Interview
Interview with Dr John Morris, 28 February 2013
Dementia 2015, Vol. 14(3) 335–342 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1471301214562142 dem.sagepub.com
Stephen Katz and Kevin R Peters Background John C Morris, MD is one of the most recognised, awarded, published and honoured neurologists working today on Alzheimer disease (AD). From his base at Washington University in St. Louis, Missouri, Dr Morris has been particularly innovative in identifying early, pre- and asymptomatic stages of AD. His work is aimed at one of our most fundamental challenges in the field of ageing and cognitive health, which is the value of early intervention for cognitive dysfunction. This is a challenge that goes beyond the laboratory and involves complex relationships between research, clinical practice, public perception, entitlements and services, and the health of future ageing populations. Hence, Dr Morris’ reflections on mild cognitive impairment are particularly important. Question: Dr Morris, thank you for talking to us today. Our first question is about the development of your career and how you became interested in Mild Cognitive Impairment (MCI). JM: Well, my interest in MCI relates to the early symptomatic expression of AD. Many people view MCI as a risk factor for developing symptomatic AD, whereas I consider it to be the earliest symptomatic stage of AD (when AD indeed is the underlying disorder causing MCI). I became interested in neurodegenerative disease during my year of doing neuropathology in my neurology residency programme. I was invited to study a family that had an unusual dominantly inherited dementing illness that we termed ‘hereditary dysphasic dementia.’ We published our clinico-pathologic findings about the family in the Annals of Neurology in 1984 and afterward got calls from physicians who were seeing individuals with similar clinical presentations. In some cases, the physicians sent me brain tissue from their deceased patients. This allowed us to characterise another very similar family, ‘hereditary dysphasic dementia II’; years later we discovered that it is the largest known family with a progranulin mutation causing fronto-temporal lobar degeneration. My original foray into an academic career thus began with a clinico-pathologic correlative study. When I came to Washington University and joined its Alzheimer programme in 1984, it was not particularly strong on clinico-pathological studies. I was just a young faculty member but thought we should try to see if our research participants might consider brain donation when they died. It turns out they did. One such person was a retired investment banker who enrolled in our project as a control participant. He was very
Downloaded from dem.sagepub.com at University of Sydney on November 15, 2015
336
Dementia 14(3)
highly educated and cognitively high functioning and he performed very well on our cognitive measures over several times of testing. For his fourth annual evaluation, I happened to be the physician who interviewed both the participant and his wife. We spend a great deal of time here in obtaining not only objective cognitive data, but also subjective data from people who know the individual well. His wife said that he was still doing ‘pretty well’ cognitively but in the past six months or so she thought he was gradually becoming ‘a little vague’ in his memory and thinking. I asked her to describe what she meant by ‘vague’ and she reported that for the first time in their married life that year he was unable to complete their income tax return. Now, I have never been able to do my own income tax return; this is not something I could even envision! But for this man it was an example of subtle but definite intra-individual cognitive decline. I rated him on the Clinical Dementia Rating (CDR) scale as a 0.5, indicating very mild impairment, and thought it was likely due to AD. My mentor and the other senior neurologists in the programme were surprised with this diagnosis as they would have attributed his very mild change to normal ageing (he scored normally on our cognitive test battery). Six months after that assessment the participant died, came to autopsy, and had florid AD neuropathology, suggesting that his mild symptoms were indeed the initial clinical expression of that disorder and not simply due to ageing. I became identified with clinically recognising the earliest symptomatic changes that could be ascribed to neurodegenerative processes such as AD. As CDR 0.5 also was being used to characterise MCI, my interests overlapped this entity. In discussions about MCI, I ask why are people mildly cognitively impaired? What is the underlying aetiology? Rather than using the term ‘mild cognitive impairment’ in our research programme, we try to provide an aetiologic diagnosis even at the CDR 0.5 level. Because you now realise that I am not an advocate of leaving the diagnosis simply at ‘‘MCI,’’ you may not want to continue with this interview because I am not really an MCI person [laughter]. Question: We gather from reading your publications that you are more interested in this pre-symptomatic AD? JM: Yes, we are most interested in presymptomatic or preclinical AD because we know that when people die in the earliest symptomatic stage of AD (CDR 0.5), up to 60% of neurons in layer 2 of the entorhinal cortex already are lost. So the likelihood of a truly meaningful benefit from therapeutic agents in persons with symptomatic AD is made much more challenging because the brain already is substantially damaged by the time treatment begins. We are trying to identify the pre-clinical stage to hopefully allow interventions to begin before there is substantial brain damage. Question: Would it be more fruitful for us today to use pre-symptomatic AD instead of MCI? For example, if you make diagnoses, what is the process you use in your clinic? If you do not use the term MCI, how do you go about this process for someone who has minimal or no cognitive deficits?
Downloaded from dem.sagepub.com at University of Sydney on November 15, 2015
Katz and Peters
337
JM: If a person has minimal or mild cognitive deficits, we do our best to determine why. Did symptoms develop gradually or abruptly? Are symptoms progressively worsening? Do they resemble the clinical phenotype of fronto-temporal dementia, Lewy body dementia, vascular dementia, or AD dementia? If the person has difficulty carrying out accustomed activities due to cognitive loss, even when very mild, and fits the AD phenotype, then we diagnose symptomatic AD. Fortunately we have been able to track enough of these people to confirm that even when they are identified in the mild cognitive impairment stage, our diagnosis of very mild symptomatic AD is supported with the neuropathologic diagnosis of Alzheimer’s in 92% of our patients. We differ from some other programmes in that we spend a great deal of time trying to find out how the individual is doing in carrying out his or her usual activities and for that we need an informant, not only to tell us what the person once was able to do, but whether or not they are continuing to function at that level. We do not utilise neuropsychologic test data in our clinical diagnostic algorithm. We keep these data separate because if neuropsychologic test data are used to help classify a person as impaired or unimpaired, it confounds following that person longitudinally with cognitive testing. It would be no surprise, for example, that people classified as having amnestic MCI do poorly on memory tests over time because they already had to perform poorly in memory at initial assessment to receive that classification. For scientific reasons we always keep the two procedures separate: a clinical classification based upon the principle of intra-individual decline and then independent neuropsychologic monitoring. Again, the main question is: Has the person declined in cognitive and functional abilities compared to their previously attained levels? Question: We understand that you try to avoid the circularity problem with which we are familiar. Then, is the term pre-symptomatic AD for you just a predominantly research-based label or is it something you use in the clinic? JM: No, we do not use this term, ‘preclinical AD,’ in the clinic. It is for research purposes only. The use of AD biomarkers allows the identification of cognitively normal individuals who have the neuropathologic lesions of AD. Molecular indicators of Alzheimer pathology during life include reduced levels of amyloid-beta 42 (Ab42) in their cerebrospinal fluid (CSF), elevated levels of Tau in their CSF, or a positive amyloid imaging scan using an amyloid tracer such as C11 PiB or F18 florbetapir (or another tracer). Question: It sounds like the practices at your clinic are a little different than at other places. Have you had any experiences where people ask you about that? As you know, the Internet today allows people to track down all of this information, whether good or not. So, have you noticed people asking you about this MCI label at your clinic? JM: No, our patients do not inquire about MCI. In general, people want to know what illness they are dealing with, so we provide (when appropriate) the diagnosis of very mild AD. We do face scrutiny each time we submit an application for funding to the National Institute on Aging, since we are sometimes considered unorthodox in our approach. All I can say is that we have plenty of experience and plenty of data to support our position.
Downloaded from dem.sagepub.com at University of Sydney on November 15, 2015
338
Dementia 14(3)
Question: This leads directly to our next question: what treatments do you offer and in what stages do you offer them? JM: If patients are symptomatic and have AD as their presumed underlying aetiology, then we offer the currently available symptomatic FDA-approved medications, such as cholinesterase inhibitors. All three of the currently available cholinesterase inhibitor drugs demonstrate very modest benefit, so we offer them with the caveat that the drugs are unlikely to considerably benefit the patients. The drugs may help slow the rate of progression at least somewhat and at least for some period of time. We treat based upon the diagnosis of an underlying dementing illness that now is symptomatic, even if the symptoms are minimal or mild. Question: One of the interesting things in the literature is about the prevalence of mixed cases that come to autopsy. As you are aware, there are cases that are diagnosed clinically with AD, but found to have a mixed presentation at autopsy. What has been your experience with this situation, since you mentioned in this interview that AD was based on identifying the aetiology? JM: Older people clearly are at risk for multiple brain disorders and there’s nothing about having AD that protects from also having, say, a cerebral infarct. In our clinico-pathologic experience, about 40–50% of people who die and have neuropathologic AD also have cerebral infarcts and about a third also have other neurodegenerative lesions, such as Lewy bodies, TDP-43 proteinopathy, or other disorders such as hippocampal sclerosis. Demented individuals who come to autopsy often have multiple pathologies. It is difficult to know how or whether each of these pathologies contributes to the clinical features or to what degree. Our cognitively healthy control participants also often have cerebral infarcts at autopsy, so the presence of an infarct does not always produce clinical deficits. By the same token, preclinical AD is defined by plaques and tangles that clinically are ‘silent.’ Attributing the clinical presentation to one or many co-existing pathologies is difficult. Question: What would be your comment when you get cases that present to autopsy which were cognitively normal but also found to have substantial plaque or tangle burden. What is your view on those cases? JM: My now emeritus colleague, Joseph L. Price, a neuroanatomist here at Washington University, and I began publishing in 1991 findings from individuals who were cognitively normal during life but had substantial AD pathology when they came to autopsy. Here we have called it preclinical AD, simply meaning that we could not detect clinical decline, at least using our currently available instruments. Our hypothesis is that if these individuals continued to live, ultimately they would develop symptomatic AD. It is not yet possible to confirm this hypothesis and there may be some people who are ‘protected’ and can harbour Alzheimer pathology without ever demonstrating cognitive impairment. In one of our programme project grants, we assess all of our cognitively normal older adult participants for molecular biomarkers of AD. Since 2004, we have been doing PET scans with the amyloid tracer, Pittsburgh compound B, as well as CSF collection for levels of Ab42 and Tau and phosphorylated Tau. We have been able to demonstrate that, depending
Downloaded from dem.sagepub.com at University of Sydney on November 15, 2015
Katz and Peters
339
on age and APOE4 status, somewhere between 25% and 30% of cognitively normal older individuals are biomarker positive. We’re following those people to determine whether they are at increased risk of becoming symptomatic over time. We have demonstrated that there is increased risk for the group as a whole but we do not yet have sufficient data to make precise individual predictions. We cannot say that an older adult with a positive PiB scan and a low CSF Ab42 inevitably will become symptomatic or when. It also is unknown when those biomarker changes begin. Do they first develop in the 70 s, 60 s, 50 s, or even earlier? To address this, we developed another programme project of middle-aged people, half of whom are at risk of developing AD because they have an affected parent. We are looking at people 45 years and over with biomarkers and are now able to determine that biomarker abnormalities, either in amyloid imaging scans or in the CSF measures, seem to begin around age 50 or 55. This finding fits with a 20-year period of preclinical AD wherein a slow accumulation of AD lesions eventually culminates in symptomatic AD. Because 90% of people with the clinical diagnosis of AD are over the age of 70, if the pathology begins around age 55 at least in some people, that is consistent with a 20-year period of the pre-symptomatic stage. We just recently took a very special group of adult children, who are asymptomatic individuals with an affected parent with AD, but in this case the parent is affected because they have a causative mutation in the presenilin-1, presenilin-2 or APP genes. This means that each biological child of that affected parent has a 50/50 chance of inheriting the causative mutation. If they do, they are destined to develop AD and will become symptomatic generally at about the same age as the parent did. That is, in this admittedly very rare form of AD all mutation carriers will develop symptomatic AD and we can predict the approximate age at onset, enabling us to temporally order the biomarker changes. In 2012, we published the cross-sectional data from this study of dominantly inherited AD and found that, indeed, the biomarker changes occur only in mutation carriers. They do not occur in their sibling non-carriers, that is, people who did not inherit the mutation, thus helping to validate them as biomarkers of AD. The first biomarker abnormality seems to be in CSF Ab42 as it begins to fall from its elevated levels in the mutation carriers about 20 years prior to the age at which we expect them to become symptomatic (based on the age of onset of their affected parent). Importantly, the biomarker data confirm that there is a 20-year asymptomatic window to consider intervening to try to prevent or at least delay the onset of symptoms. Question: Thank you for bringing up the DIAN (Dominantly Inherited Alzheimer Network) studies.1 These are fascinating and we wish we could talk to you longer about them. But for now, where do you think all this is going? Is the field going to continue with this research down the MCI course or is it going to turn more towards the pre-symptomatic labels? JM: The 2011 reports of the working groups from the National Institute on Aging and the Alzheimer Association proposed new criteria for the clinical diagnosis of ‘AD dementia’ that are similar to the criteria for ‘probable AD’ in the 1984 McKhann et al. paper.2 The new
Downloaded from dem.sagepub.com at University of Sydney on November 15, 2015
340
Dementia 14(3)
criteria do suggest that for AD dementia one can incorporate molecular AD biomarkers to help support the clinical diagnosis. There also are proposed criteria for Mild Cognitive Impairment or ‘MCI due to AD.’ I think this is an important advance toward an aetiology-based classification for MCI. The third working group is on ‘Preclinical AD,’ defined by biomarkers in cognitively normal older adults and underscoring the great interest in preclinical AD and pre-symptomatic AD. The DIAN study and the Alzheimer Prevention Initiative (API) both are conducting trials of anti-amyloid compounds in asymptomatic mutation carriers. The DIAN study enrolls asymptomatic individuals with a number of different mutations throughout the world and the API focuses on the largest known dominantly inherited AD family with the E280A presenilin-1 mutation in Colombia, South America. In both trials, interventions in asymptomatic people aim to delay or even prevent the onset of symptomatic AD. A third preclinical AD intervention study, the A4 study, will launch this year [2013], in older individuals without a dominantly inherited history of AD.3 This study proposes to examine 1000 older adults who are cognitively normal but biomarker positive (amyloid imaging positive individuals) and also is investigating whether anti-amyloid compounds might delay the onset of symptomatic AD. It is clear that the field is moving towards prevention, which makes a lot of sense. AD is the only major killer in North America for which rates of death are increasing as more and more people are reaching an age when they become vulnerable to AD and there are no truly effective therapies. For all other major killers – heart disease, stroke and cancer – the death rates are falling because there are better therapies for these diseases and there is an emphasis on disease prevention. The prevention strategy is finally coming to AD. We should never abandon our efforts in trying to find effective therapies for people with symptomatic AD. However, using only a single agent may not be desirable, because by the time the symptoms are manifest, even at the MCI stage, there are multiple pathologic processes. Therapies likely cannot simply target Ab or Tau because there also is neuroinflammation, microglial activation, oxidative stress, vascular insufficiency, and other disease processes in persons with symptomatic AD. Combination therapy targeting multiple mechanisms, in my opinion, may be needed to truly benefit the people who have symptomatic AD. Targeting a single mechanism at the symptomatic stage is unlikely to be successful, as we have unfortunately seen in the past decade and a half with all the failed trials. Question: During the 20-year period you mentioned, between an early biomarker test for asymptomatic people and then the probability that they would become symptomatic later, how do you deal with the people themselves when you consult with them about this? It must be an odd situation for them, since they are given an indicator of a possible disease progression which they have not yet actually experienced in their lives. JM: It is a very important question. When people enroll in our research studies, they are told up front: ‘we will not disclose your individual research results.’ We do not tell them if they have a positive amyloid scan or a low CSF Ab42 or hippocampal shrinkage on structural MRI or seem to have poor performance on their cognitive testing. If they really
Downloaded from dem.sagepub.com at University of Sydney on November 15, 2015
Katz and Peters
341
want to know, they do not have to sign the informed consent document or participate in our studies and can go elsewhere if they can get the specific study. However, I think we’re going to have to continually consider the implications of our position. In our adult children study, the cohort of middle-aged people generally is in favor of learning their individual research results. Some are adamant that they do want to know whether they’re biomarker positive or not, and others do not want to know. We meet with our cohort annually to discuss research advances to seek their input in planning our research studies as they go forward. We just launched a survey of our participants regarding their wishes in having their individual research results disclosed to them. After they complete the survey, then there is an intervention about limitations: knowing that you have a low CSF Ab42 is one thing, but what you probably want to know is what does this mean in terms of risk for developing AD in the future. Then we indicate that we do not know what that risk is for any particular person. We also try to let them know the pros and the cons of disclosure and that the potential cons include possible risk for employability and insurability, for driver’s licensing, and so forth. They often have not considered the potential implications of their personal test results possibly being known by others. In the clinic, it is premature to offer a cognitively normal person biomarker testing to know whether they are positive or not, because that information currently cannot be used in any clinically meaningful way. We can say, ‘if you are biomarker positive you should have a durable power of attorney, you should make sure your will and last testament are updated, and you should live a healthy lifestyle,’ but we recommend these steps anyway. Question: That is an interesting response and to follow up on it, we ask a question about costs. We assume there are costs to these tests in the United States. If they did become part of common clinical practice, what do you foresee in terms of what you know about Medicaid or Medicare coverage? Do you envision some resistance to using such testing because of costs? JM: There are lots of issues with costs and access. For example, these tests may not be available in some areas. In April of 2012 the FDA (Federal Drug Agency) approved florbetapir for amyloid imaging for individuals who are being evaluated for cognitive dysfunction caused by Alzheimer’s or other disorders. The approval was worded carefully so that the imaging was only approved for people who have cognitive dysfunction and not for cognitively normal people. The Centre for Medicaid and Medicare Services (CMS) in January 2013 considered whether or not to reimburse people for amyloid imaging and decided not to. Other payers are not reimbursing either. So individuals under evaluation for dementia have to pay out of pocket for these scans. For CSF testing, there is a commercial laboratory that determines amyloid Ab42 and tau levels in the CSF. This test costs about US$1500. Many, but not all, insurance companies and CMS will reimburse for this assay, so CSF testing is more likely at present to be reimbursed. We are really at the dawn of molecular biomarkers for AD. The field currently lacks standardisation in the CSF assays as different laboratories use different methods. Most of the results for what is normal or abnormal come from research populations, and only very
Downloaded from dem.sagepub.com at University of Sydney on November 15, 2015
342
Dementia 14(3)
few results are available from clinic patients. There is the conceptual issue of imposing a binary distinction of ‘normal’ versus ‘abnormal’ on a continuous process of neuronal deterioration as occurs in AD, so there are bound to be ambiguous findings. We have a long way to go to sort everything out! But in the end I believe that biomarkers will be very helpful clinical tools. They have the potential to change the diagnosis of dementia aetiology, particularly if they are affordable and widely available. Up to half of the demented people in the United States have not been recognised as such by their primary care physicians. Objective tests through biomarkers will help to identify the number of people who truly have underlying AD. Question: Thank you very much for your time Dr Morris. It has been a very enlightening conversation and so helpful for our project. JM: You are welcome, and I am sorry for being so unorthodox (laughing) in relation to MCI. Good luck with your research. Notes 1. For more information on the DIAN studies, please visit http://www.dian-info.org/ 2. McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984). Clinical diagnosis of AD: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on AD. Neurology, 34(7), 939–944. 3. For more information on the A4 study, please visit http://a4study.org/
Selected Publications Bateman, R. J., Xiong, C., Benzinger, T. L., Fagan, A. M., Goate, A., Fox, N. C., . . . Dominantly Inherited Alzheimer Network (2012). Clinical and biomarker changes in dominantly inherited AD. The New England Journal of Medicine, 367(9), 795–804. Morris, J. C. (2012). Revised criteria for mild cognitive impairment may compromise the diagnosis of AD dementia. Archives of Neurology, 69(6), 700–708. Morris, J. C., Roe, C. M., Xiong, C., Fagan, A. M., Goate, A. M., Holtzman, D. M., . . . Mintun, M. A. (2010). APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Annals of Neurology, 67(1), 122–131. Roe, C. M., Fagan, A. M., Grant, E. A., Hassenstab, J., Moulder, K. L., Dreyfus, D. M., . . . Morris, J. C. (2013). Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later. Neurology, 80, 1784–1791. Vos, S. J., Xiong, C., Visser, P. J., Jasielec, M. S., Hassenstab, J., Grant, E. A., . . . Fagan, A. M. (2013). Preclinical AD and its outcome: A longitudinal cohort study. The Lancet Neurology, 12(10), 957–965.
Downloaded from dem.sagepub.com at University of Sydney on November 15, 2015
Interview with Dr John Morris, 28 February 2013
Dementia 2015, Vol. 14(3) 335–342 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1471301214562142 dem.sagepub.com
Stephen Katz and Kevin R Peters Background John C Morris, MD is one of the most recognised, awarded, published and honoured neurologists working today on Alzheimer disease (AD). From his base at Washington University in St. Louis, Missouri, Dr Morris has been particularly innovative in identifying early, pre- and asymptomatic stages of AD. His work is aimed at one of our most fundamental challenges in the field of ageing and cognitive health, which is the value of early intervention for cognitive dysfunction. This is a challenge that goes beyond the laboratory and involves complex relationships between research, clinical practice, public perception, entitlements and services, and the health of future ageing populations. Hence, Dr Morris’ reflections on mild cognitive impairment are particularly important. Question: Dr Morris, thank you for talking to us today. Our first question is about the development of your career and how you became interested in Mild Cognitive Impairment (MCI). JM: Well, my interest in MCI relates to the early symptomatic expression of AD. Many people view MCI as a risk factor for developing symptomatic AD, whereas I consider it to be the earliest symptomatic stage of AD (when AD indeed is the underlying disorder causing MCI). I became interested in neurodegenerative disease during my year of doing neuropathology in my neurology residency programme. I was invited to study a family that had an unusual dominantly inherited dementing illness that we termed ‘hereditary dysphasic dementia.’ We published our clinico-pathologic findings about the family in the Annals of Neurology in 1984 and afterward got calls from physicians who were seeing individuals with similar clinical presentations. In some cases, the physicians sent me brain tissue from their deceased patients. This allowed us to characterise another very similar family, ‘hereditary dysphasic dementia II’; years later we discovered that it is the largest known family with a progranulin mutation causing fronto-temporal lobar degeneration. My original foray into an academic career thus began with a clinico-pathologic correlative study. When I came to Washington University and joined its Alzheimer programme in 1984, it was not particularly strong on clinico-pathological studies. I was just a young faculty member but thought we should try to see if our research participants might consider brain donation when they died. It turns out they did. One such person was a retired investment banker who enrolled in our project as a control participant. He was very
Downloaded from dem.sagepub.com at University of Sydney on November 15, 2015
336
Dementia 14(3)
highly educated and cognitively high functioning and he performed very well on our cognitive measures over several times of testing. For his fourth annual evaluation, I happened to be the physician who interviewed both the participant and his wife. We spend a great deal of time here in obtaining not only objective cognitive data, but also subjective data from people who know the individual well. His wife said that he was still doing ‘pretty well’ cognitively but in the past six months or so she thought he was gradually becoming ‘a little vague’ in his memory and thinking. I asked her to describe what she meant by ‘vague’ and she reported that for the first time in their married life that year he was unable to complete their income tax return. Now, I have never been able to do my own income tax return; this is not something I could even envision! But for this man it was an example of subtle but definite intra-individual cognitive decline. I rated him on the Clinical Dementia Rating (CDR) scale as a 0.5, indicating very mild impairment, and thought it was likely due to AD. My mentor and the other senior neurologists in the programme were surprised with this diagnosis as they would have attributed his very mild change to normal ageing (he scored normally on our cognitive test battery). Six months after that assessment the participant died, came to autopsy, and had florid AD neuropathology, suggesting that his mild symptoms were indeed the initial clinical expression of that disorder and not simply due to ageing. I became identified with clinically recognising the earliest symptomatic changes that could be ascribed to neurodegenerative processes such as AD. As CDR 0.5 also was being used to characterise MCI, my interests overlapped this entity. In discussions about MCI, I ask why are people mildly cognitively impaired? What is the underlying aetiology? Rather than using the term ‘mild cognitive impairment’ in our research programme, we try to provide an aetiologic diagnosis even at the CDR 0.5 level. Because you now realise that I am not an advocate of leaving the diagnosis simply at ‘‘MCI,’’ you may not want to continue with this interview because I am not really an MCI person [laughter]. Question: We gather from reading your publications that you are more interested in this pre-symptomatic AD? JM: Yes, we are most interested in presymptomatic or preclinical AD because we know that when people die in the earliest symptomatic stage of AD (CDR 0.5), up to 60% of neurons in layer 2 of the entorhinal cortex already are lost. So the likelihood of a truly meaningful benefit from therapeutic agents in persons with symptomatic AD is made much more challenging because the brain already is substantially damaged by the time treatment begins. We are trying to identify the pre-clinical stage to hopefully allow interventions to begin before there is substantial brain damage. Question: Would it be more fruitful for us today to use pre-symptomatic AD instead of MCI? For example, if you make diagnoses, what is the process you use in your clinic? If you do not use the term MCI, how do you go about this process for someone who has minimal or no cognitive deficits?
Downloaded from dem.sagepub.com at University of Sydney on November 15, 2015
Katz and Peters
337
JM: If a person has minimal or mild cognitive deficits, we do our best to determine why. Did symptoms develop gradually or abruptly? Are symptoms progressively worsening? Do they resemble the clinical phenotype of fronto-temporal dementia, Lewy body dementia, vascular dementia, or AD dementia? If the person has difficulty carrying out accustomed activities due to cognitive loss, even when very mild, and fits the AD phenotype, then we diagnose symptomatic AD. Fortunately we have been able to track enough of these people to confirm that even when they are identified in the mild cognitive impairment stage, our diagnosis of very mild symptomatic AD is supported with the neuropathologic diagnosis of Alzheimer’s in 92% of our patients. We differ from some other programmes in that we spend a great deal of time trying to find out how the individual is doing in carrying out his or her usual activities and for that we need an informant, not only to tell us what the person once was able to do, but whether or not they are continuing to function at that level. We do not utilise neuropsychologic test data in our clinical diagnostic algorithm. We keep these data separate because if neuropsychologic test data are used to help classify a person as impaired or unimpaired, it confounds following that person longitudinally with cognitive testing. It would be no surprise, for example, that people classified as having amnestic MCI do poorly on memory tests over time because they already had to perform poorly in memory at initial assessment to receive that classification. For scientific reasons we always keep the two procedures separate: a clinical classification based upon the principle of intra-individual decline and then independent neuropsychologic monitoring. Again, the main question is: Has the person declined in cognitive and functional abilities compared to their previously attained levels? Question: We understand that you try to avoid the circularity problem with which we are familiar. Then, is the term pre-symptomatic AD for you just a predominantly research-based label or is it something you use in the clinic? JM: No, we do not use this term, ‘preclinical AD,’ in the clinic. It is for research purposes only. The use of AD biomarkers allows the identification of cognitively normal individuals who have the neuropathologic lesions of AD. Molecular indicators of Alzheimer pathology during life include reduced levels of amyloid-beta 42 (Ab42) in their cerebrospinal fluid (CSF), elevated levels of Tau in their CSF, or a positive amyloid imaging scan using an amyloid tracer such as C11 PiB or F18 florbetapir (or another tracer). Question: It sounds like the practices at your clinic are a little different than at other places. Have you had any experiences where people ask you about that? As you know, the Internet today allows people to track down all of this information, whether good or not. So, have you noticed people asking you about this MCI label at your clinic? JM: No, our patients do not inquire about MCI. In general, people want to know what illness they are dealing with, so we provide (when appropriate) the diagnosis of very mild AD. We do face scrutiny each time we submit an application for funding to the National Institute on Aging, since we are sometimes considered unorthodox in our approach. All I can say is that we have plenty of experience and plenty of data to support our position.
Downloaded from dem.sagepub.com at University of Sydney on November 15, 2015
338
Dementia 14(3)
Question: This leads directly to our next question: what treatments do you offer and in what stages do you offer them? JM: If patients are symptomatic and have AD as their presumed underlying aetiology, then we offer the currently available symptomatic FDA-approved medications, such as cholinesterase inhibitors. All three of the currently available cholinesterase inhibitor drugs demonstrate very modest benefit, so we offer them with the caveat that the drugs are unlikely to considerably benefit the patients. The drugs may help slow the rate of progression at least somewhat and at least for some period of time. We treat based upon the diagnosis of an underlying dementing illness that now is symptomatic, even if the symptoms are minimal or mild. Question: One of the interesting things in the literature is about the prevalence of mixed cases that come to autopsy. As you are aware, there are cases that are diagnosed clinically with AD, but found to have a mixed presentation at autopsy. What has been your experience with this situation, since you mentioned in this interview that AD was based on identifying the aetiology? JM: Older people clearly are at risk for multiple brain disorders and there’s nothing about having AD that protects from also having, say, a cerebral infarct. In our clinico-pathologic experience, about 40–50% of people who die and have neuropathologic AD also have cerebral infarcts and about a third also have other neurodegenerative lesions, such as Lewy bodies, TDP-43 proteinopathy, or other disorders such as hippocampal sclerosis. Demented individuals who come to autopsy often have multiple pathologies. It is difficult to know how or whether each of these pathologies contributes to the clinical features or to what degree. Our cognitively healthy control participants also often have cerebral infarcts at autopsy, so the presence of an infarct does not always produce clinical deficits. By the same token, preclinical AD is defined by plaques and tangles that clinically are ‘silent.’ Attributing the clinical presentation to one or many co-existing pathologies is difficult. Question: What would be your comment when you get cases that present to autopsy which were cognitively normal but also found to have substantial plaque or tangle burden. What is your view on those cases? JM: My now emeritus colleague, Joseph L. Price, a neuroanatomist here at Washington University, and I began publishing in 1991 findings from individuals who were cognitively normal during life but had substantial AD pathology when they came to autopsy. Here we have called it preclinical AD, simply meaning that we could not detect clinical decline, at least using our currently available instruments. Our hypothesis is that if these individuals continued to live, ultimately they would develop symptomatic AD. It is not yet possible to confirm this hypothesis and there may be some people who are ‘protected’ and can harbour Alzheimer pathology without ever demonstrating cognitive impairment. In one of our programme project grants, we assess all of our cognitively normal older adult participants for molecular biomarkers of AD. Since 2004, we have been doing PET scans with the amyloid tracer, Pittsburgh compound B, as well as CSF collection for levels of Ab42 and Tau and phosphorylated Tau. We have been able to demonstrate that, depending
Downloaded from dem.sagepub.com at University of Sydney on November 15, 2015
Katz and Peters
339
on age and APOE4 status, somewhere between 25% and 30% of cognitively normal older individuals are biomarker positive. We’re following those people to determine whether they are at increased risk of becoming symptomatic over time. We have demonstrated that there is increased risk for the group as a whole but we do not yet have sufficient data to make precise individual predictions. We cannot say that an older adult with a positive PiB scan and a low CSF Ab42 inevitably will become symptomatic or when. It also is unknown when those biomarker changes begin. Do they first develop in the 70 s, 60 s, 50 s, or even earlier? To address this, we developed another programme project of middle-aged people, half of whom are at risk of developing AD because they have an affected parent. We are looking at people 45 years and over with biomarkers and are now able to determine that biomarker abnormalities, either in amyloid imaging scans or in the CSF measures, seem to begin around age 50 or 55. This finding fits with a 20-year period of preclinical AD wherein a slow accumulation of AD lesions eventually culminates in symptomatic AD. Because 90% of people with the clinical diagnosis of AD are over the age of 70, if the pathology begins around age 55 at least in some people, that is consistent with a 20-year period of the pre-symptomatic stage. We just recently took a very special group of adult children, who are asymptomatic individuals with an affected parent with AD, but in this case the parent is affected because they have a causative mutation in the presenilin-1, presenilin-2 or APP genes. This means that each biological child of that affected parent has a 50/50 chance of inheriting the causative mutation. If they do, they are destined to develop AD and will become symptomatic generally at about the same age as the parent did. That is, in this admittedly very rare form of AD all mutation carriers will develop symptomatic AD and we can predict the approximate age at onset, enabling us to temporally order the biomarker changes. In 2012, we published the cross-sectional data from this study of dominantly inherited AD and found that, indeed, the biomarker changes occur only in mutation carriers. They do not occur in their sibling non-carriers, that is, people who did not inherit the mutation, thus helping to validate them as biomarkers of AD. The first biomarker abnormality seems to be in CSF Ab42 as it begins to fall from its elevated levels in the mutation carriers about 20 years prior to the age at which we expect them to become symptomatic (based on the age of onset of their affected parent). Importantly, the biomarker data confirm that there is a 20-year asymptomatic window to consider intervening to try to prevent or at least delay the onset of symptoms. Question: Thank you for bringing up the DIAN (Dominantly Inherited Alzheimer Network) studies.1 These are fascinating and we wish we could talk to you longer about them. But for now, where do you think all this is going? Is the field going to continue with this research down the MCI course or is it going to turn more towards the pre-symptomatic labels? JM: The 2011 reports of the working groups from the National Institute on Aging and the Alzheimer Association proposed new criteria for the clinical diagnosis of ‘AD dementia’ that are similar to the criteria for ‘probable AD’ in the 1984 McKhann et al. paper.2 The new
Downloaded from dem.sagepub.com at University of Sydney on November 15, 2015
340
Dementia 14(3)
criteria do suggest that for AD dementia one can incorporate molecular AD biomarkers to help support the clinical diagnosis. There also are proposed criteria for Mild Cognitive Impairment or ‘MCI due to AD.’ I think this is an important advance toward an aetiology-based classification for MCI. The third working group is on ‘Preclinical AD,’ defined by biomarkers in cognitively normal older adults and underscoring the great interest in preclinical AD and pre-symptomatic AD. The DIAN study and the Alzheimer Prevention Initiative (API) both are conducting trials of anti-amyloid compounds in asymptomatic mutation carriers. The DIAN study enrolls asymptomatic individuals with a number of different mutations throughout the world and the API focuses on the largest known dominantly inherited AD family with the E280A presenilin-1 mutation in Colombia, South America. In both trials, interventions in asymptomatic people aim to delay or even prevent the onset of symptomatic AD. A third preclinical AD intervention study, the A4 study, will launch this year [2013], in older individuals without a dominantly inherited history of AD.3 This study proposes to examine 1000 older adults who are cognitively normal but biomarker positive (amyloid imaging positive individuals) and also is investigating whether anti-amyloid compounds might delay the onset of symptomatic AD. It is clear that the field is moving towards prevention, which makes a lot of sense. AD is the only major killer in North America for which rates of death are increasing as more and more people are reaching an age when they become vulnerable to AD and there are no truly effective therapies. For all other major killers – heart disease, stroke and cancer – the death rates are falling because there are better therapies for these diseases and there is an emphasis on disease prevention. The prevention strategy is finally coming to AD. We should never abandon our efforts in trying to find effective therapies for people with symptomatic AD. However, using only a single agent may not be desirable, because by the time the symptoms are manifest, even at the MCI stage, there are multiple pathologic processes. Therapies likely cannot simply target Ab or Tau because there also is neuroinflammation, microglial activation, oxidative stress, vascular insufficiency, and other disease processes in persons with symptomatic AD. Combination therapy targeting multiple mechanisms, in my opinion, may be needed to truly benefit the people who have symptomatic AD. Targeting a single mechanism at the symptomatic stage is unlikely to be successful, as we have unfortunately seen in the past decade and a half with all the failed trials. Question: During the 20-year period you mentioned, between an early biomarker test for asymptomatic people and then the probability that they would become symptomatic later, how do you deal with the people themselves when you consult with them about this? It must be an odd situation for them, since they are given an indicator of a possible disease progression which they have not yet actually experienced in their lives. JM: It is a very important question. When people enroll in our research studies, they are told up front: ‘we will not disclose your individual research results.’ We do not tell them if they have a positive amyloid scan or a low CSF Ab42 or hippocampal shrinkage on structural MRI or seem to have poor performance on their cognitive testing. If they really
Downloaded from dem.sagepub.com at University of Sydney on November 15, 2015
Katz and Peters
341
want to know, they do not have to sign the informed consent document or participate in our studies and can go elsewhere if they can get the specific study. However, I think we’re going to have to continually consider the implications of our position. In our adult children study, the cohort of middle-aged people generally is in favor of learning their individual research results. Some are adamant that they do want to know whether they’re biomarker positive or not, and others do not want to know. We meet with our cohort annually to discuss research advances to seek their input in planning our research studies as they go forward. We just launched a survey of our participants regarding their wishes in having their individual research results disclosed to them. After they complete the survey, then there is an intervention about limitations: knowing that you have a low CSF Ab42 is one thing, but what you probably want to know is what does this mean in terms of risk for developing AD in the future. Then we indicate that we do not know what that risk is for any particular person. We also try to let them know the pros and the cons of disclosure and that the potential cons include possible risk for employability and insurability, for driver’s licensing, and so forth. They often have not considered the potential implications of their personal test results possibly being known by others. In the clinic, it is premature to offer a cognitively normal person biomarker testing to know whether they are positive or not, because that information currently cannot be used in any clinically meaningful way. We can say, ‘if you are biomarker positive you should have a durable power of attorney, you should make sure your will and last testament are updated, and you should live a healthy lifestyle,’ but we recommend these steps anyway. Question: That is an interesting response and to follow up on it, we ask a question about costs. We assume there are costs to these tests in the United States. If they did become part of common clinical practice, what do you foresee in terms of what you know about Medicaid or Medicare coverage? Do you envision some resistance to using such testing because of costs? JM: There are lots of issues with costs and access. For example, these tests may not be available in some areas. In April of 2012 the FDA (Federal Drug Agency) approved florbetapir for amyloid imaging for individuals who are being evaluated for cognitive dysfunction caused by Alzheimer’s or other disorders. The approval was worded carefully so that the imaging was only approved for people who have cognitive dysfunction and not for cognitively normal people. The Centre for Medicaid and Medicare Services (CMS) in January 2013 considered whether or not to reimburse people for amyloid imaging and decided not to. Other payers are not reimbursing either. So individuals under evaluation for dementia have to pay out of pocket for these scans. For CSF testing, there is a commercial laboratory that determines amyloid Ab42 and tau levels in the CSF. This test costs about US$1500. Many, but not all, insurance companies and CMS will reimburse for this assay, so CSF testing is more likely at present to be reimbursed. We are really at the dawn of molecular biomarkers for AD. The field currently lacks standardisation in the CSF assays as different laboratories use different methods. Most of the results for what is normal or abnormal come from research populations, and only very
Downloaded from dem.sagepub.com at University of Sydney on November 15, 2015
342
Dementia 14(3)
few results are available from clinic patients. There is the conceptual issue of imposing a binary distinction of ‘normal’ versus ‘abnormal’ on a continuous process of neuronal deterioration as occurs in AD, so there are bound to be ambiguous findings. We have a long way to go to sort everything out! But in the end I believe that biomarkers will be very helpful clinical tools. They have the potential to change the diagnosis of dementia aetiology, particularly if they are affordable and widely available. Up to half of the demented people in the United States have not been recognised as such by their primary care physicians. Objective tests through biomarkers will help to identify the number of people who truly have underlying AD. Question: Thank you very much for your time Dr Morris. It has been a very enlightening conversation and so helpful for our project. JM: You are welcome, and I am sorry for being so unorthodox (laughing) in relation to MCI. Good luck with your research. Notes 1. For more information on the DIAN studies, please visit http://www.dian-info.org/ 2. McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984). Clinical diagnosis of AD: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on AD. Neurology, 34(7), 939–944. 3. For more information on the A4 study, please visit http://a4study.org/
Selected Publications Bateman, R. J., Xiong, C., Benzinger, T. L., Fagan, A. M., Goate, A., Fox, N. C., . . . Dominantly Inherited Alzheimer Network (2012). Clinical and biomarker changes in dominantly inherited AD. The New England Journal of Medicine, 367(9), 795–804. Morris, J. C. (2012). Revised criteria for mild cognitive impairment may compromise the diagnosis of AD dementia. Archives of Neurology, 69(6), 700–708. Morris, J. C., Roe, C. M., Xiong, C., Fagan, A. M., Goate, A. M., Holtzman, D. M., . . . Mintun, M. A. (2010). APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Annals of Neurology, 67(1), 122–131. Roe, C. M., Fagan, A. M., Grant, E. A., Hassenstab, J., Moulder, K. L., Dreyfus, D. M., . . . Morris, J. C. (2013). Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later. Neurology, 80, 1784–1791. Vos, S. J., Xiong, C., Visser, P. J., Jasielec, M. S., Hassenstab, J., Grant, E. A., . . . Fagan, A. M. (2013). Preclinical AD and its outcome: A longitudinal cohort study. The Lancet Neurology, 12(10), 957–965.
Downloaded from dem.sagepub.com at University of Sydney on November 15, 2015
