Diagnosing Alzheimer’s Disease

Happy to see you all again. My name is Serggio Lanata and we met last week. I'm glad to see you again to learn a little more about neurodegenerative

disease

s. I think we had a pretty good first session where we were able to give you an overview of neurodegenerative

disease

s, distinguish between different brain diseases and the clinical syndromes they cause. Give you an overview of how we think about neurodegenerative diseases. I think we also had a pretty good discussion to start with. Today we're going to start limiting things a little. I invited my colleague, Dr. George Naasan.

He is the director of our clinical services at the UCSF Memory and Aging Center. He and a dear colleague of mine will give you a more detailed description of a specific disease, Alzheimer's disease, which you learned about when we last met, is the most common neurodegenerative disease worldwide. It will delve into the pathology and then into the clinical syndrome that causes this disease. Following his talk, we will have an interactive Q&A session with him, as well as two guests from the Memory and Aging Center. Dr. Lea Grinberg, who heads our neural pathology department in the neuropathology core, and Dr.

La Joie. We meet La Joie, who is a neuroscientist, a researcher who is really spending his time thinking about what tests we can order to diagnose Alzheimer's in life, specifically PET scans. Without further ado, meet my colleague, Dr. Naasan. Take it. Alright. Thank you all. I'm very excited to be here. I think this is the first time I've talked to a group of people who aren't medical students or doctors, so I hope I do a good job. Today we are going to talk about Alzheimer's disease. I'm going to start with a story. On November 25, 1901, more than 100 years ago, Karl, who was a German office worker, took his wife, Auguste, who was 51 years old at the time, to a mental institution in Frankfurt, Germany.

He was having difficulty caring for her at home and said she had started having memory difficulties a few years earlier. He also described that she had paranoid delusions, feelings of jealousy and thought he slept with other women. She was convinced that there were people trying to kill her. She also had difficulty speaking and verbalizing her thoughts and ideas. She was described as having some auditory hallucinations, hearing things when no one was talking and also unpredictable behavior. That night, the doctor on duty who examined her was named Alois Alzheimer. He was 27 years old. This is a photo of Auguste, it was taken about a year later or maybe it's actually a drawing, I'm not sure, but it was documented that it was a year after her admission.

Interestingly, not necessarily with that photo, but some of Dr. Alzheimer's notes the night he admitted her, said she was sitting up in bed with a helpless expression. It's interesting that this was the photo captured of her. These are some of Alzheimer's notes from his conversation with this patient. He asked her: what is your name? She answered: Augustus. Last name? August. What's your husband's name? Augustus, I think. Your husband? My husband, and then it seems that he did not understand the question. All this is from his notes. He is married? To Augustus. Mrs. D? Yes, yes Auguste D, that was his name.

How long have you been here? She seems to be trying to remember three weeks. What is this? I showed her a pencil and she responded with a pen. That I show you? I do not know i do not know. It is difficult right? So anxious, so anxious. Those were some of the notes that there were more, but these were some excerpts from the notes of that first dialogue that Alzheimer had with Auguste. She then died on April 8, 1906, about 5 years after being admitted to the institution. Alois Alzheimer asked about her brain and described some of the findings he found under the microscope in brain cells.

He described what we now know, which we will discuss later, as neurofibrillary tangles and amyloid plaques, which have become the pathological hallmark of this disease. The actual term Alzheimer's disease was not coined until 1910, a few years later, by another psychiatrist in the Manual of Psychiatry. These are the drawings of Alzheimer's, and later I will show you what they really look like under a microscope. Today we will cover a few things. We are going to talk about how Alzheimer's disease presents when it affects people and what are the different symptoms it can manifest. How do they present in the clinic?

We will see that there are different ways in which Alzheimer's disease can manifest. These are four of the most common ways. It could be a memory syndrome, and I'll talk a little bit about that, a visual syndrome, a language syndrome, or a frontal lobe syndrome and we'll talk about that. Then we'll dive a little bit into the neuropathology just to discuss these findings that Alois Alzheimer described. We will talk about some of the genetic factors of the disease and then finish with some of the biomarkers or modern techniques to detect this disease today. Let's say this is a person over the course of his life, from, say, when he's 30 and he's healthy and nothing's happening to when he's 90 and maybe he has Alzheimer's disease.

There appears to be a gradual progression of Alzheimer's disease in which it begins to affect the brain long before we can detect any signs. We call this the asymptomatic phase of Alzheimer's disease. They can then start to show up in people's thinking, memory behavior, etc., but they could be quite mild and we'll discuss what that means and call them mild cognitive impairment. Or there could be more progress and make people dependent on others for their well-being in their daily lives, and then we call that dementia. Mild cognitive impairment, or MCI, is actually described as a clinical state in which a person has cognitive or behavioral impairment from any cause, but it is specifically here, Alzheimer's disease, that it does not significantly interfere with independent living.

They are people who may forget, but can continue to take care of themselves. Remember to take your medications, you can shop and cook, pay bills and take care of your hygiene, etc. In contrast, the term dementia describes a clinical state in which we do have cognitive or behavioral impairment, again from any cause, but this time, it significantly interferes with a person's independence in completing daily functions. They progressively become more dependent on their family members, loved ones, and hired caregivers to provide them with the different levels of care they need. It's really important to understand that not everyone who has dementia or mild cognitive impairment necessarily has Alzheimer's disease.

Both terms MCI and dementia are just clinical terms and many things can cause them. Additionally, not all people with MCI will necessarily progress to dementia. We have all the possibilities. A person may be clinically asymptomatic, may have mild cognitive impairment, or may have dementia. One can progress towards the other but not necessarily. Alright. So let's start to delve a little deeper into Alzheimer's disease and how it manifests. I'll talk a little bit about the pathology of Alzheimer's disease that you see on the left side, but let's focus first on the clinical syndromes, that is, the way the disease manifests in humans.

These are, as I said before, the four most common syndromes. The first one we are going to start talking about, memory syndrome, is probably what is considered the most typical or classic manifestation of Alzheimer's disease. When people in the community say Alzheimer's disease, this is usually what they think. They think about memory loss. I would like to start. This is a poem I love by Emily Dickinson. This is even before Alois Alzheimer described this finding. It's from the 19th century, but I find it very interesting how it describes what we can feel when we have memory problems.

I'm going to read it very quickly. Today a thought came to mind that I had had before, but didn't finish. Some time ago I could not determine the year, nor where he went, nor why he came, the second time to me, nor definitively what it was, I have the art to say it, but somewhere in my soul, I know that I have met him. the thing from before He just reminded me that it was all over and he didn't come my way again. Let me start by talking about memory syndrome. People who have this typical or classic manifestation, what we call amnesia, of Alzheimer's disease.

The first sign is usually a sign of short-term memory loss, which means they start to forget things that happened recently, not long ago, last week, three weeks ago, this morning. As the disease progresses, that delay can become shorter and shorter, to the point that they may forget a conversation that took place an hour ago or something someone said 10 minutes ago. Usually, memories of things that happened a long time ago remain preserved even in a later stage of the disease. However, we do know that the past can begin to recede in the sense that people begin to progressively remember things more vividly from earlier periods of their time.

In fact, some patients, as they progress, may begin to recall very vivid memories from when they were in school or when they were children, etc. The way it manifests is that people can forget events they attended, they can forget conversations, they can repeat stories to you, they can tell you something that they have just told you or that they told you three days ago. They may lose their belongings because they forget where they left something and go looking for it. Over time, other symptoms may arise that are not necessarily related to memory. They may begin to have difficulty navigating and get lost.

This is a combination of not remembering where things are on your internal map, but also having some visual problems. In a moment we will talk a little about visuospatial difficulties in Alzheimer's disease. It can also progress to include language difficulties, forgetting words they previously knew how to say. It can affect behavior. Some people may become anxious, others may become more detached. At the end of the disease, other cognitive domains may also be affected, such as accuracy of functions, problem solving, etc. When classic or typical Alzheimer's disease occurs, we believe that memory is happening because the disease is affecting a very particular part. of the brain called the hippocampus, which in this cartoon you can see right here.

This is an MRI of a patient who does not have the disease. You can see that the hippocampus is nice and plum colored. It's that rounded gray area and it's quite large and bulky. I'll show you in a moment what it looks like in the disease. I really like the word hippocampus, it's a little interesting what it's called. It is named after a seahorse. If you pull this out, it looks like this. Because it looks so much like a seahorse, hippocampus is seahorse in Greek. In patients who have Alzheimer's disease, the hippocampus might actually lose a lot of volume, because brain cells die as time goes on, and so instead of having that kind of really nice, plump hippocampus, you might have a space and a place where that's supposed to be the case, and you may not see the hippocampus anymore.

In short, this was kind of a presentation from someone with a primary memory problem. Now people with Alzheimer's disease may also present primary difficulties in visual processing, which do not necessarily affect their memory. This is a syndrome that is currently known as posterior cortical atrophy. Some people refer to it as the later variant of Alzheimer's disease. In these people, the disease usually occurs earlier for reasons we do not understand, they are younger, perhaps between 60 and 50 years old. The first sign and symptom of this is visual processing disability and they begin to have difficulty locating things in space.

They may open a refrigerator to look for milk, and there are a lot of things in the refrigerator, and they can't visually process where the carton of milk is in the refrigerator. They may have difficulty with the size of things, they go to look for a large glass or cup and look for a smaller one or the location of how to set the table. They also have difficulty navigating their own space. A room like this would be very difficult to navigate for someone with this type of Alzheimer's disease, because in order to get through where is the door and which side do I have to go, and how do I not bump into people.

It is very difficult. They may also have difficulty recognizing faces or objects. These patients may have difficulty, earlier in the course of the disease, recognizing family members or famous people on television. Over time, the disease may progress to include memory problems and then may begin to resemble the amnestic form of Alzheimer's disease, but most of the time, in the first two or threeyears, it is mainly a visual problem for these patients. These patients are the least likely to have no idea about their illness, meaning that of all the people with Alzheimer's disease, they are the most likely to recognize that there is a problem and that they cannot manage their space. .

Some people believe that because of that, but also perhaps other factors related to where the illness strikes, they may be very depressed or very anxious. This is an image we often show our patients to determine how well they are processing visual cues and stimuli. We ask them to describe to us what is happening in the image and as you can see, there is a lot going on in this image, there is water running right there. The mother has her back turned to her children, who may be stealing cookies from the cookie jar. This would be the way you would like someone to describe that image, but people with this type of Alzheimer's disease may not actually be able to do this because they may not be able to attend to all the visual stimuli occurring at the same time. .

They may be able to describe one thing. I have had patients who simply describe what is outside the window and do not talk at all about what is happening inside the kitchen. This is one way we can test this on the back end. In people with this type of falls and illnesses, it affects a very different part of the brain, which is the back of the brain. Let me guide you a little. This is an MRI of a person with this type of Alzheimer's disease and this is the front of the head and this is the back, imagining that they are lying on the scanner on the table and you are looking through their feet, not through the top of the head but through the feet.

This is the right side. This is the left side, this is the front and this is the back. We're starting at the top of the brain, the top of the head, and as you see, if you compare the front to the back, you'll see that there are a lot of these black spaces in the back that don't exist. in front. The front is mostly made up of brain which is nice, full, plump and gray and the back has a lot of deep spaces that are black like the one I'm showing here, or here, or here. This is a part of the brain called the parietal lobe and it is responsible for much of our visual processing, but also for other things like mathematics and calculation.

It plays a role in language and it plays other sensory roles in how we feel things, etc. You can see how much volume loss there is in the back of the brain, while the rest of the brain looks more or less fine. This is the hippocampus, it's a different slice than I showed you before, but it's relatively a little bit thicker than we expect for someone with Alzheimer's disease, so the main problem is here at the back. So far, there are two different ways and two different parts of the brain that are affected. Language syndrome, also known as logopenic variant of Alzheimer's disease, is a third form of presentation of Alzheimer's disease.

It also tends to occur mainly in younger people. The first sign is a language difficulty, and specifically, people have a hard time finding words and speaking spontaneously. They were talking and suddenly they were speechless. They may try to avoid it. Like if they say a hanger, they might say what goes in the closet and then you put your clothes on it and they just blank out the word and say all these things around the word. The exact process that is affected in these patients is that everything that includes the sounds of language is very difficult for them.

To explain this a little, let me invite you to think a little about language with me. Languages ​​are a very abstract concept, who decided that if I say the sound door, that means something to us, the door that we open to enter a place and if I say the sound, that is nothing, it doesn't mean anything, but that is It's still a sound, it's a very abstract concept that we've learned since we were young and that these particular sounds are associated with a particular meaning or concept. There is a part in our brain that is responsible at all times for examining all the sounds that you receive from your environment and allows you to differentiate between environmental sound and language sounds and then once you are able to process all of that, you attach it . the meaning of each of the sounds and this is how even language begins to be processed in the brain.

There are other parts that take over for you to add the richness and texture of what they're saying to you, how you're going to respond, etc. These are some other things we won't cover today. but that initial process of understanding the sounds of language is what is affected in these patients and show that that is why they begin to leave the words blank because they cannot hear them, they cannot hear how they sound and they also begin to have difficulties to listen to them. people talk, especially if you tell them something that is very long because it has more sounds, if I said "Get out", these are two sounds, two syllables.

It's a lot easier to process than if I say, "Make sure you get ready, we're going to dinner now. We'll be late. It starts at 08:00 PM." This is a large number of sounds that the brain now has to process, as people who suffer from this variant of Alzheimer's disease will have difficulty with these long phrases instead of shorter phrases. As the disease progresses, they may have more and more difficulties with language, so communication can be really impaired. Some patients become almost mute or unable to carry on a meaningful conversation. At first it might also affect their calculation skills because we will see that this is the part of the brain that is close to where we process language sounds and then they may start to develop more visual problems similar to the first group that I showed them. before this one.

These patients probably also have a lot of memory problems that can be difficult to detect because if you can't talk, you may not have a chance to know that you forgot something because it may not come up in conversation. Let me show you just a video of a patient who has this and this is a test that we do on this patient to see how he processes language sounds. The test is really simple. We ask them to repeat a sentence, and repeating a sentence doesn't require you to actually understand it, or what it requires is that you be able to process the sounds in that sentence and reproduce those sounds.

People may not understand what they say, but they can still repeat it. However, people who suffer from this Alzheimer's disease have a very difficult time. Let me play this real quick. Can you repeat this phrase? Today was a warm and sunny day. Today was a wonderful and fun day. Today was a warm and sunny day. Can you repeat that again? Yes, there was a sun today, oh God. Summer and... I'm trying to go too fast. It's complicated, isn't it? Let's start with something easier. What if today is Monday? Today is Monday. How about the flowers that were in the park?

The flowers were on the block. You notice how he really struggles with these sounds even when those sentences were relatively simple. Which is interesting, and if you notice, there were some mistakes in the words he said, they sounded like what you're saying but they weren't the right words. He said summer as opposed to sunny day. This is a mistake that these patients often make because as they search for sounds, the brain picks up other sounds and goes there. This is to show you where in the brain this is. Again I'm going to reorient it like we did the first time.

The front of the head or actually, you can see here, this is the top of the eyes. That's the face here, that's the back, this is your left side, this is your right side. I'm going to draw your attention to this part of the brain where you see that there are a lot of spaces like some of these spaces here compared to that side of the brain. This is the right, this is the left. This is part of the parietal lobe that I showed you before, but it's a little further down. It's where we process some of these language sounds.

This is why these patients struggle. The last variant we are going to talk about today, but no less important, is executive syndrome or frontal syndrome. This is a variant that also occurs at younger ages and affects the front part of the brain, which we have not talked about yet. The front part of the brain is responsible for a lot of really important everyday things. I consider it the CEO of our brain. He is a little guy sitting there making decisions that allow us to know what we want to do today, plan our day, and execute that plan.

Motivate us to move forward with our plan. He motivated all of you to come here today and listen to this lecture and helps us organize, etc. When affected by Alzheimer's disease, people begin to lose this ability and may begin to have difficulty solving problems. Maybe they always go to the mechanics and stop knowing how to do that. Maybe they took care of their garden and knew how to organize it and they stopped doing it. Many people may show up at work because they remember that these are people who could be younger, in their 50s. They are often still working and may begin to make mistakes or have poor judgment at work.

Yes, we have a question. It is also known as frontotemporal dementia. The question is whether this is known as frontotemporal dementia. Not necessarily. It can depending on how it is presented. Frontotemporal dementia is another syndrome that describes, it has a particular criterion about what patients present. I think this will be talked about in the next lecture after this one, but this can be called frontotemporal dementia as a syndrome if the main presentation is that of a behavioral change, but the cause of it would still be Alzheimer's disease. That's a great question to pursue. Next thought, which is because the front part of the brain, in addition to being the decision maker and executive processor, is also the part of the brain that helps us select the best behavior and any particular social environment we may have .

If you think about social situations, you could be in a very professional situation or a family situation, or you could be with friends having drinks. If the same scenario or conversation occurs in each of these situations, you may respond differently because you are in a different space. You may be having fun at night with your friends, but with your boss you have to take things seriously. The front part of the brain is what allows us to process what comes to us from the environment all the time and to be able to select what is the best way to behave at this moment given the environment in which I find myself.

Patients may begin to have difficulties. with knowing what to do from a social perspective. Many of them become an appropriate or uninhibited social environment, etc. Again, over time this condition progresses to also involve other cognitive domains such as memory, language and vision, as we saw previously. Next I'm going to talk a little about the neuropathology of Alzheimer's disease or what happens inside the brain. We talk about how it manifests itself. Now let's try to dive into the pathology. The hallmark, as we saw in the first story I told you about Alzheimer's, is the presence of two main findings.

One is called amyloid plaques and the other is called neurofibrillary tangles which are made up of a protein called tau. Let's delve into the brain to better understand what that means, in our brain cells we all have this molecule called amyloid precursor protein and amyloid precursor protein, we're not quite sure what they do but we know that when it is cut in such a way that it causes what we call beta amyloid, which is the smaller yellow portion that you see here on the screen. These beta amyloids can aggregate and form what we call an amyloid beta plaque.

Amyloid beta plaque can occur in two forms. Or what we call diffuse plaques, like what you see here, all these spots or what we call neuritic plaque. They are both outside of a brain cell, this is the brain cell, which is being cut out. Outside of this, we have all these aggregates together. I really want to thank Dr. Legrum, who will be joining us later today as moderator. She provides us with many of these beautiful photographs and images to talk about pathology. She knows a lot more about this than I do. If I make a mistake, I'm sure she could clear it up later.

This is the amyloid protein that is part of Alzheimer's disease. Then there is another part of Alzheimer's disease that is related to another protein called tau. Tau is a protein that is often part of a cell's architecture. Any cell in our body and specifically our brain cells are made up of a skeleton. That skeleton that holds the cell together is made up of proteins called tau. They like to join together to form these tubules like here to form the skeleton of the cell. However, sometimes when something goes wrong inside the cell, we are notvery sure what it is.

Tau proteins can become hyperphosphorylated, meaning they have too much phosphorus attached to them and can't form these pretty tubules. Then instead they aggregate and form this unwanted part of the cell. I'll show you here in this scan. This is a neurofibrillary tangle here or here you can see it in black. These are actually inside a brain cell because the tau protein is supposed to be inside to form the skeleton. Then, when it can't do so, it aggregates inside the cell and contributes to brain cells dying over time. Alzheimer's disease is the term we use to describe the specific neurodegenerative disease of the brain that is associated with the progressive accumulation of these amyloid plaques and tau tangles that over time lead to irreversible degeneration of neurons, that is, the neurons They die with the passage of time.

There are different ways we can stage Alzheimer's disease from a pathological perspective. In fact, let me start with amyloid beta staging. We had talked about these two different types of amyloid, diffuse deposits and then neuritic plaques. So there are two different ways that pathologists look at the brain and decide how much amyloid plaque there is or what its distribution is. Below you see different forms of staging according to the distribution of diffuse neuritic plaques within the brain. Phases 1 to 5 tell us where in the brain these amyloid plaques are located. This is another scheme by which we can quantify, is simply looking at the neuritic plaques and seeing how dense they are on any microscope slide.

You can see, for example, there is nothing here, but I also think I'm cheating. This is just a blank square. This doesn't actually come from a patient, but it is when they are rare. You see some of them, but it's not too many. This is moderate when you see a little more and often you see a lot more on a slide. These are two ways we quantify the presence of amyloid in the brain. Yes. Is this an autopsy? Correct. All this is in the autopsy. Occasionally, very rarely, patients have a biopsy of their brain because people aren't quite sure what's going on and think this might be a good way to diagnose, and sometimes we find that on the biopsy, but most part is in the autopsy.

Correct. In terms of tau staging, tau seems to have a much more predictable way in which it spreads in the brain, and it seems to always start near the hippocampus and this region called the transentorhinal region. You don't need to remember that. Some of us sometimes don't even remember it. It then begins to spread from there to the hippocampus. Then it involves more of the hippocampus and that part of the brain called the temporal lobe. Then, as it spreads further into the cortex and involves different cortices, it spreads further and further into the brain. Each of them has a stage that was first described by Braak and Braak, so we call it the Braak stage of tau presence in the brain.

The higher the Braak staging in the brain, the more diffuse the tau tangles are, and this usually correlates with the severity of symptoms. So the more tau you have, the more symptoms you have, but amyloid buildup doesn't always necessarily correlate with the severity of symptoms. Yes. The question was, as this moves from one stage to the next, is anything being done for patients who have this? Unfortunately, we have not yet scientifically found how we can stop the spread of this disease and we currently do not have medications that have been shown to keep it in place.

There are several experimental drugs, some of which have been tested over the last decade to try to remove amyloid plaques from the brain, and so far we have had unfavorable results. In some patients we were able to demonstrate that the amyloid plaque had been removed, but this was not accompanied by an improvement in the disease or a stop to its progression. There may be other factors that we do not yet understand or know about. There are also other current medications that are trying to remove the tangle of tau from cells and see if we can prevent it from continuing to form.

But this is also still in the experimental phase and we are not quite sure where we are going to go. But what we hope is 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, we may have more specific drugs to try to contain this process or even reverse it if we can. . We talk about the pathology, we talk about the manifestation and let me talk a little bit about the genetics of Alzheimer's disease before we delve into the ways we can detect it in our current era.

In reality, Alzheimer's disease is rarely caused by a single genetic variant. This is what we call a pie chart. It's like a cake and we're cutting it. What you see in orange here are all the cases of people with Alzheimer's disease that we call sporadic, meaning we were not presented with any family history of Alzheimer's disease, and this is the majority, 75 percent of people . Then, in purple, you see the part of the segment of patients with Alzheimer's disease who presented to us with familial Alzheimer's disease. But this is also defined as a serious disease in people who have two or three family members with Alzheimer's disease, but do not necessarily have a dominant gene, that is, a gene that, if you had it, you would have the disease, without a doubt.

These are a very small slice of the pie in green, you can barely see it here. They are less than one percent, and the figure can be seen better here. Seventy-five percent of patients with sporadic Alzheimer's disease have no family history, 24 percent of patients with familial Alzheimer's disease have two or more relatives, and less than one percent of patients have a Alzheimer's disease of autosomal dominant genetic transmission. Of these, less than one percent, the majority have a gene called presenilin 1, 65 percent, the second group have a gene called APP, which stands for amyloid precursor protein, and a rare group have a gene called presenilin 2.

We will talk in detail about some of these genes. Presenilin 1 is located on chromosome number 14. We all have 23 pairs of chromosomes in each cell of our body. These chromosomes truly contain all the codes of who we are. Internally, externally, everything, it is genetics that dictates everything about us, and each different cell in our body sometimes expresses different parts of these 23 chromosomes. You can imagine that a skin cell is very different from a heart cell than from a brain cell. So these three cells have the same 23 chromosomes with all the codes. However, they express different parts of them to become these different cells of the body.

Presenilin 1 is on chromosome 14. When patients have it, they can develop Alzheimer's disease at a fairly early age. Onset typically occurs between the ages of 25 and 60, with the average age around 14 years. The symptoms can be quite different from those we just talked about. It's not just memory problems, but people can have movement problems similar to Parkinson's, ataxia, which means lack of coordination in their movements. They may have behavioral changes. Of course, the mutation causes amyloid beta to build up in our brain cells, and this is what causes the disease. There are some founder variations, which means these are the places in the world where we have found families that have this gene.

You see, it is actually in very specific parts of the world where this gene is present. Presenilin 2, let us remember, is extremely rare. So most cases are presenilin 1 or APP. This is extremely rare and is present on chromosome 1. Again, the onset is young, between 40 and 75 years old, with a median of 50, and occurs mainly in people of German, Italian and Spanish ancestry. Again, this leads to the buildup of amyloid protein. The amyloid precursor protein, which is the second most common gene, is on chromosome 21. For those of you who know this, people with Down syndrome who have trisomy 21, this is that chromosome.

You will have three copies of that chromosome instead of the normal one we all have. Some, because of all three copies, have a very high risk of developing Alzheimer's disease. In fact, most, if not all, people with trisomy 21, if they live long enough, will develop Alzheimer's disease. Again, this is also caused by the buildup of amyloid beta. Yes, sorry, I can't see you. Forward. The question was, what is being done with families who suffer from this to try to better understand this disease? Of course, there are studies that seek to better understand the biology, but they also try to analyze treatment in this population.

Because what's unique about this population is that we know that they are going to get Alzheimer's if they have the gene, so even when they are young and have no symptoms and no buildup in the brain, we already know that this is going to happen. to lead to that. This is a great group of people that we can, if we find a good drug that can stop or even prevent Alzheimer's disease in the first place, this is a good group of people that we can try this on. I'm aware of a couple of studies that look at that.

I don't think there are any results yet that are translatable to our community, but I hope we have more information as time goes on. Thank you. Of course. Before we continue with this, I would like to talk a little bit about apolipoprotein E or APOE, which some of you may have heard of and many people now and at the age of 23 and me, are getting their genetics. testing on their own with several private companies, and they are getting results on whether or not they are "at risk" for things like Alzheimer's disease. Apolipoprotein E is a gene that has three main different forms.

You have two copies because we all have, like I said, a pair of chromosomes. You can have two of any of these three shapes, E2, E3 and E4. E2 is considered to protect against Alzheimer's disease. E3 is considered to be neutral, it does not necessarily do anything, and E4 is considered to confer risk to patients who have it for developing Alzheimer's disease. None of these are causal. You do not need apoE4 to have Alzheimer's disease, and having apoE4 does not mean you will develop Alzheimer's disease. So this is not a cause, it just increases the likelihood or risks that you may develop it, perhaps due to another factor.

Having E4 may mean that you develop Alzheimer's disease earlier in life than people who do not have apoE4. But like I said, it's neither necessary nor sufficient for the disease and actually, medically, we don't recommend that people get tested for the apoE4 gene and know what their status is because we may not have any recommendations. to give it one way or another. . This just shows what most people have. As you can see, almost everyone in the world has an E3, E3, that is two E3s for 61 percent of the people. About 25 percent have at least one apoE4 or two and then the rest have like E2 or E2, E3.

This is just to show you the risk of Alzheimer's disease. This is the risk if we don't look at the genotype at all. It is about 10 to 11 percent in men and 14 to 17 percent in women. This is a lifelong risk at all ages. Having E2, as you can see, can be protective. So the risk is lower, 4 to 5 percent or 6 to 8 percent in women. Having E3 is neutral, so it doesn't really change the percentage much, but when you start having E4, that's when the percentages increase, in both men and women. In general, one copy of E4 is associated with an 18 to 35 percent lifetime risk of Alzheimer's disease, and two copies of E4 are associated with a 31 to 40 percent lifetime risk of Alzheimer's disease.

Alzheimer disease. Before we continue with this, I just want to thank our genetic counselor, Jamie Fong, who does a great job with us and really gave me most of the information on these slides. I just want to thank you. We talk about how it presents, we talk about how it looks in the brain, we talk about some genetic factors that can affect it. Let's end by talking about, well, how can we detect or be more confident in Alzheimer's disease when we're still alive and we're not doing an autopsy? Today, we have biomarkers for Alzheimer's disease, which are like proof of evidence, if I like to think about it.

Having a biomarker that is "positive" increases the certainty that whatever syndrome you are seeing, i.e. the memory problem, the vision problem, or the language problem, is actually being caused by Alzheimer's disease. Biomarkers are divided into three categories. There are biomarkers of amyloid deposition, where we can detect if there is amyloid pathology. These come in twoways I'm going to talk about. One is to measure levels of amyloid protein in the fluid surrounding the brain and spine. If you can imagine, at all times our brain and spine are actually floating inside a cavity and our brain is filled with a liquid.

This fluid is called cerebrospinal fluid because we are not very creative. That cavity extends from the skull to the spine. People here who have received or seen people receive an epidural, you know, this is what a lumbar puncture is and I'll show you some pictures of that in a moment. 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 about what the findings might be. Or another technique for amyloid is to do a PET scan, which I'll describe later, and check for amyloid plaques or amyloid deposits in the brain.

The second biomarker, which is really cutting edge and still under investigation, but really promising, is a PET scan for the tau protein. It is a PET scan that can allow us to visualize or see a biomarker of tau deposits in the brains of people suffering from Alzheimer's disease. Then the third type of biomarker is actually a neuronal injury biomarker, which means that it may not necessarily be specific for Alzheimer's disease in the sense that it doesn't show us the amyloid plaques that show that or the tangles, but It tells us that brain cells are dying. We can see this again in the cerebrospinal fluid or what we call CSF.

I'll show you in a moment or in an MRI, like the one I showed you before, a brain scan or a PET scan that is done with just sugar to see how the brain eats and uses sugar. We will talk about all these things. Let's start with the cerebrospinal fluid of truth, is what I call it. This is how a lumbar puncture is done. We go with a needle in the lower part of a person's back after, of course, having cleaned it very well and given it an anesthetic so that it does not feel the pain and we go into space.

These are your vertebral bones. Then they are there to protect that cavity that is filled with that liquid and in which the column is. Now, where we enter the needle, the spine is already finished, but there are nerves going down, so we are not at risk of injuring the spinal cord that extends from the brain. But we just want to get to that cavity to get the fluid out. This fluid is in continuity with the fluid that surrounds the brain. It's really the same. It is a puddle and the fluid passes all the time throughout this puddle.

It contains information that is also important for the brain. Once we get this fluid, we send it to the lab and it comes back with a report showing us the amyloid protein levels in that fluid and the top protein in that fluid. Now this may not make much sense, but bear with me if amyloid protein is low and CSF fluid is the marker for Alzheimer's disease. We don't understand this biology very well, but the way I tried to think about it to make sense of it is that if amyloid is forming the plaque, then there isn't enough of it circulating in the fluid for us to detect it, so keep that in mind.

If the amyloid level is low, it is a biomarker of Alzheimer's disease. If the level of tau is high, it is a biomarker of neuronal loss. It is not necessarily a biomarker of tau deposition. It doesn't necessarily tell you that there are tangles of tau in the brain, but it tells you that the brain cells are dying and as they die, they explode and put all that tau protein in the fluid. This is what we are collecting. The really nice thing about doing a lumbar puncture or lumbar puncture is that we can also measure other things that can sometimes cause memory problems and are not Alzheimer's disease, such as inflammations in the brain, infections in the brain, tumors, lymphomas, things like that.

Obtaining a sample of the fluid allows us to detect things other than Alzheimer's disease, and that is always good and complements the study. Now, let's talk a little about the PET scan. I really want to thank Renaud La Joie, who you will meet in a little while. He will also be part of our panel because he gave me all these slides. He is much more eloquent than me, but I will try to explain it well. A PET scan stands for positron emission topography. It is a complicated process that we are going to try to simplify. Basically, we have some material, whatever we want, that we label with a substance that is radioactive.

Something that is radioactive constantly emits a positron, which looks a bit like nuclear molecules. Then we inject the blood with that substance. Then that substance passes through the bloodstream and reaches our brain because it is in the blood and our brain receives blood all the time from the heart. Then, depending on what we are targeting, it will go to places in the brain. For example, if we put a piece that fits into the amyloid plaque and then label that piece as something radioactive, the piece will go to the amyloid plaque and then emit the positron. and then that complicated machine will detect the positron and say, aha, I see this molecule that you marked is hanging in the brain.

Whereas if there's nothing in the brain, it'll pass through the blood, go to the brain, it won't fight anything to stick, then it'll be removed and then we'll take a picture and nothing will happen. We're not going to get any positrons. Makes sense? Excellent. It really depends on what you injected into it. We call what we inject a tracer because it's actually like going and trying to hold on to what looks like that. It may have an amyloid marker or a tau marker. Or we see at one point that we could simply have sugar that is being traced and labeled with a radioactive material.

When we use an amyloid marker, this is what happens. It goes to the brain. If there is amyloid, it will stick to the amyloid and they will be able to detect it. Above is an amyloid PET scan from a patient who does not have Alzheimer's disease. If you look at the colors, anything that is dark or blue means nothing was taken. There is very low absorption of the tracer. Then, the more you use the colors yellow, orange and red, there is a great acceptance. This is a patient who does not have Alzheimer's disease. Notice there's a little bit of absorption 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. The best way to think of it is all the wires that connect different brain cells to each other rather than to the surface of the brain while most brain cells live. Then down here you see the scan of a person who has Alzheimer's disease. You can notice the big difference between the two, where there is now a lot of acceptance. There is no longer any differentiation between the white matter that is inside and the gray matter that is outside. The whole scan is what we call hot, there is a really high signal.

This is because the tracer has fixed on all the amyloid plaques and emits all these signals. This is just to show you the correlation of the amyloid PET scan with the actual autopsy results. This was done in 179 patients who died three years after having a PET scan. Then we did an autopsy on their brains. Watch as the PET scan begins to detect a signal. Remember that before I showed you these different phases. For the Thal phase, already in Phase 3, maybe even with two, we start to see a signal, but actually 3,4,5. Then for the CERAD score when the PET scan is moderate and frequent as it did when detecting it.

It's really faithful and correlates very well with the autopsy. It is a very specific way to detect amyloid plaques in the brain. Now, tau PET is a similar concept where instead of the tracer sticking to the amyloid plaque, it will stick to the tau protein. This is not yet as refined as the amyloid PET scan. It's still under investigation because we're finding other molecules in the brain that what we call tracer tau attaches to. The tau marker doesn't seem to be as specific to the tau protein now, but it's latching on to other things. However, in Alzheimer's disease, it is actually incredibly specific.

This is mainly because there is a very high tau signal in the parts of the brain affected by Alzheimer's disease that I showed you earlier. The hippocampus, seahorse, parietal lobe, temporal lobe, etc. It is still being refined, but I hope it is a very promising technique. The really cool thing about this is that tau correlates with symptoms as we mentioned above. I think it will provide a really excellent overview once it's very well defined where we are in the stages of the disease. Finally, this is a PET scan. That's when people just say PET, usually that's what they mean.

Many people may be familiar with PET scanning in the world of cancer or other medical fields. This is a PET scan that we call an FDG-PET scan. Basically these are radioactively labeled sugar molecules. What we are looking for is how the different cells in the body and, in the situation, the brain cells are consuming the sugar. Healthy cells should consume sugar very well because they take in blood and feed on it. We're supposed to see a high signal, as seen here in a clinically normal person, you see a high signal everywhere and it's hot everywhere because we want it to be.

We want sugar to be used throughout the brain. So for someone who has Alzheimer's disease, they may have lost brain cells in these areas. That's the temporal lobe here, the parietal lobe there. You'll see that you start to lose that good signal here. There is not as much absorption as in other parts of the brain. This is because the cells do not work well enough to absorb the sugar. That's another way we can detect lesions, but it's not specific to either the amyloid protein or the tau protein. To summarize, here are some things you'll hopefully remember from all of this if you remember nothing else.

The neuropathological hallmark of Alzheimer's disease is the accumulation of amyloid and tau protein within the brain. Alzheimer's disease can cause significantly different clinical syndromes, and the patient can go through different stages, from a silent or asymptomatic disease to mild cognitive impairment and even dementia. Not all patients with mild cognitive impairment or dementia necessarily have Alzheimer's disease. Less than one percent of cases are truly genetically dominant. Then there are modern biomarkers that can improve the accuracy of our diagnosis, but currently autopsy remains the gold standard for confirming the disease. Thank you all very much, I congratulate all these people who helped me put together this talk.

Thank you. Alright. Thank you so much. Now we are going to open the space for some questions. Today we have two guests. We have Dr. Lea Grinberg, who, as I said before, co-teaches our neuropathology course. She would be the right person to ask questions about neuropathology. We also have Renaud La Joie, is that correct, La Joie? Good. I guess I didn't say it correctly last time. Who is a neuroscientist at the Center and is focused on researching biomarkers, especially PET biomarkers. She would be the right person to ask all your PET questions. Then clinical questions to our colleague, Dr.

Naasan. Last time I started with questions in the front row and went back row by row, maybe today we can start with the back row and go to the front and start the questions, maybe I have two questions to get the motor going. Perhaps the first would be for Renaud. So maybe he can help us understand the difference between the sensitivity and specificity of the tests and how that relates to PET scans. In the context of AD, what are basically the limitations of these PET scans? Thanks for the question and thanks for inviting me. I am very happy to speak in front of you today and answer some questions.

You saw nice images and I'm trying to talk a little bit about what can be tricky when using these images. So you mentioned sensitivity and specificities. They are two terms that we use a lot in the biomedical field. They are basically complementary measures to measure how good a test can be in detecting a disease. An ideal test would always detect the disease when it is present. I would always tell you, oh, there is no disease when the disease does not exist, but we know that there are no tests in medicine that are like that. So sensitivity is very important.

A sensitive test is a test that will actually tell you when the disease is present. When a patient has a disease, the test will be positive. It's going to be, oh, something's going on with this patient. So you want a test to be very sensitive but also very specific. Because specificity consists of being able to rule out the disease when there is none. So we don't want a test that is going to be positive in everyone, we want it to only be positive when there is adisease. This is like the balance between any biomarker in medicine.

It is really difficult for us to find tests that are both sensitive and specific. I think George showed good data on amyloid PET and compared the amyloid PET results to autopsy data, which is our gold standard. What I can tell you is that amyloid PET, amyloid imaging, is a fairly sensitive measure. It's also very specific, meaning that when we have the signal on imaging, almost all the time, it means there is amyloid in the brain, but the amyloid PET scan is a lot of amyloid plaques. I think George made a very good point explaining that Alzheimer's is not just amyloid, but amyloid and tau.

We're actually having problems with a lot of people who may be cognitively normal and have amyloid in their brain. We know this from pathology studies. We can see that now with images, but amyloid is not Alzheimer's disease. Therefore, the test itself, amyloid PET, is not very specific for Alzheimer's disease. It is specific to amyloid and I hope this distinction is very clear. Good. Excellent. I also have a question for Dr. Grinberg so we can think about other questions that may arise. So far we have presented a purposeful way of thinking about these diseases in a structured and simple way, but as you and we know, there are many more complexities in this.

So you, who are looking at the brains. Sometimes we come across a patient who has arrived at autopsy, for example, who has been clinically characterized as having one of the variants of Alzheimer's disease, but when we look inside the brain, we may find that there is no real evidence of the Alzheimer disease. So I want you to talk a little bit about this dissociation that sometimes occurs when a clinical syndrome seems to point toward Alzheimer's disease, but we find a different pathology and that's because that's something that my colleague next week is going to expand on a little bit. more about.

What does that mean to you and how important is history in your evaluation as a neuropathologist? I'll start by saying good night everyone and thank you for coming here. It's really a pleasure talking to you. This is a very relevant question. We pathologists have a joke that we are always right, but we are always late. Most of our research revolves around not only learning what process occurs in the brain when someone develops dementia, but also what we can do to better predict what is causing dementia in living patients. Then we can treat it. Because of these types of studies, we also cause a lot of confusion because the more we learn, we change the naming and nomenclature.

So if you had been here three years ago, you're probably hearing something slightly different this time because we're evolving so quickly. One of what becomes very clear when we do these types of studies where we have the opportunity to contrast what we see in the brain with the clinical history is that we have many patients who will come to our clinics and say that they fit perfectly with Alzheimer's disease. . They start to have memory problems and they develop in the way that we associate them with Alzheimer's disease, but actually when we look at the brain, they have something different.

So what are these things that can cause something very similar to Alzheimer's disease? The first of them, and I think it is very important because it is very common and we don't talk about it much, is what we call vascular dementia. So in the same way that when our vessels are not well and we have heart problems, we also have brain problems. These brain problems are very similar to Alzheimer's disease. In most people, they will have a combination of plates and tangles. These vascular changes in the brain and the more we put these things together, the worse it is.

So anything we can do to prevent blood vessel problems will help the brain, so this is the first thing. The second thing is increasingly evident to us and we have been learning. There is a lot of news about these athletes, especially football players, having what they call repetitive brain injuries. This leads many years later to a disease we call chronic traumatic encephalopathy, have you ever heard of it? A very complicated name. CTE. We've been learning that people who had brain trauma, not as severe as these football players, maybe because they were in car accidents when we made the new seat belt, or even they were playing amateur sports, would get some kicks. in your head.

It could predispose to dementia later in life in a way that clinically closely resembles Alzheimer's disease. This opens up many opportunities for us because the two conditions I talked about can be prevented to some extent. That is why we believe that only by preventing these two diseases can we greatly reduce the incidence of dementia. I hope so. Thank you very much for these enlightening answers. Additionally, one of the sessions we will have in the future will also address prevention. So I thought maybe we could start with the last row and go in order. Some questions in the back row.

Yes sir. Nice question. The question is, what is it about these brain regions that makes them predisposed to Alzheimer's pathology? Who wants to answer that question? It's an area of ​​research, I'll say that. I can accept that question. This is, I think, one of the most important questions we are trying to solve today; We call this phenomenon selective vulnerability. The question is why some neurons in the brain are more vulnerable to a disease and others are resistant to the disease. The truth is that we don't know very well. So what are we doing to find out?

So the first step is to really map, understand what's going on, identify which are the neurons that are most vulnerable and which are the least vulnerable. This seems relatively simple, but it is not. The reason for this is that one of the only ways we can do this is through post-mortem studies. Because the images, although they are getting better every day, still do not have the resolution necessary to see individual cells. Most brains that come into our hands for research are donated by research participants we enroll in a memory clinic. So they are already very sick when the brain reaches us.

So it's very difficult to really understand the early stages of the disease, but we have some of these brains and then with these brains we have mapped which cells work first. In the past we used to do biochemical studies, immunohistochemical studies to understand what they have, but now we have much better tools. For example, something we use today is called single-nucleus RNA sequencing. So today we can put barcodes on each of the cells that we are studying, and then genetic studies or any other type of biochemical studies and understand what comes out of each of these cells.

So by doing this, we are comparing what is the difference between these vulnerable cells and these non-vulnerable cells because the idea is to create treatments that can create a shield in the vulnerable cells so that they are not susceptible to the disease. Excellent. I'll just add briefly and I learn something new every time I listen to Lea's talks, but thank you. I will just briefly add that there is increasing evidence that it is still in the early stages. I think there is more work to be done to prove it, but people are starting to see that sometimes when patients develop syndromes that are not memory syndromes, such as language syndrome.

There is a part of these people who have had some type of language problem all their lives. Maybe they had dyslexia when they were younger, maybe not. That doesn't mean that people with dyslexia will develop these, but they do seem to be represented in that population at a much higher frequency than would be expected simply by chance. The same goes for people who have visual syndrome, there has been some mild evidence that is yet to be shown that they may have had some eye injury or some vision problem or something that somehow leads to that region of the eye. brain is weaker or more vulnerable.

So when the disease hurts for whatever reason we don't understand, it affects 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 affected by Alzheimer's disease. . Yes. Oh, go ahead. Actually, just a last word on this, I didn't think about it until you started talking about the 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, APOE, especially the APOE4 form of the gene. And we know that it is not just a random risk factor for the disease.

It is a risk factor specifically, or more strongly, for the amnestic form of the disease. When we look at patients with the language variant or the visuospatial variant, they actually don't have that gene as much. We think that the APOE4 gene actually makes the brain more vulnerable to Alzheimer's disease, but especially like the hippocampal system and these amnesic forms of the disease. I think there is a mix of genetic factors in the process. I think we have a question behind. Lady back. Yes. Great question. The question is: do all the syndromes develop in the last stage of dementia?

Perhaps Dr. Naasan can address how the disease changes as dementia progresses? Yeah, this is a really important question and I think it's really hard to answer for a lot of reasons and I'll say why, but a long time ago, I was a medical student and I learned about this, I think people thought that, yeah, like A As dementia progresses, all dementias will eventually look the same because they affect the entire part of the brain. But I don't necessarily know if we see this and Lea can talk more about some type of pathology, but I think what happens is that the parts of the brain that are most affected are affected enough that you can't see them. whether the other areas are still active or not.

Let me give you an example, which I think we mentioned briefly for language. If someone has a language problem and it progresses enough that they become mute or unable to communicate, we will never know if this disease progressed to affect memory or not because there is no way we can do that. Ask them to remember something because they can't communicate. The same thing if someone can't see things, can't leave the room, can't do something, it can be hard to think, well, is he doing this because he can't find his way, or is it a behavioral problem?

I think the symptoms start to blur each other as the disease progresses and I think as we become more specific in

diagnosing

these, we need to be careful to provide adequate and appropriate support to patients, taking into account what they are. the predominant symptoms they have. . With that in mind, I guess, you want to talk about pathology too? Thanks for your question. Even in the early stages of the disease, it is not that the entire brain is affected. We still have many areas of the brain, they are preserved. The case of Alzheimer's disease is a very long disease because the areas of the brain that are important for our survival are affected very late in the disease, but even at this point, we do not see these areas affected.

Just to make a contrast, this is completely opposite to Lou Gehrig's disease, amyotrophic lateral sclerosis, because in this disease, the areas that we need to survive for breathing and motor control are affected very early. In part the person will pass because of this, even with all cognition still working very well, so it depends on the area and even in the later stages the whole brain will not be needed. Let me add to this and summarize the concept that I think is important for us to keep in mind throughout this series: These diseases, as I explained in the first lecture, are our focal onset.

Which means that there are certain, like Dr. Grinberg, who just explained certain areas that are affected earlier and therefore, if we see patients early, we can detect the signs and symptoms that lead us to that region of the brain and then they make us think about what is the pathology that can get there? But as the patient progresses in their disease, these substrates, these proteinopathies, will travel to different regions of the brain or expand and therefore the clinical syndrome will change. So, a person who starts out with just an amnesic presentation will eventually have language problems, will have visual problems, and if they live long enough with this disease, then, as you just heard, that disease will begin to affect those vital centers of the brain that controls things like walking, swallowing, and breathing.

Unfortunately, this is where things get complicated. The next row, then yes, sir. Vascular dementia is a causedifferent from dementia. Think what we were hearing before is that what you were trying to introduce is the concept that a lot of times, especially the older the patient is, they're not always very clean, which means it's not like they just have Alzheimer's disease. in your brain. Alzheimer's disease as we advance in age tends to also be accompanied by vascular changes. We would say that this person had both Alzheimer's disease and a vascular disease that was causing his dementia. Makes sense?

In other words, has erectile dysfunction been linked to vascular dementia? Is that what you're saying? I'd say that's a fair statement, especially for patients older than what age? You would say harsh. I think perhaps the correct statement based on the evidence we have now is that both are so prevalent that they often occur together. There is some doubt as to whether they will feed each other. I know it synergistically. I don't think we have very strong evidence to say yes or no, but they are certainly very common and they work together. So we know this is for post mortem studies.

It is very possible for someone to die with a large amount of amyloid and tau in the brain without showing any symptoms. However, it is not possible to see the same situation if the person on top also has these microvascular changes in the brain. If the structure of the brain is not right to begin with because there is a lack of oxygen and no, the same goes for the heart. The brain has a harder time overcoming this buildup of proteins there, and again, this can be prevented to some extent. Maybe around here. And then we'll move on.

Yes. We will talk more in a later session, but I can say that diabetes is recognized as one of the risk factors for cognitive decline later in life. It is an association. We have a few hypotheses about why one would be that diabetes causes vascular changes in the brain as well as the heart and other parts of the body. Yes sir. So we'll move over here. That's a great question. The question is, what do we think about cerebrospinal fluid and why does it contain proteins that we are measuring in the first place? It is a fluid that, like any fluid in our body, is made up of different types of molecules and things.

For example, if you take a blood sample, in your blood you can measure several different things, sodium level, potassium level, enzymes, etc. Cerebrospinal fluid is another type of fluid. It is not blood, but it contains a lot of information about the cells found in the brain and spine. It may contain, first of all, cells, like cells that are there to protect the brain. If there is an infection, sometimes the number of cells in the fluid would be very high because they all come to the brain's rescue. May contain blood. If you are bleeding somewhere, it will appear in the cerebrospinal fluid and it may contain different types of proteins that if you are not measuring them you will not know they are there, but if you measure them then you will be able to know the level of them.

One of them is amyloid, and normally all of us, if we took a sample of everyone present from their cerebrospinal fluid, we would have a level of amyloid protein. It's usually pretty high and 800 is kind of a number, and the more that level goes down, the more likely we are to have Alzheimer's disease. Or I guess I should correct and say that there is amyloidosis, which means that there is some amyloid protein process in the brain. Does that help frame that a little bit? It no longer has the possibility of going to the cerebrospinal fluid. That's how we understand it.

The amyloid begins to solidify somehow and settles into these blocks. So there is less amyloid going into the cerebrospinal fluid, but tau is the opposite. Tau is inside the cell and begins to kill it. When the cell dies, this tau is released, so there is an increase in tau in the cerebrospinal fluid. One question here and then we'll move on to the next row. When we talk about Alzheimer's in other primates. Oh, maybe for Lea. Alzheimer's is a human disease. What we have in primates, in some of them we can have amyloid accumulation. We do not necessarily have cognitive impairment.

I once had the opportunity to examine a collection of very old chimpanzees. They were almost over 40 years old, which is a very old age for chimpanzees, and they only had tau in very specific structures of the brain stem, which is this part of the brain that is in our neck. They don't accumulate it. Nor do they accumulate in rodents, not even amyloid itself. When we produce animal models to study Alzheimer's disease, we have to artificially add these proteins there because they are not produced naturally. But eventually, dogs accumulate amyloid and that causes them to go blind when they grow up, and some dogs can also become agitated because they can't see very well and become anxious and may bite.

This happens a lot to dogs. Is it because amyloid accumulates in the cortical cortex or does it accumulate especially in the areas that control vision? And in fact, in humans, we know that amyloid also has this tendency to accumulate in individual areas of the vessels. Therefore, it is an area vulnerable to amyloid in dogs and humans. We'll go down here. Is there a synergistic effect between Macular Degeneration and Alzheimer's? I do not think. It's not that we have very strong scientific evidence, however, having said that, there are more and more studies being done on the retina and the changes that occur in the retina that could reflect changes that are happening in the brain.

In many ways, the eyes are just one part of the brain. So it's just the direct extension of the brain. There are many theories that the changes that are occurring in the brain could manifest or affect the eyes, and there are other neurodegenerative diseases that I think we are starting to have more evidence for. I don't know if they will talk about Lewy body disease in another session. Briefly, yes. Yes, but Lewy body disease is another type of neurodegenerative disease that causes brain cells to also die and can sometimes resemble Alzheimer's disease, and progressively there is evidence that there are changes in the retina that are very similar to those. changes we experience are seen in the brain in Lewy body disease, so I think this is something that hopefully we'll learn more about as time goes on and more scientists can look into it.

I think I've been alerted that we have time for one more question. Maybe follow the path of democracy. The question is: what is the association between hearing loss in the brain and why do we treat the hearing loss in the first place if that doesn't treat the brain? I believe that having hearing loss may predispose some parts of the brain to be vulnerable to disease because they are not being stimulated by sound when they do not receive enough sound to process it within the brain, and so in the same way as being blind, it could predispose the visual parts of the brain to degenerate because they are not functioning.

Not hearing could predispose the auditory part of the brain to also degenerate. But having said that, if you have some cells that are still working to try to understand language or what's going on in the environment. It will be great to help them by making sure they receive clear sound and speech. I think the hearing aid is therapeutically important and I spend a lot of time in the clinic trying to convince my patients why it is important. I think that's exactly what it's for, even if it's not necessarily treating the disease itself, whatever remaining brain cells you have that are really doing their best to support your cognitive function, it would be great to not make them work. even harder to hear, but allow them to receive the sound as clearly as possible.

Does that answer your question? What do you think, Lea, do you want? I doubt neurogenesis or neuroplasticity is something that is still very controversial. We don't know exactly how it happens and if it happens, but what we do know is that neurons have the ability to try to work harder, at least for a certain time, to overcome the disease, at least in the early stages of the disease. disease. What we see biologically in Alzheimer's disease, for example, is when a region of the brain is affected instead of decreasing in terms of function, it increases at least for a few moments and then it can't handle it anymore.

In a way, it is about plasticity, not more neurons, but higher functioning of these neurons. But I think we still have a lot to learn about this, and again, one of the problems in studying this has to do with the difficulties in reaching people who don't have dementia, but who want to participate in this type of research. risk. With that hint that we need volunteers. It was great having you.