Interview
Interview with Dr Constantine Lyketsos, 14 May 2013
Dementia 2015, Vol. 14(3) 318–327 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1471301214562138 dem.sagepub.com
Stephen Katz and Kevin R Peters Background Dr Constantine Lyketsos is Elizabeth Plank Althouse Professor and Chair of Psychiatry, at Johns Hopkins Bayview Medical Center, and Professor of Psychiatry and Behavioral Sciences. He was foundational to the establishment of The Johns Hopkins Neuropsychiatry Service, which, along with Dr Lyketsos, is known for its leading research and expertise in dementia and traumatic brain injury. While the relationship between the epidemiological, physical, psychological, cognitive, and neurological aspects of the ageing mind is crucial to understanding in the field of Alzheimer disease (AD) and related dementias, much more theoretical and practical research is needed in order to temper the biomedical model with these other dimensions of the ageing process. As evident from his many publications, honours, and awards, Dr Lyketsos fulfils this need with his innovative concerns about the patients he treats, the families he supports, and the way he combines humanistic and scientific approaches. Question: Thank you Dr Lyketsos for taking the time to talk to us this morning. Please tell us about your career background and how you became interested in dementia and Mild Cognitive Impairment (MCI). CL: I am a physician trained in psychiatry, neuropsychiatry, and epidemiology. I came to the dementia area from a neuropsychiatric background, interested in the relationship between brain disease and the development of behavioural and psychiatric symptomatology. I have stayed in that field since about 1993. Question: How was it that you came to focus on ageing, psychiatry, dementia, and MCI? CL: I am not exactly sure if there was one factor. My father was a psychiatrist, so that had a role. But I have always been interested in brain–behaviour relationships, from the scientific point of view as a way to understand how the brain relates to behaviour. Then I started seeing patients and their families and felt that I could make a contribution. Question: So some of your research interests have been informed by your clinical practice. CL: Yes, quite a bit, but I consider myself a physician first, followed by everything else.
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Question: Regarding MCI, what is your view of it as a diagnostic category? Where to you see it as useful and where do we have much to learn? CL: I have mixed feelings about MCI because it is so heterogeneous. In a clinical setting there is utility to identifying people who have MCI, even if we haven’t perfectly defined it. I prefer the more agnostic term ‘not normal, not demented’ for older people. There is value there because there are preventive opportunities. For a variety of reasons, perhaps because of the media attention and so forth, people are noticing the symptoms and they’re asking for information and help in some situations. I’m not quite ready to think of it as a clear diagnostic entity. In psychiatry there is a new diagnostic entity in the DSM-5 called ‘minor neurocognitive disorder’, a term I don’t particularly like, but it is another way of defining a diagnostic entity in this space. What we need to understand, and hopefully soon, is the ability to differentiate the MCI subgroups that have an adverse prognosis (e.g. progression to dementia or disability), so that from the public health point of view we can focus our attention either on prevention or on prognosis, which is ultimately where I see myself as a physician serving patients. Question: You have been in this field for quite some time now, so what is your assessment of the forces that shaped MCI? In addition to the well-known Petersen/Mayo criteria from 1999, there are other labels and criteria that have been used in the past. In particular we would like to know your view of the play between psychiatric symptoms and cognitive symptoms? CL: Cognitive symptoms are psychiatric symptoms. As for the forces that have shaped the field, first certainly is the dementia pandemic and the appreciation that a person doesn’t go from normal to dementia overnight without some sort of intermediate stage. So there is an emerging focus on secondary prevention in trying to detect a symptomatic pre-dementia state, which could provide opportunities for interventions. I think this is one major force coming out of the medical setting. Secondly, in the social setting, as people are ageing in a healthy fashion, there are many questions being asked about the status of what is ‘normal’. At what point do certain complaints, experiences, and functional changes become pathological, or abnormal, beyond usual ageing. For me those are the two major forces. However, I think a third force that builds on these two is the emergence of the idea that pharmaceuticals can help with the symptoms, to improve them, or to delay or prevent worsening. This is a market force that is trying to define an entity, which I wouldn’t assess as appropriate or inappropriate, it is just a reality that product development has become mixed in with the medical and social settings. Question: That is an interesting response. Could you elaborate on your comment that cognitive symptoms are psychiatric symptoms? When people present their bullet-point lists of symptoms when they talk about MCI, they usually present memory impairment and related issues. CL: Psychiatric symptoms are disturbances in mental life, so memory impairment is a disturbance in mental life. If you look at the predominant classification of disorders of cognition, perception, and behaviour, they have been under the psychiatric realm going
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back to the days of Hippocrates. I do understand that there is a recent movement to say that cognition is ‘neurologic’, but these are semantic differences. My point is that we’re talking about disturbances in the realm of mental life and behaviour, what I consider a traditional top-down approach to classification. If these disturbances are in the realm of mental life or behaviour, they are of interest to me as a psychiatrist. Question: So when we talk about psychiatric symptoms, you are saying that the disturbances of mental life are your focus. What we think of as psychiatric symptoms, perhaps naively, are problems such as depression, agitation, or related symptoms. What do you see as their role in being used either to define MCI or being a predictor of conversion in MCI? CL: To me this is a definitional question, which one can approach from different angles. My preferred approach is empirical, so rather than create an entity around the specific symptoms like MCI, I prefer to look at what kinds of symptom constellations appear within individuals across time, while appreciating that if they are occurring around the same time in the same person or in a certain predictable sequence, then they’re probably arising out of similar causes which I would imagine frequently relate to the brain. I think the definition of MCI has really emerged from expert groups who have been interested in studying memory primarily and have therefore defined the syndrome around memory. But if you start studying the people who fit this kind of narrow definition of MCI, you appreciate that they have a variety of other disturbances in mental life and behaviour. To be even more specific, I think there is an entity called ‘mild behavioural impairment’. We, and others, have published on this entity, where the change that is occurring in the person relates to some aspect of mental life/behaviour other than cognition. There is a lot of overlap within and across people who have this range of symptoms. It is a complicated issue. Question: You have highlighted a very important distinction amongst how different groups of people might approach MCI; with some focused on memory only or other aspects of cognition, and others taking a more global view. You mentioned the DSM-5 classification of ‘minor neurocognitive disorder’, about which you are not particularly satisfied. Could you tell us how this classification differs from the conventional Petersen/Mayo definition of MCI? CL: I would have to look at the specifics of the criteria, which I do not have entirely memorized, but I think the construct is basically the same. The Petersen criteria generally imply, although not clearly state, that the cause of MCI is an underlying pathology in the brain that looks like what we would call Alzheimer’s pathology; whereas I think the DSM construct is more intended to describe a syndrome or constellation of symptoms that might have many different causes. If you look at the people actually involved in writing the DSMology in this particular area, you will see the convergence of the Petersen MCI group, the HIV group with Igor Grant who was involved in developing the concept of minor and major neurocognitive disorder of HIV, and epidemiologists like Mary Ganguli. I have pretty well described the committee for you, which tried to merge their perspectives in defining this new entity. And as with other aspects of the DSM-ology, the process has been a compromise of people trying to merge different perspectives. Honestly, I don’t know how it is all going to play out in patients empirically, because I don’t think anybody has really sat down and taken
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the criteria and considered whether it makes sense to have similar syndromes of different causes classified in the same way just based on the phenomenology. Question: This is very interesting, thank you. If you make diagnoses of MCI, what is the process you use in your own clinical practice? CL: The first process begins with somebody coming to me with a complaint. This contact is very important because if you go out and do other studies where you’re identifying people who might have the MCI syndrome, but did not self-present to a clinical setting, then you have a very different context. For me, number one is the clinical setting where somebody is showing up with a complaint, which could be coming from a patient or from a family member. The second process is pretty standard and involves history-taking, examination, and then diagnostic tests and studies. The history-taking typically involves taking history of symptoms, and the emergence of presentation from the patient and from knowledgeable informants (people who know them well) in a temporal fashion. So we start with the period when the person was last well and then try to understand how the cognitive and associated symptoms emerged and progressed over time; this is the history component. The examination is also very typical based on mental status and a physical or neurologic exam. The diagnostic testing depends on what one has seen, but will frequently involve some kind of standardized cognitive assessment as well. Occasionally, depending again on the setting, testing might involve a blood test, brain imaging, and so forth. All these procedural steps lead to a formulation about whether there is a recognizable syndrome present, its associated features, and its severity. Then we try to make sense about the possible causes and what could be done to help the patient. One of the interesting questions is when a person actually becomes a patient? We see a lot of folks who present with a cognitive complaint who think they have MCI. Many of them are children of people with dementia or people who cared for someone with dementia, like a spouse. They consider themselves patients, but after we go through this evaluation process we conclude that they’re really fine from the medical point of view. Question: They have also likely been given different labels in the field as well, such as ‘not cognitively impaired’ (NCI). What is your assessment of this group? Is it a matter of the cognitive tests not being sensitive enough? Or does this group fall into the ‘worried-well’ side? Or is it just too hard to characterize them all that way? CL: Let me ask you: Do you know the definition of a normal person? Question: Very good question. CL: It is someone who hasn’t had enough tests, right? So if you have a sensitive enough test, you will always be able to call someone abnormal. When you raised the question of context of test sensitivity, I don’t think that for those people it’s purely a matter of sensitivity. It’s a matter of defining the specific context of their concern. Is it that they have an underlying brain disease? We now have this view that is well supported by evidence, which is that if you are to get the syndrome of dementia in your 80s, then there is unfolding in your brain a degenerative brain pathology detectable presumably for a number of years beforehand. We haven’t quite settled on what we think will be there, but then that context might be, ‘I’m the
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child of someone who got dementia at 75. I’m 62 right now. I’m starting to have the same symptoms that my parents had. Do I have the same brain disease? Can you do something about it?’ This is the most common context I see. There are other contexts to do with concerned family members, which might bring forward other motives or concerns. Question: Regarding the measuring of ‘normal’ and as you know Dr Lyketsos, there are several critics of current dementia studies who say that normal could be inclusive of memory impairment and cognitive impairment when it comes to ageing. That this is normal ageing. What you think of this particular perspective? CL: I think it’s an important and fair question, but I don’t like the term ‘normal ageing’ and prefer instead the term ‘usual ageing’ for the reason that I implied before. Under my postulate, and I recognize it is my postulate right now, from what we know now, most people who reach very old age will have a dementia syndrome, if you wanted to use that term. However, a number of projections suggests that maybe a quarter or a third of the population are resistant to the development of dementia even into centenarian age. So between the idea that as we age there is a change in our ability to mentate and that this would imply usual ageing, all the way to the idea that we have a change to the extent that it is pathological, there is a lot of room and it’s a matter of what we define as pathological. As a doctor who sees patients, what becomes a problem is when individuals identify themselves as patients. There are all kinds of forces that get them to that point, so whether it’s because of normal ageing or usual ageing, if a cognitive change becomes a problem for them and they seek my help, then I would argue that it’s pathological. Question: Can you also tell us, from your experience, how these diagnoses affect the person and the family when either they receive the diagnosis of MCI or the results that indicate nothing is wrong with them. How do they react? CL: The situations are variable. Remember we’re talking about a context where people have shown up with a complaint, so they’re concerned about something. And in this context, most of the time when you provide reassurance, it is well received. If people show up with a complaint and are told that their assessment concludes that their memory testing profile puts them at risk for developing dementia, hence there is a suspicion there may be Alzheimer’s pathology unfolding in their brain, then of course most people would become upset. However, because they’ve come to me with a complaint, they’re usually not terribly surprised. There are exceptions, but where I have greater concern is in the context of research or in the context of less-than-careful assessment. We’ve seen many individuals who have been in the primary care setting or a research study, and who have developed a complaint and been given a diagnosis of MCI by someone else, inappropriately. We do see the harm side of this idea that MCI is by necessity a pathological entity, especially where people are not careful when they attach that label. Question: We have talked to other people about a similar point because some countries are entertaining the idea of annual screening for older adults. Yet, from what you have said, there is room for some concern in the clinician’s ability to make correct diagnoses. If local screening of older people by general practitioners becomes a widespread phenomenon, do you foresee future problems with accurate diagnoses?
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CL: Well putting on my epidemiologist hat, I would say that screening should have some kind of justifiable public health purpose such that the purpose and screening procedure are very closely calibrated. If screening is applied to detect dementia at an early stage, then it needs to be related to helpful interventions for people. I think there is good evidence that early detection of dementia, especially in late life, is very effective in improving quality of life and potentially delaying progression. In this context you could see screening of the population where the prevalence of dementia is sufficiently high, such that most of your test positives are going to be people who will be helped by a future intervention. What this means to me is thinking of screening at age 70 or higher because at younger ages the prevalence of dementia is too low and screening would produce many more false positives than true positives. If people are starting to talk about population-wide screening, I would have to understand more about which countries are moving in this direction and more specifically with what techniques and for what reasons they are screening. Are we talking about using a PET scan to detect amyloid accumulation in the brain of a 55-year-old? If so, I think we’re very far from wanting to do that. If we’re talking about doing thorough and wellestablished dementia screening in an 80-year-old, I think that is probably appropriate and makes sense both from the individual and public health point of view. Question: These are good points and relate to your mentioning of effective interventions. Can you tell us about treatments that you offer and your overall view of their effectivity? CL: Are we talking about MCI now or about dementia? If MCI, there is really nothing which I can think that is evidence-based effective treatment, so I could answer that one easily. The value of diagnosing (and again I don’t like the term diagnosing MCI) is really prognostic at this point and perhaps to provide reassurance as well. In the context of dementia, even in early dementia, there have been treatments oriented towards the problems of dementia patients and caregivers that have come from many different settings. In addition to the cholinesterase inhibitor drugs, memantine, and the emerging development of drugs for symptoms like agitation, apathy, and depression, there are nonpharmacological interventions that help with quality of life. Some of these interventions are oriented to the patient and some to the caregiver, so there is a sizeable body of knowledge where some treatments hold up to generally having small benefits for most people. In rare cases, there have been more than just small benefits for a smaller group; for example, in the treatment of late-life depression with anti-depressants to help with cognition or the dementia of depression. What has happened in the last couple of decades is the accumulation of that knowledge into a package that we, and many others, refer to as ‘dementia care’, with the view that delivering this package at an early stage to someone with dementia can help them in various ways. One way is to improve their symptoms. Other ways might be to improve their quality of life or to help them to stay in their homes longer, along with a variety of other outcomes. So we’ve gone from randomized trials or not-so-randomized research studies that suggested the benefits of individual intervention to a variety of studies where the package has been evaluated against a broader range of outcomes. We can now suggest, with fair consistency, that this package of dementia care, if thoughtfully individualized and followed up, helps patients and caregivers. It doesn’t necessarily change whatever underlying brain pathology might be taking place, but it makes a difference in a variety of important outcomes. However, there is not very good evidence right now for a similar package that could be
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applied to MCI. As for what treatments we offer, we have developed a Johns Hopkins model of dementia care about which we reported last year in a fairly large population-based randomized trial.1 This model is quite effective at helping people continue to live at home for as long as a year in some cases, improving their quality of life and very likely keeping them out of the hospital. Our field is not particularly surprised by this result. But these studies are hard to do and expensive, with probably less than half a dozen of these kinds of randomized trials out there. Question: Your work in this regard is very impressive. On a speculative note, what do you see as the future of MCI? If the DSM-V has introduced new diagnostic entities, where does that leave MCI in terms of diagnostic and treatment issues? And more recently, do you see the role of biomarkers becoming more prominent? CL: I think we will just have to watch and see the answers. I’ll give you my own opinion and I emphasize that it is just an opinion. Let’s use the analogy of prostate cancer and think of its historical evolution applied to a cognitive setting. Many years ago, prostate cancer was primarily diagnosed when a patient was symptomatic, or if there was blood in their urine or urinary obstruction. Basically the emergence of pretty severe symptoms over time increased our understanding of the emergence of prostate cancer. Now those in the medical field are able to detect it at earlier stages, through rectal examinations or other methodologies. Thus, we are getting better at differentiating prostrate cancer from another very common condition that affects older men, which is prostatic hypertrophy of the noncancerous form. This condition can have similar symptoms to prostrate cancer. One of the biomarkers that has been in the media and has been debated for a long time is a blood test called a prostate-specific antigen (PSA). So, for a while, there was a general recommendation that men should be screened over age 40 with a PSA test because that would detect prostate cancer at an early point in time. Today, PSA testing is being recommended at older ages, but not all positive PSA results are followed up with any intervention. All to say, it is a hotly contested debate. So we have two conditions, prostatic hypertrophy and prostate cancer, that both increase with frequency over time. They may have a relationship in that prostatic hypertrophy not uncommonly turns into prostate cancer. But it can be detected at various stages where you have at least one biomarker, so you can see the relatedness to the dementia field. Where we are now is that we have defined this entity, which might be starting to have prostatic-like symptoms, which by analogy is like MCI. But we have yet to confidently figure out the subgroup of people who have a prostate cancer equivalent, which by analogy is like the AD pathology stage or other relevant brain pathologies about which we might intervene. But first we have to figure out the right biomarker. This is where the MCI construct needs to go, hopefully rapidly, in order to validate the heterogeneity of the relevant subgroups for which something needs to be done in order to try to prevent the emergence of dementia. But we also wish to provide reassurance to everybody else and this is going to involve a combination of biomarkers or maybe a sequence of biomarkers that have yet to be sorted out. In the prostate cancer setting, if a patient is 78 and has a prostatism, then they get a PSA test, and if the results are high, they get a rectal exam. A nodule is felt, followed by an ultrasound and the discovery of cancer. The common intervention is that the prostrate gland is removed. A similar sequence might show up in MCI where, following a blood test, a biomarker emerges that is the equivalent of prostatism in terms of presenting an abnormal
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pathology. Maybe it’s high amyloid or tau that justifies secondary screenings which could lead to and be followed by a helpful therapy. Question: This is an interesting analogy. We read about the great interest in the role of biomarkers in diagnosing early AD, yet there also seems to be a fear that biomarkers will come to dominate the diagnoses of symptoms and interpretations of screenings, such that patients will become less willing to question their conditions and experiences of them. Do you think the focus on biomarkers will exclude the ‘patient context’ and that is this a realistic fear? CL: I do think there is a real danger that we will be treating lab tests and not patients. That is certainly something that medicine has repeatedly shown it is very capable of doing. I was at a meeting last Saturday where a similar phenomenon is starting to happen with organized sports, where people have apparent head injuries and where well-meaning scientists are developing increasingly sensitive tests. There is the risk in this setting where a very sensitive test might conclude that somebody should never play football or soccer again because the test is still abnormal, even though the person is completely asymptomatic. For me it comes down to the idea that ultimately the validation has to tie into symptomatic expression. Again, the PSA test is a very good example. By the time you are 90 you are close to a 100% chance that there’s cancer in your prostate; we know this from autopsy studies. The question is how this emerges for the individual, since even with a condition like prostate cancer, where there’s little argument that it’s a disease, there are still situations where it doesn’t matter to the patient whether it’s known or not. Similarly, in the case of dementia testing, we will need to be very careful and thorough about concluding that an abnormal amyloid brain image at age 55 means that everything should be done for everybody. Question: We certainly share these speculations and concerns. What you think about the current public concerns about ageing and cognitive health, in light of the many ageist and anti-ageing messages that have turned memory loss into a widespread social anxiety? CL: Well I do think that there is a role for that. If you grow older and start developing wrinkles, you can appreciate this is an ageing phenomenon. But whether or not you need or choose to have plastic surgery is clearly influenced by culture. Outside of instances where wrinkles are indicative of a serious disease for which treatment is required, wrinkles change with age, but cultural norms will determine whether or not such changes are desirable or acceptable. People then will try to fit the culturally normative to their own subjective experience. Question: There is also the proliferation of new lifestyle products and promotions for cognitive health, although what cognitive health actually means to the public is not certain. Still, products like brain gyms, brain supplements, and brain exercises have been added to physical exercise to emphasize that healthy ageing now includes cognitive care. CL: Yes I hear this too, and I generally agree, but I’m not sure it’s all that new. After all, the idea of using chemicals to alter our mental state goes back a very long time, but it’s just
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slightly different today. It does relate to the fact that we are living much older now, and that most of us who plan to live a long life have an expectation that we will not be disabled or seriously challenged by multiple chronic illnesses. Question: Our last question is whether or not you see dementia as a scientifically competitive field? There seems to be a defined and desirable dementia territory in terms of research investment by various professions, such as psychiatry, neurology, gerontology, social gerontology, and psychogeriatrics. It is interesting to us that memory has become a contested ground in terms of research attention and funding, the development of new centres, and global health initiatives. CL: My response depends on what you mean by ‘contested’. For example, I am about to give a talk later this afternoon that will compare the societal costs of dementia to the societal costs of heart disease and cancer, suggesting that the societal costs at least in the United States are very comparable, but the research dollars spent on dementia are in some cases a fifth or even a tenth of what are spent on cardiovascular disease or cancer. Sure, you could argue that it is a contested field because there are such few resources available for such a huge public health problem. Because of the severity of the public health pandemic, if we were to have the right resources available, I don’t think it would be a contested field. Question: In other words, you see more interdisciplinary cooperation in dementia research than competition? CL: Yes, absolutely. At Johns Hopkins University and elsewhere pretty much everything I do is part of a collaborative in the research world. It is also true in the clinical world. Our own Memory and Alzheimer’s Treatment Center here is collaborative across several disciplines both within medicine and beyond medicine. I am not saying that rivalry doesn’t exist within research and university environments, but I don’t see specificity of such in the dementia field. Question: Dr Lyketsos, we thank you for your time and for sharing your experience and perspectives. Your work and publications have made an enormous contribution to the field and this conversation has been very helpful. CL: I appreciate that. Thank you and good luck with your project.
Note 1. Samus, Q. M., Johnston, D., Black, B. S., Hess, E., Lyman, C., Vavilikolanu, A., . . . Lyketsos, C. G. (2014). A multidimensional home-based care coordination intervention for elders with memory disorders: The maximizing independence at home (MIND) pilot randomized trial. The American Journal of Geriatric Psychiatry, 22, 398–414. doi:10.1016/j.jagp.2013.12.17. Preliminary results of this trial were presented at the Alzheimer’s Association International Conference held in Vancouver, BC, Canada in July of 2012.
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Selected Publications Lyketsos, C. G., Colenda, C. C., Beck, C., Blank, K., Doraiswamy, M. P., Kalunian, D. A., . . . Task Force of American Association for Geriatric Psychiatry (2006). Position statement of the American Association for Geriatric Psychiatry regarding principles of care for patients with dementia resulting from Alzheimer disease. The American Journal of Geriatric Psychiatry, 14, 561–572. doi:10.1097/01.JGP.0000221334.65330.5 Porsteinsson, A. P., Drye, L. T., Pollock, B. G., Devanand, D. P., Frangakis, C., Ismail, Z., . . . CitAD Research Group (2014). Effect of citalopram on agitation in Alzheimer disease: The CitAD randomized clinical trial. JAMA, 311, 682–691. doi:10.1001/jama.2014.9 Rosenberg, P. B., Johnston, D., & Lyketsos, C. G. (2006). A clinical approach to mild cognitive impairment. American Journal of Psychiatry, 163, 1884–1890. Rosenberg, P. B., Mielke, M. M., Appleby, B., Oh, E., Leoutsakos, J. M., & Lyketsos, C. G. (2011). Neuropsychiatric symptoms in MCI subtypes: The importance of executive dysfunction. International Journal of Geriatric Psychiatry, 26, 364–372. doi:10.1002/gps.253 Tighe, S. K., Oishi, K., Mori, S., Smith, G. S., Albert, M., Lyketsos, C. G., . . . Mielke, M. M. (2012). Diffusion tensor imaging of neuropsychiatric symptoms in mild cognitive impairment and Alzheimer’s dementia. The Journal of Neuropsychiatry and Clinical Neurosciences, 24, 484–488. doi:10.1176/appi.neuropsych.1112037 Trzepacz, P. T., Cummings, J., Konechnik, T., Forrester, T. D., Chang, C., Dennehy, E. B., . . . Lyketsos, C. (2013). Mibampator (LY451395) randomized clinical trial for agitation/aggression in Alzheimer’s disease. International Psychogeriatrics, 25, 707–719. doi:10.1017/S104161021200214
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Interview with Dr Constantine Lyketsos, 14 May 2013
Dementia 2015, Vol. 14(3) 318–327 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1471301214562138 dem.sagepub.com
Stephen Katz and Kevin R Peters Background Dr Constantine Lyketsos is Elizabeth Plank Althouse Professor and Chair of Psychiatry, at Johns Hopkins Bayview Medical Center, and Professor of Psychiatry and Behavioral Sciences. He was foundational to the establishment of The Johns Hopkins Neuropsychiatry Service, which, along with Dr Lyketsos, is known for its leading research and expertise in dementia and traumatic brain injury. While the relationship between the epidemiological, physical, psychological, cognitive, and neurological aspects of the ageing mind is crucial to understanding in the field of Alzheimer disease (AD) and related dementias, much more theoretical and practical research is needed in order to temper the biomedical model with these other dimensions of the ageing process. As evident from his many publications, honours, and awards, Dr Lyketsos fulfils this need with his innovative concerns about the patients he treats, the families he supports, and the way he combines humanistic and scientific approaches. Question: Thank you Dr Lyketsos for taking the time to talk to us this morning. Please tell us about your career background and how you became interested in dementia and Mild Cognitive Impairment (MCI). CL: I am a physician trained in psychiatry, neuropsychiatry, and epidemiology. I came to the dementia area from a neuropsychiatric background, interested in the relationship between brain disease and the development of behavioural and psychiatric symptomatology. I have stayed in that field since about 1993. Question: How was it that you came to focus on ageing, psychiatry, dementia, and MCI? CL: I am not exactly sure if there was one factor. My father was a psychiatrist, so that had a role. But I have always been interested in brain–behaviour relationships, from the scientific point of view as a way to understand how the brain relates to behaviour. Then I started seeing patients and their families and felt that I could make a contribution. Question: So some of your research interests have been informed by your clinical practice. CL: Yes, quite a bit, but I consider myself a physician first, followed by everything else.
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Question: Regarding MCI, what is your view of it as a diagnostic category? Where to you see it as useful and where do we have much to learn? CL: I have mixed feelings about MCI because it is so heterogeneous. In a clinical setting there is utility to identifying people who have MCI, even if we haven’t perfectly defined it. I prefer the more agnostic term ‘not normal, not demented’ for older people. There is value there because there are preventive opportunities. For a variety of reasons, perhaps because of the media attention and so forth, people are noticing the symptoms and they’re asking for information and help in some situations. I’m not quite ready to think of it as a clear diagnostic entity. In psychiatry there is a new diagnostic entity in the DSM-5 called ‘minor neurocognitive disorder’, a term I don’t particularly like, but it is another way of defining a diagnostic entity in this space. What we need to understand, and hopefully soon, is the ability to differentiate the MCI subgroups that have an adverse prognosis (e.g. progression to dementia or disability), so that from the public health point of view we can focus our attention either on prevention or on prognosis, which is ultimately where I see myself as a physician serving patients. Question: You have been in this field for quite some time now, so what is your assessment of the forces that shaped MCI? In addition to the well-known Petersen/Mayo criteria from 1999, there are other labels and criteria that have been used in the past. In particular we would like to know your view of the play between psychiatric symptoms and cognitive symptoms? CL: Cognitive symptoms are psychiatric symptoms. As for the forces that have shaped the field, first certainly is the dementia pandemic and the appreciation that a person doesn’t go from normal to dementia overnight without some sort of intermediate stage. So there is an emerging focus on secondary prevention in trying to detect a symptomatic pre-dementia state, which could provide opportunities for interventions. I think this is one major force coming out of the medical setting. Secondly, in the social setting, as people are ageing in a healthy fashion, there are many questions being asked about the status of what is ‘normal’. At what point do certain complaints, experiences, and functional changes become pathological, or abnormal, beyond usual ageing. For me those are the two major forces. However, I think a third force that builds on these two is the emergence of the idea that pharmaceuticals can help with the symptoms, to improve them, or to delay or prevent worsening. This is a market force that is trying to define an entity, which I wouldn’t assess as appropriate or inappropriate, it is just a reality that product development has become mixed in with the medical and social settings. Question: That is an interesting response. Could you elaborate on your comment that cognitive symptoms are psychiatric symptoms? When people present their bullet-point lists of symptoms when they talk about MCI, they usually present memory impairment and related issues. CL: Psychiatric symptoms are disturbances in mental life, so memory impairment is a disturbance in mental life. If you look at the predominant classification of disorders of cognition, perception, and behaviour, they have been under the psychiatric realm going
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back to the days of Hippocrates. I do understand that there is a recent movement to say that cognition is ‘neurologic’, but these are semantic differences. My point is that we’re talking about disturbances in the realm of mental life and behaviour, what I consider a traditional top-down approach to classification. If these disturbances are in the realm of mental life or behaviour, they are of interest to me as a psychiatrist. Question: So when we talk about psychiatric symptoms, you are saying that the disturbances of mental life are your focus. What we think of as psychiatric symptoms, perhaps naively, are problems such as depression, agitation, or related symptoms. What do you see as their role in being used either to define MCI or being a predictor of conversion in MCI? CL: To me this is a definitional question, which one can approach from different angles. My preferred approach is empirical, so rather than create an entity around the specific symptoms like MCI, I prefer to look at what kinds of symptom constellations appear within individuals across time, while appreciating that if they are occurring around the same time in the same person or in a certain predictable sequence, then they’re probably arising out of similar causes which I would imagine frequently relate to the brain. I think the definition of MCI has really emerged from expert groups who have been interested in studying memory primarily and have therefore defined the syndrome around memory. But if you start studying the people who fit this kind of narrow definition of MCI, you appreciate that they have a variety of other disturbances in mental life and behaviour. To be even more specific, I think there is an entity called ‘mild behavioural impairment’. We, and others, have published on this entity, where the change that is occurring in the person relates to some aspect of mental life/behaviour other than cognition. There is a lot of overlap within and across people who have this range of symptoms. It is a complicated issue. Question: You have highlighted a very important distinction amongst how different groups of people might approach MCI; with some focused on memory only or other aspects of cognition, and others taking a more global view. You mentioned the DSM-5 classification of ‘minor neurocognitive disorder’, about which you are not particularly satisfied. Could you tell us how this classification differs from the conventional Petersen/Mayo definition of MCI? CL: I would have to look at the specifics of the criteria, which I do not have entirely memorized, but I think the construct is basically the same. The Petersen criteria generally imply, although not clearly state, that the cause of MCI is an underlying pathology in the brain that looks like what we would call Alzheimer’s pathology; whereas I think the DSM construct is more intended to describe a syndrome or constellation of symptoms that might have many different causes. If you look at the people actually involved in writing the DSMology in this particular area, you will see the convergence of the Petersen MCI group, the HIV group with Igor Grant who was involved in developing the concept of minor and major neurocognitive disorder of HIV, and epidemiologists like Mary Ganguli. I have pretty well described the committee for you, which tried to merge their perspectives in defining this new entity. And as with other aspects of the DSM-ology, the process has been a compromise of people trying to merge different perspectives. Honestly, I don’t know how it is all going to play out in patients empirically, because I don’t think anybody has really sat down and taken
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the criteria and considered whether it makes sense to have similar syndromes of different causes classified in the same way just based on the phenomenology. Question: This is very interesting, thank you. If you make diagnoses of MCI, what is the process you use in your own clinical practice? CL: The first process begins with somebody coming to me with a complaint. This contact is very important because if you go out and do other studies where you’re identifying people who might have the MCI syndrome, but did not self-present to a clinical setting, then you have a very different context. For me, number one is the clinical setting where somebody is showing up with a complaint, which could be coming from a patient or from a family member. The second process is pretty standard and involves history-taking, examination, and then diagnostic tests and studies. The history-taking typically involves taking history of symptoms, and the emergence of presentation from the patient and from knowledgeable informants (people who know them well) in a temporal fashion. So we start with the period when the person was last well and then try to understand how the cognitive and associated symptoms emerged and progressed over time; this is the history component. The examination is also very typical based on mental status and a physical or neurologic exam. The diagnostic testing depends on what one has seen, but will frequently involve some kind of standardized cognitive assessment as well. Occasionally, depending again on the setting, testing might involve a blood test, brain imaging, and so forth. All these procedural steps lead to a formulation about whether there is a recognizable syndrome present, its associated features, and its severity. Then we try to make sense about the possible causes and what could be done to help the patient. One of the interesting questions is when a person actually becomes a patient? We see a lot of folks who present with a cognitive complaint who think they have MCI. Many of them are children of people with dementia or people who cared for someone with dementia, like a spouse. They consider themselves patients, but after we go through this evaluation process we conclude that they’re really fine from the medical point of view. Question: They have also likely been given different labels in the field as well, such as ‘not cognitively impaired’ (NCI). What is your assessment of this group? Is it a matter of the cognitive tests not being sensitive enough? Or does this group fall into the ‘worried-well’ side? Or is it just too hard to characterize them all that way? CL: Let me ask you: Do you know the definition of a normal person? Question: Very good question. CL: It is someone who hasn’t had enough tests, right? So if you have a sensitive enough test, you will always be able to call someone abnormal. When you raised the question of context of test sensitivity, I don’t think that for those people it’s purely a matter of sensitivity. It’s a matter of defining the specific context of their concern. Is it that they have an underlying brain disease? We now have this view that is well supported by evidence, which is that if you are to get the syndrome of dementia in your 80s, then there is unfolding in your brain a degenerative brain pathology detectable presumably for a number of years beforehand. We haven’t quite settled on what we think will be there, but then that context might be, ‘I’m the
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child of someone who got dementia at 75. I’m 62 right now. I’m starting to have the same symptoms that my parents had. Do I have the same brain disease? Can you do something about it?’ This is the most common context I see. There are other contexts to do with concerned family members, which might bring forward other motives or concerns. Question: Regarding the measuring of ‘normal’ and as you know Dr Lyketsos, there are several critics of current dementia studies who say that normal could be inclusive of memory impairment and cognitive impairment when it comes to ageing. That this is normal ageing. What you think of this particular perspective? CL: I think it’s an important and fair question, but I don’t like the term ‘normal ageing’ and prefer instead the term ‘usual ageing’ for the reason that I implied before. Under my postulate, and I recognize it is my postulate right now, from what we know now, most people who reach very old age will have a dementia syndrome, if you wanted to use that term. However, a number of projections suggests that maybe a quarter or a third of the population are resistant to the development of dementia even into centenarian age. So between the idea that as we age there is a change in our ability to mentate and that this would imply usual ageing, all the way to the idea that we have a change to the extent that it is pathological, there is a lot of room and it’s a matter of what we define as pathological. As a doctor who sees patients, what becomes a problem is when individuals identify themselves as patients. There are all kinds of forces that get them to that point, so whether it’s because of normal ageing or usual ageing, if a cognitive change becomes a problem for them and they seek my help, then I would argue that it’s pathological. Question: Can you also tell us, from your experience, how these diagnoses affect the person and the family when either they receive the diagnosis of MCI or the results that indicate nothing is wrong with them. How do they react? CL: The situations are variable. Remember we’re talking about a context where people have shown up with a complaint, so they’re concerned about something. And in this context, most of the time when you provide reassurance, it is well received. If people show up with a complaint and are told that their assessment concludes that their memory testing profile puts them at risk for developing dementia, hence there is a suspicion there may be Alzheimer’s pathology unfolding in their brain, then of course most people would become upset. However, because they’ve come to me with a complaint, they’re usually not terribly surprised. There are exceptions, but where I have greater concern is in the context of research or in the context of less-than-careful assessment. We’ve seen many individuals who have been in the primary care setting or a research study, and who have developed a complaint and been given a diagnosis of MCI by someone else, inappropriately. We do see the harm side of this idea that MCI is by necessity a pathological entity, especially where people are not careful when they attach that label. Question: We have talked to other people about a similar point because some countries are entertaining the idea of annual screening for older adults. Yet, from what you have said, there is room for some concern in the clinician’s ability to make correct diagnoses. If local screening of older people by general practitioners becomes a widespread phenomenon, do you foresee future problems with accurate diagnoses?
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CL: Well putting on my epidemiologist hat, I would say that screening should have some kind of justifiable public health purpose such that the purpose and screening procedure are very closely calibrated. If screening is applied to detect dementia at an early stage, then it needs to be related to helpful interventions for people. I think there is good evidence that early detection of dementia, especially in late life, is very effective in improving quality of life and potentially delaying progression. In this context you could see screening of the population where the prevalence of dementia is sufficiently high, such that most of your test positives are going to be people who will be helped by a future intervention. What this means to me is thinking of screening at age 70 or higher because at younger ages the prevalence of dementia is too low and screening would produce many more false positives than true positives. If people are starting to talk about population-wide screening, I would have to understand more about which countries are moving in this direction and more specifically with what techniques and for what reasons they are screening. Are we talking about using a PET scan to detect amyloid accumulation in the brain of a 55-year-old? If so, I think we’re very far from wanting to do that. If we’re talking about doing thorough and wellestablished dementia screening in an 80-year-old, I think that is probably appropriate and makes sense both from the individual and public health point of view. Question: These are good points and relate to your mentioning of effective interventions. Can you tell us about treatments that you offer and your overall view of their effectivity? CL: Are we talking about MCI now or about dementia? If MCI, there is really nothing which I can think that is evidence-based effective treatment, so I could answer that one easily. The value of diagnosing (and again I don’t like the term diagnosing MCI) is really prognostic at this point and perhaps to provide reassurance as well. In the context of dementia, even in early dementia, there have been treatments oriented towards the problems of dementia patients and caregivers that have come from many different settings. In addition to the cholinesterase inhibitor drugs, memantine, and the emerging development of drugs for symptoms like agitation, apathy, and depression, there are nonpharmacological interventions that help with quality of life. Some of these interventions are oriented to the patient and some to the caregiver, so there is a sizeable body of knowledge where some treatments hold up to generally having small benefits for most people. In rare cases, there have been more than just small benefits for a smaller group; for example, in the treatment of late-life depression with anti-depressants to help with cognition or the dementia of depression. What has happened in the last couple of decades is the accumulation of that knowledge into a package that we, and many others, refer to as ‘dementia care’, with the view that delivering this package at an early stage to someone with dementia can help them in various ways. One way is to improve their symptoms. Other ways might be to improve their quality of life or to help them to stay in their homes longer, along with a variety of other outcomes. So we’ve gone from randomized trials or not-so-randomized research studies that suggested the benefits of individual intervention to a variety of studies where the package has been evaluated against a broader range of outcomes. We can now suggest, with fair consistency, that this package of dementia care, if thoughtfully individualized and followed up, helps patients and caregivers. It doesn’t necessarily change whatever underlying brain pathology might be taking place, but it makes a difference in a variety of important outcomes. However, there is not very good evidence right now for a similar package that could be
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applied to MCI. As for what treatments we offer, we have developed a Johns Hopkins model of dementia care about which we reported last year in a fairly large population-based randomized trial.1 This model is quite effective at helping people continue to live at home for as long as a year in some cases, improving their quality of life and very likely keeping them out of the hospital. Our field is not particularly surprised by this result. But these studies are hard to do and expensive, with probably less than half a dozen of these kinds of randomized trials out there. Question: Your work in this regard is very impressive. On a speculative note, what do you see as the future of MCI? If the DSM-V has introduced new diagnostic entities, where does that leave MCI in terms of diagnostic and treatment issues? And more recently, do you see the role of biomarkers becoming more prominent? CL: I think we will just have to watch and see the answers. I’ll give you my own opinion and I emphasize that it is just an opinion. Let’s use the analogy of prostate cancer and think of its historical evolution applied to a cognitive setting. Many years ago, prostate cancer was primarily diagnosed when a patient was symptomatic, or if there was blood in their urine or urinary obstruction. Basically the emergence of pretty severe symptoms over time increased our understanding of the emergence of prostate cancer. Now those in the medical field are able to detect it at earlier stages, through rectal examinations or other methodologies. Thus, we are getting better at differentiating prostrate cancer from another very common condition that affects older men, which is prostatic hypertrophy of the noncancerous form. This condition can have similar symptoms to prostrate cancer. One of the biomarkers that has been in the media and has been debated for a long time is a blood test called a prostate-specific antigen (PSA). So, for a while, there was a general recommendation that men should be screened over age 40 with a PSA test because that would detect prostate cancer at an early point in time. Today, PSA testing is being recommended at older ages, but not all positive PSA results are followed up with any intervention. All to say, it is a hotly contested debate. So we have two conditions, prostatic hypertrophy and prostate cancer, that both increase with frequency over time. They may have a relationship in that prostatic hypertrophy not uncommonly turns into prostate cancer. But it can be detected at various stages where you have at least one biomarker, so you can see the relatedness to the dementia field. Where we are now is that we have defined this entity, which might be starting to have prostatic-like symptoms, which by analogy is like MCI. But we have yet to confidently figure out the subgroup of people who have a prostate cancer equivalent, which by analogy is like the AD pathology stage or other relevant brain pathologies about which we might intervene. But first we have to figure out the right biomarker. This is where the MCI construct needs to go, hopefully rapidly, in order to validate the heterogeneity of the relevant subgroups for which something needs to be done in order to try to prevent the emergence of dementia. But we also wish to provide reassurance to everybody else and this is going to involve a combination of biomarkers or maybe a sequence of biomarkers that have yet to be sorted out. In the prostate cancer setting, if a patient is 78 and has a prostatism, then they get a PSA test, and if the results are high, they get a rectal exam. A nodule is felt, followed by an ultrasound and the discovery of cancer. The common intervention is that the prostrate gland is removed. A similar sequence might show up in MCI where, following a blood test, a biomarker emerges that is the equivalent of prostatism in terms of presenting an abnormal
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pathology. Maybe it’s high amyloid or tau that justifies secondary screenings which could lead to and be followed by a helpful therapy. Question: This is an interesting analogy. We read about the great interest in the role of biomarkers in diagnosing early AD, yet there also seems to be a fear that biomarkers will come to dominate the diagnoses of symptoms and interpretations of screenings, such that patients will become less willing to question their conditions and experiences of them. Do you think the focus on biomarkers will exclude the ‘patient context’ and that is this a realistic fear? CL: I do think there is a real danger that we will be treating lab tests and not patients. That is certainly something that medicine has repeatedly shown it is very capable of doing. I was at a meeting last Saturday where a similar phenomenon is starting to happen with organized sports, where people have apparent head injuries and where well-meaning scientists are developing increasingly sensitive tests. There is the risk in this setting where a very sensitive test might conclude that somebody should never play football or soccer again because the test is still abnormal, even though the person is completely asymptomatic. For me it comes down to the idea that ultimately the validation has to tie into symptomatic expression. Again, the PSA test is a very good example. By the time you are 90 you are close to a 100% chance that there’s cancer in your prostate; we know this from autopsy studies. The question is how this emerges for the individual, since even with a condition like prostate cancer, where there’s little argument that it’s a disease, there are still situations where it doesn’t matter to the patient whether it’s known or not. Similarly, in the case of dementia testing, we will need to be very careful and thorough about concluding that an abnormal amyloid brain image at age 55 means that everything should be done for everybody. Question: We certainly share these speculations and concerns. What you think about the current public concerns about ageing and cognitive health, in light of the many ageist and anti-ageing messages that have turned memory loss into a widespread social anxiety? CL: Well I do think that there is a role for that. If you grow older and start developing wrinkles, you can appreciate this is an ageing phenomenon. But whether or not you need or choose to have plastic surgery is clearly influenced by culture. Outside of instances where wrinkles are indicative of a serious disease for which treatment is required, wrinkles change with age, but cultural norms will determine whether or not such changes are desirable or acceptable. People then will try to fit the culturally normative to their own subjective experience. Question: There is also the proliferation of new lifestyle products and promotions for cognitive health, although what cognitive health actually means to the public is not certain. Still, products like brain gyms, brain supplements, and brain exercises have been added to physical exercise to emphasize that healthy ageing now includes cognitive care. CL: Yes I hear this too, and I generally agree, but I’m not sure it’s all that new. After all, the idea of using chemicals to alter our mental state goes back a very long time, but it’s just
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slightly different today. It does relate to the fact that we are living much older now, and that most of us who plan to live a long life have an expectation that we will not be disabled or seriously challenged by multiple chronic illnesses. Question: Our last question is whether or not you see dementia as a scientifically competitive field? There seems to be a defined and desirable dementia territory in terms of research investment by various professions, such as psychiatry, neurology, gerontology, social gerontology, and psychogeriatrics. It is interesting to us that memory has become a contested ground in terms of research attention and funding, the development of new centres, and global health initiatives. CL: My response depends on what you mean by ‘contested’. For example, I am about to give a talk later this afternoon that will compare the societal costs of dementia to the societal costs of heart disease and cancer, suggesting that the societal costs at least in the United States are very comparable, but the research dollars spent on dementia are in some cases a fifth or even a tenth of what are spent on cardiovascular disease or cancer. Sure, you could argue that it is a contested field because there are such few resources available for such a huge public health problem. Because of the severity of the public health pandemic, if we were to have the right resources available, I don’t think it would be a contested field. Question: In other words, you see more interdisciplinary cooperation in dementia research than competition? CL: Yes, absolutely. At Johns Hopkins University and elsewhere pretty much everything I do is part of a collaborative in the research world. It is also true in the clinical world. Our own Memory and Alzheimer’s Treatment Center here is collaborative across several disciplines both within medicine and beyond medicine. I am not saying that rivalry doesn’t exist within research and university environments, but I don’t see specificity of such in the dementia field. Question: Dr Lyketsos, we thank you for your time and for sharing your experience and perspectives. Your work and publications have made an enormous contribution to the field and this conversation has been very helpful. CL: I appreciate that. Thank you and good luck with your project.
Note 1. Samus, Q. M., Johnston, D., Black, B. S., Hess, E., Lyman, C., Vavilikolanu, A., . . . Lyketsos, C. G. (2014). A multidimensional home-based care coordination intervention for elders with memory disorders: The maximizing independence at home (MIND) pilot randomized trial. The American Journal of Geriatric Psychiatry, 22, 398–414. doi:10.1016/j.jagp.2013.12.17. Preliminary results of this trial were presented at the Alzheimer’s Association International Conference held in Vancouver, BC, Canada in July of 2012.
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Selected Publications Lyketsos, C. G., Colenda, C. C., Beck, C., Blank, K., Doraiswamy, M. P., Kalunian, D. A., . . . Task Force of American Association for Geriatric Psychiatry (2006). Position statement of the American Association for Geriatric Psychiatry regarding principles of care for patients with dementia resulting from Alzheimer disease. The American Journal of Geriatric Psychiatry, 14, 561–572. doi:10.1097/01.JGP.0000221334.65330.5 Porsteinsson, A. P., Drye, L. T., Pollock, B. G., Devanand, D. P., Frangakis, C., Ismail, Z., . . . CitAD Research Group (2014). Effect of citalopram on agitation in Alzheimer disease: The CitAD randomized clinical trial. JAMA, 311, 682–691. doi:10.1001/jama.2014.9 Rosenberg, P. B., Johnston, D., & Lyketsos, C. G. (2006). A clinical approach to mild cognitive impairment. American Journal of Psychiatry, 163, 1884–1890. Rosenberg, P. B., Mielke, M. M., Appleby, B., Oh, E., Leoutsakos, J. M., & Lyketsos, C. G. (2011). Neuropsychiatric symptoms in MCI subtypes: The importance of executive dysfunction. International Journal of Geriatric Psychiatry, 26, 364–372. doi:10.1002/gps.253 Tighe, S. K., Oishi, K., Mori, S., Smith, G. S., Albert, M., Lyketsos, C. G., . . . Mielke, M. M. (2012). Diffusion tensor imaging of neuropsychiatric symptoms in mild cognitive impairment and Alzheimer’s dementia. The Journal of Neuropsychiatry and Clinical Neurosciences, 24, 484–488. doi:10.1176/appi.neuropsych.1112037 Trzepacz, P. T., Cummings, J., Konechnik, T., Forrester, T. D., Chang, C., Dennehy, E. B., . . . Lyketsos, C. (2013). Mibampator (LY451395) randomized clinical trial for agitation/aggression in Alzheimer’s disease. International Psychogeriatrics, 25, 707–719. doi:10.1017/S104161021200214
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