Mild Cognitive Impairment In Older People

An analysis of systems of classifying mild cognitive impairment in older people Alexander Collie, Paul Maruff

Objective: Over the past two decades, a number of systems have been developed for the classification of cognitive and behavioural abnormalities in older people, in order that individuals at high risk of developing neurodegenerative disease, particularly Alzheimer’s disease, may be identified well before the disease manifests clinically. This article critically examines the inclusion and exclusion criteria of a number of such classification systems, to determine the effect that variations in criterion may have on clinical, behavioural and neuroimaging outcomes reported from older people with mild cognitive impairment. Method: Qualitative review of the literature describing systems of classifying mild cognitive impairment, and outcomes from clinical, behavioural, neuroimaging and genetic studies of older people with mild cognitive impairment. Results: The exclusion and inclusion criteria for these classification systems vary markedly, as do the design of studies upon which the validity of these systems has been assessed. Minor changes to individual exclusion/inclusion criterion may result in substantial changes to estimates of the prevalence and clinical outcome of mild cognitive impairment, while inadequate experimental design may act to confound the interpretation of results. Conclusions: As a result of these factors, accurate and consistent estimates of the outcome of mild cognitive impairments in otherwise healthy older people are yet to be obtained. On the basis of this analysis of the literature, optimal criteria via which accurate classifications of mild cognitive impairment can be made in future are proposed. Keywords: cognitive impairment, ageing, memory, diagnosis, neuropsychology. Australian and New Zealand Journal of Pschiatry 2002; 36:133–140

Many recent studies report that a small proportion of older people perform in the abnormal or borderline range on neuropsychological tests [1,2], and that these abnormalities occur predominantly in the domain of episodic memory [3]. While these people do not meet the clinical criteria for any neurodegenerative disease, their performance indicates that their cognitive functions

Alexander Collie, Centre for Neuroscience, The University of Melbourne (Correspondence); Paul Maruff, School of Psychology, Latrobe University Neuropsychology Laboratory, Mental Health Research Institute of Victoria, Locked Bag 11, Parkville, Victoria 3052, Australia. Email: [email protected] Received 11 October 2000; revised 24 August 2001; accepted 28 August 2001.

are not normal. Three accounts of the aetiology of such mild cognitive impairment have been put forward recently. The first proposes that it represents the early stages of Alzheimer’s disease (AD), while the second proposes that it is a product of normal ageing [4]. The third, and most likely, account is that mild cognitive impairment is a heterogeneous disorder with multiple possible outcomes [3–5]. These proposals have been investigated recently through epidemiological, genetic, cognitive and neuroradiological studies of older people classified as having mild cognitive impairment. Results from these studies have been varied, which has added to the current confusion and contradiction occurring in the ageing and dementia literature. We argue that the major cause of this confusion is the inconsistency among the

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many different systems that are currently used to classify mild cognitive impairment (hereafter referred to as ‘classification systems’). Identifying older people at high risk for AD is important for both the patient and their carers as it may allow therapeutic intervention in the very earliest stages of the disease, which in turn may delay or even prevent the onset of the disease process. In the worst case it allows for the planning of patient care. Such identification is currently hampered by the use of inadequate and inconsistent diagnostic criteria for mild cognitive impairment. Nine such criteria have been developed, and a number of other terms have been used to describe cognitive dysfunction in older individuals. Table 1 describes these terms and provides an acronym for each. As well as being an individual classification system, the term mild cognitive impairment is used increasingly to describe cognitive dysfunction associated with ageing. Used in this context, the term mild cognitive impairment implies that the different classification systems may be uniform and comparable, however, as discussed below this is not the case. Because there are so many terms used for this phenomenon (see Table 2), mild cognitive impairment will be used in this review to describe the concept of cognitive impairment associated with ageing that is not clearly dementia. The acronyms listed in Table 2 will be used when referring to individual classification systems. In order to determine whether mild cognitive impairment represents the earliest stages of AD, recent studies

Table 1. Acronym AACD AAMI ACMD ACMI ARCD ARMD BSF IMD IMI IML LCD LLF MCD MCI MD MND QD

have followed individuals classified as impaired according to one of the many available criteria over time (Table 2). Other recent studies have sought to determine whether impaired older individuals show increased rates of other risk factors for AD, including the apolipoprotein E (ApoE) epsilon 4 allele, hippocampal volume reduction, and self-reported memory loss (Table 2). Both types of investigation hypothesize that cognitively impaired older individuals are at greater risk of developing AD than non-impaired individuals. Despite many such studies being conducted recently, there is still disagreement about the clinical significance and outcome of mild cognitive impairments in older people. In fact, there is still debate about the population prevalence of such impairment among older individuals [5]. Potential reasons for these differences include inconsistent inclusion and exclusion criteria (Table 3), and variation in study design (e.g. sample size, baseline/follow-up interval), both of which may have considerable effects on study outcome. This review aims to compare and contrast the inclusion and exclusion criteria of the published systems for classifying mild cognitive impairment, and to determine the effects that changes to these criteria may have on study outcome. The effect that differences in experimental design may have on conclusions drawn from recent studies will also be considered. Based on this analysis of the literature, optimal criteria for the accurate identification of mild cognitive impairments are proposed.

Diagnostic and descriptive terminology for mild cognitive impairment in older people Title Ageing Associated Cognitive Decline Age-Associated Memory Impairment Age Consistent Memory Decline Age Consistent Memory Impairment Age-Related Cognitive Decline Age-Related Memory Decline Benign Senescent Forgetfulness Isolated Memory Decline Isolated Memory Impairment Isolated Memory Loss Limited Cognitive Disturbance Late Life Forgetfulness Mild Cognitive Disorder Mild Cognitive Impairment Minimal Dementia Mild Neurocognitive Disorder Questionable Dementia

Reference Levy [34] Crook et al. [35] Crook [24] Blackford and La Rue [36] DSM-IV [11] Blesa et al. [37] Kral [38] Small et al. [12] Berent et al. [39] Bowen et al. [40] Gurland et al. [41] Blackford and La Rue [36] Reisberg et al. [25] Petersen et al. [2] Roth et al. [42] DSM-IV [11] Morris et al. [8]

DSM-IV = Diagnostic and Statistical Manual of Mental Disorders – Version 4, published by the American Psychiatric Association (1994).

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Table 2.

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Results from selected studies of older people classified as impaired according to different systems

Study Smith et al. [5] Barker and Jones [22] Barker et al. [43] Soininen et al. [44] Forstl et al. [29] Laakso et al. [45] Krasuski et al. [46] Jack et al. [47] Tierney et al. [48] Bowen et al. [40] Berent et al. [39] Petersen et al. [2] Forstl et al. [29] Blesa et al. [37] Bartres-Faz et al. [49] Hanninen et al. [50] Fowler et al. [28] Petersen et al. [2]

System of Classification AAMI AAMI AAMI AAMI AAMI AAMI MCI MCI N/S IML IMI MCI AAMI ARMD AAMI AAMI QD MCI

Outcome measure Prevalence Prevalence Prevalence Brain volume Brain volume Brain volume Brain volume Brain volume Clinical outcome Clinical outcome Clinical outcome Clinical outcome ApoE genotype ApoE genotype ApoE genotype Cognitive function Cognitive function Cognitive function

Result 7–96% depending on memory test used 15–58% depending upon criteria 5.8–15.8% depending on individual criteria Normal hippocampal volume; hippocampal asymmetry ↓ hippocampal volume Normal amygdala volume ↓ entorhinal, hippocampal, amygdale volume ↓ hippicampal volume 24% develop AD 2 years after baseline 48% develop AD 31 months after baseline 50% develop AD 3 years after baseline; 15% pseudodementia 48% develop AD 2 years after baseline 58% carry e4 allele; 56% carry e4 allele; 37% e3/3 homozygous; 4% carry e2 allele 18% carry e4 allele; 64% e3/3 homozygous; 18% carry e2 allele ↓ executive function performance 43% display ↓ episodic memory function over 12 month period ↓ episodic memory performance

AAMI = Age-Associated Memory Impairment; MCI = Mild Cognitive Impairment; ARCD = Age-Related Cognitive Decline; IML = Isolated Memory Loss; IMI = Isolated Memory Impairment; QD = Questionable Dementia; ↓ = decreased; AD = Alzheimer’s disease; ApoE = Apolipoprotein; N/S = system of classification system not specified. Results from studies of older people classified as having cognitive impairment can vary substantially according to the criteria used to classify impairment. This is true for a number of different outcome variables, including estimated prevalence of impairment, brain volume measured with Magnetic Resonance Imaging, apolipoprotein E genotype, clinical outcome (the number of people subsequently meeting criteria for AD), and performance on tests of cognitive function.

Inclusion and exclusion criteria Memory impairment All published classification systems propose as an inclusion criterion evidence of a memory deficit (Table 3). This arises from repeated findings that memory is the first cognitive domain affected by the AD process [2,3,6], and is also affected by the normal ageing process [7]. However, the classification systems differ as to whether the memory impairment needs to be identified objectively. For example, the Age-Associated Memory Impairment (AAMI) and Mild Cognitive Impairment (MCI) criteria require that memory test performance be abnormal relative to a control group, whereas the Age-Related Cognitive Decline (ARCD) criterion requires only a subjective report of problems recalling names and events. Of those classification systems that require objective evidence of a memory deficit, there are differences between the composition of the group against which memory test performance is compared. For example, the comparison group specified by the AAMI criterion is normal young adults, whereas the MCI criterion requires an ageappropriate control group. Healthy young people generally have superior memory test performance than healthy

older people [7], and it is therefore likely that a greater proportion of older individuals will be classified as impaired when the AAMI criterion is employed. The composition of groups of impaired subjects classified according to AAMI and MCI criteria are also likely to be different, and their relationships to outcome measures (e.g. prevalence, progression to AD) not comparable [4]. Other cognitive impairment Some classification systems propose that memory impairment be accompanied by deficits in other cognitive domains, although this is not required universally (Table 3). For example, an individual can be classified as having Questionable Dementia (QD) when mild impairments are evident in a number of cognitive domains. In contrast, the criteria for AAMI specifies that cognitive processes other than memory remain unaffected. Deficits in cognitive domains other than memory occur predominantly in more advanced stages of AD [8] or in other neurodegenerative diseases (e.g. vascular dementia [9]), whereas the earliest stages of AD are characterized by an isolated memory impairment [3,10]. Therefore, classification systems which require impairment in multiple cognitive domains are likely to identify individuals in

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Table 3.

System of Classification Age Associated Memory Impairment Age Related Cognitive Decline

Components of systems of classifying cognitive impairment in older people

Memory Impairment Yes Objective

Other cognitive impairment No

Cognitive decline Yes Subjective

Subjective memory Recommended loss cognitive tests Yes Yes

Associated Neurological disturbance No

Associated mood disturbance No

Impaired daily living N/S

Yes Subjective

N/S

N/S

N/S

No

N/S

N/S

N/S

Benign Senescent Yes Forgetfulness Subjective

No

No

No

No

N/S

N/S

N/S

Yes* Objective

Yes* Objective

Yes Objective

N/S

No

N/S

N/S

Yes*

Mild Neurocognitive Yes Disorder Objective

Yes Objective

Yes Objective

No

No

Yes

N/S

Yes

Mild Cognitive Yes Decline (GDS 3) Objective

N/S

N/S

Yes

Yes

N/S

Yes

Yes

Mild Cognitive Impairment

Yes Objective

No

N/S

No

No

No

No

No

Limited Cognitive Yes Disturbance Objective

No

Yes Subjective

Yes

No

N/S

N/S

No

Yes Objective

No

No

Yes

N/S

N/S

Yes

Questionable Dementia (CDR 0.5)

Minimal Dementia

Yes Objective

Note: N/S = Not specified; Yes = required to meet criteria; No = not required to meet criteria; Objective = objectively identified; Subjective = subjectively identified. *A Clinical Dementia Rating (CDR) of 0.5 may be reached in a number of ways, and memory impairment may not necessarily be accompanied by deficits in other cognitive domains for CDR 0.5 to be obtained. Similarly, a CDR of 0.5 may be reached in the absence of memory impairment, provided that impairment is observed in a number of other domains of function.

whom the AD process is already advanced. Despite this, it is important to obtain an overall picture of the individuals cognitive function prior to classification according to any system. Cognitive decline An issue yet to be addressed adequately is whether people with mild cognitive impairment progress to develop clinically identifiable dementia, or remain impaired without displaying evidence of deteriorating cognitive function [10]. Diagnostic criteria for probable AD requires objective evidence of cognitive decline [11], however, many classification systems for mild cognitive impairment fail to specify whether decline should be evident (Table 3). These varied criteria reflect the different theoretical basis of the individual classification systems. While some emphasize that mild cognitive impairments represent early AD, others propose that they are benign and unrelated to any disease process. This means that the same mildly impaired individual could be rated as either

normal or dementing depending on which classification system is employed. The results of a recent functional neuroimaging study may shed some light on this issue. Small and colleagues [12] used functional Magnetic Resonance Imaging (fMRI) to reveal two separate patterns of hippocampal dysfunction during facial encoding among 12 people classified as having Isolated Memory Decline (IMD). The first pattern was observed in four IMD subjects, involved all hippocampal regions (entorhinal cortex, hippocampus proper and subiculum), and closely resembled that observed in four patients with clinically recognizable AD. The second pattern of dysfunction was observed in eight IMD subjects and was restricted to the subiculum. Recent postmortem findings suggest that selective subicular damage may occur as a result of normal ageing [13,14]. These results suggest the existence of two subgroups within the IMD group; one in the early or preclinical stages of AD, and another with memory decline associated with normal ageing. An ideal system of classifying mild cognitive impairment must therefore be able

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to differentiate impairment associated with ageing and impairment associated with neurodegenerative processes. Self-reported cognitive impairment The classification systems also differ as to whether the individual need have insight into his/her cognitive impairment (Table 3). There have been conflicting reports regarding the extent to which subjective complaints of cognitive loss are predictive of impairment and the future development of AD [15–19]. While some reports indicate that subjective complaints are related to objectively identifiable cognitive impairment [17], other recent findings have challenged this view [19]. Other recent work has suggested that self-reported cognitive impairment may be more closely related to the presence of depressive symptomatology than to objective cognitive impairment [18]. Until a consensus is reached regarding the value of subjective cognitive function in predicting cognitive dysfunction, it seems specious to include it as an inclusion criteria for mild cognitive impairment. Recommended neuropsychological tests The psychometric properties of individual neuropsychological tests can vary widely, and an individual may be rated as impaired on one test but normal on another depending on the sensitivity of the test to the cognitive domain under study. For example, an older individual with a mild memory impairment may be rated as normal on a cognitive screening measure such as the MiniMental State Examination, but impaired on an alternative and more psychometrically reliable and sensitive test of memory function [10]. Therefore, another important distinction between these classification systems is the extent to which they emphasize the use of specific neuropsychological measures for identifying cognitive abnormalities. This is perhaps best demonstrated by analysis of estimates of prevalence for the more common classification systems, which vary widely according to the neuropsychological test used to rate cognition. For example, Smith et al. [20] reported that the proportion of a normal older cohort meeting objective criteria for AAMI varied between 7% and 96% depending on the neuropsychological test used. An important issue appropriate to discuss here is that of circularity. That is, mild cognitive impairment is often diagnosed with the same or similar neuropsychological measures that are then used to characterize cognitive function in individuals with the disorder (for review see [3,4]). This situation has arisen as a convenience, because in the absence of behavioural and cognitive investigation of individuals with mild cognitive impairment,

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the utility of a classification system would take years (and perhaps decades) to establish were the ‘gold standard’ outcome of conversion to probable AD required. Ideally, diagnostic instruments should be independent of techniques used to measure outcome in individuals with mild cognitive impairment [2], which raises the question of whether neuropsychological tests are appropriate outcome measures. A resolution to this issue is important for the planning of future studies and the interpretation of current studies. Activities of daily living Another inconsistency between the classification systems is that some exclude older people with impaired activities of daily living (ADL) while others do not. Impairments in everyday activities are not often observed until well into the AD process, and it could be argued that such impairment is related to the severity of the cognitive deficit experienced by the individuals. Therefore, classification systems that require impairment in ADL are likely to identify individuals with more severe cognitive deficits than those that do not. Alternatively, such systems may identify individuals with neurodegenerative diseases other than AD, where executive function and physical disorders may cause impaired ADL [9]. Other exclusion criteria The remaining exclusion criteria are relatively consistent among the classification systems. For example, most specify the exclusion of individuals with a history of medical and/or psychiatric illness that could account for the observed cognitive impairment (Table 3). Most also require that a classification of impairment be made only when other possible aetiologies have been ruled out. However, there are exceptions to this rule. For instance, classification of Mild Neurocogntive Disorder (MND) is made only when it can be attributed to the onset of a medical condition. The specificity of exclusion criteria varies widely between the classification systems, and this may have led to the poor predictive ability of some classification systems. One potential reason that only approximately 50% of all older people with mild cognitive impairments progress to develop AD may be the failure to exclude individuals with other causes of mild impairment unrelated to degenerative processes. Experimental design Inconsistent and/or inadequate experimental design may also have contributed to the variable outcomes reported from studies of mildly impaired older individuals.

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For example, in many studies, the proportion of individuals meeting criteria for cognitive impairment is determined from within a small sample (often N < 100). The increased variability in test scores associated with small sample sizes means that the degree to which that estimate is an accurate representation of the expression of cognitive impairment in the population is questionable. Small sample sizes may also operate to increase the variability in the reported rates of progression to AD in these studies. The specificity of inclusion and exclusion criteria may also affect reported outcomes. For example, estimates of prevalence for the more strict and explicit classification systems are generally found to be lower than for the less strict and poorly defined systems [21]. A recent study by Barker and Jones [22] found that 18.5% of people aged between 50 and 94 years met the criterion for AAMI described by Crook et al. [23]. A modified AAMI criterion has also been described, in which the memory test cut-scores below which performance is said to be impaired were relaxed [24]. When this modified criterion was applied to the same cohort, estimated prevalence for people aged between 50 and 94 years was recorded at 25.5%, an increase of 40% on the previous estimate. The rigor of the exclusion and inclusion criteria adopted may also affect the observed rate of progression to AD among these studies, which have range from five per cent [25] to 69% [26]. Investigations which classify subjects as impaired according to more strict and well-defined criteria observe higher rates of conversion to AD than investigations which utilize less strict and poorly defined classification systems [21,27]. The amount of time between the classification of mild cognitive impairment and the follow-up assessment at which clinical outcome is determined may also affect these estimates. Some studies report outcome five years after initial classification [2], while others have left as little as 2 years between classification and follow-up [28,29]. There is evidence to suggest that the biochemical and neuropsychological changes that precede AD can be detected up to 20 years before the disease manifests clinically [30–32]. An accurate determination of the rate of conversion to AD would therefore require longer periods of observation than have been reported recently. Summary and conclusions While all available classification systems for mild cognitive impairment require that the individual display evidence of a memory deficit, other inclusion and exclusion criteria are much less uniform (Table 3). These inconsistencies have led to discrepant reports regarding the prevalence, clinical outcome and genetic correlates of mild cognitive impairment (Table 2). The ultimate aim

of identifying older people with cognitive impairment is to allow intervention into the preclinical stages of the neurodegenerative process. However, before the utility of any such intervention can be determined, precise estimates of the outcome of such impairment need to be obtained. The acquisition of these estimates in turn requires the development and implementation of an accurate classification system for mild cognitive impairment. Given the considerable differences between the inclusion and exclusion criteria of published classification systems, there is surprising consensus regarding the cognitive, genetic and cortical correlates of mild cognitive impairment. Episodic memory impairment, hippocampal atrophy, and the ApoE e4 allele are all consistently shown to be associated with cognitive impairment in older people (Table 2). Although there is substantial variability, the rate of expression of these outcome measures in older people with mild cognitive impairment is broadly similar to that observed in patients with clinically diagnosed AD. Other consistent results become evident upon analysis of the literature. For example, criteria that require the individual to display moderate deficits report a higher rate of progression to AD, and a lower estimated rate of prevalence, than classification systems that require only mild impairment [21]. A large proportion of older individuals with mild cognitive impairment do not progress to develop clinically recognizable AD, regardless of the severity of their deficit [3]. There are two potential reasons for this common finding. First, the period of time between classification of impairment and determination of clinical outcome in many studies may not have been sufficient for all incipient cases of AD to be expressed clinically. Second, the systems for classifying cognitive impairment may not be specific to the preclinical stages of AD. Conclusions regarding the optimal criteria for identifying older individuals at high risk for AD can be drawn from analysis of studies that have employed the existing systems of classification. First, it seems evident that at least a moderate episodic memory impairment should be requisite, and that this memory impairment need not occur concurrently with deficits in other cognitive domains. Second, the determination of impairment should be made against the performance of an age-appropriate group of normal controls. Third, objective evidence of cognitive decline from a baseline (or previous) level of performance should be obtained prior to classification of impairment. Fourth, the neuropsychological measures on which such comparisons are made should have sufficient sensitivity to allow the identification of subtle changes in cognitive function. Fifth, individuals exhibiting depressive and anxiety symptomatology should be assessed more thoroughly and excluded if the observed

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