EDITORIAL
Risk of dementia after fluctuating mild cognitive impairment When the yo-yoing stops
Alan B. Zonderman, PhD Friends, family members, and medical caretakers notice Gregory A. Dore, PhD that sometimes we have good days and sometimes we have bad days. If we are older, the bad days may involve making poor judgments, acting impulsively, forgetting Correspondence to information we just heard, or repeating ourselves in Dr. Zonderman: conversations. If these oscillations persist, then [email protected] one we know well may suggest consulting a physician ® because our bad days are interfering with our daily Neurology 2014;82:290–291 activities. Presented with variable symptoms on different occasions, physicians legitimately may diagnose us with mild cognitive impairment (MCI) on one occasion and then equally legitimately retract the diagnosis on another occasion. Many in the field have observed that patients and study participants may yo-yo between normal cognitive performance and MCI, but until now, the import of these diagnostic fluctuations was unclear. In this issue of Neurology®, Roberts et al.1 present a prospective, population-based, 5-year follow-up study on the rate of conversion from MCI to dementia or reversion from MCI to normal cognitive performance and the risk of dementia associated with these changes in diagnoses. As has been observed before, they found increased risk of dementia associated with MCI, but, more importantly, they also found increased risk of dementia among those who reverted (temporarily) from MCI to normal cognitive performance. This study has several important strengths, not the least of which were frequent follow-ups and disregarding ancillary information based on imaging or putative biomarkers. Data for this study were drawn from residents of Olmsted County in Minnesota who were aged 70 to 89 years. Diagnoses were based on in-person examinations and diagnostic case conferences repeated at 15-month intervals, or chart reviews and telephone interviews for those who declined follow-up in-person examinations. As expected, MCI was a risk for subsequent dementia (hazard ratio 5 28.8; 95% confidence interval 17.9– 46.4), but importantly, so was MCI with reversion to unimpaired (hazard ratio 5 6.6; 95% confidence interval 3.2–13.6). Those who were married, had nonamnestic or single-domain MCI, had no APOE e4 alleles, and
had greater everyday functioning and higher scores on cognitive tests were more likely to revert to normal cognitive functioning. Interestingly, reversion to normal cognition was not associated with age, sex, or educational attainment. Although uncommented upon by the authors, it would appear that those with fewer severe risk factors were more likely to revert to normal cognitive performance but were not guaranteed protection from eventually converting to dementia. These data may also cast doubt on the notion that educational attainment contributes to a cognitive reserve that protects us from pathologic cognitive decline. Until these data, it has been unclear whether changes in diagnostic status were attributable to inconsistent diagnostic procedures or whether they were true changes in cognitive performance. Although it is likely that increased variability in performance over time is a risk for dementia,2 the present evidence suggests that dementia is associated with any diagnosis of MCI, despite episodes of reversion to unimpaired performance. These data also reinforce MCI as an important diagnostic category. It is important to study the progression from MCI to dementia, and, for understanding and preventing the onset of dementing disease, it is probably even more important to study the predictors of MCI. Cerebrovascular impairments and cardiovascular dysfunction are sources for risk of dementia among those who revert to unimpaired cognition after a diagnosis of MCI. Management of these cardiovascular risk factors, while perhaps not preventing or reversing MCI, may at least delay the onset of dementia. The role of other mechanisms in the onset of MCI and the reversion to normal cognitive function is unclear. For example, the role of alcohol consumption, sleep changes, and depression and social isolation secondary to cognitive impairment needs further study. The authors suggest that individuals who revert from MCI are candidates for intervention trials. This is worth pursuing, but we should temper this by the likelihood that such individuals may already have the disease. It is most likely that only the manifestation of the disease reverted, probably not the underlying brain pathology. However, this line of research may help to identify
See page 317 From the Behavioral Epidemiology Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging Intramural Research Program, Biomedical Research Center, Baltimore, MD. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 290
© 2014 American Academy of Neurology
additional treatment options for those just entering the MCI range. For example, physical exercise has shown some promise in improving cognitive function in MCI.3 Exercise may be most beneficial early in the onset of MCI, although large-scale clinical trials are needed. This seems a fruitful area for future studies. Presence of at least one e4 allele of the APOE gene is a known risk factor for dementia and MCI. There are no treatments for this risk factor at present, but several theoretical treatments have been proposed.4 These include pharmacologic methods of converting APOE e4 to a molecule resembling APOE e3, increasing APOE levels, and increasing APOE receptor expression, among others. Although these interventions are theoretical, future research may provide insight into these possible treatment strategies. The authors mention their population-based design as a strength, and indeed it is. However, they were unable to examine race differences because the vast majority of participants were of Northern European ancestry. This suggests an important limitation in that these results may not generalize to nonwhite races, especially those residing in other than rural and suburban areas. Although the sample had variation by educational attainment, it is likely that the participants were sufficiently literate so that neuropsychological assessment provided a true indication of cognitive performance. Such literacy skills are not universally present in nationally representative populations. What was high functioning among those who reverted to unimpaired cognitive performance in this
sample may prove rarer in the ethnically and socioeconomically diverse general population. Although these data may not explain why we have good days and bad days, they do further our understanding of the implications and likely prognoses for those who yo-yo—for a while—between normal cognitive performance and MCI. AUTHOR CONTRIBUTIONS Alan B. Zonderman: drafting/revising the manuscript, study supervision. Gregory A. Dore: drafting/revising the manuscript.
STUDY FUNDING Supported in full by the Intramural Research Program of the National Institute on Aging/NIH.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
REFERENCES 1. Roberts RO, Knopman DS, Mielke MM, et al. Higher risk of progression to dementia in mild cognitive impairment cases who revert to normal. Neurology 2014;82:317–325. 2. Gamaldo AA, An Y, Allaire JC, Kitner-Triolo MH, Zonderman AB. Variability in performance: identifying early signs of future cognitive impairment. Neuropsychology 2012;26:534–540. 3. Smith JC, Nielson KA, Antuono P, et al. Semantic memory functional MRI and cognitive function after exercise intervention in mild cognitive impairment. J Alzheimers Dis 2013;37:197–215. 4. Bu G. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 2009;10:333–344.
Neurology 82
January 28, 2014
291
Risk of dementia after fluctuating mild cognitive impairment: When the yo-yoing stops Alan B. Zonderman and Gregory A. Dore Neurology 2014;82;290-291 Published Online before print December 18, 2013 DOI 10.1212/WNL.0000000000000065 This information is current as of December 18, 2013 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/4/290.full.html
References
This article cites 4 articles, 1 of which you can access for free at: http://www.neurology.org/content/82/4/290.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Cognitive Disorders/Dementia http://www.neurology.org//cgi/collection/all_cognitive_disorders_dem entia MCI (mild cognitive impairment) http://www.neurology.org//cgi/collection/mci_mild_cognitive_impairm ent
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Risk of dementia after fluctuating mild cognitive impairment When the yo-yoing stops
Alan B. Zonderman, PhD Friends, family members, and medical caretakers notice Gregory A. Dore, PhD that sometimes we have good days and sometimes we have bad days. If we are older, the bad days may involve making poor judgments, acting impulsively, forgetting Correspondence to information we just heard, or repeating ourselves in Dr. Zonderman: conversations. If these oscillations persist, then [email protected] one we know well may suggest consulting a physician ® because our bad days are interfering with our daily Neurology 2014;82:290–291 activities. Presented with variable symptoms on different occasions, physicians legitimately may diagnose us with mild cognitive impairment (MCI) on one occasion and then equally legitimately retract the diagnosis on another occasion. Many in the field have observed that patients and study participants may yo-yo between normal cognitive performance and MCI, but until now, the import of these diagnostic fluctuations was unclear. In this issue of Neurology®, Roberts et al.1 present a prospective, population-based, 5-year follow-up study on the rate of conversion from MCI to dementia or reversion from MCI to normal cognitive performance and the risk of dementia associated with these changes in diagnoses. As has been observed before, they found increased risk of dementia associated with MCI, but, more importantly, they also found increased risk of dementia among those who reverted (temporarily) from MCI to normal cognitive performance. This study has several important strengths, not the least of which were frequent follow-ups and disregarding ancillary information based on imaging or putative biomarkers. Data for this study were drawn from residents of Olmsted County in Minnesota who were aged 70 to 89 years. Diagnoses were based on in-person examinations and diagnostic case conferences repeated at 15-month intervals, or chart reviews and telephone interviews for those who declined follow-up in-person examinations. As expected, MCI was a risk for subsequent dementia (hazard ratio 5 28.8; 95% confidence interval 17.9– 46.4), but importantly, so was MCI with reversion to unimpaired (hazard ratio 5 6.6; 95% confidence interval 3.2–13.6). Those who were married, had nonamnestic or single-domain MCI, had no APOE e4 alleles, and
had greater everyday functioning and higher scores on cognitive tests were more likely to revert to normal cognitive functioning. Interestingly, reversion to normal cognition was not associated with age, sex, or educational attainment. Although uncommented upon by the authors, it would appear that those with fewer severe risk factors were more likely to revert to normal cognitive performance but were not guaranteed protection from eventually converting to dementia. These data may also cast doubt on the notion that educational attainment contributes to a cognitive reserve that protects us from pathologic cognitive decline. Until these data, it has been unclear whether changes in diagnostic status were attributable to inconsistent diagnostic procedures or whether they were true changes in cognitive performance. Although it is likely that increased variability in performance over time is a risk for dementia,2 the present evidence suggests that dementia is associated with any diagnosis of MCI, despite episodes of reversion to unimpaired performance. These data also reinforce MCI as an important diagnostic category. It is important to study the progression from MCI to dementia, and, for understanding and preventing the onset of dementing disease, it is probably even more important to study the predictors of MCI. Cerebrovascular impairments and cardiovascular dysfunction are sources for risk of dementia among those who revert to unimpaired cognition after a diagnosis of MCI. Management of these cardiovascular risk factors, while perhaps not preventing or reversing MCI, may at least delay the onset of dementia. The role of other mechanisms in the onset of MCI and the reversion to normal cognitive function is unclear. For example, the role of alcohol consumption, sleep changes, and depression and social isolation secondary to cognitive impairment needs further study. The authors suggest that individuals who revert from MCI are candidates for intervention trials. This is worth pursuing, but we should temper this by the likelihood that such individuals may already have the disease. It is most likely that only the manifestation of the disease reverted, probably not the underlying brain pathology. However, this line of research may help to identify
See page 317 From the Behavioral Epidemiology Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging Intramural Research Program, Biomedical Research Center, Baltimore, MD. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 290
© 2014 American Academy of Neurology
additional treatment options for those just entering the MCI range. For example, physical exercise has shown some promise in improving cognitive function in MCI.3 Exercise may be most beneficial early in the onset of MCI, although large-scale clinical trials are needed. This seems a fruitful area for future studies. Presence of at least one e4 allele of the APOE gene is a known risk factor for dementia and MCI. There are no treatments for this risk factor at present, but several theoretical treatments have been proposed.4 These include pharmacologic methods of converting APOE e4 to a molecule resembling APOE e3, increasing APOE levels, and increasing APOE receptor expression, among others. Although these interventions are theoretical, future research may provide insight into these possible treatment strategies. The authors mention their population-based design as a strength, and indeed it is. However, they were unable to examine race differences because the vast majority of participants were of Northern European ancestry. This suggests an important limitation in that these results may not generalize to nonwhite races, especially those residing in other than rural and suburban areas. Although the sample had variation by educational attainment, it is likely that the participants were sufficiently literate so that neuropsychological assessment provided a true indication of cognitive performance. Such literacy skills are not universally present in nationally representative populations. What was high functioning among those who reverted to unimpaired cognitive performance in this
sample may prove rarer in the ethnically and socioeconomically diverse general population. Although these data may not explain why we have good days and bad days, they do further our understanding of the implications and likely prognoses for those who yo-yo—for a while—between normal cognitive performance and MCI. AUTHOR CONTRIBUTIONS Alan B. Zonderman: drafting/revising the manuscript, study supervision. Gregory A. Dore: drafting/revising the manuscript.
STUDY FUNDING Supported in full by the Intramural Research Program of the National Institute on Aging/NIH.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
REFERENCES 1. Roberts RO, Knopman DS, Mielke MM, et al. Higher risk of progression to dementia in mild cognitive impairment cases who revert to normal. Neurology 2014;82:317–325. 2. Gamaldo AA, An Y, Allaire JC, Kitner-Triolo MH, Zonderman AB. Variability in performance: identifying early signs of future cognitive impairment. Neuropsychology 2012;26:534–540. 3. Smith JC, Nielson KA, Antuono P, et al. Semantic memory functional MRI and cognitive function after exercise intervention in mild cognitive impairment. J Alzheimers Dis 2013;37:197–215. 4. Bu G. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 2009;10:333–344.
Neurology 82
January 28, 2014
291
Risk of dementia after fluctuating mild cognitive impairment: When the yo-yoing stops Alan B. Zonderman and Gregory A. Dore Neurology 2014;82;290-291 Published Online before print December 18, 2013 DOI 10.1212/WNL.0000000000000065 This information is current as of December 18, 2013 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/4/290.full.html
References
This article cites 4 articles, 1 of which you can access for free at: http://www.neurology.org/content/82/4/290.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Cognitive Disorders/Dementia http://www.neurology.org//cgi/collection/all_cognitive_disorders_dem entia MCI (mild cognitive impairment) http://www.neurology.org//cgi/collection/mci_mild_cognitive_impairm ent
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
