NEWS & VIEWS DEMENTIA
Mild cognitive impairment —not always what it seems Edo Richard and Carol Brayne
Mild cognitive impairment is widely viewed as an early stage of dementia but, as a new study highlights, some people never progress, and might even revert to normal cognition. Poor predictive validity of prodromal conditions has clear implications for the principle of ‘do no harm’, as overtreatment becomes a possibility. Richard, E. & Brayne, C. Nat. Rev. Neurol. 10, 130–131 (2014); published online 18 February 2014; doi:10.1038/nrneurol.2014.23
The concept of mild cognitive impairment (MCI; Box 1) has gained widespread acceptance in clinical research since its diagnostic criteria were introduced.1 Increased focus on MCI has both fuelled and been fuelled by the search for an ever-earlier diagnosis of Alzheimer disease (AD), in the hope that treatment at an earlier stage will be effective, given the lack of effectiveness of current approaches to dementia treatment. Some have also suggested that targeting of patients with ‘early’ cognitive i mpairment— assuming that reliable identification is possible—might prevent further cognitive decline and dementia.2 Any clinician encountering patients with memory difficulties will know that a substantial proportion of individuals with MCI will remain stable, or revert to ‘normal’ cognitive function. These observations are borne out by a recent paper published in Neurology,3 in which researchers from the Mayo Clinic reported in detail on a Box 1 | Mild cognitive impairment The concept of mild cognitive impairment (MCI) was introduced to categorize older individuals who exhibit cognitive decline but do not fulfil the criteria for dementia. When MCI has been operationalized in large cohorts, it has proved to be a heterogeneous condition, encompassing patients with an early stage of dementia as well as a myriad of other, often reversible, conditions. Subdivision into amnestic, nonamnestic, single-domain and multi-domain MCI has been proposed to further differentiate people with cognitive impairments that do not interfere with activities of daily living. The criteria were not originally proposed for populationbased application, but they have been applied to numerous large population-based cohorts, which has led to wide variations in test characteristics.
130 | MARCH 2014 | VOLUME 10
group of MCI ‘reverters’ identified within a population-based sample of 1,939 people aged 70–89 years at baseline. After a median follow-up of 5.1 years, 534 cases of prevalent or incident MCI were reported. Of these, 36% did not progress to dementia, and 38% reverted to normal cognition—though a little over half of the reverters fulfilled MCI criteria again during a later follow-up, suggesting unstable cognition. Notably, less than 10% of these unstable cases eventually developed dementia. The ‘incidence’ rate of reversion to normal cognition was 175 cases per 1,000 person- years, which was much higher than the rate of progression to dementia at 77 per 1,000 person-years.3 Not surprisingly, those with the poorest cognitive performance, those with multiple cognitive domains affected, and those with the most severe impairment in daily functioning were at highest risk of progression to dementia. These characteristics are known risk factors for dementia within population studies, irrespective of any intermediate diagnosis. Uncertainty about progression from MCI to dementia probably reflects the mixed nature of the MCI population. Due to the raised awareness of dementia resulting from societal concerns and heightened fear about risk, people might seek help for any perceived deficits in cognition in mid to late life. Cases of MCI that are seen in clinical settings will, therefore, include temporary cognitive impairment attributable to a variety of causes, as well as truly prodromal dementia. To understand the clinical relevance of the latest results, and how they can be interpreted at the individual level, analyses that fully account for mortality, dropout, frequency of measurements, and fluctuation in and out of different states are required. These analytical approaches were not used
in the current study.3 Previous investigations of population-based samples report similar rates of reversion from MCI to normal cognitive function, 4,5 supporting the view that the MCI concept, which has been so enthusiastically embraced by the biomedical and clinical worlds, is perhaps not readily applicable to population settings. Does the Mayo Clinic study 3 support this emerging view? Yes and no—the results underscore the problems with the MCI concept, but at the same time the authors suggest that the concept is valuable, as it identifies people at higher risk of progression, even in population samples. Absolute rates of progression to dementia are, how ever, much lower in population-based sam ples (well below 10%) than in clinic-based samples.6 Neither the benefits nor the harms of diagnosing MCI at the population level have been rigorously explored. At present, insufficient evidence exists for a beneficial effect of screening for dementia itself.7 It is unlikely, therefore, that screening for MCI, which is not an early stage of dementia in a considerable proportion of people, will be effective. Application of MCI criteria to the general population does not always lead to reliable prediction of those most at risk of dementia,8 and probably results in overdiagnosis of MCI.
‘‘
Application of MCI criteria to the general population … probably results in overdiagnosis of MCI
’’
Despite these caveats, continued research in this area is warranted, but always with attention to the value of its translation into practice. Many clinicians argue that the MCI concept is useful in the setting of a memory clinic, where the positive predictive value—that is, the capacity of the concept to identify those at risk of progressive decline—is more clear. Despite the heterogeneity of the MCI population, and the high rate of reversion to normal cognition, the overall risk of dementia in the years after diagnosis is considerable, as demonstrated in Roberts and colleagues’ well-conducted and rigorous population study. 3 This increased risk suggests that people with MCI are a potentially useful group for studies on (secondary) prevention of cognitive decline and dementia. In newly proposed criteria for AD, 9 exploration of more-accurate prediction www.nature.com/nrneurol
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS of progression to dementia has been suggested, which may require defining criteria for prodromal AD based on cerebrospinal fluid (CSF) or neuroimaging biomarkers. Whether such an approach will lead to better prediction of dementia is as yet unknown, but analysis of CSF or MRI biomarkers after cognitive testing has not been shown to lead to better prediction of dementia in patients with MCI. 10 Before such criteria can be applied to population settings, large studies in relevant age brackets, including people with comorbid disorders, are required. These studies must also take all aspects of false-positive and false-negative results into account. MCI remains a complex concept, and its causes are heterogeneous. Considering MCI as a fixed concept based on clinical criteria is a slippery slope. Some might argue that people with cognitive impairment in multiple domains and in the bottom range of the MCI spectrum—that is, those with the worst impairment—would previously have been diagnosed with minimal or mild dementia. Because of the boundary changes that occur as a result of fashions in research and clinical practice, however, these cases would now be called MCI. On the basis of the findings by Roberts et al., and previous reports from population- based samples, the early signs of MCI have limited sensitivity and specificity for the prediction of the development of dementia. Clearly, therefore, the value of a MCI diagnosis warrants consideration. Diagnoses should be communicated carefully in order to avoid the potential harms of diagnosing a pre-dementia state in i ndividuals who might never progress to dementia. Department of Neurology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands (E.R.). Department of Public Health and Primary Care, Cambridge Institute of Public Health, Cambridge University, Forvie Site, Robinson Way, Cambridge CB2 0SR (C.B.). Correspondence to: E.R. [email protected] Acknowledgements The authors thank Blossom Stephan for substantial and constructive comments. Competing interests The authors declare no competing interests. 1.
2.
Petersen, R. C. Mild cognitive impairment as a diagnostic entity. J. Intern. Med. 256, 183–194 (2004). Vellas, B. et al. Designing drug trials for Alzheimer’s disease: what we have learned from the release of the phase III antibody trials: a report from the EU/US/CTAD
3.
4.
5.
6.
Task Force. Alzheimers Dement. 9, 438–444 (2013). Roberts, R. O. et al. Higher risk of progression to dementia in mild cognitive impairment cases who revert to normal. Neurology 82, 317–325 (2014). Gao, S. et al. Mild cognitive impairment, incidence, progression, and reversion: findings from a community-based cohort of elderly African Americans. Am. J. Geriatr. Psychiatry http://dx.doi.org/10.1016/ j.jagp.2013.02.015. Sachdev, P. S. et al. Factors predicting reversion from mild cognitive impairment to normal cognitive functioning: a population-based study. PLoS ONE 8, e59649 (2013). Ward, A., Tardiff, S., Dye, C. & Arrighi, H. M. Rate of conversion from prodromal Alzheimer’s
disease to Alzheimer’s dementia: a systematic review of the literature. Dement. Geriatr. Cogn. Dis. Extra 3, 320–332 (2013). 7. Fox, C. et al. Screening for dementia—is it a no brainer? Int. J. Clin. Pract. 67, 1076–1080 (2013). 8. Stephan, B. et al. Optimizing mild cognitive impairment for discriminating dementia risk in the general older population. Am. J. Geriatr. Psychiatry 18, 662–673 (2010). 9. Dubois, B. et al. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 9, 1118–1127 (2010). 10. Richard, E. et al. MRI and cerebrospinal fluid biomarkers for predicting progression to Alzheimer’s disease in patients with mild cognitive impairment: a diagnostic accuracy study. BMJ Open 3, e002541 (2013).
CLINICAL TRIALS
Measuring abuse liability —is the risk worth taking? Eija A. Kalso and Kaarlo Simojoki
Early trials that supported short-term opioid treatment in the management of chronic non-cancer pain excluded patients at high risk of drug abuse, and might have overestimated the efficacy of this approach. The recent IMMPACT recommendations suggest inclusion of high-risk groups in future clinical trials of potentially addictive drugs. Is the risk worth taking? Kalso, E. A. & Simojoki, K. Nat. Rev. Neurol. 10, 131–133 (2014); published online 11 February 2014; doi:10.1038/nrneurol.2014.16
The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consortium convened in 2009 to develop consensus recommendations for assessing abuse liability—that is, the propensity of a drug to be susceptible to abuse (Box 1)—in analgesic clinical trials. The recently published IMMPACT recommendations on trial design1 state that to adequately assess abuse liability, at least some of the study samples should represent the population of individuals who will be exposed to the drug in practice, including patients who are at significant risk. Chronic pain—in particular, neuropathic pain—is often difficult to manage. The efficacy of opioids in the management of cancer-related pain encouraged their use in the management of chronic non- cancer pain. A fervent discussion regarding whether neuropathic pain is sensitive to opioids ensued, and over the past 25 years several randomized controlled trials (RCTs), systematic reviews and clinical guidelines have addressed the topic.2 Current evidence suggests that opioids
NATURE REVIEWS | NEUROLOGY
have short-term benefit in management of neuropathic pain and osteoarthritisrelated pain, and the European Federation of Neurological Societies guidelines recommend opioids as second-line pharmacological therapy for the management of neuropathic pain.3 In the Western world, o steoarthritis pain and lower back pain constitute a larger market for opioids than does cancer pain. Indeed, the past 10 years have seen a twofold to threefold increase in the use of prescription opioids in the USA and Canada, and opioid use is also rapidly increasing in Europe. 4 According to the Centers for Disease Control and Prevention, in the USA, prescription opioids currently account for a higher proportion of overdose mortality than does heroin. As a consequence, regulation agencies, such as the State of Washington in the USA, have imposed restrictions on prescription of opioids. Several screening tools have been developed to identify patients who are at risk of opioid abuse; however, limitations for their clinical use have now been VOLUME 10 | MARCH 2014 | 131
© 2014 Macmillan Publishers Limited. All rights reserved
Mild cognitive impairment —not always what it seems Edo Richard and Carol Brayne
Mild cognitive impairment is widely viewed as an early stage of dementia but, as a new study highlights, some people never progress, and might even revert to normal cognition. Poor predictive validity of prodromal conditions has clear implications for the principle of ‘do no harm’, as overtreatment becomes a possibility. Richard, E. & Brayne, C. Nat. Rev. Neurol. 10, 130–131 (2014); published online 18 February 2014; doi:10.1038/nrneurol.2014.23
The concept of mild cognitive impairment (MCI; Box 1) has gained widespread acceptance in clinical research since its diagnostic criteria were introduced.1 Increased focus on MCI has both fuelled and been fuelled by the search for an ever-earlier diagnosis of Alzheimer disease (AD), in the hope that treatment at an earlier stage will be effective, given the lack of effectiveness of current approaches to dementia treatment. Some have also suggested that targeting of patients with ‘early’ cognitive i mpairment— assuming that reliable identification is possible—might prevent further cognitive decline and dementia.2 Any clinician encountering patients with memory difficulties will know that a substantial proportion of individuals with MCI will remain stable, or revert to ‘normal’ cognitive function. These observations are borne out by a recent paper published in Neurology,3 in which researchers from the Mayo Clinic reported in detail on a Box 1 | Mild cognitive impairment The concept of mild cognitive impairment (MCI) was introduced to categorize older individuals who exhibit cognitive decline but do not fulfil the criteria for dementia. When MCI has been operationalized in large cohorts, it has proved to be a heterogeneous condition, encompassing patients with an early stage of dementia as well as a myriad of other, often reversible, conditions. Subdivision into amnestic, nonamnestic, single-domain and multi-domain MCI has been proposed to further differentiate people with cognitive impairments that do not interfere with activities of daily living. The criteria were not originally proposed for populationbased application, but they have been applied to numerous large population-based cohorts, which has led to wide variations in test characteristics.
130 | MARCH 2014 | VOLUME 10
group of MCI ‘reverters’ identified within a population-based sample of 1,939 people aged 70–89 years at baseline. After a median follow-up of 5.1 years, 534 cases of prevalent or incident MCI were reported. Of these, 36% did not progress to dementia, and 38% reverted to normal cognition—though a little over half of the reverters fulfilled MCI criteria again during a later follow-up, suggesting unstable cognition. Notably, less than 10% of these unstable cases eventually developed dementia. The ‘incidence’ rate of reversion to normal cognition was 175 cases per 1,000 person- years, which was much higher than the rate of progression to dementia at 77 per 1,000 person-years.3 Not surprisingly, those with the poorest cognitive performance, those with multiple cognitive domains affected, and those with the most severe impairment in daily functioning were at highest risk of progression to dementia. These characteristics are known risk factors for dementia within population studies, irrespective of any intermediate diagnosis. Uncertainty about progression from MCI to dementia probably reflects the mixed nature of the MCI population. Due to the raised awareness of dementia resulting from societal concerns and heightened fear about risk, people might seek help for any perceived deficits in cognition in mid to late life. Cases of MCI that are seen in clinical settings will, therefore, include temporary cognitive impairment attributable to a variety of causes, as well as truly prodromal dementia. To understand the clinical relevance of the latest results, and how they can be interpreted at the individual level, analyses that fully account for mortality, dropout, frequency of measurements, and fluctuation in and out of different states are required. These analytical approaches were not used
in the current study.3 Previous investigations of population-based samples report similar rates of reversion from MCI to normal cognitive function, 4,5 supporting the view that the MCI concept, which has been so enthusiastically embraced by the biomedical and clinical worlds, is perhaps not readily applicable to population settings. Does the Mayo Clinic study 3 support this emerging view? Yes and no—the results underscore the problems with the MCI concept, but at the same time the authors suggest that the concept is valuable, as it identifies people at higher risk of progression, even in population samples. Absolute rates of progression to dementia are, how ever, much lower in population-based sam ples (well below 10%) than in clinic-based samples.6 Neither the benefits nor the harms of diagnosing MCI at the population level have been rigorously explored. At present, insufficient evidence exists for a beneficial effect of screening for dementia itself.7 It is unlikely, therefore, that screening for MCI, which is not an early stage of dementia in a considerable proportion of people, will be effective. Application of MCI criteria to the general population does not always lead to reliable prediction of those most at risk of dementia,8 and probably results in overdiagnosis of MCI.
‘‘
Application of MCI criteria to the general population … probably results in overdiagnosis of MCI
’’
Despite these caveats, continued research in this area is warranted, but always with attention to the value of its translation into practice. Many clinicians argue that the MCI concept is useful in the setting of a memory clinic, where the positive predictive value—that is, the capacity of the concept to identify those at risk of progressive decline—is more clear. Despite the heterogeneity of the MCI population, and the high rate of reversion to normal cognition, the overall risk of dementia in the years after diagnosis is considerable, as demonstrated in Roberts and colleagues’ well-conducted and rigorous population study. 3 This increased risk suggests that people with MCI are a potentially useful group for studies on (secondary) prevention of cognitive decline and dementia. In newly proposed criteria for AD, 9 exploration of more-accurate prediction www.nature.com/nrneurol
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS of progression to dementia has been suggested, which may require defining criteria for prodromal AD based on cerebrospinal fluid (CSF) or neuroimaging biomarkers. Whether such an approach will lead to better prediction of dementia is as yet unknown, but analysis of CSF or MRI biomarkers after cognitive testing has not been shown to lead to better prediction of dementia in patients with MCI. 10 Before such criteria can be applied to population settings, large studies in relevant age brackets, including people with comorbid disorders, are required. These studies must also take all aspects of false-positive and false-negative results into account. MCI remains a complex concept, and its causes are heterogeneous. Considering MCI as a fixed concept based on clinical criteria is a slippery slope. Some might argue that people with cognitive impairment in multiple domains and in the bottom range of the MCI spectrum—that is, those with the worst impairment—would previously have been diagnosed with minimal or mild dementia. Because of the boundary changes that occur as a result of fashions in research and clinical practice, however, these cases would now be called MCI. On the basis of the findings by Roberts et al., and previous reports from population- based samples, the early signs of MCI have limited sensitivity and specificity for the prediction of the development of dementia. Clearly, therefore, the value of a MCI diagnosis warrants consideration. Diagnoses should be communicated carefully in order to avoid the potential harms of diagnosing a pre-dementia state in i ndividuals who might never progress to dementia. Department of Neurology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands (E.R.). Department of Public Health and Primary Care, Cambridge Institute of Public Health, Cambridge University, Forvie Site, Robinson Way, Cambridge CB2 0SR (C.B.). Correspondence to: E.R. [email protected] Acknowledgements The authors thank Blossom Stephan for substantial and constructive comments. Competing interests The authors declare no competing interests. 1.
2.
Petersen, R. C. Mild cognitive impairment as a diagnostic entity. J. Intern. Med. 256, 183–194 (2004). Vellas, B. et al. Designing drug trials for Alzheimer’s disease: what we have learned from the release of the phase III antibody trials: a report from the EU/US/CTAD
3.
4.
5.
6.
Task Force. Alzheimers Dement. 9, 438–444 (2013). Roberts, R. O. et al. Higher risk of progression to dementia in mild cognitive impairment cases who revert to normal. Neurology 82, 317–325 (2014). Gao, S. et al. Mild cognitive impairment, incidence, progression, and reversion: findings from a community-based cohort of elderly African Americans. Am. J. Geriatr. Psychiatry http://dx.doi.org/10.1016/ j.jagp.2013.02.015. Sachdev, P. S. et al. Factors predicting reversion from mild cognitive impairment to normal cognitive functioning: a population-based study. PLoS ONE 8, e59649 (2013). Ward, A., Tardiff, S., Dye, C. & Arrighi, H. M. Rate of conversion from prodromal Alzheimer’s
disease to Alzheimer’s dementia: a systematic review of the literature. Dement. Geriatr. Cogn. Dis. Extra 3, 320–332 (2013). 7. Fox, C. et al. Screening for dementia—is it a no brainer? Int. J. Clin. Pract. 67, 1076–1080 (2013). 8. Stephan, B. et al. Optimizing mild cognitive impairment for discriminating dementia risk in the general older population. Am. J. Geriatr. Psychiatry 18, 662–673 (2010). 9. Dubois, B. et al. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 9, 1118–1127 (2010). 10. Richard, E. et al. MRI and cerebrospinal fluid biomarkers for predicting progression to Alzheimer’s disease in patients with mild cognitive impairment: a diagnostic accuracy study. BMJ Open 3, e002541 (2013).
CLINICAL TRIALS
Measuring abuse liability —is the risk worth taking? Eija A. Kalso and Kaarlo Simojoki
Early trials that supported short-term opioid treatment in the management of chronic non-cancer pain excluded patients at high risk of drug abuse, and might have overestimated the efficacy of this approach. The recent IMMPACT recommendations suggest inclusion of high-risk groups in future clinical trials of potentially addictive drugs. Is the risk worth taking? Kalso, E. A. & Simojoki, K. Nat. Rev. Neurol. 10, 131–133 (2014); published online 11 February 2014; doi:10.1038/nrneurol.2014.16
The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consortium convened in 2009 to develop consensus recommendations for assessing abuse liability—that is, the propensity of a drug to be susceptible to abuse (Box 1)—in analgesic clinical trials. The recently published IMMPACT recommendations on trial design1 state that to adequately assess abuse liability, at least some of the study samples should represent the population of individuals who will be exposed to the drug in practice, including patients who are at significant risk. Chronic pain—in particular, neuropathic pain—is often difficult to manage. The efficacy of opioids in the management of cancer-related pain encouraged their use in the management of chronic non- cancer pain. A fervent discussion regarding whether neuropathic pain is sensitive to opioids ensued, and over the past 25 years several randomized controlled trials (RCTs), systematic reviews and clinical guidelines have addressed the topic.2 Current evidence suggests that opioids
NATURE REVIEWS | NEUROLOGY
have short-term benefit in management of neuropathic pain and osteoarthritisrelated pain, and the European Federation of Neurological Societies guidelines recommend opioids as second-line pharmacological therapy for the management of neuropathic pain.3 In the Western world, o steoarthritis pain and lower back pain constitute a larger market for opioids than does cancer pain. Indeed, the past 10 years have seen a twofold to threefold increase in the use of prescription opioids in the USA and Canada, and opioid use is also rapidly increasing in Europe. 4 According to the Centers for Disease Control and Prevention, in the USA, prescription opioids currently account for a higher proportion of overdose mortality than does heroin. As a consequence, regulation agencies, such as the State of Washington in the USA, have imposed restrictions on prescription of opioids. Several screening tools have been developed to identify patients who are at risk of opioid abuse; however, limitations for their clinical use have now been VOLUME 10 | MARCH 2014 | 131
© 2014 Macmillan Publishers Limited. All rights reserved
