Prof. Carol Brayne
Carol Brayne 教授
Public health defines prevention in several ways. There's primary prevention, secondary prevention and tertiary prevention.
Primary prevention is removing a cause of a disease, so the classic example is smoking and lung cancer. You remove the smoking, you remove the lung cancer that is attributed to smoking. There will be other lung cancers but they are not lung cancers caused by smoking.
Secondary prevention is early detection of a disorder at the point where you can change its natural history in a way that means the survival of the person with the early disease, or the quality of life of that person, is enhanced.
Tertiary prevention is when a disorder is fully manifest, is fully there, and it's about the treatment and the interventions, the care that we can provide that will improve the quality of life of that person in the presence of the disorder, and that includes palliative care, so that includes dying as well as we can.
Put those all together and you have the balance of care and activity required for a society to do the best it can with the resources that it has.
Secondary prevention is effectively screening. That can be done in an intensive case identification method or it can be done at a population level. To implement screening and/or early detection, we need really rigorous evidence and that is - in the UK and many countries such as the US, there are whole commissions looking at screening evidence.
At the moment, dementia is not one of the conditions that is recommended for screening, for systematic screening in the population. At present, our research investments across the world are focused on early detection and diagnostics. The implications of this kind of research is that there will be, in the future, some sort of screening program, whether it's applied at population level or within clinic settings. So we need an evidence base that is robust enough to meet the requirements of a screening program. At present, despite massive investment, the evidence is not sufficient for that and the implications in terms of cost are enormous for societies of implementing that kind of approach. It doesn't mean it won't be possible in the future but it needs to be thought about very, very carefully.
Primary prevention; we have evidence already about the approaches that we can take to reduce the conditions that are themselves risk factors for dementia. We have evidence of reduction in the prevalence, that is the proportion of people with dementia, in many countries and the incidence, that is the new occurrence of disease in populations. So we have that evidence from the US, from the UK, from some European countries. So we have good evidence that we can change the course of people's ageing and brain ageing.
We also have evidence on how to support people when they have dementia - that's the tertiary prevention side - increasing evidence about improvements in provision of care in care homes and the nature of the interventions that we can make to support people with dementia. So at present we have an imbalance of investment into what effectively would lead to a screening program for dementia and less investment into the primary and the tertiary, and it is clear from a public health point of view that we need to rebalance that.
Thinking about primary prevention of dementia, we need to take into account the context in which that prevention needs to occur. We have a constellation of different risk factors which relate to early, mid and later life, and we have very many different populations across the world that are experiencing ageing, so that the kinds of primary prevention activities that we might want to undertake in Australia might be very different in different groups within the population.
So for example, those in the clusters where, say, smoking and drinking excessively or to harmful levels is more prevalent, we might want to have a different approach to one where people are already doing physical activity and already having very good diets. That might relate to increasing the educational levels or one might think about groups in the population who are socially isolated. So these are all the different types of risk factors that one needs to take into account.
When we think about low and middle income countries or even a country like Japan, the profile of risk factors across the life course will have been very different for the people who are entering old age now. So it is absolutely not one size fits all, but a sense of needing to understand the risk factors that are operating for different age groups in different cultures and what is the evidence base for approaching those risk factors in those cultures.
If I was in the happy position of being in charge of the public health program in Australia, I would first want to map very carefully our knowledge of dementia in the population and different sectors of the population in different regions and different groups. I would then want to map our knowledge of the risk factor and protection factor profiles - so education is a key one there and social integration is another key one - to understand that across the population. Then I would want to bring to bear the evidence base that we have about how to change those factors and what works best, what our understanding is about what works best, at the individual level and at the population level and at the community level.
Then I'd want to create a community-based program which integrated that knowledge for a community and work with the community on the concerns of the community. And then, with embedded evaluation, look to see or basically implement combined interventions going from individual to population in those communities and then follow up the impact over time. So that would be integrating community and individual.
What I would also do, though, is look at the life course risk factors that we know we need national action on, and with that it would need to be a very careful discussion with the commercial sector. So sugar, alcohol and tobacco would probably need national activity.
Thinking from a whole population perspective and from the public health evidence, individually based interventions are pretty ineffective if one thinks about the resources required for individual interventions. So, for example, smoking cessation programs, although they're effective, they're nothing like as effective as doing things at community and population level, at national level. So when we think about the barriers, we need to think very carefully about each individual risk factor and what influences people's behaviours and what approaches we need to use. So a good example of the exultation to eat well is that, in socioeconomically-deprived areas of the UK, so my own nation's experience, fast food companies target opening in socioeconomically deprived areas. So the populations within those areas are at a particular disadvantage because what's available to them in their environment is an obesogenic environment. So it's very difficult to behave in a healthy way if you live in a place which has no areas for physical activity and also you don't have much money and low cost fast food outlets.
从大众群体的角度与从公共健康方面得来的统计数据来考虑，如果考量到个体干预所需的资源，进行个体基本干预效果会很不理想。举例，个体的戒烟项目，尽管它有效果，但是却不如社区，群体及整个国家层面来得有效果。由于这些不利因素，我们需要非常周全地考虑到每个不同个体的风险因素，影响个人行为的因素和其相应的对处方法。举一个恰当的例子，是饮食喜好的定位，在英国本土，快餐业把目标人群定位在这些低收入的经济底层地区。那结果就是生活在这些地区的人群被置于了一种不利的环境 — 一种容易引起肥胖的生活环境里。所以如果你生活在这样一个缺乏运动、低收入以及低成本不健康食物的地区，你很难拥有一个健康的生活方式。
So we have to work with communities and with businesses to shift the way that these things are operating within communities, because in the end businesses don't want to kill people and don't want to make their dementia risk higher. But they do need to make a profit, so we do need to think about what are the huge barriers that exist in terms of vested interests in our own ill health, and even in dementia occurrence. So we need to try to work to turn that around.
丁宇欣 Yuxin Ding
锦州医科大学高级护理专业、注册护士、中国人民大学公共管理学院进修2年。英国阿尔茨海默症协会Dementia Friends认证的认知症好朋友、获得澳洲塔斯马尼亚大学Wicking认知症研究中心Preventing Dementia课程证书和UnderstandingDementia课程证书。
Prof. James Vickers
Dementia is a term that we use to refer to a change in functioning from previous levels. The domains that are affected by dementia include your higher cognitive abilities, personality and behaviour. There are many dozens of diseases that will actually cause dementia, and most of these are associated with advanced ageing, although some, particularly with a high genetic predisposition, can occur at much younger ages.
The four major neurodegenerative diseases that cause dementia are Alzheimer’s Disease, Lewy Body Disease, Frontotemporal Dementia and Vascular Dementia. And sometimes these occur singularly and they can also occur in combination. And it’s these four that we’ll focus on in the presentation today.
The major cause of dementia is Alzheimer’s Disease, and this probably accounts for around 50% to 60% of cases. We know that Alzheimer’s Disease is characterised by specific pathological changes that occur inside the brain, and these were originally described by Alois Alzheimer at the beginning of the 20th century. The three changes include those that happen at the macroscopic level, which involves shrinkage or atrophy of the brain, and this can affect particular structures of the cerebral cortex, including the frontal lobe, temporal lobe and parietal lobe. The other two pathological changes occur at the microscopic level, and these are neurofibrillary tangles and amyloid plaques. Amyloid plaques are spherical structures that occur between nerve cells and are comprised of a protein known as A-beta. Now A-beta is a normal protein that you would find in all of our brains, but in Alzheimer’s Disease, it undergoes an abnormal transformation. It forms small fibrils that accumulate together to form plaques, and where plaques form in the brain, they cause damage to nerve cells, particularly the processes of nerve cells, the axons, the dendrites, as well as synaptic connections between those nerve cells. The other major microscopic change that occurs inside the brains of people with Alzheimer’s Disease is the neurofibrillary tangle. Now, within all nerve cells there’s a fine meshwork of filamentous proteins that we refer to as the cytoskeleton. When a nerve cell is affected by Alzheimer’s Disease, this cytoskeleton collapses and is replaced by the neurofibrillary tangle. The main protein that comprises this tangle is an altered form of a normal brain protein we refer to as tau. Now, tangles probably take many years to actually develop within nerve cells, and they seem to follow the initial development of plaques within the brain. They are also very insoluble structures, which means they don’t dissolve very easily. So when a nerve cell dies, usually the tangle is left behind, and we refer to this as a tombstone or ghost tangle. There are new imaging technologies that are being developed for Alzheimer’s Disease that might help us visualise these amyloid plaques and neurofibrillary tangles inside the brains of people while they’re alive. If we combine the data from these new studies with that which has been derived from pathological studies, we now appreciate that there’s a particular sequence of pathological change that occurs inside the brain with Alzheimer’s Disease. It seems likely then that plaques may occur many years, sometimes as many as ten to fifteen years, before you develop overt symptomatology. The plaques appear to precede the neurofibrillary tangles and the neurofibrillary tangles themselves are more closely linked with the loss of synaptic connections between nerve cells, which lead to the pattern of symptoms. In this regard, Alzheimer’s Disease is a degenerative and progressive disorder in that the disease develops from one stage to the next - from a clinical silent period, where plaques develop inside the brain, through to the initial stages of the disease, which can be insidious and often difficult to detect, then through to the progressive deterioration in higher cognitive functions. One of the early cognitive functions that seems to be affected by Alzheimer’s Disease is short-term memory and the ability to form new memories.
导致认知的主要原因是阿尔茨海默病，可能约占50％至60％的病例。我们知道，阿尔茨海默病的特征是在脑内发生特定的病理性变化，这些特征最初在20世纪初由Alois Alzheimer所描述。这三种变化包括在宏观水平发生的改变，其涉及脑的收缩或萎缩，并且影响包括额叶，颞叶和顶叶在内的大脑皮质的特定结构。其他两种病理性改变发生在微观水平，它们是神经原纤维缠结和淀粉样斑块。淀粉样的蛋白斑块是存在于神经细胞之间的球形结构，并由称为A-beta的蛋白质所构成。在我们所有正常的大脑中，A-beta是一种正常的蛋白质。但在阿尔茨海默病患者的大脑中，这种蛋白发生异常的转变。它形成小的原纤维，进而这些原纤维聚集在一起形成斑块，并且这些在脑中形成的斑块对神经细胞，特别是神经轴突和树突以及这些神经细胞之间的突触连接造成损害。在阿尔茨海默病患者脑内发生的另外一个主要的微观变化是神经原纤维缠结。在所有的神经细胞中都有一个由丝状蛋白构成的细丝网络，我们目前称之为细胞骨架。当神经细胞受阿尔茨海默症影响时，该细胞骨架塌陷并被神经原纤维缠结所替代。构成该缠结的主要蛋白质是一种正常脑蛋白的改变形式，我们称为tau蛋白。缠结可能需要许多年才真正在神经细胞内发展，并且它们似乎在脑内的最初的斑块的发展之后形成。它们也是非常不溶的结构，这意味着它们非常不易溶解。因此，当神经细胞死亡时，通常会留下缠结，我们将其称为墓碑或幽灵缠结。有一些为阿尔茨海默病而正在开发的新的成像技术，可能会帮助我们活体观察人类大脑内的这些淀粉样斑块和神经原纤维缠结。如果我们将来自这些新研究的数据与来自病理学研究的数据相结合，现在我们会认识到在阿尔茨海默氏病患者的脑内发生了特定的病理变化序列。斑块似看起来似乎在症状出现之前已经存在了许多年，有时多达十至十五年。斑块似乎出现在神经原纤维缠结之前，并且神经原纤维缠结本身与神经细胞之间的突触连接的丧失更紧密地相关，从而导致症状的产生。在这方面，阿尔茨海默病是一种退行性和进行性疾病，其中疾病从一个阶段发展到下一个阶段 - 从斑块在脑内发展的临床沉默期，直到疾病发生的初始阶段，这个过程可能是隐蔽的并且经常难以检测的，然后进入更高的认知功能逐渐恶化时期。似乎受阿尔茨海默病影响的早期认知功能之一是短期记忆和形成新的记忆的能力。
In Alzheimer’s Disease, we know that particular brain regions are vulnerable to degeneration, and even within those brain regions, certain nerve cells are particularly susceptible. One of the structures of the brain that’s affected early in the disease is the medial temporal lobe, and as this degenerates, you may see some symptoms, such as an inability to form new memories and difficulties generally in short-term memory. But then the disease progresses to other brain regions, to other lobes of the cerebral cortex, and as this occurs you will see difficulties in other higher cognitive areas, as well as behaviour and personality, and this might include planning ability, logical thinking, orientation in space and time, as well as language.
The speed of progression, as well as the age of onset, of Alzheimer’s Disease does vary between individuals. We don’t really understand why this is the case, but it’s likely mainly due to genetic predisposition, but other lifestyle factors may well play a role.
In Alzheimer’s Disease, there are likely to be a range of genetic risk factors that contribute to your relative risk of developing this condition. The best known one, and the one that has the most impact on your risk, is the apolipoprotein E gene. Now, this comes in three variations – Epsilon II, Epsilon III and Epsilon IV. You inherit one version of this gene from each of your parents. Essentially, the more of the Epsilon IV version of this gene you have, the higher risk you have of developing dementia as you get older. In less than 5% of cases, there’s a much stronger genetic predisposition and we often refer to this as familial forms of Alzheimer’s Disease. We know of three genes that carry a range of mutations that can cause familial Alzheimer’s Disease. One of these is the amyloid precursor protein gene, and we know that this is then linked potentially to the production of amyloid beta that forms the plaques in Alzheimer’s Disease.
在阿尔茨海默病中，可能存在一系列遗传风险因素，这些因素会促进您发展这种疾病的相对风险。最著名的一个，对你的风险影响最大的是载脂蛋白E基因。现在，这有三种基因变异 - Epsilon II，Epsilon III和Epsilon IV。你每个人从各自的父母继承这个基因的一个版本。基本上，你如果拥有更多的Epsilon IV版本的基因， 等你变老时你就有更高的发展为老年认知症的风险。在不到5％的病例中，有更强的遗传倾向，我们经常将其称为家族型阿尔茨海默病。我们知道三个携带一系列可导致家族性阿尔茨海默病的突变的基因。其中之一是淀粉样蛋白前体蛋白基因，并且我们知道这可能与在阿尔茨海默病中形成斑块的淀粉样蛋白β的产生有关。
Another cause of dementia is Lewy Body Disease. Now, this is known by a variety of terms, including diffuse Lewy Body Disease, Dementia of the Lewy Body Type and Alzheimer’s Disease with Lewy Bodies. The cardinal pathological feature of Lewy Body Disease is the presence of an abnormal proteinaceous inclusion inside nerve cells called the Lewy Body. Now, the Lewy Body is a spherical structure made up of proteins, fine filaments and lipids. It also occurs as the main pathological feature of Parkinson’s Disease, and we think that Parkinson’s Disease and Lewy Body Disease are related to each other. Some of the clinical features of Lewy Body Disease may well include motor problems that you see in Parkinson’s Disease, such as tremor. Similarly, if you have Parkinson’s Disease for a long period of time, you may then develop cognitive issues that are very similar to what we see in Lewy Body Disease. Inside the brains of people with Lewy Body Disease, you’ll often also see amyloid plaques, and this probably speaks to some kind of interrelationship between Lewy Body Disease and also Alzheimer’s Disease.
Another cause of dementia is Frontotemporal Dementia, and this is really a spectrum of different diseases. Broadly, they’re characterised by dramatic shrinkage, or atrophy, of brain regions, such as the frontal lobe, and the frontal sections of the temporal lobe. The symptomatology of the disease broadly follows the damage to these cortical areas – for example, with frontal lobe damage, comes changes in personality and behaviour, as well as higher cognitive skills, such as planning and judgement. With damage to the temporal lobe, there’s often problems with language and speech production.
认知症的另一个原因是额颞叶痴呆，这其实是一系列不同的疾病。广泛地讲，它们的特征是脑部的急剧收缩或萎缩，例如额叶和颞叶的正面部分。疾病的症状学大致广泛存在于对这些皮质区域的损伤 - 例如，伴随额叶损伤，发生个性和行为上的变化，以及更高的认知技能，例如规划和判断能力。由于颞叶损伤，语言的产生常常出现问题。
Of all of the conditions that cause dementia, frontotemporal dementia probably has the strongest genetic predisposition. So around about 30% to 40% of cases of frontotemporal dementia are likely linked to particular genetic mutations. And because of this genetic predisposition, these cases tend to have a relatively early onset.
Vascular dementia is sometimes known as multi-infarct dementia, and this involves an interruption to the normal blood flow into the brain. In most cases of vascular dementia, this involves damage and disruption to the small blood vessels that penetrate through the brain, particularly in the white matter tracks underlying the cerebral cortex. In other cases of vascular dementia, there might be a series of small strokes occurring in different regions of the brain. Vascular pathology is actually quite common with advanced ageing and this vascular disease can coexist with other forms of dementia, such as Alzheimer’s Disease.
These different forms of dementia are the focus of intense study globally. We are trying to understand the sequence of pathological changes that lead to dementia. In many cases, this is probably largely attributed to advanced ageing, as well as your genetic predisposition, but we’re also interested in how more modifiable risk factors may play out in terms of the disease pathology. Ultimately, we’re interested in therapeutic agents that might modify disease progression, so might have an effect on the specific pathological hallmarks, or it might be that we can look at interventions that might improve on your relative resilience to these dementing disorders.
丁宇欣 Yuxin Ding
锦州医科大学高级护理专业、注册护士、中国人民大学公共管理学院进修2年。英国阿尔茨海默症协会Dementia Friends认证的认知症好朋友、获得澳洲塔斯马尼亚大学Wicking认知症研究中心Preventing Dementia课程证书和UnderstandingDementia课程证书。
We can look at figures from perhaps two sources here. One is of course the global observatory in London, which was set up by the ADI some years ago. That observatory, run by Professor Martin Prince, has been collecting data, and these data were actually published by the Alzheimer's Disease International in 2015. The estimate was that there were roughly about 45 to 50 million people, I think the figure they came to was 47.8 or something like that, around the world. More recently there was another publication that’s from the Global Burden of Disease group, which is run from Washington DC. They came to very similar figure, about 45 million, so that’s really the number of people overall in the world, with a diagnosis of dementia.
我们也许可以从两个地方查找全球认知症患者的数据。其中一个当然是伦敦的全球天文台，它是由ADI在多年前建立的。Martin Prince教授一直在用这个天文台收集数据，而这些数据于2015年刊登在了国际阿尔兹海默病期刊上。该数据估计全球有4.5-5千万人被诊断为认知，我认为他们得到的数据应该大约在4.78千万左右。最近，另一份来自华盛顿的全球疾病负担小组的出版物也指出全球有4.5千万人被诊断为认知症。这个数据和之前Martin Price教授他们采集的数据（4.5-5千万）非常接近。所以，全球真的有这么多认知症患者。
But I must emphasise that this is not a precise figure, and for various reasons. One is that the data we have from many countries, is secondary data, we do not have good surveys. Even from high income countries or developed countries, the figures on dementia vary depending upon what criteria have been used, what the sampling strategy has been. This is a very rough guide.
I think there are two points I want to make here. First point is that there is an increase in the number of people, and that is quite a rapid increase projected over the next 30 to 40 years. Primarily that increase is driven by the increase in the total number of people, who are over the age of 60 or 65. We know that dementia increases exponentially with age, and especially after the age of 65, there is a doubling of the number of people with dementia. Every 6 years or 6.3 years to be precise, I think is probably the estimate. The more older people there are, the more people with dementia there will be. We know there are going to be more and more older people around the world.
In particular in the developing countries or low income countries and low and middle income countries, there is going to be a rapid increase, because those populations are ageing now. Whereas in the high income countries, the population has already aged to a significant degree. But ageing is happening very quickly in those countries. In fact they're going to contribute more and more towards people with dementia in the future. That’s really one reason that there is going to be more and more people with dementia around the world. It's projected that by the middle of the century, the number is going to be more than twice as many. One projection is maybe about 150 million people by the middle of the century around the world.
The second point I want to make is that there are some other trends we are seeing. Especially this trend has come from developed countries, high income countries, that in fact the incidence of dementia may actually not be rising, may in fact be falling. I think here we need to distinguish between the overall numbers, the prevalence of dementia, and incidence. By incidence we mean people with a new diagnosis of dementia, so how many new people are coming in to this fold of getting a diagnosis of dementia. There have been some studies from Europe and from North America, which have suggested that in fact the incidence of dementia in the developed countries may be falling, or may have been falling for the last two decades or so, and may continue to fall for some more time. Although we think that that will plateau, sometime in the future.
In particular I want to highlight three studies here. The first study perhaps, is from the UK, which is called the MRC CFAS study. Essentially it was a large study from six centres in the United Kingdom, which was done twice. Once this study was done to look at the overall prevalence of dementia in the UK in the early ‘90s. Then the study was repeated 20 years later, so to see after a generation what has happened. The short message from that study is that what they had projected was that the rate would be about 8.1% 20 years later. But actually the rate that they found on this survey, on this, was much lower, about 6.7%. There were fewer people with dementia than they had projected from the earlier estimates. In fact the total number had not gone up very much, even though the number of people who were at risk, of that old age population, had gone up significantly, suggesting that fewer people were developing dementia than 20 years earlier.
Then there’s another study from The Netherlands, that's the Rotterdam study, and the Rotterdam study is interesting because they've been following people in Rotterdam as they grow older over several years now. They looked at their rates of dementia and here they're looking at new cases, which is the incidence of dementia, 10 years apart. They found that 10 years later, the incidence was lower. Although not significantly lower, but slightly lower, not statistically significant. But a very interesting study that’s been published from the United States and that’s from a place called Framingham in Massachusetts. The audience will be familiar with the Framingham study, which actually is a study of cardiovascular health, which has been going on now for 40 to 50 years.
They started with heart health and now they've gone on to brain health. They've been looking at dementia cases now for about 40 years. They looked at rates in the late ‘70s, and then the ‘80s, ‘90s and the 2000s and see what has happened. They found that each decade, the incidence of dementia has actually gone down, to the extent that over this period of 30 years, there was about a 44% reduction in the incidence or new cases of dementia. So in fact there's both a bad news story and a good news story in this. The bad news story is that overall the number of people with dementia around the world is increasing and is likely to increase. The greatest increase is going to be in low and middle income countries. But high income countries, still there's going to be maybe an increase, but not as much as we had feared in the past. Because there is probably a levelling off or even a slight decline in these people. Unfortunately in the low and middle income countries, this decline is not likely to happen very soon, in fact at this point, there is some suggestion that the rates may be increasing to some extent because of certain risk factors.
We do not know for sure why the numbers in low and middle income countries are increasing. But definitely the major increase is because there are more older people, the life span is increasing so more people are at risk of developing dementia. So that’s the big bulk. But whether there is another contribution being made by factors such as obesity, diabetes, poor metabolic health, cardiovascular disease, stroke, we’re not sure. Because some of these are increasing, unfortunately in many low and middle income countries, with changes with industrialisation, changes in dietary patterns, changes in physical activity levels. Rates of diabetes are increasing, rates of stroke are increasing. This is happening in India, in China, which are major populations really in terms of total world population. It is possible that this will flow on through in terms of rates of dementia in the future. At this point we do not know, but that’s something that we have to watch out for.
Studies that have looked at the changes in prevalence and incidence of dementia across say a 20 year span or over a generation, have tried to hone in to the possible reasons. If you look at the Framingham study, they found that the major change was in vascular dementia, not in Alzheimer's disease, so it is suspected that it could be vascular risk factors, such as better control of hypertension, better control of diabetes, good management of cardiovascular disease. But that did not explain all of the change really.
There is a suspicion that it may be other factors, and starting off with early life factors, such as good education. We find that getting a good education early in life, sets you up for a good health lifestyle, throughout your life. It also gives you protection in terms of cognitive ageing, of decline in your cognitive function as you age. This is evidence that comes from the European studies as well and in fact even from our own study in Sydney. Early education is a significant protective factor. It may work through various different ways. But certainly better control of vascular risk factors, good diet through life, management of obesity, physical activity through life, are all important and maybe all are playing a role in this, in terms of the improvements we are seeing.
I think I should add then, that we suspect that if we are seeing an improvement in the high income countries, in the last two to three decades, we cannot take it for granted. Because it’s very likely that this will level off and then we are also seeing that in our younger populations, in developed countries, rates of obesity are increasing, and poor diet, dietary patterns are increasing as well. It’s possible that we might reverse some of these gains in the future. We cannot actually sit back on our laurels, we have to be vigilant forever.