Transcript
[Beginning of recorded material]
[Title card: Mild Cognitive Impairment]
Associate Professor Michael: Hello, I'm Associate Professor Michael Woodward, and honorary medical advisor to Dementia Australia, and I'd like to talk to you today about mild cognitive impairment. I'd like to start by acknowledging the Wurundjeri Woi-wurrung people, traditional custodians of the land on which I'm standing today, and pay my respects to their elders, past and present. I extend that respect to Aboriginal and Torres Strait Islander people that may be watching today, and those who may be suffering from dementia, or caring for people with dementia and mild cognitive impairment.
Now, this is a very familiar story. "Doctor, I've been worried about my, or her, or his memory for years, and I've bought this up several times, but in the past, I've been told, "This is just normal ageing, what you expect at your age, but your memory's better than mine. Nothing can be done about it, so the diagnosis isn't important." Well, I'm trying to convince you today that I feel that that's not really the way we should regard it. Impaired cognition, usually memory, can be a sign of mild cognitive impairment. It's a matter of extremity.
In other words, if a person is just occasionally forgetting where they put their keys, that might be normal. But if a person is repeating themselves, if they're repeatedly losing objects, if they're leaving things on or open, forgetting what happened yesterday, forgetting what they promised to do, then that is suggestive that their memory impairment could be due to mild cognitive impairment. But other domains can also be solely or additionally impaired, including executive function, our judgement, our reasoning, our insight, and in fact, there's loss of insight that sometimes means that people with mild cognitive impairment don't want to go and talk to their doctor about it, which makes it even more complex in some cases. There's also of course, stigmatisation that, "Well, if I'm losing my memory, I'm going to be labelled as dithering, as old, as perhaps having dementia, and I don't want to be diagnosed." So, there's a number of reasons that a person with mild cognitive impairment may not present to their health practitioner, and some of it is the loss of insight that's part of the loss of executive function.
Other changes could be loss of language. We might forget words. Words were commonly used to stick on the tip of our tongue. Now we all have that occasionally, but this could be happening more repeatedly and more commonly, we might also have visuospatial changes. We can't quite sign in the right spot, or we keep bumping into the doorframe, or not quite sitting exactly as we should on the chair. Usually, in the early stages, our activities are fully preserved. Now, there may be a loss of very, very high functioning, such as our very high IT skills, but generally, a person can still pay bills, can shop independently, can do all the things that they used to do. So, when we see this sort of pattern, we think about mild cognitive impairment.
In fact, mild cognitive impairment is part of the continuum from normal cognition right through to the severe stages of dementia. And in this case, I'm looking at the underlying cause being Alzheimer's disease. So, when we start in the very early stages, we might be accumulating amyloid, but we have essentially normal memory. When we get to the second stage, there's subtle cognitive decline changes from the baseline level of cognition, poor performance on more challenging cognitive tests, but this still may not quite meet the criteria for mild cognitive impairment. When we reach the MCI stage, however, we certainly do have quite significant loss of memory as I said before, we have difficulty learning and remembering new information, long-term memory and some reasoning, however, remain. And then, we cross the threshold at some stage into the dementia stage of our illness. So, the important point here is that Alzheimer's disease can be without symptoms, can be causing mild cognitive impairment, or it can be causing dementia. And in fact, what we want to do is catch it at the earlier stages so we can push back the movement into the dementia stage for as long as possible.
Now, correlating with these changes in cognition and eventually behaviour and function, we also have changes in the brain's substance. What's happening is, initially, amyloid and neurodegeneration are occurring, and these can occur even when there's no symptoms. But by the time we get to mild cognitive impairment, there's accumulation of amyloid, there's accumulation of tau tangles, but there's also shrinkage in an important part of the brain for memory called the hippocampus. And then, by the time we get into the more advanced stages, there's more significant changes in the pathology of the brain, there's more shrinkage of the brain, and it can be easily seen on certain forms of imaging, which I'll talk about in a moment.
So, we move from the preclinical to the clinical stages of Alzheimer's with mild cognitive impairment being the earliest clinical stage of Alzheimer's, but before the dementia stage. Now, how many Australians have mild cognitive impairment? It's not clear. There are few official figures, but it's at least twice as common as those who have dementia, and probably, therefore, around about 1 million people. It's not a stable diagnosis. People can move in and out of mild cognitive impairment. Unfortunately, it is, at this stage, a progressive disease, and given enough time, and if there's no other illnesses that take us from this earth, then most people will move into the dementia stage. Most of it is due to Alzheimer's, but it's also important to understand that mild cognitive impairment and then dementia can be due to other processes, not just Alzheimer's. You can get it from Lewy body disease, from vascular disease, from a cause of dementia called frontotemporal degeneration, and there are actually about 200 different causes of dementia, and most of these would progress through a mild cognitive impairment stage.
Mild cognitive impairment affects about somewhere around 10 to 15% of people over 65. The studies vary considerably in the results that they come up with, but it also depends on their methodology. In specialist settings, it can be as high as 39%. And in population studies, 22% of people with mild cognitive impairment develop dementia in the next three to 10 years, but nearly half with amnestic or memory loss, predominant mild cognitive impairment, will develop dementia within the next three years. Now, if we actually have a test that shows that our mild cognitive impairment is due to Alzheimer's, we call that prodromal Alzheimer's disease, and that's where we basically have the symptoms of mild cognitive impairment with memory loss, and some sort of biomarker or biological marker of Alzheimer's disease. And if we've got that, in other words, it's more certain that the mild cognitive impairment is due to Alzheimer's, they are more likely to progress to the stage of dementia, diabetes, pre-diabetes, metabolic syndrome, low serum folate and neuropsychiatric symptoms also increase the risk of progression to dementia.
The Mediterranean diet decreases this risk. Interestingly, the educational achievement that we've had, usually from earlier life, does not affect our risk of progressing to dementia, but other studies have had somewhat contrary results to that. Now, stroke, risk factors such as hypertension and atrial fibrillation, but also depression and the use of anticholinergics in women increase our risk of progressing to dementia.
Now, neuropsychiatric symptoms can be common even in those who are not yet in the dementia stage, in other words, those with mild cognitive impairment - somewhere between a third and three quarters of people will have mild changes in personality, mood, and behaviour, including depression, anxiety, apathy, and irritability. It's not clear if these symptoms merely identify people further along the path towards dementia, or they represent actual risk factors for mild cognitive impairment and progression to dementia. But it is certainly recognised that people can present with these along with memory loss, and whether we treat these to prevent the progression of the memory loss to the dementia stage is not yet clear. We certainly do need to identify these features and to treat them if possible.
Now, we can talk about what's called population attributable fraction. In other words, the fraction theoretically prevented by the elimination of a risk factor shows that whilst treating diabetes might reduce the risk of developing dementia by about 4%. Treating neuropsychiatric symptoms in studies show that we might reduce the risk of progression to dementia by as much as 30%. Also modifying our diets, particularly the Mediterranean diet, reduces our risk of progression to dementia by about 23%. So, that's underlining the importance of diagnosing mild cognitive impairment because we can be even more fastidious about treating depression and diet, and reducing our risk of progression to dementia, but the diagnosis is often delayed.
One study of 600 people, using data provided by 60 physicians showed that the mean time from initial symptoms to first consultation was about six months. Most of this, two thirds of these were with a general practitioner. 20% of patients had moderate or severe cognitive impairment at their first GP consultation. The mean time from this first consultation to formal diagnosis was four months, but it was up to nearly a year on average in some cases, and it was even longer after being referred to one specialist, had to go and see another specialist - so, sometimes, the person will be referred to a neurologist who may not be an expert in dementia, and then, they'd then get referred onto another neurologist or a geriatrician with a particular expertise in dementia.
The time from first consultation to diagnosis was significantly associated with the severity of cognitive impairment at the first consultation. It was shorter the more severely impaired the patient was at their initial consultation. Now, here's a hypothetical model of what happens with Alzheimer's. We move from normal cognition on the left, through to the dementia stage on the right. And the first change is the accumulation of amyloid or abeta, which is the peptide that makes up the amyloid. We then have changes with tau, which leads to neurofibrillary tangles, which cause neuronal injury and neuronal dysfunction. We then have changes in brain structure, particularly shrinkage, and it's only then that we develop the memory changes of initially mild cognitive impairment, and then the loss of function that moves us into the dementia stage. And you'll see by that green line on the right that we can have some early functional change and still largely fulfill the criteria for mild cognitive impairment, but that functional change is at a very high level, as I said earlier.
Now, we have diagnostic advances. We can better diagnose the underlying cause of a person's cognitive disorder using either imaging of the brain or biomarkers, and I'll go through each of those now. So, here's an example of a person with mild cognitive impairment, and this is their MRI. And this is a cross section using what's called the coronal view, and you'll see, in the middle, there's a circle, looks like it's got a couple of ears on it, and just to the left of those ears, there's the hippocampus. Now, a person with mild cognitive impairment has shrinkage of that hippocampus. I'm showing the second image there, and I think if you're looking at that area, I'll go back, and then go forward again, you'll see that hippocampus shrinking over a period of two years. That's often a marker of Alzheimer's disease. And interestingly, some of the treatments we have, and I'll talk about one of them later, seem to reduce that shrinkage in the hippocampus.
PET scanning is also being used now that it's covered by Medicare. One form of PET scan called the FDG, or fludeoxyglucose, or if you like, glucose PET scan, shows a lot of promise in diagnosing the various forms of dementia and mild cognitive impairment, not just Alzheimer's disease, it shows that you get reduced activity or metabolism of the brain in certain regions where there's the build-up of dementia pathology. So, in Alzheimer's disease, we see a certain pattern. We see different patterns in other forms of neurodegeneration such as frontotemporal dementia and Lewy body disease.
We can also use PET to actually image amyloid, the most common cause of mild cognitive impairment, and that's Alzheimer's disease where amyloid accumulates. These amyloid imaging PETs are very helpful if we strongly suspect Alzheimer's, but they're not covered by Medicare, and charges for these vary around Australia from $1,000 at my centre, to sometimes $2,000 or more. We are also able to image tau, the other protein that builds up in Alzheimer's, but that's usually, at this stage, only done in a research context. So, here's an example of amyloid imaging. At the top, you see very little amyloid because amyloid shows up in this scan as yellow and red, but down the bottom, we're looking at two different sections of the brain, we see the typical feature of Alzheimer's disease. The front of the brain is towards the top of the picture, and interestingly, we see most of the amyloid accumulating at the front of the brain.
The amyloid on PET matches the spread of amyloid that we see under the microscope when we look at a person who's died from Alzheimer's disease, or the early stages of Alzheimer's, we call these Braak stages, and you can see on the bottom, the spread of brown showing the spread of amyloid throughout the brain, and that correlates very nicely with the changes we see with amyloid PET from normal through to the more advancing stages of Alzheimer's dementia. The changes in Tau are also shown in this slide on the right-hand side, and they more or less correlate with the build-up of amyloid. Tau more closely correlates with the degeneration of neurons. So, the accumulation of amyloid indicates Alzheimer's is present. The accumulation of tau often correlates with the severity of the clinical features of that Alzheimer's disease.
We can also use a combination of all of these scans to better characterise what's going on, but we really only need one. We only use multiple scans in research settings. So, on the left, we have a Tau scan. In the middle column, we have the amyloid scan, and on the right, we have the glucose PET scan, all showing characteristic changes of Alzheimer's, and on the very right, we've got an MRI, which also shows shrinkage in the hippocampal region.
Now, we also have blood tests - there's a number that have been developed. C2N is already available in some countries, and it is available in Australia, but I think we're going to have other blood tests more easily accessible. Roche are developing blood tests, and you can see some of the other companies there. Some of these blood tests measure amyloid in the blood, some measure ApoE4, which is a gene, which is a risk factor for Alzheimer's, and some measure what we call phosphorylated tau. The general consensus is the test that measure phosphorylated tau are the most accurate.
So, these are, if you like, a screening test to determine whether we need to do more assessment of somebody with mild cognitive impairment to see if they indeed do have underlying Alzheimer's or other pathology. They're not yet freely available, they're used in research, they can be accessed outside of research, but I would suggest that they'll be much more freely available to specialists, and eventually, general practitioners over the next year or two. And basically, the combination of biomarkers and changes in memory can be very useful in picking up the risk of progression from mild cognitive impairment to Alzheimer's dementia. So, for instance, if you have a positive amyloid PET and shrinkage of the hippocampus, you are almost a hundred percent certain to develop dementia over three years. This is data from the AIBL study. Whereas if you have, for instance, just the ApoE4 gene, you have about a 76% chance of developing dementia over the next 36 months. And these are for people who already have clinically diagnosed mild cognitive impairment.
Now, why does missing or delaying the diagnosis matter? It means that the person and their family, their carers are less able to understand what is happening, are less able to plan, are less able to focus on dementia prevention, and are less able to access medical management. I think it's very important to diagnose and accurately understand the cause of mild cognitive impairment for these reasons. With respect to prevention, we should all be living our life as if we have a risk of developing Alzheimer's and developing dementia, but certainly, from midlife, if we have untreated hearing loss or have traumatic brain injury, and I feel for those people who engage in sports where that's happening repeatedly. If we have hypertension, if alcohol excess is current, if we have a body that's overweight, we have an increased risk of developing dementia, and our risk of developing dementia is shown by the size of those circles, or the percentages within them. In later life, smoking, depression, social isolation, physical activity, interestingly, air pollution and diabetes all contribute to our increased risk of developing Alzheimer's dementia. And in fact, if we add all those percentages up, about 40% of dementia is potentially modifiable. In other words, we can reduce our risk at least in a population study by about 40%, but some of the risk is either unknown or unmodifiable, such as our genes, family history, et cetera.
Another way of thinking about the importance of diagnosing mild cognitive impairment is how it's led to a better understanding what goes on in the brain, which has, in turn, led to potential therapies. So, we learnt by the 1980s that there was a deficit of a chemical called acetylcholine in the brain. That was really the first major advance from the finding of Alzheimer's a hundred years earlier that we have the amyloid plaques and tangles in the brain. We then better defined what Alzheimer's was, we developed clinical definitions, and these are under constant revision, but because we knew there was a cholinergic deficit, by the early nineties, we started using cholinesterase inhibitors. We started with ones that had quite a lot of side effects and were inconvenient to administer like physostigmine and tacrine, but then we moved on to drugs, which are still the standard of care for the treatment of Alzheimer's in the dementia stage, this was the cholinesterase inhibitors such as Donepezil.
About 10 years later, we developed memantine for those in the moderately severe stages of Alzheimer's, but then we realised that if we could just attack the underlying amyloid, we might be able to actually modify the progression of the disease, and reduce the risk of either developing mild cognitive impairment or developing dementia. So, we use inhibitors of the enzymes that make the amyloid, but we also started using monoclonal antibodies that target the amyloid that's accumulating. About the same time, evidence showed that a medical food I'll talk about in a moment called Souvenaid was also useful in slowing down the progression of symptoms in people with mild cognitive impairment due to Alzheimer's disease, but what we've found in the last few years, and we've actually achieved breakthroughs here, is that anti-abeta monoclonal antibodies actually do work. We've got two now that are undergoing registration in Australia. They're before the TGA, the Therapeutic Goods Administration right now, and I'll talk about them at the very end.
So, we can see the evolution of our knowledge as leading to an evolution in not only understanding what's going on in the brain, but also treatments. And many have been tried, over 200 in my site at the Austin and around Australia, but we now have actually reached the end of the beginning. We now have treatments that can potentially slow down the disease process. What we do know is, as I said before, the damage to the brain is what causes symptoms, and the main cause of these symptoms is loss of synapses, the connection between brain cells. And on the right, we see curves like those I showed earlier. Synapses are built up of membranes, what we call the phospholipid membrane, and that's composed of choline, uridine, and polyunsaturated fatty acids, and we also need some trace elements such as B group vitamins.
Now, there is a food that actually feeds these into the membrane cycle, we take it by mouth, but it actually provides the substrates that the brain can use to make more of these membranes, and therefore, if you like, replenish the synapses that are being damaged by attack from Alzheimer's processes such as accumulation of amyloid, the plaques, but also inflammation and what we call oxidation. So, this food, Fortasyn Connect, goes by the trade name Souvenaid, I think is very important for those in the mild cognitive impairment stage of Alzheimer's. This food might work for the other courses of mild cognitive impairment, but that hasn't been convincingly shown yet. There has been a very extensive trial looking at this food, Souvenaid, I won't go through all the details, but the most convincing relevant to the talk today is its usefulness in prodromal Alzheimer's which, as I said, is mild cognitive impairment due to Alzheimer's pathology.
The main study here is what's called the LipiDiDiet study, it had over 300 patients with mild cognitive impairment due to Alzheimer's. We now have data out to three years - the two year and the three-year data have been published in very prestigious Alzheimer's research journals. The primary endpoint is what we call the neuropsychiatric test battery, and particularly, the overall cognitive score, but we also have some other secondary endpoints. And what it's actually shown is a positive benefit, I'll show that in some graphs in just a moment. This is the first randomised control trial in nutrition in this population, that has supported the role of such an intervention in the prodromal phase, the mild cognitive impairment phase of Alzheimer's.
So, here's the primary endpoint, the neuropsychiatric test battery, and on the left, you see the composite score. At two years, there was certainly a difference between the treatment group in red and the placebo group in blue, but that difference became statistically significant out at three years. In fact, the slope reduction was 60%. They were deteriorating 60% less rapidly than the placebo group, and the memory score also showed a similar benefit out to three years, that also was statistically significant just at two years.
Some of the other subscales of this neuropsychiatric test battery were not as convincing. If we look at hippocampal volume, we also showed about a 33% slower shrinkage or loss of volume of the hippocampus in those on Souvenaid at three years compared to those who were on the placebo. Again, perhaps showing the underlying way that this medical food was slowing down the decline of memory in people with early stages of Alzheimer's disease. But we now have a new era. I said we're at the end of the beginning. We now have Anti-Amyloid Monoclonal Antibodies, which have been shown to reduce amyloid plaque shown on PET scans. They also have shown the benefit of biomarkers, and I'll explain what I mean by that in a moment.
Overall, the two studies that have been finished and have positive results have shown a 30% slowing of disease progression over 18 months. These are the first potentially disease-modifying therapies for Alzheimer's. It is a first step. We need to do better and develop multiple therapies, potentially, and use them at an earlier stage to slow down the progression of the disease, or to even prevent the progression to the dementia stage. They're going to be demands on our practice, we're going to have to learn how to use these drugs carefully, where to use them, and how to monitor for their safety. At the moment, they have to be given intravenously, we have to look for side effects, and one of the areas that we look at is in the brain for what's called amyloid-related imaging abnormalities, and we also have to prove that the person has Alzheimer's by using something like an amyloid PET, but we are at an era where we can consider using disease-modifying therapies.
So, on the left, we see a person on placebo, there's no change in their amyloid, the amount of, in this case, yellow and greenness hasn't changed between baseline and 18 months. But on the right, somebody treated with one of these monoclonal antibodies, Lecanemab, they show a significant reduction. Look at the middle column on the right, you'll see at the top brain with significant amyloid, that's the yellow and green areas, but down the bottom, below that, you'll see a brain where the amyloid has actually disappeared. We know we can actually remove enough amyloid to have people go back to what we would regard as normal amounts of amyloid. In other words, the amount of amyloid that doesn't cause any symptoms over an 18-month period. Now, they don't lose all their symptoms, but we see here biomarker evidence that the drugs are doing what they're meant to do, remove amyloid, and that does show a reduction in the rate of decline, and that's not ending there.
On the slide you see, here, you'll see where we are with our research. In the middle circle, we have phase three studies. They're the studies that are most advanced, phase two studies in the circle outside that, and phase one studies in the circle outside that. And the wedges show where these particular drugs are targeting. So, at the top, we've got drugs that are potentially disease modifying, such as anti-amyloid drugs. We have cognitive enhancers on the left. Further around the circle, we have drugs that are targeting the neuropsychiatric or behavioural symptoms, and we also have small oral drugs, they're in the bigger wedge on the bottom right-hand part of the circle. So, this universe of drug development is really inspiring. It shows that, in the future, we might have more breakthroughs and have a range of drugs that we can use for people, both to prevent mild cognitive impairment, but also to prevent mild cognitive impairment moving onto the Alzheimer's stage.
What's interesting at the moment is that we actually have more drugs that are targeting other mechanisms, that are targeting amyloid in the development stage. So, we will soon have a range of medications, hopefully, that we can use. So, in conclusion, I'd like to point out that mild cognitive impairment matters. Poor memory does impact on our life and, in fact, can also be a marker of the risk of progressing to dementia. Some mild cognitive impairment is due to the prodromal early stages of Alzheimer's, but other dementias probably also have a prodromal stage, frontotemporal dementia, Lewy body dementia, vascular dementia, Parkinson's head trauma, et cetera.
Early diagnosis is valuable. And the best way to achieve an early diagnosis is the clinical features of mild cognitive impairment combined with some form of biomarkers such as imaging, and I include there also PET imaging. And as I've said, we may also have blood tests that can be used, at least to screen, there'll probably never be a complete diagnostic test on their own. Once diagnosed, we need to focus even more on dementia prevention. We should be focusing on that now, particularly from middle life, but if we have a diagnosis of mild cognitive impairment, we should be even more focused on prevention.
We do have a high chance of eventual progression to dementia, particularly if we've been shown to have amyloid, but we still can delay this progression. We can still reduce the risk of developing dementia in our lifetime. And this means we need to focus on diet, exercise, mental and social activity. We need to avoid brain toxins such as excess alcohol, cigarette smoking. We need to avoid damaging the brain through head trauma, and the metabolic syndrome including obesity and blood pressure, and other factors also increase the risk of progression, so we can attack these as well.
Interestingly, we need to also make sure we wear our hearing aids, not just so we can hear information. Sure, we can't remember information if we don't hear it, but it seems that addressing hearing loss also provides stimulation to the brain that slows down, potentially, the pathology that eventually leads to the dementia stage, so hearing aids are not just amplifiers of sound, they're also having a direct stimulating effect on our brain.
Souvenaid should be standard of care, I believe, for people who have mild cognitive impairment due to Alzheimer's disease. And in the not very distant future now, we'll have anti-amyloid, and potentially disease-modifying therapies that can be used for people both to prevent mild cognitive impairment in those who are at risk of developing it, but also, to prevent progression from mild cognitive impairment to the dementia stage. So, thank you very much for listening, and I'm sure you'll be able to go and have another listen to this talk on the Dementia Australia website at some stage, if that's been a little bit too fast for you, do slow it down because there's a lot of information there, but the real optimistic take home message is that we can diagnose mild cognitive impairment, it makes a difference, and we can do something about it.
Thank you.
[Title card: Together we can reshape the impact of dementia.]
[Title card: Dementia Australia. 1800 100 500. Dementia.org.au]
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