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Current Concepts in Mild Cognitive Impairment

Current Concepts in Mild Cognitive Impairment The field of aging and dementia is focusing on the characterization of the earliest stages of cognitive impairment. Recent research has identified a transitional state between the cognitive changes of normal aging and Alzheimer's disease (AD), known as mild cognitive impairment (MCI). Mild cognitive impairment refers to the clinical condition between normal aging and AD in which persons experience memory loss to a greater extent than one would expect for age, yet they do not meet currently accepted criteria for clinically probable AD. When these persons are observed longitudinally, they progress to clinically probable AD at a considerably accelerated rate compared with healthy age-matched individuals. Consequently, this condition has been recognized as suitable for possible therapeutic intervention, and several multicenter international treatment trials are under way. Because this is a topic of intense interest, a group of experts on aging and MCI from around the world in the fields of neurology, psychiatry, geriatrics, neuropsychology, neuroimaging, neuropathology, clinical trials, and ethics was convened to summarize the current state of the field of MCI. Participants reviewed the world scientific literature on aging and MCI and summarized the various topics with respect to available evidence on MCI. Diagnostic criteria and clinical outcomes of these subjects are available in the literature. Mild cognitive impairment is believed to be a high-risk condition for the development of clinically probable AD. Heterogeneity in the use of the term was recognized, and subclassifications were suggested. While no treatments are recommended for MCI currently, clinical trials regarding potential therapies are under way. Recommendations concerning ethical issues in the diagnosis and the management of subjects with MCI were made.The boundary between normal aging and early or mild Alzheimer's disease (AD) is an area of intense interest for theoretical and practical reasons. Basic research, such as the identification of secretase inhibitors and the development of an immunization model for the prevention of amyloid deposition, underscores the importance of developing techniques for early detection.Parallel with these endeavors, clinical research aimed at identifying the earliest signs of cognitive impairment has progressed.A slight impairment in cognitive function, typically memory, with otherwise normal performance has been designated mild cognitive impairment(MCI) and has become a topic of considerable research.From June 24 through 26, 1999, investigators from around the world gathered in Chicago, Ill, at the Current Concepts in Mild Cognitive Impairment conference to review the world's literature regarding the concept of MCI and to suggest directions for future research.MILD COGNITIVE IMPAIRMENTMild cognitive impairment refers to a transitional state between the cognition of normal aging and mild dementia.As shown in Figure 1, the criteria for definitive AD, while still controversial, have been reasonably well established on a neuropathological basis.Similarly, in recent years, the criteria for clinically probable AD have also been well characterized,and the correlation between clinical and pathological findings in suspected cases of AD has been good.However, as Figure 1depicts, most, if not all, patients with AD experience a subtle cognitive decline before reaching the clinical threshold for the diagnosis of clinically probable AD. This transitional period has become known as MCI and is now the subject of several multicenter treatment trials involving more than 4000 subjects. The current clinical trials use an adaptation of the MCI criteria shown in Table 1.Figure 1.Theoretical progression of a person developing Alzheimer's disease (AD). The inflection point in the curve indicates the onset of mild cognitive impairment before the development of clinically probable AD. Reprinted with permission from W.B. Saunders.Criteria for Amnestic Mild Cognitive ImpairmentMemory complaint, preferably corroborated by an informantImpaired memory function for age and educationPreserved general cognitive functionIntact activities of daily livingNot dementedBecause other presentations of MCI exist, the type just described has been termed amnestic MCIbecause its definition emphasizes memory loss. Most of these subjects will progress to AD at a rate of 10% to 15% per year, compared with healthy control subjects who convert at a rate of 1% to 2% per year.Data from the Mayo Alzheimer's Disease Research Center, Rochester, Minn, which has been observing a group of these subjects for more than 10 years, have demonstrated a conversion to AD of up to 80% during approximately 6 years (Figure 2). Other definitions of MCI and the imaging and neuropathological features of these subjects are discussed in subsequent sections.Figure 2.Survival curve of persons characterized as having a mild cognitive impairment for 6 years. Approximately 80% have converted to dementia during this time. Reprinted with permission from John Wiley & Sons, Inc.RATING SCALESThere are several useful rating scales available for characterizing subjects along a continuum from normal aging through various stages of dementia.Although these scales are useful for describing subjects at various levels of involvement, they do not necessarily coincide with the clinically relevant conditions of normal aging, MCI, and mild AD. For example, the Clinical Dementia Rating (CDR) is a popular scale used to classify subjects along a continuum from normal aging through AD.This scale describes a continuum from normal (CDR 0) through questionable dementia (CDR 0.5) to mild (CDR 1), moderate (CDR 2), and severe (CDR 3) dementia. Although some investigators believe that CDR 0.5 is equivalent to MCI, others contend that CDR 0.5 actually describes a broader population that includes subjects with MCI and mild AD.Another instrument, the Global Deterioration Scale (GDS) stages subjects from GDS 1 (normal) to GDS 2 (normal with subjective memory impairment), GDS 3 (mild dementia), and GDS 4 through 7 (more severe stages of dementia).Within this rating scale, subjects with MCI could correspond to a GDS of either 2 or 3. These potential relationships are depicted in Figure 3. The amnestic form of MCI is an identifiable entity that does not necessarily map to a specific stage on these rating scales, thereby justifying a separate terminology.Figure 3.Comparison of the clinical diagnoses of normal aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD), compared with the approximate stages on the rating scales, Clinical Dementia Rating (CDR) and Global Deterioration Scale (GDS). Adapted from the American Medical Association.13NORMAL AGINGThe differentiation of MCI from normality is an important area of study. Whereas clear diagnostic and research criteria for dementia are now available in international disease classification systems, the notion of normal aging is less well understood. As disabilities associated with aging become treatable, they may be considered pathologic conditions rather than inevitable features of the physiological aging process. Because of evolving ideas of what constitutes normal aging, cross-sectional comparisons of older and younger populations are likely to be misleading because of these age-cohort effects.Within population studies, the concept of successful aging is sometimes proposed as an alternative to normality. Successful aging refers to a state of health in which there are measurable positive features across a spectrum of health measures. It extends beyond cognitive and functional definitions by considering the value of self-related psychological well-being. The Canadian Study of Health and Aging concluded that self-rated psychological well-being is a potential outcome measure for longitudinal investigation of individuals with either no cognitive impairment or minimal cognitive impairment.Previous attempts at characterizing cognitive changes intrinsic to normal aging have produced several terms, such as benign senescent forgetfulness, age-associated memory impairment, and age-associated cognitive decline.These terms are generally meant to reflect the extremes of normal aging rather than to describe a precursor of pathologic aging. While some investigations of these concepts demonstrate dementia conversion rates that are not different from those of healthy subjects,others have indicated an increased conversion rate.Subjects with MCI have a condition that is different from normal aging, and longitudinal outcome results indicate that they are likely to progress to AD at an accelerated rate.EPIDEMIOLOGYThere has been little work on the incidence or prevalence of MCI as defined herein. This is partially because of the recent characterization of this condition. Population-based studies, especially those that ascertain cases based on psychometric test results rather than symptoms, may identify a population of individuals with mild cognitive dysfunction that differs from the amnestic MCI described clinically. Prevalence rates for age-associated memory impairment in these studies range from 17% to 34%,while age-associated cognitive decline has been estimated as having a prevalence of 26%.Other investigators have indicated that the prevalence rate for conditions such as age-associated memory impairment can range up to 85%, depending on the specific memory tests used to fulfill the criteria.In the Canadian Study of Health and Aging, the classification of cognitive impairment with no dementia had a prevalence rate of 17%; this is likely a more inclusive term than MCI alone.An important factor in considering the frequency of MCI concerns the source of subjects for a given study. It is likely that a small number of subjects with MCI will present to memory disorders or dementia clinics. Most individuals who present to a dementia clinic probably already have dementia. However, if one surveys a community population, it is probable that more cases of MCI will be found.HETEROGENEITYAll individuals who present clinically with mild cognitive symptoms may not share the same fate ultimately. Some may go on to develop AD, while others may progress to another dementia. It is possible that some of the subjects will never progress to any significant extent. This broad group of individuals with mild cognitive complaints could be considered as having MCI. Recognizing that there are multiple sources of heterogeneity in such a classification, it is desirable to further specify criteria for subsets of MCI.Thus far, we have focused herein on the most common subset of subjects with MCI, those with amnestic MCI. These are individuals who present with a subjective memory complaint, preferably corroborated by an informant, and have an objective memory impairment compared with age and education norms, but who are performing reasonably well on indexes of general cognitive function and have generally preserved activities of daily living. As discussed earlier, these subjects do not meet standard criteria for AD. While subjects with amnestic MCI usually progress to AD at a high rate,not all will progress (Figure 2). On the other hand, some subjects who present with amnestic MCI may have other pathologic processes involving the medial temporal lobes, eg, hippocampal sclerosis.It is as yet uncertain whether clinical variations of AD or disorders with concomitant AD, such as dementia with Lewy bodies, can present as amnestic MCI. There is evidence that subjects with dementia associated with Lewy bodies have relative preservation of the hippocampi, making this amnestic MCI presentation less likely for subjects diagnosed as having dementia with Lewy bodies.It theoretically should be possible to select a different subset of subjects with MCI by altering the core definition and criteria. Figure 4depicts other hypothetical presentations of MCI in addition to amnestic MCI. Although none of these other prodromal conditions have been validated, MCI could be defined as mild impairment in multiple cognitive domains, without requiring memory deficit.These subjects may have multiple areas of cognitive impairment that fall outside of predicted norms, but none are sufficiently severe to constitute dementia. Subjects with MCI defined in this fashion may also progress to AD, but they could also progress to other disorders.Figure 4.Heterogeneity of the term mild cognitive impairment.Finally, MCI could conceivably present as impairment in a single cognitive domain other than memory. For example, a pronounced language disturbance might progress to primary progressive aphasia, or an alteration in attentional abilities or comportment and a dysexecutive syndrome might progress to frontotemporal dementia. Although no such MCI cases have been reported, it is reasonable to posit a prodromal period for frontotemporal dementia, analogous to amnestic MCI as a precursor of AD.It has become apparent that heterogeneity of MCI is derived from differences in causes, clinical symptoms, and research methods. For clarity, it is recommended that the term MCIbe qualified with an appropriate modifier, such as amnestic MCI, to inform the reader as to the specific criteria being used to characterize the condition and its most likely outcome.NEUROPSYCHO http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Neurology American Medical Association

Current Concepts in Mild Cognitive Impairment

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American Medical Association
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Copyright 2001 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
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2168-6149
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2168-6157
DOI
10.1001/archneur.58.12.1985
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Abstract

The field of aging and dementia is focusing on the characterization of the earliest stages of cognitive impairment. Recent research has identified a transitional state between the cognitive changes of normal aging and Alzheimer's disease (AD), known as mild cognitive impairment (MCI). Mild cognitive impairment refers to the clinical condition between normal aging and AD in which persons experience memory loss to a greater extent than one would expect for age, yet they do not meet currently accepted criteria for clinically probable AD. When these persons are observed longitudinally, they progress to clinically probable AD at a considerably accelerated rate compared with healthy age-matched individuals. Consequently, this condition has been recognized as suitable for possible therapeutic intervention, and several multicenter international treatment trials are under way. Because this is a topic of intense interest, a group of experts on aging and MCI from around the world in the fields of neurology, psychiatry, geriatrics, neuropsychology, neuroimaging, neuropathology, clinical trials, and ethics was convened to summarize the current state of the field of MCI. Participants reviewed the world scientific literature on aging and MCI and summarized the various topics with respect to available evidence on MCI. Diagnostic criteria and clinical outcomes of these subjects are available in the literature. Mild cognitive impairment is believed to be a high-risk condition for the development of clinically probable AD. Heterogeneity in the use of the term was recognized, and subclassifications were suggested. While no treatments are recommended for MCI currently, clinical trials regarding potential therapies are under way. Recommendations concerning ethical issues in the diagnosis and the management of subjects with MCI were made.The boundary between normal aging and early or mild Alzheimer's disease (AD) is an area of intense interest for theoretical and practical reasons. Basic research, such as the identification of secretase inhibitors and the development of an immunization model for the prevention of amyloid deposition, underscores the importance of developing techniques for early detection.Parallel with these endeavors, clinical research aimed at identifying the earliest signs of cognitive impairment has progressed.A slight impairment in cognitive function, typically memory, with otherwise normal performance has been designated mild cognitive impairment(MCI) and has become a topic of considerable research.From June 24 through 26, 1999, investigators from around the world gathered in Chicago, Ill, at the Current Concepts in Mild Cognitive Impairment conference to review the world's literature regarding the concept of MCI and to suggest directions for future research.MILD COGNITIVE IMPAIRMENTMild cognitive impairment refers to a transitional state between the cognition of normal aging and mild dementia.As shown in Figure 1, the criteria for definitive AD, while still controversial, have been reasonably well established on a neuropathological basis.Similarly, in recent years, the criteria for clinically probable AD have also been well characterized,and the correlation between clinical and pathological findings in suspected cases of AD has been good.However, as Figure 1depicts, most, if not all, patients with AD experience a subtle cognitive decline before reaching the clinical threshold for the diagnosis of clinically probable AD. This transitional period has become known as MCI and is now the subject of several multicenter treatment trials involving more than 4000 subjects. The current clinical trials use an adaptation of the MCI criteria shown in Table 1.Figure 1.Theoretical progression of a person developing Alzheimer's disease (AD). The inflection point in the curve indicates the onset of mild cognitive impairment before the development of clinically probable AD. Reprinted with permission from W.B. Saunders.Criteria for Amnestic Mild Cognitive ImpairmentMemory complaint, preferably corroborated by an informantImpaired memory function for age and educationPreserved general cognitive functionIntact activities of daily livingNot dementedBecause other presentations of MCI exist, the type just described has been termed amnestic MCIbecause its definition emphasizes memory loss. Most of these subjects will progress to AD at a rate of 10% to 15% per year, compared with healthy control subjects who convert at a rate of 1% to 2% per year.Data from the Mayo Alzheimer's Disease Research Center, Rochester, Minn, which has been observing a group of these subjects for more than 10 years, have demonstrated a conversion to AD of up to 80% during approximately 6 years (Figure 2). Other definitions of MCI and the imaging and neuropathological features of these subjects are discussed in subsequent sections.Figure 2.Survival curve of persons characterized as having a mild cognitive impairment for 6 years. Approximately 80% have converted to dementia during this time. Reprinted with permission from John Wiley & Sons, Inc.RATING SCALESThere are several useful rating scales available for characterizing subjects along a continuum from normal aging through various stages of dementia.Although these scales are useful for describing subjects at various levels of involvement, they do not necessarily coincide with the clinically relevant conditions of normal aging, MCI, and mild AD. For example, the Clinical Dementia Rating (CDR) is a popular scale used to classify subjects along a continuum from normal aging through AD.This scale describes a continuum from normal (CDR 0) through questionable dementia (CDR 0.5) to mild (CDR 1), moderate (CDR 2), and severe (CDR 3) dementia. Although some investigators believe that CDR 0.5 is equivalent to MCI, others contend that CDR 0.5 actually describes a broader population that includes subjects with MCI and mild AD.Another instrument, the Global Deterioration Scale (GDS) stages subjects from GDS 1 (normal) to GDS 2 (normal with subjective memory impairment), GDS 3 (mild dementia), and GDS 4 through 7 (more severe stages of dementia).Within this rating scale, subjects with MCI could correspond to a GDS of either 2 or 3. These potential relationships are depicted in Figure 3. The amnestic form of MCI is an identifiable entity that does not necessarily map to a specific stage on these rating scales, thereby justifying a separate terminology.Figure 3.Comparison of the clinical diagnoses of normal aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD), compared with the approximate stages on the rating scales, Clinical Dementia Rating (CDR) and Global Deterioration Scale (GDS). Adapted from the American Medical Association.13NORMAL AGINGThe differentiation of MCI from normality is an important area of study. Whereas clear diagnostic and research criteria for dementia are now available in international disease classification systems, the notion of normal aging is less well understood. As disabilities associated with aging become treatable, they may be considered pathologic conditions rather than inevitable features of the physiological aging process. Because of evolving ideas of what constitutes normal aging, cross-sectional comparisons of older and younger populations are likely to be misleading because of these age-cohort effects.Within population studies, the concept of successful aging is sometimes proposed as an alternative to normality. Successful aging refers to a state of health in which there are measurable positive features across a spectrum of health measures. It extends beyond cognitive and functional definitions by considering the value of self-related psychological well-being. The Canadian Study of Health and Aging concluded that self-rated psychological well-being is a potential outcome measure for longitudinal investigation of individuals with either no cognitive impairment or minimal cognitive impairment.Previous attempts at characterizing cognitive changes intrinsic to normal aging have produced several terms, such as benign senescent forgetfulness, age-associated memory impairment, and age-associated cognitive decline.These terms are generally meant to reflect the extremes of normal aging rather than to describe a precursor of pathologic aging. While some investigations of these concepts demonstrate dementia conversion rates that are not different from those of healthy subjects,others have indicated an increased conversion rate.Subjects with MCI have a condition that is different from normal aging, and longitudinal outcome results indicate that they are likely to progress to AD at an accelerated rate.EPIDEMIOLOGYThere has been little work on the incidence or prevalence of MCI as defined herein. This is partially because of the recent characterization of this condition. Population-based studies, especially those that ascertain cases based on psychometric test results rather than symptoms, may identify a population of individuals with mild cognitive dysfunction that differs from the amnestic MCI described clinically. Prevalence rates for age-associated memory impairment in these studies range from 17% to 34%,while age-associated cognitive decline has been estimated as having a prevalence of 26%.Other investigators have indicated that the prevalence rate for conditions such as age-associated memory impairment can range up to 85%, depending on the specific memory tests used to fulfill the criteria.In the Canadian Study of Health and Aging, the classification of cognitive impairment with no dementia had a prevalence rate of 17%; this is likely a more inclusive term than MCI alone.An important factor in considering the frequency of MCI concerns the source of subjects for a given study. It is likely that a small number of subjects with MCI will present to memory disorders or dementia clinics. Most individuals who present to a dementia clinic probably already have dementia. However, if one surveys a community population, it is probable that more cases of MCI will be found.HETEROGENEITYAll individuals who present clinically with mild cognitive symptoms may not share the same fate ultimately. Some may go on to develop AD, while others may progress to another dementia. It is possible that some of the subjects will never progress to any significant extent. This broad group of individuals with mild cognitive complaints could be considered as having MCI. Recognizing that there are multiple sources of heterogeneity in such a classification, it is desirable to further specify criteria for subsets of MCI.Thus far, we have focused herein on the most common subset of subjects with MCI, those with amnestic MCI. These are individuals who present with a subjective memory complaint, preferably corroborated by an informant, and have an objective memory impairment compared with age and education norms, but who are performing reasonably well on indexes of general cognitive function and have generally preserved activities of daily living. As discussed earlier, these subjects do not meet standard criteria for AD. While subjects with amnestic MCI usually progress to AD at a high rate,not all will progress (Figure 2). On the other hand, some subjects who present with amnestic MCI may have other pathologic processes involving the medial temporal lobes, eg, hippocampal sclerosis.It is as yet uncertain whether clinical variations of AD or disorders with concomitant AD, such as dementia with Lewy bodies, can present as amnestic MCI. There is evidence that subjects with dementia associated with Lewy bodies have relative preservation of the hippocampi, making this amnestic MCI presentation less likely for subjects diagnosed as having dementia with Lewy bodies.It theoretically should be possible to select a different subset of subjects with MCI by altering the core definition and criteria. Figure 4depicts other hypothetical presentations of MCI in addition to amnestic MCI. Although none of these other prodromal conditions have been validated, MCI could be defined as mild impairment in multiple cognitive domains, without requiring memory deficit.These subjects may have multiple areas of cognitive impairment that fall outside of predicted norms, but none are sufficiently severe to constitute dementia. Subjects with MCI defined in this fashion may also progress to AD, but they could also progress to other disorders.Figure 4.Heterogeneity of the term mild cognitive impairment.Finally, MCI could conceivably present as impairment in a single cognitive domain other than memory. For example, a pronounced language disturbance might progress to primary progressive aphasia, or an alteration in attentional abilities or comportment and a dysexecutive syndrome might progress to frontotemporal dementia. Although no such MCI cases have been reported, it is reasonable to posit a prodromal period for frontotemporal dementia, analogous to amnestic MCI as a precursor of AD.It has become apparent that heterogeneity of MCI is derived from differences in causes, clinical symptoms, and research methods. For clarity, it is recommended that the term MCIbe qualified with an appropriate modifier, such as amnestic MCI, to inform the reader as to the specific criteria being used to characterize the condition and its most likely outcome.NEUROPSYCHO

Journal

JAMA Neurology – American Medical Association

Published: Dec 1, 2001

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