Is Dementia Inevitable?

- It's probably not the done thing to give the answer to a question right at the beginning, but I'm going to risk it. In a trivial sense, I think dementia is inevitable. Given our current biology, if somebody lived to 150, we recognize that organisms and their organs decay and fail. Given our current biology, if somebody lives a normal maximum lifestyle, I think the answer is a definite no, it is not inevitable. And to get there, what I'd like to do is to start with reviewing a little bit about the history of dementia, and our perceptions about failing faculties as people get older, then to discuss some of the different diseases, there are hundreds of diseases that can cause dementia, but just pick out a few of them, and how our understanding has advanced, and then talk a little bit about possibilities of prevention, because although some dementias are definitely treatable, they tend to be rare, we tend not to think of them in the way that we do the commoner dementias, but there probably are windows of opportunity for prevention. Dementia, actually, is a horrible word, it has a lot of emotional connotations, and conceptually, it's probably now become unhelpful, it's been useful in the past, but not now. People talk about a tsunami of cases, about, this is the big problem of the future, equal to that of global warming, and much of this I think is true as we have lived longer. The predictions are that, currently, now, the costs of dementia are about the entire gross domestic product of a country the size of Turkey. And people wonder, is this new, is it just that we're diagnosing cases, or is there something about our modern lifestyle that means dementia has indeed become an epidemic? But no, it's been around for a long time. Nearly 4,500 years ago, Ptahhotep, who was a vizier of the 5th Dynasty, began to forget what he'd done the previous day. He was, in his time, quite a famous philosopher, and wrote advice on young people, how they should grow up, no longer be childish or adolescent, but then he himself, in the evenings, began to become adolescent. And there are many writings, and it's become a major feature in literature, poor King Lear asking not to be mocked when he has trouble recognizing his daughter Cordelia and his loyal supporter Kent, and of course, Jaques' famous soliloquy ending with, "sans everything." I'd like to come back to that phrase again later,'cause it could not be further from the truth. And then there's the wonderful episode in "Gulliver's Travels," where he comes across the Struldbruggs, and in this community, some, rarely, are born with a small mark on their forehead, and that marks them out as people who are going to be immortal, and Lemuel Gulliver thinks, oh how wonderful that here is immortality, but unfortunately, it's immortality with aging, and not eternal youth, and as the Struldbruggs age, they begin to lose their senses, and they all invariably dement. Cleverly, society doesn't allow them to own anything after the age of 50, otherwise they would acquire so many resources that the rest of society would be at a disadvantage. And is it just human? If you lose cognitive function and you're in the wild, you're not going to last very long, but for companion animals, there's now increasing evidence, and quite a big commercial market, for recognizing senile dementia in cats and in dogs. But is this just a feature of age? Well no, and early on in the Greco-Roman period, people were beginning to distinguish a cognitive impairment associated purely with age from a number of other causes. Hippocrates took the view that if you lived to be 80, you would develop what he called morosis, or a type of stupidity that was associated with aging. But even then, Posidonius developed another term, leros, to describe other causes that were unrelated to age that could cause cognitive impairment. The term dementia started to appear in medical literature around the 1400s, and had developed quite a lot by the 19th century. This is "A Treatise on Insanity," written by Esquirol, and in fact, in terms of the causes there, interestingly, quite a few would be recognized now as causes of significant cognitive impairment, or dementia, so progress of age, we've talked about that, falls upon the head, so brain injury certainly is a cause of cognitive impairment, or dementia, syphilis, abuse of mercury, and abuse of wine. I think we'd not recognize quite so much the moral causes of dementia, certainly, if political shocks were true, then we really may be in for quite an epidemic of new cases. Things really changed in terms of distinguishing dementia that might be associated with the progression of age from other causes came with Alzheimer, and I'll come back to this again in a moment because, very commonly, people conflate dementia with Alzheimer's disease. But this rather nice photo from the Tubingen Ramblers Club has Alzheimer on the far left, and there's Kraepelin, who was his strong supporter, and did much to champion to eponym of Alzheimer's disease, and then there's Gaupp, who was Nietzsche's psychiatrist, and Nissl at the end on the right. And actually, Nissl was quite important in this because, as with so much in science, it depends on new technologies being developed, and at the time, the German dye industry was very strong, particularly with the development of aniline dyes, and Nissl used these to stain brain tissue slices, and was able to show the nuclei and individual neurons. And Alzheimer saw a patient when he was working in Frankfurt, a lady called Auguste Dieter, and she developed cognitive impairment at a young age, she was only 54 when Alzheimer first met her, and those are the case reports that were subsequently unearthed by colleagues at Frankfurt. She developed a number of paranoid delusions of infidelity, she had difficulty with word finding, and had quite a prominent difficulty with her memory for day-to-day events. Alzheimer moved from Frankfurt to Munich, but when he heard that Auguste Dieter had died, he arranged for the brain to be transported to his laboratory in Munich, and he applied some of the dyes that had been developed and used by Nissl. And what he showed was there were two key features that he could identify using the stains. On the left is a neurofibrillary tangle, which is within the neurons themselves, it's now known to be an abnormality in a protein called tau, which is critical for small micro-tubules in a brain cell to aggregate properly and to provide the internal cytoskeleton, which is critically important for maintaining network structure of cells within the brain, and for transporting down neuronal processes, axons and dendrites, to maintain metabolism. On the right is the amyloid plaque, which has come to be seen as almost a sine qua non of this disease, Alzheimer's, and relates to a misfolded protein. Amyloid just refers to the way that the proteins fold and become insoluble, and there's a class of proteins that are like that, but there is a specific one with Alzheimer's disease. When Alzheimer moved to Munich, he moved to work with Kraepelin, and it was Kraepelin who really championed the eponym of Alzheimer's disease for this apparent new disease. It was, at the time, thought to be rare and early onset, as indeed Auguste Dieter had early onset form of dementia. I'd like to pause here,'cause I said that dementia really is quite a problematic term, and I'll show this slide more than once, because it's important to recognize what people mean by dementia. It's a syndrome, it's a cluster of clinical features, and it means that somebody is sufficiently impaired that it prevents their normal day-to-day function, and it implies that there's a number of different cognitive impairments. It's not the same as Alzheimer's disease, and I emphasize that because people often conflate the two. If they do, it's a category error, thinking that a specific disease is the same as the syndrome. It's very commonly mixed up when people are talking about dementia, particularly by politicians, but also by doctors, and I find myself doing it as well, so if you hear me slipping between Alzheimer's and dementia, I'm sorry about that, one just ends up doing it, but we really have to be very, very precise as to what we're talking about, otherwise we're never going to be able to answer the question posed in the lecture. There have been a number of definitions of dementia, I put this one up, which is now 40 years old. It's become better defined, but this, I think, has done a lot of harm, and was very influential at the time, and the problem here is this term global. Dementia as a syndrome has had its uses in the past. Before we had the era of very successful brain imaging, somebody who's developing a cognitive impairment, it was important to understand whether this was focal, maybe just a language impairment, because that might mean there was a surgically amenable abnormality, like a meningioma, or a relatively benign glioma, and without imaging, that was quite a big call to make, to operate. If it was quite a widespread impairment, then people would assume this was a degenerative process, and that was helpful. This term global impairment, it has echoes of Jaques' sans everything, and it could not be further from the truth, and I think that's very important to recognize. It's important because these diseases, I'll come on to show, can have very selective effects, and that tells us a lot about how the brain is wired, how the brain works, how the brain perceives the environment, and it's also important because, otherwise, if one just views things as global, we do a disservice to our patients, because it emphasizes what's missing, what's not working, and does not emphasize or celebrate what works. And although diseases do progress, if cancers can progress to metastasize widely, it's not the end stage of diseases that are important, it's the 15 to 20 years during which somebody is living with a condition that's important. So I'll come back to this again, global is horrible, it's not sans everything, and that's why dementia, I think, is somewhat a problematic syndromic term. But to come back to Alzheimer's disease, because we do now understand a lot more about this particular condition, following the description, it was thought to be an early-onset dementia. It was referred to as a pre-senile dementia, conventionally, that's coming on before the age of 65. But work that took place, really, in the 1970s and 1980s looking at people with what was referred to then as senile dementia, it was recognized that they had the same neurofibrillary tangles and senile plaques that were seen in Auguste Dieter, Alzheimer's first patient. What's been very helpful in understanding what's going on is by the examination of a very rare form of Alzheimer's disease which is hereditary. Alzheimer's disease often will run in families, but I'm afraid all of us carry the burden of what runs in our families, whether it's a predisposition to diabetes, to arthritis, to eczema, or whatever, we carry genetic variations that make us prone to particular diseases, and that's true for Alzheimer's. Rarely, and it is rare, it can be inherited as an autosomal dominant, where the probability is that 50% of offspring of an affected parent will develop the disease. It comes on very young, I have seen people in their 20s developing familial autosomal dominant Alzheimer's disease, but it often comes on in people in their 40s, 50s, or 60s. I said before about, so often, advances in science and in medicine depend on techniques, well we had Alzheimer and the German dye industry as a major technical advance, genetics has made a big difference here because it was possible to identify, in these families, the culprit gene, and there's more than one gene that's been identified, but they all are critically involved in the production of the amyloid protein. And I'll just go through this schematic demonstration of what we've now learned about this, and that is that the amyloid protein that gets deposited that we see in the Alzheimer's brain is abnormal, it just clumps, it becomes insoluble, it shouldn't be doing what it should be. It probably is toxic, but we don't quite understand yet how it's toxic, and how it leads to the other cascade of the neurofibrillary tangle, the collapse of the neural network, and the loss of brain cells themselves. But there is an amyloid precursor protein molecule that's shown in red, and embedded in the middle there is this A-beta protein, that's the one that gets spliced out by two main enzymes, a beta-secretase and a gamma-secretase, and what then happens is that that molecule gets released. When everything's going well, it's soluble, it has a function, that's all good, but if you have a mutation, it makes it prone to be insoluble. A lot of the proteins that we have, and that evolution has, in a sense, produced, are right at the edge of their solubility. Why that should be, I don't know, but then, if something mischievous happens, either because there's a mutation in the gene for that protein, or some environmental process happens, it just flips and becomes insoluble, and often, then, there's a cascade. And if something rarely flips, of course, that may be a link to age, because if you just go on for long enough, the probability of something not quite happening increases, so these proteins are on the edge of their solubility. And so what happens is that we get what should be these nice A-beta molecules doing their job, but in fact, they become insoluble, they form fibrils, they clump together, and then we see the amyloid plaques that are typical of Alzheimer's disease. And there's been a lot of interest in, can we interfere with that cascade in order to treat people with Alzheimer's disease, or prevent them if it's early enough. A study of people with this rare form of Alzheimer's disease has also been very important in understanding the natural history and how the disease develops. It's very difficult, and very expensive to take a group of healthy, let's say, 50 year-olds, and follow them all to see if any of them develop Alzheimer's disease, that's clearly very, very difficult, but by looking at people with familial Alzheimer's disease who carry a disease mutation, obviously you're then able to follow the disease. It tends to come on at a very characteristic age for a given family, and you can also use the siblings who don't carry a mutation as very good control, because they would have had an early life development where they would have shared the same environmental factors as they were growing up, and where they'll be sharing a lot of their genome. And what one can do is follow such people with imaging, and imaging, as I said, has become so important now in how one diagnoses and manages these conditions, that what one can do is actually follow the atrophy itself. This is over just a couple of years of somebody with familial Alzheimer's disease, and you can see the ventricles in the middle there expanding as brain tissue is being lost. And you can see this in individual people, that's an aggregated series of scans that I showed you there, this slide shows an individual with a particular mutation causing familial Alzheimer's disease, and the three scans at the bottom are all registered to an early scan, and where you see green or blue, it means things are shrinking, and where you see red and yellow, things are getting bigger, expanding. So the ventricles are expanding as the cerebrospinal fluid is filling up the space of lost brain cells, and particularly, here are the hippocampi, which are so critical to our memory processing. You see here, it's not until this stage that the individual actually fulfills the criteria for making a diagnosis of Alzheimer's disease. Symptoms are sort of starting here, but you can see the brain volume is beginning to go down well beforehand. And if you look at what's happening to some of the molecular markers of Alzheimer's disease in these familial Alzheimer's disease cases, there's a very long prodrome. There's a very large international consortium now, led out of the States, to look at families with these mutations, and looking at a number of measures that are now available, looking at the A-beta molecules, and looking at the tau, that makes up those neurofibrillary tangles, looking at brain shrinkage, and particularly looking at the volumes of the hippocampus, which is where, in the common situation, Alzheimer's tends to start. This is an aggregate of all the various data, it was published a few years ago now. I think the way I would interpret it is that, probably, there's about 15 years where things are going amiss. Just because somebody carries a gene, it doesn't mean they're diseased, it would seem counterintuitive to say that a very fit, well, intelligent five year-old who happens, unfortunately, to carry one of these genes is diseased in some way, but things begin to go wrong about 10 to 20 years before it's clear that there is something amiss, and that's very, very important in terms of a potential window of opportunity for prevention, and I'll come back to that. Of course, what this depends on is that what we see in the autosomal dominant familial cases can be generalized to the more common sporadic disease that occurs in people particularly in their 60s, 70s, and 80s, and that remains to be seen. But it's not all about memory, and I'd like to just give a couple of examples here, because I think it pulls out two very important points. One is that these degenerative diseases, when these proteins that are at the very edge of their solubility go awry, it doesn't just wipe out all the brain, it can be very selective for networks of neurons that subserve particular functions in the brain, and we understand a lot more now about the parcellation of cognitive function, about the fact that cognitive function is modular, with particular networks fulfilling particular functions. And although we think of Alzheimer's disease as being a disorder of the memory, that's not necessarily the case, and there are many, which are now viewed as atypical, but they are quite frequent. This is an example of somebody where the disease starts at the back of the brain, and using that same registration process, so blue and green is where there's shrinkage, but you can see it's all at the back of the brain, it's all around the occipital lobe, which is where we process visual information. The graph underneath is just two measures, one of which is looking at vocabulary as an intelligence measure, the other is much more dependent on visual processing. And in this individual, this was a very surprising case,'cause this was somebody who was a control in our studies of people with the disease, who just happened to, unfortunately, develop this posterior form of Alzheimer's disease, but we did have serial imaging, and we were able to show that the disease started at the back of the brain. I'm just going to show one patient we'd seen, William Utermohlen, and this is in the public domain, who was quite a well known portrait artist, and did a series of self-portraits, and this is an example of an early self-portrait. He unfortunately developed Alzheimer's disease, he came to our center for a clinical trial, and had stopped painting, and our research nurse, who got to know him very well, Ron Isaacs, suggested that he should continue painting, and he did. This is the series of self-portraits that he then went on to create. This I found a particularly harrowing one, because he did ask us at one point, how do you know I've got Alzheimer's disease, and we said we can't be sure. He said, how can you be sure, we said, the only way one can be sure is actually to look at the brain, and hence that handsaw on the right-hand side of his self-portrait. He was aware of the difficulty, he would say, I can't get the ear right here, I don't know how to do this, and yet the emotional valence of this is enormous. Again, global, sans everything? I don't think so. So that comes back, sorry to keep harking back to it, that's why this term dementia is just so, in so many ways, dangerous, and this problem of conflating Alzheimer's disease with dementia, because there are many other causes of dementia. It's impossible to go into all of them, but I would just like to go into a little bit more detail about another one, because, again, it's important in understanding what we mean by memory. We normally think of what is referred to as episodic memory, memory for episodes in our lives, our autobiographical memory, and that's where the hippocampus comes in. There are many other types of memory, the memory of how we do motor programs, riding a bike, et cetera, but there's also a semantic memory system, which is our knowledge of facts, facts and meaning. I use my episodic, or autobiographical memory to remember that, actually, on a Tuesday, I came to Barnard's Inn, I gave a lecture, but I require my semantic memory to know what a lecture means. Just very briefly, a couple of other conditions, one, dementia with Lewy bodies. This overlaps with Parkinson's disease. It's important because it's another protein, a protein called synuclein, that again is near its solubility, and what we now realize is so many of these diseases do overlap, and as they progress, you get a cascade of these proteins that are misfolding. Dementia with Lewy bodies, Mervyn Peake was a patient at Queen's Square, and somebody went back to look at his case notes, it wasn't clear what he had at the time, but he almost certainly had dementia with Lewy bodies. These patients, as well as developing a Parkinsonian syndrome, develop hallucinations. They're quite distinct from those in psychotic disease, they rarely speak, and these are some of the sketches that Mervyn Peake made of the hallucinations that he was experiencing with his Lewy body disease. And the other cause, and it's important, this, because at one time, vascular disease, strokes, little strokes with hypertension, big strokes, were thought to be a major cause of cognitive impairment in later life. It still is, and I'll come back to that in a moment. I've put here vascular dementia, I prefer the term vascular cognitive impairment, and it very frequently is seen in combination, particularly in the older person, with these other degenerative diseases such as Alzheimer's, et cetera, and that's a problem. The traditional way of approaching diagnosis is using Ockham's razor, or the principle of parsimony. If I've got 10 observations, I could come up with 10 explanations. If I've got 10 observations and I can come up with a single explanation for those 10 observations, then Bishop Ockham says that's the one you go to, a nice principle of parsimony. And that's worked very well for medicine, and a number of situations, particularly with genetics, where we thought there might be two different diseases, actually can be explained by one single genetic disorder. But as you get older, life's not quite like that. John Hickam is an American physician, and his dictum was that a patient can have as many disease as he darn well wants. And Ockham's razor, the parsimony principle, does begin to break down as we get older, and we're having to deal with a multitude of different disease processes. I'm just going to pause here, because I want to rebalance things slightly, because being forgetful has had a very bad press, and I've presented it as being bad. And as Rochefoucauld said in one his maxims, everyone complains of their memory, but very, very few ever complain of their judgment. And we do complain about our memory, it's a very, very common presentation at GP surgeries, and particularly with all the media attention around cognitive impairment, or dementia. But forgetting's important, we don't remember everything. We don't remember our infant years, we can't remember exactly what happened on July 7th, 2013, and we can't remember all the semantic knowledge that might have come our way. There was a very nice review just last month about the fact that forgetting has an important role in plasticity, we can't afford to remember everything. In the Penguin Classics of the Argentinian writer Jorge Borges, there's a wonderful short story about Funes the Memorious, and the writer describes seeing Funes when he was a young man, and had the ability to know exactly what time of the day it was, and he was intrigued by that, and then he'd heard that Funes had been thrown from a horse, and was now paralyzed, but he also had a perfect memory. And he went to visit him, and Funes could remember everything. And sometimes, to keep himself interested, because he was now paralyzed, he would recall everything that had happened the previous day, but it took him the whole day to recall what had happened the previous day. And he developed a naming system for every single little, I'm slightly paraphrasing here, but it gives the idea of every pebble on a river shore, and then he realized that wasn't sufficient'cause he had to account for the passage of time, because every stone that he remembered would be different from moment to moment because the context was different. And he described, Funes, how, for him to see somebody, or an object straight ahead, that was a different object from looking at it from the side. The brain has this ability, our perception, to create a visual object depending on which angle you look at it, so if we had perfect memory, how would we subtract knowledge, how would we generalize, how would we have wisdom? It would be impossible if everything were discrete, autobiographical chunks of our memory. So I'm putting in a plea for forgetfulness, it actually is quite an important thing, but clearly, what we're talking about is where it just tips over into not being so good. So can we live to an old age and still function well? The famous case of Jeanne Calment, who lived to 121, she was in the village of Arles, she remembered van Gogh coming and buying his paints from the local store. Sadly, she outlived her daughter and her grandson, who actually died in a road traffic accident. When she was 90, a local attorney went into a viager arrangement with her whereby she was allowed to live in her house, he paid her 2,500 French francs a month, and you can see where this going, she outlived him, the family had to keep paying the arrangement, so by the time she did die some 30 years later, she'd been paid an enormous amount of money, far more than her house was worth. In the 1990s, people did examine her, she had a CT scan, which was not normal, but it did not show dramatic changes that one might have anticipated, she had difficulty with hearing and with vision, but her memory was well preserved. And there are other good examples, particularly in the arts, Picasso and Grandma Moses painting into their 90s, Rubinstein performing, and in science, Hans Kosterlitz was working on the discovery of the enkephalins when he was in his 70s. So yes, it is possible to remain cognitively intact well into late life. But what can we do, how can we maintain that? Of course, if you want to look for what the answer is, you go to "The Daily Express,"(audience laughs) lots of claims, there's all sorts of treatments that all sound wonderful. I did say that some dementias are treatable. There are a number of rare diseases that, in the past, were viewed as a dementia. We don't think of it now because we have this mindset that it's a global catastrophe of the brain, and it's untreatable, but even simple things like hypothyroidism in infants, so called cretinism, before it was recognized and treated, these people would grow up to adults with dementia. But for the degenerative diseases at the moment, for Alzheimer's, we don't have a simple cure. There's a lot of research going on particularly looking at the amyloid pathways, it's all very encouraging, but we need to be careful thinking about terms like cure. We rarely cure diseases. Orthopedics can be pretty good at it, infectious diseases experts can be pretty good at it, but a lot of things we just learn to live with, people learn to live as long-term conditions, their cancers, or their diabetes, or whatever, and what will happen, I suspect, or I would hope so, is that we learn how to manage these abnormal protein accumulations so that they become long-term conditions that are ameliorated, and one can try and maximize what function there is. But what are the options for prevention? Colleagues at UCL undertook a review on behalf of "The Lancet" to look at what factors there were that might be reversible that were linked to a higher risk of dementia, and they were throughout life. And you can see here things like education, there is pretty robust evidence that a higher education provides some sort of cognitive reserve against the onslaught of some of these diseases, and a number of mid-life ones. And what they then did is to perform estimates of what the population-attributable fraction would be if you could intervene. They tried to account for the fact that some of these might overlap, and some extent allowed for, and came up with an indication of around about 30% as an upper bound, i.e. this is if people absolutely could get rid of these factors, you might be able to prevent dementia in up to 30% of cases. That's important. And there is some evidence that in the Western World, certainly in the US and in much of Europe, that actually, the incidence rate of dementia may be going down. The prevalence, the amount that there is in the general population, is still increasing, because we're getting older, but the new cases per year may be coming down, and that's probably due to better management of hypertension, high blood pressure, of people in their 40s and 50s that tended to be overlooked before. But I would finish with, coming back to this issue of dementia, dementia really isn't, I think, helpful. It is only the tip of the iceberg, so that prevention commission,"The Lancet" commission, was talking about all-caused dementia, so when we're talking about dementia, this is severe cognitive impairment, it's not global, it's certainly not global, but it's causing problems. I think we need to focus a lot more on cognition generally. Showing those data about the course of people with familial Alzheimer's disease, where we can follow their progression, obviously, people are going to have their cognition beginning to be blunted before anybody thinks about a diagnosis, and that's a lot of that submerged part of the iceberg. But there's a lot of other things, ill health, cognition is a bit like the canary in the coal mine, it's one of the first things that goes if we're not well. If you got COVID, your cognition is just not good, it's very sensitive. And some of these are short-term effects, but they're still very important. Medication, an awful lot of medication causes problems with cognition, poor education, we talked about that, pollution, good evidence that pollution is not good both when you're an adult and when you're a child, injury, particularly head injury, but then things like poverty, wicked problems, really difficult to solve problems, are going to impair people's cognition, and stress. We need to shift away from just discussing dementia, to thinking about cognition more generally. Whatever we do will have a cognitive footprint in the same way that we think about what we do having a carbon footprint, and we've got to maximize, or reduce, whichever way you want to do the sums of the metric, to maximize our cognitive potential. So what about cognitive health? This is my own particular list that's culled from things I quite like, and things where there's good evidence. Do protect your head, and don't smoke, I think they're good, diet, there is increasing, I think, evidence that diet is good, the old story of the Mediterranean diet, wine, I think there's very good evidence that wine is helpful, though I have to recognize that nearly all the best data from the University of Bordeaux.(audience laughs) Sleep's important, there's now evidence that we get rid of some of these toxic deposited proteins when we're asleep, meditation, relaxation, exercise, curiosity, a bit of, is that cause or effect. The key thing is maintain activity, whether that's physical or mental, and so I guess keep coming to Gresham lectures. Thank you.(audience applauds)- I've got some questions, I'm going to start with some questions from online and then we'll go to the room. You've answered quite a lot of these already, but could I start with one about the lack of sleep, what is the effect of a lack of sleep on the onset of dementia?- First of all, I'll take it that it's not just about dementia. And I'm looking at the camera'cause I think I've got to the look at the camera, so if you're wondering why I'm looking into the distance, I'm looking at the camera. There's the short-term effect of lack of sleep, and that's really important. Coming back to that issue about maximizing cognition, if you don't sleep, your cognition goes, and if you're sleep deprived for long periods of time, the brain just goes haywire, people start hallucinating. In terms of its effect on degeneration, there's increasing evidence that we have a system, the glymphatic system, it's referred to, whereby we actually move some of these proteins out of the brain, and sleep seems to be quite an important component of that. The other thing to mention is that some of the early brain networks that are impaired in Alzheimer's disease, and some of the other degenerative dementias, are also those that are involved in modulating and maintaining our sleep.- I've got a question here about treatments,"Do we have any evidence"that any treatments can slow or even prevent dementia?"- I think, here, it depends again what type of dementia we're talking about. For Alzheimer's disease, there are some symptomatic treatments, i.e. they'll help some of the symptoms, if you stop them, you go back to how you were. Despite the claims, and there is one drug, aducanumab, that's been licensed in the States, hasn't been licensed in Europe, I think most people feel that the evidence is not at all good. But there are a number of other diseases, even degenerative diseases I've mentioned, where treatments are available.- [Questioner] I was going to ask you about what you said about the connection with age. If I understood correctly, a protein's on the solubility limit, and a mutation occurs, and that pushes it over the solubility limit, which means that you get a cascading effect, and so you develop a condition. How is that related to age? Why is that mutation effect related to age?- I think what you're asking there, and it's a really interesting question, is why some of these diseases don't happen straightaway. And it's the same with something like Huntington's disease, which again rarely can come on in young children. But why some of these diseases don't come on for 20, 30, 40 years when they're genetic is just not known. I think it's an intriguing question, and I don't know the answer.- [Questioner] Are you able to describe what that patient would have been seeing when he was unable to locate your hand?- I might come back to it, and I don't know how much clinical neurology expertise there is in the room, but if you're a neurologist and you saw that person, you would assume that they had what's called hemianopia, and that he actually couldn't see anything in his right visual field, but we know that's not the case'cause he could see moving objects in the right visual field, so it's not that he'd lost part of the occipital lobe that does any visual processing. The fact is that there were some other subtle signs, I didn't show it in that video, but often, what these patients will have, they can't do that computation of where the object is, so they can't reach for it, but if you sometimes do slight change in hand gestures, they will actually mimic them. But the main reason, and I may not have run it long enough, but when we threw the shuttlecock into his right visual field, and he had to go backhand, he picked it up straightaway. So he can see something, but he just can't see where it is, and then he can't trigger the appropriate motor program to get his hand to it.- Professor Rossor, I'm going to ask one more question from online before going back to the room. A lot of people asked this question, I know you mentioned the Mediterranean diet, are there any additional gut bacteria, or probiotics, or anything else that helps?- This is suddenly such a hot topic. I have to say, I find it difficult keeping up with it. I think the microbiome has been absolutely fascinating, and it all seems so obvious. We think of ourselves as being independent of everything, it's a bit like the way we think of our brains as just being independent, but everything is so embedded in the environment, our brains don't exist unless we are interacting all the time, we don't exist unless all our organs are interacting, and this wonderful environment with all these nice microbes. The interaction between the brain and the body, both in terms of the microbiome, around the immunology, and the way that things can be affected, sorry, I should be looking at the camera, affected by stress, and other things, is very important. I think it will become increasingly important, I think the evidence is that the microbiome likes things that have been fermented, so if you like sauerkraut, a lot of Japanese things, that's good, and it quite likes coffee, I think that's very good.- [Questioner] I wanted to ask you to think about the future in light of the present, and try and project for us how cognitive impairment might suffer from failures in care for and protection from two broad groups, the medical profession, healthcare profession, and families, because I think people with cognitive impairment spend much of their time with either one or the other, or both of those broad groups. How much care and protection are they going to need in the future as more people become afflicted with cognitive impairment?- It's a very important question because we have got a crisis of care at the moment, not able to give the sort of support. I do think that we need to change as a society, to become much more supportive and tolerant of people's cognitive function, so I think that's going to be important. The medical profession can provide guidance, my own particular area, because neurologists are like that, is around diagnosis, and getting that bit right. And I think I hinted at the fact that there's a danger it can be overwhelmed as we get more and more publicity about cognition. I would just like to see us move towards thinking about maximizing cognition rather than just think about dementia per se, because I do think that's important.- Thank you so much, Professor Rossor, I'm afraid I'm going to have to draw that to a close now. But our next medical lecture is going to be on

"Law, Ethics, and Society," it's by Professor Imogen Goold, and it's next Monday, the 11th of April, so please do come along for that. Thank you so much, Professor Rossor.(audience applauds)