Interview
Interview with Dr Carol Brayne, 5 April 2013
Dementia 2015, Vol. 14(3) 351–360 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1471301214562137 dem.sagepub.com
Stephen Katz and Kevin R Peters
Background Dr Carol Brayne is a leading epidemiologist, population, and public health researcher and author, in the Institute of Public Health at the University of Cambridge. She is an innovator in developing new perspectives and approaches to ageing, cognitive function, and the sciences of dementia. Her books and articles, and major research projects spanning the last three decades raise the questions we need to be asking: what is the relationship between normal brain ageing and dementia? Are current neuroscientific screening methods and data analyses accurate? How should we be using population studies and trials to inform practices of clinical utility for individuals? How is the future of gerontological care dependent on our better understanding of the meaning of dementia? These and other questions stemming from her work are discussed in this illuminating interview. Question: Thank you for speaking with us today. Could you tell us about your background and how you became interested in dementia and Mild Cognitive Impairment (MCI)? CB: My career was in general medical training and then I became interested in epidemiology when I was a medical student. I sought advice and the advice was: ‘Go and get properly trained, be a medic, go and work as a doctor, get the next level of training and then we will see you again’. All of which I did. But I needed neurology while I was training in general medicine, during which time there was an advertisement for an epidemiology fellowship. Since I was just at the point of deciding whether to go on with general medicine and neurology, or whether to go into epidemiology, this opportunity nudged me into that path. Then I had to raise the money obviously to start, so I applied for the fellowship at the Royal Free Hospital. Anthony Mann was a professor of psychiatry at the Royal Free and also at the Institute of Psychiatry. He was quite influential in training people and he put one or two people through the Master’s of Epidemiology program. He sung the importance of epidemiology and now I had an association to the psychiatric world. I wanted to do something in neurology and his advice was ‘do something in dementia because dementia is such an important field’. Because I was interested in the mind– body-philosophical angle of what it means to be human, I suppose the issue of the relationship between normal and abnormal, or deviant ageing, seemed very interesting. So I came away with some very interesting areas with which to work intellectually, which also fed the need of having a topic area about which to write the application.
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The original application was about evaluating whole populations and looking at the distribution of the dementia syndromal features. They are basically characteristics that make up the dementia syndrome. Looking at them in an itemized sort of deconstructed way within a whole population sample resulted in my very first outline proposal and eventually the Medical Research Council funded studies. Then I went into epidemiology and later into public health. This was my first experience of seeing whole populations, where I would interview everybody with everything: Informants on everybody, taking blood on everybody, doing neurological examinations on everybody. So for the first time for me there were no filters such as primary, secondary, and tertiary care. I had already worked in secondary and tertiary settings so I still knew the extremes of what we see at Queen’s Square and in the Hospital of Nervous Diseases and I wanted to apply the methods from tertiary settings on the whole population. It was very crude in those days (in the 1980s), but it was as close as you could get to an extensive phenotype. After pure epidemiology, my medical specialty became public health. I suppose from the point of view of dementia and MCI research, I have had a slightly non-traditional background. I have had training in generic public health, which means that I can see how dementia fits into the wider picture of resource allocation and how decisions are made about the distribution of those resources across ages, cohorts, and geography. Question: We are aware that Alois Alzheimer himself was not sure if what he was seeing was actually a disease or not. We are also familiar with your work from late 1980s and early 1990s, including your co-edited book Normal Aging and Dementia (1994) which was revelatory in raising related ideas about the status of Alzheimer Disease (AD). What was it like to be writing about those ideas at that time? CB: At first it was like going against the tide. In terms of those who have developed dementia and AD, I could not see anything in the literature that could really say that there was a separate disorder, so I tried to test and challenge that assumption in the population. At the time, it was very clear that such a challenging view was not going to be warmly accepted because there was the reification of AD, even though it was not clear exactly what the neurobiological signatures were, apart broadly from the plaques and tangles. I felt well grounded because I had read thousands of papers in preparation for the fellowship, including literature searches in the Index Medicus, which you might remember. Using cross-referencing, serendipity, and reading a large volume of materials, all provided me with a view of the study designs that were being used to create what seemed to be a separation between normal ageing and dementia, through Alzheimer specific subtypes. AD was sort of more fashionable because vascular dementia went out of fashion. If you didn’t critique the methodology you would think there was a separation, when in fact if you looked at the methodology you couldn’t really tell. Hence wanting to go out into the community to take state-of-the-art measures that existed at the time and apply them to an unselected population was the true test. But it was a true test of whether there was a separation of the variables associated with these diseases as they were, as opposed to the syndrome. In hindsight I realized that trends and fashions come and go in these great streams of thinking and clearly that was just the wrong time to be doing that sort of work. In the UK there was quite an impact of my Lancet paper (see selected publications
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below); it was widely quoted and so for a short time there was a sense that our questioning was a reasonable thing, but soon afterward it was much more difficult to get similar material published. I don’t know whether that was because I was in the UK or whether it was everywhere. Question: We have many assumptions about what diseases are and AD seems especially entrenched in the disease model. What do you think has happened between the 1980s and today, in terms of whether or not dementia is a variant of normal ageing or whether it is a separate disease? CB: I think AD has moved forward because there is more diversity now and many other things have happened, such as the recognition that vascular factors are very important. There are many vascular changes in the brain and the findings of mixed pathology, and the fact that new factors such as the Lewy bodies have been recognized. Looking at ordinary older populations we got a mixture of all these things. Today there is also the tremendously exciting opportunity of being able to look at specific proteins and CSF and think about understanding of the brain over time. Although we have studies like the Alzheimer’s Disease Network, the imaging initiative of which is effectively a repeat of CERAD (The Consortium to Establish a Registry for Alzheimer’s Disease, 1986), nobody seems to acknowledge that these modern designs have exactly the same methodological drawback: they are based on a convenience sample of people with AD who happen to come into a particular study. This means that, although the research is very interesting, it does not tell us some of the things that we want to know, for example, what these categories and pathologies really mean if you apply them to populations. And what about people who do not progress to dementia over time? What I wrote about in my 1993 editorial about brains (see selected publications below) suggested that we need to be able to measure the continuity of all of these things (e.g. proteins and accumulation of burden) alongside clinical phenotypes in order to understand what’s going on. But then I would have said that AD continues to be interpreted in the disease paradigm rather than interpreted differently if researched at the populational level. Question: What is your view on MCI as a diagnostic category, from a medical but also from public health and epidemiological points of view? How far has MCI taken us and where do we still have much to learn? CB: The purpose of any diagnostic MCI category from the literature and from our own medical practices is to give some sort of meaning to a state that has a known prognosis or a known likelihood of outcome, and determine how intervention can affect the mental history or the natural history of the thing. In neurology we often make diagnoses for which there is no known treatment. MCI sort of fits that category because it has been created not necessarily by the needs of the population but by the enthusiasm of the medical fraternity and the pharmaceutical industry due to the failure of the drugs at the diagnostic point (i.e. a dementia diagnosis). Interventions that start later do not seem to work, so it is not unreasonable to think that trying to intervene earlier could be beneficial. However, I think the problem is that MCI as a diagnostic set of criteria does not in itself work very well. It is very nebulous and implemented in completely different ways. For example, clinicians will use it in different ways so it has
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come to mean, like AD, a reified entity when in fact it is not a singular thing. Yet the literature is full of MCI and people talk about it loosely as though if you take one person in Cambridge who has got an MCI diagnosis made by a neurologist and compare them with somebody with MCI diagnosed by a geriatric psychiatrist in Australia, that somehow this will mean the same thing. But of course it does not and cannot mean the same thing. Hence, while I think MCI is a very flawed entity, I can also see why it has become so useful to some constituencies. There is also the issue of timing because the concept has been around in some form for 17–20 years, such as the earlier idea of ‘benign forgetfulness’. Given that the concept has been around for such a long time, signifying what we would call ‘intermediate cognition’, then we should also try to avoid its heavy loading and instead allow people to move in and out of this state. Indeed, it has been labelled in so many different ways that somehow its traction today seems to be due more to a societal development. I think MCI is being driven by ageing and society and the desire to do something about it and prevent it upstream, hence the need for the market to have drugs that work. So there are many reasons now for MCI’s traction. How useful it is for an individual? I think that depends on whether that individual is troubled by symptoms and the accuracy of their prognosis. Question: We agree with you that it has been very interesting to listen to people make comparisons between MCI and dementia and AD. In the past we used a construct called ‘cognitively impaired not demented’ (CIND), which is far more heterogeneous than MCI. CB: I think CIND is a much more useful category. Question: However, CIND was criticized for being a ‘messy’ category, yet it reflected the messiness of dementia itself. Why do you think people want such a purely amnestic form of MCI to predict what we know is a category of dementia that can be extremely heterogeneous? CB: I suppose it is the neurologists who want to refine the category with increasing precision. If you follow the Lewy body dementia or other discussions, the momentum is basically towards molecular definitions such as synucleinopathy. The physicians and researchers are desperate to have a narrow focus to study, which makes it understandable as to why something like MCI becomes tractable or potentially tractable and also attractive in terms of funding opportunities. Question: What is your current view of treatments for MCI and for dementia now and into the future? CB: I think the treatments for AD and the specific treatments for MCI are not doing well. The trials are there but they are not terribly promising, which perhaps reflects the fact that MCI is likely a very mixed entity. That is to say, treatments may not be effective against whatever it is that is causing the cognitive decline, assuming that it is cognitive decline and not just a static condition. One of the problems with a fluctuating condition is that we are screening for it in the absence of proper screening trials. People who get treatment when they have MCI will assume that if they remain stable, then they have proven the effectiveness of
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the drug on a one-to-one basis. But, unless you have good trial evidence, we have absolutely no idea whether that is the case or just regression to the mean or a fluctuation or some sort of other improvement for that person. There needs to be much more compelling evidence available for that group of the population before one calls for a recommendation for screening and treatment. What I think is reasonable is normal medical care, on the basis of good evidence, which means evaluating people’s general physical health, where there may be conditions that might exacerbate this sort of co-morbidity. Where there is good evidence for those individual conditions such as diabetes or heart disease, for example, it is that treatment that is effective. There is evidence from the treatment trials that does not necessarily suggest that you prevent dementia in massive numbers, but at least you make the person healthier and less likely to have a disablement from those conditions, so that is bound to help the cognitive state even if it is about functional mobility. In other words, treating the whole person better is really important, not just the isolated cognitive problem in this case. This is what the evidence is really saying. Question: There are important parallels between what you have been recently writing about and what you have been telling us today regarding the disconnection between clinic-based samples and population-based samples with respect to prevalence, incidence, and so on. How do you think that disconnection translates to the area of clinical trials because clinical trial samples are usually very tightly screened? And, as you know, there is great difficulty of trying to transpose what we gain from understanding randomized control trial data to the general public. Do you think there is also a disconnection there? CB: Absolutely yes, but I do think that we could be much smarter about how we use the information from the trials and extrapolate it to the populations. Of course the drivers are very strong to extrapolate any positive findings straight out and that happened to a certain extent with the cholinesterase inhibitors, where that kind of caution and how it works in real populations was not really applied, so we never found out which selective groups will do better. Clearly clinicians do claim that some people do quite well on them, but many other psychiatrists that I talk to say the drugs are ‘a waste of money’. And we are spending a huge amount of money on these drugs because they make people feel better to have something, even if the drug costs are possibly not a great way to spend state-health funding, on drugs that are just not effective. There is very important work that could be done between trials and their application to populations and also done on the basis of the population type data, but this kind of work requires rigor and patience. We should think across trials instead of lumping together everything and then trying to muddle through what one might expect in true older populations where the median incident age is something like 83, yet in the trials it is in the mid-70 s. So there is much more that we could do as a research community, but it is quite difficult because we are disconnected in that way and there is not a great deal of investment in what people see as research that puts a break on things. I have been arguing for years that these are the kinds of data that we should generate if we are to work with our clinical colleagues, such as the kinds of data that NICE (National Institute for Health and Care Excellence) would want. What we have instead is a racing ahead with unrepresentative trials and, if there are positive results the pharmaceutical companies will go
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to the NICE and respond to the question of, ‘does it work in the real population?’ by saying, ‘we’re not really sure about that’. Question: It is interesting that various pharmaceutical companies have been asked to do subgroup responder analyses and nothing has come out of those. This is unfortunate because other researchers to whom we have talked believe there are people who respond very favourably to cholinesterase inhibitors, yet the problem is that we do not know who those responders are ahead of time. What do you think it will take to get to that point, in terms of starting to do those types of analyses? What kind of ‘political will’ might be required? CB: If it were possible for those in the neurology and psychiatry worlds to be slightly less impatient and get together with the public health community, then I think there are plenty of people who are keen to collaborate. It involves pulling together public health and a public health orientation, which I have been trying to do for a quite a long time. Gradually more research papers and abstracts around this kind of orientation are beginning to emerge and I do know there is some initiative where they are going to try and pull all the trial data together. That is the kind of thing we are thinking about, and with public health input or population modelling input into that, we could do some really good work. I do feel that the truth will out in the end, or if that is the truth indeed or some other truth, because that might not be right. But we are obliged constantly to try to disprove ourselves. Question: That would be very exciting because so far no one has really been able to access those data. There could be some very interesting analyses to see what is different about the responders, but the data seem locked away in a safe somewhere. CB: That’s right. Question: Dr Brayne, what do you see for the future of MCI in the next 10–20 years? Is MCI going to continue to exist? If biomarkers are shown to predict pre-clinical AD with some degree of certainty, will we cease to talk about MCI and go straight to biomarkerbased diagnoses? CB: I think that to some extent clinicians will find that MCI is a useful concept when somebody comes to see them, and they say ‘well you’re not quite normal but you haven’t got dementia and you might develop something’. I suspect that MCI, as a clinical utility, might continue in that regard and be around for a while, particularly in settings where there are not major investments in blood and CSF and imaging. The biomarker story is a difficult one because biomarkers can be taken as being predictors, but until we have studies which are in truly unselected populations and follow them up for long enough, we will not know whether they actually are predictors of dementia outcomes. We will know whether they are predictors maybe of pure positivity and people who are recruited into certain studies have a higher probability of progression to dementia that exhibit positivity, but that does not mean that such predictors have clinical utility for the individual. So the question is what is the value added of the biomarkers over the things that we already know enhance the risk for dementia just through education or family risk. These are the kinds of questions unanswered and I would hope that we would be able to assemble decent cohorts to test them in combination in order to evaluate the value of these measurements.
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My concern, however, is about biomarkers as diagnostic aids. A diagnostic aid would be if somebody comes forward with problems and we say we are not sure what might be underlying their MCI or early dementia. Then we run some tests to see if the problem is more likely that they have a vascular aetiology or a mixed aetiology or something else, and then we do whatever we can, such as using Alzheimer type imaging and whatever else may be possible in the future. All these responses are like adding to the diagnostic armamentarium and that seems more straightforward and much more like the advances that have happened in the past. So I think there are different uses of the biomarkers in terms of prediction, diagnosis, and then monitoring of the effects of treatment over time. The evidence base for each of these, in turn, requires different evidence and so I would hope that we do not rush into starting to test populations when we really do not know whether or not we are doing harm or good. It feels to me as though we are on a roller coaster or a juggernaut, and we might spend a lot of money doing things which are rather ineffective for people, to prevent problems about which we do not know if they will even occur during their lifetimes. So that’s my worry, that in a time of austerity, such testing will be seen as good business and that will stimulate the markets and the stock market shares of imaging companies and diagnostics and so on, but it will not necessarily do much good for public health. Yet, all our pensions depend on the stock market too, so we are in a kind of interesting double bind there. I was thinking that there might be a parallel with vascular disease, where we accept that the evidence was so much better for cholesterol and we had trials to show that changing cholesterol really does change the outcomes. So we still look at the vessels in the heart and ask people about angina because angina and atherosclerosis are still diagnostic entities. In time, the new modalities get added to what is there already, so to come back to that MCI question, I suspect MCI might be knocking around for a while. Question: At the front line of primary care, we understand that general physicians are often not sufficiently trained to deal with or know about the kinds of research testing now being developed and sophisticated in clinics. Some of your papers suggest that this situation could lead to unnecessary testing, over-testing, and unwanted expenses as well. What are your views on this situation? CB: Yes, I can give an example of that, having been at Queen’s Square and then going out to rural Fenland. To begin, you have to recalibrate because people in real-life situations are very different from those in the clinic setting, to which we referred earlier on. One of the problems of the rules of public health has been to moderate the enthusiasm of the tertiary specialist because the tests used in the tertiary setting do not perform in the same way as applied to a population. Once we have a refined population, which has been through many selective filters, the tests can look different. Different, as well, are the population’s educational level and diverse contextual factors. If you think that you have something that will work in that setting and it has been validated in that setting, that is absolutely fine. But if you change the nature of the population that you are applying to it, then you have to revalidate it. Yet, what we have at the moment are many specialists who claim that test will perform in the same way in any setting, as if this is just basic epidemiology and basic public health. But that is not the case and once you apply the test(s) out into the population you have to recalibrate and revalidate. For example, tests that perform extremely well in a
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higher prevalence setting, such as prostate specific antigens in the prostate cancer clinic, are terrible in the general practice. When I started my extensive phenotyping out in the population sample, I was using the CAMCOG (which was state of the art standardized neuropsychology test designed by Felicia Huppert), I found that many people in my population could not do the testing. Their verbal fluency was quite low and they would fall into the MCI category, but there is no way that they would have benefitted from any intensive investigation because this is how they probably have always been and that was their environment. The problem is that we do not train our physicians in population epidemiology and those kinds of disciplines, so they have a particular perspective and get very irritated with my disciplinary community advising them to be really careful about the application of these methods in an unselected setting. I remember sending out a clinician to do some of our diagnostic interviews in one of the early studies in the 1980s and he came back and he said ‘oh my god they’re all demented out there!’ He had to recalibrate and then he was able to apply the diagnostic criteria, but the absolute cutoff points he took from the tests would not have worked at all. Question: We read in your work that old age is still the largest determinant of dementia. A dominant theme in the gerontological literature is the separation of ageing from dementia. As detached, dementia is a disease apart from ageing, which makes a discussion about cognitive decline as part of normal ageing difficult. However, you suggest that looking at age and dementia together is actually a healthier way to look at ageing because it allows people to be in and out of a category rather than isolated by it. CB: Yes, this is what we should expect if we look at the continuum of cognitive change with age, that people not only fluctuate individually but they represent a huge spread across the age groups. It could be re-normalizing dementia in some ways and hence less stigmatizing, than this current massive focus on dementia being something very specific, that places people in particular categories. If a person has cognitive impairment and does not fit a specific category, and if all the resources are pulled into dementia, then the people with severe cognitive impairment who have not got dementia are left out in the cold. A more whole-person approach allows you to know about a person’s cognition in a particular setting and ask if or how they can cope within this setting. We can also ask: What can we do about it? Is there any evidence that we have that will help us improve that cognition, whether it is as aides, or support, or some kind of medication? We would be better off approaching cognitive impairment in these ways than by pursuing ‘a magic bullet’ to address the altered brain without the evidence that it really will do some good or it is likely to do more good than harm to that person at their age. We must stick with the movement coming from the population to the individual; that using the population view will hopefully suggest better models for the individual. Question: That is a very clear and useful response because at the individual level this approach creates a dialogue with individuals as active agents in their own lives, given that so much intervention creates a sense of passivity amongst individuals. CB: Yes, and this approach applies just as much to MCI as it does to dementia and the questions we do ask of patients, especially where diagnostic labels are applied spontaneously.
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In England, the government is considering obliging GPs to ask questions rather than just be sensitive to families. It is incumbent on us as researchers and clinicians to know that, if we are going to label somebody with a diagnostic label that we should also be reasonably sure that they are going to benefit from that label rather than be harmed by it. My evaluation of the literature is that we do not have that evidence yet. Question: In our view, your ideas and research share common ground with a number of other bold and creative thinkers who are challenging strictly medical models of dementia. What are your plans for the future? Do you have any new projects or directions or are you expanding your current ones in the next couple of years? CB: I have always wanted to do deep phenotyping on whole populations; this has been my aspiration for many years and the methods really are only available now, so carrying on in this direction is one of my plans. While it has been somewhat overtaken, there is still a need to try to do that in the population setting because it is very hard to do, so the more people trying to do it, the better. We also have a new generation of prevalence issues getting ready to report on, so I have been looking at change in dementia over time. Now I have to say that this whole activity was because I was being asked: ‘Is dementia getting more or less common?’ Sure, it is obviously getting more common because people are getting older, but is it getting more or less common within specific age groups? This is why I, and colleagues, designed a study to address this question while trying to hold the methods steady, which is very difficult to do when you have this blurring and shifting of boundaries around the evidence for minimal dementia. Today this is called MCI, whereas 25 years ago, according to Martin Roth it was already on the cusp of dementia and he called it ‘minimal dementia’, yet most people now call this MCI because it does not quite satisfy the dementia criteria.1 This blurring of boundaries creates a difficulty for epidemiology, so we have tried to hold it steady. Another area of work is based, obviously, on the fact that I am known for being sceptical for screening for dementia, because I do not feel the evidence is there. I think it is incumbent upon us to try to do screening studies but we also have done this baseline new generation study and we want to try to see whether we can offer people something that might make a difference to their healthy brain ageing. Such interventions will not just affect the brain but the body as well, because any dimensions that reduce dementia pick up on other good work on physical activity and cognitive enhancement, vascular risk, etc. If you treat a whole person and run a set of trials to see whether those kinds of interventions do in fact reduce dementia incidence, then you are likely to improve people’s lives in some way. So, in my further work, I will look forward to trying to explore these areas. Question: Dr Brayne, thank you for this very enlightening conversation. We also appreciate your time and greatly learn from your innovative perspective on dementia, which combines research in epidemiology, medicine, and public health. CB: Thank you very much.
Note 1. Roth, M., Tym, E., Mountjoy, C. Q., Huppert, F. A., Hendrie, H., Verma, S. , . . . , Goddard, R. (1986). CAMDEX: A standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. British Journal of Psychiatry, 149: 698–709.
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Selected Publications Brayne, C. (1993). Clinicopathological studies of the dementias from an epidemiological viewpoint. British Journal of Psychiatry, 162, 439–446. Brayne, C., & Calloway, P. (1988). Is Alzheimer’s disease distinct from normal ageing? Lancet, 332, 514–515. Brayne, C., & Davis, D. (2012). Making Alzheimer’s and dementia research fit for populations. Lancet, 380, 1441–1443. Christa Maree Stephan, B., Minett, T., Pagett, E., Siervo, M., Brayne, C., & McKeith, I. G. (2013). Diagnosing mild cognitive impairment (MCI) in clinical trials: A systematic review. BMJ Open, 3, e001909. Huppert, F. A., Brayne, C., & O’Connor, D. W. (1994). Dementia and normal aging. Cambridge, UK: Cambridge University Press. Le Couteur, D. G., Doust, J., Creasey, H., & Brayne, C. (2013). Political drive to screen for predementia: Not evidence based and ignores the harms of diagnosis. BMJ (Clinical Research Ed.), 347, f5125. Matthews, F. E., Stephan, B. C., McKeith, I. G., Bond, J., Brayne, C., & Medical Research Council Cognitive Function, Ageing Study (2008). Two-year progression from mild cognitive impairment to dementia: To what extent do different definitions agree? Journal of the American Geriatrics Society, 56, 1424–1423. Richards, M., & Brayne, C. (2010). What do we mean by Alzheimer’s disease? BMJ, 341, c4670. Wright, C. F., Hall, A., Matthews, F. E., & Brayne, C. (2009). Biomarkers, dementia, and public health. Annals of the New York Academy of Sciences, 1180, 11–19 (doi: 10.1111/j.17496632.2009.04942.
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Interview with Dr Carol Brayne, 5 April 2013
Dementia 2015, Vol. 14(3) 351–360 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1471301214562137 dem.sagepub.com
Stephen Katz and Kevin R Peters
Background Dr Carol Brayne is a leading epidemiologist, population, and public health researcher and author, in the Institute of Public Health at the University of Cambridge. She is an innovator in developing new perspectives and approaches to ageing, cognitive function, and the sciences of dementia. Her books and articles, and major research projects spanning the last three decades raise the questions we need to be asking: what is the relationship between normal brain ageing and dementia? Are current neuroscientific screening methods and data analyses accurate? How should we be using population studies and trials to inform practices of clinical utility for individuals? How is the future of gerontological care dependent on our better understanding of the meaning of dementia? These and other questions stemming from her work are discussed in this illuminating interview. Question: Thank you for speaking with us today. Could you tell us about your background and how you became interested in dementia and Mild Cognitive Impairment (MCI)? CB: My career was in general medical training and then I became interested in epidemiology when I was a medical student. I sought advice and the advice was: ‘Go and get properly trained, be a medic, go and work as a doctor, get the next level of training and then we will see you again’. All of which I did. But I needed neurology while I was training in general medicine, during which time there was an advertisement for an epidemiology fellowship. Since I was just at the point of deciding whether to go on with general medicine and neurology, or whether to go into epidemiology, this opportunity nudged me into that path. Then I had to raise the money obviously to start, so I applied for the fellowship at the Royal Free Hospital. Anthony Mann was a professor of psychiatry at the Royal Free and also at the Institute of Psychiatry. He was quite influential in training people and he put one or two people through the Master’s of Epidemiology program. He sung the importance of epidemiology and now I had an association to the psychiatric world. I wanted to do something in neurology and his advice was ‘do something in dementia because dementia is such an important field’. Because I was interested in the mind– body-philosophical angle of what it means to be human, I suppose the issue of the relationship between normal and abnormal, or deviant ageing, seemed very interesting. So I came away with some very interesting areas with which to work intellectually, which also fed the need of having a topic area about which to write the application.
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The original application was about evaluating whole populations and looking at the distribution of the dementia syndromal features. They are basically characteristics that make up the dementia syndrome. Looking at them in an itemized sort of deconstructed way within a whole population sample resulted in my very first outline proposal and eventually the Medical Research Council funded studies. Then I went into epidemiology and later into public health. This was my first experience of seeing whole populations, where I would interview everybody with everything: Informants on everybody, taking blood on everybody, doing neurological examinations on everybody. So for the first time for me there were no filters such as primary, secondary, and tertiary care. I had already worked in secondary and tertiary settings so I still knew the extremes of what we see at Queen’s Square and in the Hospital of Nervous Diseases and I wanted to apply the methods from tertiary settings on the whole population. It was very crude in those days (in the 1980s), but it was as close as you could get to an extensive phenotype. After pure epidemiology, my medical specialty became public health. I suppose from the point of view of dementia and MCI research, I have had a slightly non-traditional background. I have had training in generic public health, which means that I can see how dementia fits into the wider picture of resource allocation and how decisions are made about the distribution of those resources across ages, cohorts, and geography. Question: We are aware that Alois Alzheimer himself was not sure if what he was seeing was actually a disease or not. We are also familiar with your work from late 1980s and early 1990s, including your co-edited book Normal Aging and Dementia (1994) which was revelatory in raising related ideas about the status of Alzheimer Disease (AD). What was it like to be writing about those ideas at that time? CB: At first it was like going against the tide. In terms of those who have developed dementia and AD, I could not see anything in the literature that could really say that there was a separate disorder, so I tried to test and challenge that assumption in the population. At the time, it was very clear that such a challenging view was not going to be warmly accepted because there was the reification of AD, even though it was not clear exactly what the neurobiological signatures were, apart broadly from the plaques and tangles. I felt well grounded because I had read thousands of papers in preparation for the fellowship, including literature searches in the Index Medicus, which you might remember. Using cross-referencing, serendipity, and reading a large volume of materials, all provided me with a view of the study designs that were being used to create what seemed to be a separation between normal ageing and dementia, through Alzheimer specific subtypes. AD was sort of more fashionable because vascular dementia went out of fashion. If you didn’t critique the methodology you would think there was a separation, when in fact if you looked at the methodology you couldn’t really tell. Hence wanting to go out into the community to take state-of-the-art measures that existed at the time and apply them to an unselected population was the true test. But it was a true test of whether there was a separation of the variables associated with these diseases as they were, as opposed to the syndrome. In hindsight I realized that trends and fashions come and go in these great streams of thinking and clearly that was just the wrong time to be doing that sort of work. In the UK there was quite an impact of my Lancet paper (see selected publications
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below); it was widely quoted and so for a short time there was a sense that our questioning was a reasonable thing, but soon afterward it was much more difficult to get similar material published. I don’t know whether that was because I was in the UK or whether it was everywhere. Question: We have many assumptions about what diseases are and AD seems especially entrenched in the disease model. What do you think has happened between the 1980s and today, in terms of whether or not dementia is a variant of normal ageing or whether it is a separate disease? CB: I think AD has moved forward because there is more diversity now and many other things have happened, such as the recognition that vascular factors are very important. There are many vascular changes in the brain and the findings of mixed pathology, and the fact that new factors such as the Lewy bodies have been recognized. Looking at ordinary older populations we got a mixture of all these things. Today there is also the tremendously exciting opportunity of being able to look at specific proteins and CSF and think about understanding of the brain over time. Although we have studies like the Alzheimer’s Disease Network, the imaging initiative of which is effectively a repeat of CERAD (The Consortium to Establish a Registry for Alzheimer’s Disease, 1986), nobody seems to acknowledge that these modern designs have exactly the same methodological drawback: they are based on a convenience sample of people with AD who happen to come into a particular study. This means that, although the research is very interesting, it does not tell us some of the things that we want to know, for example, what these categories and pathologies really mean if you apply them to populations. And what about people who do not progress to dementia over time? What I wrote about in my 1993 editorial about brains (see selected publications below) suggested that we need to be able to measure the continuity of all of these things (e.g. proteins and accumulation of burden) alongside clinical phenotypes in order to understand what’s going on. But then I would have said that AD continues to be interpreted in the disease paradigm rather than interpreted differently if researched at the populational level. Question: What is your view on MCI as a diagnostic category, from a medical but also from public health and epidemiological points of view? How far has MCI taken us and where do we still have much to learn? CB: The purpose of any diagnostic MCI category from the literature and from our own medical practices is to give some sort of meaning to a state that has a known prognosis or a known likelihood of outcome, and determine how intervention can affect the mental history or the natural history of the thing. In neurology we often make diagnoses for which there is no known treatment. MCI sort of fits that category because it has been created not necessarily by the needs of the population but by the enthusiasm of the medical fraternity and the pharmaceutical industry due to the failure of the drugs at the diagnostic point (i.e. a dementia diagnosis). Interventions that start later do not seem to work, so it is not unreasonable to think that trying to intervene earlier could be beneficial. However, I think the problem is that MCI as a diagnostic set of criteria does not in itself work very well. It is very nebulous and implemented in completely different ways. For example, clinicians will use it in different ways so it has
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come to mean, like AD, a reified entity when in fact it is not a singular thing. Yet the literature is full of MCI and people talk about it loosely as though if you take one person in Cambridge who has got an MCI diagnosis made by a neurologist and compare them with somebody with MCI diagnosed by a geriatric psychiatrist in Australia, that somehow this will mean the same thing. But of course it does not and cannot mean the same thing. Hence, while I think MCI is a very flawed entity, I can also see why it has become so useful to some constituencies. There is also the issue of timing because the concept has been around in some form for 17–20 years, such as the earlier idea of ‘benign forgetfulness’. Given that the concept has been around for such a long time, signifying what we would call ‘intermediate cognition’, then we should also try to avoid its heavy loading and instead allow people to move in and out of this state. Indeed, it has been labelled in so many different ways that somehow its traction today seems to be due more to a societal development. I think MCI is being driven by ageing and society and the desire to do something about it and prevent it upstream, hence the need for the market to have drugs that work. So there are many reasons now for MCI’s traction. How useful it is for an individual? I think that depends on whether that individual is troubled by symptoms and the accuracy of their prognosis. Question: We agree with you that it has been very interesting to listen to people make comparisons between MCI and dementia and AD. In the past we used a construct called ‘cognitively impaired not demented’ (CIND), which is far more heterogeneous than MCI. CB: I think CIND is a much more useful category. Question: However, CIND was criticized for being a ‘messy’ category, yet it reflected the messiness of dementia itself. Why do you think people want such a purely amnestic form of MCI to predict what we know is a category of dementia that can be extremely heterogeneous? CB: I suppose it is the neurologists who want to refine the category with increasing precision. If you follow the Lewy body dementia or other discussions, the momentum is basically towards molecular definitions such as synucleinopathy. The physicians and researchers are desperate to have a narrow focus to study, which makes it understandable as to why something like MCI becomes tractable or potentially tractable and also attractive in terms of funding opportunities. Question: What is your current view of treatments for MCI and for dementia now and into the future? CB: I think the treatments for AD and the specific treatments for MCI are not doing well. The trials are there but they are not terribly promising, which perhaps reflects the fact that MCI is likely a very mixed entity. That is to say, treatments may not be effective against whatever it is that is causing the cognitive decline, assuming that it is cognitive decline and not just a static condition. One of the problems with a fluctuating condition is that we are screening for it in the absence of proper screening trials. People who get treatment when they have MCI will assume that if they remain stable, then they have proven the effectiveness of
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the drug on a one-to-one basis. But, unless you have good trial evidence, we have absolutely no idea whether that is the case or just regression to the mean or a fluctuation or some sort of other improvement for that person. There needs to be much more compelling evidence available for that group of the population before one calls for a recommendation for screening and treatment. What I think is reasonable is normal medical care, on the basis of good evidence, which means evaluating people’s general physical health, where there may be conditions that might exacerbate this sort of co-morbidity. Where there is good evidence for those individual conditions such as diabetes or heart disease, for example, it is that treatment that is effective. There is evidence from the treatment trials that does not necessarily suggest that you prevent dementia in massive numbers, but at least you make the person healthier and less likely to have a disablement from those conditions, so that is bound to help the cognitive state even if it is about functional mobility. In other words, treating the whole person better is really important, not just the isolated cognitive problem in this case. This is what the evidence is really saying. Question: There are important parallels between what you have been recently writing about and what you have been telling us today regarding the disconnection between clinic-based samples and population-based samples with respect to prevalence, incidence, and so on. How do you think that disconnection translates to the area of clinical trials because clinical trial samples are usually very tightly screened? And, as you know, there is great difficulty of trying to transpose what we gain from understanding randomized control trial data to the general public. Do you think there is also a disconnection there? CB: Absolutely yes, but I do think that we could be much smarter about how we use the information from the trials and extrapolate it to the populations. Of course the drivers are very strong to extrapolate any positive findings straight out and that happened to a certain extent with the cholinesterase inhibitors, where that kind of caution and how it works in real populations was not really applied, so we never found out which selective groups will do better. Clearly clinicians do claim that some people do quite well on them, but many other psychiatrists that I talk to say the drugs are ‘a waste of money’. And we are spending a huge amount of money on these drugs because they make people feel better to have something, even if the drug costs are possibly not a great way to spend state-health funding, on drugs that are just not effective. There is very important work that could be done between trials and their application to populations and also done on the basis of the population type data, but this kind of work requires rigor and patience. We should think across trials instead of lumping together everything and then trying to muddle through what one might expect in true older populations where the median incident age is something like 83, yet in the trials it is in the mid-70 s. So there is much more that we could do as a research community, but it is quite difficult because we are disconnected in that way and there is not a great deal of investment in what people see as research that puts a break on things. I have been arguing for years that these are the kinds of data that we should generate if we are to work with our clinical colleagues, such as the kinds of data that NICE (National Institute for Health and Care Excellence) would want. What we have instead is a racing ahead with unrepresentative trials and, if there are positive results the pharmaceutical companies will go
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to the NICE and respond to the question of, ‘does it work in the real population?’ by saying, ‘we’re not really sure about that’. Question: It is interesting that various pharmaceutical companies have been asked to do subgroup responder analyses and nothing has come out of those. This is unfortunate because other researchers to whom we have talked believe there are people who respond very favourably to cholinesterase inhibitors, yet the problem is that we do not know who those responders are ahead of time. What do you think it will take to get to that point, in terms of starting to do those types of analyses? What kind of ‘political will’ might be required? CB: If it were possible for those in the neurology and psychiatry worlds to be slightly less impatient and get together with the public health community, then I think there are plenty of people who are keen to collaborate. It involves pulling together public health and a public health orientation, which I have been trying to do for a quite a long time. Gradually more research papers and abstracts around this kind of orientation are beginning to emerge and I do know there is some initiative where they are going to try and pull all the trial data together. That is the kind of thing we are thinking about, and with public health input or population modelling input into that, we could do some really good work. I do feel that the truth will out in the end, or if that is the truth indeed or some other truth, because that might not be right. But we are obliged constantly to try to disprove ourselves. Question: That would be very exciting because so far no one has really been able to access those data. There could be some very interesting analyses to see what is different about the responders, but the data seem locked away in a safe somewhere. CB: That’s right. Question: Dr Brayne, what do you see for the future of MCI in the next 10–20 years? Is MCI going to continue to exist? If biomarkers are shown to predict pre-clinical AD with some degree of certainty, will we cease to talk about MCI and go straight to biomarkerbased diagnoses? CB: I think that to some extent clinicians will find that MCI is a useful concept when somebody comes to see them, and they say ‘well you’re not quite normal but you haven’t got dementia and you might develop something’. I suspect that MCI, as a clinical utility, might continue in that regard and be around for a while, particularly in settings where there are not major investments in blood and CSF and imaging. The biomarker story is a difficult one because biomarkers can be taken as being predictors, but until we have studies which are in truly unselected populations and follow them up for long enough, we will not know whether they actually are predictors of dementia outcomes. We will know whether they are predictors maybe of pure positivity and people who are recruited into certain studies have a higher probability of progression to dementia that exhibit positivity, but that does not mean that such predictors have clinical utility for the individual. So the question is what is the value added of the biomarkers over the things that we already know enhance the risk for dementia just through education or family risk. These are the kinds of questions unanswered and I would hope that we would be able to assemble decent cohorts to test them in combination in order to evaluate the value of these measurements.
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My concern, however, is about biomarkers as diagnostic aids. A diagnostic aid would be if somebody comes forward with problems and we say we are not sure what might be underlying their MCI or early dementia. Then we run some tests to see if the problem is more likely that they have a vascular aetiology or a mixed aetiology or something else, and then we do whatever we can, such as using Alzheimer type imaging and whatever else may be possible in the future. All these responses are like adding to the diagnostic armamentarium and that seems more straightforward and much more like the advances that have happened in the past. So I think there are different uses of the biomarkers in terms of prediction, diagnosis, and then monitoring of the effects of treatment over time. The evidence base for each of these, in turn, requires different evidence and so I would hope that we do not rush into starting to test populations when we really do not know whether or not we are doing harm or good. It feels to me as though we are on a roller coaster or a juggernaut, and we might spend a lot of money doing things which are rather ineffective for people, to prevent problems about which we do not know if they will even occur during their lifetimes. So that’s my worry, that in a time of austerity, such testing will be seen as good business and that will stimulate the markets and the stock market shares of imaging companies and diagnostics and so on, but it will not necessarily do much good for public health. Yet, all our pensions depend on the stock market too, so we are in a kind of interesting double bind there. I was thinking that there might be a parallel with vascular disease, where we accept that the evidence was so much better for cholesterol and we had trials to show that changing cholesterol really does change the outcomes. So we still look at the vessels in the heart and ask people about angina because angina and atherosclerosis are still diagnostic entities. In time, the new modalities get added to what is there already, so to come back to that MCI question, I suspect MCI might be knocking around for a while. Question: At the front line of primary care, we understand that general physicians are often not sufficiently trained to deal with or know about the kinds of research testing now being developed and sophisticated in clinics. Some of your papers suggest that this situation could lead to unnecessary testing, over-testing, and unwanted expenses as well. What are your views on this situation? CB: Yes, I can give an example of that, having been at Queen’s Square and then going out to rural Fenland. To begin, you have to recalibrate because people in real-life situations are very different from those in the clinic setting, to which we referred earlier on. One of the problems of the rules of public health has been to moderate the enthusiasm of the tertiary specialist because the tests used in the tertiary setting do not perform in the same way as applied to a population. Once we have a refined population, which has been through many selective filters, the tests can look different. Different, as well, are the population’s educational level and diverse contextual factors. If you think that you have something that will work in that setting and it has been validated in that setting, that is absolutely fine. But if you change the nature of the population that you are applying to it, then you have to revalidate it. Yet, what we have at the moment are many specialists who claim that test will perform in the same way in any setting, as if this is just basic epidemiology and basic public health. But that is not the case and once you apply the test(s) out into the population you have to recalibrate and revalidate. For example, tests that perform extremely well in a
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higher prevalence setting, such as prostate specific antigens in the prostate cancer clinic, are terrible in the general practice. When I started my extensive phenotyping out in the population sample, I was using the CAMCOG (which was state of the art standardized neuropsychology test designed by Felicia Huppert), I found that many people in my population could not do the testing. Their verbal fluency was quite low and they would fall into the MCI category, but there is no way that they would have benefitted from any intensive investigation because this is how they probably have always been and that was their environment. The problem is that we do not train our physicians in population epidemiology and those kinds of disciplines, so they have a particular perspective and get very irritated with my disciplinary community advising them to be really careful about the application of these methods in an unselected setting. I remember sending out a clinician to do some of our diagnostic interviews in one of the early studies in the 1980s and he came back and he said ‘oh my god they’re all demented out there!’ He had to recalibrate and then he was able to apply the diagnostic criteria, but the absolute cutoff points he took from the tests would not have worked at all. Question: We read in your work that old age is still the largest determinant of dementia. A dominant theme in the gerontological literature is the separation of ageing from dementia. As detached, dementia is a disease apart from ageing, which makes a discussion about cognitive decline as part of normal ageing difficult. However, you suggest that looking at age and dementia together is actually a healthier way to look at ageing because it allows people to be in and out of a category rather than isolated by it. CB: Yes, this is what we should expect if we look at the continuum of cognitive change with age, that people not only fluctuate individually but they represent a huge spread across the age groups. It could be re-normalizing dementia in some ways and hence less stigmatizing, than this current massive focus on dementia being something very specific, that places people in particular categories. If a person has cognitive impairment and does not fit a specific category, and if all the resources are pulled into dementia, then the people with severe cognitive impairment who have not got dementia are left out in the cold. A more whole-person approach allows you to know about a person’s cognition in a particular setting and ask if or how they can cope within this setting. We can also ask: What can we do about it? Is there any evidence that we have that will help us improve that cognition, whether it is as aides, or support, or some kind of medication? We would be better off approaching cognitive impairment in these ways than by pursuing ‘a magic bullet’ to address the altered brain without the evidence that it really will do some good or it is likely to do more good than harm to that person at their age. We must stick with the movement coming from the population to the individual; that using the population view will hopefully suggest better models for the individual. Question: That is a very clear and useful response because at the individual level this approach creates a dialogue with individuals as active agents in their own lives, given that so much intervention creates a sense of passivity amongst individuals. CB: Yes, and this approach applies just as much to MCI as it does to dementia and the questions we do ask of patients, especially where diagnostic labels are applied spontaneously.
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In England, the government is considering obliging GPs to ask questions rather than just be sensitive to families. It is incumbent on us as researchers and clinicians to know that, if we are going to label somebody with a diagnostic label that we should also be reasonably sure that they are going to benefit from that label rather than be harmed by it. My evaluation of the literature is that we do not have that evidence yet. Question: In our view, your ideas and research share common ground with a number of other bold and creative thinkers who are challenging strictly medical models of dementia. What are your plans for the future? Do you have any new projects or directions or are you expanding your current ones in the next couple of years? CB: I have always wanted to do deep phenotyping on whole populations; this has been my aspiration for many years and the methods really are only available now, so carrying on in this direction is one of my plans. While it has been somewhat overtaken, there is still a need to try to do that in the population setting because it is very hard to do, so the more people trying to do it, the better. We also have a new generation of prevalence issues getting ready to report on, so I have been looking at change in dementia over time. Now I have to say that this whole activity was because I was being asked: ‘Is dementia getting more or less common?’ Sure, it is obviously getting more common because people are getting older, but is it getting more or less common within specific age groups? This is why I, and colleagues, designed a study to address this question while trying to hold the methods steady, which is very difficult to do when you have this blurring and shifting of boundaries around the evidence for minimal dementia. Today this is called MCI, whereas 25 years ago, according to Martin Roth it was already on the cusp of dementia and he called it ‘minimal dementia’, yet most people now call this MCI because it does not quite satisfy the dementia criteria.1 This blurring of boundaries creates a difficulty for epidemiology, so we have tried to hold it steady. Another area of work is based, obviously, on the fact that I am known for being sceptical for screening for dementia, because I do not feel the evidence is there. I think it is incumbent upon us to try to do screening studies but we also have done this baseline new generation study and we want to try to see whether we can offer people something that might make a difference to their healthy brain ageing. Such interventions will not just affect the brain but the body as well, because any dimensions that reduce dementia pick up on other good work on physical activity and cognitive enhancement, vascular risk, etc. If you treat a whole person and run a set of trials to see whether those kinds of interventions do in fact reduce dementia incidence, then you are likely to improve people’s lives in some way. So, in my further work, I will look forward to trying to explore these areas. Question: Dr Brayne, thank you for this very enlightening conversation. We also appreciate your time and greatly learn from your innovative perspective on dementia, which combines research in epidemiology, medicine, and public health. CB: Thank you very much.
Note 1. Roth, M., Tym, E., Mountjoy, C. Q., Huppert, F. A., Hendrie, H., Verma, S. , . . . , Goddard, R. (1986). CAMDEX: A standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. British Journal of Psychiatry, 149: 698–709.
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Selected Publications Brayne, C. (1993). Clinicopathological studies of the dementias from an epidemiological viewpoint. British Journal of Psychiatry, 162, 439–446. Brayne, C., & Calloway, P. (1988). Is Alzheimer’s disease distinct from normal ageing? Lancet, 332, 514–515. Brayne, C., & Davis, D. (2012). Making Alzheimer’s and dementia research fit for populations. Lancet, 380, 1441–1443. Christa Maree Stephan, B., Minett, T., Pagett, E., Siervo, M., Brayne, C., & McKeith, I. G. (2013). Diagnosing mild cognitive impairment (MCI) in clinical trials: A systematic review. BMJ Open, 3, e001909. Huppert, F. A., Brayne, C., & O’Connor, D. W. (1994). Dementia and normal aging. Cambridge, UK: Cambridge University Press. Le Couteur, D. G., Doust, J., Creasey, H., & Brayne, C. (2013). Political drive to screen for predementia: Not evidence based and ignores the harms of diagnosis. BMJ (Clinical Research Ed.), 347, f5125. Matthews, F. E., Stephan, B. C., McKeith, I. G., Bond, J., Brayne, C., & Medical Research Council Cognitive Function, Ageing Study (2008). Two-year progression from mild cognitive impairment to dementia: To what extent do different definitions agree? Journal of the American Geriatrics Society, 56, 1424–1423. Richards, M., & Brayne, C. (2010). What do we mean by Alzheimer’s disease? BMJ, 341, c4670. Wright, C. F., Hall, A., Matthews, F. E., & Brayne, C. (2009). Biomarkers, dementia, and public health. Annals of the New York Academy of Sciences, 1180, 11–19 (doi: 10.1111/j.17496632.2009.04942.
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