 5.2 million to 7.7 million by 2030 and up to 11 to 16 million by 2050. For me that's very selfrelevant if you do the math. I'm 43, it's a little concerning. So the greatest risk factor for Alzheimer's disease is increasing age. The older you get the more likely you are to develop Alzheimer's disease. The prevalence rises exponentially between the ages of 60 and 90 years of age. There's some other genetic factors. If you have a positive family history, specifically a firstdegree relative of Alzheimer's your [inaudible] goes up, your risk goes up. And also Jean will talk about later that's not causable by any means but it's a risk factor. So here's something for the health care perspective it's about in 2015 they're spending about 2026 billion, with a B, dollars, on the treatment and care for people with Alzheimer's disease.

 

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This is projected to go up to about 1.2 trillion by 2050. So you can see there's been a lot of health care expenditures going toward the treatment and care and management of people with Alzheimer's disease. And there's some estimate that if you could delay the onset by five years, develop a treatment, some kind of intervention that could take the individual from developing at 65, pump that up to 70, you can be saving around $367 billion of this 1.1 trillion by 2050. So right now we really want to try to find early preventions to slow or change the course of the disease we're going to talk about. So just to give you an idea of general symptoms of Alzheimer's disease  and if you think one Alzheimer patients looks just like the next patient that's really incorrect. Patients are very dramatic in their clinical presentation. But one thing that's hallmark in Alzheimer's disease is memory loss. And we'll talk a little bit more about this at the top. These people have amnesia or inability to remember what seemed to happen in the past. Not so much the very distant past but more recent past, and also learning new information. They have encoding problems and they have retrieval problems. And they also have maintenance problems. What they do learn they tend to forget. We'll talk more about that. They show disorientation, space, and time. They get lost often times especially if they're going to the store by a new route. They always take the same route walking down their street they usually can get there okay. Something changes or some construction, have to take a different route, that can really throw them off.

 

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In later stages they could become so disoriented they get lost in their own house. They also can be disoriented in time and that they'll do things at the wrong time of day. They might make breakfast at night for example. [Inaudible] up in the night sleeping during the day that's [inaudible] disorientation as well. Personality change is fairly common. You don't really know which direction it's going to go, but people can have just personality change where they could elude problems as well. Language problems are common. They have problems finding words, thinking of words, kind of tipofthetongue phenomenon experience called aphasia. So we won't go into any detail. They have the inability to execute motor activities, so slight having to function. Basically if you ask show me how you do something like comb your hair they have a hard time doing it. So if you ask them to do it they have a hard time showing you, but they're capable of combing their hair if they wanted to. This is called apraxia. They have problems recognizing faces and objects. So as these get more and more substantial like problems recognizing objects telling you what it is, what it's used for, even recognizing familiarly odd spaces. [Inaudible] are called executive functions. Some examples of executive functions are planning and problem solving. We'll talk more about this later as well. And then mood problems, anxiety, and depression are common. So but the symptoms one thing to keep in mind is these symptoms have to cause significant impairment.

 

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So it really have to cause functional problems and activities with daily living. They also have to cause, can cause, or usually do cause social problems or occupational function. If they have problems in their job, maintaining their jobs if they're still working, and problems with social interactions as well. And the thing about Alzheimer's disease another dementia that differentiates things like strike is the cause of these has to be characterized by gradual onset. People don't develop Alzheimer's disease overnight. This is something that develops over the course of weeks, months, and years, and its character [inaudible] will continue to decline. These people will start accumulating symptoms, will get worse and worse with time. And the last thing that's real important to find out is what are the causes of the impairment. Older adults who get very depressed can show significant causes in a [inaudible] test. And that should look like they meet the criteria for early Alzheimer's. You treat the depression, cognitive symptoms go away. So ruling out depression is very important. One will often have things like thyroid problems and vitamin deficiency like specifically vitamin B12. Vitamin B12 deficiency can cause cognitive impairment that's worse in older adults. Any questions about the symptoms? Okay, again, we'll go over how we assess these and measure these in the next few slides. So diagnosing Alzheimer's disease is challenging. Someone has diabetes look at blood glucose level. Passing blood glucose level over 100, yep, you got diabetes. What are the test they got for Alzheimer's? You can't give them any single cognitive test, can't give them any single medical tests.

 

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You can't do a spinal [inaudible], cerebral spinal fluid. And, you know, these things give you definitive diagnosis. Then we're going to make a definitive diagnosis through autopsy by going in and actually counting the pathologies under a microscope. If you have a certain number you know it's Alzheimer's. So a living patient we basically give a diagnosis of probable ID, okay, or major [inaudible] disorders. Let's call them DSM now. And this is based primarily on neuropsychological assessment. Administering cognitive test we know how people should perform based on norms and see what these people thought are relative norms. We'll talk a bit about that. And more and more  and so these are some examples of some these standardized [inaudible] test I've administered. Participants sits at a table, completes a bunch of paper and pencil test. And now imaging is being used more and more in the diagnoses of Alzheimer's. I'll show you some examples, but right now we're doing structural known imaging. And it's not that we can necessarily look at this and say okay, yeah, that brand looks like Alzheimer's, but you can look at it and say okay, it doesn't look like other things. We don't see strokes, bunch of micro vascular veins. We don't see a brain tumor in there. We don't see pathology consistent with other things that look like Alzheimer's disease. So neuroimaging it's structural images are mostly used now that will rule out other issues. Okay, so what is a neuropsychological profile? So what we do in my role is neuropsychological assessment. We give people tests. They've been given to hundreds of people. They've been norm for things like age, education, gender. So if we give this to one specific patient we can say okay, is this patient in the normal range, are they border line, are they minimally impaired, severely impaired, or are they above average.

 

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So we know based on the norms how these people should perform. Maybe talk about norms at all [inaudible] take the test, okay. So the neuropsychological profile looks like this. Memory is the key feature of Alzheimer's disease, so we expect to see memory loss on these tests. We expect to see poor learning, poor encoding. They have problems learning new things. They also show rapid forgetting. Once they learn something they tend to forget this. And we  a lot of test we use are test with a little lack of list of words, for example. We test them over and over to see how well they, we give them a label and see what they remember. So these people will often learn stuff and then when we test them with a label forgot a lot of what they've learned. We look at recognition versus recall. Recall is just tell me what you remember from the story you read as part of the test or from a list of words you heard. So you just have to think of the things they remember. Recognition is when you might give them some kind of a clue. Is this something  a word you saw from the list or not. So outsourced patients don't benefit from recognition. So if you give them words or words that I suppose is on a list they don't tend to benefit from that if they have recall [inaudible] because they're getting this poor maintenance.

 

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They don't remember it so these cues don't really help them. Verses patients like Parkinson's patients, Huntington's disease patients, they benefit from that recognition because they learn things, they maintain things, and so those cues help them recall what they learned. And you also see a lot of interference. These people put words  tell you they remember words that was not actually on the list. These are intrusions. So if you have a lot of problems with things intruding into their memory that shouldn't be intruding. So intrusive language, these are basically domains that assess. Assess memory, we assess language. These people have problems with object naming. I'll tell you about test of  lots of naming test we use a lot. They're showing these black and what drawings of objects. [Inaudible] what is this? And we call this confrontation naming. So basically confronted with a picture and they have to tell you what it is. They also show problems with verbal fluency. We have some real simple tests will tell them think of all the words you can think of that begin with the letter F. So we have to go to the sematic storage of all the things that begin with the letter F and say the words that come to mind. And semantic influence is just give them a category, animals. Tell me all the animals you can think about. So one of the things happening with Alzheimer's disease is there's a lot of that semantic network. That network in the brain where you store semantics, facts, what things are, what they're called, what they look like. That network starts to degrade and so you don't have access to that semantic memory. So the next thing we would access would be attention domain. So attention domain is just being able to focus attention, shift attention. And in the early stages the stage to focus attention, attention is pretty good in Alzheimer's patients.

 

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So if they'll focus on one test they can usually pay attention quite well. You can contrast that with developmental disorders like attention deficit disorder where I can't maintain attention. With Alzheimer's that focused attention is pretty good in the early stages. When they have problems with that they disengage and shift their attention. So if they're paying attention to something that have to change, they'll pay attention to something different now, that's when they start to have problems even early on the disease course. So they have problems maintaining attention later on and really shifting and disengaging attention early on. They also have visual spatial problems being able to just perceive space visually. So they have problems doing construction tasks. A very specific example is you give them a picture, it's a little red and white design, and you give them blocks that are red and white, and they basically have to construct their blocks to match the picture. It's called the block design test. Sometimes you might have to look at a picture that's kind of a complicated picture and draw it. And you see how they go about drawing it. And that's your visual spatial impairment. So this is also very common in Alzheimer's patients. And finally executive function. So again these are real frontal lobe kind of processes like planning, problem solving. Very [inaudible] you may have seen is the tower of London test. There's these three pegs, those little three to five kind of test.

 

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Different disk. And you have to move the disks one by one from one peg to the other. There's rules to solving the tests so you have to get all the disks from one side to the next moving just one at a time. And there's also Wisconsin card sorting test you might have seen where you have to sort cards according to different rules and you switch the rule on them. So they have to be able to plan, cope with new rules to solve the test. So this gives you kind of idea of the domain's recess in neuropsychology for Alzheimer's and the kinds of test these people impair. All right, so the other key to Alzheimer's disease is these cognitive systems have the things hacked on daily function. Patients with Alzheimer's disease even in early stages show impairments in activities of daily living. I'm assuming this groups familiar with activities of day to day living, am I correct? Okay. So you're well aware of differences between instrumental verses basic activities of day to day living. One thing with Alzheimer's disease with patients is early on they often don't show problems with basic activities of daily living. Early on the things you see over on your right side of the screen tend to be intact. The problems we start to see are in the IADL's. And something I really tend to see just  practice that tends to come out the most are magic finances. One thing that's very common especially older adults still balance their checkbooks pen and paper. They don't use a lot of the online tools, make it a lot easier. And they'll say gosh, I've just been noticing I've been having a lot of problems. I'm overspending, underspending, having money left over or spending too much. And imagine medications. They'll say I report that I'm forgetting to take my medication, I'm taking double doses, I'm taking the wrong one when I should be taking them.

 

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Those are ones that come up very early on and these people generally pretty are aware of them. And so as things progress most of these ideas fall apart pretty quickly. And then the BADL's start to come on more in the moderate to later stages where they start to loose function and basic activities in daily living. So what's going on in the brain? What's driving all of these changes? I don't have these answers. No one has the answers. If you invited ten different people to give this talk, we'd probably all give you ten different answers what we think is going on. I could tell what pathology looks like. That we know. That we agree on. But describing pathology is what's debatable. So one thing that's very clear is there's slow loss in the brain of Alzheimer's patients. I'm going to show you brains. You'll be able to see if you've never seen an MRI in your life you'll say wow, there's cell loss. That brain's smaller. There's also granulovacuolar degeneration. We like to have fancy terms to make it sound smart. This is just holes in the brain case the tissue under the microscope has holes. That's cell loss. Neurons, glycol should of been there. When those die you wind up with holes. And the two things that people argue about the most is what's really contributing to Alzheimer's are these neurotic plaques and neurofibulator tangles. These are microscopic pathologies you cannot see on an MRI. The MRI's I'm going to show you you can see these things.

 

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You have to look at them under a microscope. Now we have some new aminoflourescent labels attached to these guys. And you can use some functional scans to look those, and I'll show you some pictures of those later. You're still not actually seeing the plaque and tangles. Let me show you what those look like. Oh, let me show you this first. So the progression neuropathology in Alzheimer's disease is fairly typical from patient to patient, and it tends to start in general in one part of the brain and spreads to other parts of the brain kind of [inaudible] across patients. And one starts at the medial temple lobe. So you can know your temple lobe is on the side of your head. And just inside those medial temple lobes right about straight through here maybe about a half a finger in is where these changes start. They start moving in internal cortex in the hippocampus. These are primary memory centers of the brain. The hippocampus is what really helps you lay down memories. Your internal cortex is the input to that. So this is where these plaques start, where these tangles start, and where the cell loss starts. And where it progresses to other parts of the temple lobe, play a role in a motion like the insula probably contribute some emoded regulation in your temporal cortex where you store a lot of your memories, flow, objects, and faces; it's probably why we see the agnosia problems, problems identifying faces and objects. Then it starts to square up in the prefrontal cortex. There's a lot prefrontal cortex up in here regulates executive functions, the planning and problem solving regulates potential networks. Some of the inferior regions down in here regulate move. Again probably [inaudible] problems.

 

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And the later stage tends to progress back in the post-parietal cortex. Plays a big role in spatial learnings, learn where you are in space, where things are in space relative to each other. What you notice is there's minimum pathology in the occipital lobe processing vision. And there's lots of pathology in the brain stem. We don't see as much brain stem pathology as we see in some other disorders related to Alzheimer's. And some are a lot like them except they have some motor symptoms as well. Okay, so now what to do with plaques. Let me see if there's one missing. Go forward one, please. Yep, I guess from the [inaudible] picture. So I was going to show you what those plaque containers look like but that slide didn't seem to want to show up. So what these plaques are is they're basically an accumulation of these proteins. And these proteins clump together and form  I wish you could see it up here  a little plaque in the brain. So microscopic very small plaque. For Alzheimer's disease there's about 70 or more of these in square milliliter. So you can see these things are really, really small but they can become highly dense. Maybe if you go back one slide I can give you a little information about these plaques. So I don't want to go into details here, but basically a normal molecule gets cleaned improperly. Two enzymes team up. We don't know why they team up. And they make this protein that's nonfunctional. It sticks together and clumps up to form a plaque, okay.

 

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So that's one the pathology. And the next pathology are the cows, the tangles. And the tangles are formed by something called cow protein. So these things actually occur inside the neurons. Those are what neurons look like. These are neurons in the brain that we use to think. These cow proteins clump together and basically the cell dies forming these tangles. And so these plaques, or these abnormal clumps of proteins outside of the cell, these tangles are abnormal clumps of protein inside the cell. These are the two characteristic neuropathology's we see in Alzheimer's disease. Now are ID's causing Alzheimer's disease? There's debate about that believe it or not. And there's also some evidence. One of these is playing the bigger role than the other, but I'll get to that in just a few minutes. Okay, I think we're missing some slides in their possibly, but we'll get through a little early in that case. So just to show you I was not lying about the pathology, what you're looking at is a normal brain on one side and a brain with Alzheimer's on the other. This is kind of moderate Alzheimer's not real severe. But take a look at this here. This is a picture of the brain. This is a structural MRI. And the images taken at the top have been cut off. And we're looking down on the brain. And so this would be the front part. These are actually the sinuses, okay. And so this is just the part of the brain that's right above the sinuses. And while these is normal ones with Alzheimer's, any guess which one might be the Alzheimer's brain left or right? The right, you guys are right. What's the clue? What's the big thing that shows us pathology?

 

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[ Inaudible Comment ]

>> So you can't see plaques in this one. [Inaudible]. Honestly, what's abnormal, what's the clue? Go ahead.

>> In the middle one side is longer [inaudible].

>> There is something to that. So if you notice in the middle you see these kind of butterflyshaped things. These are called ventricles. These are actually fluidfilled spaces in the brain. These are filled with cerebral spinal fluid, the same stuff that goes on the spine that's pulled out in the lumbar puncture is also work on the brain. And what happens when the brain gets smaller these ventricles start to expand, they get bigger. Because basically there's a lot of brain in the middle when you're young and healthy. You guys have some nice, fat, meaty brains right now. They're pressing in on those ventricles. When you start to get older and especially if you get Alzheimer's disease the brain starts to shrink, that pressure in the ventricle is relieved, and those ventricles start to swell up.

 

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So you see ventricles getting larger that's a set of pathology. We see ventricles are A symmetrical which is something you picked up on. This is probably because the heads not leveled and the scanner is tilted. But it might also be there's some asymmetry here and if you got more [inaudible] left side which is [inaudible] than the right. Okay, that's true. Next slide, please. Okay, and so this one looks like a gross pathology. So let's go and show you what it looks like. So gross pathology means the persons died and take out the brain and fix it. Come look at it. So here's a normal brain. You can see those ventricles here. They're nice and tight and small. You can see the brain is nice and tight, there's not a lot of space. Over here is a brain with Alzheimer's disease, and you can see these ventricles are significantly enlarged. This is another ventricle down here. This is the same ventricle here. And you could see this is those temporal lobes I was just talking about. The hippocampus sits right in here. How many of you even seen the hippocampus before? Probably maybe never. You can clearly though see the difference between this medial temple lobe in the hippocampus and that one. It's almost done, okay. So this is that. Gross pathology is the cell loss you can see. Next slide, please. And one thing I want to show you on the MRI's  what I'd like to show you on those MRI's which is not there is  go back two slides, if you wouldn't mind. One more. You can kind of see it on this one.

 

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So you can see these little grooves in the brain. So these are the  there's bumps and there's grooves. These are the grooves. And the grooves in the nice healthy brain are small because there's a lot of brain in there, they're very tight. And so you don't like to see a lot of the white out in the cortex. And you notice this is the best picture. You can start to see where it's more white. What that basically mean is there's cell loss, there's volume loss. The brain's getting smaller. And so you're seeing over here especially in these temple lobes, and this is actually the prime lobe because of the way its cut. These parts of the brain are getting smaller. So this actually can be helpful. If you make a diagnosis of Alzheimer's, let's say you give the standardized neuropsychological test I showed you, and the person's showing what you expect to see; it's the memory problems, executive problems, language problems, and then you start to see some pathology like this, it can help give you some clues in making your diagnosis. Okay, so next one. Oh, boy, okay, I'm trying to think what was in there. [Inaudible] Okay, so how  this is turning toward the MCI. So what I want to shift gears now to is a way from Alzheimer's. This one thing we're sort of studying Alzheimer's, studying the patients giving extensive neuropsychological test, giving them cerebral spinal fluid, neuroimaging analysis. We learned a lot about what's going on with this disease is started.

 

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But why do we want to shift toward kind of predict it early in life? Why is it so important we identify this person might have Alzheimer's, might be starting to develop all these things in their brain as early as possible? The reason is once it starts, once those cell loss occurs, once those plaques are deposited, once those tangles are deposited, especially those tangles, there's not much you can do. Cluttering those things out we're finding it's  there's new drugs being developed to try to do this. We'll talk about that at the end. We don't know if they're going to work. We don't know if we could remove those plaques. Let's say you can remove them. There's some magical thing that just shrinks them, eats them, whatever it is, could that person's cognition come back? Probably not. So what we want to do now is to identify people early in life set as soon as possible and say okay, this person's not heading down a normal aging trajectory, they're headed towards Alzheimer's. Let's start these new interventions that mostly haven't developed yet, we're working on them, as early possible. Stop all that stuff we talked about from happening to keep that brain as functional as long as possible. So really  and what I'm in the business of working on in my lab is identifying people with cognitive changes as early in the disease progression as we can. And we're trying to go back to middle age right now, kind of the portion of my age range in the 40's and 50's to try to identify people, and we're not quite there yet. So what we're trying to identify now is people who are in the state called mild cognitive impairment.

 

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So mild cognitive impairment is referred to as MCI. Mild cognitive impairment basically means these people don't look normal, okay. They're not showing normal age related cognitive change but they don't show Alzheimer's disease either. So if a person fits the criteria for Alzheimer's disease  for MCI they're at greater risk of developing Alzheimer's disease. And they might not but they're at a greater risk. And so how do we assess that? So we basically access  and you kind cut off a little bit  but those five  say five domains we talked about earlier are the domains we assessed in these neuropsychic assessments. These take about three to four hours, you give them a battery standardized neuropsych test and then you score them, access them, and see where they fall relative to the norms. So we look at memory. Episodic memory specifically. You're not worried about the test we give. These are very standardized neuropsych tests. We know how people shift, perform based on their age.

>> And Paul [inaudible] as we go over  and would you guys say 6:45 am we'll talk about some of these neuropsych tests like the CVLT and then the[inaudible], things like that.

>> Great. So you'll get an idea of what these things are in the assessments class, but right now that doesn't matter. We just know them as standardized memory test. Executive functions, looking at things like problem solving, planning, shifting, some of the things we talked about. This constant card sorting test, those kind of tests. We also  the language, Boston naming test, a very common one that we use.

 

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There's fluency test like I mentioned earlier. Think of everything you can think of that starts with the letter S or all the animals you can name. We access visual spatial and visual perception function. This is that block test I mentioned earlier. So here's a little design of what they're supposed to make. And you've got the blocks and you put them in fun little picture. Simple test, clock drawing. Draw a clock with the hands at 3:30. That's actually  should be second. That's only a quarter [inaudible]  one of the sensitive things we have for Alzheimer's. People who have problems with clock drawing tests is a real red flag. Now, should you ever give the clock driving test? The person performs poorly say oops, they got Alzheimer's, let's put them on Alzheimer's medication. Definitely not, okay, but it's maybe yeah, we should refer this person out for an assessment. We'll get to a little bit more about that in a second. And then attention is this last one. You can't see under here. Real simple. You might of heard of the digit span test. You give them numbers in sequence, say, like I say say those numbers back to me in the same sequence and see how many they can remember. And then there's some other measures as well. So we basically we're trying to access them for mild cognitive impairment giving them battery standardized neuropsych tests accessing these five different domains and then we see how they do using this criteria hopefully show up.

 

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>> Paul, we have a question online. I guess we probably didn't get to this, but the question is so, you know, with this kind of early identification can you actually slow the progression of the impairments that you're seeing?

>> That's a great question. So we can identify it [inaudible] MCI. The ability to actually slow the disease progression not really. There are some newer drugs, they're starting to help people maintain function longer. And one of them might be slowing with cell loss, but you're not going to change what that persons headed toward, you might be able to change the slope a little bit right now. The next drug to change that progression could be around the corner, we just don't know. So that's the challenge. So what we really want to do is we try to get everything to stage set. So drugs that's developed it could be implemented very early on. So that's kind of our role in neuropsychology of MCI. Okay, so let's hope this next slide shows it. Ahh, great. So let me see what the next one is.

 

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Let me see if it happens now. We lost a really key slide which is how do you characterize MCI? So if you can go back I want to just show below the screen so it's not distracting looking at that. All right, so one thing about MCI. This is relevant for people in this room who are very interested in function abilities in individuals and ideal functioning. One key to MCI is these people have to show normal activities of daily living, okay. So actually have to  they don't show problems in IADL's and definitely not in BADL's. That's a big difference between MCI and Alzheimer's disease. These people function fairly well a normal life but they have subjective cognitive complaints. They say although I function pretty well, I can balance my medication, I'm managing my finances, I'm cooking and transporting properly. I have memory problems, or I have problems with executive planning and problem solving issues, and language problems. They also have problems that are recognized by a caregiver, for example. The caregivers will also say in a proxy report they also have impairment, all right. So that's one of the main differences between Alzheimer's and MCI. The other thing is they're not showing severely impaired performance on a standardized test. We usually look at a Zscore, a Tscore. Familiar with these at all?

 

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>> We talked a little bit about the Tscores.

[ Inaudible Comment ]

>> Okay, so you guys know what a T score and Z score is? So you know that a Tscore of 40 or a Zscore of minus one is basically we're going to have long [inaudible] cut off? So these people who have Alzheimer's disease are usually below the 270 deviations below norms. So two, or three, four, fives, sometimes they're really impaired in severe stages. People at MCI do not show that level of impairment. I'm going to tell you in just a second. I wish you could see here on the screen there's some debate about where that cut off should be. Should it be 1.5 standard deviations or 1% deviation, but there's some debate on that. Oh, I'm still talking about what you got on it screen. So ideals are in tact. Now, the cognition has to be measurably impaired. So you have to be able to give these standardized tests I just talked to you about and be able to actually see impairment on these test. Now, the original criteria that were first put out in about 1999 was based on one test which is on awareness, it's the logical memory subtest of awareness which you'll learn about is basically a story. You hear a story, and you recall the story, and then it's scored. And that was the original test. If someone was 1.5% standard deviations below their age of suggested norm on that they would give a diagnosis with MCI. Around that time people were also using things like dementia rating scales which is basically an IQ test scaled down for dementia populations, so if you gave a dementia individual an IQ test they're going to just ball out, they're going to go basement on it.

 

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But this test is a scale down so you can actually differentiate different levels of impairment. And people are using a cut off score of around 130 on this measure to diagnose MCI. I've seen people use a mini mental state exam. You guys may have heard of that, the MMSC. If not you will. It's used all the time. It's misused all the time. But some people using a cut off score on that as being enough to diagnose MCI. That's not appropriate. You can either use a standardized battery to really get an idea of where people fall. So the new criteria that came out in 2005 by Peterson, the same gentleman developed the original criteria, basically said that for people to have MCI they need to be 1.5 standard deviations below norms on a test within a domain. So, for example, if they have amnestic MCI, memorybased MCI, [inaudible] disease, you need to be 1.5 standard of deviations or more below your age of suggested norm, okay, so just on one test. Now, you can see a few liabilities issues on that test: That person was tired, if they got distracted they might fall in the impaired range. And so recently in 2009, a group here at UCSD, Amy Jack and Mark Bondy [assumed spelling]. Amy was the lead investigator, Mark's the senior investigator, came up with a couple of comprehensive criteria. They changed the game a little bit.

 

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Haven't fully caught on, but I think they've got a good idea. Rather than saying they just have to be in parallel one test within a domain, 1.5 standard deviations, they actually made it so you don't have to be quite as impaired. It's one standard deviation but on two measures within a domain. So you get diagnosed with MCI you have to be impaired on two measures within a domain, that's more reliable, but you don't have to be as impaired or 1% standard deviation or more below we'll give you the diagnosis, which I think is a pretty revolutionary and it's a pretty interesting approach to this. So those are called the comprehensive criteria. So right now we're really using a traditional criteria clinically in the most research. These comprehensive criteria have shown to be more reliable. And one thing you find with MCI is some of these people will have been diagnosed with MCI and they'll follow up a year later they won't meet criteria any longer. That's a problem, okay. You don't want to send someone home and say you've got MCI, what's the risk factor for Alzheimer's disease, and they actually say, oh, just kidding. Okay, you don't want to be doing that clinically. And these comprehensive criteria we think are more robust to that. Again, we'll find out. So next slide, please. So what I wanted to show you  oh, please.

>> Yeah, so does true MCI that you were saying in this [inaudible], does true MCI always leads to Alzheimer's?

>> That's a great question.

 

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So does  I don't know if we can call it true but does diagnosed Alzheimer's  MCI leads to Alzheimer's, no. Not always. So we might not have seen this slide, it might have been blank, and if so I'll catch up on the next slide if we missed that one, the people who have amnestic MCI, so if they're problems are in memory domain they tend to be okay in executive function, language, those are people to be most likely going to have Alzheimer's. If people show MCI but not in memory domain but in other domains like [inaudible] language based, visual spatial executive, those people are problem projecting towards something not Alzheimer's. Might be frontal temple dementia, which I haven't talked about, ASCO, dementia. And there's also some dementias that are a mix of Parkin's and Alzheimer's disease which is a really unfortunate disorder. They might be turning more toward that. But amnestic MCI subtype is the one that turns more towards Alzheimer's. But there's no guarantee that if you get that diagnosis you will get Alzheimer's even if you live to be 90. So what you're look at here is these are MRI's of the exact same patient taken over the course of about 11 years. From this patient  this patient was enrolled in  studied in ADRC, Alzheimer's Disease Research Center. It wasn't ours, but where they had these MRI's annually, and this just showing them across 11 years. There's some gaps between them. So in '93 this person was a healthy, normal, older adult.

 

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I cannot remember the person's age in this picture, but it's a really good looking brain for a person over the age of 65. Want you to focus on these temple lobes. Now, remember that temple lobe I showed you earlier of the young adult. They have a really nice, thick temporal lobes. This person is showing some atrophy but not nothing overly concerning. When you look at it more finely, yeah, there might be something going on there but it's not something that's real concerning. Four years later you can start to see these black spaces getting bigger. Okay, so the black, that's the space. That's the  should be very little space. You see the brains kind of opening up. That means the brains getting smaller. Don't forget the hippocampi on each side. You notice there's more black space around the hippocampus than there was four years earlier. [Inaudible] early on. Four years later the [inaudible] temple. For example, look at this space right here. See how that's just gotten bigger and bigger across the years. That mean that temple lobe is getting smaller. Look at the space right here getting bigger and bigger over time. The medial, medium temple over the hippocampus is getting larger. Look at these spaces here over time. And this is when a person's actually diagnosed with moderate Alzheimer's disease. So you can see going from pretty normal, not quite, to MCI, early Alzheimer's to moderate Alzheimer's, you can see the change in the brain, it's getting smaller. They're losing cells. Now, you can't see plaques, you can't see tangles, those are microscopic. You can't see those in light. You sort of can, I hope. This picture show a really good picture. But we can certainly image those. We can't see them physically under these scans. Okay, next slide.

 

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>> I have a question.

>> Sure.

>> So the question is what about genetic testing. Is there a real benefit to if your mother, father, or sibling has Alzheimer's or there are no preventive measures, or are there no preventive measures that can be taken, so basically the value, you know, of doing genetic testing?

>> Yeah, the value of genetic testing is so  if you have early onset for medial Alzheimer's which if you have this you would know it. People getting Alzheimer's in their 50's, absolutely, because it's a dominant gene. But that will only account for less than 5% of Alzheimer's cases. 95% of the cases we don't know it's a gene. If you have a firstdegree relative, a mother or father who has it or a sibling that has it then you're at a much higher risk. But the genetic testing now will not tell you anything because we don't know what we're looking for. There is one gene it's called the APO-E [assumed spelling] gene. It's APO with a protein E gene that  and specifically one isoform of that I'm going to tell that in a second when the slide shows up is the [inaudible]. And that put you at greater risk. About 25% of all Alzheimer's cases catapulted by this gene but it is not causable, it is just simply a risk factor. Carrying it you're at a greater risk. If you have two copies you're at a five times greater risk. If you have one copy you're at three time's greater risk. So I mean that would be the only benefit to gene testing is to see if you're positive for B [inaudible], if you're homozygous you have two copies, one from mom and one from dad or if you just have the one. And all that says you're at a greater risk. And so if you are at a greater risk you start noticing how I'm forgetting things, I'm telling the same story over and over, I'm forgetting to take my pills. In your 60's maybe you might want to go in for an assessment and maybe get on some of these drugs [inaudible] that might give you better benefit for a longer period of time.

 

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>> And you seem to have really done some interesting research with the investigating the role of that gene providing different tests, you know, for MCI?

>> Yeah. Yeah, we've done quite a bit in my lab watching the people with carriers for this gene. And even when they're healthy [inaudible] we're seeing cognitive changes in these people and brain changes too. Did you have a question?

>> Yeah. Are MRI's used to identify the mild diagnosis for the MCI?

>> You know that's a good question is the MRI's useful diagnosing MCI. Probably not. The set up changes in MCI are very subtle on a structural level. And these are kind of gross in that they're not real fine pictures in terms of resolution. I don't think it's useful quite yet. I think it might become useful in the future when we are able to get better pictures. But I think the change are pretty subtle. So I don't know how you're saying that it's going to be possible, but right now, no. It probably is not going to help you a heck of a lot. It'll help you out with other things which would be the big use for them. Okay, next slide. Oh, these are the good ones. And these are back track. One thing that didn't show up  and there's a slide completely lost in there  is subtypes of MCI. Before I get to some exciting stuff with the pictures here, there are basically two subtypes of MCI. We've talked about it very briefly. There's amnestic subtype and there's nonamnestic.

 

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So amnestic subtype means that people have MCI and there are certain problems on those memory tests. Results of different people who don't show problems on their memory test but show on the other test: Executive function, language, visual, spatial tension. Those people are nonamnestic MCI, okay. Now, you can even get more complicated than that. You can have single domain versus multiple domain. So some people have amnestic MCI and they'll do fine in the other domains, that single domain. Some people have amnestic MCI but could also be imperative language and maybe visual spatial function as well. So they're amnestic MCI multiple domain. Does that kind of make sense? You can see it can get complicated really fast. So I just want to at least tell you it's not simple as MCI or not, it's MCI or not, and if you have MCI, amnestic or nonamnestic. And next are you single domain or multiple domain. So again for an introductory lecture on this I'm not going to say another word about it because it gives you a headache very fast. Just know it's a pretty complicated set of criteria. Now, what about imaging plaques, imaging tangles. Again, we can't see them on MRI's, we can't see them here. But what we can do is we can put immunofluorescent labels into the blood stream that can take care of the brain and can actually bind with these plaques and tangles. And using PET, positron emission tomography, and PET scans you can actually light these guys up. So what you're looking at here is this is the F18 fluorescent deoxyglucose positron test where basically this is what's injected, this F18 dioxyglucose. And it binds to these plaques and we take the image that lights up.

 

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So if you see a lit up image that means there are plaques present. So this thing can be in a living individual that's not terribly invasive other than after getting injected into the thermal vein. They get the radioactive dye injected. You can actually light up the plaques, okay, beta-amyloid plaques. You're lighting up the proteins  these beta-amyloid plaques that are made up of proteins. And this is a newer  well, actually no, it's not new  this is an older one that's still used. It's a Pittsburg compound called the PIB, PIB. It's a different compound. And so what you're looking at here is a much more informative gauge on what's going on. So this is the controlled subject. You don't see any red. That's what you'd expect. There's none in that particular individual. And so red means plaques. Red means beta amyloid being present in the brain. So in the control, the healthy individual, you wouldn't expect to see anything and you don't. That's good because the other end of the spectrum is the Alzheimer's patient, you see lots of red. And this is actually the lowest. This is going to get up higher using the [inaudible] lobes, the temporal lobes, and the parietal lobes. Actually, that's lower parietal. We don't care why. But anyway, you can see lots of plaque growing. So that's what you'd expect. Now here's why plaques might not be the answer. Here's why MCI is such a tricky business. Look at these three patients.

 

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MCI patient one, two, and three. What do you notice? They look completely different, don't they? They are not remotely homogenous with their plaque deposition. MCI patient one looks almost just almost like a control. If I looked at that not knowing any better I'd say that's a control, they're perfectly normal. But on the standardized neuropsych test, no, they're not. This person here if I looked at that, you looked at that, probably a neurologist looked at, they'd say that's an Alzheimer's patient. They're not. They don't meet the criteria. This persons actually MCI and this person is somewhere in between. So it shows us, first of all, MCI is a fuzzy business. This people will be showing these cognitive changes that are measureable using  well, these tests are really psychometrically sound but look very similar, but we look at their brains, the brain composition, especially plaque deposition, is very, very different. That's problematic, okay. And this brings in the question are these plaques driving that cognitive impairment? And you might say the answer is no. Because look at this person. Very little plaques, commonly impaired, okay. So I'll get to what's next. Hopefully that'll show up too. That will look good. Let me see what's next. Are there anymore? Okay, well, that's all right. Fortunately, I've done this a lot, so I can pretend like there's things up there. So let me think what was I going to talk about next?

>> Just this previous one, tau.

 

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>> Tau, okay. I'll talk about tau. All right, so the tau might be the more interesting story. And so the tau protein there was a paper published in brain and just this year and actually showed that tau is probably driving the cause of impairment; it's not the plaques. And so [inaudible] plaques and of tau, and they found that tau was related but not beta-amyloid which is in the plaques to age of onset, duration of disease, and most importantly cognitive decline and cognitive function at the last test before death. Now, I probably won't say what I think about how they measure the cognition of MMSC which is not ideal, okay. But it was sufficient enough to give us this clue that might not be the beta-amyloid and the plaques driving this cause of impairment, it's probably the tau. It's probably the tau protein they've obtained those they are driving the actual cause of impairment in Alzheimer's. Have you guys heard about tau protein anywhere else? In your field, if you haven't, you're assumed to be.

[ Inaudible ]

Yep. So chronic traumatic encephalopathy. These are things we've seen in people with chronic  well, actually maybe not even chronic but just head injury, mild MTBI. So if you have multiple MTBI's or showing these tangled up positions those tangles are really similar with Alzheimer's on a microstructural level. They tend to be deposited higher surfaces of the neurons, so they're not quite as deep in the layers of the brain, and they tend to be a little more sporadic, not quite as organized as what's in AD. So basically the same things. And so these tau proteins are getting a lot of attention these days.

 

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>> Is that like inflammatory response from like traumatic injury?

>> Well, the inflammatory response, again, you can bring people who are going to argue with what I'm about to say. We do know it might be secondary. So if any of these plaques might cause inflammatory response [inaudible] cause inflammatory responses. See these chunks of proteins, these tau proteins, or intracellular are going to be seen by themselves, hey, this shouldn't be here. It's not an inflammatory response so get rid of it. The plaques outside are also interpreting similar responses. So I personally think the inflammatory response is secondary. Those people tell me I'm flat wrong. Some people say that's really key. So that's what keeps us in business unfortunately is that we don't know these answers. The bad thing is we don't know what to do clinically about it. Right now there's a whole bunch of companies developing anti-beta amyloid antiplaque drugs try to close mock depositions. This new study suggest it might be absolutely no good at all. And even if they did maybe the plaques were driving the impairment. Getting rid of them might not bring back the function. It might stop future dysfunction but it might not drive function or gain function.

 

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Yeah, it's kind of where we stand, but then there's also a beautiful picture down here, and you can't see. We can now label this tau as well. So it's kind of like what I just showed you, you can label the taus. So that's really good. You can also look at tau and beta-amyloid through cerebral spinal fluid as well. I won't go into why, but low beta amyloid is actually, in the case of Alzheimer's, a high tau. Okay, so if you see those two things: Tau going up, beta-amyloid going down the CSF, that's another clue we're now starting to use clinically as well. Couple of these new imaging. This might be really useful in clinical diagnosing in the future, but right now this is not happening where you take ground for ground for an Alzheimer's evaluation. They'll be given some behavioral tests, maybe an MRI, and a diagnosis with prescription. That's kind of reality right now. Okay, so what's next? More blank screens. How am I doing on time [laughter]?

>> Great.

>> Yeah.

>> Okay, I've got just a couple more minutes.

[ Inaudible ]

 

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>> Oh, great. So I'll tell you a little bit about the [inaudible] of this app  of this gene. So I said earlier there's this gene called the APO-E gene. And specifically the inheritance of the flow wheel is a respect for Alzheimer's disease. And so there's three basic genes floating around the gene pool. There is a E2, E3, and E4. It you inherit the E2 or E3 it does not increase your risk of Alzheimer's. You see that the E3 is the most prominent which is good news. The E2 is the least common and E4 is second least common. So all of us in this room have some combination of 2's, 3's and 4's. If you a four or two four's, you're at greater risk for Alzheimer's. Doesn't mean you're going to get it. You could easily live to be 90. I see people all the time who have two copies of a four wheel, 90 years old, no signs of Alzheimer's. I see people who have two threes of 80 in their 60's. It just increases your risk. About 20% of AD cases are accounted for by the C40 wheel. So you can see if you have a mom who had a  her gene type was a two and a four. You had a dad who has a three and a four. These are the possible genetic compositions the offspring could have. So the worst case scenario would be inheriting a four from mom, four from dad, you're a homozygote. You're at a five times greater risk for developing Alzheimer's. If you're a heterozygote, you have the three, four or the two, four, you have about a three times increased risk. If you happen to be the lucky one about the two, three, and you go to Vegas, you got some luck right now, take advantage of it. But genetically you've gotten lucky as well. Your chances are pretty low of getting Alzheimer's disease.

 

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But, receive two three's that do get it. So this is not the answer, it's is a risk factor. And personally, I think that if you have this gene it just puts you at risk of a poor outcome if you have a brain insult. If you have a stroke, if you have MTBI, if you get Alzheimer's, if you get Parkinson's disease, something bad happens to your brain, you have one or two causes of this gene, you'll more likely have a bad outcome. I don't think it's any specifically to do with Alzheimer's. But, to be honest, something could come in tell me you're absolutely crazy for thinking that, you know. We don't all agree on this. So that's kind of my take on the E4 wheel, all right. I'll just talk about what happens to show up. Anything else showing up? Hey, that's where I was going to end. So this is great. We'll end with the slide you can actually see. So the drug treatments for Alzheimer's disease really are not targeting these plaques. They're not targeting tangles, they're not targeting the cell loss, they're targeting neurotransmitters or chemicals in the brain that are affecting by these things. Directly or indirectly that's a whole other debate. There's a drug called Aricept on the market that's a new version of something that's out for a long time called Cognex.

 

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And what this basically does it tries to keep levels of the chemical called the phenylcholine high in the brain. So phenyl choline levels drop and phenyl choline is a neurotransmitter which is released by neurons in the brain. It's very important in cognition and memory functioning. This drops as you develop Alzheimer's. The cells of acetylcholine starts dying. What this drug does is it protects acetylcholine from breaking down. So once it's made your brain starts to break it down. That's natural. It tries to stop that from happening. So once the acetylcholine is being made it's able to be utilized by the brain. But again, you can think about it, over time as it starts to lose the cells that makes acetylcholine this stuff is going to lose efficacy. So this drugs good in the early to moderate stage of the disease. It's also almost useless in the later stage of this disease. We usually invoke a few people on it because it has side effects. A new drug now on the market and [inaudible] is the brand name. Memantine is the generic for it. This drug works really different. This one's got, I think, some good promise. It blocks for stuff with different transmitters called glutamate. Now glutamates a neurotransmitter. It's a really explanatory in the brain. It turns things on, it stimulates the brain and increase activity.

 

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Too much exhortation in the brain is bad. It equals cell loss. If you get your brain over excited with too much glutamate, for example, as receptors get bound, calcium comes in the cells and it causes toxicity. And so what this drug does, what blocks receptors for glutamate. So glutamate really can't overstimulate the brain cells to try to protect these cells from dying because there's some evidence that maybe glutamate levels are elevated or receptors might be more sensitive causing cells to die. So let's try and protect some cells from dying. Again, this looks moderate. Maybe one of these are magic pills. You don't give this to grandpa and grandma in moderate stages and they come back to their normal selves. They might improve a little bit. They might start recognizing people they weren't recognizing. They might start remembering things, might be making better judgments. It might help but only in early to moderate stages. And usually you give these two drugs in combination. It tends to work really well. A brand new drug came on the market just this past couple of months, it's called Namzaric, which is just a combination of these two drugs. One pill, both drugs in it. Nothing magical. But it's probably the newest drug out there that we're using to treat it treated. And then there's one called Axona. It's a new drug. I don't see a lot patients on it, but it's trying to increase the reserves that neurons can use to function. Ketones are something basically neurons can use to increase the function of energy source and it makes them more available in the brain throughout their own function ability called like food for the neurons. Yeah?

 

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>> Can I [inaudible] with one more other question. Are there like preventative dietary measures that you can do like you tell [inaudible] available to stimulate neuron functioning and [inaudible]?

>> That's a good question. What I've seen is not been overwhelmingly encouraging for clinical trials and stuff. So you're trying to increase and alter your diet hasn't seemed to do heck of a lot, the one dietary thing I have seen have some function is vitaminE. So there are some neurologists giving their patients vitamin E supplementation above and beyond what you'd  what they normally need. And it might have some antioxidant protective properties for neurons. I'm not wildly convinced it's terribly effective. You can also go overboard on vitamine, have some problems with that. But that's probably the only dietary thing I think that's gotten any  anything I think really might show some efficacy, but if you're trying to increase for the diet I don't think it works as well as Axona does. And then there's these new experimental drugs that probably not are even close to being on the market yet. So you guys are going to try to slow the deposition of plaques and tangles or try to clear the ones that are there. The slowing of the deposition of tangles I think is the key. If one of you can develop a drug that does that you're going to be very wealthy and you're going to save a lot of people's lives and extend them. I personally think that's the key. But I might be wrong in three or four weeks because they might find something new, but I think that's where we stand right now.

 

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That would probably be the most effective drug.

>> What about like for the ones that target tau for the football players because you can't diagnose CT until death. I mean you can just give [inaudible] and stuff like that.

>> That would be the hope, you know. You take everyone in the NFL. My brotherinlaw plays in the NFL. I've talked to him. Some of his friends have had multiple concussions. The retirees he know are real similar. Had the same problems. Yeah, you put them on a prophylactic treatment [inaudible] not a great idea. It's not a great idea. I said go ahead and get your concussions, we'll just treat that. Obviously, there's other effects besides the tau deposition, but yeah, that would be the approach to try to slow that deposition so those plaques, those tangles could not get formed and deposited. But clearing it, that's a good question. Is that even going to help? I don't know.

>> Would anybody who like started and are at a greater risk category like in the wheels, having those certain deposits, getting multiple concussions over their life time or [inaudible] they'd be more at high risk at that point, [inaudible]?

 

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>> Yeah, I would definitely think having  let's say a homozygous four wheel playing in the NFL for 17 years and get eight, nine concussions I think your outcome is going to be a lot worse. And there's some evidence now to support that. There's people looking at the E4 wheel, head injury, and on cow deposition. There's some preliminary studies coming out [inaudible] problematic. Any other questions? That was about where I was going to end since. I probably left off some things I wanted to say because the slides didn't show up, but any questions? Great. All right, well, thanks for your time. I really appreciate it.

>> Thanks so much Paul, it was wonderful.

>> Sure. Thank you.

[ Applause ]

>> All right, so for you guys online we're going to end. And for those in the room we're going to continue talking about the cognitive disability special edition.